[1]3 . 1 7 6 6 , 2 5 6 United States Patent Office Patented Oct. 16, 1973 2 of this invention enable the preparation of 9p,loa-ste3,766,256 roids of the androstane series of the formula SUBSTITUTED-3,5.SECO-A-NOR-PREGNAN3-OIC ACIDS RI Mflan Radoje Uskokovic, Upper Montclair, N.J., assignor to Hoffmann-La Roche Inc., Nutley, N.L ]E[3(li --- R2 No Drawing. Application June 13, 1968, Ser. No. 736,568, which is a division of application Ser. No. 499,094, RI Oct. 20, 1965, which in turn is a continuation-in-part c 11 of application Ser. No. 400,206, Sept. 29, 1964. Divided and this appreation May 24, 1971, Ser. No. 146,440 10 int. Cl. C07c 61130, 61136 U.S. Cl. 260-514 3 Claims 0 ABSTRACT OF THE DISCLOSURE This invention is directed to substituted-3,5-seco-A1 5 n orpregnan-3-oic acids and derivatives thereof which are u seful as intermediates in the synthesis of known 9#,10ast eroids of the pregnane series. The latter compounds can b e utilized as both progestational and salt-retaining agents. 2 0 RELATED APPLICATIONS This application is.a division of applicant's copending a pplication Ser. No. 736,568, filed June 13, 1968, which 2 5 is a division of applicant's copending application Ser. No. 4 99,094, filed Oct. 20, 1965, entitled "Intermediates and P rocesses," now U.S. Pat. 3,574,761, dated Apr. 13, 1971, which is a continuation-in-part of applicanfs copending a pplication Ser. No. 400,206, filed Sept. 29, 1964, entitled 3 0 " Intermediates and Processes," now U.S. Pat. No. 3,412,- 1 07, issued Nov. 19, 1968. DETAILED DESCRIPTION OF THE INVENTION This invention relates to novel chemical intermediates a nd processes useful in the preparation of steroids. Nat3 5 u ral steroids possess a 9a,10p-stereochemical configurati on. Steroidal compounds possessing the unnatural 9 ,6,10a-configuration represent a pharmaceutically valuab le class of compounds which, even though numerous 4 0 members are known in the art, cannot be obtained by t otally classical chemical means. In fact, the only known methods for obtaining steroids possessing the unnatural 9 #110,x-configuration involve at least one photochemical r eaction. Such photochemical reactions involve irradia4 5 ti on with ultraviolet light of strong intensity for long peri ods of time and, in comparison with purely chemical r eactions, are very inefficient and give only small yields. It is an object of the present invention to provide i ntermediate and processes which enable the preparation 5 0 o f 9p,10a-steroids without the necessity of proceeding t hrough a photochemical reaction. It is also an object of t his invention to provide novel intermediates and proce sses which will enable the further exploration of steroids having the unnatural 9p,10a-configuration. It is also an r,5 object of this invention to provide novel 9P,10(x-steroids. The novel intermediates and processes of this invention are valuable and provide a new synthetic route completely of a classical chemical nature, i.e. involving no photochen-iical reaction, for converting steroids having the nor- 60 mal configuration into steroidal compounds possessing the unnatural 9p,10a-configuration. In one aspect, the novel intermediates and processes wherein R, is, individually, selected from the group consisting of hydroxy and lower alkanoyloxy; R2 is, individually, hydrogen or lower alkyl and R, and R2, taken together, are selected from the group consisting of (17,6OH, 17oz-1ower alkanoic acid lactone) and oxo; R3 iS selected from the group consisting of hydrogen, lower alkyl, hydroxy and lower alkanoyloxy; Y is selected from the group consisting of hydrogen and lower alkyl and X is a substituent in the'6- or 7-position selected from the group consisting of hydrogen, lower alkyl, lower alkylthio, lower alkanoylthio and halogen. Compounds of Formula I are useful as anabolic agents Other 9p,10a-androstanes, the prepaartion of which is enabled by the intermediates and processes of this invention, are of the formulae HSC RI --- lower alkenyl R3 H30 0 H3 alkynyl H o@ (Til) wherein RI, R3, Y and X have the same meaning as above. Compounds of Formula IH are useful as progestational agents and compounds of Formula II are useful as anti-androgenic agents. In another embodiment of this invention, the novel compounds and intermediates provided by this invention
[2]3,766,256 3 enable the preparation of 9,p,10a-steroids of the 179pregnane series-of the formula CH2-RB 6=0 Hsc HIC H 0 (IV) wherein Y and X have the same meaning as above; R's is selected from the group consisting of hydrogen, lower alkyl, fluoro, hydroxy and lower alkanoyloxy; R5 is selected from the group consisting of hydrogen and halogen; and R6 is selected from the group consisting of hydrogen, lower alkyl, hydroxy and halogen. Compounds of Formula IV are useful as progestational agents. Other 9p,10a-steroids of the 17,6-pregnane series, preparable from the novel compounds and process of this invention, are of the formula CH20H =0 H c R's H 0i (V) wherein R'3, R6, Y and X have the same meaning as above. compounds of Formula V are useful as - salt-retaining . agents, i.e. are useful in the treatment of Addison s disease. As -used herein, the term lower comprehends both straight and branched chain saturated hydrocarbon groups, such as methyl, ethyl, propyl, isopropyl and the like. Similarly, the term lower alkanoyl cornprehends groups such as acetyl and the like, and the term lower alkanoyloxy comprehends groups e.g. formyloxy, acetoxy and the like. In the same nianner, the term lower alkenyl comprehends groups such as vinyl and the like, and the term lower alkynyl comprehends groups such as ethinyl and the like. Halogen comprehends all four halogens, i.e. iodine, bromine, chlorine and fluorine. The expression "(17p-OH, 17a-lower alkanoic acid lactone)" refers to a configuration on the C-17 carbon atom illustrated as follows: 0 0-8 /17\ wherein W is lower alkylene e.g. polymethylenes such as el@;lene, propylene or the like. With respect to substitutents in the 6- and 7- position, preferred compounds are those having hydrogen or lower alkyl in 6- or 7-positibn, and those having halogen in the 7-position. In one aspect, this invention comprises a method for the preparation of 9P,10aandrostanes of Formulae I-III and of 9,6,10a-17,6-pregnanes of Formulae IV-V which comprises the hydroge iQn nat of d@,@A-4ndrost-9-en-5-ones 4 or of desA-17-pregn-9-en-5-ones to 9,6,10p-desA-androstan-5-ones or 9P,10#- desA-17,e-pregnan-5-ones, respectively, followed by condensation with a lower alkyl vinyl ketone with methyl @ or ethyl vinyl ketone preferred (as well as substitutes therefor such as 1-tertiary a mino-3butanone, 1-tertiary amino3-pentanone and quaternary ammbnium salts thereof), l-Q-butan-3-one, l-Q-butan3one lower alkylene ketal, 1-3-butan-3-ol, esterified l-Qbutan-3-ol, 1-Q-butan-3-ol ether, 1,3-dichlorobut-2-ene, 10 1,3-dichloropent-2-ene ' I-pentan-3-one, I-Q-pentan-3-one lower alkylene ketal, I-Q-pentan-3-ol, esterified l-Qpentan-3-ol or I-Q-pentan-3-ol ether, which condensation yields the desired 9p,10a-steroids. The symbol Q is bromine, chlorine or iodine, with the former two being pre15 ferred. This invention also provides a number of different methods for the preparation of said desA-androst-9-en-5one or desA17,3-pregn-9-en-5-one starting materials from natural steroids. In one embodiment, a steroid of the 3-oxo-androst-4- 20 ene or 3-oxo-17g-pregn-4-ene series is subjected to an oxidative ring opening of the A-ring yielding a 5-oxo-3,5- seco-A-norandrostan-3-oic acid or a 5-oxo-3,5-seco-A-nor17,3-pregnan-3-oic acid, which 3-oic acid can then be converted to a mixture of a lOa-desA-androstan-5-one and 2z; a lOp-desA-androstan-5-one or a mixture of a lO a-desA17g-pregnan-5-one and a lOp-desA-17,6-pregnan-5-one. The conversion of the 3-oic acid to the desa-compound can be effected eidier by pyrolysis of a salt of said 3-oic acid or via the enol lactone, i.e. a 4-oxoandrost-5-en-3- 30 one or a 4-oxo-17g-pregn-5-en-3-one, which upon reaction with a Grignard reagent. gives an aldol, which in. turn can be converted into the desired desacompound. The desa-compound can then be converted into the starting material desA-androst-9-en-5-one or desA-17p-pregn35 9-en-5-one via a two-step sequence of halogenation and dehydrohalogenation. In another embodiment of this invention, desa-androst9-en-5-one or desA-17,3- pregn-9-en-5-one starting materials can be prepared from 11-hydroxy steroids of the 3- 40 oxo-androst-4-ene or 3-bxo-17,8-pregn-4-ene series. This can be effected in a variety of ways. In one approach, an 11-hydroxy group of a steroid of the 3-oxoandrost-4-ene or 3-oxo-17p-pregn-4-ene series is converted, into a leaving group, for example, a sulfonic acid ester or carboxylic 45 acid ester. Oxidative ring opening of the A-ring of the thus formed I 1-(esterified hydroxy) -containing compound yields the corresponding ll-(esterified hydroxy)-5- oxo3,5-seco-A-norandrostan-3-oic acid or II-(esterified hydroxy) . 5 - oxo - 3,5 - seco - A-nor-17,8-pregnan-3-oic acid which upon pyrolysis of a salt of said 3-oic acid yields 50 the desired desA-androst-9-en-5-one or desA-17g-pregn9-en-5-one starting material. A further approach involves formation of an 11-hydr oxy-desA-androstan-5-one or 11-hydroxy-desA-17,8- 55 pregnan-5-one from an 11-hydroxy steroid of the 3-oxoandrost-4-ene or 3-oxo17,6-pregn-4-ene series via an oxidative ring operung of the A-ring of said 11- hydroxy steroid which yields an 11-hydroxy-5-oxo-Anor-3,5-secoandrostan-3- oic acid 3,11-lactone or an 11-hydroxy-5- r,o oxo-3,5-seco-17,6-pregnan-3-oic acid 3,11-lactone which, in turn is converted into a salt of the corresponding keto acid which salt, upon pyrolysis gives the I 1- hydroxy-desAandrostan-5-one or 11-hydroxy-desA-17p-pregnan-5-one. Esterification of the I 1-hydroxy moiety of the so-obtained 65 compound with an acid moiety yields an II-(esterified hydroxy)-desAandrostan-5-one or an 11-esterified hydroxy)-desA-17,6-pregnan-5-one which upon elimination of the leaving group (i.e., the esterified hydroxy moiety) gives the desired desA-androst-9-en-5-one or desA-17,8- 70 pregn-9-en-5-one starting material. Though, in the above reaction sequence either I la-OH or llp-OH starting material steroids can e used, it is pre d to use lla-OH starting materials. As will be appreciated ftom the'above discussion, -Pe c - -0 75 neither the s cifi rea-cti n steps nor the reaction se-
[3]3,766,256 quences of this invention involve any - modification of substituents found in the 16- and/or 17-position of the starting material natural steroids. However, in order to obtain unnatural 9,6,10a-steroids of Formulae I-V, it is necessary or desirable to protect certain of the 16- and/or 5 17-substituents against one or more of the reaction steps involved. It is also convenient to initially protect such a substituent in the starting material natural steroid and maintain the substituent in its protected form throughout the entire reaction sequence, regenerating the desired sub- 10 stituent only when the steroid of Formula IV possessing the unnatural 9,6,10a-configuration is obtained. On the othre hand, it is sometimes convenient to insert a protecting group only before a certain reaction step or sequence of reaction steps. Said protecting group can then be main- 15 tained until the final reaction step or can be split off at some intefmediate stage. The protecting groups can be inserted and split off by means known per se. The desirability of having protecting groups present wiU be further discussed below when the specific reaction steps are dis- 20 cussed in detail. The various substituents which are susceptible to being protected are exemplified by the 16- hydroxy group in a compound of any of Formulas I-V, the 17p-hydroxy group in a compound of any of Formulas I-111, the 17m-hydroxy or 20-oxo group in a cOm25 pound of any of Formulas IV-V, the 21-hydroxy group of a compound of Formula V or the 17-oxo group of a compound of Formula I. The 17-oxo or 20-oxo group is suitably protected by ketalization, i.e., by reaction with a lower alkanediol, tO 30 yield a 17-lower alkylene dioxy or 20-lower alkylene dioxy compound, i.e., a 17-ketal or a 20-ketal. The 16-hydroxy, 17a-hydroxy, 17p-hydroxy or 21- hydroxy moieties can be protected by esterification and/ or etherification of the hydroxy group. Any available acid 35 which will form an ester that can subsequently be hydrolyzed to regenerate the hydroxy group is suitable. Exemplary acids useful for this purpose are lower alkanoic acids, e.g. acetic acid, caproic acid, benzoic acid, phos40 phoric acid and lower alkane dicarboxylic acids, e.g. succinic acid. Also, protection for the 16a-hydroxy, 17a-hydroxy, or 21-hydroxy substituent can be effected by forming the lower alkyl ortho ester thereof, i.e. 16a,17a- or 17cL,21-lower alkyl ortho esters. A suitable ether protecting group is, for example, the tetrahydropyranyl ether. 45 Others are arylmethyl ethers such as, for example, the benzyl, benzhydryl and trityl ethers, or a-lower alkoxylower alkyl ethers, for example, the methoxymethyl, or allylic ethers. In compounds containing the dihydroxyacetone side 50 chain at C-17 (for example, compounds of Formula V wherein R6 is hydroxy), the side chain at C-17 can be protected by forming the 17,20; 2 0,21-bis-methylenedioxy group or by forming a 17,21-acetal or ketal group, or by forming a 17,20-diester. The 17,21-acetat or ketal and 55 17,21-diester hinder the 20-ketone group and nu'nimize the possibility of its participating in unwanted side reactions. On the other hand, the 17, 20;20,21-bis-methylenedioxy derivatives actually convert the ketone to a nonreactive derivative. When both a 16cc-hydroxy and 17a- (;0 hydroxy substituent are present, these groups can be protected via formation of a 16a-17a-acetal or ketal. The various protecting groups mentioned above can be removed by means known per se, for example, by mild acid hydrolysis. 65 In conipounds wherein there is present neither a 17ahydroxy nor 21-hydroxy substituent but there is present a 20-oxo group, the 20-oxo group can be protected via reduction to the corresponding carbinol (hydroxy) group. Thus, for example, the 17-acetyl side chain can be 70 protected via conversion to a 1 7-(a-hydroxyethyl)-side chain. Regeneration of the 17-acetyl side chain can be simply effected via conventional oxidation means, for example, via oxidation with chromium trioxide in an organic solvent such as glacial acetic acid. Similarly in com- 75 6 pounds containing a 17-oxo, this group can be protected by reduction to the corresponding @carbinal (hydroxy) group. Thus, the 17-oxo group can be reduced to a 17,6OH, 17a.-H moiety, from which, when desired, the 17-oxo moiety can be regenerated by oxidation, as described above. 'Furthermore, a 20-hydroxy or 17ghydroxy group, can itself be protected by esterification, for example, with a lower alkanoic acid such as acetic acid, caproic acid, or the like; or by etherification with moieties such as tetrahydropyranyl, benzyl, benzhydryl, trityll allyl, or the like' The 16a17(x or 17(x,21-acetals and ketals above discussed can be formed by reacting 16a,17cc-bis-hydroxy or 17a,21-4bis-hydroxy starting materials with an aldehyde or a ketone; preferably it is done by reacting a simple acetal or ketal (i.e. a lower alkylene glycol acetal or ketal of a suitable aldehyde or ketone) with the moieties sought to be protected. Suitable aldehydes and ketones include lower alkanals of at least two carbon atoms, such as paraldehyde, propanal and hexanal; di(lower alkyl)ketones, such as acetone, diethylketone, dibutylketone, methylethylketone, and methylisobutylketone; cycloalkanones, such as cyclobutanone, cyclopentanone and cyclohexanone; cycloalkyl (lower alkanals), such as cyclopentylearboxafdehyde andcyclohexylcarboxaldehyde; cycloalkyl lower alkyl ketones, such as cyclopentyl propyl ketone, cycloliexylmethyl ethyl ketone; dicycloalkyl -ketones, such as dicyclopentyl ketone, dicyclohexyl ketone and cyclopentyl cyclohexyl ketone; cycloalkyl monocyclic aromatic ketones, such as cyclohexyl p-chlorophenyl ketone, cyclopentyl o-methoxyphenyl ketone, cyclopentyl o,p-dihydroxy-phenyl ketone and cyclohexyl m-tolyl ketone; cycloalkyl-lower alkyl monocyclic aromatic ketones, such as cyclopentylmethyl phenyl ketone; cycloalkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentyl benzyl ketone and cyclohexyl phenethyl ketone; cycloalkyl-lower alkyl monocyclic aromatic-lower alkyl ketones, such as cyclopentylmethyl benzyl ketone; halolower alkanals, such as chloral hydrate, trifluoroacetaldehyde hemiacetal, and heptafluorobutanal ethyl emiacetal; halo-lower alkanones such as 1,1,1-trifluoroacetone; monocyclic carbocyclic aromatic aldehydes, such as benzaldehyde, halobenzaldehydes (e.g. p-chlorobenzaldehyde and p-fluorobenzaldehyde), lower alkoxy-benzaldehydes (e.g.- o-anisaldehyde), di(lower alkoxy)benzaldehydes (e.g. veratraldehyde), hydroxybenzaldehydes (e.g. salicylaldehyde), lower alkyl benzaldehydes (e.g. rn-toluaidehyde and pethylbenzaldehyde), di(lower alkyl)benzaldehydes (e.g. o-p-dimethylbenzaldehyde); monocyclic carboxylic aromatic lower alkanals, such as phenylacetaldehyde, aphenylpropionaldehyde, p-phenylpropionaldehyde, 4-phenylbutyraldehyde, and aromaticallysubstituted halo, lower alkoxy, hydroxy and lower alkyl cyano derivatives thereof; monocyclic carbocyclic aromatic ketones, such as acetopherione, a,a,atrilluoroacetophenone, propiophenone, butyrophenone, valerophenone, halophenyl lower alkyl ketones (e.g. p-chloroacetophenone and p-chlorapropiophenone); (lower alkoxy) phenyl lower alkyl ketones (e.g. p-anisyl methyl ketone); di-(lower alkoxy) phenyl lower alkyl ketones; hydroxyphenyl lower alkyl ketones; (lower alkyl)phenyl lower alkyl ketones (e.g. methyl p-tolyl ketone); di(lower alkyl) phenyl lower alkyl ketones (o,p-xylyl methyl ketone; benzophenone, and mono-or bis-substituted halo, lower alkoxy, hydroxy and lower alkyl derivatives thereof; monocyclic carbocyclic aromatic lower alkanones, such as I-phenyl-3-butanone and I-phenyl-4-pentanone, and aromatically substituted derivatives thereof. Especially suitable are those aldehydes or ketones which, with the 16a,17a- or 17a,21- ;bis-hydroxy grouping form an acetal or ketal group of the formula -0 p c -0 0
[4]3,766@256, 7 wherei@1--@P@-i -iiidividu@lly.'sele-cted@-*Om,fb@,groiin@con-@ sisting of @ hydrogen @ and -lower a"-l-'@Q is individually selected from the group consisting of lower alkyl and aryl; @4n4@ p a-nd @Q@ ta@o@ Oi@4ho * lo@we@ alkyl ene.. The term@'llower alkylene" r-omprehends polymethylene 5 chains such as -tetramethylene @and pentamethylene. In discussing the various starting materials, intermediates and end-products of this invention, the various pro-. tecting groups discussed above will not necessarily be specifically mentioned, but @it should be-@unddrstood, that @lO@ mention of any substituent, comprehends the various protected forms thereof, unless specifically mentioned to the contrary. In one embodiment of this invention, compounds of Formulas I through V are prepared from 9,3,10,6-desA- 15 androstan-5-ones or 9P, 1097desA-pregnan-5-ones of. the formula HSC 20 H HBC 0 25 (VI) wherein X has the same meaning as above and D represents the carbon and hydrogen atoms;necessary to complete the steroid D-ring, as well@ as@ the atoms in the sub. 30 stituents in the 16- and 17-positions, as defined in@For,mulae I-V above. Thus,, 9,6,10a-androstanes@ of,Formula, I.,can be prer,ared. - from 9,6,110p-desA-an&ostan-5-ones of the@formula 35 RI lerso --R2 Rs 40 ]E[aC 0 (VII) -@m . 6,eov@@ -@0,1@@a@-17p-pregnanes 6f @Fbrmulae IV and ; - V;c@a@ @e prepared from 9#,10#-d esA-pregnan-5-ones Of Formulae X and XI, respectively. 113C R, R's (H H c (X) CH2011 H R13 H HC H 0 wherein lU3, R5, R6 and X have the same meaning as above. The conversion of a 99,10,3-desA-compound of Formula @VI to a 9,8,10a-steroid of Formulae I-V (i.e., @VII->I,:VIII-411, IX-IIL X->IV and XI--.>,V) is efferted by condensing the 9,0110[3-desA-compound with a compound selected from the group consisting of lower alkyl vinyl ketone (as well as substitutes therefor such as 1tertiary amino-3-butanone, 1-tertiary amino-3-pentarione and quaternary ammonium salts thereof), 1,3-dichlorobut-2-ene, 1,3-d ichloropent-2-ene, I-Q-butan-3-one, I-Q'butan-5-@ote lower alkylene ketal, I-Q-butan-3-ol, I-Q-butan-3-ol ether, esterified l-Q-butan-3-ol, I-Q-pentan-3-one, I-Q-pentan-3-one @lower alkylene ketal, l-Q-pentan-3!-ol, I-Q-pentan-3-ol ether or esterified I-Q-pentan-3-ol. Q is r6mo @6 oro or iod th the@ fornie two @beiiig preb hl 0, WI r ferred. Methyl vinyl ketone and 1-tertiary amino-3-butanone are@the preferred reagents, and the former is es45, pecially preferred.@Prior to the condensation it is desirable -to rotect th@ 20-ke-to group present in compounds of' wherein RI, R2, R, and X have the -same meaning as p , above. Formulae,X and XI, then it is not necessary to protect 16ce, 17a or 21- hydroxy groups which are present, but groups Similarly, 9,6,10aandrostane s of Formula@l l can, be preprotecting these moieties can be retained through the pared from @@ 9,3, 10,6-desAandrostan5- one@@@o f - Formula@ @o@@ condensati on reactioii. VIII and 9,6,10a-andr6stanes of@ Formula III from 9,6,10,6- The above indicated substitutes for lower alkyl vinyl desA-androstan-5-ones of Formula IX. ketones@are compounds wherein the vinyl moiety is replaced by i@m6iety of the formula RI 3C --- lower alkenyl- 55 R. R wherein@ each R@ is lower alkyl or taken together both R's H3c 60 are lower alkylene oxalower alkylene or aza4ower 0 @"ene. Such moieties are, for example,@ dimethylaminol, diethylamino, -pyrrolidino, piperldino morpholino@ or the,.; like. The quaternary ammonium salts there(f are formed via the @utilization of conventional quaternizing agents, @'65 for example, lower alkyl-c)r phenyl.lower@OkA@(especially benzyl) halides, mesylates or tosylates. lower 4@" When a lower alkyl vinyl ketone or substitute therefor, I.Qbiitan-3- one:or I.Q@pentan-3-one is used as the reaction@,partne r for the condensation, ring closure to 7o, ring A (containing a 3-oxo moiety) of the desired 9.0-,loccsteriod:@ of Formulae IV occurs simulta0 neously with the condensation. However, when 1,3-dir - h l o r o b u t - 2 - e n e , 1 , 3 - d i c h l o r o p e n t - 2 - e n e @ , , I - @ Q @ b u t a n @ 3 - o n e I w o er 7@lkylene ketali@ IQ-butan-3- ol, l-Qbutan-3- 01@ whereinRI, R,,andXha vethesame mea@m'ng asaboVe. @ @75 ether; @6t&rified I-Q-butan3-ol, IQ-pentan3-one lower
[5]alkylene ketal, I-Q-pentan-3-ol, I-Q-pentan-3- ol ether, or esterified I-Q-pentan-3-ol is used as the reaction partner a subsequent step to generate the 3-oxo moiety is required. When I-Q-butan-3-ol or I-Q-pentan-3-ol is used as the reaction partner, the oxo moiety can be generated by oxidation and for this purpose, it is suitable to use oxidation means known per se, for example, chromic acid, chromium trioxide in acetic acid or the like. When esterifled or etherified I-Q-butan-3-ol or esterified or etherified I-Q-pentan-3-ol is used as the reaction partner, hydrolysis of the esterified or etherified hydroxy group should be effected prior to oxidation. Suitable ester forming moieties are, fc>r example, carboxylic acids, e.g. lower alkanoic acid such as acetic acid, benzoic acid, -and the like; and hydrolysis of the reaction products. obtained by reacting such I-Q-butan-3-ol or IQ-pentan-3-ol esters is suitably conducted by alkaline hydrolysis, e.g., via the use of an aqueous alkali metal hydroxide such as aqueous sodium hydr(>xide. Suitable ethers are, for example, lower alkyl ethers, i.e. 3-methoxy, 3-ethoxy or the like; and these are suitably hydrolyzed by acid hydrolysis, e.g. via the use of an aqueous mineral acid such as liydrochloric acid, sulfuric acid or the like. When a l-Q-butan-3-one lower alkylene ketal or a I-Q-pentan-3-one lower alkylene ketal is used as the reaction partner, mild acid hydrolysis of the ketal moiety results in generation of the 3-oxo moiety. Finally, when 1,3-dichlorobut-3-ene or 1,3-dichloropent3-ene is used as the reaction partner, the 3-oxo moiety can be generated by treatment with a concentrated mineral acid, preferably a strong acid such as hydrochloric,acid or sulfuric acid. It should be noted, that 1,3dichlorobut-2-ene and 1,3-dichloropent-2-ene may be used as reaction partners with compounds of Formulae X and XI, but not with the 17a4ower alkyl, alkenyl or alkynyl compounds of Formulae VU-IX. As will be apparent, when a reaction partner based on butane (i.e. having a four carbon atom skeleton) is utilized a compound of Formulae I-V wherein Y is hydrogen is obtained. Similarly, when a reaction partner based on pentane is utilized a compound of Formulae I-V wherein Y is methyl is obtained. In addition to the preparation of compounds of Formulae I-V from compounds of Formulae VI-XI by the use of the above mentioned reaction partners, it is also possible by the procedures of this invention to prepare compounds of Formulae I-V which, in the A-ring, in addition to containing an unsaturation between the 4- and 5-positions also contain an unsaturation between the land 2-positions. Such 1,4-diene products corresponding to the compounds of Formulae I-V can be prepared from compounds of Formulae VI-)a by condensation of the latter with a reaction partner selected from the -group consisting of ethinyl methyl ketone and ethinyl ethyl ketone (as well as substitutes therefor such as 6-tertiary aminovinyl methyl or ethyl ketone, quaternary ammonim salts thereof, and #-lower alkoxy-vinyl methyl or ethyl ketone). Condensation to prepare such a 1,4-diene product corresponding to the compounds of Formulae I-V is effected under the same conditions as in the condensation to prepare a compound of Formulae I-V. The so-obtained 1,4-dienes are useful in the same way as the correspondingly substituted 4-ene-compounds of Formulae I-V. The condensation is suitably effected at, below or above room temperature. For example, at the reflux temperature of the reaction medium or at ice temperature (O' C.) or below. Moreover the condensation is suitably effected in an organic me@ium. Preferably the solvent is a lower alkanol, such as methanol, isopropanol, tert-butanol, ethanol, or another non-ketonic organic solvent, such as an ether, e.g. dioxane, diethyl ether, diisopropyl ether, aromatic hydrocarbon, e.g. benzene, toluene, xylene, organic acid, such as acetic acid, or the like. Lower alkanols are the preferred solvents. It is suitable to catalyze the condensation, and this can be effected via use 8,766,256 of a catalyst such as an alkali metal lower alkoxide, for example sodium ethoxide, potassium t-butoxide, sodium tamylate, or the like, alkali metal hydroxide such as sodium, lithium or potassium hydroxide, a quaternary ammonium hydroxide, for example, a benzyl tri-lower alkyl ammonium hydroxide such as benzyl trimethyl ammonium hydroxide, para-toluene suffonic acid, or the like. When using a substitute for methyl or ethyl vinyl ketone, or for methyl or ethyl ethinyl ketone, the con10 densation should be effected under alkaline conditions. As indicated above, among such substitutes are 1-tetrtiary amino-3-butanone, 1-tertiary amino-3-pentanone and 6tertiary amino-vinyl methyl or ethyl ketone. -Preferred tertiary amino groups are dilower alkylamino groups such 15 as dimethylamino, diethylamino, pyrrolidino, piperidino, morpholino, or the like. Preferred quatemary ammonium salts of such tertiary amino groups are, for example, those formed from lower alkyl halides such as methyl iodide. An exemplary a-lower alkoxy vinyl methyl or ethyl 20 ketone is p-methoxyvinyl ethyl ketone. One aspect of this invention is the hydrogenation of desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones to 9g,10,8-desA-androstan-5-ones of Formulae VIIDC or to 9,6,10[3-desA-pregnan-5-ones of Formulae X-XI. Thus, 9,6, 25 lOp-desA-androstan-5-ones of Formula VH can be prepared via hydrogenation of desA-androst-9-en-5-ones of the formulae H3 30 R3 IE(a C 35 0 (XH) RI 40 -lower alkenyl R3 H I 113C 45 0 (Xlli) RI 50 lower alkenyl Rs IE[SC 55 0 (XIV) wherein RI, R2, R3 and X have the same meaning as 60 above. Also, 9p,10p-desA-pregnan-5-ones of Formulae X and XI can be prepared by hydrogenation of desA-pregn-9-en5-ones of the formulae 65 CH2-Rs H3c @=0 L -Ra R'S 70 H30 0 75 (XV)
[6]3,766 ,256 12 CH20H involves as a first step an oxidative ring opening of ring A of the: natural steroid. For this oxidative ring opening 11 c there can@ be used as starting materials, natural steroids of --- Re the 3- OX07androst-4-ene or 3-oxo-17,8-pregn-4-ene series of the, formula: rH Hsc n 3 c z 10 x (XVI) H wherein R'3, R5, R(I and X have the @same meaning as 0 above. Kl (Xvil , 15 Prior to hydrogenation, the C-20 keto group in comwher ein X' is a substituent in the 6-position selected from poun ds of Formulae XV and XVI or C-17 keto group in the group consisting of hydrogen, lower alkyl, lower com pounds of Formula XII should be protected either by alkyl thio and lower alkanoylthio or a substituent in the conv ersion to the corresponding carbinol or by ketaliza7- p6sition selected from the group consisting of hydrotion as described above. The hydrogenation can, however, 20 gen, lower alkyll lower alkylthio, lower alkanoylthio be effected without protecting such keto groups. and halogen, and Z represents the carbon and hydrogen Mor eover, it should be noted that the hydrogenation, atom s necessary to complete the steroid D-ring, as well besi desinsertingahydrogena mineachofthe9-andloas the atoms in the substituents in the 16,- and 17-posiposi tions, can also simultaneously efrect@hydrogenation of tions as defined in Formulae 1, IV, and V above. othe r groups in the molecule. For example, the C-20- keto 25 The oxidative ring opening of a natural st--roid of Forgrou p can be hydrogenated to the corresponding carbinol mula XVII yields a 5-oxo,-315-seco-A-norandrostan-3-oic; or the C-17- lower alkenyl group in 'compounds of Formula XIII or the C-17 lower alkynyl group in compounds of Formula XIV can be hydrogenated to the corresponding C-17-16wer alkyl 'comp6unds, Compounds of Formulae 30 VIII and IX can, in turn, be prepared @from compounds of@ Formula VII wherein R, and R2 together are oxo via reaction with a lower alkenyl or- lower alkynyl Grignard reagent, with prior protection 6f the @5-keto group, for example, by forming 5-ketals without concurr ent-blocking 3 of the 17-keto group. In the same manner compounds of Formulae XHI and )UV can be formed from compounds of Formula )al wherein R, and R2 taken to,-ether are OX0. The hydrogenation of desA-androst-9-en-5-ones of For- 40 mulae XII-XIV and of desA-pregn-9-en-5-ones of Formulae XV-XVI is one of the main features of this invention@ It @is effected by catalytic hydrogenation, suiltabl@ using a precious metal catalyst. Suitable precious metal catalysts are palladium, platinum, ruthenium, and rhodium, the latter two being especially, preferred. It is, par- 45 ticularly advantageous to use rhodium, for example, rho- 1 dium@ on charcoal (or carbon powder, carbon black, or the like) or rhodium on alumina. In contrast to what would be expected, it has been found that such a catalytic hydrogenation of a compound of Formulae - XII-XVI 50 gives a substantial yield of a compound of Formulae VIXi. In fact, it has been found that such catalytic hydrogenation gives a major proportion of a compoiind of the Formulae VI-XL This catalytic hydrogendtion is suitably , effected in an inert organic s6lventi for example, a lower 55 alkanol such as methanol or ethanol, an ether such as dioxane or diglyme, a hydrocarbon such as cyclohexane hexane, or the like. Lower alkanols are preferred solirents Moreover, it is suitably conducted in the presence of an acidic or basic catalyst, for example, an alkali metal or 00 alkaline earth metal hydroxide such as sodium hydroxide or the like, or a mineral acid, for example, a hydrohalic acid, such as hydrochloric acid, or the like, or an organic acid such as a lower alkanoic acid; for example, icetic elow 65 te acid. The- reaction can be conduc d,- at, above or b room tem-perature, for example, frqm @about -5'@ C. to about 100' C@ However, it is preferably conducted at a temperature between about O' C. and about 35' C. As described above, the desA-androst-9-ene-5-ones or desA-17p-pregn-9-en-5-ones of Formula6 XII-XVI can be 76 prepared from natural steroids by a variety of metbods. Thus, in one embodiment of this invention said desaandrost-9-en-5-ones or desA-17p-pregn-9-en-5-ones can be prepared fibm st6ioids of the 3-6xo-@ndrost-4-ene 6r 3-@ acid or a 5-oxo-3,5-seco-A-norpregnan-3.-oic acid of the formula: H30 H3C H P@17 Hoof, 0 X, (Xvili) wherein X' and Z have the same meaning as above. The oxidative ring opening of the compound of Formula xvil can be performed by a variety of methods. In a preferred@ embodiment is is effected by ozonolysis. The ozonolysis is suitably carried out in an organic solvent, for example ' acetic acid, ethyl acetate, methanol, chloroform, methylene chloride, or the -like, or a mixture of two or more of such solvents such as ethyl acetate/acetic acid, ethyl acetate/methylene chloride, or the like. Moreover, the ozonolysis is advantageously conducted at below room temperature. Thus, it is preferably conducted at a temperature between about -70' C. and about 25' C. The resulting ozonides can be decomposed by conventional means, for example, by treatment with water, hydrogen peroxide in water, acetic acid or ethyl acetate, or the like. The oxidative ring opening of a compound of Formul-a XVII to a compound of Formula XVIII can also be effected by 6ther oxidation means, for example, by treatment with hydrogen peroxide. It should be noted that, an oxidative ring openming by either ozonolysis or by treatrnent ith hydrogen peroxide, does not require protection 6f any of the substituents at C-16 or C17@ However, as stated above,,it inay be desirable to protect these substituents against some subsequent reaction in the total reaction sequence being practiced. On the other hand, the oxidative ring opening can also be effected by oxidation with chromium trioxide or via treatment w-ith@ sodium periodate and p ssium pertnanganate in potas ota sium carbonate@ solu_ tion @ and if these oxidation means are used, it is necessary to protect any secondary hydroxy groups which might be present such as a 16,17,3- or 21-hydroxy group-, preferably, for the purpose of this reaction, with non-aromatic protecting groups. Following the oxidat@ve ring opemng of the A-ring, the so-obtained 5-oxo-3,5-seco-Anorandrostati@!3-oic acid or 570XO-3,5-s@co-A-norpregnan-3-oic acid: of FortiWIa XVIII loxo-17,6-pregn-4-ene@ series by a reaction sequence which@ 75 isconverteld into a mixture of a lOa-desA-androstan-5-one
[7]13 atid a lOp-desA-androstan-5-one or a mixture of a lOadesApregnan-5-one and a 10#-desA-pregnan-5-one as illustrated below: xviii alkah metal salt of XVIII Hac ]E[30 0 (XIX) (XX) wherein in Formulae XIX and XX, X' and Z have the same meaning as above. The compounds of Formula XIX are lOa-desA-androstan5-ones or lOa-desA-pregnan-5-ones, depending on the meaning of Z, and the compounds of Formula XX are 10,6-desA-androstan-5-ones or 10,6 desA-pregnan-5-ones. The conversion of a compound of Formula XVIII into the compounds of Formulae XIX and XX is'effected by pyrolysis. In effecting the pyrolysis, it is desirable to convert the 3- oic acid of Formula XVHI into a corresponding metal salt, for example, an alkali metal salt such as the sodium or lithium salt. This conversion to a metal salt can be effected prior to pyrolysis, e.g., by treating the acid with sodium hydroxide or in situ during the course of the -pyrolysis, e.g., by fusing the 3-oic acid with a n-tixture of sodium acetate and potassium acetate. 'Ihe pyrolysis can be conducted at atmospheric pressure or in a vacuum. One preferable embodiment is to conduct the pyrolysis in a vacuum, at a temperature from about 200' C. to about 350' C. in the presence of a proton acceptor, e.g. an alkali metal or alkaline earth metal salt of a weak organic acid, for example, potassium acetate, sodium acetativ,, sodium phenyl-ar-etate, sodium bicarbonate, or the like; especially p'@referred is a vacuum of from about .001 to about .5 mm. Hg. Accordingly, it is a@dvantageous to conduct the pyrolysis under alkaline conditions, i.e. at a pH greater than 7. The pyrolysis can be effected in solution or by fusion. An especially preferred method of effecting the pyrolysis is by fusion of an alkali metal salt of a weak acid, for example, an organic carboxylic acid such as a lower alkanoic acid or a phenyl4ower alkanoic acid such as phenyl-acetic acid. Another method of effecting the pyrolysis is to heat, preferably at atmospheric pressure, a solution of an alkali metal salt, such as the sodium or lithium salt, of a 3-oic acid of Formula XVHI in a basic organic solvent. The basic organic solvent should, of course, be one which is in the liquid state at the temperature at which the pyrolysis is effected. Thus, the pyrolysis can be effected at a temperature up to the boiling point of the basic organic solvent being used. Suitable basic organic solvents are, for example, nitrogen containing organic solvents such as piperidine, pyridine, isoquinoline, quinoline, triethanolamine, or the like. When utilizing this approach using a basic organic solvent it is suitable to heat to temperature between about 200' C. and about 300' C., and preferably between about 230' C. and about 260' C. A preferred basic organic solvent for the pyrolysis of a salt of a compound of Formula XVIII to compounds of Formulae XIX and Y-X is quinoline. If a basic organic solvent is used which boils substantially below 200' C. at atmospheric pressure, it is suitable to conduct the pyrolysis in a sealed tube or an autoclave. 8,766,256 14 In another aspect, compounds of Formula XIX can be prepared from compounds of the formula 5 H3 n z Hscr-) 10 H 0 (XIXA) 15 wherein X' and Z have the same meaning as above. The compounds of Formula )GX can be prepared from 20 compounds of Formula XIXA in the same manner that compounds of Formula XIX are prepared from com pounds of Formula XVII, i.e. by oxidative ring opening of the A-ring of a compound of Formula XIYA followed by elimination of the residue of the A-ring, to yield a compound of Formula X@IV. 'ne oxidative ring opening of the 2,5 compound of XIXA can be performed by ozonolysis as described above for the conversion of a compound of Formula XVII to a compound of Formula XVIII. Such ozonolysis of a compound of Formula XIXA yields a compound of the formula 30 Hao rH Z 35 40 (XIXB) wherein X' and Z have the same meaning as above, and 45 A is carboxy or formyl. A compound of Formula XIXB can then be converted to a compound of Formula XIX. This removal of the residue of the A-ring, ie.,derarboxylation and deformylation, can be effected by heating in an acidic or basic medium. It is 50 preferred to heat to the reflux temperature of the medium which is preferably an inert organic solvent such as a lower alkanol, e.g. ethanol, dioxane, ether or the like. The decarboxylation and deformylation yields mainly a compound of Formula =, but also a minor yield of 55 the corresponding lop-isomer of Formula XX. Compounds of Formula XIX can also be formed from a compound of Formula XVIH via the formation of an enollactone of a compound of Formula XVIII, i.e. via the formation of a 4-oxo-androst-5-en-3-one or a 4-oxo60 pregn-5-en-3-one of the formula: 65 0 z 70 0 1 -\o (XXI) 75 wherein )C and Z have the same meaning as above,
[8]3,766,256 is which can @then be reacted with a:Grignard reagent, such as phenyl inagnesiuiii, biromide or vhenvl lithium. to @foiid the resulting,,aidol of, for example, the formula cils H4c 0 z C2 H (Xxil) wherein, X' and@ Z@have @the same meaning as above., which, upon treatment with an alkali metal hydroxide, such as potassium, hydroxidp@ at an; elevated temperature, for example, @ from about@ 200' C. to about 940' @ C., is converted to the corresponding, 1 Oa-desA-androstan-5- one or 10-des-A-pre'gnan-5-one of Formula XIX. It should be@ noted that though the py;rolysis of a compound 6f Formuld XVIIT yields both. the 10#-c oun (MP, dsof For'mula XX and the lOc4-c6mpoundsof Formula XIX, and though either of these isomers can be used@ in the sub_ 25 same suit able cata lysts are,, fox exa mpl e, acet ir, acid , ben zoyl @ sequent halogenation and;dehydro-halogenation steps@of peroxide, or the like. this reaction sequence, it is sometimes preferable to con-@ 'The @subseq uent dehydro halogena tion of a compound yert the log-compound of Formula @XX into the corre-- of the @Formul-a XXIII is preferably - conducted@ under -mild sponding I-Oa-compound of Formula XIX. This conver- 30' dehydrohalogenating conditions; for exaniple, by the use 16 XV and XVI. Keto groups except for the@ 5-keto grgupl may requiie protection p.,rior to the halogenation. In the case of compounds: of Formulas XIX and XX rontaining the C-17 dihydroxyacetone side chain, represented in For@ mula V wherein R6 is hydroxy, this protection can be effected by formation of the 17a,20;20,21-bis-methylened!6)(@@ derivative,@ In cases where- in a C-17 oXo or other C-20, oxo group is present, protection can, be effected by i6@@the corresponding r redu@@6ii carbinol @eithe directly prior to the halogenation step or prior to some other step i& the- reaction sequence, leading to the compounds of Formulas XIX and XX. T@he halogenation @can he effected with, halogenating,,, agents such as bromine,, sulfuryl chloride, @ or the like. i E@-romination is especially preferred. The bromination is suitably'@ftded by treatment@ with @bromine at room temperature or below, preferably at ice temp erature or below Suitably it is conducted in an organic medium; for examplie, an orizanic 4ei@d such a@ acetic acid- an' ether suck as I 20 an anhydrous ether, dioxane, tetrahydrofuran-,,a chlorinated organic solvent such as methylene chloride, chloroform, clarbon tetrachloride-, or the -like; with the addition of, hydrogen brbmide as a catalyst. When effecting halo-g6nation , with sulfuryl chloride, it % is @ suiteible to use@ the type of orgaiiic medium as when' br6minating; and si6n can be effected by treating a lOp-desA-androstan-5- one or 10,8-desA-pregnan-5-one of 'Formula X.X with any base capable @of producing a catbanion; for example, it is suitable to use an alkali metal lower alkoxide in an or I - ganic solventi such as a lower alkanoll for. example, sodium . 35 ethoxide in an ethanol solution or sodium methoxide m a methanol solution. The above-discussed conversion via the alkali metal s6lt and pyrolysis of compounds of Formula XVIII to compounds of Formulas XIX and XX can be effected without 40 pr6tecti6n of any@ of the:substituents which might be present at C-16 or C-17. However, if it is a desired for eitherpreceding or succeeding reaction steps -of the total reacl-, tion- sequence, the conversion of a compound of Forinula XVIII to compounds of 'Formulas XIX and XX can be ts j, 15. effected with vrotecting groups present'oii substituej the C-16 or C-17 position. As stated above, the lOa-desA-androstan-5-ones or@@lomdesA-pregnan@5-ones of , Formuia' XIX or the 1 Op-desAandrostan-5-ones of 10,6-desA-pregnan-5-6nes of Formula XX can be converted via a'two-gtep sequenceof halogena- 50 tion and dehydrohalogenation into the desired starting materi,al -.desA-androSt-97en-5-one, or,,desA-pregn-9 !en- 5-one Of Formulas XI[, XV, anA XVI. - In a preferred emb6diment a lOadesA-androstan-5-one or a 10ce-desA-pregnan-5-one of-Formula-XIX is subjected 55 to the two-step seciuence @ of halogenation and dehydrohalogenation. @Hal6genati6n of a compound@ of Fbrmula XIX:or a compound 6f Formula, XX yields a mixture of unds including oi, corresponding halo @ie of genated compo 0 the formula ]Elsa z Hal 65 H30-- O@ (.N,,xili) .70 wherein X" and Z have tne same eaning as aoove, and Hal is a halogen atom (preferably Br or CI). Dehydrohalogenation of a compound@ of. Formula XXIII then yields a desired startifig material of F-ormulas XIL 75 of an alkali metal carbonate (e.g. lithium, carbonate) or an alkali metal halogenide (eg. lithium halide) in an orgamc solvent such as a di-loweralkyl-formamide, or with an organic base such as collidine, pyridine, or the like. The dehydrohalogenation is advantageously conducted at slightly elevated temperatures, for example,, from about 50' C. to about 150' C., preferably from, about 80' C. to ab6ut 120' C. Separation @of the desired product desA-androst-9-en-5one @ or@ desA-pr6gn-9-en5-one of F<)rmulas@ XII, XV and XVI can be effected by conventional means, As indicated above the halogenation procedure mai result in halogenated by-products in addition to the desired intermediate of ]@oimula XXIII. Accordingly, the separation is prefeiably effected after first subjecting:the reaction mix ture t6 dehalogenating conditions in 6rder to dehalogena-e the halogenated by-products formed by the halogenation procedure, but not deha-logena-ted by the dehydrohalogenation. Following such dehalogenati6n the reaction mixture-can then easily be se,parated by conventional means, for example, by column chromatography, to yield the desired compound of Formulas XII, XV, XVL An exemplary dehalogenati6n ineam is@ treatment@ with zinc and s6dium acetate in an acetic acid sol-ution at an elevated temperature, for example, about 80' C. In It'he' case of compounds of Formulas XIX or XX which dontain i a halogen atom on a carbon atom directly adjacent to a keto group, it is preferable to protect such la halogen-atom against dehalogenation - ptior @ to subjecting t4e compound of Formulas XIX or.,XX to the two step sequence-of halogenation anddehydrohalogenation of this embodiment. Such a grouping, con,taining a halogen atom on a carbon atom directly adja,cent to a keto group, is@illustrated in a compound of Fot'mulas IV or V wherein Rs or R6 is halogen. Thus, if IO"- or 10#-desApregnan- one 5- of Formula XIX or XX contai@@g a 17aor 21-halo substituent is to be subjected @o the halogenation-dehydroalogenation sequence it is",,desirable tor'first effect protec@tion, of the 17cx- oT 2 1-halo Isubstituent, This protection can be effected, for example, by ketalization of- the@ 20-pxo group., As stated above, the desired desA-androst-9-en-5-ones or desA-pregn-9-en-5-ones starting materials can also be prepared - 'from @ steroids of the 3-oxo-androstr4-ene I or 3-OXe-17,6@-pregn-4-ene series containing an 11-hydroxy
[9]3)7661256 17 substituent. In one embodiment an 11-hydroxy steroid of the formula H3c HO-/\ H3C H 5 0 10 x (XXIV) wherein X and Z have the same meaning as above, is reacted with an acid or a reactive derivative thereof to form a leaving group in the 11- position. By reactive 1,5 derivative is meant, for example, a halide, e.g. a chloride, an anhydride, or the like. Though either lip- or ilahydroxy starting materials can be used, it is preferable to utilize a-hydroxy compounds of Formula XXIV as starting materials. Prior to the esterification reaction, it 20 is preferable to protect hydroxy groups present in the C-16, C-17, or C-21 position. Suitable acids for the esterification of the 11-hydroxy group, which can be used to form a leaving group in the 11-position are inorganic acids such as phosphoric acid, organic carboxylic acids 25 such as anthraquinone p-carboxylic acid or organic sulfonic acids, for example, toluene-sulfonic acids, especially p-toluene sulfonic acid, lower alkyl-sulfonic acids such as methane-sulfonic acid and nitrophenyl-sulfonic acids, especially p-nitrophenylsuffonic acid. Especially preferred 30 as the leaving grounp in the 11-position is a lower alkylsulfonyloxy group such as the mesoxy group. However, when it is desired to react a compound of Formula XXIV with a sulfonyloxy forming moiety, then a compound of Formula X)UV having an Ila-configuration should be 35 used as a starting material. The above described esterification of 11-hydroxy steroid starting materials of Formula XXIV yields compounds of the formula 40 LO@,^ 113C 11 z 45 0 (XXV ) wherein X and Z have the same meaning as above, and LO represents the leaving group. 50 in the next step of this reaction sequence, the so-formed ll-(esterified hydroxy)-compound of Formula XXV is subjected to an oxidative ring opening of the A-ring to yield the corresponding I 1- (esterified hydroxy) -5-oxo-3,5- seco-A-norandrostan-3-oic acid or II-(esterified hy- 55 droxy)-5-oxo-3,5-seco-A-norpregnan-3-oic acid of the formula H3c LO@,^ 60 0 H HOO 65 (XXVI) wherein X, Z and LO have the same meaning a s above. The oxidative ring opening of the A-ring of a compound of Formula XXV to a compound of Formula XXVI can 7o be effected by ozonolysis as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. Pyroylsis of the soformed compound of Formula XXVI under the conditions described above for the pyrolysis of a compound of 75 18 Formula XVIR to compounds of theformulas XIX and XX directly yields the desired desA-androst-9-en-5-one or desA-pregn-9-en-5-one of Formulas XII, XV, XVI. Thus, pyrolysis of a compound of Formula XXVI directly results in elimination of the leaving group in the I 1-position as well as a splitting off of the residue of ring A attached to the I 0-position. This procedure of starting from an I Ihydroxy steroid (preferably llc&- hydroxy) of Formula XXIV and proceeding through intermediates of Formulas XXV and XXVI to compounds of Formulas XII, XV, XVL represents a particularly elegant procedure for preparing the latter compounds. An especially preferred method of effecting the pyrolysis of a salt of a 3-oic acid of Formula XXVI is the method described above wherein the salt of the 3-oic acid is heated in a liquid basic organic solyent. Especially preferred solvents for the pyrolysis of a salt of a compound of Formula XXVI are triethanolamine and,quinoline. As indicated in the foregoing paragraph the pyrolysis of a salt of a compound of Formula XXVI involves two separate chemical attacks; one being the elimination of the 11-leaving group and the other being the splitting off of the A-ring residue. Instead of effecting these two attacks simultaneously, as described above, it is also possible to effect them sequentially by just prior t(> formation of the salt, effecting elimination of the leaving group of the compound of Formula XXVI. This elimination yields a A9(")-seco acid of the formula H30 Hac I I IIYZ HOO 0 (XXVIA) wherein X and Z have the same meaning as above. The elimination can be effected by any conventional elimination means. It is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXVI with either an inorganic or organic acid or base results in the formation of the desired compound of Formula XXVIA. Preferably a weak base is used, for example, a salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline earth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous organic solvent; suitable are solvents such as dilower alkyl-formamides, e.g. dimethylformamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyformamide, is used, it itself can serve as the base for the purpose of this elimination reaction; i.e. if the solvent is basic then the elimination can be conducted without the addition of a separate basic material. Similarly, if the solvent is acidic, then the elimination can be conducted without the addition of a separate acidic material. After the elimination is effected the A9(")-seCG acid product of @Formula XXVIA can then be converted to a salt, for example, an alkali nietal salt, and the so-formed salt pyrolyzed according to the conditions described above for the pyrolysis of a compound of Formula XXVI to compounds of Formulas XII, XV and XVI. After the above-described 11-leaving group elimination and A-ring residue splitting, conducted either simultaneously or sequentially, the desired desA-9-en-5-one compounds of Formulas XII, XV and XVI can be isolated by conventional means. However, it has been found particularly suitable with compounds of Formulas XV and XVI
[10]3)766,256 19 to isblate by forming the disemicarbazone of the pyrolysis product and then regenerating therefrom the desired 5,20-dione of Formulas XV or XVII br if the 20-oxo group has been protected, for example, by reduction to a 20-hydroxy moiety, by forming the semicarbazone at the 5 5-p6sition and then regenerating therefrom the desired 5-- one compound. In yet another embodiment of this invention starting material -11-hydroxy steroids of Formula XXIV can be directly subjected to an oxidative ring opening of the A- 10 ring by ozonoylsis or treatment with hydroxide - peroxide, as described above for the oxidative ring opening of the A-ring of a compound of Formula XVII to a compound of Formula XVIII. This oxidative ring opening of the A-ring of a compound of Formula XXIV yields@ an 1 1-hydroxy-5- 15 oxo-3,5-seco-A-norandrostan-5-oic acid 3,1 I-lactone or an 11-hydroxy-3-oxo-3,5-seco-A-norpregnan-3-oic acid 3,11- lactone'of the formula 0 Hs I - 20 /IL <\ 113 z .... H 25 0 (XXVH) wherein X and Z have the same meaning as above. Treatment of the 3,1 I-lactone of Formula XXVII with an 30 alkali metal hydroxide such as sodium hydroxide gives the salt of the same keto acid. Without isolation, this salt can then be subjected to pyrolysis yielding a mixture of an 11-hydroxy-IOa-desA-andrbstan - 5 - one and an 11 - hydroxy-10,6-desA-androstan-5-one or a mixture of an 11- 35 hydroxy-10cc-desA-pregnan-5-one and an 1 1-hydroxy-IOpdes-A-pregnan-5-one, as ill-,ustrated below: xxvii, 40 alkali nietal salt H3c HIC 45 IIO-/\ no ]El Z HsC H 50 (4 0 (XXVIII) (XXIX) wherein in Formulas XXVIll and XXIX, X and Z have 55 the same meaning as above. This pyrolysis of an alkali metal salt:derived from a compound of Formula XXVII can be effected under the same conditions as described above for the pyrolysis of a com- 60 pound of Formula XVIII to compounds of the F6rmulae XIX and XX. Though either the 10,6-compound of Formula XXVIR or the loa-compound of Formula XXIX can be subjected to the subsequent steps of this reaction sequence, it is suitable to utilize the 10#-coml>ound of 65 Formula )CXVIII. Conversion of the lom-compound of Formula XXIX to the log-compound of Formula XXVIII can be effected under the same conditions as - described above for the conversion of the compound of Formula ] XX to a compound of Formula XIX. TO In the next step of this reaction sequence, the 11-hy&oxy compound of Formula XXVIII or of Formula XXIX can be subjected to esterification whereby to convert the 11-hydroxy group to a leaving group in the 11- position. This esterification can be effected with the same 75 20 acids or a id derivatives and in the same manner as described above for the esterification of a compoand of Formula XXIV to a compound of Formula XXV. As in that instance, it is also preferred in the present instance to form a mesoxy leaving group in the ll_position, though, of course, other leaving groups as described above are useful for ins purpose. is obtained a compound of the formula H30 LO-^ H H3c 0 (XXX) wherein X, Z and LO have the same meanings@ as above. The leaving group can then be eliminated from the I 1position of a compound of Formula XXX resulting in a direct formation of a desA-androst-9-en-5-one or a DesApregn-9-en5-one of Formulae XIL XV, XVI. This elimination can be effected by any conventional elimination means. @lt is suitably conducted under alkaline conditions in an anhydrous organic solvent. Preferably, it is effected by heating, i.e. at a temperature between about room temperature and the reflux temperature of the reaction mixture. Thus, treatment of a compound of Formula XXX with either an inorganic or organic base results in the formation of the desired compound of Formulae XII XV, XVI. Preferably a weak base is uscd, for example, @ salt of a carboxylic acid (e.g. a lower alkanoic acid) with an alkali metal or an alkaline ea-rth metal, for example, sodium acetate, potassium acetate, or the like. As indicated, the elimination is suitably conducted in an anhydrous orgamc s6lvent; suitable are solvents such as dilower alkylformamides, je.g. dimethyl formamide, lower alkanoic acids, e.g. acetic acid, or the like. When a proton accepting solvent, such as dimethyl formamide, is used, it itself can serve as -the base for the purpose of this elimination reaction; ie.-if the solvent is basic then the elimi@nation can be conducted without the addition of a separate basic material. In another aspee t, compounds of Formula XXX can be prepared frorn comvounds of the fonnula LO@ 0 (XXXA) wherein X, Z and LO have the same meanings as above. @The comp6unds of Formula XXXA can b6 prepared from corresponding I 1-hydroxy compounds by esterification as described above for the preparation of compounds, of Formula XXV from compounds of Formula XXIV. The compounds of Formula XXX can be prepared from compounds of Formula XXXA, in the same manner that compounds of Formula XXX are prepared from co-rnpounds of Formula XXV, i.e. by oxidative ring opening of the A-ring of a compound of Forrnula XXXA followed by elimination of the residue of the A-ring to yield a compound of Formula XXX. Tbe oxidative ring opening of the compounds of Formula XXXA can be performed by ozonolysis as described above for conversion of a compound of Formula XXV to a compound of Formula
[11]3)7661256 21 XXVI. Such ozonolysis of a compound of Formula XXXA yields a compound of the formula iisc ]EL Z 113 HOO 10 (XXXB) wherein X, Z and LO have the same meaning as above., 15 A compound of Formula XY-XB can then be converted to a compound of Formula XXX. This removal of the residue of the A-ring, i.e. decarboxylation, can be effected as described above for the conversion of a compound of Formula XIXB to a compound of Formula Xix. 20 The compounds of Formulae I-V preparable by the methods of this invention are not only pharmaceutically useful compounds as described above, but also are themselves useful as intermediates for other 9p,10a-steroids; for example, compounds wherein X is hydrogen or lower 2,5 alkyl can be modified so as to introduce unsaturation between C-6 and C-7. This can be effected by dehydrogenation means, for example, by halogenation followed by dehydrohalogenation or by means of 2,3-di chloro-5,6- 30 dicyanobenzoquinone, according to known methods. Thus, for example, a 9i3,10m-progesterone of Formula IV wherein X is hydrogen or lower alkyl can be converted to a 9p,10-pregna-4,6-dien-3,20-dione. A further embodiment of this invention comprises the 35 preparation of 9p,10v,-steroids of Formulae I-V containing an 11-hydroxy substituent. This can be effected by utilizing an 11-hydroxy-10ce-desA-androstan-5-one or 11- hydroxy-10,x-desA-pregnan-5-one of Formula XXIX or an 11-hydroxy-IOg-desA-androstan-5-one or 11-h ydroxy-10p- 40 desA-pregnan-5-one of Formula XXVHI as the starting materials. It is preferred in this embodiment to use the 10@-isomers of Formula XXVIII as starting materials. As a first step in this the I 1-hydroxy group of the compound of Formulae XXVIII or XXIX should be pro- 45 tected. This is suitably effected by esterification, preferably with a carboxylic acid, for example, a lower alkanoic acid such as acetic acid, benzoic acid, or the like. Conversion of the so-obtained 11-esterified hydroxy compound then yields an ll-(esterified hydrox y)-desA-an- 50 drost-9-en-5-one (i.e. a compound of Formula XII containing an 11-esterified hydroxy moiety) or an 11-esterified hydroxy-desA-pregn-9-en-5-one (i.e. a compound of Formulae XV-XVI containing an lla-esterified hydroxy moiety). This conversion can be effected by h alogenation 55 followed by dehydrohalogenation, as described above for the conversion of a compound of Formulae XIX or XX to a compound of Formulae XII, XV or XVI. Catalytic hydrogenation of the so-obtained compound of the formula 60 I irac EO H z 65 H (XXXI) 70 wherein X' and Z have the same meaning as above, and EO is an esterified hydroxy group as described above in this paragraph, 75 22 yields an 11-esterified hydroxy-desA-9p,10p-androstan-5one or 11-esterified hydroxydesA-9p,10p-pregnan-5-one, of the formula EO H3c HSC 0 (XXXII) wherein X', Z and EO have the same meaning as above. This hydrogenation can be conducted in the same manner as described above for the hydrogenation of a compound of Formulae XII-XVI to a compound of Formulae VII, X, XI. Also, compounds of Formula XXXII containing a 17-oxo moiety can be converted to a corresponding compound containing -a 17p-hydroxy, 17a-lower alkenyl or lower alkynyl moiety by the methods described above. Also, compounds of Formula XXXII can be hydrolyzed to yield corresponding 11-hydroxy compounds of Formula XXXII, i.e. wherein EO is hydroxy. Condensation of the so-obtained compound of Forniula XXXIT or the corresponding 17phydroxy, 17a-lower alkenyl or lower alkynyl compound (i.e. a compound of Formula VI containing a free or I I-esterified hydroxy group) then yields the desired end-product 9p,10a-steroid of Formulae I-V containing an 11-hydroxy group. Such condensation can be effected as described above for the preparation of a compound of Formulae I-V from a compound of Formulae VI-XI. The so-obtained 9,6,10ocsteroids containing an 11- esterified hydroxy group can be hydrolyzed to the corresponding compounds containing an 11-hydroxy group, which latter compounds are themselves useful as intermediates, for example, the 11hydroxy group can be oxidized by methods known per se to yield corresponding 11-oxo steroids analogous to compounds of Formulas I-V. The pharmaceutically useful compounds prepared by the methods of this invention can be administered internally, for example, orally or parenterally, with dosage adjusted to individual requirements. They can be administered in conventional pharmaceutical forms, e.g. capsules, tablets, suspensions, solutions, or the like. The following examples are illustrative but not limitative of this invention. All temperatures are in degrees centigrade. The Florisil adsorbent used infra is a synthetic magnesia-silica gel available from the Floridin Company, P. 0. Box 989, Tallahassee, Fla. (cf. p. 1590, Merck Index, 7th Editi6n, 1960). 100-200 mesh material was used. The moiety designated by tetrahydropyranyloxy is tetrahydro-2-pyranyloxy. When it is stated that a procedure is effected in the cold, it should be understood that it is commenced at O' C. Throughout this application when compounds of the pregnane series are referred to it should be understood that it is compounds of the 17,6-pregnane series that are being referred to, unless specifically indicated to the contrary, and whether or not the compound of the pregnane series is specifically indicated as of the 17p-series. Example 1 A solution of 3.Z g. of 17a-ethyltestosterone in 50 ml. methylene chloride and 25 ml. of ethyl acetate was ozonized at -70' (acetone-Dry @Ice bath) until the solution was blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The syrupy residue was then dissolved in 100 ml. of glacial acetic acid, and after addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 0-51. Following this time, it was evaporated to dryness, dissolved in 1500 nil. ether, and extracted with 2 N sodium car-
[12]3)766)256 23 bonate solution. The alkaline extract was poured in ice cold hydrochloric acid. The resultant crystalline 17aethyl-17,6-hydroxy@5-oxo@- 3,5 - seco-A7norandrostan-3' acid was filtered; washed with water and dried. being recrystallized from acetone, it melted at 196 Example 2 A solution of 1.5 g. of 17a-ethyl-17,,g-hydroxy-5-o xo3,5-seco-A-norandrostan-3@@oic acid in 100 mL of methanol was titrated with 2 N sodium metboxide to i@he reddish color of phenolphthaleine, -and then evaporated to dryness in vacuo, giving as the residue, the sodium salt of 17ce-eth'yl4l7p-hydroxy-5-ox o-3,5-seco-A-norandrostan3-oic acid. 15, g. of sodium-phenylacetate was heated to@ the residue, and the mixture pyrolyzed in vacuo (<0.11 nim.) at 285-2951, for 2.5 hours. The sublimate was dissolved in acetone, filtered and the filtrate concentrated in vacuo. The Tesultant syrupy iesi was chromatographed on a 60 g. Florisil (adsorbent) column. The fractions eluted with benzene and 0.5 percent ethylacetate in benzene were combined and gave 17a-ethyl17p-hydroxy-IOa-desA-androstan-5-one M.P.@94-950 after recrystallization from petroleum ether. The fractions eluted with 2 percent and 5 percent ethylacetate in benzene were combined and gave 17a-ethyl-17,6-hydro xy-10@PdesA-androstan-5-one, M.P. 185--185@5', after two recrystallizations from petroleum ether. Example 2a To a solution of 100 mg. of 17a-ethyl--17p-hydroxy'OPdeSA-androstan-5-one iii 10 mli of @bsolute ethanol was added one equivalent of sbdiii-iii ethoxide dissolved in 5 ml of absolijte ethanol@ This reactioti mixture was maintained at room temperature overnight, then acidified with glacial acetic acid, poured in water and extracted with methylene chloride. The extract was washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo. Thin layer chromatography showed the product to be 17cc-ethyl17,6-hydroxy-10a-desA-androstan-5-one. It was obtainedcrystalline firom petroleum ether-ether and melted at 89-95'. Example 3 I ' 13 g. of 17m-ethyl-17#-hydroxy-IOa-desA-androstan5-one was dissolved in 120 ml. of anyhdrous ether (or 11.13 g. of 10,8-isomer was dissolved in 300 ml. of anhydrous ether), and after cooling in a salt-ice bath, several drops of 30 percent hydrobromic acid in acetic acid were added. This was followed by the dropwise additionduring five minutes 6f 0.684 g. of bromine dissolved in 2 ml. of acetic acid. This addition was synchronized with the decoloration rate of the reaction mixture. Immedi;ately after this, 5 ml. of a saturated solution of sodium bisulfite and 5 ml. of 2 N sodium carbonate solution were added. The mixture was then transferred into a separatory funnel, 500 ml.: of ether -added,,,shaken - and@ separated. The ether part was washed with water, dried and evaporated. The r6sultant bromides were dissolved in 100 ml. of dim ethylformamide, and after addition of 3 g. of lithium carbonate, the solution was heated at 100' for 45 rninutes. After cooling, it was poured into one liter of ether, washed with water, I N hydrochloric acid, 2 N sodium carbonate, water, dried and evaporated. The residue was dissolved in 40 ml; of glacial acetic acid, 1.2 g. of sodium acetate and 1.2 g. of zinc powder added, and the soformed mixture heated 10 minutes at 80', It was then poured into one liter of ethylacetate and the resultant solution washed with saturated sodium bicarbonate, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column. The fraction with benzene and 11/2 percent ethylacetate in benzene gave regenerated starting material. Fractions with I and 2 percent ethylacetate in benzene gave @17a-ethyl-17pbydroxy-desA-androst-9-en-5-one, which after sublimation (140' and 0.1 mm. Hg vacuum), was obtained as a glass. [a]25 -36.6' (c.=l, CHC13)- 24 Example 4 . A suspension of 262 ing. of 5 pe-reent rhodiuni on alu@ mina caialyst in a mixture of 26 ml@ of 95 percent ethanol and 5.25 ml. bf 2 N sodium hydroxide solution was prereduced (i.e. hydrogenated at room temperature and atmospheric pressure). To this was added a solution of 262 . mg. bf tl7a-ethyl-17p-hydroxydesA-androst-9-on-5one in 15:ml. of 95 percent ethanol, and. the mixture then hydrogenated at atmospheric pressiire and room tempera10 fter ture. A one mole-equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was separated:by filtration, and the filtrate evaporated in vacuo. 'Glacial acetic acid (I ml.) was added to the residue, 15 which Was then dissolved in I liter of et-her. The cloudy solution which resulted was washed with 2 N Na@COa solution, then with water, dried and evaporated to dryness in vacuo. The reaction was repeated 3 more times, and the com20 bined products chromatographed on a Florisil (adsorbent) column. The eluates with I percent ethyl acetate -in benzene gave first crys talline,-fractions, which @were followed by non-crystabine fractions. The non-crystalline@ fractions were dissolved in 100 ml. of methylene chloride 25 and after the addition of 2.5 ml. of 2 percent CrO3 in 90 percent acetic acid, stirred overnight@ The excess of chromic acid was removed by washing the methylene: chloride solution with 10 ml. of 10 percent sodium hydrogen sulfite solntion, followed by washing with 2N Na,cOa, 30 solution and th--n with water. It was then dried and evaporated - iia vacuo. @The residue was dissolved in 50 ML of anhydr6us ethanol containitig 172 mg. of sodium ethoxide, and left @ overnight@ The next day, after addition of 0.5 ml. of glacial acetic, acid, the solution was evaporated 35 in vacuo, and the residue was taken up in 1 1 of ether. The ether solution was washed with 2 N Na2CO3 solution, then with water, dried and evaporated. The residue was chromatographed on Florisil (adsorbent) column and gavecrystalline 17methyl@17p-hydroxy-desA-!@p,10p40 androstan-5-one identical (by thin layer chromatography) with the ctystalline material obtained in the first chromatographic separation. After two recrystallizations from ether, it melted at @142-144'-,- [a]E@5-11.65' Lmethanol, c.-- 1.245 percent]. -Example 5 45 To a solution of 132 mg. of 17a-ethyl-17#-hydroxydesa - 9,6,10p - androstan-5-one in 12.5 ml. of absolute ethanol containin.- 34 mg. of sodium ethoxide, 0.15 ml. of freshly chstilled methylvinyl ketone was added. The 50 reaction mixture was@ then refluxed for -two hours in a nitrogen atinosphere. After cooling the reaction mixture, 0.1 ml. of glacial acetic acid was added thereto and the resulting mixture was the poured into 1 liter of ether. The resultant ether solution was washed with water, dried 55- over anhydroizs sodaum@ Sulfate and evaporated in vacuo. The residue was chromatographed on fluorescent silicagel plates, with the solvent system, 60 percent@ethyl acetate 40 percent heptane. The fluorescent part of the layers was extracted with ethyl acetate. The residue obtained 60 after evaporation of ethyl acetate was first crystallized from ether-petroleum ether, then a second time from pure ether, yielding 17a-et hyl-9,6,10a-testosterone, M.P. 1311350. Example 6 65 A solution of 6.4 g. of II a@hydroxy-progesterone in 100 ml. of ethylacetate and 50 ml. of methylene chlbride was treated with ozone at -70' until the solution became blue in col6r. Oxygen was then passed through and the 70 solution evaporated at room temperature in vacuo. The so-obtained syrupy residue was dissolved in 100 ml. of glacial acetic acid, and after the addition of 5 ml. of 30 percent hydrogen peroxide, left for 24 hours at 2' (in an ice box). The solution was then evaporated in vacuo, and 75 the residue triturated with ether yielding crystals. Re-
[13]37766,256 25 crystallization from acetone yielded 1 1 a-hydroxy3,5-secoA-nor-pregnane-5,20- dione-3-oic acid 3,11-lactone, M.P. 253-256'.IUJD 25+193.3' c.=I, in chloroform). Example 7 A methanolic solltion of 7.5 g. of Ilee -hydroxy-3, 5seco-A-nor-pregnane-5,20-dione-3- oic acid 3,11 - lactone was treated with one equivalent of 10 N sodium hydroxide solution and then evaporated to dryness. Sodium phenylacetate (26 g.) was added to the so-obtained sodium salt and the mixture pyrolyzed at 295' for two hours in vacuo. The crude sublimate was chromatographed on a silica-gel column and eluted with 10 percent ethylacetate in benzene. The amorphous solid lla-hydroxy-IOadesApregnane-5,20-dione was first eluted from the column. IRspectrum in chloroform: 3620 and 3600 cm.-' (-OH); 1706 cm.-' (carbonyl gorup). NMR-spectrum in deuterochloroform: a doublet for 10(x-CH3 at 73.5 and 80.5 c.p.s., downfield from TMS at 60 me./see. Further elution of the column with 10 percent ethylacetate in benzene yielded crystalline lla-hydroxy-10p-desA-pregnane-5,20dione which was recrystallized from methylene chloridepetroleum ether, M.P. 150-152'; [(X]D25+84.0' (c.=O. in absolute ethanol). Example 8 To a solution of 100 mg. of methanesulfonylchloride in 0.7 ml. of pyridine, there was added 100 mg. of Ila-hydroxy-10g-desA-pregnane-5,20 - dione. The mixture was then allowed to stand overnight at 2' (in a refri.-erator), then was diluted with water (100 ml.) and extracted with chloroform (3X 150 ml.) and methylene chloride (100 ml.). The combined organic extracts were washed with water, I N hydrocloric acid and again with water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The crystalline residue was recrystallized from ether, giving Ila-hydroxy-10p-desApregnane-5,20-dione methanesulfonate, M.P. 139-140'; [MID 25+46' (C.=0.5 in absolute ethanol). Example 9 A solution of 200 m-. of llm - hydroxy - lOp-desApr egfiane-5,20-dione methanesulfonate in 50 ml. of dimethylformamide was refluxed for eight hours and then evaporated to dryness. The residue was chromatographed on a Florisit(adsorbent) column. Elution was 2 percent ethylacetate/benzene and evaporation of the eluant yielded desA-pregn9-ene-5,20-dione in the form of colorless needles, M.P. 11 1-1 13'. It was shown by mixed melting point to be identical with a sample of the same com. pound prepared as described in Example 12. Example 10 To a solution of 20 g. of I 1 a-hydroxy-progesterone in 150 ml. of pyridine maintained at O', there was add.ed 6 ml. of methanesulfonylchloride, and the reaction mixture allowed to stand overnight at O'. It was then diluted with a large excess of water and extracted with chloroform. The organic extracts were washed with 2 N hydrochloric acid and water, then dried over anhydrous sodium sulfate and evaporated in vacuo. The solid residue was recrystallized from methanol to give lla-mesyloxy-progesterone, M.P. 159.5-160'; la]D 25 + 145.6 (c. = 1, chloroform). Example I I A solution of 12 g. of lla-mesyloxy-progesterone in 300 ml. of methylene chloride/ethyl acetate (2:1) was treated with ozone at -70' until the solution became blue in color. The excess of ozone was removed by bubbling oxygen throuih the reaction mixture for five minutes. Methylene chloride was then removed under reduced pressure, and the solution diluted with ethyl acetate to 200 ml. After addition of 12 ml. of 30 percent aqueous hydrogen peroxide, the reaction mixture was then allowed to stand overnight at 2' (i.e., in the refrigerator), then evaporated to a volume of 75 ml. and diluted with 125 26 ml. of benzene. The aqueous solution, obtained by extraction with 8 parts of 75 ml. 2 N sodium carbonate followed by combining the aqueous extracts was acidified with cold concentrated hydrochloric acid to pH 2 and extracted with methylene chloride. This extract was dried over anhydrous sodium suffate and evaporated in vacuo to dryness. The residue crystallized when triturated with ether-acetone mixture, yielding crude lla-mesoxy-5, 20-dioxo-3,5-secoA-norpregnan-3-oic acid. After recrystallization from ace10 tone-petroleum ether, M.P. 152-153'; la]D 25+47.9 (e. =I), chloroform). Example 12 A solution of 6 g. of lla-mesoxy-5,20-dioxo3,5-secoA-nor-pregnan-3-oic acid in 150 ml. of methanol was 15 mixed with a solution of 1.5 g. of sodium carbonate in 55 ml. of water. The mixture was then transferred into a 1 liter sublimation flask, and evaporated to dryness. To the thus formed sodium salt, 20 g. of sodium phenyl acetate is added, and after closing the top part of the apparatus, 20 this mixture was pyrolyzed at 290' and 0.02 mm. for four hours. The product, which collects on the cold finger, was dissolved in ether and filtered. The filtrate was then evaporated to dryness. Purification of the residue by chromatography on a 40 g. silica-gel column (benzene eluant) 25 gave crystalline desA-pregn-9-ene-5,20-dione; M.P. 111113' (after recrystallization from ether). [aID25+56.8' (c.=0.25 percent in methanol). Example 13 30 To a solution of 1.2 g. of desA-pregn-9-ene-5,20-dione in 20 ml. of methanol maintained at O', there was slowly added a cooled solution of 1.2 g. of sodium borohydride in 22 ml. methanol, and the resultant mixture was left for 72 hours at O'. It was then diluted with 100 ml. of water and 35 extracted with four 100 ml. portions of chloroform. The extract was dried over anhydrous sodium sulfate and evaporated in vacuo, yielding a colorless oily product. This product was dissolved in 250 ml. of chloroform and 40 6 g. of manganese dioxide was added to the solution which was then stirred for 72 hours at room temperature, filtered and the filtrate evaporated to dryness in vacuo. The residue was chromatographed on a silica-gel colunin and the eluates with 5 percent ethyl acetate in benzene, 45 after concentration gave crystalline 20p-hydroxy -desApregn-9-en-5-one which upon recrystallization from methylene chloride-petroleum ether formed colorless needles, M.P. 122-123'; [aID25 -33' (c.=0.5, absolute ethanol). Example 14 50 A suspension of 262 mg. of 5 percent rhodium on alumina catalyst in a mixture of 26 ml. of 95 percent ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was hydrogenated at room temperature and atmospheric pres55 sure. To this was added a solution of 262 mg. of 20phydroxy-desA-pregn-9-en-5- one in 15 ml. of 95 percent ethanol, and the reaction mixture then hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction 60 was stopped, and the catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added I ml. of glacial acetic acid, and it was then dissolved in I liter of ether. The cloudy solution was washed with 2 N aqueous sodium car65 bonate solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. It yielded a colorless oil, which was chromatographed on a silica-gel column using I percent ethyl acetate in benzene as the elutant. First eluted was 20p-hydroxy7o lOa-desA-pregnan-5-one, M.P. 107-108' after recrystallization from methylenechloride/petroleum ether. R.D. (in methanol); [a]500 -25.3'; [Oe]400 -89'; 1-1350 -274'; [c,],,, -1335'; lm]300 -1165'. Furthermore elution yielded 20p-hydroxy-9p,10#-desA75 pregnan-5-one as a colorless oil. R.D. (in methanol);
[14]3,766,256 27 E,x] 5oo -14.8*; la]400 -4.4'; ECL]35 +22.2'. 0 ECLI310 +21 48'. Exa mple 15 A suspension of 262 mg. of 5 percent rhodium on alumin a catalyst in a mixture of 2 Ml. of 3 N aqueous hydro- 5 chlo ric acid and 18 ml. of 95 percent ethanol was hydrogen ated at room temperature ture and atmospheric pressure . A solution. of 262 mg. of 20p-hydroxy-des.A-pregn-9- en5-one in 5 ml. of absolute ethanol was introduced into the hydrogenation flask, and the reaction mlxture was then 10 hyd rogenated at room temperature and atmospheric pressure . After one mole-equivalent of hydroegn was absorbed sure . After one mole-equivalent of hydrogen was absorb ed, the reaction was stopped, the catalyst was separate d by filtration, and the filtrate neutralized with 2 N 15 aqu eous sodium hydroxide solution. An excess of 5 ml. of 2 N aqueous sodium hydroxide was added anid the solu tion allowed to stand overnight. Ethanol was then rem oved by evaporation at reduced pressure, and after addi tion of 1 ml. of glacial acetic acid, it was extracted 20 with I liter of ether. The extract was washed with 2 N aqu eous sodium carbonate solution, then with water, dried and concentrated in vacuo. It gave a colorless oil, which was chromatographed on a silica-gel column using 2 per- 25 cent ethyl acetate in benzene as the elutant. The first frac tions of the eluate yielded, upon concentration, 20phyd roxy-IOa-pregnan-5-one. From the iinmediately subseque nt fraction, 20p-hydroxy-9,6,10,6-desA-pregnan-5-one was obtained. Both products were identical with the same 30 com pounds obtained inexample 14. Exa mple 16 20phydroxy-9p,10a-pregn-4-en-3-one is prepared by con densation,of 20g-hydroxy-9p,10g-desA pregnan-5-one 35 with methyl vinyl ketone acoording t6 the procedure of Exa mple 5. The product melts at 176.5-178.5'; La]D25 - 143' (chloroform). Exa mple 17 40 A medium is prepared of 20 g. of Edamine enzymatic dige st of lactalbumin, 3 g. of corn steep liquor and 50 g. of technical dextrose diluted to I liter with tap water and adju sted to a pH of 4.3-4@5. Twelve liters of this sterilized med ium is inoculated with Rhizopus nigricans minus 45 strai n (A.T.C.C. 6227b) and incubated for 24 hours at 28' using a rate of aeration and stirring such that the oxy gen uptake is 6.3-7 millimoles per hour per liter of Na2 SO3 accordin.- to the method of Cooper et al., Ind. Eng . Chem., 36, 504 (1944). To this medium containing 50 a 24 hour growth of Rhizopus nigricans minus strain, 6 g. of 17a-acetoxy-progesterone in 150 ml. of acetone is add ed. The resultant suspension of tlle steroid in the culture is incubated under the same conditions of temperature and aeration for an additional 24 hour period after ti5 whi ch the beer and mycelium are extracted. The mycelium is then filtered, washed twice, each time with a volume of acet one approximately equal in volume to the mycelium, extr acted twice, each time with a volume of methylene chlo ride approximately equal to the volume of the my- 60 celi um. The acetone and methylene chloride extracts includ ing solvent are then added to the beer filtrate. The mix ed extracts and beer filtrate are then extracted success ively with 2 portions of methylene chloride, each port ion being I/z the volume of the mixed extracts and 65 bee r filtrate, and then with-2 portions of methylene chloride, each portion being 1/4 the -volume of the mixed extrac ts and beer filtrate. The combined methylene chloride extr acts are then washed with 2 portions of a 2 percent aqu eous solution of sodium bicarbonate, each portion 70 bein g Ylo the volume of the combined methylene chloride extr acts. The methylene chloride extracts are then dried with about 3-5 g. of anhydrous sodium sulfate per liter o,f solvent, and then filtered. The,solvent is then removed fro m the filtrate by distillation, and the residue is dis- 75 28 solved in a minimum of methylene chloride, filtered and the solvent evaporated from the ffltrate. The resulting crystals are then dried and washed five times, each time with a 5 ml. portion of ether per gram of crystal The crystals are then recrystallized from ether giving 17a-acetoxy- II ahydroxy-progesterone. 17c& - acetoxy - Ila-mesoxyprogesterone is prepared by treatment of 17a-acetox y-Ilochydroxy-progesterone with methanesulfonyl chloride, according to the procedure of Example 10. Example 18 17a - acetoxy - 5,20 - dioxo - lla - mesoxy-A-nor-3 ,5secopregnan-3-oic acid is prepared by ozonolysis of 17aacetoxy-llcc-mesoxy-progesterone, according to the procedure of Example 1 1. Example 19 17a - actoxy - desa - pregn - 9 - ene-5,20-dione is prePared 'from 17cc-acetoxy-5,20- dioxo-Ila-mesoxy-A-nor3 5-secopregnan-3-oic acid by conversion of the latter to tl i s sodium salt followed by pyrolysis, according to the procedure of Example 12. Example 20 17a - actoxy - 20p - hydroxy - desA-pregn-9-en-5-one is prepared from 17a-acetoxydesA-pregn-9-en-5,20-dione by reduction and reoxidation according to the procedure of Example 13. Example 21 17c& - acetoxy - 20p - hydroxy - 9p,10p-desA pregnan5-one is prepared from 17aacetoxy-20p-hydroxy-desApregn-9-en-,5-one by hydrogenation under acidic conditions in the presence of a rhodium catalyst, according to the procedure of Example 15. Exa mple 22 17a - actoxy - 20,3 - hydroxy - 9p,10,x-pregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 17aactoxy - 20,3-hydroxy-9 p,10,6-desA-pregnan-5-one according to the procedure of Example 5 except instead of conducting the condensation in absolute ethanol and catalyzing it with sodium ethoxide, the condensation is conducted in acetic acid and is catalyzed with p-toluene sulfonic acid. Example 23 20,6 - hydroxy - 4 - mthyl - 9,6,10a - pregn-4-en-3-one is prepared by condensing 20phydroxy-9p,10p-desA-pregnan-5-one and ethyl vinyl ketone according to the procedure of Example 5. Example 24 17,6 - hydroxy - 5 - oxo-3,5-seco-A-nor-androstan-3-oic acid is prepared by ozonolysis of testosterone according to the procedure of Example 1. Example 25 1113 - hydr6xy - 10a - desA-ndrostan-5-one and 17phydroxy - I Op - desa-androstan - 5 - one are prepared from 17,8 - hydroxy - 5 - oxo - 3 5-seco-A-norandrostan3-oic acid by conversion of the @atter to its sodium salt followed bypyrolysis, according to the procedure of Example 2. Example 26 17p - hydroxy - desa - androst - 9 - en - 5 - one is prepared from l7j3 - hydroxy - lOadesA-androstan@5-one by bromination followed by deh ydrobromination, according to the procedure of Example 3. Example 26a DesA-androst-9-ene-5117-dione is prepared from 17,3 hydroxy-desA-androst-9-en-5- one by oxidation of the latter with a 2 percent chromic acid solution in 90 percent acetic acid. The so-obtained desA-androst-9-ene@5,17dione is recrystallized from cyclohexane and melts at 123-123.5'; L-1589 25=+83' (c.@0.1021, dioxane).
[15]37766,256 29 Example 27 A soltition of 236 mg. of 17p-hydroxy-desA-androst9-en-5-one in 40 ml. percent ethanol and 5.Z5 ml. 2 N aqueous sodium hydroxide solution was hydrogenated with one mole equivalent of hydrogen over 236 mg. of prereduced 5 percent rhodium on alumina catalyst. After separation of catalyst, the solution was concentrated in vacuo to dryness, and the residue taken up in one liter of ether. The ether solution was washed with water, dried over anhydrotis sodium sulfate and evaporated to dryness in vacuo. From the residue 17g-hydroxy-9p,10p-desAandrostan-5-one was obtained by crystallization. M.P. 144.5-145'; la]D 25-22' (c.=0.103; dioxane). The 170acetate (i.e. 170- acetoxy-9p,10,3-desA-androstan-5-one) is obtained by acetylation of testosterone followed by ozonlysis, pyrolysis, bromination and d ehydrobromination, and reduction according to the methods of Examples 24, 25, 26 and Z7 respectively, and melts and 118-119'; la]D 25-28' (c.=0.103; dioxane). Example 28 A solution of 238 mg. of 17p-hydroxy-9,3,10#-desAandrostan-5-one, I ml. of ethylene glycol and catalytic amount of p-toluene sulfonic acid in 100 ml. of anhydrous benzene was slowly distilled until no more water was coming over. The solution was then concentrated in vacuo to a small volume, and 17p-hy droxy-9p,10pdesa - androstan - 5 - one 5-ethylene ketal was obtained from the residue by crystallization. M.P. 115-116'; [CCID 25-91 (c.=0.0987; doxane). Example 29 To a solution of 282 mg. of 17p-hydr(yxy-9p,10@-des Aandrostan-5-one 5-ethylene ketal in 50 ml. of methylene chloride was added 1 equivalent of 2 percent chromic acid in pyridine, and the reaction mixture then stirred overnight. Tbe reaction mixture was then washed with 10 percent aqueous sodium hydrogen sulfite, 2 N aqueous sodium carbonate, water, then dried over anhydrous sOdium sulfate and concentrated in vacuo to dryness. Crystallization of the residue gave 9p,10p-desA-androstane5,17- dione 5-monoethylene ketal. Splitting of the ketal in acetone solution in the presence of a catalytic amount of p-toluene sulfonic acid gives 9p,10p-desA-androstane-5, 17-dione which melts, after recrystallization from cyclohexane, at 77.5-78'; IUID 25 +55' (c.=0.107; dioxane). Example 30 To a preformed solution of one mole equivalent of prop-l'-inyl lithium in 100 ml. of anhydrous liquid ammonia was added tetrahydrofuran solution of 200 mg. of 9p,10p - desa - androstane - 5,17 - dione 5-mono-ethylene ketal, and the reaction mixture stirred for two hours. After addition of one gram of ammonium chloride' cooling was discontiliued, and the reaction mixture allowed to evaporate. The residue was extracted with methylene chloride, the extract was washed with water, dried over anhydrous sodium sulfate and evaporated. The residue was dissolved in 20 ml. of acetone and the catalytic amount of p-toluenesulfonic acid added, and the solution was refluxed for two hours, then poured in water and extracted in methylene chloride. The methylene chloride extract was washed with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. Crystallization of the residue gave 17a(prop-l'inyl)-17p-hydroxy-9p,10#-desA-androstan-5-one. Example 31 17v.-(prop-l'-inyl) - 17p - hydroxy-9p,10a-androstan-4en-3-one is prepared by condensing methyl vinyl ketone with 17v-(pr op-l'-inyl)-17p-hydroxy-9p,10p-desAandrostan-5-one according to the procedure of Example 5. The product melts at 164- 165'. 30 Example 32 To a stirred solution of one mole equivalent of 2-m ethyl-prop-2-enyl magnesium bromide in 100 ml. of ether at room temperature was added dropwise a solution of 280 mg. of 9p,10,8-desA-androstane-5,17-dione 5-mono-ethylene ketal in 100 ml. of tetrahydrofuran. The reaction mixture was refluxed for one hour. After cooling in an icesalt bath, a saturated solution of sodium sulfate was slowly added to decompose the Grignard complex. This was 10 followed by addition of anhydrous sodium sulfate. The solution was separated by filtration and concentrated in vacuo to dryness. The solution of the residue and of a catalytic amount of 13-toluene sulfonic acid in 20 ml. of acetone was refluxed for two hours, then poured in water 15 and extracted in methylene chloride. Methylene chloride extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness. From the residue 17a(2'-methyl-prop-2'-enyl)-17p - hydroxy -- 9,3,10,8-desAandrostan-5- one was obtained. 20 Example 33 17a-(2'-methyl-prop-2'-enyl) - 17p - hydroxy-9,6,10 aandrost-4-en-3-one is prepared from 17a-(2'-methyl-prop2'-enyl)-17p-hydroxy - 9p,10p - desAandrostan-5-one by 25 condensation of the latter with methyl vinyl ketone ar-cording to the procedure of Example 5. The product melts at 106-108'. Example 34 16a-acetoxy - 20 - ethylenedioxy-pregn-4-en-3-one is 30 prepared by acetylation of 16cc-hydroxy-20-ethyl enedioxypregn-4-ene-3,20-dione with one equivalent of acetic anhydride in pyridine solution at room temperature for 2 hours, followed by concentration to dryness in vacuo. 35 16a-acetoxy-20-etbylenedioxy - 5 - oxo-3,5-secoA-norpregnan-3-oic acid is prepared by ozonolysis of 16ct-acetoxy-20-ethylened ioxy-pregn-4-en-3-one according to the procedure of Example 1. Example 35 40 16a-acetoxy-20-ethylenedioxy-IOY,-desA-pregnan-5-one and 16a - acetoxy20-ethylenedioxy-10@-desA-pregnan-5one are prepared from 16(x-acetoxy20-ethylenedioxy-5oxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis (according 45 to the procedure of Example 2) and reacetylation with acetic anhydride and pyridine. Example 36 16a-acetoxy - 20 - ethylenedioxy-desA-pregn-9-en-5-one 50 is prepared from 16Ge-acetoxy-20-ethylenedioxy-1 0a-desApreg@ian-5-one by bromination followed by dehydrobromination, according to the procedure of Example 3. Example 37 55 16c&-acetoxy - 20 - ethylenedioxy-9,8,10p-desA-pregnan5-one is prepared from 16a - acetoxy-20-ethylenedioxydesA-pregn-9-en-5-one by hydrogenation under basic conditions in the presence of a rhodium catalyst, according to the procedure of Example 14. 60 Example 3 8 16u-hydroxy - 20 - ethylenddioxy-9,6,10ce-pregn-4-en-3one is prepared by condensing 16a-acetoxy-20-ethylenedioxy-desA-9p,IOP-pregnan-5-one with methyl vinyl ketone 65 according to the procedure of Example 5. Example 39 3p-hydroxy - 16a - methyl-pregn-5-en-20-one ethylene ketal is prepared by ketalization of 3,3-hydroxy-16cL-meth70 yl-pregn-5-en-20-one in benzene solution with ethylene glycol using ptoluenesulfonic acid as catalyst. Pyridinechromic acid oxidation of the so-obtained 3g-hydroxy-16amethyl-pregn-5-en-20-one ethylene ketal yields 16a-methyl-20- ethylenedioxy-pregn - 4 - en-3-one. 16ce-methyl-20- 75 ethylenedioxy - 5 - oxo-3,5-seco-A-norpregnane-3-oic acid
[16]3,766.256 32 is@prepared by ozonolysis of 16m-riiethyl-20- ethylene@di. Example 50, oxypregn-4-en-3-c,ne according@to the procedure of Exam_ ple 1. 5,20--dioxo-ll,%-mesoxy-16a,17aisopropylidenedioxy3, acid is p,,pard by@ ozonolysis Example 40 of 11@%@mesoxy-16a,17(i-isopropylidenedioxy-progesterone, 16&-methyl-20-ethylenedioxy, - 10ce desA-pregnan-,5- 5 according to the procedure of Example I 1. one and 16a-methvl-20-ethylenediox y-10p-desA7pregnan@@: Examplo 51 5-one are prepared@from@'16cc-methYl@20 -ethylenedioxy-5-, oxo-3.5-seco-A-norpregnan-3-oic acid by conversion 6i the 16a,17cc isopropylidenedioxy-desa-pregn - 9-en-5,20- latter to its sodium salt followed by pyrolysis,@ according dione is'prepared from 5,20 -dioxo-Ilct-mesoxy-16a,17ato the prbcedure of Example 2. o isopropylidenedioxy-3,5- seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt, followed by Example 41 16m"methyl - 20 - ethylenedioxy-desA-p regn-9-en-5-one IS @prepared from 16a-methyl-20-ethyl6 nedioxy-10ot-desApregnan-5-one by -brominatiori followed b-y - dehydrobromi- 15 nation, according to the procedure of Example 3. Example 42 16@@methvl - 20 - ethylenedioxy-9p,10, 8-desA-pregnan5-one is prepared from 16ce - methyl -ZO@ethylenedioxy- 20 desA-pregn-9-en-5-one by hydrogenation under basic conditions in the -presence of a rhodium catalyst, according the procedure of Example 14. Example 43 25 16m@methyl @ 20 - @et4ylenedio@"XIOmpregnT.4-cli-3- one is prepared by condensing 16ce-m ethyl-20-ethylenedioxy-9p,10p-desA-pregnan-5-one with methyl vinyl ketone, according to,the procedure@of Example 5. Example 44 21-acetoxy-lla-hydroxy - 20 @- ethylen edioxy-pregn-4- en-3-one is prepared by mier6biological @treatrnent of -21- ac to e XY- 20-ethvienedi6xy-pregn-'@ 4 - en-3-Gne, according to the procedure of Example 17. 21-a cetoxy-llx-mesoxy, 20-ethylenedioxy-pregn-4-en-3-one is T)repared b@y treatment of 21,-, acetoxy-lla-hydr6iS@@2O@et hylenedioxyl3regn4-ene-3-one with methanesulfonyl chloride,,, accord,ing to the@prpcedure of Exa le 10.@@ MP 40 Example 45 21L@,qretoxy mesoxy-20-ethylenedioxy-5@oxo-3i5- : seco-A-norpregnan-3-oic acid is prepared by ozonolysisof 21-acetoxy-Ilo@-mesoxy-20-ethyle,nedioxy-pregn - 4 - one,,@@4, ac@ording to the procedure of Example 1 1. - Exainple@ 46@ 21-acetoxy - 20@ - ethylenedioxy-desA-pr egn-9-en-5-one is prepared from 21-acetoxy-20-ethylenedioxy-Ila-mes. 50 OXY-3,5-seco-Anorpregnan-3-oic acid by conversion of the latter - to its sodium sdlt@followed -by iyrolysis, according to the procedure of Exaniple 12, except that the crude product is reacetylated by treatment@ with acetic anhyAridt@@ri or-t6 its-being i@@ 55 -UP. Example 47 21 acetoxy-20-@thylen&dloxy-9p, tOp-desA-in@regnan-5one is prepared from 21-acetoxy,-@20,-ethylenedioxy-desAprc)gn-9-en-5-oji'e by h@drogen,ation@@iih@ acidi@ cbndi- 60 tions in the presence of a rhodium catalyst, accori ing to@ the procedure@of Example 15@ Ex44@pk 48 21-hydroxy-20-ethylenedioX@@9,6,10a--Pregn-4-en-3-ono is 65 prepared from 21-acetoxv-20-ethylenedio xy-9,6110,8-desApre@gnan-5-one lby@condensing thelatterwith.methyl ketone,.according@tothei@@e4o@@@ofi@@4mple,22-@@ Exaiiiple 49 70 is prepared by treatment of ll(X - hydroxy-16a,17aisopropylidenedioxy-progesterone with methane sulfonyl chloride, according to the procedure of Example 10. pyrolysis according to the procedure of Example 12. Example 52 20p-hydroxy@16ct,17a-iso opylid d desa-pregn9-en-@- PT ene ioxyone is prepared from 16c&, 17a-isopropylidenedioxydesa-prega -. 9-ene5,20-dione by reduction and reoxidation accordin to fhe procedure of Exam@le 13. Example 53 20p-hydroxy-16a,17a-isopropylidenedioxy-9,6,10,8-de sApregnan-5-one isprepared from 20p-hydroxy-16m,17a-isoPropylidenedioxy-desA-pregn . 9-en-5- one by hydrogena. tion according to the procedure of Exainple 14. Example 54 20p hydroxy - 16ce,17a - isopropylidenedioxy-9,6,lC @apregn-4-en-3-one is prepared by condensing methyl vinyl ketone with 20,8 - hydroxy16a,17a-isopropylidenedioxy@30 desA-9,6,10p-pregnan-5-Gne accor4ing- to the procedure of Exaii@@ 5 Example 55 7cc,17LX-dimethyl-17#-hydroxy-5-oxo-3@5-seco-A-norandrostan @ 3 @- oic acid is prepared from 7a,17a-ditnethylt6stosterone@ by ozonolysis of the latter,, according to the procedure @6f- Example 1. Example 5 6@ 7ot,17a. - dimethyl - 17p-hydroxy-IOa-desA-androstan-5@ afid 7cc.17@- diniethyl 17p-hydroxy-to one -, 6-desA-andro. stan - 5-one are prepared from 7a#17%-dimethyl-17#-hydroxy-5- seco@@norandrostan-3-oic alcid by conversion of the'laitet to its sodi-um salt followed- by pyrolysis according to the proccdure of Example 2. Example 57, 9 7o,,17ii4t)iethyl-17,8-bydroxy-desA-androst- -en-5-one is:prepared from 7a,17a-dimethyl-17p-hydroxy-10v.-desAandrostan-5-one bybromination followed by dehydrobromination, according to the procedure of Example 3. Example 58 7a,17L% - dimethyl- 17,6-hydroxy-desA-9p, 10,6-androstan5 one is prepared from 7ct,17m-dimethyl-17,6-hydroxydesA-androst-9-en-5-one by, hydrogenation i@n the@ presence of a rhodium@catalyst, according to the procedure of Exa4lp@e 4@ Exaniple@@59 7ce,17a-dimethyl-9p,10a-testosterone is prepared@ from 7a 17a @- @@dimethyl@17p-hydroxy-de@A790;109-androstan-5one by condensing the latter with methyl-vinyl ketone, according,to the procedure of-Example;5. Example 60-4@ 1 Ict-mesoxy- 17a-methyl-progesterone is prepared from I la7hydroxy- 17(xmethyl-progesterone by @treatment of the latter with@@methane@sulfonyll@chloridei. accordi#g to the Example 61 Ilix-m,,esoxy-17m@niethy@5;20-dioxci@3,5-se eg--: nan-3-oic -acid is prepared from Ila.-mesoxy@17a-me thylprogesterone by ozonolysis of the latter, according to the, prgc dure of Example II,
[17]33 31766,256 34 Example 62 17a - methyl-desA-pregn-9-ene-5,20-dione is prepared from Ila - mesoxy-17a-methyl5,20-dioxo-3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 12. Exam,ple 63 20,6 - hydroxy-17Lx-methyl-desA-pregn-9-en-5-one is prepared from 17a - methyldesA-pregn-9-en-5,20-dione according to the procedure of Example 13. Example 64 20,6-hydroxy-17a-methyl-9p,10p-desA-pregnan-5-one is prepared from 17cc - methyl20p-hydroxy-desA-pregnan-9ene-5-one according to the procedure of Example 15. Example 65 20p-hydroxy-17a-methyl-9p,10a-pregn-4-en-3-one is prepared by condensing 17at - methyl - 20p-hydroxy-9#,10pdesA-pregnan-5-one with methyl vinyl ketone, accor . to the procedure of Example 4. Example 66 A solution of 12.8 g. of 17a-methyltestosterone in 200 ml. of methylene chloride and loo ml. of ethyl acetate was ozonized for I hour and 5 minutes at -70' (acetoneDry Ice bath) until a blue color developed. After oxygen was bubbled through, the solution was then concentrated at room temperature in vacuo. The residue was dissolved in 300 ml. of acetic acid, and after addition of 30 ml. of 30% hydrogen peroxide, the solution was left overnight at O'. It was then evaporated to dryness in vacuo, the residue taken up in ether, and the ether solution extracted with 2 N aqueous sodium carbonate (12X 50 ml.). The combined carbonate extracts were cooled in ice, and acidified with concentrated hydrochloric acid. The aqueous suspension of precipitated organic acid was extracted with methylene chloride, this extract was washed with water, dried over anhydrous sodium sulfate and evaporated giving as a colorless crystalline material 17p-hydroxy - 17a-methyl-5-oxo-3,5-seco-A-nor-androstan-3-oic acid. After recrystallization from acetone-hexane, it melted at 195-197', la]D 25@9.8' (c.=I.O in chloroform). Example 67 A solution of 10 g. of 17p-hydroxy-17Lx-methyl-5-ox o3,5-seco-A-nor-androstan-3-oic acid in 250 ml. of methanol was made alkaline to phenolphthalein with sodium cthoxide, and evaporated to dryness. The residual powdery sodium salt was mixed well with 32 g. of sodium phenylacetate and 40 g. of neutral alumina (Woelm, Grade I), and the mixture heated at 290' in vacuo for 4 hours. After cooling to room temperature, a large excess of water was added, and the resultant suspension extracted with 2 liters of ether. The ether extract was washed with water, aqueous 2 N sodium carbonate solution, and again with water, dried and evaporated. This gave a sirupy residue, which by thin layer chromatograms and infrared spectra consisted of 17p-hydroxy-17amethyllOa-desA-androstan-5-one as the major and 17g-hydroxy17a - methyl - 10p - desA-androstan-5-one as the minor product. Three additional pyrolyses were performed as described above, and the combined products so-obtained was chromatographed on a 850 g. silica gel column, using 5% ethylacetate in benzene as the eluent. This chromatography yielded 17,6-hydroxy17m-rnethyl-IOa-desA-androstan-5-one, which after r ecrystallization from petroleum ether melted at 96-970, [MID 25=28.2' (C.=0.5 in chloroform). Further eluates of the column gave product, 17,6-hy droxy-17cc-methyl-IOp-desAandrostan-5-one which, when recrystallized from ether, melted at 165-167', [CCID 25= -19.8' (c.=0.5 in chloroform). To a solution of 2.2 g. of the mixture of 17p-hydro xy17m-methyl-IOa-desAandrostan-5-one and 17#-hydroxy17a-methyl-IOp-desAandrostan-5-one (obtained by the above pyrolysis procedure) in 50 ml. of absolute ethanol were added 2-0.1 ml. of a solution prepared by dissolving 2.48 g. of sodium metal in 250 ml. of absolute ethanol. The reaction mixture was stirred overnight at room temperature. It was then acidified with 2 ml. of glacial acetic acid, and evaporated to dryness. The residue was extracted 10 in ether (1 liter) and the ether extract washed with water, dried, and evaporated. The residue was crystallized from petroleum ether giving a quantitative yield of 17#-hydroxy-17,x-methyl-IOv.-desA-androstan-5-one. 15 Example 68 To a solution of 11.2 g. of 17p-hydroxy-17a-methyll Oa-desA-androstan-5-one in 1260 ml. of anhydrous ether, stirred and cooled in an ice-salt bath, were added first several drops of 30% hydrogen bromide in acetic acid, 20 then dropwise a solution of 7.16 g. of bromine in 20 ml. of glacial acetic acid. The rate of addition of the bromine solution was synchronized with the rate of disappearance of excess bromine. After bromination was complete, 53 ml of 10% sodium hydrogen sulfite solution and 53 ml. 2,5 of , aqueous 2 N sodium carbonate solution were added to the reaction mixture while stirring. The ether layer was then'separated, washed with water, dried, and evaporated to dryness in vacuo. The residue was dissolved in 250 ml. 30 of dimethylformamide, and heated with 7.5 g. of lithium carbonate at 100' for 45 minutes. After cooling, 2 liters of ether were added and the ether solution washed with water, 1 N hydrochloric acid, and then again with water, dried and evaporated. The residue was dissolved in 200 35 ml. of glacial acetic acid, 12.6 g. of sodium acetate and 12.6 g. of zinc powder were added and the mixture heated for ten minutes at 80'. After cooling to room temperature, the reaction mixture was filtered, and evaporated. The residue was dissolved in ethylacetate, and washed 40 with saturated sodium bicarbonate solution, then with water, dried and evaporated. The so-obtained residue was chromatographed on a silica gel column using 10% ethylacetate in benzene as the eluent which gave first 17,6hydroxy17a.-methyl-loce-desA-androstan-5-one, followed 45 by 17p - hydroxy - 17L% - methyl-desA-androst-9-en-5-one. After recrystallization from ether, the latter compound melted at 103-104-, la]D 25=-63.2- (c.=0.5 in chloroform). Example 69 50 A suspension of 1.25 g. of 5% rhodium on alumina catalyst in a mixture of 130 ml. of 95% ethanol and 26 ml. of 2 N sodium hydroxide was prereduced. To this was then added a solution of 1.25 g. of 17g-hydroxy-17a5 5 methyl-desA@androst-9-en-5-one in 75 ml. of 95% ethanol, and then the mixture was hydrogenated at atmospheric pressure and room temperature. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, the catalyst was removed by filtration, and the filtrate 60 evaporated in vacuo. To the residue 5 ml. of glacial acetic acid was added, the soformed mixture then dissolved in 2 liters of ether, and the resultant cloudy solution was washed with water, then dried and evaporated@ The residue was dissolved in 50 ml. of methylene chloride and 65 oxidized with 5 ml. of 2% chromic acid in 90% acetic acid until green color of reaction mixture. After then being washed with sodium hydrogen sulfite solution 2 N sodium carbonate solution and water, the reaction mixture was dried over sodium sulfate and evaporated. ne 70 residue was chromatographed very slowly on a 50 g. silica gel column, with 5% ethylacetate in benzene, and followed with thin layer chromatography. First, 17phydroxy-17a-methyl-9cc,10m-desA-androstan-5-one was eluted. After a minor amount of mixed material, 17p-hydroxy75 17c& - methyl - 9,6,10#-desA-androstan-5-one was eluted.
[18]3,766 256 35 After recrystallization from ether-petroleum ether, it melted at 94-961. Example @70 17a-methyl-9g,loa-testosterone is prepared@ from 17a5 M&thyl-17p-hydroxy-ddsA-90,10p-,@,hdfostan@5-one, by con-,,-,, densation.of thellatt@erwithm6thyl- il@yl--ketone,-ac(@ord @,- @ 1, I -7- I 'I'll@'ll-l@@"-l" ing to ti@le, 'procedure of 5. The product melts . at 128-1291. Example 71 10 A solution of 6 g. of llc,,20,6-diacet oxy-pregn-4-dn-3- one in 100 ml. methylene chloride and 50 m@l. of ethylacetate was ozonized at -70'. After methylene chloride was removed by distillation in vac-uo, the residual solution was diluted to 100 ml. with ethylacetate@ To this 5 15 ml. of 30 percent hydrogen peroxide was added and@ left overnight at robm temperature. The reaction mixture was concentrated to dryness in vacuo, the residue ta@ken up in 1 liter of ether, and the resulting solution extracted 10 times with 50 ml. portions of 2 N aqeous 20 sodium carbonate. The carbonate'extract was then, a,cidi-, fied with ice-cold concentrated hydrochloric acid. The precipitated product was separated by filtration, and crystallized to give Ila,20,8-diaceto xy-5-oxo-3,5-seco-Anor-pregnan-3-oic acid. 215 Example 72 A methanolic solution of 5 g. of I la, 20,6-diacetoxy-5- oxo-3,5-seco-A-nor-pregnan-3-oic acid was treated w,th one-h@alf niole equivalent of sodium carbonate, and evapo- 30 rated to dryness in vacuo. Potassium acetate (5 g.)- was added to @the residue which was then pyrolyzed at 295' and 0.02 mm.@ The sublimate was chromatographed on a silica-gel column to give llct,20,6 -diacetoxy-IOp-desApregnan-5-one. 35 Example 73 Bromination and dehydrobromination starting with Ila,20,6-diacetoxy-10,8-desA-pregnan-5-one according to the procedure of Example 3. gave ll&,20,6-diacetoxydesA-pregn-9-en-5-one. 40 Example 74 HydTogenation of llcz,90,6-diacetoxy -desA-pregn-9-en5-one in ethanolic hydrochloric acid over 5 percent rhodium on alumina catalyst at room temperature and 45 atmospheric pressure according to the procedure of Example 15 gave lla,20,6-diacetoxy-9,3, 10,6-desA-pregnan-5- one. Example 75 Ila,20,6-diacetoxy-9,6,10,6-desA-pregnan-5-one was hy- 50 drolyzed in methanol solution with one mole equivalent of potassium carbonate to give lla ,20,6-dihydroxy-9,6, lOj3-desA-pregnan-5-one. Example 76 55 Condensation of Ila,20,6-dihydroxy-9 p,10,3-desA-preg@ nan-5-one with methyl vinyl ketone according to the procedure of Example 5 gave Ila,20 p-dihydroxy-9,6,10apregn-4-en-3-one. 60 -Example 77 A solution of 3 g. of 17a-ethyl-17phydroxy-androsta1,4-dien-3-one in 75 ml. of methylene chloride and 25 ml. of ethyl acetate was ozonized at -701 till it became blue. After evaporaation@ to dryness, the residue was - 65 dissolved in 100 ml. of glacial acetic acid containing 5,ml. of 30 percent hydrogen peroxide, and set at room temperature for 2 days@ The @reaction mixture was concentrated to dryness and the residue @ dissolved in gne , 36 tration and dried, then disolved, in 135 ml. of absoiutc ethan6l, -,and after addition of '9 ml. of aqueous 2 N sodium hydroxide, boiled for I hr. The reaction mixture was. concentrated in vacuo to a small volume, and diluted -W'Ith A750 -nil. of @ ethfr..@ The eth@@@@@n was washed with @ water, dried over -anhydrous so iu @ iWf@W and. d',M@@ 11 11 -Icoicentrated in vaeuo @to dryness. @T& was@ c-rysta @ @ @ Ilized from ether-petroleum ether, to give 17,x-eth yl-17phydroxy-10(x-desAandrostan-5-o M.P. 89-90'. ne, Example 78 3-(17,6-hydroxy-5-oxo - 3,5-seco-A-nor-androstan-17ctyl-3-oic acid)-propionic acid lactone is prepared by ozonolysis of 3-(3-oxo-17,6- hydroxy-andrest-4-en-17aYl)- ProPlonic acid lactone, according to the procedure of Example 1. Example 79 3-(17#-hydroxy-5 - oxo-10cc@desA-androstan - 17,-Yl)propionic acid lactone and 3- (17p-hydroxy-5-oxo-10,6desA-androstan-17ce-yl)-propionic acid lactone are prepared ftom 3-(17,8-hydroxy-5-oxo-3,5-seco-A-nor-andro. st an-17a-yl-3-oic acid)-pfopionic acid,lactone by conversion of the latter to its sodium salt followed by pyrolysis, according to the procedure of Example 2. Example 80 3-(17#-hydroxy-5-&xo-desA - androst-9-en-17a-yl)-pro. d lactone is prepared from 3-(17,6-hydroxy-5 plonic aci oxo-10a-desA-androstan-17a-yl)-propionic acid lactone by,bromination followed by dehydrobromination, according to the procedure of Example 3. Example 81 3@(17,6-hydroxy-5-oxo-9#,10,6 - desA-androstan-1704-yi). propionic acid lactone is prepared from 3-(17,6-hydroxy5-oxo-desA@androst-9-e n-17c&-yl)-propionic acid lactone by hydrogenation in the presence of a rhodium catalyst, according to the procedure of Example 4. Example 82 3-(17,6-hydroxy - 3-oxo-9,6,10,z - androst-4-en-17cc-yl)propionic acid lactone is prepared by condensing 3-(17#hydroxy-5-oxo-9p,10,6-desA - androstan-17a-yl)- propionic acid lactone with methyl vinyl ketone, according to the procedure of Example 5. Example 83 17a,20;20,21-bis - methylenedioxy - Ila - mesyloxyp regn-4-en-3-one is prepared by treatment of 17a,20;201 2 1-bis-meihylenedioxy- I l a-hydroxy-pregn-4-en-3-one with methanesulfonyl chloride according to the procedure of Example 10. Example 84 17a,20-120,21-bis - methylenedioxy-l I a-mesyloxy-5-oxo3,5-seco- a-3-oic acid is prepared by ozonolysis of 17a,20;20,21-bis-methylenediGxy-lla-me syloxy-pregn4-en-3-one according to the procedure of Example 11. Example 85 17ce,20;20,21-bis - methylenedioxy-desA-pregn-9-en-5one is prepared from lla,20;20,21-bis-methylenedioxyIla.-mesyloxy-5-oxo3,5-seco-A-norpregnan-3-oic acid by conversion of the latter to its sodium salt followed by pyroly ' according to the procedure of Ex-ample 12. Si Exaniple 86 17a,20;20,21 - bis - methylenedioxy - 9,8,10p-desA-pregnan-5-one is prepared from 17a,20;20,21-bis-methylenedioxy-desA-pregnr9-en-5-one@ by hydrogenation in the presliter of ether. The ether solution was then extracte(i 10 @7o ence of a rhodium catalyst according to the, procedure of times with 25 ml. portions of aqueous 2 N sodium carExample 14. bonate solution, and the carbonate extracts were acidified, Example 87 with ice-cold concentrated hydrochloric acid. The noncrystalline precipitate containing 17a-ethyl-17p-hydroxy17a,20;20,21 - bis - methylenedioxy - 9#, 10,%-pregn4-enlOct-carboxy-des A-androstan-5-one, was separated by@ fil- 75 3-one is prepared by condensing methylvinyl ketone with
[19]317661256 :97 17a,20;20,21 - bis - methylenedioxy-9,6,10p-desA-pregnan5-one, according to the procedure of Example 5. Example 88 20,6 - hydroxy - 9p,10a - pregna-1,4-dien-3-one was pre- 5 pared by condensation of 20p-hydroxy-9p,10p-desA-pregnan-5-one with 1 equivalent of methyl ethinyl ketone in boiiing benzene solution, catalyzed by sodium hydride. Example 89 One ml. of Jones reagent (0.04 mole CrO3) is added 10 to 200 mg. of 17p-hydroxy-9,6,10p-desA-androstan-5-one in 20 ml. of acetone at -IO'. The mixture is then left for 15 minutes at room temperature, and 5 ml. of ethanol then added. The resulting suspension is evaporated to 15 dryness in vacuo, water is added to the residue and the undissolved moiety taken up in ether. The ether phase is then washed with a solution of sodium bicarbonate and then water, dried over sodium sulfate and evaporated to dryness. There is so obtained an oil which c rystallizes 20 upon the addition of a smar portion of petroleum ether. The so-obtained crystals of 9p,10p-desA-androstane-5,17- dione melt, after recrystallization from cyclohexane, at 77.5-78'; [a]58925=+55' (c.=0.107, dioxane); R.D. in dioxane (c.=0.107%): x in mu ([a]-value in '); 550 25 (+70); 400(+297)- 350(+798); 320(+2968) max.; 300(+467)1 299(0); 290(-1890). Example 90 A solution of 250 mg. of 17g-hydroxy-9p, lOp-desA-androstan-5-one dissolved in 2.5 ml. of pyridine and 2.5 ml. of 30 acetic anhydride, is left at room temperature for 18 hours. The mixture is then evaporated to dryness at 80'/ 1 1 mm., the residue taken up in ether, and the ether phase washed witli I N hydrochloric acid, sodium bicarbonate and 35 water, and then dried over sodium sulfate. After filtration and evaporation of the ether, the residue is then treated with a small quantity of petroleum ether yielding crystals of 17p-acetoxy-9#,10p-desA-androstan-5-one which, upon recrystallization from methanol, melt at 118-119'; 40 [M]5,,25=-28' (c.,=0.103%, dioxane); R.D. in dioxane (c.@0.103%): x in mIL ([a]-value in '); 400 (-30); 356 (0); 350 (+10); 313 (+449) max.; 307 (+374) min.; 305 (+380) max.; 300 (+224); 293 (0); 280 (-652). 45 Example 91 A solution of 250 mg. of 17p-acetoxy-9p,10p-desAandrostan-5-one in 60 ml. of 95% methanol containing 144 mg. of potassium hydroxide is refluxed for 60 minutes. The resulting mixture is evaporated to dryness in - vacuo, .50 water added to the residue and the suspension extracted with ether. The ether phase is washed with water, dried over sodium sulfate, filtered off, the solvent removed and the crystalline residue then crystallized from a small volume of cyclohexane, yielding crystals of 1 7p-hydroxy- 55 9p,10,6-desA-androstan-5-one which upon being recrystallized from ethylacetate melt at 144.5-145'; [M]589 25 =-22' (c.--0.103, dioxane), R.D. in dioxane (c. =0.103); x in mA ([a-]-value in '); 400 (-7); 390 (0); 350 (+52); 313 (+571) max.; 307 (+492) min.; 305 60 (+504) max.; 300 (+324); 293 (0); 290 (-202). Example 92 A solution of 10 g. of 119-formyloxy-androsta-1,4- diene-3,17-dione in 100 ml. of acetic acid was ozonized 65 at 01 untfl thin layer chromatography did not show any starting material. The reaction mixture was then poured into 100 ml ' of water and the mixture was then heated to 100' for 30 minutes. The mixture was then concentrated in vacuo and treated with 50 ml. of saturated - sodium 70 bicarbonate solution. The undissolved material was extracted with 100 ml. of ether. The extract was chromatographed on silica gel using methylene chloride. The cluates were concentrated and gave, on addition of hexane, I lpformyloxy - 10@ - desA-androstane-5,17-dione, M.P. 117- 75 38 117.5' (recrystallized from acetone-cyclohexane), Ea]D 25 =93' (dioxane). Example 93 By hydrolysis of 11,6-formyloxy-10@-desA-androstane5,17-dione in 2% methanolic potassium hydroxide there is obtained llp-hydroxy-1 0@-desA-androstan-5,17-dione, which melts at 154'; [OCID25=+96' (dioxane). Example 94 250 mg. of llp-hydroxy-10@-desA-androstane-5,17dione and 250 mg. of p-toluene sulfonic acid monohydrate in 20 ml. of benezne were refluxed in a nitrogen atmosphere for 6 hours. The reaction mixture was then washed with an aqueous solution of sodium bicarbonate and then with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was then chromatographed over silica gel (5 g. in dichloromethane. Triturating the residue obtained from the first 250 ml. eluted, yielded crystals of desA-androst-9-ene-5,17-dione, which upon recrystallization from cyclohexane melted at 123-123@5'. Example 95 The compound, llg-formyloxy-5,17-dioxo-3,5-seco-Ano randrostan-3-oic acid is prepared from llp-formyloxyandros-4-ene-3,17-dione by ozonolysis according to the procedure of Example 11. The so-obtained product nielts at 220-221'; [ixlr@25=+107' (dioxane). Example 96 3.7 g. of the sodium salt of llp-formyloxy-5,17-dio xo3,5-seco-A-nor-androstan-3- oic acid and 12 g. 6f sodium phenylacetate are fused together in vacuo (0.1 torr). When the bath temperature reaches 220' the molten mass begins to decompose. The bath is then heated further (within 30 minutes) to a temperature of 290'. Once this temperature has been reached the mixture is left for another 10 minutes at the initial pressure of 0.1 torr. The distilled material is then chromatographed over 30 g. of aluminum oxide (activity grade 3). Elution with a total of 200 ml. of petroleum etherbenzene (2:1), followed by evaporation of the solvent and trituration of the residue in the presence of petroleum ether, yields desA-andrOst-9ene-5,17-dione which upon recrystallization from cyclo. hexane melts at 123-123.5'; la]D 25=+83' (c.--0.1021, dioxane). Example 97 20,6-acetoxy-5-oxo-3,5-seco-A-nor-pregnan-3-oic acid is prepared by ozonolysis of 2OP-acetoxy-pregn-4-en-3-one according to the procedure of Example 1. Exam@ple 98 A solution of 15.15 g. of 20g-acetoxy-5-oxo-3,5-sec o-Anor-pregnan-3-oic acid in 250 ml. of 75% methanol containing 10 g. of potassium hydroxide was refluxed for 2 hours. The mettianol was then removed in vacuo and the residue was dissolved in 100 ml. of water. The solution -,,@as chilled to O' and acidified to ml. of water. The solution was chilled to O' and acidified to Congo red by the addition of 20% hydrochloric acid. There was thus obtained 20p-hydroxy - 5 - oxo-3,5-seco-A-nor-pregnan-3-oic acid, M.P. 181-182', fa]D 25=13' (dioxane). A solution of 4.7 g. of 20p-hydroxy-5-oxo-3,5-secoAnor-pregnan-3-oic acid in 100 ml ' of methanol was neu_ tralized with 1 N sodium methylate solution against phenolphthalein. The solution was then evaporated and the residue, consisting of 20phydroxy-5-oxo-3,5-seco-Anor-pregnan-3-oic acid sodium salt, was refluxed with 100 ml. of quinoline for 8 hours. The cooled mixture was poured on a mixture of 150 g. of ice and 100 ml. concentrated hydrochloric acid and extracted with ether. The ether extract was worked up and the 6ily residue was chromatographed on silica gel. Elution with methylene chloride gave lOa-desA-pregnane-5,20-dione, M.P. 126127' (crystallized from isopropyl ether), (OCID 25-82-
[20]39@ (dioxane). Elution with, methyleTi6 chloride cont n 1 @"o -,acetone ii" 20#-h@y'drox@'y-'I'Ox'-d@,iA-pT e'gnan-5-one,@@@ M.P. 104- 104.5' (crystallized ftom ether-hexane), [ccID25--10' (dioxane). The fractions obtained with methylene chloride containing @ 5-10% acetone, were, evaiporated and thd oily tesidiie-was dissolved in 40 Thl. acetone. @,The @solution was treated- with 3 ml. o@E Jones reagent (0.004 mole CrO3) at -10' and kept at the same temperature for 10 minutes. After the @addition of 5 ml@Of methan6L the solution @@as@ @@iated@ and ih@@ residue 10 was dilut6d with water and extracted with ether. The ether extract was worked UP and gave 10ce-desA-pregnane5,20-dione. Example@ 9,P i5 20fl-hydroxy-desA-pregn-9-en-5-one is prepared from 20p-hydroxy-10a-desA-pregnan-5-one by brominatioin followed by dehydrobromination, according to the procedure of Example@@Jhe soobtained-Droduct,-after@te@r@talliza-" tion from methylene chloride-petroleum ether, melts at 4 0 @ O@b"ate 40 w ter,@ 4*4: 41* - v a c u o a t H - g a n d 8 0 1 . T h e r e s i d u e c o n s i s t i n g o f 2 0 , a - a n d , 2 0 , 6 - t e t r a h y d r o p y r a n y l o x y - p r e g A - 4 @ e n - 3 - o n e w a s d i s s o l v e d i n 2 l i t e r s o f t t r t , b u t a n o l - w a t e r : @ a z e o t r o p e f o l l o w e d b y t h e a d d i t i o n o f a s o l u t i o n o f 3 3 g . o f p o t a s s i u m @ a @ a t e ' 4 1 8 0 m i . O f w a t e r a n d 6 2 0 @ m l . : a 7 . , 7 o @ a q @ e A D U s m e t a p e r i o d a t e s o l u t i o n . T o t h e r e a c t i o n m i x t u r e t h e r e w a s , f i r s t a d d e d w i t h - v i g o r o u s s t i r r i n g a t r o o m t e m p e r a t u r e , 7 5 m L o f 0 , 8 % p o t a s s i u m p e r m a n g a n a t i . - a n d t h e r e a f t e r @ s i i n u l t a n c o - u s l y w i t h i n 3 0 m i n i n 6 s - 1 3 5 0 - m l . o f 7 % s o d i u m m e t a p e r i o d a t e s o - l u t i o n a n d 1 0 0 m l . o f 0 . 8 % p o t a s s i u m p e r m a n g a n a t e s o l u t i o n . A n o t h e r 1 0 8 0 m l . , o f 7 % s o d i u l n r n e t a p e r i ( > d a t e @ s o l u t i o n a n d 1 0 0 ' m l . o f 0 . 8 % p o t a s s i u m p e r m a n g a n a t e s o l u t i o n w e r e t h e n a d d e d w i t The reaction mixture was then stirred for 1 'hour, filtered over a filter aid (Hyflo) and the residue was washed with 250 ml. of tert. butanol-watex azeotrope. The filtrate was eva por4t4 the,- residuo@@take @up.itl .8.00,, ml.,of, wat r, an"4 flitered@ The alkaline filtrate was chilw to O., acidi. 122-123'. 2o fled with cold 20% hydrochloric acid and extracted with methylene chloride. After@ working up, the extract afforded -a, MLxtiite Of 26@- @@ i4o@@rdt@k@ny bo-5-oxo5,20@dioxo-3,5-seco-A-nor-pregnan - 3 - oic acid is prel3,5-seco-A-nor-pregnan-3-oic acid as a viscous oil. This pared by ozonolysis of progesterone according @to the,.pro,, oil . w;is dissolvp @d @irL 300.ml. of raethanol and neutrali--ed was evapomtea Example 101 to dryness in vaciio. The oily residue was dissolved in 300 -ml. of benzene, evaporated again and dried at I 1 @ mm, ioa-desa-pregna - 5,20 - dione and 1 0,6-desA-pregnanHg and 100' for 2 hours. There. was obtained a mixture 5,20-dione are prepared from 2 0-dioxo-3,5-seco-A--norof the lithium salts of 20cc-I and 20,6-tetrahy&opyranylpregnan-3-oic acid by conversion of the latter tO its 30 oxy-'5-OXO-3,5-seco-A-nor-pregnan-3-oic acid as an@ amor. sodium salt followed by pyrolysis, according to the pro. phous powder. cedure of Example 2. Example 105 Example 102 A solution,(>f 9 g. ic)f 20fl-tetrahydropyranyloxy-5-oxo3,5-s@aco-A-nor!- prq"n4@@oic,- aCI4 @in @ I 00 rnl-,.- @ df me-t-h-;! The. compound, desA-pre-gn@9@iefi@-5,20@dione is prejaz@red 3a' fr@ m toa desA-pregna-5,20-dione b-vji@iomination folioi@6d anol @was neutralized with I N lithium @methylate solution by dehydrobromination according to the procedure @of against phenolphthaleine, @ followed by; evaporation iii vacuo to dryness. The soobtained residue was taken up in Example 3. The so obtained product, after @recrystalliza-- fion from @ethe@@ melts at@ 111-1 13;. benzene, and the benzene evaporated@.yieliling-20,6-tetrabydropyra nyl<)xy-5- oi6@@5- sei@,o@@ nor--pregnan, - 3 - Ole Example 103 4 acid lithium salt as a semi@crystallin e I wder. PO ium permanganate solution was@, 5 . of this lithium salt 7.5 g. of anhydrous sodium 15 ml@@of,0.8% potass' 9 @ I added to @a mixture of II g. of 20p ,-tetrahydropyranyloKy, ai@etate and 7.5 g. @ of anhydrous potassium, @ace@tate were pregn-4-en-3-one, 500 ml. 6t a r, of mixed and pyrolyzed at 0.02@0.1 mm.@ 14g and 29Q, f,, o r 4 n @ a z e ot r o pi c m ix tu tertiary butanol and water, 7 g. of potassiumcarbc)natel 45 hours. The distillate was chromatographed o* silica @et 20 ml@ of water and 120 ml. of 7% sodium m taperiodate,@ - iising methylene chloride, and methylene chloride containe at@room@temperatuire 250;@@ ing P.5-1% acetoiae as the,@elution 4ents., The fractio-ns solution@ with; vigoious, stirrin ml. of @7% sodium metaperiodate and 20 ml.- of O@8% were evaporated amd gave on treat-ment with-etherhexpotassium permanganate solution -were then simult ane- ane 20,3 - tetrahydropyranyloxy-IOa-desA-pr e-gnan-5-one, ously added Within 15- minutes. -To the so-obtaiiied sus- M.P. 125.5-127' (crystallized from methano.1) 50 pension, 220: ml. of 7, % @ @6dium @metaperiodate solution taln2s=53' and, in order to@ keep the mixture@ violet in color,, 15 mi@ , (dioxan^-). of 0.8% potassium permanganate solution were then The oily part of the evaporation residue contai-ning beadded @'m the course of 30 minijtes. The mixture wasthen @sides the latter compound;the- co-mpound 20,6@tetrahydroth stifiid for 90 @minutes, @@i futer @aid,@ (14yflo)5 -t5,,.pyrai@34oxy10,8.desA-pregnan-5.-one ethanol. After 6@@ and the resid e wa @adition of @10 xnl. of of p-toluenesul@; ue was washed with 100, ml. of terl@ butandi@, water and 200 ni-g., water a@eotrove. The nitr-ate -was- evapor@ated in vacuo fonic acid monohydra% the solution 1 was refluxed for 60 at 50' and - the@ residue -. diluted@ w, th; 150 ml@ of water. minutes and evaporated in vacuo. The residue@ was then Thd s6lut-ion was@acidified @with@@coid@@20%:@ hy@drochloric@ ir6ated-@ with wa@kt and-' extract& @@ @eth-c, - !le r . acid to Congo @red, and the resultant oily material taken up, 60 extract was worked up and gave 20,8-hydroxy-locc-desA-@ pregnan-5-one, M.P. 104.5-105:1 (crystallized from etherhexane)!. E x a m p l e @ 1 , 0 6 250 mg. of:20ce - tetrahydropyranyloxy-10,x-desA-pregnan-5-one was dissolved, in 8 mL of ethanol and after the addition of I ml.- of water i and @15 @ ing. of @p-toluene@6@ fonic acid monohydrate refluxed for I hour. The reaction@ mixture was then evaporated and the residue taken @up in ether. The ether extract was worked iip and gave 20phydr XY@ o lOa-desA-pregnan-5 one, M.P. 104.5-1051 (crystallized from ether-h-.xane). E x a m p l e 1 0 7 10 g@@ of a mixture of 20aand 20,6- tetrah ydropyranyloxy-5-oxo--3,5-secoA,-nor@pregnan-3.oic acid lithium salt ce ure@ o with I N@ffthium in 150 ml. of methylene chloride. The organic extract was washed - with water, dried i and @ evaporated and @th6 residue was purified-by filtration over silica gel@ using methylene chloride and methylene chloride - containing 1-2% ethanol as the elution agents., There was thus obtained 20p-tetrahydropyranyl6xy - 5- - - oxo-3,5-seco-A-nor- 65 pregnan-3-ole@acidasavistous@oil. Example 104 To a solution of 35.8 g. of a mixture 6f 20a- and 20p-@ 70 hydroxy-pregn74-en-3-one in 50 ML of anhydrous benzene, there were added 75 ml. 6f 1% p-toluenesulfonic acid in benzene and then 35 ml. of dihvdropyran. The, reaction mixture. was @allolwed to@ stand at @ room I temperature for 16 hours, washed- with 2% aque6us sodium: bi 75
[21]8)766)256 41 was mixed with 15 g. each of anhydrous sodium acetate and anhydrous potassium acetate and pyrolyzed at 0.01- 0.1 mm. Hg and 290' for 5 hours. The distillate was dissolved in 100 mI. of ethanol and, after the addition of 15 ml. of water and 250 mg. of p-toluenesulfonic acid mono- 5 hydrate refluxed for 70 minutes. The reaction mixture was then evaporated, the residue was treated with 50 ml. of $% sodium bicarbonate solution and extracted with ether. On working up, the extract gave an oily residue of 20aand 20,6-hydroxy-10ot-desA-pregnan-5-one, which was dis- 10 solved in 80 ml. of acetone, treated with 10 ml. of Jones reagent at -10' and kept at -10' for 15 minutes. The suspension obtained was treated with 15 ml. of ethanol, kept for 10 minutes at room temperature and evaporated. The residue was diluted with water and extracted with 15 ether. The extract was worked up and gave, on addition of hexane, 10ce-desA-pregnane-5,20-dione, M.P. 126-127' (crystallized from isopropyl ether). The above pyrolysis was carried out in the same manner using 10 g. of the lithium salt mixture and 30 g. of sodium phen ylacetate. 20 Example 108 40 ml. of 0.8% potassium permanganate solution was added with vigorous stirring to a mixture prepared from 25 g. of testosterone acetate, 1000 ml. of ter t.butanol- 25 water azeotrope, 16.8 g. of potassium carbonate and 300 ml. of 7% aqueous sodium metaperiodate solution. In the course of 15 minutes, 660 ml. of 7% sodium metaperiodate solution and 40 ml. of 0.8% potassium permanganate solution were then simultaneously added.to 30 the so-formed reaction mixture, followed by the addition of 540 ml. of 7% sodium metaperiodate solution and ml. of 0.8% potassium permanganate solutiori in the course of 30 minutes. The mixture was then stirred for 90 minutes, filtered over a filter aid (Hyflo) and the residue 35 was washed with 150 ml. of tert.butanol-water azeotrope. The ffitrate was worked up as described in Example 104 and gave 17,6 - acetoxy-5-oxo-3,5-seco-A-nor-androstan-3- oic acid, a viscous oil. This oil was disgolved in 2!50 ml. of methanol, the solution was mixed with a solution of 15 40 g. of potassium hydroxide in 100 ml. of water and allowed to stand for 16 hours. The solution was then concentrated in vacuo. The residue was dissolved in 1()O ml. of water, acidified with 20% hydrochloric acid aiid extracted with methylene chloride. The extract was worked 45 up and gave 17g-hydroxy - 5 - oxo-3,5-seco-A-nor-androstan-3-oic acid, M.P. 202.5-2030 (crystallized from ethanol). Example 109 50 A solution of 14.2, g. of 17p-hydroxy-5-oxo-3,5-seco-Anor-androstan-3-oic acid in 280 ml. of anhydrous benzene was allowed to stand with 25 ml. of 1 % p-toluenesulfonic acid in benzene and II ml. of dihydropyran at room temperature for I hour. The reaction mixture was then 55 poured on ice and extracted with ether. The ether extract was washed with sodium hydrogen carbonate solution and water and evaporated. The oily residue consisted of a mixture of 17p-tetrahydropyranyloxy-5-oxo-3,5-seco-Anor-androstan-3-oic acid and its tetrahydropyranyl ester. ro The mixture was converted into the free acid by alkaline hydrolysis. Example 110 5 g. of 17#-tetrahydropyranyloxy-5-oxo-3,5-seco-A-nor- 65 androstan-3-oic acid lithium salt (prepared by treating the free acid with I N lithium methylate according to the procedure of Example 105) was pyrolyzed in a mixture of 7.5 g. each of sodium acetate and potassium acetate at 0.05-0.01 mm. Hg and 280-310' for 80 minutes. The dis- 70 tillate was worked up and the neutral part was chromatographed on silica gel. Using petroleum ether-ether (8:2 to 6:4) there was obtained partly crystalline 17p-tetrahydropyranyloxy-IOa-desA-androstan - 5 - one, Eall@5=-16' (dioxane). 75 42 The same product was obtained by pyrolysis of the sodium salt at normal pressure under nitrogen and by pyrolysis of the lithium salt in quinoline at 300' and 4.5 atmospheres. However, better yields were achieved by carrying out the pyrolysis in molten sodium phenylacetzcte. Example I II 30 ml. of 0.8% potassium permanganate solution was added under vigorous stirring to a solution prepared from 19.8 g. of 11,6-formyloxy-an drost-4-en-3,17-dione, 600 ml. of tert. butanol-water azeotrope, 12.6 g. of potassium carbonate and 225 ml. of 7% sodium metaperiodate solution. In the course of 15 minutes, 500 ml. of 7% sodium metaperiodate solution and 20 ml. of 0.8% potassium permanganate solution were then simultaneously added to the reaction mixture followed by the addition of another 500 ml. of 7% sodium metaperiodate solution and 15 ml. of 0.8% potassium permanganate solution in the course of 30 minutes. The so-obtained mixture was then stirred for 90 minutes, filtered over a filter aid (Hyflo) and the residue was washed with 60 ml. of tert. butanol-water azeotrope. The filtrate was then worked up as described in Example 104 and gave llfl-formyloxy5,17-dioxo-3,5-seco - A - nor-androstan-3-oic acid, M.P. 220-221' (from ethanol), IUID 2@=107' (dioxane). The starting Ilp-formyloxy-androst-4-ene-3,17-dione was prepared from llp-hydroxyandrost-4-ene-3,17-dione by dissolving the latter in excess formic acid in the presence of a catalytic amount of perchloric acid and, after 20 hours at room temperature, pouring the reaction mixture on ice, extracting with methylene chloride and evaporating. There was obtained a product melting at 139139.5' (crystallized from ethyl acetate), [OCID 25=188' (dioxane). Example 112 A solution of 10 g. of llp,17#-diformyloxy-androsta1,4-dien-3-one in 100 ml. of acetic acid was ozonized at O' until thin layer chromatography did not show any starting material. The solution was then diluted with 100 ml. of water, heated to 100' for 30 minutes and evaporated. The residue was worked up according to the procedure of Example 92, giving Ilp,17p-diformyloxylOt-desA-androstan-5-one, M.P. 164-166' (crystallized from methanol), [a]D25=21' (chloroform). Further elution using methylene chloride containing 1% acetone gave llp-formyloxy - 17,6 - hydroxy-10@-desAandrostan5-one, M.P. 128-128.5' (crystallized from isopropyl ether), [aID25,=51' (chloroform). 'fhe starting Ilp,17,6-diformyloxy-androsta-1,4-dien-3one was prepared from 11,6,17pdihydroxy-androsta-1,4dien-3-one by a procedure analogous to that of Example 1 1 1. The product melts at 253-254' (crystallized from me thanol-methylene chloride), [aID25=72' (dioxane). Example 113 A solution of 800 mg. of llp-formyloxy-17fl-hydroxy 10@-desA-androstan-5-one in 15 ml. of methanol was mixed with a solution of 600 mg. of potassium hydroxide in 1.5 ml. of water and kept at room temperature for I hour. The solution was then treated with 0.5 ml. of acetic acid and evaporated in vacuo to dryness. The residue was taken up in methylene chloride and the extract was worked up. There was obtained llp,17#- dihydroxy10@-desA-androstan-5-one, M.P. 174.5-175' (crystallized from ethyl acetate-hexane), [a]D25=36' (chloroform). Example 114 1500 ml. of 16% aqueous sodium metaperiodate solution and 300 ml. of 0.8% potassium permaganate solution were added in the course of 50 minutes at room temperature to a solution of 25 g. of 17p-tetrahydropyranyloxy-androst-4-en-3-one, 1000 ml. of tert. butanol-water azeotrope, 16.8 g. of potassium carbonate and 40 n-d. of water. The reaction mixture was then stirred for another 1.5 hours and Mtered through a filter aid (Speedex).
[22]3 7662256 43 44 The precipitate was then washed with tert. butanolwater The same compound was obtained in an analogous azeotrope and worked up as described in Example 104 manner starting, with 17p-hydroxy-5-oxo-3,5-seco-5 affording 17p-tetrahydropyranyloxy-5-oxo - 3,5 - seco-Aandrostan-3-oic acid sodium salt. nor-androstan-3-oic acid as an oil. Example 120 Example@ 115 5 4 ', 8 5 -- g. , I of .1 7, 6- b e n z o yl o x y5 @ 4 D x o'3 ,5 - s el c; o @ A - n o ra n120@@ml.@@of,Z% ether,eal d@cizbmet@a@ne solution,-was-@ drostan@3- Gic acild lithiuin salt (.prepared b@y tre@i@@the@ added@lnlhd@eourseof 3,0,@minutesi@@cooling-to@asui ;@@:@@@@,free;@cid,4@h I N Ifthi@am@methylate@a 9 pension of 10 g. of 20p-hydroxy-5-oxo -3,5-secb-A-norpregnan-3-oic acid in 100 ml. of methylene chloride. The 10 so-obtained solution was kept at room temperature for 30 minutes and the excess diazometh ane was destroyed by the addition of a small amount of acetic- acid. The solution was then evaporated and the residue gave, :on recrystallization from ethyl acetate, 20p-hydroxy-5-oxo- 15 3,5-seco-A-nor-pregnan-3- oic acid methyl ester, M.P. 110-1111, [M]D2@=16' (dioxane). Example 116 15 ml. of 1% p-toluenesulfonic acid in benzene and then 7 ml. of dihydropyran were added to a solution of 20 10 g. of 20p-hydroxy-5-oxo-3,5-seco -A-nor-pregnan-3- oic acid methyl ester in 130 ml. of anhydrous benzene. The reaction mixture was kept at room temperature for 4 hours and then poured on 50 ml. of ice water. The organic layer was washed wtih, 2% sbdium bicarbonate 25 solution and then with water@ dried and evaporated in vacuo, yielding 20,6-tetrahydropyranylox y-5-oxo-3,5-secoA-nor-pregnan-3-oic acid methyl ester as a colorless, viscous oil. Example 117 30 50 ml. of 20% aqueous potassium hydroxide was added to a solution of 10 g. of 20p-tetrahydro pyranyloxy-5-oxo. 3,5-seco-A-nor-pregnan-3-oic acid methyl ester in 1J;o ml. of methanol. The reaction mixture was then refluxe@d for 70 minutes and evaporated. The so-obtained residue was 35 diluted with 100 ml. of water, acidified with 10% cold hydrochloric acid and extracted with ether. The ether extract was worked up and gave 20,8-tetr ahydropyranyloxy5-oxo-3,5-seco-A-nor-pregnan-3-oic acid as a colorless 40 viscous oil. Example 118 A solution of 5,17-dioxb-3,5-seco-A-no r-androstan-3- oic acid in methanol was neutralized with 1 N lithium methylate solution against phenolphthaleine. The solution 45 was evaporated to dryness,@ the residue dissolved in benzene and the so-obtained solution evaporated yielding 5,17-dioxo-3,5-seco-A-nor-androstan-3-oic acid lithium salt as an amorphous powder. procedure of Example 116) was refluxed in 100 ml. of quinoline for 7 hours. The reaction mixture was then extracted with ethet. The extract was washed with hy-, drochloric acid, sodium hydroxide solution and water and the crude product was then rebenzoylated with benzoyl chloride in pyridine. Chromatography on silica gel gave 17- benzoyloxy-IOa-desA-androstan-5-one, M.P. I 10-1 I l' (crystallized from acetonehexane), [a]D25=48' (dioxane) @ The same product was obtained by pyrolyzing the lithium salt in a mixture of 15 g. of sodium acetate a@nd potassium acetate at 0.5-0.05 mm. Hg, and .275-320' for 2 hours and analogous working up of the distillate. The same or better yields were, achieved by carrying out the pyrolysis in sodium phenylpropionate, sodium phthalate or sodium propionate. Furthermore, sodium salicylate, sodium benzoate, sodium terephthalate and sodium furoate were also used as the reaction medium. Example 121 1.5 g@ of 17a-methyl-17,8-hydroxy-desA-9p,10,6-androI stan-5-one was dissolved in 30 ml. of acetic anhydride and after the addition of 200 mg@ of anhydrous sodium acetate refluxed for 2 bours. The reaction mixture was evaporated, the residue was taken up in etber and the extract was worked up yielding 17a-methyl-17fiacetoxydesA-9,8,10,6-androstan-5-one, M.P. 124-125', [aID2,5= - 16' (dioxane). I Example 12Z A solution of I g. of testosterone in 10 ml. of pyridine was refluxed under nitrogen with a solution of I ml. of monochlorodimethyl ether in 20 ml. of pyridine at 115120' for 2 hours. The rear-,tion mixture was the-n poured on ice and extracted with ether. The ether extract-was worked up yielding testosterone-17,6-methoxymetbyl ether, M.P. 120- 122'. This compound was treated with sodium metaperiodate and potassium permanganate according to the procedure of Example 114 and the resulting seco acid was pyrolyzed according to the procedure of Example 110. There are thus obtained 17pmethoxymethyl6xy-desA-androstan-5- 5 g. of the above lithium salt was refluxed in 100 ml 50 ..one, an oil, as a mixture of the I Occ- and the 10,8-isomer. of quinoline for 6 hours After cooling, the reaction Example 123 To 15.0 g. of 5% rhodium/alumina catalyst in a 3 liter round bottom flask was added 120 ml. of 3 N hydrochloric acid followed by 300 ral.-of absolute ethanol. The so-obtained mixture w@s prereduced by being shaken for 95 minutes under hydrogen. To the so-prepared prereduced-mixture was added a solution of 30.0 g. of 17#- hydroxy-desA-androst-9-en-5one in 900 ml. of absolute ethanol. The reaction mixture was then hydrogenated for 60 minutes at which pgint the rate of uptake leveled off and the reac'tion was stopped. The catalyst was removed @by filtration over a :fllter aid (Celite), the fil,trate was neutralized with saturated aqueous sodium.bicarbonate, and the solution was concentrated in v-acuo to ca. 350 ml. This concentrate was then extracted with ether (3X 350 ml.), the organic phase was washed with water (3x .225 mL) and saturated sodium chloride (2X 225 ml.), and dried over anhydrous sodium sulfate. The ether solution was filtered and concentrated on the steam bath to a final solutioii of 80-100 ml., cooled at room temperature for 3 hours, then overnight at -20' yielding as white crystals, 17,6-hydroxy-9,6,10,6-desA-an'ether yielded pure lOa-desAandrostane-5,17-dione. 75 drostan-5-6ne which was dissolved in the minimum amount niixture was filtered and i@e filtrate was poured, on a mixture of 150 g. of ice and 100 ml. of conc. hydrochloric acid and extracted with ether. The ether extract was worked up and chromatographed on aluminium ox- 55 ide. The fractions obtained with hexane-benzene (5:1) were evaporated and gave, on addition of hexane, IOMdesA-androstane-5,17-dione, M.P. 121.5-122' (crystallized from ethyl acetate-hexane). Example 119 60 5.56 g. of 17#-hydroxy-5-oxo-3,5-sec o-A-nor-androstan-3-oic acid lithium salt (prepared by treating the free acid with I N lithium methylate according to the procedure of Example 116) was refluxed in 100 MI. Of 65 quinoline at a bath temperature of 260' for 2 hours. The reaction mixture was then poured on ice and taken up in ether. The ether extract yielded on working up an amorphous residue, which was @oxidized with 15 ml. of Jones reagent in 150 ml. of acetone at O'. The@ reaction 70 mixture was then worked up and the crude product obtained was refluxed with 60 ml. of 2 N sodium methylate solution for I hour. Chronlatography of the reaction product followed by recrystallization from ether-petroleum
[23]45 3)766,256 46 of anhydrous ether and the ether solution was concentrated down to about one-tenth original volume and the solution then was cooled one hour at room temperature, then overnight at 20'. The crystals were then separated and melted at 143-145.5', [a]1)2@=-12.9' (CHC13, 5 C@=1.065%). Example 124 A solution of 10.0 g. of 1 1-mesoxy-5,20- dioxo-3,5-secoA-nor-pregnane-3-oic acid in 100 ml. glacial acetic acid was refluxed under a nitrogen atmosphere for 40 minutes. 10 The solution was then concentrated at 50-55' (water pump), the brown residue was taken up in ether, washed with water and,dried over sodium sulfate. Evaporation of the solvent afforded A9(")-5,20-diox o-3,5-seco-A-norpregnene-3-oic acid. 15 The sodium salt of A9(")-5,20-dioxo3,5-seco-A-norpregnene-3-oic acid was prepared by treating a solution of 7.5 g. of the acid, in 50 ml. of methanol, with a slight excess of sodium methoxide (1.3 g.). The final solution (pH 8-9; indicator paper) was taken to dryness at the 20 water pump, bath temperature 55' and stripped with benzene (2X 10 ml.). The tan colored semi-solid residue was thoroughly blended with 25.0 g. of sodium phenyl@cetate and pyrolyzed for 3 hours, bath temperature 295', intemal temperature ca. 250', initial pressure 100 microns 25 (diffusion pump) and final pressure 30 microns. The total contents of the reaction vessel (hard9 brown resin) were partitioned between water (300 ml.) and ether (100 ml.). The aqueous phase was extracted with ether (3X 100 ml.); the ether phase was washed with water (2X loo 30 nil.) and dried over sodium sulfate, yielding a yellow oil which was triturhted with etlier and cooled at O', affording desA-pregnan-9-ene-5,20-dione as slightly yellow crystals, which upon recrystallization from a small volume of ether melted at 112-115' (sintering). 35 Example 125 A mixture of 10 g. of Ilc@-mesoxy-5,20 -dioxo-3,5-secoA-norpregnan,e-3-oic acid and 100 g. of 1:1 (by weight) mixture of fused sodium acetate aiid fused potassium ace- 40 tate was charged to a 250 ml. stirred flask which was equipped with a gas inlet tube and an air condenser protected with a salt bath. The reaction mixture was then heated at 275-300' for 3 hours while a gentle stream of nitrogen was passed over the surface of the melt. With 45 stirring the mixture was cooled to 90', 100 nil. of water and 35 ml. of methylene chloride were added and stir - ring was continued until all of the salt had dissolved. The aqueous layer was then extracted with 2X 100 ml. 50 of methylene chloride and the combined organic extract, after being washed with 2X 75 ml. of 2 N sodium carbonate and 2X 100 ml. of water was dried with sodium sulfate and evaporated. The neutral residual oil Was determined by thin layer chromatographic analysis (silica 55 gel, with ethyl acetate-benzene 2:1, developed by means of sulfuric acid-methanol, 1:1 v./v. and 10% phosphomolybdic acid-methanol sprays) to contain by weight ca. 60% desA-pregn-9-ene-5,20-dione. Example 126 60 To a solution of 2OG mg. of Ilm-h ydroxy-10m-desApregnane-5,20-dione in I ml. pyridine, 0.2 ml. of acetic anhydride was added, and the mixture was then allowed to stand overnight at room temperature. It was then poured into water an-d the resultant suspension extracted with 65 chloroform. The extract was washed with water, dried over anhydrous sodium sulfate, and evaporated. The crystalline residue was recrystallized from ethyl acetate-petroleum ether giving Ila-hydroxy-IOa-des A-pregnane@-5,20- dione acetate, M.P. 157-1581. 70 Example 127 One mole of llx-hydroxy-10,6-de sA-pregnane-5,20. dione was acetylated with one mole of acetic anhydride in pyridine. The crude product, obtained in quantitative 75 yield, was recrystallized from ether-petroleum ether to give Ilix-hydroxy-10,6-desApregnane-5,20-dione acetate, M.P. 127-129'. Example 128 A solution of 6.4 g. of I la-acetoxy-progesterone in 100 ml. ethyl acetate and 50 ml. rnethylene chloride was ozonized at -700 until the solution became blue in color. After oxygen was passed through, the solution was evaporated at room temperature in vacuo. The sirupy residue was dissolved in 100 ml. of glacial acetic acid, and after addition of 5 ml. of 30% hydrogen peroxide, kept at 2' for 24 hours. The reaction mixture was then evaporated to dryness, the residue dissolved in 1 liter of ether' and the ether solution extracted ten times, each time with 50 ml. portion of 2 N sodium carbonate solution. The combined carbonate extracts were acidified with concentrated hydrochloric acid and the noncrystalline precipitate was extracted with methylene chloride. The combined extracts were dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. The residue was chromatographed on a Florisil column and eluted with ethyl acetate. Upon evaporation of the solvent, the crystalline product obtained gave, after several recrystallizations from methylene chloridehexane, lla-hydroxy-520-dioxo-3,5-seco-Anor-pregnan-3-oic acid acetate, M.P' 171- 172'@ EUID25=64.6' (c.=l, in chloroform). Example 129 - A solution of 4.5 g. of 1 1 a-hydroxy-5,20-dioxo-3, 5-secoA-nor-pregnan-3-oic acid acetate in one equivalent of aqueoiis sodium carbonate solution was evaporated to dryness in vacuo. The residual sodium salt was mixed well with 15 g. of sodium phenylacetate and the mixture pyrolyzed at 290' in vacuo (0.02 mm.) for 2.5 hours. The crude sublimate was chromatographed on a silica gel column and elution with petroleum ether/ether (3-7) gave a fraction which was recrystallized from acetone/ petroleum ether. This gave Ila-hydroxy-10p-desA-pr egnane-5,20-dione, which was identified by mixed melting point, and by comparison of optical rotation with a sample of the same compound prepared by the procedure of Example 7. Exaniple 130 7a-methyl-IOadesA-androstan-5- one in 100 ml. of carbon tetrachloride To a solution of 1.5 g. of 17g-hydroxy1 was added 1.62 g. of sulfuryl chloride dissolved in 75 ml. of carbon tetrachloride, and the reaction mixture stirred and heated at 45' for 24 hours. It was then transferred to a separatory funnel, washed with water, dried over sodium sulfate and evaporated. Separation by preparative thin layer chromatography gave 10fl-chloro-17fthydroxy17a-methyl-desA-androstan-5-one, which was recrystallized from acetonehexane, M.P. 127-128', [al]:)25=59@2' (c@=0.5 in chloroform). Example 131 A mixture of 1.75 g. of crude chlorination product, obtained by the procedure of Example 130, and 4.3 g. of lithium carbonate in 100 ml. of dimethyfformamide was stirred and heated at 100' for 3 hours. After cooling to room temperature, it was diluted with 1.5 liters of ether, and washed successively with water, 1 N hydrochloric adid, and water, dried over sodium sulfate, and evaporated. Separation on preparative thin layer chromatograms gave crude non-crystalline 17#-hydrox y-17a-methyl-desA-androst-9- en-5-one. Example 132 A solution of 2 g. of 17,6-hydroxy-IOa-desA-androstan5-one in 2 ml. of pyridine and 2 ml. of acetic anhydride was kept overnight at room temperature, and then poured into 50 g. of crushed ice. After two hours, the crystalline
[24]3,766,256 47 pre6ipitate@was collected byfiltration, washed with water, and dried, giving 17pacetoxy-10a-desA-androstan-5-one, M.P. 69.5-70.5'p [a] D25--6' (c@=0.5 in chloroform). Example 133 To a solution of I g. of 17p-acetoxyIOa-desA-androstan-5-one m 50 ml. of carbon @tetrachloride was added dropwise a solution of 0,936 g; of stilfuryl chloride(2 mole equivalents) in 103 ml. of carbon tetrachloride. The reaction mixture was illuminated with a 250-watt infra- 0 red lamp during stirring at 40-50' for 160 hours@ It was then washed with water, 2 N sodium carbonate solution, and with water again,@ dried over sodium sulfate and evaporated.. A crystalline product was obtained which contained (gas-liquid chromatography) starting material and 17p-acetoxy-IOp-chloro@desA-androstan-5-one. To a solution of I g. of 17,6-acetoxyIOa-desA-androstan-5-one in 150 -ml. of carbon tetrachloride was added 75 mg. of benzoylperoxide and dropwise a solution of 0.936 g. of sulfuryl chloride in @100 ml. carbon tetrach,lo- 20 ride. The reaction mixture was then stirred at room terhperature for 160 hours. It was worked up in the same@ way as in@Example 133'yielding a crystalline product which contained starting material and 17,6-ace toxy-10,3-chlorodesA-androstan-5-one. 25 To a solution of 0.5 g. of 17p-acetoxy-1 0,x.desA-androstan-5-one in 50 ml@ of acetic acid-carbon tetrachloride (1:9 v;/v@) was added in four portions 0.332 g. (1.33@rriol4e, equivalents) of sulfuryl chloride dissolved in 20 ml. acetic, acid-carbon tetrachloride (1:9). The second ' third and 30@ fourth portions were added 71 @24 and 96@ hours respectively, afteraddition of the-first.@The reaction mixture:was stirred at room temperature adn worked up after 120 hours. A crystalline produet containing starting materilal and 17,6@-acetoxy-IOg-chloro-de@@@dr osta6@@one@was-ob 36 tained. th. Recrystallization of the c,rude products @obtained in f -I-, "@h .-@ I I roit@-@ tt et @ gav- e @ 1 j@@ai:et6@@"P. chloro-desA-androstan-5-6ne M.P. 137-141' [.ID26--93-8- -40 (c.--0.5 in chloroform). Example@ 134 A mixture of 0.5 g of -17p-acetox I YIOp-chlor67desA-@ ml. of dimethylformamide was stirred at 100' for two and three-ciuarter hours. After cooling to room.temjpera- ture, the mixture was diluted with 750 ml. of ether, and the ether solution washed with water, I N hydrochloric acid, aqueous 2 N sodium carbonate, and again with @50 giving water dried over sodium sulfate and evaporated 17,6-acetoxy-desA-androst-9-en-5-one, M.P. 65--70', [0,1,25=25.2- 55 (C. 1.05 in @hlorof6rm). Alternatively, the crude, pr-oducts:of,@the chlorinations, of Example 13 3 were, without purific@Ltion,; dehydrochlorinated under the above ec)nditions, and 17p-ace'toxydesA-androst-9-en-5-o ' I :by -predarative thin layer chromatography. ne is6 ated 60 Example 135 A solution of 1.5, g. of I ix-mesoxy-5,20-d ioxo-3,5-secoA-nor-pregnan-3-bic a@id in 45 ml@ of methanol was miied 6,5 -with@ .385 g. of sodium carboriate., in 15 ml.,of water and @o evaporated to dryness@ Th6 last- trace. of water. was re-. moved @by adding benzeiie and@ evaporating to dryness again. To @the: residual salt :was added 5o ml. 6t fr@@W,@ distilled triethan6lamine, adn the r6action mixture was then heated for 3-4: hours in a metal bath of' 21 70 under a nitrogen atmospheri@@ Tht temperature of action solution varied between@ 190 and 205'. After cooling, the reactibn mixture was diluted with I liter of water, and extracted with ether (lOxl5O ml.). The combined 48 acid@, and with water@ again, dried and evaporated, yielding a crude product which was detetmined by ultrolviolet spectroscopy and by gas chromatography to contain a sub, stantial amount of desA-pregn-9-ene-5,20-dione. When the reacti6ii time was extended to 5 or 6 hours, the yield dropped slightly. A solution of 2.418 g. of the crude product obtained by the foregoin.- procedure a-nd 1.4 g. of semicarbazide in 60 ml. of 95% ethanol and 9 ml. of glacial acetic acid was stirred and refluxed for 2 hours. After cooling in ice, the precipitate was filtered off and washed, with ethanol. Evaporation of the mother liquors and gmt allizat-ionfrom 10 ml. of 95% ethanol gave additional product. Both crops were combined, suspended in 1.00 ml. of 95% ethanol, refluxed for one hour, and concentrated to a volume of 50 ml-., cooled in@an.ice bath) and filteied, giving desa - pregn - 9 ' ene-5,20-dione disemicarbazone, which does not melt below 340', but showed slight decomposition above 270'. - A solution of 1.87 g. of the so-formed disemicarbazone in 75 ml@ acetic acid, 25 ml. of water, and 6.5 mL of,1.66 N pyruvic acid was warmed for two minutes at 40o, then left ovemight at room temperature@@ It was then diluted with 1.5 liters of ether, washed with water, aqueous 2 N sodium carbonate, and with water again, dried, and evaporated. The crystalline residue was dissolved alrnost completely in 50 ml. of hot heptane, filtered, and the filtrate was evaporated. The last operation:was repeated with the residue and 20 mL of heptane,@ and the so-obtained residue recrystallized from et yi ing 9-ene-5,20-dione, which melted at 1 1,3-1 1-@3.,5' C. (c.= I in chloroform). tx-ample 1 @6@ 20g-hydroxy-desA-pregn-9-en-5-one was reacted- with semicarbaz n a: tion@to give 20,3-hydroxy-desA-pregn-9-en-5-one.semicarbazoneas colotless needles, M.P.- 196-138' ex et-hyl- 460@ tate, [aID25=110' (c@=0.5 in ethanol). EXample 137 A:solution,:of 524 mg. (f de@A-pregn-9-ene-5,2G-dione in absolute methanol (65 ml.) was stirred at 5'. Over a androstan-5-one and 1.18 9. of lithitim carbonate in: 50 @46 period of@,forty minutes, sodium borohydridp_ (0@5 g.) was , r e then added thereto. The tota 'action time allowed was One , hour. Cold glacial@ acetic. acid, @ was thcn added drol)-- wise until the pH was abotit 7.5, the solution was concentrated, to dryness in vacuo, chloroform (150 ml,) adijed, and the solution washed with water until it was neutrttl. ; t h e n d r i o d w i t h d The organic layer wa@ sodium sulfate, an ielding a cldar oil. Chloroform evaporated to dryness,@ y (50 ml. dried over silica gel), was added to 551 mg. of this oil, and stirred with 10 g. of precipitated manganese dioxide (Code No@ @37, General- Metallic Oxides) for hours. The suspension was then filtered through a sinteredglass funnel, using a fftti@r aid (Celite)@ and evaporated to dryness m vacuo giving a colorless 6iL Crystallization of 520 mg. of this oil gave 2OP-h-y-droxy-desA-pregn-9-en-5-@ one as colorless needles, MIP. 116-122"@. A further amolu.nt of this compound was isolated from thin@ layer chromatograms. At the same time, a second band which t was e@luted was fluorescent ubdtf ultraviolet ligh gIvIng@ 20o@-hydroxy-de@@rega-9-en-5-one,. whicli. was acetylate with acetic- anhydride@- in pyridine @!gi4g @ 20a.@@r(ii@ desA-pregn-9-en-5@one ac@o@, as colorless needles, M.P.@ 87@891 @ ex ethe-r/petroleum ether, EuID25--37.8' - - anol) (c. 0,31 2 in eth Example 138 - o n e l - ( O @ 2 5 , 0 w a s d i s - 2ophydroxydesApregn9@@5 solved in 2 ml. of (1: I v./v.) acetic anhydridc in pyridine and allowed to stand overnight.@ The solution was then obured onto crushed ice and the crystalline @precipita I te ether extracts were@washbd with wate4 I N hydroichloric :7.5 collected @,and sui@W dry. ThD rcsidue was.@ crystallized7
[25]3,766,256 49 from methanol/water giving 20g-acetoxy-desA-pregn-9en-5-one as needles -which were recrystallized from petroleum ether yielding the product as colorless needles, M.P. 84-85', [CC]I)251=12.6' (c.@0.5 in ethanol). 5 Example 139 A suspension of 238 mg. of 5% rhodium on alumina catalyst in a mixture of 26 ml. of 95% ethanol and 5.25 ml. of 2 N aqueous sodium hydroxide was prereduced. 10 To this was then added a solution of 262 mg. of 17p-hydroxy-desA-androst-9-en-5-one in 15 ml. 95% ethanol, and the whole mixture hydrogenated at room temperature and atmospheric pressure. After one mole equivalent of hydrogen was absorbed, the reaction was stopped, and the 15 catalyst was separated by filtration. After standing overnight the filtrate was concentrated in vacuo. To the residue was added I ml. of glacial acetic acid, and the soi-formed mixture dissolved in 1 liter of ether. The resultant clear solution was washed with 2 N aqueous sodium carbonate 20 solution, then with water, then dried over anhydrous sodium sulfate and evaporated to dryness in vacuo, yielding a pale yellow oil containing a substantial amount of 17,6- hydroxy-9#,10,6-desA-androstan-5-one. 25 Example 140 20,6-hydroxy-9p,10,6-desA-pregnan-5-one (45 mg.) was dissolved in pyridine (0.1 ml.) and acetic anhydride (0.1 ml.) and the reaction mixture allowed to stand overnight 30 at room temperature, evaporated to dryness in vacuo, and passed through a silica gel column. The crystalline fraction was recrystallized from aqueous methanol giving 20,6- acetoxy-9p,10p-desA-pregnan-5-one as colorless needles which upon crystallization from petroleum and then from 35 ether/petroleum ether formed colorless needles, M.P. 100-100.5', EaID25=27.1' (c.,=0.5 in ethanol). Example 141 40 Hydrogenation of I g. of 20p-hydro xy-desA-pregn-9- en-5-one was performed under acidic conditions according to the procedure of Example 15. After separation of catalyst an excess of 20 ml. 2 N sodium hydroxide solution was added and allowed to stand ovemiglit. The solu- 45 tion was acidified, dissolved in ether, and washed witli sodium carbonate an water, dried and evaporated to dryness yielding a colorless oil which was dissolved in benzene (3 ml.) with warming. A solution (3 ml., equivalent to about 50% excess) of sodium t-amylate in benzene was 5o added in the cold under a nitrogen atmosphere and the reaction mixture allowed to stand for one hour at room temperature. Freshly distilled (B.P. 80') methyl vinyl ketone (2 ml. in 4 ml. of dry benzene) was then added thereto in six equal portions at a regular interval during 5,5 the course of two hours. The resultant suspension was then refluxed for two hours, and allowed to stand overnight. The reaction mixture was acidified with glacial acetic acid, dissolved in ether, washed with 2 N aqueous sodium carbonate and water, dried over sodium sulfate and 60 evaporated to give a yellow oil. From this oil two fractions were separated by preparative thin layer chromatography [twenty-five (I mm. thick) silicic acid plates]. First fraction was further purified by column chromatography giving 20@-hydroxy-9p,10pdesA-pregnan-5-one. The sec- 6,5 ond fraction was further fractionated by preparative thin layer chromatography to give an oily product which was dissolved in methylene chloride (50 ml.), and oxidized with chromic acid in acetic acid solution (1 ml.), washed with bisulfite, and the organic layer dried and evaporated 7o yielding an oily product which was purified by thin layer chromatography giving an oil, which crystallized upon addition of a drop of ethanol. Recrystallization from ethanol yielded 9p,10a-pregn-4-ene3,20-dione as colorless needles, M.P. 163-164'. 75 50 Example 142 The crude product of the hydrogenation of Example 141 was dissolved in benzene (3 ml.) with warming. A solution (3 ml., equivalent to about 50% excess) of sodium tamylate in benzene was then added thereto in the cold under a nitrogen atmosphere and the reaction m'lx. ture allowed to stand for one hour at room temperature. 4- diethylaminobutan-2-one (3 g. in 4 ml. dry benzene) was added in six equal portions at regular intervals during the course of two hours. The resultant suspension was then refluxed for two hours, and allowed to stand overnight. The reaction mixture was acidified with glacial acetic acid, dissolved in ether, washed with 2 N aqueous sodium carbonate and water, dried over sodium sulfate, and evaporated to give a yellow oil. By using the same procedure as in Example 141 after chromic acid oxidation, crystalline material was isolated which was purified, giving 9,8, 10oc-pregn-4-ene3,20-dione, M.P. and mixed M.P. 163164'. Example 143 The crude product of the hydrogenation according to the procedure of Example 141 of 1.2 g. of 20,6-hydroxydesA-pregn-9-en-5-one was dissolved in benzene (5 ml.). A solution (3 ml., equivalent to about 50% excess) of sodium t-amylate in benzene was then added in the cold under a nitrogen atmosphere, and the reaction mixture allowed to stand for one hour at room temperat@are. 4-diethylaminobutan-2-one methiodide (6 g., M.P. 85-86' ex acetone/chloroform) as a suspension in benzene (5 ml.) was added in six equal portions at regular intervals during the course of two hours. The resultarit suspension was then refluxed overnight. The reaction mixture was acidified wtih glacial acetic acid, dissolved in ether, washed with 2 N aqueous sodium carbonate and water, dried over sodium sulfate, and evaporated to give a yellow oil. By using the same procedure as in Example 141, after chromic acid oxidation, crystalline material was isolated, which afforded after recrystallization 99,10a-pregn-4-ene3,20-dione, M.P. and mixed M.P. 163-164'. Example 144 To the solution of 108 g. of 20p-hydroxy-9,6,10#-de sApregnan-5-one (regenerated from its acetate by hydrolysis using aqueous sodium hydroxide) in ethanol (8.2 ml.) was added I ml. of sodium ethoxide solution (prepared by dissolving 2.36 g. of sodium to make 250 ml. of an ethanolic solution) i.e. I mole of sodium ethoxide per mole of 20p-hydroxy-9p,10p-desA-pregnan-5-one. The reaction mixture was then allowed to stand for half an hour and freshly distilled 4-d iethylaminobutan-2-one (0.5 ml.) added thereto, and the resultant mixture allowed to stand for two hours. Refluxed for one And one-half hours, and added two more portions (0.5 ml. each) of 4- diethylaminobutan-3-one in the cold under a nitrogen atmosphere. The solution was refluxed for one hour between the last two additions, and then overnight. The solution was cooled to room temperature and acidified using glacial acetic acid, poured into 10 N sodium carbonate solution (100 ml.) on an ice-bath, extracted with ether (4X 100 ml.) and methylene chloride (4X 100 ml.), and washed with water. Evaporation then gave a pale yellow oil which was processed according to procedure of Example 141 and which after oxidation with chromic acid yielded 9#,10ccpregn-4-ene-3,20-dione, M.P. and mixed M.P. 163-1,64'. Example 145 To a solution of 0.104 g. of 20p-hydroxy-9#,10p-desApregnan-5-one (prepared via a crystalline acetate by saponification) in ethanol (2 ml.) was added 0.4 U. "Triton B" (35% of benzyltrimethylammonium hydroxide in methanol). A solution of freshly distilled methyl vinyl ketone (0.08 g.) in ethanol (4 ml.) was then added to the reaction mixture under a nitrogen atmosphere. After refluxing for two hours, the reaction mixture was
[26]3,766,2 56 51 cooled and acidified with, 3 N@ hydroebloric acid (I mi@) and again heated on a steam bath for ten minutes. The reaction mixture was then again cooled and poured into crushed ice (10 g.) and taken up in 1 liter of ether. The ether layer @was washed successlively with I -N hydrol 5 chloric acid (50 ml.), water (50 ml.), I N sodium biearbonate solution and water (3 X 50 ml.). The ether soluI tion was then dried over sodium sulfate and evaPOrated giving a yellow oil which by using preparative thin layer plates was separated into unchanged starting mate10 rial and a yellow oil, which crystallized spontaneously.' Recrystallization from ethanol gave 20p-hydroxy-9p,10apregn-4-en-3-one as colorless needles ex ethanol, M.P. and mixed M.P. 175-176'. After oxidation witli chromic acid, the latter gave 9p,10a-pregn-4 -ene-3,90-dione, M.P. and 1,5 mixed M.P. 163-164' ex ethanol. Example 146 To a solution of 200 mg. of desA-pregnan-9 ene-5,20 dione in 15.0 ml. of absolute ethanol there was added 20 40.4 mg. of 5% rhodium on alumina catalyst, To this mixture there was then added 0.4-ml. of 3 N hydroehloric acid. The reaction mixture was then hydrogenated in a round bottom flask@with moderate shaking at atmospheric pressure and room temperature. The hydrogenationwas 25 terminated at the end of 60 minutes and,the reaction mixture neutralited to pH 7 with@sodium carbonate, filtered over a@ filter aid (Celite) and concentrated in vacuo at 40'. The residue Was t@Lken up in ether, partitioned@ between ether and water, and the ether layer@ washed with 30 brine, dried over sodium sulfate, and evaporated in vacuo at 25' yielding an oil which was recrystallized from ether yielding crude reaction product containing desa9,8, 1 Op-pregnane-5120-dione. Utilizing the same procedure as above desa-pregnan9-ene-5,20-dione was also hydrogenated to desA-9,6,10,3- pregnane-5,20-dione utilizing the following: Weight Hydro - ratio genati on catalyst to, time, Catalyst substrate Medium minut es 5% rhodium/aluriaina ------------ 1:5 3N HCI/ ethanol--- 60 Do -------------------------- 1:20 - - -do -- ----------- so rliodium/carbon powder----- 1:5 -:---do -- ----------- 65 5% ruthenium/carbon powder--- 1:5 Ethanol ----------- 270 I Neutral (i.e. no acid). Example 147- A mixture of 200 mg. of 20p-acetoxy-desA-pregnan-9- en-5-one, 25 mg. of 5% rhodium on alumina catalyst, 50 0.4 ml. of 3 N hydrochloric acid and 15 ml. of absolute, ethanol was hydr6genated at atmosplieric pressure and room temperature with' moderate shaking of the flask con. , taining the reaction mixture. The hydrogenation was terminated at the end of 45 minutes the catalyst removed 55 by filtration@ and the filtrate neutralized t-o pH 7 with aqueous sodium bicarbonate. The so-obtained neutral mixture was then concentrated in vacuo at 45', and partitioned between 40 ml. of dichloromethane and ?O ml. I of water. The organic layer was - then separated, washed 60 with water, dried over aqueous sodium sulfate and concentrated in vacuo at 400 yielding 20,3-acetoxy-desA-9plop-- pregnan-4-one. Example 148 1.0 g. of 17p-hydroxy-desA -9p,10p-androstan-5-one was 65 dissolved in 50 ml. of anhydrous benzene. Then 20 ml. of solvent was boiled off and, after flushing the reaction flask with nitrogen, 25 mg. of potassium t-butylate was added, thereto. Another 10 ml. of the solvent was then@ boiled off and in the course of one hour, with stirring and re70 fluxing, a solution of 0.5 ml; of 4-diethylaminobutan-2-, one in 10 ml. of benzene was gradually added to the reaction mixture. The reaction mixture was then stirred and reffuxed for a further hour, after which the reaction mixture was cooled and filtered through 10 g. of alumi,na 75 52 (neutral,- 'Grade HI.). The column was washed with 100 ml.@ of ether and the combined filtrates were evaporated, yielding a yellow reaction product which was dissolved in 30 ml. of benzene and chromatographed on a column of 100 g. of @ alummina (neutral, Grade:lll). Elution with benzene and benzene:ether (19:1) (10 fractions ' 100 inL e ach) yielded some unreacted starting material. The desired product, 99,10,x-testosterone, was then eluted with benzene:ether [(9:1), (4:1), and (2:1)] (6 fractions, 100 ml. each). Evaporation of these fractions and crystallization of the, residue@ frbm diisopropyl ether yielded 9,6,10m-testosterone, M.P. 153-154'. Example 149 To a mixture of 100 g. of 17p-hydroxy-desA@9p,10pandrostan-5-one and 20 mg, of potassium hydroxide in 30 ml. of t-butanol at 60', a solution of 0.455 g. of 4diethylaminobutan-2-one in 5 ml. of benzene was added gradually in the course of 30 minutes under a nitrogen atmosphere with stirring. The reaction mixture was then stirred at 60' for an additional 30 minutes and then cooled to 20'. To the so-cooled reaction mixture, 0.1 ml. of acetic acid was added and the resulting mixture evaporated in vacuo at 30'. The crude product was then chromatographed as described in Example 148 and the fractions containing 9p,10m-testosteron@ (by thin layer Cbro@matography) were combined, evaporated and the residue crystallized from ether yielding 9,3,10a-testosterone, M.P. 155-156". The same procedtire as above was repeated utilizing isoopanol in place of t-butanol and effecting the reaction Pr at 50' rather than 60'. The reaction so-conducted also yielded 1 Oa-testAosterone. Example 150 To a mixture of 1.0 g. of 17p-hydroxy-desA-9,6,10,e androstan-5-one and 20 mg. of potassium hydroxide in M. moles of acid/mg. of catalyst 3/100 12/100 30/100 (1) 30 ml. of t-butanol at 50', a solution of 0.243 g@ of 4dimethylaminobutan-2-one was added gradually in the course of 30 minutes under a nitrogen atmosphere and with stirring. The reactio-n mixture was-then stirred at 50' for an additional 30 minutes and then cooled to 20'. To the so-cooled reaction mixture O@l ml. of acetic acid was added and the resulting mixture evaporated.in vacuo at 30'. The crude product was chromatographed as de,scribed in Example 148 and, the @fractions @containing: 9,8,10a,-testosteTone (by thin layer chromatography) were combined, evaporated, and-the residue crystallized from ethet yielding 9@,6,10,x testosterone. The same procedure as above was repeated but in place of the 4-dimethylaminobutan2-one, O@30 g. of 4-(N-pyr rolidyl)-butan-2-one, was utilized-. This reaction soconducted also yielded 9p,10ct-testosterone. Example 151 T, a stirred solution of 1.0@g. of desA-9,8,10p-androst5,17-dione and 20 mg. of sodium hydroxide in 30 ml. Of t-butanol maintained at 500 and under a nitrogen atmosphere, there was added gradually within the course of 30 minutes a solution of 0.30 g. of methyl vinyl ketone in 5 ml. of benzene. The reaction mixture was then stirred under a nitrogen atmosphere at 501 for an additional 30 minutes and then cooled at 201. To the s(@-cooled reaction mixture 0.1 ml. of acetic acid was@ added and the resulting mixture evaporated in vacuo at 301. The crude produ@t @was then chromatographed as described in Exam.
[27]53 ple 148 and the fractions containing 9p,10,x-andros t-4ene-3,17-dione (by thin layer chromatography) were combined, evaporated, and the residue crystallized from ether yielding the product as crystals melting at 153-154'. Example 152 A 57% sodium hydride in mineral oil dispersion (285 mg.) was washed free of oil with ether, and then suspended in 20 ml. dry dimethylformamide under a nitrogen atmosphere. 17,6-(tetra-hydro-2-pyranyloxy)-9j3,10p desA-androstane-5-one (2.17 g.) in 20 ml. dry dimethylformaniide was added in one portion to the sodium hydride suspension, and the reaction mixture was then stirred at 100' under a nitrogen atmosphere for I hour. The resulting solution was cooled to 20', and 791 mg. of 1- chloro-3-butanone in I ml. dry dimethylformamide in one portion, was added thereto with stirring. After standing at 20' for 16 hours under a nitrogen atmosphere, the solution was evaporated in vacuo. The last traces of dimethylformamide were removed in high vacuo at about 80o bath temperature. The residual oil was dissolved in ethyl acetate, the ethyl acetate solution was washed with water, dried with sodium sulfate, and evaporate d 'In vacuo giving an oil; 2.32 g. of which was dissolved in 24 ml. of 0.5 N sodium methoxide in methanol. 'Ihe mixture was then arowed to stand at 20' for 72 hours under a nitrogen atmosphere. It was then poured on ice and the pH was adjusted to 7.5 with 1 N HCI. Most of the methanol was then evaporated off in vacuo and the residue was extracted at 20' with ethyl acetate. The ethyl acetate extract was washed with water, dried with sodium sulfate, charcoaled (with Norite A) and evaporated in vacuo, giving an oil. This oil was placed in a mixture of 18 ml. of methanol and 6 ml. of 2 N HCI and the resultant mixture was refluxed under a nitrogen atmosphere for 90 minutes. It was then poured on ice, neutralized with 1 N NAOH, and concentrated in vacuo. The residue was extraced at 20' with ethyl acetate and ether. The combined extracts were then washed with aqueous sodium chloride, dried with sodium sulfate, charcoaled (with Norite A), and evaporated in vacuo giving an oil, which according to thin layer chromatography consisted of two mam components, 17p-hydroxy9)3,10,3-desA-androstane-5- one and 90,10atestosterone. The above-described crude oil was chromatographed using a Florisil column (34 g. of adsorbent) with benzene, benzene-chloroform and benzene-ethyl acetate eluents. First 17,6-hydroxy-9p,10p-desA-androstane-5-one was eluted, followed by crude 9,3,10a-testosterone. Mixed melting point determination with an authentic sample of 9P,10ce-testosterone showed no depression of the melting point. Recrystallization from ether gave purified 9,,e,IOMtestosterone, M.P. 155-156', la]D 25=-150' (chloroform). Example 153 A 57% sodium hydride in mineral oil dispersion (84 mg., 2 m.moles) was washed free of oil with ether and then suspended in 8 ml. of dry dimethylformamide under a nitrogen atmosphere. 17p-hydroxy-9p,10,6-desA-androstane-5-one (236 mg., I m.mole) in 8 ml. of dry dimethylformamide was added to the stirred suspension, and the reaction mixture was heated under a nitrogen atrnosphere at 55' for I hour. It was then cooled to 20', and 117 mg. of 1-chloro-3-butanone was added in one portion. The reaction mixture was then stirred at 20' under a nitrogen atmosphere for 1 hour, poured on ice and neutralized with 1 N HCI. The water and some dimethylformamide were evaporated in vacuo. The last of the dimethylformamide was removed in high vacuo at about 80' bath temperature. The residual oil was then dissolved in ethyl acetate, the ethyl acetate solution was washed with water, d,ried with sodium sulfate, and evaporated in vacuo giving crude product which was put in a mixture of 6 ml. methanol and 2 ml. of 2 N HCI. The resultant mixture was refluxed under nitrogen for 90 niinutes. It was then 317661256 54 poured on ice, neutralized with I N NAOH, and concentrated in vacuo. The residue was extracted with ethyl acetate and with ether. The combined extracts were washed with aqueous sodium chloride, dried with sodium sulfate, and evaporated in vacuo giving an oil containing as the two main components, 17,6- hydroxy-9p,10,6-desA-androstane-5-one and 9P,10a-testosterone. The latter compound can be separated by chromatographic means. Example 154 10 20g-hydroxy-9p,10#-desA-pregnan - 5 - one (100 mg.) and 0.15 ml. of freshly distilled 1,3-dichloro-2-butene (B.P. 130') in 0.3 ml. of dry benzene was cooled in an ice-bath. To the reaction mixture there was then added, 15 in an atmosphere of dry nitrogen, sodium t-amylate solution (0.3 ml.) prepared by refluxing in an atmosphere of nitrogen 4.41 g. of t-amyl alcohol and 25 ml. of dry benzene over 1.77 g. sodium. The reaction mixture was then diluted with 7 ml. of benzene, washed with 2 ml. of 20 water, dried with sodium sulfate, and concentrated to a volume of 2 ml. Chromatography of the so-concentrated solution on 50 g. of silicic acid using 1% ethyl acetate in benzene as the eluent gave a 50:50 (indicated by thin layer chromatograpfiy) mixture containing 3-chloro-20,6- 25 hydroxy - 3 - methyl-3,5-seco-9p,10a-A-nor-pregn-2-en-5ones and the corresponding log-isomer. The so-obtained substance was dissolved in methylene chloride, oxidized overnight with chromic acid solution (prepared from 40 mg, chromium trioxide dissolved in 30 0.2 ml. of water and 2 ml. of acetic acid), the resulting product containing 3-chloro3-methyl-3,5-seco-9p,10a-Anor-pregn-2-ene-5,20-dione was dissolved in an equal volume of cold concentrated sulfuric acid, diluted with water, extracted with methylene chloride, and refluxed in 35 benzene in the presence of p-toluene sulfonic acid for one hour. The reaction mixture was washed with aqueous sodium carbonate solution, water, dried over sodium sulfate and evaporated to dryness yielding an oil ' Thin layer chromatography yielded 9p,10a-progesterone. 40 Example 155 A solution of 17p-hydroxy-9p,10p-desA-androstane-5one in anhydrous benzene was reacted with dihydropyran n the presence of 1% p-toluene suffonic acid in benzene according to the procedure of Example 109. 'fhis reaction 45 yielded 17#-tetrahydropyranyloxy-9p, lop-desA-androstane-5-one, which upon recrystallization from ether/petroleum ether melted at 109-111', I(XID 25=+62.9 (in chloroform, c.=I%). I
