[1]United States Patent Office 31499,913 P a t e n t e d M a r . 1 0 , 1 9 7 0 2 3,499,913 Another object of the invention is the obtention of a 4-OXA STEROIDS AND PROCESS 4- oxa steroidof the formula Robert Joly, Montinorency, Julien Warnant, NeuillysurSeine, and Jean Jolly, Clichy-sous-Bois, France, assign- R ors to Roussel-UCLAF, Paris, France, a corporation of -Y France No Drawing Filed Jan. 3, 1968, Ser. No. 695,364 Claims priority, application France, Jan. 6, 1967, 90,264, 90,265 Int. Cl. C07d 101/00; C07c 167102, 169110 U.S. Cl. 260-345.2 25 Claims 10 CH@)\ R'O 0 R . . . ABSTRACT OF THE DISCLOSURE wherein R and R' represent lower alkyl, R" and R... 7 his invention relates to a 4-oxa steroid of the formula 15 represent a member selected from the group consisting of hydrogen , Lx-lower alkyl and p-lower alkyl, Riv and Rv R -Y Ri@ 20 CH- lryr" 25 where R and R' represent lower alkyl, R" and R... represent a member selected from the group consisting of hydrogen, a-lower alkyl and,3-lower alkyl, Riv and Rv represent a member selected from the group consisting 3( of hydrogen, a-methyl and 6-metyhl, Y represents a member selected from the group consisting of 0, OR,i COCH3 and 3 5 Rvii R,iii wherein Rvi represents a member selected from the group consisting of hydrogen, lower alkyl and the acyl of an organic carboxylic acid having 1 to 7 carbon atorns, Rvii 40 represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkylnyl and lower haloakynyl, and Rviii represents a member selected from the group consisting of hydrogen and methyl. These compounds are useful as intermediates in the preparation 45 of known physiolo.-ically active steriods, particularly due to the stability of the A ring allowing chemical reactions to be performed on the C and D rings. CLAIM OF PRIORITY The right of priority under 35 USC 1 19 is hereby claimed, based on the corresponding French patent applications P.V. 90,264 and P.V. 90,265, both filed Jan. 6, 55 1967, on our behalf. THE PRIOR ART 3 - alkoxy - 19-nor-3-methyl-4@oxa-A5(10)-[9p]- andro- 60 stene-17@3-ol and its derivatives in the 17 position have previously been reported in French Patent 1,366,725. However, these cornpounds are not suitable for the preparation of steroid compounds of natural configuration due to the inverted configuration on the 9 carbon atom. Moreover, they are prepared by a different method. 65 OBJECTS OF THE INVENTION An object of the invention is the obtention of a 4-oxa steroid intermediate having a stable A ring useful in 70 ,steroid synthesis for the further reactions on the C and 1) rings. represent a member selected from the group consisting of hydrogen, a-methyl and p-methyl, Y represents a member selected from the group consisting of 0, OR@i COCH3 a.d R@ii R@iii wherein Rvi represents a member selected from the group consisting of hydrogen, lower alkyl and the acyl of an organic carboxylic acid having I to 7 carbon atoms, Rvii represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyll lower alkynyl and lower haloalkyny, and Rvii" represents a member selected from the group consisting of hydrogen and methyl. A further object of the invention is the development of a process for the production of the above 4-oxa steroid which cornprises the steps of reacting a 3,5-dioxo-4,5seco-A9-steroid of the formula R Ri, R, 0 CEI 0 wherein R represents lower alkyl, R" and R... represent a member selected from the group consisting of hydrogen, a-lower alkyl and p-lower alkyl, Riv and Rv represent a ,5o member selected from the group consisting of hydrogen, a-methyl and p-methyl, Y represents a member selected from the group consisting of 0, OR@i COCH3 and R@iii wherein Rvi represents a member selected from the group consisting of hydro,-en, Ic)wer alkyl and the acyl of an organic carboxylic acid having I to 7 carbon atoms, Rvii represents a member selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl and lower haloalkynyl, and Rviii represents a member methyl, with a lower alkyl orthoformiate of the formula HC(OR')3 wherein R' represents lower alkyl, in the presence of an acid a.-ent and recovering said 4-oxa steroid. A yet further object of the invention is the development of processes for the obtention of known steroids through the intermediary of the above 4-oxa steroid. These and other objects of the present invention will become niore apparent as the description thereof proceeds.
[2]3 DESCRIPTION OF THE INVENTION These (>bjects have now been achieved in the discovery of novel 4-oxa steroids of the general Formula I: R //\\I -Y C::] R" R'O /\O/ I R... wherein here and thereafter. R is a lower alkyl radical, R' is a lower alkyl radical, R" is a lower alkyl radical or a hydrogen atom, R... is a lower alkyl radical or a hydro@en atom, Riv is the methyl radical or a hydrogen'atom, Rv is the methyl radical or a bydrogen atom, Y is one of the groupings: OH 0 lower acyl COCE@ COCH3 0 lower alkyl o, H H H CH3 H or OR@i lower saturated or unsaturated, substituted or unsubstituted hydrocarbon, Rvi being selected from the group consisting of a hydrogen atom, a lower alkyl radical and a lower acyl radical. The substituents R", R"', Riv and Rv can be in the alpha or beta configuration. 'ne lower acyl can be the acyl of an organic carboxylic acid having 1 to 7 carbon atoms and particularly benzoyl and lower alkanoyl such as acetoxy. More particularly the 4-oxa steroids of the invention are those steroids of the general Formula 1, wherein R is a lower alkyl radical comprising from 1 to 4 carbon atoms, R' is a lower alkyl radical comprising I or 2 carbon atoms, R" is a hydrogen atom or a methyl, R... is a hydrogen atom or a methyl, Riv is a hydrogen atom or a methyl, Rv is a hydrogen atom or a methyl. Preferred are the 4oxa steroids of the formula R z RIO wherein R is lower alkyl and especially methyl, ethyl, propyl or @butyl, R' is lower alkyl and especially methyl or ethyl, and Z is 0, OH 0 lower acyl COCH3 I and H H H The novel compounds of Formula I are valuable intermediates for the preparation of steroid derivatives. They have an advantage in that they practically do not exhibit any reactive function at the level of the A ring at the time of certain substitutions or conversions at the level of the C and D rings, which will be described later on. These compounds of Formula I have a good stability in alkaline medium. However, the opening of their pyranic ring is easily effected in acid medium with formation of the corre$ponding 4,5-seco-3,5-diketonic de.rivatives, the cycl!5ation of wbich, when performed ac314991913 4 cording to the described methods, allows the A ring to be completed in normal steroid configuration. Some 4-oxa-steroids are already known (see for example the French Patent 1,366,725). However, these compounds are not suita:ble for the preparation of steroid compounds of natural configuration, due to the inversion of configuration which they exhibited at the level of the carbon in the 9 position as discussed above. Moreover, they were prepared according to 10 a method (the catalytic hydrogenation in an acid medium of 3,5-dioxo-4,5-seco-A9 steroids in the presence of a lower aliphatic alcohol, the latter determining the nature of the 3-alkoxy grouping of the formed pyranic derivative), which was entirely different to that used to obtain 15 the compounds of Formula 1. Now, it has been found, and the process of the invention is based thereon, that 4,5-seco-3,5-diketonic steroid derivatives having a 9, 10 double bond, when reacted with a lower alkyl ortho-formiate, in the presence of an acid 20 agent, provided the derivatives with pyranic structure of Formula I and that the reaction proceeds gently and gives satisfactory yields. Thus, the compounds of the @eneral Formula I offer another advantage in that their access is easy, whereas, 25 as has previously been reported, a 1,5-dione reacted in either an acid medium or in an alkaline medium gives rise @enerally to the formation of a cyclohexenic ring havF ing a conjugated ketone function. The process for the preparation of the 4-oxa steroids 30 of Formula I comprises the reaction of a 3,5-dioxo-4,5seco-A9 steroid of the general Formula 11 R y 35 R,l 0 40 0 CH R... with a lower alkyl orthoformiate of the general Formula III 45 HC(OR')3 in the presence of an acid agent and the desired compound is isolated. Preferably, the lower alkyl orthoformiate used in the 50 process of the invention is methyl or ethyl or-thoformiate and the reaction is conducted in the presence of a catalytic amount of a strong acid, such as paratoluene sulfonic acid, methane siilfonic acid, perchloric acid, or sulfuric acid. The choice of the orthoformiate de55 termines the nature of the alkoxy grouping of the resulting pyranic derivative. Thus, methyl orthoformiate leads to the methoxy-pyranicderivative, whereas ethyl orthoformiate provides the corresponding ethoxylated compound. The condensation with orthoformi60 ate is preferably effected in a polar organic solvent such as methanol, ethanol or dioxane, and it occurs quickly at temperatures approximating room temperature. As is mentioned above, the novel 4-oxa steroids of the general Formula I are valuable intermediates for the 65 preparation of steroid derivatives. The ketonic functions in the 3 and 5 positions are protected and do not undergo reaction while substitutions are made on the C and D rings. This has led to a general and unobvious method of producing the said steroids. 70 For example, it has been ascertained, that the 4-oxa steroids of the general Formula I are easily suitable for the introduction, by bromination and dehydrobromination, of the 11, 12 double bond, so as to give thus, after closing the A ring, a 4,9,11-triene steroid. They are also 75 suitable for the introduction of a sub5t!tiient in the 17oL
[3]position, so as to prepare monoene, diene or triene steroids alkylated, ethynylated, etc., in this position. A few cases of utilization of these compounds of Formula I in the synthesis of physiologically active derivatives are described hereinafter. It is evident that this utilization is a part of the present invention. A preferred use of a compound of the Formula I consists in preparing 17,6-benzoyloxy4,5-seco-A9,11-estra-diene-3,5-dione. To obtain this compound, a 3-methyl-3alkoxy-4- oxa-17p-benzoyloxy-A5(10),9(11) - estradiene is selectively brominated in the 11 position. The 11-bromo17p-benzoyloxy-4,5-seco-A9-e strene-3,5-dione formed is dehydrabrominated and the d-,sired 17p-benzoylox y-4,5seco-A9,11-estradiene-3,5- dione is obtained. This compound is then cyclised in alkaline medium, according to the French Patent 1,380,414 so as to form 17p-benzoylOXy-A4911 - estratriene - 3 - one, which is endowed with a high anabolising and androgenicactivity. The 3 - methyl - 3 - alkoxy - 4 - oxa - 17p - benzo yloxy-A5(10),9(")-estradiene used is preferably the 3-ethoxylated d.-rivative. Bromine is advantageously used to effect the selective bromination in the I 1 positio-@l of 3 - methyl - 3 - ethoxy-4oxa-17g-benzoyloxy-A5(1 0),9(")-estradiene, and it is convenient to operate in a polar organic solvent, such as dimethylformamide, in the presence of a basic agent, such as alkali metal acetate. The further dehydrobromination of the 11-brominated derivative is conveniently effected in the presence of a basic agent, such as lithium carbonate and of a lithium halide, such as the bromide. The reaction is condticted in a polar or.-anic solvent, such as dimethylformamide. Another important use of a compound of the Formula 1 is the preparation of 17aethynyl - 4,4-seco - A9 estrene - 17g-ol-3,5-dione. For this purpose, an ethyiiylation agent is reacted in basic medium with a 3-methyl-3alkoxy - 4 -oxa-A5(10),9(")- estradiene - 17 - one. The 3methyl-3-alkoxy - 4 - oxa - 17m-ethynyt-A5(10),9(")- estradiene - 17p-ol-formed is hydrolysed in aqueous acid medium to obtain 17(x-ethynyl - 4,5 - seco-A9-estre-ne-17P-ol-3,5-dione. This comnound is easily converted into 17a-ethynylA4,9-estradiene - 17p-ol-3-one by applying the process d-.scribed in the French Patent 1,497,593. This process involves reacting the compound with a basic cylisation agent in anhydrous medium or an acid cyclisation agent in th.- presence of a small amount of water. From the 17a-ethynyl - A4,9-estradiene-17p-ol-3 - one prepared in this way, there is obtained, according to the process of U.S. Patent 3,136,790, 17,x-ethynylA5(10)- estrene-17p - ol - 3 - one, which is a well known pro.aestative agent. Th-@ 3 - methyl - 3 - alkoxy - 4 - oxa-A5(10),9(")- estradiene-17-one used is preferably the 3 - ethoxylated derivative. To ethynylate the 3 - methyl - 3 - ethoxy - 4 - oxa A5(10),9(")-estradiene - 17 - one, an alkali metal acetylide ,in an aprotic medium (for example toluene or benzene) may be conveniently used. The subsequent hy&olysis is advantageously effected in aqueous medium with a strong acid, such as hydrochloric acid and in a polar -solvent or a mixture of polar solvents. Another important use of a compound having the Fo,rmula I consists in preparing 13gethyl-17cz-ethynylA4,9-gonadien,- - 17p-ol-3-one. For the preparation of this con,potind, an etbyiiylation agent is reacted, in basic medium, with a 3 - methyl-3- alkoxy-4-oxa - 13g-ethylA5(10),9(")-gonadiene-17-one. The 3 - -methyl - 3 - alkoxy4- oxa-13g - ethyl - 17a-ethynyl-A5(10),9(")-gonad@ene-!7pol l'ormed is hydrolysed in acid medium and there is obtai-ned 13p-ethyl-17a-ethynyl - 4,5 - seco-A9-gonene-179- 3,5-dione. This compound is eas-@ly converted into 13p-ethyl - 17aethynyl-A4,9-gonadiene - 17pol-3-one by applying the process described in the French Patent 1,497,593. This 3)4992913 process involves reacting the compound with a basic cylisation agent in anhydrous medium or an acid cyclisation agent, in the presence of a small amount of water. Start-ing from the thus prepared 1.3,3-ethyl -17a-ethynylA4,9-goiadiene - 17)3-ol-3-one and by applying the process of the U.S. Patent 3,136,790, 13@-ethyl-'17a-ethynylA5(10)-gon.-ne - 17g - ol - 3 - one, wh@'ch is a very active progestomimetic agent, is easily obtain,,d. The 3 - methyl - 3 - alkoxy - 4 - oxa - 13,3-ethyl10 A5(10),9(")-gonadiene - 17 - one, preferably used, is the 3-ethoxylated derivative. The ethynylation of 3 - methyl - 3 - ethoxy - 4 - oxa13p-ethyl - A5(10),9(")- gonadiene - 17 - one and the further hydroly-sis of the formed ethynylated derivative are ef15 fected in an analogous way to that described above in the case of the corresponding 13,3 - methylated derivative. Another important use of a compound of the general Formula I is in the preparation of 13,3-ethyl-A4,9,11-gonatriene - 3,17 - dione. 20 This product is a valuable intermediate in the synthesis of 4,9,11- gonatriene derivatives and this is particularly useful for the preparation of 13,3- ethyl - 17a-ethynylA4,9,11-gonatriene-17,3-ol-3-one, which is a strongly active pro,-estomimetic agent (,see the Belgian Patent 679,368). 25 Until now, to obtain this compound, 13,3-ethyl-4,5seco-A9-gonene - 17p - ol - 3,5-dione was cyclised into 13,6-ethyl - A4,9-,@onadiene - 17p-ol-3-one, then after a previous protection of the ketone in the 3 pc>sition in the form of ketal, the alcohol in the 17 position was oxidized 30 into a ketone, and, at the end of the process, the 11,12 double bond was introduced. See Belgian Patents 657,260 and 674,178 as well as U.S. patent application S.N. 517,061, filed Dec. 28, 1965, now P'at. No. 3,453,267. Now, it has been found in the preparation of 139-ethyl35 A4,9,11-gonatriene-3,17-dione, that it i@s advantageous to start from a 3-methyl 3 alkoxy - 4 - oxa-!3p-ethylA 5(10),'(")-gonadiene 17 one, which is selectively br(>minated in the 11 position with a bromina-tion agent, and to dehydrobrominate the 11-bromo - 130-ethyl-4,5- 40 seco-Ag'-gonene - 3,5,17 - trione by the action of a basic agent, 13g-ethyl-4,5-secoA9@,11gonadiene - 3,5,17 - trione is obtained, which is cyclised by acting an alkaline agent in anhydrous medium and the desired 13,3-ethyl-A4,9,11gonatriene - 3,17-dione is isolated. 45 The selected bromination in the II position of 3 -methyl3-alkoxy - 4 - oxa - 13p - ethyl - A5(10),9(")-gonadiene17-one is effected by the action of N-bromosuccinimide and 'Lhe reaction is conducted in a polar organic solvent, such as formamide or dimethylformamide. 50 T4e dehydrobromination of the 11-brominated derivative is advantageously effected in situ without isolating intermediately the brominated derivative from the reaction medium. The basic agent used to effect this dehydrobromination, is preferably lithium carbonate and it 55 is advantageous to operate in the presence of a lithiurn halide, such as the chloride or bromide and in a polar organic solvent, such as formamide or dimethylformamide. When the dehydrobromination is effected in situ, it is convenient to proceed in the same solvent as that used 60 for the bromination. The alkaline a@-ent used to effect the cyclisation of the A ring of 13,8-ethyl-4,5-seco-A9,11-- nadiene-3,5,17-trione @o is, for example, an alkali metal lower alkanolate or an alkali metal hydroxide and the reaction is conducted in 65 an anhydrous meditim. The actually preferred cyclisation agent is potassium hydroxide, which is used in a methanolie m@-dium, but it is evident that other alkaline agents, such as caustic soda or an alkali rnetal lower alkanolate may also be suitable. 70 The following examples illustrate the invention both for the preparation of the pyranic alkoxy derivatives as for the applications of these derivatives for the preparation of physiologically active compounds. These examples, however, are not deemed to give to the inventioi any 75 limitative character.
[4]3@499@913 7 Exaniple,v of the preparatioiz of conipouizds of Foi-nittla I Example I.-Preparation of 3-methyl3-ethoxy-4-oxa, 17@-benzoyloxy-A5(10),9(")-estradiene 20 gm. of 17p-b--nzoyloxy-4,5-seco-A9-estrene-3 5-dione, a product described in French Patent No. 1,36@,556 '5 and in United States Patent No. 3,101,354, ai-e - introduced into 20 cc. of ethanol under an atmosphere of - nitro.-en. 0.005 gm. of para-toluene sulfonic acid is added. The mixture is stirred for 15 niinl@tes at room temperature 10 and 16 cc. of ethyl orthoformiate are introdLIced. The agitation is maintained for 2 hours at room temperature. Then the pH of the reaction modium is brought to 8.0 by addin@ triethylamine. The reaction mixture is poured into water and extracted with m-.thylene chloride. The 15 methylene chloride extracts are combined. The obtained organic solution is washed with water, dried and concentrated to dryness under reduced pressure and under an atmosphere of nitrogen to obtain 25.6 -m. of crude 3 - m2thyl - 3 - ethoxy-4-oxa-17,3-benzoylox y-A5('O)'9(11)- 20 esti-adiene, containing ethyi orthoformiate. As far as is known, this pi@odLiCt is not described in the literature. Example 2.-Preparation of 3-methyl-3 -methoxy-4-oxaA5(10),9(1 I)-estradiene- 17-one 25 4 gm. of 4,5-seco-A9-estrene-3,5,17-trione, a product described in French Patent No. 1,305,992, then 2.85 cc. of m,-thyl orthoformiate are introdLiCed into 4 cc. of methanol under an atmosphere of niti-ogen. The mixture is a-itated for 15 minutes at a temperature between 0 and +5' C. 0.001 gm. of paratoluene sulfonic acid is then introduced and the agitation is maintained for 15 hours at a temperature betweeii 0 and +5' C. The temperature of the reaction medilim is brought to 20' C. 35 and agitation is continued for 2 hours at this temperatu@-e. The pH of the reaction medium is then brought to 8.0 by addin- triethylamine. The whole is poured into water, extracted with methylene chloi-ide and the isolation is completed as in the preceding example. 40 Accordingly, 3 - methyl - 3 - methoxy-4-oxa -A5(10),9(11)- estradiene-17-one is obtained. As far as is known, this product is not described in the literature. Example 3.-Preparation of 3-methy l-3-ethoxy-4-oxa- 45 A5(10),9(")-estradiene-17-one 30 gm. of 4,5-seco-A9-estrene-3,5,17-trione, a prodtict described in French Patent No. 1,305,992, then 36 cc. of ethyl orthoformiate are introduced into 30 cc. of ethanol under an atmosphere of nitrogen. This mixture is 50 agitated for 15 minutes between 0 and +5' C. 0. gm. of para-toluene sulfonic acid is then introduced and the agitation is maintained for 16 hours at a temperature between O' and +5' C. Thereafter, the temperature of the reaction mixture is brought to +20', +25' C. and main- r)5 tained for 2 hours. The pH of the reaction medium is brou.-ht to 8.0 by adding triethylamine and the whole is poured into water and agitated for 15 minutes at room temperature. The aqueous mixture is extracted with methylene chloride, and the methylene chloride extracts are 60 combined. The obtained solution is washed with water and dried. To this methylene chloride solution, 30 gm. of magnesium silicate are added while a.-itating. The magnesitim silicate is filtered off and the solution is concentrated to dryness under reduced pressure under an at- 65 mosphere of nitro-en to obtain 35.4 gm. of crude 3-methyl-3-ethoxy-4-oxa-A5(10),9(")-estradiene-17-or,e, containing a small amount of ethyl orthoformiate. N.M.R. sp-@ctrum: 70 Methyl in 13 position-at 54 hz. Methyl of ethoxy groijping-triplet at 60-67-73.5 hz. Methyl i-@i the 3 position-at 86 hz. Methyl of ethoxy grotipin,,--qLiadrLiplet at 203-2 1 0- 217-226 hz, 75 8 As fir as is known, this product is not described in the literature. Example 4.-Preparation of 3-methyl-3-ethoxy-4-oxa13,6-ethyl-A5(10),9(")-,-Onadiene-17-one 11.6 gm. of 13p-ethyl-4,5 - seco - A9 - goriene-3,5,17trione are introduced at a temperature between 0 and +5' C. into a mixture of 11.6 cc. of ethanol and 13.8 cc. of ethyl orthoformiate. The mixture is agitatedfor 15 minittes. Then 2.8 mg. of paratoluene sulfonic acid are added. The agitation is maintained for 15 hours at a temperature between 0 and +5' C. under an atmosphere of nitrogen. The temperature of the reaction medium is brought to 20' C. and the whole is agitated for o@ie hour at 20' C. The pH of the reaction medium is brought to 8.0 by adding triethylamine. Water and methylene chloride are added and the mixture a.@itated. The organic phase is decanted off. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined with the main organic phase. The obtained methylene chloride solution is washed with water, dried and concentrated to dryness under reduced pressure. Thus, 13.4 gm. of 3-methyl - 3 - ethoxy-4-oxa-13pet hyl-A5(10),9(")-gonadiene-17-one are obtained. 1. R. spectrum: Presence of ketone in the 17 position Band at 1653 CM. -1 COTresponding to C=c-oPresence of C-0-C I As far as is known, this product is not described in th-. literature. The 13,3-ethyl - 4,5 - seco - A9-gonene-3,5,17-trione, used as starting material in the above example, is prepared in the following way: A sulfochromic acid solution is prepared by dissolving 27.5 gm. of chromic acid in a rnixture of 60.5 cc. of wafer an.d 20.6 cc. of an aqueous solution of 66' B6. sulfuric acid. On the other hand, 106 gm. of crude 13,3-ethyl-4,5seco - A9 - gonene - 17p-ol-3,5-dione, described in Belgian Patent No. 657,260 (an oily product obtained in paragraph 4 of stage F, after the acid hydrolysis, prior to the chromatography through magnesium silicate) are dissolved in 1,060 cc. of acetone, under an atmosphere of nitrogen. The solution is cooled to -10' C. and the previously prepared sulfochromic acid solution is introduced with agitation at -10' C. in about 15 minutes. The mixture is agitated for one hour at -10' C.; then a mixture -of 53 cc. of an aqueous solut-ion of 35' B6. sodium bisulfite and 159 cc. of water is intrdduced at a temperature between 0 and +5' C. The mixture is agitated for 15 minutes at a temperature between 0 and +5' C. Acetone is distilled off under reduced pressure and water is added. The aqueous phase is extracted with methylene cbloride. The extracts are combined and the obtained organic solution is washed with water, then with an aqueous solution of sodium bicarbonate, and finally with water. The organic solution is dried, concentrated to dryness under reduced pressure to obtain 98 gm. of crude product. This crude product is chromatographed through magnesium silicate. By elutin.- with methylene chloride, there is obtained a fraction which, after triturating in an ethyl etherisopropyl ether mixture provides a first yield of 27.5 gm. of crystals having a melting point of 85' to 86' C. The elution is continued with methylene chloride containing 0.5% of -methanol. The obtained solution is combined with the ethereal mother liquors of purification from the first yield and concentrated to dryness. The obtained residue is chromatographed through ma.-nesium silicate and, first, eluted with a benzene-eyelohexane mixture (1 to 2) so as to climinate an oily fraction, then with
[5]31499)913 9 methylene chloride containing 1% of methanol to provide a second fraction, which, purified by triturating in ether, provides a second yield of 7.3 gm. of crystals having a melting point of 85' to 86' C. When the elution is continlied with methylene chloride, a third fraction is abtained which, tipon purification bycrystallization from ether, provides a third yield of 13.66 gm. of crystals having a meltin.- point of 85 to 86' C. Accordingly, there are obtained, as a whole, 48.46 gm. of 13p - ethyl - 4,5 - seco-A9- gonene-3,5,17-trione, having a melting point of 85' to 86' C. and a specific rotation [CC]20D=+21'-I' (c.=1.1% in methanol). U. V. Spectrum (ethanol): X max. at 248-249 mg 6= 14,700. As far as is known, this product is not described in the literature. Example 5.-Preparation of 1,3 - dimethyl - 3 - etho xy4-oxa-17p-acetoxy-AB(10),9(")- estradiene Proceeding in the same manner as in Example 1, and starting from 1-methyl - 17,6 - acetoxy-4,5-seco-A9-estrene3,5 - dione there is obtained 1,3-dirnethyl-3-ethoxy-4- oxa179-acetoXy-A5(10),,9(")-estradiene. As far as is known, this product is not described in the literature. The starting product, 1-methyl 17p-acetoxy 4,5-secoA9estrene 3,5-dione, may be prepared as follows: 19.71 gm. of I-acetoxy 2-methyl 4-pentanone are treated with 44 cc. of a 40% aqueous solution of hydrobromic acid. The mixture is heated to 125' C. and distilled over. The aqueous phase is extracted with ether and the ether distilled off. 14.3 gm. of 1-bromo 2-,methyl 4-pentanone are obtained which, upon treatment with ethylene-glycol in the presence of p-toluenesulfonic acid gives 1-bromo 2-niethyl 4,4ethylene-dioxy pentane which appears in the form of a colorless liquid. Boiling point: 61' C. under 1.4 mm./H.-. 1-bromo 2-methyl 4,4-ethylenedioxy pentane, when submitted to the action of magnesium in tetrahydrofuran, gives a solution of the corresponding magnesiurn compound which is reacted with the a-lactone of dextrorotatory lo-acetoxy 4-(2'- carboxyethyl)-7a,o-methyl 3aa, 4#,7,7a-tetrahydroindane 5-ol, described in U.S. patent application Ser. No. 361,872 filed Apr. 22, 1964, now Pat. No. 3,413,314. By applying the process described in this patent application 1-methyl 17p-acetoxy-4,5-seco-@9 estrene 3,5-dione may be obtained. Example 6.-Preparation of 3,6a-dimethyl-3-ethoxy-4o xa-170-acetoxy-A5(10),9(")- estradiene Proceeding in the same manner as in Example 1, and startin- from 6a-methyl-17pacetoxy-4,5-seco--A9-estrene3,5-dione, described in C.R. 1967 (2), Serie C, p. 1396, there is obtained 3,6c&-dimethyl-3- ethoxy-4-oxa-17 C toXy-A5(lo) 3-ac - ,9(")-estradiene. As far as is known, this product is not described in the literature. Example 7.-Preparation of 3,7a-dimethyl-3-ethoxy-4- oxaA5(10),9(")-estradiene-17-one Proceeding in the same manner as in Example 3, and starting from 7a-methyl-4,5-secoA9-estrene-3,5,17-trionc, described in French Patent No. 1,456,779, there is obtained 3,7a-dimethyl-3-ethoxy-4-oxa - A5(10),9(11) - estra diene-17-one. As far as is known, this product is not described in the literature. Example 8.-Preparation of 2,3-dimethyl-3-ethoxy-4-o xa17p-benzoyloxy-A5(10),9(")- estradiene Proceeding in the same manner as in the Example 1, and starting from 2-methyl-170- benzoyloxy-4,5-seco-A9estrene-3,5-dione, described in French Patent No. 1,284,566, there is obtained 2,3-dimethyl-3-ethoxy-4-oxa-17gbe nzoyloxy-A5(10),9(")-estradiene. As far as is known, this product is not described in the literature. 10 Example 9.-Preparation of 3-methyl-3-etboxy-4-oxa13p-propyl-A5(10),9(")-gonadiene 17-one Using the process described in Example IV but starting from 13g-propyl-4,5-secoA9-gonene-3,5,17-trione, 3-methyl-3-ethoxy-4-oxa-130-propyl-A5(10),9(11) - gonadiene - 17one is obtained. Infrared spectra: Presence of 17 keto group Presence of a band at 1653 cm.-' corresponding to 10 the C=C-Ogroup 15 Presence of the -@-0- ICI 20 group. As far as is known, this compound is not described in the literature. The starting product, 13,6-prapyl-4,5-seco-A9-gonene-3,- 5,17-trione is prepared usirig the process described in Ex25 ample IV starting from 139-propyl-4,5-seco-A9--, onene17p-ol-3,5-dione described in the Belgian Patent 657,260. The 13p-propyl-4,5-seco-A9-gonene-3,5,17-trione melts at 109o C.; la]D 20=+311-21 (c.,=0.5% in methanol). As far as is known, this compound is not described in 30 the literature. EXAMPLES FOR THE USE OF COMPOUNDS OF FORMULAI Example 10.-Preparation of 17p-benzoyloxy-4,5-seco35 A9,11-estradiene-3,5-dione Stage A.-11-bromo-17p-benzoylbxy4,5-seco-A9-estrene-3,5-dione: 20 gm. of crude 3-methyl-3-ethoxy-4oxa-17)3-benzoyloxy-A5( lO),9(11)_estradiene, described in Example 1, then 15.5 gm. of anhydrous sodium acetate 40 are dissolved in 200 cc. of dimethylformamide under an inert atmosphere. 60 cc. of a 10% by weight solution of bromine in dimethylformamide are added over a period of about one hour with agitation. The agitation is then continued for 15 minutes at room temperature. The ob45 tained suspension is poured into a w;ater-ice-methylene chloride mixture. The suspension is stirred and the organic phase is decanted off. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined with the main organic solution. 50 Then, the obtained organic solution is m@ashed with water, then with an aqueous solution of sodium bicarbonate, and finally with water. The solution is dried and concentrated to dryness under reduced pressure, under an atmosphere of nitrogen. Isopropyl ether is added to the obtained resi55 due. The formed precipitate is filtered with suction to obtain 25 ' 6 gm. of crude 11- bromo-17p-benzoyloxy-4,5seco-A9-estrene-3,5-dione, used as such for the next stage. As far as is known, this product is not described in the literature. 60 Stage B-17p-benzoyloxy-4,5-seco-A9, 11-estradiene-3.5- dione: 20 gm. of anhydrous lithium bromide and 20 gm. of lithium carbonate are introduced under inert atmosphere into 300 cc. of dimethylforrnami.de. The temperature of the reaction mixture is brought to 95' C. and 65 25-65 gm. of crude 11-bromo-17p-benzoyloxy-4,5-s ecoA9-estrene-3,5-dione, suspended in 39 cc. of dimethylformamide are introduced. The reaction medium is agitated for 18 hours under inert atmosphere. The temperature of the reaction mixture is then brought to 20' C. and, 70 slowly, the mixture is poured into a wa.ter-ice-acetic acid mixture. Agitation is maintained for 30 minutes. Then the aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined. The combined organic solution is washed with water, then with 75 an aqueous solution of sodium bicarbonate and finally
[6]with water. The solution is dried, and 40 gm. of magnesium silicate are slowly added thereto. Agitation is continued for 30 minutes. The magnesium silicate is then filtered off and the solution is concentrated to dryness under reduced pressure under at atmosphere of nitrogen. Sulfuric ether is added to the obtained residue. With a.-itation, the temperature is maintained for 15 hours between O' C. and +5' C. The formed precipitate is ther, filtered off with suction and dried to obtain 3.98 gm. of 17pbenzoyloxy - 4,5 - seco--A9,11-estradiene-3,5-dione, having a melting point of 136' C. and a specific rotation la]D=-33'-3' (c.=0.5% ethanol). U.V. spectrum (ethanol): x max. 290 mA e=25,400. This product, when admixed with 17p-benzoyloxy-4,5s eco-A9,11-estradiene-3,5-dione, which is prepared according to the process described in French Patent No. 1,380,414, does not give a depression of the melting point. By cyclization in an alkaline medium according to the process described in French Patent 1,380,414, 17p-benz0yloxy-4,5-seco-A9,11-estradiene - 3,5 - dione provides 17pbenzoyloxy-A4,9,11-estratriene-3-one, described in the said patent. This triene compound is endowed with a high anabolizing and andro.-enic activity. Example I l.-Preparation of 17cc-ethynyl-A4,9-estra diene17g-ol-3-one ' State A.-3-methyl-3-ethoxy-4-oxa-17oc - ethynyl-A5(10),- 9(")-estradiene-17,3-ol: Acetylene is bubbled for 2 hours 20' C. through 142 cc. of a solution of sodium tert.amylate, containing 4.59 gm. of sodium per hundred cc. to fo.rm sodium acetylide. Thereafter, a solution of 30 gm. of crude 3 - methyl-3-ethoxy-4-oxa-A5('O),9(")-estradiene-17one, described in Example 3, in 68 cc. of toluene is introduced. The mixture is agitated for 4 hours at room temperature while bubbling acetylene therethrough. Then, the reaction medium is brought to +10' C. and a solution of 30 gm. of ammonium chloride in 120 cc. of water is slowly introduced under an atmosphere of nitrogen. The whole is agitated for one hour at room temperature. The toluene is then eliminated under reduced pressure under an atmosphere of nitrogen. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined and the obtained organic solution is washed with water, dried, decolorized with animal charcoal, concentrated to dryness under reduced pressure under an atmosphere of nitrogen to obtain 34.6 gm. of crude 3-methyl-3-ethoxy-4-oxa-17ctethynyl-A5(10),9(11)estradiene-17,6-ol, used as such for the following stage. As far as is known, this product is not described in the literature. Stage B.-17a-ethynyl-4,5-seco-A9-estrene - 17p-ol-3,5dione: 20 gm. of crude 3-methyl-3-ethoxy4-oxa-17cðynyl-A5(10),9(")-estradiene-17p-ol are dissolved in 120 cc. of acetone containing 20% of water by volume, under an atmosphere of nitrogen. 20 cc. of an aqueous solution of 2N hydrochloric acid are added and the solution is agitated for 21/2 hours at room temperature. The pH of the reaction medium is then brought to 8.0 to 8.5 by adding an aqueous solution of sodium bicarbonate The acetone is distilled off under reduced pressure and'the aqueous phase extracted with methylene chloride. The methylene chloride extracts are combined. The obtained organic solution is washed with water, dried, and 20 gm. of ma.-nesium silicate are slowly added thereto, then filtered off The obtained solution is concentrated to dryness under reduced pressure and under an atmosphere of nitrogen. The residue is admixed with sulfuiie ether, taken to reflux for 15 minutes, cooled between 0 and +5' C. and filtered with suction to obtain 5.88 gm. of 17ocethynyl4,5-seco-A9-estrene-17,6-ol-3,5-dione having a melting point of 124' C. and a specific rotation [OCID@-73'-+-2.5' (c.=0.6% in methanol). U-5. spectrLIM (ethanol): X max at 248 to 249 mli c= 15,000. 3)499)913 12 This product, admixed with 17a-ethynyl-4,5-seco-A9e strene-17p-ol-3,5-dione, which is obtained accordin- to the process described in French Patent 1,497,593, does not give any depression of the melting point. Stage C.-17a - ethynyl - A4,9-estradiene-17p-ol-3-one: 0.600- gm. of 17cc-ethynyl-4,5-seco-A9-estrene-17p-ol-3,5dione are introduced into 2.2 cc. of benzene under an inert atmosphere. Then, attemperatures between O' C. and +3' C., and in 20 minutes, 1.4 cc. of a solution of sodium 10 tert.-amylate in toluene, containing 2.45 gm. of sodium per hundred cc., are added thereto. The whole is agitated for 2 hours, while maintaining the temperature in the above-mentioned range. Thereafter one cc. of benzene, then a mixture of 0.3 cc. of tert.butyl alcohol and 15 0.5 cc. of benzene is added. The temperature is allowed to rise to 20' C. and the whole is agitated for one hour at this temperature. Tfie pH is adjusted to 7 by adding a benzene solution of acetic acid. The mixture is agitated for 45 minutes and water is then added. The solvents are 20 eliminated under reduced pressure. The precipitate formed is filtered with suction, washed and dried, to obtain 570 M,-. of a product melting at 178' C. This @product is purified by crystallization from ethyl acetate to obtain 416 mg. of 17a-ethylA4,9-estradiene25 17,3-ol-3-one, havin.- a melting point of 183' C. and a specific rotation [ UID=355' (c.=0.2% in methanol). U.V. spectrtim (ethanol): Xmax. at 215 mg E=5,850 30 infl. 235-236 mg e=4,590 infl. 247 mg C=3,550 Xmax. at 304 mlk E=20,000 This preparation of 17a-ethynyl-A4,9-estrad iene-17,6-ol35 3-one is described in French Patent 1,497,593. From the thus prepared 17a-ethynyl-A4,9-estradiene17)3-ol-3-one, there is obtained, by applying the Process which is described in U.S. Patent 3,136,790; 17cz-ethynylA5(10)- estrene-l7j3-ol-3-one, which is a well knowd pro.@es40 tative agent. Example 12.-Preparation of 13g-ethyl-17cx-ethynyl-A4,9- gonadiene-17g-ol-3-one 45 Stage A.-3-methyl-3-ethoxy-4-oxa-13pethyl-17,x-ethynyl-A5(10),9(")-gonadiene-17p-ol: Acetylene is bubbled for 2 hours at room temperattire through 61 cc. of a toluene solution of sodium tert.-amylate containin- 2.7 @m. of sodium per hundred cc., so as to form sodium acetylide. 50 A solution of 4 @m. of 3-methyl-3-ethoxy-4-oxa-1 3,3ethyl-A5(10),9(")-gonadiene-17-one, prepared accordin,@ to Example 4, in 8 cc. of toluene, is slowly introduced. The mixture is then agitated for 6 hours at room temperature while bubbling acetylene therethrough. The temperature 55 of the reaction medium is brought to +10' C. and a solution of 4 gm. of ammonium chloride in 16 cc. of water is slowly introduced, without exceedin- a temperature of +15' C. The solution is then agitated for 30 minutes under an atmosphere of nitrogen. Toluene is dis60 tilled off under reduced pressure and under an atmosphere of nitrogen. The aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined; the combined organic solution is washed with 65 water, dried, decolorized with animal charcoal and concentrated to dryness under reduced pressure and under an atniosphere of nitrogen to obtain 4.21 gm. of crude 3 - methyl - 3 - ethoxy - 4 - oxa - 13,3 - ethyl - 17a - ethynyl@A5(10),9(")-gonadiene-17p-ol, used as such for the next stage. 70 As far as is known, this product is not described in the literature. Stage B.-13p-ethyl-17v.-ethynyl - 4,5-seoo-A9-gonene17,6-ol-3,5-dione: 0.6 am. of crude 3-methyl-3-ethoxy-4- 75 oxa-13,6-ethyl-17(x-ethynyl-A5(10),9(")-,alonadiene-l7i3-ol is
[7]3)4991913 13 dissolved in 3.6 cc. of acetone containing 20% of water by volume, under an atmosph.-re of nitrogen. 0.6 cc. of an aqueoi-,s soltition of 2 N hydrochloric acid is added. The mixttire is agitaled for 4 hours at room temperature and, thereaf,ler, the reaction mixture is slowly poured into 5 water. The. aqueous phase is extracted with methylene chloride. The methylene chloride extracts are combined. The obtained organic solution is was@ed with water, then with an aqueous solution of sodium bicarbonate and finally with water. The solution is dried. 1.2 gm. of mag10 nesium silicate is slowly added with agitation. The magnesium silicate is then filtered off and the solution is concentrated to dryness under reduced pressure and under an atmosrhere of nitrogen. The residue is admixed with ethyl ether and cooled to O' to +5' C. The precipitate 1,5 formed is filt-,red with suction and dried to obtain 0.12 gm. of 13p-ethyl-17a-ethynyl-4,5-seco -A9-gonene-17g-ol3,5-dione, having a melting point of 128' to 129' C. A sample of this product crystallized from ethyl ether has a melting point of 129'-130' C. and a specific rc>ta20 tion [-]D=-951-2' (c.=l% in methanol). Analysi.g.-Calculated fOr C2lH2803 (percent), molecular weight@328.43: C, 76.79; H, 8.59. Found (percent): C, 77. 1; H, 8.9. U.V. spectrum (ethanol): 25 Nmax. at 249 mu e= 14,900. As far as is known, this product is not described in the literature. 30 Stage C.-13p-ethyl-17a-elhynyl-A4,9-g onadiene-17g-ol3-one: From 13p-ethyl-17a-ethynyl-4, 5-seco-A9-,-Onene17g-ol-3,5-dione and proceeding according to the process which is described in French Patent 1,497,593, that is, by using a mode of operation similar to that of Stage C 35 in Example 11, there is obtained 13petbyl-17a-ethynylA4,9-gonad;eiie-17p-ol-3-one, havidg a melting point of 130' C. 'and a specific rotation - la]D=-368'-4' (c.=4.5% in methanol). 40 U.V. spectrum (ethanol): Xmax. at 306 mA e=20,700 infl. at 235 mA E=4,850 From the thus prepared 13p-ethyl-17 ci-ethynyl-A4,9- 45 gonadiene-17p-ol-3-one, there is obtained, by applying the process which is described in U.S. Patent 3,136,790, 13p-ethyl-17ot-ethynyl-A5(10)-gonene-17p-ol-3-one, which is a very active progestomimetic a,-ent. Example 13.-Preparation of 13p-ethyl-A4 ,9,11-,-onatriene50 3,17-dione Stage A.-13j3-ethyl-4,5-seco-Ag,"-g onadiene-3,5,17- trione: 13.4 gm. of 3-methyl-3-ethox y-4-oxa-13g-ethylA5(10),9(")-gonadiene-17-one, described in Example 4, 55 are dissolved in a mixture of 38 cc. of dimethylformamide and 0.8 cc. of water, under an inert atmosphere. Then, N-bromosuccinimide (about 6.4 gm.) is introduced at a temperature between O' and +5' C., until obtention of a slight excess of bromine, wbich is detectable with starch60 potassium iodide paper. The mixture is agitated for a furth,z@r 15 minutes at a temperature between O' and +5' C. The obtained 11-bromo-13,6-ethyl-4 ,5-seco-A9-gonene3,5,17-trione is not isolated from the reaction meditim. 6.33 gm. of lithium carbonate and 3.16 gm. of lithium 65 bromide are added to the reaction medium. The temperature of the reaction medium is then raised to 95' C. over a period of approximately 30 minutes. Then, the whole is agitated at 95' C. under an inert atmosphere for 3 70 hours. The reaction mixture is cooled to 20' C. and slowly poured into a water-ice-acetic acid mixture. The formed precipitate is extracted with methylene chloride. The methylene chloride extracts are combined, and the obtained organic solution is washed with water and dried. 75 14 To the obtained solution, 25 gm. of @magnesium silicate are slowly added with agitation, and the solution is agitated for a further 15 minutes. Then, the magnesium silicate is filtered off and the solution is concentrated to dryness under reduced pressure under an atmosphere of nitrogen. The residue obtained is admixed with ethyl ether, taken to reflux, then cooled to between O' and +5' C. The formed precipitate is filtered with suction to obtain 6.95 gm. of 13p-ethyl-4,5-se co-A9,11-gonadiene-3,5,17trione, having a melting point of 128' C. A sample of this product purified by crystallizing from methanol has a melting point of 129' to 130' C. and a specific rotation IUID=-64'-1.5' (c.=l% in methanol). Analysis.-Calculated for Cl9H2403 (percent), molecular weight=300.38: C, 75.96; H, 8.05. Found (percent): C, 75.8; H, 8.1. U.V. spectrum (ethanol): Xmax. at 290 m/i e=23.800. As far as is known, 11-bromo-13#-ethyl-4,5-seco-A9g onene-3,5,17-trione and 13,6- ethyl-4,5-seco-A9,11-gonadiene-3 5,17-trione are not described in the literature. Stage B.-13,6-ethyl-A4,9,11-gonatriene-3,17-dione: I gm. of 13,3-ethyl-4,5-seco-A9,11- gonadiene-3,5,17-trione is introduced, under an inert atmosphere, into 8 cc. of a methanolic solution of potassium hydroxide, containing 5 gm. per hundred cc. and previously freed. from oxygen by bubbling an inert gas therethrough. Th.e reaction mixture is agitated for an hour and a half at 25o to 30' C. Then, the reaction mixture is neutralized by adding acetic acid and poured into a water-ice-mixture. The formed precipitate is filtered with suction, washed and dried to obtain 0.89 gm. of 13,e-ethylA4,9,11-gonatriene-3,17-dione, having a melting point of 140' C. and a specific rotation la]D=+200'-3.5' (c.=0.5% in chloroform). A sample of this product purified by crystallization form ethanol has a melting point of 145' C. and a specific rotation IC&ID 20=+202' (c.=0.54% in chloroform). U.V. spectrum (ethanol). xmax. at 339 mA e=29,550. This product is identical to that obtained in Belgian Patent No. 674,178 and U.S. patent application Ser. No. 517,061 filed Dec. 28, 1965, now Patent No. 3,453,267. From the 13#-ethyl-A4,9,11-gonatriene-3,17-dione thus prepared, there is obtained, by applying the process which is described in Belgian Patent No. 679,368, the 13#- ethyl17a-ethynyl-A4,9,11-gonatriene-17p-ol-3-one, which is a -strongly active progestomimetic agent. Example 14.-Preparation of 13,8-propyl-A4,9,11gonat riene-3,17-dione Using the process described in Example 13, Stage A, first by subjecting the 3-methyl-3- etboxy-4-oxa-13j3-propylA6(10),9(")-gonadiene-17-one, obtained in Example 9, to selective bromination in position 11, 11@bromo-13ppropyl-4,5-seco-A9-gonene-3,5,17- trione is obtained, then by dehydrobromination with a basic agent, 13j3-propyl-4,5secoA9,11-gonadiene-3,5,17-trione is obtained, F.=89' C. [OCID 20@-59'5-1'5 (c.=0.95% in m@ethanol). As far as is known, 11-bromo-13,6-propyl-4,5-secoA9 -gonen-3,5,17-trione and 13,3- propyl-4,5-seco-A9,11-gonadiene3,5,17-trione are not described in the literature. Then, using the process described in Example 13, Stage B, but starting from 13,8- propyl-4,5-seco-A9,11-gonadiene3,5,17-trione, 13,6 - propyl-A4,9,11-gonatriene-3,17- dione is obtained, F.@125- C., la]D'O=+250'-3' (c.@1%, methanol). This product is identical to that described in the Belgian Patent 664,389. The preceding specific embodiments are illustrative of the practice of the invention. It is to be understood, however, that other expedients known to those skilled in the art may be employed without departing from the spirit of the invention,
