[1]United States Patent Office 39305@566 3,305,566 16-METIIYL-6a,9ce-DINALO-21- DESOXY CO@.IITICOIDS la'ov,7ard S. Ringold and Carl Djerassi, Mexico City, Mexico, assignoxs, by mesne assignments, to Syntex Corpora@le'l, a corporation of Panama No Drawing. Filed Apr. 28, 1960, Ser. No. 25,198 Clmms priority, application Mexico, May 18, 1959, 54,598 9 CWnis. (Cl. 260-397.45) The presert invention relates to ncrvel cyclopentano-, phenar@threne derivatives. More particularly, the present invention relates to new derivatives of A4-pregnen-17a-ol-3,20-dione haviii.- in its molecule a halo.-en atom such as chlorine or fluorine at C-9c, and at C-6, an oxynn ftiiiction such as keto or g-hydroxy at C-11, and an a-methyl or p-methyl group at C-16. Moreover, there may be present in the raoleclile double bonds at C-1,2 and/or C-6,7. These new compounds show a strong anti-inflammatory effect, particularly on topical administration, and are represented by the following general formulas: CH3 CHS I @=0 u=O 0 I-T 0 H y - R y/l - R x x z z IV IVA In the above formulas, Z indicates a saturated linkage or a double bond between C-1 and C-2; X and X' represent chlorine or fluorine; Y represents keto or p-hyd,-oxy; and R is a methyl group in ce or p steric configuration. The new compounds IV of this invention wherein X' is fluorine may be prepared by a process illustrated by the follo,@vin.- reaction diagrani: C@II20H CH@-0 S.Cff3 @@o '6 OH Y/\ R y -R x z O', z @rx 0 C 113 C H21 1 1 U=u U@u Oil (H Y//,\ R y R x x z z 0 IV Patented Feb. 21, 1967 2 When a 6-dehydro or 1,6-bis-dehydro compound is utilized as the startin- mater;al, the following equation serves to illustrate the course of the reaction: 5 0 CH20H 1 C=C) @=0 0 1.... . O H I.... .OH I,/\ - R y -R 10 x x z z 0 15 IA II A I 20 C Hs C H2I I I U= O U= U ""'OH 1..... OH y R y X @X 25 z z 0 0 30 IVA IIIA In these reactions Z, X, X', Y and R have the same significance as hereinabove set forth. 35 For transforming the 17-ketol side chain of such starting compounds into the 17p-acetyl group, that is, for producing the desired final compounds, there was first formed 21-mesylate (11) by reaction with methanesulfonyl oi-ide in pyridine; the mesylate group was then substitut40 ed by iodine by reaction with sodium iodide in mixture i,/ith acetone, and finally the resulting 21-iodo-compound (111) was transformed into the 17@-acetyl-compound (IV) by refluxin.@ with sodium bisulfite in mixture with aqueous methanol, or by reaction with chromous ch-loride in ace45 tone. I-lowever where the staiting compounds contained the 6-chloro-A4-3-keto-grouping, it was necessary to protect the chlorine atom at C-6 prior to traiisformation of the 17,6-ketol side chain into the 17,6-acetyl group. This was 50 accomplished by reacting the 6(a or p)- chloro-9a-halo(chloro or fluoro)-11-(keto or 3-hydroxy)-16(a or 3)methyl - A4 - pregnene - 17a,21 - diol - 3,20 - diones 21acetate with ethyl orthoformate for 1 hour at room temperature in a solvent such as dioxane and in the presence 55 of p-toluenesiilfonic acid to form the 3-ethyl enol ether derivative. Tle ester group at C-21 was hydrolyzed as by treatment with 1% methanolic potassium hydroxide at O' C. and the resulting 21-hydroxy compound was then transformed sequentiafly iiito the 21-mesylate, the 60 21-iodo and finally into the 21-desoxy compound as hereinabove set forth. Upon subsequent treatment with a mineral acid, such as dilute hydrochloric acid in acetic acid, at room temperature, the enol ether group was hydrolyzed to regenerate the A4-3-keto group, thus affording 65 the corresponding 6m-ch-loro-9a-halo (fluoro or chloro)16 (a or p)-methyl-A4-pre-nene compound. A double bond may then be introduced at C-1,2 by refluxing with selenium dioxide, preferably in tertiary butanol, irl the presence of pyridine and under an atmosphere of ni70 trogen for 48 hours, or a double bond may then be introduced at C-6,7 by refluxing with chloranil preferably in mixture with ethyl acetate and acetic acid or in mixture
[2]3,305,566 3 4 with xylene or tertiary butyl alcohol. By a combination Thus for example, instead of the 21-mesylate, there was of these methods or by refluxing the A4 compound with prepared the 21-tosylate; a 21-alkyl (aryl)-sulfonate chloranil in n-amyl alcohol, there was obtained the may be converted in only one step into the desired 21- Al,4,6-trienes. desoxy compound by refluxing with sodium iodide in Protection of the chlorine atom at C-6 was not neces- 5 mixture with acetic acid. sary when the 6-dehydro or 1,6-bisdehydro compoiind The following examples serve to - illustrate but are not sei-ved as the starting compound. intended to limit the scope of the invention: Thus the preparation of the novel compounds IV of the present invention wherein X' is chlorine may be illustrated Example I by the following reaction equation: 10 A solution of 5 g. of 16(x-methyl-6m, 9oc-difluoroCII20 Acetyl CH20 Acetyl I I L;=O U@U I..... OH OH Yr -R Y/,^\ -R X X x 0 ETO el C112-0-S-CHo CH3011 I C=O ..... OH OH R x Yrx @nETO ETO CH21 CHI I I u@O 01-1 OH y/\ -R -R I x x ETO ETO ci I CH2 CH2 I I u@O C=O OH I.... OH Y//,\ - R y/\ x x 01\// 0 Oi ci In practicing the process according to the above recortisone described in copending application Serial No. action equations, there were used as starting materials the 789,242 filed on January 27, 1959, in 100 cc. of a mix6-halo (fluoro or chloro)-9a-halo (chloro or iluoro)-Ilture of pyridine and chloroform (9:1) was cooled to (keto or p-hydroxy) 16(u. or - p)-methyl-A4-pregnene17a, O' C. Under stirring there was added batchwise 1.3 g. 21-diol-3,20-diones and their 1-dehydro, 6-dehydro and 70 of methanesulfonyl chloride, the mixture was kept for 1,6-bisdehydro derivatives, as hereinafter more fully de14 hours at O' C., diluted with 100 cc. of chloroform, scribed. washed with dilute hydrochloric acid, water, aqueous The reactions may be modified within wide limits both sodium bicarbonate solution and again with water, dried with respect to the reagents and solvents employed as over anhydrous sodium sulfate and the solvent was with respect to the conditions of temperature and time. 75 evaporated under reduced pressure. Thus there was ob-
[3]tained the crude 21-mesylate of 16Lx-met hyl-6a,9a-difluoro-cortisone. A solution of the crude compound in 200 cc. of acetone was treated with 3 g. of. sodium iodide and refluxed for 2 hours. Most of the acetone was removed 5 by distillation, the residue was diluted with water and the precipitate formed was collected by filtration, washed with water and dried under vacuum. There was thus obtained crude 16a - methyl-6a,9v,-difluor o-21-iodo-A4- pregnen-17a-ol-3,11,20- trione. 10 To a solution of this iodo-compound in 200 cc. of methanol and 20 cc. of water was added 5 g. of sodium bisulfite and the mixture was mfluxed for 2 hours. Most of the rnethanol was removed by distillation under reduced pres.,ure, the residue was diluted with water and 15 the prccipitate was collected, washed with water, dried and recrystallized from acetone-hexane. There was thus ,obtained 16a - methyl-6a,9a-difluoro-A4-pr egnen-17a-ol3,11,20-trione. Example II 20 By the method of Example 1, but employing p-toluenesulfonyl chloride instead of methanesulfonyl chloride, there was prepared the 21-tosylate of 16amethyl-6a,9adifluorocortisone. 2 5 A solution of 2.5 g. of the above compound in 100 cc. of glacial acetic acid was treated with 7 g. of sodium iodide and the mixture was refluxed for 2 hours, poured into ice water and extracted several times with methylene chloride; the extracts were combined, washed successive30 ly with aqueous sodium carbonate solution, sodium sulfite solution and water and then evaporated. By - crystallization of the residue from acetone-hexane there was obtained 16a - methyl-6cz,9cz-difluoro-A4-pregnen-17a-ol3,11,20-trione, identical with the one prepared in ac- 55 cordance with Example 1. Example III A mixture of 5 g. of 16oc-methyl-6a,9a-difluoro-cortisone 21-acetate, 8 g. of chloranil and 200 cc. of xylene 40 was refluxed for 12 hours, cooled and diluted with ether. The solution was washed with water, 5% sodium carbonate solution and again with water to neutral, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure. By chromatography of the residue on neutral alumina there was obtained 16m45 methyl-6,9a-difluoro-6-dehydro-cortis-one 21-acetate. A suspension of I g. of 16a-methyl-6,9a-difluoro-6- dehydro-cortisone 21-acetate in 10 cc. of absolute methanol was treated with 10 cc. of a s,olution of sodiuni methoxide in absolute methanol (prepared by dissolving 50 60 mg. of sodiu-m metal in 10 cc. of a@bsoltite methanol), with stirring, under an atmosphere of nitrogen, at O' C. for I hour. After precipitating with saturated aqueous sodium chloride solution containing a few drops of acetic acid, the product was filtered, and re crystallized 55 from acetone-hexane, thus affording the free 16ce-methyl6,9a-difluoro-6-dehydro-cortisone. In accordance with the methods of Examples I and IL the 16ce-methyl-6,9a-difluoro-6-dehydro-cortisone was converted into 16a-methyl-6,9a-difluoro-A4,6-pregnadien60 17.-ol-3,11,20-trione. A mixture of 2.0 g. of the latter compound, 100 cc. of t-butanol, 300 mg. of selenium dioxide and 0.2 cc. of pyridine was refluxed under an atmospbere of nitrogen for 48 bours, filtered through celite and the filtrate was @5 evaporated to dryness under reduced pressure. The residue was refluxed for I hour with decolorizing charcoal in acetone, filtered frbm the charcoal and the filtrate was evaporated to dryness. Chromatography of the residue on washed alumina yielded 16a-methyl-6,9a-difluoro70 Al,4,6-pregnatrien-17a-ol-3,11,20-trione. Example IV In accordance with the methods described in Examples I and II, 16a-methyl-6a-fluoro-9a-chloro-cortisone, 16cc- 75 methyl-6(x-fluoro-9,x-chloro-hydrocortisone, 16a. - methyl6(x-fluoro-9a-chloroprednisone, 16a-methyl-6a-Ruoro-9cechloro-prednisolone, 16a - methyl - 6a,9adifluoro-hydrocortisone, 16a-methyl-6a,9a-difiuoro-prednisolone, and 16a-luethyl6oc,9a-difluoro-prednisone, described in copendin,a application Serial No. 789,242, filed oii January 27, 1959, were -convel-ted into the correspoidiiig 21desoxy com-oounds, i.e., 16a-methyl-6a-fluoro-9o@-chloroA4-pregnene-17a-ol-3,11,20-trione; 16a-methyl6m-fluoro9oc-chloro-_A4-pregnene-llg,17a - diol - 3,20 - dione; 16CL,methyl-6u.-fluoro9a-chloro-AI,4-pre.-nadien-17a - ol - 3,1 1, 20-trione; 16a - methyl-6a-Ruoro-9czchloro-AI,4-pre-nadiene-11,3,17a-diol-3,20-dione; 16,x - methyl-6a,9a-difluoroA4- pregnene-11,3,17a-diol-3,20-dio@ie; 16a - methyl-6a ,9ccdifluoro-AI,4-pre.-nene11,0,17o6-diol-3,20-dione and 16amethyl-6u,9m-diflu oro-AI,4-pregnadien-17(x - ol - 3,11,20trione. Exan7ple V In accordance with the method of Example 111, 16aM-thyl -6a,9a-difluoro-hydrocortisone, 16a-methyl-6 a,9adifluoro-prednisone, 16ce-methyl6a,9,x-diflLioro-orednisolone, 16cx-methyl-6a-Ruoro -9a-chloro-cortisone, f6.-methyl6a-fluoro-9m-chloro-hydrocortisone, 16a - methyl - 6cxfluoro-9a-chloro-prednisone and 16oc-methyl-6a-fluoro-9achloro-prednisolone were converted into the corresponding 6-fluoro-6-dehydro compounds and then by the methods described in Examples I and 11 were fiiially converted into the corresponding 2 1-desoxy-compoi-inds, i.e., 16amethyl-6,9a-difluoro-A4,6-pregiiadiene-llg,17a-diol - 3,20dione, 16ix-methyl-6,9adifluoro-AI,4,6-pregnatrien-17a-ol3,11,20-trione (identical with the one produced in Example III), 16m-methyl-6,9(x-diflLioro-AI,4,6-pre gnatrienellp,17a-diol-3,20-dione, 16oL - methyl-6-fluoro-9u--chloroA4,6-pregnadien-17,6-ol-3,11,20-trione, 16a-methyl-6-fluoro9a-chloroA4,6-pregnadiene-llg,17a-diol-3,20-dione, 16amethyl - 6 - fluoro-9a-chloro-AI,4,6-pregnitriene17a-ol-3, 11,20-trione and 16,x-methyl-6-fluoro-9uchloro-AI,4,6-llp, 17a-diol-3,20-dione. Example VI A mixture of 5 g. of the 21-acetate of 16a-methyl-6 achloro-9u,-fluoro-cortisone, described in our copending application Serial No. 825,665, filed on July 8, 1959, now abandoned, 5 cc. of ethyl orthoformate, 50 cc. of d,'@oxane and 500 mg. of ptoluenesulfonic acid monohydrate was stirred at room temperature for 1 hour; 50 cc. of pyridine was then added followed by the portionwise addition of ice water, under stirring and until complete precipitation of the reaction product. The mixture was kept in the refrigerator for 2 hours and the precipitate was -collected by filtration, washed with water, dried @and recrystallized from acetone-hexane; there were thiis obtained 16amethyl - 6-chloro-9(x-fluoro-3-ethoxy-21-acetoxy -A3,5-pregnadien-17ce-ol-11,20-dione, namely the 3-ethyl-enol ether of the 21-acetate of 16a-met hyl-6-chloro-9a-fluoro-cortisone. In order to obtain the enol ether compound with the free 21-hydroxyl group, the steroid was treated with 1% methanolic potassium hydroxide solution for I hour at O' C. and under an,atmosphere of nitrogen, usin.- 50 cc. of the methanolic potassium hydroxide solution for I g. of the steroid. The mixture was then nei-itralized with acetic aci , -concentrate un er re uced pressure, di uted with water and the precipitate was collected byfiltration and purified by recrystallization from acetone-hexane. A solution of 5 g. of 16a-methyl-6-chloro-9m-fluoro -3ethoxy-A3,5-pregnadiene-17a,21-diol-11,20- dione in 50 cc. of pyridine was treated with 3 cc. of methanesulfonyl chloride at O' C. and kept ovemight at this temperature, then poured into ice water and the precipitate was -collected, washed with water and dried. There was thus obtained the 21-mesylate of 16oe-methyl-6-chloro-9afluoro - 3 - ethoxy-A3,5-pregnadiene-17a,21-diol-11,20-dione, which was used for the next step without further purification.
[4]7 A solution of the above compound in 200 cc. of acetone was mixed with 3 g. of sodium iodide and refluxed for 2 hours. Most of the acetone was then removed by distillation, the residue was diltited with water and the precipitate was collected, washed with water and dried. There was thus obtained 16m-methy l-6-chloro-9a-fluoro21-iodo-3- ethoxy-A3,5-pregnadien-17a-ol - 11,20 - dione in crude form, which was dissolved in 200 cc. of methanol and 20 cc. of water; 5 cc. of sodium bisulfite was added and the mixture was refluxed for 2 hours. Most of the methanol was reinoved by distillation under reduced pressure, the residue was diluted with water and the precipitate was collected, washed with water and then treated with 2 cc. of concentrated hydrochloric acid in 200 -cc. of glacial acetic acid, kept at room temperature for 2 hours and diluted with ice-water. There was thus obtained 16(x - met hyl-6a-chloro-9(x-fluoro-A4- pregnene-17aol-3,11,20-trione which was purified by recrystallization from acetonehexane. A mixture of I -. of the above comi)ound, 2 9. Of chloranil, 25 cc. of ethyl acetate and 5 cc. of glacial acetic acid was refluxed under an atmosphere of nitrogen for 72 hours; the cooled mixture was washed with aqueous 10% sodium hydroxide solution until the washings were colorless, drie-d over anhydroi-,s sodium sulfate and the ethyl acetate was evai)oraied, Chromatography of the residue on neutral alumina yielded 16amethyl-6-cWoro9m-fluoro-A4,6-pre.@Dadiene-17o:-ol-3 ,11,20-trione. A mixttire of 500 m@@. of the above -compound, 300 mg. of selenium dioxide, 20 cc. of t-butanol and a few drops of pyridine was refluxed for IS hours under an atmosphere of nitrogen and then filtered through celite and diluted with water; the precipitate was collected, washed with water, dried and purifed by chromatography on neutral alumina. There was thus obtained 16a-methyl-6-chlo ro9m-fluoro-AI,4,6-pregnatrien17,x-ol-3,11,20-trione. 1 -. of 16m-methyl-6ce-chloro-9ot-fltioro-,\4-pregn en-17aol-3,11,20-trione (see above) was subjected to the metl-iod of dehydro.-enation with selenium dioxide described above, to produce 16a-methyl-6a-chloro-9a-fluoro-AI ,4pre.-nadiene-17a-ol-3,11,20- trione which was then subjected to the reaction with chloranil described above@ to furnish finally 16oc-methyl-6-chloro-9a-fluoro-Al,4 ,6-pregnatrien-17cc-ol-3,11,20- trione, identical with the one produced by dehydro.@enation of the A4-com@ound at C-6,7 and then at C-1,2. Exai?iple VII in accordance with the method described in the preceding example, there were prepared the 21- acetates of the 3-ethyl enol etliers of 16a-niethyl -6-chloro-9a-fluorohydrocortisone, 16oc-methyl6,9a-dichloro - cortisone and 16m-methyl - 6,9m - d ichloro-hydrocortisone (disclosed in our copendin- application Serial No. 825,665), which were converted into the free C-21 alcohols and subsequently into the corresponding 16a-methyl-6a-c hloro-9ocfluoro-A4-pregnene-llp,17oc-diol3,20-dione, 16a - methyl6.,9a-dichlorOA4-pregnen-17 a-ol-3,11,20-trione and 16aniethyl - 6oc,9u - dichloro-A4-p.-egnene-llp,17a-diol-3,20dione. By treatment with selenium dioxide as set forth in the preceding example, the latter compounds were transformed into the corresponding 1-dehydro compounds, Nvhich upon future treatment with chloranil as set forth in the precediii.- example were converted into the correspondl:ng 1,6- bisdehydro compounds, i.e., 1,6a-methyl-6chloro-9afluoro-AI,4,6-pre@natriene-11,3,17cx - diol - 3,20@dio@-ie, 16cc-methyl-6,9a-dichloro-AI,4,6-preg natrien-17a-ol3,11,20-trione, and 16amethyl-6,9m-dichloro-A',4,6-pregnatriene-llp,17oc-d iol-3,20-dione. The 6-dehydro compounds of 16ce-methyl-6a-chloro9afluoro-A4-pre.-nene-il@,17a-diol - 3,20 - dione, of 16aniethyl-6m,9m-dichloro-A4-pregnen - 17a -- ol-3,11,20-trione .and of 16a-methyl6cc,9,(x-dichl -A4-pre-riene - llp,17(x3,305,566 8 diol-3,20-dione were prepared in accordance with the niethod described in the precedin- example. Example VIII 5 In accordance with the method described in Example VI, 16p-methyl-6a-chloro9a-fluoro-cortisone, 16,8-methyl6a-chloro - 9a - fl uoro-hydrocortisone, 16p-methyl6m,9a10 dichloro-cortisone and 16p-methyl-6a,9a-dichloro -hydrocortisone described in copending applications Serial No. 824,200, filed July 1, 1959, now abandoned, and Serial No. 826,120 filed July 10, 1959 were converted by the method described in such example into the correspond15 in-, 21-desoxy compounds, i.e., 16@-methyl-6m-ch loro-9ceflUoro-A4-pregnen17a-ol-3,11,20-trione, 16,3 - methyl-6achloro - 9a _ flUoro-A4-pregnene-llp,17a-diol-3,20-dione, 16g-methyl-6a,9v.-dichloro-A4-pregnen - 17m - ol-3,11,20- trioiie and 16p - methyl-6a,9a-dichloro-A4-pregnene-llp, 20 17a-diol-3,20-dione, and finally into their 6-dehydro, 1dehydro and 1,6-bisdehydro derivatives. Example IX 25, By substituting 16g-methyl-6oc-fluoro-9a-halo (fluoro or chloro) cortisone, 16@- methyl-6cx-fluoro-9a-halo (fluoro or chloro)-hydrocortisone, 16p-methyl-6a-fluoro9a,-halo (fluoro or chloro) prednisone, 16p-methyl6a-fluoro-9a30 halo (fluoro or chloro) prednisolone, disclosed in copending application Serial No. 792,962, filed on February 13, 1959, now abandoned, and the 6-dehydro derivat'@Ves of the foregoing compounds, disclosed in copending application Serial No. 826,120 filed on July 10, 35 1959, for the startin.@ material of Examples I and 11, there were obtaiiied the corresponding 21-desoxy compounds such as 16p-methy l-6a--fluoro-9ce-chloroA4-pregnen-17aol-3,11,20-trione, 16p-methyl-6a-fluoro - 9a - chloroA4pre.@nene-llg,17m-diol-3,20 - dione, 16p-mcthyl-6a-fluoro40 9a-chloro-Al,4-pregnadien - 17a - ol - 3,11,20-trione, 16pmethyl - 6a - ffuoro-9cxchloro-Al.4-pregnadiene-11,3,17adiol-3,20-dibne, 16@-methyl-6-fluoro-9v--chloro-A4, 6-pregnadien-17a-ol-3,11,20- trione, 16p-methyl - 6 - fluoro-9achloro-A4,6-pregnadiene - llp,17ce - diol-3,20- dione, 16p15 methyl-6-fluoro - 9a - chloro - AI,4,6-pregnatrien-17m-ol-3, 11,20-trione, 16g-methyl-6- fluoro-9a-chloro - AI,4,6 - pregnatriene-llp,17a-diol-3,20-dione and the corresponding derivatives of the 6a,9a-difluoro compounds, such as 16pmethyl-6,x,9m-difluoro-A4-pregnen - 17(x-ol-3,11,20-trione; 50 169 - methyl - 6ix,9a - difluoro-A4-pregnene-11( 3,17a-diol3,20-dione; 16p-rhethyl - 6a,9a - diiluoro-AI,4-pre.-nadien17a-ol - 3,11,20 - trio-@ie, 16g-methyl-6(x,9a-difluoroAI,4pre,@nadiene-llp,17a-diol-3,20-dione; 16,3 - methyl - 6,9adifluoro-A4,6-pregnadien-17aol-3,11,20 - trione, 16[3-meth55 yl-6,9v.-difluoro-A4,6-pregnadiene - llp,17m - diol - 3,20- - dione, 16,3-methyl-6,9oc-difluoro- AI,4,6-pregnat rien-17cc-ol3,11,20 - trione and 16p-methyl6,9(x-difluoro-AI,4,6-pregnatriene-1 1,3,17a-diol-3,20-dione. We
