Патент USA US3093676код для вставки
- United vStates Patent ‘O 3,093,664 I‘ ' ‘Patented June 11‘, 1963 1 3,093,664 :t HClorABr l! , 4-HALO-6-DEHYDRO AND 4-HALO-1,6-BIS DEHY DRO DERIVATIVES 0F 17u-HYDROXY PROGES TERONE ' ‘ _ ‘ ~ John A. Edwards, Howard J. Ringold, and Fred A. Kincl, Mexico City, Mexico, assignor‘s, by mesn'e assignments, ‘I338 ‘ 0=° 5 No Drawing. Filed Nov. 30, 1959, Ser. N0.'19,438 Claims priority, application Mexico, Nov. 28, 1958 > p , 15 Claims. 10 (Cl. 260-3974) > This invention relates to certain new Icyclopent-a'no phcnanthrene derivatives. ‘ a ' ' i - ‘ - ‘ " V ' dehydro- I/lxo? I genatiou ' - ———-> '0_. I on, h=o ‘ | ‘iv-OH to Syntex Corporation, a corporation of Panama t r ‘ chloranil O__ ‘More particularly, it relates to the ‘novel ~4-halo-6-dei hydro and 4-halo-1,6-bis‘dehydro' derivatives of 17u-hy Y droxyprogesterone, and their esters, represented by the following formula: '7 X _ .15 HI‘ X ‘ I . " IV A esteri-. ?cation 20 _ CH’ ' ' 0H, --OAcyl ' ‘ i—-OAcyl dehydro‘ / ' a. genatlon I *———-—-—--> ' ( dehydro- No. 647,503, ?led on March 21, 1957, their 17-esters de The new compounds according to the invention were produced by meausof a process illustrated in the reaction l . I > _ I ' .O 7 t I I VA I ‘TIC ' I VIA, lsapom?éation OH; 7 s (3H, h=0 I _ | "OH ‘ I 02?‘ V * ‘w ’ ' 0Q, ' V X VI As preparatory steps in the above-illustrated process, the well known and conventional starting compound I, 65 17a-hydroxy-poogesterone, is epoxidized with the aid of hydrogen peroxide and sodium hydroxide to the epoxide II and the latter is then halogenated in its acetonic or the i ___..____> o___ l __OAcy1 ' / ‘a X 55 “ I lj-on 'l I ( xylene I , I "OH '60 on, $=0 epoxidation CH1 ~é=0 diagram given below and described thereafter in detail. ‘ (A) or (G) \l genation‘ 50 scribed by Edwards, Ringold rand Rosenkranz, in patent application Serial No. 811,019, ?led on May 5, 1959, or the l-dehydro derivatives of such compounds, also de scribed in the latter patent application. ‘ dehydrogenation amyl alcohol 525,313: l yesteri?catlon chloro- and 4-bromo-17a-hydroxyprogesterone described I jh-orr'f I (0) Ohloranil genatiou -———~——--——> ' by Ring-old and Rosenkranz, in patent application Serial 5:0 I IVA dehydrd- dehydro- ‘ o1k/ ' ' The new compounds which vare the object of the present I invention, are valuable drugs which inhibit ovulation, , For their preparation, we used as starting materials 4 _1 ‘ ~ B) Chloranil ' t V CH3 ’ 45 ‘ ' V (\I cinate, caproate, henzoate, ltrirnethylacetaite, phenoxy acetate, phenylpropionate, cyclopentylpropionate and 13 on, O“ I "OAcyI alkoxy (of 1 .to 8 carbon atoms) or halogen (?uorine, chlorine or bromine). Among others, typical esters of such acids are the acetate, propionate, butylrate, hernisuc ' ' - of straight, branched, cyclic or mixed straight (branched) cyclic chain, optionally substituted with functional groups such as hydroxyl, acyloxy (of 1 to ‘12 carbon atoms), " xylene 1111\- wherein Z is a‘ member of the group consisting of a single and a double carbon-to-carbon bond, X is a member of genation; the group consisting of chlorine and bromine,‘ and Rise. 8,11%; member of the ‘group consisting of hydrogen and the acyl Oxide radical of a hydrocarbon earboxylic acid having from-'1 35 to 12 carbon atoms andbeing saturated or unsaturated, chloropropionate. B) Chloranil I like solution with the aid of concentrated hydrochloric or hydrobromic acid to the corresponding 4-chloro or 4 HnOaNaOH 0_ bromo compound III, in which X represents either chor-ine \0 .I _ a, a I n, ,3‘; or ‘bromine as the case may be. 1 Esteri?oation ‘of compound III is‘ carried out in a con; 3,093,664: 4 3 respective acid and p-toluenesulfonic 'acid, and esters of A mixture of 5 g. of 4-chloro-17a-hydroxyprogesterone prepared in the above manner, 10 g. of chloranil, 75 cc. the general Formula IIIA are obtained. The esters VA of the A1-4-dienes are obtained from under an atmosphere of nitrogen for 96 hours. The compounds IIIA by dehydrogenation with selenium di cooled mixture was washed with cold aqueous 10% so oxide, t-butanol and pyridine, as described in patent ap dium hydroxide solution until the washings were color less, the solution was dried over anhydrous sodium sul fate and the ethyl acetate was evaporated. Chromatog raphy of the residue on neutral alumina afforded 4-chlo ventional manner, ‘for instance with the ‘anhydride of the of ethyl acetate and 25 cc. of acetic acid was re?uxed plication 811,019 supra, and the -free Alv‘i-‘dienes V by conventional saponi?cati-on from esters VA. In order to introduce a single ‘additional double bond at C-6,7 into 4-halo-17a-hydroxyprogesterone III or its 10 ro-ti?-pregnadien-17a-ol-3,20-dione. esters IIIA to 'obtain compounds IV and IVA, the steroid Example II is re?uxed with chloranil in mixture with ethyl acetate To a solution of 1 g. of 4-chloro-17a-hydroxy-proges acetic acid or in mixture with xylene; in order to intro terone prepared as described in Example I, in 50 cc. of duce two double bonds vat C-1,2 and C-6,7, the esteri?ed A‘i-compouud is re?uxed with chloranil in mixture with 15 anhydrous benzene there was added 2 cc. of acetic an hydride and 200 mg. of p-toluenesulfonic acid and the n-amyl alcohol to obtain directly the esteri?ed ALM compounds VIA and upon conventional saponi?cation the mixture was 'kept at room temperature for 24 hours and free compounds VI. then diluted with water; the benzene layer was separated Alternatively, we obtained the 1,4,6qtrienes VIA by re and washed with aqueous 5% sodium carbonate solu ?uxing the above-mentioned 1,4-dienes VA, that is, the 20 tion and with water to neutral, dried over anhydrous so l-dehydro-derivatives of the 4-‘halo-l7a-hydroxy-proges dium sulfate and evaporated to dryness. The residue terones, with chloranil in mixture with the solvents men crystallized from acetone-hexane to yield 4-chloro-17a-hy tioned above, or by re?uxing the 4,6-dienes IVA with droxy-progesterone 17-acetate, M.P. 177-179” C. selenium dioxide, preferably in mixture with t-butanol, The latter ester was further treated in the same man in the presence of catalytic amounts of pyridine, or by 25 ner as described when using the free 4-chloro compound re?uxing the same 4,6»dienes with chloranil in mixture in Example I. The 17-acetate of 4-chloro-A‘i-6-pregna with n-amyl alcohol. dien-l7a-o1-3,20-dione was obtained. Although the object of the present invention is the prep aration of the novel 4-chloro and 4~bromo-A4-6-pregnadi en-17a-ol-3,20-diones and ‘AWG-pregnatrien-I7a-ol-3,20 Example III 30 diones and their 17-esters, the above-described process may also be applied to the preparation of the 6-dehydro and 1,6-bis-dehydro derivatives of other 4-halo(chloro or Example I was repeated, but hydrobromic acid solu tion was substituted for the hydrochloric acid and there was obtained 4~bromo-17a-hydroxy-progesterone. The latter compound was esteri?ed to its 17-acetate by the ?rst step described in Example II. bromo)-A4-3-ketones, for example of the 4-halo analogs of cortexone (or desoxycorticosterone), of cortexolone 35 A mixture of 5 g. of they resulting 4-bromo-l7a-hy (or Reichstein’s substance “S”), of cortisone and of hy droxyprogesterone 17-acetate, 10 g. of chloranil and 50 drocortisone, which compounds may be optionally halo cc. of xylene was re?uxed for 16 hours under an atmos genated at 09 and/or substituted at C-16 (a-hyd-roxyl, phere of nitrogen, cooled, washed with 5% aqueous so u-methyl or ?-methyl, a-alkoxy or a-?uorine) and/or at dium bicarbonate solution and water, dried over anhy C-2 (a-alkyl), and/or at C-2l (?uorine) and/ or have at 40 drous sodium sulfate and the xylene was evaporated un C-1‘6,17 a cyclic acetal or ketal group, as well as to the der reduced pressure. By chromatography of the residue preparation of such dehydro derivatives of the esters of on neutral alumina there was obtained the l7-acetate of the above-enumerated compounds. 4-bromo-A4'6-pregnadien-17a-ol-3,20-dione. ’ The reactions involved in the above-described process may be modi?ed within wide limits. For example, the reaction time may be varied without much in?uence in 45 the result; for introducing the third double bond into the 4,6-dienes with selenium dioxide, a solvent different from t4butanol may be employed, such as acetic acid or anoth Example IV 4-chloro-17a-hydroxy-progesterone was esteri?ed with caproic anhydride by following the procedure described in Example II. A mixture of 5 g. of the resulting 17-caproate of 4 chloro-l7a-hydroxyprogesterone, 0.4 g. of selenium di er lower tertiary alcohol; pyridine may be substituted 50 oxide and 0.3 cc. of pyridine was re?uxed under an at by another basic catalyst; the introduction of the double mosphere of nitrogen for 72 hours and then ?ltered bond at C-1 may also be achieved by biochemical meth through celite, washing the ?lter with hot butanol; the ods, for example by incubation with Corynebacterium ?ltrate ‘and washings were combined and evaporated to simplex ATCC 6946. The following speci?c examples serve to illustrate but 55 dryness under reduced pressure; the residue was dissolved in acetone, treated with decolorizing charcoal, re?uxed are not intended to limit the present invention. for half an hour, cooled, ?ltered and evaporated to dry Example I ness. The residue was puri?ed by chromatography on A solution of 10 g. of 17a-hydroxy-progesterone in 300 neutral alumina. There was thus obtained 4-chloro-A1-4 cc. of methanol was cooled to 0° C. and mixed with 20 60 pregnadien-17a-ol-3,20-dione 17-caproate. tion and 50 cc. of a 4% sodium hydroxide solution. 3,20-dione 17-acetate with 10 cc. of a methanol solution cc. of previously cooled 32% hydrogen peroxide solu The A mixture of 1 g. of \4-chloro-A1A-pregnadien-17a-ol~ of sodium methoxide, prepared from 160 mg. of sodium mixture was kept standing for 48 hours at 0° C., poured and absolute methanol, was stirred at 20° C. under an into water, extracted with methylene dichloride, the di chloride solution was evaporated to dryness and the resi 65 atmosphere of nitrogen for 72 hours. It was then poured into 50 cc. of aqueous saturated sodium chloride solution due crystallized from acetone~hexane. There was thus containing a few drops of acetic acid and the precipitate obtained 7.8 g. of 45,5[3-epoxido-pregnane-17a-ol-3-20 formed was collected by ?ltration, washed with a little dione. cold water, dried and recrystallized from acetone-hexane. 1 g. of this compound was dissolved in 20 cc. of ace There was thus obtained the free 4-chloro-A1-4-pregna— tone and mixed with 1 cc. of concentrated aqueous solu 70 dien-17a-ol-3,20-dione. tion of hydrochloric acid. The mixture was kept for 4 A mixture of 6 g. of the free 4-chloro-AL4-pregnadien hours at room temperature and then poured into water. 17a-ol-3,20-dione, 100 cc. of anhydrous benzene, 10 g. of The product was ?ltered, washed to neutral, dried under cyclopentylpropionic anhydride and 3 g. of p-toluene vacuum and crystallized from acetone-hexane, thus giv sulfonic acid was kept at room temperature for 3 days 75 and then diluted with water. The benzene layer was ing 800 mg. of 4-chloro-17a-hydroxy-progesterone. 3,093,664 5 6 separated, washed several times with 5% aqueous sodium wherein Z is a member of the group consisting of a single and a double carbon-to-carbon bond, X is a member of the group consisting of chlorine and bromine, and R is a member of the group consisting of hydrogen and the carbonate solution and water, dried over anhydrous so dium ‘sulfate and the benzene was evaporated. Crystal lization of the residue from acetone-hexane yielded the cyclopentylpropionate of 4-chloro-A1'4-pregnadien-17a-ol 3,20-dione. acyl radical of a hydrocarbon carboxylic acid having from 5 g. of the above compound was treated with chloranil 2. 4-chioro-A4ys-pregnadien-17uJol-3,20-dione. 3. An ester of 4-chloro-A4?-pregnadien-l7a-ol-3,20-di one having an hydrocarbon carboxylic acyl group which 1 to 12 carbon atoms. in mixture with xylene, exactly as described in Example II, .thus producing the cyclopentylpropionate of 4-chloro Ald-s-pregnatrien-17a-o1-3,20-dione. 10 contains up to 12 carbon atoms. 4. 4-chloro-A1res-pregnatrien-17a-ol-3,20~dione. Example V By following the method of esteri?cation described in 5. An ester of 4-chloro-Ali‘i'?-pregnatrien-17a-ol-3,20 dione having an hydrocarbon carboxy-lic acyl group which the preceding example, 4-bromo-17a-hydroxy-pnogester contains up to 12 carbons atoms. one prepared as described in Example III was converted 6. 4-br0mo-A416-pregnadien-l7a-ol-3,20-dione. into its iso-butyrate by reaction with the anhydride of iso~butyric acid; in turn, this iso-butyrate was converted into the iso-butyrate of 4-bronro-A4'6-pregnadien-17a-ol 3,20-dione by the reaction with chloranil described in Example I. 5 g. of the above compound was re?uxed with sele 7. An ester of 4-bromo-A4I6-pregnadien-17a-ol-3,20-di one having an hydrocarbon carboxylic acyl group which contains up to 12 carbon atoms. 8. 4-bromo-A1?l?-pregnatrien-17u-ol-3,20-dione. 20 ni-um dioxide, essentially ‘following the method of Exam 9. An ester of 4-bromo-A1'4’6-pregnatrien-17a-ol-3,20 dione having an hydrocarbon carboxylic acyl group which contains up to 12 carbon atoms‘ ple IV, to produce the isobutyrate of 4-bromo-A1'4'6-preg 10. A compound as described in claim 1 wherein R natrien-17ot-ol-3,20~dione. is the acyl group of propionic acid. 25 11. is the 12. 3,20~dione obtained as described in Example II was re is the ?uxed with chlorani-l in mixture with n-amyl alcohol, in 13. accordance with the procedure described in Example IV, 30 is the thus furnishing the acetate of 4-chloro-A1'4»6-pregnatrien 14. 17a-ol-3,20-di'one. is the We claim: 15. 1. A compound of the general formula: is the Example VI 5 g. of the acetate of 4»ch1oro—A416-pregnadien~17a-ol CH: A compound as described in claim acyl group of acetic acid. A compound as described in claim acyl group of isobutyric acid. A compound as described in claim acyl group of hemisuccinic acid. -A compound as described in claim acyl group of caproic acid. A compound as described in claim 1 wherein R 1 wherein R 1 wherein R 1 wherein R 1 wherein R acyl group of cyclopentylpropionic acid. 35 References Cited in the ?le of this patent UNITED STATES PATENTS 2,883,379 2,895,969 Moreland et a1. _______ __ Apr. 21, 1959 Ringold et a1 __________ __ July 21, 1959 OTHER REFERENCES Kirk et al.: “Journal Chemical Soc.” (1956), pages 1184-6. 45 , Kirk et al.: “Journal Chemical Soc." (1956), pages 627-9.