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UNITED STATES PATENT OFFICE 2,231,017 ALLO-PREGNANE COMPOUNDS and METH OD of OBTAINING the SAME Russell Earl Marker, State

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UNITED STATES PATENT OFFICE 2,231,017 ALLO-PREGNANE COMPOUNDS and METH OD of OBTAINING the SAME Russell Earl Marker, State Patented Feb. 11, 1941 2,231,017 UNITED STATES PATENT OFFICE 2,231,017 ALLO-PREGNANE COMPOUNDS AND METH OD OF OBTAINING THE SAME Russell Earl Marker, State. College, Pa., assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan No Drawing. Application March 12, 1937, Serial No. 130,582 6 Claims. (CI. 260-397) The invention relates to a new keto-alcohol of with a ketone reagent capable of reacting with the sterol series, and particularly to epi-allo the epi-allo-pregnane-ol- (3)-one- (20) but not pregnanol- (3)-One- (20) and its isolation from with the non-ketonic alcohols. mixtures with other sterol derivatives of a non 7. Separating the reaction product of step (6) 5 ketonic nature. from non-ketonic alcohols, and, It is known that the two non-ketonic alcohols 8. Decomposing the reaction product to obtain having a cyclopentano-10,13-dimethyl polyhy epi-allo-pregnane-ol- (3) -one- (20), which can drophenanthrene nucleus, pregnanediol and allo be readily separated by means of Organic Sol pregnanediol, belonging to the pregnane or pro vents from the decomposition products of this O gesterOne chemical group, may be isolated from Step. O the neutral or alcoholic fraction of human preg . The above series of eight steps is of Special nancy urine. However, no compounds of a keton value when the original mixture to be treated ic nature have been heretofore isolated from is a neutral carbinol fraction from human preg these or other like mixtures. nancy urine. In step (6) above the use of a It is an object of the invention to separate hydrazine compound capable of forming a and isolate the new ketonic alcohol, epi-allo water-soluble hydrazine derivative With the epi 5 pregnanol- (3)-One- (20), from its mixtures with allo-pregnanol- (3)-one- (20) is preferred as a pregnanediol and allo-pregnanediol or other like ketone reagent. non-ketonic alcohols or sterols. When starting with human pregnancy urine, A further object of the invention is the ulti the phenolic estrogenic hormones, including 20 lization of epi-allo-pregnanol- (3) -one- (20) for those known as theelin and theelol (estrin and 20 the preparation of a new diol compound, epi-allo estriol), may be separated by the method of pregnanediol, and its derivatives, and for prep Doisy et al., J. Biol. Chem. 87, 357 (1930), to aration by a new method of the known com leave a carbinol residue or fraction. In this 25 pound, allo-pregnanedione. case, the carbinol residue contains the straight 25 It has now been found that the above and carbinols, such as pregnanediol and allo-preg other objects of the invention may be realized nanediol, along with ketonic carbinols like the by Way of the following steps: new epi-allo-pregnanol- (3)-one- (20) of this in 1. Treating a mixture comprising epi-allo vention and any hydrocarbons which may be pregnane-ol- (3)-one- (20) and non-phenolic present. The carbinol fraction is first purified 30 30 non-ketonic neutral alcohols having a cyclopen and separated from any hydrocarbons and like tano - 10,13-dimethyl polyhydrophenanthrene impurities present. This may be done by con nucleus with an acylating agent derived from a verting the carbinols into their acid phthalates, dibasic Organic acid to convert the alcohols, the alkali metal Salts of Which are Water-solu 35 both ketonic and non-ketonic, into their cor ble whereas the hydrocarbons are insoluble. 35 responding acid mono-esters. The separated phthalates are hydrolyzed to re 2. Reacting the acid mono-esters with basic generate the original carbinols and the ketonic or alkaline reagents to convert them into their carbinols separated by means of their water water-soluble ester-salts. soluble betaine hydrazine compounds from the 40 3. Separating the soluble ester-salts in aque 40 ous solution from water-insoluble impurities, water-insoluble non-ketonic carbinols. The such as hydrocarbons soluble in water-immis water-Solubie reaction product of betaine hy cible. Organic Solvents. drazine chloride with the ketonic carbinois is 4. Converting the separated and thus purified easily hydrolyzed to regenerate the ketonic car 45 ester-salts back into their acid mono-esters by binols which, in the case where human preg 45 treatment with acid. nancy urine Was the starting material, may con 5. Saponifying the mono-esters to produce a sist practically entirely of epi-allo-pregnanol purified mixture of epi-allo-pregnane-ol- (3) - (3)-one- (20). If necessary, the epi-allo-preg one- (20) and non-ketonic alcohols. nanol- (3)-One- (20) thus obtained may be puri 50 6. Treating the purified mixture from step (5) fied by Way of its semicarbazone, from which the 50 2 2,281,017 free ketonic alcohol can be regenerated in pure acetate and 11.1 g. of semicarbazide hydrochlo form. ride. The alcohol is distilled to dryness and the The epi-allo-pregnanol- (3)-one- (20) can be Semicarbazone residue Washed With hot Water converted to its acylated derivatives by reac and finally with ether. The white solid (7.3 g.) tion with acylating agents, e. g. acetic anhydride is crystallized from alcohol to a constant melting or like acylating agent. point of 248-250 dec. Allo-pregnanedione can be obtained from the Anal. calcd. for C22H37N3O2: C, 70.3; H, 9.9. new epi-allo-pregnanolone by Oxidation, e. g. Found: C, 69.9; H, 9.9. using chromic oxide in acetic acid. Epi-allo-pregnanol-3-one-20.--To a solution of O The new 3-epi-allo-pregnanediol-20 is obtain 3 g. Of Semicarbazone in 150 cc. of alcohol are 0 able from the epi-allo-pregnanol- (3)-one- (20) added 15 cc. of Sulfuric acid in 30 cc. of Water. by catalytic reduction. The resulting diol com The product is refluxed for one-half hour, poured pound may be converted to its acylated deriva into water and thoroughly extracted with ether. tives in similar manner to that stated above for The ether is distilled and the residue sublimed in the acyl derivatives of epi-allo-pregnanol- (3)- high Vacuum at 130°. The Sublimate is crystal One- (20). lized from 70 percent alcohol and then from 70 The following examples will serve to illus percent acetone, m. 162-164. It does not absorb trate the invention: bromine in the cold, and does not precipitate with Separation of carbinols from hydrocarbons digitonin. 20 and Other impurities.-The residue left from 10,000 gallons of human pregnancy urine after 20 the separation of theelin and theelol by the (a)3= +91.0°c=1 percent Doisy method is hydrolyzed by refluxing With an excess of alkali. This is then steam distilled in alcohol. until no more volatile oils come over. The resi Anal. calcd, for C21H34O2: C, 79.2; H, 10.8. due is cooled, filtered, the solid precipitate Found: C, 79.3; H, 10.8. 25 washed well with water, dried, and finally Oacidation of epi-allo-pregnanol-3-One-20 to shaken. With ice-cold ether. The ether-insoluble allo-pregnanedione.--To a solution of 180 mg. of portion consists of a mixture of pregnanediol epi-allo-pregnanol-3-one-20 in 15 cc. of glacial 30 and allo-pregnanediol. acetic acid are added 58 mg. of chromic oxide in 30 The ether-soluble portion is concentrated leav 30 cc. of 90 percent acetic acid. It is allowed to ing 777 g. of tarry residue. This is dissolved in Stand at 15-20 for 16 hours. Water is added benzol and the carbinols present converted into and the precipitate filtered off and dried. This is sublimed in high vacuum at 115°. The sublimate their acid phthalates according to the following is then crystallized from acetone. The crystals 35 procedure: To 50 g. of the tar are added 25 g. of melt at 198-200. Mixed with allo-pregnanedione, phthalic anhydride and 25 cc. of dry pyridine. m. 200, it gives no depression in melting-point. The solution is heated on a steam bath for 2 Anal. calcd. for CallH32O2: C, 79.7; H, 10.2. hours, ether added, and the pyridine removed Found: C, 79.5; H, 10.1. 40 by Washing with dilute sulfuric acid. The ether Acetate of epi-allo-pregnanol-3-One-20. To 1 solution is shaken with a solution of 50 g. of g. of epi-allo-pregnanol-3-one-20 are added 5 cc. 40 sodium carbonate in 200 cc. of water. The ether of acetic anhydride. The product is refluxed for layer contains the non-carbinol fraction. The 30 minutes and the excess acetic anhydride dis carbonate solution which is extracted thoroughly tilled under reduced pressure. The residue is sub with ether, is acidified with sulfuric acid and then limed at 130° with a mercury vapor pump. It is extracted with ether. The ether is evaporated crystallized from 70 percent alcohol and then and the phthalates Saponified by refluxing for 2 from 70 percent acetone, m. 139-140°. hours with 200 cc. of alcohol containing 50 g. of potassium hydroxide in 40 cc. of Water. Water (c)3= --112 c = 1.g. per 100 cc. is added and the alcohol distilled. The alkaline 50 Solution. With its suspended Solids is extracted in alcohol. with ether giving 31.4 g. of carbinols. Anal. calcd. for C23H36O3: C, 76.8; H, 10.1. Separation of epi-allo-pregnanol-3-One-20 from Found: C, 77.0; H, 10.0. y 5 carbinol fraction.--To 31.4 g. of total carbinols 3-epi-allo-pregnanediol-20.--To a solution of 5 are added 30 cc.
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