3,418,415 United States Patent Office Patented Dec. 24, 1968 1. 2 The novel compounds are prepared by methods known 3,418,415 in themselves. ESTROGENIC STEROIDAL COMPOSITIONS COM PRISING 1-HYDROXY-ESTRADIOL AND DE The 17-ketone is reacted in a suitable solvent with an RVATIVES THEREOF alkyne, a chloroalkyne, or a dialkyne and an alkali metal, Klaus Prezewowsky and Friedmund Neumann, Berlin, 5 preferably in the presence of a tertiary alcohol or in the and Rudolf Wiechert, Berlin-Wannsee, Germany, as presence of ammonia, and under elevated pressure if signors to A. G. Schering, Berlin, and Bergkamen, needed. Chloroalkynes and dialkynes are preferably Germany formed during the reaction from halogenated alkenes or No Drawing. Filed May 10, 1966, Ser. No. 548,830 halogenated alkynes with alkali metal. Alkynyl magnesi Claims priority, application Germany, May 19, 1965, 0 um halide may be used instead of alkali metal alkynylide. Sch. 37,082 Suitable solvents include ethers, such as diethyl ether, 24 Claims. (Cl. 424-238) tetrahydrofuran, and dioxane, or hydrocarbons such as benzene or toluene. Suitable tertiary alcohols include tert butyl and tert-amyl alcohol. ABSTRACT OF THE DISCLOSURE 5 The 1-hydroxyestrone not being a very stable com Compounds of the formula: pound, it may be preferable to start from a compound in which the hydroxyl groups in positions 1 and 3 are ether OR ified. If the ether radicals are to be introduced only as temporary protective radicals, it is preferred to etherify 20 with dihydropyran, because these ether radicals are readily removed after alkynylation of the 17-position, as is well known. The free or liberated hydroxyl groups may then be modified by partial or total esterification and/or ether RO 25 ification, by partial removal of initially introduced groups or by transesterification. Pyridine and acid anhydrides are preferably employed have been found to have strong estrogenic and ovulation at room temperature for selective acylation in positions 1 preventing effects in oral and parenteral application if R1 and 3. and R are hydrogen, lower alkyl, tetrahydropyranyl, or 30 Diazomethane and dialkyl sulfate are the preferred acyl radicals of a physiologically tolerated carboxylic acid, alkylating agents for etherification in positions 1 and 3. and R is hydrogen, chlorine, lower alkyl, or lower alky If the 17B-hydroxyl group of the 1,3-diesters or 1,3-di nyl. Various methods of preparing the compounds are ethers so obtained is to be esterified, the steroid may be being described. reacted with acid anhydrides in the presence of strong uTu-r acids, such as p-toluenesulfonic acid, or pyridine/acid an hydride at elevated temperature. The last-mentioned The invention relates to 1-hydroxy-estradiol derivatives methods may also be employed for converting the free of the formula trihydroxy-compounds directly into the triacylates. The 1 and 3-hydroxyl groups of the triacylates may be liberated OR 40 by careful partial saponification. 1,3-diesters and 1,3-diethers may be converted into the corresponding 17-tetrahydropyranyl ethers by means of dihydropyran in the presence of a strong acid such as p-toluenesulfonic acid. If it is desired to etherify the 17 OH group in the 1,3-diethers of the invention with an alkyl radical, alkyl halides in liquid ammonia are prefer ably employed. The two last-mentioned methods also make it possible to etherify all three OH groups of the trihydroxy compound in a single operation. wherein R and R2 are members of the group consisting 50 The 1- and the 3-hydroxyl groups of the 1,3-diacyl-17 of hydrogen, lower alkyl, tetrahydropyranyl, and the acyl tetrahydropyranyl derivatives can be liberated by alkaline radical of a physiologically tolerated carboxylic acid; R3 saponification. is a member of the group consisting of hydrogen, chlorine, If it is desired to produce 1,3,176-trihydroxy com lower alkyl and lower alkynyl. In preparing the com pounds whose 17-OH group is alkylated or acylated, it is pounds of the invention, the keto group in position 17 of 55 particularly advantageous to etherify the 1-hydroxyestrone 1-hydroxyestrone, with or without prior etherification of with dihydropyran, to introduce the desired alky1 or acyl radical after alkynylation into the 176-OH group, and the 1,3-dihydroxy groups, is converted to the 17B-hydroxy finally to split the tetrahydropyranyl group selectively 17o-alkynyl group by means of RC=CMgBr or a corre from positions 1,3. The 1,3-dihydroxy compounds may sponding alkali metal alkynylide, whereupon the free or 60 thereafter be etherified or esterified in the desired manner. etherified hydroxyl groups are hydrolyzed, esterified, or The compounds produced by the method of the inven etherified depending on the desired nature of R1 and R2. tion have valuable therapeutic properties. They show, sur Physiologically tolerated carboxylic acids whose acyl prisingly strong estrogenic and ovulation-preventing radicals may constitute R1 and R2 include acetic acid, pro effects. The compounds may be applied orally, intramus pionic acid, hydroxypropionic acid, (3-chloropropionic 65 cularly or subcutaneously. The often superior effects of acid, cyclopentylpropionic acid, caproic acid, heptanoic the compounds of the invention are shown in the follow acid, benzoic acid, mono- and dichloracetic acid, succinic ing table of ovulation prevention tests and Allen-Doisy acid, and the like. tests in which 1-hydroxy-17a-ethynyl-estradiol (I), the In view of the pharmaceutical application of the prod corresponding di-acetate (II), and 1-hydroxy-17a-butadi ucts, the ether radicals are preferably methyl, ethyl, and 70 ynylestradiol-1,3-diacetate (III) were compared with tetrahydropyranyl radicals. known estrogens IV and V. 3,418,415 4 TABLE cipitate was formed with ice water after a reaction period Estrogenic effect, Ovulation pre of five hours, and the triacetate precipitated was filtered threshold value in venting effect, off after one hour's agitation, washed until neutral, and Compound Allen-Doisy median effective dried. There were obtained 2.6 g. of 1-hydroxy-17a-ethy Test, oral dose, oral nylestradiol-triacetate. (gamma) (gamma) (d) A mixture of 3 g. of 1-hydroxy-17o-ethynyl-1,3- -hydroxy-17a-ethynyl estradiol (I)------3 10 diacetate with 15 ml. of pyridine and 10 ml. acetic anhy -Hydroxy-17oz-ethinyl dride was heated for ten hours on an oil bath having a 1-Hydroxy-17a-butadiynylestradiol-1,3-diacetate (II)---- I 10-30 temperature of 150° C. under nitrogen. The reaction mix estradiol-l,8-diacetate (III)------10-30 ture was cooled to room temperature and then added to 7a-Ethynyl-estradiol (V).------10 100 17a-Ethynyl-estradiol-3- ice water. After one hour's stirring, the precipitate was methylether (V)------00 100 filtered off, washed with water, and dried. 2.8 g. 1-hy droxy-17a-ethynyl-estradiol-triacetate were obtained. The novel estratriol derivatives of the invention are UV: ego=18,500, e266=410. incorporated for therapeutic use in the medicinal compo Example 2 sitions usual in galenic pharmacy which include the usual addition agents, carriers, and taste correcting ingredients, 3 g. 1-hydroxy-17 oz-ethynylestradiol were acetylated as by means of conventional methods. They may be applied described in Example 1 (c) or 1 (d) to the 1-hydroxy-17a orally in the form of tablets, dragees, capsules, pills, sus ethynyl-estradiol-triacetate. pensions, or solutions, and may be applied parenterally, UV: e20=18,500, e266=410. particularly in oily solutions, for example in sesame oil Example 3 or castor oil solutions which may contain a diluent such (a) A solution of diazomethane in ether was added to as benzyl benzoate or benzyl alcohol. The concentration a solution of 2 g. of 1-hydroxy-17-ethynylestradiol in of the active agents of the invention in the medicinal com 150 ml. of ether until the yellow color of diazomethane positions depends on the form of application. Tablets may 25 persisted. The solvent was then evaporated in a vacuum, contain about 20 y, and oily solutions for intramuscular and the 1,3-dimethylether of 1-hydroxy-17a-ethynylestra injection may contain about 50 y per milliliter. diol was obtained as a residue. The medicinal agents of the invention are useful in ail (b) 1 g. of 1-hydroxy-17a-ethynylestradiol was dis ments which respond to treatment with estrogen, or with solved in 100 ml. of aqueous potassium hydroxide con estrogen in combination with compounds having gestage 30 taining 2 mol equivalents of KOH, and 2 mol equivalents nous effects. Examples of ailments susceptible of treat of dimethyl sulfate were added with cooling. The precipi ment include the climacteric and its sequelae, disturbances tated dimethyl ether was extracted with ether after an of peripheral blood circulation and amenorrhea. When hour, the organic phase was washed with water and dried. combined with nor-ethisterone acetate, the compounds of The solvent was evaporated, and 1-hydroxy-17 oz-ethynyl the invention also are suitable for putting the ovary at rest. estradiol-1,3-dimethyl ether was obtained. The following examples illustrate the method of pre UV: e205=38,200, e284=2,060. paring the compounds of the invention. (c) 1. g. of 1 - hydroxy - 17 or - ethynylestradiol-1,3-di Example 1 methyl ether was esterified according to Example 1 (c) or 1 (d) to the 1-hydroxy-17a-ethynylestradiol-1,3-dimethyl (a) A Grignard solution was prepared from 30 g. of 40 magnesium chips and 91.4 ml. of ethyl bromide in 400 ether-176-acetate. ml. of tetrahydrofuran, and was converted to the acetylene UV: e205=38,100, e284=2,050. magnesium bromide compound by charging the solution Example 4 with acetylene gas for 1 to 2 hours. A solution of 7 g. of A trace of ferric nitrate was added at -80° to -60 1-hydroxyestrone in 150 ml. of tetrahydrofuran was added 45 C. to about 100 ml. of liquid ammonia, and thereafter dropwise to the suspension, and the mixture was agitated 0.134 g. of sodium in small pieces. After the blue color for 20 hours at 70° C. under argon. The reaction mix had disappeared, 1.8 g. of 1-hydroxy-17a-ethynyl-estra ture was cooled and decomposed with saturated aqueous diol-1,3-dimethyl ether in 50 ml. of tetrahydrofuran were ammonium chloride solution, the organic phase was sepa added dropwise within 10 minutes, and the mixture was rated, and the aqueous phase was extracted repeatedly 50 agitated for 1 to 2 hours. Thereafter, 1 g. of methyl iodide with ether. The combined organic phases were washed in 10 ml. of tetrahydrofuran was added, and stirring was with saturated sodium chloride solution and dried over continued for three hours. The mixture was then poured desiccated sodium sulfate. The residue obtained after over ice, neutralized with acetic acid, and extracted with evaporation of the solvent was chromatographed over methylene chloride. The organic phase was washed with silica gel, and 1-hydroxy-17 oz-ethynylestradiol was eluted 55 water and dried over sodium sulfate. When the solvent with a mixture of benzene and ethyl acetate 97:3. The was evaporated, 1-hydroxy-17 oz-ethynylestradiol-1,3,179 raw product was dissolved in ethyl acetate, filtered over trimethyl ether was obtained as a residue. carbon, and recrystallized from ethyl acetate/hexane. UV: es=38,300, e285=2,040. There were obtained 2 g. of 1-hydroxy-17a-ethynyl Example 5 estradiol having a melting point of 189/190-191 C. 60 UV: e20=38,400, e286=2,160. 550 mg. of 1-hydroxy-17 oz-ethynylestradiol were con (b) 2. g. of 1-hydroxy-17a-ethynylestradiol were dis verted by the method of Example 4 to 1-hydroxy-17a solved with cooling in 5 ml. pyridine and 5 ml. acetic an ethynylestradiol-trimethyl ether by means of 0.134 g. hydride. The reaction mixture was left to stand for 15 sodium and 1 g. methyl iodide. hours at room temperature, and was then poured into a 65 UV: e205=38,300, e285=2,040. tenfold amount of ice water. The precipitate formed was Example 6 filtered off with suction, washed with water, dried, and re crystallized from isopropyl ether and methylene chloride. 2 g. of 1-hydroxy-17ox - ethynylestradiol - 1,3,176 - tri There were obtained 2 g. of 1-hydroxy-17o-ethynylestra acetate were suspended in 100 ml. of methanol. A solu diol-1,3-diacetate of M.P. 197/198-199° C. 70 tion of 1. g. of potassium carbonate in 10 ml. of distilled UV: e20=18,900, e266=412. water was added to the suspension with stirring at room (c) 2.5 g. of 1-hydroxy-17 oz-ethynylestradiol-1,3-diace temperature. The reaction mixture was made weakly acid tate were dissolved in 30 ml. acetic anhydride, and were after 1.5 hours, and added to ice water with agitation. gradually mixed with cooling and agitation with 1.9 g of The precipitate formed was filtered with suction after p-toluenesulfonic acid in 18 ml. acetic anhydride. A pre 75 Some time, and washed with water until neutral, then 1.2 3,418,415 5 6 g. of 1-hydroxy-17-ethynylestradiol-176-acetate were ob 17a-ethylyl-estradiol-17,3-tetrahydropyranyl ether-1,3-di tained. acetate of a melting point 134-135 C. UV: es=38,500, e2=2,150. UV: e2=16,800, e266=394. Example 7 Example 13 5.7 g. of methyl iodide in 100 ml. of absolute ether were (a) 2. g. of 1-hydroxyestrone were dissolved in 70 ml. added to 550 mg. of lithium chips in 200 ml. of absolute absolute benzene. The solution was evaporated to 50 ml. ether. After brief heating, the mixture was cooled to 0 20 mg. of p-toluenesulfonic acid were dissolved in 30 ml. C. and 20 g. of trans-dichloroethylene in 50 ml. of abso benzene, and the solution was evaporated to 15 ml. The lute ether were added over a period of 30 minutes under concentrates were cooled and combined. 4 ml. of freshly nitrogen atmosphere. The cooling bath was removed and O distilled dihydropyran were added to the mixture which stirring was continued at room temperature for 1.5 hours. was then stirred at room temperature for two hours, and The resulting solution of lithium-chloroacetylene was thereafter diluted with ether. The organic phase was mixed over a period of 30 minutes with 1.45 g. of 1-hy washed with sodium bicarbonate solution and with water, droxyestrone dissolved in 300 ml. of absolute toluene. 5 dried, and evaporated. The residue was 1-hydroxy-estrone The mixture was heated with stirring for 1.5 hours, and 1,3-ditetrahydropyranyl ether. was then cooled to -60° C. It was decomposed at this UV: e205=38,500, e284=2,100. temperature with a saturated aqueous Solution of 2.5 g. (b) A Grignard solution was prepared from 15 g. of ammonium chloride. The mixture was Warned to room magnesium chips and 45.7 ml. of ethyl bromide in 400 ml. temperature and extracted with ether. The ether extract 20 absolute tetrahydrofuran, and acetylene was introduced was dried over sodium sulfate, and the solvent was dis for 1-2 hours. A solution of 5.5 g. of 1-hydroxyestrone-1, tilled off. A residue of 1-hydroxy-17a-chloroethynylestra 3-ditetrahydropyranyl ether in 100 ml. of absolute tetra diol was obtained. hydrofuran was added drop by drop to the suspension of UV: e20s=33,300, e285=2,200. acetylene magnesium bromide, and the mixture was stirred 25 for 20 hours at 70° C. under argon. The reaction mixture Example 8 was cooled, then saturated aqueous ammonium chloride 13.8 g. of sodium in small pieces were added to about Solution was added, the organic phase was separated, and 300 ml. of liquid ammonia at -80 to-60 C. after ad the aqueous phase was extracted repeatedly with ether. dition of a trace of ferric nitrate. When the blue color The combined organic phases were washed with saturated had disappeared, 24.6 g. of 1,4-dichlorobutyne-(2) were 30 Sodium chloride solution and dried over sodium sulfate. added drop by drop, and thereafter 5g. of 1-hydroxy When the solvent was evaporated, there was obtained estrone dissolved in absolute tetrahydrofuran. The mix 1 - hydroxy-17a-ethynylestradiol-1,3-ditetrahydropyranyl ture was permitted to react with stirring at -40 C. for ether. two hours. It was then decomposed by means of Saturated UV: e205=38,500, e284=2,100. aqueous ammonium chloride solution. The ammonia was (c) 11.4g. of methyl iodide in 200 ml of absolute ether evaporated by letting the mixture stand, and the product were added drop by drop to 1.1 g. of lithium chips in 400 was extracted with methylene chloride. The extract was mi. of absolute ether. The mixture was briefly heated and washed with water, dried over Sodium sulfate, and purged then cooled to 0 C., whereupon 40 g. of trans-dichloroeth of solvent. 1-hydroxy-17 oz-butadiynylestradiol was ob ylene in 100 ml. of absolute ether were added under nitro tained. 40 gen within 30 minutes. The cooling bath was removed, and the reaction mixture was stirred at room temperature for UV: e206=38,300, e285=2,200. 1.5 hours. A solution of 4.6 g. 1-hydroxyestrone-1,3-di Example 9 tetrahydropyranyl ether in 150 ml. of absolute toluene 1.2 g. 1-hydroxy-17 oz-ethynylestradiol-176-acetate were Was added to the resulting solution of lithium chloro ethylene within 30 minutes. The mixture was heated with etherified by means of an ether solution of diazomethane 45 stirring for 1.5 hours, and was then cooled to -60° C. It as described in Example 3 (a) above. 1-hydroxy-17a was decomposed at this temperature with a saturated ethynylestradiol-1,3-dimethyl ether-17 3-acetate was ob aqueous Solution of 5 g. of ammonium chloride, heated tained. to room temperature, and extracted with ether. The ex UV: e205=38,100, e284=2,050. tract was dried over sodium sulfate and evaporated to dry Example 10 50 neSS. The residue was 1-hydroxy-17a-chloroethynyl-estra diol-1,3-di-tetrahydropyranyl ether. 1.8 g. 1-hydroxy-17a-chlorethinyl-estradiol were acetyl UV: e206=38,300, e285=2,200. ated to 1-hydroxy-17a-chlorethinyl-estradiol-1,3-diacetate (d) A trace of ferric nitrate and 6.9 g, of sodium in melting at 225 to 227 C. (from hexane/acetone) by Small pieces were added to about 150 ml. of liquid am the method described Example 1(b). UV: E206=22,600, 55 nonium at -80 to -60 C. When the blue color had e266=400. disappeared, 12.3 g. of 1,4-dichloro-2-butyne were added Example 11 drop by drop, and thereafter 4.2 g. of 1-hydroxyestrone 1,3-di-tetrahydropyranyl ether dissolved in absolute tetra 1 g. 1-hydroxy-17 oz-butadiynyl-estradiol was acetylated hydrofuran. The mixture was permitted to react with agita as described in Example 1 (b) above to 1-hydroxy-17a 60 tion for 2 hours at -40° C., and was then decomposed butadiynylestradiol-1,3-diacetate of melting point 184 C. with Saturated aqueous ammonium chloride solution. The (from hexane/acetone). ammonia was permitted to evaporate, and the product UV: e206 19,200, e253-494, €286=171, e305=155, Was extracted with methylene chloride. The extract was e264=449. Washed with Water, dried over sodium sulfate and evapo Example 12 65 rated to yield 1-hydroxy-17a-butadiynyl-estradiol-1,3-di Solutions of 1.06 g. of 1-hydroxy-17a-ethynyl-estradio tetrahydropyranyl ether. 1,3-diacetate in 70 ml. of benzene, and of 10 mg. of UV: e206=38,300, e291=5,300, e285=2,040, E230=7,800, p-toluenesulfonic acid in 20 ml. of benzene were each e297=5,370. evaporated to one-half of their original volume, cooled, 70 Example 14 combined, and mixed with 1 ml. dihydropyran. The mix A trace of ferric nitrate and 0.134 g. of sodium in small ture was stirred at room temperature for one hour, then pieces were added to about 100 ml. of liquid ammonia Shaken with ice cold sodium bicarbonate solution, washed at -80 to -60° C. When the blue color disappeared, with water until neutral, dried, and evaporated. The resi a Solution of 2.5 g. of 1-hydroxy-17a-ethynylestradiol-1,3- due was recrystallized from hexane and was 1-hydroxy 75 di-tetrahydropyranyl ether in 50 ml. of absolute tetra 3,418,415 7 8 hydrofuran was added drop by drop over a period of ten Example 22 minutes, and the mixture was stirred for one to two hours. A Grignard solution was prepared from 3.65 g. of mag 1 g of methyl iodide in 10 ml. of absolute tetrahydrofuran nesium chips, 16.3 g. of ethyl bromide, 150 ml. absolute were then added, and stirring was continued for 3 hours, tetrahydrofuran, and a solution of 8 g. propyne in 60 ml. whereupon the mixture was poured over ice, neutralized absolute tetrahydrofuran was added drop by drop while with acetic acid, and extracted with methylene chloride. the temperature was kept at - 60° C. When gas develop The organic phase was washed with water, dried over ment stopped, a solution of 6.8 g. of 1-hydroxyestrone sodium sulfate, and evaporated. 1-hydroxy-17a-ethynyl 1,3-di-tetrahydropyranyl ether in 100 ml. of absolute estradiol-1,3-di-tetrahydropyranyl-17,8-methyl ether was tetrahydrofuran was added, and the mixture was heated obtained. O under nitrogen and under anhydrous conditions for 20 UV: egos=38,300, e285=2,040. hours to 70° C. The reaction product was worked up as described in Example 13(b), and 1-hydroxy-17 oz-propynyl Example 15 estradiol-1,3-di-tetrahydropyranyl ether was obtained. 1 g. of 1-hydroxy-17a-ethynylestradiol-1,3-di-tetrahy UV: e204=38,300, E285=2,105. dropyranyl ether-176-methyl ether was refluxed 45 minutes 5 We claim: with 1 g. of oxalic acid and 1 ml. of water in 50 ml. of 1. A compound of the formula methanol, and the mixture was then cooled, and added to ice water. The precipitate was filtered, washed, and OR2 dried. It was 1-hydroxy-17a-ethynylestradiol-17 3-methyl ether. 20 UV: e20=38,500, 6286-2,160. Example 16 1 g. 1-hydroxy-17a-ethynylestradiol-17,3-methyl ether was dissolved in 5 ml. of pyridine and 5 ml. of acetic an 25 hydride with cooling. The reaction mixture was kept at room temperature for 15 hours, and was then poured into wherein R1 and R2 are members of the group consisting a tenfold amount of ice water. The precipitate formed was of hydrogen, lower alkyl, tetrahydropyranyl, and the acyl filtered with suction, washed with water, and dried. It radical of a physiologically tolerated carboxylic acid and 30 physiologically tolerated acid radicals and R3 is hydrogen, was 1-hydroxy-17a-ethynylestradiol-17f8-methyl ether-1,3- chlorine, lower alkyl or lower alkynyl. diacetate. 2. A compound as set forth in claim 1, which is: UV: e207–18,800, e266=410. droxy-17 oz-ethynyl-estradiol. Example 17 3. A compound as set forth in claim 1, which is: A solution of diazomethane in ether was added to a droxy-17a-ethynyl-estradiol-1,3-diacetate. solution of 1.5 g. 1-hydroxy-17a-ethynylestradiol-17B 4. A compound as set forth in claim 1, which is: methyl ether in 150 ml. ether until the yellow color of droxy-17a-ethynyl-estradiol-triacetate. diazomethane persisted, whereupon the solvent was dis 5. A compound as set forth in claim 1, which is: tilled off in a vacuum, and 1-hydroxy-17 oz-ethynylestradiol droxy-17 ca-ethylnyl-estradiol-1,3-dimethyl ether. 40 6. A compound as set forth in claim 1, which is: 1-hy 1,3,176-trimethyl ether was obtained. droxy-17a-ethylnyl-estradiol-1,3-dimethyl ether-176- ace UV: e205=38,200, eass=2,050. tate. Example 18 7. A compound as set forth in claim 1, which is: 1-hy A mixture of 3 g. of 1-hydroxy-17a-ethynylestradiol droxy-17a-ethynyl-estradio-trimethyl ether. 1,3-di-tetrahydropyranyl ether, 15 ml. of pyridine, and 10 8. A compound as set forth in claim 1, which is: 1-by m. of acetic anhydride was heated in a 150° C. oil bath droxy-17 oz-ethynyl-estradiol-17,3-acetate. for ten hours under nitrogen. The mixture was then cooled 9. A compound as set forth in claim 1, which is: 1-hy to room temperature, added to ice water, and stirred for droxy-17a-chloroethynyl-estradiol. one hour, whereupon the precipitate formed was filtered 10. A compound as set forth in claim 1, which is: 1-hy 5 droxy-17a-butadiynyl-estradiol. off, washed with water, and dried. 1-hydroxy-17 oz-ethynyl 11. A compound as set forth in claim 1, which is: 1 estradiol-1,3-di-tetrahydropyranyl ether-178-acetate Was hydroxy-17a-chloroethynyl-estradiol-1,3-diacetate. obtained. 12. A compound as set forth in claim 1, which is: 1 UV: e25–38,400, e284=2,100. hydroxy-17a-butadiynyl-estradiol-1,3-diacetate. Example 19 13. A compound as set forth in claim 1, which is: 1 55 hydroxy - 17cc - ethynyl-estradiol-17 3-tetrahydropyranyl 1.5 g. 1-hydroxy-17a-ethynylestradiol-1,3-di-tetrahydro ether-1,3-diacetate. pyranyl ether-17 3-acetate were hydrolyzed as described in 14. A compound as set forth in claim 1, which is: 1 Example 15 to 1-hydroxy-17a-ethynylestradiol-17,3-ace hydroxy-17 c. ethynyl-estradiol-1,3-di-tetrahydropyranyl tate. 60 ether. UV: e20=38,500, e286=2,150. 15. A compound as set forth in claim 1, which is: 1 Example 20 hydroxy - 17 c. - chloroethynyl-estradiol-1,3-di-tetrahydro 2 g. 1-hydroxy-17a-ethynylestradiol-17B-acetate were pyranyl ether. acetylated as described in Example 16 above, to the 1 16. A compound as set forth in claim 1, which is: 1 65 hydroxy - 17 oz-butadiynyl-estradiol-1,3-di-tetrahydropyran hydroxy-17c-ethynylestradiol-1,3,175-triacetate. yl ether. UV: egoi-18,700, e266=420. 17. A compound as set forth in claim 1, which is: 1 Example 21 hydroxy-17 oz-ethynyl-estradiol - 1,3-di-tetrahydropyranyl 17,3-methyl ether. 1.5 g. of 1-hydroxy-17a-ethynylestradiol-1,3-di-tetrahy 18. A compound as set forth in claim 1, which is: 1 dropyranyl ether were hydrolyzed as described in Example O hydroxy-17a-ethynyl-estradiol-176-methyl ether. 15 above to prepare 1-hydroxy-17 oz-ethynylestradiol. 19. A compound as set forth in claim 1, which is: 1 When recrystallized from ethyl acetate and hexane, the hydroxy-17 oz-ethynyl-estradiol-17 (3-methyl ether - 1,3-di compound melts at 189-191 C. acetate. UV: e20=38,400, E286=2,160. 75 20. A compound as set forth in claim 1, which is: 1 3,418,415 9 10 hydroxy-17a-ethynyl - estradiol-1,3-di-tetrahydropyranyl References Cited ether-17,3-acetate. 21. A compound as set forth in claim 1, which is: 1 UNITED STATES PATENTS hydroxy-17a-propynyl-estradiol-1,3-di-tetrahydropyranyl 3,291,814 12/1966 Marshall ------260-397.4 ether. OTHER REFERENCES 22. A medicinal composition having estrogenic and anti-ovulatory activity essentially consisting of a carrier Hecker: “Chem. Berichte,” vol. 97, (1964) pp. 1940 and an active agent which is a derivative of 1-hydroxy 1951 relied on. estradiol as set forth in claim 1. ELBERT L. ROBERTS, Primary Examiner. 23. A composition as set forth in claim 22 which is a O tablet for oral administration. 24. A composition as set forth in claim 22, wherein said U.S. C. X.R. carrier is an oil which contains the active agent in solu 260-239.55, 397.5; 424-241 tion for intramuscular injection.