NO128766B - - Google Patents

Description

Analogous process for the production of progestatively active 4,6-dichloro-A'6-pregnadien-20-one-3B-ols and their esters.

The present invention relates to an analog method for the production of progestatively active 4,6-dichloro-A 4' 6-pregnadien-20-one-3(3-ols or their esters with the formula where Q denotes hydroxy or alkanoyloxy with 1-4 carbon atoms, and ;R hydroxy or alkanoyloxy with 1-4 carbons. ;A C^-C^-alkanoyloxy group is, for example, the acetyloxy, butyroyloxy or caproyloxy group. ;The compounds of formula I can find use as progestative agents. When R means hydroxy, the compounds can be administered parenterally, and when R means alkanoyloxy, the compounds can be administered orally or parenterally. Preferred are the compounds in which Q means hydroxy or acetoxy. The method according to the invention is characterized by reducing the 3-kto group in a steroid with the formula ;where R has the above meaning, ;optionally under the protection of the 20-keto group of the hydroxy group and, if desired, alkanoylates this. ;The reduction of the 3-oxo group in a steroid with fo rmel II to a 3-hydroxy group can be carried out with common reagents, e.g. by treatment with a complex metal hydride such as lithium-aluminum-tri-tert.butoxyhydride or sodium borohydride. The protection of an optionally present 20-oxo group can be carried out in a manner known per se, e.g. by introducing an ester group in the 17oc position or by forming 17a, 20; ;20,21-bis-methylenedioxy deriv. Such a protecting group can, if desired, be cleaved off after the reduction process. For example, a bis-methylenedioxy group can be cleaved off by treatment with a weak acid. The conversion of a 3-hydroxysteroid of formula I to a 3-lower alkanoyl derivative can be carried out with common alkanoylating agents, such as a lower alkanecarboxylic anhydride, in the presence of a base such as pyridine. ;Below, the progestative effect is given for: ;A: 4, 6-dichloro-3(3,17oc-dihydroxy-16-methylenepregna-4, 6-diene- 20-one 17-acetate. ;B: 4, 6-dichloro-3(3,17a-dihydroxy-16-methylsnpregna-4,6-dien-20-one diacetate. ;C: 4, 6-dichloro-17oc-hydroxypregna-4, 6-diene -3, 20-dione acetate. ;D: 4, 6-dichloro-17oc-hydroxy-16a-methylpregna-4, 6-diene-3,20-dione ;acetate. ;The progestative activity of the above-mentioned compounds was determined by to administer the compounds for five alternate days to estrogen-pretreated, immature female rabbits. At autopsy, the uterus is removed and the histological preparation is prepared by uterine cross-section. The histological section is assessed microscopically for the purpose of progestative activity, which is determined by an endometrial response of a secretory nature ;This test was carried out at different dose levels to ;determine the lowest dose at which significant progestative activity was observed. ;Results; ;;The following examples will further explain the invention: ;EXAMPLE 1 ;To a solution of 0.5 g 4,6-dichloro-17oc-acetoxy-16-methylene-pregna-4,6-diene-3,20-dione in 10 ml absolute tetrahydrofuran t a solution of 1.3 g of lithium-aluminium-tri-tert-butoxyhydride in 10 ml of dry tetrahydrofuran is added dropwise. After stirring for 2 hours at room temperature, the solution is cooled in an ice bath and 1 ml of acetone is added. After 15 minutes, the reaction mixture is poured into 150 ml of chloroform, the chloroform solution is extracted twice each time with 125 ml of 10% acetic acid, then with 5% sodium bicarbonate solution. The aqueous washing solutions are combined and extracted with ether. The combined organic phases are dried, and the solvent is removed under reduced pressure. 4, 6-dichloro-3[3,17o-dihydroxy-16-methylenepregna-4, 6-dien-20-one 17-acetate is obtained, which after crystallization from methylene chloride-ether melts at 220 - 222°. The starting steroid can be prepared as follows: To a solution of 3.9 g of 6-chloro-17oc-acetoxy-16-methylene-pregna-4,6-diene-3,20-dione in 25 ml of alcohol-free chloroform is added dropwise at 0° 11.3 ml of a 0.87 molar solution of chlorine in carbon tetrachloride. The solution is stirred for 1 hour at 0°, then the solvent is removed under reduced pressure. The resulting foam is treated with 10 ml of dry pyridine and stirred for 2 hours at room temperature. 200 ml of ether are then added, and the mixture is extracted twice each time with 150 ml of 1-N hydrochloric acid. The ethereal solution is dried, the solvent is removed under reduced pressure. The residue is triturated with ether and gives 2.4 g of substance, which is chromatographed on 100 g of silica gel. Elution with 2% ethyl acetate in benzene gives 2a,4,6-trichloro-17a-acetoxy-16-methylene-pregna-4,6-diene-3,20-dione, melting point 235 - 238°, initial decomposition at 225 ° (from methylene chloride-ether). Further elution with 5% ethyl acetate in benzene gives 4,6-dichloro-17a-acetoxy-16-methylenepregna-4,6-diene-3,20-dione, melting point 218 - 219° (from methylene chloride-ether). ;EXAMPLE 2 ;A solution of 0.5 g of 4,6-dichloro-3(3,17a-dihydroxy-13-m.?.tylene-pregna-4,6-dien-20-one 17-acetate, 5 ml distilled acetic anhydride and 5 ml of pyridine are stirred overnight at room temperature. The reaction mixture is then poured into 200 ml of ice water, the precipitate is filtered off and dried in air. 4,6-dichloro-3(3,17a-diacetoxy-16-methylenepregna- 4,6-dien-20-one, mp 227.5 - 229° (from methylene chloride-ether). ;EXAMPLE 3 ;A solution of 0.3 g of 4,6-dichloro-17a-acetoxy-16a-methylpregna-4 ,6-diene-3,20-dione in 10 ml of anhydrous tetrahydrofuran is added dropwise over the course of 15 minutes under nitrogen to a solution of 0.511 g of lithium aluminum tri-t-butoxyhydride in 7 ml of anhydrous tetrahydrofuran„ After 2 hours of stirring at room temperature, 3 ml of acetone and then 1 ml of water are added. The mixture is concentrated under reduced pressure and 30 ml of chloroform and 30 ml of 10% acetic acid are added in sequence. The organic layer is washed with 5% sodium bicarbonate solution, dried over magnesium sulfate and concentrated eres» One obtains 4, 6-dichloro-3[3,17a-dihydroxy-16a-methylpregna-4,6-dien-20-one 17-acetate, melting point 188.0 - 191.5°, ;(from acetone hexane) >\ jjj£° H 256 mu (e 17,900). ;The starting material can be prepared as follows: ;To 1.051 g of 6-chloro-17a-acetoxy-16a-methylpregna-4,6-diene-3,20- ;dione in 10 ml of alcohol-free chloroform, at 0° quickly add 2.97 ml of a 0.93 molar solution of chlorine in carbon tetrachloride. After 1 hour at 3°, the solvent is removed under reduced pressure, and the crude product is treated with 6.5 ml of pyridine. It is allowed to stand for 1 hour at room temperature, the pyridine is removed under reduced pressure, the residue is taken up in methylene chloride, the solution is washed with dilute hydrochloric acid and water. The organic phase is dried over magnesium sulfate and evaporated. The crude product is chromatographed on 30 g of silica gel. Elution with 5% of ethyl acetate in benzene gives 4, 6-dichloro-17oc-hydroxy-16oc-methylpregna-4, 6-diene-3, 20-dione acetate, melting point 170 - 173°; (from ethyl acetate-hexane) ;* <EtOH> 2gg (£16/250).

Claims (1)

Analogous process for the production of progestatively active 4,6-dichloro-A 4 ' 6-pregnadien-20-one-3[3-ols or their esters of the formula where Q means hydroxy or alkanoyloxy with 1-4 carbon atoms and R hydroxy or alkanoyloxy with 1-4 carbon atoms, characterized by reducing the 3-keto group in a steroid with the formula where R has the above meaning, optionally under protection of the keto group of the hydroxy group and, if desired, alkanoylates this.