DE1158966B - Process for the preparation of 6-chloro-1,2ª‡-methylene-í¸-17ª‡-hydroxyprogesterone esters - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY KL. 12 O 25/05 INTERNAT. KL. C 07 C

GERMAN

PATENT OFFICE

EXPLAINING EDITORIAL 1158 966

Sch 29643 IVb / 12 ο

REGISTRATION DATE: APRIL 29, 1961

NOTIFICATION OF REGISTRATION AND ISSUE OF EDITORIAL: DECEMBER 12, 1963

The invention relates to the introduction of a 6-chlorine atom in 1,2a-methylene-zJ ⁶ -17a-hydroxyprogesterone ester. The inventive method is that one l, ^2a-e Methylenzl -17a-hydroxyprogesteronester in a known manner, preferably by means of a percarboxylic acid. in particular benzoic acid, first converted into the corresponding 6,7a-epoxides, that this is then treated with hydrochloric acid, preferably in glacial acetic acid solution, whereby in one operation the cyclopropane ring with formation of a la-chloromethyl group and the epoxy ring with elimination of water and formation of 6-chlorine -zl ^ grouping are opened, and that finally the la-chloromethyl group of the reaction product is converted back into the 1,2a-methylene group with a preferably organic base, in particular collidine, as explained in more detail below:

Method of manufacture

of o-chlorine-l ^ a-methylene

Δ ⁶ - hydroxyprogesteronestern 17a

Applicant:

Schering Aktiengesellschaft, Berlin N 65, Müllerstr. 170-172

Dr. Rudolf Wiechert, Berlin-Lichterfelde West, has been named as the inventor

CH ₃

Oac

CH ₂ Cl

CH ₃

Oac

CHr

ac = acyl

The process products. in particular the just sufficient minimum quantity shows clearly

17-acetate, are surprisingly strong stems borrowed the superior effectiveness of 6-chloro

genes, especially for peroral application. The 50 I, 2a-methylene-zi ⁶ -17a-hydroxyprogesterone acetate

The following comparison of the gestures that are known to be highly effective in order to achieve

positive Clauberg tests on infantile rabbits genes:

309 768/430

link

6-chloro-1.2a-methylenzl ⁶ -17a-hydroxyprogesterone acetate ....

19-nor-17a-hydroxyprogesterone acetate ....

17a-hydroxy-progesterone acetate

19-nor-17a-ethinyltestosterone

l ^ Nor-na-ethinyl testosterone acetate

Required dose

in milligrams

subcutaneous I peroral

Application

0.003

0.003

0.03

0.06

0.03

0.01

0.1

0.9

0.1

0.03

The esters of 6-chloro-1,2a-methylene-zl ⁶ -17a-hydroxylprogesterone show similar increases in activity compared to the corresponding comparison substances. In the case of the higher homologues, beginning for example with enanthate, there is also a valuable reduction in effectiveness. Instead of esters of aliphatic carboxylic acids, the esters of other carboxylic acids commonly used in the therapeutic use of steroids, e.g. B. the alicyclic. aromatic or mixed open-chain cyclic carboxylic acids are prepared in an analogous manner. They show similar, similarly high efficacies.

example 1

2.34 g of 1,2a - methylene - / I ⁴ · ⁶ - pregnadiene - 17a - ol-3.20-dione-17-acetate are dissolved in 18.25 ml of ethylene chloride containing 844 mg of benzoeperic acid. The solution is kept for 16 hours at +5 ⁰ C and 7 hours at room temperature. It is then diluted with methylene chloride and washed neutral with aqueous iron (II) sulfate solution, sodium hydrogen carbonate solution and with water. After drying over sodium sulfate, the organic phase is concentrated to dryness. 1.62 g of the crude 1,2a-methylene-6,7a-oxido-J ⁴ -pregnen-17a-ol-3,20-dione-17-acetate thus obtained are dissolved in 109 ml of glacial acetic acid. This solution is then saturated with hydrochloric acid gas at room temperature and stored for 20 hours. It is then diluted with methylene chloride and washed neutral with water. After drying over sodium sulfate, the organic phase is concentrated to dryness. The crude 6-chloro- ^{1α-chloromethyl-J 4 6} -pregnadien-17a-ol-3,20-dione-17-acetate obtained in this way is heated to boiling in 20 ml of collidine for 20 minutes under nitrogen. After dilution with ether, it is washed neutral with 4N hydrochloric acid and with water.

The residue remaining after drying over sodium sulfate and concentration to dryness is chromatographed on silica gel. With a benzene-ethyl acetate mixture 19: 1, 900 mg of 6-chloro-1,2a-methylene- Δ ⁴ · ⁶ - pregnadiene-17a-ol-3,20-dione-17-acetate are eluted, which is recrystallized from isopropyl ether , melts at F. = 200 to 201 ^{0 C.} UV = £ ₂ 8i = 17,820 (methanol).

Example 2

8.7 g of 1,2a-methylene-zt ⁴ · ⁶ -pregnadiene-17a-ol-3,20-dione-17-capronate are mixed with 2.77 g of benzoic acid in 52.9 ml of ethylene chloride for 17 hours at 5 ° C and Stored for 7 hours at room temperature. It is then, as described in Example 1, worked up and the crude 1,2a-methylene-6,7a-oxido- Δ ⁴ - pregnen-17a-oil-3.20-dione-17-capronate in 585 ml of glacial acetic acid solved. This solution is saturated with hydrochloric acid gas at room temperature and stored for 20 hours, then diluted with methylene chloride and washed neutral with water.

The organic phase is dried over

Sodium sulfate concentrated to dryness. This gives 9.4 g of crude 6-chloro-la-chloromethyl-zl ⁴ ' ⁶ -pregnadien-17a-ol-3,20-dione-17-capronate, which, dissolved in 87 ml of freshly distilled collidine, takes 30 minutes Refluxed with nitrogen. It is worked up and chromatographed as described in Example 1.
3.1 g of 6-chloro-1,2a-methylene-zl ⁴ ' ⁶ -pre- are obtained

gnadien-17a-ol-3,20-dione-17-capronate as an oil.

UV = £ ₂ 82 = Π 500.

Analysis:

Calculated
found

... Cl 7.5%;
... Cl 7.4%.

Claims (1)

PATENT CLAIM: Process for the preparation of 6-chloro- ^{1,2a-methylene-d e} -17a-hydroxyprogesterone esters, characterized in that a ^{1,2a-methylend e} -17a-hydroxyprogesterone ester is used in a manner known per se, preferably with a percarboxylic acid, in particular benzoeperic acid , epoxidized, treated the corresponding 6,7a-epoxide with hydrochloric acid, preferably in glacial acetic acid solution, and the resulting la-chloromethyl-6-chloro-zl ^e compound is reacted with a preferably organic base, in particular collidine.