DE1227902B - Process for the preparation of 19-norsteroids - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C 07 c

German K) .: 12 ο - 25/05

Number: 1 227 902

File number: S 88024 IVb / 12ο

Filing date: October 25, 1963

Open date: November 3, 1966

The present invention relates to a process for the preparation of 19-NorsU.roids, in particular the new J ⁶ -dehydro-19-nor-progesterone and its 16 "- and 16 / J-methyl derivatives, which are characterized by the following formula will:

in which R stands for a hydrogen atom or an α-methyl or ß-methyl group.

The compounds of the above formula which can be prepared according to the invention are effective anti-estrogens and progestatic agents suitable for controlling fertility and when administered orally show a strong efficacy, thereby increasing the treatment of patients in the condition Sensitivity and mental agitation, which is often an exaggerated aversion to parenteral treatment show is much simplified. It has been used to produce 19-norsteroids

Applicant:

Syntex Corporation, Panama (Panama) Representative:

Dr. W. Schalk, Dipl.-Ing. P. Wirth, Dipl.-Ing. G. E. M. Dannenberg and Dr. V. Schmied-Kowarzik, patent attorneys, Frankfurt / M., Große Eschenheimer Str.

Named as inventor:

Dr. Albert Bowers, Mexico (Mexico)

Claimed priority:

Mexico 7 November 1962 (69 652)

found that the l ⁶ -dehydro-19-nor-progesterone orally six times more effective than 19-nor-progesterone. The process for the preparation of these new compounds is represented by the following scheme:

IV

III

609 709

In the above formulas, R has the meaning given.

When carrying out the above process, the 19-oxyprogesterone derivative used as starting compound (I) is treated by methods known per se with a benzoquinone having an oxidation reduction potential of less than -0.5 V., e.g. B. with chloranil in a high-boiling solvent such as tert-butanol, preferably at reflux temperature for about 8 hours or with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, in the presence of a strong acid, preferably one Mineral acid, such as. B. hydrogen chloride, treated for about 100 minutes, preferably at room temperature, whereby the corresponding 19 - oxy ^{- I 6} - dehydro - progesterone compound (II) is obtained. The 19-hydroxyl group of the latter compound is oxidized with chromium trioxide; This produces the corresponding J ⁴ - ⁶ -Pregnadien-3,20-dione-19-oic acid (III), by treatment with a mineral acid in a lower aliphatic alcohol such as methanol, at reflux temperature for a period between 30 minutes and 2 hours , preferably 1 hour, to form the corresponding 19-norj4,6.p _re g _nac ii _en .3 ₎ 20-dione (IV) is decarboxylated. All procedural measures are carried out according to methods known per se.

The following examples explain the process according to the invention.

example 1

a) A stream of dry hydrogen chloride was passed through a solution of 3 g of 19-oxy-progesterone in 200 ecm of anhydrous dioxane at room temperature for 15 seconds; then 2.8 g of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone were added and dry hydrogen chloride was introduced for a further 45 seconds. The reaction mixture was kept at room temperature for 90 minutes, the hydroquinone formed was filtered off and the filtrate was diluted with methylene chloride. The resulting solution was washed with 1% aqueous potassium hydroxide solution until the washing waters were colorless, washed neutral with water, dried over anhydrous sodium sulfate and evaporated to dryness. The residue was recrystallized from ethyl acetate and then the pure 19 - oxy - J ⁶ - dehydro - progesterone having a melting point 202-203 ⁰ C; [ _{α] 0} = + 182 ° (CHCl ₃ ); λ & Ηγ, οη ^ ₂ 84 πΐμ; log. e 4.41; obtain.

The same procedure was used to produce 16a-methyl-19-θλ. " -progesterone and 16 /? - methyl-19-oxy-progesterone in the corresponding.! ^{6 converted} dehydro compounds.

Example 2

In the process of Example 1, a), instead of the stream of hydrogen chloride, the reaction mixture was formed 0.3 ecm of sulfuric acid added; the same results were obtained.

Example 3

a) A mixture of 1 g of 19-oxy-progesterone, 2 g of chloranil and 50 ecm of tert-butanol was refluxed for 8 hours, the mixture was cooled, the excess chloranil was filtered off and washed with ethyl acetate and the organic extracts were treated with a cold, aqueous 10% sodium hydroxide solution until the wash waters were colorless. It was then dried over anhydrous sodium sulfate and evaporated to dryness. Recrystallization from methylene chloride-ether gave the 19-Oxy-J ⁶ -dehydro-progesterone, which was identical to the product of Example 1, after decolorization with clay.

b) A solution of 1 g of 19-oxy- / l ⁶ -dehydro-progesterone in 80 ecm acetone was ^{cooled to 5 to 10 0} C and under a nitrogen atmosphere and with stirring with 1 ecm of an 8 N chromic acid solution (prepared by mixing treated of 26 g of chromium trioxide with 23 ecm of concentrated sulfuric acid and dilution with water to 100 ecm); the reaction mixture was stirred for 10 minutes at the same temperature. A further 2 ecm of the reagent were then added dropwise over the course of one hour while stirring, and the mixture was stirred for a further 30 minutes. The excess reagent was decomposed with sodium bisulfite, water was added and the product was extracted with ethyl acetate. The organic solution was then extracted with 2% strength potassium hydroxide solution and water and the alkaline extract was acidified with concentrated hydrochloric acid to a pH value of 1 and extracted again with ethyl acetate. This organic extract was washed with ice-water, evaporated over anhydrous sodium sulfate and dried under reduced pressure at room temperature to dryness to give 850 mg of 3,20-diketo-zl ⁴ - ⁶ -Pregnadien-19-oic acid were obtained, which was purified by recrystallization from ethyl acetate became. The pure material had a melting point of 152 to 153 ° C; [a] o = + 155 ° (CHCl ₃ ); A «W> h = 286 πΐμ; log. e 4.37.

c) A solution of 500 mg of the above compound in 20 ecm of methanol was treated with 0.35 ecm of concentrated hydrochloric acid and the reaction mixture was refluxed for 1 hour, neutralized with 1% sodium hydroxide solution and concentrated to a small volume under vacuum; it was then diluted with water, the precipitate formed was filtered off, washed with water and air-dried; 380 mg of ^{I 6} -dehydro-19-nor-progesterone were thus obtained, which were purified by recrystallization from methanol; the product had a melting point of 158 to 159 ° C; [ _{α] D} = + 114 ° (CHCb); H- 284 πΐμ; log. c 4.40.

Claims (3)

Patent claims: 1. Process for the preparation of 19-norsteroids of the general formula: 55 in which R stands for a hydrogen atom or a -methyl or ß-methyl group, thereby characterized in that a corresponding 19-oxy- progesterone treated with a benzoquinone with an oxidation reduction potential of less than -0.5 V, the 19-oxy-.l ⁶ -dehydro-progesterone obtained is oxidized with chromium trioxide and the 3,20-diketo-J ⁴ - ⁶ -pregnadiene-19 obtained -carboxylic acid decarboxylated with a mineral acid in a lower aliphatic alcohol. 2. The method according to claim 1, characterized in that the benzoquinone is chloranil in Presence of tert-butanol used. 3. The method according to claim 1, characterized in that the benzoquinone is 2,3-dichloro-5,6-dicyano-1,4-benzoquinpn used in the presence of a mineral acid, preferably hydrochloric acid.