DE1211185B - Process for the production of 19-halo-delta 5-androsten-3-ol compounds - Google Patents

Description

FEDERAL REPUBLIC OF GERMANY

GERMAN

PATENT OFFICE

EDITORIAL

Int. Cl .:

C 07 c

German class: 12 ο - 25/04

Number:
File number:
Registration date:
Display day:

1 211185
S86170IVb / 12o
July 15, 1963
February 24, 1966

The present invention relates to a process for the preparation of new ^ -halogenide ^5- andestrene-3; 3-ol derivatives.

The novel compounds that can be prepared according to the invention are represented by the following formulas reproduced:

XO X OR '

In the above formulas, R and R 'each represent a hydrogen atom or a hydrocarbyl carboxylic acid group having fewer than 12 carbon atoms; R ² represents a hydrogen or a lower alkyl, alkenyl or alkynyl group, and X represents a fluorine or chlorine atom.

The acyl group is made up of hydrocarbyl carboxylic acids with fewer than 12 carbon atoms derived, the saturated, unsaturated, straight, branched-chain, cyclic or cyclic-aliphatic, aromatic and with functional groups such as hydroxyl groups, alkoxy groups with up to 5 carbon atoms, Acyloxy groups with up to 12 carbon atoms, nitro, amino or halogen groups can be substituted. Typical ester groups are acetate, propionate, oenanthate, benzoate, trimethyl acetate, tert-butyl acetate, phenoxyacetate, cyclopentylpropionate, aminoacetate or / 3-chloropropionate.

AcylO

Process for the preparation of 19-halogen- / J ⁵ -androsten-3-ol compounds

Applicant:

Syntex Corporation, 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. 39

Named as inventor:

Dr. Albert Powers, Mexico (Mexico)

The compounds of the above formulas show anabolic-androgenic activities and inhibit the production of gonadotrophic pituitary hormones and ACTH. They also have anti-estrogens Properties and reduce blood, liver and adrenal cholesterol levels. Also are they are suitable for regulating fertility and in psychotic states, and they are appetizing.

The novel compounds which can be prepared according to the invention are obtained by the following Process shown in the equation:

RO

RO

III

In the above formulas, R, R ', R ² and X have the meanings already given.

The inventive method is characterized in that a corresponding 19-To-

609 509/408

sylate (I) with a corresponding alkali metal halide such as lithium chloride or fluoride, or metal halide such as silver fluoride, in a suitable inert organic solvent, such as. B. dimethylformamide or acetonitrile, treated and so the corresponding 19-fluoro-chloro-zI ⁵ -androsten-3 / S-ol-17-one acetate (II; R = acetyl) is prepared, which after the usual saponification corresponding free 3/3 alcohol (II; R = H) provides.

The reduction of the 17 - keto - 3 - acetate (II; R = acetyl) with a double metal hydride, such as. B. sodium borohydride, provides the corresponding 19 - halogen - Δ ⁵ - androsten - 3 / 9.17 /? - diol - 3 - acetate (III; R '= R ² = H; R = acyl), which after customary saponification with a base, the corresponding 19-halo-zf ⁵ -androsten-3 / ?, 17jS-diol (III; R = R '= R ² = H) yields.

The 19-fluoro or -Chlor-zl ⁵ -androsten-3/9-ol-17-on acetate (II) is with a lower (alkyl, alkenyl or alkynyl) magnesium halide, such as. B. methyl magnesium bromide, vinyl magnesium bromide or ethynyl magnesium bromide, in a solvent inert to the reagent, such as. B. ether, to the corresponding 19-halo-17a- (alkyl-, -alkenyl- or -alkinyi) -zl ⁵ -androsten-3 | S, 17 /? - diöl (III; R = R '= H, R ² = lower [alkyl, alkenyl or alkynyl]).

The secondary hydroxyl groups of the compounds according to the invention, namely the 3- hydroxyl group and the 17-hydroxyl group of the 17a-unsubstituted Derivatives are in the usual way with an acylating agent, such as. B. one of one. Hydrocarbon carboxylic acid of the type described above derived anhydride, in pyridine to the acylated corresponding acylates.

The tertiary hydroxyl groups of the compounds according to the invention, namely the 17 / S-hydroxyl group of the 17a-substituted derivatives are usually in the presence of p-toluenesulfonic acid with an acylating agent, such as. B. acetic anhydride or caproic anhydride, esterified to the corresponding 17-esters.

The following examples illustrate the invention Procedure. For the production of the starting materials, in the context of the present Invention Protection not sought.

example

A solution of 5 g <d ⁵ -androstene-3 / ?, 19-diol-17-one-3-acetate in 25 ecm pyridine was cooled to ^{0 ° C.} 1.3 g of tosyl chloride were added with stirring, the mixture was kept at 0 ° C. for 16 hours, diluted with 100 ecm of chloroform, washed with dilute hydrochloric acid, water, aqueous sodium bicarbonate solution and again with water, dried over anhydrous sodium sulfate and then reduced under reduced pressure Evaporated to dryness. Thus, the crude 19-tosylate of the starting compound was obtained.

A suspension of 10 g of lithium chloride in 50 ecm of dimethylformamide was heated to the boil and then a solution of 2 g of the crude tosylate in 10 ecm of dimethylformamide was added. The mixture was refluxed for 5 hours, cooled and poured into water. The precipitate thus formed was filtered off and recrystallized and yielded the 19-chloro-zl ⁵ -androsten-3 / S-ol-17-one acetate. M.p. = 151 to 152 ° C; [a] _D -10 ° (CHCl ₈ ).

A suspension of 1 g of 19-chloro-zl ⁵ -androsten-3ß-ol-17-one-3-acetate in 60 ecm of methanol was treated with a solution of 1 g of potassium carbonate in 6 ecm of water, and the mixture was refluxed for an hour Heated to boiling, then cooled in ice and diluted with water. The precipitate formed was collected and recrystallized from acetone-hexane; 19-chloro-.d ⁵ -androsten-3/3-ol-17-one was obtained in this way.

M.p. = 194 to 196 ^° C; [o] _'0 -19 ° (CHCl _3).

Claims (2)

Patent claims: 1. Process for the preparation of 19-HalogenzI ⁵ -androsten-3-ol compounds of the general formula X Y in which R is a hydrogen atom or a hydrocarbon carboxylic acid residue with less than 12 carbon atoms, X a fluorine or chlorine atom and Y a keto group or the grouping / OR ' \ _R 2 denotes, where R 'stands for a hydrogen atom or a hydrocarbon ^{carboxylic acid radical with fewer than 12 carbon atoms and R 2 stands} for a hydrogen atom, a lower alkyl, alkenyl or alkynyl radical, characterized in that a compound of the general formula OTosyl Y H ₂ C in which Y has the abovementioned meaning and R is a hydrocarbon carboxylic acid radical with less than 12 carbon atoms, in an inert organic solvent treated with an appropriate alkali metal halide or metal halide and after per se known methods if necessary a) saponified 3-acylates obtained and / or b) 17-keto compounds obtained reduced and / or c) 17-ketones obtained with a lower alkyl, alkenyl or alkynyl magnesium halide alkylated and / or d) the hydroxy compounds obtained are esterified. 2. The method according to claim 1, characterized in that the metal halide Lithium chloride and dimethylformamide as a solvent.