DE1493168B - Process for the preparation of 5alpha-androstanolone derivatives - Google Patents

Description

OR

c R ₁

CH ₃

described, in which R _{1 is} a hydrogen atom or a lower alkyl radical and R ₂ and R _{3 are} hydrogen atoms or radicals of physiologically acceptable acids, characterized in that 2-halogen steroids of the general formula

IO

. ■ '5

in which R ₁ denotes a lower alkyl radical and R ₂ and R _{3 represent} hydrogen atoms or the radicals of physiologically acceptable acids, according to Patent 1,236,502, characterized in that a corresponding 2-halo steroid of the general formula

30th

in which X is a chlorine or bromine atom and R _{3 has} the above meaning, dehalogenated in a manner known per se, then in a manner known per se by Grignardation or in a chemically equivalent route after prior ketalization of the 3-keto group a 17 α- Introduces alkyl radical and then splits off the protective group and, depending on the meaning of R ₂ and R ₃ in the end product, esterifies any free hydroxyl groups present and saponifies any 17-acyloxy group after prior ketalization of the 3-keto group and then splits off the ^ protective group.

45

According to main patent 1,236,502, a process for the preparation of 5u-Andrqstanolonderivaten of general formula '' '

OR ₂ .

CH ₃

in which X is a chlorine or bromine atom, dehalogenated and, depending on the meaning of R ₂ and R ₃ in the end product, the 17-acyloxy group which may be present is saponified or any free hydroxyl groups present are esterified.

It has now been found that compounds in which R ₁ denotes a lower alkyl radical can also advantageously be obtained by using 2-halogen steroids of the general formula

, CH ₃

in which -X and R _{3 have} the above meaning, X is eliminated by methods known per se and then introduced in a manner also known per se by Grignardation or in a chemically equivalent route after prior ketalization of the 3-keto group, a 17α-alkyl radical and then the protective group is split off and, depending on the meaning of R ₂ and R _3, esterified free hydroxyl groups present in the end product and any 17-acyloxy group present is saponified after prior ketalization of the 3-keto group and then the protective group is split off.

The compounds that can be produced according to the invention are characterized by the same as those according to main patent 1,236,502 available compounds, characterized by strong anabolic effects.

In addition to catalytic hydrogenation, suitable methods for eliminating halogen are also for example reduction with metals or metal salts. If a 17-acyloxy group is saponified an intermediate ketalization of the 3-keto group is required.

The substances used as starting material according to the invention, for which no protection is sought within the scope of this invention, are obtained by the addition of hypochlorous or hypobromous acid to the Δ ^ double bond of 7a-methyl- ^ I ^ Sa-androstene-3 by methods known per se , 17-dions made.

example

a) To prepare the starting material, 4 g of 7 <x-methyl- / ^{I 1} -5a-androstene-17 /? - ol-3-one are dissolved in 80 ml of pyridine and at ⁰ ° C. with stirring to form a pyridine-chromic acid complex ( made from 8 g of CrO ₃ and 80 ml of pyridine). The reaction mixture is stirred

mixture for 5 hours at room temperature, then the pyridine is distilled off in vacuo and the residue taken up in methylene chloride is filtered through neutral Al ₂ O ₃ . After concentrating the methylene chloride solution, 3.58 g of 7a-methyl-zl ¹ -5 <x-androstene-3,17-dione are obtained.

The analytically pure substance melts after recrystallization from isopropyl ether at a temperature of 190.5 to 192 ° C .; UV: ε ₂₂₈ = 10 400.

3.2 g of 7a-methyl- ^ ^{I 1} -5 (x-androsten-3,17-dione are dissolved in 93 ml of dioxane and mixed with 9.3 ml of water and 0.93 ml of HClO _{4 in} ^{succession at 0 ° C. while stirring} (70%) and 1.4 g of N-bromoacetamide are added The reaction mixture is stirred for 2 hours at room temperature, then the excess of perchloric acid is destroyed with dilute sodium sulfite solution, the reaction mixture is stirred into ice water and extracted with methylene chloride. After washing, drying and concentration in vacuo is chromatographed on silica gel, giving 900 mg of 2/3-bromo-7α-methyl-5-x-androstan-1α-ol-3,17-dione, mp 182 ° to 186 ° C. (decomposition).

b) For dehalogenation according to the invention, 890 mg of 2/3-bromo-7 "-methyl-5" -androstane-1 "-ol-3,17-dione are dissolved in 30 ml of tetrahydrofuran + methanol (1: 1), 0.3 g of sodium acetate and 0.18 ml of glacial acetic acid are added, and the mixture is hydrogenated with 116 mg of Pd / CaCO ₃ 10% (pre-hydrogenated in 15 ml of tetrahydrofuran + methanol 1: 1) until 1 molar equivalent of hydrogen is absorbed. The catalyst is then filtered off, stirred into ice water and extracted with methylene chloride. After washing, drying and concentrating in vacuo, it is chromatographed on silica gel. 345 mg of 7oc-methyl-5a-androstanl «-ol-3,17-dione are obtained. F. 210 to 213 ⁰ C.

c) 334 mg of 7% - methyl-5 "-androstane-l" -ol-3,17-dione are dissolved in 5 ml of methylene chloride (abs.), 0.45 ml of ethylene glycol and 4.5 mg of toluenesulphonic acid are added and at Stirred at room temperature for 24 hours. After stirring into dilute soda solution and extraction with methylene chloride, 370 mg are obtained. The analytically pure 7a - methyl-5a - androstane - la - oil - 3,17 dione-3-ethylene ketal melts after recrystallization from isopropyl ether at 148 to 149 ⁰ C.

d) To a prepared from 2,4 g of magnesium, 31 ml of ether and 5.5 ml of methyl iodide Grignard solution added dropwise to ₂₃₇₀ mg 7a-methyl-5a-androstan-la-ol-3,17-dione-3-äthylenketal under N , dissolved in 70 ml of abs. Benzene, and the reaction mixture is stirred for 5 hours at room temperature. After decomposition of the Grignard solution with saturated ammonium chloride solution and extraction with ether, 380 mg of 7a, 17a-dimethyl-5a-androstan-la, 17 /? - diol-3-one-3-ethylene ketal are obtained. This is dissolved in 51 ml of acetone, 25 mg of p-toluenesulfonic acid are added and the mixture is heated under nitrogen and reflux for 1 hour. The mixture is then stirred into ice water and extracted with methylene chloride. After washing with sodium bicarbonate solution and water, it is dried over sodium sulfate and concentrated in vacuo. After chromatography on silica gel, 190 mg of 7Ä, 17a-dimethyl-5a-androstan-la-17 ^ -diol-3-one are obtained.

F. 183 to 183.5 ° C.

Claims (1)

Claim: Further development of the process for the preparation of 5a-androstanolone derivatives of the general formula OR, OR ₃