CH626639A5 - Process for the preparation of D-homosteroids - Google Patents

Abstract

D-Homosteroids which have endocrine activity and the formula <IMAGE> in which R<18> is hydrogen or methyl; R<17a beta > is hydrogen, acyl, lower alkyl, cycloalkyl-lower-alkyl; benzyl, furfuryl or tetrahydropyranyl and R<17a alpha > is hydrogen, lower alkyl, ethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadiynyl or chloroethynyl, are prepared. They can be obtained by treatment of a corresponding D-homosteroid-5(10),16-diene with pyridine hydrobromide perbromide in the presence of an organic base. Resulting compounds of the formula I in which R<17a beta > is hydrogen can be acylated, and those in which R<17a beta > is acyl can be hydrolysed.

Description

The invention relates to a process for the preparation of new D-homosteroids of the formula in which R18, R17aa and R17a'5 have the meaning given, treated with pyridine hydrobromide perbromide in the presence of an organic base.

For the above process, the organic base comes e.g. Pyridine, collidine or triethylamine into consideration. Pyridine is preferably used and the process is carried out at about 0 ° C. to room temperature.

3rd

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A 17a-free hydroxy group in a resulting D-homosteroid of formula I can be obtained by treatment with a reactive acid derivative e.g. an acid halide or acid anhydride in the presence of a base such as pyridine, collidine or 4-diethyaminopyridine. 5

A 17a-acyloxy group in a D-homosteroid of formula I obtained can be prepared in a manner known per se, e.g. are saponified with aqueous-alcoholic bases, such as aqueous-methanolic potassium carbonate.

The starting materials for the inventive preparation of the compounds of the formula I, if they are not known or their preparation is described here, can be prepared by methods known per se or in analogy to the methods described below. The compounds of formula I are hormonally active. In particular, the compounds of the formula I in which R17aa represent unsaturated radicals have a progressive effect.

The process products can be used as healing agents e.g. in the form of pharmaceutical preparations which are used in a mixture with a pharmaceutical, organic or inorganic inert carrier material suitable for enteral, percutaneous or parenteral administration, such as e.g. Contain water, gelatin, gum arabic, milk sugar, starch, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly, etc. The pharmaceutical preparations can be in solid form, e.g. as tablets, dragées, suppositories, capsules; or in liquid form, e.g. as solutions, suspensions or emulsions. If necessary, they are sterilized and / or contain auxiliary substances such as preservatives, stabilizers,

Wetting or emulsifying agents, salts for changing the osmotic pressure or buffer. They can also contain other therapeutically valuable substances.

Example 1 35

2.0 g of 18-methyl-D-homo-19-nor-androsta-5 (10), 16-diene-17ass-oI-3-one are dissolved in 105 ml of pyridine and 2.32 g of pyridine hydrobromide perbromide are added while cooling with ice . The mixture is stirred for 4 hours while cooling with ice under argon and left in the refrigerator for a further 14 hours at -5 °. Then it is poured into 2N HCl and extracted with ethyl acetate. 1.46 g of 18-methyl-D-homo-oestra-4,9,16-triene-17ass-ol-3-one are obtained; M.p. 163-165

[cx] D = - 375 0 (CHCI3) (MeCl2 / isopropyl ether 1: 4).

45

Production of the starting material:

A solution of 2.0 g of 3-methoxy-18-methyl-D-homo-oestral, 3,5 (10), 16-tetraen-17a-one in 30 ml of benzene is added dropwise with a 20 % solution of diisobutyl aluminum hydride in toluene 50. The mixture is stirred for a further 30 minutes at room temperature, then 3 ml of water are carefully added while cooling with ice and the mixture is stirred for a further 15 minutes at room temperature. The precipitate formed is filtered off and washed thoroughly with benzene. After concentrating the filtrate, 1.92 g of 3-meth-55 oxy-18-methyl-D-homo-oestra-l, 3.5 (10), 16-tetraen-17ass-ol (colorless prisms made from isopropyl ether / methylene chloride) are obtained 4: 1). Mp 134-136 °;

[o] "= + 4.1 ° (CHC13).

A solution of 4.5 g of 60 3-methoxy-18-methyl-D-homo-estra-l, 3.5 (10), 16-tetraen-17ass-ol in 90 is added dropwise to 220 ml of NH3 at -60 ° ml THF and 10 ml tert-butanol. Over the course of 60 minutes, 2.25 g of lithium are added and the mixture is stirred at -50 to -60 ° for a further 3 hours. Then so much ethanol is added dropwise to the reaction solution that the blue color disappears, 65 ammonia evaporate, the residue is mixed with about 400 ml of saturated sodium chloride solution and extracted with ether.

The crude product obtained in this way is dissolved in 180 ml of acetone and 22

ml of water dissolved. After adding 3.6 g of oxyacid, the mixture is stirred at 40 ° for 50 minutes, then poured into 500 ml of saturated NaHC03 solution and extracted with ethyl acetate. After chromatography on aluminum oxide (neutral, Act. III) with petrol / ethyl acetate 0-12%, 3.4 g of 18-methyl-D-homo-19-nor-androsta-5 (10), 16-dien-17ass- ol-3-one; Mp 123-125 ° (acet / isopropyl ether 1: 8); [a] D = + 112.4 ° (benzene).

Example 2

A solution of 34.5 g of 17ass-hydroxy-D-homoöstra-5 (10), 16-dien-3-one in 1000 ml of pyridine was mixed with 44.6 g of pyridine-hydrobromide-perbromide at 0 ° and the mixture was mixed Stirred for 16 hours at room temperature under argon. After removing the pyridine on a roller evaporator, the mixture was taken up in ether, washed once with aqueous hydrochloric acid and twice with water, dried over magnesium sulfate and the evaporation residue was adsorbed on 1 kg of silica gel 0.06-0.2 mm. Elution with 1: 1 hexane-ethyl acetate gave 17ass-hydroxy-D-homoöstra-4,9,16-trien-3-one; Mp 158-159 ° (dichloromethane ether); [aj ijjj ", -310 ° (dioxane; c = 0.102).

Production of the starting material:

A boiling solution of 44 g of 3-methoxy-D-homoöstra-l, 3,5 (10) -trien-17a-one in 100 ml of dichloromethane and 200 ml of methanol was mixed in with a suspension of 62 g of copper (II) bromide 40 ml of methanol and 30 ml of dichloromethane were added, and the reaction mixture was stirred under reflux for 5 hours. The crystalline precipitate was filtered off with suction, washed with dichloromethane and the filtrate was evaporated to dryness on a rotary evaporator. The residue was taken up in dichloromethane, washed three times with water and the aqueous phases were extracted two more times with dichloromethane. The organic phases were dried over sodium sulfate and concentrated on a rotary evaporator. The crude 17β-bromo-3-meth-oxy-D-homoöstra-1,3,5 (10) -trien-17a-one was crystallized from dichloromethane-hexane; Mp 183-184 °; [a] ^ 5 + 32 ° (CHC13; c = 1.0).

A solution of 49 g of 17β-bromo-3-methoxy-D-homo-oestra, 3,5 (10) -trien-17a-one in 400 ml of dimethylformamide was mixed with 43.5 g of lithium bromide and with 18.5 g Lithium carbonate was added and the mixture was stirred at 110 ° bath temperature for 10 hours under argon. The reaction mixture was poured onto ice water and extracted three times with dichloromethane. The organic extracts were washed twice with water, dried over sodium sulfate and concentrated on a rotary evaporator. The last residues of dimethylformamide were removed at 0.5 torr / 700. Crystallization from di-chloromethane-acetone gave 3-methoxy-D-homoöstra-l, 3,5 (10), 16-tetraen-one; M.p. 161-162 °; [ajp ± 0 ° (CHC13; c =

1.0).

A solution of 36.5 g 3-methoxy-D-homoöstra-1,3,5 (10), 16-tetraen-17a-one in 750 ml abs. Tetrahydrofuran was added in portions with 3.8 g of lithium aluminum hydride in an argon atmosphere at 0-5 °. After stirring at 0 ° for 2 hours, ethyl acetate, then ice water were carefully added and the mixture was filtered through Speedex. The filtrate was extracted three times with ethyl acetate, the organic phases were washed twice with water, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. Crystallization of the crude product from ether-hexane provided 3-methoxy-D-homoöstra-1,3,5 (10), 16-tetraen-17ass-ol, mp 100-101 °; [a] ^ + 28 ° (chloroform; c = 1.0).

A solution of 33 g of 3-methoxy-D-homoöstra-1,3,5 (10), 16-tetraen-17ass-ol in 300 ml abs. Tetrahydrofuran and 300 ml of tert-butanol was within 15 minutes to 750 ml of abs. liquid ammonia added dropwise at -33 °. For the milky

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10.2 g of sodium were added in portions to the suspension. The dark blue mixture was stirred for 2 hours at -33 °, carefully mixed with 100 ml of methanol and freed from ammonia by slowly warming to room temperature. It was poured onto ice water and extracted with dichloromethane. The organic phases were washed twice with water, dried over sodium sulfate and evaporated to dryness on a rotary evaporator. Crystallization from ether-hexane gave 3-methoxy-D-homoöstra-2,5 (10), 16-triene-17ass-ol; mp. 119-120 °; [a] ^ 5 + 90 ° (chloroform; c = 1.0).

A solution of 53 g of 3-methoxy-D-homeostra-2.5 (10),

A solution of 5 g of oxalic acid in 50 ml of water was added to 16-trien-17ass-ol in 200 ml of dichloromethane and 500 ml of methanol and the mixture was 2 '/? Stirred at 25 ° for hours. After neutralization with aqueous ammonium 5-hydroxide, the methanol was removed on a roller evaporator and the aqueous residue was extracted with dichloromethane. The evaporation residue obtained after washing with water and drying over magnesium sulfate gave 17 aß-Hydroxy-D-homoöstra-5 (10), 16-io dien-3-one after crystallization from dichloromethane ether; M.p. 151-153 °;

[a] d + 152 ° (dioxane; c = 0.101).

C.

Claims (5)

626 639 PATENT CLAIMS 1. Process for the preparation of D-homosteroids of the formula 17a.n rL »? R, 7a, 7 a a 10th 15 wherein R18 is hydrogen or methyl; R17aP is hydrogen, acyl, lower alkyl, cycloylkyl lower alkyl; Benzyl, furfuryl or tetrahydropyranyl and R17aa are hydrogen, lower alkyl, ethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadienyl or chloroethynyl, characterized in that a D-homosteroid of the formula 20th 25th 17ass, R17aa 30th 35 40 II in which R18, R17aa and R17ass have the meaning given, treated with pyridine hydrobromide perbromide in the presence of an organic base. 2. The method according to claim 1, characterized in that compounds of the formula I are prepared in which R17aa is hydrogen or methyl and R17afi is hydrogen, lower alkanoyl, lower alkyl or benzyl. 3. The method according to claim 1, characterized in that compounds of formula I are prepared in which R17aa are ethynyl and R17ass are hydrogen, lower alkanoyl, lower alkyl or benzyl. 4. The method according to claim 1 for the preparation of a 17ass-acylated D-homosteroid of the formula I, characterized in that one obtains a 17ass-hydroxy-D-homosteroid of the formula I obtained. 5. The method according to claim 1 for the preparation of a 17ass-hydroxy-D-homosteroids of the formula I, characterized in that one saponifies a 17ass-acyloxy-D-homosteroid of the formula I obtained. 50 wherein R18 is hydrogen or methyl; R17a (i is hydrogen, acyl, lower alkyl, cycloalkyl-lower alkyl; benzyl, furfuryl or tetrahydropyranyl and R17act is hydrogen, lower alkyl, ethynyl, vinyl, allyl, methallyl, propadienyl, 1-propynyl, butadiynyl or chloroethynyl. The term "acyl" is intended in particular to denote organic acid residues, e.g. Residues of lower (up to 7 carbon atoms) alkane carboxylic acids such as acetic acid, propionic acid, butyric acid, valeric acid, caproic acid, oenanthic acid; or oxalic acid, succinic acid, citric acid; or residues of preferably monocyclic aromatic carboxylic acids such as benzoic acid, phenylacetic acid, or phenoxyacetic acid; or heterocyclic carboxylic acids such as nicotinic acid or cycloaliphatic carboxylic acids e.g. Cycloalkylalkanecarboxylic acids such as cyclopentylpropionic acid, cyclohexylacetic acid, cyclopropylacetic acid; or cycloalkylcarboxylic acids such as cyclopropyl, cyclopentyl or cyclohexylcarboxylic acid. Lower alkyl radicals can contain up to 7 carbon atoms and can be straight-chain or branched. Examples include methyl, ethyl, propyl, isopropyl, butyl and isomers thereof. Preferred lower alkyl radicals are methyl and ethyl. A preferred connecting group within the formula I are the compounds in which R17aa are hydrogen, methyl or ethynyl and R17ass is hydrogen, lower alkanoyl, lower alkyl or benzyl. Examples of compounds of formula I are 17 a-Hy droxy-D-homo-19-nor-17 aa-pregna-4,9,16-trien-20-in-3-one, 13-ethyl-17a-hydroxy-D-homo-18,19-dinor-17aa-pre-gna-4,9,16-trien-20-in-3-one. The D-homosteroids of the formula I can be obtained according to the invention by eating a D-homosteroid of the formula rÎ8 0R17 \ P 55 60 II