CH627192A5 - Process for preparing novel cholesterol derivatives - Google Patents

Abstract

25,26-Ketals which are usable in the synthesis of 24,25-dihydroxycholecalciferol have the formula <IMAGE> where R and R' are singly, and independently of each other, lower alkyl or together lower alkylene and the absolute configuration at C-24 is R or S, and are prepared by ketalisation of the corresponding 24,25-dihydroxycholestadienes.

Description

627 192 1

PATENT CLAIM Process for the preparation of a cholestadiene of the formula

H °

where tion on the C-24 is R or S, characterized in that

R and R 'independently of one another are lower alkyl or together that a compound of the formula men is lower alkylene, and the absolute configuration

wherein the absolute configuration at C-24 is R or S, with a compound of the formula

RiO ^^ ^ OR2 C

/ \ R R '

III

wherein

R and R 'have the above meaning,

R 1 and R 2 independently represent lower alkyl or together lower alkylene,

ketalized in the presence of an acid and an inert solvent at low temperature.

The term “alkyl group” used in the following refers to straight-chain or branched hydrocarbon radicals having 1 to 20 carbon atoms. Examples of alkyl groups 55 are methyl, ethyl, n-propyl, i-propyl, tert-butyl, hexyl,

Octyl. The term “alkylene” denotes a divalent hydrocarbon residue with 1-20 carbon atoms, which can be straight-chain or branched and whose free valences originate from two different carbon atoms. Examples of alkylene 60 groups are methylene, ethylene and propylene. Examples of alkanoyloxy groups are formyloxy, acetoxy, butyryloxy and hexanoyloxy.

The term "lower" refers to groups with 1 to 8 carbon atoms.

65 The present invention relates to a process for the preparation of novel cholesterol derivatives of the formula which can be used in the preparation of 24 R, 25- and 24S.25-dihydroxy-cholecalciferol and of 3-lower alkanoylates thereof

627192

wherein R and R 'represent lower alkyl or together lower alkylene and the absolute configuration at C-24 is R or S.

The process for the preparation of these compounds is characterized in that a compound of the formula in which the absolute configuration at C-24 is R or S, with a compound of the formula means are organic solvents, such as alkanols, for. B. methanol, ethanol, or 2-propanol; and alkanones of the formula so

RiO

R

OR2

R '

III

where R and R 'have the above meaning,

R 1 and R 2 independently represent lower alkyl or together lower alkylene,

ketalized in the presence of an acid and an inert solvent at low temperature.

Suitable strong acids for the ketalization of a compound of formula II are inorganic acids such as hydrochloric acid, hydrobromic acid; organic acid, such as sulphonic acid, e.g. B. methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, organic sulfonic acid, in particular p-toluenesulfonic acid being preferred. Suitable inert solution

RCOR '

ss wherein R and R 'have the above meaning, but preferably mean lower alkyl, in particular methyl,

e.g. B. acetone, 2-butanone, 3-pentanone or cyclohexanone.

It is preferred to use an alkanol of the formula IV corresponding to the ketal of the formula III as an inert solvent. Is z. B. 3-pentanone ketal used as a ketalizing agent, 3-pentanone is preferably used as a solvent. The combination of 2,2-dimethoxypropane-acetone is particularly preferred. The temperature at which the ketalization is carried out is not critical. However, in order to avoid side reactions, such as dehydration from the hydroxyl radicals, work is preferably carried out at a temperature between about -20 and 4- 200 C, preferably at about 00 C.

The compounds of formula II can start from

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the 24R, 25- and 24S, 25-dihydroxycholesteryl-3,24-diacylates of the formula wherein R'i and R3 are lower alkanoyloxy and the absolute configuration at C-24 is R or S,

be preserved.

For example, diacylates of the formula V can be allylic to a mixture of 7a and 7β-halo-24R, 25- or 24S, 25-di-hydroxycholesteryl-3,24-diacylates of the formula in which R'i and R3 have the above meaning halogenate and then the compounds of formula

X denotes halogen and the absolute configuration on the C-24 R VI is 3.24R, 25- or 3.24S, 25-trihydroxy-5,7-cholestadiene or S, 3,24-diacylates of the formula

5

627192

where R'i and R3 have the above meaning and the absolute configuration at the C-24 is R or S,

and 3,24R, 25- or 3,24S, 25-trihydroxy-4,6-choIestadien-3,24-diacylates of the formula in which R'i and R3 have the above meaning and the absolute then by selective dehydroacyloxylation in the 3-position in

Configuration at C-24 R or S is a mixture of the diene of formula II 'and a 24R, 25-

dehydrohalogenate. or 24S, 25-dihydroxy-2,4,6-cholestatriene-24-acylates or

The crude mixture of the dienes of the formulas II 'and VII can have 2s formula in which R3 has the above meaning and the absolute configuration on the C-24 is R or S,

be transferred.

The diene of formula II 'can then be isolated either by direct crystallization of the mixture or by filtration of the mixture through a suitable absorbent.

The diene diacylate of formula II 'is saponified to give 3.24R, 25- or 3.24S, 25-trihydroxy-5,7-cholestadiene of formula II.

The isolation and the saponification can be carried out in any order, for example a mixture of compounds of the formulas II 'and VII can first be mixed with carbinols of the formulas II and

VII '

HO

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6

wherein the absolute configuration at C-24 is R or S, saponify and then by selective dehydration into a mixture of a diene of formula II and a diene of formula where the absolute configuration is at C-24R or S triene and 0.10 g (3%) 3,24S, 25-trihydroxy-5,7-cholestadiene,

convict. The diene can have a melting point of 228-230 ° C. from the latter mixture.

mei be separated by the above-mentioned crystallization or filtration. 2s B) The process a) 3S, 24R, 25-trihydroxy-5,7-cholestadiene-24,25-acetonide

Example A mixture of 2.10 g of 3S, 24R, 25-trihydroxy-5,7-chole-

A) Preparation of the starting material stages, 60 ml of 2,2-dimethoxypropane and 0.24 g of p-toluene

3S, 24S, 25-trihydroxy-5,7-cholestadiene and 24S, 25-sulfonic acid monohydrate are stirred at 25 ° C. for 15 minutes.

Dihydroxy-2,4,6-cholestatrien 30 A total of 60 ml of methanol is added and

A solution of a 65:35 mixture of 3.75 g of 3S, 24S, 25 - the solution was stirred for 45 minutes. The mixture is mixed with 20 ml

Trihydroxy-5,7-cholestadiene-3,24-diacetate and 3S, 24S, 25-tri-saturated aqueous sodium bicarbonate solution and 100 ml of hydroxy-4,6-cholestadiene-3,24-diacetate, 30 ml of dioxane and water. The mixture is 4 times 100 ml Me

75 ml of a solution of 5% potassium hydroxide in methanol is extracted from ethylene chloride. The organic extracts are stirred at 0 ° C for 1 hour. A solution of 100 ml of cold 35 washed with 100 ml of water and over anhydrous sodium

0.5 N sulfuric acid is added and the mixture is dried with 4 times sulfate. The solvent is removed, and after

Extracted 100 ml of ethyl acetate. The organic layers are recrystallized from ethyl acetate to give 2.06 g (90%)

washed with twice 100 ml of sodium chloride solution and 3S, 24R, 25-trihydroxy-5,7-cholestadiene-24,25-acetonide,

dried over anhydrous magnesium sulfate. The solution melting point 176-179 ° C

medium is removed and 3.05 g of a 65:35 mixture is obtained

of 3S, 24S, 25-trihydroxy-5,7-cholestadiene and [a] g> -105.80 (c 1.01, CHCI3). 3S, 24S, 25-trihydroxy-4,6-cholestadiene.

The mixture is taken up in 100 ml of dioxane containing 0.5 g of p-toluenesulfonic acid monohydrate and the b) 3S, 24S, 25-trihydroxy-5,7-cholestadiene-24,25-acetonide solution is heated at 700 ° C. for 1 hour. The cooled solution 45 A mixture of 1.79 g of 3S, 24S, 25-trihydroxy-5,7-chole is mixed with 50 ml of ice water and 25 ml of saturated sodium bi-stages, 50 ml of 2,2-dimethoxypropane and 0.20 g Diluted p-toluene carbonate solution. The mixture is filtered and sulfonic acid monohydrate is stirred for 15 minutes at 25 ° C., 1.76 g of crude solid is obtained. After recrystallization from a total amount of 50 ml of methanol is added and dimethylformamide is obtained 1.25 g (40%) of 3S, 24S, 25-tri- the solution is stirred for 45 minutes. The mixture is diluted with 20 ml of hydroxy-5,7-cholestadiene, melting point 228-230 ° C., saturated sodium bicarbonate solution and 100 ml of water and the solution with 4 times 100 ml of methylene chloride extrades _ 102.6 ° (c 1.02, dimethylformamide ). Value. The organic extracts are washed with 100 ml of water and dried over anhydrous sodium sulfate. The solvent is removed and after recrystallization

The filtrate is extracted with 3 times 200 ml of ethyl acetate. From ethyl acetate, 1.76 g (90%) of 3S, 24S, 25-tri-

and the combined organic extracts are washed with 200 ml of hydroxy-5,7-cholestadiene-24,25-acetonide, melting point of saturated sodium chloride solution and over water at 188-190 ° C,

free sodium sulfate dried. The solvent is removed and after chromatography of the residue with silica gel, 1.06 g (35%) of 24S, 25-dihydroxy-2,4,6-cholesta-60 [a] ^ 5 -96.4® (c 1 , 00, CHCb).

B