NO136139B - BARKEAPPARAT. - Google Patents

Description

Process for the preparation of steroid compounds which are substituted in the 6-position with fluorine or a lower alkyl group.

The present invention relates to a new

method for the production of compounds which are advantageous intermediates in the production of 6-fluoro- or 6-lower alkyl-substituted hydrocortisone, -prednisolone and esters of these compounds, as well as corresponding 5a-hydroxysteroids.

The method according to the invention

makes it possible to produce 6-substituted hydrocortisone and 6-substituted prednisolone with a higher yield than is possible to achieve with other methods where the same starting material is used. Thus, with the method according to the invention, yields of 28 per cent have been obtained, while in the method according to the U.S. patent 2,752,366 received dividends of 20-22 per cent. The dividend is therefore increased by approx. 33 percent

by the method according to the invention.

This increased yield is achieved despite the fact that the method according to the invention comprises relatively many steps.

In the method according to the invention

a monoketal of a polyketosteroid which will be described in the following is used there. This compound is new and is the product of a selective ketalization of the corresponding polyketosteroid and is obtained in surprisingly high yield under conditions that one would expect to give a polyketalized steroid.

The products obtained by the method according to the invention correspond to the following general formula:

in which R denotes fluorine or a lower alkyl group, preferably a methyl group, and R' denotes 2,2-dimethyl-trimethylene.

The main characteristic features of the invention are that in the presence of p-toluenesulfonic acid as a catalyst, 2,2-dimethyl-1,3-propanediol is reacted with a compound corresponding to the general formula:

In which R has the meanings indicated above, whereby a compound with the general formula is obtained:

in which R and R' have the meanings given above, and condenses this compound

split with an alkyl oxalate, a lower alkyl formate or a lower trifluoroacetate, in the presence of a basic condensation catalyst, preferably a lower alcoholate of an alkali metal, such as e.g. sodium methylate, whereby a 21-carbonyl-substituted compound is obtained which is halogenated with approx. 2 molar equivalents of chlorine or bromine, preferably bromine, in the presence of an alkaline substance,

preferably an alkali metal acetate, in quantities sufficient to react with the hydrogen halide formed and react the compound thus obtained with a lower alcoholate of an alkali metal such as e.g. sodium methylate, in the presence of an alkanol, such as methanol.

This procedure can be shown by the following reaction scheme:

In this reaction scheme, R and R' have the meaning given above, R" denotes hydrogen, a carbo-lower alkoxy group or a trifluoromethyl group, M denotes hydrogen or an alkali metal and X denotes chlorine or bromine.

In the reaction scheme, the general formula for the compound used in the preparation of the starting material is denoted by I. By reacting this with 2,2-dimethyl-1,3-propanediol, a 3-ketalized 5α-hydroxy-6|3-substituted -pregnan-3,11,20-trione of the general formula II. This compound is condensed as indicated above to the corresponding 21-carbonyl compound which has the general formula III. The latter compound is dihalogenated with chlorine or bromine in the same way as stated above, and the corresponding 21,21-dihalogen compound with the general formula V is then obtained. By reacting this dihalogen compound with a lower alcoholate of an alkali metal in an alkanol, one then obtains the product (VI) which is a lower alkyl ester of a 3-ketalized 3,11-diketo-5α-hydroxy-6-substituted 17(20) - (cis) -

pregnene-21-acid.

The selectivity of the ketalization is conveniently achieved by carrying out the reaction with the ketalizing agent (2,2-dimethyl-1,3-propanediol) at temperatures around room temperature, i.e. from approx. 20 to 30° C, but temperatures from approx. 10 to 40° C can also be used. At higher temperatures, the selectivity decreases and at lower temperatures, the reactivity decreases.

The compounds (I) used in the preparation of the starting materials for the method according to the invention can, in cases where R is a lower alkyl group excluding a methyl group, be prepared by the method according to Spero et al., J. Am. Chem. Soc, 78, 6813 (1956), i.e. by using a molar equivalent amount of the relevant lower alkyl Grignard reagent, e.g. ethylmagnesium bromide, propylmagnesium bromide, etc. instead of the methylmagnesium bromide used according to the mentioned reference.

The steps for transferring compounds corresponding to the general formula II to compounds corresponding to the general formula VI can be carried out according to methods known per se.

In the condensation step, the alkyl oxalate, the lower alkyl formate or

the trifluoroacetate, preferably in an amount of

at least one molar equivalent and preferably the methyl or ethyl ester of oxalic acid

respectively the formic acid. The basic condensation catalyst is preferably used in approximately molar equivalent amounts. Sodium methylate, sodium ethylate or potassium tertiary butylate are preferably used as lower alcoholates of alkali metals. An alkali metal can also be used as such catalysts, e.g. sodium or et al-potassium metal amide, e.g. sodium amide. One can use temperatures and reaction times within a large range and carry out the condensation in the presence of various inert solvents, e.g. temperatures from 0 to 100° C, time from 5 minutes to 48 hours and as solvents tertiary butyl alcohol, benzene, toluene or ether or mixtures of these substances.

As a basic substance in the halogenation step, e.g. potassium acetate, sodium acetate or sodium propionate in amounts sufficient to react with the entire amount of hydrogen halide formed during the reaction. Appropriately, an organic acid is added, e.g. glacial acetic acid in amounts sufficient to transfer the alkali metal enolate (III, M = alkali metal) formed in the condensation step to the free enol (III, M=H). When bromine is used for the halogenation, the end point of the reaction can be determined by the fact that the bromine color does not disappear. The halogenation is generally carried out at temperatures below room temperature, e.g. from approx. — 10 to 10° C. The reaction product from the halogenation (V) can be isolated or used directly in situ in the rearrangement step.

In the last step of the method, as a lower alcoholate of an alkali metal in a lower alkanol, e.g. sodium methylate in methanol or sodium ethylate in ethanol. It is preferred to use an alkanol and an alkali metal alcoholate in which the alkyl group is the same to prevent the formation of mixed esters of compound VI.

The products from the process according to the invention, i.e. the lower alkyl esters of 3-ketalized-3,11-diketo-5α-hydroxy-6(5-substituted 17,20-(cis )-pregnen-21-acid (VI), can be transferred to compounds with glucocorticoid and anti-inflammatory effects in reactions shown in the reaction diagram below:

In this reaction scheme, R and R' have the meanings given above, while Ac denotes the radical of a hydrocarbon-carboxylic acid with from 1 to 12 carbon atoms in the molecule.

The 11-keto and 21-carbonyloxy groups in a compound corresponding to the general formula VI are reduced with lithium aluminum hydride, thereby obtaining the corresponding 3-ketal of 5a,11|3,21-trihydroxy-6|3-substituted -17(20)-pregnen-3-one (VII). The 21-hydroxyl group in the compound thus obtained is then esterified, e.g. so that you get a 21-ester with a hydrocarbon-carboxylic acid which has from and including 1 to 12 carbon atoms in the molecule (compound VIII). This ester is then hydroxylated under oxidizing conditions, e.g. with osmium tetroxide and hydrogen peroxide, whereby the corresponding 3-ketal of 5a,lip,17a,21-tetrahydroxy-6(5-substituted

pregnane-3,20-dione (IX). The ketal group i

this compound is then removed to regenerate the 3-keto group and the 5α-hydroxyl group is dehydrated, preferably simultaneously, e.g. with hydrogen chloride in methylene chloride containing methanol or ethanol. This gives a 21-ester of a 6-substituted hydrocortisone (X).

6a-lower-alkyl-hydrocortisone, 6a-fluoro-hydrocortisone and 2i-esters of these compounds (X) have glucocorticoid and anti-inflammatory action and are thus advantageous for use in pharmacology instead of hydrocortisone and hydrocortisone acetate.

By means of the method according to the invention, advantageous starting materials for the production of such valuable therapeutic agents are thus obtained.

In the following, some embodiments of the method according to the invention are described as examples.

Example 1.

Preparation of 3-(2', 2'-dimethyltrimethylenedioxy)-5a-hydroxy-6$-methylene-pregnan-11,20-dione.

A mixture of 13.0 g of 2,2-dimethyl-1,3-propanediol, 9.0 g of 5α-hydroxy-6[3-methyl-pregnan-3,11,20-trione and 87.5 g of p-toluene -sulfonic acid monohydrate in 87.5 ml of methylene chloride was stirred for approx. 16 hours at room temperature in a closed vessel. The mixture was then washed with five 100 ml portions of 2% aqueous sodium bicarbonate solution, dried and evaporated to dryness. The residue was dissolved in 55 ml of acetone, filtered, the filtrate diluted with cyclohexane and filtered again. This second filtrate was evaporated, whereby 4.6 g of 3-(2,2-dimethyl-trimethylenedioxy)-5a-hydroxy-6|3-methylpregnan-11,20-dione was obtained with a melting point of 174-177° C. [a ]D + 50° (CHCl.,). As a further portion of the same product, 4.6 g with a melting point of 160-170° C were obtained.

By proceeding as indicated above using other 5α-hydroxy-6β-lower alkylpregnan-3,11,20-triones, e.g. those where the lower alkyl group is ethylpropyl, isopropyl, butyl, octyl, etc., the corresponding 3-(2',2'-dimethyl-propanediol)-ketals were obtained from these trions.

In a similar way, by replacing the starting material with 5a-hydroxy-6p-fluoropregnan-3,11,20-trione, the compound 3-(2',2'-dimethyl-trimethylenedioxy)-5a-hydroxy-6p-fluoropregnan was obtained -11,20-dione.

Example 2.

Preparation of 3-(2',2'-dimethyltrimethylenedioxy)-5a-hydroxy-6$-methyl-11-keto-17(20)-(cis)-pregnene-21-acid methyl ester.

A solution of 8.93 g of 3-(2',2'-dimethyl-trimethylene-dioxy)-5a-hydroxy-5|3-methylenepregnane-11,20-dione in 100 ml of tertiary butyl alcohol was in a nitrogen atmosphere at 55°C added 8.75 g of ethyl oxalate and 1 minute later 8.64 g of a 25% solution of sodium methylate in methanol. The addition of the latter solution was carried out as quickly as possible. The mixture was then allowed to cool to room temperature with stirring for 45 minutes. The resulting solution containing 3-(2,2-dimethyl-trimethylenedioxy)-5a-hydroxy-6|3-methyl-21-ethoxy-oxalyl-pregnan-11,20-dione sodium enolate was added to 2,4 g glacial acetic acid to form the free enol and then

3.28 g of anhydrous sodium acetate in 160 ml of methanol. The mixture was cooled to approx. 0° C and added dropwise an ice-cold solution of 6.4 g of bromine in 64 ml of methanol. 23.3 g of a 25% solution of sodium methylate in methanol was then added, after which the mixture was stirred for 20-24 hours at room temperature. It was then cooled to approx. 0° C and stirred at this temperature for approx.

2 hours. The mixture was then filtered and

the precipitate was first washed with 10 ml of cold methanol and then with water. The 3-(2',2'-dimethyl-trimethylenedioxy)-5a-hydroxy-6p-methyl-11-keto-17(20)-(cis)-pregnene-21-acid methyl ester thus obtained was dried in vacuum at a temperature between 50 and 60° C, whereby 6.84 g of crystals were obtained which melted at 202-208° C. By recrystallization from ethyl acetate crystals were obtained which melted at 219.5-220° C.

[a]_n — 9° (CHCl,).

By proceeding as in this example, but using other 3-2',2'-dimethyl-trimethylenedioxy)-5a-hydroxy-6fj-lower alkylpregnan-11,20-diones as starting material, e.g. those in which the lower alkyl group is ethyl, propyl, isopropyl, butyl, octyl, etc., the corresponding 3-(2',2'-dimethyl-propanediol)-5a-hydroxy-6fS-lower-alkyl-11-keto- 17(20)-(cis)-pregnene-21-acid methyl esters.

In a similar way, by using 3-2',2'-dimethyl-trimethylenedioxy)-5a-hydroxy-6p-fluoropregnan-11,20-dione as starting material, the compound 3-(2',2'-dimethyl-trimethylenedioxy- 5α-hydroxy-6β-fluoro-11-keto-17(20)-(cis)-pregnene-21-acid methyl ester.

Example 3.

Preparation of 3-(2',2'-dimethyltrimethylenedioxy-5a,11fi,21-trihydroxy-6ft-methyl-17(20)-(cis)- as appropriate.

A solution of 9.6 g of 3-(2',2'-dimethyl-trimethylenedioxy)-5α-:hydroxy-6(3-methyl-11-keto-17(20)-(cis)-pregnene-21-acid -methyl ester in a mixture of 120 ml of anhydrous benzene and 190 ml of anhydrous ether was added to a mixture of 3.2 g of lithium aluminum hydride and 190 ml of ether. The resulting mixture was stirred for iy2 hours and then split with 12.5 ml ethyl acetate followed by the addition of 40 ml of water. The organic layer was decanted from, and the inorganic solids extracted twice with 50 ml portions of ether. The organic layers were mixed and washed twice with 200 ml portions of water, dried and evaporated to dryness.

The residue which consisted of 8.81 g of 3-(2,2-dimethyl-trimethylenedioxy)-5α,11|3,21-tr|1-hydroxy-6β-methyl-17(20)-(cis)-pregnene

was dissolved in 90 ml of ethyl acetate, the solution was evaporated to a volume of 50 ml and cooled overnight. 6.89 g of crystals were obtained which melted at 190-194° C. [a]n

— 9° (CHCl:i). A sample recrystallized twice from acetone melted at 193-194°C and had [a]n of -11°

(CHC1;)).

Using 3-(2,2-dimethyl-trimethylenedioxy)-5α-hydroxy-6(3-fluoro-11-keto-17(20)-(cis)-pregnene-21-acid methyl ester as steroid starting material and going as stated above, 3-(2',2'-dimethyl-trimethylenedioxy)-5a,lip,21-trihydroxy-6(3-fluoro-17 (20)-(cis)-pregnene is obtained.

Example 4.

Preparation of 3-(2',2'-dimethyltrimethylenedioxy)-5a,11fi:21-trihydroxy-6fi-methyl-17(20)-(cis)-pregnene-21-acetate.

A solution of 28.1 g of 3-(2',2'-dimethyl-trimethylenedioxy)-5a,11fi,21-trihydroxy-6p-methyl-17(20)-(dis)-pregnene in 100 ml of pyridine was added 70 ml of acetic anhydride, and the mixture was kept at room temperature overnight. It was then added to 500 ml of water and extracted with two 200 ml portions of methylene chloride. The extracts were washed with four 100 ml portions of water. The aqueous layer and the washing water were washed with 50 ml of methylene chloride each. The methylene chloride extracts were combined and evaporated to dryness under reduced pressure, whereby 30.7 g of 3-(2',2'-dimethyl-trimethylenedioxy)-5a,lip,21-trihydroxy-6p-methyl-17(20) was obtained -(cis)-pregnene-21-acetate which melted at 136—141° C. [a]„ — 3° (CHC1.,). An analytically pure sample melted at 140— 141° C and had [a],, —5° (CHC1.,)..

By proceeding in a similar manner using 3-(2',2'-dimethyl-trimethylenedioxy)-5a,lip,21-trihydroxy-6p-fluoro-17(20)-(cis)-pregnene as starting material, one obtained 3-(2',2'-dimethyltrimethylenedioxy)-5α,lip,21-trihydroxy-6β-fluoro-17(20)-(cis)-pregnene-21-acetate.

The two starting materials stated above can be transferred to other 21-acylates of the same by esterification of the 21-hydroxyl group, e.g. by reaction with the appropriate acid anhydride, acid chloride or acid bromide. To desired esters by transesterification or from the acid by reaction in the presence of an esterification catalyst. Among the esters that can be prepared in this way are those whose acid radical is a lower aliphatic acid, e.g. formic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, trimethylacetic acid, 2-methylbutyric acid, 3-ethylbutyric acid, hexanoic acid, diethylacetic acid, triethylacetic acid, heptanoic acid, octanoic acid, α-ethylisovaleric acid, a cyclic acid, e.g. cyclopentyl formic acid, cyclopentyl acetic acid, p-cyclopentyl propionic acid, cyclohexyl formic acid, cyclohexyl acetic acid, p-cyclohexyl propionic acid, an aryl or alkaryl acid, e.g. benzoic acid, 2-, 3- or 4-methylbenzoic acid, 2,6- and 3,5-dimethylbenzoic acid, ethylbenzoic acid, 2,4,6-trimethylbenzoic acid, 2,4,6-triethylbenzoic acid, a-naphthoic acid, 3-me -thyl-α-naphthoic acid, an aralkyl acid, e.g. phenylacetic acid, phenylpropionic acid, diphenylacetic acid, triphenylacetic acid, and a dibasic acid (which can be transferred to water-soluble salts, e.g. sodium salts), e.g. succinic acid, glutaric acid, α-methylglutaric acid, p-methylglutaric acid, p,p-dimethylglutaric acid, adipic acid, pimelic acid, suberic acid.

Preparation of 3-(2',2'-dimethyl-trimethylenedioxy)-5(i,lip,17a,21-tetrahydroxy-6p-methyl-pregnan-20-one-21-acetate from the product obtained in example 4 : To a solution of 15 g of 3-(2',2'-dimethyl-trimethylenedioxy)-5α,lip,21-trihydroxy-6β-methyl-17(20)(cis)-pregnene-21-acetate in 273 ml of tertiary butyl alcohol, 3.9 ml of pyridine, then 2.75 molar equivalents of N-methylmorpholinoxydperoxide in tertiary butyl alcohol and finally 17.8 ml of osmium tetroxide in 5.0 ml of tertiary butyl alcohol were added there at room temperature. The mixture was kept at room temperature overnight and 6.3 g of filter aid (Magne-sol) and a solution of 0.48 g of sodium hydrosulphite in 96 ml of water were then added. The mixture was stirred for 30 minutes. It was then filtered, and the filter cake washed with two 50 ml portions of methylene chloride. The filtrate was evaporated to a volume of about 90 ml under reduced pressure and then mixed with 600 ml of water. The mixture was extracted four times with 300 ml portions of methylene chloride. The organic layer was washed with two 300 ml portions of water and then evaporated to dryness under reduced pressure. The residue which consisted of 3-(2',2'-dimethyl-trimethylenedioxy)-5a,lip,17a,21-tetrahydroxy-6p-methylpregnan-20-one-21-acetate was dissolved under heating in 25 ml ethyl acetate, and the solution was allowed to cool. The resulting precipitate was filtered off, whereby crystals were obtained in three portions, the first of which melted at 236-240° C, the second at 222-225° C and the third at 214-219° C. An analytically pure sample melted at 224—225° C. [a]D + 40° (ethanol).

In a similar way one obtains by using

3-(2',2'-dimethyl-trimethylenedioxy)-5a,

11|3,21-trihydroxy-6β-fluoro-17(20)-(cis)-pregnene-21-acetate as starting material

the compound 3-(2',2'-dimethyl-trimethylenedioxy)-5α,lip,17α,21-tetrahydroxy-6β-fluoro-pregnan-20-one-21-acetate.

Claims (1)

Procedure for the preparation of compounds of the general formula: (in which R denotes fluorine or a lower alkyl group, preferably a methyl group, and R' denotes 2,2-dimethyl-trimethylene), and which are suitable for use as starting materials for the preparation of 6-fluoro- or 6-lower alkyl-substituted hydrocortisone, -prednisolone, esters of these compounds and corresponding 5a-hydroxysteroids, characterized in that in the presence of p-toluenesulfonic acid as a catalyst, 2,2-dimethyl-1,3-propanediol is reacted with a compound corresponding to the general for- flour: in which R has the meanings given above, whereby a compound with the general formula is obtained: in which R and R' have the meanings given above, and condenses this compound with an alkyl oxalate, a lower alkyl formate or a lower trifluoroacetate, in the presence of a basic condensation catalyst, preferably a lower alcoholate of an alkali metal such as e.g. sodium methylate, whereby a 21-carbonyl-substituted compound is obtained which is halogenated with approx. 2 molar equivalents of chlorine or bromine, preferably bromine, in the presence of an alkaline substance, preferably an alkali metal acetate, in amounts sufficient to react with the hydrogen chloride or bromide thus formed and react the compound thus obtained with a lower alcoholate of an alkali metal like for example. sodium methylate, in the presence of an alkanol, such as methanol.