DE960818C - Process for the preparation of 3ª ‰ -oxy-5 (6) -cholenic acid - Google Patents

Description

ISSUED MARCH 28 IS57

V 5699 IVbI12

Dr. Alfred Schubert, Jena

has been named as the inventor

VEB Jenapharm, Jena

The invention relates to a method of manufacture of 3 /? - Oxy-5 (6) -cholenic acid from hyodeoxycholic acid and / or its functional derivatives. the Compounds which can be prepared by the process according to the invention are intermediates for the partially synthetic Extraction of hormones.

It is known that 3 / S-oxy-5 (6) -cholenic acid is made from Cholesterol via the cholesterol acetate through subsequent bromination and through conventional oxidation processes and subsequent saponification occurs. This oxidation reaction is inconsistent; and the yield obtained is very unsatisfactory.

It is also known from German Patent 909 935 that 3-oxysteroids are unsaturated in the 5 (6) position from 3, 6-dioxysteroids by reaction with mineral acids or with phosphorus oxychloride in pyridine can be prepared (cf. also Proc. Jap. Acad., Vol. 28, 1952, p. 546).

It has now been found that 3j8-oxy-5 (6) -cholenic acid also by reacting 3, 6-dioxycholanoic acid and its functional derivatives with Phosphorus trichloride or phosphorus tribromide in the absence of pyridine by partial dehydration between the carbon atoms 6 and 5 with the formation of a 5 (6) double bond can produce.

The process according to the invention is carried out at higher temperatures, preferably between 90 and 100 °, carried out and proceeds with good yield and considerable speed. The one becoming free

Hydrogen halide escapes in gaseous form or initially does not remain, especially if one is used Hydrocarbons involved in the reaction and only used as solvents, such as benzene, xylene or a paraffin. The implementation proceeds particularly advantageously when inert gases, e.g. B. carbon dioxide or nitrogen, are forced through the reaction solution. The reaction then proceeds primarily in the direction of the formation of 3-halo-5 (6) -cholenic acid derivatives. The inert gases then protect not only, as is known, the solution z. B. from oxidation, but they also wash the formed Hydrogen halide.

From the 3 /? - halogen- ■ 5 (6) -cholenic acid derivatives are obtained by transesterification and subsequent saponification, the 3 ^ -oxy-5 (6) -cholenic acid and as a by-product 3cc-oxy-5 (6) -cholenic acid.

If, on the other hand, the process according to the invention is carried out in the absence of an inert gas, the hydrogen halide is re-deposited on the double bond initially formed, with the formation of corresponding 3,5-dihalogen derivatives. The 3, 5-D1-bromallocholansäuremethylester has z. B. a melting point of 131 ⁰ . These 3,5-dihalogen compounds can also be transesterified and saponified by customary methods. In each case, s ^ -alkoxy-S-cholenic acid derivatives are formed.

The achievable yields are about 65 ° / ,, and can be described as high compared to the yields obtained by the processes previously used will. The products obtained are of a high degree of purity and can easily be used for the Hormone synthesis are used.

The method according to the invention is illustrated by the following formula diagrams and examples:

CH _a

Dehydration

in attendance
of inert gas

HO

Hc-CH ₂ -CH ₂ -COOCH ₃

Dehydration

in the absence of inert gas

(I)

CH ₃

HC-CH ₂ -Ch ₂ -COOCH ₃

CH ₃ |

CH ₃

HC-Ch ₂ -CH ₂ -COOCH ₃ CH,

HC-CH ₂ -CH ₂ -COOR ₂ CH ₃ !

Transesterification

Saponification

(III)
R ₁ = —H, CH ₃ CO-; R ₃ = —H, CH ₃ -.

Example r

ίο parts of methyl hyodeoxycholate are dissolved in 100 parts of xylene at 70 °; it is then cooled to 50 ° and a solution of 7 parts of phosphorus tribromide in 15 parts of xylene is slowly run in over the course of 30 minutes. After a further 30 minutes, the temperature is increased to 100 ° and the reaction mixture is kept at this temperature for 1 hour. After cooling, the reaction mixture is decomposed with ice water, washed thoroughly and then dried. After the xylene has been evaporated off in vacuo, 20 parts of alcohol are added to the residue. Crystals separate out and can be recrystallized from alcohol. You then have a melting point of 131 to 133 °; [afg = + 4.2 ° F + 4 °. This 3, 5-dibromocholanic acid methyl ester is transesterified with potassium acetate and glacial acetic acid using customary methods. The work-up is done in such a way that, after the transesterification, the 3/9-acetoxy-5 (6) -cholenic acid methyl ester formed is taken up in benzene. After this solvent has evaporated off, the pure methyl 3/3-oxy-5 (6) -cholenate crystallizes with a melting point of 157 ° on addition of methyl alcohol.

'Example 2

The treatment of methyl hyodeoxycholic acid with phosphorus tribromide is carried out as described in Example 1, the only difference being that, after the xylene has been evaporated off, the crude methyl 3,5-D1-bromocholenate is not separated off, but is immediately subjected to transesterification with potassium acetate in glacial acetic acid. After the usual work-up with good yield immediately pure 3 / J-acetoxy-5 (6) -cholensäuremethylester a melting point of 157 to ^0, the no special cleaning immediately with 3% methanolic NaOH is boiled for 1 hour produced. When the methanolic solution is diluted with water, sodium 3 / S-oxy-5 (6) -cholenic acid precipitates. The crude sodium salt was dissolved in hot glacial acetic acid, from which the crystallized 3js-oxy-5 (6) -cholensäure of melting point 235 ⁰ upon cooling.

Example 3

IO parts Hyodesoxycholsäuremethylester are dissolved in 100 parts of xylene at 70 ^0th 7 parts of phosphorus tribromide in 25 parts of xylene are added over the course of 10 minutes. At the same time, a vigorous stream of nitrogen is introduced through a glass frit attached to the bottom of the reaction vessel. After a short time, streams of hydrogen bromide escape from the reaction vessel and are collected in a suitable receiver. After the reaction mixture

I ¹ Z was _{kept at a temperature of 90 ° for 2} hours, the mixture is cooled to room temperature after the reaction has ended. The reaction solution is decomposed in ice water. The xylene is dried and evaporated in vacuo. The methyl 3 /? - bromo-5 (6) -cholenic acid precipitates spontaneously from the residue with a melting point of 123 °. This ester is already so pure that it immediately, without recrystallization, by transesterification with potassium acetate-glacial acetic acid in the 3/5-acetoxy-5 (6) -cholensäuremethylester, which according to the known saponification at 3 ° / _o methanolic KOH followed by acidification, the supplies free 3 /? - oxy-5 (6) -cholenic acid with a melting point of 235 ⁰ , can be converted.

Example 4

65.6 parts of phosphorus trichloride are slowly added dropwise over 15 minutes to a solution of 10 parts of methyl hyodeoxycholic acid in 100 parts of toluene. Carbon dioxide is introduced through a glass frit attached to the bottom of the reaction vessel, and the temperature is increased to 100 to 105 °. After a short time, hydrogen chloride escapes. The reaction has ended after 2 hours. The reaction vessel is cooled to room temperature and the reaction solution is decomposed with ice water while stirring vigorously. The toluene containing the reaction product is washed neutral, dried and evaporated in vacuo. The initially oily reaction product partially crystallizes after a few hours. The .Kristalle are 3 _J 8-chloro-5 (6) -choIensäuremethylester, they have a melting point of ii8 °. Without any particular impairment, the entire reaction product is transesterified with potassium acetate and glacial acetic acid, as described in the other exemplary embodiments, and then saponified. 3.5 parts of 3/3-oxy-5 (6) -cholenic acid are obtained.

Claims (1)

Claim = Process for the preparation of 3) 3-oxy-5 (6) -cholenic acid from hyodeoxycholic acid or its functional derivatives by elimination of water with an acid halide and subsequent transesterification and saponification, optionally in the presence of inert gases, characterized in that hyodeoxycholic acid or its functional derivatives with Phosphorus tribromide or phosphorus trichloride in an inert solvent, optionally with passage of an inert gas, at elevated temperature, preferably at temperatures between 90 and ^{100 ° C.} , and the 3-bromo-5 (6) -cholenic acid or 3,5-dibromocholanoic acid compound obtained transesterified and saponified in a known manner. 609 656/490 9. » (609845 3.57)