CS236228B1 - Process for the preparation of 3? -Acetoxy bile acid derivatives - Google Patents

Abstract

A method for producing 3<-acetoxy derivatives of bile acids by selective acetylation of the 3«;-hydroxyl group of methyl esters of bile acids, containing in the molecule an additional hydroxyl group in position 6*, 7 dc , 12 oc or two hydroxyl groups in positions 7<sc and 12x,, with acethydria in an internal organic solvent of the toluene type in the presence of potassium bicarbonate and at the boiling temperature of the reaction mixture.

Description

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of bile acid methyl β-acetoxy derivatives and bile acid methyl ethers. The Nα-acetoxy bile methyl ester derivatives are of great importance in the synthesis of steroid compounds.

Partial 3α-β-acetylation of bile acids, which contain another hydroxyl group in addition to the 30-hydroxyl group in the molecule, is a relatively difficult matter, with the exception of those substances whose hydroxyl groups differ significantly in their reactivity. Thus, for example, acetylation of the methyl ester of deoxycholic acid pyrobes preferably at the hydroxyl group at the 3 o b position in a yield of about 40% (Reichstein and Sorkin: Helv.Chim.Acta 25 · 797, 1942; Callagher and longs J.Biol.Chem. 162, 521, 1946], while selective 3o6-acetylation of methyl choline ester with acetic anhydride in anhydrous benzene at elevated temperature, followed by isolation of the product by column chromatography on alumina provides only a low yield of 3 cb-monoacetate (Plattner and Heussert Helv.Chim.Icta) 27, 748 (1944). An even more complicated situation is in the methyl ester of chenodesoxycholic acid, where the 3o6-monoacetate was obtained by the following procedure: By the Kernin-Wolff reduction of the 12-oxo group of the methyl ester, 30o, 7o-diacetoxy-12-oxo-5 (zoholanic acid) diazomethane, acetylated with acetic anhydride in pyridine, and the resulting ester mixture was isolated by low column chromatography on alumina in low yield Jeb-monoacetate alongside Jeb, 1bb-diacetate (feauser et al., Helv. Chim.Acta 43, 1595, 1960). preparation of β-monoacetate derived from ob -hyodesoxycholic acid methyl ester requires a multi-step reaction sequence (Hoehn et al., J. Am. Chem. Soc. 68, 1855, 1946).

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The above-mentioned disadvantages are overcome by the process for the preparation of 3 &apos; -ethoxy derivatives. bile acids in a solvent medium according to the invention, characterized in that the methyl esters of bile acids substituted with a hydroxyl group at the 3 ° position and another hydroxyl group at the 6 position of (ω -hyodesoxycholic acid), 7% (ohenodesoxycholic acid), 12 or (two hydroxyl groups at the 7t and 12bp positions) are selectively acetylated with acetic anhydride in an inert organic solvent of the toluene type in the presence of potassium bicarbonate and at the boiling point of the reaction mixture. Under these conditions, selective aetylation of the hydroxyl group in the lot position takes place in a single reaction stage and satisfactorily yields β. The inert organic solvent used is an aromatic hydrocarbon, preferably toluene, wherein the acetyl is carried out at an elevated temperature, preferably the boiling point of the reaction mixture. The high selectivity of the α-ethyl-ω-hydroxyl group under the above conditions is also demonstrated by the results of gas chromatographic analyzes of the crude reaction products.This 30 minutes of acetylation under the given conditions gives cholic acid methyl ester 88.4 methyl ehenodeeoxycholic acid 84.3 methyl deeoxyalcohol 71.4% and methyl ester φ -hyodeeozycholic acid 92.3% of the corresponding 3Ot-monoaoetate ·

Three embodiments of the process of the present invention include a mixture of 1 part by weight of bile acid methyl ether, 0.75 part by weight of acetic anhydride, 1 part by weight of potassium bicarbonate and 10 parts by weight. Anhydrous toluene was heated to reflux for 30 minutes, and after working up the reaction mixture, the product was isolated by crystallization or silica gel column chromatography.

The following examples illustrate the invention but do not limit it.

For example, 1

A mixture of 1 g of sodium methyle ether, 0.75 ml of acetic anhydride, 1 g of potassium hydrogencarbonate and 10 ml of anhydrous toluene is heated to boiling for 30 minutes. ml of water · The precipitated crude product is sucked off, washed with water until neutral, dried and crystallized with a mixture of oetone and n-hexane. 0.56 g of methyl -eoetoxy 7oó-12 (/, -dihydroxy-5 / # -cholanové, mp 148-150 ° C / 6 ^ / _D · ** ♦ 49 / chloroform /.

Example 2

A mixture of 5% dry methyl chenodesoxycholic acid, 3.75 ml acetic anhydride, 5 g potassium bicarbonate and 50 ml anhydrous toluene is heated to boiling. 30 minutes. The reaction was quenched with water, the toluene layer was separated, washed with water until neutral, and the solvent was distilled off in vacuo. The residue was crystallized from a mixture of petrol and acetone. There were obtained 2.61 g of methyl 3OO-acetoxy-7 <X ' -hydroxy-5/3 -cholanové, mp 53-55 0 ° »/ HR / * ^ ♦ 26 ^0> / chloroform /.

Example 3

A mixture of 1 g of dry desoxycholic acid methyl ester, 0.75 ml of acetic anhydride, 1 g of potassium bicarbonate and 10 ml of anhydrous toluene is heated to boiling for 30 minutes. The reaction mixture was quenched with water, the separated toluene layer was washed with water until neutral, and the solvent was distilled off in vacuo. The residue was dissolved in benzene and chromatographed on a column of 30 g of silica gel containing 10% water. Blending with a 97: 3, 96: 4, and 95: 5 by volume mixture of benzene and acetone gave 3d .alpha.-acetoxy-12H-hydroxy-5/3-cholanic acid methyl ester, which was crystallized from a mixture of acetone and heptanes. 0.62 g solid, mp 126 DEG-127.5 DEG C. / ^ / _D «T64 ° ^r / acetone /.

EXAMPLE 4 g of dry methyl .alpha. -odesoxycholic acid methyl ester is acetylated in analogy to Example 1 and the reaction mixture is worked up as in Example 2. Crystallization of the crude product from aqueous azetone yields 0.49 g of 3 &apos; 5 (3-cholans, m.p. 119-121 ° C, &lt;% (j)) < 445 &gt;

Claims (1)

Process for the preparation of 3-acetoxy derivatives of bile acids and methylation of bile acid methyl ethers in a solvent with a hydroxyl group in the 6-position, Ία, 12oL · or two hydroxyl groups in the 7oC and 12ob positions selectively acetylated with acetic anhydride in an inert organic solvent of toluene presence of potassium bicarbonate and heat of reaction mixture ·