FR2653127A1 - Process for the preparation of 12-oxocholanates - Google Patents

Abstract

There is described the preparation of 12-oxocholanates from alkyl cholate 3,7-diacetates by oxidation with an alkali metal hypochlorite and acetic acid in stoichiometric quantities in the presence of an alkali metal bromide and at a temperature of less than 40 DEG C.

Description

 The present invention relates to a process for the oxidation of hydroxycholanates by the action of an alkaline hypochlorite and acetic acid.

 This reaction, which is known in the literature and is conducted using an excess of acetic acid, has the disadvantage of releasing chlorine and thus containing control problems to avoid ecological damage.

 It has now been found that the oxidation reaction with an alkaline hypochlorite can be carried out efficiently and without control problems using the stoichiometric amount of acetic acid and operating in the presence of an alkaline bromide at a temperature below 400C preferably less than 10oC.

dans laquelle les-deux R et R' représentent l'hydrogène ou bien les deux R, identiques, représentent un groupe acétyle et R' représente méthyle, éthyle ou n-propyle, caractérisé en ce qu'on

Thus, the present invention relates to a process for the preparation of a 12-oxocholanate of formula

in which the two R and R 'are hydrogen or the two R, identical, represent an acetyl group and R' represents methyl, ethyl or n-propyl, characterized in that

<tb> treats <SEP> a <SEP> 12a-hydroxycholanate <SEP> of <SEP> formula <SEP>: <SEP> COOL
<tb><SEP> OH
<tb><SEP> CH <SEP> CCND <SEP><SEP> O-COCH3
wherein R 'is hydrogen or methyl ethyl or n-propyl with alkaline hypochlorite and acetic acid in stoichiometric amounts in the presence of an alkaline bromide and at a temperature below 400C, and optionally saponifies the product thus obtained.

 As the preferred starting hydroxycholanate, there is used 3α, 7α-diacetoxy-12-hydroxy-5-cholanic acid (or cholic acid 3,7-diacetate) or its methyl ester.

 The reaction can be carried out in an organic or organic-aqueous solvent, the organic solvent being a halogenated hydrocarbon, for example methylene chloride or 1,2-dichloroethane, ethyl acetate or an ether, for example dimethoxyethane. or tetrahydrofuran.

 The alkaline bromide is advantageously used in a proportion of 0.34-1.15 mol per mole of starting hydroxycholanate, the cation being preferably that of the hypochlorite used. Preferably, sodium hypochlorite and sodium bromide are used.

 The reaction temperature should be less than 400C to avoid the release of chlorine, but it is advantageous to conduct the oxidation below 100C and, preferably, below OOC.

 In general, according to a preferred procedure, the reaction is terminated after 16-24 hours at a temperature between -10 and 0 ° C and the final product is isolated according to conventional techniques.

 For example, the product thus obtained can be isolated in crystalline form by pouring the reaction mixture into water, optionally in the presence of an alkaline sulfite which serves to destroy the excess of oxidizing agent still present, by eliminating the aqueous phase. and evaporating the solvent.

 A 3a, 7cc-diacetoxy-12-oxo-5ss-cholanic acid ester is thus obtained which can be saponified using an aqueous solution of sodium hydroxide to isolate 3a, 7a-dihydroxy-12-12 acid. -oxo-5 cholanic.

 The following examples illustrate the invention without limiting it.

Example 1
To a solution of 17 kg of methyl 3a, 7a-diacetoxy-12a-hydroxy-5ss-cholanate and 1.04 kg of sodium bromide in 46 kg of ethyl acetate, 3.6 kg of acetic acid and 3 4 kg of water, cooled to -100 ° C.-OOC, 18.48 liters of a 14.9% weight / volume solution of sodium hypochlorite are added over 5 hours. The reaction mixture is left for 16 hours at the same temperature, then 17 kg of a 10% sodium sulphite solution are added and heated to 400 ° C. The aqueous phase is removed, neutralized with sodium bicarbonate solution and the solvent is evaporated on a water bath. By cooling and filtration, 16.93 kg of methyl 3a, 7a-diacetoxy-12-oxo-5ss-cholanate are obtained, identical to an authentic sample. Quantitative yield.

Example 2
The operation is carried out as described above until the solvent is evaporated from the solution containing methyl 3α, 7α-diacetoxy-12-oxo-3-cholanate and then 4 equivalents of 40% sodium hydroxide are added. and refluxing until saponification is complete. Acidification with hydrochloric acid gives 3a, 7a-dihydroxy-12-oxo-5ss-cholanic acid having a titer greater than 99% with respect to an authentic sample. Quantitative yield.

Claims (4)

1. Process for the preparation of a 12-oxocholanate of formula

 in which the two R and R 'are hydrogen or the two R, identical, represent an acetyl group and R' represents methyl, ethyl or n-propyl, characterized in that a 12a-hydroxycholanate of formula

 in which R 'represents hydrogen or a methyl, ethyl or n-propyl group with alkaline hypochlorite and acetic acid in stoichiometric amounts in the presence of an alkaline bromide and at a temperature below 400 C, and is saponified possibly the product thus obtained. 2. Method according to claim 1, characterized in that methyl 3a, 7a-diacetoxy-12a-hydroxy-5ss-cholanate is used as starting material. 3. Method according to one of claims 1 or 2, characterized in that the alkali bromide is used in a proportion of 0.34-1.15 moles per mole of starting hydroxycholanate. 4. Process according to any one of claims 1 to 3, characterized in that sodium hypochlorite and sodium bromide are used.