CS225020B1 - The production of chenodesoxycholic acid - Google Patents

Description

The invention relates to a process for the preparation of chenodesoxycholic acid of the formula I

a valuable drug of inoperable gallstones of cholesterol origin. This acid, belonging to the natural substances contained in animal bile, especially poultry, is usually produced for therapeutic purposes by one of the partial syntheses, which are always based on cheap and easy

(ll)

The first practical synthesis was described by Fieser (J. AM. Chem. Soc. 71, 3935, 1949; ibid. 72, 5530, 1950), which used a Kizner-Wolff reduction of the corresponding 12-ketoderivative. The same methods were used by Hoffmann (Adta Chem. Scand. 17, 173, 1963) and Hauser (Helv. Chim. Acta 43, 1595, 1960), who modified the original Fieser procedure. Sato and Ikekawa (J. Org. Chem. 24, 1367, 1959) utilized desulfuration of the corresponding 12-thioketal moiety by Raney nickel. Another possibility is the preparation of the 12-p-toluenesulfonylhydrszone derivative and its reduction with a selective reducing agent (Czech Patent Certificate No. 186067)

225020 2

A different process has been described by Chen (Synthesis 1976, 125), whose most efficient and industrially useful synthesis so far is based on the preparation of the 12rt-methanesulfonyloxy derivative of formula III

CH ₂ CO ₂ os ₂ ch ₃ ch ₃

OCOCH ₃

COOCH ·, (III) accessible in three reaction steps from the starting cholic acid of formula II, from which the methanesulfonic acid is cleaved to give the 11,12-unsaturated compound of formula IV

(iv)

This cleavage is performed with potassium acetate in hexamethylphosphoric triamide (HMPA) at elevated temperature. After catalytic hydrogenation of the 11,12-unsaturated compound of formula IV and hydrolysis of the ester functions, the title compound is obtained in good yield and quality. Despite a number of advantages, the disadvantage of this process is the need for a large amount of readily available HMPA, which acts as both a solvating agent and a solvent; moreover, HMPA is one of the potential carcinogens, so manipulation with it on an industrial scale is undesirable for health reasons. In addition, the reaction sequence described in the penultimate step, i.e. catalytic hydrogenation, requires the treatment of uncomfortably large volumes of solvents.

in

These disadvantages are overcome by the process for producing chenodesoxycholic acid of the above formula I by cleavage of methanesulfonic acid from 3alpha, 7'-diacetoxy-12a-methanesulfonyloxy-5'-oxoic acid methyl ester of the above formula III by an anhydrous alkali metal acetate, e.g. solvent, at elevated temperature, to form the 11,12-unsaturated compound of the above formula IV, which is hydrolyzed and then hydrogenated, according to the invention, characterized in that cleavage of methanesulfonic acid from the compound of formula III is carried out to produce the compound of formula IV in dimethylformamide or dimethylsulfoxide, in the presence of a quaternary ammonium salt solvating agent of formula V

, is an atom in which R ₁ is an alkyl of 1 to 4 carbon atoms, R 1 is ethyl, chlorine or bromine. The solvating agent is preferably used in an amount of 1 mol, based on 1 mol of the starting material of the formula III.

Under these conditions, the 11,12-unsaturated compound of formula IV produces smoothly and in good yield. The quaternary ammonium salts of formula (V) used as the solvating agent are inexpensive, readily commercially available substances, of low toxicity, usually serving as bactericidal or fungicidal agents. By further processing of the product obtained by advantageous modification of the Chen process, chenodesoxycholic acid can be obtained in satisfactory yields and quality.

In general, a solution of the starting methanesulfonate of formula III in dimethylformamide or dimethylsulfoxide is mixed with melted alkali metal acetate, preferably potassium acetate, and a solution of anhydrous solvating agent of formula V in the same solvent at a ratio of 1 mol reagent per 1 mole of starting material of formula III. Cleavage of the methanesulfonic acid is accomplished by heating the reaction mixture to a temperature of about 100 ° C, from slow stirring, under anhydrous conditions, in a non-oxidizing gas atmosphere. After the reaction is complete, the alkali metal acetate and solvent and solvating agent are removed preferably by filtration through an ion exchanger.

The resulting crude product of formula IV is crystallized from a suitable organic solvent, preferably a lower alkanol. The purified product is then subjected to hydrolysis, for example by boiling with an aqueous methanolic potassium hydroxide solution. By treating the reaction mixture, the product obtained is then converted to the ohenodesoxyalcohol of the formula I in good yield and good quality by one of the known methods of hydrogenation, for example in ethanol, using a palladium catalyst at atmospheric pressure.

Further details of the process according to the invention will be apparent from the following examples, which are not to be construed as limiting.

Example 1

29.5 g of the methanesulfonyl derivative of formula III in 195 ml of dimethylformamide are mixed with 11.8 g of fused potassium acetate and a solution of 17.7 g of anhydrous dimethyl (C8-C8) alkyl (alkenyl) -benzylammonium chloride in 100 ml of dimethylformamide. Heat at 100 ° C under nitrogen, with slow stirring, for 30 hours. The reaction mixture was filtered, the undissolved potassium acetate was washed thoroughly with toluene, and the filtrate was evaporated to dryness under slight vacuum.

The residue is stirred with water and the aqueous phase is stirred with 200 g of ion exchanger for 2-3 hours. The ion exchanger with the adsorbed product and the quaternary ammonium salt is filtered off with suction, extracted with ethanol, and the ethhenol extract is concentrated to crystallize. 15 g of 11-dehydro compound of formula IV are obtained, m.p. M.p. 137-141 ° C.

Example 2

The procedure was as in Example 1 except that an equal volume of dimethylsulfoxide was used instead of dimethylformamide. Analogous work-up gave 14.7 g of the 11-dehydro compound of formula IV, m.p. Mp 137-140 ° C.

Example 3

The procedure was as in Example 1 except that 11 g of triethylbenzylemonium chloride (or an equivalent amount of tetrabutylammonium bromide or α-carbethoxypentadeoyltrimethylammonium bromide) was used as the solvating agent. Analogous work-up and work-up gave 14.9 g of the 11-dehydro compound of formula IV, m.p. 138-141 ° C.

Example 4 g of the 11-dehydro compound of formula IV is mixed with 12 ml of methanol and 19 ml of 50% aqueous potassium hydroxide solution and the mixture is refluxed for 15 hours. It is then concentrated to a small volume, the residue is poured into water and acidified with hydrochloric acid. The precipitate is filtered off with suction, washed with water to neutrality and the isolated product (yield 11.8 g, mp 129 DEG -13 DEG C.) is dissolved in 130 ml of ethanol and hydrogenated to 1.18 g of palladium catalyst until the consumption of hydrogen is stopped. After hydrogenation, the catalyst is filtered off with suction, washed with ethanol and the filtrate is evaporated to dryness in vacuo. The residue was crystallized from ethyl acetate. 10.5 g of chenodesoxycholic acid, m.p. 138-141 ° C.

Claims (2)

1. A process for the preparation of chenodesoxycholic acid of formula I (1) by cleavage of methanesulfonic acid from methyl 3a, 7n-diacetoxy-1α-methanesulfoate by the action of anhydrous alkali metal acetate such as potassium acetate in an inert aprotic solvent at elevated temperature to give 11, A 12-unsaturated compound of formula IV (• v) which is hydrolyzed and then hydrogenated, characterized in that the cleavage of methanesulfonic acid from the compound of formula III to form the compound of formula IV is carried out in dimethylformamide or dimethylsulfoxide medium from a quaternary ammonium salt solvating agent. (V) wherein R 1 is alkyl of 1 to 4 carbon atoms, R 8 is alkyl of 1 to 18 carbon atoms, or alkenyl of 2 to 18 carbon atoms, R 6 is ethyl, butyl, benzyl, or α- carbethoxypentadecyl, X is a chlorine or bromine atom. 2. A process according to claim 1, wherein the solvating agent of the formula V is used in an amount of 1 mol, based on 1 mol of the starting material of the formula III.