Preparation of Chenodeoxycholic Acid

The method (Fig. 8) is based on that described by Fieser and Raja-gopalan (51) with modification. 

Selective acetylation at positions 3a and 7a of methyl cholate (XXVa, 25 g) is effected in benzene (125 ml) containing acetic anhydride (30 ml) and pyridine (30 ml). The mixture is kept at room temperature for 24 hr and then poured into ice water in a separatory funnel. The benzene layer is washed 

A solution of CrOg (2.7 g) in water (5 ml) is diluted with acetic acid (20 ml) and added slowly to a solution of the above 12a-hydroxy methyl ester (XXVI, 19g) in acetic acid (100 ml) while the mixture is cooled under a 

3a-Hydroxy-7a-acetoxy-17-keto-5 -cholanic Acid (XXVIII) 

In the original procedure described by Fieser and Rajagopalan (51) for the preparation of chenodeoxycholic acid, methyl esters were used throughout the sequence of reactions. Since methyl esters form hydrazides with hydrazine used in the Wolff-Kishner reduction, this side reaction is avoided by hydrolysis of the methyl ester (XXVII) to the free acid (XXVIII) before Wolff-Kishner reduction is attempted. 

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This keto acid was detected in human feces (121) but is not known to occur elsewhere as a natural product. This acid and its esters have been valuable as intermediates in the preparation of chenodeoxycholic acid. The keto acid may be prepared by Cr03 oxidation of the methyl ester diacetate of cholic acid (163) followed by rigorous hydrolysis. Mild hydrolysis yields the 7-monoacetate (m.p. 239 °C) which may also be reduced by the Wolff-Kishner procedure to the 3,7-dihydroxy acid. 

Hofmann, A.F., The preparation of chenodeoxycholic acid and its glycine and taurine conjugates. Acta Chem. Scand., 1963.17 173-186. 

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