CS236229B1 - Process for the preparation of the methyl ester of 3 ', 12' - X-diacetoxy-7'-hydroxy-5'-chloroanate - Google Patents

Abstract

A method for producing methyl ester of 3-[alpha],12-[alpha]-acetoxy-7-hydroxy-5-[beta]-cholanic acid by selective acylation of methyl ester of cholic acid with acetic anhydride in an internal organic solvent of the toluene type, in the presence of a base of the anhydrous potassium acetate or calcium carbonate type and at the boiling temperature of the reaction mixture. The compound is used as an intermediate in the synthesis of steroid compounds, in the preparation of radioisotope-labeled substances, in the study of bile acid metabolism, etc.

Description

The present invention relates to a process for the preparation of 3oc, 12ot-diacetoxy-Vu-hydroxy-5/3-cholanic acid methyl ester. The title compound has utility as an intermediate in the synthesis of steroid compounds, in the preparation of radiolabelled substances, in the study of bile acid metabolism etc.

Selective acetylaee of cholic acid methyl ester is a relatively complex matter · The usual acetyl anhydride and pyridine at room temperature results in a mixture of 3o6-mono-, 3a /, 7oc-di- and 3,7cx-, 12ot-triacetate at the elevated temperature to form triaoetate as the major product / Plattner and Heussers Helv. Chim.Acta 27 «748, 1944 / · It is known to prepare 3ot, 7ot -diacetoxy-12ot-hydroxy-5/3-toluic acid methyl ester, a key intermediate for the production of important drugs chenodesoxycholic and ursodesoxyalcohol, acetic anhydride and pyridine in anhydrous benzene, which gives satisfactory yields / Fieaers J. lm · Ohem.Soo. 21 * 3935, 1949} Pieser and Bajagopalan: J. Am. Chem. Soc., 72, 5530 (1950). On the other hand, the preparation of the analogous 3a, 12a-diacetate requires a multi-step reaction sequence: selective oxidation of cholic acid H-bromauccinimideni at position 7; methylalo of the carboxyl group, acetyl to give the methyl ester of 3α, 1200-diacetoxy-7-oxo-5/3-cholanic acid and conversion of the 7-oxo group to the 7 °-hydroxy group by reduction with sodium borohydride or catalytic hydrogenation / Samuelsson: J. Biol. Chem. 235-361, 1960; Parméntier and Byssen: Steroids 26, 721, 1975; Tserng and Klein: Steroids 33, 167, 1979; Goto et al.: Ohem.Pharm Bull. 2? 1402, 1979; Goto et al., Chem.Pharm Bull. 28, 3389, 1980

These disadvantages are overcome by the process for the preparation of the 3α, 12α-diacetoxy-7H-hydroxy-5/3-thanoic acid methyl ester as described in 2,236,229

The reaction is characterized in that the cholic acid methyl ester (3%, 7%, 12α-6-trihydroxy-5-oxoic acid) is converted to the title compound by selective acetylation with acetic anhydride in an inert organic solvent of toluene type in the presence of anhydrous potassium vinegar base; calcium carbonate and at the boiling point of the reaction mixture. This surprising tendency of those skilled in the art to the above-mentioned reaction conditions for selective acetylaryl hydroxyl groups at the 3 and 12 rpm position is also evidenced by gas chromatographic analysis of the crude reaction products, which under the same conditions yields the hydrochloric acid methyl ester of 5.9% 3-monoacetate.

5.1% of 3%, 7% -diacetate and 59.3% of the title 3%, 12.0% -diacetate, chenodesoxycholic acid methyl ester (i.e., 3o6, 7% -dihydroxy -5 (3-carbonate) / 67) , 4 &apos; -monoacetate and 30.0 .mu.l of 3.alpha., 7 <% -dietoate, methyl desoxycholic acid / i.e. 3 <%, 12o-dihydroxy-5 (3-oholanic) / 29.4 $ 3-monoacetate and 69.3. From these figures, it follows that the ohenodesoxycholic acid methyl ester, which does not contain a 12-hydroxy group in the molecule, under the given conditions gives as the main product 3 oL-monoacetate, while the dasoxycholic acid methyl ester, which 12-hydroxyethyl, the group contains, converting to 3α, 12β-diacetate in considerable yield.

In a 2-step process (according to the invention, a mixture of the starting dry cholic acid methyl ester (1 part by weight), acetic anhydride (0.75 part by weight), anhydrous potassium acetate or calcium carbonate (1 part by weight) and an aromatic hydrocarbon (8 parts by weight) was heated to boiling for 3-4 hours, after which the title compound was isolated by column chromatography on silica gel.

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

Example 1

A mixture of 4 g of dry methyl choline ester, 3 ml of acetic anhydride, 4 g of freshly melted potassium acetate and 32 ml of toluene is heated to boiling for 4 hours. The reaction was quenched by the addition of water, the toluene layer was separated, washed to neutrality

- 3 236 229 with water, and the solvent was distilled off in vacuo. The residue was dissolved in benzene and chromatographed on a 140 g silica gel column. Elution with a 98: 2 and 96: 4 by volume of benzene / acetone yields 2.1 g of product which, after crystallization from acetone / hexane, yields 1.6 g of 3,12cc-diaeetate, m.p. 142-144 ° C. identical to authentic preparation ·

Example 2 g of dry methyl ester of acetic acid are acetylated in analogy to Example 1, but instead of potassium acetate, 4 g of calcium carbonate are used. The reaction mixture, silica gel column chromatography and crystallization of the crude product are carried out as in Example 1. 47 g of 3? -, 12? -Diacetate, m.p. 144-146 ° C.

Claims (1)

The process for the preparation of 5 [alpha], 12 [alpha], 12-diacetoxymethyl ester of cholic acid is subjected to selective acetylation or acetic anhydride in an inert organic solvent with toluene, in the presence of anhydrous potassium ootane or calcium carbonate base and boiling point.