KR850001573B1 - Preparation of bileacide condensed with amino acid - Google Patents

Abstract

A bile acid I (R1=R2=H, OH; R3 = H, alkyl, phenyl or substituted phenyl; X = COOH, CH2SO3H) condensed with an amino acid was prepared. Thus, bile acid was reacted with KOH to form a bile calcium phosphate, which was reacted with alkylchloroformate to give an anhydro-mixture of bile acid. TEA salt condensed with amino acid was prepd. from TEA salt of amino acid II in a nonpolar solvent such as toluene, bentene, methylenechloride and dichloroethane. The TEA salt condensed with amino acid was then dissolved in a non-polar solvent and passed through dried HCl gas to give I.

Description

Method for preparing amino acid condensed bile acid

The present invention is a method for producing amino acid condensed bile acids of general formula (I) by condensing triethylamine salts of amino acids of general formula (II) and bile acids of general formula (III).

Where R ₁ and R ₂ represent hydrogen, a hydroxyl group, R ₃ represents hydrogen, alkyl, phenyl or a substituted phenyl group, X represents a -COOH, -CH ₂ SO ₃ H group and TEA represents triethylamine.

The substance of general formula (I) is a known substance, and its preparation method is also known by F. Cortess A. Norman, A. F. Hoffmann, L. Lack and the like.

Looking at these known methods

1) According to the method of F. Cortess et al., The carboxyl group of triformylcholine acid is treated with a halogenating agent to prepare a reactive triformylcholine halide, and then reacted with an amino acid to prepare an amino acid condensed triformylcholine acid, and a hydroxyl group. The amino acid condensed bile acid was prepared by hydrolyzing formyl group, which is a protecting group, but the method has a long reaction process and a low yield.

2) A. Norman method or A.F. In the Hoffmann method, amimic acid condensed bile acids were prepared by reacting mixed acid anhydrides of bile acids and rapid salts of amino acids with water or alcohol as a solvent. As a result, the separation method such as the use of an ion exchange resin to remove free bile acid, which is a by-product, from the target material is complicated, and the yield is low at 60-80%. Can't.

3) The method developed by L. Lack is prepared by reacting bile acid with a metal salt of amino acid in the presence of EEDQ ethoxy carbony 1-2-ethoxy-1, 2-dihydro quinoline, but the reagent of EEDQ is too expensive and used as a solvent. Since water reacts with bile acid mixed anhydride, which is an intermediate of reaction, bile free acid is produced, so the yield is low, side reactions and unreacted substances are present, and high purity target substances that can be used for external medicine cannot be prepared.

The present invention, which improves the disadvantages of the known method, is prepared by reacting bile acid with a metal hydroxide to prepare a metal salt of bile acid, followed by turbidity in toluene, benzene, merylene chloride dichloroethane, and the like, followed by reaction with pivaloyl chloride, alkylchloroformate, and the like. Then, the carboxyl group of the bile acid is prepared to produce highly reactive mixed anhydride, and triethylamine salt of the amino acid prepared separately is added to react at room temperature. This reaction should be carried out in a non-polar solvent, so that the mixed acid anhydride of bile acid generated when using a polar solvent is decomposed to produce a free bile acid, thereby minimizing mixing with the target substance. In the preparation of mixed anhydrides of bile acids, mixed anhydrides of bile acids are produced in high yield by using bases such as diethylamine, triethylamine, pyridine, N, N-dimethylaniline, 2,6-rutidine, and the like. Yield increases.

After the reaction was completed, the reaction solution was concentrated and n-hexane, ether or a mixture thereof was added to the residue, followed by stirring to obtain triethylamine salt of the target substance. The triethylamine salt was dissolved in a nonpolar solvent and dried. The amino acid condensed bile acid is prepared by passing through.

Example 1

Potassium salt of urodesoxycholic acid was prepared by dissolving 7.8 grams (0.02 mol) of urosodes oxycholine acid in 50 milliliters of KOH dissolved in 1.3 g of KOH, and then suspended in 100 millimeters of methylene chloride. After adding 3 grams of pivaloyl chloride, 2.5 grams of 2, 6-rutinine and continuously stirring the reaction solution at -10 ° C, the solution was made clear, and 2.5 grams of taurine and 3 millimeters of TEA were added to 15 millimeters of methylene chloride and stirred. A small amount of one taurine TEA salt is added dropwise. After the addition, the anti-solution is raised to 30-40 ℃ and stirred for 3 hours. After the reaction was completed, distilled under reduced pressure until the reaction solution became 20-30 milliliters, and n-hexane and ether (1: 2) mixed solution were added to the residue, stirred for 2 hours in ice jade, and the precipitated crystals were filtered and washed with ether. do. After dissolving the filtrate in toluene and passing through the dried HCl gas while stirring in ice jade, white crystals precipitate. The precipitated solution was stirred for 2 hours in ice jade, filtered, washed with ether and dried in an oven at 50 ° C. to obtain 8.5 grams (85.4%) of taurusodesoxycholic acid.

Melting Point: 188-197 ℃

Example 2

7.5 grams (0.02 mol) of lithocholic acid was added to 50 milliliters of KOH 1.3 g of water in which KOH was dissolved, followed by distillation under reduced pressure and drying to obtain a potassium salt of lithocholic acid.

This was suspended in 100 millimeters of methylene chloride and operated in accordance with the method of Example 1 to obtain 7.8 grams (81.1%) of taurolycholic acid.

Melting Point: 220-225 ℃

Claims (4)

After preparing the potassium salt of bile acid with KOH of bile acid of general formula (III), reacting with pavaroyl chloride, alkylchloroformate, etc. to prepare mixed anhydride of bile acid, and toluene, benzene, methylene chloride, dichloroethane, etc. TEA salt of amino acid condensed bile acid by reaction of amino acid TEA salt (II) in a non-polar solvent, dissolved in a non-polar solvent and passed through dry HCl gas to produce amino acid condensed bile acid of general formula (I)

R ₁ and R ₂ represent hydrogen, a hydroxyl group, R ₃ represents a hydrogen, alkyl, phenyl or substituted phenyl group, X represents -COOH, CH ₂ SO ₃ H, and TEA represents a triethylamine salt. Method of using a non-polar solvent such as benzene, toluene, methylene chloride dichloroethane during the condensation reaction in claim 1. However, it is not limited to the above four kinds of solvents. A method of using a mixed solvent of n-hexane and ether in crystallization of TEA salt of amino acid condensed bile acid in claim 1. Method of preparing the general formula (I) as a target substance from the TEA salt of amino acid condensation synthesized acid in claim 1 by dissolving the TEA salt in a non-polar solvent and passing through a dry HCl gas.