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Synthetic method of 13C marked glycocholic acid

A technology for the synthesis of glycocholic acid and its synthesis method, which is applied in the field of synthesis of 13C-labeled glycocholic acid, and can solve the problems that selective hydrolysis is not easy to control and the selectivity is not high enough.

Active Publication Date: 2012-12-05
SHANGHAI RES INST OF CHEM IND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

There are two problems in this method. One is that the selectivity of the EEDQ condensation reagent is not high enough. The carboxyl group on the cholic acid can react with the amino group on the glycine ethyl ester, and can also react with the hydroxyl group on another cholic acid molecule (note: cholic acid There are 3 hydroxyl groups in the molecule), and the by-product bis-cholic acid or polycholic acid is generated; the second is that the selective hydrolysis of ethyl glycocholate hydrolysis is not easy to control, and hydrolysis at the amide group will occur to generate cholic acid and glycine ethyl ester or glycine

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0020] A kind of benzyl glycocholate-glycyl-1- 13 The synthetic method of C, this method comprises the following steps: under nitrogen protection, glycine benzyl ester hydrochloride (glycyl-1- 13 C, 0.03mol) and cholic acid (0.05mol) were dissolved in 80ml tetrahydrofuran, and diethyl dicyanophosphate (0.06mol) and 3-(2'-oxygen-1', 3', 2 '-dioxaphosphorinyl)-oxygen-1,2,3-phenylcotriazin-4(3H)-one (0.07mol), control the temperature at 10°C, react for 24 hours, after the reaction , the product is separated and purified on a silica gel column to obtain benzyl glycocholate-glycyl-1- 13 C, the product yield is 85%.

[0021] 13 Analysis of C-labeled Glycocholic Acid

[0022] Product's 13 The abundance of C is analyzed by TSQ Quantum Access liquid chromatography-mass spectrometry, the product purity is analyzed by liquid chromatography (the detector is an evaporative light detector), and the optical rotation of the product is analyzed by WZZ-2B automatic polarimeter Test, use l...

Embodiment 2

[0024] A kind of benzyl glycocholate-glycyl-1,2- 13 C 2 A synthetic method comprising the following steps: under nitrogen protection, glycine benzyl ester hydrochloride (glycyl-1,2- 13 C 2 , 0.04mol) and cholic acid (0.07mol) were dissolved in 70ml N,N-dimethylformamide, and 3-(diethoxyphosphoryloxy)-1,2,3-benzene was added at -5°C Triazin-4-one (0.09mol) and 3-(2'-oxy-1',3',2'-dioxaphosphorinyl)-oxy-1,2,3-benzene Triazin-4(3H)-one (0.08mol), control the temperature at 50°C, and react for 1 hour. After the reaction, the product is separated and purified on a silica gel column to obtain benzyl glycocholate-glycyl-1,2 - 13 C 2 , The product yield is 83%.

Embodiment 3

[0026] A kind of benzyl glycocholate-glycyl-2- 13 The synthetic method of C, this method comprises the following steps: under nitrogen protection, glycine benzyl ester hydrochloride (glycyl-2- 13 C, 0.02mol) and cholic acid (0.04mol) were dissolved in 75ml dimethyl sulfoxide, and 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazine was added at -5°C -4-ketone (0.05mol) and diethyl dicyanophosphate (0.06mol), control the temperature at 0 ° C, react for 48 hours, after the reaction, the product is separated and purified on a silica gel column to obtain benzyl glycocholate- Glycyl-2- 13 C, the product yield is 82%.

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Abstract

The invention relates to a synthetic method of 13C marked glycocholic acid, and the method comprises the following steps: under the protection of nitrogen, 13C marked glycine benzyl ester hydrochloride and cholic acid are mixed and dissolved in a polar solvent, then coupling reagent is added, the reaction temperature is controlled between minus 20 and 150DEG C, the reaction time is 0.1 to 120h, and then the product is obtained after separation and purification by a silica gel column. The method adopts the coupling agent to synthesize the 13C marked glycocholic acid, the yield of the glycocholic acid can achieve above 80 percent, the abundance of 13C can achieve 99atm%, the optical purity can achieve 98 percent, and the chemical purity can achieve 98 percent. The obtained 13C marked glycocholic acid can be used as medical diagnosis reagent and can be used for enterohepatic circulation of the cholic acid, overgrowth of intestinal bacteria, activity evaluation of bacterial metabolism andthe like.

Description

technical field [0001] The present invention relates to a kind of synthetic method of glycocholic acid, especially relate to a kind of 13 Synthetic method of C-labeled glycocholic acid. Background technique [0002] 13 C-labeled glycocholic acid is a medical diagnostic reagent that can be used for the enterohepatic circulation of bile acid, the overgrowth of intestinal bacteria, the evaluation of bacterial metabolic activity, etc. (J.S. Sukhodolski, C.G. Ruaukos, J.M. Na et al., Assessing the metabolic activity of bacteria in the canine small intestine 13 C-glycocholic acid blood test progress, Canadian Journal of Veterinary Research (Canadian J. Veterinary Research), 2005, 69: 313-317; N.M. Solomon, D.A. Scheele, J.B. Wagonfield et al., stable isotopes 13 Application of C-labeled glycocholic acid breath test in the diagnosis of small intestinal bacterial overgrowth and ileal dysfunction, Journal of Medical Clinical Experiments (J.Lab.Clin.Med.) 1977, 90: 431-439; C.E. Ki...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07J41/00
Inventor 徐仲杰卢伟京徐静安李孝武卢浩李帅侯秀红李美华石洵予
Owner SHANGHAI RES INST OF CHEM IND
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