Synthesis method of histidine and proline cyclodipeptide

A synthesis method and cyclic dipeptide technology are applied in the field of synthesizing pro-group cyclic dipeptide, which can solve problems such as the influence of the optical purity of the product, and achieve the effect of avoiding the change of the optical purity.

Active Publication Date: 2017-05-17
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The disadvantage of this method is that the protected dipeptide methyl ester, in the ethyl acetate solution of hydrogen chloride, reacts under high temperature reflux for a long time, which will cause an irreversible impact on the optical purity of the product.

Method used

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  • Synthesis method of histidine and proline cyclodipeptide
  • Synthesis method of histidine and proline cyclodipeptide
  • Synthesis method of histidine and proline cyclodipeptide

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preparation example Construction

[0027] According to the first specific embodiment of the present invention, the method for synthesizing cyclic dipeptides of the present invention comprises the following steps:

[0028] (1) Preparation of amino-protected progroup dipeptide methyl ester

[0029] Preparation of amino-protected pro group dipeptide methyl ester from histidine methyl ester hydrochloride and amino-protected proline. Specifically, proline whose amino group is protected by fluorenyl moxycarbonyl and N-hydroxysuccinimide generate active ester under the action of N,N'-dicyclohexylcarbodiimide, and then further react with histidine methyl ester Hydrochloride under alkaline conditions (for example, NaHCO 3 In the presence of) react to generate the pro group dipeptide methyl ester whose amino group is protected by fluorenylmethoxycarbonyl.

[0030] Among them, the molar ratio of proline whose amino group is protected by fluorenyl moxycarbonyl, N-hydroxysuccinimide, N,N'-dicyclohexylcarbodiimide, and his...

Embodiment 1

[0055] Example 1 L-L type proline group cyclic dipeptide

[0056] 1. Add Fmoc-L-Pro-OH (30g, 0.08mol), 500mlTHF into an eggplant-shaped bottle, stir magnetically, and stir to dissolve it all, then add HOSu (10.2g, 0.09mol), DCC (18.3g , 0.09mol), stirred overnight at room temperature, a large amount of white precipitate appeared, filtered, took the filtrate, added THF to make up the volume of 500ml, stirred at room temperature, and added L-H-His-OCH to the filtrate respectively 3 .2HCl (23g, 0.096mol), NaHCO 3 (30g, 0.36mol), H 2 O150ml, stirred overnight at room temperature, TLC showed that the reaction was complete, treated, evaporated THF to dryness, added ethyl acetate and water, stirred, separated layers, took the ethyl ester layer, extracted the water layer with ethyl ester once, poured it off, and combined the ethyl ester layers , the ethyl ester layer was washed twice with dilute hydrochloric acid aqueous solution to remove excess H-His-OCH 3 , washed 3 times with b...

Embodiment 2

[0058] Example 2 L-D type proline group cyclic dipeptide

[0059] 1. Add Fmoc-L-Pro-OH (30g, 0.08mol), 500mlTHF into an eggplant-shaped bottle, stir magnetically, stir to make it all dissolve, then add HOSu (10.2g, 0.09mol), DCC (18.3g , 0.09mol), stirred overnight at room temperature, a large amount of white precipitate appeared, filtered, took the filtrate, added THF to make up the volume of 500ml, stirred at room temperature, and added D-H-His-OCH to the filtrate respectively 3 .2HCl ((23g, 0.096mol), NaHCO 3 (30g, 0.36mol), H 2 O150ml, stirred overnight at room temperature, TLC showed that the reaction was complete, treated, evaporated THF to dryness, added ethyl acetate and water, stirred, separated layers, took the ethyl ester layer, extracted the water layer with ethyl ester once, poured it off, and combined the ethyl ester layers , the ethyl ester layer was washed twice with dilute hydrochloric acid aqueous solution to remove excess H-His-OCH 3 , washed 3 times with...

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Abstract

The invention provides a synthesis method of histidine and proline cyclodipeptide. The method comprises the steps of preparing histidine and proline dipeptide methyl ester with protected amino from histidine and proline, wherein one of histidine and proline is in a form of ester hydrochloride and the other one is in a form of the protected amino; and carrying out deprotection on dipeptide methyl ester with the protected amino and forming histidine and proline cyclodipeptide through cyclization.

Description

technical field [0001] The invention belongs to the technical field of polypeptide synthesis, and in particular, the invention relates to a method for synthesizing a procyclic dipeptide. Background technique [0002] Histidine-proline cyclic dipeptide (Cyclo (His-Pro), referred to as CHP, Cyclo (His-Pro) is a kind of active peptide substances, specifically endogenous cyclic dipeptide, which is widely distributed and is widely distributed in humans. It exists in monkeys, dogs, cats, rats and frogs. It is formed by cyclization of thyrotropin-releasing hormone (TRH) through pyroglutamic acid aminopeptidase hydrolysis to remove pyroglutamic acid. . The pro-group cyclic dipeptide has various biological activities. In recent years, studies have shown that it has a good effect on lowering blood sugar, and it is expected to be put into the market as a drug. [0003] The Chinese invention patent application with the application number of 200510109439.9 discloses a method for prepar...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04
Inventor 王惠嘉王慧苏晨灿张忠旗李乾王万科高长波郭添韩广赵金礼杨小琳
Owner SHAANXI HUIKANG BIO TECH CO LTD
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