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Method for synthesizing tetra-glycylglycine

A synthetic method and technology of tetraglycine peptide, applied in the preparation method of peptides, chemical instruments and methods, peptides, etc., can solve the problems of strict impurity requirements, poor solubility, low yield, etc., and achieve product qualification rate High, good solubility, high yield effect

Inactive Publication Date: 2013-07-17
SICHUAN TONGSHENG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, glycine is synthesized by dehydrating glycine in glycerol at high temperature, hydrolyzing with alkali, neutralizing acid, and crystallizing alcohol to obtain the product. In this method, water is added to glycerin for comprehensive use, which cannot be applied mechanically, and chlorine will be generated in the subsequent treatment. Sodium chloride, for the use as a finished product, the requirements for impurities are strict, and it is difficult to pass
Triglycyl peptide is obtained by reaction of chloroacetyl chloride and glycyl peptide under alkaline conditions and then ammonolysis, but it is difficult to control the single impurity to 0.2% in this process
Tetraglycyl peptide mainly uses the condensation reaction of Z-GLY-GLY-OSU and GLY-GLY ester in an organic solvent, and then hydrogenolyzes to obtain the product. In this reaction, due to the poor solubility of Z-GLY-GLY-OSU, the yield The efficiency is low, and the esterification of glycyl peptide needs to be reacted in an organic solvent, and the cost is correspondingly high

Method used

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  • Method for synthesizing tetra-glycylglycine
  • Method for synthesizing tetra-glycylglycine
  • Method for synthesizing tetra-glycylglycine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0018] Add 50L ethylene glycol and 10KG glycine into a 100L oil bath, stir and heat up to 170-175°C for 45-60 minutes, cool to 60°C, add 10L water, cool to room temperature and centrifuge to obtain 8KG crude product, which is hydrolyzed by adding 15L hydrochloric acid Cool and centrifuge for 1-2 minutes to obtain 7KG solid, add lithium hydroxide solution to adjust pH5.5-6, add about 0.2KG activated carbon, refine and decolorize, add 2-3 times alcohol to filter to obtain double 5KG crude glycine peptide, and then water Recrystallize, add 2-3 times of alcohol, filter and wash until the chlorine is qualified, and dry to obtain 3.5KG of glycylglycine (content 99.2%). In this example, the reaction formula is as follows:

[0019]

Embodiment 2

[0021] Add 50L1. centrifuged ethylene glycol mother liquor and 10KG glycine to a 100L oil bath, stir and heat up to 170-175°C for 45-60 minutes, cool to 60°C, add 10L water, cool to room temperature and centrifuge to obtain 8.2KG crude product, crude product Add 20L 2N lithium hydroxide aqueous solution and keep it warm at 30-40°C for 30-60 minutes, neutralize the pH5.5-6.0 with hydrochloric acid, add about 0.2KG activated carbon to refine and decolorize, add 2-3 times of alcohol to filter to obtain double 5KG glycine peptide The crude product was recrystallized with water, added 2-3 times of alcohol, filtered, washed, and dried to obtain 3.8KG (content 99.0%) of glycylglycine. In this example, the reaction formula is as follows:

[0022]

[0023] 2. Synthesis of triglycyl peptide

[0024] See the reaction below:

[0025]

[0026]

[0027]

Embodiment 3

[0029]Add 50% of water and 15KG of glycine into a 100L reaction tank, use 4N aqueous sodium hydroxide solution to maintain the pH=9-10, keep the temperature at 5-10°C, add 37KG of methyl chloride benzyl dropwise, and naturally heat up the reaction after the dropwise addition , TLC to test the reaction until the reaction of benzyl chloroformate is complete, add 30L ethyl acetate, neutralize the pH2.2-2.5 with hydrochloric acid, stir and crystallize, centrifugally wash and dry to obtain 27KG Z-glycine; Add 12KG HOSU and 23KG DCC, react at 25-30°C for 36 hours, spot on TLC plate until the reaction is complete, and filter off the solid to obtain 1,20L Z-GLY-OSU / ethyl acetate solution; -GLY-OSU / ethyl acetate solution was dropped into (13 KG glycylglycyl peptide, 50 L water, 17 KG sodium bicarbonate mixed solution), reacted at room temperature for 24 hours, TLC plated until Z-GLY-OSU reacted 98. 0% or more (liquid phase monitoring), the ethyl acetate layer was separated at the end o...

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Abstract

The invention provides a sequential synthesis method of tetra-glycylglycine. The method includes steps: 1, producing glycylglycine after condensating and ring opening of glycine; 2, producing tri-glycylglycine after activated ester condensation of glycylglycine and N-protected glycine and deprotection; and 3, producing tetra-glycylglycine after activated ester condensation of tri-glycylglycine and N-protected glycine and deprotection.

Description

technical field [0001] The invention relates to a synthesis method of tetraglycine peptide, which belongs to the technical field of chemical synthesis. Background technique [0002] Glycine peptide is used as a biochemical reagent, and used as a stabilizer for blood preservation and protein drug cytochrome C water injection in biological research and medicine. Triglycyl peptide is the main raw material for the synthesis of renal function imaging drugs. Tetraglycyl peptide is formed by orderly linking four glycine molecules through peptide bonds. It, triglycyl peptide and bisglycyl peptide are all used in the synthesis of peptides and drugs. Tetraglycyl peptide is a synthetic antithrombin drug. An important short peptide of bivalirudin, see patents CN201110170669.1, CN200910028793.7, CN 200980152943.3. [0003] At present, glycine is synthesized by dehydrating glycine in glycerol at high temperature, hydrolyzing with alkali, neutralizing acid, and crystallizing alcohol to o...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K5/103C07K1/06
Inventor 李德勇伍万兵陈纹锐蒲国波曾凯
Owner SICHUAN TONGSHENG BIOTECH
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