Preparation method of polymer polypeptide

A technology of solution and glatiramer acetate, which is applied in the preparation of polymer polypeptides and the field of preparation of glatiramer acetate, which can solve the problems of unsuitability for the industrial production of glatiramer acetate, complicated process, and low yield of glatiramer acetate. , to achieve considerable economic and practical value, high purity and low impurity content

Active Publication Date: 2012-10-10
HYBIO PHARMA
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] Yet above-mentioned preparation method process is complicated, the yield of glatiramer acetate is low, is not suitable for the industrialized production of glatiramer acetate

Method used

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  • Preparation method of polymer polypeptide
  • Preparation method of polymer polypeptide

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Experimental program
Comparison scheme
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Embodiment 1

[0031] Embodiment 1: have the preparation of protective group polymer

[0032] Add 103.5g (0.9mol) of alanine carboxylate anhydride, ξ-trifluoroacetyllysine carboxylate anhydride 187.6g (0.70mol), γ-benzyl glutamic acid carboxylate anhydride into a 5L three-necked round bottom flask 78.9g (0.3mol), 41.4g (0.20mol) of tyrosine carboxyl anhydride and 3L of dioxane, stirred to dissolve. Then 0.01% diethylamine was added to initiate the polymerization reaction, stirred at room temperature for 24 hours, then poured into 30 L of water to quench the reaction, the solid was washed with 10 L of water, filtered, and dried to obtain 313.9 g of white solid with a yield of 76.3%.

Embodiment 2

[0033] Embodiment 2: Preparation of trifluoroacetyl glatiramer

[0034] Add 3g of the polymer with protective group prepared in Example 1 into a 50mL round-bottomed flask, add 30mL of 25% hydrogen bromide acetic acid solution, stir at 25°C for 23h, and pour the reaction solution into 300mL of ice water to precipitate a solid after the reaction, filter The collected solid was washed with water (300 mL), filtered and sucked dry. The collected solid was washed three times with 50 mL of diethyl ether, stirred for 25 min each time, filtered and dried to obtain 2.2 g of white solid with a yield of 73.3%.

Embodiment 3

[0035] Embodiment 3: the preparation of trifluoroacetyl glatiramer

[0036] Add 300g of the polymer with protective group prepared in Example 1 into a 5L round bottom flask, add 3000mL of 20-25% hydrogen bromide acetic acid solution, stir at 25°C for 23h, and pour the reaction solution into 30L of ice water to precipitate Solid, collected by filtration, washed with 30 L of water, filtered and sucked dry. The collected solid was washed three times by adding 5 L of ether, stirring for 25 min each time, and the sample was filtered and dried to obtain 216.9 g of white solid with a yield of 72.3%.

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Abstract

The invention belongs to the technical field of pharmaceutical chemistry, relates to a preparation method of polymer polypeptide, and discloses a method for preparing glatiramer acetate. According to the invention, carboxy anhydrides of alanine, zeta-trifluoro-indole-3-acetyl lysine, gamma-benzyl glutamate and tyrosine is used as raw materials; diethylamine is used as a trigger in dioxane to trigger polymerization, so as to obtain a polymer with a protecting group; the obtained polymer with a protecting group experiences debenzylation reaction with 20 to 25% of acetic acid solution of hydrogen bromide at the temperature of 18 to 30 DEG C; the reaction liquid is poured into ice water to separate out solids; the obtained solids are cleaned with diethyl ether; after being filtered, the solids are collected; water solution of piperidine is added to remove trifluoroacetyl, so as to obtain coarse product solution of glatiramer, and after purification, glatiramer acetate is obtained. Compared with the prior art, the preparation method has the advantages of simpleness in operation, little impact on molecular weight of glatiramer acetate, and high yield of glatiramer acetate, so as to be suitable for the large-scale industrial production of glatiramer acetate.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry and relates to a preparation method of a polymer polypeptide, in particular to a method for preparing glatiramer acetate. Background technique [0002] Glatiramer acetate, English name Glatiramer acetate, is a synthetic peptide compound developed by Teva and Marion for the treatment of multiple sclerosis (Multiple Sclerosis, MS), trade name Copaxone The molecular formula of glatiramer acetate is C 25 h 45 N 5 o 13 , is a polymer composed of four amino acids L-Alanine, L-Lysine, L-Glutamic, and L-Tyrosine. The molar ratio of the four amino acids is 0.427:0.338:0.141:0.095, and the average molecular weight is 4.7~11KDa. For: (Ala,Lys,Glu,Tyr)x XCH 3 COOH or (C 3 h 7 NO 2 ·C 6 h 14 N 2 o 2 ·C 5 h 9 NO 4 ·C 9 h 11 NO 3 )X·XC 2 h 4 o 2 ). [0003] Pharmacological studies have shown that glatiramer acetate binds to regulatory factors in the immune system and enters the...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C08G69/48C08G69/42
Inventor 曾国良刘飞马亚平袁建成
Owner HYBIO PHARMA
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