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Synthetic method for liraglutide

A technology of liraglutide and a synthesis method, which is applied in the field of peptide synthesis and preparation, can solve the problems of difficult removal of impurities, long synthesis cycle, high cost and the like

Active Publication Date: 2016-07-06
SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Recombinant DNA processes require the use of complex equipment and may introduce viruses into the product, detrimental to the medicinal purpose of the product
Chinese patents CN201110271342.3, CN200610110898.3, CN201210369966.3, and CN200510107588 have reported the method of direct solid-phase synthesis of liraglutide. However, due to the hydrophobicity of hexadecyl on the peptide chain, the impurities produced by this process are very Difficult to remove
The existing synthesis method of liraglutide has the disadvantages of cumbersome operation, two-step purification, long synthesis cycle, large waste liquid, unfavorable environmental protection, large amount of acetonitrile, high cost and unfavorable for large-scale production

Method used

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  • Synthetic method for liraglutide
  • Synthetic method for liraglutide
  • Synthetic method for liraglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Embodiment 1, a synthetic method of liraglutide, comprises the following steps:

[0064] A. Fragment condensation into various liraglutide intermediates:

[0065] (1) Synthesis of R-His(R1)-Ala-Glu(R2)-Gly-R3;

[0066] (2) Synthesis of R-Thr(R4)-Phe-Thr(R4)-Ser(R4)-Asp(R5)-R3;

[0067] (3) Synthesis of R-Val-Ser(R4)-Ser(R4)-Tyr(R4)-Leu-Glu(R2)-Gly-R3;

[0068] (4) Synthesis of R-Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu(R2)]-Lys-Glu(R2)-Phe-R3;

[0069] (5) Synthesis of R-Ile-Ala-Trp(R6)-Leu-Val-Arg(R7)-Gly-Arg(R7)-Gly-R3;

[0070] (6) Synthesis of R-His(R1)-Ala-Glu(R2)-Gly-Thr(R4)-Phe-Thr(R4)-Ser(R4)-Asp(R5)-R3;

[0071] (7) R-His(R1)-Ala-Glu(R2)-Gly-Thr(R4)-Phe-Thr(R4)-Ser(R4)-Asp(R5)-Val-Ser(R4)-Ser( Synthesis of R4)-Tyr(R4)-Leu-Glu(R2)-Gly-R3;

[0072] (8) R-His(R1)-Ala-Glu(R2)-Gly-Thr(R4)-Phe-Thr(R4)-Ser(R4)-Asp(R5)-Val-Ser(R4)-Ser( R4)-Tyr(R4)-Leu-Glu(R2)-Gly-Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu(R2)]-Lys-Glu(R2)-Phe-R3 Synthesis;

[0073] (9) R-Thr(R4)-Phe...

Embodiment 2

[0098] Example 2, in the synthesis method of liraglutide described in Example 1: the coupling system used in the synthesis process of the 14 polypeptide fragments is selected from: single condensing agent: DIC, DCC, EDC , chloroacetyl chloride, azide, TBTU, PyBOP, HBTU; or two-system condensing agent: DIC / HOBT, DCC / HOBT, EDC / HOBT.

Embodiment 3

[0099] Example 3, in a synthetic method of liraglutide described in Example 1: (1) R-Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu]-Lys-Glu( The synthesis of R2)-Phe-R3 adopts pure liquid phase synthesis, including a variety of fragment synthesis methods, the specific fragments are as follows:

[0100] R-Gln-Ala-OH, R-Gln-Ala-Ala-OH, R-Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu]-Lys(R8)-OH, R-Gln -Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu]-Lys(R8)-Glu(R2)-R3, R-Phe-R3, R-Glu(R2)-Phe-R3, R- N6-[N-(1-oxohexadecyl)-Glu]-Lys(R8)-Glu(R2)-Phe-R3, R-Ala-N6-[N-(1-oxohexadecyl)-Glu]-Lys(R8) -Glu(R2)-Phe-R3, R-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu]-Lys(R8)-Glu(R2)-R3;

[0101] (2) Synthesis of N-(1-oxohexadecyl)-Glu(R2)]-R3:

[0102] The target product is obtained by reacting NH2-Glu(R2)-OH with active ester of stearic acid; the single condensing agent and condensing agent compound used in the synthesis of active ester method are: DIC, DCC, EDC, TBTU, PyBOP, HBTU , DIC / HOBT, DCC / HOBT, EDC / HOBT; or use N...

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Abstract

The invention relates to products in the field of medicines, and provides a synthetic method for liraglutide, which includes the following steps: 1) condensing fragments to obtain various liraglutide intermediates; 2) deprotecting and cracking full-protected liraglutide; and 3) purifying and freeze-drying the liraglutide. The method employs a 4+5+7+6+9 synthetic method, wherein synthesis on five fragments is carried out at the same time, so that synthetic time of the product is greatly reduced. Meanwhile, through step-by-step analysis of synthesis factors, comprising His-Ala-Glu-Gly, Thr-Phe-Thr-Ser-Asp, Val-Ser-Ser-Tyr-Leu-Glu-Gly, Gln-Ala-Ala-N6-[N-(1-oxohexadecyl)-Glu]Lys-Glu-Phe, and Ile-Ala-Trp-Leu-Val-Arg-Gly-Arg-Gly-OH, synthesis difficulty of difficult peptide sequence in solid-phase synthesis is reduced, scale amplification in solid-phase synthesis is solved and synthetic efficiency is improved. Because fragment synthesis reduces purifying difficulty effectively, the production cost is greatly reduced.

Description

technical field [0001] The invention belongs to the field of polypeptide synthesis and preparation, and in particular relates to a synthesis method of liraglutide. Background technique [0002] Liraglutide is a drug approved in 2010: its structural formula is as follows: [0003] [0004] At present, biological methods such as genetic engineering are available for preparation, but the investment is high, the equipment is complicated, and the difficulty is great. At the same time, U.S. Patents US6268343B1 and US6458924B2 reported the solid-liquid synthesis method of liraglutide. The intermediate GLP-1(7-37)-OH needs to be purified by reverse phase HPLC, and then combined with N under liquid phase conditions. α -alkanoyl-Glu(ONSu)-OtBu reaction, and because the GLP-1(7-37)-OHN end is not protected and the side chain protection groups are all removed, many impurities will be produced, it is difficult to purify, and the operation is cumbersome. US Patent Nos. 6268343, 64589...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/10C07K1/06
CPCC07K14/605
Inventor 谷海涛徐峰刘标王良友伏帅孙美禄
Owner SINOPEP ALLSINO BIOPHARMACEUTICAL CO LTD
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