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Synthesis method of semaglutide

A technology of semaglutide and synthetic method, which is applied in the field of preparation of semaglutide, can solve the problems of high cost, low purity and yield, and many impurities, so as to reduce the cost of synthesis, improve the purity and yield, and reduce the difficulty Effect

Pending Publication Date: 2021-11-12
深圳市健翔生物制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] In order to solve the problems of many impurities, low purity and yield, high cost, cumbersome operation steps and unfavorable industrial production in the existing synthesis process, the present invention provides a semaglutide with high yield and high purity synthesis method

Method used

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  • Synthesis method of semaglutide
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  • Synthesis method of semaglutide

Examples

Experimental program
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Effect test

Embodiment 1

[0033] Example 1 Preparation of Boc-His(Trt)-Aib-Glu(OtBu)-OH

[0034] A. Add 150g of 2-CTC resin with a degree of substitution of 1.06mmol / g into the reactor, add 500ml of dichloromethane, mix for 2 minutes, filter out the dichloromethane, then add 500ml of dichloromethane, mix for 40min, filter out the dichloromethane methane, and finally add 500ml of dichloromethane, after mixing for 2min, filter out the dichloromethane, and the resin is set aside.

[0035]B. Weigh 135.30g of Fmoc-Glu(OtBu)-OH into a beaker, add 500ml of DMF and 78.83ml of DIEA, stir the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A, and put it at 20-25°C Under the condition of mixing reaction for 4h. After the reaction was completed, DMF was filtered off. Add a mixed solution of 25ml of methanol and 250ml of DMF, a mixed solution of 50ml of DIEA and 250ml of DMF to the resin, and continue to mix and react for 1h. After the reaction, filter with suction, wash the resin 5 time...

Embodiment 2

[0041] Example 2 Preparation of Fmoc-His(Boc)-Aib-Glu(OBzl)-OH

[0042] A. Add 100g of 2-CTC resin with a degree of substitution of 1.12mmol / g into the reaction kettle, add 300ml of dichloromethane, mix for 2 minutes, filter out the dichloromethane, then add 300ml of dichloromethane, mix for 40min, filter out the dichloromethane Methane, and finally add 300ml of dichloromethane, after mixing for 2min, filter out the dichloromethane, and the resin is set aside.

[0043] B. Weigh 102.93g of Fmoc-Glu(OBzl)-OH into a beaker, add 300ml of DMF and 55.53ml of DIEA, stir the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A, and put it at 20-25°C Under the condition of mixing reaction for 4h. After the reaction was completed, DMF was filtered off. Add a mixed solution of 20ml of methanol and 150ml of DMF, a mixed solution of 30ml of DIEA and 150ml of DMF to the resin, and continue to mix and react for 1h. After the reaction, filter with suction, wash the re...

Embodiment 3

[0049] Example 3 Preparation of Fmoc-His(Trt)-Aib-Glu(OtBu)-OH

[0050] A. Add 120g of 2-CTC resin with a degree of substitution of 1.06mmol / g into the reaction kettle, add 400ml of dichloromethane, mix for 2 minutes, filter out the dichloromethane, then add 400ml of dichloromethane, mix for 40min, filter out the dichloromethane methane, and finally add 400ml of dichloromethane, after mixing for 2min, filter out the dichloromethane, and the resin is set aside.

[0051] B. Weigh 108.24g of Fmoc-Glu(OtBu)-OH into a beaker, add 400ml of DMF and 63.06ml of DIEA, stir the solution at 0-10°C for 5min, pour it into the CTC resin obtained in step A, and put it at 20-25°C Under the condition of mixing reaction for 4h. After the reaction was completed, DMF was filtered off. Add a mixed solution of 20ml methanol and 200ml DMF, a mixed solution of 30ml DIEA and 200ml DMF to the resin, and continue to mix and react for 1h. After the reaction, filter with suction, wash the resin 5 times ...

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Abstract

The invention discloses a synthesis method of semaglutide, which comprises the following steps: respectively synthesizing full-protection S1-S3 fragments and S4-S6 fragments of the semaglutide for synthesizing semaglutide resin, and cracking and purifying to obtain the semaglutide. The method further comprises the step of synthesizing lysine with a side chain radical at the 20 site of the semaglutide, and the segment is beneficial to completing coupling of main chains of the semaglutide, so that the purity and the yield of a crude product of the semaglutide are greatly improved, and the synthesis cost is reduced. According to the method, full-protection S1-S3 fragments and S4-S6 fragments of the semaglutide are prepared and used as key starting materials to be applied to solid-phase synthesis of the semaglutide, generation of D-His, D-Glu, D-Thr and D-Phe racemization impurities and +Gly impurities is greatly reduced, the purification difficulty of a crude product is remarkably reduced, the purity and yield of the semaglutide are greatly improved, the synthesis cost is reduced, and the method is beneficial to industrial large-scale production.

Description

technical field [0001] The invention relates to the field of polypeptide synthesis, in particular to a method for preparing semaglutide. [0002] technical background [0003] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by human intestinal L cells, which can promote the secretion of insulin and inhibit the secretion of glucagon, and has the effect of reducing blood sugar concentration. For the treatment of type II diabetes. However, natural GLP-1 is unstable in vivo and is easily degraded by dipeptidyl peptidase-IV (DPP-IV). [0004] Semaglutide, whose English name is Semaglutide, is a new type of long-acting glucagon-like peptide-1 (GLP-1) analog developed and produced by Novo Nordisk, Denmark, for the treatment of type II diabetes. Semaglutide has the effects of lowering blood sugar, losing weight and protecting cardiovascular system, and was approved by the FDA for marketing in December 2017. After the Lys side chain of semaglutide is modified by PEG, ...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 张利香付玉清姚林朱亮平李文静
Owner 深圳市健翔生物制药有限公司
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