Synthetic method of semaglutide

A technology of semaglutide and synthetic method, which is applied in the field of solid phase synthesis of peptides, can solve the problems of difficult control of D-His racemic impurities, unfavorable industrial production, low purity and yield, and reduce production costs and difficulties , The effect of simplifying the process steps

Pending Publication Date: 2020-11-17
SHENZHEN JYMED TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0014] In order to solve the problem that the D-His racemic impurity existing in the existing semaglutide synthesis process is difficult to control, the purity and yield are

Method used

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  • Synthetic method of semaglutide
  • Synthetic method of semaglutide
  • Synthetic method of semaglutide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Embodiment 1 substitution degree is the preparation of the Fmoc-Gly-CTC resin of 0.8mmol / g

[0044] A. Add 10g (13mmol) of 2-CTC resin with a substitution degree of 1.3mmol / g into the reaction kettle, add 100ml of dichloromethane, mix for 2min, filter out the dichloromethane, then add 100ml of dichloromethane, and mix for 40min , filtered off dichloromethane, and finally added 100ml of dichloromethane, mixed for 2 minutes, filtered off dichloromethane, and the resin was set aside.

[0045] B. Weigh 9.81g of Fmoc-Gly-OH and 5.35g of HOBT into a beaker, add 100ml of DMF and 5.46ml of DIEA, stir and activate the solution at 0-10°C for 5min, then pour it into the CTC resin obtained in step A , Mixed for 4h at 20-25°C. After the reaction was finished, 100ml of DMF was added, and the DMF was filtered off. 4 ml of methanol and 5.46 ml of DIEA were added and mixing was continued for 1 h. After the reaction, filter with suction, wash the resin 5 times with DMF, 100ml each tim...

Embodiment 2

[0047] Embodiment 2 substitution degree is the preparation of the Fmoc-Gly-CTC resin of 1.2mmol / g

[0048] A. Add 10g (18mmol) of 2-CTC resin with a substitution degree of 1.8mmol / g into the reaction kettle, add 100ml of dichloromethane, mix for 2min, filter out the dichloromethane, then add 100ml of dichloromethane, and mix for 40min , filtered off dichloromethane, and finally added 100ml of dichloromethane, mixed for 2 minutes, filtered off dichloromethane, and the resin was set aside.

[0049] B. Weigh 9.81g of Fmoc-Gly-OH and 5.35g of HOBT into a beaker, add 100ml of DMF and 5.46ml of DIEA, stir and activate the solution at 0-10°C for 5min, then pour it into the CTC resin obtained in step A , Mixed for 4h at 20-25°C. After the reaction was finished, 100ml of DMF was added, and the DMF was filtered off. 4 ml of methanol and 5.46 ml of DIEA were added and mixing was continued for 1 h. After the reaction, filter with suction, wash the resin 5 times with DMF, 100ml each tim...

Embodiment 3

[0051] Example 3 Preparation of semaglutide S1-S4 peptide resin Boc-His(π-MBom)-Aib-Glu(OtBu)-Gly-CTC resin

[0052] A. Pour all the Fmoc-Gly-CTC resin obtained in Example 1 into the reaction kettle, swell and mix with 100ml DCM for 15min, and then drain it. Add 100 ml of 20% piperidine / DMF solution, mix at 20-30° C. for 5 min, and drain. Add DMF100ml, mix for 5min, and drain. Add 100ml of 20% piperidine / DMF solution, mix at 20-30°C for 10min, and drain. Add DMF100ml, mix for 5min, and drain. Repeat washing with DMF 8 times, 100ml each time, mix 5min each time, and after the seventh washing, test the filtrate with pH test paper, the result shows that the pH is 6.5-7.0 is qualified.

[0053] B. Weigh 8.50g of Fmoc-Glu(OtBu)-OH, 3.03gDIC and 2.7g HOBT in turn in a clean 1L beaker, add 100ml of DMF / DCM solution with a volume ratio of 1:1, place in ice water at 0 Stir and dissolve with a mechanical stirrer at -10°C. After the temperature is constant, continue to maintain the t...

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Abstract

The invention discloses a solid-phase synthesis method of semaglutide. The method comprises the following steps of carrying out solid-phase synthesis on semaglutide S1-S4 fragment resin, and performing cracking and purifying to obtain a first fragment; synthesizing lysine, with a side chain group, of the semaglutide S20 as a second fragment; and sequentially coupling amino acids or peptide fragments according to a peptide sequence of the semaglutide to obtain semaglutide resin, and then performing cracking and purifying to obtain the semaglutide. According to the method, a solid-phase synthesis process combining fragmentation and gradual synthesis is adopted, so that technological process steps are simplified, and industrial large-scale production is facilitated; and full-protection 1-4 fragments of the semaglutide are prepared and applied to solid-phase synthesis of the semaglutide as key starting materials, so that the generation of D-His racemization impurities and +Gly impurities is reduced, the purification difficulty of a crude product is obviously reduced, the purity and yield of the semaglutide are greatly improved, and the production cost is reduced.

Description

technical field [0001] The invention relates to the field of solid-phase synthesis of polypeptides, in particular to a solid-phase synthesis method of 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 semag...

Claims

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Application Information

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IPC IPC(8): C07K14/605C07K1/06C07K1/04
CPCC07K14/605Y02P20/55
Inventor 姚林张利香涂敏敏李新宇吴丽芬
Owner SHENZHEN JYMED TECH
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