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A kind of synthetic method of bivalirudin

A technology of bivalirudin and a synthesis method, which is applied in the field of polypeptide drug preparation, can solve the problems of application limitation, difficulty in product extraction and recovery, low expression efficiency, etc., and achieves the effects of improving utilization rate, increasing yield, and reducing the generation of impurities

Active Publication Date: 2022-02-18
浙江湃肽生物股份有限公司南京分公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

In general, recombinant DNA technology, due to the need for a long-term, expensive research and development stage, and the problems of low expression efficiency and difficult product extraction and recovery in the fermentation stage
Its application is very limited

Method used

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  • A kind of synthetic method of bivalirudin
  • A kind of synthetic method of bivalirudin
  • A kind of synthetic method of bivalirudin

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Synthesis of Bivalirudin

[0047] 1. Activation of resin

[0048] Take 45g of Wang resin and add 690g of activation solution, 100r / min oscillating reaction for 2h; after the reaction, filter out the resin, wash and dry to obtain the activated resin; the activation solution includes 600g of methylene chloride, 60g of B-butyrolactone, Nadic anhydride 30g.

[0049] 2. Synthesis of Leu-resin

[0050] Take 50g of swelled activated resin and 0.08mol Fmoc-Leu, add 0.08mol DMF to swell, then ice-bath, continue to add 0.08mol DCC, 0.08mol HOBt and 0.0025mol DMAP, after 2h in ice-bath, 4°C, 100r / min stirring overnight; After stirring, filter, wash and dry to obtain Fmoc-Leu-resin; add 100g of pyridine / dichloromethane / DMF mixed solution (V / V / V=1:1:3) to Fmoc-Leu-resin, react for 30min, suction filter and Wash and dry to obtain Leu-resin.

[0051] 3. Synthesis of bivalirudin-resin

[0052] According to the operation method in step 2, amino acids were sequentially coupled to pr...

Embodiment 2

[0062] Synthesis of Bivalirudin

[0063] 1. Activation of resin

[0064] Take 30g of Wang resin and add 573g of activation solution, oscillate at 100r / min for 1h; filter out the resin after the reaction, wash and dry to obtain the activated resin; the activation solution is 540g of dichloromethane, 30g of B-butyrolactone, Nadic anhydride 3g.

[0065] 2. Synthesis of Leu-resin

[0066] Take 30g of swelled activated resin and 0.05mol Fmoc-Leu, add 0.05mol DMF to swell, then ice-bath, continue to add 0.05mol DCC, 0.05mol HOBt and 0.001mol DMAP, after 1h in ice-bath, stir overnight at 2°C at 100r / min; After stirring, filter, wash and dry to obtain Fmoc-Leu-resin; add 90g of pyridine / dichloromethane / DMF mixed solution (V / V / V=0.25:1:1) to Fmoc-Leu-resin, react for 20min, suction filter and Wash and dry to obtain Leu-resin.

[0067] 3. Synthesis of bivalirudin-resin

[0068] With embodiment 1.

[0069] 4. Deprotection

[0070] Take 100g of 90% TFA solution, 10g of (S)-glycidol...

Embodiment 3

[0074] Synthesis of Bivalirudin

[0075] 1. Activation of resin

[0076] Take 60g of Wang resin and add 915g of activation solution, oscillate at 120r / min for 4h; filter out the resin after the reaction, wash and dry to obtain the activated resin; the activation solution is 780g of methylene chloride, 90g of B-butyrolactone, Nadic anhydride 45g.

[0077] 2. Synthesis of Leu-resin

[0078] Take 60g of swollen activated resin and 0.15mol Fmoc-Leu, add 0.15mol DMF to swell, then ice-bath, continue to add 0.15mol DCC, 0.15mol HOBt and 0.005mol DMAP, after 5h in ice-bath, stir overnight at 4°C at 120r / min; After stirring, filter, wash and dry to obtain Fmoc-Leu-resin; add 120g of dichloromethane / DMF mixed solution (V / V / V=1:1:3) to Fmoc-Leu-resin and react for 50min, then suction filter and wash and dry Dry to obtain Leu-resin. (modified according to the content of the invention)

[0079] 3. Synthesis of bivalirudin-resin

[0080] With embodiment 1.

[0081] 4. Deprotection ...

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Abstract

The invention discloses a synthesis method of bivalirudin, which belongs to the technical field of polypeptide medicine preparation. The synthetic method of bivalirudin comprises: step (1), activates resin, adopts activation liquid to carry out activation treatment to resin to obtain activated resin, and described activation liquid comprises dichloromethane, B-butyrolactone, nadic acid anhydride; (2), the synthesis of Leu-resin, the swelled activated resin and Fmoc-Leu are synthesized into Leu-resin by solid-phase synthesis; step (3), the synthesis of bivalirudin-resin, is synthesized by solid-phase synthesis Bivalirudin-resin; step (4), deprotection, deprotecting bivalirudin-resin to obtain bivalirudin. The yield of bivalirudin synthesized by the synthetic method of the present invention is higher.

Description

technical field [0001] The invention relates to the technical field of preparation of polypeptide drugs, in particular to a synthesis method of bivalirudin. Background technique [0002] Biologically active peptides have unique advantages as drugs: first, small molecular weight, non-immunogenicity, and relatively safe; second, relatively simple structure, clear functions, specificity, and small side effects; third, small molecules, easy synthesis, and easy structure Transformation, low production cost; Fourth, peptide drugs are easy to absorb from multiple channels, so the route of administration can be diversified (such as: oral, spray, transdermal absorption, etc.); Fifth, the synthetic peptide has high purity and no heat source question. Because of this, special attention has been paid to the research on peptide drugs at home and abroad. [0003] Bivalirudin is a hirudin-based, synthetic anticoagulant drug. It is a polypeptide chain composed of 20 amino acids, and the m...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/815C07K1/04C07K1/06
CPCC07K14/815
Inventor 刘志国魏祝宇潘海良叶有志汪岳斌
Owner 浙江湃肽生物股份有限公司南京分公司
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