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Liquid-phase synthesis method for cyclic peptides Alaptide

A liquid-phase synthesis and cyclic peptide technology, applied in the field of polypeptide liquid-phase synthesis, can solve the problem of high synthesis cost and achieve the effects of low synthesis cost, low environmental pressure and mild reaction conditions

Active Publication Date: 2018-04-13
SHAANXI HUIKANG BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method synthesis cost is higher, and Alaptide yield is only 39%

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0022] 1. Add 12.9g (0.1mol) of H-Cycloleucine-OH, 100mL of tetrahydrofuran, and 150mL of water into a 500mL single-necked bottle, stir until the solid is dissolved, then add 21.2g (0.2mol) of sodium carbonate, and then slowly Add 35mL (0.15mol) of di-tert-butyl dicarbonate dropwise, react at room temperature for 6 hours after the dropwise addition, TLC shows that the reaction is complete, filter out insoluble matter, remove tetrahydrofuran under reduced pressure, adjust pH=3 with citric acid, and then use acetic acid Ethyl ester extraction (100 mL×3 times), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 20 g of Boc-Cycloleucine-OH.

[0023] 2. Add 17.8g (0.2mol) H-Ala-OH and 200mL methanol into a 500mL single-necked bottle, stir until the solid dissolves, add 29mL (0.4mol) thionyl chloride dropwise at 0-5°C, and dropwise add Afterwards, the reaction was carried out at 0-10°C ...

Embodiment 2

[0027] 1. Add 19.3g (0.15mol) of H-Cycloleucine-OH, 100mL of dichloromethane, and 200mL of water into a 500mL single-necked bottle, stir until the solid dissolves, then add 41g (0.3mol) of potassium carbonate, and slowly Add 51mL (0.22mol) of di-tert-butyl dicarbonate dropwise, react at room temperature for 6 hours after the dropwise addition, TLC shows that the reaction is complete, filter out insoluble matter, remove dichloromethane under reduced pressure, adjust pH=3 with citric acid Extracted with ethyl acetate (100 mL×3 times), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 31 g of Boc-Cycloleucine-OH.

[0028] 2. Add 17.8g (0.2mol) H-Ala-OH and 200mL methanol into a 500mL single-necked bottle, stir until the solid dissolves, add 34mL (0.4mol) oxalyl chloride dropwise at 0-5°C, after the dropwise addition, The reaction was carried out at 0-10° C. for 2 hours, then the tem...

Embodiment 3

[0032] 1. Add 50g (0.38mol) H-Cycloleucine-OH, 150mL tetrahydrofuran, and 500mL water into a 1000mL single-necked bottle, stir until the solid dissolves, then add 80g (0.76mol) sodium carbonate, and slowly add 130mL dropwise at 5-15°C (0.57mol) di-tert-butyl dicarbonate, react at room temperature for 6 hours after the dropwise addition, TLC shows that the reaction is complete, filter off the insoluble matter, remove THF under reduced pressure, adjust pH=3 with citric acid, and extract with ethyl acetate (200 mL×3 times), the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure to obtain 80 g of Boc-Cycloleucine-OH.

[0033] 2. Add 38.2g (0.43mol) H-Ala-OH and 500mL methanol into a 1000mL single-necked bottle, stir until the solid dissolves, add 62mL (0.86mol) thionyl chloride dropwise at 0-5°C, and dropwise add Afterwards, the reaction was carried out at 0-10°C for 2 hours, then the temperature w...

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PUM

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Abstract

The invention discloses a liquid-phase synthesis method for cyclic peptides Alaptide. The liquid-phase synthesis method includes carrying out reaction on L-cycloleucine with Boc protected N ends, N-hydroxysuccinimide and N, N'-dicyclohexylcarbodiimide by the aid of Boc strategies of liquid-phase synthesis processes so as to obtain active ester; carrying out condensation on the active ester and hydrochloride of alanine methyl ester to obtain cyclo-leucyl alanine methyl ester with Boc protected N ends; removing Boc protecting groups; carrying out cyclization reaction on amine and carboxylate ester under alkaline conditions to obtain the cyclic peptides Alaptide. The liquid-phase synthesis method has the advantages that the liquid-phase synthesis method includes simple operation steps and islow in cost and high in product yield, and the problems of high material cost and environmental stress, low product yield, difficulty in scale expansion and the like of existing synthesis methods canbe solved.

Description

technical field [0001] The invention belongs to the technical field of polypeptide liquid-phase synthesis, and in particular relates to a liquid-phase synthesis method of a cyclic peptide drug Alaptide. Background technique [0002] Alaptide, also known as CPA, is a cyclic peptide of cycloleucine and alanine. As a chemical drug, it has been used to treat skin diseases and has active therapeutic effects in the fields of anti-inflammatory and antibacterial chemistry. The current clinical phase III study shows that Alaptide has great potential in the treatment of upper respiratory tract diseases, and at the same time, it also has positive therapeutic potential in the treatment of blood pressure in hypertensive patients. CPA can be used as a nootropic drug for improving brain function, and many of its derivatives have obvious memory-enhancing activity, which can prolong the memory retention time of female rats. [0003] Respiratory distress syndrome refers to serious diseases i...

Claims

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Application Information

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IPC IPC(8): C07K5/12C07K1/08C07K1/06C07K1/02
CPCC07K5/12Y02P20/55
Inventor 李晨陈科王惠嘉张忠旗苏晨灿杨小琳赵金礼
Owner SHAANXI HUIKANG BIO TECH CO LTD
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