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Method for synthesizing Alisporivir

An alisporivir and a certain amount of technology are applied in the field of chemical synthesis of polypeptides, which can solve the problems of low yield and the like, and achieve the effects of improving yield and quality, mild reaction conditions, and easy industrial production.

Inactive Publication Date: 2013-06-12
HYBIO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In order to solve the problem of low yield in the preparation method of the prior art, it is necessary to further study the synthesis process of alisporivir

Method used

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  • Method for synthesizing Alisporivir

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Experimental program
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Embodiment 1

[0029] Under the protection of nitrogen, at room temperature, add the dichloromethane solution dissolved in 100mL (concentration: 1g / 3mL) of triphosgene dropwise to H-D-MeAla-EtVal-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal - A solution of MeBmt-αAbu-OH (200 mg, 0.162 mmol), HOAt (110 mg, 0.81 mmol), DIC (102 mg, 0.81 mmol) in 1 L of dichloromethane. After the dropwise addition, continue to react for 24 hours and then neutralize the reaction system to pH=10 with 10% aqueous sodium carbonate solution. Dichloromethane was evaporated and extracted three times with ethyl acetate. The combined organic phases were sequentially washed with 0.1M hydrochloric acid, protected aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purified by column to obtain 150mg (80%) DEB025 with a purity of >95%. MS: 1217.8[M+H] +

Embodiment 2

[0031]Under the protection of nitrogen, at room temperature, add the dichloromethane solution dissolved in 100mL (concentration: 1g / 3mL) of triphosgene dropwise to H-D-MeAla-EtVal-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal - A solution of MeBmt-αAbu-OH (200 mg, 0.162 mmol), HOAt (110 mg, 0.81 mmol), DIC (102 mg, 0.81 mmol) and 10 mg of activated carbon in 1 L of dichloromethane. After the dropwise addition was completed, the reaction was continued for 24 hours, and the gac was removed by filtration. Neutralize the reaction system to pH=10 with 10% sodium carbonate aqueous solution. Dichloromethane was evaporated and extracted three times with ethyl acetate. The combined organic phases were sequentially washed with 0.1M hydrochloric acid, protected aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purified by column to obtain 160mg (86%) DEB025. Purity>95%.

Embodiment 3

[0033] Under the protection of nitrogen, at room temperature, add the dichloromethane solution dissolved in 100mL (concentration: 1g / 3mL) of triphosgene dropwise to H-D-MeAla-EtVal-Val-MeLeu-Ala-(D)Ala-MeLeu-MeLeu-MeVal - A solution of MeBmt-αAbu-OH (200 mg, 0.162 mmol), HOAt (110 mg, 0.81 mmol), DIC (102 mg, 0.81 mmol) and 10 mg of pyridine in 1 L of dichloromethane. After the dropwise addition, the reaction was continued for 24 hours, and the reaction system was neutralized to pH=10 with 10% aqueous sodium carbonate solution. Dichloromethane was evaporated and extracted three times with ethyl acetate. The combined organic phases were sequentially washed with 0.1M hydrochloric acid, protected aqueous sodium bicarbonate solution and saturated brine, dried over anhydrous sodium sulfate, and concentrated. Purified by column to obtain 158mg (85%) DEB025 with a purity of >95%.

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Abstract

The invention provides a method for synthesizing Alisporivir. The method comprises the following steps of dropwise adding solution with triphosgene dissolved therein into an organic solvent to dissolve H-D-MeAla-EtVal-Val-Meleu-Ala-(D)Ala-MeLeu-MeLeu-MeVal-MeBmt-alphaAbu-OH, HOAt and DIC solution under the protection of inert gases, reacting for a plurality of times after dropwise adding, adding alkaline solution to adjust pH to alkalinity, and further purifying to obtain Alisporivir. The method for synthesizing Alisporivir, which is simple to operate, high in yield and high in purity and is benefit for achieving industrialization, is provided by the invention.

Description

technical field [0001] The invention relates to a method for chemically synthesizing a polypeptide, in particular to a method for synthesizing alisporivir. Background technique [0002] Currently, approximately 170 million people worldwide are infected with hepatitis C (HCV). The initial course of infection is usually mild, however the immune system is often unable to clear the virus, and people with persistent infection are at high risk of liver cirrhosis and hepatocellular carcinoma (see Poynard et al., Lancet 349, (1997), 825-832). There is no effective vaccine to prevent HCV (see Manns et al., India J.Gastroenterol.20 (Suppl.1), (2001), C47-51; Tan et al., Nat.Rev.Drug Discov.1, (2002), 867 -881). [0003] Recently, a new method of treating HCV infection with cyclosporine was described by clinical observation data (see Teraoka et al., Transplant Proc, 1988, 20(3suppl.3), 868-876; Inoue et al., J.Gastroenterol, 2003, 38, 567-572). Studies have shown that cyclosporine ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/64C07K1/107
Inventor 李国弢马亚平袁建成
Owner HYBIO PHARMA