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Synthesis process of polypeptide condensation reagent COMU

A technology of condensation reagent and synthesis process, which is applied in the field of synthesis technology of the third-generation polypeptide condensation reagent COMU, can solve the problems of unsuitability for large-scale industrial production, long reaction time, complicated post-processing, etc. Short reaction time and good quality of pure product

Inactive Publication Date: 2017-11-03
成都巴赛泰德生物科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] The synthesis of COMU has been reported in relevant literature, but this operation process has low yield, complicated post-treatment, and long reaction time, which is not suitable for large-scale industrial production.

Method used

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  • Synthesis process of polypeptide condensation reagent COMU

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Effect test

Embodiment 1

[0031] A synthetic process for the polypeptide condensation reagent COMU, which uses ethyl cyanoacetate and N,N-dimethylmorpholine-4-carboxamide as raw materials, and includes the following steps:

[0032] (1) Preparation of 2-oxime ethyl cyanoacetate potassium salt

[0033] a. Add ethyl cyanoacetate (30g), water (90mL), and sodium nitrite (19.2g) into a 250mL three-necked flask. After stirring, add 62.5% sulfuric acid aqueous solution (22.9g) dropwise at 35℃. , Adjust the pH to 3, continue to control the temperature after 30 minutes of dripping, and stir for 30 minutes at 35°C. TLC monitors that the reaction is complete, then stop heating, continue stirring for 2 hours, while cooling the reaction solution to a temperature below 15°C, when the temperature of the reaction solution is below 15°C, a large amount of solids precipitate out, filter, and filter the cake with water (wash two Wash each time with 10 mL of water each time) and then wash with petroleum ether (wash twice, 15 m...

Embodiment 2

[0041] A synthetic process for the polypeptide condensation reagent COMU, which uses ethyl cyanoacetate and N,N-dimethylmorpholine-4-carboxamide as raw materials, and includes the following steps:

[0042] (1) Preparation of 2-oxime ethyl cyanoacetate potassium salt

[0043] a. Add ethyl cyanoacetate (1Kg), water (3L), and sodium nitrite (640g) into a 10L three-necked flask. After stirring, add 62.5% sulfuric acid aqueous solution (764g) dropwise at 30℃ and adjust The pH value is 4, after 1h dripping, continue to control the temperature and stir the reaction at 30℃ for 35min. TLC monitors that the reaction is complete, then stop heating, continue to stir for 2h, while cooling the temperature of the reaction liquid to below 15°C, when the temperature of the reaction liquid is below 15°C, a large amount of solids precipitate out, filter, filter cake with water ( Wash twice, with 300mL water each time) and petroleum ether (wash twice, 500mL petroleum ether each time) successively, an...

Embodiment 3

[0051] A synthetic process for the polypeptide condensation reagent COMU, which uses ethyl cyanoacetate and N,N-dimethylmorpholine-4-carboxamide as raw materials, and includes the following steps:

[0052] (1) Preparation of 2-oxime ethyl cyanoacetate potassium salt

[0053] a. Add ethyl cyanoacetate (1000kg), water (3000L), and sodium nitrite (640kg) into the reaction vessel, stir evenly, and add 62.5% acetic acid aqueous solution (22.9kg) dropwise at 40℃, adjust The pH value is 3.5. After the dropping, the temperature is controlled and the reaction is stirred at 40°C for 25 minutes. TLC monitors that the reaction is complete, then stop heating, continue stirring for 2 hours, while cooling the reaction solution to a temperature below 15°C, when the temperature of the reaction solution is below 15°C, a large amount of solids precipitate out, filter, and filter the cake with water (wash two Wash each time with 300L of water each time) and then wash with petroleum ether (wash twice,...

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Abstract

The invention discloses a synthesis process of a polypeptide condensation reagent COMU. The synthesis process uses ethyl cyanoacetate and N,N-dimethylmorpholine-4-carboxamide as raw materials, and comprises: (1) preparing an intermediate oxime salt by using ethyl cyanoacetate; (2) preparing an intermediate hexafluorophosphate by using N,N-dimethylmorpholine-4-carboxamide; and (3) carrying out a substitution reaction on the intermediate oxime salt obtained in the step (1) and the intermediate hexafluorophosphate obtained in the step (2) to prepare a COMU crude product, and re-crystallizing the COMU crude product to obtain the pure product. According to the present invention, the synthesis process has advantages of simple process, strong operability, high yield and low cost, and the synthesized product has high purity.

Description

Technical field [0001] The present invention relates to the technical field of medicines and synthetic processes, in particular to the synthetic process of the third-generation polypeptide condensation reagent COMU. Background technique [0002] Polypeptide condensation reagents are mainly used in the synthesis of peptide drug molecules, and are widely used in solid and liquid phases. Compared with the traditional first-generation condensation reagents represented by DCC (carbodiimides) and HATU as the representative The second generation of condensation reagents (onium salts), COMU has better solubility, stability, reactivity, low risk and hypoallergenic to the human body; at the same time, the by-products produced are easily soluble in water and can be better Therefore, the synthesis of COMU peptide drug molecules, especially in solid-phase synthesis, has obvious advantages. [0003] The synthesis of COMU has been reported in related literature, but the operation process has low...

Claims

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Application Information

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IPC IPC(8): C07D295/125
CPCC07D295/125
Inventor 易磊邢桂燕
Owner 成都巴赛泰德生物科技有限公司
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