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Phosphamide-containing polypeptide condensation agent for synthesizing polypeptide medicine and preparation method thereof

A polypeptide condensing agent and phosphoramide-containing technology, applied in the field of amino acid polypeptides, can solve the problems of poor solubility, rare reports, and limited further application.

Inactive Publication Date: 2019-01-18
重庆科脉生物化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Organophosphorus condensing agents are also very important. The organophosphorus condensing agents based on 3-hydroxy-1,2,3-benzotriazin-4(3H)-one mainly include 3-(diethoxyphosphoryloxy base)-1,2,3-benzotriazin-4-one (DEPBT) (CAS 165534-43-0) and 3-(2'-oxo-1',3',2'-dioxaphosphorus Heterocyclohexylphosphoryloxy)-1,2,3-benzotriazin-4-one (DOPBT), the disadvantage of DOPBT is poor solubility, and it can only be better dissolved in DMF, which limits its further application
Currently, 1-hydroxy-1,2,3-benzotriazin-4(3H)-one based organophosphoramide peptide condensing agents are rarely reported

Method used

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  • Phosphamide-containing polypeptide condensation agent for synthesizing polypeptide medicine and preparation method thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0012] In the reaction flask, add 178g of hexamethylphosphoric triamide, add 600mL of solvent dichloromethane, add 231g of trichloroisocyanuric acid, react at 0°C for 2 hours, then slowly add 68.5g of hydrazine hydrochloride, and then add o-nitrate 181g of methyl o-nitrobenzoate and 165mL of diisopropylethylamine were heated and refluxed until the reaction of methyl o-nitrobenzoate was monitored by TLC. After the reaction of methyl o-nitrobenzoate was completed, 200g of potassium hexafluorophosphate was added while it was hot, and the target product phosphoramide-containing polypeptide condensation was obtained by cooling. Mixture 3,4-dihydro-4-oxo-1,2,3-benzotriazin-1-yl-O-tripyrrolidinyl phosphorus hexafluorophosphate I, the yield is 91.3%, and the purity is 98.5 %.

Embodiment 2

[0014] In the reaction flask, add 267g of hexamethylphosphoric triamide, add 600mL of solvent dichloromethane, add 346g of trichloroisocyanuric acid, react at 0°C for 2 hours, then slowly add 68.5g of hydrazine hydrochloride, and then add o-nitrate 181g of methyl o-nitrobenzoate and 165mL of diisopropylethylamine were heated and refluxed until the reaction of methyl o-nitrobenzoate was monitored by TLC. After the reaction of methyl o-nitrobenzoate was completed, 200g of potassium hexafluorophosphate was added while it was hot, and the target product phosphoramide-containing polypeptide condensation was obtained by cooling. Mixture 3,4-dihydro-4-oxo-1,2,3-benzotriazin-1-yl-O-tripyrrolidinyl phosphorus hexafluorophosphate I, yield 93.3%, purity 98.4 %.

Embodiment 3

[0016] In the reaction bottle, add 178g of hexamethylphosphoric triamide, add 600mL of solvent acetonitrile, add 231g of trichloroisocyanuric acid, react at 0°C for 2 hours, then slowly add 68.5g of hydrazine hydrochloride, and then add o-nitrobenzene Ethyl formate 195g and diisopropylethylamine 165mL, heat up and reflux reaction until TLC monitors methyl o-nitrobenzoate after reaction, add potassium hexafluorophosphate 200g while hot, cool to obtain the target product phosphoramide-containing polypeptide condensing agent 3 ,4-Dihydro-4-oxo-1,2,3-benzotriazin-1-yl-O-tripyrrolidinylphosphonium hexafluorophosphate I, the yield was 87.3%, and the purity was 98.6%.

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Abstract

The invention discloses a phosphamide-containing polypeptide condensation agent for synthesizing a polypeptide medicine and a preparation method thereof and belongs to the technical field of amino acid polypeptides. According to the essentials of the technical scheme, the phosphamide-containing polypeptide condensation agent for synthesizing the polypeptide medicine is characterized in that the phosphamide-containing polypeptide condensation agent is 3,4-dihydro-4-oxo-1,2,3-phentriazine-1-yl-O-tripyrrolidinylphosphonium hexafluorophosphate and a structural formula is as follows: a formula is shown in the description. The invention further specifically discloses a preparation method of the phosphamide-containing polypeptide condensation agent for synthesizing the polypeptide medicine. In the preparation method, raw materials are common reagents and a synthetic route is simple; a multi-step one-pot method has moderate reaction conditions and is simple to operate.

Description

technical field [0001] The invention belongs to the technical field of amino acid polypeptides, and in particular relates to a phosphoramide-containing polypeptide condensing agent used for the synthesis of polypeptide drugs and a preparation method thereof. Background technique [0002] Polypeptides are a class of compounds formed by linking multiple amino acids through peptide bonds in the same way as proteins, usually consisting of 10 to 100 amino acid molecules, with a relative molecular mass of less than 10,000. Peptides are widely involved in regulating the functional activities of various systems, organs, tissues and cells in the body. Some drugs are derived from peptides. Peptide drugs that were listed earlier are mainly peptide hormones, such as salmon calcitonin, somatostatin, human glucagon, and oxytocin. With the continuous deepening of new drug research and development and the advancement of peptide synthesis technology, the development of peptide drugs has dev...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6521C07F9/6558
CPCC07F9/65583
Inventor 崔振伟过治军李天蓝李玲
Owner 重庆科脉生物化工有限公司