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Preparation method of N-carbobenzoxy-3-amino-alanine tert-butyl ester

A technology of tert-butyl alanine and benzyloxycarbonyl, applied in the field of preparation of N-benzyloxycarbonyl-3-amino-alanine tert-butyl ester, can solve the problems of low yield and high cost, and reduce production cost effect

Inactive Publication Date: 2019-03-29
GL BIOCHEM SHANGHAI +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The technical purpose of the present invention is to overcome the problem of low yield and high cost in the original process, and provides a preparation method of N-benzyloxycarbonyl-3-amino-alanine tert-butyl ester. The method is simple and easy to control, and the yield is high. High, low cost, suitable for large-scale production

Method used

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  • Preparation method of N-carbobenzoxy-3-amino-alanine tert-butyl ester
  • Preparation method of N-carbobenzoxy-3-amino-alanine tert-butyl ester
  • Preparation method of N-carbobenzoxy-3-amino-alanine tert-butyl ester

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Effect test

Embodiment 1

[0022] In the first step, suspend 10KG asparagine in a mixture of 100KG water and 25KG acetone, stir, adjust the pH value between 8-9 with a 20% mass fraction of sodium carbonate solution, cool down to 0°C, and slowly add chlorine Benzyl formate 16KG, keep the temperature below 3°C, add it in 1 hour, then raise the temperature to 18-20°C to react, and react for 10 hours. According to TLC detection, the reaction of the raw materials was completed, acidified with 4 equivalents of hydrochloric acid to pH = 1, and a solid was precipitated, filtered to obtain the intermediate N-benzyloxycarbonylasparagine, and dried to obtain a solid of 18.14KG, with a yield of 90%.

[0023] In the second step, 18.14KG N-benzyloxycarbonylasparagine is suspended in 330KG dichloromethane, stirred, the temperature is lowered to T<-5°C, 33KG of isobutylene is introduced, and 1.81KG of concentrated sulfuric acid with a mass fraction of 98% is added dropwise. Afterwards, the reaction was heated naturally...

Embodiment 2

[0026] In the first step, suspend 100G asparagine in a mixture of 1000G water and 300G acetone, stir, adjust the pH value between 8-9 with a 20% mass fraction of sodium carbonate solution, cool down to 0°C, and slowly add chlorine Benzyl formate 150G, keep the temperature below 3°C, add in 1-2 hours, then raise the temperature to 18-20°C for reaction, and react for 10 hours. According to TLC detection, the reaction of the raw materials was completed, acidified with 4 equivalents of hydrochloric acid to pH = 1, and a solid was precipitated, filtered to obtain the intermediate N-benzyloxycarbonylasparagine, and dried to obtain a solid of 182G, with a yield of 90.3%.

[0027] In the second step, 182G N-benzyloxycarbonyl asparagine is suspended in 2730G dichloromethane, stirred, the temperature is lowered to T<-5°C, 364G of isobutylene is introduced, and 18.2G of concentrated sulfuric acid with a mass fraction of 98% is added dropwise. Natural heating reaction. Sealed and reacted...

Embodiment 3

[0030]In the first step, suspend 2KG asparagine in a mixture of 20KG water and 4KG acetone, stir, adjust the pH value between 8-9 with a 20% mass fraction of sodium carbonate solution, cool down to 0°C, and slowly add chlorine Benzyl formate is 3.6KG, keep the temperature below 3°C, add it in 2 hours, then raise the temperature to 18-20°C to react, and react for 10 hours. According to TLC detection, the reaction of the raw materials was completed, acidified with 4 equivalents of hydrochloric acid to pH = 1, and a solid was precipitated, and the intermediate N-benzyloxycarbonylasparagine was obtained by filtration, and dried to obtain 3.6KG of a solid, with a yield of 89.3%.

[0031] In the second step, 3.6KG of N-benzyloxycarbonyl asparagine is suspended in 72KG of dichloromethane, stirred, the temperature is lowered to T<-5°C, 5.4KG of isobutylene is introduced, and 0.36KG of concentrated sulfuric acid with a mass fraction of 98% is added dropwise. After completion, the react...

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Abstract

The invention discloses a preparation method of tert-butyl N-carbobenzoxy-3-amino-alanine tert-butyl ester, and mainly solves the technical problem of low total yield and high cost in the original process. The preparation method comprises the following steps of 1, suspending asparagine into a mixed solution of water and acetone; regulating the pH value to a basic state by a sodium carbonate solution; lowering the temperature; adding carbobenzoxy chloride; then, raising the temperature for reaction; after the reaction is finished, performing acidification by hydrochloric acid; separating out solid; performing filtering to obtain an intermediate N-benzoxycarbonyl asparagine; 2, suspending the N-benzoxycarbonyl asparagine into dichloromethane; introducing isobutene; adding concentrated sulfuric acid; performing sealed reaction for two days; performing treatment to obtain N-carbobenzoxy asparagine tert-butyl ester; 3, dissolving the N-carbobenzoxy asparagine tert-butyl ester into water andN,N-dimethylformamide; adding iodobenzene diacetate for reaction first; then adding pyridine; continuously performing reaction till the completion; performing treatment to obtain a final product.

Description

technical field [0001] The invention relates to a preparation method of N-benzyloxycarbonyl-3-amino-alanine tert-butyl ester. Background technique [0002] N-benzyloxycarbonyl-3-amino-alanine tert-butyl ester is an important intermediate in organic synthesis, and is often used in liquid phase synthesis of peptides. The general preparation method of N-benzyloxycarbonyl-3-amino-alanine tert-butyl ester is: N-benzyloxycarbonyl-3-aminoalanine is reacted with isobutene and concentrated sulfuric acid to obtain N-benzyloxycarbonyl-3-amino tert-Butyl alanine, in Journal of Labeled Compounds and Radiopharmaceuticals [Hamill, Terence G.; Askew, Ben C.; Hartman, George D.; Claremon, David A.; McIntyre, Charles J.; Burns, H . Donald; Journal ofLabelled Compounds and Radiopharmaceuticals; vol. 41; nb. 4; (1998); p. 273 -277], the yield is 75%; also in the literature Bioorganic and Medicinal Chemistry Letters [Egbertson; Bednar; Hartman; Gould; Lynch; Vassallo; Young; Bioorganic and Med...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C269/04C07C269/06C07C271/22
CPCC07C269/04C07C269/06C07C271/22
Inventor 徐红岩李仲才
Owner GL BIOCHEM SHANGHAI
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