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Industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester

A technology of benzyl pyroglutamate and tert-butoxycarbonyl is applied in the field of industrial production of high-quality N-tert-butoxycarbonyl-L-benzyl pyroglutamate, which can solve the problems of high raw material cost, low product yield, Product purity does not meet market requirements and other issues

Inactive Publication Date: 2019-05-07
GENCHEM & GENPHARM CHANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The present invention is mainly aimed at the production process of the existing N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester, the cost of raw materials is high, the product yield is low, and the purity of the obtained product cannot meet market requirements. A series of problems provides a method for the industrial production of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester

Method used

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  • Industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester
  • Industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester
  • Industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] (1) Add 413g toluene, 103.2g L-pyroglutamic acid (molar weight 129.11, mole number 0.80mol), 129.3g DIPEA (molar weight 129.24, mole number 1.0mol), 106.4g benzyl chloride (molar number 1.0mol) into a 1000mL flask Quantity 126.58, mole number 0.84mol), 0.8g potassium iodide (molar weight 166, mole number 0.0048mol), heated to 80°C, and reacted overnight.

[0024] (2) After the middle control reaction is finished, cool to room temperature, add water, slowly add saturated sodium carbonate solution, adjust the pH of the water phase to be about 8-9, and layer. The aqueous phase was extracted with toluene, the toluene layers were combined, washed once with saturated sodium chloride solution, the organic phase was dried by adding anhydrous sodium sulfate, and the sodium sulfate was filtered off for use;

[0025] (3) filtrate was transferred into 1000mL flask, 262g Boc acid anhydride (1.2mol) was added, 2g catalyst DMAP (0.02mol) was heated to 50°C to react overnight;

[0026...

Embodiment 2

[0028] (1) Add 413g toluene, 103.2g L-pyroglutamic acid (molar weight 129.11, mole number 0.80mol), 161.9g triethylamine (molar weight 101, mole number 1.60mol), 143.6g benzyl bromide in a 1000mL flask (molar weight 171.04, mole number 0.84mol), 0.66g potassium iodide (molar weight 166, mole number 0.004mol), heated to 80°C, and reacted overnight.

[0029] (2) After the middle control reaction is finished, cool to room temperature, add water, slowly add saturated sodium carbonate solution, adjust the pH of the water phase to be about 8-9, and layer. The aqueous phase was extracted with toluene, the toluene layers were combined, washed once with saturated sodium chloride solution, the organic phase was dried by adding anhydrous sodium sulfate, and the sodium sulfate was filtered off for use;

[0030] (3) filtrate was transferred into 1000mL flask, 262g Boc acid anhydride (1.2mol) was added, 1g catalyst 4-PPY (0.01mol) was heated to 50°C to react overnight;

[0031] (4) After t...

Embodiment 3

[0033] (1) 516g of dichloromethane, 103.2g of L-pyroglutamic acid (129.11 moles, 0.80mol moles), 155.2g DIPEA (129.24 moles, 1.20mol moles), 101.3g benzyl chloride ( Molar weight 126.58, mole number 0.80mol), 0.8g potassium iodide (molar weight 166, mole number 0.0048mol), heated to reflux, and reacted overnight.

[0034] (2) After the middle control reaction is finished, cool to room temperature, add water, slowly add saturated sodium carbonate solution, adjust the pH of the water phase to be about 8-9, and layer. The aqueous phase was extracted with dichloromethane, the dichloromethane layers were combined, washed once with saturated sodium chloride solution, the organic phase was dried by adding anhydrous sodium sulfate, and the sodium sulfate was filtered off for use.

[0035] (3) The filtrate was transferred to another 1500 mL flask, 349.3 g of Boc acid anhydride (1.6 mol), 3 g of catalyst DMAP (0.03 mol) were added, and the reaction was heated to reflux overnight.

[00...

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Abstract

The invention relates to the technical field of biochemical industry, and in particular relates to an industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzylester. The method comprises the following steps: reacting raw material L-pyroglutamic acid with benzyl chloride or benzyl bromide in the presence of an acid binding agent and a catalyst to obtain intermediate L-pyroglutamic acid benzyl ester; reacting the intermediate L-pyroglutamic acid benzyl ester organic phase with a Boc acid anhydride under the catalyst conditions to obtain target crude N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester; and performing recrystallization on the crude N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester in a mixed crystallization solvent to obtain thehigh-purity N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester. Compared with the prior art, the industrialized production method of the N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester provided by the invention has the following beneficial effects: the method can efficiently and stably produce the high-quality powdered N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester, the purityis greater than 99.5%, and the content of single impurities is less than 0.1%.

Description

technical field [0001] The invention relates to the technical field of biochemical industry, in particular to an industrialized production method of high-quality N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester. Background technique [0002] N-tert-butoxycarbonyl-L-pyroglutamate benzyl ester, Chinese alias: BOC-L-pyroglutamate benzyl ester. English name: 2-benzyl1-tert-butyl(2S)-5-oxopyrrolidine-1,2-dicarboxylate; BOC-L-Pyr Obzl, CAS number: 113400-36-5, molecular formula: C 17 H 21 NO 5 , molecular weight: 319.35. [0003] The chemical structural formula is: [0004] [0005] N-tert-butoxycarbonyl-L-pyroglutamic acid benzyl ester is used in the synthesis of polypeptides, antibacterial drugs, widely used in the synthesis of various products such as medicine, biochemistry, food, cosmetics, etc., and is commonly used in the synthesis of various antibacterial drugs . There are few domestic reports on the production of high-quality N-tert-butoxycarbonyl-L-pyroglut...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/28
Inventor 王玉琴狄聚财孟硕
Owner GENCHEM & GENPHARM CHANGZHOU CO LTD