Synthetic method of PHBA

A technology of phthaloylaminobutyric acid and its synthesis method, which is applied in the direction of organic chemistry, can solve the problems of high energy consumption, environmental pollution, and high cost, and achieve the effects of low preparation cost, less pollution of "three wastes" and stable quality

Active Publication Date: 2014-10-15
CHENGDU LIKAI CHIRAL TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] The purpose of the present invention is to provide a synthetic method of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid to solve the above-mentioned problems of large energy consumption, high cost and environmental pollution

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0035] A kind of synthetic method of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid, comprises the following steps:

[0036] (1) Preparation of (S)-γ-butyrolactone

[0037] Add 600g of water into the reaction bottle, add 330g of hydrochloric acid and 147g of L-glutamic acid (purified according to the content) in turn under stirring, after dissolving, slowly add NaNO 2 solution (103.5g NaNO 2, 400g water preparation), controlled within 3 to 5 hours (due to the exothermic reaction, it is difficult to keep the cooling environment consistent each time, and the dropping time is also difficult to control at a specific time, and the dropping within this time period will not affect the reaction ) was added, the dropwise addition was completed, and the reaction was continued at 40 to 45°C for 0.5 hours; the reaction was stopped, water was evaporated under reduced pressure, cooled to room temperature, the residue was extracted with 65g × 2 ethyl acetate, and the ethyl acetat...

Embodiment 2

[0047] A kind of synthetic method of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid, comprises the following steps:

[0048] (1) Preparation of (S)-γ-butyrolactone

[0049] Add 600g of water into the reaction bottle, add 541g of sulfuric acid and 147g of L-glutamic acid (purified according to the content) in sequence under stirring, after dissolving, slowly add NaNO dropwise 2 solution (103.5g NaNO 2 , prepared with 400g water), control the addition in 3-5 hours, dropwise, continue the reaction at 40-45°C for 0.5 hours; stop the reaction, distill off the water under reduced pressure, cool to room temperature, and use 65g×2 ethyl acetate for the residue Extracted, evaporated ethyl acetate under reduced pressure to obtain (S)-γ-butyrolactone 140g, content 89.1%, yield 95.9%;

[0050] (2) Preparation of (S)-α-hydroxyglutarate monoamide sodium salt

[0051] Cool 314.3g of 25% ammonia solution to below 10°C, add (S)-γ-butyrolactone 135g in batches under stirring, ...

Embodiment 3

[0059] A kind of synthetic method of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid, comprises the following steps:

[0060] (1) Preparation of (S)-γ-butyrolactone

[0061] Pump 204 kg of pure water and 32.7kg of 2N sulfuric acid into the reaction kettle through the bottom valve, add 52.4kg of L-glutamic acid under stirring, add dropwise 35.2kg of sodium nitrite aqueous solution, and keep the reaction at 40-45°C after the dropwise addition 2 hours. Concentrate under reduced pressure until no fraction distills out, add 55kg of ethyl acetate, extract, concentrate the extract until dry to obtain (S)-γ-butyrolactone 60.0Kg content 89.1%, yield 95.9%;

[0062] (2) Preparation of (S)-α-hydroxyglutarate monoamide sodium salt

[0063] Put 400Kg of 25% ammonia solution into the reaction kettle, lower the temperature to below 10°C, add 60Kg of (S)-γ-butyric acid lactone in batches under stirring, and continue to react for 3 to 5 hours until the lactone is completely dissolv...

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Abstract

The invention discloses a synthetic method of PHBA, and belongs to the technical field of pharmaceutical synthesis. According to the method, L-glutamic acid is taken as the raw material, and is subjected to diazotization, hydrolysis, aminolysis and Hoffman degradation to obtain (S)-4-amino-2-hydroxybutyrate which is not purified and used directly for synthesizing (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid. The synthetic method solves the problems that the conventional method is cumbersome in operation, high in energy consumption and serious in environmental pollution due to the fact that ion exchange resin is required to be used repeatedly for separation and purification of a product, steps of reactions are organically combined, the whole process is considered, and numerous distillation and purification processes are omitted, so that the whole process is greatly simplified, the total yield of the product is larger than 60%, the content of the product is larger than 99.0%, the optical purity is higher than 99.0%, the quality is stable, reaction conditions are mild, pollution of the three wastes is little, the preparation cost is low, and the method is suitable for industrial preparation of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of (S)-alpha-hydroxyl-gamma-N-phthaloylaminobutyric acid. Background technique [0002] Amikacin is the third generation of semi-synthetic aminoglycoside antibiotics. It has strong pharmacological effects on Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Proteus, and has the advantages of low ototoxicity and nephrotoxicity. It is one of the antibiotics widely used clinically in my country. [0003] (S)-α-Hydroxy-γ-N-phthaloylaminobutyric acid (the structural formula is as formula Ⅰ, referred to as "PHBA" in this application) is an important intermediate for the synthesis of drug amikacin. There are many literatures reporting its synthesis method. [0004] According to the different starting materials used, its synthesis method is divided into two routes. [0005] Method 1: The preparation method using L-glutamic acid as the sta...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D209/48
CPCC07D209/48
Inventor 肖勋周鸣强雷三忠王川袁仕雪郑宁川刑志奎雷继忠牟行彦龙超久
Owner CHENGDU LIKAI CHIRAL TECH
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