Method for preparing chiral alpha-alkyl substituted glycine hydrochloride

A glycine hydrochloride, hydrocarbyl substitution technology, applied in the field of synthesis of chiral amino acid hydrochloride, can solve the problems of high requirements, unstable optical purity of products, and low yield

Active Publication Date: 2012-06-27
LIAONING ASYMCHEM LAB CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The resolution reagent used in this method can be recovered, and the process is simple, but the high temperature reaction has high requirements on equipment, high energy consumption, and the optical purity of the obtained product is unstable, and the yield is low, so it is not suitable for large-scale production

Method used

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  • Method for preparing chiral alpha-alkyl substituted glycine hydrochloride
  • Method for preparing chiral alpha-alkyl substituted glycine hydrochloride

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] A kind of preparation L-allylglycine hydrochloride The method is characterized in that the specific preparation steps are as follows:

[0035] (1) Condensation: Add toluene 470kg (1g / 6mL), (S)-camphor 90kg (1.0eq), and main raw material glycine tert-butyl ester 116kg (1.5eq) to a 1000L reactor in sequence. After stirring evenly, add 1.26 kg boron trifluoride diethyl ether (0.015eq), after dropping, raise the temperature to 90±5°C for reaction; after the reaction, lower the temperature, wash the system with sodium bicarbonate solution until pH=7~8, and concentrate the organic phase to obtain the product 141kg, yield 90.0%, gas chromatography purity (GC): 96.8%;

[0036] (2) Substitution: Add 400kg of tetrahydrofuran (1g / 10mL) and 26.6kg (1.4eq) of potassium tert-butoxide into a 1000L reactor, cool down to -10±2°C, add dropwise 45kg of tetrahydrofuran (1g / 2mL) solution 125kg, after stirring for 0.5 hours, add 28.7kg (1.4eq) of 3-bromopropene dropwise, and react at -1...

Embodiment 2

[0042] A kind of preparation D-ethylglycine hydrochloride The method is characterized in that the specific preparation steps are as follows:

[0043] (1) Condensation: Add 66kg (1g / 1mL) of n-heptane, 100kg (1.0eq) of (S) camphor, and 86kg (1.0eq) of tert-butyl glycine as the main raw material into a 500L reactor. Boron trifluoride diethyl ether 932g (0.01eq), after dropping, raise the temperature to 80±2°C for reaction; after the reaction, cool down, wash the system with sodium bicarbonate solution until pH=7~8, and concentrate the organic phase to obtain the product 155kg, yield 89.0%, gas chromatography purity (GC) 96.5%;

[0044] (2) Substitution: Add 103kg (1g / 6mL) of 2-methyltetrahydrofuran (1g / 6mL) and 7.2kg (1.0eq) of sodium tert-butoxide into a 500L reaction kettle, cool down to -20-10°C, and dropwise add 20kg of 2-methyltetrahydrofuran (1g / 4mL) solution 90kg, after stirring for 0.3 hours, add 8.2kg (1.0eq) of bromoethane dropwise, and react at -20±2°C for 2 hours...

Embodiment 3

[0050] A kind of preparation L-benzylglycine hydrochloride The method is characterized in that the specific preparation steps are as follows:

[0051] (1) Condensation: 870kg (1g / 10mL) of xylene, 100kg (1.0eq) of (S) camphor, and 155kg (1.8eq) of tert-butyl glycine, the main raw material, were added in turn to a 2000L reactor. After stirring evenly, three Boron fluoride diethyl ether 1.86kg (0.02eq), after dropping, raise the temperature to 110±2°C for reaction; after the reaction, cool down, wash the system with sodium bicarbonate solution until pH=7~8, and concentrate the organic phase to obtain the product 160kg; yield 91.8%, gas chromatography purity (GC) 96.0%;

[0052] (2) Substitution: add 266kg methyl tert-butyl ether (1g / 12mL) and 28kg potassium carbonate (1.8eq) to a 1000L reactor, cool down to 10±2°C, add the main raw material dropwise 30kg of methyl tert-butyl ether (1g / 6mL) solution 164kg, after stirring for 1 hour, add 34.8kg of benzyl bromide (1.8eq) dropwi...

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Abstract

The invention discloses a method for preparing chiral alpha-alkyl substituted glycine hydrochloride. The method comprises steps of: selecting commercialized or easily prepared tert-butyl glycinate as an initial raw material; inducing alpha position chiral alkyl substitution through a chiral adjuvant (S) camphor; carrying out chemical split to obtain alpha-alkyl substituted glycine ester; and finally hydrolyzing to obtain optically pure alpha-alkyl substituted glycine hydrochloride. R represents C1-C12 saturated or unsaturated alkyl, or C1-C12 saturated or unsaturated alkyl substituted phenyl. The method uses cheap and easily available raw materials, has high reaction yield, stable technical condition, simple operation and no pollution; the obtained product has an optical purity greater than 99%; therefore, the invention provides a new idea and method for large-scale production of amino acid with high chiral purity.

Description

(1) Technical field: [0001] The invention relates to a synthesis method of chiral amino acid hydrochloride, in particular to a method for preparing chiral α-hydrocarbyl substituted glycine hydrochloride. (two) background technology: [0002] Chiral amino acids are important intermediates for the synthesis of drugs such as peptides and lactam antibiotics, and are widely used in the fields of pharmaceutical synthesis, pesticide synthesis, food additives, new material synthesis, and development of fine chemicals. However, most of the artificially synthesized amino acids are racemates, and the two enantiomers of racemic amino acids often have significant differences in activity, metabolic process and toxicity, such as the notorious "reactine" ( Thalidomide (Thalidomide) is used as a sedative to eliminate the early pregnancy reaction of pregnant women, but it was soon discovered that the babies born to pregnant women who took this drug were deformed. It was found that the (R)-ena...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C227/34C07C227/18C07C229/30C07C229/08C07C229/36
Inventor 洪浩韦建陈元东
Owner LIAONING ASYMCHEM LAB CO LTD
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