Method for preparing high-purity chiral 2-smethylcysteine s and hydrochloride of high-purity chiral 2-smethylcysteine s

A technology of cysteine ​​hydrochloride and methylcysteine, which is applied in the field of medicine and biochemistry, can solve the problems of high purity and achieve good industrial application value, simple operation process and low production cost

Inactive Publication Date: 2015-11-18
SYNCOZYMES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Chiral 2-methylcysteine ​​and its hydrochloride are key intermediates of many active drugs, and their high purity (ie, the presence of low-level 2-methyl-cystine impurities) is conducive to the effective subsequent reactions. and high yield, to ensure the quality of the final bulk drug, although there are many synthetic methods about chiral 2-methylcysteine ​​and its hydrochloride, there is no high-purity (i.e. related impurities<0.1%) so far ) literature reports on chiral 2-methylcysteine ​​and its hydrochloride
In addition, chiral 2-methylcysteine ​​and its hydrochloride are also easily oxidized by air to generate 2-methylcystine impurities during storage

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Embodiment 1 Preparation of high-purity 2-methyl-D-cysteine ​​and its hydrochloride

[0018] A) Crude product of 2-methyl-D-cysteine ​​hydrochloride

[0019] Add (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid (19g, 0.085mol) and 6N hydrochloric acid (100ml, 1.207mol) into a 500mL single-necked bottle , heated to reflux for 24h, and concentrated under reduced pressure to obtain a crude product (purity>95%, 2-methyl-D-cystine impurity>1%).

[0020] B) High purity 2-methyl-D-cysteine ​​hydrochloride

[0021] Add tetrahydrofuran (100ml) and triphenylphosphine (3g) to the crude 2-methyl-D-cysteine ​​hydrochloride above, N 2 Protected, heated at 60°C to dissolve, stirred for 3 hours, HPLC detected that the 2-methyl-D-cystine impurity disappeared, cooled to 0-5°C, a large amount of white solid precipitated, filtered, and dried to obtain white solid 2-methyl-D- - Cysteine ​​hydrochloride 11.1 g, yield: 76%. HPLC: 99.93%, 2-methyl-D-cystine impuri...

Embodiment 2

[0024] Embodiment 2 Preparation of high-purity 2-methyl-L-cysteine ​​and its hydrochloride

[0025] A) Crude product of 2-methyl-L-cysteine ​​hydrochloride

[0026] Add (2R,4R)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid (19g, 0.085mol) and 6N hydrochloric acid (100ml, 1.207mol) into a 500mL single-necked bottle , heated to reflux for 24h. Concentrate under reduced pressure to obtain a crude product (purity>95%, 2-methyl-D-cystine impurity>1%).

[0027] B) High purity 2-methyl-L-cysteine ​​hydrochloride

[0028] Add tetrahydrofuran (100ml) and triphenylphosphine (3g) to the crude product of 2-methyl-L-cysteine ​​hydrochloride above, N 2 Protected, heated at 60°C to dissolve, stirred for 3 hours, HPLC detected that 2-methyl-L-cystine impurity disappeared, cooled to 0-5°C, a large amount of white solid precipitated, filtered, and dried to obtain white solid 2-methyl-L- - Cysteine ​​hydrochloride 11.3 g, yield: 77%. HPLC: 99.95%, 2-methyl-L-cystine imp...

Embodiment 3

[0031] Embodiment 3 Preparation of high-purity 2-methyl-D-cysteine ​​and its hydrochloride

[0032] A) Crude product of 2-methyl-D-cysteine ​​hydrochloride

[0033] Add (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid (19g, 0.085mol) and 6N hydrochloric acid (100ml, 1.207mol) into a 500mL single-necked bottle , heated to reflux for 24h, and concentrated under reduced pressure to obtain a crude product (purity>95%, 2-methyl-D-cystine impurity>1%).

[0034] B) High purity 2-methyl-D-cysteine ​​hydrochloride

[0035] Add tetrahydrofuran (100ml) and zinc powder (2.7g) / acetic acid (10ml) to the above-mentioned 2-methyl-D-cysteine ​​hydrochloride crude product, N 2 Protected, heated at 40°C to dissolve, stirred for 6h, HPLC detected that the 2-methyl-D-cystine impurity disappeared, cooled to 5-10°C, a large amount of white solid precipitated, filtered, and dried to obtain white solid 2-methyl-D- - cysteine ​​hydrochloride 10.6 g, yield: 73%. HPLC: 99.91...

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PUM

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Abstract

The invention discloses a method for preparing high-purity chiral 2-smethylcysteine s and hydrochloride of high-purity chiral 2-smethylcysteine s. The method comprises the steps that crude chiral 2-methyl cysteine hydrochloride and a reducing agent are added to an organic solvent, crude chiral 2-methyl cysteine hydrochloride is dissolved at room temperature or under the heating condition, stirring and cooling crystallization are carried out to obtain high-purity chiral 2-methyl cysteine hydrochloride; aftertreatment is carried out on high-purity chiral 2-methyl cysteine hydrochloride to obtain high-purity chiral 2-smethylcysteine s. Compared with the prior art, the adopted method is simple in operation process, low in production cost and high in product purity, and good industrial application value is achieved.

Description

technical field [0001] The invention belongs to the field of medicine and biochemistry, and in particular relates to a preparation method of high-purity chiral 2-methylcysteine ​​and its hydrochloride. Background technique [0002] Chiral 2-methylcysteine ​​and its hydrochloride are versatile unnatural amino acids, which exist in many natural products and active drug molecules with good biological activity. Wherein 2-methyl-D-cysteine ​​hydrochloride is the key intermediate of oral iron removal agent main component Desferrithiocin, and 2-methyl-L-cysteine ​​hydrochloride is histone deacetylase ( HDAC) inhibitor Largazole's key intermediate, so the synthesis technology of chiral 2-methylcysteine ​​and its hydrochloride has been widely researched and concerned. [0003] Jiang Sheng and others carried out the methylation reaction of (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-carboxylate with methyl iodide under the action of NaHMDS, and the methylated product was Reflu...

Claims

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Application Information

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IPC IPC(8): C07C323/58C07C319/28
Inventor 竺伟史学松赖亮
Owner SYNCOZYMES SHANGHAI
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