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Preparation method of chirality 2-methyl cysteine and hydrochloride thereof

A technology of methylcysteine ​​and hydrochloride, which is applied in the field of preparation of chiral 2-methylcysteine ​​and its hydrochloride, can solve the difficulty in purification of methylated products, which cannot meet the requirements of industrial production, Low production efficiency and other issues, to achieve the effect of high product purity and optical purity, good industrial application value, and improved production efficiency

Inactive Publication Date: 2015-09-09
SYNCOZYMES SHANGHAI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, this method still uses column chromatography to purify the methylated product, and the reaction time is long, the production efficiency is low, and the cost is high, which cannot meet the needs of industrial production.
At the same time, the researchers of our company refer to the above literature methods to carry out repeated experiments, but the yield reported in the literature has not been obtained, especially the purification of methylated products is difficult, and the method reproducibility is poor.

Method used

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  • Preparation method of chirality 2-methyl cysteine and hydrochloride thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] Example 1 Preparation of 2-methyl-D-cysteine ​​and its hydrochloride

[0024] A) (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid

[0025] At -90°C, (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-carboxylic acid methyl ester (23.1g, 0.1mol) was dissolved in anhydrous THF ( 230ml), under nitrogen protection, add iodomethane (28.6g, 0.20mol) under stirring, and keep warm for 10min after the dropwise addition. Slowly add NaHMDS (22 g, 0.20 mol) in batches, and keep the reaction for 2 h after the addition is complete.

[0026] At room temperature, add 1N aqueous sodium hydroxide solution (100ml) to the reaction system, stir overnight, add 500ml of water, extract with ethyl acetate (300ml*3), separate the organic layer, add 1N hydrochloric acid dropwise to the aqueous layer until pH = 4. Filter to obtain a white solid. The white solid was recrystallized in toluene to obtain 20 g of white solid, yield: 87%.

[0027] B) 2-Methyl-D-cysteine ​​hy...

Embodiment 2

[0031] Example 2 Preparation of 2-methyl-L-cysteine ​​and its hydrochloride

[0032] A) (2R,4R)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid

[0033] At -90°C, (2R,4R)-2-tert-butyl-3-formyltetrahydrothiazole-4-carboxylic acid methyl ester (23.1g, 0.1mol) was dissolved in anhydrous THF ( 230ml), and methyl iodide (28.6g, 0.20mol) was added with stirring. Slowly add NaHMDS (22 g, 0.2 mol) in batches, and keep the reaction for 2 hours after the addition is complete.

[0034] At room temperature, 1N aqueous sodium hydroxide solution (100 ml) was poured into the reaction system, and left overnight at room temperature. Add 500ml of water and extract with ethyl acetate (300ml*3). 1N hydrochloric acid was added dropwise to the aqueous layer until pH = 4, a large amount of white solids precipitated, and the white solids were obtained by filtration. The white solids were recrystallized in toluene to obtain 20.8 g of white solids, yield: 90%.

[0035] B) 2-Methy...

Embodiment 3

[0039] Example 3 Preparation of 2-methyl-D-cysteine ​​and its hydrochloride

[0040] A) (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-methyl-4-carboxylic acid

[0041] At -40°C, (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-carboxylic acid methyl ester (23.1g, 0.1mol) was dissolved in anhydrous THF ( 230ml), under nitrogen protection, add iodomethane (28.6g, 0.20mol) under stirring, and keep warm for 10min after the dropwise addition. Slowly add LiHMDS (22 g, 0.20 mol) in batches, and keep the reaction for 2 h after the addition is complete.

[0042] At room temperature, add 1N aqueous sodium hydroxide solution (100ml) to the reaction system, stir overnight, add 500ml of water, extract with ethyl acetate (300ml*3), separate the organic layer, add 1N hydrochloric acid dropwise to the aqueous layer until pH= 4. Filter to obtain a white solid. The white solid was recrystallized in toluene to obtain 16 g of white solid, yield: 70%.

[0043] B) 2-Methyl-D-cysteine ​​hydro...

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Abstract

The invention discloses a preparation method of chirality 2-methyl cysteine and hydrochloride thereof. The preparation method comprises the following steps: chirality 2-tert-butyl-3-formoxyl thiaxolidine-4-carboxylic ester, a methylation reagent and organic base are subjected to methylation in organic solvent to obtain reaction solution, inorganic base is added in the reaction solution, chirality-invariable 2-tert-butyl-3-formoxyl thiaxolidine-4-methyl-4-carboxylic acid is obtained through one-pot reaction, then the chirality-invariable 2-tert-butyl-3-formoxyl thiaxolidine-4-methyl-4-carboxylic acid is subjected to reflux reaction in hydrochloric acid solution to obtain chirality 2-methyl cysteine hydrochloride, and finally, chirality 2-methyl cysteine is obtained through aftertreatment. Compared with the prior art, the preparation method disclosed by the invention is simple in operating process, the production cost is lower, the reaction yield and the optical purity of products are higher, and excellent industrial application value is realized.

Description

technical field [0001] The invention belongs to the field of medicine and biochemistry, and in particular relates to a preparation method of 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] The preparation of 2-methyl-D-cysteine ​​hydrochloride reported in the literature is based on (2S,4S)-2-tert-butyl-3-formyltetrahydrothiazole-4-carboxylic acid methyl ester as raw material, Carry out methylation reaction...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C323/58C07C319/28
Inventor 竺伟史学松赖亮
Owner SYNCOZYMES SHANGHAI
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