Preparation method of D-cycloserine

A technology of cycloserine and serine, applied in the directions of organic chemistry, antibacterial drugs, etc., can solve the problems of cumbersome post-processing operation, unstable product quality, low reaction yield, etc., and achieves improved total reaction yield, stable product quality, The effect of easy availability of raw materials

Active Publication Date: 2015-12-30
CHANGZHOU VOCATIONAL INST OF ENG
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] The technical problem to be solved by the present invention is: based on the above problems, the present invention provides a preparation method of D-cycloserine to overcome the disadvantages of cumbersome post-processing operations, unstable product quality, and low reaction yield in the prior art.

Method used

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  • Preparation method of D-cycloserine
  • Preparation method of D-cycloserine

Examples

Experimental program
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Embodiment 1

[0029] (1) Preparation of N-trifluoroacetyl-D-serine

[0030] Add 21.0g of D-serine to a mixed solvent of 140ml of methanol and 40ml of triethylamine, add 18g of ethyl trifluoroacetate under nitrogen protection, react at 20-25°C for 14 hours, cool to 5°C, and filter to obtain 39.0g of crude compound II. Yield 97.1%.

[0031] (2) Preparation of (1-trifluoroacetylamino-2-hydroxyl) ethyl hydroxamic acid

[0032] Mix 61.7g of PPAA and 57.6g of triethylamine evenly and add to 39.0g of compound II obtained in the above step (1), then add 80ml of ethyl acetate and 400ml of acetonitrile, stir at room temperature for 0.5h, add 26.4g of hydroxylamine hydrochloride, and stir at room temperature After reacting for 10 h, it was washed with 600 ml of saturated brine, the organic phase was dried over anhydrous sodium sulfate, and the solvent was recovered by distillation, and the concentrated solution was cooled at room temperature for use.

[0033] (3) Preparation of D-4-trifluoroacetylam...

Embodiment 2

[0038]Step (2) Preparation of (1-trifluoroacetamido-2-hydroxyl) ethyl hydroxamic acid: 57.4gPPAA and 38.5g triethylamine are mixed uniformly, then added to compound II obtained in the above step (1), and then added 80ml Ethyl acetate and 400ml of acetonitrile, stirred at room temperature for 0.5h, then added 26.4g of hydroxylamine hydrochloride, stirred at room temperature for 10h, washed with 600ml of saturated saline, the organic phase was dried with anhydrous sodium sulfate, and the solvent was recovered by distillation, and the concentrated solution was cooled at room temperature until use. Other steps adopt the same operation process as in Example 1 to obtain 10.1 g of D-cycloserine with a total yield of 52.1% and a content of more than 98%.

Embodiment 3

[0040] Step (3) Preparation of D-4-trifluoroacetamido-3-oxazolidinone: Mix 57.6g of anhydrous triethylamine, 7.0g of DMAP and 400ml of anhydrous toluene and add to step (2) to prepare In the concentrated solution of Methanesulfonyl chloride, slowly add the anhydrous toluene solution of methanesulfonyl chloride (17.4g methanesulfonyl chloride is dissolved in 120ml of anhydrous toluene) to the reaction system, react at room temperature for 4 hours after the drop, and recover the solvent toluene by distillation under reduced pressure to obtain Concentrate containing compound IV. Other steps adopt the same operating process as in Example 1 to obtain 7.8 g of D-cycloserine with a total yield of 40.3% and a content of over 98%.

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Abstract

The invention relates to a preparation method of D-cycloserine. The preparation method comprises steps of preparation of N-trifluoroacetyl-D-serine, preparation of (1-trifluoroacetylamino-2-hydroxyl) ethyl hydroxamate, preparation of D-4-trifluoroacetylamino-3-oxazolidinone and hydrolysis of D-4-trifluoroacetylamino-3-oxazolidinone. The preparation method has the benefits as follows: raw materials are easy to obtain, the reaction condition is mild, and the technological operation is simple; the racemization degree of D-cycloserine prepared with a synthetic route is reduced, the optical purity is improved, the product quality is stable, the follow-up three steps are performed with a 'one-pot' method, accordingly, emission of the three wastes and product loss are reduced, and the total yield of a reaction is improved.

Description

technical field [0001] The invention relates to a preparation method of D-cycloserine. Background technique [0002] D-cycloserine, also known as D-4-amino-3-oxazolidinone, is an antibiotic drug that has a good inhibitory effect on Mycobacterium tuberculosis. Because bacteria are not easy to develop drug resistance to it, it is mainly used clinically to treat the infection of drug-resistant Mycobacterium tuberculosis. In addition, studies have found that D-cycloserine is a special regulator of excitatory amino acid NMDA (N-methyl-D-aspartate) receptors in the central nervous system, and it is effective in the treatment of psychological phobias, depression, schizophrenia, etc. Disease also has a good auxiliary effect, and it is also an important intermediate in the synthesis of atypical β-lactam antibiotic Lactivicin. Therefore, D-cycloserine has broad application prospects and huge market demands. Its structural formula is: [0003] [0004] In the prior art, the rese...

Claims

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Application Information

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IPC IPC(8): C07D261/04A61P31/04
CPCC07D261/04
Inventor 陈绘如秦海芳张文雯李岩松
Owner CHANGZHOU VOCATIONAL INST OF ENG
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