Synthesis methods of deuterine, hippuric acid-L-menthol ester (2,2-D2) and intermediates thereof

A 2-D2, synthetic method technology, applied in the direction of organic chemical methods, chemical instruments and methods, carboxylic acid amide preparation, etc., can solve the problems of harsh reaction conditions, strict equipment requirements, unfavorable preparation, etc., and achieve easy access to raw materials, equipment Corrosion reduction, easy to scale up the effect of preparation

Pending Publication Date: 2018-08-03
CHANGSHA BEITA PHARMATECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] In summary, the current synthesis of glycine (2,2-D 2 ) method has higher cost, or strict requirements on equipment, or harsh reaction conditions, which are not conducive to large-scale preparation

Method used

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  • Synthesis methods of deuterine, hippuric acid-L-menthol ester (2,2-D2) and intermediates thereof
  • Synthesis methods of deuterine, hippuric acid-L-menthol ester (2,2-D2) and intermediates thereof
  • Synthesis methods of deuterine, hippuric acid-L-menthol ester (2,2-D2) and intermediates thereof

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0055] After successively adding 1.0 g of glycine and 100 mg of pyridoxal hydrochloride into the single-mouth bottle, the oil pump was replaced three times under the protection of argon, and then 10 mL of 10% (mass percentage) deuterium deuterium oxide aqueous solution was added under an argon atmosphere, and the reaction was refluxed for 2 hours. . After the reaction is finished, cool, (filter with a needle filter), spin out about 50% of deuterium water in a vacuum to recover, add 10 mL of distilled water after cooling, add 2.2 mL of benzoyl chloride, stir at room temperature overnight, then add crude ice, use Concentrated hydrochloric acid was used to adjust the pH value of the reaction solution to 2-3. After cooling, a large amount of solids were precipitated, filtered, and the filter cake was washed with ice water. Filter cake is recrystallized with hot water again, separates out white crystal, filters and dries, obtains 2.2g hippuric acid (2,2-D 2 ) pure product, yield 9...

Embodiment 2

[0058] After adding 1.0g of glycine, 100mg of pyridoxal hydrochloride, and 420mg of lithium metal in the three-neck flask, the oil pump was replaced three times under the protection of argon. After the reaction of lithium and deuterium water was complete, the temperature was raised to reflux for 2.5 hours. After the reaction is finished, cool, (filter with a needle filter), spin out about 50% of deuterium water in a vacuum to recover, add 10 mL of distilled water after cooling, add 2.2 mL of benzoyl chloride, stir at room temperature overnight, then add crude ice, use Concentrated hydrochloric acid was used to adjust the pH value of the reaction solution to 2-3. After cooling, a large amount of solids were precipitated, filtered, and the filter cake was washed with ice water. Filter cake is recrystallized with hot water again, separates out white crystal, filters and dries, obtains 2.0g hippuric acid (2,2-D 2 ) pure product, yield 82.9%, product purity>99% (HPLC), LC-MS and ...

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Abstract

The invention discloses synthesis methods of deuterine, hippuric acid-L-menthol ester (2,2-D2) and intermediates thereof, wherein the synthesis method includes the steps: (1) carrying out a reaction of glycine with a deuterium aqueous solution of alkali metal deuterium oxide under the action of pyridoxal or salts thereof, to obtain a deuterated reaction solution; and (2) recycling a part of deuterium water from the deuterated reaction solution obtained in the step (1) through reduced pressure distillation, then adding water and benzoyl chloride, carrying out an amidation reaction, and after the end of the reaction, posttreating to obtain hippuric acid (2,2-D2). The raw materials and reagents used in the synthesis method are cheap and easy to obtain, and the operation is simple; the purityand the deuterium abundance of the obtained deuterated reagents are high.

Description

technical field [0001] The invention belongs to the field of preparation of deuterated reagents, in particular to a synthetic glycine (2,2-D 2 ) and glycine (2,2-D 2 ) method for synthesizing a kind of α-deuterated amino acid module (hippuric acid-L-menthyl ester), especially relates to a kind of method directly using cheap glycine, deuterium water or sodium deuterium oxide etc. as raw materials to synthesize glycine (2,2-D 2 ) method, and glycine (2,2-D 2 ) is a method for further synthesizing an α-deuterated amino acid module (hippuric acid-L-menthyl ester) as a raw material. Background technique [0002] Glycine (2,2-D 2 ) is an important stable isotope-labeled amino acid, which has a wide range of applications in biomedicine, peptide research, protein metabolism and other biological and chemical aspects. Glycine (2,2-D 2 ) can be used to synthesize a variety of stable isotope-labeled polypeptide compounds, and it is also the synthetic precursor of amino acids used i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C233/83C07C227/20C07C229/08C07C231/14C07B59/00C07C227/16
CPCC07B59/001C07B2200/05C07C227/16C07C227/20C07C231/02C07C231/14C07C2601/14C07C233/83C07C229/08
Inventor 蔡定龙张雄伍君李刚
Owner CHANGSHA BEITA PHARMATECH CO LTD
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