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Preparation method of N (tau)-methyl-L-histidine derivative and application of derivative in synthesis of anserine

A technology of histidine and derivatives, applied in the field of preparation of N-methyl-L-histidine derivatives, can solve the problems of difficulty in removing protective groups, high price, poor atom economy and the like

Inactive Publication Date: 2018-11-02
NANJING NUTRABUILDING BIO TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] It is difficult to remove the protecting group in the above-mentioned route 1, and the chiral center is easy to racemize in the process of removing the protecting group; in the route 2, trityl should be used as the protecting group, which is expensive and has poor atom economy, and the column used in the route Chromatography cannot be industrialized

Method used

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  • Preparation method of N (tau)-methyl-L-histidine derivative and application of derivative in synthesis of anserine
  • Preparation method of N (tau)-methyl-L-histidine derivative and application of derivative in synthesis of anserine
  • Preparation method of N (tau)-methyl-L-histidine derivative and application of derivative in synthesis of anserine

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Step a, preparation of tert-butyl (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxypropyl)-1H-imidazolyl-1-carbonate

[0041]

[0042] L-Histidine methyl ester dihydrochloride (10g, 41mmol) was dissolved in 100mL of dichloromethane, and sodium bicarbonate (15.5g, 184.5mmol) was added in batches at 20-30°C. After the addition, 20-30 Stir at °C for 1 hour; cool to 0-10 °C, add di-tert-butyl dicarbonate (26.8 g, 123 mmol) in batches, slowly rise to 20-30 °C, stir for 24 hours, TLC detects that the reaction is complete, filter, and wash with water Slurry with methanol, filter and dry to obtain 12.1 g of white solid with a molar yield of 80%.

[0043] Preparation of step b and step c, N(τ)-methyl-L-histidine methyl ester dihydrochloride

[0044]

[0045] tert-butyl (S)-4-(2-((tert-butoxycarbonyl)amino)-3-methoxy-3-oxypropyl)-1H-imidazolyl-1-carbonate (10g, 27mmol) Dissolve in 100mL acetonitrile, add iodomethane (5.75g, 40.5 mmol) at 20-30°C, raise the temperature...

Embodiment 2

[0054] The preparation of step a, compound (III)

[0055]Dissolve L-histidine methyl ester dihydrochloride (41mmol) in 100mL acetonitrile, add potassium carbonate (41mmol) in batches at 20-30°C, after the addition, stir at 70-80°C for 1 hour; cool to 0-10 °C, benzyl chloroformate (73.8 mmol) was added in portions. Slowly rise to 70-80°C, and after stirring for 12 hours, the reaction is complete as detected by TLC. Filter, wash with water and beat with methanol. After filtering and drying, 12.2 g of white solid was obtained, and the molar yield was 80.7%.

[0056] Preparation of step b and step c, compound (I)

[0057] Methyl (S)-4-(2-((ethyloxycarbonyl)amino)-3-methoxy-3-oxypropyl)-1H-imidazolyl-1-carbonate (27mmol) was dissolved in 100mL In tetrahydrofuran, add dimethyl sulfate (27mmol) and sodium bicarbonate (27mmol) at 20-30°C, raise the temperature to 80-90°C and reflux, stir for 12h, TLC shows that the reaction is basically complete, and the crude product obtained aft...

Embodiment 3

[0064] The preparation of step a, compound (III)

[0065] L-Histidine methyl ester dihydrochloride (41mmol) was dissolved in 100mL of isopropyl acetate, and triethylamine (82mmol) was added in batches at 20-30°C, and stirred at 80-90°C for 1 hour after the addition; After cooling to 0-10°C, fluorenylmethyl chloroformate (102.5 mmol) was added in portions. Slowly rise to 80-90°C, and after stirring for 1 hour, the reaction is complete as detected by TLC. Filter, wash with water and beat with methanol. After filtering and drying, 12.3 g of white solid was obtained, and the molar yield was 81%.

[0066] Preparation of step b and step c, compound (I)

[0067] Isopropyl (S)-4-(2-((isopropyloxycarbonyl)amino)-3-methoxy-3-oxypropyl)-1H-imidazolyl-1-carbonate (27mmol) In 100 mL of ethyl acetate, dimethyl carbonate (54 mmol) and potassium carbonate (54 mmol) were added at 20-30 ° C, the temperature was raised to 80-90 ° C, stirred for 1 h, and the reaction was basically complete as...

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Abstract

The invention provides a preparation method of an N (tau)-methyl-L-histidine derivative and a method for preparing anserine through the synthesized N (tau)-methyl-L-histidine derivative. According tothe method, raw materials are cheap and easy to obtain, the selectivity is good, and the yield is high; the operation is simple and practicable, the process is stable, the control is easy, the treatment after reaction is convenient, the product yield is good, the purity is high, and the preparation method can be economically and conveniently used for industrialized production.

Description

technical field [0001] The invention relates to a preparation method of N(τ)-methyl-L-histidine derivatives. The invention also provides a method for preparing anserine from N(τ)-methyl-L-histidine derivatives. Background technique [0002] Anserine is a kind of histidine dipeptide that naturally exists in vertebrates. It has significant functions such as reducing uric acid, anti-oxidation, and anti-aging, and is widely used in the food industry. Anserine from natural sources is mainly extracted from deep-sea fish or the muscles of livestock and poultry, and its sources are limited and often of low purity. With the deepening of research, the demand for anserine in the fields of food and medicine is increasing, so it is particularly urgent to develop an industrialized preparation method for anserine to replace the traditional extraction process. [0003] [0004] There have been research reports on the preparation method of anserine, and Hamari Pharmaceutical Co., Ltd. r...

Claims

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Application Information

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IPC IPC(8): C07D233/64C07K5/02
CPCC07B2200/07C07D233/64C07K5/0202
Inventor 张健廖琪林
Owner NANJING NUTRABUILDING BIO TECH CO LTD