Preparation methods of two kinds of anserine and immediate of anserine

A technology of anserine and intermediates, applied in the field of medicinal chemistry, can solve the problems of unindustrialization of column chromatography, difficulty in removing protective groups, easy racemization of chiral centers, etc., and achieve convenient post-reaction treatment, easy control, and simple operation easy effect

Inactive Publication Date: 2019-05-14
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 one, and the chiral center is easy to racemize in the process of removing the protecting group; in the route two, trityl should be used as the protecting group and 1-(3-dimethylaminopropyl)- 3-Ethylcarbodiimide hydrochloride is a condensing agent, which is expensive and has poor atom economy, and the column chromatography used in the route cannot be industrialized

Method used

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  • Preparation methods of two kinds of anserine and immediate of anserine
  • Preparation methods of two kinds of anserine and immediate of anserine
  • Preparation methods of two kinds of anserine and immediate of anserine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046]

[0047] The preparation of step a, compound (IV)

[0048] N(τ)-methyl-L-histidine methyl ester (10 g, 55 mmol) and 3-(tert-butoxycarbonyl)-4,5-dihydro-1,3-oxazine-2,6-dione (14.2g, 66mmol) was dissolved in 100mL acetonitrile, and triethylamine (6.6g, 65mmol) was added in batches at 20-30°C; after the addition was complete, it was stirred at 20-30°C for 4 hours; TLC detected that the reaction was complete. Concentrate, liquidize with dichloromethane water, concentrate the organic phase and recrystallize with ethyl acetate / n-heptane. After filtering and drying, 14.6 g of white solid N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine methyl ester was obtained. Molar yield 75%.

[0049] Preparation of step b and step d, compound (II) and compound (I)

[0050] N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine methyl ester (10 g, 28 mmol) was dissolved in 50 mL of methanol and 20 mL of water. Add 1M sodium hydroxide (...

Embodiment 2

[0057]

[0058] The preparation of step a, compound (IV)

[0059] N(τ)-methyl-L-histidine benzyl ester (10 g, 39 mmol) and 3-(tert-butoxycarbonyl)-4,5-dihydro-1,3-oxazine-2,6-dione (9.2g, 43mmol) was dissolved in 100mL tetrahydrofuran, and sodium carbonate (5.0g, 47mmol) was added in batches at 20-30°C; after the addition was complete, it was stirred at 20-30°C for 6 hours; TLC detected that the reaction was complete. Concentrate, liquidize with dichloromethane water, concentrate the organic phase and recrystallize with ethyl acetate / n-heptane. After filtering and drying, 11.4 g of white solid N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine methyl ester was obtained. The molar yield is 68%.

[0060] Preparation of step b and step d, compound (II) and compound (I)

[0061] N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine benzyl ester (10 g, 23 mmol) was dissolved in 50 mL of methanol and 30 mL of water. Add 10% Pd-C ...

Embodiment 3

[0068]

[0069] The preparation of step a, compound (IV)

[0070] N(τ)-methyl-L-histidine isopropyl ester (55mmol) and 3-(tert-butoxycarbonyl)-4,5-dihydro-1,3-oxazine-2,6-dione ( 44mmol) was dissolved in 100mL toluene, and 0.8 potassium bicarbonate (44mmol) was added in batches at 20-30°C; after the addition was complete, it was stirred at 20-30°C for 8 hours; TLC detected that the reaction was complete. Concentrate, liquidize with dichloromethane, and recrystallize the organic phase with ethyl acetate / n-heptane after concentration. After filtration, dry to obtain white solid N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine isopropyl ester, molar yield 78% .

[0071] Preparation of step b and step d, compound (II) and compound (I)

[0072] N(α)-(3-((tert-butoxycarbonyl)amino)propylcarbonyl)-N(τ)-methyl-L-histidine isopropyl ester (28mmol) was dissolved in 50mL methanol and 20mL water, 20- Add 1M formic acid (28mL) at 30°C, stir at this tempera...

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Abstract

The invention provides preparation methods of two kinds of anserine and a preparation method of a synthetic anserine intermediate. The preparation methods are simple to operate, easy to implement, stable in process, easy to control, convenient for reaction post-treatment, good in product yield, high in purity and capable of being economically and conveniently used for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of two kinds of anserine. The invention also provides a preparation method of anserine intermediate. Background technique [0002] Anserine is a kind of important natural histidine dipeptide, which has remarkable functions of reducing uric acid, anti-oxidation and anti-aging, and is widely used in the food industry. Studies have shown that the muscle of deep-sea fish or livestock and poultry contains a certain amount of anserine, but its content is often low, and the extraction process is complex and often of low purity. In recent years, 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 anserin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D233/64
Inventor 张健廖琪林
Owner NANJING NUTRABUILDING BIO TECH CO LTD
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