New synthetic method of high-optical activity prolinamide

A technology of prolinamide and optical activity, which is applied in the synthesis of organic compounds and the synthesis of high optical chiral prolinamide, which can solve the problems of less side reactions, high yield, racemization, etc., and achieve low cost and easy industrialization Operation, high yield effect

Inactive Publication Date: 2013-10-23
LIANYUNGANG DUXIANG CHEM +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the yield is higher and the side reaction is less
The main problem is that when the first step is carried out under alkaline conditions, there will be some racemization, which will affect the quality of the final product

Method used

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  • New synthetic method of high-optical activity prolinamide
  • New synthetic method of high-optical activity prolinamide
  • New synthetic method of high-optical activity prolinamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0024] Synthesis of N-Benzyloxycarbonyl-D-Proline Methyl Ester

[0025] Put 330 g of D-proline methyl ester into 2.4 L of water, cool in an ice-water bath, and simultaneously add 500 g of benzyl chloroformate and 10% aqueous sodium hydroxide solution dropwise, and control the temperature in the reaction system at 5 to 15 degrees. The pH value is 8±0.5. Continue to react for 3 hours after dropping. until the reaction is complete. The organic phase was extracted twice with 500 mL of dichloromethane. Combine the organic phases. Dry over anhydrous sodium sulfate. The solvent was removed to obtain a light yellow oily liquid.

[0026] Synthesis of N-Benzyloxycarbonyl-D-prolineamide

[0027] Dissolve the N-benzyloxycarbonyl-D-proline methyl ester obtained in the previous step in 2000 mL of methanol, and cool to 0°C with an ice-water bath. Ammonia gas is introduced and a pressure of 1.5-2 kg is maintained. React for 5 hours, heat up to 50 degrees, and react for 2 hours. After...

Embodiment 2

[0031] Synthesis of N-Benzyloxycarbonyl-D-Proline Methyl Ester

[0032] Put 330 g of D-proline methyl ester into 2.4 L of water, cool in an ice-water bath, and simultaneously add 654 g of benzyl chloroformate and 10% aqueous sodium hydroxide solution dropwise, and control the temperature in the reaction system at 30-45 degrees. The pH value is 9±0.5. Continue to react for 3 hours after dropping. until the reaction is complete. The organic phase was extracted twice with 500 mL of dichloromethane. Combine the organic phases. Dry over anhydrous sodium sulfate. The solvent was removed to obtain a yellow oily liquid.

[0033] Synthesis of N-Benzyloxycarbonyl-D-prolineamide

[0034] Dissolve the N-benzyloxycarbonyl-D-proline methyl ester obtained in the previous step in 2000 mL of ethanol, and cool to 0°C with an ice-water bath. Ammonia gas is introduced and a pressure of 3-4 kg is maintained. React for 5 hours, heat up to 65 degrees, and react for 2 hours. After the reacti...

Embodiment 3

[0038] Synthesis of N-Benzyloxycarbonyl-D-Proline Methyl Ester

[0039] Put 330 g of D-proline methyl ester into 2.4 L of water, and cool in an ice-water bath. At the same time, 741 g of benzyl chloroformate and 10% aqueous sodium hydroxide solution were added dropwise, and the temperature in the reaction system was controlled at -10-0 degrees. The pH value is 10±0.5. Continue to react for 3 hours after dropping. until the reaction is complete. The organic phase was extracted twice with 500 mL of dichloromethane. Combine the organic phases. Dry over anhydrous sodium sulfate. The solvent was removed to obtain a light yellow oily liquid.

[0040] Synthesis of N-Benzyloxycarbonyl-D-prolineamide

[0041] Dissolve the N-benzyloxycarbonyl-D-proline methyl ester obtained in the previous step in 2000 mL of isopropanol, and cool to 0°C with an ice-water bath. Introduce ammonia gas, and keep 4-5 kilograms of pressure. React for 2 hours, heat up to 80 degrees, and react for 2 hou...

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Abstract

The invention relates to a synthetic method of high-optical chirality prolinamide, wherein the synthetic method has industrial prospect; no racemization is caused in the synthetic process, and only three steps of operations and reactions are carried out in the whole synthetic process; the first step, N-benzyloxycarbonyl proline methyl ester is generated from proline methyl ester and benzyl chloroformate under an alkaline condition; the second step, the N-benzyloxycarbonyl proline methyl ester is exchanged with ammonia in a protonic solvent to generate N-benzyloxycarbonyl prolinamide; the third step, the N-benzyloxycarbonyl prolinamide is oxidized, hydrogenated and deprotected in the protonic solvent, and then chiral prolinamide is obtained. Compared with the prior art, the preparation method provided by the invention has the advantages of low cost, high yield, easiness for realization of industrial operations and the like.

Description

technical field [0001] The invention relates to a method for synthesizing organic compounds, in particular to a method for synthesizing highly optical chiral prolinamide with industrial prospects, and belongs to the field of organic chemistry. Background technique [0002] Chiral prolinamide is an important optically active pyrrole derivative. As the end group moiety of polypeptide compounds, it has a wide range of applications. At the same time, it is also used as a chiral intermediate to synthesize some chiral drugs. For example: L-prolineamide is an important raw material for the synthesis of Vildagliptin; D-prolineamide is an important raw material for the synthesis of Remoxipride . Another wide application is that prolinamide is often used as a resolution agent for chiral compounds and an inducer for chiral synthesis in drug synthesis. [0003] At present, the methods for obtaining chiral prolineamide mainly contain the following: [0004] 1. Utilize thionyl chlorid...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D207/16
Inventor 金浩王玉祥王川民李民权
Owner LIANYUNGANG DUXIANG CHEM
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