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A kind of preparation method of n-phenylacetyl-1-proline

A technology of phenylacetyl and proline, applied in directions such as organic chemistry, can solve the problems of low yield, difficult purification, low product purity, etc., and achieves the effects of high purity, simple product separation, and easy-to-obtain raw materials

Active Publication Date: 2021-10-15
ZHONGBEI UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] In order to solve the problems of low product purity, difficult purification and low yield in the prior art, the present invention discloses a preparation method of N-phenylacetyl-L-proline. Under the action of a catalyst in an anhydrous organic solvent, L - Proline reacts directly with phenylacetyl chloride, avoiding the hydrolysis of phenylacetyl chloride, the reaction is more efficient and thorough, the product yield is high, the synthesis process is simple, the operation is simple, easy to purify, and the product purity is high

Method used

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  • A kind of preparation method of n-phenylacetyl-1-proline
  • A kind of preparation method of n-phenylacetyl-1-proline
  • A kind of preparation method of n-phenylacetyl-1-proline

Examples

Experimental program
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Effect test

Embodiment 1

[0028] Weigh 3 g (0.026 mol) L-proline, 12.058 g (0.078 mol) phenylacetyl chloride, 7.18 g (0.052 mol) K 2 CO 3 For standby, add 40mL of dried acetone and L-proline into a 100mL three-necked flask equipped with a drying tube, a thermometer, a mechanical stirrer, and a condenser tube, and slowly drip it into the three-necked flask with a needle tube under stirring in an ice-water bath at -2-0°C Add phenylacetyl chloride, during which K is added in batches 2 CO 3 Acid-binding agent, continue to add 5 mol % PEG-400 at low temperature 0°C, keep stirring and react for 1h, heat and stir in the oil change pot at 20°C for 6h, filter the reaction solution while it is hot, wash the filtrate with water, dry the organic phase, and distill under reduced pressure to obtain a white solid , the white solid was recrystallized to obtain the product N-phenylacetyl-L-proline, with a melting point of 150.5-151.4°C and a yield of 97.8%.

[0029] The white solid obtained in Example 1 was detected...

Embodiment 2

[0033] Weigh 4.49 g (0.039 mol) L-proline, 4.02 g (0.026 mol) phenylacetyl chloride, 15.12 g (0.117 mol) N,N-diisopropylethylamine (DIEA) respectively, and dry 40 mL Add benzene and L-proline into a 100mL three-necked flask equipped with a drying tube, a thermometer, a mechanical stirrer, and a condenser, and slowly add phenylacetyl chloride dropwise into the three-necked flask with a needle while stirring in an ice-water bath at 0-5°C, and simultaneously separate Add DIEA acid-binding agent in batches, continue to add 0.5 mol % tetrabutylammonium bromide (TBAB) at a low temperature of 0°C, keep stirring and react for 7 hours, heat up the oil change pot at 80°C and reflux for 2 hours, filter the reaction solution while it is hot, wash the filtrate with water, and organically The phase was dried and distilled under reduced pressure to obtain a white solid, which was recrystallized to obtain the product N-phenylacetyl-L-proline with a melting point of 150.4-151.6°C and a yield of...

Embodiment 3

[0035] Weigh 3 g (0.026 mol) L-proline, 8.04 g (0.052 mol) phenylacetyl chloride, and 10.28 g (0.13 mol) pyridine for later use, add 40 mL of dried chloroform and L-proline to a dry In a 100mL three-necked flask with tube, thermometer, mechanical stirring, and condenser tube, slowly add phenylacetyl chloride dropwise into the three-necked flask with a needle tube under stirring in an ice-water bath at -5-3°C, and at the same time add pyridine acid-binding agent in batches, and continue at a low temperature of 0°C Add 2.5 mol % cyclodextrin under low pressure, keep stirring and react for 5 hours, heat up the oil change pot at 60°C and reflux for 4 hours, filter the reaction solution while it is hot, wash the filtrate with water, dry the organic phase, distill under reduced pressure to obtain a white solid, and recrystallize the obtained white solid to obtain Product N-Phenylacetyl-L-Proline. The melting point is 150.4-151.7°C, and the yield is 98.4%.

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Abstract

The invention discloses a preparation method of N-phenylacetyl-L-proline. At low temperature, phenylacetyl chloride and an acid-binding agent are added dropwise into an organic solvent in which L-proline is dissolved, and then phase transfer Catalyst, stirred and reacted for 1-9h, then heated to 20-80°C and continued to stir for 2-8h, obtained reaction solution was filtered while hot, the filtrate was washed with water, the organic phase was dried and evaporated to remove the solvent, recrystallized to obtain a white solid, and the obtained white solid was Pure N-Phenylacetyl-L-Proline. The invention carries out the reaction in anhydrous organic solvent, avoiding the hydrolysis of phenylacetyl chloride. The synthesis process is simple, the operation is simple, and the product purity is high; the use of the phase transfer catalyst accelerates the solid-liquid phase reaction rate, makes the reaction more efficient and thorough, and improves the reaction yield.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and relates to a preparation method of a drug intermediate, in particular to a preparation method of N-phenylacetyl-L-proline. Background technique [0002] N-phenylacetyl-L-proline is an amide compound, which is widely used in the fields of medicinal chemistry, polymer chemistry and biochemistry, and is one of the important compounds in organic synthesis. Studies have shown that the vast majority of drugs belong to amides, so the preparation of amides has a good prospect in drug synthesis, and N-phenylacetyl-L-proline is a synthetic nutritional enhancer N-[1- An important intermediate of (phenylacetyl)-L-prolyl]glycine ethyl ester. [0003] In 1996, Gudasheva et al. first mentioned in their article that L-proline was changed into L-proline sodium salt by using sodium hydroxide aqueous solution, and then prepared by reacting with sodium hydroxide as an acid-binding agent in water and i...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D207/16
CPCC07D207/16
Inventor 崔建兰李艳如钟丛杉于思源王宁王晓
Owner ZHONGBEI UNIV