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Improved preparation method for lacosamide intermediate

A technology of benzylamine and reaction time, applied in the field of preparation of 2-(1-butyric acid-4-yl)-amino-substituted butanamide, can solve the problem of reduced yield, product racemization, and lack of effective removal methods and other problems, to achieve the effect of easy temperature and mild reaction conditions

Inactive Publication Date: 2021-03-19
BEIJING VENTUREPHARM BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

While this preparation is a promising starting point for high standards, it has the major disadvantage of costly O-methylation of N-protected D-serine using silver oxide and methyl iodide , the most important thing is that it will cause racemization of some products (about 15%), which will reduce the yield
Furthermore, there is a lack of effective removal methods for the S-enantiomer produced during the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide

Method used

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  • Improved preparation method for lacosamide intermediate

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Experimental program
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Effect test

Embodiment 1

[0026] Weigh 50.0 g of N-(tert-butoxycarbonyl)-O-methylserine and 500 ml of dichloromethane into a three-neck flask, cool down in an ice-water bath, and stir. 27.2 g of ethyl chloroformate and 25 ml of 2,6-di-tert-butylpyridine were added dropwise in sequence. After diluting 25.0 g of benzylamine with 50 ml of dichloromethane, it was slowly added dropwise to the system in an ice-water bath. React at 0-10°C for 1 hour and 40 minutes. Stop the reaction, add 500 ml of water solution, and collect the organic phase. Add 125 ml of 3N hydrochloric acid to the organic phase, separate the layers, and collect the organic phase. Add 200 ml of saturated sodium bicarbonate solution to the organic phase, separate the layers, and collect the organic phase. Add 500 ml of water to wash the organic phase, and separate the layers. After the organic phase was collected, the solvent was spinned off, 350 ml of petroleum ether was added, and the temperature was crystallized in an ice-water bath....

Embodiment 2

[0028] Weigh 100.0 g of N-(tert-butoxycarbonyl)-O-methylserine and 1000 ml of dichloromethane into a three-neck flask, cool down in an ice-water bath, and stir. 54.4 g of ethyl chloroformate and 50 ml of 2,6-di-tert-butylpyridine were added dropwise in sequence. After diluting 50.0 g of benzylamine with 100 ml of dichloromethane, it was slowly added dropwise to the system in an ice-water bath. React at 0-10°C for 2 hours and 10 minutes. Stop the reaction, add 1000 ml water solution, and collect the organic phase. Add 250 ml of 3N hydrochloric acid to the organic phase, separate the layers, and collect the organic phase. Add 400 ml of saturated sodium bicarbonate solution to the organic phase, separate the layers, and collect the organic phase. Add 1000 ml of water to wash the organic phase, and separate the layers. After the organic phase was collected, the solvent was spun off, 700 ml of petroleum ether was added, and the temperature was cooled in an ice-water bath for cr...

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Abstract

The invention discloses an improved preparation method for a lacosamide intermediate, belonging to the field of medicinal chemistry. The invention mainly relates to a preparation method of 2-(1-butyric acid-4-yl)-amino-substituted butyramide. The preparation method is simple to operate and easy for industrial production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and mainly relates to a preparation method of 2-(1-butyric acid-4-yl)-amino-substituted butanamide represented by formula I. Background technique [0002] (R)-2-Acetamido-N-benzyl-3-methoxypropionamide (lactamide) is an anticonvulsant drug that can be used in the treatment of epilepsy and pain. Two methods of preparing this compound are disclosed in US 6,048,899. [0003] Method 2 of US 6,048,899 involves benzamide formation followed by O-methylation. However, this method produces various impurities, which are difficult to achieve industrially, although they can be removed by chromatography. And the single-step yield is only 80-85% [0004] Method 1 of US 6,048,899 involves O-methylation of N-protected D-serine followed by benzamide formation, N-deprotection and N-acetylation. While this preparation is a promising starting point for high standards, it has the major disadvantage of costly O-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C271/22C07C269/06C07C231/12C07C237/22
CPCC07B2200/07C07C231/12C07C269/06C07C271/22C07C237/22
Inventor 白思宸李恩民赵国磊
Owner BEIJING VENTUREPHARM BIOTECH
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