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Process for the synthesis of lacosamide

A technology for synthesizing lacosamide and compounds, which is applied in the field of preparation of 2--N-benzyl-3-methoxypropionamide, can solve the undeveloped resolution of lacosamide racemic mixture, R enantiomer Isomer purification is complex and other issues

Inactive Publication Date: 2012-12-12
EUTICALS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] The reason is that a method for resolving the racemic mixture of lacosamide has not been developed so far and the purification of the R enantiomer has been described as extremely complicated

Method used

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  • Process for the synthesis of lacosamide
  • Process for the synthesis of lacosamide
  • Process for the synthesis of lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1 (synthesis of V from III)

[0035] 100 g of compound III and 332 g of benzylamine were charged into a 1 liter reactor equipped with mechanical stirrer, reflux condenser, thermometer and placed under nitrogen atmosphere. The mixture was heated to 65° C. and kept stirring at this temperature for 12 hours. It was distilled under vacuum to remove excess benzylamine. It was cooled to about 55-60° C. and 50 ml of THF were added. It was then cooled to 20°C and the resulting solid was filtered off, which was then dried under vacuum at 40°C. 123.2 g of compound V are obtained.

[0036] 84% molar yield.

Embodiment 2

[0037] Embodiment 2 (synthetic VI from V)

[0038] 148 g of compound V, 7.4 g of tetrabutylammonium sulfate, 740 ml of THF, 350 g of methyl p-toluenesulfonate and 440 g of 20% sodium hydroxide were charged into a 3 Liter reactor and placed under nitrogen atmosphere. The mixture thus obtained was heated to 35°C and kept stirring at this temperature for 4 hours. It was then cooled to 20-25°C and 165 g of 28% ammonium hydroxide were added. It was cooled to 5°C and the pH was adjusted to 7 using hydrochloric acid.

[0039] It was distilled under vacuum to remove THF and diluted with 1 liter of water.

[0040] It was extracted 4 times with 500 ml of dichloromethane, then the organic phases were combined and distilled to a small volume. Dichloromethane was replaced with 600 ml of isopropyl acetate. The resulting suspension was filtered and the resulting solid was washed with isopropyl acetate and dried under vacuum at 40°C.

[0041]115 g of compound VI are obtained. 73% mol...

Embodiment 3

[0042] Embodiment 3 (synthesis of VIII from VI)

[0043] Legenda

[0044] Riflusso=reflux

[0045] 63.5 g of compound VI, 850 ml of water and 65 g of 37% HCl were charged into a 2 liter reactor with mechanical stirrer, reflux condenser, thermometer and inertized with nitrogen. The mixture was heated to reflux and kept stirring for 6 hours, then it was cooled to 20-25°C. The pH was corrected to 11.5 ± 0.5 using 30% sodium hydroxide. The resulting mixture was extracted twice with 300 ml of dichloromethane. The combined organic phases were concentrated to a small volume, 300 ml of ethyl acetate and 35 g of 2-(S)-chloromandelic acid were added. Half of the solvent was distilled off and allowed to stir at room temperature until precipitation was complete. The solid was filtered off and dried under vacuum at 40°C. 84.3 g of diastereomeric mixture VIII are obtained.

[0046] 84.1% molar yield.

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PUM

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Abstract

A novel process for the synthesis of Lacosamide using D,L-serine as starting material is described, where the methylation reaction of hydroxyl is carried out using an inexpensive base such as NaOH and an inexpensive alkylating agent, non-toxic and non-carcinogenic, such as methyl p-toluenesulfonate; the R enantiomer is isolated from the racemic mixture of Lacosamide after selective hydrolysis of the acetamide, salification of the racemic mixture with a chiral acid (HX*) in an organic solvent, resolution of the diastereoisomeric mixture, preferably by precipitation of the R enantiomer, and subsequent acetylation of the optically pure intermediate.

Description

technical field [0001] The present invention relates to a novel process for the preparation of (2R)-2-(acetylamino)-N-benzyl-3-methoxypropionamide, said (2R)-2-(acetylamino)-N-benzyl-3 - Methoxypropionamide is an active ingredient used in the treatment of neuropathy, known as lacosamide and represented by formula I below. [0002] [0003] The process according to the invention is carried out starting from D,L-serine methyl ester, ie a molecule having the following formula II, [0004] [0005] It is preferably used in the form of the hydrochloride. [0006] Alternatively, the process according to the invention can be carried out starting from the acetamide of D,L-serine methyl ester, which corresponds to the molecule of formula III as follows: [0007] Background technique [0008] Lacosamide is an active ingredient used in the treatment of pain and for the treatment of various neurological disorders including epilepsy. Although the mechanism of action is not fu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/12C07C231/20C07C237/06C07C237/22
CPCC07C231/20C07C231/12C07C237/06C07C237/22C07B2200/07C07C2601/08
Inventor A·博洛尼亚P·卡斯托蒂D·韦尔加尼G·贝托里尼
Owner EUTICALS
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