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Process for the preparation of lacosamide

A technology of lacosamide and benzyl amide, applied in the field of preparing lacosamide, can solve the problems of high cost and the like

Inactive Publication Date: 2017-03-29
DIVI S LAB LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

(DL)-serine-based methods involve several steps and are expensive even if the unwanted isomer is recovered

Method used

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  • Process for the preparation of lacosamide
  • Process for the preparation of lacosamide
  • Process for the preparation of lacosamide

Examples

Experimental program
Comparison scheme
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preparation example Construction

[0036] The present invention provides a novel method for preparing lacosamide of formula (I),

[0037] Include the following steps:

[0038] (a) make the N-acetyl-D-serine methyl ester of formula (II)

[0039]

[0040] With the benzylamine of formula (III)

[0041]

[0042] Reaction in the presence of a non-nucleophilic base to produce (R)-2-acetamido-N-benzyl-3-hydroxyl propionamide of formula (IV); and

[0043]

[0044] (b) Methylation of benzylamides of formula (IV) to obtain lacosamides of formula (I).

[0045] The required starting material, namely the N-acetyl-D-serine methyl ester of formula (II), can be found in the literature (J. Medicinal Chemistry, 2010, 53, 1288-1305, Supporting Information, S-101) Prepared by the method described.

[0046] Choi et al. (J. Medicinal Chemistry, 1996, 39, 1907-1916) have described a significant racemization during the preparation of D-serine benzamide (Scheme-8).

[0047]

[0048] Reaction of D-serine with methanol c...

example

[0059] Chemical purity is determined under the following conditions using high performance liquid chromatography (High Performance Liquid Chromatography, HPLC):

[0060] Column: BDS Hypersil C18, 250×4.6mm, 5μm

[0061] Mobile phase: water: acetonitrile (80:20); flow rate: 1.0ml / min

[0062] Column temperature: 30°C

[0063] Detection: 210nm

[0064] Enantiomeric purity was determined using HPLC under the following conditions:

[0065] Column: Chiralcel AD-H, 150×4.6mm, 5μ[5μm]

[0066] Mobile phase: n-hexane: ethanol: TFA (60:40:0.1), flow rate: 0.5ml / min

[0067] Column temperature: 27°C

[0068] Detection: 210nm

example -1

[0069] Example-1: Preparation of D-serine methyl ester hydrochloride:

[0070] D-serine (100 g, 0.9515 mol) was suspended in 600 ml methanol at room temperature. Acetyl chloride (224.0 g, 2.8545 mol) was added dropwise at -5°C to 0°C and stirred for 30 minutes. The reaction mixture was refluxed for 15 hours. The reaction mixture was evaporated under reduced pressure, and the resulting residue was subsequently crystallized from methanol and methyl tert-butyl ether to give D-serine methyl ester hydrochloride as a colorless solid (134.7 g, yield: 91%, HPLC: 99.6%)

[0071] M.R: 165°C-167°C (Document: 163°C-165°C, Tetrahedron Letters, 2012, 53, 1668-1670,) [α] D 20 =-3.7 (C=4 in EtOH); IR (KBr): 3361, 2921, 2660, 2732, 2550, 2488, 2134, 2079, 1922, 1747, 1592, 1505, 1471, 1444, 1431, 1382, 1343 , 1297, 1258, 1187, 1158, 1128, 1094, 1038, 969, 900, 793, 844, 580, 469Cm -1 ;H 1 NMR: (300MHz, DMSO), δ3.745(s, 3H), 3.82(s, 2H), 4.11(s, 1H), 5.63(s, 1H), 8.58(s, 2H); 13 CNMR: (...

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Abstract

A novel process for the preparation of (R)-2-acetamido-N-benzyl-3-methoxypropionamide (Lacosamide) is described. It comprises reacting N-acetyl-D-serine methyl ester with benzylamine catalyzed by a non-nucleophilic base to obtain (R)-2-acetamido-2-N-benzyl-3-hydroxy propionamide followed by its methylation.

Description

technical field [0001] The invention relates to a method for preparing Lacosamide. Background technique [0002] Lacosamide is a chiral molecule useful for the treatment of convulsions and pain. It was approved by the United States Food and Drug Administration (USFDA) in 2008 and is sold by UCB under the trade name Sale. It is chemically (R)-2-acetamido-N-benzyl-3-methoxypropionamide (formula (I)) having the following structure: [0003] [0004] US Patent 5,773,475 describes three procedures for the preparation of lacosamide. Scheme-1 involves conversion of D-serine to its methyl ester hydrochloride followed by amidation with benzylamine. Acetylation of the benzylamide followed by Williamson etherification yields lacosamide. [0005] [0006] In this scheme, the benzamide intermediate is obtained with poor chiral purity due to racemization. Additionally, the methylation stage involves the use of the dangerous low-boiling reagent methyl iodide and expensive silv...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C231/02C07C231/14C07C237/22
CPCC07C231/02C07C231/14C07C237/22C07C231/12
Inventor 沙产德拉·希兰·迪比迈索尔·阿沙塔·那罗亚那·拉奥帅可·那树顶
Owner DIVI S LAB LTD
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