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A preparing process of lacosamide

A technology for lacosamide and compounds, which is applied in the field of preparation of lacosamide, can solve the problems of many by-products, troublesome post-processing, unfavorable industrial production, etc., and achieve the effect of high yield and easy operation

Active Publication Date: 2014-09-10
福安药业集团重庆博圣制药有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although this type of method has a simple route, post-processing is cumbersome, and there are many by-products, which need to be purified by column chromatography. The total yield is between 7% and 30%, which is not conducive to industrial production.

Method used

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  • A preparing process of lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0095] Embodiment 1: Preparation of N-Boc-D-serine (compound of formula I)

[0096] Dissolve sodium hydroxide (8.4g, 0.210mol) in water (53ml) at room temperature, cool to 5-10°C, and add D-serine (10.5g, 0.100mol) and di-tert-butyl dicarbonate at ≤10°C Ester (26.2 g, 0.120 mol) was heated to 30-35 ° C for 20 hours to obtain an aqueous solution of the compound of formula I (the yield was 100%, HPLC purity 99.1%, chiral purity 99.4%). The compound of formula I does not need to be separated, and the reaction solution is directly used for the next step of synthesis.

[0097] HPLC purity testing conditions and methods:

[0098] HPLC detection conditions: Instrument: Shimadzu LC-20A high performance liquid chromatograph; Chromatographic column: C18 column, 250×4.6mm, 5μm; Mobile phase: 0.1mol / L diammonium hydrogen phosphate (phosphoric acid to adjust the pH value to 6.2) - methanol (65:35); detection wavelength: 210nm; flow rate: 1ml / min;

[0099] Determination method: Take an a...

Embodiment 2

[0103] Embodiment 2: Preparation of N-Boc-O-methyl-D-serine (compound of formula II)

[0104] The aqueous solution of the compound of formula I (20.5 g, 0.100 mol) prepared above was cooled to 0-10°C. While maintaining 0-10°C, dimethyl sulfate (50.5g, 0.400mol) and 50% sodium hydroxide (36.0g, 0.450mol) were added dropwise, and the reaction mixture was reacted at 0-10°C for 6 hours. After the reaction is completed, the reaction solution is kept at 0-10°C, acidified with 50% citric acid to pH=2-3, then extracted with dichloromethane (1×123ml, 2×82ml), dried with anhydrous sodium sulfate, and then distilled under reduced pressure To dryness, 21.9 g of the compound of formula II was obtained (yield 100%, HPLC purity 92.9%, chiral purity 98.0%).

[0105] HPLC purity testing conditions and methods:

[0106] Detection conditions: HPLC method; instrument: Shimadzu LC-20AT high performance liquid chromatography; column: CHIRALPAK AD-H (4.6mm×250mm, 5μm); column temperature: 30°C; de...

Embodiment 3

[0112] Example 3: Preparation of N-Boc-O-methyl-D-serine pivalic anhydride (compound of formula III)

[0113] The compound of formula II (21.9g, 0.100mol) obtained above was dissolved in dichloromethane (110ml), cooled to 0°C, and pivaloyl chloride (12.6g, 0.100mol) was added at 0-5°C. Add N-methylmorpholine (11.1g, 0.110mol) at 5°C and react at 0-5°C for 1 hour to obtain a methylene chloride solution of the compound of formula III. The methylene chloride solution of the compound of formula III is directly used without treatment synthesized in the next step.

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Abstract

A preparing process of lacosamide is disclosed. D-serine is adopted as an initial raw material. The method includes: performing amino protection, performing methylation, condensing with benzylamine under a condition of existence of a carboxyl activator, removing an amino protection group, and performing amidation to obtain the lacosamide. The total yield is higher than 66%. The method is high in yield, simple and convenient to operate, high in product purity and especially suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of chemical pharmacy, and in particular relates to a preparation method of lacosamide. Background technique [0002] Lacosamide, the chemical name is (R)-2-acetamido-N-benzyl-3-methoxypropionamide (its structural formula is shown below), produced by UCBPharma, Belgium A novel N-methyl-D-aspartate (NMDA) receptor glycine site-binding antagonist developed by German subsidiary Schwarz BioSciences. In September and October 2008, the European Union and the United States successively approved the marketing of lacosamide with the product name Vimpat. [0003] [0004] There are three main types of synthetic routes for lacosamide reported in the literature, all of which use D-serine as a starting material: [0005] Route 1. The route for preparing D-serine methyl ester disclosed in the patent international application WO9733861 is as follows: [0006] [0007] This route uses D-serine as the starting materi...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/22C07C231/02
CPCY02P20/55
Inventor 廖兴龙樊启海周熙云
Owner 福安药业集团重庆博圣制药有限公司
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