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Preparation method for lacosamide

A technology of lacosamide and acetylation, which is applied in the field of preparation of lacosamide, can solve problems such as non-compliance, and achieve the effects of low equipment requirements, high yield, and high product purity

Active Publication Date: 2017-05-24
上海医药集团(本溪)北方药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] All the preparation methods described so far use expensive methyl iodide or highly toxic dimethyl sulfate for methylation, which do not conform to the currently advocated "green synthesis" route (ie chemical synthesis with low toxicity and low pollution) and will be eliminated

Method used

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  • Preparation method for lacosamide
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  • Preparation method for lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] Example 1 Compound I Generates Compound II

[0037] Into a 1000mL three-necked flask, add 400mL of toluene and 40g of N-tert-butoxycarbonyl-D-serine (Boc-D-serine), lower the stirring temperature to 0-5°C, and add dropwise 36.5g of 30% potassium hydroxide solution. After stirring for 30 minutes, 72.65 g of methyl p-toluenesulfonate and 4 g of tetrabutylammonium bromide were added, and then 43.68 g of 50% potassium hydroxide solution was added dropwise. After reacting at 0-5°C for 8 hours, 200 mL of water was added and the layers were separated. The aqueous layer was washed with 100 mL of toluene, and the organic layer was discarded. The combined aqueous layers were then cooled to below 15°C and acidified with 50% phosphoric acid to pH=2-3.5, extracted with dichloromethane (200 mL*3), and the combined organic layers were added with 30 g of anhydrous sodium sulfate and stirred overnight. The next day it was filtered, and the filtrate was concentrated to dryness under red...

Embodiment 2

[0038] Embodiment 2 compound II generates compound III

[0039] 42.9 g of compound II was dissolved in 400 mL of anhydrous methanol, cooled to 0-5°C, 50 g of thionyl chloride was added dropwise at this temperature, and the solution was raised to room temperature for 2 hours to react. Part of the solvent was distilled off under reduced pressure, and when the remainder was 50 g, 400 mL of dry ethyl acetate was added with stirring. After stirring for 30 minutes, it was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 32.5 g of a white solid. Yield: 89.2%, HPLC purity: 98.2%. NMR data ( 1 H NMR, DMSO-d6, 400MHz): δppm 8.77 (2H, s, NH), 4.28 (1H, m, CH), 3.79 (2H, d, CH 2 ),3.75(3H,s,CH 3 ),3.29(3H,s,CH 3 ).

Embodiment 3

[0040] Embodiment 3 compound III generates compound IV

[0041] Add 32g of compound III into 300mL of dichloromethane, stir and cool to 0-5°C, add 52g of triethylamine, add 19.8g of acetyl chloride dropwise at 0-5°C, and keep stirring for 4 hours after dropping. Add 150 mL of cold water, separate the layers, take the organic layer, and then wash with 150 mL of 1N hydrochloric acid, 150 mL of water, and 150 mL of saturated sodium chloride solution. Finally, it was dried with 10 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain 29.4 g. Yield: 88.2%, HPLC purity: 98.8%, chiral purity: 99.2%. NMR data ( 1 H NMR, DMSO-d6, 400MHz): δppm 8.35 (1H, s, NH), 4.50 (1H, m, CH), 3.64 (3H, s, CH 3 ),3.51(1H,m,CH 2 ),3.34(1H,m,CH 2 ),3.25(3H,s,CH 3 ),1.87(3H,s,CH 3 ).

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Abstract

The invention provides a preparation method for lacosamide. According to the invention, easily available Boc-serine (a compound I) is used as a starting material for preparation of lacosamide, and the quality of prepared lacosamide is identical to the quality of an original drug. The preparation method provided by the invention uses easily available raw materials, does not need expensive iodomethane or severely toxic dimethyl sulfate, and is high in product purity and yield and low in toxicity and pollution, and requirements of reaction conditions on equipment are not high; thus, the method is suitable for industrial production.

Description

technical field [0001] The invention relates to the fields of organic chemistry and medicinal chemistry, in particular, the invention relates to a preparation method of lacosamide. Background technique [0002] (2R)-2-(Acetamido)-N-benzyl-3-methoxypropionamide is the active ingredient used in the treatment of neuropathy and is known as lacosamide. [0003] It was first reported in U.S. Patent No. 6,048,899 (patent owner: Research Corporation Tech., Inc., publication date: 200-04-01), which also pointed out the use of D-serine and iodine as starting materials in this document. Methane and silver oxide, used in the methylation synthesis of OH. This method is expensive and results in partial racemization (about 15%). [0004] Another patent US20080027137 (published date: 2008-01-31, Chinese patent of the same family: CN 1989102) improving the synthesis method of lacosamide uses N-Boc-D-serine as the raw material, and the published route is as follows: [0005] [0006] Th...

Claims

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Application Information

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IPC IPC(8): C07C237/22C07C231/02
Inventor 陆世红魏宪民赵亮
Owner 上海医药集团(本溪)北方药业有限公司
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