Preparation method of lacosamide

A technology of lacosamide and acetyl, which is applied in the field of preparation of lacosamide, can solve the problems of tediousness, long reaction route, and the total yield is only about 30-40%, and achieve simplified operation steps, stable product quality, and omission of The effect of the processing step

Active Publication Date: 2015-07-08
SICHUAN TONGSHENG BIOTECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the reaction route of this method is relatively long, and the step-by-step yield reaches 91%, but the total yield is only about 30-40%. The step of removing the protecting group is relatively cumbersome

Method used

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  • Preparation method of lacosamide
  • Preparation method of lacosamide
  • Preparation method of lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0045] The preparation method of lacosamide is as follows:

[0046] (1) Preparation of N-acetyl-D-serine methyl ether with D-serine

[0047] Add 100g of D-serine, 300mL of water to a 500mL three-neck flask, dropwise add 243.07g of acetic anhydride, react at 25-35°C for 2-3h, TLC analysis shows that the residual D-serine is less than 3%; add dropwise 10mol / L of sodium hydroxide Solution 300mL, 25-35 ℃ heat preservation reaction 3-4h, TLC analysis N, O-diacetyl-D-serine is less than 2%, lower the temperature to 10-15 ℃, drop 180.2g dimethyl sulfate, react 3-5h, The reaction was complete; acidified with hydrochloric acid to PH 2-3, extracted three times with dichloromethane, washed the dichloromethane layer with water, dried over anhydrous magnesium sulfate for 3 hours, and concentrated to dryness under reduced pressure to obtain a light yellow oil, which was kept in a freezer for 24 hours. Obtained 133.5g of white solid, yield 86.97%, HPLC: 97.3%, the compound confirmation spec...

Embodiment 2

[0051] The preparation method of lacosamide is as follows:

[0052] (1) Preparation of N-acetyl-D-serine methyl ether with D-serine

[0053] Add 100g D-serine, 300mL water to a 500mL three-necked flask, drop 200g acetic anhydride, react at 25-35°C for 2-3h, TLC analysis shows that the residual D-serine is less than 3%; add 10mol / L sodium hydroxide solution dropwise 300mL, keep warm at 25-35°C for 3-4h, TLC analysis N, O-diacetyl-D-serine is less than 2%, cool down to 10-15°C, add 170g trimethyl sulfate dropwise, react for 3-5h, the reaction is complete ; Acidify with hydrochloric acid to PH 2-3, extract three times with chloroform, wash the chloroform layer with water, dry over anhydrous magnesium sulfate for 3 hours, and concentrate to dryness under reduced pressure to obtain a light yellow oil, which is left in the freezer for 24 hours to obtain a white Solid 122.3g, yield 79.67%, HPLC: 96.0%;

[0054] (2) Preparation of Lacosamide

[0055] Add 800mL of chloroform to a 10...

Embodiment 3

[0057] The preparation method of lacosamide is as follows:

[0058] (1) Preparation of N-acetyl-D-serine methyl ether with D-serine

[0059] Add 100g D-serine, 300mL water, dropwise add 300g acetic anhydride to a 500mL three-neck flask, react at 25-35°C for 2-3h, TLC analysis shows that the residual D-serine is less than 3%; add dropwise 10mol / L potassium hydroxide solution 300mL, keep warm at 25-35°C for 3-4h, TLC analysis N, O-diacetyl-D-serine is less than 2%, cool down to 10-15°C, add 170g trimethyl sulfate dropwise, react for 3-5h, the reaction is complete Acidify with hydrochloric acid to PH 2-3, extract the mixture of chloroform and tetrahydrofuran three times, wash the layer of chloroform and tetrahydrofuran with water, dry over anhydrous magnesium sulfate for 3 hours, and concentrate to dryness under reduced pressure to obtain a light yellow oil, which is placed on After 24 hours in the freezer, 111.2 g of white solid was obtained, with a yield of 72.44%, HPLC: 94.8%...

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Abstract

The invention provides a preparation method of lacosamide, which comprises following steps: (A) performing a reaction between D-serine and acetic anhydride to generate an intermediate product N,O-diacetyl-D-serine; (B) performing methylation to the N,O-diacetyl-D-serine to obtain N-acetyl-D-serine methyl ether; (C) carrying out a reaction to the N-acetyl-D-serine methyl ether with benzylamine to obtain (R)-2-acetamido-N-benzyl-3-methoxyl propionamide. The preparation method is short in reaction route, can avoid racemization, and is high in yield and purity of a reaction product.

Description

technical field [0001] The invention relates to the field of pharmacy, in particular to a preparation method of lacosamide. Background technique [0002] Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropionamide) is an anticonvulsant drug that can be used to treat epilepsy and pain, and was approved in September 2008 Approved for marketing by the European Union, it is a drug for the treatment of epilepsy and neuropathic pain developed by Schwarz BioSciences in Germany. US 6048899 patent discloses two methods for preparing this compound. [0003] In US 6048899 patent, one method is to form benzamide first and then O-methylate. However, this reaction method produces various impurities which must be removed by chromatography, which is not practical on an industrial scale. Moreover, the yield of a single step is only 80-85%. The other is to O-methylate N-protected D-serine and then form benzamide, then N-deprotect and N-acetylate to obtain the product. Although this prepara...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C237/22C07C231/02
Inventor 李德勇陈纹锐伍万兵黄青春张丽
Owner SICHUAN TONGSHENG BIOTECH
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