High-efficiency racemic lacosamide preparation method

A lacosamide, high-efficiency technology, applied in the field of lacosamide preparation, can solve the problems of complex steps, long route, easy allergies, etc., and achieve the effect of high atom utilization rate, good economic benefit and simple post-treatment

Active Publication Date: 2018-05-29
天台宜生生化科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

According to the classification of starting materials, there are mainly the following routes: (1) Use Boc-protected D-serine as raw material to synthesize lacosamide (EP1642889A1) through methyl etherification, amidation, deprotection and amidation. The classic synthetic route is also the commonly used industrialized process route at present; (2) Starting from benzyloxymethyl oxirane, it undergoes ring-opening etherification, azidation, hydrogenation, Boc protection, hydroxyl oxidation, Amidation, and finally deprotection, acetylation to synthesize lacosamide (US20140012044A1), the route is long and complicated, the yield is low, and it is not suitable for industrial production; One-step reaction (WO2016125178A1), or using halomethyl propylene oxide as raw material to synthesize lacosamide through 7-step reaction (WO2016030911A2), both of which have the problem that the route is too long and the steps are complicated; (3) N-benzyl acrylamide Lacosamide (WO2012069855A1) is synthesized from alkenes as raw materials through halogenation, methoxylation, ammoniation, and finally acetylation (WO2012069855A1), which is also a commonly used industrialization method, but liquid bromine is used in this method.

Method used

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  • High-efficiency racemic lacosamide preparation method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0028] Example 1: Synthesis of 2-acetylamino-3-methoxypropionic acid methyl ester

[0029] According to the amount ratio of N-acetylserine: bromide: sodium hydride is 1.0:2.0:3.0 feeding; N-acetylserine 44.1g, bromide 57.0g, sodium hydride 36.0g; anhydrous organic solvent A is DMF 660mL, its The volume dosage is 15 times the mass of N-acetylserine (mL / g).

[0030] In a dry and clean reaction flask, protect it with nitrogen gas, slowly add DMF, sodium hydride and N-acetylserine in sequence, stir, cool down to -10~-5°C in an ice-salt bath, slowly introduce methyl bromide, and control the reaction temperature at 0°C the following. After the dropwise addition was completed, the reaction was carried out at 80° C. for 3 hours. The reaction solution was quenched with ice water, extracted with methyl tert-butyl ether, and the organic phase was concentrated under reduced pressure to obtain 36.8 g of methyl 2-acetylamino-3-methoxypropionate intermediate, with a yield of 70.0%.

Embodiment 2

[0032] According to the ratio of N-acetylserine: methyl bromide: sodium hydride is 1.0: 2.0: 2.1 feeding; N-acetylserine 44.1g, methyl bromide 57.0g, sodium hydride 25.2g; anhydrous organic solvent A is DMSO 880mL, its The volume dosage is 20 times the mass of N-acetylserine (mL / g).

[0033] The reaction temperature was 20°C, and the reaction was carried out for 10 hours. Other operations were the same as in Example 1 to obtain 42.5 g of methyl 2-acetylamino-3-methoxypropionate, with a yield of 80.9%.

Embodiment 3

[0035] N-acetylserine: methyl bromide: sodium hydride is 1.0: 2.5: 3.5 according to the amount of material; N-acetylserine 44.1g, methyl bromide 71.2g, sodium hydride 42.0g; anhydrous organic solvent A is N,N- Dimethylacetamide 660mL, its volume is 15 times the mass of N-acetylserine (mL / g).

[0036] The reaction temperature was 40°C, and the reaction was carried out for 8 hours. Other operations were the same as in Example 1 to obtain 42.0 g of methyl 2-acetylamino-3-methoxypropionate, with a yield of 79.9%.

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Abstract

The invention discloses a high-efficiency racemic lacosamide preparation method. The preparation method is characterized in that N-acetyl serine shown in a formula (II) is utilized as a raw material and completely reacts with methyl bromide under the action of sodium hydride to obtain 2-acetamido-3-methoxy methyl propionate shown in a formula (III), and then the 2-acetamido-3-methoxy methyl propionate generates ester exchange reaction with benzylamine under the catalyst of trifluoromethanesulfonate to obtain a product namely racemic lacosamide. The suspended lacosamide preparation method disclosed by the invention has an industrial process route which has the advantages of short reaction line, high yield, high atom utilization rate, simpleness in aftertreatment and low cost.

Description

technical field [0001] The invention discloses a preparation method of mixed-rotating lacosamide. Background technique [0002] Lacosamide, chemical name R -(-)-2-Acetamido-3-methoxy-N-benzylpropionamide is the third-generation drug for the treatment of epilepsy and neuropathic pain developed by Belgium UCB Pharmaceutical Co., Ltd. The drug was launched in September 2008 and in October 2008 were approved by the European Commission and the US Food and Drug Administration (FDA). The drug has a unique dual mode of action, thereby stabilizing the hyperexcitatory nerve cell membrane and inhibiting the repeated discharge of neurons. It is different from other antiepileptic drugs currently used clinically. , has received extensive attention. [0003] [0004] At present, there are many synthetic methods of lacosamide reported at home and abroad. According to the classification of starting materials, there are mainly the following routes: (1) Use Boc-protected D-serine as raw...

Claims

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Application Information

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IPC IPC(8): C07C231/02C07C237/22C07C231/12C07C233/47
CPCC07C231/02C07C231/12C07C237/22C07C233/47
Inventor 夏建胜孙坚方元文陈斌陈德响何亚文
Owner 天台宜生生化科技有限公司
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