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Synthetic route of lacosamide

A technology of lacosamide and synthesis route, applied in the field of medicinal chemistry, can solve the problems of low yield, complex route, large environmental pollution and the like, and achieves the effects of high yield, avoidance of use and high atom economy

Active Publication Date: 2021-03-30
珠海润都制药股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0008] The technical problem to be solved by the present invention is to overcome the defects of the existing lacosamide preparation method, such as high production cost, low atom utilization rate, use of highly toxic reagents, generation of a large amount of waste water, large environmental pollution, complex route and low yield, And a kind of synthetic method of lacosamide is provided, the reaction route has high atom economy, avoids the use of isopropyl chloroformate to prepare amides, and avoids the use of methylating reagent methyl iodide or dimethyl sulfate use, high yield, etc., suitable for industrial production

Method used

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Examples

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Effect test

Embodiment 1

[0027] Dissolve 50g of glycine ethyl ester hydrochloride in water, add sodium bicarbonate to adjust pH7-8, add dichloromethane for extraction, concentrate the dichloromethane layer under reduced pressure to obtain glycine ethyl ester oil; add toluene to glycine ethyl ester oil And 50g of benzophenone and catalytic amount of p-toluenesulfonic acid, reflux water separation; after the reaction is completed, add water to extract after cooling, concentrate the toluene layer, add petroleum ether to carry out crystallization, dry to obtain 61.88g of intermediate M1, yield 84.92 %, purity 99.3%, 1 H NMR (500MHz, CDCl 3 ), 7.41-7.7 (m, 10H, CH), 4.51 (s, 2H, NCH 2 ), 4.13(t,2H,OCH 2 ), 1.29(t,3H,CH 3 ).

Embodiment 2

[0029] Dissolve 50g of intermediate M1 and a catalytic amount of NaI in DMF, cool down and add sodium hydride, stir for 1h, add chloromethyl methyl ether dropwise, and raise the temperature to 55°C for reaction; after the reaction is complete, add dichloromethane and Extracted with water, concentrated dichloromethane, purified, dried to obtain 45.1g of intermediate M2, yield 78%, purity 99.5%, 1 HNMR (500MHz, CDCl 3 ), 7.41-7.7(m,10H,CH), 4.31(d,H,NCH), 4.13(t,4H,OCH 2 ), 3.3(s,3H,OCH 3 ), 1.29(t,3H,CH 3 ).

Embodiment 3

[0031] Dissolve 30g of intermediate M2 and 11.5g of benzylamine in ethanol, add 0.1 times of newly prepared sodium ethoxide (sodium block dissolved in ethanol) to reflux reaction; after the reaction is completed, concentrate ethanol under reduced pressure, add dichloromethane and water for extraction, and concentrate di Chloromethane layer, purified, dried to obtain 28.2g intermediate M3, yield 79%, purity 99.05%, 1 HNMR (500MHz, CDCl 3 ), 7.9(m,2H,CH), 7.58-7.62(m,8H,CH), 7.23-7.33(m,5H,CH), 4.3-4.4(s,2H,NCH 2 ), 4.45 (m, H, NCH), 3.85-4.18 (d, 2H, OCH 2 ), 3.3(s,3H,OCH 3 ).

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Abstract

The invention discloses a new synthesis route of lacosamide. The new synthesis route comprises the following steps: taking glycine ethyl ester hydrochloride as an initial raw material to react with methylbenzene, benzophenone and p-toluenesulfonic acid to obtain a compound of formula M1; reacting the compound of formula M1 with Xmethyl methyl ether to generate a compound of formula M2; reacting the compound of formula M2 with benzylamine under the catalytic action of sodium ethoxide to generate a compound of formula M3; reacting the compound of formula M3 under the action of acid to generate acompound of formula M4; reacting the compound of formula M4 with Ltartaric acid to generate a compound of formula M5; and enabling the compound of formula M5 to react with acetic anhydride to generate the lacosamide compound. The synthesis route has the advantages that the atom economy is high, the use of isopropyl chloroformate highly toxic products for preparing amide is avoided, the use of methylation reagents methyl iodide or dimethyl sulfate is avoided, the yield is high, and the like.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new synthetic route of lacosamide, a drug for treating epilepsy and neuropathic pain. Background technique [0002] Lacosamide is a novel N-methyl-D-aspartate (NMDA) receptor glycine site-binding antagonist, belonging to a new class of functional amino acids, suitable for epilepsy patients aged 16 and above Combination therapy for partial seizures. Approved by the US FDA and the European EMA in 2008, it can be administered orally or intravenously. Epilepsy, the second most common disease in neurology after headache, has become a global public health problem. Its pathogenesis is a chronic disease of sudden abnormal discharge of brain neurons, leading to transient brain dysfunction. [0003] Lacosamide has the potential to be the first drug that can intervene in the onset and progression of epilepsy. Several studies have shown that it has a significant effect on patients wit...

Claims

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Application Information

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IPC IPC(8): C07C231/14C07C237/22C07C231/20C07C231/12C07C237/06C07C249/02C07C251/24
CPCC07C231/14C07C231/20C07C231/12C07C249/02C07C237/22C07C237/06C07C251/24Y02P20/55
Inventor 张榕芳李厚俭覃志俊蔡强王晴晴
Owner 珠海润都制药股份有限公司
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