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Synthesis method of lacosamide

A technology of lacosamide and synthetic method, which is applied in the field of drug synthesis, can solve the problems of low product purity and yield, expensive raw materials, cumbersome process, etc., and achieve the effect of easy operation, simple steps and shortened process steps

Active Publication Date: 2017-06-20
山东安信制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

But the process is more cumbersome, the price of raw materials is more expensive, and the cost is high
[0019] In summary, the current synthetic method mainly uses D-serine as the starting material, and needs to go through two steps of amino protection and deprotection during the reaction process, resulting in cumbersome steps and low product purity and yield.

Method used

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  • Synthesis method of lacosamide
  • Synthesis method of lacosamide
  • Synthesis method of lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] Embodiment 1 (the synthesis of 2-methoxymethyl-oxirane)

[0051]

[0052]Add 50g of ethyl oxide methanol to 200ml of water, cool down to -5°C, and at the same time add 426g of dimethyl sulfate and 30% sodium hydroxide solution dropwise (to maintain the pH of the reaction solution at 8-9), stir for 5h after dropping, lemon Adjust the pH value of the acid solution to 7, add 200ml of dichloromethane to extract twice, combine the organic phases, then add anhydrous sodium sulfate to dry, filter with suction to obtain the dichloromethane solution of intermediate A, and directly proceed to the next step of reaction.

Embodiment 2

[0053] Embodiment 2 (the synthesis of R-2-hydroxyl-3-methoxypropionic acid)

[0054]

[0055] Slowly add 100ml of dichloromethane solution containing 42.5g of nitric acid dropwise to the dichloromethane solution of intermediate A, after the drop is completed, heat up to reflux, stir for 5-6 hours, TLC detects that the reaction is complete, wash with 300ml of water, and add 300ml of 8% sodium bicarbonate The solution was washed, and the dichloromethane layer was dried by adding anhydrous sodium sulfate, and filtered with suction, and the filtrate was directly carried out to the next reaction.

Embodiment 3

[0056] Embodiment 3 (the synthesis of R-2-hydroxyl-N-benzyl-3-methoxy propionamide)

[0057]

[0058] Add 87.3g of isobutyl chloroformate dropwise to the above-mentioned dichloromethane phase, control the temperature at 0~-5°C during the dropwise addition, after the drop is complete, slowly add 64.8g of triethylamine dropwise, control the temperature at ℃ drop completed. Slowly add 68 g of benzylamine dropwise, and control the dropping temperature at -15°C to -10°C, and the reaction is complete after the dropwise addition. Then 300ml of water was extracted, and the organic phase was washed with 300ml of hydrochloric acid solution, 300ml of 8% sodium bicarbonate solution, and 300ml of water. The dichloromethane phase was dried with anhydrous sodium sulfate and filtered with suction, and the filtrate was directly used in the next reaction.

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Abstract

The invention discloses a synthesis method of lacosamide. The synthesis method is characterized in that epoxy ethyl carbinol is used as a starting raw material, and is sequentially subjected to five-step reaction of methylation, acidic ring opening, condensation with benzylamine, azidation and reductive acylation to obtain the lacosamide. The synthesis method has the advantages that the raw material is simple and is easily obtained; reaction conditions are mild; the aftertreatment is simple; the product purity is high; the yield is high. Formulas are shown as the accompanying drawing.

Description

technical field [0001] The invention relates to a synthetic method of lacosamide, which belongs to the technical field of drug synthesis. Background technique [0002] Lacosamide, Chinese chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide, structural formula is as follows: [0003] [0004] Lacosamide is a third-generation drug for the treatment of epilepsy and neuropathic pain developed by UCB Pharmaceutical Co., Ltd. in Belgium. Lacosamide is the first new antiepileptic drug for the treatment of partial seizures in the past three years, and it provides a new treatment method for patients with uncontrolled partial seizures. Lacosamide is a new type of N-methyl-D-aspartate (NMDA) receptor glycine site-binding antagonist, which belongs to a new type of functional amino acid anticonvulsant drug, and has dual effects of anticonvulsant and analgesia. The drug has been approved by the European Medicines Agency (EMEA) and the US Food and Drug Administration (FDA) i...

Claims

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Application Information

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IPC IPC(8): C07C237/22C07C231/14
CPCC07C51/31C07C231/02C07C231/14C07C247/12C07D301/00C07D303/22C07C237/22C07C235/06C07C59/125
Inventor 周显峰李卓华左景冉李法东张兆珍董廷华吴柯李保勇
Owner 山东安信制药有限公司
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