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One-pot method for preparing lacosamide

A technology for preparing lacosamide and lacosamide, applied in the field of medicine, can solve the problems of high cost, expensive raw materials, complicated process and the like, and achieve the effects of reducing time cost, reducing production cost and simplifying reaction steps

Active Publication Date: 2017-10-31
QILU PHARMA HAINAN +1
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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

Method used

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  • One-pot method for preparing lacosamide
  • One-pot method for preparing lacosamide
  • One-pot method for preparing lacosamide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] (1) Add 50g of D-serine to 200ml of dichloromethane, control the reaction temperature at 20-25°C, slowly add 48.6g of acetic anhydride dropwise, and after 2 hours of reaction, adjust the pH to 12-13 with sodium methoxide solution;

[0040] (2) Add 78.1 g of methyl trifluoromethanesulfonate dropwise under temperature control at -5 to 0°C, and after the drop is completed, raise the temperature to room temperature and react for 3 hours;

[0041] (3) Cool down to -30~-25°C, add 91.1g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCL), 1-hydroxybenzotri Nitriazole (HOBt) 64.75g, 51g of benzylamine was slowly added dropwise, and then reacted for 2 hours; the temperature was controlled at 32-38°C and the dichloromethane was concentrated under reduced pressure to obtain the crude product of lacosamide;

[0042] (4) Dissolve the above solid in 100ml of ethyl acetate, add 100ml of n-heptane dropwise, stir and cool down to 0-10°C for crystallization after dropp...

Embodiment 2

[0044] (1) Add 100 g of D-serine to 350 ml of dichloromethane in turn, control the reaction temperature at 20-25 ° C, slowly add 97.3 g of acetic anhydride dropwise, and react for 2.5 hours, adjust the pH to 12-13 with triethylamine solution;

[0045] (2) Add 156 g of methyl trifluoromethanesulfonate dropwise under temperature control at -5 to 0° C. After the drop is completed, heat up to room temperature and react for 3.5 hours;

[0046] (3) Cool down to -30°C to -25°C, add 182g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCL), 1-hydroxybenzotri Nitriazole (HOBt) 129g, slowly dropwise add 100g benzylamine to react for 2.5 hours, control temperature at 33-38°C and concentrate to dry dichloromethane under reduced pressure to obtain crude lacosamide;

[0047](4) Dissolve the above solid in 300ml of ethyl acetate, stir and cool down to 0-10°C to crystallize, filter with suction, and rinse the filter cake with 50ml of ethyl acetate. 167.3 g of the product wa...

Embodiment 3

[0049] (1) Add 50g of D-serine to 200ml of dichloromethane, control the reaction temperature at 20-25°C, slowly add 48.7g of acetic anhydride dropwise, after 2.5 hours of reaction, use N,N-diisopropylethylamine solution Adjust the pH to 12-13;

[0050] (2) Add 78.2 g of methyl trifluoromethanesulfonate dropwise under temperature control -5 to 0°C. After the drop is completed, raise the temperature to room temperature and react for 2.5 hours;

[0051] (3) Cool down to -30~-25°C, add 90.5g of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCL), 1-hydroxybenzotri Add 64.0 g of nitrogen azole (HOBt), slowly dropwise add 50 g of benzylamine, and then react for 2.5 hours; control the temperature at 32-38°C and concentrate to dry dichloromethane under reduced pressure to obtain the crude product of lacosamide;

[0052] (4) Dissolve the above solid in 100ml of ethyl acetate, add 100ml of n-hexane dropwise, stir and cool down to 0-10°C to crystallize after dropping, fi...

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Abstract

The invention discloses a method for preparing Lacosamide by a one-pot method. The method comprises the steps: subjecting D-serine and an acetylation reagent to a reaction in a manner of taking dichloromethane as a solvent, and adjusting the pH of a reacted substance to 12-13 by an organic base after the reaction ends; then, controlling the temperature to -5 to 0 DEG C, and adding methyl trifluoromethanesulfonate into the reacted substance for a reaction; and cooling a reacted substance to the temperature of -30 to -25 DEG C, adding a dehydrating agent and benzylamine into the reacted substance for a reaction, carrying out depressurized-concentration drying on material liquid after the reaction ends so as to obtain crude Lacosamide, and then, carrying out recrystallization, thereby obtaining pure Lacosamide. The preparation method is simple and easy in operation, and the prepared Lacosamide has the purity of 99.90% or more and the chiral purity of 99.90%.

Description

technical field [0001] The invention relates to a method for preparing lacosamide in one pot, and belongs to the technical field of medicine. Background technique [0002] Lacosamide, Chinese chemical name: (R)-2-acetamido-N-benzyl-3-methoxypropionamide, molecular formula C 13 h 18 N 2 o 3 , the molecular weight is 250.29, and the 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. [0005] 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 a...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C237/22C07C231/02
CPCC07C231/02C07C231/12C07C233/47C07C237/22
Inventor 左景冉周显峰李法东李文华李卓华
Owner QILU PHARMA HAINAN
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