Refining method of lacosamide

Abstract

The invention discloses a method for refining lacosamide, which comprises the following specific steps: dissolving a lacosamide crude product in a good solvent, then adding into an inert solvent, cooling the system to a certain temperature, stirring for crystallization, stirring for 2-3 hours, and filtering to obtain a lacosamide refined product, wherein the mass volume ratio of the crude product to the good solvent to the inert solvent is 1g: (4-6) mL: (9-24) mL, the good solvent is dichloromethane, and the inert solvent is methyl tert-butyl ether. The crystallization refining of lacosamide is realized by adopting an anti-solvent method, the refining effect is good, the isomer clearance rate is high, the operation is simple, and the method is particularly suitable for industrial production.

Description

Technical Field

[0001] The present invention relates to a refining method, in particular to a refining method of lacosamide, belonging to the technical field of medicines. Background Art

[0002] Lacosamide, also known as lacosamide, has a chemical name of (R)-2-acetamido-N-benzyl-3-methoxypropionamide, CAS number: 175481-36-4, and the structural formula is as follows:

[0003] Lacosamide is a drug developed by Schwarz Pharma of Germany for the treatment of epilepsy and neuropathic pain. In September 2008, the European Union approved the marketing of Lacosamide Tablets of UCB of Belgium for the adjuvant treatment of partial epileptic seizures in patients aged 16 years and above with or without secondary grand mal seizures. In October 2008, the US FDA approved the marketing of Lacosamide as an adjuvant drug used in combination with other drugs for partial epileptic seizures, with the trade name Vimpat®. Lacosamide is an anticonvulsant drug with a new dual mechanism of action. It selectively promotes the slow inactivation of sodium channels and regulates collapse response mediator protein 22 (CRMP22), thereby slowing down or even preventing epileptic seizures and alleviating diabetic neuropathic pain.

[0004] There are many reported preparation methods for lacosamide, and the chiral purity and crystal state of the target compound obtained by the refining process are relatively few. The properties of lacosamide materials in different crystal forms are different. At present, lacosamide is used as an active ingredient in preparations, and the pharmaceutical crystal form is generally type I or a mixture of type I and type II, among which type I raw materials have the best physical state.

[0005] US5773475 states that the optical purity of lacosamide can be improved by further separating the (S)-enantiomer from the (R)-enantiomer by standard methods known in the art, such as chiral chromatography using standard chiral supports known in the art.

[0006] PCT Patent Application No. WO2009146325 describes polycrystalline Forms I, II and III and an amorphous form of lacosamide, and methods for their preparation.

[0007] PCT patent application No. WO2010060624 discloses lacosamide in polymorphic forms R, S and T, and methods for their preparation. According to WO2010060624, the lacosamide used as a starting material in the examples is prepared by means of the method described in WO97033861, and the enantiomeric purity is not mentioned.

[0008] In view of the above situation, it is hoped to obtain a stable, reliable, low-cost, high-chirality-pure solid form of lacosamide that can be used in pharmaceutical dosage forms. Summary of the invention

[0009] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for refining lacosamide. To achieve the above purpose, the present invention adopts the following technical scheme: A method for refining lacosamide, the specific steps are as follows: The crude lacosamide is dissolved in a good solvent, and then an inert solvent is added, stirred for 2 to 4 hours, solids are precipitated, filtered, and post-treated to obtain a refined lacosamide; wherein the mass volume ratio of the crude product to the good solvent and the inert solvent is 1 g: 4 to 6 mL: 9 to 24 mL, the good solvent is dichloromethane, and the inert solvent is ethyl acetate.

[0010] Preferably, the stirring time is 3 hours.

[0011] Preferably, the mass volume ratio of the crude product to the good solvent and the inert solvent is 1 g:6 mL:20 mL.

[0012] Preferably, the good solvent is dichloromethane.

[0013] Preferably, the crude lacosamide is mixed with a good solvent and then heated to dissolve.

[0014] Preferably, the heating and dissolving temperature is 35-45°C.

[0015] Preferably, the temperature of the inert solvent is -5 to 10°C.

[0016] Preferably, the crystallization temperature is controlled at 5-15° C., and the crystallization time is 2-3 hours.

[0017] Beneficial effects of the present invention: The present invention adopts an anti-solvent method to realize the crystallization purification of lacosamide, that is, lacosamide is dissolved in a good solvent halogenated hydrocarbon, namely dichloromethane, and then an inert solvent methyl tert-butyl ether is added for crystallization, and the purification effect is good.

[0018] The obtained lacosamide finished product has a purity of more than 99.7%, all single impurities are less than 0.1%, the product yield is high, the operation is simple, and it is particularly suitable for industrial production. DETAILED DESCRIPTION

[0019] The present invention is further described below in conjunction with embodiments. It should be noted that the following description is only for explaining the present invention and does not limit its contents.

[0020] The crude lacosamide synthesis route of the present invention is as follows, which is prepared by referring to the method in patent CN200580024175: Example 1

[0021] Add 10 g of crude lacosamide and 40 ml of dichloromethane into a three-necked flask, heat until the system is clear, add 90 ml of methyl tert-butyl ether at room temperature, cool to room temperature, stir, filter, and dry to obtain a white solid. Example 2

[0022] Add 10 g of crude lacosamide and 60 ml of dichloromethane into a three-necked flask, raise the temperature to 39-45°C, and when the system becomes clear, add 120 ml of methyl tert-butyl ether at room temperature, cool to room temperature, stir, filter, and dry to obtain a white solid. Example 3

[0023] Add 10 g of crude lacosamide and 60 ml of dichloromethane into a three-necked flask, heat until the system is clear, add 150 ml of methyl tert-butyl ether at room temperature, cool to room temperature, stir, filter, and dry to obtain a white solid. Example 4

[0024] To a 50L reactor, add 1050g of crude lacosamide and 6300ml of dichloromethane, heat until the system is clear, filter, heat again to dissolve, cool to 30°C, add 25200ml of 5°C methyl tert-butyl ether, cool to 5-10°C, stir for 2-3h, filter, and dry to obtain 969.97g of white solid.

[0025] Table 1 Investigation of different solvent dosages

[0026] Table 2 Investigation of solvent dosage

[0027] It can be seen from Comparative Examples 1 to 5 that the removal rate of isomers using dichloromethane and methyl tert-butyl ether as crystallization solvents is higher than that of other solvent systems.

[0028] It can be seen from Examples 1 to 4 that the optimal conditions are when the mass volume ratio of crude product: dichloromethane: tert-methyl ether is 1 g: 6 mL: 24 mL, and the yield and purity are both high.

[0029] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

[0030] Although the present invention has been illustrated and described with specific embodiments, it will be appreciated that many other changes and modifications may be made without departing from the spirit and scope of the present invention. Therefore, it is intended to include all such changes and modifications within the scope of the present invention in the appended claims.

Claims

1. A method for refining and preparing lacosamide, characterized in that: The steps include: The crude lacosamide is dissolved in a good solvent, and then added into an inert solvent. The system is cooled to a certain temperature, stirred and crystallized, stirred for 2 to 3 hours, and filtered to obtain a refined lacosamide; wherein the mass volume ratio of the crude product to the good solvent and the inert solvent is 1 g: 4 to 6 mL: 9 to 24 mL, the good solvent is dichloromethane, and the inert solvent is methyl tert-butyl ether.

2. The method for preparing lacosamide according to claim 1, characterized in that: The benign solvent used was dichloromethane.

3. The method for preparing lacosamide according to claim 1, characterized in that: The inert solvent used was methyl tert-butyl ether.

4. The method for preparing lacosamide according to claim 1, characterized in that: The volume ratio of the crude lacosamide to the dichloromethane is 1:4-6.

5. The method for preparing lacosamide according to claim 1, characterized in that: The volume ratio of the crude lacosamide to the methyl tert-butyl ether is 1:9-24.

6. The method for preparing lacosamide according to claim 1, characterized in that: The temperature for adding the inert solvent methyl tert-butyl ether is -5 to 30°C.

7. The method for preparing lacosamide according to claim 1, characterized in that: The crystallization temperature is controlled at 5~30℃ and the crystallization time is 2~3h.

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