Preparation method of lacosamide

Abstract

The invention provides a preparation method of lacosamide, which comprises the following steps: carrying out methylation reaction on a lacosamide intermediate shown as I in the presence of alkali and dimethyl carbonate to obtain lacosamide and # imgabs0 #. Dimethyl carbonate is used as a methylation reagent, so that the use of cancerogen or high toxicity is avoided, and the preparation method is environment-friendly, and is suitable for industrial production. And the reaction system can better inhibit the generation of deacetylation impurities of lacosamide, the impurities can be removed only by pulping with methyl tert-butyl ether in post-treatment, the dosage of a purification solvent is reduced, the yield is high, the chiral purity is high, and the method is suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and particularly relates to a preparation method of lacosamide. Background Art

[0002] Lacosamide, chemical name (R)-2-acetylamino-N-benzyl-3-methoxypropionamide, trade name It is a new type of N-methyl-D-aspartate (NMDA) receptor glycine site binding antagonist. Different from other anti-epileptic drugs used in clinical practice, it has a unique dual effect. It not only reduces the increased sodium channel activity in Yichang, but also interacts with collapse response mediator protein-2 (CRMP-2) to control epileptic seizures. The drug was approved for marketing by the European EMA and the US FDA in September 2008 and October 2008, respectively. It is approved for adjuvant treatment of partial seizure epilepsy patients aged 16 years and above with or without secondary generalized seizures. It has no interaction with traditional drugs, is effective, well tolerated, and has a good effect on intractable epilepsy.

[0003] The chemical structure of lacosamide is shown below:

[0004]

[0005] Patent US RE38551 discloses three routes:

[0006] Route 1: Using D-serine as a raw material, HCl gas is passed through a methanol solution to obtain D-serine methyl ester hydrochloride, which is then condensed with benzylamine for amidation, and then acetylated with acetic anhydride to obtain lacosamide intermediate I. Finally, under the catalysis of silver oxide, it is subjected to O-methylation reaction with iodomethane to obtain lacosamide. The reaction formula is shown below:

[0007]

[0008] Route 2: Using D-serine as a raw material, first react with acetic anhydride in acetic acid to obtain N-acetyl-D-serine, then in the presence of N-methylmorpholine, after being activated by isobutyl chloroformate, react with benzylamine to obtain the lacosamide intermediate IR-2-acetamido-N-benzyl-3-hydroxy-propionamide, and finally react with iodomethane under the catalysis of silver oxide to obtain lacosamide. The reaction formula is shown below:

[0009]

[0010] Route 3: Using D-serine as the raw material, benzyl chloroformate is used for amino protection, then O-methylated with iodomethane under the catalysis of silver oxide, then hydrolyzed, condensed with benzylamine for amidation, then deprotected by palladium-carbon catalysis hydrogenation, and finally acetylated under the catalysis of DMAP to obtain lacosamide. The reaction formula is shown below:

[0011]

[0012] The above routes all involve an O-methylation step. In US RE38551, silver oxide is used as a catalyst and methyl iodide is used as a methylating agent for the reaction. However, methyl iodide is a strong carcinogen that is harmful to the human body and the environment. It decomposes under light and is highly volatile, making it extremely inconvenient to store. In addition, silver oxide is expensive and easily leads to partial racemization of the product. Therefore, this process is not suitable for large-scale industrialization.

[0013] CN103113256 discloses a method for preparing lacosamide. The synthetic route of the method is the same as route 2, wherein the methylation step is improved, and sodium hydroxide and dimethyl sulfate are added to react in the presence of a phase transfer catalyst such as tetrabutylammonium bromide.

[0014] CN106543018 discloses a method for preparing lacosamide, the synthetic route of which is the same as route 2, wherein the methylation step is carried out in a suitable solvent (such as acetonitrile, tetrahydrofuran or dimethylformamide) and in the presence of a base (such as sodium hydroxide aqueous solution), and finally recrystallized from acetone and diisopropyl ether to obtain lacosamide. The methylation reagent dimethyl sulfate used in this process is a highly toxic substance, and a large amount of radical toxic impurities such as monomethyl sulfate will be generated after the methylation reaction, and radical toxic impurities need to be controlled in subsequent production.

[0015] Since the reagents used in the prior art methods for preparing lacosamide are expensive or highly toxic and are not suitable for large-scale industrial production, it is very necessary to develop a method for preparing lacosamide that is simple to operate, economical and environmentally friendly for large-scale industrial production. Summary of the invention

[0016] In view of the shortcomings and deficiencies of the prior art, the present invention provides a method for preparing lacosamide, which has cheap and readily available raw materials, is economical and environmentally friendly, can effectively control the content of isomers and impurities, has simple and easy post-treatment, and is suitable for large-scale industrial production.

[0017] The present invention provides a method for preparing lacosamide, which comprises subjecting a lacosamide intermediate as shown in formula I to a methylation reaction in the presence of a base and dimethyl carbonate to obtain lacosamide.

[0018] .

[0019] The inventors unexpectedly found that although the methylating agent dimethyl carbonate used in the present invention is less active than dimethyl sulfate reported in the prior art, harsh reaction conditions such as high temperature and strong alkali are not required during the reaction process, and the reaction system can better inhibit the formation of lacosamide deacetylation impurities, and the post-reaction treatment becomes simple, and the impurities can be removed by pulping with methyl tert-butyl ether, and the amount of purification solvent used is reduced. The lacosamide deacetylation impurity is the European Pharmacopoeia impurity D, and the structural formula is shown below:

[0020]

[0021] In some embodiments, the base is selected from one or more of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide;

[0022] In some embodiments, the base is sodium hydride, sodium tert-butoxide;

[0023] In some embodiments, the methylation reaction solvent is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran;

[0024] In some embodiments, the methylation reaction solvent is one or more of tetrahydrofuran, 2-methyltetrahydrofuran, and N,N-dimethylformamide;

[0025] In some embodiments, the methylation reaction temperature is -15 to 30°C;

[0026] In some embodiments, the methylation reaction temperature is 0 to 10°C;

[0027] In some embodiments, the molar ratio of the lacosamide intermediate, the base and dimethyl carbonate as shown in Formula I is 1:1-10:1-10;

[0028] In some embodiments, the molar ratio of the lacosamide intermediate, the base and dimethyl carbonate as shown in Formula I is 1:2-5:3-5;

[0029] In some embodiments, the weight ratio of the lacosamide intermediate as shown in Formula I to the reaction solvent is 1:4 to 10;

[0030] In some embodiments, after the methylation reaction is completed, the reaction mixture containing lacosamide is extracted and concentrated, and then the concentrate is added to an organic solvent for pulping and purification;

[0031] In some embodiments, the extraction solvent is dichloromethane;

[0032] In some embodiments, the organic solvent is one or more of methyl tert-butyl ether, methanol, ethyl acetate, and n-heptane;

[0033] In some embodiments, the organic solvent is methyl tert-butyl ether;

[0034] In some embodiments, the mass volume ratio of the lacosamide intermediate represented by Formula I to the organic solvent is 1:4 to 1:25.

[0035] Compared with the prior art, the present invention has the following positive technical effects:

[0036] 1. The present invention uses dimethyl carbonate as a methylating agent, thereby avoiding the use of carcinogen methyl iodide or highly toxic dimethyl sulfate, is environmentally friendly, and the wastewater produced has a single component and is easy to handle. At the same time, excessive dimethyl carbonate is degraded into carbonic acid during the reaction, making the system weakly acidic, and the reaction system can better inhibit the generation of lacosamide deacetylation impurities, and the post-treatment becomes simple, and impurities can be removed by pulping with methyl tert-butyl ether, and the amount of purification solvent used is reduced.

[0037] 2. The preparation method provided by the present invention has mild reaction conditions, does not require high temperature and strong acid conditions, has a higher conversion rate, produces fewer by-products, and has high chiral purity, and is suitable for large-scale industrial production. Specific embodiment:

[0038] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0039] All ranges recited in the present invention include those endpoints of the range between two values, and no matter whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value. When the error degree is not recorded, all values ​​recited in the present invention include the range of ± 10% of the recorded value.

[0040] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0041] The HPLC analysis method used in the present invention to determine the chiral purity of lacosamide is:

[0042] Instrument: High performance liquid chromatography equipped with UV detector

[0043] Chromatographic column: Chiralpak AD 250*4.6mm, 10μm

[0044] Mobile phase: water: isopropanol: n-heptane = 3:100:900 (V / V / V)

[0045] Detection wavelength: 215nm

[0046] Flow rate: 1.0ml / min

[0047] Injection volume: 20 μL

[0048] Column temperature: 30°C

[0049] Running time: 60 minutes

[0050] The HPLC analysis method used in the present invention to determine the purity of lacosamide:

[0051] Instrument: High performance liquid chromatography equipped with UV detector

[0052] Chromatographic column: Agilent Eclipse XDB-C8, 150*4.6mm, 3.5μm

[0053] Mobile phase A: 1.0 ml trifluoroacetic acid dissolved in 1000 ml water

[0054] Mobile phase B: trifluoroacetic acid: acetonitrile: methanol = 0.3:500:500 (% V / V)

[0055] Detection wavelength: 258nm

[0056] Flow rate: 1.2ml / min

[0057] Injection volume: 20 μL

[0058] Column temperature: 30°C

[0059] Run time: 28 minutes

[0060] Time (min) Mobile phase A (% V / V) Mobile phase B (% V / V) 0 89 11 2 89 11 14.2 69 31 19.5 23 77 20 0 100 21 0 100 21.1 89 11 28 89 11

[0061] Example 1: Prepare the lacosamide intermediate shown in Formula I with reference to Examples 1-3 of CN106543018

[0062] At room temperature, 200 g of D-serine and 1200 ml of methanol were added to a four-necked bottle, the temperature was controlled at -5-0°C, 448 g of acetyl chloride was added dropwise, and the reaction was refluxed for 15 hours. After the reaction was completed, the solvent was evaporated under reduced pressure, and methanol and methyl tert-butyl ether were added to obtain a white solid of D-serine methyl ester hydrochloride.

[0063] The whole batch of D-serine methyl ester hydrochloride and 1300 ml of dichloromethane were added to a four-necked bottle, the temperature was controlled at 0-5 ° C, 355 g of triethylamine was added dropwise, and then 138 g of acetyl chloride was added dropwise at -10 ° C. After the addition was completed, the reaction was kept warm for 3 hours, the triethylamine hydrochloride was filtered to remove the dichloromethane, the filtrate was evaporated to remove the dichloromethane, 1040 ml of ethyl acetate was added and stirred for 1 hour, filtered, and the filtrate was evaporated to remove the ethyl acetate under reduced pressure to obtain an oily substance N-acetyl-D-serine methyl ester.

[0064] The whole batch of N-acetyl-D-serine methyl ester and 320 g of benzylamine were added to a four-necked bottle, and 30 g of triethylamine was added. The mixture was reacted at room temperature for 12 hours. Methyl tert-butyl ether was added, and the mixture was stirred for 6 hours. The mixture was filtered and dried to obtain lacosamide intermediate I. The yield was 327.2 g. Its chemical HPLC was 98.6%, and its chiral HPLC was 99.1%.

[0065] Example 2: Synthesis of Lacosamide

[0066] 10 g (0.04 mol) of the lacosamide intermediate shown in formula I and 50 g of N, N-dimethylformamide were added to a four-necked bottle, the temperature was controlled at 0-10°C, 3 g (0.08 mol) of sodium hydride (60% content) was added, stirring was continued for 20 minutes after the addition was completed, the temperature was controlled at 0-10°C, 11.5 g (0.13 mol) of dimethyl carbonate was added dropwise, the addition was completed, and the reaction was continued for 5 hours. After the reaction was completed, the reaction solution was slowly added dropwise to 50 ml of ice water, stirred for 20 minutes after the addition was completed, and then 100 ml of dichloromethane was added, the layers were separated, the water layer was extracted once with 100 ml of dichloromethane, the organic layers were combined, and the concentrate containing lacosamide was evaporated under reduced pressure to obtain a concentrate containing lacosamide, with a chemical HPLC of 93.2% and a chiral HPLC of 97.6%, wherein the content of lacosamide deacetylated impurity (i.e., impurity D of the European Pharmacopoeia) was 0.6%.

[0067] Then, the lacosamide concentrate was added with 150 ml of methyl tert-butyl ether and stirred at room temperature for 1 hour, filtered and dried to obtain lacosamide with a yield of 8.5 g and a yield of 80.5%. Its chemical HPLC was 99.3%, its chiral HPLC was 99.4%, and the deacetylated impurity content of lacosamide was ND.

[0068] Example 3 Synthesis of Lacosamide

[0069] 10 g (0.04 mol) of the lacosamide intermediate shown in formula I and 50 g of tetrahydrofuran were added to a four-necked bottle, the temperature was controlled at 0-10 ° C, 3 g (0.08 mol) of sodium hydride (60% content) was added, and stirring was continued for 20 minutes after the addition was completed. The temperature was controlled at 0-10 ° C, and 11.5 g (0.13 mol) of dimethyl carbonate was added dropwise. After the addition was completed, the reaction solution was slowly added dropwise to 50 ml of ice water. After the addition was completed, it was stirred for 20 minutes, the temperature was slowly raised, and the temperature was controlled to be ≤50 ° C. The tetrahydrofuran was evaporated under reduced pressure, and then 100 ml of water and 100 ml of dichloromethane were added. The layers were separated, and the water layer was extracted once with 100 ml of dichloromethane. The organic layers were combined and evaporated to dryness under reduced pressure to obtain a concentrate containing lacosamide, with a chemical HPLC of 93.4% and a chiral HPLC of 97.2%, wherein the content of lacosamide deacetylated impurities (i.e., impurity D in the European Pharmacopoeia) was 0.8%.

[0070] 150 ml of methyl tert-butyl ether was added to the lacosamide concentrate, stirred at room temperature for 1 hour, filtered and dried to obtain lacosamide with a yield of 8.9 g and a two-step yield of 83.7%. Its chemical HPLC was 99.3%, and its chiral HPLC was 99.7%. The content of lacosamide deacetylated impurity (i.e., impurity D in the European Pharmacopoeia) was ND.

[0071] Example 4 Synthesis of Lacosamide

[0072] 10 g (0.04 mol) of the lacosamide intermediate shown in formula I and 70 g of tetrahydrofuran were added to a four-necked bottle, the temperature was controlled at 0-10°C, 4 g (0.10 mol) of sodium hydride (60% content) was added, stirring was continued for 20 minutes after the addition was completed, the temperature was controlled at 0-10°C, 13 g (0.14 mol) of dimethyl carbonate was added dropwise, the addition was completed, and the reaction was continued for 5 hours. After the reaction was completed, the reaction solution was slowly added dropwise to 50 ml of ice water, stirred for 20 minutes after the addition, the temperature was slowly raised, the temperature was controlled to be ≤50°C, tetrahydrofuran was removed by distillation under reduced pressure, and then 100 ml of water and 100 ml of dichloromethane were added, the layers were separated, the water layer was extracted once with 100 ml of dichloromethane, the organic layers were combined, and the concentrate containing lacosamide was evaporated under reduced pressure to obtain a concentrate containing lacosamide, chemical HPLC 93.6%, chiral HPLC 97.2%, wherein the content of lacosamide deacetylated impurity (i.e., impurity D of the European Pharmacopoeia) was 0.7%.

[0073] 150 ml of methyl tert-butyl ether was added to the lacosamide concentrate, stirred at room temperature for 1 hour, filtered and dried to obtain lacosamide with a yield of 8.8 g and a two-step yield of 83.1%. Its chemical HPLC was 99.5%, and its chiral HPLC was 99.2%. The content of lacosamide deacetylated impurity (i.e., impurity D in the European Pharmacopoeia) was ND.

[0074] Example 5 Synthesis of Lacosamide

[0075] 10 g (0.04 mol) of the lacosamide intermediate shown in formula I and 60 g of tetrahydrofuran were added to a four-necked bottle, the temperature was controlled at 0-10 ° C, 10.9 g (0.11 mol) of sodium tert-butoxide was added, and stirring was continued for 20 minutes after the addition was completed. The temperature was controlled at 0-10 ° C, and 13.8 g (0.15 mol) of dimethyl carbonate was added dropwise. After the addition was completed, the reaction solution was slowly added dropwise to 50 ml of ice water. After the addition was completed, it was stirred for 20 minutes, the temperature was slowly raised, and the temperature was controlled to be ≤50 ° C. The tetrahydrofuran was evaporated under reduced pressure, and then 100 ml of water and 100 ml of dichloromethane were added. The layers were separated, and the water layer was extracted once with 100 ml of dichloromethane. The organic layers were combined and evaporated to dryness under reduced pressure to obtain a concentrate containing lacosamide, with a chemical HPLC of 92.9% and a chiral HPLC of 97.8%, wherein the content of lacosamide deacetylated impurities (i.e., impurity D of the European Pharmacopoeia) was 0.8%.

[0076] 150 ml of methyl tert-butyl ether was added to the lacosamide concentrate, stirred at room temperature for 1 hour, filtered and dried to obtain lacosamide with a yield of 8.4 g and a two-step yield of 79.7%. Its chemical HPLC was 99.1%, and its chiral HPLC was 99.2%. The content of lacosamide deacetylated impurity (i.e., impurity D in the European Pharmacopoeia) was ND.

[0077] Example 6 Synthesis of Lacosamide

[0078] 10g of the lacosamide intermediate shown in formula I and 60g of 2-methyltetrahydrofuran were added to a four-necked bottle, the temperature was controlled at 0-10°C, 5g (0.13mol) of sodium hydride (60% content) was added, and stirring was continued for 20 minutes after the addition was completed. The temperature was controlled at 0-10°C, and 12.8g (0.14mol) of dimethyl carbonate was added dropwise, and the addition was completed, and the reaction was continued for 6 hours. After the reaction was completed, the reaction solution was slowly added dropwise to 50ml of ice water, stirred for 20 minutes after the addition, slowly heated, and the temperature was controlled to be ≤50°C. 2-methyltetrahydrofuran was removed by distillation under reduced pressure, and then 100ml of water and 100ml of dichloromethane were added, and the layers were separated. The water layer was extracted once with 100ml of dichloromethane, and the organic layers were combined and evaporated to dryness under reduced pressure to obtain a concentrate containing lacosamide, with a chemical HPLC of 93.4% and a chiral HPLC of 97.5%, wherein the content of lacosamide deacetylated impurity (i.e., impurity D of the European Pharmacopoeia) was 0.9%.

[0079] 150 ml of methyl tert-butyl ether was added to the lacosamide concentrate, stirred at room temperature for 1 hour, filtered and dried to obtain lacosamide with a yield of 8.7 g and a two-step yield of 82.2%. Its chemical HPLC was 99.3%, and its chiral HPLC was 99.2%. The content of lacosamide deacetylated impurity (i.e., impurity D in the European Pharmacopoeia) was ND.

[0080] Comparative Example 1: Repeat Example 12 of CN106543018

[0081] At room temperature, 10 g (0.04 mol) of the lacosamide intermediate shown in formula I and 50 ml of acetonitrile were added to a four-necked bottle. Sodium hydroxide solution (2.5 g in 6 ml, 0.06 mol) was added dropwise, followed by 10.7 g (0.08 mol) of dimethyl sulfate. The reaction mixture was stirred for 1 hour and then concentrated under reduced pressure. The resulting residue was dissolved in 80 ml of dichloromethane and the solution was washed with water 40 ml*3. 0.4 g of charcoal was added to treat the organic layer and stirred for 1 hour. It was filtered and the filtrate was concentrated under reduced pressure, and the solid was evaporated to dryness, with a chemical HPLC of 88.6% and a chiral HPLC of 97.2%, wherein the content of lacosamide deacetylated impurities (i.e., impurity D of the European Pharmacopoeia) was 3.5%.

[0082] The obtained solid residue was dissolved in acetone and precipitated by adding diisopropyl ether to obtain lacosamide. Yield: 7.4 g, yield: 70.1%, chemical HPLC: 99.8%, chiral HPLC: 99.7%, wherein the content of lacosamide deacetylated impurity (i.e., impurity D of European Pharmacopoeia) was 0.09%.

Claims

1. A method for preparing lacosamide, characterized in that: The method comprises subjecting the lacosamide intermediate shown in formula I to a methylation reaction in the presence of a base and dimethyl carbonate to obtain lacosamide; 。 2. The preparation method according to claim 1, characterized in that: The base is selected from one or more of sodium hydride, sodium amide, potassium tert-butoxide, sodium tert-butoxide; preferably sodium hydride or sodium tert-butoxide.

3. The preparation method according to claim 1, characterized in that: The solvent for the methylation reaction is selected from one or more of N,N-dimethylformamide, dimethyl sulfoxide, dioxane, tetrahydrofuran or 2-methyltetrahydrofuran; preferably one or more of tetrahydrofuran, 2-methyltetrahydrofuran and N,N-dimethylformamide.

4. The preparation method according to claim 1, characterized in that: The temperature of the methylation reaction is -15 to 30°C; preferably, the reaction temperature is 0 to 10°C.

5. The preparation method according to claim 1, characterized in that: The molar ratio of the lacosamide intermediate shown in Formula I, the base and dimethyl carbonate is 1:1-10:1-10, preferably 1:2-5:3-5.

6. The preparation method according to claim 3, characterized in that: The weight ratio of the lacosamide intermediate shown in formula I to the reaction solvent is 1:4-10.

7. The preparation method according to any one of claims 1 to 6, characterized in that: After the methylation reaction is completed, the reaction mixture containing lacosamide is extracted and concentrated, and then the concentrate is added with an organic solvent for pulping and purification.

8. The preparation method according to claim 7, characterized in that: The extraction solvent is dichloromethane.

9. The preparation method according to claim 7, wherein the organic solvent is selected from one or more of methyl tert-butyl ether, methanol, ethyl acetate, and n-heptane; preferably methyl tert-butyl ether. 10 . The preparation method according to claim 7 , wherein the mass volume ratio of the lacosamide intermediate represented by formula I to the organic solvent is 1:4 to 1:25.

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