Preparation method of lacosamide

Abstract

The invention discloses a preparation method of an anti-epileptic drug lacosamide, and belongs to the field of organic synthesis. According to the preparation method, S-epoxy propionic acid and benzylamine are taken as starting materials, and lacosamide is prepared through four steps of dehydration condensation, ring-opening substitution, amidation and methylation reaction. The method is simple in route, the same solvent is used from the first step to the last step, the steps are simple, post-treatment is convenient, impurities are few, the method is suitable for industrial production, in addition, in the ring opening process of the epoxy raw material, generation of isomers is avoided, material waste is reduced, atom economy is improved, and the market competitiveness of the technology is improved.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and specifically relates to a method for synthesizing a drug for treating epilepsy and neuropathic pain, in particular to a method for preparing (R)-2-acetamido-N-benzyl-3-methoxypropionamide (lacosamide). Background Art

[0002] Lacosamide is a drug developed by Schwarz BioSciences of Germany for the treatment of epilepsy and neuropathic pain. Lacosamide is a new NMDA receptor glycine site binding antagonist and an anticonvulsant with a new dual mechanism of action. Compared with other anti-epileptic drugs, lacosamide has the ability to regulate the activity of sodium ion channels. Sodium ion channels play a very important role in regulating the activity of the nervous system and promoting conduction between nerve cells. Therefore, epilepsy can be treated by reducing the excessive activity of sodium ion channels and controlling the activity of nerve cells.

[0003] In September 2008, the European Union approved UCB's lacosamide for the adjunctive treatment of partial seizures in patients aged 16 years and above with or without secondary grand mal seizures. In October 2008, the U.S. FDA approved lacosamide as an adjunctive drug in combination with other drugs for partial seizures. Schwarz is confident that lacosamide, a new dual-mode drug, will become a leader among competing anti-epileptic drug products such as Keppra's levetiracetam and Pfizer's gabapentin, and will help patients who have not responded to existing drugs.

[0004] Using D-serine as the starting material, the amino group is protected with benzyl chloroformate, and then methyl iodide is used as a methylating agent to perform O-methylation under the catalysis of silver oxide, and the carboxyl group undergoes esterification to obtain intermediate 4. 4 is hydrolyzed under alkaline conditions and then acidified and condensed with benzylamine through a mixed acid anhydride method to obtain 6. The benzyloxycarbonyl protecting group is hydrogenated and removed by palladium-carbon catalysis to obtain 7, which is then reacted with acetic anhydride through the catalysis of 4-dimethylaminopyridine (DMAP) to obtain lacosamide 1, with a total yield of 42%. The disadvantages of this method are that there are many reaction steps, the catalyst silver oxide and the methylating agent methyl iodide are expensive, the toxicity of methyl iodide is strong, extremely low temperature is required for condensation, it is not easy to operate and the post-processing is cumbersome, about 15% of the intermediates are racemized, the removal of the S-enantiomer is difficult, the deamination protection is carried out by palladium-carbon reduction, the production cost is high, and the atomic utilization rate is low.

[0005]

[0006] Methyl acrylate (8) is used as a raw material and bromine is added to obtain methyl 2,3-dibromopropionate, which is then methoxylated under the action of sodium methoxide, hydrolyzed under alkaline conditions, and in the presence of N-methylmorpholine, 3-methoxy-2-bromopropionic acid 11 reacts with isobutyl chloroformate to generate a mixed anhydride, which is then condensed with benzylamine to obtain 12, which is then reacted with ammonia to generate N-benzyl-2-amino-3-methoxypropionamide, and then chemically resolved or chirally resolved to obtain lacosamide. This route produces a lot of impurities and a low yield. The chemical resolution yield is less than 30%, and the separation rate is low after separation on a chiral chromatographic column. It is also not suitable for industrial production. In addition, liquid bromine is used in this method, which is a toxic and harmful substance and is very easy to be allergic.

[0007]

[0008] Benzyl alcohol and epichlorohydrin were used as raw materials to react to generate benzyl glycerol glycidyl ether (17), which was then subjected to stereoselective asymmetric resolution with (R,R)-SalenCo(Ⅲ) catalyst to obtain 18 and 19. 18 was selectively ring-opened under alkaline conditions and reacted with methanol to generate 20, which was then reacted with diphenylphosphoryl azide (DPPA) under Mitsunobu conditions to generate 21, which was then protected by Boc to generate 22, which was then catalytically oxidized to generate compound 23, which was further reacted with benzylamine to generate compound 24, and finally deprotected and reacted with acetyl chloride to generate 1. The reaction process is relatively novel, but the reaction steps are long and complicated. At the same time, due to the hydrolysis of the intermediate product, more than half of the product is lost. Considering the atom economy, the process lacks market competitiveness.

[0009]

[0010] Using 2-vinyl oxirane and phthalimide as raw materials, after 5 steps of reaction, (R,R)-DACH and [η 3 -C3H5PdCl]2 to obtain (26), and then 26 reacts with methyl iodide to obtain (27), 27 is oxidized with osmium tetroxide and sodium perchlorate to obtain (28), 28 is amidated with benzylamine to obtain (29), 29 reacts with hydrazine hydrate to remove phthalic acid and then acetylated with acetyl chloride to obtain lacosamide 1, with a total yield of 52%. The reaction process produces a lot of impurities, the operation steps are complicated, the raw materials used are expensive, osmium tetroxide and sodium perchlorate are expensive, methyl iodide and hydrazine hydrate are highly toxic, and the post-treatment is difficult, which is not suitable for industrial production.

[0011]

[0012] Epoxymethanol is used as a raw material, and after being treated with a methylating agent, compound 31 is obtained. 31 is heated under reflux under strong acid conditions to open the ring to obtain compound 32, which is then reacted with isobutyl chloroformate to generate a mixed anhydride, which is then condensed with benzylamine to obtain 33. Compound 33 and diphenylphosphoryl azide (DPPA) are catalyzed by the catalyst 8-diazabicycloundec-7-ene to undergo azidation, and finally methylchlorosilane is added to heat under reflux and amidate with the anhydride to obtain lacosamide, a total of 5 steps. The diphenylphosphoryl azide used in this reaction process is relatively expensive, which makes the cost of lacosamide relatively high, and the azide is unstable and explosive, and the safety risks of production and storage are relatively high. In addition, the reaction is carried out under reflux conditions, which is highly dangerous and not suitable for non-industrial production.

[0013] Summary of the invention

[0014] Technical problem solved: The present invention solves the problems of long and complicated reaction steps, many impurities, cumbersome operation and expensive raw materials used in the prior art preparation of lacosamide.

[0015] Technical conception: Based on the analysis of the existing problems of the prior art, the experimenters used S-epoxypropionic acid, which is simpler and more readily available, as the starting material in order to reduce the types of solvents used, reduce the danger of solvent reflux, and reduce the use of explosive azides. Lacosamide was finally prepared through a series of reactions. The post-processing was a simple conventional operation, which not only reduced energy consumption, but also brought safety and convenience to the production, making it more suitable for industrial production. The specific plan is as follows: The first step: using S-epoxypropionic acid and benzylamine as starting materials, a dehydration condensation reaction occurs under the condition of a dehydrating agent; Step 2: introducing ammonia gas into the reaction solution obtained in the first step to generate (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide by ring-opening substitution; Step 3: Add acetic anhydride to the reaction solution obtained in step 2 to carry out acylation reaction; Step 4: The reaction solution obtained in step 3 is subjected to a methylation reaction under alkaline conditions to obtain lacosamide In the first step, dichloromethane is used as solvent, and starting materials S-epoxypropionic acid and benzylamine are added, and a dehydrating agent is reacted at below 25° C. After the reaction is completed, an organic phase is taken.

[0016] The further dehydrating agent is EDC or DCC or its corresponding hydrochloride.

[0017] Furthermore, when the dehydrating agent is the corresponding hydrochloride, an organic base reagent can also be added to the dehydration condensation reaction.

[0018] Furthermore, the organic base reagent is any one of triethylamine, diisopropylethylamine, pyridine or N-methylmorpholine.

[0019] After the second step ring-opening substitution reaction is completed under the condition of controlling the temperature below 25° C., the mixture is allowed to stand and the organic phase is collected.

[0020] In the third step, the temperature is controlled below 30° C. and acetic anhydride is added dropwise to cause an acylation reaction. After the reaction is completed, the reaction is filtered to remove the organic phase.

[0021] Furthermore, the base added in the third step is an inorganic base, any one of sodium hydroxide, potassium hydroxide or sodium bicarbonate.

[0022] Furthermore, in the fourth step of the methylation reaction, the methylation reagent is added dropwise at low temperature under controlled temperature. After the reaction is completed, ammonia water and water are added, stirred and allowed to stand, and the liquids are separated to retain the dichloromethane layer.

[0023] Furthermore, the base added in the fourth step is an inorganic base, any one of sodium hydroxide, potassium hydroxide or sodium bicarbonate.

[0024] The low temperature in the fourth step is further controlled to be below 0°C.

[0025] Furthermore, the crude product obtained in the fourth step is heated to reflux with ethyl acetate, then cooled to precipitate a solid, filtered and dried.

[0026] Technical effect: The technical solution of the present invention has the following technical advantages compared with the prior art: The present invention provides a novel preparation route, in which the same solvent is used from the first step to the last step, the steps are simple, and the post-treatment is convenient. Compared with the prior art, the yield has made great progress, the yield has reached more than 78%, and the chiral purity has reached 99.9% and above.

[0027] The raw materials used are cheap and are all commonly used reagents, which reduces material costs, improves economic applicability, and is suitable for industrial production.

[0028] The ring-opening process of epoxy raw materials avoids the formation of isomers, reduces material waste, improves atom economy, and enhances the market competitiveness of the process. Specific embodiments Example 1

[0029] Synthesis of (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide At room temperature, add 1000 mL of dichloromethane, 50.0 g of S-epoxypropionic acid, 96.67 g of EDC hydrochloride, 51.03 g of triethylamine and 51.46 g of benzylamine to a 2L reaction bottle, and react at 20°C for 5 hours. After the reaction is completed, add 200 mL of water to the system, let it stand, separate the liquids, retain the dichloromethane phase, and wash it once with 200 mL of water. Keep the dichloromethane phase in the 2000 mL reaction bottle. Control the temperature at 20°C and add 68.0 g of ammonia water to the dichloromethane phase. Stir the reaction for 6 hours, separate the liquids, and keep the dichloromethane phase in the 2L reaction bottle.

[0030] Synthesis of Lacosamide Add 30.54g sodium carbonate to the dichloromethane solution in the previous step, and add 49.03g acetic anhydride at 30℃. After addition, keep warm for 1h and filter. Rinse the filter cake with 100mL dichloromethane and combine the filtrate in a 2L reaction bottle. Cool the system to below 0℃ and add 35.03g KOH to the system. Stir and cool to -15℃, add 72.69g dimethyl sulfate dropwise, add, keep warm at -15℃ for 10h, and monitor the reaction of the raw materials by HPLC. Add 50g ammonia water and 200mL water to the system, stir and heat to 10~20℃, let stand, separate the liquids, and retain the dichloromethane layer. Wash once with 100mL water. The dichloromethane layer was evaporated under reduced pressure in a 2000 mL reaction bottle, and 900 mL of ethyl acetate was added, heated to reflux to dissolve, cooled to 10-15°C and kept warm for 1 h, filtered, and dried to obtain 93.76 g of lacosamide with a yield of 78% and a purity of 99.90%. Example 2

[0031] Synthesis of (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide At room temperature, add 1000 mL of dichloromethane, 50.0 g of S-epoxypropionic acid, 104.05 g of DCC, and 51.46 g of benzylamine to a 2L reaction bottle, react at 25°C for 7 hours, filter, and keep the dichloromethane phase in a 2000 mL reaction bottle. Control the temperature at 25°C, add 70.0 g of ammonia water to the dichloromethane phase, stir and react for 7 hours, separate the liquids, and keep the dichloromethane phase in the 2L reaction bottle.

[0032] Synthesis of Lacosamide Add 39.83 g potassium carbonate to the dichloromethane solution in the previous step, and add 49.03 g acetic anhydride at 20°C. After addition, keep warm for 1h and filter. Rinse the filter cake with 100 mL of dichloromethane, combine the filtrate and put it in a 2L reaction bottle. Cool the system to below 0°C and add 36.38 g KOH to the system. Stir and cool to -10°C, add 75.72 g dimethyl sulfate dropwise, add, keep warm at -10°C for 8h, and monitor the reaction of the raw materials by HPLC. Add 60 g ammonia water and 200 mL water to the system, stir and heat to 10~20°C, let stand, separate the liquids, and retain the dichloromethane layer. Wash once with 100 mL of water. The dichloromethane layer was evaporated under reduced pressure in a 2000 mL reaction bottle, and 800 mL of ethyl acetate was added, heated to reflux to dissolve, cooled to 10-15°C and kept warm for 1 h, filtered, and dried to obtain 97.37 g of lacosamide with a yield of 81% and a purity of 99.86%. Example 3

[0033] Synthesis of (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide At room temperature, add 1000mL of dichloromethane, 50.0g of S-epoxypropionic acid, 109.00g of DCC, and 53.01g of benzylamine to a 2L reaction bottle. React at 25℃ for 8h. Filter and keep the dichloromethane phase in a 2000mL reaction bottle. Control the temperature at 25℃, add 72.0g of ammonia water to the dichloromethane phase, stir and react for 7h, and separate the liquids. Keep the dichloromethane phase in the 2L reaction bottle.

[0034] Synthesis of Lacosamide Add 48.42 g of sodium bicarbonate to the dichloromethane solution in the previous step, and add 51.48 g of acetic anhydride at 20°C. After addition, keep warm for 2h and filter. Rinse the filter cake with 100 mL of dichloromethane, combine the filtrate and put it in a 2L reaction bottle. Cool the system to below 0°C and add 25.94 g of NaOH to the system. Stir and cool to -10°C, add 78.75 g of dimethyl sulfate dropwise, add, keep warm at -10°C for 9h, and monitor the reaction of the raw materials by HPLC. Add 65 g of ammonia water and 200 mL of water to the system, stir and heat to 10~20°C, let stand, separate the liquids, and retain the dichloromethane layer. Wash once with 100 mL of water. The dichloromethane layer was evaporated under reduced pressure in a 2000 mL reaction bottle, and 800 mL of ethyl acetate was added, heated to reflux to dissolve, cooled to 10-15°C and kept warm for 1 h, filtered, and dried to obtain 96.17 g of lacosamide with a yield of 80% and a purity of 99.88%. Example 4

[0035] Synthesis of (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide At room temperature, add 1000 mL of dichloromethane, 50.0 g of S-epoxypropionic acid, 94.83 g of EDC hydrochloride, 68.28 g of diisopropylethylamine and 52.49 g of benzylamine to a 2L reaction bottle, and react at 25°C for 6 hours. After the reaction is completed, add 200 mL of water to the system, separate the liquids, retain the dichloromethane phase, and wash it once with 200 mL of water. Keep the dichloromethane phase in the 2000 mL reaction bottle. Control the temperature at 20°C, add 69.0 g of ammonia water to the dichloromethane phase, stir and react for 6 hours, and separate the liquids. Keep the dichloromethane phase in the 2L reaction bottle.

[0036] Synthesis of Lacosamide Add 28.85g potassium bicarbonate to the dichloromethane solution in the previous step, and add 51.97g acetic anhydride at 25℃. After addition, keep warm for 1h and filter. Rinse the filter cake with 100mL dichloromethane, combine the filtrate and put it in a 2L reaction bottle. Cool the system to below 0℃ and add 25.94g NaOH to the system. Stir and cool to -15℃, add 75.72g dimethyl sulfate dropwise, add, keep warm at -15℃ for 12h, and monitor the reaction of the raw materials by HPLC. Add 55g ammonia water and 200mL water to the system, stir and heat to 10~20℃, let stand, separate the liquids, and retain the dichloromethane layer. Wash once with 100mL water. The dichloromethane layer was evaporated under reduced pressure in a 2000 mL reaction bottle, and then 900 mL of ethyl acetate was added, heated to reflux to dissolve, cooled to 5-10°C and kept warm for 1 h, filtered, and dried to obtain 94.96 g of lacosamide with a yield of 79% and a purity of 99.85%.

Claims

1. A method for preparing the anti-epileptic drug lacosamide, characterized in that The following steps are involved: The first step: using S-epoxypropionic acid and benzylamine as starting materials, a dehydration condensation reaction occurs under the condition of a dehydrating agent; Step 2: introducing ammonia gas into the reaction solution obtained in the first step to generate (2R)-2-amino-3-hydroxy-N-(benzyl)-propionamide by ring-opening substitution; Step 3: Add acetic anhydride to the reaction solution obtained in step 2 to carry out acylation reaction; Step 4: The reaction solution obtained in step 3 is subjected to a methylation reaction under alkaline conditions to obtain lacosamide 。 2. The preparation method according to claim 1, characterized in that The specific steps described are: Step 1: using dichloromethane as solvent, adding starting materials S-epoxypropionic acid and benzylamine, and a dehydrating agent to react at below 25°C, and after the reaction is completed, taking the organic phase; Step 2: After the ring-opening substitution reaction is completed under the condition of controlling the temperature below 25°C, let it stand and take the organic phase; Step 3: Control the temperature below 30°C and add acetic anhydride to cause acylation reaction. After the reaction is completed, filter and take the organic phase; Step 4: During the methylation reaction, the methylation reagent is added dropwise at a controlled low temperature. After the reaction is completed, ammonia water and water are added, stirred and allowed to stand, and the liquids are separated, retaining the dichloromethane layer.

3. The preparation method according to any one of claims 1 or 2, characterized in that The dehydrating agent is EDC or DCC or its corresponding hydrochloride.

4. The preparation method according to claim 3, characterized in that When the first step dehydrating agent is the corresponding hydrochloride, an organic base reagent may also be added to the dehydration condensation reaction.

5. The preparation method according to claim 4, characterized in that The organic base reagent in the first step is triethylamine or diisopropylethylamine.

6. The preparation method according to any one of claims 1 or 2, characterized in that The fourth step methylation reaction is carried out under low temperature conditions.

7. The preparation method according to claim 6, characterized in that The low temperature is below -10°C.

8. The preparation method according to any one of claims 1 or 2, characterized in that The base added in the fourth step is an inorganic base.

9. The preparation method according to any one of claim 7, characterized in that The inorganic base added in the fourth step is KOH or NaOH.

10. The preparation method according to any one of claims 1 or 2, characterized in that The lacosamide obtained in the fourth step is further recrystallized from ethyl acetate.

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