Method for preparing lacosamide

Abstract

The invention discloses a method for preparing lacosamide, the preparation method adopts a new intermediate, compared with other routes, the synthesis steps are reduced, the atom utilization rate is improved, and the method is greener and more environmentally friendly; the reaction system has the advantages of less difficult-to-treat solvent, convenient post-treatment, simple product purification, high yield and high purity, and is more beneficial to industrial application.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical pharmaceuticals, and particularly to a method for preparing lacosamide. Background Art

[0002] Lacosamide ((R)-2-acetamido-N-benzyl-3-methoxypropanamide, CAS: 175481-36-4) is a drug developed by Schwarz Biotech in Germany for the treatment of epilepsy and neuropathic pain, and is used as an adjuvant in the treatment of partial-onset seizures in patients 16 years of age and older with or without secondary generalized tonic-clonic seizures. Lacosamide is also known as lacosamide, and its mode of action is different from all other currently marketed anti-epileptic drugs. It is used to modulate sodium channel activity, while other marketed anti-epileptic drugs block sodium channels. Sodium channels play a crucial role in regulating the nervous system activity that helps nerve cell communication. Sometimes, abnormal overactivity of sodium channels can cause epileptic seizures. Therefore, the mode of action of lacosamide is considered to reduce the overactivity of sodium channels, and this regulation of nerve cell activity can control epileptic seizures. Preclinical studies also show that lacosamide binds to collapsin response mediator protein-2 (CRMP-2, a phosphoprotein mainly distributed in the nervous system that regulates neuronal differentiation and controls axonal overgrowth), and it is the only marketed anti-epileptic drug that interacts with CRMP-2.

[0003] Several synthetic methods of lacosamide have been published in the literature:

[0004] The first method was proposed by ACS Omega (2019), 4(4), 6546-6550, CN102816083B, EP1642889A1, etc. Using Boc-protected D-serine as the raw material, lacosamide is obtained through 4 steps of reaction. The yield is 107% * 94.8% * 130.9% * 58% = 77%, and the yield is relatively low.

[0005]

[0006] The second method was proposed by Bioorganic & Medicinal Chemistry (2008), 16(19), 8968-8975. Using etherified-protected D-serine as the raw material, lacosamide is obtained through 5 steps of reaction. This route is relatively niche and uses boron trifluoride diethyl ether, which is not suitable for industrialization.

[0007]

[0008] The third method was proposed by CN103319366 A. Using D-serine as the raw material, lacosamide was obtained through 5 steps of reactions. In the third step of this route, the amide was obtained by reacting the methyl ester intermediate with benzylamine. The reported yields were 133% * 128% * 100% * 56% * 96% = 91.5%, and the yield was relatively low:

[0009]

[0010] The fourth method was proposed by CN104710324A. Using L-cystine dimethyl ester dihydrochloride as the raw material, lacosamide was obtained through 4 steps of reactions. The raw materials in this process are rare, and chlorine gas is used, which is not suitable for industrialization:

[0011]

[0012] The fifth method was proposed by CN106866456A. Using glycidol as the raw material, lacosamide was obtained through 5 steps of reactions. The route is relatively long and azide compounds are used, which is not conducive to industrial production:

[0013]

[0014] The sixth method was proposed by CN110950770A. Using ethyl acetoacetate as the raw material, lacosamide was obtained through 4 steps of reactions. This route uses a noble metal catalyst to react with azide compounds, which is not conducive to industrialization:

[0015]

[0016] The seventh method was proposed by CN112574058A. Using ethyl 2-aminoacetate hydrochloride as the raw material, lacosamide was obtained through 6 steps of reactions. This route requires resolution and has a low yield, which is not suitable for industrialization:

[0017]

[0018] In summary, the main problems existing in the existing methods for preparing lacosamide are that the optical purity of lacosamide fails to meet the requirements and the yield is low. SUMMARY OF THE INVENTION

[0019] The present invention provides a method for preparing lacosamide, which is used to solve the defects of low purity and low yield of the product obtained by the existing methods for preparing lacosamide.

[0020] In view of this, the solution of the present invention is as follows:

[0021] A method for preparing lacosamide, the steps include:

[0022] S1. Adding a base and a methyl etherification reagent to an N-Boc-D-serine solution, and heating the reaction to obtain compound 1;

[0023] S2. Compound 1 reacts with ammonia water under sealed and pressurized conditions to obtain Compound 2;

[0024] S3. Compound 2 reacts with benzyl chloride to obtain Compound 3;

[0025] S4. Compound 3 removes Boc under acidic conditions to obtain Compound 4;

[0026] S5. Compound 4 undergoes an acetylation reaction to obtain lacosamide;

[0027] The reaction process route is as follows:

[0028]

[0029] Furthermore, in step S1, the base is an inorganic base; and / or, the methyl etherification reagent is dimethyl sulfate or methyl iodide.

[0030] Preferably, the molar dosage of the base is 4 - 4.5 times that of N - Boc - D - serine; the molar dosage of the methyl etherification reagent is 2.5 - 3.5 times that of N - Boc - D - serine.

[0031] Furthermore, in step S1, the temperature of the reaction is 20 - 40 °C; preferably 30 - 40 °C.

[0032] Furthermore, in step S2, the concentration of the ammonia water is 28%, and the dosage is 2 - 3 times the mass of N - Boc - D - serine; and / or, the pressurized condition is 0.3 - 0.5 MPa.

[0033] Furthermore, in step S2, the temperature of the reaction is 10 - 20 °C; preferably 13 - 16 °C.

[0034] Furthermore, in step S3, the molar dosage of the benzyl chloride is 1.05 - 1.1 times that of Compound 2; and / or, the temperature of the reaction is 0 - 20 °C, preferably 5 - 10 °C.

[0035] Furthermore, in step S4, the acidic condition is obtained by adding hydrochloric acid, sulfuric acid or aqueous glacial acetic acid to the system; and / or, the temperature of the reaction is 10 - 30 °C, preferably 15 - 20 °C.

[0036] Furthermore, in step S5, the temperature of the reaction is 0 - 15 °C, preferably 5 - 10 °C.

[0037] Furthermore, in step S5, the reagent used for the acetylation reaction is glacial acetic acid or acetic anhydride.

[0038] Compared with the prior art, the present invention has the following beneficial effects:

[0039] The preparation method of the present invention uses a new intermediate, which reduces the synthesis steps, improves the atom utilization rate, and is more green and environmentally friendly compared with other routes; there are fewer difficult-to-treat solvents in the reaction system, the post-treatment is convenient, the product purification is simple, the yield is high, and the purity is high, which is more conducive to industrial application.

[0040] The preparation method of the present invention avoids using volatile, flammable and explosive, water-unstable mixed anhydride reagents (such as ethyl chloroformate, isobutyl chloroformate) and catalysts with obvious pungent odors, flammable and explosive (such as N-methylmorpholine); during the amine-ester exchange process, the methyl ester is easier to exchange with ammonia water, and compared with acid-amine condensation and other ester exchanges, the generation of side reactions is reduced, and the reaction yield is improved. Detailed implementation manners

[0041] The technical solutions of the present invention will be clearly and completely described below in conjunction with the preferred embodiments. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. All other embodiments obtained by those of ordinary skill in the art based on the embodiments of the present invention without creative efforts shall fall within the protection scope of the present invention.

[0042] Example 1

[0043] 1) Take 10 g of N-Boc-D-serine, dissolve it in 50 ml of dichloromethane, add 19.14 g of 50% potassium hydroxide solution and 18.44 g of dimethyl sulfate, react at 40 °C for 8 h. After the reaction is completed, add 30 ml of concentrated hydrochloric acid, stir evenly, separate the aqueous layer, wash the organic layer twice with 30 ml of saturated brine, dry it with anhydrous magnesium sulfate, distill off the solvent under negative pressure, add 20 ml of methyl tert-butyl ether, stir evenly, cool down to crystallize, filter, and dry to obtain Compound 1, 11.03 g of off-white solid, yield 97.03%, HPLC purity 98.671%.

[0044] 2) Take 10 g of the above Compound 1 solid, add 20 ml of methanol, control the temperature at 15 °C, stir evenly, add 25 g of 28% ammonia water. After adding, pressurize to 0.5 MPa and react for 3 h. After the reaction is completed, adjust the pH to 6-7 with 10% dilute hydrochloric acid, add 40 ml of water, filter, wash, and dry the filter cake to obtain Compound 2, 9.18 g of off-white solid, yield 98.11%, HPLC purity 99.022%.

[0045] 3) Take 9 g of the above Compound 2 solid, add 18 ml of methanol, stir evenly, cool down to 8 °C, add 5.5 g of benzyl chloride, control the temperature at 8 °C and react for 5 h. After the reaction is completed, add 54 ml of water, stir for 1 h, filter, wash the filter cake and dry to obtain Compound 3, 12.46 g of off-white solid, yield 97.98%, HPLC purity 99.356%.

[0046] 4) Take 10 g of the above-mentioned solid compound 3, add 60 ml of dichloromethane, stir evenly, adjust the pH to 1 - 2 with 30% dilute hydrochloric acid, stir for 1 h, adjust the pH to 7 - 8 with 30% sodium hydroxide solution, stir for 0.5 h, let stand, separate the aqueous layer, wash the organic layer twice with 36 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under negative pressure, stop concentration when the volume is reduced to 0.5 times, cool down for crystallization for 1 h, filter, and dry to obtain compound 4, 6.24 g of off-white solid, yield 92.4%, HPLC purity 99.103%.

[0047] 5) Take 5 g of the above-mentioned solid compound 4, add 20 ml of dichloromethane, stir evenly, cool down to 8 °C, add 2.9 g of triethylamine and 2.5 g of acetic anhydride, keep the temperature for reaction for 6 h, wash twice with 20 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent during the reaction, stop concentration when the volume is reduced to 0.5 times, cool down for crystallization for 1 h, filter, and dry to obtain 5.54 g of off-white solid, that is, lacosamide, yield 92.19%, HPLC purity 99.552%.

[0048] Example 2

[0049] 1) Take 10 g of N-Boc-D-serine, dissolve it in 50 ml of dichloromethane, add 18.26 g of 50% potassium hydroxide solution and 18.44 g of dimethyl sulfate, react at 25 °C for 11 h. After the reaction is completed, add 30 ml of concentrated hydrochloric acid, stir evenly, separate the aqueous layer, wash the organic layer twice with 30 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under negative pressure, add 20 ml of methyl tert-butyl ether, stir evenly, cool down for crystallization, filter, and dry to obtain compound 1, 10.91 g of off-white solid, yield 95.97%, HPLC purity 98.767%.

[0050] 2) Take 10 g of the above-mentioned solid compound 1, add 20 ml of methanol, control the temperature at 10 °C, stir evenly, add 27 g of 28% ammonia water. After adding, pressurize to 0.4 MPa and react for 4 h. After the reaction is completed, adjust the pH to 6 - 7 with 10% dilute hydrochloric acid, add 40 ml of water, filter, wash, and dry the filter cake to obtain compound 2, 9.25 g of off-white solid, yield 98.86%, HPLC purity 99.015%.

[0051] 3) Take 9 g of the above-mentioned solid compound 2, add 18 ml of methanol, stir evenly, cool down to 5 °C, add 5.5 g of benzyl chloride, control the temperature at 5 °C and react for 6 h. After the reaction is completed, add 54 ml of water, stir for 1 h, filter, wash the filter cake and dry to obtain compound 3, 12.61 g of off-white solid, yield 99.16%, HPLC purity 98.266%.

[0052] 4) Take 10 g of the above-mentioned solid compound 3, add 60 ml of dichloromethane, stir evenly, adjust the pH to 1 - 2 with 30% dilute sulfuric acid, stir for 1 h, adjust the pH to 7 - 8 with 30% sodium hydroxide solution, stir for 0.5 h, let it stand, separate the aqueous layer, wash the organic layer twice with 36 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under negative pressure, stop concentration when the volume remains 0.5 times, cool down for crystallization for 1 h, filter, and dry to obtain compound 4, 6.33 g of off-white solid, yield 93.73%, HPLC purity 99.413%.

[0053] 5) Take 5 g of the above-mentioned solid compound 4, add 20 ml of dichloromethane, stir evenly, cool down to 5 °C, add 2.9 g of triethylamine and 2.5 g of acetic anhydride, keep the temperature for reaction for 7 h, wash twice with 20 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent during the reaction, stop concentration when the volume remains 0.5 times, cool down for crystallization for 1 h, filter, and dry to obtain 5.49 g of off-white solid, namely lacosamide, yield 91.36%, HPLC purity 99.713%.

[0054] Example 3

[0055] 1) Take 100 g of N-Boc-D-serine, add it to 500 ml of dichloromethane for dissolution, add 175 g of 50% potassium hydroxide solution and 158 g of dimethyl sulfate, react at 35 °C for 10 h. After the reaction is completed, add 300 ml of concentrated hydrochloric acid, stir evenly, separate the aqueous layer, wash the organic layer twice with 30 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under negative pressure, add 20 ml of methyl tert-butyl ether, stir evenly, cool down for crystallization, filter, and dry to obtain compound 1, 110.96 g of off-white solid, yield 97.61%, HPLC purity 99.211%.

[0056] 2) Take 100 g of the above-mentioned solid compound 1, add 200 ml of methanol, control the temperature at 12 °C, stir evenly, add 260 g of 28% ammonia water. After adding, pressurize to 0.5 MPa for reaction for 3 h. After the reaction is completed, adjust the pH to 6 - 7 with 10% dilute hydrochloric acid, add 40 ml of water, filter, wash, and dry the filter cake to obtain compound 2, 92.61 g of off-white solid, yield 98.98%, HPLC purity 99.136%.

[0057] 3) Take 90 g of the above-mentioned solid compound 2, add 180 ml of methanol, stir evenly, cool down to 10 °C, add 55 g of benzyl chloride, control the temperature at 10 °C for reaction for 4 h. After the reaction is completed, add 540 ml of water, stir for 1 h, filter, wash the filter cake and then dry to obtain compound 3, 125.93 g of off-white solid, yield 99.02%, HPLC purity 98.832%.

[0058] 4) Take 100 g of the above-mentioned solid compound 3, add 500 ml of dichloromethane, stir evenly, add 30% dilute hydrochloric acid to adjust the pH to 1 - 2, stir for 1 h, use 30% sodium hydroxide solution to adjust the pH to 7 - 8, stir for 0.5 h, let stand, separate the aqueous layer, wash the organic layer twice with 200 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent under negative pressure, stop concentration when the remaining volume is 0.5 times the original volume, cool down for crystallization for 1 h, filter, and dry to obtain 63.54 g of compound 4 as a pale white solid, with a yield of 94.08% and an HPLC purity of 99.532%.

[0059] 5) Take 50 g of the above-mentioned solid compound 4, add 200 ml of dichloromethane, stir evenly, cool down to 5 - 10 °C, add 30 g of triethylamine and 25 g of acetic anhydride, keep the temperature for reaction for 5 - 7 h, wash twice with 50 ml of saturated brine, dry with anhydrous magnesium sulfate, distill off the solvent during the reaction, stop concentration when the remaining volume is 0.5 times the original volume, cool down for crystallization for 1 h, filter, and dry to obtain 56.32 g of a pale white solid, namely lacosamide, with a yield of 93.72% and an HPLC purity of 99.883%.

[0060] Comparative Example 1

[0061] This comparative example was carried out with reference to ACS Omega (2019), 4(4), 6546 - 6550, and the specific steps are as follows:

[0062] 1) Take 100 g of N - Boc - D - serine, dissolve it in 50 ml of dichloromethane, add 5.2 g of tetrabutylammonium bromide and 500 ml of toluene, stir, cool down to 0 - 10 °C, control the temperature at 0 - 10 °C and add 97.5 g of 20% sodium hydroxide solution, stir for 0.5 h; control the temperature at - 5 - 5 °C and add 246 g of dimethyl sulfate and 179.5 g of 50% sodium hydroxide solution, stir for 12 h, add 300 ml of water, adjust the pH of the aqueous layer to < 3.5 with 50% citric acid, extract twice with 500 ml of dichloromethane, combine the organic layers, and obtain 106.45 g of a pale white solid after evaporating the organic layer to dryness, with a yield of 99.64% and an HPLC purity of 92.421%.

[0063] 2) Dissolve the solid obtained in step 1) in 800 ml of dichloromethane, cool down to - 10 - 0 °C, add 66.6 g of isobutyl chloroformate and 78.9 g of N - methylmorpholine, stir at - 10 - - 5 °C for 0.5 h, add 53.8 g of benzylamine, warm up to 10 - 15 °C and react for 2 h, wash successively with 200 ml of water, 200 ml of 1N hydrochloric acid, 200 ml of 8% sodium bicarbonate solution, and 200 ml of water to obtain a yellow solution.

[0064] 3) Cool the yellow solution in step 2) to 0 - 10 °C, add 245 g of concentrated hydrochloric acid, stir for 2 h, add 300 ml of water, separate the layers, collect the aqueous layer, extract the organic layer once with 100 ml of water, combine the aqueous layers, adjust the pH of the aqueous layer to 10 - 12 with 40% sodium hydroxide solution at 25 - 35 °C, extract twice with 500 ml of dichloromethane, combine the organic layers, wash the organic layer with 200 ml of water, evaporate the organic layer to dryness to obtain 98.13 g of a white solid, with a yield of 97.04% and an HPLC purity of 94.832%.

[0065] 4) Dissolve the solid in step 3) in 1000 ml of dichloromethane, cool to 0 - 5 °C, add 56 g of 85% phosphoric acid, stir for 2 h, filter, wash the filter cake with 500 ml of dichloromethane, and dry to obtain 127.3 g of a white solid, with a yield of 88.21% and an HPLC purity of 98.603%.

[0066] 5) Mix the solid in step 4), 260 ml of water and 1060 ml of dichloromethane, add 54.4 g of sodium bicarbonate, cool to 0 - 5 °C, slowly add 44.4 g of acetic anhydride, stir at 20 - 25 °C for 3 h, separate the layers, wash the organic layer successively with 260 ml of 8% sodium bicarbonate solution and 260 ml of water, evaporate to dryness to obtain the crude product; add 500 ml of ethyl acetate to the crude product, heat to reflux, stir until clear, cool the temperature programatically to 0 °C, stir at 0 °C for 2 h, filter, and dry to obtain 72.96 g of lacosamide, with a yield of 70.13% and an HPLC purity of 99.533%.

[0067] Comparative Example 2

[0068] The difference between this comparative example and Example 1 is that steps 2) and 3) are combined into one step, that is, take 10 g of solid compound 1, add 20 ml of methanol, then control the temperature at -5 - 0 °C and dropwise add 1.1 times the molar equivalent of benzylamine to react fully, wash successively with 200 ml of water, 200 ml of 1N hydrochloric acid, 200 ml of 8% sodium bicarbonate solution and 200 ml of water, filter, and wash and dry the filter cake to obtain compound 3, 10.37 g of a white solid, with a yield of 82.41% and an HPLC purity of 98.158%.

[0069] It can be easily seen from the above results that the yields of the intermediate products obtained in Examples 1-3 are all relatively high, and the total yield can reach over 80%. This avoids the use of volatile, flammable, explosive, and water-unstable mixed anhydride reagents (such as ethyl chloroformate and isobutyl chloroformate) as well as catalysts with obvious pungent odors, flammability, and explosiveness. Moreover, the purification process for each step is simple, making it suitable for industrial production. Comparative Example 1 has a similar route to this solution. However, since isobutyl chloroformate and N-methylmorpholine are used as mixed anhydride reagents in the synthesis process, by-products will be generated. Subsequently, the product is purified by forming a salt with phosphoric acid, resulting in a low yield, low atom utilization rate, and a large amount of waste. In Comparative Example 2, compound 1 directly reacts with benzylamine. Without the activation of a mixed anhydride reagent, the yield significantly decreases. The above shows that the stepwise reaction in the amine-ester exchange process of this solution has obvious advantages.

[0070] Although the embodiments of the present invention have been shown and described, it will be understood by those of ordinary skill in the art that various changes, modifications, substitutions, and variations can be made to these embodiments without departing from the principles and spirit of the present invention. The scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing lacosamide, characterized in that the steps include: S1. Add a base and a methyl etherification agent to the N-Boc-D-serine solution, and heat the reaction to obtain compound 1; S2. Compound 1 reacts with aqueous ammonia under sealed and pressurized conditions to obtain compound 2; S3. Compound 2 reacts with benzyl chloride to obtain compound 3; S4. Compound 3 is subjected to Boc removal under acidic conditions to obtain compound 4; S5. Compound 4 is acetylated to obtain lacosamide; The reaction process route is as follows: 。 2. The method for preparing lacosamide according to claim 1, characterized in that: In step S1, the base is an inorganic base; and / or the methyl etherification agent is dimethyl sulfate or methyl iodide.

3. The method for preparing lacosamide according to claim 2, characterized in that: The molar amount of the base is 4-4.5 times that of N-Boc-D-serine; the molar amount of the methyl etherification agent is 2.5-3.5 times that of N-Boc-D-serine.

4. The method for preparing lacosamide according to claim 1, characterized in that: In step S1, the reaction temperature is 20-40°C.

5. The method for preparing lacosamide according to claim 1, characterized in that: In step S2, the concentration of the aqueous ammonia is 28%, and the amount used is 2-3 times the mass of N-Boc-D-serine; And / or, the pressurization condition is 0.3~0.5MPa.

6. The method for preparing lacosamide according to claim 1, characterized in that: In step S2, the reaction temperature is 10-20°C.

7. The method for preparing lacosamide according to claim 1, characterized in that: In step S3, the molar amount of benzyl chloride is 1.05-1.1 times that of compound 2; and / or, the reaction temperature is 0-20°C.

8. The method for preparing lacosamide according to claim 1, characterized in that: In step S4, the acidic condition is obtained by adding hydrochloric acid, sulfuric acid or glacial acetic acid aqueous solution to the system; and / or the reaction temperature is 10-30°C.

9. The method for preparing lacosamide according to claim 1, characterized in that: In step S5, the reaction temperature is 0-15°C.

10. The method for preparing lacosamide according to claim 1, characterized in that: In step S5, the reagent used in the acetylation reaction is glacial acetic acid or acetic anhydride.

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