A preparation method of lasmiditan

Abstract

The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a preparation method of lasmiditan. The method for preparing lasmiditan according to the present invention includes: under the protection of an inert gas, adding a catalyst, a ligand, a base, and a solvent A into a closed device, controlling the temperature for reaction. After the reaction is completed, the reaction solution is cooled to room temperature, and compound SM-1 and compound SM-2 are added, and the temperature is raised for reaction. After the reaction ends, compound I is obtained through post-treatment. The preparation process route is simple, the obtained compound has high purity and high yield, and it is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and particularly relates to a preparation method of lasmiditan. Background Art

[0002] Lasmiditan, chemically named 2,4,6-trifluoro-N-[6-[(1-methylpiperidin-4-yl)carbonyl]-2-pyridinyl]benzamide, is an oral prescription drug developed by Eli Lilly. Clinically, its succinate is used for the acute treatment of migraine with or without aura symptoms in adults. It was approved by the US FDA in October 2019 (trade name ), and it is the first new class of acute migraine treatment drug approved by the FDA in more than 20 years. Lasmiditan is an oral, central nervous system penetrant, selective, 5-hydroxytryptamine 1F (5-HT 1F ) agonist, which is different from currently approved migraine drugs in structure and mechanism and has no vasoconstrictive activity. Its chemical structural formula is as follows:

[0003]

[0004] Currently, the synthesis process of Lasmiditan has been disclosed in many patents, such as WO2011123654A1, US2019233393A1, CN03807363, US8697876B2, WO2011123654, CN110386918A. However, its idea is generally the same as that of the original research patent WO03084949, and the disclosed synthesis method is as follows: N-methylpiperidine-4-carboxylic acid hydrochloride reacts with DMF / oxalyl chloride to obtain the hydrochloride of N-methylpiperidine-4-carbonyl chloride, then a THF solution of dimethylamine and triethylamine are added dropwise, and after post-treatment, N,N'-dimethyl-N-methylpiperidine-4-carboxamide is obtained; then it reacts with 2,6-dibromopyridine and n-butyllithium at about -70 °C to obtain 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine; then in a sealed autoclave, ethylene glycol is used as a solvent, and it reacts with ammonia at high temperature and pressure for 20 h to obtain the hydrochloride of 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine, and then the base is adjusted and it is freed to obtain 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine; then under nitrogen protection, 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)-pyridine reacts with 2,4,6-trifluorobenzoyl chloride in anhydrous THF to obtain 2,4,6-trifluoro-N-[6-(1-methylpiperidin-4-ylcarbonyl)-pyridin-2-yl]-benzamide; finally, it forms a salt with succinic acid in acetone to obtain the target product.

[0005]

[0006] However, the following deficiencies exist in this method: ① When preparing 2-bromo-6-(1-methylpiperidin-4-ylcarbonyl)pyridine, n-butyllithium, which is sensitive to water and requires harsh reaction conditions, needs to be used, which is not conducive to industrial scale-up production; ② When ammoniating to prepare 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine, a reaction under about 50 psi (345 kPa) of ammonia pressure is required, which has high requirements for equipment; and 2-amino-6-(1-methylpiperidin-4-ylcarbonyl)pyridine needs to be repeatedly adjusted with acid and alkali for purification, which is not only complex in operation but also has a low yield (63%); ③ When preparing lasmiditan, nitrogen protection is required, and the solvent THF used needs to be strictly anhydrously treated. At the same time, the post-treatment also needs to be repeatedly adjusted with acid and alkali for purification, and the operation is cumbersome.

[0007] In summary, there are many deficiencies in the current preparation method of lasmiditan in terms of process safety, cumbersome operation, low yield, and high production cost. Therefore, it is still a problem to be solved at present to study and find a reaction route suitable for industrial production of lasmiditan with mild reaction conditions, simple operation process, high product yield, and high purity. Summary of the Invention

[0008] In view of the problems existing in the current existing lasmiditan preparation technology, the present invention provides a new preparation method of lasmiditan.

[0009] The specific technical solution of the present invention is as follows:

[0010] Compound I is obtained by reacting compound SM-1 and compound SM-2. The specific route is as follows:

[0011]

[0012] A preparation method of lasmiditan specifically includes the following steps:

[0013] Under the protection of an inert gas, a catalyst, a ligand, a base, and solvent A are added to a closed device, the temperature is controlled for reaction. After the reaction is completed, the reaction solution is cooled to room temperature, compound SM-1 and compound SM-2 are added, and the temperature is raised for reaction. After the reaction ends, compound I is obtained through post-treatment.

[0014] Preferably, the catalyst is one or a combination of rhodium(III) chloride triphenylphosphine, rhodium(II) acetate dimer, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, rhodium(I) dicarbonylacetylacetonate, (1,5-cyclooctadiene)rhodium(I) chloride dimer, and further preferably rhodium(III) chloride triphenylphosphine.

[0015] Preferably, the ligand is one or a combination of 1,10-phenanthroline, 2,2'-bipyridine, 3,8-bis(thiophen-2-yl)-1,10-phenanthroline, 2,2'-bipyridine-4,4'-dicarboxaldehyde, 3-bromo-1,10-phenanthroline, and more preferably 1,10-phenanthroline.

[0016] Preferably, the base is one or a combination of potassium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride, and more preferably sodium tert-butoxide.

[0017] Preferably, the solvent A is one or a combination of toluene, xylene, N,N-dimethylformamide, N-methylpyrrolidone, and more preferably toluene.

[0018] Preferably, for the temperature-controlled reaction and the temperature-raising reaction, the sealing device can be placed in a heating device at a temperature of 100-120°C. The heating device can be an oil bath heater, an electric heating mantle, a steam heater, an electric furnace, etc.; the sealing device can be a sealed glass tube, a stainless steel reaction kettle with good sealing performance, a sealed Schlenk device, etc. In the present invention, the Schlenk device is preferably used for verification.

[0019] Preferably, the molar ratio of the feed of SM-1, SM-2, the catalyst, the ligand, and the base is 1:1.05-1.3:0.06-0.10:0.06-0.10:0.1-0.5, and more preferably 1:1.1:0.08:0.08:0.3.

[0020] Preferably, the temperature of the temperature-controlled reaction is 100-120°C.

[0021] Preferably, the temperature of the temperature-raising reaction is 100-120°C.

[0022] Preferably, the post-treatment steps are as follows: filter the reaction solution, concentrate the filtrate under reduced pressure to dryness, dissolve it with hydrochloric acid, filter, wash the filtrate with solvent B, adjust the pH with sodium hydroxide solution, extract with solvent C, combine the organic phases, wash with purified water, dry with anhydrous sodium sulfate, filter, and concentrate the obtained filtrate under reduced pressure to dryness to obtain Compound I.

[0023] Preferably, the concentration of the hydrochloric acid solution is 1-5 mol / L.

[0024] Preferably, the solvent B is one or a combination of ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether, and more preferably dichloromethane.

[0025] Preferably, the concentration of the sodium hydroxide solution is 4-7.5 mol / L.

[0026] Preferably, the pH is adjusted within the range of 12 to 14, more preferably pH is 13.

[0027] Preferably, the solvent C is one or a combination of ethyl acetate, dichloromethane, chloroform, and methyl tert-butyl ether, and more preferably methyl tert-butyl ether.

[0028] In the present invention, the inert gas is generally selected from nitrogen and argon, and more preferably argon.

[0029] Beneficial effects achieved by the present invention:

[0030] 1. The present invention provides a new preparation method of lasmiditan.

[0031] 2. The preparation process route of the present invention is simple, and the obtained compound has high purity and high yield, which is suitable for industrial production. Specific embodiments

[0032] The present invention will be further illustrated by the following examples. It should be correctly understood that the examples of the present invention are only used to illustrate the present invention, rather than to limit the present invention. Therefore, any simple improvement of the present invention under the premise of the method of the present invention falls within the scope of protection required by the present invention.

[0033] The structure of the lasmiditan compound obtained in the present invention was confirmed as follows:

[0034]

[0035] ESI-HRMS (m / z): 378.1441 [M + H] + ;

[0036] 1 HNMR (400 MHz, DMSO-d6) δ: 8.16 (s, 1H), 7.91 - 7.78 (m, 1H), 7.66 - 7.52 (m, 1H), 7.50 - 7.39 (m, 1H), 6.84 - 6.66 (m, 2H), 2.98 - 2.83 (m, 1H), 2.79 - 2.61 (m, 2H), 2.28 (s, 3H), 2.25 - 2.11 (m, 2H), 1.99 - 1.87 (m, 2H), 1.75 - 1.58 (m, 2H);

[0037] 13CNMR(100MHz, DMSO-d6) δ 199.62, 165.31, 162.59, 162.00, 160.34, 155.53, 151.19, 144.25, 125.64, 119.18, 109.24, 101.16, 101.16, 53.77, 46.05, 43.90, 28.03;

[0038] The present invention uses HPLC to determine the purity of lasmiditan, and the chromatographic conditions are as follows:

[0039] Chromatographic column: Welch Ultimate XB-C 18 (4.6 mm × 250 mm, 5 μm) or a chromatographic column with equivalent performance;

[0040] Mobile phase: Mobile phase A: 0.02 mol / L ammonium dihydrogen phosphate + 2.1 ml triethylamine, adjusted to pH 7.0 with phosphoric acid, Mobile phase B: acetonitrile, gradient elution (0 min: A 85%, 25 min: A 65%, 35 min: 50%, 60 min: 85%);

[0041] Column temperature: 35 °C;

[0042] Detection wavelength: 223 nm;

[0043] Flow rate: 1.0 ml / min;

[0044] Injection volume: 10 μl;

[0045] The retention time of lasmiditan is about 26.3 min.

[0046] In the following examples, various processes and methods not described in detail are conventional methods well known in the art.

[0047] Example 1

[0048] Under argon protection, rhodium(III) chloride triphenylphosphine (7.61 g, 8.0 mmol), 1,10-phenanthroline (1.44 g, 8.0 mmol), sodium tert-butoxide (2.88 g, 0.03 mol), and toluene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C for reaction. After the reaction was completed, the reaction solution was cooled to room temperature. Then SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the reaction solution was filtered. The filtrate was concentrated under reduced pressure to dryness, then dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (50 ml × 2). The pH was adjusted to about 13 with sodium hydroxide (5 mol / L) solution, and extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to dryness to obtain Compound I (36.49 g), with a yield of 96.5% and a purity of 99.92%.

[0049] Example 2

[0050] Under argon protection, rhodium(II) acetate dimer (2.65 g, 6.0 mmol), 2,2'-bipyridine (0.94 g, 6.0 mmol), potassium tert-butoxide (3.36 g, 0.03 mol), and N-methylpyrrolidone (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then SM-1 (21.93 g, 0.1 mol) and SM-2 (17.02 g, 0.105 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, it was filtered. The filtrate was concentrated under reduced pressure to dryness, then dissolved in hydrochloric acid (1 mol / L, 300 ml), filtered, and the filtrate was washed with dichloromethane (70 ml × 2). The pH was adjusted to about 13 with sodium hydroxide (7.5 mol / L) solution, and extracted with methyl tert-butyl ether (40 ml × 3). The organic phases were combined, washed with purified water (40 ml × 2), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to dryness to obtain Compound I (35.66 g), with a yield of 94.3% and a purity of 99.85%.

[0051] Example 3

[0052] Under argon protection, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (4.95 g, 8.0 mmol), 3,8-bis(thiophen-2-yl)-1,10-phenanthroline (2.76 g, 8.0 mmol), potassium carbonate (4.14 g, 0.03 mol), and N,N-dimethylformamide (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then SM-1 (21.93 g, 0.1 mol) and SM-2 (16.21 g, 0.1 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with ethyl acetate (50 ml × 2). The pH was adjusted to about 12 with sodium hydroxide (5 mol / L) solution, and then extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to dryness to obtain compound I (34.83 g), with a yield of 92.1% and a purity of 99.83%.

[0053] Example 4

[0054] Under argon protection, rhodium(I) acetylacetonate dicarbonyl (2.07 g, 8.0 mmol), 2,2'-bipyridine-4,4'-dicarboxaldehyde (1.69 g, 8.0 mmol), sodium hydride (2.24 g, 0.03 mol), and toluene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then SM-1 (21.93 g, 0.1 mol) and SM-2 (21.07 g, 0.13 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (5 mol / L, 100 ml), filtered, and the filtrate was washed with dichloromethane (30 ml × 2). The pH was adjusted to about 13 with sodium hydroxide (4 mol / L) solution, and then extracted with methyl tert-butyl ether (30 ml × 3). The organic phases were combined, washed with purified water (30 ml × 2), dried over anhydrous sodium sulfate, filtered, and the obtained filtrate was concentrated under reduced pressure to dryness to obtain compound I (35.74 g), with a yield of 94.5% and a purity of 99.79%.

[0055] Example 5

[0056] Under argon protection, (1,5-cyclooctadiene)rhodium(I) chloride dimer (3.95 g, 8.0 mmol), 3-bromo-1,10-phenanthroline (2.07 g, 8.0 mmol), sodium bicarbonate (2.52 g, 0.03 mol), and xylene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (22.70 g, 0.14 mol) were added, and the reaction continued at 105 - 110 °C. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (1 mol / L, 200 ml), filtered, and the filtrate was washed with chloroform (50 ml × 2). The pH was adjusted to approximately 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (34.64 g), with a yield of 91.6% and a purity of 99.78%.

[0057] Example 6

[0058] Under argon protection, triphenylphosphine rhodium(III) chloride (5.56 g, 6.0 mmol), 1,10-phenanthroline (1.08 g, 6.0 mmol), sodium tert-butoxide (2.88 g, 0.03 mol), and N-methylpyrrolidone (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the reaction continued at 105 - 110 °C. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with methyl tert-butyl ether (50 ml × 2). The pH was adjusted to approximately 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (34.98 g), with a yield of 92.5% and a purity of 99.79%.

[0059] Example 7

[0060] Under argon protection, rhodium(III) chloride triphenylphosphine (4.63 g, 5.0 mmol), 1,10-phenanthroline (0.9 g, 5.0 mmol), sodium tert-butoxide (2.88 g, 0.03 mol), and N,N-dimethylformamide (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the reaction was continued at 105 - 110 °C. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with ethyl acetate (50 ml × 2). The pH was adjusted to approximately 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with chloroform (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (34.34 g) with a yield of 90.8% and a purity of 99.77%.

[0061] Example 8

[0062] Under argon protection, rhodium(III) chloride triphenylphosphine (9.25 g, 10.0 mmol), 1,10-phenanthroline (1.8 g, 10.0 mmol), sodium tert-butoxide (2.88 g, 0.03 mol), and xylene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 105 - 110 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the reaction was continued at 105 - 110 °C. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (50 ml × 2). The pH was adjusted to approximately 14 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (35.09 g) with a yield of 92.8% and a purity of 99.73%.

[0063] Example 9

[0064] Under argon protection, rhodium(III) chloride triphenylphosphine (9.16 g, 11.0 mmol), 1,10-phenanthroline (1.78 g, 11.0 mmol), sodium tert-butoxide (2.88 g, 0.03 mol), and xylene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 95 - 100 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (50 ml × 2). The pH was adjusted to approximately 14 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with dichloromethane (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain compound I (34.30 g) with a yield of 90.7% and a purity of 98.73%.

[0065] Example 10

[0066] Under argon protection, rhodium(III) chloride triphenylphosphine (5.71 g, 6.0 mmol), 1,10-phenanthroline (1.08 g, 6.0 mmol), sodium tert-butoxide (0.96 g, 0.01 mol), and N,N-dimethylformamide (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 100 - 105 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with methyl tert-butyl ether (50 ml × 2). The pH was adjusted to approximately 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain compound I (35.47 g) with a yield of 93.8% and a purity of 99.74%.

[0067] Example 11

[0068] Under nitrogen protection, rhodium(III) chloride triphenylphosphine (5.71 g, 6.0 mmol), 1,10-phenanthroline (1.08 g, 6.0 mmol), sodium tert-butoxide (4.8 g, 0.05 mol), and N,N-dimethylformamide (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 110 - 120 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (50 ml × 2). The pH was adjusted to about 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (35.43 g) with a yield of 93.7% and a purity of 99.72%.

[0069] Example 12

[0070] Under nitrogen protection, rhodium(III) chloride triphenylphosphine (5.71 g, 6.0 mmol), 1,10-phenanthroline (1.08 g, 6.0 mmol), sodium tert-butoxide (0.48 g, 0.005 mol), and xylene (250 ml) were added to a Schlenk apparatus. The temperature was controlled at 120 - 125 °C. After the reaction was completed, the reaction solution was cooled to room temperature. Then, SM-1 (21.93 g, 0.1 mol) and SM-2 (19.61 g, 0.11 mol) were added, and the temperature was continuously controlled at 105 - 110 °C for reaction. After the reaction was completed, the mixture was filtered. The filtrate was concentrated under reduced pressure to dryness, dissolved in hydrochloric acid (2 mol / L, 200 ml), filtered, and the filtrate was washed with dichloromethane (50 ml × 2). The pH was adjusted to about 13 with sodium hydroxide (5 mol / L) solution, and the mixture was extracted with methyl tert-butyl ether (50 ml × 3). The organic phases were combined, washed with purified water (50 ml × 2), dried over anhydrous sodium sulfate, filtered, and the resulting filtrate was concentrated under reduced pressure to dryness to obtain Compound I (34.30 g) with a yield of 90.7% and a purity of 99.70%.

Claims

1. A preparation method of lasmiditan, characterized in that, Compound SM-1 reacts with compound SM-2 to obtain compound I, and the synthetic route is as follows: ； The specific preparation method is as follows: Under the protection of an inert gas, a catalyst, a ligand, a base, and solvent A are added to a closed device, and the temperature is controlled for the reaction. After the reaction is completed, compound SM-1 and compound SM-2 are added, and the temperature is raised for the reaction. After the reaction ends, compound I is obtained through post-treatment; wherein, the catalyst is one or a combination of rhodium(III) chloride triphenylphosphine, rhodium(II) acetate dimer, dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer, rhodium(I) acetylacetonate dicarbonyl, (1,5-cyclooctadiene)rhodium(I) chloride dimer; the ligand is one of 1,10-phenanthroline, 2,2'-bipyridine, 3,8-bis(thiophen-2-yl)-1,10-phenanthroline, 2,2'-bipyridine-4,4'-dicarboxaldehyde, 3-bromo-1,10-phenanthroline; the base is one or a combination of potassium carbonate, sodium bicarbonate, sodium tert-butoxide, potassium tert-butoxide, sodium hydride; the solvent A is one or a combination of toluene, xylene, N,N-dimethylformamide, N-methylpyrrolidone.

2. The preparation method according to claim 1, characterized in that, The molar ratio of the feed of SM-1 to SM-2, the catalyst, the ligand, and the base is 1:1.05~1.3:0.06~0.10:0.06~0.10:0.1~0.

5.

3. The preparation method according to claim 1, characterized in that, The temperature for the temperature-controlled reaction is 100~120 °C; the temperature for the temperature-raising reaction is 100~120 °C.

4. The preparation method according to claim 1, wherein The post-treatment steps are as follows: The reaction solution is filtered. After the filtrate is concentrated to dryness under reduced pressure, it is dissolved with hydrochloric acid, filtered, the filtrate is washed with solvent B, the pH is adjusted with sodium hydroxide solution, and it is extracted with solvent C. The organic phases are combined, the combined organic phase is washed with purified water, dried over anhydrous sodium sulfate, filtered, and the obtained filtrate is concentrated to dryness under reduced pressure to obtain compound I.

5. The preparation method according to claim 4, wherein, The solvent B is one or a combination of ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether; the solvent C is one or a combination of ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether; the pH adjustment range is 12~14.

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