A lasmiditan intermediate compound

Abstract

The present invention provides a new intermediate and a new method for synthesizing lasmiditan using the intermediate. This method uses 2-bromo-6-(1-methylpiperidin-4-ylacyl)-pyridine as a starting material, reacts with biboronic acid pinacol ester to obtain a new intermediate 2-(1-methylpiperidin-4-ylacyl)-6-pyridine borate, and then reacts with 2,4,6-trifluorobenzonitrile to obtain lasmiditan. The preparation process for synthesizing lasmiditan using the intermediate in the present invention can significantly shorten the process route compared to the prior art, and the obtained lasmiditan has a higher purity and yield, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of drug synthesis, and in particular relates to a lasmiditan intermediate compound, a preparation method thereof, and use thereof in synthesizing lasmiditan. Background Art

[0002] Lasmiditan, chemically known as 2,4,6-trifluoro-N-[6-[(1-methyl-4-piperidinyl)carbonyl]-2-pyridinyl]benzamide, is an oral prescription drug developed by Eli Lilly. Its succinate salt is clinically used for the acute treatment of migraine with or without aura in adults. It was approved by the US FDA in October 2019 (trade name: ), is the first new class of acute migraine treatment drugs 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 structurally and mechanistically different from currently approved migraine drugs and lacks vasoconstrictive activity. Its chemical structure 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, etc. However, its concept is generally consistent with the original patent WO03084949, which discloses a synthesis method as follows: N-methyl-4-piperidinylcarboxylic acid hydrochloride is reacted with DMF / oxalyl chloride or with thionyl chloride in THF to obtain N-methyl-4-piperidinyl chloride hydrochloride, followed by dropwise addition of a THF solution of dimethylamine and triethylamine, followed by post-treatment to obtain N,N'-dimethyl-N-methylpiperidinyl-4-carboxamide; the amide is then reacted with 2,6-dibromopyridine and n-butyllithium at approximately -70°C or with a Grignard reagent (i-PrMgCl-LiCl in THF) in THF to obtain 2-bromo-6-(1-methylpiperidin-4-yl)acyl. -pyridine crude product, and then purified by column chromatography or salt formation with HBr solution; the purified 2-bromo-6-(1-methylpiperidin-4-yl acyl)-pyridine is reacted with ammonia gas at high temperature and pressure for 20 hours in a sealed autoclave with ethylene glycol as a solvent to obtain 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine crude product, which is salted with concentrated hydrochloric acid for purification and then treated with alkali to obtain 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine; then, under nitrogen protection, it reacts with 2,4,6-trifluorobenzoyl chloride in anhydrous THF or chlorobenzene to obtain lasmiditan; finally, it is salted with succinic acid in acetone to obtain lasmiditan succinate.

[0005]

[0006] However, this method has the following shortcomings: ① When preparing 2-bromo-6-(1-methylpiperidin-4-yl acyl)-pyridine, n-butyl lithium is required, which is water-sensitive, flammable, and has harsh reaction conditions, making it unfavorable for industrial scale-up production; ② When preparing 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine by amination, the ammonia pressure is about 50 psi (345 kPa), which places high demands on equipment; and 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine requires repeated acid and base adjustments for purification, which is complicated and has a low yield (63%); ③ When preparing lasmiditan, nitrogen protection is required, and the solvent THF used needs to be strictly anhydrous. At the same time, the post-treatment also requires repeated acid and base adjustments for purification, which is cumbersome.

[0007] In addition, patent CN1642939A (CN100352817C) and literature JCS Perkin, T (24), 3597-3600 (1997) use 2-chloropyridine as the starting material, and N-methoxy-N-methyl-1-methylpiperidine-4-carboxamide in the presence of n-butyl lithium and N,N-dimethylaminoethanol in hexane to obtain 6-chloro-2-(1-methylpiperidin-4-) formyl pyridine after ultra-low temperature metal lithiation, and then react with benzophenone imine under the action of Pd2(dba)3 and sodium tert-butoxide, and then remove the benzophenone protection to obtain 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine, and finally react with 2,4,6-trifluorobenzoyl chloride to obtain lasmiditan. This route also involves ultra-low temperature operation at -70°C, has high requirements on process conditions, is complicated and has low yield, and the raw materials used are expensive, which is not conducive to industrial production.

[0008]

[0009] Patent CN110386918B uses 2,3-butanedione as the starting material. It first reacts with 2-haloacrylonitrile through a 1,4-addition reaction, followed by a pyridine cyclization reaction with ammonia to produce 2-amino-6-acetylpyridine. The amino group is then protected to produce 2-disubstituted methylideneamino-6-acetylpyridine. This is then reacted with ethylene oxide for hydroxyethylation without isolation, directly sulfonated, and then cyclized with methylamine to produce 2-disubstituted methylideneamino-6-(1-methylpiperidin-4-yl)formylpyridine. The protecting group is then removed under the action of an acid catalyst, and finally, the product is amidated with 2,4,6-trifluorobenzoyl chloride to produce lasmiditan. However, this route uses ethylene oxide, which is flammable, explosive, and carcinogenic. The synthesis steps are long and the operation is cumbersome, making it unsuitable for industrial production.

[0010]

[0011] As can be seen from the above, the current difficulty in the preparation of lasmiditan lies in the preparation of relevant raw materials when constructing the amide bond. In addition, the existing technology involves the use of highly corrosive 2,4,6-trifluorobenzoyl chloride when constructing the amide bond, which places high demands on equipment. At the same time, the preparation process of another intermediate 2-amino-6-(1-methylpiperidin-4-yl)-pyridine has relatively harsh reaction conditions and the operation is also relatively cumbersome.

[0012] In summary, the current preparation methods of lasmiditan have problems such as low process safety, complicated operation, low yield, and high production cost. Therefore, it is still a problem that needs to be solved to find a reaction route suitable for the industrial production of lasmiditan with mild reaction conditions, simple operation process, high product yield and high purity. Summary of the Invention

[0013] To address the shortcomings of existing lasmiditan preparation technologies, the present invention provides a new intermediate compound II and a novel method for synthesizing lasmiditan using the intermediate. The method is simple and efficient, and the target product obtained by the method has high purity and yield.

[0014] The present invention is specifically implemented through the following technical solutions:

[0015] A lasmiditan intermediate compound is shown in Formula II, and the structural formula is as follows:

[0016]

[0017] A method for preparing an intermediate compound II comprises using 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1) as a raw material and reacting it with diboronic acid pinacol ester under an alkaline environment to obtain the intermediate compound II. The reaction formula is as follows:

[0018]

[0019] The specific steps include:

[0020] Under inert gas protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1), bipyraclostrobin, a base, and a catalyst were added to the reaction solvent A. The temperature was controlled and the reaction was completed by TLC. After post-treatment, the intermediate compound II was obtained.

[0021] Preferably, the catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd2(dba)3 or a combination thereof, preferably Pd(dppf)Cl2.

[0022] Preferably, the base is one of sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate or a combination thereof, preferably potassium acetate.

[0023] Preferably, the molar ratio of SM-1 to biboric acid pinacol ester, base, and catalyst is 1:1.05-1.3:1.1-1.7:0.03-0.08.

[0024] Preferably, the molar ratio of SM-1 to bipyraclostrobin is 1:1.05 to 1.3, preferably 1:1.2.

[0025] Preferably, the molar ratio of SM-1 to alkali is 1:1.1 to 1.7, preferably 1:1.4.

[0026] Preferably, the molar ratio of the SM-1 to the catalyst is 1:0.03 to 0.08, preferably 1:0.05.

[0027] Preferably, the reaction solvent A is selected from one or a combination of dimethyl sulfoxide, N,N-dimethylformamide, 1,4-dioxane and acetonitrile, preferably 1,4-dioxane.

[0028] Preferably, the temperature of the temperature-controlled reaction is 80-110°C, preferably 90-95°C.

[0029] In the present invention, the inert gas is usually nitrogen or argon, preferably argon.

[0030] In a preferred embodiment, the post-treatment step is as follows: after the reaction is completed, the reaction solution is filtered, the filter cake is washed with ethyl acetate, the organic phases are combined, and the mixture is concentrated to dryness under reduced pressure by a rotary evaporator; 正己烷 :V 乙醚 =5:1) mixed solvent for recrystallization, filtration, the filter cake was washed with n-hexane / ether (V 正己烷 :V 乙醚 =20:1) mixed solvent, and dried to obtain intermediate compound II.

[0031] On the other hand, the present invention provides a method for preparing lasmiditan from an intermediate compound represented by formula II, comprising the following steps: reacting the intermediate compound II with 2,4,6-trifluorobenzonitrile under alkaline conditions with a catalyst to obtain lasmiditan, as shown in the following reaction formula:

[0032]

[0033] The specific steps include:

[0034] Intermediate II, 2,4,6-trifluorobenzonitrile, a catalyst, and a base are added to the reaction solvent B, and the temperature is controlled until the reaction is completed. After post-treatment, lasmiditan is obtained.

[0035] Preferably, the catalyst is one of CuSO4, Cu(OAc)2, CuCl2, CuBr2, CuI2, Cu(OTf)2, Cu(NO3)2, CuCl, CuBr, CuI or a combination thereof, preferably CuCl2.

[0036] Preferably, the base is one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium n-butoxide, potassium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof, preferably potassium tert-butoxide.

[0037] Preferably, the reaction solvent B is one of methanol, ethanol, isopropanol, n-butanol, tert-butanol, or a combination thereof, preferably tert-butanol.

[0038] Preferably, the molar ratio of the intermediate II to 2,4,6-trifluorobenzonitrile, catalyst and base is 1:1.05-1.4:0.03-0.08:1.5-4

[0039] Preferably, the molar ratio of the intermediate II to 2,4,6-trifluorobenzonitrile is 1:1.05-1.4, preferably 1:1.15.

[0040] Preferably, the molar ratio of the intermediate II to the catalyst is 1:0.03 to 0.08, preferably 1:0.06.

[0041] Preferably, the molar ratio of the intermediate II to the base is 1:1.5 to 4, preferably 1:2.5.

[0042] Preferably, the temperature of the temperature-controlled reaction is 15-40°C.

[0043] In a preferred embodiment, the post-treatment step is: after the reaction is completed, the reaction solution is poured into purified water, extracted with an organic solvent, the organic phases are combined, washed with purified water, dried, filtered, and the obtained filtrate is concentrated to dryness under reduced pressure, and recrystallized from methyl tert-butyl ether to obtain lasmiditan; the extraction solvent can be one of ethyl acetate, dichloromethane, chloroform, methyl tert-butyl ether, or a combination thereof, preferably dichloromethane.

[0044] Beneficial effects of the present invention:

[0045] The present invention provides a new lasmiditan intermediate compound II and a new method for preparing lasmiditan using the compound II. SM-1 is used as a starting material, and the N- group in the amide bond is constructed from 2,4,6-trifluorobenzonitrile, which can effectively avoid the problems of cumbersome operation and low overall yield when 2-amino-6-(1-methylpiperidin-4-yl acyl)-pyridine is used as a raw material for preparation. The preparation process for synthesizing lasmiditan using the intermediate compound of the present invention can significantly shorten the process route compared with the prior art, and the prepared lasmiditan has high purity and yield, and is suitable for industrial production. DETAILED DESCRIPTION

[0046] The present invention is 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, simple improvements to the present invention based on the method of the present invention fall within the scope of protection claimed by the present invention.

[0047] In the following examples, various processes and methods not described in detail are conventional methods known in the art, and all reagents used without indicating their sources and specifications are commercially available of analytical grade or chemically pure.

[0048] The structure of the intermediate compound II obtained in the present invention is confirmed as follows:

[0049] ESI-HRMS (m / z): 331.2188 [M+H] + ; 1 H-NMR (400MHz, DMSO-d6) δ: 8.02 (t, J = 12.2Hz1H), 7.91~7.75 (m, 2H), 2.87~2.74 (m, 1H), 2.70~2 .64(m,2H),2.44~2.28(m,2H),2.24(s,3H),2.15~2.03(m,2H),1.90~1.75(m,2H),1.24(s,12H); 13 C-NMR (101MHz, DMSO-d6) δ: 199.60, 156.43, 148.13, 136.36, 131.76, 125.00, 86.49, 52.77, 46.43, 43.85, 28.06, 22.70.

[0050] The structure of the lasmiditan compound obtained in the present invention is confirmed as follows:

[0051] ESI-HRMS (m / z): 378.1442 [M+H] + ; 1 H-NMR (400MHz, 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); 13 C-NMR (101MHz, 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.

[0052] The present invention adopts HPLC to measure the purity of lasmiditan, and the chromatographic conditions are as follows:

[0053] Column: Welch Ultimate XB-C 18 (4.6mm×250mm,5μm) or chromatographic column with equivalent performance;

[0054] Mobile phase: Mobile phase A: 0.02 mol / L ammonium dihydrogen phosphate + 2.1 ml triethylamine, pH adjusted to 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%);

[0055] Column temperature: 35°C;

[0056] Detection wavelength: 223nm;

[0057] Flow rate: 1.0 ml / min;

[0058] Injection volume: 10 μl;

[0059] The retention time of lasmiditan is about 26.3 minutes.

[0060] Example 1

[0061] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.32 g, 0.1 mol), bipyraclostrobin (30.47 g, 0.12 mol), potassium acetate (13.74 g, 0.14 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to a dry round-bottom flask, and dry 1,4-dioxane (250 ml) was added. The temperature was controlled at 90-95°C for reaction. After TLC detection, the reaction was completed, and the mixture was filtered through diatomaceous earth. The filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was eluted with n-hexane / ether (V 正己烷 :V 乙醚 =5:1) mixed solvent for recrystallization, filtration, the filter cake was washed with n-hexane / ether (V 正己烷 :V 乙醚 =20:1) and washed to obtain the intermediate compound II with a yield of 95.3% and a purity of 99.1%.

[0062] Example 2

[0063] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.34 g, 0.1 mol), bipyraclostrobin (26.66 g, 0.105 mol), potassium acetate (13.72 g, 0.14 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to a dry round-bottom flask, and dry dimethyl sulfoxide (250 ml) was added. The reaction was controlled at 95-100°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain intermediate compound II with a yield of 92.7% and a purity of 99.0%.

[0064] Example 3

[0065] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.31 g, 0.1 mol), bipyraclostrobin (25.39 g, 0.10 mol), sodium acetate (11.48 g, 0.14 mol), and Pd(dppf)Cl2 (3.66 g, 5.0 mmol) were added to a dry round-bottom flask, and dry N,N-dimethylformamide (250 ml) was added. The reaction was controlled at 105-110°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain intermediate compound II with a yield of 88.7% and a purity of 98.0%.

[0066] Example 4

[0067] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.34 g, 0.1 mol), biboronic acid pinacol ester (33.01 g, 0.13 mol), sodium bicarbonate (11.76 g, 0.14 mol), and Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) were added to a dry round-bottom flask, and acetonitrile (250 ml) was added. The reaction was refluxed under controlled temperature. After completion of the reaction, TLC was performed, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain intermediate compound II with a yield of 94.2% and a purity of 98.6%.

[0068] Example 5

[0069] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.33 g, 0.1 mol), diboronic acid pinacol ester (35.55 g, 0.14 mol), potassium bicarbonate (14.02 g, 0.14 mol), and Pd2(dba)3 (4.58 g, 5.0 mmol) were added to a dry round-bottom flask, and N,N-dimethylformamide (250 ml) was added. The reaction was controlled at 80-85°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain the intermediate compound II with a yield of 90.2% and a purity of 97.9%.

[0070] Example 6

[0071] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.33 g, 0.1 mol), bipyraclostrobin (30.47 g, 0.12 mol), potassium acetate (10.80 g, 0.11 mol), and Pd(PPh3)2Cl2 (3.51 g, 5.0 mmol) were added to a dry round-bottom flask, and 1,4-dioxane (250 ml) was added. The reaction was controlled at 85-90°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain the intermediate compound II with a yield of 93.5% and a purity of 98.5%.

[0072] Example 7

[0073] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.32 g, 0.1 mol), bipyraclostrobin (30.48 g, 0.12 mol), potassium acetate (16.68 g, 0.17 mol), and Pd(PPh3)4 (5.78 g, 5.0 mmol) were added to a dry round-bottom flask, and acetonitrile (250 ml) was added. The reaction was refluxed under controlled temperature. After completion of the reaction, TLC was performed, the mixture was filtered through celite, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain intermediate compound II with a yield of 94.0% and a purity of 98.1%.

[0074] Example 8

[0075] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.35 g, 0.1 mol), diboronic acid pinacol ester (30.47 g, 0.12 mol), potassium bicarbonate (14.02 g, 0.14 mol), and Pd(dppf)Cl2 (2.20 g, 3.0 mmol) were added to a dry round-bottom flask, and 1,4-dioxane (250 ml) was added. The reaction was controlled at 95-100°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain the intermediate compound II with a yield of 92.0% and a purity of 99.0%.

[0076] Example 9

[0077] Under argon protection, 2-bromo-6-(1-methylpiperidin-4-yl)-pyridine (SM-1, 28.30 g, 0.1 mol), diboronic acid pinacol ester (30.45 g, 0.12 mol), sodium acetate (11.48 g, 0.14 mol), and Pd(dppf)Cl2 (5.85 g, 8.0 mmol) were added to a dry round-bottom flask, and dimethyl sulfoxide (250 ml) was added. The reaction was controlled at 90-95°C. After completion of the reaction by TLC, the mixture was filtered through diatomaceous earth, and the filter cake was washed with ethyl acetate (20 ml × 3). The organic phases were combined and concentrated to dryness under reduced pressure on a rotary evaporator. The mixture was recrystallized with a mixed solvent of n-hexane / diethyl ether = 5 / 1, filtered, and the filter cake was washed with n-hexane / diethyl ether = 20 / 1 to obtain intermediate compound II with a yield of 93.9% and a purity of 98.3%.

[0078] Example 10

[0079] Intermediate II (16.51 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (9.03 g, 0.0575 mol), CuCl2 (0.40 g, 3.0 mmol), and potassium tert-butoxide (14.03 g, 0.125 mol) were added to tert-butanol (150 ml) and reacted at room temperature. After the reaction was completed by TLC, the reaction solution was poured into purified water (600 ml) and extracted with dichloromethane (200 ml×3). The organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan with a yield of 94.7% and a purity of 99.3%.

[0080] Example 11

[0081] Intermediate II (16.50 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (8.25 g, 0.0525 mol), CuSO4 (0.48 g, 3.0 mmol), and sodium methoxide (6.75 g, 0.125 mol) were added to methanol (150 ml), and the reaction was controlled at 30-35°C. After TLC detection, the reaction solution was poured into purified water (600 ml), extracted with ethyl acetate (200 ml×3), and the organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan with a yield of 91.9% and a purity of 98.6%.

[0082] Example 12

[0083] Intermediate II (16.54 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (7.85 g, 0.05 mol), Cu(OAc)2 (0.55 g, 3.0 mmol), and sodium ethoxide (8.51 g, 0.125 mol) were added to ethanol (150 ml), and the reaction was controlled at 35-40°C. After the reaction was completed, the reaction solution was poured into purified water (600 ml) and extracted with dichloromethane (200 ml×3). The organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 89.1% and a purity of 98.1%.

[0084] Example 13

[0085] Intermediate II (16.51 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (11.00 g, 0.07 mol), CuBr2 (0.67 g, 3.0 mmol), and potassium isopropoxide (12.27 g, 0.125 mol) were added to isopropanol (150 ml), and the reaction was controlled at 15-20°C. After the reaction was completed, the reaction solution was poured into purified water (600 ml), extracted with ethyl acetate (200 ml×3), and the organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 93.8% and a purity of 99.0%.

[0086] Example 14

[0087] Intermediate II (16.52 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (11.78 g, 0.075 mol), CuI2 (0.95 g, 3.0 mmol), and sodium isopropoxide (10.26 g, 0.125 mol) were added to isopropanol (150 ml), and the reaction was controlled at 15-20°C. After the reaction was completed, the reaction solution was filtered, and the filtrate was poured into purified water (600 ml), extracted with dichloromethane (200 ml×3), and the organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 90.6% and a purity of 97.4%.

[0088] Example 15

[0089] Intermediate II (16.55 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (9.03 g, 0.0575 mol), CuCl2 (0.20 g, 1.5 mmol), and sodium n-butoxide (12.01 g, 0.125 mol) were added to n-butanol (150 ml), and the reaction was controlled at 25-30°C. After the reaction was completed, the reaction solution was poured into purified water (600 ml) and extracted with chloroform (200 ml×3). The organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 92.0% and a purity of 98.5%.

[0090] Example 16

[0091] Intermediate II (16.49 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (9.03 g, 0.0575 mol), Cu(NO3)2 (0.75 g, 4.0 mmol), and potassium n-butoxide (14.03 g, 0.125 mol) were added to n-butanol (150 ml), and the reaction was controlled at 15-20°C. After the reaction was completed, the reaction solution was poured into purified water (600 ml), extracted with chloroform (200 ml×3), and the organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 94.0% and a purity of 98.2%.

[0092] Example 17

[0093] Intermediate II (16.51 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (9.03 g, 0.0575 mol), Cu(OTf)2 (1.09 g, 3.0 mmol), and potassium tert-butoxide (8.42 g, 0.075 mol) were added to tert-butanol (150 ml), and the reaction was controlled at 25-30°C. After the reaction was completed, the reaction solution was poured into purified water (600 ml) and extracted with methyl tert-butyl ether (200 ml×3). The organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 92.3% and a purity of 98.8%.

[0094] Example 18

[0095] Intermediate II (16.50 g, 0.05 mol), 2,4,6-trifluorobenzonitrile (9.03 g, 0.0575 mol), CuBr (0.43 g, 3.0 mmol), and sodium tert-butoxide (19.22 g, 0.20 mol) were added to tert-butanol (150 ml), and the reaction was controlled at 15-20° C. After the reaction was completed, the reaction solution was poured into purified water (600 ml), extracted with methyl tert-butyl ether (200 ml×3), and the organic phase was collected, washed with purified water (150 ml×2), dried, and filtered. The filtrate was concentrated to dryness under reduced pressure and recrystallized from methyl tert-butyl ether to obtain lasmiditan I with a yield of 93.4% and a purity of 99.1%.

Claims

1. A lasmiditan intermediate compound, the structure of which is shown in Formula II: 。 2. A method for preparing the compound according to claim 1, characterized in that: Using SM-1 as raw material, it is catalyzed by the reaction with diboronic acid pinacol ester in an alkaline environment to obtain the intermediate compound II. The reaction formula is as follows: 。 3. The preparation method according to claim 2, characterized in that The method specifically comprises the following steps: under the protection of inert gas, SM-1, bipyraclostrobin, a base, and a catalyst are added to a reaction solvent A, the temperature is controlled for reaction, and after TLC detection, the intermediate compound II is obtained by post-treatment.

4. The preparation method according to claim 3, characterized in that The catalyst is one of Pd(PPh3)4, Pd(PPh3)2Cl2, Pd(dppf)Cl2, Pd2(dba)3 or a combination thereof.

5. The preparation method according to claim 3, characterized in that The base is one of sodium acetate, potassium acetate, sodium bicarbonate, potassium bicarbonate or a combination thereof.

6. The preparation method according to claim 3, characterized in that The molar ratio of SM-1 to biboric acid pinacol ester, base and catalyst is 1:1.05-1.3:1.1-1.7:0.03-0.

08.

7. The preparation method according to claim 3, characterized in that The reaction temperature is 80-110°C.

8. The method for preparing lasmiditan from compound II according to claim 1, characterized in that: The steps include: The intermediate compound II reacts with 2,4,6-trifluorobenzonitrile in the presence of a catalyst under alkaline conditions to obtain lasmiditan. The reaction formula is as follows: ； Wherein, the catalyst is one of CuSO4, Cu(OAc)2, CuCl2, CuBr2, CuI2, Cu(OTf)2, Cu(NO3)2, CuCl, CuBr, CuI or a combination thereof.

9. The preparation method according to claim 8, characterized in that The base is one of sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium isopropoxide, potassium isopropoxide, sodium n-butoxide, potassium n-butoxide, sodium tert-butoxide, potassium tert-butoxide, or a combination thereof.

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