A process for the preparation of a compound useful in the treatment of migraine

Abstract

The application provides a preparation method of a compound for treating migraine. Specifically, the method comprises the following steps: subjecting N-methyl-4-piperidine formyl chloride to a Friedel-Crafts reaction with pyridine to obtain a compound of formula III, subjecting the compound of formula III to nitration with nitric acid to obtain a compound of formula IV, subjecting the compound of formula IV to amination to obtain a compound of formula V, and subjecting the compound of formula V to a reaction with a compound of formula VI (2,4,6-trifluorobenzoyl chloride) to obtain a target compound of formula VII. The method has high yield, simple operation and is easy for industrialized production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of a migraine treatment drug, i.e., Lasmiditan BACKGROUND

[0002] Lasmiditan is a central nervous system penetrating, selective, 5-hydroxytryptamine 1F (5-HT1F) agonist oral preparation, and Lasmiditan is the first drug in the ditan class of drugs for the acute treatment of adult migraine, which is different from the approved migraine drugs in structure and mechanism, and does not have vasoconstrictor activity; if approved, it will represent a major innovation in the treatment of migraine. On November 16, 2018, Lilly submitted a new drug application (NDA) for Lasmiditan to the US FDA for the acute treatment of migraine with or without aura in adult patients.

[0003] In the currently reported patents for synthesizing Lasmiditan, basically, a key intermediate compound of formula V is required to be synthesized:

[0004]

[0005] The synthesis method or condition reported in the existing patents is harsh, or a dangerous lithium reagent is used, which is difficult to be industrialized, and the yield is not high, resulting in high product cost.

[0006] Therefore, there is a need in the art to develop a Lasmiditan preparation method with high yield, simple operation and easy industrialization. SUMMARY

[0007] The purpose of the present application is to provide a Lasmiditan preparation method with high yield, simple operation and easy industrialization.

[0008] In the first aspect of the present application, a preparation method of a compound of formula VII is provided, which comprises the following steps:

[0009] (i) a Friedel-Crafts reaction of N-methyl-4-piperidinecarbonyl chloride with pyridine to obtain a compound of formula III;

[0010]

[0011] (ii) a nitration reaction of formula III with nitric acid to obtain a compound of formula IV;

[0012]

[0013] (iii) a nitro reduction reaction of the compound of formula IV to obtain a compound of formula V; and

[0014]

[0015] (iv) reacting the compound of formula V with a compound of formula VI to obtain a compound of formula VII;

[0016]

[0017] In another preferred embodiment, the method comprises the steps of:

[0018] (i) subjecting N-methyl-4-piperidinecarboxyl chloride to a Friedel-Crafts reaction with pyridine in an inert solvent in the presence of a catalyst to obtain a compound of formula III;

[0019] (ii) subjecting the compound of formula III to a nitration reaction in the presence of concentrated nitric acid and concentrated sulfuric acid to obtain a compound of formula IV;

[0020] (iii) subjecting the compound of formula IV to a nitro reduction reaction in an inert solvent in the presence of a metal catalyst under H2atmosphere to obtain a compound of formula V; and

[0021] (iv) reacting the compound of formula V with a compound of formula VI in the presence of a base catalyst in an inert solvent to obtain a compound of formula VII.

[0022] In another preferred embodiment, step (i) has one or more characteristics selected from the group consisting of:

[0023] (1) the catalyst of the reaction is selected from the group consisting of anhydrous aluminum trichloride, anhydrous zinc chloride, ferric trichloride, titanium tetrachloride, or a combination thereof, preferably anhydrous aluminum trichloride, ferric trichloride, or a combination thereof, more preferably anhydrous aluminum trichloride;

[0024] (2) the molar ratio of the compound of formula I to the compound of formula II is 1:1-1.5, preferably 1:1.1-1.3, more preferably 1:1.15-1.25;

[0025] (3) the temperature of the reaction is 35-50°C, preferably 40-45°C; and / or

[0026] (4) the time of the reaction is 1-6h, preferably 1.5-4h.

[0027] In another preferred embodiment, step (i) comprises a post-treatment step (i-1):

[0028] (i-1) cooling the reactants of step (i) to 0±4°C after cooling (20±5°C), adding water dropwise, controlling the temperature to 10-30°C, stirring for 10-30min, standing to separate the layers, taking the organic phase, drying, and removing the solvent by rotary evaporation to obtain the compound of formula III.

[0029] In another preferred embodiment, step (ii) has one or more characteristics selected from the group consisting of:

[0030] (1) the reaction is that the compound of formula III is added into sulfuric acid, and a mixture of nitric acid and sulfuric acid is added dropwise;

[0031] (2) the molar ratio of the compound of formula III to nitric acid is 1:1-3.0, preferably 1.5-2.5, more preferably 1.8-2.2;

[0032] (3) the temperature of the reaction is -10-5°C, preferably -5-0°C; and / or

[0033] (4) the time of the reaction is 0.5-6h, preferably 1-3h.

[0034] In another preferred embodiment, step (iii) has one or more features selected from the group consisting of:

[0035] (1) the catalyst is selected from the group consisting of palladium on carbon, platinum on carbon, Raney nickel, iron powder or a combination thereof, preferably palladium on carbon;

[0036] (2) the inert solvent is selected from the group consisting of C1-C6 alcohol, or a mixed solvent of C1-C6 alcohol and water, preferably the mixed solvent contains 80-95% C1-C6 alcohol, preferably 90-95% alcohol-water mixed solvent, more preferably the alcohol is methanol;

[0037] (3) the mass ratio of the compound of formula IV to the catalyst is 1:0.05-0.2, preferably 1:0.1-0.15;

[0038] (4) the hydrogen pressure is 0.1-1 MPa, preferably 0.15-0.6 MPa, more preferably 0.2-0.5 MPa;

[0039] (5) the temperature of the reaction is 15-35°C, preferably 20-35°C; and / or

[0040] (6) the time of the reaction is 1-8h, preferably 2-6h.

[0041] In another preferred embodiment, the palladium content of the palladium on carbon is 3-15wt%, preferably 5-10wt%, more preferably 8-10wt%.

[0042] In another preferred embodiment, step (iii) comprises the step that the nitro reduction reaction of the compound of formula IV is carried out in a mixed solvent of methanol and water in the presence of 8-10wt% palladium on carbon catalyst under 0.2-0.5 MPa H2atmosphere at 15-35°C to obtain the compound of formula V.

[0043] In another preferred embodiment, step (iv) has one or more features selected from the group consisting of:

[0044] (1) the base catalyst is selected from the group consisting of ammonia, trimethylamine, triethylamine, sodium carbonate, or a combination thereof;

[0045] (2) the molar ratio of the compound of Formula V to the compound of Formula VI is 1:0.5-2.0, preferably 0.8-1.5, more preferably 1.0-1.2;

[0046] (3) the temperature of the reaction is -5-10°C, preferably 0-5°C; and / or

[0047] (4) the time of the reaction is 1-8h, preferably 2-6h.

[0048] In a second aspect, the present application provides a method for preparing a compound of Formula V, the method comprising the steps of:

[0049] (i) subjecting N-methyl-4-piperidinecarboxamide chloride to a Friedel-Crafts reaction with pyridine to obtain a compound of Formula III;

[0050]

[0051] (ii) subjecting the compound of Formula III to a nitration reaction in the presence of concentrated nitric acid and concentrated sulfuric acid to obtain a compound of Formula IV;

[0052]

[0053] (iii) subjecting the compound of Formula IV to a nitro reduction reaction to obtain a compound of Formula V; and

[0054]

[0055] In another preferred embodiment, the method comprises the steps of:

[0056] (i) subjecting N-methyl-4-piperidinecarboxamide chloride to a Friedel-Crafts reaction with pyridine in the presence of a catalyst in an inert solvent to obtain a compound of Formula III;

[0057] (ii) subjecting the compound of Formula III to a nitration reaction in the presence of concentrated nitric acid and concentrated sulfuric acid to obtain a compound of Formula IV;

[0058] (iii) subjecting the compound of Formula IV to a nitro reduction reaction in the presence of a metal catalyst in an inert solvent under H2atmosphere to obtain a compound of Formula V.

[0059] It should be understood that, within the scope of the present application, each of the technical features described above and each of the technical features described in detail below (e.g., in the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0060] The present inventors have made extensive and intensive studies, and through a large number of screening and testing, provided a preparation method of lasmiditan. Specifically, the inventors developed a very simple and efficient preparation method of the compound of formula V. On this basis, the present application is completed.

[0061] The term

[0062] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.

[0063] As used herein, the term "about," when used in reference to a particular recited numerical value, means that the value can vary from the recited value by not more than 1%. For example, as used herein, the expression "about 100" includes all values between 99 and 101, and all values in between (e.g., 99.1, 99.2, 99.3, 99.4, etc.).

[0064] As used herein, the term "comprising" or "including" can be open, semi-closed or closed. In other words, the term also includes "consisting essentially of" or "consisting of".

[0065] As used herein, the term "room temperature", "ambient temperature" means a temperature of 4-40°C, preferably 25±5°C.

[0066] Any suitable inert solvent can be used in the method of the present application. Representative inert solvents include, but are not limited to, C1-C6 alkyl, C1-C6 alcohol, petroleum ether, cyclopentane, benzene, toluene, xylene, trifluorotoluene, halogenated benzene such as chlorobenzene, fluorobenzene, dichlorobenzene and difluorobenzene, dichloromethane, chloroform, DMF, DMSO, acetone, ethyl acetate, diethyl ether, tetrahydrofuran, or a combination thereof. In some embodiments, the solvent can be tetrahydrofuran, chloroform, methanol, isopropanol, or a combination thereof.

[0067] Preparation of the compound of formula III

[0068] The present application provides a preparation method of a compound of formula III, comprising the steps of:

[0069] (i) a Friedel-Crafts reaction of N-methyl-4-piperidinecarbonyl chloride with pyridine to obtain the compound of formula III.

[0070]

[0071] Specifically, comprising (i) a Friedel-Crafts reaction of N-methyl-4-piperidinecarbonyl chloride with pyridine in an inert solvent in the presence of a catalyst to obtain the compound of formula III.

[0072] In another preferred embodiment, step (i) has one or more features selected from the group consisting of:

[0073] (1) The catalyst for the reaction is selected from the group consisting of anhydrous aluminum trichloride, anhydrous zinc chloride, ferric chloride, titanium tetrachloride, or combinations thereof, preferably anhydrous aluminum trichloride, ferric chloride, or combinations thereof; more preferably anhydrous aluminum trichloride;

[0074] (2) The molar ratio of compound I to compound II is 1:1 to 1.5, preferably 1:1.1 to 1.3, and even more preferably 1:1.15 to 1.25;

[0075] (3) The reaction temperature is 35-50°C, preferably 40-45°C; and / or

[0076] (4) The reaction time is 1-6 hours, preferably 1.5-4 hours.

[0077] In another preferred embodiment, step (i) includes a post-processing step (i-1):

[0078] (i-1) Cool the reactants from step (i) to 0±4℃ after cooling (20±5℃), add water dropwise, control the temperature at 10-30℃, stir for 10-30 min, let stand to separate the layers, take the organic phase, dry it, remove the solvent by rotary evaporation, and obtain compound III.

[0079] Preparation of Formula IV compounds

[0080] This invention provides a method for preparing a compound of formula IV, comprising the following steps:

[0081] (ii) Formula III reacts with nitric acid to undergo a nitration reaction, yielding compound of formula IV.

[0082]

[0083] Specifically, this includes (ii) in the presence of concentrated nitric acid and concentrated sulfuric acid, the compound of formula III undergoes a nitration reaction to obtain the compound of formula IV.

[0084] In another preferred embodiment, step (ii) has one or more features selected from the group consisting of:

[0085] (1) The reaction is to add the compound of formula III into sulfuric acid and then add a mixture of nitric acid and sulfuric acid dropwise;

[0086] (2) The molar ratio of the compound of formula III to nitric acid is 1:1-3.0, preferably 1.5-2.5, and more preferably 1.8-2.2;

[0087] (3) The reaction temperature is -10 to 5°C, preferably -5 to 0°C; and / or

[0088] (4) The reaction time is 0.5-6h, preferably 1-3h.

[0089] Preparation of Compound V

[0090] This invention provides a method for preparing a compound of formula V, comprising the steps of:

[0091] (iii) Compound IV undergoes a nitro reduction reaction to obtain compound V.

[0092]

[0093] Specifically, including (iii) in an inert solvent, in the presence of a metal catalyst, and in an H2 atmosphere, the compound of formula IV undergoes a nitro reduction reaction to obtain the compound of formula V.

[0094] In another preferred embodiment, step (iii) has one or more features selected from the group consisting of:

[0095] (1) The catalyst is selected from the group consisting of palladium on carbon, platinum on carbon, Raney nickel, iron powder or a combination thereof, preferably palladium on carbon;

[0096] (2) The inert solvent is selected from the group consisting of C1-C6 alcohols or a mixture of C1-C6 alcohols and water. Preferably, the mixture contains 80-95% C1-C6 alcohols, more preferably, 90-95% alcohol-water mixture, and even more preferably, the alcohol is methanol.

[0097] (3) The mass ratio of compound IV to catalyst is 1:0.05-0.2, preferably 1:0.1-0.15;

[0098] (4) The hydrogen pressure is 0.1-1 MPa, preferably 0.15-0.6 MPa, and even better 0.2-0.5 MPa;

[0099] (5) The reaction temperature is 15-35°C, preferably 20-35°C; and / or

[0100] (6) The reaction time is 1-8h, preferably 2-6h.

[0101] In another preferred embodiment, the palladium content of the palladium on carbon is 3-15 wt%, more preferably 5-10 wt%, and even more preferably 8-10 wt%.

[0102] Particularly preferably, step (iii) includes the step of: in a mixed solvent of methanol and water in a specific ratio (e.g., 90-95% methanol), in the presence of 8-10 wt% palladium on carbon catalyst, in a 0.2-0.5 MPa H2 atmosphere, at 15-35 °C, the compound of formula IV undergoes a nitro reduction reaction to obtain the compound of formula V.

[0103] Preparation of Rasmidetan (Compound VII)

[0104] This invention provides a method for preparing a compound of formula V, comprising the steps of:

[0105] (iv) The compound of formula V reacts with the compound of formula VI to give the compound of formula VII.

[0106]

[0107] Specifically, this includes (iv) reacting compound V with compound VI in an inert solvent in the presence of a base catalyst to give compound VII.

[0108] In another preferred embodiment, step (iv) has one or more features selected from the group consisting of:

[0109] (1) The alkaline catalyst is selected from the group consisting of: ammonia, trimethylamine, triethylamine, sodium carbonate, or a combination thereof;

[0110] (2) The molar ratio of compound V to compound VI is 1:0.5-2.0, preferably 0.8-1.5, and more preferably 1.0-1.2;

[0111] (3) The reaction temperature is -5 to 10°C, preferably 0 to 5°C; and / or

[0112] (4) The reaction time is 1-8h, preferably 2-6h.

[0113] The main advantages of this invention include:

[0114] This invention provides a novel synthetic route that avoids the use of highly hazardous lithium reagents and directly uses readily available and simple raw material pyridine for synthesis, thereby reducing material costs and greatly increasing the added economic value of the product.

[0115] The method of this invention uses low reaction temperatures in each step and has low toxicity of raw materials, which greatly improves reaction safety and is more suitable for industrial production compared with existing methods.

[0116] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Percentages and parts are by weight unless otherwise stated.

[0117] Example 1

[0118]

[0119] Dichloromethane (100 ml) was added to a reaction flask. Compound I (10.0 g, 0.062 mol) was added to the flask and stirred until dissolved. Anhydrous aluminum trichloride (12.4 g, 0.093 mol) was added, and the tail gas tube was connected. Tail gas absorption was ensured, and the mixture was stirred thoroughly. Pyridine (5.9 g, 0.0744 mol) was added dropwise. The mixture was heated to 40 °C and reacted for 2 h. The reaction progress was confirmed by TLC. After the reaction was complete, the temperature was lowered to 20 °C, and then cooled to 0 °C in an ice bath. Purified water (100 ml) was added dropwise, and the temperature was maintained between 15-20 °C. The mixture was stirred for 20 min, allowed to stand for separation, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a white solid (10.8 g). Yield: 86.2% (relative to Formula I). ​​MS (ESI): [M+1] + =205.27.

[0120] Example 2

[0121]

[0122] Compound III (15.0 g, 0.073 mol) was added to sulfuric acid (80 ml) and stirred until homogeneous. The mixture was cooled to 0°C with ice salt while stirring. A 1:1 solution of nitric acid (9.4 ml, 0.146 mol) / sulfuric acid (9.4 ml) (concentrated nitric acid (68%), concentrated sulfuric acid (98%)) was prepared and added dropwise to the reaction solution at 0°C. The reaction was maintained at 0°C for 1 h. The reaction solution was then quenched in ice, extracted with dichloromethane, and the organic phase was collected. The mixture was washed once with purified water and once with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by distillation to obtain compound IV (17.1 g), yield: 93.7% (relative to compound III). MS (ESI): [M+1] + =250.27.

[0123] Example 3

[0124]

[0125] Compound IV (50.0 g, 0.20 mol) was added to methanol (450 ml) and water (50 ml), purged three times with nitrogen, and then 10% palladium on carbon (4 g) was added under nitrogen protection. The mixture was stirred thoroughly, and hydrogen gas was introduced at a pressure of 0.5 MPa. The reaction was maintained at 25°C for 4 h. The palladium on carbon was removed by filtration, and compound V (39.3 g) was obtained by distillation. Yield: 89.3% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0126] Example 4

[0127]

[0128] Compound V (50.0 g, 0.23 mol) was added to anhydrous tetrahydrofuran (500 ml), stirred, and the temperature was maintained at 0-5 °C. Compound VI (49.2 g, 0.25 mol) was then added, followed by triethylamine (27.9 g, 0.28 mol). The reaction was maintained at 0-5 °C for 4.5 h. After the reaction was complete, 1.0 M HCl was added dropwise to adjust the pH to acidic, resulting in the precipitation of a large amount of solid. The crude compound VII (85.6 g) was obtained by filtration. Acetonitrile (500 ml) was added, and the mixture was recrystallized. The temperature was lowered to 0 °C, and the mixture was stirred for 1 h to allow crystallization. The purified product VII (77.5 g) was obtained by filtration. Yield: 90.1% (relative to compound V). MS (ESI): [M+1] + =378.36.

[0129] Example 5

[0130]

[0131] Dichloromethane (100 ml) was added to a reaction flask. Compound I (10.0 g, 0.062 mol) was added to the flask and stirred until dissolved. Anhydrous aluminum trichloride (12.4 g, 0.093 mol) was added, and the tail gas tube was connected. Tail gas absorption was ensured, and the mixture was stirred thoroughly. Pyridine (6.9 g, 0.0868 mol) was added dropwise. The mixture was heated to 40 °C and reacted for 2 h. The reaction progress was confirmed by TLC. After the reaction was complete, the temperature was lowered to 20 °C, and then cooled to 0 °C in an ice bath. Purified water (100 ml) was added dropwise, and the temperature was maintained between 15-20 °C. The mixture was stirred for 20 min, allowed to stand for separation, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain a white solid (10.0 g). Yield: 84.9% (relative to Formula I). ​​MS (ESI): [M+1] + =205.27.

[0132] Example 6

[0133]

[0134] Dichloromethane (100 ml) was added to a reaction flask. Compound I (10.0 g, 0.062 mol) was added to the flask and stirred until dissolved. Anhydrous aluminum trichloride (12.4 g, 0.093 mol) was added, and the tail gas tube was connected. Tail gas absorption was ensured, and the mixture was stirred thoroughly. Pyridine (5.9 g, 0.0744 mol) was added dropwise. The mixture was heated to 40 °C and reacted for 2 h. The reaction progress was confirmed by TLC. After the reaction was complete, the temperature was lowered to 20 °C, and then cooled to 0 °C in an ice bath. Purified water (100 ml) was added dropwise, and the temperature was maintained at approximately 30 °C. The mixture was stirred for 20 min, allowed to stand for separation, and the organic phase was collected. The organic phase was dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation to obtain an off-white solid (8.8 g). Yield: 69.5% (relative to Formula I). ​​MS (ESI): [M+1] + =205.27.

[0135] Example 7

[0136]

[0137] Compound IV (50.0 g, 0.20 mol) was added to methanol (450 ml) and water (50 ml), purged three times with nitrogen, and then 5 g of 8% palladium on carbon was added under nitrogen protection. The mixture was stirred thoroughly, hydrogen was introduced, and the reaction was maintained at 25°C for 4 h at a pressure of 0.5 MPa. The palladium on carbon was removed by filtration, and compound V (32.6 g) was obtained by distillation, yielding 74.1% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0138] Example 8

[0139]

[0140] Compound IV (50.0 g, 0.20 mol) was added to methanol (450 ml) and water (50 ml), purged three times with nitrogen, and then 10 g of 5% palladium on carbon was added under nitrogen protection. The mixture was stirred thoroughly, hydrogen was bubbled through, and the reaction was maintained at 25°C for 4 h at a pressure of 0.5 MPa. The palladium on carbon was removed by filtration, and compound V (28.1 g) was obtained by distillation, yielding 63.9% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0141] Example 9

[0142]

[0143] Compound IV (50.0 g, 0.20 mol) was added to methanol (450 ml) and water (50 ml), purged three times with nitrogen, and then 10% palladium on carbon (4 g) was added under nitrogen protection. The mixture was stirred thoroughly, and hydrogen gas was introduced at a pressure of 1 MPa. The reaction was maintained at 25°C for 4 h. The palladium on carbon was removed by filtration, and compound V (30.1 g) was obtained by distillation, yielding 68.4% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0144] Example 10

[0145]

[0146] Compound IV (50.0 g, 0.20 mol) was added to methanol (450 ml) and water (50 ml), purged three times with nitrogen, and then 10% palladium on carbon (4 g) was added under nitrogen protection. The mixture was stirred thoroughly, and hydrogen gas was introduced at a pressure of 0.2 MPa. The reaction was maintained at 25°C for 4 h. The palladium on carbon was removed by filtration, and compound V (37.6 g) was obtained by distillation. Yield: 85.5% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0147] Example 11

[0148]

[0149] Compound IV (50.0 g, 0.20 mol) was added to methanol (500 ml), purged three times with nitrogen, and then 10% palladium on carbon (4 g) was added under nitrogen protection. The mixture was stirred thoroughly, and hydrogen gas was introduced at a pressure of 0.2 MPa. The reaction was maintained at 25 °C for 4 h. The palladium on carbon was removed by filtration, and compound V (22.1 g) was obtained by distillation, yielding 50.3% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0150] Example 12

[0151]

[0152] Compound IV (50.0 g, 0.20 mol) was added to methanol (350 ml) and water (150 ml), purged three times with nitrogen, and then 10% palladium on carbon (4 g) was added under nitrogen protection. The mixture was stirred thoroughly, hydrogen was introduced, and the reaction was maintained at 25°C for 4 h at a pressure of 0.2 MPa. The palladium on carbon was removed by filtration, and compound V (8.8 g) was obtained by distillation. Yield: 20.1% (relative to formula IV). MS (ESI): [M+1] + =220.28.

[0153] In summary, the method of this invention enables the simple and efficient synthesis of compound V at low temperatures with high yield. This allows for the low-cost synthesis of rasemidant.

[0154] All documents mentioned in this invention are incorporated herein by reference as if each document were individually incorporated by reference. Furthermore, it should be understood that after reading the foregoing teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A process for the preparation of a compound of formula VII ###0001### VII characterized in that, The method comprises steps of: (i) a Friedel-Crafts reaction of N-methyl-4-piperidinecarboxyl chloride with pyridine to obtain a compound of formula III; (ii) a nitration reaction of the compound of formula III with nitric acid to obtain a compound of formula IV; (iii) a nitro reduction reaction of the compound of formula IV in an inert solvent in the presence of a metal catalyst under H2 atmosphere to obtain a compound of formula V; wherein the inert solvent is a 90-95% alcohol-water mixed solvent, and the alcohol is methanol; the catalyst is 8-10wt% palladium on carbon; the mass ratio of the compound of formula IV to the catalyst is 1:0.05-0.2; the hydrogen pressure is 0.2-0.5 MPa; and the reaction temperature is 20-35°C; and (iv) a reaction of the compound of formula V with a compound of formula VI to obtain a compound of formula VII; 2. The method of claim 1, wherein, The method comprises steps of: (i) a Friedel-Crafts reaction of N-methyl-4-piperidinecarboxyl chloride with pyridine in an inert solvent in the presence of a catalyst to obtain a compound of formula III; (ii) a nitration reaction of the compound of formula III in the presence of concentrated nitric acid and concentrated sulfuric acid to obtain a compound of formula IV; (iii) a nitro reduction reaction of the compound of formula IV in an inert solvent in the presence of a metal catalyst under H2 atmosphere to obtain a compound of formula V; wherein the inert solvent is a 90-95% alcohol-water mixed solvent, and the alcohol is methanol; the catalyst is 8-10wt% palladium on carbon; the mass ratio of the compound of formula IV to the catalyst is 1:0.05-0.2; the hydrogen pressure is 0.2-0.5 MPa; and the reaction temperature is 20-35°C; and (iv) a reaction of the compound of formula V with a compound of formula VI in an inert solvent in the presence of a base catalyst to obtain a compound of formula VII.

3. The method of claim 2, wherein, Step (i) has one or more characteristics selected from the group consisting of: (1) the catalyst for the reaction is selected from the group consisting of anhydrous aluminum chloride, anhydrous zinc chloride, ferric chloride, titanium tetrachloride, or a combination thereof; (2) the molar ratio of the compound of formula I to the compound of formula II is 1:1-1.5; (3) the reaction temperature is 35-50°C; and / or (4) the reaction time is 1-6h.

4. The method of claim 2, wherein, Step (ii) has one or more characteristics selected from the group consisting of: (1) the reaction is to add the compound of formula III into sulfuric acid, and drop a mixture of nitric acid and sulfuric acid; (2) the molar ratio of the compound of formula III to nitric acid is 1:1-3.0; (3) the reaction temperature is -10-5°C; and (4) the reaction time is 0.5-6h.

5. The method of claim 2, wherein, Step (iii) has one or more characteristics selected from the group consisting of: (1) the inert solvent is a 90% alcohol-water mixed solvent, and the alcohol is methanol; (2) the mass ratio of the compound of formula IV to the catalyst is 1:0.1-0.15; and (3) the reaction time is 2-6h.

6. The method of claim 5, wherein, The palladium content of the palladium on carbon is 10wt%.

7. The method of claim 2, wherein, In step (i), the catalyst for the reaction is anhydrous aluminum chloride.

8. The method of claim 2, wherein, Step (iv) has one or more characteristics selected from the group consisting of: (1) the base catalyst is selected from the group consisting of aqueous ammonia, trimethylamine, triethylamine, sodium carbonate, or a combination thereof; (2) the molar ratio of the compound of formula V to the compound of formula VI is 1:0.5-2.0; (3) the temperature of the reaction is -5-10℃; and (4) the time of the reaction is 1-8h.

9. A process for the preparation of a compound of formula V, characterized by, The method comprises the steps of: (i) the Friedel-Crafts reaction of N-methyl-4-piperidinecarboxyl chloride with pyridine to obtain the compound of formula III; (ii) the nitration reaction of the compound of formula III to obtain the compound of formula IV; (iii) the nitro reduction reaction of the compound of formula IV in the presence of a metal catalyst under H2 atmosphere in an inert solvent to obtain the compound of formula V; wherein the inert solvent is a 90-95% alcohol-water mixed solvent, and the alcohol is methanol; the catalyst is 8-10wt% palladium on carbon; the mass ratio of the compound of formula IV to the catalyst is 1:0.05-0.2; the hydrogen pressure is 0.2-0.5MPa; and the temperature of the reaction is 20-35℃.

10. The method of claim 9, wherein, The method comprises the steps of: (i) the Friedel-Crafts reaction of N-methyl-4-piperidinecarboxyl chloride with pyridine in the presence of a catalyst in an inert solvent to obtain the compound of formula III; (ii) the nitration reaction of the compound of formula III in the presence of concentrated nitric acid and concentrated sulfuric acid to obtain the compound of formula IV; (iii) the nitro reduction reaction of the compound of formula IV in the presence of a metal catalyst under H2 atmosphere in an inert solvent to obtain the compound of formula V; wherein the inert solvent is a 90-95% alcohol-water mixed solvent, and the alcohol is methanol; the catalyst is 8-10wt% palladium on carbon; the mass ratio of the compound of formula IV to the catalyst is 1:0.05-0.2; the hydrogen pressure is 0.2-0.5MPa; and the temperature of the reaction is 20-35℃.

11. The production method according to any one of claims 1 to 10, wherein The step (iii) comprises the steps of: adding 50.0g of the compound of formula IV into 450ml of methanol and 50ml of water, replacing with nitrogen for 3 times, adding 4g of 10% palladium on carbon under the protection of nitrogen, stirring uniformly, passing in hydrogen, the gas pressure is 0.5MPa, reacting for 4h under the temperature of 25℃, removing the palladium on carbon by filtration, and distilling to obtain the compound V; or adding 50.0g of the compound of formula IV into 450ml of methanol and 50ml of water, replacing with nitrogen for 3 times, adding 4g of 10% palladium on carbon under the protection of nitrogen, stirring uniformly, passing in hydrogen, the gas pressure is 0.2MPa, reacting for 4h under the temperature of 25℃, removing the palladium on carbon by filtration, and distilling to obtain the compound V.

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