A method for synthesizing indole derivatives

Abstract

The invention relates to a method for synthesizing an indole derivative. The method avoids the step of column chromatography purification, has a simpler synthesis process, a high yield of a target product, good purity, and is more suitable for industrial production.

Description

[0001] This application is a divisional application of the invention patent application with the application date of July 24, 2019, application number CN201980047176.3, and invention name "A method for synthesizing quinoline derivatives".

[0002] This application claims the rights and priority of Chinese invention patent application No. 201810824213.4 filed with the State Intellectual Property Office of the People's Republic of China on July 24, 2018, the entire contents of which are hereby incorporated by reference into this document in their entirety. Technical Field

[0003] The present invention relates to the pharmaceutical field, and in particular to a method for preparing quinoline derivatives, such as anlotinib. Background Art

[0004] Anlotinib can effectively inhibit kinases such as VEGFR, PDGFR, FGFR, and c-Kit, and has the dual effects of anti-tumor angiogenesis and inhibiting tumor growth. It was approved for marketing in China on May 9, 2018 for the treatment of advanced non-small cell lung cancer.

[0005] CN107771078A discloses a method for synthesizing anlotinib using 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline as a starting material.

[0006]

[0007] CN101809012A discloses the following method for preparing anlotinib or its analogs and intermediates, wherein the preparation method of Example 2 is as described in route (1), and the preparation method of Example 9 is as shown in route (2).

[0008] Route (1)

[0009]

[0010] Route (2)

[0011]

[0012] CN102159078A discloses the preparation of 4-(4-fluoro-2-methyl-1H-indol-5-yloxy)-6-methoxy-7-hydroxyquinoline using 7-benzyloxy-4-chloro-6-methoxyquinoline as a starting material. This route requires four steps of reaction, has a low yield, contains many impurities, and generates hydroxylamine impurities during the reaction in the penultimate step, which is difficult to remove and is not suitable for industrial production.

[0013] Summary of the invention

[0014] The present invention provides a method for preparing a compound of formula V, comprising:

[0015] (1) in the presence of a reducing agent, the compound of formula III is converted into the compound of formula IV,

[0016]

[0017] (2) converting the compound of formula IV into the compound of formula V,

[0018]

[0019] Wherein R1 is independently H or a hydroxyl protecting group, and the hydroxyl protecting group can be a hydroxyl protecting group in the fifth edition of Greene's Protective Groups in Organic Synthesis, 5th Edition, for example, ether, silyl ether, ester, carbonate, carbamate, phosphite, sulfonate, etc. can be formed to protect the hydroxyl group on the benzene ring, and examples thereof include but are not limited to methyl, methoxymethyl, methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, methylthiomethyl, azidomethyl, cyanomethyl, phenylthiomethyl, 2,2-dichloro-1,1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilylethyl, tetrahydro 1-Hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl, 1-hydroxyethyl

[0020] R2 and R3 are each independently C 1-6 Alkyl, substituted C 1-6 Alkyl, benzyl, substituted benzyl, C 1-6 Alkyl C(O)-, substituted C 1-6Alkyl C(O)-, examples include but are not limited to methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2, R3 and the connected atoms together form a five-membered, six-membered or seven-membered ring, wherein two or three of the ring atoms of the five-membered, six-membered or seven-membered ring are oxygen atoms, and the remaining ring atoms are carbon atoms, and the hydrogen on the ring carbon atoms may be substituted; in some embodiments, R2, R3 and the connected atoms together form the following structure.

[0021]

[0022] In some embodiments of step (1), while the nitro group of the compound of formula III is reduced to an amino group, the protecting group of the hydroxyl group on the benzene ring can also be removed, that is, R1 of the compound of formula IV is H at this time.

[0023] In some embodiments of step (1), when the nitro group of the compound of formula III is reduced to an amino group, the substituent R1 on the phenyl ring remains unchanged.

[0024] In some embodiments of step (1), when the nitro group on the benzene ring is reduced to an amino group, the R2 and R3 substituents are not affected.

[0025] In step (1), the reducing agent is a reducing agent known to those skilled in the art that can reduce the nitro group on the benzene ring to an amino group, and a conventional solvent can be selected according to methods known in the art. The reaction conditions that can be listed include: using sulfides (sulfides, hydrogen sulfides, polysulfides) and oxygen-containing sulfides (including sodium dithionite (hydrosulfite), sodium sulfite or sodium bisulfite) as reducing agents, reacting in the presence of ammonia water or sodium hydroxide; using platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as catalysts, reacting in the presence of hydrogen or ammonium formate or formic acid as reducing agents, and the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; using aluminum amalgam as reducing agent, and the solvent is, for example, ether, methanol; using metal hydride salts (such as lithium aluminum tetrahydride (LAH), sodium borohydride) as reducing agents, reacting in the presence of solvents (such as tetrahydrofuran); or using Zn as reducing agent and reacting in the presence of sodium hydroxide; using iron (such as iron powder) as reducing agent and reacting in the presence of ammonium chloride; or using SnCl2 as reducing agent, reacting in the presence of solvents (such as ethanol).

[0026] In some embodiments, a metal is a catalyst (eg, Ranney nickel, palladium on carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent for the reaction; in some embodiments, palladium on carbon is a catalyst; in a specific embodiment, ammonium formate is a reducing agent.

[0027] In step (1), the molar ratio or mass ratio of the reducing agent to the compound of formula III can be selected within the range known to those skilled in the art. In some embodiments, the mass ratio of ammonium formate to the compound of formula III is 2 to 4:1, preferably 3:1.

[0028] In some embodiments, the solvent in step (1) is one or more of alcohols, alkyl halides (such as alkyl chlorides), tetrahydrofuran, ethyl acetate, and DMF. Alcohol solvents include methanol and ethanol, and alkyl halides include dichloromethane and 1,2-dichloroethane.

[0029] In step (2), the method known in the art, such as the method for removing the ketal protecting group in the fifth edition of Greene's Protective Groups in Organic Synthesis, 5th Edition, can be used. In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acids and organic acids, inorganic acids include but are not limited to sulfuric acid, hydrochloric acid, and hydrobromic acid, and organic acids include but are not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4, formic acid, acetic acid, trichloroacetic acid, oxalic acid, and phthalic acid; in some embodiments, the acid is hydrochloric acid. Solvents include but are not limited to one or more of alcohols, alkyl halides (such as alkyl chlorides), tetrahydrofuran, acetone, acetonitrile, DMSO, and water, alcohols include but are not limited to methanol and ethanol, and alkyl halides include but are not limited to dichloromethane, 1,2-dichloroethane, and chloroform.

[0030] In some embodiments, the present invention provides a method for preparing a compound of formula V-1, comprising:

[0031] (1) in the presence of a reducing agent, the compound of formula III-1 is converted into the compound of formula IV-1,

[0032]

[0033] (2) converting the compound of formula IV-1 into the compound of formula V-1,

[0034]

[0035] Wherein R is independently selected from H, C 1-6 Alkyl, C 1-6 Alkoxy, halogen, -CON(C 1-6 alkyl) 2; n is 1 or 2; in some embodiments, the hydroxyl protecting group on the benzene ring is benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl or 4-(dimethylamino)carbonylbenzyl.

[0036] R2 and R3 are each independently C 1-6 Alkyl, substituted C1-6 Alkyl, benzyl, substituted benzyl, C 1-6 Alkyl C(O)-, substituted C 1-6 Alkyl C(O)-, examples include but are not limited to methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2, R3 and the connected atoms together form a five-membered, six-membered or seven-membered ring, wherein two or three of the ring atoms of the five-membered, six-membered or seven-membered ring are oxygen atoms, and the remaining ring atoms are carbon atoms, and the hydrogen on the ring carbon atoms may be substituted; in some embodiments, R2, R3 and the connected atoms together form the following structure.

[0037]

[0038] Wherein, in step (1), the reducing agent is a reducing agent known to those skilled in the art that can reduce the nitro group on the benzene ring to an amino group, and the process can be carried out according to methods known in the art and by selecting a conventional solvent. In some embodiments of the present invention, when the nitro group on the benzene ring is reduced to an amino group, the substituents R2 and R3 are not affected. The reaction conditions that can be listed include: using sulfides (sulfides, hydrogen sulfides, polysulfides) and oxygen-containing sulfides including sodium dithionite (hydrosulfite), sodium sulfite or sodium bisulfite as reducing agents, reacting in the presence of ammonia water or sodium hydroxide; using platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as catalysts, reacting in the presence of hydrogen or ammonium formate or formic acid as reducing agents, and the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; using aluminum amalgam as reducing agent, and the solvent is, for example, ether, methanol; using metal hydride salts (such as lithium aluminum tetrahydride (LAH), sodium borohydride) as reducing agents, reacting in the presence of solvents (such as tetrahydrofuran); or using Zn as reducing agent and reacting in the presence of sodium hydroxide; using iron (such as iron powder) as reducing agent and reacting in the presence of ammonium chloride; or using SnCl2 as reducing agent, reacting in the presence of solvents (such as ethanol).

[0039] In some embodiments, the metal is a catalyst (e.g., Ranney nickel, palladium carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent for the reaction; in some embodiments, palladium carbon is a catalyst; in a specific embodiment, ammonium formate is a reducing agent. In step (1), the molar ratio or mass ratio of the reducing agent to the compound of formula III can be selected within the range known to those skilled in the art. In some embodiments, the mass ratio of ammonium formate to the compound of formula III is 2 to 4:1, preferably 3:1. In some embodiments, the solvent in step (1) is one or more of alcohols, alkyl halides (e.g., alkyl chlorides), tetrahydrofuran, ethyl acetate, and DMF. Alcohol solvents include methanol and ethanol, and alkyl halides include dichloromethane and 1,2-dichloroethane.

[0040] In step (2), the method known in the art, such as the method for removing the ketal protecting group in the fifth edition of Greene's Protective Groups in Organic Synthesis, 5th Edition, can be used. In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acids and organic acids, inorganic acids include but are not limited to sulfuric acid, hydrochloric acid, and hydrobromic acid, and organic acids include but are not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4, formic acid, acetic acid, trichloroacetic acid, oxalic acid, and phthalic acid; in some embodiments, the acid is hydrochloric acid. Solvents include but are not limited to one or more of alcohols, alkyl halides (such as alkyl chlorides), tetrahydrofuran, acetone, acetonitrile, DMSO, and water, alcohols include but are not limited to methanol and ethanol, and alkyl halides include but are not limited to dichloromethane, 1,2-dichloroethane, and chloroform.

[0041] In a specific embodiment, the present invention provides a method for preparing a compound of formula V-1, comprising:

[0042] (1) in the presence of a reducing agent, the compound of formula III-2 is converted into the compound of formula IV-2,

[0043]

[0044] (2) converting the compound of formula IV-2 into the compound of formula V-1,

[0045]

[0046] Wherein, in step (1), the reducing agent is a reducing agent known to those skilled in the art that can reduce the nitro group on the benzene ring to an amino group, and the process can be carried out according to methods known in the art and using conventional solvents. The reaction conditions that can be listed include: using sulfides (sulfides, hydrogen sulfides, polysulfides) and oxygen-containing sulfides including sodium dithionite (hydrosulfite), sodium sulfite or sodium bisulfite as reducing agents, reacting in the presence of ammonia water or sodium hydroxide; using platinum oxide, platinum, Pd (such as 5% palladium carbon or 10% palladium carbon, palladium hydroxide, palladium oxide, palladium acetate, palladium chloride), Ni as catalysts, reacting in the presence of hydrogen or ammonium formate or formic acid as reducing agents, and the solvent can be methanol, dichloromethane, ethanol, ethyl acetate, DMF, etc.; using aluminum amalgam as reducing agent, and the solvent is, for example, ether, methanol; using metal hydride salts (such as lithium aluminum tetrahydride (LAH), sodium borohydride) as reducing agents, reacting in the presence of solvents (such as tetrahydrofuran); or using Zn as reducing agent and reacting in the presence of sodium hydroxide; using iron (such as iron powder) as reducing agent and reacting in the presence of ammonium chloride; or using SnCl2 as reducing agent, reacting in the presence of solvents (such as ethanol).

[0047] In some embodiments, the metal is a catalyst (e.g., Ranney nickel, palladium carbon, or platinum is a catalyst), and hydrogen or ammonium formate or formic acid is a reducing agent for the reaction; in some embodiments, palladium carbon is a catalyst; in a specific embodiment, ammonium formate is a reducing agent. In step (1), the molar ratio or mass ratio of the reducing agent to the compound of formula III can be selected within the range known to those skilled in the art. In some embodiments, the mass ratio of ammonium formate to the compound of formula III is 2 to 4:1, preferably 3:1. In some embodiments, the solvent in step (1) is one or more of alcohols, alkyl halides (e.g., alkyl chlorides), tetrahydrofuran, ethyl acetate, and DMF. Alcohol solvents include methanol and ethanol, and alkyl halides include dichloromethane and 1,2-dichloroethane.

[0048] In step (2), the method known in the art, such as the method for removing the ketal protecting group in the fifth edition of Greene's Protective Groups in Organic Synthesis, 5th Edition, can be used. In some embodiments, step (2) is reacted under acidic conditions; the acid includes inorganic acids and organic acids, inorganic acids include but are not limited to sulfuric acid, hydrochloric acid, hydrobromic acid, organic acids include but are not limited to trifluoroacetic acid, p-toluenesulfonic acid, LiBF4, formic acid, acetic acid, trichloroacetic acid, oxalic acid, phthalic acid; in some embodiments, the acid is hydrochloric acid. Solvents include but are not limited to one or more of alcohols, alkyl halides (such as alkyl chlorides), tetrahydrofuran, acetone, acetonitrile, DMSO, and water, alcohols include but are not limited to methanol and ethanol, and alkyl halides include but are not limited to dichloromethane, 1,2-dichloroethane, and chloroform.

[0049] On the other hand, the present invention also provides a method for preparing a compound of formula III-3, comprising: reacting a compound of formula I with a compound of formula II in the presence of a solvent and a base, wherein the base includes but is not limited to an inorganic base and an organic base. In some embodiments, the base is an organic base. In some embodiments, the organic base is selected from one or more of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine. In some embodiments, the base is N,N-diisopropylethylamine; in some embodiments, the molar ratio of the compounds of formula I to formula II is 1.0:1.0~1.5. In a specific embodiment, the molar ratio of the compounds of formula I to formula II is 1.0:1.1.

[0050]

[0051] Wherein R4 is a hydroxyl protecting group, and the hydroxyl protecting group can be a hydroxyl protecting group in the fifth edition of Greene's Protective Groups in Organic Synthesis, 5th Edition, for example, ether, silyl ether, ester, carbonate, carbamate, phosphite, sulfonate, etc. can be formed to protect the hydroxyl group on the benzene ring, and examples thereof include but are not limited to methyl, methoxymethyl, methoxyethoxymethyl, 2-trimethylsilylethoxymethyl, methylthiomethyl, azidomethyl, cyanomethyl, phenylthiomethyl, 2,2-dichloro-1,1-difluoroethyl, 2-chloroethyl, 2-bromoethyl, tert-butyldimethylsilylethyl, tetrahydro Pyranyl, 1-ethoxyethyl, phenacyl, 4-bromophenacyl, cyclopropylmethyl, isopropyl, tert-butyl, cyclohexyl, o-nitrobenzyl, 2,6-dichlorobenzyl, 4-methylsulfinylbenzyl, tert-butylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, benzyloxymethyl, allyl, acetyl, benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, 4-(dimethylamino)carbonylbenzyl.

[0052] In some embodiments, R4 is benzyloxycarbonyl, benzyl, 2,4-dimethylbenzyl, 4-methoxybenzyl, 3,4-dichlorobenzyl, or 4-(dimethylamino)carbonylbenzyl.

[0053] R2 and R3 are each independently C 1-6 Alkyl, substituted C 1-6 Alkyl, benzyl, substituted benzyl, C 1-6 Alkyl C(O)-, substituted C 1-6 Alkyl C(O)-, examples include but are not limited to methyl, isopropyl, ethyl, 2,2,2-trichloroethyl, benzyl, 2-nitrobenzyl, acetyl; or R2, R3 and the connected atoms together form a five-membered, six-membered or seven-membered ring, wherein two or three of the ring atoms of the five-membered, six-membered or seven-membered ring are oxygen atoms, and the remaining ring atoms are carbon atoms, and the hydrogen on the ring carbon atoms may be substituted; in some embodiments, R2, R3 and the connected atoms together form the following structure.

[0054]

[0055] In a particular embodiment, R4 is benzyl, and R2, R3 and the attached atoms together form In some embodiments, the solvent is chlorobenzene, and the base is N,N-diisopropylethylamine; in some embodiments, 2,6-lutidine can be used as the solvent and the base, and the reaction is carried out at 100° C. to 150° C.

[0056] On the other hand, the present application also provides a method for preparing anlotinib or a pharmaceutically acceptable salt thereof, comprising: further converting the compound of formula V into anlotinib, wherein R1 is hydrogen or a hydroxyl protecting group, wherein the definition of the hydroxyl protecting group is the same as above, and when R1 is not hydrogen, the protecting group can be removed according to methods known in the art before participating in the reaction.

[0057]

[0058] On the other hand, the present application also provides a compound of formula IV, and the use of the compound of formula IV as an intermediate in the preparation of a compound of formula V or anlotinib or a pharmaceutically acceptable salt thereof; in a specific embodiment, the present application also provides a compound of formula IV-1, formula IV-2, and the use of the compound of formula IV-1, formula IV-2 as an intermediate in the preparation of a compound of formula V-1 or anlotinib or a pharmaceutically acceptable salt thereof.

[0059]

[0060] The term "alkyl" refers to a group of the formula C n H 2n+1 The alkyl group may be straight chain or branched. For example, the term "C 1-6 The term "alkyl" refers to an alkyl group containing 1 to 6 carbon atoms (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.).

[0061] "TMS" refers to trimethylsilyl.

[0062] "Ph" means phenyl.

[0063] "Bn" means benzyl.

[0064] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxo (i.e., =O), it means that two hydrogen atoms are replaced, and the oxo will not occur on the aromatic group. The substituent includes, but is not limited to, alkoxy, cyano, carboxyl, phenyl, halogen, hydroxyl, haloalkyl, nitro, trimethylsilyl, and trimethylsilylalkyl.

[0065] The term "alkoxy" refers to an -O-alkyl group.

[0066] The term "hydroxy" refers to an -OH group.

[0067] The term "cyano" refers to a -CN group.

[0068] The term "nitro" refers to a -NO2 group.

[0069] The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

[0070] When any variable (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 2 R's, each R has an independent choice.

[0071] The preparation method provided in the present application first converts the nitro group into an amino group and then cyclizes to form an indole ring; it not only avoids the formation of hydroxylamine by-products on the N of the indole ring, but also avoids the step of column chromatography purification. The synthesis process is simpler, the yield of the target product is high, the purity is good, and it is more suitable for industrial production. DETAILED DESCRIPTION

[0072] Example 1

[0073]

[0074] 140.0 kg of chlorobenzene, 9.0 kg of 7-(benzyloxy)-4-chloro-6-methoxyquinoline, 8.5 kg of 2-fluoro-3-((2-methyl-1,3-dioxolan-2-yl)methyl)-4-nitrophenol and 7.8 kg of N,N-diisopropylethylamine were added to a 200 L electrically heated reaction tank under stirring, and the temperature was raised. The heating temperature was controlled at 135±5°C, and the reaction was stirred for 48 hours. Samples were taken and monitored by TLC until the reaction endpoint (7-(benzyloxy)-4-chloro-6-methoxyquinoline was less than 5%).

[0075] After the reaction is completed, the liquid is concentrated under reduced pressure to a volume of 50-100L, and then transferred to a 200L glass-lined reaction tank and continued to be concentrated under reduced pressure until no liquid flows out. After the concentration is completed, 72.0kg of anhydrous ethanol is added, the temperature is raised, and the liquid temperature is controlled at 75-80°C and stirred for 5 hours, and then the temperature is slowly lowered to 0-10°C and stirred for 2 hours. Filter until no liquid flows out. The filter cake is rinsed with 18.0kg of anhydrous ethanol, filtered until no liquid flows out, the filter cake is collected, and air-dried for 4 hours to obtain the target product, Formula III-2 compound, with a purity of 99.1%.

[0076] ESI:521.17([M+H] + ).

[0077] 1H NMR (DMSO-d6, 500MHz) (ppm): δ = 8.54 (d, J = 5.0MHz, 1H); 7.89 (dd, J = 5.0MHz, J = 1.0MHz, 1H); 7.58-7.52 (m, 5H); 7.44 (dt, J = 8.0MHz, J = 1.5M Hz, 2H); 7.37 (t, J = 7.5MHz, 1H); 6.61 (d, J = 5.0MHz, 1H); 5.33 (s, 2H); 3.96 (s, 3H); 3.81-3.79 (m, 2H); 3.46 (t, J = 2.0MHz, 4H); 1.29 (s, 3H).

[0078] Example 2 Preparation of the compound of formula IV-2

[0079]

[0080] In a 500L glass-lined reaction tank, 25kg of dichloromethane and 1.0kg of the compound of formula III-2 were added under stirring, and the vacuum nitrogen was replaced 5 times. 0.3kg of 10% palladium carbon was added, and the vacuum nitrogen was replaced 5 times. The temperature was raised to 30-40°C, and 3.0kg of ammonium formate was added under nitrogen protection. The temperature of the feed liquid was controlled at 30-40°C, and the reaction was stirred for 2 hours. Samples were taken and monitored by TLC tracking until the reaction end point (the reaction raw materials and intermediate spots basically disappeared).

[0081] After the reaction is completed, transfer to a 1000L glass-lined reaction tank containing 1.6kg of anhydrous methanol and 10.6kg of dichloromethane, stir for 30 minutes, and filter press until no liquid flows out. The filtrate is transferred to a 300L glass-lined reaction tank and concentrated under reduced pressure. After concentrating to dryness, beat with 13.6kg of purified water twice, each time for 1 hour, shake and filter until no liquid flows out, and collect the filter cake.

[0082] 4.0 kg of anhydrous methanol and the filter cake obtained in the previous step were added to a 300 L glass-lined reaction tank under stirring, the temperature of the feed liquid was raised, the feed liquid temperature was controlled at 60-70 ° C and stirred for 4 hours, the temperature was lowered, the feed liquid temperature was controlled at 0-10 ° C and stirred for 2 hours. The mixture was filtered until no liquid flowed out, the filter cake was rinsed with 0.8 kg of anhydrous methanol, and filtered until no liquid flowed out to obtain the compound of formula IV-2 with a purity of 99.4%.

[0083] ESI: 401.15 ([M+H]+).

[0084] 1H NMR (DMSO-d6, 500MHz) (ppm): δ = 10.06 (s, 1H); 8.39 (d, J = 5.0MHz, 1H); 7.52 (s, 1H); 7.28 (s, 1H); 7.01 (t, J = 9.0MHz, 1H) ; 6.60 (d, J = 9.0MHz, 1H); 6.28 (d, J = 5.0MHz, 1H); 5.22 (s, 2H); 3.96 (s, 3H); 3.89-3.80 (m, 4H); 2.91 (s, 2H); 1.30 (s, 3H).

[0085] Example 3 Preparation of the compound of formula V-1:

[0086]

[0087] Under stirring, add 12.0kg of anhydrous methanol, 1.0kg of compound of formula Ⅳ-2 and 0.4L of hydrochloric acid solution to a 300L glass-lined reaction tank, raise the temperature, control the feed temperature at 60-70℃, react for 6 hours, take samples, and track and monitor the reaction end point by TLC (the spots of compound of formula Ⅳ-2 basically disappear). After the reaction is completed, cool to below 20℃, and adjust the pH of the feed solution to 8-9 with ammonia water. After the adjustment, transfer to a 500L glass-lined reaction tank, add 30.0kg of purified water, control the feed temperature at 0-10℃ and stir for 2 hours. Filter until no liquid flows out, rinse the filter cake with 1.0kg of purified water, filter until no liquid flows out, collect the filter cake, and air dry to obtain the compound of formula Ⅴ-1 with a purity of 99.5%.

[0088] ESI:339.11([M+H] + ).

[0089] 1 H NMR (DMSO-d6, 500MHz) (ppm): δ = 11.40 (s, 1H); 10.10 (s, 1H); 8.37 (d, J = 5.0MHz, 1H); 7.59 (s, 1H); 7.3 0 (s, 1H); 7.22 (d, J = 9.0 MHz, 1H); 6.99 (t, J = 8.0 MHz, 1H); 6.28-6.26 (m, 2H); 3.98 (s, 3H); 2.43 (s, 3H).

Claims

1. A method for preparing a compound of formula V-1, comprising: (1) In the presence of ammonium formate, the compound of formula III-2 is converted into the compound of formula IV-2, wherein the mass ratio of ammonium formate to the compound of formula III-2 is 3:1, the reaction solvent is one or more of methanol, ethanol and dichloromethane, the catalyst is palladium carbon, and the reaction temperature is 30-40°C, (2) Under hydrochloric acid conditions, with methanol or ethanol as solvent, the compound of formula IV-2 is converted into the compound of formula V-1, the mass volume ratio of hydrochloric acid to the compound of formula IV-2 is 0.4L / kg, and the reaction temperature is 60-70°C,

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