Method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine or salt thereof

Abstract

The present invention provides a method for preparing a compound of formula I or a salt thereof. In the method, the compound of formula I or the salt thereof is prepared from a compound of formula V serving as a starting material, and a compound of formula II or a salt thereof, a compound of formula III, a compound of formula IV or a mixture thereof formed in any ratio. Compared with the prior art, the present invention has the following significant features and advantages: (1) a key intermediate is prepared by means of different preparation strategies; and (2) compared with the prior art, the present invention has good selectivity, high yield, and higher product quality, and is more suitable for industrial production.

Description

A method for preparing 2-aminoethyl-3-chloro-5-trifluoromethylpyridine or a salt thereof Technical Field

[0001] This invention relates to the field of chemical synthesis, and more specifically to a method for preparing a compound of formula I or its salt. Background Technology

[0002] Patent WO2004016088A2 reports a three-step process to prepare compound I or its salts from compound X and ethyl cyanoacetate. The difficulty of this route lies in the reduction of compound XI to compound I, which generates related byproducts that affect product quality and yield. These byproducts include compounds of formulas VI, VII, VIII, and IX, with the following structures:

[0003] Compound VI

[0004] Compound VII

[0005] Compound VIII

[0006] Compound IX

[0007] wait.

[0008] Its synthetic route is as follows:

[0009] Patent WO2015071230A1 reports the reduction of compound XI to compound I. The generation of dehalogenated impurities can be suppressed and well controlled within 5% using palladium catalysts, catalyst modifiers and acids. However, the hydrogenation reaction conditions are only applicable to expensive palladium catalysts, resulting in high costs.

[0010] Patent WO2018114810A1 reports the conversion of compound XI into compound I by reduction, replacing the palladium catalyst with a Raney cobalt catalyst, but the reported yield is only 74.74%-76.59%, which is low.

[0011] Patent CN117417293A reports the conversion of compound XI into compound I by reduction, using sodium borohydride as a reducing agent. This raw material is expensive, and three equivalents of sodium borohydride are required for the reaction to proceed smoothly, generating a large amount of boron-containing byproducts that are difficult to dispose of.

[0012] Patent CN111004170A reports a three-step yield of 73.7%-76%, but the hydrogenation reaction conditions are only applicable to expensive palladium catalysts, resulting in high costs. The synthetic route is as follows:

[0013] To overcome the problems of the above route, patent WO20006067106A1 reported a route for preparing compound I or its salt from compound X through four steps. In step XI, compound XII is converted by reduction, and an acylation reagent is introduced to suppress the formation of impurities. The overall yield is 61%. However, this method has a relatively long reaction time and a low overall yield. The synthetic route is as follows: Summary of the Invention

[0014] To overcome the above problems, the present invention provides a method for preparing a compound of formula I or a salt thereof.

[0015] Therefore, the present invention provides a method for preparing compounds as shown in Formula I or salts thereof:

[0016] Make a compound having formula (II) or a salt thereof

[0017] Or compounds having formula (Ⅲ)

[0018] Or compounds having formula (Ⅳ)

[0019] A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or an agrochemically acceptable salt thereof.

[0020] in:

[0021] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0022] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl;

[0023] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0024] Hydrolysis involves adding one or a mixture of two or more of the following reagents: Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, Ca(OH)₂, Mg(OH)₂, triethylamine, N,N-diisopropylethylamine, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, methanesulfonic acid, citric acid, formic acid, or acetic acid; the hydrolysis solvent is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide.

[0025] Those skilled in the art should know that the use of two or more hydrolysis reagents in combination refers to the mixing of acids with acids and bases with bases.

[0026] The present invention also provides a method for preparing compounds as shown in Formula II or salts thereof:

[0027] Compound V is reduced in a solvent by catalyst A and reducing agent A to give compound II or its industrially acceptable salt.

[0028] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0029] Catalyst A is selected from one or more of palladium catalysts, platinum catalysts, nickel catalysts, cobalt catalysts, ruthenium catalysts, and rhodium catalysts, or a mixture of two or more of them in any proportion;

[0030] Reducing agent A is selected from one or a mixture of two or more of the following: hydrogen, hydrazine hydrate, methylhydrazine, cyclohexene, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate, and isopropanol.

[0031] The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, and 1,4-dioxane.

[0032] The present invention also provides a method for preparing compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or mixtures thereof in any proportion:

[0033] Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion;

[0034] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0035] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl;

[0036] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0037] The acylation reagent is one or a mixture of two or more of the following: acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, malonyl chloride, valeryl chloride, pteropenoyl chloride, 2-methylbutyryl chloride, n-hexanoyl chloride, benzoyl chloride, phthaloyl chloride, trifluoroacetyl chloride, 2-trifluoromethylbenzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, succinic anhydride, valeric anhydride, 2-methylbutyric anhydride, isovaleric anhydride, glutaric anhydride, pteropenoyl anhydride, n-hexanoic anhydride, benzoic anhydride, phthalic anhydride, trifluoroacetic anhydride, maleic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic acid propionic anhydride, methyl acetic anhydride, and propionic butyric anhydride.

[0038] Catalyst B is selected from one or more of palladium catalysts, platinum catalysts, nickel catalysts, cobalt catalysts, ruthenium catalysts, and rhodium catalysts, or a mixture of two or more of them in any proportion;

[0039] Reducing agent B is selected from one or a mixture of two or more of hydrogen, cyclohexene, cyclohexadiene, formic acid, sodium formate or potassium formate;

[0040] The solvent is selected from one or a mixture of two or more of the following: N-methylpyrrolidone, N-ethylpyrrolidone, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolium ketone, tetramethylurea, sulfolane, dimethyl sulfoxide, ethylene carbonate, 1,3-propanediol carbonate, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amylmethyl ether, 2-methyl-tetrahydrofuran, cyclopentylmethyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, toluene, xylene, ethylbenzene, acetic acid, acetic anhydride, or propionic anhydride.

[0041] Preferably, the present invention provides a method for preparing compounds or salts thereof as shown in Formula I.

[0042] Make a compound having formula (II) or a salt thereof

[0043] Or compounds having formula (Ⅲ)

[0044] Or compounds having formula (Ⅳ)

[0045] A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or an agrochemically acceptable salt thereof.

[0046] in:

[0047] R1 is selected from hydroxyl, amino, C1-C5 alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C5)amino, di(C6-C5)amino 12 Aryl)amino; further, when R1 is selected from di(C1-C5 alkyl)amino, the two C1-C5 alkyl groups can be linked together with N atoms to form a 3- to 10-membered ring structure; even further, the two C1-C5 alkyl groups can be linked together with N atoms to form a 5- to 6-membered ring structure;

[0048] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl;

[0049] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0050] Hydrolysis is performed by adding one or more of the following reagents: Na2CO3, NaHCO3, K2CO3, KHCO3, NaOH, KOH, Ca(OH)2, Mg(OH)2, triethylamine, N,N-diisopropylethylamine, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, methanesulfonic acid, citric acid, formic acid, or acetic acid.

[0051] The hydrolysis solvent is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide; the reaction temperature is 0°C to 150°C.

[0052] More preferably, the present invention provides a method for preparing compounds as shown in Formula I or salts thereof.

[0053] Make a compound having formula (II) or a salt thereof

[0054] Or compounds having formula (Ⅲ)

[0055] Or compounds having formula (Ⅳ)

[0056] A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or a chemically acceptable salt thereof.

[0057] in:

[0058] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy.

[0059] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, 2-Trifluoromethylphenyl;

[0060] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent Hydrolysis involves adding one or a mixture of two or more of the following reagents: Na₂CO₃, NaHCO₃, K₂CO₃, KHCO₃, NaOH, KOH, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, formic acid, or acetic acid; the hydrolysis solvent is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide.

[0061] The reaction temperature is from 0℃ to 150℃.

[0062] More preferably, after hydrolysis and decarboxylation under acidic conditions, the acidic water is removed by adding solvents such as toluene, xylene, chlorobenzene, trifluorotoluene, and trimethylbenzene that are azeotropic with water. The compound of formula I or its salt will precipitate as dispersed solid particles, and the product is obtained by filtration and drying.

[0063] Preferably, the present invention provides a method for preparing a compound as shown in Formula II or a salt thereof, wherein the compound of Formula V is reduced in a solvent by a catalyst A and a reducing agent A to obtain the compound of Formula II or an industrially acceptable salt thereof.

[0064] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 aryl)amino; when R1 is selected from di(C1-C1)amino; 10 When alkyl)amino, the two C1-C 10Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0065] Catalyst A is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon;

[0066] When reducing agent A is selected from hydrogen, the pressure is selected from 0.1-5 MPa; when reducing agent A is selected from hydrazine hydrate, methylhydrazine, cyclohexene, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate or isopropanol, the amount of reducing agent A is 0.5-20 equivalents of compound V.

[0067] The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and ammonia.

[0068] More preferably, the present invention provides a method for preparing compounds as shown in Formula II and their salts, wherein the compound of Formula V is reduced in a solvent by a catalyst A and a reducing agent A to obtain the compound of Formula II or its industrially acceptable salt.

[0069] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy. Catalyst A is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon;

[0070] Reducing agent A is selected from one or a mixture of two or more of the following: hydrogen, hydrazine hydrate, methylhydrazine, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate, and isopropanol.

[0071] The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and ammonia.

[0072] More preferably, the intermediate in this step can be obtained through simple post-processing methods such as filtration, solvent extraction, water washing, and concentration under normal or reduced pressure, which are common in this field. It can be used directly in the next reaction without the need for complex purification methods.

[0073] A preferred method for preparing compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or mixtures thereof in any proportion,

[0074] Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion;

[0075] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 aryl)amino; when R1 is selected from di(C1-C1)amino; 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0076] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl;

[0077] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0078] The acylation reagent is one or a mixture of two or more of the following: acetyl chloride, propionyl chloride, butyryl chloride, malonyl chloride, valeryl chloride, pteropenoyl chloride, n-hexanoyl chloride, benzoyl chloride, phthaloyl chloride, trifluoroacetyl chloride, 2-trifluoromethylbenzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, succinic anhydride, valeric anhydride, isovaleric anhydride, glutaric anhydride, pteropenoyl anhydride, n-hexanoic anhydride, benzoic anhydride, phthalic anhydride, trifluoroacetic anhydride, maleic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic acid propionic anhydride, methyl acetic anhydride, and propionic butyric anhydride.

[0079] Catalyst B is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon;

[0080] When reducing agent B is selected from hydrogen, the pressure is selected from 0.1-5 MPa; when reducing agent B is selected from cyclohexene, cyclohexadiene, formic acid, sodium formate, potassium formate or ammonium formate, the amount of reducing agent B is 0.5-20 equivalents of compound V;

[0081] The solvent is selected from one or a mixture of two or more of the following: toluene, xylene, ethylbenzene, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amylmethyl ether, 2-methyl-tetrahydrofuran, cyclopentylmethyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, acetic anhydride, or propionic anhydride.

[0082] The amount of acylation reagent used is 0.1-20 equivalents of compound of formula V;

[0083] The reaction temperature is 10-160℃.

[0084] A more preferred method for preparing compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or mixtures thereof in any proportion:

[0085] Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion;

[0086] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy.

[0087] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, 2-Trifluoromethylphenyl;

[0088] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0089] The acylation reagent is one or a mixture of two or more of the following: acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic and propionic anhydride, methyl acetic anhydride, propionic and butyric anhydride, methyl formate, and ethyl formate.

[0090] Catalyst B is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon;

[0091] The reducing agent B is selected from hydrogen gas, and the pressure is selected from 0.1-5 MPa;

[0092] The solvent is selected from one or a mixture of two or more of the following: toluene, xylene, ethylbenzene, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amylmethyl ether, 2-methyl-tetrahydrofuran, cyclopentylmethyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, acetic anhydride, or propionic anhydride.

[0093] The amount of acylation reagent used is 0.1-20 equivalents of compound of formula V;

[0094] The reaction temperature is 20-130℃.

[0095] Preferably, the compound of formula II or its salt, compound of formula III, compound of formula IV, or a mixture thereof formed in any proportion, obtained from the reaction contains two or three of the compounds of formula II or its salt, compound of formula III, and compound of formula IV.

[0096] More preferably, the intermediate in this step can be obtained through simple post-processing methods such as filtration, solvent extraction, water washing, and concentration under normal or reduced pressure, which are common in this field. It can be used directly in the next reaction without the need for complex purification methods.

[0097] This invention provides compounds of formula II or salts thereof:

[0098] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or heteroaryloxy group containing one or two atoms selected from nitrogen, oxygen, and sulfur. When R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0099] This invention also provides compounds of formula III:

[0100] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0101] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, Or 2-trifluoromethylphenyl.

[0102] This invention also provides compounds of formula IV:

[0103] R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures;

[0104] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent

[0105] Preferred compounds of formula II or their salts,

[0106] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy.

[0107] The preferred compound of formula III,

[0108] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy.

[0109] R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, Or 2-trifluoromethylphenyl.

[0110] The preferred compound of formula IV,

[0111] R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy.

[0112] R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent

[0113] The beneficial effects of the present invention are as follows: Compared with the prior art, the present invention has the following significant features and advantages: (1) different preparation strategies are adopted for key intermediates; (2) compared with the existing methods, the present invention has good selectivity, high yield, higher product quality, and is more suitable for industrial production. Detailed Implementation

[0114] The following examples are for illustrative purposes only and should not be construed as limiting the invention in any way. The scope of protection of this invention is defined by the claims. Simple substitutions or modifications made to this invention by those skilled in the art are all within the scope of the technical solutions protected by this invention.

[0115] Several methods for preparing the compounds of the present invention are described in detail in the following schemes and examples. The raw materials can be commercially available or prepared by methods known in the literature or as detailed in the description. Those skilled in the art will understand that other synthetic routes can also be used to synthesize the compounds of the present invention. Although specific raw materials and conditions in the synthetic routes have been described below, they can be easily replaced with other similar raw materials and conditions. Variations or modifications to the preparation methods of the present invention, such as various isomers of the compounds, are included within the scope of the present invention. Furthermore, the preparation methods described below can be further modified according to the disclosure of the present invention using conventional chemical methods well known to those skilled in the art. For example, protecting appropriate groups during the reaction process, etc.

[0116] The following method examples are provided to further illustrate the preparation methods of the present invention. The specific substances, types, and conditions used are intended to further explain the invention and are not intended to limit its reasonable scope. The reagents used in the synthetic compounds described below are either commercially available or can be easily prepared by those skilled in the art.

[0117] The analytical instruments described in the examples are as follows:

[0118] I. High Performance Liquid Chromatography (hereinafter referred to as HPLC): Using an Agilent Technologies 1260 Infinity II instrument.

[0119] Column: Agilent InfinityLab Poroshell 120EC-C18, 4.6*75mm, 2.7Micron

[0120] Mobile phase: A: 0.1% phosphoric acid-water solution; B: acetonitrile; Temperature: 30℃

[0121] Gradient: 10% B to 95% B in 8.68 min; 95% B in 1.32 min

[0122] Flow rate: 1.3 mL / min

[0123] Detection wavelength: 220nm.

[0124] In addition, the proton nuclear magnetic resonance spectra described below (hereinafter referred to as...) 1 The chemical shift values ​​of H-NMR were measured at 400 MHz (Bruker, AVANCE III HD 400M) in deuterated chloroform (CDCl3) using Me4Si (tetramethylsilane) as the reference material. When measured in deuterated dimethyl sulfoxide, the chemical shift values ​​are shown as "(DMSO-d6)" in the data. It should be noted that... 1 The symbols in the chemical shift values ​​of H-NMR have the following meanings:

[0125] s: singlet, d: doublet, dd: doublett, dt: doublettuplet, td: triplettuplet, ddd: doublettuplet, t: triplet, q: quartet, sep: septet, m: multiplet, brs: broad singlet. Furthermore, in cases where two or more stereoisomers are present, the chemical shift values ​​for the resolvable signal are marked with "and".

[0126] Examples of representative compounds are given below. The synthesis methods of other compounds are similar and will not be described in detail here.

[0127] Example 1: Preparation of the hydrochloride salt of compound I

[0128] Step (A):

[0129] In an autoclave, Raney nickel catalyst (2.00 g), toluene (30 mL), V-1 (10.00 g, 35.89 mmol), and acetic anhydride (18.32 g, 179.45 mmol) were added, and hydrogen gas at 4 MPa was introduced. The mixture was heated to 120 °C and reacted for 25 hours. HPLC analysis showed that compound II-1 accounted for 0.04%, compound III-1 accounted for 49.33%, and compound IV-1 accounted for 45.00%. After the reaction was completed, the temperature was lowered to 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0130] Step (B):

[0131] Add 50 mL of 35% hydrochloric acid solution to the above oily substance, heat to reflux, and react for 16 hours. HPLC analysis showed that compound I accounted for 93%. Add 50 mL of toluene to the reaction solution, heat to reflux for 5 hours to remove water, cool and filter, wash with a small amount of 2-methyl-tetrahydrofuran, and dry to obtain the hydrochloride salt of compound I (8.07 g). The two-step yield was 86.13%, and the purity was 99%.

[0132] NMR data for compound III-1: 1 H NMR (400MHz, DMSO-d6) δ8.97–8.88(m,1H),8.52–8.45(m,1H),7.89(t,J=6.0Hz,1H),4.57(dd, J=8.1,5.9Hz,1H),3.83(dt,J=13.3,6.1Hz,1H),3.57(s,3H),3.51–3.40(m,1H),1.69(s,3H).

[0133] NMR data for compound IV-1: 1 H NMR (400MHz, DMSO-d6) δ9.00–8.91(m,1H),8.53–8.40(m,1H),4.74(dd,J=8.0,6.5Hz,1H ), 4.38 (dd, J=14.5, 6.5Hz, 1H), 4.17 (dd, J=14.5, 8.0Hz, 1H), 3.58 (s, 3H), 2.23 (s, 6H).

[0134] NMR data of the hydrochloride salt of compound I: 1 H NMR (400MHz, Deuterium Oxide) δ8.76(brs,1H),8.26(m,1H),3.53–3.44(m,2H),3.43–3.35(m,2H).

[0135] Example 2: Preparation of the hydrochloride salt of compound I

[0136] Step (A):

[0137] In a high-pressure reactor, Raney nickel catalyst (2.00 g), ethyl acetate (70 mL), V-2 (10.00 g, 34.17 mmol), and acetic anhydride (11.00 g, 107.84 mmol) were added, and hydrogen gas at 4 MPa was introduced. The mixture was heated to 120 °C and reacted for 25 hours. HPLC analysis showed that compound II-2 accounted for 0.2%, compound III-2 accounted for 51.17%, and compound IV-2 accounted for 40.36%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0138] Step (B):

[0139] Add 35% hydrochloric acid (30 mL) to the above oily substance, heat to reflux, and react for 16 hours. HPLC analysis showed that compound I accounted for 90.11%. Add toluene (50 mL) to the reaction solution, heat to reflux and dehydrate for 4 hours, cool and filter, wash with a small amount of 2-methyl-tetrahydrofuran, and dry to obtain the hydrochloride salt of compound I (7.60 g). The two-step yield was 85.26%, and the purity was 99%.

[0140] NMR data for compound II-2: 1 H NMR(400MHz, CDCl3-d)δ8.77–8.72(m,0.55H),8.71–8.64(m,0.45H),7.97–7.93(m,0.55H),7.93–7.88(m,0.45H), 4.56–4.47(m,0.45H),4.44–4.36(m,0.55H),4.25–4.08(m,2H),3.57–3.16(m,2H),2.18(s,2H),1.33–1.15(m,3H).

[0141] NMR data for compound III-2: 1 H NMR (400MHz, DMSO-d6) δ8.96–8.92(m,1H),8.48–8.44(m,1H),7.93(t,J=6.0Hz,1H),4.60(dd,J=8.0,6 .1Hz,1H),4.14–4.05(m,2H),3.93–3.83(m,1H),3.61–3.47(m,1H),1.74(s,3H),1.10(t,J=7.1Hz,3H).

[0142] NMR data for compound IV-2: 1 H NMR (400MHz, DMSO-d6) δ8.93–8.84(m,1H),8.45–8.37(m,1H),4.75–4.64(m,1H),4.37(dd,J=14.5, 6.7Hz, 1H), 4.14 (dd, J=14.5, 7.9Hz, 1H), 4.02 (q, J=7.1Hz, 2H), 2.20 (s, 6H), 1.03 (t, J=7.1Hz, 3H).

[0143] Example 3: Preparation of the hydrochloride salt of compound I

[0144] Step (A):

[0145] In a high-pressure reactor, Raney nickel catalyst (0.40 g), 2-methyl-tetrahydrofuran (14 mL), V-2 (2.00 g, 6.83 mmol), and di-tert-butyl dicarbonate (4.47 g, 20.49 mmol) were added, and hydrogen gas was introduced at 3 MPa. The mixture was heated to 120 °C and reacted for 20 hours. HPLC analysis showed that compound II-2 accounted for 0.12%, compound III-3 accounted for 89.06%, and compound IV-3 was not observed. After the reaction was completed, the temperature was lowered to 10-20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0146] NMR data for compound III-3: 1 H NMR (400MHz, DMSO-d6) δ8.99–8.91(m,1H),8.55–8.44(m,1H),6.83(t,J=6.0Hz,1H),4.58(dd,J=8.4,5 .4Hz,1H),4.15–3.98(m,2H),3.78–3.62(m,1H),3.58–3.39(m,1H),1.30(s,9H),1.11(t,J=7.1Hz,3H).

[0147] Step (B):

[0148] Add 20 mL of 35% hydrochloric acid solution to the above oily substance, heat to 100 °C, and react for 3 hours. HPLC analysis showed that compound I accounted for 92.11%. Add 20 mL of toluene to the reaction solution, heat to reflux and dehydrate for 5 hours, cool and filter, wash with a small amount of 2-methyl-tetrahydrofuran, and dry to obtain the hydrochloride salt of compound I (1.53 g). The two-step yield was 85.86%, and the purity was 99%.

[0149] Example 4: Preparation of the hydrochloride salt of compound I

[0150] Step (A):

[0151] In a high-pressure reactor, Raney nickel catalyst (1.00 g), V-2 (10.00 g, 34.17 mmol), and acetic anhydride (50 mL) were added, and hydrogen gas at 3 MPa was introduced. The mixture was heated to 130 °C and reacted for 22 hours. HPLC analysis showed that compound II-2 accounted for 0.10%, compound III-2 accounted for 6.97%, and compound IV-2 accounted for 88.46%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0152] Step (B):

[0153] Add 50 mL of 35% hydrochloric acid solution to the above oily substance, heat to reflux, and react for 16 hours. HPLC analysis showed that compound I accounted for 96.53%. Add 50 mL of toluene to the reaction solution, heat to reflux and dehydrate for 4 hours, cool and filter, wash with a small amount of tetrahydrofuran, and dry to obtain the hydrochloride salt of compound I (8.27 g). The two-step yield was 92.94%, and the purity was 99%.

[0154] Example 5: Preparation of the hydrochloride salt of compound I

[0155] Step (A):

[0156] In a high-pressure reactor, Raney nickel catalyst (0.50 g), V-3 (2.00 g, 6.86 mmol), 2-methyl-tetrahydrofuran (15 mL), and acetic anhydride (2.80 g, 27.43 mmol) were added, and hydrogen gas at 3 MPa was introduced. The mixture was heated to 115 °C and reacted for 22 hours. HPLC analysis showed that compound II-3 accounted for 0.02%, compound III-4 accounted for 58.66%, and compound IV-4 accounted for 27.77%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0157] Step (B):

[0158] 35% hydrochloric acid (15 mL) was added to the above oily substance, and the mixture was heated to reflux and reacted for 16 hours. HPLC analysis showed that compound I accounted for 89.51%. Toluene (15 mL) was added to the reaction solution, and the mixture was heated to reflux for dehydration for 10 hours. The mixture was then cooled, filtered, washed with a small amount of 2-methyl-tetrahydrofuran, and dried to obtain the hydrochloride salt of compound I (1.52 g). The two-step yield was 85.00%, and the purity was 99%.

[0159] NMR data for compound III-4: 1 H NMR(400MHz,DMSO-d6)δ9.00–8.93(m,1H),8.51–8.45(m,1H),7.94(t,1H),4.80–4.65 (m,1H),3.77–3.66(m,1H),3.62–3.49(m,1H),2.94(s,3H),2.85(s,3H),1.75(s,3H).

[0160] NMR data for compound IV-4: 1 H NMR (400MHz, DMSO-d6) δ9.04–8.96(m,1H),8.51(d,J=2.0Hz,1H),4.94(t,J=7.2Hz,1H),4.27–4.13(m,2H),2.83(s,3H),2.83(s,3H),2.25(s,6H).

[0161] Example 6: Preparation of hydrobromide of compound I

[0162] Step (A):

[0163] In a high-pressure reactor, Raney nickel catalyst (1.25 g), V-4 (5.00 g, 16.30 mmol), toluene (15 mL), and acetic anhydride (3.50 g, 34.30 mmol) were added, and hydrogen gas was introduced at 4 MPa. The mixture was heated to 100 °C and reacted for 22 hours. HPLC analysis showed that compound II-4 accounted for 0.11%, compound III-5 accounted for 82.21%, and compound IV-5 accounted for 8.39%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0164] Step (B):

[0165] Add 20 mL of 30% hydrobromic acid aqueous solution to the above oily substance, heat to reflux, and react for 20 hours. HPLC analysis showed that compound I accounted for 92.17%. Add 30 mL of toluene to the reaction solution, heat to reflux and dehydrate for 10 hours, cool and filter, wash with a small amount of 2-methyl-tetrahydrofuran, and dry to obtain hydrobromide of compound I (4.24 g). The two-step yield was 85.05%, and the purity was 99%.

[0166] NMR data for compound III-5: 1 H NMR (400MHz, DMSO-d6) δ9.00–8.95(m,1H),8.54–8.49(m,1H),7.92(t,1H),4.99–4.85(m,1H),4.59–4. 50(m,1H),3.91–3.80(m,1H),3.58–3.46(m,1H),1.74(s,3H),1.17–1.15(m,3H),1.07(d,J=6.2Hz,3H).

[0167] Example 7: Preparation of Compound I

[0168] Step (A):

[0169] In a high-pressure reactor, Raney nickel catalyst (0.1 g), V-5 (2.00 g, 6.52 mmol), ethyl acetate (15 mL), and benzoic anhydride (7.76 g, 34.30 mmol) were added, and hydrogen gas at 3 MPa was introduced. The mixture was heated to 115 °C and reacted for 22 hours. HPLC analysis showed that compound II-5 accounted for 0.33%, compound III-6 accounted for 87.9%, and compound IV-6 was not observed. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0170] Step (B):

[0171] 35% hydrochloric acid (10 mL) was added to the above oily substance, and the mixture was heated to reflux and reacted for 20 hours. HPLC analysis showed that compound I accounted for 88.5%. Toluene (10 mL) was added to the reaction solution, and the mixture was heated to reflux for dehydration for 10 hours. The temperature was lowered, and the pH was adjusted to 8-10 with 5% sodium hydroxide solution. The toluene phase was separated into layers, and the solvent was removed by vacuum distillation to obtain compound I (1.27 g). The two-step yield was 86.92%, and the purity was 96%.

[0172] NMR data for compound III-6: 1H NMR(400MHz, DMSO-d6)δ9.02–8.95(m,1H),8.60(t,J=5.8Hz,1H),8.47(d,J=2.0Hz,1H),7.80–7.74(m,2H),7.52–7.45(m,1H),7.46 –7.39(m,2H),4.93–4.81(m,1H),4.25–4.13(m,1H),4.09–3.93(m,2H),3.85–3.74(m,1H),1.57–1.41(m,2H),0.72(t,J=7.4Hz,3H).

[0173] Example 8: Preparation of the hydrochloride salt of compound I

[0174] Step (A):

[0175] In a high-pressure reactor, Raney cobalt catalyst (0.25 g), V-6 (5.00 g, 15.59 mmol), toluene (15 mL), and acetic anhydride (3.50 g, 34.30 mmol) were added, and hydrogen gas was introduced at 2 MPa. The mixture was heated to 115 °C and reacted for 22 hours. HPLC analysis showed that compound II-6 accounted for 0.02%, compound III-7 accounted for 71.46%, and compound IV-7 accounted for 18.27%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney cobalt catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0176] Step (B):

[0177] 15 mL of 35% hydrochloric acid solution was added to the above oily substance, and the mixture was heated to reflux and reacted for 20 hours. HPLC analysis showed that compound I accounted for 91.21%. Toluene (25 mL) was added to the reaction solution, and the mixture was heated to reflux for dehydration for 10 hours. The mixture was then cooled, filtered, washed with a small amount of 2-methyl-tetrahydrofuran, and dried to obtain the hydrochloride salt of compound I (3.54 g). The two-step yield was 86.75%, and the purity was 99%.

[0178] NMR data for compound III-7: 1 H NMR(400MHz,DMSO-d6)δ8.97–8.92(m,1H),8.53–8.46(m,1H),7.96(t,1H),4.70–4.51(m,1H),4.08–3.97(m,2H) ,3.94–3.84(m,1H),3.58–3.46(m,1H),1.73(s,3H),1.49–1.38(m,2H),1.17–1.08(m,2H),0.75(t,J=7.4Hz,3H).

[0179] Example 9: Preparation of the hydrochloride salt of compound I

[0180] 35% hydrochloric acid (15 mL) was added to Ⅲ-2 (5.00 g, 14.76 mmol), the mixture was heated to reflux, and the reaction was carried out for 20 hours. HPLC analysis showed that compound I accounted for 98%. Toluene (25 mL) was added to the reaction solution, and the mixture was heated to reflux for dehydration for 10 hours. The mixture was then cooled, filtered, washed with a small amount of 2-methyl-tetrahydrofuran, and dried to obtain the hydrochloride salt of compound I (3.81 g), with a yield of 98.9% and a purity of 99%.

[0181] Example 10: Preparation of Compound I

[0182] Add 15% sodium hydroxide solution (15 mL) to IV-4 (5.00 g, 13.17 mmol), heat to reflux, and react for 8 hours. HPLC analysis showed that compound I accounted for 98%. Ethyl acetate (25 mL) was added to the reaction solution, and the layers were extracted. The solvent was removed under reduced pressure to obtain 2.75 g of compound I.

[0183] Example 11: Preparation of the hydrochloride salt of compound I

[0184] Step (A):

[0185] In a high-pressure reactor, Raney nickel catalyst (1.5 g), V-2 (10.00 g, 34.17 mmol), 2-trifluoromethylbenzoic anhydride (18.54 g, 51.20 mmol), and toluene (50 mL) were added. Hydrogen gas at 3.5 MPa was introduced, and the temperature was raised to 110 °C for 22 hours. HPLC analysis showed that compound II-2 was not observed, compound III-8 accounted for 88.35%, and compound IV-8 accounted for 2.41%. After the reaction was completed, the temperature was lowered to about 20 °C, and the Raney nickel catalyst was removed by filtration. The solvent in the filtrate was removed by vacuum distillation to obtain an oily substance. This oily substance was directly added to the next reaction without purification.

[0186] Step (B):

[0187] Add 35% hydrochloric acid (50 mL) to the above oily substance, heat to 100 °C, and react for 20 hours. HPLC analysis showed that compound I accounted for 91.19%. Add toluene (25 mL) to the reaction solution, heat to reflux and dehydrate for 10 hours, cool and filter, wash with a small amount of 2-methyl-tetrahydrofuran, and dry to obtain the hydrochloride salt of compound I (7.81 g). The two-step yield was 87.51%, and the purity was 99%.

[0188] NMR data for compound III-8: 1 H NMR(400MHz, DMSO-d6)δ9.00–8.91(m,1H),8.63(t,J=5.8Hz,1H),8.58–8.50(m,1H),7.77–7.66(m,2H),7. 65–7.57(m,1H),7.43–7.36(m,1H),4.83–4.71(m,1H),4.05–4.01(m,1H),3.91–3.76(m,1H),3.63(s,3H).

[0189] Example 12: Preparation of Compound I

[0190] Step (A):

[0191] In a high-pressure reactor, 5% palladium hydroxide / carbon (40 mg), V-2 (1.00 g, 3.47 mmol), concentrated sulfuric acid (0.22 mL), and ethanol (5 mL) were added. Hydrogen gas at 3 MPa was introduced, and the temperature was raised to 90 °C for 18 hours. HPLC analysis showed that compound II-2 accounted for 68%. After the reaction was completed, the temperature was lowered to about 20 °C, the catalyst was removed by filtration, and the solvent was removed by vacuum distillation of the filtrate to obtain a yellow solid. This solid was directly added to the next reaction without purification.

[0192] NMR data of compound II-2: 1 H NMR(400MHz, CDCl3-d)δ8.77–8.72(m,0.55H),8.71–8.64(m,0.45H),7.97–7.93(m,0.55H),7.93–7.88(m,0.45H), 4.56–4.47(m,0.45H),4.44–4.36(m,0.55H),4.25–4.08(m,2H),3.57–3.16(m,2H),2.18(s,2H),1.33–1.15(m,3H).

[0193] Step (B):

[0194] Add 5 mL of 15% sulfuric acid aqueous solution to the above oily substance, heat to reflux, and react for 2 hours. HPLC analysis showed that compound I accounted for 65%. Remove the solvent under reduced pressure, add 5 mL of tetrahydrofuran to slurry, filter to obtain a filter cake, add the filter cake to a mixture of 5 mL of 5% sodium hydroxide solution and 5 mL of ethyl acetate, extract and separate the layers to obtain the ethyl acetate phase, and distill to remove the solvent to obtain compound I (0.48 g). The two-step yield was 62.63%, and the purity was 96%.

[0195] NMR data for compound I:1 H NMR (400MHz, CDCl3-d) δ8.71(s,1H),7.89(s,1H),3.20–3.14(m,4H),1.26(s,2H).

[0196] According to the present invention, the combinations of R1, R2, R3, R4, catalyst B and reducing agent B are shown in Table 1:

[0197] Table 1

[0198] According to the present invention, the combination of R1, catalyst A and reducing agent A is shown in Table 2:

[0199] Table 2

[0200] Comparative Example

[0201] Comparative examples were conducted using the method disclosed in patent CN111004170A:

[0202] The method disclosed in Example 6 of CN111004170A was used to prepare the hydrochloride salt of compound I from compound X, and the following experiments were repeated:

[0203] 22.6 g of ethyl cyanoacetate, 160 ml of methanol, and 2% tetramethylammonium chloride were added to a 250 ml reaction flask. 5.8 g of sodium hydride was added in portions under uniform stirring. The mixture was stirred at 25°C for 0.5 h, and then 43 g of 2,3-dichloro-5-(trifluoromethyl)pyridine was slowly added dropwise. After the addition was complete, the temperature was raised to 70°C and the reaction was stopped for 1 h. The insoluble matter was filtered off to obtain the reaction mother liquor of ethyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyanoacetate, with a purity of 98% and a theoretical yield of 95%. The above ethyl 2-[3-chloro-5-(trifluoromethyl)-2-pyridyl]cyanoacetate reaction mother liquor after filtering out the insoluble matter was directly added to a 500 ml hydrogenation reactor. 5% palladium on carbon and 2 ml of ammonia water were added as catalyst. Hydrogen gas was introduced to maintain the hydrogen pressure at atmospheric pressure. The temperature was raised to 60°C and the reaction was stirred for 3 h. The reaction was stopped, the catalyst was filtered off, and the product was distilled under reduced pressure. Under the given conditions, 90 ml of solvent was collected, and the residue was transferred to a 250 ml reaction vessel. 100 ml of N,N-dimethylformamide, with pH adjusted to 3 using 5% sulfuric acid, was used as the solvent. The mixture was heated to 110°C and refluxed for 3 hours. After cooling, it was distilled under reduced pressure. Under the conditions, 100 ml of N,N-dimethylformamide was collected and recovered. The residue was a black solid. After rinsing and filtering with a small amount of petroleum ether, 37.8 g of white solid was obtained, which was 3-chloro-5-(trifluoromethyl)-2-ethylaminopyridine hydrochloride, with a yield of 76% and a purity of 98%.

[0204] Under these conditions, the following problem was found in the preparation of the hydrochloride salt of compound I from compound X according to Example 6 of patent CN111004170A:

[0205] (1) The raw material used is ethyl cyanoacetate, and the solvent is methanol. The first step of the reaction only yields a small amount of compound V-2. The main impurities are separated and purified. After NMR identification, the structure of the separated compound is compound V-1, which is inconsistent with the patent description. In the presence of a large amount of methanol and alkali, it is obvious to a person skilled in the art that transesterification occurs under the above conditions.

[0206] The NMR spectra of compound V-1 are as follows: 1 H NMR(400MHz,DMSO-d6)δ14.49(s,0.84H),9.13–8.86(m,0.16H),8.66–8.59(m,0.16 H),8.51–8.42(m,0.84H),8.29–8.19(m,0.84H),6.28(s,0.16H),3.76–3.62(m,3H).

[0207] (2) Following the operating procedure reported in the above patent, the experimental results showed that the hydrochloride salt of Formula I compound could not be detected, which is inconsistent with the results described in the above patent.

Claims

1. A method for preparing a compound or a salt thereof as shown in Formula I, characterized in that: To make a compound having formula (II) or a salt thereof, Or compounds having formula (Ⅲ), Or compounds having formula (Ⅳ), A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or a chemically acceptable salt thereof. in: R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, Or 2-trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent The hydrolysis process involves adding one or a mixture of two or more of the following reagents: Na2CO3, NaHCO3, K2CO3, KHCO3, NaOH, KOH, Ca(OH)2, Mg(OH)2, triethylamine, N,N-diisopropylethylamine, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, methanesulfonic acid, citric acid, formic acid, or acetic acid. The solvent used for the hydrolysis is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide.

2. A method for preparing a compound as shown in Formula II or a salt thereof, characterized in that: Compound V is reduced in a solvent by catalyst A and reducing agent A to give compound II or its industrially acceptable salt. R1 is selected from hydroxyl, amino, C1-C. 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures; The catalyst A is selected from one or more of palladium catalysts, platinum catalysts, nickel catalysts, cobalt catalysts, ruthenium catalysts, or rhodium catalysts, or a mixture of two or more of them in any proportion; The reducing agent A is selected from one or a mixture of two or more of the following: hydrogen, hydrazine hydrate, methylhydrazine, cyclohexene, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate, or isopropanol. The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, or ammonia.

3. A method for preparing compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or mixtures thereof in any proportion, characterized in that: Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion; R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, Or 2-trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent The acylation reagent is one or a mixture of two or more of the following: acetyl chloride, propionyl chloride, butyryl chloride, isobutyryl chloride, malonyl chloride, valeryl chloride, pteropenoyl chloride, 2-methylbutyryl chloride, n-hexanoyl chloride, benzoyl chloride, phthaloyl chloride, trifluoroacetyl chloride, 2-trifluoromethylbenzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, succinic anhydride, valeric anhydride, 2-methylbutyric anhydride, isovaleric anhydride, glutaric anhydride, pteropenoyl anhydride, n-hexanoic anhydride, benzoic anhydride, phthalic anhydride, trifluoroacetic anhydride, maleic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic acid propionic anhydride, methyl acetic anhydride, propionic butyric anhydride, methyl formate or ethyl formate. The catalyst B is selected from one or more of palladium catalysts, platinum catalysts, nickel catalysts, cobalt catalysts, ruthenium catalysts, or rhodium catalysts, or a mixture of two or more of them in any proportion; The reducing agent B is selected from one or more of hydrogen, cyclohexene, cyclohexadiene, formic acid, sodium formate, or potassium formate, in any proportion. The solvent is selected from one or more of N-methylpyrrolidone, N-ethylpyrrolidone, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolium ketone, tetramethylurea, sulfolane, dimethyl sulfoxide, ethylene carbonate, 1,3-propanediol carbonate, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amylmethyl ether, 2-methyl-tetrahydrofuran, cyclopentylmethyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, toluene, xylene, ethylbenzene, acetic acid, acetic anhydride, or propionic anhydride, in any proportion.

4. A method for preparing a compound of formula I or a salt thereof according to claim 1, characterized in that: To make a compound having formula (II) or a salt thereof, Or compounds having formula (Ⅲ), Or compounds having formula (Ⅳ), A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or a chemically acceptable salt thereof. in: R1 is selected from hydroxyl, amino, C1-C 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino or di(C6-C) 12 aryl)amino; when R1 is selected from di(C1-C1)amino; 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, Or 2-trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent The hydrolysis process involves adding one or a mixture of two or more of the following reagents: Na2CO3, NaHCO3, K2CO3, KHCO3, NaOH, KOH, Ca(OH)2, Mg(OH)2, triethylamine, N,N-diisopropylethylamine, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, methanesulfonic acid, citric acid, formic acid, or acetic acid. The solvent used in the hydrolysis is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide. The reaction temperature of the preparation method is from 0°C to 150°C.

5. A method for preparing a compound of formula I or a salt thereof according to claim 1, characterized in that: Make a compound having formula (II) or a salt thereof Or compounds having formula (Ⅲ) Or compounds having formula (Ⅳ) A mixture of compounds of formula II or their salts, compounds of formula III, compounds of formula IV, or such compounds in any proportion may be decarboxylated by hydrolysis to produce a compound having formula (I) or a chemically acceptable salt thereof. in: R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy. R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, Or 2-trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent The hydrolysis process involves adding one or a mixture of two or more of the following reagents: Na2CO3, NaHCO3, K2CO3, KHCO3, NaOH, KOH, sulfuric acid, hydrochloric acid, hydrobromic acid, nitric acid, formic acid, or acetic acid. The solvent used for hydrolysis is one or a mixture of two or more of the following: water, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, or dimethyl sulfoxide. The reaction temperature is between 20℃ and 150℃.

6. A method for preparing a compound of formula II or a salt thereof according to claim 2, characterized in that: The compound of formula V is reduced in a solvent by a catalyst A and a reducing agent A to obtain the compound of formula II or an industrially acceptable salt thereof. R1 is selected from hydroxyl, amino, C1-C. 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino or di(C6-C) 12 aryl)amino; when R1 is selected from di(C1-C1)amino; 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures; The catalyst A is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon; When the reducing agent A is selected from hydrogen, the pressure is selected from 0.1-5 MPa; when the reducing agent A is selected from hydrazine hydrate, methylhydrazine, cyclohexene, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate or isopropanol, the amount of reducing agent A is 0.5-20 equivalents of compound V. The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and ammonia.

7. A method for preparing compounds as shown in Formula II and their salts according to claim 2, characterized in that: Compound V is reduced in a solvent by catalyst A and reducing agent A to give compound II or its industrially acceptable salt. R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, The catalyst A is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon; The reducing agent A is selected from one or a mixture of two or more of the following: hydrogen, hydrazine hydrate, methylhydrazine, cyclohexadiene, formic acid, sodium formate, potassium formate, ammonium formate, and isopropanol. The solvent is selected from one or a mixture of two or more of the following: methanol, ethanol, n-propanol, isopropanol, n-butanol, toluene, ethyl acetate, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 2-methyl-tetrahydrofuran, methyl tert-butyl ether, 1,4-dioxane, and ammonia.

8. A method for preparing a compound of formula II or its salt, a compound of formula III, a compound of formula IV, or a mixture thereof in any proportion, according to claim 3, characterized in that: Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion; R1 is selected from hydroxyl, amino, C1-C5 alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 aryl)amino; when R1 is selected from di(C1-C1)amino; 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent The acylation reagent is one or a mixture of two or more of the following: acetyl chloride, propionyl chloride, butyryl chloride, malonyl chloride, valeryl chloride, pteropenoyl chloride, n-hexanoyl chloride, benzoyl chloride, phthaloyl chloride, trifluoroacetyl chloride, 2-trifluoromethylbenzoyl chloride, acetic anhydride, propionic anhydride, butyric anhydride, succinic anhydride, valeric anhydride, isovaleric anhydride, glutaric anhydride, pteropenoyl anhydride, n-hexanoic anhydride, benzoic anhydride, phthalic anhydride, trifluoroacetic anhydride, maleic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic acid propionic anhydride, methyl acetic anhydride, and propionic butyric anhydride. The catalyst B is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon; When reducing agent B is selected from hydrogen, the pressure is selected from 0.1-5 MPa; when reducing agent B is selected from cyclohexene, cyclohexadiene, formic acid, sodium formate or potassium formate, the amount of reducing agent B is 0.5-20 equivalents of compound V; The solvent is selected from one or a mixture of two or more of the following: toluene, xylene, ethylbenzene, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amyl methyl ether, 2-methyl-tetrahydrofuran, cyclopentyl methyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, acetic anhydride, or propionic anhydride. The amount of the acylation reagent used is 0.1-20 equivalents of compound of formula V; The reaction temperature of the preparation method is 10-160℃.

9. A method for preparing a compound of formula II or a salt thereof, a compound of formula III, a compound of formula IV, or a mixture thereof in any proportion, according to claim 3 or 8, characterized in that: Compound V and acylation reagent undergo reduction and acylation reactions in a solvent under the action of catalyst B and reducing agent B to obtain compound II or its salt, compound III, compound IV or a mixture thereof in any proportion; R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy. R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, 2-Trifluoromethylphenyl; R3 and R4 are independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. 2-Trifluoromethylphenyl; or R3 and R4 together represent The acylation reagent is one or a mixture of two or more of the following: acetic anhydride, propionic anhydride, butyric anhydride, benzoic anhydride, di-tert-butyl dicarbonate, 2-trifluoromethylbenzoic anhydride, acetic and propionic anhydride, methyl acetic anhydride, propionic and butyric anhydride, methyl formate, and ethyl formate. The catalyst B is selected from one or a mixture of two or more of palladium / carbon, platinum / carbon, Raney cobalt, Raney nickel, palladium hydroxide, and palladium hydroxide / carbon; The reducing agent B is selected from hydrogen gas, and the pressure is selected from 0.1-5 MPa; The solvent is selected from one or a mixture of two or more of the following: toluene, xylene, ethylbenzene, acetic acid, tetrahydrofuran, 1,2-dimethoxyethane, 1,4-dioxane, diethyl ether, methyl tert-butyl ether, tert-amylmethyl ether, 2-methyl-tetrahydrofuran, cyclopentylmethyl ether, bis(2-methoxyethyl) ether, anisole, ethyl acetate, isopropyl acetate, butyl acetate, amyl acetate, 3,3-dimethylbutanone, diethyl carbonate, dimethyl carbonate, acetic anhydride, or propionic anhydride. The amount of the acylation reagent used is 0.1-20 equivalents of compound of formula V; The reaction temperature of the preparation method is 20-130℃.

10. Compounds of formula II or their salts: R1 is selected from hydroxyl, amino, C1-C. 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or heteroaryloxy group containing one or two atoms selected from nitrogen, oxygen, and sulfur. When R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can bond with nitrogen atoms to form 3- to 10-membered ring structures.

11. Compounds of Formula III: R1 is selected from hydroxyl, amino, C1-C. 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures; R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, trifluoromethyl, 2-Trifluoromethylphenyl.

12. Compounds of Formula IV: R1 is selected from hydroxyl, amino, C1-C. 10 Alkoxy, C1-C 10 Alkylamino, C6-C 12 arylamino, di(C1-C) 10 alkyl)amino, di(C6-C) 12 (aryl)amino, C6-C 12 Aryloxy group or containing one or two heteroaryloxy groups selected from nitrogen, oxygen, and sulfur atoms; when R1 is selected from di(C1-C1) 10 When alkyl)amino, the two C1-C 10 Alkyl groups can be linked with nitrogen atoms to form 3- to 10-membered ring structures; R3 and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, phenyl, and trifluoromethyl. Or 2-trifluoromethylphenyl; or R3 and R4 together represent 13. The compound of formula II or a salt thereof according to claim 10, characterized in that: R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, 14. The compound of formula III according to claim 11, characterized in that: R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, R2 is selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, 2-Trifluoromethylphenyl.

15. The compound of formula IV according to claim 12, characterized in that: R1 is selected from methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, isobutoxy, sec-butoxy, n-pentoxy, R3 and R4 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, phenyl, etc. Or 2-trifluoromethylphenyl; or R3 and R4 together represent

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