Preparation method of halauxifen-methyl

Abstract

The invention relates to the technical field of pesticides and herbicides, and discloses a preparation method of halauxifen-methyl as shown in a formula (I). The preparation process of the halauxifen-methyl and the key intermediate of the halauxifen-methyl provided based on the new intermediate compound has the obvious advantages of mild reaction conditions, low cost of raw materials and reagents, less impurity generation, high reaction yield, high product content and the like.

Description

Technical Field

[0001] This invention relates to the field of pesticide and herbicide technology, and specifically to a method for preparing chlorofluoropyridine ester as shown in formula (I). Background Technology

[0002] Chloropyridine ester is a novel and highly effective herbicide developed by Dow. Existing literature all uses benzyl 6-chloro(bromo)pyridinecarboxylate for coupling reaction to synthesize chloropyridine ester.

[0003] CN115298167A discloses a method for synthesizing chlorofluoropyridine esters using benzyl 6-bromopyridinecarboxylate (A2) via coupling. The coupling step yields 89%, but uses a large excess of phenylboronic acid (or ester, B1) (20.8%). Phenylboronic acid (B1) is expensive, increasing costs, and the impurities produced by phenylboronic acid (or ester, B1) are difficult to remove. Furthermore, the two-step esterification and diacytization yields only 80-88%; the esterification step is time-consuming, prone to decarboxylation impurities, and uses large amounts of alcohol solvents, making recovery difficult. The three-step bromination, hydrolysis, and benzyl esterification yields only 44.4-87.3%, and the bromination step uses a large excess of hydrobromic acid solution, making the excess hydrobromide difficult to recover and reuse, significantly increasing costs.

[0004] CN115551833A discloses a method for coupling using benzyl 6-chloro(bromo)pyridinecarboxylate, with a yield of only 74-81%.

[0005] CN115819334A discloses a method for coupling 6-bromopyridinecarboxylate (compound A) using cuprous iodide as a catalyst. This method uses expensive and large quantities of cuprous iodide and cesium carbonate, and cuprous iodide is difficult to recover, leading to increased costs. The large quantities of N-ligand and phase-transfer catalyst used result in severe pollution. While the crude product yield is relatively high, the purified yield is only 84.2%. The reaction temperature is as high as 120℃, at which compound B is unstable and requires a large excess. Furthermore, the reaction time is as long as 24 hours.

[0006] Benzyl 6-chloro(bromo)pyridinecarboxylate exhibits low activity, requiring a significant excess of phenylboronic acid or high temperatures for the process, and also results in low yields. Therefore, a more active compound is needed for coupling to achieve higher yields. Furthermore, the overall process for preparing chlorofluoropyridine esters from atrazine as a starting material requires optimization. Summary of the Invention

[0007] The purpose of this invention is to overcome the problems existing in the prior art and provide a method for preparing chlorofluoropyridine ester.

[0008] To achieve the above objectives, a first aspect of the present invention provides a compound of formula (X) or a salt thereof:

[0009] Among them, R 5 Selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy or nitro; R 6 Selected from OH or Cl; n is any integer selected from 1 to 4.

[0010] A second aspect of the present invention provides a compound of formula (XI) or a salt thereof.

[0011] Among them, R 7 Selected from H, benzyl or C1-C 12 alkyl; R 8 Selected from H or R 3 SO2; where R 3 Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted C7-C 15 Aryl group.

[0012] A third aspect of the present invention provides a method for preparing a compound of formula (VI) or a salt thereof, wherein the method comprises the following steps:

[0013] (1) In the presence of a first solvent and a first base, the compound shown in formula (IX) is made

[0014] With the compounds shown in formula (B1) or formula (B2)

[0015] The first reaction yields intermediate compound A; (2) In the presence of the first acid or the first dehydrating agent, intermediate compound A is reacted with R. 4 OH undergoes a second reaction; or, in the presence of a second base, intermediate compound A reacts with R. 4 Z undergoes a third reaction to yield the compound shown in formula (VI); or, (2') React intermediate compound A with a chlorinating reagent in a fourth reaction to obtain intermediate compound B; react intermediate compound B with R 4 The OH radical undergoes a fifth reaction to yield the compound shown in formula (VI); Among them, R4 Selected from substituted or unsubstituted C1-C 12 Alkyl, C3-C 12 alkynyl group, C3-C 12 alkenyl or C7-C 13 Aryl groups; R 5 and n as defined in the first aspect; Hal is selected from Cl or Br; Z is selected from halogen or R 3 SO3, where R 3 As defined in the second aspect.

[0016] A fourth aspect of the present invention provides a method for preparing chlorofluoropyridine ester of formula (I), wherein the method comprises:

[0017] In the presence of a catalyst, the compound shown in formula (II) undergoes a seventh reaction with the compound shown in formula (A) to give the chlorofluoropyridine ester shown in formula (I).

[0018] Among them, R 1 and R 2 Each is independently selected from H or C1-C8 alkyl, or R 1 R 2 Together with the O and B atoms they are attached to, they form five- to eleven-membered heterocyclic alkyl groups; R 3 As defined above; Bn is benzyl.

[0019] A fifth aspect of the present invention provides a method for preparing chlorofluoropyridine ester of formula (I), wherein the method comprises the following steps: (1) The compound of formula (VI) is prepared from the compound of formula (IX) by the method described in the third aspect; (2) React the compound shown in formula (VI) with a fluorinating agent to obtain the compound shown in formula (V); (3) The chlorofluoropyridine ester of formula (I) is prepared from the compound of formula (V) by the method described in the fourth aspect.

[0020] The beneficial technical effects achieved by the present invention through the above technical solution are as follows: (1) The present invention provides a compound of formula (X) or a salt thereof, which, when used to prepare a key intermediate of chlorofluoropyridine ester (i.e., the compound of formula (VI)), can reduce the amount of alcohol solvent used in the esterification step, reduce the reaction time and increase the reaction yield. (2) The present invention provides a compound of formula (XI) or a salt thereof, which can avoid the use of expensive and difficult-to-recover hydrobromic acid solution, reduce the amount of phenylboronic acid (or ester, formula A) when used to prepare chlorofluoropyridine ester, and can also reduce reaction time, lower reaction temperature and increase yield. (3) The overall preparation process of chlorofluoropyridine ester provided by the present invention has obvious advantages such as mild reaction conditions, low cost of raw materials and reagents, low generation of impurities, high total reaction yield (up to 75.95%), and high product content (up to 97.8%). Detailed Implementation

[0021] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein.

[0022] The alkyl groups referred to herein are straight-chain or branched alkyl groups and cycloalkyl groups. For example, straight-chain or branched alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, isopropyl, isobutyl, tert-butyl, pentyl, and hexyl, etc., and cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, etc. The substituted alkyl groups refer to the aforementioned alkyl groups having substituents, and the substituents include, but are not limited to, at least one of fluorine, chlorine, bromine, iodine, cyano, nitro, alkoxy, and substituted alkoxy groups. The aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, tetrahydronaphthyl, phenylcyclopropyl, and indanyl. The aralkyl groups refer to the aforementioned aryl-substituted alkyl groups, the substituted aryl groups refer to aryl groups substituted by the aforementioned substituents, and the substituted aralkyl groups refer to aralkyl groups substituted by the aforementioned substituents.

[0023] The first aspect of the present invention provides a compound of formula (X) or a salt thereof:

[0024] Among them, R 5 Selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy or nitro; R 6 Selected from OH or Cl; n is any integer selected from 1 to 4.

[0025] In some embodiments of the present invention, R 5 Selected from H, halogen, methyl, methoxy, halomethyl, halomethoxy or nitro.

[0026] In some embodiments of the present invention, R 5 Selected from H, F, Cl, or Br, optionally R 5 For H.

[0027] In some embodiments of the present invention, R 6 It is OH or Cl.

[0028] In some embodiments of the present invention, n is 1 or 2.

[0029] In some embodiments of the present invention, the compound represented by formula (X) is selected from the following compounds:

[0030] Among them, R 5 And n, as defined above, can optionally be R 5 Let H be the integer part of the set, and n be 1.

[0031] A second aspect of the present invention provides a compound of formula (XI) or a salt thereof.

[0032] Among them, R 7 Selected from H, benzyl or C1-C 12 alkyl; R 8 Selected from H or R 3 SO2; where R 3 Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted C7-C 15 Aryl group.

[0033] In some embodiments of the present invention, R 7 It is H or benzyl.

[0034] In some embodiments of the present invention, R 3 It is selected from substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted C7-C9 aralkyl.

[0035] In some embodiments of the present invention, R 3 It is selected from substituted C1-C3 alkyl, substituted C6-C8 aryl or substituted C7-C9 aralkyl, and optionally from substituted methyl, substituted phenyl or substituted benzyl.

[0036] In some embodiments of the present invention, R 3The substituents are each independently selected from at least one of halogen, cyano or nitro, optionally selected from at least one of fluorine, chlorine, cyano or nitro, and further optionally selected from at least one of fluorine, chlorine or nitro.

[0037] In some embodiments of the present invention, R 3 It is trichloromethyl.

[0038] In some embodiments of the present invention, R 3 It is trifluoromethyl.

[0039] In some embodiments of the present invention, R 3 It is 2-nitrophenyl.

[0040] In some embodiments of the present invention, R 3 It is 3-nitrophenyl.

[0041] In some embodiments of the present invention, R 3 It is 4-nitrophenyl.

[0042] In some embodiments of the present invention, the compound represented by formula (XI) is selected from the following compounds:

[0043]

[0044] Among them, R 3 As defined above, Bn is benzyl, R 9 For C1-C 12 alkyl.

[0045] In some embodiments of the present invention, R 3 It is trichloromethyl.

[0046] In some embodiments of the present invention, R 3 It is trifluoromethyl.

[0047] In some embodiments of the present invention, R 3 It is 2-nitrophenyl.

[0048] In some embodiments of the present invention, R 3 It is 3-nitrophenyl.

[0049] In some embodiments of the present invention, R 3 It is 4-nitrophenyl.

[0050] In the compound represented by formula (XII), R 9 Optionally, it can be a C1-C3 alkyl group.

[0051] In the compound represented by formula (XII), R 9 Optionally, it can be methyl.

[0052] In the compound represented by formula (XII), R 9 Optionally, it can be propyl.

[0053] A third aspect of the present invention provides a method for preparing a compound of formula (VI) or a salt thereof, wherein the method comprises the following steps:

[0054] (1) In the presence of a first solvent and a first base, the compound shown in formula (IX) is made

[0055] With the compounds shown in formula (B1) or formula (B2)

[0056] The first reaction yields intermediate compound A; (2) In the presence of the first acid or the first dehydrating agent, intermediate compound A is reacted with R. 4 OH undergoes a second reaction; or, in the presence of a second base, intermediate compound A reacts with R. 4 Z undergoes a third reaction to yield the compound shown in formula (VI); or, (2') React intermediate compound A with a chlorinating reagent in a fourth reaction to obtain intermediate compound B; react intermediate compound B with R 4 The OH radical undergoes a fifth reaction to yield the compound shown in formula (VI); Among them, R 4 Selected from substituted or unsubstituted C1-C 12 Alkyl, C3-C 12 alkynyl group, C3-C 12 alkenyl or C7-C 13 Aryl groups; R 5 and n as defined in the first aspect; Hal is selected from Cl or Br; Z is selected from halogen or R 3 SO3, where R 3 As defined in the second aspect.

[0057] In some embodiments of the present invention, R 4 For C1-C 12 Alkyl, optionally C1-C7 alkyl.

[0058] In some embodiments of the present invention, R 4Replaced by one or more cyano, halogen, or nitro groups, optionally R 4 It is replaced by one or more halogens.

[0059] In some embodiments of the present invention, the structural formulas of intermediate compound A and intermediate compound B are shown in formula (X):

[0060] Among them, R 6 As defined in the first aspect.

[0061] In some embodiments of the present invention, the method includes the following steps: (1) In the presence of a first solvent and a first base, the compound shown in formula (IX) is reacted with the compound shown in formula (B1) or formula (B2) in a first reaction to give the compound of formula (VIII). ; (2) In the presence of a first acid or a first dehydrating agent, the compound shown in formula (VIII) is reacted with R. 4 A second reaction occurs with OH; or, in the presence of a second base, the compound shown in formula (VIII) reacts with R. 4 Z undergoes a third reaction to yield the compound shown in formula (VI); or, (2') The compound shown in formula (VIII) undergoes a fourth reaction with a chlorinating reagent to give the compound shown in formula (VII). ; Make the compound shown in formula (VII) react with R 4 The OH radical undergoes a fifth reaction to yield the compound shown in formula (VI).

[0062] In some embodiments of the present invention, in step (1), the first solvent is selected from C1-C1. 12The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, optionally selected from acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and N,N-dimethylformamide. At least one of (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and sulfolane, further optionally selected from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, chloroform, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone (MIBK).

[0063] In some embodiments of the present invention, in step (1), the first base is selected from at least one of inorganic bases and tertiary amines.

[0064] In some embodiments of the present invention, in step (1), the substituents on the nitrogen of the tertiary amine are each independently selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings.

[0065] In some embodiments of the present invention, in step (1), the first alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N - At least one of diethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline and 4-dimethylaminopyridine (DMAP), optionally selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine and diisopropylethylamine.

[0066] In some embodiments of the present invention, in step (1), the first alkali is added to the reaction system by dropping, adding in batches, or adding all at once.

[0067] In some embodiments of the present invention, in step (1), the compound represented by formula (B1) or (B2) is added to the reaction system by dropping, adding in batches, or adding all at once.

[0068] In some embodiments of the present invention, in step (1), the temperature of the first reaction is 30-150°C, optionally 30-100°C, and further optionally 50-90°C.

[0069] In some embodiments of the present invention, in step (1), the time for the first reaction is 5-48 hours, optionally 6-12 hours.

[0070] In some embodiments of the present invention, in step (2), the first acid is selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid and substituted sulfonic acid, and optionally from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and further optionally from at least one of trifluoromethanesulfonic acid and sulfuric acid.

[0071] In some embodiments of the present invention, in step (2), the first dehydrating agent is selected from at least one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI or EDC), thionyl chloride, sulfone chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride.

[0072] In some embodiments of the present invention, in step (2), the first dehydrating agent is used in combination with a catalyst, optionally selected from 4-dimethylaminopyridine (DMAP), N-hydroxysuccinimide (NHS) or 1-hydroxybenzotriazole (HOBt).

[0073] In some embodiments of the present invention, in step (2), the second base is a tertiary amine.

[0074] In some embodiments of the present invention, in step (2), the substituents on the nitrogen of the tertiary amine are each independently selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings.

[0075] In some embodiments of the present invention, in step (2), the second base is selected from at least one of trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, and 4-dimethylaminopyridine, and optionally selected from at least one of triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, and diisopropylethylamine.

[0076] In some embodiments of the present invention, the temperature of the second reaction is 60-120°C, and optionally 70-110°C (e.g., 70°C, 80°C, 90°C, 100°C or 110°C).

[0077] In some embodiments of the present invention, the second reaction time is 24-48h, optionally 30-42h (e.g., 30h, 36h or 42h).

[0078] In some embodiments of the present invention, the temperature of the third reaction is 20-100°C, optionally 30-90°C (e.g., 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, or 90°C).

[0079] In some embodiments of the present invention, the third reaction takes 4-10 hours, and optionally 5-9 hours (e.g., 5 hours, 6 hours, 7 hours, 8 hours or 9 hours).

[0080] In some embodiments of the present invention, in step (2), the second reaction is carried out in the presence of a second solvent.

[0081] In some embodiments of the present invention, in step (2), the second solvent is selected from C1-C1. 12The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

[0082] In some embodiments of the present invention, in step (2), the third reaction is carried out in the presence of a third solvent.

[0083] In some embodiments of the present invention, in step (2), the third solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

[0084] In some embodiments of the present invention, in step (2'), the fourth reaction is carried out in the presence of a fourth solvent.

[0085] In some embodiments of the present invention, in step (2'), the fourth solvent is selected from C1-C2. 12The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, optionally selected from acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and N,N-dimethylformamide. At least one of (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and sulfolane, further optionally selected from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, chloroform, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone (MIBK).

[0086] In some embodiments of the present invention, in step (2'), the fifth reaction is carried out in the presence of a fifth solvent.

[0087] In some embodiments of the present invention, in step (2'), the fifth solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone.

[0088] In some embodiments of the present invention, in step (2'), the chlorinating agent is selected from at least one of thionyl chloride, phosgene, solid phosgene, phosphorus oxychloride, and phosphorus trichloride.

[0089] In some embodiments of the present invention, in step (2'), the temperature of the fourth and fifth reactions is 30-150°C, optionally 30-100°C, and further optionally 50-90°C.

[0090] In some embodiments of the present invention, in step (2'), the fourth reaction takes 1-12 hours, or optionally 2-6 hours.

[0091] In some embodiments of the present invention, in step (2'), the time for the fifth reaction is 3-24 hours, optionally 4-12 hours.

[0092] In some embodiments of the present invention, the mass ratio of the first solvent to the compound represented by formula (IX) is (0.2-20):1, and optionally (0.5-5):1.

[0093] In some embodiments of the present invention, the molar ratio of the first base to the compound represented by formula (IX) is (2-6):1, and optionally (2.5-4):1.

[0094] In some embodiments of the present invention, the molar ratio of the compound represented by formula (B1) or formula (B2) to the compound represented by formula (IX) is (1-4):1, and optionally (2-3):1.

[0095] In some embodiments of the present invention, the molar ratio of the first acid to the compound represented by formula (IX) is (0.05-1):1, and optionally (0.1-0.5):1.

[0096] In some embodiments of the present invention, the molar ratio of the first dehydrating agent to the compound shown in formula (IX) is (1-3):1, or optionally (1-1.5):1.

[0097] In some embodiments of the present invention, the R 4 The molar ratio of OH to the compound shown in formula (IX) is (1-10):1, or optionally (1-2):1.

[0098] In some embodiments of the present invention, the mass ratio of the second solvent to the compound shown in formula (IX) is (1-10):1, and optionally (2-5):1.

[0099] In some embodiments of the present invention, the molar ratio of the second base to the compound shown in formula (IX) is (1-3):1, and optionally (1-1.5):1.

[0100] In some embodiments of the present invention, the R 4 The molar ratio of Z to the compound shown in formula (IX) is (1-2):1, or optionally (1-1.3):1.

[0101] In some embodiments of the present invention, the mass ratio of the third solvent to the compound represented by formula (IX) is (2-12):1, and optionally (2-4):1.

[0102] In some embodiments of the present invention, the molar ratio of the chlorinating agent to the compound shown in formula (IX) is (1-5):1, and optionally (1.1-1.5):1.

[0103] In some embodiments of the present invention, the mass ratio of the fourth solvent to the compound represented by formula (IX) is (2-15):1, optionally (2.5-6):1.

[0104] In some embodiments of the present invention, the mass ratio of the fifth solvent to the compound represented by formula (IX) is (1-20):1, and optionally (2-4):1.

[0105] A fourth aspect of the present invention provides a method for preparing chlorofluoropyridine ester of formula (I), wherein the method comprises:

[0106] In the presence of a catalyst, the compound shown in formula (II) undergoes a seventh reaction with the compound shown in formula (A) to give the chlorofluoropyridine ester shown in formula (I).

[0107] Among them, R 1 and R 2 Each is independently selected from H or C1-C8 alkyl, or R 1 R 2 Together with the O and B atoms they are attached to, they form five- to eleven-membered heterocyclic alkyl groups; R 3 As defined in the second aspect; Bn is benzyl.

[0108] In some embodiments of the present invention, R 1 and R 2 Each is independently selected from H or C1-C3 alkyl groups, or R 1 R 2 Together with the O and B atoms they are attached to, they form five- to seven-membered heterocyclic alkyl groups.

[0109] In some embodiments of the present invention, R 1 and R 2 All are H or methyl, or the compound shown in formula (A) is ethylene glycol 4-chloro-2-fluoro-3-methoxyphenylboronic acid ester.

[0110] In some embodiments of the present invention, the seventh reaction is carried out in the presence of a sixth solvent.

[0111] In some embodiments of the present invention, the sixth solvent is selected from C1-C2. 12 Alcohol solvents, C1-C12 The solvent is selected from at least one of nitrile solvents, ether solvents, aromatic solvents, ketone solvents, amide solvents, sulfone or sulfoxide solvents, and water, and optionally from at least one of methanol, ethanol, propanol, isopropanol, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and water. The solvent is further optionally selected from at least one of acetonitrile, propionitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidine (NMP), and water; and even more optionally selected from at least one of a mixed solvent of acetonitrile and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methyl isobutyl ketone (MIBK) and water, or a mixed solvent of N,N-dimethylformamide (DMF) and water.

[0112] In some embodiments of the invention, the seventh reaction is carried out in the presence (typically required) of a palladium or nickel catalyst and an optional ligand.

[0113] In some embodiments of the present invention, the palladium catalyst is selected from at least one of palladium chloride, palladium bromide, palladium acetate, palladium sulfate, palladium nitrate and supported palladium catalysts (e.g., palladium on carbon), and optionally from at least one of palladium chloride, palladium acetate and palladium sulfate.

[0114] In some embodiments of the present invention, the ligand of the palladium catalyst is selected from at least one of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tris(o-tolyl)phosphine, 1,2-bis(diphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane and 1,1′-ferrocenediyl-bis(diphenylphosphine) (dppf), and optionally selected from at least one of triphenylphosphine and tricyclohexylphosphine.

[0115] In some embodiments of the present invention, the palladium catalyst is a palladium coordination compound, optionally selected from at least one of bis(triphenylphosphine)dichloride palladium(II), bis(acetic acid)bis(triphenylphosphine)palladium(II), tetra(triphenylphosphine)palladium(O), tri(diphenylmethyleneacetone)dipalladium(O) and dichloroditert-butyl-(4-dimethylaminophenyl)phosphine palladium(II) (Pd-132), optionally selected from at least one of bis(triphenylphosphine)dichloride palladium(II) and bis(acetic acid)bis(triphenylphosphine)palladium(II).

[0116] In some embodiments of the present invention, the nickel catalyst is selected from at least one of nickel dichloride, nickel dibromide, nickel acetate, nickel sulfate, nickel nitrate, nickel dimethyl ether bromide (NiBr2(dme)), or a supported nickel catalyst.

[0117] In some embodiments of the present invention, the ligand of the nickel catalyst is selected from at least one of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1′-ferrocene di-bis(diphenylphosphine), 4,4'-di-tert-butyl-2,2'-bipyridine (Dtbbpy), 4,7-diphenyl-1,10-phenanthroline (BPhen), and 4,4'-dimethoxy-2,2'-bipyridine (4,4'-(MeO)2-BiPy).

[0118] In some embodiments of the present invention, the seventh reaction is carried out in the presence of a palladium catalyst in which the molar ratio of the palladium catalyst to the compound represented by formula (II) is (0.001-0.1):1, or optionally (0.002-0.05):1.

[0119] In some embodiments of the present invention, the seventh reaction is carried out in the presence of a palladium catalyst and a ligand for the palladium catalyst, wherein the molar ratio of the ligand to the palladium catalyst is (1.8-18):1, or optionally (2-8):1.

[0120] In some embodiments of the present invention, the seventh reaction is carried out in the presence of a nickel catalyst in which the molar ratio of the nickel catalyst to the compound represented by formula (II) is (0.01-0.2):1, or optionally (0.03-0.1):1.

[0121] In some embodiments of the present invention, the seventh reaction is carried out in the presence of a third base.

[0122] In some embodiments of the present invention, the third base is selected from at least one of inorganic bases and organic bases, and is optionally selected from at least one of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, triethylamine, tripropylamine and pyridine, and is further optionally selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate and potassium dihydrogen phosphate.

[0123] In some embodiments of the present invention, the temperature of the seventh reaction is 30-150°C, optionally 40-120°C, and further optionally 50-90°C.

[0124] In some embodiments of the present invention, the time for the seventh reaction is 2-24 hours, optionally 5-12 hours.

[0125] In some embodiments of the present invention, the molar ratio of the compound represented by formula (A) to the compound represented by formula (II) is (0.95-1.2):1, and optionally (1-1.1):1.

[0126] In some embodiments of the present invention, the mass ratio of the sixth solvent to the compound represented by formula (II) is (1-20):1, and optionally (2-6):1.

[0127] In some embodiments of the present invention, the molar ratio of the third base to the compound represented by formula (II) is (1.5-7):1, and optionally (2-4):1.

[0128] In some embodiments of the present invention, the compound represented by formula (II) is prepared by the following method: (1) In the presence of water and a second acid or a fourth base, the compound shown in formula (V) is made...

[0129] The eighth reaction occurs, yielding the compound shown in formula (IV). ; Among them, R 4 As defined in the third aspect; R 5 and n as defined in the first aspect; or, (1') In the presence of a reducing agent, the compound shown in formula (V) is reduced to give the compound shown in formula (IV); (2) In the presence of the fifth base, the compound shown in formula (IV) undergoes a ninth reaction with BnZ to give the compound shown in formula (III).

[0130] Wherein, Bn is benzyl, and Z is as defined in the third aspect; or, (2') In the presence of a second dehydrating agent, the compound shown in formula (IV) undergoes a tenth reaction with benzyl alcohol to give the compound shown in formula (III); or, (3) In the presence of the sixth base, the compound shown in formula (III) is reacted with R. 3 SO2Cl or (R) 3 SO2)2O undergoes the fourteenth reaction to give the compound shown in formula (II), wherein R 3 As defined in the second aspect, .

[0131] In this invention, the compound represented by formula (V) can also be the following variants, all of which can be used to synthesize chlorofluoropyridine esters:

[0132]

[0133] Among them, R 4 R 5 n is as defined above.

[0134] The method for synthesizing the variant and the method for preparing the compound of formula (IV) from the variant are similar to those for the compound of formula (V).

[0135] During the preparation of the compound of formula (III) in steps (2) and (2'), at least one of the impurities of formulas (a), (b), and (c) will be generated. The structure of formula (a) is identifiable and its content is the highest, while the contents of (b) and (c) are relatively low. The three impurities are preliminarily identified as isomers. These three impurities are characteristic impurities of this scheme and will remain in trace amounts in pure chlorofluoropyridine ester.

[0136]

[0137] In some embodiments of the present invention, in step (1), the temperature of the eighth reaction is 20-200°C.

[0138] The eighth reaction in this invention is a hydrolysis reaction.

[0139] In some embodiments of the present invention, the second acid is selected from at least one of inorganic acids and organic acids, optionally from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, organic acids, substituted organic acids, and substituted sulfonic acids, further optionally from at least one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid, and sulfuric acid, and even further optionally from at least one of acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, and sulfuric acid. When the acid has a low boiling point, the reaction can be carried out in a pressure vessel.

[0140] In some embodiments of the present invention, the fourth alkali is selected from at least one of organic alkali and inorganic alkali, and optionally from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate, and further optionally from at least one of sodium hydroxide and potassium hydroxide.

[0141] In some embodiments of the present invention, in step (1'), the reducing agent is selected from at least one of hydrogen and hydrazine hydrate.

[0142] In some embodiments of the present invention, the temperature of the reduction reaction is 30-200°C, optionally 40-180°C, and further optionally 50-100°C.

[0143] In some embodiments of the present invention, the reduction reaction takes 4-16 hours, optionally 5-10 hours.

[0144] In some embodiments of the present invention, the reduction reaction is carried out in the presence of an inert solvent.

[0145] In some embodiments of the present invention, in step (2'), the second dehydrating agent is selected from at least one of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI or EDC).

[0146] In some embodiments of the present invention, the second dehydrating agent is used in combination with a catalyst, optionally 4-dimethylaminopyridine (DMAP), N-hydroxysuccinimide (NHS) or 1-hydroxybenzotriazole (HOBt).

[0147] In some embodiments of the present invention, the temperature of the tenth reaction is 50-150°C, and optionally 60-120°C.

[0148] In some embodiments of the present invention, the time for the tenth reaction is 6-18 hours, and optionally 7-10 hours.

[0149] In some embodiments of the present invention, the ninth and / or tenth reactions are carried out in the presence of a seventh solvent.

[0150] In some embodiments of the present invention, the seventh solvent is selected from C1-C2. 12 At least one of nitrile solvents, ether solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, optionally selected from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), and sulfolane, further optionally selected from at least one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidine (NMP), dimethyl sulfoxide (DMSO), and sulfolane.

[0151] In some embodiments of the present invention, the fifth base is one or more tertiary amines.

[0152] In some embodiments of the present invention, the substituents on the nitrogen of the tertiary amine are selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings.

[0153] In some embodiments of the present invention, the fifth base is selected from at least one or more of trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentanamine, N,N-diethylcyclopentanamine, N,N-dipropylcyclopentanamine, N,N-diisopropylcyclopentanamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, and 4-dimethylaminopyridine (DMAP), and is further optionally selected from at least one of triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, and diisopropylethylamine.

[0154] In some embodiments of the present invention, the fifth alkali is added to the reaction system by dropping or adding it in batches.

[0155] In some embodiments of the present invention, the BnZ is added to the reaction system by dropwise addition.

[0156] In some embodiments of the present invention, the temperature of the ninth reaction is 30-150°C, optionally 40-100°C, and further optionally 60-90°C.

[0157] In some embodiments of the present invention, the time for the ninth reaction is 4-24 hours, optionally 5-12 hours.

[0158] In some embodiments of the present invention, the ninth reaction is a continuous reaction. A mixture of the compound represented by formula (IV), a solvent, and a base, along with BnZ, is continuously added to the reactor, and the reactor continuously flows out after the reaction is complete.

[0159] In this invention, the compound represented by formula (III) can also be synthesized from the compound represented by formula (IV) via step (2''): (2'')(a) In the presence of a third acid or a third dehydrating agent, the compound shown in formula (IV) is reacted with R. 9 OH undergoes the eleventh reaction; or, in the presence of an organic amine, the compound shown in formula (IV) undergoes the twelfth reaction with an alkylating agent to give the compound shown in formula (XII); Among them, R 9As defined in the second aspect; (b) In the presence of an ester exchange catalyst, the compound shown in formula (XII) is reacted with benzyl alcohol in a thirteenth reaction to give the compound shown in formula (III).

[0160] In some embodiments of the present invention, in step (2''), the third acid is selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid and substituted sulfonic acid, and optionally from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and further optionally from at least one of trifluoromethanesulfonic acid and sulfuric acid.

[0161] In some embodiments of the present invention, the third dehydrating agent is selected from at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, thionyl chloride, sulfone chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride.

[0162] In some embodiments of the present invention, the third dehydrating agent is used in combination with a catalyst, optionally selected from 4-dimethylaminopyridine, N-hydroxysuccinimide or 1-hydroxybenzotriazole.

[0163] In some embodiments of the present invention, the alkylating agent is a haloalkane or an alkyl sulfate ester.

[0164] In some embodiments of the present invention, the transesterification catalyst is a phthalate ester or a sulfonic acid ester, optionally selected from at least one of tetraisopropyl phthalate, tetrabutyl phthalate, trifluoromethanesulfonic acid and p-toluenesulfonic acid.

[0165] In some embodiments of the present invention, the fourteenth reaction is carried out in the presence of an eighth solvent.

[0166] In some embodiments of the present invention, the eighth solvent is selected from C1-C2. 12The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, optionally selected from acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone (MIBK), and N,N-dimethylformamide. At least one of (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), and sulfolane, further optionally selected from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, chloroform, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone (MIBK).

[0167] In some embodiments of the present invention, the sixth base is at least one of an inorganic base and a tertiary amine.

[0168] In some embodiments of the present invention, the substituents on the nitrogen of the tertiary amine are selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings.

[0169] In some embodiments of the present invention, the sixth alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-diethylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclopent ...pentylamine, N,N-diethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N, The ingredient is selected from at least one of hexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, and 4-dimethylaminopyridine (DMAP), and optionally from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, and diisopropylethylamine.

[0170] In some embodiments of the present invention, the sixth alkali is added to the reaction system by dropping, adding in batches, or adding it all at once.

[0171] In some embodiments of the present invention, the R 3 SO2Cl or (R) 3SO2)2O is added to the reaction system dropwise.

[0172] In some embodiments of the present invention, the temperature of the fourteenth reaction is -10 to 100°C, optionally 0-50°C, and further optionally 0-20°C.

[0173] In some embodiments of the present invention, the fourteenth reaction takes 1-10 hours, optionally 2-6 hours.

[0174] In some embodiments of the present invention, the molar ratio of the second acid to the compound shown in formula (V) is (0.5-100):1, and optionally (5-20):1.

[0175] In some embodiments of the present invention, the molar ratio of the fourth base to the compound represented by formula (V) is (4-10):1, and optionally (6-8):1.

[0176] In some embodiments of the present invention, the molar ratio of the reducing agent to the compound represented by formula (V) is (2-20):1, and optionally (4-10):1.

[0177] In some embodiments of the present invention, the molar ratio of the fifth base to the compound represented by formula (V) is (1-4):1, and optionally (1-1.5):1.

[0178] In some embodiments of the present invention, the molar ratio of BnZ to the compound shown in formula (V) is (1-4):1, and optionally (1-1.5):1.

[0179] In some embodiments of the present invention, the molar ratio of the second dehydrating agent to the compound shown in formula (V) is (1-5):1, and optionally (2-3):1.

[0180] In some embodiments of the present invention, the molar ratio of benzyl alcohol to the compound represented by formula (V) is (1-6):1, and optionally (1.5-2):1.

[0181] In some embodiments of the present invention, the mass ratio of the seventh solvent to the compound represented by formula (V) is (1-10):1, and optionally (2-4):1.

[0182] In some embodiments of the present invention, the molar ratio of the sixth base to the compound shown in formula (V) is (1-5):1, and optionally (1-2):1.

[0183] In some embodiments of the present invention, the R 3 The molar ratio of SO2Cl to the compound shown in formula (V) is (1-5):1, or optionally (1-2):1.

[0184] In some embodiments of the present invention, the (R) 3 The molar ratio of SO2)2O to the compound shown in formula (V) is (1-6):1, or optionally (1-2):1.

[0185] In some embodiments of the present invention, the mass ratio of the eighth solvent to the compound represented by formula (V) is (1-15):1, and optionally (2-8):1.

[0186] Alternatively, as an alternative to preparing the compound represented by formula (II), the compound represented by formula (II) can also be prepared by a method comprising the following steps: .

[0187] A fifth aspect of the present invention provides a method for preparing chlorofluoropyridine ester of formula (I), wherein the method comprises the following steps: (1) The compound of formula (V) is prepared from the compound of formula (IX) by the method described in the third aspect; (2) React the compound shown in formula (VI) with a fluorinating agent to obtain the compound shown in formula (V); (3) The chlorofluoropyridine ester of formula (I) is prepared from the compound of formula (V) by the method described in the fourth aspect.

[0188] In some embodiments of the present invention, in step (2), the fluorinating agent is selected from at least one of hydrogen fluoride, sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, diethylaminosulfur trifluoride (DAST), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor), optionally selected from at least one of sodium fluoride, potassium fluoride, and cesium fluoride, and further optionally selected from at least one of sodium fluoride and potassium fluoride.

[0189] In some embodiments of the present invention, in step (2), the sixth reaction is carried out in the presence of a phase transfer catalyst (PTC), optionally selected from at least one of polyethers, cyclic crown ethers, and quaternary ammonium salts; further optionally, the polyethers are selected from at least one of PEG400, PEG600, and polyethylene glycol dimethyl ether; the cyclic crown ethers are selected from at least one of 18-crown 6, 15-crown 5, and cyclodextrin; the quaternary ammonium salts are selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide (TBAB), tetrabutylammonium chloride, tetrabutylammonium bisulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, and benzyltriethylammonium chloride (TEBA); and even further optionally, the phase transfer catalyst is selected from at least one of PEG400, tetramethylammonium chloride, and tetrabutylammonium chloride.

[0190] In some embodiments of the present invention, the sixth reaction is carried out in the presence of a polar solvent, optionally selected from at least one of amide solvents and sulfone or sulfoxide solvents, further optionally selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide and sulfolane, and even further optionally selected from at least one of N-methylpyrrolidine, dimethyl sulfoxide and sulfolane.

[0191] In some embodiments of the present invention, the temperature of the sixth reaction is 30-150°C, optionally 30-120°C, and further optionally 50-100°C.

[0192] In some embodiments of the present invention, the time for the sixth reaction is 4-18 hours.

[0193] In some embodiments of the present invention, the molar ratio of the fluorinating agent to the compound represented by formula (IX) is (2-10):1, and optionally (2-4):1.

[0194] In some embodiments of the present invention, the mass ratio of the polar solvent to the compound represented by formula (IX) is (1.5-10):1, and optionally (2-4):1.

[0195] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0196] In the following examples and comparative examples, compound (*) refers to the compound shown in formula (*); HPLC content is the content value determined by area normalization using liquid chromatography (HPLC), and quantitative content is the content value determined by external standard method.

[0197] Example 1-1 This example is used to illustrate compound (VI-1) (R) 5 It is hydrogen, R 4 It is the synthesis of isopropyl.

[0198]

[0199] 1) Compound (VIII-1)(R 5 Synthesis of hydrogen

[0200] Add 146 g (97%, 586.4 mmol, 1.0 eq) of toxicine (formula (IX) compound), 292 g of acetonitrile, and 59.3 g (586.4 mmol, 1 eq) of triethylamine to a 3000 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Start stirring, then add phthalic anhydride (193.1 g, 99%, 1290 mmol, 2.2 eq), heat to 80 °C, and add triethylamine (89 g, 879.6 mmol, 1.5 eq) dropwise over 5 h. After the addition is complete, keep warm at 80-83 °C for 8 h. Add 1168g of water, cool to 30℃, and add hydrochloric acid (58.6g, 36.5%, 586.4mmol, 1eq) dropwise. After the addition is complete, cool to 10℃, keep warm for 30min, and filter. Wash twice with 300g of 20% acetonitrile aqueous solution, dry, and obtain a white solid, which is compound (VIII-1) (214.6g, HPLC purity 99.6%, yield 98.1%).

[0201] m / z (ESI) 368.93 ([M-1] - ); 1 H NMR (400 MHz, CDCl3) δ: 8.170-8.129(m 2H), 8.072-8.029(m, 2H); 13 C NMR (400 MHz, DMSO) δ: 164.574, 164.024, 148.563, 147.674, 139.878, 136.659, 132.814, 131.042, 129.003, 125.369.

[0202] 2) Compound (VII-1)(R5 Synthesis of hydrogen

[0203] Compound (VIII-1) (199.9 g, HPLC purity 99.6%, 535.8 mmol, 1.0 eq), dichloroethane (1000 g), and DMF (1.36 g) were added to a 2000 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The temperature was raised to 80-83 °C, and thionyl chloride (70.1 g, 589.4 mmol, 1.1 eq) was added dropwise over 4 h. After the addition was complete, the temperature was maintained until the concentration of compound (VIII-1) was <0.1%, and the process was stopped. 100 g of solvent was distilled off under normal pressure, and the residue was a solution of compound (VII-1) (1117.4 g, HPLC purity 99.5%, conversion rate of compound (VIII-1) 99.9%).

[0204] 3) Synthesis of compound (VI-1)

[0205] A solution of the above compound (VII-1) (953.3 g, HPLC purity 99.5%, 456.7 mmol, 1.0 eq) was added to a 2000 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The temperature was raised to 80 °C, and isopropanol (30.1 g, 502.4 mmol, 1.1 eq) was added dropwise over 4 h at a temperature of 80-83 °C. After the addition was complete, the temperature was maintained until the concentration of compound (VII-1) was <0.1%, then the addition was stopped. The solvent was evaporated under reduced pressure to obtain a white solid, which was compound (VI-1) (189.85 g, HPLC purity 99.3%, three-step yield calculated according to atrazine 97.81%).

[0206] m / z (ESI) 412.98 ([M+1 ]+ ); 1 H NMR (400 MHz, CDCl3) δ: 8.159-8.137(m, 2H), 8.60-8.039(m, 2H), 5.378-5.317 (m, 1H), 1.360(d, 6H); 13 C NMR (400 MHz, DMSO) δ: 164.503, 161.861, 148.002, 147.006, 140.035, 136.672, 133.583, 131.037, 129.527, 125.375, 71.781, 21.787.

[0207] Examples 1-2 This example is used to illustrate compound (VI-2) (R) 5 It is hydrogen, R 4 Synthesis of methyl group

[0208] 1) Compound (VIII-1)(R 5 Synthesis of hydrogen

[0209] Add 10 g of toxicetin (compound (IX), 97%, 40.2 mmol, 1.0 eq), 60 g of dichloroethane, 13.41 g of triethylamine (132.6 mmol, 3.3 eq), and 0.1 g of DMAP (0.02 eq) to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Start stirring and heat to 80 °C. Add phthaloyl chloride (9.15 g, 98%, 44.2 mmol, 1.10 eq) dropwise over 2 h. After the addition is complete, maintain the temperature at 80-83 °C for 2 h. Add 100g of water, cool to 30℃, and separate the dichloroethane layer; add hydrochloric acid (4.4g, 36.5%, 44.2mmol, 1.1eq) dropwise to the aqueous phase. After the addition is complete, cool to 10℃, keep warm for 30min, and filter; wash twice with 30g of water, dry, and obtain a white solid, which is compound (VIII-1) (14.72g, HPLC purity 99.3%, yield 97.9%).

[0210] 2) Compound (VII-1)(R 5 Synthesis of hydrogen

[0211] Compound (VIII-1) (14.72 g, HPLC purity 99.3%, 39.4 mmol, 1.0 eq) and dichloroethane (73.5 g) were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The temperature was raised to 80-83 °C, and thionyl chloride (5.16 g, 43.3 mmol, 1.1 eq) was added dropwise over 4 h. After the addition was complete, the temperature was maintained until the concentration of compound (VIII-1) was <0.1%, and the process was stopped. 20 g of solvent was distilled off under normal pressure, and the residue was a solution of compound (VII-1) (HPLC purity 99.2%, conversion rate of compound (VIII-1) 99.9%).

[0212] 3) Synthesis of compound (VI-2)

[0213] Methanol (1.9 g, 58.9 mmol, 1.5 eq) was added dropwise to a 250 mL four-necked flask containing the above-mentioned solution of compound (VII-1) (HPLC purity 99.2%, 39.29 mmol, 1.0 eq) over a period of 2 h at a temperature of 60-65 °C. After the addition was complete, the mixture was kept warm until the concentration of compound (VII-1) was <0.1%, then the addition was stopped. The solvent was evaporated under reduced pressure at -0.095 MPa to obtain a white solid, which was compound (VI-2) (15.24 g, HPLC purity 99.1%, three-step yield calculated according to atrazine 97.51%).

[0214] m / z (ESI) 384.95 ([M+1] + ).

[0215] Examples 1-3 This example is used to illustrate compound (VI-3) (R) 5 It is hydrogen, R 4 It is the synthesis of ethyl groups.

[0216]

[0217] Compound (VIII-1) (14.7 g, HPLC purity 99.6%, 39.3 mmol, 1.0 eq, from Step 1 of Example 1-1)), ethanol (2.36 g, 51.1 mmol, 1.3 eq), dichloroethane (60 g), and DMF (0.1 g) were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. The mixture was heated to reflux, and thionyl chloride (6.32 g, 53.1 mmol, 1.35 eq) was added dropwise over 2 h. After the addition was complete, the mixture was kept at a temperature until compound (VII-1) < 0.1%, then the reaction was stopped. The solvent was evaporated under reduced pressure at -0.095 MPa to obtain a white solid, which was compound (VI-3) (15.64 g, HPLC purity 98.8%, yield 96.43% based on atrazine).

[0218] m / z (ESI) 398.96 ([M+1] + ).

[0219] Examples 1-4 This example is used to illustrate compound (VI-4) (R) 5 It is hydrogen, R 4 It is the synthesis of trifluoroethyl.

[0220]

[0221] A dichloroethane solution of compound (VII-1) (82.2 g, HPLC purity 99.5%, 39.37 mmol, 1.0 eq, from step 2 of Example 1-1) was added dropwise to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Trifluoroethanol (4.33 g, 43.3 mmol, 1.1 eq) was added dropwise at a temperature of 80-83 °C for 3 h. After the addition was complete, the mixture was kept warm until the concentration of compound (VII-1) was <0.1%, then the mixture was stopped. The solvent was evaporated under reduced pressure of -0.095 MPa to obtain a pale yellow solid, which was compound (VI-4) (17.89 g, HPLC purity 97.8%, three-step yield 96.04% based on atrazine).

[0222] m / z (ESI) 452.93 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 8.163-8.129(m, 2H), 8.079-8.045(m, 2H),5.167 (q, 2H); 13 C NMR (400 MHz, DMSO) δ: 164.473, 160.526, 147.938, 144.106, 140.433, 136.679, 134.876, 131.180, 131.03 6, 127.810, 125.380, 125.047, 122.290, 119.530, 62.530, 62.172, 61.818, 61.470; 19 F NMR (400 MHz, DMSO) delta: -71.942.

[0223] Examples 1-5 This example is used to illustrate compound (VI-5) (R) 5 It is hydrogen, R 4 It is the synthesis of cyclohexyl.

[0224]

[0225] A dichloroethane solution of compound (VII-1) (82.2 g, HPLC purity 99.5%, 39.37 mmol, 1.0 eq, from step 2 of Example 1-1) was added dropwise to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. A dichloroethane solution of cyclohexanol (4.34 g, 43.3 mmol, 1.1 eq, containing 10 g of dichloroethane) was then added dropwise at a temperature of 80-83 °C for 2 h. After the addition was complete, the mixture was kept warm until the concentration of compound (VII-1) was <0.1%, then the mixture was stopped. The solvent was evaporated under reduced pressure of -0.095 MPa to obtain a white solid, which was compound (VI-5) (17.88 g, HPLC purity 98.4%, three-step yield 96.53% based on atrazine).

[0226] m / z (ESI) 453.01([M+1] + ).

[0227] Comparative Example 1 This comparative example is used to illustrate compound (VI-1)(R) 5 It is hydrogen, R 4 Synthesis of isopropyl (refer to CN115298167A).

[0228]

[0229] 1) Synthesis of compound (IX-1)

[0230] Toluidine (compound (IX), 10 g, 97%, 40.2 mmol, 1.0 eq) and isopropanol (74.6 g, 1241 mmol, 30.9 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a condenser. Thionyl chloride (2.46 g, 20.6 mmol, 0.51 eq) was added dropwise to the reaction system at room temperature, and the reaction mixture was heated under reflux for 24 h. The reaction mixture was cooled to room temperature and concentrated to dryness. The residue was co-evaporated twice with acetonitrile (10 mL) to give a white solid, compound (IX-1) (11.46 g, HPLC purity 92.9%, yield 93.5%).

[0231] m / z (ESI) 282.97 ([M+1] + ).

[0232] 2) Synthesis of compound (VI-1)

[0233] The above compound (IX-1) (11.46 g, HPLC purity 92.9%, 39.2 mmol, 1.0 eq), acetonitrile (70 mL), triethylamine (10.68 g, 99%, 104 mmol, 2.66 eq), and DMAP (0.496 g, 4 mmol, 0.1 eq) were added dropwise through a feeding funnel. Phthaloyl chloride (9.15 g, 98%, 44.2 mmol, 1.13 eq) was added dropwise while maintaining the temperature below 55 °C. The reaction mixture was stirred at room temperature for 3 h. Water (25 mL) was added to the mixture. The resulting suspension was stirred for 30 min and filtered. The solid was washed with water (3 × 10 mL) and hexane (2 × 10 mL) and dried. The solid was co-evaporated with toluene (2 × 25 mL), dried, washed twice with hexane (20 mL), and dried again. A pale yellow solid was obtained, which was compound (VI-1) (15.45 g, HPLC purity 98.5%, yield 93.8%, overall yield of two steps 87.7%).

[0234] In Comparative Example 1, compound VI-1 was prepared by a process of esterification followed by acylation. The esterification step has a long reaction time, is prone to generating impurities, and uses a large amount of alcohol solvent, making recovery and treatment difficult. The yield of the acylation step is also not high, with a two-step yield of only 87.7%. In the examples of this invention, a process of acylation followed by chlorination and esterification is used, which can avoid the above problems and significantly improve the yield, with a three-step yield of up to 97.81%.

[0235] Example 2-1 This example is used to illustrate compound (V-1) (R) 5 It is hydrogen, R 4 It is the synthesis of isopropyl.

[0236]

[0237] Compound (VI-1) (16.37 g, HPLC purity 99.3%, 39.3 mmol, 1.0 eq, from Example 1-1), DMSO (anhydrous, 50 g), tetramethylammonium chloride (0.6 g), and potassium fluoride (6.85 g, 117.9 mmol, 3.0 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser under a nitrogen atmosphere. The mixture was heated to 95 °C and held at that temperature for 6 h. The temperature was then lowered to 30 °C, and water (50 g) was added, causing a solid to precipitate. The temperature was then lowered to 5 °C and held at that temperature for 30 min. The mixture was filtered, washed twice with 20 g of 20% DMSO aqueous solution, and a yellow solid was obtained, which was compound (V-1) (15.01 g, HPLC purity 95.9%, yield 96.2%).

[0238] m / z (ESI) 381.01([M+1] +); 1 H NMR (400 MHz, DMSO) δ: 8.138-8.104(m, 2H), 8.055-8.022(m, 2H), 5.262-5.199 (m, 1H), 1.354 (d, 6H); 13 C NMR (400 MHz, DMSO) δ: 164.393, 161.723, 151.376, 151.232, 148.979, 148.837, 145.384, 145.080, 142.656, 142.352, 140.689, 140.620 , 140.557, 136.458, 131.304, 130.785, 130.735, 130.674, 130.624, 127.287, 127.256, 125.229, 71.431, 21.779; 19 F NMR (400 MHz, DMSO) δ: -83.446 (d, J=29.36Hz), -133.752 (d, J=26.08Hz).

[0239] Example 2-2 This example is used to illustrate compound (V-1) (R) 5 It is hydrogen, R 4 It is the synthesis of isopropyl.

[0240]

[0241] DMSO (anhydrous, 510 g), benzyltriethylammonium chloride (6 g), and potassium fluoride (59.27 g, 1020 mmol, 2.5 eq) were added to a 2000 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 90 g of solvent was distilled off under reduced pressure of -0.1 MPa. The mixture was then cooled to 90 °C under a nitrogen atmosphere, and compound (VI-1) (170 g, HPLC purity 99.3%, 408 mmol, 1.0 eq, from Example 1-1) was added. The mixture was kept at 90 °C for 6 h, cooled to 25 °C, and water (420 g) was added. A solid precipitated, and the mixture was cooled to 5 °C and kept at that temperature for 30 min. The mixture was filtered and washed twice with 150 g of 20% DMSO aqueous solution to obtain a yellow solid, which was compound (V-1) (156 g, HPLC purity 96.1%, yield 96.5%).

[0242] Example 2-3 This example is used to illustrate compound (V-2)(R) 5 It is hydrogen, R 4It is the synthesis of methyl groups.

[0243]

[0244] Compound (VI-2) (15.24 g, HPLC purity 99.1%, 39.2 mmol, 1.0 eq, from Examples 1-2), DMF (anhydrous, 91 g), and tetrabutylammonium fluoride (30.73 g, 117.5 mmol, 3.0 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser under a nitrogen atmosphere. The mixture was heated to 60 °C and held at this temperature for 4 h. The temperature was then lowered to 30 °C and slowly introduced into water (200 g), causing a solid to precipitate. The mixture was then cooled to 5 °C and held at this temperature for 30 min. After filtration, the solid was washed twice with 20 g of 20% DMF aqueous solution to obtain a light yellow solid, which was compound (V-2) (13.39 g, HPLC purity 93.2%, yield 90.3%).

[0245] m / z (ESI) 353.01([M+1] + ).

[0246] Example 3-1 This example illustrates the synthesis of compound (IV).

[0247]

[0248] To a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, compound (V-1) (12.0 g, HPLC purity 95.9%, 30.2 mmol, 1.0 eq, from Example 2-1), acetic acid (75 g), and water (5 g) were added. Stirring was started, and sulfuric acid (30 g, 98%, 306 mmol, 10.1 eq) was added dropwise over 10 min. After the addition was complete, the mixture was heated to reflux and held at this temperature for 8 h. Then, 300 g of ice water was slowly added, precipitating a solid. The mixture was cooled to 10 °C, filtered, and washed twice with 100 g of water to obtain a yellow solid. This solid was then added to 100 g of ethanol, heated, refluxed for 1 h, cooled to 30 °C, filtered, and the filter cake was washed with 20 g of ethanol and dried to obtain a light yellow solid, which was compound (IV) (6.25 g, HPLC purity 95.4%, yield 95.5%).

[0249] m / z (ESI) 204.99 ([M-1] - ); 1 H NMR (400 MHz, DMSO) δ: 12.559(br, 2H), 6.452(s, 2H); 13C NMR (400 MHz, DMSO) δ: 164.230, 152.259, 152.106, 141.360, 141.244, 136.570, 136.339, 133.961, 105.367, 105.348; 19 F NMR (400 MHz, DMSO) delta: -159.686.

[0250] Example 3-2 This example illustrates the synthesis of compound (IV).

[0251]

[0252] Compound (V-1) (156 g, HPLC purity 96.1%, 393.8 mmol, 1.0 eq, from Example 2-2), acetic acid (156 g), and water (35.4 g) were added to a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Stirring was started, and sulfuric acid (78 g, 98%, 795.9 mmol, 2.02 eq) was added dropwise over 20 min. After the addition was complete, the temperature was raised to reflux and maintained for 10 h. The mixture was distilled to 155 °C, then cooled to 100 °C, and water (195 g) was slowly added dropwise. A solid gradually precipitated out. The mixture was cooled to 10 °C, filtered, and washed twice with 100 g of water to obtain a yellow solid. Add methanol (260g), heat, reflux for 1h, cool to 30℃, filter, wash the filter cake with 40g methanol, dry, and obtain a light yellow solid, which is compound (IV) (81.59g, HPLC content 95.5%, yield 95.8%).

[0253] Example 3-3 This example illustrates the synthesis of compound (IV).

[0254]

[0255] Compound (V-2) (13.39 g, HPLC purity 93.2%, 32.8 mmol, 1.0 eq, from Examples 2-3) and water (60 g) were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. Stirring was started, and sodium hydroxide (26.2 g, 30%, 196.6 mmol, 6 eq) was added dropwise over 40 min. After the addition was complete, the mixture was heated to reflux and held at that temperature for 12 h. The mixture was then cooled to room temperature, and hydrochloric acid (20.65 g, 36.5%, 206.5 mmol, 6.3 eq) was added dropwise, precipitating a solid. The mixture was cooled to 10 °C, filtered, and washed twice with 30 g of water to obtain a pale yellow solid. This solid was then added to methanol (80 g), heated, refluxed for 1 h, cooled to 25 °C, filtered, and the filter cake was washed with 20 g of methanol and dried to obtain a slightly yellow solid, which was compound (IV) (6.76 g, HPLC purity 95.0%, yield 94.9%).

[0256] Example 4-1 This example illustrates the synthesis of compound (III).

[0257]

[0258] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMSO (30 g), and triethylamine (1.95 g, 19.2 mmol, 1.3 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and kept at 30-35 °C for 30 min. The temperature was then lowered to 5 °C, and benzyl bromide (3.10 g, 98%, 17.7 mmol, 1.2 eq) was added dropwise at 5-10 °C for 1 h. After the addition was complete, the mixture was kept at 4 h and poured into 100 g of ice water. The mixture was stirred at 5 °C for 30 min, filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (4.39 g, purity 90%, yield 90%). Add 50g of methylcyclohexane, heat, reflux for 1 hour, cool to 25°C, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a light yellow solid, which is compound (III) (4.06g, HPLC content 95.4%, yield 88.2%).

[0259] m / z (ESI) 297.04 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 11.582(s, 1H), 7.472-7.337(m, 5H), 6.562(s, 2H), 5.331(s, 2H); 13C NMR (400 MHz, DMSO) δ: 163.546, 151.707, 151.583, 141.793, 141.679, 137.370, 137.310, 136 .037, 135.751, 133.602, 128.994, 128.950, 128.843, 107.239, 67.565; 19 F NMR (400 MHz, DMSO) delta: -158.239.

[0260] Example 4-2 This example illustrates the synthesis of compound (III).

[0261]

[0262] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMF (30 g), and dimethylisopropylamine (1.61 g, 18.5 mmol, 1.25 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and heated to 80 °C. Benzyl chloride (2.20 g, 98%, 17.0 mmol, 1.15 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept at this temperature for 9 h. The solution was then poured into 100 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (4.34 g, purity 88%, yield 87%). Add 50g of methylcyclohexane, heat, reflux for 1h, cool to 25℃, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a light yellow solid, which is compound (III) (4.04g, HPLC content 92.5%, yield 85.2%).

[0263] Example 4-3 This example illustrates the synthesis of compound (III).

[0264]

[0265] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMF (30 g), and 1-methylpyrrolidine (1.57 g, 18.5 mmol, 1.25 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and heated to 80 °C. Benzyl chloride (2.20 g, 98%, 17.0 mmol, 1.15 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept at this temperature for 9 h. The solution was then poured into 100 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (4.22 g, purity 79%, yield 76%). Add 50g of methylcyclohexane, heat, reflux for 1 hour, cool to 25°C, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a pale yellow solid, which is compound (III) (3.94g, HPLC content 83%, yield 74.5%).

[0266] Example 4-4 This example illustrates the synthesis of compound (III).

[0267]

[0268] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMSO (30 g), and DMAP (2.35 g, 19.2 mmol, 1.3 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and heated to 80 °C. Benzyl chloride (2.29 g, 98%, 17.8 mmol, 1.2 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept warm for 4 h. The solution was poured into 100 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (3.84 g, purity 80%, yield 70%). Add 50g of methylcyclohexane, heat, reflux for 1 hour, cool to 25°C, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a pale yellow solid, which is compound (III) (3.51g, HPLC content 85%, yield 68%).

[0269] Examples 4-5 This example illustrates the synthesis of compound (III).

[0270]

[0271] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMSO (30 g), and tri-n-propylamine (2.76 g, 19.2 mmol, 1.3 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer under a nitrogen atmosphere. The mixture was stirred and heated to 80 °C. Benzyl chloride (2.29 g, 98%, 17.8 mmol, 1.2 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept at this temperature for 5 h. The solution was then poured into 100 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (4.49 g, purity 90%, yield 92%). Add 50g of methylcyclohexane, heat, reflux for 1h, cool to 25℃, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a light yellow solid, which is compound (III) (4.17g, HPLC content 95.9%, yield 91%).

[0272] Examples 4-6 This example illustrates the synthesis of compound (III).

[0273]

[0274] Compound (IV) (3.2 g, HPLC purity 95.5%, 14.8 mmol, 1.0 eq, from Example 3-2), DMF (30 g), and tri-n-propylamine (2.65 g, 18.5 mmol, 1.25 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and heated to 80 °C. Benzyl chloride (2.20 g, 98%, 17.0 mmol, 1.15 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept at this temperature for 6 h. The solution was then poured into 100 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 20 g of water, and dried to obtain a yellow solid (4.47 g, purity 91%, yield 92.6%). Add 50g of methylcyclohexane, heat, reflux for 1 hour, cool to 25°C, filter, wash the filter cake with 10g of methylcyclohexane, dry, and obtain a pale yellow solid, which is compound (III) (4.19g, HPLC content 95.8%, yield 91.5%).

[0275] Examples 4-7 This example illustrates the synthesis of compound (III).

[0276]

[0277] Compound (IV) (61.4 g, HPLC purity 95.5%, 283.9 mmol, 1.0 eq, from Example 3-2), DMF (123 g), and tri-n-propylamine (50.8 g, 354.8 mmol, 1.25 eq) were added to a 500 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and heated to 80 °C. Benzyl chloride (42.2 g, 98%, 326.5 mmol, 1.15 eq) was added dropwise at 80 °C for 1 h. After the addition was complete, the mixture was kept warm for 7 h. The solution was poured into 184 g of ice water and stirred at 5 °C for 30 min. The mixture was filtered, washed twice with 100 g of water, and dried to obtain a yellow solid (85.5 g, purity 90.8%, yield 92.2%). Add 550g of methylcyclohexane, heat, reflux for 1 hour, cool to 25°C, filter, wash the filter cake with 100g of methylcyclohexane, dry, and obtain a pale yellow solid, which is compound (III) (80.4g, HPLC content 95.5%, yield 91.2%).

[0278] Example 5-1 This example is used to illustrate compound (II-1)(R) 3 It is the synthesis of methyl groups.

[0279]

[0280] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound III (5.0 g, HPLC purity 95.5%, 16.09 mmol, 1.0 eq, from Examples 4-7), acetonitrile (40 g), and triethylamine (1.79 g, 17.7 mmol, 1.1 eq), start stirring, cool to 8 °C, and dropwise add a solution of acetonitrile (10 g) containing methanesulfonyl chloride (1.94 g, 16.9 mmol, 1.05 eq) at 8-10 °C for 30 min. After the addition is complete, keep warm for 2 h, add hydrochloric acid (0.16 g, 36.5%, 1.6 mmol, 0.1 eq), evaporate the solvent under reduced pressure, add 40 g of dichloromethane, wash twice with 30 g of water, evaporate the solvent under reduced pressure, and obtain a dark red oily substance, which is compound II-1 (6.26 g, HPLC purity 96.1%, yield 99.76%).

[0281] m / z (ESI) 375.01 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 7.472-7.348(m, 7H), 5.392(s, 2H), 3.644(s, 3H); 13C NMR (400 MHz, DMSO) δ: 13C NMR (400 MHz, DMSO) δ: 163.503, 144.618, 144.502, 142.625, 142.514, 140.552, 140.503, 138.882, 136.316 , 135.752, 128.943, 128.850, 128.790, 128.607, 114.242, 114.219, 67.666, 41.150; 19 F NMR (400 MHz, DMSO) delta: -149.858.

[0282] Example 5-2 This example is used to illustrate compound (II-2)(R) 3 It is the synthesis of phenyl.

[0283]

[0284] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound III (5.0 g, HPLC purity 95.5%, 16.09 mmol, 1.0 eq, from Examples 4-7), dichloromethane (40 g), and triethylamine (3.58 g, 17.7 mmol, 1.1 eq). Start stirring and cool to 5 °C. Add dropwise a solution of phenylsulfonyl chloride (2.98 g, 16.9 mmol, 1.05 eq) in dichloromethane (20 g) at a temperature of 5-10 °C for 30 min. After the addition is complete, keep warm for 1 h. Add hydrochloric acid (0.16 g, 36.5%, 1.6 mmol, 0.1 eq), wash twice with 30 g of water, and evaporate the solvent under reduced pressure to obtain a yellow solid, which is compound II-2 (7.32 g, HPLC purity 95.6%, yield 99.55%).

[0285] m / z (ESI) 437.03 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 7.994-7.973(t, 2H), 7.799-7.762(t, 1H), 7.603-7.564(q, 2H), 7.431-7.369(m, 5H), 7.348(s, 2H), 5.325(s, 2H); 13C NMR (400 MHz, DMSO) δ: 163.395, 144.496, 144.380, 142.102, 141.990, 140.566, 140.518, 138.998, 136.428, 136.105 , 135.722, 135.542, 130.014, 128.994, 128.960, 128.856, 128.795, 114.252, 114.230, 67.620; 19 F NMR (400 MHz, DMSO) delta: -149.259.

[0286] Example 5-3 This example is used to illustrate compound (II-3)(R) 3 It is the synthesis of 4-nitrophenyl.

[0287]

[0288] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound (III) (10.0 g, HPLC purity 95.5%, 32.19 mmol, 1.0 eq, from Examples 4-7), acetonitrile (40 g), and triethylamine (3.58 g, 35.4 mmol, 1.1 eq). Stir and cool to 3 °C. Add dropwise a solution of 4-nitrophenylsulfonyl chloride (7.49 g, 33.8 mmol, 1.05 eq) in acetonitrile (20 g) at a temperature of 3-5 °C for 30 min. After addition, keep warm for 1 h. Add hydrochloric acid (0.32 g, 36.5%, 3.2 mmol, 0.1 eq), then pour into 120 g of water. The solid precipitates, is filtered, washed twice with 30 g of 20% acetonitrile, and dried to obtain a pale yellow solid, which is compound (II-3) (15.93 g, HPLC purity 96.8%, yield 99.4%).

[0289] m / z (ESI) 482.01([M+1] + ) 1 H NMR (400 MHz, DMSO) δ: 8.354-8.326(m, 2H), 8.292-8.264(m, 2H), 7.424(s, 2H), 7.386-7.364(m, 5H), 5.311(s, 2H); 13C NMR (400 MHz, DMSO) δ: 163.146, 151.419, 144.743, 144.628, 141.892, 141.783, 141.387, 140.232, 140.185, 138.719, 136 .143, 135.687, 130.728, 128.935, 128.848, 128.594, 128.490, 125.115, 114.781, 114.760, 67.577; 19 F NMR (400 MHz, DMSO) delta: -149.502.

[0290] Example 5-4 This example is used to illustrate compound (II-4) (R) 3 It is the synthesis of trifluoromethyl.

[0291]

[0292] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound (III) (10.0 g, HPLC purity 95.5%, 32.19 mmol, 1.0 eq, from Examples 4-7), dichloroethane (40 g), and triethylamine (3.58 g, 35.4 mmol, 1.1 eq). Stir and cool to 3 °C. Add a solution of trifluoromethanesulfonyl chloride (5.7 g, 33.8 mmol, 1.05 eq) in dichloroethane (20 g) at a temperature of 3-5 °C for 30 min. After addition, keep warm for 2 h. Add hydrochloric acid (0.32 g, 36.5%, 3.2 mmol, 0.1 eq), wash twice with 50 g of water, and evaporate the solvent under reduced pressure to obtain a brown solid, which is compound (II-4) (14.35 g, HPLC purity 95.9%, yield 99.7%).

[0293] m / z (ESI) 428.99 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 7.672(s, 2H), 7.460-7.343(m, 5H), 5.399(s, 2H); 13C NMR (400 MHz, DMSO) δ: 163.105, 145.246, 145.133, 140.990, 140.945, 140.674, 140.553, 138.283, 135.700, 135.626, 128 .853, 128.790, 128.743, 128.527, 123.240, 120.047, 116.861, 115.735, 115.707, 113.680, 67.768; 19 F NMR (400 MHz, DMSO) delta: -73.169, -149.391.

[0294] Example 5-5 This example is used to illustrate compound (II-4) (R) 3 It is the synthesis of trifluoromethyl.

[0295]

[0296] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound (III) (10.0 g, HPLC purity 95.5%, 32.19 mmol, 1.0 eq, from Examples 4-7), acetonitrile (40 g), and dimethylisopropylamine (3.09 g, 35.4 mmol, 1.1 eq). Stir and cool to 5 °C. Add dropwise a solution of trifluoromethanesulfonyl chloride (5.7 g, 33.8 mmol, 1.05 eq) in acetonitrile (20 g) at a temperature of 5-10 °C for 30 min. After addition, keep warm for 3 h. Add hydrochloric acid (0.32 g, 36.5%, 3.2 mmol, 0.1 eq). Evaporate the solvent under reduced pressure. Add 60 g of dichloromethane and wash twice with 50 g of water. Evaporate the solvent under reduced pressure to obtain a brown solid, which is compound (II-4) (14.36 g, HPLC purity 95.7%, yield 99.6%).

[0297] Examples 5-6 This example is used to illustrate compound (II-4) (R) 3 It is the synthesis of trifluoromethyl.

[0298]

[0299] To a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer, add compound (III) (10.0 g, HPLC purity 95.5%, 32.19 mmol, 1.0 eq, from Examples 4-7), methyl isobutyl ketone (40 g), and triethylamine (3.58 g, 35.4 mmol, 1.1 eq). Start stirring and cool to 2 °C. Add a solution of trifluoromethanesulfonyl chloride (5.7 g, 33.8 mmol, 1.05 eq) in methyl isobutyl ketone (20 g) at a temperature of 3-5 °C for 1 h. After addition, keep warm for 2 h. Add hydrochloric acid (0.32 g, 36.5%, 3.2 mmol, 0.1 eq), wash twice with 50 g of water to obtain a brownish-red solution. Evaporate the solvent under reduced pressure of -0.098 MPa to obtain a brown solid, which is compound (II-4) (14.33 g, HPLC purity 96.1%, yield 99.8%).

[0300] Examples 5-7 This example is used to illustrate compound (II-4) (R) 3 It is the synthesis of trifluoromethyl.

[0301]

[0302] Compound (III) (24.40 g, HPLC purity 95.5%, 78.5 mmol, 1.0 eq, from Examples 4-7), methyl isobutyl ketone (48.8 g), and triethylamine (8.74 g, 86.4 mmol, 1.1 eq) were added to a 250 mL four-necked flask equipped with a mechanical stirrer and a thermometer. The mixture was stirred and cooled to 1 °C. Trifluoromethanesulfonyl chloride (13.9 g, 82.4 mmol, 1.05 eq) was then added dropwise. A solution of methyl isobutyl ketone (27.8 g) was added at a temperature of 1-5℃ for 1 h. After the addition was complete, the solution was kept warm for 2 h. Hydrochloric acid (0.79 g, 36.5%, 7.85 mmol, 0.1 eq) was added. The solution was washed twice with 50 g of water. The aqueous layer was extracted with 44.4 g of methyl isobutyl ketone. The oil layers were combined to obtain a brownish-red solution, which was a solution of compound (II-4) (156 g, HPLC purity 96.2%, conversion rate of compound (III) 100%).

[0303] Comparative Example 2 This comparative example is used to illustrate the synthesis of compound (II-a) (corresponding to CN115298167A).

[0304]

[0305] 1) Synthesis of compound (III-a)

[0306] Step 1: Add compound (V-1) (90 g, HPLC purity 96.3%, 227.6 mmol, 1.0 eq, prepared according to the method in CN115298167A) and a solution of hydrogen bromide in acetic acid (279 g, 33%, 1138.2 mmol, 5 eq) to a 500 mL reaction flask equipped with a mechanical stirrer and thermometer. Start stirring, heat to 50 °C, and maintain the temperature for 25 h. Pour the reaction solution into 900 g of water, stir at 25 °C for 30 min, filter, wash twice with 200 g of water, and dry to obtain a mixture (79 g).

[0307] m / z (ESI) 440.96([M+1] + ).

[0308] Step 2: Add the mixture from Step 1 and sulfuric acid (900 g, 80%, 7346.9 mol, 32.3 eq) to a 2000 mL four-necked flask, start stirring, and stir at 110 °C for 24 h. Cool to 0 °C, and then pour the reaction solution into water (3600 g). Stir at room temperature for 30 min, and filter. Suspend the solid in water (3600 g), heat at 100 °C for 1 h, filter while hot, and then dry to obtain compound (III-a) (47 g, HPLC purity 85.3%, two-step yield 65.4% based on compound (V-1)).

[0309] m / z (ESI) 266.91 ([M-1] - ).

[0310] 2) Synthesis of compound (II-a)

[0311] Compound (III-a) (47 g, HPLC purity 85.3%, 148.9 mmol, 1.0 eq), potassium carbonate (22.9 g, 99%, 163.8 mmol, 1.1 eq), and DMSO (210 g) were added to a 1000 mL reaction flask equipped with a mechanical stirrer and thermometer. The mixture was stirred at room temperature for 30 min, then benzyl chloride (21.4 g, 97%, 163.8 mmol, 1.1 eq) was added. The mixture was heated to 50 °C and maintained at this temperature for 5 h. 600 g of water was added, and the mixture was stirred at 25 °C for 30 min. The mixture was filtered, washed twice with 300 g of water, and dried to obtain compound (II-a) (53.8 g, HPLC purity 94.9%, yield 95.3%, three-step yield 62.3% based on compound (V-1)).

[0312] m / z (ESI) 358.95 ([M+1] + ).

[0313] In Comparative Example 2, the bromination step uses a large excess of hydrobromic acid solution, which easily leads to the escape of hydrogen bromide during the reaction, and the excess hydrogen bromide is difficult to recover and reuse. The hydrolysis process uses a large amount of sulfuric acid, generating a large amount of sulfuric acid-containing wastewater. These two steps result in long reaction times and the generation of numerous impurities, leading to a low yield; the three-step yield based on compound (V-1) is only 62.3%. The embodiments in this invention avoid these problems, significantly improving the yield; the three-step yield based on compound (V-1) can reach up to 87.2%.

[0314] Example 6-1 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0315]

[0316] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-1) (2.5 g, HPLC purity 96.1%, 6.4 mmol, 1.0 eq, from Example 5-1), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.38 g, 6.7 mmol, 1.05 eq), potassium bicarbonate (1.6 g, 16 mmol, 2.5 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.4 g, 1.5 mmol, 0.238 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.069 eq) were added. The mixture was stirred, heated, and kept at 70-75 °C for 7 h. After cooling, the mixture separated into layers and was washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure to obtain a brown oily substance, which was compound (I) (3.18 g, quantitative content 26%, yield 29%).

[0317] Example 6-2 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0318]

[0319] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-2) (3.0 g, HPLC purity 95.6%, 6.6 mmol, 1.0 eq, from Example 5-2), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.45 g, 7 mmol, 1.08 eq), potassium bicarbonate (1.64 g, 16.4 mmol, 2.5 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.4 g, 1.5 mmol, 0.232 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.068 eq) were added. The mixture was stirred, heated, and kept at 70-73 °C for 6 h. After cooling, the mixture separated into layers and was washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, 10g of tetrahydrofuran was added to dissolve it, and then 30g of water was added to precipitate the solid. The solid was filtered, washed with 20g of water, and a brown solid was obtained, which was compound (I) (2.92g, quantitative content 52.3%, yield 53%).

[0320] Example 6-3 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0321]

[0322] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-3) (3.5 g, HPLC purity 96.8%, 7 mmol, 1.0 eq, from Example 5-3), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.55 g, 7.6 mmol, 1.08 eq), potassium bicarbonate (1.76 g, 17.6 mmol, 2.5 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.4 g, 1.5 mmol, 0.217 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.063 eq) were added. The mixture was stirred, heated, and kept at 70-73 °C for 7 h. After cooling, the mixture separated into layers and was washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, 10g of tetrahydrofuran was added to dissolve it, and then 30g of water was added to precipitate the solid. The solid was filtered, washed with 20g of water, and a brown solid was obtained, which was compound (I) (3.18g, quantitative content 77.1%, yield 79.5%).

[0323] Example 6-4 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0324]

[0325] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-4) (3.5 g, HPLC purity 96.1%, 7.8 mmol, 1.0 eq, from Examples 5-6), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.73 g, 8.5 mmol, 1.08 eq), potassium bicarbonate (1.96 g, 19.6 mmol, 2.5 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.4 g, 1.5 mmol, 0.194 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.057 eq) were added. The mixture was stirred, heated, and kept at 70-72 °C for 6 h. After cooling, the mixture separated into layers and was washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, 10g of tetrahydrofuran was added to dissolve it, and then 30g of water was added to precipitate the solid. The solid was filtered, washed with 20g of water, and a brown solid was obtained, which was compound (I) (3.51g, quantitative content 88.2%, yield 89.9%).

[0326] Example 6-5 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0327]

[0328] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-4) (3.5 g, HPLC purity 96.1%, 7.8 mmol, 1.0 eq, from Examples 5-6), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.73 g, 8.5 mmol, 1.08 eq), potassium bicarbonate (1.96 g, 19.6 mmol, 2.5 eq), acetonitrile (60 g), water (10 g), triphenylphosphine (0.4 g, 1.5 mmol, 0.194 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.057 eq) were added. The mixture was stirred, heated, and kept at 70-72 °C for 6 h. After cooling to room temperature, the mixture was filtered to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, 10g of tetrahydrofuran was added to dissolve it, and then 30g of water was added to precipitate the solid. The solid was filtered, washed with 20g of water, and a brownish-yellow solid was obtained, which was compound (I) (3.56g, quantitative content 85.3%, yield 88.2%).

[0329] Example 6-6 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0330]

[0331] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-4) (3.5 g, HPLC purity 96.1%, 7.8 mmol, 1.0 eq, from Examples 5-6), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 1.73 g, 8.5 mmol, 1.08 eq), sodium bicarbonate (1.65 g, 19.6 mmol, 2.5 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.48 g, 1.8 mmol, 0.233 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.057 eq) were added. The mixture was stirred, heated, and kept at 70-72 °C for 7 h. After cooling, the mixture separated into layers and washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, 10g of tetrahydrofuran was added to dissolve it, and then 30g of water was added to precipitate the solid. The solid was filtered, washed with 20g of water, and a light brown solid was obtained, which was compound (I) (3.55g, quantitative content 90.5%, yield 93.2%).

[0332] Examples 6-7 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0333]

[0334] In a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, a solution of compound (II-4) (156 g, HPLC purity 96.2%, 78.5 mmol, 1.0 eq based on compound III, from Examples 5-7), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 17 g, 83.2 mmol, 1.06 eq), and sodium bicarbonate (16.49 g, 196 mmol, 2.5 eq) was added. Methyl isobutyl ketone (89 g), water (70 g), triphenylphosphine (1.2 g, 4.58 mmol, 0.058 eq), palladium acetate (0.25 g, 1.1 mmol, 0.014 eq) were stirred and heated to 70-72 °C for 7 h. The mixture was then cooled and separated into layers. The layers were washed with water (70 g) and extracted with methyl isobutyl ketone (100 g) to extract the aqueous layer. The oil layers were combined to obtain a brown solution, which was a solution of compound (I) (346 g, quantitative concentration 9.6%, yield 96.3%). After removing palladium, the solvent was evaporated under reduced pressure, acetonitrile (350 g, 60%) was added, the mixture was heated and refluxed for 10 min, cooled to 15 °C, kept at that temperature for 30 min, filtered, and the filter cake was washed with acetonitrile (30 g, 20%) to obtain an off-white solid, which was compound (I) (32.48 g, quantitative content 97.8%, two-step yield 92.1% based on compound III in Examples 5-7).

[0335] m / z (ESI) 439.03 ([M+1] + ); 1 H NMR (400 MHz, DMSO) δ: 7.471-7.274(m, 7H), 7.116(s, 2H), 5.384(s, 2H); 13 C NMR (400 MHz, DMSO) δ: 164.743, 154.840, 152.340, 146.750, 145.123, 145.080, 144.426, 144.290, 144.196, 142.161, 142.019, 136.978, 136.846, 135.775, 129.071, 129.038, 128.980, 128.847, 126.356, 126.330, 126.064, 126.028, 123.450, 123.410, 123.310, 123.270, 113.403, 113.380, 67.572, 62.111, 62.068; 19 F NMR (400 MHz, DMSO) δ: -129.097(d, J=29.36), -137.611(d, J=14.26).

[0336] Examples 6-8 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0337]

[0338] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-4) (3.5 g, HPLC purity 96.3%, 7.8 mmol, 1.0 eq), dimethyl 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-2, 1.97 g, 8.5 mmol, 1.08 eq), sodium bicarbonate (1.72 g, 20.4 mmol, 2.6 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.48 g, 1.8 mmol, 0.233 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.057 eq) were added. The mixture was stirred, heated, and kept at 68-70 °C for 5 h. After cooling, the mixture separated into layers and was washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, acetonitrile (35 g, 60%) was added, the mixture was heated and refluxed for 10 min, cooled to 15 °C, kept at that temperature for 30 min, filtered, and the filter cake was washed with acetonitrile (6 g, 20%) to obtain an off-white solid, which was compound (I) (3.26 g, quantitative content 98.1%, yield 92.7% based on compound II-4).

[0339] Examples 6-9 This example illustrates the synthesis of compound (I) (chlorofluoropyridine ester).

[0340]

[0341] In a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, under a nitrogen atmosphere, compound (II-4) (3.5 g, HPLC purity 96.3%, 7.8 mmol, 1.0 eq), ethylene glycol 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-3, 1.96 g, 8.5 mmol, 1.08 eq), sodium bicarbonate (1.78 g, 20.4 mmol, 2.7 eq), methyl isobutyl ketone (60 g), water (10 g), triphenylphosphine (0.48 g, 1.8 mmol, 0.233 eq), and palladium acetate (0.1 g, 0.445 mmol, 0.057 eq) were added. The mixture was stirred, heated, and kept at 65-69 °C for 6 h. After cooling, the mixture separated into layers and washed with water (10 g) to obtain a brownish-red solution. The solvent was evaporated under reduced pressure, acetonitrile (35 g, 60%) was added, the mixture was heated and refluxed for 10 min, cooled to 15 °C, kept warm for 30 min, filtered, and the filter cake was washed with acetonitrile (3 g, 20%) to obtain an off-white solid, which was compound (I) (3.28 g, quantitative content 97.9%, yield 92.9% based on compound II-4).

[0342] Comparative Example 3 This comparative example is used to illustrate the synthesis of compound (I) (chlorofluoropyridine ester) (corresponding to CN115298167A).

[0343]

[0344] To a 500 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, add benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (compound II-a, HPLC purity 94.9%, 31.45 g, 83.0 mmol, 1.0 eq, from Comparative Example 2), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 18.8 g, 92 mmol, 1.108 eq), potassium bicarbonate (18.7 g, 187 mmol, 2.25 eq), and T... HF (250 mL) and water (83 mL) were added, stirred, and purged with nitrogen. Triphenylphosphine (438 mg, 1.67 mmol, 0.02 eq) and palladium acetate (186 mg, 0.83 mmol, 0.01 eq) were then added. The mixture was heated to 60 °C and maintained at 60 °C for 5 h. 4-chloro-2-fluoro-3-methoxyphenylboronic acid (1.90 g, 9.3 mmol, 0.111 eq) was added, and the mixture was kept at this temperature for another 3 h. The mixture was then cooled to room temperature, and the layers were separated. The aqueous phase was extracted with THF (50 mL). The oil phases were combined, and after removing palladium, the oil phase was concentrated to approximately 100 mL. Water (300 mL) was added with stirring, and the mixture was filtered. The filter cake was washed with water (100 mL) and dried to obtain a yellow solid, which was compound (I) (35.8 g, quantified content 87%, yield 85.43%).

[0345] Comparative Example 4 This comparative example is used to illustrate the synthesis of compound (I) (chlorofluoropyridine ester) (corresponding to CN115551833A).

[0346]

[0347] Under a nitrogen atmosphere, triphenylphosphine (53 mg, 0.2 mmol, 0.01 eq), palladium acetate (23 mg, 0.1 mmol, 0.005 eq), 4-chloro-2-fluoro-3-methoxyphenylboronic acid (A-1, 4.7 g, 23 mmol, 1.15 eq), benzyl 4-amino-6-bromo-3-chloro-5-fluoropyridinecarboxylate (compound II-a, 7.58 g, 94.9%, 20 mmol, 1.0 eq, from Comparative Example 2), potassium bicarbonate (4 g, 40 mmol, 2.08 eq), THF (8 mL), and 2 wt% TPGS 750 were added to a 250 mL four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. M (36 mL), start stirring, heat to 50 °C, keep warm for 25 h, cool to room temperature, filter, wash with water (20 mL), and dry to obtain compound (I) (7.88 g, quantitative content 88%, yield 79%).

[0348] In Comparative Examples 3 and 4, bromopyridine was used for coupling, resulting in a large amount of compound A-1 that was difficult to recover using water-soluble solvents. Furthermore, Comparative Example 3 involved two feedings, making the process complex, and Comparative Example 4 required a reaction time of up to 25 hours. Both comparative examples showed low yields and contents. This invention uses sulfonates instead of bromopyridine for coupling, achieving improved results. Different sulfonates exhibit different activities, leading to variations in yield; trifluoromethanesulfonate showed the best yield. This invention uses a non-water-soluble solvent, making recovery easier, reducing the amount of compound A-1 required, shortening the reaction time, and significantly improving both yield and content.

[0349] The preferred embodiments of the present invention have been described in detail above; however, the present invention is not limited thereto. Within the scope of the inventive concept, various simple modifications can be made to the technical solutions of the present invention, including combinations of various technical features in any other suitable manner. These simple modifications and combinations should also be considered as the content disclosed in the present invention and are all within the protection scope of the present invention.

Claims

1. A compound of formula (X) or a salt thereof: in, R 5 Selected from H, halogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 haloalkyl, C1-C4 haloalkoxy or nitro; R 6 Selected from OH or Cl; n is any integer selected from 1 to 4.

2. The compound or a salt thereof according to claim 1, wherein, R 5 Selected from H, halogen, methyl, methoxy, halomethyl, halomethoxy, or nitro; Optionally, R 5 Selected from H, F, Cl, or Br, optionally R 5 For H; And / or, R 6 It is OH or Cl; And / or, n is 1 or 2; And / or, the compound represented by formula (X) is selected from the following compounds: Among them, R 5 and n are as defined above; Optionally, R 5 Let H be the integer part of the set, and n be 1.

3. A compound of formula (XI) or a salt thereof, in, R 7 Selected from H, benzyl or C1-C 12 alkyl; R 8 Selected from H or R 3 SO2; Among them, R 3 Selected from substituted or unsubstituted C1-C 12 Alkyl, substituted or unsubstituted C6-C 12 Aryl or substituted or unsubstituted C7-C 15 Aryl alkyl group.

4. The compound or a salt thereof according to claim 3, wherein, R 7 It is H or benzyl; And / or, R 3 Selected from substituted or unsubstituted C1-C3 alkyl, substituted or unsubstituted C6-C8 aryl, or substituted or unsubstituted C7-C9 aralkyl; Optionally, R 3 It is selected from substituted C1-C3 alkyl, substituted C6-C8 aryl or substituted C7-C9 aralkyl, and optionally from substituted methyl, substituted phenyl or substituted benzyl; Optionally, R 3 The substituents in each group are independently selected from at least one of halogen, cyano or nitro, optionally selected from at least one of fluorine, chlorine, cyano or nitro, and further optionally selected from at least one of fluorine, chlorine or nitro; Optionally, R 3 It is trichloromethyl; Optionally, R 3 It is trifluoromethyl; Optionally, R 3 It is 2-nitrophenyl; Optionally, R 3 It is 3-nitrophenyl; Optionally, R 3 It is 4-nitrophenyl; And / or, the compound represented by formula (XI) is selected from the following compounds: Among them, R 3 As defined above, Bn is benzyl; Optionally, R 3 It is trichloromethyl; Optionally, R 3 It is trifluoromethyl; Optionally, R 3 It is 2-nitrophenyl; Optionally, R 3 It is 3-nitrophenyl; Optionally, R 3 It is 4-nitrophenyl.

5. A method for preparing a compound of formula (VI) or a salt thereof, characterized in that, The method includes the following steps: (1) In the presence of a first solvent and a first base, the compound shown in formula (IX) is made With the compounds shown in formula (B1) or formula (B2) The first reaction yields intermediate compound A; (2) In the presence of the first acid or the first dehydrating agent, intermediate compound A is reacted with R. 4 OH undergoes a second reaction; or, in the presence of a second base, intermediate compound A reacts with R. 4 Z undergoes a third reaction to yield the compound shown in formula (VI); or, (2') React intermediate compound A with a chlorinating reagent in a fourth reaction to obtain intermediate compound B; react intermediate compound B with R 4 The OH radical undergoes a fifth reaction to yield the compound shown in formula (VI); Among them, R 4 Selected from substituted or unsubstituted C1-C 12 Alkyl, C3-C 12 alkynyl group, C3-C 12 alkenyl or C7-C 13 Aryl alkyl groups; R 5 and n as defined in claim 1 or 2; Hal is selected from Cl or Br; Z is selected from halogen or R 3 SO3, where R 3 As defined in claim 3 or 4.

6. The method according to claim 5, wherein, R 4 For C1-C 12 Alkyl, optionally C1-C7 alkyl; And / or, R 4 Replaced by one or more cyano, halogen, or nitro groups, optionally R 4 Replaced by one or more halogens; And / or, the structural formulas of intermediate compound A and intermediate compound B are shown in formula (X): Among them, R 6 As defined in claim 1 or 2; And / or, the method includes the following steps: (1) In the presence of a first solvent and a first base, the compound shown in formula (IX) is reacted with the compound shown in formula (B1) or formula (B2) in a first reaction to give the compound of formula (VIII). ； (2) In the presence of a first acid or a first dehydrating agent, the compound shown in formula (VIII) is reacted with R. 4 A second reaction occurs with OH; or, in the presence of a second base, the compound shown in formula (VIII) reacts with R. 4 Z undergoes a third reaction to yield the compound shown in formula (VI); or, (2') The compound shown in formula (VIII) undergoes a fourth reaction with a chlorinating reagent to give the compound shown in formula (VII). ； Make the compound shown in formula (VII) react with R 4 The OH radical undergoes a fifth reaction to yield the compound shown in formula (VI); And / or, in step (1), the first solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, in step (1), the first base is selected from at least one of inorganic bases and tertiary amines; Optionally, in step (1), the substituents on the nitrogen of the tertiary amine are each independently selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings; Optionally, in step (1), the first alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-di-dimethylcyclohexylamine, N,N-di-dimethylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N ... The ingredient is at least one of ethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, and 4-dimethylaminopyridine, and optionally at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, and diisopropylethylamine. And / or, in step (1), the first alkali is added to the reaction system by dropping, adding in batches, or adding all at once; And / or, in step (1), the compound represented by formula (B1) or formula (B2) is added to the reaction system by dropping, adding in batches or adding all at once; And / or, in step (1), the temperature of the first reaction is 30-150°C, optionally 30-100°C, and further optionally 50-90°C; And / or, in step (2), the first acid is selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid and substituted sulfonic acid, optionally selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid, and further optionally selected from at least one of trifluoromethanesulfonic acid and sulfuric acid; And / or, in step (2), the first dehydrating agent is selected from at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, thionyl chloride, sulfone chloride, phosphorus oxychloride, phosphorus trichloride, and phosphorus pentachloride; And / or, in step (2), the first dehydrating agent is used in combination with a catalyst, optionally selected from 4-dimethylaminopyridine, N-hydroxysuccinimide or 1-hydroxybenzotriazole; And / or, in step (2), the second base is a substituted or unsubstituted tertiary amine; Optionally, in step (2), the substituents on the nitrogen of the tertiary amine are each independently selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings; Optionally, in step (2), the second base is selected from at least one of trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline and 4-dimethylaminopyridine, and optionally selected from at least one of triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine and diisopropylethylamine; And / or, the temperature of the second reaction is 60-120°C; And / or, the second reaction takes 24-48 hours; And / or, the temperature of the third reaction is 20-100°C; And / or, the duration of the third reaction is 4-10 hours; And / or, in step (2), the second reaction is carried out in the presence of a second solvent; Optionally, in step (2), the second solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, in step (2), the third reaction is carried out in the presence of a third solvent; Optionally, in step (2), the third solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, in step (2'), the fourth reaction is carried out in the presence of a fourth solvent; Optionally, in step (2'), the fourth solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, in step (2'), the fifth reaction is carried out in the presence of a fifth solvent; Optionally, in step (2'), the fifth solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, in step (2'), the chlorinating agent is selected from at least one of thionyl chloride, phosgene, solid phosgene, phosphorus oxychloride and phosphorus trichloride; And / or, in step (2'), the temperature of the fourth and fifth reactions is 30-150°C, optionally 30-100°C, and further optionally 50-90°C; And / or, the molar ratio of the first base to the compound shown in formula (IX) is (2-6):1, optionally (2.5-4):1; And / or, the molar ratio of the compound represented by formula (B1) or formula (B2) to the compound represented by formula (IX) is (1-4):1, optionally (2-3):1; And / or, the molar ratio of the first acid to the compound shown in formula (IX) is (0.05-1):1, optionally (0.1-0.5):1; And / or, the molar ratio of the first dehydrating agent to the compound shown in formula (IX) is (1-3):1, or optionally (1-1.5):1; And / or, the R 4 The molar ratio of OH to the compound shown in formula (IX) is (1-10):1, or optionally (1-2):1; And / or, the molar ratio of the second base to the compound shown in formula (IX) is (1-3):1, or optionally (1-1.5):1; And / or, the R 4 The molar ratio of Z to the compound shown in formula (IX) is (1-2):1, or optionally (1-1.3):1; And / or, the molar ratio of the chlorinating agent to the compound shown in formula (IX) is (1-5):1, optionally (1.1-1.5):

1.

7. A method for preparing a chlorofluoropyridine ester of formula (I), characterized in that, The method includes: In the presence of a catalyst, the compound shown in formula (II) undergoes a seventh reaction with the compound shown in formula (A) to give the chlorofluoropyridine ester shown in formula (I). Among them, R 1 and R 2 Each is independently selected from H or C1-C8 alkyl, or R 1 R 2 Together with the O and B atoms they are attached to, they form five- to eleven-membered heterocyclic alkyl groups; R 3 As defined in claim 3 or 4; Bn is benzyl.

8. The preparation method according to claim 7, wherein, R 1 and R 2 Each is independently selected from H or C1-C3 alkyl groups, or R 1 R 2 Together with the O and B atoms they are attached to, they form five- to seven-membered heterocyclic alkyl groups; Optionally, R 1 and R 2 All are H or methyl, or the compound shown in formula (A) is ethylene glycol 4-chloro-2-fluoro-3-methoxyphenylboronic acid; And / or, the seventh reaction is carried out in the presence of the sixth solvent; Optionally, the sixth solvent is selected from C1-C1. 12 Alcohol solvents, C1-C 12 The solvent is selected from at least one of nitrile solvents, ether solvents, aromatic solvents, ketone solvents, amide solvents, sulfone or sulfoxide solvents, and water, optionally selected from methanol, ethanol, propanol, isopropanol, acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and water. At least one, further optionally selected from at least one of acetonitrile, propionitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, toluene, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine and water, and further optionally selected from at least one of a mixed solvent of acetonitrile and water, a mixed solvent of tetrahydrofuran and water, a mixed solvent of methyl isobutyl ketone and water, or a mixed solvent of N,N-dimethylformamide and water; And / or, the seventh reaction is carried out in the presence of a palladium or nickel catalyst and optional ligands; Optionally, the palladium catalyst is selected from at least one of palladium chloride, palladium bromide, palladium acetate, palladium sulfate, palladium nitrate and supported palladium catalysts, and is optionally selected from at least one of palladium chloride, palladium acetate and palladium sulfate; Optionally, the ligand of the palladium catalyst is selected from at least one of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tri(o-tolyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane and 1,1′-ferrocenediyl-bis(diphenylphosphine), and optionally selected from at least one of triphenylphosphine and tricyclohexylphosphine; Optionally, the palladium catalyst is a palladium coordination compound, optionally selected from at least one of bis(triphenylphosphine)dichloride palladium(II), bis(acetic acid)bis(triphenylphosphine)palladium(II), tetra(triphenylphosphine)palladium(O), tri(diphenylmethyleneacetone)dipalladium(O) and dichloroditert-butyl-(4-dimethylaminophenyl)phosphine palladium(II), and more preferably selected from at least one of bis(triphenylphosphine)dichloride palladium(II) and bis(acetic acid)bis(triphenylphosphine)palladium(II); Optionally, the nickel catalyst is selected from at least one of nickel dichloride, nickel dibromide, nickel acetate, nickel sulfate, nickel nitrate, ethylene glycol dimethyl ether nickel bromide, or supported nickel catalyst; Optionally, the ligand of the nickel catalyst is selected from at least one of tri-tert-butylphosphine, tricyclohexylphosphine, di-tert-butylphenylphosphine, dicyclohexylphenylphosphine, triphenylphosphine, tris(o-tolyl)phosphine, 1,2-bis(diphenylphosphino)ethane, 1,3-bis(diphenylphosphino)propane, 1,4-bis(diphenylphosphino)butane, 1,1′-ferrocene di-bis(diphenylphosphine), 4,4'-di-tert-butyl-2,2'-bipyridine, 4,7-diphenyl-1,10-phenanthroline, and 4,4'-dimethoxy-2,2'-bipyridine; And / or, the seventh reaction is carried out in the presence of a palladium catalyst, wherein the molar ratio of the palladium catalyst to the compound shown in formula (II) is (0.001-0.1):1, optionally (0.002-0.05):1; And / or, the seventh reaction is carried out in the presence of a palladium catalyst and a ligand for the palladium catalyst, wherein the molar ratio of the ligand to the palladium catalyst is (1.8-18):1, or optionally (2-8):1; And / or, the seventh reaction is carried out in the presence of a nickel catalyst, wherein the molar ratio of the nickel catalyst to the compound shown in formula (II) is (0.01-0.2):1, optionally (0.03-0.1):1; And / or, the seventh reaction is carried out in the presence of a third base; Optionally, the third base is selected from at least one of inorganic bases and organic bases, and is optionally selected from at least one of lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate, triethylamine, tripropylamine and pyridine, and is optionally selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, potassium hydrogen phosphate and potassium dihydrogen phosphate. And / or, the temperature of the seventh reaction is 30-150°C, optionally 40-120°C, and further optionally 50-90°C; And / or, the duration of the seventh reaction is 2-24 hours, optionally 5-12 hours; And / or, the molar ratio of the compound shown in formula (A) to the compound shown in formula (II) is (0.95-1.2):1, optionally (1-1.1):1; And / or, the molar ratio of the third base to the compound shown in formula (II) is (1.5-7):1, optionally (2-4):

1.

9. The method according to claim 7 or 8, wherein, The compound represented by formula (II) is prepared by the following method: (1) In the presence of water and a second acid or a fourth base, the compound shown in formula (V) is made... The eighth reaction occurs, yielding the compound shown in formula (IV). ； Among them, R 4 As defined in claim 5 or 6; R 5 and n as defined in claim 1 or 2; or, (1') In the presence of a reducing agent, the compound shown in formula (V) is reduced to give the compound shown in formula (IV); (2) In the presence of the fifth base, the compound shown in formula (IV) undergoes a ninth reaction with BnZ to give the compound shown in formula (III). Wherein, Bn is benzyl, and Z is as defined in claim 6; or, (2') In the presence of a second dehydrating agent, the compound shown in formula (IV) is reacted with benzyl alcohol in the tenth reaction to give the compound shown in formula (III); (3) In the presence of the sixth base, the compound shown in formula (III) is reacted with R. 3 SO2Cl or (R) 3 SO2)2O undergoes the fourteenth reaction to give the compound shown in formula (II), wherein R 3 As defined in claim 3 or 4, ； And / or, in step (1), the temperature of the eighth reaction is 20-200°C; And / or, the second acid is selected from at least one of inorganic acids and organic acids, optionally selected from at least one of hydrochloric acid, hydrobromic acid, sulfuric acid, organic acid, substituted organic acid and substituted sulfonic acid, further optionally selected from at least one of formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydrochloric acid, hydrobromic acid and sulfuric acid, and even more optionally selected from at least one of acetic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid and sulfuric acid; And / or, the fourth base is selected from at least one of organic bases and inorganic bases, and optionally from at least one of lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate and potassium carbonate, and further optionally from at least one of sodium hydroxide and potassium hydroxide; And / or, in step (1'), the reducing agent is selected from at least one of hydrogen and hydrazine hydrate; And / or, the temperature of the reduction reaction is 30-200°C, optionally 40-180°C, and further optionally 50-100°C; And / or, the reduction reaction is carried out in the presence of an inert solvent; And / or, in step (2'), the second dehydrating agent is selected from at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide; And / or, in step (2'), the second dehydrating agent is used in combination with a catalyst, optionally selected from 4-dimethylaminopyridine, N-hydroxysuccinimide or 1-hydroxybenzotriazole; And / or, the temperature of the tenth reaction is 50-150°C, optionally 60-120°C; And / or, the ninth and / or tenth reactions are carried out in the presence of the seventh solvent; Optionally, the seventh solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine dimethyl sulfoxide, and sulfolane, and further optionally from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane; And / or, the fifth base is one or more tertiary amines; Optionally, the substituents on the nitrogen of the tertiary amine are selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings; Optionally, the fifth base is selected from at least one of trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, N,N-diethylcyclohexylamine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline, and 4-dimethylaminopyridine, and is optionally selected from at least one of triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, and diisopropylethylamine; And / or, the fifth base is added to the reaction system by dropping or in batches; And / or, the BnZ is added to the reaction system dropwise; And / or, the temperature of the ninth reaction is 30-150°C, optionally 40-100°C, and further optionally 60-90°C; And / or, the ninth reaction is a continuous reaction; And / or, the fourteenth reaction is carried out in the presence of the eighth solvent; Optionally, the eighth solvent is selected from C1-C1. 12 The solvent is selected from at least one of nitrile solvents, ether solvents, alkane solvents, aromatic solvents, ketone solvents, amide solvents, and sulfone or sulfoxide solvents, and optionally from at least one of acetonitrile, propionitrile, butyronitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, benzene, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide, and sulfolane, and further optionally from at least one of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, cyclohexane, methylcyclohexane, dichloromethane, trichloromethane, dichloroethane, toluene, xylene, acetone, methyl ethyl ketone, and methyl isobutyl ketone; And / or, the sixth base is at least one of an inorganic base and a tertiary amine; Optionally, the substituents on the nitrogen of the tertiary amine are selected from C1-C1. 12 Alkyl, C6-C 12 Aryl or C7-C 13 Aryl groups, or forming five-membered or six-membered rings; Optionally, the sixth alkali is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine, diisopropylethylamine, N,N-dimethylcyclopentylamine, N,N-diethylcyclopentylamine, N,N-dipropylcyclopentylamine, N,N-diisopropylcyclopentylamine, N,N-dimethylcyclohexylamine, and N,N-diethylcyclohexylamine. The amine, N,N-dipropylcyclohexylamine, N,N-diisopropylcyclohexylamine, N-methylmorpholine, N-ethylmorpholine, N-methylpyrrolidine, N-ethylpyrrolidine, N-methylpiperidine, N-ethylpiperidine, N,N-dimethylaniline and 4-dimethylaminopyridine, optionally selected from at least one of sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, triethylamine, tri-n-propylamine, triisopropylamine, tributylamine, dimethylisopropylamine, diethylisopropylamine and diisopropylethylamine; And / or, the sixth alkali is added to the reaction system by dropping, adding in batches, or adding all at once; And / or, the R 3 SO2Cl or (R) 3 SO2)2O is added to the reaction system dropwise. And / or, the temperature of the fourteenth reaction is from -10 to 100°C, optionally from 0 to 50°C, and further optionally from 0 to 20°C; And / or, the molar ratio of the second acid to the compound shown in formula (V) is (0.5-100):1, optionally (5-20):1; And / or, the molar ratio of the fourth base to the compound shown in formula (V) is (4-10):1, optionally (6-8):1; And / or, the molar ratio of the reducing agent to the compound shown in formula (V) is (2-20):1, optionally (4-10):1; And / or, the molar ratio of the fifth base to the compound shown in formula (V) is (1-4):1, optionally (1-1.5):1; And / or, the molar ratio of BnZ to the compound shown in formula (V) is (1-4):1, optionally (1-1.5):1; And / or, the molar ratio of the second dehydrating agent to the compound shown in formula (V) is (1-5):1, optionally (2-3):1; And / or, the molar ratio of the benzyl alcohol to the compound shown in formula (V) is (1-6):1, optionally (1.5-2):1; And / or, the molar ratio of the sixth base to the compound shown in formula (V) is (1-5):1, optionally (1-2):1; And / or, the R 3 The molar ratio of SO2Cl to the compound shown in formula (V) is (1-5):1, or optionally (1-2):1; And / or, the (R) 3 The molar ratio of SO2)2O to the compound shown in formula (V) is (1-6):1, or optionally (1-2):

1.

10. A method for preparing a chlorofluoropyridine ester of formula (I), characterized in that, The method includes the following steps: (1) The compound of formula (VI) is prepared from the compound of formula (IX) by the method of claim 5 or 6; (2) React the compound shown in formula (VI) with a fluorinating agent to obtain the compound shown in formula (V); (3) The chlorofluoropyridine ester of formula (I) is prepared from the compound of formula (V) by the method of claim 9; Optionally, in step (2), the fluorinating agent is selected from at least one of hydrogen fluoride, sodium fluoride, potassium fluoride, cesium fluoride, tetramethylammonium fluoride, tetraethylammonium fluoride, tetrapropylammonium fluoride, tetrabutylammonium fluoride, diethylaminosulfur trifluoride and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt, and is optionally selected from at least one of sodium fluoride, potassium fluoride and cesium fluoride, and is further optionally selected from at least one of sodium fluoride and potassium fluoride; Optionally, in step (2), the sixth reaction is carried out in the presence of a phase transfer catalyst. Optionally, the phase transfer catalyst is selected from at least one of polyethers, cyclic crown ethers, and quaternary ammonium salts. Further, the polyethers are selected from at least one of PEG400, PEG600, and polyethylene glycol dimethyl ether; the cyclic crown ethers are selected from at least one of 18-crown 6, 15-crown 5, and cyclodextrin; the quaternary ammonium salts are selected from at least one of tetramethylammonium chloride, tetramethylammonium bromide, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen sulfate, trioctylmethylammonium chloride, dodecyltrimethylammonium chloride, tetradecyltrimethylammonium chloride, and benzyltriethylammonium chloride; and even further, the phase transfer catalyst is selected from at least one of PEG400, tetramethylammonium chloride, and tetrabutylammonium chloride. Optionally, the sixth reaction is carried out in the presence of a polar solvent, which is optionally selected from at least one of amide solvents and sulfone or sulfoxide solvents, further optionally selected from at least one of N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidine, dimethyl sulfoxide and sulfolane, and even further optionally selected from at least one of N-methylpyrrolidine, dimethyl sulfoxide and sulfolane; And / or, the temperature of the sixth reaction is 30-150°C, optionally 30-120°C, and further optionally 50-100°C; And / or, the duration of the sixth reaction is 4-18 hours; And / or, the molar ratio of the fluorinating agent to the compound shown in formula (IX) is (2-10):1, optionally (2-4):1.

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