Preparation of imidazopyridine-2-carboxylic acid

Abstract

The present invention provides a compound of formula D (wherein each R1 is independently selected from halogen, nitro, SF5, N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), SON(C1-C8 alkyl)(C1-C8 alkyl), OSO2(C1-C8 alkyl), OSON(C1-C8 alkyl)(C1-C8 alkyl), N(C1-C8 alkyl)SO2(C1-C8 alkyl), C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C2-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl or phenyl, n is 0, 1, 2, 3 or 4, and R 2 is H, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C3-C8 alkynyloxy, C3-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 The present invention provides a method for preparing a compound of formula (I) wherein the compound is a cycloalkyl group, ...

Description

[Technical Field]

[0001] Priority This application claims priority to U.S. Provisional Patent Application No. 63 / 383,170, filed November 10, 2022, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Certain nematicidal sulfonamides, such as imidazopyridine-2-carboxylic acid, and methods for preparing them and their intermediates have been disclosed, for example, in International Publication No. 2010 / 129500, International Publication No. 2012 / 054233, and Chinese Patent Application Publication No. 108276352A. However, certain previously disclosed synthetic processes still have certain drawbacks, such as increased levels of impurities produced. Therefore, there remains a need for alternative methods for preparing certain nematicidal sulfonamides and their intermediates. Summary of the Invention

[0003] In one aspect, Formula D: [ka] (In the formula, each R 1 are independently halogen, nitro, SF5, N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), SON(C1-C8 alkyl)(C1-C8 alkyl), OSO2(C1-C8 alkyl), OSON(C1-C8 alkyl)(C1-C8 alkyl), N(C1-C8 alkyl)SO2(C1-C8 alkyl), C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl or phenyl; n is 0, 1, 2, 3 or 4, and R 2 is H, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl, or phenyl) A method for preparing a compound of formula (I) is provided as follows: (a1) Formula A in solvent S1 [ka] wherein X is Cl, Br, I, OSO2Me, OSO2(C6H4)CH3, or OSO2CF3, and R 3 is C1-C8 alkyl or C1-C8 haloalkyl by contacting a compound of formula B with a compound of formula C [ka] and forming a compound of (b1) adding an aqueous acid to the reaction mixture of step (a1); (c1) adding a base to the reaction mixture of step (b1) to form a compound of formula D; Includes.

[0004] In some embodiments, each R 1 is independently Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or phenyl. 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or phenyl. In some embodiments, R 2 is H, CH, CHCH, or phenyl. In some embodiments, R 2 is not halogen or cyano.

[0005] In one embodiment, a compound of formula D: [ka] (In the formula, each R 1 are independently halogen, nitro, SF5, N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), SON(C1-C8 alkyl)(C1-C8 alkyl), OSO2(C1-C8 alkyl), OSON(C1-C8 alkyl)(C1-C8 alkyl), N(C1-C8 alkyl)SO2(C1-C8 alkyl), C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl or phenyl; n is 0, 1, 2, 3 or 4, and R 2is H, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl, or phenyl) 1. A method for preparing a compound of the formula (b1) reacting an aqueous acid with a compound of formula C [ka] (In the formula, R 3 is C1-C8 alkyl or C1-C8 haloalkyl to form a reaction mixture; (c1) adding a base to the reaction mixture of step (b1) to form a compound of formula D; The method includes:

[0006] In one aspect, Formula D: [ka] (In the formula, each R 1 are independently halogen, nitro, SF5, N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), SON(C1-C8 alkyl)(C1-C8 alkyl), OSO2(C1-C8 alkyl), OSON(C1-C8 alkyl)(C1-C8 alkyl), N(C1-C8 alkyl)SO2(C1-C8 alkyl), C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl or phenyl; n is 0, 1, 2, 3 or 4, and R 2 is H, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl, or phenyl) 1. A method for preparing a compound of the formula (b1) reacting an aqueous acid with a compound of formula C [ka] (In the formula, R 3 is C1-C8 alkyl or C1-C8 haloalkyl to form a reaction mixture; (b2) adding a buffer to the reaction mixture of step (b1); (c1) adding a base to the reaction mixture of step (b1) to form a compound of formula D; The method includes:

[0007] The choice of solvent for S1 is: (a) a C4-C8 hydrocarbon (e.g., hexane) or a C6-C 10Aromatic hydrocarbons (e.g., benzene, toluene, xylene (pure ortho-, meta-, and para-isomers, mixtures thereof, or mixtures with ethylbenzene), ethylbenzene, and cumene (isopropylbenzene)); (b) halogenated benzenes (e.g., chlorobenzene and 1,2-dichlorobenzene); (c) haloalkanes (e.g., dichloromethane, 1,2-dichloroethane, and 1-chlorobutane); (d) ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl- ... (e) ethers (e.g., ethyl acetate, propyl acetate, and isopropyl acetate), (f) alcohols (e.g., methanol, ethanol, and isopropanol), and / or (g) other solvents including 1,4-diazabicyclo[2.2.2]octane (DABCO), methylene chloride (DCM), DMF, DMSO, acetonitrile (MeCN), and benzonitrile.

[0008] In some embodiments, solvent S1 is a C6-C 10 Solvent S1 includes aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, isopropylbenzene, and mixtures thereof). In some embodiments, solvent S1 does not include acetonitrile (MeCN). In some embodiments, solvent S1 does not include ethers, such as 1,2-dimethoxyethane. In some embodiments, solvent S1 does not include tetrahydrofuran (THF).

[0009] Examples of acids suitable for use in step (b1) include inorganic acids such as hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (HPO), sulfuric acid (HSO), and boric acid (HBO), and organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, citric acid, malic acid, and sulfonic acid. Further examples of sulfonic acids include paratoluenesulfonic acid, methanesulfonic acid, triflic acid, and toluenesulfonic acid as a mixture of isomers. In some embodiments, the acid comprises hydrochloric acid (HCl).

[0010] Examples of bases suitable for use in step (c1) include inorganic hydroxides such as sodium hydroxide and potassium hydroxide, organic bases such as alkali metal salts of alcohols (examples of which include sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide, potassium 1-propoxide, and potassium 2-propoxide), and amine bases such as ammonia, monoalkylamines (e.g., methylamine and ethylamine), dialkylamines (e.g., dimethylamine), and triethylamine, trialkylamines (e.g., trimethylamine and triethylamine), and aromatic amines (e.g., pyridine). In some embodiments, the base comprises sodium hydroxide (NaOH).

[0011] In some embodiments, the present invention provides a compound of Formula 1: [ka] 1. A method for preparing a compound of the formula (A1) Formula 2 in a solvent S1 selected from benzene, toluene, xylene, ethylbenzene, isopropylbenzene and mixtures thereof [ka] (wherein X is Cl, Br or I) by contacting a compound of formula 3 with a compound of formula 4: [ka] and forming a compound of (B1) adding an aqueous acid selected from hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (HPO), sulfuric acid (HSO), boric acid (HBO), or a mixture thereof, to the reaction mixture of step (A1); and (C1) adding an aqueous base selected from ammonia, sodium hydroxide, potassium hydroxide, or a mixture thereof, to the reaction mixture of step (B1) to produce a compound of formula 1. The present invention provides a method comprising:

[0012] In some embodiments, solvent S1 is selected from benzene, toluene, xylene, and mixtures thereof. In some embodiments, solvent S1 does not contain acetonitrile (MeCN). In some embodiments, solvent S1 does not contain ethers, such as 1,2-dimethoxyethane. In some embodiments, solvent S1 does not contain tetrahydrofuran (THF).

[0013] In some embodiments, the methods provided herein reduce the amount of at least one of the following impurities to less than 50 ppm: [ka]

[0014] In some embodiments, the methods provided herein reduce the amount of at least one of the following impurities to less than 50 ppm: [ka]

[0015] In some embodiments, the methods provided herein do not produce more than 50 ppm of any of the following impurities: [ka]

[0016] In some embodiments, the methods provided herein do not produce more than 50 ppm of any of the following impurities: [ka]

[0017] In another aspect, the present invention provides a compound of formula D: [ka] (In the formula, each R 1are independently halogen, nitro, SF5, N(C1-C8 alkyl)(C1-C8 alkyl), C(=S)N(C1-C8 alkyl)(C1-C8 alkyl), SON(C1-C8 alkyl)(C1-C8 alkyl), OSO2(C1-C8 alkyl), OSON(C1-C8 alkyl)(C1-C8 alkyl), N(C1-C8 alkyl)SO2(C1-C8 alkyl), C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10 Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C1-C8 alkylthio, C1-C8 alkylsulfinyl, C1-C8 alkylsulfonyl, C3-C8 cycloalkylthio, C3-C8 cycloalkylsulfinyl, C3-C8 cycloalkylsulfonyl, C4-C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl or phenyl; n is 0, 1, 2, 3 or 4, and R 2 is H, C1-C8 alkyl, C1-C8 haloalkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C 10 Cycloalkyl, C3-C 10 Halocycloalkyl, C4-C 10Alkylcycloalkyl, C4-C 10 Cycloalkylalkyl, C6-C 14 CycloalkylCycloalkyl, C5-C 10 Alkylcycloalkylalkyl, C3-C8 cycloalkenyl, C1-C8 alkoxy, C1-C8 haloalkoxy, C3-C8 cycloalkoxy, C3-C8 halocycloalkoxy, C4-C 10 Cycloalkylalkoxy, C2-C8 alkenyloxy, C2-C8 alkynyloxy, C 11 ~C8 alkylthio, C1~C8 alkylsulfinyl, C1~C8 alkylsulfonyl, C3~C8 cycloalkylthio, C3~C8 cycloalkylsulfinyl, C3~C8 cycloalkylsulfonyl, C4~C 10 Cycloalkylalkylthio, C4-C 10 Cycloalkylalkylsulfinyl, C4-C 10 cycloalkylalkylsulfonyl, C2-C8 alkenylthio, C2-C8 alkenylsulfinyl, C2-C8 alkenylsulfonyl, C2-C8 alkynylthio, C2-C8 alkynylsulfinyl, C2-C8 alkynylsulfonyl, or phenyl) 1. A method for preparing a compound of the formula (a3) Compounds of formula A in solvent Sα containing toluene (PhCH3) and / or acetonitrile (MeCN) [ka] wherein X is Cl, Br, I, OSO2Me, OSO2(C6H4)CH3, or OSO2CF3, and R 3 is C1-C8 alkyl or C1-C8 haloalkyl by contacting a compound of formula B with a compound of formula C: [ka] and forming a compound of (b3) adding a base in solvent Sβ to the reaction mixture of step (a3) ​​(or the isolated compound of formula C) to form a compound of formula E: [ka] (In the formula, M + is an inorganic or organic cation) and producing an intermediate of The present invention provides a method comprising:

[0018] In some embodiments, each R 1 is independently Cl, Br, I, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or phenyl. 2 is H, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, or phenyl. In some embodiments, R 2 is H, CH, CHCH, or phenyl. In some embodiments, R 2 is not halogen or cyano.

[0019] The solvent choices for Sβ include: (a) C4-C8 hydrocarbons (e.g., hexane) or C6-C 10 Aromatic hydrocarbons (e.g., benzene, toluene, xylene (pure ortho-, meta-, and para-isomers, mixtures thereof, or mixtures with ethylbenzene), ethylbenzene, and cumene (isopropylbenzene)); (b) halogenated benzenes (e.g., chlorobenzene and 1,2-dichlorobenzene); (c) haloalkanes (e.g., dichloromethane, 1,2-dichloroethane, and 1-chlorobutane); (d) ethers (e.g., tetrahydrofuran (THF), 2-methyltetrahydrofuran (2-methyl- ... Other solvents include (e) methyl ether (2-Me-THF), tert-butyl methyl ether, 1,4-dioxane, and PhO (diphenyl ether), (e) esters (e.g., ethyl acetate, propyl acetate, and isopropyl acetate), (f) alcohols (e.g., methanol, ethanol, and isopropanol), and / or (g) 1,4-diazabicyclo[2.2.2]octane (DABCO), methylene chloride (DCM), DMF, DMSO, acetonitrile (MeCN), and benzonitrile.

[0020] In some embodiments, solvent Sβ includes water, methanol, ethanol, isopropanol, and mixtures thereof. In some embodiments, solvent Sα and / or solvent Sβ do not include ethers, such as 1,2-dimethoxyethane. In some embodiments, solvent Sα and / or solvent Sβ do not include tetrahydrofuran (THF).

[0021] Examples of bases suitable for use in step (b3) include inorganic hydroxides such as sodium hydroxide and potassium hydroxide, organic bases such as alkali metal salts of alcohols (examples of which include sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium n-propoxide, potassium methoxide, potassium ethoxide, potassium 1-propoxide, and potassium 2-propoxide), and amine bases such as ammonia, monoalkylamines (e.g., methylamine and ethylamine), dialkylamines (e.g., dimethylamine), and triethylamine, trialkylamines (e.g., trimethylamine and triethylamine), and aromatic amines (e.g., pyridine). In some embodiments, the base comprises sodium hydroxide (NaOH).

[0022] In some embodiments, M + is an inorganic cation selected from sodium, potassium, ammonium, lithium, and mixtures thereof. In some embodiments, M + is sodium. In some embodiments, M + is an organic cation selected from trimethylammonium, triethylammonium, tri-n-propylammonium, triisopropylammonium and tributylammonium.

[0023] In some embodiments, the provided method further comprises step (c3): (c3) adding an acid to the reaction mixture of step (b3) to produce a compound of formula D Further includes:

[0024] Examples of acids suitable for use in step (c3) include inorganic acids such as hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (HPO), sulfuric acid (HSO), and boric acid (HBO), and organic acids such as formic acid, acetic acid, propionic acid, benzoic acid, citric acid, malic acid, and sulfonic acid. Further examples of sulfonic acids include paratoluenesulfonic acid, methanesulfonic acid, triflic acid, and toluenesulfonic acid as a mixture of isomers. In some embodiments, the acid comprises hydrochloric acid (HCl).

[0025] In some embodiments, the present invention provides a compound of Formula 1: [ka] 1. A method for preparing a compound of the formula (A2) A compound of formula 2 in a solvent S selected from toluene (PhCH), acetonitrile (MeCN), or a combination thereof [ka] (wherein X is Cl, Br or I) by contacting a compound of formula 3 with a compound of formula 4: [ka] and forming a compound of (B2) adding a base selected from ammonia, sodium hydroxide, potassium hydroxide, or mixtures thereof in a solvent Sβ selected from water, methanol, ethanol, isopropanol, and mixtures thereof to the reaction mixture of step (A2) (or the isolated compound of Formula 4) to form a compound of Formula 9: [ka] (In the formula, M + is an inorganic cation selected from sodium, potassium, lithium and mixtures thereof and producing an intermediate of (C2) adding an acid selected from hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H3PO4), sulfuric acid (H2SO4) or mixtures thereof to the reaction mixture of step (B2) to produce a compound of formula 1; The present invention provides a method comprising:

[0026] In some embodiments, solvent Sα and / or solvent Sβ do not include an ether, such as 1,2-dimethoxyethane. In some embodiments, solvent Sα and / or solvent Sβ do not include tetrahydrofuran (THF).

[0027] In some embodiments, the methods provided herein reduce the amount of at least one of the following impurities to less than 50 ppm: [ka]

[0028] In some embodiments, the methods provided herein reduce the amount of at least one of the following impurities to less than 50 ppm: [ka]

[0029] In some embodiments, the methods provided herein do not produce more than 50 ppm of any of the following impurities: [ka]

[0030] In some embodiments, the methods provided herein do not produce more than 50 ppm of any of the following impurities: [ka]

[0031] In another embodiment, Formula 9 and / or Formula 10: [ka] (In the formula, M + is an inorganic or organic cation) An intermediate compound having the structure:

[0032] In some embodiments, M + is an inorganic cation selected from sodium, potassium, ammonium, lithium, and mixtures thereof. In some embodiments, M + is sodium. In some embodiments, M + is an organic cation selected from trimethylammonium, triethylammonium, tri-n-propylammonium, triisopropylammonium and tributylammonium. DETAILED DESCRIPTION OF THE INVENTION

[0033] As used herein, the terms "comprise," "including," "include," "including," "having," "having," "containing," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitations expressly stated. For example, a composition, mixture, process, method, article, or device that includes a list of elements is not necessarily limited to only those elements and may include other elements not expressly listed or inherent in such composition, mixture, process, method, article, or device.

[0034] The transitional phrase "consisting of" excludes any element, step, or ingredient not specified. When in a claim, such a phrase excludes from the claim the inclusion of materials other than those recited, except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in a clause in the body of a claim rather than immediately following a preamble, it limits only the elements recited in that clause and does not exclude other elements from the claim as a whole.

[0035] It should be readily understood that where applicant defines an invention or a portion thereof with open-ended terms such as "comprising," this description should (unless otherwise specified) be construed as also describing such invention using the terms "consisting essentially of" or "consisting of."

[0036] Furthermore, unless expressly stated to the contrary, "or" means an inclusive "or" and not an exclusive "or." For example, condition A or condition B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and A and B are both true (or exist).

[0037] The indefinite articles "a" and "an" preceding an element or component of the invention are also intended to be open-ended regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural, unless the number is clearly intended to be singular.

[0038] As used in this disclosure, the term "ambient temperature" or "room temperature" refers to a temperature between about 18°C ​​and about 28°C.

[0039] In the above list, the term "alkyl" includes straight-chain or branched-chain alkyls, such as methyl, ethyl, n-propyl, i-propyl, or the different butyl isomers. As used herein, a haloalkane is an alkane that is partially or fully substituted with a halogen atom (fluorine, chlorine, bromine, or iodine). Examples of haloalkanes include CH2Cl2, ClCH2CH2Cl, ClCH2CH2CH2CH3, and CCl3CH3. A halogenated benzene is a benzene that is partially or fully substituted with a halogen atom (fluorine, chlorine, bromine, or iodine). Examples of halogenated benzenes include chlorobenzene, 1,2-dichlorobenzene, and bromobenzene. C7-C 10Aromatic hydrocarbons are compounds containing one benzene ring substituted with an alkyl group. C7 to C 10 Examples of aromatic hydrocarbons include toluene, xylene, ethylbenzene, and cumene (isopropylbenzene). 10 Aliphatic hydrocarbons are straight or branched chain hydrocarbons. C5-C 10 Examples of aliphatic hydrocarbons include n-hexane, mixed hexanes, n-heptane, and mixed heptanes. 10 Alicyclic hydrocarbons are cyclic hydrocarbons that may be substituted with straight or branched chain alkyl groups. C5-C 10 Examples of alicyclic hydrocarbons include cyclopentane, methylcyclopentane, cyclohexane, and methylcyclohexane.

[0040] As mentioned above, impurities can be generated during the synthesis of a compound of formula D. These impurities can cause the product to have a darker color, and often require recrystallization to remove these impurities, which can be time-consuming, expensive, and / or can reduce the overall yield. Surprisingly, by reversing the order of addition of the base and acid, or even by adding only the acid (i.e., by adding the acid first or by adding the acid only), the generation of such impurities can be eliminated or reduced to insignificant amounts. In some embodiments, the methods disclosed herein eliminate at least one of these impurities or do not generate any of these impurities at all, and are therefore superior to previously disclosed methods. A first aspect of the present invention relates to a method for synthesizing a compound of formula D, in which the acid is first added to a compound of formula C, which is equivalent to formula 4. [ka] The present invention provides a method for preparing a compound of formula D, wherein

[0041] In some embodiments as shown in Scheme 1, a compound of formula 2 can be reacted with a compound of formula 3 to form a compound of formula 4, which can then be converted to a compound of formula 1 with an acid or an acid followed by a base (to adjust the pH as needed).

[0042] In some embodiments as shown in Scheme 1, a compound of formula 4 can be converted to a compound of formula 1 with an acid, followed by a buffer, followed by a base (to adjust the pH as needed). [ka]

[0043] The cyclization and deesterification reactions shown in Scheme 1 can be carried out over a wide range of temperatures, i.e., temperatures ranging from 20°C to 150°C or from 50°C to 200°C. Temperatures ranging from 50°C to 180°C or from 60°C to 100°C are particularly useful. Temperatures ranging from 60°C to 95°C are particularly useful. Temperatures ranging from 75°C to 95°C are particularly useful.

[0044] Suitable solvents include, but are not limited to, solvents such as benzene, toluene, xylene, chlorobenzene, dichlorobenzene, and the like.

[0045] A variety of inorganic acids can be used to convert the compound of Formula 4 to the compound of Formula 1 (and the compound of Formula C to the compound of Formula D). Suitable mineral acids include, but are not limited to, HF, HCl, HBr, HI, HSO, HPO, HNO, and HClO. Suitable concentrations of aqueous acid can range from about 10% to about 50%, from about 10% to about 40%, from about 15% to about 37%, or from about 20% to about 30%. Various molar equivalents of acid relative to the compound of Formula 4 (Formula C) can be used. Exemplary molar equivalents of acid include about 1.5 to about 6.2 molar equivalents, about 1.5 to about 5.0 molar equivalents, about 1.5 to about 4 molar equivalents, and about 1.5 to about 3.1 molar equivalents.

[0046] The reaction temperature during acid neutralization and pH adjustment may be in the range of about 5°C to about 105°C, about 10°C to about 100°C, about 15°C to about 95°C, about 20°C to about 90°C, about 25°C to about 85°C, about 30°C to about 85°C, about 35°C to about 85°C, about 40°C to about 85°C, about 45°C to about 85°C, about 50°C to about 85°C, about 55°C to about 85°C, about 60°C to about 85°C, about 65°C to about 85°C, about 70°C to about 85°C, about 75°C to about 85°C, or about 75°C to about 80°C.

[0047] A variety of buffers with pKa values ​​of 0 to 4 can be used, including, but not limited to, sodium acetate, sodium citrate, sodium oxalate, sodium malonate, trisodium phosphate, and sodium succinate. The buffer can be added to the reaction mixture as a solid or as an aqueous solution. The aqueous buffer solution can have a variety of concentrations, such as about 10% to about 90% by weight, about 10% to about 80% by weight, about 10% to about 70% by weight, about 10% to about 60% by weight, about 10% to about 50% by weight, about 10% to about 40% by weight, or about 10% to about 30% by weight.

[0048] A variety of bases can be used. The base can be added to the reaction mixture as a solid or an aqueous solution. A variety of aqueous bases can be used, including, but not limited to, basic solutions made from LiOH, NaOH, KOH, CaO, MgO, Ca(OH), NaCO, and KCO.

[0049] The final pH after addition of the buffer and base can be in the range of about pH -1 to about pH 3.5, about pH 0 to about pH 3.5, about pH 1 to about pH 3.5, about pH 1.5 to about pH 3.0, about pH 1.75 to about pH 2.75, about pH 2.0 to about pH 2.7, or about pH 2.2 to about pH 2.7.

[0050] The process depicted in Scheme 1 is efficient and reduces the cost of producing compounds of Formula 1.

[0051] [ka] Another aspect of the present invention provides methods for preparing a compound of Formula 1 in which a base is first added to a compound of Formula 4. In some embodiments, as shown in Scheme 2, a compound of Formula 2 can be reacted with a compound of Formula 3 in a solvent containing toluene to form a compound of Formula 4. A base in a solvent containing a water / alcohol mixture is then added to the compound of Formula 4 to form an intermediate of Formula 9, and then an acid is added to convert the intermediate of Formula 9 to a compound of Formula 1. The main difference compared to previously disclosed methods is the initial use of the solvent toluene, followed by the use of a base in a solvent containing a water / alcohol mixture, where the intermediate of Formula 9 is produced. Such differences, as described herein, lead to unexpected results in eliminating or reducing undesired impurities.

[0052] Suitable temperatures for the hydrolysis step may be between 0°C and 60°C, preferably between 20°C and 40°C. Suitable temperatures for the acidification step may be between -10°C and 60°C, preferably between 0°C and 40°C. [Example]

[0053] Preparation Example 1 Purge a 250 mL jacketed reactor equipped with a twin-blade stirrer, Dean-Stark trap, condenser, programmable jacket heating bath, and aqueous caustic scrubber with N for 30 min. Charge the compound of formula 2 (25.05 g crude, 79.5 wt%, 102 mmol, 1.18 equiv.) followed by toluene (PhCH3, 101.46 g) and the compound of formula 3 (17.04 g, 86.7 mmol, 1.0 equiv.). Start the stirrer at 400 rpm and begin an N2 headspace sweep at 1-2 N2 bubbles / sec. Turn on the condenser and fill the Dean-Stark trap with toluene (PhCH3). Warm the jacket bath to 110 °C and heat the reaction for 6.5 h, sampling for reaction completion by HPLC.

[0054] The vessel is cooled to 35°C and the agitation is increased to 600 rpm. Concentrated aqueous HCl (99.0 g solution, 35.5 wt%, 11 equiv.) is charged over approximately 30 seconds. The reaction changes from an orange slurry to an orange two-phase mixture with the solids dissolved. The N2 sweep is switched to the active pad. The reaction is stirred at 80°C for 3.5 hours and sampled for completion by HPLC. The jacket bath is then cooled to 20°C and the resulting orange slurry is stirred at 20-25°C for an additional hour. The slurry is then vacuum filtered and collected in a Buchner funnel. The vessel and product cake are washed with two 50 g portions of fresh PhCH3. Further dry the final product wet cake overnight in a vacuum oven (approximately 40-60 Torr, 100-105 °C) to obtain an off-white solid compound of Formula 1 (18.72 g cake, containing 0.2 wt% HO, 18.68 g, 81% yield from the compound of Formula 3).

[0055] Preparation Example 2 A jacketed reactor was charged with water (40 g, 2 wt.%) and the compound of Formula 4 (X = Br) (20 g, 61.63 wt.%), and the mixture was stirred at 35-45 °C. IPA (40 g, 2 wt.%) was added to the mixture, followed by the addition of aqueous NaOH [prepared by dissolving NaOH (4.71 g, 2.27 eq.) in water (20 g, 1 wt.)] over 1 h. Aqueous HCl [prepared by dissolving HCl (36 wt.%, 7.85 g, 1.54 eq.) in water (20 g, 1 wt.)] was gradually added over 30 min at 35-37 °C. The reaction mixture was cooled to approximately 10 °C and held for 30 min. The reaction mixture was filtered, and the solid was washed with water (20 g × 2). The filter cake is dried overnight at 103° C. and a vacuum of −0.096 MPa to give 12.95 g of the compound of Formula 1 (99.5% by weight, 97.0% yield).

[0056] Preparation Example 3 A 500 mL jacketed reactor equipped with a twin-blade stirrer, Dean-Stark trap, thermowell, and dip tube was purged with N2 for 30 minutes. 39.84 g of the compound of formula 3 (1.0 equiv., 203 mmol) was added to the reactor, followed by 274.68 g of PhCH3 and 50.45 g of the compound of formula 2 (X = Br) (1.16 equiv., 236 mmol). Stirring (400 rpm) was initiated, followed by a N2 headspace sweep set to 1-2 bubbles / second and the condenser turned on. The Dean-Stark trap was filled with PhCH3. The jacket bath was then set to 115 °C for 10 hours. The reaction mixture changed from a yellow, cloudy mixture to a dark orange slurry. The reaction supernatant was sampled for completion (measured 99.0% conversion of the compound of formula 3) and deemed complete. A few grams of HO were observed in the Dean-Stark trap and were removed.

[0057] The reaction was cooled to 35 °C and deionized HO (78.25 g) was added, followed by 90.90 g of 37 wt% HCl (aq), resulting in a yellow-orange slurry. The N sweep was changed to a pad. The jacket bath was set to 105.0 °C, and after 35 minutes, a temperature of 92.0 °C (reflux) was achieved in the vessel. After 4 hours at 92-93 °C, stirring was stopped and the lower aqueous layer was sampled via dip tube for reaction completion. The reaction achieved 99.8% conversion and was deemed complete. The jacket temperature was reduced to 80.0 °C. The recovered distilled water solution (38.54 g) was collected and analyzed for EtOH content (140 mol % relative to the compound of Formula 3) and pH <0. A solution of trisodium citrate dihydrate (22.31 g solid in 66.28 g deionized water) was prepared and placed in a newly equipped 250 mL addition funnel. The citrate solution was fed into the vessel at T = 78.8-72.7°C over 11 minutes.

[0058] The dip tube was then removed and replaced with a calibrated pH probe and meter. Caustic solution (95.93 g, 50 wt. % NaOH in HO) was charged to the addition funnel. The solution was fed over 11 minutes with the vessel T ranging from 74.8 to 86.2 °C to a pH reading of 2.21, which was then held for 15 minutes and the pH observed to change to 2.18. Neutralization was considered complete. The total caustic solution used was 68.15 g. The jacket T was then set to 20.0 °C, and the mixture was stirred for 90 minutes until the vessel T reached 21.0 °C.

[0059] The pH of the container was observed to be 2.09 at T=21.0°C. The slurry was filtered by vacuum filtration, and both the container and cake were washed successively with 100 g of PhCH3 and deionized HO adjusted to pH 1.95. The wet cake of the compound of Formula 1 was then placed in a vacuum oven and dried overnight (approximately 60-70 Torr, 100-105°C, approximately 20 hours). The resulting off-white, free-flowing solid (49.45 g) was then analyzed by LC and confirmed to be >99.9 wt% of the compound of Formula 1. The yield from the compound of Formula 3 was calculated to be 92.1%. The solid was stored in a desiccator at ambient laboratory temperature.

[0060] Preparation Example 4 A 500 mL jacketed reactor equipped with a twin-blade stirrer, Dean-Stark trap, thermowell, and dip tube was purged with N2 for 30 minutes. 70.02 g of the compound of Formula 4 (X = Br) solid (50.4 g) was added to the reactor, followed by 249.01 g of PhCH3. Stirring (300 rpm) was initiated, followed by a N2 pad set at 1-2 bubbles / second and the condenser turned on. The Dean-Stark trap was filled with PhCH3. Deionized H2O (71.14 g) and 83.71 g of 37 wt% HCl (aq) were added to obtain a yellow-orange slurry.

[0061] The jacket temperature was set to 105.0 °C, and after 35 minutes, 92.0 °C (reflux) was achieved in the vessel. After 4 hours at a vessel temperature of 92-93 °C, stirring was stopped and the lower aqueous layer was sampled via dip tube for reaction completion. The reaction achieved 99.9% conversion and was deemed complete. The jacket temperature was reduced to 80.0 °C. The recovered distilled water solution (18.72 g) was collected and analyzed for EtOH content (50.9 mol%) and pH <0. A solution of trisodium citrate dihydrate (20.23 g solid in 60.72 g deionized water) was prepared and placed in a newly equipped 250 mL addition funnel. The citrate solution was fed over 10 minutes at a vessel temperature of 77.4-74.7 °C.

[0062] The dip tube was then removed and replaced with a calibrated pH probe and meter. Caustic solution (76.26 g, 50 wt. % NaOH in HO) was charged to the addition funnel. Agitation was increased to 400 rpm for better mixing. The solution was fed over 29 minutes with the vessel T ranging from 78.7 to 84.9 °C until a pH reading of 2.31 was measured, which was then held for 10 minutes and the pH observed to change to 2.38. Neutralization was considered complete. The total caustic solution used was 73.48 g. The jacket T was then set to 20.0 °C and the mixture was stirred overnight.

[0063] The next morning, the pH was observed to be 2.65, and the pot temperature was 20.2°C. The slurry was filtered by vacuum filtration, and both the pot and cake were washed successively with 91 g of PhCH3 and deionized HO. The wet cake of the compound of Formula 1 was then placed in a vacuum oven and dried overnight (approximately 60-70 Torr, 100-105°C, approximately 20 hours). The resulting off-white, free-flowing solid (46.47 g) was then analyzed by LC and confirmed to be 97.8 wt% compound of Formula 1. The yield from the compound of Formula 4 (X = Br) was 92.0%. The solid was stored in a desiccator at ambient laboratory temperature.

[0064] Preparation Example 5 A 500 mL jacketed reactor equipped with a twin-blade stirrer, thermowell, and dip tube was purged with N2. The reactor was charged with 80.04 g of the compound of Formula 4 (X = Br) (57.56 g), followed by 284.59 g of PhCH3. Agitation (300 rpm) was initiated, followed by a N2 pad set at 1-2 bubbles / sec. Deionized HO (81.22 g) and 95.39 g of 37 wt% HCl (aq) were charged, resulting in a yellow-orange slurry.

[0065] The jacket temperature was set to 85.0°C, and the vessel temperature reached 82-83°C after 30 minutes. After 8 hours at a vessel temperature of 82-83°C, stirring was stopped and the lower aqueous layer was sampled via dip tube for reaction completion. The reaction achieved 99.2% conversion and was deemed complete. The jacket temperature was lowered to 80.0°C. A solution of trisodium citrate dihydrate (23.05 g solid in 69.53 g deionized water) was prepared and placed in a newly equipped 250 mL addition funnel. The citrate solution was fed over 12 minutes at a vessel temperature of 76.8-73.2°C.

[0066] The dip tube was then removed and replaced with a calibrated pH probe and meter. Caustic solution (92.39 g, 50 wt. % NaOH in HO) was charged to the addition funnel. Agitation was increased to 400 rpm for better mixing. The caustic solution was fed over 30 minutes with the vessel T ranging from 74.8 to 84.3°C until a pH reading of 2.35 was measured, which was then held for 25 minutes and the pH observed to change to 2.39. Neutralization was considered complete. A total of 80.04 g of caustic solution was used. The jacket T was then set to 20.0°C, and the vessel reached 22.4°C after 90 minutes at a pH of 2.35.

[0067] The slurry was filtered by vacuum filtration, and both the container and cake were washed successively with 105 g of PhCH3 and deionized HO adjusted to pH 2.11. The wet cake of the compound of Formula 1 was then placed in a vacuum oven and dried overnight (approximately 60-70 Torr, 100-105 °C, approximately 20 hours). The resulting white, free-flowing solid (55.37 g) was then analyzed by LC and confirmed to be 99.9 wt% of the compound of Formula 1. The yield from the compound of Formula 4 was 98.5%. The solid was stored in a desiccator at ambient laboratory temperature.

[0068] Analysis Example 1 The product was analyzed by high-pressure liquid chromatography on an Agilent Zorbax SB-Phenyl column, 100 x 4.6 mm, 1.8 μm [P / N: 828975-912], with a column temperature of 40°C and a flow rate of 1.0 mL / min. An injection volume of 2 μL and a maximum pressure of 240 bar were used. Two eluents, A and B, were used. Eluent A contained water and 0.1% formic acid. Eluent B contained acetonitrile. The following times and compositions were used for gradient elution:

[0069] [Table 1]

[0070] A 3 minute post-time was used, with methanol used for needle washing. Peaks were monitored at 250 nm using a UV detector. Peaks were analyzed using an Agilent Open Lab integrator. The following retention times were observed:

[0071] [Table 2]

Claims

1. Formula D: 【Chemical 1】 (In the formula, each R １ are independently halogen, nitro, SF ５ , N(C １ ~C ８ alkyl) (C １ ~C ８ alkyl), C(=S)N(C １ ~C ８ alkyl) (C １ ~C ８ alkyl), SO ２ N (C １ ~C ８ alkyl) (C １ ~C ８ alkyl), OSO ２ (C １ ~C ８ alkyl), OSO ２ N (C １ ~C ８ alkyl) (C １ ~C ８ alkyl), N(C １ ~C ８ alkyl)SO ２ (C １ ~C ８ alkyl), C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Halocycloalkyl, C ４ ~C １０ Alkylcycloalkyl, C ４ ~C １０ Cycloalkylalkyl, C ６ ~C １４ Cycloalkylcycloalkyl, C ５ ~C １０ Alkylcycloalkylalkyl, C ３ ~C ８ Cycloalkenyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ３ ~C ８ Cycloalkoxy, C ３ ~C ８ Halocycloalkoxy, C ４ ~C １０ Cycloalkylalkoxy, C ２ ~C ８ Alkenyloxy, C ２ ~C ８ Alkynyloxy, C １ ~C ８ Alkylthio, C １ ~C ８ Alkylsulfinyl, C １ ~C ８ Alkylsulfonyl, C ３ ~C ８ Cycloalkylthio, C ３ ~C ８ Cycloalkylsulfinyl, C ３ ~C ８ Cycloalkylsulfonyl, C ４ ~C １０ Cycloalkylalkylthio, C ４ ~C １０ Cycloalkylalkylsulfinyl, C ４ ~C １０ Cycloalkylalkylsulfonyl, C ２ ~C ８ Alkenylthio, C ２ ~C ８ Alkenylsulfinyl, C ２ ~C ８ Alkenylsulfonyl, C ２ ~C ８ Alkynylthio, C ２ ~C ８ Alkynylsulfinyl, C ２ ~C ８ alkynylsulfonyl or phenyl; n is 0, 1, 2, 3 or 4, and R ２ is H, C １ ~C ８ Alkyl, C １ ~C ８ Haloalkyl, C ２ ~C ８ Alkenyl, C ２ ~C ８ Alkynyl, C ３ ~C １０ Cycloalkyl, C ３ ~C １０ Halocycloalkyl, C ４ ~C １０ Alkylcycloalkyl, C ４ ~C １０ Cycloalkylalkyl, C ６ ~C １４ Cycloalkylcycloalkyl, C ５ ~C １０ Alkylcycloalkylalkyl, C ３ ~C ８ Cycloalkenyl, C １ ~C ８ Alkoxy, C １ ~C ８ Haloalkoxy, C ３ ~C ８ Cycloalkoxy, C ３ ~C ８ Halocycloalkoxy, C ４ ~C １０ Cycloalkylalkoxy, C ２ ~C ８ Alkenyloxy, C ２ ~C ８ Alkynyloxy, C １ ~C ８ Alkylthio, C １ ~C ８ Alkylsulfinyl, C １ ~C ８ Alkylsulfonyl, C ３ ~C ８ Cycloalkylthio, C ３ ~C ８ Cycloalkylsulfinyl, C ３ ~C ８ Cycloalkylsulfonyl, C ４ ~C １０ Cycloalkylalkylthio, C ４ ~C １０ Cycloalkylalkylsulfinyl, C ４ ~C １０ Cycloalkylalkylsulfonyl, C ２ ~C ８ Alkenylthio, C ２ ~C ８ Alkenylsulfinyl, C ２ ~C ８ Alkenylsulfonyl, C ２ ~C ８ Alkynylthio, C ２ ~C ８ Alkynylsulfinyl, C ２ ~C ８ alkynylsulfonyl or phenyl) 1. A method for preparing a compound of formula (I), comprising: (b1) reacting an aqueous acid with a solution of a compound of formula C 【Chemistry 2】 (In the formula, R ３ is C １ ~C ８ Alkyl or C １ ~C ８ haloalkyl) to form a reaction mixture; (c1) adding a base to the reaction mixture of step (a1) to form a compound of formula D; A method comprising:

2. Each R １ are independently Cl, Br, I, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy, C １ ~C ６ haloalkoxy or phenyl, and / or R ２ is H, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, C １ ~C ６ Alkoxy or C １ ~C ６ The method of claim 1 , wherein the alkyl group is a haloalkoxy group.

3. The acid used in step (a1) is hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H ３ P.O. ４ ), sulfuric acid (H ２ SO ４ 3. The method according to claim 1, wherein the hydroxybenzoate is selected from the group consisting of hydroxybenzoates, ...

4. Step (b2): (b2) adding a buffer to the reaction mixture of step (b1) prior to step (c1); The method of any one of claims 1 to 3, further comprising:

5. 5. The process according to any one of claims 1 to 4, wherein the base used in step (c1) is selected from sodium hydroxide, potassium hydroxide or a mixture thereof.

6. 6. The method of claim 4 or 5, wherein the buffering agent is selected from sodium acetate, sodium citrate, sodium malonate, sodium succinate, sodium triphosphate, or mixtures thereof.

7. Formula 1: 【Chemistry 3】 for preparing a compound of formula D, (A1) Hydrochloric acid (HCl), hydrobromic acid (HBr), phosphoric acid (H ３ P.O. ４ ), sulfuric acid (H ２ SO ４ ) or mixtures thereof, with an aqueous acid selected from the group consisting of a carboxylic acid having formula 4: 【Chemistry 4】 adding to a compound of formula C, (B1) adding a buffer selected from sodium acetate, sodium citrate, sodium malonate, sodium succinate, sodium phosphate, or a mixture thereof to the reaction mixture of step A1; (C1) adding a base selected from sodium hydroxide, potassium hydroxide, or a mixture thereof to the reaction mixture of step (B1); The method of claim 4, comprising:

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