A benzoate pesticide and pharmaceutical intermediate and a preparation method thereof

Abstract

The application discloses a benzoate pesticide and medical intermediate and a preparation method thereof, and belongs to the technical field of organic chemical synthesis, and a general formula is shown in VII, wherein R X is a methylthio group or a nitro group, and R X is a methylthio group or a nitro group. The pesticide and medical intermediate with the general formula I and II has high yield, good purity and low cost.

Description

Technical Field

[0001] This invention relates to the field of organic chemical synthesis technology, and in particular to a pesticide and pharmaceutical intermediate, its preparation method, and its application. Background Technology

[0002] p-Hydroxyphenylpyruvate dioxidase (HPPD) is widely present in various organisms. It plays a very important role in the biosynthesis of many physiological compounds and is involved in the biosynthesis of plastoquinones and tocopherols in plants. It is also involved in the catabolism of phenylalanine in most organisms.

[0003] HPPD inhibitor herbicides are one of the main types of herbicides. They inhibit HPPD activity, blocking the conversion of p-hydroxyphenylpyruvic acid to hydantoin, thus preventing the normal production of tocopherols, plastoquinones, and carotenoids. This leads to bleaching symptoms in plant meristems and new tissues, ultimately causing plant death. These herbicides have advantages such as high activity, broad weed control spectrum, and good safety. They can be divided into three main categories: triketones, pyrazolones, and isoxazolones. Representative products include sulfadiazine, furazolidone, mesotrione, triazolidone, benzoxazole-fluoxazol, bicyclosulfadiazine, sulfadiazine, flupyrazole, pyrazosulfuron, benzoxazole-fluoxazol, pyrazosulfuron, benzoxazole-fluoxazol, pyrazosulfuron, benzalkonium chloride, and isoxazol.

[0004] Compounds with the parent structure of 2-chloro-3-methyl-4-methanesulfonylbenzoate can be used as common intermediates for products such as cyclosulfonone, furazolidone, triazolesulfonone, and benzosulfonone, therefore, the study of their preparation process is of great significance.

[0005] The preparation of 2-chloro-3-methyl-4-methanesulfonylbenzoate in the prior art mainly includes the following methods:

[0006] I. Patent publication number CN104292137 discloses the preparation of methyl 2-chloro-3-methyl-4-methanesulfonylbenzoate from 2-chlorotoluene via Friedel-Crafts acylation, oxidation, and esterification reactions. The reaction route is as follows:

[0007]

[0008] The product 2-chloro-6-methanesulfonyltoluene after the first acylation of this method has a passivated benzene ring due to the strong electron-withdrawing property of the methanesulfonyl group, making it impossible to undergo a second Friedel-Crafts acylation. Therefore, this route cannot be implemented.

[0009] II. Patents CN105601548 and US5846906 disclose the preparation of methyl 2-chloro-3-methyl-4-methanesulfonylbenzoate from 3-chloro-2-methylaniline via a series of reactions including diazotization, Friedel-Crafts acylation, two oxidation processes, and esterification. The reaction route is as follows:

[0010]

[0011] The diazotization reaction of the method has defects of many impurities and high reaction danger; and the reaction is complex, a large amount of three wastes is generated in the production process, the cost is high, and industrialized production is not conducive. SUMMARY

[0012] The present application aims at solving the problems in the prior art and provides a benzoate pesticide and medical intermediate and a preparation method thereof.

[0013] In order to achieve the above-mentioned purpose, the present application adopts the following technical scheme:

[0014] A benzoate pesticide and medical intermediate, the general formula of which is shown as VII:

[0015]

[0016] In the formula, R X is methylthio or nitro, R X The general formula of the pesticide and medical intermediate in which R

[0017]

[0018] Preferably, R1 represents hydrogen, cyano, C 2～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formylalkyl, cyanoalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, R5-(CO)-NR6R7-, R5-S(O)m-(alkyl)-, R5-O-(alkyl)n-, R5-(CO)-(alkyl)n-, R5-O-(alkyl)n-(CO)-, R5-(CO)-O-(alkyl)n-, R5-S-(CO)-(alkyl)n-, R5-O-(CO)-(alkyl)n- or R5-O-(CO)-O-(alkyl)n-, wherein:

[0019] The "alkyl", "alkenyl" or "alkynyl" is independently unsubstituted or substituted by at least one of halogen, alkoxy or alkoxycarbonyl,

[0020] the "amino", "aminoalkyl", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" are independently of each other unsubstituted or substituted by one or two radicals selected from -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6,

[0021] the "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently of each other unsubstituted or substituted by at least one radical selected from oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, cycloalkyl substituted by alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with the two adjacent carbon atoms in the ring with -OCH2CH2- or -OCH2O- unsubstituted or substituted by halogen;

[0022] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl or benzyl;

[0023] R5, R6, R7independently of each other represent hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, formylalkyl, cyanoalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl or arylalkyl, wherein:

[0024] the "alkyl", "alkenyl" or "alkynyl" are independently of each other unsubstituted or substituted by at least one radical selected from halogen, alkoxy or alkoxycarbonyl,

[0025] the "amino", "aminoalkyl", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" are independently of each other unsubstituted or substituted by one or two radicals selected from -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6,

[0026] said "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently from each other unsubstituted or substituted by at least one group selected from oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, halogenalkyl, halogenalkenyl, halogenalkynyl, halogencycloalkyl, cycloalkyl substituted by alkyl, -OR5, -SR5, -(CO)0R5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with the two adjacent carbon atoms in the ring by -OCH2CH2- or -OCH2O- which are unsubstituted or substituted by halogen;

[0027] m represents 0, 1, 2, 3 or 4; n independently represents 0, 1, 2, 3 or 4.

[0028] Preferably, R1 represents hydrogen, cyano, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formyl C 1～8 alkyl, cyano C 1～8 alkyl, amino, amino C 1～8 alkyl, aminocarbonyl, aminocarbonyl C 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkyl C 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8 cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclyl C 1～8 alkyl, aryl, aryl C 1～8 alkyl, R5-(CO)-NR6R7-, R5-S(O)m-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-, R5-(CO)-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-(CO)-, R5-(CO)-O-(C 1～8 alkyl)-, R5-S-(CO)-(C 1～8 alkyl)-, R5-O-(CO)-(C 1～8 alkyl)- or R5-O-(CO)-O-(C 1～8 alkyl)-, wherein:

[0029] said "alkyl", "alkenyl" or "alkynyl" are independently from each other unsubstituted or substituted by at least one group selected from halogen, alkoxy or alkoxycarbonyl,

[0030] said "amino", "amino C 1～8alkyl", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" are each, independently of one another, unsubstituted or substituted by one or more radicals selected from the group consisting of -R5, -OR5, -(CO)OR5, -C 1～8 alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6,

[0031] said "C 3～8 cycloalkyl", "C 3～8 cycloalkylC 1～8 alkyl", "aryl", "heterocyclyl", "arylC 1～8 alkyl" or "heterocyclylC 1～8 alkyl" are each, independently of one another, unsubstituted or substituted by one or more radicals selected from the group consisting of oxo, halogen, cyano, nitro, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, C 3～8 cycloalkyl, halogen-C 1～8 alkyl, halogen-C 2～8 alkenyl, halogen-C 2～8 alkynyl, halogen-C 3～8 cycloalkyl, C 1～8 alkyl-substituted C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-C 1～8 alkyl-(CO)OR5, or form a fused ring with -OCH2CH2- or -OCH2O- in which the two carbon atoms which are adjacent in the ring are unsubstituted or substituted by halogen;

[0032] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl or benzyl;

[0033] R5, R6, R7represent, independently of one another, hydrogen, halogen, C 1～8 alkyl, halogen-C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formylC 1～8 alkyl, cyanoC 1～8 alkyl, amino, aminoC 1～8 alkyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkylC 1～8 alkyl, C 3～8 cycloalkenyl, C3～8 cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclylalkyl, aryl or aryl C 1～8 alkyl, wherein:

[0034] said "C 1～8 alkyl", "C 2～8 alkenyl" or "C 2～8 alkynyl" are each, independently of one another, unsubstituted or substituted by at least one radical from the group consisting of halogen, C 1～8 alkoxy or C 1～8 alkoxycarbonyl,

[0035] said "amino", "amino C 1～8 alkyl", "aminocarbonyl", "aminocarbonyl C 1～8 alkyl", "aminosulfonyl" are each, independently of one another, unsubstituted or substituted by one or two radicals from the group consisting of -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6 or -(SO2)NR5R6,

[0036] said "cycloalkyl", "cycloalkyl C 1～8 alkyl", "aryl", "heterocyclyl", "aryl C 1～8 alkyl" or "heterocyclyl C 1～8 alkyl" are each, independently of one another, unsubstituted or substituted by at least one radical from the group consisting of oxo, halogen, cyano, nitro, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, C 3～8 cycloalkyl, halogenated C 1～8 alkyl, halogenated C 2～8 alkenyl, halogenated C 2～8 alkynyl, halogenated C 3～8 cycloalkyl, C 1～8 alkyl, C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with -OCH2CH2- or -OCH2O- which are unsubstituted or substituted by halogen, with adjacent carbon atoms in the ring;

[0037] m represents 0, 1, 2, 3 or 4; n independently represents 0, 1, 2, 3 or 4.

[0038] A process for the preparation of benzoic acid ester pesticides and pharmaceutical intermediates, comprising the following steps for the preparation of benzoic acid ester pesticides and pharmaceutical intermediates of general formula I:

[0039] A compound of the formula II is dissolved in a first solvent and reacted with a methylthio-forming reagent to produce a compound of the formula I, as shown in the following reaction scheme:

[0040]

[0041] in which

[0042] R1represents hydrogen, cyano, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formyl C 1～8 alkyl, cyano C 1～8 alkyl, amino, amino C 1～8 alkyl, aminocarbonyl, aminocarbonyl C 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkyl C 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8 cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclyl C 1～8 alkyl, aryl, aryl C 1～8 alkyl, R5-(CO)-NR6R7-, R5-S(O)m-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-, R5-(CO)-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-(CO)-, R5-(CO)-O-(C 1～8 alkyl)-, R5-S-(CO)-(C 1～8 alkyl)-, R5-O-(CO)-(C 1～8 alkyl)- or R5-O-(CO)-O-(C 1～8 alkyl)-, wherein:

[0043] said "alkyl", "alkenyl" or "alkynyl" is, independently of each other, unsubstituted or substituted by at least one of the groups halogen, alkoxy or alkoxycarbonyl,

[0044] said "amino", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" is, independently of each other, unsubstituted or substituted by one or two of the groups -R5, -OR5, -(CO)OR5, -C 1～8 alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6 or -(SO2)NR5R6, 1～8 ​

[0045] said "C 3～8 cycloalkyl", "C 3～8 ycloalkylC 1～8 alkyl", "aryl", "heterocyclyl", "arylC 1～8 alkyl" or "heterocyclylC 1～8 alkyl" are independently from each other unsubstituted or substituted by at least one radical selected from the group consisting of oxo, halogen, cyano, nitro, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, C 3～8 ycloalkyl, halogen-C 1～8 alkyl, halogen-C 2～8 alkenyl, halogen-C 2～8 alkynyl, halogen-C 3～8 ycloalkyl, C 1～8 alkyl, C 3～8 ycloalkyl, -OR5, -SR5, -(CO)0R5, -(SO2)R5, -NR5R6, or -O-C 1～8 alkyl-(CO)OR5, or form a fused ring with the -OCH2CH2- or -OCH2O- being unsubstituted or substituted by halogen with the adjacent two carbon atoms in the ring;

[0046] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl or benzyl;

[0047] R5, R6, R7independently from each other represent hydrogen, halogen, C 1～8 alkyl, halogen-C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formyl-C 1～8 alkyl, cyano-C 1～8 alkyl, amino, amino-C 1～8 alkyl, aminocarbonyl, aminocarbonyl-C 1～8 alkyl, aminosulfonyl, C 3～8 ycloalkyl, C 3～8 ycloalkylC 1～8 alkyl, C 3～8 ycloalkenyl, C 3～8 ycloalkenylC 1～8 alkyl, heterocyclyl, heterocyclylalkyl, aryl or arylC 1～8 alkyl, wherein:

[0048] said "C 1～8 alkyl", "C 2～8 alkenyl" or "C 2～8 alkynyl" are independently from each other unsubstituted or substituted by halogen, C1～8 Alkoxy or C 1～8 The group substituted by at least one group in the alkoxycarbonyl group,

[0049] The "amino" and "amino C" 1～8 Alkyl", "aminocarbonyl", "aminocarbonyl C" 1～8 The "alkyl" and "aminosulfonyl" groups are independently unsubstituted or substituted by one or two groups selected from -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6 or -(SO2)NR5R6.

[0050] The "cycloalkyl", "cycloalkyl C" 1～8 Alkyl, aryl, heterocyclic, aryl C 1～8 Alkyl or heterocyclic C 1～8 Alkyl groups are independently unsubstituted or selected from oxo, halogen, cyano, nitro, C 1～8 Alkyl, C 2～8 alkenyl, C 2～8 alkynyl group, C 3～8 cycloalkyl, halogenated C 1～8 Alkyl, Halogenated C 2～8 alkenyl, halogenated C 2～8 alkynyl, halogenated C 3～8 cycloalkyl, C 1～8 Alkyl-substituted C 3～8 The ring is substituted with at least one of the following groups: cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or the ring forms a fused ring with two adjacent carbon atoms and an unsubstituted or halogen-substituted -OCH2CH2- or -OCH2O-.

[0051] m represents 0, 1, 2, 3, or 4; n independently represents 0, 1, 2, 3, or 4.

[0052] Preferably, the first solvent is selected from at least one of dichloromethane, dichloroethane, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolinone, N-methylpyrrolidone, phenylcyanide, or sulfolane.

[0053] The methylthiolation reagent is selected from any one of methanethiol, alkali metal salts of methanethiol, or dimethyl disulfide.

[0054] A method for preparing benzoate pesticide and pharmaceutical intermediate, comprising the following steps of preparing benzoate pesticide and pharmaceutical intermediate of general formula II:

[0055] (1) using the compound of general formula IV and the compound of general formula V to add to the second solvent, adding the acid binding agent to react, to prepare the compound of general formula III;

[0056] (2) using the compound of general formula III to go through a) or b) step to obtain the compound of general formula II:

[0057] when R2 = H, using a) step, when R2 is other group except hydrogen, using b) step,

[0058] a) step is: dissolving the compound of general formula III in the third solvent, reacting with the first oxidant, to prepare the compound of general formula II,

[0059] b) step is: dissolving the compound of general formula III in the fourth solvent, esterifying under the action of the first catalyst, to prepare the compound of general formula II;

[0060] The reaction equation is as follows:

[0061]

[0062] In the formula, X represents any one of fluorine, chlorine, bromine or iodine;

[0063] R1 represents hydrogen, cyano, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formyl C 1～8 alkyl, cyano C 1～8 alkyl, amino, amino C 1～8 alkyl, aminocarbonyl, aminocarbonyl C 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkyl C 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8 cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclyl C 1～8 alkyl, aryl, aryl C 1～8 alkyl, R5-(CO)-NR6R7-, R5-S(O)m-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-, R5-(CO)-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-(CO)-, R5-(CO)-O-(C 1～8R5-S-(CO)-(C 1～8 R5-O-(CO)-(C 1～8 R5-O-(CO)-O-(C 1～8 R5-O-(CO)-O-(C

[0064] said "alkyl", "alkenyl" or "alkynyl" is independently of each other unsubstituted or substituted by at least one of halogen, alkoxy or alkoxycarbonyl,

[0065] said "amino", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" is independently of each other unsubstituted or substituted by one or two of -R5, -OR5, -(CO)OR5, -C 1～8 alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6, 1～8

[0066] said "C 3～8 ycloalkyl", "C 3～8 ycloalkyl", "C 1～8 ycloalkyl", "C 1～8 ycloalkyl", "C 1～8 ycloalkyl" is independently of each other unsubstituted or substituted by at least one of oxo, halogen, cyano, nitro, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, C 3～8 ycloalkyl, halogenated C 1～8 ycloalkyl, halogenated C 2～8 alkenyl, halogenated C 2～8 alkynyl, halogenated C 3～8 ycloalkyl, C 1～8 ycloalkyl, C 3～8 ycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-C 1～8 ycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-C

[0067] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl or benzyl;

[0068] ​R3, R4 independently of one another represent hydrogen, halogen, halogenalkyl, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, aryl, arylalkyl, heterocycle, heterocyclealkyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, -(CO)0R5, -(SO2)R5;

[0069] R5, R6, R7 independently of one another represent hydrogen, halogen, C 1～8 alkyl, halogenC 1～8 alkyl, C 2～8 alkyl, C 2～8 alkyl, formylC 1～8 alkyl, cyanoC 1～8 alkyl, amino, aminoC 1～8 alkyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkylC 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8 cycloalkenylC 1～8 alkyl, heterocycle, heterocyclealkyl, aryl or arylC 1～8 alkyl, wherein:

[0070] the "C 1～8 alkyl", "C 2～8 alkenyl" or "C 2～8 alkynyl" are independently of one another unsubstituted or substituted by at least one radical from the group consisting of halogen, C 1～8 alkoxy or C 1～8 alkoxycarbonyl,

[0071] the "amino", "aminoC 1～8 alkyl", "aminocarbonyl", "aminocarbonylC 1～8 alkyl", "aminosulfonyl" are independently of one another unsubstituted or substituted by one or two radicals from the group consisting of -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6 or -(SO2)NR5R6,

[0072] the "cycloalkyl", "cycloalkylC 1～8 alkyl", "aryl", "heterocycle", "arylC 1～8 alkyl" or "heterocycleC 1～8 alkyl" are independently of one another unsubstituted or substituted by one or two radicals from the group consisting of oxo, halogen, cyano, nitro, C 1～8 alkyl, C2～8 alkenyl, C 2～8 alkynyl, C 3～8 cycloalkyl, haloC 1～8 alkyl, haloC 2～8 alkenyl, haloC 2～8 alkynyl, haloC 3～8 cycloalkyl, substituted with at least one group selected from C 1～8 alkyl, substituted with at least one group selected from C 3～8 cycloalkyl, -OR5, -SR5, -(CO)0R5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or a fused ring formed by the adjacent two carbon atoms in the ring and -OCH2CH2- or -OCH2O- which are unsubstituted or substituted with halogen;

[0073] m represents 0, 1, 2, 3 or 4; n independently represents 0, 1, 2, 3 or 4.

[0074] Preferably, the second solvent is selected from at least one or a combination of two or more of water, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidinone, benzonitrile or sulfolane;

[0075] the acid binding agent is selected from at least one of an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal acetate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkali metal alcoholate, triethylamine, diisopropylethylamine or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU);

[0076] the third solvent is selected from at least one or a combination of two or more of water, methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, benzyl alcohol, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidinone, benzonitrile or sulfolane;

[0077] the first oxidizing agent is selected from at least one of hydrogen peroxide, nitric acid, sodium perborate, pyridine-N-oxide, potassium chlorate, sodium chlorate, metal perchlorate, oxygen, ozone, chlorine, nitric acid, caro's acid, osmium tetroxide, periodate, lead tetraacetate, chromic anhydride pyridine, basic copper hydroxide, active manganese dioxide, dimethylsulfoxide, ferric trichloride, peroxy acids and salts thereof, peroxy metal salts, metal hypochlorite;

[0078] the fourth solvent is selected from at least one of methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, benzyl alcohol, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethylsulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidinone, benzonitrile, or sulfolane, or a combination of two or more thereof;

[0079] the first catalyst is selected from at least one of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, oxalyl chloride, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkali metal acetate, an alkali metal phosphate, an alkali metal hydrogen phosphate, an alkali metal alkoxide, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

[0080] 4-methanesulfonylbenzoic acid ester pesticides and pharmaceutical intermediates, having the general formula VI:

[0081]

[0082] R1represents hydrogen, cyano, C 2～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formylalkyl, cyanoalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, R5-(CO)-NR6R7-, R5-S(O)m-(alkyl)-, R5-O-(alkyl)n-, R5-(CO)-(alkyl)n-, R5-O-(alkyl)n-(CO)-, R5-(CO)-O-(alkyl)n-, R5-S-(CO)-(alkyl)n-, R5-O-(CO)-(alkyl)n-, or R5-O-(CO)-O-(alkyl)n-, wherein:

[0083] the "alkyl", "alkenyl", or "alkynyl" is, independently of each other, unsubstituted or substituted by at least one of halogen, alkoxy, or alkoxycarbonyl,

[0084] the "amino", "aminoalkyl", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" is, independently of each other, unsubstituted or substituted by one or two groups selected from -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6, or -(SO2)NR5R6,

[0085] said "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently of each other unsubstituted or substituted by at least one radical selected from the group consisting of oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, cycloalkyl substituted by alkyl, -OR5, -SR5, -(CO)0R5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with the -OCH2CH2- or -OCH2O- being unsubstituted or substituted by halogen, between two adjacent carbon atoms of the ring;

[0086] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl or benzyl;

[0087] R5, R6, R7independently of each other represent hydrogen, halogen, alkyl, haloalkyl, alkenyl, alkynyl, formylalkyl, cyanoalkyl, amino, aminoalkyl, aminocarbonyl, aminocarbonylalkyl, aminosulfonyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, aryl or arylalkyl, wherein:

[0088] said "alkyl", "alkenyl" or "alkynyl" are independently of each other unsubstituted or substituted by at least one radical selected from the group consisting of halogen, alkoxy or alkoxycarbonyl,

[0089] said "amino", "aminoalkyl", "aminocarbonyl", "aminocarbonylalkyl", "aminosulfonyl" are independently of each other unsubstituted or substituted by one or two radicals selected from the group consisting of -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6,

[0090] said "cycloalkyl", "cycloalkylalkyl", "aryl", "heterocyclyl", "arylalkyl" or "heterocyclylalkyl" are independently of each other unsubstituted or substituted by at least one radical selected from the group consisting of oxo, halogen, cyano, nitro, alkyl, alkenyl, alkynyl, cycloalkyl, haloalkyl, haloalkenyl, haloalkynyl, halocycloalkyl, cycloalkyl substituted by alkyl, -OR5, -SR5, -(CO)0R5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with the -OCH2CH2- or -OCH2O- being unsubstituted or substituted by halogen, between two adjacent carbon atoms of the ring;

[0091] m represents 0, 1, 2, 3 or 4; n independently represents 0, 1, 2, 3 or 4.

[0092] Preferably, the 4-methanesulfonylbenzoate pesticide and pharmaceutical intermediate comprises the following preparation steps:

[0093] The compound as shown in general formula I is dissolved in a fifth solvent, and reacted with a second oxidant with or without the addition of a second catalyst to prepare a compound as shown in general formula VI;

[0094] The reaction equation is as follows:

[0095]

[0096] In the formula,

[0097] R1 represents hydrogen, cyano, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, formyl C 1～8 alkyl, cyano C 1～8 alkyl, amino, amino C 1～8 alkyl, aminocarbonyl, aminocarbonyl C 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkyl C 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8 cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclyl C 1～8 alkyl, aryl, aryl C 1～8 alkyl, R5-(CO)-NR6R7-, R5-S(O)m-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-, R5-(CO)-(C 1～8 alkyl)-, R5-O-(C 1～8 alkyl)-(CO)-, R5-(CO)-O-(C 1～8 alkyl)-, R5-S-(CO)-(C 1～8 alkyl)-, R5-O-(CO)-(C 1～8 alkyl)- or R5-O-(CO)-O-(C 1～8 alkyl)-, wherein:

[0098] the "alkyl", "alkenyl" or "alkynyl" is independently unsubstituted or substituted with at least one of halogen, alkoxy or alkoxycarbonyl,

[0099] the "amino", "amino C 1～8alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C

[0100] said "C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 3～8 cycloalkylC 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl" or "heterocyclylC 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkenyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkynyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkenyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkynyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C

[0101] R2is selected from any one of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, phenyl, 4-nitrophenyl, 4-methoxyphenyl, or benzyl;

[0102] R5, R6, R7independently represent hydrogen, halogen, C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 1～8 alkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkenyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -0-C 2～8 alkynyl, formylC 1～8 alkyl, cyanoC 1～8 alkyl, amino, aminoC 1～8 alkyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, C 3～8 cycloalkyl, C 3～8 cycloalkylC 1～8 alkyl, C 3～8 cycloalkenyl, C 3～8cycloalkenyl C 1～8 alkyl, heterocyclyl, heterocyclylalkyl, aryl or aryl C 1～8 alkyl, wherein:

[0103] said "C 1～8 alkyl", "C 2～8 alkenyl" or "C 2～8 alkynyl" are each independently unsubstituted or substituted with at least one group selected from halogen, cyano, nitro, C 1～8 alkoxy or C 1～8 alkoxycarbonyl,

[0104] said "amino", "amino C 1～8 alkyl", "aminocarbonyl", "aminocarbonyl C 1～8 alkyl", "aminosulfonyl" are each independently unsubstituted or substituted with one or two groups selected from -R5, -OR5, -(CO)OR5, -alkyl-(CO)OR5, -(SO2)R5, -(SO2)OR5, -alkyl-(SO2)R5, -(CO)NR5R6or -(SO2)NR5R6,

[0105] said "cycloalkyl", "cycloalkyl C 1～8 alkyl", "aryl", "heterocyclyl", "aryl C 1～8 alkyl" or "heterocyclyl C 1～8 alkyl" are each independently unsubstituted or substituted with at least one group selected from oxo, halogen, cyano, nitro, C 1～8 alkyl, C 2～8 alkenyl, C 2～8 alkynyl, C 3～8 cycloalkyl, halogenated C 1～8 alkyl, halogenated C 2～8 alkenyl, halogenated C 2～8 alkynyl, halogenated C 3～8 cycloalkyl, C 1～8 alkyl, C 3～8 cycloalkyl, -OR5, -SR5, -(CO)OR5, -(SO2)R5, -NR5R6, or -O-alkyl-(CO)OR5, or form a fused ring with -OCH2CH2- or -OCH2O- unsubstituted or substituted with halogen, between two adjacent carbon atoms of the ring;

[0106] m represents 0, 1, 2, 3 or 4; n independently represents 0, 1, 2, 3 or 4.

[0107] Preferably, the fifth solvent is selected from any one of water, acetonitrile, N,N-dimethylformamide, dimethylsulfoxide, formic acid, acetic acid, trifluoroacetic acid;

[0108] The second catalyst is selected from any one of sulfuric acid, hydrochloric acid, phosphoric acid, formic acid, acetic acid, trifluoroacetic acid;

[0109] The second oxidizing agent is selected from any one of hydrogen peroxide, peroxyacetic acid, meta-chloroperoxybenzoic acid.

[0110] In the definition of the compounds of the above formula and in all the structural formulae below, the professional terms used, whether used alone or in a composite, represent the following substituents: alkyl groups having more than two carbon atoms can be straight or branched. As in the composite "alkyl-(CO)OR5", the alkyl group can be -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH(CH3)-, -CH2CH2CH2-, -C(CH3)2-, and the like. Alkyl groups are, for example, C1 alkyl - methyl; C2 alkyl - ethyl; C3 alkyl - propyl, such as n-propyl or isopropyl; C4 alkyl - butyl, such as n-butyl, isobutyl, tert-butyl or 2-butyl; C5 alkyl - pentyl, such as n-pentyl; C6 alkyl - hexyl, such as n-hexyl, isohexyl and 1,3-dimethylbutyl. Similarly, alkenyl is, for example, ethenyl, allyl, 1-methylprop-2-en-1-yl, 2-methylprop-2-en-1-yl, but-2-en-1-yl, but-3-en-1-yl, 1-methylbut-3-en-1-yl and 1-methylbut-2-en-1-yl. Alkynyl is, for example, ethynyl, propargyl, but-2-yn-1-yl, but-3-yn-1-yl, 1-methylbut-3-yn-1-yl. The multiple bonds can be in any position of each unsaturated group. Cycloalkyl is a carbocyclic saturated ring system having, for example, three to six carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Similarly, cycloalkenyl is a monocyclic alkenyl having, for example, three to six carbon ring members, such as cyclopropenyl, cyclobutenyl, cyclopentenyl and cyclohexenyl, wherein the double bonds can be in any position. Halogen is fluorine, chlorine, bromine or iodine.

[0111] Unless otherwise specified, "aryl" as used herein includes, but is not limited to, phenyl, naphthyl, anthryl, quinonyl and the like; "heterocyclyl" as used herein includes, but is not limited to, saturated or unsaturated non-aromatic cyclic groups

[0112] and the like, but also aromatic cyclic groups, i.e. containing, for example, 3 to 6 ring atoms, of which 1 to 4 (e.g. 1, 2, 3 or 4) are heteroatoms selected from oxygen, nitrogen and sulfur, and optionally also benzo-fused, such as:

[0113] and the like;

[0114] If a group is substituted by a group, this is to be understood as meaning that the group is substituted by one or more identical or different groups selected from those mentioned as being possible substituents. In addition, the same or different substituents contained in identical or different substituents are each selected independently of one another, can be identical or different. The same applies to ring systems formed by different atoms and elements. The scope of the claims is to be understood to exclude those compounds which are known to be chemically unstable under standard conditions to the person skilled in the art.

[0115] In addition, unless specifically limited otherwise, the foregoing recitations of multiple, parallel substituents (separated by "or" or "and") apply to each and every substituent following the preceding qualifier, e.g., "unsubstituted or halogen-substituted -OCH2CH2- or -OCH2O-" in which "unsubstituted or halogen-substituted" applies to each and every group "-OCH2CH2-" and "-OCH2O-" following the preceding qualifier; "alkylamino" means an amino group mono- or di-substituted with alkyl groups, and other substituted amino groups are defined similarly; groups not designated as to the position of attachment (including heterocyclyl, aryl, etc.) can be attached in any position, including to C or N, and if substituted, the substituents can be in any position, provided that the valency rules are observed. For example, a heteroaryl group substituted with 1 or 2 methyl groups may represent etc.

[0116] If various functional groups are present, the present application also includes any keto and enol tautomers and mixtures thereof.

[0117] Preferably, the reaction temperature in the preparation step is -10-150°C.

[0118] Compared with the prior art, the present application has the beneficial effects that:

[0119] 1. The preparation method provided by the present application has high yield, good purity and low cost.

[0120] 2. The present application uses methyl mercaptan or its salt to replace the nitro group on the benzene ring, and the reaction conditions are mild, rapid, high conversion rate, mild conditions and easy to control.

[0121] 3. The present application has the advantages of easy availability of raw materials, simple reaction operation, few reaction steps, less waste, no use of flammable, explosive, toxic or difficult-to-store reagents commonly used in existing preparation methods, mild reaction conditions, avoidance of harm to the environment and operators, good industrialization prospects, and provision of a new idea suitable for industrial large-scale production. DETAILED DESCRIPTION

[0122] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present application but not all the embodiments of the present application.

[0123] The following examples are provided to better further understand the present application and are not limited to the best mode, and do not constitute a limitation to the content and protection scope of the present application. Any person under the inspiration of the present application or combining the present application with other prior art features to obtain any product same or similar to the present application falls within the protection scope of the present application.

[0124] The specific experimental steps or conditions not mentioned in the embodiments can be performed according to the conventional experimental steps or conditions described in the literature in the art. The reagents or instruments not mentioned by the manufacturer are conventional reagent products that can be obtained by purchase.

[0125] I. The following table shows a series of compounds having the structure shown in formula (I) prepared according to the method of the present application:

[0126]

[0127]

[0128]

[0129]

[0130] The preparation of representative compounds is as follows:

[0131] Example 1 Preparation of 2-chloro-3-methyl-4-methylthio-benzoic acid ethyl ester (A1-2)

[0132]

[0133] 18 g of compound A1-1 was mixed with 150 mL of toluene, and 50 mL of 20% sodium methyl mercaptide aqueous solution was added dropwise under vigorous stirring at 40°C. After 6 h of reaction, the mixture was separated. The organic phase was washed with water and 1% hydrochloric acid successively, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 17.3 g of light yellow solid. The yield was 95.5%, and the HPLC purity was >96%. MS (m / z): 244.03.

[0134] Example 2 Preparation of 2-chloro-3-(tetrahydrofuran-2-methoxymethyl)-4-methylthio-benzoic acid methyl ester (A2-2)

[0135]

[0136] 25 g of compound A2-1 was dissolved in 100 mL of toluene, 20 g of anhydrous potassium carbonate was added, and the temperature was raised to 60°C, and methyl mercaptan was bubbled into the solution until saturation, and the reaction was stirred for 16 hours, and then the temperature was lowered to room temperature, and filtered. The filtrate was washed with water, dried, and concentrated to obtain 23.6 g of a white solid, with a yield of 94.4% and a purity of >95%.

[0137]

[0138] 28 g of compound A3-1 was dissolved in 60 mL of N-methylpyrrolidone, and 40 g of 20% aqueous sodium methyl mercaptan solution was added dropwise while stirring, and stirred for 4 hours at room temperature, and the solvent was recovered under reduced pressure. The residue was diluted with water, and suction filtered, and the filter cake was washed with water and dried to obtain 26.3 g of a white solid, with a yield of 94% and a purity of >96%.

[0139] Example 4 Preparation of isopropyl 2-chloro-3-(tetrahydrofuran-2-yl)oxymethyl-4- methylthiobenzoate (A4-2)

[0140]

[0141] 28 g of compound A4-1 was dissolved in 100 mL of N,N-dimethylacetamide, and 20 g of anhydrous potassium carbonate was added, and the temperature was raised to 60°C, and methyl mercaptan was bubbled into the solution until saturation, and the reaction was stirred for 6 hours, and then the temperature was lowered to room temperature, and filtered. The filtrate was washed with water, dried, and concentrated to obtain 26.6 g of a white solid, with a yield of 95% and a purity of >95%.

[0142] Example 5 Preparation of methyl 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-methylthiobenzoate (A5-2)

[0143]

[0144] 24 g of compound A5-1 was dissolved in 60 mL of N,N-dimethylformamide, and 20 g of anhydrous potassium carbonate was added, and 9 g of dimethyl disulfide was added, and the reaction was stirred for 16 hours, and diluted with water, and extracted with ethyl acetate, and the organic phase was washed with water, dried, and concentrated to obtain 22.3 g of a white solid, with a yield of 92.9% and a purity of >96%.

[0145] Example 6 Preparation of methyl 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methylthiobenzoate (A6-2)

[0146]

[0147] 26g of compound A6-1 was dissolved in 100 mL of tetrahydrofuran, 40g of 20% sodium methanethiolate aqueous solution was added under stirring, and the reaction was carried out at elevated temperature under reflux for 4h. After the reaction solution was cooled to room temperature, it was separated into two layers, and the aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water, dried, and concentrated to obtain 24g of a yellowish solid, in a yield of 92.3%, and HPLC purity >97%.

[0148] II. The following table shows a series of compounds having the structure of general formula (II) prepared according to the method of the present application:

[0149]

[0150]

[0151]

[0152] Representative compounds are prepared as follows:

[0153] Example 7 Preparation of ethyl 2-chloro-3-methyl-4-methanesulfonylbenzoate (A1-1)

[0154] 1) Preparation of 2-methyl-3-chloro-4-(nitromethyl)nitrobenzene (B1-2)

[0155] 6.4g of nitromethane was dissolved in 20 mL of N,N-dimethylacetamide, and 17g of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) was added dropwise under stirring at a temperature of 0°C, followed by the addition of 20.6g of 2,3-dichloro-6-nitrotoluene. The reaction solution was stirred at room temperature for 16h, diluted with 100 mL of water, and then adjusted to a pH of about 3 with 5% hydrochloric acid, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 23g of a yellowish syrup. The yield was 100%, and the HPLC purity was >95%.

[0156] 2) Preparation of 2-chloro-3-methyl-4-nitrobenzoic acid (B1-3)

[0157] 23g of compound B1-2 was added to 60 mL of concentrated nitric acid and 45 mL of water, and the reaction was carried out at a temperature of 90°C for 3h. After the reaction solution was cooled to room temperature, it was diluted with water, and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 16.2g of a yellowish solid. The yield was 75.0%, and the HPLC purity was >97%.

[0158] 3) Preparation of ethyl 2-chloro-3-methyl-4-nitrobenzoate (A1-1)

[0159] 16g of compound B1-3 was dissolved in 100 mL of ethanol, and stirred to cool to 00C. 15g of sulfoxide chloride was slowly added dropwise, and after the dropwise addition was completed, the reaction was heated to reflux for 2h, and then cooled to room temperature. The solvent was recovered by reduced pressure distillation, and the residue was diluted with ethyl acetate, washed with water and saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to obtain 18g of a light yellow solid. Yield: 97.3%, HPLC purity: >97%.

[0160] Example Eight Preparation of 2-chloro-3-(tetrahydrofuran-2-methoxymethyl)-4-nitrobenzoic acid methyl ester (A2-1)

[0161] 1) Preparation of compound B2-2

[0162] 30g of compound B2-1 was dissolved in 60 mL of acetonitrile, and stirred to cool to 00C. 8g of sodium hydroxide dissolved in 10 mL of water was slowly added dropwise. After the dropwise addition was completed, the reaction was stirred at 40°C for 2h, and then cooled to room temperature. The solvent was recovered by reduced pressure distillation. The residue was stirred in 100 mL of ice water, and filtered. The filter cake was washed with water to obtain 35.1g of a white solid. Yield: 95.1%, HPLC purity: >99%.

[0163] 2) Preparation of compound B2-3

[0164] 35g of compound B2-2 was dissolved in 30 mL of N,N-dimethylformamide, and 20g of potassium carbonate was added. 15g of 30% hydrogen peroxide was added dropwise to the reaction solution while stirring, and the dropwise addition was controlled so that the temperature of the reaction solution did not exceed 45°C. After the reaction was completed, 100 mL of ice water was added, and the pH was adjusted to about 4.0 with 15% hydrochloric acid. A large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed with water to obtain 28.2g of a white solid. Yield: 94.1%, HPLC purity: >98.5%.

[0165] 3) Preparation of 2-chloro-3-(tetrahydrofuran-2-methoxymethyl)-4-nitrobenzoic acid methyl ester (A2-1)

[0166] 28g of compound B2-3 was dissolved in 60 mL of 1,2-dichloroethane, and 19g of N,N'-dicyclohexylcarbodiimide was added. The reaction was stirred at room temperature for 16h. The reaction solution was filtered, and the filtrate was washed with water, dried over anhydrous sodium sulfate, and concentrated to obtain 29.2g of a white solid. Yield: 100%, HPLC purity: >98%.

[0167] Example Nine Preparation of 2-chloro-3-(3,5-dimethyl-lH-pyrazol-l-yl)methyl-4-nitrobenzoic acid methyl ester (A3-1)

[0168]

[0169] 1) Preparation of compound B3-2

[0170] 30 g of compound B3-1 was dissolved in 150 mL of toluene, 17 g of 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU) was added dropwise under stirring, the reaction solution was heated to 80 °C and stirred for 4 h, and then cooled to room temperature. The reaction solution was adjusted to pH 5-6 with 5% hydrochloric acid, and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 33 g of a light yellow solid with a yield of 100% and an HPLC purity of >95%.

[0171] 2) Preparation of compound B3-3

[0172] 33 g of compound B3-2 was dissolved in a solution of 30 mL of N,N- dimethylformamide, 10 mL of water and 8 g of sodium hydroxide were added, and then 15 g of pyridine-N-oxide was added dropwise under heating to 45 °C and stirring. After the reaction was completed, 100 mL of ice water was added, 15% hydrochloric acid was added to adjust the pH to about 4.5, and a large amount of white solid was precipitated. Filtration under suction and washing of the filter cake with water yielded 28.0 g of a white solid with a yield of 90.3% and an HPLC purity of >98%.

[0173] 3) Preparation of compound A3-1

[0174] 28 g of compound B3-3 was dissolved in 50 mL of methanol, 15.0 g of thionyl chloride was slowly added dropwise under stirring while cooling to 0 °C. After the dropwise addition was completed, the reaction solution was heated to reflux for 4 h, and then the solvent was distilled off under reduced pressure. The residue was diluted with water, the pH was adjusted to about 7 with sodium bicarbonate, and then filtered under suction, and the filter cake was washed with water and dried to obtain 28.5 g of a white solid with a yield of 97.3% and an HPLC purity of >96%.

[0175] Example 10 Preparation of isopropyl 2-chloro-3-(tetrahydrofuran-2-yl)oxymethyl-4- nitrobenzoate (A4-1)

[0176]

[0177] 1) Preparation of compound B4-2

[0178] 29.2 g of compound B4-1, 13.9 g of dimethyl malonate, 16 g of anhydrous potassium carbonate, and 60 mL of N,N-dimethylformamide were mixed, and then stirred and heated to 65 °C for 8 h. After the solvent was recovered under reduced pressure, 100 mL of water and 100 mL of dichloromethane were added to the residue, the mixture was separated, the organic phase was washed with water, dried, and concentrated to obtain 38.5 g of a light yellow oily substance with a yield of 99.5% and an HPLC purity of >96%.

[0179] 2) Preparation of compound B4-3

[0180] 38.5 g of Compound B4-2 was dissolved in 40 mL of N,N-dimethylacetamide, and 20 g of potassium carbonate was added. While stirring, 15 g of 30% hydrogen peroxide was added dropwise to the reaction solution, and the dropping rate was controlled so that the temperature of the reaction solution was not higher than 45°C. After the reaction was completed, 100 mL of ice water was added, and 15% hydrochloric acid was added to adjust the pH to about 4.0, and a large amount of white solid was precipitated. The solid was suction filtered, and the filter cake was washed with water to obtain 28.1 g of a white solid, with a yield of 92.6% and HPLC > 98%.

[0181] 3) Preparation of Compound A4-1

[0182] 28 g of Compound B4-3 was dissolved in 90 mL of 1,2-dichloroethane, and 13 g of triethylamine and 17 g of carbonyldiimidazole were added, and the reaction was stirred at room temperature for 6 hours. The reaction solution was adjusted to pH 4 with 5% dilute hydrochloric acid, and the organic phase was washed with water and saturated sodium bicarbonate solution, and dried over anhydrous sodium sulfate, and concentrated to obtain 29.8 g of a white solid, with a yield of 93.4% and HPLC > 96%.

[0183] Example XI Preparation of 2-chloro-3-(4,5-dihydroisoxazol-3-yl)-4-nitrobenzoic acid methyl ester (A5-1)

[0184]

[0185] 1) Preparation of Compound B5-2

[0186] 26 g of Compound B5-1, 12.0 g of ethyl acetoacetate, 12.0 g of potassium hydroxide, and 50 mL of N,N-dimethylformamide were mixed, and the temperature was raised to 45°C and stirred until the reaction was completed. The reaction solution was cooled to room temperature, diluted with water, and extracted with dichloromethane. The organic phase was washed with water, dried, and concentrated to obtain 34 g of a yellowish oily substance, with a yield of 100% and HPLC > 98%

[0187] 2) Preparation of Compound B5-3

[0188] 30 g of Compound B5-2 was dissolved in 100 mL of tetrahydrofuran, and 20 g of potassium carbonate was added. While stirring, 15 g of 30% hydrogen peroxide was added dropwise, and the dropping rate was controlled so that the temperature of the reaction solution was not higher than 45°C. After the reaction was completed, 100 mL of ice water was added, and 15% hydrochloric acid was added to adjust the pH to about 4.0, and the reaction solution was separated into layers, and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water, dried, and concentrated to obtain 23.1 g of a yellowish solid, with a yield of 96.9% and HPLC > 99%.

[0189] 3) Preparation of Compound A5-1

[0190] 23g of compound B5-3 was dissolved in 50 mL of dichloromethane, 20 g of oxalyl chloride was added, and the reaction was stirred for 1 h, then cooled to 00C, and 7 g of methanol was slowly added dropwise. The reaction solution was stirred at room temperature for 16 h, and the solvent was recovered under reduced pressure to obtain 24.2 g of a white solid, with a yield of 100% and HPLC > 95%.

[0191] Example 12 Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-nitrobenzoic acid methyl ester (A6-1)

[0192]

[0193] 1) Preparation of compound B6-2

[0194] 29 g of compound B6-1 was dissolved in 50 mL of dimethyl sulfoxide, 28 g of anhydrous potassium carbonate was added, and the reaction was stirred while being heated to 55 °C. After the reaction was completed, water was added to the reaction solution to dilute it, and a solid was precipitated. The solid was suction filtered, washed with water, and dried to obtain 30 g of a white solid, with a yield of 90.0% and HPLC > 95%.

[0195] 2) Preparation of compound B6-3

[0196] 30 g of compound B6-2 was mixed with 250 mL of sodium hypochlorite, and the reaction was stirred while being heated to 55 °C. After the reaction was completed, the temperature was lowered to 00C, 15% hydrochloric acid was added to adjust the pH to about 3.0, a solid was precipitated, and the solution was suction filtered to obtain 25.6 g of a white solid, with a yield of 90.8% and HPLC > 96%.

[0197] 3) Preparation of compound A6-1

[0198] 25 g of compound B6-3 was dissolved in 50 mL of dichloroethane, 13 g of thionyl chloride was added, and the reaction was refluxed for 2 h. The reaction solution was cooled to room temperature, and 8 g of methanol was slowly added dropwise. After the addition was completed, the reaction solution was further stirred for 2 h, and was concentrated under reduced pressure to obtain 26 g of a yellowish solid, with a yield of 100% and HPLC > 96%.

[0199] Example 13 Preparation of 2-chloro-3-(1,3-dioxolan-2-yl)methyl-4-nitrobenzoic acid methyl ester (A7-1)

[0200]

[0201] 1) Preparation of compound B7-2

[0202] 31 g of compound B7-1 was dissolved in 50 mL of dimethyl sulfoxide, 28 g of anhydrous potassium carbonate was added, and the reaction was stirred and heated to 55°C. After the reaction was completed, water was added to the reaction solution to dilute it, and a solid was precipitated. The solid was filtered, washed with water, and dried to obtain 30 g of a white solid, with a yield of 90.9% and an HPLC purity of more than 95%.

[0203] 2) Preparation of compound B7-3

[0204] 30 g of compound B7-2 was dissolved in 150 mL of dichloroethane, and freshly prepared ozone was bubbled into the solution while stirring until the reaction was completed. After the reaction was completed, the temperature was lowered to 0°C, and dilute hydrochloric acid was added to adjust the pH to about 5.0. The mixture was separated, the filtrate was washed with water, dried, and concentrated to obtain 25 g of a white solid, with a yield of 100% and an HPLC purity of more than 96%.

[0205] 3) Preparation of compound A7-1

[0206] 25 g of compound B7-3 was dissolved in 100 mL of dichloromethane, and 13 g of oxalyl chloride was added. The reaction was heated to reflux for 2 hours. After the reaction solution was cooled to room temperature, 8 g of methanol was slowly added dropwise. After the addition was completed, the reaction solution was stirred for 2 hours, and then concentrated under reduced pressure to obtain 26 g of a yellowish solid, with a yield of 98.9% and an HPLC purity of more than 96%.

[0207] Example Fourteen Preparation of 2-chloro-3-(2-piperidinone-l-yl)-4-nitrobenzoic acid methyl ester (A8-1)

[0208]

[0209] 1) Preparation of compound B8-2

[0210] 29 g of compound B8-1 was dissolved in 150 mL of toluene, and 27 g of tetramethyl guanidine was added dropwise. The reaction was heated to 80°C and stirred for 4 hours, and then cooled to room temperature. The reaction solution was adjusted to pH 3 with 5% hydrochloric acid, and then separated. The organic phase was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 31.8 g of a yellowish solid, with a yield of 100% and an HPLC purity of more than 95%.

[0211] 2) Preparation of compound B8-3

[0212] 31 g of compound B8-2 was dissolved in 30 mL of dimethyl sulfoxide, and 10 mL of water and 8 g of sodium hydroxide were added. The temperature was raised to 45°C, and 17 g of sodium perborate was added portionwise while stirring. After the reaction was completed, 100 mL of ice water was added, and the pH was adjusted to about 4.5 with 15% hydrochloric acid. A large amount of white solid was precipitated. The solid was filtered, and the filter cake was washed with water to obtain 27.5 g of a white solid, with a yield of 94.7% and an HPLC purity of more than 98%.

[0213] 3) Preparation of compound A8-1

[0214] 27g of compound B8-3 was dissolved in 100 mL of methanol, hydrogen chloride was bubbled into the solution until saturation, the reaction solution was heated to 60°C and stirred for 4 hours, and then the solvent was removed by evaporation under reduced pressure. The residue was diluted with water, the pH was adjusted to about 7 with sodium bicarbonate, and then filtered, washed with water, and dried to obtain 28.5 g of a white solid, with a yield of 99% and HPLC purity >96%.

[0215] Example 15 Preparation of 2-chloro-3-methylthiomethyl-4-nitrobenzoic acid methyl ester (A9-1)

[0216] 1) Preparation of compound B9-2

[0217] 25 g of compound B9-1 was dissolved in 50 mL of N,N-dimethylformamide, 9.2 g of sodium amide was added, the reaction solution was stirred at room temperature for 6 hours, and then slowly poured into 100 g of ice water. The pH was adjusted to 3 with 5% hydrochloric acid, and then the organic phase was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 26.2 g of a yellow solid, with a yield of 93.8% and HPLC purity >95%.

[0218] 2) Preparation of compound B9-3

[0219] 26 g of compound B9-2 was dissolved in 30 mL of dimethyl sulfoxide, 10 mL of water and 8 g of sodium hydroxide were added, and then 150 mL of sodium hypochlorite was added dropwise while stirring at room temperature. After the reaction was completed, 15% hydrochloric acid was added dropwise to adjust the pH to about 3, and a large amount of solid was precipitated. The solid was filtered, and then washed with water to obtain 24.1 g of a yellow solid, with a yield of 99.8% and HPLC purity >98%.

[0220] 3) Preparation of compound A9-1

[0221] 24 g of compound B9-3 was dissolved in 60 mL of N,N-dimethylformamide, 15 g of anhydrous potassium carbonate was added, and then 10 g of bromoethane was added dropwise while stirring, and the reaction solution was heated to 60°C and stirred for 4 hours. The reaction solution was diluted with water, and then extracted with ethyl acetate. The organic phase was washed with water, and then dried to obtain 25 g of a yellow solid, with a yield of 94.1% and HPLC purity >96%.

[0222] III. Typical examples of the preparation of representative compounds of 4-methanesulfonylbenzoic acid esters by an oxidation reaction are as follows:

[0223] Example 16 Preparation of 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4-methanesulfonylbenzoic acid methyl ester (C1-1)

[0224]

[0225] 19g Compound A1-2 was mixed with 30 mL acetic acid, stirred to warm to 40 °C, 20g 30% hydrogen peroxide was added dropwise slowly, and the reaction was maintained at 40 °C for 4h, then cooled to room temperature, diluted with 100 mL water, and a large amount of solid precipitated. The solid was filtered, washed with water, and dried to give 19g of a white solid. Yield 89%, HPLC purity >98%. HNMR [CDC13, 300MHz] δ 8.10 (d, J = 9.0 Hz, IH), 7.62 (d, J = 9.0 Hz, IH), 4.48 (q, J = 9.0 Hz, 2H), 3.12 (s, 3H), 2.80 (s, 3H), 1.48 (t, J = 9.0 Hz, 3H).

[0226] Example 17 Preparation of methyl 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4- methanesulfonylbenzoate (C2-1)

[0227]

[0228] 24g Compound A6-2 was mixed with 20 mL acetic acid, stirred to warm to 40 °C, 100 mL 10% peracetic acid was added dropwise slowly, and the reaction was maintained at 40 °C. After the reaction was completed, 1g sodium thiosulfate was added to the reaction solution and stirred for 1h. Acetic acid was recovered under reduced pressure. The residue was stirred with water, filtered, washed with water, and dried to give 24.1g of a yellowish solid, yield 91.5%, HPLC >98%. HNMR [DMSO-d6, 300MHz] δ 8.28 (d, J = 9.0 Hz, IH), 7.85 (d, J = 9.0 Hz, IH), 4.82 (s, 2H), 3.79-3.90 (m, 5H), 3.33 (s, 3H).

[0229] Example 17 Preparation of methyl 2-chloro-3-(2,2,2-trifluoroethoxy)methyl-4- methanesulfonylbenzoate (C2-1)

[0230]

[0231] 9g Compound A19-2 was dissolved in 50 mL dichloromethane, and 6.5g m-chloroperbenzoic acid was added slowly while stirring. After the reaction was completed, 1g sodium bisulfite was added to the reaction solution and stirred for 1h. The reaction solution was stirred with 5% sodium hydroxide solution, and the organic phase was separated, washed with water, and dried to give 9.2g of a yellowish solid, yield 92.3%, HPLC >97%. HNMR [DMSO-d6, 300MHz] δ 8.11 (d, J = 9.0 Hz, IH), 7.65 (d, J = 9.0 Hz, IH), 3.33 (s, 3H), 2.00-1.62 (m, 14H).

[0232] The application is explained in detail above with reference to the preferred embodiments and exemplary examples. However, it is to be understood that these embodiments are merely exemplary of the application and that other embodiments, being obvious from the above teaching to one skilled in the art, are intended to be within the scope of the application. Accordingly, reference should be made to the appended claims rather than to the foregoing specification as indicating the scope of the application.

Claims

1. A method for preparing benzoate pesticides and pharmaceutical intermediates represented by general formula I, characterized in that, Preparation steps of a compound as shown in the following general formula I: The compound as shown in the general formula II is dissolved in a first solvent and reacted with a methylthio reagent to prepare the compound as shown in the general formula I, and the reaction equation is as follows: ， In the formula, R1represents ; R2 represents H, methyl, ethyl, n-propyl, or isopropyl; The first solvent is at least one selected from dichloromethane, dichloroethane, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone, benzonitrile, or sulfolane; The methylthio reagent is dimethyl disulfide.

2. The process for the preparation of benzoic acid ester pesticides and pharmaceutical intermediates of the general formula I according to claim 1, characterized by that, Preparation steps of a benzoate pesticide and pharmaceutical intermediate general formula II: (1) The compound as shown in the general formula IV and the compound as shown in the general formula V are added to a second solvent, an acid binding agent is added for reaction to prepare the compound as shown in the general formula III; (2) The compound as shown in the general formula III is subjected to a) or a)+b) steps to obtain the compound as shown in the general formula II: When R2=H, the a) step is adopted, and when R2 is other groups except hydrogen, the a)+b) step is adopted, The a) step is that the compound as shown in the general formula III is dissolved in a third solvent and reacted with a first oxidizing agent to prepare the compound as shown in the general formula II, The b) step is that the compound as shown in the general formula II with R2=H is dissolved in a fourth solvent and subjected to esterification under the action of a first catalyst to prepare the compound as shown in the general formula II with R2 being other groups except hydrogen; The reaction equation is as follows: ， In the formula, X represents any one of fluorine, chlorine, bromine, or iodine; R1represents ; R2 represents H, methyl, ethyl, n-propyl, or isopropyl; R3represents hydrogen, halogen, haloalkyl, cyano, nitro, alkyl, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, -(CO)OR5, -(SO2)R5; R4represents cyano, nitro, alkylcarbonyl, alkoxycarbonyl, alkylsulfonyl, aminocarbonyl, aminocarbonylC 1～8 alkyl, aminosulfonyl, -(CO)OR5, -(SO2)R5; R5represents hydrogen, halogen, C 1～8 alkyl; The second solvent is at least one selected from water, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, chlorobenzene, dichlorobenzene, nitromethane, nitrobenzene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone, benzonitrile, or sulfolane; The acid binding agent is at least one selected from alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, alkali metal alcoholate, triethylamine, diisopropyl ethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); The third solvent is at least one selected from water, methanol, ethanol, isopropanol, n-propanol, tert-butanol, n-butanol, benzyl alcohol, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone, benzonitrile, or sulfolane; The first oxidizing agent is at least one selected from hydrogen peroxide, nitric acid, sodium peroxoborate, pyridine-N-oxide, or metal hypochlorite; The fourth solvent is selected from at least one of methanol, ethanol, isopropanol, n-propanol, t-butanol, n-butanol, benzyl alcohol, dichloromethane, dichloroethane, acetonitrile, benzene, toluene, xylene, ethyl acetate, tetrahydrofuran, 2-methyltetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, 1,3-dimethylimidazolidinone, N-methylpyrrolidone, benzonitrile, or sulfolane; The first catalyst is selected from at least one of p-toluenesulfonic acid, sulfuric acid, hydrochloric acid, phosphoric acid, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, oxalyl chloride, alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, alkali metal alkoxide, triethylamine, diisopropylethylamine, or 1,8-diazabicyclo[5.4.0]undec-7-ene.

3. The method for preparing the benzoate pesticide and pharmaceutical intermediate of general formula I according to claim 1 or 2, characterized in that, The reaction temperature in the preparation step is -10-150°C.

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