A method for preparing a uracil compound containing a carboxylate fragment under alkaline conditions

Abstract

The present application relates to the field of pesticide herbicide, and in particular to a preparation method of 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidine-1(2H)-yl)benzoate compound, the present application adopts a method for constructing a uracil ring under alkaline conditions, the intermediate prepared by the method can be used to prepare a novel efficient uracil herbicide with a structural formula of formula (I), the novel efficient uracil herbicide has stable chemical properties and better herbicidal activity, the synthesis route is simple, and the novel efficient uracil herbicide has a wide application prospect in agriculture, and the present application further provides an intermediate compound used in the method and a method for producing the intermediate compound.

Description

Technical Field

[0001] This invention relates to the field of pesticides and herbicides, specifically to a method for preparing uracil compounds containing carboxylic acid ester fragments. These uracil compounds can be used to prepare the herbicide 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate compounds. Background Technology

[0002] Patent CN114621150A discloses a method for preparing uracil compounds containing carboxylic acid ester fragments:

[0003]

[0004] Patent CN114621150A also reports the following synthesis method:

[0005]

[0006] In the above formula:

[0007] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0008] R3 is selected from C 2～5 Alkyl group, CH3CH=CHCH2-, C substituted with one or more halogens 3～6 Alkenyl group, CH3C≡CCH2-, C substituted with one or more halogens 3～6 alkynyl group, C 4～7 cycloalkyl, C 3～6 cycloalkyl-C 1～3 Alkyl or C 1～6 Halogenated alkyl groups;

[0009] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them can be of the R type or S type, or a mixture of the two.

[0010] Existing methods for preparing uracil-based herbicides mostly involve first protecting the carboxyl group with esterification, then synthesizing the uracil ring, followed by a one-step hydrolysis, and finally splicing it with the corresponding fragments to synthesize the final compound. This method requires high-temperature, strongly acidic conditions for the hydrolysis step, resulting in harsh reaction conditions, impurity generation, and stringent requirements for the materials used in the reaction apparatus. Most hydrolysis methods use a hydrochloric acid-acetic acid system, generating large amounts of waste acid that are difficult to recover, and the strong acids are corrosive, posing safety hazards during operation. These methods suffer from poor atom economy, lengthy steps, high costs, low yields, environmental unfriendliness, and difficult post-processing. Currently, the key step in the preparation of uracil-based herbicides lies in the synthesis of the uracil ring. Existing reports on cyclization methods for uracil-based herbicides are mostly limited to a single approach, hindering industrial-scale development. Summary of the Invention

[0011] The technical problem to be solved by the present invention is to provide a method for preparing uracil compounds containing carboxylic acid ester fragments under alkaline conditions, in order to address the shortcomings of the prior art.

[0012] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0013] A method for preparing uracil compounds containing carboxylic acid ester fragments under alkaline conditions, the reaction formula of which is as follows:

[0014]

[0015] The compound of formula (V) was reacted with 3-amino-4,4,4-trifluoro-2-butenoic acid R5 ester in an organic solvent at -20°C to the solvent boiling point, and the reaction was carried out in the presence of a base to prepare uracil compound (VI).

[0016] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0017] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3 Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0018] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R-type or S-type, or a mixture of the two;

[0019] R4 and R5 are respectively selected from C 1～4 alkyl.

[0020] Preferably, the above-described synthesis method:

[0021] R1 and R2 are selected from hydrogen or methyl, respectively;

[0022] R3 is selected from C 1～3 Alkoxy-C 1～3 Alkyl, C 1～3 Halogenated alkoxy-C 1～3 Alkyl, C 2～6 Enoxy-C 1～3 Alkyl, C 2～6 Halo-alkeneoxy-C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl or C 2～6 Halogenated alkyne-C 1～3 alkyl;

[0023] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R type or S type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1;

[0024] R4 and R5 are selected from methyl or ethyl groups, respectively;

[0025] The organic solvent is selected from methanol, ethanol, isopropanol, butanol, tert-butanol, cyclohexanol, ethylene glycol, pentane, n-hexane, cyclohexane, heptane, octane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, petroleum ether, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate, benzene, toluene, o-xylene, m-xylene, p-xylene, xylene, chlorobenzene, acetone, butanone, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide;

[0026] The base is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, tert-butyllithium, diisopropylaminolithium (LDA), hexamethyldisilaminolithium (LiHMDS), 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH;

[0027] The amount of alkali is between 1.0 and 2.0 equivalents;

[0028] The reaction temperature is from room temperature to the solvent boiling point.

[0029] More preferably, the above-described synthesis method:

[0030] The organic solvent is selected from N,N-dimethylformamide;

[0031] The alkali is selected from K2CO3;

[0032] The amount of alkali is between 1.0 and 1.5 equivalents;

[0033] The reaction temperature is 100℃.

[0034] Furthermore, the present invention also provides a method for synthesizing a compound having the formula (V) phenylcarbamate, wherein the reaction formula is as follows:

[0035]

[0036] The compound of formula (IV) is reacted with a substituted formic acid R4-based ester in an organic solvent at a temperature from -20°C to the solvent boiling point, in the presence of a base, to give compound (V). X is selected from leaving groups, such as fluorine, chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, or p-methylbenzenesulfonate.

[0037] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0038] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3 Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0039] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R-type or S-type, or a mixture of the two;

[0040] R4 is selected from C 1～4 alkyl.

[0041] Preferably, the above-described synthesis method:

[0042] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0043] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 acetylacetonate C 1～3 Alkyl or C 2～6 Halogenated alkyne oxygen C 1～3 alkyl;

[0044] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R type or S type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1;

[0045] R4 is selected from C 1～4 alkyl;

[0046] X is selected from halogens, including fluorine, chlorine, bromine, and iodine;

[0047] The organic solvent is selected from pentane, n-hexane, cyclohexane, heptane, octane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, petroleum ether, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate, benzene, toluene, o-xylene, m-xylene, p-xylene, xylene, chlorobenzene, acetone, butanone, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide;

[0048] The base is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH;

[0049] The amount of alkali is between 1.0 and 2.0 equivalents;

[0050] The reaction temperature is from 0°C to room temperature.

[0051] More preferably, the above-described synthesis method:

[0052] R1 and R2 are selected from hydrogen or methyl, respectively;

[0053] R3 is selected from C 1～3 Alkoxy-C 1～3 Alkyl, C 1～3 Halogenated alkoxy-C 1～3 Alkyl, C 2～6 Enoxy-C 1～3 Alkyl, C 2～6 Halo-alkeneoxy-C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl or C 2～6 Halogenated alkyne-C 1～3 alkyl;

[0054] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R type or S type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1;

[0055] R4 is selected from methyl or ethyl;

[0056] X is selected from chlorine;

[0057] The organic solvent is selected from dichloromethane;

[0058] The base is selected from pyridine;

[0059] The amount of alkali is between 1.0 and 1.5 equivalents;

[0060] The reaction temperature was 0–5°C, and then raised to room temperature.

[0061] The above-described aniline compound of formula (IV) can be prepared by the following method:

[0062]

[0063] Compounds having formula (IV) are typically prepared by reacting a compound of formula (III) with a reducing agent in water or an organic solvent at a temperature ranging from -20°C to the solvent's boiling point. The preferred reaction temperature is 40–45°C; the reaction time is 0.5–48 hours, preferably 8–10 hours. Solvents can be water, alcohols such as methanol, ethanol, isopropanol, etc., or ethers such as diethyl ether, tetrahydrofuran, dioxane, etc., with methanol being preferred. Suitable reducing agents are selected from hydrogen, metal hydrides, half-metal hydrides and their derivatives, such as lithium aluminum hydride, diisobutyl aluminum hydride, sodium borohydride, borane, etc., with hydrogen being preferred. The pressure is 1.5-2 MPa. Hydrogen can be supplied by hydrogen storage cylinders or can be generated in situ by active metals (such as reduced iron powder, reduced zinc powder, etc.) under acidic conditions (such as hydrochloric acid, sulfuric acid) and participate in the reduction reaction. The amount of transition metal or transition metal compound is catalytically added. The transition metal can be a group 8 subgroup compound, preferably Ni, Pd, Pt, etc. (used directly or supported by media such as activated carbon, alumina, silicon dioxide, etc.), more preferably Pt / C (1%), and the feeding ratio is 1%-5% of the mass of the compound of formula (III).

[0064] The definitions of R1, R2, and R3 are as described above.

[0065] The present invention also provides a method for synthesizing nitrobenzene compounds having formula (III), wherein the reaction formula is as follows:

[0066]

[0067] Compound (II) is reacted with a substituted acetate in an organic solvent in the presence of a base at a temperature ranging from -20°C to the solvent's boiling point to produce compound (III). The amount of base is typically between 1.0 and 3.0 equivalents. L is a leaving group selected from chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, or p-methylbenzenesulfonate.

[0068] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0069] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0070] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them can be of the R type or S type, or a mixture of the two.

[0071] Preferably, the above-described synthesis method:

[0072] R1 and R2 are selected from hydrogen or methyl, respectively;

[0073] R3 is selected from C 1～3 Alkoxy-C 1～3 Alkyl, C 1～3 Halogenated alkoxy-C 1～3 Alkyl, C 2～6 Enoxy-C 1～3 Alkyl, C 2～6 Halo-alkeneoxy-C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl or C 2～6 Halogenated alkyne-C 1～3 alkyl;

[0074] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R type or S type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1;

[0075] L is a leaving group, such as chlorine, bromine, iodine, methanesulfonate, trifluoromethanesulfonate, benzenesulfonate, or p-methylbenzenesulfonate;

[0076] The organic solvent is selected from pentane, n-hexane, cyclohexane, heptane, octane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, petroleum ether, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate, benzene, toluene, o-xylene, m-xylene, p-xylene, xylene, chlorobenzene, acetone, butanone, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide;

[0077] The base is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH;

[0078] The amount of alkali is between 1.0 and 2.0 equivalents;

[0079] The reaction temperature is from 0°C to room temperature.

[0080] More preferably, the above-described synthesis method:

[0081] L is selected from chlorine or bromine;

[0082] The organic solvent is selected from N,N-dimethylformamide;

[0083] The alkali is selected from K2CO3;

[0084] The amount of alkali is between 1.0 and 1.5 equivalents;

[0085] The reaction temperature was room temperature.

[0086] The present invention further provides a phenylcarbamate compound of formula (V):

[0087]

[0088] R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring;

[0089] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3 Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0090] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R-type or S-type, or a mixture of the two;

[0091] R4 is selected from C 1～4 alkyl.

[0092] Preferably, a phenylcarbamate compound of formula (V):

[0093] R1 and R2 are selected from hydrogen or methyl, respectively;

[0094] R3 is selected from C 1～3 Alkoxy-C 1～3 Alkyl, C 1～3 Halogenated alkoxy-C 1～3 Alkyl, C2～6 Enoxy-C 1～3 Alkyl, C 2～6 Halo-alkeneoxy-C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl or C 2～6 Halogenated alkyne-C 1～3 alkyl;

[0095] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R type or S type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1;

[0096] R4 is selected from methyl or ethyl.

[0097] Some of the intermediate compounds of the present invention can be described using the specific compounds listed in Table 1, but the present invention is not limited to these compounds.

[0098] Table 1. Structures of some compounds of general formula (V)

[0099]

[0100]

[0101]

[0102]

[0103]

[0104]

[0105]

[0106]

[0107]

[0108]

[0109]

[0110]

[0111]

[0112]

[0113]

[0114]

[0115]

[0116]

[0117]

[0118]

[0119]

[0120]

[0121]

[0122]

[0123]

[0124]

[0125]

[0126]

[0127]

[0128] The present invention also provides the use of a phenylcarbamate compound of formula (V) in the preparation of a uracil compound of formula (VI) containing a carboxylic acid ester fragment.

[0129]

[0130] In the formula, R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon they are attached to form a three-membered ring;

[0131] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3 Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0132] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it can be selected from R-type or S-type, or a mixture of the two;

[0133] R4 and R5 are respectively selected from C 1～4 alkyl.

[0134] The uracil compound containing a carboxylic acid ester fragment, as shown in formula (VI), prepared by this invention, can be used to prepare the herbicide 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate compound of formula (I), as follows:

[0135]

[0136] Compounds having formula (I) are typically prepared by reacting a compound of formula (VI) with a methylating agent in an organic solvent in the presence of a base at a temperature from -20°C to the solvent's boiling point to obtain compound (I). The methylating agent is selected from dimethyl sulfate, chloromethane, bromomethane, iodomethane, methyl p-toluenesulfonate, or methyl trifluoromethanesulfonate. Dimethyl sulfate is preferred. Suitable bases include, but are not limited to, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU), or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH, or KOH, preferably K2CO3.

[0137] In the formula, R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon they are attached to form a three-membered ring;

[0138] R3 is selected from C 1～3 Alkoxy C 1～3 Alkyl, C 1～3 Halogenated alkoxy C 1～3 Alkyl, C 2～6 Enoxy C 1～3 Alkyl, C 2～6 Halogenated alkenyloxy C 1～3 Alkyl, C 2～6 Alkyne-O-C 1～3 Alkyl, C 2～6 Halogenated alkyne oxygen C 1～3 Alkyl or C 1～3 Alkane S(O) n C 1～3 Alkyl group, where n represents 0, 1, or 2;

[0139] When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them can be of the R type or S type, or a mixture of the two.

[0140] In the definitions of general formula compounds given above, the terms used in the compilation are generally defined as follows:

[0141] Halogens: Refers to fluorine, chlorine, bromine, or iodine. Alkyl groups: Straight-chain or branched alkyl groups, such as methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, or sec-butyl, and their isomers. Alkenyl groups: Straight-chain or branched alkenes, such as vinyl, 1-propenyl, 2-propenyl, and various butenyl, pentenyl, and hexenyl isomers. Alkenyl groups also include polyenes, such as 1,2-propadienyl and 2,4-hexadienyl. Alkynyl groups: Straight-chain or branched alkynes, such as ethynyl, propynyl, and various butynyl, pentynyl, and hexynyl isomers. Alkynyl groups also include polykynes, such as 2,4-hexadiynyl. Cycloalkyl groups: Substituted or unsubstituted cyclic alkyl groups, such as cyclobutyl and cyclopentyl. Substituents include methyl, halogen, cyano, etc. Cycloalkylalkyl: Substituted or unsubstituted alkyl groups containing cyclic alkyl groups, such as cyclopropylmethyl and cyclobutylmethyl. Substituents include methyl, halogen, and cyano groups. Halogenated alkyl: Straight-chain or branched alkyl groups where the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, such as chloropropyl and bromopropyl. Alkoxyalkyl: Alkyl-O-alkyl-, such as CH3OCH2-. Halogenated alkoxyalkyl: Alkyl-O-alkyl-, where the hydrogen atoms on these alkyl groups may be partially or completely replaced by halogen atoms, such as ClCH2OCH2-. Alkenyloxyalkyl: Alkenyl-O-alkyl-, such as CH2=CHCH2OCH2CH2-. Halogenated alkenyloxyalkyl: Alkenyl-O-alkyl-, where the O and CH2=CH are not directly connected, and the hydrogen atoms on these alkenyl groups may be partially or completely replaced by halogen atoms, such as ClCH=CHCH2OCH2CH2-. Alkynoalkyl groups: alkynyl-O-alkyl-, e.g., CH≡CCH₂OCH₂CH₂-, where O and CH≡C are not directly bonded. Haloalkynylalkyl groups: alkynyl-O-alkyl-, where the hydrogen atom on these alkynyl groups can be replaced by a halogen atom, e.g., ClC≡CCH₂OCH₂CH₂-. Alkane S(O) n Alkyl: Alkyl-S(O) n -alkyl-, n=0, 1 or 2, such as CH3SCH2CH2-, CH3SOCH2CH2-, CH3SO2CH2CH2-.

[0142] The aforementioned method of the present invention may further include necessary pretreatment of the raw materials and necessary post-treatment of the reaction products. Pretreatment and post-treatment operations include, but are not limited to, drying, washing, pulping, filtration, centrifugation, column chromatography, and recrystallization. The examples section of the present invention provides several specific processing methods, which should not be construed as limiting the present invention by those skilled in the art.

[0143] Unless otherwise noted, the definitions of the groups in the reaction formula are the same as above.

[0144] The herbicide 2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-(trifluoromethyl)-3,6-dihydropyrimidin-1(2H)-yl)benzoate compound prepared by this invention has outstanding killing activity against a wide range of economically important monocot and dicot annual pests. It can effectively control a variety of weeds and achieve good results at low doses, and can be used as a herbicide.

[0145] In this invention, if there is a conflict between the Chinese name and the structural formula of a compound, the structural formula shall prevail, unless the structural formula is obviously incorrect.

[0146] The beneficial effects of this invention are as follows: The synthetic approach uses 2-chloro-4-fluoro-5-nitrobenzoic acid as a starting material, first splicing small side-chain fragments with carboxyl groups, and finally synthesizing uracil rings using different methods. This avoids the need for protecting groups, improves atom economy, shortens the total synthetic steps, reduces impurity formation, and greatly improves the utilization rate of raw materials and reagents. Furthermore, this invention offers diverse cyclization methods for uracil rings, providing a good approach for industrial development and facilitating conversion to industrial production. The raw materials and reagents are readily available, the reaction conditions are mild, the operation and post-processing are simple, and the product yield and purity are high, significantly reducing costs. Detailed Implementation

[0147] The present invention is illustrated below with reference to examples, but is not intended to limit the invention. Any simple substitutions or modifications made to the present invention by those skilled in the art are within the scope of the technical solutions protected by this invention.

[0148] Several methods for preparing the compounds of the present invention are described in detail in the following schemes and examples. The raw materials can be commercially available or prepared by methods known in the literature or as detailed in the description. Those skilled in the art will understand that other synthetic routes can also be used to synthesize the compounds of the present invention. Although specific raw materials and conditions in the synthetic routes have been described below, they can be easily replaced with other similar raw materials and conditions. Such variations or modifications to the preparation methods of the present invention, such as various isomers of the compounds, are all included within the scope of the present invention. Furthermore, the preparation methods described below can be further modified according to the disclosure of the present invention using conventional chemical methods well known to those skilled in the art. For example, protecting appropriate groups during the reaction process, etc.

[0149] The following method examples are provided to further illustrate the preparation methods of the present invention. The specific substances, types, and conditions used are intended to further explain the invention and are not intended to limit its reasonable scope. The raw materials and reagents used in the synthetic compounds described below are either commercially available or can be easily prepared by those skilled in the art.

[0150] The analytical instruments described in the examples are as follows:

[0151] I. High Performance Liquid Chromatography (hereinafter referred to as HPLC): Using an Agilent Technologies 1260 Infinity II instrument.

[0152] Pillar: Agilent Eclipse Plus C18 3.5μm, 4.6*100mm

[0153] Mobile phase: A: water + 0.1% phosphoric acid; B: acetonitrile; Temperature: 30℃

[0154] Gradient: 10%B to 95%B over 15 minutes; 95%B over 3 minutes

[0155] Flow rate: 1 mL / min

[0156] II. Ultra-high performance liquid chromatography-tandem mass spectrometry (hereinafter referred to as LC-MS): Waters, ACQUITY H-Class UPLC-SQ Detector 2 instrument.

[0157] Column: ACQUITY BEH C18 1.7μm,2.1*50mm Column

[0158] Mobile phase: A: Water + 0.2% formic acid; B: Acetonitrile; Temperature: 30℃

[0159] Gradient: 10%B to 95%B over 5 minutes; 95%B over 1 minute

[0160] Flow rate: 0.5 mL / min

[0161] MS method: ESI positive, negative, quality range (m / z): 100-800

[0162] III. Gas Chromatograph (hereinafter referred to as GC): Agilent Technologies, 7890B GC equipment was used.

[0163] Detector: FID

[0164] Chromatographic column: HP-1 30m*530μm*10.5μm

[0165] Inlet temperature: 250℃

[0166] Flow split ratio: 40:1

[0167] Flow rate: 20 mL / min

[0168] H2: 30 mL / min

[0169] Air: 300mL / min

[0170] He: 25 mL / min

[0171] Detector temperature: 280℃

[0172] Method: Hold at 40℃ for 2 min, increase temperature to 260℃ at 20℃ / min, hold at 260℃ for 5 min, total time 18 min.

[0173] IV. Gas Chromatography-Tandem Mass Spectrometry (hereinafter referred to as GC-MS): Agilent Technologies, 7890B GCSystem-5977A MSD instrument was used.

[0174] Column: Agilent Technologies, HP-5MS UI 0.25μm, 30m*0.250mm

[0175] Injector temperature: 250℃

[0176] Column flow rate: Helium 1 mL / min

[0177] Method: Hold at 40℃ for 2 min, increase temperature to 280℃ at 20℃ / min, hold at 280℃ for 5 min, total time 19 min.

[0178] MSD transmission line temperature: 280℃

[0179] EI ion source temperature: 230℃, MS quadrupole temperature: 150℃, scan range: 30.00-400.00.

[0180] In addition, the proton nuclear magnetic resonance spectra described below (hereinafter referred to as...) 1 The chemical shift values ​​of H-NMR were measured at 400 MHz (Bruker, AVANCE III HD 400M) in deuterated chloroform solvent, using Me4Si (tetramethylsilane) as the reference material. When measured in deuterated dimethyl sulfoxide solvent, the chemical shift values ​​are shown as "(DMSO-d6)" in the data. It should be noted that... 1 The symbols in the chemical shift values ​​of H-NMR have the following meanings.

[0181] s: singlet, d: doublet, dd: doublett, dt: doublettuplet, td: triplettuplet, ddd: doublettuplet, t: triplet, q: quartet, sep: septet, m: multiplet, brs: broad singlet. Furthermore, in cases where two or more stereoisomers are present, the chemical shift values ​​for the resolvable signal are marked with "and".

[0182] Examples of representative compounds are given below. The synthesis methods of other compounds are similar and will not be described in detail here.

[0183] Example 1: Synthesis of the intermediate 2-bromo-2-methylpropionic acid 2-methoxyethyl ester

[0184]

[0185] 16.55 g (217.49 mmol) of ethylene glycol monomethyl ether and 250 g of chloroform were added to a reaction flask and stirred. 50 g (217.49 mmol) of 2-bromoisobutyryl bromide was added dropwise. The mixture was cooled to 0-5 °C and 26.4 g (260.98 mmol) of triethylamine was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 12 hours. After the reaction was complete, 50 g of water was added, and the mixture was extracted to separate the layers. The organic phase was separated, and the solvent was removed by vacuum evaporation. The residue was product 1a, yielding 28.4 g, with a yield of 80.52% and a gas chromatographic area-normalized purity of 98.6%. 1 HNMR (400MHz, DMSO-d6) δ4.18–4.14(m,2H),3.55–3.49(m,2H),3.36(s,3H),1.92(s,6H).

[0186] Example 2: Synthesis of intermediate 2-(2-chloro-4-fluoro-5-nitrobenzoyloxy)-2-methylpropionic acid methoxyethyl ester

[0187]

[0188] 20 g (91.1 mmol) of compound II, 22.55 g (100.2 mmol) of compound 1a, 1.5 g (10.02 mmol) of sodium iodide, 60 g of N,N-dimethylformamide, and 13.85 g (100.2 mmol) of potassium carbonate were added to a reaction flask and reacted at room temperature for 3 h. After the disappearance of starting material II was detected, 30 g of water and 100 g of ethyl acetate were added and stirred for 10 min. The mixture was allowed to stand and separate into layers. The organic phase was separated, washed twice with saturated brine, and then dissolved to obtain 28.65 g of the title compound III-179, with a yield of 86.48% and a normalized purity of 92.6% according to liquid chromatography. The product is a pale yellow oil. 1 HNMR (400MHz, DMSO-d6) δ8.53(d,J=8.0Hz,1H),8.12(d,J=11.1Hz,1H),4.27–4.14(m,2H),3.56–3.48(m,2H),3.22(s,3H),1.66(s,6H).

[0189] Example 3: Synthesis of intermediate 2-(2-chloro-4-fluoro-5-aminobenzoyloxy)-2-methylpropionic acid methoxyethyl ester

[0190]

[0191] 100g of compound III-179 was dissolved in 500g of methanol and added to a 1000mL autoclave. 3g of Pt / C (1%) was added, and the mixture was purged five times with hydrogen. The temperature was raised to 45℃, and the hydrogen pressure inside the autoclave was controlled at 2MPa. The reaction was allowed to proceed for 8 hours. A sample was taken, and the starting material III-179 was found to be gone. The insoluble matter was removed by filtration, and the solvent was removed from the filtrate under reduced pressure to obtain 87.72g of the title compound IV-179, with a yield of 95.6% and a normalized purity of 96.2% according to liquid chromatography. The product is a brownish-yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ7.30(d,J=11.1Hz,1H),7.24(d,J=9.4Hz,1H),4.23–4.18(m,2H),3.54–3.49(m,2H),3.22(s,3H),1.60(s,6H).

[0192] Example 4: Synthesis of intermediate 2-methoxyethyl 2-{2-chloro-5-[(methoxycarbonyl)amino]-4-fluorobenzoyloxy}-2-methylpropionate

[0193]

[0194] 20 g (59.9 mmol) of compound IV-179, 20 g of dichloromethane, and 5.3 g (71.9 mmol) of pyridine were added to a reaction flask. The temperature was maintained at 0–5 °C in an ice bath. 7.1 g (74.9 mmol) of methyl chloroformate was dissolved in 20 g of dichloromethane, and this solution was added dropwise to the reaction flask. After the addition was complete, the mixture was brought to room temperature and reacted for 2 h. A sample was taken, and the starting material IV-179 disappeared. 50 g of water was added to quench the reaction, and the organic phase was separated and evaporated to dryness to obtain 20 g of compound V-179, with a yield of 85.17% and a normalized purity of 89.1% according to liquid chromatography. It is a pale yellow solid with a melting point of 64 °C–65 °C. 1 H NMR (400MHz, DMSO-d6) δ9.76 (s, 1H), 8.24 (d, J = 8.3Hz, 1H), 7.65 (d, J = 10.6Hz, 1 H),4.28–4.13(m,2H),3.70(s,3H),3.57–3.46(m,2H),3.21(s,3H),1.62(s,6H).

[0195] Example 5: Synthesis of intermediate 2-methoxyethyl 2-{2-chloro-5-[(ethoxycarbonyl)amino]-4-fluorobenzoyloxy}-2-methylpropionate

[0196]

[0197] 17.8 g (55.5 mmol) of compound IV-179, 20 g of dichloromethane, and 5.3 g (66.6 mmol) of pyridine were added to a reaction flask. The temperature was maintained at 0–5 °C in an ice bath. 7.5 g (69.3 mmol) of ethyl chloroformate was dissolved in 20 g of dichloromethane, and this solution was added dropwise to the reaction flask. After the addition was complete, the mixture was brought to room temperature and reacted for 2 h. A sample was taken, and the starting material IV-179 disappeared. 50 g of water was added to quench the reaction, and the organic phase was separated and evaporated to dryness to obtain 20 g of compound V-443, with a yield of 92.6% and a normalized purity of 91.7% according to liquid chromatography. It is a pale yellow oily substance. 1 H NMR (400MHz, DMSO-d6) δ9.69(s,1H),8.22(d,J=8.3Hz,1H),7.64(d,J=10.5Hz,1H),4.24–4.19(m ,2H),4.15(q,J=7.1Hz,2H),3.53–3.49(m,2H),3.21(s,3H),1.62(s,6H),1.24(t,J=7.1Hz,3H).

[0198] Example 6: Synthesis of intermediate 2-methoxyethyl-2-[2-chloro-5-(2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)-4-fluorobenzoyloxy]-2-methylpropionate

[0199]

[0200] 50 g (127.62 mmol) of compound V-179, 28.04 g (153.14 mmol) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate, 21.16 g (153.14 mmol) of potassium carbonate, and 250 g of N,N-dimethylformamide were added to a reaction flask. The mixture was heated to 100 °C and reacted for 4 h. After 4 h, the starting material V-179 disappeared. The reaction solution was poured into 50 g of water, and 200 g of ethyl acetate was added for extraction. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with saturated brine, and the organic phase was evaporated to dryness. The crude product was slurried with 50 g of solvent at room temperature (petroleum ether:ethyl acetate = 3:1) for 1 h, and then filtered. The filter cake was dried to give 51.6 g of the title compound VI-179, with a yield of 81.39% and a normalized purity of 95.1% according to liquid chromatography. It is a pale yellow solid with a melting point of 142.4 °C–143.3 °C. 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.09(d,J=7.7Hz,1H),7.90(d,J=9.5Hz,1 H),6.43(s,1H),4.24–4.19(m,2H),3.53–3.49(m,2H),3.20(s,3H),1.63(s,6H).

[0201] Example 7: Synthesis of intermediate 2-methoxyethyl-2-[2-chloro-5-(2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)-4-fluorobenzoyloxy]-2-methylpropionate

[0202]

[0203] 50 g (123.21 mmol) of compound V-443, 27.07 g (147.85 mmol) of ethyl 3-amino-4,4,4-trifluoro-2-butenoate, 20.44 g (147.85 mmol) of potassium carbonate, and 250 g of N,N-dimethylformamide were added to a reaction flask and heated to 100 °C. After reacting for 4 h, the starting material V-443 disappeared. The reaction solution was poured into 50 g of water, and 200 g of ethyl acetate was added for extraction. The mixture was allowed to stand and separate into layers. The organic phase was washed twice with saturated brine, and the organic phase was evaporated to dryness. The crude product was slurried with 50 g of solvent at room temperature (petroleum ether:ethyl acetate = 3:1) for 1 h, filtered, and the filter cake was dried to give 51.2 g of the title compound VI-179, with a yield of 83.66% and a normalized purity of 94.7% according to liquid chromatography. It is a pale yellow solid with a melting point of 142.4 °C–143.3 °C. 1 H NMR (400MHz, DMSO-d6) δ12.85(s,1H),8.09(d,J=7.7Hz,1H),7.90(d,J=9.5Hz,1 H),6.43(s,1H),4.24–4.19(m,2H),3.53–3.49(m,2H),3.20(s,3H),1.63(s,6H).

[0204] The herbicidal compound of formula (I) can be prepared by the following reaction using the method of the present invention:

[0205]

[0206] Example 8: Synthesis of 2-methoxyethyl-2-[2-chloro-4-fluoro-5-(3-methyl-2,6-dioxo-4-trifluoromethyl-1,2,3,6-tetrahydropyrimidin-1-yl)benzoyloxy]-2-methylpropionate

[0207]

[0208] 100 g (201.28 mmol) of compound VI-179, 58.42 g (422.7 mmol) of potassium carbonate, and 500 g of N,N-dimethylformamide were added to a reaction flask and stirred at room temperature for 0.5 h. 27.93 g (221.42 mmol) of dimethyl sulfate was slowly added dropwise. After the addition was complete, the reaction continued until the starting material VI-179 disappeared. The reaction solution was poured into 500 g of water and extracted with 1000 g of ethyl acetate. The organic phase was washed twice with saturated brine and evaporated to dryness to give 94.76 g of the title compound I-179, with a yield of 92% and a normalized purity of 93.7% according to liquid chromatography. 1 H NMR(400MHz,DMSO-d6)δ8.07(d,J=7.8Hz,1H),7.92(d,J=9.6Hz,1H),6.63(s,1H),4.25–4 .17(m,2H),3.52–3.49(m,2H),3.42(d,J=1.3Hz,3H),2.51(d,J=1.8Hz,3H),1.63(s,6H).

[0209] Some of the prepared compounds (I) are shown in Table 2.

[0210]

[0211] Table 2 shows the structures of some compounds of general formula (I).

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227] The above description is only a preferred embodiment of the present invention. It should be noted that those skilled in the art can make several changes and improvements without departing from the inventive concept of the present invention, and these all fall within the protection scope of the present invention.

Claims

1. A method for preparing uracil compounds containing carboxylic acid ester fragments under alkaline conditions, wherein the reaction formula is as follows: The compound of formula (V) was reacted with 3-amino-4,4,4-trifluoro-2-butenoic acid R5 ester in an organic solvent at -20°C to the solvent boiling point, and the reaction was carried out in the presence of a base to prepare uracil compound (VI). R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3is selected from C 1~3 alkyl, C 1~3 alkyl, C 1~3 haloalkyl, C 1~3 alkyl, C 2~6 alkyl, C 1~3 alkyl, C 2~6 haloalkyl, C 1~3 alkyl, C 2~6 alkyl, C 1~3 alkyl, C 2~6 haloalkyl, C 1~3 alkyl or C 1~3 alkyl, C n alkyl, C 1~3 alkyl, n represents 0, 1 or 2; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two; in the mixture, the ratio of R to S is 1:99 to 99:1; R4, R5are each selected from C 1~4 alkyl.

2. The method as described in claim 1, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; R3 is selected from C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Halogenated alkoxy-C 1~3 Alkyl, C 2~6 Enoxy-C 1~3 Alkyl, C 2~6 Halo-alkeneoxy-C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl or C 2~6 Halogenated alkyne-C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two; in the mixture, the ratio of R to S is 1:99 to 99:1; R4 and R5 are selected from methyl or ethyl, respectively.

3. The method as described in claim 1, characterized in that: The alkali is selected from sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, n-butyllithium, tert-butyllithium, diisopropylaminolithium (LDA), hexamethyldisilaminolithium (LiHMDS), 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH.

4. The method of claim 1, wherein the method for synthesizing a compound having formula (V) phenylcarbamate is as follows: The compound of formula (IV) is reacted with a substituted formic acid R4-based ester in an organic solvent at a temperature from -20°C to the boiling point of the solvent, and the reaction is carried out in the presence of a base to obtain compound (V); X is selected from fluorine, chlorine, bromine, iodine, methyl sulfonate group, trifluoromethyl sulfonate group, benzene sulfonate group or p-methylbenzene sulfonate group. R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3 is selected from C 1~3 Alkoxy C 1~3 Alkyl, C 1~3 Halogenated alkoxy C 1~3 Alkyl, C 2~6 Enoxy C 1~3 Alkyl, C 2~6 Haloene Oxide C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl, C 2~6 Halogenated alkyne oxygen C 1~3 Alkyl or C 1~3 Alkane S(O) n C 1~3 Alkyl group, where n represents 0, 1, or 2; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two; R4 is selected from C 1~4 alkyl.

5. The method as described in claim 4, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3 is selected from C 1~3 Alkoxy C 1~3 Alkyl, C 1~3 Halogenated alkoxy C 1~3 Alkyl, C 2~6 Enoxy C 1~3 Alkyl, C 2~6 Haloene Oxide C 1~3 Alkyl, C 2~6 acetylacetonate C 1~3 Alkyl or C 2~6 Halogenated alkyne oxygen C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1; R4 is selected from C 1~4 alkyl; X is selected from fluorine, chlorine, bromine, or iodine.

6. The method as described in claim 5, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; R3 is selected from C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Halogenated alkoxy-C 1~3 Alkyl, C 2~6 Enoxy-C 1~3 Alkyl, C 2~6 Halo-alkeneoxy-C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl or C 2~6 Halogenated alkyne-C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1; R4 is selected from methyl or ethyl; X is selected from chlorine.

7. The method as described in claim 4, characterized in that: The base is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH.

8. The method of claim 4, a method for synthesizing aniline compounds having a carboxylic acid ester segment of formula (IV), wherein the reaction formula is as follows: Compound (III) is reacted with a reducing agent in water or an organic solvent at a temperature from -20°C to the boiling point of the solvent to prepare compound (IV); R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3 is selected from C 1~3 Alkoxy C 1~3 Alkyl, C 1~3 Halogenated alkoxy C 1~3 Alkyl, C 2~6 Enoxy C 1~3 Alkyl, C 2~6 Haloene Oxide C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl, C 2~6 Halogenated alkyne oxygen C 1~3 Alkyl or C 1~3 Alkane S(O) n C 1~3 Alkyl group, where n represents 0, 1, or 2; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them is selected from R-type or S-type, or a mixture of the two.

9. The method as described in claim 8, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3 is selected from C 1~3 Alkoxy C 1~3 Alkyl, C 1~3 Halogenated alkoxy C 1~3 Alkyl, C 2~6 Enoxy C 1~3 Alkyl, C 2~6 Haloene Oxide C 1~3 Alkyl, C 2~6 acetylacetonate C 1~3 Alkyl or C 2~6 Halogenated alkyne oxygen C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them is selected from R-type or S-type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:

1.

10. The method as described in claim 8, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; R3 is selected from C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Halogenated alkoxy-C 1~3 Alkyl, C 2~6 Enoxy-C 1~3 Alkyl, C 2~6 Halo-alkeneoxy-C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl or C 2~6 Halogenated alkyne-C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them is selected from R-type or S-type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:

1.

11. The method as described in claim 8, characterized in that: The reducing agent is selected from hydrogen, metal hydrides, semi-metal hydrides and their derivatives, reduced iron powder or reduced zinc powder.

12. The method of claim 8, wherein the method for synthesizing a nitrobenzene compound having formula (III) comprises the following reaction: Compound (II) is reacted with a substituted acetate in an organic solvent in the presence of a base at a temperature from -20°C to the boiling point of the solvent to prepare compound (III); where L is a leaving group selected from chlorine, bromine, iodine, methyl sulfonate, trifluoromethyl sulfonate, benzene sulfonate or p-methylbenzene sulfonate. R1 and R2 are selected from hydrogen or methyl, respectively; or R1 and R2 together with the carbon atom they are attached to form a three-membered ring; R3 is selected from C 1~3 Alkoxy C 1~3 Alkyl, C 1~3 Halogenated alkoxy C 1~3 Alkyl, C 2~6 Enoxy C 1~3 Alkyl, C 2~6 Haloene Oxide C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl, C 2~6 Halogenated alkyne oxygen C 1~3 Alkyl or C 1~3 Alkane S(O) n C 1~3 Alkyl group, where n represents 0, 1, or 2; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to them is selected from R-type or S-type, or a mixture of the two.

13. The method as described in claim 12, characterized in that: R1 and R2 are selected from hydrogen or methyl, respectively; R3 is selected from C 1~3 Alkoxy-C 1~3 Alkyl, C 1~3 Halogenated alkoxy-C 1~3 Alkyl, C 2~6 Enoxy-C 1~3 Alkyl, C 2~6 Halo-alkeneoxy-C 1~3 Alkyl, C 2~6 Alkyne-O-C 1~3 Alkyl or C 2~6 Halogenated alkyne-C 1~3 alkyl; When R1 is selected from hydrogen and R2 is selected from methyl, the carbon atom attached to it is selected from R-type or S-type, or a mixture of the two, in which the ratio of R to S is 1:99 to 99:1; L is selected from chlorine, bromine, iodine, methyl sulfonate group, trifluoromethyl sulfonate group, benzene sulfonate group or p-methylbenzene sulfonate group.

14. The method as described in claim 12, characterized in that: The base is selected from 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, pyridine, 2-methylpyridine, 1,8-diazabicycloundec-7-ene (DBU) or 2,6-rutidine, or NaH, NaNH2, NaHCO3, Na2CO3, K2CO3, KHCO3, Cs2CO3, NaOH, LiOH or KOH.

15. The method as described in any one of claims 1, 4, 8 or 12, characterized in that: The organic solvent is selected from one or more of alcohols, alkanes, chloroalkanes, ethers, esters, aromatics, halogenated aromatics, ketones, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide.

16. The method as described in claim 15, characterized in that: The organic solvent is selected from one or more of methanol, ethanol, isopropanol, butanol, tert-butanol, cyclohexanol, ethylene glycol, pentane, n-hexane, cyclohexane, heptane, octane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, petroleum ether, diethyl ether, methyl tert-butyl ether, ethylene glycol dimethyl ether, tetrahydrofuran, 1,4-dioxane, ethyl acetate, butyl acetate, benzene, toluene, o-xylene, m-xylene, p-xylene, chlorobenzene, acetone, butanone, 4-methyl-2-pentanone, cyclohexanone, N-methylpyrrolidone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethyl sulfoxide.

Images