Preparation method of benzoxazole intermediate

Abstract

The invention belongs to the field of chemical synthesis of pesticides, and discloses a preparation method of a benzoxazole intermediate, which comprises the following steps: (1) carrying out substitution reaction on a compound with a structure as shown in a formula III to obtain a compound with a structure as shown in a formula IV; (2) carrying out oxidation reaction on the compound with the structure as shown in the formula IV prepared in the step (1) to obtain a benzoxazole intermediate with a structure as shown in a formula V; # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of pesticide chemical synthesis, and particularly relates to a preparation method of a benzoxazole intermediate. Background Art

[0002] Oxazosulfyl (trade name: ALLESTM, structural formula shown below) is the first new type of benzoxazole insecticide containing an ethylsulfonylpyridine structural fragment, which has been newly researched and developed by Sumitomo Chemical Co., Ltd. of Japan. This variety is mainly used for controlling rice pests and diseases, and the estimated commercial value of this project is relatively high.

[0003]

[0004] The amide cyclization method and the aldehyde-amine condensation method are two effective methods for preparing Oxazosulfyl. Among them, although the amide cyclization method has more synthesis steps, the reaction yield is relatively high, the catalyst used in the cyclization process such as p-toluenesulfonic acid is easy to obtain, and the whole reaction process is also easy to operate; while the aldehyde-amine condensation method obviously has the advantage of short synthesis steps, but the raw material 3-chloropyridine-2-carboxaldehyde is expensive and difficult to obtain, and a prepared iron-activated carbon catalyst needs to be used in the cyclization process.

[0005] 3-Ethylsulfonylpyridine-2-carboxylic acid is the key intermediate for synthesizing Oxazosulfyl.

[0006] Currently, the processes for synthesizing the intermediate mainly include the following two processes:

[0007] (1) WO2015199006A1 is obtained by acylating, thiolating, oxidizing, and reducing 3,6-dichloropyridine-2-carboxylic acid; this route requires an excessive amount of ethanethiol and is completely oxidized during the oxidation process, resulting in a large amount of sulfur waste and expensive raw materials;

[0008]

[0009] 2) EP3453706A1 uses 2-cyano-3-chloropyridine as the raw material, and is obtained through sulfidation, oxidation, and hydrolysis. The raw materials of this route are not easy to obtain, and the oxidation reagent m-CPBA is expensive, making it difficult to achieve industrial production.

[0010]

[0011] Regarding the current synthesis reports of 2-chloro-3-ethylsulfonylpyridine, in US20050277643A1, 3-amino-2-chloropyridine is used as the raw material, reacted with sodium ethanethiolate through diazotization, and then oxidized with m-CPBA to obtain 2-chloro-3-ethylsulfonylpyridine; in the diazotization, it is in the form of forming fluoroborate, which has high corrosion to equipment and a large risk factor, and the oxidation reagent m-CPBA is expensive.

[0012] In summary, when preparing intermediates, the existing methods have disadvantages such as high cost and unsuitability for industrial production. SUMMARY OF THE INVENTION

[0013] To solve the above problems, the present application invents a preparation method for a novel benzoxazole insecticide Oxazosulfyl intermediate, which solves the problems existing in the above process, reduces the raw material cost, simplifies the process route, reduces the three wastes, improves the reaction yield, and realizes green industrial production.

[0014] The first aspect of the present invention provides a preparation method for a benzoxazole intermediate, characterized in that the preparation method comprises the following steps:

[0015] (1) The compound with the structure shown in Formula III undergoes a substitution reaction to obtain a compound with the structure shown in Formula IV;

[0016] (2) The compound with the structure shown in Formula IV prepared in step (1) undergoes an oxidation reaction to obtain a compound with the structure shown in Formula V;

[0017]

[0018] The method provided by the present invention has a simple process and less three wastes. It can use 3-amino-2-halopyridine as a raw material and obtain a benzoxazole intermediate through a series of reactions. The raw materials involved in this route have low cost and high reaction yield, which is conducive to improving market competitiveness. DETAILED DESCRIPTION OF THE INVENTION

[0019] In the ranges disclosed herein, the endpoints and any values are not limited to the exact ranges or values. These ranges or values should be understood to include values close to these ranges or values. For numerical ranges, between the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values, they can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0020] The following provides a detailed description of the specific embodiments of the present invention. It should be understood that the specific embodiments described herein are only for explaining and illustrating the present invention, and are not used to limit the present invention.

[0021] The first aspect of the present invention provides a preparation method for a benzoxazole intermediate, the preparation method comprising the following steps:

[0022] (1) The compound with the structure shown in Formula III undergoes a substitution reaction to obtain a compound with the structure shown in Formula IV;

[0023] (2) The compound having the structure shown in Formula IV prepared in step (1) undergoes an oxidation reaction to obtain a compound having the structure shown in Formula V;

[0024]

[0025] X is a halogen atom; preferably, X is selected from a bromine atom;

[0026] R is -OR a or R b , wherein, R a and R b each independently is selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, and a substituted aryl group; preferably, R a and R b each independently is selected from a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, and a phenyl group;

[0027] R1 is selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, and a substituted aryl group; preferably, R1 is selected from a hydrogen atom, an alkyl group having 1 to 3 carbon atoms, and a phenyl group;

[0028] R2 and R3 each independently are selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, -NO2, -COOR c , -CN, -CONH2, -COCR d and a pyridyl group, and R2 and R3 are not simultaneously selected from an alkyl group, a nitro group, a halogen, a pyridyl group, or a hydrogen atom;

[0029] R c and R d each independently is selected from a hydrogen atom or a C1-C6 alkyl group; preferably, R c and R d each independently is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms.

[0030] The alkyl group having 1 to 6 carbon atoms may be selected from a straight-chain alkyl group or a branched-chain alkyl group having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, n-propyl, 1-methylethyl, 1-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 2-methylbutyl, 3-methylbutyl, 4-methylbutyl, 1-ethylpropyl, 2,2-dimethylpropyl, 1,3-dimethylpropyl, 3,3-dimethylpropyl, n-hexyl, 1-methylpentane, 2-methylpentane, 3-methylpentane, 4-methylpentane, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, preferably methyl, ethyl, propyl.

[0031] The aryl or substituted aryl is selected from any organic compound group including an aromatic ring, including but not limited to phenyl, benzyl, 1-naphthyl, 2-naphthyl, 3-naphthyl, chlorophenyl, dichlorophenyl, trichlorophenyl, nitrophenyl, dinitrophenyl, and preferably phenyl.

[0032] According to the present invention, the substitution reaction in step (1) includes the following steps:

[0033] (1-1) Mix the compound shown in Formula III, an organic solvent, and an acid-binding agent to obtain a mixed solution k;

[0034] (1-2) Add a cyanating reagent to the mixed solution k to obtain a mixed solution l containing the compound shown in Formula IV, wherein the cyanating reagent is selected from at least one of methyl cyanoacetate, ethyl methyl cyanoacetate, methyl nitroacetate, ethyl methyl nitroacetate, nitroethane, 2-cyanopropionic acid, methyl / ethyl 2-cyanopropionate, dimethyl methylmalonate, methyl / ethyl lactate, pyridinium chloroacetate salt, 2-halopropionic acid, and methyl 2-halopropionate, and preferably methyl nitroacetate.

[0035] According to a preferred embodiment of the present invention, the oxidation reaction in step (2) includes the following steps:

[0036] In the presence of a catalyst, add an oxidizing agent to the mixture l containing the compound shown in Formula IV to obtain the compound shown in Formula V.

[0037] According to a preferred embodiment of the present invention, the acid-binding agent is selected from at least one of organic bases, inorganic bases, and basic inorganic salts.

[0038] More preferably, the inorganic base is at least one of hydroxides of alkali metals or alkaline earth metals; the basic inorganic salt is selected from at least one of carbonates of alkali metals and / or alkaline earth metals and bicarbonates of alkali metals and / or alkaline earth metals.

[0039] More preferably, the hydroxides of alkali metals and / or alkaline earth metals are selected from at least one of potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, and magnesium hydroxide; the carbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, and magnesium carbonate; the bicarbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium bicarbonate, sodium bicarbonate, barium bicarbonate, calcium bicarbonate, and magnesium bicarbonate.

[0040] More preferably, the inorganic base is sodium hydroxide and / or potassium hydroxide; the basic inorganic salt is selected from potassium carbonate or / and sodium carbonate.

[0041] Preferably, the organic base is selected from at least one of triethylamine, pyridine and DBU.

[0042] More preferably, the organic base is selected from triethylamine.

[0043] According to the present invention, the molar ratio of the compound shown in Formula III to the acid-binding agent is preferably 1:(1 - 1.5).

[0044] According to a preferred embodiment of the present invention, the reaction temperature of the substitution reaction in step (1) is 50 - 120°C, preferably 75 - 105°C; the reaction time is 1 - 8 h, preferably 3 - 4 h.

[0045] According to the present invention, the oxidation reaction in step (2) is carried out in the presence of an oxidizing agent, and the oxidizing agent is preferably selected from at least one of air, oxygen, ozone, chlorine, liquid bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sodium p-toluenesulfonchloramide, thionyl chloride, sulfuryl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, iodobenzene diacetate, performic acid, peracetic acid, perchlorodiacetic acid, perfluorodiacetic acid, perfluorotriacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfate, nitrous acid, nitrogen dioxide, sodium nitrite, nitric acid, sodium nitrate, ammonium cerium nitrate, substituted and unsubstituted nitrobenzene, m-chlorobenzoic acid.

[0046] More preferably, the oxidizing agent is hydrogen peroxide or air.

[0047] Preferably, the oxidation reaction is carried out in the presence of a metal catalyst, wherein the metal catalyst is selected from at least one of metal elements and metal salts.

[0048] More preferably, the metal element is selected from at least one of copper, nickel, iron, cobalt, vanadium, chromium, manganese, tungsten, osmium, molybdenum, ruthenium, palladium, platinum, silver, gold, cerium.

[0049] More preferably, the metal salt is selected from at least one of anionic metal salts and metal oxoacids;

[0050] More preferably, the anion in the anionic metal salt is selected from at least one of fluoride ion, chloride ion, bromide ion, iodide ion, sulfide ion, sulfate radical, nitrate radical, molybdate radical, acetate radical, phosphate radical, hydroxide radical.

[0051] More preferably, the metal salt is selected from copper acetate.

[0052] More preferably, the metal oxoacid is selected from (NH4)3[FeMo6O24 H6]·7H2O, (TBA)3FeMo6O 18 Any one of (OH)6, wherein TBA is tetrabutylammonium ion.

[0053] According to the present invention, for the compound shown in Formula IV: the molar ratio of oxidant: catalyst is preferably 1:(1 - 1.5):(0.001 - 0.1).

[0054] According to a preferred embodiment of the present invention, the reaction temperature of the oxidation reaction in step (2) is 10 - 100 °C, preferably 40 - 80 °C; the reaction time is 3 - 12 h, preferably 6 - 8 h.

[0055] The present invention also provides a preparation method of the compound shown in Formula III, and the preparation method includes the following steps:

[0056] (i) The compound shown in Formula I undergoes a diazotization reaction to obtain the compound shown in Formula II;

[0057] (ii) The compound shown in Formula II obtained in step (i) undergoes an oxidation reaction to obtain the compound shown in Formula III;

[0058]

[0059] According to a preferred embodiment of the present invention, the diazotization reaction method in step (i) includes the following steps:

[0060] (a) The compound shown in Formula I undergoes a diazotization reaction with a diazotizing reagent under the action of an inorganic acid to obtain a mixed solution m containing diazonium salt;

[0061] (b) A sulfur coupling reagent, a catalyst, and an organic solvent are mixed to obtain a mixed solution n;

[0062] (c) The mixed solution n is added to the mixed solution m to obtain a mixed solution p;

[0063] (d) In the presence of a deacidifying agent, a halogenated hydrocarbon is added to the mixed solution p and mixed to obtain the compound shown in Formula II.

[0064] Preferably, the inorganic acid is selected from one of hydrochloric acid, phosphoric acid, and sulfuric acid, and more preferably hydrochloric acid.

[0065] Preferably, the diazotizing reagent is selected from sodium nitrite.

[0066] Preferably, the catalyst is selected from copper powder and / or inorganic copper salts; the copper salts are selected from at least one of copper chloride, copper sulfate, and copper nitrate; the catalyst is preferably copper powder.

[0067] Preferably, the sulfur-containing coupling reagent is selected from any one of sodium thiocyanate, ammonium thiocyanate, potassium thiocyanate, cuprous thiocyanate, copper thiocyanate, ferric thiocyanate, sodium hydrosulfide, sodium sulfide, potassium ethyl xanthate, potassium thiopropionate, sodium thiopropionate, sodium thio pivalate, potassium thio pivalate, sodium 2,2-dimethylthiobutyrate, potassium 2,2-dimethylthiobutyrate, potassium 3,3-dimethylthiobutyrate, and more preferably sodium thiocyanate.

[0068] Preferably, the organic solvent is selected from at least one of acetonitrile, tetrahydrofuran, acetone, methyl isopropyl ketone, ethyl acetate, methyl acetate, dichloromethane, dichloroethane, dioxane, cyclohexane, n-hexane, toluene, and more preferably toluene and / or acetone.

[0069] According to the present invention, for the compound shown in Formula I: the molar ratio of inorganic acid: diazotizing reagent: catalyst: sulfur-containing coupling reagent is preferably 1:(2.5 - 4):(1.01 - 1.1):(0.01 - 0.1):(1.05 - 1.25).

[0070] According to the preferred embodiment of the present invention, the reaction temperature in step (a) is -10°C to 8°C, preferably -2°C to 5°C; the reaction temperature in step (b) is -10°C to 10°C, preferably -5°C to 5°C; the mixture n is added to the mixture m within the range of 0.5 - 3 h; the reaction time in step (d) is 1 - 3 h; the halogenated hydrocarbon is added to the mixture p within the range of 0.5 - 1.5 h.

[0071] According to the preferred embodiment of the present invention, the acid-binding agent in step (d) is selected from inorganic bases; the inorganic bases are selected from at least one of hydroxides of alkali metals and / or alkaline earth metals, carbonates of alkali metals and / or alkaline earth metals, and bicarbonates of alkali metals and / or alkaline earth metals.

[0072] More preferably, the hydroxides of alkali metals and / or alkaline earth metals are selected from at least one of potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, and magnesium hydroxide; the carbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, and magnesium carbonate; the bicarbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium bicarbonate, sodium bicarbonate, barium bicarbonate, calcium bicarbonate, and magnesium bicarbonate.

[0073] More preferably, the acid-binding agent is selected from at least one of potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0074] More preferably, the acid-binding agent is selected from sodium hydroxide and / or potassium hydroxide.

[0075] According to the present invention, for the compound shown in Formula I: the molar ratio of the acid-binding agent in step (d): the halogenated hydrocarbon is preferably 1:(1.0 - 2.5):(1.05 - 1.25); the reaction temperature of step (d) is 0 - 100 °C, preferably 10 - 55 °C; the reaction time of step (d) is 3 - 6 h.

[0076] According to a preferred embodiment of the present invention, the oxidation reaction in step (ii) comprises the following steps:

[0077] In the presence of an organic solvent, an oxidizing agent is added to the compound shown in Formula II. The oxidizing agent is selected from the group consisting of air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sodium p-toluenesulfonchloramide, thionyl chloride, sulfuryl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, urea peroxide, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, iodobenzene diacetate, performic acid, peracetic acid, perchloroacetic acid, perfluorodichloroacetic acid, perfluorotrichloroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfate, nitrous acid, nitrogen dioxide, sodium nitrite, nitric acid, sodium nitrate, ammonium cerium nitrate, substituted and unsubstituted nitrobenzene, m-chlorobenzoic acid; more preferably hydrogen peroxide.

[0078] Preferably, the molar ratio of the compound shown in Formula II: the oxidizing agent is 1:1.0 - 1.5, wherein the molar number of the compound shown in Formula II is calculated based on the molar number of the compound shown in Formula I.

[0079] According to the present invention, the reaction temperature of the oxidation reaction in step (ii) is 0 - 80 °C, preferably 20 - 70 °C; the reaction time is 1 - 10 h, preferably 4 - 7 h.

[0080] According to the present invention, the substitution reaction in step (1), the oxidation reaction in step (2), the diazotization reaction in step (i) and the oxidation reaction in step (ii) are all carried out in an organic solvent, wherein the organic solvents are each independently selected from at least one of methanol, ethanol, acetonitrile, acetone, dichloromethane, dichloroethane, water, tetrahydrofuran, formic acid, acetic acid, dioxane, toluene, xylene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone, preferably toluene and N,N-dimethylformamide.

[0081] The present invention will be described in detail below by way of examples. In the following examples:

[0082] The amounts of reactants and products were measured by liquid chromatography (Agilent HPLC 1260).

[0083] The yield of the reaction was calculated by the following formula:

[0084] Yield = actual mass of the target product represented by Formula V / theoretical mass of the target product calculated based on the compound represented by Formula I × 100%

[0085] Unless otherwise specified, all raw materials used were commercially available Aladdin products.

[0086] Example 1

[0087] In a four-necked reaction bottle equipped with a mechanical stirrer, a thermometer and a condenser, 129.9 g of 3-amino-2-chloropyridine (purchased from Aladdin, 99%) was added, 547.5 g of 20 wt % hydrochloric acid was slowly added, stirred for 2 h, cooled to 0° C., 289.8 g of 25 wt % sodium nitrite solution was added dropwise, and the temperature was controlled at 0° C. and stirred for 2 h;

[0088] In another reaction bottle, add 98.3 g of sodium thiocyanate, 792.3 g of toluene, and 3.2 g of copper powder in sequence, and cool to 0°C;

[0089] The above diazonium salt solution was added dropwise to the toluene system. The temperature during the addition process did not exceed 5°C and the addition was completed within 1 hour. The reaction was kept warm for 2 hours.

[0090] After the reaction, the pH was adjusted to 8, and the mixture was allowed to stand and separate into layers. 40 g of sodium hydroxide was added to the organic phase, and the mixture was kept at 10°C. 79.0 g of liquid ethyl chloride was added dropwise over 1 hour, and the reaction was kept at this temperature for 3 hours.

[0091] After the reaction is completed, the temperature is raised to 50°C, 158.7 g of 30 wt% hydrogen peroxide is slowly added dropwise, and the temperature is kept at 60°C for 5 hours. After the reaction is complete, the mixture is allowed to stand and separate into layers. The solvent is removed to obtain 167.0 g of 2-chloro-3-(ethylsulfonyl)pyridine with a yield of 81.2%.

[0092] Example 2

[0093] The difference from Example 1 is that chloroethane is replaced by chloromethane, and other molar ratios remain unchanged. The reaction yields 139.3 g of 2-chloro-3-(methylsulfonyl)pyridine with a yield of 72.8%.

[0094] Example 3

[0095] The difference from Example 1 is that sodium thiocyanate is replaced by ammonium thiocyanate, and other molar ratios remain unchanged. The reaction yields 124.4 g of 2-chloro-3-(ethylsulfonyl)pyridine with a yield of 60.5%.

[0096] Example 4

[0097] The difference from Example 1 is that copper sulfate is replaced with copper powder, and other molar ratios remain unchanged. Reacting gives 155.1 g of 2-chloro-3-(ethylsulfonyl)pyridine with a yield of 75.4%.

[0098] Example 5

[0099] The difference from Example 1 is that 3-amino-2-bromopyridine is replaced with 3-amino-2-chloropyridine, and other molar ratios remain unchanged. Reacting gives 200.3 g of 2-bromo-3-(ethylsulfonyl)pyridine with a yield of 80.1%.

[0100] Example 6

[0101] In a four-necked flask equipped with a mechanical stirrer, a thermometer, and a condenser, 205.7 g (1.0 mol) of the compound 2-chloro-3-(ethylsulfonyl)pyridine, 600 g of DMF, and 207.3 g of potassium carbonate were successively added. The temperature was maintained at 100 °C, and 148.5 g of methyl cyanoacetate was added dropwise. The mixture was stirred and reacted for 3 h, and HPLC was used to detect that the raw materials were completely consumed.

[0102] The temperature was lowered to 60 °C, copper acetate was added, and air was slowly introduced. The mixture was stirred and reacted at about 60 °C for 8 h. After the raw materials were completely consumed, the pH was adjusted with acidified water, and extraction and desolvation were carried out to obtain 191.5 g of 3-ethylsulfonylpyridine-2-carboxylic acid with a yield of 89.0%.

[0103] Example 7

[0104] The difference from Example 6 is that 2-bromo-3-(ethylsulfonyl)pyridine is replaced with 2-chloro-3-(ethylsulfonyl)pyridine, and other molar ratios remain unchanged. Reacting gives 179.1 g of 3-ethylsulfonylpyridine-2-carboxylic acid with a yield of 83.2%.

[0105] Example 8

[0106] The difference from Example 6 is that hydrogen peroxide is replaced with air, and other molar ratios remain unchanged. Reacting gives 189.8 g of 3-ethylsulfonylpyridine-2-carboxylic acid with a yield of 88.2%.

[0107] Example 9

[0108] The difference from Example 6 is that 1-(2-ethoxy-2-oxoethyl)pyridinium bromide is replaced with methyl cyanoacetate, and other molar ratios remain unchanged. Reacting gives 150.9 g of 3-ethylsulfonylpyridine-2-carboxylic acid with a yield of 70.1%.

[0109] Example 10

[0110] The difference from Example 6 is that methyl nitroacetate is replaced with methyl cyanoacetate, and other molar ratios remain unchanged. Reacting gives 194.1 g of 3-ethylsulfonylpyridine-2-carboxylic acid with a yield of 90.2%.

[0111] Example 11

[0112] The difference from Example 6 is that nitroethane replaces methyl cyanoacetate, and other molar ratios remain unchanged. Reacting gives 188.1 g of 2-acetyl-3-ethylsulfonylpyridine with a yield of 88.3%.

[0113] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and fall within the protection scope of the present invention.

Claims

1. A method for preparing a benzoxazole intermediate, characterized in that, The preparation method comprises the following steps: (1) The compound with the structure shown in Formula III undergoes a substitution reaction to obtain a compound with the structure shown in Formula IV; (2) The compound with the structure shown in Formula IV prepared in step (1) undergoes an oxidation reaction to obtain a benzoxazole intermediate with the structure shown in Formula V; X is a halogen atom; R is -OR a or R b , wherein, R a and R b are each independently selected from a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an aryl group, and a substituted aryl group; R1 is selected from one of a hydrogen atom, an alkyl group with 1-6 carbon atoms, an aryl group, and a substituted aryl group; R2 and R3 are each independently selected from a hydrogen atom, a halogen atom, an alkyl group having 1 to 6 carbon atoms, -NO2, -COOR c , -CN, -CONH2, -COCR d and any one of pyridyl groups, and R2 and R3 are not simultaneously selected from an alkyl group, a nitro group, a halogen, a pyridyl group or a hydrogen atom; R c and R d are each independently selected from a hydrogen atom or an alkyl group having 1 to 6 carbon atoms.

2. The preparation method according to claim 1, wherein, The substitution reaction described in step (1) comprises the following steps: (1-1) Mix the compound shown in Formula III, an organic solvent, and an acid-binding agent to obtain a mixed solution k; (1-2) Add a cyanating reagent to the mixed solution k to obtain a mixed solution l containing the compound shown in Formula IV, wherein the cyanating reagent is selected from any one of methyl cyanoacetate, ethyl cyanoacetate, methyl nitroacetate, methyl nitroacetate, ethyl nitroacetate, nitroethane, 2-cyanopropionic acid, methyl 2-cyanopropionate, ethyl 2-cyanopropionate, dimethyl methylmalonate, methyl / ethyl lactate, pyridinium chloroacetate salt, 2-halopropionic acid, and methyl 2-halopropionate.

3. The preparation method according to claim 1 or 2, wherein The oxidation reaction in step (2) comprises the following steps: In the presence of a catalyst, add an oxidizing agent to the mixture l containing the compound shown in Formula IV to obtain the compound shown in Formula V.

4. The preparation method according to claim 2 or 3, wherein, The acid-binding agent is selected from at least one of an organic base, an inorganic base, and a basic inorganic salt; Preferably, the inorganic base is at least one of hydroxides of alkali metals or alkaline earth metals; the basic inorganic salt is selected from at least one of carbonates of alkali metals and / or alkaline earth metals and bicarbonates of alkali metals and / or alkaline earth metals; Preferably, the hydroxides of alkali metals and / or alkaline earth metals are selected from at least one of potassium hydroxide, sodium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide, and magnesium hydroxide; the carbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium carbonate, sodium carbonate, lithium carbonate, barium carbonate, calcium carbonate, and magnesium carbonate; the bicarbonates of alkali metals and / or alkaline earth metals are selected from at least one of potassium bicarbonate, sodium bicarbonate, barium bicarbonate, calcium bicarbonate, and magnesium bicarbonate; Preferably, the inorganic base is sodium hydroxide and / or potassium hydroxide; the basic inorganic salt is selected from potassium carbonate or / and sodium carbonate; Preferably, the organic base is selected from at least one of triethylamine, pyridine, and DBU; Preferably, the organic base is triethylamine.

5. The preparation method according to any one of claims 2-4, wherein, The molar ratio of the compound shown in Formula III to the acid-binding agent is 1:(1-1.5).

6. The preparation method according to any one of claims 1-5, wherein, The reaction temperature of the substitution reaction described in step (1) is 50-120 °C, preferably 75-105 °C; the reaction time is 1-8 h, preferably 3-4 h.

7. The preparation method according to any one of claims 1-6, wherein, The oxidation reaction in step (2) is carried out in the presence of an oxidant, wherein the oxidant is selected from at least one of air, oxygen, ozone, chlorine, liquid bromine, elemental iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sodium p-toluenesulfonyl chloride, sulfuryl chloride, thionyl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, iodobenzene diacetate, peroxyformic acid, peracetic acid, peroxydichloroacetic acid, peroxydifluoroacetic acid, peroxytrifluoroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfonate, nitrous acid, nitrogen dioxide, sodium nitrite, nitric acid, sodium nitrate, cerium ammonium nitrate, substituted and unsubstituted nitrobenzene, and meta-chlorobenzoic acid; Preferably, the oxidant is hydrogen peroxide or air; More preferably, the oxidant is air; Preferably, the oxidation reaction is carried out in the presence of a metal catalyst, wherein the metal catalyst is selected from at least one of a metal element and a metal salt; Preferably, the metal element is selected from at least one of copper, nickel, iron, cobalt, vanadium, chromium, manganese, tungsten, osmium, molybdenum, ruthenium, palladium, platinum, silver, gold, and cerium; Preferably, the metal salt is selected from at least one of anionic metal salts and metal oxo salts; Preferably, the anion in the anionic metal salt is selected from at least one of fluoride, chloride, bromide, iodide, sulfide, sulfate, nitrate, molybdate, acetate, phosphate and hydroxide; More preferably, the metal salt is selected from copper acetate; Preferably, the metal oxysalt is selected from (NH4)3[FeMo6O 24 H6]·7H2O and / or (TBA)3FeMo6O 18 (OH)6, where TBA is tetrabutylammonium ion.

8. The preparation method according to any one of claims 1-7, wherein, The molar ratio of the compound represented by formula IV: the oxidant: the catalyst is 1: (1-1.5): (0.001-0.1), wherein the molar amount of the compound represented by formula IV is calculated based on the molar amount of the compound represented by formula III.

9. The preparation method according to any one of claims 1-8, wherein, The reaction temperature of the oxidation reaction in step (2) is 10-100° C., preferably 40-80° C.; the reaction time is 3-12 h, preferably 6-8 h.

10. The preparation method according to any one of claims 1-9, wherein, The preparation method also includes the following steps: (i) subjecting the compound of formula I to diazotization to obtain the compound of formula II; (ii) the compound of formula II obtained in step (i) is subjected to oxidation reaction to obtain a compound of formula III; Preferably, the diazotization reaction method in step (i) comprises the following steps: (a) the compound as shown in formula I undergoes a reverse diazotization reaction with a diazotizing agent under the action of an inorganic acid to obtain a mixed solution m containing a diazonium salt; (b) mixing a sulfur coupling reagent, a catalyst and an organic solvent to obtain a mixed solution n; (c) adding the mixed solution n to the mixed solution m to obtain a mixed solution p; (d) adding a halogenated hydrocarbon to the mixed solution p in the presence of an acid binding agent to obtain a compound as shown in Formula II; Preferably, the catalyst is selected from copper powder and / or inorganic copper salt; the copper salt is selected from at least one of copper chloride, copper sulfate and copper nitrate; the catalyst is preferably copper powder; Preferably, the sulfur coupling reagent is selected from any one of sodium thiocyanate, ammonium thiocyanate, potassium thiocyanate, cuprous thiocyanate, copper thiocyanate, ferric thiocyanate, sodium hydrosulfide, sodium sulfide, potassium ethyl xanthate, potassium thiopropionate, sodium thiopropionate, sodium thiopivalate, potassium thiopivalate, sodium 2,2-dimethylthiobutyrate, potassium 2,2-dimethylthiobutyrate, potassium 3,3-dimethylthiobutyrate, and preferably sodium thiocyanate; Preferably, the organic solvent is selected from at least one of acetonitrile, tetrahydrofuran, acetone, methyl isopropyl ketone, ethyl acetate, methyl acetate, dichloromethane, dichloroethane, dioxane, cyclohexane, n-hexane, toluene, and preferably toluene and / or acetone; Preferably, the halogenated hydrocarbon is selected from at least one of chloromethane, chloroethane, and chloropropane, and preferably chloroethane; Preferably, the oxidant in the step (ii) is selected from air, oxygen, ozone, chlorine, bromine, iodine, NCS, NBS, dichlorohydantoin, sodium trichloroisocyanurate, sodium tosylchloramide, thionyl chloride, sulfuryl chloride, KMnO4, MnO2, Cr2O3, K2Cr2O7, ferric chloride, sodium tungstate, ferric nitrate, H2O2, hypochlorous acid, sodium hypochlorite, sodium chlorite, sodium chlorate, hypobromous acid, sodium hypobromite, bromic acid, sodium bromate, iodobenzene diacetate, performic acid, peracetic acid, perchloroacetic acid, perfluorodichloroacetic acid, perfluorotrichloroacetic acid, sodium percarbonate, sulfur trioxide, sulfuric acid, sodium persulfate, potassium persulfate, ammonium persulfate, potassium peroxymonosulfate, nitrous acid, nitrogen dioxide, sodium nitrite, nitric acid, sodium nitrate, ammonium cerium nitrate, substituted and unsubstituted nitrobenzene, m-chlorobenzoic acid, and preferably hydrogen peroxide.

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