Topramezone intermediate and preparation method thereof

Abstract

The invention discloses a novel 3-formyl-2-methyl-4-(methylthio) benzoate compound as shown in a general formula VI, wherein R is an ester group, carboxylic acid, amide or cyano group. The invention also provides a synthesis method of the intermediate shown in the formula VI and application of the intermediate in preparation of topramezone. The reaction selectivity for preparing topramezone by using the formula VI is higher, and the whole process route is more suitable for realizing industrial production;

Description

[0001] This application is a divisional application of the invention patent application filed on April 14, 2022, with application number 202210390195.X and invention title "Benzoxam intermediate and preparation method thereof". Technical Field

[0002] This invention relates to an intermediate of benzoxazine, its preparation method and uses, and particularly to a class of 3-formyl-2-methyl-4-(methylthio)benzoate compounds, their preparation methods and uses. Background Technology

[0003] Toramezone, a benzyl ester pyrazolone herbicide pioneered by BASF, belongs to the class of p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitors. Its common English name is toramezone, and its Chinese name is Benzyl ester pyrazolone or Benzyl ester pyrazolone. It is marketed under the brand names CampusR or "Baowei". Toramezone effectively controls annual grasses and broadleaf weeds in cornfields, is safe for corn, and its application has gradually expanded to crops such as rice and sugarcane. It can also be safely used in combination with other pesticides. In 2018, the global toramezone market size was approximately US$109 million, with a total application volume of approximately 269.35 tons of technical grade herbicide. Cornfields accounted for 65.55% of the market, while other crops accounted for approximately 34.45%. While toramezone boasts excellent efficacy and a broad market prospect, its highly complex synthesis process results in a high price, thus limiting its widespread use.

[0004] The reported preparation processes for benzoxazine mainly include the following two:

[0005] Route 1:

[0006]

[0007] The preparation of compound (8) in this route is as follows (see patent: CN 103788083 A): it requires the nitrite ester to be converted into an oxime through an ultra-low temperature reaction, and there is a selectivity problem for the two methyl groups on the benzene ring. In addition, the synthesis of benzoxazine from this intermediate also uses highly toxic carbon monoxide and expensive palladium catalyst, resulting in high costs.

[0008]

[0009] Route 2:

[0010]

[0011] The intermediate compound (7) in this route has been reported to have the following preparation method:

[0012] 1) See patent: US6100421

[0013]

[0014] The starting materials required for the preparation of this intermediate are not readily available. Although the strong electron-withdrawing effect of the sulfone group activates the subsequent bromination reaction to some extent, steric hindrance during bromination leads to low yields. Furthermore, in the preparation of benzoxazolone from sulfone aldehydes, the large steric hindrance of the sulfone group results in low yields in the subsequent cyclization reaction with ethylene.

[0015] 2) See patent: CN201410083163

[0016]

[0017] The source of starting materials for this route is difficult, and carbon dioxide is used in the process of converting to carboxyl groups. The reaction of n-butyllithium is carried out at ultra-low temperature conditions of -100 to -60℃, making industrial production difficult.

[0018] 3) See patent: CN 110183392 A

[0019]

[0020] The starting materials in this route are also difficult to obtain. During the reaction of hydroxylamine and nitrile groups, a large number of impurities are inevitably generated due to the fact that hydroxylamine has two reactive functional groups, resulting in a low yield. Furthermore, the need for diazotization to remove ammonia increases the risk of the reaction.

[0021] In summary, existing methods for preparing benzoxazine intermediates suffer from drawbacks such as high waste volume, high cost, and harsh production environment, which are factors contributing to the persistently high cost of benzoxazine preparation. Therefore, developing a process route with milder reaction conditions, environmentally friendly practices, and reduced costs for benzoxazine preparation is of paramount importance. Summary of the Invention

[0022] This invention addresses some of the defects and shortcomings of current commercially available processes for preparing benzoxazine by providing a mild, environmentally friendly, and low-cost process for the preparation of benzoxazine.

[0023] To achieve the above objectives, the present invention adopts the following technical solution: a method for preparing benzoxazine, comprising the following steps:

[0024] Step (I): Compound VI is prepared by reacting with a salt of hydroxylamine under alkaline conditions to form an oxime. The resulting oxime is then cyclized with ethylene to prepare compound VII. The salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate.

[0025] Step (II): Compound VII is oxidized with an oxidizing agent to obtain the corresponding sulfone product, and the sulfone product is then subjected to alkaline hydrolysis to obtain Formula VIII.

[0026] Step (III): Compound VIII reacts with an acylation reagent to obtain an acylated product. The acylated product is then esterified with 1-methyl-5-hydroxypyrazolol. Finally, benzoxazol technical grade is obtained by rearrangement reaction under catalytic conditions.

[0027] The structures of formulas VI, VII, VIII, and benzoxazine are as follows:

[0028] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group.

[0029] Preferably, a compound of formula VI is provided.

[0030] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group.

[0031] Alternatively, a method for preparing formula VI is provided, comprising the following steps: reacting a compound of formula V with sodium methanethiol under alkaline conditions in a polar aprotic solvent via a substitution reaction to obtain formula VI.

[0032]

[0033] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0034] This invention also provides the application of Formula VI in the preparation of benzoxazine.

[0035] Furthermore, the present invention also provides compounds of formulas V, IV and III, respectively.

[0036] in,

[0037] Compound of formula V,

[0038]

[0039] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0040] Compounds of formula IV,

[0041]

[0042] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0043] Compound of Formula III,

[0044] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0045] Furthermore, the present invention also provides methods for preparing compounds of formula III, IV and V and their applications in the preparation of benzoxazine.

[0046] Because the preparation conditions for the intermediates of benzoxazine prepared by this invention are mild, the process is green and environmentally friendly, the raw materials are readily available and relatively inexpensive, the intermediates and preparation methods for benzoxazine provided by this invention, as well as their application in the preparation of benzoxazine, have achieved good results.

[0047] The beneficial effects of this invention are:

[0048] 1. The benzoxazine intermediate prepared by the present invention has higher selectivity in the preparation of benzoxazine, which can avoid the use of highly toxic carbon monoxide and expensive palladium catalysts in the previous process, reduce the cost of benzoxazine preparation, and facilitate the promotion and application of benzoxazine.

[0049] 2. In the process of synthesizing compound VII from compound VI in this invention, the requirement of ultra-low temperature for constructing the isoxazole ring in the prior art is avoided. The reaction conditions for constructing the isoxazole ring in this invention are mild and highly selective.

[0050] 3. The compounds of formula VI, formula V, formula IV, and formula III used in this invention are easy to synthesize, the reaction conditions are mild, and the process is green and environmentally friendly, which makes the synthesis of benzoxazine have a high yield and plays a significant role in reducing the synthesis cost of benzoxazine. Attached Figure Description

[0051] Figure 1 1H NMR spectrum of ethyl 4-chloro-3-formyl-2-methylbenzoate

[0052] Figure 2 1H NMR spectrum of ethyl 3-formyl-2-methyl-4-(methylthio)benzoate

[0053] Figure 3 1H NMR spectrum of 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoic acid Detailed Implementation

[0054] Embodiments of the invention are described in detail below. However, these embodiments are exemplary, and the invention is not limited thereto; rather, the invention is defined by the scope of the claims.

[0055] As used herein, unless otherwise specifically defined, the following terms used in the specification and claims have the following meanings.

[0056] In this invention, the ester group refers to -COOR1; where R1 refers to an alkyl group, or a substituted or substituted aryl or heteroaryl group.

[0057] In this invention, the amide group refers to -CONR2R3; wherein R2 and R3 are the same or different hydrogens, alkyl groups, substituted or substituted aryl or heteroaryl groups;

[0058] In this invention, alkyl or alkane refers to straight-chain or branched alkyl groups, preferably C1-C. 10 Alkyl groups, specifically, for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, and decyl, and more preferably lower alkyl groups containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, or tert-butyl.

[0059] The aryl group in this invention is preferably phenyl or naphthyl.

[0060] Heteroaryl groups: refer to five-membered or six-membered rings containing one or more N, O, or S heteroatoms. Examples include pyrrole, furanyl, thiophene, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyridazinone, indolyl, benzofuranyl, benzoxazolyl, benzothiophene, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzoimidazolyl, benzopyrazolyl, quinoxalinyl, etc.

[0061] “Cyano” refers to -CN.

[0062] HMPA refers to hexamethylphosphoric acid triamine.

[0063] DMSO refers to dimethyl sulfoxide.

[0064] When the group is substituted, the substituent can be alkyl, halogen, -OH, NO2, -CN, or amino.

[0065] Halogens refer to fluorine, chlorine, bromine, and iodine. Halogenated alkanes refer to alkanes in which hydrogen atoms are partially or completely replaced by halogens.

[0066] In general, this invention provides a method for preparing benzoxazine, comprising the following steps:

[0067] Step (1): Compound VI is reacted with a salt of hydroxylamine under alkaline conditions to form an oxime. The resulting oxime is then cyclized with ethylene to prepare compound VII. The salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate.

[0068] Step (II): Compound VII is oxidized with an oxidizing agent to obtain the corresponding sulfone product, which is then subjected to alkaline hydrolysis to obtain Formula VIII;

[0069] Step (III): Compound VIII reacts with an acylation reagent to obtain the corresponding acyl chloride compound. The obtained acyl chloride compound is then esterified with 1-methyl-5-hydroxypyrazolol. The esterification product is then rearranged under catalytic conditions to obtain benzoxazine technical grade.

[0070] The structures of Formulas VI, VII, VIII, and benzoxazine are as follows:

[0071] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group.

[0072] The reaction formula for step (one) is as follows:

[0073]

[0074] Step (I) involves reacting compound VI with a salt of hydroxylamine under alkaline conditions to form an oxime. The salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate. The base is an inorganic base, preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, more preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. The reaction is carried out in an organic solvent, preferably acetonitrile, ethyl acetate, or dichloromethane, preferably acetonitrile. The reaction temperature is preferably room temperature, and the reaction time is 1-10 h, preferably 2-8 h. The process of cyclizing the resulting oxime with ethylene to obtain compound VII further includes the addition of a base and an oxidizing agent. The base is one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, and potassium hydroxide, more preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate. The oxidizing agent is sodium hypochlorite, preferably a sodium hypochlorite solution, most preferably an 8% sodium hypochlorite solution. The further generated oxime product is then cyclized with ethylene to prepare compound VII. The cyclization reaction is carried out in an autoclave, preferably at a pressure of 2-8 MPa. Studies have shown that the reaction temperature during cyclization should not be too high, preferably -10°C to -10°C, more preferably -5°C to -0°C, because excessively high temperatures will cause a small amount of dimethyl sulfide to be oxidized. The molar ratio of the oxidant to the compound shown in formula VI is preferably 1:1.2-2.2, more preferably 1:1.6-2.

[0075] The reaction formula in step (2) is as follows:

[0076] The oxidant in step (ii) is a peroxide, oxygen, or hypochlorite. The preferred peroxide compound is hydrogen peroxide or peroxybenzoic acid, more preferably hydrogen peroxide, and most preferably a 30% hydrogen peroxide solution. The reaction temperature for the oxidation process is 80-120℃, preferably 90-110℃. Studies have shown that oxidation is ineffective at lower reaction temperatures. The alkali used in the further alkaline hydrolysis of the sulfone product is either sodium hydroxide or potassium hydroxide, preferably an aqueous solution of sodium hydroxide and potassium hydroxide. The hydrolysis process is carried out in a solvent selected from toluene, xylene, and nitrobenzene, preferably toluene. Hydrolysis needs to be carried out at a relatively high temperature, preferably 100-120℃. Too low a temperature results in incomplete hydrolysis, while too high a temperature decomposes part of the oxazole ring.

[0077] The reaction formula in step (iii) is as follows:

[0078]

[0079] Step (III) The compound of formula VIII reacts with an acylation reagent to obtain the corresponding acyl chloride compound. The acyl chloride reagent is thionyl chloride, sulfonyl chloride, oxalyl chloride, phosphorus oxychloride, etc., preferably thionyl chloride. The reaction is carried out in a solvent, preferably dichloroethane or ethyl acetate. The reaction temperature is preferably 70-75℃. The reaction time is preferably 1-5h. The molar ratio of compound of formula VIII to acylation reagent is 1:1-1.5, preferably 1:1.05-1.2. When the molar ratio is less than 1:1.05, the reaction is incomplete.

[0080] Furthermore, the obtained acyl chloride compound is reacted with 1-methyl-5-hydroxypyrazolol at low temperature in the presence of an acid-binding agent, wherein the acid-binding agent is one of triethylamine, pyridine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, and potassium carbonate, preferably triethylamine. The reaction temperature is preferably -5 to 25°C, more preferably 0 to 10°C.

[0081] Furthermore, potassium carbonate powder and a catalyst were added to the esterified product solution obtained above, and benzoxazine technical grade was obtained through a rearrangement reaction; the catalyst was 4-dimethylaminopyridine (DMAP) and acetone cyanohydrin.

[0082] The present invention also provides a compound of formula VI,

[0083] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group.

[0084] Compound VI is prepared by the following method, comprising the steps of reacting compound V with sodium methanethiol under alkaline conditions in a polar aprotic solvent to obtain compound VI.

[0085]

[0086] Where R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group; X is Cl or Br.

[0087] In the preparation method of the above-mentioned compound VI, the base is an organic or inorganic base; the inorganic base is preferably one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; the organic base is preferably one or more of sodium methoxide, sodium ethoxide, sodium acetate, and ammonium acetate; more preferably sodium bicarbonate, sodium acetate, and ammonium acetate; the aprotic polar solvent is any one or a combination of hexamethylphosphoric triamine, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and dioxane; preferably any one or a combination of hexamethylphosphoric triamine, dimethyl sulfoxide, and N,N-dimethylformamide; the molar ratio of the compound V, the base, and sodium methanethiol is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3. The reaction temperature is room temperature. The reaction temperature conditions of this invention are mild, and the reaction can be completed well at room temperature.

[0088] This invention also provides the use of a compound of formula VI in the preparation of benzoxazine. The preparation of benzoxazine using the compound of formula VI of this invention is more suitable for industrial production, avoiding the use of toxic gases, expensive catalysts, and harsh reaction conditions in existing technologies.

[0089] The present invention also provides compounds of formula V,

[0090]

[0091] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0092] This invention also provides a compound of formula V above and a method for preparing the same, the reaction formula of which is as follows:

[0093]

[0094] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0095] In the above method for preparing compound V, the oxidant used in the oxidation reaction is one or more of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride, and sulfur trioxide, preferably hydrogen peroxide, thionyl chloride, or sulfur powder. The preferred reaction temperature is in the range of 30℃-50℃; the reaction time is 1-5 h; and the molar ratio of compound IV to oxidant is 1:0.1-5, preferably 1:1-2.

[0096] The present invention also provides the use of compound of formula V in the preparation of benzoxazine.

[0097] This invention provides compounds of formula IV.

[0098]

[0099] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0100] This invention also provides the above-described compound IV and its preparation method, the reaction formula of which is as follows:

[0101] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0102] The hydrolysis reaction described in the above preparation method is carried out under acidic conditions, wherein the acid includes sulfuric acid, phosphoric acid, nitric acid, and hydrochloric acid, preferably hydrochloric acid. The temperature range during the above reaction is 0-30℃, preferably 10-25℃. Under these conditions, the hydrolysis yield is relatively high. Further, an organic solvent is added to the above hydrolysis reaction; the organic solvent is a haloalkane, preferably dichloromethane or dichloroethane. This invention also provides the application of compound of formula IV in the preparation of benzoxazine.

[0103] This invention provides compounds of formula III,

[0104] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0105] The present invention also provides a compound of formula III and a method for preparing the same. The preparation method includes the following steps: preparing compound III by halogenation of compound II.

[0106]

[0107] Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

[0108] The halogenating reagent used in the halogenation reaction is one of phosphorus oxychloride, phosphorus tribromooxychloride, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfonyl chloride, oxalyl chloride, succinate, carbon tetrachloride, NBS, and NCS, preferably sulfonyl chloride, succinate, oxalyl chloride, phosphorus oxychloride, or phosphorus tribromooxychloride; in the preparation method, the molar ratio of the compound of formula (II) to the halogenating reagent is 1:0.1-3, preferably 1:0.3-1.5. The compound of formula II is prepared by reacting the compound of formula (I) with a complex of N,N-dimethylformamide methyl acetal or DMF and dimethyl sulfate.

[0109]

[0110] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group. The reaction temperature is 60-110℃, preferably 80-100℃. Studies have found that N,N-dimethylformamide methyl condensate is more effective than the reaction using DMF and dimethyl sulfate complex; the yield is lower if the reaction temperature is too high, and the reaction is incomplete if the reaction temperature is too low.

[0111] Furthermore, the present invention provides a method for preparing a compound of formula VI.

[0112]

[0113] It includes the following reaction steps: Step (1) Formula I prepares Formula II

[0114]

[0115] Step (2) Formula II prepares Formula III

[0116]

[0117] Step (3) Formula III prepares Formula IV

[0118]

[0119] Step (4) Preparation of Formula IV: Formula V

[0120]

[0121] Step (5) Preparation of Formula V into Formula VI

[0122]

[0123] Wherein R is an ester group, carboxylic acid group, amide group, or cyano group, preferably an ester group, and X is a halogen, preferably Cl or Br. The preparation methods of Formulas II, III, IV, V, and VI are as described above.

[0125] The present invention will be described in detail below through examples. In the following examples, the amounts of reactants and products were determined by liquid chromatography (Agilent HPLC 1260). In the following examples, the conversion and selectivity of the reaction were calculated using the following formulas:

[0126] Conversion rate = (Molar amount of raw material input - Molar amount of raw material remaining in the product) / Molar amount of raw material input × 100% Selectivity = Actual molar amount of target product / Theoretical molar amount of target product × 100%

[0127] Example 1

[0128] Synthesis of ethyl 3-((dimethylamino)methylene)-2-methyl-4-oxocyclohex-1-ene-1-carboxylate

[0129]

[0130] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 19 g of ethyl hagmannate (0.1 mol) and 12 g of N,N-dimethylformamide methyl acetal (0.11 mol) were added. The temperature was then raised to 95 °C and the reaction was continued for 3 hours. After the reaction was completed under controlled conditions, the crude product was obtained with a quantitative yield of 90%. EI-MS (m / e): 237 (M).

[0131] Example 2 used an N,N-dimethylformamide and dimethyl sulfate complex as raw materials, and the remaining reaction conditions were the same as in Example 1. Examples 3 and 4 used different reaction temperatures than Example 1, but the remaining reaction conditions were the same as in Example 1. The reaction results of Examples 1-4 are as follows:

[0132] Table 1. Reaction results of Examples 1-4

[0133]

[0134] Example 5

[0135] Synthesis of ethyl 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylate

[0136]

[0137] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 23.7 g of ethyl 3-((dimethylamino)methylene)-2-methyl-4-oxocyclohexyl-1-ene-1-carboxylate (0.1 mol) and 200 g of dichloromethane (DCM) were added. 14 g of oxaloyl chloride (0.11 mol) was slowly added dropwise below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 0.5 hours until complete, yielding compound ethyl 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylate in a quantitative yield of 89%. EI-MS (m / e); 255 (M)

[0138] Examples 6-9 use phosphorus oxychloride, sulfonyl chloride, solid phosgene, and thionyl chloride instead of oxaloyl chloride in Example 5, respectively. The molar ratios of phosphorus oxychloride, sulfonyl chloride, solid phosgene, thionyl chloride, and oxaloyl chloride are the same or different. Other conditions are the same as in Example 5. The reaction results of Examples 5-9 are as follows:

[0139] Table 2 Experimental Results of Examples 5-9

[0140] Example raw material Moor ratio Conversion rate (%) Yield (%) 5 Oxaloyl chloride 1.1 99 89 6 Phosphorus oxychloride 0.5 99 85 7 sulfonyl chloride 1.1 97 83 8 solid phosgene 0.5 99 86 9 thionyl chloride 1.2 98 75

[0141] Example 10

[0142] Synthesis of ethyl 4-bromo-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylate

[0143]

[0144] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 23.7 g (0.1 mol) of ethyl 3-((dimethylamino)methylene)-2-methyl-4-oxocyclohexyl-1,4-diene-1-carboxylate and 200 g of dichloromethane (DCM) were added. 14 g (0.05 mol) of phosphorus tribromide was slowly added dropwise below 10 °C. After the addition was complete, the reaction was maintained at this temperature for 0.5 hours, with the reaction proceeding under controlled conditions until complete, yielding compound ethyl 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylate in 88% yield. EI-MS (m / e): 299 (M)

[0145] Example 11

[0146] Synthesis of compound ethyl 4-chloro-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylate

[0147]

[0148] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 27 g of compound 4-chloro-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100 g of DCM were added. Then, 10 g (36.5%) of hydrochloric acid and 50 g of water were added. The mixture was stirred at room temperature for 1 hour under controlled conditions until complete. After standing and separating into layers, the organic phase was evaporated to dryness to give compound 4-chloro-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylic acid ethyl ester, with a yield of 99%. CI-MS (m / e): 229 (M+1)

[0149] Example 12

[0150] Synthesis of compound ethyl 4-bromo-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylate

[0151]

[0152] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 30 g of compound 4-bromo-3-((dimethylamino)methylene)-2-methylcyclohexane-1,4-diene-1-carboxylate (0.1 mol) and 100 g of DCM were added, followed by the addition of 10 g of hydrochloric acid and 50 g of water. The mixture was stirred at room temperature for 1 hour to ensure complete reaction. After standing and separating into layers, the organic phase was evaporated to dryness to give compound 4-bromo-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylate in 99% yield. CI-MS (m / e): 273 (M+1).

[0153] Example 13

[0154] Synthesis of compound ethyl 4-chloro-3-formyl-2-methylbenzoate

[0155]

[0156] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 22.8 g of compound ethyl 4-chloro-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylate (0.1 mol) and 200 g of DCM were added. 14.1 g of thionyl chloride (0.12 mol) was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 2 hours. A sample was taken to ensure the reaction was complete, yielding compound ethyl 4-chloro-3-formyl-2-methylbenzoate. 1 ¹H NMR (500 MHz, CDCl₃) δ = 10.61 (s, ¹H), 7.83 (d, J = 8.4, ¹H), 7.36 (d, J = 8.4, ¹H), 4.38 (q, J = 7.1, ²H), 2.70 (s, ³H), 1.40 (t, J = 7.1, ³H), yield 80%. CI-MS (m / e); 227 (M+1)

[0157] In Example 14, the amount of thionyl chloride used differed from that in Example 13, while the other conditions remained the same. In Example 15, sulfur dichloride was used instead of thionyl chloride in Example 13, and the molar ratio was also slightly different; otherwise, the same conditions were applied as in Example 14. The reaction results of Examples 13-15 are as follows.

[0158] Table 3 Reaction results of Examples 13-15

[0159] Example raw material Moor ratio Conversion rate (%) Yield (%) 13 thionyl chloride 1.2 99 80 14 Hydrogen peroxide (30%) 1 99 92 15 sulfur powder 1.2 98 88

[0160] Example 16

[0161] Synthesis of compound ethyl 4-bromo-3-formyl-2-methylbenzoate

[0162]

[0163] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 27.8 g (0.1 mol) of ethyl 4-bromo-3-formyl-2-methylcyclohexane-1,3-diene-1-carboxylate and 200 g of DCM were added. 14.1 g (0.12 mol) of thionyl chloride was slowly added dropwise at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was carried out for 2 hours. A sample was taken to ensure the reaction was complete, yielding ethyl 4-bromo-3-formyl-2-methylbenzoate in 88% yield. CI-MS (m / e): 271 (M+1)

[0164] Example 17

[0165] Synthesis of compound ethyl 3-formyl-2-methyl-4-(methylthio)benzoate

[0166]

[0167] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 22.6 g of compound ethyl 4-chloro-3-formyl-2-methylbenzoate (0.1 mol) and 100 g of HMPA were added, followed by 4.2 g of sodium bicarbonate (0.05 mol). 105 g of 20% sodium methanethiol solution (0.3 mol) was slowly added dropwise at room temperature. After the addition was complete, the reaction was maintained at this temperature for 0.5 hours until complete. 100 g of DCM and 100 g of water were added to the reaction mixture, and the layers were extracted and dried under rotary evaporation to obtain compound ethyl 3-formyl-2-methyl-4-(methylthio)benzoate. 1 ¹H NMR (400MHz, CDCl₃) δ = 10.65 (s, ¹H), 7.91 (d, J = 8.6, ¹H), 7.22 (d, J = 8.6, ¹H), 4.38 (q, J = 7.1, ²H), 2.84 (s, ³H), 2.48 (s, ³H), 1.40 (t, J = 7.1, ³H), yield 95%. CI-MS (m / e): 239 (M+1).

[0168] Examples 18-23 involved varying the types of sodium methanethiol, solvents, and the type and amount of alkali used, with other reaction conditions as described in Example 17. The reaction results are shown in the table below.

[0169] Table 4. Reaction results of Examples 17-23

[0170]

[0171] Example 24

[0172] Synthesis of compound ethyl 3-formyl-2-methyl-4-(methylthio)benzoate

[0173]

[0174] In a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser, 27 g (0.1 mol) of ethyl 4-bromo-3-formyl-2-methylbenzoate and 100 g of DMSO were added, followed by 4.2 g (0.05 mol) of sodium bicarbonate. 105 g (0.3 mol) of a 20% sodium methanethiol solution was slowly added dropwise at room temperature. After the addition was complete, the reaction was maintained at this temperature for 0.5 hours until complete. 100 g of DCM and 100 g of water were added to the reaction mixture, and the layers were extracted and dried under rotary evaporation to obtain ethyl 3-formyl-2-methyl-4-(methylthio)benzoate in 93% yield. CI-MS (m / e): 239 (M+1)

[0175] Example 25

[0176] Synthesis of ethyl 3-((hydroxyimino)methyl)-2-methyl-4-(methylthio)benzoate

[0177]

[0178] 23.8 g (0.1 mol) of ethyl 3-formyl-2-methyl-4-(methylthio)benzoate was weighed into a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. It was dissolved in 200 g of acetonitrile, and 7.9 g of sodium carbonate (0.74 mol) and 9 g of hydroxylamine hydrochloride (0.13 mol) were added. The mixture was stirred at room temperature for 5 hours. After the reaction was complete, the solvent was concentrated, 100 g of water was added, and the mixture was extracted with 100 g of DCM to separate the layers. The organic phase was concentrated to give ethyl 3-((hydroxyimino)methyl)-2-methyl-4-(methylthio)benzoate in 98% yield. CI-MS (m / e): 254 (M+1)

[0179] Example 26

[0180] Synthesis of ethyl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylthio)benzoate

[0181]

[0182] 25.3 g (0.1 mol) of compound 3-((hydroxyimino)methyl)-2-methyl-4-(methylthio)benzoate, 4.2 g sodium bicarbonate (0.05 mol), and 200 g DCM were added to an autoclave. 187 g (0.2 mol) of 8% sodium hypochlorite solution was slowly added dropwise at -5°C. After the addition was complete, the mixture was kept at this temperature for half an hour. Then, while maintaining the reaction temperature below 0°C, 4 MPa ethylene gas was introduced into the autoclave, continuously replenishing the gas until the pressure in the autoclave no longer decreased. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5, and the mixture was allowed to stand and separate into layers. The organic phase was then evaporated to dryness, yielding 95%. CI-MS (m / e), 280 (M+1).

[0183] Example 27

[0184] Synthesis of ethyl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylthio)benzoate

[0185]

[0186] 25.3 g (0.1 mol) of compound 3-((hydroxyimino)methyl)-2-methyl-4-(methylthio)benzoate, 4.2 g of sodium bicarbonate (0.05 mol), and 200 g of DCM were added to an autoclave. 280 g (0.2 mol) of 8% sodium hypochlorite solution was slowly added dropwise at -5°C. After the addition was complete, the mixture was kept at this temperature for half an hour. Then, ethylene gas at 4 MPa was introduced into the autoclave while maintaining the reaction temperature at room temperature. Gas was continuously added until the pressure in the autoclave no longer decreased. After the reaction was completed, the pH of the reaction solution was adjusted to 4-5, and the mixture was allowed to stand and separate into layers. The organic phase was evaporated to dryness, and the product yielded approximately 30% sulfoxide. CI-MS (m / e): 280 (M+1), 296 (M+1).

[0187] Example 28

[0188] Synthesis of compound ethyl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoate

[0189]

[0190] 27.9 g (0.1 mol) of ethyl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylthio)benzoate was weighed into a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 200 g of toluene, 1 g of concentrated sulfuric acid, 3 g of acetic acid, and 0.3 g of sodium tungstate were added. The mixture was heated to 75 °C, and 45.5 g (0.4 mol) of 30% hydrogen peroxide was slowly added dropwise. After the addition was complete, the mixture was refluxed for 3 hours. After the reaction was complete, the mixture was cooled and allowed to stand for phase separation. The quantitative yield was 98%. CI-MS (m / e): 312 (M+1)

[0191] Example 29

[0192] Synthesis of compound 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoic acid

[0193]

[0194] 31.1 g (0.1 mol) of ethyl 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoate was weighed into a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 200 g of toluene and 80 g of 10% sodium hydroxide solution (0.2 mol) were added. The mixture was heated to reflux for 2 hours. After the reaction was completed, the mixture was allowed to stand and separate into layers. The pH of the aqueous phase was adjusted to 2-3, and a white solid precipitated, with a yield of 99%. 1 H NMR (500 MHz, DMSO) δ = 8.02 (d, J = 8.3, 1H), 7.97 (d, J = 8.3, 1H), 4.48 (t, J = 10.0, 2H), 3.32 (t, J = 10.0, 2H), 3.25 (s, 3H), 2.42 (s, 3H). CI-MS(m / e);282(M-1)

[0195] Example 30

[0196] Synthesis of 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoyl chloride

[0197]

[0198] 28.3 g (0.1 mol) of compound 3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methanesulfonyl)benzoic acid was weighed into a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 200 g of DCE and 1 mL of DMF were added. The temperature was raised to 75 °C, and 14.2 g of thionyl chloride (0.12 mol) was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for 3 h. Excess thionyl chloride was distilled off after the reaction, yielding 99%. CI-MS (m / e): 312(M+OCH3+1)

[0199] Example 31

[0200] Synthesis of 1-methyl-1H-pyrazole-5-yl-3-(4,5-dihydroisoxazol-3-yl)-2-methyl-4-(methylsulfonyl)benzoate

[0201]

[0202] 9.8 g of 1-methyl-5-hydroxypyrazole (0.1 mol) and 100 g of DCE were weighed into a four-necked flask equipped with a mechanical stirrer, thermometer, and condenser. 15 g of triethylamine was added, and the temperature was lowered to below 10 °C. The above acyl chloride solution was slowly added dropwise. After the addition was complete, the reaction was maintained at this temperature for half an hour, and samples were taken for monitoring. After the reaction was complete, the mixture was allowed to stand and separate into layers. The organic phase was refluxed for dehydration, with a yield of 97%. CI-MS (m / e): 364 (M+1)

[0203] Example 32

[0204] Synthesis of benzoxazine

[0205]

[0206] Add 20.7 g (0.15 mol) of potassium carbonate powder and 1 g of DMAP to the above solution, heat to reflux, and react for about 5 hours. After the reaction is complete, cool to room temperature, add 200 g of water and adjust the pH to about 3. Concentrate the organic phase and purify, with a yield of 93%. CI-MS (m / e): 364 (M+1)

[0207] The method for preparing 3-formyl-2-methyl-4-(methylthio)benzoate compounds according to the present invention can achieve high reaction conversion rate and selectivity, and the cost will be greatly reduced.

[0208] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

Claims

1. Compound of formula V, Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

2. The method for preparing the compound of formula V as described in claim 1, characterized in that, The process includes the following steps: compound IV is reacted with an oxidizing agent to produce compound V; Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

3. The preparation method according to claim 2, characterized in that, The oxidant is one of air, hydrogen peroxide, sodium hypochlorite, sulfur powder, sulfur dioxide, thionyl chloride, sulfonyl chloride, concentrated sulfuric acid, sulfur dichloride, and sulfur trioxide, preferably one of hydrogen peroxide, thionyl chloride, and sulfur powder; the molar ratio of the compound of formula IV to the oxidant is 1:0.1-5, preferably 1:1-2, and the reaction temperature range is 10-50℃.

4. The use of the compound of formula V according to claim 9 in the preparation of benzoxazine.

5. Compounds of formula IV, Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

6. The method for preparing the compound of formula IV according to claim 5, characterized in that, The process includes the following steps: the compound of formula III is hydrolyzed to obtain the compound of formula IV. Wherein R is an ester group, carboxylic acid group, amide group or cyano group, preferably an ester group; X is a halogen, preferably Cl or Br.

7. The method for preparing the compound of formula IV according to claim 6, characterized in that, The hydrolysis reaction is carried out under the action of an acid at room temperature. The acid is selected from one or more of sulfuric acid, hydrochloric acid, and nitric acid, with hydrochloric acid being preferred.

8. The use of the compound of formula IV according to claim 5 in the preparation of benzoxazine.

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