CN116947837A - Topramezone intermediate and preparation method thereof - Google Patents

Topramezone intermediate and preparation method thereof Download PDF

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CN116947837A
CN116947837A CN202210390195.XA CN202210390195A CN116947837A CN 116947837 A CN116947837 A CN 116947837A CN 202210390195 A CN202210390195 A CN 202210390195A CN 116947837 A CN116947837 A CN 116947837A
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compound
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ester group
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sodium
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刘彬龙
谭徐林
李生学
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Purpana Beijing Technologies Co Ltd
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    • C07C323/57—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being further substituted by nitrogen atoms, not being part of nitro or nitroso groups
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    • C07C69/757—Esters of carboxylic acids having an esterified carboxyl group bound to a carbon atom of a ring other than a six-membered aromatic ring having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
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Abstract

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

Description

Topramezone intermediate and preparation method thereof
Technical Field
The invention relates to an intermediate of topramezone, a preparation method and application thereof, in particular to a 3-formyl-2-methyl-4- (methylthio) benzoate compound, a preparation method and application thereof.
Background
Topramezone is a benzyl ester pyrazolone herbicide developed by Pasteur for the first time, belongs to a p-hydroxyphenylpyruvate dioxygenase (HPPD) inhibitor, has the English common name topramezone and the Chinese name topramezone or topramezone, and has the commodity name campusR or bract. The topramezone can effectively prevent and remove annual gramineae weeds and broadleaf weeds in corn, is safe to corn, has the application range gradually expanded to crops such as rice and sugarcane, and can be safely compounded with other pesticides. The global topramezone market size in 2018 was about 1.09 billion dollars, the total amount of active ingredients applied was about 269.35t, with the corn field market being 65.55% and other crops being about 34.45%. The topramezone has excellent drug effect and wide market prospect, but the extremely difficult synthesis process makes the topramezone high in selling price, and therefore, the wide application of the topramezone is limited.
The preparation process of the topramezone reported at present mainly comprises the following two steps:
route 1:
the preparation of the compound (8) in the route is as follows, (see patent: CN 103788083A) needs nitrous acid ester to be subjected to ultralow temperature reaction to construct oxime, and two methyl groups on benzene rings have selectivity problems, and meanwhile, the intermediate is used for synthesizing topramezone, and extremely toxic carbon monoxide and an expensive metal palladium catalyst are used, so that the cost is high.
Route 2:
wherein the intermediate compound (7) in this route is reported as the following preparation method:
1) See patent nos.: US6100421
The starting materials required for the preparation of the intermediate are not easily available, and although the strong electron-withdrawing effect of the methylsulfonyl activates the next bromination reaction to a certain extent, steric hindrance selection problems exist in bromination, so that the yield is lower. In addition, when the methyl sulfonyl aldehyde is used for preparing the topramezone, the steric hindrance of the methyl sulfonyl is larger, so that the yield of the subsequent cyclization reaction with ethylene is lower.
2) See patent nos.: CN201410083163
The source of the initial raw materials in the route is difficult, carbon dioxide is used in the process of converting into carboxyl, n-butyllithium reacts at the ultralow temperature of minus 100 ℃ to minus 60 ℃, and industrial production is difficult;
3) See patent nos.: CN 110183392A
The starting materials in this route are also difficult to source, and because hydroxylamine has double reactive functional groups during the reaction of hydroxylamine with nitrile groups, a large amount of impurities are inevitably produced, resulting in lower yields, and the need to carry out deamination of diazotization increases the risk of the reaction.
In conclusion, the existing method has the defects of large three wastes, high cost, severe production environment and the like when the topramezone intermediate compound is prepared, and is also a factor which causes high cost and no residence of the topramezone preparation. Therefore, the development of a process route which is mild in reaction condition, green and environment-friendly and reduces the cost of preparing topramezone is particularly urgent.
Disclosure of Invention
Aiming at some defects and defects of the technical route of topramezone in the current market, the invention provides a process for preparing topramezone, which has the advantages of mild reaction conditions, environment friendliness and low cost.
In order to achieve the above purpose, the invention adopts the following technical scheme that the preparation method of topramezone comprises the following steps:
step one, a compound of a formula VI is subjected to oxime formation with a salt of hydroxylamine under alkaline conditions, and the prepared product oxime is subjected to ring closure with ethylene to prepare a compound of a formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis on the sulfone product to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating agent to obtain an acylated product, forming ester by the acylated product and 1-methyl-5-hydroxypyrazol, and then preparing the topramezone technical product through a rearrangement reaction under the condition of a catalyst;
wherein, the structures of the formula VI, the formula VII, the formula VIII and the topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
Preferably, there is provided a process for preparing a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
More optionally, a preparation method of the formula VI is provided, which comprises the following steps of carrying out substitution reaction on a compound of the formula V and sodium methyl mercaptide in a polar aprotic solvent under alkaline conditions to obtain the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides an application of the formula VI in preparing topramezone.
In addition, the invention provides compounds of formula V, formula IV and formula III,
wherein,,
the compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The compound of the formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
A compound of the formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a preparation method of the compounds shown in the formula III, the formula IV and the formula V and application of the compounds in preparation of topramezone.
The intermediate for preparing the topramezone has the advantages of mild preparation conditions, environment-friendly process, easily available raw material sources and relatively low price, and the intermediate for preparing the topramezone, the preparation method and the application of the intermediate in preparing the topramezone have good effects.
The invention has the beneficial effects that:
1. the topramezone intermediate prepared by the method has higher selectivity, can avoid using extremely toxic carbon monoxide and expensive metallic palladium catalyst in the prior art, reduces the cost of topramezone preparation, and is favorable for popularization and application of topramezone.
2. The method avoids the need of ultralow temperature construction of the isoxazole ring in the prior art in the process of synthesizing the compound of the formula VII by using the compound of the formula VI, and has mild condition and high selectivity in the reaction process of constructing the isoxazole ring.
3. The compounds of the formula VI, the formula V, the formula IV, the formula III and the like are easy to synthesize, the reaction condition is mild, and the process is environment-friendly, so that the synthesized topramezone has higher yield, and plays a great role in reducing the synthesis cost of the topramezone.
Drawings
Fig. 1: nuclear magnetic hydrogen spectrum of 4-chloro-3-formyl-2-methyl ethyl benzoate
Fig. 2: nuclear magnetic hydrogen spectrum of 3-formyl-2-methyl-4- (methylthio) ethyl benzoate
Fig. 3: nuclear magnetic hydrogen spectrum of 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid
Detailed Description
Hereinafter, embodiments of the present invention are described in detail. However, these embodiments are exemplary, the invention is not limited thereto, and the invention is defined by the scope of the claims.
As used herein, when no specific definition is otherwise provided, the following terms used in the specification and claims have the following meanings.
The ester group in the present invention means-COOR 1; wherein R1 is alkyl, substituted or substituted aryl or heteroaryl;
the amide group in the present invention means-CONR 2R3; wherein R2 and R3 are the same or different hydrogen, alkyl, substituted or substituted aryl or heteroaryl;
alkyl or alkane in the context of the present invention means a straight-chain or branched alkyl group, preferably C 1 -C 10 Alkyl groups, specifically for example, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl and the like, more preferably lower alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or tert-butyl and the like.
Aryl in the present invention is preferably phenyl or naphthyl.
Heteroaryl group: refers to five-membered or six-membered rings containing 1 or more N, O, S heteroatoms. For example, pyrrolyl, furanyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, isoxazolyl, isothiazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyridazinonyl, indolyl, benzofuranyl, benzoxazolyl, benzothienyl, benzothiazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, benzopyrazolyl, quinoxalinyl, and the like.
"cyano" refers to-CN.
HMPA refers to hexamethylphosphoric triamide.
DMSO refers to dimethylsulfoxide.
When the group is substituted, the substituents are alkyl, halogen, -OH, NO2, -CN, amino.
Halogen means fluorine, chlorine, bromine and iodine, and haloalkane means that hydrogen on alkane is partially or completely substituted by halogen.
The invention provides a preparation method of topramezone, which comprises the following steps:
step one, reacting a compound of the formula VI with a salt of hydroxylamine under alkaline conditions to form oxime, and then closing a ring with ethylene to obtain a compound of the formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating reagent to obtain a corresponding acyl chloride compound, forming ester with 1-methyl-5-hydroxypyrazol, and carrying out rearrangement reaction on an esterification product under the condition of a catalyst to obtain the topramezone technical product;
the structures of formula VI, formula VII, formula VIII and topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
Wherein, the reaction formula of the step (I) is as follows:
step (one) forming an oxime by reacting a compound of formula VI with a salt of hydroxylamine, preferably hydroxylamine hydrochloride or hydroxylamine sulfate, under basic conditions, wherein the base is an inorganic base, preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, more preferably one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate; the reaction is carried out in an organic solvent, wherein the solvent can be one of acetonitrile, ethyl acetate and dichloromethane, preferably acetonitrile, the reaction temperature is preferably room temperature, and the reaction time is 1-10h, preferably 2-8h. The process of preparing the compound of the formula VII by closing the ring with ethylene further comprises the steps of adding alkali and oxidant, wherein the alkali 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 oxidant is sodium hypochlorite, preferably a sodium hypochlorite solution, most preferably an 8% sodium hypochlorite solution. The further product oxime is then cyclized with ethylene to give the compound of the formula VII, the cyclizing reaction being carried out in an autoclave, the pressure in the autoclave preferably being 2-8MPa. It has been found that the reaction temperature during the ring closure should not be too high, preferably between-10 ℃ and 10 ℃, more preferably between-5 ℃ and 0 ℃, since too high a reaction temperature will result in oxidation of a small amount of dimethyl sulphide. The molar ratio of oxidizing agent to compound of formula VI is preferably 1:1.2-2.2, more preferably 1:1.6-2.
Wherein, the reaction formula in the step (2) is as follows:
the oxidizing agent in step (two) is peroxide, oxygen or hypochlorite, and the peroxy compound is preferably hydrogen peroxide, peroxybenzoic acid, more preferably hydrogen peroxide, and most preferably a 30% hydrogen peroxide solution. The reaction temperature in the oxidation process is 80-120 ℃, preferably 90-110 ℃, and researches show that the oxidation effect is not good due to the too low reaction temperature. The base used in the alkaline hydrolysis of the further sulfone product is selected from one of sodium hydroxide, potassium hydroxide, preferably aqueous solutions of sodium hydroxide and potassium hydroxide, and the hydrolysis is carried out in a solvent selected from one of toluene, xylene, nitrobenzene, preferably toluene. The hydrolysis is carried out at a relatively high temperature, preferably 100-120 ℃, and the reaction is too low to hydrolyze completely, and too high a temperature can decompose part of the oxazole ring.
Wherein, in the step (III), the reaction formula is as follows:
step (III), reacting the compound shown in the formula VIII with an acylating reagent to obtain a corresponding acyl chloride compound, wherein the acyl chloride reagent is thionyl chloride, sulfonyl chloride, oxalyl chloride, phosphorus oxychloride and the like, and the thionyl chloride is preferred; the reaction is carried out in a solvent, preferably dichloroethane, ethyl acetate; the reaction temperature is preferably 70-75 ℃; the reaction time is preferably 1 to 5 hours; the molar ratio of compound of formula VIII to acylating agent 1:1-1.5, preferably 1:1.05-1.2 when the molar ratio is less than 1: at 1.05 the reaction was incomplete.
Further, the obtained acyl chloride compound is reacted with 1-methyl-5-hydroxypyrazolol at a 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, and triethylamine is preferred. The reaction temperature is preferably from-5 to 25℃and preferably from 0 to 10 ℃.
Furthermore, adding potassium carbonate powder and a catalyst into the obtained esterified product solution, and preparing the topramezone technical product through a rearrangement reaction; the catalyst is 4-Dimethylaminopyridine (DMAP) and acetone cyanohydrin.
The invention also provides a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
The compound of the formula VI is prepared by the following method, which comprises the following steps of carrying out substitution reaction on the compound of the formula V and sodium methyl mercaptide in a polar aprotic solvent under alkaline conditions to prepare the compound of the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is Cl or Br.
In the preparation method of the compound of the formula VI, the alkali is organic alkali or inorganic alkali; 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, ammonium acetate; the aprotic polar solvent is any one or a combination of a plurality of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone and dioxane; preferably hexamethylphosphoric triamide, dimethyl sulfoxide, N, N-dimethylformamide; the molar ratio of the compound of formula V to the alkali to the sodium methyl mercaptide is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3. The reaction temperature was room temperature. The invention has mild reaction temperature condition and can well complete the reaction at room temperature.
The invention also provides application of the compound shown in the formula VI in preparation of topramezone. The preparation of topramezone by using the compound of the formula VI is more suitable for industrial production, and avoids the use of toxic gas, expensive catalyst and harsh reaction conditions in the prior art.
The present invention also provides a compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a compound of the formula V and a preparation method thereof, wherein the reaction formula is as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
In the method for preparing the compound shown in the formula 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, and is preferably hydrogen peroxide, thionyl chloride and sulfur powder. The preferred reaction temperature for the above reactions is in the range of 30 ℃ to 50 ℃; the reaction time is 1-5h; the molar ratio of the formula IV to the oxidant is 1:0.1-5, preferably 1:1-2.
The invention also provides application of the compound shown in the formula V in preparation of topramezone.
The present invention provides a compound of formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides the compound of the formula IV and a preparation method thereof, and the reaction formula is as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The hydrolysis reaction in the above preparation method is hydrolysis under acidic conditions, and the acid includes sulfuric acid, phosphoric acid, nitric acid and hydrochloric acid, preferably hydrochloric acid. The temperature during the above reaction is in the range of 0 to 30 ℃, preferably 10 to 25 ℃. The hydrolysis reaction yield is higher under the above conditions. Further, the hydrolysis reaction is carried out by adding organic solvent, which is halogenated alkane, preferably dichloromethane and dichloroethane. The invention also provides application of the compound shown in the formula IV in preparation of topramezone.
The present invention provides a compound of formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The invention also provides a compound of the formula III and a preparation method thereof, the preparation method comprises the following steps of preparing the compound of the formula III by halogenating the compound of the formula II,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
The halogenating reagent used in the halogenation reaction is one of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfonyl chloride, oxalyl chloride, solid light, carbon tetrachloride, NBS and NCS, preferably sulfonyl chloride, solid light, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide; in the preparation method, the molar ratio of the compound of the formula (II) to the halogenating agent is 1:0.1-3, preferably 1:0.3-1.5. Wherein the compound of formula II is prepared by reacting a compound of formula (I) with N, N-dimethylformamide methylal or DMF and dimethyl sulfate complex,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group. The reaction temperature of the reaction is 60-110 ℃, preferably 80-100 ℃. The research shows that the N, N-dimethylformamide has better effect than the reaction of DMF and dimethyl sulfate complex, the reaction temperature is too high, the yield is lower, and the reaction is insufficient if the reaction temperature is too low.
The invention further provides a process for the preparation of a compound of formula VI,
the method comprises the following reaction steps:
step (1) preparation of formula II
Step (2) preparation of formula III
Step (3) preparation of formula IV
Step (4) preparation of formula V
Step (5) preparation of formula VI
Wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group, and X is halogen, preferably Cl or Br. The preparation method of the formula II, the formula III, the formula IV, the formula V and the formula VI is as described above.
The present invention will be described in detail by examples. The amounts of reactants and products in the following examples were determined by liquid chromatography (Agilent HPLC 1260). In the following examples, the conversion and selectivity of the reaction were calculated by the following formulas:
conversion = (molar amount of raw material charged-molar amount of raw material remaining in product)/molar amount of raw material charged x 100% selectivity = actual molar amount of target product/theoretical molar amount of target product x 100%
Example 1
Synthesis of Compound 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 19g of Hagman ethyl ester (0.1 mol) and 12g of N, N-dimethylformamide methylal (0.11 mol) were charged, and then the reaction was continued at a temperature of 95℃for 3 hours, after which the reaction was completed under a medium control, a crude product was obtained in a quantitative yield of 90%. EI-MS (m/e); 237 (M).
Example 2 the starting material used was N, N-dimethylformamide and dimethyl sulfate complex, the remaining reaction conditions were referred to in example 1, the reaction temperatures of examples 3 and 4 were different from those of example 1, and the remaining reaction conditions were referred to in example 1. The reaction results for examples 1-4 are as follows:
TABLE 1 results of examples 1-4 reactions
Example 5
Synthesis of Compound 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester
To a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser were added 23.7g of ethyl 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylate (0.1 mol) and 200g of Dichloromethane (DCM), and 14g of oxalyl chloride (0.11 mol) was slowly added dropwise at a temperature of below 10℃to complete the reaction for 0.5 hour under thermal insulation, followed by completion of the reaction under central control to give ethyl 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylate as a compound in a quantitative yield of 89%. EI-MS (m/e); 255 (M)
Examples 6 to 9 use phosphorus oxychloride, sulfonyl chloride, solid phosgene and thionyl chloride in place of the oxalyl chloride in example 5, respectively, the molar ratios of phosphorus oxychloride, sulfonyl chloride, solid phosgene, thionyl chloride and oxalyl chloride used were the same or different, and the remaining conditions were referred to example 5, and the reaction results of examples 5 to 9 were as follows:
table 2 experimental results for examples 5-9
Examples Raw materials Molar ratio of Conversion (%) Yield (%)
5 Oxalyl 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
Example 10
Synthesis of Compound 4-bromo-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 23.7g (0.1 mol) of 3- ((dimethylamino) methylene) -2-methyl-4-oxocyclohex-1-ene-1-carboxylate and 200g of Dichloromethane (DCM) were added, and 14g (0.05 mol) of phosphorus tribromoxide was slowly added dropwise at a temperature below 10℃to complete the reaction for 0.5 hour under thermal insulation, and the reaction was completed under central control to obtain the compound 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylate in a yield of 88%. EI-MS (m/e); 299 (M)
Example 11
Synthesis of 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with mechanical stirring, a thermometer and a condenser, 27g of 4-chloro-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100g of DCM were added, 10g (36.5%) of hydrochloric acid and 50g of water were then added, stirring was carried out at room temperature for 1 hour, the reaction was completed under a medium control, the mixture was allowed to stand for delamination, and the organic phase was dried by spinning to obtain the compound 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester in a yield of 99%. CI-MS (m/e); 229 (M+1)
Example 12
Synthesis of 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester
In a four-necked flask equipped with mechanical stirring, a thermometer and a condenser tube, 30g of the compound 4-bromo-3- ((dimethylamino) methylene) -2-methylcyclohexa-1, 4-diene-1-carboxylic acid ethyl ester (0.1 mol) and 100g of DCM were added, 10g of hydrochloric acid and 50g of water were then added, stirring was carried out at room temperature for 1 hour, the reaction was completed under a medium control, the mixture was allowed to stand for delamination, and the organic phase was dried by spinning to obtain the compound 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester in a yield of 99%. CI-MS (m/e); 273 (M+1).
Example 13
Synthesis of 4-chloro-3-formyl-2-methylbenzoic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 22.8g of 4-chloro-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester (0.1 mol), 200g of DCM and 14.1g of thionyl chloride (0.12 mol) were slowly added dropwise at room temperature, and after the completion of the dropwise addition, the temperature was raised to 40℃for 2 hours, and the reaction was completed by sampling and central control. ( 1 H NMR(500MHz,CDCl 3 ) 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)
The amount of thionyl chloride used in example 14 was varied from example 13, the remaining conditions were the same, and example 15 replaced the thionyl chloride used in example 13 with sulfur dichloride, the molar ratio used was slightly varied, and the remainder was made reference to example 14. The reaction results of examples 13 to 15 are as follows.
TABLE 3 reaction results for examples 13-15
Examples Raw materials Molar ratio of Conversion (%) Yield (%)
13 Thionyl chloride 1.2 99 80
14 Hydrogen peroxide (30%) 1 99 92
15 Sulfur powder 1.2 98 88
Example 16
Synthesis of 4-bromo-3-formyl-2-methylbenzoic acid ethyl ester
Into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser tube, 27.8g (0.1 mol) of 4-bromo-3-formyl-2-methylcyclohexa-1, 3-diene-1-carboxylic acid ethyl ester, 200g of DCM and 14.1g (0.12 mol) of thionyl chloride were slowly added dropwise at room temperature, the temperature was raised to 40℃after the completion of the dropwise addition and the reaction was carried out for 2 hours, and the sampling and the central control reaction were completed to obtain the compound ethyl 4-bromo-3-formyl-2-methylbenzoate, the yield was 88%. CI-MS (m/e); 271 (M+1)
Example 17
Synthesis of the Compound ethyl 3-formyl-2-methyl-4- (methylthio) benzoate
22.6g of 4-chloro-3-formyl-2-methylbenzoic acid ethyl ester (0.1 mol) and 100g of HMPA are added into a four-port bottle provided with a mechanical stirring device, a thermometer and a condenser, 4.2g of sodium bicarbonate (0.05 mol) is added, 105g of 20% sodium methyl mercaptan solution (0.3 mol) is slowly added dropwise at room temperature, the dropwise reaction is carried out for 0.5 hour after the heat preservation, the central control reaction is complete, 100g of DCM (DCM), 100g of water are added into the reaction solution, the mixture is extracted and layered, and the organic phase is dried by spinning to obtain the compound 3-formyl-2-methyl-4- (methylthio) ethyl benzoate 1 H NMR(400MHz,CDCl 3 ) 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).
Examples 18-23 the remaining reaction conditions were as described in example 17 by varying the respective sodium methyl mercaptide, the type of solvent and the type and amount of base. The reaction results are shown in the following table.
TABLE 4 EXAMPLES 17-23 EXAMPLES reaction results
Example 24
Synthesis of the Compound ethyl 3-formyl-2-methyl-4- (methylthio) benzoate
In a four-port bottle equipped with a mechanical stirrer, a thermometer and a condenser tube, 27g (0.1 mol) of ethyl 4-bromo-3-formyl-2-methylbenzoate and 100g of DMSO are added, then 4.2g (0.05 mol) of sodium bicarbonate is added, 105g (0.3 mol) of 20% sodium methyl mercaptan solution is slowly added dropwise at room temperature, the dropwise addition is completed for 0.5 hour of thermal insulation reaction, the medium control reaction is complete, 100g of DCM (DCM), 100g of water are added into the reaction solution, the extraction and delamination are carried out, and the organic phase is dried by spinning, thus obtaining the compound 3-formyl-2-methyl-4- (methylthio) ethyl benzoate with the yield of 93%. CI-MS (m/e); 239 (M+1)
Example 25
Synthesis of Compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
23.8g (0.1 mol) of ethyl 3-formyl-2-methyl-4- (methylthio) benzoate was weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, dissolved in 200g of acetonitrile, 7.9g of sodium carbonate (0.74 mol), 9g of hydroxylamine hydrochloride (0.13 mol) were added, stirred at room temperature for 5 hours, after the completion of the reaction, the solvent was concentrated, 100g of water was added, 100g of DCM was extracted and separated, and the organic phase was concentrated to give ethyl 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) benzoate as a compound in a yield of 98%. CI-MS (m/e); 254 (M+1)
Example 26
Synthesis of Compound 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
25.3g (0.1 mol) of the compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) ethyl benzoate, 4.2g of sodium bicarbonate (0.05 mol), 200g of DCM and 187g (0.2 mol) of 8% sodium hypochlorite solution are slowly added dropwise at-5 ℃ for half an hour after the dropwise addition, 4MPa ethylene gas is introduced into the autoclave at the reaction temperature of lower than 0 ℃ until the pressure of the autoclave is not reduced, after the reaction, the pH of the reaction solution is adjusted to 4-5, the mixture is stood for layering, the organic phase is dried by spinning, and the yield is 95%. CI-MS (M/e), 280 (M+1).
Example 27
Synthesis of Compound 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylthio) benzoic acid ethyl ester
25.3g (0.1 mol) of the compound 3- ((hydroxyimino) methyl) -2-methyl-4- (methylthio) ethyl benzoate, 4.2g of sodium bicarbonate (0.05 mol), 200g of DCM and 280g (0.2 mol) of 8% sodium hypochlorite solution are slowly added dropwise at-5 ℃ for half an hour after the dropwise addition, 4MPa ethylene gas is introduced into the autoclave at room temperature, the air pressure of the autoclave is continuously supplemented until the air pressure of the autoclave is not reduced, after the reaction is finished, the pH value of the reaction solution is adjusted to 4-5, the reaction solution is kept still for layering, and the organic phase is dried by spinning, so that about 30% of sulfoxide product is formed. CI-MS (m/e); 280 (M+1), 296 (M+1).
Example 28
Synthesis of Compound 3- (4, 5-Dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid ethyl ester
27.9g (0.1 mol) of ethyl 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylthio) benzoate as a compound is weighed in a four-port bottle provided with a mechanical stirrer, a thermometer and a condenser, 200g of toluene, 1g of concentrated sulfuric acid, 3g of acetic acid and 0.3g of sodium tungstate are added, the temperature is raised to 75 ℃, 45.5g (0.4 mol) of 30% hydrogen peroxide is slowly added dropwise, after the dropwise addition is completed, the temperature is raised to reflux for 3 hours, and after the reaction is completed, cooling, standing and layering are carried out, and the quantitative yield is 98%. CI-MS (m/e); 312 (M+1)
Example 29
Synthesis of the Compound 3- (4, 5-Dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid
31.1g (0.1 mol) of ethyl 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoate as a compound was weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, 200g of toluene and 80g of 10% sodium hydroxide solution (0.2 mol) were added, the temperature was raised to reflux for 2 hours, and after the reaction was completed, the mixture was allowed to stand and separate, the pH of the aqueous phase was adjusted to 2-3, a white solid was precipitated, and the yield was 99% 1 H NMR(500MHz,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)
Example 30
Synthesis of 3- (4, 5-dihydro-isoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoyl chloride
28.3g (0.1 mol) of 3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoic acid, 200g of DCE and 1mL of DMF are weighed into a four-necked flask equipped with a mechanical stirrer, a thermometer and a condenser, the temperature is raised to 75 ℃, 14.2g of thionyl chloride (0.12 mol) is slowly added dropwise, the reaction is carried out for 3 hours after the dropwise addition, and the superfluous thionyl chloride is distilled off after the reaction is finished, so that the yield is 99%. CI-MS (m/e); 312 (M+OCH3+1)
Example 31
Synthesis of 1-methyl-1H-pyrazol-5-yl-3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4- (methylsulfonyl) benzoate
9.8g of 1-methyl-5-hydroxypyrazole (0.1 mol) and 100g of DCE are weighed in a four-mouth bottle with a mechanical stirrer, a thermometer and a condenser, 15g of triethylamine is added, the temperature is reduced to below 10 ℃, the acyl chloride solution is slowly added dropwise, the reaction is kept for half an hour after the dropwise addition, sampling monitoring is carried out, standing and layering are carried out after the reaction is completed, and the organic phase is refluxed and dehydrated, so that the yield is 97%. CI-MS (m/e); 364 (M+1)
Example 32
Synthesis of topramezone
To the above solution, 20.7g (0.15 mol) of potassium carbonate powder and 1g of DMAP were added, the temperature was raised to reflux, the reaction was allowed to proceed for about 5 hours, after the completion of the reaction, the reaction was cooled to room temperature, 200g of water was added and the pH was adjusted to about 3, and the organic phase was concentrated, purified and the yield was 93%. CI-MS (m/e); 364 (M+1)
According to the method for preparing the 3-formyl-2-methyl-4- (methylthio) benzoate compound, higher reaction conversion rate and selectivity can be obtained, and the cost is greatly reduced.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited to the specific details of the above embodiments, and various simple modifications can be made to the technical solution of the present invention within the scope of the technical concept of the present invention, and all the simple modifications belong to the protection scope of the present invention.

Claims (21)

1. The preparation method of topramezone is characterized by comprising the following steps:
step one, a compound of a formula VI is subjected to oxime formation with a salt of hydroxylamine under alkaline conditions, and the prepared product oxime is subjected to ring closure with ethylene to prepare a compound of a formula VII, wherein the salt of hydroxylamine is preferably hydroxylamine hydrochloride or hydroxylamine sulfate;
oxidizing the compound of the formula VII by an oxidant to obtain a corresponding sulfone product, and performing alkaline hydrolysis on the sulfone product to obtain a formula VIII;
step three, reacting a compound shown in a formula VIII with an acylating agent to obtain an acylated product, forming ester by the acylated product and 1-methyl-5-hydroxypyrazol, and then preparing the topramezone technical product through a rearrangement reaction under the condition of a catalyst;
wherein, the structures of the formula VI, the formula VII, the formula VIII and the topramezone are as follows:
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
2. The process according to claim 1, wherein the base in step (one) is an inorganic base, and the inorganic base is one of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide and potassium hydroxide, preferably sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
3. The method of claim 1, wherein the oxidizing agent in step (two) is one of peroxy compound, oxygen, and hypochlorite, preferably one of hydrogen peroxide, oxygen, and sodium hypochlorite, most preferably hydrogen peroxide.
4. The method according to claim 1, wherein the acid chloride reagent in step (iii) is one of thionyl chloride, sulphuryl chloride, oxalyl chloride and phosphorus oxychloride, preferably thionyl chloride; the transposition catalyst is one of 4-dimethylaminopyridine and acetone cyanohydrin.
5. The compound of the formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group.
6. A process for the preparation of a compound of formula VI as claimed in claim 5, comprising the step of substitution reaction of a compound of formula V with sodium methyl mercaptide in a polar aprotic solvent to give a compound of formula VI,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
7. The preparation method according to claim 6, wherein a base is further added in the reaction, and the base may be an organic base or an inorganic base; the inorganic alkali is 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 one or more of sodium bicarbonate, sodium acetate, ammonium acetate; the polar aprotic solvent is any one or a combination of more than one of hexamethylphosphoric triamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone and dioxane; preferably one or a combination of more than one of hexamethylphosphoric triamide, dimethyl sulfoxide and N, N-dimethylformamide; the molar ratio of the compound of formula V to the alkali to the sodium methyl mercaptide is 1:0.1-2:1-4, preferably 1:0.1-0.5:1-3.
8. The use of a compound of formula VI as claimed in claim 5 for the preparation of topramezone.
9. The compound of formula V,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
10. The process for preparing a compound of formula V as claimed in claim 9, comprising the steps of oxidizing a compound of formula IV with an oxidizing agent to obtain a compound of formula V;
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
11. The method according to claim 10, wherein the oxidizing agent 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 amount of oxidant is 1:0.1-5, preferably 1:1-2, and the reaction temperature is 10-50 ℃.
12. The use of a compound of formula V according to claim 9 for the preparation of topramezone.
13. The compound of the formula IV,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
14. The compound of formula IV of claim 13The preparation method of the compound is characterized by comprising the following steps of preparing a compound of a formula IV by hydrolysis reaction of the compound of the formula III;
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
15. The process for the preparation of a compound of formula IV according to claim 14, wherein the hydrolysis reaction conditions are reaction at room temperature under the action of an acid selected from one or more of sulfuric acid, hydrochloric acid, nitric acid, preferably hydrochloric acid.
16. The use of a compound of formula IV as defined in claim 13 for the preparation of topramezone.
17. A compound of the formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is halogen, preferably Cl or Br.
18. A process for the preparation of a compound of formula III as claimed in claim 17, comprising the step of reacting a compound of formula II with a halogenating agent to produce a compound of formula III,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; x is Cl or Br.
19. The method according to claim 18, wherein the halogenated reagent is one of phosphorus oxychloride, phosphorus oxybromide, phosphorus trichloride, phosphorus pentachloride, phosphorus tribromide, thionyl chloride, sulfuryl chloride, oxalyl chloride, solid light, carbon tetrachloride, N-bromosuccinimide (NBS) and N-chlorosuccinimide (NCS), preferably one of sulfuryl chloride, solid light, oxalyl chloride, phosphorus oxychloride and phosphorus oxybromide; the molar ratio of the compound of formula (II) to the halogenating agent is 1:0.1-3, preferably 1:0.3-1.5, and the reaction temperature is in the range of-10 ℃ to 30 ℃.
20. The process according to claim 18 or 19, comprising the step of reacting a compound of formula II with N, N-dimethylformamide methylal or a complex of N, N-dimethylformamide and dimethyl sulfate,
wherein R is an ester group, carboxylic acid, amide or cyano group, preferably an ester group; the reaction temperature of the reaction is 60-110 ℃, preferably 80-110 ℃.
21. The use of a compound of formula III according to claim 17 for the preparation of topramezone.
CN202210390195.XA 2022-04-14 2022-04-14 Topramezone intermediate and preparation method thereof Pending CN116947837A (en)

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