CN112745270A - Novel compound and method for preparing topramezone intermediate by using same - Google Patents

Novel compound and method for preparing topramezone intermediate by using same Download PDF

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CN112745270A
CN112745270A CN202011624421.3A CN202011624421A CN112745270A CN 112745270 A CN112745270 A CN 112745270A CN 202011624421 A CN202011624421 A CN 202011624421A CN 112745270 A CN112745270 A CN 112745270A
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CN112745270B (en
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李林
何瑞红
李媛媛
张欣悦
汪改欣
田梦
张云
刘兰
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Hebei Medical University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C319/00—Preparation of thiols, sulfides, hydropolysulfides or polysulfides
    • C07C319/14—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides
    • C07C319/20—Preparation of thiols, sulfides, hydropolysulfides or polysulfides of sulfides by reactions not involving the formation of sulfide groups

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Abstract

The invention provides a compound shown as a general formula A, R1Is haloalkyl, hydroxyalkyl, aldehyde group, carboxylic acid group; r2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is an alkyl substituted thio group, an alkylsulfonyl group, an alkylsulfide group, said alkyl group being independently selected from the group consisting of methyl, ethyl, propyl, isopropyl. The invention also provides the compound as one or more intermediates for preparing topramezone. In addition, the present invention provides a process for the preparation of topramezone compounds, which is prepared from the compounds of formula a as intermediates, by chloromethylation or hydroformylation, hydrolysis, hydroxylamination, diazotization, halogenation, dipolar halogenationAnd (3) performing cycloaddition and oxidation reaction to finally prepare the key intermediate of topramezone. The method has the advantages of mild and controllable reaction conditions, good reaction selectivity in each step, high yield, avoidance of generation of some byproducts and guarantee of product quality. The whole process route is easy to realize industrialization.

Description

Novel compound and method for preparing topramezone intermediate by using same
Technical Field
The present invention relates to a series of new compounds and a preparation method thereof for herbicides. Specifically, the invention provides a synthesis method of a key intermediate of topramezone.
Background
Currently, inhibitors of p-hydroxyphenylpyruvate acetate dioxygenase (4-HPPD) are novel herbicide targets established in the 90 s of the 20 th century, indirectly influence the synthesis of carotenoids by inhibiting 4-hydroxyphenylpyruvate dioxygenase (4-HPPD) in the biosynthesis of plastoquinones, interfere with the synthesis and function of chloroplasts under light and finally cause the death of weeds. The 4-HPPD inhibitor has different action mechanisms in animals and plants, and is safe to mammals. The HPPD inhibitor class of herbicides that have been developed to date is still one of the current classes of herbicides with the least toxicity to mammals. Therefore, the herbicide is a herbicide with good development prospect.
Topramezone is a p-hydroxyphenylpyruvate acetate dioxygenase (4-HPPD) inhibitor developed by Pasteur Germany, can be used for treating stems and leaves of corn seedlings, is a herbicide with wide weed control spectrum, wide application range, high action speed, high safety and good compatibility with other herbicides, and has good application prospect.
The synthesis of topramezone has been reported in patents from Pasteur Germany (WO9958509A1) and from Nippon Caoda corporation (WO 9735851). The initial raw material 2, 3-dimethyl-4-methylsulfonyl methyl benzoate in the patent route reported by Caoda company is not sold as a commercial product, and the synthesis process has incomplete multi-step reaction and low yield, and the industrial production cannot be realized because column chromatography separation and purification are required. The basf company reports two complete synthetic routes and several possible synthetic routes, wherein the total yield of the two complete routes can reach more than 20%, but high-pressure and heating equipment is required for multiple steps, and the requirement on the equipment is high; in addition, catalysts of noble metal compounds such as palladium and platinum are needed, and the catalysts are expensive and difficult to recover, so that the total cost is relatively high.
In the synthesis of topramezone. The following two methods are generally employed:
Figure BDA0002874513630000021
3- (2-methyl-3-bromo-6-methylsulfonyl) phenyl-4, 5-dihydroisoxazole (A) is taken as an intermediate, and is subjected to palladium catalytic carbonylation with carbon monoxide and 1-methyl-5-hydroxypyrazole to prepare topramezone.
And the other one is prepared by condensing 2-methyl-3- (4, 5-dihydroisoxazol-3-yl) -4-methylsulfonylbenzoic acid (B) serving as an intermediate with 1-methyl-5-hydroxypyrazole.
The synthesis methods of the intermediates I and II mainly comprise the following three methods:
route one: 2, 3-dimethyl-4-methylsulfonylbenzoate process
Figure BDA0002874513630000022
And a second route: 3-nitro-o-xylene process
Figure BDA0002874513630000023
And a third route: 2, 3-dimethylaniline process
Figure BDA0002874513630000031
The three methods have defects, which are as follows:
1. in the process of constructing the isoxazole ring, the chloridization of aldoxime uses chlorine with strong toxicity or NCS with high price.
2. In the diazotization process for converting amino into methylthio, a primary inflammable substance dimethyl disulfide is adopted.
3. In the second route, the nitro group is reduced, and the N-O bond of the isoxazole ring has the possibility of bond breaking.
4. In the first route, bromination reaction has poor selectivity and side reactions are inevitable.
In view of this, there is a need in the industry for a new process route that can overcome the potential safety hazards and reduce the by-products in the prior art.
Disclosure of Invention
The invention provides a compound shown as the following general formula A
Figure BDA0002874513630000032
Wherein R is1Is haloalkyl, hydroxyalkyl, aldehyde group, carboxylic acid group; r2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is an alkyl substituted thio group, an alkylsulfonyl group, an alkylsulfidenyl group, said alkyl group being independently selected from methyl, ethyl, propyl, isopropyl; preferably, R1Is halomethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is alkyl substituted sulfenyl, alkyl sulfonyl, alkyl sulfoxide, the alkyl is independently selected from methyl, ethyl, propyl, isopropyl, the halogenated alkyl is alkyl chloride, alkyl bromide; more preferably, R1Is chloromethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is methylthio.
Wherein the compound shown as the general formula A is
Figure BDA0002874513630000041
3-chloromethyl-2-methyl-6-methylthiobenzonitrile;
Figure BDA0002874513630000042
3-formyl-2-methyl-6-methylthiobenzonitrile;
Figure BDA0002874513630000043
3-hydroxymethyl-2-methyl-6-methylthiobenzonitrile;
Figure BDA0002874513630000044
(Z) -N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine;
Figure BDA0002874513630000045
(Z) -N-hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzimidoyl chloride;
Figure BDA0002874513630000046
(3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylthio) phenylmethanol.
The invention also provides the compound as one or more intermediates for preparing topramezone.
The invention also provides application of the compound in preparing topramezone.
The invention also provides a preparation method of the compound shown in the general formula IV, which is characterized in that the compound is prepared from the raw material shown in the general formula I
Figure BDA0002874513630000051
Preferably, the preparation process is that the compound of the general formula II or the general formula III is prepared by the general formula I, and the general formula IV is prepared;
Figure BDA0002874513630000052
the invention also provides a preparation method of the compound of the general formula II, which is characterized in that the compound is obtained by the preparation reaction of the compound of the general formula I
Figure BDA0002874513630000053
Preferably, the conditions of the preparation reaction are: reacting the compound I with aldehyde in a protic solvent or a weak polar aprotic solvent under the action of acid;
preferably, the aldehyde is formaldehyde, paraformaldehyde, methylal or chloromethyl methyl ether, more preferably paraformaldehyde or methylal;
the protic solvent or the weak polar aprotic solvent is hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane, chloroform, ethyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, diethyl ether or isopropyl ether, more preferably, the protic solvent or the weak polar aprotic solvent is one or more of hydrofluoric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane or isopropyl ether, and more preferably a dichloromethane mixed solution of hydrofluoric acid and phosphoric acid;
the acid is protonic acid or Lewis acid, and more preferably hydrogen chloride or aqueous hydrochloric acid thereof, hydrogen fluoride or aqueous hydrofluoric acid thereof, sulfuric acid or phosphoric acid; more preferably, the lewis acid is aluminum trichloride, zinc chloride, ferric trichloride, stannic chloride; preferably, hydrogen chloride or aluminum trichloride;
preferably, the reaction temperature is between-10 ℃ and reflux temperature, preferably 0-80 ℃; the molar ratio of the reaction reagent to the substrate compound shown in the formula I is (1-100): 1, preferably 1 to 10: 1.
the invention also provides a preparation method of the compound shown in the general formula IV, which is characterized in that the compound is obtained by the following general formula II preparation reaction
Figure BDA0002874513630000061
Preferably, the reaction conditions of the preparation method are that the compound II is reacted in a solvent under basic conditions;
preferably, the alkaline agent of the alkaline condition is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, preferably one or more than two of sodium acetate, potassium carbonate or sodium hydroxide;
the solvent is preferably methanol, ethanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, etc., and more preferably any one or two of methanol, ethanol or N, N-dimethylformamide;
preferably, the reaction temperature is from room temperature to reflux temperature, preferably from 20 ℃ to 80 ℃; the molar ratio of the reaction alkaline reagent to the substrate compound shown in the formula II is (1-100): 1, preferably (1 to 10): 1.
the invention also provides a preparation method of the compound shown in the general formula III, which is characterized in that the compound is obtained by the preparation reaction of the compound shown in the general formula I
Figure BDA0002874513630000062
Preferably, the conditions of the preparation reaction are: adding urotropine into acetic acid or trifluoroacetic acid to react to obtain the compound;
preferably, the reaction is carried out at a temperature ranging from room temperature to reflux temperature, preferably reflux temperature; more preferably, the molar ratio of the urotropine to the substrate compound of formula I is (1-20): 1, preferably (5-10): 1.
the invention also provides a preparation method of the compound shown in the general formula IV, which is characterized in that the compound is obtained by the following general formula III preparation reaction
Figure BDA0002874513630000063
Preferably, the preparation reaction conditions are that the reduction reaction is carried out in a solvent under alkaline conditions;
preferably, the alkaline reagent under alkaline conditions is sodium borohydride or lithium aluminum hydride, preferably any one or more of sodium borohydride, lithium aluminum hydride and borane;
preferably, the solvent is one or two of tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethanol, acetonitrile, dimethyl sulfoxide or water solution of the above solvents; (ii) a More preferably any one or two of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or an aqueous solution of the above solvents;
preferably, the reaction temperature is between room temperature and reflux temperature, and more preferably 20-80 ℃;
preferably, the molar ratio of the reaction alkaline reagent to the substrate compound of the formula III is (1-100): 1, preferably (1 to 10): 1.
the invention also provides a preparation method of the compound shown in the general formula V, which is characterized in that the compound is obtained by the following general formula IV preparation reaction
Figure BDA0002874513630000071
Preferably, the conditions of the preparation reaction are that hydroxylamine is reacted in a protic solvent under alkaline conditions;
preferably, the protic solvent is water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; more preferably the protic solvent is one or more of water, methanol, ethanol or isopropanol;
preferably, the hydroxylamine is selected from the group consisting of free hydroxylamine and aqueous or alcoholic solutions thereof, hydroxylamine hydrochloride, hydroxylamine sulphate, hydroxyurea; preferably hydroxylamine hydrochloride or an aqueous solution of hydroxylamine;
preferably, the agent of alkaline conditions used is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, more preferably either or both potassium carbonate or sodium hydroxide;
preferably, the reaction temperature is between room temperature and reflux temperature, preferably 20-100 ℃, and more preferably 50-80 ℃; the molar ratio of the reaction reagent to the substrate compound shown in the formula IV is (1-100): 1, preferably (1 to 10): 1.
the invention also provides a preparation method of the compound shown in the general formula VI, which is characterized in that the compound is prepared from the compound shown in the general formula V
Figure BDA0002874513630000081
Preferably, the preparation reaction condition is that hydrohalic acid is added into a protic solvent to react with sodium nitrite;
preferably, the protic solvent is hydrochloric acid, hydrobromic acid, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; preferably one or more of hydrochloric acid, hydrobromic acid, methanol or ethanol;
preferably, the reaction temperature is-10 ℃ to 10 ℃; preferably-5 ℃ to 5 ℃, and the ratio of the added amount of the sodium nitrite to the substrate compound of the formula V is (1-5): 1, preferably (1-2): 1.
the invention also provides a preparation method of the compound of the general formula VII, which is characterized in that the compound is obtained by the preparation reaction of the compound of the general formula VI
Figure BDA0002874513630000082
Preferably, the conditions of the preparation reaction are a reaction with ethylene in the presence of a base in a nonpolar or weakly polar aprotic solvent;
preferably, the non-polar or weakly polar aprotic solvent is petroleum ether, cyclohexane, dichloromethane, dichloroethane, chloroform, chlorobenzene, tetrahydrofuran, acetonitrile; more preferably dichloromethane or dichloroethane;
preferably, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine; more preferably, the alkali is one or more of sodium carbonate, potassium carbonate and triethylamine;
preferably, the reaction temperature is 0 ℃ to reflux temperature; preferably 20-50 ℃; the ratio of the base added to the substrate compound of formula VI is (1-5): 1, preferably (1-2): 1.
the invention also provides a preparation method of the compound of the general formula VIII, which is characterized in that the compound is obtained by the following general formula VII preparation reaction
Figure BDA0002874513630000083
Preferably, the conditions of the preparation reaction are a reaction with an oxidizing agent in an aprotic solvent;
preferably, the aprotic solvent is selected from dichloromethane, dichloroethane, dioxane, dimethyl sulfoxide, ethyl acetate, acetonitrile, N-dimethylformamide, N-dimethylacetamide, pyridine, nitrobenzene, and the like;
preferably, the oxidant is selected from oxygen, hydrogen peroxide and its aqueous solution, m-chloroperoxybenzoic acid, sodium tungstate, manganese dioxide, sodium chlorate, potassium permanganate and the like, preferably oxygen, hydrogen peroxide, manganese dioxide, sodium chlorate;
preferably, the reaction temperature is from room temperature to reflux, preferably the reaction temperature is reflux temperature;
the invention also provides a preparation method of the compound shown in the general formula VIII, which is characterized in that the compound is prepared by the following intermediate reaction of the raw material shown in the general formula I
Figure BDA0002874513630000091
Preferably, the reaction of each step is as follows:
(1) chloromethylating the compound of formula I to produce a compound of formula II;
(2) hydrolyzing the compound shown in the formula II to generate a compound shown in the formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
the invention also provides a preparation method of the compound shown in the general formula VIII, which is characterized in that the compound is prepared by the following intermediate reaction of the raw material shown in the general formula I
Figure BDA0002874513630000101
Preferably, the reaction of each step is as follows:
(1) the compound of formula I is subjected to aldehyde group formation to generate a compound of formula III;
(2) hydrolyzing the compound shown in the formula III to generate a compound shown in a formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
the invention also provides a preparation method of the compound shown in the general formula VIII, which is characterized in that the compound is prepared by reacting the raw material shown in the general formula I through the following intermediates under the following reaction conditions:
Figure BDA0002874513630000102
Figure BDA0002874513630000111
more specifically, the invention also provides a method for preparing the compound shown in the general formula VIII, which is characterized in that the method is prepared by the following intermediate reaction of the raw material shown in the general formula I
Figure BDA0002874513630000112
(1) Chloromethylating the compound of formula I to produce a compound of formula II;
(2) hydrolyzing the compound shown in the formula II to generate a compound shown in the formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
the invention has the following beneficial technical effects:
the synthetic route provided by the invention is characterized in that a cyano compound (IV) is converted into an N-hydroxybenzamidine compound (V), and then a 3-substituted phenyl-4, 5-dihydroisoxazole intermediate (VII) is synthesized through diazo chlorination reaction and dipolar cycloaddition reaction.
The synthetic route provided by the invention avoids the chlorine with higher toxicity and the expensive NCS (N-chlorosuccinimide) used in the aldoxime chlorination process reported in the prior literature.
The reaction provided by the invention does not involve reduction reaction, and avoids the side reaction of bond breaking by reduction of N-O bond in isoxazole.
The synthetic route provided by the invention avoids using primary flammable dimethyl disulfide in the diazotization and methylation reaction, and the production is safe and controllable.
The synthetic route provided by the invention avoids using a noble metal catalyst and carbon monoxide gas in the palladium catalytic carbonylation reaction, reduces the production cost, and has safe and controllable production.
The method has the advantages of mild and controllable reaction conditions, good reaction selectivity in each step, high yield, avoidance of generation of some byproducts and guarantee of product quality. The whole process route is easy to realize industrialization.
Detailed Description
The present invention provides a series of novel compounds and processes for preparing such compounds, as well as processes for preparing topramezone from such compounds.
In one embodiment of the present invention, there is provided a series of compounds represented by formula A,
Figure BDA0002874513630000121
wherein R is1Is haloalkyl, hydroxyalkyl, aldehyde group, carboxylic acid group; r2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is an alkyl substituted thio group, an alkylsulfonyl group, an alkylsulfidenyl group, said alkyl group being independently selected from methyl, ethyl, propyl, isopropyl;
preferably, R1Is halomethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is alkyl substituted sulfenyl, alkyl sulfonyl, alkyl sulfoxide group, the alkyl is methyl, ethyl, propyl, isopropyl, the halogenated alkyl is chloroalkyl, bromoalkyl;
more preferably, R1Is chloromethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is methylthio.
The group defined above is a plurality of researches on intermediates of topramezone synthesis conducted by the inventor, and the novel compound of the type can be used as an important intermediate for synthesizing topramezone.
With respect to the synthesis reaction conditions in the preparation method provided by the present invention, it will be understood by those skilled in the art that any conditions that can achieve the conversion from reactants to products should be within the scope of the present invention, and the contribution of the inventors is firstly reflected in designing a route to obtain products via suitable intermediates, and is also reflected in giving optimized reaction conditions to achieve the above conversion. Considering that new synthesis technologies, such as microbial transformation, use of new catalysts, etc., may be created in the future in the course of continuous progress of the synthesis technologies, it is within the scope of the present invention that the above-described conversion from reactants to products is achieved.
In a specific embodiment, the invention also provides a preparation method for synthesizing topramezone intermediate by using the compound.
The invention provides a preparation method of a compound of a general formula II, which is obtained by the preparation reaction of a compound of a general formula I
Figure BDA0002874513630000131
This reaction is analogous to the Blanc chloromethylation reaction, which introduces chloromethyl to the parent nucleus structure of the phenyl ring compound. The reaction conditions to be selected are relatively many as long as the above-mentioned target compound II can be synthesized. Compared with the introduction of acyl by Friedel-crafts acylation, the method has the advantages of mild reaction conditions, relatively simple post-treatment and satisfactory yield.
In particular, the reagent used is formaldehyde, paraformaldehyde, methylal or chloromethyl methyl ether, preferably paraformaldehyde, methylal or chloromethyl methyl ether. The reaction solvent is a protic solvent or a weakly polar aprotic solvent, and is preferably hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane, chloroform, ethyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, diethyl ether, isopropyl ether, or the like, and preferably hydrofluoric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane, or isopropyl ether. The acids used are protic acids or Lewis acids, protic acids such as: hydrochloric acid as hydrogen chloride or its aqueous solution, hydrofluoric acid as hydrogen fluoride or its aqueous solution, sulfuric acid, phosphoric acid, etc. Lewis acids such as: aluminum trichloride, zinc chloride, ferric trichloride, stannic chloride, and the like. Preference is given to hydrogen chloride or aluminum trichloride. The reaction temperature is from-10 ℃ to the reflux temperature, preferably 0-80 ℃. The molar ratio of the reaction reagent to the substrate compound shown in the formula I is 1-100: 1, preferably 1 to 10: 1.
process for the preparation of compounds IV
Figure BDA0002874513630000141
The reaction was carried out under the following conditions: the reaction reagent is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, preferably one or more of sodium acetate, potassium carbonate or sodium hydroxide. The reaction solvent is a protic solvent or an aprotic solvent, and is preferably methanol, ethanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, or the like, and most preferably one or two or more of ethanol and N, N-dimethylformamide. The reaction temperature is from room temperature to reflux temperature, preferably 20-80 ℃. The molar ratio of the reaction reagent to the substrate compound shown in the formula II is 1-100: 1, preferably 1 to 10: 1.
in one embodiment, the compounds of formula III are prepared as follows:
Figure BDA0002874513630000142
preferably, the conditions of the preparation reaction are: adding urotropine into formic acid, acetic acid, trifluoroacetic acid or propionic acid for reaction; preferably, the reaction is carried out at a temperature ranging from room temperature to reflux temperature, preferably reflux temperature; more preferably, the molar ratio of the urotropine to the substrate compound of formula I is (1-20): 1, preferably (1-5): 1.
the above reaction achieves the formylation of the benzene ring by the Duff reaction, and it will be understood by those skilled in the art that any method by which formylation can be achieved should be within the scope of the present invention. This reaction introduces an aldehyde carbonyl group into the parent structure of the benzene ring compound. The reaction conditions to be selected are relatively many as long as the above-mentioned target compound II can be synthesized. Compared with the introduction of acyl by Friedel-crafts acylation, the method has the advantages of mild reaction conditions, relatively simple post-treatment and satisfactory yield. In one embodiment, the compounds of formula IV are prepared as follows:
Figure BDA0002874513630000143
the above reaction is a reduction reaction of aldehyde to alcohol, the reaction system and reagents for the reduction reaction should be various, and the types of reduction reaction can be selected as follows: catalytic hydrogenation, lithium aluminum hydride, sodium borohydride, diborane and the like are used as reducing agents to carry out the reaction.
Preferably, the preparation reaction conditions are that the reduction reaction is carried out in a solvent under alkaline conditions;
preferably, the alkaline reagent under alkaline conditions is sodium borohydride or lithium aluminum hydride, preferably any one or more of sodium borohydride and lithium aluminum hydride;
the solvent is preferably tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethanol, acetonitrile, dimethyl sulfoxide, or an aqueous solution of the above solvents. More preferably one or two of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or the above solvent aqueous solution;
preferably, the reaction temperature is between room temperature and reflux temperature, and preferably 20-80 ℃;
more preferably, the molar ratio of the reaction alkaline reagent to the substrate compound of formula II is (1-100): 1, preferably (1 to 10): 1.
in one embodiment of the present invention, the compound of formula V is prepared by the following reaction of formula IV
Figure BDA0002874513630000151
The reaction was carried out under the following conditions: the solvents used are protic solvents such as: water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, etc.; water, methanol, ethanol or isopropanol are preferred. The reaction temperature is between room temperature and reflux temperature; preferably 50 to 80 ℃. The hydroxylamine is selected from free hydroxylamine and aqueous or alcoholic solutions thereof, and may also be in the form of its salts: hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxyurea; preferably, one or two of hydroxylamine hydrochloride and a hydroxylamine water solution are selected, wherein the molar ratio of hydroxylamine to the substrate II compound is 1-100: 1, preferably 5 to 20.
In one embodiment, the reaction is carried out under the following conditions: the reaction reagent is one or more of hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine aqueous solution or hydroxylamine alcohol solution, and hydroxyurea, preferably hydroxylamine hydrochloride or hydroxylamine aqueous solution. The alkali is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, preferably one or more of potassium carbonate or sodium hydroxide. The reaction solvent is a protic solvent, and preferably one or more of methanol, ethanol, and water. The reaction temperature is from room temperature to reflux temperature, preferably 20-100 ℃. The molar ratio of the reaction reagent to the substrate compound shown in the formula II is 1-100: 1, preferably 1 to 10: 1.
in one embodiment, compound VI is prepared as follows:
Figure BDA0002874513630000161
the reaction was carried out under the following conditions: the solvents used are protic solvents such as: hydrochloric acid, hydrobromic acid, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol, and the like. Hydrochloric acid, hydrobromic acid, methanol or ethanol, or a mixed solution thereof is preferred. The reaction temperature is-10 to 10 ℃; preferably-5 to 5 ℃. Sodium nitrite may be added in an amount of 1 to 5 equivalents, preferably 1 to 2 equivalents.
In some embodiments of the invention: the above reaction conditions were as follows: adding halogen acid into the substrate formula V compound, cooling to low temperature, adding sodium nitrite to react to obtain the formula VI compound. The low temperature is-10 to 10 ℃, and the optimal temperature is 0 to 5 ℃. The amount of sodium nitrite added is 1-5 equivalents relative to the substrate compound of formula V. Adding alcoholic protic solvent, preferably one or more of methanol, ethanol, propanol, isopropanol, n-butanol and isobutanol.
In one embodiment, the compound of formula VII is prepared as follows:
Figure BDA0002874513630000162
the reaction in the step is cyclized by ethylene under the alkalescent condition, and the reaction in the step has the advantages of high efficiency and mild reaction condition. The reaction was carried out under the following conditions: the solvents used are nonpolar or weakly polar aprotic solvents such as: petroleum ether, cyclohexane, dichloromethane, dichloroethane, chloroform, chlorobenzene, tetrahydrofuran, acetonitrile, and the like. Preferably dichloromethane or dichloroethane. The temperature is 0 ℃ to the reflux temperature; preferably 20 to 50 ℃. The alkali can be selected from: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine, ethylene oxide, and the like. Preferred are sodium carbonate, potassium carbonate, triethylamine and the like. 1-5 equivalents, preferably 1-2 equivalents, may be added.
In some embodiments of the invention, the reaction conditions are as follows: adding a substrate compound shown in formula VI into a solvent, adding alkali, and introducing ethylene gas to react to obtain a compound shown in formula VII. The solvent is selected from nonpolar or weak polar aprotic solvent, preferably one or more of petroleum ether, cyclohexane, dichloromethane, dichloroethane, chloroform, chlorobenzene, tetrahydrofuran and acetonitrile, and most preferably dichloromethane or dichloroethane. The reaction temperature is 0 ℃ to reflux temperature, and preferably 20-50 ℃. The base is selected from: sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, or triethylamine, or a combination of two or more thereof, and sodium carbonate, potassium carbonate, or triethylamine is most preferable. The amount of the base added is 1 to 5 equivalents, preferably 1 to 2 equivalents.
In one embodiment, the compounds of formula VIII are prepared by the following method
Figure BDA0002874513630000171
The reaction in this step is actually a step of oxidizing an alcohol to an acid, and it is generally considered that the oxidizing agent is a strong oxidizing agent such as potassium permanganate, chromium trioxide, potassium dichromate, ruthenium tetroxide, etc., which can also be used in the present invention, but in view of the yield and purity of the final product and the occurrence of side reactions, it is preferable to carry out the oxidation reaction by oxygen, which is relatively inexpensive and green, without a large amount of post-oxidation product treatment, and the post-treatment is greatly simplified as compared with sodium tungstate oxidation. Compared with the oxidation of m-chloroperoxybenzoic acid, the separation and purification of m-chloroperbenzoic acid are avoided.
Preferably, the conditions of the preparation reaction are a reaction with an oxidizing agent in an aprotic solvent;
preferably, the aprotic solvent is selected from dioxane, acetonitrile, chloroform, dimethyl sulfoxide, ethyl acetate, N-dimethylformamide, N-dimethylacetamide, pyridine, nitrobenzene, and the like;
preferably, the reaction temperature is from room temperature to reflux, preferably the reaction temperature is reflux temperature.
The preparation method of the 4, 5-dihydroisoxazole-3-benzoic acid provided by the invention comprises the following steps:
Figure BDA0002874513630000181
(1) chloromethylating the compound of formula I to produce a compound of formula II;
(2) hydrolyzing the compound shown in the formula II to generate a compound shown in the formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
in order to make the objects, technical solutions and advantages of the present invention clearer, the following specifically describes the present invention with reference to specific examples, which are only used to limit the specific methods and do not limit the scope of the present invention.
Examples
EXAMPLE 1 preparation of Compound II (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) 1
16.3g of Compound I (2-methyl-6-methylthiobenzonitrile) are dissolved in a mixed solution of 100mL of hydrofluoric acid and 50mL of 85% phosphoric acid, 30.0g of paraformaldehyde are added with stirring, hydrogen chloride gas is continuously and slowly introduced, stirring is carried out at 50 ℃ for 4 hours, the consumption of Compound 1 is almost complete as monitored by thin-layer chromatography, and the introduction of hydrogen chloride gas is stopped. After cooling to room temperature, 200mL of distilled water was added, ethyl acetate extraction (50mL × 3) was performed, the organic phase was collected and washed with 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and 18.0g of the objective product (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) was obtained by column chromatography, yield: 85.2 percent.
ESI-MS：[M+1]+212，1H NMR(400MHz,CDCl3)δ7.45(d,J＝8.2Hz,1H,Ar-H),7.11(d,J＝8.2Hz,1H,Ar-H),4.58(s,2H,CH2),2.61(s,3H,SCH3),2.55(s,3H,CH3).
EXAMPLE 1 preparation of Compound II (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) 2
16.3g of compound I (2-methyl-6-methylthiobenzonitrile) are dissolved in 100mL of dichloromethane solvent, 13.3g of aluminum trichloride are added with stirring, then 30.0g of methylal are added, hydrogen chloride gas is continuously and slowly introduced, stirring is carried out at a temperature of 30 ℃ for 6 hours, monitoring by thin layer chromatography, the starting compound I is almost completely consumed, and the introduction of gas is stopped. After cooling to room temperature, 200mL of distilled water was added, methylene chloride was extracted (50mL × 3), the organic phase was collected and washed with 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off under reduced pressure, and 16.5g of the objective product (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) was obtained by column chromatography, yield: 77.8 percent, and the compound is confirmed by mass spectrum. ESI-MS: [ M +1 ]]+212。
EXAMPLE 2-1 preparation of Compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile)
21.2g of compound II (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) was dissolved in 150mL of methanol, and a solution of 12.0g of NaOH in 30mL of methanol was added dropwise at room temperature, and stirred at room temperature for 4 hours, and it was found that the compound II was almost completely consumed by monitoring by thin layer chromatography, and then the solution was filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 18.5g of the objective product (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) in yield: 95.6 percent.
ESI-MS：[M+1]+194，1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.0Hz,1H,Ar-H),7.14(d,J＝8.0Hz,1H,Ar-H),4.68(s,2H,CH2),2.61(s,3H,SCH3),2.54(s,3H,CH3).
EXAMPLE 2 preparation of Compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) 2-2
21.2g of compound II (2-methyl-3-chloromethyl-6-methylthiobenzonitrile) was dissolved in 150mL of 95% ethanol, 12.0g of potassium carbonate in 30mL of 95% ethanol was added dropwise at room temperature, and after completion of the addition, the mixture was heated to reflux, stirred for 6 hours, and monitored by thin layer chromatography to find that compound II was almost completely consumed, and then filtered, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 16.8g of the objective product (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) in yield: 87.9%, identified as the compound by mass spectrometry, SI-MS: [ M +1 ]]+194。
EXAMPLE 3-1 preparation of Compound III (2-methyl-3-cyano-4-methylthiobenzaldehyde)
Dissolving 16.3g of compound I (2-methyl-6-methylthiobenzonitrile) in 150mL of acetic acid, adding 14.0g of urotropin (hexamethylenetetramine), heating under reflux for 6 hours, monitoring by thin layer chromatography, finding that compound I is almost completely consumed, distilling off most of the acetic acid under reduced pressure, adding 200mL of distilled water, extracting with ethyl acetate (50mL × 3), collecting the organic phase and washing with 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of a saturated aqueous salt solution in this order, drying over anhydrous sodium sulfate, filtering, distilling off the solvent, subjecting the residue to column chromatography to obtain 17.6g of the objective product (2-methyl-3-cyano-4-methylthiobenzaldehyde) in yield: 92.2 percent. ESI-MS: [ M +1 ]]+192
EXAMPLE 3-2 preparation of Compound III (2-methyl-3-cyano-4-methylthiobenzaldehyde)
16.3g of Compound I (2-methyl-6-methylthiobenzonitrile) was dissolved in 150mL of trifluoroacetic acid, 14.0g of urotropin (hexamethylenetetramine) was added, heated under reflux for 6 hours, and monitored by thin layer chromatography, and it was found that Compound I was almost completely consumed, most of the acetic acid was distilled off under reduced pressure, 200mL of distilled water and ethyl acetate (50 mL. times.3) were added, the organic phase was collected and washed with 50mL of a saturated aqueous sodium bicarbonate solution and 50mL of a saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, filtered, and the solvent was distilled off, and the residue was subjected to column chromatography to obtain 18.6g of the objective product (2-methyl-3-cyano-4-methylthiobenzaldehyde) in yield: 97.4 percent. ESI-MS: [ M +1 ]]+192
EXAMPLE 4-1 preparation of Compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile)
19.1g of Compound III (2-methyl-3-cyano-4-methylthiobenzaldehyde) was dissolved in 100mL of tetrahydrofuran, 5.67g of sodium borohydride was added, stirring was carried out at 50 ℃ for 4 hours, monitoring by thin layer chromatography revealed that Compound III was almost completely consumed, most of the solvent was distilled off under reduced pressure, 200mL of distilled water was carefully added, ethyl acetate (50 mL. times.3) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the residue was subjected to column chromatography to obtain 18.6g of the objective product (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) in yield: 96.4 percent.
ESI-MS：[M+1]+194，1H NMR(400MHz,CDCl3)δ7.53(d,J＝8.0Hz,1H,Ar-H),7.14(d,J＝8.0Hz,1H,Ar-H),4.68(s,2H,CH2),2.61(s,3H,SCH3),2.54(s,3H,CH3)
EXAMPLE 4 preparation of Compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) 2
19.1g of Compound III (2-methyl-3-cyano-4-methylthiobenzaldehyde) was dissolved in 100mL of tetrahydrofuran, 5.67g of lithium aluminum hydride was added, and the mixture was stirred at 0 ℃ for 4 hours and monitored by thin layer chromatography to find that Compound III was almost completely consumed, 200mL of distilled water was carefully added, ethyl acetate (50 mL. times.3) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was evaporated, and the residue was subjected to column chromatography to obtain 17.4g of the objective product (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) in yield: 90.5 percent.
EXAMPLE 5 preparation of Compound V (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) 1
19.3g of compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) was dissolved in 200mL of ethanol, 20.8g of hydroxylamine hydrochloride and 12.0g of sodium hydroxide were added, the mixture was refluxed for 8 hours, and after monitoring by thin layer chromatography, the compound IV was found to be almost completely reacted, and when the temperature was lowered to room temperature, sodium chloride was filtered off, the solvent was distilled off under reduced pressure, 200mL of distilled water was added, ethyl acetate (50 mL. times.3) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the residue was subjected to column chromatography to obtain 19.6g of the objective product (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) in yield: 86.7 percent.
ESI-MS：[M+1]+227，1H NMR(400MHz,DMSO)δ9.21(s,1H,NOH),7.35(d,J＝8.0Hz,1H,Ar-H),7.10(d,J＝8.0Hz,1H,Ar-H),5.64(s,2H,NH2),5.10(t,J＝5.3Hz,1H,OH),4.45(d,J＝5.1Hz,2H,CH2),2.36(s,3H,SCH3),2.15(s,3H,CH3).
EXAMPLE 5 preparation of Compound V (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) 2
19.3g of compound IV (2-methyl-3-hydroxymethyl-6-methylthiobenzonitrile) was dissolved in 200mL of ethanol, 20.0g of hydroxylamine was added, the mixture was refluxed for 8 hours, and when it was found by monitoring through thin layer chromatography that the compound IV was almost completely reacted and cooled to room temperature, sodium chloride was filtered off, the solvent was distilled off under reduced pressure, 200mL of distilled water was added, ethyl acetate (50 mL. times.3) was extracted, the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the solvent was distilled off, and the residue was subjected to column chromatography to obtain 19.0g of the objective product (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) in yield: 84.0%, confirmed by mass spectrometry as the compound, ESI-MS: [ M +1 ]]+227。
EXAMPLE 6 preparation of Compound VI (N-hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzimidoyl chloride) of 1
Suspending 11.3g of compound V (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) in 100mL of 6N hydrochloric acid, cooling to 0 ℃, slowly adding dropwise 3.62g of an aqueous solution of sodium nitrite 10mL, stirring while maintaining the temperature for 1 hour, monitoring by thin layer chromatography to find that the compound V is almost completely consumed, extracting with toluene (50mL × 3), collecting the organic phase, washing the organic phase with 50mL of a saturated aqueous solution of sodium bicarbonate and 50mL of a saturated aqueous solution of sodium chloride, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, subjecting the residue to column chromatography to obtain a target product, and subjecting the residue to column chromatography to obtain 8.9g of the target product (N-hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidoyl chloride), wherein the yield is as follows: 72.5 percent.
ESI-MS：[M+1]+247，1H NMR(400MHz,CDCl3)δ10.19(s,1H,NOH),7.43(d,J＝8.0Hz,1H,Ar-H),7.09(d,J＝8.0Hz,1H,Ar-H),4.67(s,2H,CH2),2.51(s,3H,SCH3),2.45(s,3H,CH3).
EXAMPLE 6 preparation of Compound VI (N-hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzimidoyl chloride) 2
Suspending 11.3g of compound V (N' -hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzamidine) in 100mL of 6N (molar equivalent) hydrochloric acid, cooling to 0 ℃, slowly adding 10mL of an aqueous solution of 3.62g of sodium nitrite dropwise, stirring at a constant temperature for 1 hour, adding 1.2g of cuprous chloride, monitoring by thin-layer chromatography to find that the compound V is almost completely consumed, extracting with toluene (50 mL. times.3), collecting an organic phase, washing the organic phase with 50mL of a saturated aqueous solution of sodium bicarbonate and 50mL of saturated saline solution in sequence, drying with anhydrous sodium sulfate, filtering, evaporating the solvent, carrying out column chromatography on the residue to obtain 9.0g of a target product (N-hydroxy-3-hydroxymethyl-2-methyl-6-methylthiobenzimidinimidoyl chloride), yield: 73.3%, confirmed by mass spectrometry as the compound, ESI-MS: [ M +1 ]]+247。
EXAMPLE 7 preparation of Compound VII ((3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfanyl) benzyl alcohol)
12.3g of the compound was dissolved in 150mL of methylene chloride, 5.57g of triethylamine was added, and after the gas in the reaction flask was replaced with ethylene three times, the ethylene gas pressure was maintained at 20mmHg, and the mixture was stirred at room temperature for 18 hours. Upon monitoring by thin layer chromatography, it was found that compound VI was almost completely consumed, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 10.6g of the objective product ((3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylthio) benzyl alcohol), yield: 89.2 percent.
ESI-MS：[M+1]+238，1H NMR(400MHz,CDCl3)δ7.38(d,J＝8.1Hz,1H,Ar-H),7.16(d,J＝8.1Hz,1H,Ar-H),4.61(s,2H,OH),4.53(t,J＝10.0Hz,2H,NOCH2),3.26(t,J＝10.0Hz,2H,CH2),2.44(s,3H,SCH3),2.21(s,3H,CH3).
EXAMPLE 8 preparation of the Compound VIII ((3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonyl) benzoic acid)
11.9g of compound VII was dissolved in 100mL of 1, 4-dioxane, heated to reflux, then oxygen was slowly introduced, after 8 hours, monitoring by thin layer chromatography revealed that compound VII was almost completely consumed, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography to obtain 11.2g of the target product ((3- (4, 5-dihydroisoxazol-3-yl) -2-methyl-4-methylsulfonyl) benzoic acid), yield: 78.8 percent.
ESI-MS：[M-1]-282，1H NMR(400MHz,DMSO)δ13.60(br,1H,CO2H)7.99(m,2H,Ar-H),4.47(t,J＝10.0Hz,2H,NOCH2),3.33(t,J＝10.0Hz,2H,CH2),3.24(s,3H,SO2CH3),2.42(s,3H,CH3)。

Claims (10)

1. A compound of formula A, characterized in that,
Figure FDA0002874513620000011
wherein R is1Is haloalkyl, hydroxyalkyl, aldehyde group, carboxylic acid group; r2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is an alkyl substituted thio group, an alkylsulfonyl group, an alkylsulfidenyl group, said alkyl group being independently selected from methyl, ethyl, propyl, isopropyl; preferably, R1Is halomethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is alkyl substituted sulfenyl, alkyl sulfonyl, alkyl sulfoxide, the alkyl is independently selected from methyl, ethyl, propyl, isopropyl, the halogenated alkyl is alkyl chloride, alkyl bromide; more preferably, R1Is chloromethyl, hydroxymethyl, aldehyde group, carboxylic acid group, R2Is methyl; r3Is cyano, chloro-substituted oximino, 4, 5-dihydroisoxazol-3-yl; r4Is methylthio.
2. A preparation method of a compound shown in a general formula IV is characterized in that the compound is prepared by raw materials shown in a general formula I
Figure FDA0002874513620000012
Preferably, the preparation process is that the compound of the general formula II or the general formula III is prepared by the general formula I, and the general formula IV is prepared;
Figure FDA0002874513620000013
3. a preparation method of a compound of a general formula II is characterized in that the compound is obtained by the following preparation reaction of a compound of a general formula I
Figure FDA0002874513620000021
Preferably, the conditions of the preparation reaction are: reacting the compound I with aldehyde in a protic solvent or a weak polar aprotic solvent under the action of acid;
preferably, the aldehyde is formaldehyde, paraformaldehyde, methylal or chloromethyl methyl ether, more preferably paraformaldehyde or methylal;
the protic solvent or the weak polar aprotic solvent is hydrofluoric acid, hydrochloric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane, chloroform, ethyl acetate, butyl acetate, acetonitrile, tetrahydrofuran, 1, 4-dioxane, diethyl ether or isopropyl ether, more preferably, the protic solvent or the weak polar aprotic solvent is one or more of hydrofluoric acid, sulfuric acid, phosphoric acid, dichloromethane, dichloroethane or isopropyl ether, and more preferably a dichloromethane mixed solution of hydrofluoric acid and phosphoric acid;
the acid is protonic acid or Lewis acid, and more preferably hydrogen chloride or aqueous hydrochloric acid thereof, hydrogen fluoride or aqueous hydrofluoric acid thereof, sulfuric acid or phosphoric acid; more preferably, the lewis acid is aluminum trichloride, zinc chloride, ferric trichloride, stannic chloride; preferably, hydrogen chloride or aluminum trichloride;
preferably, the reaction temperature is between-10 ℃ and reflux temperature, preferably 0-80 ℃; the molar ratio of the reaction reagent to the substrate compound shown in the formula I is (1-100): 1, preferably 1 to 10: 1.
4. a preparation method of a compound shown in a general formula IV is characterized in that the compound is obtained by the following general formula II preparation reaction
Figure FDA0002874513620000022
Preferably, the reaction conditions of the preparation method are that the compound II is reacted in a solvent under basic conditions;
preferably, the alkaline agent of the alkaline condition is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, preferably one or more than two of sodium acetate, potassium carbonate or sodium hydroxide;
the solvent is preferably methanol, ethanol, acetonitrile, tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, dimethyl sulfoxide, etc., and more preferably any one or two of methanol, ethanol or N, N-dimethylformamide;
preferably, the reaction temperature is from room temperature to reflux temperature, preferably from 20 ℃ to 80 ℃; the molar ratio of the reaction alkaline reagent to the substrate compound shown in the formula II is (1-100): 1, preferably (1 to 10): 1.
5. a preparation method of a compound shown in a general formula III is characterized in that the compound is obtained by the following general formula I preparation reaction
Figure FDA0002874513620000031
Preferably, the conditions of the preparation reaction are: adding urotropine into acetic acid or trifluoroacetic acid to react to obtain the compound;
preferably, the reaction is carried out at a temperature ranging from room temperature to reflux temperature, preferably reflux temperature; more preferably, the molar ratio of the urotropine to the substrate compound of formula I is (1-20): 1, preferably (5-10): 1.
6. a preparation method of a compound shown in a general formula IV is characterized in that the compound is obtained by the following general formula III preparation reaction
Figure FDA0002874513620000032
Preferably, the preparation reaction conditions are that the reduction reaction is carried out in a solvent under alkaline conditions;
preferably, the alkaline reagent under alkaline conditions is sodium borohydride or lithium aluminum hydride, preferably any one or more of sodium borohydride, lithium aluminum hydride and borane;
preferably, the solvent is one or two of tetrahydrofuran, 1, 4-dioxane, N-dimethylformamide, methanol, ethanol, acetonitrile, dimethyl sulfoxide or water solution of the above solvents; (ii) a More preferably any one or two of tetrahydrofuran, 1, 4-dioxane, methanol, ethanol or an aqueous solution of the above solvents;
preferably, the reaction temperature is between room temperature and reflux temperature, and more preferably 20-80 ℃;
preferably, the molar ratio of the reaction alkaline reagent to the substrate compound of the formula III is (1-100): 1, preferably (1 to 10): 1.
7. a preparation method of a compound shown in a general formula V is characterized in that the compound is obtained by the following general formula IV preparation reaction
Figure FDA0002874513620000041
Preferably, the conditions of the preparation reaction are that hydroxylamine is reacted in a protic solvent under alkaline conditions;
preferably, the protic solvent is water, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; more preferably the protic solvent is one or more of water, methanol, ethanol or isopropanol;
preferably, the hydroxylamine is selected from the group consisting of free hydroxylamine and aqueous or alcoholic solutions thereof, hydroxylamine hydrochloride, hydroxylamine sulphate, hydroxyurea; preferably hydroxylamine hydrochloride or an aqueous solution of hydroxylamine;
preferably, the agent of alkaline conditions used is potassium hydroxide, sodium acetate, sodium carbonate or potassium carbonate, more preferably either or both potassium carbonate or sodium hydroxide;
preferably, the reaction temperature is between room temperature and reflux temperature, preferably 20-100 ℃, and more preferably 50-80 ℃; the molar ratio of the reaction reagent to the substrate compound shown in the formula IV is (1-100): 1, preferably (1 to 10): 1.
8. a method for preparing a compound of a general formula VI, which is characterized in that the compound is prepared by a compound of a general formula V
Figure FDA0002874513620000042
Preferably, the preparation reaction condition is that hydrohalic acid is added into a protic solvent to react with sodium nitrite;
preferably, the protic solvent is hydrochloric acid, hydrobromic acid, methanol, ethanol, propanol, isopropanol, n-butanol, isobutanol; preferably one or more of hydrochloric acid, hydrobromic acid, methanol or ethanol;
preferably, the reaction temperature is-10 ℃ to 10 ℃; preferably-5 ℃ to 5 ℃, and the ratio of the added amount of the sodium nitrite to the substrate compound of the formula V is (1-5): 1, preferably (1-2): 1.
9. a preparation method of a compound of a general formula VII is characterized in that the compound is obtained by the following preparation reaction of a compound of a general formula VI
Figure FDA0002874513620000051
Preferably, the conditions of the preparation reaction are a reaction with ethylene in the presence of a base in a nonpolar or weakly polar aprotic solvent;
preferably, the non-polar or weakly polar aprotic solvent is petroleum ether, cyclohexane, dichloromethane, dichloroethane, chloroform, chlorobenzene, tetrahydrofuran, acetonitrile; more preferably dichloromethane or dichloroethane;
preferably, the base is selected from sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, triethylamine; more preferably, the alkali is one or more of sodium carbonate, potassium carbonate and triethylamine;
preferably, the reaction temperature is 0 ℃ to reflux temperature; preferably 20-50 ℃; the ratio of the base added to the substrate compound of formula VI is (1-5): 1, preferably (1-2): 1.
10. a preparation method of a compound of a general formula VIII is characterized in that the compound is obtained by the following preparation reaction of a compound of a general formula VII
Figure FDA0002874513620000052
Preferably, the conditions of the preparation reaction are a reaction with an oxidizing agent in an aprotic solvent;
preferably, the aprotic solvent is selected from dichloromethane, dichloroethane, dioxane, dimethyl sulfoxide, ethyl acetate, acetonitrile, N-dimethylformamide, N-dimethylacetamide, pyridine, nitrobenzene, and the like;
preferably, the oxidant is selected from oxygen, hydrogen peroxide and its aqueous solution, m-chloroperoxybenzoic acid, sodium tungstate, manganese dioxide, sodium chlorate, potassium permanganate and the like, preferably oxygen, hydrogen peroxide, manganese dioxide, sodium chlorate;
preferably, the reaction temperature is from room temperature to reflux, preferably the reaction temperature is reflux temperature;
preferably, the preparation method of the compound of the general formula VIII is characterized in that the compound is prepared by the following intermediate reaction of the raw material of the general formula I
Figure FDA0002874513620000061
Preferably, the reaction of each step is as follows:
(1) chloromethylating the compound of formula I to produce a compound of formula II;
(2) hydrolyzing the compound shown in the formula II to generate a compound shown in the formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
more preferably, the preparation method of the compound of the general formula VIII is characterized in that the compound is prepared by the following intermediate reaction of the raw material of the general formula I
Figure FDA0002874513620000062
Preferably, the reaction of each step is as follows:
(1) the compound of formula I is subjected to aldehyde group formation to generate a compound of formula III;
(2) hydrolyzing the compound shown in the formula III to generate a compound shown in a formula IV;
(3) carrying out a hydroxylamination reaction on the compound shown in the formula IV to generate a compound shown in the formula V;
(4) diazotizing and halogenating the compound of the formula V to generate a compound of a formula VI;
(5) carrying out dipolar cycloaddition on the compound shown in the formula VI to generate a compound shown in the formula VII;
(6) oxidizing the compound shown in the formula VII to generate a compound shown in the formula VIII;
more preferably, the preparation method of the compound of the general formula VIII is characterized in that the method is prepared by reacting the raw material of the general formula I through the following intermediates under the following reaction conditions:
Figure FDA0002874513620000071
CN202011624421.3A 2020-12-30 2020-12-30 Novel compound and method for preparing topramezone intermediate by using same Active CN112745270B (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114907234A (en) * 2022-05-07 2022-08-16 南京杰运医药科技有限公司 Preparation method of 2-fluoro-5-formylbenzonitrile
CN116640071A (en) * 2023-05-04 2023-08-25 四川青木制药有限公司 Method for preparing 2-methyl 4-formaldehyde oximino benzoic acid and ester derivatives thereof
WO2024088279A1 (en) * 2022-10-25 2024-05-02 帕潘纳(北京)科技有限公司 Preparation method for topramezone intermediate

Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000319251A (en) * 1998-07-14 2000-11-21 Nippon Soda Co Ltd Production of aromatic thioether compound
US20080242666A1 (en) * 2004-12-23 2008-10-02 Colin Andrew Leach 1-6-Substituted (3R,6R)-3-(2,3-Dihydro-1H-Inden-2-Yl)-2,5-Piperazinedione Derivatives as Oxytocin Receptor Antagonists For the Treatment of Preterm Labour, Dysmenorrhea and Endometriosis
US20100261698A1 (en) * 2008-06-27 2010-10-14 Christopher Adams Organic compounds
CN101928233A (en) * 2009-10-23 2010-12-29 湖北迅达药业股份有限公司 Cholromethylation method of benzoic acid derivative
US20120101134A1 (en) * 2009-06-26 2012-04-26 Glaxo Group Limited 5-membered heteroaryl derivatives used as sphingosine 1-phosphate receptor agonists
CN103788083A (en) * 2014-03-10 2014-05-14 中国药科大学 Method for preparing herbicide topramezone
CN103880775A (en) * 2012-12-21 2014-06-25 安徽省庆云医药化工有限公司 Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat
US20150353581A1 (en) * 2013-03-15 2015-12-10 Eli Lilly And Company 1-hydroxy-benzooxaboroles as antiparasitic agents
CN108218851A (en) * 2018-03-09 2018-06-29 安徽久易农业股份有限公司 It is a kind of to improve the method for preparing topramezone
US20190077814A1 (en) * 2016-03-02 2019-03-14 Yong-Kang Zhang Boron-containing small molecules
CN110183392A (en) * 2019-06-14 2019-08-30 河北医科大学 A kind of preparation method and its usage and intermediate of 3- substituted-phenyl -4,5- dihydro-isoxazole derivative

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2000319251A (en) * 1998-07-14 2000-11-21 Nippon Soda Co Ltd Production of aromatic thioether compound
US20080242666A1 (en) * 2004-12-23 2008-10-02 Colin Andrew Leach 1-6-Substituted (3R,6R)-3-(2,3-Dihydro-1H-Inden-2-Yl)-2,5-Piperazinedione Derivatives as Oxytocin Receptor Antagonists For the Treatment of Preterm Labour, Dysmenorrhea and Endometriosis
US20100261698A1 (en) * 2008-06-27 2010-10-14 Christopher Adams Organic compounds
US20120101134A1 (en) * 2009-06-26 2012-04-26 Glaxo Group Limited 5-membered heteroaryl derivatives used as sphingosine 1-phosphate receptor agonists
CN101928233A (en) * 2009-10-23 2010-12-29 湖北迅达药业股份有限公司 Cholromethylation method of benzoic acid derivative
CN103880775A (en) * 2012-12-21 2014-06-25 安徽省庆云医药化工有限公司 Preparation methods of compound 2-(3-formyl-4-isobutoxy phenyl)-4-methyl thiazole-5-ethyl formate and febuxostat
US20150353581A1 (en) * 2013-03-15 2015-12-10 Eli Lilly And Company 1-hydroxy-benzooxaboroles as antiparasitic agents
CN103788083A (en) * 2014-03-10 2014-05-14 中国药科大学 Method for preparing herbicide topramezone
US20190077814A1 (en) * 2016-03-02 2019-03-14 Yong-Kang Zhang Boron-containing small molecules
CN108218851A (en) * 2018-03-09 2018-06-29 安徽久易农业股份有限公司 It is a kind of to improve the method for preparing topramezone
CN110183392A (en) * 2019-06-14 2019-08-30 河北医科大学 A kind of preparation method and its usage and intermediate of 3- substituted-phenyl -4,5- dihydro-isoxazole derivative

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
F. FRINGUELLI等: "CHEMOSELECTIVE OXIDATIONS IN WATER OF FUNCTIONAL GROUPS", 《SYNTHETIC COMMUNICATIONS》 *
SIMON J. TEAGUE等: "Synthesis of 6-substituted 5-cyano-7-hydroxy-2-carboxybenzofurans", 《TETRAHEDRON LETTERS》 *
STAMATIA VASSILIOU等: "Structure-Guided, Single-Point Modifications in the Phosphinic Dipeptide Structure Yield Highly Potent and Selective Inhibitors of Neutral Aminopeptidases", 《J. MED. CHEM.》 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114907234A (en) * 2022-05-07 2022-08-16 南京杰运医药科技有限公司 Preparation method of 2-fluoro-5-formylbenzonitrile
CN114907234B (en) * 2022-05-07 2024-07-16 南京杰运医药科技有限公司 Preparation method of 2-fluoro-5-formylbenzonitrile
WO2024088279A1 (en) * 2022-10-25 2024-05-02 帕潘纳(北京)科技有限公司 Preparation method for topramezone intermediate
CN116640071A (en) * 2023-05-04 2023-08-25 四川青木制药有限公司 Method for preparing 2-methyl 4-formaldehyde oximino benzoic acid and ester derivatives thereof

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