CN112441983B - Benzimidazole-substituted nitrobenzene-based compound and preparation method thereof - Google Patents

Benzimidazole-substituted nitrobenzene-based compound and preparation method thereof Download PDF

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CN112441983B
CN112441983B CN201910807646.3A CN201910807646A CN112441983B CN 112441983 B CN112441983 B CN 112441983B CN 201910807646 A CN201910807646 A CN 201910807646A CN 112441983 B CN112441983 B CN 112441983B
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sodium
potassium
acid
magnesium
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CN112441983A (en
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孙长亮
朱富强
张骏驰
李锐
沈敬山
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Shandong Fuchang Pharmaceutical Co ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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Shandong Fuchang Pharmaceutical Co ltd
Shanghai Institute of Materia Medica of CAS
Topharman Shanghai Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/18—Benzimidazoles; Hydrogenated benzimidazoles with aryl radicals directly attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/80—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings

Abstract

The present disclosure relates to benzimidazole substituted nitrobenzene based compounds and methods of making the same. The method can avoid nitration and polyphosphoric acid cyclization reaction, and avoid the generation of a large amount of waste acid reaction liquid from the source. The synthesis method has the advantages of low material cost, less pollutant, simple and convenient operation, mild condition and the like, and is suitable for development into a green sustainable production process.

Description

Benzimidazole-substituted nitrobenzene-based compound and preparation method thereof
Technical Field
The present disclosure relates to a pharmaceutical compound and a method of preparing the same. In particular, the present disclosure relates to benzimidazole substituted nitrobenzene based compounds and methods of making the same.
Background
Telmisartan (telmsiartan) is a novel non-peptide angiotensin II (ATII-type) receptor antagonist, a novel antihypertensive drug for clinical treatment. Telmisartan was first developed by the bringen john pharmaceutical company (Boehringer Ingelheim) and was first marketed in the united states in 3 months 1999 and subsequently in many other countries around the world. Telmisartan has the chemical name 4'- [ (1, 4' -dimethyl-2 '-propyl [2,6' -di-1H-benzoimidazole ] -1 '-yl) methyl ] - [1,1' -biphenyl ] -2-carboxylic acid, and the structure is as follows:
The telmisartan molecular structure contains two connected benzimidazole rings, and the construction of the bisbenzimidazole ring structure is the important strategy for synthesizing the telmisartan molecules. Of the many bis-benzimidazole intermediate compounds, 2-n-propyl-4-methyl-6- (1' -methylbenzo [ d ] imidazol-2-yl) benzimidazole, the most involved intermediate compound in the known telmisartan synthesis route, is the most typical.
In the currently known synthetic method route, a synthetic strategy of constructing a benzimidazole ring in the middle of a structure and then constructing another benzimidazole ring in the terminal position of the structure is mainly adopted. For the construction of benzimidazole ring in the middle of the structure, substituted n-butyrylaniline is generally used as a raw material, and the steps of introducing nitro group through ortho-nitration of the aromatic ring of n-butyrylamino, reducing the nitro group into amino group, condensing and closing the ring and the like are carried out. There are still many problems in the synthetic route under this strategy, such as the problem of safety in the nitration reaction and the problem of disposal of the nitration waste liquid, the problem of disposal of a large amount of waste acid liquid and waste acid neutralization waste liquid generated by forming the second imidazole ring in polyphosphoric acid or strong acid, and the like.
Therefore, it is important to find and develop a new synthesis route and process condition of telmisartan bisbenzimidazole intermediate compound which is safer, more environment-friendly, simpler, more efficient, mild in condition and low in cost and is suitable for industrial production. Meanwhile, the new method also meets the requirements of an ESH management system, accords with the higher pursuit and concept of safe and environment-friendly green synthesis, and is suitable for development into a green sustainable production process.
Disclosure of Invention
It is an object of the present disclosure to provide benzimidazole substituted nitrobenzene based compounds or salts thereof.
It is an object of the present disclosure to provide a process for the preparation of benzimidazole substituted nitrobenzene based compounds.
According to one embodiment of the present disclosure, there is provided a compound represented by formula III:
in particular, the salt is a salt III.HX formed by a compound shown in formula III and an acid, wherein HX is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, formic acid and acetic acid. According to one embodiment of the present disclosure, there is provided a process for preparing a compound of formula III, which is one of the following processes:
the method comprises the following steps: is prepared by reacting a compound shown in a formula IV-1 with a methylating agent,
in particular, the methylating agent is selected from methyl iodide, dimethyl sulfate and dimethyl carbonate;
in particular, the reaction is carried out in a solvent under an alkaline reagent,
in particular, the alkaline agent is a mixture of one or more selected from the group consisting of alkali metal inorganic bases, alkaline earth metal inorganic bases, alkali metal organic bases, alkaline earth metal organic bases and other organic bases, preferably from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium phosphate monobasic, potassium phosphate monobasic, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, the solvent is one or a mixture of more selected from tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methanol, ethanol, isopropanol, N-butanol, tertiary butanol, ethylene glycol, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide and water;
the second method is as follows: prepared from a compound represented by formula V-1,
step (1), 3-methyl-4-nitrobenzoyl chloride V-2 is prepared by taking 3-methyl-4-nitrobenzoic acid V-1 as a starting material through chlorination reaction;
step (2), reacting the compound shown in the formula V-2 with N-methyl o-phenylenediamine to obtain compounds shown in the formulas IV-2 and IV-3;
step (3), the compounds shown in the formulas IV-2 and IV-3 undergo condensation reaction in the presence of an acidic reagent, an alkaline reagent or a condensation reagent to obtain a compound shown in the formula III;
in particular, in the step (1), the chlorinating agent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate (triphosgene);
in particular, in step (1), the chlorination is carried out in a solvent, in particular, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether, preferably dichloromethane;
In particular, in step (2), an alkaline agent is added or not, and the added alkaline agent can be used as an acid-binding agent; in particular, the alkaline reagent is one or a mixture of several selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium hydrogen phosphate, potassium hydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
in particular, step (2) is carried out in a solvent, in particular, the solvent used is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water;
In particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
in particular, in the step (3), the acidic reagent used is one or a mixture of several selected from conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (3), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (3), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
in particular, in the step (3), the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
And a third method: prepared from a compound represented by formula V-1,
step (1), 3-methyl-4-nitrobenzoic acid reacts with N-methyl o-phenylenediamine in the presence of an acidic reagent or a condensation reagent to obtain compounds shown in formulas IV-2 and IV-3;
Step (2), the compounds shown in the formulas IV-2 and IV-3 are reacted under the conditions of the acidic reagent, the condensation reagent or the alkaline reagent in the step (1) to obtain the compound shown in the formula III;
in particular, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compounds shown in the formulas IV-2 and IV-3 prepared by the step (1) are not separated under the condition of an acid reagent or a condensation reagent, and the compound shown in the formula III is continuously prepared under the reaction condition of the step (1);
in particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (1), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
In particular, in step (2), the acidic reagent or condensing reagent used is as defined in step (1).
In particular, in step (2), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in the step (1) and the step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
The method four: prepared from a compound represented by the formula V-3 or V-4,
step (1), 3-methyl-4-nitrobenzoic acid methyl ester or 3-methyl-4-nitrobenzoic acid ethyl ester reacts with N-methyl o-phenylenediamine in the presence of an acidic reagent or an alkaline reagent to obtain compounds shown in formulas IV-2 and IV-3;
Step (2), reacting the compounds shown in the formulas IV-2 and IV-3 under the conditions of the acidic reagent, the alkaline reagent or the condensing reagent in the step (1) to obtain a compound shown in the formula III;
in particular, the step (1) and the step (2) are carried out by using a one-pot method, namely, the compounds shown in the formulas IV-2 and IV-3 prepared by the step (1) are not separated under the condition of an acid reagent or an alkaline reagent, and the compound shown in the formula III is continuously prepared under the reaction condition of the step (1);
in particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (1), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (2), the acidic reagent or basic reagent used is as defined in step (1).
In particular, in step (2), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
in particular, step (1) and step (2) are carried out in a solvent, in particular, a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
And a fifth method: prepared from a compound represented by formula V-5,
step (1), 3-methyl-4-nitrobenzonitrile is used as a starting material, and reacts with N-methyl o-phenylenediamine in the presence of an acidic reagent to prepare a compound shown in a formula IV-5;
step (2), cyclizing the compound shown in the formula IV-5 to prepare a compound shown in the formula III, wherein in step (1), the acid reagent is one or a mixture of more selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
in particular, in step (1), the reaction is carried out in a solvent or using solvent-free reaction conditions, in particular, the solvent is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene.
According to one embodiment of the present disclosure, wherein, in method five, step (2) is performed according to one of three methods:
the method comprises the steps of (a) reacting a compound shown in a formula IV-5 with an electrophilic halogenated reagent, and then reacting with an alkaline reagent to obtain a compound shown in a formula III;
In particular, in process (a), the electrophilic halogenating agent used is selected from Cl 2 、Br 2 、I 2 One or a mixture of several of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dichlorohydantoin, dibromohydantoin, trichloroisocyanuric acid, sodium hypochlorite and calcium hypochlorite, preferably N-chlorosuccinimide (NCS);
in particular, in the method (a), the alkaline agent used is one or a mixture of several selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide.
The method (b) is that the compound shown in the formula IV-5 reacts with a +3 iodine reagent to generate oxidation cyclization reaction to obtain a compound shown in the formula III;
in particular, in process (b), the +3 valent iodine reagent used is selected from iodobenzene acetate (PhI (OAc) 2 ) Iodobenzene trifluoroacetate (PhI (OTFA) 2 ) Iodobenzene pivalate (PhI (OPiv) 2 ) Iodobenzene oxide (PhIO), diiodobenzene (PhICl) 2 ) One or a mixture of several of them;
in particular, the process (b) is carried out in a solvent selected from acetonitrile, benzonitrile, anisole, toluene, chlorobenzene, acetic acid, trifluoroacetic acid, trifluoroethanol, hexafluoroisopropanol, N-dimethylformamide, acetone, water or a mixture of several thereof, preferably trifluoroethanol.
In the method (c), a compound shown in a formula IV-5 undergoes an oxidative cyclization reaction in the presence of a copper catalyst and an oxidant to obtain a compound shown in a formula III;
in particular, in the method (c), the copper catalyst used is one or a mixture of several selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate and cupric nitrate;
in particular, in the method (c), the oxidizing agent used is one or a mixture of several selected from oxygen, hydrogen peroxide, potassium peroxodisulfate, sodium peroxodisulfate, ammonium peroxodisulfate, tert-butyl peroxide, peracetic acid, benzoyl peroxide, m-chloroperoxybenzoic acid, pyridine-N-oxide, p-benzoquinone, dichloro Dicyanobenzoquinone (DDQ), N-chlorobutyronimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dichlorohydantoin, dibromohydantoin, trichloroisocyanuric acid, sodium hypochlorite, calcium hypochlorite;
In particular, the process (c) is carried out in a solvent selected from acetonitrile, benzonitrile, dioxane, anisole, toluene, xylene, chlorobenzene, acetic acid, trifluoroacetic acid, trifluoroethanol, hexafluoroisopropanol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, water or a mixture of several thereof.
According to one embodiment of the present disclosure, wherein the compound of formula IV-1 is prepared by one of the following methods:
method I:
step (1), 3-methyl-4-nitrobenzoyl chloride V-2 is prepared by taking 3-methyl-4-nitrobenzoic acid as a starting material through chlorination reaction;
step (2), reacting a compound shown in a formula V-2 with o-phenylenediamine, and reacting under the condition of an alkaline reagent to obtain a compound shown in a formula IV-4;
step (3), the compound shown in the formula IV-4 undergoes condensation reaction in the presence of an acidic reagent, an alkaline reagent or a condensation reagent to obtain a compound shown in the formula IV-1;
in particular, in the step (1), the chlorinating agent used in the chlorination reaction is one or a mixture of more selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene and bis (trichloromethyl) carbonate (triphosgene);
In particular, in step (1), the chlorination is carried out in a solvent, in particular, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether, preferably dichloromethane;
in particular, in step (2), an alkaline agent is used as an acid-binding agent, in particular, the alkaline agent is one or a mixture of several selected from lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium isopropoxide, sodium isopropoxide, lithium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, step (2) is carried out in a solvent, in particular, the solvent used is selected from one or more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water;
in particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula V-2 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
in particular, in the step (3), the acidic reagent used is one or a mixture of several selected from conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (3), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (3), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
in particular, in the step (3), the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, tert-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
Method II:
step (1), 3-methyl-4-nitrobenzoic acid reacts with o-phenylenediamine in the presence of an acidic reagent or a condensation reagent to obtain a compound shown in a formula IV-4;
step (2), reacting the compound shown in the formula IV-4 under the conditions of the acidic reagent and the condensation reagent in the step (1) or under the alkaline reagent to obtain the compound shown in the formula IV-1;
in particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula IV-4 prepared in the step (1) is directly subjected to the reaction of the step (2) without separation;
in particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (1), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
in particular, in step (2), the acidic reagent or condensing reagent used is as defined in step (1).
In particular, in step (2), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in the step (1) and the step (2), the solvent used is one or a mixture of several selected from methylene chloride, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
Method III:
step (1), 3-methyl-4-nitrobenzoic acid methyl ester or 3-methyl-4-nitrobenzoic acid ethyl ester reacts with o-phenylenediamine in the presence of an acidic reagent or an alkaline reagent to obtain a compound shown in a formula IV-4;
step (2), reacting the compound shown in the formula IV-4 under the conditions of the acidic reagent and the alkaline reagent in the step (1) or under the condition of a condensation reagent to obtain the compound shown in the formula IV-1;
in particular, the step (1) and the step (2) are carried out by a one-pot method, namely, the compound shown in the formula IV-4 prepared by the step (1) is not separated under the condition of an acid reagent or an alkaline reagent, and the compound shown in the formula IV-1 is continuously prepared under the reaction condition of the step (1);
in particular, in the step (1), the acidic reagent used is one or a mixture of several selected from the group consisting of conventional inorganic proton acids, organic carboxylic acids, organic sulfonic acids, organic phosphoric acids, organic lewis acids and inorganic lewis acids. Preferably hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride and titanium tetrachloride;
In particular, in step (1), the alkaline agent used is selected from alkali metal organic bases, alkaline earth metal organic bases, alkali metal fluorides, preferably lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, or a mixture of several thereof.
In particular, in step (2), the acidic reagent and the basic reagent used are as defined in step (1).
In particular, in step (2), the condensation reagent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-dicyanoimidazole, N' -carbonyldiimidazole, dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, 1-hydroxybenzotriazole, O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium hexafluorophosphate, tri-orthoformate, tetra-orthoformate, tri-orthoacetate, tetra-orthoacetate;
in particular, step (1) and step (2) are carried out in a solvent, in particular, a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, or a solvent-free reaction condition is used.
Method IV:
step (1), 3-methyl-4-nitrobenzonitrile is taken as a starting material, and reacts with aniline in the presence of an acidic reagent to prepare a compound shown in a formula IV-6;
step (2), cyclizing the compound shown in the formula IV-6 to prepare the compound shown in the formula IV-1,
in particular, in step (1), the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride;
in particular, in step (1), the reaction is carried out in a solvent or using solvent-free reaction conditions, in particular, the solvent is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene.
According to one embodiment of the present disclosure, wherein, in method IV, step (2) is performed according to one of three methods:
the method comprises the steps of (a) reacting a compound shown in a formula IV-6 with an electrophilic halogenated reagent, and then reacting with an alkaline reagent to obtain a compound shown in a formula IV-1;
In particular, in process (a), the electrophilic halogenating agent used is selected from Cl 2 、Br 2 、I 2 One or a mixture of several of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dichlorohydantoin, dibromohydantoin, trichloroisocyanuric acid, sodium hypochlorite and calcium hypochlorite, preferably N-chlorosuccinimide (NCS),
in particular, in the method (a), the alkaline agent used is one or a mixture of several selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide;
the method (b) is that the compound shown in the formula IV-6 reacts with a +3 iodine reagent to generate oxidation cyclization reaction to obtain the compound shown in the formula IV-1,
in particular, in process (b), the +3 valent iodine reagent used is selected from iodobenzene acetate (PhI (OAc) 2 ) Iodobenzene trifluoroacetate (PhI (OTFA) 2 ) Iodobenzene pivalate (PhI (OPiv) 2 ) Iodobenzene oxide (PhIO), diiodobenzene (PhICl) 2 ) One or a mixture of several of them;
in particular, the process (b) is carried out in a solvent selected from acetonitrile, benzonitrile, anisole, toluene, chlorobenzene, acetic acid, trifluoroacetic acid, trifluoroethanol, hexafluoroisopropanol, N-dimethylformamide, acetone, water or a mixture of several thereof, preferably trifluoroethanol,
in the method (c), the compound shown in the formula IV-6 undergoes an oxidative cyclization reaction in the presence of a copper catalyst and an oxidant to obtain the compound shown in the formula IV-1,
in particular, in the method (c), the copper catalyst used is one or a mixture of more selected from cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, cuprous cyanide, cuprous acetate, cupric chloride, cupric bromide, cupric oxide, cupric acetate, cupric sulfate and cupric nitrate,
in particular, in the process (c), the oxidizing agent used is one or a mixture of several selected from oxygen, hydrogen peroxide, potassium peroxodisulfate, sodium peroxodisulfate, ammonium peroxodisulfate, tert-butyl peroxide, peracetic acid, benzoyl peroxide, m-chloroperoxybenzoic acid, pyridine-N-oxide, p-benzoquinone, dichloro Dicyanobenzoquinone (DDQ), N-chlorobutyronimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dichlorohydantoin, dibromohydantoin, trichloroisocyanuric acid, sodium hypochlorite, calcium hypochlorite,
In particular, the process (c) is carried out in a solvent selected from acetonitrile, benzonitrile, dioxane, anisole, toluene, xylene, chlorobenzene, acetic acid, trifluoroacetic acid, trifluoroethanol, hexafluoroisopropanol, pyridine, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, acetone, water or a mixture of several thereof.
According to one embodiment of the present disclosure, there is provided an intermediate for preparing a compound represented by formula III or a salt thereof, the intermediate being selected from the following compounds: )
According to one embodiment of the present disclosure, there is provided a method for preparing a compound represented by formula II, the method comprising:
step (1), using a compound shown in a formula III as a starting material, and reacting in the presence of a reducing agent to obtain a compound shown in a formula VI;
step (2), performing condensation reaction on the compound shown in the formula VI and the compound shown in the general formula VII to obtain the compound shown in the formula VIII;
step (3), preparing a compound shown in a formula II by continuously reacting the compound shown in the formula VIII by a one-pot method;
according to one embodiment of the present disclosure, in the step (1), the reducing agent used is a catalytic hydrogenation reaction system of an immobilized palladium catalyst and hydrogen, a catalytic hydrogenation reaction system of a raney nickel catalyst and hydrogen, an acid-iron powder reduction reaction system, an acid-zinc powder reduction reaction system or a tin dichloride reduction reaction system, preferably a catalytic hydrogenation reaction system of a raney nickel catalyst and hydrogen.
According to one embodiment of the present disclosure, wherein, in step (2), R 3 Is chlorine, bromine, n-butyryloxy, hydroxy, methoxy or ethoxy,
in particular, step (2) is carried out according to one of the following three reaction methods:
process (a), R 3 In the case of chlorine, bromine or n-butyryloxy, reacting the compound shown in the formula VII with n-butyryl chloride, n-butyryl bromide or n-butyric anhydride to prepare a compound shown in the formula VIII;
in particular, the process (a) is carried out with or without addition of an alkaline agent selected from the group consisting of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium carbonate, magnesium hydroxide, calcium carbonate, calcium hydroxide, calcium oxide, magnesium oxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, aqueous ammonia, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
In particular, the process (a) is carried out in a solvent, in particular, the solvent used for the reaction is one or a mixture of several selected from tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene chloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide, water.
Process (b), R 3 In the case of methoxy or ethoxy, the compound shown in the formula VII reacts with methyl n-butyrate or ethyl n-butyrate to prepare the compound shown in the formula VIII;
in particular, the process (b) is carried out in the presence of an acidic reagent or an alkaline reagent, in particular, the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, polyphosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride;
in particular, in the process (b), when an acidic reagent is used, the reaction is carried out in a solvent or using solvent-free reaction conditions, in particular, when an acidic reagent is used, the solvent is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, tert-butanol, ethylene glycol;
In particular, in the process (b), the alkaline agent used is one or a mixture of several selected from the group consisting of lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium isopropoxide, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, preferably sodium methoxide;
in particular, in the method (b), when an alkaline reagent is used, the reaction is carried out in a solvent, and in particular, when an alkaline reagent is used, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, N-butanol, t-butanol, ethylene glycol, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
Process (c), R 3 In the case of hydroxyl, the compound shown in the formula VII reacts with n-butyric acid in the presence of an acidic reagent or a condensation reagent to prepare a compound shown in the formula VIII;
in particular, in the process (c), the acidic reagent used is one or a mixture of several selected from hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydrofluoric acid, acetic acid, propionic acid, trifluoroacetic acid, malonic acid, benzoic acid, nitrobenzoic acid, methanesulfonic acid, p-toluenesulfonic acid, boric acid, boron trifluoride, boron tribromide, boron trichloride, aluminum trichloride, trimethylaluminum, ferric trichloride, zinc dichloride, indium trichloride, titanium tetrachloride;
In particular, in the process (c), when an acidic reagent is used, the reaction is carried out in a solvent or using a solvent-free reaction condition, and in particular, when an acidic reagent is used, the solvent is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, methanol, ethanol, isopropanol, n-butanol, t-butanol, ethylene glycol;
in particular, in the method (c), the condensing agent used is one or a mixture of several selected from concentrated sulfuric acid, polyphosphoric acid, 4, 5-Dicyanoimidazole (DCI), N' -Carbonyldiimidazole (CDI), dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), 1- (3-dimethylaminopropyl) -3-Ethylcarbodiimide (EDCI), 1-hydroxybenzotriazole (HOBt), O- (7-azabenzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HATU), O- (benzotriazol-1-yl) -bis (dimethylamino) carbonium Hexafluorophosphate (HBTU), trio-orthoformate, tetraorthoformate, trioxyacetate, tetraorthoacetate, etc.;
in particular, in the method (c), when a condensing agent is used, the reaction is carried out in a solvent, and in particular, when a condensing agent is used, the solvent used is one or a mixture of several selected from dichloromethane, chloroform, benzene, toluene, xylene, tetrahydrofuran, dioxane, ethylene glycol dimethyl ether, acetone, acetonitrile, N-dimethylformamide, N-dimethylacetamide, N-methylpyrrolidone.
According to one embodiment of the present disclosure, wherein,
the step (3) is a one-pot continuous reaction process, and is carried out according to the following characteristic operation step sequence: (3a) A solution of the compound shown in formula VIII (or a salt thereof formed with an acid) is reacted with a chlorinating agent, and the resultant reaction mixture is directly subjected to the next operation without isolation or the like; (3b) The chloro reaction mixture obtained in the previous step directly reacts with ammonia or the derivative thereof, and the obtained reaction mixture directly enters the next operation step without separation and other operations; (3c) Adding an alkaline reagent into the reaction mixture obtained in the previous step for reaction, and directly entering the next operation step without separation and other operations of the obtained reaction mixture; (3d) And adding electrophilic halogenated reagent into the reaction mixture obtained in the previous step to react, thus obtaining the compound shown in the formula II.
In particular, in step (3 a), the chlorinating agent used is one or a mixture of several selected from thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phosgene, bis (trichloromethyl) carbonate (triphosgene);
in particular, step (3 a) is carried out in a solvent, in particular, a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether;
In particular, in step (3 b), the ammonia compound used comprises an ammonia gas, or an aqueous ammonia solution, or an organic solvent solution of ammonia, or a salt thereof with an acid;
in particular, in step (3 c), the alkaline reagent used is one or more selected from lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium carbonate, magnesium hydroxide, magnesium phosphate, magnesium oxide, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine, 2, 6-tetramethylpiperidine;
in particular, step (3 c) is carried out in a solvent, in particular, the solvent used is selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tertiary butyl ether, water;
In particular, in step (3 d), the electrophilic halogenating agent used is selected from chlorine (Cl) 2 ) Bromine (Br) 2 ) Elemental iodine (I) 2 ) One or a mixture of several of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS), dichlorohydantoin, dibromohydantoin, trichloroisocyanuric acid, tribromoisocyanuric acid, sodium hypochlorite and calcium hypochlorite, preferably N-chlorosuccinimide (NCS);
in particular, step (3 d) is carried out in a solvent, in particular, a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether, water is used.
According to one embodiment of the present disclosure, wherein R in the compound of formula VII 3 The substituent is chlorine (-Cl), bromine (-Br) or n-butyryloxy (-O-CO- n Pr), the step (2) and the step (3) are carried out by using a one-pot method.
Advantageous effects
The invention provides a preparation method and application of benzimidazole substituted nitrobenzene. The main characteristic is that benzimidazole substituted nitrobenzene is prepared by using readily available chemicals 3-methyl-4-nitrobenzoic acid (ester) and the like as starting materials through various methods. One of the most important applications of the compound is that a bisbenzimidazole intermediate of Telmisartan (telmihartan) can be conveniently obtained through multi-step synthesis, and the method can avoid nitration and polyphosphoric acid cyclization reaction, and avoid the generation of a large amount of waste acid reaction liquid from the source. The synthesis method has the advantages of low material cost, less pollutant, simple and convenient operation, mild condition and the like, and is suitable for development into a green sustainable production process. The invention is also one of the research results under the guidance of the source control strategy of the research team.
Detailed Description
So that those having ordinary skill in the art can appreciate the features and effects of the present invention, the following general description and definitions apply to the terms and expressions set forth in the specification and claims. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, in the event of a conflict, the present specification shall control.
As used herein, the terms "comprising," "including," "having," "containing," or any other similar language, are intended to cover a non-exclusive inclusion, as an open-ended connection (open-ended transitional phrase). For example, a composition or article comprising a plurality of elements is not limited to only those elements listed herein, but may include other elements not explicitly listed but typically inherent to such composition or article. In addition, unless explicitly stated to the contrary, the term "or" refers to an inclusive "or" and not to an exclusive "or". For example, any one of the following conditions satisfies the condition "a or B": a is true (or present) and B is false (or absent), a is false (or absent) and B is true (or present), a and B are both true (or present). Furthermore, the terms "comprising," "including," "having," "containing," and their derivatives, as used herein, are intended to be open ended terms that have been specifically disclosed and encompass both the closed and semi-closed terms, consisting of …, and consisting essentially of ….
All features or conditions defined herein in terms of numerical ranges or percentage ranges are for brevity and convenience only. Accordingly, the description of a numerical range or percentage range should be considered to cover and specifically disclose all possible sub-ranges and individual values within the range, particularly integer values. For example, a range description of "1 to 8" should be taken as having specifically disclosed all sub-ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., particularly sub-ranges defined by all integer values, and should be taken as having specifically disclosed individual values such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. The foregoing explanation applies to all matters of the invention throughout its entirety unless indicated otherwise, whether or not the scope is broad.
If an amount or other numerical value or parameter is expressed as a range, preferred range, or a series of upper and lower limits, then it is understood that any range, whether or not separately disclosed, from any pair of the upper or preferred value for that range and the lower or preferred value for that range is specifically disclosed herein. Furthermore, where a range of numerical values is recited herein, unless otherwise stated, the range is intended to include the endpoints thereof, and all integers and fractions within the range.
In this context, numerical values should be understood to have the accuracy of the numerical significance of the numerical values provided that the objectives of the present invention are achieved. For example, the number 40.0 is understood to cover a range from 39.50 to 40.49.
In this document, where Markush group (Markush group) or option-type language is used to describe features or examples of the present invention, those skilled in the art will appreciate that a sub-group of all elements within a Markush group or option list or any individual element may also be used to describe the present invention. For example, if X is described as "selected from X 1 、X 2 X is X 3 The group "of which X is X has been fully described 1 Is claimed and X is X 1 And/or X 2 Is claimed. Furthermore, where markush groups or option expressions are used to describe features or examples of the present invention, those skilled in the art will appreciate that any combination of sub-groups or individual elements of all elements within a markush group or option list may also be used to describe the present invention. Accordingly, for example, if X is described as "selected from X 1 、X 2 X is X 3 A group of "and Y is described as" selected from Y 1 、Y 2 Y and Y 3 The group "of groups indicates that X has been fully described as X 1 Or X 2 Or X 3 And Y is Y 1 Or Y 2 Or Y 3 Is claimed.
The following detailed description is merely exemplary in nature and is not intended to limit the invention and its uses. Furthermore, there is no intention to be bound by any theory presented in the preceding prior art or summary or the following detailed description or examples.
Embodiments of the present invention are illustrated by the following examples. It is to be understood, however, that the embodiments of the present invention are not limited to the specific details set forth in the following examples, since other variations will be known and apparent to those of ordinary skill in the art in view of the present disclosure, and are intended to be included herein.
Example 1
A process for preparing intermediate compound III starting from intermediate compound IV-1.
Compound IV-1 (506 mg,2 mmol), dimethyl sulfate (277 mg,2.2mmol,1.1 eq), potassium carbonate (414 mg,3.0mmol,1.5 eq) were added to acetone (10 mL) at room temperature and stirred well. The reaction was heated at reflux for 2 hours, concentrated to remove the vast majority of the solvent, then added with water (20 mL), the precipitated solid was collected and dried thoroughly to give 507mg of pale yellow solid with a yield of 95%.
Compound III characterization data:
1 H NMR(CDCl 3 400MHz)δ:2.71(s,3H),3.93(s,3H),7.34-7.45(m,3H),7.74(d,J＝8Hz,1H),7.84-7.86(m,1H),7.87(s,1H),8.14(d,J＝8Hz,1H).
LR-MS(ESI)m/z:268(M+H) + .
example 2
A process for preparing the compound III starting from 3-methyl-4-nitrobenzoic acid (V-1) via intermediates V-2, IV-3.
1) Preparation of intermediate Compounds IV-2 and IV-3
To the flask was added 3-methyl-4-nitrobenzoic acid (V-1, 5g,27.6 mmol), followed by addition of a mixed solvent of N, N-dimethylformamide (200. Mu.L) and methylene chloride (30 mL), and the mixture was dissolved with stirring until clear. Oxalyl chloride (2.8 mL,33mmol,1.2 eq) was slowly added dropwise to the reaction from the constant pressure funnel with ice bath stirring at 0-5℃and after completion of the dropwise addition, the stirring was maintained at room temperature for 2 hours to give a dichloromethane solution of 3-methyl-4-nitrobenzoyl chloride (V-2) which was transferred to the constant pressure funnel for further use. Another three-necked flask was charged with N-methylparaben hydrochloride (5.65 g,29mmol,1.05 eq) followed by dichloromethane (30 mL) and diisopropylethylamine (19 mL,110mmol,4 eq) and stirred well. Slowly dripping the prepared acyl chloride into the reaction from a constant pressure funnel under the ice bath stirring at the temperature of 0-5 ℃, and keeping the room temperature for stirring for 2 hours after the dripping is completed. The reaction was quenched by addition of saturated aqueous ammonium chloride (30 mL), the organic phase was washed once with saturated aqueous ammonium chloride (30 mL), once with saturated brine, the organic phase was concentrated to dryness, and the precipitated solid was collected and dried sufficiently to give 6.7g of a yellow solid in 85% yield as a mixture of intermediate compounds IV-2 and IV-3, which was directly fed to the next step.
Characterization data for compound IV-2:
1 H NMR(CDCl 3 400MHz)δ:2.66(s,3H),2.86(s,3H),6.86(m,2H),7.23(d,1H),7.39(d,1H),7.86(d,1H),7.93(s,1H),8.03(m,2H).
LR-MS(ESI)m/z:286(M+H) + .
characterization data for compound IV-3:
1 H NMR(CDCl 3 400MHz)δ:2.47(s,3H),3.35(s,3H),6.56(t,1H),6.70(d,1H),6.74(d,1H),7.03(t,1H),7.24(d,1H),7.42(s,1H),7.71(d,1H).
LR-MS(ESI)m/z:286(M+H) + .
2) Preparation of intermediate compound III
A mixture of intermediate compounds IV-2 and IV-3 (1.3 g,4.56mmol,1 eq) and p-toluene sulfonic acid monohydrate (173 mg,0.912mmol,0.2 eq) was added to toluene (20 mL) and stirred well. The reaction was heated to reflux and water was separated overnight, and after cooling, a solid was precipitated. After concentrating to remove most of the solvent, dichloromethane (20 mL) was added, the organic phase was added to a saturated aqueous sodium bicarbonate solution and washed once with saturated brine, and the organic phase was dried and concentrated to give 1.1g of a pale yellow solid with a yield of 92%.
Compound III characterization data:
1 H NMR(CDCl 3 400MHz)δ:2.71(s,3H),3.93(s,3H),7.34-7.45(m,3H),7.74(d,J＝8Hz,1H),7.84-7.86(m,1H),7.87(s,1H),8.14(d,J＝8Hz,1H).
LR-MS(ESI)m/z:268(M+H) + .
the characterization data are identical to those of the product III obtained in example 1.
Example 3
A process for preparing intermediate compound IV-1 starting from compound V-1.
3-methyl-4-nitrobenzoic acid (3.6 g,20 mmol), boric acid (433 mg,7mmol,0.35 eq), and o-phenylenediamine (2.2 g,21mmol,1.05 eq) were added to toluene (40 mL) and stirred well. The reaction is heated, refluxed and separated for 30 hours, and solid is separated out after the reaction is cooled. Concentrating to remove most of the solvent, adding sodium hydroxide aqueous solution (with the concentration of about 10%), adjusting the pH to 11-12, fully stirring, collecting precipitated solid, fully drying to obtain 3.3g of bright yellow solid with the yield of 65%.
Characterization data for compound IV-1:
1 H NMR(d 6 -DMSO 400MHz)δ:2.63(s,3H),7.28(m,2H),7.65(m,2H),8.16-8.22(m,2H),8.29(s,1H).
LR-MS(ESI)m/z:254(M+H) + .
example 4
A process for preparing intermediate compound IV-1 starting from compound V-3.
To a three-necked flask, compound V-3 (3.9 g,20 mmol), p-toluenesulfonic acid monohydrate (380 mg,2mmol,0.1 eq), and o-phenylenediamine (2.3 g,21mmol,1.05 eq) were added to toluene (40 mL) and stirred well. The reaction was heated to reflux and water was separated for 30 hours, and after cooling, a solid was precipitated. Concentrating to remove most of the solvent, adding sodium hydroxide aqueous solution (with the concentration of about 10%), adjusting the pH to 11-12, fully stirring, collecting precipitated solid, fully drying to obtain 2.8g of bright yellow solid with the yield of 55%.
Characterization data for compound IV-1:
1 H NMR(d 6 -DMSO 400MHz)δ:2.63(s,3H),7.28(m,2H),7.65(m,2H),8.16-8.22(m,2H),8.29(s,1H).
LR-MS(ESI)m/z:254(M+H) + .
characterization data are identical to those of the product IV-1 obtained in example 3.
Example 5
A method for preparing an intermediate IV-1 from 3-methyl-4-nitrobenzonitrile (V-5) through an intermediate IV-6.
1) Preparation of intermediate compound IV-6
3-methyl-4-nitrobenzonitrile (1.6 g,10 mmol), anhydrous aluminum trichloride (2.7 g,20mmol,2.0 eq) and aniline (930 mg,10mmol,1.0 eq) were added to toluene (20 mL) and heated at 110-115℃under reflux for 10 hours under nitrogen. After the reaction was cooled to room temperature, ice water was added to the reaction mixture and stirred sufficiently, the organic phase was discarded, and then an aqueous sodium hydroxide solution (about 10%) was added to the aqueous phase to adjust the pH to 11 to 12, and the precipitated solid was collected by filtration and dried sufficiently to obtain 1.8g of pale yellow solid with a yield of 71%.
Characterization data for compound IV-6:
1 H NMR(CDCl 3 400MHz)δ:2.66(s,3H),4.91(brs,2H),6.98(d,J＝8Hz,1H),7.09-7.12(m,1H),7.36-7.40(m,2H),7.78(d,J＝8Hz,1H),7.91(s,1H),8.01(d,J＝8Hz,1H).
LR-MS(ESI)m/z:256(M+H) + .
2) Preparation of intermediate compound IV-1
Compound IV-6 (1.5 g,5 mmol) was added to acetonitrile (10 mL), N-chlorosuccinimide (800 mg,6mmol,1.2 eq) was added in an ice bath at 0-5℃and after 1 hour the reaction was carried out, aqueous sodium hydroxide solution (1.0 g,5eq, dissolved in 5mL of water) was added in an ice bath at 0-5℃and stirred for half an hour at 0-5℃with solid precipitation, ethyl acetate (20 mL) was added for extraction, and the organic phase was concentrated to dryness to give 1.0g as a pale yellow solid in 81% yield.
Characterization data for compound IV-1:
1 H NMR(d 6 -DMSO 400MHz)δ:2.63(s,3H),7.28(m,2H),7.65(m,2H),8.16-8.22(m,2H),8.29(s,1H).
LR-MS(ESI)m/z:254(M+H) + .
characterization data are identical to those of the product IV-1 obtained in example 3.
Example 6
A process for preparing bisbenzimidazole compounds II starting from compound III via intermediate compounds VI, VIII.
1) Preparation of intermediate compound VI
Intermediate compound III (300 mg,1.12 eq) was dissolved in tetrahydrofuran (20 mL) with stirring until clear, and Raney nickel (Raney Ni,30 mg), aqueous ammonia (35%, 6 mL) was added. The reaction was stirred at room temperature under an atmospheric hydrogen atmosphere for 4 hours. After the reaction, the mixture is filtered, the filter residue is washed by a small amount of mixed solvent of dichloromethane/ethanol (30 mL, 1/1), the organic phase is washed once by saturated saline, most of the solvent is concentrated and removed, the ethanol (10 mL) and the hydrochloric acid (6N, 10 mL) are added, the mixture is fully stirred into salt, the mixture is concentrated and dehydrated, and the mixture is beaten in the ethanol to obtain 269mg of yellow solid with the yield of 90 percent.
Compound VI characterization data:
1 H NMR(d 6 -DMSO 400MHz)δ:2.18(s,3H),4.05(s,3H),6.16(brs,2H),6.87(d,J＝8Hz,1H),7.56-7.65(m,4H),7.79(d,J＝8Hz,1H),7.96(d,J＝4Hz,1H).
LR-MS(ESI)m/z:238(M+H) + .
2) Preparation of intermediate compound VIII
In a three-necked flask, compound VI (237 mg,1.0 mmol) was added to acetonitrile (5 mL) and an aqueous sodium hydroxide solution (80 mg,2.0mmol,2.0eq, dissolved in 5mL of water), and stirred well in an ice bath at 0 to 5 ℃. A solution of n-butyryl chloride (106 mg,1.0mmol,1.0 eq) in acetonitrile (3 mL) was slowly added dropwise to the reaction under stirring at 0-5deg.C in an ice bath, and the mixture was stirred at room temperature for half an hour after completion of the dropwise addition. Water (20 mL) was added to the reaction and the mixture was stirred well. The precipitated solid was collected and dried sufficiently to give 292mg of an off-white solid in a yield of 95%.
Compound VIII characterization data:
1 H NMR(d 6 -DMSO 400MHz)δ:1.02(t,J＝8Hz,3H),1.76-1.83(m,2H),2.28(s,3H),2.44(t,J＝8Hz,2H),3.83(s,3H),7.31-7.34(m,2H),7.38-7.40(m,1H),7.45(d,J＝8Hz,1H),7.54(s,1H),7.80-7.93(m,1H).
LR-MS(ESI)m/z:308(M+H) + .
3) Preparation of Compound II
Intermediate compound VIII (hydrochloride) (6.88 g,20 mmol), bis (trichloromethyl) carbonate (2.38 g,8mmol,0.4 eq) and acetonitrile (30 mL) were heated to 80-85℃and stirred well. N, N-dimethylformamide (73 mg,1.0mmol,0.05 eq) was then added thereto and the mixture was heated and stirred at 80 to 85℃for 2 hours. After cooling to room temperature, a methanol solution of ammonia (4.3 mL,7M,30mmol,1.5 eq) was added with stirring and kept at room temperature for 1 hour with stirring. Then 20mL of water was added, and after stirring thoroughly, the mixture was allowed to stand for demixing, and the aqueous phase was removed by separation. Then, aqueous sodium hydroxide (3.2 g,80mmol,4.0 eq) was added to the reaction, then N-chlorosuccinimide (2.9 g,22mmol,1.1 eq) was slowly added to the reaction at 0-5℃and the reaction was completed and allowed to stand at room temperature for 3-4 hours. Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give 5.2g of an off-white solid in 85% yield.
Compound II characterization data:
1 H NMR(400MHz,CDCl 3 )δ:0.79(t,J＝8Hz,3H),1.68(m,2H),2.47(s,3H),2.70(t,J＝8Hz,2H),3.85(s,3H),7.26(s,1H),7.30-7.42(m,3H),7.68(s,1H),7.74-7.77(m,1H).
LR-MS(ESI)m/z:305(M+H) + .
example 7
Starting from compound VI, a "one pot" process for the preparation of bisbenzimidazole compound II.
In a three-necked flask, compound VI (4.7 g,20 mmol) was added to acetonitrile (20 mL) and stirred well at 0-5℃in an ice bath. A solution of n-butyryl chloride (2.3 g,22mmol,1.1 eq) in acetonitrile (5 mL) was slowly added dropwise to the reaction with stirring in an ice bath at 0-5℃and after completion of the dropwise addition, the mixture was stirred at room temperature for 2 hours. Bis (trichloromethyl) carbonate (2.38 g,8mmol,0.4 eq) and acetonitrile (20 mL) were then added to the reaction and heated to 80-85℃and stirred well. N, N-dimethylformamide (73 mg,1.0mmol,0.05 eq) was then added thereto and the mixture was heated and stirred at 80 to 85℃for 2 hours. After cooling to room temperature, a methanol solution of ammonia (4.3 mL,7M,30mmol,1.5 eq) was added with stirring and kept at room temperature for 1 hour with stirring. Then 20mL of water was added, and after stirring thoroughly, the mixture was allowed to stand for demixing, and the aqueous phase was removed by separation. Then, aqueous sodium hydroxide (3.2 g,80mmol,4.0 eq) was added to the reaction, then N-chlorosuccinimide (2.9 g,22mmol,1.1 eq) was slowly added to the reaction at 0-5℃and the reaction was completed and allowed to stand at room temperature for 3-4 hours. Ethyl acetate (10 mL) was added for extraction, the aqueous phase was discarded, the organic phase was washed once with aqueous sodium hydroxide (10%, 10 mL), the organic phase was concentrated, solids precipitated, and the precipitated solids were collected and dried sufficiently to give compound II as an off-white solid, 4.3g, in 70% yield.
Compound II characterization data:
1 H NMR(400MHz,CDCl 3 )δ:0.79(t,J＝8Hz,3H),1.68(m,2H),2.47(s,3H),2.70(t,J＝8Hz,2H),3.85(s,3H),7.26(s,1H),7.30-7.42(m,3H),7.68(s,1H),7.74-7.77(m,1H).
LR-MS(ESI)m/z:305(M+H) + .

Claims (6)

1. a process for preparing a compound of formula II, the process comprising:
step (1), using a compound shown in a formula III as a starting material, and reacting in the presence of a reducing agent to obtain a compound shown in a formula VI;
step (2), performing condensation reaction on the compound shown in the formula VI and the compound shown in the general formula VII to obtain the compound shown in the formula VIII;
step (3), the compound shown in the formula VIII is continuously reacted by a one-pot method to prepare the compound shown in the formula II,
wherein, in step (2), R 3 Is the compound of chlorine or bromine,
the step (3) is a one-pot continuous reaction process, and is carried out according to the following operation sequence: (3a) The compound shown in the formula VIII reacts with a chlorinating agent, and the generated reaction mixture directly enters the next operation step without separation operation; (3b) The chloro reaction mixture obtained in the previous step directly reacts with an ammonia compound, and the obtained reaction mixture directly enters the next operation step without separation operation; (3c) Adding an alkaline reagent into the reaction mixture obtained in the previous step for reaction, and directly entering the obtained reaction mixture into the next operation step without separation operation; (3d) Adding electrophilic halogenated reagent into the reaction mixture obtained in the previous step to react, so as to obtain a compound shown in a formula II;
In step (3 a), the chlorinating agent used is bis (trichloromethyl) carbonate;
step (3 a) is carried out in a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether and methyl tertiary butyl ether;
in step (3 b), the ammonia compound used is selected from ammonia gas, or aqueous ammonia solution, or organic solvent solution of ammonia, or salt thereof with acid;
in step (3 c), the alkaline reagent used is selected from one or more of lithium carbonate, lithium hydroxide, lithium tert-butoxide, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, sodium methoxide, sodium ethoxide, sodium isopropoxide, sodium tert-butoxide, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate, potassium methoxide, potassium ethoxide, potassium tert-butoxide, cesium carbonate, cesium hydroxide, magnesium phosphate, magnesium methoxide, magnesium ethoxide, magnesium isopropoxide, magnesium tert-butoxide, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine, piperidine;
Step (3 c) is carried out in a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether and water;
in step (3 d), the electrophilic halogenating agent used is selected from one or more of N-chlorosuccinimide (NCS), N-bromosuccinimide (NBS), N-iodosuccinimide (NIS);
step (3 d) is carried out in a solvent selected from one or more of dichloromethane, chloroform, benzene, toluene, xylene, chlorobenzene, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, ethylene glycol dimethyl ether, methyl tert-butyl ether and water.
2. The method of claim 1, wherein,
in step (3 d), the electrophilic halogenating agent used is N-chlorosuccinimide (NCS).
3. The method of claim 1, wherein,
in the step (1), the reducing agent is a catalytic hydrogenation reaction system of an immobilized palladium catalyst and hydrogen, a catalytic hydrogenation reaction system of a Raney nickel catalyst and hydrogen, an acid-iron powder reduction reaction system, an acid-zinc powder reduction reaction system or a tin dichloride reduction reaction system.
4. The method of claim 3, wherein,
the reducing agent is a catalytic hydrogenation reaction system of Raney nickel catalyst and hydrogen.
5. The method of claim 1, wherein,
step (2) is carried out according to the following reaction method:
the method (a), the compound shown in the formula VI reacts with n-butyryl chloride or n-butyryl bromide to prepare the compound shown in the formula VIII,
the method (a) is carried out by adding an alkaline agent selected from one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, potassium monohydrogen phosphate, lithium hydroxide, sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, lithium methoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, lithium isopropoxide, sodium isopropoxide, potassium tert-butoxide, sodium tert-butoxide, magnesium methoxide, magnesium ethoxide, magnesium tert-butoxide, ammonia water, triethylamine, diisopropylamine, diisopropylethylamine, tri-n-butylamine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine, 4-dimethylaminopyridine, tetrahydropyrrole, morpholine and piperidine,
the method (a) is carried out in a solvent, and the solvent used in the reaction is selected from one or a mixture of more of tetrahydrofuran, dioxane, 2-methyltetrahydrofuran, ethylene glycol dimethyl ether, methyl tertiary butyl ether, toluene, xylene, methylene dichloride, chloroform, acetonitrile, acetone, pyridine, N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide and water.
6. The method of any one of claims 1 to 5, wherein step (2) and step (3) are performed using a "one pot" approach.
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