CN118684601A - Preparation method of acylsulfamoylbenzamide - Google Patents

Abstract

The present invention relates to the field of preparation of herbicide safeners, and discloses a method for preparing acylaminosulfonamide benzamide, which comprises: in the presence of a solvent, a compound of formula (II) is subjected to a halogenation reaction with a halogenating agent to obtain a compound of formula (III); in the presence of a solvent, a compound of formula (IV) is subjected to a halogenation reaction with a halogenating agent to obtain a compound of formula (V); in the presence of a base, the compound of formula (V) is subjected to an acyl halide reaction with a compound of formula (VI) to obtain a compound of formula (VII); in the presence of a base, the compound of formula (VII) is subjected to an acyl halide reaction with a compound of formula (III); _R1 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; _R2 is a C1-C6 alkoxy group; and m is 0 or 1. The method improves the purity of the product, avoids the generation of impurities by side reactions, and ensures the yield.

Description

Preparation method of acylsulfamoylbenzamide

Technical Field

The invention relates to the field of preparation of herbicide safeners, and in particular to a method for preparing acylaminosulfonamide benzamide.

Background Art

WO9916744A1 provides an acylsulfamoylbenzoic acid derivative and its use as a safener for controlling weeds in herbicides, and discloses methods for preparing such compounds. However, these methods are limited to laboratory scale and are not applicable to industrial scale production.

WO200500797A1 discloses a two-step method for preparing acylaminosulfonylbenzoic acid derivatives, which comprises reacting a carboxybenzenesulfonamide derivative with a benzoic acid derivative in the presence of a chlorinating agent, and then reacting the obtained compound with an amine derivative in the presence of a base. The method involves a small number of reaction steps and can be applied to industrial-scale production, but there are still problems such as incomplete conversion of reactants leading to dimer formation and formation of by-products.

Therefore, a preparation method is needed to reduce the generation of dimers and reaction by-products during the preparation of acylsulfonamide benzamide compounds.

Summary of the invention

The purpose of the present invention is to overcome the problem that in the process of preparing acylsulfonamide benzamide compounds in the prior art, incomplete conversion of reactants leads to dimer formation, and the yield and purity of the product are reduced. A preparation method of acylsulfonamide benzamide is provided. The method comprises the following steps: performing halogenation reaction on a compound having a structure represented by formula (II) and a compound having a structure represented by formula (IV), respectively, and then performing acyl halogenation reaction on the obtained products in two steps, thereby effectively avoiding the formation of dimers in the reaction process. The reaction is carried out step by step to obtain corresponding purified intermediates, thereby improving the purity of the product, avoiding the generation of impurities by side reactions, and ensuring the yield of the product. The method has industrial practicability.

In order to achieve the above object, the present invention provides a method for preparing acylaminosulfonamide benzamide on the one hand, wherein the method comprises the following steps:

(1) in the presence of a first solvent, subjecting the compound of the structure represented by formula (II) to a first halogenation reaction with a first halogenating agent to obtain a compound of the structure represented by formula (III);

(2) in the presence of a second solvent, subjecting the compound of formula (IV) to a second halogenation reaction with a second halogenating agent to obtain a compound of formula (V);

(3) in the presence of a first base, subjecting the compound of the structure represented by formula (V) to a first acyl halide reaction with the compound of the structure represented by formula (VI) to obtain a compound of the structure represented by formula (VII);

(4) in the presence of a second base, subjecting the compound of the structure represented by formula (VII) to a second acyl halide reaction with the compound of the structure represented by formula (III) to obtain an acylsulfonamide benzamide of the structure represented by formula (I);

R ₁ -NH ₂ Formula (VI);

In the formula, _R1 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; _R2 is a C1-C6 alkoxy group; and m is 0 or 1.

Preferably, R ₁ is a C3-C6 alkyl group or a C3-C5 cycloalkyl group.

Preferably, R ₂ is a C1-C3 alkoxy group.

Preferably, m is 1.

Preferably, the conditions of the first halogenation reaction include: reaction temperature of 20-60°C, preferably 30-50°C; reaction time of 0.5-5h, preferably 1-3h.

Preferably, the first halogenating agent is selected from at least one of thionyl chloride, sulfuryl chloride, phosphorus pentachloride, oxalyl chloride, phosgene and chlorine.

Preferably, relative to 1 mole of the compound of the structure represented by formula (II), the amount of the first halogenating agent added is 1-2 moles, preferably 1.1-1.5 moles.

The first solvent is an organic solvent, preferably at least one selected from ethylene glycol diethyl ether, ethylene glycol dimethyl ether, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, chlorobenzene and toluene, more preferably toluene and/or ethylene glycol diethyl ether.

Preferably, the mass ratio of the first solvent to the compound having the structure represented by formula (II) is 1-10:1, preferably 2-5:1.

Preferably, the second halogenation reaction is carried out in the presence of an optional catalyst.

Preferably, the conditions of the second halogenation reaction include: reaction temperature of 80-180°C, preferably 100-160°C; reaction time of 2-8h, preferably 3-5h.

Preferably, the catalyst is N,N-dimethylformamide.

Preferably, the mass ratio of the catalyst to the compound of the structure represented by formula (IV) is 0-0.1:1, preferably 0.0005-0.01:1.

Preferably, the second halogenating agent is selected from at least one of thionyl chloride, sulfuryl chloride, phosphorus pentachloride, oxalyl chloride and phosgene.

Preferably, relative to 1 mole of the compound of the structure represented by formula (IV), the amount of the second halogenating agent added is 1-2 moles, preferably 1.2-1.5 moles.

Preferably, the second solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether.

Preferably, the mass ratio of the second solvent to the compound having the structure represented by formula (IV) is 3-20:1, preferably 5-8:1.

Preferably, the first acyl halide reaction is carried out in the presence of a third solvent.

Preferably, the conditions of the first acyl halide reaction include: reaction temperature of 0-100°C, preferably 20-50°C; reaction time of 1-10h, preferably 2-5h.

Preferably, the added amount of the compound of the structure represented by formula (VI) is 1-2 moles, preferably 1-1.2 moles, relative to 1 mole of the compound of the structure represented by formula (V).

Preferably, the third solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether.

Preferably, the mass ratio of the third solvent to the compound of the structure represented by formula (V) is 1-10:1, preferably 2-5:1.

Preferably, the first base is selected from at least one of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate and anhydrous sodium carbonate.

Preferably, relative to 1 mole of the compound having the structure represented by formula (V), the amount of the first base added is 1-2 moles, preferably 1.05-1.5 moles.

Preferably, the second acyl halide reaction is carried out in the presence of a fourth solvent.

Preferably, the second acyl halide reaction conditions include: reaction temperature of 80-180°C, preferably 100-160°C; reaction time of 2-8h, preferably 3-5h.

Preferably, for 1 mole of the compound of the structure represented by formula (VII), the added amount of the compound of the structure represented by formula (III) is 1-2 moles, preferably 1-1.1 moles.

Preferably, the fourth solvent is a polar organic solvent, preferably at least one selected from acetonitrile, ethyl acetate and N,N-dimethylformamide.

Preferably, the mass ratio of the fourth solvent to the compound of the structure represented by formula (VII) is 1-10:1, preferably 2-5:1.

Preferably, the second base is selected from at least one of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate and anhydrous sodium carbonate.

Preferably, the amount of the second base added is 1-2 moles, preferably 1.05-1.5 moles, relative to 1 mole of the compound of the structure represented by formula (VII).

Preferably, the preparation method further comprises the step of adjusting the pH value of the second acyl halide reaction product to 4-5 after the second acyl halide reaction is completed, and performing solid-liquid separation to obtain a solid product.

Through the above technical solution, the beneficial effects obtained are as follows:

In the present invention, the method provides a new reaction path for preparing acylaminosulfonamide benzamide, wherein the compound having the structure represented by formula (II) and the compound having the structure represented by formula (IV) are subjected to chlorination reaction respectively, and the obtained products are subjected to acyl halide reaction in two steps, and the conditions of the two acyl halide reactions are controlled, so that the formation of dimers in the reaction process is effectively avoided, the yield and purity of the product are improved, the preparation cost is reduced, and the method has industrial practicability.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG1 is a 1H-NMR chart of the compound represented by formula (I) obtained in Example 1.

DETAILED DESCRIPTION

The endpoints and any values of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and the individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges, which should be regarded as specifically disclosed in this article.

One aspect of the present invention provides a method for preparing acylsulfamoyl amide benzamide, wherein the method comprises the following steps:

(1) in the presence of a first solvent, subjecting the compound of the structure represented by formula (II) to a first halogenation reaction with a first halogenating agent to obtain a compound of the structure represented by formula (III);

(2) in the presence of a second solvent, subjecting the compound of formula (IV) to a second halogenation reaction with a second halogenating agent to obtain a compound of formula (V);

(3) in the presence of a first base, subjecting the compound of the structure represented by formula (V) to a first acyl halide reaction with the compound of the structure represented by formula (VI) to obtain a compound of the structure represented by formula (VII);

(4) in the presence of a second base, subjecting the compound of the structure represented by formula (VII) to a second acyl halide reaction with the compound of the structure represented by formula (III) to obtain an acylsulfonamide benzamide of the structure represented by formula (I);

R ₁ -NH ₂ Formula (VI);

In the formula, _R1 is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; _R2 is a C1-C6 alkoxy group; and m is 0 or 1.

The invention provides a novel method for synthesizing acylaminosulfonamide benzamide, wherein a compound having a structure represented by formula (II) and a compound having a structure represented by formula (IV) are subjected to chlorination reaction respectively, and the obtained products are subjected to acyl halide reaction in two steps, and the conditions of the two acyl halide reactions are controlled to effectively avoid the formation of dimers in the reaction process, thereby improving the yield and purity of the product and having industrial practicability.

According to the present invention, preferably, R ₁ is a C3-C6 alkyl group or a C3-C5 cycloalkyl group.

The C1-C6 alkyl group may be a branched chain alkyl group or a straight chain alkyl group, but is preferably a straight chain alkyl group. Specific examples thereof include methyl, ethyl, n-propyl, 1-methylethyl, n-butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-ethylpropyl, n-hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl, 1-ethyl-1-methylpropyl, and 1-ethyl-2-methylpropyl. Among them, a C3-C6 alkyl group is preferred.

In a preferred embodiment of the present invention, R ₁ is at least one selected from n-propyl, n-butyl, n-pentyl and n-hexyl.

Examples of the C3-C6 cycloalkyl group include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

In a preferred embodiment of the present invention, R ₁ is selected from at least one of cyclopropyl, cyclobutyl and cyclopentyl, among which cyclopropyl is particularly preferred.

In a preferred embodiment of the present invention, R ₁ is at least one selected from cyclopropyl, n-propyl and n-butyl.

According to the present invention, preferably, R ₂ is a C1-C3 alkoxy group.

The C1-C6 alkoxy group may be a branched chain alkoxy group or a straight chain alkoxy group, but is preferably a straight chain alkoxy group. Specific examples thereof include a methoxy group, an ethoxy group, an n-propoxy group, a 1-methylethoxy group, an n-butoxy group, a 1-methylpropoxy group, a 2-methylpropoxy group, a 1,1-dimethylethoxy group, an n-pentoxy group, a 1-methylbutoxy group, a 2-methylbutoxy group, a 3-methylbutoxy group, a 2,2-dimethylpropoxy group, a 1-ethylpropoxy group, an n-hexyloxy group, a 1,1-dimethylpropoxy group, a 1,2-dimethylpropoxy group, a 1-methylpentoxy group, a 2-methylpentoxy group, a 3-methylpentoxy group, a 4-methylpentoxy group, a 1,1-dimethylbutoxy group, a 1,2-dimethylbutoxy group, a 1,3-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a 2,3-dimethylbutoxy group, a 3,3-dimethylbutoxy group, a 1-ethylbutoxy group, a 2-ethylbutoxy group, a 1,1,2-trimethylpropoxy group, a 1,2,2-trimethylpropoxy group, a 1-ethyl-1-methylpropoxy group, and a 1-ethyl-2-methylpropoxy group. Among them, a methoxy group, an ethoxy group and an n-propoxy group are preferred.

In the present invention, the position of substitution of R ₂ in the compound of the structure represented by formula (II) is not particularly limited, and can be ortho-, meta- or para-substituted.

According to the present invention, preferably, m is 1.

In the present invention, preferably, the acylaminosulfonamide benzamide is selected from at least one of N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide, N-[4-(n-propylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide and N-[4-(n-butylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide. Wherein, the N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide (cyprosulfamide) can be used as a safener for herbicides.

The present invention is described in the following steps.

The first halogenation reaction

According to the present invention, in the presence of a first solvent, a compound of the structure represented by formula (II) is subjected to a first halogenation reaction with a first halogenating agent to obtain a compound of the structure represented by formula (III). The first halogenation reaction has a conventional interpretation in the art, and a halogenation reaction refers to a reaction in which hydrogen or other groups in an organic compound are replaced by halogen to generate a halogen-containing organic compound.

According to the present invention, preferably, the conditions of the first halogenation reaction include: reaction temperature of 20-60°C, preferably 30-50°C; reaction time of 0.5-5h, preferably 1-3h.

According to the present invention, the type of the first halogenating agent is not particularly limited, and is a conventional sulfur and/or phosphorus-containing halogenating agent in the art or a carbon-based halogenating agent capable of converting a carboxylic acid into a corresponding acid halide. Preferably, the first halogenating agent is selected from at least one of a chlorinating agent, a brominating agent, and an iodinating agent, preferably a chlorinating agent, more preferably selected from at least one of thionyl chloride, sulfuryl chloride, phosphorus pentachloride, oxalyl chloride, phosgene, and chlorine.

In the present invention, preferably, the compound with the structure represented by formula (II) is selected from at least one of o-methoxybenzoic acid, o-ethoxybenzoic acid and o-propoxybenzoic acid.

In the present invention, preferably, the compound with the structure represented by formula (III) is selected from at least one of o-methoxybenzoic acid, o-ethoxybenzoic acid and o-propoxybenzoic acid.

According to the present invention, preferably, relative to 1 mole of the compound of the structure represented by formula (II), the added amount of the first halogenating agent is 1-2 moles, for example, 1 mole, 1.1 moles, 1.2 moles, 1.3 moles, 1.4 moles, 1.5 moles, 1.6 moles, 1.7 moles, 1.8 moles, 1.9 moles, 2 moles, or any range between the two, preferably 1.1-1.5 moles.

According to the present invention, preferably, the first solvent is an organic solvent, and the type of the organic solvent is not particularly limited. It is preferably selected from at least one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, isopropyl acetate, isobutyl acetate, dichloromethane, acetonitrile, chlorobenzene and toluene, and more preferably toluene and/or ethylene glycol diethyl ether.

According to the present invention, preferably, the mass ratio of the first solvent to the compound of the structure represented by formula (II) is 1-10:1, preferably 2-5:1. In the present invention, the first solvent is used to mix the compound of the structure represented by formula (II) with the first halogenating agent evenly, so that the first halogenation reaction proceeds more thoroughly and the yield of the first halogenation reaction product is increased.

According to a preferred embodiment of the present invention, the first halogenating agent is slowly added to the compound of the structure shown in formula (II) to carry out the first halogenation reaction. The addition rate is not particularly limited, and those skilled in the art can adaptably adjust the addition rate according to the amount of reaction raw materials added. When the first halogenating agent is added dropwise, the reaction time of the first halogenation reaction includes the dropwise addition time and the insulation time.

In the present invention, preferably, the first halogenation reaction is carried out in the presence of an optional catalyst, and the catalyst is a conventional halogenation reaction catalyst in the art, preferably N,N-dimethylformamide. The amount of the catalyst added is not particularly limited, as long as it can catalyze the first halogenation reaction. Those skilled in the art can adaptably adjust the amount of the catalyst added according to the situation of the first halogenation reaction. Preferably, the mass ratio of the catalyst to the compound of the structure shown in formula (II) is 0-0.1:1, preferably 0.0005-0.01:1.

In the present invention, preferably, step (1) further comprises the step of removing the first solvent and the excess first halogenating agent from the reaction product after the first halogenation reaction is completed. The method for removing the solvent and the excess first halogenating agent is not particularly limited, and is preferably selected from at least one of distillation, rectification and suction filtration to remove the solvent and the excess first halogenating agent.

In the present invention, after the first halogenation reaction is completed, only the first solvent and the excess first halogenating agent need to be removed from the reaction product to obtain the compound of the structure shown in formula (III) with high yield and high purity, and the post-treatment is very simple. Of course, after the first halogenation reaction is completed, other conventional refining methods in the art can also be used for refining.

Second halogenation reaction

According to the present invention, in the presence of a second solvent, a compound of the structure shown in formula (IV) is subjected to a second halogenation reaction with a second halogenating agent to obtain a compound of the structure shown in formula (III). Preferably, the conditions of the second halogenation reaction include: a reaction temperature of 80-180°C, such as 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C, or any range therebetween, preferably 100-160°C, more preferably 100-120°C; a reaction time of 2-8h, preferably 3-5h.

In a particularly preferred embodiment of the present invention, the second halogenation reaction is carried out under the above reaction conditions, the reaction proceeds more thoroughly and the product yield is high.

In the present invention, preferably, the compound of the structure represented by formula (IV) is substituted or unsubstituted p-sulfonylaminobenzoic acid. The substituted p-sulfonylaminobenzoic acid may be ortho-substituted and/or meta-substituted. Preferably, the substituted substituent is selected from at least one of an alkyl, an alkoxy and a halogen.

In the present invention, preferably, the compound having the structure represented by formula (V) is p-sulfonamidobenzoyl chloride.

According to the present invention, the type of the second halogenating agent is not particularly limited, and may be the same as or different from the first halogenating agent. Preferably, the second halogenating agent is preferably a chlorinating agent, more preferably at least one selected from thionyl chloride, sulfonyl chloride, phosphorus pentachloride, oxalyl chloride, phosgene and chlorine.

According to the present invention, preferably, the second halogenation reaction is carried out in the presence of an optional catalyst, and the catalyst is a conventional halogenation catalyst in the art, preferably N, N-dimethylformamide. The amount of the catalyst added is not particularly limited, and it can catalyze the second halogenation reaction. Those skilled in the art can choose whether to add a catalyst and adaptably adjust the amount of the catalyst added according to the situation of the second halogenation reaction.

According to the present invention, preferably, the mass ratio of the catalyst to the compound of the structure represented by formula (IV) is 0-0.1:1, preferably 0.0005-0.01:1.

In the present invention, preferably, the second halogenation reaction is carried out under stirring conditions, and the stirring rate is not particularly limited. It can accelerate the second halogenation reaction and make the reaction proceed more thoroughly. Those skilled in the art can adjust the stirring rate adaptively.

According to the present invention, preferably, relative to 1 mole of the compound of the structure represented by formula (IV), the added amount of the second halogenating agent is 1-2 moles, for example, 1 mole, 1.1 moles, 1.2 moles, 1.3 moles, 1.4 moles, 1.5 moles, 1.6 moles, 1.7 moles, 1.8 moles, 1.9 moles, 2 moles, or any range between the two, preferably 1.2-1.5 moles.

According to the present invention, the second solvent is an organic solvent, and the type of the organic solvent is not particularly limited. Preferably, the second solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether, more preferably ethylene glycol diethyl ether. In the present invention, the first solvent and the second solvent may be the same or different. The boiling point of ethylene glycol diethyl ether is higher, and the state is more stable in the second halogenation reaction, and the product yield of the second halogenation reaction is higher.

According to the present invention, preferably, the mass ratio of the second solvent to the compound of the structure represented by formula (IV) is 3-20:1, preferably 5-8:1. In the present invention, the second solvent is added according to the above mass ratio to dissolve the compound of the structure represented by formula (IV) so that the reaction between the second solvent and the second halogenating agent can proceed uniformly.

According to a preferred embodiment of the present invention, a second halogenating agent is slowly added to the compound of the structure shown in formula (IV) to carry out a second halogenation reaction. Those skilled in the art can adaptively adjust the addition rate of the second halogenating agent according to the progress of the second halogenation reaction. Preferably, when the second halogenating agent is added dropwise, the reaction time of the second halogenation reaction includes the dropwise addition time and the insulation time.

In the present invention, preferably, step (2) further comprises the step of removing the second solvent and the second halogenating agent from the reaction product after the second halogenation reaction is completed. The method for removing the second solvent and the second halogenating agent and separating the product is not particularly limited, and is preferably selected from at least one of distillation, rectification and suction filtration.

In the present invention, preferably, the separated second halogenation reaction product can be purified by conventional purification methods in the art, such as filtration followed by washing, to obtain a compound with a structure shown in formula (V) for use in the first acyl halide reaction in step (3). The treatment method is simple and the yield of the product is high.

The first acyl halogenation reaction

According to the present invention, in the presence of a first base, a compound of the structure represented by formula (V) and a compound of the structure represented by formula (VI) are subjected to a first acyl halide reaction to obtain a compound of the structure represented by formula (VII). In the present invention, the acyl halide reaction refers to the reaction of the compound of the structure represented by formula (V) obtained by the second halogenation reaction with the compound of the structure represented by formula (VI) containing an amine group to obtain a compound of the structure represented by formula (VII) and hydrogen halide.

In the present invention, the compound of the structure represented by formula (V) is the compound of the structure represented by formula (V) obtained in step (2) described above.

In the present invention, preferably, the compound having the structure represented by formula (VI) is selected from at least one of cyclopropylamine, n-propylamine and n-butylamine.

According to the present invention, preferably, the added amount of the compound of the structure represented by formula (VI) is 1-2 moles, preferably 1-1.2 moles, relative to 1 mole of the compound of the structure represented by formula (V).

According to the present invention, preferably, the conditions of the first acyl halide reaction include: reaction temperature of 0-100°C, preferably 20-50°C; reaction time of 1-10h, preferably 2-5h.

According to the present invention, the first base is an organic base and/or an inorganic base conventional in the art. Preferably, the first base is selected from at least one of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate and anhydrous sodium carbonate.

In the present invention, the first base can be used as a reaction raw material or as a neutralizing base of the target product during or after the reaction. When used as a reaction raw material, preferably, the amount of the first base added is 1-2 moles, preferably 1.05-1.5 moles, relative to 1 mole of the compound of the structure shown in formula (V). In addition, when used as a reaction raw material and as a neutralizing base of the target product, the additional amount of the first base added is 1-2 moles relative to 1 mole of the compound of the structure shown in formula (V).

According to a preferred embodiment of the present invention, during the reaction, the amount of the first base added is 1-2 moles relative to 1 mole of the compound of the structure shown in formula (V); after the reaction, a base is added to neutralize the target product to purify it. Specifically, the added base reacts with the sulfonic acid amine to form a salt, which is dissolved in the aqueous phase, which is equivalent to purifying the organic phase. The resulting aqueous phase is acidified to directly obtain the target product without further purification. Of course, it can be understood in the art that the base added after the reaction is completed can be the same as the first base added during the reaction, or it can be different.

In addition, in a preferred embodiment of the present invention, after the reaction is completed, sodium hydroxide is used as the base to neutralize the target product. Since sodium hydroxide has a small molecular weight, low cost, and good purification effect, it is preferred.

According to the present invention, preferably, the first acyl halide reaction is carried out in the presence of a third solvent.

According to the present invention, preferably, the third solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether. In the present invention, the types of the first solvent, the second solvent and the third solvent may be the same or different.

According to the present invention, preferably, the mass ratio of the third solvent to the compound having the structure represented by formula (V) is 1-10:1, preferably 2-5:1.

According to a preferred embodiment of the present invention, preferably, a compound with a structure represented by formula (VI) is added to a compound with a structure represented by formula (V) to carry out a first acyl halide reaction, ensuring that the compound with a structure represented by formula (VI) is in excess in the reaction.

In the present invention, in order to fully carry out the first acyl halide reaction, the compound of the structure represented by formula (V) is slowly added, and stirred to make the reactants uniformly mixed. The stirring rate is not particularly limited, as long as the reaction is fully carried out.

In the present invention, preferably, step (3) further comprises the step of adjusting the pH value of the first acyl halide reaction product to 4-5 after the first acyl halide reaction is completed, and performing solid-liquid separation to obtain a compound with a structure represented by formula (VII).

In the present invention, after the first acyl halide reaction is completed, the reaction product can be precipitated from the reaction system only by adjusting the pH value. The method for separating the first acyl halide reaction product is simple, and a high-purity compound of the structure represented by formula (VII) can be obtained by washing the solid-liquid separation product.

In the present invention, an acid is added to perform solid-liquid separation to obtain a compound having a structure represented by formula (VII), wherein the acid may be an organic acid and/or an inorganic acid conventional in the art, and preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid and nitric acid. The acid may be added in the form of an acid solution, and the concentration of the acid solution is not particularly limited, and is preferably an acid solution of 10-50 wt%.

Second acyl halide reaction

According to the present invention, preferably, in the presence of a second base, a compound of the structure represented by formula (VII) is subjected to a second acyl halide reaction with a compound of the structure represented by formula (III) to obtain an acylaminosulfonamide benzamide of the structure represented by formula (I).

According to the present invention, preferably, the second acyl halide reaction conditions include: reaction temperature of 80-180°C, preferably 100-160°C; reaction time of 2-8h, preferably 3-5h.

According to the present invention, preferably, for 1 mole of the compound of the structure represented by formula (VII), the added amount of the compound of the structure represented by formula (III) is 1-2 moles, preferably 1-1.1 moles.

In the present invention, preferably, the compound represented by the structure of formula (VII) is the first acyl halide reaction product of step (3), preferably at least one selected from 4-(cyclopropylcarbamoyl)benzenesulfonamide, N-[4-(n-propylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide and N-[4-(n-butylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide.

According to the present invention, preferably, the second base is selected from at least one of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate and anhydrous sodium carbonate.

According to the present invention, preferably, the amount of the second base added is 1-2 moles, preferably 1.05-1.5 moles, relative to 1 mole of the compound having the structure represented by formula (VII).

According to the present invention, preferably, the second acyl halide reaction is carried out in the presence of a fourth solvent.

According to the present invention, preferably, the fourth solvent is a polar organic solvent, preferably at least one selected from acetonitrile, ethyl acetate and N,N-dimethylformamide. Using the fourth solvent for the second acyl halide reaction can promote the reaction and avoid side reactions.

According to the present invention, preferably, the mass ratio of the fourth solvent to the compound having the structure represented by formula (VII) is 1-10:1, preferably 2-5:1.

According to the present invention, preferably, the preparation method further comprises the step of adjusting the pH value of the second acyl halide reaction product to 4-5 after the second acyl halide reaction is completed, and performing solid-liquid separation to obtain a solid product.

In the present invention, the method for adjusting the pH value of the second acyl halide reaction product is not particularly limited, and the pH value can be 4-5, and the pH value is usually adjusted by adding acid. The type of the acid can be an organic acid and/or an inorganic acid conventional in the art, and preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid and nitric acid. The acid can be added in the form of an acid solution, and the concentration of the acid solution is not particularly limited, preferably an acid solution of 10-50wt%.

In the present invention, the solid product obtained by solid-liquid separation is purified to obtain the acylaminosulfonamide benzamide of the structure shown in formula (I). The solid product can be purified by conventional purification methods, and preferably, the precipitated solid product is filtered and washed.

The present invention provides a novel method for preparing acylsulfamoylamine benzamide. Acylsulfamoylamine benzamide is prepared by the method. During the reaction, the yield and purity of the product can be better controlled by adjusting the feeding and two-box reaction conditions of each step, thereby improving the yield of the finally prepared acylsulfamoylamine benzamide and reducing the waste of reaction raw materials.

The present invention will be described in detail below through examples and comparative examples. In the following examples and comparative examples, unless otherwise specified, the reagents used in the present invention are all commercially available;

In the present invention, the room temperature is 25°C.

In the following examples, the product yield and product purity of the preparation of acylsulfonamide benzamide are shown in Table 1.

Wherein, Y: yield, %;

_mactual : actual yield calculated by multiplying the weight of the obtained acylsulfonamide benzamide by the purity, g;

m _: theoretical yield of the product calculated based on the amount of the compound represented by formula (VII) participating in the reaction, g;

The purity of the product was determined by liquid chromatography.

Example 1

(1) Preparation of o-Anisyl Chloride

At 30-50°C, add thionyl chloride dropwise to a toluene solution containing 1 mol of o-anisylbenzoic acid, the molar ratio of thionyl chloride to o-anisylbenzoic acid is 1.2:1, the mass ratio of toluene to o-anisylbenzoic acid is 3:1, and a small amount of N,N-dimethylformamide is added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to o-anisylbenzoic acid is 0.005:1. After adding, continue stirring for 1 hour, distill off excess thionyl chloride and toluene, and obtain o-anisyl chloride liquid.

(2) Preparation of p-sulfonamidobenzoyl chloride

At room temperature, dithionyl chloride was added dropwise to a solution of ethylene glycol diethyl ether containing 1 mol of p-sulfonylaminobenzoic acid, the molar ratio of dithionyl chloride to p-sulfonylaminobenzoic acid was 1.2:1, the mass ratio of ethylene glycol diethyl ether to p-sulfonylaminobenzoic acid was 6:1, a small amount of N,N-dimethylformamide was added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to p-sulfonylaminobenzoic acid was 0.005:1, the temperature was raised to 120°C and refluxed, stirring was continued for 3-4 hours to obtain a clear solution, stirring was continued for 1 hour, free acid was no longer present, excess dithionyl chloride and part of ethylene glycol diethyl ether (about 50wt% of the original amount) were distilled off, the obtained suspension was cooled to room temperature and filtered to obtain p-sulfonylaminobenzoyl chloride, the filter cake was rinsed with a small amount of ethylene glycol diethyl ether, and the filtrate could be recovered for reuse.

(3) Preparation of 4-(cyclopropylcarbamoyl)benzenesulfonamide

At room temperature, cyclopropylamine was added dropwise to 1 mol of p-sulfonamidebenzoyl chloride and a toluene suspension containing anhydrous potassium carbonate, the molar ratio of cyclopropylamine to p-sulfonamidebenzoyl chloride being 1.1:1, the molar ratio of anhydrous potassium carbonate to p-sulfonamidebenzoyl chloride being 1.1:1, the mass ratio of toluene to p-sulfonamidebenzoyl chloride being 3:1, and stirring was continued for 1 h after the addition, an aqueous solution containing 10 wt % of sodium hydroxide was added, the molar ratio of sodium hydroxide to p-sulfonamidebenzoyl chloride being 1:1, the system was dissolved and separated into layers, the aqueous layer was separated, 10 wt % of HCl solution was added dropwise until the pH value of the aqueous layer was 4-5, a white solid was precipitated from the solution, and 4-(cyclopropylcarbamoyl)benzenesulfonamide was obtained by suction filtration and washing with water.

(4) Preparation of N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide

At 120°C, to 1 mol of 4-(cyclopropylcarbamoyl)benzenesulfonamide and N,N-dimethylformamide solution containing anhydrous potassium carbonate, an N,N-dimethylformamide solution containing o-anisyl chloride was added dropwise, the molar ratio of o-anisyl chloride to 4-(cyclopropylcarbamoyl)benzenesulfonamide was 1.02:1, the molar ratio of anhydrous potassium carbonate to 4-(cyclopropylcarbamoyl)benzenesulfonamide was 1.1:1, and the total N The mass ratio of N-dimethylformamide to 4-(cyclopropylcarbamoyl)benzenesulfonamide was 3:1. After the addition was completed, the reaction was continued with stirring for 2-3 hours. After cooling to room temperature, water was added, and solids precipitated. 10wt% HCl solution was added dropwise until the pH value of the reaction system was 4-5. Solids further precipitated, and the mixture was filtered and washed with water to obtain N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide. The yield and purity are shown in Table 1.

The H NMR spectrum of the compound of formula (I) prepared in Example 1 is shown in FIG1 . The solvent used for the H NMR spectrum test is dimethyl sulfoxide (DMSO) and the test is performed using a Bruker 500 MHz NMR spectrometer. As can be seen from FIG1 , the specific structural formula of the compound prepared in Example 1 is shown in formula (VIII), which satisfies the structure shown in formula (I);

Example 2

(1) Preparation of o-Anisyl Chloride

At 30-50°C, add thionyl chloride dropwise to a toluene solution containing 1 mol of o-anisylbenzoic acid, the molar ratio of thionyl chloride to o-anisylbenzoic acid is 1.2:1, the mass ratio of toluene to o-anisylbenzoic acid is 3:1, and a small amount of N,N-dimethylformamide is added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to o-anisylbenzoic acid is 0.005:1. After adding, continue stirring for 1 hour, and distill off excess thionyl chloride and toluene to obtain o-anisyl chloride liquid.

(2) Preparation of p-sulfonamidobenzoyl chloride

At room temperature, dithionyl chloride was added dropwise to a solution of ethylene glycol diethyl ether containing 1 mol of p-sulfonylaminobenzoic acid, the molar ratio of dithionyl chloride to p-sulfonylaminobenzoic acid was 1.2:1, the mass ratio of ethylene glycol diethyl ether to p-sulfonylaminobenzoic acid was 6:1, a small amount of N,N-dimethylformamide was added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to p-sulfonylaminobenzoic acid was 0.005:1, the temperature was raised to 120°C and refluxed, stirring was continued for 3-4 hours to obtain a clear solution, stirring was continued for 1 hour, free acid was no longer present, excess dithionyl chloride and part of ethylene glycol diethyl ether (about 50wt% of the original amount) were distilled off, the obtained suspension was cooled to room temperature and filtered to obtain p-sulfonylaminobenzoyl chloride, the filter cake was rinsed with a small amount of ethylene glycol diethyl ether, and the filtrate could be recovered for reuse.

(3) Preparation of 4-(n-propylcarbamoyl)benzenesulfonamide

At room temperature, n-propylamine was added dropwise to 1 mol of p-sulfonamidebenzoyl chloride and a toluene suspension containing anhydrous potassium carbonate, the molar ratio of cyclopropylamine to p-sulfonamidebenzoyl chloride was 1.1:1, the molar ratio of anhydrous potassium carbonate to p-sulfonamidebenzoyl chloride was 1.1:1, the mass ratio of toluene to p-sulfonamidebenzoyl chloride was 3:1, stirring was continued for 1 h after the addition, an aqueous solution containing 10 wt % of sodium hydroxide was added, the molar ratio of sodium hydroxide to p-sulfonamidebenzoyl chloride was 1:1, the system was dissolved and separated, the aqueous layer was separated, 10 wt % of HCl solution was added dropwise until the pH value of the aqueous layer was 4-5, a white solid precipitated from the solution, filtered and washed with water to obtain 4-(n-propylcarbamoyl)benzenesulfonamide.

(4) Preparation of N-[4-(n-propylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide

At 120°C, to 1 mol of 4-(n-propylcarbamoyl)benzenesulfonamide and N,N-dimethylformamide solution containing anhydrous potassium carbonate, an N,N-dimethylformamide solution containing o-anisyl chloride was added dropwise, the molar ratio of o-anisyl chloride to 4-(n-propylcarbamoyl)benzenesulfonamide was 1.02:1, the molar ratio of anhydrous potassium carbonate to 4-(n-propylcarbamoyl)benzenesulfonamide was 1.1:1, and the total N,N-dimethylformamide and The mass ratio of 4-(n-propylcarbamoyl)benzenesulfonamide is 3:1. After the addition is completed, the reaction is continued with stirring for 2-3 hours. After cooling to room temperature, water is added, and solid is precipitated. A 10wt% HCl solution is added dropwise until the pH value of the reaction system is 4-5, and solid is further precipitated. The solid is filtered and washed with water to obtain N-[4-(n-propylcarbamoyl)phenylsulfonyl]-2-methoxybenzamide (confirmed by nuclear magnetic resonance in the same way as in Example 1). The yield and purity are shown in Table 1.

Example 3

(1) Preparation of o-ethoxybenzoyl chloride

At 30-50°C, add thionyl chloride dropwise to a toluene solution containing 1 mol of o-ethoxybenzoic acid, the molar ratio of thionyl chloride to o-ethoxybenzoic acid is 1.2:1, the mass ratio of toluene to o-ethoxybenzoic acid is 3:1, and a small amount of N,N-dimethylformamide is added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to o-ethoxybenzoic acid is 0.005:1. After adding, continue stirring for 1 hour, distill off excess thionyl chloride and toluene, and obtain o-ethoxybenzoyl chloride liquid.

(2) Preparation of p-sulfonamidobenzoyl chloride

At room temperature, dithionyl chloride was added dropwise to a solution of ethylene glycol diethyl ether containing 1 mol of p-sulfonylaminobenzoic acid, the molar ratio of dithionyl chloride to p-sulfonylaminobenzoic acid was 1.2:1, the mass ratio of ethylene glycol diethyl ether to p-sulfonylaminobenzoic acid was 6:1, a small amount of N,N-dimethylformamide was added to catalyze the reaction, the mass ratio of N,N-dimethylformamide to p-sulfonylaminobenzoic acid was 0.005:1, the temperature was raised to 120°C and refluxed, stirring was continued for 3-4 hours to obtain a clear solution, stirring was continued for 1 hour, free acid was no longer present, excess dithionyl chloride and part of ethylene glycol diethyl ether (about 50wt% of the original amount) were distilled off, the obtained suspension was cooled to room temperature and filtered to obtain p-sulfonylaminobenzoyl chloride, the filter cake was rinsed with a small amount of ethylene glycol diethyl ether, and the filtrate could be recovered for reuse.

(3) Preparation of 4-(cyclopropylcarbamoyl)benzenesulfonamide

At room temperature, cyclopropylamine was added dropwise to 1 mol of p-sulfonamidebenzoyl chloride and a toluene suspension containing anhydrous potassium carbonate, the molar ratio of cyclopropylamine to p-sulfonamidebenzoyl chloride being 1.1:1, the molar ratio of anhydrous potassium carbonate to p-sulfonamidebenzoyl chloride being 1.1:1, the mass ratio of toluene to p-sulfonamidebenzoyl chloride being 3:1, and stirring was continued for 1 h after the addition, an aqueous solution containing 10 wt % of sodium hydroxide was added, the molar ratio of sodium hydroxide to p-sulfonamidebenzoyl chloride being 1:1, the system was dissolved and separated into layers, the aqueous layer was separated, 10 wt % of HCl solution was added dropwise until the pH value of the aqueous layer was 4-5, a white solid was precipitated from the solution, and 4-(cyclopropylcarbamoyl)benzenesulfonamide was obtained by suction filtration and washing with water.

(4) Preparation of N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-ethoxybenzamide

At 120°C, to 1 mol of 4-(cyclopropylcarbamoyl)benzenesulfonamide and N,N-dimethylformamide solution containing anhydrous potassium carbonate, an N,N-dimethylformamide solution containing o-ethoxybenzoyl chloride was added dropwise, the molar ratio of o-ethoxybenzoyl chloride to 4-(cyclopropylcarbamoyl)benzenesulfonamide was 1.02:1, the molar ratio of anhydrous potassium carbonate to 4-(cyclopropylcarbamoyl)benzenesulfonamide was 1.1:1, and the total N,N-dimethylformamide and The mass ratio of 4-(cyclopropylcarbamoyl)benzenesulfonamide is 3:1. After the addition is completed, the reaction is continued with stirring for 2-3 hours. After cooling to room temperature, water is added, and solid is precipitated. A 10wt% HCl solution is added dropwise until the pH value of the reaction system is 4-5, and solid is further precipitated. The solid is filtered and washed with water to obtain N-[4-(cyclopropylcarbamoyl)phenylsulfonyl]-2-ethoxybenzamide (confirmed by nuclear magnetic resonance in the same way as in Example 1). The yield and purity are shown in Table 1.

Example 4

The method of Example 1 is followed, except that the reaction temperature in step (2) is changed to 80° C. The other conditions are the same as those of Example 1. The yield and purity are shown in Table 1.

Example 5

The method of Example 1 is followed, except that the second solvent in step (2) is replaced with an equal mass of ethylene glycol dimethyl ether to carry out a reflux reaction. Other conditions are the same as those of Example 1. The yield and purity are shown in Table 1.

Example 6

The method of Example 1 is followed, except that the second solvent in step (2) is replaced with toluene of equal mass, and the reflux reaction is carried out. The other conditions are the same as those of Example 1. The yield and purity are shown in Table 1.

Table 1

serial number Product yield (wt%) Product purity (wt%) Example 1 96 99 Example 2 96 99 Example 3 95 99 Example 4 83 99 Example 5 85 98 Example 6 88 98

It can be seen from the results in Table 1 that the method of the embodiment of the present invention is used to prepare acylaminosulfonamide benzamide, which can improve the product yield while ensuring high product purity.

The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims (10)

1. A process for the preparation of an acyl sulfamide benzamide, said process comprising the steps of:

(1) In the presence of a first solvent, carrying out a first halogenation reaction on a compound with a structure shown in a formula (II) and a first halogenating agent to obtain a compound with a structure shown in a formula (III);

(2) In the presence of a second solvent, carrying out a second halogenation reaction on a compound with a structure shown in a formula (IV) and a second halogenating agent to obtain a compound with a structure shown in a formula (V);

(3) In the presence of a first base, carrying out a first acyl halogenation reaction on a compound with a structure shown in a formula (V) and a compound with a structure shown in a formula (VI) to obtain a compound with a structure shown in a formula (VII);

(4) In the presence of a second base, carrying out a second acyl halogenation reaction on a compound with a structure shown in a formula (VII) and a compound with a structure shown in a formula (III) to obtain acyl sulfamide benzamide with a structure shown in a formula (I);

r ₁-NH₂ is of formula (VI);

Wherein R ₁ is a C1-C6 alkyl group or a C3-C6 cycloalkyl group; r ₂ is C1-C6 alkoxy; m is 0 or 1.

2. The process according to claim 1, wherein R ₁ is a C3-C6 alkyl group or a C3-C5 cycloalkyl group;

Preferably, R ₂ is C1-C3 alkoxy;

Preferably, m is 1.

3. The production method according to claim 1 or 2, wherein the conditions of the first halogenation reaction include: the reaction temperature is 20-60 ℃, preferably 30-50 ℃; the reaction time is 0.5 to 5 hours, preferably 1 to 3 hours;

Preferably, the first halogenating agent is selected from at least one of thionyl chloride, sulphuryl chloride, phosphorus pentachloride, oxalyl chloride, phosgene and chlorine gas;

preferably, the first halogenating agent is added in an amount of 1 to 2 moles, preferably 1.1 to 1.5 moles, relative to 1 mole of the compound of the structure represented by the formula (II).

4. A production method according to any one of claims 1 to 3, wherein the first solvent is an organic solvent, preferably at least one selected from ethylene glycol diethyl ether, ethylene glycol dimethyl ether, isopropyl acetate, isobutyl acetate, methylene chloride, acetonitrile, chlorobenzene and toluene, more preferably toluene and/or ethylene glycol diethyl ether;

Preferably, the mass ratio of the first solvent to the compound of the structure represented by formula (ii) is 1-10:1, preferably 2-5:1.

5. The process of any one of claims 1-4, wherein the second halogenation reaction is carried out in the presence of an optional catalyst;

Preferably, the conditions of the second halogenation reaction include: the reaction temperature is 80-180 ℃, preferably 100-160 ℃; the reaction time is 2-8h, preferably 3-5h;

Preferably, the catalyst is N, N-dimethylformamide;

Preferably, the mass ratio of the catalyst to the compound of the structure represented by formula (iv) is 0-0.1:1, preferably 0.0005 to 0.01:1.

6. The production process according to any one of claims 1 to 5, wherein the second halogenating agent is selected from at least one of thionyl chloride, sulfuryl chloride, phosphorus pentachloride, oxalyl chloride and phosgene;

preferably, the second halogenating agent is added in an amount of 1 to 2 moles, preferably 1.2 to 1.5 moles, relative to 1 mole of the compound of the structure represented by formula (iv);

Preferably, the second solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether;

Preferably, the mass ratio of the second solvent to the compound of the structure shown in the formula (IV) is 3-20:1, preferably 5-8:1.

7. The production process according to any one of claims 1 to 6, wherein the first acyl halogenation reaction is performed in the presence of a third solvent;

Preferably, the conditions of the first acyl halogenation reaction include: the reaction temperature is 0-100 ℃, preferably 20-50 ℃; the reaction time is 1 to 10 hours, preferably 2 to 5 hours;

preferably, the compound of the structure represented by the formula (VI) is added in an amount of 1 to 2 moles, preferably 1 to 1.2 moles, relative to 1 mole of the compound of the structure represented by the formula (V);

Preferably, the third solvent is selected from one of ethylene glycol diethyl ether, ethylene glycol dimethyl ether, dichloromethane, acetonitrile, chlorobenzene and toluene, preferably toluene and/or ethylene glycol diethyl ether;

preferably, the mass ratio of the third solvent to the compound of the structure represented by formula (v) is 1-10:1, preferably 2-5:1.

8. The production method according to claim 7, wherein the first base is at least one selected from the group consisting of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate and anhydrous sodium carbonate;

Preferably, the first base is added in an amount of 1 to 2 moles, preferably 1.05 to 1.5 moles, relative to 1 mole of the compound of the structure represented by formula (v).

9. The production process according to any one of claims 1 to 8, wherein the second acyl halogenation reaction is performed in the presence of a fourth solvent;

Preferably, the second acyl halogenation reaction conditions comprise: the reaction temperature is 80-180 ℃, preferably 100-160 ℃; the reaction time is 2-8h, preferably 3-5h;

Preferably, the compound of the structure represented by the formula (III) is added in an amount of 1 to 2 moles, preferably 1 to 1.1 moles, to 1 mole of the compound of the structure represented by the formula (VII);

Preferably, the fourth solvent is a polar organic solvent, preferably at least one selected from acetonitrile, ethyl acetate and N, N-dimethylformamide;

preferably, the mass ratio of the fourth solvent to the compound of the structure represented by formula (VII) is 1-10:1, preferably 2-5:1.

10. The production method according to any one of claims 1 to 9, wherein the second base is selected from at least one of triethylamine, pyridine, sodium hydroxide, anhydrous potassium carbonate, and anhydrous sodium carbonate;

Preferably, the second base is added in an amount of 1 to 2 moles, preferably 1.05 to 1.5 moles, relative to 1 mole of the compound of the structure represented by the formula (VII);

preferably, the preparation method further comprises the step of adjusting the pH value of the second acyl halogenation reaction product to be 4-5 after the second acyl halogenation reaction is finished, and carrying out solid-liquid separation to obtain a solid product.