WO2017076213A1

WO2017076213A1 - Benzimidazole compound, preparation method thereof and usage

Info

Publication number: WO2017076213A1
Application number: PCT/CN2016/103492
Authority: WO
Inventors: 吴春晖; 何洋; 张健; 杨飞瀑; 田广辉
Original assignee: 苏州旺山旺水生物医药有限公司; 中国科学院上海药物研究所
Priority date: 2015-11-02
Filing date: 2016-10-27
Publication date: 2017-05-11

Abstract

Disclosed in the present invention are a benzimidazole compound shown in formula (I), preparation method thereof and use thereof in preparing flibanserin or a pharmaceutically acceptable salt of flibanserin.

Description

Benzimidazole compound, preparation method and use thereof

Technical field

The present invention is in the field of medicinal chemistry, and in particular, the present invention relates to a benzimidazole compound, a process for the preparation thereof and use thereof for the preparation of a pharmaceutically acceptable salt of flurbine or flurbine.

Background technique

Flibanserin is a 5-HT1A receptor agonist, a 5-HT2A receptor antagonist, and has partial agonistic activity at the dopamine D4 receptor. It was approved by the FDA in August 2015 for the treatment of female libido. Its chemical name is: 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-2,3-dihydro-1H-benzimidazole-2 - Ketone, the structural formula is as shown in formula (III):

European Patent EP 526 434 reports that the synthesis of flurbin is via 1-(2-chloroethyl)-1H-benzimidazole-2(3H)-one and 1-(3-(trifluoromethyl)phenyl) Piperazine condensation is obtained. As shown in Reaction Scheme 1:

Reaction formula 1:

Patent US2007/0032655 reports that the synthesis of flurbin is by first linking a di-carbon chain with a leaving group through 1-(3-(trifluoromethyl)phenyl)piperazine, followed by a nitrogen-protected benzimidazole. The ketone is condensed and finally deprotected. As shown in Reaction 2:

Reaction 2:

R' represents a suitable amino protecting group;

X' represents chlorine, bromine, iodine, mesylate, triflate, p-toluenesulfonate;

Patent WO 2010128516A2 reports that 1-(prop-1-en-2-yl)-1H-benzimidazole-2(3H)-one is reacted with 1,2-dibromoethane to give 1-(2-bromoethyl) -3-(prop-1-en-2-yl)-1H-benzimidazole-2(3H)-one, after reacting with ethylene glycol amine, the hydroxyl group is made into a leaving group with toluenesulfonyl chloride, It is then reacted with m-trifluoromethylaniline to form a piperazine ring, and finally deprotected to give flurbine. As shown in Reaction 3:

Reaction 3:

In the existing method for synthesizing flurbine, most of the protecting groups on the nitrogen of the imidazole ring are used for the subsequent reaction. After a nitrogen protection is substituted, the remaining nitrogen atom and oxygen atom are active reactive sites, and the subsequent reaction tends to produce impurities that are difficult to remove, reducing yield and product purity, and is not suitable for industrial large-scale production. Therefore, it is particularly urgent to find a route with simple process, high yield, low cost and suitable for industrial production.

Summary of the invention

In order to solve the problems of high production cost, low yield, and difficult removal of impurities in the prior art, the present invention provides a benzimidazole compound represented by the following formula (I), and adopts the formula (I). The compound shown can be synthesized in an economical, convenient, and high yield form of flubanser or a pharmaceutically acceptable salt thereof.

It is an object of the present invention to provide a benzimidazole compound of the formula (I).

Another object of the present invention is to provide a process for producing a benzimidazole compound represented by the formula (I).

Still another object of the present invention is to provide a use of the benzimidazole compound of the formula (I) for the preparation of flurbin.

In order to attain the above object, the present invention provides a benzimidazole compound of the formula (I):

Wherein R is a hydroxy protecting group, and R is selected from a C1-C6 straight or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted arylalkyl group, an alkyl silicon group, a C1-C6 alkane. An oxymethyl group, a C1-C6 alkanoyl group, a substituted or unsubstituted aroyl group; wherein the substitution means substitution with a hydroxyl group, a halogen, a C1-C6 alkyl group or a C1-C6 alkoxy group; Base is selected from phenyl, naphthyl, etc.;

X is a leaving group, and X is selected from halogen, a substituted or unsubstituted C1-C6 alkylsulfonyloxy group, a substituted or unsubstituted benzenesulfonyloxy group, a substituted or unsubstituted naphthalenesulfonyloxy group, The substitution means substitution with one or more of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, hydroxy, amino and C1-C6 alkanoyl.

Preferred in the present invention,

R is selected from C1-C4 straight or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, alkylsilyl, C1-C4 alkoxymethyl, C1-C4 An alkanoyl group, a substituted or unsubstituted aroyl group; wherein the substituent means a hydroxy group, a halogen, a C1-C4 alkyl group or a C1-C4 alkoxy group or the like; the aryl group is selected from a phenyl group, a naphthyl group, etc. ;

X is selected from halogen, substituted or unsubstituted C1-C4 alkylsulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, substituted or unsubstituted naphthalenesulfonyloxy, said substituent being halogen, One or more of the C1-C4 alkyl group, the C1-C4 alkoxy group, the nitro group, the hydroxyl group, the amino group, and the C1-C4 alkanoyl group are substituted.

Further preferred in the present invention,

R is selected from benzyl, methyl, ethyl, tert-butyl, triphenylmethyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, acetyl or benzoyl;

X is selected from the group consisting of chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthylsulfonyloxy, Methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzenesulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy or methoxybenzenesulfonyloxy.

In a still further preferred embodiment of the invention, the compound of formula (I) is selected from the group consisting of:

(1) 1-(2-chloroethyl)-2-ethoxy-1H-benzimidazole;

(2) 1-(2-bromoethyl)-2-ethoxy-1H-benzimidazole;

(3) 1-(2-chloroethyl)-2-methoxy-1H-benzimidazole;

(4) 1-(2-Bromoethyl)-2-methoxy-1H-benzimidazole;

(5) 1-(2-methanesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(6) 1-(2-methanesulfonyloxyethyl)-2-methoxy-1H-benzimidazole;

(7) 1-(2-p-toluenesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(8) 1-(2-p-toluenesulfonyloxyethyl)-2-methoxy-1H-benzimidazole;

(9) 1-(2-benzenesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(10) 1-(2-Benzenesulfonyloxyethyl)-2-methoxy-1H-benzimidazole;

The present invention provides a process for the preparation of a benzimidazole compound represented by the formula (I), which comprises the step of substituting a compound of the formula (II) and a compound XCH ₂ CH ₂ X1 in the presence of a base in a suitable solvent. The reaction gives the compound of formula (I) as shown in Reaction Scheme 4:

Reaction 4:

Where R and X are as defined above, and X1 is defined as X.

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether, etc.; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and Toluene, nitrobenzene, chlorobenzene, etc.; the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl- 2-pentanone or the like; the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, etc.; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, and dichloroethane. Alkane, carbon tetrachloride; the esters are selected from the group consisting of ethyl acetate, ethyl formate, and Methyl ester, isopropyl acetate; the other class is selected from the group consisting of dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone and the like. Preferably, the suitable solvent is water, acetonitrile, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethyl A mixture of one or more of carbachamide, dimethyl sulfoxide, 1,2-dichloroethane.

The base may be selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal carbonate such as sodium carbonate, Potassium carbonate, cesium carbonate, lithium carbonate; alkali metal hydrogen carbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate; alkali metals, such as: potassium, sodium; others, such as: sodium amide, potassium amide, sodium hydride Potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, Quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4 .0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2 ] Octane (DABCO). The base may be used alone or in combination of two or more. Preferably, the base is one of sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate or Several mixtures.

The above reaction is carried out at room temperature to 200 ° C, preferably at room temperature to 150 ° C. The reaction time is from 0.5 hours to 36 hours, preferably from 0.5 hours to 24 hours;

The molar ratio of the compound XCH ₂ CH ₂ X1 to the compound of the formula (II) is 1:1 to 10:1, preferably, the molar ratio of the compound XCH ₂ CH ₂ X1 to the compound represented by the formula (II) It is 1:1~5:1.

The molar ratio of the base to the compound of the formula (II) is from 1:1 to 10:1, preferably, the molar ratio of the base to the compound of the formula (II) is from 1:1 to 8:1.

The present invention also relates to the use of the benzimidazole compound represented by the formula (I), and the benzimidazole compound represented by the formula (I) can be prepared by the following methods: Flubensin or a pharmaceutically acceptable salt thereof.

method one:

The compound I and 1-(3-(trifluoromethyl)phenyl)piperazine or a salt thereof are subjected to a substitution reaction to obtain a compound IV; the compound IV is subjected to a cleavage reaction to deprotect the group to obtain a flubanstein (ie, a compound III) or a salt thereof. , as shown in Reaction Scheme 5. Flubenbanin can be dissolved in a solvent according to actual needs, and a suitable acid can be added to obtain a fluorine class. The pharmaceutically acceptable salt of the chromophore; or the pharmaceutically acceptable salt of the flubanerin is obtained by directly adding a suitable acid without isolation after the deprotection of the cleavage reaction occurs.

Reaction formula 5:

The substitution reaction takes place in the presence of a base in a suitable solvent.

The base may be selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal carbonate such as sodium carbonate, Potassium carbonate, cesium carbonate, lithium carbonate; alkali metal hydrogen carbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate; alkali metals, such as: potassium, sodium; others, such as: sodium amide, potassium amide, sodium hydride Potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, Quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4 .0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2 ] Octane (DABCO). These bases may be used alone or in combination of two or more. If necessary, the above substitution reaction can be carried out by adding an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator. If necessary, a phase transfer catalyst such as tetrabutylammonium iodide, tetrabutylammonium bromide or benzyltriethylammonium chloride may be added to promote the substitution reaction.

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether, etc.; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and Toluene, nitrobenzene, chlorobenzene, etc.; the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl- 2-pentanone or the like; the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, etc.; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, and dichloroethane. An alkane, carbon tetrachloride; the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate; the other is selected from the group consisting of dimethyl sulfoxide, acetonitrile, and 1-methyl-2. Pyrrolidone; preferably, the suitable solvent is water, acetonitrile, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N, N -dimethyl Carboxamide, dimethyl sulfoxide, 1,2- a mixture of one or more of dichloroethane.

The molar ratio of the 1-(3-(trifluoromethyl)phenyl)piperazine or a salt thereof to the compound of the formula (I) is from 1:1.5 to 1.5:1, preferably, the 1-(3) The molar ratio of -(trifluoromethyl)phenyl)piperazine or a salt thereof to the compound of the formula (I) is from 1:1.2 to 1.2:1.

The molar ratio of the base to the compound of the formula (I) is from 1:1 to 10:1, preferably, the molar ratio of the base to the compound of the formula (I) is from 1:1 to 5:1.

The above substitution reaction is usually carried out at room temperature to 200 ° C, preferably at room temperature to 150 ° C. The reaction time is from 0.5 hours to 36 hours, preferably from 0.5 hours to 24 hours;

The cleavage reaction removes the hydroxy protecting group and is removed according to a conventional method depending on the protecting group. For example, when R is a benzyl group or a substituted benzyl group, it can be removed in hydrochloric acid, and the concentration of hydrochloric acid can be selected from the range of 5% to 36%; or it can be removed in the presence of palladium carbon, formic acid and ammonium formate; In a suitable solvent, in the presence of a metal catalyst, hydrogen removal, the metal catalyst may be selected from palladium carbon, Raney nickel or platinum dioxide; the suitable solvent comprises a mixture of one or more of the following solvents: water, ether Classes, alcohols, ketones, amides, halogenated hydrocarbons and esters; the ethers are selected from the group consisting of tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, ethylene glycol dimethyl ether, etc.; The alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, and ethylene glycol; and the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, and the like. The halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, dichloroethane, and carbon tetrachloride; and the ester is selected from the group consisting of ethyl acetate, ethyl formate, and methyl acetate. When R is a methyl group or an ethyl group, an acid system such as hydrobromic acid, boron tribromide, hydrochloric acid, a hydrogen chloride/ethanol solution, or a hydrogen chloride/1,4-dioxane solution may be used to deprotect the group. The concentration of hydrochloric acid may range from 5% to 36%. When R is an alkyl silicon group, it may be removed with a quaternary ammonium salt of hydrochloric acid, hydrogen fluoride, formic acid or a fluorine-containing ion such as tetrabutylammonium fluoride (TBAF) or pyridine hydrofluoride, preferably tetrabutylammonium fluoride. (TBAF) or hydrochloric acid removal. The above deprotection group reaction can be carried out in a suitable organic solvent or a mixture thereof with water, such as tetrahydrofuran, 1,4-dioxane, dichloromethane, methanol, ethanol, isopropanol or any combination thereof.

The acid group of the 1-(3-(trifluoromethyl)phenyl)piperazine salt may be an inorganic acid or an organic acid, and the inorganic acid is one of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and hydroiodic acid. ; organic acids are formic acid, acetic acid, propionic acid, butyric acid, oxalic acid, malic acid, tartaric acid, amino acids, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, taurine, rich One of horse acid, maleic acid, citric acid, succinic acid, cholic acid, and deoxycholic acid.

Or method two:

Compound I and piperazine are substituted to obtain compound V; compound V is coupled with compound VI in the presence of a base and a palladium catalyst to obtain compound IV; compound IV undergoes a cleavage reaction to deprotect the group to obtain flurbanserin (compound III) or Its salt, as shown in Reaction Scheme 6:

Reaction 6:

Wherein X2 is chlorine, bromine, iodine or trifluoromethanesulfonyloxy.

The base may be selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal carbonate such as sodium carbonate, Potassium carbonate, cesium carbonate, lithium carbonate; alkali metal hydrogen carbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate; alkali metals, such as: potassium, sodium; others, such as: sodium amide, potassium amide, sodium hydride Potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, Quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4 .0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2 ] Octane (DABCO). If necessary, the above substitution reaction can be carried out by adding an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator.

Preferably, the base is one of sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate or Several mixtures.

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether, etc.; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and Toluene, nitrobenzene, chlorobenzene, etc.; the alcohol is selected from the group consisting of methanol and ethanol. Isopropyl alcohol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; the amide is selected from N, N-dimethyl methyl An amide, N,N-dimethylacetamide or the like; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, dichloroethane, carbon tetrachloride; the ester is selected from the group consisting of ethyl acetate and ethyl formate , methyl acetate, isopropyl acetate; the other class is selected from the group consisting of dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone.

Preferably, the suitable solvent is water, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylmethyl a mixture of one or more of an amide, dimethyl sulfoxide, 1,2-dichloroethane.

The above substitution reaction is usually carried out at room temperature to 200 ° C, preferably at room temperature to 150 ° C.

The palladium catalyst is palladium acetate (Pd(OAc) ₂ ), bis(triphenylphosphine)palladium dichloride ((Ph ₃ P) ₂ PdCl ₂ ), bis(benzonitrile)palladium chloride ((PhCN)) ₂ PdCl ₂ ), tetrakis(triphenylphosphine)palladium (Pd(PPh ₃ ) ₄ ), bis(triphenylphosphine)palladium acetate ((Ph ₃ P) ₂ Pd(OAc) ₂ ), 1,2-di (diphenylphosphino)ethane palladium dichloride ((PdCl ₂ (dppe) ₂ )), bis(1,2-bis(diphenylphosphino)ethane)palladium (Pd(dppe) ₂ ), double (dibenzylideneacetone) palladium (Pd(dba) ₂ ), tris(dibenzylideneacetone)dipalladium (Pd ₂ (dba) ₃ ), [1,3-bis(diphenylphosphino)propane] Palladium dichloride (PdCl ₂ (dippp)) or [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(dppf)Cl ₂ ).

The base is sodium bis(trimethylsilyl)amide, potassium t-butoxide, sodium t-butoxide, cesium carbonate, potassium phosphate, sodium phosphate, sodium methoxide, sodium ethoxide, potassium hydroxide, sodium hydroxide, potassium fluoride, One or more of sodium fluoride, tetrabutylammonium fluoride (TBAF), sodium acetate, potassium acetate, cesium carbonate, potassium carbonate, and sodium carbonate.

The reaction solvent of the coupling reaction is not particularly limited as long as it does not interfere with the reaction, including water; ethers such as dioxane, tetrahydrofuran, etc.; aromatic hydrocarbons such as toluene, xylene, etc.; alcohols Such as: tert-butanol, etc.; ketones, such as acetone; amides, such as: N, N-dimethylformamide; other classes, such as: dimethyl sulfoxide, acetonitrile, etc.; or a mixture of the above solvents If necessary, the above reaction can be carried out by adding a suitable ligand as a reaction accelerator. Suitable ligands are 2,2'-diphenylphosphino-1,1'-binaphthyl (BINAP), tri-tert-butyl (P(t-Bu) ₃ ), 1,1'-di-(diphenyl) Phosphyl)ferrocene (dppf), 2-dicyclohexylphosphine-2,4,6-triisopropylbiphenyl (x-phos), 4,5-bisdiphenylphosphine-9,9-di Xantphos, tri-tert-butylphosphine tetrafluoroborate or tris(2-methylphenyl)phosphine (P(o-tolyl) ₃ ).

The process in which the compound IV undergoes a cleavage reaction deprotection group is the same as in the first method.

Or method three:

Compound IF and diethanolamine are substituted to give compound VII; compound VII is reacted with a halogenating reagent or a sulfonylating reagent to obtain compound VIII; compound VIII and 3-(trifluoromethyl) The aniline is substituted to obtain the compound IV; the compound IV is cleaved to deprotect the group to obtain the flubanerin III, as shown in the reaction formula 7:

Reaction 7:

Wherein X3 is chlorine, bromine, iodine, methanesulfonyloxy or trifluoromethanesulfonyloxy.

The base may be selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide; an alkali metal carbonate such as sodium carbonate, Potassium carbonate, cesium carbonate, lithium carbonate; alkali metal hydrogen carbonate, such as: sodium hydrogencarbonate, potassium hydrogencarbonate, lithium hydrogencarbonate; alkali metals, such as: potassium, sodium; others, such as: sodium amide, potassium amide, sodium hydride Potassium hydride; organic bases include sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, Quinoline, piperidine, piperazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4 .0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2 ] Octane (DABCO). If necessary, the above substitution reaction can be carried out by adding an alkali metal iodide such as potassium iodide and sodium iodide as a reaction accelerator. The above substitution reaction is usually carried out at room temperature to 200 ° C, preferably at room temperature to 150 ° C. Preferably, the base is one of sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate, cesium carbonate or Several mixtures.

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether, etc.; The aromatic hydrocarbons are selected from the group consisting of benzene, toluene, xylene, nitrobenzene, chlorobenzene, etc.; the alcohols are selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketones Selected from acetone, methyl ethyl ketone, 4-methyl-2-pentanone, etc.; the amides are selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, etc.; the halogenated hydrocarbons Selected from chloroform, dichloromethane, dichloroethane, carbon tetrachloride; the esters are selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; the other classes are selected from dimethyl Sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone.

In the hydroxyl group conversion reaction, the reaction conditions of the leaving group (X3) which are not converted to the leaving group of the compound VII are carried out according to the leaving group, and are carried out according to a conventional method depending on the leaving group. For example, when X3 is a halogen, a corresponding halogenating agent such as thionyl chloride, hydrobromic acid or the like is used; when X3 is a methanesulfonyloxy group, the reaction can be carried out under basic conditions using methanesulfonyl chloride.

The acid salt of the pharmaceutically acceptable salt of the fluoxetine may be an inorganic acid or an organic acid, and the inorganic acid is one of hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid and hydroiodic acid; the organic acid is formic acid, Acetic acid, propionic acid, butyric acid, malic acid, oxalic acid, tartaric acid, amino acids, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid, taurine, fumaric acid, maleic acid, One of citric acid, succinic acid, cholic acid and deoxycholic acid.

A preferred embodiment of the benzimidazole compound of the formula (I) of the present invention for producing flurbanserin or a pharmaceutically acceptable salt thereof is as follows:

R is a methyl group, an ethyl group or a benzyl group.

Another preferred embodiment of the invention is as follows:

R is a methyl group, an ethyl group or a benzyl group.

Another preferred embodiment of the invention is as follows:

R is a methyl group, an ethyl group or a benzyl group.

Advantageous effects of the invention:

The compound I of the method of the invention has fewer reaction sites than the intermediates reported in other patent documents, and can greatly reduce the generation of impurities, improve the yield and the purity of the final product. Compound I can be used to construct a benzimidazole ring by an orthoester condensation reaction, which is low in cost, mild in reaction conditions, and high in yield. The method has the advantages of high reaction yield, simple operation, low cost and easy availability of the reagents used, green environmental protection, etc., and can economically and conveniently realize the industrial production of flurbin or its pharmaceutically acceptable salt.

detailed description

The following examples further illustrate the invention but are not to be construed as limiting the invention in any way.

Example 1 2-Ethoxy-1H-benzimidazole

O-phenylenediamine (20 g, 185 mmol), tetraethyl orthoformate (37.3 g, 194 mmol) was added to acetic acid (11.1 g, 185 mmol) and heated at 80 ° C for 1.5 h. TLC showed the reaction was completed. The reaction solution was concentrated to a small volume, then poured into 200 ml of water, stirred for 10 min, suction filtered, and the filter cake was washed once with water and dried at 65 ° C. The product was 27 g in a yield of 90%.

^{1 H NMR (400MHz, DMSO)} δ11.78 (s, 1H), 7.35 (s, 1H), 7.21 (s, 1H), 7.07-6.96 (m, 2H), 4.47 (q, J = 7.1Hz, 2H ), 1.37 (t, J = 7.1 Hz, 3H).

ESI-[M+H] ⁺ =162.99

Example 2 2-Ethoxy-1H-benzimidazole

O-phenylenediamine (0.8 kg, 7.39 mol), tetraethyl orthoformate (1.49 kg, 7.76 mol) was added to acetic acid (444 g), and reacted at 70 ° C for 2 h. TLC showed the reaction was completed. The reaction solution was cooled to room temperature, and a 5% aqueous potassium hydroxide solution (6.4 L) was slowly added, and the mixture was stirred for 1 hour. The precipitated solid was filtered, and the filtered cake was washed with water. ^{1 H NMR (400MHz, DMSO-} d 6) δ11.80 (brs, 1H), 7.29 (m, 2H), 7.03 (m, 2H), 4.48 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1Hz, 3H) .ESI- MS (m / z): 163.5 [m + H] +, 161.2 [MH] -; HPLC: retention time 12.2 min, 96.3% purity.

Example 3 1-(2-Chloroethyl)-2-ethoxy-1H-benzimidazole

The product of Example 1 (2 g, 12.3 mmol), potassium carbonate (6.8 g, 49.4 mmol), 1,2-dichloroethane (6.1 g, 61.5 mmol) was added to acetonitrile (10 ml) and refluxed for 15 h. complete. After suction filtration, the cake was washed with ethyl acetate, and the filtrate was concentrated to yield 2.77 g, and the crude product yield was 99.8%.

¹ H NMR (400 MHz, DMSO) δ 7.46 - 7.38 (m, 2H), 7.14 - 7.05 (m, 2H), 4.55 (q, J = 7.1 Hz, 2H), 4.37 (t, J = 5.9 Hz, 2H) ), 3.96 (t, J = 5.9 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

^{ESI- [M + H] + =} 225.04

Example 4 1-(2-Chloroethyl)-2-ethoxy-1H-benzimidazole

The product of Example 1 (1 g, 6.16 mmol), cesium carbonate (3 g, 9.24 mmol), 1-bromo-2- Ethyl chloride (1.94 g, 13.55 mmol) was added to acetonitrile (10 ml), which was reacted at 40 ° C for 12 h. The reaction mixture was cooled to rt.

Example 5 1-(2-Chloroethyl)-2-ethoxy-1H-benzimidazole

The product of Example 1 (1 g, 6.16 mmol), potassium carbonate (2.13 g, 15.4 mmol), 1-bromo-2-chloroethane (1.76 g, 12.32 mmol) was added to N,N-dimethylformamide ( 10 ml), reacted at 40 ° C for 12 h, and TLC showed the reaction was completed. The reaction mixture was cooled to rt.

Example 6 1-(2-Chloroethyl)-2-ethoxy-1H-benzimidazole

The product of Example 2 (1 kg, 6.16 mol), potassium carbonate (5.11 kg, 36.99 mol), 1-bromo-2-chloroethane (2.21 kg, 15.41 mol) was added to acetone (10 L) for reflux for 10 h, TLC The reaction is shown to be complete. The reaction mixture was cooled to room temperature, filtered, and the filtrate was evaporated. ^{_{1 H NMR (500MHz, CDCl 3}} ) δ7.52 (d, J = 7.6Hz, 1H), 7.17-7.06 (m, 3H), 4.58 (q, J = 7.1Hz, 2H), 4.17 (t, J = 6.6 Hz, 2H), 3.69 (t, J = 6.6 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H). ¹³ C NMR (125 MHz, CDCl ₃ ) δ 156.9, 140.0, 133.3, 121.6, 120.9, 117.6 , 107.9, 66.3, 43.4, 41.2, 14.6. ESI-MS (m/z): 225.3 [M+H] ⁺ ; HRMS (ESI) calcd [M+H] ⁺ for C ₁₁ H ₁₄ ClN ₂ O 225.0795, found225 .0798. HPLC: retention time is 16.0 min, purity 97.5%.

Example 7 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (712 mg, 2.67 mmol), KI (440 mg, 2.67 mmol), 1.1 g, 8.01 mmol), added to 20 ml of acetonitrile and refluxed for 24 h. The solvent was concentrated, and the title compound wasjjjjjjj

^{1 H NMR (400MHz, DMSO)} δ7.47-7.37 (m, 3H), 7.23 (d, J = 8.5Hz, 1H), 7.19 (s, 1H), 7.14-7.05 (m, 3H), 4.54 (q , J = 7.1 Hz, 2H), 4.24 (t, J = 6.1 Hz, 2H), 3.27 (br, 4H), 2.91 (t, J = 6.1 Hz, 2H), 2.82 (br, 4H), 1.43 (t , J = 7.1 Hz, 3H).

^{ESI- [M + H] + =} 419.01

Example 8 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (0.5 kg, 2.23 mol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (0.68 kg, 2.56 mol), NaI (1.0 kg, 6.68 mol), Potassium carbonate (0.92 kg, 6.68 mol) was added to N,N-dimethylformamide (3 L) and reacted at 70 ° C for 10 h. The reaction mixture was cooled to room temperature, ethyl acetate and water was evaporated. ^{_{1 H NMR (500MHz, CDCl 3}} ) δ7.56 (m, 1H), 7.32 (t, J = 8.0Hz, 1H), 7.21-7.12 (m, 3H), 7.10 (brt, J = 1.9Hz, 1H) , 7.07 (d, J = 7.7 Hz, 1H), 7.02 (dd, J = 8.4, 2.4 Hz, 1H), 4.62 (q, J = 7.1 Hz, 2H), 4.11 (t, J = 6.8 Hz, 2H) , 3.19 (brt, J = 5.0Hz , 4H), 2.75 (t, J = 6.9Hz, 2H), 2.66 (t, J = 5.0Hz, 4H), 1.49 (t, J = 7.1Hz, 3H). 13 C NMR (125MHz, CDCl ₃ ) δ 157.4, 151.3, 140.3, 133.6, 131.4 (q, J = 31.8 Hz), 129.6, 124.4 (q, J = 272.5 Hz), 121.5, 120.8, 118.7, 117.7, 115.9 (q, J = 3.9 Hz), 112.2 (q, J = 3.8 Hz), 108.1, 66.2, 56.4, 53.1 × 2, 48.6 × 2, 39.7, 14.9. ESI-MS (m/z): 419.6 [M+H] ⁺ ;HRMS(ESI)calcd[M+H] ⁺ for C ₂₂ H ₂₆ F ₃ N ₄ O 419.2059, found 419.2071. HPLC: retention time 21.7 min, purity 97.7%.

Example 9 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (852 mg, 3.20 mmol), NaI (400 mg, 2.67 mmol), 1.84 g, 13.35 mmol), added water (10 mL), and refluxed for 24 h. The reaction mixture was cooled to room temperature, and ethyl acetate was evaporated.

Example 10 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (781 mg, 2.94 mmol), NaI (400 mg, 2.67 mmol), 1.31 g, 4.00 mmol), added water (10 mL), and refluxed for 24 h. The reaction mixture was cooled to room temperature, EtOAc was evaporated.

Example 11 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (646 mg, 2.43 mmol), NaI (400 mg, 2.67 mmol), 1.47g, 10.68mmol), Add acetonitrile-water (8 ml / 4 ml) system, and heat to reflux for 24 h. The reaction mixture was cooled to room temperature, evaporated, evaporated, evaporated, evaporated.

Example 12 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (592 mg, 2.23 mmol), NaI (400 mg, 2.67 mmol), 0.81 g, 5.87 mmol), added to a system of ethanol (10 ml), and heated under reflux for 24 h. The reaction mixture was cooled to EtOAc.

Example 13 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (781 mg, 2.94 mmol), NaI (400 mg, 2.67 mmol), 0.737 g, 5.34 mmol) was added to a 1,4-dioxane (10 ml) system and heated to reflux for 24 h. The reaction mixture was cooled to EtOAc.

Example 14 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (781 mg, 2.94 mmol), NaI (400 mg, 2.67 mmol), 0.81 g, 5.87 mmol) was added to a system of N-methylpyrrolidone (10 ml), and the reaction was heated at 70 ° C for 24 h. The reaction mixture was cooled to room temperature, EtOAc (EtOAc m.

Example 15 2-Ethoxy-1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole

The product of Example 6 (600 mg, 2.67 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine hydrochloride (781 mg, 2.94 mmol), NaI (400 mg, 2.67 mmol), 0.81 g, 5.87 mmol), added to acetone (10 ml), and heated to reflux for 24 h. The reaction mixture was cooled to EtOAc.

Example 16 Hydrochloride of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole-2(3H)-one

The product of Example 15 (200 mg, 0.478 mmol) was dissolved in 5 ml of acetone. The solvent was concentrated, a small amount of acetonitrile was added, and a solid was precipitated, which was filtered with suction to give 150 mg of fluban.

^{1 H NMR (400MHz, DMSO)} δ11.27 (s, 1H), 11.08 (s, 1H), 7.48 (t, J = 7.9Hz, 1H), 7.40-7.34 (m, 1H), 7.31 (d, J = 8.8 Hz, 2H), 7.16 (d, J = 7.6 Hz, 1H), 7.09 - 7.01 (m, 3H), 4.32 (t, J = 6.6 Hz, 2H), 4.01 (d, J = 9.9 Hz, 2H) ), 3.75 (d, J = 8.6 Hz, 2H), 3.48 (d, J = 4.0 Hz, 2H), 3.33 - 3.15 (m, 4H).

ESI-[M+H] ⁺ =391.14

Example 17 Hydrochloride of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole-2(3H)-one

The product of Example 15 (200 mg, 0.478 mmol) was dissolved in 5 ml of 30% hydrogen chloride/ethanol and stirred at 70 ° C for 2 h. The solvent was concentrated, a small amount of acetonitrile was added, and a solid was precipitated, which was filtered with suction to give 155 mg of fluban.

Example 18 Hydrochloride of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole-2(3H)-one

The product of Example 15 (200 mg, 0.478 mmol) was dissolved in 5 ml of 4M hydrogen chloride / 1,4-dioxane solution and stirred at 70 ° C for 2 h. The solvent was concentrated, a small amount of acetonitrile was added, and a solid was precipitated, which was filtered with suction to give <RTIgt;

Example 19 Hydrochloride of 1-(2-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole-2(3H)-one

The product of Example 8 (0.98 kg, 2.34 mol) was dissolved in isopropyl alcohol (3L) and concentrated hydrochloric acid (0.78L, 9.37 mol). The reaction mixture was stirred at 70 ° C for 3 h. The solvent was concentrated, purified by EtOAc (EtOAc) (EtOAc)

Example 20 1-(2-(4-(3-(Trifluoromethyl)phenyl)piperazin-1-yl)ethyl)-1H-benzimidazole-2(3H)-one

The product of Example 19 (0.97 kg, 2.27 mol) was obtained, and ethyl acetate (3 L) and aqueous sodium hydroxide (140 g of sodium hydroxide dissolved in 1.5 L of water) were added and stirred at room temperature for 30 min. The organic phase was dried, concentrated and purified by ethylamine (EtOAc) (EtOAc) ^{1 H NMR (400MHz, DMSO-} d 6) δ10.83 (s, 1H), 7.40 (t, J = 8.0Hz, 1H), 7.20 (dd, J = 8.4Hz, 2.4Hz, 1H), 7.12-7.17 (m, 2H), 7.05 (d, J = 7.6 Hz, 1H), 6.94 - 7.02 (m, 3H), 3.94 (t, J = 6.6 Hz, 2H), 3.17 (brt, 4H), 2.58-2.65 ( m, 6H); ESI-MS (m/z): 391.6 [M+H] ⁺ ; HPLC: retention time 14.28 min, purity 99.86%.

Claims

A class of benzimidazole compounds of formula (I):

among them,

R is a hydroxy protecting group selected from a C1-C6 straight or branched alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted aryl substituted C1-C6 straight or branched alkyl group, C1- a C6 linear or branched alkyl-substituted silicon group, a C1-C6 alkoxymethyl group, a C1-C6 alkanoyl group, a substituted or unsubstituted aroyl group; wherein the substitution means a hydroxyl group, a halogen, a C1- Substituted by a C6 alkyl group or a C1-C6 alkoxy group; the aryl group is a phenyl group or a naphthyl group;

X is a leaving group selected from halogen, substituted or unsubstituted C1-C6 alkylsulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, substituted or unsubstituted naphthalenesulfonyloxy, Substituted means substituted by one or more groups selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 alkoxy, nitro, hydroxy, amino and C1-C6 alkanoyl.
The benzimidazole compound according to claim 1,

Wherein R is selected from C1-C4 straight or branched alkyl, substituted or unsubstituted aryl, substituted or unsubstituted aryl substituted C1-C4 straight or branched alkyl, C1-C4 straight chain Or a branched alkyl-substituted silicon group, a C1-C4 alkoxymethyl group, a C1-C4 alkanoyl group, a substituted or unsubstituted aroyl group; wherein the substitution means a hydroxyl group, a halogen, a C1-C6 alkyl group Or a C1-C6 alkoxy group; the aryl group is a phenyl or naphthyl group;

X is selected from halogen, substituted or unsubstituted C1-C4 alkylsulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, substituted or unsubstituted naphthalenesulfonyloxy, said substituted means A plurality of groups selected from the group consisting of halogen, C1-C4 alkyl, C1-C4 alkoxy, nitro, hydroxy, amino, and C1-C4 alkanoyl are substituted.
The benzimidazole compound according to claim 1,

Wherein R is benzyl, methyl, ethyl, tert-butyl, triphenylmethyl, methoxymethyl, trimethylsilyl, tert-butyldimethylsilyl, acetyl or benzoyl ;

X is chlorine, bromine, methanesulfonyloxy, trifluoromethanesulfonyloxy, benzenesulfonyloxy, naphthalenesulfonyloxy, methylbenzenesulfonyloxy, nitrobenzenesulfonyloxy, aminobenzene Sulfonyloxy, chlorobenzenesulfonyloxy, bromobenzenesulfonyloxy Or methoxybenzenesulfonyloxy.
The benzimidazole compound according to any one of claims 1 to 3, which is a compound selected from the group consisting of:

(1) 1-(2-chloroethyl)-2-ethoxy-1H-benzimidazole;

(2) 1-(2-bromoethyl)-2-ethoxy-1H-benzimidazole;

(3) 1-(2-chloroethyl)-2-methoxy-1H-benzimidazole;

(4) 1-(2-Bromoethyl)-2-methoxy-1H-benzimidazole;

(5) 1-(2-methanesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(6) 1-(2-methanesulfonyloxyethyl)-2-methoxy-1H-benzimidazole;

(7) 1-(2-p-toluenesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(8) 1-(2-p-toluenesulfonyloxyethyl)-2-methoxy-1H-benzimidazole;

(9) 1-(2-benzenesulfonyloxyethyl)-2-ethoxy-1H-benzimidazole;

(10) 1-(2-Benzenesulfonyloxyethyl)-2-methoxy-1H-benzimidazole.
A process for the preparation of the benzimidazole compound according to any one of claims 1 to 4, the reaction route is as follows:

The compound of the formula (II) and the compound XCH 2 CH 2 X1 are subjected to a substitution reaction in the presence of a base in a suitable solvent to give a benzimidazole compound of the formula (I) wherein X1 is the same as X.
The preparation method according to claim 5, wherein:

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylene , nitrobenzene, chlorobenzene; the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl-2- Pentanone The amide is selected from the group consisting of N,N-dimethylformamide and N,N-dimethylacetamide; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, dichloroethane and carbon tetrachloride; The esters are selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate; the other classes are selected from the group consisting of dimethyl sulfoxide, acetonitrile, and 1-methyl-2-pyrrolidone; preferably, the Suitable solvents are water, acetonitrile, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide, a mixture of one or more of methyl sulfoxide and 1,2-dichloroethane;

The base is selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal, a sodium amide, a potassium amide, a sodium hydride, a potassium hydride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperidine Pyrazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane; the base may be used alone Or a combination of two or more; preferably, the base is sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate a mixture of one or more of cesium carbonate.
Use of the benzimidazole compound according to any one of claims 1 to 4 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) Compound I and 1-(3-(trifluoromethyl)phenyl)piperazine or a salt thereof are subjected to a substitution reaction to obtain a compound IV;

(2) Compound IV undergoes a cleavage reaction to remove a hydroxy protecting group to obtain a flubanserline or a salt thereof;

Wherein R and X are as defined in the corresponding claims.
Use of the benzimidazole compound according to claim 7 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, characterized in that:

The substitution reaction of the step (1) is carried out in the presence of a base in a suitable solvent;

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons Classes, alcohols, ketones, amides, halogenated hydrocarbons, esters and others; the ethers are selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, digan Alcohol dimethyl ether, ethylene glycol dimethyl ether; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, xylene, nitrobenzene, chlorobenzene; the alcohols are selected from the group consisting of methanol, ethanol, isopropanol, butanol, Tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, and 4-methyl-2-pentanone; and the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl The acetamide is selected from the group consisting of chloroform, dichloromethane, dichloroethane, carbon tetrachloride; the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, and isopropyl acetate. The other class is selected from the group consisting of dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone; preferably, the suitable solvent is water, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tetrahydrofuran a mixture of one or more of 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, 1,2-dichloroethane;

The base is selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal, a sodium amide, a potassium amide, a sodium hydride, a potassium hydride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperidine Pyrazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane; the base may be used alone Or a combination of two or more; preferably, the base is sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate a mixture of one or more of cesium carbonate.
Use of the benzimidazole compound according to any one of claims 1 to 4 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) Compound I and piperazine are substituted to obtain compound V;

(2) Compound V is coupled with compound VI in the presence of a base and a palladium catalyst to obtain compound IV;

(3) Compound IV undergoes a cleavage reaction to remove a hydroxy protecting group to obtain flurbanserin or a salt thereof;

Wherein R and X are as defined in the corresponding claims; X2 is bromo, chloro, iodo or trifluoromethanesulfonyloxy.
Use of the benzimidazole compound according to claim 9 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, characterized by:

The substitution reaction of the step (1) is carried out in the presence of a base in a suitable solvent;

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylene , nitrobenzene, chlorobenzene; the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl-2- Pentanone; the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, dichloroethane, tetrachloro Carbon; the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; the other is selected from the group consisting of dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone; The suitable solvent is water, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide Methyl a mixture of one or more of a sulfoxide, 1,2-dichloroethane;

The base is selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal, a sodium amide, a potassium amide, a sodium hydride, a potassium hydride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperidine Pyrazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane; the base may be used alone Or a combination of two or more; preferably, the base is sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate a mixture of one or more of cesium carbonate.
Use of the benzimidazole compound according to any one of claims 1 to 4 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, comprising the steps of:

(1) Compound I and diethanolamine are substituted to obtain compound VII;

(2) Compound VII is reacted with a halogenating reagent or a sulfonylating reagent to obtain a compound VIII;

(3) Compound VIII and 3-(trifluoromethyl)aniline are substituted to give compound IV;

(4) Compound IV undergoes a cleavage reaction to remove a hydroxy protecting group to obtain flurbin III or a salt thereof;

Wherein R and X are as defined in the corresponding claims, and X3 is bromo, chloro, iodo, methanesulfonyloxy or trifluoromethanesulfonyloxy.
Use of a benzimidazole compound according to claim 11 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, characterized by:

The substitution reaction of the step (1) is carried out in the presence of a base in a suitable solvent;

The suitable solvent includes a mixture of one or more of the following solvents: water, ethers, aromatic hydrocarbons, alcohols, ketones, amides, halogenated hydrocarbons, esters, and the like; The class is selected from the group consisting of dioxane, tetrahydrofuran, diethyl ether, methyl tert-butyl ether, diisopropyl ether, diglyme, ethylene glycol dimethyl ether; the aromatic hydrocarbons are selected from the group consisting of benzene, toluene, and xylene , nitrobenzene, chlorobenzene; the alcohol is selected from the group consisting of methanol, ethanol, isopropanol, butanol, tert-butanol, ethylene glycol; the ketone is selected from the group consisting of acetone, methyl ethyl ketone, 4-methyl-2- Pentanone; the amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide; the halogenated hydrocarbon is selected from the group consisting of chloroform, dichloromethane, dichloroethane, tetrachloro Carbon; the ester is selected from the group consisting of ethyl acetate, ethyl formate, methyl acetate, isopropyl acetate; the other is selected from the group consisting of dimethyl sulfoxide, acetonitrile, 1-methyl-2-pyrrolidone; The suitable solvent is water, acetonitrile, acetone, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethylformamide Methyl a mixture of one or more of a sulfoxide, 1,2-dichloroethane;

The base is selected from an inorganic base or an organic base, and the inorganic base includes an alkali metal hydroxide, an alkali metal carbonate, an alkali metal hydrogencarbonate, an alkali metal, a sodium amide, a potassium amide, a sodium hydride, a potassium hydride; Sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium acetate, triethylamine, pyridine, diisopropylamine, diisopropylethylamine, tripropylamine, diethylamine, pyrimidine, quinoline, piperidine, piperidine Pyrazine, imidazole, dimethylaminopyridine, trimethylamine, N-ethyldiisopropylamine, N-methylmorpholine, dimethylaniline, 1,8-diazabicyclo[5.4.0]undecene- 7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane; the base may be used alone Or a combination of two or more; preferably, the base is sodium hydride, triethylamine, diisopropylethylamine, sodium hydroxide, potassium hydroxide, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium carbonate a mixture of one or more of cesium carbonate.
The use of the benzimidazole compound according to any one of claims 7 to 12 for the preparation of flurbanserin or a pharmaceutically acceptable salt thereof, wherein R is a methyl group, an ethyl group or a benzyl group.