WO2017076213A1 - Composé benzimidazole, son procédé de préparation et son utilisation - Google Patents

Composé benzimidazole, son procédé de préparation et son utilisation Download PDF

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WO2017076213A1
WO2017076213A1 PCT/CN2016/103492 CN2016103492W WO2017076213A1 WO 2017076213 A1 WO2017076213 A1 WO 2017076213A1 CN 2016103492 W CN2016103492 W CN 2016103492W WO 2017076213 A1 WO2017076213 A1 WO 2017076213A1
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group
sodium
potassium
benzimidazole
methyl
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PCT/CN2016/103492
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English (en)
Chinese (zh)
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吴春晖
何洋
张健
杨飞瀑
田广辉
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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
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Priority claimed from CN201610527244.4A external-priority patent/CN106632066A/zh
Application filed by 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 filed Critical 苏州旺山旺水生物医药有限公司
Publication of WO2017076213A1 publication Critical patent/WO2017076213A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/26—Oxygen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • 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.
  • 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):
  • 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:
  • 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:
  • 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.
  • 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.
  • the present invention provides a benzimidazole compound of the formula (I):
  • R is a hydroxy protecting group
  • 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.
  • 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.
  • 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.
  • 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.
  • the compound of formula (I) is selected from the group consisting of:
  • 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:
  • 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 suitable solvent is water, acetonitrile, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethyl
  • the suitable solvent is water, acetonitrile, acetone, methanol, ethanol, isopropanol, n-butanol, tetrahydrofuran, 1,4-dioxane, N-methylpyrrolidone, N,N-dimethyl
  • carbachamide dimethyl sulfoxide
  • 1,2-dichloroethane 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
  • the base may be used alone or in combination of two or more.
  • 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.
  • 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.
  • 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
  • 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.
  • an alkali metal iodide such as potassium iodide and sodium iodide
  • 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
  • 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.
  • 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.
  • R 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;
  • the metal catalyst 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 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.
  • 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%.
  • R 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.
  • TBAF tetrabutylammonium fluoride
  • pyridine hydrofluoride preferably tetrabutylammonium fluoride. (TBAF) or hydrochloric acid removal.
  • TBAF tetrabutylammonium fluoride
  • hydrochloric acid removal a fluorine-containing ion
  • 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,
  • 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.
  • X2 is chlorine, bromine, iodine or trifluoromethanesulfonyloxy.
  • 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
  • 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.
  • 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.
  • 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
  • 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.
  • TBAF tetrabutylammonium fluoride
  • 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 ).
  • BINAP 2,2'-diphenylphosphino-1,1'-binaphthyl
  • P(t-Bu) 3 tri-tert-butyl
  • dppf 1,1'-di-(diphenyl) Phosphyl
  • X3 is chlorine, bromine, iodine, methanesulfonyloxy or trifluoromethanesulfonyloxy.
  • 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
  • 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.
  • 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
  • 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 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.
  • X3 is a halogen
  • a corresponding halogenating agent such as thionyl chloride, hydrobromic acid or the like is used
  • 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.
  • R is a methyl group, an ethyl group or a benzyl group.
  • R is a methyl group, an ethyl group or a benzyl group.
  • 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.
  • Example 2 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%.
  • Example 2 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 2 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 2 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.
  • Example 6 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
  • Example 6 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.
  • Example 6 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 6 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 6 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 6 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 6 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 15 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.
  • Example 15 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 15 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 8 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 19 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé benzimidazole représenté par la formule (I), son procédé de préparation et son utilisation dans la préparation de flibansérine ou d'un sel de flibansérine pharmaceutiquement acceptable.
PCT/CN2016/103492 2015-11-02 2016-10-27 Composé benzimidazole, son procédé de préparation et son utilisation WO2017076213A1 (fr)

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CN201610527244.4A CN106632066A (zh) 2015-11-02 2016-07-06 苯并咪唑类化合物、其制备方法及用途
CN201610527244.4 2016-07-06

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020026162A1 (fr) 2018-08-01 2020-02-06 Richter Gedeon Nyrt. Procédé à flux continu multi-étapes pour la préparation de flibansérine
CN115819353A (zh) * 2023-02-08 2023-03-21 长沙晶易医药科技股份有限公司 一种制备2-芳基氨基苯并咪唑和n1-芳基-2-氨基苯并咪唑的方法
CN115894247A (zh) * 2021-09-30 2023-04-04 迈克斯(如东)化工有限公司 一种1,3-二取代-2-丙酮类化合物的制备方法及其中间体

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526434A1 (fr) * 1991-07-30 1993-02-03 BOEHRINGER INGELHEIM ITALIA S.p.A. Dérivés de benzimidazolone comme antagonistes de 5-HT1A et 5-HT2
WO2010128516A2 (fr) * 2009-05-04 2010-11-11 Symed Labs Limited Procédé de préparation de la flibansérine impliquant de nouveaux intermédiaires
WO2011163594A2 (fr) * 2010-06-24 2011-12-29 Alkermes, Inc. Promédicaments de composés nh-acides : dérivés esters, carbonates, carbamates et phosphonates
CN104926734A (zh) * 2015-07-07 2015-09-23 苏州立新制药有限公司 氟班色林的制备方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0526434A1 (fr) * 1991-07-30 1993-02-03 BOEHRINGER INGELHEIM ITALIA S.p.A. Dérivés de benzimidazolone comme antagonistes de 5-HT1A et 5-HT2
WO2010128516A2 (fr) * 2009-05-04 2010-11-11 Symed Labs Limited Procédé de préparation de la flibansérine impliquant de nouveaux intermédiaires
WO2011163594A2 (fr) * 2010-06-24 2011-12-29 Alkermes, Inc. Promédicaments de composés nh-acides : dérivés esters, carbonates, carbamates et phosphonates
CN104926734A (zh) * 2015-07-07 2015-09-23 苏州立新制药有限公司 氟班色林的制备方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020026162A1 (fr) 2018-08-01 2020-02-06 Richter Gedeon Nyrt. Procédé à flux continu multi-étapes pour la préparation de flibansérine
CN115894247A (zh) * 2021-09-30 2023-04-04 迈克斯(如东)化工有限公司 一种1,3-二取代-2-丙酮类化合物的制备方法及其中间体
CN115819353A (zh) * 2023-02-08 2023-03-21 长沙晶易医药科技股份有限公司 一种制备2-芳基氨基苯并咪唑和n1-芳基-2-氨基苯并咪唑的方法
CN115819353B (zh) * 2023-02-08 2023-06-30 长沙晶易医药科技股份有限公司 一种制备2-芳基氨基苯并咪唑和n1-芳基-2-氨基苯并咪唑的方法

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