合成路线:The synthesis of moxifetin was described according to the following methods:1) The first synthesis starts from the acid (I),which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper,or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper.The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide.Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III),which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane,generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol).The reaction of (III) with phosphoryl chloride,followed by sodium borohydride in ethanol,also results in the amine (IV).This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C,by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid.2) A shorter synthesis begins with the aldehyde (VI),obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate.Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV).Even a procedure via intermediates (VII) and (VIII),i.e.,without protection of the phenolic hydroxyl,is feasible.Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield.The following reaction with dimethylamine (XII),leading to the hydroxy amide (VIII),proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane.The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran.The moxifetin base is converted by reactions with acids to crystalline salts,viz.hydrobromide and hydrogen maleate.
参考文献标题:A novel series of potential antidepressants and selective 5-HT uptake inhibitors
文献作者:J韑ek,J.; Valch醨,M.; Protiva,M.; Metysov? J.; Sindel醨,K.
参考来源:XIth Int Symp Med Chem (Sept 2-7,Jerusalem) 1990,3
合成路线:The synthesis of moxifetin was described according to the following methods:1) The first synthesis starts from the acid (I),which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper,or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper.The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide.Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III),which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane,generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol).The reaction of (III) with phosphoryl chloride,followed by sodium borohydride in ethanol,also results in the amine (IV).This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C,by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid.2) A shorter synthesis begins with the aldehyde (VI),obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate.Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV).Even a procedure via intermediates (VII) and (VIII),i.e.,without protection of the phenolic hydroxyl,is feasible.Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield.The following reaction with dimethylamine (XII),leading to the hydroxy amide (VIII),proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane.The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran.The moxifetin base is converted by reactions with acids to crystalline salts,viz.hydrobromide and hydrogen maleate.
参考文献标题:Moxifetin Hydrogen Maleate
文献作者:Protiva,M.
参考来源:Drugs Fut 1991,16(10),911
合成路线:The synthesis of moxifetin was described according to the following methods:1) The first synthesis starts from the acid (I),which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper,or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper.The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide.Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III),which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane,generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol).The reaction of (III) with phosphoryl chloride,followed by sodium borohydride in ethanol,also results in the amine (IV).This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C,by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid.2) A shorter synthesis begins with the aldehyde (VI),obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate.Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV).Even a procedure via intermediates (VII) and (VIII),i.e.,without protection of the phenolic hydroxyl,is feasible.Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield.The following reaction with dimethylamine (XII),leading to the hydroxy amide (VIII),proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane.The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran.The moxifetin base is converted by reactions with acids to crystalline salts,viz.hydrobromide and hydrogen maleate.
参考文献标题:Crystal and molecular structure of 2-dimethylaminomethyl-3'-hydroxydiphenyl sulfide maleate
文献作者:Schneider,B.; Hasek,J.; Jecny,J.
参考来源:Coll Czech Chem Commun 1990,551529-34
合成路线:The synthesis of moxifetin was described according to the following methods:1) The first synthesis starts from the acid (I),which is prepared either by reaction of 3-methoxythiophenol (V) with 2-iodobenzoic acid (IX) in boiling aqueous potassium hydroxide in the presence of copper,or by reaction of thiosalicylic acid (X) with 3-bromoanisole (XI) in boiling dimethylformamide in the presence of potassium carbonate and copper.The acid (I) is transformed to the acid chloride (II) by treatment with thionyl chloride in boiling benzene in the presence of a small quantity of dimethylformamide.Treatment of the benzene solution of (II) with dimethylamine (XII) under various conditions results in the amide (III),which is reduced to the amine (IV) either with lithium aluminum hydride in ether or with diborane,generated in situ by reaction of sodium borohydride with boron trifluoride etherate in tetrahydrofuran (this method proceeds via the corresponding amine borane which has to be hydrolyzed with sodium hydroxide in boiling aqueous ethanol).The reaction of (III) with phosphoryl chloride,followed by sodium borohydride in ethanol,also results in the amine (IV).This methoxy compound is demethylated in the final step to the desired compound (V) either by heating with pyridine hydrochloride to 210-220 C,by treatment with boron tribromide in chloroform or by refluxing with hydrobromic acid.2) A shorter synthesis begins with the aldehyde (VI),obtained by reaction of 3-methoxythiophenol (XIII) with 2-chlorobenzaldehyde (XIV) in dimethylformamide at 90 C in the presence of potassium carbonate.Leuckart reaction of (VI) with dimethylformamide and formic acid at 180 C directly affords the methoxy amine (IV).Even a procedure via intermediates (VII) and (VIII),i.e.,without protection of the phenolic hydroxyl,is feasible.Refluxing 3-hydroxythiophenol (XV) with 2-iodobenzoic acid (XVI) in aqueous potassium hydroxide in the presence of copper affords the hydroxy acid (VII) in a reasonable yield.The following reaction with dimethylamine (XII),leading to the hydroxy amide (VIII),proceeds in the presence of the complex of triphenylphosphine and tetrachloromethane.The final reduction of (VIII) to moxifetin (V) is carried out with lithium aluminum hydride in tetrahydrofuran.The moxifetin base is converted by reactions with acids to crystalline salts,viz.hydrobromide and hydrogen maleate.
参考文献标题:Neurotropic and psychotropic agents.LXIII.7-Methoxy-10-(4-methylpiperazino)dibenzo[b,f]thiepin and its 10,11-dihydro derivative
文献作者:Nemec,J.; Metysov? J.; Protiva,M.; B醨tl,V.; Metys,J.
参考来源:Coll Czech Chem Commun 1973,382301-6
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