Method for preparing tetrazole methanesulfonic acid salts, and novel compound used in same

#The present invention relates to a method for preparing tetrazole methanesulfonic acid salts and a novel compound used therein.

#Pharmaceutically acceptable salts of 4-oxo-4H-chromene-2-carboxylic acid [2-(2-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2H-tetrazol-5-yl)-4,5-dimethoxyphenyl]-amine, as P-glycoprotein inhibitor, are useful as a multidrug resistance inhibitor. PCT Publication No. WO 2005/033097 discloses a preparation method thereof.

#According to the publication, as shown in Reaction Schemes 1 and 2, nitro-based compounds (1 and 3) undergo hydrogenation in a solvent such as methanol, ethanol, chloroform, dichloromethane, tetrahydrofuran, ethyl ether and hexane toluene, in the presence of a metal catalyst such as palladium, platinum and zinc to obtain amino compounds (2 and 4). The resulting compound is then subjected to an acylation using a condensing agent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, N,N-dicyclohexyldiimide, N,N-diisoprocarbodiimide and 1-cyclohexyl-3-(2-morpholinoethyl)carbodiimide methyl-p-toluenesulfonate, in the presence of a catalyst such as 4-(dimethylamino)pyridine in a solvent such as dichloromethane, chloroform, N,N-dimethylformamide, tetrahydrofuran, and 1,4-dioxane, to obtain a tetrazole compound (5) as a final product.

#Hereinafter, the present invention is described in detail.

#The preparation method according to the present invention employs an acylation process using a novel compound, 4-oxo-4H-chromene-2-carbothionic acid S-benzothiazol-2-yl ester, instead of using a condensing agent as in conventional methods, to obtain tetrazole methanesulfonic acid salts with a high purity at a high yield, without an additional purification process such as a column chromatography.

#As shown in Reaction Scheme 3 below, the method for preparing tetrazole methanesulfonic acid salts according to the present invention comprises: (Step 1) acylating the compound of formula (II) with the compound of formula (III) to obtain the compound of formula (IV); and (Step 2) adding methanesulfonic acid to the compound of formula (IV) obtained in the above step.