合成路线1

The condensation of 2,3-dimethyl-4-nitropyridine N-oxide (I) with 2,2,2-trifluoroethanol (II) by means of K2CO3 in hot HMPT gives 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine N-oxide (III), which by isomerization in acetic anhydride at 100 C is converted to 2-(hydroxymethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridine (IV). The reaction of (IV) with SOCl2 in refluxing CHCl3 affords the corresponding chloromethyl derivative (V), which is condensed with 2-mercaptobenzimidazole (VI) by means of sodium methoxide in refluxing methanol to yield 2-(2-benzimidazolylthiomethyl)-3-methyl-4-(2,2,2-trifluoroethoxy)pyridin (VII). Finally, this compound is oxidized with m-chloroperbenzoic acid in CHCl3.

合成路线2

The chlorination of 2,3-dimethyl-4-(2,2,2-trifluoroethoxy)pyridine-N-oxide (I) with trichloroisocyanuric acid in hot chloroform gives the 2-chloromethyl derivative (II), which is condensed with 2-mercapto-1H-benzimidazole (III) by means of NaOH in methanol to yield the adduct (IV). The reaction of (IV) with PCl3 and acetic acid eliminates the N-oxide group, affording the sulfanylmethylpyridine (V). Finally, this compound is oxidized with tert-butyl hydroperoxide (VI) in ethanol to provide the target sulfoxide. Alternatively, the intermediate adduct (IV) can also be obtained as follows: The chlorination of 2,3-dimethyl-4-nitropyridine-N-oxide (VII) with trichloroisocyanuric acid as before gives the chloromethyl derivative (VIII), which is condensed with 2-mercapto-1H-benzimidazole (III) as before to yield the adduct (IX). Finally, this compound is treated with 2,2,2-trifluoroethanol (X), benzyltrimethylammonium chloride and K2CO3 in acetonitrile to afford the target intermediate (IV).

合成路线3

The synthesis of IY-81149 can be obtained according to Scheme 22875502a. The oxidation of 2,3-lutidine (I) with hydrogen peroxide in acetic acid affords 2,3-dimethylpyridine-N-oxide (II), which is treated with sulfuric acid and nitric acid to give the corresponding nitro compound (III). The treatment of (III) with NaOH in methanol gives 2,3-dimethyl-4-methoxypyridine-N-oxide (IV), which is reacted with acetic acid and acetic anhydride and oxidized in refluxing NaOH, yielding 3-methyl-4-methoxypyridine-2-methanol (V). The chlorination of (V) with thionylchloride in CH2Cl2 affords 3-methyl-4-methoxy-2-chloromethylpyridine (VI). The reaction of 2-mercapto-5-nitrobenzimidazole (VII) with iron and concentrated HCl in refluxing ethanol and water gives monoamine (VIII), which by condensation with 2,5-dimethoxytetrahydrofuran (IX) in acetic acid yields 2-mercapto-5-(1-pyrrolyl)benzimidazole (X). The condensation of (VI) with (X) by means of NaOH in methanol gives 2-[(4-methoxy-3-methyl-2-pyridinyl)methylsulfanyl]-5-(1H-pyrrol-1-yl)-1H-benzimidazole (XI), which is finally treated with m-chloroperoxybenzoic acid (m-CPBA) in chloroform.

合成路线4