Addition of 2,5-difluorophenylmagnesium bromide (I) to the O-tetrahydropyranyl lactic acid amide (II) afforded the propiophenone derivative (III). Oxirane (IV) was then obtained by reaction of ketone (III) with the sulfur ylide generated from trimethylsulfoxonium iodide and either NaH or BuLi. Epoxide ring opening with the sodium salt of 1,2,4-triazole (V) led to the triazolyl alcohol (VI) as a mixture of diastereoisomers. After acid hydrolysis of the tetrahydropyranyl protecting group of (VI), the resultant mixture of diols was separated by column chromatography. The desired (R,R) diastereoisomer (VII) was converted to epoxide (IX) via formation of mesylate (VIII), which was subsequently cyclized in the presence of NaOMe. Nitrile (X) was then obtained by reaction of oxirane (IX) with either trimethylsilyl cyanide, followed by desilylation with Bu4NF, or with acetone cyanohydrin and LiH. Conversion of nitrile (X) into thioamide (XI) was accomplished by treatment with diethyl dithiophosphate. Cyclization of thioamide (XI) with 4-cyanophenacyl bromide (XII) gave rise to the thiazole derivative (XIII).

The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.

The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.

The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.

The intermediate amino alcohol (XVIII) was prepared by two ways. 2-Chloronicotinic acid (XIV) was converted to the corresponding acid chloride (XV) by treatment with oxalyl chloride, and then reacted with potassium tert-butoxide to afford the tert-butyl ester (XVI). Displacement of the chloride group of (XVI) with methanolic methylamine gave rise to the 2-(methylamino)nicotinic ester (XVII), which was then reduced to alcohol (XVIII) employing LiAlH4. Alternatively, 2-aminonicotinic acid (XIX) was esterified to (XX) by means of 2-chloro-1,3-dimethylimidazolinium chloride in MeOH. The amino group of (XX) was acylated with formic acetic anhydride to give formamide (XXI). Amino alcohol (XVIII) was then obtained by reduction of amido ester (XXI) in the presence of LiAlH4. Condensation of (XVIII) with 1-chloroethyl chloroformate produced the carbamate alcohol (XXII), which was subsequently esterified with N-Boc-sarcosine (XXIII) by means of EDC yielding (XXIV) (2). Quaternization of the triazole compound (XIII) with the chloroethyl carbamate (XXIV) in the presence of NaI furnished the corresponding triazolium salt, which was finally subjected to acidic Boc group cleavage to produce the title compound.