Thionyl Chloride → Lercanidipine Impurity 5

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Compounds of formula 1 may also be prepared by the following variation of Scheme IV, especially where optically active compounds are desired. A suitable dihydropyridine derivative acid is prepared and the optical isomers separated (where desired) following the procedure set forth by T. Shibanuma, et al., Chem. Pharm. Bull., 28, 2809-2812 (1980). For example, 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is N-protected, and subsequently resolved with an optically active amine, e.g., cinchonine, to prepare (+)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (12+) and (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine (after deprotection). The resolved dihydropyridine acid derivative is then treated with SOCl2 in a suitable solvent, e.g., dichloromethane, to produce a dihydropyridine acyl chloride for condensation with an intermediate of the formula X--A--OH, where X is halo. For example, (-)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-carboxy-1,4-dihydropyridine is reacted with SOCl2 to yield 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-chlorocarbonyl-1,4-dihydropyridine, which is then reacted 3-bromopropanol to give the 3-bromopropoxy carbonyl derivative, which is then reacted with 4-(2-tetrahydropyran- 2-yloxyethyl)phenol (10) in CH2Cl2 with triethylamine to generate (S,RS)-2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-tetrahydropyran-2-yloxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (1+).

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