Regioselective preparation of alkyl 4-alkanoylamino-3-alkyl-5-nitrobenzoic acid derivatives, useful as intermediates for benzimidazole derivative drugs, by nitration of 5-unsubstituted analogs under controlled conditions

摘要

The preparation of alkyl 4-alkanoylamino-3-alkyl-5-nitrobenzoic acid derivatives (I) by nitration of 5-unsubstituted analogs (II) involves: (1) dissolving (II) in a solvent mixture of sulfuric acid (1.5-2.5 moles), nitric acid (1.5-2.5 moles) and water (2-6 moles); and (2) treating the mixture with nitric acid (6-10 moles). The preparation of alkyl 4-alkanoylamino-3-alkyl-5-nitrobenzoic acid derivatives of formula (I) by nitration of 5-unsubstituted analogs of formula (II) involves: (1) dissolving (II) in a solvent mixture of sulfuric acid (1.5-2.5 moles), nitric acid (1.5-2.5 moles) and water (2-6 moles); and (2) treating the mixture with nitric acid (6-10 moles). R1, R2 = H or 1-6C alkyl; R3 = H or (1-5C) alkylcarbonyl; R4 = H; or R3 + R4 = succinyl, glutaryl or adipyl. Independent claims are also included for: (1) 2-propyl-4-methyl-6-methoxycarbonyl-benzimidazole (IIIa), prepared by nitration of methyl 4-butyrylamino-3-methyl-benzoate (IIa) as described above, reduction of the nitro group to amino and condensing the carbonyl function of the butyryl residue with the primary amino function; and (2) 2-propyl-4-methyl-6-(N-methyl-benzimidazol-2-yl)-benzimidazole (IIIb), prepared from (IIIa) (as defined in (1)) by saponification of the methoxycarbonyl group followed by reaction with o-N-methyl-phenylene diamine.