Intermediates for the synthesis of benzimidazole derivatives and a process for the preparation thereof
AssigneeSankyo Company, Limited
InventorsNaoyuki Kishi, Yoshitaka Nakamura, Narumi Abe, Toyonori Takebayashi
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Abstract
This invention provides a process for the preparation of a benzimidazole derivative (I) or a pharmaceutically acceptable salt thereof, 1 wherein R1 is C1-C6 alkyl, C1-C6 alkoxyl, etc., R2 is C1-C6 alkyl, and R3 is hydrogen or a protecting group, which exhibits excellent hyopoglycemic action, said process comprising condensation of an amine derivative (III) with a carboxylic acid derivatives (II) to afford a compound (IV), followed by cyclization of compound (IV) in the presence of an acid.
Claims43
A compound of formula (1) or a pharmaceutically acceptable salt thereof,
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- wherein R1a, R2a, R3a and R4a are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5a and R6a are each independently an amino protecting group.
A compound of formula (2) or a pharmaceutically acceptable salt thereof,
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- wherein R1b, R2b, R3b and R4b are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7b is C1-C6 alkyl and R8b is an amino protecting group.
A compound of formula (3) or a pharmaceutically acceptable salt thereof,
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- wherein R1c, R2c, R3c and R4c are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7c is C1-C6 alkyl and R8c is hydrogen or an amino protecting group.
A process for the preparation of a compound of formula (5) or a pharmaceutically acceptable salt thereof by a reaction of compound (4) with alkali metal alkoxide,
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- wherein R1d, R2d, R3d and R4d are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, and R5d and R6d are each an amino protecting group,
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- wherein R1d, R2d, R3d, R4d, and R5d are as defined above.
A process for the preparation of a benzimidazole derivative of formula (9) or a pharmaceutically acceptable salt thereof by condensation of a compound of formula (6) with a compound of formula (7) in the presence of a condensing agent to afford a compound of formula (8), followed by, if necessary removal of the amino protecting group of compound (8), and then cyclization of compound (8) in the presence of an acid,
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- wherein R1e, R2e, R3e and R4e are each independently hydrogen, hydroxyl, C1-C6 alkyl, C1-C6 alkoxy, benzyloxy, acetoxy, trifluoromethyl or halogen, R7e is C1-C6 alkyl and R8e is hydrogen or an amino protecting group,
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- wherein R1e, R2e, R3e, R4e, R7e and R8e are as defined above,
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- wherein R1e, R2e, R3e, R4e, and R7e are as defined above.
Dependencies are inferred from the claim text.