Process for the Preparation of Pyridine Heterocycle Cgrp Antagonist Intermediate
An efficient syntheses for the preparation of the intermediate 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride, and other salt forms of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine.
1 - 13 . (canceled)
14 . A process for the preparation of an acid salt of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, said process comprising the steps of:
(1) reacting 3-amino-2-chloropyridine with C 1-4 alkyl 4-oxo-1-piperidinecarboxylate to form C 1-4 alkyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(2) reacting the C 1-4 alkyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with chlorosulfonyl isocyanate to form C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(3) reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate to form C 1-4 alkyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate;
(4) reacting the C 1-4 alkyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate with a strong acid to form an acid salt of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine.
15 . The method of claim 14 , wherein step (3) comprises reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with NaHCO 3 , i-PrOH and bis(diphenylphosphino)butane in the presence of a palladium catalyst.
16 . The method of claim 14 , wherein the C 1-4 alkyl in steps (1) to (4) is ethyl.
17 . The method of claim 14 , wherein the acid salt of steps (1) and (4) is selected from the group consisting of HCl, HBr, HI, H 2 SO 4 and HNO 3 .
18 . A process for the preparation of2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine dihydrochloride, said process comprising the steps of:
(1) reacting 3-amino-2-chloropyridine with ethyl 4-oxo-1-piperidinecarboxylate to form ethyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(2) reacting the ethyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with chlorosulfonyl isocyanate to form ethyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(3) reacting the ethyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate to form ethyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate;
(4) reacting the ethyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate with HCl.
19 . The method of claim 18 , wherein step (3) comprises reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with NaHCO 3 , i-PrOH and bis(diphenylphosphino)butane in the presence of a palladium catalyst.
20 . A process for the preparation of an acid salt of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, comprising the steps of:
(1) reacting 3-amino-2-chloropyridine with C 1-4 alkyl 4-oxo-1-piperidinecarboxylate to form C 1-4 alkyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(2) reacting the C 1-4 alkyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with chlorosulfonyl isocyanate to form C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate;
(3) reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate to form C 1-4 alkyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate;
(4) reacting the C 1-4 alkyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate with a strong base, followed by a strong acid, to form an acid salt of 2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine.
21 . The method of claim 20 , wherein step (3) comprises reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with NaHCO 3 , i-PrOH and bis(diphenylphosphino)butane in the presence of a palladium catalyst.
22 . The method of claim 20 , wherein the C 1-4 alkyl in steps (1) to (4) is ethyl.
23 . The process of claim 20 , wherein said strong base is selected from NaOH, LiOH and KOH.
24 . The process of claim 20 , wherein said strong acid is selected from HCl, HBr, HI, H 2 SO 4 and HNO 3 .
25 . A process for the preparation of an acid salt of2-oxo-1-(4-piperidinyl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine, said process comprising the steps of:
(1) reacting C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate to form ethyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate; and
(2) reacting the C 1-4 alkyl 4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate with an acid salt.
26 . The process of claim 25 , wherein step (1) comprises reacting the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with NaHCO 3 , i-PrOH and bis(diphenylphosphino)butane in the presence of a palladium catalyst.
27 . The process of claim 25 , wherein the C 1-4 alkyl of steps (1) and (2) is ethyl.
28 . The process of claim 25 , wherein the acid is selected from the group consisting of HCl, HBr, HI, H 2 SO 4 and HNO 3 .
29 . The process of claim 25 , further comprising the step of forming the C 1-4 alkyl 4[(aminocarbonyl)(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate of step (1) by reacting C 1-4 alkyl 4[(2-chloropyridin-3-yl)amino]piperidine-1-carboxylate with chlorosulfonyl isocyanate.