US 6,784,297 B2Granted

Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate

AssigneeKopran Limited

InventorsArun Kumar Purohit, Brahmader Chilu Desai, Balasaheb Dashrath Shete, Salim Abbas Bagwan

Life of this patent

Estimating the term…

Loading patent…

Abstract

Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate [2-{(2-aminoethoxy)-methyl-4-(2-chlorophenyl) 3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate]. Phthalic anhydride is condensed with monoethanol amine at 150-190° C. The resulting N-(2-hydroxyethyl) phthalimide is coupled with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at −11 to −15° C. Ethyl-4-[-2(phthalimido) ethoxy] acetoacetate formed is coupled with orthochloro benzaldehyde in the presence of pyridine salt at 70-90° C. Ethyl-2-(2-chloro benzylidine)4-[-2(phthalimido) ethoxy] acetoacetate fanned is condensed with methyl amino crotonate at 20-40° C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2-Phthalimidoethoxy) methyl-3-carboethoxy 1(chlorophenyl)-S-carbomethoxy-6-methyl-1,4-dihydropyridin] which is purified by dissolving in an organic solvent in the ratio 1:2-1:5 w/v and precipitated by the addition of water at 35-60° C. Purified phthaloyl amlodipine is hydrolysed with methylamine in the presence of a protic solvent at 20-50° C. Amlodipine base [2-(aminoethoxy) methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] formed is reacted with benzene sulfonic acid. The resulting amlodipine besylate is purified in an organic solvent at 30-70° C. and precipitated by the addition of an insoluble solvent.

A process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate [2-{(2-aminoethoxy)-methyl-4-(2-chlorophenyl)3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate] of a formula I

comprising:
(a) condensating phthalic anhydride of a formula II
with monoethanol amine at a temperature of between about 150° C. and about 190° C. to form N-(2-hydroxyethyl)phthalimide of a formula III
(b) coupling the compound of the formula III with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at a temperature of about −11° C. to about −15° C. to form ethyl-4-[-2(phthalimido) ethoxy] acetoacetate of a formula IV
(c) coupling the compound of the formula IV with orthochloro benzaldehyde in the presence of pyridine salt at a temperature of about 70° C. to about 90° C. to form ethyl-2-(2-chloro benzylidine) 4-[-2(phthalimido)ethoxy] acetoacetate of a formula V
(d) condensing the compound of the formula V with methyl amino crotonate at a temperature of about 20 to about 40° C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2Phthalimidoethoxy)methyl-3-carboethoxy 1(chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] of a formula VI
(e) purifying the compound of the formula VI by dissolving it in an organic solvent in a ratio of about 1:2 and about 1:5 w/v followed by precipitation by the addition of water at a temperature between about 35° C. and about 60° C.;
(f) hydrolyzing the purified compound of the formula VI with methylamine in the presence of a protic solvent at a temperature of about 20° C. to about 50° C. to form amlodipine base [2-(aminoethoxy) methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] of a formula VII
(g) reacting the amlodipine base of the formula VII with benzene sulfonic acid to form amlodipine besylate;
(h) purifying amlodipine besylate by dissolving it in an organic solvent at a temperature of about 30° C. and about 70° C. and precipitating it by addition of an insoluble solvent.

7 more elements

Abstract

Claims9