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Process for the Manufacture of Azelnidipine

IP.com Disclosure Number: IPCOM000208546D
Publication Date: 2011-Jul-12
Document File: 5 page(s) / 162K

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Abstract

A process for the manufacture of Azelnidipine compound of Formula I, using 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester formic acid salt of Formula II, as one of the key intermediate

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PROCESS FOR THE MANUFACTURE OF AZELNIDIPINE

ABSTRACT

A process for the manufacture of Azelnidipine compound of Formula I, using 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester formic acid salt of Formula II, as one of the key intermediate

I

II

.

                                                                                                               

Azelnidipine or 2-amino-1,4-dihydro-6-methyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-[1-(diphenylmethy)-3-azetidinyl] 5-(1-methylethyl) ester, is the active agent in CALBLOCK®, which is approved as Calcium channel antagonist.

US 4,772,596 discloses a process to prepare Azelnidipine, by condensing 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester acetic acid salt with 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid-1-methylethyl ester, followed by purification using column chromatography.

            Further, JP 3491506 B2 discloses a process to prepare Azelnidipine, by condensing 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester acetic acid salt with 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid-1-methylethyl ester to obtain crude Azelnidipine, which is recrystallized from methanol to yield Azelnidipine methanol adduct. Thereafter, Azelnidipine methanol adduct was desolvated to yield pure Azelnidipine.

We have now developed a process, which gives Azelnidipine in high yields with        > 99% purity. This process involves the condensation of 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester formic acid salt with 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid-1-methylethyl ester, which is depicted in the scheme 1:

Scheme 1

Steps I & II - Cyanoacetic acid-1-(diphenylmethyl)-3-azetidinyl ester is reacted with ethanol in the presence of dry hydrochloric acid followed by ammonia to obtain (ethoxyiminomethyl)acetic acid 1-(diphenylmethyl)-3-azetidinyl ester, which is then reacted with ammonium formate to obtain 3,3-diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester formic acid salt.

            Step III - 3,3-Diamidoacrylic acid (1-diphenylmethaneazetidine-3-yl)ester formic acid salt is condensed with 2-[(3-nitrophenyl)methylene]-3-oxobutanoic acid-1-methylethyl ester in the presence of sodium bicarbonate to obtain crude Azelnidipine.

            Step IV – Optionally crude Azelnidipine is isolated and treated with methanol or in situ treated with methanol to obtain Azelnidipine methanol adduct.

            Step V – Desolvation of methanol adduct gives Azelnidipine in a-form.

           

EXAMPLE 1

PREPARATION OF 2-[(3-NITROPHENYL)METHYLENE]-3-OXOBUTANOIC ACID-1-METHYLETHYL ESTER

Isopropylacetoacetate (2.54 Kg), piperidine (0.09 Kg) and acetic acid (0.063 Kg) were added to isopropyl alcohol (8.8 l) at 20-25°C.  3-Nitrobenzaldehyde (2.66 Kg) was added...