Process for making amlodipine, derivatives thereof, and precursors therefor
Purification of the phthalimidoamlodipine intermediate, especially by recrystallization, can provide an easier route to obtaining pharmaceutically pure amlodipine or its salts.
1 . A process for producing amlodipine, which comprises:
(a) isolating in a solid state a compound of formula (2a) from a reaction mixture
(b) recrystallizing said compound of formula (2a) from a solvent to form a purified compound of formula (2a); and
(c) deprotecting said purified compound of formula (2a) to form amlodipine.
2 . The process according to claim 1 , wherein said recrystallization step (b) achieves a purity of at least 98%.
3 . The process according to claim 2 , wherein said recrystallization step (b) achieves a purity of at least 99%.
4 . The process according to claim 3 , wherein said recrystallization step (b) achieves a purity of at least 99.5%.
5 . The process according to claim 1 , wherein said recrystallizing is carried out from a solvent selected from the group consisting of ethyl acetate, methanol, ethanol, isopropanol, and mixtures of two or more thereof.
6 . The process according to claim 5 , wherein said solvent is ethyl acetate.
7 . The process according to claim 6 , wherein said recrystallization step (b) achieves a purity of at least 99%.
8 . The process according to claim 1 , wherein said isolating step comprises precipitating said compound of formula (2a) from acetic acid to obtain said compound of formula (2a) in solid state.
9 . The process according to claim 1 , which further comprises forming said compound of formula (2a) in said reaction mixture by reacting a compound of formula (3a)
with a compound of formula (B 1)
in a suitable solvent.
10 . The process according to claim 9 , wherein said suitable solvent is isopropanol.
11 . The process according to claim 9 , wherein said recrystallization step (b) achieves a purity of at least 99%.
12 . The process according to claim 11 , wherein said recrystallizing is carried out from a solvent selected from ethyl acetate.
13 . The process according to claim 9 , which further comprises forming said compound of formula (3a) by reacting an o-chlorobenzaldehyde with a compound of formula (C1):
in an organic solvent to form said compound of formula (3a).
14 . The process according to claim 13 , wherein said compound of formula (3a) is recovered from said organic solvent before being reacted with said compound of formula (B1).
15 . The process according to claim 13 , wherein said solvent is isopropanol.
16 . The process according to claim 1 , which further comprises converting said amlodipine into a pharmaceutically acceptable salt of amlodipine.
17 . In a process for making amlodipine, or a pharmaceutically acceptable salt thereof, that includes forming phthalimidoamlodipine of formula (2a)
and deprotecting it to form amlodipine of formula (1a)
the improvement for which comprises:
purifying said phthalimidoamlodipine by recrystallization to a purity greater than 98% before said deprotecting step.
18 . The process for making amlodipine according to claim 17 , wherein said phthalimidoamlodipine has a purity of greater than 99% before being subjected to said deprotecting step.
19 . A process, which comprises the steps of:
(a) assaying a sample from a batch of phthalimidoamlodipine for at least one phthalimidoamlodipine impurity selected from the group consisting of compounds 2b-2f:
(b) determining whether said at least one phthalimidoamlodipine impurity is contained in said sample below a predetermined limit; and, if below said predetermined limit,
(c) subjecting said phthalimidoamlodipine batch to deprotection to form a batch of amlodipine.
20 . The process according to claim 19 , which further comprises crystallizing said batch of phthalimidoamlodipine prior to said assaying step.
21 . The process according to claim 20 , which further comprises converting said batch of amlodipine to a pharmaceutically acceptable salt of amlodipine; and combining said pharmaceutically acceptable salt of amlodipine with a pharmaceutically acceptable excipient to form pharmaceutical unit dosage forms containing an effective amount of said amlodipine salt.