Method for preparing lifitegrast
An improved method for preparing lifitegrast is provided. The method is efficient and cost-effective and produces lifitegrast with high purity.
1 . A process for preparing a compound of the following formula (1), which comprises the steps of:
(i) chlorinating a carboxyl group of a compound of the following formula (2) and subjecting a compound of the following formula (3) to amide coupling therewith to obtain a compound of the following formula (4);
(ii) subjecting the compound of the following formula (4) to demethylation to obtain a compound of the following formula (5);
(iii) chlorinating a carboxyl group of the compound of the following formula (5) in the presence of a tertiary amine, subjecting a compound of the following formula (6) to amide coupling therewith to obtain a compound of the following formula (7), and recrystallizing the compound of the following formula (7) using butanone; and
(iv) subjecting an ester group of the compound of the following formula (7) to hydrolysis to obtain the compound of the following formula (1), wherein the compound of formula (1) has a purity of 99.6% or more:
2 . The process according to claim 1 , wherein the chlorination of step (i) is carried out using oxalyl chloride.
3 . The process according to claim 1 , wherein the compound of formula (3) of step (i) is in a form of hydrochloride.
4 . The process according to claim 1 , wherein the amide coupling of step (i) is carried out in the presence of a base.
5 . The process according to claim 4 , wherein the base is diisopropylethylamine.
6 . The process according to claim 1 , wherein the demethylation of step (ii) is carried out using lithium halide.
7 . The process according to claim 1 , wherein the tertiary amine of step (iii) is diisopropylethylamine.
8 . The process according to claim 1 , wherein the chlorination of step (iii) is carried out using oxalyl chloride.
9 . The process according to claim 1 , wherein the compound of formula (6) of step (iii) is in a form of hydrochloride.
10 . The process according to claim 1 , wherein the amide coupling of step (iii) is carried out in the presence of a base.
11 . The process according to claim 10 , wherein the base is diisopropylethylamine.
12 . The process according to claim 1 , wherein the hydrolysis of step (iv) is carried out in the presence of a base.
13 . The process according to claim 12 , wherein the base is lithium hydroxide.
14 . A process for preparing a compound of the following formula (1), which comprises the steps of:
(iii) chlorinating a carboxyl group of a compound of the following formula (5) in the presence of a tertiary amine, subjecting a compound of the following formula (6) to amide coupling therewith to obtain a compound of the following formula (7), and recrystallizing the compound of the following formula (7) using butanone; and
(iv) subjecting an ester group of the compound of the following formula (7) to hydrolysis to obtain the compound of the formula (1), wherein the compound of formula (1) has a purity of 99.6% or more: