Process for preparation of dapagliflozin
The present invention relates to a process for the preparation of amorphous dapagliflozin. The present invention relates to 2,3-butanediol solvate of dapagliflozin and process for its preparation.
1. A process for the preparation of dapagliflozin in amorphous form, the process comprising:
(a) reducing a compound of formula II to a compound of formula III in the presence of a Lewis acid;
wherein the compound of formula II is prepared by reacting 5-bromo-2-chlorobenzoyl chloride with ethoxybenzene;
(b) silylating a compound of formula IV with hexamethyldisilazane to form a compound of formula V;
(c) reacting the compound of formula III with the compound of formula V in the presence of a strong base followed by treatment with an acid in the presence of an alcohol to prepare a compound of formula VII, wherein R is an alkyl group selected from C 1-5 alkyl;
(d) converting the compound of formula VII to dapagliflozin;
(e) acetylating dapagliflozin to give D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, 2,3,4,6-tetraacetate, (1S)-, a compound of formula VIII;
(f) purifying the compound of formula VIII by a series of crystallizing steps to obtain the compound of formula VIII with a purity of ≥99.6%, wherein the series of crystallizing steps comprises:
(1) crystallizing the compound of formula VIII with methanol,
(2) crystallizing the product of step (f)(1) with diisopropyl ether, and
(3) crystallizing the product of step (f)(2) with methanol;
(g) hydrolyzing the compound of formula VIII obtained in step (f) to give dapagliflozin;
(h) dissolving dapagliflozin of step (g) in isopropyl alcohol to form a solution; and
(i) recovering amorphous dapagliflozin from the solution of step (h), wherein the recovering comprises one of:
(1) removing the isopropyl alcohol from the solution obtained in step (h) comprising concentrating the solution of step (h) and degassing; or
(2) treating the solution of step (h) with cyclohexane,
wherein the amorphous dapagliflozin is obtained in a purity of ≥99.8% and wherein a level of impurity A and impurity B is less than 0.15%
2. The process of claim 1 , wherein step (c) comprises reacting the compound of formula III with the compound of formula V in the presence of a strong base to obtain a compound of formula VI; and reacting the compound of formula VI with an acid in the presence of an alcohol to obtain the compound of formula VII wherein R is an alkyl group selected from C 1-5 alkyl