Continuous process for preparing the crystalline form II of sotagliflozin
The present document relates to a process for the preparation of the crystalline form II of sotagliflozin from compound of formula (A), said process being continuously performed and comprising at least the steps of: a) performing in a reaction chamber the reaction of said compound of formula (A) in solution in toluene or in xylene or in mixture thereof, and preferably in toluene, and at least sodium methoxide and methanol, at a temperature below the boiling point of methanol, to form sotagliflozin in mixture with sodium salts; b) conducting in a crystallization chamber the crystallization of sotagliflozin formed in step a), in a non-aqueous solvent medium including at least toluene, or xylene or mixture thereof, and free of sodium salts, at a temperature of crystallization of the form II of sotagliflozin; and c) isolating the crystalline form II of sotagliflozin.
1 . A process for preparing crystalline form II of sotagliflozin from a compound of formula (A):
said process being continuously performed and comprising the steps of:
a) in a reaction chamber, contacting a solution compound of formula with sodium methoxide and methanol under conditions sufficient to form a mixture of sotagliflozin and sodium salts, wherein: the solution comprises the compound of formula (A) and toluene, xylene, or a mixture thereof; and the conditions are at a temperature below the boiling point of methanol;
b) in a first crystallization chamber, crystallizing sotagliflozin in from a non-aqueous solvent medium to provide crystallized form II of sotagliflozin free of sodium salts, wherein the non-aqueous solvent medium comprises toluene, xylene, or a mixture thereof; and
c) isolating the crystalline form II of sotagliflozin.
2 . The process of claim 1 , wherein the solution comprises toluene.
3 . The process of claim 1 or 2 , wherein the non-aqueous solvent medium comprises toluene.
4 . The process of claim 1 , wherein the temperature in step a) is below 65° C., at atmospheric pressure.
5 . The process of claim 1 , wherein the sotagliflozin resides in the reaction chamber for at least 10 minutes.
6 . The process of claim 1 , which further comprises removing sodium salts from the mixture by aqueous washing of and the mixture followed by dehydration of the mixture.
7 . The process of claim 6 , wherein the mixture is dehydrated by evaporation.
8 . The process of claim 1 , wherein the sotagliflozin is crystallized at a temperature of from 60° C. to 70° C. at atmospheric pressure.
9 . The process of claim 1 , wherein the crystallization chamber in step b) is sown with pre-existing crystalline form II of sotagliflozin.
10 . The process of claim 1 , wherein the sotagliflozin resides in the crystallization chamber for at least 10 minutes.
11 . The process of claim 1 , wherein the crystallized form II of sotagliflozin is harvested, wet milled, and fed back into the crystallization chamber.
12 . The process of claim 1 , further comprising an additional step b′), between steps b) and c), of feeding a second crystallization chamber with the crystallized form II of sotagliflozin obtained at the end of step b), which second crystallization chamber is maintained at a temperature below the temperature of the first crystallization chamber.
13 . The process of claim 12 , wherein the temperature in step b′) is from 20° C. to 30° C., at atmospheric pressure.
14 . The process of claim 1 , wherein the crystallized form II of sotagliflozin free of sodium salts is filtered and washed with toluene, xylene, or mixture thereof.
15 . The process of claim 14 , wherein the filtration and washing are followed with drying.
16 . The process of claim 15 , wherein the drying is performed at a temperature of from 45° C. to 65° C.
17 . The process of claim 12 , wherein the reaction and/or crystallization chamber(s) is/are continuous stirred-tank reactor(s).