PROCESS FOR PREPARING THE CRYSTALLINE FORM II OF SOTAGLIFLOZIN

Abstract

The present document relates to a process for the preparation of the crystalline form II of sotagliflozin, wherein said crystalline form II of sotagliflozin is directly obtained from the following compound of formula (A) and by using toluene or xylene or mixture thereof as solvent medium for the crystallization.

Claims

1. A process for the preparation of the crystalline form II of sotagliflozin: ##STR00004## wherein said crystalline form II of sotagliflozin is directly obtained from the following compound of formula (A): ##STR00005## and by using toluene or xylene, or mixture thereof, as solvent medium for the crystallization.

2. The process according to claim 1, wherein said crystalline form II of sotagliflozin is directly obtained from the compound of formula (A) by using toluene as solvent medium for the crystallization.

3. The process according to claim 1 or 2, comprising the following steps: a) reacting the compound of formula (A) with an alcohol, in a non-aqueous solvent medium comprising a base and including at least toluene or xylene or mixture thereof, and preferably at least toluene; b) performing an aqueous washing of said solvent medium; c) dehydrating said solvent medium; d) crystallizing the form II of sotagliflozin; and e) recovering the crystalline form II of sotagliflozin.

4. The process according to claim 3, wherein said solvent medium further comprises sodium methoxide and methanol.

5. The process according to any one of claim 3 or 4, wherein step a) is performed at a temperature below the boiling point of methanol.

6. The process according to any one of claims 3 to 5, wherein step a) is performed at a temperature below 65° C., and preferably below 63° C., at the atmospheric pressure.

7. The process according to any one of claims 3 to 6, wherein step c) is performed by evaporation.

8. The process according to any one of claims 3 to 7, wherein step d) is performed at the temperature of the crystallization of form II of sotagliflozin.

9. The process according to any one of claims 3 to 8, wherein step d) is performed at a temperature from 60° C. to 70° C., preferably from 62° C. to 67° C., and more preferably at 65° C., at the atmospheric pressure.

10. The process according to any one of the preceding claims, wherein the formation of said crystalline form II of sotagliflozin is initiated with pre-existing crystalline form II of sotagliflozin.

11. The process according to any one of claims 3 to 10, wherein step d) is followed by filtration and washing, preferably with toluene or xylene, or mixture thereof.

12. The process according to the preceding claim, wherein the filtration and washing are followed with a drying step.

13. The process according to the preceding claim, wherein the drying step is performed at a temperature from 45° C. to 65° C., and in particular from 50° C. to 55° C.

14. The process according to any one of the preceding claims, wherein the crystalline form II of sotagliflozin is synthetized in a batch process.

15. The process according to any one of the claims 1 to 13, wherein the crystalline form II of sotagliflozin is synthetized in a continuous process.

Description

EXAMPLES

Example 1: Batch Process of Preparation of Crystalline Form II of Sotagliflozin with Toluene

[0108] Synthesis of Sotagliflozin in Toluene

[0109] Sotagliflozin was synthetized in a batch reactor at a temperature of 60° C. under atmospheric pressure with 10 Volumes of toluene, 0.6 equivalent of MeONa and 12 equivalents of MeOH. The content in compound (A) was equal to 30 g in 10 Volumes of toluene.

[0110] The time of residence in the batch reactor was 15 minutes.

[0111] Sotagliflozin was synthetized with a yield of 99.5%.

[0112] Aqueous Washing

[0113] An aqueous wash of the reaction medium was performed at 60° C. with 1 Volume of water. Sodium salts were well removed.

[0114] Dehydration

[0115] The medium was dehydrated by evaporation of 15% v/v of the solution.

[0116] Crystallization

[0117] The crystallisation of sotagliflozin was performed at 67° C. by seeding with 7.5% w/w of form II of sotagliflozin and cooling until 40° C.

[0118] Filtration

[0119] A filtration of the suspension was performed at 40° C. on filtration cell.

[0120] Washing

[0121] A wash of the medium was performed at 25° C. with 2 Volumes of toluene.

[0122] Drying

[0123] A drying of the medium was then performed at 50° C. in a vacuum oven.

[0124] Form II of sotagliflozin was crystallized with a yield of 92%.

[0125] An XRPD (X-ray diffraction) analysis confirmed that Form II of sotagliflozin was obtained.

Example 2: Continuous Process of Preparation of Crystalline Form II of Sotagliflozin with Toluene

[0126] Synthesis of Sotagliflozin in Toluene

[0127] Sotagliflozin was synthetized in a continuous stirred-tank reactor with a volume reactor of 230 mL, and a stirring at 500 tr/min.

[0128] 450 g of compound (A) was used with 10 Volumes of Toluene to prepare a solution of compound (A) in toluene of 92.3 g/l (893 kg/m.sup.3). The reactor was fed with this solution with a flow of 372 g/h.

[0129] 0.6 equivalent of MeONa and 15 equivalents of MeOH was used to prepare a methanolic solution of MeONa of 828 kg/m.sup.3. The reactor was fed with this solution with a flow of 35.8 g/h.

[0130] The synthesis was performed at 60-61° C.

[0131] The time of residence in the reactor was 30 minutes.

[0132] Sotagliflozin was synthetized with a yield of 98%.

[0133] Aqueous Washing

[0134] An aqueous wash of the reaction medium was performed with a mixer (264 ml) and a settler (631 ml), under stirring at 450 tr/min.

[0135] The wash was performed with 1 Volume of water/reaction medium, with a flow of 460 g/h, at 61° C.

[0136] The time of residence in the mixer was 15 minutes.

[0137] The time of residence in the settler was 45 minutes.

[0138] Sodium salts were well removed.

[0139] Dehydration

[0140] The medium was dehydrated by evaporation of 15% v/v of the solution at 67-109° C. After evaporation, the content of MeOH was 0% w/w, the content of AcOMe was 0.15% w/w and the content of water was 140 ppm.

[0141] The concentration of the toluenic solution of sotagliflozin was adjusted to 50 g/l by adding toluene.

[0142] The toluenic solution of sotagliflozin (50 g/l) was maintained at a temperature of 70-75° C.

[0143] Crystallization

[0144] The crystallisation of sotagliflozin was performed in a cascade of two continuous stirred-tank reactors (each of 600 ml).

[0145] The solution was taken to the reactor by pressure.

[0146] At the beginning, the first reactor was sown with 10% w/w of form II of sotagliflozin.

[0147] The first reactor was fed with the toluenic solution of sotagliflozin (50 g/l, 829 kg/m.sup.3) at 65-66° C. with a flow of 1160 g/h (1400 ml/h), under stirring at 400 tr/min. The time of residence in the reactor was 30 minutes.

[0148] The medium obtained in the first crystallization chamber was harvested, was subjected to a wet milling, and was fed back in said first crystallization chamber.

[0149] The suspension of sotagliflozin obtained at the end of the first reactor was taken to the second reactor with a peristaltic pump.

[0150] The second reactor was fed with the suspension of sotagliflozin obtained at the end of the first reactor, at 25-26° C., under stirring at 600 tr/min. The time of residence in the reactor was 30 minutes.

[0151] The suspension obtained at the end of the second reactor was recovered for its isolation (filtration, washing, and drying).

[0152] Filtration

[0153] A filtration of the suspension was performed at 25° C. on a rotary pressure filter.

[0154] Washing

[0155] A wash of the medium was performed at 25° C. with 2 Volumes of toluene.

[0156] Drying

[0157] A drying of the medium was then performed at 50° C. under pressure below 50 mbar.

[0158] Form II of Sotagliflozin was crystallized with a yield of 97%.

[0159] An XRPD (X-ray diffraction) analysis confirmed that Form II of sotagliflozin was obtained.

Example 3: Continuous Process of Preparation of Crystalline Form II of Sotagliflozin with Toluene in an Intensified Reactor

[0160] Synthesis of Sotagliflozin in Toluene

[0161] Sotagliflozin was synthetized in an intensified reactor at 113° C. under a pressure of 8 bar.

[0162] The reactor was fed with the solution of compound (A) in 10 Volumes of toluene with a flow of 1194.6 g/h and the methanolic solution of MeONa (0.6 equivalent of MeONa and 15 equivalents of MeOH) with a flow of 114.6 g/h, which were preheated at 113° C.

[0163] The time of residence in the reactor was 20 seconds.

[0164] The system was maintained at a pressure of 8 bar.

[0165] Sotagliflozin was synthetized with a yield of 99.7%.

[0166] Aqueous washing, dehydration, crystallization, filtration, washing, drying were performed according to example 2.

[0167] An XRPD (X-ray diffraction) analysis confirmed that Form II of sotagliflozin was obtained.