DESC:FIELD OF THE INVENTION

The present invention relates to an improved process for preparation of Empagliflozin of formula (I). The invention further relates to preparation of crystalline form of Empagliflozin and its particle size having coarser particle or D50equal or greater than 60 µm and D90equal or greater than 180 µm.

(I)

BACKGROUND OF THE INVENTION

Empagliflozin is chemically known as 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene.Itis indicated for the treatment of type-2 diabetes. It is marketed under the brand name JARDIANCE®.

The U.S. Patent no. 7,579,449B2, discloses Empagliflozin, stereo isomers, mixtures and salts thereof, and a pharmaceutical composition containing Empagliflozin. It also disclosed the preparation of Empagliflozin using tetrahydrofuran-3-yl(R)-toluene-4-sulphonate. The document does not disclose the preparation and process for isolation of its crystalline form.

The U.S. Patent no. 7,772,191B2 discloses the preparation of Empagliflozin by coupling of 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone (TMS-gluconolactone)with (S)-3-[4-(5-bromo-2-chloro-benzyl)-phenoxy]-tetrahydrofuran (Bromo intermediate) using butyllithium (BuLi) in presence of C3-C4-alkylmagnesium chloride or bromide such as isopropylmagnesium chloride (i-PrMgCl) or butylmagnesium chloride (BuMgCl)and with or without lithium chloride (LiCl), followed by methylation, reduction using triethylsilane, boron trifluoride etherate and finally Empagliflozin isolated in isopropyl acetate and water.

The U.S. Patent no. 7,713,938B2 discloses the crystalline form of Empagliflozin which is isolated in methanol, ethanol, isopropanol, ethyl acetate, diethylether, acetone, water and mixture.

The patent application no. IN201621015480 discloses the preparation of pure stable crystalline Empagliflozin by coupling of TMS-gluconolactone and Bromo intermediate using n-BuLi, methylation using methanesulphonic acid, methanol, followed by reduction using triethyl silane, boron trifluoride etherate and crystallization of Empagliflozin using methanol, ethanol, isopropanol or n-propanol.

The patent application no. IN201711011423 discloses the preparation of Empagliflozin by coupling TMS-gluconolactone and (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]-tetrahydrofuran (Iodo compound), methylation, reduction, acetylation to form tetraacetyl Empagliflozin & further deacetylation to obtain Empagliflozin. Also discloses the preparation/purification of crystalline form I of Empagliflozin using solvents methanol, ethanol, isopropanol, n-propanol or mixture thereof or using ethyl acetate, propyl acetate, butyl acetate or mixture thereof with anti-solvents such as cyclopentane, cyclohexane, cycloheptane, cycloctane, n-pentane, n-hexane, n-heptane, octane or mixture thereof.

The prior art processes for preparation Empagliflozin are involved more number of reaction steps, tedious processes with the use of alkyl magnesium halide or lithium halide. Further, the prior art processes involved more unit operations, long cycle time for the preparation of Empagliflozin. Thus, inventors of the present invention have developed an improved process which involve single production operation for isolation of solid Empagliflozin in minimum number of reaction steps. The process is suitable for large scale operations thereby commercially viable.

The patent publication WO2010092126A1 discloses composition of Empagliflozin wherein particle size distribution D90less than 200 µm provides good dissolution profile, good bioavailability and allows high content uniformity. Another patent publication WO2020058095A1 discloses a composition of Empagliflozin where Empagliflozin particle size distribution D90 in arrange between 25 pm up to 500 pm to exhibit good dissolution profile and high bioavailability. Hence it is a demand from formulators for uneven particle size of Empagliflozin. The supply and maintenance of inventory of various particle size as per demand of formulators is practically difficult. Hence, it is still an unmet need for other particle size(s), especially for coarser particle which is a reserve source to obtain small particle size of Empagliflozin, the inventors have achieved with a robust technology. The inventors of present invention further developed a process to obtain particle size having coarser particle or D50 equal or greater than 60 µm and D90 equal or greater than 180 µm

SUMMARY OF THE INVENTION

One aspect of the present invention is to provide an improved process for the preparation of Empagliflozin of formula (I).

In another aspect, the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) using organolithium reagent, Lewis acid and catalyst.

In another aspect, the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) which involve single step for solid isolation, where the process comprising of sequential reaction steps:

(I)
a) coupling a glycoside of formula (II) where TMS is trimethylsilyl, with compound of formula (III) using organolithium reagent in presence of a catalyst in a solvent to obtain compound of formula (IV);
b) methylating the hydroxy group using methanol in presence of acid to obtain compound of formula (V), and;
c) demethoxylation using a reducing agent in presence of Lewis acid in a solvent to obtain Empagliflozin of formula (I).
.
In another aspect, the present invention where Empagliflozin is further isolated in ethanol and o-xylene to obtain crystalline form of Empagliflozin.

In another aspect, the present invention relates to an improved process for the preparation of crystalline form of Empagliflozin of formula (I) which comprising the steps of:
a) dissolving Empagliflozin of formula (I) in a mixture of ethanol and o-xylene;
b) cooling the reaction mixture to precipitate the solid;
c) isolating the obtained solid;
d) drying the solid.

In another aspect, the present invention where Empagliflozin is further isolated in water to obtain a coarser particle size D50 equal or greater than 450 µm and D90 equal or greater than 900 µm.

In another aspect, the present invention relates to a process to obtain coarser particle size of Empagliflozin of formula (I) having particle size D50 equal or greater than 450 µm and D90 equal or greater than 900 µm which comprising the steps of:
a) heating Empagliflozin of formula (I) in water;
b) cooling the reaction mixture to precipitate the solid;
c) isolating the obtained solid;
d) drying the solid.

In another aspect, the present invention relates to a process to obtain Empagliflozin of formula (I) having particle size D50equal or greater than 60 µm and D90equal or greater than 180 µm which comprising the steps:
a) dissolving Empagliflozin of formula (I) in a mixture of ethanol and o-xylene;
b) cooling the reaction mixture to precipitate the solid;
c) isolating the obtained solid;
d) drying the solid.

BRIEF DESCRIPTION OF THE FIGURES

The FIG. 1 shows an X-ray powder diffractogram of the crystalline form of Empagliflozin of formula (I) prepared as per example 2.
The FIG. 2 shows the DSC thermogram of the crystalline form Empagliflozin of formula (I) prepared as per example 2.
The FIG. 3 shows the specimen of particle size distribution data of Empagliflozin of formula (I) prepared as per example 2.
The FIG. 4 shows the specimen of particle size distribution data of Empagliflozin of formula (I) prepared as per example 3.

DETAILED DESCRIPTION OF THE INVENTION

The present invention now will be described more detail hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The term D50 equal or greater than 60µm as used herein, refers to 50% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 60 µm.

The term D50 equal or greater than 450µm as used herein, refers to 50% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 450 µm.

The term D90equal or greater than 180µm as used herein, refers to 90% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 180 µm.

The term D90equal or greater than 900 µm as used herein, refers to 90% of the volume of particles of Empagliflozin of formula (I) have a diameter equal or greater than 900 µm.

In an embodiment, the instant invention provides the preparation of Empagliflozin, wherein the compounds of formula (IV), (V) were not isolated, thus the process is economic.

In another embodiment, the present invention relates to an improved process for the preparation of Empagliflozin of formula (I) without using alkyl magnesium halide or lithium halide in coupling reaction.

In another embodiment of the present invention, wherein the organolithium reagent is selected from the group consisting of n-, sec- or tert-butyllithium (BuLi), n-hexyllithium and the like.

In another embodiment of the present invention, wherein the catalyst is selected from the group consisting of boron trifluoride etherate, trimethylsilyl chloride or triflate and the like.

In another embodiment of the present invention, wherein the solvent used in coupling reaction is selected from the group consisting of toluene, diethylether, tetrahydrofuran (THF), hexane, heptane, dioxane, dimethyl sulfoxide (DMSO), chlorinated solvents such as dichloromethane (DCM), and the like or mixture of solvents thereof.

In another embodiment of the present invention, wherein the coupling reaction is carried at temperature -80°C to -60°C.

In another embodiment of the present invention, wherein the acid used in methylation step is selected from methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

In another embodiment of the present invention, wherein the methylation reaction is carried at temperature -80°C to 40°C.

In another embodiment of the present invention, wherein the pH of the reaction mixture in methylation reaction is adjusted between pH 6.5 to 8.5.

In another embodiment of the present invention, wherein the reducing agents used is selected from triethyl silane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, and diisobutyl aluminum hydride.

In another embodiment of the present invention, wherein the Lewis acid used is selected from aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, and acetic acid.

In another embodiment of the present invention, wherein the solvent used in step of demethoxylation is selected from acetonitrile, dichloromethane, chloroform, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, water, or mixtures thereof.

In another embodiment of the present invention, wherein the demethoxylation of compound of formula (V) is carried at temperature 10°C to 25°C.

In another embodiment of the present invention, wherein the solvent used for preparing crystalline form of Empagliflozin of formula (I) is mixture of ethanol and o-xylene.

In another embodiment of the present invention, wherein the Empagliflozin of formula (I) having coarser particle size D50 equal or greater than 450 µm and D90 equal or greater than 900 µm is isolated by using water.

In another embodiment of the present invention, wherein the Empagliflozin of formula (I) having particle size D50equal or greater than 60 µm and D90 equal or greater than 180 µm is isolated by using mixture of ethanol and o-xylene.

In another embodiment of the present invention, where ethanol and o-xylene are used in 1:1 for dissolving Empagliflozin of formula (I).

In another embodiment of the present invention, wherein the Empagliflozin of formula (I) is dissolved at temperature 75?C to 85?C.

In another embodiment of the present invention, wherein the Empagliflozin of formula (I) is heated with water at temperature 90?C to 100?C.

In another embodiment, the present invention relates to an improved process for the preparation of crystalline form of Empagliflozin of formula (I) or an improved process for the preparation of Empagliflozin of formula (I) with particle size D50equal or greater than 60 µm and D90equal or greater than 180 µm wherein the solution of Empagliflozin of formula (I) is cooled to 20°C to 30°C for 4 to 12 hours (hr).

In another embodiment of the present invention, wherein the solid is isolated by filtration or any other known method.

In another embodiment of the present invention, wherein the drying of the solid in is carried at 25°C to 30°C for 2 to 3 hours and/or further dried at 70°C to 80°C for 8 to 12 hours.

In another embodiment of the present invention, wherein the Empagliflozin having coarser particles or particle size D50equal or greater than 60 µm and D90equal or greater than 180 µm can further micronized or milled by the conventional methods like jet milling, cad milling or multi milling to get smaller particle size required to meet the need of formulator.

In another embodiment of the present invention, wherein the Empagliflozin particle size may differ based on type of reactor and speed of the agitator, which should not be construed to limit the scope of the invention in anyway.

In another embodiment of the present invention, wherein the Empagliflizin used for the preparation of crystalline Empagliflozin and Empagliflozin with coarser particles or particle size D50 equal or greater than 60 µm and D90 equal or greater than 180 µm is prepared by as process disclosed in present invention.

In another embodiment of the present invention, wherein the crystalline Empagliflozin of formula (I) is characterized by powder X-ray diffraction pattern and recorded on Bruker D8 advance diffractometer (Bruker-AXS, Karlsruhe, Germany) using Cu-Ka X-radiation (? = 1.5406 Å) at 40 kV and 40 mA powers. X-ray diffraction patterns were collected over the 2? range 2° to 40° with time per step 0.5(s).

In another embodiment of the present invention, wherein the crystalline Empagliflozin of formula (I) is having an X-ray diffraction pattern that comprises peaks at 14.69, 18.84, 19.16, 19.50, 20.36 and 25.21 degrees 2?±0.05 degrees 2?. The X-ray diffraction pattern is shown in FIG. 1.

In another embodiment of the present invention, wherein the crystalline Empagliflozin of formula (I) is further characterized using Differential Scanning Calorimetry (DSC 3+), measured using a Differential Scanning calorimeter from Mettler Toledo.

In another embodiment of the present invention, wherein the crystalline form of Empagliflozin of formula (I) is characterized by a melting point of about 149°C ±3° C (determined via DSC; evaluated as on set temperature; heating rate 10 K/min), DSC curve is shown in FIG. 2.

In another embodiment of the present invention, wherein the particle size is measured by using Malvern particle size analyzer MS 3000.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

EXPERIMENTAL

Example 1: Preparation of Empagliflozin (compound I)

In a dry RBF (round bottom flask) under inert atmosphere, 300 ml of toluene, 100 g (1.0 eq.) of (3S)-3-[4-[(2-Chloro-5-iodophenyl)methyl]phenoxy]-tetrahydrofuran (compound III) were charged at room temperature (RT) and stirred for 20 to 30 min. 135.1g (1.2 eq.) of 2,3,4,6-tetrakis-O-trimethylsilyl-D-glucono-1,5-lactone (compound II) and 300 ml of tetrahydrofuran were charged at 20°C to 40°C. The reaction mixture was cooled to -80°C to -60°C. 6 ml (0.1 eq.) of boron trifluoride diethyl etherate was charged to the reaction mixture and 188.4 ml (1.25 eq.) of n-BuLi (1.6M in hexane) was added to the reaction mixture at -80°C to -60°C and further maintained for 1 to 2 hrs. The reaction completion for the absence of compound of formula (III) and formation of compound of formula (IV) was ensured by HPLC.

To the above reaction mixture, methane sulfonic acid (MTSA) in methanol (3 V) was slowly added at -80°C to -40°C. Then the reaction mass was warmed to -5°C to 5°C and slowly added 2.0 V of methane sulfonic acid in methanol. The reaction mixture was warmed to 30°C to 40°C, maintained for about 6 to 8 hrs. The reaction completion for the formation of compound of formula (V) was ensured by HPLC. It was cooled to 0°C to 15°C, the pH was adjusted between 6.5 to 8.5 using 10% aq. sodium bicarbonate solution. The reaction mixture was concentrated till to arrive a minimum volume of reaction mixture and allowed it to 20°C to 40°C. The 1000 ml (10V) of dichloromethane (DCM) was charged in reaction mixture at room temperature. The aqueous and organic layers were separated. The aqueous layer was extracted with DCM and layers were separated. The combined organic layer was washed with brine and concentrated till to a minimum volume and cooled to room temperature.

To the above reaction mixture, 330 ml (3.3 V) of acetonitrile was added. In second RBF, 140 ml (1.4V) of DCM was added at room temperature and cooled at 0°C to 10°C. Further, 67.54 g (2.1 eq.) of aluminium chloride in three equal lots were charged to the reaction mixture at 0°C to 10°C and stirred for 15 to 45 min. Then, to this reaction mixture, 160 ml (1.6V) of acetonitrile (lot-2) at 0°C to10°C and stirred for 15 to 45 min. 78.49 g (2.8 eq.) of triethyl silane was added to the reaction mixture at 0°C to10°C and stirred for 30 min. The reaction mixture was allowed to 10°C to 25°C. To this reaction mixture (in second RBF), the reaction mixture from first RBF was added at 10°C to 25°C and maintained for 2 to 4 hrs. The reaction completion for the absence of compound of formula (V) was ensured by HPLC. 500 ml (5V) of water (lot 1) was added drop wise manner to the reaction mixture at 10°C to 35°C and maintained for 2 to 4 hrs. The solvent was distilled out till 9.5 to 10.5 volume. The upper organic layer was separated at about 40°C to 50°C. 700 ml (7V) of DCM was added in aqueous layer and stirred for 30 to 90 min. The lower organic layer was separated. The organic layers were combined and allowed at room temperature. It was stirred for solid formation and further maintained 3 to 4 hrs. at 0°C to 10°C. The solid was filtered and washed with DCM and suck dry for about 2 to 4 hrs. In RBF, the wet cake and 300 ml (3V) isopropyl alcohol (lot 1) were charged and stirred for about 3 to 4 hrs. The solid was filtered and washed with isopropyl alcohol (lot 2, 200 ml (2V)) and suck dried for 2 to 4 hrs. The wet cake was dried to obtain Empagliflozin (I) (yield - 65.24g, 60 %, purity by HPLC - 99.45%).

Example 2: Preparation of crystalline Empagliflozin of formula (I)

In a dry RBF, 75 ml o-xylene, 75ml ethanol, 25gm of Empagliflozin were heated to 75?C to 85?C and further stirred for 15 to 45 min. To the reaction mixture, 2.5gm of activated carbon was charged at 75?C to 85?C and maintained for 30 to 45 min. The reaction mixture was filtered and washed the bed with mixture of o-xylene and ethanol (1:1, 0.5V each). The clear reaction mass was transferred to other RBF and heated to 75?C to 85?C. The reaction mass was maintained for 30 to 45 min at 75?C to 85?C. The reaction mixture further cooled to 20°C to 30°C for 8 to 12hrs.and maintained for 2 to 4hrs.at same temperature. The solid was filtered, washed with 75 ml of ethanol. The solid was initially dried at 25°C to 30°C for 2 to 4hrs. and further dried at 70°C to 80°C for 4 to 12hrs. to obtain crystalline Empagliflozin of formula (I). (yield – 19.80 gm, 79.2% (w/w), purity by HPLC – 99.87%, PSD – D50 164 µm, D90 347 µm).

Example 3: Preparation of Empagliflozin of formula (I)particle size D50 equal or greater than 450 µm and D90 equal or greater than 900 µm

In a reactor, 9.6V of water and 40.0 gm of Empagliflozin were charged. To this, 2.4V of water was added and mixture was heated to 98?C for 1h and stirred at 98?C for 1 to 2hrs. The reaction mixture was cooled to 20°C to 30°C for 4hrs. and further stirred at same temperature for 2 to 3hrs. The solid was filtered, washed with water and dried to obtain crystalline Empagliflozin (yield –39 gm, 97.5%, purity by HPLC – 99.99%, PSD –D50 582 µm, D901310 µm).
Sr. No. Reactor type Cooling time PSD (µm)
D10 D50 D90
1 RBF 2 h 108 469 906
2 Cylindrical reactor 4 h 146 582 1310
,CLAIMS:WE CLAIM:

1. An improved process for preparation of Empagliflozin of formula (I) in single isolation step, where the process comprising steps of:

a) coupling a glycoside of formula (II) where TMS is trimethylsilyl, with compound of formula (III) using organolithium reagent in presence of a catalyst in a solvent to obtain compound of formula (IV);
b) methylating the hydroxy group using methanol in presence of an acid to obtain compound of formula (V), and;
c) demethoxylation using a reducing agent in presence of Lewis acid in a solvent to obtain Empagliflozin of formula (I).

2. An improved process for preparation of crystalline Empagliflozin of formula (I), where the process comprising steps of:
a) dissolving Empagliflozin of formula (I) in mixture of ethanol and o-xylene, where Empagliflozin is obtained by a process claimed in claim1;
b) cooling the reaction mixture to precipitate the solid;
c) isolating the obtained solid;
d) drying the solid.

3. An improved process for preparation of Empagliflozin of formula (I) having particle size D50 equal or greater than 450 µm and D90 equal or greater than 900 µm, where the process comprising the steps of:
a) heating Empagliflozin of formula (I) in water, where Empagliflozin is obtained by a process claimed in claim1;
b) cooling the reaction mixture to precipitate the solid;
c) isolating the obtained solid;
d) drying the solid.

4. The process as claimed in claim 2, where Empagliflozin have particle size D50 equal or greater than 60 µm and D90 equal or greater than180 µm.

5. The process as claimed in claim 1, wherein said organolithium reagent is selected from n-, sec- or tert-butyllithium (BuLi), and n-hexyllithium; and said catalyst is selected from boron trifluoride etherate, trimethylsilyl chloride, and triflate.

6. The process as claimed in claim 1, wherein said acid is selected from methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and hydrochloric acid.

7. The process as claimed in claim 1, wherein said reducing agent is selected from triethyl silane, tripropylsilane, triisopropylsilane, diphenylsilane, sodium borohydride, sodium cyanoborohydride, zinc borohydride, borane complexes, and diisobutylaluminum hydride; and said Lewis acid is selected from aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, copper(II) triflate, zinc iodide, hydrochloric acid, toluene sulfonic acid, trifluoroacetic acid, and acetic acid.

8. The process as claimed in claim 1, wherein said solvent used in coupling reaction is selected from toluene, diethylether, tetrahydrofuran (THF), hexane, heptane, dioxane, dimethyl sulfoxide (DMSO), dichloromethane (DCM); and in demethoxylation is selected from acetonitrile, dichloromethane, chloroform, toluene, hexane, diethylether, tetrahydrofuran, dioxane, ethanol, and water.

9. The process as claimed in claim 1, wherein coupling reaction is carried out at temperature -80°C to -60°C; methylation is carried out at -80°C to 40°C; and demethoxylation is carried out at 10°C to 25°C.

10. The process as claimed in claim 1, wherein dissolution temperature is 75?C to 85?C, heating temperature is 90°C to100°C,and cooling temperature is 20°C to 30°C.