WO2021260498A1

WO2021260498A1 - An improved purification process for the preparation of ertugliflozin and ertugliflozin l-pyroglutamic acid co-crystal

Info

Publication number: WO2021260498A1
Application number: PCT/IB2021/055316
Authority: WO
Inventors: Nandi Sukumar; Gona Bala Narashimha Reddy; Akkina NARESH; Sivakumaran Meenakshisunderam
Original assignee: Aurobindo Pharma Limited
Priority date: 2020-06-22
Filing date: 2021-06-16
Publication date: 2021-12-30

Abstract

The present invention relates to an improved purification process for the preparation of Ertugliflozin (I) and its further conversion to Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal (II).

Description

AN IMPROVED PURIFICATION PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN AND ERTUGLIFLOZIN L-PYROGLUTAMIC ACID CO-CRYSTAL

FIELD OF THE INVENTION The present invention relates to a purification process of Ertugliflozin (I).

The present also relates to a purification process of Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal (II).

BACKGROUND OF THE INVENTION

(lS,2S,3S,4R,5S)-5-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-l- (hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol is generically known as Ertugliflozin. Ertugliflozin has been approved as L-pyroglutamic acid (L-PGA) co-crystal, which is marketed under the brand name Steglatro^®.

FDA approved Steglatro^® Tablets for the treatment of an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.

Ertugliflozin (I) and Ertugliflozin L-pyroglutamic acid co-crystal (II) are disclosed in US 8080580, which is hereby incorporated by reference. US ‘580 patent discloses a process for the preparation of Ertugliflozin (I) and Ertugliflozin L-pyroglutamic acid co-crystal (II), which is shown below; Methoxy Dapagliflozin (III) is reacted with TMS -Chloride to produce TMS Methoxy Dapagliflozin (IV). In- situ treatment of Compound (IV) with p-toluene sulfonic acid (p-TSA) in the presence of pyridine to produce monodeprotected TMS Methoxy Dapagliflozin (V). In- situ treatment of Compound (V) with sulfur trioxide pyridine complex to produce formyl TMS Methoxy Dapagliflozin (VI). In-situ treatment of Compound (VI) with formaldehyde to produce Hydroxymethyl Methoxy Dapagliflozin (VII). Cyclisation of Compound (VII) using SiliaBond® tosic acid to produce Ertugliflozin (I), which is treated with L- pyroglutamic acid to produce Ertugliflozin L-pyroglutamic acid co-crystal (II).

The process as shown in Scheme-I below:

Scheme-I

US ‘580 also discloses a process for the preparation of protected Ertugliflozin compounds, by treating Ertugliflozin (I) with para-nitrobenzoyl chloride (PNBC1) in presence of N,N-diisopropylethylamine and 4- dimethylaminopyridine to produce PNB protected Ertugliflozin (VIII) and treating Ertugliflozin (I) with para-bromobenzoyl chloride (PBBC1) in presence of N,N- diisopropylethylamine and 4-dimethylaminopyridine to produce PBB protected Ertugliflozin (IX).

Scheme-II

US 9573959 discloses a process for the preparation of Ertugliflozin (I), wherein reduction of Benzyl intermediate Compound using triethyl silane to give Benzyl (Bn) protected Ertugliflozin (X), followed by hydrogenation of Benzyl (Bn) protected Ertugliflozin (X) using Pd-C to produce Ertugliflozin (I).

Scheme-Ill

This route, due to the chirality of the benzyl or benzyloxy group in the product, multiple pairs of diastereomers are generated, which makes the purification of the product more difficult, and in the subsequent steps to remove the benzyl or benzyloxy group, triethylsilane reduction is required.

US 8669380 discloses a process for the purification of Ertugliflozin (I), wherein crude Ertugliflozin (I) is treated with acetic anhydride in presence of N,N-diisopropylethylamine and 4-dimethylaminopyridine to produce acetyl (Ac) protected Ertugliflozin (XI) followed by hydrolysis using sodium methoxide in methanol to produce pure Ertugliflozin (I).

Scheme-IV

CN 107382952 discloses a process for the purification of Ertugliflozin (I), wherein crude Ertugliflozin (I) is treated with pivaloyl chloride (PivCl) in presence of N,N-diisopropylethylamine and 4-dimethylaminopyridine to produce pivaloyl (Piv) protected Ertugliflozin (XII) followed by hydrolysis using sodium ethoxide in ethanol to produce pure Ertugliflozin (I).

Scheme-V

Considering the importance of Ertugliflozin there is always a need for an alternative purification process, which provides a higher purity. Moreover, the prior art processes do not disclose preparation of pure Ertugliflozin L-pyroglutamic acid, substantially free from impurities. The removal of the impurities from the final API is very essential as the compound is known to have impurities.

In view of this, the present inventors have developed the present invention; it has now surprisingly been found that the pure Ertugliflozin and its L- pyroglutamic acid solvate, which have numerous advantages over the reported processes.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is a process for the purification of Ertugliflozin and Ertugliflozin L-pyroglutamic acid co-crystal with high purity and good yield on commercial scale.

SUMMARY OF THE INVENTION

In one embodiment, the present invention provides a crystalline Compound of Formula (XIII) having a Powder X-ray Diffraction (PXRD) pattern shown in Fig- 1 :

In another embodiment, the present invention provides a purification process of Ertugliflozin (I):

which comprises,

(i) hydrolyzing of a crystalline Compound of Formula (XIII); and

(ii) isolating pure Ertugliflozin (I).

In another embodiment the present invention provides a process for the preparation of a crystalline Compound of Formula (XIII):

a) treating a solution or suspension of crude Ertugliflozin (I);

with propionic acid or propionic anhydride or propionyl halide; b) isolating crystalline Compound of Formula (XIII); and c) converting crystalline Compound of Formula (XIII) to Ertugliflozin (I).

In another embodiment, the present invention provides purification process of Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal (II):

which comprises:

(a) providing a solution of Ertugliflozin L-pyroglutamic acid co crystal (II) in a suitable solvent;

(b) optionally, filtering the resulting solution; (c) adding an anti-solvent to the resulting solution; and

(d) isolating the pure Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal

(II).

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 - PXRD of a Compound of Formula (XIII)

Figure 2 - DSC of a Compound of Formula (XIII)

The Powder X-ray diffraction (PXRD) pattern measured on an X-ray diffractometer (mention the instrument name_Bruker D8 Advance) with measured using CuKa radiation. Methodology of X-ray diffraction is as follows:

Scanning rate: 0.5 sec Detector: Lynx Eye Voltage: 40kV Current: 40mA Scan range: 3-40°

Step size: 0.02°

The Differential Scanning Calorimetry (DSC) thermograms were obtained on a DSC Q2000. Methodology of DSC is as follows:

Mass flow: 50.0 mL/min

Equilibrate: 25.00°C

Ramp: 10.00°C/min to 300.00°C DETAILED DESCRIPTION OF THE INVENTION

In one embodiment of the present invention, crystalline Compound of Formula (XIII):

In another embodiment of the present invention, crystalline Compound of Formula (XIII) is characterized by an X-ray powder diffraction pattern, made using CuKod radiation, which comprises peaks at degrees 2Q (±0.02 degrees) as shown in FIG. 1.

Furthermore, the crystalline form of Compound of Formula (XIII) is characterized by a melting point of about 91.69° C ±2° C. (determined via DSC; evaluated as onset -temperature; heating rate 10 K/min). The obtained DSC curve is shown in FIG. 2.

In yet another embodiment the present invention relates to the use of crystalline form Compounds of Formula (XIII) hereinbefore or hereinafter for preparing Ertugliflozin (I) and Ertugliflozin L-pyroglutamic acid (L-PGA) co crystal (II).

In another embodiment the present invention provides a process for the preparation of a crystalline Compound of Formula (XIII): a) treating a solution or suspension of crude Ertugliflozin (I) with propionic acid or propionic anhydride or propionyl halide; b) isolating crystalline Compound of Formula (XIII); and c) optionally converting crystalline Compound of Formula (XIII) to Ertugliflozin (I). In another embodiment, in step (a), the hydroxyl groups of a crude Ertugliflozin (I) could be protected by the appropriate protecting groups for example, propionyl group may be introduced by treatment with propionic acid or propionic anhydride or propionyl halide like propionyl chloride.

In another embodiment, in the above reaction step (a) is carried out in the presence of a base and a solvent.

The base is organic or inorganic base. The inorganic base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, and/or mixtures thereof. The organic base comprises pyridine; diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof.

In still another embodiment, the solvent used in the reaction step comprises polar protic solvent or polar aprotic solvent or non-polar solvent and/or mixtures thereof.

In another embodiment, polar protic solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixture thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone and/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2CI2) and/or mixtures thereof.

In one more embodiment, the reaction is carried out at a temperature ranging from about 0 degrees Celsius to about 80 degrees Celsius depending upon the solvent used in the reaction for a time period of 2-5 hours.

In still another embodiment, in step (a) for compound of Formula (XIII), the crude mixture comprising compound (I) in solvent is treated with a base, cooled to 5° C., and is treated with an excess of 4 equivalents of reagent. The resulting mixture is stirred at 5° C for 1 hour, then at 20° Cfor 23 hours to afford a compound of Formula XIII. Crude compound of Formula XIII is readily recrystallized from a variety of solvents, such as isopropanol, to yield white crystalline solid.

In one embodiment, the present invention provides a process of Ertugliflozin L-pyro glutamic acid co-crystal (II):

which comprises,

(i) treating a crude mixture comprising Ertugliflozin (I):

with a propionyl halide or propionic acid or propionic anhydride; to produce a crystalline Compound of Formula (XIII);

(ii) hydrolyzing of a crystalline Compound of Formula (XIII) to produce a pure Ertugliflozin (I); and

(iii) optionally, converting Ertugliflozin (I) to Ertugliflozin L-pyroglutamic acid co-crystal (II).

In another embodiment, in step (i), the hydroxyl groups of a crude Ertugliflozin (I) could be protected by the appropriate protecting groups for example, propionyl group may be introduced by treatment with propionic acid or propionic anhydride or propionyl halide like propionyl chloride.

In another embodiment, in the above reaction step (i) is carried out in the presence of a base and a solvent.

In another embodiment, polar protic solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, and/or mixtures thereof; polar aprotic solvent comprises dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone and/or mixtures thereof; and non-polar solvents comprises hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2CI2) and/or mixtures thereof.

In still another embodiment, in step (i) for compound of Formula (XIII), the crude mixture containing compound (I) in solvent is treated with base, cooled to 5° C., and is treated with an excess of 4 equivalents of reagent. The resulting mixture is stirred at 5° C for 1 hour, then at 20° C for 23 hours to afford a compound of Formula XIII. Crude compound of Formula XIII is readily recrystallized from a variety of solvents, such as isopropanol, to yield white crystalline solid.

In still another embodiment, hydrolyzing of a Compound of Formula (XIII) in step (ii) is carried out using an alkali or an acid or metal alkoxides in a suitable solvent.

In still another embodiment, alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metal alkoxides comprises sodium methoxide, sodium ethoxide and/or mixtures thereof.

In still another embodiment, as the solvent used in hydrolysis, comprises water; a lower alcohol comprises methanol, ethanol, propanol, isopropyl alcohol; a water soluble organic solvent such as acetone, tetrahydrofuran, dioxane and the like, and a mixture of solvents selected from the same can be illustrated.

In still another embodiment, the hydrolysis reaction may be performed usually at from 0° C. to a boiling point of used solvent for 30 minutes to 48 hours, and then Ertugliflozin (I) can be obtained by a usual procedure. The obtained compound may be used in the next reaction directly or optionally after further purification.

Yet another embodiment the invention further comprises the method of preparing the Ertugliflozin L-pyroglutamic acid co-crystal (II) comprising the Ertugliflozin (I) and L-pyroglutamic acid in a ratio of approximately 1:1.

In still another embodiment, in step (iii) a compound (I) in methanol or ethanol or isopropanol is treated with L-PGA in water. The resulting mixture is heated to 80° C and then cooled to 40° Cat 3° C./minute and seeded. The mixture is granulated for 10 hours at 40° C then further cooled to 20° C. at 0.1° C/minute to afford white crystalline solid of Ertugliflozin L-pyroglutamic acid co-crystal (II). Surprisingly, it has been found that the existing Compound of Formula

(XIII), which fulfills important requirements mentioned hereinbefore.

In another embodiment, the present invention provides an improved purification process of Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal (II):

which comprises:

(a) providing a solution of Ertugliflozin L-pyroglutamic acid (L-PGA) co crystal (II) in a suitable solvent;

(b) optionally, filtering the resulting solution;

(c) adding an anti-solvent to the resulting solution; and (d) isolating the pure Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal

(II). In still another embodiment, suitable solvent used in step (a) comprises, methylene chloride, ethylene chloride, diisopropyl ether, methyl tert-butyl ether (MTBE), diethyl ether, dimethyl sulfoxide (DMSO), N,N-dimethylacetamide, N- methyl-pyrrolidine, tetrahydrofuran, or N,N-dimethylformamide and/or mixtures thereof.

In yet another embodiment of the present invention, the organic solvent in step (a) is optionally concentrated to remove water and striped of with same or different organic solvent before the addition of anti- solvent.

In still another embodiment, anti-solvent used in step (c) comprises n- heptane, n-hexane, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol and/or mixtures thereof.

In still another embodiment, after adding suitable solvent in step (a) heating the reaction mixture to 50-70°C, preferable 65-70°C and further stirred the reaction mixture up to 30 minutes, preferable 20 minutes. Filtering the resulting solution through micron filter and cooled to 40-45 °C.

In still another embodiment, after adding anti-solvent in step (c) stirred the reaction mixture up to 1-2 hours, preferably 1 hour and cooled to 20-30°C.

In still another embodiment, isolation of the resulting pure Ertugliflozin L- pyroglutamic acid (L-PGA) co-crystal (II) may involve methods such as removal of solvent by filtration, distillation under vacuum or removal of solvent under reduced pressure.

In another embodiment, the present invention provides Ertugliflozin and Ertugliflozin L-pyroglutamic acid (L-PGA) co-crystal can be investigated using known analytical methods, e.g. by Powder X-Ray Diffraction (PXRD) Methods or by Differential Scanning Calorimetry (DSC). As used herein, the term "reduced pressure" refers to a pressure below 50 mmHg.

Drying may be suitably carried out in a tray dryer, vacuum oven, Buchi® Rotavapor®, air oven, fluidized bed dryer, spin flash dryer, flash dryer, cone dryer, agitated nutsche filter cum dryer, nauta dryer or the like or any other suitable dryer. The drying may be carried out at temperature of less than 100°C, or less than about 70°C, or any other suitable temperature. The drying may be carried out under reduced pressure, that is, less than standard atmospheric pressure or at atmospheric pressure or any other suitable pressure. The drying may take place over a period of about 30 minutes to about 12 hours, or any other suitable time period.

The starting compound crude Ertugliflozin (I) is prepared by any process known in the art.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXAMPLES:

EXAMPLE 1: Preparation of a compound of Formula (XIII)

The crude Ertugliflozin (100 g) was dissolved in methylene chloride (800 ml) at 20-30°C. Pyridine (114.13 g) was added to it at the same temperature. It was cooled to 15-20°C and propionyl chloride (126.57 g) was added slowly to the above solution. Thereafter, the temperature of the reaction mass was raised to 20-

30°C. The stirring was continued at this temperature for 6 hrs and the completion of the reaction was confirmed by HPLC. Thereafter it was quenched by adding water (500 ml). The methylene chloride layer was separated and washed with 2% w/w aqueous sodium bicarbonate solution (500 ml) and finally with 10% w/w aqueous sodium chloride solution (500 ml). The methylene chloride layer was concentrated at 40-45°C under vacuum to obtain the product as viscous residue, which was subsequently crystallized from Isopropanol (300 ml). The product was dried under vacuum at 40°C. The PXRD obtained is shown in Fig.l.

Yield: 50 g.

HPLC Purity: 97.49%.

NMR (300 MHz, DMSO-d₆) 0.82, 1.04, 1.09, 1.13 & 1.39 (5t, 15H), 1.87 - 2.42 (m, 8H), 3.68 - 4.09 (m, 6H), 4.43 & 4.54 (2d, 2H), 5.33 & 5.51 (2d, 2H), 5.42 (t, 1H), 6.79 (d, 2H), 7.06 (d, 2H), 7.32 - 7.36 (m, 3H).

EXAMPLE 2: Preparation of a compound of Formula (XIII)

The crude Ertugliflozin (10 g) was dissolved in toluene (100 ml) at 20- 30°C. Pyridine (14.5 g) was added to it at the same temperature. Thereafter, propionyl chloride (12.73 g) was added slowly to the above solution. The stirring was continued at this temperature for 6 hrs and the completion of the reaction was confirmed by HPLC. Thereafter it was quenched by adding water (50 ml). The toluene layer was separated and concentrated at 40-50°C under vacuum to obtain the product as viscous residue, which was subsequently crystallized from Isopropanol (40 ml). The product was dried under vacuum at 40°C. The PXRD obtained is shown in Fig.l.

Yield: 5 g.

HPLC Purity: 97.7%.

EXAMPLE 3: Preparation of a compound of Formula (XIII)

The crude Ertugliflozin (10 g) was dissolved in toluene (100 ml) at 20- 30°C. Pyridine (14.5 g) was added to it at the same temperature. Thereafter, propionic anhydride (17.88 g) was added slowly to the above solution. The stirring was continued at this temperature for 24 hrs and the completion of the reaction was confirmed by HPLC. Thereafter, it was quenched by adding water (50 ml). The toluene layer was separated and concentrated at 40-50°C under vacuum to obtain the product as viscous residue, which was subsequently crystallized from Isopropanol (40 ml). The product was dried under vacuum at 40°C. The PXRD obtained is shown in Fig.l.

Yield: 5 g.

HPLC Purity: 98.33%.

NMR (300 MHz, DMSO-d₆) 0.82, 1.04, 1.09, 1.13 & 1.39 (5t, 15H), 1.87 - 2.42 (m, 8H), 3.68 - 4.09 (m, 6H), 4.43 & 4.54 (2d, 2H), 5.33 & 5.51 (2d,

2H), 5.42 (t, 1H), 6.79 (d, 2H), 7.06 (d, 2H), 7.32 - 7.36 (m, 3H).

EXAMPLE 4: Preparation of Ertugliflozin L-Pyroglutamic acid Co-crystal

(II) The compound of Formula (XIII) (82 g) was suspended in methanol at 20-

30°C. 30% w/w Sodium methoxide solution in methanol (2.44 g) was added to it at the same temperature. The stirring was continued at this temperature for 3 hrs and the completion of the reaction was confirmed by HPLC. Thereafter, it was concentrated at 40-50°C under vacuum to obtain the product as viscous residue. The obtained concentrated mass was dissolved in Isopropanol (328 ml) and heated it to 60-65°C. A solution of aqueous L-Pyroglutamic acid (17.5 g dissolved in water (656 ml)) and carbon (8.2 g) was added to the above solution at 60-65°C. Further it was heated to 70-80°C and stirred for 30 min at the same temperature. The carbon was filtered through hyflo and the filtrate was concentrated at 40-50°C under vacuum to obtain the product as viscous residue, which was crystallized from Methyl tert-butyl ether (246 ml) and n-Heptane (492 ml). The product was dried under vacuum at 40°C.

Yield: 71 g.

HPLC Purity: 100%. EXAMPLE 5: Preparation of Ertugliflozin (I)

The compound of Formula (XIII) (5 g) was suspended in methanol (50 ml) at 20-30°C. A solution of 0.32 g lithium hydroxide monohydrate dissolved in 10 ml of DM water was slowly added at 5-10°C over a period of 20 minutes. The stirring was continued at this temperature for 3 hrs. and the completion of the reaction was confirmed by HPLC. Thereafter, it was concentrated at 30-35°C under vacuum to obtain the product as viscous residue, which was crystallized from DM water (50 ml) and Isopropanol (2.5 ml). The product was dried under vacuum at 40°C.

Yield: 3.2 g.

HPLC Purity: 99.89 %.

EXAMPLE 6: Preparation of Ertugliflozin (I)

The compound of Formula (XIII) (4 g) was suspended in 30% w/w Sodium methoxide solution in methanol (0.55 g) 16ml at 20-30°C. The stirring was continued at this temperature for 2 hrs. and the completion of the reaction was confirmed by HPLC. Thereafter, it was concentrated at below 40°C under vacuum to obtain the product as viscous residue. To the concentrated mass added DM water (16 ml) followed by Methyl tert-butyl ether (24 ml) at 20-30°C and acetic acid was added (0.18 g) and continued stirred at 20-30°C for 20 min. separated the upper organic layer and again extracted the aqueous layer with Methyl tert-butyl ether (16 ml) 20-30°C. Collected total Methyl tert-butyl ether layer washed with DM water (16 ml) at 20-30°C. Add carbon (0.2g) to the Methyl tert-butyl ether layer at 20-30°C and stirred at 20-30°C for 30 min. The carbon was filtered through hyflo and the filtrate was concentrated at below 45 °C under vacuum to obtain the product as viscous residue, which was crystallized from isopropanol (2 ml) and DM water (48 ml). The product was dried under vacuum at 35-45°C.

Yield: 2.2 g.

HPLC Purity: 99.90 %. EXAMPLE 7: Preparation of Ertugliflozin L-Pyroglutamic acid Co-crystal

(II)

Ertugliflozin (35 g) was dissolved in Isopropanol (175 ml) and heated it to 40-50°C. A solution of aqueous L-Pyroglutamic acid (10.33 g dissolved in water (35 ml)) and carbon (3.5 g) was added to the above solution at 40-50°C. Further it was heated to 40-50°C and stirred for 30 min at the same temperature. The carbon was filtered through hyflo and the filtrate was concentrated at 40-50°C under vacuum to obtain the product as viscous residue, which was crystallized from Methyl tert-butyl ether (175 ml) and n-Heptane (210 ml). The product was dried under vacuum at 40°C.

Yield: 42 g.

HPLC Purity: 99.95 %.

Claims

WE CLAIM:

1. A purification process of Ertugliflozin (I):

which comprises,

(i) hydrolyzing of a crystalline compound of Formula (XIII); and

(ii) isolating pure Ertugliflozin (I).

2. The process as claimed in claim 1, hydrolyzing of a compound of Formula (XIII) in step (i) is carried out using an alkali or an acid or metal alkoxides in a suitable solvent.

3. The process as claimed in claim 1 and claim 2, alkali comprises sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, or acid comprises hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, metal alkoxides comprises sodium methoxide, sodium ethoxide and/or mixtures thereof and solvent used in hydrolysis, comprises water; a lower alcohol comprises methanol, ethanol, propanol, isopropyl alcohol; a water soluble organic solvent such as acetone, tetrahydrofuran, dioxane and /or mixture thereof.

4. A process for the preparation of a crystalline Compound of Formula

(XIII):

with propionic acid or propionic anhydride or propionyl halide; b) isolating crystalline Compound of Formula (XIII); and c) optionally converting crystalline Compound of Formula (XIII) to Ertugliflozin (I).

5. The process as claimed in claim 4, step (a) is carried out in the presence of a base and a solvent.

6. The process as claimed in claim 5, the base comprises potassium carbonate, lithium carbonate, sodium carbonate, sodium ethoxide, sodium bicarbonate, potassium bicarbonate, pyridine, diisopropylamine, diisopropylethylamine triethylamine, dimethylamine, trimethyl amine, 1,8- diazabicyclo[5.4.0]undec-7-ene (DBU), and/or mixtures thereof and the solvent comprises water, methanol, ethanol, isopropyl alcohol, n-butanol, dimethylformamide (DMF), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), acetonitrile, acetone, ethyl acetate, N-methylpyrrolidone, hexane, benzene, toluene, 1,4-dioxane, chloroform, diethyl ether, methylene chloride (CH2CI2) and/or mixtures thereof.

7. A purification process of Ertugliflozin L-pyroglutamic acid (L-PGA) co crystal (II):

which comprises:

(b) optionally, filtering the resulting solution;

(II).

8. The process as claimed in claim 7, the suitable solvent used in step (a) comprises, methylene chloride, ethylene chloride, diisopropyl ether, methyl tert-butyl ether (MTBE), diethyl ether, dimethyl sulfoxide

(DMSO), N,N-dimethylacetamide, N-methyl-pyrrolidine, tetrahydrofuran, or N,N-dimethylformamide and/or mixtures thereof.

9. The process as claimed in claim 7, the suitable anti-solvent used in step (c) comprises n-heptane, n-hexane, ethanol, methanol, ethyl acetate, isopropyl alcohol, n-butanol and/or mixtures thereof.

10. A crystalline Compound of Formula (XIII), which is characterized by an X-ray powder diffraction pattern, made using CuKod radiation, which comprises peaks at degrees 2Q (±0.02 degrees) as shown in FIG. 1.