Claims:WE CLAIM:

1. An improved process for the preparation of Dapagliflozin Propanediol monohydrate (I), comprising the steps of;
a) 4-bromo-1-chloro-2-[(4-ethoxy phenyl)methyl]-benzene (I) is reacted with 3,4,5-Tris-trimethylsilanyloxy- 6-trimethylsilanyloxymethyl- tetrahydro-pyran-2-one (II) in presence of strong base, acid and organic solvent to obtain in-situ 2-methoxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyI-tetrahydro-pyran-3,4,5-triol (III),

b) In-situ the compound of formula (III) with reducing agent in the presence of an activating group and organic solvent to obtain in-situ Dapagliflozin,

c) In-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents to obtain L-Proline complex of Dapagliflozin,

d) L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol in presence of organic solvents-2 to obtain Dapagliflozin Propanediol monohydrate.

2. The process as claimed in claim 1, wherein the strong base is selected from methyl lithium, n-butyl lithium, lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

3. The process as claimed in claim 1, wherein the acid is selected from hydrochloric acid, sulphuric acid, methane sulphonic acid, phosphoric acid,hydrofluoric acid, hydrobromic acid and nitric acid.

4. The process as claimed in claim 1, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF),dichloromethane (MDC), n-hexane,ethyl acetate, acetonitrile (AcCN), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, and water or mixtures thereof.

5. The process as claimed in claim 1, wherein the reducing agent is triethylsilane.

6. The process as claimed in claim 1, wherein the activating group is boron trifluoride etherate (BF3OEt2) or boron trifluoride acetic acid complex (BF3. 2CH3 COOH)

7. The process as claimed in claim 1, wherein mixture of solvents selected from ethyl acetate (EtoAC) and methanol (MeOH).

8. The process as claimed in claim 1, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, calcium bicarbonate, cesium hydroxide, cesium carbonate, barium hydroxide, barium carbonate and lithium hydroxide.

9. The process as claimed in claim 1, wherein the organic solvent-2 is selected from such as cyclohexane, iso-octane or methyl cyclohexane,

Dated this seventh (07th) day of May, 2021
, Description:“IMPROVED PROCESS FOR DAPAGLIFLOZIN PROPANE DIOL MONOHYDRATE”

FIELD OF THE INVENTION

The present invention relates to an improved process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol(2S)-1,2-propanediol, hydrate i.e, Dapagliflozin Propanediol monohydrate (I), simple, efficient more economical and eco-friendly.

BACKGROUND OF THE INVENTION

Dapagliflozin is an orally active sodium glucose co-transporter 2 (SGLT 2) inhibitor, The active ingredient of the approved product is chemically designated as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]~D-glucitol, (2S)-propylene glycol, monohydrate and is marketed for the treatment of type 2 Diabetes mellitus. It is also used to treat adults with heart failure with reduced ejection fraction to reduce the risk of cardiovascular death and hospitalization for heart failure.

The most common side effect in people with type 2 diabetes is hypoglycaemia, especially when used in combination with a sulphonylurea or insulin. The most common side effect in people with type 1 diabetes is genital infection, especially in women and a common side effect is diabetic ketoacidosis. It is of the gliflozin (SGLT2 inhibitor) class.

It was developed by Bristol-Myers Squibb in partnership with AstraZeneca. In 2017, it was the 259th most commonly prescribed medication in the United States, with more than one million prescriptions.

Currently various SGLT2 inhibitor drugs have been approved or in clinical phase for treatment of type 2 diabetes. A significant numbers of SGLT2 are ß-C-arylglucosides derived drug candidates, most of which comprises a central 1-deoxyglucose ring moiety that is arylated at C1. Dapagliflozin is one of the approved SGLT2 inhibitor which is marketed under the trade name Farxiga® and Forxiga in Europe.

The empirical formula is C21H25CIO6.C3H8O2.H2O and the molecular weight is 502.98. The structural formula is;

Dapagliflozin Propanediol Monohydrate (I)

U.S. Patent No. 6,515,117 discloses the compound dapagliflozin and a process for its preparation wherein the process involves preparation of halogenated benzene derivative by reaction oi 5-bromo-2-chlorobenzoyl chloride with phenetole thereby isolating S-bromo^-chloro^'-ethoxybenzophenone, which upon reduction in acetonitrile at 50°C gives 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene of Formula III, coupling of TMS protected gluconolactone of Formula IV with halogenated benzene derivative of Formula 111 in presence of n-butyl lithium followed by methane sulfonic acid solution in presence of methanol to obtain O-methyiglucoside intermediate of Formula V. By the reduction of resulting O-methylglucoside intermediate of Formula Vwith triethylsilane and boron trifluoride gives crude dapagliflozin, which upon purification by first converting it into tetra acetylated dapagliflozin of Formula VI followed by hydrolysis with lithium hydroxide gives pure dapagliflozin as an amorphous glassy off-white solid with purity 94%.

The scheme representation is shown in scheme-I.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry.
Process for preparation of is disclosed in US 7,375,213 B2 and J.Med.Chem.2008, 51, 1145-1149. Prior art US'213 describes reaction of 2-chloro-5-bromo-4'-ethoxy-diphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, n-BuLi in presence of THF and Heptane. After basification with TEA, the oily residue of methyl- l-C-(2-chloro-4'- ethoxy-diphenylmethan-3-yl)-a-D-glucopyranose obtained as solid compound after workup. This compound reacts with acetic anhydride in presence of THF, DIPEA and DMAP to get oily residue of methyl-2,3,4,6 tetra-0-acetyl-l-C-(2-chloro-4'-ethoxydiphenylmethan-3-yl)-a-D-glucopyranose which further undergoes reduction reaction in presence of acetonitirle, t riethylsilane, boron trifluorideetherate to yield 2,3,4,6-tetra-0-acetyl-l-C-(2-chloro-4'-ethoxydi henylmethan-3-yl)-ß-D-glucopyranose which is further deprotected by reacting with LiOH monohydrate in presence of THF/MeOH/H2O to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The scheme representation is shown in scheme-II.

The said prior art describes multiple, time consuming process steps which involves getting the intermediate products as oily residue at various stages of the process, which is difficult to purify and handle for further process step. More over the workup involves multiple evaporation of product which may result in decomposition. Another drawback of the process is that the process describes n-BuLi reaction with two pot reaction. It is very difficult to transfer the material from one reactor to second reactor at -78°C at industrial level with highly moisture sensitive reaction mass. This makes process uneconomical, cumbersome and commercially not viable. Further when practically the said method followed, a-Isomer of the final product is formed in the range of 6-8% along with Des-bromo impurity formed in the range of 7-9 %, which increases after addition of n-butyllithium and kept the mass for overnight reaction. Moreover lactone ring cleavage is also observed in the range of 3-4% after addition of Methanesulphonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product.

PCT publication WO 2016147197 discloses process for the preparation of Dapagliflozin Propanediol monohydrate, which comprises the compound of formula (II) is reacted with the compound of formula (III) in presence of Toluene / THF / dry ice acetone / n-BuLi in hexanes methane sulphonic acid allyl alcohol / NaHCO3 and H2O to obtain the compound of formula (III). The compound of formula (III) converts into Dapagliflozin in presence of MDC / ACN / dry ice acetone / triethylsilane BF3OEt2 and NaHCO3. Dapagliflozin is reacted with L-proline in presence of EtOAc to obtain Lproline complex of Dapagliflozin, which is conerts into Dapagliflozin in resence of EtOAc /n-heptane and NaHCO3.

The scheme representation is shown in scheme-III.

US 7919598 discloses a process for the preparation of Dapagliflozin propanediol monohydrate, which comprises the compound (A) converts into Dapagliflozin in presence of NaOH /MeOH, which is insituly converts into Dapagliflozin propanediol monohydrate in presence of AcOH / isopropyl acetate (S)-(+)-1,2-propanediol and cyclohexane.

The scheme representation is shown in scheme-IV:

There is always need for alternative preparative routes, which for example use reagents, solvents that are less expensive and / or easier to handle, consume smaller amounts of reagents and solvents provide a higher yield of product involve fewer steps, have smaller and / or more eco-friendly waste products and / or provide a product of higher purity.
The processes taught by prior art have several drawbacks namely not suitable for scale up at plant level, difficult, giving lower yields and less user friendly. Considering the drawbacks of prior art for the preparation of the Dapagliflozin propanediol monohydrate, there is a urgent and pressing need for simple, energy economical, financially cheaper plant friendly process, environment friendly process for the preparation of Dapagliflozin propanediol monohydrate with better yields and purity.
Hence, there is consequently a need development for improved methods to sort out prior art existing methods. So, our inventors have developed an improved method for the preparation of Dapagliflozin propanediol monohydrate. The present invention is providing a simple, cost effective with high purity and good yield on industrial applicable process.

SUMMARY OF THE INVENTION

The present invention relates to an improved process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol(2S)-1,2-propanediol, hydrate i.e, Dapagliflozin Propanediol monohydrate, simple, efficient more economical and eco-friendly.
.

In one aspect of the present invention provides an improved process for the preparation of Dapagliflozin Propanediol monohydrate (I), comprising the steps of;

a) 4-bromo-1-chloro-2-[(4-ethoxy phenyl)methyl]-benzene (I) is reacted with 3,4,5-Tris-trimethylsilanyloxy- 6-trimethylsilanyloxymethyl- tetrahydro-pyran-2-one (II) in presence of strong base, acid and organic solvent to obtain in-situ 2-methoxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyI-tetrahydro-pyran-3,4,5-triol (III),

b) In-situ the compound of formula (III) with reducing agent in the presence of an activating group and organic solvent to obtain in-situ Dapagliflozin,

c) In-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents to obtain L-Proline complex of Dapagliflozin,

d) L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol in presence of organic solvents-2 to obtain Dapagliflozin Propanediol monohydrate.

Another aspect of the present invention provides, in-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents to obtain L-proline complex of Dapagliflozin.

In yet another aspect of the present invention provides, L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol in presence of organic solvents-2 to obtain Dapagliflozin Propanediol monohydrate.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for preparing (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol(2S)-1,2-propanediol, hydrate i.e, Dapagliflozin Propanediol monohydrate, simple, efficient more economical and eco-friendly.

In one aspect of the present invention provides an improved process for the preparation of Dapagliflozin Propanediol monohydrate (I), comprising the steps of;

a) 4-bromo-1-chloro-2-[(4-ethoxy phenyl)methyl]-benzene (I) is reacted with 3,4,5-Tris-trimethylsilanyloxy- 6-trimethylsilanyloxymethyl- tetrahydro-pyran-2-one (II) in presence of strong base, acid and organic solvent to obtain in-situ 2-methoxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyI-tetrahydro-pyran-3,4,5-triol (III),

b) In-situ the compound of formula (III) with reducing agent in the presence of an activating group and organic solvent to obtain in-situ Dapagliflozin,

c) In-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents to obtain L-Proline complex of Dapagliflozin,

d) L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol in presence of organic solvents-2 to obtain Dapagliflozin Propanediol monohydrate.

Another aspect of the present invention provides, in-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents to obtain L-proline complex of Dapagliflozin.

In yet another aspect of the present invention provides, L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol in presence of organic solvents-2 to obtain Dapagliflozin Propanediol monohydrate.

According to embodiment of the present invention, which comprises 4-bromo-1-chloro-2-[(4-ethoxy phenyl)methyl]-benzene (I) is reacted with 3,4,5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl- tetrahydro-pyran-2-one (II) in presence of strong base, acid and organic solvent and the reaction is carried out at 25-30°C for 15-16 hours to obtain in-situ 2-methoxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6- hydroxymethyI-tetrahydro-pyran-3,4,5-triol (III). In-situ the compound of formula (III) with reducing agent in the presence of an activating group and organic solvent and the reaction is carried out at -15 to -10°C for 5-6 hours to obtain in-situ Dapagliflozin. The in-situ Dapagliflozin is reacted with L-proline in presence of mixture of solvents and the reaction is carried out at 60-65°C for 4-6 hours to obtain L-Proline complex of Dapagliflozin. The L-Proline complex of Dapagliflozin treated with inorganic base/purified water in presence of organic solvents and followed by treated with (S)-(+)-1,2-propanediol, wherein the reaction is carried out at 60-65°C for 1-3 hours and followed by charged organic solvents-2, wherein the reaction is carried out at 20-45°C for 18-26 hours to obtain Dapagliflozin Propanediol monohydrate.

According to an embodiment of the present invention, wherein the strong base is selected from methyl lithium, n-butyl lithium, lithium diisopropylamide and lithium bis(trimethylsilyl)amide.

According to an embodiment of the present invention, wherein the acid is selected from hydrochloric acid, sulphuric acid, methane sulphonic acid, phosphoric acid,hydrofluoric acid, hydrobromic acid and nitric acid.

According to an embodiment of the present invention, wherein the organic solvent is selected from acetone, acetonitrile, ethyl acetate, water, isopropyl alcohol, methanol, ethanol, toluene, dimethyl sulfoxide (DMSO), dimethylformamide (DMF),dichloromethane (MDC), n-hexane,ethyl acetate, acetonitrile (AcCN), isopropyl acetate and n-butyl acetate, methyl ethyl ketone, methyl isobutyl ketone and cyclohexanone, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran (THF), 1,2-dimethoxyethane, and water or mixtures thereof.

According to an embodiment of the present invention, wherein the reducing agent is triethylsilane and the activating group is Boron trifluoride etherate (BF3OEt2) or Boron trifluoride acetic acid complex (BF3. 2CH3 COOH)

According to an embodiment of the present invention, wherein mixture of solvents selected from ethyl acetate (EtoAC) and methanol (MeOH).

According to an embodiment of the present invention, wherein the inorganic base is selected from sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, calcium bicarbonate, cesium hydroxide, cesium carbonate, barium hydroxide, barium carbonate and lithium hydroxide.

According to an embodiment of the present invention, wherein the organic solvent-2 is selected from such as cyclohexane, iso-octane or methyl cyclohexane.

According to embodiment of the present invention, which comprises by L-Proline complex of Dapagliflozin from 4-bromo-1-chloro-2-[(4-ethoxy phenyl)methyl]-benzene (I) via without isolation/in-situ compound of compound of formula (III) and Dapagliflozin.

The following examples illustrate the present invention, but should not be construed as limiting the scope of the invention.

EXAMPLES

Example -1:

Preparation of 2-methoxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-triol (III):

Charge Tetrahydrofuran (200 ml), Toluene (400ml) and 4-bromo-1-chloro-2-4-ethoxybenzyl) benzene (100gm) at 25-30°C under nitrogen atmosphere, cool the reaction mixture to -75 to -65°C. Add n-butyllithoum 2.5M Solution in n-hexane (200ml) and Trimethyl silyl Glucono lactone (190gm) to the reaction mixture and stir for 2 hours at -75 to -65°C. Add methanol (500ml) and con HCl (100ml) to the reaction mixture at -75 to -65°C, stir for 30min, raise the reaction mixture temperature to 25-30°C for 15-16 hours. After completion of the reaction separate two layers, take toluene layer extracted with mixture of con HCl (40ml) and methanol (200ml), again separate two layers, take bottom product layer washing with toluene (3x200ml) Separate the two layers. Take bottom product layer into RB flask, add purified water (1200ml) and ethyl acetate (1000ml). adjust the pH 7.0-8.0 with 10% sodium bicarbonate solution the obtained reaction mixture then separatetwo layers. Take organic layer and was with purified water (2x500ml) Separate the layers, take organic layer washing with 10% Sodium chloride solution (100ml), Separate the layers, then distil out the solvent completely at below 50°C under reduced pressure, to obtained the title compound with residue.

Yield: 85gms (63.4%)

Purity: 85.29

Example-2:

Preparation of Dapagliflozin:

Take above residue compound of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (85gm), Charge dichloromethane (425ml) and acetonitrile(425ml) at 25-30°C,Cool the reaction mixture to -15 to -10°C, to add triethylsilane (98.6gm) Stir for 15 min, then to add BF3 etherate (BF3Et2O) (81.6gm) at -15 to -10°C, maintain the reaction mixture for 5-6 hours, send sample HPLC, Raised the temperature of the reaction mixture to 10-15°C, then reaction mixture adjust the PH 7.0-8.0 with 10% Sodium bicarbonate solution (1000ml), distil out the solvent completely at below 40°C under reduced pressure, cool the mass to 25-30°C, Charge Ethyl acetate(850ml), Separate the both layers, take Organic layer washing with purified water(2x500ml) Separate the both layers, take Organic layer washing with 10% Sodium chloride (85ml), Separate the both layers, Distil out the solvent completely at below 50°C under reduced pressure, to obtained the title compound with residue.

Yield: 76gms (96%)

Purity: 88.64,

Example-3:

Preparation of L-Proline complex of Dapagliflozin:

Take above compound of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (80gm), Charge methanol (400ml), Heat the reaction mixture to 60-65°C, to Add L-Proline (48gm), maintain the reaction mixture for 2 hours, to add Ethyl acetate (1000ml), Stir for 5hours at 60-65°C, Cool the reaction mixture 0-5°C, filter the material. Wash the material with Ethyl acetate (160 ml)wet wt: 120gm, take about wet material (120gm), Charge methanol(200ml), Heat the reaction mixture to 60-5°C Stir for 30min, to add ethyl acetate(800ml) at 60-65°C, stir for 1-2hours, Cool the reaction mixture 0-5°C, filter the material. Wash the material with Ethyl acetate (160 ml), and dried to get title compound.

Yield: 80gm (78%)

Purity: 99.97

Example-4:

Preparation of L-Proline complex of Dapagliflozin:

Take above compound of (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol (80gm), Charge Ethyl acetate (800ml), Heat the reaction mixture to 80-85°C, to Add L-Proline (48gm), maintain the reaction mixture for 2 hours, cool to the mass 60-65°C to add n-hexane (1600ml), Stir for 5hours at 60-65°C, Cool the reaction mixture 0-5°C, filter the material. Wash the material with n-hexane (160 ml)wet wt: 120gm, take about wet material (120gm), Charge methanol(200ml), Heat the reaction mixture to 60-65°C Stir for 30min, to add ethyl acetate(800ml) at 60-65°C, stir for 1-2hours, Cool the reaction mixture 0-5°C, filter the material. Wash the material with Ethyl acetate (160 ml), and dried to get title compound.

Yield: 78 gm (76.2%)

Purity: 99.95

Examples-5:

Purification of crude L-Prolinecomplex of Dapagliflozin:

Purification of the crude material in methanol and n-hexane:

Charge methanol (400ml), and charge 2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline (100gm), Heat the reaction mixture to 60-5°C Stir for 30min, to add n-hexane (800ml) at 60-65°C, stir for 1-2hours, Cool the reaction mixture 0-5°C, filter the material. Wash the material with n-hexane(200 ml), and dried to get title compound.

Yield: 80 gm

Solid purity: 99.96

Examples-6:

Purification of crude L-Proline complex of Dapagliflozin:

Purification of the crude material in Ethyl acetate and n-heptane:

Charge Ethyl acetate (1000ml), and charge 2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl) methyl] phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline (100gm), Heat the reaction mixture to 80-85°C Stir for 30min, to add n-heptane (2000ml) at 80-85°C, stir for 1-2hours, Cool the reaction mixture 0-5°C, filter the material. Wash the material with n-heptane (200 ml), and dried to get title compound.

Yield: 75gm

Purity: 99.83

Examples-6:

Purification of crude L-Proline complex of Dapagliflozin:

Purification of the crude material in Ethanol and n-heptane

Charge Ethanol (500ml), and charge 2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline (100gm), Heat the reaction mixture to 60-65°C Stir for 30min, to add n-heptane (1000ml) at 50-55°C, stir for 1-2hours, Cool the reaction mixture 0-5°C, filter the material. Wash the material with n-heptane (200 ml), and dried to get title compound.

Yield: 80 gm

Solid purity: 99.84

Examples-7:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml), then PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C , then Charge Isopropyl acetate (500ml) stir for 15-20min Separate two layers , Organic layer washed with 10% sodium chloride solution (100ml) ,separate two layers ,Organic layer washed with water (2x 500ml) separate two layers , Take Isopropyl acetate layer in to RB flask, add (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 60-65°C, Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min. Filter the mass through hyflow bed and wash with Isopropyl acetate(100ml) , Cool the reaction mixture to 35-40°C, Charge cyclohexane (1200ml) in to an another RB flask cool to 0-10°C, add above isopropyl acetate product layer in to Cyclohexane , stir for 1-2 hours at 0-10°C, then raise to 25-30°C, stir for 20-24hrs, filter the material and wash the material with cyclohexane (50 ml) and dried to get title compound.

Yield: 62 gm(65.2%)

Solid purity: 99.90

Examples-8:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml). PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C. Charge methyl tertiary butyl ether (500ml) . Stir for 15-20min Separate the layers, Organic layer washed with 10% sodium chloride solution (100ml),separate the layers ,Organic layer washed with water (2x 500ml) separate the layers , Take methyl tertiary butyl ether in to RB flask. charge (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 50-55°C. Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min. Filter the mass through hyflow bed wash with methyl tertiary butyl ether (100ml) , Cool the reaction mixture to 35-40°C. Charge cyclohexane (1200ml) in to an another RB flask cool the Mixture to 0-10°C, add above methyl tertiary butyl ether product layer in to R.B.flask , stir for 1-2 hours at 0-10°C. then raise temp to 25-30°C, stir for 20-24hrs. filter the material. Wash the material with cyclohexane (50 ml) and dried to get title compound.

Yield: 55gm (58%)

Solid purity: 99.85

Examples-9:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml), then PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C , then Ethyl acetate (500ml) stir for 15-20min Separate the layers , Organic layer washing with 10% sodium chloride solution (100ml) ,separate the layers ,Organic layer washing with water (2x 500ml) separate the layers , Take ethyl acetate in to RB flask, to charge (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 60-65°C, Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min filter the mass hyflowbed wash with ethyl acetate (100ml) , then cool the reaction mixture to 35-40°C, Take another RB flask , Charge cyclohexane (1200ml) in to RB flask cool to 0-10°C, to add above ethyl acetate product layer in to RBflask , stir for 1-2 hours at 0-10°C then raise to 25-30°C, stir for 20-24hrs, then filter the material. Wash the material with cyclohexane (50 ml) and dried to get title compound.

Yield: 60 gm (63.2%)

Purity: 99.82

Examples-10:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml), then PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C , then Charge methyl tertiary butyl ether (500ml) stir for 15-20min Separate the layers , Organic layer washing with 10% sodium chloride solution (100ml) ,separate the layers ,Organic layer washing with water (2x 500ml) separate the layers , distil out the reaction mixture at below 50°C , to charge Isopropyl acetate (500ml) in to RB flask, to charge (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 60-65°C, Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min filter the mass hyflowbed wash with Isopropyl acetate (100ml) , then cool the reaction mixture to 35-40°C, Take another RB flask , Charge cyclohexane (1200ml) in to RB flask cool to 0-10°C, to add above Isopropyl acetate product layer in to RBflask , stir for 1-2 hours at 0-10°C then raise to 25-30°C, stir for 20-24hrs, then filter the material. Wash the material with cyclohexane (50 ml) and dried to get title compound.

Yield: 60 gm(63.2%)

Examples-11:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml), then PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C , then Charge methyl tertiary butyl ether (500ml) stir for 15-20min Separate the layers , Organic layer washing with 10% sodium chloride solution (100ml) ,separate the layers ,Organic layer washing with water (2x 500ml) separate the layers , distil out the reaction mixture at below 50°C,to charge Isopropyl acetate (500ml) in to RB flask, to charge (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 60-65°C, Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min filter the mass hyflowbed wash with Isopropyl acetate (100ml) , then cool the reaction mixture to 35-40°C, Take another RB flask ,Charge n-hexane (1200ml) in to RB flask cool to 0-10°C, to add above Isopropyl acetate product layer in to RBflask , stir for 1-2 hours at 0-10°C then raise to 25-30°C, stir for 20-24hrs, then filter the material. Wash the material with n-hexane (50 ml) and dried to get title compound.

Yield: 58gm (61%),

Examples-12:

Preparation of Dapagliflozin (2S)-1,2-propanediol monohydrate:

Charge(2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-(hydroxymethyl)oxane-3,4,5-triol, L-Proline co crystal (100gm) and Water (1000ml), then PH 6.5-7.5 adjust with 10% Sodium bicarbonate solution (100ml) at 25-30°C , then Ethyl acetate (500ml) stir for 15-20min Separate the layers , Organic layer washing with 10% sodium chloride solution (100ml) ,separate the layers ,Organic layer washing with water (2x 500ml) separate the layers , distil out the reaction mixture below 60°C ,to charge Isopropyl acetate (500ml) in to RB flask, to charge (S)-(+)-1,2-Propanediol (10gm) in to reaction mixture at 25-30°C, Heat the reaction mixture at 60-65°C, Stir for 1-2 hours, then charge activated carbon (5gm) stir for 20-30min filter the mass hyflowbed wash with Isopropyl acetate (100ml) , then cool the reaction mixture to 35-40°C, Take another RB flask , Charge n-hexane (1200ml) in to RB flask cool to 0-10°C, to add above Isopropyl acetate product layer in to RB flask , stir for 1-2 hours at 0-10°C then raise to 25-30°C, stir for 20-24hrs, then filter the material. Wash the material with n-hexane (50 ml) and dried to get title compound.

Yield: 60 gm (63.2%)