DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN, FREE OF ACID AND FURANOSE IMPURITIES”

GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block, Madhapur, Hyderabad,
Telangana, INDIA - 500 081

The following specification particularly describes the invention and the manner in which it is performed.
AN IMPROVED PROCESS FOR THE PREPARATION OF DAPAGLIFLOZIN, FREE OF ACID AND FURANOSE IMPURITIES

FIELD OF INVENTION:
The present invention relates to an improved process for the preparation of Dapagliflozin, its solvates or hydrates and amorphous form thereof with higher purity and yield.

BACKGROUND OF THE INVENTION:
Dapagliflozin is an orally active sodium-glucose co-transporter-2 (SGLT2) inhibitors and is used in the treatment of patients with type 2 diabetes. Dapagliflozin is chemically known as (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (or) (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol, having structural formula as represented by formula (I).

Formula I

Dapagliflozin (S)-propylene glycol ((S)-1,2-propanediol) monohydrate is chemically known as (1S)-1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-D-glucitol compounded with (2S)-1,2-propanediol, hydrate (1:1:1) having structural formula as represented by formula Ia.

Formula Ia
Dapagliflozin developed by Bristol-Myers Squibb in partnership with AstraZeneca. Dapagliflozin is marketed in USA under the trade name FARXIGA® and Europe as FORXIGA® in the form of tablets having strengths 5mg and 10mg. Dapagliflozin inhibits the transporter protein SGLT2 in the kidneys and thereby reduces renal glucose reabsorption, leading to urinary glucose excretion and a reduction in blood glucose levels.

U.S. Patent no. 6,515,117 discloses the Dapagliflozin, or a pharmaceutically acceptable salt, a stereoisomer thereof, or a prodrug ester thereof. This patent also disclosed the preparation of Dapagliflozin by isolating unprotected O-methyl compound, which involves removing O-methyl group using triethylsilane, boron trifluoride etherate (BF3.Et2O) in presence of dichloromethane and acetonitrile followed by acetylation reaction using acetic anhydride, pyridine in presence of dichloromethane and dimethylaminopyridine (DMAP), finally deprotecting tetraacetylated Dapagliflozin using lithium hydroxide monohydrate in presence of tetrahydrofuran/methanol/water to provide Dapagliflozin as an off-white solid with purity 94%.

U.S. Patent no. 7,919,598 discloses the crystalline form (form SC-3) of Dapagliflozin (S)-propylene glycol ((S)-PG) monohydrate and its preparation which involves treating tetraacetylated Dapagliflozin with an alcohol solvent such as methanol or ethanol, and aqueous base such as sodium hydroxide, water and acid such as hydrochloric acid to provide Dapagliflozin followed by treating Dapagliflozin with an organic solvent such as methyl t-butyl ether, an alkyl acetate such as ethyl acetate, methyl acetate, isopropyl acetate, or butyl acetate and (S)-propylene glycol, optionally adding seeds of crystalline Dapagliflozin (S)-PG monohydrate. Further, this patent also disclosed in column 5, lines 1-2 that “The compound of formula I (Dapagliflozin) in the form of a non-crystalline solid (amorphous) Dapagliflozin is disclosed in US‘117”.

U.S. Patent no. 7,375,213 discloses process for the preparation of Dapagliflozin by isolating unprotected O-methyl compound, which involves acetylation of O-methyl compound using acetic anhydride, N,N'-diisopropylethylamine and DMAP in presence of tetrahydrofuran to provide tetraacetylated O-methyl Dapagliflozin followed by reducing O-methyl group using triethylsilane, boron trifluoride etherate in presence of acetonitrile and water, finally deprotection reaction using lithium hydroxide monohydrate in presence of tetrahydrofuran/methanol/water to provide Dapagliflozin as an off-white solid.

U.S. Patent no. 8,999,941 discloses an amorphous form of Dapagliflozin and its preparation which involves treating Dapagliflozin with toluene and n-heptane.

U.S. Patent no. 9,550,747 discloses crystalline form of Dapagliflozin and process for its preparation which involves dissolving Dapagliflozin in good organic solvent such as ether solvents and poor solvent such as alkane solvent.

PCT publication no. 2015104658 discloses process for the preparation of an amorphous form of Dapagliflozin which involves dissolving Dapagliflozin in solvent selected from methanol, dichloromethane, acetonitrile, acetone, methyl isobutyl ketone, methyl ethyl ketone, 2-methyl tetrahydrofuran or mixtures thereof and removing the solvent. This publication also disclosed an amorphous solid dispersion of Dapagliflozin together with one or more pharmaceutically acceptable carriers as well as process for its preparation.

The above prior-art methods have one or more disadvantages, for example, those as mentioned as follows:
(i) reduction of O-methylated Dapagliflozin in presence of mixture of solvents i.e. acetonitrile and dichloromethane.
(ii) the intermediate for manufacturing Dapagliflozin is either having higher impurities or involve further purification which indicates Dapagliflozin with low purity and high residual solvents which is not suitable for pharmaceutical preparations.
(iii) more number of reaction steps, more unit operations and long cycle time.
(iv) involve harmful reaction/reagents for instance use of pyridine.

However, the present inventors surprisingly found that the in-situ O-methylated Dapagliflozin extracted from aqueous methanol followed by reduction of O-methylated Dapagliflozin in the presence of single solvent system i.e preferably in the presence of dichloromethane as a solvent to give highly pure Dapagliflozin with substantially free of furanose impurities and free of acid impurities and this reduction step plays an important role in the preparation of amorphous Dapagliflozin and Dapagliflozin solvates or its hydrates thereof.

Further, the present invention avoids multiple isolation steps at intermediate stages and involves single isolation step to get Dapagliflozin solvates or its hydrates thereof with high yield and purity. Therefore, the present invented process is suitable for large scale operations and thereby commercially viable.

OBJECTIVES OF THE INVENTION:
In one aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I and Dapagliflozin solvates or its hydrates thereof of formula Ia, which is substantially free of the furanose impurities.

In another aspect of the present invention provides an improved process for the preparation of O-methylated dapagliflozin of formula VI or amorphous Dapagliflozin of formula I and Dapagliflozin solvates or its hydrates thereof of formula Ia, which is free of the acid impurity.

In another aspect of the present invention relates to an improved process for the preparation of Dapagliflozin solvates or its hydrates thereof of formula Ia, which involves the single isolation step.

SUMMARY OF THE INVENTION:
The main aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I and Dapagliflozin solvates or its hydrates thereof of formula Ia, which is substantially free of the following furanose impurities:

Furanose Impurity 1

Furanose Impurity 2

In another aspect of the present invention provides an improved process for the preparation of Dapagliflozin (S/RS)-1,2-propanediol or its hydrate of formula Ia which involves the single isolation step, wherein the process comprising following reaction steps:
a) reacting D(+)Gluconolactone compound of formula II with silylating agent selected from Hexamethyldisilazane or Trimethylsilyl chloride in a suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV by with condensing agent in presence of suitable solvent followed by desilylation using suitable acid and suitable solvent to provide a compound of formula V (in-situ);

c) methylating the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ); optionally washing with aqueous alcohol solvent;

d) reducing the compound of formula VI (in-situ) with a reducing agent and Lewis acid in presence of a suitable solvent to provide a Dapagliflozin of formula VII (in-situ); and

e) treating Dapagliflozin of formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide a Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia.

In another aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I, wherein the process comprising following reaction steps:
a) reducing the compound of formula VI with a reducing agent and Lewis acid in presence of dichloromethane to provide a Dapagliflozin of formula VII (in-situ);

b) treating Dapagliflozin of formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide a Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia;

c) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with suitable solvent to provide a reaction mixture;
d) heating and stirring the reaction mixture at 50°C to 70°C;
e) slowly adding reaction mixture to suitable solvent at room temperature; and
f) isolating amorphous Dapagliflozin of formula I.

In another aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I, wherein the process comprising following reaction steps:
a) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with Methyl tert-butyl ether to provide a reaction mixture;
b) heating and stirring the reaction mixture at 50°C to 70°C;
c) slowly adding reaction mixture to n-Heptane at room temperature; and
d) isolating amorphous Dapagliflozin of formula I.

In another aspect of the present invention provides an improved process for the preparation of Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof, wherein the process comprising following reaction steps:
reducing the compound of formula VI with a reducing agent and Lewis acid in presence of dichloromethane as a single solvent to provide a Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof.

In another aspect of the present invention provides an improved process for the preparation of O-methylated Dapagliflozin of formula VI or Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof, which is free of acid impurity of the formula.

Acid Impurity

DETAILED DESCRIPTION:
The main embodiment of the present invention provides an improved process for the preparation of Dapagliflozin of formula I and Dapagliflozin solvates or its hydrates thereof of formula Ia, which is free of acid and furanose impurities.

The suitable “solvent” used in the present invention is selected from the group comprising of water, alcohols, ethers, amides, esters, nitriles, sulfoxides, ketones, hydrocarbons and halogenated hydrocarbons; wherein alcohol is selected from the group consisting of methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like; ester is selected from the group consisting of ethyl acetate, isopropyl acetate; ketone is selected from the group consisting of acetone, methyl isobutyl ketone, methyl ethyl ketone; ether is selected from the group consisting of methyl tert-butyl ether, diisopropyl ether, diethyl ether tetrahydrofuran, 2-methyl tetrahydrofuran, cyclopentyl methyl ether, dioxane and the like; halogenated solvent is selected from the group consisting of dichloromethane chloroform, chlorobenzene, bromobenzene and the like; hydrocarbons is selected from the group consisting of toluene, xylene, cyclohexane and the like; nitrile is selected from the group consisting of acetonitrile, propionitrile and the like; amide is selected from the group consisting of N,N-dimethylformamide, N,N-dimethyl acetamide and the like; sulfoxide such as dimethyl sulfoxide; sulfone; or mixtures thereof.

The “acid” selected from but not limited to methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid, and hydrochloric acid. optionally washing with aqueous alcohol solvent selected from but not limited to methanol, ethanol, iso-propanol, n-butanol, iso-butanol and the like.

The suitable “reducing agents” selected from but not limited to silanes (such as e.g. triethylsilane, 1,1,3,3-tetramethyldisiloxane (TMDS), tripropylsilane, triisopropylsilane (TIPS), diphenylsilane), borane complexes (such as e.g. sodium cyanoborohydride (NaCNBH3), zinc borohydride) or aluminium hydrides (such as e.g. lithium aluminium hydride (LiAlH4), diisobutylaluminum hydride or lithium triisopropyl-aluminum hydride (Li(iPr)3AlH)). Suitable Lewis acids are for example aluminium chloride, boron trifluoride etherate (BF3.Et2O), trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, zinc iodide, or copper (II) triflate and the like.

The term “substantially free of” used in the present invention is means that less than about 0.2 area-% as measured by HPLC.

In one embodiment, the present invention relates to an improved process for the preparation of Dapagliflozin (S/RS)-1,2-propanediol or its hydrate of formula Ia, which involves the single isolation step, wherein the process comprising following reaction steps:
a) reacting D(+)Gluconolactone compound of formula II with silylating agent selected from Hexamethyldisilazane or Trimethyl silyl chloride in suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV with condensing agent in presence suitable solvent followed by desilylation using suitable acid and suitable solvent to provide a compound of formula V (in-situ);

c) methylating the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ);

d) reducing the compound of formula VI (in-situ) with a reducing agent and Lewis acid in presence of a suitable solvent to provide a Dapagliflozin of Formula VII (in-situ);

e) treating Dapagliflozin of Formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide a Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia.

The starting compound of formula II can be prepared according to the methods known in the art and it is also commercially available.

In an embodiment, in step b) process the Grignard or Lithium reagent of benzylbenzene compound IV may be prepared from the benzylbenzene compound IV either via a so-called halogen-metal exchange reaction or by inserting the metal into the carbon-halogen bond. The halogen-metal exchange to synthesize the corresponding lithium compound IV may be carried out for example with an organolithium compound such as e.g. n-, sec- or tert-butyllithium.

The analogous magnesium compound may also be generated by a halogen-metal exchange with a suitable Grignard reagent such as C3-4-alkylmagnesium chloride or bromide, for example isopropyl- or sec-butylmagnesium bromide or chloride or diisopropyl- or di-sec-butylmagnesium without or in the presence of an additional salt such as e.g. lithium chloride that may accelerate the metalation process.

The desilylation process can be carried out in the presence of suitable “acid” selected from but not limited to methane sulfonic acid under suitable reaction conditions and temperature.

In an embodiment, in step c) the methylation process can be carried out in the presence of “acid” selected from but not limited to methane sulfonic acid under suitable reaction conditions and temperature.

In an embodiment, in step c) the reaction of a compound of formula V with methanol in presence of acid is carried out by the addition of a mixture of an acid and methanol in a single lot to provide a compound of formula VI.

In an embodiment, in step d) the reduction may be conducted with one or more ‘reducing agents” selected from but not limited to triethylsilane in the presence of one or more Lewis acids selected from but not limited to boron trifluoride etherate or without a Lewis acid under suitable reaction conditions and temperature.

In an embodiment, in step e) involves preparation of Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia from Dapagliflozin of formula VII (in-situ) is treated with (S/RS)-1,2-propanediol under suitable reaction conditions and temperature.

In another embodiment of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I, wherein the process comprising following reaction steps:
a) reducing the compound of formula VI with a reducing agent and Lewis acid in presence of dichloromethane to provide a Dapagliflozin of Formula VII (in-situ);

b) treating Dapagliflozin of formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide a Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia;

c) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with suitable solvent to provide a reaction mixture;
d) heating and stirring the reaction mixture at 50°C to 70°C;
e) slowly adding reaction mixture to suitable solvent at room temperature; and
f) isolating amorphous Dapagliflozin of formula I.

The starting compound of formula VI can be obtained according to the methods described above. Further, the compound of formula VI can be isolated form or without isolation as directly obtained in reaction mass from previous reaction step.

In an embodiment, in step a) the reduction may be conducted with one or more ‘reducing agents” selected from but not limited to triethylsilane in the presence of one or more Lewis acids selected from but not limited to boron trifluoride etherate or without a Lewis acid under suitable reaction conditions and temperature.

In an embodiment, in step b) involves preparation of Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia from Dapagliflozin of formula VII (in-situ) is treated with (S/RS)-1,2-propanediol under suitable reaction conditions and temperature.

In an embodiment, in steps c, d, e & f) involves treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with suitable solvent to provide a reaction mixture, heating and stirring the reaction mixture at 50°C to 70°C, slowly adding reaction mixture to suitable solvent at room temperature, and stirred for 1 to 2 hours then isolating amorphous Dapagliflozin of formula I.

In another aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I, wherein the process comprising following reaction steps:
a) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with Methyl tert-butyl ether to provide a reaction mixture;
b) heating and stirring the reaction mixture at 50°C to 70°C;
c) slowly adding reaction mixture to n-Heptane at room temperature; and
d) isolating amorphous Dapagliflozin of formula I.

The starting compound of formula Ia can be obtained according to the methods described above or can be prepared according to the methods known in the art.

In another aspect of the present invention provides an improved process for the preparation of amorphous Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof, wherein the process comprising following reaction steps:
reducing the compound of formula VI with a reducing agent and Lewis acid in presence of a single dichloromethane solvent to provide a Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof.

The starting compound of formula VI can be obtained according to the methods described above. Further, the compound of formula VI can be isolated form or without isolation as directly obtained in reaction mass from previous reaction step.

In the above embodiment, the reduction may be conducted with one or more ‘reducing agents” selected from but not limited to triethylsilane in the presence of one or more Lewis acids selected from but not limited to boron trifluoride etherate or without a Lewis acid under suitable reaction conditions and temperature.

In the above embodiment, Dapagliflozin solvated form selected from but not limited to (S)-propylene glycol, (R)-propylene glycol, (RS)-propylene glycol, methanol, ethanol, ethylene glycol, 1,4-butyne-diol and the like;

In an embodiment, use of aqueous methanol for extraction of O-methylated Dapagliflozin of formula VI and water content controlled by azeotropic distillation before reduction process. Further, a single solvent dichloromethane in reduction process of O-methylated Dapagliflozin of formula VI facilitate to substantially free of following furanose impurities:

Furanose Impurity 1

Furanose Impurity 2

In another embodiment, the instant invention provides the preparation of amorphous Dapagliflozin of formula I and Dapagliflozin (S/RS)-1,2-propanediol or its hydrate of formula Ia, wherein the compounds of formula (III), (V), (VI) and (VII) were not isolated, thus the process is economic.

In another embodiment, the present invention relates to an improved process for the preparation of O-methylated Dapagliflozin of formula VI or Dapagliflozin of formula I or its solvates with free of acid impurity.

Acid Impurity
comprising reacting compound of formula V with a mixture of methanesulphonic acid and methanol in a single lot to provide a compound of formula VI.

ANALYSIS OF ACID AND FURANOSE IMPURITY LEVELS:
To summarize, we have used HPLC as an analytical method for validating and estimating acid and furanose impurities content in Dapagliflozin.

Table 1: Describes the batch analysis results for reduction step i.e. O-methyl Dapagliflozin to Dapagliflozin in process using different solvent system dichloromethane (DCM), mixture of dichloromethane, acetonitrile and acetonitrile (CH3CN).

Table 1:
Batch No. Solvent Purity by HPLC (% area)
DAP (Pharma) Alpha Isomer Methoxy Int. Fura nose-1 Fura nose-2 Ethyl DAP SM UI Total
Imp.
DAP/C036/
2B/17 DCM 89.07 0.09 ND 0.30 1.41 0.52 1.86 10.93
DAP/C036/
1C/28 DCM / CH3CN
83.36 1.92 ND 0.76 2.92 1.30 1.58 16.64
DAP/C036/
1C/29 CH3CN
75.54 2.89 ND 1.95 3.99 1.24 7.10 24.46

Table 2: Describes the batch analysis results for methylation step i.e. methylation of compound of formula V to O-methylated Dapagliflozin of formula VI in process using different mode of addition of a mixture of methanesulphonic acid and methanol.

Table 2:
Batch Mode of addition Purity by HPLC (% area)

DAP/C114/1(iii)B/04-P2 Acid impurity Remarks
Slow addition / Lot wise addition
(In process) 4-6% Gummy residue of DAP-1B
DAP-C114-1B-09 Single lot addition
(In process) ND Solid

The process details of the invention are provided in the examples given below, which
are provided by way of illustration only and therefore should not be construed to limit
the scope of the invention.

EXAMPLES
Example-1:
Preparation of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (Formula III):
To a clean and dry RBF (Round-bottom flask), D(+)Gluconolactone (100 g), Hexamethyldisilazane (271.8 g), and Iodine (0.6 g) in Dichloromethane (600 ml) were added at 25 to 35oC under nitrogen atmosphere, heated to 35 to 45oC and maintained for 6 to 8 hours at the same temperature. After completion of reaction, the solvent was distilled off under vacuum and co-distilled with Toluene (2 x 100 ml) at below 45oC under vacuum, to obtained the title compound and it was used for next reaction without further purification.
Yield: 262 g

Example-2:
Preparation of (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (Formula III):
To a clean and dry RBF, D(+)Gluconolactone (100 g; 1 eqv), 4-dimethylaminopyridine (DMAP) (0.2 eqv) in Toluene (8 vol) were added at room temperature under nitrogen atmosphere, cooled to 0 to 5°C and Triethylamine (7 eqv) followed by drop wise addition of Trimethylsilyl chloride (6 eqv) at the same temperature. Then slowly warmed to room temperature and maintained for 12 hours at room temperature. After completion of reaction, the reaction mass was cooled to 0 to 5°C, water (4 vol) was added at below 10°C then stirred for 10 min and separated the organic layer and washed with water (4 vol) and 10% Sodium chloride solution (2 vol), dried over sodium sulfate and distilled off under vacuum followed by co-distilled with Toluene (2 x 100 ml) at below 45°C under vacuum to obtained the title compound and it was used for next reaction without further purification.
Yield: 262 g

Example-3:
Preparation of Dapagliflozin (S/RS)-1,2-propanediol monohydrate (Formula Ia) using methane sulfonic acid in methanol solution lot wise:
To a clean and dry RBF, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (Formula IV) (1 eqv) in Tetrahydrofuran (2.5 vol) and Toluene (5 vol) were added at room temperature under nitrogen atmosphere, cooled to -70 to -85oC then drop wise addition of n-BuLi in n-hexane solution (1.2 eqv) over a period of 1 to 2 hours and maintained for 1 hour at the same temperature followed by (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (In-situ Formula III) (1.3 eqv) in Toluene (2 vol) was added drop wise over a period of 1 to 2 hours and maintained for 2 hour at the same temperature. Methane sulfonic acid (2 eqv) in Methanol (3 vol) solution lot-1 was added to reaction mass over a period of 1 to 2 h at below -50oC. Slowly warmed the reaction mass to 25 to 30oC then Methane sulfonic acid (2 eqv) in Methanol (3 vol) solution lot-2 was added to reaction mass over a period of 1 to 2 h at the same temperature and stirred for 36 hours at 25 to 35°C. After completion of reaction, the reaction mass was cooled to 0 to 10°C, 3% aq.Sodium hydroxide solution (5 vol) was added and warmed to room temperature, stirred for 10 min then separated the aqueous layer and organic layer. The compound was extracted with aqueous methanol (Methanol: Water: 8:1) (3 x 2 vol) from organic layer. Combined aqueous layers and distilled the solvents and the obtained compound was extracted from Dichloromethane (3 x 3 vol). The combined Dichloromethane layer was washed with 10% aq.Sodium chloride solution (3 vol). Water was removed through azeotropic distillation at reflux temperature, cooled the reaction mass to -15 to -5oC then Triethylsilane (1.53 eqv) followed by Boron trifluoride etherate (1.53 eqv) were added and maintained for 3 hours at the same temperature. Slowly warmed the reaction mass to -5 to 5oC and stirred for 2 hours at the same temperature. After completion of reaction, 8% aqueous sodium bicarbonate solution (10 vol) was added, then the organic layer was separated and successively washed with water (2 x 3 vol). The organic layer was separated, dried over sodium sulfate and distilled off completely followed by co-distilled with Ethyl acetate (2 x 0.5 vol) under vacuum to obtain Dapagliflozin (in-situ). The Dapagliflozin (in-situ) was dissolved into Ethyl acetate (5 vol) and (S/RS)-1,2-propanediol (1.5 eqv), water (1.1 eqv) were added to the reaction mixture at room temperature, stirred for 10 min followed by Cyclohexane (5 vol) was added at room temperature, stirred for 2 hours. The solid obtained was filtered, washed with Ethyl acetate/Cyclohexane (1:1) to obtained the title compound.
Yield: 65 g; Purity by HPLC: >99%

Example-4:
Preparation of Dapagliflozin (S/RS)-1,2-propanediol monohydrate (Formula Ia) using methane sulfonic acid in methanol as a single lot:
To a clean and dry RBF, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (Formula IV) (1 eqv) in Tetrahydrofuran (2.5 vol) and Toluene (5 vol) were added at room temperature under nitrogen atmosphere, cooled to -70 to -95oC then drop wise addition of n-BuLi in n-hexane solution (1.2 eqv) over a period of 1 to 2 hours under nitrogen atmosphere followed by (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (In-situ Formula III) (1.3 eqv) in Toluene (2 vol) was added drop wise over a period of not less than 30 minutes and maintained for 2 to 3 hour at the same temperature. Methane sulfonic acid (2 eqv) in Methanol (6 vol) solution as a single lot was added to reaction mass at below -20oC to 0oC. Slowly warmed the reaction mass to 25 to 35oC and stirred for 22 to 26 hours at the same temperature. After completion of reaction, the reaction mass was cooled to 0 to 10°C, 3% aq.Sodium hydroxide solution (5 vol) was added and warmed to room temperature, stirred for 10 min then separated the aqueous layer and organic layer. The compound was extracted with aqueous methanol (2 vol followed by 2x2 vol) from organic layer. Combined aqueous layers and distilled the solvents and the obtained compound was extracted from Dichloromethane (4 vol followed by 2 x 2 vol). The combined Dichloromethane layer was washed with 10% aq.Sodium chloride solution (3 vol). Water was removed through azeotropic distillation at reflux temperature, cooled the reaction mass to -15 to -5oC then Triethylsilane (1.53 eqv) followed by Boron trifluoride etherate (1.53 eqv) were added dropwise and maintained for 20 to 30 minutes at the same temperature under nitrogen atmosphere. Slowly warmed the reaction mass to 0 to 5oC and stirred for 2 to 3 hours at the same temperature. After completion of reaction, 8% aqueous sodium bicarbonate solution (5 vol) was added at below 30oC, then warmed the reaction mass to room temperature and stirred for 15-30 min at room temperature and separated the both layers. The organic layer washed with 8% aqueous sodium bicarbonate solution (5 vol) and 10% aqueous sodium chloride solution (5 vol). Treating organic layer with water (1 eqv) and (S/RS)-1,2-propanediol (2 eq) at room temperature. Heat the reaction mass to 35 to 40oC and stirred for 1 hour at the same temperature. Cool the reaction mass to room temperature and stirred for 1 hour at the same temperature, then (S/RS)-1,2-propanediol (0.1 g) was added and stirred for 1 to 2 hours at the same temperature. Cool the reaction mass to 10 to 15oC and stirred for 3 to 4 hours at the same temperature. The solid obtained was filtered, washed with pre cooled dichloromethane (1 vol). The wet solid was dissolved into dichloromethane (5 vol) at room temperature. Heat the reaction mass to 35 to 40oC, stirred for 1 to 2 hours and cool to room temperature and stirred for 1 to 2 hours. Cool the reaction mass to 10 to 15oC and stirred for 3 to 4 hours. The solid obtained was filtered, washed with pre cooled dichloromethane (0.5 vol). The wet solid was dissolved into dichloromethane (5 vol) at room temperature. Heat the reaction mass to 35 to 40oC, stirred for 1 to 2 hours and cool to room temperature and stirred for 1 to 2 hours. Cool the reaction mass to 10 to 15oC and stirred for 3 to 4 hours. The solid obtained was filtered, washed with pre cooled dichloromethane (0.5 vol) and dried to obtained the title compound.
Yield: 77.2 g; Purity by HPLC: >99%

Example-5:
Preparation of amorphous Dapagliflozin (Formula I):
To a clean and dry RBF, 4-bromo-1-chloro-2-(4-ethoxybenzyl)benzene (Formula IV) (1 eqv) in Tetrahydrofuran (2.5 vol) and Toluene (5 vol) were added at room temperature under nitrogen atmosphere, cooled to -70 to -85oC then drop wise addition of n-BuLi in n-hexane solution (1.2 eqv) over a period of 1 to 2 hours and maintained for 1 hour at the same temperature followed by (3R,4S,5R,6R)-3,4,5-tris((trimethylsilyl)oxy)-6-(((trimethylsilyl)oxy)methyl)tetrahydro-2H-pyran-2-one (In-situ Formula III) (1.3 eqv) in Toluene (2 vol) was added drop wise over a period of 1 to 2 hours and maintained for 2 hour at the same temperature. Methane sulfonic acid (2 eqv) in Methanol (3 vol) solution was added to reaction mass over a period of 1 to 2 h at below -50oC. Slowly warmed the reaction mass to 25 to 30oC then Methane sulfonic acid (2 eqv) in Methanol (3 vol) solution was added to reaction mass over a period of 1 to 2 h at the same temperature and stirred for 36 hours at 25 to 35°C. After completion of reaction, the reaction mass was cooled to 0 to 10°C, 3% aq.Sodium hydroxide solution (5 vol) was added and warmed to room temperature, stirred for 10 min then separated the aqueous layer and organic layer. The compound was extracted with aqueous methanol (Methanol: Water: 8:1) (3 x 2 vol) from organic layer. Combined aqueous layers and distilled the solvents and the obtained compound was extracted from Dichloromethane (3 x 3 vol). The combined Dichloromethane layer was washed with 10% aq.Sodium chloride solution (3 vol). Water was removed through azeotropic distillation at reflux temperature, cooled the reaction mass to -15 to -5oC then Triethylsilane (1.53 eqv) followed by Boron trifluoride etherate (1.53 eqv) were added and maintained for 3 hours at the same temperature. Slowly warmed the reaction mass to -5 to 5oC and stirred for 2 hours at the same temperature. After completion of reaction, 8% aqueous sodium bicarbonate solution (10 vol) was added, then the organic layer was separated and successively washed with water (2 x 3 vol). The organic layer was separated, dried over sodium sulfate and distilled off completely followed by co-distilled with Ethyl acetate (2 x 0.5 vol) under vacuum to obtain Dapagliflozin (in-situ). The Dapagliflozin (in-situ) was dissolved into Ethyl acetate (5 vol) and (S/RS)-1,2-propanediol (1.5 eqv), water (1.1 eqv) were added to the reaction mixture at room temperature, stirred for 10 min followed by Cyclohexane (5 vol) was added at room temperature, stirred for 2 hours. The solid obtained was filtered, washed with Ethyl acetate/Cyclohexane (1:1) to obtain Dapagliflozin (S/RS)-1,2-propanediol monohydrate (Formula Ia). Methyl tert-butyl ether (325 ml; 5 vol) was added at room temperature, heated to 50 to 60°C and stirred for 30 min to 1 hour to obtain a clear solution. The clear solution was dropwise addition to n-Heptane (975 ml; 15 vol) at room temperature under nitrogen atmosphere, stirred for 2 hours at room temperature. The solid obtained was filtered, washed with n-Heptane (65 ml; 1 vol) and dried to obtained the title compound.
Yield: 44.9 g (85%); Purity by HPLC: >99%

Example-6:
Preparation of amorphous Dapagliflozin (Formula I):
To a clean and dry RBF, (S/RS)-1,2-propanediol monohydrate (65 g) obtained in example-3 and Methyl tert-butyl ether (325 ml; 5 vol) was added at room temperature, heated to 50 to 60°C and stirred for 30 min to 1 hour to obtain a clear solution. The clear solution was dropwise addition to n-Heptane (975 ml; 15 vol) at room temperature under nitrogen atmosphere, stirred for 2 hours at room temperature. The solid obtained was filtered, washed with n-Heptane (65 ml; 1 vol) and dried to obtained the title compound.
Yield: 44.9 g (85%); Purity by HPLC: >99%

Dated this: 03rd day of January, 2024.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081
,CLAIMS:We claim:
1. An improved process for the preparation of Dapagliflozin (S/RS)-1,2-propanediol or its hydrate of formula Ia, in a single isolation step, which comprises:
a) reacting D(+)Gluconolactone compound of formula II with Hexamethyldisilazane or Trimethylsilyl chloride in a suitable solvent to provide a compound of formula III (in-situ);

b) condensing the compound of formula III (in-situ) with a compound of formula IV with condensing agent in presence of suitable solvent followed by desilylation using suitable acid and suitable solvent to provide a compound of formula V (in-situ);

c) methylating the compound of formula V (in-situ) with methanol in presence of acid to provide a compound of formula VI (in-situ); optionally washing with aqueous alcohol solvent;

d) reducing the compound of formula VI (in-situ) with a reducing agent and Lewis acid in presence of a suitable solvent to provide a Dapagliflozin of formula VII (in-situ); and

e) treating Dapagliflozin of formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide a Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia.

2. The process as claimed in claim 1, wherein in step b) the condensing agent is selected from Grignard reagent such as n-butyllithium, sec- butyllithium or tert-butyllithium or Lithium reagent such as C3-4-alkylmagnesium chloride or bromide.

3. The process as claimed in claim 1, wherein in steps b) and c) the acid is selected from methane sulfonic acid, toluene sulfonic acid, sulfuric acid, acetic acid, trifluoroacetic acid or hydrochloric acid.

4. The process as claimed in claim 1, wherein in step d) the suitable reducing agent is selected from silanes, borane complexes or aluminium hydrides; and the Lewis acid is selected from aluminium chloride, boron trifluoride etherate, trimethylsilyl triflate, titanium tetrachloride, tin tetrachloride, scandium triflate, zinc iodide or copper (II) triflate.

5. The process as claimed in claim 1, wherein in steps a), b) and e) the suitable solvent is selected from alcohols, ethers, amides, esters, nitriles sulfoxides, ketones, hydrocarbons, halogenated hydrocarbons, water or mixture thereof, and wherein in step d) the suitable solvent is dichloromethane.

6. An improved process for the preparation of O-methylated Dapagliflozin of formula VI or Dapagliflozin of formula I or it’s solvates/ hydrates thereof, which is free of acid impurity;

Acid Impurity
comprising reacting compound of formula V with a mixture of methanesulphonic acid and methanol in a single lot to provide a compound of formula VI.

7. An improved process for the preparation of Dapagliflozin of formula I or it’s solvated forms/hydrates thereof, which is substantially free of furanose impurity 1 & 2:

Furanose Impurity 1

Furanose Impurity 2
comprising reducing O-methylated Dapagliflozin of formula VI with reducing agent and Lewis acid in presence of dichloromethane as a single reaction solvent to provide a Dapagliflozin of formula I or it’s solvated forms/ hydrates thereof.

8. An improved process for the preparation of amorphous Dapagliflozin of formula I, which comprises:
a) reducing the compound of formula VI with a reducing agent and Lewis acid in presence of dichloromethane to provide Dapagliflozin of formula VII (in-situ);

b) treating Dapagliflozin of formula VII (in-situ) with (S/RS)-1,2-propanediol in presence of a suitable solvent to provide Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia;

c) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with suitable solvent to provide a reaction mixture;
d) heating and stirring the reaction mixture at 50°C to 70°C;
e) slowly adding reaction mixture to suitable solvent at room temperature; and
f) isolating amorphous Dapagliflozin of formula I.

9. An acid impurity, 4-chloro-3-(4-ethoxybenzyl)benzoic acid.

10. An improved process for the preparation of amorphous Dapagliflozin of formula I, which comprises:
a) treating Dapagliflozin (S/RS)-1,2-propanediol or its monohydrate of formula Ia with Methyl tert-butyl ether to provide a reaction mixture;
b) heating and stirring the reaction mixture at 50°C to 70°C;
c) slowly adding reaction mixture to n-Heptane at room temperature; and
d) isolating amorphous Dapagliflozin of formula I.

Dated this: 03rd day of January, 2024.
Signature:
Name: Mr. Rama Rao Javvaji
Patent Agent Reg. No.: IN/PA-1669
GRANULES INDIA LIMITED
My Home Hub, 2nd Floor, 3rd Block,
Madhapur, Hyderabad, Telangana, INDIA-500 081