FIELD OF THE INVENTION
The present invention relates to novel compounds of Formula I, II and III and process for preparation thereof. Further, the present invention relates to use of compounds of Formula I, II and III as intermediates for the preparation of compounds useful for both SGLT1 and SGLT2 inhibition, such as Sotagliflozin,
.
Particularly, the present invention relates to a novel process for the preparation of Sotagliflozin by using novel compounds of Formula I, II and III.

BACKGROUND OF THE INVENTION
SGLT2 is a member of the sodium glucose co-transporter family which are sodium-dependent glucose transport proteins. SGLT2 is the major co-transporter involved in glucose reabsorption in the kidney. SGLT2 inhibitors are the compounds that lead to the reduction in blood glucose levels and therefore, SGLT2 inhibitors have potential use in the treatment of type II diabetes. SGLT2 enhances glycemic control as well as reduce body weight and systolic and diastolic blood pressure.

Sotagliflozin chemically known as (2S,3R,4R,5S,6R)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol, is an orally bioavailable inhibitor of the sodium-glucose co-transporter subtype 1 (SGLT1) and subtype 2 (SGLT2), with potential antihyperglycemic activity.

US patent 8,026,347 discloses a process of preparing sotagliflozin. The scheme-1 mentioned below illustrates the method of the preparation of sotagliflozin as disclosed in US’347.
Scheme-1:

.

Based on the process known from the prior published literature, the present invention is focused towards the development of a simple process for the preparation of Sotagliflozin using novel intermediates.

OBJECT OF THE INVENTION
The main object of the present invention is to develop novel compounds of Formula I, II, III that can be used as intermediates for the synthesis of compounds useful for both SGLT1 and SGLT2 inhibition, such as Sotagliflozin,

, , and .

SUMMARY OF THE INVENTION
The present invention relates to the novel compounds of Formula I, II and III and use of said compounds as intermediates for the preparation of compounds useful for both SGLT1 and SGLT2 inhibition, such as Sotagliflozin.

, ,

Accordingly, in the main aspect, the present invention provides novel compounds of Formula I,

wherein R1 is selected from hydrogen; hydroxyl; alkoxy; haloalkoxy or hydroxyalkoxy group; aralkyl; halide; (un)substituted amine; heterocyclic rings; cycloalkyl ring with one or more carbon optionally substituted with heteroatom; -OCORA; -ORB; aryl optionally substituted with one to three substituents independently selected from halogen and alkyl, (un)protected hydroxyl alkyl group;
wherein RA and RB are independently selected from straight or branched chain alkyl; (un)substituted aryl or heterocyclic rings or heteroaryl rings;
P1 and P2 are independently selected from hydrogen; alkyl; (un)substituted aryl; (un)substituted aralkyl; (un)substituted aromatic heterocyclic ring; C3-C7 cycloalkyl ring with one or more carbon atom optionally substituted with heteroatom such as N, O, S, wherein said cycloalkyl ring may be substituted with C1-C4 alkyl group or C1-C4 alkoxy group; P1 and P2 together may form C3-C7 cyclic rings; and
Q is –CH2 or –C=O.

In another aspect, the present invention provides novel compounds of Formula II,

wherein, P3 is selected from hydrogen or a hydroxyl protecting group; R2 is selected from heterocyclic rings, cycloalkyl ring with one or more carbon optionally substituted with heteroatom, aryl optionally substituted with one to three substituents selected from halogen, alkyl, haloalkyl, and (un)protected hydroxyl alkyl group.

In another aspect, the present invention provides novel compounds of Formula III,

wherein, P3 is selected from hydrogen or a hydroxyl protecting group; R2 is selected from heterocyclic rings, cycloalkyl ring with one or more carbon optionally substituted with heteroatom, aryl optionally substituted with one to three substituents selected from halogen, alkyl, haloalkyl, and (un)protected hydroxyl alkyl group.

In one another aspect, the present invention provides a process for preparation of Sotagliflozin of Formula A, wherein said process comprising the condensation of compound of Formula XIII with compound of Formula XVI as represented below:
,
OR, by halogenating compound of Formula XV in presence of halogenating agent to give compound of Formula XVII or XXV followed by reaction with compound of Formula XVIII to give Sotagliflozin of Formula A:

DETAILED DESCRIPTION
Definitions:
As used herein, unless otherwise indicated, the term “alkyl” alone or in combination refers to a monovalent saturated aliphatic hydrocarbon.

As used herein, unless otherwise indicated, the terms “alkoxy” refers to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, neopentoxy, tertiary pentoxy, hexoxy, isohexoxy, heptoxy, octoxy and the like.

As used herein, unless otherwise indicated, the terms “hydroxyalkoxy” and “hydroxyalkyloxy” alone or in combination refers to hydroxymethoxy, hydroxyethoxy, hydroxyethoxy, hydroxypropoxy, hydroxyisopropoxy, hydroxybutoxy, hydroxyisobutoxy, hydroxy-tert-butoxy, hydroxypentoxy, hydroxyisopentoxy, hydroxyhexoxy, hydroxyisohexoxy, hydroxyheptoxy, hydroxyoctoxy and the like.

As used herein, unless otherwise indicated, the term “cycloalkyl” alone or in combination refers to a monovalent alicyclic saturated hydrocarbon radical having three or more carbons forming a carbocyclic ring.

As used herein, unless otherwise indicated, the term “heterocycloalkyl” alone or in combination refers to a cycloalkyl group in which one or more carbons in the ring is replaced by a heteroatom selected from N, S and O.

As used herein, the term “aryl” refers to a monocyclic, bicyclic, tricyclic or greater, aromatic ring assembly.

As used herein, the term “heteroaryl” or “aromatic heterocyclic group” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing heteroatom such as N, O or S.

Accordingly, in one embodiment, the present invention provides novel compounds of Formula I,

wherein R1, P1, P2 and Q are as defined above.

In another embodiment, the present invention provides compounds of Formula I, wherein said compounds are selected from the group comprising of compound of Formula IV, V, VI, VII, XXI, XXII, XXIII, XXIV, and XXI;
, , , ,
, , ,and .

In further embodiment, the present invention provides a novel compound of Formula II,

wherein, P3 and R2 are as defined above.

In another embodiment, the present invention provides compounds of Formula II, wherein said compounds are selected from the group comprising of compound of Formula VIII, IX, X and XI;
, , , and .

In yet another embodiment, the present invention provides a compound of Formula III,

wherein, R2 and P3 are as defined above.

In another embodiment, the present invention provides compounds of Formula III, wherein said compounds are selected from the group comprising of compound of Formula XII, XIII, XIV, XV, XVII, and XXV;
, , , , , and .

In one another embodiment, the present invention provides a process of preparation of Sotagliflozin of Formula A, wherein said process comprising the condensation of compound of Formula XIII with compound of Formula XVI as represented below:
,
OR, by halogenating compound of Formula XV in presence of halogenating agent to give compound of Formula XVII or XXV followed by reaction with compound of Formula XVIII to give Sotagliflozin of Formula A:
.

In another embodiment, the condensation of compound of Formula XIII with compound of Formula XVI is carried out in presence of lewis acid such as AlX3, FeX3, BX3, BX3.OEt2, ZnX2, InX3, SbX5, TiX4, BiX3, SnX4, GaX3, ScX3, HfX4, wherein X is halogen, OTf; bronsted acids such as HF, H2SO4, H3PO4; and acidic oxides such as silica-alumina type or cation-exchange resins.

The said condensation of compound of Formula XIII with compound of Formula XVI is carried out in presence of organic solvent selected from the group comprising of halogenated solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, benzene, nitrobenzene, hexane, chlorobenzene, carbon disulphide, and mixture thereof.

In further embodiment, the halogenating agent used for preparation of compound of Formula XVII is selected from the group comprising of hydrogen bromide, NBS, 1,3-dibromo-5,5-dimethylhydantoin, and tetrabutyl ammonium bromide.

In further embodiment, the condensation of compound of Formula XVIII with compound of Formula XVII or XXV is performed in presence of lewis acid such as AlX3, FeX3, BX3, BX3.OEt2, ZnX2, InX3, SbX5, TiX4, BiX3, SnX4, GaX3, ScX3, HfX4, wherein X: halogen, OTf; bronsted acids such as HF, H2SO4, H3PO4; and acidic oxides such as silica-alumina type or cation-exchange resins. The said condensation is carried out in presence of organic solvent selected from the group comprising of halogenated solvent such as dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, tetrahydrofuran, benzene, nitrobenzene, hexane, chlorobenzene, carbon disulphide, and mixture thereof.

In one another embodiment, the present invention provides a process for the preparation of Sotagliflozin of Formula A by employing novel compounds of Formula IV, V, VI, VIII, IX, XII and XIII, wherein said process comprising of reaction steps as mentioned in the scheme below:


.

In one another embodiment, the present invention provides a process of preparation of Sotagliflozin of Formula A by using compounds of Formula IV, V, VII, X, XI, XIV, XV, and XVII wherein said process comprising of reaction steps as mentioned in the scheme below:


.

In one another embodiment, the present invention provides a process of preparation of Sotagliflozin of Formula A by using compounds of Formula I, wherein P1 and P2 together forms cyclohexane group.

Accordingly, in one embodiment the present invention provides a process of preparation of Sotagliflozin of Formula A by using compounds of Formula XXII, XXIII, VIII, IX, XII and XIII as represented in the scheme below:


.

In one another embodiment, the present invention provides a novel process of preparation of Sotagliflozin by using compounds of Formula XXII, XXIV, X, XI, XIV, XV, and XXV as represented in the scheme below:


.

In a preferred embodiment, the chlorinating agent used for chlorinating compound of formula XV is selected from the group comprising of thionyl chloride, phosphorus pentachloride, dichloroiodobenzene, potassium chloride, trichloroisocyanuric acid, N-chlorosuccinamide and the like.

In still another embodiment, the present invention provides amorphous form of Sotagliflozin.
In a preferred embodiment, the present invention provides a substantially pure amorphous form of Sotagliflozin, wherein said amorphous form is substantially free of any crystalline form.

In further embodiment, the present invention provides Sotagliflozin of Formula A characterized by particle size distribution wherein, d90 is between 0.1µm to 200µm, specifically d90 is between 2.0 µm to 150µm.

In one another embodiment, the Sotagliflozin prepared as per the process of the present invention is characterized with purity above 99%, preferably above 99.5%, and more preferably above 99.9%.

In further embodiment, the present invention provides a substantially pure crystalline form of Sotagliflozin.

In a preferred embodiment, the present invention provides a substantially pure crystalline form of Sotagliflozin, wherein said crystalline form is substantially free of amorphous form.

In another preferred embodiment, the present invention provides a solid dispersion of Sotagliflozin together with a pharmaceutically acceptable carrier, processes for preparation thereof, and pharmaceutical compositions prepared therefrom.

In one another embodiment, the present invention further provides a composition comprising Sotagliflozin and one or more pharmaceutical acceptable excipients.

In one another embodiment, the present invention further provides use of Sotagliflozin in the treatment of type I or type II diabetes.

The embodiments of the present invention are exemplified herein below:
EXAMPLES
Example 1: Synthesis of {(3aS, 5S, 6R, 6aS)-2-cyclohexyl-5-(hydroxymethyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol} of Formula XXI
To a 5.0 L, three-necked round bottom flask fitted with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose of Formula XIX (150.1 g, 1.0 M), cyclohexanecarboxaldehyde of Formula XX (2.0 L) and anhydrous MgSO4 powder (240.7 g, 2.0 M, 2.0 eq.). The suspension was stirred at an ambient temperature and then added concentrated H2SO4 (14.9 ml, 0.28 M, 0.28 eq.) and the reaction was allowed to stir at ambient temperature overnight. After completion of reaction, the reaction mixture was filtered and the collected solids were washed twice with cyclohexanecarboxaldehyde (150 ml ×2). The filtrate was neutralized with concentrated NH4OH solution (10 ml) to pH 8.5 to 9.0. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford an oily crude material (250 g). The oil was suspended in water (750 ml) stirring in a 2.0 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (~50 ml) and stirred at room temperature for 6 h until GC showed sufficient conversion of the oily crude material to compound of Formula XXI. The reaction mass was neutralized by the addition of 50% w/w aq. K2HPO4 until pH is equal to 7. The solvent was then evaporated and ethyl acetate (300 ml) was added. The resulting suspension was filtered. The filtrate was concentrated in vacuo to afford an oil (Compound of Formula XXI: 195.4 g, 80% yield, 95 % on GC).
Example 2: Synthesis of {(3aS, 5R, 6S, 6aS)-2-cyclohexyl-6-hydroxytetrahydrofuro[2,3-d][1,3]dioxole-5-carboxylic acid} of Formula IV:
To a solution of compound of Formula XXI (100 g, 0.41 M) in acetone (1.5 L) and H2O (500 ml) was added NaHCO3 (103.3 g, 1.23 M, 3.0 eq.), NaBr (8.4 g, 0.082 M, 20 mol%) and TEMPO (1.3 g, 0.0082 M, 2 mol %) at 20°C. The mixture was cooled to 0-5°C and solid trichloroisocyanuric acid (95.3 g, 0.41 M, 1.0 eq.) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (80 mL) was added and the mixture was stirred at 20°C for 1 h. The mixture was filtered, washed with acetone (200 ml ×2). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (1.0L ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (500 ml) was added and the mixture was filtered. The filtrate was then concentrated and the desired acid (compound of Formula IV: 79.3 g, 75% yield, 97 % on GC) was obtained as a solid.
Example 3: Synthesis of {(3aS, 5R, 6S, 6aS)-2-cyclohexyl-5-(morpholin-4-ylcarbonyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-ol} of Formula V:
To a solution of compound of Formula IV (75 g, 0.29 M) in THF (1.5 L) was added TBTU (139.6 g, 0.43 M, 1.5 eq.), N-methylmorpholine (43.4 g, 0.43 M, 1.5 eq.) and the mixture was stirred at 20°C for 30 min. Morpholine (37.4 g, 0.43 M, 1.5 eq.) was then added, and the reaction mixture was stirred at 20° C for 6h. The solid was filtered off and the cake was washed with THF (150 ml ×2). The filtrate was concentrated under vacuum. Silica gel column chromatography of the resulting residue afforded the desired morpholine amide (compound of Formula V) as a solid material (57g, 60 % yield, 95 % on GC).
Example 4: Synthesis of {(4-chloro-3-methylphenyl)[(3aS, 5R, 6S, 6aS)-2-cyclohexyl-6-hydroxytetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanone} of Formula VII:
To a solution of 4-bromo-1-chloro-2-methylbenzene (compound of Formula XXIII, 78 g, 0.38 M, 2.5 eq.) in THF (200 ml) was added iPrMgCl (2.0 M in THF, 300 ml, 0.6 M, 4.0 eq.) at 0-5°C and the mixture was stirred for 1.5 h at 0-5°C. A solution of compound of Formula V (50 g, 0.15 M) in THF (300 mL) was added drop wise at 0-5°C and the mixture was kept stirring for 1 h. Reaction mass was then warmed to 20°C and stirred for 2 hours. The reaction was quenched with saturated aq. NH4Cl (250 ml), extracted with MTBE (100 ml ×3), washed with brine (100 ml ×2). The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (compound of Formula VII: 45.9 g, 82% yield, 96% on HPLC).
Example 5: Synthesis of {(2S, 3S, 4R, 5R, 6S)-6-(4-chloro-3-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrol of Formula X:
To a solution of the compound of Formula VII (50 g, 0.136 M) in MeOH (500 ml) was added CeCl3.7H2O (49.4 g, 0.16 M, 1.2 eq.) and the mixture was stirred at 20° C until all solids were dissolved. The mixture was then cooled to -78°C and added NaBH4 (6.0 g, 0.16 M, 1.2 eq.) in portions so that the temperature of the reaction does not exceed -70°C. The mixture was stirred at -78°C for 1 hour and then gradually warmed to 0°C. Reaction mass was quenched with saturated aq. NH4Cl (250 ml). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (500 ml ×2) and washed with brine (250 ml). The combined organics were concentrated under vacuum to afford the alcohol intermediate (44.9 g) as colorless oil. To the oily mass was added AcOH (300 ml) and H2O (200 ml). The reaction mixture was heated to 100°C and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated under vacuum to end up with an oily material (compound of Formula X: 30.3 g, 81% yield, 94% on HPLC).
Example 6: Synthesis of {(2R, 3S, 5R, 6S)-6-(4-chloro-3-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetrabenzoate} of Formula XI
To compound of Formula X (50 g, 0.18 M) in DCM (500 ml), was added pyridine (250 ml) and the mixture was cooled to 0°C. Benzoyl chloride (169.1 ml, 1.45 M, 8.0 eq.) was then added drop wise and the mixture was warmed to 20°C and stirred for 12 h. The reaction was quenched with H2O (250 ml) and diluted with EtOAc (400 ml). The organic layer was separated and concentrated under vacuum to remove EtOAc and pyridine. The residue was diluted with EtOAc (400 ml) and washed with aq. NaHSO4 (1N, 200 ml ×2) and brine (150 ml). The organic layer was concentrated to afford the tetrabenzoate intermediate (compound of Formula XI: 108.1 g, 86% yield, 93% on HPLC).
Example 7: Synthesis of {(2S, 3R, 5S, 6R)-2-(4-chloro-3-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,5-triyl tribenzoate} of Formula XIV
To a solution of compound of Formula XI, 50 g, 0.072 M) and thiourea (11.0 g, 0.144M, 2.0eq.) in dioxane (200 ml) was added trimethylsilyl trifluoromethanesulfonate (19.9 ml, 0.11 M, 1.5 eq.). The reaction mixture was heated to 80°C and stirred for 4 hours. The mixture was cooled to 20°C and MeI (11.2 ml, 0.18 M, 2.5 eq.) and N, N-diisopropylethylamine (62.7 ml, 0.36 M, 5.0 eq.) were added. The mixture was stirred at 20°C for 3 h. The mixture was then diluted with methyl tertiary-butyl ether (500 ml) and washed with H2O (250 ml ×2). The organic layer was separated and concentrated under vacuum to give a solid. To this solid was added MeOH (250 ml) and the mixture was reslurried at 60°C for 2 h. The material was cooled to 0°C and stirred for 1 h. The mixture was filtered and the cake was washed with MeOH (25 ml ×3). The cake was dried under vacuum at 45°C overnight to afford the desired tribenzoate (compound of Formula XIV: 29 g, 65% yield, 95% on HPLC).
Example 8: Synthesis of {(2S, 3R, 4R, 5S, 6R)-2-(4-chloro-3-methylphenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol} of Formula XV
To a slurry of compound of Formula XIV (25 g, 0.04 M) in MeOH (250 ml) was added NaOMe in MeOH (25 wt%, 15 ml) at 20°C and the mixture was stirred at 20°C for 2 hours until all solids disappeared. The mixture was then concentrated to 100 mL, added to H2O (250 ml) and stirred for 1 hour. The solid was filtered and washed with H2O (25 ml ×3) and the cake was dried under vacuum at 45°C overnight to afford the compound of Formula XV (11.3 g, 92% yield, 98% on HPLC).
Example 9: Synthesis of {(2S, 3R, 4R, 5S, 6R)-2-[3-(bromomethyl)-4-chlorophenyl]-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol} of Formula XVII
To a suspension of aluminium (III) chloride (0.9g, 0.0065 M, 10 mol%) in dichloromethane (200mL) was added a solution of compound of Formula XV (20g, 0.065 M) and 1,3-dibromo-5,5-dimethylhydantoin (9.4g, 0.0328 M, 0.5 eq.) in dichloromethane (100 mL) at room temperature. The mixture was stirred for 6 h at room temperature under room light. The reaction was quenched with saturated aq. NaHCO3 solution and extracted by ethyl acetate (100 ml ×3). Organic layers were combined and evaporated under vacuum to obtain compound of Formula XVII (18.9 g, 75% yield, 94% on HPLC).
Example 10: Synthesis of Sotagliflozin of Formula A:
In a 4-Neck, 1.0 L RBF was taken dichloromethane (250 ml) and AlCl3 (20.8 g, 0.15 M, 1.2 eq.). Cooled the reaction mass to 0°C. Added ethoxybenzene (compound of Formula XVIII, 17.5 g, 0.14 M, 1.1 eq.) drop wise maintaining the temperature below 0°C. Stirred the reaction mass for 1 h. To the reaction mass, added compound of Formula XVII (50 g, 0.13 M) at 0±5°C. Slowly raised the temperature to 20-25°C and stirred the reaction mass for 12 h. Quenched the reaction mass into ice cooled water (200 ml) at 0-20°C and stirred for 30 min at 10-20°C. Add conc. HCl (100 mL) into the mass slowly at 10-20°C. Stirred the mass for 10-15 min at 10-20°C and separated the layers. Aqueous layer was again extracted by ethylacetate (50 ml ×2). Organics were combined and concentrated under vacuum. To the concentrate, added methanol (150 ml) and stirred for 15 min at 25-30°C. Added water (500 ml) and stirred for 1 hour. The solid was filtered and washed with water (50 ml ×3). Cake was finally dried under vacuum at 45°C to obtain the Sotagliflozin of Formula A (31.5 g, 57 % yield, 99.9 % on HPLC).
Example 11: Synthesis of {(4-chlorophenyl)[(3aS, 5R, 6S, 6aS)-2-cyclohexyl-6-hydroxytetrahydrofuro[2,3-d][1,3]dioxol-5-yl]methanone} of Formula VI
To a solution of 4-chlorobromobenzene (compound of Formula XXII, 72.7 g, 0.38 M, 2.5 eq.) in THF (200 ml)was added iPrMgCl (2.0 M in THF, 300 ml, 0.6 M, 4.0 eq.) at 0-5°C, and the mixture was stirred for 1.5 h at 0-5°C. A solution of compound of Formula V (50 g, 0.15 M) in THF (300 mL) was added dropwise at 0-5°C and the mixture was kept stirring for 1 h. Reaction mass was then warmed to 20°C and stirred for 2 h. The reaction was quenched with saturated aq. NH4Cl (250 ml), extracted with MTBE (100 ml ×3) and washed with brine (100 ml ×2). The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (compound of Formula VI: 43.1 g, 80 %yield, 93 % on HPLC).
Example 12: Synthesis of {(2S, 3S, 4R, 5R, 6S)-6-(4-chlorophenyl)tetrahydro-2H-pyran-2,3,4,5-tetrol} of Formula VIII
To a solution of the compound of Formula VI (50 g, 0.14 M) in MeOH (500 ml) was added CeCl3.7H2O (51.6 g, 0.17 M, 1.2 eq.) and the mixture was stirred at 20°C until all solids were dissolved. The mixture was then cooled to -78°C and added NaBH4 (6.4 g, 0.17 M, 1.2 eq.) in portions so that the temperature of the reaction did not exceed -70°C. The mixture was stirred at -78°C for 1 hour and then gradually warmed to 0°C. Reaction mass was quenched with saturated aq. NH4Cl (250 ml). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (500 ml ×2) and washed with brine (250 ml). The combined organics were concentrated under vacuum to afford the alcohol intermediate (47.8 g) as colourless oil. To the oily mass was added AcOH (300 ml) and H2O (200 ml).The reaction mixture was heated to 100°C and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated under vacuum to end up with an oily material (compound of Formula VIII: 31.4 g, 85% yield, 92% on HPLC).
Example 13: Synthesis of {(2R, 3S, 4R, 5S, 6S)-6-(4-chlorophenyl)tetrahydro-2H-pyran-2,3,4,5-tetrayl tetrabenzoate} of Formula IX
To compound of Formula VIII (50 g, 0.19 M) in DCM (500 ml), was added pyridine (250 ml) and the mixture was cooled to 0°C. Benzoyl chloride (177.6 ml, 1.53 M, 8.0 eq.) was then added dropwise and the mixture was warmed to 20°C and stirred for 12 h. The reaction was quenched with H2O (250 ml) and diluted with EtOAc (400 ml). The organic layer was separated and concentrated under vacuum to remove EtOAc and pyridine. The residue was diluted with EtOAc (400 ml) and washed with aq. NaHSO4 (1N, 200 ml ×2) and brine (150 ml). The organic layer was concentrated to afford the tetrabenzoate intermediate (compound of Formula IX: 103.0 g, 85 % yield, 96 % on HPLC).
Example 14: Synthesis of {(2S, 3S, 4R, 5S, 6R)-2-(4-chlorophenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triyl tribenzoate} of Formula XII
To a solution of compound of Formula IX (50 g, 0.074 M) and thiourea (11.4 g, 0.147M, 2.0eq.) in dioxane (200ml) was added trimethylsilyltrifluoro methanesulfonate (19.9 ml, 0.11 M, 1.5 eq.). The reaction mixture was heated to 80°C and stirred for 4 hours. The mixture was cooled to 20°C and MeI (11.5 ml, 0.185 M, 2.5 eq.) and N,N-diisopropylethylamine (64.4 ml, 0.37 M, 5.0 eq.) were added. The mixture was stirred at 20°C for 3 h. The mixture was then diluted with methyl tertiary-butyl ether (500 ml) and washed with H2O (250 ml×2). The organic layer was separated and concentrated under vacuum to give a solid. To this solid was added MeOH (250 ml) and the mixture was re-slurried at 60°C for 2 h. The material was cooled to 0°C and stirred for 1 h. The mixture was filtered and the cake was washed with MeOH (25 ml ×3). The cake was dried under vacuum at 45°C overnight to afford the desired tribenzoate (compound of Formula XII: 26.7 g, 60% yield, 97% on HPLC).
Example 15: Synthesis of compound of Formula XIII, {(2S, 3R, 4R, 5S, 6R)-2-(4-chlorophenyl)-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol}
To a slurry of compound of Formula XII (25 g, 0.041 M) in MeOH (250 ml) was added NaOMe in MeOH (25 wt%, 15 ml) at 20°C and the mixture was stirred at 20°C for 2 hours until all the solids disappeared. The mixture was then concentrated to 100 mL, added to H2O (250 ml) and stirred for 1 hour. The solid was filtered and washed with H2O (25 ml ×3) and the cake was dried under vacuum at 45°C overnight to afford Formula XIII (11.4 g, 95% yield, 93% on HPLC).
Example 16: Synthesis of Sotagliflozin of Formula A
In a 4-Neck, 1.0 L RBF was taken dichloromethane (250 ml) and AlCl3 (27.5 g, 0.2 M, 1.2 eq.). Cooled the reaction mass to 0°C. Added 1-(bromomethyl)-4-ethoxybenzene (compound of Formula XVI, 40.7 g, 0.19 M, 1.1 eq.) drop wise maintaining the temperature below 0°C. Stirred the reaction mass for 1 h. To the reaction mass, added compound of Formula XIII (50 g, 0.172 M) at 0±5°C. Slowly raised the temperature to 20-25°C and stirred the reaction mass for 12 h. Quenched the reaction mass into ice cooled water (200 ml) at 0-20°C and stirred for 30 min at 10-20°C. Added conc. HCl (100 mL) into the mass slowly at 10-20°C. Stirred the mass for 10-15 min at 10-20 °C and separated the layers. Aqueous layer was again extracted by ethylacetate (50 ml ×2). Organics were combined and concentrated under vacuum. To the concentrate, added methanol (150 ml) and stirred for 15 min at 25-30°C. Added water (500 ml) and stirred for 1 hour. The solid was filtered and washed with water (50 ml ×3). Cake was finally dried under vacuum at 45°C to obtain the Sotagliflozin of Formula A (40 g, 55% yield, 99.9% on HPLC).
Example 17: Synthesis of compound of Formula XXVI {(3a'S,5'S,6'R,6a'S)-5'-(hydroxymethyl)tetrahydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxol]-6'-ol)}

To a 5.0 L, three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler was charged L-(-)-xylose of Formula XIX (150.1 g, 1.0 M), cyclohexanone (2.0 L) and anhydrous MgSO4 powder (240.7 g, 2.0 M, 2.0 eq.). The suspension was set stirring at ambient temperature and then concentrated H2SO4 (14.9 ml, 0.28 M, 0.28 eq.) was added and the reaction was allowed to stir at ambient temperature overnight. After 16 hours, TLC suggested all L-xylose had been consumed. The reaction mixture was filtered and the collected solids were washed twice with cyclohexanone (150 ml ×2).The filtrate was neutralized with concentrated NH4OH solution (10 ml) to pH 8.5 to 9.0. After stirring for 10 min, the suspended solids were removed by filtration. The filtrate was concentrated to afford an oily crude of Formula XXVII (250 g). The oil was suspended in water (750 ml) stirring in a 2.0 L three-necked round bottom flask with mechanical stirrer, rubber septum with temperature probe and gas bubbler. The pH was adjusted from 9 to 2 with 1N aq. HCl (~50 ml) and stirred at room temperature for 6 h until GC showed sufficient conversion. The reaction mass was neutralized by the addition of 50% w/w aq. K2HPO4 until pH=7. The solvent was then evaporated and ethyl acetate (300 ml) was added. The resulting suspension was filtered. The filtrate was concentrated in vacuo to afford an oily mass (Compound of Formula XXVIII: 184.2 g, 80% yield, 95 % on GC).
Example 18: Synthesis of compound of Formula XXIX {(3a'S,5'R,6'S,6a'S)-6'-hydroxytetrahydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxole]-5'-carboxylic acid)}

To a solution of compound of Formula XXVIII (100 g, 0.43 M) in acetone (1.5 L) and H2O (500 ml) was added NaHCO3 (108.3 g, 1.29 M, 3.0 eq.), NaBr (8.8 g, 0.086 M, 20 mol %) and TEMPO (1.36 g, 0.0086 M, 2 mol %) at 20° C. The mixture was cooled to 0-5°C and trichloroisocyanuric acid (99.9 g, 0.43 M, 1.0 eq.) was then added in portions. The suspension was stirred at 20°C for 24h. Methanol (80 mL) was added and the mixture was stirred at 20°C for 1 h. The mixture was filtered, washed with acetone (200 ml ×2). The organic solvent was removed under vacuum and the aqueous layer was extracted with EtOAc (1.0L ×3) and the combined organic layers were concentrated to afford an oily mixture with some solid residue. Acetone (500 ml) was added and the mixture was filtered. The filtrate was then concentrated and the desired acid (compound of Formula XXIX) (79.5 g, 75% yield, 97% on GC) was obtained as a solid.
Example 19: Synthesis of compound of Formula XXII {[(3a'S,5'R,6'S,6a'S)-6'-hydroxytetrahydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxol]-5'-yl](morpholin-4-yl)methanone}
To a solution of compound of Formula XXVII (75 g, 0.3 M) in THF (1.5 L) was added TBTU (146.1 g, 0.45 M, 1.5 eq.), N-methylmorpholine (45.4 g, 0.45 M, 1.5 eq.) and the mixture was stirred at 20°C for 30 min. Morpholine (39.1 g, 0.45 M, 1.5 eq.) was then added, and the reaction mixture was stirred at 20°C for 6h. The solid was filtered off and the cake was washed with THF (150 ml ×2). The filtrate was concentrated under vacuum. Silica gel column chromatography of the resulting residue afforded us the desired morpholine amide (compound of Formula XXII) as solid (57.7 g, 60% yield, 95% on GC).
Example 20: Synthesis of compound of Formula XXIII {(4-chlorophenyl)[(3a'S,5'R,6'S,6a'S)-6'-hydroxytetrahydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxol]-5'-yl]methanone}
To a solution of 4-chlorobromobenzene (76.5 g, 0.4 M, 2.5 eq.) in THF (200 ml) was added iPrMgCl (2.0 M in THF, 320 ml, 0.64 M, 4.0 eq.) at 0-5 °C, and the mixture was stirred for 1.5 h at 0-5°C. A solution of compound of Formula XXII (50 g, 0.16 M) in THF (300 mL) was added dropwise at 0-5 °C and the mixture was kept stirring for 1 h. Reaction mass was then warmed to 20°C and stirred for 2 h. The reaction was quenched with saturated aq. NH4Cl (250 ml), extracted with MTBE (100 ml ×3) and washed with brine (100 ml ×2). The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (compound of Formula XXIII: 43.2 g, 80% yield, 93% on HPLC).
Example 21: Synthesis of compound of Formula VIII {(2S, 3S, 4R, 5R, 6S)-6-(4-chlorophenyl)tetrahydro-2H-pyran-2,3,4,5-tetrol}
To a solution of the compound of Formula XXIII (50 g, 0.147 M) in MeOH (500 ml) was added CeCl3.7H2O (53.7 g, 0.177 M, 1.2 eq.) and the mixture was stirred at 20°C until all solids were dissolved. The mixture was then cooled to -78°C and added NaBH4 (6.6 g, 0.177 M, 1.2 eq.) in portions so that the temperature of the reaction did not exceed -70°C. The mixture was stirred at -78°C for 1 hour and then gradually warmed to 0°C. Reaction mass was quenched with saturated aq. NH4Cl (250 ml). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (500 ml ×2) and washed with brine (250 ml). The combined organics were concentrated under vacuum to afford the alcohol intermediate (47.8 g) as colorless oil. To the oily mass was added AcOH (300 ml) and H2O (200 ml).The reaction mixture was heated to 100°C and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated under vacuum to end up with an oily material (Compound of Formula VIII: 32.7 g, 85% yield, 92% on HPLC).
Example 22: Synthesis of compound of Formula XXIV {(4-chloro-3-methylphenyl)[(3a'S,5'R,6'S,6a'S)-6'-hydroxytetrahydrospiro[cyclohexane-1,2'-furo[2,3-d][1,3]dioxol]-5'-yl]methanone}
To a solution of 4-bromo-1-chloro-2-methylbenzene (compound of Formula XXIII, 82.1 g, 0.4 M, 2.5 eq.) in THF (200 ml) was added iPrMgCl (2.0 M in THF, 320 ml, 0.64 M, 4.0 eq.) at 0-5° C and the mixture was stirred for 1.5 h at 0-5°C. A solution of compound of Formula XXII (50 g, 0.16 M) in THF (300 mL) was added drop wise at 0-5°C and the mixture was kept stirring for 1 h. Reaction mass was then warmed to 20°C and stirred for 2 hours. The reaction was quenched with saturated aq. NH4Cl (250 ml), extracted with MTBE (100 ml ×3), washed with brine (100 ml, ×2). The organic layer was concentrated and the residue was purified by silica gel column chromatography to afford the desired ketone (compound of Formula XXIV: 46.1 g, 82% yield, 96% on HPLC).
Example 23: Synthesis of compound of Formula X {(2S, 3S, 4R, 5R, 6S)-6-(4-chloro-3-methylphenyl)tetrahydro-2H-pyran-2,3,4,5-tetrol
To a solution of the compound of Formula XXIV (50 g, 0.14 M) in MeOH (500 ml) was added CeCl3.7H2O (52.5 g, 0.17 M, 1.2 eq.) and the mixture was stirred at 20°C until all solids were dissolved. The mixture was then cooled to -78°C and added NaBH4 (6.4 g, 0.17 M, 1.2 eq.) in portions so that the temperature of the reaction did not exceed -70° C. The mixture was stirred at -78°C for 1 hour and then gradually warmed to 0°C. Reaction mass was quenched with saturated aq. NH4Cl (250 ml). The mixture was concentrated under vacuum to remove MeOH and then extracted with EtOAc (500 ml ×2) and washed with brine (250 ml). The combined organics were concentrated under vacuum to afford the alcohol intermediate (44.9 g) as colorless oil. To the oily mass was added AcOH (300 ml) and H2O (200 ml). The reaction mixture was heated to 100°C and stirred for 15 hours. The mixture was then cooled to room temperature and concentrated under vacuum to end up with an oily material (compound of Formula X: 31.5 g, 81% yield, 94% on HPLC).
Example 24: Synthesis of Compound of Formula XXV {(2S, 3R, 4R, 5S, 6R)-2-[3-(chloromethyl)-4-chlorophenyl]-6-(methylthio)tetrahydro-2H-pyran-3,4,5-triol}
To a stirred solution of Compound of Formula XV (20 g, 0.065 M) and Pd(PPh3)4 (0.15 g, 0.002 Mol%, 0.13 mM) in THF (120 ml) was drop wise added SO2Cl2 (17.6 g, 0.13 M, 2.0 eq.) at 0-5°C. The reaction mixture was allowed to attain ambient temperature. Raised the temperature of reaction mass and refluxed for 6 hrs. Reaction mass was distilled off. The reaction was quenched with saturated aq. NaHCO3 solution (100 ml) and extracted by ethyl acetate (100 ml ×3). Organic layers were combined and evaporated under vacuum to obtain Compound of Formula XXV (16.7 g, 75 % yield, 94 % on HPLC).
Example 25: Synthesis of Sotagliflozin of Formula A
In a 4-Neck, 1.0 L RBF was taken dichloromethane (250 ml) and AlCl3 (24.5 g, 0.177 M, 1.2 eq.). Cooled the reaction mass to 0°C. Added ethoxybenzene (compound of Formula XVIII, 20 g, 0.16 M, 1.1 eq.) drop wise maintaining the temperature below 0 °C. Reaction mass was stirred for 1 h. To the reaction mass, added compound of Formula XXV (50 g, 0.147 M) at 0±5°C. Slowly raised the temperature to 20-25 °C and stirred the reaction mass for 12 h. Quenched the reaction mass into ice cooled water (200 ml) at 0-20°C and stirred for 30 min at 10-20°C. Add conc. HCl (100 mL) into the mass slowly at 10-20°C. Stirred the mass for 10-15 min at 10-20°C and separated the layers. Aqueous layer was again extracted by ethylacetate (50 ml ×2). Organics were combined and concentrated under vacuum. To the concentrate, added methanol (150 ml) and stirred for 15 min at 25-30°C. Added water (500 ml) and stirred for 1 hour. The solid was filtered and washed with water (50 ml ×3). Cake was finally dried under vacuum at 45°C to obtain the API, Sotagliflozin of Formula A (35.7 g, 57 % yield, 99.9 % on HPLC).
Example 26: Synthesis of Sotagliflozin of Formula A
In a 4-Neck, 1.0 L RBF was taken dichloromethane (250 ml) and AlCl3 (27.5 g, 0.2 M, 1.2 eq.). Cooled the reaction mass to 0°C. Added 1-(chloromethyl)-4-ethoxybenzene (compound of Formula XXX, 32.4 g, 0.19 M, 1.1 eq.) dropwise maintaining the temperature below 0°C. Stirred the reaction mass for 1 h. To the reaction mass, added compound of Formula XIII (50 g, 0.172 M) at 0±5°C. Slowly raised the temperature to 20-25°C and stirred the reaction mass for 12 h. Quenched the reaction mass into ice cooled water (200 ml) at 0-20°C and stirred for 30 min at 10-20°C. Added conc. HCl (100 mL) into the mass slowly at 10-20°C. Stirred the mass for 10-15 min at 10-20°C and separated the layers. Aqueous layer was again extracted by ethylacetate (50 ml ×2). Organics were combined and concentrated under vacuum. To the concentrate, added methanol (150 ml) and stirred for 15 min at 25-30°C. Added water (500 ml) and stirred for 1 hour. The solid was filtered and washed with water (50 ml ×3). Cake was finally dried under vacuum at 45°C to obtain the API, Sotagliflozin of Formula A (40 g, 55% yield, 99.9% on HPLC).
Example 27: Synthesis of Crystalline form of Sotagliflozin:
In a 4-neck round bottomed flask was taken sotagliflozin (10 g) was added 6V (60 ml) of methanol. Heated the mixture to 40-45°C till clear solution is obtained. Stirred the solution for 1 hour followed by addition of 15V water (150 ml) drop wise at 40-45°C. Stirred the solution for 2 hrs and then cooled to 20-25°C. Stirred for 4 hrs and filtered and washed the crystals so obtained for 1:3 methanol: water (2×2V). Dried the crystals so obtained under vacuum at 40-45°C.
Example 28: Synthesis of Amorphous form of Sotagliflozin:
In a 4-neck round bottomed flask was taken sotagliflozin (10 g) and added 4V (40 ml) of tetrahydrofuran. Heated the mixture to 60-65°C till reflux. Cooled the reaction mass to 40-45°C followed by addition 10V water (100 ml) at 40-45°C. Cooled the material so obtained to 10°C at the rate of 5°C per min. Stirred the material for 30 min and then filtered and washed by a 1:3 of THF: water (2×2V). Dried the amorphous form so obtained under vacuum at 40-45°C.

WE CLAIM
1. Compounds of Formula I

wherein R1 is selected from hydrogen; hydroxyl; alkoxy; haloalkoxy or hydroxyalkoxy group; aralkyl; halide; (un)substituted amine; heterocyclic rings; cycloalkyl ring with one or more carbon optionally substituted with heteroatom; -OCORA; -ORB; aryl optionally substituted with one to three substituents independently selected from halogen, alkyl, haloalkyl, and (un)protected hydroxyl alkyl group;
wherein RA and RB are independently selected from straight or branched chain alkyl; (un)substituted aryl or heterocyclic rings or heteroaryl rings;
P1 and P2 are independently selected from hydrogen; alkyl; (un)substituted aryl; (un)substituted aralkyl; (un)substituted aromatic heterocyclic ring; C3-C7 cycloalkyl ring with one or more carbon atom optionally substituted with heteroatom such as N, O, S, wherein said cycloalkyl ring may be substituted with C1-C4 alkyl group or C1-C4 alkoxy group; P1 and P2 together may form C3-C7 cyclic rings; and
Q is –CH2 or –C=O.

2. Compounds of Formula II,

wherein, P3 is selected from hydrogen or a hydroxyl protecting group; R2 is selected from heterocyclic rings, cycloalkyl ring with one or more carbon optionally substituted with heteroatom, aryl optionally substituted with one to three substituents selected from halogen, alkyl, haloalkyl, and (un)protected hydroxyl alkyl group.

3. Compounds of Formula III,

wherein, P3 is selected from hydrogen or a hydroxyl protecting group; R2 is selected from heterocyclic rings, cycloalkyl ring with one or more carbon optionally substituted with heteroatom, aryl optionally substituted with one to three substituents selected from halogen, alkyl, haloalkyl, and (un)protected hydroxyl alkyl group.

4. The compounds as claimed in claim 1, wherein said compounds are selected from the group comprising of compound of Formula IV, V, VI, VII, XXI, XXII, XXIII, XXIV, and XXI;
, , , , , , ,and .

5. The compounds as claimed in claim 2, wherein said compounds are selected from the group comprising of compound of Formula VIII, IX, X and XI;
, , , and
.

6. The compounds as claimed in claim 3, wherein said compounds are selected from the group comprising of compound of Formula XII, XIII, XIV, XV, XVII, and XXV;
, , , , , and .

7. A process for the preparation of Sotagliflozin of Formula A, wherein said process comprising the condensation of compound of Formula XIII with compound of Formula XVI as represented below:
,
OR, by halogenating compound of Formula XV in presence of halogenating agent to give compound of Formula XVII or XXV followed by reaction with compound of Formula XVIII to give Sotagliflozin of Formula A:

8. The process as claimed in claim 7, wherein said condensation is carried out in presence of acid selected from the group comprising of AlX3, FeX3, BX3, BX3.OEt2, ZnX2, InX3, SbX5, TiX4, BiX3, SnX4, GaX3, ScX3, HfX4, HF, H2SO4, H3PO4, silica-alumina type, and cation-exchange resins, wherein X is halogen, or OTf.

9. The process as claimed in claim 7, wherein said halogenating agent is selected from the group comprising of hydrogen bromide, NBS, 1,3-dibromo-5,5-dimethylhydantoin, and tetrabutyl ammonium bromide.

10. Substantially pure Sotagliflozin free of impurities wherein the total impurities is less than about 1.0%w/w, and wherein each impurity is less than about 0.3%w/w.