Claims:1. An isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl.

Formula III
2. An isolated compound of Formula IIIa

Formula IIIa
characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.15, 9.22, 19.98, 20.57, 21.28, and 23.36 ± 0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 83°C.
3. An isolated compound of Formula IIIb.

Formula IIIb
characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.75, 17.25, 17.60, 18.47, 19.34, 20.48, 21.56, 22.14, 23.35, and 24.41±0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 96°C.
4. A process for the preparation of isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula III
comprising protecting a compound of Formula IV, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula IV
with propionic anhydride or propionyl chloride to obtain isolated compound of Formula III.
5. A process for the preparation of a compound of Formula V, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula V
comprising hydrolysing an isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula III
in the presence of a base to obtain a compound of Formula V.
6. A process for the preparation of a compound of Formula V, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula V
comprising the steps of:
a) protecting a compound of Formula IV, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula IV
with propionic anhydride or propionyl chloride to obtain isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl; and

Formula III
b) hydrolysing the isolated compound of Formula III in the presence of a base to obtain a compound of Formula V.
7. A method for the purification of isolated compound of Formula IIIa or isolated compound of Formula IIIb;

Formula IIIa Formula IIIb
comprising the steps of:
a) contacting isolated compound of Formula IIIa or isolated compound of Formula IIIb with a suitable solvent; and
b) isolating pure isolated compound of Formula IIIa or pure isolated compound of Formula IIIb.
8. A compound of Formula VI.

Formula VI
9. The compound of Formula VI according to claim 8, characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.77, 7.91, 9.39, 18.01, 19.21, 19.39, 19.59, 20.16, 21.87, 22.13, and 24.38 ± 0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 113°C.
10. A process for the preparation of a compound of Formula VI,

Formula VI
comprising protecting a compound of Formula VII;

Formula VII
with propionic anhydride or propionyl chloride to obtain a compound of Formula VI.
11. A process for the preparation of a compound of Formula VIII,

Formula VIII
comprising hydrolysing a compound of Formula VI,

Formula VI
in the presence of a base to obtain a compound of Formula VIII.
12. A process for the preparation of empagliflozin, comprising the steps of:
a) protecting a compound of Formula VII;

Formula VII
with propionic anhydride or propionyl chloride to obtain a compound of Formula VI;

Formula VI
b) hydrolysing the compound of Formula VI in the presence of a base to obtain a compound of Formula VIII; and

Formula VIII
c) converting the compound of Formula VIII to empagliflozin.
13. A method for the purification of a compound of formula VI,

Formula VI
comprising the steps of:
a) contacting a compound of Formula VI with suitable solvent; and
b) isolating pure compound of Formula VI.
14. A method of purification according to claims 7 and 13, wherein the solvent is selected from the group comprising alcohols, esters, ethers, hydrocarbons, water and mixtures thereof.
, Description:PROCESS FOR THE PREPARATION OF SGLT2 INHIBITORS AND ISOLATED INTERMEDIATES THEREOF

FIELD OF THE INVENTION
The present invention relates to isolated intermediates of SGLT2 inhibitors, process for their preparation, and processes for the preparation of SGLT2 inhibitors. In particular, the present invention relates to isolated intermediate of dapagliflozin, isolated intermediates of empagliflozin, and process for their preparation. The present invention also relates to processes for the preparation of SGLT2 inhibitors.

BACKGROUND OF THE INVENTION
Sodium-glucose co-transporter-2 (SGLT2) inhibitors are a new group of oral medications used for treating type 2 diabetes. The drugs work by helping the kidneys to lower blood glucose levels.
Drugs in the SGLT2 inhibitors class include, but are not limited to, dapagliflozin, empagliflozin and the like.
Dapagliflozin, chemically known as D-glucitol, 1,5-anhydro-1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-, (1S)-, compounded with (2S)-1,2-propanediol, hydrate (1:1:1) is being marketed in the name of Farxiga® in USA for the treatment of type 2 diabetes mellitus. Its chemical structure is represented by the following Formula I.

Formula I
U.S. Patent No. 6,515,117 discloses a process for the preparation of dapagliflozin by reacting 5-bromo-2-chloro-4’-ethoxydiphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl-ß-D-glucolactone to obtain (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol, which is then reduced with triethylsilane and boron trifluoride diethyl etherate to obtain dapagliflozin as yellow foam. The obtained crude dapagliflozin is then acetylated with acetic anhydride to obtain tetraacetyl dapagliflozin, which is then deacetylated with lithium hydroxide to obtain dapagliflozin. The purity of dapagliflozin obtained by this process is 94%.
Organic Letters (2012), 14(6), 1480-1483 discloses a process for the preparation of dapagliflozin by protecting crude dapagliflozin with pivaloyl chloride followed by deprotection to obtain dapagliflozin. Since pivaloyl chloride is lacrimetric, its use for the manufacture of a drug product is not desirable.
Dapagliflozin prepared by deprotection of acetyl group using lithium hydroxide generates impurities resulting in low purity of dapagliflozin. Hence, it is desirable to ascertain suitable dapagliflozin intermediate which overcomes these drawbacks and provides desired quality and yield of dapagliflozin.
Empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor, chemically designated as D-Glucitol,1,5-anhydro-1-C-[4-chloro-3-[[4-[[(3S)-tetrahydro-3¬ furanyl]oxy]phenyl]methyl]phenyl]-, (1S). and is being marketed for the treatment of type 2 diabetes mellitus. Its chemical structure is represented by the following Formula II.

Formula II
U.S. Patent No. 7,579,449 discloses a process for the preparation of empagliflozin, which comprises protection of 4-(5-bromo-2-chloro-benzyl)-phenol with tert-butyldimethylsilylchloride and triethylamine followed by reaction of [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane with 2,3,4,6-tetrakis-O-(trimethylsilyl)-D-glucopyranone in the presence of tert-butyllithium and then reaction with methanesulfonic acid in methanol. The obtained product is then reduced with triethylsilane and boron trifluoride etherate to obtain 1-chloro-4-(ß-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene which is further reacted with (R)-3-(4-methylphenylsulfonyloxy)-tetrahydrofuran to obtain empagliflozin. The above reduction step involves a tedious work-up like multiple extractions with ethyl acetate and chromatographic purification, which is not desirable for commercial scale production.
PCT Publication No. WO 2006/120208 discloses a process for the preparation of empagliflozin, which comprises reduction of 1-Chloro-4-(1-methoxy-D-glucopyranos-1-yl)-2-(4-(S)-tetrahydrofuran-3-yloxy-benzyl)-benzene followed by protection with acetic anhydride. The obtained product is then deprotected in the presence of aqueous potassium hydroxide to obtain empagliflozin. Empagliflozin prepared by deprotection of acetyl group using potassium hydroxide generates impurities resulting in low purity of empagliflozin. Hence, it is desirable to ascertain suitable empagliflozin intermediate which overcomes these drawbacks and provides desired quality and yield of empagliflozin.
Chinese Publication No. CN105399735 discloses a process for the preparation of pivaloyl protected empagliflozin followed by deprotection to obtain empagliflozin. Since pivaloyl chloride is lacrimetric, its use for the manufacture of a drug product is not desirable.

SUMMARY OF THE INVENTION
A first aspect of the present invention provides an isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula III
In one embodiment, the isolated compound of Formula IIIa;

Formula IIIa
is characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.15, 9.22, 19.98, 20.57, 21.28, and 23.36 ± 0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 83°C.
In another embodiment, the isolated compound of Formula IIIa is characterized by an XRPD or a DSC as depicted in Figure 1 and Figure 2, respectively.
In another embodiment, the isolated compound of Formula IIIb;

Formula IIIb
is characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.75, 17.25, 17.60, 18.47, 19.34, 20.48, 21.56, 22.14, 23.35, and 24.41±0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 96°C.
In yet another embodiment, the isolated compound of Formula IIIb is characterized by an XRPD or a DSC as depicted in Figure 3 and Figure 4, respectively.
A second aspect of the present invention provides a process for the preparation of isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula III
comprising protecting a compound of Formula IV, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula IV
with propionic anhydride or propionyl chloride to obtain isolated compound of Formula III.
A third aspect of the present invention provides a process for the preparation of a compound of Formula V, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula V
comprising hydrolysing an isolated compound of Formula III, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula III
in the presence of a base to obtain a compound of Formula V.
A fourth aspect of the present invention provides a process for the preparation of a compound of Formula V, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula V
comprising the steps of:
a) protecting a compound of Formula IV, wherein R is ethyl or (S)-tetrahydrofuran-3-yl;

Formula IV
with propionic anhydride or propionyl chloride to obtain isolated compound of Formula III,

Formula III
wherein R is ethyl or (S)-tetrahydrofuran-3-yl; and
b) hydrolysing the isolated compound of Formula III in the presence of a base to obtain a compound of Formula V.
A fifth aspect of the present invention provides a method for the purification of isolated compound of Formula IIIa or isolated compound of Formula IIIb;

Formula IIIa Formula IIIb
comprising the steps of:
a) contacting isolated compound of Formula IIIa or isolated compound of Formula IIIb with a suitable solvent; and
b) isolating pure isolated compound of Formula IIIa or pure isolated compound of Formula IIIb.
A sixth aspect of the present invention provides the use of an isolated compound of Formula IIIa for the preparation of dapagliflozin.
In one embodiment of the sixth aspect, the dapagliflozin is amorphous or crystalline.
A seventh aspect of the present invention provides the use of an isolated compound of Formula IIIb for the preparation of empagliflozin.
In one embodiment of the seventh aspect, the empagliflozin is amorphous or crystalline.
An eighth aspect of the present invention provides a compound of Formula VI.

Formula VI
In one embodiment, the compound of Formula VI is characterized by at least one of:
a) an X-ray powder diffraction (XRPD) peaks with 2-theta values of about 6.77, 7.91, 9.39, 18.01, 19.21, 19.39, 19.59, 20.16, 21.87, 22.13, and 24.38 ± 0.2°, or
b) a differential scanning calorimetry (DSC) thermogram with at least one endothermic peak at about 113°C.
In another embodiment, the compound of Formula VI is characterized by an XRPD or a DSC as depicted in Figure 5 and Figure 6, respectively.
A ninth aspect of the present invention provides a process for the preparation of a compound of Formula VI,

Formula VI
comprising protecting a compound of Formula VII;

Formula VII
with propionic anhydride or propionyl chloride to obtain a compound of Formula VI.
A tenth aspect of the present invention provides a process for the preparation of a compound of Formula VIII,

Formula VIII
comprising hydrolysing a compound of Formula VI,

Formula VI
in the presence of a base to obtain a compound of Formula VIII.
An eleventh aspect of the present invention provides a process for the preparation of empagliflozin, comprising the steps of:
a) protecting a compound of Formula VII;

Formula VII
with propionic anhydride or propionyl chloride to obtain a compound of Formula VI;

Formula VI
b) hydrolysing the compound of Formula VI in the presence of a base to obtain a compound of Formula VIII; and

Formula VIII
c) converting the compound of Formula VIII to empagliflozin.
A twelfth aspect of the present invention provides a method for the purification of a compound of formula VI,

Formula VI
comprising the steps of:
a) contacting a compound of Formula VI with suitable solvent; and
b) isolating pure compound of Formula VI.
A thirteenth aspect of the present invention provides the use of a compound of Formula VI for the preparation of empagliflozin.
In one embodiment of the thirteenth aspect, the empagliflozin is amorphous or crystalline.

BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts the X-ray powder diffraction (XRPD) pattern of isolated compound of Formula IIIa.
Figure 2 depicts the differential scanning calorimetry (DSC) of isolated compound of Formula IIIa.
Figure 3 depicts the X-ray powder diffraction (XRPD) pattern of isolated compound of Formula IIIb.
Figure 4 depicts the differential scanning calorimetry (DSC) of isolated compound of Formula IIIb.
Figure 5 depicts the X-ray powder diffraction (XRPD) pattern of a compound of Formula VI.
Figure 6 depicts the differential scanning calorimetry (DSC) of a compound of Formula VI.

DETAILED DESCRIPTION OF THE INVENTION
Various embodiments and variants of the present invention are described hereinafter.
The term "about", as used herein, refers to any value which lies within the range defined by a number up to ±10% of the value.
The term “solvent”, as used herein, refers to a solvent which may include but not limited to alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol or t-butyl alcohol; alkyl acetates such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate or isobutyl acetate; ethers such as diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran or dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile or isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride; ketones such as acetone, ethyl isopropyl ketone, methyl isopropyl ketone, methyl isobutyl ketone; aromatic hydrocarbons such as benzene, toluene or xylene; non polar solvent such as hexane, heptane, or cyclohexane; polar aprotic solvent such as dimethylsulfoxide, N,N-dimethylformamide or N-methylpyrrolidone; water; or mixture(s) thereof.
The term “base”, as used herein, refers to an inorganic base or organic base which may include but not limited to the group comprising of inorganic base like hydroxides of alkali metal or alkaline earth metal such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide and the like; carbonates of alkali metal or alkaline earth metal such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and the like; and phosphates such as disodium monohydrogen phosphate, dipotassium monohydrogen phosphate, trisodium phosphate, tripotassium phosphate and the like; or organic base like methyl amine or tertiary amines such as triethylamine, diisopropylethylamine, tri(n-propyl)amine, tri(n-butyl)amine, cyclohexyl-dimethylamine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine and the like; and aromatic amines such as pyridine, lutidine, N,N-dimethylaniline, N,N-dimethylaminopyridine and the like.
The term “contacting” as used herein, refers to bringing two or more components together by dissolving, mixing, suspending, blending, slurrying, stirring, or a combination thereof.
In a preferred embodiment of the first aspect, the isolated compound of Formula IIIa is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Table-1;

Table-1
Position
[°2?] d-spacing
[A°] Relative Intensity
[%]
3.12 28.30 5.63
6.15 14.35 100.00
8.46 10.44 3.63
8.93 9.89 24.81
9.22 9.58 31.39
10.30 8.58 9.69
12.23 7.23 7.78
12.77 6.93 2.54
14.61 6.06 1.42
15.25 5.80 1.73
16.08 5.51 4.94
16.59 5.34 15.44
17.20 5.15 20.28
17.84 4.97 14.86
18.39 4.82 4.95
19.16 4.63 8.83
19.98 4.44 36.37
20.57 4.31 51.53
21.28 4.17 27.93
23.36 3.80 29.01
24.55 3.62 4.80
25.47 3.49 17.66
28.21 3.16 6.19
28.69 3.11 5.00
29.34 3.04 2.67
30.50 2.93 5.62
30.88 2.89 3.78
32.64 2.74 1.90

In a preferred embodiment of the first aspect, the isolated compound of Formula IIIb is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Table-2;
Table-2
Position
[°2?] d-spacing
[A°] Relative Intensity
[%]
3.67 24.05 9.57
6.75 13.07 87.80
7.37 11.99 5.33
8.14 10.85 21.92
8.69 10.16 31.89
9.18 9.62 26.91
11.09 7.97 18.68
13.49 6.56 9.37
14.74 6.00 13.94
16.29 5.44 33.14
17.25 5.13 93.13
17.60 5.03 78.07
18.47 4.80 91.50
19.34 4.58 43.18
20.48 4.33 62.60
21.56 4.12 100.00
22.14 4.01 57.07
23.35 3.80 43.86
24.41 3.64 41.89
25.84 3.44 32.33
27.64 3.22 35.92
29.16 3.06 21.83
30.78 2.90 10.11
32.08 2.78 11.57
34.89 2.57 5.61
38.06 2.36 4.62

In a preferred embodiment of the second aspect and fourth aspect, the reaction of a compound of Formula IV with propionic anhydride or propionyl chloride is carried out in the presence of a base. Preferably, the base is trimethylamine, N,N-dimethylaminopyridine, or mixture thereof.
The protection of a compound of Formula IV with propionic anhydride or propionyl chloride is carried out in the presence of a solvent. Preferably, the solvent is dichloromethane.
The protection of a compound of Formula IV with propionic anhydride or propionyl chloride is carried out at a temperature of about 0°C to about 45°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 30°C.
The protection of a compound of Formula IV with propionic anhydride or propionyl chloride is carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 2 hours to about 3 hours.
The compound of Formula III can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the third aspect and fourth aspect, the hydrolysis of isolated compound of Formula III in the presence of a base is carried out in the presence of a solvent.
Preferably, the base is inorganic base selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, or organic base selected from the group comprising methyl amine, triethylamine, diisopropylethylamine, tri(n-propyl)amine, tri(n-butyl)amine, cyclohexyl-dimethylamine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, pyridine, lutidine, N,N-dimethylaniline, and N,N-dimethylaminopyridine.
Preferably, the solvent is methanol, tetrahydrofuran, or mixture thereof.
The hydrolysis of isolated compound of Formula III in the presence of a base is carried out at a temperature of about 0°C to about 45°C. Preferably, the reaction is carried out at a temperature of about 0°C to about 30°C.
The hydrolysis of isolated compound of Formula III in the presence of a base is carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 1 hour to about 2 hours.
The compound of Formula V can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the fifth aspect, contacting isolated compound of Formula IIIa or isolated compound of Formula IIIb with a suitable solvent is carried out by dissolving isolated compound of Formula IIIa or isolated compound of Formula IIIb in a suitable solvent followed by cooling the reaction mixture, or by dissolving isolated compound of Formula IIIa or isolated compound of Formula IIIb in a suitable solvent followed by addition of anti-solvent to obtain pure isolated compound of Formula IIIa or pure isolated compound of Formula IIIb.
The suitable solvent or anti-solvent is selected from the group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, hexane, heptane, cyclohexane, or mixtures thereof.
The pure isolated compound of Formula IIIa or pure isolated compound of Formula IIIb can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the eighth aspect, the compound of Formula VI is characterized by an X-ray powder diffraction (XRPD) pattern substantially as depicted in Table-3;
Table-3
Position
[°2?] d-spacing
[A°] Relative Intensity
[%]
2.05 43.02 17.07
3.55 24.85 2.80
6.77 13.04 100.00
7.11 12.43 15.53
7.91 11.16 57.99
9.39 9.41 71.44
10.66 8.29 13.18
12.10 7.30 9.00
13.68 6.47 17.26
14.29 6.19 33.03
15.78 5.61 11.70
16.27 5.44 23.01
16.61 5.33 55.79
18.01 4.92 63.72
18.48 4.79 25.79
19.21 4.62 54.83
19.39 4.57 70.18
19.59 4.53 69.08
20.16 4.40 67.77
20.98 4.23 31.53
21.87 4.06 55.02
22.13 4.01 46.48
22.45 3.95 27.90
23.55 3.77 33.44
24.38 3.64 45.40
25.03 3.55 20.37
26.44 3.37 20.56
26.84 3.32 20.48
27.42 3.25 20.77
28.19 3.16 25.33
29.00 3.07 20.39
29.40 3.03 16.35
30.37 2.94 16.53
31.00 2.88 12.75
31.94 2.80 12.55
32.89 2.72 10.64
34.84 2.57 12.31
36.79 2.44 10.04
38.96 2.31 9.23

In a preferred embodiment of the ninth aspect and eleventh aspect, the reaction of a compound of Formula VII with propionic anhydride or propionyl chloride is carried out in the presence of a base. Preferably, the base is trimethylamine, N,N-dimethylaminopyridine, or mixture thereof.
The reaction of a compound of Formula VII with propionic anhydride or propionyl chloride is carried out in the presence of a solvent. Preferably, the solvent is dichloromethane.
The reaction of a compound of Formula VII with propionic anhydride or propionyl chloride is carried out at a temperature of about 0°C to about 50°C. Preferably, the reaction is carried out at a temperature of about 20°C to about 40°C.
The reaction of a compound of Formula VII with propionic anhydride or Propionyl chloride is carried out for about 1 hour to about 5 hours. Preferably, the reaction is carried out for about 2 hours to about 3 hours.
The compound of Formula VI can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the tenth aspect and eleventh aspect, the hydrolysis of a compound of Formula VI in the presence of a base is carried out in the presence of a solvent.
Preferably, the base is inorganic base selected from the group comprising sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide, barium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydrogen carbonate, and potassium hydrogen carbonate, or organic base selected from the group comprising methyl amine, triethylamine, diisopropylethylamine, tri(n-propyl)amine, tri(n-butyl)amine, cyclohexyl-dimethylamine, N-methylpiperidine, N-methylpyrrolidine, N-methylmorpholine, pyridine, lutidine, N,N-dimethylaniline, and N,N-dimethylaminopyridine.
Preferably, the solvent is methanol, tetrahydrofuran, or mixture thereof.
The hydrolysis of a compound of Formula VI in the presence of a base is carried out at a temperature of about 0°C to about 45°C. Preferably, the reaction is carried out at a temperature of about 0°C to about 30°C.
The hydrolysis of a compound of Formula VI in the presence of a base is carried out for about 1 hour to about 3 hours. Preferably, the reaction is carried out for about 1 hour to about 2 hours.
The compound of Formula VIII can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
In a preferred embodiment of the twelfth aspect, contacting a compound of Formula VI with a suitable solvent is carried out by dissolving a compound of Formula VI in a suitable solvent followed by cooling the reaction mixture, or by dissolving a compound of Formula VI in a suitable solvent followed by addition of anti-solvent to obtain pure compound of Formula VI.
The suitable solvent or anti-solvent is selected from the group comprising methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, t-butyl alcohol, methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, diethyl ether, n-propyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyl tetrahydrofuran, dimethoxyethane, hexane, heptane, cyclohexane, or mixtures thereof.
The pure compound of Formula VI can be isolated by methods including concentration, distillation, decantation, filtration, evaporation, centrifugation, or a combination thereof.
The compound of Formula IV (wherein R is ethyl) used as a starting material may be prepared by process known in the art, such as by the process described in the U.S. Patent No. 6,515,117.
The compound of Formula IV (wherein R is (S)-tetrahydrofuran-3-yl) used as a starting material may be prepared by process known in the art, such as by the process described in the U.S. Patent No. 7,579,449.
The compound of Formula VII used as a starting material may be prepared by process known in the art, such as by the process described in the U.S. Patent No. 7,579,449.
The compound of Formula VIII may be converted to empagliflozin by process known in the art, such as by the process described in the U.S. Patent No. 7,579,449.
While the present invention has been described in terms of its specific aspects and embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Examples:
Example-1: Preparation of isolated compound of Formula IIIa
To a stirred mixture of a compound of Formula IV (wherein R is ethyl) (60 g) in dichloromethane (430 mL), triethylamine (144 mL) was added at 12°C to 18°C. To this mixture, propionic anhydride (113 mL) was slowly added at 12°C to 18°C. Subsequently, N,N-dimethylaminopyridine (0.8 g) was added and stirred for 2 hours at 22°C to 28°C. The mixture was cooled to 17°C to 23°C and then water (300 mL) was added and stirred for 15 minutes. The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (2x3000 mL), water (3x300 mL), and 10% aqueous sodium chloride solution (300 mL). The organic layer was dried over sodium sulphate and distilled under vacuum at 35°C to 40°C to obtain residue. To the obtained residue, heptane (500 mL) was added at 17°C to 23°C and stirred for 30 minutes at 17°C to 23°C. The separated solid was filtered and dried at 25°C to 30°C for 10 hours.
Yield: 65 g
HPLC purity: 98.63%

Example-2: Purification of isolated compound of Formula IIIa
A stirred mixture of a compound of Formula IIIa (65 g) in n-heptane (210 mL) was heated to 77°C to 83°C and stirred for 60 minutes to obtain clear solution. The solution was slowly cooled to 22°C to 28°C, filtered the separated solid, and dried at 33°C to 37°C for 6 hours.
Yield: 53 g
HPLC purity: 99.29%
1H NMR (DMSO-d6): d 0.73(t,3 H), 0.91-1.02(m,9 H), 1.29(t,3 H), 1.83-2.01(m, 2 H), 2.13-2.35 (m, 6 H), 3.95-4.01(m,4 H), 4.06-4.16 (m,3 H),4.66-4.69(m, 1 H), 4.94-4.99(m,1 H), 5.08-5.13(m, 1 H), 5.35-5.39(m, 1 H), 6.80-6.82(d, 2 H), 7.04-7.06(d, 2 H), 7.22-7.26(m, 2 H), 7.41-7.43(m, 1H).

Example-3: Preparation of dapagliflozin
To a stirred mixture of isolated compound of Formula IIIa (50 g) in methanol (750 mL), aqueous sodium carbonate (16.74 g sodium carbonate in 150 mL water) was added at 12°C to 18°C. The reaction mixture was stirred for 1 hour 30 minutes at 18°C to 22°C and distilled under vacuum at 32°C to 38°C to obtain residue. To the obtained residue, ethyl acetate (500 mL) was added and washed with water (500 mL), 10% aqueous sodium chloride solution (500 mL). The layers were separated and the organic layer was washed with water (500 mL). The organic layer was dried over sodium sulphate and distilled under vacuum at 30°C to 35°C to obtain dapagliflozin.
Yield: 30 g
HPLC purity: 99.73%

Example-4: Purification of dapagliflozin
A stirred mixture of dapagliflozin (30 g) in methyl tert-butyl ether (120 mL) was slowly added into n-heptane (420 mL) at 0±5°C in 30 minutes. The reaction mixture was stirred for 10 minutes at 0±5°C and the separated solid was filtered. The filtered solid was washed with n-heptane (100 mL) and dried at 35±2°C for 14 hours.
Yield: 28 g
HPLC Purity: 99.8%

Example-5: Preparation of isolated compound of Formula IIIb
To a stirred mixture of a compound of Formula IV (3.5 g) in dichloromethane (35 mL), triethylamine (5.48 g) was added at 12°C to 18°C. To this mixture, propionic anhydride (6.06 g) was slowly added at 5°C to 10°C. Subsequently, N,N-dimethylaminopyridine (0.057 g) was added and stirred for 2 hours at 30°C to 35°C. The mixture was cooled to 17°C to 23°C and then water (35 mL) was added at 22°C to 28°C and stirred for 15 minutes. The layers were separated and the organic layer was washed with 1N aqueous hydrochloric acid (2x70 mL), water (2x70 mL), and 20% aqueous sodium chloride solution (70 mL). The organic layer was dried over sodium sulphate and distilled under vacuum at 40°C to 45°C to obtain residue. To the obtained residue, isopropyl alcohol (35 mL) was added at 15°C to 20°C and stirred for 60 minutes at 15°C to 20°C. The separated solid was filtered, washed with isopropyl alcohol (7 mL) and suck dried.
Yield: 4.5 g
HPLC purity: 98.71%
1H NMR (CDCl3): d 0.86 (t, 3H), 1.05 (t, 3H), 1.08-1.15 (m, 6H), 1.85-2.07 (m, 2H), 2.14-2.20 (m, 2H), 2.19-2.26 (m, 2H), 2.27-2.37 (m, 4H), 3.77-3.83 (m, 1H), 3.87-3.92 (m, 1H), 3.94-4.01 (m, 5H), 4.15 (dd, 1H), 4.27 (dd, 1H), 4.33 (d, 1H), 4.85-4.92 (m, 1H), 5.09 (t, 1H), 5.23 (t, 1H), 5.31 (t, 1H), 6.78 (d, 2H), 7.05 (d, 2H), 7.10 (d, 1H), 7.18 (dd, 1H), 7.34 (d, 1H).

Example-6: Preparation of empagliflozin
To a stirred mixture of isolated compound of Formula IIIb (4 g) in methanol (36 mL) and tetrahydrofuran (24 mL), aqueous lithium hydroxide solution (0.248 g lithium hydroxide in 12 mL water) was added at 0°C to 2°C. The reaction mixture was stirred for 1 hour 30 minutes at 25°C to 30°C and distilled under vacuum at 30°C to 35°C to obtain residue. To the obtained residue, water (80 mL) was added and extracted with ethyl acetate (3x40 mL). The combined organic layers were washed with 20% aqueous sodium chloride solution (80 mL), dried over sodium sulphate, and distilled under vacuum at 40°C to 45°C to obtain residue. Ethyl acetate (64.8 mL) was added to the obtained residue and heated to 55±2°C. Subsequently, water (2 mL) was added and stirred for 10 minutes at 55±2°C. The reaction mixture was cooled to 7±2°C and stirred for 1 hour. The separated solid was filtered, washed with ethyl acetate (12 mL), and dried under vacuum at 40°C for 2 hours.
Yield: 1.8 g
HPLC purity: 99.24%

Example-7: Preparation of compound of Formula VI
To a stirred mixture of a compound of Formula VII (3.5 g) in dichloromethane (35 mL), triethylamine (6.5 g) was added at 12°C to 18°C. To this mixture, propionic anhydride (7.17 g) was slowly added at 5°C to 10°C. Subsequently, N,N-dimethylaminopyridine (0.067 g) was added and stirred for 2 hours at 30°C to 35°C. The mixture was cooled to 17°C to 23°C and then water (35 mL) was added at 22°C to 28°C and stirred for 15 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane (35 mL). The combined organic layer was washed with 1N aqueous hydrochloric acid (70 mL), water (70 mL), and 20% aqueous sodium chloride solution (70 mL). The organic layer was dried over sodium sulphate and distilled under vacuum at 40°C to 45°C to obtain residue. To the obtained residue, ethanol (52.5 mL) was added and stirred for 60 minutes at 10°C to 15°C. The separated solid was filtered, washed with ethanol (17.5 mL) and dried at 45°C to 50°C for 4 hours.
Yield: 3.5 g
HPLC purity: 98.32%
1H NMR (CDCl3): d 0.86(t, 3H), 1.05 (t, 3H), 1.08-1.15 (m, 6H), 1.25 (t, 3H), 1.95 (m, 1H), 2.05 (m, 1H), 2.30 (dd, 2H), 2.35-2.37 (m, 4H), 2.57 (t, 2H), 3.82 (m, 1H), 4.07 (d, 2H), 4.17 (d, 1H), 4.32-4.35 (m, 2H), 5.1 (t, 1H), 5.23-5.31 (m, 2H), 6.99 (m, 2H), 7.12-7.13 (m, 2H), 7.15(s, 1H), 7.21(dd, 1H), 7.35(dd, 1H).

Example-8: Preparation of compound of Formula VIII
To a stirred mixture of a compound of Formula VI (3.0 g) in methanol (27 mL) and tetrahydrofuran (18 mL), aqueous lithium hydroxide solution (0.38 g lithium hydroxide in 9 mL water) was added at 0°C to 2°C. The reaction mixture was stirred for 1 hour 30 minutes at 25°C to 30°C and distilled under vacuum at 30°C to 35°C to obtain residue. To the obtained residue, water (60 mL) was added and extracted with ethyl acetate (3x30 mL). The combined organic layer was washed with 20% aqueous sodium chloride solution (60 mL), dried over sodium sulphate, and distilled under vacuum at 40°C to 45°C to obtain residue. To the obtained residue, ethyl acetate (18 mL) was added and stirred for 3 hours at 30°C to 32°C. The separated solid was filtered, washed with ethyl acetate (7.5 mL), and dried under vacuum to obtain compound Formula VIII.
Yield: 1.0 g
HPLC purity: 98.68%

Example-9: Preparation of empagliflozin
To a stirred solution of a compound of Formula VIII (1.0 g) and (3R)-Tetrahydrofuran-3-yl-4-methyl-benzenesulfonate (0.95 g) in N,N-dimethylformamide (10 mL), cesium carbonate (2.13 g) was added, heated to 60±2°C and stirred for 10 hours at 60±2°C. After completion of the reaction, the reaction mixture was cooled to 20°C to 30°C and then water (120 mL) was added. The reaction mixture was stirred for 4 hours at 7±2°C, filtered, washed with water (30mL), and dried at 55°C for 3 hours to obtain residue. To the obtained residue, ethyl acetate (21 mL) was added and heated to 55±2°C. Subsequently, water (0.6 mL) was added, heated to 55±2°C and stirred for 10 minutes. The reaction mixture was slowly cooled to 7±2°C and stirred for 1 hour. The separated solid was filtered and dried under vacuum at 45°C for 2 hours.
Yield: 0.4 g
HPLC purity: 99.03%

Example-10: Preparation of compound of Formula VIII
A stirred solution of a compound of Formula VI (600 mg) in methanol (12 mL) was cooled to 10±3°C, and then aqueous sodium carbonate solution (480 mg dissolved in 6 mL water) was slowly added. The reaction mixture was stirred for 1 hour 30 minutes at 45±2°C. After completion of the reaction, water (18 mL) was added and extracted with ethyl acetate (15 mL x 3). The combined organic layer was distilled under vacuum at 30°C to 40 °C to obtain title compound.
Yield: 0.29 g
HPLC purity: 98.13 %

Example-11: Preparation of empagliflozin
A stirred solution of a compound of Formula IIIb (400 mg) in methanol (8 mL) was cooled to 10±3°C, and then aqueous sodium carbonate solution (251 mg dissolved in 4 mL water) was slowly added. The reaction mixture was stirred for 1 hour 30 minutes at 25°C to 30°C and then at 45±2°C for 1 hour. After completion of the reaction, the reaction mixture was distilled under vacuum at 35°C to 40°C to obtain residue. To the obtained residue, water (40 mL) was added and extracted with ethyl acetate (20 mL x 3). The combined organic layer was distilled under vacuum at 30°C to 40 °C to obtain title compound.
Yield: 0.22 g
HPLC purity: 99.38%