DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENT RULE
COMPLETE SPECIFICATION
(Section 10, rule 13)

“AN IMPROVED PROCESS FOR THE PREPARATION OF ERTUGLIFLOZIN AND INTERMEDIATE THEREOF”

Hikal Limited, an Indian company, of 3A, International Biotech Park, Hinjewadi, Pune – 411 057, India

The following specification describes the invention and the manner in which it is to be performed.

Field of the Invention
The present invention relates to an improved process for the preparation of ertugliflozin of formula (I) and intermediate thereof, in an environment friendly and commercially viable manner in safe conditions with high yield and high chemical purity.

(I)
Background of the Invention
Ertugliflozin (I), is chemically known as (1S,2S,3S,4R,5S)-5-{4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl}-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol. Ertugliflozin is a sodium-glucose co-transporter-2 (SGLT2) inhibitor used to help improve glycemic control in adults with type II diabetes. Ertugliflozin and its co-crystal ertugliflozin L-pyroglutamic acid (Ia), ertugliflozin L-proline (Ib) are disclosed first in the US Patent 8,080,580 (henceforth ‘580). A tablet formulation of ertugliflozin L-pyroglutamic acid is available under the name Steglatro® from Pfizer, Inc. The chemical structure of ertugliflozin L-pyroglutamic acid (Ia) and ertugliflozin L-proline (Ib) is depicted below:

(Ia) (Ib)
The aforesaid US patent ‘580 discloses the preparations of ertugliflozin free base and its derivatives, which is schematically presented in scheme-1. In the scheme-1, allyl 2,3,4-tri-O-benzyl-D-glucopyranoside is prepared by procedures described by Shinya Hanashima, et al., in Bioorganic & Medicinal Chemistry, 2001, 9, 367. The hydroxymethylene group is introduced onto the glycoside compound 1 by means of a Swern oxidation using oxalyl dichloride, dimethyl sulfoxide (DMSO), triethyl amine (TEA) followed by treatment with formaldehyde in the presence of an alkali metal hydroxide such as sodium hydroxide (NaOH) to obtain compound (2). The p-Methoxybenzyl (PMB) groups is introduced by treatment of compound 2 with p-methoxybenzyl bromide or p-methoxybenzyl chloride in the presence of sodium hydride, in a solvent like N,N-dimethylformamide (DMF) to obtain compound 3. The allyl protection group of a compound 3 is removed by treatment with palladium chloride in methanol and co-solvent like dichloromethane. The oxidation of the unprotected hydroxyl group of a compound 4 to an oxo group by Swern oxidation, then formed the lactone compound (5). The said lactone compound (5) is reacted with N,O-dimethyl hydroxylamine hydrochloride and an activating agent such as trimethylaluminum to form the corresponding Weinreb amide, compound (6). The arylbenzyl group is introduced to the compound 6 using organo lithium compound (ArLi) in tetrahydrofuran (THF) at a temperature ranging from about -780C to about 200C followed by hydrolysis (upon standing in protic conditions) to the corresponding lactol (8). Further, the bridged ketal motif compound (9) is prepared by removing the PMB protecting groups by treatment with trifluoroacetic acid in the presence of anisole and dichloromethane (DCM) at about 00C to about 230C. The remaining benzyl protecting group of the compound 9 is removed by treatment with formic acid and palladium black in protic solvents such as ethanol (EtOH), THF to the corresponding final compound (10), as mixture of diastereomers, which is separated by preparative HPLC to yield final ertugliflozin (I).

In this scheme, the number of reaction steps are more, palladium chloride and palladium black catalysts are used. Moreover, the two diastereomers of ertugliflozin are formed and the yield of required isomer is only 29 %.

Scheme-1

The Organic Process Research & Development, 2014, 18, 66-81, by Pfizer discloses another alternative synthetic procedure for preparation of ertugliflozin and ertugliflozin L-pyroglutamic acid (Ia). The said procedure is schematically presented in scheme-2 which is depicted below:

Scheme-2:

In scheme-2, tetra-O-benzyl gluconolactone (12) is synthesized from 2,3,4,6-tetra-O-benzyl-D-glucopyranose (11) using modified Swern oxidation condition by using acetic anhydride in DMSO solvent. The formed lactone (12) is further treated with N-methylpiperazine in toluene to obtain open chain methylpiprazine compound (13), containing the basic tertiary nitrogen, which is further oxidized via Parikh-Doering oxidation using sulfurtrioxide-pyridine complex, DMSO and N,N-diisopropyl ethylamine base to get ketoamide compound (14), which is treated with chloromethylsiloxane in dry THF solvent by Grignard reaction gives the intermediate (15) as a 3:2 mixture of distereoisomers (favoring the 5R isomer) via Tamao-Fleming oxidation, however, the both compounds are converged to diol isomers (16) using hydrogen peroxide (H2O2), potassium fluoride (KF) and sodium bicarbonate (NaHCO3) base. The dimethylacetonide of compound 16 is formed with acetone or DMP in the presence of methanesulfonic acid (MsOH) or p-toluenesulfonic acid (p-TSA) to diastereomeric mixture of products as sticky mass, which then converted to oxalic acid salt as a solid compound (17). The freebase compound (18) is reacted with aryl anion obtained by treatment of aryl bromide with n-butyllithium (n-BuLi) in THF to obtain aryl ketone (compound 19). The aryl ketone compound (19) is subjected to mild hydride source that is triethylsilane in presence of trifluoroacetic acid (TFA) lead to deprotection of both acetonide and benzhydryl ethers affording a mixture of two diastereomer compound (20). The benzyl groups of a compound (20) are removed via metal catalyzed hydrogenolysis under acidic condition to obtain ertugliflozin freebase (21). The ertugliflozin (21) is acylated using acetic anhydride, pyridine and purified by crystallization process to obtain a compound (22). Finally, the acetate groups of a compound (22) are removed by catalytic amount of sodium methoxide (NaOMe) providing pure ertugliflozin freebase, which is taken for cocrystal formation with L-pyroglutamic acid in isopropanol (IPA)-water solvent to obtain ertugliflozin L-pyroglutamic acid (Ia). The drawbacks of this scheme are: the number of reaction steps are more; palladium is used as catalyst for benzyl deprotection; moreover, the atom economy is not good due to additional steps.

Scheme-3:

The PCT patent publication number WO2015/043511 discloses the process for preparation of benzyl protected ertugliflozin as depicted in scheme-3. The gluconolactone (23) is reacted with trimethylsilyl chloride in the presence of N-methyl morpholine using THF solvent to afford TMS-gluconolactone (24). The coupling reaction of TMS-gluconolactone with bromo compound (25) in the presence of n-butyllithium gives the hydroxy compound, which is treated with methanol in presence of methanesulfonic acid to afford O-methyl compound (26). The O-methyl compound (26) is reacted with tert-butyldimethylsilyl chloride in the presence of base to afford trihydroxy compound (27). The trihydroxy compound (27) is further reacted with benzyl bromide in the presence of base to form benzyl protected compound (28). The primary alcohol of protected compound (28) is selectively deprotected using tetra-n-butylammonium fluoride (TBAF) in a polar solvent to afford monohydroxy compound (29). The monohydroxy compound (29) is then converted to aldehyde compound (30) using oxidizing agent such as 2-iodoxy benzoic acid in DCM at reflux temperature for 36 hours. The aldehyde compound (30) is reacted with formaldehyde in presence of base such as sodium hydroxide in mixture of solvent IPA and dioxane to afford diol compound (31), which is cyclized to benzyl protected ertugliflozin (32) using p-toluenesulfonic acid monohydrate in DCM at room temperature.

The drawbacks of this scheme are, use of sodium hydride for benzyl protection, hence handling in scale up is difficult. The tetra-n-butylammonium fluoride (TBAF) used for deprotection of tert-butyl dimethyl silyl group is an expensive reagent. The palladium metal is used for deprotection of benzyl group. The reduction reaction in DCM takes 36 hours for completion which makes operation lengthier and costly.

Scheme-4:

The Organic Letters, 2010, 12, 2940-2943 discloses the preparation of ertugliflozin as depicted in scheme 4. The a-D-mannofuranose (33) is protected using acetone and p-TSA to afford diacetone-a-D-mannofuranose compound (34). The free hydroxyl group of diacetone-a-D-mannofuranose (34) is protected using tert-butyldimethyl silyl chloride in presence of imidazole as base in DMF to obtain compound (35). The side chain of compound (35) is selectively deprotected by using acetic acid water at 55oC to obtain compound (36). Further oxidation of side chain of compound (36) is performed using sodium periodate (NaIO4), water, ethanol to obtain compound (37). The lithium anion derived from crystalline dithiane (38) is added diastereoselectively to aldehyde compound (37) at low temperature in THF to produce intermediate (39) as a single diastereomer via Si face addition to the aldehyde. Further, the compound (39) is treated with TBAF in THF at low temperature to produce lactol compound (40); further treatment of compound40in MeOH/H2O at 85oC with excess formaldehyde in the presence of potassium carbonate (K2CO3) provided intermediate (41). The lactol (41) is reduced by sodium borohydride in MeOH at 23 °C to produce acyclic advanced intermediate (42). Further, the compound (42) is stirred at 23°C in a mixture of TFA/H2O under air, deprotection/cyclization occurred to produce ertugliflozin free base.

The drawbacks of this scheme are number of reaction steps are more in this route and the expensive reagent like TBAF is used for deprotection.

In synthesis of ertugliflozin, all steps are important, however, oxidation step (stage 6, scheme 3; stage 4, scheme 4) is critical, and the aldehyde compound is unstable. In reported scheme-3, reaction is done in dichloromethane solvent at reflux temperature for 36 hours, which makes the process uneconomical. Hence, oxidation step is modified using 2-iodoxy benzoic acid reagent in acetonitrile at reflux temperature which completes the conversion within two hours. Also, the preparation of ertugliflozin involved the multiple steps and use of more solvents, which makes the process uneconomical. Hence, the instant inventors are motivated to explore the research in preparation of ertugliflozin and intermediate thereof with cost-saving and industrially convenient way, which can be further used for the preparation of co-crystal of ertugliflozin with L-pyroglutamic acid or L-proline.

Objectives of the Invention

The main object of the present invention is to provide an improved process for the preparation of a compound of formula (I) and intermediate thereof, which is simple, economical, user- friendly, safer and commercially viable.

Another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I), which would be easy to implement on commercial scale, and to avoid excessive use of reagent(s) and organic solvent(s), which makes the present invention environment friendly as well.

Yet another objective of the present invention is to provide an improved process for the preparation of a compound of formula (I) in a high yield with high chemical purity.

Yet another objective of the present invention is to provide an improved process for the preparation of a compound of formula (Ia) or (Ib) from compound of formula (I) in a high yield with high chemical purity.

Summary of the Invention
Accordingly, the present invention provides an improved process for the preparation of ertugliflozin of formula (I) and intermediate thereof, which comprises the steps of:

(I)

a) obtaining a compound of formula (C) by reacting a compound of formula (A) with a compound of formula (B) in presence of organolithium compound in a suitable solvent or mixture of solvents thereof;
b) obtaining a compound of formula (D) from a compound of formula (C);
c) obtaining a compound of formula (E) by reacting a compound of formula (D) with oxidizing agent in a suitable solvent or mixture of solvents thereof;
d) obtaining a compound of formula (F) from a compound of formula (E);
e) obtaining a compound of formula (I) by reacting a compound of formula (F) with acid in a suitable solvent or mixture of solvents thereof;
f) optionally converting a compound of formula (I) to a compound of formula (Ia) or (Ib).
The above process is illustrated in the following general synthetic scheme:

Detailed Description of the Invention

The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a”, “an”, “the”, include plural referents unless the context clearly indicates otherwise.

The instant invention relates to an improved process for preparation of ertugliflozin (I) and intermediate thereof. The invention also relates to the conversion of a compound of formula (I) to a compound of formula (Ia) or (Ib) using L-pyroglutamic acid or L- proline, respectively.

In an embodiment of the present invention, wherein the said protecting group may be selected from group consisting of acetyl (Ac), silyl like trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS), trityl (Tr) and the like.

In an embodiment of the present invention, wherein the said organolithium compound used in step (a) may be selected from the group consisting of n-butyllithium (n-BuLi), n-hexyllithium and the like.

In another embodiment of the present invention, wherein the said solvent used in step (a) may be selected from the group consisting of heptane, chlorinated solvents such as dichloromethane (DCM), cyclic ethers such as tetrahydrofuran (THF) and the like or mixture of solvents thereof.

In another embodiment of the present invention, wherein the said oxidizing agent used in step (c) may be selected from 2-iodoxy benzoic acid, dess martin periodinane (1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one).

In another embodiment of the present invention, wherein the said solvent used in step (c) may be selected from the non-polar hydrocarbon solvents such as acetonitrile or nitrile derivatives as solvents and the like or mixture of solvents thereof.

In another embodiment of the present invention, wherein the said acid used in step (e) may be selected from the group consisting of organic or inorganic acids such as trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA), sulfuric acid and the like.

In another embodiment of the present invention, wherein the said solvent used in step (e) may be selected from the non-polar hydrocarbon solvents such as dichloromethane (DCM), tetrahydrofuran (THF), heptane and the like or mixture of solvents thereof.

In another embodiment of the present invention, wherein the preparation of a compound of formula (I) may be performed in an in-situ manner.

In another embodiment of the present invention, wherein all the crude compound may be used as such or may be purified by distillation or crystallization or by different techniques well understood by those skilled in the art.

The ertugliflozin of formula (I) is prepared with the process of instant invention may be further use for the preparation of compound of formula (Ia) or (Ib). Further, ertugliflozin of formula (I) may be converted into ertugliflozin L-pyroglutamic acid (Ia) or ertugliflozin L-proline (Ib) by improved process or by following the process described in the art.

The preparation of the starting materials and reagents used in the present invention are well known in prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Experimental
Example 1: Preparation of (2S,3R,4S,5S,6R)-2-(4-Chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound C)

To a solution of 100 g of 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether (bromo compound) in 400 ml dry THF, 230 ml of 1.6 M n-BuLi in hexane and 144 g of 2,3,4,6-tetra-O-trimethylsilyl-ß-D-glucolactone (TMS-glucolactone) in 100 ml dry THF were added simultaneously at -70 to -90oC by addition funnel and stirred for 10 minutes. 36 ml methanesulfonic acid in 300 ml methanol was added in reaction mass by addition funnel at -70 to -90oC. The temperature was raised to 35 to 40oC and stirred for 3 hours. The reaction mass was cooled to 0 to 10oC and quenched with NaHCO3 solution and further extracted with DCM and the organic layer was concentrated to yield 148 g of semi solid O-methyl compound. The crude compound was dissolved in 200 ml DCM and the solution was slowly charged into 1500 ml heptane. The precipitated solid was separated by decantation, dissolved in 100 ml DCM and concentrated to yield 115 g floppy solid compound.
1H NMR (400 mHz, DMSO-d6) d (ppm): 1.25-1.30 (t, 3H), 2.86-2.88 (m, 3H), 2.88-3.75 (m, 6H), 3.93-4.04 (m, 4H), 4.54-4.57 (t, 1H), 4.76-4.80 (dd, 2H), 4.98-5.00 (d, 1H), 6.80-6.83 (d, 2H), 7.05-7.07 (d, 2H), 7.38 (s, 2H), 7.52 (s, 1H).
MS (ESI): 456 [M+NH3]+
IR in KBr (Frequency (cm-1), 826.38 (C-Cl stretching), 1244.5 (C-O stretching), 2926.1 (C-H stretching), 3415.2 (O-H stretching).
HPLC purity: 90.03%

Example 2: Preparation of ((2R,3R,4S,5R,6S)-6-(4-Chloro-3-(4-ethoxybenzyl) phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-yl)methanol (Compound D)

To a solution of 25 g O-methyl compound in 250 ml DCM, 19 g imidazole was added at room temperature. The reaction mass was cooled to 0 to 10oC and charged 34 ml trimethylsilyl chloride by addition funnel. The temperature of reaction mass was raised to 20 to 30oC and stirred for 1 hour. After complete conversion of O-methyl compound on TLC, quenched the reaction mass with 125 ml water and organic layer was separated. The organic layer was stirred with mixture of 61g of p-toluenesulfonic acid monohydrate, 28.5 g pyridine and 75 ml water for 16 hours. The organic layer was separated, washed with water and brine and further concentrated and purified by column chromatography (hexane:ethyl acetate) to yield 25 g thick oily mass of monohydroxy compound.
1H NMR (400 mHz, DMSO-d6) d (ppm): -0.43 (s, 9H), 0.13 (s, 9H), 0.16 (s, 9H), 1.26-130 (t, 3H), 2.94 (s, 3H), 3.16-3.19 (d, 1H), 3.36-3.39 (m, 1H), 3.51-3.67 (m, 3H), 3.87-4.07 (m, 5H), 4.60-4.63 (m, 1H), 6.80-6.82 (d, 2H), 7.08-7.10 (d, 2H), 7.34-7.44 (m, 3H).
HPLC purity: 96.71%

Example 3: Preparation of (2S,3R,4S,5R,6S)-6-(4-Chloro-3-(4-ethoxybenzyl) phenyl)-6-methoxy-3,4,5-tris-(trimethylsilyloxy)tetrahydro-2H-pyran-2-carbaldehyde (Compound E)

To a solution of 10 g monohydroxy compound in 100 ml acetonitrile, 8.54 g 2-iodoxybenzoic acid (IBX)was added at room temperature. The reaction mass was stirred to 60 to 70oC for 2 hours. After complete oxidation of primary alcohol on TLC, the reaction mass was cooled to 20 to 30oC and filtered the solid. The filtrate was concentrated. The semisolid residue was stirred in 100 ml hexane, and filtered to remove byproduct of 2-iodoxybenzoic acid. The filtrate was concentrated to yield 9.2 g of thick oily reaction mass.
1H NMR (400 mHz, CDCl3) d (ppm): -0.34 (s, 9H), 0.13 (s, 9H), 0.18 (s, 9H), 1.36-139 (t, 3H), 3.00 (s, 3H), 3.25-3.28 (d, 1H), 3.64-3.69 (t, 1H), 3.94-4.09 (m, 6H), 4.05-4.09 (t, 1H), 4.12-4.16 (d, 1H), 6.77-6.80 (d, 2H), 7.06-7.08 (d, 2H), 7.30-7.38 (m, 3H), 9.70-9.71 (d, 1H).
HPLC purity: 41.08 % & 40.33 % (two isomers)

Example 4: Preparation of (2S,3R,4S,5S)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6,6-bis(hydroxymethyl)-2-methoxytetrahydro-2H-pyran-3,4,5-triol (Compound F)

To a solution of 2 g aldehyde compound in 20 ml ethanol, 1.84 g paraformaldehyde was added and the reaction mass was heated to 50 to 55oC temperature. At 50 to 55oC temperature, 0.417 g NaOEt in 4 ml EtOH was charged slowly by addition funnel and stirred at same temperature for 4 hours. The reaction mass was quenched with 5.7g NaHSO3 in 50 ml water then cooled to 20 to 30oC and the organic solvent was distilled. The resulting residue was extracted with 20 ml methyl tert-butyl ether(MTBE). The organic layer was separated, then washed with brine and concentrated and purified by column chromatography (DCM:MeOH) to obtain 0.8 g solid pentahydroxy compound.
1H NMR (400 mHz, DMSO-d6) d (ppm): 1.27-1.30 (t, 3H), 2.80-2.83 (m, 1H), 3.01 (s, 3H), 3.52-3.57 (m, 1H), 3.66-3.69 (m, 2H), 3.75-3.79 (m, 2H), 3.82-3.86 (dd, 1H), 3.93-4.03 (m, 4H), 4.23-4.25 (t, 1H), 4.51-4.54 (t, 1H), 4.70-4.75 (m, 2H), 5.05-5.06 9d, 1H), 6.80-6.82 (d, 2H), 7.05-7.07 (d, 2H), 7.32-7.34 (d, 1H), 7.42-7.45 (dd, 1H), 7.56 (d, 1H).
MS (ESI): 467 [M-H]-

Example 5: Preparation of (1R,2S,3S,4R,5R)-5-(4-Chloro-3-(4-ethoxybenzyl) phenyl)-1-(hydroxymethyl)-6,8-dioxabicyclo-[3.2.1]octane-2,3,4-triol (I)

To a solution of 0.1 g pentahydroxy compound in 3 ml DCM, 0.122 g TFA was added at 0 to 10oC. The temperature was raised to 20 to 30oC and the reaction mass was stirred for 16 hours. The reaction mass was quenched with 0.2 g NaHCO3 in 3 ml water, then the organic layer was separated. The organic layer was washed with brine and concentrated and purified to obtain 0.05g solid compound ertugliflozin.
1H NMR (400 mHz, DMSO-d6) d (ppm): 1.27-1.31 (t, 3H), 3.37-3.55 (m, 5H), 3.60-3.65 (m, 1H), 3.94-3.98 (m, 5H), 4.75-4.78 (t, 1H), 4.90-4.92 (d, 1H), 4.98-4.99 (d, 1H), 5.19-5.21 (d, 1H), 6.81-6.83 (d, 2H), 7.07-7.09 (d, 2H), 7.28-7.31 (dd, 1H), 7.38-7.40 (m, 2H)
MS (ESI): 454 [M-18]& 435 [M-H]-

Abbreviations

Ac : Acetyl
Ac2O : Acetic anhydride
AcOH : Acetic acid
AlMe3 : Trimethylaluminium
BnBr : Benzyl bromide
CDCl3 : Deuterated Chloroform
cm-1 : Per centimetre
COCl2 : Phosgene/ Carbonyl chloride
DCM : Dichloromethane
DMF : N,N-dimethylformamide
DMSO : Dimethyl sulfoxide
eq : Equivalent
g : Gram
EtOH : Ethanol
GC : Gas chromatography
h : Hour/s
HCHO : Formaldehyde
HCOOH : Formic acid
HF : Hydrogen fluoride
H2O : Water
H2O2 : Hydrogen peroxide
HPLC : High performance liquidchromatography
IBX : 2-Iodoxybenzoic acid
IPA : Isopropanol
IR : Infrared
KBr : Potassium bromide
K2CO3 : Potassium carbonate
Kg : Kilogram
L : Litre
L-PGA : L-pyroglutamic acid
ml : Millilitre
MeOH : Methanol
MsOH : Methanesulfonic acid
MS : Mass spectrometry
MTBE : Methyl tert-butyl ether
NaBH4 : Sodium Borohydride
NaH : Sodium hydride
NaHCO3 : Sodium bicarbonate
NaHSO3 : Sodium bisulfite
NaIO4 : Sodium periodate
NaOEt : Sodium ethoxide
NaOH : Sodium hydroxide
NaOMe : Sodium methoxide
n-BuLi : n-Butyllithium
NMP : N-Methyl-2-pyrrolidone
NMR : Nuclear magnetic resonance
PdCl2 : Palladium(II) chloride
PMB : p-Methoxybenzyl
p-TSA : p-Toluenesulfonic acid
RBF : Round bottom flask
RM : Reaction mixture
rt : Room temperature
SGLT2 : Sodium-glucose co-transporter-2
SO3 : Sulfur trioxide
TBAF : Tetra-n-butylammonium fluoride
TBDMSCl : tert-Butyldimethylsilyl chloride
TBS : tert-Butyldimethylsilyl
TEA : Triethyl amine
TES : Triethylsilane
TFA : Trifluoroacetic acid
THF : Tetrahydrofuran
TLC : Thin layer chromatography
TMS : Trimethylsilyl
TMSCl : Trimethylsilyl chloride
Tr : Trityl
V : Volume

Advantages of the present invention

1. The instant invention produces ertugliflozin (I) in a high yield with high chemical purity.
2. The instant invention produces ertugliflozin (I) and intermediate thereof in lesser time and in economical manner.
3. The instant robust invention leads to low effluent generation, hence makes the process more environmental friendly, safer and thereby commercially viable.
4. The instant invention for the preparation of ertugliflozin (I) avoids hazardous substance such as sodium hydride.
,CLAIMS:We claim:

1. An improved process for the preparation of ertugliflozin of formula (I) and intermediate thereof, which comprises the steps of:

(I)

a) obtaining a compound of formula (C) by reacting a compound of formula (A) with a compound of formula (B) in presence of organolithium compound in a suitable solvent or mixture of solvents thereof;

(A) (B)

(C)
b) obtaining a compound of formula (D) from a compound of formula (C);

(D)
wherein, P1 is H or protecting group selected from acetyl (Ac), silyl like trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS), trityl (Tr);
P2 is protecting group selected from acetyl (Ac), silyl like trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS), trityl (Tr);
c) obtaining a compound of formula (E) by reacting a compound of formula (D) with oxidizing agent in a suitable solvent or mixture of solvents thereof;

(E)
wherein P2 is protecting group selected from acetyl (Ac), silyl like trimethylsilyl (TMS) or tert-butyldimethylsilyl (TBS), trityl (Tr);
d) obtaining a compound of formula (F) from a compound of formula (E);

(F)
e) obtaining a compound of formula (I) by reacting a compound of formula (F) with acid in a suitable solvent or mixture of solvents thereof;

(I)

f) optionally converting a compound of formula (I) to a compound of formula (Ia) or (Ib).

(Ia) (Ib)
2. The process as claimed in claim 1, wherein the said organolithium compound used in step (a) is selected from the group consisting of n-butyllithium (n-BuLi), n-hexyllithium.

3. The process as claimed in claim 1, wherein the said solvent used in step (a) is selected from the group consisting of heptane, chlorinated solvents such as dichloromethane (DCM), cyclic ethers such as tetrahydrofuran (THF) or mixture of solvents thereof.

4. The process as claimed in claim 1,wherein the said oxidizing agent used in step (c) is selected from 2-iodoxy benzoic acid, dess martin periodinane[1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one].

5. The process as claimed in claim 1, wherein the said solvent used in step (c) is selected from the non-polar hydrocarbon solvent such as acetonitrile or nitrile derivatives as solvent or mixture of solvents thereof.

6. The process as claimed in claim 1, wherein the said acid used in step (e) is selected from the group consisting of organic or inorganic acids such as trifluoroacetic acid (TFA), p-toluenesulfonic acid (p-TSA), sulfuric acid.

7. The process as claimed in claim 1, wherein the said solvent used in step (e) is selected from the non-polar hydrocarbon solvents such as dichloromethane (DCM), tetrahydrofuran (THF), heptane or mixture of solvents thereof.