DESC:RELATED PATENT APPLICATION(S)

This application claims the priority to and benefit of Indian Patent Application No. 201941003486 filed on January 29, 2019, Indian Patent Application No. 201941021160 filed on May 28, 2019 and Indian Patent Application No. 201941047211 filed on November 19, 2019; the disclosures of which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation of Ertugliflozin or its pharmaceutically acceptable salt thereof.

BACKGROUND OF THE INVENTION

Ertugliflozin is a selective sodium glucose cotransporter 2 inhibitor used for the treatment of type 2 diabetes mellitus.
Ertugliflozin is chemically known as (1S,2S,3S,4R,5S)-5-(4-chloro-3-(4­ethoxybenzyl)phenyl)-1-(hydroxymethyl)-6,8- dioxabicyclo[3.2.1]octane-2,3,4-triol, represented by the Formula (I).

Ertugliflozin was first disclosed in the US Patent No. 8,080,580 assigned to Pfizer Inc. This patent discloses a process for the preparation of Ertugliflozin as mentioned below,


and discloses the preparation of Ertugliflozin from the diol intermediate using trifluoroacetic acid or acidic resin in dichloromethane at -10°C.
This process employs siliabond tosic acid or trifluoroacetic acid or acidic resin for the preparation of Ertugliflozin from the diol intermediate. The reusing of siliabond tosic acid is not possible, it is costly and also not commercially available.
The publication Journal of Organic Chemistry Vol. 61, No. 26, 1996 discloses the oxidation of alcohol into carbonyl compound with the use of Dess Martin Periodinane.
The PCT Publication WO 2013038429 assigned to Panacea Biotec Ltd discloses the process for the preparation of Ertugliflozin derivatives (generically).
The PCT publication WO 2015043511 (assigned to Sunshine Pvt. Ltd.) discloses the below mentioned process in Scheme-2 for the preparation of Ertugliflozin derivatives.

Hence, there remains a need for an improved process for the preparation of Ertugliflozin L-pyroglutamic acid which is commercially and economically viable, being well-suited for use on an industrial scale.

OBJECTIVE OF THE INVNETION

The objective of present invention is to provide an improved process for the preparation of Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof.

SUMMARY OF THE INVENTION

Accordingly, there is provided an improved process for preparing the Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof.
In one of the aspects of the present invention, there is provided a process for the preparation of Ertugliflozin of formula (I) or its pharmaceutical acceptable salt thereof, comprising the steps of:
(a) oxidising the compound of formula (IV)

in the presence of an oxidizing agent selected from Dess Martin Periodinane or 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and sodium hypochlorite in suitable solvent to obtain the aldehyde intermediate compound of formula (III);

(b) converting the aldehyde intermediate compound of formula (III) into diol intermediate compound of formula (II); and

(c) cyclizing the diol compound of formula (II) in the presence of cationic resin or acidic catalyst at 30°C to obtain a free Ertugliflozin compound of formula (I) or its pharmaceutically acceptable salt thereof.

In another aspect of the present invention, there is provided a process for the preparation of Ertugliflozin of formula (I) or its pharmaceutical acceptable salt thereof by cyclizing the diol compound of formula (II) in the presence of cationic resin at 30°C.

In yet another aspect of the present invention, there is provided an improved process for preparing Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof by treating the compound of formula (II) with acid catalyst selected from the group consisting of para toluene sulfonic acid, poly phosphoric acid, trifluoroacetic acid in organic solvent(s).

In some embodiment, the oxidizing agent in the above described process for the preparation of Ertugliflozin is Dess Martin Periodinane.
In some other embodiment, the solvent used in process for the preparation of Ertugliflozin is selected from the group comprising aromatic solvent including benzene, toluene or xylene; ester solvent including n-butyl acetate, isopropyl acetate, methyl acetate or ethyl acetate; ether solvent including di-isopropyl ether or tetrahydrofuran; amide solvent including dimethyl formamide or 2-pyrrolidone; chlorinated solvents including dichloromethane or dichloroethane; alcohol solvent including methanol, ethanol or isopropanol or mixture thereof. In some embodiment, the solvent used in step (a) of the above described process for the preparation of Ertugliflozin is chlorinated solvent selected from dichloromethane or dichloroethane.
In some embodiment, the process according to invention employs the cationic resin selected from the group comprising methyl acrylic acid type or acrylic acid type having carboxylic acid group, gel polyacrylic acid copolymer having carboxylic acid group, macro porous strong acidic cation exchange resin-polystyrene co-polymer or polystyrene copolymer matrix having sulfonic acid. In some other embodiment, the cationic resin is macro porous strong acidic cation exchange resin-polystyrene co-polymer. In some other embodiment, the cationic resin used in the process according to invention is polystyrene copolymer matrix having sulfonic acid.
In some embodiment, the conversion of compound of formula (III) to compound of formula (II) is carried in presence of paraformaldehyde and sodium ethoxide in ethanol.
In some other embodiment, the acidic catalyst used in step (c) of the above described process for the preparation of Ertugliflozin is selected from para toluene sulfonic acid, poly phosphoric acid or trifluoroacetic acid.
In some embodiment, the obtained Ertugliflozin of formula (I) is further treated with L-pyroglutamic acid to obtain Ertugliflozin L-pyroglutamic acid salt.

DETIALED DESCRIPTION OF THE INVENTION

The present invention provides an improved process for the preparation of Ertugliflozin or its pharmaceutically acceptable salt thereof.
The term “pharmaceutically acceptable salt” refers inorganic or organic acid addition salts, co-crystals and solvates.
In one aspect of the present invention, there is provided a process for the preparation of Ertugliflozin of formula (I) or its pharmaceutical acceptable salt thereof, comprising the steps of:
(a) oxidising the compound of formula (IV)

in the presence of an oxidizing agent selected from Dess Martin Periodinane or 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and sodium hypochlorite in suitable solvent to obtain the aldehyde intermediate compound of formula (III);

(b) converting the aldehyde intermediate compound of formula (III) into diol intermediate compound of formula (II); and

(c) cyclizing the diol compound of formula (II) in the presence of cationic resin or acidic catalyst at 30°C to obtain a free Ertugliflozin compound of formula (I) or its pharmaceutically acceptable salt thereof.

In some embodiment, the oxidizing agent used in the process according to invention for the conversion of compound of formula (IV) to compound of formula (III) is Dess Martin Periodinane. In some other embodiment, step (a) of the present invention may be carried out in the presence of (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and sodium hypochlorite in suitable solvents.
The inventors of the present invention, surprisingly got a good conversion and good yield by the use of Dess Martin Periodinane as an oxidizing agent during the oxidation of the compound of formula (IV) to provide the compound of formula (III).
According to some embodiment, step (b) of the present invention for converting compound of formula (III) to compound of formula (II) is carried out in the presence of paraformaldehyde and sodium ethoxide in ethanol.
According to some embodiment, step (c) of the present invention for converting compound of formula (II) to compound of formula (I) is carried out in the presence of cation exchange resin or acidic catalyst selected from para toluene sulfonic acid, poly phosphoric acid or trifluoroacetic acid..
In some other embodiment, the present invention may be carried out in a solvents selected from the group comprising the organic solvents including aromatic solvents such as benzene, toluene, xylene and like; ester solvents such as n-butyl acetate, isopropyl acetate, methyl, acetate, ethyl acetate and like; ester solvents such as di-isopropyl ether, tetrahydrofuran and like; amide solvents such as dimethyl formamide, 2-pirolidone and like; chlorinated solvents such as dichloromethane, dichloroethane and like; alcohol solvents such as methanol, ethanol or isopropanol or mixture thereof.
In some embodiment, the step (a) for converting compound of formula (IV) to compound (III) is carried in presence of chlorinated solvent selected from dichloromethane or dichloroethane.
In another aspect of the present invention provides a process for the preparation of Ertugliflozin of formula (I) or its pharmaceutical acceptable salt thereof by cyclizing the diol compound of formula (II) in the presence of cationic resin at 30°C.

In some embodiment, the process according to invention employs the cationic resin selected from the group comprising methyl acrylic acid type or acrylic acid type having carboxylic acid group, gel polyacrylic acid copolymer having carboxylic acid group, macro porous strong acidic cation exchange resin-polystyrene co-polymer or polystyrene copolymer matrix having sulfonic acid. In some other embodiment, the cationic resin is macro porous strong acidic cation exchange resin-polystyrene co-polymer. In some other embodiment, the cationic resin used in the process according to invention is polystyrene copolymer matrix having sulfonic acid. In some embodiment, the cationic resin used for the conversion of compound of formula (II) to compound of formula (I) is polystyrene copolymer matrix having sulfonic acid.
The inventors of the present invention, surprisingly got a better conversion and good yield by the use of cationic exchange resin, during the cyclisation of the compound of formula (II) to provide the compound of formula (I) and this cationic exchange resin is commercially available and economically good for the manufacturing.
In yet another aspect of the present invention is to provide an improved process for preparing Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof by treating the compound of formula (II) with acid catalyst selected from the group consisting of para toluene sulfonic acid, poly phosphoric acid, trifluoroacetic acid in organic solvent(s).

According to this embodiments of the present invention, the said organic solvent(s) includes aromatic solvents such as benzene, toluene, xylene and like; ester solvents such as n-butyl acetate, isopropyl acetate, methyl acetate, ethyl acetate and like; ether solvents such as di-isopropyl ether, tetrahydrofuran and like; amide solvents such as dimethyl formamide, 2-pyrrolidone and like; chlorinated solvents such as dichloromethane, dichloroethane and like; alcohol solvents such as methanol, ethanol or isopropanol or mixture thereof.
Surprisingly the inventors of the present invention found that, the cyclising reaction of the compound of formula (II) with acid catalyst consisting of para toluene sulfonic acid, poly phosphoric acid, trifluoroacetic acid provides better conversion and good yield. Handling of these catalyst are easy and removal of acid catalyst is easy from the reaction mass. Further, it is commercially available and economically significant.
In some embodiment, the Ertugliflozin of formula (I) obtained is further treated with L-pyroglutamic acid to obtain Ertugliflozin L-pyroglutamic acid salt.
The present invention is explained in detail with reference to the following examples described below, which are given for the purpose of illustration only and are not intended to limit the scope of the invention.

EXAMPLES

Example-1: Process for preparing the compound of formula (II)

Step-a
To a mixture of (2S,3R,4S,5S,6R)-2-(4-chloro-3-(4-ethoxybenzyl)phenyl)-6-(hydroxyMethyl)-2-Methoxytetrahydro-2H-pyran-3,4,5-triol (93 gm) and dichloromethane (744 mL), imidazole (93.75 gm) was added at 30°C followed by the addition of trimethyl silyl chloride (148 mL) at 5°C. The obtained reaction mixture was then heated to 30°C and maintained at the same temperature for 2 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, process water (1000 mL) was charged into the reaction mass, organic layer was separated from the biphasic mixture and cooled to 5°C.
Step-b
To the mixture of cooled organic layer obtained in step (a), the freshly prepared pyridinium p-toluene sulfonic acid monohydrate solution (201.50 gm of p-toluene sulfonic acid monohydrate in 279 mL of water and cooled to 15°C followed by addition of 94 mL of pyridine) was added slowly. Then the reaction mixture was heated to 30°C and maintained at the same temperature for 14 hours. The progress of the reaction was monitored by GC. After completion of the reaction, the organic layer was separated from the reaction mass. Freshly prepared phosphate buffer (pH 7) (465 mL) (30.69 gm of disodium phosphate and 12.1 gm of monosodium phosphate in 465 ml of water) was added to the obtained organic layer to form a biphasic mixture then the organic layer was separated and cooled to 5°C.
Step-c
To the cooled reaction mass obtained in step (b), Dess-Martin Periodinane (134.8 gm) was added under nitrogen atmosphere and maintained the temperature at 5°C for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, 25% of sodium thiosulfate solution (930 mL) was added to the reaction mass followed by the addition of saturated sodium bicarbonate solution (930 mL) at 5°C and heated the mass to 30°C and maintained for 1 hour. The organic layer was separated from the resulted reaction mixture and washed with 465 mL of process water. The organic layer was separated from the resulted reaction mixture and concentrated under reduced pressure at 40°C then co-concentrated with ethanol (186 mL) under reduced pressure at 40°C to obtain pale yellow oily mass.

Step-d
To a mixture of oily mass obtained in step (c), ethanol (744 mL) paraformaldehyde (127.2 gm), sodium ethoxide in ethanol (137.38 gm) was added at 60°C and maintained the same temperature for 6 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, 30% sodium bisulphite solution (930 mL) was added at 60°C and maintained the temperature for 30 minutes. The resulted reaction mass was concentrated at 40°C under reduced pressure, then cooled to 30°C followed by the addition of methyl tert-butyl ester to form a biphasic mixture. The organic layer was separated, washed with water (465 mL), concentrated at 40°C under reduced pressure and then co-concentrated with methanol (186 mL) to the obtained oily mass. The methanol (465 mL) was charged to the obtained oily mass at 40°C followed by the addition of pencarb-N (4.65 gm) and maintained the temperature for 30 minutes at 40°C. The obtained reaction mass was filtered through hyflo bed. Seeding material (93 mg) was added to the obtained filtrate at 30°C then cooled to 2°C and maintained the cooling for 6 hours to obtain the thick mass. The resulted mass was filtered under nitrogen atmosphere then washed with pre-cooled methanol (46.5 mL) followed by heptane (186 mL) and dried to obtain compound of formula (II). Yield: 38 gm
Example-2: Process for preparing the Ertugliflozin of the formula (I)
To a mixture of the compound of formula (II) (24 gm) obtained from Example-1 and dichloromethane (240 mL), cation exchange resin (2.4 gm) was added at 30°C. The reaction mixture was maintained at 30°C for 8 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was filtered through hyflo bed, followed by micron filtration to obtain a clear solution. The resulted clear solution was concentrated at 45°C under reduced pressure to provide oily mass. The obtained oily mass was dissolved in methyl tert-butyl ethyl acetate (30 ml) at 30°C then crystallized with heptane (160 ml) at the same temperature. The resulted reaction mass was filtered and dried to obtain Ertugliflozin. Yield: 18.5 gm.
Example-3: Process for the preparation of Ertugliflozin Pyroglutamic acid
Step-a
To a mixture of the compound of formula (II) (10 gm) obtained from Example-1 and dichloromethane (100 mL), macro porous strong acidic cation exchange resin-polystyrene-co-polymer (1.0 gm) was added at 30°C. The reaction mixture was maintained at 30°C for 20 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mass was filtered through hyflo bed, followed by micron filtration to obtain a clear solution. The resulted clear solution was concentrated at 45°C under reduced pressure to provide oily mass.
Step-b
To the oily mass obtained in step (a), isopropyl alcohol (24 mL) water (14 mL) and L-pyroglutamic acid solution (8.2 gm in 42 mL of water) were slowly added at 60°C. Then the reaction mass was gradually cooled to 25°C. The seeding material was added to the cooled mass and maintained the temperature at 25°C for 20 hours. Further the reaction mass was cooled to 3 °C and maintained the temperature for 5 hours. The resulted reaction mass was filtered and washed with heptane (20 ml) and dried to obtain Ertugliflozin Pyroglutamic acid. Yield: 10.6 gm
Example-4: Process for preparing the compound of formula (III)
To a mixture of dichloromethane (50 mL), potassium bromide (0.15 gm), sodium bicarbonate (2.85 gm) and (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) (0.01 gm), the compound of formula (IV) (5 gm) were added slowly at 0°C and maintained the temperature for 25 minutes. Freshly prepared sodium hypochlorite solution (0.7 gm of sodium bicarbonate in 7.6 ml of sodium hypochlorite solution at 5°C) was added to the reaction mixture at 0°C and maintained the temperature for 1 hour. The progress of the reaction was monitored by TLC. After completion of the reaction, 10% sodium thiosulfate (50 mL) was added to the reaction mass at 0°C to form a biphasic mixture. The resulted biphasic mixture was heated to 25°C and separated the organic layer. The obtained organic layer was concentrated under reduced pressure to provide compound of formula (III) as oily mass. Yield: 4.5 gm.
Example-5: Process for preparing the Ertugliflozin of the formula I
To a mixture of the compound of formula (II) (30 gm) and dichloromethane (300 mL), para toluene sulfonic acid monohydride (1.50 gm) was added at 30°C. The reaction mixture was maintained at 30°C for 22 hours. The progress of the reaction was monitored by HPLC. After completion of the reaction, 1% sodium bicarbonate solution (300 mL) was added to the reaction mass to form biphasic mixture. The organic layer was separated from the resulted biphasic mixture then washed with 5% sodium chloride solution (300 mL). The obtained organic layer was distilled under reduced pressure to form the titled compound. % Yield: 96.70%.
Example-6: Process for the preparation of Ertugliflozin of the formula (I)
To a mixture of the compound of formula (II) (2 gm) and dichloromethane (25 mL), poly phosphoric acid (0.20 gm) was added at 30°C. The reaction mixture was maintained at 30°C for 19 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water (20 mL) was added to the reaction mass to form biphasic mixture and then the organic layer was separated. The resulting organic layer was distilled under reduced pressure to form the titled compound. % Yield: 97.0 %
Example-7: Process for the preparation of Ertugliflozin of the formula (I)
To a mixture of the compound of formula (II) (2 gm) and dichloromethane (25 mL), trifluoro acetic acid (0.20 gm) was added at 30°C. The reaction mixture was maintained at 30°C for 19 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, water (20 mL) was added to the reaction mass to form biphasic mixture then the organic layer was separated. The resulting organic layer was distilled under reduced pressure to form the titled compound. % Yield: 96.0 %
Example-8: Process for preparing Ertugliflozin L-pyroglutamic acid
To a mixture of Ertugliflozin (50 g), water (50 ml) and isopropanol (100 ml), L-pyroglutamic acid solution was added (41.3 g of L-pyroglutamic acid dissolved in 200 ml of water) at 30°C then heated to 55°C and maintained the temperature for an hour. The heated reaction mass was allowed to cool at 30°C followed by stirring for 18 hours at the same temperature. And then the isopropanol was concentrated under reduced pressure, cooled to 25°C and stirred for 5 hours at 25°C. The resulted solid was filtered, washed with n-heptane (200 ml) and dried. Yield: 47.5 g.
Example-9: Process for preparing Ertugliflozin L-pyro glutamic acid
To a mixture of Ertugliflozin (50 g), water (50 ml) and isopropanol (100 ml), L-pyroglutamic acid solution was added (41.3 g of L-pyroglutamic acid dissolved in 200 ml of water) at 30°C then heated to 55°C and maintained the temperature for an hour. The heated reaction mass was allowed to cool at 30°C followed by stirring for 18 hours at the same temperature. And then the isopropanol was concentrated under reduced pressure, cooled to 25°C and stirred for 3 hours. Further the reaction mass was cooled to 5°C followed by the addition of isopropanol (50 ml) and stirred for 3 hours at 0-5°C. The resulted solid was filtered, washed with n-heptane (200 ml) and dried to obtain Ertugliflozin L-pyro glutamic acid. Yield: 53.5 g.
Example-10: Process for preparing Ertugliflozin L-pyro glutamic acid
To a mixture of Ertugliflozin (40 g) and L-pyroglutamic acid (9.92 g), dichloromethane (480 ml) was added at 30°C and stirred for 18 hours at the same temperature. Then reaction mass was filtered, washed with methyl tert-butyl ether (160 ml) and dried. Yield: 37 g. (Amount of dichloromethane in Ertugliflozin L-pyroglutamic acid co-crystal: 1099 ppm).
Example-11: Process for preparing Ertugliflozin L-pyro glutamic acid
To a mixture of Ertugliflozin (70 g) and isopropanol (910 ml), L-pyroglutamic acid (18.2 g) was added at 30°C and maintained the temperature for an hour. Then half of the solvent was concentrated under reduced pressure from the reaction mass, cooled to 30°C and stirred for 18 hours at the same temperature. Reaction mass was further cooled to 2°C and stirred for 5 hours at the same temperature. The resulted solid was filtered, washed with methyl tert-butyl ether (140 ml) and dried to obtain Ertugliflozin L-pyro glutamic acid. Yield: 66 g.
,CLAIMS:
1. A process for preparing Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof, comprising the steps of:
(a) oxidising the compound of formula (IV)

in the presence of an oxidizing agent selected from Dess Martin Periodinane or 2,2,6,6-Tetramethylpiperidin-1-yl)oxyl (TEMPO) and sodium hypochlorite in suitable solvent to obtain the aldehyde intermediate compound of formula (III);

(b) converting the aldehyde intermediate compound of formula (III) into diol intermediate compound of formula (II); and

(c) cyclizing the diol compound of formula (II) in the presence of cationic resin or acidic catalyst at 30°C to obtain a free Ertugliflozin compound of formula (I) or its pharmaceutically acceptable salt thereof.

2. A process for the preparation of Ertugliflozin of formula (I) or its pharmaceutically acceptable salt thereof by cyclizing the diol compound of formula (II) in the presence of cationic resin at 30°C; or
treating the compound of formula (II) with acid catalyst selected from the group consisting of para toluene sulfonic acid, poly phosphoric acid, trifluoroacetic acid in organic solvent(s).

3. The process as claimed in claim 1, wherein the oxidizing agent is Dess Martin Periodinane.
4. The process as claimed in claim 1, wherein the solvent is selected from the group comprising aromatic solvent including benzene, toluene or xylene; ester solvent including n-butyl acetate, isopropyl acetate, methyl acetate or ethyl acetate; ether solvent including di-isopropyl ether or tetrahydrofuran; amide solvent including dimethyl formamide or 2-pyrrolidone; chlorinated solvents including dichloromethane or dichloroethane; alcohol solvent including methanol, ethanol or isopropanol or mixture thereof
5. The process as claimed in claim 1, wherein the suitable solvent in step (a) is chlorinated solvent selected from dichloromethane or dichloroethane.
6. The process as claimed in claim 1, wherein the cationic resin used in step (c) is selected from the group comprising methyl acrylic acid type or acrylic acid type having carboxylic acid group, gel polyacrylic acid copolymer having carboxylic acid group, macro porous strong acidic cation exchange resin-polystyrene co-polymer or polystyrene copolymer matrix having sulfonic acid.
7. The process as claimed in claim 6, wherein the cationic resin is macro porous strong acidic cation exchange resin-polystyrene co-polymer.
8. The process as claimed in claim 1, wherein step (b) is carried in presence of paraformaldehyde and sodium ethoxide in ethanol.
9. The process as claimed in claim 1, wherein the Ertugliflozin of formula (I) is further treated with L-pyroglutamic acid to obtain Ertugliflozin L-pyroglutamic acid salt.
10. The process as claimed in claim 1, wherein the acidic catalyst is selected from para toluene sulfonic acid, poly phosphoric acid or trifluoroacetic acid.