DESC:FIELD OF THE INVENTION

The present invention provides a process for the preparation of Remogliflozin etabonate and intermediates thereof. The present invention further relates to process for purification of Remogliflozin etabonate.

BACKGROUND OF THE INVENTION

5-Methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (Remogliflozin etabonate) is represented with structure as follows:

Formula II.

Remogliflozin of Formula I belongs to the class of gliflozins and is a sodium-glucose transporter 2 inhibitor and works by reducing blood sugar levels by eliminating excess sugars from the body through urine. It is used for the treatment of non-alcoholic steatohepatitis ("NASH") and type 2 diabetes and was discovered by the Japanese company Kissei Pharmaceuticals.

IN 226624 discloses Remogliflozin and process for the preparation thereof, and
Remogliflozin etabonate is disclosed in IN 243093.

WO 2019/193572 discloses process for the preparation of Remogliflozin and etabonate salt thereof, wherein said process includes preparation of 1-(chloromethyl)-4-(propan-2-yloxy) benzene intermediate of Remogliflozin by treating [4-(propan-2-yloxy) phenyl] methanol with oxalyl chloride in presence of mixture of solvents such as dimethyl formamide and acetonitrile. The 1-(chloromethyl)-4-(propan-2-yloxy) benzene once formed is then isolated and further treated with methyl acetoacetate in presence of dimethyl formamide and inorganic base which on further reaction(s) provides Remogliflozin.

The major drawback of the above said process is that the process includes time consuming work up processes which results not only the wastage of solvents but also make the process lengthy.

IN 2013/KOLNP/2011 discloses process of preparation of Remogliflozin and etabonate salt thereof, wherein said process includes preparation of 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate intermediate by treating 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1,2-dihydro-3H-pyrazol-3-one with mesyl chloride in presence of acetonitrile and base.

The major disadvantage of the above said process lies in use of acetonitrile as a solvent. It is generally known that acetonitrile is highly flammable solvent that releases hydrogen cyanide fumes on heating resulting into cyanide contamination in the reaction. Hence, use of acetonitrile requires extra precautions to reduce contamination. Moreover, it is known that even minimum amount of acetonitrile can cause severe damage to human body as it has a tendency of immediate conversion to hydrogen cyanide. Hence, it is required to replace the highly toxic solvent with the solvent that yield good overall results and is less toxic as compared to acetonitrile.

Although there are several patent applications that discloses various processes for preparation of intermediates of Remogliflozin and use of same for the preparation of Remogliflozin and its etabonate salt, however, the prior published references describe processes that involves multiple toxic solvents and chlorinating agents for the preparation of Remogliflozin. Hence, there is always a need to develop an improved process of preparation of Remogliflozin which is economical at large scale production. In view of above, the present invention is focussed towards the manufacturing of Remogliflozin and its etabonate salt wherein the process is simple, economical and results into desired product without use of extreme toxic solvents.

OBJECT OF THE INVENTION

The main object of the present invention is to provide a process for the preparation of Remogliflozin or its etabonate salt.

Another object of the present invention is to provide a process for the preparation of intermediates of Remogliflozin and use of said intermediates in the preparation of Remogliflozin.

SUMMARY OF THE INVENTION

In main aspect, the present invention provides a process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting 4-hydroxy benzyl alcohol of Formula III to [4-(propan-2-loxy)phenyl]methanol of Formula IV in presence of isopropyl halide and suitable solvent, wherein said compound of Formula IV is not isolated;
b) in situ converting [4-(propan-2-yloxy)phenyl]methanol of Formula IV to 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V in presence of hydrochloric acid, wherein said compound of Formula V is not isolated;
c) in situ converting 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V to methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI in presence of methylacetoacetate;
; and
b) converting methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI to Remogliflozin and/or Remogliflozin etabonate salt thereof.

In another aspect, the present invention provides a process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI to 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII in presence of hydrazine hydrate and alcohol solvent or hydrocarbon solvent, wherein said compound of Formula VII is optionally not isolated;
;
b) reacting 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII with mesyl chloride in presence of hydrocarbon solvent and suitable base to give 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or salt thereof;
; and
c) converting 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or salt thereof to Remogliflozin and/or its etabonate salt.

In another aspect, the present invention provides a process for the preparation of Remogliflozin etabonate, comprising the steps of:
a) providing a solution of Remogliflozin in a suitable solvent;
b) treating with diethylpyrocarbonate in presence of catalyst and base at a temperature ranging from 40-60oC;
c) isolating Remogliflozin etabonate and treating with mixture of alcohol and n-heptane at a temperature ranging from 50-100oC;
d) isolating the crude Remogliflozin etabonate as a wet mass;
e) treating the wet mass with ether solvent at temperature ranging from 40-60oC and isolating the solid mass;
f) optionally repeating process of step e), followed by addition of water and n-heptane to get a reaction mass;
g) cooling followed by heating the reaction mass at 30-50oC;
h) treating the reaction mass of step g) with mixture of ether and n-heptane; and
i) cooling and isolating pure Remogliflozin etabonate.

DETAILED DESCRIPTION OF THE INVENTION
Drawings:
Fig. 1 depicts X-Ray Powder Diffraction (XRPD) of crystalline Remogliflozin Etabonate
Fig. 2 depicts Differential Scanning Calorimetry (DSC) of Crystalline Remogliflozin Etabonate
Fig. 3 depicts Thermogravimetric analysis (TGA) of Crystalline Remogliflozin Etabonate.

Definitions:
“Salts” as used in the context of the present invention refers to organic or inorganic acid. Inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid; and the like.

In context of the present invention, the term “suitable solvent” or “solvent” provides solvents that are used for preparing remogliflozin and its intermediates or its etabonate salt are selected from the group comprising of, but not limited to, C1-C6 alcohols, C1-C8 hydrocarbons, halogenated hydrocarbons, ethers, C3-C8 ketones, esters, nitriles, sulphonamides, acetamides, pyrrolidines, formamides, water and mixture thereof. For Example, some of the suitable solvents comprises of methanol, ethanol, butanol, t-butanol, isopropyl alcohol, n-propyl alcohol, iso-butanol, pentanol, glycols, toluene, chlorobenzene, acetonitrile, dimethyl acetamide (DMA), dimethylformamide (DMF), N-methyl pyrrolidine (NMP), dimethyl sulfoxide (DMSO), hexamethyl phosphoramide (HMPA), tetrahydrofuran (THF), methyl tetrahydrofuran, methyl tert. butyl ether (MTBE), dioxane, acetone, methyl ethyl ketone (MEK), methyl isobutyl ketone (MIBK), methyl t-butyl ketone, dicholoromethane, dichloroethane, chloroform, tetrachloromethane, chlorobenzene, ethyl acetate, propyl acetate, propenyl acetate, t-butyl acetate, hexane, n-heptane, cyclohexane, petroleum benzine, water and mixture thereof.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

In main embodiment, the present invention provides a process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting 4-hydroxy benzyl alcohol of Formula III to [4-(propan-2-yloxy)phenyl]methanol of Formula IV in presence of isopropyl halide and suitable solvent, wherein said compound of Formula IV is not isolated;
b) in situ converting [4-(propan-2-yloxy)phenyl]methanol of Formula IV to 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V in presence of hydrochloric acid, wherein said compound of Formula V is not isolated;
c) in situ converting 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V to methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of formula VI in presence of methylacetoacetate;
; and
b) converting methyl a-acetyl-4-(1-methylethoxy) benzenepropanoate of Formula (VI) to Remogliflozin and/or Remogliflozin etabonate salt thereof.

In another embodiment, the suitable solvent used in step a) is selected from alcohols, hydrocarbons, halogenated solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, toluene, o/m/p-xylene, dichloromethane or mixture thereof, and the like.

In another embodiment, the compound of Formula IV, once formed is treated with solvents selected from the group comprising of water, toluene, o/m/p-xylene, and acetone or mixture thereof, which is then proceeded into the next reaction without isolation.

In another embodiment, the isopropyl halide used in step a) is selected from isopropyl bromide, isopropyl iodide or isopropyl chloride.

In another embodiment, compound of Formula IV and V are isolated and purified before proceeding for next step or may proceed directly into the next step of chemical transformation.

In another embodiment, present inventors surprisingly found use of HCl for chlorination of Formula IV to give Formula V results in pure compound without any further purification, as well as it is a cost viable reagent and easy to handle at industrial level when compared to prior art used reagents.

In a preferred embodiment, compounds of Formulae IV and V are not isolated and are proceeded as such in next step.

In another embodiment, the present invention provides a process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting methyl a-acetyl-4-(1-methylethoxy) benzenepropanoate of Formula VI to 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII in presence of hydrazine hydrate and hydrocarbon solvent or alcohol solvent, wherein said compound of Formula VII is optionally not isolated;
;
b) reacting 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII with mesyl chloride in presence of hydrocarbon solvent and suitable base to give 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or salt thereof;
; and
c) converting 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or salt thereof to Remogliflozin and/or its etabonate salt.

In another embodiment, the hydrocarbon solvent used for preparing compounds of Formula VII and VIII are selected from, but not limited to, toluene, o/m/p-xylene, chlorobenzene, cyclohexane and the like and alcohol used are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or the like or its mixtures thereof.

In another embodiment, compound of Formula VII is isolated and purified before proceeding for next step or may proceed directly into the next step of chemical transformation.

In another embodiment, compound of Formula VIII is prepared by reacting compound of Formula VII with mesyl chloride in presence of suitable base selected from, but not limited to, triethyl amine, diisopropyl ethyl amine, diisopropyl amine, dimethyl amino pyridine, pyridine, trimethyl amine and the like.

In another embodiment, the present invention provides a process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting 4-hydroxy benzyl alcohol of Formula III to [4-(propan-2-yloxy) phenyl] methanol of Formula IV in presence of isopropyl halide and suitable solvent;
b) chlorinating [4-(propan-2-yloxy)phenyl]methanol of Formula IV to 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V in presence of hydrochloric acid;
c) converting 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V to methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of formula VI in presence of methylacetoacetate;
;
d) converting methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI obtained in step c) to 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII in presence of hydrazine hydrate and hydrocarbon solvent or alcohol solvent;
;
e) reacting 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII with mesyl chloride in presence of hydrocarbon solvent and suitable base to give 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or its salt thereof;
;
f) converting compound of formula VIII to compound of formula IX;
;
g) reacting compound of formula IX with acetobromoglucose in presence of phase transfer catalyst to give acetyl protected Remogliflozine;
;
h) deprotecting acetyl protected Remogliflozin to give Remogliflozin free base
; and
i) optionally converting Remogliflozin free base to Remogliflozin etabonate.

In another embodiment, phase transfer catalyst used for the reaction between compound of Formula VIII and acetobromoglucose are selected from tetra-n-butylammonium bromide, methyltrioctylammonium chloride benzyltriethylammonium chloride, methyltricaprylammonium chloride and methyltributylammonium chloride, hexadecyltributylphosphonium bromide,KI, crown ethers and the like.

In another embodiment, wherein compound of Formula IV, Formula V and compound of Formula VI, VIII, VIIIa and IX are either isolated or proceeded directly into the next step of chemical transformation. Preferably reactions are conducted in one-pot/reactor/rbf without isolating intermediates formed.

In another embodiment, wherein compounds of formula VIII and IX are not purified.
In another embodiment, the present invention provides a process for the preparation of Remogliflozin etabonate, comprising the steps of:
a) providing a solution of Remogliflozin in a suitable solvent;
b) treating with diethylpyrocarbonate in presence of catalyst and base at a temperature ranging from 40-60oC;
c) isolating Remogliflozin etabonate and treating with mixture of alcohol and n-heptane at a temperature ranging from 50-100oC;
d) isolating the crude Remogliflozin etabonate as a wet mass;
e) treating the wet mass with ether solvent at temperature ranging from 40-60oC and isolating the solid mass;
f) repeating process of step e), followed by addition of water and n-heptane to get a reaction mass;
g) cooling followed by heating the reaction mass at 30-50oC;
h) treating the reaction mass of step g) with mixture of ether and n-heptane; and
i) cooling and isolating pure Remogliflozin etabonate.

In another embodiment, the suitable solvent used for preparing Remogliflozin etabonate is selected from, but not limited to, methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, toluene, o/m/p-xylene, dichloromethane, water and mixture thereof.

In another embodiment, the ether solvent used for purification of Remogliflozin etabonate is selected from, but not limited to, methyl tert. butyl ether, dioxane, tetrahydrofuran, methyl ethyl ether and the like.

In another embodiment, the Remogliflozin and/or its etabonate salt is characterized by particle size distribution of D90 less than about 200 microns. Preferably, D90 less than about 190 microns. More preferably D90 in the range of 110-190 microns.

In another embodiment, Remogliflozin etabonate prepared according to present invention show weight loss in thermogravimetric analysis (TGA) in the range of 1.02% to 1.05%.

In another embodiment, Remogliflozin etabonate prepared according to present invention shows endothermic peak at 80-90ºC in DSC. Preferably at 81.2ºC

In another embodiment, Remogliflozin etabonate prepared according to present invention shows purity of greater than 99.5%. Preferably purity of greater than 99.9%.

Certain specific aspects and embodiments of the present application will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES
Example 1: Preparation of [4-(propan-2-yloxy)phenyl]methanol

Charged methanol (300 ml) in RBF at 20-25°C. Potassium hydroxide (79.0 g) was added and stirred for 30.0 min followed by addition of 4-hydroxy benzyl alcohol (100g) isopropyl bromide (300g) at 20-30°C. Reaction mass was heated at 40-45 °C for 25 hours. After reaction completion, reaction mass was extracted with toluene (1000 ml) and DM water (1000 ml) at 20-40°C. Separated the layers and organic layer used as such for next stage.

Example 1a: Preparation of [4-(propan-2-yloxy)phenyl]methanol
After repeating Example 1 above, organic layer obtained is distilled out completely and used for next step/reaction.

Example 2: Preparation of 1-(chloromethyl)-4-(propan-2-yloxy)benzene

To the above organic layer, charged hydrochloric acid (400 ml) and stirred the reaction mass for 2-3 h at 20-25°C. After reaction completion, charged DM water (100.0 ml) at 25-30°C. Separated the layers at 25-30°C. Washed the organic layer with 8% Sodium bicarbonate solution (300.0 ml); brine solution (200.0ml) at 25-30°C and distilled out approx. 5.0 -6.0 V of the toluene layer under vacuum. Remaining reaction mass was proceeded as such for next Stage.

Example 2a: Preparation of 1-(chloromethyl)-4-(propan-2-yloxy)benzene
Toluene (400.0 ml) was added to [4-(propan-2-yloxy)phenyl]methanol obtained in Example 1a. Hydrochloric Acid (400.0 ml) was added and stirred for 2-3 h at 20-25 °C. After reaction completion, separate the layers at 25-30 °C and distilled out organic layer under vacuum at 45-50 °C. Degas the reaction mass under vacuum.

Example 3: Preparation of methyl a-acetyl-4-(1-methylethoxy) benzene propanoate

To the above reaction mass was added N, N-diisopropylethylamine (162.0 g) at 25-30°C. Charged sodium iodide (13.0 g) at 25-30°C followed by slow addition of lithium chloride (30.0 g) at 25-30°C. Added 110.0g of methylacetoacetate at 25-30°C. Heated the reaction mass to 60°C for10-12 h. After reaction completion, added DM water (500 ml) at 40-45°C. Separated the layers at 40-45°C. Washed the organic layer with DM water (500.0 ml) at 25-30°C and distilled out followed by degassed the toluene layer under vacuum to obtain methyl a-acetyl-4-(1-methylethoxy)benzene propanoate (180.0g)

Example 3a: Preparation of methyl a-acetyl-4-(1-methylethoxy) benzene propanoate
To the above reaction mass was added toluene (1000 ml) at 20-25°C. Charged dimethyl formamide (250 ml) at 20-25°C. Added Potassium Carbonate (376 gm) and methyl acetoacetate (263 gm) at 20-25°C. Heated the reaction mass to 60-65°C for 40-45 hours. After completion of reaction, cooled the reaction mass to 20-25°C. Added DM water (500 ml) at 20-25°C and separated the layers at 20-25°C. Washed the combined organic layer with DM Water (310.0 ml *2) and distilled out toluene under vacuum. Degassed the reaction mass under vacuum to obtain methyl a-acetyl-4-(1-methylethoxy) benzene propanoate.

Example 3b: Preparation of methyl a-acetyl-4-(1-methylethoxy) benzene propanoate
To the reaction mass obtained in example 2a, charged Toluene (1000.0 ml), DMF (250.0 ml), Potassium Iodide (2.99 g), Potassium Carbonate (376.0 g), methyl acetoacetate (263.0 g) at 20-25°C. Reaction mass was heated to 60-65 °C and stirred for 40-45 hours. After reaction completion, reaction mass cooled to 20-25°C and DM water (500 ml) was added. Separate the layers at 20-25 °C and washed the combined organic layer with DM Water (310.0 ml *2). Distil out organic layer (toluene layer) under vacuum and degas the reaction mass under vacuum to obtain methyl a-acetyl-4-(1-methylethoxy) benzene propanoate.

Example 4: Preparation of 5-methyl-4-[4-(propan-2-yloxy) benzyl]-1,2-dihydro-3,7-pyrazol-3-one

Charged methanol (200 ml) in to a RBF at 25-30°C. Charged methyl a-acetyl-4-(1-methylethoxy) benzenepropanoate (100.0 g) at 25-30°C. Added Hydrazine Hydrate (39 g) at 25-30°C and stirred for 4.0 h. After reaction completion, added DM water (800 ml) at 25-30°C. Filtered the reaction mass and washed with DM water (100ml). To the wet cake was added toluene (300 ml) at 25-30°C. Heated the reaction mass at 60°C under stirring for 2.0 hours. Filtered the reaction mass and washed with toluene (100 ml). Dried the material under vacuum at 50-55 °C to give 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one (95.0 g)

Example 4a: Preparation of 5-methyl-4-[4-(propan-2-yloxy) benzyl]-1,2-dihydro-3,7-pyrazol-3-one
Toluene (940 ml) was added to methyl a-acetyl-4-(1-methylethoxy) benzenepropanoate obtained in example 3 at 25-30°C. Added Hydrazine Hydrate (204.0 g) at 25-30 °C via slow addition. Stirred the reaction mass for 4.0 h at 60-65 °C. After reaction completion, cooled the reaction mass to 0-5 °C. Filtered the reaction mass and washed with mixture of toluene and DM water. Dried the material in ATD at 55-60°C to get 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one.

Example 5: Preparation of 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl} methyl) -1H-pyrazol-3-yl methanesulfonate

Charged toluene (285 ml) in 3.0 litre RBF at 25-30°C and added 95.0 g of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one at 25-30°C. Added 34.0 g of pyridine at 5-10°C followed by slow addition of 50.0 g of mesyl chloride at 5-10°C. Stirred the reaction mass at 25-30°C for 4.0 h. After reaction completion, distilled out toluene under vaccum. Degassed the reaction mass under vaccum. Treated obtained mass using methanol and DM water. Dried the material under vacuum at 50-55°C to get 115.0 g of 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate.

Example 6: Preparation of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one

To 575.0 ml of N-methyl pyrrolidine was added 115.0 g of 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate at 25-30°C. Charged 26.0 g of lithium hydroxide monohydrate at 15-20°C. Added 130.0 g of isopropyl bromide and stirred the reaction mass at 25-30°C for 10-12.0h. After reaction completion, added 65.0 g of ethanol amine at 25-30°C. Heated the reaction mass at 60.0 C for 2.0 h. Cooled the reaction mass to 25-30°C. Added 920.0 ml of methanol at 25-30°C followed by slow addition of 265.0 ml of 4N Sodium hydroxide solution at 25-30°C. Heated the reaction mass to 60°C for 2.0 h. After reaction completion, adjusted the pH of reaction mass to 7-9 by using conc. HCl and stirred at 15°C for 6.0 h. Filtered the reaction mass through buckner funnel and washed with 400.0 ml of DM water. Dried the material under vacuum at 55 °C to get 64.0 g of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one.

Example 6a: Preparation of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one
Charged 300.0 ml of Dimethylacetamide in 3.0 litre RBF at 25-30°C and added 100.0 g of 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate at 20-25 °C. Charged 34.52 g of Potassium Hydroxide at 20-25 °C. Cooled the reaction mass to 0-5 °C. Added Slowly 75.83 g of Isopropyl bromide at 0-5°C. Stirred the reaction mass at 20-30° C for 15.0-18.0 h. After consumption of starting materials, cooled the reaction mass to 25-30°C. Added 55.65g of Ethanolamine and heated the reaction mass to 60°C for 2.0 h followed by cooling to 20-25°C. Added mixture of 800 ml methanol and sodium hydroxide solution in DM water (36.50 g NaOH in 226ml DM water) and heated the reaction mass so obtained at 60-65°C for 3 h. After completion of reaction, cooled the reaction mass to 15-20°C and adjusted the pH to 7.5- 9 by using 6N HCl followed by heating to 60-65°C for 30-60 min. Stirred the reaction mass at 25-30 °C for 12.0 h. Filtered the reaction mass through Buckner funnel and washed with 200.0 ml*2 of DM water. Again washed with 200.0 ml of methanol and then dried the material under vaccum at 55-60 °C to get 45.0 gm of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one.

Example 7: Preparation of Remogliflozin

Charged toluene (164 ml) in RBF at 20-25°C and added glucose pentaacetate (54 g) at 20-25°C. Cooled the reaction mass to 15°C and added HBr acetic acid (95.0 ml) at 15-20°C. After reaction completion, charged 216.0 ml of 5.0% brine solution. Separated the layers at 25-30°C. Washed the organic layer with 257.0 ml of 8.0% sodium bicarbonate solution. Washed the organic layer with 54.0 ml of 10.0 % brine solution at 25-30 °C. Distilled out the organic layer under vacuum at 40-45°C. Charged 200.0 ml of t-butanol and 20.0 g of 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one at 20-25 °C. Added 4.2 g of lithium hydroxide at 20-25°C. Heated the reaction mass to 35-40°C. Cooled the reaction mass to 20-25°C. Added 80.0 ml of Sodium Hydroxide Solution at 20-25°C. Heated the reaction mass to 35-40°C. Cooled the reaction mass to 20-25°C. Separated the layers at 20-25°C. Distilled out t-butanol layer under vacuum at temperature 45-50°C. Crystalized the material by using t-butanol and DM Water. Filtered and dried under vacuum at temperature 40-45°C to get 27.0 g of Remogliflozin.

Example 7A: Charged acetic anhydride (151.3 g) and D-Glucose (34.0g) in RBF at 25-30°C add to this 17.0g sodium acetate at 25-30°C. Reaction mass was raised to 80-85 °C and maintained for 3.0 hours. After reaction completion, cooled to 25-30°C. Added DM water (100 ml) and further cooled to 15-20°C. Sodium hydrixde solution [80.0g NaOH in 200 ml DM Water] was added at 25-30°C. MDC (120.0 ml) was charged to this reaction mass at 25-30°C and stirred for 20-30 minutes. Separate organic layer and charged into RBF. Cooled the reaction mass to 15°C-20°C. Slowly added HBr in Acetic Acid (95 ml). After reaction completion, brine solution (216.0 ml) was charged and layers was separated, washed with sodium carbonate solution followed by brine solution and sodium bisulfite solution at 25-30 °C. Organic layer was distilled under vacuum at 40-45 °C and was charged MDC (100 ml) and stirred at 25-30°C to get clear solution. Charged 4-(4-isopropoxybenzyl)-1-isopropyl-5-methyl-1,2-dihydro-3H-pyrazol-3-one (20 g) and TBAB (1.12 g) at 25-30 °C. Added 1M KOH solution (100.0 ml) followed by 4M KOH solution (108 ml) again at 20-25 °C and PH was adjusted to 13 and stirred the reaction mass at 25-30°C for 2.0 h. After reaction completion sodium hydroxide 20.0 g was added at 25-30 °C and stirred the reaction mass for 2.0 hrs. layer was separated to and pH was adjusted to 8.0-9.5 with acetic acid. Separate the layer at 25-30°C and distilled out MDC layer under vacuum at temperature 45-50°C. Crystalized using t-buatnol and DM water and dried under vacuum at temperature 40-45°C.

Example 8: Preparation of Remogliflozin Etabonate

Charged Remogliflozin (25 g), toluene (160 ml) and ethanol (40 ml) in to a RBF at 20-25ºC. Charged scandium triflate (41 mg) and diethylpyrocarbonate (10.4 g) at 25-30°C. Heated the reaction mass at 45-50°C. After reaction completion, reaction mass quenched with 2.5 % of acetic acid solution (75 ml). Separated the layers and washed the toluene layer with dilute acetic acid solution (75 ml). Distilled and degassed the toluene layer under vacuum at 40-45°C. To the crude material so obtained was added ethanol and n-Heptane at 20-25ºC. Heated the reaction mass to 65-70°C. Gradually cooled the mass to 0-25 °C and filtered the solids to get 35.0 g crude title compound.
Example 9: Purification of Remogliflozin Etabonate
Remogliflozin Etabonate crude (35.0 g) was added 350.0 ml of methyl tert. butyl ether at 25-30°C. Heated the reaction mass to 48-52°C. Distilled out methyl tert. butyl ether under vacuum at temp 45 °C. Degassed the reaction mass under vacuum at 45°C. To the crude material was added 162.0 ml of methyl tert. butyl ether at 25-30°C. Heated the reaction mass to 40-45 °C. Charged 0.5 ml of DM water at 40-45°C. Added 90.0 ml of n-Heptane at 40-45 °C. Gradually cooled the reaction mass to 25-30 °C. Again heated the reaction mass to 40-45°C. Added mixture of 10.0 ml of methyl tert. butyl ether and 60.0ml of n-Heptane at 40-45 °C. Gradually cooled the reaction mass to 0-25°C. Filtered the reaction mass through Buchner funnel. Dried the material under vacuum at 40 °C to get 21.5 g of pure Remogliflozin etabonate. (Purity: 99.8% by HPLC)

,CLAIMS:WE CLAIM
1. A process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting 4-hydroxy benzyl alcohol of Formula III to [4-(propan-2-yloxy)phenyl]methanol of Formula IV in presence of isopropyl halide and suitable solvent;
b) chlorinating [4-(propan-2-yloxy)phenyl]methanol of Formula IV to 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V in presence of hydrochloric acid;
c) converting 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V to methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of formula VI in presence of methylacetoacetate;
; and
d) converting methyl a-acetyl-4-(1-methylethoxy) benzenepropanoate of Formula VI to Remogliflozin or its etabonate salt.

2. The process as claimed in claim 1, wherein said solvent used in step a) is selected from alcohols, hydrocarbons, halogenated solvents such as methanol, ethanol, isopropyl alcohol, n-butanol, tert-butanol, toluene, o/m/p-xylene, dichloromethane or mixture thereof.

3. A process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI to 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII in presence of hydrazine hydrate and hydrocarbon solvent or alcohol solvent;
;
b) reacting 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII with mesyl chloride in presence of hydrocarbon solvent and suitable base to give 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or salt thereof;
; and
c) converting 5-methyl-4-({4-[(1-methylethyl)oxy]phenyl}methyl)-1H-pyrazol -3-yl methanesulfonate of Formula VIII or salt thereof to Remogliflozin or its etabonate salt.

4. The process as claimed in claim 3, wherein said suitable base used in step b) is selected from, triethyl amine, diisopropyl ethyl amine, diisopropyl amine, dimethyl amino pyridine, pyridine, trimethyl amine or mixture thereof.

5. A process for the preparation of Remogliflozin or its etabonate salt, comprising the steps of:
a) converting 4-hydroxy benzyl alcohol of Formula III to [4-(propan-2-yloxy) phenyl] methanol of Formula IV in presence of isopropyl halide and suitable solvent;
b) chlorinating [4-(propan-2-yloxy)phenyl]methanol of Formula IV to 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V in presence of hydrochloric acid;
c) converting 1-(chloromethyl)-4-(propan-2-yloxy)benzene of Formula V to methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of formula VI in presence of methylacetoacetate;
;
d) converting methyl a-acetyl-4-(1-methylethoxy)benzenepropanoate of Formula VI obtained in step c) to 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII in presence of hydrazine hydrate and hydrocarbon solvent or alcohol solvent;
;
e) reacting 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3,7-pyrazol-3-one of Formula VII with mesyl chloride in presence of hydrocarbon solvent and suitable base to give 5-methyl-4-({4-[(1-methyl ethyl)oxy]phenyl}methyl)-1H-pyrazol-3-yl methanesulfonate of Formula VIII or its salt thereof;
;
f) converting compound of formula VIII to compound of formula IX;
;
g) reacting compound of formula IX with acetobromoglucose in presence of phase transfer catalyst to give acetyl protected Remogliflozine;

;
h) deprotecting acetyl protected Remogliflozin to give Remogliflozin free base
; and
i) optionally converting Remogliflozin free base to Remogliflozin etabonate.

6. The process as claimed in claims 1 or 5, wherein compound of Formula IV, Formula V, Formula VI, VIII, VIIIa and IX are either isolated or proceeded directly into the next step of chemical transformation.

7. The process as claimed in claim 3 or 5, wherein said hydrocarbon solvent is selected from toluene, o/m/p-xylene, chlorobenzene, cyclohexane or mixture thereof.
8. The process as claimed in claim 3 or 5, wherein said alcohol solvent used are selected from methanol, ethanol, n-propanol, isopropanol, n-butanol or mixtures thereof.

9. The process as claimed in claims 1, 3 or 5, wherein said Remogliflozin etabonate salt prepared further involves purification, comprising the steps of:
a) providing a solution of Remogliflozin in a suitable solvent;
b) treating with diethylpyrocarbonate in presence of catalyst and base at a temperature ranging from 40-60oC;
c) isolating Remogliflozin etabonate and treating with mixture of alcohol and n-heptane at a temperature ranging from 50-100oC;
d) isolating the crude Remogliflozin etabonate as a wet mass;
e) treating the wet mass with ether solvent at temperature ranging from 40-60oC;
f) repeating process of step e), followed by addition of water and n-heptane to get a reaction mass;
g) cooling followed by heating the reaction mass at 30-50oC;
h) treating the reaction mass of step g) with mixture of ether and n-heptane; and
i) cooling and isolating pure Remogliflozin etabonate.

10. The process as claimed in claims 1, 3, 5 or 9, wherein said Remogliflozin etabonate is isolated as stable crystalline form having a purity of greater than 99.5%.

Dated this, 20th ¬¬day of Jul, 2022. For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer