DESC:FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
AND
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

HIGH GRADE REMOGLIFLOZIN ETABONATE AND AN IMPROVED PROCESS FOR ITS PREPARATION

Glenmark Pharmaceuticals Limited
B/2, Mahalaxmi Chambers,
22 Bhulabhai Desai Road,
Mumbai – 400026, India.

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

HIGH GRADE REMOGLIFLOZIN ETABONATE AND AN IMPROVED PROCESS FOR ITS PREPARATION

Field of the Invention
The present invention provides a high grade Remogliflozin composition that comprises Remogliflozin or Remogliflozin prodrug or pharmaceutically acceptable salt thereof, and not more than 1% impurity. The invention also provides an improved process for the synthesis of a high grade Remogliflozin, Remogliflozin prodrug or pharmaceutically acceptable salt thereof. In addition, the present invention provides a pharmaceutical composition comprising such high grade product, and a method for treating a disease associated with hyperglycemia.
Background of the Invention
Remogliflozin etabonate, 5-methyl-4-[4-(1-methylethoxy)benzyl]-1-(1-methylethyl)-1H-pyrazol-3-yl 6-O-(ethoxycarbonyl)-ß-D-glucopyranosid (a pro-drug of Remogliflozin) is known to inhibit the sodium dependent glucose transporter 2 (SGLT2). This compound is useful in the treatment of a disease associated with hyperglycemia, which includes, but not limited to, diabetes, diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcer or macroangiopathy), obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and lipid metabolism disorder and NASH.
Process for the preparation of Remogliflozin etabonate is disclosed in US7084123, US8022192, WO2010/127067 and WO2019193572, the disclosure of these prior arts are herein incorporated by reference which describe the various process for making Remogliflozin or Remogliflozin etabonate. Problems associated with the variability in the quality of Remogliflozin or Remogliflozin etabonate, present invention exhibit a high quality of final active pharmaceutical ingredient by using the improved process of purification and achieved the following:
1. None of the processes disclosed in prior art is efficient and scalable. The process disclosed in prior art requires several purification steps to yield pure Remogliflozin, which meets the requirements of ICH guidelines.
2. Multiple solvents are used in prior art process, a complete removal of said solvents can be difficult. This leads to issue of residual solvents in final product.
3. Use of expensive Scandium or Copper catalyst, which is not feasible on industrial scale.
4. All of the processes discussed above results in incomplete reactions with excessive impurity formation due to incomplete conversion
The inventors of the present invention have made extensive efforts to prepare pharmaceutical products of a high grade and with a minimum amount of impurities present. The control of impurities means exploring various options to decide upon the conditions and protocols necessary to insure that drugs which are administered to the public are pure.
Surprisingly, the inventors of the present invention have come up with an improved process which ends up having high grade product (e.g., chemically stable, good dissolution properties, meets the requirements of ICH guidelines) with minimum amount of impurities.
Summary of the Invention
Accordingly, the present invention provides a high grade composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and an amount of a compound selected from:

(a) (b)

(c) (d)

or
(e) (f) (g)
and the concentration of said compound(s) is not more than 1%, or not more than 0.5%, or not more than about 0.1% or not more than about 0.01%. In one embodiment, the concentration is 1%. In another embodiment, the concentration is 0.5%. In another embodiment, the concentration is 0.1%. In another embodiment, the concentration is 0.01%. In yet another embodiment, the high grade Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof is devoid of any such compound (impurity).
The invention further provides a pharmaceutical composition for treating in a mammal a disease associated with hyperglycemia comprising an amount of the composition disclosed herein effective in treating said disease and a pharmaceutically acceptable carrier. In one embodiment, the invention provides a pharmaceutical composition, wherein Remogliflozin prodrug is Remogliflozin etabonate.
The invention also provides a method for treating in a mammal in need thereof a disease associated with hyperglycemia, which method comprises administering to said mammal an amount of a composition disclosed herein effective in treating said disease or disorder. In one embodiment, the method is carried out, wherein the Remogliflozin prodrug is Remogliflozin etabonate.
The present invention also provides a use of composition disclosed herein for the manufacture of a pharmaceutical composition for the prevention or treatment of a disease associated with hyperglycemia.
In another aspect, the invention provides a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% as determined, for example, by High Performance Liquid Chromatography (HPLC).
The present invention further provides a compound selected from:
Methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a);
Methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b);
4-(1,2-Bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c);
4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d);
4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e);
4-(1,2-Bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f); and
4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl -6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) or a pharmaceutically acceptable salt thereof.
In one particular aspect, the present invention provides a method for the preparation of Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the concentration of a compound selected from (a), (b), (c), (d), (e), (f) or (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01%. In one embodiment, the concentration is 1%. In another embodiment, the concentration is 0.05%. In another embodiment, the concentration is 0.1%. In another embodiment, the concentration is about 0.01%. In yet another embodiment, the high grade Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof is devoid of any such compound (impurity).
The aforementioned aspects and embodiments, and other aspects, objects, features advantages of the present invention will be apparent from the following detailed description.
Detailed Description of the Invention
Those skilled in art will be aware that invention described herein is subject to variations and modifications other than those specifically described. It is to be understood that the invention described herein includes all such variations and modifications. The invention also includes all such steps, features, compositions and methods referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more said steps or features.
For convenience, before further description of the present invention, certain terms employed in the specification, examples are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art. The terms used throughout this specification are defined as follows, unless otherwise limited in specific instances.
It should be understood that unless expressly stated to the contrary, the singular forms “a” “an” and “the” include plural reference unless the context clearly dictates otherwise.
The term “Remogliflozin” as used herein, includes Remogliflozin free base and is used interchangeably throughout the disclosure. In should also be understood that unless expressly stated to the contrary, Remogliflozin includes its solvates, crystalline forms or amorphous forms. The term “Remogliflozin etabonate” as used herein also intends to include solvates, crystalline or amorphous forms.
The term “salt” or “pharmaceutically acceptable salt” as used herein, is intended to mean those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit to risk ratio, and effective for their intended use.
The term “crystalline” as used herein, means having a regularly repeating arrangement of molecules or external face planes.
Unless stated otherwise, percentages stated throughout this specification are weight/weight (w/w) percentages.
The term “room temperature” unless stated otherwise, essentially means temperature in range of 25-30 °C.
The term “about” as used herein refers to ± 10% of the numerical value of the number with which it is being used.
In the specification, the term mammal refers to human and other animal subjects. In this context, the terms “subject”, “animal subject”, and the like refer to human such as men and women, and non-human vertebrates, for example mammals such as non-human primates, sports and commercial animals and pets. Preferably the mammal is human subject.
In one aspect of the present invention, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and an amount of a compound selected from:

(a) (b) (c) (d)
or
(e) (f) (g)
and the concentration of said compound(s) is not more than 1%, or not more than 0.5%, or not more than about 0.1% or not more than about 0.01% or devoid of all or any one of them.
In one embodiment, Remogliflozin prodrug is Remogliflozin etabonate.
In another embodiment, the salts of Remogliflozin or Remogliflozin etabonate include acid addition salts with mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
In another embodiment, the salts of Remogliflozin or Remogliflozin etabonate include acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maieic acid, lactic acid, malic acid, carbonic acid, glutamic acid, aspartic acid, adipic acid, oleic acid, stearic acid and the like.
In yet another embodiment, the salts of Remogliflozin or Remogliflozin etabonate include salts with inorganic bases such as a sodium salt, a potassium salt, a calcium salt, a magnesium salt and the like.
In one aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a), wherein the concentration of (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), wherein the concentration of (b) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c), wherein the concentration of (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d), wherein the concentration of (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e), wherein the concentration of (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f), wherein the concentration of (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a composition comprising Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, and 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g), wherein the concentration of (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
To ascertain the purity of Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof or Remogliflozin intermediates, the level of each compound (a) to (g) or any other impurity should be determined and that can be accomplished using standard analytical techniques known to those of ordinary skill in the art, for example it may be determined by normal phase HPLC, reverse phase HPLC, or gas chromatography methods.
According to one aspect, the present invention provides a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, there is provided a substantially pure Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof having the purity of more than about 99% or more than about 99.5% or 99.9% by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
In one aspect, the present invention provides a compound methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside or a pharmaceutically acceptable salt thereof.
In another aspect, the invention provides a compound 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl -6-O-(ethoxycarbonyl)-ß-D-glucopyranoside or a pharmaceutically acceptable salt thereof.
In another aspect, the present invention provides a pharmaceutical composition for treating in a mammal a disease associated with hyperglycemia comprising an amount of the composition disclosed herein effective in treating said disease and a pharmaceutically acceptable carrier. In one embodiment, Remogliflozin prodrug is Remogliflozin etabonate. In another embodiment, the pharmaceutical compositions of the present invention include dosage forms such as powders, granules, fine granules, dry syrups, tablets, capsules, injections, solutions, ointments, gels, suppositories, poultices and the like. The formulation of the present invention can be administered orally, parenterally or topically, preferably oral administration.
In another aspect, the invention provides a method for treating in a mammal in need thereof a disease associated with hyperglycemia, which method comprises administering to said mammal an amount of a composition disclosed herein effective in treating said disease or disorder. In one embodiment, the method is carried out, wherein the Remogliflozin prodrug is Remogliflozin etabonate. In another embodiment, the disease associated with hyperglycemia includes, but not limited to, diabetes, diabetic complications (e.g., retinopathy, neuropathy, nephropathy, ulcer or macroangiopathy), obesity, hyperinsulinemia, glucose metabolism disorder, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, lipid metabolism disorder, atherosclerosis, hypertension, congestive heart failure, edema, hyperuricemia, gout or the like.
The invention also provides a method for the preparation of Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the concentration of a compound selected from (a), (b), (c), (d), (e), (f) or (g) (herein interchangeably referred to as impurity) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or devoid of all or any of them.
Hence in one aspect, the present invention provides a process (Process A) to prepare substantially pure Remogliflozin of Formula (I) or Remogliflozin etabonate or pharmaceutically acceptable salts thereof;

which process comprises the steps of
i) reacting the compound of formula (II) with a sulfonyl halide in presence of
a base in a suitable solvent to obtain a compound of formula (III)

Formula (II) Formula (III)
wherein R is alkyl such as methyl

ii) converting a compound of Formula (III) to substantially pure Remogliflozin of Formula (I)
iii) optionally converting Remogliflozin of Formula (I) to pharmaceutically acceptable salts thereof.
According to an embodiment, the reaction in step (i) of Process A is carried out in the presence of a base in a suitable solvent. In another embodiment, the solvent is selected from N,N dimethylformamide, acetonitrile, and n-methyl pyrrolidinone. In another embodiment, the base is selected from pyridine, triethylamine and lithium hydroxide. In a preferred embodiment, the reaction is carried out in a weak base, preferably pyridine.
In another embodiment, the compound of Formula (III) obtained by Process A is converted to Remogliflozin of Formula (I) following any methods disclosed in the prior art, preferably the process steps disclosed hereinafter.
In another aspect of the present invention, Remogliflozin of Formula (I) obtained by Process A is substantially pure. For the purpose of the present invention, the term “substantially pure” as used herein includes reference to purity of, or more than, 98%, more preferably 99%, more preferably 99.5%, more preferably 99.9% purity as determined, for example, by HPLC.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process A is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
In one embodiment, the compound of Formula (II) in Process A can be prepared following the specific examples disclosed hereinafter, however that does not restrict the scope of the present invention. Any processes which are available and known to a person of ordinary skill in the art can also be utilized for the preparation of a compound of Formula (II).
The process of the present invention during the synthesis of compound (II) as disclosed hereinafter, yields a novel compound (b) having the structural formula

in the concentration of 5% to 7%. After intensive studies, the inventors of the present invention discovered purification steps using single and /or binary solvent system to remove this compound and related compounds from being part of the final product as per the merits of the present invention. In a particular embodiment, the concentration of compound (b) in the final product, Remogliflozin or Remogliflozin etabonate, is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.1% or even this impurity is absent.
Thus in another aspect, the present invention provides a process (Process B) to prepare substantially pure Remogliflozin of Formula (I) or pharmaceutically acceptable salts thereof;

which process comprises the steps of:
i) purifying a compound of Formula (III);

Formula (III)
ii) reacting the purified compound of Formula (III) with haloalkane followed by
desulfonation to obtain compound of Formula (IV)

Formula (IV)
iii) converting compound of formula (IV) to Remogliflozin of Formula (I); and
iv) optionally, converting Remogliflozin of Formula (I) or Remogliflozin etabonate to pharmaceutically acceptable salt thereof.
According to one embodiment, the purification in step (i) of Process B is carried out in a single solvent or a binary solvent system. In another embodiment, the single solvent is selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran. In another embodiment, the binary solvent consist of aromatic solvent such as toluene or xylene and ether solvent selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran. In one particular embodiment, the purification is carried out in a binary solvent. In yet another embodiment, the purification is carried out in toluene and diisopropyl ether.
According to another embodiment, the alkylation in step (ii) of Process B is carried out by reaction with alkyl halide, such as 2-chloropropoane, 2-bromopropane and 2-iodopropane, in presence of a base and solvent. In another embodiment, the base is selected from lithium hydroxide, sodium hydroxide, potassium hydroxide, potassium tert-butoxide, cesium carbonate, potassium carbonate, sodium tert-butoxide, lithium tert-butoxide, lithium carbonate, and sodium carbonate, 1, 8- diazabicyclo [5.4.0 ]undec-7-ene, triethylamine, pyridine. In another embodiment, the solvent is selected from N-methyl-2-pyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile or dichloromethane. In a particular embodiment, the base is lithium hydroxide and the solvent is N-methyl-2-pyrrolidone. In another embodiment, desulfonation is carried out conventionally using a base such as sodium hydroxide or potassium hydroxide. In another embodiment, the alkylation is quenched with mild base such as triethanolamine prior to desulfonation.
According to an embodiment, the compound of Formula (IV) obtained by Process B is converted to Remogliflozin of Formula (I) following any methods disclosed in the prior art; preferably the process steps disclosed hereinabove.
In one aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having the purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process B is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
According to another aspect, the present invention provides a process (Process C) to prepare substantially pure Remogliflozin of Formula (I) or Remogliflozin etabonate or pharmaceutically acceptable salts thereof;

which process comprises the steps of:
i) purifying a compound of Formula (IV);

Formula (IV)
ii) reacting the purified compound of Formula (IV) with protected glucose derivative of Formula (V)

wherein PG is a protecting group, to form substantially pure compound of Formula (I);
iii) optionally, converting Remogliflozin of formula (I) to its pharmaceutically acceptable salt.
According to an embodiment, in step (i) of Process C, the purification is carried out in a single solvent or a binary solvent system. In another embodiment, the single solvent is selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran. In another embodiment, the binary solvent consist of aromatic solvent such as toluene or xylene and ether solvent selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran. In one particular embodiment, the purification is carried out in a single solvent. In yet another embodiment, the purification is carried out in diisopropyl ether.
According to another embodiment, in step (ii) compound of formula (IV) is reacted with protected glucose derivative of Formula (V) in presence of a base in a suitable solvent. After completion of reaction, the product is hydrolysed in presence of a strong base such as sodium hydroxide to cleave the protecting group and obtain Remogliflozin of formula (I). The protecting group used in the process may be selected from, but are not limited to, acetyl group, pivaloyl group a benzoyl group or a benzyl group. In another embodiment, the base is selected from organic or inorganic base, preferably inorganic base such as sodium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, lithium tertbutoxide, sodium tert-butoxide or potassium tert-butoxide. In another embodiment, the solvent is selected from toluene, acetone, 2-butanone, methyl-isobutyl ketone, ethanol, methanol, isopropanol, butanol, tertbutanol, tetrahydrofuran, 2-methyl tetrahydrofuran, methyl tert-butyl ether or dichloromethane. In one particular embodiment, the base is lithium hydroxide and solvent is tert-butanol.
According to another embodiment, the compound of Formula (I) obtained in step (ii) is subjected to purification in a binary solvent system. In another embodiment, the binary solvent consist of aliphatic solvent such as hexane and ether solvent selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran. In yet another embodiment, the purification is carried out in binary solvent, for example hexane and diisopropyl ether.
In one aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having the purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin of Formula (I) obtained by Process C is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
Amorphous forms of pharmaceutical products are usually known to have better dissolution properties than their crystalline forms. It can be formulated to a pharmaceutical composition having good dissolution properties. Remogliflozin in amorphous form has higher bioavailability and that the amorphous form of Remogliflozin has adequate chemical stability upon storage and therefore can be used in pharmaceutical formulation.
According to another aspect, Remogliflozin obtained by following any of the processes disclosed herein can be converted to amorphous form by using the methods known to a person of ordinary skill in the art, for example the process as disclosed hereinafter in the experimental section (Example 11).
Thus, in another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, substantially pure Remogliflozin of Formula (I) obtained by any processes disclosed herein is converted to the Remogliflozin etabonate of Formula (I?)

Formula (I?)
by following the process steps known to a person of ordinary skilled in the art. In a preferred embodiment, the inventors of the present invention intend, but not limiting the scope, to prepare Remogliflozin etabonate of Formula (I?) following the reaction steps of:
i) reacting Remogliflozin of formula (I) with ethyl haloformate of formula (VI)

Formula (VI)
wherein X is any halogen selected from Cl, Br, F or I
ii) treating the reaction mixture with an acid, separating an organic layer and concentrating the organic layer to obtain a residue
iii) treating the residue with a mixture of ethanol and n-heptane to obtain Remogliflozin etabonate
iv) converting the Remogliflozin etabonate to isopropyl alcohol solvate of Remogliflozin etabonate, followed by treatment with mixture of acetonitrile and water to obtain Remogliflozin etabonate
In one embodiment, the reaction in step i) is carried out in presence of an organic base and an aromatic hydrocarbon. In another embodiment, the organic base is selected from 2,6-Lutidine, pyridine, triethylamine, diisopropylamine, diisopropylethylamine or mixture thereof. In another embodiment, the aromatic hydrocarbon is selected from toluene, xylene or benzene. In another embodiment, the reaction is carried out at temperature ranging from 0 to -20° C. In yet another embodiment, Formula (VI) is preferably ethyl chloroformate.
In another embodiment, the acid used in step ii) is organic acid or inorganic acid selected from hydrochloric acid, sulfuric acid, acetic acid, trilfuoroacetic acid, hydrobromic acid, nitric acid, mesyl acid, tosyl acid, besyl acid, fumaric acid, succinic acid, ethanedisulfonic acid, citric acid, malic acid, maleic acid, malonic acid or phosphoric acid.
In another embodiment, the step iv) comprises treating the Remogliflozin etabonate with isopropyl alcohol to obtain isopropyl alcohol solvate of Remogliflozin etabonate.
In one aspect, Remogliflozin etabonate of Formula (I?) obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC.
According to another aspect of the present invention, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, Remogliflozin etabonate obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In yet another aspect, Remogliflozin etabonate of Formula (I?) obtained by process disclosed herein is substantially pure having the purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
In one aspect of the present invention, substantially pure Remogliflozin etabonate obtained by processes disclosed herein is a stable hemihydrate, which can be characterized by data selected from a differential scanning calorimetric (DSC) thermogram, a powder X-ray diffraction (PXRD) pattern or a thermogravimetric analysis curve (TGA).
Thus, according to another aspect of the present invention, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In yet another aspect, stable hemihydrate of Remogliflozin etabonate obtained by process disclosed herein has purity of more than 99% or more than 99.5%, or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
According to an aspect of the present invention, Remogliflozin etabonate obtained by following the process disclosed herein can be converted to amorphous form by using the methods known to a person of ordinary skill in the art, for example the process as disclosed hereinafter in the experimental section (Example 12).
Thus, in another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (a) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b), is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (b) is present it should not be more than about 0.5% or not more than about 0. 1%.
In another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (c) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl methanesulfonate (d) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (d) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3H-pyrazol-3-one (e) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (e) is present it should not be more than about 0.1% or not more than about 0.01%.
In another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (f) is present it should not be more than about 0.1% or not more than about 0.01%.
In yet another aspect, amorphous Remogliflozin etabonate obtained by above process is substantially pure having purity of more than 98% or more than 99% or more than 99.5% or 99.9% purity as determined, for example, by HPLC, wherein the concentration of 4-(1,2-bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) is not more than about 1%, or not more than about 0.5%, or not more than about 0.1% or not more than about 0.01% or even absent. In one embodiment, if (g) is present it should not be more than about 0.1% or not more than about 0.01%.
The Remogliflozin of Formula (I) has quality meeting the ICH guidelines. The Remogliflozin obtained by the process of the present invention is chemically stable and has good dissolution properties.
The processes according to this invention offer a significant advantage with respect to the technical demand factor, yield and environmental burden compared to the known methods. Remogliflozin etabonate prepared via this method can be utilized in the pharmaceutical industry for the manufacture of pharmaceuticals.
Examples
The following examples are presented to provide what is believed to be the most useful and readily understood description of procedures and conceptual aspects of this invention. The examples provided below are merely illustrative of the invention and are not intended to limit the same to disclosed embodiments. Variations and changes obvious to one skilled in the art are intended to be within the scope and nature of the invention.
Example 1
Preparation of [4-(propan-2-yloxy)phenyl]methanol
In a round bottom flask, potassium hydroxide (398.77 g) was added to methanol (1500 mL), followed by stirring for 60-70 minutes at 25-35 0C. 4-Hydroxy benzyl alcohol (500 g) was added to the reaction mixture, followed by stirring for 100-120 minutes at the same temperature. Isopropyl bromide (1487 g) was added using dropping funnel. The mixture was warmed to 40-45 °C and maintained for 22-25 hours. After confirming the reaction completion by thin layer chromatography, water (5 L) and toluene (5 L) were added, the mixture was stirred for 15-25 minutes and the layers were separated. Toluene layer was washed with 10 % brine solution (2.5L). The organic layer was then distilled out under vacuum and degassed to obtain 565 - 615 g oily product [4-(propan-2-yloxy)phenyl]methanol from flask (yield is 1.13 - 1.28 w/w, based on 4-(hydroxymethyl)phenol).
Example 2
Preparation of 1-(chloromethyl)- 4-(propan-2-yloxy)benzene
To the mixture of phosphorus oxychloride (830.25 g) and acetonitrile (2 L) was added dimethyl formamide (439.2 g) using dropping funnel, the mixture was stirred for 60-65 minutes at 0 to 10 0C. To the mixture was then added [4-(propan-2-yloxy)phenyl]methanol (500 g) and acetonitrile (500 mL), the mixture thus obtained was stirred for about 4 hours at 25-35 °C. After completion of reaction, the reaction mass was concentrated under vacuum. To the residue was added toluene (4+1 L), the mixture was stirred for 30 minutes and layers were separated. The organic layers were mixed and the solvent was distilled off under vacuum at 55-60 °C to obtain 500 g oily product 1-(chloromethyl)- 4-(propan-2-yloxy)benzene of formula (yield is 1.0 – 1.12 w/w, with respect to 4-(propan-2-yloxy)phenyl]methanol).
Example 3
Preparation of methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate
To a mixture of dimethylformamide, (900 mL) and toluene (900 mL) was added 1-(chloromethyl)- 4-(propan-2-yloxy)benzene (500 g), followed by slowly adding diisopropyl ethylamine (699.78 g), lithium chloride (126.22 g) and sodium iodide (55 g). To the reaction mixture was added methyl acetoacetate (471.50 g) at 25-40 0C. The temperature of reaction mass was raised to 60-65°C over a period of 3 to 4 hours. After completion of reaction, to the reaction mass was added DM water (5 L) and toluene (5 L), the mixture was stirred; toluene layer was separated and washed with DM water (5 L). The toluene layer was then subjected to distillation under vacuum and then degassed to obtain 607-625 g of oily product i.e. methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl] butanoate (yield is 1.21-1.30 w/w, with respect to 1-(chloromethyl)- 4-(propan-2-yloxy)benzene).
Example 4
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one
To the mixture of methanol (1L) and methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate (500 g) was added hydrazine hydrate (191.66 g), and maintain for around 4 to 5 hours. After confirming the reaction completion by thin layer chromatography, the DM water (4 L) was added, stirred for 4 to 5 hours, and filtered. The wet cake thus obtained was washed with DM water (1 L). To the wet product was added toluene (1.5 L). The temperature was raised to 50-60 0C, stirred the slurry mass, filtered and washed with toluene (500 mL) and dried under vacuum at 55-65°C for 12 hours to provide 337.50-360 g 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one having HPLC purity of >99 % (yield is 0.675-0.72 w/w with respect to methyl 3-oxo-2-[4-(propan-2-yloxy)benzyl]butanoate).
Example 5
Preparation of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-ylmethanesulfonate
Methane sulfonyl chloride (159.05 g) was added dropwise to the mixture of acetonitrile (1425 mL) and 5-methyl-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H- pyrazol-3-one (285 g), the reaction mass was cooled to 5-10 °C followed by addition of pyridine (118.98 g). The reaction mixture was maintained at said conditions till completion of reaction. After completion of reaction, DM water (4275 mL) was added and mixture was stirred, subsequently the product was filtered out. The product thus obtained was washed with DM water (1140 mL), dried in air oven for 8-10 hours at 55-60 °C to get 356-362 g of 5-methyl- 4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate having HPLC purity of >99%.
Example 6
Purification of 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-ylmethanesulfonate
To the mixture of diisopropyl ether (1 L) and toluene (1 L) was added crude 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-ylmethanesulfonate. The temperature was raised to 50-55 0C, and maintained for 40-60 minutes. The reaction mass was cooled, stirred and filtered out. The product thus obtained was washed with diisopropyl ether (250 mL) and dried under vaccum for 12 hours to obtain 375 - 400 g (0.75 to 0.80 w/w, based on 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-ylmethanesulfonate crude).
Example 7
Preparation of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one
To N-methyl-2-pyrrolidone (1.5 L) was added 5-methyl-4-[4-(propan-2-yloxy)benzyl]-2,3-dihydro-1H-pyrazol-3-yl methanesulfonate (300 g) at about 25-35 0C. To this mixture was then lithium hydroxide (116.51 g) and isopropyl bromide (369.67 g) at about 10-15 0C. The temperature was raised to 25-35 0C and maintained at this temperature for about 12.5 hours. After completion of reaction, triethanolmine (171.44 g) was added to reaction mixture and the mixture was heated to 60-65°C and maintained at this temperature for 2 to 2.5 hours. The reaction mixture was then neutralized by sequential addition of sodium hydroxide and methanol (1.5 L). The temperature was raised to 60-65 0C and maintained at this temperature for 2 to 2.5 hours. After completion of reaction, the pH was adjusted to 6.7-7.5 by using dilute hydrochloric acid. The mixture was then heated to 60-65 0C and maintained for 10-15 minutes, cooled to room temperature, stirred for around 14 to 16 hours, and filtered out. Wet cake obtained was washed with DM water (300 mL) and dried to obtain 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one.
Example 8
Purification of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one
To diisopropyl ether (200 mL) was added crude 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one. The temperature was raised to 50-55 0C, and maintained at this temperature for 30-40 minutes. The reaction mass was cooled, stirred and filtered out. The product thus obtained was washed with diisopropyl ether (100 mL) and dried under vaccum for 12 hours to obtain 83-87 g of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one having HPLC purity of >99% (Yield is 0.83 to 0.87 w/w, based on crude 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one).
Example 9 (a)
Preparation of Remogliflozin free base of Formula (I)
Lithium hydroxide monohydrate (43.6 g) was added to the mixture of tert.Butanol (1 L) 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one (100 g) and O-Acetyl D glucopyranosyl bromide (268 g). The reaction mass thus obtained, was stirred for around 5 hours at about 40-45 0C. After completion of reaction (confirmed by thin layer chromatography), sodium hydroxide solution was added and the mixture was stirred for 3-4 hours, followed by addition of water (100 mL). The organic layer was distilled out under vacuum and degassed the residue under vaccum. To a mixture of DM water (500 mL0 and DM water (200 mL) was added the product, and stirred for 15-20 minutes, followed by pH adjustment (6.7-7.5) using acetic acid. The aqueous layer was washed with diisopropyl ether and hexane (1:1, 500 mL x 4). The aqueous layer was then extracted using ethyl acetate (600 mL x 2). The combined organic layers was washed with 20% brine solution, treated with 10 gm activated charcoal, stirred and filtered out through hyflo-bed. The bed was washed with ethyl acetate (100 mL), distilled out the clear filtrate under vaccum and degassed the residue mass. To the residue was charged tert-butanol and ethyl acetate (100 mL each), and the temperature was raised to 45-50 0C followed by slow addition of n-hexane, dried under vaccum to obtain 135 - 139 g the title compound (Yield is 1.35 – 1.39 w/w based on input of 5-methyl-1-(propan-2-yl)-4-[4-(propan-2-yloxy)benzyl]-1,2-dihydro-3H-pyrazol-3-one).
Example 9 (b)
Preparation of Isopropyl solvate of Remogliflozin Etabonate
To mixture of toluene (250 ml), Ethanol (250 ml) Remogliflozin free base (100 g), 0.60 g of Scandium (III) Trifluromethanesulfonate, and 41.40 g of Diethyl Pyrocarbonate (DEPC) was added and reaction mass was stirred at 35 – 50°C for 3-5 hours. After completion of reaction, toluene (250 ml) Acetic acid (5 g) and water (500 ml) was charged in reaction mass at 25-30°C, and organic layer was separated, aqueous layer again extracted with toluene (250 ml).
Combine organic layer was wash with brine solution then concentrate under vacuum, the residue was stripped with Isopropanol (100 ml), to the residue isopropanol and N-heptane mixture was charged and heated to 75 - 85°C to obtained clear solution. The clear solution was then cooled to 25°C and stirrer for 8 -10 hrs. Isolated wet cake by filtration again crystallized from isopropanol to obtain Isopropanol solvate of Remogliflozin Etabonate.
Example 10 (a)
Preparation of isopropyl solvate of Remogliflozin Etabonate
To mixture of Toluene (1350 mL), Remogliflozin free base (135 g), 2,6- Lutidine (57.8 g) and Pyridine (1.35 g) was slowly added ethyl chloro formate (45.51 g) and the reaction mass was cooled to about -10 0C and stirred for 3 to 4 hours. After completion of reaction, water (675 mL) was added to reaction mass and the mixture was stirred. The layers were separated and the organic layer was washed subsequently with dilute hydrochloric acid (675 mL) and water (675 mL). The organic layer was then concentrated under vacuum, the residue was stripped out with ethanol (270 mL) and degassed. To the residue was then added mixture of ethanol (810 mL) and n-Heptane (810 mL) and the mixture was heated to about 70 0C to obtain a clear solution. The
clear solution was then cooled to 25 0C and stirred for 8 to 10 hours. Remogliflozin etabonate thus obtained was isolated by filtration and crystallized from isopropyl alcohol (1350 mL) to obtain isopropyl alcohol solvate of Remogliflozin etabonate.
Example 10 (b)
Preparation of Remogliflozin Etabonate hemihydrate
The Isopropanol solvate of Remogliflozin etabonate obtained above was subjected to conversion to stable hemihydrate remogliflozin etabonate by dissolving in acetonitrile and water (1:1) followed by addition of 10 vol water. The hemihydrate remogliflozin etabonate obtained was dried at 40 - 50°C for 10 hours to get 90 g (0.90 w/w) of final product having HPLC purity more than 99.0%.
Example 11
Preparation of Remogliflozin etabonate hemihydrate
The isopropyl solvate of remogliflozin etabonate obtained above was subject to conversion to stable hemihydrate remogliflozin etabonate by dissolving in acetonitrile and water (1:1) followed by addition of 18 volume of water. The hemihydrate remogliflozin etabonate obtained was dried at 40 0C for 10 hours to get 81g (0.6 w/w) of final product having HPLC purity of more than 99.0%.
Example 12
Preparation of amorphous form of Remogliflozin
Dissolve Remogliflozin (25 g) in methylene dichloride (125 mL) and stir to get clear solution. Distilled out solvent completely under vacuum at 40-45°C and degas for 12 hours to get 23g of the product, which is substantially pure amorphous Remogliflozin having HPLC purity of more than 99%.
Example 13
Preparation of amorphous form Remogliflozin etabonate
Dissolve Remogliflozin etabonate (50 g) in methylene dichloride (500 mL) and stir to get clear solution. Distilled out solvent completely under vacuum at 40-45 °C and degas for 9.0 hours at 50°C to get final product (48 g), which is substantially pure amorphous Remogliflozin etabonate having HPLC purity of more than 99%. ,CLAIMS:1. Remogliflozin or pharmaceutically acceptable salts thereof, having a purity (according to HPLC) of more than 99.9%, comprising less than 0.01% of any impurity from the compound selected from:

(a) (b) (c) (d)

or
(e) (f) (g)
or a pharmaceutically acceptable salt thereof, all stereoisomers thereof, or a prodrug thereof.
2. A substantially pure Remogliflozin or Remogliflozin etabonate or a pharmaceutically acceptable salt thereof having a purity (according to HPLC) of greater than 99.5% or 99.9%, substantially free of any impurities determined by HPLC.
3. A pharmaceutical composition comprising substantially pure Remogliflozin or Remogliflozin etabonate or a pharmaceutically acceptable salt thereof having a purity (according to HPLC) of greater than 99.9%, substantially free of any impurities determined by HPLC.
4. Remogliflozin in a purity (according to HPLC) of more than 99.9%, comprising a method for the preparation of Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the concentration of a compound selected from (a), (b), (c), (d), (e), (f) or (g) is not more than about 1%, or not more than about 0.5%.
5. Remogliflozin in a purity (according to HPLC) of more than 99.9%, comprising a method for the preparation of Remogliflozin, a prodrug thereof or a pharmaceutically acceptable salt thereof, wherein the concentration of a compound selected from (a), (b), (c), (d), (e), (f) or (g) is not more than about 0.1% or preferably not more than about 0.01% or without any of them.
6. Remogliflozin of claim 1, having less than 0.01% of any impurity from the compound selected from:
a) Methyl 3-oxo-2,2-bis({4-[(propan-2-yl)oxy]phenyl}methyl)butanoate (a)
b) Methyl 2-acetyl-3,4-bis{4-[(propan-2-yl) oxy]phenyl}butanoate (b)
c) 4-(1,2-Bis{4-[(propan-2-l)oxy]phenyl}ethyl)-5-methyl-1,2-dihydro-3H-pyrazol-3-one (c)
d) 4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1H-pyrazol-3-yl-methanesulfonate (d)
e) 4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1,2-dihydro-3Hpyrazol-3-one (e)
f) 4-(1,2-Bis{4-[(propan-2yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl ß-D-glucopyranoside (f)
g) 4-(1,2-Bis{4-[(propan-2-yl)oxy]phenyl}ethyl)-5-methyl-1-(propan-2-yl)-1H-pyrazol-3-yl-6-O-(ethoxycarbonyl)-ß-D-glucopyranoside (g) or a pharmaceutically acceptable salt thereof.
7. Remogliflozin in a purity (according to HPLC) of more than 99.9% according to claim 1, comprising for the prevention or treatment of a disease associated with hyperglycemia.
8. The pharmaceutical compositions as claimed in 3, comprising co-administering the substantially pure Remogliflozin of compound of formula (I), in combination with at least one other drug useful for the treatment of type II diabetes.

9. An amorphous Remogliflozin or pharmaceutically acceptable salts thereof, having a purity (according to HPLC) of more than 99.9%, comprising less than 0.01% of any impurity from the compound selected from:

(a) (b) (c) (d)

or
(e) (f) (g)
or a pharmaceutically acceptable salt thereof, all stereoisomers thereof, or a prodrug thereof.
10. A pharmaceutical composition comprising substantially pure amorphous Remogliflozin or Remogliflozin etabonate or a pharmaceutically acceptable salt thereof having a purity (according to HPLC) of greater than 99.9%, substantially free of any impurities determined by HPLC
11. A compound having the structure

(a) (b) (c) (d)

or
(e) (f) (g)
or a pharmaceutically acceptable salt thereof, all stereoisomers thereof, or a prodrug thereof.
12. The process for producing Remogliflozin comprises;
(i) purification step by using single solvent system to remove related compounds selected from (a), (b), (c), (d), (e), (f) or (g);
(ii) optionally using binary solvent system for isolation of purified compound
13. A process for producing Remogliflozin of Formula (I) or pharmaceutically acceptable salts thereof;

which process comprises the steps of:
i) purifying a compound of Formula (III);

Formula (III)
ii) reacting the purified compound of Formula (III) with haloalkane followed by desulfonation to obtain compound of Formula (IV)

Formula (IV)
iii) converting compound of formula (IV) to Remogliflozin of Formula (I); and
iv) optionally, converting Remogliflozin of Formula (I) or Remogliflozin etabonate or its pharmaceutically acceptable salt thereof having a purity (according to HPLC) of greater than 99.9%.
14. A process for producing Remogliflozin of Formula (I) or pharmaceutically acceptable salts thereof;

which process comprises the steps of:
i) purifying a compound of Formula (IV);

Formula (IV)
ii) reacting the purified compound of Formula (IV) with protected glucose derivative of Formula (V)

wherein PG is a protecting group, to form substantially pure compound of Formula (I);
iii) optionally, converting Remogliflozin of formula (I) or Remogliflozin etabonate or to its pharmaceutically acceptable salt having a purity (according to HPLC) of greater than 99.9%.
15. The process of any preceding claim, wherein the solvent is selected from toluene or xylene and ether solvent selected from simple ether such as diethyl ether, dimethyl ether, dipropyl ether or diisopropyl ether, mixed ether such as ethyl methyl ether, tert amyl ethyl ether or methyl phenyl ether or cyclic ether such as1,4-dioxane or tetrahydrofuran.