DESC:
FIELD OF THE INVENTION
The present invention relates to process for the preparation of lobeglitazone or salt thereof.
BACKGROUND OF THE INVENTION
Lobeglitazone sulfate, also known as 5-[4-[2-[N-[6-(4-Methoxyphenoxy) pyrimidin-4-yl]-N-methylamino]ethoxy]benzyl]thiazolidine-2,4-dione sulfate, is represented by the following structure.

Lobeglitazone sulfate is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of lobeglitazone, the compound of formula I, or a salt thereof, comprising: I
a) reacting 5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino} ethoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione, a compound of formula II,
II
with a catalytic mixture comprising a solution of cobalt ion and dimethyl glyoxime in a solvent, and a reducing agent in presence of a base; and
b) optionally converting lobeglitazone to lobeglitazone salt.
In one embodiment, the present invention provides sodium metabisulfite adduct, a compound of formula VI;
VI
characterised by 1H NMR having peaks at about 3.086, 3.360, 3.70, 4.12, 4.89, 5.75, 6.06, 6.822, 7.06, 7.38, 7.85, 8.18.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig. 1 is a characteristic XRPD of lobeglitazone as obtained in example 4.
Fig. 2 is a characteristic XRPD of lobeglitazone sulfate as obtained in example 5.
Fig. 3 is a characteristic 1H NMR of sodium metabisulfite adduct of 4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl)amino}ethoxy) benzaldehyde, as obtained in example 2.
DETAILED DESCRIPTION OF THE INVENTION
In one embodiment, the present invention provides a process for the preparation of lobeglitazone, a compound of formula I, or a salt thereof, comprising:
I
a) reacting 5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino} ethoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione, a compound of formula II,
II
with a catalytic mixture comprising a solution of cobalt ion and dimethyl glyoxime in a solvent and a reducing agent in presence of a base; and
b) optionally converting lobeglitazone to lobeglitazone salt.
In one embodiment, the source of cobalt ion is cobalt chloride hexahydrate.
In one embodiment, in step a) of the above process, the reducing agent is selected from the group consisting of an alkali hydride, alkali borohydride or alkali butoxide. The alkali hydride may be sodium hydride and lithium hydride; alkali borohydride may be selected from the group consisting of sodium borohydride, potassium borohydride, sodium cyano borohydride and the like; the alkali butoxide may be selected from the group consisting of sodium tertiary butoxide, potassium tertiary butoxide and the like.
In one embodiment, the reduction may also be achieved using hydrogen in presence of a suitable catalyst. The catalyst may be selected from the group consisting of palladium, platinum, copper, nickel, rhodium and alumina.
The palladium catalyst, may be in the form of palladium on carbon or palladium salts such as palladium hydroxide, palladium hydroxide on carbon, and the like. The palladium content in the catalyst may be about 5% to about 20 % wt/wt on carbon.
The pressure for hydrogenation can range from about 1 kg/cm2 to about 30 kg/cm2 by using hydrogen gas, preferably about 5kg/cm2 to about 20kg/cm2.
In one embodiment, in step a) of the above process, the base may be an organic base or an inorganic base.
In one embodiment, the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates, and alkali or alkaline earth metal bicarbonates.
Inorganic bases may be selected from the group consisting of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. Organic bases may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine and N-methylmorpholine.
In one embodiment, the base is sodium carbonate.
In one embodiment, the reaction of step (a) may be carried out in the presence of a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as cyclohexane, toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, propionitrile and the like; dimethyl sulfoxide (DMSO); amides such as formamide, N,N-dimethylformamide, N,N-dimethylacetamide; nitriles such as acetonitrile, propionitrile and the like; dimethylsulfoxide and the like, glycols such as polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600, polyethylene glycol-2000 and the like; sulpholane, water; or mixtures thereof.
In one embodiment, the solvent is dimethyl formamide.
In one embodiment, the catalytic mixture comprises a source of cobalt ion and dimethyl glyoxime in a suitable solvent. The solvent for the catalytic mixture may be selected from amides such dimethyl formamide, dimethyl acetamide and DMSO.
In one embodiment, step a) of the above reaction is carried out at a temperature of about -10°C to about reflux temperature of the solvent. Preferably, the reaction is carried out at a temperature between 25°C to 30°C.
In one embodiment, the catalytic mixture comprises cobalt chloride hexahydrate in an amount less than 1 % and dimethyl glyoxime in an amount less than 1 % relative to the compound of formula II.
In one embodiment, lobeglitazone or salt thereof is prepared by a process comprising reacting 5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl) amino} ethoxy) phenyl]methylidene}-1,3-thiazolidine-2,4-dione, a compound of formula II, in a mixture of PEG-400, water and sodium carbonate with a catalytic mixture comprising a solution of cobalt ion and dimethyl glyoxime in dimethylformamide to obtain a reaction mixture. The reaction mixture is reacted with an aqueous solution of sodium borohydride in presence of sodium carbonate to obtain a reaction mixture comprising lobeglitazone.
In one embodiment, the compound of formula II is converted to lobeglitazone using Hantzsch ester in a solvent. Hantzsch ester refers to an organic compound with the formula HN(MeC=C(CO2Et))2CH2 where Me = methyl and Et = ethyl
In one embodiment, lobeglitazone is purified by treatment with an acid. The acid may be selected from the group consisting of acetic acid, hydrochloric acid, phosphoric acid, oxalic acid and the like.
In one embodiment, the present invention provides a process for the purification of lobeglitazone comprising:
a) dissolving lobeglitazone in a solvent or a mixture of solvents;
b) optionally, cooling the solution of step a);
c) optionally, adding an anti-solvent to the solution of step a) or step b); and
c) isolating lobeglitazone.
In one embodiment, the present invention provides a process for the preparation of lobeglitazone comprising:
a) suspending lobeglitazone in a solvent or mixture of solvents to obtain a slurry,
b) optionally heating the slurry of step a);
c) stirring the slurry of step a) or step b); and
c) isolating lobeglitazone.
In one embodiment, the solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, propionitrile and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the anti-solvent may be selected from the group consisting of hydrocarbons such as cyclohexane, toluene, xylene and the like; alcohols such as methanol, ethanol, isopropanol and the like; water or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of lobeglitazone comprising:
a) suspending lobeglitazone in a ketone solvent to obtain a reaction mixture;
b) heating the above reaction mixture of step a) to a temperature of about 50°C to about 65°C;
c) cooling the reaction mixture of step b) to a temperature of about 25°C to about 30°C; and
d) isolating crystalline lobeglitazone.
In one embodiment, the isolation is carried by distillation, filtration or centrifugation.
In one embodiment, the present invention provides crystalline lobeglitazone characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 11.26, 11.68, 16.06, 18.00, 22.44 and 25.06 ±0.2 degrees 2 theta.
In one embodiment, the present invention provides crystalline lobeglitazone characterized by X-ray diffraction (XRD) spectrum having peak reflections at about 11.26, 11.68, 16.06, 18.00, 22.44 and 25.06 ±0.2 degrees 2 theta, which is substantially in accordance with Fig. 1.
In one embodiment, the present invention provides crystalline lobeglitazone having a melting point of 145-146°C.
In one embodiment, the present invention provides lobeglitazone having a purity greater than 90%, as measured by HPLC.
In one embodiment, the present invention provides lobeglitazone having a purity greater than 99%, as measured by HPLC.
In one embodiment, the present invention provides lobeglitazone obtained by the above process free of following impurities, a diphenoxy thiazolidinedione, a compound of formula X and phenoxy thiazolidine-2-one compound of formula XI.
X XI
The compound of formula XI characterised by 1HNMR having peaks at about 8.175, 7.99, 7.16-7.14, 7.07-7.048, 6.96-6.94, 6.87-6.85, 6.06, 4.13-4.07, 3.92, 3.75, 3.53-3.49, 3.24-3.22, 3.07, 2.97-2.96, 2.87-2.85.
In one embodiment, the present invention provides process for preparation of lobeglitazone salt comprising:
a) reacting lobeglitazone with an acid in a suitable solvent to obtain a reaction mixture;
b) stirring the reaction mixture; and
c) isolating lobeglitazone salt.
In the context of the present invention, the term ‘isolating’ refers to removal of solvent by filtration, centrifugation, partial or complete removal of solvent by distillation.
In one embodiment, the acid may be selected from the group consisting of acetic acid, hydrochloric acid, sulphuric acid, carboxylic acid such as oxalic acid, malonic acid, maleic acid, succinic acid and the like.
In one embodiment, lobeglitazone is reacted with sulphuric acid in a solvent to obtain lobeglitazone sulfate.
The solvent is as discussed supra.
In one embodiment, lobeglitazone is reacted with sulphuric acid in methanol at 0°C to 5°C. The solution is stirred for a period of about 30 min to 180 min. Lobeglitazone sulfate is isolated by methods known in the art such as centrifugation or filtration.
In one embodiment, lobeglitazone sulfate obtained by the process of the present invention is amorphous in nature.
In one embodiment, lobeglitazone sulfate obtained by the process of the present invention is crystalline in nature.
In one embodiment, the present invention provides a process for the purification of lobeglitazone sulfate comprising:
a) dissolving lobeglitazone sulfate in a solvent or mixture of solvents;
b) optionally, cooling the solution of step a);
c) optionally adding an anti-solvent to step a) or step b); and
d) isolating crystalline lobeglitazone sulfate.
In one embodiment, the present invention provides a process for the preparation of lobeglitazone sulfate comprising:
a) suspending lobeglitazone sulfate in a solvent or a mixture of solvents to obtain a slurry;
b) stirring the slurry in step a); and
c) isolating lobeglitazone sulfate.
In one embodiment, the solvent is as discussed supra.
In one embodiment, the present invention provides a process for the preparation of amorphous lobeglitazone sulfate comprising:
a) suspending lobeglitazone sulfate in an ether solvent to obtain a reaction mixture;
b) optionally, heating the above reaction mixture of step a),
c) cooling the reaction mixture of step b); and
d) isolating amorphous lobeglitazone sulfate.
In one embodiment, the present invention provides a process for the preparation of lobeglitazone sulfate comprising:
a) suspending lobeglitazone sulfate in methyl tert butyl ether to obtain a reaction mixture,
b) stirring the reaction mixture of step a); and
c) isolating amorphous lobeglitazone sulfate .
In one embodiment, the lobeglitazone sulfate is amorphous in nature and is substantially in accordance with Fig. 2.
In one embodiment, the present invention provides lobeglitazone sulfate having a purity of at least 90%, as measured by HPLC.
In one embodiment, the present invention provides lobeglitazone sulfate having a purity of at least 95%, as measured by HPLC.
In one embodiment, the present invention provides lobeglitazone sulfate having a purity of 100%, as measured by HPLC.
In one embodiment, the present invention provides a process for the preparation of compound of formula II comprising:
a) reacting 2{[6-(4-methoxyphenoxy) pyrimidin-4-yl] (methyl)amino}ethan-1-ol, a compound of formula IV
IV III
with 4-fluorobenzaldehyde to form a compound of formula III;
b) treating the above compound of formula III with sodium metabisulfite to obtain a reaction mixture comprising sodium metabisulfite adduct, a compound of formula VI;
VI
c) isolating the compound of formula VI from the reaction mixture;
d) hydrolysing the compound of formula VI in a suitable solvent to obtain compound of formula III; and
e) reacting the compound of formula III obtained in step d) with 2,4-thiazolidinedione in presence of a base and a solvent to obtain the compound of formula II.
In one embodiment, in step a) of the above process, 2{[6-(4-methoxyphenoxy) pyrimidin-4-yl] (methyl)amino}ethan-1-ol, a compound of formula IV is reacted with 4-fluorobenzaldehye in a suitable solvent and a base to form a compound of formula III .
In one embodiment, the reaction may be carried out in the presence of a solvent selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, propionitrile and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the base may be an inorganic base or an organic base.
In one embodiment, inorganic bases may be selected from the group consisting of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkali or alkaline earth metal carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like.
In one embodiment, the organic base may be selected from the group consisting triethyl amine, diisopropylethylamine (DIPEA) and the like; 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5 5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (Dabco) piperidine, pyridine, pyrimidine, 4-(dimethylamino)pyridine (DMAP) and the like or mixtures thereof.
In one embodiment, in step b) of the above process, the compound of formula III is reacted with a sodium metabisulfite in presence of a solvent to obtain a reaction mixture comprising a sodium metabisulfite adduct, a compound of formula VI.
The solvent is as discussed supra.
In one embodiment, in step c) of the above process the sodium metabisulfite adduct the compound of formula VI is isolated from the reaction mixture by removal of the solvent.
The solvent is as discussed supra.
In one embodiment, it was surprisingly found that the purity of compound of formula III increased from 50-60% to more than 90% when obtained via its sodium metabisulfite adduct, the compound of formula VI.
In one embodiment, the compound of formula VI is the sodium metabisulfite adduct of compound of formula III.
In one embodiment, in step d) of the above process the sodium metabisulfite adduct, the compound VI is hydrolysed to obtain the compound of formula III.
In one embodiment, the hydrolysis may be an acid hydrolysis or a base hydrolysis.
In one embodiment, the hydrolysis may be carried out using an acid selected from acetic acid, hydrochloric acid, citric acid and the like.
In one embodiment, the hydrolysis may be carried out with a base.
In one embodiment, the base is an inorganic base selected from the group consisting of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkali or alkali earth metal carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. In one embodiment, the hydrolysis of the sodium metabisulfite adduct, the compound of formula VI is carried out using sodium hydroxide in an alcohol solvent.
In one embodiment, the compound of formula III thus obtained may be purified in suitable solvent.
The solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, propionitrile and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, the present invention provides a compound of formula VI
VI
characterised by 1H NMR having peaks at about 3.086, 3.360, 3.70, 4.12, 4.89, 5.75, 6.06, 6.822, 7.06, 7.38, 7.85, 8.18.
In one embodiment, it was found that the compound of formula III obtained after hydrolysis of the sodium metabisulfite adduct, the compound of formula VI, is substantially free of ([4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino}ethoxy)phenyl]methanol, a compound of formula VII, (4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino}ethoxy)benzoic acid, a compound of formula VIII, diphenoxy aldehyde compound of formula IX, and the starting materials the compound of formula IV and 4-fluorbenzaldehyde:
VII VIII
IX
In one embodiment, the present invention provides a compound of formula III having a purity greater than 90% as measured by HPLC.
In one embodiment, the present invention provides a compound of formula III having a purity greater than 95% as measured by HPLC.
In one embodiment, in step e) the compound of formula III obtained in step d) is reacted with 2, 4-thiazolidinedione in presence of a base and a solvent to obtain the compound of formula II.
In one embodiment, the base is an organic base or an inorganic base.
In one embodiment, inorganic bases may be selected from the group consisting of alkali or alkali earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkali or alkali earth metal carbonate such as of sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like.
In one embodiment, the organic base may be selected from the group consisting triethyl amine, diisopropylethylamine (DIPEA) and the like; 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5 5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO) piperidine, pyridine, pyrimidine, 4-(dimethylamino)pyridine (DMAP) and the like or mixtures thereof.
In one embodiment, the solvent is as discussed supra.
In one embodiment, the reaction is carried out in presence of an acid selected from acetic acid, hydrochloric acid.
In one embodiment, the sodium metabisulfite adduct, the compound of formula VI is not hydrolysed.
In one embodiment, the compound of formula VI is reacted with 2,4 thiazolidinedione to obtain a compound of formula II.
In one embodiment, the present invention provides a process for the preparation of
2{[6-(4-methoxyphenoxy) pyrimidin-4-yl] (methyl) amino} ethan-1-ol, a compound of formula IV comprising:
IV
a) reacting 4,6-dichloropyrimidine with 4-methoxy phenol in the presence of a base and a solvent to obtain a compound of formula V; and

4, 6 dichloropyrimidine 4-methoxy phenol V
b) reacting the compound of formula V with 2-(methylamino)-ethan-1-ol to obtain a compound of formula IV.
In one embodiment, step a) of the above process involves reaction of 4, 6-dichloropyrimidine with 4-methoxyphenol in presence of base.
The base may be selected from the group consisting of organic or inorganic base.
Inorganic bases may be selected from the group consisting of alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide; alkali or alkaline earth metal carbonate such as sodium carbonate, potassium carbonate, calcium carbonate, lithium carbonate; alkoxide such as sodium methoxide, potassium methoxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate; ammonia and the like. Organic bases may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, N-methylmorpholine.
The solvent may be selected from the group consisting of esters such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, tert-butyl acetate and the like; hydrocarbons such as toluene, xylene, chlorobenzene, heptane, hexane and the like; ethers such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, dioxane and the like; ketones such as acetone, ethyl methyl ketone, methyl isobutyl ketone and the like; alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, tert-butyl alcohol, pentanol, octanol and the like; haloalkanes such as dichloromethane, chloroform, ethylene dichloride, and the like; nitriles such as acetonitrile, propionitrile and the like; dimethyl sulfoxide; dimethyl acetamide; water; or mixtures thereof.
In one embodiment, in step a) of the process, above compound of formula V may not be isolated.
In one embodiment, in step b) the compound of formula V is reacted with 2-(methylamino)-ethan-1-ol to obtain a compound of formula IV in presence of a solvent.
The solvent used is as discussed supra.
In one embodiment, the compound of formula V is not isolated and insitu reacted with 2-(methylamino)-ethan-1-ol to obtain the compound of formula IV.
HPLC method: High performance liquid chromatography (HPLC) was performed with the conditions described below for detecting chemical purity:
Column: Inertsil ODS 3V, 250 X 4.6 mm, 5µ; Column Temperature: 45?C
Mobile phase: Mobile Phase A: 0.1% Perchloric acid in water (100%): Mobile Phase B =Acetonitrile
Time (min) % Mobile Phase A % Mobile Phase B
0.01 90 10
38 20 80
39 90 10
44 90 10
Diluent: Water: Acetonitrile (50:50 v/v); Flow Rate: 1.2mL/Min; Detection: 210 nm; Injection Volume:20µL
In one embodiment, the present invention provides preparation of an amorphous solid dispersion of lobeglitazone sulfate together with at least one pharmaceutically acceptable carrier, the process comprising:
(a) providing a solution or mixture of lobeglitazone sulfate together with at least one pharmaceutically acceptable carrier in a solvent; and
(b) obtaining the amorphous solid dispersion of lobeglitazone sulfate together with at least one pharmaceutically acceptable carrier from solution or mixture of step (a).
In one embodiment, the pharmaceutically acceptable carrier is selected from gelatines, ovalbumin, soybean proteins, gum arabic, non-sucrose fatty acid esters, starches, modified starches, cellulose, methylcellulose (MC), ethylcellulose (EC), hydroxy ethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hypromellose acetate succinate (HPMC AS), polycarbophil, polyethylene glycol (PEG), polyethylene oxides, polyoxyalkylene derivatives, polymethacrylates, polyvinyl pyrrolidone (PVP, povidone), polyvinyl acetate (PVAc), PVP-vinylacetate-copolymer (PVP-VA), Kollidon VA 64 (a vinylpyrrolidone-vinyl acetate copolymer), lactose, sorbitol, mannitol, maltitol, saccharose, isomalt, cyclodextrins such as a-cyclodextrins, ß-cyclodextrins, ?-cyclodextrins and hydroxyl-propyl-ß-cyclodextrins, sodiumcarboxymethylcellulose, sodium alginate, xantham gum, caavageenan, locust bean gum (ceratonia), chitosan, guar gum, cross-linked high amylase starch, and cross-linked polyacrylic acid (carbopol).
In one embodiment, the present invention provides a lobeglitazone sulfate premix comprising lobeglitazone, and premixing agents which process comprises:
(i) providing an intimate mixture comprising the solvent system, lobeglitazone sulfate and premixing agents and optionally, water;
(ii) removing any solvent present from the mixture;
(iii) dissolving in another solvent; and
(iv) precipitating the premix of lobeglitazone sulfate
wherein the lobeglitazone sulfate used is amorphous or crystalline.
In one embodiment, lobeglitazone sulfate premix comprises of lobeglitazone sulfate which is amorphous or crystalline in combination with suitable premixing agent wherein the premixing agents is selected from group of cellulose derivatives but not limited to croscarmellose sodium, micro crystalline cellulose (MCC), hydroxyethylcellulose (HEC), hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), hydroxymethylethylcellulose (HEMC), ethylcellulose (EC), methylcellulose (MC), cellulose esters, cellulose glycolate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate phthalate, polymethylacrylate (HPMCP), hypromellose, vinylpyrrolidone, polyvinylpyrrolidone, mannitol, polyvinyl acetate phthalate, polyethylene glycol, copovidone and the like.
In one embodiment, the present invention provides pharmaceutical compositions comprising lobeglitazone sulfate obtained by processes herein described, having a D90 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention provides pharmaceutical compositions comprising lobeglitazone sulfate obtained by the processes herein described, having a D50 particle size of less than about 250 microns, preferably less than about 150 microns, more preferably less than about 50 microns, still more preferably less than about 20 microns, still more preferably less than about 15 microns and most preferably less than about 10 microns.
In one embodiment, the present invention provides pharmaceutical compositions comprising lobeglitazone sulfate obtained by the processes herein described, having D90 particle size less than 150 microns, D50 particle size of less than 75 microns and D10 particle size less than 35 microns.
The particle size disclosed here can be obtained by, for example, any milling, grinding, micronizing or other particle size reduction method known in the art to bring the solid state lobeglitazone sulfate into any of the foregoing desired particle size range.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention and should not be read as limiting the scope of the invention.

Examples
Example 1: Preparation of 2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl)amino} ethan-1-ol (IV)
In a 3.0 lit 4 neck round bottom flask, anhydrous dimethylformamide (300 mL) was charged with 4,6- dichloropyrimidine (100 gm) and stirred for 10-15 min followed by addition of potassium fluoride (116.5 gm) under stirring. To the reaction mixture, 4-methoxyphenol (83.30 gm) was added at 25-30°C. Temperature of the reaction was raised to 80-85°C and maintained stirring for 2 hrs. After completion, the reaction mass was cooled to 25-30°C followed by addition of N-methyl amino ethanol (151.22 gm) under stirring. Further, temperature of the reaction was raised to 80-85°C and maintained stirring for additional 2 hrs. After completion of the reaction, the reaction mixture was cooled to 25-30°C and stirred for further 30 mins. The reaction mass was filtered and washed with toluene and dried under suction. The above filtrate was charged with water and the layers were separated. The toluene layer was distilled under vacuum to furnish oily mass. The oily mass was degassed under vacuum to get 2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl)amino} ethan-1-ol (IV) in light yellow to brown colour with yield of 170 to 175 gm.
Example 2. Preparation of 4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino}ethoxy) benzaldehyde (III)
In 2.0 lit 4 neck round bottom flask, dimethylformamide (300 mL) was charged with compound IV (175 gm), potassium hydroxide flakes (107.09 gm) and 4-flouro benzaldehyde (102.50 gm) under stirring for 12 hrs. After completion of reaction, the reaction mass was extracted with ethyl acetate followed by washing with brine solution. The aqueous layer was extracted with ethyl acetate, combined both organic layers and distilled under vacuum to obtain oily residue. HPLC purity: 69.36%. The oily residue was further degassed under vacuum. Ethanol was added to the residue to get a clear solution followed by addition of sodium metabisulfite solution (132.68 gm in water) and stirred for 1 hr. The reaction mass was filtered and slurry was subjected to washing with ethanol followed by vacuum dry to get a sodium metabisulfite adduct, a compound of formula VI, HPLC purity: 84.4%. The above adduct was charged with sodium hydroxide solution and ethyl acetate. The layers were separated and the ethyl acetate layer was distilled out under vacuum to get oily residue. The above degassed residue was charged with ethanol and raised the temperature to 60-70°C. The residue was stirred for 1 to 1.5 hrs at the same temperature followed by cooling the reaction mixture and stirred for additional 1 hr to obtain a slurry. The slurry was filtered and dried under vacuum to afford the desired product 4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl) amino}ethoxy)benzaldehyde (III) in 140-160 gm yield, HPLC purity: 97.6%.
1H NMR (400 MHz, CDCl3) d 3.14, 3.83, 4.30, 4.67, 5.86, 6.94, 7.02, 7.08, 7.84, 8.32, 9.90.
Example 3. Preparation of 5-5-{[4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl) amino} ethoxy) phenyl]methylidene}-1,3-thiazolidine-2,4-dione (II):
Method I: In 3.0 lit 4 neck RBF, compound III (110 gm) was charged with toluene (1320 mL), piperidine (7.40 gm) and 2,4-thiazolidinedione (37.35 gm) followed by addition of acetic acid (5.21 gm) under stirring. The temperature of reaction was raised to 105-110°C and stirred for 12-13 hrs. After completion of reaction, the reaction mixture was cooled further for 2 to 2.5 hrs. The reaction mass was filtered and washed with toluene. The residue was dissolved in methanol under stirring at 60-65°C for 30-40 mins. The reaction mass was cooled to 25-30°C and stirred for 30-40 mins. The reaction mass was filtered and washed with methanol followed by vacuum dry to afford 5-5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl)amino}ethoxy)phenyl]methylidene}-1,3-thiazolidine-2,4-dione (II) with 104.5-114.4 gm yield. MP-145-146°C.
IR (KBr) 3427, 3112, 2924, 2835, 2752, 1749, 1693, 1590, 1545, 1506, 1444, 1363 cm-1;
1H NMR (400 MHz, CDCl3) d 3.12, 3.45, 3.83, 4.00, 4.16, 4.50, 5.84, 6.83, 7.06, 7.15, 8.31, 8.89;
13C NMR (100 MHz, CDCl3) d 37.9, 38.1, 49.7, 54.0, 55.9, 66.6, 85.9, 115.0, 122.8, 128.8, 130.7, 146.7, 157.3, 157.9, 158.4, 164.2, 170.8, 171.1, 174.9.
Method II: In 3.0 lit 4 neck RBF, compound VI (5.0 gm) was charged with toluene (150 mL), piperidine (0.22 gm) and 2,4-thiazolidinedione (1.22 gm) followed by addition of acetic acid (0.16 gm) under stirring. The temperature of reaction was raised to 105-110°C and stirred for 12-13 hrs. After completion of reaction, the reaction mixture was cooled further for 2 to 2.5 hrs. The reaction mass was filtered with methanol followed by vacuum dry to afford 5-{[4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4yl] (methyl)amino} ethoxy)phenyl] methylidene}-1,3-thiazolidine-2,4-dione (II) with 3.7 g yield. MP-145-146°C.
Example 4. Preparation of 5-{[4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl] (methyl) amino} ethoxy) phenyl] methyl}-1, 3-thiazolidine-2, 4-dione (I).
Method I: In 50.0 lit 4 neck RBF, compound of formula II (300 gm) was charged with sodium carbonate (72 gm), PEG-400 (1.2 L), water (2.4 L), cobalt (II) chloride hexahydrate (1.2 gm), dimethylglyoxime (4.8 gm) and dimethylformamide (90 mL) under stirring at 25-30oC for 60-70 mins. The reaction mixture was charged with aqueous solution of sodium borohydride (72 gm) and sodium carbonate (8.4 gm) in water (900 mL). The reaction was maintained at 25-30oC for 60-70 mins. After completion of reaction, the reaction mixture was charged with water and acetone followed by acetic acid and adjusted the pH 6.5 to 7.0. The above reaction mass was stirred for 1 hour, filtered and washed with water to get a wet cake. The above wet cake was charged with methylene dichloride and brine solution followed by stirring for 10-20 mins. The organic layer was separated and dried over of sodium sulphate followed by filtration. The organic layer was distilled under reduced pressure. The above reaction mass was charged with acetic acid (300 mL) heated to 60?C to 70?C. Again ethanol (2.1 L) and cooled to 25oC to 30oC. The reaction mass was filtered and washed with industrial solvent followed by vacuum dry to afford 275 gm of 5-{[4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl) amino} ethoxy) phenyl] methyl}-1,3-thiazolidine-2,4-dione (I).
Purification: The above product was charged with methyl ethyl ketone (690 mL) and heated to 70-75°C under stirring for 30-40 min. After completion of reaction, the reaction mass was cooled to 25-30oC and stirred for 1 hr. The solid was filtered. Methyl ethyl ketone (500 mL) was added and heated to 70-75°C, maintained for about 40 mins and cooled to 25-30oC. The product was filtered and dried under vacuum drying to afford 151 gm of 5-{[4-(2-{[6-(4-methoxyphenoxy) pyrimidin-4-yl](methyl) amino} ethoxy) phenyl] methyl}-1,3-thiazolidine-2,4-dione (I). HPLC Purity<99%, M.P range: 145-146°C;
IR (KBr) 3427, 3112, 2924, 2835, 2752, 1749, 1693, 1590, 1545, 1506, 1444, 1363 cm-1;
1H NMR (400 MHz, CDCl3) d 3.12, 3.45, 3.83, 4.00, 4.16, 4.50, 5.84, 6.83, 7.06, 7.15, 8.31, 8.89;
13C NMR (100 MHz, CDCl3) d 37.9, 38.1, 49.7, 54.0, 55.9, 66.6, 85.9, 115.0, 122.8, 128.8, 130.7, 146.7, 157.3, 157.9, 158.4, 164.2, 170.8, 171.1, 174.9.
Method II: To the stirred solution of polyethyleneglycol-400 (20 mL), water (40 mL), was added compound of formula II (5 gm) and sodium carbonate (1.2 gm). Followed by addition of cobalt (II) chloride hexahydrate (20 mg), dimethylglyoxime (80 mg) and N, N-dimethylacetamide (1 mL) at 25-30°C. To the stirred reaction mixture, aq. solution of sodium borohydride (1.2 gm) and of sodium carbonate (140 mg) in water (7.5 mL) was added. After completion of reaction, water and acetone were added, followed by addition of acetic acid to bring pH to 6.5 to 7.0. The reaction mixture was filtered and dissolved in methylene dichloride (MDC) and washed with sodium chloride solution. The MDC layer was distilled. To the residue acetic acid and ethanol were added. And the precipitate was filtered and dried to obtain 4.5 gm of product. The product was purified in methyl ethyl ketone at 70-75°C to yield 2.5 g of compound of formula I.
Method III: To the stirred solution of compound (II) 150 gm in toluene (3 L) were successively added the Hantzsch ester (100.4 gm and silica gel (450 gm). After each addition, the reaction mixture was stirred at reflux temperature for 26 hrs to obtain compound I.
Example 5: Preparation of 5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl) amino} ethoxy) phenyl] methyl}-1,3-thiazolidine-2,4-dione sulfate.
In 20.0 Lit 4 neck RBF, Lobeglitazone obtained from example 4 (100 gm) was charged with methanol (3.0 lit) under stirring at 0-5°C followed by slow addition of sulphuric acid (21.4 gm) and stirred the reaction. After 1 hr clear solution was observed which was filtered through hyflow and washed with methanol and distilled under reduced pressure to afford amorphous solid. Further, the solid is charged with methyl tert butyl ether and solvent is distilled under reduced pressure to afford amorphous solid. The wet cake is dried under vacuum to afford 5-(4-{2-[6-(4-methoxyphenoxy) pyrimidin-4-yl] methylamino ethoxy} benzyl) thiazolidine-2,4-dione sulfate, 109 gm. HPLC Purity:< 99%, M.P: 111.4°C;
IR (KBr) 3437, 3037, 2937, 2775, 1751, 1698, 1648, 1610, 1503, 1439, 1301, 1246, 1215, 1183 cm-1;
1H NMR (400 MHz, CDCl3) d 3.09, 3.29, 3.76, 3.97, 4.14, 4.86, 6.06, 6.86, 7.00, 7.13, 8.30, 11.99;
13C NMR (100 MHz, CDCl3) d 37.1,38. 2, 53.7, 53.8, 56.3, 62.2, 65.8, 86.0, 115.1, 116.0, 123.0, 129.8, 131.2, 145.7, 153.4, 157.9, 158.1, 161.1, 166.5, 172.4, 172.5, 176.3, 176.5.

,CLAIMS:1] A process for the preparation of lobeglitazone the compound of formula I, or a salt thereof, comprising:

I
a) reacting 5-{[4-(2-{[6-(4-methoxyphenoxy)pyrimidin-4-yl](methyl) amino} ethoxy) phenyl]methylidene}-1,3-thiazolidine-2,4-dione, a compound of formula II;

II
with a catalytic mixture comprising a solution of cobalt ion and dimethyl glyoxime in a solvent and a reducing agent in presence of a base to obtain lobeglitazone; and
b) optionally converting lobeglitazone to its salt.
2] The process as claimed in claim 1, wherein the reducing agent is selected from the group consisting of an alkali hydride, alkali borohydride or alkali butoxide.
3] The process as claimed in claim 2, wherein the alkali hydride is selected from the group consisting of sodium hydride and lithium hydride; the alkali borohydride is selected from the group consisting of sodium borohydride, potassium borohydride and cyano borohydride.
4] The process as claimed in claim 1, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, alkali or alkaline earth metal carbonates and alkali or alkaline earth metal bicarbonates.
5] The process as claimed in claim 1, wherein the compound of formula II is prepared by a process comprising:
a) reacting 2{[6-(4-methoxyphenoxy) pyrimidin-4-yl] (methyl)amino}ethan-1-ol, a compound of formula IV

IV III
with 4-fluorobenzaldehyde to form a compound of formula III;
b) treating the above compound of formula III with sodium metabisulfite to obtain a reaction mixture comprising sodium metabisulfite adduct, a compound of formula VI;

VI
c) isolating the sodium metabisulfite adduct, the compound of formula VI from the reaction mixture;
d) hydrolysing the above adduct in a suitable solvent to obtain the compound of formula III; and
e) reacting the compound of formula III obtained from step d) with 2,4-thiazolidinedione in presence of a base and a solvent to obtain the compound of formula II.
6] The process as claimed in claim 5, wherein the purity is greater than 90%.
7]A sodium metabisulfite adduct, a compound of formula VI

VI
characterised by 1H NMR having peaks at about 3.086, 3.360, 3.70, 4.12, 4.89, 5.75, 6.06, 6.822, 7.06, 7.38, 7.85, 8.18.
8] The process as claimed in claim 1, wherein the obtained lobeglitazone sulfate is amorphous.