FIELD OF THE INVENTION
The present invention relates to an industrially advantageous process for the preparation of thiazohdine derivatives In particular, the present invention relates to a novel process for preparing pioghtazone of formula I and its pharmaceutically acceptable salts
(Formula Removed)
This invention also relates to novel synthetic intermediates useful in the process for the preparation oi pioghtazone
BACKGROUND OF THE INVENTION
Pioghtazone of formula I is an oral antihyperglycemic agent that acts primarily by decreasing insulin resistance and is chemically known as (i)-5-|[4-[2-(5-cthyl-2-pyndinyl)ethoxy]phenyl]methyl]-2,4-thiazohdinedione
(Formula Removed)
Pharmacological studies indicate that pioglita/one improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis Pioghta/one improves glucose resistance while reducing circulating insulin levels Pioghta/one is currently marketed as its hydrochloride salt under trade name AC I OS
Pioghtazone and its hydrochloride have been disclosed in US patent 4 687,777 This patent discloses preparation of pioghta/one by the reaction of 2-(5-cthyl-2-pyndyl)ethanol with 4-fluoronitroben/ene to give 4-[2-(5-ethyl-2-pyndyl)ethoxy [ nitrobenzene, which is reduced to yield the corresponding amino compound 4-[2-(5-ethyl-2-pyndyl)ethoxy]aminobenzene This amino compound is then diazotized and treated with aqueous hydrobromic acid and methylacrylate to give
methyl-2-bromo-3-(4-[2-(5-ethyl-2 pyndyl)ethoxy] phenyl J propionate which in turn is treated with thiourea to yield a crucial intermediate 5-{4-[2-(5-cthyl-2-pyridyl)ethoxy]ben/yl}-2-imino-4-thia/ohdinonc, which is further hydroly/cd to obtain pioghtazone of formula I Several methods for production of various thiazohdinedione derivatives are described in Drugs of Future, 15, 1080 (1990) Chemical and Pharmaceutical Bulletin, 30, 3563 (1982) 30 3580 (1982) and 32 2267(1984)
These methods invariably comprise low temperature diazotisation condensation with lachrymetric and readily polymenzable reagent acrylic ester in the presence of a copper catalyst by Meerwein arylation reaction, to give a haloestcr reacting it with thiourea to give an iminothiazolidinone and finally hydrolyzing the same to get the required thiazohdinedione derivative
Meerwein arylation is associated with exothermicity, evolution ol large amounts of nitrogen gas tarry byproducts requiring cumbersome purification lower yields and use of an excess of toxic and irritant acrylic ester Moreover the bromo ester intermediate itself is lachrymatory in nature
The above disadvantages and the problem of waste disposal coupled with eflluent treatment of environmentally unfriendly substances and heavy metals make the known route technically and commercially unattractive
US patent 4,812,570 discloses a process for the preparation of pioglita/one by reacting alkyl pyridyl ethanol with a halogenating agent or a sulfonyl halide to give a halo or alkyl- or aryl-sulfonyloxy derivatives which when reacted with alkali metal salt of hydroxy benzaldehyde gives alkyl pyridyl ethoxy benzaldehyde, which on further reaction with 2,4-thiazohdinedione followed by catalytic reduction gives pioghtazone However this process leads to the formation of side products such as 2-vinyl-5-ethyl pyridine from tosylates An alternative method for the preparation ot alkyl pyridyl ethoxy ben/aldehyde requires high temperature in presence of Raney nickel for the conversion of cyanide to formyl group Additionally, the purification of the inteimediates is also difficult in this process and the product is obtained in low overall yield
The processes of the prior art as described above to prepare pioghta/onc and its pharmaceutically acceptable salts, involve technically arduous methods like low temperature diazotization evolution of large excess of nitrogen gas, handling of problematic reagents that are corrosive and toxic intermediates which arc lachrymetric, not-amenable for easy scale up, formation of impurities long reaction times, higher costs and special methods for effluent management and waste disposal etc Iherefore commercial applicability of the said processes is limited
In view of the above mentioned drawbacks and disadvantages of the prior art procedures, it is desirable to develop an improved, efficient cost effective operationally facile environmentally benign and amenable to scale up synthesis of pioghtazone
Thus the present invention meets the need in the art and provides an improved process for the preparation of thiazolidine derivatives particularly pioglita/one, which is unique with respect to its simplicity cost effectiveness, and scalability b> using mild reaction conditions and novel intermediates
SUMMARY OF THE INVENTION
The present invention relates to a novel and efficient process for the preparation ol thiazolidine derivatives such as pioghtazone of formula I,
(Formula Removed)
and pharmaceutically acceptable salts thereof which comprises reacting 4-[2-(5-ethyl-pyndin-2-yl)ethoxy]benzaldehyde of formula II
(Formula Removed)
with a thiazolone compound of formula IIIa or salt thereof
(Formula Removed)
wherein R1 and R2 are same or different and R1 and R2 can be hydrogen or
R1 can be hydrogen and R2 can be C1-6, alkyl group wherein alkyl can be linear branched or cycloalkyl or alkenyl or alkyml or aryl or alkaryl or heterocyclic with one or two hetero atoms selected pom nitrogen, oxygen or sulfui or
R1 and R2 can be C1-6 alkyl group wherein alkyl can be linear branched or cycloalkyl or alkenyl or alkynyl or aryl or alkaryl or heterocyclic with one or two hetero atoms selected from nitrogen oxygen or sulfur or
R1 and R2 are C1-6 alkyl groups joined to each other at the terminal carbons forming five or six membered ring containing one or two heteio atoms selected from nitrogen oxygen or sulfur such as piperidino morpholmo pipenzino pyrrohdino, 4-alkyl piper izino, thiomorphohno azetidino aziridino or
R can be hydrogen or C1-6 alkyl and R~ can be sidfonylalkvl or sulfonvlalkylanl or sulfonylaryl wherein aryl can be optionally substituted with alkvl or halo alkanoyl or aranoyl or heteroaranoyl groups C1-6 alkoxy group or dialkylamino or piperidino morpholmo pipenzino, pyrrohdino, 4-alkyl pipenzino thiomorphohno, azetidino aziridino and the like
under mild reaction conditions to form a novel benzylidene derivative of formula IVa,
(Formula Removed)
wherein R1 and R2 are as defined abon e
or optionally with variable amounts of deprotected nnine compound 5-{4-[2-(5-ethyl-pyndin-2-yl)-etho\y]-benzylidene}-2-imino-thiazolidin-4-one of formula V
(Formula Removed)
reducing the resulting benzylidene deivative of formula IVa to form novel bcnzy derivative of formula VIa,

(Formula Removed)
wherein R1 and R2 are as defined above,
and converting the benzyl derivative of formula VIa to pioglitazone and pharmaceutically acceptable salt thereof
DETAILED DESCRIPTION OF THE INVENTION
The process of this invention is a high throughput, novel and efficient process for the preparation of highly pure thiazolidine derivatives such as pioglitazone of formula I
(Formula Removed)
and pharmaceutically acceptable salts thereof
One embodiment of the present invention provides an improved and efficient process for preparing pioglitazone of formula I and pharmaceutically salt thereof starting from 4-[2-(5-cthyl-pyridin-2-yl)etho\y]benzaldehydc of formula II
(Formula Removed)
Generally aldehyde compound of formula II is reacted with a thia/olone compound of formula Ilia or salt thereof,
(Formula Removed)
wherein R1 and R2 are same or difjerent and R1 and R2 can he hydrogen or
R1 can he hydrogen and R2 can he C1-6 alkyl group wherein alkvl can he linear branched or cycloalkyl or alkenyl or alkvnvl or aryl or alkaryl or heterocxchc with one or two hetero atoms selected from nitrogen, oxygen or sulfur or
R1 and R2 can he C1-6 alkyl group wherein alkyl can be linear, blanched or cycloalkyl or alkenyl or alkynvl or aryl or alkaryl, or heterocyclic with one or two hetero atoms selected from nitrogen oxygen or sulfur or
R1 and R2 are C1-6 alkyl groups joined to each other at the terminal carbons forming five or six membeied ring containing one or two hetero atoms selected from nitrogen, oxygen or sulfur such as piperidmo, morphohno, piperizino pyrrolidino, 4-alkyl piperizino, thiomorpholino, azetidino aziridino, or
R can be hydrogen or C1-6 alkyl and R2 can be sulfonylalkyl or sulfonylalkylaryl or sulfonylaryl wherein aryl can be optionally substituted with alkyl or halo alkanoyl or aranoyl or heteroaranoyl groups C1-6 alkoxy group or dialkxlanuno or piperidino morphohno piperizino pyrrolidino 4-alkvl piperizino thiomorpholino azetidino, aziridino and the like
under mild reaction conditions to form a benzylidenc derivative of formula IVa including isomers tautomer, salts, solvates or mixtures thereof that further forms the part of invention
(Formula Removed)
wherein R and R' are as defined above
It has been observed that in some cases compound of formula IVa, wherein alleast
one of the R1 or R2 is hydrogen, is found to have variable percentage of
deprotected lmine compound 5-{4-[2-(5-ethyl-pyndin-2-yl)-ethoxyl]-
benzylidene}-2-imino-thiazolidin-4-one of formula V,
(Formula Removed)
However conditions favoring the formation of either pure compound of formula IVa or compound of formula V or mixture thereof depend upon choice and amount of solvent, base and catalyst, temperature variation, and concentration of reactants
It has been observed that the presence of variable amount of compound of formula V in compound of formula IVa does not interfere with the lurther course of the reaction and its formation doesn't reduce the yield and purity of the ensuing intermediates in the preparation of pioghtazone
Generally the thiazolone compound of formula IIIa or salts thereof is reacted with aldehyde compound of formula 11 in the presence of base in suitable solvent Usually the reaction can be conducted at a temperature range of 20 to 120°C preferably at a temperature range of 20 to 90°C and it takes about 1-20 hours preferably 3-10 hours for completion of reaction The completion of reaction can be monitored by thin layer chromatography (TLC) or high performance liquid chromatography (HPLC) When absence of starting material is observed during the course of reaction the solvent is optionally, completely or partially distilled off and the reaction mixture is cooled to a temperature of about 0°C to room temperature and filtered The crude product is optionally neutralized with appropriate amount of aqueous mineral acid particularK hydrochloric acid to obtain benzyhdene derivative of formula IVa
Suitable solvent can be selected from amongst C1-6 aliphatic alcohols such as methanol ethanol, isopropanol n-propanol, C5-8 aliphatic or aromatic hydrocarbons such as hexane pentane, heptane toluene xylene C3-6, esters such
as ethyl acetate, butyl acetate, C2-5 ethers such as diethyl ether dusopropyl ether t-butyl methyl ether, 1,2 dimethoxy ethane tetrahydrofuran and dioxanc C3-6 ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone C1-3, aliphatic halogenated hydrocarbons such as dichloromethane chloroform carbon tetrachloride, dichloroethane nitrites such as acetonitnle, and amides such as N,N-dimethylformamide or mixtures thereof
The base can be selected from but not limited to ammonia, ammonium acetate methylamine, ethylamine, butylamine pyrrolidine, pipendine, morpholinc piperazine, diethylamine, dusopropylamine and tricthylaminc, or their salts with aliphatic carboxylic acids preferably acetic acid, alkali metal alkoxidcs such as sodium methoxide and sodium ethoxide, alkali metal carbonate such as potassium carbonate and sodium carbonate, alkali metal hydroxide such as sodium hydroxide, potassium hydroxide, alkali metal bicarbonate such as sodium bicarbonate, potassium bicarbonate, alkali metal hydride such as sodium hydride alkali metal acetate such as sodium acetate and potassium acetate, alkaline earth metal oxides such as calcium oxide and the like
The base can be used as pure or a mixture thereof in a given ratio with or without a phase transfer catalyst such as benzyltriethylammomum chloride cetyltrimcthyl ammonium bromide, tetrabutylammonium bromide and the like
It has been observed that in some cases, preferably wherein R1 is hxdiogen or C1-6 alkyl and R2 is alkanoyl, aranoyl or heterocnanoyl group, the use of base like ammonium acetate gives exclusively compound of formula IVa and use of excess of pipendine gives exclusively compound of formula V as the product
In one specific embodiment of the present invention, aldehyde compound of formula II is reacted with thiazolone compound of formula IIIa (wherein R1 is hvdrogen and R2 is sulfonyl-p-tolyl), 4-methyl-N-(4-oxo-4,5-dihydrothiazol-2-yl)benzenesulfonamide in the presence of base in suitable solvent such as given above at a temperature of 20-90°C After completion of reaction solvent is distilled off and the reaction mixture is cooled and neutralized with dilute mineral acid such as hydrochloric acid to give N-(5-{4-f2-(5-cthyl-pyndin-2-
yl)ethoxy]benzyhdene}-4-oxo-45-dihydrothiazol-2-yl)-4-methyl-benzenesulfonamide
The starting material, aldehyde compound of formula II can be prepared by conventional procedures reported in prior art in patents such as U S Patent Nos 4,812,570, 4,898,947, 5,554,758. 5,952,509, 6 100 403 and I P 1 694 646 etc Typically, aldehyde compound of formula II can be prepared by dissolving 5-ethyl-2-(2-hydro\y-ethyl)pyndine in inert solvent like toluene, tetrahydrofuran and the like, in the presence of base like triethylamine, aqueous sodium hydroxide and the like The solution is cooled to 0°C to ambient temperature followed by the dropwise addition of methanesulfonyl chloride or p-tolucnesulfonyl chloride or any other suitable protecting group The reaction mixture is stiired for few hours at 0°C to ambient temperature After workup the isolated product is treated with sodium or potassium salt of 4-hydroxy-benzaldehydc and stirred at ambient temperature under inert atmosphere for a period of about 1-4 hours After work up, aldehyde compound of formula II is isolated
Yet another starting material, thiazolone compound of formula Ilia can be procured from commercial source or prepared by conventional procedures reported in prior art such as EP 0126934, Organic Synthesis Collection Vol 3 p-751 (1955) and Khimiko-Farmatsevticheskn Zhurnal, 9(6), 12-15, 1975, Farmatsevtichnu Zhurnal (kiev) (1965), 20(1) 6-9, Dyes & Pigments 57 (2) 107-114 2003 etc
According to yet another embodiment of the present invention benzyhdinc derivative of formula IVa optionally with variable amounts of 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzylidene}-2-imino-thiazohdin-4-one of formula V is further reduced to benzyl derivative of formula VIa, or an isomer or mixture or a tautomer form or a salt, or a solvate thereof
(Formula Removed)
wherein R1 and R2 are as defined above Compound of formula VIa or an isomer or mixture or a tautomer form or a salt, or a solvate thereof, represents yet another novel and crucial intermediate in the preparation of pioglita/one that further represents part of the invention
The compound of formula VIa, wherein atleast one of the R1 or R2 is hxdrogen is found to have variable percentage of deprotected imine compound of formula VI
(Formula Removed)
a known and crucial intermediate in the preparation of pioglita/one
The reduction conditions employed for reducing compound of formula IVa may be selected from the known reduction methods and preferably can be performed by using known reducing agent selected from, but not limited to borane compounds and metal hydrides such as boranc-tetrahydrofuran, boranc-dimethylsulfide borane-amine borane-lewis acid borane-tnphcnylphosphinc lithium aluminium hydride sodium borohydnde, lithium borohydndc diborane potassium borohydnde, tetraalkylammomum borohydnde zinc borohydride and the like
Along with reducing agent a metal ion and/or a ligand can also be used Preferred metal ion is cobalt (II) Sources of cobalt (II) ion include cobalt chloride, cobalt diacetate cobalt sulfate and the like The ligand can be selected from dimethylglyoxime 2,2-bipyndyl or 1,10-phenanthroline optionally coligands like ethanolamines such as triethanolamine diethanolamine ethanolamine, cinchonine, cinchonidine, quinine, quinidine and the like can be used
Specifically, the reduction of compound of formula IVa is conducted at a temperature range of about -20 to 45°C for a period of about 1-60 hours using an appropriate reducing agent as described above in a suitable solvent in the presence or absence of base or salt
Base or salt can be selected from sodium hydroxide, potassium hydroxide sodium carbonate, lithium carbonate, potassium carbonate potassium bicarbonate ammonium carbonate, ammonium bicarbonate, potassium bromide, potassium iodide, lithium iodide lithium bromide, sodium halides and the like Optionally the base can be used in mixture with a phase transfer catalyst such as benzyltriethylammonium chloride, cetyltrimethyl ammonium bromide tetrabutylammonium bromide
The appropriate solvent can be mixture of water and C1-8 aliphatic alcohols selected from methanol ethanol, isopropanol, n-propanol the like or mixtures thereof Additionally one can also add a solvent selected from ethers such as diethyl ether dusopropyl ether t-butyl methyl ether 1,2-dimcthoxycthanc tetrahydrofuran and dioxanc, aromatic hydrocarbons such as toluene and xylene aliphatic halogenated hydrocarbons such as dichloromethanc, chloroform and 1 2-dichloroethane aliphatic hydrocarbons such as pentane hexane and heptane, esters such as ethyl acetate and butyl acetate nitnles such as acetonitnle, N N-dimethylformamide, dimcthylsulfoxide sulfolane or mixtures thereof
In the present invention, the reaction is conducted preferably in the presence of water In this case, the volume ratio of water to the solvent (the solvent using a lower alcohol singly, or a mixture of a lower alcohol and the organic solvent) ranges, for example, from 1 to 30 volume %, preferably from 10 to 20 volume %
The completion of reaction is monitored by TLC and/or HPLC After completion of reaction, the reaction mixture is quenched by the addition of a suitable quenching agent at low temperature to afford compound of formula Via
Suitable quenching agent can be selected from ammonium chloride inorganic acids selected from sulfuric acid, hydrochloride acid, the like or organic acid selected from acetic acid, formic acid, benzoic acid, the like or any other reagent selected from ketones such as acetone, ethyl methyl ketone, mcthyhsobutyl ketone
In one specific embodiment of the present invention, compound of formula IVa (wherein R1 is hydrogen and R2 is sulfonyl-p-tolyl) N-(5-{4-[2-(5-ethyl-pyndin-2-
yl)ethoxy]benzylidene}-4-o\o-4,5-dihydrothiazol-2-yl)-4-methyl-ben/encsulfon amide is treated with hydrated cobaltous chloride in the presence or absence of ligand such as dimethylglyoxime in suitable solvent as defined above followed by treatment with reducing agent like sodium borohydnde at a temperature of 0-15°( for 4-9 hours After complete reduction the reaction mass is quenched with suitable quenching agent like ammonium chloride and N-(5-{4-(2-(5-ethyl-pyndin-2-yl)ethoxy[benzyl}-4-oxo-4,5-dihydrothiazol-2-yl)-4-methyl-benzenesulfonamide is isolated after removal of solvent and work up
In yet another embodiment of the present invention, benzyl derivative of formula VIa can be hydrolysed and converted to pioghtazone of formula 1 and acid addition salts thereof by following the conventional procedures reported in the prior art Typically compound of formula VIa is hydrolysed using stoichiometric to excess of mineral acid such as sulfuric acid, hydrochloric acid and the like preferably hydrochloric acid
The compound of formula I may be isolated as free base, but it is usually more convenient to isolate the compounds of the instant invention as acid addition salts Such acid salts are exemplified by mineral salts like hydrochloride, hydrobromide sulfate, organic acid salts like succinate maleate, fumarate, malate tartrate oxalate and sulfonates like methanesulfonate benzenesulfonate, toluenesulfonate etc
These salts are prepared in the usual manner, i e , by reaction of the free base with a suitable organic or inorganic acid, for example, one of the pharmaceutical 1\ acceptable acids as described above Typically, the base of formula I is treated with a suitable solvent such as a ketone e g acetone or straight chain or blanched C1-8 alcohol preferably methanol ethanol nitnles of general formula RCN wherein R is C2-5 alkyl, tetrahydrofuran dioxane, dimethylformamidc dimethylsulfoxide N-methylpyrrohdone, sulfolane, halogenatcd solvents and/or mixture thereof and the like and acidified with an acid dissolved in a like solvent Although it is advantageous to dissolve pioghtazone free base and acid in different solvents The acid solution is added until the salt formation is complete
According to yet another embodiment of the present invention acid hydrolysis of benzyl derivative of formula VIa by hydrochloric acid directly yields pioghtazone hydrochloride Generally benzyl derivative of formula VIa is treated with mineral acid such as hydrochloric acid in a suitable solvent, the reaction being performed at a temperature of from room temperature to reflux temperature of the solvent to yield pioghtazone hydrochloride Solvent can be selected from C1-4 alcohols such as methanol, ethanol, isopropanol, n-propanol n-butanol, isobutanol the like and mixtures thereof The reaction can also be performed in the absence of solvents The choice of solvent and strength of hydrochloric acid used depends upon the nature of protecting group and specific illustrations of suitable procedures can be had by reference to the examples herein below
In one specific embodiment of the present invention benzyl derivative ol formula VIa (where R1 is hydrogen and R2 is sulfonyl-p-tolyl) N-(5-{4-[2-(5-ethyl-pyndin-2-yl)ethoxy]benzyl]-4-oxo-4,5-dihydrothiazol-2-yl)-4-mcthyl-benzenesulfonamide is hydrolysed with concentrated hydrochloric acid to obtain pioghtazone hydrochloride
If desired the pioghtazone hydrochloride can readily be converted to the corresponding free base by treatment with a suitable base such as potassium carbonate, sodium carbonate ammonium hydroxide, potassium hydroxide sodium hydroxide and the like
In yet another embodiment of the present invention, pioghtazone hydrochloride can also be prepared from other organic carboxylic acid addition salts of pioghtazone by treating with hydrochloric acid, the said reaction being performed in the presence or absence of suitable solvents selected from C3-10 ketone preferably selected from acetone, ethyl methyl ketone methyl isobutyl ketone straight chain or branched C1-8 alcohol preferably methanol, cthanol nitrilcs of general formula RCN wherein R is C2-5 alkyl, tetrahydrofuran, dioxanc dimethylformamide dimethylsulfoxide N-methylpyrrolidone, sulfolane halogenated solvents and/or mixture thereof
Isolation and purification of the compounds and intermediates described above can be effected, if desired, by any suitable separation or purification procedure such as for example, filtration, centrifugation, extraction, acid-base treatment crystallization conventional isolation and refining means such as concentration concentration under reduced pressure, solvent-extraction, crystallization phasic-transfer or chromatography column chromatography, or by a combination of these procedures Specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below However, other equivalent separation or isolation procedures could, of course also be used According to yet another embodiment of the present invention, pioglitazone hydrochloride can further be purified by treatment with suitable organic solvents like acetonitnle, acetone, methanol, ethanol, isopropanol, n-propanol, methyl isobutyl ketone ethyl methyl ketone, toluene C1-6 ester C2-5 nitnlcs the like and/or mixtures thereof Alternatively, pioglitazone hydrochloride can further be purified by treatment with hydrochloride such as ethyl acetate hydrochloride alcoholic hydrochloride and the like, in the presence of suitable organic solvents like acetone, methanol, ethanol, isopropanol, n-propanol methyl isobutyl ketone ethyl methyl ketone, toluene, C1-6 ester, C2-5 nitnles, the like and/or mixtures thereof The reaction is preferably conducted at a temperature of room temperature to 60°C for a period of 1 -10 hours
Major advantages realized in the present invention are that process may be easilv and conveniently scaled-up for industrial large-scale production and the process is simple, economical high throughput and environment friendly
Although, the following examples illustrate the present invention in more detail but should not be construed as limiting the scope of the invention
EXAMPLES
Example 1. Preparation of N-(5-{4-[2-(5-ethvl-pyridin-2-vl)etho\v|
benzvlidene}-4-oxo-4,5-dihvdrothiazoI-2-vl)-4-methylbenzenesulfonamide
4-Methyl-N-(4-oxo-4,5-dihydrothiazol-2-yl)benzenesulfonamide (200g) was added to a solution of sodium hydroxide (62 2g) in methanol (15 It) at 40°C
followed by the addition of 4-[2-(5-ethyl-pyndin-2-yl)etho\y |ben/aldehyde (185g) and the mixture was refluxed for 7 hours After completion of reaction a part of methanol (1 It) was distilled off under reduced pressure The resulting slurry was cooled to 0-5°C and filtered The residue was dried and slurried in a dilute hydrochloric acid The resulting mixture was filtered washed with water and dried to obtain 35 lg of the title compound
DSC (240 32°C peak)
IR(KBr cm-1) 3434 1683. 1595 1440 1248 1178 1149 1086, 1020 900 580
1HNMR(CDCl3-DMSO-d6)(δppm, 300 MHz) 8 35(111 bs) 7 84(211 d)
7 48(1H dd), 7 44(1H, s), 7 43 (2H, d) 7 23 (2H, d) 7 20(111, d) 6 94 (2H, d)
4 37(2H, t), 3 53 (1H, bs), 3 20 (2H, t), 2 61 (211 q) 2 36 (311, s), 1 22(311, t)
13CNMR (CDCl3-DMSO-d6) (8 ppm, 300 MHz) 182 03,176 31,158 93
154 81,148 34,14134 140 19,13648 135 34,13087 128 51,127 52,127 47
127, 126 22, 122 78, 114 57 66 82, 36 74, 25 06 20 90, and 14 99
MS m/z 507 90(M+1)
Example 2: Preparation of N-(5-{4-[2-(5-ethvl-pvridin-2-yl)cthoxy]benzyl}-4-oxo-4,5-dihvdrothiazol-2-yl)-4-methvl-benzenesulfonamide
N-(5-{4-[2-(5-Ethyl-pyridin-2-yl)ethoxy]benzyhdene}-4-oxo-4,5-dihydrothidzol-2-yl)-4-methyl-benzencsulfonamide (150g) was added to a solution of cobaltous chloride hexahydrate (2lg) and dimethylglyoxime (2 lg) in a mixture of methanol, water and tetrahydrofuran (2 71t, 4 11) The resulting suspension was cooled to 0-5°C followed by addition of sodium borohydndc (29 lg) 1 he reaction mixture was further stirred at 0-5°C for 9 hours Thereafter, the reaction was quenched by addition of ammonium chloride and further stirred for 2 hours I he organic solvents were distilled off under vacuum The resulting product was filtered and dried to obtain 148g of the title compound
DSC (180 14°C peak)
IR(KBr cm1) 3446 1736 1568 1509, 1325 1086 830 660 570 lHNMR(CDCl3-DMSO-d6)(δppm 300 MHz) 8 37 (1H bs), 7 67 (211, d) 7 54 (1H, dd), 7 35 (2H, d) 7 26 (1H, d), 7 11 (2H, d), 6 81 (2H d) 4 67 (111
dd) 4 28 (2H, m) 3 27 (1H, dd), 3 15 (2H t), 3 05 (111 dd) 2 59 (211 q) 2 37 (3H, s) 1 19(311, t)
13CNMR(CDCl3-DMSO-d6)(δppm 300 MHz) 175 22 170 49 157 48 155 19 148 3,143 36,137 57,136 58,135 61 130 28,129 42 127 74 126 33, 122 95, 114 16, 66 62, 51 07 36 73, 35 84 24 96 20 94, 15 22
MS m/z 509 92(MH)
Example 3 Preparation of pioghtazone hydrochloride
N-(5-{4-[2-(5-Lthylpyndin-2-yl)ethoxy]bcnzyl}-4-oxo-4 5-dihydrothiazol-2-yl)-4-methylbenzenesulfonamide (110g) was retluxed in concentrated hydrochloric acid (770 ml) for 8 hours The resulting solid was filtered and dried to obtain crude product which was then stirred in ethyl acetate hydrochloride (455 ml, 1%) for 2 hours, filtered and dried to obtain 69g of crude pioghtazone hydrochloride having purity of 98 56% by HPLC
Pioghtazone hydrochloride obtained above was taken in acetone (260 ml) and treated with methanohc hydrochloride (86 ml, 10%) at 45-50°C and stirred for 2 hours Thereafter, the reaction mixture was cooled to 25-30°C filtered and dried to obtain 61 g of pure title compound having purity of 99 71% by HPI C
Example 4: Preparation of 5-{4-[2-(5-ethyl-pyridin-2-yl)ethoxy]benzylidene}-2-morpholin-4-yl-thiazol-4-one
4-[2-(5-Ethyl-pyndin-2-yl)ethoxy]benzaldehyde (15g) was added to a solution of sodium hydroxide (2 47g), methanol (150 ml) and 2-morpholin-4-yl-thiazol-4-one (10 93g) at 25-30°C and the reaction mixture was stirred for 4 hours 1 hen reaction mixture was filtered, washed with isopropanol and dried to obtain 18 7g of the title compound
IR (KBr, cm-1) 3435, 1692 1602, 1573 1512 1392, 1280 1255 1238, 1228 1109, 1030,888,572
1HNMR (CDC13 -DMSO-d6) (δ ppm, 300 MHz) 8 40 (1H bs) 7 45 (311 m) 7 26(1H s), 7 18(1H, d) 6 96 (2H d) 4 4 (2H, t), 4 08 (211, m) 3 8 (4H, m) 3 63 (2H m), 3 24 (2H, t), 2 63 (2H, q), 1 24 (3H t)
Example 5: Preparation of 5-{4-[2-(5-ethvl-pyridin-2-vl)ethoxv|benzvlidenei-2-morpholin-4-yl-thiazol-4-one
4-[2-(5-Ethyl-pyndin-2-yl)-etho\y]-benzaldehyde (lOOg) was added to a solution of sodium hydroxide (47g), methanol (1 0 It) and 2-morpholin-4-ylthia7ol-4-one hydrochloride (82 9g) at 25-30°C and the reaction mixture was stnred for 4 hours Then reaction mixture was filtered, washed with isopropanol and dried to obtain 130g of the title compound
Example 6 Preparation of 5-{4-[2-(5-ethyl-pvridin-2-vl)-ethoxy|-ben/yl}-2-morpholin-4-yl-thiazol-4-one
5-{4-f2-(5-Ethyl-pyndin-2-yl)-ethoxy)-bcn7ylidene}-2-iTiorpholin-4-yl-thia7ol-4-one (110g) was added to a solution of cobaltous chloride hexahydratc (3 71 g) and dimethylglyoxime (3 62g) in a mixture of methanol, water and tetrdhydrofuran (1 981t 4 11) I he resulting suspension was cooled to 0-5°C followed b\ addition of sodium borohydndc (9 83g) at a temperature of 0-5°C I he reaction mixture was further stirred for 30 minutes Thereafter, the reaction mixture was quenched by addition of ammonium chloride and stirred for 2 hours The organic solvents were distilled off under vacuum and the resulting solid was extracted with ethyl acetate Ethyl acetate was then distilled off under vacuum to obtain 94g of the title compound
IR(KBr cm-1) 3440, 1693 1611 1555, 1511, 1490, 1390 1280 1239,
1109, 1028,887, 830
1HNMR (CDCl3) (5 ppm, 300 MHz) 8 30 (1H, bs), 7 37 (1H d), 7 11 (1H, d) 7 04 (2H, d), 6 74 (2H, d) 4 36 (1H dd), 4 23 (2H t), 3 85 (2H, m) 3 48 (7H m), 3 14 (2H, t) 2 84 (1H dd) 2 53 (2H q), 1 15 (3H t)
Example 7 Preparation of Pioglitazone hydrochloride
5-{4-[2-(5-Ethyl-pyndin-2-yl)-ethoxy]-benzyl}-2-morpholin-4-yl-thiazol-4-one (35g) was taken in a solution of 4N hydrochloric acid (175 ml) and isopropanol (175 ml) and was refluxed for 8 hours The solvent was distilled off under vacuum and cold water was added The reaction mixture was filtered and dried to obtain 31 g of crude title compound which was recrystalhzed from acetomtrilc
Example 8 Preparation of 5-{4-[2-(5-ethvl-pyridin-2-yl)-ethoxyl-benzvlidene}-2-imino-thiazolidin-4-one
4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzaldehyde (88 8g) and pipendinc (8 3g) were added to a stirred suspension of N-(4-oxo-4 5-dihydro-thrazol-2-yl)-acetamide ( 55g ) in ethanol (500 ml) The reaction mixture was refluxed for 5 hours Progress of the reaction was monitored with TLC for the absence of starting material After the completion of the reaction, the reaction mixture was cooled to room temperature filtered and dried to obtain 98g of the title compound
1HNMR (DMSO-d6) (δ ppm, 300 MHz) 8 37 (1H, bs) 7 58 (1H dd) 7 55 (IH. s), 7 51 (2H, d) 7 29 (1H d), 7 08 (2H d), 4 4 (2H t) 3 17 (2H, t) 2 58 (2H. q), 1 18(3H t)
Example 9 Preparation of 5-{4-[2-(5-ethvl-pyridin-2-yl)-ethoxyl-benzyl}-2-imino-thiazolidin-4-one
Method A-
5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzylidene}-2-immo-thiazolidin-4-one (20g) was added to a solution of cobaltous chloride hexahydrate (0 04g) and dimethylglyoxime (0 04g) in a mixture of methanol, water and tctrahvdrofuran (36ml, 4 11) The resulting suspension was stirred for 10 minutes followed by addition of sodium borohydnde (0 56g) at 15-20°C The reaction mixture was further stirred at 15-20°C for 10 hours Progress of the reaction was monitored with TLC and HPLC After completion of the reaction, the reaction mixture was cooled to 0°C I hen reaction mixture was quenched by the addition of ammonium chloride solution and stirred for 30 minutes at 0°C The resulting product was filtered and dried to give 1 8 g of the title compound
1HNMR (DMSO-d6) (δ ppm, 300 MHz) 8 38 (1H, bs) 7 57 (1H, dd), 7 28 (1H, d), 7 12 (2H, d), 6 81 (2H. d), 4 36 (111, dd), 4 31 (2H t), 3 42 (111, dd), 3 23 (2H, t), 2 9 (1H, dd), 2 66 (2H q), 1 23 (311, t)
Method B
5-{4-[2-(5-Ethyl-pyndin-2-yl)-ethoxy]-benzylidene}-2-imino-thiazolidin-4-one (5g) and benzyl triethyl ammonium chloride (0 32g) were added to a solution of
cobaltous chloride hexahydrate (0 lg) and dimethylglyoxime (0 lg) in a mixture of methanol, water and tetrahydrofuran (172ml, 4 5 115) I he resulting suspension was stirred for 10 minutes followed by addition of sodium borohydride (1 4g) at a temperature of 15-20°C The reaction mixture was further stirred at 15-20°C for 10 hours Thereafter, the reaction mixture was quenched b\ addition of ammonium chloride and stirred for 30 minutes I he resulting product was filtered and dried to give 4 2 g of the title compound
Example 10 Preparation of Ar-(5-{4-f2-(5-ethvl-pyridin-2-vl)-cthox\|-benzvlidene}-4-oxo-4,5-dihvdro-thia7ol-2-vl)acetamide
4-[2-(5-Lthyl-pyndin-2-yl)-ethoxy]-benzaldehyde (88 8g ) and ammonium acetate (2 7g) were added to a stirred suspension of N-(4-oxo-4 5-dihydro-thia/ol-2->l)-acetamide (55g ) in ethanol (500 ml) Ihe reaction mixture was refluxed for 5 hours Progress of the reaction was monitored by FLC After the completion of the reaction, the reaction mixture was cooled to room temperature filtered and dried to obtain 125g of title compound
1HNMR (DMSO-d6) (δ ppm, 300 MHz) 8 33 (III bs), 7 55 (411 m) 7 25 (1H, d), 7 08 (2H, d), 4 38 (2H t), 3 13 (2H t) 2 53 (2H q), 2 03 (311 s) 1 13 (3H, t)
Example 11 Preparation of 5-{4-[2-(5-ethvl-pvridin-2-vl)-ethoxyl-benzyl}-2-imino-thiazolidin-4-one
Method A
N-(5-{4-f2-(5-Ethyl-pyndin-2-yl)-ethoxy]-benzylidenc}-4-oxo-4,5-dih\dro-thiazol-2-yl)acetamide (2 0g) was added to a solution of cobaltous chloride hexahydrate (0 4g) and dimethylglyoxime (0 4g) in a mixture of methanol, water and tetrahydrofuran (35ml, 4 11) Ihe resulting suspension was stirred for 10 minutes followed by the addition of sodium borohydride (0 5g) to the reaction mass at a temperature of 15-20°C The reaction mixture was further stirred at 15-20°C for 10 hours cooled to 0°C Thereafter, the reaction was quenched by the addition of ammonium chloride solution (10 ml) and then stirred for 30 minutes at
0°C The resulting product was filtered and dried to obtain 1 7 g of the title compound
Method B
N-(5-{4-[2-(5-Lthyl-pyndin-2-yl)-ethoxy]-benzyhdene}-4-oxo-4 5-dihydro-thiazol-2-yl)-acetamide (5g) and ben/yltriethylammonium chloride (0 32g) were added to a solution of cobaltous chloride hexahydrate (0 1g) and dimethylglyoxime (0 1g) in a mixture of methanol, water and tctrahydrofuran (172ml, 4 5 1 15) The resulting suspension was stirred for 10 minutes followed by the addition of sodium borohydnde (1 39 g) at a temperature oi 15-20"C I he reaction mixture was further stirred at 15-20°C for 10 hours 1 hereafter the reaction mixture was quenched by the addition of ammonium chloride and stirred for 30 minutes The resulting product was filtered and dried to obtain 3 6 g of the title compound
Example 12: Preparation of pioglitazone hydrochloride
Method A
5-{4-[2-(5-Lthyl-pyridin-2-yl)-ethoxy]-ben/ylj-2-imino-thia/ohdin-4-onc (2g ) was taken in 2N hydrochloric acid (22 ml) and refluxed for 15 hours I he icaction mixture was cooled to 25°C Charcoal powder (0 lg) was added to icaction mixture and refluxed for 20 minutes The reaction mixture was filtered hot to remove charcoal The filtrate was concentrated to remove water and excess of hydrochloric acid and kept at 25°C for 10 hours Chilled water was added to the resulting solid, filtered, washed with water followed by n-heptane and dried to obtain 0 7g of the title compound
Method B
A solution of oxalic acid dihydrate (0 355g ) in methanol (5ml) were added to stirred solution of 5-{4-[2-(5-ethyl-pyndin-2-yl)-ethoxy|-ben/yl}-2-imino-thiazohdin-4-one (1 g) in mixture of methanol and dichloromethane (10ml, 1 1) The reaction mixture was stirred at room temperature for 30 minutes and filtered followed by distillation To the resulting residue, 2N hydrochloric acid (10ml) was added and refluxed for 12 hours The reaction mixture was cooled to 25°C
filtered and washed with chilled water and n-heptane and dried to obtain 0 75 g of the title compound
Example 13 Preparation of N-(5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy]-benzvlidene}-4-oxo-4,5-dihvdro-thiazol-2-yl)-methanesulfonamide
N-(4-Oxo-4,5-dihydro-thiazol-2-yl)-methanesulfonamide (18 4g) was added to a solution of sodium hydroxide (8 23g) in methanol (250 ml) at 40°C followed by the addition of 4-[2-(5-ethyl-pyndin-2-yl)-cthoxy]-ben/aldehyde (25g) and mixture was rcfluxed for 4 hours A part of methanol was distilled off under reduced pressure, cooled to 0-5°C I he resulting residue was slurried in a solution of water (100 ml) and 2N hydrochloric acid (50 ml) The resulting slurry was filtered washed with water and dried to obtain 40 23g of the title compound
IR(KBr, cm-1) 3516, 1718, 1594, 1510, 1252 1179, 1133, 1027 965 847 692,
548
lHNMR(CDCl3-DMSO-d6)(δppm 300 MHz) 8 37(1H bs), 7 68(111 s). 7 53 (3H, m), 7 26(1H d), 7 05 (2H d) 4 43 (2H t) 3 22 (2H t) 3 10(311 s) 2 63 (2H, q), 1 23 (3H, t)
Example 14 Preparation of N-(5-{4-f2-(5-ethyl-pvridin-2-vl)-etho\y|-benzyl}-4-oxo-4,5-dihvdro-thiazol-2-yl)- methanesulfonamide N-(5-{4-[2-(5-Cthyl-pyndin-2-yl)-ethoxy]-benzylidene}-4-0X0-4,5-dihydro-thiazol-2-yl)-methanesulfonamide (25g) was added to a solution of cobaltous chloride hexahydrate (0 41 g) and dimethylglyoxime (0 4g) in a mixture of methanol water and tetrahydrofuran (450ml 4 11) The resulting suspension was cooled to 0-5°C followed by the addition of sodium borohydride (5 7g) at a temperature of 0-5°C The reaction mixture was further stirred at 0-5°C for about 7 hours Thereafter, the reaction mixture was quenched by addition of formic acid and stirred for 2 hours The organic solvents were distilled off under vacuum Water (150 ml) was added to the resulting reaction product and extracted with dichloromethane, distilled completely to obtain 16g of the title compound IR(KBr cm-1) 3429 1738, 1580, 1511, 1324 1300 1261 1133, 1024 968 802 538
1HNMR (CDCl3) (δ ppm, 300 MHz) 8 44 (111 bs) 7 51 (1 H dd) 7 23 (111, d) 7 12 (2H, d), 6 82(211 d), 4 33(1H dd), 4 27 (2H, t), 3 38 (1H dd) 3 27(211 t) 3 08 (1H, dd), 2 97 (3H, s), 2 64 (2H, q), 1 24 (3H t)
Example 15 Preparation of Pioglitazone hydrochloride
A'-(5-{4-[2-(5-[thyl-pyridin-2-yl)-ethoxyl-ben7yl}-4-oxo-4 5-dihydro-thia/ol-2-yl)-methanesulfonamide (8g) was refluxed in concentrated hydrochloric acid (56ml) for 3 hours The resulting solid was filtered and dried to obtain 4 5g of title compound
Example 16' Preparation of N-(5-{4-[2-(5-Ethyl-pyridin-2-yl)-ethoxy]-benzvlidene}-4-oxo-4,5-dihydro-thiazol-2-vl)-4-methvl-benzenesulfonamide
4-Methyl-Ar-(4-oxo-4,5-dihydro-thia7ol-2-yl)-ben7enesulfonamide (380g) was added to a solution of sodium hydroxide (123 7g) in methanol (4 18 It) at 40°C followed by the addition of 4-[2-(5-ethyl-pyndin-2-yl)-ethoxy]-benzaldehyde (352g) and reaction mixture was refluxed for 7 hours A part of methanol was distilled off under reduced pressure, and the resulting slurry was cooled to 0-5"C and filtered 'I he crude compound was dried and slurried in a solution oi water (2 It) and IN hydrochloric acid The resulting slurry was filtered washed with water and dried to obtain 654g of the title compound
Example 17 Preparation of N-(5-{4-[2-(5-ethyl-pvridin-2-yl)-ethoxy]-benzyl}-4-oxo-4,5-dihvdro-thiazol-2-yl)-4-methyl-benzenesulfonamide
N(5-{4-[2-(5-Fhyl-pyridin-2-yl)-ethoxy]-benzyhdene}-4-oxo-4,5-dih}dro-thiazol-2-yl)-4-methyl-benzenesulfonamide (500g) was added to a solution ol cobaltous chloride hcxahydrate (7g) and dimethylglyoxime (6 9g) in a mixture of methanol, water and tetrahydrofuran (91t, 4 11) Ihe resulting suspension was cooled to 0-5°C followed by addition of sodium borohydride (97g) at a temperature of 0-5°C The reaction mixture was further stirred at 0-5°C for about 9 hours Thereafter the reaction was quenched by the addition of formic acid and stirred for 2 hours The organic solvents were distilled off under vacuum followed by the addition of water (2 5 It) Above solution was filtered and dried to obtain 480g of the title compound
Example 18 Preparation of Pioglita/onc hydrochloride
N-(5-{4-[2-(5-Ethyl-pyndin-2-yl)-ethoxyJ-benzyl}-4-oxo-4,5-dihydro-thia/ol-2-yl)-4-methyl-benzenesulfonamide (450g) was refluxcd in concentrated hydrochloric acid (3 15 It) for 8 hours I he reaction mixture was filtered and the resulting residue was dried to obtain crude product The crude product was taken in methanol (1 25 It) followed by distillation Ethyl acetate hydrochloride (250 ml 1%) was added to above product at 25-30°C stirred for 2 hours, filtered and dried to obtain 248 g of pioglitazone hydrochloride having purity 97 21% by 11PLC
Pioglitazone hydrochloride (248g), obtained above was taken in acetone (927ml) and treated with methanolic hydrochloride (308ml, 10%) at 45-50°C and lurther stirred for 2 hours fhc reaction mixture was cooled to 25-30°C filtered and dried to obtain 204 g of pure title compound having purity 99 71% b> 11 PI C

WE CLAIM
1. A process for the preparation of thiazolidine derivative, namely pioglitazonc of formula (SEQ ID NO Removed)
(Formula Removed)
or pharmaceutical acceptable salt thereof which comprises: (a) reacting 4-[2-(5-ethyl-pyridin-2-yl)ethoxy]benzaldehyde of formula II.
(Formula Removed)
with a thiazolone compound of formula IIIa, Formula IIIa
(Formula Removed)
wherein R1 and R2 are same or different and R1 and R2 can he hydrogen, or
R1 can be hydrogen and R2 can be C1-6 alkyl group wherein alkyl can be linear, branched or cycloalkyl or alkenyl or alkynyl or aryl or alkaryl ,or heterocyclic with one or two helero atoms selected from nitrogen, oxygen or sulfur, or
R1 and R2 can be C1-6 alkyl group wherein alkyl can be linear, branched or cycloalkyl or alkenyl or alkynyl or aryl or alkaryl, or heterocyclic with one or two hetero atoms selected from nitrogen, oxygen or sulfur, or
R1 and R2 are C1-6 alkyl groups joined to each other at the terminal carbons forming five or six memhered ring containing one or two hetero atoms selected from nitrogen, oxygen or sulfur such as piperidino, morpholino, piperizino, pyrrolidino, 4-alkyl piperizino, thiomorpholino, azetidino, aziridino, or
R1 can be hydrogen or C1-6 alkyl and R2 can be sulfonylalkyl or sulfonylalkylaryl, or sulfonylaryl wherein aryl can be optionally substituted with alkyl or halo; alkanoyl or aranoyl or heteroaranoyl groups, C1-6 alkoxy group or dialkylamino or piperidino, morpholino, piperizino, pyrrolidino, 4-alkyl piperizino, thiomorpholino, azetidino, aziridino and the like
or salt thereof in the presence of base in suitable solvent to form a benzylidcnc derivative of formula IVa,

(Formula Removed)
wherein R and R~ are as defined above,
(b) reducing the resulting benzylidene derivative of formula IVa to form a benzyl derivative of formula VIa.
(Formula Removed)
wherein R1 and R2- are as defined above,
(c) hydrolysing the benzyl derivative of formula VIa to form pioglitazonc or pharmaceutically acceptable salt thereof.
(d) isolating pioglitazonc pharmaceutically acceptable salt thereof.
2. The process according to claim 1 step a), wherein base is selected from ammonia, ammonium acetate, methylamine, ethylamine. butylamine. pyrrolidine, piperidine, morpholine, piperazine, diethylamine, diisopropylaminc, triethylamine, or its salt with aliphatic carboxylic acid and preferably acetic acid; alkali metal alkoxides; alkali metal carbonate; alkali
metal hydroxide; alkali metal bicarbonate; alkali metal hydride; alkali metal acetate.
3. The process according to claim 1 step a), wherein solvent is selected from C1-6 alcohols, C5-8 aliphatic or aromatic hydrocarbons, C3-6 esters, C2-5 ethers, C3-6 ketones, C1-3 aliphatic halogenated hydrocarbons, acetonitrile. N,N-dimethylformamide, tetrahydrofuran, dioxane.
4. The process according to claim 1 step a), wherein benzylidcne derivative of formula IVa may have variable percentage of deprotected imine compound. 5-{4-[2-(5-ethyl-pyridin-2-yl)-ethoxy)-benzylidcne}-2-imino-thiazolidin-4-onc of formula V,
(Formula Removed)
5. The process according to claim 1 step b). wherein benzylidene derivative of formula IVa is reduced with a complex hydride reducing agent or a source of complex hydride reducing agent selected from borane compounds and metal hydrides, in the presence of suitable metal ion, ligand, optionally a coligand. base or a salt.
6. The process according to claim 1 step b), wherein reduction is performed using reducing agent selected from diborane, borane-tetrahydrofuran, boranc-dimethylsulfide, borane-amine, borane-lewis acid, borane-triphenylphosphinc lithium aluminium hydride, sodium borohydride, lithium borohydride, potassium borohydride, tetraalkylammonium borohydride. zinc borohydride. and the like.
7. The process according to claim 1 step b), wherein reduction is performed in the presence of suitable metal ion like cobalt(II) including cobalt chloride, cobalt diacetate, cobalt sulfate and the like; and/or ligand selected from dimethylglyoxime, 2,2'-bipyridyl, 1,10-phenanthrolinc.
8. The process according to claim 1 step b). wherein reduction is optionally performed in the presence of base or salt selected from sodium hydroxide, potassium hydroxide, sodium carbonate, lithium carbonate, potassium carbonate, potassium bicarbonate, ammonium carbonate, ammonium bicarbonate, potassium bromide, potassium iodide, lithium iodide, lithium bromide, sodium halides and the like; optionally in mixture with a phase transfer catalyst such as benzyltriethylammonium chloride, cetyltrimcthyl ammonium bromide, tetrabutylammonium bromide; a coligand selected from ethanolamincs such as triethanolamine, diethanolamine, ethanolaminc. cinchonine. cinchonidine, quinine, quinidine.
9. The process according to claim 1 step c). wherein hydrolysis is performed in the presence of mineral acid like sulfuric acid, hydrochloric acid.
10. The process according to claim 1, wherein pioglitazone is isolated as hydrochloride.
11. The process according to claim 1, wherein preferably R1 is hydrogen and R2 is selected from amongst C1-6 alkyl group, morpholino, alkanoyl. aranoyl, sulfonylalkyl and sulfonylalkylaryl.
12. The process according to claim 1. further comprising purifying pioglitazone hydrochloride in suitable solvent such as acctonitrile. acetone, methanol, ethanol, isopropanol, n-propanol, methyl isobutyl ketone, ethyl methyl ketone, toluene, C1-6 ester, C2-5 nitriles, the like and/or mixtures thereof.
13. The process according to claim 1, further comprising purifying pioglitazone hydrochloride by treating with hydrochloride such as ethyl acetate hydrochloride, alcoholic hydrochloride and the like in the presence of suitable organic solvents like acctonitrile, acetone, methanol, ethanol, isopropanol. n-propanol, methyl isobutyl ketone, ethyl methyl ketone, toluene, C1-6 ester, C2-5 nitriles, the like and/or mixtures thereof.
14. A bcnzylidene derivative of formula IVa. including isomers, tautomcrs. salts, solvates or mixtures thereof.

1D2
(Formula Removed)
wherein R1 and R2 are as defined above.
15. A benzyl derivative of formula VIa, including isomers, tautomcrs, salts, solvates or mixtures thereof,

(Formula Removed)
wherein R1 and R2 are as defined above, provided together R1 and R2 are not hydrogen.