WO2006035459A1

WO2006035459A1 - An improved process for the production of derivatives of thiozolidinediones and their precursors

Info

Publication number: WO2006035459A1
Application number: PCT/IN2005/000323
Authority: WO
Inventors: Sanjay Suri; Gurdeep Singh Sarin
Original assignee: Morepen Laboratories Limited
Priority date: 2004-09-28
Filing date: 2005-09-26
Publication date: 2006-04-06

Abstract

The invention provides a process for preparing derivatives of thiozolidinediones and their precursors comprising, (a) reacting a compound of general formula I wherein R1, R2 and R3 may be same or different and represent H, alkyl or alkoxy with C varying from 1 to 6, halogens, mono or di-substituted alkyl and aryl amines, and M represents hydrogen (H) or alkali metal selected from Na, K or Li with a compound of formula II, wherein R4 has the same meaning as R1 or R2 or R3 and X is halogen in presence or absence of solvent(s) under effective conditions to produce nitro ethers of general formula III, where in R1 to R4 has the same meaning as given above, provided when M is H and not its alkali metal salt, an alkali metal salt such as hydroxide or carbonate is required to be added while conducting the said reaction, (b) subjecting the said nitro ethers, with or without isolation, to Raney nickel-catalyzed reduction under conditions effective to produce corresponding nitro aniline ethers (c) coupling the said aniline ether with acrylates under Meerwein arylation conditions in presence of hydrobromic acid to produce α bromo substituted carboxylic acid derivatives followed by subjecting to solvent extractive purification (d) cyclising the purified derivative of α bromo substituted carboxylic acid as obtained in step (c) with thiourea to yield 2-imino -4-thiazolidinones then (e) hydrolyzing the said 2-imino-4-thiazolidinones to produce 2, 4-thiazolidinones and converting the same to its hydrochloride salts as white crystalline solids known to exhibit antidiabetic activity, by conventional methods.

Description

AN IMPROVED PROCESS FOR THE PRODUCTION OF DERIVATIVES OF THIOZOLIDINEDIONES AND THEIR PRECURSORS

The invention relates to An Improved Process For The Production Of Derivatives of Thiozolidinediones And Their Precursors. FIELD OF INVENTION:

This invention particularly, relates to an improved process for the production of 2,4- thiozolidinediones and pharmaceutically acceptable salts thereof. More particularly, the invention provides a process for the production of pioglitazone, its hydrochloride salt and its precursors exemplified by aromatic nitro ether derivatives, it's corresponding aniline ethers, α halo (preferably bromo) derivatives of the said corresponding aniline ethers and corresponding 2-imino-4-thiazolidinines having anti- diabetic activity. Further, the invention provides a process that employs, commercially available, substituted pyridine alcohols or their alkali metal salts and substituted 1-halo (preferably fluoro)-4-nitro benzenes as the basic raw materials. Still more particularly, the invention provides a process that is technically and commercially feasible. Even more particularly, the invention provides a process with minimal risk factors during production. Additionally the process does not require any stringent operational conditions and special infrastructure. Yet more particularly, the process of the present invention is easy to operate, safe, simple, cost effective, environment friendly, high yielding. Further, the title product obtained by the process of the present invention is more pure compared to the one obtained by existing processes and meets ICH guidelines in respect of residual solvent. BACKGROUND OF THE INVENTION:

The invention described herein relates to an improved process for producing substituted 2, 4-thiazolidinediones and their hydrochloride salts as well as their intermediates possessing hypoglycemic and hypolipidemic activities which are useful for the treatment of diabetes. Blood sugar lowering activities of Pioglitazone hydrochloride are well documented. Carbamoyl derivatives of substituted l-fluoro-4- nitro benzenes are known to exhibit herbicidal and fungicidal activities (JP 59110673). Methods for generating such pharmacologically useful thiazolidinediones and their precursors are described in Japanese Kokai Tokkyo Koho Sho, Unexamined Patent Publication Nos.55-22636 and 55-64586 and Chemical & Pharmaceutical Bulletin, 30, 3563 (1982), 30, 3580 (1982), and 32, 2267 (1984). These compounds, however, have not yet been put to practical use. As the reasons, (1) insufficient activities or and (2) serious toxicities may be mentioned. These methods invariably comprise the steps of diazotizing an aniline derivative, condensing it with an acrylic ester in the presence of copper catalyst by the so-called Meerwein Arylation reaction to give haloester, which is then reacted with thiourea followed by hydrolysis to afford corresponding 2, 4- thiazolidinediones. These methods include multi-step reaction process. The relevant literature including patents known to the inventor includes US Patent Nos. (a) 4,687,777 ('777), (b) 4,582,839 ('839) both granted to K. Meguro et al, (Chem. Pharm.Bull. 32, 2267-2278 1984; Chem. Pharm.Bull. 30, 3580-3600, 1982; Chem. Pharm.Bull. 39, 1440-1445, 1991; Arzneimettel-forsch, 43, 859-872, 1993). These documents, in general describe a process (refer to schematic representation- A process A below), for preparing substituted 2, 4-thiazolidinediones and it's salts where in the ethyl substituted pyridyl ethanol of formula (I) is reacted with l-fluoro-4- nitrobenzenes (II) in the presence of sodium hydride in dimethylformamide and tetrahydrofuran under controlled conditions (low temperature, anhydrous conditions) to form the 4-nitrophenol ethers of formula III, which after Pd/C catalyzed reduction of the nitro group with hydrogen gas, yield the aniline ether derivatives of formula IV, which in turn, upon diazotization in presence of hydrogen halide preferably hydrobromic acid is subjected to Meerwein arylation reaction that involves reaction with acrylic acid or esters (V) in the presence copper catalyst exemplified by cuprous/cupric oxide, chloride, bromide lead to the α-bromo substituted carboxylic acid derivatives of formula VI. The unstable VI upon reaction with thiourea (VII) undergo facile cyclization to form the 2-imino-4-thiazolidinones (VIII), which after hydrolysis with dilute acid followed by neutralization with base provide the 2, 4- thiazolidinediones (IX). The thiazolidinediones I upon treatment with hydrochloric acid form the corresponding hydrochloride salts (X).

In accordance with '777, during the reaction with thiourea, hydrogen bromide is produced as a by-product, and, for capturing this by-product, the reaction may be conducted in the presence of sodium or potassium acetate.

The above general methodology for synthesizing 2, 4-thiazolidinediones IX has many operational disadvantages and inefficiencies, which circumvent its successful implementation on commercial scale. First of all, the use of highly moisture sensitive and explosive sodium hydride in the synthesis of nitro ethers (III) is an aspect, which is very difficult to handle particularly on commercial scale. Moreover, the reaction has to be performed under controlled and anhydrous conditions at low temperature (-10 to +5⁰C) since at higher temperature (10-20⁰C) formation of impurities occurs and at room temperature (25-35⁰C) complete decomposition of the product (nitro ether III) takes place. Also aqueous workup of the reaction mixture is very difficult as well as dangerous and lot of care has to be taken to avoid initiation of fires.

Secondly, Pd/C catalyzed reduction of the nitro group with hydrogen gas requires high pressure and is associated with the problems arising of handling pyrophoric Pd/C and hydrogen gas. This makes the process industrially unsafe if not commercially unfeasible. SCHEMATIC REPRESENTATION -A

Thirdly, Meerwein's arylation of the aniline ethers (IV) in the presence of alkyl acrylates leads to the formation of relatively unstable α-bromo carboxylic acid derivates (VI) containing lot of polymeric and tarry material and have to be purified by column chromatography on silica gel before being cyclized with thiourea to yield the 2- imino-4- thiazolidinones (VIII). Use of impure and tarry carboxylic derivatives (VI) leads to darkish gray or brown 2-imino-4- thiazolidinones (VIII), which contains additional impurities and are not easy to purify. After hydrolysis with dilute acids and subsequent neutralization with base, the said compound of formula VIII containing impurities lead to impure 2,4- thiazolidinones (IX), which have to be repeatedly purified to remove the impurities and coloured materials present in them. So, many operational problems associated with the process make it an unprofitable and unfeasible propo- sition for commercial scale production of 2, 4-thiazolidinediones (IX) and their salts (X).

An alternative, has been disclosed in the following patents for preparing 2, 4- thiazolidinediones :

US- 4,812,570; US- 4,895,947; US- 5,554,758; US- 5,952,509; US- 6,100,403; US- 36,575 and EP-0257781. According to these patents more simple and commercially viable method (please see process~B given below), which eliminates some of the difficulties, associated with the first process has been developed and disclosed therein. The process involves the formation of benzaldehyde ether derivatives of formula (XIII), via the base assisted Williamson coupling of 4-hydroxybenzaldehydes with a mesylate or tosylate derivatives (XI) of alcohol (1), wherein 4-hydroxybenzaldehydes may be substituted/unsubstituted with lower alkyl as substituent. Compound of formula XI is obtained from reaction between pyridine alcohols and halogenating agent or sulfonyl halide. The compound of formula XIII then undergoes facile base assisted Knoevengel condensation with 2, 4-thiazolidinedione (XIV) to afford the benzylidine-2, 4-thiazolidinediones (XV). Purification followed by reduction of the double bond of compound (XV) results in the formation of crude compound of formula IX, which after purification and treatment with dilute hydrochloric acid yield the corresponding hydrochloride salts (X). In accordance with column 4, line 26, of '575, the base assisted Williamson coupling is effected in presence of phase transfer catalyst. For the reduction of double bond of XV, several transition metal catalyzed hydrogenation conditions are reported in literature. References mentioned herein above paragraph (for alternate route) describe several low yielding extremely inconvenient and commercially unviable experimental conditions for the reduction double bond of XV with hydrogen gas in the presence of Pd/C in a variety of organic solvents. In order to obtain reasonably pure samples of the formula IX, in most of the reported conditions, the reduction has been performed with 100-300% w/w excess of Pd/C, under very high pressure ranging between 50-100 kg cm^"2 and the temperature varying between room temperature to 100⁰C. Yields ranging between 54-76% for such a well established reaction clearly indicate the complex nature of the 2, 4- thiazolidinedione functionality of the systems under the experimental condition employed.

EP0618915 teaches an alternate route involving cobalt-catalyzed reduction of the double bond of the compound of formula XV. In accordance with the disclosure in page 5 lines 8-10, the new reduction method described in the said EP patent is faster, easier, results in improved yield and convenient to scale up to production equipment.

The cobalt-catalyzed reduction of double bond is carried out using sodium borohydride in the presence of ligand, polar solvent such as water or tetrahydrfuran (THF) and dilute solution of sodium hydroxide. The method claims to eliminate the operational and safety problems associated with handling of pyrophoric Pd/C as catalyst and high pressure hydrogenation using hydrogen gas externally. However, it is not always reproducible during scale up as a number of impurities can be generated via cleavage of the 2, 4-thiazolidinedione ring by sodium hydroxide. Thus, the resulting crude product of formula IX obtained through cobalt-catalyzed reduction also requires repeated purification so as to obtain the product of acceptable purity to be used as a drug. The method also suffers from the disadvantage of the possibility of higher heavy metal content in the final product since cobalt salts are used in the penultimate stage of the sequence. In accordance with the disclosure in page 6, the starting material i.e. compound of formula XV is prepared as described in Y. Momose et al., Chem. Pharm. Bull, 39:1440 (1991); Japan Patent 139182 (1988);and Chem. Abstr., 109:6504(1988). In addition to the operational problems related to the chemistry involving the preparation of 2, 4-thiazolidinediones IX, the extent of impurity profiling varies considerably and depends on the route being followed for their generation. Consequently, to eliminate such inherent impurities, different solvents systems and conditions have been developed for purifying the samples of IX and their salts that have been prepared by following different routes. The disadvantages associated with the process described in Chem. Pharm. Bull., 39:1440 (1991) are well pointed out in column 1, lines 55 to 60 of US Patent 6,100,404. According to the said Patent, since the reaction is conducted in the two-layer system of methylene chloride and water, use of benzyl tributyl ammonium chloride is required as phase transfer catalyst. In their opinion, since the solvent employed is not homogeneous, control of stirring conditions is difficult, and the method can hardly be considered industrially advantageous one. This endorses the need for alternate more convenient procedure for producing derivatives of thiozolidinediones and their precursors. SUMMARY OF THE INVENTION: One of the objects of the present invention is to provide a process for the production of 2,4- thiozolidinediones and pharmaceutically acceptable salts thereof obviating most of the problems associated with hither to known processes.

Other object of the present invention is to provide a process for the production of pioglitazone its pharmaceutically acceptable salts preferably hydrochloride salt and its precursors exemplified by aromatic nitro ether derivatives, it's corresponding aniline ethers, α halo (preferably bromo) derivatives of the said corresponding aniline ethers and corresponding 2-imino-4-thiazolidinines having anti-diabetic activity.

Another object of the present invention is to provide a process that employs, commercially available or easily prepared, substituted pyridine alcohols or their alkali metal salts and substituted 1-halo (preferably fluoro)-4-nitro benzenes as the basic raw materials.

Still other object of the present invention is to provide a process that is technically and commercially feasible.

Still another object of the present invention is to provide a process with minimal risk factors during production. Specifically, the process does not require any stringent operational conditions and special infrastructure.

Yet other object of the present invention is to provide a process that is easy to operate, safe, simple, cost effective, environment friendly, high yielding.

Yet another object of the present invention is to provide a process resulting in to a product that is more pure compared to the one obtained by existing processes and meets ICH guidelines in respect of residual solvent.

Further object of the present invention is to provide a process, which replaces employing highly moisture sensitive and explosive sodium hydride and expensive, pyrophoric palladium on Carbon (Pd/C). The process also eliminates use of Pd/C under external pressure of hydrogen. The novelty of the invention resides in (i) eliminating employing sodium hydride, palladium on carbon, high pressure hydrogenation using hydrogen gas externally;(ii) using commercially and readily available starting materials; (iii) providing simple economic alternate purification process for carboxylic acid derivative(s); (iv) minimizing solvent requirement and producing the title compound and it's pharmaceutically acceptable salts with increased purity and yield specifically with reference to the amount of residual solvents in the final product. STATEMENT OF THE INVENTION:

Accordingly the present invention provides an improved process for the production of derivatives of thiozolidinediones and their precursors which comprises,

(a) reacting a compound of general formula I wherein Ri, R₂ and R₃ may be same or

different and represent H, alkyl or alkoxy with C varying from 1 to 6, halogens, mono or di-substituted alkyl and aryl amines, and M represents hydrogen (H) or alkali metal

selected from Na, K or Li with a compound of formula 2, wherein R₄ has the same

meaning as Ri or R₂ or R₃ and X is halogen in presence or absence of solvent(s) and

or phase transfer catalyst under effective conditions to produce nitro ethers of general

formula III, where in Ri to R₄ has the same meaning as given above, provided when M

is H and not its alkali metal salt, an alkali metal salt such as hydroxide or carbonate is required to be added while conducting the said reaction,

M = H, Na, K, Li (b) subjecting the said nitro ethers, with or without isolation, to Raney nickel- catalyzed reduction under conditions effective to produce corresponding nitro aniline ethers of general formula IV

(c) coupling the said aniline ether of formula IV with acrylates under Meerwein arylation conditions in presence of halo acids preferably hydrobromic acid to produce α halo substituted carboxylic acid derivatives, particularly α bromo substituted carboxylic acid derivatives of formula V wherein R5 is H or alkyl with C ranging from 1 to 3 followed by subjecting to solvent extractive purification to get a purified derivative of pale yellow colour viscous oil,

(d) cyclising the said purified derivative of α halo substituted carboxylic acid as obtained in step (c) with thiourea to yield 2-imino -4-thiazolidinones VI,

(e) hydrolyzing the said 2-imino -4-thiazolidinones VI, to produce 2, 4-thiazolidinones of formula VII, followed by converting the same to its pharmaceutically acceptable salts specifically hydrochloride salts of formula VIII as white crystalline solids, which are known to exhibit anti-diabetic activity by any conventional methods.

VII

In the above mentioned general formula I, alkyl groups with 1-6 carbon atoms may be such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl or n-hexyl, preferably those having 1 to 4 carbon atoms; alicyclic groups may include without restriction cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; alkoxy groups having 1 to 4 carbon atoms may be such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, or t-butoxy, preferably those having 1-3 carbon atoms. The halogen atoms in formula II may be such as fluorine, chlorine, bromine, iodine preferably fluorine.

The alkali metal salt when used may be hydroxide, carbonate, preferably hydroxide. The alkali metal hydroxides could be sodium, potassium or lithium hydroxides and may be used singly or as mixtures in any suitable composition. The amount of alkali metal hydroxide employed may vary between 1-8 molar equivalents, preferably between 2-6 molar equivalents and most suitably 3-4 molar equivalents.

The amount of alkali metal carbonates employed may preferably be potassium carbonate and the amount added may vary between 1 to 25 molar equivalents, preferably 2 to 15 molar equivalents, more preferably 5 to 10 molar equivalents. The reaction temperature may vary between 5-100⁰C, preferably between 5-7O⁰C and most suitably between 20-40⁰C. The quantity of water used may be between 3-30 times v/w w.r.t the alcohol (I), preferably between 3-10 times v/w and most appropriately between 3-5 times v/w.

The reaction in step (a) works equally well in the of presence all common and easily available Phase transfer catalysts (PTC) selected from quaternary ammonium compounds like tetrabutyl ammonium chloride, tetra butyl ammonium hydrogen sulfate etc, which may be used singly or as mixtures in any suitable composition. The quantity of PTC when used may vary between 0.5% to 100% w/w and above with reference to pyridine alcohols (I).

Also, the reaction may be performed with equal efficiency in a mixture of water and most water miscible organic solvents like dimethyl sulfoxide, acetonitirile, 1,4- dioxane, acetone, diethyl ketone, methyl isobutyl ketone, dimethylacetamide, tetrahydrofuran, 1, 2-dimethoxy ethane and diglyme etc and aliphatic alcohols where C≥ 3 and ≤ 8 without making any changes in the reaction or work up conditions. In the most appropriate experimental condition, 3-4 molar equivalents of sodium or potassium hydroxide dissolve in water (3 times) is slowly added to a stirred solution of the pyridine alcohol I, substituted l-fluoro-4-nitrobenzenes II in water at 20-25⁰C and the mixture is heated at 30-40⁰C with stirring and monitored by TLC. The reaction may be equally effective in the presence of water immiscible organic solvents in the presence or absence of PTC.

The nitro ethers III can also be prepared under anhydrous conditions by reacting the compound of formula II with the anhydrous powder of the alkali metal salts such as sodium or potassium salts.

The reduction of nitro ethers may be carried out by in the absence of external source of hydrogen gas pressure. The nitro ethers (III) may be reduced in the presence of Raney nickel and hydrazine. The reduction may be performed, preferably, in polar water

miscible organic solvents like alcohol with C₃ to Cs exemplified by methanol, ethanol

n-propanol, iso-propanol, n-butanol, iso-butanol; tetrahydrofuran, 1,4-dioxane, 1,2- dimethoxye thane, 1,2-diethoxy ethane, dimethylsulf oxide, dimethylformamide, dimethylacetamide preferably dimethylformamide, dimethylacetamide either in isolation or as a mixture in any suitable composition and the reaction may be preformed in the presence or a absence of water. The quantity of Raney Nickel used may vary between 25 to 100% w/w and that of hydrazine hydrate between 2-6 or more molar equivalents preferably between 2-4 molar equivalents at a temperature between 5-7O⁰C. The reaction may be performed in an efficient hood with an easy out let for the smooth release of the in situ generated hydrogen gas. In the preferred reactions conditions, hydrazine hydrate is slowly added to a stirred suspension of nitro ethers and Raney Nickel in alcoholic solvents like methanol, ethanol, n-propanol, iso- propanol etc. at 30-55⁰C under TLC monitoring.

The nitroethers III may also be reduced by subjecting them to hydrogen gas pressure in the presence of Raney Nickel in polar solvent mixture over a period of time. The reaction time may vary between 6-24 hrs. The reaction temperature may vary between -15 to 9O⁰C and the pressure of the applied hydrogen gas could be between 2-6 kg per cm^"2. The reactions can be can be performed in all polar water miscible and organic solvents like methanol, ethanol, n-propanol, iso-propanol, butanol, iso-butanol dimethylformamide, dimethylacetamide, ethers like 1,4-dioxane, 1,2-dimethyl ether, tetrahydrofuran in isolation or mixtures thereof. The reaction may also be performed in a suitable mixture of water immiscible solvents like diethyl ether, diisopropyl ether, diphenyl ether, dibutyl ether, tertiary butyl methyl ether, aromatic hydrocarbon solvents like, benzene, toluene, ortho and para xylenes and halogenated solvents like methylene dichloride, chloroform and dichloro ethane and polar protic solvents like methanol, ethanol, n-proponol, iso-propanol, n-butanol, iso-butanol. The oc-bromo derivatives (V) may be purified by successively extracting with aliphatic or alicyclic nonpolar hydrocarbon solvents then treating the pooled organic layer with activated charcoal followed by filtration and recovery of solvent Alternately the derivative V may be purified by extracting with highly polar water immiscible halogenated solvents such as methylene dichloride, chloroform, 1,2- dichloroethane.

As herein above described the invention provides alternate routes for the preparation of nitro ethers avoiding employing explosive reagent such as NaH, it's corresponding aniline replacing palladium on carbon by Raney nickel and using hydrogen gas externally under high pressure by hydrazine. Further a simple purification was adopted over complex chromatographic purification. Thus the novel steps are involved in the preparation of precursors of formulae III, IV, V and VI.

The invention particularly relates to the preparation of pioglitazone and its hydrchloride salt, which is illustrated by the following synthetic scheme.

Synthetic Scheme for Pioglitazone Hydrochloride:

X

EXAMPLES:

General All the chemicals used were of commercial grade and were analysed before use. IR spectrum was recorded on NICOLET-AVATAR 320 FTIR spectrophotometer, ¹H- NMR and ¹³C-NMR spectrum were recorded on BRUKER DPX-300 spectrometer at ambient temperature. Electron Ionization Mass Spectrum (EIMS) were recorded on VG-70-250S mass spectrometer and Atmospheric Pressure Chemical Ionization Mass Spectrum (APCI-MS) were recorded on FINNIGAN MATT LCQ mass spectrometer. CHNS elemental analysis were estimated using Elementar Analysen Systeme GmbH VARIO EL CHNS Elementar Analyser.

Example-1: Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III).

Process A : To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I), (100.0 g, 0.66 mol,) l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7 mol), in D.M. water (250 ml) at 20 to25°C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35⁰C. The reaction mixture was stirred at

30 to 35°C for 16 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O⁰C) was added and the mixture was stirred for 1.5 hr, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O⁰C) and suck dried under vacuum for 25 to 30 minutes. The light green to yellow solid was dried at

35 to 40⁰C for 15 hr to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 55 to 6O⁰C) and filtered hot through cloth to remove un- dissolved particles. The solution was then cooled to 0 to 5⁰C, stirred for 1 hr filtered, washed with cold diisopropyl ether (25 ml, 0 to 5⁰C) and dried at 35 to 4O⁰C to obtain pure 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III ) as a light yellow solid.

Yield =159.2g (88.40%); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w.;

Melting point =45 to 47°C.

Alternately, the wet crude product after filtration can also be dissolved in hot isopropyl ether and crystallized at 0 to 5°C to obtain the pure product. IR(KBr, Cm .-^"U¹)= 2972.44, 2928.67, 1602.22, 1593.00, 1508.2, 1339.73, 1264.27, 1109.55, 853.89, 751.44, 657.50. ¹H-NMR ( 300 MHz, CDCl₃ ) δ = 1.24(t, 3H, CH₂- CH₃); 2.62 (q, 2H, CH₂-CH₃); 3.26 (t, 2H, CH₂-CH₂-O); 4.01(t, 2H, CH₂-CH₂-O); 6.93-8.40(m, 7H, aromatic H ).¹³C-NMR (75.47 MHz, CDCl₃) δ =14.86 (CH₂-CH₃); 25.24 (CH₂-CH₃); 36.70 (CH₂-CH₂-O); 67.63(CH₂-CH₂-O); 114.05 122.84, 125.30,135.40, 136.80, 140.87,148.67, 154.42, 163.52 (aromatic C) APCIMS MH⁺ =273 (M+l) Elemental analysis for C₁₅H₁₆N₂O₃,

Example-2: Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III).

Process B: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I)(100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (H), (100 g, 0.7 mol), dimethyl sulfoxide (200 ml) and water (50 ml ) at 20 to 25⁰C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35°C. The reaction mixture was stirred at 30 to 35⁰C for 12 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O⁰C ) was added and the mixture was stirred for 1.5 hr, filtered washed with ice-cold water (2 x 250 ml, 5- 1O⁰C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 to 40⁰C for 15 hr to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O⁰C) and filtered through cloth to remove un- dissolved particles. The solution was then cooled to 0 to +5⁰C, stirred for 1 hr, filtered, washed with cold diisopropyl ether (25 ml, 0 to +5°C) and dried at 35 to 4O⁰C to obtain pure 4-[2-(5-EthyI-2-pyridyl)ethoxy]nitrobenzene (III ) as a light yellow solid. Yield = 158.6 g (88.11 %); Purity (HPLC) >99.50%, Assay > 98.0% w/w; Melting point = 45 to 47⁰C Alternately, the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +5⁰C to obtain the pure product.

Example 3: Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) Process C: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7 mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), and water (250 ml) at 20 to 25⁰C, sodium hydroxide (70.0 g, 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 30 to 35⁰C. The reaction mixture was stirred at 30 to 35⁰C for 12 hrs and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O⁰C) was added and the mixture was stirred for 1.5 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O⁰C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35⁰C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O⁰C) and filtered hot through cloth to remove un-dissolved particles. The solution was then cooled to 0 to +5⁰C, stirred for 1 hr, filtered, washed with cold diisopropyl ether (25 ml, 0 to +5°C) and dried at 35 to 4O⁰C to obtain pure 4-[2-(5- Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 158.1 g (87.83 %); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 47°C Alternately, the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +5°C to obtain the pure product.

Example 4: Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III). Process D: To a stirred solution of 2-(5-Ethyl-2-pyridyl)ethanol (I) (100.0 g, 0.66 mol), l-fluoro-4-nitrobenzene (II), (100.0 g, 0.7mol), tetra butyl ammonium chloride (5.0 g, 70% solution in water), dimethylsulf oxide (200 ml) and water (50 ml) at 20 to 25°C, sodium hydroxide (70.0 g 1.75 mol) dissolved in water (200 ml) was slowly added keeping the temperature below 35°C. The reaction mixture was stirred at 35°C for 12 hr. and progress of the reaction was monitored by TLC. After the reaction was over, ice cold water (2.0 It., 5 to 1O⁰C) was added and the mixture was stirred for 2 hrs, filtered washed with ice-cold water (2 x 250 ml, 5 to 1O⁰C) and suck dried under vacuum for 30 minutes. The light green to yellow solid was dried at 35 to 4O⁰C for 15 hrs to get crude product, which was then dissolved in hot diisopropyl ether (350 to 400 ml, 50 to 6O⁰C) and filtered hot through cloth to remove un-dissolved particles. The solution was then cooled to 0 to +5⁰C and stirred for 1 hr, filtered, washed with cold diisopropyl ether (25 ml, 0 to +5⁰C) and dried at 35 to 4O⁰C to obtain pure 4-[2-(5- Ethyl-2-pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid.. Yield = 157.3 g (87.3%); Purity (HPLC) >99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 47°C.

Alternately, the wet crude product after filtration can also be dissolved in hot diisopropyl ether and crystallized at 0 to +5°C to obtain the pure product. The reaction can also be performed in other common solvents like methylene dichloride, chloroform, 1, 2-dichloroethane, benzene, toluene, ortho and para xylenes, diethyl ether, diisopropyl ether, dibutyl ether, tertiary butylmethyl ether, 1, 4-dioxane, tetrahydrofuran, 1, 2-dimethoxyethane, 1, 2-diethoxyethane and acetonitrile. However, since the compound was completely or partially soluble in these solvents, it does not crystallized out from the mixture as such and has to be extracted in hot solvent, the aqueous layer was separated, washed with water, dried on sodium sulphate and evaporated to give the crude product which was then re-crystallized from diisopropyl ether. The yield varies between 75 to 91%. When the reaction was carried out in methanol and ethanol, in addition to the product, large amounts of other impurities are also formed and the product can not be easily isolated or crystallized. However with n- propanol, iso-propanol, n-butanol, iso-butanol and other long chain alcohols, less amount of impurities where formed and the pure product can be was isolated in relatively lower yields (60 to 70 ⁰Zo).

Example-5: Preparation of 4-[2-(5-Ethyl-2-pyridyl)ethoxy]nitrobenzene (III). Process E : A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (I) (100 g, 0.66 mol), l-fluoro-4-nitrobenzene (II) (100.0 g, 0.70 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (200 ml) was heated at 55 to 60°C over a period of 24 hrs, when the TLC of the mixture indicated it to be complete. The mixture was cooled to 45⁰C, diisopropyl ether (800 ml), followed by water (1.0 It) was added and the mixture was vigorously stirred at 45 to 5O⁰C. The organic layer was separated, washed with water (3 x 200 ml), and evaporated to give crude residue which was then crystallized from diisopropyl ether (400 ml) at 0 to +5⁰C to afford 4-[2-(5-Ethyl-2- pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 132.6 g (73.66%); Purity (HPLC) > 99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 47⁰C. Alternatively, after the reaction was over, the hot mixture was filtered through cloth to remove the inorganic salts and the filtrate was diluted with excess of water and extracted with diisopropylether and worked up and crystallized as mentioned above.

Example-6: Preparation of 4-[2-(5-Ethyl-2-pyridyI)ethoxy]nitrobenzene (III). Process F : A suspension of finely powdered anhydrous potassium carbonate (400.0 g, 4.37 mol) 2-(5-ethyl-2-pyridyl)ethanol (T) (50.0 g, 0.33 mol), and l-fluoro-4- nitrobenzene (H) (50.0 g, 0.35 mol) and tetra n-butyl ammonium hydrogen sulfate (20.0 g) in dry dimethylformamide (100 ml) was heated at 85 to 9O⁰C over a period of 60 hrs, when the TLC of the mixture indicated it to be complete. The mixture was cooled to 45⁰C, diisopropyl ether (400 ml), followed by water (500 ml) was added and the mixture was vigorously stirred at 45 to 50⁰C. The organic layer was separated, washed with water (3 x 200 ml), and evaporated to give crude residue which was then crystallized from diisopropyl ether (200 ml) at 0 to +5⁰C to afford 4-[2-(5-Ethyl-2- pyridyl)ethoxy]nitrobenzene (III) as a light yellow solid. Yield = 58.10 g (64.50%); Purity (HPLC) > 99.50%; Assay (HPLC) > 98.0% w/w; Melting point = 45 to 46⁰C. Example-7: Preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (IV). Process A: Under an atmosphere of nitrogen gas, Raney Nickel (20.0 g wet) was added to a cooled (-10 to -15⁰C) solution of 4-[2(-ethyl-2-pyridyl)ethoxy]nitrobenzene (III)(100.0 g) in methanol ( 600 ml) and the mixture was shaken under a pressure of 3 to 4 kg cm^"2 hydrogen gas at 0 to +5 ⁰C . The temperature of the mixture was slowly allowed to rise to 25 to 3O⁰C and progress of reaction was monitored by TLC. The mixture was filtered through high flow bed (0.1kg) under atmosphere of nitrogen gas and washed with of methanol (1.0 It). Recovery of methanol under vacuum affords crude 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (IV) as a pale yellow oil, which turns dark over a period of time and was as such used in the next stage. Alternatively the mixture after filtration through hyflow (before the recovery of methanol) can be subjected to Meerwein Arylation conditions as mentioned below. Yield = 84.0 g (94.30 %); Purity (HPLC) >98.0%. ¹H-NMR ( 300 MHz, CDCl₃ ) δ = 2.23(t, 3H, CH₂-CH₃ ); 2.60(q, 2H, CH₂-CH₃ ); 3.17(t, 2H, CH₂-CH₂-O); 3.42 (bs, 2H₅ NH₂, exchange able with D₂O ); 4.24(t, 2H, CH₂-CH₂-O ); 6.54-8.37 (m, 7H, aromatic H ). IR ( neat ), cm^"1 = 3446.1, 3217.9, 2965.5, 2930.8, 2872.4, 1628.5, 1604.4, 1510.8, 1396.3, 1233.1, 1032.0, 826.5, 721.9.

Example 8: Preparation of 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (IV).

Process B : To 3 lt/4 neck round bottom flask with a with a nitrogen gas inlet and a hydrogen gas out let and a stirring blade, Raney Nickel (60.0 g wet) was added to a solution of 4-[2(ethyl-2-pyridyl)ethoxy]nitrobenzene (III) (100.0 g) in methanol (1.0 It ) at 25 to 30⁰C and the mixture was stirred for 15 min under an atmosphere of nitrogen gas. Hydrazine hydrate (100.0 g) was then very slowly added drop wise to the reaction mixture at 25 to 35⁰C and progress of reaction was monitored by TLC. During the addition of hydrazine hydrate, evolution of hydrogen gas takes place and the reaction becomes exothermic and the addition of hydrazine hydrate to the reaction mixture has to be controlled accordingly. After the reaction was over, (the colour of solvent in the reaction mixture becomes colour less from yellow) the mixture was filtered through high flow bed under atmosphere of nitrogen gas and washed with methanol (250 ml). The filtrate was diluted with water ( 2.0 It) and extracted with methylene dichloride ( 3 x 1.0 It), the combined methylene chloride fractions were washed with water (3 x 1.0 It), dried over sodium sulfate, filtered, and evaporated to afford crude 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniUne (IV) as a pale yellow oil, which turns dark over a period of time and was as such used in the next stage. Yield = 74.20 g (83.28 %); Purity (HPLC) >97.0 %.

Example 9: Preparation of (+)Ethyl-2-bromo-3-{4-[2-(5-ethyl-2- pyridyl)ethoxy] phenyl}propionate (V): Hydrobromic acid (47% in water) was slowly added to a cooled (10 to 15⁰C) solution of 4-[2-(5-ethyl-2-pyridyl)ethoxy]aniline (TV) (120.0 g) in acetone (852 ml), methanol (340 ml) and the mixture was cooled to 0 to +5°C. Sodium nitrite solution (34.0 g dissolved in 60 ml water) was slowly added to the mixture at 0 to +5°C and the mixture was stirred for 30 minutes at that temperature. Ethyl acrylate (255.0 g) was added to the mixture and temperature was gradually raised to 22 to 25⁰C followed by the addition of cuprous oxide (4.0 g) in small lots during which the temperature was not allowed to rise above 35⁰C. Vigorous evolution of nitrogen gas takes place during the addition of cuprous oxide. After evolution of nitrogen had ceased (~60 min.), the progress of the reaction was monitored by TLC. The reaction mixture was cooled to 0 to +5⁰C, neutralized by aqueous ammonia (120 to 150 ml, 30% solution) and pH was raised to ~6.8 to 7.3 while keeping the temperature at 0 to +5°C. At this stage the reaction can be worked-up in two different ways, which are as follows, Process A: The mixture was extracted with diisopropyl ether (2 x 1.25 It), the combined organic layers are washed with water (2 x 1.0 It), stirred with activated charcoal (10.0 g) for 30 minutes, and filtered through high flow bed. Recovery of diisopropyl ether under vacuum at 40 to 45°C yields (+) Ethyl-2-bromo-3-{4-[5- ethyl-2-pyridyl)ethoxy]phenyl]propionate (V) as a light yellow to orange coloured viscous oil which was used as such in the next stage. Yield = 128.5 g; Purity (HPLC) = 73.0%. [Yield after correction = 93.44 g (46.72%) Process B: Diisopropyl ether (400 ml) was added to the reaction mixture, temperature was raised to 25 to 3O⁰C, and stirred for 10 minutes. The diisopropyl ether layer was separated and the aqueous layer was again extracted with diisopropyl ether (200 ml). The combined diisopropyl ether layers were washed with water (200 ml), separated and evaporated under vacuum keeping the temperature below 5O⁰C. The dark oily residue thus obtained was successively extracted with hexanes (5 x 500 ml) at 30 to 35°C, and combined hexane layers were treated with activated charcoal (10.0 g) and the mixture was stirred for approx. 30 min. Filtration through high flow bed, followed by washing with hexanes (100 ml) and recovery of hexanes under vacuum at 45 to 5O⁰C affords (+1 Ethyl-2-bromo-3-{4-[2-(5-ethyl-2-pyridyl)ethoxy]pheny]

Propionate (V) as a light yellow to orange coloured viscous oil. Yield = 130.2 g; Purity (HPLC) = 74.22 % [Yield after correction = 96.35 g (48.17%)] IR ( neat ) cm ^"1 = 2966.6, 2932.8, 2874.2, 1737.6, 1608.9, 1512.3, 1300.8, 1247.3, 175.8, 1029.0. ¹H-NMR ( 300 MHz, CDCl₃) δ = 1.19-13.1(2t, 6H, CH₂-CH₃ and O- CH₂-CH₃ ); 2.58-2.66( q, 2H, CH₂-CH₃ ); 3.14-3.20( dd, IH, CH₂-CH-Br ); 3.22( t, 2H, CH₂-CH₂-O ); 3.34-3.41(dd, IH, CH₂-CH- Br ); 4.12-4.18( m, 2H, 0-CH₂-CH₂ ); 4.31( t, 3H, 0-CH₂-CH₃) 6.50-8.42(m, 7H, aromatic H). APCI-MS MH+ = 408 (M+l).

Example 10: Preparation of (+)5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl}-2- imino-4-thiazolidinone (VI). Thiourea (26.0 gm) and sodium acetate (anhydrous 27.3 gm) were charged into a solution of (+) Ethyl-2-bromo-3-{4-[2-(5-ethyl-2- pyridyl)ethoxy]phenyl}propionate (V) (130.0 g; purity 74.22 %) and iso-propanol

(910 ml) at ambient temperature. The temperature was raised and the mixture was refluxed at 78 to 85°C for 6 hrs and progress of the reaction was monitored by HPLC. After the reaction was over, the mixture was cooled to 10 to 15⁰C, and neutralized to pH=7.5-8.0 with sodium bicarbonate (10% solution), stirred for 3 hrs, filtered, slurry washed successively with water (25 to 30⁰C, 260 ml) and chilled iso-propanol (0 to +5⁰C, 130 ml) and dried at 55 to 60°C for 4 hrs to afford crude product (55.0 gm). The crude product was then refluxed in methanol (550 ml) for 60 minutes and approx (230 ml) of methanol was distilled off at atmospheric pressure below 7O⁰C. The mixture was cooled to 0 to +5°C, stirred for 6 hrs at 0 to +5⁰C, filtered, washed with chilled methanol (30 ml) and dried at 50 to 60⁰C for 6 hrs to obtain pure 5-{4-[2-[(5-ethyl-2- pyridyl)ethoxy]benzyl}-2-imino-4-thiozolidinone (VI) as a off white to pale yellow solid. Yield = 47.0 g; (56.20%); Purity (HPLC) >98.0% IR (KBr) cm ^-1 = 3238.65, 2961.46, 2932.12, 1684.89, 1512.49, 1490.12, 1253.54, 817.22, 717.43. ¹H-NMR ( 300 MHz, CD₃OD ) δ =1.24 (t, 3H, CH₂-CH₃ ); 2.62 (q, 2H, CH₂-CH₃ ); 2.29-2.98( IH, dd, CH₂-CH-S ); 3.18(t, 2H, CH₂-CH₂-O ); 3.30- 3.39(dd, IH, CH₂-C-S ); 4.26(t, 2H, CH₂-CH₂-O ); 4.53-4.89(dd, IH, CH₂-CH-S); 6.79-8.31(m, 7H, aromatic H ). ¹³C-NMR (75.47 MHz, CD₃OD) δ = 15.61( CH₂-CH₃ ); 26.60( CH₂-CH₃ ); 38.35 (CH₂-CH-S); 39.23( CH₂-CH₂-O ); 60.50(CH₂-CH-S); 68.64( CH₂-CH₂-O ); 115.95, 124.98, 131.36, 131.52, 137.92, 139.26, 149.33, 157.20, 159.51( aromatic C ); 186.23( C=N ); 192.29( C=O ). EIMS m/z=355 (M⁺) Elemental analysis for

Example 11: Preparation of (+)5-(4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl}-2, 4- thiazolidinedione (VII). To a mixture of methanol (410.0 ml), hydrochloric acid (36 %, 69.7 ml), pure (±)5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl}-2-imino-4- thiazolidinone (VI) was added at ambient temperature and the mixture was stirred with heating to reflux for 18 hrs at 78 to 83⁰C. After the reaction was over (monitored by TLC), the mixture was cooled to 10 to 15°C and pH of the solution was adjusted to 7.5 to 8.0 by slow addition of sodium bicarbonate solution (10% w/v, approx 600 to 800 ml). After stirring for 2.0 hrs at 10 to 15°C, the solid was filtered, slurry washed with water (500 ml) and dried at 50 to 60⁰C for 12 hrs to obtain crude product (41.0 g) as a pale yellow solid.

The crude product was dissolved in a mixture of 1, 4-dioxane (1.025 It.) and methanol (410 ml) at 65 to 75°C, treated with activated charcoal (2.0 g), filtered hot through high flow bed and the bed was washed with hot methanol (20 ml). The solution was slowly cooled to 5 to 10⁰C, stirred for 3 hrs, filled and washed with chilled methanol (20 ml, 0 to 5⁰C) and dried at 55 to 6O⁰C for 6 hrs. to obtain pure (+)2-(5-ethyl-2- pyridyϊ)ethoxy]benzyl]-2, 4-thiazolidinedione (VII). Yield = 36.9 g (90%), Purity (HPLC) > 99.0%, Melting point = 188 to 187⁰C.

IR (KBr ) cm ^~l =2962.57, 2925.49, 1704.98, 1515.19, 1253.94, 1038.83, 832.22, 720.81, 657.22. ¹H-NMR ( 300 MHz, CDCl₃ + TFA) δ =1.29 (t, 3H, CH₂-CH₃, ); 2.78-2.86 (q, 2H, CH₂-CH₃ ); 2.95-3.00 (dd, IH, CH₂-CH-S ); 3.31-3.37 (dd, IH, CH₂-CH-S); 3.52 (t, 2H, CH₂-CH₂-O ); 4.31 (t, 2H, CH₂-CH₂-O); 4.36-4.40 (dd, IH, CH₂-CH-S); 6.80-8.55 (m, 7H, aromatic H ).¹³C-NMR( 75.47 MHz, CDCI₃ + TFA ) δ = 13.18 ( CH₂-CH₃ ); 24.46 ( CH₂-CH₃ ); 31.94 ( CH₂-CH-S ); 36.57 ( CH₂-CH₂- O ); 52.55 ( CH₂-CH-S ); 64.26 ( CH₂-CH₂-O ); 116.6, 126.5, 127.95, 129.38, 139.32, 141.01, 144.31, 150.90, 156.26 ( aromatic C ); 170.42 ( C=O ); 174.11 ( C=O ). APCI MS at MH⁺ =358 (M+l) Elemental analysis for C₁₉H₂₀N2O3S

Example 12: Preparation of (+) 5-{4-[2-(5-Ethyl-2-pyridyl)ethoxy]benzyl}-2,4- thiazolidinedione hydrochloride (VIII). Purified (±) 5-{4-[2-(5-ethyl-2- pyridyl)ethoxy]benzyl-2,4-thiazolidinedione (VII) (35.0 g) was heated at to dissolve in a mixture of water (210 ml), hydrochloric acid (36%, 70 ml) and acetone (52.5 ml). Activated charcoal (3.5 g) was then added and the mixture was heated at 70 to 80°C with stirring for 30 min, filtered, slowly cooled to 10 to 15⁰C and stirred for 3 hr. Filtration followed by washing with cold water (35 ml, 10 to 15⁰C) , drying at 50 to 6O⁰C for 6 hrs affords (±)5-{4-[2-(5-ethyl-2-pyridyI)ethoxy]benzyl- 2, 4- thiazolidinedione hydrochloride (VIII) (Pioglitazone Hydrochloride) as a white solid. Yield 31.3 g (82.2%); Purity (HPLC) > 99.50%; Assay > 99.5% w/w; Melting point =192 to 194 ⁰C. IR ( KBr ) cm ^~l = 3416, 2928.45, 2743.97, 1742.90, 1693.05, 1609.01, 1510.24, 1552.70, 1243.45, 1154.52, 712.00: ¹H-NMR ( 300 MHz, CD₃OD ) δ=1.30 (t, 3H, CH₂-CH₃ ); 2.70 (q, 2H, CH₂-CH₃ ); 3.0-3.10 (dd, IH, CH₂-CH-S ); 3.36-3.42 (dd, IH, CH₂-CH₂-O ); 3.60 (t, 2H, CH₂-CH₂-O ); 4.42-4.47 (m, 3H, CH₂-CH₂-O + CH₂- CH-S); 6.80-8.55 ( 7H, several dd,l s, aromatic H ); ¹³C-NMR (75.47 MHz, CD₃OD) δ =15.50 (CH₂-CH₃); 26.95(CH₂-CH₃); 34.86 (CH₂-CH-S); 38.58 (CH₂-CH₂-O); 55.32 (CH₂-CH₂-S); 67.46 (CH₂-CH₂-O);116.26, 129.33, 130.94, 132.45, 141.60, 144.45, 147.84, 153.80, 159.43 (aromatic C); 174.68 (C=O); 178.40 (C=O):EIMS m/z= 357. Elemental analysis for C₁₉H₂₁CIN₂O₃S

ADVANTAGES:

1. The process involves minimal risk factors during production.

2. The process does not require any stringent operational conditions and special infrastructure.

3. The process employs readily and commercially available starting materials.

4. The process is technically and commercially feasible.

5. The process has minimal risk factors during production.

6. The process is easy to operate, safe,- simple, cost effective, environment friendly and high yielding.

7. The process eliminates employing sodium hydride, palladium on carbon, high pressure hydrogenation using hydrogen gas externally.

8. The process results in the title product with increased yield and purity meeting ICH guidelines.

Claims

WE CLAIM:

1. An improved process for the production of derivatives of thiozolidinediones and their precursors which comprises,

(a) reacting a compound of general formula I wherein Ri, R₂ and R₃ may be

same or different and represent H, alkyl or alkoxy with C varying from 1 to 6, halogens, mono or di-substituted alkyl and aryl amines, and M represents hydrogen (H) or alkali metal selected from Na, K or Li with a compound of

formula 2, wherein R₄ has the same meaning as Ri or R₂ or R₃ and X is halogen

in presence or absence of solvent(s) and or phase transfer catalyst under effective

conditions to produce nitro ethers of general formula III, where in Ri to R₄ has

the same meaning as given above, provided when M is H and not its alkali metal salt, an alkali metal salt such as hydroxide or carbonate is required to be added while conducting the said reaction,

M = H, Na, K, Li

(b) subjecting the said nitro ethers, with or without isolation, to Raney nickel- catalyzed reduction under conditions effective to produce corresponding nitro aniline ethers of general formula IV

(c) coupling the said aniline ether of formula IV with acrylates under Meerwein arylation conditions in presence of halo acids preferably hydrobromic acid to produce a halo substituted carboxylic acid derivatives, particularly α bromo substituted carboxylic acid derivatives of formula V wherein R5 is H or alkyl with C ranging from 1 to 3 followed by subjecting to solvent extractive purification to get a purified derivative of pale yellow colour viscous oil,

(e) hydrolyzing the said 2-imino -4-thiazolidinones VI, to produce 2, 4- thiazolidinones of formula VII, followed by converting the same to its pharmaceutically acceptable salts specifically hydrochloride salts of formula VIII as white crystalline solids, which are known to exhibit anti-diabetic activity by any conventional methods.

V Il

2. An improved process as claimed in claim 1 wherein in the above mentioned general formula I, alkyl groups with 1-6 carbon atoms are such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, n-pentyl, iso-pentyl, neo-pentyl or n-hexyl, preferably those having 1 to 4 carbon atoms; alicyclic groups that include without restriction cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; alkoxy groups having 1 to 4 carbon atoms may be such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, or t-butoxy, preferably those having 1-3 carbon atoms.

3. An improved process as claimed in claim 1 wherein the halogen atoms in formula II are fluorine, chlorine, bromine, iodine preferably fluorine.

4. An improved process as claimed in claim 1 wherein the alkali metal salt when used are hydroxide, carbonate, preferably hydroxide of sodium, potassium or lithium hydroxides, are be used singly or as mixtures in any suitable composition and are employed in the range of 1-8 molar equivalents, preferably between 2-6 molar equivalents and most suitably 3-4 molar equivalents when hydroxides are used and between 1 to 25 molar equivalents, preferably 2 to 15 molar equivalents, more preferably 5 to 10 molar equivalent when carbonates are added.

5. An improved process as claimed in claim 1 wherein the reaction in step (a) is effected at a temperature in the range of 5-100⁰C, preferably 5-70°C and most suitably 20-40⁰C.

6. An improved process as claimed in claim 1 wherein the quantity of water used in step (a) varies between 3-30 times v/w w.r.t the alcohol (I), preferably between 3-10 times v/w and most appropriately between 3-5 times v/w.

7. An improved process as claimed in claim 1 wherein the reaction in step (a) is conducted optionally in presence of all common and easily available Phase transfer catalysts (PTC) selected from quaternary ammonium compounds exemplified by tetrabutyl ammonium chloride, tetra butyl ammonium hydrogen sulfate either in isolation or as mixtures in any suitable composition and the quantity of PTC when used varies between 0.5% to 100% w/w and above with reference to pyridine alcohols (I).

8. An improved process as claimed in claim 1 wherein the reaction is also performed in a mixture of water and most water miscible organic solvents such as dimethyl sulfoxide, acetonitirile, 1,4-dioxane, acetone, diethyl ketone, methyl isobutyl ketone, dimethylacetamide, tetrahydrofuran, 1, 2-dimethoxy ethane and diglyme etc and aliphatic alcohols where C≥ 3 and ≤ 8 using 3-4 molar equivalents of sodium or potassium hydroxide dissolve in water (3 times) with stirring and monitoring by TLC or in the presence of water immiscible organic solvents in the presence or absence of PTC.

9. An improved process as claimed in claim 1 wherein the reaction in step (a) is carried out using anhydrous powder of the alkali metal salts such as sodium or potassium salts.

10. An improved process as claimed in claim 1 wherein the reduction of nitro ethers is carried out in the presence of Raney nickel and hydrazine in the absence of external source of hydrogen gas pressure preferably, in water miscible polar organic solvents like alcohol with C₃ to Cg exemplified by

methanol, ethanol n-propanol, iso-propanol, n-butanol, iso-butanol; tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, 1,2-diethoxye thane, dimethylsulfoxide, dimethylformamide, dimethylacetamide preferably dimethylformamide, dimethylacetamide either in isolation or as a mixture in any suitable composition or in the presence or absence of water employing Raney Nickel in the range of 25 to 100% w/w and hydrazine hydrate between 2-6 or more molar equivalents preferably between 2-4 molar equivalents at a temperature between 5-70⁰C.

11. An improved process as claimed in claim 1 wherein the reaction is performed by slowly adding hydrazine hydrate to a stirred suspension of nitro ethers and Raney Nickel in alcoholic solvents like methanol, ethanol, n-propanol, iso- propanol at 30-55°C under TLC monitoring.

12. An improved process as claimed in claim 1 wherein the nitroethers III are also reduced by subjecting them to hydrogen gas pressure in the presence of Raney

Nickel in polar solvent mixture over a period of 6-24 hrs. at a temperature between —15 and 9O⁰C and by applying pressure of hydrogen gas between 2-6 kg per cm^"2.

13. An improved process as claimed in claim 1 wherein the reactions in step (b) is performed in all polar water miscible and organic solvents like methanol, ethanol, n-propanol, iso-propanol, butanol, iso-butanol dimethylformamide, dimethylacetamide, ethers like 1,4-dioxane, 1,2-dimethyl ether, tetrahydrofuran in isolation or mixtures thereof or in a suitable mixture of water immiscible solvents like diethyl ether, diisopropyl ether, diphenyl ether, dibutyl ether, tertiary butyl methyl ether, aromatic hydrocarbon solvents like, benzene, toluene, ortho and para xylenes and halogenated solvents like methylene dichloride, chloroform and dichloro ethane and polar protic solvents like methanol, ethanol, n-proponol, iso-propanol, n-butanol, iso-butanol.

14. An improved process as claimed in claim 1 wherein the α-bromo derivatives (V) are purified by successively extracting with aliphatic or alicyclic nonpolar hydrocarbon solvents then treating the pooled organic layer with activated charcoal followed by filtration and recovery of solvent or by extracting with highly polar water immiscible halogenated solvents such as methylene dichloride, chloroform, 1,2-dichloroethane.

15. An improved process as claimed in claim 1& 14 wherein the non polar solvents are aliphatic and cyclic hydrocarbons like cyclopentane, n-pentane or their higher homologues where C=5 to 8; ethers like diethylether, diisopropyl ether, and methyl tertiary butyl ether; the aromatic solvents like, benzene, toluene, ortho and para xylenes whereas the polar solvents are considered to be methylene dichloride, chloroform and dichloroethane .

16. An improved process as claimed in claim 1 wherein the thiazolidones (VI) obtained in step (d) are purified by refluxing in presence of 5 to 25 times v/w of alcohols preferably 10 times of methanol for 60 minutes.