FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "AN IMPROVED PROCESS FOR HYDEROGENATION OF 5-[SUBSTITUTED BENZYLIDENE]2,4-THIAZOLIDINE DIONE COMPOUNDS TO GIVE CORRESPONDING (+/-) 5-[SUBSTITUTED BENZYL] 2,4-THIAZOLIDINE DIONE COMPOUNDS"
2. CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA, AN INDIAN COMPANY.
3. THE FOLLOWING SPECIFICATION DESCRIBES AND ASCERTAINS THE NATURE OF THIS INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED.

TITLE : An improved process for hydrogenation of 5- [substituted benzylidene ] 2,4-thiazolidine dione compounds to give corresponding (+/-) 5- [substituted benzyl ] 2,4-thiazolidine dione compounds.
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FIELD OF INVENTION
The present invention relates to an improved process for hydrogenation of 5-[
substituted benzylidene]-2,4-thiazolidinedione compounds to give (+/-) -5- [substituted
benzyl ] - 2,4-thiazolidinedione compounds.
BACKGROUND OF INVENTION :
Some common antidiabetic insulin sensitizers have general structure [ formula-I ] as
follows.

wherein R is
N-methyl - N-2-pyridinylamino;
Or
(5-ethyl-2-pyridinyl)
which are generally prepared from compounds of formula-II

wherein R is as defined above,
by reduction of exocyclic double bond at 5 position of thiazolidine 2,4-dione.
Thus both the structures [ formula-I] describe Rosiglitazone and Pioglitazone
respectively.
US5002953 describes the conversion of compound of formula- (II)
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wherein Ar is different aromatic substituents as described in example nos.
1,3,5,7,9,11,13,15,17,19,21,23,27,28,30,33,35)
Various methods to effect this conversion include :
(a) catalytic hydrogenation 10 % palladium on carbon at ambient temperature and atmospheric pressure until hydrogen uptake is ceased in solvents such as 1,4 dioxane ( as given in example nos. 1,3,5,21,27,28,30,33,35);
(b) alternatively charging the reactant in a 1:1 mixture of methanol and 1,4-dioxane and using magnesium turning for reducing benzylidene double bond( as given in example nos. 7,9,11,13,15,17,19);
(c) using 10 % palladium on charcoal in DMF and carrying out hydrogenation at 200 psi of hydrogen as given in example-23.
Different catalyst loading are required for different substarates. The following table summarises different weight % of catalyst used per weight of compound to be reduced with example Nos.
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ExampleNoUS5002953 Substrate in Gm. Wt. of 10%Pd/C In Gms Wt% of 10% Pel/C
1 2 3 150
3 1.5 2 133
5 2.4 3 125
21 1.2 2.5 208
27 2.4 4.8 200
The amount of precious metal catalyst such as palladium used for reaction is very high and poses a serious recovery problems and makes these methods unsuitable to commercial manufacture.
In all preparations the yields are not mentioned so it is difficult even to know the commercial application of this process.
Bioorganic Medicinal Chemistry Letters , 1994 , vol. 4, pages 1181-84 discloses the use of magnesium metal and methanol for reduction of 5-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]benzylidene]thiazolidine-2,4-dione to 5-[4-[2-[N-methyl—N-(2-pyridyl)amino]ethoxy]phenylmethyl]thiazolidine-2,4-dione. US20050043539 mentions that the use of large quantities of magnesium metal, formation of alkoxide with methanol are inherent drawbacks of this process, which necessitate a better option if available.
Other associated drawbacks include uncontrolled evolution of hydrogen and therefore a
safety issues, removal of magnesium alcoholate from methanol and discoloration.
W093, 93/10254 ; Journal of Chemical society, Perkin Transactions 1, 1994, 3319-24
relates to biotransformation by Rhodoturola yeast for conversion of 5-[4-[2-[N-methyl-
N-(2-pyridyl)amino]ethoxy]benzylidene]thiazolidine-2,4-dione to 5-[4-[2-[N-methyl-N-
(2-pyridyl)amino]ethoxy]phenylmethyl]thiazolidine-2,4-dione. WO2005/108394
mentions that in abovementioned process , the enzymatic biotransformation by fungi requires high dilution and strictly controlled conditions resulting in a product with considerable amounts of biological substances. Such biotransformations always involve
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lot of sophisticated infrastructure and capital expenditure and process is highly sensitive and therefore prone for failures. Precise controls and sensitivity being main drawbacks.
US 20020042519 [ equivalent to WO98/37073 ]discloses preparation of 5-{4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione (IA) via reduction of
5- {4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy] benzylidene} -2,4-thiazolidinedione (IIB)
using Lithium Tri-sec.butyl borohydride in THF solvent to give 79% yield.
This method uses dirty extractive work-up for isolating product and the crude product is
crystallized from 20 times volume of solvent per gram of crude product. In another
embodiment, (IIB) is converted into (IA) in 77 % yield using lithium borohydride in a
mixture of THF and pyridine and the product is isolated by aqueous
quenching.WO2005108394 Al mentions that the reaction with lithium borohydride and
pyridine is dangerous due to copious evolution of heat and gas.
This method uses a mixture of solvents which are also water soluble and as the work-up
requires aqueous quenching, the recovery of solvent is difficult ; moreover isolation
involves multi-step extractive work-up.
In yet another embodiment of US 20020042519 , (IIB) is converted to (IA) in 88% yield
using lithium borohydride which is prepared in-situ from sodium borohydride and
lithium chloride. This process also uses a mixture of pyridine and THF which also
involves dirty aqueous work-up disregarding the issue of solvent recovery.
In yet another embodiment of US 20020042519, (IIB) is converted to (IA) in THF using
Lithium aluminum hydride in 69 % yield.
This process uses LiAlH4 in THF , which has its own problems of handling on
commercial level. The reported yield is also low.
WO2005021541A2 discloses preparation of Rosiglitazone free base by reduction of 5-[4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene]thiazolidine-2,4-dione(II) , in the presence of cobalt ion , a ligand and a reducing agent , wherein the cobalt ion is provided in the form of compounds such as cobaltous chloride, cobaltous diacetate, and
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cobaltic chloride; the ligand is selected from the group consisting of dimethyl glyoxime,
2,2'-bipyridyl and 1,10-phenanthroline.
The reducing agent is selected from group consisting of sodium borohydride ,lithium
borohydride , potassium borohydride, tetraalkyl ammonium borohydride and zinc
borohydride.
US20020120150 describes reduction of (Z) 5-{4-[2-(N-methyl-N-(2-
pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione ( 123 Kg) to 5-{4-[2-(N-
methyl-N-(2-pyridyl)amino)ethoxy]benzyl}-2,4-thiazolidinedione in 70 to 80 % yield in
glacial HO Ac (1232 L) using 10 % palladium on charcoal (123 Kg containing 50 %
w/w water i.e. catalyst loading is 50 % w/w), at 70-80 psi hydrogen pressure at about
95°C.
US20020120150 also summarises in tabular form reaction time and conditions of
hydrogen pressure and different catalyst loading as follows:

Reaction Number Conditions Reaction time In Hours
1 75 psi, 50% cat 15-20hr.
2 1000 psi, 50% cat <2hr
3 1000 psi, 25% cat 7hrs
4 500 psi , 50% cat. 4hrs
5 500 psi, 25 % cat. Ca. 12 hrs.
WO 2005/049610 discloses a process for reducing an exocyclic double bond at the 5-position of a thiazolidinedione moiety of a thiazolidinedione precursor comprising the steps of: (a) preparing a solution or suspension of the thiazolidinedione precursor in a non-ether solvent medium with a base, and (b) combining the solution or suspension with a dithionite source. Preferred solvent media include aqueous N.N-dimethylformamide. Sodium dithionite is a preferred dithionite source. In particular the application discloses preparation processes for Pioglitazone, Rosiglitazone and Troglitazone.
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WO2005108394A1 describes that when reaction with sodium dithionite is carried out under basic conditions, lead to high amount of impurities due to side reactions.
US20030153765 describes a method of catalytically hydrogenating exocyclic double bond of a penultimate thiazolidinedione precursor comprising steps of:
a) providing a solution of the penultimate thiazolidinedione precursor in a high capacity solvent (formic acid),
b) combining the solution with a supported metal hydrogenation catalyst in a reactor, and
c) exposing the combination of solution and hydrogenation catalyst to hydrogen gas.
The supported metal hydrogenation cat. comprises a metal selected from the group consisting of platinum, palladium ,ruthenium, rhodium, osmium, and iridium. The invention describes use of this process for preparing Troglitazone, Pioglitazone and Rosiglitazone.
Li, Jiaming; Li, Feng; Cha, Dajun describe in Zhongguo Yaowu Huaxue Zazhi (2001), 11(5), 291-292, 294 , Synthesis of antihyperglycemic agent rosiglitazone wherein Rosiglitazone was synthesized from 2-chloropyridine by substituting with 2-methylaminoethanol at 120°C for 18 h under bubbling N2, substituting with 4-fluorobenzaldehyde in DMF in the presence of KOH and TEBA at 120°C for 10 h under bubbling N2 to obtain 4-[2-(N-methyl-2-pyridylamino)ethoxy]benzaldehyde, condensing with 2,4-thiazolidinedione, and hydrogenating in dioxane in the presence of 10% Pd/C. The overall yield was 36.2%.
As described in WO2006032218A1:
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WO9923095 has described possibilities to carry out the catalytic hydrogenation in mediums other than the initially used dioxane, e.g. in acetic acid and its mixtures with water,in alcohols, mineral acids, and in mixtures of these solvents. The reduction was carried out under the catalyst 10 % palladium on carbon at higher temperatures (80 to 115°C) and under the pressure of hydrogen 0.35 to 10.5 Mpa. The catalyst consumption was , in comparison with the aforementioned method, lower; nevertheless, it was still very high(5 to 100 %, preferably 25 to 50 % based on the weight of the substance of formula-II-i.e. benzylidene compound). The product was obtained after filtration and evaporation of the solvent with a yield in the interval of 70 to 80 %).
A method of the reduction of the compound of formula-II i.e. benzylidene compound, using magnesium turnings in boiling methanol was published in J. Med. Chem. 37, 3977(1994).The product was isolated from the reaction mixture , after adjustment of pH to 7.5 to 8 ( using diluted hydrochloric acid ) , by extraction using dichloromethane. The crude product was, after evaporation of solvent, purified using column chromatography ( Si02 , 2 % methanol in dichloromethane). The yield of the product was , however , only 62 %.
WO 2005/108394 Al discloses a process for the preparation of 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzyl} -2,4-thiazolidinedione (Rosiglitazone), which comprises reaction of 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione with a 1,4-dihydropyridine of general formula-Ill.

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The yields reported in this process in different embodiments are 67% ,76% ,35% ,43% ,50% ,39%, and 61 % which are low hence unsuitable to commercial manufacture.
The prior art processes described above suffers from several drawbacks such as : Use of Heavy catalyst loading per weight of compound to be reduced to effect reduction of double bond; Use of hazardous reagents like LiBH4 in pyridine, Lithium aluminum hydride generating copious evolution of heat and gas; low yield of the reduction product; multistep extractive workup; use of high pressures , long reaction times and in several cases formation of impurities during the reaction.
It is therefore a long felt need of the industry to provide an industrially scalable process for reduction of 5-[ substituted arylidene]-2,4-thiazolidinedione to (+/-) -5- [substituted aryl methyl ] - 2,4-thiazolidinedione compounds.
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SUMMARY OF THE INVENTION :
The main object of the invention is to provide an improved process for the conversion of 5- [substituted benzylidene ]- 2,4 thiazolidine dione to corresponding (+/-) 5-[substituted benzyl]- 2,4 thiazolidine dione compounds using perchloric acid as hydorgenation activator during catalytic hydrogenation using hydrogen and a precious metal catalyst.
Another object of the invention is to provide an improved method to prepare antidiabetic insulin sensitizer molecules belonging to the the family of (+/-) 5- [substituted benzyl] 2,4 thiazolidine dione compounds such as Rosiglitazone, Pioglitazone , Yet another object of the invention is to develop a process which does not involve use of hazardous reagents like Lithium borohydride in pyridine , Lithium aluminum hydride in THF.
Yet another object of the invention is to develop a process which does not involve multistep extractive work up or chromatographic separation Yet another object of the invention is to develop a process which use moderate pressures.
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DETAILED DESCRIPTION
Thus in accordance with the present invention compounds of formula-II
wherein R is
N-methyl - N-2-pyridinylamino;
Or
(5-ethyl-2-pyridinyl)
is hydrogenated using hydrogen and a precious metal catalyst at 25 to 125 C and at 2 to
6 kg hydrogen pressure in an autoclave using perchloric acid as catalyst to give a
compound of formula-I

wherein R is as defined above.
A suitable hydrogenation catalyst is selected from the group consisting of platinum, palladium ,ruthenium, rhodium, osmium, and iridium; more suitable is a palladium catalyst.
Favoured catalysts are supported metal catalyst such as palladium on carbon catalyst, typically comprising 5% to 10 % on carbon catalyst. A more preferred catalyst is a 10% palladium on carbon catalyst having 50 % w/w water.
Catalyst loadings ( expressed as w/w % of catalyst to substrate) in the reaction are typically in the range from 5 to 100 %, usually 20 to 100 % preferably 60 to 80 %.
The reaction may be carried out using any suitable solvent such as acetic acid, formic acid , aqueous acetic acid, an alkanol ,such as methanol or ethanol; ethers such as THF, 2-Methyl THF, 1,4- dioxane, monoglyme, dibutyl ether and their like;
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The reaction is carried out at a temperature which provides a proper rate of formation of required product, suitably at an elevated temperature, preferably above 60 C, for example in the range of 60 to 115°C.
The compounds of formula-I are isolated from the reaction by filtration and purified by conventional purification methods such as crystallization / recrystallization.
Present invention is illustrated with following examples which do not limit the scope of this invention
Example-1
In an autoclave / hydrogenator were charged a mixture of 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione (10 gm), DMF (150 ml), 10 % Palladium on charcoal [ with 50 % w/w moisture] ( 8 gms) and 70 % w/v perchloric acid (3 ml) . The autoclave was freed from air by pressurizing with nitrogen and degassed 3 to 4 times and finally pressurized with hydrogen till 5 kg . The reaction mass was stirred at 500 rpm and heated to 100°C and maintained at this temperature for about 12 hours to give a conversion of >98 % The reaction mass was filtered on Buchner funnel and filtrate was distilled under reduced pressure. The residue was dumped into isopropyl alcohol and water and neutralized to give Rosiglitazone .
Example-2
In an autoclave / hydrogenator were charged a mixture of 5-{4-[2-(N-methyl-N-(2-pyridyl)amino)ethoxy]benzylidene}-2,4-thiazolidinedione (10 gm) , formic acid (150 ml), 10 % Palladium on charcoal [ with 50 % w/w moisture] ( 8 gms) and 70 % w/v perchloric acid (3 ml) . The autoclave was freed from air by pressurizing with nitrogen and degassed 3 to 4 times and finally pressurized with hydrogen till 5 kg . The reaction mass was stirred at 500 rpm and heated to 60°C and maintained at this temperature for about 12 hrs. The reaction mass was filtered on Buchner funnel and filtrate was distilled under reduced pressure. The residue was dumped into isopropyl alcohol and water and neutralized to give Rosiglitazone having conversion of >99.5 % and starting benzylidene compound of about < 0.3 %.
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