FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
THE PROVISIONAL SPECIFICATION
(See section 10)
1. "PROCESS FOR PREPARING RHODANINE-3-ACETIC ACID: A KEY INTERMEDIATE OF EPALRESTAT".
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.

PROCESS FOR PREPARING RHODANINE-3-ACETIC ACID: A KEY INTERMEDIATE OF EPALRESTAT
FIELD OF INVENTION
The present invention relates to a novel and improved process for the preparation of rhodanine-3- acetic acid, having CAS No. [ 5718-83-2] -[ compound of formula-Il ] which is used for the preparation of (E,E)-5-(2-Methyl-3-phenyl-2-propenylidene)-4-Dxo-2-thioxo-3-thiazolidineacetic acid, known as Epalrestat [I] . Epalrestat is used in the treatment of diabetic neuropathy. Epalrestat has CAS No. [82159-09-9].

Toshimasa ISHIDA et al. in Tetrahedron Letters vol30, No. 8, pages 959-962 (1989)
published the structure elucidation of of all four geometrical isomers of Epalrestat
(ONO-2235) based on NMR and UV spectroscopic evidences and assigned (Z)-3-
carboxymethyl-[(2E)-methylphenylpropenylidene]-rhodanine as clinically important
compound.
Epalrestat is marketed as (Z,E) form by Ono Pharmaceuticals Co. Ltd. under the
trade name 'Kinedak' since 1992.

BACKGROUND OF INVENTION :
Li, Yuezhen et.al. in Chinese Journal Zhongguo Yaowu Huaxue Zazhi (2001), 1 1(3), 165-167 describe synthesis of Rhodanine-3- acetic acid of formula-II as shown in scheme-I in which carbon disulphide is added to glycine in NH4OH using phase transfer catalyst followed by the reaction with sodium chloroacetate and cyclizing it using concentrated HC1 to give Rhodanine-3- acetic acid of formula [II].

Li, Duxin et. al. in Chinese Journal Shanxi Daxue Xuebao, Ziran Kexuban (1995), 18(4), 413-16 describe the preparation of II [refer scheme-I], wherein, reaction of compound -[IV] with Chloroacetic acid in aqueous Na2C03 gives compound of formula [V] . Compound of formula [V] reacts with HCI and gives Rhodanine-3-acetic acid [II] .
A publication in Journal of Zhejiang University, Medical Science (2003 Aug), 32(4), 356-8 ,describes method of synthesis of Rhodanine-3- acetic acid of formula-[H] which involves reaction of glycine with carbon disulfide and sodium chloroacetate to give Rhodanine 3-acetic acid .
All processes disclosed in prior art use Carbon disulfide which is hazardous and generally undesirable in large scale commercial processes. It is hence desirable to develop a process for preparing Rhodanine-3-acetic acid without using carbon disulfide.

SUMMARY
The process of present invention overcomes the disadvantages of prior art processes by avoiding the use of carbon disulfide in preparation of Rhodanine-3- acetic acid. The present invention also discloses a novel method for the preparation of Rhodanine-3-acetic acid which involves formation and use of novel intermediate having a structure of formula- [IX] .
In accordance with the present invention Rhodanine-3-acetic acid [II] is prepared as per scheme-II comprising steps:
1. Aminoacetic acid [VI] is reacted with methanol in HCI to give methyl aminoacetate hydrochloride [VII ; where R is Me]
2. Methyl aminoacetate hydrochloride [VII ; where R is Me] is reacted with chloroacetyl chloride [VIIA ; where X and Y is CI] to give methyl[(chloroacetyl)amino]acetate [VIII ; where Y is CI and R is Me ],
3. Methyl[(chloroacetyl)amino]acetate [VIII ; where Y is CI and R is Me ] is reacted with Alkali metal ethylxanthate [VHIA ; where M is K] i.e. potassium ethyl xanthate to give methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate [IX ; where R is Me andRl is Et ],
4. Methyl({[(ethoxyearbonothioyl)thio]acetyl}amino)acetate [IX ; where R is Me andRl is Et ], is cyclised to give methyl(4-oxo-2-thioxo-l,3-thiazoIidin-3-yl)acetate [X ; whereR is methyl],
5. Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate [X ; whereR is methyl] is hydrolysed to give Rhodanine-3-acetic acid [II].

DETAILED DESCRIPTION OF THE INVENTION :
It may be noted that these reactions are carried out without the use of carbon disulfide which is hazardous and undesirable on large scale commercial processes. Rhodanine 3- acetic acid is the key intermediate in the synthesis of Epalrestat; It is prepared from glycine by following steps which are described in Scheme-II as follows:

Where R is C1-8 alkyl, benzyl,cycloalkyl,alkyleneCl-6, phenyl, substituted phenyl etc

X is CI, Br, I,OTs,OMs
Yis CI, Br, I,OTs,OMs
Rl is selected from C1-C4 alkyl, benzyl, aryl etc. and preferably Rl is Ethyl or
isopropyl and more preferably ethyl. In step-1
The solvents in step-1 is selected from
alcohol, such as MeOH, EtOH, IPA, BuOH, etc.; aromatic hydrocarbons such as toluene, benzene, Xylene ; Cycloalkanes such as cyclohexane, cyclopentane ; nitrile group of solvents like acetonitrile, propionitrile or mixtures thereof
In step-2
The solvents used in step-2 is selected from
(a) Water,
(b) Aromatic hydrocarbons like benzene, toluene, xylene, cyclohexane
(c) Halogenated solvents like dichloromethane, 1,2 dichloroethane, chloroform etc
(d) Ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether,
(e) Nitriles such as acetonitrile. or mixtures thereof.
The preferred solvent is water. Temperature of reaction is between 0°C to 40°C
The base used for the neutralization is selected from inorganic alkalimetal bicarbonate, carbonates and hydroxides such as sodium bicarbonate, sodium carbonate, sodium hydroxide, potassium bicarbonate, potassium carbonate etc, preferably sodium bicarbonate, organic tertiary amines such as NEt3, N-Methylmorpholine, N-Methylpyrrolidine, N-Ethylpiperidine, DBU, DBN, diisopropylethyl amine etc.
In step-3
Solvent for the reaction is water.
Temperature of the reaction is between 0 to100°C preferably 30 to 35°C.
In step-4
The base used for cyclization is selected from:

(a) tertiary amine like triethyl amine, N-methyl morpholine, N-methyl pyrrolidine, N-ethyl pyrrolidine,diisopropyl ethyl amine , DBU DBN ;
alkoxide group of bases like.NaOMe , NaOEt , Sodium or pottasium isopropoxide, Sodium or potassium tert. butoxide. The preferred base is NaOMe.
The solvent for the reaction may be selected from :
(a) Halogen group of solvents such as dichloromethane, dichloroethane, chloroform,
carbon tetrachloride and optionally mixtures thereof,
(b) Aromatic hydrocarbon group of solvents such as benzene, toluene, xylene and
optionally mixtures thereof
(c) Nitrile group of solvents such as acetonitrile, propionitrile and optionally mixtures thereof.
In step-5
In the hydrolysis reaction, the acid used is selected from aq. hydrochloric acid, aq. sulfuric acid, aq. phosphoric acid, aq. hydrobromic acid etc.
The temperature of the reaction is from 25-125nC , preferably carried out at the reflux temperature (about 100°C)
The present invention is illustrated by the following non-limiting examples.
Example-1
(a) Preparation of methylaminoacetate hydrochloride [VII ; where R is Me]
In 3 lit. multi- necked round bottom flask equipped with stirrer, condenser,
thermometer and HCl gas purging arrangement, aminoacetic acid (300g, 4mol) is
stirred with 1.5 L methanol under cooling. Purge dry HCl gas into cooled mass. The
reaction mass is refluxed and maintained at reflux temperature for 2 hours. The
absence of aminoacetic acid is checked on TLC. The reaction mass is cooled to room
temperature and maintained for 1 hour. The white crystalline product is filtered and
washed with 300ml of methanol and sucked dry. The product is dried at 50-55°C for
6 hours.
Yield of methyl aminoacetate hydrochloride = 460gms.
M.P.= 175°C.

(b) Preparation of methyl aminoacetate hydrogen sulfate
In 500 ml three necked round bottom flask equipped with stirrer, condenser, water
bath
aminoacetic acid (25gm, O.33mol) is stirred with 125ml of methanol al 10°C. Added
(34.96g, 0.349mol) sulfuric acid drop wise at 10"C during 1 hour. Heated to reflux
and maintained it for 2 hours. The absence of amino acetic acid is checked by TLC.
Distilled out methanol to get methyl aminoacetate hydrogen sulfate as oil.
Yield = 60 gm.
Example-2
Preparation ofmethyl(chloroacetylamino)acetale [VIII ; where R is Me and Y is CI]
In 10 L multi-necked round bottom flask equipped with mechanical stirrer, addition
funnel, thermometer placed in ice bath , is charged sodium bicarbonate (301 g,
3.58mol) and stirred with 4.5L of water and cooled to 0-5°C. Methylaminoacelate
hydrochloride (450g, 3.58mol) is added slowly at 0-5°C. Chloroacetyl chloride
(286ml, 3.58mol) is then added dropwise at 0-5°C by maintaining pM of 6-7 with
sodium bicarbonate (400g, 4.76mol). The mass is stirred at 0-5°C for I hour and then
at 25-30°C for 1 hour. The absence of starting material is checked by TLC. After the
disappearence of starting material on TLC, reaction mass is extracted with chloroform
(4.5L). Chloroform is distilled out completely to give
methyl(chloroacetylamino)acetate obtained as as oil. Yield = 460g (%Yield=77%)
Example-3
Preparation of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate [ IX ;
where R is Me and Rl is Et ]
In 5 Lit. multi-necked round bottom flask equipped with stirrer, thermometer and
dropping funnel, potassium ethyl xanthate (27lg, 1.69mol) is stirred with 2.2L of
water at 30-35"C. The solution of melhyl[(chloroacetyl)amino]acetate (280g,
1.69mol), dissolved in 600ml of water is added at 30-35°C. The reaction mass is
stirred for 5 hours. The absence ormethyl[(chloroacetyl)amino]acetate is checked by
TLC. The reaction mass is filtered and washed with 1800ml water. The wet cake is
unloaded and dried in oven at 55-60°C for 5-6 hours.
Yield of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate = 366g

(%Yield=86%)
Example-4
(a) Preparation ofmethyl(4-oxo~2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R
is Me ]
In 1 Lit multi-necked round bottom flask equipped with mechanical stirrer, water bath
thermometer ,condenser, Nitrogen gas purging arrangement, sodium methoxide
(32.3g, 0.6mol) is stirred with 150ml methylene dichloride at 5-10°C under nitrogen
atmosphere. The solution of
methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (50g, 0. !989mol) dissolved into 150ml of dichlorotnethane is added at 5-10QC during 1 hour. The reaction mass is stirred for 4 hours at 5-10°C. The absence of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino) acetate is checked by TLC. The reaction mass is dumped into cooled (0-5°C) 70ml 30% Hydrochloric acid. 300ml of water is added at 0-5°C and temperature is raised to 25-30°C. The organic layer is separated. Aqueous layer is extracted with 500ml ethyl acetate. Organic layer is combined with main organic layer and distilled to give methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] as orange-red coloured oil. Yield = 40gm (%Yield=97%)
(b) Preparation of methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl) acetate [X ; where R
is Me ]
In 100 ml three necked round bottom flask
Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (2g, 0.0079mol) is stirred
with toluene(20 ml) at 60-65°C. Added trietliylamine solution (8ml, 0.0569mol in
10ml of toluene) at 60-65°C slowly under nitrogen atmosphere. The reaction mass is
stirred and heated to 80-85°C for 12 hours. The absence of
methyl({[(ethoxycarbonothioyl)thio]acetyl) amino)aeetate is checked by TLC. Reaction mass is dumped into 250ml of ice-water. The toluene layer is separated . Aqueous layer is again extracted with 25ml of toluene. The toluene layer is collected and washed with water (50ml) thrice. The toluene layer is distilled out to give an

orange-red colour oily mass. 95mg of methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] is obtained by column chromatography.
(c) Preparation of methy\(4-oxo-2-thioxo~l,3-thiazolidine-3-yl)acetate [X ; where R is
Me]
In 100 ml cap. three necked round bottom flask equipped with stirrer, thermometer Potassium tert. Butoxide (10.03g, 0.089mo!) is stirred with 20ml of ethylenedichloride at 5-10°C under nitrogen atmosphere. Added the solution of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (5g, 0.019mol dissolved into 20ml of ethylenedichloride) at 5-l0°C during 1hour. Maintained 5-10°C for 3 hours. The absence of methyl({[(ethoxycarbonolhioyl)thio]acetyl} amino)acetate is checked by TLC. Dumped the reaction mass into ice chilled aqueous HC1 solution (50ml 30% HC1 in 200ml water). Ethylene dichloride layer is separated at 25-30°C. The aqueous layer is extracted with 100ml of ethyl acetate. Both the organic layers are combined. The organic layer is distilled to give methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate [X ; where R is Me ] as orange-red colour oily mass. Yield = 4gm(%Yield=97%)
(d) Preparation of methyI(4-oxo-2-thioxo-l ,3-thiazolidine-3-yl)acetafe [X ; where R
is Me]
In 250 ml cap. three necked round bottom flask equipped with stirrer, thermometer,
ice bath Sodium methoxide (6.5g, 0.12mol) is stirred with 50m! of dichloroethane at
5-10°C under nitrogen atmosphere. Added solution of
methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (l0g, 0.039mol dissolved into 50ml of dichloroethane) to above solution at 5-10°C during 1 hour. Stir at 5-10°C for 3 hours. The absence of methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate is checked by TLC. The reaction mass is dumped into chilled (0-5°C) 100ml 15% aqueous Hydrochloric acid solution. Temperature of reaction mass is raised to 25-30°C. The organic layer is separated . Aqueous layer is extracted with 50ml ethylacetate. Both the organic layers are combined and distilled out to give methyl(4-oxo-2-thioxo-l,3-thiazolidine-3-yl)acetate[X ; where R is Me ] as orange-red coloured oil. Yield = 8gm (%YieId = 97%)

(e) Preparation of methyl(4-oxo-2-lhioxo-1,3-thiazo!idine-3-yl)acetafe [X ; where R is Me]
In 500 ml three necked round bottom flask equipped with stirrer, ice hath propping funnel, and thermometer Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino)acetate (15.0g, 0.059mol) is dissolved in methylenechloride (150ml) and cooled to 10°C. The solution of sodium methoxide (9.68g, 0.179mol dissolved into 30ml of methanol) under nitrogen atmosphere at 8-12°C is added in to the reaction mass during 1 hour. The temperature is maintained at 8-12°C for 1 hour. The absence (if Methyl({[(ethoxycarbonothioyl)thio]acetyl}amino) acetate is checked by TLC. The Reaction mass is dumped into chilled 5-10°C phosphoric acid solution (15ml H1PO4 with 40ml water). To the reaction mass is charged 100ml of water at 5-10X. The temperature is raised to 25-30°C. The organic layer is separated. Aqueous layer is extracted with (75ml) ethyl acetate. Organic layers are combined and distilled out organic layer to give methyl(4-oxo-2-thioxo-l,3~thiazolidine-3-yl)acetate [X ; where R is Me ] as orange-red coloured oil. Yield- 12g (%Yield = 97%)
Example-5
(a) Preparation of (4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid [II]
In 100 ml three necked round bottom flask equipped with stirrer, condenser, thermometer, oil bath, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (8g, 0.038mol) is stirred with mixture of 25ml acetic acid and 20ml of 25% sulfuric acid solution at reflux temperature for 2 hours. 20ml 33% aqueous acetic acid solution is added in the reaction mass. Reflux is maintained for 21 hours. The absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acctale is checked by TLC. The reaction mass is dumped into cooled water. Aqueous layer is extracted with ethyl acetate, ethyl acetate layer is distilled out and triturated with 20ml hexane to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acelic acid [II] as yellow colored product. Yield = 4gm (%Yield - 53.7%)
(b) Preparation of (4~oxo-2-thioxo-l ,3-thiazolidin-3-yl)acetic acid [II]

In 250 ml cap. three necked round bottom flask equipped with stirrer, thermometer condenser, and oil bath , Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (28g, 0.1364mol) is stirred with 48% aqueous HBr (60ml) at reflux for 4 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate is checked with TLC. The reaction mass is dumped into chilled water. Aqueous layer is extracted with ethyl acetate and ethyl acetate layer is distilled out to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acelic acid [II] as dark red colour product. Yields 19gm (%Yield-72.8%)
(c) Preparation of (4-oxo-2~thioxo-l\3-thiazolidin-3-yl) acetic acid [II]
In 100 ml cap. three necked round bottom flask equipped with stirrer, thermometer, condenser, and oil bath, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (8g, 0.038mol) is stirred with a mixture of (32ml acetic acid and 32ml Hydrochloric acid) at reflux temperature for 40 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazo!idin-3-yl)acetate is checked by TLC. The reaction mass is dumped into ice-water. Reaction mass is extracted with ethylacetate. The organic phase is distilled out (o give oily mass which is triturated with hexane to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid [ II] as yellow solid. Yield - 3.3gm (%Yield - 44%)
(d) Preparation of (4-oxo-2-thioxo-l ,3-thiazolidin-3-yl)acetic acid [ II]
In 250 ml three necked round bottom flask equipped with stirrer, thermometer, condenser, and oil bath Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (10 gm, 0.048 mol) is stirred with 30% Aqueous Hydrochloric Acid solution(70 ml) at reflux temperature for 15 hours. Absence of methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate is checked by TLC. The reaction mass is quenched with DM Water. Aqueous layer is extracted with ethyl acetate. The organic layer is collected and distilled out it to give (4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetic acid [II] as the oily mass which is triturated with hexane to obtain yellow colour product. Yield = 7 gm
(e) Preparation of (4-oxo-2-thioxo-l ,3-thiazolidin-3-yl)acetic acid [II]

In 100 ml three necked round bottom flask equipped with thermometer, stirrer, oil bath, condenser, Methyl(4-oxo-2-thioxo-l,3-thiazolidin-3-yl)acetate (12 gm, 0.058 mol) is stirred with mixture of solution of (10 mi 85% H3PO4 and 40 ml water) to reflux temperature for 50 hours. TLC is checked for the completion o\: starting material, and reaction mass is quenched into ice water. The reaction mass is extracted with ethyl acetate, dried over sodium sulfate and distilled out ethyl acetate and applied high vacuum to get an oily mass, triturated it with hexane to give (4-oxo-2-thioxo-1,3-thiazolidin-3-yl)acetic acid [II] as yellow color product. Yield=4 gm