FIELD OF THE INVENTION
The present invention relates to an improved, environment friendly and industrially viable process for the preparation of substituted benzopyran imidazolidine diones preferably optically active 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2,5'-diones represented by formula-I, or their pharmaceutically acceptable salts, derivatives, intermediates, esters, amides, solvates, hydrates, analogues, enantiomers, or mixtures thereof. The improved process according to the present invention preferably leads to the formation of substantially pure enantiomers preferably the "S" enantiomers of 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2,5-diones represented by formula-I:
(Formula Removed)
Formula -1
Wherein:
RI denotes a halogen, an alkyl or an alkoxy, and
R2 denotes carboxy, alkoxy carbonyl or an amide.
More preferably the novel process of the present invention is useful for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5"-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide also known as fidarestat having a structure as shown in formula-II:
(Formula Removed)
Formula - II
BACKGROUND OF THE INVENTION
(2S,4S)-6-Fluoro-2,3-dihydro-2,5"-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide also known as Fidarestat (SNK 860) is a potent aldose reductase (AR) inhibitor
useful for both preventing and treating diabetic neuropathy. Many potent AR inhibitors have been developed which can be structurally classified into two main groups, the spiro-hydantoins, such as sorbinil and fidarestat and the acetic acid compounds, such as zopolrestat, tolrestat, alrestatin, epalrestat, and zenarestat. Fidarestat has a spiro-hydantoin ring and a carbamoyl group, which shows higher activity and higher selectivity towards aldose reductase inhibition as compared to sorbinil.
The process of preparation of racemic 3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid derivatives is already disclosed in Japanese Patent Application no. 2009911986. 4-chromenone derivative is brominated to yield the 4-chromenone bromo derivative, which on further treatment with triethylamine removes hydrogen bromide and forms an intermediate. The intermediate is treated with trimethylsilylcyanide to give the cyano compound, which on further treatment with concentrated hydrochloric acid yields 3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid. The said process disclosed in the prior art is not industrially and commercially viable as it requires the use of large quantities of expensive reagent trimethylsilylcyanide.
Another process is disclosed in "J. Med. Chem" vol. 14, No. 8, and pages 758-766 (1971). According to the process disclosed in the said publication, the racemic derivative of carboxylic acid is prepared by condensation reaction of 4-chlorophenol with a-bromo-y-butylolactone to form 4-chlorophenol-lactone derivative. The ring of 4-chlorophenol-lactone derivative is opened upon oxidation with chromium trioxide to form the dicarboxylic acid derivative, which on further treatment with concentrated sulfuric acid results in ring closure, thus yielding the compound 3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid.
Leibigs Ann. Chem., pages 1552-1556 (1973), discloses the preparation of racemic derivative of 3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid by Fries rearrangement using aluminium chloride and sodium carbonate solution, thus causing ring closure. The Fries rearrangement reaction generally has a low yield of the end product from about 30% to about 52% and further, the end product obtained by such conventional process has no optical activity.
Another process for the preparation of optically active compound of 3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxyIic acid has been disclosed in Japanese Patent no. 63250373. The said patent discloses Friedel-Craft's reaction that involves the treatment of substituted anisole with maleic anhydride and aluminium chloride followed by cyclization with the base to yield racemic
3,4-dihydro-4-oxo-2H-1-benzopyran-2-carboxylic acid. The said racemic compound on further treatment with thionyl chloride and (-)-l-methylbenzylamine yields diastereomeric mixture of the amide derivative followed by fractional recrystallization to obtain (+)-amide derivative that undergoes acid hydrolysis to yield the optically active compound of formula 4-oxo-l-benzopyran-2-carboxylic acid. The said process has several drawbacks such as the requirement of a number of steps in the said process and production of hazardous waste by-products of sulphur-dioxide and aluminium hydroxide during the synthesis. Further, as per the abovesaid Japanese patent, the synthesis of compound of formula-I is disclosed wherein the process involves the reaction of compound of formula 4-oxo-l-benzopyran-2-carboxylic acid with potassium cyanide and ammonium carbonate under Bucherer-Berg's reaction conditions to yield the 3:1 mixture of cis- and trans-2-carboxylic acid which on further recrystallization with water yields the hydantoin derivative, which upon esterification followed by condensation with aqueous ammonia yields the compound of formula-I as described herein.
According to another Japanese Patent no. 193588, the compound of formula-II as described herein can be prepared by taking 4-oxo-l-benzopyran-2-carboxylic acid as starting material and thermally treating the said compound with sodium cyanide by "Bucherer's hydantoin synthesis" to form a hydantoin ring and then converting the carboxyl derivative at 2-position into an amide derivative of formula-II.
However, the major drawback associated with the processes disclosed in Japanese Patent no. 63250373 and Japanese Patent no. 193588 is the release of hydrogen cyanide gas upon isolation of imidazolidine compound, which is undesirable and not a commercially viable process as the gas that is liberated is highly poisonous.
Another Japanese Publication no. 2001302670 discloses a method by which an imidazolidine compound can be synthesized by adding hydrochloric acid to the reaction mixture of compound of 4-oxo-1-benzopyran-2-carboxylic acid with ammonium carbonate and potassium cyanide and then heating the reaction mixture to 85°C-105°C to decompose the cyanide present in the reaction solution as an impurity. This subsequently results in the evolution of hydrogen cyanide gas which is hazardous in nature.
Hence, based on the discussion provided pertaining to the various prior arts available for preparation of substituted benzopyran imidazolidine diones preferably 2-substituted-6-
substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2,5'-diones, particularly fidarestat, it can be clearly implied that there still exists an unmet need for developing an efficient, safe and commercially viable process for the synthesis of fidarestat. The present invention overcomes such drawbacks of the prior art by providing an improved, efficient, safe and commercially viable process, which avoids the use of potentially hazardous chemicals and also avoids the release of hazardous gases such as the hydrogen cyanide gas.
SUMMARY OF THE INVENTION
It is an objective of the present invention to provide an improved, environment friendly and industrially viable process for the preparation of substituted benzopyran imidazolidine diones preferably 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2\5'-diones represented by formula-I as described herein, or their pharmaceutically acceptable salts, derivatives, intermediates, esters, amides, solvates, hydrates, analogues, enantiomers, or mixtures thereof.
It is also an objective of the present invention to provide a process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2',5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide represented by formula-II as described herein or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof,
(Formula Removed)
Formula - II
wherein the process comprises the following steps:
(Formula Removed)
Formula-Ill
i) Reacting 4-haIophenol of formula-Ill taken as starting material with maleic acid under acidic conditions to obtain compound of formula-(±)-IV,
Wherein X is a halogen atom.
(Formula Removed)
Formula-(±)-IV
ii) Condensation of compound of formula-(±)-lV with (S)-(-)-l-phenyl alkylamine in the presence of coupling agent and a catalyst to obtain a diastereomeric mixture,
iii) Crystallization of the diastereomeric mixture in aliphatic alcohol(s) to give 2S isomer of formula-V followed by hydrolysis under acidic conditions to give compound of formula-(Formula Removed) Formula-V
(Formula Removed)
Formula-(+)-IV
iv) Diasteroselective hydantoination of compound of formula-(+)-IV in the presence of metal cyanide, ammonium carbonate and suitable solvent to obtain compound of formula-VI followed by removal of excess of unreacted metal cyanide by reacting with α-substituted aromatic aldehyde, (Formula Removed)

Formula-VI
v) Optionally, condensation of compound of formula-VI to obtain the ester derivative of formula-VII, and
(Formula Removed)
Formula-VII
Wherein R3 denotes lower alkyl.
vi) Treating the compound of formula-VI of step (iv) as described herein or the compound of formula-VII of step (v) as described herein to obtain the desired product of formula-II as described herein.
(Formula Removed)

Formula-II

It is also an objective of the present invention to provide an improved process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4"-imidazolidine]-2-carboxamide or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof represented by formula-II as described herein comprising the following steps: (i) Reacting 4-halophenol of formula-Ill taken as starting material with maleic acid under
acidic conditions to obtain compound of formula-(±)-IV as described herein, (ii) Condensation of compound of formula-(±)-lV with (S)-(-)-l-phenyl alkylamine in the
presence of coupling agent and a catalyst to obtain a diastereomeric mixture, (iii) Crystallization of the diastereomeric mixture in aliphatic alcohol(s) to give 2S isomer of
formula-V as described herein followed by hydrolysis under acidic conditions to give
compound of formula-(+)-IV as described herein, (iv) Diasteroselective hydantoination of compound of formula-(+)-IV in the presence of metal
cyanide, ammonium carbonate and suitable solvent to obtain compound of formula-VI as
described herein followed by removal of excess of unreacted metal cyanide by reacting
with a-substituted aromatic aldehyde,
(v) Condensation of compound of formula-VI with lower alcohol(s) using acid or base as a catalyst to obtain the ester derivative of formula-VII as described herein, and
(vi) Treatment of the ester derivative of formula-VII with ammonia gas in the presence of suitable solvent to obtain the desired compound of formula-II as described herein.
It is also an objective of the present invention to provide an improved process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2\5'-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof represented by formula-II as described herein comprising the following steps: i) Reacting 4-halophenol of formula-Ill as described herein taken as starting material with maleic
acid under acidic conditions to obtain compound of formula-(±)-IV as described herein, ii) Condensation of compound of formula-(±)-IV as described herein with (S)-(-)-l-phenyl
alkylamine in the presence of coupling agent and a catalyst to obtain a diastereomeric mixture, iii) Crystallization of the diastereomeric mixture in aliphatic alcohol(s) to give 2S isomer of
formula-V as described herein followed by hydrolysis under acidic conditions to give
compound of formula-(+)-IV as described herein, iv) Diasteroselective hydantoination of compound of formula-(+)-IV as described herein in the
presence of metal cyanide, ammonium carbonate and suitable solvent to obtain compound
of formula-VI followed by removal of excess of unreacted metal cyanide by reacting with
a-substituted aromatic aldehyde as described herein, and v) Treating the compound of formula-VI as described herein with aqueous ammonia in the
presence of ammonium chloride under pressure at a temperature of 120-125°C to obtain the
desired product of formula-II as described herein.
It is also an objective of the present invention to provide a process for the preparation of a substantially pure enantiomer preferably the "S" enantiomer of 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2,5'-diones.
The improved process of the present invention provides an improved, efficient, safe, environment friendly and commercially viable process for the preparation of substituted benzopyran imidazolidine diones preferably 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4-imidazolidine]-2,5'-diones, which avoids the use of potentially hazardous chemicals and also avoids the release of hazardous gases during the manufacturing process.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides an improved, environment friendly and industrially viable process for the preparation of substituted benzopyran imidazolidine diones. Preferably the present invention provides an improved process for the preparation of 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2',5'-diones represented by formula-I as described herein, or their pharmaceutically acceptable salts, derivatives, intermediates, esters, amides, solvates, hydrates, analogues, enantiomers, or mixtures thereof.
In an embodiment of the present invention is provided an improved process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2\5'-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof represented by formula-II as described herein comprising the following steps: i) Reacting 4-halophenol of formula-Ill as described herein taken as starting material with maleic
acid under acidic conditions to obtain compound of formula-(±)-IV as described herein, ii) Condensation of compound of formula-(±)-IV with (S)-(-)-l-phenyl alkylamine in the presence
of coupling agent and a basic catalyst to obtain a diastereomeric mixture, iii) Crystallization preferably single, of the diastereomeric mixture in aliphatic alcohol(s) to give 2S
isomer of formula-V as described herein followed by hydrolysis under acidic conditions to give
compound of formula-(+)-IV as described herein, iv) Diasteroselective hydantoination of compound of formula-(+)-IV in the presence of metal
cyanide, ammonium carbonate and suitable solvent to obtain compound of formula-VI as
described herein followed by removal of excess of unreacted metal cyanide by reacting with ot-
substituted aromatic aldehyde, v) Optionally, condensation of compound of formula-VI to obtain the ester derivative of formula-
VII as described herein, and vi) Treating compound of formula-VI of step (iv) as described herein or the compound of formula-
VII of step (v) as described herein to obtain the desired product of formula-II as described herein.
In a preferred embodiment of the present invention is provided an improved process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof represented by formula-II as described herein wherein the process step (v) as described herein above comprises
condensation of compound of formula-VI with lower alcohol(s) using acid or base as a catalyst to obtain the ester derivative of formula-VII as described herein followed by treatment of the ester derivative of formula-VII with ammonia gas in the presence of suitable solvent to obtain the desired compound of formula-II as described herein.
In another preferred embodiment of the present invention is provided an improved process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2',5-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof represented by formula-II as described herein wherein the compound of formula-VI obtained in the process step (iv) as described herein above is treated with aqueous ammonia in the presence of ammonium chloride under pressure at a temperature of 120-125°C to obtain the desired product of formula-II as described herein.
In an embodiment, the present invention provides a process for the preparation of a substantially pure enantiomer preferably the "S" enantiomer of 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2',5-dione.
In a preferred embodiment, the present invention provides an improved, efficient, safe, environment friendly and commercially viable process for the preparation of substituted benzopyran imidazolidine diones preferably 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2\5'-diones, which avoids the use of potentially hazardous chemicals and also avoids the release of hazardous gases during the manufacturing process.
The schemes showing the process of preparation of the compound of formula-II are presented as Figures 1 and 2. In an embodiment of the present invention, in the step for the preparation of compound of formula-VI from compound of formula-(+) IV as stated in Figures 1 and 2, the excess of unreacted metal cyanide in the preparation of compound of formula-VI is consumed by treating with a-substituted aromatic aldehyde to yield aminonitrile thus avoiding the release of the poisonous hydrogen cyanide gas upon acidification during the isolation of compound of formula-VI. An illustration of the same is provided below.
(Formula Removed)
Further, the aminonitrile thus obtained can be used commercially as an intermediate for the synthesis of α-amino acids.
According to an embodiment of the present invention, the starting material used in the present process for the preparation of compound of formula-II is a 4-halophenol, preferably 4-flourophenol.
In another embodiment, the catalyst used in the present invention is an acid or base, or mixtures thereof. The acid catalyst used in the process is preferably a sulphonic acid derivative selected from but not limited to a group comprising methane sulphonic acid, ethane sulphonic acid, p-toluene sulphonic acid and the like or mixtures thereof. The basic catalyst used in the present invention is selected from but not limited to a group comprising 4-dimethyl amino pyridine, pyridine and the like or mixtures thereof.
In a further embodiment of the present invention, the present process comprises the use of acid selected from but not limited to a group comprising hydrochloric acid, sulphuric acid and the like or mixtures thereof.
In a still further embodiment of the present invention, the solvent used in the process is selected from but not limited to a group comprising ethanol, methanol, n-propyl alcohol, tetrahydrofuran, dioxane and the like or mixtures thereof; water immiscible solvent selected from but not limited to a group comprising toluene, ethylacetate and the like or mixtures thereof; and lower aliphatic hydrogenated alkanes such as dichloromethane and the like or mixtures thereof.
In a further embodiment of the present invention, the coupling agent used in the process of synthesis is selected from but not limited to a group comprising cycloalkylcarbodiimides e.g. N,N'-dicyclohexylcarbodimide or l-ethyl-3,3-(dimethylamino)propylcarbodimide and the like or mixtures thereof. In a preferred embodiment, the coupling agent useful according to the process of the present invention is N,N"-dicyclohexylcarbodimide (DCC).
In an embodiment of the present invention, the metal cyanide used in the process is selected from but not limited to a group comprising sodium cyanide, potassium cyanide and the like, or mixtures thereof. In a preferred embodiment, the metal cyanide used is sodium cyanide.

In a further embodiment of the present invention, the α-substituted aromatic aldehyde is selected from but not limited to a group comprising benzaldehyde, anisaldehyde and the like, or mixtures thereof.
The examples of process of preparation of the compound of formula-II provided herein serves to illustrate embodiments of the present invention. However, they do not intend to limit the scope of invention in any manner whatsoever.
Example-1:
i) Preparation of (±)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid [Formula-(±)IV]:
1.0 g of 4-fluorophenol was treated with 2.07 g of maleic acid and 50 ml of methanesulfonic acid. The mixture was heated to 90°C for 20 hours. The mixture was cooled to obtain a precipitate, which was then washed with water and filtered to obtain (±)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid as a brown solid (1.125g, 60%). IR (KBr, cm-1): 1752, 1654 'HNMR (DMSO-d6): δ 2.96 (1H, dd), 3.09 (1H, dd), 5.33 (1H, dd), 7.1-7.5 (3H, m)
ii) Preparation of (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l-
benzopyran-2-carboxamide [Formula-VJ:
2.0 g (9.5 mmol) of (±)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid was dissolved in 30 ml of ethyl acetate to form a solution. 2.55 g (12.3 mmol) of N,N'-dicyclohexylcarbodimide (DCC) was added to the above solution at room temperature in the presence of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. 1.15 g (9.4 mmol) of (S)-(-)-l phenyl ethylamine in 10 ml of ethyl acetate and 1.16 g (9.5 mmol) of 4-dimethyl aminopyridine (DMAP) was added to the reaction mixture. The resulting solution was stirred for 20 hours at room temperature. The solution was filtered and solid obtained was washed with ethyl acetate. The ethyl acetate layer was washed with 20 ml of water and dried over sodium sulfate. The solvent was removed under reduced pressure to give a diasteromeric crystalline mixture, which on single crystallization in ethanol, gave (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l-benzopyran-2-carboxamide (1.19g, 40%). IR(KBr,cm-'): 1694, 1654
1HNMR (DMSO-d6): δ 1.41 (3H, d), 3.02 (2H, d), 4.95 (1H, m), 5.2 (1H, t), 7.2-7.5 (8H, m), 8.7 (2H, d)
iii) Preparation of (2S)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid [Formula-(+) IV]:
127.0 g (410 mmol) of (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l benzopyran-2-carboxamide in 600 ml of concentrated hydrochloric acid (HC1) and 800 ml of 1,4-dioxane was refluxed for 2 hours with stirring. After cooling, the reaction mixture was extracted twice with dichloromethane. The combined organic layer was dried and evaporated in vacuo to produce (2S)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid (72.9 g, 85.5%). IR(KBr, cm'1): 1752, 1654 1HNMR (DMSO-d6): δ 2.96 (1H, dd), 3.09 (1H, dd), 5.33 (1H, dd), 7.1-7.5 (3H, m)
iv) Preparation of (2S-4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxylic acid [Formula-VI]:
32.6 g (670 mmol) of sodium cyanide, 191.0 g (2.0 mmol) of ammonium carbonate and 70 g (330 mmol) of (2S)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid were mixed and stirred at 65-70°C for 24 hours and then at 90°C for 1 hour. After heating, the reaction mixture was brought to room temperature. 140.0 g (1320.0 mmol) of benzaldehyde dissolved in 250 ml of dichloromethane was added to the reaction mixture. The reaction mixture was stirred vigorously for 12 hours at room temperature and analyzed for cyanide contents (<3ppm). The two layers were separated and aqueous layer was extracted with dichloromethane. The aqueous layer was further acidified with concentrated HC1 to pH 1.0 to form crystals. The crystals were filtered to give a diasteromeric mixture which was further crystallized using water to yield (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4"-imidazolidine]-2-carboxylic acid (57.9 g, 62.7%). IR (KBr, cm'1): 3338, 1790, 1733, 1714
1HNMR (DMSO-d6):δ 2.08 (1H, dd), 2.49 (1H, dd), 5.17 (lh, dd), 6.9-7.1 (3H, m), 8.39 (1H. s), 11.05(1H, s)
v) Preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxylic acid n-propyl ester [Formula-VII]:
5.0 g (18.0 mmol) of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxylic acid was dissolved in 0.125 ml (2.4 mmol) of concentrated sulphuric acid, 5.0 ml of toluene and 20 ml of n-propyl alcohol. The mixture was refluxed in Dean and Stark trap apparatus for 5 hours with continuous stirring. The residue was recovered under vacuum and 50 ml of water was added to the residue and stirred for 15 minutes followed by filtration to obtain a precipitate. The precipitate was washed with excess of water to remove the acid to give (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4"-imidazolidine]-2-carboxylic acid n-propyl ester (5.60 g, 97.1%).
IR(KBr, cm'1): 3342, 3268, 1790, 1716, 1749
1HNMR (DMSO-d6): δ 0.8S (3H, t), 1.6 (2H, m), 2.11 (1H, dd), 2.57 (1H, dd), 4.08 (2H, m), 5.2 (1H, dd), 6.9-7.1 (3H, m), 8.4 (1H, s), 11.07 (1H, s)
vi) Preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4"-imidazolidine]-2-carboxamide [Formula-II]:
1.0 g (3.11 mmol) of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxylic acid n-Propyl ester was dissolved in 5.0 ml of methanol and excess of dry ammonia gas was introduced at conditions below 24°C. The reaction mixture was stirred for 4 hours at 20-24°C and then evaporated in vacuo to leave a residue. 10 ml of water was added to the residue and stirred for about 1 hour. After stirring for about 1 hour, the aqueous solution was acidified with 6N HC1 to form crystals. The crystals were filtered and recrystallized from methanol to produce (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4-imidazolidine]-2-carboxamide (800 mg, 92.2%). IR (cm'1): 3507, 3391, 1779, 1726, 1683
1HNMR(DMSO-d6): δ 2.09 (dd,lH), 2.54 (dd,lH), 5.17 (dd,lH), 6.91-6.97 (m,3H), 7.30 (A, 1H), 7.42 (A, 1H), 8.25 (A, 1H), 10.8 (A, 1H)
Example-2:
i) Preparation of (±)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid [Formula-(±)IV]:
1 .0g of 4-fluorophenol was treated with 2.07 g of maleic acid and 50 ml of ethanesulfonic acid. The mixture was heated from 90°C-95°C for 20 hours. The mixture was cooled to obtain a precipitate, which was then washed with water and filtered to obtain (±)-6-
Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid as a brown solid (1.068 g,
57%).
lR(KBr, cm-1): 1752, 1654
1HNMR (DMSO-d6): δ 2.96 (1H, dd), 3.09 (1H, dd), 5.33 (1H, dd), 7.1-7.5 (3H, m)
ii) Preparation of (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l-
benzopyran-2-carboxamide [Formula-V]:
2.0g (9.5 mmol) of (±)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid was dissolved in 30 ml of ethyl acetate to form a solution. 2.55 g (12.3 mmol) of N,N"-dicyclohexylcarbodimide (DCC) was added in the above solution at room temperature in the presence of nitrogen. The reaction mixture was stirred at room temperature for 30 minutes. 1.15 g (9.4 mmol) of (S)-(-)-l phenyl ethylamine in 10 ml of ethyl acetate and 1.16 g (9.5 mmol) of 4-dimethyl aminopyridine (DMAP) was added to the reaction mixture. The resulting solution was stirred for 20 hours at room temperature. The solution was filtered and solid obtained was washed with ethyl acetate. The ethyl acetate layer was washed with 20 ml of water and dried over sodium sulfate. The solvent was removed under reduced pressure to give a diasteromeric crystalline mixture which on single crystallization in ethanol gave (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l-benzopyran-2-carboxamide (1.19g, 40%). IR (KBr, cm-1): 1694, 1654
1HNMR (DMSO-d6): δ 1.41 (3H, d), 3.02 (2H, d), 4.95 (1H, m), 5.2 (1H, t), 7.2-7.5 (8H, m), 8.7 (2H, d)
iii) Preparation of (2S)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid [Formula-(+)IV]:
127.0 g (410 mmol) of (2S)-6-Fluoro-3,4-dihydro-4-oxo-N-((S)-l-phenylethyl)-2H-l benzopyran-2-carboxamide in 600 ml of concentrated hydrochloric acid (HC1) and 800 ml of tetrahydrofuran was refluxed for 2 hours with stirring. After cooling, the reaction mixture was made to saturate with NaCl and then the two layers namely the aqueous and organic layers were separated. The aqueous layer was extracted with tetrahydrofuran and the organic layer was combined. The combined organic layer was dried and evaporated in vacuo to give (2S)-6-Fluoro-3,4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid (72.9 g, 85.5%). IR(KBr, cm-1): 1752, 1654
1HNMR (DMSO-d6): 5 2.96 (IH, dd), 3.09 (1H, dd), 5.33 (1H, dd), 7.1-7.5 (3H, m)
iv) Preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4"-imidazolidine]-2-carboxylic acid [Formula-VI]:
32.6 g (670 mmol) of sodium cyanide, 191.0 g (2.0 mmol) of ammonium carbonate and 70.0 g (330 mmol) of (2S)-6-Fluoro-3, 4-dihydro-4-oxo-2H-l-benzopyran-2-carboxylic acid was mixed and stirred at 65-70°C for 24 hours and then at 90°C for 1 hour. After heating the reaction mixture was brought to room temperature. 140.0 g (1320.0 mmol) of benzaldehyde dissolved in 250 ml of dichloromethane was added to the reaction mixture. The reaction mixture was stirred vigorously for 12 hours at room temperature and analyzed for cyanide contents (<3ppm). The two layers were separated and aqueous layer was extracted with dichloromethane. The aqueous layer was further acidified with concentrated HCI to pH 1.0 to form crystals. The crystals were filtered to give a diasteromeric mixture which was further crystallized with water to give (2S,4S)-6-Fluoro-2,3-dihydro-2,5"-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxylic acid (57.9 g, 62.7%). IR (KBr, cm'1): 3338, 1790, 1733, 1714
1HNMR (DMSO-d6):δ 2.08 (1H, dd), 2.49 (1H, dd), 5.17 (1h, dd), 6.9-7.1 (3H, m), 8.39 (1H, s), 11.05 (lH,s)
v) Preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2,5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide [Formula-11]:
1.0 g (3.57 mmol) of (2S,4S)-6-Fluoro-2,3-dihydro-2\5>-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxylic acid was dissolved in 10 ml of aqueous ammonia and 3.4 g (63.53 mmol) of ammonium chloride. The mixture was heated to 120-125°C under pressure for 6 hours. After heating, the reaction mixture was cooled to room temperature and aqueous solution was acidified with 6N HCl to form crystals. The crystals were filtered and recrystallized from methanol to yield (2S,4S)-6-Fluoro-2,3-dihydro-2\5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide (850 mg, 85%). IR (cm-1): 3507, 3391, 1779, 1726, 1683
1HNMR(DMSO-d6): δ 2.09 (1H, dd), 2.54 (1H, dd), 5.17 (1H, dd), 6.91-6.97 (3H, m), 7.30 (1H, ∆), 7.42 (1H, ∆), 8.25 (1H, ∆), 10.8 (1H, ∆)

We claim:
A process for the preparation of (2S,4S)-6-FIuoro-2,3-dihydro-2',5'-dioxospiro-[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide represented by formula-II as described herein or its pharmaceutically acceptable salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures thereof,

(Formula Removed)
Formula - II
Wherein the process comprises the following steps:
i) Reacting 4-halophenol of formula-Ill taken as starting material with maleic acid under acidic conditions to obtain compound of formula-(±)-IV,

(Formula Removed)

Formula-Ill
Wherein X is a halogen atom
(Formula Removed)
Formula-(±)-IV
ii) Condensation of compound of formula-(±)-IV with (S)-(-)-l-phenyl alkylamine in the presence of coupling agent and a catalyst to obtain a diastereomeric mixture,
iii) Crystallization of the diastereomeric mixture in aliphatic alcohol(s) to give 2S isomer of formula-V followed by hydrolysis under acidic conditions to give compound of formula-(+)-IV,
(Formula Removed)

Formula-V

(Formula Removed)
Formula-(+)-IV
iv) Diasteroselective hydantoination of compound of formula-(+)-IV in the presence of metal cyanide, ammonium carbonate and suitable solvent to obtain compound of formula-Vl followed by removal of excess of unreacted metal cyanide by reacting with a-substituted aromatic aldehyde,
(Formula Removed)
Formula-VI
v) Optionally, condensation of compound of formula-VI to obtain the ester derivative of formula-VII, and
(Formula Removed)
Formula-VII
Wherein Rj denotes lower alkyl.
vi) Treating the compound of formula-VI of step (iv) as described herein or the
compound of formula-VII of step (v) as described herein to obtain the desired product
of formula-Il as described herein.
(Formula Removed)
Formula-II
2. A process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2',5'-dioxospiro-[4H-l-
benzopyran-4,4"-imidazolidine]-2-carboxamide according to claim 1 represented by
formula-II as described herein wherein the process step (v) of claim 1 comprises
condensation of compound of formula-VI with lower alcohol(s) using acid or base as a
catalyst to obtain the ester derivative of formula-VII as described herein followed by
treatment of the ester derivative of formula-VII with ammonia gas in the presence of
suitable solvent to obtain the desired compound of formula-II as described herein.
3. A process for the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2\5'-dioxospiro-[4H-l-
benzopyran-4,4-imidazolidine]-2-carboxamide according to claim 1 represented by
formula-II as described herein wherein the compound of formula-VI as described herein
obtained in the process step (iv) of claim 1 is treated with aqueous ammonia in the
presence of ammonium chloride under pressure at a temperature of 120-125°C to obtain
the desired product of formula-II as described herein.
4. A process according to claims 1 to 3, wherein the 4-halophenol is 4-fluorophenol.
5. A process according to claims 1 to 3, wherein the coupling agent used in the process is
selected from a group comprising cycloalkylcarbodiimides or mixtures thereof.
6. A process according to claims 1 to 3, wherein the solvent is selected from a group
comprising ethanol, methanol, n-propyl alcohol, tetrahydrofuran, dioxane or mixtures
thereof; water immiscible solvent and lower aliphatic hydrogenated alkanes.
7. A process according to claims 1 to 3, wherein the metal cyanide used in the process is
selected from a group comprising sodium cyanide, potassium cyanide or mixtures
thereof.
8. A process according to claims 1 to 3, wherein the a-substituted aromatic aldehyde is
selected from a group comprising benzaldehyde, anisaldehyde or mixtures thereof.
9. A process according to any of the preceding claims, wherein the process enables the
formation of 2-substituted-6-substituted-2,3-dihydrospiro-[4H-l-benzopyran-4,4-
imidazolidine]-2,5'-diones as herein described substantially as pure "S" enantiomer.
10. An improved process for the preparation of 2-substituted-6-substituted-2,3-dihydrospiro-
[4H-l-benzopyran-4,4'-imidazolidine]-2',5'-diones represented by formula-I as
described herein or the preparation of (2S,4S)-6-Fluoro-2,3-dihydro-2',5'-dioxospiro-
[4H-l-benzopyran-4,4'-imidazolidine]-2-carboxamide or its pharmaceutically acceptable
salts, derivatives, intermediates, solvates, hydrates, analogues, enantiomers, or mixtures
thereof represented by formula-II as described herein by examples and illustrations.