Claims:1) A process for production of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate, in intermediate of Garenoxacin which comprises:
a) Reacting 2,4-Dibromo-3-difluoro methoxy benzoic acid with chloroformic ester in THF at room temperature followed by addition of imidazole to obtain imidazole amide;
b) Reacting imidazole amide in-situ with Potassium mono ethyl malonate in dimethlformamide in presence of magnesium chloride and triethylamine to obtain Ethyl-2,4-dibromo-3-difluoro methoxy benzoyl acetate;
c) Generating an anion from Ethyl2,4-difluoro-3-difluoro methyl benzoyl acetate by reacting with a base followed by reacting with DMF.DMS complex to obtain Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate;
d) Reacting Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate with Cyclopropyl amine in isopropyl alcohol to obtain Ethyl 2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate;
e) Cyclising Ethyl 2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate by reacting with a base in presence of DMSO to obtain Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate.
2) The process according to claim 1, wherein, the chloroformic ester can be selected from Methyl, Ethyl, Phenyl and Benzyl chloroformate.
3) The process according to claim 1, wherein, the base used in generating anion from Ethyl2,4-difluoro-3-difluoro methyl benzoyl acetate is selected from Sodium hydride, Sodium amide, metal alcoholates like Sodium methoxide, ethoxide, isopropoxide etc.
4) The process according to claim 1, wherein, the base used in step (e) is selected from alkali metal hydroxides and alkali metal - carbonates.
5) The process according to claim 1, wherein, the addition of DMF.DMS complex is carried out at a temperature of 15 to 30°C.
6) The process according to claim 1, wherein, the addition of cyclopropylamine is carried out at a temperature of 10-20°C.
7) The process according to claim 1, wherein, the cyclization reaction is carried out at a temperature of 90-100°C.
8) The process according to claim 1, wherein, the DMF.DMS complex is prepared by a process comprising the steps of:
a) Charging dimethyl formamide at RT under Nitrogen atmosphere followed by slow heating up to 50-60°C;
b) Charging dimethyl sulphate at 50-60°C followed by heating the mass up to 70-80°C under Nitrogen under stirring for 2 hrs at 70-80°C and
c) Cooling the mass to room temperature under N2 atmosphere.
9) The process for preparation of Garenoxacin comprising;
a) Reacting Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate prepared in accordance with claim 1 with 2-[(lR)]-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lHisoindol-5-yl]-l,3,6,2-dioxazaborocane to obtain trityl Garenoxacin ester;
b) Detritylaing the ester followed by hydrolysis to obtain Garenoxacin;
c) Converting Garenoxacin into its mesylate salt.
10) The process according to claim 9, wherein, the detritylation and hydrolysis is conducted in presence of an inorganic acid.
, Description:Technical field:
This invention relates to an improved process for the synthesis of Garenoxacin, a Fluoro quinolone antibacterial agent useful in treatment of infections due to Gram +ve organisms. It is also useful in the treatment of MRSA.

Background and Prior art:
Garenoxacin differs from the other Fluoro quinolone antibacterials in that it contains carbon-carbon bond at C-7 of the quinolone ring. Garenoxacin is commercially available under the brand name: Geninax®
Garenoxacin and its synthesis was first reported in US 6025370A. The synthetic scheme adopted is shown in scheme-1.

US 6337399B1 and WO 2013121439 reports an improved process for the synthesis of Fluoro quinolone nucleus. The process uses ethyl ester of 2,4-Dibromo 3-hydroxy benzoic acid as the starting material instead of 2,4-Difluoro derivative used in the US 6025370A, as shown in scheme II below.

WO 2001066512 A1 teaches use of 3,3-Dimethylamino acrylate of formula A for the synthesis of quinoline nucleus.

WO 00/00460 discloses a safe and economical process for the synthesis of Dimethyl amino acrylate.

Der Pharma chemical 1020, 2(3):178-186 discloses a new reagent N,N-Dimethyl amino methoxy methylenium methyl sulphate which is easily prepared from DMF/DMS, useful in the synthesis of Fluoro quinolones and pyrazoles and other heterocycles.

As is evident from the foregoing, there remains a need in the art to provide an efficient and robust process for the preparation of Garenoxacin by the use of cost-effective reagents without compromising on the yields and purity.

Therefore, it is an objective of the present invention to provide an efficient process for the production of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate an intermediate of Garenoxacin.

Another objective is to provide a process for preparation of Garenoxacin by reacting Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate with 2-[(lR)]-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lH-isoindol-5-yl]-l,3,6,2-dioxazaborocane under the condition that affects the production of Garenoxacin.
Summary of the invention:
In line with the above objectives, the present invention provides an efficient process for production of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate, which comprises:
a) Reacting 2,4-Dibromo-3-difluoro methoxy benzoic acid with chloroformic ester in THF at room temperature followed by addition of imidazole to obtain imidazole amide.
b) Reacting imidazole amide with Potassium mono ethyl malonate in dimethyl formamide presence of magnesium chloride and triethylamine to obtain Ethyl-2,4-dibromo-3-difluoro methoxy benzoyl acetate;
c) Generating an anion from Ethyl-2,4-difluoro-3-difluoro methyl benzoyl acetate by reacting with a base followed by reacting with DMF.DMS complex to obtain Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate;
d) Reacting Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate with Cyclopropyl amine in isopropyl alcohol to obtain Ethyl 2-(2,4-dibromo-3-difluoro methoxy benzoyl)-3-cyclopropyl amino acrylate;
e) Cyclising Ethyl-2-(2,4-dibromo-3-difluoro methoxy benzoyl)-3-cyclopropylamino acrylate by reacting with a base in presence of DMSO to obtain Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate.

In another aspect, the Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylatethus obtained can be converted into Garenoxacin by condensing the same with 2-[(lR)]-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lHisoindol-5-yl]-l,3,6,2-dioxazaborocane to obtain trityl Garenoxacin ester, with is further detritylated, hydrolysed to obtain Garenoxacin. Garenoxacin thus obtained can be converted into its mesylate salt.

Detailed description:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Accordingly, the present invention provides a process for preparation of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate, an intermediate of Garenoxacin which is simpler, easy to handle and provides higher yields at all the steps.

The present invention provides an efficient process for production of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate, which comprises:
a) Reacting 2,4-Dibromo-3-difluoro methoxy benzoic acid with chloroformic ester in THF at room temperature followed by addition of imidazole to obtain imidazole amide.
b) Reacting imidazole amide in-situ with Potassium mono ethyl malonate in dimethyl formamide presence of magnesium chloride and triethylamine to obtain Ethyl-2,4-dibromo-3-difluoro methoxy benzoyl acetate;
c) Generating an anion from Ethyl2,4-difluoro-3-difluoro methyl benzoyl acetate by reacting with a base followed by reacting with DMF.DMS complex to obtain Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate;
d) Reacting Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate with Cyclopropyl amine in isopropyl alcohol to obtain Ethyl 2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate;
e) Cyclising Ethyl 2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate by reacting with a base in presence of DMSO to obtain Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate.
In another embodiment, the Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate thus obtained can be converted into Garenoxacin by condensing the same with 2-[(lR)]-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lH-isoindol-5-yl]-l,3,6,2-dioxaza borocane to obtain trityl Garenoxacin ester, with is further detritylated, hydrolysed to obtain Garenoxacin. Garenoxacin thus obtained can be converted into its mesylate salt.

The detritylation and hydrolysis is carried out in presence of an inorganic base.

The chloroformic ester can be selected from Methyl, Ethyl, Phenyl and Benzyl chloroformate.

The base used in generating anion from Ethyl-2,4-difluoro-3-difluoro methyl benzoyl acetate is selected from Sodium hydride, Sodium amide, metal alcoholates like Sodium methoxide, ethoxide, isopropoxide etc.

The base used in step (e) is selected from alkali metal hydroxides, carbonates etc.

The process for preparation of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate according to the invention is shown in scheme III below.

The prior art process as described in WO 2013121439 involves conversion of 2,4- dibromo-3-difluoro methoxy benzoic acid to the corresponding Imidazole amide by using thionyl chloride. The use of thionyl chloride results in the formation of impurities due to which Ketoesterification was not going well. To avoid impurities and to further proceed with ketoesterification smoothly, this step needs purification.

By reacting 2,4- dibromo-3-difluoro methoxy benzoic acid with chloroformate ester to form imidazole amide via anhydride, impurities were not formed which enables in-situ & direct reaction with Potassium monoethyl malonate without any difficulty. The use of chloroformate ester made it possible to carry out multiple steps involved in the preparation of Ethyl-7- bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate without isolation of the intermediates.
Further, the present invention has made substantial improvement in the production of the intermediate, Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate which utilizes DMF.DMS complex instead of DMF di alkyl acetal, unlike in the prior art reports. The use of DMF.DMS complex enhances the yields of the product and also facilitates easy separation of the product, Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate.

The addition of DMF.DMS complex is carried out at a temperature of 15 to 30°C, preferably at 20°C.

The addition of cyclopropylamine is carried out at a temperature of 10-20°C
The cyclization reaction is carried out at a temperature of 90-100°C for 5 hrs. In another embodiment, the invention provides a process for the preparation of DMF. DMS complex which comprises:
a) Charging dimethyl formamide at RT under Nitrogen atmosphere followed by slow heating up to 50-60°C;
b) Charging dimethyl sulphate at 50-60°C followed by heating the mass up to 70-80°C under Nitrogen under stirring for 2 hrs at 70-80°C and
c) Cooling the mass to room temperature under N2 atmosphere to isolate the complex.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:
Example-1:
Preparation of 2,4-Dibromo-3-difluoromethoxy benzoic acid:
100 gm of Methyl-2,4-dibromo-3-hydroxy benzoate was dissolved in 300 ml of DMF at RT. 50 gm of Potassium carbonate was added at RT. Slowly heat to 80-850C, Chlorodifluoro methane gas was purged into the reaction. After completion of reaction, the mass was cooled and water was added to it at about 15-250C in 40-45 min. The slurry mass obtained was filtered and washed with water. The wet cake obtained was suspended in a mixture of about 10% W/V aqueous Sodium hydroxide solution and Ethanol. Stirred, Water and Toluene were added and R.M was stirred. The layers were separated; aqueous layer was washed with Toluene. The pH of the aqueous layer was adjusted to less than 2.0 with aq. HCl. The slurry mass was cooled to about 10-150C and stirred for about 1 hr. The product was filtered, washed with Water and dried.
Output: 90 gm.

Example-2:
100 gm of Methyl-2,4-dibromo-3-hydroxy benzoate was dissolved in 300 ml of ACN at RT. 50 gm of Potassium carbonate was added at RT. Slowly heat to 80-850C, Chlorodifluoro methane gas was purged into the reaction. After completion of reaction, the mass was cooled and water was added to it at about 15-250C in 40-45 min. The slurry mass obtained was filtered and washed with water. The wet cake obtained was suspended in a mixture of about 10% W/V aqueous Sodium hydroxide solution and Ethanol. Stirred, Water and Toluene were added and R.M was stirred. The layers were separated; aqueous layer was washed with Toluene. The pH of the aqueous layer was adjusted to less than 2.0 with aq. HCl. The slurry mass was cooled to about 10-150C and stirred for about 1 hr. The product was filtered, washed with Water and dried.
Output: 89 gm.

Example 3:
Preparation of Ethyl-2,4-dibromo-3-difluoro methoxy benzoyl acetate:
100 gm of 2,4- dibromo-3-difluoro methoxy benzoic acid was dissolved in 1000 ml of THF. 35 gm of Triethylamine and 31 gm of Ethyl chloro formate was added at RT. The reaction mixture was stirred at RT for 20 min meanwhile 21 gm of Imidazole was dissolved in 600 ml of THF and the solution was added to the reaction mass at RT. Stirred at RT for 24 hrs, THF was distilled under vacuum. 600 ml of DM Water and 600 ml of MDC were charged. Separated the layers. Aq. Layer was taken and given MDC extractions of 200 ml, layers were separated and combined the total organic layer and given water washings for combined organic layer, total MDC layer and dried on Sodium sulfate and distilled under vacuum.
The residue was dissolved in 800 ml MDC, cooled to 0-50C. Subsequently 42 gm of magnesium chloride, 90 gm of Triethyl amine and 152 gm of Potassium monoethyl malonate and 100 ml of DMF was added. Temperature was raised to RT, stirred at RT for 12 hrs, cooled to 00C. Added DM Water at 0-50C, pH was adjusted to 1.0 with 6 molar HCl. Layers were separated. Organic Layer was washed with saturated aq. solution, which was dried over anhydrous sodium sulfate, after which solvent is removed by distillation under reduced pressure.
Output: 112 gm.

Example 4:
100 gm of 2,4- dibromo-3-difluoro methoxy benzoic acid was dissolved in 1000 ml of THF. 35 gm of Triethylamine and 31 gm of Ethyl chloro formate was added at RT. The reaction mixture was stirred at RT for 20 min meanwhile 21 gm of Imidazole was dissolved in 600 ml of THF. Solution was added to the reaction mass at RT. Stirred at RT for 24 hrs, THF was distilled under vacuum. 600 ml of DM Water and 600 ml of MDC were charged. The layers Separated. Aq. Layer was taken and given MDC extractions of 200 ml, layers were separated and combined the total organic layer and given water washings for combined organic layer, total MDC layer and dried on Sodium sulfate and distilled under vacuum.

Crude mass was dissolved in 800 ml MDC, cooled to 0-50C. Subsequently 42 gm of magnesium chloride, 90 gm of Triethyl amine and 152 gm of Potassium monoethyl malonate and 100 ml of DMF was added. Temperature was raised to 450C, stirred at 450C for 6 hrs, cooled to 00C. Added DM Water at 0-50C, pH was adjusted to 1.0 with 6 molar HCl. Layers were separated. Organic Layer was washed with saturated aq. solution, which was dried over anhydrous sodium sulfate, after which solvent is removed by distillation under reduced pressure.
Output: 113 gm.

Example 5:
Preparation of Ethyl-2-(2,4-dibromo-3-difluoro methyl benzoyl)-3-dimethyl amino acrylate:
9.46 gm of Sodium hydride was added in 800 ml of Toluene then cooled to 15-200C. 112 gm of Ethyl-2,4-dibromo-3-difluoro methyl benzoyl acetate (as per Example 3) was added slowly in 200 ml of Toluene over a period of 1 hr. Stirred at 15-200C for 1 hr, then slowly heated to 80-850C and stirred for 1 hr. Cooled to 15-200C. 50 gm of DMF-DMS complex was added at 200C and stirred for 2 hrs at RT. Cooled to 00C, 600 ml of water was added slowly and 600 ml of Toluene. Toluene and aqueous layers were separated. Total Toluene layer was taken and washed with saturated NaCl. Organic layer was taken and distilled out under vacuum at 45-500C.
Crude: 112 gm.

Example 6:
16 gm of Sodium methoxide was added in 800 ml of Toluene then cooled to 15-200C. 112 gm of Ethyl-2,4-dibromo-3-difluoro methyl benzoyl acetate (as per Example 4) was added slowly in 200 ml of Toluene over a period of 1 hr. Stirred at 15-200C for 1 hr, then slowly heated to 80-850C and stirred for 1 hr. Cooled to 15-200C. 50 gm of DMF-DMS complex was added at 200C and stirred for 2 hrs at RT. Cooled to 00C, 600 ml of water was added slowly and 600 ml of Toluene. Toluene and aqueous layers were separated. Total Toluene layer was taken and washed with saturated NaCl. Organic layer was taken and distilled out under vacuum at 45-500C.
Crude: 112 gm.

Example 7:
Preparation of Ethyl 2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate:
112 gm of Dimethyl amino acrylate (as per Example 6) dissolved in 500 ml of Isopropyl alcohol at RT. Cooled to 5-100C. CycloPropylAmine was slowly added at 10-150C and the temperature was slowly raised to RT. Stirred for 1 hr at RT, then cooled to 00C. Maintained for 2 hrs at 00C, compound was filtered and washed with chilled Isopropyl alcohol.
Dry wt: 110 gm.
Example 8:
Preparation of Ethyl-7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxo quinoline-3-carboxylate:
100 gm of Ethyl-2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate and 34 gm of Potassium carbonate was added in 400 ml of DMSO. Reaction mixture was stirred at 90-950C for 5 hrs, cooled to 20-250C, stirred for 1 hr, filtered and was finally washed with DMSO. Wet cake was charged in 1000 ml water and heated to 60-650C, stirred for 1 hr, filtered and washed with hot water.
Dry wt: 76 gm.

Example 9:
100 gm of Ethyl-2-(2,4-dibromo-3-difluoromethoxy benzoyl)-3-cyclopropyl amino acrylate and 34 gm of Potassium carbonate was added in 400 ml of DMSO. Reaction mixture was stirred at 90-950C for 5 hrs, cooled to 20-250C, stirred for 1 hr, filtered and was finally washed with DMF. Wet cake was charged in 1000 ml water and heated to 60-650C, stirred for 1 hr, filtered and washed with hot water.
Dry wt: 75 gm.

Example 10:
Preparation of DMF-DMS complex:
50 gm of DMF charged at RT under Nitrogen atmosphere, slowly heated to 50-600C under N2 slowly. 86 gm of DMS was added at 50-600C. After complete addition heated to 70-800C under Nitrogen, stirred for 2 hrs at 70-800C, cooled to RT under N2 atmosphere.
Density: 1.26; Weight: 135.6 gm.

Example 11:
Preparation of l-cyclopropyl-8-(difluoromethoxy)-7-(lR)-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lH-isoindol-5-yl]-l,4-dihydro-4-oxo-3-quinoline carboxylic acid ethyl ester:
50 g of, 2-[(lR)]-2,3-dihydro-l-methyl-2-(triphenylmethyl)-lH-isoindol-5-yl]-l,3,6,2-dioxazaborocane. 45.4g of ethyl 7-bromo-l-cyclopropyl-8-(difluoromethoxy)-4-oxo-l ,4- dihydroquinoline-3-carboxylate, 0.85g of bis(triphenylphosphine) palladium (II) dichloride and 1.35 g of triphenylphosphine were added in 300 ml of ethyl acetate at about 25-30°C. The reaction mass was heated to about 50°C. 125ml 20% aqueous potassium carbonate solution was added in reaction mass at about 50°C and the contents were stirred. The temperature of the reaction mass was raised to about 75-80°C and stirring was continued for about 12 hrs. The reaction mass was cooled to about 20-25°C and the contents were stirred for 3 hrs. The solid obtained was filtered through hyflo bed and washed with ethyl acetate. The organic layer was washed with water. Activated carbon was added to the organic layer at about 20-25°C. The contents were filtered at about 20-25°C through hyflo bed and washed with ethyl acetate. The organic layer was concentrated at about 50-55°C. Absolute ethanol was added to the residue at about 50-55°C and distillation of the solvent was continued at about 50-55°C. The residue was cooled to about 25-30°C and the contents were stirred for about 2hrs. The product was filtered, washed with absolute ethanol at about 25-30°C and dried.
Output: 66gms.

Example 12:
Preparation of 1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid:
In 264 ml of ethanol was suspended 66.00 g of ethyl (-)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2-tritylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylate, followed by adding there to 17.16 ml of 6N hydrochloric acid, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered, after which 49.5 ml of a 5N aqueous sodium hydroxide solution was added to the filtrate and the resulting mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 16 ml of water, neutralized with 6N HCl followed by filtration. The crystals were collected by filtration to obtain 36 g of light-yellow (-)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.

Example 13:
Preparation of l-cyclopropyl-8-(difluoromethoxy)-7-(lR)-2,3-dihydro-l-methyI-2-lH-isoindol-5-yl]-l,4-dihydro-4-oxo-3-quinoline carboxylic acid methanosulfonate
36g of the compound prepared in example 12 was added to tetrahydrofuran (50 ml) under nitrogen atmosphere at about 20-25°C and the contents were stirred for about 10 min. A solution of methanesulphonic acid (about 21.2 g) in tetrahydrofuran (about 4 5 ml) at about 25-30°C was added to the reaction mass at about 20-25°C and stirring was continued for 30 min. Tetrahydrofuran (108 ml) was added to the reaction mass at about 20-25°C and stirring was continued for about 3hrs. The product was filtered at about 20-25°C. The wet cake was washed with tetrahydrofuran. The wet cake was added in ethyl acetate at about 25-30°C under nitrogen atmosphere and the contents were stirred for about 10 min. The temperature of the slurry mass was raised to reflux temperature at about 75-80°C and stirring was continued at about the reflux temperature for about 1 hrs. The slurry mass was cooled to about 50-60°C. The product was filtered, washed with ethyl acetate and dried under vacuum to obtain l-cyclopropyl-8-(difluoromethoxy)-7-[(lR)-2,3-dihydro-l-methyl-lH-isoindoI-5-yl-l,4-dihydro-4-oxo-3-quionoline carboxylic acid methanesulfonate.
Output: 36gms.

Example 14:
Purification of l-cyclopropyl-8-(difluoromethoxy)-7-[(lR)-2,3-dihydro-l-methyl-lH-isoindoI-5-yl-l, 4-dihydro-4-oxo-3-quionolinecarboxylic acid methanesulfonate:
36 g of the compound prepared in example 13 was added to methylene chloride (300 ml). Methanol (72 m l) was added and the contents were stirred at about 25-30°C. The temperature of reaction mass was raised to about 35-40°C followed by addition of activated charcoal and stirring was continued for about 60 min. The reaction mass was cooled to 'about 30-35°C, filtered and the residue was washed with a mixture of methylene chloride and methanol (8:2 mixture) at about 25-30°C. The solvent was distilled out, methanol was added and the reaction mass was heated to about 60-65°C and stirring was continued for about 10 min. Solvent was distilled under reduced pressure at about 50-55°C. Ethyl acetate was added to reaction mass and temperature was raised to about 65-75°C. The solvent was distilled under atmospheric pressure at about 65-75°C. The reaction mass was cooled to about 55-60°C. The product was filtered at about 55-60°C and the wet cake was washed with ethyl acetate. The product was further recrystallized from ethyl acetate. The wet material was dried under vacuum.
Output: 30gms; Purity: 99.7%.