Title of Invention

AN IMPROVED PROCESS FOR THE PREPARATION OF LEVOFLOXACIN

Abstract Present invention discloses an improved process for the preparation of levofloxacin of formula (I) which comprises reacting 2,4-dichloro-5-fluoro-3-n2troben2oic acid with thionyl chloride followed by methyl 3-dimethylaminoacrylate to get the acrylate derivative of formula (XXIV). Reacting the compound of formula (XXIV) with 1-alaninol gave the alanine derivative of formula (XXV), treating the alanine derivative with a base gave the quinolone derivative of formula (XXVI) which on reaction with N-methy piperazine gives the corresponding piperazine derivative of formula (XXVII). Cyclization of the piperazine derivative of formula (XXVII) with a base gave the methyl ester of levofloxacin (XXVII) which upon hydrolysis gave levofloxacin.
Full Text FIELD OF INVENTION
The present invention relates to an improved process for the preparation of levofloxacin. Levofloxacin is ((-)-9-fluoro-2,3-dihydro-S-methyl-10-(4-methyI-1-piperizinyl)-7"0X0" 7H-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acid) having the formula-I given below.

Levofloxacin is a broad-spectrum fluorinated quinolone antibacterial. Levofloxacin has been in the market for quite some time.
BACKGROUND OF INVENTION
Ofloxacin, a racemic mixture of levofloxacin was first disclosed by I. Hayakawa and Y. Tanaka, Daiichi Seiyanku Co. ltd., in US Patent No. 4,382,892, 1983. Subsequently, synthesis and activity of optical isomers of ofloxacin was studied by S. Atarashi, et al in Chem. Pharm. Bull. 1986,34,4098. Series of articles on pharmacology and toxicology of levofloxacin are discussed in Arzneimittel-Forsch. 1992,42, 368-418.
Levofloxacin is 8 to 128 times more active than ofloxacin depending upon the bacteria tested, J. Med. Chem. 1987, 30, 2283-2286, Drugs of the Future 1992, 17(7), 559-563, Antimicrob. Agents Chemother, 1989,32,1336-1340.
A process for the preparation of levofloxacin is described in US Pat, No. 4,672,831; 4,859,773; 4,958,045; and DE 3522406A1 which is shown in Scheme-I. Basic raw material used in this process is 2,3,4,5-tetraflurobenzoic acid of the formula (II). The reaction sequence is shrove in the Scheme I.


In this process, 2,354,5-tetraflurobenzoic acid is reacted with thionyl chloride followed by ethyl magnesium malonate to get the keto ester of formula (III). Reaction of keto ester of formula (III) with triethyl orthoformate and acetic anhydride gave the enol ether of formula (IV) which upon reaction with 1-alaninol gave the enamino derivative of formula (V). Cyclization of the enamino compound of formula (V) in the presence of base gave the compound of formula (VI) which upon hydrolysis gave the compound of formula (VII). Condensation of compound of formula (VII) with N-methylpiperazine gave levofloxacin of formula (I).
Another route for the preparation of levofloxacin is described in Chem. Pharm. Bull., 1986, 34(10), 4098-4102 starting from keto-ester of the formula (III) which is shown in Scheme 11.


According to the process disclosed involves reacting keto-ester of the formula (III) with N-methylpiperizine to get the compound of the forcible (VIII). Condensation of the compound of the formula-VIII vest N,N-dimethylfomiamide dimethylacetal gave the enamino derivative of the formula (IX). Replacement of dimethylamino group present in compound of the formula (IX) with 1-alaninol gave the enamino derivative of the formula (X). Cyclization under basic conditions gave the quinolone derivative of the formula (XI). Hydrolysis of the compound of the formula (XI) gave levofloxacin of the formula
(I).
Main disadvantage in this process is the formation of ortho-piperazinyl impurity during coupling of keto-ester of the formula (VIII) with N-methylpiperazine. Removal of this impurity requires column chromatography which is not only difficult but also expensive which makes the process not suitable for commercial viability.

A process for the preparation of levofloxacin is also described in Heterocycles, 1997, 45, 137 which is shown in Scheme III.

According to the process given in this reference, S-alaninol of the formula (XII) is reacted with ethyl propiolate of the formula (XIII) to get the enamino derivative of the formula (XIV) after protection of the hydroxy group as acetate. Coupling of this intermediate with the benzoyl chloride of the formula (XV) gave the a-benzoyl-p-enaminoacrylate ester of the formula (XVI). Treatment of the compound of the formula (XVI) with a strong base followed by hydrolysis gave the quinolonic acid intermediate of formula-XVII. Condensation of this acid with N-methylpiperizine gave levofloxacin of the formula (I).
Main drawback in this process is non-availability of ethyl propiolate on commercial scale. Also, this cowpox is not stable under normal conditions of storage. Another compound, 2,3,4,5-tetrafluorobenzoic acid used in the process is very expensive. Therefore the process is not economically viable.

Recently a process for the preparation of levofloxacin is disclosed in US pat 6316618 Bl employing low priced starting materials (Scheme IV). According to the process disclosed in this patent ethyl 2-(2,3-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propyl-amino)acrylate of formula (XVIII) is protected at hydroxy position and cyclized to get the quinolone derivative of formula (XIX). Quinolone derivative of formula (XIX) is reacted with N-methylpiperazine and deprotected the hydroxyl protecting group to get the compound of formula (XX). Hydrolysis of the ester group followed by cyclization with a base gave levofloxacin of formula (I).

Scheme IV In this patent, preparation and yield of the starting compound of formula (XVIII) is not mentioned. Also, number of steps is more as protection and deprotection of hydroxy

group is involved. This makes the process not economically viable. Overall yield of levofloxacin is only 32-38% from starting compound of formula (XVIII).
Keeping in view of the difficulties in commercialization of the above mentioned known processes and cost constraints, we initiated R & D for developing a simple and cheap and at the same time economically and commercially viable process for the preparation of levofloxacin of the formula (I).
One of the major drawbacks in all the above-mentioned prior art processes is the requirement of the use of poly-fluorinated benzene derivatives. In general, fluorinated benzene compounds are very expensive and not readily and easily available.
Accordingly, the main objective of the present invention is to provide an improved process for the preparation of levofloxacin of the formula (I) which is commercially viable, simple, and also economical.
Another objective of the present invention is to provide an improved process for the preparation of levofloxacin of the formula (I) which will not require rare, noncommercial or expensive raw materials.
Still another objective of the present invention is to provide an improved process for the preparation of levofloxacin of the formula (I) which does not require the use of poly-fluorinated benzene derivatives.
During our sustained research work for the development of processes for the preparation of levofloxacin, we observed that the protection of hydroxy group as disclosed in US pat 6316618 Bl (see Scheme IV) is not necessary while building the quinolone ring system and also during the piperazine condensation. Accordingly, compound of formula (XVIII) is reacted with a strong base to get the quinolone ring system of levofloxacin. This modification lead to further implications of the process disclosed in Us pat 6316618 Bl and the yield improved by more than 20%.

While developing a process for the preparation of levofloxacin of the formula (I) based on the above observation we also established a process for the preparation of intermediate of formula (XVIII). Accordingly, we utilized 254-dichloro-5-fluoro-3-nitrobenzoic acid as the starting material, as it is a cheap and readily available compound to carry out the above reaction.
The above mentioned approach was successful to achieve the objectives mentioned above. This observation helped to develop a cost-effective and simple process for the preparation of levofloxacin of the formula (I) which can be easily and conveniently adapted for its application on a commercial scale.
The process for the preparation of levofloxacin of the formula (I) according to the present invention is shown in Scheme V.


Accordingly, the present invention provides an improved process for the preparation of levofloxacin of formula-I,

which comprises:
(i) Reacting 254-dichloro-5-fluoro-3-nitrobenzoyl chloride with methyl 3-dimethylaminoacrylate in the presence of a base in a solvent system at a temperature in the range of 50-120 °C to get the compound of the formula (XXIV),

(ii) Reacting the compound of the formula (XXIV) with 1-alaninol in a solvent system at a temperature in the range of 0-40 °C to get the compound of the formula (XXV)

(iii) Reacting the resulting compound of the formula (XXV) with a base in a solvent at a temperature in the range of-10 to 60 °C to get the cyclized compound of the formula (XXVI),


(iv) Reacting the resulting compound of the formula (XXVI) with N-methylpiperazine in the presence or absence of a base and in a solvent medium at a temperature in the range of 20-100 °C to get the compound of the formula (XXVII),

(v) Reacting the resulting compound of the formula (XXVII) with a base in a non-polar solvent system at a temperature in the range of 20-100 °C to get the cyclized compound of the formula (XXVIII),

(vi) Hydrolyzing the ester derivative of the formula (XXVIII) so formed using acid or base to get levofloxacin of the formula (I)
In the reaction of 2,4-dichloro5-fluoro-3-nitrobenzoyl chloride with methyl 3-dimethylaminoacrylate in step (i) to get the compound of formula (XXIV) the base employed may be selected from pyridine, alkyl pyridine, dialkyl amine, preferably

dialkylamine. The solvent employed may be selected from hydrocarbon solvents such as hexane, heptanes, toluene, xylene, ether solvents such as diethyl ether, isopropyl ether, tetrahydrofuran, acetonitrile, preferably toluene, acetonitrile. The preferred temperature of the reaction is 50-100 °C.
The reaction of compound of the formula (XXIV) with 1-alaninol, in step (ii), to get the compound of the formula (XXV), as a crystalline solid, in high yield (more than 90%) may be carried out in a solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane, toluene, methylene chloride, acetonitrile, THF, dioxane, ether, DMF, Preferred temperature of reaction is 20-30 ^C.
The base employed in step (iii) may be selected from the group consisting of lithium diisopropylamide, alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (l,4-dia2abicycloocatne, DBN (l,5-diazabicyclonon-5-ene, pyridine, dimethylaminopyridine, and triethylamine. The solvent, which may be employed in step (iii), may be selected from THF, toluene, heptane, DMF. Preferred temperature of the reaction is 10-40 °C.
In step (iv), the base employed may be selected from metal carbonates, metal bicarbonates, and metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, pyridine
The cyclized product of the formula (XXVI) has been isolated and characterized. Alternately the compound of the formula (XXVI) is used in situ for the next reaction (N-methylpiperazine condensation. The N-methylpiperazine condensation reaction in step (iv) may preferably be carried out in the same solvent as used in step (iii). The temperature used for the reaction may be in the range of 20-60°C, preferably 20-30°C.
The base employed in step (v) may be selected from a group consisting of metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-imdec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (1,5-diazabicyclonon-5-ene. The solvent

employed in step (v) may be selected from acetonitrile, toluene, cyclohexane, THF, DMF, DMAc and the like. Preferred temperature of the reaction is 40-80 °C.
The base such as metal hydroxides, metal carbonates, metal bicarbonates may be used for the hydrolysis of the ester group present in compound of the formula (XXVIII) to get the compoimd of the formula (I) in step (vi). In the acid hydrolysis of compound of formula (XXVIII) in step (vi) aqueous acids such as sulfuric acid, acetic acid, phosphoric acid, hydrobromic acid, hydrochloric acid may be used. The temperature used for the reaction may be in the range of 15-60 °C.
Overall yield of levofloxacin made by the present process is more than 60% and the purity is more than 99.8%.
The details of the process of the invention are provided in the Example given below which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Example 1
Preparation of Levofloxacin
(i) Preparation of methyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl) acrylate of formula-XXIV

Into a 2L, three-necked RB flask was charged 800ml of toluene and 108g of methyl 3-dimethylaminoacrylate. Triethylamine (94 g) was added to the reaction mass. A solution of methyl 2,4-dichloro-5-fluoro-3-nitroben2oyl chloride (prepared from 200g of 2,4-

dichloro-5-fluoro-3-nitrobenzoic acid using thionyl chloride) in toluene (400ml) was added to the reaction mass at 25-30 °C. The reaction mass was heated to 100-105°C and maintained for 4hr. Reaction mass was cooled to RT and filtered the solid. To the filtrate water was added and extracted product into toluene. Toluene layer was treated with carbon and distilled off solvent under vaccum to get 320g of crude compound. To the crude 300ml of IPA was added and heated to 60-65°C. The resultant solution was cooled under stirring to 0-5°C and filtered the solid. The wet cake was washed with 100ml of chilled IPA and dried at 50-60°C to get 250 g of methyl 2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-dimethylamino acrylate of the formula (XXIV)), as light yellow colored solid. Melting point is 125-126°C. IR (KBr): 3444, 3068, 2946, 1690, 1627, 1569, 1549, 1453, 1427, 1395, 1378, 1359, 1312, 1199, 1130, 1107, 1058, 1037, 968, 833, 802, 787, 760, and 745 cm"^
(ii) Preparation of methyl (+)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate (cis/trans ratio 1:3) of the formula (XXV)

Into a 500ml, three-necked RB flask was charged 67g of methyl 2-(2,4-dichloro-5-fluoro-3 -nitrobenzoyl)-3 -dimethylamino acrylate of the formula (XXIV) and 240ml of methylene chloride. The reaction mass stirred and cooled to 10-15 °C. A solution of (S)-(+)-2-amino-l-propanol (19g) in methylene chloride (25ml) was added to the reaction mass over a period of Ihr. Temperature of the reaction mass was raised to 25-30 °C and maintained for 4hr. TLC of the reaction mass indicated the absence of starting compound of formula (XXV). Water (200ml) was added to the reaction mass and extracted product into methylene chloride. Methylene chloride layer was washed with water died and distilled under vacuum to get 80g of crude chiral compound of formula (XXV). The residue was dissolved in isopropyl ether and crystallized to get 70g of title compound,

as light yellow colored solid. Melting point is 125-126 °C. Optical rotation is 34.7 (c - 1, CHCI3). IR (KBr): 3445, 3196, 2952, 1687, 1626, 1547, 1445, 1426, 1404, 1363, 1327, 1260, 1154, 1063, 1029, 850, and 765cm"^ . ^H-NMR (300MHz, CDCI3): 11.06 (br. s, IH, exch. with D2O, -NH); 8.27 (d, J = 14.28Hz, IH, -CHNH-); 7.14 (d, J = 8.06Hz, IH, Ar. H); 3.48-3.84 (m, 3H, -NCH(CH3)CH20H); 3.59 (s, 3H, -CO2CH3); 2.08 (br. s, IH, exch. with D2O, -OH); 1.39 (d, J =- 6.23Hz, 3H, -CHCH3).
(iii) Process for the preparation of methyl (+)-l-(3-hydroxy-2-propyl)-6-fluoro-7-chIoro-8-nitro-4-oxo-quinoIine-3-carboxylate of the compound of formula (XXVI)

Into 500ml, three-necked, RB flask was added 170ml of dry THF and 6g of sodium hydride (55% in paraffin oil). To the suspension was added a solution of 20 g of methyl (+)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate, (prepared by the process described in step (ii)) in THF (30ml) keeping the temperature below 25 °C. The reaction mass was stirred at 25-27 °C and maintained for 2hr. TLC of the reaction mass indicated the absence of starting material. The reaction mass was cooled to 5-10°C and quenched by adding 2ml of acetic acid. Water was added to the reaction mass and the product extracted into methylene chloride (2 x 200ml). Methylene chloride was distilled off under vaccum and the residue suspended in a mixture of isopropanol-isopropyl ether to get 15g of light yellow crystals of the title compound. A small sample was purified by column chromatography to get analytically pure sample. Melting point is 202-203°C. Optical rotation is -332.3 (c = 0.5, Methanol). IR (KBr): 3379, 3069, 2954, 1725, 1650, 1605, 1547, 1478, 1434, 1390, 1343, 1327, 1298, 1256, 1212, 1192, 1178, 1141, 1066, 1049, 978, 919, 802, 773, and 702cm"V 1H-NMR (300MHz, CDCI3): 8.73 (s, Ih, 2-H); 7.72 (d, J = 8.42Hz, IH, 5-H); 4.60-4.72 (m, IH,

exch. with D2O, -OH); 4.34-4.42 (m, IH, -NCHCH3-); 4.03-4.12 (m, IH, -CH(OH)); 3.88 (s, 3H, -CO2CH3); 3.71-3.82 (m, IH, -CH(OH)); 1.66 (d, J = 6.59Hz, 3H, .CHCH3).
(iv) Preparation of methyl (+)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methyl-piperazinyl)-8-nitro-4-oxo-quinoline-3-carboxylate of the formula (XXVII)

Into 500ml, three-necked, RB flask was added 170ml of dry THF and 6g of sodium hydride (55% in paraffin oil). The suspension was cooled to 5 *^C and added a solution of 20 g of solid methyl (+)-2-(2,4-dichloro-5-fluoro-3-nitrobenzoyl)-3-(3-hydroxy-2-propylamino)-acrylate, prepared by the process described in step (iii) in THF (30ml) keeping the temperature below 20 °C. The reaction mass was stirred at 25-27 ^C and maintained for 3hr. TLC of the reaction mass indicated the absence of starting material. Acetic acid (9.5ml) was added to the reaction mass keeping the temperature below 20 °C. N-Methylpiperazine (25g) was added to the reaction mass over a period of Ih keeping the temperature below 20°C. After stirring the reaction mass at 25-30 °C for 10-12hr, THF was distilled under vaccum keeping the temperature below 40°C Water was added to the residue and stirred for 2hr, fibered and the wet cake washed with water and hexane to get 20g of the title compound as light yellow colored solid. Melting point is 225-225.5 °C. Optical rotation is -356.5 (c = 1, CHCls). IR (KBr): 3392, 2936, 2845, 2798, 2771, 1730, 1713, 1637, 1609, 1544, 1478, 1453, 1372, 1321, 1288, 1260, 1221, 1201, 1142, 1101,1069,1009,953, 912, 801, andn4cm\ ^H-NMR(300MHz, CDCI3): 8.74 (s, IH, 2-H); 7.42 (d, J = 11.72Hz, IH, H-5); 5.12 (br. s, IH, exch. with D2O, -OH); 4.42-4.58 (m, IH, -NCHCH3); 4.16-4.22 (m, IH, -CH(OH)); 3.87 (s, 3H, -CO2CH3); 3.68-3.74 (m, IH, -CH(OH)); 3.12-3.22 (m, 4H, 2 x -NCH2-); 2.51 (br, s, 4H, 2 x -NCH2-); 2.36 (s, 3H, -NCH3); 1.68 (d, J = 6.59Hz, 3H, -CHCH3).

(v) Preparation of methyl (-)-9-fluoro-2,3-dihydro-3-methyl-10-(4-methyl-l-piperizinyl)-7-oxo-7H-pyrido[l^,3-de]-l,4-benzoxazine-6-carboxylate

Into a 250ml three-necked RB flask was added 12.5g of methyl (-)-l-(3-hydroxy-2-propyl)-6-fluoro-7-(4-methyl-piperazinyl)-8-nitro-4-oxo-quinoline-3-carboxylate obtained in step (iv) above, DMF (100ml), and potassium carbonate (14.5g). The suspension heated to 120-125 °C and maintained for 4hr. TLC of the reaction mass indicated the absence of starting material. Reaction mass was cooled to 0-5 °C and maintained for Ihr. Reaction mass was filtered and the wet cake washed with water to get log of the title compound as white solid. Melting point is 260 Optical rotation is -98.3 (c - 1, CHCI3). IR (KBr): 2940, 2840, 2792, 1718, 1621, 1580, 1550, 1478, 1442, 1346, 1323, 1296, 1243, 1204, 1155, 1094, 1071, 1006, and 801cm'^ ^H-NMR (300MHz, CDCI3): 8.60 (s, IH, -NCH-); 7.41 d, J = 12.82Hz, IH, Ar. H); 4.68-4.72 (m, IH, -NCHCH3); 4.49 (d, J = 11.72Hz, IH, -CH2O-); 4.30 d, J = 11.72Hz, IH, -CH2O); 3.73 (s, 3H, -CO2CH3); 3.22-3.42 (m, 4H, 2 x -NCH2); 2.40-2.44 (m, 4H, 2 x -NCH2); 2.21 (s, 3H, -NCH3); 1.39 (d, J = 6.60Hz, 3H, -CHCH3).

Into a 250ml three-necked RB flask was charged 8g of methyl (-)-9-fluoro-2,3-dihydro-3-methyl-l 0-(4-methyl-1-piperizinyl)-7-oxo-7H-pyrido[ 1,2,3-de]-l ,4-benzoxazine-6-

:carboxylate, obtained in step (v) above and 2% aqueous sodium hydroxide (50ml). The exaction mass was heated to 70-80 °C and maintained for 30min. Activated carbon (Ig) kvas added to the reaction mass and filtered. Filtrate was cooled to 10-15 °C and adjusted the pH to 7.0 using acetic acid. Sodium chloride was added to the reaction mass and stirred at 10-15 °C for Hire. Solid was filtered and washed with chilled water. Drying of the wet solid gave 6g of levofloxacin as white solid. Melting point is 225 °C. Optical rotation is -76.3 (c = 0.4, 2% aq. NaOH)
Advantages of present invention
1. The yield of levofloxacin prepared by the process of the invention is more than 60% and purity (>99.8%).
2. Process does not require the use of costly poly-fluorinated benzene derivatives thereby making he process simple and economical.
3. Process can be used for commercial production of levofloxacin of the formula (I).
4. Process, if required, can be carried out continuously without isolating the intermediates.
5. The process is environmentally safe.




We Claim:
1. An improved process for the preparation of levofloxacin of formula-I,

which comprises:
(i) Reacting 2,4-dichloro-5-fluoro-3-nitrobenzoyl chloride with methyl 3-dimethylaminoacrylate in the presence of a base in a solvent system at a temperature in the range of 50-120 °C to get the compound of the formula (XXIV),

(ii) Reacting the compound of the formula (XXIV) with 1-alaninol in a solvent system at a temperature in the range of 0-40 *^C to get the compound of the formula (XXV)


(iii) Reacting the resulting pompoms of the formula (XXV) with a base in a solvent at a temperature in the range of-10 to 60 °C to get the cyclone compound of the formula (XXVI),

(iv) Reacting the resulting pompom of the formula (XXVI) with N-methy piperazine in the presence or absence of a base and in a solvent medium at a temperature in the range of 20-100 °C to get the compound of the formula (XXVII),

(v) Reacting the resulting compound of the formula (XXVII) with a base in a non-polar solvent system at a temperature in the range of 20-100 °C to get the cyclone compound of the formula (XXVIII),

(vi) Hydrolyzing the ester derivative of the formula (XXVIII) so formed using acid or base to get levofloxacin of the formula (I)

2. A process as claimed in claim 1 wherein the base employed in step (i) is selected from pyridine, alkyl pyridine, dialkyl amine, and preferably dialkyl amine such as triethylamine.
3. A process as claimed in claims 1 and 2 wherein the solvent employed in step (i) is selected from hydrocarbon solvents like hexane, heptane, toluene, xylene, ether solvents like diethyl ether, isopropyl ether, tetrahydrofuran, acetonitrile, preferably toluene, acetonitrile.
4. A process as claimed in claims 1 to 3 wherein the solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane^ toluene, methylene chloride, acetonitrile, THF (tetrahydrofuran), dioxane, ether, DMF (N,N-dimethylformamide), preferably methanol, THF or toluene is used in step (ii).
5. A process as claimed in claims 1 to 4 wherein a base such as lithium diisopropylamide, alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (1,5-diazabicyclonon-5-ene, pyridine, dimethylaminopyridine, and triethylamine, preferably potassium t-butoxide or sodium hydride is used in step (iii).
6. A process as claimed in claims 1 to 5 wherein the solvent such as toluene,
cyclohexane, heptane, THF (tetrahydrofuran), dioxane, DMF (N,N-dimethylformamide),
preferably THF or DMF is used in step (iii).
7. A process as claimed in claims 1 to 6 wherein the base such as metal carbonates, metal bicarbonates, metal alkoxides, DBU (l,8-diazabicycIo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (l,5-diazabicyclonon-5-ene, preferably metal carbonates or bicarbonates is used in step (iv).
8. A process as claimed in claims 1 to 7 wherein the solvent such as methanol, ethanol, isopropanol, heptane, cyclohexane, toluene, methylene chloride, acetonitrile, THF

(tetrahydrofuran), dioxane, ether, DMF (N,N-dimethylformainide), preferably methanol, THF or toluene is used in step (iv).
9. A process as claimed in claims 1 to 8 wherein a base such as lithium diisopropylamide,
alkyl lithium, metal hydrides, metal carbonates, metal bicarbonates, metal alkoxides,
DBU (l,8-diazabicyclo-undec-7-ene, DABCO (1,4-diazabicycloocatne, DBN (1,5-
diazabicyclonon-5-ene, pyridine, 4-dimethylaminopyridine, and triethylamine,
preferably, metal carbonates, metal bicarbonates, or triethylamine is used in step (v).
10. A process as claimed in claims 1 to 9 wherein a solvent such as methanol, ethanol,
isopropanol, acetonitrile, THF (tetrahydrofuran), dioxane, ether, DMF (N,N-
dimethylformamide), DMAs (N,N-dimethylacetamide), pyridine, DMSO (dimethyl
sulfoxide), preferably methanol, THF, DMF or toluene is used in step (v).
11. A process as claimed in claims 1 to 10 wherein the acid such as aqueous sulfuric acid,
nitric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, preferably sulfuric acid
the base such as sodium or potassium hydroxide, carbonate, bicarbonate, preferably
sodium or potassium hydroxide is used in step (vi).


Documents:

0305-che-2005 complete specification as granted.pdf

305-che-2005 correspondance others.pdf

305-che-2005 form-5.pdf

305-che-2005-abstract.pdf

305-che-2005-claims.pdf

305-che-2005-correspondnece-others.pdf

305-che-2005-correspondnece-po.pdf

305-che-2005-description(complete).pdf

305-che-2005-form 1.pdf

305-che-2005-form 5.pdf

305.jpg

EXAMINATION REPORT REPLY.PDF


Patent Number 237257
Indian Patent Application Number 305/CHE/2005
PG Journal Number 51/2009
Publication Date 18-Dec-2009
Grant Date 11-Dec-2009
Date of Filing 23-Mar-2005
Name of Patentee NATCO PHARMA LIMITED,
Applicant Address NATCO HOUSE ROAD NO.2 BANJARA HILLS HYDERABAD-500 033.
Inventors:
# Inventor's Name Inventor's Address
1 DR. PULLAREDDY MUDDASANI NATCO HOUSE ROAD NO.2 BANJARA HILLS HYDERABAD-500 033.
2 MR. RAJASEKHARA REDDI PEDDI NATCO HOUSE ROAD NO.2, BANJARA HILLS, HYDERABAD,
3 MR.VENKAIAH CHOWDARY NANNAPANENI, NATCO HOUSE ROAD NO 2,BANJARAHILLS HYDERABAD,
PCT International Classification Number C07D498/06
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA