Title of Invention

A PROCESS FOR THE PREPARATION OF DIHYDROPYRIDINE COMPOUND

Abstract A process for the preparation of a dihydropyridine compound comprising steps: (a) reacting a bis-aldehyde compound having the formula, wherein X is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 arylalkyl, halo, aryl and substituted aryl with a compound having formula, (R'0)2P(0) CH2C(0) OR2, wherein, R1 and R2 are C1-C6 straight and branched chain alkyl or phenyl, under biphasic conditions employing water and an organic solvent with a phase transfer catalyst in quantities of 0.1%-10% and a base at 0 to 50°C to form a benzylidine intermediate of formula (b) reacting said benzylidene intermediate with compound of formula wherein R3 is C1-C6 alkyl in presence of a carboxylic acid salt of secondary amine in hydrocarbon solvents with azeotropic removal of water to form an intermediate of formula (c) reacting intermediate formed in step (b) with suitably substituted enamine of formula wherein R4 is C1-C6 alkyl in a suitable low molecular weight alcohol solvent at the reflux temperature of solvent for 3-10 hours to form 1,4-dihydropyridine compound. (d) cooling the reaction mass to ambient temperature for sufficient amount of time optionally with seeding to allow crystallization of the formed dihydropyridine compound (d) isolating of the crystallized 1,4-dihydropyridine by filtration or centrifugation.
Full Text FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
PROVISIONAL SPCCIFICTAION / COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION A PROCESS FOR THE PREPARATION OF DIHYDROPYRIDINE COMPOUND
2. APPLICANT(S)
(a) NAME : CADILA PHARMACEUTICALS LTD
(b) NATIONALITY : An INDIAN Company
(c) ADDRESS : "Cadila Corporate Campus", Sarkhej - Dholka Road, Bhat,
Ahmedabad - 382210, Gujarat, India
3. PREAMBLE TO THE DESCRITION
COMPLETE SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed
4. DESCRIPTION
(Description starts from next page)



FIELD OF INVENTION:
The present invention discloses an improved and cost effective synthesis of (E) t-butyl-2-formylcinnamate and its conversion to dihydropyridine compound such as lacidipine.
BACKGROUND OF THE INVENTION:
Lacidipine is a second-generation calcium channel antagonist that reduces the transmembrane influx of calcium ions, blocking the type L voltage-dependent channels. Lacidipine is one of the most vascular selective dihydropyridine derivatives. It has a long duration of action because of its high degree of lipophilicity, its storage in the deep lipid compartment of the membrane and its continuous release to receptor. Anti-hypertensive effect apart, Lacidipine has also been shown to have anti-atherosclerotic, antioxidant, platelet anti-aggregant & blockade of endothelin-1 induced vasoconstriction effects.
Lacidipine is also known as (E)-4-[2-[3-(l,l-dimethylethoxy)-3-oxo-l-propenyl] phenyl]-l,4-dihydro-2, 6-dimethyl-3, 5-pyridine dicarboxylic acid diethyl ester and has a CAS Reg. No. 103890-78-4. The structure of Lacidipine (I) is given below.

Processes for the preparation of Lacidipine and similar compounds are described in US Patent nos. 4801599; 4935548; 5011848; 5051432 and European Patent no. 245919. The US patents 4801599 and 5011848 describe several methods of preparation of Lacidipine (I) and similar compounds. These methods are given in Scheme-1.


Lacidipine is prepared by condensation of ethyl 3-aminocrotonate with tert-butyl 2-formylcinnamate (II) in acetic acid or trifluoroacetic acid (Reaction - B). The formyl cinnamate ester is prepared by a Wittig reaction of benzene 1,2-dicarbaldehyde with tert-butoxycarbonyl methylene triphenyl phosphorane (Reaction - A). In another process, Lacidipine is prepared by condensation of ethyl aminocrotonate with ketoester (III), which is prepared by reacting tert-butyl 2-formylcinnamate (II) with ethyl acetoacetate (Reaction - C). Lacidipine is also prepared by reacting compound II with a mixture of ethyl acetoacetate and ethyl aminocrotonate in alcoholic solvent in the presence of strong acids like trifluoroacetic acid. (Reaction - D). US Patent 4801599 also describes a method of preparation of lacidipine, in which compound (IV) is reacted with triphenylphosphorane (V) to give lacidipine. (Reaction - E)

According to US 4801599 and US 5011848, Lacidipine and similar compounds are prepared by treating compound of formula VI (where X represents a bromine or iodine atom) with tert-butyl acrylate in presence of a catalytic amount of a palladium salt such as palladium acetate and triphenylphosphine as ligand in solvents like dimethylformamide in the presence of alkyl amines as depicted in Scheme-2.

EP 534520 and US 5310917 describe a process for the preparation of felodipine and other dihydropyridine compounds by heating intermediates like (VII) with suitably substituted amino crotonate compound in alcoholic solvents at elevated temperature for a sufficiently long time followed by treating the resultant mixture with a strong acid. In a variation of this process, after the reaction has been heated for sufficient time, the reaction mass is cooled in ice bath and then diluted with 1:1 ethanol-water and the product is isolated by filtration as depicted in Scheme-3.

The above methods of lacidipine preparation use expensive reagents, or strongly acidic conditions and involve extractive work up procedures to isolate the product.
In developing an improved process for the preparation of Lacidipine, an alternative method for the formation of the cinnamate ester is desired. The objective is to avoid use of solvents like diethyl ether to remove phosphine oxide by-products and column

chromatography for purification. In a variation of the Wittig reaction, phosphonate esters such as VIII have been used as reagents for the preparation of olefins (Horner-Wadsworth-Emmons reaction). These olefination reactions are performed in alkaline conditions involving bases like sodium hydride and in solvents like tetrahydrofuran and are selective in producing the E isomers (B.E. Maryanoff and A. B Reitz, Chem. Revs. (1989) 89, 863; L. A. Yanovskaya Zh. Vses. Khim Mendeleeva (1986), 31, 38 CA: 1986, 105, 41961u). These reactions are also carried out under biphasic conditions using strong solutions of aqueous sodium hydroxide at reflux temperature of solvents used. In one case, the olefination reaction is conducted in water without any organic solvent (J. Villieras and M. Rambaud, Synthesis (1983), 300-303).
The literature methods describe reactions of single carbonyl functionality. In the present case, o-phthalaldehyde, a compound with.two identical carboxaldehyde functional groups is to be selectively reacted at only one of these groups, hi the process of making t-butyl-2-formyl cinnamate, the olefination reaction was conducted in water without any organic solvent as previously reported by Villieras and Rambaud. Several products are formed and no selectivity is observed. Upon further reactions of the gum with ethyl acetoacetate and ethyl amino crotonate, no lacidipine could be obtained (example - 1). Another reaction was conducted in biphasic solvent system without a phase transfer catalyst. In the second case the rate of conversion is very slow (example - 2). Therefore, a different method is required for selective mono olefination of the bis-aldehyde functionality.
SUMMARY OF THE INVENTION:
It is an object of the present invention to develop a process for the preparation of lacidipine (I) giving the product in higher yields having lower percentage of undesirable impurities than previously described processes without using phosphine reagents (which necessitates use of hazardous solvents like diethyl ether or chromatographic methods) or expensive palladium salts or strong acids. It is further an object of the invention to provide a process for the preparation of lacidipine wherein the product crystallizes from the reaction mixture and is isolated by conventional techniques such as filtration, thereby eliminating the need for more expensive and time consuming extractive isolation procedures. In the present invention, lacidipine is prepared by 1) reaction of o-phthalaldehyde with tert-butyl phosphonoacetate in a biphasic solvent system comprising water and an organic solvent in the presence of a base and a phase transfer catalyst; 2) condensing the resulting cinnamate ester with ethyl acetoacetate in hydrocarbon solvents at reflux temperature of the solvent in

the presence of a carboxylate salt of a secondary amine with the water formed in the reaction being removed azeotropically; 3) reacting the resulting compound with ethyl aminocrotonate in alcoholic solvents at reflux temperature of the solvent; 4) cooling the reaction mixture to crystallize lacidipine and isolation of lacidipine by conventional methods such as filtration or centrifugation.
DETAILED DESCRIPTION OF INVENTION:
In the present invention (Scheme - 4) the olefin derivative is synthesized by a process involving tert-butyl phosphonoacetate (VIII) and o-phthalaldehyde under biphasic conditions employing water and an organic solvent with a phase transfer catalyst and alkali metal carbonates are bases. The preferred base in the present invention is potassium carbonate. Organic solvents like benzene, toluene, xylene, chloroform, dichloromethane (MDC), ethylene chloride, diethyl ether etc can be used. The preferred solvent is dichloromethane. The phase transfer catalyst can be selected from any commonly available ones like benzyltriethylammonium chloride, tetra butyl ammonium bromide, cetrimide etc in 0.1 to 10% quantities. The preferred catalyst is cetrimide with about 1% being most suitable. The reactions are normally complete in about 6-24hours. The reaction can be carried out at temperature ranging from 0-50 °C and preferably between 25 and 35°C. Furthermore, inert atomosphere is not required; the reaction can be carried out exposed to atmosphere. When the reaction has proceeded to a desired stage (typically less than 3% of o-phthalaldehyde), the organic layer is separated from aqueous phase and evaporated to obtain the desired product in around 90% purity. Optionally, the product tert-butyl-2-formyl [£]-cinnamate may remain in solution and can be utilized as it is in the next step.


The olefin compound (II) thus obtained is condensed with a p-keto acid ester such as ethyl acetoacetate in the presence of a catalyst such as carboxylic acid salt of a secondary amine. The carboxylic acids can be acetic acid, benzoic acid etc and organic base can be piperidine, morpholine, pyrrolidine, dialkyl amines like dimethylamine, diethylamine etc. The preferred catalyst combination is piperidine and acetic acid. Suitable solvents for the reaction are hydrocarbon solvents selected from benzene, toluene, xylene, hexane, heptane or cyclohexane etc. with the preferred solvents being cyclohexane and heptane. The reaction is carried out in a temperature range of 70-120°C, preferably 80-90°C. After the reaction has proceeded to the desired stage (typically less than 1% of the starting ester), the solvent is removed under vacuum to leave an oily product (III) as a cis/trans mixture.
Compound (III) is then reacted with ethyl-3-aminocrotonate, in suitable low molecular weight alcohol solvent such as methanol, ethanol, isopropanol and the like. The preferred solvent is methanol. The reaction is conducted at reflux temperature of the solvent and is complete generally in 3-10 hours, preferably 4-6 hours. It was found that addition of a strong acid to speed up the reaction is not required. After the said period of heating, the reaction mass is cooled to ambient temperature for 10-15 hours for the product to crystallize. Optionally, the reaction mass may be seeded with the product to speed up crystallization. The product is isolated by simple filtration. Washing the crude product with chilled methanol removes most of the impurities. The product can be re-crystallized from suitable alcoholic solvents like methanol, ethanol or isopropanol or from solvents like ethyl acetate or acetonitrile. The solvent of choice is ethyl acetate. Lacidipine thus obtained is more than 99.8% pure and it contained less than 0.1% impurities.

Advantages of the present invention include: 1) use of a biphasic system and phase transfer catalytic conditions for the formation of 2-forraylcinnamate ester; 2) easy and cost efficient isolation of Lacidipine without purification of any intermediates by crystallization from the reaction mixture; 3) Replacement of a triphenyl phosphine ylid with tert-butyl phosphonoacetate and minimal extractive work up procedures.
The following examples are provided to further illustrate the practice of present invention and are not intended to limit the scope or utility thereof.
EXAMPLES:
Example-1
A mixture of potassium carbonate (8.3g, 0.06mol), o-phthalaldehyde (4g, 0.03mol) and t-butyl phosphonoacetate (8.7g, 0.0358mol) in 6ml water is stirred at room temperature for lhr. Reaction is diluted with 25ml of water and 50ml chloroform. The layers are separated and the organic layer is washed with water (2x25ml). The chloroform solution is dried over sodium sulfate and solvent is distilled off under vacuum to get red viscous oil. The above product is dissolved in 50ml cyclohexane. To this solution are added 0.2 lg of piperidine, 0.15g of acetic acid and 4.8g of ethyl acetoacetate. The mixture is stirred under reflux for 4 hours. Solvent is distilled off under vacuum and the residue is dissolved in 25ml methanol. 4.6g of ethyl-3-aminocrotonate is added and the solution is stirred under reflux for 6 hours. The solvent is distilled off under vacuum and the residue is washed repeatedly with hexane to leave a reddish brown gum. No lacidipine could be obtained from this gum.
Example ~ 2
Preparation of(E) t-butyl-2-formylcinnamate (II) without phase transfer catalyst:
To a stirred mixture of dichloromethane (25ml) and aqueous solution of potassium carbonate
(17.5g in 50ml) are added o-phthalaldehyde (5g), and t-butyl phosphonoacetate (9.2g). The
reaction is stirred at ambient temperature for 24 hours and the layers are separated. The
aqueous layer is extracted with methylene dichloride (2x25ml). The combined organic layers
is washed with water (4X25ml), dried over sodium sulfate and filtered. Concentration of the
solution leaves 10.2g of oil containing 53.7% cinnamate ester and 17.4% o-phthalaldehyde.
Example - 3
Preparation of(E) t-butyl-2-formylcinnamate:

To a stirred mixture of dichloromethane (900ml) and aqueous solution of potassium carbonate (314.8g in 1.8L) are added sequentially, o-phthalaldehyde (90.0g), t-butyl phosphonoacetate (207.0g) and cetrimide (1.3g). The reaction is stirred vigorously at ambient temperature for 12 hours and the layers are separated. The aqueous layer is extracted with methylene dichloride (2x200ml). The combined organic layers is washed with water (3X450ral), dried over sodium sulfate and filtered. Concentration of the solution leaves 208g of the product. Purity (HPLC): 90%
Example - 4
Preparation of(E) t-butyl 2-formytcinnamate using sodium carbonate as base
To a stirred mixture of dichloromethane (250ml) and aqueous sodium carbonate solution
(67.2g in 500ml water) are added sequentially o-phthalaldehyde (25g), t-butyl dimethyl
phosphonoacetate (46g) and cetrimide (0.4g). The reaction mixture is stirred for 16 hours at
20-30°C and the layers are separated. The aqueous layer is extracted with 125ml of
dichloromethane. The combined organic layer is washed with water (3X125ml), dried over
sodium sulfate and filtered. Concentration of the solution leaves 46g of the product (Purity:
80%)
Example - 5
Preparation of (E) t-butyl 2-formylcinnamate using tetra butyl ammonium bromide as
catalyst:
To a stirred mixture of dichloromethane (250ml) and aqueous potassium carbonate solution
(87.2g in 500ml water) are added o-phthalaldehyde (25g), t-butyl dimethyl phosphonoacetate
(46g) and tetra butyl ammonium bromide (0.2g) sequentially. The reaction mixture is stirred
for 18 hours at 20-30°C. The layers are separated and the aqueous is extracted with
dichloromethane (125ml). The combined organic layer is washed with water (3X125ml),
dried over sodium sulfate and filtered. Concentration of the solution leaves 48g of the product
(84% pure)
Example - 6
Preparation of (E)-4-[2-[3-(l,l-dimethylethoxy)-3-oxo-l-propenyl]phenyl]-l,4-dihydro-2, 6-
dimethyl-3, 5-pyridine dicarboxylic acid diethyl ester (lacidipine):

302 g of (£)-tert-butyl-2-formylcinnamate (from 150g of o-phthalaldehyde) prepared according to example - 3 is added to a solution of piperidine (9.5g) and acetic acid (6.7g) in cyclohexane (1.2L). Ethyl acetoacetate (218.3g) is then added and the reaction mixture is refluxed with a Dean-Stark water separator for 3 hours. After required amount of water has been collected, the solvent is distilled off under vacuum and the residue (462g) is dissolved in methanol (750mL). Ethyl 3-aminocrotonate (174g) is added to the solution and whole mass is heated under reflux for 6 hours under nitrogen atmosphere. The reaction mass is cooled to ambient temperature and stirred for 12-15 hours. The crystallized product is filtered off and washed with chilled methanol (2x150ml) and dried in air. Yield: 155 g; Purity: 99.6% (HPLC)
!H NMR (CDC13): 8 8.46-8.41 (d, J=15.9Hz, IH); 7.48-7.09 (m, AH), 6.28-6.23 (d, J=15.9Hz, \H), 5.84 (s, \H), 5.32 (s, \H), 4.11-3.8 (m, AH), 2.32 (s, 6H), 1.54 (s, 9H), 1.16-l.ll(t,6tf).
13C NMR (CDCI3): 14.21; 19.43; 28.21; 35.68; 59.64; 80.02; 104.52; 120.13-131.8; 143.7; 144.10; 148.24; 166.67; 167.37 ppm
Example - 7
Preparation oflacidipine:
To a stirred mixture of toluene (2L) and aqueous solution of potassium carbonate (700.2g in 4L water) are added sequentially o-phthalaldehyde (200g), t-butyl dimethyl phosphonoacetate (398g) and cetrimide (2g). The reaction mixture is stirred vigorously at 20-30°C for 10 hours and the layers are separated. The aqueous layer is extracted with toluene (1L). The combined organic layer is washed with water (3X1L). About one third of the solvent (1L) is distilled off and piperidine (11.4g), acetic acid (8.06g) and ethyl acetoacetate (291.4g) are then added. The solution is refluxed for 3hours with Dean-Stark water separator. After the sufficient amount of water has separated, the solvent is distilled off under vacuum and the residue (540g) is dissolved in methanol (1L). Ethyl 3-aminocrotonate (289.1g) is added to the methanol and the mixture is refluxed for 8 hours under nitrogen atmosphere. The reaction mixture is cooled to ambient temperature and stirred for 10 hours. The crystallized product is filtered off and washed with hexane and dried in air. Product weight: 125g (18.4%); Purity: 97.3%

Example - 8
Preparation of Lacidipine:
553g of (E) t-butyl 2-formylcinnamate are added to a solution of piperidine (13g) and acetic acid (9.6g) in benzene (2.68L). Ethyl acetoacetate (390.4g) is then added and the reaction mixture is refluxed for 6h with dean stark water separator. The solvent is distilled off under vacuum and the residue (888g) is dissolved in methanol (1L). Ethyl-3-amino crotonate (306.6g) is added to the solution and the mixture is heated to reflux for 6 hours under nitrogen atmosphere. Reaction mixture is cooled to ambient temperature and stirred for 12-14 hours. The product separated is filtered off and washed with chilled methanol (300ml) dried in air. Product weight: 300g (32%); Purity: 98.9%
Example - 9 Preparation of Lacidipine:
421g of (E) t-butyl 2-formyl cinnamate are added to a solution of piperidine (12.6g) and
acetic acid (9g) in toluene (2L). Ethyl acetoacetate (291.3g) is then added and the reaction
mixture is refluxed with a Dean-Stark water separator for 3 hours. After required amount of
water has been collected, the solvent is distilled off under vacuum and the residue (634.4g) is
dissolved in methanol (1.2L). Ethyl-3-aminocrotonate (231.3g) is added and the solution is
heated under reflux for 6hours and under nitrogen atmosphere. The reaction mixture is cooled
to ambient temperature and stirred for 10-12 hours. The crystallized product is filtered off
and washed with chilled methanol and dried in air. Product weight: 120g (18%); Purity: 98%
Example- 10 Preparation of Lacidipine:
20g (E) t-butyl 2-formylcinnamate is added to a solution of piperidine (0.4g) and acetic acid (0.28g) in heptane (75ml). The reaction mixture is refluxed with Dean-Stark water separator. After 2 hours solvent is distilled off and the residue (25.8g) is dissolved in Methanol (50ml). Ethyl-3-aminocrotonate (9.6g) is added to it and the mixture is heated to reflux for 6 hours under nitrogen atmosphere. The reaction mixture is cooled to ambient temperature and stirred for 6-7 hours. The crystallized product is filtered and washed with chilled methanol (25ml). 7g of crude lacidipine is obtained with purity 99.3%
Example -11

Preparation of Lacidipine:
(E) t-butyl-2-formyl cinnamate (30g) is added to a solution of morpholine (0.87g) and acetic acid (0.6g) in cyclohexane (200ml). Ethyl acetoacetate (13.2g) is then added and the reaction mixture is refluxed for 8 hours. After required amount of water has been collected, the solvent is distilled off under vacuum and the residue (43.4g) is dissolved in methanol (87ml). Ethyl 3-aminocrotonate (15.4g) is added and die solution is heated under reflux for 7 hours under nitrogen atmosphere. The reaction mixture is cooled to ambient temperature and stirred for 10 hours. The product separated after seeding is filtered and washed with chilled methanol dried in air. Product Weight: 10.2g; Purity: 99.5%
Example -12 Preparation of Lacidipine:
To a solution of 166g of 2-(2-(3-(l,l dimethylethoxy)-3-oxo-l-propenyl) phenyl) methylene-3-oxo butanoic acid ethyl ester (III) in ethanol (250ml), ethyl-3-aminocrotonate (57.8g) is added and the mixture is heated under reflux for 6 hours under nitrogen atmosphere. It is then cooled to ambient temperature for 10-12 hours. The crystallized product is filtered and washed with chilled ethanol (50ml). The crude product is crystallized from ethyl acetate to get 35g of 99.8% purity lacidipine..
Example -13 Preparation of Lacidipine:
Ethyl-3-amino crotonate (7.07g) is added to a solution of 20g 2-(2-(3-(l,l dimethyl ethoxy)-3-oxo- 1-propenyl) phenyl) methylene-3-oxo butanoic acid ethyl ester (III) in IPA (60ml). The solution is heated to reflux for 6hours under nitrogen atmosphere. The reaction mixture is cooled to ambient temperature for 10-12 hours. The crystallized product after seeding is filtered and washed with chilled IPA (10ml) and hexane. The crude product after crystallization from ethyl acetate yielded 2.5g of 99.7% pure lacidipine.

We claims,
1. A process for the preparation of a dihydropyridine compound



comprising steps:
(a) reacting a bis-aldehyde compound having the formula,



wherein X is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy, C1-C6

arylalkyl, halo, aryl and substituted aryl with a compound having formula, (R'0)2P(0) CH2C(0) OR2, wherein, R1 and R2 are C1-C6 straight and branched chain alkyl or phenyl, under biphasic conditions employing water and an organic solvent with a phase transfer catalyst in quantities of 0.1%-10% and a base at 0 to 50°C to form a benzylidine intermediate of formula
(b) reacting said benzylidene intermediate with compound of formula

wherein R3 is C1-C6 alkyl in presence of a carboxylic acid salt of secondary amine in hydrocarbon solvents with azeotropic removal of water to form an intermediate of formula


(c) reacting intermediate formed in step (b) with suitably substituted enamine of formula

wherein R4 is C1-C6 alkyl in a suitable low molecular weight alcohol solvent at the reflux temperature of solvent for 3-10 hours to form 1,4-dihydropyridine compound.
(d) cooling the reaction mass to ambient temperature for sufficient amount of time optionally with seeding to allow crystallization of the formed dihydropyridine compound
(d) isolating of the crystallized 1,4-dihydropyridine by filtration or centrifugation.
2. A process of preparation of lacidipine as per claim 1 wherein the bis-aldehyde is o-phthalaldehyde.
3. A process according to claim 1, wherein the phase transfer catalyst used is benzyl tri ethyl ammonium chloride, tetra butyl ammonium bromide and cetrimide in quantities of about 0.1% to about 10%.
4. A process according to claim 3, wherein preferred phase transfer catalyst is cetrimide in quantity of about 1 %.
5. A process according to claim 1 wherein, organic solvent in biphasic system is benzene, toluene, xylene, chloroform, dichloromethane, ethylene chloride and diethyl ether.
6. A process according to claim 5 wherein, preferred organic solvent in biphasic system is dichloromethane.
7. A process according to claim 1 wherein, the base is alkali metal carbonate.
8. A process according to claim 7 wherein, preferred base is potassium carbonate.
9. A process according to claim 1 wherein, the temperature of reaction of step a) is ranging from about 0°C to about 50"C at atmospheric conditions.

10. A process according to claim 9 wherein, the preferred temperature is 25-35*C.
11. A process according to claim 1 wherein, carboxylic acid salt of secondary amine includes carboxylic acids such as acetic acid, benzoic acid and bases such as piperidine, morpholine, pyrrolidine, dialkylamines.
12. A process according to claim 11 wherein, the preferred salt as a catalyst is acetic acid salt of piperidine.
13. A process according to claim 1 wherein the hydrocarbon solvent is benzene, cyclohexane, heptane and toluene.
14. A process according to claim 13 wherein the preferred hydrocarbon solvent is cyclohexane.
15. A process according to claim 1 wherein step (c) is conducted in methanol, ethanol, propanol, isopropanol and n-butanol.
16. A process according to claim 15 wherein the preferred alcoholic solvents are methanol and ethanol.
17. A process according to claim 1 wherein the cooling time in step (d) is 12-15 hours to allow for crystallization optionally with seeding and isolation of the product by filtration or centrifugation.

Documents:

858-MUM-2003-ABSTRACT(13-08-2008).pdf

858-mum-2003-cancelled pages(13-8-2008).pdf

858-mum-2003-claims(granted)-(13-8-2008).doc

858-mum-2003-claims(granted)-(13-8-2008).pdf

858-MUM-2003-CLAIMS-(13-08-2008).pdf

858-MUM-2003-CORRESPONDENCE(13-08-2008).pdf

858-mum-2003-correspondence(13-8-2008).pdf

858-MUM-2003-CORRESPONDENCE(19-6-2009).pdf

858-mum-2003-correspondence(ipo)-(20-2-2009).pdf

858-MUM-2003-DESCRIPTION(COMPLETE)-(13-08-2008).pdf

858-MUM-2003-FORM 1(11-08-2008).pdf

858-mum-2003-form 1(13-8-2008).pdf

858-mum-2003-form 1(29-8-2003).pdf

858-mum-2003-form 18(5-7-2007).pdf

858-MUM-2003-FORM 2(13-08-2008).pdf

858-mum-2003-form 2(granted)-(13-8-2008).doc

858-mum-2003-form 2(granted)-(13-8-2008).pdf

858-MUM-2003-FORM 2(TITLE PAGE)-(13-08-2008).pdf

858-mum-2003-form 3(13-8-2008).pdf

858-mum-2003-form 3(19-8-2003).pdf

858-mum-2003-form 3(21-6-2004).pdf

858-mum-2003-form 5(21-6-2004).pdf


Patent Number 229742
Indian Patent Application Number 858/MUM/2003
PG Journal Number 13/2009
Publication Date 27-Mar-2009
Grant Date 20-Feb-2009
Date of Filing 29-Aug-2003
Name of Patentee CADILA PHARMACEUTICALS LTD.
Applicant Address "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
Inventors:
# Inventor's Name Inventor's Address
1 KHAMAR BAKULESH MAFATLAL CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
2 MODI INDRAVADAN AMBALAL CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
3 VENKATASUBBU SHYLAJA CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
4 RAJAPPA MURALI CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
5 MEREYALA HARI BABU CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
6 POLA PALLAVI CADILA PHARMACEUTICALS LTD., "CADILA CORPORATE CAMPUS", SARKHEJ-DHOLKA ROAD, BHAT, AHMEDABAD - 382210, GUJARAT, INDIA.
PCT International Classification Number N/A
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA