Title of Invention

PROCESS FOR THE PREPARATION OF CYCLOPROPYL CARBOXYLIC ACID ESTERS AND DERIVATIVES

Abstract

A process for the preparation of a compound of a formula (I): wherein: R is phenyl substituted with one or more halogen; and Y is OR1, where R1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group; which comprises: reacting a trimethylsulfoxonium salt with a solid metal hydroxide in dimethylsulfoxonium at ambient or an elevated temperature to produce dimethylsulfoxonium methylide; and, contacting compound of formula (II) in which R and Y area as defined above, with the dimethylsulfoxonium methylide in the presence of a solvent at a temperature of -10°C-90°C.

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10] "PROCESS FOR THE PREPARATION OF CYCLOPROPYL CARBOXYLIC ACID ESTERS AND DERIVATIVES" ASTRAZENECA AB, a Swedish company, of S-151 85 Sodertalje, Sweden, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- The present invention relates to a process for the preparation of cyclopropyl carboxyiic acid esters and derivatives. FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of certain cyclopropyl carboxyiic acid esters and other cyclopropyl carboxyiic acid derivatives; a novel process for the preparation fo dimethylsulfoxonium methylide and dimethylsulfonium methylide; to the use of certain cyclopropyl carboxyiic acid esters in a process for the prepataion of intermediates that can be used in the synthesis of pharmaceutically active entities; and to certain intermediates provided by these processes. DESCRIPTION OF THE INVENTION In a first aspect of the invention therefore provides a process for the preparation of a compound of formula (I): wherein: R is phenyl substituted with one or more halogen; Y is OR1, where R1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group (eg bornyl), which comprises contacting a compound of formula (II): where R and Y are as defined above, with dimethylsulfoxonium methylide in the presence of a solvent. Suitably the solvent is a polar solvent, preferably dimethyl sulfoxide. Suitably, the reaction is carried out at -10°C - 90°C, preferably 25°C. The dimethylsulfoxonium methylide can be prepared by reacting a trimethylsulfoxoniurn salt with a solid strong base, preferably in solid form, in dimethyl sulfoxide at ambient or an elevated temperature. Suitably, the base is a metal hydroxide, eg NaOH, LiOH, or alkali metal hydride, eg NaH. Preferably the base is sodium hydroxide. Preferably, trimethylsulfoxonium iodide is stirred with sodium hydroxide powder in dimethyl sulfoxide (in the absence of a phase transfer catalyst), optionally under nitrogen, at 20-25°C for 90 minutes. Alternatively, the dimethylsulfoxonium methylide can be prepared from a trimethylsulfoxonium salt (preferably iodide or chloride) using sodium hydroxide in dimethyl sulfoxide with a phase transfer catalyst, for example tetrabutyl-n-ammonium bromide, or with other strong bases, such as alkali metal hydrides, in dimethyl sulfoxide. A compound of formula (II) can be prepared by reacting a compound of formula (III): where R is as defined above, with a suitable chlorinating agent in the presence of an inert 'Solvent and an optional catalyst at at a temperature-of 0-200°C. Preferably Y is OR the chlorinating agent is thionyl chloride, the inert solvent is toluene, and the catalyst is pyridine. Suitably the reaction temperature is 70oC. The. resulting acid chloride is then reacted with YH or Y", (where Y" is an anionic species of Y), Y is as defined above, optionally at an elevated temperature, such as 100°C. A compound of formula (III) can be prepared using standard chemistry, for example by contacting a compound of formula (IV): where R is as defined above, with malonic acid in the presence' of pyridine and piperidine at an elevated temperature, preferably 50-90°C. A compound of formula (I) can be hydrolysed using basic hydrolysis to yield a compound of formula (V): where R is as defined above. For example, ester groups are preferably removed by basic hydrolysis using an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent, such as water, an aqueous alcohol or aqueous tetrahydrofuran, at a temperature from 10 - 100°C. Most preferably the base is sodium hydroxide, the solvent is ethanol, and the reaction temperature is 50°C. A compound of formula (V) can be used to generate a compound of formula (VI): where R is as defined above, by reaction with thionyl chloride or another suitable chlorinating agent in the presence of toluene, or another suitable solvent, and an optional catalyst, preferably pyridine, at 0-200°C. Preferably the temperature is to 65-70°C. A compound of formula (VI) can be used in the synthesis of a compound of formula (VII): where R is as defined above, by reaction with an alkali metal azide (preferably sodium azide) in the presence of a phase transfer catalyst (preferably tetra-n-butylammorriurn bromide), aqueous potassium carbonate and an inert solvent (preferably toluene). Preferably the reaction temperature is 0 - 10°C. A compound of formula (VII) can be used in the synthesis of a compound of formula (VIII): where R is as defined above, by rearrangement in toluene at temperatures between O°C and 200°C, preferably at a reaction temperature of 90-100°C., after which the isocyanate intermediate is reacted with hydrochloric acid at elevated temperatures, preferably 85-90oC. An unprotonated parent amine (free base) of formula-(IX): where R is as defined above, can be liberated by adjusting the pH of an aqueous solution of the salt of a compound of formula (VIII) to 10 or more. This can then be converted to other salts of organic acids or inorganic acids, preferably mandelic acid. The R-(-)-mandelic acid salt of a compound of formula (IX) can be generated by addition of R-(-)-mandelic acid at ambient or an elevated temperature to a solution of a compound of formula (IX) in a solvent, preferably ethyl acetate. Preferably the temperature is 20°C. Suitably R is phenyl optionally substituted by one or more halogen atoms. Preferably, R is phenyl substituted by one or more fluorine atoms. More preferably R is 4-fluoropbenyl or 3,4-difluorophenyl. Preferably Y is D-menthoxy, or more preferably, L-menthoxy. Compounds of formulae (I) to (IX) can exist in different isomeric forms (such as cis/trans, enantiomers, or diastereoisorners). The process of this invention includes all such isomeric form's and mixtures thereof in all proportions. Where Y is chiral, a compound of formula (I) will be a mixture of diastereoisorners and can be resolved to yield a diastereomerically-enriched compound of formula (Ia); where R and Y are as defined above, by crystallisation or by chromatographic methods. Preferably the crystallisation is carried out in situ following the synthesis of a compound o: formula (I), as described above, by heating the crude reaction mixture until total or near-tota dissolution is achieved, then cooling at an appropriate rate until sufficient crystals of th A compound of formula (Ia) can be hydrolysed to yield a compound of formula (Va): where R is as defined above, using the method described above for the hydrolysis of a compound of formula (I) to yield a compound of formula (V). A compound of formula (Va) can be used to generate a compound of formula (VIa): where R is as defined above, using the method described above for the conversion of a compound of formula (V)'to yield a compound of formula (VI). A compound of formula (VIa) can be used in the synthesis of a compound of formula (VIIa): where R is as defined above, using the method described above for the conversion of a compound of formula (VI) to yield a compound of formula (VII). A compound of formula (VIIa) can be used in the synthesis of a compound of formula (VIIIa): where R is as defined above, using the method described above for the conversion of a compound of formula (VII) to yield a compound of formula (VIII). A compound of formula (Villa) can be used in the synthesis of a compound of formula-(IXa): where R is as defined above, using the method described above for the conversion of a compound of formula (VIII) to yield a compound of formula (DC). The R-(-)-mandelic acid salt of a compound of formula (IXa) can be generated using the method described above for the generation of the mandelic acid salt of a compound of formula (IX). Novel compounds form a farther aspect of the invention. In a further aspect the invention therefore provides compounds of formula (I), (Ia), (II), (III), (V), (Va), (VI), (VIa), (VII), (VIIa), (VIII), (VIIIa), (IX) and (IXa) as defined above. . Particularly preferred compounds include: (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-diflulorophenyl)cyclopropanecarboxylate; (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans- (1R, 2R)-2-(3,4-difluorophenyl)cyclopropane carboxylate; (1R,2S, 5R)-2-isopropyI-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate; (E)-3-(3,4-difluorophenyl)-2-propenoic acid; (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride; trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide; trans-(1R, 2R)-2-(3,4-difluorophenyl) cyclopropyl amine; and trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2- phenylethanoate Examples The invention is illustrated by the following non-limiting examples. Example 1. This example illustrates the preparation of (E)-3-(3,4-difiuorophenyI)-2~propenoic acid A stirred mixture of pyridine (15.5 kg) and piperidine (0.72 kg) were heated to 90°C. Malonic acid (17.6 kg) was added, followed by slow addition, over 50 minutes, of 3,4-difluorobenzaldehyde (12.0 kg). The reaction mixture was stirred at 900C for a further 4 hours and 36 minutes. Water (58.5 kg) was added and 32 litres of the pyridine/water mixture then was distilled out of the reactor under reduced pressure. The reaction mixture was acidified to pH 1 with 37% hydrochloric acid (6.4 kg) over a 40-minute period, then cooled to 25°C with strong stirring. The solids were collected by filtration, washed twice with I % hydrochloric acid (34.8 L per wash), once with water (61 L) and then deliquored thoroughly in the filter. The product was then dried under vacuum at 40°C for 24 hours and "'40 minutes, affording 13.7 kg of the crystalline product- Example 2. This example illustrates the preparation of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride. A stirred mixture of (E)-3-(3,4-difluorophenyl)-2-propenoic acid (8.2 kg), toluene (7.4kg) and pyridine (0.18kg) was heated to 65°C and then thionyl chloride (7.4kg) was added over 30 minutes. The reaction was stirred for a further 2h 15 minutes after the addition was complete, then diluted with toluene (8.7kg). Excess thionyl chloride, sulfur dioxide and hydrogen chloride were then distilled out, together with toluene (10 L), under reduced pressure, yielding a solution of the (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (approximately 9 kg) in toluene. Example 3. This example illustrates the preparation of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate. A solution of L-menthol (7.1kg) in toluene (8.5kg) was added over a 20 minute period to the solution of (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride (prepared as in Example 2) and pyridine (0.18kg, 2.28 mol) stirring at 65°C. The reaction mixture was stirred at 65°C for a further 4 hours and 40 minutes after the addition was complete, then cooled to 25°C and stirred for a 14 hours. The solution was diluted with toluene (16kg), washed with 5% aqueous, sodium chloride (6.4kg), then 6% sodium hydrogen carbonate (6.47kg), then water (6.1kg). The solution was dried azeotropically by distillation of the solvent (20 L) under reduced pressure. Dimethyl sulfoxide (33.9 kg) was added and the remaining toluene was distilled off under reduced pressure, affording 47.3kg of a solution of (lR,2S,5R)-2- isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoate (approx. 13.3 kg) in dimethyl sulfoxide. Example 4. This example illustrates a method of preparing dimethylsulfoxonium methylide (dimethyl(methylene)oxo-λ6-sulfane). Sodium hydroxide powder (1.2kg), prepared by milling sodium hydroxide pellets in a rotary mill through a 1mm metal sieve, and trimethylsulfoxonium iodide (6.2kg) were stirred in dimethyl sulfoxide (25.2kg) under a nitrogen atmosphere at 25°C for 90 min. The solution was used directly in the preparation of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate. Example 5. This example illustrates a method of preparing dimethylsulfonium methylide (dimethyl(methylene)-λ4-sulfane). Sodium hydroxide powder (970mg), prepared by milling sodium hydroxide pellets in a rotary mill through a 1mm metal sieve, and trimethylsulfonium iodide (4.66 g) were stirred in dimethyl sulfoxide (17 ml) under a nitrogen atmosphere at 20-25°C for 10 rain. The solution was used directly in the preparation of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate. Example 6. This example illustrates the preparation of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate A solution of (lR,2S,5R)-2-isopropyl-5-merhylcyclohexyl 3,4-difluorophenyl)-2-propenoate (approximately 8.6 kg) in dimethyl sulfoxide (approximately 27.9 kg) was added with stirring over 20 minutes to a mixture of dimethylsulfoxonium methylide (approximately 2.6kg, prepared as described above), sodium iodide (E)-3-(approximately 4.2 kg), water (approximately 500 g) and sodium hydroxide (approximately 56 g) in dimethyisulfoxide (27.7 kg) at 25°C. The reaction mixture was stirred for a further 2 hours and 50 minutes at 25oC, then used directly for the preparation of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate. Example 7. This example illustrates the preparation of (1R,2S,5R)-2-isopropyl-5-methycyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropancecarboxylate. A crude solution of (1R, 2S, 5R)-2-isopropyl-5-methylcyc]ohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate produced as described in example 6 was heated with stirring from 25°C to 50°C over a 1 hour period and the temperature was maintained for a further hour. The mixture was then cooled with stirring from 50oC to 35°C over 4 hours, kept at 35°C for 1 hour, then cooled to 26°C over 4 hours, kept at 26°C for 1 hour, then cooled to 19°C over 3 hours and kept at 19°C for 5 hours and 10 minutes. The product crystallised and was collected by filtration, affording a crystalline solid (2.7 kg) which was shown to contain a mixture of (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difiuorophenyl)cyclopropanecarboxylate (1.99 kg) and (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1S,2S)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (85 g). Example 8. This example illustrates an alternative method of preparing (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylat.e n-Heptane (82.5 L) was distilled under reduced pressure from a solution of (1R, 2S, 5R)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4-difluorophenyl)cyclopropanecarboxylate (14.3 kg, 44.4 mol) in heptane (128.6 L). The mixture was then cooled from'34°C to 24°C over a period of 3 hours and 20 minutes. Seed crystals of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate were then added and the mixture was cooled to 0°C over a period of 5 hours and 50 minutes. Filtration afforded the product as a crystalline solvent wet solid (7.05 kg) which was shown to contain a mixture of (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1R,2R)-2-(3,4-difmorophenyl)cycIopropanecarboxylate (4.7 kg) and (lR,2S,5R)-2-isopropyl-5-methylcyclohexyl trans-(1S,2S)-2-(3,4-difluorophenyI)cycIopropanecarboxylate (1.1 kg). Example 9. This example illustrates a method of preparing trans-(lR, 2R)-2-{3,4-difluorophenyl)cyclopropanecarboxylic acid. (\R,2S,5R)-2-isoPropyl-5-meihy\cyclohexyl trans-(1R,2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (9.6 kg, 91.8% diastereomeric excess) was dissolved in ethanol (13.8 kg) and heated with stirring to 46'C. 45% Aqueous sodium hydroxide (3.1 kg) was added over a 20 minute period and the mixture was stirred for a further 2 hours and 27 minutes. Solvent (28 L) was distilled out of the mixture under reduced pressure, then the mixture was cooled to 24oC and diluted with water (29.3 kg), after which the liberated menthol was extracted into toluene (3 washes of 3.3 kg each). The remaining aqueous material was acidified to pH 2 with 37% hydrochloric acid (33 L) and the product was extracted into toluene (8.6 kg, then 2 more washes of 4.2 kg and 4.3 kg). The combined toluene extracts were washed with 1% hydrochloric acid (4.9 L), then diluted with further toluene (4.2 kg) and azeotropically dried by distillation of the solvent (25 L) under reduced pressure. A final dilution with toluene (24.2kg) was followed by distillation of the solvent under reduced pressure (10 L) affording a solution containing trans-(lR, 2R)-2-(3,4-difiuorophenyl)cyclopropanecarboxylic acid (approximately 3.45 kg) suitable for the production of trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride. Example 10. This example illustrates a method of preparing trans-(lR, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride. Pyridine (70 ml) was added to a solution of trans-(lR, 2R)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid (approximately 3.45 kg) in toluene (approximately 12 -15 kg) prepared as described above,and the mixture was then heated to 65°C. Thionyl chloride (2.3kg) was added over a period of 1 hour and the mixture was stirred at 70"C for 3 hours. Thionyl chloride (0.5 kg) was added and the mixture was stirred a further 2 hours at 70°C. A final aliquot of thionyl chloride (0.5 kg) was added and the reaction mixture was stirred for 1 hour at 70°C, then cooled to 40oC. Periodic additions of toluene (45 kg, 3 additions of 15 kg each) were made during distillation of solvent (approximately 60 L) from the mixture under reduced pressure, then the solution of trans-(1R, 2R)-2-(3,4-difiuorophenyl)cyclopropanecarbonyl chloride-(approximately 3.8 kg) in toluene (approximately 6 - 9 L) was cooled to 20°C. Example 11. This example illustrates a method of preparing trans-(1R, 2R)-2-(3,4-difiuorophenyl)cyclopropanecarbonyl azide. A solution of trans-(lR, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride (approximately 3.8 kg) in toluene (approximately 6 - 9 L) at 1 oC was added over a period of 74 minutes to a mixture of sodium azide (1.24 kg), tetrabutylammonium bromide (56 g) and sodium carbonate (922 g,) in water (6.2 kg), stirring at 1.5*C. The mixture was stirred at 0°C for 1 hour and 55 minutes, then the aqueous layer was diluted with cold water (3.8 kg), stirred briefly, then separated. The toluene layer was washed once more at 0"C with water (3.8 kg), then with 20% aqueous sodium chloride (3.8 L), then stored at 3 °C for further use. Example 12. This example illustrates a method of preparing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine. A cold solution of trans-(1R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide prepared as described in Example 11 was added over a period of 41 minutes to toluene (6.0 kg) stirring at 100°C. The mixture was stirred for a further 55 minutes at 100°C, then . cooled to 20'C and added over a period of 2 hours and 15 minutes to hydrochloric acid (3M, 18.2 kg) stirring at 80oC After 65 minutes the solution was diluted with water (34 kg) and cooled to 25"C. The toluene layer was removed and the aqueous layer was basified to pH 12 with 45% sodium hydroxide (3.8 kg) and the product was then extracted into ethyl acetate (31 kg) and washed twice with water (13.7 kg per wash), affording a solution containing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess) in ethyl acetate (29.5 L). Example 13. This exampl illustrates a method of preparing trans-(1R,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate. R-(-)-Mandelic acid (2.26 kg) was added to a solution containing trans-(1R,2S)-2-(3,4-difiuorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess), stirring at 17°C in ethyl acetate (45.3 L). The mixture was stirred at 25oC for 3 hours and 8 minutes, then filtered and washed twice with ethyl acetate (13.8 kg total). The crystalline product was dried at 40°C under reduced pressure for 23 hours, affording trans-(lR,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2R)-2-hydroxy-2-phenylethanoate (4.45 kg). WE CLAIM: 1. A process for the preparation of a compound of a formula (I): wherein: R is phenyl substituted with one or more halogen; and Y is OR1, where R1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group; which comprises: reacting a trimethylsulfoxonium salt with a solid metal hydroxide in dimethylsulfoxonium at ambient or an elevated temperature to produce dimethylsulfoxonium methylide; and, contacting compound of formula (II) in which R and Y area as defined above, with the dimethylsulfoxonium methylide in the presence of a solvent at a temperature of -10°C-90°C. 2. A process as claimed in claim 1 wherein: R is phenyl substituted with one or more halogen; and Y is OR1, where R1 is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group; which comprises: group; which comprises: chlorinating a compound of formula (III) by reaction with a chlorinating agent in the presence of an inert solvent and a catalyst at a temperature of 0-200°C; and then reacting the resulting solution with YH or Y-, where Y is as claimed in claim 1, at an elevated temperature to provide a compound of formula (II): reacting a trimethylsulfoxonium salt with a solid metal hydroxide in dimethyl sulfoxide at ambient or an elevated temperature to produce dimethylsulfoxonium methylide; and, contacting the compound of formula (II) with the dimethylsulfoxonium methylide in the presence of a solvent at a temperature of -10°C-90°C. 3. A process as claimed in claim 1 or 2, in which the metal hydroxide is sodium hydroxide. 4. A process as claimed in claim 1 in which a compound of formula (III) is reacted with thionyl chloride in the presence of an inert solvent and pyridine at a temperature of 0-200°C, and the resulting solution is then reacted with YH or Y-, where Y is as claimed in claim 1, at an elevated temperature. 5. A process as claimed in any one of the preceding claims in which YH represents L-menthol. 6. A process as claimed in any one of claims 1 to 5 in which a compound of formula (III) is prepared by contacting a compound of formula (IV): where R is as claimed in claim 1, with malonic acid in the presence of pyridine and piperidine at elevated temperature. 7. A process as claimed in any one of the preceding claims in which R is phenyl substituted by one or more fluorine atoms. 8. A process as claimed in claim 7, in which R is 3,4-difluorophenyl. 9. A process as claimed in any one of the preceding claims in which Y is chiral. 10. A process as claimed in claim 9 in which Y is L-menthoxy. 11. A process as claimed in any one of claims 1 to 10 in which a compound of formula (I) is resolved to yield a compound of formula (Ia): where R and Y are as defined above, by a crystallization or chromatographic method. 12. A process as claimed in claim 11 in which the resolution is carried out by extracting a compound of formula (I) into heptane and then effecting crystallisaiton from the heptane extracts. Dated this 12th day of November, 2002. [DEEPA K. TIKU] Of REMFRY & SAGAR ATTORNEY FOR THE APPLICANTS

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