PROCESS FOR THE PREPARATION OF CYCLOPROPYL CARBOXYLIC ACID ESTERS AND DERIVATIVES

Abstract: The invention relates to a novel process for the preparation of certain cyclopropyl carboxylic acid esters and other cyclopropyl carboxylic acid derivatives; a novel process for the preparation of dimethylsulfoxonium methylide and dimethylsulfonium methylide; to the use of certain cyclopropyl carboxylic acid esters in a process for the preparation of intermediates that can be used in the synthesis of pharmaceutically active entities; and to certain intermediates provided by these processes.

Description: PROCESS FOR THE PREPARATION OF CYCLOPROPYL CARBOXYLIC ACID ESTERS AND DERIVATIVES FIELD OF THE INVENTION The present invention relates to a novel process for the preparation of certain cyclopropyl carboxylic acid esters and other cyclopropyl carboxylic acid derivatives; a novel process for the preparation of dimethylsulfoxonium methylide and dimethylsulfonium methyhde; to the use of certain cyclopropyl carboxylic acid esters in a process for the preparation 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 the invention therefore provides a process for the preparation of a compound of formula (I) : (I) wherein: R is phenyl substituted with one or more halogen; Y is OR , where R is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group (eg bornyl), which comprises contacting a compound of formula (II): O I! ■ R-CH=CH- C — (π) 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 trimethylsulfoxonium 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 trimethylsulfoxpnium 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): O II R-CH=CH- C — OH (HI) 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 70°C. 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): O R— C — H (TV) 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): (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): (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): O R- . 1. C— N, (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-7j-butylammonium 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): R — t — ± NH 3 +CI- (vπi) 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- 90°C. An unprotonated parent amine (free base) of formula (IX): R^ NH 2 (LX) 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 - z ?-(-)-mandelic acid salt of a compound of formula (IX) can be generated by addition of i?-(-)-mandelic acid at ambient or an elevated temperature to a solution of a compound of foπnula (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-fluorophenyl 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 diastereoisomers). The process of this invention includes all such isomeric forms and mixtures thereof in all proportions. Where Y is chiral, a compound of formula (I) will be a mixture of diastereoisomers and can be resolved to yield a diastereomerically-enriched compound of formula (la): 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 the desired quality are formed. The crystals are then collected by filtration. Alternatively, the resolution can be carried out in any other suitable solvent, such as a hydrocarbon, eg heptane by extracting a compound of formula (I) into a suitable amount of the solvent, heating the extracts until total dissolution is achieved, then cooling at an appropriate rate until sufficien crystals of the desired quality are formed. Optionally the organic extracts can be washed wit! water, dried over magnesium sulfate and filtered prior to the crystallisation described above. A compound of formula (la) 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 foπnula (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 foπnula (Via) can be used in the synthesis of a compound of fonnula (Vila): where R is as defined above, using the method described above for the conversion of a compound of fonnula (VI) to yield a compound of formula (VII). A compound of formula (Vila) can be used in the synthesis of a compound of fonnula (Villa): (Vllla) where R is as defined above, using the method described above for the conversion of a compound of fonnula (VII) to yield a compound of foπnula (VIII). A compound of fonnula (Villa) can be used in the synthesis of a compound of foπnula (IXa): (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 (IX). The i?-(-)-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 foπnula (IX). Novel compounds form a further aspect of the invention. In a further aspect the invention therefore provides compounds of formula (I), (la), (II), (III), (V), (Va), (VI), (Via), (VII), (Vila), (VIII), (Villa), (IX) and (IXa) as defined above. Particularly preferred compounds include: (1R, 2S, 5i?)-2-isopropyl-5-ιnethylcyclohexyl trans-2-(3,4- diflμorophenyl)cyclopropanecarboxylate; (li?,2S,5i?)-2-isopropyl-5-methylcyclohexyl trans- (1R, 2R)-2-(3,4- difluorophenyl)cyclopropane carboxylate; (li?,2S,5i?)-2-isopropyl-5-me t hylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-piOpenoate; (E)-3-(3,4-difluorophenyl)-2-ρropenoic acid; (E)-3 -(3 ,4-difluorophenyl)-2-propenoyl chloride; trans-(lR, 2i?)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid; trans-(lR, 2i?)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride; trans-(lR, 2R)-2-(3 ,4-difluorophenyl)cy clopropanecarbonyl azide; tra/M-(li?,2S)-2-(3,4-difluorophenyl) cyclopropyl amine; and trα7W-(li?,2S)-2-(3,4-difluorophenyl)cyclopropanaminium (2i?)-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-difluorophenyl)-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 strrred at 90°C 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 1 % 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 stiff ed 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 (li?,2S,5i?)-2-isopropyl-5-mefhylcyclohexyl (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 (li?,2S,5i?)-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 (dunethyl(rnethylene)oxo-λ 6 -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 stined 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 t7- /w-2-(3,4-difluorophenyl)cyclopropanecarboxylate. Example 5. This example illustrates a method of preparing dimethylsulfonium methylide (dimethyl(methylene)-λ 4 -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 stined in dimethyl sulfoxide (17 ml) under a nitrogen atmosphere at 20-25°C for 10 min. The solution was used directly in the preparation of (1R, 2S, 5i?)-2-isopropyl-5- methylcyclohexyl trø/zs-2-(3,4-difluorophenyl)cyclopropanecarboxylate. Example 6. This example illustrates the preparation of (1R, 25, 5i?)-2-isopropyl-5-methylcyclohexyl t7Yrøs-2-(3,4-difluorophenyl)cyclopropanecarboxylate A solution of (li?,2S,5i?)-2-isopropyl-5-methylcyclohexyl 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 dimethylsulfoxide (27.7 kg) at 25 C C. The reaction mixture was stined for a further 2 hours and 50 minutes at 25°C, then used directly for the preparation of (li?,2S,5i?)-2-isopropyl-5- methylcyclohexyl t7-Ω7« , -(1^2i?)-2-(3,4-difluorophenyi)cycloproρanecarboxylate. Example 7. This example illustrates the preparation of (li?,2S,5i?)-2-isopropyl-5-methylcyclohexyl trans-( lR,2R)-2-{3 5 4-difluorophenyl)cyclopropanecarboxylate A crude solution of (1R, 2S, 5i?)-2-isopropyl-5-methylcyclohexyl 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 50°C 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 (li?,2S,5i?)-2-isopropyl-5-methylcyclohexyl trans-(lR,2R)- 2-(3,4-difluorophenyl)cyclopropanecarboxylate (1.99 kg) and (li?,2S,5i-)-2-isopropyl-5- methylcyclohexyl t7O7«-(lS,2S)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (85 g). Example 8. This example illustrates an alternative method of preparing (li?,2S,5 J R)-2-isopropyl-5- methylcyclohexyl t7- 7W-(li?,2/?)-2-(3,4-difluorophenyl)cyclopropanecarboxylate n-Heptane (82.5 L) was distilled under reduced pressure from a solution of (1R, 2S, 5R)-2- isopropyl-5-rnethylcyclohexyl t7-α7«-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 (li?,2S,5i?)-2-isopropyl-5- methylcyclohexyl t7-α7i5 , -(li?,2i?)-2-(3,4-difluorophenyl)cycloproρanecarboxylate 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 (li?,2S,5 ?)-2-isopropyl-5-methylcyclohexyl trans-(lR,2R)- 2-(3,4-difluorophenyl)cyclopropanecarboxylate (4.7 kg) and (li?,2S,5i?)-2-isopropyl-5- methylcyclohexyl t7^ms-(lS,2S)-2-(3,4-difluorophenyl)cyclopropanecarboxylate (1.1 kg). Example 9. This example illustrates a method of preparing trans-(lR, 2R)-2-(3,4- difluorophenyl)cyclopropanecarboxylic acid. (li?,2S,5i?)-2-isoPropyl-5-methylcyclohexyl t7-α7M-(li?,2i?)-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 24 ° C 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 (3.3 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-difluorophenyl)cyclopropanecarboxylic acid (approximately 3.45 kg) suitable for the production of trans-(lR, 2i?)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride. Example 10. This example illustrates a method of preparing trans-(lR, 2i?)-2-(3,4- difluorophenyl)cyclopropanecarbonyl chloride . Pyridine (70 ml) was added to a solution of trans-(lR, 2i?)-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 stined at 70°C for 3 hours. Thionyl chloride (0.5 kg) was added and the mixture was stined a further 2 hours at 70°C. A final aliquot of thionyl chloride (0.5 kg) was added and the reaction mixture was stined for 1 hour at 70°C, then cooled to 40°C. 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 t7-ατM- (1R, 2i?)-2-(3,4-difluorophenyl)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-(lR, 2R)-2-(3,4- difiuorophenyl)cyclopropanecarbonyl azide. A solution of trans-(lR, 2 ?)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride (approximately 3.8 kg) in toluene (approximately 6 - 9 L) at 1°C 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 stined 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 5 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-(lR,2S)-2-(3,4- l o difluorophenyl)cyclopropylamine. A cold solution of trans-(lR, 2i?)-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 is cooled to 20°C and added over a period of 2 hours and 15 minutes to hydrochloric acid (3M, 18.2 kg) stirring at 80°C 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%o 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 20 containing t7O72s-(l ?,2S)-2-(3,4-difluorophenyl)cyclopropylamine (2.6 kg, 91.8% enantiomeric excess) in ethyl acetate (29.5 L). Example 13. This example illustrates a method of preparing trα7W~(li?,2S)-2-(3,4- 5 difluorophenyl)cyclopropanaminium (2i?)-2-hydroxy-2-phenylethanoate. i?-(-)-Mandelic acid (2.26 kg) was added to a solution containing t7"Ω7W-(li?,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 25°C for 3 hours and 8 minutes, then 0 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 (2i?)-2~hydroxy-2-phenylethanoate (4.45 kg).

Claims: Claims 1. A process for the preparation of a compound of fonnula (I): (I) wherein: R is phenyl substituted with one or more halogen; Y is OR , where R is a straight chain alkyl, branched alkyl, cycloalkyl, or a substituted bicycloheptyl group; which comprises contacting a compound of fonnula (II): O II R-CH=CH- C — Y (II) where R and Y are as defined above, with dimethylsulfoxonium methylide in the presence of a solvent at a temperature of -10°C - 90°C. 2. A process for the preparation of a compound of formula (I) as claimed in claim 1 comprising the steps of; i) reacting a trimethylsulfoxonium salt with a solid metal hydroxide in dimethyl sulfoxide at ambient or an elevated temperature to produce dimethylsulfoxonium methylide; and ii) contacting compound of foπnula (II) with dimethylsulfoxonium methylide in the presence of a solvent at a temperature of -10°C - 90°C. A process according to claim 2 in which the metal hydroxide is sodium hydroxide. 4. A process according to any one of the preceding claims in which the compound of foπnula (II) is prepared from a compound of formula (III): O II R-CH=CH- C — OH (III) where R is as defined in claim 1 , by reaction with a chlorinating agent in the presence of an inert solvent and a catalyst at at a temperature of 0-200°C, and then reacting the resulting solution with YH or Y ~ , where Y is as defined in claim 1, at an elevated temperature. 5. A process according to claim 4 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 defined in claim 1, at an elevated temperature. 6. A process according to any one of the preceding claims in which YH represents L- menthol. 7. A process according to any one of claims 4 to 6 in which a compound of formula (III) is prepared by contacting a compound of fonnula (IV): O R— C — H (IV) where R is as defined in claim 1 , with malonic acid in the presence of pyridine and piperidine at elevated temperatures. 8. A process for the preparation of a compound of fonnula (V): (V) where R is as defined in claim 1, comprising base hydrolysis of a compound of foπnula (I). 9. A process according to claim 8 wherein base hydrolysis is achieved using an alkali metal hydroxide and solvent at 10 - 100°C. 10. A process for the preparation of a compound of foπnula (VI) : (VI) where R is as defined in claim 1, from a compound of foπnula (V) by reaction with thionyl chloride in the presence of solvent and a catalyst at 0-200°C. 11. A process for the preparation of a compound of formula (VII): (VII) where R is as defined in claim 1, from a compound of fonnula (VI), by reaction with an alkali metal azide in the presence of a phase transfer catalyst, aqueous potassium carbonate and an inert solvent. 12. A process for the preparation of a compound of fonnula (VIII): R— ^ NH 3 +CI- (viπ) where R is as defined in claim 1, from a compound of formula (VII), by reanangement in toluene at elevated temperatures, and subsequent reaction with hydrochloric acid at elevated temperatures. 13. A process for the preparation of a compound of formula (IX): R^ NH 2 . (ix) where R is as defined in claim 1, by adjusting to pH 10 or more an aqueous solution of the salt of a compound of formula (VIII). 14. A process for the preparation of a compound the mandelic acid salt of a compound of formula (IX) by addition of i?-(-)-mandelic acid to the compound of formula (IX) as made in claim 13, at ambient or an elevated temperature. 15. A process according to any one of the preceding claims in which R is phenyl substituted by one or more fluorine atoms. 16. A process according to claim 15 in which R is 3,4-difluorophenyl. 17. A process according to any one of the preceding claims in which Y is chiral 18. A process according to claim 17 in which Y is L-menthoxy. 19. A process according to any one of claims 1 to 18 in which a compound of formula (I) is resolved to yield a compound of formula (la): where R and Y are as defined in claim 1, by crystallisation or by chromatrographic methods 20. A process according to claim 19 in which the resolution is earned out by extracting a compound of formula (I) into heptane and then effecting crystallisation from the heptane extracts. 21. The intermediate compounds of fonnulae (I), (la), (II), (III), (V), (Va), (VI), (Via), (VII), (VIIa\ (VIII), (Villa), (IX) and (IXa) above. 22. The intermediate compounds; (\R, IS, 5#)-2-isopropyl-5-methylcyclohexyl trans-2-(3,4- difluorophenyl)cyclopropanecarboxylate; (lΛ,25,5Λ)-2-isopropyl-5-methylcycIohexyl trans- (1Λ, 2/?)-2-(3,4- difluorophenyl)cyclopropane carboxylate; (l ?,2S,5 ?)-2-isopropyl-5-methylcyclohexyl (E)-3-(3,4-difluorophenyl)-2-propenoatε; (E)-3-(3,4-difluorophenyl)-2-propenoιc acid; (E)-3-(3,4-difluorophenyl)-2-propenoyl chloride; trans-{ 1R, 2Λ)-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid; frans-(lR, 2Λ)-2-(3,4-difluorophenyl)cyclopropanecarbonyl chloride; trans-(\R, 2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyi azide; trans-( 1 Λ,2S)-2-(3,4-difluorophenyl) cyclopropyl amine; ιnd tra«5-(l/?,2S)-2-(3,4-difluorophenyl)cyclopropanammium (2/?)-2-hydroxy-2- henylethanoate

Inventors: CLARK ADRIAN, JONES ELFYN, LARSSON ULF, MINIDIS ANNA, CLARK, ADRIAN, JONES, ELFYN, LARSSON, ULF, MINIDIS, ANNA
Applicants: ASTRAZENECA AB, CLARK ADRIAN, JONES ELFYN, LARSSON ULF, MINIDIS ANNA, CLARK, ADRIAN, JONES, ELFYN, LARSSON, ULF, MINIDIS, ANNA
Application year: 2001
Main classification: C07C67
IPC codes: C07B61, C07C27, C07C57, C07C61, C07C67, C07C69, C07C209, C07C211, C07C247