This application claims priority to Indian patent application 1551/CHE/2010 filed on June 04, 2010 the contents of which are incorporated by reference in their entity.

FIELD OF THE INVENTION:

Present invention relates to an improved process for the preparation of Voriconazole enhanced yield.

BACKGROUND OF THE INVENTION:

Voriconazole is a triazole antifungal agent, used for the treatment of invasive aspergillosis, Fusarium and Scedosporium infections as well as the treatment of resistant candidiasis.

Voriconazole, chemically identified as (2R.,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-l-(lH-l,2,4-triazol-l-yl)-2-butanol shown in formula I. Voriconazole is marketed under the trade name of VFEND by Pfizer in the form of tablets which contain 50 mg or 200 mg of voriconazole for oral administration, Lyophilized powder for solution in intravenous injection and as powder for oral suspension.

Formula I

US patent No's: 5,278,175 and 5,567,817 [Pfizer] discloses Voriconazole and its pharmaceutically acceptable salts. These also discloses a process for the preparation of Voriconazole comprising reacting l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazole-l-yl)ethanone with 4-chloro-6-ethyl-5-fluoropyrimidine in presence of lithium diisopropylamide and in THF medium to yield 3-(4-chloro-5-pyrimidin-6-yl)-2-(2,4-
difluorophenyl)-l-(lH-l,2,4-triazole-l-yl)-butane-2-ol, which is further purified by column chromatography to give 2R,3S / 2S,3R enantiomeric pair. This, on dehalogenation with a 10% Pd/C catalyst in ethanol in presence of sodium acetate, followed by purification using flash chromatography to yield 2R,3S/2S,3R 2-(2,4-difluorphenyl)-3 -(5-fluoropyrimidin-4yl)-1 -(1H-1,2,4-traizol-1 yl)butan-2ol. This on resolution with R-(-)-10-camphorsulfonic acid in methanol and subsequent hydrolysis of camphor sulfonate salt to free base with aqueous sodium bicarbonate solution gives Voriconazole of formula I.

US patent No. 6,586,594 discloses a process for the preparation of Voriconazole comprising condensing 6-(l-bromoethyl)-2,4-dichloro-5-fluoropyrimidine with l-(2,4-difluorophenyl)-2-lH-l,2,4-triazol-l-yl)ethanone in presence of Zinc, lead, Iodine in tetrahydrofuran to yield 2R,3S/2S,3R 3-(4-Chloro5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l-(lH-l,2 ,4-triazol-l-yl)butan-2-ol. This compound on further dehalogenation with 10% Pd/C followed by resolution with R-(-)-10-camphorsulfonic acid and further hydrolized to give Voriconazole of Formula I.

PCT publication WO2006/065726 discloses form A, Form B and Amorphous forms of Voriconazole. It also describes a process for the preparation of Voriconazole. The process includes condensing l-(2,4-difluorophenyl)-2-(l H-l ,2,4-triazole-l-yl) ethanone with 4-ch!oro-6-ethyl-5-fluoropyrimidine, in a ketone, ether, aliphatic hydrocarbon, or aromatic hydrocarbon solvent, to give (2R,3S/2S,3R)-3-(4-chloro- 5-fluoropyrimidin-6-yl)-2-(2,4-diflurophenyl)-l -(1 H-l ,2,4-triazole-l -yl)butan-2-ol which is dehalogenated to give (2R,3S/2S,3R)-2- (2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l -(1 H-l ,2,4-triazol-1 yl)butan-2-ol; resolving (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoro pyrimidin-4-yl)-l-(l H-l ,2,4-triazol-lyl)butan-2-ol to afford a diastereomeric salt of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(l H-l ,2,4-triazol-lyl)butan-2-ol; and converting a diastereomeric salt to voriconazole.

Still there exists a need in the art for the preparation of Voriconazole with enhanced yield and purity.

OBJECT AND SUMMARY OF THE INVENTION:

The principle object of the present invention is to provide an improved process for the preparation of Voriconazole with enhanced yield.

The main aspect of the present invention is to provide an improved process for the preparation of Voriconazole, comprising the steps of:

a) condensing 4-Chloro-6-ethyl-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of a diluted base and suitable solvent to get (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol and treating it with hydrochloride;

b) converting compound of step (a) to its free base and dehalogenating (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(1H-1,2,4-triazol-1 -yl)butan-2-ol;

c) resoluting the obtained compound of step (b); and

d) isolating 2R,3S Voriconazole

DETAILED DESCRIPTION OF THE INVENTION:

The present invention relates to an improved process for the preparation of Voriconazole
comprising condensing 4-Chloro-6-ethyl-5-fluoro pyrimidine and l-(2,4-
difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of a diluted base and suitable solvent to get chloro Voriconazole and converting it to its HC1 salt; treating with base and dehalogenating the chloro Voriconazole; resoluting the obtained compound; and hydrolyzing the obtained compound to isolate Voriconazole.

Accordingly, the present invention provides an improved process for the preparation of Voriconazole comprising the steps of;

a) condensing 4-Chloro-6-ethyl-5-fluoro pyrimidine and 1-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of a diluted base and suitable solvent to get (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol and treating it with hydrochloride

b) converting compound of step (a) to its free base and dehalogenating (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difiuoro phenyl)-1-(1H-1,2,4-triazol-1 -yl)butan-2-ol;

c) resoluting the obtained compound of step (b); and

d) isolating 2R,3S Voriconazole.

The prior art US' 817 process, involves condensation of 4-Chloro-6-ethyl-5-fluoro pyrimidine with l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in the presence of Lithium diisopropylamide (LDA; which is prepared from 1.6 M n-BuLi and diisoproylamine) to yield 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol, in which the desired and undesired diastereomeric percentage is 50-50%. Present inventors surprisingly found that, employing the diluted base such as Lithium diisopropylamide (LDA); for the condensation of 4-Chloro-6-ethyl-5-fluoro pyrimidine with l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone enriches the yield of the desired diastereomer percentage from 50-50% to 67-33 %.

WO 2009020323 discloses that, US' 817 process involves isolation of the desired enantiomeric pair in a yield of only 12 to 25%. Present inventors also found that, during the isolation of 3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro pheny 1)-1-(1H-1,2,4-triazol-l-yl)butan-2-ol the percentage of the desired diastereomer is enriched by filtration, in which the undesired diastereomer is filtered along with the l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone compound since the solvent used for dilution of base is more in the reaction mixture, the ratio of the desired isomer rises to 85%. In addition to this, in the present invention the above obtained compound is further isolated as an acid addition salt, which leads to increase in the percentage of the desired diastereomer from 85 to 98%.

In one embodiment of the present invention, 4-Chloro-6-ethyl-5-fluoro pyrimidine is condensed with l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of a suitable diluted base to give (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol hydrochloride in a suitable solvent selected from aprotic solvents such as THF, 1,4 dioxane, and non-polar solvents selected from diethylether, dimethylether, n-hexane/hexanes, n-heptane, benzene, toluene. Preferably THF.

In another embodiment of the present invention, the diluted base used for condensation of 4-Chloro-6-ethyl-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone is a organo metallic base selected from butyl zinc, lithium diisopropylamide, magnesium isopropylamide, Zinc isopropylamide, preferably lithium diisopropylamide.
In another embodiment of the present invention, the diluted lithium diisopropylamide is prepared by reacting less than 1.6 M n-butyllithium with diisopropylamine to obtain lithium diisopropylamide (LDA). The molarity of the n-butyllithium used for preparing LDA is in the range of 0.30 to 0.45 M, preferably 0.35 to 0.40 M by diluting n-butyllithium with suitable solvent. Solvent used for dilution of n-butyl lithium is selected from non-polar solvents such as n-heptane, n-hexane/hexanes, benzene, toluene, diethylether, preferably n-hexane.

In another embodiment of the present invention, 4-Chloro-6-ethyl-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone is added to the above obtained LDA solution to give (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol hydrochloride in a suitable solvent selected from aprotic solvents such as THF, 1,4 dioxane, and non-polar solvents selected from diethylether, dimethylether, n-hexane/hexanes, n-heptane, benzene, toluene, preferably THF.

In another embodiment of the present invention, (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difiuorophenyl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol hydrochloride is treated with base such as Sodium acetate, Potassium acetate, and dehalogenated with a suitable catalyst and suitable solvent. Catalyst used for dehalogenation is selected form Palladium/C, Rhodium, Raney nickel, a suitable hydrogen donor such as ammonium formate or potassium formate. Preferably Pd/C. Solvent used for dehalogenation is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, butanol, preferably methanol.

In another embodiment of the present invention, the above obtained compound is resoluted with a resoluting agent in suitable solvent, wherein the resoluting agent is selected from R-(-)-10-Camphor sulphonic acid, L-(-)-tartaric acid, L (+)-mandelic acid and P-toluoyl tartaric acid, preferably R-(-)-10-Camphor sulphonic acid. Solvent used for resolution is selected from alcohols such as methanol, ethanol, n-propanol, iso-propanol, butanol, ketones such as acetone, methylbutylketone or mixture of solvents selected form alcohols and ketones such as methanol and acetone. Preferably mixture of solvents.
In another embodiment of the present invention, the above obtained compound is hydrolysed in presence of a base to isolate Voriconazole.

As per the present invention, 4-Chloro-6-ethyl-5-fluoro pyrimidine is condensed with 1-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of 0.30 to 0.40 molar LDA and THF to yield (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol hydrochloride. This on dehalogenation with Pd/C in methanol gives racemic Voriconazole. Resolution of racemic Voriconazole with R-(-)-10-Camphor sulphonic acid in mixture of methanol and acetone gives 2R,3S Voriconazole.

According to present invention, Overall yield of the Voriconazole is higher. And better diastereomeric ratio is obtained at the condensation step of Pyrimidine derivative with Ethanone derivative over the prior art.

The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in
any way.

Comparative Example: Preparation of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol hydrochloride:

To a solution of 600 ml of THF, 63.2 g of Diisopropylamine was added; stirred at room temperature and cooled to -20 to -30 °C. To this 392 ml of 1.6 M n-butyllithium in hexane was added at -20 to -30 °C and further cooled to -65 to -70°C. To the resulting lithium diisopropylamide solution was added 100 g of 4-Chloro-6-ethyl-5-fluoro pyrimidine and 139.2 g of l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone dissolved in THF at -65 to -70 °C. After completion of the reaction, (Ratio of desired and undesired disteroisomer (37:63) 100 ml of acetic acid was added at -70 to -30 °C followed by addition of 1000 ml of DM water and slowly temperature was raised to -10 to 5 °C. The organic layer was separated from filtrate and washed with 1800 ml of water. Organic layer was concentrated to get residue by distilling off hexane and THF under reduced pressure .The obtained solid was taken in ethyl acetate and was added 100 ml of hydrogen chloride in IPA at 25-30 °C. The slurry was cooled and obtained solid was filtered to yield ethanone hydrochloride salt and mother liq. contains the tilted compound. Ratio of desired and undesired disteroisomer is 39:61.

Examples:

Preparation of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro
phenyl)-1 -(1 H-l ,2,4-triazol-l -yl)butan-2-ol hydrochloride:

To a solution of 100 ml THF 125 g of Diisopropylamine was added, stirred at room temperature and cooled to -18 to -23 °C. To this 548 ml of 1.6 M n-butyllithium in hexane diluted with 1650 ml of n-hexane/hexanes was added at -14 to -26 °C and further cooled to -65 to -74°C. To the resulting lithium diisopropylamide solution, was added 100 g of 4-Chloro-6-ethyl-5-fluoro pyrimidine and 271 g of 1-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone dissolved in THF at -65 to -74 °C. After completion of the reaction, 100 ml of acetic acid was added at -70 to -30 °C followed by addition of 1000 ml of DM water and slowly temperature was raised to -10 to 5 °C. The reaction mixture was filtered and the residue washed with hexanes. The wet residue was dried to get 180 g of dry solid. The organic layer was separated from filtrate and washed with 1800 ml of water. Organic layer was concentrated to get residue by distilling off hexane and THF under reduced pressure to get 160 g of solid. The obtained solid was taken in ethyl acetate and was added 100 ml of hydrogen chloride in IPA at 25-30 °C. The slurry was cooled and obtained solid was filtered to yield the tilted compound. (Ratio of desired and undesired disteroisomer is 98:2

Preparation of (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl..)butan-2-ol (Racemic Voriconazole):

To the 1000 ml of methanol, was added 100 g of (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol hydrochloride and stirred. To this was added 48.8 g of sodium acetate and stirred to form slurry. The obtained slurry was transferred into hydrogenator and was added 10 g of 5% Pd/C, After completion of the reaction, hydrogen gas was released from autoclave and the reaction mass was filtered through hyflow bed. The obtained residue was washed with methanol and collected filtrate. The collected filtrate was concentrated under reduced pressure at below 50 °C to get solid residue and cooled to 23-30 °C and then added 1000 ml of water, stirred, filtered, and the resulted product was washed with water and dried to get 66-70 g of racemic Voriconazole.

Preparation of (2R, 3S)- 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol R(-)-10-camphor sulphonate (Voriconazole Camphor sulphonate):

100 g of Racemic Voriconazole was taken in 1000 ml of acetone. 66.50 g of R-(-)-10-Camphorsulfonic acid dissolved in methanol, to this was added racemic Voriconazole solution in acetone at 23-30 °C, stirred for 30 mins and heated to reflux for 20 mins at 57-65 °C. The reaction mixture was slowly cooled to 23-30 °C and continued stirring for 2 hrs. The reaction mixture was filtered and washed with acetone, dried under reduced pressure to get 55-59 g of product.

Preparation of (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l, 2, 4-triazol-l-yl)butan-2-ol (Voriconazole):

To the 100 g of Voriconazole camphor sulphonate was added 500 ml of DM water and 500 ml of dichloromethane at 23-30 °C and stirred. pH of the reaction mass was adjusted 9.4 to 9.8 with sodium carbonate. Stirred the reaction mass for 10 mins and separated the organic layer. Product was extracted from aqueous layer with dichloromethane. Both the organic layers were combined and washed with DM water. The solvent was distilled off completely form organic layer to obtain a residue, to this IPA was added and distilled off to remove the traces of dichloromethane. To the residue 240 ml of IPA was added and heated to 47-50 °C and maintained for 20 mins to form slurry. The slurry was cooled to 0-5 °C. Filtered, separated solid was washed with IPA and dried to get 47-51 g of 2R, 3S Voriconazole.

We Claim:

1. An improved process for the preparation of Voriconazole comprising:

a) condensing 4-Chloro-6-ethyl-5-fluoro pyrimidine and 1-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone in presence of a diluted base and suitable solvent to get (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol and treating it with hydrochloride

b) converting compound of step (a) to its free base and dehalogenating (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(1H-1,2,4-triazol-1 -yl)butan-2-ol;

c) resoluting the obtained compound of step (b); and

d) isolating 2R,3S Voriconazole.

2. The process according to claim 1, wherein the diluted base is selected from organo metallic bases.

3. The process according to claim 2, wherein the organo metallic base is lithium diisopropylamide which is diluted with an organic solvent.

4. The process according to claim 3, wherein the organic solvent is selected from non-polar organic solvent.

5. The process according to claim 4, wherein the non-polar organic solvent is selected from n-heptane, n-hexane/hexanes, benzene, toluene, diethylether, preferably n-hexane.

6. The process according to claim 1, wherein the dehalogenating agent is used for dehalogenation is selected from palladium/C, Rhodium, Raney nickel in presence of a suitable hydrogen donor.

7. The process according to claim 6, wherein the suitable hydrogen donor is selected from ammonium formate, potassium formate and the like.

8. An improved process for preparing (2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluoro phenyl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol by condensing 4-Chloro-6-ethyl-5-fluoro pyrimidine and l-(2,4-difluorophenyl)-2-(lH-1,2,4-triazol-l-yl)ethanone in presence of a diluted LDA.

9. The process according to claim 8, wherein diluted LDA is prepared by using 0.30 to 0.45 M n-BuLi.

10. The process according to claim 8, wherein (2R, 3S/2S, 3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2, 4-diffuoro phenyl)- 1-(1H-1, 2, 4-triazol-l-yl) butan-2-ol is further converted into Voriconazole.