EP1899327A1

EP1899327A1 - Improved process for the preparation of 2r, 3s-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1h-1,2,4-triazol-1-yl) butan-2-ol (voriconazole)

Info

Publication number: EP1899327A1
Application number: EP06780522A
Authority: EP
Inventors: Manne Satyanarayana Reddy; Chakilam Nagaraju; Achampeta Kodanda Ramprasad
Original assignee: MSN Laboratories Pvt Ltd
Current assignee: MSN Laboratories Pvt Ltd
Priority date: 2005-06-30
Filing date: 2006-06-26
Publication date: 2008-03-19
Also published as: WO2007013096A8; WO2007013096A1

Abstract

The present invention relates to an improved process for the preparation of 2R, 3S-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl) butan-2-ol. It may be represented as Formula (I).

Description

Improved process for the preparation of 2R, 3S-2-(2,4-Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-1, 2,4- triazol-1-yl) butan-2-ol (Voriconazole)

FIELD OF THE INVENTION

The present invention relates to a improved process for the preparation of 2R, 3S-2-(2,4- Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol It may represented as Formula ( I )

Formula ( I )

BACK GROUND OF THE INVENTION

Voriconazole exhibits excellent antifungal activity against a wide range of yeasts and filamentous fungi as demonstrated by in vitro and in vivo infection models. Viroconazole has excellent activity in vitro against Aspergillus species, shows efficacy in vivo models of aspergillosis and has demonstrated efficacy in both acute and chronic aspergillosis, with few observed side effects. Depending on the results of future clinical trials, this drug promises to become an important new agent in the treatment of invasive infections due to Aspergillus and other life- threatening fungal infections. US 5,567,817 patent discloses relates to 2-aryl 3-(3-haloρyridin-4-yl or 5- halopyridin-4-yl)-l-(lH-l,2,4 triazol-l-yl)alkane-2ol derivatives which are useful in the treatment of fungal infections in animals,including human beings.

The US 5567817 discloses process for the preparation comprises of reacting 4- chloro-6-ethyl-5-fluoropyrimidine with l-(2,4-difluorophenyl)-2-(lH- 1 ,2,4- triazol-l-yl)ethanone in presence of Lithium diisopropy amine in Tetrahydrofuron as a solvent to get 2-(2,4-difluoroρhenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-l- (lH-l,2,4triazol-l-yl)butan-2-ol the compound, which is further dehaloginated with 5% palladium charcol to give a Racemic Voriconazole and then resolution with camphorsufonic acid in presence of methanol medium and subsequently converted to free base with alkaline medium to give (-) Isomer of Voriconazole of Formula ( I )

Many other related patents disclose the process for the preparation of Voriconazole and its intermediates but none of those patents are related to the process of the present invention.

The prior art procedures the usage of hazardous and costly rawmaterials such as palladium on charcol and the process of the prior art reference involves a tedious work up to isolate the required product and thus results in excess time cycle which is turns resulted low yields and more scale up problems, due to that this process disclosed in the prior art become commercially not viable and not recommendable for commercial scale up.

As the Voriconazole compound of formula ( I ), which is useful in the treat ment of antigungal hence it is important to have alternate process which is cost effective and commercially viable for preparing the compound of Formula ( I ). Therefore the main objective of the present invention is to prepare Voriconzole in improved method, which is cost effective, commercially viable and easily scalable.

The Voriconazole is prepared in the present invention, in an improved process that is cost effective and the Voriconazole obtained in this process is suitable for pharmaceutical formulations

SUMMERY OF THE INVENTION

The present invention provides an improved process for the preparation of Voriconazole and its pharmaceutically acceptable salts, the improved process of the present invention comprises, the condensation of 4-chloro-6-ethyl-5- ffluoropyrimidine with 1 -(2,4-difluorophenyl)-2-( IH- 1 ,2,4-triazol- 1 -yl)ethanone in presence of Lithium diisopropylamine as a base and n-Heptane as a solvent mixture with tetrahydrofuron to get the resulting compound 2-(2,4- difluorophenyl)-3 -(4-chloro-5-fluoropyrimidin-4-y I)- 1 -( 1 H- 1 ,2,4triazol- 1 - yl)butan-2-ol as solid. Which is then dehalogination with Raney nickel to give racemic compound of Voriconazole, which is further resolution with camphour sulfonic acid in acetone and methanol mixture to give camphor sulfonate slat of Voriconazole, which is then basified in aqueous alkaline medium and subsequent extraction with methylene chloride and distillation of solvent then isolation of the Voriconazole compound of formula ( I ) using alcohol medium as a solvent.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to an improved process for the preparation of 2R, 3S-2-(2,4- difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol (commonly known as Voriconazole) The process of the present invention is schematically represented as follows.

Formula (II) (III)

Raney Nickel/Sodium aoetate/Methanol

Voriconazole Formula (I)

4-Chloro-6-ethyl-5-fluoropyrimidine (having pH above 5) reacts with 1- (2,4difluorophenyl)2-(lH-l,2,4-triazol-l-yl)ethanone in presence of Lithium diisopropylamine as a base and a mixture of n-Heptane ,n-Hexan and tetrahydrofuron as solvent medium to yield 2-(2,4 -difluorophenyl) -3-(4-chloro-5-fluoropyrimidin-4-yl)-l- ( IH-1, 2,4- l-yl)butan-2-ol Formula ( IV ).The compound of formula (IV ) is then dehalogination with Raney nickel under Hydrogen pressure in methanol as a solvent medium to give a 2R,3S/2S,3R)-2-(2,4difluoroρhenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol Formula ( V ), the compound of formula (V) further resolution with R-( - ) 10- camphour sulfonic acid with the mixture of solvents Acetone and Methanol to gives an improved yields of Formula (VI) .

Accordingly, the present invention provides an improved process for the preparation of the 2R, 3S-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l -(1H-1, 2,4- triazol-1-yl) butan-2-ol (commonly known as Voriconazole)

a) Taking n-Heptane and diisopropylamine then adding n-Butylithium at below - 2O⁰C b) Adding 4-chloro-6-ethyl-5-fluoropyrimidine and l-(2,4-difluorophenyl)-2-(l H- 1,2,4- triazol-1-yl) ethanone in Tetrahydrofuran at a temperature of about -50 to -75°C, preferably at a temperature of about -50°C, c) Stirring the resulting reaction mixture at a temperature of about -50 to -80°C, preferably at a temperature of about -65 to -75 °C for 3 - 6 hours, d) Adding the Acetic acid at below-50°C followed by addition of water to the reaction mixture at below -10°C, e) Raising the reaction mixture temperature to 10 to 15⁰C, f) Filtering the separated unwanted product and wash with chilled n-Heptane, g) Washing the filtrate with water 2 - 6 times, preferably 4 -5 times and separate the organic phase, h) Cooling the organic phase to -15 to -2O⁰C for isolation of the product i) Stirring the reaction mixture further for 1-6 hours, preferably for 2-3 hours and filter the obtained product, j) Drying the obtained wet material under vacuum at below 40⁰C to get the compound of formula (IV) pH of the 4-chloro-6-ethyl-5-fluoropyrimidine is checked by talcing the 1% of compound in methanol and water to the ratio of 9:1, In the same reaction, after the addition of butyl lithium to diisopropyl amine, metal exchanges can be done with Zinc chloride or with Zinc bromide as well as with magnesium halide to prepare respective organo metallic bases to get the chiral ratio in more percentage from other unwanted isomer of the title compound.

The another embodiment of present invention provides process for the preparation of compound of (2R,3S/2S,3R)-2-(2,4-difiuorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol formula (V), which comprises of ;

a) Adding the compound of Formula (IV ), Raney nickel, methanol and sodium acetate in a pressure vessel, b) Maintaining the hydrogen pressure at 4-6 kg/cm² at 40-50°C for 4-6 hours, c) After completion of the reaction filtering the raney nickel and distill the methanol, d) Basification of the obtained crude material with sodium hydroxide solution, e) Isolation of the title compound and wash with water, f) Drying the product at below 6O⁰C under vacuum.

Another embodiment of the present invention is to provide process for the 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 (-)-lO-camphor sulphonate compound of formula (VI) which comprises of ;

a) Dissolving the compound of formula (V) in acetone, b) Dissolving the R-(-) 10-camphorsulphonic acid in methanol, c) Adding step-b solution to step-a and stirring the reaction mixture at 5-25°C for 1- 4 hours, preferably at 15-2O⁰C for 2-3 hours, d) Filtering the obtained product and optionally drying the compound at 40-80⁰C, preferably at 60-70⁰C to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l(lH-l,2,4-triazol-l-yl)-butan-2-ol, R (-)-lO-camphor sulphonate compound of formula (VI). Above obtained product was carried over to next stage to obtain the product, 2R,3S-2- (2₅4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan-2-ol (commonly known as Voriconazole), the process which comprises of;

a) Adjusting the pH of the compound of formula (VI) in water by treatment with an alkali or alkaline earth metal hydroxide or carbonates, preferably sodium hydroxide solution, b) Extracting the compound using water insoluble solvent, namely chloro solvents, ester solvents, less polar solvent like toluene, xylene, cyclohexane and n-heptane, preferably using chloro solvent, most preferably dichloromethane as a solvent, c) Distillation of the solvent to obtain crude Voriconazole, d) Adding alcoholic or ketonic solvent, preferably alcoholic solvent, most preferably 2-propanol to the residue, e) Stirring the reaction mixture at 0-10⁰C for 30 miuntes to 2 hours, f) Filtering the obtained pure Voriconazole, g) Drying the Voriconazole at a temperature of about 50-80°C, preferably at a temperature of about 60-70°C.

The Voriconazole obtained in the present improved process is free flowing and non- solvated solid; hence it is well suited for pharmaceutical formulations, The process of the present invention is cost effective and getting a more yields, eco- friendly and well suited for scale up.

The examples mentioned below demonstrate specific preparations of the present invention. The examples are provided to illustrate the details of the invention and should not be construe the limit of the scope of the present invention.

EXAMPLES

Example-1 :

Preparation of 4-chloro-6-ethyI-5-fluoropyrimidine.

To a mixture of 6-ethyl-5-fluoro-4-hydroxy pyrimidine (lOOgr), dichloromethane (300ml) and triethylamine (70 gr) was slowly added phosphorous oxychloride (118 gr) over three hours stirring the reaction mixture temperature below 4O⁰C during the addition. The mixture was heated under reflux for 5 hours, cooled to 25 °C and cautiously quenched into 3N aqueous hydrochloric acid solution (440 ml) maintaining the temperature below 20°C during this operation layers were separated, the aqueous layer extracted with 100 ml of dichloromethane, the obtained organic layer was washed with water (250 ml) and then with 10% sodium bicarbonate solution till to get the aqueous layer pH above 7.0. stripped of the solvent under reduced pressure at below 60°C. the residue is distilled under reduced pressure (at 70-80°C, Vac 750mm/Hg) to get highly ρure 4-chloro-6-ethyl-5-fluoropyrimidine. Yield : 84 gr (Purity by HPLC : >99.0%, pH of the product 6.8).

Example -2 :

Preparation of (2R,3S/ 2S,3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)- 2-(2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yI) butan-2-ol n-Heptane 112.5 ml and diisopropylamine 9.4g were taken, cooled the solution to -20 ⁰C to - 25.O⁰C and then added n-Butyl lithium (41.0ml) slowly. Stirred the reaction mixture at a temperature of about -20 to -25°C for 2-4 hours. This freshly prepared lithium diisopropylamide is further cooled to -65 to -7O⁰C, added 4-chloro - 6- ethyl - 5- fluoropyrimidine (7.5g)(having pH range between 5 to 8) slowly to the above solution at a temperature of about -65 to -70⁰C and then added a solution of l-(2,4-difluorophenyl)- 2-(lH-l,2,4-triazol -l-yl)ethanone (20.8grams) in Tetrahydrofuran (75.0ml) at a temperature of about -65 to -7O⁰C and the reaction mixture stirred at below -70⁰C for forther 3-4 hours added acetic acid (7.5ml) to the reaction mixture at below -50⁰C and then added water (75.0ml) at below -10°C. Allowed the reaction mass temperature to 15°C and separated the unwanted material by filteration and collected the filtered organic layer separated the bottem aqs layer and organic layer washed with a water then cooled this organic layer to -15 to -20°C and maintained the same temperature for further 2.0hours and filtered the reaction mass and washed the material with chilled n-Heptane (7.5ml) and dried under vacuum at below 50°C to affored 5.5grams of (2R,3S/ 2S,3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)-2-(2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yl) butan-2-ol (2R,3S/2S,3R isomer ratio 75% : 25%).

EXAMPLE -3:

Preparation of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-

(lH-l,2,4-triazol-l-yI) butan-2-ol.

20.0grams of (2R, 3 S/ 2S, 3R): (2R,3R/2S,3S)-3-(4-chloro-5-fluoropyrimidin-6- yl)-2- (2,4 - difluorophenyl)-l-(lH - 1,2,4-triazol-l-yl) butan-2-ol,7.2 grams of sodium acetate ,7.0 grams of Raney nickel and 100.0ml of methanol were charged in hydrogenation vessel. Maintained Hydrogen pressure at 4-6 kg/cm² at the temperature 40-50°C for 4-6 hours and after completion of the reaction by the TLC separated the raney nickel at 25- 35⁰C by filteration, filterate distilled off under reduced pressure at below 70°C, 150 ml of water added to this crude and adjusted the pH between 11.0 to 12.0 with sodium hydroxide solution. Stirred the reaction mixture at 25-35°C for 90 min. Filtered the isolated solid and washed with 20 ml of water. Dry the material at 50-60⁰C to afford 14.0 grams of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fluoroρyrimidin-4-yl)-l-(lH- 1,2,4-triazol-l-yl) butan-2-ol. Yield : 14.0 grams.

EXAMPLE - 4:

Preparation of (2R,3S) -2-(2,4difluorophenyI )-3-(5-fluoropyrimidin-4-yl)-l-(lH~

1,2,4 triazol-1-yl) -butan-2ol R(-) -10-camphor sulphonate:

50.0 grams of (2R,3S/2S,3R)-2-(2,4difluorophenyl)-3-(5-fiuoropyriinidin-4-yl)-l-(lH- 1,2,4-triazol-l-yl) butan-2-ol dissolved in 350.0 ml of acetone and dissolved 33.2 grams of R (- ) 10 camphor sulfonic acid in 185.0 ml of Methanol and added this solution to acetone solution at 25-35°C and heated the reaction mixture to 60 to 65°C maintained for 15 to 20 min, cooled the reaction mixture to 15- 20°C and stirred for 3 hours. Filtered the separated solid and washed with 25 ml of acetone. Dried the compound at 60-70°C to afford a 30.0 grams of (2R.3S) -2-(2,4difluorophenyl )-3-(5-fluoroρyrimidin-4-yl)-l- ^• (1H-1₅2,4 triazol-1-yl) -butan-2ol R(-) -10-camphor sulphonate Yield : 30.0 gr (Chiral Purity > 99.5%).

EXAMPLE - 5:

Preparation of (2R,3S) -2-(2,4difluorophenyl )-3-(5-fluoropyrimidin-4-yl)-l-(lH- 1,2,4 triazol-1-yl) -butan-2ol (Voriconazole)

To a solution of 50 grams of (2R,3S) -2-(2,4difluorophenyl )-3-(5-fluoropyrimidin-4-yl)- 1-(1H-1,2,4 triazol-l-yl) -butan-2ol R(-) -10-camphor sulphonate, 250 ml of water and 150 ml of dichloromethane is cooled to 25-35°C and adjusted the pH of the reaction mixture to 11 to 12 with sodium hydroxide solution. Separated the organic layer and washed with water. Concentrated the organic layer under reduced pressure at below 60°C. Added 200 ml of 2-propanol to the above obtained crude and cooled to 0-5°C, stirred for 3 hours. Filtered the separated solid and washed with chilled 2-propanol. Yield : 25.0 grams, HPLC Purity and chiral purity > 99.8%).

Claims

We claim:

1. An improved process for the preparation of 2R, 3S-2-(2,4-Difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-l -(1H-I, 2,4- triazol-1-yl) butan-2-ol (Voriconazole), which comprises:

a) Reacting 4-chloro-6-ethyl-5-fluoropyrimidine compound of formula (II) having pH range between 5 to 8,with l-(2,4-difluorophenyl)-2-(lH-l,2,4triazol-l-yl)ethanone compound of formula (III) in presence of an organo metallic base and solvent selected from non-polar solvents like n-Heptane ,n-Hexane ,cyclohexane petroleum ether, along with ethereal solvents like diethyl ether, tetrahydrofuran and mixtures thereof, gives the compound of formula (IV),

b) Dehalogenating (2R,3S/2S,3R): (2R,3R/ 2S,3S) -3-(4-chloro-5- fluoropyrimidin-6- yl)-2-(2,4-difluorophenyl)-l-(l H-l,2,4 triazol-l-yl)butane-2-ol compound of formula (IV) using a metal catalyst like Raney Nickel, Zinc/Acetic aicd in a suitable solvent selected from C1-C4 alcoholic solvents like methanol, ethanol, preferably methanol to give (2R₅3S/2S,3R)-2-(2,4-difluoroρhenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- l,2,4-triazol-l-yl)butan-2-ol compound of formula (V),

c) Adding R-(-)10-Camphorsulphonic acid dissolved in C1-C4 alcohol preferably methanol to the compound of formula (V) dissolved in ketonic solvents selected from acetone, butanone, propanone and mixtures thereof, preferably acetone or adding vice versa to give (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l(lH- l,2,4-triazol-l-yl)-butan-2-ol, R (-)-lO-camphor sulphonate compound of formula (VI), d) Adjusting the pH of the compound of formula (VI) in water by treatment with an alkali or alkaline earth metal hydroxide or carbonates, preferably sodium hydroxide solution, extracting with water immiscible solvents like methylene chloride, chloroform, ethylacetate, preferably methylene chloride, isolating the Voriconazole compound of formula (I) by distillation of solvent then by adding alcoholic or ketonic solvent, preferably alcoholic solvent, most preferably 2-propanol.

2. The organo metallic base according to claim 1 a) is freshly prepared Lithium diisopropylamide, Magnesium Isopropyl amide, Zinc isopropylamide, butyl zinc, butyl magnesium, LithiuniHMDS, Sodium HMDS, Magnesium HMDS, preferably Lithium diisopropylamide and Zinc isopropyl amide, most preferably Lithium diisopropyl amide.

3. The non-polar solvent according to claim 1 a) is selected from n-Heptane ,n-Hexane, cyclohexane petroleum ether and mixtures thereof, preferably n-Heptane along with tetrhydrofuran,

4. The pH of the 4-chloro-6-ethyl-5-fluoropyrimidine according to claim 1 a) is about 5.0 to 8.0, preferably 6.0 to 7.0, more preferably 6.0.

5. Using Raney Nickel for the dehalogenation reaction of (2R,3S/2S,3R): (2R,3R/ 2S,3S) -3-(4-chloro-5- fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-l-(l H-1,2,4 triazol-1- yl)butane-2-ol, compound of formula (IV) to give (2R,3S/2S,3R)-2-(2,4- difluorophenyl)-3 -(5 -fluoropyrimidin-4-y I)- 1 -( 1 H- 1 ,2,4-triazol- 1 -yl)butan-2-ol compound of formula (V).

6. Using mixture of solvent such as acetone and methanol for the resolution 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 compound of formula (V) with R-(-)10-Camphor sulfonic acid to get chiral pure camphor sulfonate salt of Voriconazole.

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