WO2009024214A1 - Process for the production of voriconazole - Google Patents

Process for the production of voriconazole Download PDF

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WO2009024214A1
WO2009024214A1 PCT/EP2008/005649 EP2008005649W WO2009024214A1 WO 2009024214 A1 WO2009024214 A1 WO 2009024214A1 EP 2008005649 W EP2008005649 W EP 2008005649W WO 2009024214 A1 WO2009024214 A1 WO 2009024214A1
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process
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Audun Heggelund
Kjell Undheim
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Axellia Pharmaceuticals Aps
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D403/00Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Abstract

A process for the preparation of voriconazole is described wherein alkylthio substituted pyrimidines are key intermediates. The alkylthio substituents render the pyrimidines particularly suitable for metal mediated addition to ketones. This is demonstrated in a cross-coupling reaction for the preparation of voriconazole.

Description

PROCESS FOR THE PRODUCTION OF VORICONAZOLE

The present invention relates to an improved process for the preparation of voriconazole and to intermediates useful in that process. Voriconazole is (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1 H-1 ,2,4-triazoM- yl)butan-2-ol and is represented by Formula I:

Figure imgf000002_0001

Voriconazole is a chiral antifungal agent belonging to the class of triazole antifungals. The drug is indicated for the treatment of invasive aspergillosis (Aspergillus fumigatus) and esophageal candidiasis (Candida albicans), as well as infections caused by Scedospohum apiospermum and Fusarium spp.

Voriconazole falls within the general structures within EP 0 357 241 A1. However, the first document specifically describing the preparation of voriconazole is EP 0440 372 A1. The process described therein included the reaction of 4-chloro-6-ethyl-5-fluoropyrimidine with 1-(2,4-difluorophenyl)- 2-(1H-1 ,2,4-triazol-1-yl)ethanone in the presence of a strong base under cryogenic conditions. The coupling product was isolated by chromatography in 12% yield as the wanted (2R,3S/2S,3R)-enantiomeric pair. The chloro- substituent in the intermediate pyrimidine was removed by hydrogenolysis and the product isolated after chromatography. The racemate was resolved by crystallisation with R-(-)-10-camphorsulfonic acid followed by basification and crystallisation of voriconazole as the free base. The synthesis potentially suffers from several disadvantages in scale-up and manufacturing work. The preparation gave a low diastereoselectivity and provided the desired product in a low chemical yield. Furthermore, separation of the enantiomeric pairs was by costly chromatographic methods. Hence, improvements of the voriconazole synthesis were needed.

US 6,586,594 B1 discloses an improved coupling step in the synthesis of voriconazole. In the original process the ethyl side-chain in the pyrimidine was deprotonated by treatment with a strong base for the coupling reaction. In the improved procedure the coupling partner is an α-bromoethylpyrimidine which was zincated by activated zinc metal. In this way the US 6,586,594 B1 allowed cryogenic conditions employed in EP 0 440 372 A1 to be avoided. The diastereoselectivity was increased to about 9 : 1 in favor of the desired (2R.3S/2S.3R) enantiomeric pair over the (2R,3R/2S,3S) enantiomeric counterpart. The chemical yield was about 65%. However, the process suffered from partial dimerisation of the electrophilic pyrimidine substrate resulting in an unwanted consumption of starting material besides formation of other unwanted byproducts (described in more detail in Butters et al., Org. Proc. Res. Dev. 2001, 5, 28-36).

WO 2006/065726 A2 claims a process for preparing voriconazole, a polymorphic form A as well as amorphous voriconazole. The patent application suggests voriconazole of a purity more than 95%, 99% and 99.5% by HPLC can be obtained, but no HPLC conditions were given. A process for the production of voriconazole was also disclosed.

In WO 2007/013096 A1 , a further process is disclosed for the production of voriconazole. The process is similar to that of EP 0 440 372 A1 and uses a strong base under cryogenic conditions. Small improvements over the original process were reported.

Clearly an improved process for the preparation of voriconazole is still required.

The present invention relates to a new process for production of voriconazole. A key step in this process is the coupling of a 4-(1- halogenoethyl)-5-fluoro-6-thiopyrimidine derivative (Vl) or analogue with 1- (2,4-difluorophenyl)-2-(1H-1 ,2,4-triazol-1-yl)ethanone (VII), (see Scheme I). It has been found that in this way unwanted side-reactions are avoided, or greatly reduced, possibly because the substituted thio group renders the pyrimidine ring less electrophilic than its 6-chloro analogue. The incorporation of the substituted thio group has also been found to lead to usefully modified chemical reactivities and physicochemical properties, possibly because of increased electron density in the pyrimidine ring.

Figure imgf000004_0001

(ID (III) (IV) (V) (Vl)

Figure imgf000004_0002

Scheme I.

It has been realized that most of the difficulties reported for the coupling of the zincated pyrimidines with 1-(2,4-difluorophenyl)-2-(1H-1 ,2,4-triazol-1- yl)ethanone (VII) can be overcome by using pyrimidine substrates carrying electron donating -SR substituents. This particular electron donating substituent can readily be removed at a later stage in the overall synthesis of the final target compound. The new substrates of the invention are pyrimidine-4(6)-sulfides such as (VIII), (Vl), (V) and (IV).

The positive effect of the electron donating substituents is illustrated by the coupling of 4-(1-bromoethyl)-5-fluoro-6-(methylthio)pyrimidine with 1-(2,4- difluorophenyl)-2-(1H-1 ,2,4-triazol-1-yl)ethanone (VII). The desired product, compound of Formula (VIII) (R=methyl), was isolated in 79% yield, which is a considerable improvement from 65% yield reported in US 6,586,594 B1.

The useful intermediate 6-ethyl-5-fluoropyrimidine-4-thiol (of the formula IV in Scheme I) can be prepared as described in Example 3 and 4 herein.

The group R in compounds shown in Scheme I, may be any suitable moiety other than H such that -SR increases the electron density on the pyrimidine ring and which is removable in a subsequent step.

Aptly R may be an alkyl, alkenyl, alkylaryl, aryl, alkylheteroaryl or like group. Such groups will generally be of up to 12 carbon atoms, more suitably up to 8 carbon atoms. Alkyl in alkyl aryl or alkylheteroaryl aptly contain 1 to 3 carbon atoms.

Suitable alkyl and alkenyl groups include straight or branched alkyl groups and which may include cyclic portions.

Such R groups, especially alkyl groups R, may be unsubstituted or substituted, for example, by one or more hydroxyl groups, chlorine, bromine of fluorine atoms or by lower alkoxy, lower alkylthio, lower alkylamine, lower dialkylamine groups, aryloxy, aminoaryl, lower alkyl-amino aryl groups, and for aryl or heteroaryl, by lower alkyl groups.

When used herein the term "lower" means containing 1 , 2, 3, 4, 5 or 6 carbon atoms.

Particularly apt groups R include methyl, ethyl, 2-methoxyethyl, 2- ethoxylethyl, benzyl and substituted benzyl where the substituents are 1, 2 or 3 groups selected from chlorine, bromine, fluorine, hydroxyl, methoxy, ethoxy, methyl or ethyl.

Certain apt groups R will be chiral. A preferred group R is the methyl group.

Compounds of the formulae (IV), (V), (Vl) and particularly (VIII) form important aspects of this invention. The invention also provides the use of the compounds of the formulae (IV)1 (V)1 (Vl) and particularly (VIII) as useful intermediates in the preparation of voriconazole. In such compounds R may have the values given above particularly methyl.

The pyrimidine of the formula (Vl) is a key compound in the present invention. The substituent X is aptly a good leaving group such as a chlorine, bromine, iodine, triflate or tosylate or the like. Preferably X is bromine. The compound of Formula (Vl), as a racemate, may be prepared from compound (II) as depicted in Scheme I. The 4(6)-chloro compound (III) is obtained from compound (II) in reaction with phosphorus oxychloride. Treatment of the 4(6)-chloro compound (III) with sodium hydrosulfide provides the corresponding thiol (IV). Alkylation of the -SH group in (IV) with formation of a compound of Formula (V) is effected by reaction with X1-R where X1 is a good leaving group such as one mentioned above. A particularly favoured compound X1 -R is iodomethane. Halogenation under radical conditions provides the key intermediate (Vl) where X is Br, Cl or I. Other compounds of formula (Vl) where X is an alternative leaving group can be made by conventional chemistry. Compounds where X is Br or Cl can serve as substrate for halogen exchange reactions or for conversion to derivatives with alternative, displaceable groups.

When the compound of Formula (III) is treated with a thiolate such as R-S-

Na, chemoselective reaction in the pyrimidine 4(6)-position occurs with formation of a 4(6)-sulfide (V).

The nature of the R-substituent affects physicochemical properties, and hence yields in reactions, and very importantly, it affects the stereoselectivities of the following reactions. The stereoselectivities can further be affected by using sulfides where the R-substituent has at least one stereogenic center and is enantiomerically homogenous.

As already stated, in a preferred case, the R-substituent is a methyl group. The methyl sulfide is readily prepared as described above. Benzyl or substituted benzyl sulfides are also very readily available and apt for uses. Chiral S-substituents can either be introduced by S-alkylation of a pyrimidine- 4(6)-thiol, or more generally by the reaction of a chiral thiol with a 4(6)- halogenopyrimidine .

A particularly favoured aspect of this invention comprises the reaction of a compound of the formula (VIII) with a reducing agent to produce a compound of the formula (IX).

This reaction may be effected with conventional reducing agents such as Raney nickel. The reaction may be effected in a solvent such as an alkanol, for example methanol, ethanol or a propanol of which ethanol is preferred. The reaction is effected at a non-extreme temperature, for example , 5°C - 7O0C, 5°C - 300C1 10°C -700C more aptly 10°C - 25°C. Most aptly the reaction is carried out at ambient temperature.

Alternatively, the conversion of a compound of formula (VIII) to a compound of formula (IX) may be effected with nickel boride, Ni2B. Nickel boride may either be purchased and used as such, or the reagent may be prepared in situ from a Ni(II) compound such as nickel(ll) chloride and a reducing agent such as sodium borohydride. The reaction may be performed in an alcohol/ether solvent system, for example where the alcohol is a C1-4 alcohol such as methanol or ethanol and the ether contains 4 to 6 carbon atoms and may be a cyclic ether. Particularly apt solvents include methanol/tetrahydrofuran. Imidazole may optionally be present as an additive. The reaction may be carried out at a non-extreme temperature, for example -2O0C to 30 0C, aptly -15 0C to 20 0C, for example -10 0C to 5 0C. Ambient temperature may be employed. A further particularly favoured aspect of this invention comprises the reaction of a compound of the formula (Vl) with the compound of the formula (VII) to produce a compound of the formula (VIII).

This reaction is generally effected in the present of a metal reagent, for example zinc or magnesium of which zinc is preferred. The zinc will most suitably be finely divided, for example as zinc dust. Lead may be present as an additional reagent. This reaction is preferably performed in an inert solvent such as dry tetrahydrofuran.

The reaction is aptly carried out under an inert atmosphere, for example under nitrogen or argon. Iodine is aptly employed to enhance the reaction. The reaction is most suitably performed at, for example -100C to 700C, - 5°C to 15°C, most suitably 00C - 100C, for example 00C to 2°C.

The reaction yields are sufficiently high to obtain the desired product without needing to resort to chromatographic purification.

FIG. 1 shows the 13C NMR spectrum of compound I. FIG. 2 shows the IR spectrum of compound I.

Examples

HPLC and LC-MS analyses were performed on a Dionex HPLC Module with a Dionex UVD 170U Detector and ThermoFinnigan MS. Column: Phenomenex Gemini C18, 4.6 x 50 mm, Mobile phase A: 0.1% aqueous formic acid, Mobile phase B: acetonitrile. Flow: 1 ml/min, Injection volume: 5-

20 μl, UV-detection: 254 nm, Gradient: 0 to 100% B in 5 min, ZQ with APCI-,

APCI+, MS 100-850, Cone V30. 1H NMR spectra were recorded in CDCI3 or

DMSO-d6 as solvent and internal standard on a Varian Gemini 300 spectrometer operating at 300 MHz or a Varian INOVA spectrometer operating at 600 MHz.

Example 1

4-Chloro-6-ethyl-5-fluoropyrimidine. compound of Formula (III) Phosphorus oxychloride (47.2 g, 0.31 mol) was added slowly over 3 h to a mixture of 6-ethyl-5-fluoropyrimidin-4(1H)-one (40.0 g, 0.28 mol), triethylamine (28.4 g, 0.28 mol) and dichloromethane (120 ml), maintaining the reaction temperature below 40 0C. The mixture was heated at reflux for 5 h and cooled to 25 0C. The mixture was slowly poured into aqueous hydrochloric acid (3 N, 176 ml), while the temperature was kept below 20 0C. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic layers were washed with water (50 ml), and the organic layer was concentrated at reduced pressure. Yield: 40.7 g (90%) of an oil. Purity, HPLC: 99.8% (RT=4.98 min).

Example 2

4-Chloro-6-ethyl-5-fluoropyrimidine. compound of Formula (III)

A reactor was charged with dichloromethane (20 I) and 6-ethyl-5- fluoropyrimidin-4(1 H)-one (5.00 kg, 35.2 mol) at 25-30 0C. The reaction mixture was stirred for 15 min, and triethylamine (3.60 kg, 35.6 mol) was added. Phosphorus oxychloride (5.95 kg, 38.8 mol) was added over 3 h, while the reaction temperature was kept below 35 0C. The reaction mass was heated at reflux (40-48 0C) for 3 h. The mixture was cooled to 5 0C, and hydrochloric acid (3.7 M, 20 I, 74 mol) was added over 1 h. The mixture was stirred for 30 min at 20 0C. The layers were separated, and the aqueous layer was extracted twice with dichloromethane (2 x 5.0 I). The combined organic layers were washed with water (5.0 I), and the solvents were removed at reduced pressure (550 mmHg) at 28-46 0C. 5.61 kg (99% yield) of the title compound was obtained as a brown liquid. Purity, HPLC: 99.6%.

Example 3

6-Ethyl-5-fluoropyrimidine-4-thiol. compound of Formula (IV) Sodium hydrosulfide hydrate (5 M aq. sol., 43 ml, 0.21 mol) was dissolved in methanol (25 ml), and the mixture was heated to 50 0C. A solution of 4- chloro-6-ethyl-5-fluoropyrimidine (26.4 g, 0.16 mol) in methanol (40 ml) was added over 30 min. The reaction mixture was heated at 50 0C for 2 h, and additional sodium hydrosulfide hydrate (2.56 g, 34 mmol) was added in one portion. The mixture was stirred for 1 h 45 min at 50 0C and cooled to rt. Approximately 60 ml of solvent was removed at reduced pressure. Water (200 ml) and aqueous hydrochloric acid (1 M, 75 ml) were added, and the mixture was stirred for 10 min. The precipitate was isolated by filtration and washed with water. Drying at reduced pressure overnight at 45 0C afforded 23.8 g (91% yield) of the title compound as a pale yellow crystalline solid. Purity, HPLC: >99.9% (RT=3.92 min). MS, m/z (% rel. int.): 143.1 (8), 159.1 (100, [M+HD, 175.0 (5), 315.0 (7). 1H NMR (300 MHz, CDCI3): δ 8.05 (1H, s), 2.74 (2H, q, J 7.3 Hz), 1.28 (3H, t, 7.3 Hz).

Example 4

6-Ethyl-5-fluoropyrimidine-4-thiol. compound of Formula (IV) A reactor was charged with acetonitrile (7 I) at 25-30 0C, and aqueous sodium hydrosulfide (5.0 M1 9.8 I, 49 mol) was added. The mixture was stirred for 15 min, and the temperature was raised to 50 0C. A solution of 4- chloro-6-ethyl-5-fluoropyrimidine (5.60 kg, 34.9 mol) in acetonitrile (14 I) was added over 45 min, and the reaction mixture was stirred at 48-52 0C for 8 h. Solvents were removed at reduced pressure (550 mmHg) at 45-50 0C, and the reaction mass was cooled to 30 0C. Water (14 I) was added, and the mixture was stirred for 15 min at 25-30 0C. The mixture was cooled to 14 0C, and the pH was adjusted to 3.7 by the addition of hydrochloric acid (1.1 M1 1.2 I1 1.3 mol). After stirring at 10-15 0C for 30 min, the reaction mass was centrifuged, and the solid cake was washed with chilled water (6 I). The solid cake was dissolved in ethyl acetate (22 I)1 and the mixture was stirred at 60- 65 0C for 15 min. The clear solution was cooled to 40 0C, and hexane (28 I) was added. The mixture was cooled to 5 0C, centrifuged, and the solid cake washed with chilled hexane (6.7 I). The solid material was harvested and dried at 50 0C for 16 h. 4.0 kg (73% yield) was obtained of the title compound as a pale green crystalline powder. Purity, HPLC: 99.7%.

Example 5

4-Ethyl-5-fluoro-6-(methylthio)pyrimidine. compound of Formula (V). R = methyl. 6-Ethyl-5-fluoropyrimidine-4-thiol (73.9 g, 0.47 mol) was dissolved in DMF (450 ml) and cooled in an ice-bath, lodomethane (73.0 g, 32.0 ml, 0.51 mol) was added over 3 min. The mixture was allowed to reach rt and stirred over the weekend. Cold water was added, and the product was extracted into diisopropyl ether (500 ml, 200 ml, 2 x 150 ml). The combined organic layers were washed with aqueous sodium thiosulfate (1 M, 150 ml) and brine (200 ml), and dried with sodium sulfate (180 g). The mixture was filtered and the filtrate concentrated at reduced pressure. Purification by distillation (13.2- 13.5 mbar, Bp 91-92 0C) provided 76.1 g (95% yield) of the title compound as a colourless liquid. Purity, HPLC: >99.9% (RT=5.29 min). MS1 m/z (% rel. int.): 172.9 (100, [M+H]+), 214.0 (15). 1H NMR (300 MHz, CDCI3): δ 8.65 (1H1 s), 2.77 (2H, q, J 7.3 Hz), 2.56 (3H1 s), 1.27 (3H, t, J 7.3 Hz).

Example 6

4-Ethyl-5-fluoro-6-(methylthio)pyrirnidine. compound of Formula (VV R = methyl

A reactor was charged with DMF (22 I) and 6-ethyl-5-fluoropyrimidine-4-thiol (3.60 kg, 22.8 mol) at 25-30 0C. After stirring for 15 min, the mixture was cooled to 1 0C, and iodomethane (3.60 kg, 25.4 mol) was added. The mixture was stirred for 30 min at 0-5 0C1 and the temperature was raised to 25-30 0C. The mixture was stirred at this temperature for 15 h, followed by cooling to 16 0C. Water (48 I) and diisopropyl ether (25 I) were added. The mixture was stirred for 15 min, and the layers were separated. The aqueous layer was extracted twice with diisopropyl ether (11 I + 7 I), and the combined organic layers were washed with aqueous sodium thiosulfate (1.6 M, 14.4 I, 23.0 mol) and sodium chloride (4.3 M, 14.4 I). The organic layer was dried with sodium sulfate (1.8 kg), and the liquid layer was transferred to a second reactor. The solvents were removed by heating up to 60 0C at reduced pressure (550-600 mmHg). The crude material was purified by distillation at reduced pressure. 3.90 kg (99% yield) was isolated of the title compound as a colorless liquid. Purity, HPLC: 99.9%.

Example 7 4-(1-Bromoethyl)-5-fluoro-6-(methylthio)pyrimidine. compound of Formula (Vl). R = methyl. X = bromine.

A mixture of 4-ethyl-5-fluoro-6-(methylthio)pyrimidine (40.8 g, 0.24 mol), N- bromosuccinimide (NBS) (52.7 g, 0.30 mol), α.α'-azoisobutyronitrile (AIBN) (0.49 g, 3.0 mmol) and methyl acetate (300 ml) was heated at reflux under argon atmosphere. After 3 h additional AIBN (0.49 g, 3.0 mmol) in methyl acetate (10 ml) was added. The mixture was stirred overnight and cooled to rt. The mixture was poured into aqueous sodium metabisulfite (0.5 M, 300 ml), the layers separated, and the aqueous layer was extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with brine (200 ml), and dried (Na2SC»4). The solvent was partially evaporated at reduced pressure, petroleum ether (250 ml) was added, and the mixture was stirred for 10 min. The precipitate (succinimide) was filtered off and rinsed with petroleum ether/ethyl acetate (9:1 , 3 x 20 ml). Concentration of the filtrate in vacuo afforded a crude material (83.5% pure by HPLC, RT=5.67 min) which was purified by distillation. The product was collected in 4 fractions: Fraction 1: 0.39 g (0.7% yield), 96.5% pure by HPLC (bp. 92-102 0C, 0.84-0.55 mbar), Fraction 2: 7.15 g (12%), 96.9% pure (bp. 92-102 0C, 0.84-0.55 mbar), Fraction 3: 38,9 g (65%), 97.1% pure (bp. 105-106 0C, 0.25-0.16 mbar), Fraction 4: 9.23 g (16%), 88.2% pure (bp. 100-98 °C, 0.16 mbar). Total yield: 55.7 g (94% yield). MS, m/z (% rel. int.): 171.2 (4), 251.0 (100, [M+Hf), 292.0 (12). 1H NMR (300 MHz, CDCI3): δ 8.74 (1H, s), 5.32 (1 H, q, J 6.6 Hz), 2.59 (3H, s), 2.03 (3H, d, J 6.6 Hz).

Example 8

4-(1 -Bromoethviy-5-fluoro-6-(methylthiobyrimidine. crude material. compound of Formula (Vl). R = methyl. X = bromine.

A mixture of 4-ethyl-5-fluoro-6-(methylthio)pyrimidine (20.2 g, 0.12 mol), NBS (26.1 g, 0.15 mol), AIBN (576 mg, 3.5 mmol, 2.3 mol%) and methyl acetate (100 ml) was heated at reflux for 22 h under argon atmosphere. The mixture was poured into aqueous sodium metabisulfite (0.5 M, 150 ml), and the layers were separated. The aqueous layer was extracted with methyl acetate (2 x 50 ml). The combined organic layers were washed with brine, and concentrated at reduced pressure to about 150 ml. Heptane (120 ml) was added, and the mixture was stirred for 10 min. The precipitate (succinimide) was filtered off and rinsed with heptane (2 x 10 ml), and the filtrate was concentrated at reduced pressure. The material was redissolved in toluene (50 ml) and concentrated at reduced pressure three times, providing 30.0 g (>100%, theoretical yield: 29.5 g) of a crude material that was used in Example 11 without further purification. Purity: 88.9% by HPLC (RT=5.65 min).

Example 9 4-(1-Bromoethyl)-5-fluoro-6-(methylthio)pyrimidine. compound of Formula (VO. R = methyl. X = bromine.

A reactor was charged with 4-ethyl-5-fluoro-6-(methylthio)pyrimidine (5.21 kg, 30.3 mol), N-bromosuccinimide (NBS) (8.06 kg, 45.3 mol), 2,2'-azobis(2- methylbutyronitrile) (Vazo® 67) (174 g, 0.91 mol) and methyl acetate (32 L). The resulting mixture was heated at reflux for 24 h, and additional NBS (1.29 kg, 7.25 mol) and Vazo® 67 (28 g, 0.15 mol) were added. The mixture was stirred for another 22 h at reflux, and additional NBS (0.65 kg, 3.65 mol) and Vazo® 67 (14 g, 73 mmol) were added. The stirring was continued for another 32 h at reflux, and the temperature was lowered to 5 0C. Aqueous sodium metabisulfite (0.5 M, 36 L) was added, the layers separated, and the aqueous phase extracted with methyl acetate (16 L). The combined organic phases were washed with aqueous sodium thiosulfate (1.0 M1 32 L), followed by water (21 L)1 and brine (33 L). The solvent was gradually changed from methyl acetate to toluene via evaporation at reduced pressure. The toluene solution was filtered through silica gel, eluting with heptane and heptane/toluene (1 :1 ) to remove byproducts, followed by toluene to elute the target compound. Removal of the solvent at reduced pressure afforded 4.50 kg (59% yield) of the title compound. Purity, HPLC: >94%.

Example 10 f2R.3S/2S.3R)-2-(2.4-Difluorophenyl)-3-r5-fluoro-6-(methylthio)pyrimidin-4- vn-1-(1H-1.2.4-triazol-1-yl)butan-2-ol. compound of Formula VIII. R = methyl. A mixture of zinc dust (3.27 g, 50.0 mmol), lead (0.16 g, 0.79 mmol) and dry THF (18 ml) was stirred at rt in inert atmosphere for 10 min. A solution of iodine (2.28 g, 9.0 mmol) in dry THF (9 ml) was added over 7 min. The reaction mixture was cooled to 2 0C, and a solution of 4-(1-bromoethyl)-5- fluoro-6-(methylthio)pyrimidine (2.93 g, 11.7 mmol), 1-(2,4-difluorophenyl)-2- (1H-1 ,2,4-triazol-1-yl)ethanone (2.23 g, 10.0 mmol) and iodine (0.25 g, 1.0 mmol) in dry THF (18 ml) was added over 10 min. The temperature in the mixture was maintained below +10 0C during the addition. The mixture was stirred for 1 h 30 min below +5 0C. LC/MS analysis demonstrated full consumption of starting material and formation of the desired compound as a mixture of diastereoisomers. Acetic acid (2.9 ml) and water (30 ml) were added while maintaining the temperature below 25 0C. The mixture was poured into ethyl acetate (100 ml) and stirred for 15 min. The solvents were removed at reduced pressure, and ethyl acetate was added. Aqueous sodium hydrogencarbonate (~100 ml) was added until pH 8, the solids filtered off, and the layers separated. The aqueous layer was extracted with ethyl acetate (3 x 50 ml), and the combined organic layers were washed with aqueous sodium thiosulfate (1 M, 50 ml), brine (150 ml), and dried (Na2SO4). Removal of the solvents in vacuo left 4.26 g of crude material as a white solid, diastereoisomer ratio: 9.5 : 1 in favor of the (2R.3S/2S.3R) enantiomeric pair (RT(2R,3R/2S,3S)=5.36 min, RT(2R,3S/2S,3R)=5.68 min). The crude material (4.26 g) was dissolved in ethyl acetate (6 ml) at reflux temperature. Heptane (90 ml) was added at this temperature, and the mixture was stirred at 90 0C for 3 min when a clear solution was obtained. The mixture was allowed to cool to rt overnight while stirring. The crystalline product thus formed was collected by filtration and rinsed twice with heptane (2 x 10 ml). Drying at 50 0C at reduced pressure afforded 3.14 g (79% yield) of a white solid. Purity: 97.5% by HPLC. The unwanted enantiomeric pair amounted to 0.18%. MS, m/z (% rel. int.): 173.1 (10), 224.1 (36), 265.0 (10), 396.2 (100, [IvHH]+), 437.2 (38). 1H NMR (300 MHz, DMSO-d6): δ 8.84 (1H, s), 8.23 (1H, s), 7.61 (1H, s), 7.28 (1H1 q, J 8.8 Hz), 7.19 (1H, t, J 9.5 Hz), 6.92 (1H1 1, J 8.8 Hz), 6.04 (1H, bs), 4.76 (1H, d, J 14.6 Hz), 4.35 (1H, d, J

14.6 Hz), 3.85 (1H, q, J 6.6 Hz), 2.61 (3H, s), 1.08 (3H, d, J 6.6 Hz).

Example 11

(2R.3S/2S.3R)-2-(2.4-Difluorophenyl)-3-r5-fluoro-6-(methylthio)pyrimidin-4- yl|-1-(1 H-1.2.4-triazol-1-yl)butan-2-ol. compound of Formula VIII. R = methyl. A mixture of zinc dust (31.9 g, 0.49 mol), lead (1.59 g, 7.7 mmol, 5 wt% to zinc) and THF (175 ml) was stirred vigorously at rt under inert atmosphere for 1 h. A solution of iodine (22.3 g, 87.9 mmol) in THF (85 ml) was added over 22 min, and the mixture was cooled to 0 0C. A solution of 4-(1- bromoethyl)-5-fluoro-6-(methylthio)pyrimidine (30.0 g, crude material as obtained in Example 8, 0.12 mol theoretical amount), iodine (2.48 g, 9.77 mmol) and 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (21.8 g,

97.7 mmol, HPLC RT=4.21 min) in THF (175 ml) was added over 14 min. The temperature was kept below 6 0C during the addition. The reaction mixture was stirred at -1 0C for 45 min. HPLC indicated full conversion of the starting material and formation of the target compound as a mixture of diastereomers in a ratio of 10 : 1 in favour of the desired (2R,3S/2S,3R)- enantiomeric pair. The mixture was allowed to warm to 10-15 0C, and a solution of acetic acid (5.9 ml) in water (20 ml) was added while maintaining the temperature below 25 0C. Saturated aqueous sodium carbonate (150 ml) was added whereupon a precipitate was formed. The solids were filtered off and rinsed with ethyl acetate (3 x 50 ml). THF was removed from the filtrate by concentration at reduced pressure until water started to distill. Ethyl acetate (300 ml) and water (100 ml) were added, the layers separated, and the aqueous layer extracted with ethyl acetate (50 ml). The combined organic layers were washed with an aqueous solution of EDTA disodium salt dihydrate (2 wt%, 300 ml), aqueous sodium thiosulfate (1 M1 150 ml), and brine (200 ml). The organic layer was concentrated at reduced pressure. Dissolution of the residue in toluene (100 ml) and reconcentration was carried out twice, and 42.9 g (>100% yield, theoretical yield: 38.6 g) of an off- white solid was obtained. Diastereomeric ratio (HPLC): 10 : 1.

The crude material (42.9 g) was dissolved in ethyl acetate (50 ml) at reflux, and heptane (500 ml) was added slowly at this temperature. The mixture was stirred at 95 0C for 5 min and allowed to cool to rt overnight with stirring. A crystalline solid was collected by filtration and rinsed with heptane (3 x 20 ml). Drying at 50 0C and reduced pressure for 1 h afforded 35.1 g (91% yield from 1-(2,4-difluorophenyl)-2-(1H-1 ,2,4-triazol-1-yl)ethanone) of the title compound as an off-white solid. Purity: 91.1% by HPLC (RT=5.64 min). The unwanted (2R,3R/2S,3S)-enantiomeric pair was not detected by HPLC after the crystallisation. Subjecting the isolated material to a second crystallisation provided material with a purity of 94.3% in 79.5% yield.

Example 12 (2R.3S/2S.3R)-2-(2.4-Difluorophenyl)-3-f5-fluoro-6-fmethylthio)pyrimidin-4- yll-1-(1 H-1.2.4-triazol-1-yl)butan-2-ol. compound of Formula VIII. R = methyl. A mixture of zinc dust (4.87 kg, 74.5 mol) and lead (0.24 kg, 1.2 mol) in THF (13 L) was stirred for 12 h at rt, followed by addition of a solution of iodine (3.41 kg, 13.4 mol) in THF (13 L) during 35 min. The temperature was lowered to -5 0C, and a mixture of 1-(2,4-difluorophenyl)-2-(1H-1 ,2,4-triazol- 1-yl)ethanone (3.33 kg, 14.9 mol), iodine (0.38 kg, 1.5 mol) and 4-(1-bromo- ethyl)-5-fluoro-6-(methylthio)pyrimidine (4.50 kg, 17.9 mol) in THF/toluene (3:2, 50 L) was added at a continuous rate during 17 min. The temperature was gradually raised to 23 0C1 and additional zinc (2.48 kg, 37.9 mol) was added. The mixture was stirred for 4 days 20 h at 25 0C, whereupon HPLC demonstrated full conversion of the substrate. The temperature was lowered to 15 0C1 and aqueous acetic acid (10%, 23 L) was added. The biphasic mixture was filtered, and the organic solvents were gradually changed to ethyl acetate via evaporation. The layers were separated, and the aqueous phase was extracted with ethyl acetate (33 L). The combined organic phases were washed with aqueous EDTA (2%, 33 L) and brine (17 L). The ethyl acetate solution was filtered and reduced to ca. 20 L. The mixture was heated to reflux, and isopropanol (63 L) was added, giving a clear brown solution. The mixture was slowly allowed to cool, and the product crystallised within 20 min at 50 0C. The slurry was aged for 20 h at 18 0C, and the solid material was harvested by filtration and washed with isopropanol (10 L). The crude material was suspended in ethyl acetate (11 L) at reflux, and isopropanol (33 L) was added. After 30 min the temperature was lowered to 18 0C, and the mixture was stirred for 2.5 h. The white crystalline material was collected by filtration and washed with isopropanol (6 L). Drying of the product on the filter afforded 4.16 kg (70% yield) of the target compound. Purity, HPLC: >99%.

Example 13

(2R.3S/2S.3R)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-vn-1 -d H-1.2.4- triazol-1-vπbutan-2-ol. compound of Formula (IX). (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-[5-fluoro-6-(methylthio)pyrimidin-4- yl]-1-(1H-1 ,2,4-triazol-1-yl)butan-2-ol (3.95 g, 10.0 mmol) was dissolved in methanol (30 ml), and the solution was heated to 30 0C (internal temperature control). A suspension of Raney nickel (27.7 g, previously washed with 3 x 20 ml methanol) in methanol (20 ml) was added, and the mixture was stirred for 1 h 40 min. At this point HPLC indicated 93.5% product and 4.0% starting material in the reaction mixture. The mixture was cooled to 20 0C, and nickel was removed by filtration through celite. The filter cake was washed with methanol, and the combined filtrate was concentrated at reduced pressure. Drying of the residue in vacuo at 50 0C for 3 h afforded 2.39 g (68% yield) of the title compound. Purity, HPLC: 91.5% (RT=4.91 min). MS, m/z (% rel. int.): 224.1 (8), 265.2 (24), 350.3 (70, [M+H]+), 391.2 (100), 507.8 (10), 624.4 (15).

Example 14

(2R.3S/2S.3R)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1 H-1.2.4- triazol-1-yl)butan-2-ol. compound of Formula (IX).

(2R,3S/2S,3R)-2-(2,4-DifIuorophenyl)-3-[5-fluoro-6-(methylthio)pyrimidin-4- yl]-1-(1H-1 ,2,4-triazol-1-yl)butan-2-ol (150 g, 75% pure, 0.28 mmol) and nickel(ll) chloride hexahydrate (181 g, 0.76 mmol) were dissolved in methanol/THF (3:1 , 1200 mL) and cooled to 5 0C. Imidazole (90.5 g, 1.33 mmol) was added in small portions, and the temperature was lowered to -10 0C. A solution of sodium borohydride (86 g, 2.27 mmol) in water (270 mL) was added drop wise to the reaction mixture with an addition rate adjusted to control the evolution of hydrogen gas (about 2.5 h). Another portion of imidazole (90.5 g, 1.33 mmol) was added, the temperature was allowed to reach rt, and the reaction mixture was stirred for 16.5 h. The black solid was filtered off and washed with methanol/THF (1:1 , 400 mL), and the blue filtrate was concentrated at reduced pressure to a volume of ~1 L. Dichloromethane (300 mL) and water (300 mL) were added to the residue, and the phases were separated. The aqueous phase was extracted twice with dichloromethane (300 + 240 mL), and the combined organic phases were washed with water (4 x 300 mL), followed by concentration at reduced pressure. The residue (a brownish semisolid) was dissolved in dichloromethane (200 mL) and passed through a pad of silica (200 g), eluting with ethyl acetate (1000 mL). Removal of the solvent at reduced pressure afforded 43.4 g (44% yield) of the title compound as a beige solid. Purity, HPLC: >93%.

Example 15

(2R.3S/2S,3R)-2-(2.4-Difluorophenyl)-3-( 5-fluoropyrimidin-4-yl)-1 -d H-1.2,4- triazol-1-yl)butan-2-ol. compound of Formula (IX). (2RI3S/2S,3R)-2-(2I4-Difluoropheny1)-3-[5-fluoro-6-(methylthio)pyrimidin-4- yl]-1-(1H-1 ,2,4-triazol-1-yl)butan-2-ol (3.70 kg, 75% pure, 7.0 mol) and nickel(ll) chloride hexahydrate (4.50 kg, 18.9 mol) were dissolved in methanol/THF (3:1 , 30 L), and the mixture was cooled to 4 °C. Imidazole (2.26 kg, 33.2 mol) was added during 7 min, and the temperature was lowered to -9 0C. A solution of sodium borohydride (2.15 kg, 56.8 mol) in water (7.5 L) was added drop wise to the reaction mixture with an addition rate adjusted to control the evolution of hydrogen gas (about 3 h). Additional imidazole (2.26 kg, 33.2 mol) was added, and the reaction mixture was heated to 20 0C and stirred for 16.5 h. The mixture was filtered, and the solid material was washed with methanol/THF (1 :1 , 10 L). The clear blue filtrate was concentrated at reduced pressure to about 14 L, and water (7.5 L) was added. The mixture was extracted with dichloromethane (8 + 7.5 + 4 L), and the combined organic layers were washed with water (4 x 7.5 L). The organic layer was concentrated to 3.5 L and passed through a pad of silica gel (5 kg), eluting with ethyl acetate (58 L). The eluate was concentrated at reduced pressure giving 1.1 kg (45% yield) of the target compound. Purity, HPLC: 87%.

Example 16

(2R.3S)-2-(2.4-difluorophenvn-3-f5-fluoropyrimidin-4-yl1-1 -f 1 H-1.2.4-triazol-1 - yl)butan-2-ol (R)-10-camphorsulfonate

(2R,3S/2S,3R)-2-(2)4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1 H-1 ,2,4- triazol-1-yl)butan-2-ol (74.1 g, 212 mmol) was dissolved in ethyl acetate (222 mL) and acetone (296 mL). At 20 0C a solution of (R)-(-)-camphor-10- sulfonic acid (37.0 g, 159 mmol) in ethanol (111 mL) was added during 5 min. A clear solution was obtained. Seeding of the solution resulted in immediate crystallisation. The resulting white slurry was stirred for 17 h before the product was isolated by filtration and washed with acetone (2 x 63 mL). 56.4 g (46% yield, 92% of theoretical maximum) of the target salt was obtained as a white solid. Purity, HPLC: 96.9%. Optical purity, HPLC: 99.2%. Example 17

(2R.3S)-2-(2,4-difluorophenyl)-3-[5-fluoropyrimidin-4-vn-1 -d H-1.2.4-triazol-1 - vObutan-2-ol (R)-10-camphorsulfonate

To a suspension of (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5- fluoropyrimidin-4-yl)-1-(1 H-1 I2,4-triazol-1-yl)butan-2-ol (1.1 kg, 3.15 mol) in ethyl acetate (2.5 L) was added acetone (4.5 L). The mixture was heated, and at 24.5 0C internal temperature the material was completely dissolved, and a clear, yellow solution was obtained. The temperature was adjusted to 19 0C1 and a solution of (R)-(-)-camphor-10-sulfonic acid (475 g, 2.04 mol) in ethanol (1.4 L) was added during 6 min. After stirring for 20 min, the solution was seeded with 100 mg of the target salt from a previous batch, and crystallisation occurred immediately. The suspension was stirred at 19 0C for 19 h, and the solid material was collected by suction filtration. The product was washed with acetone (2.5 L) and dried on the filter for 20 h. The crude material (975 g) was dissolved in ethanol (3.5 L) at 50 0C, and acetone (8.2 L) was added. The mixture was cooled to -5 0C and stirred for 2 h. The crystalline product was harvested by suction filtration, washed with acetone (1 L) and dried on the filter for 4.5 h. 656 g (41% yield, 82% of theoretical maximum) of the target salt was obtained as a white solid. Optical purity, HPLC: 99.6%.

Example 18

(2R.3S)-2-(2.4-Difluorophenvn-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-

1-yl)butan-2-ol (voriconazole), compound of Formula (\) To a solution of the racemic material as obtained in example 15 (1.28 g, 3.66 mmol) in acetone (29 ml) was added a solution of (1R)-10-camphorsulfonic acid (0.85 g, 3.66 mmol) in methanol (9.6 ml). The solvents were removed at reduced pressure, and the residue was dissolved in a mixture of acetone (10 ml) and methanol (2 ml). Crystals formed spontaneously after 3 h. Acetone (10 ml) was added, and the mixture was stirred overnight. The solid was isolated by filtration, washed with a small amount of acetone and dried. The solid was dissolved in a mixture of acetone (14 ml) and methanol (4 ml) at reflux. The solution was cooled to rt and stirred for 90 min. Isolation of the precipitate formed by filtration, washing with acetone and drying afforded 0.72 g of the acid addition salt. 0.70 g of the solid material was taken up in dichloromethane (10 ml) and water (10 ml), and the pH was adjusted to 11 by addition of aqueous sodium hydroxide (15% sol.). The layers were separated, and the aqueous layer was extracted with dichloromethane (5 ml). The combined organic layers were washed with water (3 x 10 ml) and brine, and dried (sodium sulfate). Concentration at reduced pressure afforded 0.36 g (28% yield, 56% of the available enantiomer) of voriconazole as a white crystalline solid. Purity, HPLC: 99.8% (RT=4.91 min). Mp. 122.6 0C (Lit. 134 0C). MS, m/z (% rel. int.): 224.0 (27), 350.1 (100), 391.0 (10). 1H NMR (600 MHz, DMSO-d6): δ 9.02 (1H, d, J 3.0 Hz)1 8.83 (1 H1 d, J 1.8 Hz), 8.21 (1 H1 s), 7.59 (1 H1 s), 7.24 (1H1 ddd, J 7.0 Hz, J 9.0 Hz, J 9.0 Hz), 7.16 (1H, ddd, J 2.4 Hz, J 9.0 Hz, J 11.8 Hz), 6.89 (1H, ddd, J 2.4 Hz, J 8.4 Hz, J 8.4 Hz), 5.95 (1 H, s), 4.77 (1 H, d, J 14.4 Hz), 4.31 (1H, d, J 14.4 Hz), 3.90 (1 H, q, J 7.0 Hz), 1.08 (3H1 d, J 7.0 Hz).

Example 19

(2R.3S)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -d H-1.2.4-triazol-

1 -yl)butan-2-ol (voriconazole), compound of Formula (I) (2R,3S)-2-(2,4-Difluorophenyl)-3-[5-fluoropyrimidin-4-yl]-1-(1 H-1 ,2,4-triazol- 1-yl)butan-2- ol (R)-10-camphorsulfonate (656 g, 1.13 mol) was parted between dichloromethane (3 L) and water (3 L), and the pH of the aqueous phase was slowly adjusted to pH 12.3 with aqueous sodium hydroxide (40% w/v, 130 mL). The phases were separated, and the aqueous layer was extracted with dichloromethane (1 L). The combined organic layers were washed with water (3 x 1.5 L) and filtered. The solvent was changed to isopropanol (1.3 L) via gradual addition/evaporation at reduced pressure. After stirring for 3 h at 20 0C, the temperature was lowered to -5 0C. The mixture was stirred for another 1.5 h, and the product was isolated by suction filtration, washed with isopropanol (0.3 L) and dried at 20 0C and vacuum for 2.5 days. 285 g (72% yield) of the title compound was obtained as a white solid. Purity, HPLC: 99.8%. Optical purity, HPLC: >99.9%. 1H NMR (300 MHz, DMSO-d6): δ 9.05 (1H1 d, J 3.0 Hz), 8.86 (1H1 d, J 1.8 Hz), 8.24 (1H, s), 7.62 (1H, s), 7.24 (2H, m), 6.92 (1H, dt, J 2.1, 8.0 Hz), 5.99 (1H, s), 4.81 (1H1 d, J 14.1 Hz), 4.34 (1H1 d, J 14.4 Hz), 3.93 (1H, q, J 7.2 Hz), 1.11 (3H1 d, J 6.9 Hz). 13C NMR spectrum and IR spectrum for the isolated compound are attached.

Claims

Claims
1. A process for the preparation of a compound of the formula (VIII):
Figure imgf000023_0001
which comprises the coupling of a compound of formula (VII):
Figure imgf000023_0002
(VII)
with a compound of the formula (Vl):
Figure imgf000023_0003
(Vl)
wherein R is a C1.12 alkyl (aptly C1^ alkyl), C2-12 alkenyl, Ci-3 alkylaryl, aryl, heterocyclic, Ci-3 alkylheterocyclic, C1-12 alkyl substituted by C1.6 alkoxy, C1-12 alkylthio, C1-12 alkylamino, C1-12 dialkylamino, COCM2 alkyl, aryl, aryloxy or an 0-C1^ alkylaryl group wherein any aryl group may be substituted with 1 , 2 or 3 groups selected from chlorine, bromine, fluorine, methoxy, ethoxy, methyl or ethyl and X is a leaving group.
2. A process as claimed in Claim 1 wherein R is methyl.
3. A process as claimed in Claim 1 wherein X is selected from chlorine, bromine, iodine, triflate or tosylate.
4. A process as claimed in Claim 1 wherein X is bromine.
5. A process as claimed in Claim 1 wherein the coupling is effected using activated zinc and iodine.
6. A process as claimed in any of Claims 1 to 5 carried out at -100C to 700C.
7. A process as claimed in Claim 6 carried out at -100C to 25 0C.
8. A process as claimed in any of Claims 1 to 7 wherein the solvent is methyl acetate, ethyl acetate, or other aprotic solvent such as tetrahydrofuran.
9. A process for the preparation of a compound of the formula (IX):
Figure imgf000024_0001
wherein a compound of the formula (VIII):
Figure imgf000025_0001
(VIII)
is reduced; wherein R is as defined in Claim 1.
10. A process as claimed in Claim 9 wherein R is methyl.
11. A process as claimed in Claim 9 or 10 wherein reduction is effected with Raney nickel.
12. A process as claimed in any of Claims 9 to 11 wherein the reduction is effected at 1O0C to 700C.
13. A process as claimed in Claim 12 wherein the reduction is effected at 10°C to 300C.
14. A process as claimed in any of Claims 9 to 13 wherein the solvent is ethanol.
15. A process as claimed in any of Claims 9-14 wherein the compound of formula (VIII) is prepared by a process as claimed in any of Claims 1 to 8.
16. A process as claimed in Claim 9 or 10 wherein reduction is effected with nickel boride.
17. A process as claimed in claim 16 wherein the reaction is effected at -15°C to 20°C.
18. A process as claimed in claim 16 wherein the reaction is effected at -10°C to 5°C.
19. A process as claimed in any of claims 16 to 19 wherein the solvent is a C1-4 alcohol/C4-6 ether mixture.
20. A process as claimed in claim 19 wherein the solvent is methanol/THF.
21. A process as claimed in any of claims 16 to 20 wherein imidazole is present.
22. A process as claimed in any of claims 16 to 21 wherein nickel boride is generated in situ from nickel chloride and a borohydride.
23. A compound of the formula (IV), (V) or (Vl):
Figure imgf000026_0001
(IV) (V)
Figure imgf000026_0002
wherein X is Cl, Br, I or OSO2R2 wherein R2 is C1-6 alkyl or aryl such as phenyl or tolyl or trifluoromethyl and R is as defined in Claim 1.
24. A compound of the formula (V) or (Vl) as defined in Claim 23 wherein R is methyl.
25. A compound of the formula (Vl) as defined in Claim 23 or 24 wherein X is Br.
26. A compound of the formula (IV), (V), or (Vl) as defined in Claim 23 for use as an intermediate in the synthesis of a compound of the formula (VIII) as defined in Claim 1.
27. A compound of the formula VIII as defined in claim 1.
28. The use of the compound of the formula VIII as defined in claim 1 as a chemical intermediate in the manufacture of voriconazole.
29. A process as claimed in claim 9 wherein a compound of the formula (IX) is resolved to provide voriconazole.
30. A process for the preparation of voriconazole which comprises:
Figure imgf000027_0001
(IV) (V) (Vl)
Figure imgf000027_0002
Scheme I.
wherein R and X are as defined in claim 1.
31. A process for the preparation of voriconazole which comprises:
Figure imgf000028_0001
(ID (III) (IV) (V) (Vl)
Figure imgf000028_0002
Scheme I. wherein R and X are as defined in claim 1. 07161 sp
PCT/EP2008/005649 2007-08-21 2008-07-10 Process for the production of voriconazole WO2009024214A1 (en)

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