A NOVEL PROCESS TO MANUFACTURE (2R,3S)-2-(2,4-DIFLUOROPHENYL)-3-(5-FLUOROPYRIMIDIN-4-YL)-l-(lH-l,2,4-TRIAZOL-l-YL)BUTAN-2-OL

FIELD OF THE INVENTION

The present invention relates to a novel industrially viable, cost effective process to manufacture substantially pure form of (2R,3S)-2-(2,4-difluorophenyl)-3-{5-fIuoropyrimidin-4~yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol (Voricaonazole) with a chiral purity level of greater than 99.9% and impurity level of less than 0.1%..

BACKGROUND OF THE INVENTION
(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol of Formula-I, commonly known as Voriconazole,
Formula-I is a triazole antifungal medication used to treat various fungal infections. These include invasive candidiasis, invasive aspergillosis, and emerging fungal infections. It is commercially available as VFEND® in the form of lyophilized powder for solution in intravenous injection, fitm-coated tablets for oral administration, and as a powder for oral suspension.
US5,567,817 and US5,278,175 discloses a process for the preparation of voriconazole comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula IV with l-(2,4-difluoorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula VI in the presence of lithium diisopropylamine to yield 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-4-yl)-1 -(IH-1,2,4-triazole-1 -yl) butan-2-ol which is further purified by column chromatography to give (2R,3S/2S,3R) enantiomeric pair of 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol of Formula VII which was dehalogenated with a 10% Pd/C in the presence of sodium acetate, followed by purification using flash chromatography to yield (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol of Formula VIII and then resolved with R-(-)-10-camphor sulfonic acid in the presence of methanol and subsequent hydrolysis of the camphor sulfonate salt to free base with alkaUne medium to yield Voriconazole of Formula I. The process can be represented as in scheme-I given below,

The drawbacks of this process are use of hazardous reagents like lithium diisopropylamine for the condensation, which is carried at very low temperature of-TS^C. It is difficult to maintain all the time at plant scale. The process describes chromatographic separation of the enantiomeric pair which is not advisable at plant scale. This process further uses palladium on carbon for dehalogenation under pressure which is associated with safety problems at plant scale. Moreover the yield is very low.

US 6,586,594 and Organic Process Research & Development (2001), 5(1), 28-36, discloses a process for the preparation of voriconazole comprising reacting 6-(l-bromoediyI)-2,4-dichloro-5-fluoropyrimidine of Formula IX with l-(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula V in the presence of Zinc, lead, iodine and tetrahydrofuran to yield the compoimd of Formula VII. It also has been disclosed that the
compoimd after the condensation yields two different diastereomeric pairs such as (2R, 3S: 2S, 3R and 2S, 3S; 2R, 3R). The desired pair is separated by forming hydrochloride salt.

This hydrochloride salt is further dehalogenated with 10%Pd/C to yield compound of Formula VIII, which on resolution with R-(-)-camphor-10-sulphonic acid and further basification to give Voriconazole of Formula I. The process is represented in scheme-II given below

The drawback of this process is the formation of HCl salt and further dehalogenation in presence of palladium on carbon. This requires further basification and involves an additional step, which makes the reaction time. Moreover, the use of palladium on carbon for dehalogenation is not advisable because of the safety reasons.

WO2006065726 discloses a process for the preparation of voriconazole comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula V with 1 -(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula VI in the presence of diisopropylamine, n-heptane/THF, n-butyl lithium to yield (2R,3S/2S,3R) 2-(2,4-difluorophenyl)-3-(4-chloro-5-fluoropyrimidin-6-yl)-1 -(1H-1,2,4-triazole-l -yl) butan-2-ol of Formula VII which is fiirther reduced with Raney Nickel in the presence of sodiimi acetate to yield (2R,3S/ 2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(IH-l,2,4-triazole-l-yl)butan-2-ol of Formula VIII and then resolution with R-(-)-10-camphor sulphonic acid in the presence of methanol to yield camphor sulfonate salt of Formula X followed by hydrolysis of the camphor sulfonate salt to free base with 20% sodium bicarbonate solution in the presence of dichloromethane to give Voriconazole of Formula I. The process is represented in scheme-Ill given below, The drawback of this process is use of hazardous reagents as lithium diisopropylamine for the condensation, which require low temperature i.e. -78''C. It is difficuh to maintain all the time at manufacturing scale. This reaction requires chromatographic separation of the enantiomeric pair which is not advisable at plant scale production. Further, it involves dehalogenation of the condensed compound under pressure in presence of Raney nickel, which is not advisable because of the safety concern. Moreover, the yield is also very low.

WO2007013096 discloses the process for the preparation of voriconazole
comprising reacting 4-chloro-6-ethyl-5-fluoropyrimidine of Formula V with l-(2,4-diflouorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of Formula VI in the presence of lithium diisopropylamine, n-heptane, letrahydrofuran to yield (2R,3S/2S,3R) 2-(2,4-difluorophenyi)-3-(4-chloro-5-fluoropyrimidin-6-yl)-1 -(IH-1,2,4-triazole-1 -yl) butan-2-Oi of Formula VII which is further reduced with Raney Nickel in the presence of sodium acetate to yield (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-
l,2,4-triazole-l-yl)butan-2-ol of Formula VIII (racemic Voriconazole) and then resolution with R-(-)-10-camphor sulphonic acid in the presence of methanol to yield camphor sulfonate salt of Formula X followed by hydrolysis of the camphor sulfonate salt to free base with sodium hydroxide solution in the presence of dichloromethane and 2-propanol gives voriconazole of Formula I. The process is represented in scheme-IV given below, Scheme IV

The drawbacks of this process are use of hazardous reagents as lithium diisopropylamine for the condensation, the reaction has to be maintained at very low temperature of -78°C which is difficult to maintain all the time at manufacturing scale, the reaction requires chromatographic separation of the enantiomeric pair which cannot be done at plant scale, use of Raney nickel for dehaiogenation under pressure is not advisable because of the safety concern. Moreover the yields are very low.

It's apparent from most of the prior art that the preparation of voriconazole has certain disadvantages such as
• The use of hazardous and costly raw materials like lithium diisopropyl amide, iodine, Pd/C, Raney Ni and n-butyl lithiimi
• Reaction requires to be maintained at lower temperature which is difficult to maintain all the time at commercial scale
• The processes involves chromatographic purification techniques which is not viable at commercial scale
• Involves more reaction steps and lengthy work-up
• Overall higher cost of production
• Low yields and purity

Therefore, there is a continuing need for developing a new process for the
manufacturing of voriconazole which is cost effective, industrially viable and eco-friendly.

SUMMARY OF THE INVENTION

The principal aspect of present invention is to provide a novel process for the manufacturing of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol of formula I, which comprises :
a) condensation of compound of formula V with l-(2,4-difiuoro- phenyl)-2-(lH-l,2,4-triazoI-I-yI)ethanone of formula IV in the presence of zinc, Lewis acid and an aprotic organic solvent to obtain 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol of formula III;

b) resolution of the obtained compound of formula III with a suitable resolving agent to obtain (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol lR-{-)-camphor-10-sulphonate of formula II; and

c) basification of the above obtained salt of formula II and further crystalisation to obtain (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol of formula I.
The above process can be illustrated by the below scheme V:

The another aspect of the invention is to provide a novel process for the for the manufacturing of (2R,3S)-2-(2,4-dif!uorophenyl)-3-(5-fluoropyrimidin-4-yI)-1 -(1H-1,2,4-triazol-l-yl)butan-2-ol of formula I comprising the steps disclosed in the above scheme V where the compound of formula IV is condensed with compound of formula V(b).

Wherein Ri is CI, Br, or I X is -OH, -O, OBs, OTs, OTf, OMs, ONs, OCs or 4-trifluoromethylbenzenesulfonate The another aspect of the invention is to provide a novel process for the manufacturing l-(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate of formula V(a), which comprises:

a) acetylation of compound of formula IX to obtain compound of formula VIII;
b) reduction of the compound of formula VIII to obtain compound of formula VII and its optional isolation;
c) reduction of the compoxmd of formula VII to obtain compound of formula VI; and
d) converson of the compound of formula VI to obtain compound of formula V(a).
The above process can be illustrated by the below scheme VI:

Scheme VI

Another aspect of the invention is to provide a novel process for the preparation voriconazole, which comprises:
a) acetylation of compound of formula IX to obtain compoimd of formula VIII;
b) reduction of the compound of formula VIII to obtain compound of formula VII and its optional isolation;
c) reduction of the compound of formula VII to obtain compound of formula VI;
d) converson of the compoimd of formula VI to obtain compoimd of formula V(a);
e) condensation of compound of formula V(a) with I-(2,4-difluoro- phenyl)-2-(lH-
l,2,4-triazol-l-yl)ethanone of formula IV in the presence of zinc, Lewis acid and j
i

aprotic solvent, to obtain 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-{lH-l,2,4-triazoI-l-yl)butan-2-ol of formula III;
f) resolution of the obtained compound of formula III with a suitable resolving agent
to obtain (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-
triazoie-l-yl)butan-2-ol lR-(-)-camphor-10-sulphonate of formula II; and
g) basification of the above obtained salt of formula II and further crystalisation to
obtain (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-
triazole-l-yl)butan-2-ol or Voriconazole.
The above process can be illustrated by the below scheme VII:
The further aspect of the present invention is to provide novel intermediates of formula Wherein Ri and R2 are independently selected from H, CI, Br, I, OBs, OTs, OTf, OMs X is -OH, =0, OBs, OTs, OTf, OMs, ONs, OCs or 4-trifluoromethylbenzenesulfonate

DETAILED DESCRIPTION OF THE INVENTION

Accordingly in an embodiment of the invention, the condensation of compound of formula V with l-(2,4-difluoro- phenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of formula IV is carried out in presence of a suitable aprotic organic solvent such as tetrahydrofiiran, toluene, 1,2-dimethoxyetane or methylene chloride or a mixture of two or more thereof. The preferred solvent for the reaction is tetrahydrofiiran. The reaction is carried out preferably under dry and inert atmosphere such as by using dry nitrogen or argon gas. The zinc used in this reaction is preferably zinc powder. The zinc powder may be activated prior to use by stirring it in a suitable solvent preferably tetrahydrofiiran. The Lewis acid used in this reaction is selected from zinc chloride, zinc bromide, zinc iodide, titanium (IV) isopropoxide, chlorotitanium triisopropoxide, titanium tetrachloride, trimethyl borate, boron trifluoride (etherate), iron (III) chloride, and diethylaluminium chloride. The preferred Lewis acids are zinc chloride, zinc bromide, zinc iodide and particularly, zinc chloride.

The reaction may be carried out at from -15 "C to reflux temperature of the mixture. Preferably it is carried out at from -10 °C to +30 °C and most preferably at -10 "C to +15 °C.

This reaction proceeds via formation of an organozinc complex derived from insitu reaction of zinc with a compound of the formula (IV), which is used as a starting material.

The process for preparation of voriconazole reported in literature reduces intermediate formed by Reformatsky reaction. It is achieved by addition of another lot of zinc and and ammonium formate, followed by tedious work up. In order to avoid the operational difficulty the present inventors have selected starting materials that will render the product of formula III, which eliminates the reduction step.

Further, Organic Process Research & Development (2001), 5(1), 28-36 reports that in the starting material of compound of formula (V) when X was Br and R] and R2 was H, the diastereomeric selectivity (2R,3S:2R,3R) of the product was low (17.8:53.2). The present inventors found that it may be due to the low bulkier group like Br provided less stereo selectivity in Reformatsky reaction. To overcome the above drawback, the present inventors selected leaving groups, which will provide the bulkiness to the organozinc complex, which in turn will add across the carbonyl group stereoselectively.

The reaction may be carried out by the following process. A suitable Lewis acid preferably zinc chloride is heated in a suitable aprotic organic solvent preferably in toluene at reflux for 1-1.5 hrs. Toluene is distilled off and cooled to about 60°C followed by addition of toluene and metal preferably zinc dust and a solvent preferably tetrahydrofuran and ftirther heating the mixture to reflux for 3 to 4 hours to complete the activation of the metal and then cooling the mixture to 5 to 10*'C. Substituted pyrimidine compound of formula V and l-(2,4-diflouoropheny])-2-(lH-l,2,4-triazol-I-yl)ethanone dissolved in a suitable aprotic organic solvent at 5 to 10 **€, is added to the above activated metal mixture and the same temperature is maintained for 1 hour. The excess solvent is distilled of to get thick slurry, quenched with a mixture of water and acetic acid. The reaction mass is basified with saturated sodium carbonate or sodium bicarbonate solution followed by neutralization with cone, hydrochloride to form a slurry. It is filtered and the filtrate is extracted with ethyl acetate two to three times. The combined the ethyl acetate layers is washed with 5% aq. EDTA disodium solution and water, dried and the ethyl acetate layer is distilled off under reduced pressure at 43-45''C to obtain racemic 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol.

In another embodiment of the invention, the obtained racemic mixture is resolved with a suitable resolving agent in presence of organic solvent to get the corresponding salt of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol.

In another embodiment, this invention provides a process to manufacture (2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol by conversion of the salt to (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyriinidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol using appropriate base and further purification.
The metal for the above reaction can be selected form a group of organometals such as zinc, magnesium, manganese, lead metal or mixture thereof The suitable resolving agent is selected form a group consisting of R-(-)-10-camphor sulphonic acid, (+)-3-bromo-10-camphoursulphonate, (-)-3-bromo-8-camphoursulphonate, L-(-)-mandelic acid or L-(-)-tartaric acid most preferably R-(-)-10-camphor sulphonic acid in a suitable solvents selected from a group consisting of ketonic solvents such as acetone, butanone, propanone, ethylmethylketone; alcoholic solvents such as methanol, ethanol, isopropanol or their mixtures.

The salt is converted in a free base in the presence of suitable base selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate most preferably sodium hydroxide in a suitable organic solvents selected from a group consisting dichloromethane, chloroform, ethylacetate and more preferably dichlorome thane.
The other isomer (2S, 3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol can be isolated from the mother liquor by the method known to those skilled in the art.

In another embodiment of the present invention, for the preparation of starting material of compound of formula V(a), acetylation of 2,4-dichloro-5-fluoropyrimidine of formula IX is done in presence of acetic acid, sulphuric acid preferably 3N sulphiuic acid, acetaldehyde, ammonium persulphate, and ferrosulphate heptahydrate to obtain l-(2,6-dichloro-5-fluoropyrimidine-4-yl)ethanone of formula VIIL l-(2,6-dichloro-5-fluoropyrimidine-4-yl)ethanone of formula VIII is hydrogenated in a solvent preferably methanol, ethanol or tetrahydrofuran in presence of sodium acetate and a reducing agent, preferably 5 to 10% palladium-on-carbon to give an intermediate compound l-(5-fluoropyrimidin-4-yl)ethanone of formula VII. This intermediate compound of formula VII is further reduced in-situ in presence of a reducing agent preferably sodium borohydrate, a base preferably sodium hydroxide, a solvent selected from methanol, ethanol, propanol, methylene dichloride, ethylene dichloride, water or mixture thereof to obtain l-(5-fluoropyrimidin-4-yl)ethanol of formula VI. The intermediate compound l-(5-fluoropyrimidin-4-yl)ethanone of formula VII may be isolated and fiulher reduced to obtain l-(5-fluoropyrimidin-4-yl)ethanol of formula VI. l-(5-fluoropyrimidin-4-yl)ethanol of formula VI is protected by substituted or unsubstituted aryl or alkyl sulfonyl chloride in presence of base dimethylamino pyridine and triethyl amine and in presence of a solvent preferably chlorinated solvent most preferably methylene dichloride to obtain compound of formula V(a). The alkyle sulfonyl chloride may be selected from 1-hexylsulfonyl chloride, n-butyl sulfonyl chloride, ethylsulfonyl chloride, 1-pyrenesulfonyl chloride, 1-octanesulfonyl chloride, 1-butanesulfonyl chloride, methylsulfonyl chloride, 2-
thienyl sulfonyl chloride, 1 -propanesulfonyl chloride, 1 -decanesulfonylchloride, pentadecylsulfonyl chloride, frifluoromethyl sulfonyl chloride, preferably methyl sulfonyl chloride and trifluoromethyl sulfonyl chloride. The substituted or unsubstituted aryl sulfonyl chloride may be benzylsulfonyl chloride, p-toluenesulfonyl chloride, trifluromethyl benzene sulfonyl chloride and the like. Most preferred protecting agent is p-toulene sulfonyl chloride.

In the preferred embodiment of the present invention, 2,4-dichloro-5-fluoropyrimidine is used as starting material for the preparation of l-(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate, which is further reacted according to the present invention to obtain (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazol-1 -yl)butan-2-ol of Formula-I.

In another embodiment, the present invention also provides the following novel compound:

(6-chloro-5-fluoropyrimidin-4-yl)ethanol
(2-chloro-5-fluoropyrimidin-4-yl)ethanol
(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanol
(5-fluoropyrimidin-4-yl)ethanol
(2-chloro-5-fluoropyrimidin-4-yl)ethanone.
(6-chloro-5-fluoropyrimidin-4-yl)ethanone.
(2,6 -dichloro-5-fluoropyrimidin-4-yl)ethanone.
(5 -fluoropyrimidin-4-yl)ethanone.
(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
(2, 6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
(5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
(2-chIoro-5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate
(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate
(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate
(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate
(6-chloro-5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
(2--chloro-5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
(5-fIuoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
(6-chloro-5-fluoropyrimidin-4-yl)ethyl methanesulfonate
(2-chloro-5-fluoropyrimidin-4-yl)ethyl methanesulfonate

xxiii. 1 -(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl methanesulfonate
xxiv. 1 -(5-fluoropyrimidin-4-yl)ethyl methanesulfonate
XXV. l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxvi. l-(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxvii. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxviii. l-(5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxix. l-(6-chioro-5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
XXX. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxi. l-(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxii. l-(5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxiii. l-(6-chloro-5-fiuoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonate
xxxiv. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonate
XXXV. l-(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonale
xxxvi. l-(5-fluoropyrimidin-4-yl)ethyl-4-nit.robenzenesulfonate
The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLES Example 1:

Preparation of l-(2..6-dichloro-5-fluoropvrimidin-4-vl)ethanone
2,4-dichloro-5-fluoropyrimidine (200 g), acetic acid (4000 mL), 3 N sulphuric acid solution (6250 mL) taken in a round bottom flask and cooled to IO°C. Acetaldehyde (35%, 1600 mL) was added to the mixture. Ammonium persulphate solution was prepared by dissolving ammonium persulphate in DM water (2400 mL) and ferrous sulphate solution was prepared by dissolving ferrous sulphate in DM water (2400 mL). Then, the above prepared ammonium persulphate solution and ferrous sulphate solution were added dropwise simultaneously over 1 hour at 10°C and stirred for 30 minutes. The reaction mass was, filtered and washed with cyclohexane (2000 mL) to get the title compound (120 g). 'H NMR 300 Hz (CDCI3) d 2.706 (3 H, s).

Example 2:

Preparation of l-(5-fluoropvrimidin-4-vl)ethanol The above prepared compound, l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanone (120 g) was dissolved in ethanol (500 ml), sodium acetate (40 g) and 17 g of 10% w/w palladium on carbon (50% w/w water content) was added and the mixture was hydrogenated at 103 kPa (15 psi) and 25°C imtil completion of the reaction. The catalyst was removed by filtration and to the filtrate, sodium borohydride (20 g) was added and stirred for 5 hours. Dichloromethane (I L) and water (1 L) were added and the pH was adjusted to 11 using 40 % w/w aqueous sodium hydroxide solution. The layers were separated and the aqueous layer was extracted with dichloromethane (IL). The combined organic extracts were washed with water (IL), concentrated under reduced pressure to give the title compound (75 g). 'H NMR 300 Hz (CDCh) d 9.019 (IH, d, J=2.7Hz), 8.546, (IH, d, J=I.SHz), 5.147 (lH,q,J=6.3Hz), 3.969 (IH, bs), 1.533 (3H, m)

Example 3:

Preparation of l-(5-fluoropvrimidin-4-vnethvl-4-methvlbenzenesulfQnate
The above prepared compound, l-(5-fIuoropyrimidin-4-yl)ethanol (75 g) was dissolved in methylene dichloride (375 mL) at 25-30°C. 4-Dimethyl amino pyridine (4.5 g) and p-toluene sulfonyl chloride (102 g) were added. Then triethylamine (171 mL) was added at 20°C over 2 hours. The mixture was stirred till completion of the reaction. 300 mL of water was charged and stirred for 15 minutes. The layers were separated and the methylene dichloride layer was washed with 10% sodium bicarbonate solution (50 mL) and again washed with 100 mL of water. The methylene dichloride layer was concentrated and cyclohexane (300 mL) was added to it. The mixture was refluxed for 2 hours, cooled to room temperature and filtered to get the title compound (135 g). 'H NMR 300 Hz (CDCI3) d 8.937 (lH,d, J=2.4Hz), 8.480 (IH, d, J=1.8Hz), 7.724 (2H, d, J=8.1Hz), 7.259(2H, d, J=8.1Hz), 5.816 (IH, q, J=6.6Hz), 2.417 (3H, s), 1.663 (3H, d, J=6.3Hz) Example 4:
Preparation of 2-f2,4-difluorophenvH-3-f5-fluoropvrimidiii-4-vl)-l-('lH-1.2.4-triazol-l-vl)butan-2-ol. lR-(-)-camphor-10-sulphonate
Toluene (500 mL) and zinc chloride (137.8 g) were taken in a round bottom flask and heated to reflux temperature 130*^C of oil bath. The contents were maintained at reflux temperature for 1 hour and the milky layer was separated through dean stark apparatus. The toluene was distilled off completely at atmospheric pressure by maintaining oil bath
temperature 130''C. The contents were cooled to 60''C. Tetrahydrofuran (900 mL) and 80.86 gm of zinc metal powder were added and the contents were maintained at reflux temperature for 3 hours. The mixture was cooled to -5 to 0°C. THF solution was prepared by dissolving l-(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate (90 g) as above prepared in example 3 and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone (60.2 g) and further added to the mixture at 0+ 5°C within 2 hours. The reaction mass was maintained for 24 hours at 15°C and the temperature was raised to 25-30^C. The above prepared filtrate was taken into a mixture of acetic acid (50 mL) in DM water (1000 mL) and the contents were stirred for 30 minutes at 25-30°C. The pH of the reaction mass was adjusted to the 10.0-11.0 by adding 1000 mL of 10% sodium carbonate solution and stirred at for 30 minutes at 25-30°C, ethyl acetate (1000 mL) was added and stirred for 30 minutes. The mixture was filtered through filter cloth in Buckner funnel. The filtrate was taken in another flask and stirred for 15 minutes. The layers were separated and the salt was washed with ethyl acetate (500 mL) in Buckner fimnel. The aqueous layer was taken in flask and ethyl acetate (500 mL) was added to it and stirred for 15 minutes. The layers were separated and ethyl acetate layer was kept side. Aqueous layer was taken in RB flask, ethyl acetate (500 mL) was added and stirred for 15 minutes at 25-30°C. The layers were separated. The combined ethyl acetate layers were taken in another flask and DM water (1000 mL) was added to it and stirred for 30 minutes. Both layers were separated. Ethyl acetate layer was taken into flask and 1500 mL of 5% aqueous EDTA disodium solution was added and the contents were stirred for 30 minutes. The layers were settled for 15 minutes and separated. The aqueous layer was taken and ethyl acetate was added and stirred for 15 minutes at 25-30°C. The layers were settled for 15 minutes and separated. The ethyl acetate layers were taken in flask and DM water (1000 mL) and stirred for 30 minutes at 25-30°C. The layers were settled for 15 minutes and separated. Ethyl acetate layer was taken in flask and distilled off completely under vacuum (650-710 mm/Hg) at below 40'^C. The residue was dissolved in 1200 mL of acetone and the acetone solution was taken in another flask. lR-(-)-Camphor-10-sulphonic acid (57 g) was added to the above prepared contents at 25-30''C for 30 minutes. The contents were heated to reflux temperature 60-65°C and maintained for 30 minutes and again for 1 hour. The mixture was cooled slowly at 25-30°C for 30 minutes and maintained at 20^0 for 1 hour. The isolated solid was filtered and washed with 500 mL of acetone and dry the solid for 15-30 minutes. The solid was dissolved in 120 mL of methanol and the content was heated to 40 to 45 *^C. The mixture was maintained for 1 hour to get a clear solution. It was cooled 25 to 30 °C. and maintained for 2 hours. Further cooled
to 20 ''C. and maintained for 2 hours. The solid was filteredand dried over 30 minutes to render the title compound (19.3 g).

Example 5:

Preparation of r2R.3S)-2-a.4-difluorophenvn-3-(5-fluoropvrimidin-4-vlVl-(lH-l,2.4-triazol-l-vl)butan-2-ol The above prepared compound, 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol. 1 R-(-)-camphor-10-sulphonate (10 g) was taken in the flask. Methylene dichloride (52 mL) and purified water (52 mL) were added, stirred at 25-30°C and cooled to 20-25^C The pH of the mixture was adjusted to 12.0-13.0 by adding 40% sodium hydroxide solution and stirred for 15-30 minutes. The layers were settled for 15 minutes and separated. The aqueous layer and methylene dichloride (52 mL) was added, stirred for 30 minutes, settied for 15 minutes and separated. The above prepared methylene dichloride layers were combined. Purified water (52 mL) was added and stirred for 30 minutes. The layers were settled for 15 minutes and separated. The organic layer was filtered through hyflow bed and the bed was washed with methylene dichloride (10 mL). Then the organic layer and activated charcoal (10 g) was taken in a flask and and heated to reflux and was maintained at reflux for 1 hour and cooled to 25-30^C. The activated charcoal was filtered off through hyflow bed and the bed was washed with methylene dichloride (10 mL). The methylene dichloride was distilled off under reduced pressure till thick slurry is obtained and isopropyl alcohol (52 mL) was added and further the mixture was cooled to 0±2''C. The mixture was maintained and stirred for 1 hour. The separated solid was filtered and washed with cold isopropyl alcohol (10 mL). The solid was dried under vacuum at 45-50°C and vacuum was released through nitrogen to get the title compound (5g). ^H NMR 300 Hz (DMSO) d 9.041 (IH, d, J=2.7Hz), 8.846 (IH, d, J=2.1Hz), 8.229 (IH, s), 7.609 (IH, s), 7.221 (2H, m ), 6.913 (IH, m), 5.977 (IH, s), 4.797 (IH, d, J=14.4Hz), 4.332 (IH, d, J=14.4 Hz), 3.924 (IH, q, J=7.2 Hz), 1.101 (3H, d, J=6.9Hz) Example 6:
Preparation of 2-f2.4-difluorophenvn-3-(5-fluQropvrimidin-4-vn-l-(lH-l,2,4-triazQl-l-vnbutaii-2-ol. lR-(-Vcamphor-lQ-sulphonate Toluene (500 mL) and zinc chloride (275 g) were taken in a round bottom flask and heated to reflux temperature 130'^C of oil bath. The contents were maintained at reflux temperature for 1 hour and the milky layer was separated through dean stark apparatus. The toluene was distilled off completely at atmospheric pressure by maintaining oil bath temperature 130°C. The contents were cooled to 60''C. Tetrahydrofuran (900 mL) and 160 gm of zinc metal powder were added and the contents were maintained at reflux temperature for 3 hours. The mixture was cooled to -5 to 0°C. THF solution was prepared by dissolving l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate (90 g) as above prepared in example 3 and l-(2,4-difluorophenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone (60.2 g) and further added to the mixture at 0+ 5°C within 2 hours. The reaction mass was maintained for 24 hours at 15°C and the temperature was raised to 25-30'^C. The above prepared filtrate was taken into a mixture of acetic acid (50 mL) in DM water (1000 mL) and the contents were stirred for 30 minutes at 25-30°C. The pH of the reaction mass was adjusted to the 10.0-11.0 by adding 1000 mL of 10% sodium carbonate solution and stirred at for 30 minutes at 25-30°C, ethyl acetate (1000 mL) was added and stirred for 30 minutes. The mixture was filtered through filter cloth in Buckner funnel. The filtrate was taken in another flask and stirred for 15 minutes. The layers were separated and the salt was washed with ethyl acetate (500 mL) in Buckner funnel. The aqueous layer was taken in flask and ethyl acetate (500 mL) was added to it and stirred for 15 minutes. The layers were separated and ethyl acetate layer was kept side. Aqueous layer was taken in RB flask, ethyl acetate (500 mL) was added and stirred for 15 minutes at 25-30^C. The layers were separated. The combined ethyl acetate layers were taken in another flask and DM water (1000 mL) was added to it and stirred for 30 minutes. Both layers were separated. Ethyl acetate layer was taken into flask and 1500 mL of 5% aqueous EDTA disodium solution was added and the contents were stirred for 30 minutes. The layers were settled for 15 minutes and separated. The aqueous layer was taken and ethyl acetate was added and stirred for 15 minutes at 25-30*^0. The layers were setded for 15 minutes and separated. The ethyl acetate layers were taken in flask and DM water (1000 mL) and stirred for 30 minutes at 25-30°C. The layers were settled for 15 minutes and separated. Ethyl acetate layer was taken in flask and distilled off completely under vacuum (650-710 mm/Hg) at below 40**C. The residue was dissolved in 1200 mL of acetone and the acetone solution was taken in another flask. lR-(-)-Camphor-10-sulphonic acid (57 g) was added to the above prepared contents at 25-30°C for 30 minutes. The contents were heated to reflux temperature 60-65''C and maintained for 30 minutes and again for 1 hour. The mixture was cooled slowly at 25-30'*C for 30 minutes and maintained at 20'*C for 1 hour. The isolated solid was filtered and washed with 500 mL of acetone and dry the solid for 15-30 minutes. The solid was dissolved in 120 mL of methanol and the content was heated to 40 to 45 ^C. The mixture was maintained for 1 hour to get a clear solution. It was cooled 25 to 30 "^C. and maintained for 2 hours. Further cooled to 20 C. and maintained for 2 hours. The solid was filtered and dried over 30 minutes to render the title compound (18g)

Example 7:

Preparation of f2R.3S)-2-r2.4-dinuorophenvlV3-f5-nuoropvrimidin-4-vn-l-(lH-l,2.4-triazol- l-vnbutan-2-ol The above prepared compound of example 6, 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazoi-l -yl)butan-2-ol. 1 R-(-)-camphor-10-sulphonate (10 g) was taken in the flask. Methylene dichloride (52 mL) and purified water (52 mL) were added, stirred at 25-30°C and cooled to 20~25''C The pH of the mixture was adjusted to 12.0-13.0 by adding 40% sodium hydroxide solution and stirred for 15-30 minutes. The layers were settled for 15 minutes and separated. The aqueous layer and methylene dichloride (52 mL) was added, stirred for 30 minutes, settled for 15 minutes and separated. The above prepared methylene dichloride layers were combined. Purified water (52 mL) was added and stirred for 30 minutes. The layers were settled for 15 minutes and separated. The organic layer was filtered through hyflow bed and the bed was washed with methylene dichloride (10 mL). Then the organic layer and activated charcoal (10 g) was taken in a flask and and heated to reflux and was maintained at reflux for 1 hour and cooled to 25-30°C. The activated charcoal was filtered off through hyflow bed and the bed was washed with methylene dichloride (10 mL). The methylene dichloride was distilled off under reduced pressure till thick slurry is obtained and isopropyl alcohol (52 mL) was added and further the mixture was cooled to 0+2^0. The mixture was maintained and stirred for 1 hour. The separated solid was filtered and washed with cold isopropyl alcohol (10 mL). The solid was dried under vacuum at 45-50°C and vacuum was released through nitrogen to get the title compound (5g ). 'H NMR 300 Hz (DMSO) d 9.041 (IH, d, J=2.7Hz), 8.846 (IH, d, J=2.1Hz), 8.229 (IH, s), 7.609 (IH, s), 7.221 (2H, m ), 6.913 (IH, m), 5.977 (IH, s), 4.797 (IH, d, J=14.4Hz), 4.332 (IH, d, J=14.4 Hz), 3.924 (IH, q, J=7.2 Hz), 1.101 (3H, d, J=6.9 Hz)

We claim:

1. A process for the preparation of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fIuoropyrimidm-4-yl)-1 -(1H-1,2,4-triazol-l -yl)butan-2-ol of formula I, which comprises :

a) condensation of compound of formula V V Wherein, X is OBs, OTs, OTf, OMs ONs, OCs, or 4-trifluoromethylbenzene sulfonate; and where with l-(2,4-difluoro- phenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of formula IV in the presence of zinc, Lewis acid and an aprotic organic solvent to obtain 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazoI- l-yl)butan-2-ol of formula III;

b) resolution of the obtained compound of formula III with a suitable resolving agent to obtain the corresponding acid addition salt of compound of formula III; and

c) basification of the above obtained acid addition salt of formula III and further crystalisation to obtain (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol of formula I.

2. A process for the preparation of l-(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate of formula V(a), Wherein, X is as defined above which comprises:

a) acetylation of compound of formula IX to obtain compound of formula VIII;

b) reduction of the compound of formula VIII to obtain compound of formula VII and its optional isolation;

c) reduction of the compound of formula VII to obtain compoimd of formula VI; and

d) protection of the compound of formula VI using protecting group to obtain compound of formula V(a).

3. A process for the preparation voriconazole of formula I, which comprises: a) acetylation of compound of formula IX to obtain compound of formula VIII;

b) reduction of the compound of formula VIII to obtain compound of formula VII and its optional isolation; VII

c) reduction of the compound of formula VII to obtain compound of formula VI;

d) protection of the compound of formula VI to obtain compound of formula V(a);

e) condensation of compound of formula V(a) withl-(2,4-difluoro- phenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of formula IV in the presence of zinc, Lewis acid and aprotic organic solvent, to obtain 2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1 -(1H' 1,2,4-triazol-1 -yl)butan-2-ol of formula III;

f) resolution of the obtained compound of formula III with a suitable resolving agent to obtain the corresponding acid addition salt of compound of formula III; and

g) basification of the above obtained acid addition sah of formula III and further crystalisation to viriconazole of formula I.

4. A 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 of formula I, which comprises :

a) condensation of compound of formula V(b) Wherein R, is CI, Br, or I Wherein, X is OBs, OTs, OTf, OMs ONs, OCs, or -O-4-trifluoromethylbenzene sulfonate; and where I with l-(2,4-difluoTO-phenyl)-2-(lH-l,2,4-triazol-l-yl)ethanone of formula IV in the presence of zinc, Lewis acid and an aprotic organic solvent to obtain 2-(2,4-difluorophenyl)-3'(5-fluoropyrimidin-4-yl)-1 -(1H-1,2,4-triazol-1 -yl)butan-2-ol of formula III;I

b) resolution of the obtained compound of formula III with a suitable resolving agent to obtain the corresponding acid addition salt of compound of formula HI; and I

c) basification of the above obtained acid addition salt of formula III and further crystalisation to obtain (2R, 3S)-2-(2, 4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH-l,2,4-triazole-l-yl)butan-2-ol of formula I.

5. A process according to any of the preceding claim, wherein Lewis acid selected from zinc chloride, zinc bromide, zinc iodide, titanium (IV) isopropoxide, chlorotitanium triisopropoxide, titanium tetrachloride, trimethyl borate, boron trifluoride (etherate), iron (III) chloride, and diethylaluminium chloride.

6. A process according to claim 1, 3 or 4 wherein, Lewis acid is zinc chloride, zinc bromide or zinc iodide.

7. A process according to claim 1, 3 or 4 wherein, Lewis acid is zinc chloride.

8. A process according to claim 1, 3 or 4 wherein, aprotic organic solvent is tetrahydrofuran, toluene, 1,2-dimethoxyetane or methylene chloride or a mixture of two or more thereof

9. A process according to claim 1, 3 or 4 wherein, resolving agent is selected form a group consisting of R-(-)-10-camphor sulphonic acid, (+)-3-bromo-10-camphoursulphonate, (-)-3-bromo-8-camphoursulphonate, L-(-)-mandelic acid or L-(-)-tartaric acid.

10. A process according to claim 1, 3 or 4 wherein, resolving agent is R-(-
camphor sulphonic acid.

11. A process according to claim 1, 3 or 4 wherein, resolution is carried out in a suitable solvents selected from a group consisting of acetone, butanone, propanone, ethyl methyl ketone, methanol, ethanol, isopropanol or mixtures thereof.

12. A process according to claim 1, 3 or 4 wherein, the basification of the acid addition salt is done in the presence of suitable base selected from sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate or sodium bicarbonate in a suitable organic solvents selected from a group consisting dichloromethane, chloroform, ethylacetate.

13. A process according to claim 1, 3 or 4 wherein, the basification of the acid addition salt is done in the presence of a base sodium hydroxide and in presence of solvent dichloromethane.

14. A process according to claim 2, acetylation of 2,4-dichloro-5-fluoropyrimidine of formula IX is done in presence of acetic acid, sulphuric acid, acetaldehyde, ammonium persulphate, and ferrosulphate heptahydrate.

15. A process according to claim 2 wherein, reduction in step (b) is carried out in presence of a solvent selected from methanol, ethanol and tetrahydrofuran; a base sodium acetate and in presence of a reducing agent, preferably 5 to 10% palladium-on-carbon.

16. A process according to claim 2 wherein, reduction in step (c) is carried out in presence of reducing agent preferably sodium borohydrate, a base preferably sodium hydroxide, a solvent selected from methanol, ethanol, propanol, methylene dichloride, ethylene dichloride, water or mixture thereof.

17. A process according to claim 2 wherein, l-(5-fluoropyrimidin-4-yl)ethanol of formula VI in step (c) is protected by substituted or unsubstituted aryl or alkyl sulfonyl chloride in presence of base dimethylamino pyridine and triethyl amine and in presence of a chlorinated solvent most preferably methylene dichloride.

18. A process according to claim 2 wherein, l-(5-fIuoropyrimidin-4-yl)ethanol of formula VI in step (c) is protected by substituted or unsubstituted aryl or alkyl sulfonyl chloride in presence of base dimethylamino pyridine and triethyl amine and in presence of a chlorinated solvent most preferably methylene dichloride

19. A process according to claim 18 wherein, the protecting group is selected from 1-hexylsulfonyl chloride, n-butyl sulfonyl chloride, ethylsulfonyl chloride, 1-pyrenesulfonyl chloride, 1 -octanesulfonyl chloride, 1 -butanesulfonyl chloride, methylsulfonyl chloride, 2-thienylsulfonyl chloride, 1-propanesuifonyl chloride, 1-
decanesulfonylchloride, pentadecylsulfonyl chloride, frifluoromethyl sulfonyl chloride, benzylsulfonyl chloride, p-toluenesulfonyl chloride, trifluromethyl benzene sulfonyl chloride.

20. A compound of formula Wherein Ri and R2 are independently selected from H, CI, Br, I, OBs, OTs, OTf, OMs X is -OH, =0, OBs, OTs, OTf, OMs, ONs, OCs or -O-4-trifluoromethylbenzenesulfonate
21. A compound of formula V as defined in claim 20 which is

i. 1 -{6-chloro-5-fluoropyrimidin-4-yl)ethanol
ii. l-(2-chloro-5-fluoropyrimidin-4-yl)ethanol
iii. I-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethanol
iv. l-(5-fluoropyrimiclin-4-yl)ethanol
V. 1 -(2-chIoro-5-fluoropyrimidin-4-yl)ethanone.
vi. 1 -(6-chloro-5-fluoropyriinidin-4-yl)ethanone.
vii. 1 -(2,6 -dichloro-5-fluoropyrimidin-4-yl)ethanone.
viii. l-(5-fluoropyrimidin-4-yI)ethanone.
ix. l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
X. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
xi, l-(2-chloro-5-fIuoropyrimidm-4-yl)ethyl-4-boromobenzenesulfonate
xii. l-(5-fluoropyrimidin-4-yl)ethyl-4-boromobenzenesulfonate
xiii. l-(2-chloro-5-fluoropyrimidm-4-yl)ethyl-4-methyibenzenesulfonate
xiv. l-(6-chloro-5-fluoropyrimidin-4-yI)ethyl-4-methylbeiizenesulfonate
XV. l-(2,6-dichloro-5-fluoropyriinidm-4-yl)ethyl-4-methylbenzenesulfonate
xvi. l-(5-fluoropyrimidin-4-yl)ethyl-4-methylbenzenesulfonate
xvii. l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
xviii. l-(2-chloro-5-fluoropyrimidm-4-yl)ethyI-trifluoromethanesulfonate
xix. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
XX. l-(5-fluoropyrimidin-4-yl)ethyl-trifluoromethanesulfonate
xxi. 1 -(6-chloro-5-fluoropyrimidm-4-yl)ethyl methanesulfonate
xxii. l-(2-chloro-5-fluoropyrimidin-4-yI)ethyl methanesulfonate
xxiii. 1 -(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl methanesulfonate
xxiv. l-(5-fluoropyrimidin-4-yi)ethyl methanesulfonate
xxv. l-(6-chloro-5-fluoropyrimidm-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxvi. l-(2-chloro-5-fIuoropyrimidin-4-yl)ethyl-4-(trifluoromethyi)benzenesulfonate
xxvii. l-(2,6-dichloro-5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxviii.l-(5-fluoropyrimidin-4-yl)ethyl-4-(trifluoromethyl)benzenesulfonate
xxix. l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
XXX. l-(2,6-dichloro-5-fluoropyrunidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxi. l-(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxii. l-(5-fluoropyrimidin-4-yl)ethyl-4-chlorobenzenesulfonate
xxxiii.l-(6-chloro-5-fluoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonate
xxxiv. l-(2,6-dichloro-5-fluoropyrimidin-4-yI)ethyl-4-nitrobenzenesulfonate
XXXV.l-(2-chloro-5-fluoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonate
xxxvi. l-(5-fluoropyrimidin-4-yl)ethyl-4-nitrobenzenesulfonate