EP2545039A1

EP2545039A1 - A process for making voriconazole

Info

Publication number: EP2545039A1
Application number: EP10708939A
Authority: EP
Inventors: Arjanne Overeem; Jie Zhu
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2010-03-10
Filing date: 2010-03-10
Publication date: 2013-01-16
Also published as: WO2011110198A1; WO2011110198A8

Abstract

The present invention relates to a process of making a pair of trans-diastereomers of a compound of formula (I) comprising the step of reacting the compound of formula (VI) with an acid or a carboxylate salt thereof of formula (X) wherein M is hydrogen or an equivalent of a metal cation, in the presence of a metal salt in a solvent, and to the use of the compound (X) in making voriconazole.

Description

A PROCESS FOR MAKING VORICONAZOLE

Voriconazole, chemically (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin

(lH-l ,2,4-triazol-l -yl)-butan-2-ol of the following formula

is a pharmaceutically active compound, which has been developed as an antifugal agent for a manufacture of a medicament for oral and intravenous treatment of serious systemic fungal infections. It is marketed by Pfizer under the brand name VFEND.

Voriconazole molecule has two chiral carbon atoms. The compound is marketed as a single (2R,3S) diastereomer.

Voriconazole was generically disclosed within teaching of EP 357241 (US 51 16844) and specifically disclosed in EP 440372 and in Bioorganic & Medicinal Chemistry Letters, 1996, 6, 2031. The compound may form acid addition salts (see, e.g. WO 97/06160, CN 1847243), however it is marketed as a free base. Two polymorphic forms of the base were disclosed in WO 2006/065726.

As voriconazole is a single (2R,3S) diastereomer having trans-orientation of the principal substituents on the both chiral carbon atoms, any of known processes of making it comprise a step of resolution of a pair of trans-oriented 2R,3S/2S,3R diastereomers, e.g. by selective precipitation of salts with optically active acids. For instance, 10-camphorsulfonic acid is an advantageous acid for the resolution of the trans-racemic voriconazole (EP 440372).

Logically and advantageously, useful preparation processes should be directed to obtaining a product enriched with the "trans" pair of diastereomers, which is then resolved. In the original EP 440372 several processes for making voriconazole are disclosed. First of all, this document mentions a condensation of lH-l ,2,4-triazoIe (II) or a salt thereof with a "hydroxy-precursor" (III) having a leaving group L or an "epoxy-precursor" (IV). Such condensation apparently yields a racemic voriconazole.

As a second process, EP 440372 mentions a condensation of a "triazolylphenone" (2- (2,4-difluorophenyl)-l-(lH-l,2,4-triazol-l-yl)-ethane-2-one) (VI) with 6-ethyl-5- fluoropyrimidine (VII)

(VI)

in a presence of sodium bis-trimethylsilylamide at -65C in THF. After chromatographic separation of the reaction mixture, the desired product is obtained in a very low yield. The third process of the EP 440372 is a process starting from a "halo-voriconazole" formula (V), wherein X is preferably a chlorine (compound (Va).

This compound, optionally after resolution of the mixture of trans-diastereomers into single diastereomers, is dehalogenated by hydrogen in a presence of a hydrogenation catalyst to form the desired voriconazole of the same optical purity.

The compound of general formula (V) may be prepared by two basic variant procedures. In the first variant, according to EP'372, it may be made by condensation of the "triazolylphenone" (VI) with 4-chloro-6-ethyl-5-fluoropyrimidine (Vila) in the presence of lithium diisopropylamide (LDA)

The reaction proceeds only with moderate yields and lacks selectivity. After dehalogenation of the compound (V), a mixture of all four possible diastereomers of (I) was obtained, from which the desired diastereomer was obtained by separation by column chromatography. This process exhibits therefore a very low overall yield and is less suitable for industrial production.

Optimized conditions of the condensation and/or dehalogenation process have been disclosed in WO 2006/065726, WO 2007/013096, WO2007/132354 and WO 2008/075205.

In the second variant, the ethyl side chain of the synthon (Vila) may be modified by one or more additional halogen atoms. Thus, 1-monohaloethyl compound of formula (Vllb) (X=Br) has been used in WO 97/06160 (EP 871625) as well as in Chinese applications CN 1473825 and CN 1488630. A 1 -dibromoethyl compound of formula (VIIc) (X=Br,Y=Br) has been used in Chinese application CN 1814597.

(Vllb) (VIIc)

Compounds of formulas (Vllb) and (VIIc) may advantageously react with the reaction partner of the formula (VI) under conditions of Reformatsky-type reaction, i.e. as in-situ formed organozinc compounds. In an important aspect, the resulted compound (V) is then obtained in a more favourable ratio of diastereomers. The "superfluous" chlorine in the position 4 is then removed in an extra step.

For instance, WO 97/06160 (EP 871625) has disclosed that once the compounds (VI) and (Vllb) react in the presence of metallic zinc activated with iodine and/or Lewis acid (preferably zinc chloride or zinc bromide), a mixture of diastereomers of (Va) may be obtained, in which the desired "trans-pair" of diastereomers (2R,3S and 2R,3S) dominates over the corresponding "cis-pair" (2S,3S and 2R,3R) in about 9: 1 ratio. The "trans-pair" can then be easily isolated and resolved with higher overall yield of the desired (2R,3S) diastereomer.

Metal (preferably zinc) complex of (Vllb) (X=Br) has been also used

appl.1919846.

According to WO 2009/084029, the subsequent dehalogenation of (Va) may be performed in one pot with zinc powder and ammonium formate.

Also the "triazolylphenone" synthon (VI) may be modified, e.g. by halogenations on the triazole moiety (CN 101003532, CN 1473825, CN 1488630 and CN 1810806) to obtain corresponding polyhalogenated precursors of voriconazole, which are then dehalogenated.

WO 2009/020323 discloses that the compound of formula (Vllb) may be replaced by a thiol (IX- A), wherein the overall reaction exhibits less side products than in the case of halo compounds.

(IX-A) Regardless of any partial improvement, the need of the having the position 4 of the fluoropyrimidine ring substituted by a "superfluous" halogen/thio group makes the overall pathway two step longer. Furthermore, the activation of zinc represents a separate process step that may meet problems, particularly in industrial scale.

It would be desirable to have an alternate process of making voriconazole with a high selectivity in forming the desired trans-diastereomer, wherein the process does not exhibit the above disadvantages.

Brief description of the invention

The present invention relates to an improved process of making voriconazole of formula (I), wherein the process exhibits sufficient selectivity in respect to the ratio of trans- diastereomers formed, is simple in respect to process conditions and does not need

chromatography purification.

In a first aspect, the invention provides a process of making a pair of trans- diastereomers of a compound of formula (I)

comprising the step of reacting the compound of formula (VI)

(VI)

with an acid or a carboxylate salt thereof of formula (X)

(X) wherein M is hydrogen or an equivalent of a metal cation,

in the presence of a metal salt in a solvent, optionally followed by an isolation of the pair of trans-diastereomers of the compound of general formula (I) from the reaction mixture.

Optionally, the process is followed by a step of resolution of the pair of trans- diastereomers of the compound (I) to single diastereomers by a fractional crystallization of salts thereof with a chiral acid, preferably with 10-camphorsulfonic acid, from a solution in a solvent, and by an isolation of the single, preferably the (2R,3S), diastereomer of the compound of the formula (I) from the solvent.

a preferred aspect, the metal salt is a salt of a divalent metal, most preferably zinc(II) chloride.

In another preferred aspect, the carboxylate salt of the compound of formula (X) is a sodium, potassium, lithium, calcium, magnesium, barium or zinc salt.

In yet another preferred aspect, the solvent comprises a polar aprotic solvent, preferably Ν,Ν-dimethylformamide or dimethylsulfoxide

In a second aspect, the invention provides a carboxylate salt, advantageously a sodium, potassium, lithium, calcium, magnesium or barium salt, of the acid of formula (X), preferably in a solid, most preferably in a crystalline state.

The invention also provides a process for making the above carboxylate salt of the acid of formula (X) by a saponification of the ester (X-l),

(X-l) wherein R is preferably C1-C6 alkyl group and most preferably the ethyl group, by a base comprising the desired salt cation M.

The invention also relates to the use of the compound (X) in making voriconazole. Detailed description of the invention

The present invention deals with an improved process for making a pair of trans- diastereomers of a compound of general formula (I).

The "pair of trans diastereomers" as used within this invention represents the essentially equimolar mixture of diastereomers of the compound (I) having the (2R,3S) and (2S,3R) conformation, resp., of principal substituents on the both chiral carbon atoms. The (2R,3S) diastereomer of the compound of formula (I) corresponds to voriconazole.

In the process of the present invention, the starting materials are the compounds of the formula (VI) and (X), resp. They react in a presence of a metal salt in a suitable inert solvent.

^' The process of the present invention is based on an improved way of formation of the proper reaction partnerfor an addition reaction on the enolizable carbonyl group of the compound (VI), whereby such partner is the compound (VII)

(VII) formed in situ by a decarboxylation of the compound (X). Without wishing to be bound by any theory, it is believed that a carbanion of the compound (VII) is formed by such decarboxylation. For such carbanion formation, no strong base and extreme reaction temperatures are required. Nor the addition reaction requires the use of metallic zinc, which use can cause activation and stirring problems and environmental problems associated with disposal of the excess of the metal. Furthermore, there is no need to substitute, in a next extra reaction step, the ethyl- side chain by a halogen atom, which has been generally required at the Reformatsky- type of reaction. The compound of formula (VI) is a known compound (see, e.g., EP 440372) and may be prepared by procedures known in the art.

The second reagent is the compound of formula (X), wherein M is hydrogen or an equivalent of a metal cation. The "equivalent of a metal cation" is such part of the metal cation, which corresponds to a single valence. Thus, for instance, a calcium salt of the compound (X) has, in fact, the structure (X-a)

while, by using the expression "equivalent of metal cation", the M in the formula (X) corresponds to Cao.₅ and the general formula (X) is just an alternate expression of the actual structure.

As apparent, the compound (X) does not comprise any additional halogen atom on the fluoropyrimidine ring. Accordingly, the trans-racemic compound of formula (I) may be formed by a direct condensation, without any need of a subsequent dehalogenation step. This direct condensation of the compound (X) with the compound (VI) exhibits higher yields of the product than if the compound (VI) were subjected to a reaction with the compound (VII) as disclosed in the prior art.

While the compound (X) comprises one chiral carbon atom, it may be used in the process of the present invention preferably as a racemate as the decarboxylation causes the loss of chirality. Nevertheless, any single enantiomer of the compound (X) may be used as well; therefore the formula (X) embraces also any single enantiomer of the compound and/or mixtures thereof.

The compound of formula (X) wherein M = H has been disclosed in CN 100999518. When prepared according to a process disclosed therein, it appears that the acid is isolateable in a form of an oil, which is quite unstable at neutral and acidic pH. While the acid still being useful in the process of the present invention, it was found by the present inventors that it is very advantageous to isolate and use the compound (X) for making a pair of trans- diastereomers of the compound of formula (I) in a form of a carboxylate salt with an equivalent amount of a suitable cation M. Not only such salts are isolateable as solids that are easy to handle and generally more stable during storage than the parent acid, but they undergo the decarboxylation reaction under milder conditions and with less formation of side products than the acid. Thus, the carboxylate salts of the compound (X) form a specific aspect of the invention, particularly in an isolated, preferably crystalline state. The "isolated/crystalline state" also embraces any polymorphic forms, whenever isolateable, incl. hydrates and/or solvates. The suitable carboxylate salts of the compound (X) are, e.g., sodium, potassium, lithium, calcium, barium, magnesium or zinc salt. Among them, the preferred one is the sodium salt.

The carboxylate salts of the compound of formula (X) are preparable by contacting the acid of formula (X) with the corresponding base (e.g. hydroxide, carbonate) comprising the desired cation, in a suitable solvent. The base comprising the desired cation may be, e.g., sodium, potassium, lithium, calcium, barium, magnesium or zinc hydroxide or carbonate. The acid (X) may be used either in an isolated form or within a reaction mixture comprising it. For instance, the carboxylate salt of the compound of formula (X) may be made by a saponification of the corresponding ester (X-l),

(X- l) wherein R is preferably C1-C6 alkyl group and most preferably the ethyl group, in the presence of the above defined base comprising the desired cation, and the formed salt of the compound of formula (X) may be isolated from the reaction mixture directly without prior isolation of the free acid.

The solvent for formation of a carboxylate salt of (X) may be water, an aliphatic alcohol of 1 to 6 carbon atoms or mixtures thereof. The carboxylate salt may be isolated by evaporation of the solvent, by a crystallization from the solvent after cooling, by a

precipitation by adding an antisolvent and/or similar isolation methods. In case of desire or need it may be purified, e.g. by a recrystallization from a suitable crystallization solvent.

The compound of formula (VI) and the compound of formula (X) and/or a carboxylate salt thereof may be used in the process of the present invention in a molar ratio of from about 0.8 : 1 to about 5: 1 . It is advantageous to use an excess of the compound (X) to assure full conversion of (VI) as the excess of the decarboxylated reagent (VII) may be easily removed from the reaction mixture, contrary to the unreacted ketone (VI).

Any of the reaction partners may be charged into the reaction in an isolated state or within a reaction mixture comprising it.

The reaction between the compounds (VI) and (X) proceeds in the presence of a metal salt, and advantageously a salt of at least a divalent metal, which preferably is a salt, most preferably a chloride, of zinc (II), copper (II), titanium (IV) or magnesium (II). The preferred metal salt in the process of our invention is zinc(II) chloride.

In general, the metal salt and particularly the zinc(II) chloride is advantageously used in a molar excess in respect to the compound of formula (VI). Typically, up to 10 molar equivalents of the metal salt may be used, with the preferred amounts of about from 5 to 7 molar equivalents. The molar excess of the metal salt is not required but it is preferred as the molar ratio between the metal salt and the starting materials as well as the nature of the metal salt has an influence on formation of optimal ratio between the trans and cis pairs of diastereomers of the compound (I). Proper amount and nature of the metal salt may be found by routine experimentation.

The nature of the solvent, in which the reaction of the compounds (VI) and (X) takes place, is also of certain importance in respect to conversion and selectivity of the reaction. In general, the reaction proceeds in a solvent system comprising an aprotic organic solvent or a mixture of aprotic organic solvents. The preferred aprotic organic solvent is a aprotic polar solvent, for instance Ν,Ν-dimethyl formamide, Ν,Ν-dimethylacetamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphotriamide etc, and mixtures thereof. The aprotic polar solvent may be combined with another suitable aprotic organic solvent, preferably with e.g.

tetrahydrofuran, dimethoxyethane or nitromethane, to form the solvent system. The relative amount of the aprotic polar solvent(s) in the solvent system may be from 10 to 100%. In an advantageous mode, all the reactants are completely dissolved in the solvent system.

The reaction between the compounds (VI) and (X) preferably proceeds at an ambient or close to ambient temperature, i.e. in the range of between 0 and 35 C. In general, the mixture of both reagents and of the metal salt in the solvent system is stirred at the ambient or close to ambient temperature for the time sufficient to the desired degree of conversion of the compound (VI) and/or (X). The course of the reaction may be monitored by a suitable analytical technique, for instance by TLC or HPLC. As indicated above, it is preferred that essentially full conversion of the compound (VI) takes place.

After the termination of the reaction, the reaction mixture is elaborated for to isolate the reaction product therefrom. The metal salts are generally removed by an extraction with water. The obtained solution of the product in an organic solvent is concentrated by evaporation in vacuo , by which concentration also the rests of the in situ formed compound (VII) may be removed as this compound is sufficiently volatile.

The reaction between the compounds (VI) and (X) under conditions disclosed above provides the compound (I), which comprises mainly the trans- pair of diastereomers.

Typically the ratio of trans/cis diastereomeric pairs is from about 5 : 1 to about 10 : 1. The actual degree of conversion and the selectivity of formation of the trans-pair of diastereomers depend, in part, on the amount and nature of the metal salt, on the nature of the solvent system and on the temperature of the reaction. The final ratio of trans- and cis- diastereomeric pairs may also be influenced by subsequent treatment of the reaction mixture incl. ways of isolation of the compound (I) from the reaction mixture.

The compound (I) , particularly the pair of trans-diastereomers thereof, may be isolated in a form of a base or in a form of an acid addition salt. Suitable acid addition salts are, without limitation, the hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, acetate, maleate, oxalate, methane sulfonate, benzene sulfonate or p-toluene sulfonate. In particular, the compound (I) may be isolated as a salt with a chiral organic acid, whereby the isolation of such salt is advantageously associated with further improvement of the ratio between trans and cis enantiomeric pairs and/or with subsequent separation of the (2R,3S) diastereomer from the (2S, 3R) diastereomer. In general, the salt formation comprises treatment of the solution of the compound (I) with a molar equivalent or a slight molar excess of the corresponding acid, and isolation of the formed acid addition salt from the reaction mixture, e.g. by a precipitation or an extraction.

The product comprising the trans-pair of diastereomers of the compound (I) , which may be ,e.g., a crude reaction mixture, a treated reaction mixture and/or a product isolated from the reaction mixture, may be advantageously resolved into single diastereomers, wherein preferably the (2R,3S) diastereomer represents the desired final product. In this respect, a mixture of trans/cis diastereomeric pairs of (I) having the trans/cis ratio higher than 5 : 1 may be used for the resolution step without any need of prior separating the trans and cis pairs, e.g. by a chromatographic process. Such chromatographic separation may be used, however, particularly for analytical purposes.

In a suitable resolution process, the above mixture of trans/cis diastereomers of (I) is treated with a chiral acid, preferably with R(-)- 10-camphorsulfonic acid, in a suitable solvent under conditions allowing for fractional crystallization of the salt of the desired trans- diastereomer of (I) with the chiral acid. Preferably, the precipitated salt comprises the salt of the single (2R,3S) diastereomer of (I). The precipitate is separated from the reaction mixture and the isolated salt is treated with a suitable base to liberate the desired diastereomer of the compound (I) from the salt. The liberated compound (I) is then isolated from the reaction mixture , either as a free base or as a salt with a suitable acid. Suitable acid additional salts may be essentially the same as those disclosed above.

If the optical purity of the isolated compound (I) is not sufficient, the compound (I) may be recrystallized from a suitable solvent or the resolution process may be repeated.

Details of suitable resolution procedure are disclosed, e.g., in EP 440372.

While the present invention has been primarily focused to a process of making voriconazole of formula (I), the invented process may be used, without limitation, also for making the "halovoriconazole" of the above formula (V), particularly the

"chlorovoriconazole" of formula (Va), whenever its preparation is desirable or appropriate. In the corresponding alternative of the process of the present invention, the starting material for making the compounds (V) or (Va) is the acid of formula (X-A), wherein X is preferably CI .

(X-A) or a salt thereof. The conversion, isolation and resolution conditions are essentially similar to those as disclosed above.

The present invention will be further illustrated by way of the following Examples. These examples are non-limiting and do not restrict the scope of the invention. Examples

Experimental example - Synthesis of ethyl 2-(5-fluoropyrimidin-4-yl) propionate [compound ( X-n . R = ethyll

«tpr» 1

25.0 g 5-Fluoropyrimidin-4-ol was suspended in

300 ml dichloromethane.

33.7 ml Triethylamine was added, resulting in an almost clear solution. The reaction mixture was cooled with an ice-water bath.

22.5 ml Phosphorus oxychloride was added dropwise over 15 minutes. The reaction mixture was allowed to warm to ambient temperature and the resulting purple suspension was stirred for 18 hours. Reaction progress was monitored with HPLC.

300 ml Ice-water was carefully added to the reaction mixture and the two-phase system was stirred vigorously for 20 minutes. The organic layer was isolated and dried (Na₂S0₄). The solvent was removed carefully on rota evaporator at 800-900 mbar, T_water bath- 50°C. The last grams of solvent were removed by taking the flask out of the water bath and lowering the pressure to -250 mbar. To prevent loss of product,

concentration was stopped when the total weight of the product was still a few gram above the theoretical 100% yield (= 29.05 g) and the product still contained some dichloromethane. 5-fluoro-4-chloropyrimidine was isolated as a dark orange oily liquid (99.3% purity acc. HPLC, NMR confirms expected structure). The product was used without further purification in the next step .

Step 2 17.5 g Sodium hydride (60% dispersion in mineral oil) was suspended in

300 ml N,N-dimethylformamide. The reaction mixture was cooled with an ice- water bath. 70.0 ml Diethyl malonate was added dropwise over 45 minutes. The resulting clear mixture was stirred at ambient temperature for 30 minutes. 36.2 g Crude product from the preceded step was added dropwise over 20 minutes at ambient temperature. The orange reaction mixture was stirred at ambient temperature. Reaction progress was monitored with HPLC. After 18 hours, the reaction mixture was concentrated in vacuo to remove most of the N,N- dimethylformamide.

300 ml diethyl ether and

100 ml water were added and the mixture was stirred vigorously for 5 minutes. The pH of the mixture was adjusted to ~7 with aqueous hydrochloric acid (1.5 M). The layers were separated and

150 ml diethyl ether was added to the aqueous layer. The pH was again adjusted to ~7. The combined organic layers were washed with

300 ml brine, dried (Na₂S0₄) and concentrated in vacuo. The obtained yellow oily liquid contained still some mineral oil (floating on top). Most of the mineral oil was removed by using a separation funnel. The excess of diethyl malonate still present was removed by vacuum distillation (80°C, 0.65 mbar). The product diethyl (5- fluoro-4-pyrimidinyl)malonate was isolated as a yellow oily liquid (89.6% purity acc. HPLC, NMR confirms expected structure) that was used directly in the next step.

Step 3

56.2 g Crude product from the Step 2,

13.1 g sodium chloride,

6.9 ml water and

175 ml dimeth yl sulfoxide were mixed. The mixture was heated to 140°C (=Τ₀π bath)-

Reaction progress was monitored with HPLC. After 2 hours at 140°C, the reaction mixture was allowed to cool to ambient temperature.

400 ml Diethyl ether and

400 ml water were added. The organic layer was washed with

2x400ml water. The organic layer was dried (Na₂S0₄) and concentrated in vacuo, resulting in the isolation of 37.3 g of a red oily liquid (87.7% purity acc. HPLC, NMR confirms expected structure). The product ( ethyl (5-fluoro-4-pyrimidinyl) acetate ) was used without further purification in the next step.

Step 4

20.1 g Crude product from the preceded step was dissolved in

175 ml ethanol

13.6 ml Methyl iodide was added at ambient temperature.

7.2 g Sodium methoxide was added in portions. Reaction progress was monitored with HPLC.

400 ml Ethyl acetate

50 ml water and

50 ml brine were added and the mixture was stirred vigorously for 20 minutes. The organic layer was washed with

2 x 100 ml aqueous sodium carbonate (5%), dried (Na₂S0₄) and concentrated in vacuo, resulting in the isolation of 19.5 g of an orange oily liquid (75.9 % purity acc. HPLC, NMR confirms expected structure) comprising ethyl 2-(5-fluoro-4- pyrimidinyl) propionate

Example 1

Preparation of sodium 2-(5-fluoro-4-pyrimidinyl) propionate ethyl 2-(5-fluoro-4-pyrimidinyl) propionate was dissolved in

ethanol.

Sodium hydroxide was added. The mixture was stirred at ambient temperature. Reaction progress was monitored with HPLC. After stirring the mixture overnight, the solid was isolated by filtration and washed with a few millilitres of ethanol. The solid was dried under vacuum at 40°C for 4 hours. The product was obtained as an off-white solid with an isolated yield of 4.24 g (73.4%; 98.7% purity acc. HPLC, NMR confirms expected structure).

The filtrate was concentrated in vacuo to ~20 ml and the resulting solution was stirred at 4°C overnight. The solid was isolated by filtration and washed with a few millilitres of ethanol. The solid was dried under vacuum at 40°C overnight. A second batch of sodium 2-(5-fluoro-4-pyrimidinyl) propionate was obtained as an off-white solid with an isolated yield of 532 mg (9.2%; 95.0% purity acc. HPLC, NMR confirms expected structure).

Example 2

Preparation of barium 2-(5-fluoro-4-pyrimidinyl) propionate

500 mg ethyl 2-(5-fluoro-4-pyrimidinyl) propionate

190 mg barium hydroxide hydrate and

2.5 ml ethanol were mixed, giving a brown suspension. The reaction mixture was heated to 50°C. Reaction progress was monitored by HPLC. An extra addition of

150 mg barium hydroxide hydrate was made to complete the reaction. The solvent was removed by concentration in vacuo, resulting in 440 mg of an off-white solid (89.7% purity acc. HPLC).

Example 3

Preparation of potassium 2-(5-fluoro-4-pyrimidinyl) propionate

500 mg ethyl 2-(5-fluoro-4-pyrimidinyl) propionate

160 mg potassium hydroxide and

2.5 ml ethanol were mixed, giving a brown solution. The reaction mixture was stirred at ambient temperature. After 10 minutes, solid started to precipitate from the reaction mixture. Reaction progress was monitored by HPLC. After 2 hours of stirring, the solid was isolated by filtration and dried under vacuum at 40°C. An off-white solid, 160 mg was isolated. The filtrate was concentrated in vacuo, yielding again 180 mg of an off-white solid. The solids were combined (93.9% purity acc. HPLC).

Example 4

Preparation of lithium 2-(5-fluoro-4-pyrimidinyl) propionate

400 mg ethyl 2-(5-fluoro-4-pyrimidinyl) propionate was dissolved in 5 ml methanol.

60 mg Lithium hydroxide was added. The reaction mixture was stirred over weekend at ambient temperature. Reaction progress was monitored by HPLC. The mixture was concentrated in vacuo.

5 ml Diethyl ether was added and the resulting suspension was stirred for 20

minutes at ambient temperature. The solid was isolated by filtration and dried under vacuum, yielding 360 mg of an off-white solid (89.0% purity acc. HPLC)

Example 5

Preparation of trans- racemate of_2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-l-(lH- 1 ,2,4-triazol- 1 -yl)-butan-2-ol

2.5 g Zinc chloride was dissolved in

6 ml tetrahydrofuran.

10 ml Toluene was added and the solvent was removed by distillation at 130°C with the help of a bit of vacuum in order to dry the zinc chloride. To the resulting white solid,

6.5 ml tetrahydrofuran was added followed by the addition of

560 mg sodium 2-(5-fluoropyrimidin-4-yl)propanoate ,

280 mg l -(2,4-difluorophenyl)-2-(lH-l ,2,4-triazol-l-yl)ethanone and

3.5 ml Ν,Ν-dimethyl formamide . Within few minutes, a clear, yellow solution was obtained. The reaction mixture was stirred at ambient temperature. Reaction progress was monitored by HPLC. After 7 hours at ambient temperature, the solution was stirred overnight at 4°C. The mixture was then allowed to warm to ambient temperature. At ambient temperature,

50 ml ethyl acetate and

25 ml water were added and the mixture was stirred vigorously. The layers were separated and the organic layer was washed with 25 ml water, dried (Na₂S0₄) and concentrated in vacuo, resulting in the isolation of

309 mg of a yellow oil.

According to HPLC, the ratio between the desired trans-enantiomeric pair and the unwanted cis-enantiomeric pair is 6.5/1.

For analytical purposes, the product was purified by column chromatography using ethyl acetate and heptane as eluens. The desired fractions were collected and concentrated in vacuo, resulting in the isolation of 1 16 mg (26.5%) of a colorless oil, which crystallized in time .

A reference material of 98.0% purity (HPLC) containing 0.8% of the cis- enantiomeric pair was obtained. NMR confirmed the expected structure..

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1. A process of making a pair of trans-diastereomers of a compound of formula (I)

comprising the step of reacting the compound of formula (VI)

(VI)

acid or a carboxylate salt thereof of formula (X)

wherein M is hydrogen or an equivalent of a metal cation,

in the presence of a metal salt in a solvent.

2. The process according to claim 1 , wherein the compound of formula (X) is a a sodium, potassium, lithium, calcium, magnesium, barium or zinc salt, preferably the sodium salt.

3. The process according to claims lor 2, wherein the molar ratio between the compound (VI) and compound (X) is from about 0.8 : 1 to about 5: 1.

4. The process according to claims 1-3, wherein the metal salt is a salt of at least a divalent metal, most preferably a chloride of zinc (II), copper (II), titanium (IV) or magnesium (II).

5. The process according to claims 1-4, wherein the metal salt is used in an amount of up to 10 molar equivalents in respect to the compound of formula (VI).

6. The process according to claims 1 -5, wherein the solvent is an aprotic organic solvent or in a mixture of aprotic organic solvents, and preferably the aprotic organic solvent is an aprotic polar solvent, preferably Ν,Ν-dimethyl formamide, N,N-dimethylacetamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphotriamide, and mixtures thereof.

7. The process according to claim 6, wherein the aprotic polar solvent is combined with another aprotic organic solvent, preferably with, tetrahydrofuran, dimethoxyethane or nitromethane, to form a solvent system.

8. The process according to claims 1-7, wherein the reaction between the compound (VI) and compound (X) proceeds at a temperature of between 0 °C and 35 °C.

9. The process according to claims 1-8, further comprising a step of isolating the pair of trans-diastereomers of the compound of formula (I) from the reaction mixture.

10. The process according to claims 1-9, further comprising a step of resolution of the pair of trans-diastereomers of the compound of formula (I) into single diastereomers., preferably by a fractional crystallization of salts of the trans-diastereomers of (I) with a chiral acid, preferably with 10-camphorsulfonic acid, and by an isolation of the single diastereomer of the compound of the formula (I) from the solvent, and preferably the product of the resolution is (2R,3S) diastereomer of the compound of formula (I).

1 1. A carboxylate salt of the acid of formula (X), and preferably a sodium, potassium, lithium, calcium, magnesium or barium salt, and/or preferably in a solid, more preferably in a crystalline state.

12. A process of making the carboxylate salt of the acid of formula (X) of claims 1 1, wherein the ester (X-l),

(X- l ) wherein R is preferably C1-C6 alkyl group and most preferably the ethyl group, is saponified by a base comprising the desired salt cation M.

13. The process according to claim 12, wherein the base comprising the desired cations a sodium, potassium, lithium, calcium, barium, magnesium or zinc hydroxide or carbonate.

14. Use of the compound (X) as defined in claim 1-1 1 , in making voriconazole.