AP104A - Triazole antifungal agents. - Google Patents

Abstract

The invention provides antifungal agents of the formula

Description

This invention relaces to novel criazole derivatives which have antifungal activity and are useful in the treatment of fungal infections in animals, including humans.

The invention provides antifungal agents of Che formula:-

and their pharmaceutically acceptable salts, wherein X is phenyl optionally substituted by 1 to 3 subscituencs each independently selected from halo and

AP 0 0 0 1 0 4 λ-C, alkyl;

u.-u. aix

X is H or C,-C, aikvl; and 1 4

Het’’, which is attached to che 3djacenc carbon’atom by a ring carbon acorn, is selected from pyridinyl, pyridazinyl, pyrimidiny 1, pyrazinyl and triazir.yl,

Het” being optionally substituted by C.-C, alkyl, ilkoxy, halo, C?₃ , CM, NO_? , ΜΉ-, , aikanoyl) or -MHCO^(C,-C alkyl).

BAD ORIGINAL

In one aspect the invention provides compounds of the formula (I), and their pharmaceutically acceptable salts, wherein Het is selected from 2- and 4-pyridinvl, pyridazinyl, 2- and

4-pyrimidinyl, pvrazinyl and triazinyl, Het being optionally substituted by C^-C^ alkyl, C^-C^ alkoxy, halo, CF^, CN, NO,,, NH^ , -NHfC^-C^ alkanoyl) or -NHCO₂(C^-C^ alkyl); and R, R^ and R³ are as previously defined for compounds of the formula (I).

In another aspect, Het Is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl, Het being optionally substituted bv C.-C, alkyl, C.-C. alkoxy, halo, CF , NO., NH. or 1 4 i 4 3 2 2

-NH(C^-C^ alkanoyl).

When Het is substituted, it is preferably by 1 or 2, most preferably by 1, substituent.

Halo is F, Cl, Br or I.

C. and C. alkyl and alkoxy, and C, alkanoyl groups may be straight or branched chain.

Where R is a substituted phenyl group this includes, for example, 2-fluorophenyl, 2-chlorcphenyl, 2-bromophenyl,

2-iodopher.y 1, 2-trif luorowethylphenyl, 2,4-dichlorophenyl,'

2.4- difluorophenyl, 2-chlorc-4-fluorophenyl,

2-fluoro-4-chlorophenyl, 2,5-difluorophenyl, 2,4,6-trifluorophenyl and 4-bromo-2,5-difluorophenyl.

Preferably, R is a phenyl group substituted by 1 to 3 halo (preferably F or Cl) substituents.

More preferably, R is a phenyl group substituted by 1 or 2 halo (preferably F or Cl) substituents.

«

Yet more preferably, R is 2,4-difluorophenyl,

2.4- dichlorophenyl, 2-fluorophenyl or 2-chlorophenyl.

C 492

Most preferably, R is 2,4-difluorophenyl.

2

Preferably, R is nethyl and R is H or methyl.

2

Most preferably, R is methyl and R is H.

Preferably, Het is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, all optionally substituted by 1 or 2 substituents each independently selected from alkyl, C^-C^ alkoxy, halo, CF^ , CN, NOj» NH^, -NH(C^-C^ alkanoyl) and -NHCO-iC.-C, alkyl).

L 1 4

More preferably, Het is selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, all optionally substituted by 1 or 2 substituents each independently selected from C^-C_z alkyl, C.-C, alkoxv, halo, CF-, CN, NH-, -NH(C,-C, alkanoyl) and 14' J Z 14

-NHCO₉(C₁-C₄ alkyl).

Yet more preferably, Het is selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, all optionally substituted by one CN, NH_n or -NHCO,, (C^-C^ alkyl) substituent.

The preferred pyridinyl and pyrimidinyl groups are 2- and 4-pyridinyl and 2- and 4-pyrimidiny1, all optionally substituted as defined above.

More preferably still, Het is selected from pyridinyl (preferably 2- and 4-pyridinyl), pyridazinyl, 2- and 4-pyrimidiny1 and pyrazinyl, all optionally substituted by one CN, NH₉ or -NHCO^iC^-C^ alkyl) substituenc.

Most preferably, Het is 2-pyridinyl, 4-pyridinyl, or 4-pyrimidiny1.

The pharmaceutically acceptable salts of the compounds of the t

formula (I) include acid addition salts formed from acids which

O’ 101 bad original

V 0 I· 0 0 0 dV form non-toxic salts such as the hydrochloride, hydrobromide, hydroiodide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulphonate, benzenesulphonate and £-toluenesulphonate salts.

Particularly preferred individual compounds are 2-(2,4-difluorophenyl)-3-(pyridin-2-y1)-1-(13-1,2,4triazol-1- yl)butan-2-ol,

2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2,4triazol-l-yl)butan-2-ol and

2-(2,4-difluorophenyl)-3-(pyrimidin-4-y1)-1-(131,2,4-triazol-l-yl)butan-2-ol;

and pharmaceutically acceptable salts thereof.

The compounds of the formula (I) provided by the invention may be prepared by the following methods :(1) The compounds of the formula: -

1 wherein R, R and R“ are as defined for formula (I) and Het is a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group, '’Het¹”’ being optionally substituted by Cj-C^ alkyl, C^-C^ alkoxy, halo, CF^, CN or N0_2> ®sy be prepared as follows:?^T_c

Method (a)

1) Strong base/solvent

(III)

Compounds (IA)

Het¹-CH (II)

1 wherein R, R , R and Het are as defined for formula (IA).

In a typical procedure, the compound of the formula (II) is deprotonated by the addition of approximately one equivalent of a suitable strong base, e.g. lithium diisopropylamide, and the resulting salt (preferably the lithium, sodium or potassium salt) is reacted in situ with the ketone of the formula (III). The reaction is typically carried out at from -80’ to -50C’, preferably at about -70’C, in a suitable organic solvent, e.g. tetrahydrofuran or diethyl ether, and under an inert atmosphere, e.g. nitrogen or argon.

The starting materials of the formula (II) are known compounds or may be prepared by conventional procedures (see

Examples section). The starting materials of the formula (III) are known compounds (see e.g. ER-A-44605, EP-A-69442 or GB-A-1464224) or may be prepared by analogous methods; or

ΑΡ0 0 0 1 0 4 bad ORIGINAL £

Method (b)

(VI)

A base salt of a compound of the formula /solvent or

/base/solvent

Compounds (IA)

1 wherein R, R , R' and Het are as defined for formula (IA), and Y is a leaving group, e.g. chloro, bromo or C^-C^ alkanesulphonyloxy (such as methanesulphonyloxy). Examples of suitable base salts of 1H-1,2,4-triazole are alkali metal (preferably sodium) and tetraalkylammonium (preferably tetra-n-butylarnmonium [see L’S-A-4259505 ]) salts.

The reaction is preferably carried out using the epoxide (IV) as the starting material. If a compound of the formula (VI) is used in this process, it is probable that the reaction mechanism dictates, at least in part, that an epoxide of the formula (IV) is formed in situ under the reaction conditions. The process is therefore, in this respect, similar to that utilising the epoxide (IV) as the starting material.

'«hen a base salt of 1H-1,2,4-triazole is used, the reaction is typically carried out at from room temperature to 100*C, preferably at about 60°C when using the sodium salt of

1H-1,2,4-triazole, and preferably at room temperature when using the corresponding tetra-n-butylammonium salt, in a suitable organic solvent, e.g. N,N-dimethyIformamide or tetrahydrofuran.

Alternatively, the reaction may be carried out using 1H-1,2,4-triazole in the presence of an additional base, e.g. Na^CO^ or K^COy preferably at from 50’ to 100’C in a suitable organic solvent, e.g. Ν,Ν-dimethylformamide or methanol.

The intermediates of the formula (IV) and (VI) may be prepared by conventional techniques, e.g. as described in the Examples section, and as summarised by the following Schemes A and

3:Scheme A

AP 0 0 0 1 0 4

Het ^L— CH l₂

R (ID

1 wherein R, R , R and Het are as defined for formula (IA), and Y is a leaving group, preferably Cl or Br.

In a typical procedure, a compound of the formula (II) is deprotonated by the addition of approximately one equivalent of a suitable strong base, e.g. lithium diisoprcpylamide, and the resulting organometallic intermediate is reacted in situ with the compound of the formula (V). The reaction is typically carried out at from -80° to -50^eC, preferably at about -70°C, in a suitable organic solvent, e.g. tetrahydrofurar. or diethyl ether, and under an inert atmosphere, e.g. nitrogen or argon. The intermediate compound (VI) need not be isolated, and is generally cyclised in situ after a period of stirring at a higher temperature (e.g. room temperature), to provide the oxirane of the formula (IV).

The compounds of the formula (VI) when Y is chloro or bromo may also be prepared by reacting the epoxide (IV) with the appropriate hydrogen halide under anhydrous conditions; or

Scheme B

RCO₂(C₁-C^ alkyl)

He^-CH ⁹ -Hec¹

Hec¹-C⁹

alkyl)

Hec¹

R (VIII)

3ase/R²X

J^R² = C_L-C₄ alkyl)

Base/R X

V „1

Het (X)

(IX)

(V =· H)

Ί 0 I· 0 0 0 dV (IV) (R” = C,-C, alkyl)

X. -¹

1 wherein R, R , R and Het are as defined for formula (IA), and X is a suitable leaving group, e.g. Cl, Br, I or methanesulphonyloxy.

In a typical procedure, the compounds of the formula.(VIII), (IX) and (X) are prepared directly from an ester of the formula (VII) by reaction with an organometallic intermediate derived, as appropriate, by deprotonation of a compound of the formula

112 112 Het -CH, or Het -CHR R (compound II), wherein Het , R and R are as defined for formula (IA) , with approximately one equivalent of a suitable strong base, e.g. lithium diisopropylamide. The reaction is typically carried out at from -80° to -50°C, preferably at about -70°C, in a suitable organic solvent, e.g. tetrahydrofuran or diethyl ether, and under an inert atmosphere,

e.g. nitrogen or argon.

Although not shown in Scheme B, the compounds of the formula (VIII) or (IX) when Het^ is 3-pyridinyl or 5-pyrimidinyI and R and R^ are as defined for formula (IA) , may also be conveniently prepared from an ester of the formula (VII) by reaction with an organometallic derivative derived by deprotonation of a compound of the formula:-

CO_(C,-C, aikvl) wherein R^ is C^-C^ alkyl, in situ, using similar methodology to that described in the previous paragraph. The intermediate p-ketoester obtained after work-up is then subjected co hydrolysis/decarboxylation by treatment with a suitable strong mineral acid, e.g. concentrated hydrochloric acid, preferably under reflux conditions, to provide the compound of the formula (VIII) or (IX), as appropriate.

Alternatively, the compounds of the formula (IX) and (X) may be prepared by reacting, respectively, a compound of the formula (VIII) or (IX) with approximately one equivalent of a suitable base, e.g. sodium hydride, followed by alkylation of the resultant carbanion in situ with a suitable alkylating agent. The reaction is typically carried out at from 0°C to room temperature in a suitable organic solvent, e.g. N,N-dimethylformamide.

Preferably, alkylation of a compound of the formula (VIII) or (IX) is performed under phase transfer conditions, e.g. using

NaOH/[CH,(CH-)-], N* ⁹'dS0,/H.O/CHCl,I(C.-C. alkyl)X (wherein X is 323+ 4 2 314 preferably iodo), at from 0°C to room temperature, and typically at room temperature.

Epoxidation of the kecones of the formula (IX) or (X) is performed using conventional methods, e.g. using dimethyloxosulphonium methylide (see e.g. J.A.C.S. [1965], 37, 1353) or chloromethyllithium (see e.g. Tet. Lett. (1986], 795).

AP 0 0 0 1 0 4 (2) The compounds of the formula (I) in which Het is monosubstituted with a cyano group positioned on a ring carbon atom which is adjacent to a ring nitrogen atom, wherein Het is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triaziqyl, and 1 2

R, R and R are as defined for the formula (I), are most conveniently prepared from unsubstituted Het precursors by a method as shown in Scheme C:Scheme C

(CH₃)₂NCOCl·

:ΤΞ) i (ID)

The procedure is illustrated for a compound of the formula (I) when Het is pyridinyl, although similar methodology applies for all definitions of Het given previously in this method, with « the proviso that Het must have at least one unsubstituted ring carbon atom which is adjacent to the ring nitrogen atom which is

N-oxidised.

Het is preferably pyridinyl or pyrimidinyl in this method.

Depending on the specific Het group used and/or the position of attachment thereof, the possibility of the formation of two regioisomers exists in this process. Such regioisomers, where formed, may be separated by conventional techniques, e.g. by column chromatography.

In a typical procedure, a compound of the formula (IB) is oxidised co provide an N-oxide of the formula (IC). The reaction is preferably carried out using 3-chloroperoxybenzoic acid in a suitable solvent, e.g. dichloromethane, at from 0°C to the reflux temperature thereof, and preferably at room temperature. The oxidation may alternatively be carried out using hydrogen peroxide in a suitable C.-C, alkanoic acid, e.g. acetic acid. '

i. 4

Treatment of the N-oxide (IC) with Ν,Ν-dimethylcarbamoy1 chloride, followed by either trimethylsily1 cyanide or potassium cyanide according to the method of W. K. Fife (J. Org. Chem., 48, 1375 [ 1983] and, et al, Heterocycles, 22, 1121 [1984]) provided the cyano-substituted compound (IE). The reaction Is preferably carried out using Ν,Ν-dimethylcarbamoyl chloride and trimethylsily1 cyanide in dichloromethane at room temperature, and may also be carried out stepwise, i.e. by initial addition of Ν,Ν-dimethylcarbamoyl chloride to the N-oxide, followed by a period of stirring before trimethylsily1 cyanide is added.

AP 0 0 0 1 0 4 (3) Some of the compounds of the formula (I) may be prepared from other compounds of the formula (I) by functional group interconversion, as follows:» (a) A cyano group on Het may be converted to a -NHCO₂(C^-C₄ alkyl) substituent by the following stepwise procedure:(i) The cyano compound is initially treated with a C,-C, alkanol, e.g. methanol, under acidic conditions, and typically under reflux, to convert the cyano group to a -CO,(C.,-C, alkyl) group.

Alternatively, hydrolysis of the cyano compound under conventional acidic or basic conditions provides the corresponding carboxylic acid, which may then be esterified using a C^-C^ alkanol under acidic conditions .

(ii) The ester group is converted to a -CONH'NH,, group by treatment of the ester with hydrazine (preferably hydrazine hydrate) in a suitable organic solvent, e.g. a C-i-C^ alkanol such as isopropanol, at from room temperature to, and preferably at, the reflux temperature thereof.

(iii) Finally the -CONHNH^ group is converted to the required -NHCO^iC^-C^ alkyl) group under the conditions of the Curtius rearrangement reaction, i.e. by treatment of the carboxylic acid hydrazid^ with nitrous acid, preferably at about 0^eC, followed by work-up of the intermediate azide obtained and treatment thereof with a C.-C, alkanol, preferably under reflux conditions;

(b) A -NHCO_?(C^-C₄ alkyl) substituent on Het may be converted to an amino substituent by hydrolysis under basic conditions, e.g. using an aqueous solution of sodium or potassium hydroxide in a C^-C^ alkanol (e.g. ethanol or isopropanol) under reflux conditions;

(c) A nitro substituent on Het may be reduced to an amino substituent by conventional procedures. Preferably, the reduction is carried out by catalytic hydrogenation using a suitable catalyst, e.g. palladium/charcoal, and in a suitable organic solvent, e.g. ethanol. The reduction may also be carried out using stannous chloride at up to, and preferably at, the reflux temperature in a suitable organic solvent,

e.g. ethanol;

(d) An amino substituent on Hec may be converted to a substituent of the formula -NH(C.-C, alkanoyl) by acylation Z *4 <

with either a C^-C^ alkanoyl halide or with an acid anhydride of the formula (C^-C^ alkanoyl)₂0. When an alkanoyl halide is employed the reaction is typically carried out from O’C to l

j ;' room temperature in a suitable organic solvent, e.g.

methylene chloride, and in the presence of a suitable acid acceptor, e.g. triethylamine or pyridine. The reaction may also be carried out using pyridine as both the solvent and the acid acceptor. When an acid anhydride is employed, the reaction is typically carried out at up to the reflux temperature, preferably at 100°C, in a suitably compatible organic solvent, e.g. a C₀-C_z alkanoic acid;

Z 4 (e) An amino substituent on Het may be converted to a substituent of the formula -NHCHO using conventional techniques, e.g. by formylation using acetic-formic anhydride; or (f) An amino substituent on Het may be converted to a halo substituent by initial reaction with sodium nitrite in a suitably compatible aqueous mineral acid, e.g. aqueous hydrochloric or sulphuric acid, preferably at about 0°C, to form a diazonium salt intermediate. Further treatment with (i) cuprous chloride or bromide, as appropriate, introduces a chloro or bromo substituent into Het;

(ii) potassium iodide introduces an iodc substituent into Het; or (iii) fluoboric acid causes precipitation of the diazonium fluoborate, which may be filtered off, dried and thermally decomposed to introduce a fluoro substituent into Het.

All of the above reactions are conventional and appropriate reagents and reaction conditions for their performance and procedures for isolating the desired products will be well known to those skilled in the art, in accordance with literature precedents and by reference to the Examples hereto.

2

Where R is identical to R\ the compounds of the formula (I) contain at least one chiral centre and therefore exist as a pair of enantiomers or as diastereoisomeric pairs of enantiomers.

2 ’«here R and R⁴ are different, the compounds of the formula (1) contain at least two chiral centres (*) and therefore exist as at least two diastereoisomeric pairs of enantiomers, i.e.

The invention includes both the individual stereoisomers of the compounds of the formula (I) together with mixtures thereof. Resolution may be achieved by conventional techniques, e.g. by fractional crystallisation, chromatography or H.P.L.C. of the stereoisomeric mixture of the parent compound or of a suitable salt or derivative thereof. Most preferably, the individual diastereoisomers or the resolved diastereoisomerlc pairs of enantiomers of the compounds of the formula (I) containing two chiral centres are prepared from resolved intermediates as illustrated in the following Examples section.

The preferred compounds of the formula (I) when R Is H have the (2S.3S) configuration, i.e.

Particularly preferred individual diastereoisomers are (2R,3S)-2-(2,4-difluorophenyl)-3-(pyridin-2-yl)-1-(1H1.2.4- criazol-l-yl)butan-2-ol, (2R,3S)-2-(2,4-difluorophenyl)-3-(pvridin-4-yl)-1-(181.2.4- criazo1-1-yl)butan-2-ol and (2R,3S)-2-(2,4-difluorophenyl)-3-(pyrimidin-4-y1)-1-(1H1.2.4- triazol-l-vl)butan-2-ol;

and pharmaceutically acceptable salts thereof.

Pharmaceutically acceptable acid-addition salts are readily prepared by mixing solutions containing equimolar amounts of the free base and the desired acid. The salt generally precipitates « from solution and is collected by filtration, or is recovered by evaporation of the solvent.

The compounds of the formula (I) and their salts are antifungal agents, useful in the curative or prophylactic treatment of fungal infections in animals, including humans. For example, they are useful in treating topical fungal infections in man caused by, among other organisms, species of Candida, Trichophyton,

Microsporum or Epidermophyton, or in mucosal infections caused by Candida albicans (e.g. thrush and vaginal candidiasis). They can also be used in the treatment of systemic fungal infections caused by, for example, Candida albicans, Cryptococcus neoformans,

Aspergillus flavus, Aspergillus fumigatus, Coccldioides,

Paracoccidioides , Hlstoplasma or Blastomyces.

The compounds of the present invention have been found to have unexpectedly good activity against the clinically-important

Aspergillus sp. fungi.

The in vitro evaluation of the antifungal activity of the compounds can be performed by determining the minimum inhibitory concentration (m.i.c.), which is the concentration of the test compounds, in a suitable medium, at which growth of the particular micro-organism fails to occur. In practice, a series of agar plates, each having the test compound incorporated at a particular concentration is inoculated with a standard culture of, for example, Candida albicans, and each plate is then incubated for 48 hours at 3?°C. The plates are then examined for the presence or absence of growth of the fungus and the appropriate m.i.c. value is noted. Other micro-organisms used In such tests can include Aspergillus fumigatus, Trichophyton spp, Microsporum spp, Epidermophyton floccosum, Coccidioides immitis and Torulopsis glabrata.

The in vivo evaluation of the compounds can be carried out at a series of dose levels by intraperitoneal or intravenous injection, or by oral administration, to mice which are inoculated with, e.g., a strain of Candida albicans or Aspergillus fumigatus. Activity is based on the survival of a treated group of mice after the death of an untreated group of mice. The dose level at which the compound provides 50% protection against the lethal effect of the infection (Ρϋ^θ) is noted.

For human use, the antifungal compounds of the formula (I) and their salts can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. For example, they can be administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs or suspensions containing flavouring or colouring agents. They can be injected parenterally, for example, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain ether substances, for example, enough salts or glucose to make the solution isotonic with blood.

For oral and parenteral administration to human patients, the daily dosage level of the antifungal compounds of the formula (I) and their salts will be from 0.01 to 20 mg/kg (in single or divided doses) when administered by either the oral or parenteral «

route. Thus tablets or capsules of the compounds will contain from 5 mg to 0.5 g of active compound for administration singly or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.

Alternatively, the antifungal compounds of formula (I) can be administered in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder. For example, they can be incorporated into a cream consisting of an aqueous emulsion of polyethylene glycols or liquid paraffin; or they can be incorporated, at a concentration between 1 and 10%, into an ointment consisting of a white wax or white soft paraffin base together with such stabilizers and preservatives as may be required.

it has also been found that the compounds of the formula (1)

I 2 when R^-*· and R“ are H and R and Het are as defined for formula (I), have antifungal activity in animals, and that they are particularly active against Aspergillus sp fungi.

Thus, the invention further provides a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, together with a <

pharmaceutically acceptable diluent or carrier.

The invention yet further provides a compound of the formula (I), or a pharmaceutically acceptable salt or composition thereof, for use as a medicament, in particular as an antifungal agent.

The invention also provides the use of a compound of the formula (I), or of a pharmaceutically acceptable salt or composition thereof, for the manufacture of an antifungal agent.

The invention yet further provides a method of treating an animal (including a human being) to cure or prevent a fungal infection, which comprises treating said animal with an effective amount of a compound of the formula (I), or with, as appropriate, a pharmaceutically acceptable salt or composition thereof.

The invention also includes any novel intermediates disclosed herein, such as those of the formulae (IV), (VI), (IX). and (X).

The following Examples, in which all the temperatures are In ’C, illustrate the invention:23

EXAMPLE 1

2-(2, A-DifluorophenyQ-B-fpyrldin-Z-yD-l-OH-l.Z,4-triazol-lyl)butan-2-ol

AP 0 0 0 1 0 4 (i) 2-(2,4-Pi fluorophenyl·)-2-<l-[pvridin-2-yl]ethyl)oxirane n-3ucyllithium (19.7 ml of a 1.6 M solution in hexane) was added to a stirred solution of diisopropylamine (3.18 g) in dry tetrahydrofuran (50 ml) at -70’under an atmosphere of dry nitrogen. The solution was stirred at -70° for 0.17 hour, followed by 0.17 hour at 0* and Chen re-cooled to -70°. 2-Ethylpyridine (3.37 g) was added over 0.08 hour, the red solution resulting was stirred at -70’ for 0.33 hour and then added via a syringe co a stirred solution of 2-chloro-2',4’difluoroacetophenone (5.00 g) in dry teCrahydrofuran (50 ml) at

-70°. The solution was stirred at -70° for 3 hours and then at room temperature for 18 hours. Water (4 ml) was added and fhe solution was evaporated. The residual oil was partitioned between water (80 ml·) and dichloromethane (100 ml). The organic layer was separated, washed with water (80 ml) and then extracted with 2N hydrochloric acid (2 x 30 ml). The combined acidic extracts were basified to pH 12 with 2N sodium hydroxide solution and extracted with dichlorcmethane (3 x 75 ml). The combined organic layers were dried (Na_?S0,), evaporated, and the residue was chromatographed on silica gel. Elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound (2.25 g) as a yellow oil which was used directly in the next stage.

(i i) 2-(2,4-Difluoropheny1)-3-(pyridin-2-yl)-1-(1H-1,2,4-triazol1-y Dbutan-2-ol

A mixture of the product of part (i) (2.20 g) and 1H-1,2,4-triazole sodium salt (1.53 g) in Ν,Ν-dimethylformamide (15 ml) was heated at 60° with stirring for 18 hours and then evaporated. Water (50 ml) was added and the mixture was extracted with ethyl acetate (3 x 50 ml). The combined extracts were dried (Na^SO^), evaporated and che residue was chromatographed on silica gel. Elution with ethyl acetate first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.93 g), m.p. 146-148° (from ether).

Analysis X:Found: 0,61.69; H.4.73; N.16.88;

^C17^H16^F2^N4° ^reT^uires: 0,61.81; H.4.88; N.16.96.

•

Further elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair 3, (0.63 g), m.p. 151-152’ (from ether).

Analysis Z:Found: 0,61.68; H.4.79; N.17.01;

^C17^H16^F2^N4° ^reR^uires: 0,61.81; H.4.38; N,16.96.

EXAMPLE 2

2-(2,4-Difluorophenyl)-3-(pyridin-4-yl)-1-(1H-1,2, 4-triazol-lyl)butan-2-ol

Method A

CH

(i) .2-(2,4-Difluoropheny1)-2-(1-(pyridin-4-y1]ethyl)oxirane

Lithium diisopropylamide was prepared by addition of n-butyllithium (19.7 ml of a 1.6 M solution in hexane) to a solution of diisopropylamine (3.18 g) in dry tetrahydrofuran (50 ml), and the resulting solution was treated successively with 4-ethylpyridine (3.37 g) and a solution of 2-chloro-2',4*difluoroacetophenone (5.00 g) in dry tetrahydrofuran (50 ml) according to the method of Example l(i). Work-up of the reaction mixture as before afforded the title compound (1.05 g) as a yellow oil which was used directly in the next stage.

(ii) 2-(2,4-Difluoropheny1)-3-(pyridin-4-y1)-1-(1H-1,2,4-triazoll-yDbutan-l-ol

Treatment of the product of part (i) (1.02 g) with 1H-1,2,4-triazole sodium salt (0.71 g) in Ν,Ν-dimethylformamide (10 ml) by the method of Example l(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (97:3) as eluanc, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.22 g) , m.p. 161-163’ (from ether).

Analysis Z:Found: 0,61.87; H.4.89; N.16.96;

AP o 0 n 1 0 4

C.,H.,F.N,0 requires: 1 / 10 4

0,61.81; H.4.38; N.I6.96.

Further elution with dichloromethane/methanol (97:3) gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair B, (0.35 g), m.p. 156-158° (from echer).

Analysis Σ:Found:

^C17^H16^F2^N4° ^requires

0,61.79; H.4.36; N.17.31;

C.61.81; H.4.38; N.16.96.

Method B

2-(2,4-0ifluorophenyl)-3-(pyridin-4-y1)-1-(IH-1,2,4-triazol-lyl)butan-2-ol

A solution of lithium diisopropylamide was prepared as described in Example l(i) from diisopropylamine (40.4 g) and n-butyllithium (160 ml of a 2.5 M solution in hexane) in dry tetrahydrofuran (800 ml) under an atmosphere of dry nitrogen. To this solution at -70* was added 4-ethylpyridine (42.3 g), dropwise with stirring over 0.17 hour. The solution was stirred at -70* for 0.33 hour and then a solution of 1-(2,4-difluorophenyl)-2(lH-l,2,4-triazol-l-yl)ethanone (89.2 g) in dry tetrahydrofuran (350 ml) was added over 0.33 hour. The solution was stirred at

-70* for a further 0.75 hour and then acetic acid (40 ml) was added dropwise. The solution was allowed to reach room temperature and was diluted with water. The mixture was extracted three times with ether and the combined extracts were washed with water. The aqueous washings were extracted once with ethyl acetate and the organic extracts were combined, dried (Na_?S0₄) and evaporated. The residue was dissolved in boiling dichloromethane, an equal volume of ether was added and then the solution was allowed to cool. The precipitated solid was filtered off to give recovered ketone starting material (17.5 g). The filtrate was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate/'hexane (1:1) gave further recovered ketone starting material. Further elution with ethyl acetate gave fractions containing the title compound, diastereoisomeric pair A (not treated further). The solvent was then changed to ethyl acetate/methanol (19:1) and elution was continued until pure fractions containing the title compound, diastereoisomeric pair B, were obtained. These fractions were combined, evaporated and the residue was crystallised from dichloromethane/'ether to give the title compound, diastereoisomeric pair B, (20.5 g), m.p. 155-157° (N.M.R. (300 MHz] <

spectrum identical with that obtained for a sample of diastereoisomeric pair B prepared as described in Method A, part (ii)).

AP 0 0 0 1 0 4

Recrystallisation from acetonitrile gave a polymorph, m.p.

165.5-166.5°.

Analysis X:Found: C,51.69; H.4.85; N.16.85;

C,,H-,F„N,0 requires: C.61.81; H,4.88; N,16.96.

lb 2 4

X-Ray crystallography assigned the stereochemistry of diastereoisomeric pair B as being a racemic mixture of the (2R,3S) and (2S.3R) diastereoisomers.

EXAMPLE 3

2-(2,4-Dif 1ιιθΓορ1ΐ6πν1)-3-(ρνΓί:ρίάίη-4-ν1)-1-(1Η-1,2,4-triazol1-yl)butan-2-ol

η-Butyllithium (4.0 ml of a 2.5 M solution in hexane) was added to a stirred solution of diisopropylamine (1.01 g) in dry tetrahydrofuran (30 ml) at -70’ under an atmosphere of dry nitrogen. The solution was stirred at -70* for 0.17 hour,· followed by 0.17 hour at 0’ and then re-cooled to -70’. 4-Ethylpyrimidine (1.08 g) was added and the solution was stirred at -70° for 0.75 hour. A solution of 1-(2,4-difluorcphenyl)-2(1H-1,2,4-triazol-l-yl)ethanone (2.23 g) in dry tetrahydrofuran (30 ml) was added over 0.17 hour. The solution was stirred at

-70° for 1 hour and then acetic acid (1 ml) was added. The solution was allowed to reach room temperature and was then diluted with water. The mixture was extracted three times with ethyl acetate and the combined extracts were washed with water then dried (Na^SO^), The solvent was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate/hexane (3:2) gave recovered ketone starting material. Further elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.305 g) , m.p. 114-115.5* (from ether/hexane).

Analysis ”:Found: 0,57.76; H.4.45; N.21.26;

^16^15W ^re9^uires:

0,58.00; H.4.56; N,21.14.

Further elution with ethyl acetate/methanol (19:1) gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair B, (0.215 g) , m.p. 104-105° (from ether/hexane).

Analysis Z:Found: 0,57.63; H,4.44; N,21.36;

C.,H₁₌F-N,0 requires: 0,58.00; H.4.56; N.21.14.

io 15 L j

EXAMPLES 4-7

The following tabulated Examples of the general formula:CH were prepared by similar methods to that used for Example 3 by treating the appropriate ethyiheterocycie with lithium diisopropylamide, followed by reaction of the resulting carbanion in situ with the appropriate l-aryl-2-(iH-l,2,4-triazoi-iyl)ethanone derivative.

AP Ο Ο Ο 1 Ο 4

φ

-c <

133

c.

φ o

Λ *Ή

Ο u

φ υ

Φ

C z~s Φ

1—* 9)

Φ Φ

Φ

Φ Φ •»4 33 χ-ζ	33 «Ή kJ ς* •Η
Ο Γ“ C 0 S3 Γ“4 Ο . Φ U ο 'Λ U		Ό Φ kJ Φ ο 33 «Η kJ Ο c < u τΜ Φ ο- υ •*4 φ ο 33
τ* Φ Ο.		•τΜ 0 φ
Φ	33 Φ	U φ
	ΓΗ	kj
U	X	33
φ	2	Φ
a	Φ	«τΗ
ο	X	“Ο
ω Ο	Ζϋ -φ	U φ
φ	Φ	f^
U	kJ	0
φ	Φ	α.
W 0)	□	co
<9	«2	φ
•Η	Φ	φ
α	kJ	►J
ζ-* ιΉ		ζ-\ CM

EXAMPLE 8

2-(2 , 4-01 fluorophenyl)-3-methy1-3-(pyrimidln-4-y1)-1-(1H-1,2,4triazol-l-yl)butan-2-ol

(i) 4-(l-Methylethvl)pyrimidine

A solution of lithium diisopropylamide was prepared as described in Example L(i) from aiisopropylamine (6.88 g) and n-bucyllithium (27.0 ml of a 2.5 M solution in hexane) in dry tetrahydrofuran (180 ml) under an atmosphere of dry nitrogen. To this solution at -70°, a solution of 4-echylpyrimidine (7.35 g) in dry tetrahydrofuran (20 ml) was added dropwise over 0.17 hour.

The solution was stirred at -70° for 0.75 hour and then iodomethane (11.60 g) was added. The mixture was stirred for a further 3 hours and then warmed to room temperature. Water was added and the solution was evaporated to low bulk, then · partitioned between ethyl acetate and water. The organic layer was separated, the aqueous layer was extracted three times with ethyl acetate and the organic fractions were combined and dried (Na^SO^). Evaporation of the solvent gave an oil which was chromatographed on silica gel, using dichloromethane/ether (9:1) as eluant. The fractions containing the product were combined and evaporated, and the residual oil was distilled to give the title compound, (3.14 g) , b.p. 52-56° at 15 mm.

(ii) 2-(2,4-0ifluorophenyI)-3-methy1-3-(pyrlaidin-4-yl)-1-(1H1,2,4-triazol-l-yl)butan-2-ol

Treatment of the product of part (i) (2.46 g) with lithium diisopropylamide (0.02 mole) in dry tetrahvdrofuran followed by 1-(2,4-difluoropheny1)-2-(1H-1,2,4-criazol-l-yl)ethanor.e (4.49 g)

according to the method of Example 3 gave the title compound,
(0.135 g), m.p. 126-127°	(from ether).
Analysis £:-
Found :	C.59.15;	H.4.87; N.20.41;
C. _H.-Ε,,Ν,Ο requires: I i 11 L J	C.59.12;	H.4,96; N.20.28.

EXAMPLE 9

2-(2_>4-Ρΐί1υθΓορΗ6ην1)-3-(ργΓΐά3ζ1η-4-γ1)-1-(1Η-1_>2,4-£Γΐ3Ζθ11-yl)butan-2-oi

F (i) 4-Ethylpyridazine

A solution of lithium diisopropylamide was prepared as described in Example 1(1) from diisopropylamine (17.9 g) and n-butyllithium (70.4 ml of a 2.5 M solution in hexane) in <ΐΓγ tetrahydrofuran (300 ml) under an atmosphere of dry nitrogen. To this solution at -70’ was added 4-methylpyridazine, dropwise with stirring, ensuring that the temperature did not rise above -60°. Iodomethane (27.25 g) was added slowly with stirring, the solution was stirred at -70° for 1 hour and then allowed to warm to room temperature. Water was added and the solution was evaporated to low bulk. The solution was extracted three times with dichloromethane and the combined extracts were dried (Na„SO.) and 2 4 evaporated. The residue was chromatographed on silica gel using ethyl acetate as eluant. The product fractions were combined and evaporated, and the residual oil was distilled to give the title compound, (10.4 g), b.p. 65-66° at 0.1 mm.

N.M.R. (300 MHz)

(ii) 2-<2 ,4-Di fluorophenyl) -3-¹' pvridaz in-4-y1)-1-(1H-1,2,4triazol-l-yl)butan-2-ol

A solution of lithium diisopropylamide was prepared as described in Example l(i) from diisopropylamine (2.02 g) and n-butyllithium (8.0 ml of a 2.5 M solution in hexane) in dry tetrahydrofuran (60 ml). To this solucion at -70° was added 4-ethylpyridazine (2.16 g), dropwise with stirring. The yellow solution was stirred for 0.4 hour at -70° and then a solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-l-y1)ethanone (4.46 g) in dry tetrahydrofuran (20 ml) was added, keeping the temperature below -65°. The solution was stirred for a further 1 hourat this temperature and then acetic acid (1 ml) was added. The solution was allowed to warm to room temperature and diluted with water.

The mixture was extracted three times with ethyl acetate and the combined organic extracts were washed with water and dried (Na^SO^). Evaporation of the solvent gave the crude product. Further crude produce was obtained by extraction of the combined aqueous layers with dichloronethane. Both crops of crude produce thus obtained were combined and chromatographed on silica gel. Elution with dichloromethane/methanol (50:1) first gave ketone starting material. Further elution with the same solvent gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.98 g) , m.p. 172-174’ (from dichloromethane/ether).

Analysis Found: C,57.3O; K,4.57; N,21.08;

^C16^H15^?^^>''^I5^{C re}8^uires: C,58.00; H.4.56; >1,21.14,

Further elution with dichloromethane/methanol (50:1) gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair B, (1.58 g), m.p. 187-188’ (from acetonitrile).

Analysis Z:Found: C.58.00; 3,4.54; N,21.05;

^C16^H15^F2^N5° ^re4^uires: C.58.00; H.4.56; N.21.14.

EXAMPLE 10

2-(2,4-Dichloropheny1)-3-(pyridazin-4-yl)-1-(1H-1,2,4-triazoll-yPbutan-Z-ol

Treatment of 4-ethylpyridazine (2.16 g) with lithium diisopropylamide (0.02 mole) in dry tetrahydrofuran followed by 1-(2,4-dichloropheny1)-2-(lH-l,2,4-triazol-l-y1)ethanone (5.12 g) according to the method of Example 9(ii) gave the title compound, diastereoisomeric pair A, (1.24 g), m.p. 174-177*;

Analysis X:-

Found: C16H15C12N5°	requires:	C.52.22; H.4.12; N,19.05;
0,52.75;	H.4.15;	N,19.23.
and the title	compound,	diastereoisomeric	pair B,	(1.45 g), m.p
173-176’.
Analysis *:-
Found:		0,52.41;	H.4.08;	N.18.85;
C16H15C12N5°	requires:	0,52.75;	H.4.15;	N.19.23.

AP Ο Ο Ο 1 Ο 4

EXAMPLE 11

2-(2,4-Difluoropheny1)-3-(pyrazin-2-yl)-1-(1H-L,2,4-triazol-l·yl)butan-2-ol

1) [(CH₃)₂CH1₂NLi, THF

2)

N® ⁹HS0, , i 4'

Or (i) 1-(2,4-Difluoropheoyl)-2-(pyrazin-2-yl)ethanone

A solution of lithium diisopropylamide was prepared using n-butyllithium (20 ml of a 2.5 M solution in hexane) and diisopropylamine (5.06 g) in dry tetrahydrofuran (100 ml) under an atmosphere of dry nitrogen as described in Example l(i). To this solution at -70* was added 2-methylpyrazine (4.70 g) and the purple solution resulting was stirred at -70’ for 0.5 hour. A solution of methyl 2,4-difluorobenzoate (8.60 g) in dry tetrahydrofuran (75 ml) was added over 0.5 hour and stirring was continued at -70° for a further 0.5 hour. Acetic acid (10 ml) was added and the temperature was allowed to rise to room temperature. The solution was diluted with water and the pH was adjusted to 7 with sodium bicarbonate. The mixture was extracted three times with ethyl acetate and the combined organic extracts were washed with water and dried (Na^SO^). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with ethyl acetate/'hexane (3:7) gave, after combination and evaporation of appropriate fractions, a solid which was crystallised from hexane to give the title compound, (5.90 g) , m.p. 1O7-1C8*.

Analysis T:Found: C,61.50; H.3.32; N.12.02;

C ’H_oF,N_0 requires: j.- o _ L

C.61.54; H.3.44; N.11.96.

AP 0 0 0 1 0 4 (ii) 1-(2,4-Difluorophenyl)-2-(pyrazin-2-yl)propan-l-one

A solution of sodium hydroxide (1.98 g) in water (40 ml) was added dropwise to a stirred, ice-cooled solution of the product of part (i) (5.80 g), iodomethane (8.79 g) and tetra-n-butylagnnonium hydrogen sulphate (8.40 g) in chloroform (40 ml). The mixture was stirred vigorously at room temperature for 3 hours and then diluted with water and dichloromethane. Acetic acid (3 ml) was added and che pH of the aqueous layer was adjusted to 7 with sodium bicarbonate. The organic layer was separated, washed twice with water and dried (Na^SO^). Evaporation of the solvent gave the crude product as an oil (5.57 g) which was used without further purification (the presence of 10* of the starting material (the product of part (i)] was indicated by N.M.R. spectroscopy).

(iii) 2-(2,4-Difluorophenyl)-2-(1-[pyrazin-2-yl]ethyl)oxirane n-3utyllithium (9.3 ml of a 2.5 M solution in hexane) was added to a stirred, cooled (-70°) solution of the product of part (ii) (5.50 g) and bromochloromethane (3.16 g) in dry tetrahydrofuran (125 ml) under an atmosphere of dry nitrogen, at such a rate that the temperature did not rise above -65’. The solution was stirred at -70° for 6 hours and then at room temperature for 18 hours. The solution was diluted with water and extracted three times with ethyl acetate. The combined organic extracts were washed with water and dried (Na^SO^). Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with ethyl acetate/hexane (1:5) gave an oil (4.80 g) which was shown by N.M.R. spectroscopy to contain ca. 70Z of the title compound together with impurities. The product was used directly without further purification.

(iv) 2-(2 ,4-Difluorophenyl)-3-(pyrazin-2-yl)-l-(lH-l·,2,4-triazoll-yl)butan-2-ol

1H-1,2,4-Triazole tetra-n-butylammonium salt (see US-A-4259505) (5.45 g) was added to a stirred solution of the product of part (iii) (2.30 g) in dry tetrahydrofuran (25 ml) at room temperature and stirring was continued for 4 days. The solvent was then evaporated and the residue was partitioned between water and ethyl acetate. Acetic acid (1 ml) was added and the mixture was filtered through Avicel (Trade Mark for^_a cellulose-based filtration aid). The organic layer was separated, washed three times with water and dried (Na^SO,). The solvent was

L J, evaporated and the residue was chromatographed on silica gel. The column was first eluted with ethyl acetate/hexane (3:2) to remove impurities. Further elution with ethyl acetate/hexane (9:1) gave, after combination and evaporation of appropriate fractions,’ the title compound, diastereoisomeric pair A, (0.85 g), m.p. 107-109’ (from dichloromethane/hexane).

Analysis .X:Found: C.57.76; H.4.44; N.21.31;

AP 0 0 0 1 0 4

C 'd. ,F-N.O requires: 16 io 2 o ⁿ

C.58.00; H.4.56; N.21.14.

C /d.,F,N_r0 requires : lo b Z 5

Further elution with ethyl acetate/methanol (19:1) gave, after combination and evaporation of appropriate fractions, the tide compound, diastereoisomeric pair B, (0.29 g) , m.p. 133-135° (from dichloromethane/hexane).

Analysis X:Found: C,57.82; H,4.53; N,21.00;

C,53.OO; H.4,56; N.21.14.

EXAMPLE 12

2-(2,4-Dif luoropheny 1)-3-(pyr 103210-3-71)-1-(111-1,2, 4-triazoll-yl)butan-2-ol

1) ((CH₃)₂CH}₂NLi, THF

2) co₂ch₃

CH.

(i) >

AP 0 0 0 1 0 4

ClCH_?Li, THF <(iii)

(iv)

4/

F (i) . 1-(2,4-Difluorophenyl)-2-(pyridazin-3-y1)ethancne

Treatment of 3-methylpyridazine (4.70 g) with lithium diisopropylamide (0.05 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (8.60 g) according to the method of Example 11(1) gave the title compound, (3.40 g), m.p. 115.5-117.5* (from ether).

Analysis X:Found: 0,61.68; H.3.40; N.11.77;

^C12^H3^F2^N2° ^re5^uires: 0,61.54; H.3.44; N,11.96.

(ii) 1-(2,4-Difluorophenvl)-2-(pyridazin-3-yl)propan-l-one

Methylation of the product of part (i) (3.30 g) with iodomethane (5.0 g) according to the method of Example ll(ii) gave the title compound as a gum (2.25 g) which was used directly in the next stage.

(iii) 2-(2,4-Difluorophenyl)-2-(1-fpyridazin-3-yl]ethyl)oxirane

Treatment of the product of part (ii) (2.0 g) with bromochloromethane (1.15 g) and n-butyllithium (5.28 ml of a 1.6 M solution in hexane) according to the method of Example ll(iii) gave the title compound as a gum (1.20 g) which was used directly in the next stage.

(iv) 2-(2,4-Difluorophenyl)-3-(pyridazin-3-yl)-l-(LH-l,2,4triazol-l-yl)butan-2-ol

Treatment of Che product of part (iii) (1.15 g) with 1H-1,2,4-criazole sodium salt (0.80 g) in N ,N-ditnethylf ormamide (15 ml) according to the method of Example l(ii), followed by chromatography of the crude product on silica gel using dichloromethane/methanol (50:1) as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.35 g), m.p. 134-135° (from ether).

Analvsis X:Found: C.58.04; H.4.57; N.20.87;

C.,H, F^l.O requires: 0,58.00; H.4.56; N.21.14, xC i. 0

Further elution with the same solvent gave, after combination and evaporation of appropriate tractions, the title compound, diastereoisomeric pair 3, as an amorphous foam (84 mg).

N.M.R. (300 >iHz)

AP 0 0 0 1 0 4

EXAMPLE 13

2-(2,4-Dlfluoropheny1)-3-(pyrlaidin-2-y1)-1-(1H-1,2,4-trlazol1-yl)butan-2-ol

F

BAD ORIGINAL (i) 1-(2,4-DifLuorophenyl)-2-(pyrimldin-2-yl)ethanone

Treatment of 2-methylpyrimidine (8.50 g) with lithium diisopropylamide (0.09 mole) in dry tetrahydrofuran followed by methyl 2,4-difluorobenzoate (15.5 g) according to the method of Example ll(i) gave the title compound (3.65 g) , m.p. 86-88* (from hexane).

Analysis Z:Found: C.61.67; H.3.41; N,12.01;

C.-HgF^O requires: C.61.54; H.3.44; N,11.96.

iZ o z z (ii) 1-(2,4-Difluorophenyl)-2-(pyrlmidin-2-yl)propan-l-one

Methylation of the product of part (i) (3.50 g) with iodomethane (5.32 g) according to the method of Example ll(ii) gave the title compound (3.30 g), m.p. 118-119*.

Analysis %:Found: C.63.17; H.4.18; N,11.02;

C₁₃H_1CF,N\O requires: C.62.90; H.4.06; S.11.29. ' (iii) 2-(2,4-Difluorophenyl)-2-(l-(pyrimidin-2-y1)ethyl]oxirane

Treatment of the product of part (ii) (3.10 g) with chloromethyllithium (prepared from bromochloromethane (1.78 g) and a 1.6 M solution of n-butyllithium in hexane (8.20 ml)) according to the method of Example ll(iii) gave the title compound as a gum (2.25 g), which was used directly in the next stage.

BAD ORIGINAL

APO 0 0 1 0 4

O'·-' o (iv) 2-(2,4-Difluorophenyl)-3-(pyrimidin-2-yl)-1-(1H-1,2,4triazol-l-yl)butan-2-ol

Treatment of the product of part (iii) (0.80 g) with lH-l,2,4-triazole, sodium salt (0.82 g) in N,Ν-dimethylfonnamide according to the method of Example 12(iv), followed by chromatography of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (0.26 g) , m.p. 193-195” (from dichloromethane/ether).

Analysis Z:Found: 0,57.50; H.4.57; N.21.03;

C-.H^F^N.O requires: 0,58.00; H.4.56; N,21.2.4.

iO 10 i. 5

Further elution with ethyl acetate/methanol (20:1) gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair B,(0.055 g) , m.p. 1Q4-1C6’ (from echer).

Analysis Z: Found: 0,57.27; H.4,37; N.20.55;

C.,H,.F.N.O requires: 0,58.00; H.4.56; N.21.14.

io IP 2 0

BAD ORIGINAL

?LC i92 *

EXAMPLE 14

2-(2,4-Difluorophenyl)-3-(pyridin-3-y1)-1-(1H-1,2,4-triazol1-yl)butan-2-ol

AP 0 0 0 1 0 4 (i) 1-(2,4-Difluorophenyl)-2-(pyridln-3-yl)ethanone

A solution of lithium diisopropylamide was prepared using n-butyllithium (66 ml of a 1.6 M solution in hexane) and diisopropylamine (10.8 g) in dry tetrahydrofuran (200 ml) under an atmosphere of dry nitrogen as described in Example l(i). Ethyl 3-pyridylacerate was added dropwise to this solution at -70*. The thick mixture was stirred at -70’ for 0.25 hour and then a solution of methyl 2,4-difluorobenzoate (18.36 g) in dry tetrahydrofuran (100 ml) was added over 0.05 hour. The cooling bath was removed and the mixture was stirred at room temperature for 5 hours. Acetic acid (12 ml) was added and the mixture was diluted with water and ethyl acetate. The organic layer was separated, dried (Na^SO^) and evaporated to give an oil which was heated under reflux in concentrated hydrochloric acid (40 ml) for hours. The solution was evaporated, the residue was dissolved in water and concentrated ammonia solution was added to ca. pH7 .

The mixture was extracted twice with ethyl acetate and the combined extracts were washed with brine and dried (Na.SO,).

4

Evaporation of the solvent gave an oil which was chromatographed on silica gel. Elution with dichloromethane/ethy1 acetate (70:30) gave the title compound as an oil (6.98 g) which was used directly in the next stage.

(ii) 1-(2,4-Difluoropheny1)-2-(pyrid in-3-vl)propan-l-one

Methylation of the product of part (i) (5.0 g) with iodomethane (7.50 g) according to the method of Example llfii) gave the title compound as an oil (3.90 g) which was used directly in the next stage.

(iii) 2-(2,4-Pi-(luorophenyl)-2-( l-(pyridin-3-yl)ethvl] oxirane

A solution of diaethylsulphoxonium methylide (36.5 ml of a 0.6 M solution in tetrahydrofuran) was added dropwise to a stirred solution of the product of part (ii) (4.36 g) in tetrahydrofuran « (35 ml) at -20*. The solution was allowed to warm to room temperature and stirring was continued for 18 hours and then diluted with water. The mixture.was extracted with ethyl acetate

BAD ORIGINAL and the combined extracts were dried (N^SO^) . Evaporation of the solvent gave the title compound as an oil (4.50 g) which was used directly in the next stage.

(iv) 2-(2 ,4-Dlfluorophenyl)-3-(pyridln-3-yl)-l-(lH-l,2,4triazol-l-yl)butan-2-ol

Treatment of the product of part (iii) (4.30 g) with 1H-1,2,4-triazole, sodium salt (3.0 g) in N,h'-dimethylformamide (50 ml) according to the method of Example l(ii), followed by chromatography- of the crude product on silica gel using ethyl acetate as eluant, first gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair A, (1.13 g) , m.p. 113-114° (from ether).

Analysis X:Found: C,62.10; H.4.90; N.16.96;

C,₇H,,F,N,0 requires: C.61.31; H.4.38; N,16.96. ·

Further elution with ethyl acetate/methanol (20:1) gave, after combination and evaporation of appropriate fractions, the title compound, diastereoisomeric pair 3, (1.25 g) , m.p. 115-116° (from ether).

Analysis X:Found: 0,61.92; H,4.95; N,16.37;

C.61.81; H.4.88; N.16.96.

°17^H16^F2^i,4° requires:

AP ο ο o 1 o 4

EXAMPLE 15

2-(2, 4-Djfluorophenyl)-3-(2-cvanopyridin-4-y1)-1-(1H-1,2,4triazol-l-yl)butan-2-ol

(i) 2-(2,4-Difluorophenyl)-3-(l-oxidopyridin-4-yI)-1-(1H-1,2,4triazol-l-yl)butan-2-ol

A solution or 2-(2,4-difluorophenyl)-3-(pyridin-4-yl)-l(1H-I,2,4-triazo1-1-y1)butan-2-ol (diastereoisomerlc pair B from Example 2) (20.0 g) and 35% w/w 3-chloroperoxybenzoic a:id (12.3 g) in dichloromethane (250 ml) was stirred at room temperature for 18 hours. Further 3-chloroperoxybenzoic acid (2.50 g) was then added and stirring was continued for 24 hours. The solution was evaporated and the residue was dissolved in ether. A solid formed on standing which was filtered off and chromatographed on silica gel. Elution with dichloromethane/ methanol/O.88 ammonia solution (100:4:0.5) gave the title compound as a solid, (20.0 g), m.p. 195-198’.

(ii) 2-(2,4-Difluorophenyl)-3-(2-cyanopyridin-4-yl)-l-(lH1,2,4-triazol-l-yl)butan-2-ol

A mixture of the product of part (i) (20.0 g) and

N,N-dimethylcarbamoyl chloride (6.80 g) in dichloromethane (250 ml) was stirred at room temperature for 2.5 days, giving a clear solution. TrimethyIsily1 cyanide (6.35 g) was added and stirring was continued for a further 48 hours. Additional quantities of Ν,Ν-dimechylcarbamoyl chloride (1.30 g) and trimethylsilyl cyanide (1.30 g) were then added and the solution was stirred for a further 36 hours. The reaction was then washed successively with 10% potassium carbonate solution, brine and then dried (MgSO,). Evaporation of che solvent gave a solid which was stirred with ether and filtered Co give che title compound, (19.2 g), m.p.

138-189’.

Analysis %:Found:

G^gH,-F-,Ν'^Ο requires

C.60.89; H.4.26; >1,19.44;

C.60.34; H.4.25; N.19.71.

EXAMPLE 16

2-(2,4-Difluorophenyl)-3-(6-cyanopyrldin-2-yl)-l-(lH-l,2,4triazo1-l-yl)bucan-2-ο 1

(i) 2-(2, 4-Difluoropheny1)-3-(l-oxidopyridin-2-yl)-1-(1H1,2 , 4-triazcl-l-y1)butan-2-ol

A solution ot 2-(2 ^-difluorophenyli^-ipyridin^-yD-ld’d-l.l ,4-triazol-l-yl)butan-2-ol (diastereoisomeric pair B from Example 1) (1.60 g) and 35% w/w 3-chloroperoxybenzoic acid (1.60 g) in dichloromethane (10 ml) was stirred at room temperature for 36 hours and then worked up as described in Example 15(i) to give the title compound, (0.92 g) , m.p. 159-160°.

Analysis Z:Found: C.59.27; H.4.96; N.16.58;

C.58.96; H.4.45; N.15.47.

^C17^H16^F2^iI4⁰'* ^re9^uires: ^18^H15^2^5^ ^re<4^uires: (ii).2-(2,4-Difluorophenyl)-3-(6-cyanopyridin-2-v1)-1-(1H1,2,4-triazol-l-yl)butan-2-ol

A mixture of the product of part (i) (0.90 g), N,N-dimethyicarbamoyl chloride (0.80 g) and triraethylsilyl cyanide (0.80 g) in dichloromethane (10 ml) was stirred at room temperature for 7 days and the resulting solution was evaporated. The residue was treated with 5N hydrochloric acid (10 ml) and the mixture was agitated in an ultrasonic bath for 0.05 hour to give a clear solution. A solid formed on standing which was filtered off, washed with acetone followed by ether, and dried to give the title compound as the hydrochloride salt, (0.28 g), m.p. 219° (with decomposition).

Analysis Z:Found: 0,55.19; H.4.10; N.18.00;

C_igH_L.F_?N₅0.HCl requires: C.55.13; -1,4.12; N.17.87.

The acidic filtrate was basified (ca. pH8) with 0.38 ammonia solution and the solution was extracted with dichloromethahe. The organic extract was dried (hgSO^) and evaporated. The residue was triturated with ether and filtered to give the title compound as the free base, (0.13 g) , m.p. 144-146’.

Analysis %:Found: C.60.84; H.4.25; N.19.71;

C,60.48; H.4.17; N.19.90.

EXAMPLE 17

2-(2,4-Difluorophenyl)-3-(2-cyanopyridln-3-yl)-1-(1H-1,2, 4triazol-l-yL)butan-2-ol and 2-(2,4-difluorophenyl)-3-(2cvanopyridin-5-yl)-l-(1H-1,2,4-triazol-l-yl)butan-2-ol

( i) 2-(2,4-Difluorophenyl)-3-(l-oxidopyridin-3-y1)-1-(1H1,2, 4-triazol-l-y Pout an-2-ol

A solution of 2-(2,4-difluorophenyP-3-(pyridin-3-yl)-l(LH-1,2,4-triazol--l-yl)butan-2-ol (diastereoisomeric pair B from Example 14) (1.00 g) and 85% w/w 3-chloroperoxvbenzoic acid (1.30 g) in dichloromethane (20 ml) was stirred at room temperature for 18 hours and then evaporated. The residue was stirred with ether and the solid was filtered off and dried to give the title compound (0.93 g), m.p. 190-193°.

(ii) 2-(2,4-Difluorophenyl)-3-(2-cyanopyridin-3-y1)-1(1H-1,2,4-triazol-yl)butan-2-ol and 2-(2,4-difluorophenyl)-3-(2cyanopyridin-5-yl)-1-(1H-1,2,4-triazol-l-yl)butan-2-ol

A mixture of the product of part (i) (0.93 g) and Ν,Ν-dimethylcarbamoyl chloride (0.40 g) in dichloromethane (10 ml) was stirred at room temperature overnight. Trimethylsilyl cyanide (0.40 g) was added and stirring was continued for a further 60 hours. The solution was washed with 10* sodium carbonate solution and the aqueous layer was separated and washed with dichloromethane. The organic layers were combined, dried (MgSO,) and evaporated. The residue was chromatographed on silica gel using hexane/isopropanol (4:1) as eluant to give 2-(2,4difluorophenyl)-3-(2-cyanopyridin-5-yl)-1-(1H-1,2,4-triazoll-yl)butan-2-ol, (0.18 g), m.p. 136-141’.

Analysis *:Found: C,60.39; H.4.59; >1,19.47; ·

C, F-,Ν.ΰ requires: 0,60.34; H,4.25; Ν',19.71.

N.M.R. (300 MHz)

V 0 1· 0 0 0 dV

Hz, pyridine H-3) , 7.76 and 7.79 (s, 1H, criazole H), 8.10 (m, 1H, pyridine H-4), 8.80 (d, 1H, J = 1.8 Hz, pyridine H-6) p.p.m.

Further elution with the same solvent mixture gave, after combination and evaporation of appropriate fractions, 2-(2,4difluoropheny1)-3-(2-cyanopyridin-3-y1)-1-(1H-1,2,4-triazol1-yl)butan-2-ol (0.23 g), m.p. 180-182°.

Analysis S:Found: C.60.85; H,4.33; N.19.51;

C _oH._e?.N.0 requires: C.60.84; H,4.25; N.19.71.

lj 2 0

N.M.R. (300 MHz)

S (CDC1.) = 1.17 (d, 3H, J = 7.0 Hz, CH.), 3.82 and 5.17 (d, 1H,

J z

J - 13.3 Hz, CH₂), 4.05 (q, 1H, J = 7.0 Hz, CHCH ), 5.21 (s, 1H,

OH), 6.82 (m, 2H, H ), 7.46 (m, 1H, H ), 7.60 (m, 1H, arom arom pyridine H-5), 7.76 and 7.83 (s, 1H, triazole H), 8.32 (m, 1H, pyridine H-4), 3.68 (m, 1H, pyridine H-6) p.p.m.

EXAMPLE 18

2-(2,4-0ifluorophenyl)-3-(2-cyanopyrimidin-4-yl)-1-(1H-1,2,4triazol-l-yl)butan-2-ol and 2-(2,4-difluorophenyl)-3-(6-cyanopyrimidin-4-y1)-1-(18-1,2,4-triazol-l-yl)butan-2-ol

AP 0 0 0 1 0 4 (i) 2-(2,4-Difluorophenyl)-3-(l-oxidopyrimidin-4-y1)-1-(181,2,4-triazoI-l-yl)butan-2-ol

A solution of 2-(2,4-difluorophenyl)-3-(pyrinidin-4-yl)-l(18-1,2,4-triazol-l-yl)butan-2-o1 (diastereoisomeric pair B from Example 3) (3.31 g) and 852 w/w 3-chloroperoxybenzoic acid (2.03 g) in dichloromethane (20 ml) was stirred at room temperature for 48 hours. An additional 2.03 g of 85Z w/w 3-chloroperoxybenzoic acid was added and stirring was continued for a further 18 hours., Work up as described in Example 15(i) gave the title compound, (0.80 g), m.p. 157-160°.

(ii). 2-(2,4-Difluoropheny1)-3-(2-cyanopyrimldln-4-y1)-1-(1Hl, 2,4-triazol-l-yl)butan-2-ol and 2-(2,4-dlfluorophenyl)-3-(6cyanopyrimidin-4-yl)-l-(1H-1,2,4-triazol-l-yl)butan-2-ol

A mixture of the product of part (i) (0.80 g) and Ν,Ν-dimethylcarbamoyl chloride (0.50 g) in dichloromethane (10 ml) was stirred at room temperature for 2 hours. Trimethylsilyl cyanide (0.50 g) was added and stirring was continued for a further 6 days. The solution was evaporated and the residue was chromatographed on silica gel. Elution with dichloromethane/ methanol (100cl) gave a product which was rechromatographed on silica gel. Elution was commenced with ether and the polarity of the eluant was gradually increased by the addition of up to 6Z (by volume) of methanol. Combination and evaporation of the initial product-containing fractions gave 2-(2,4-difluorophenyl)-3-(6cyanopyrimidin-4-yl)-1-(1H-1,2,4-triazol-l-yl)butan-2-ol, (30 mg),

m. p. 148-149’.

N.m.k. (3QQ MHz)

1H, J = 1Hz, pyrimidine H-2) p.p.m.

Further elution gave, after combination and evaporation of appropriate fractions, 2-(2,4-difluorophenyl)-3-(2-cyanopyrimidin4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol, (203 mg), m.p.

155-157°.

Analysis Z:Found: C.57.30; H.3.96; N.23.59;

^C17^H14^F2^N6° ^re8^uires: C,57.36; H.3.97; N.23.36.

N.M.R. (300 MH2) $ (CDC1₃) = 1.17 (d, 3H, J = 7.16 Hz, CH^, 3.73 (q, 1H, J - 7.16

Hz, CHCH₃), 3.99 and 4.99 (d, 1H, J = 14.2 Hz, CH ), 5.39 (s, 1H,

OH), 6.82 (m, 2H, H ), 7.51 (m, 1H, H ), 7.71 and 7.88 (s, arom arom

1H, triazole H), 7.77 (d, 1H, J = 5.3 Hz, pyrimidine H-5), 8.84 (d, 1H, J = 5.3 Hz, pyrimidine H-6) p.p.m.

EXAMPLE 19

2-(2,4-Difluorophenvl)-3-(2-ethoxycarbonylamlnopyridin-4-y1)-1(1H-1,2,4-criazol-l-yl)butan-2-ol

>' i) 2-(2,4-Di fluoro phenyl) -3-(2-aechoxycarbonylpyridin-4-y'l)1-(1H-1,2,i-triazol-l-yl)butan-2-ol

A suspension of 2-(2,4-cifiuorophenyl)-3-(2-cyanopyridin4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol (see Example 15) (5.0 g) in methanol (50 a'.) was saturated with gaseous hydrogen chloride, heated under reflux for 2 hours and then allowed to stand at room temperature for 18 hours. The solution was evaporated and the residue basified with dilute sodium bicarbcnace solution. The mixture was extracted several times with dichloromethane and the combined extracts were dried (MgSO^) and evaporated. Crystallisation of the residue from methyl acetate gave the title compound, (4.90 g), m.p. 182-183°.

(ii) 4-(3-(2,4-Difluorophenyl)-3-hydroxy-4-(lH-l,2,4-triazol-ly1)but-2-yl]pyridine-2-carboxylic acid hydrazide

A solution of the product of part (i) (3.80 g) and hydrazine hydrate (6.0 ml) in isopropanol (20 ml) was heated under reflux for 2.5 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with dichloromethane. The combined extracts were washed with brine and dried (MgSO^). Evaporation of the solvent gave the title compound (3.30 g) as an amorphous foam which was used directly in the next stage.

(iii) 2-(2,4-Difluoropheny!)-3-(2-ethoxycarbonylaminopyridin4-yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol

The product of part (ii) (1.40 g) was dissolved in 6N hydrochloric acid and the solution was cooled to 0°. A solution of sodium nitrite (0.276 g) in water (2 ml) was added dropwise with stirring, and stirring was continued for 1 hour. The solution '.as then basified with sodium bicarbonate solution and the resulting mixture was extracted several times with dichloromethane. The combined organic extracts were dried (MgSO^) and evaporated. The residue was dissolved in ethanol (50 ml) and the solution was heated under reflux for 2.5 hours and Chen , evaporated. The residue was crystallised from ether to give the title compound, (1.12 g), m.p. 177-179*.

AP 0 0 0 1 0 4

Analysis Z:Found :

C.57.90; H.5.25; N.16.81;

21 2' 5 3

0,57.55; H.5.07; N.16.78.

EXAMPLE 20

3-(2-Απι1ηορνΓΪά1η-4-γ1)-2-(2,4-<ϋ£1υοΓορΗ6ηγ1)-1-(1Η-1,2,4triazo1-1-y1)butan-2-ol

CH

CH

A solution of the product of Example 19 (0.80 g) in e-thancl (30 ml) containing 40Z sodium hydroxide solution (2.0 ml) was heated under reflux for 2 hours and then evaporated. Water was added to the residue and the mixture was extracted several times with ethyl acetate. The combined organic extracts were dried (MgSO^) and evaporated to give a gum. The gum was dissolved in ether and the title compound, (0.45 g), crystallised on standing, m.p. 182-185°.

Analysis Z:- ,

Found:

C.59.34; H.5.03; N.19.92;

C^H^^N^O requires:

0,59.13; H.4.96; N.20.28.

EXAMPLE 21

2-(2,4-Difluorophenyl)-3-(2-ethoxycarbonylamlnopyridin-5-y1)-1(lH-1,2,4-triazol-l-y1)butan-2-ol

CH.

HNO.

(iii) (i)

->

c₉h₅oh

CONHNH, co₂ch₃

AP 0 0 0 1 0 4 (i) 2-(2, 4-P if luorophenyl)-3-(2-methoxy carbonylpv rid in-5-y-l)-l(1H-1,2,4-triazol-l-y Ubutan-2-ol

Treatment of 2-(2,i-difluorophenyl)-3-(2-cyanopyridin-5yl)-1-(LH-1,2,4-triazol-l-y1)outan-2-ol (see Example 17) (1.0 g) with methanol (20 ml) in the presence of hydrogen chloride according to the mechod of Example 19(i) gave the title compound as a gum, (0.75 g) , which was used directly in the next step.

(i i) 5-((3-(2,4-Difluoropheny1)-3-hydroxy-4-(1H-1,2,4-trlazo1-1yl) ]but-2-yl)pyridine-2-carboxylic acid hydrazide

Treatment of the product of part (i), (0.75 g) , with hydrazine hydrate (2.0 ml) in isopropanol (10 ml) according to the method of Example 19(ii) gave the title compound, (0.36 g) , as an amorphous foam which was used directly in the next stage.

(i i i) 2-(2,4-Difluorophenvl)-3-(2-ethoxycarbonylaminopyridin-5yl)-l-(lH-l,2,4-triazol-l-yl)butan-2-ol

Treatment of the product of part (ii) (0.36 g) with nitrous acid followed by heating the resulting azide intermediate in ethanol according to the method of Example 19(iii) gave a crude product which was chromatographed on silica gel. Elution with ethyl acetate gave, after combination and evaporation of appropriate fractions, a solid which was crystallised from ethyl acetate/ether to give the title compound, (0.12 g), m.p. 167-168°.

Analysis X:Found: 0,57.31; H,5.00; N,16.46;

Ο₀ο»2]_^?^5θ3 requires: 0,57.55; H,5.07; N,16.78.

. EXAMPLE 22

3-(2-Aminopyridin-5-y1)-2-(2,4-difluoropheny1)-1-(1H-1,2,4triazol-L-v1)butan-2-ol

A solution of the product of Example 21 (70 mg) in isopropanol (4 ml) containing 50% aqueous potassium hydroxide (4 drops) was heated under reflux for 4 hours and then evaporated.

Water was added to the residue and the mixture was extracted several times with ethyl acetate. The combined organic extracts were washed with water and dried (MgSO^). Evaporation of the solvent gave the title compound as an amorphous foam, (49 mg).

N.M.R. (300 MHz) £ (CDClg) = 1.06 (d, 3H, J » 7.12 Hz, CH ) , 3.23 (q, 1H, J = 7.12

Hz, CHCHg), 3.93 and 4.77 (d, 1H, J - 14.2 Hz, CHp, 4.63 (broad s, 2H, HH₂), 6.54 (d, 1H, J » 8.5 Hz, pyridine H-3), 6.75 (m, 2H,

H ), 7.45 (m, 1H, H ), ca. 7.70 (m, 1H, pyridine H-4), arom arom ——

7.71 and 7.76 (s, 1H, triazole H), 8.04 (s, 1H, pyridine H-6)

p.p.m.

(-)-(2R,3S)~2-(2,4-Difluoropheny1)-3-(pyrimidin-4-y1)-1-(1HEXAMPLE 23

1,2,4-triazol-l-yl)butan-2-ol

HO

CHj

ca. 4:1 mixture of (2S,3R)/(2R,3S):(2S,3S)/(2R,3R) diastereoisomeric pairs of enantiomers.

NaOH/CH OH (2S,3R)/(2R,3S) enantiomeric '' pair separated

?LC 492 (i) 2-Acetoxy-2¹,4 *-difluoroacetophenone

A solution of 2-chloro-2’,4’-difluoroacetophenone (19.0 g) and anhydrous sodium acetate (16.4 g) in acetic acid (50 ml) was heated under reflux for 4 hours and then evaporated. The residue was partitioned between ethyl acetate and water. The organic layer was separated, washed with sodium bicarbonate solution and dried (Na^SO^). Evaporation of the solvent gave an oil which was triturated with hexane. The resulting solid was filtered off, washed with hexane and dried to give the title compound, (16.2 g), m.p. 54-56°.

(ii) (t)-(2R,3S) and (2S,3R)-l-Acetoxy-2-(2,4-difluorophenyl)-3(?yrimldin-4-yl)butan-2-ol

A solution of diisopropylamine (30.3 g) in dry cetrahydrofuran (400 ml) was treated successively with n-butyllithium (188 ml of a 1.6 M solution in hexane) followed by

4-echvIpyrimidine (32.4 g) according to the method of Example 3.

A solution of the product of part (i) (64.0 g) in dry tetrahydrofuran (400 ml) was added with stirring over 0.58 hour at -40 to -50°. Acetic acid (30 ml) was then added and the solution was allowed to reach room temperature. Ether (1000 ml) and water (1000 ml) were added and the mixture was shaken. The organic layer was separated, washed with brine and dried (MgSO^). The solvent was evaporated and the residue was chromatographed on silica gel. Elution with ether/hexane (1:4) gave starting ketone initially. Further elution with ether/hexane (1:1), gradually

AP 0 0 0 1 0 4 decreasing the proportion of hexane until neat ether was being used, gave a semi-solid consisting of a (i)-enantiomeric mixture of the title compounds together with the (2R.3R)- and (2S,3S)-diastereoisomeric pair of enantiomers. Ether was added until a clear solution was obtained and then hexane (20Z by volume) was added. The mixture was cooled and the resulting solid was filtered off, washed with hexane and dried to give the (i)-enantiomeric mixture of the title compounds, (23.3 g), m.p.

102-103.5°.

Analvsis Z*. Found: 0,59.68; H.5.09; N,8.55;

^C16^H16^F’^N'’°3 ^re8^uires: C.59.62; H.5.00; N.8.69.

(iii) (_)-(2R,3S) and (2S,3R)-2-(2,4-Difluoropheny1)-3(pv r iinid in-4-v 1) but an-1,2-diol

2N Sodium hydroxide solution (40 ml) was added with stirring over 0.25 hour to a solution of the product of part (ii) (23.3 g) in methanol (80 ml) and stirring was continued for a further 0.25 hour. Water (150 ml) was added and the mixture was cooled. The solid was filtered off, washed with water and dried to give the title compounds, (17.4 g) , m.p. 148.5-150.5°.

Analysis Z:Found: C,59.80; H.5.09; N.10.12;

C.60.00; H.5.04; N,10.00.

^C14^H14^F'’^N2°2 quires:

*

5 (iv) (-)-(2R,3S)-2-(2,4-Difluorophenyl)-3-(pyrimidin-4-vDbutan1,2-dlol (S)-N-(Trifluoroacetyl)prolyl chloride (72 ml of 1.0 M «

solution in dichloromethane) was added dropwise over 0.5 hour to an ice-cooled solution of the product of part (iil) (16.7 g) and pyridine (3.7 ml) in dry dichloromethane (50 ml). The solution was stirred for 0.5 hour and then the dichloromethane was evaporated. Ethyl acetate and water were added and the mixture was acidified to pH3 with 2N hydrochloric acid. The organic layer was separated, washed successively with 0.1 N hydrochloric acid and water, then dried (Na₂S0^). The solvent was evaporated and the residue was chromatographed on silica gel. The column was eluted with hexane/ether/diethylanine (65:30:5) and the initial product-containing fractions were combined and evaporated. The residue was crystallised from diisopropyl ether to give the (S)-h’-(crifluoroacetyl)prolyl ester of the title (2R.3S)enantiomer, (4.73 g), m.p. 91-92.5’.

Further elution of the column gave fractions containing a mixture of both the (2R.3S)- and (2S,3R)-enantiomers as their (5)-N-(trifluoroacetyl)prolyl esters. The appropriate fractions were combined and evaporated, and this residue was combined with the residue obtained by evaporation of the mother liqucis from che crystallisation above. The combined mixture was dissol\ed in a little diisopropyl ether, the solution was seeded with a crystal of the pure (2R,3S)-product and cooled for 4 hours. Filtration afforded a further 1.90 g of the pure (2R,3S)-enantiomer as the ’ (S)-N-(trifluoroacetyl)prolyl ester.

AP 0 0 0 1 0 A *

The absolute stereochemistry of this product was confirmed by X-ray crystallography.

The above ester of the title compound (6.0 g) was dissolved in methanol (28 ml) and 2N sodium hydroxide solution (14 ’ml) was added. After 0.25 hour, water (100 ml) was added and the mixture was cooled in ice for 1 hour. The solid was filtered off, washed with water and dried to give the title compound, (2,50 g), m.p. 147.5-148.5”.

Analysis X:Found: C.59.94; H.5.16; N.9.97;

^C14^H14^F2^2°2 ^ce4^uires: C.60.00; H.5.Q4; N.10.00.

(v) (-)-(2R,3S)-2-(2,4-Difluoropheny1)-3-(pyrimidin-4-y1)-1(1H-1,2,4-triazol-l-yl)butan-2-ol

Methanesulphony1 chloride (1.15 g) was added to a stirred solution of the product of part (iv) (2.35 g) and diisopropylethylamine (2.38 g) in dry tetrahydrofuran (30 ml) at -10 to -20” under an atmosphere of dry nitrogen. The solution was stirred at the same temperature for 1 hour and then anhydrous potassium carbonate (7.0 g) and dry Ν,Ν-dimethyIformamide (25 ml) were added. The mixture was stirred at room temperature for 1.5 hours and then partitioned between water and ether. The organic layer was separated, washed with water and dried lNa_?S0^). Evaporation of the solvent gave an oil which was immediately dissolved in methanol (50 ml). 1H-1,2,4-Triazole (6.0 g) and , anhydrous potassium carbonate (6.0 g) were added and the mixture was heated at 60’ with stirring for 40 hours, then evaporated.

The residue was partitioned between ethyl acetate/ether (1:1) and water, the organic layer was separated and washed with water, then dried (Na^SO^). The solvent was evaporated and the residue was chromatographed on silica gel. Initial elution with ethyl acetate gave impurity-containing fractions, and subsequent further elution with ethyl acetate/methancl (20:1) gave, after combination and evaporation of appropriate fractions, the title compound, (0.37 g) , m.p. 55-53°, ( c*. -65.1’ (0.55Z in methanol).

N.M.R. (300 MHz) £ (CDC1 ) = 1.13 (d, 3H, J = 7.12 Hz, CH ) , 3.63 (q, 1H, J = 7.12

Hz, CHCH.), 4.16 and 4.78 (d, 1H, J = 14.1 Hz, CHJ, 6.60 (s, 1H,

OH), 6.32 (m, 2H, H ), 7.44 (d, 1H, J = 5.0 Hz, pyrimidine atom

H-5), 7.57 (m, 1H, H ), 7.61 and 7.96 (s, 1H, triazole H), a rom

8.77 (d, LH, J = 5.0 Hz, pyrimidine H-6), 9.17 (s, 1H, pyrimidine H-2) p.p.m.

It is believed that where diastereoisomeric pair 3 is isolated in Che above Hxamples, chat it is a mixture of the C2R.3S) and (2S.3R) diastereoisomers.

Claims (3)

1. A compound of the formula:- or a pharmaceutically acceptable salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and cf^;

R¹ is C,-C, alkvl;

R is H or C^-C^ alkyl; and

Het, which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl,

Het being optionally substituted by alkyl,

C.-C, alkoxy, halo, CF, , CN , NO,, NH,, -NH(C,-C. '

1 u 3 z i. i 4 alkanoyl) or -NHCO,(C,-C^ alkyl).

2. A compound of the formula (I) as claimed in claim 1 wherein Het is selec :ed from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, Het being optionally substituted by C_y-C, alkyl, C^-C^ alkoxy, halo, CF^, NO,, NH_? or -NH(C..-C, alkanoyl).

BAD ORIGINAL

17. The use of a compound of Che formula (1), or of a pharmaceutically acceptable salt or composition thereof, as claimed in any one of claims 1 to 14 and 15 respectively, for the manufacture of an antifungal agent.

18. A compound of the formula:-

AP 0 0 0 1 0 A ¹ 2 ¹ wherein R, R* and R“ are as defined in claim 1; het* is a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group,

Hec^ being optionally substituted by C^-C^ alkyl, alkoxy, halo, , CN or NO,,; and ϊ is a leaving group.

19. A compound of the formula (VI) as claimed in claim 18 wherein Y is chloro, bromo or C,-C, alkanesulphonyloxy.

PROCESS CLAIMS

20 A process for the preparation of a compound of the formula: - or a pharmaceutically acceptable salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and CF^;

PC is C,-C alkyl;

S“ is H or C.-C, alkvl; and 1 -»

Het, which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridacinyl, pyrinidiny1, pyrazinyl and triazinyl,

Het being optionally substituted by alkyl',

C.-C^ alkcxy, halo, C7,, CN, H0_?, NH,, -NHfC^-C, alkanoyl) or -HHCO,(£,-C, alkvl), comprising reacting the denroconated form of i ccnncund of the formula:het —

I i D

EC

BAD ORIGINAL ft wherein R^x and R” are as previously derined in “his C-aim 3nd Her¹ is pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or criazinyl, Het'*’ being optionally substituted by alkyu,

C,-C^ alkoxy, halo, CF^, CM or NO,, with a compound of the formula:-

- (Ill), wherein R is as previouslv defined in this claim; said process being followed by, optionally, one or more of the following sceps:AP 0 0 0 1 0 4

a) conversion of a C73no group on Het to -NHCO,(C,-C, alkyl? by tne following stepwise procedure:

i) either by treatment of the cyano-ccmpound with a ilkanol under acidic mictions, or ov irolvsis of cyanc-compcuna oncer acinic cr cssic concitions provide the corresocr.uing carbo:·:'·'Li esterificacion thereof usins a C,-C

-u 3i.<anol under acidic conditions: to convert the cvan.c grouo to

-CO,(C,-C alky/

.) conversion cr alkyl? group to -CCNHNn, by treatment of the ester with hvdrazine; and ioo bad ORIGINAL a* iii) conversion of said -CONHN'H^ group co -NHC0_? (C^-C, alkyl) by reacting the carboxylic acid hydrazide initially with nitrous acid to provide an intermediate azide, followed by treatment thereof with a C,-C. alkanol;

(b) conversion of a -NHCO-(C,-C, alkvl) substituent on Het

2 14 to an amino substituent by hydrolysis of the carbamate under basic conditions;

(c) conversion of a nitro substituent on Het” to an amino substituent by reduction of the nitro-ccmpound;

^rd) conversion of an amino substituent cn Het to -NH(C.-C.

alkanoyl) by acylation of the amine with either a C^-C^ alkanoyl halide or with an acid anhydride of the formula (C„-C, aikanovl)„0;

--4 ' ¹e' conversion of an amino substituent on Het co -NHCHO by formylation of the amine;

f conversion of an imino substituent on Het to a halo suostit-er.t 'y initially reacting the amine with nitrous acid to first give a -; azonidm salt intermediate, followed by treatment tner-of with, ss appropriate,

BAD ORIGINAL □ T , ·} ··*

i) cuprous chloride or bromide to provide a chloro or bromo substituent;

ii) potassium iodide to provide an iodo substituent; or iii) fluoboric acid, followed by thermal decomposition of the intermediate diazonium fiuoborate, to pr-vide a fluoro substituent; and (g) conversion of Che compound of the formula (1) into a pharmaceutically acceptable salt.

21 A process as claimed in a temperature of from -80° co -50

22 A process as claimed in a temperature of about -70°C.

23 A process as claimed in which said deprotonated form is a salt of the comocur.d (II).

claim 20which is carried out at

C.

claim 21 which is carried out at any one of claims 20 to 22 in lithium, sodium or pocabsiun

APO 0 0 1 n 4

BAD ORIGINAL ft

24 A process for the preparation of a compound of the formula (I), or a pharmaceutically acceptable salt thereof,

1 Ί wherein R, R, R and Het are as defined in claim 20 comprising reacting a compound of the formula:- αν) <^VI>

I J.

wherein R, R*, R~ and Het are as defined in claim 20 and '·' is a leaving group, with either a base salt of 1H-1,2,4-criazole, or with

1H-1,2,4-triazole in the presence of a base; said process being followed by, optionally, one or more of steps (a) to (g) as defined in claim 20,

25 A process as claimed in claim 24wherein ϊ is ohloro, bromo or C.-C a 1 kanesulphcr.y loxy .

26 A process as claimeo in claim 24which is carried out .sing an epoxide '27) as the starring material.

27 .-. process as claimed in sny one of claims 24 to26 in which the base salt of LH-1,2,i-triazole used is either the sodium salt or the tetra-n-butylammonium salt.

?LC 492

BAD ORIGINAL

28 A process as claimed in any one of claims 24 to 26 in which the oase used in conjunction with lH-l,2,4-triazole is sodium or potassium carbonate.

29 A process for the preparation of a compound of the formula: f.6

- CD or a pharmaceutically acceptable salt thereof, wherein Het“, which is attached to the adjacent carbon atom by a ring carbon atom, is selected from pyridinyl, pyridazir.yl, o-.-rimidir.yl, pvrazinyl and triacinyl, He/ being substituted by one halo, 'li, —SH(C,—C. alkanovl) or -l.'HCO. ' 2. —1. alkvi) i a ’ J ί - * suostituent positioned on a ring carbon atom which is adjacent to 1 2 a ring nitrogen atom: and R, R and R are as detmed in claim 2G, o 'mprisir.g reset!:.? a :otr.ocurc or the torm.ula :

z kl \

, X 2 i r.ec ?

'22 4)2 wherein het^ is an N-oxide of a pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl or triazinyl group, the N-oxido substituenc being positioned on a ring nitrogen atom of Het^ adjacent to the ring carbon atom which is to be substituted by this process, said

3 1 · 2 Het group being otherwise unsubstituted; and R, R and R are as previously defined in this claim, with N,N-dimethylcarbamoyl chloride and either trimethylsily1 cyanide or potassium cyanide to 2, provide a compound of Che formula (IF) where Het is :yano-subscituted; said process being followed by, optionally, one or more of the following steps:i) separation of the desired regioisomer;

ii) one or more of steps (a), (b), (d), (e) and (f) in claim20;

and iii) conversion of the compound of the formula (IF) into a pharmaceutically acceptable salt.

30 A process as claimed in claim 29 which is carried out using N,S—iimethylcarbamcy1 chloride anc trimethylsily1 cyanide.

31 A process as claimed in any one of claims 20 tc'28 wherein, het is selecced from pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, het being optionally substituted by a 1, u , . a 1 .<oxy , na j.o , y , NG , , Nn₃ or — NΠ > ..

32 A process -s claimed It any :ne of claims 2Qco 28'-’herein het ¹ is ;elect = c from pyridiny., pyrctazinyl, pyrimidinyl, cyrazinyl and triazinyl, all optionally substituted by 1 or 2 substituents each independently selected from C.-C. alkyl, 2,-h, alkoxv, ha.o, GF., IN, NG¹., NH, , -ΝΗι'Ί,-C. alkanovl'· and

J

-TilCO _Ί ί.3, -C, 3 Iky l· .

BAD ORIGINAL

33 A process as claimed in claim 32 wherein Het is selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, all optionally substituted by 1 or 2 substituents each independently selected from alkyl, C^-C^ alkoxy, halo, CF^,

CN, NH₂, -NH(C₁-C₄ alkanoyl) and -NHCCE (C,-C₄ alkyl).

34 a process as claimed in claim 33 wherein Het” is selected from pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl, all optionally substituted by one CN, SH, or -NHC0₉(C^-C^ alkyl) substituent.

35 a process as claimed in claim 31 or 34 wherein Het is 2-oyridinv1,4-pyniJinyl or 4-pyrimidiny1.

36 a process as claimed in any one of the preceding claims '-herein R is a phenyl group substituted by 1 to 3 halo substituents .

37 A precess as claimed in any one of the preceding claims wnerein R is 3 phenyl group substituted by 1 or 2 halo suostituents.

38 A process as claimed in any one of the preceding claims •-nerein R is 2 , 4-dif luoropheny!, 2,i-dichiorophenyl,

2-fluoropheny1 or 2-chloropheny1.

39 A process as claimed in any one of the preceding claims .-erais R is 2,- —: i:1uorophan··' 1.

40 A process as claimed in any tr.e cf the precacir.g deems •-rerain R^ is rnecnyl and R is H cr methyl.

41 A process as claimed in any cne of the preceding claims

1 ?

-nerein R is methyl and R is n.

APO 0 0 1 0 4

BAD ORIGINAL ft

42 A process as claimed in any one of claims 20 to 2&nd 31 to 41 which is used to prepare

2-(2,4-difluorophenyl)-3-(pyridin-2-yi)-1-(1H-1,2,4-triazolL-v1)butan-2-ol,

2-(2 ,4-dif luorophenyl)-3-( py rid in-4-y 1)-1-(1H-1,2,4-rtriazoLL-yl)bucan-2-ol or

2-(2,4-difiuorophenyl)-3-(pyrimidin-4-yl)-L-(lH-l,2,4triazol-l-yl)butan-2-ol;

or a pharmaceutically acceptable salt thereof.

43 A process as claimed in any one of the preceding claims wnich is used to prepare a compound of the formula (I) or (IF) in which R is H and which has the (2R,3S) configuration, i.e.:-

44 A process as claimed in claim 26 for the preparation of a ;impound of Che formula: -

BAD ORIGINAL

or a pharmaceutically acceptable salt thereo:,

-herein Hec^-' is 2-pyridinyl, 4-pyridinyl or 4-pyrimidiny1, comprising reacting a compound of che formula:CH- iet wherein '’Het⁴ is as previously defined in this claim, with eithe: a base salt, of 1H-1, 2 ,i-triacole or with 1H-1,2,-t-criazole in che oresence :: a base; said process being followed by, optionally, rcnversion of the product into a pharmaceutically acceptable salt.

45 A process for the preparation of a compound of the .-'a mu la ·’ 1) as defined in claim 20 or a pharmaceutically acceptable salt thereof, in which 3, 3 and .3“ are as defined in claim 20 and ’net' is unsubstituted pyridinyl, characterised b” either:ovrtdacinvl.

AP 0 0 0 1 0 4 as iefined in claim 20an wr.ich 3 an c . are as oeranee n : ... am c „ am as :r.y .,

~.c- ; 3mu as in claim 20 An which.

_n.ee _n ca.i.r. co; cr

BAD ORIGINAL (o'· reacting an oxirane of the formula (17) as defined i: in which R” , R wd Het' are as defined in (a) wit:

a base salt of 1H-1,2 ,.--triaco le cr with L.H-1,2 , 2-tr:

the presence of a base; said process fa) ar (b) bein: followed by, optionally, conversion of the product i; pharmaceutically acceptable salt.