GB2265900A - Furanone intermediates in pharmaceutical pyrazole preparation - Google Patents

Abstract

Pharmaceutically active pyrazoles of formula (Ia> <IMAGE> wherein R<1> represents a hydrogen atom or a group selected from C1-6alkyl or C2-6alkenyl; R<2a> represents a hydrogen atom or a group selected from C1-6alkyl, C3-7cycloalkylC1-4alkyl, C3-6alkenyl, fluoroC1-6alkyl or fluoroC3-6alkenyl; R<3a> represents a hydroxymethyl group; X represents a hydrogen atom or a halogen atom or a group of the formula <IMAGE> R<4> represents a group selected from -NH2, -CN, or a protected derivative of -CO2H, a protected derivative of -NH2 or an optionally protected C-linked tetrazolyl group; are prepared by reacting a novel furanone of formula (IV> <IMAGE> with a hydrazine of formula (III) <IMAGE>

Description

FURANONE INTERMEDIATES AND THE USE THEREOF This invention relates to novel compounds which are useful as intermediates in the preparation of pharmaceutical compounds, to processes for their preparation, and to their use in the preparation of pharmaceutical compounds.

European Patent Specification No. 0446062A describes intermediate compounds of formula (I)

wherein R1 represents a hydrogen atom or a group selected from C1 6alkyl or C2 6alkenyl; R2 represents a hydrogen atom or a group selected from C1 6alkyl, C3 7cycloalkyl, C3 7cycloalkylC1 -4alkyl, C3 6alkenyl, fluoroC1 6alkyl, fluoro C3 6alkenyl, phenyl, -(CH2)kCoR5 or -(CH2)kSo2R5;; R3 represents a hydrogen atom or a group selected from C1-6alkyl optionally substituted by a hydroxy or C1-6alkoxy group, C2 6alkenyl, fl uoroC1 6alkyl, -(CH2)mR6, -(CH2)nCOR7 or -(CH2)pNR8COR9; X represents a halogen atom or a group of the formula

R4 represents a group selected from -NH2, -CN or a protected derivative of -CO2H, a protected derivative of -NH2 or a protected derivative of a C-linked tetrazolyl group; R5 represents a group selected from C1 6alkyl, C2 6alkenyl, C1 6alkoxy or the group -NR10R11; R6 represents a phenoxy or benzyloxy group;; R7 represents a hydrogen atom or a group selected from hydroxy, C1 6alkyl, C1-galkoxy, phenyl, phenoxy or the group -NR1 0R11; R8 represents a hydrogen atom or a C1 6alkyl group; R9 represents a hydrogen atom or a group selected from C1 6alkyl, C1-6alkoxy, phenyl, benzyl, phenoxy or the group -NR1 0R1 1; R10 and R11, which may be the same or different, each independently represent a hydrogen atom or a Cm alkyl group or -NR1 0R11 forms a saturated heterocyclic ring which has 5 or 6 members and may optionally contain in the ring one oxygen atom; k represents zero or an integer from 1 to 4; m represents an integer from 1 to 4; n represents zero or an integer from 1 to 4; and p represents an integer from 1 to 4.

In particular, the compounds of formula (I) wherein the group R2 is on the nitrogen atom adjacent to the group R3 are to be preferred.

European Patent Specification No. 0446062A describes several methods for the preparation of the compounds of formula (I) as defined above. Thus, for example, a compound of formula (II)

may be reacted with a hydrazine of formula (III) R2NHNH2 (Ill).

Alternatively, a compound of formula (I) may be prepared by interconversion of a compound of formula (I) wherein R2 represents a hydrogen atom into a compound of formula (I) wherein R2 represents a C1 6alkyl, C3 7cycloalkyl or C3-7cycloalkylC1-4alkyl group, or a group of formula -(CH2)kCoR5 or -(CH2)kSo2R5 where k is 1 to 4, by an alkylation reaction with a corresponding alkylating agent, for example, an alkyl halide such as an alkyl iodide.

The product of such reactions is a mixture of regioisomers (as is evident from the worked examples in EP-A-0446062). There is therefore a need for a more regioselective synthesis of the compounds of formula (I) in order to prepare the preferred compounds wherein the group R2 is on the nitrogen atom adjacent to the group R3.

Thus, the present invention provides a process for the preparation of a compound of formula (la)

wherein R1 represents a hydrogen atom or a group selected from C1-6alkyl or C26al kenyl; R2a represents a hydrogen atom or a group selected from C1 6alkyl, C37cycloalkyl, C37cycloalkylC1 .4alkyl, C36alkenyl, fl uoroC1 6alkyl or fluoroC3 6alkenyl; R3a represents a hydroxymethyl group;; X represents a hydrogen atom or a haloaen atom or a groud of the formula

R4 represents a group selected from -NH2, -CN, or a protected derivative of -CO2H, a protected derivative of -NH2 or an optionally protected C-linked tetrazolyl group; which comprises reacting a compound of formula (lV)

(wherein R1 and X are as previously defined) with a hydrazine of formula (Illa) R2aHNNH2 (Illa) (wherein R2a is as defined above).

The reaction is optionally effected in a solvent such as acetonitrile, an aqueous alcohol e.g. ethanol, an ether e.g. tetrahydrofuran or a substituted amide e.g. dimethylformamide, at a temperature in the range of OOC to the reflux temperature of the solvent.

A preferred embodiment of the invention comprises the reaction of a compound of formula (IV) wherein R1 represents a C1 salkyl, especially an ethyl, n-propyl or n-butyl, group and X is as defined above, with a hydrazine of formula (Illa) wherein R2 represents a C1 5alkyl, especially an ethyl, isopropyl or n-butyl, group. Also preferred are those compounds wherein R2 represents a C3.5cycloalkylC1.2alkyl, especially cyclopropylmethyl, group.

It will be appreciated that the product of the reaction between a compound of formula (IV) and a hydrazine of formula (Illa) corresponds to a compound of formula (I) wherein R3 is the group -CH2OH. This group may be modified by conventional techniques, thus, for example a compound of formula (I) wherein R3 represents the group -CHO or -CO2H may be prepared by a stepwise oxidation using, for example, manganese dioxide, chromium trioxide in pyridine, or tetra-n-propylammonium perruthenate (TPAP) with 4-methylmorpholine-N-oxide to produce the aldehyde.

Subsequent oxidation to the carboxylic acid may be effected using, for example, sodium chlorite with sodium hydrogen orthophosphate, or potassium permanganate in the presence of acid, or chromic acid.

The compounds of formula (IV) are novel and represent a further aspect of the present invention.

It will be appreciated that inherent within the disclosure of the present invention will be the use of a compound of formula (IV) for the preparation of a compound of formula (la). Such use constitutes a further alternative aspect of the present invention.

As described above, the process of the present invention is a regioselective synthesis wherein the preferred isomer is ideally obtained in a ratio of at least 25:1, and preferably at least 40:1, in favour of the regioisomer shown in formula (la). Identification of the regioisomer obtained according to the process of the present invention may be achieved by techniques well known in the art, for example, by nuclear magnetic resonance (n.m.r.) spectroscopy.

The compounds of formula (IV) may be prepared, for example, by the deprotection and subsequent cyclisation of a compound of formula (V)

wherein R1 and X are as defined in general formula (I) and Y is a hydroxyl protecting group, for example, an alkyl ether such as a -butyl ether, an optionally substituted benzyl ether such as p-methoxybenzyl ether, a silyl ether such as a t-butyldimethylsilyl or t-butyldiphenylsilyl ether, or such as a tetrahydropyranyl ether.

Other suitable hydroxyl protecting groups, their method of formation and suitable means of deprotection are described in Chapter 2 of "Protective Groups in Organic Synthesis" (2nd Edition) by T W Greene and P G M Wuts, John Wiley & Sons, Inc. New York (1991).

Thus, for example, the above protecting groups may be removed under conditions of acid hydrolysis using a mineral acid such as hydrochloric acid, basic hydrolysis using a base such as sodium hydroxide, or using fluoride ions (in the case of the silyl ethers), or using an acidic ion exchange resin (in the case of tetrahydropyranyl ethers).

Particularly preferred protecting groups are silyl ethers, especially t-butyldimethylsilyl (TBDMS) ethers, especially where the compound of formula (\/) contains other protecting groups, for example, where R4 in the group X is a protected derivative of -CO2H, a protected derivative of -NH2 or a protected derivative of a C-linked tetrazolyl group. Removal of a silyl ether protecting group in such compounds, without affecting the protecting group in R4, may be effected using the basic fluoride ion from, for example, tetrabutylammoniumfluoride (TBAF) in THF, or aqueous hydrogen fluoride in acetonitrile. Both of these deprotection reactions conveniently take place at room temperature.

Another particularly preferred protecting group is the tetrahydropyranyl (THP) ether group. Removal of a THP ether group may be effected by a number of techniques well known in the art. Particularly preferred are methods which utilise an acidic ion exchange resin such as DowexTM 50W X4 in methanol at room temperature.

Intramolecular cyclisation of the hydroxymethyl diketone formed by the deprotection is preferably effected without purification of the hydroxymethyl diketone intermediate. Cyclisation is promoted by mild acid catalysis using, for example, dilute acid, e.g. hydrochloric acid, or silica gel or an acidic ion exchange resin.

It will be appreciated that where the hydroxymethyl protecting group is acid labile, deprotection and cyclisation may be effected in one step. Acidic deprotection and cyclisation may also result in the removal of any protecting group in the group R4. It will be appreciated that, following formation of the furanone, any reactive group at R4 may require further protection prior to any subsequent chemistry.

It will be appreciated that a compound of formula (IV) may be interconverted into another compound of formula (lV). For example, a compound of formula (IV) wherein X represents a halogen, especially chlorine, bromine or iodine, may be converted into a compound of formula (IV) wherein X represents a group of the formula

by reaction with a compound of formula (Vl)

wherein Z represents a halogen atom, especially iodine or the group -B(OH)2 or an ester thereof, or an alkyltin derivative, e.g. tributyltin.

Where Z represents a halogen atom, especially iodine, the reaction may be effected in the presence of copper (the Ullman reaction).

Alternatively, where Z represents a halogen atom, the compound of formula (VI) may form an organometallic intermediate with, for example, magnesium, lithium, zinc, aluminium, boron or tin. A coupling reaction with a compound of formula (IV) in which X represents a halogen atom may then be effected in the presence of a palladium catalyst, for example, tetrakis (triphenylphosphine) palladium(0). Particularly preferred is the reaction where Z represents the group -B(OH)2.

It will be appreciated that, in the same manner, a compound of formula (IV) in which X is a halogen atom may be converted to the organometallic intermediate and then coupled to a compound of formula (Vl) in which Z is a halogen atom.

These reactions may be effected in a suitable solvent such as an ether (e.g. 1,2-di 1,2-dimethoxyethane or tetrahydrofuran) or an aromatic hydrocarbon (e.g. benzene). The reactions are preferably carried out in the presence of a base such as an alkali or alkaline earth metal carbonate (e.g. sodium bicarbonate) at a temperature between room temperature and the reflux temperature of the solvent.

Such biaryl couplings may also be effected prior to formation of the furanones of formula (lV), i.e. to prepare a compound of formula (V) in which X is the group

Alternatively, the biaryl coupling may be effected at any stage subsequent to the conversion of a furanone of formula (IV) into a pyrazole of formula (la).

The compounds of formula (V) may be prepared by methods analogous to those described in European Patent Specification No.

0446062A.

The following non-limiting examples serve to illustrate the present invention. Temperatures are in C. "Dried" refers to drying using magnesium sulphate or sodium sulphate. Unless otherwise stated, thin layer chromatography (T.l.c.) was carried out on silica Flash column chromatography (FCC) was carried out on silica gel (Merck 9385) unless otherwise stated. Nuclear magnetic resonance (n.m.r.) spectra were determined at 250MHz. The following solvent systems were used: System A - ether:hexane; System B - dichloromethane:ether; System C - ethyl acetate:hexane. The following abbreviations may be used: THF - tetrahydrofuran; DME - 1 ,2-dimethoxyethane; DMAP - 4-dimethylaminopyridine.

Intermediate 1 Methyl 1-1(1,1 -dimethylethyl)dimethylsilylioxyacetate t-Butyldimethylsilylchloride (222.4g) was added to an ice-cooled solution of methyl glycolate (127g) in dimethylformamide (950ml). Imidazole (100.49) and then DMAP (4.19) were added and the mixture heated at 400C for 18h. The mixture was poured into water (300ml) and extracted with petroleum ether (3x1000ml). The combined extracts were washed with water (1000ml), aqueous copper sulphate (160g/1000ml), dried and concentrated in vacuo to afford the title compound (271.4g) as a colourless liquid.

T.l.c. System A (1:1) Rf = 0.65 Example 1 3-Butyl-4-(F2'-[(2-triphenvlmethyl) -2H-tetrazol-5-yli Fl 1 '-b phenvli-4- vll methyli-1 -(1 -methylethvl) -1 H-pvrazole-5-methanol (a) 1 -F(1 .1 -Dimethylethyl) dimethvlsilylioxv-2. 4-octandione 2-Hexanone (35ml) in dry THF (20ml) was added dropwise to a stirred solution of lithium diisopropylamide (1.5M solution, 200ml) in dry THF (80ml) at -65 to -70 C under nitrogen. The mixture was stirred for 10min before dropwise addition of methyl 1 -[(1,1 -dimethylethyl)dimethylsilyl] oxyacetate (28.5g) in dry THF (50ml) at -70 C. The mixture was then stirred at 45"C, under nitrogen, for 24h.After the addition of saturated aqueous ammonium chloride (600ml) the mixture was extracted with ether (3x400ml). The combined organic extracts were washed with brine (2x400ml), dried and concentrated in vacuo to afford the title compound (31.99) as a brown mobile oil.

T.l.c. petroleum ether:ether (50:1) Rf=0.24 (b) 1 -F(1 .1 -Dimethylethyl) dimethylsilylloxv-3-Fl2'-f(2-tri phenylmethyl)-2H- tetrazol-5-yli [1.1 '-biphenyl]-4-yl]methyl-2,4-octandione The product of step (a) (4.50g) in freshly distilled THF (25ml) was added dropwise to a rapidly stirred suspension of 60% sodium hydride (0.70g) in freshly distilled THF (250ml) causing rapid evolution of gas. After stirring for 30min a solution of 5-[4'-(bromomethyl) [1,1 '-biphenyl]-2-yl] -2- (triphenylmethyl)-2H-tetrazole (described, for example, as Intermediate 3 in European Patent Specification No. 0446062A, published 11th September 1991) (6.7g) in anhydrous THF (25ml) was added dropwise and the resulting mixture heated at reflux under nitrogen overnight. Iced water (400ml) was added and the mixture adjusted to pH4 with 2N hydrochloric acid. The mixture was extracted with ether (3x250ml) and the combined extracts washed with saturated brine (250ml), dried and concentrated in vacuo to give a brown oil. FCC eluting with System A (1:10) gave the title compound as a yellow glass (4.69g) T.l.c. System A (1:1) Rf = 0.32.

(c) 5-Butyl-4-Fl2'-l(2-triohenylmethyl) -2H-tetrazol -5-yli Fl .1 '-bihenyli -4- yllmethyll-3(2H) -furanone A solution of tetrabutylammoniumfluoride (1 M in THF;155ml) was added to a stirred solution of the product of step (b) (38g) in THF (700ml) under nitrogen. The mixture was stirred at room temperature for 3h then ether (500ml) was added. The mixture was washed with 8% aqueous sodium bicarbonate (2x500ml) and brine (2x500ml) and then dried and concentrated in vacuo. The residue was dissolved in ether (1000my) and dichloromethane (100ml). Silica (Merck 9385, 100g) was added and the mixture stirred for 48h.After filtering off the silica and removing the solvent in vacuo the material was purified by FCC eluting with System A (1:4) followed by dichloromethane:hexane:ether (20:30:5) to afford the title compound (9.8g) as a pale yellow foam.

T.l.c. hexane:dichloromethane:ether (30:20:5) Rf=0.28 n.m.r. (CDC13) 6 0.88 (3H,t), 1.3 (2H,m), 1.54 (2H,m), 2.42 (2H,t), 3.4 (2H,s), 4.47 (2H,s), 6.8-7.52 (22H,m), 7.88 (1H,dd).

(d) 3-Butyl-4-lF2'-F(2Ariphenylm ethyl) -2H-tetrazol -5-yli Fl .1 '-biphenyli -4- yll methyli-1 -(1 -methylethyl) -1 H-oyrazole-5-methanol A solution of the product of step (c) (850mg) in THF (5ml) and i-propylhydrazine (5ml) was allowed to stand under nitrogen at room temperature for 72h. Ether (100ml) was added and the mixture washed with water:saturated brine (10:1) (3x50ml) and saturated brine (50ml), dried and concentrated in vacuo to afford a yellow foam. Purification by FCC eluting with System B (9:1), gave the title compound as colourless foam (220mg).

T.l.c. System A (1:1) Rf=0.17 Mass Spec. (calc.) MH+=673 (obs.) MH+=673 Example 2 1. 3-Di butvl-4-ll2'- F(2AriDhenylmethvl) -2H-tetrazol-5-yll [1.1 '-biphenyl]-4- vilmethyll-1 H-nyrazole-5-methanol A solution of the product of step (c) of Example 1 (1.20g) in nbutylhydrazine (5ml) and freshly distilled THF (2.5ml) was allowed to stand overnight at room temperature under nitrogen. Ether (150ml) was added and the solution washed with water (3x75ml) and saturated brine (50ml), dried and concentrated in vacuo to afford a yellow oil. Trituration with System A (1:1) gave the title compound as a light yellow powder (1.15g).

T.l.c. ether Rf=0.71 n.m.r. (CDCl3) b 0.88 (3H,t) 0.93 (3H,t), 1.2-1.45 (5H,m), 1.54 (2H,m), 1.82 (2H,m), 2.51 (2H,t), 3.70 (2H,s), 4.08 (2H,t), 4.36 (2H,d), 6.88-7.53 (22H,m), 7.88 (1H,dd).

Example 3 3-Butyl-1 -methyl-4-FF2'-F(2-tri phenyl methyl) -2H-tetrazol-5-yIl Fl .1 '-biphenyl]- 4-yl]methyl]-1 H-pvrazole-5-methanol A solution of the product of step (c) of Example 1 (320mg) in freshly distilled THF (5ml) and methylhydrazine (5ml) was treated according to the method of step (d) of Example 1. Purification by FCC eluting with hexane:ethyl acetate:ethanol (100:20:1) gave the title compound as a colourless foam (180mg).

T.l.c. ethyl acetate Rf=0.65 n.m.r (CDCI3) 6 0.88 (3H,t), 1.23-1.41 (2H,m), 1.56 (2H,m), 2.50 (2H,t), 3.70 (2H,s), 3.82 (3H,s), 4.33 (2H,s), 6.88-7.53 (22H,m), 7.87 (1H,dd).

Example 4 3-Butyl-4-[(4-iodophenyl)methyl]-1 methyl-1 H-pyrazole-5-methanol (a) 1-[(1.1 -Dimethylethyl) dimethvlsilvll oxv3- r(4-iodoh envl methyl -2.4- octandione A solution of the product of step (a) of Example 1 (8.6g) in dry THF (50ml) was added slowly to a suspension of sodium hydride (60% dispersion in oil, 1.4g) in THF (50ml) with constant stirring under nitrogen. After 15 minutes p-iodobenzylbromide (9.4g) in THF (150ml) was slowly added.

The mixture was treated according to the method of step (b) of Example 1 to afford the title compound (1 6.3g) as a brown oil.

T.l.c. System A (1:4) Rf=0.52 (b) 5-Butyl-4-[(4-iodophenyl) methyl]-3(2H)furanone A solution of the product of step (a) (16.3g), concentrated hydrochloric acid (2ml) and dry THF (250ml) was stirred at room temperature under nitrogen for 16h. Ether (300ml) was added and the solution was washed with water (2x200ml), brine (2x200ml) and then dried. After concentrating in vacuo the material was purified by FCC eluting with System A (1:4) to afford the title compound (5.19) as a yellow foam.

T.l.c. System A (1:4) Rf=0.15 n.m.r. (CDC13) # 0.89 (3H,t), 1.32 (2H,m), 1.55 (2H,m), 2.48 (2H,t), 3.42 (2H,s), 4.48 (2H,s), 6.97 (2H, 1/2 AA'BB'), 7.58 (2H, 1/2 AAl BB').

(c) 3-Butyl-4-[(4-iodophenyl)methyl]-1 -methyl-1 H-pvrazole-5-methanol A solution of the product of step (b) (560mg) in freshly distilled THF (10ml) and methylhydrazine (5ml) was heated at reflux for 6h. Ether (100ml) was added and the mixture extracted with water (3x100ml). The ethereal phase was washed with saturated brine (100ml), dried and concentrated in vacuo to give an orange oil. Purification by FCC eluting with ether gave the title compound as a light yellow solid (200mg) T.l.c. ether Rf = 0.38 n.m.r. (CDC13) 6 0.85 (3H,t), 1.29 (2H,m), 1.46 (2H,m), 2.42 (2H,t), 2.84 (iH,br.s), 3.70 (2H,s), 3.79 (3H,s), 4.49 (2H,s), 6.84 (2H, 1/2 M BB), 7.55 (2H, i/2AA'BB').

Example 5 1-(1 -Methylethyl)-3-propyl-4-[2'-[(2-triphenylmethyl)-2H-tetrazol-5-yl] Fl .1 '-biphenylA-ylimethyl-1 H-nyrazole-5-methanol (a) 1-[(1,1-Dimethylethyl)dimethylsilyl]oxy-2,4-heptandione Prepared according to the method of step (a) of Example 1 using 2-pentanone (30ml) in the place of 2-hexanone.

T.l.c. 5% ether in petroleum ether Rf=0.58 (b) 1-[(1,1-Dimethylethyl)dimethylsilyl]oxy-3-[[2'-[(2triphenylmethyl) -2H-tetrazol-5-yl][1,1-biphenyl]-4-yl]methyl]-2,4-heptandione Prepared from the product of step (a) according to the method of step (b) of Example 1.

T.l.c. System A (1:4) Rf=0.13 (c) 5-Propyl-4-[[2'-[[(2-triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4 vlimethyll-3 (2H) -furanone Prepared from the product of step (b) according to the method of step (c) of Example 1.

T.I.c. Petroleum ether:dichloromethane:ether (30:20:5) Rf =0.23 n.m.r. (CDCI3) 6 0.89 (3H,t), 1.58 (2H,m), 2.39 (2H,t), 3.4(2H,s), 4.47 (2H,s), 6.85-7.53 (22H,m), 7.88 (1H,dd).

(d) 1-(1-Methylethyl)-3-propyl-4-[[2'-[(2-triphenylmethyl)-2H-tetrazol-5- vll Fl .1 '-biphenyl]-yl]methyl]-1 H-pyrazole-5-methanol Prepared from the product of step (c) according to the method of step (d) of Example 1.

T.l.c. ether Rf = 0.74 n.m.r. (CDCI3) 5 0.9 (3H,t), 1.16 (1H,t), 1.47 (6H,d), 1.58 (2H,m), 2.51 (2H,t), 3.7(2H,s), 4.35 (2H,d), 4.55 (iH,m), 6.85-7.53 (22H,m), 7.88 (1 H,dd).

Example 6 4'-[[3-Butyl-5-hydroxymethyl-1-(1 -methylethyl)-1 H-pyrazol-4-yll methyli Fl .1 '-biphenyll-2-carbonitrile (a)1-[(Tetrahydro-2H-pyran-2-yl)oxy]-2,4-octandione Prepared according to the method of step- (a) of Example 1 using 2hexanone (148ml), lithium diisopropylamide (1.5M in THF; 800ml) and methyl 1 -[(tetrahydro-2H-pyran-2-yl)oxy]acetate (104.5g) to give the title compound as a yellow oil (88g).

T.l.c. System A (1:9) Rf = 0.15 (b) 4'-F3-Oxo-2-FF(tetrahydro-2H-pyran-2-yl) oxylacetyli hetanyIi Fl I '-bishenvil-2-carbonitrile Prepared from the product of step (a) (24.2g) according to the method of step (b) of Example 1 using sodium hydride (60%, 4.76g), 4' (bromomethyl) [1,1 '-biphenyl]-2-carbonitrile (229) and potassium iodide (16.5g) to give the title compound as a yellow oil (25g).

T.l.c. System A (1:1) Rf = 0.38 (c) 4'-[(2-Butyl-4,5-dihydro-4-oxo-furanyl) methyll Fl .1 '-biphenyll -2- carbonitrile Prepared from the product of step (b) (20.1 g) according to the method of step (b) of Example 7 using DowexTM 50 WX4 cationic exchange resin (8g) to give the title compound as a yellow oil (10.5g).

T.l.c. System C (1:4) Rf = 0.33 n.m.r. (CDCl3) â 0.9 (3H,t), 1.35 (2H,m), 1.58 (2H, pent), 2.54 (2H,t), 3.56 (2H,s), 4.52 (2H,s), 7.31-7.33 (2H,d), 7.38-7.5 (4H,m), 7.58-7.67 (1H,m), 7.72-7.76 (1 H,dd).

(d) 4'-[[3-Butyl-5-hydroxymethyl-1 -(1-methylethyl)-1 H-pyrazol-4-yli methyli Fl .1 '-biphenyl-2-carbonitrile Prepared from the product of step (c) (13.8g) according to the method of step (d) of Example 1 using isopropylhydrazine (55ml) to give the title compound as a pale yellow oil (14.8g).

T.l.c. System A (2:1) Rf = 0.31 n.m.r. (CDCl3) 6 0.87 (3H,t), 1.34 (2H,m), 1.45-1.58 (8H,m), 2.55 (2H,t), 3.87 (2H,s), 4.53 (2H,s), 4.62 (1H,hept), 7.22-7.26 (2H,d), 7.39-7.51 (4H,m), 7.59-7.67 (1H,m), 7.73-7.77 (1H,dd).

Example 7 3-Butyl-4-[[2'-[(2-triphenylmethyl)-2H-tetrazol-5-yl] [1 .1 '-biphenyli-4- yllmethyl-i -(1 -methylethyl) -1 H-pyrazole-5-methanol (Alternative preparation) (a) 1-[(Tetrahydro-2H-pyran-2-yl)oxy]-3-[[2'-[2-(triphenylmethyl)-2H- tetrazol-5-yi][1]1'-biphenyl]-4-yl]methyl]-2,4-octandione Prepared from the product of step (a) of Example 6 (3g) according to the method of step (b) of Example 1 to give the title compound as a white solid (4.86g).

T.l.c. System A (1:1) Rf = 0.25 (b) 5-Butyl-4-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-3(2H)furanone A solution of the product of step (a) (3.89) in methanol (1 Sml)/dichloromethane (1 Oml) was added to DowexTM 50 WX4 (29) [which had previously been washed with methanol (3x10ml)] in methanol (iOml) and the mixture stirred vigourously for 16h. The mixture was filtered and the solvent evaporated in vacuo to give the title compound as a pale yellow gum (3.5g).

T.l.c. System A (1:1) Rf = 0.15 (c) 5-Butyl-4-FF2'-F2- (triphenylmethyl) -2H-tetrazol-5-yli Fl .1 '-biphenyll -4-yllmethyli-3 (2H)4uranone Triphenylmethyl chloride (1 64mg) was added in one portion to a solution of the product of step (b) (220mg), triethylamine (0.16ml) and DMAP (5mg) in dry dichloromethane (10ml) at room temperature under nitrogen, and the mixture stirred for 1 6h. The solution was then washed with water (2x1 0ml) and dried. The solvent was evaporated to give the title compound as a colourless foam (416mg).

T.l.c. ethyl acetate:petroleum ether (1:1) Rf = 0.8 NB: This compound is the same as the product of step (c) of Example 1.

(d) 3-Butyl-4-FF2'-F(2-triphenylmethyl) -2H-tetrazol-5-yli Fl .1 '-bi phenyli-4- yl]methyll-1-(1 -methvlethyl)-1 H-pyrazole-5-methanol A solution of the product of step (c) (1.009) in iso-propylhydrazine (5ml) was heated at 75 C for 75h. Water (100ml) and saturated brine (10ml) were added and the mixture extracted with ether (3x50ml). The combined extracts were washed with water (2x50ml) and saturated brine (50ml), dried and concentrated in vacuo to afford a yellow solid. Trituration with System A (1:10) gave the title compound as a white powder (0.759).

NB: This compound is the same as the product of step (d) of Example 1.

Example 8 3-Butyl-1 -cyclopropylmethyl4-FF2'-F2-(triphenyl methyl) -2H-tetrazol-5- yl] Fl .1 '-biphenvli-4-ylimethyll-l H-pvrazole-5-methanol Prepared from the product of step (c) of Example 1 (4.59) according to the method of step (d) of Example 1 using cyclopropylmethylhydrazine (1.959) to give the title compound as a white foam (3.259).

T.l.c. System A (1:1) Rf =0.19 n.m.r. (CDC13) â 0.3-0.6 (4H,m), 0.8-0.9 (4H,m), 1.2-1.6 (5H,m), 2.51 (2H,m), 3.62 (2H,s), 3.98 (2H,d), 4.38 (2H,d), 6.8-7.9 (23H, m).

Example 9 3-Butyl-1 -propyl-4-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl]]1.1'-biphenyl]- 4-yllmethyll-1 H-pyrazole-5-methanol Prepared from the product of step (c) of Example 1 (1.6g) according to the method of step (d) of Example 1 using n-propylhydrazine (640mg) to give the title compound as a yellow gum (1.829).

T.l.c. System B (25:2) Rf = 0.27 n.m.r. (CDC13) 6 0.87 and 0.91 (6H,t+t), 1.2-1.9 (7H,m), 2.50 (2H,m), 3.71 (2H,s), 4.36 (2H,brs), 6.9-7.9 (23H, m).

Example 10 1 3-Dibutyl-4-(phenvlmethyl) -l H-pyrazole-5-methanol (a) 3- (Phenylmethvl-l (tetrahydro-2H-pyran-2-yl)oxy]-2.4-octandione Prepared from the product of step (a) of Example 6 (10g) according to the method of step (b) of Example 1 using benzylbromide (4.9ml) to give the title compound as yellow oil (149).

T.l.c. System A (1:8) Rf =0.17 (b) 5-Butyl-4- (phenylmethyl) -3 (2H)-furanone A suspension of DowexTM 50 WX4 cationic exchange resin (7.39) in a solution of the product of step (a) (149) in methanol (200ml) was rapidly stirred at room temperature for 2h. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by FCC eluting with System A (3:7) to give the title compound as a yellow oil (5.39).

T.l.c. System B (3:7) Rf = 0.31 n.m.r. (CDC13) 5 0.87 (3H,t), 1.31 (2H,m), 1.53 (2H,m), 2.48 (2H,m), 3.48 (2H,s), 4.47 (2H,s), 7.1-7.3 (5H,s), (c) 1 ,3-Dibutyl-4-(phenylmethyl)-1 H-pvrazole-5-methanol Prepared from the product of step (b) (1g) according to the method of step (c) of Example 4 using n-butylhydrazine (3.39) to give the title compound as a yellow oil (1.07g).

T.l.c. System B (11:1) Rf = 0.50 n.m.r. (CDCl3) 6 0.87 and 0.93 (6H, t+t), 1.2-1.8 (7H,m), 2.53 (2H,m), 3.80 (2H,s), 4.09 (2H,m), 4.47 (2H,d), 7.1-7.3 (5H,m).

Example 11 3-Buty1-1 -(1 -methylethyl)-4-(phenylmethyl)-1 H-pyrazole-5-methanol Prepared from the product of step (b) of Example 10 (1g) according to the method of step (c) of Example 4 using isopropylhydrazine (5ml) to give the title compound as a white solid (0.9g).

T.l.c. System A (2:1) Rf = 0.50 n.m.r. (CDCI3) 6 0.87 (3H,m), 1.150 (1H,t), 1.32 (2H,m), 1.49 (6H,d), 1.50 (2H,m), 2.56 (2H,m), 3.81 (2H,s), 4.48 (2H,d), 4.58 (1H,m), 7.1-7.3 (5H,m).

Example 12 4-[(2-Butyl-4.5-dihydro-4-oxo-3-furanyl)methyl] Fl , 1 '-biphenyl1-2-carbonitrile Alternative Procedures to the product of step (c) of Example 6i (a) 5-Butyl-4-f(4-iodophenyl) methyll-3 (2H) 4uranone Trifluoroacetic acid (0.2ml) was added to a solution of the product of step (a) of Example 4 (lug) in dry THF (15ml) at room temperature under nitrogen. The mixture was stirred for 4h, then heated at 60 C for 2h. The mixture was cooled to room temperature and concentrated hydrochloric acid (0.2ml) was added. The mixture was stirred for 2h, concentrated (to 5ml) and diluted with ether (25ml). The solution was washed with water (2x20ml), then brine (20ml) and dried.The solvent was evaporated to give the title compound as a pale orange gum (772mg).

T.l.c. System A (1:4) Rf = 0.15.

(b) 4-[(2-Butyl-4,5-dihydro-4-oxo-3-furanyl)methyl] Fl .1 '-bi phenyli-2- carbonitrile FAlternative Prep.1 A mixture of the product of step (a) (250mg), 2-cyanobenzeneboronic acid (113mug), tetrakis(triphenylphosphine)palladium(0) (14mg) and aqueous sodium carbonate (1N; 10ml) in 'peroxide free' DME (20ml) was heated under reflux for 4h. The cooled mixture was partitioned between water (100ml) and ethyl acetate (3x100ml). The combined organic extracts were washed with sodium carbonate (2N;100ml), then brine (100ml) and dried.

The solvent was evaporated and the residue purified by FCC eluting with ether to give the title compound as a pale yellow oil (30mg).

T.l.c. ether Rf = 0.71.

Alternative Prep 2.

A mixture of the product of step (a) (250mg), 2-cyanobenzeneboronic acid (113mg), silver (I) oxide (325mg) and tetrakis (triphenylphosphine)palladium(0) (14mg) in dry THF (20ml) was stirred at room temperature for 18h. Further portions of the boronic acid (113mg), tetrakis (triphenylphosphine)palladium(0) (1 4mg) and silver (I) oxide (325mg) were added and the mixture was stirred for 16h at 600 The cooled mixture was filtered through hyflo and the solvent evaporated. The residue was purified by FCC eluting with ether to give the title compound as a pale yellow oil (113mg).

T.l.c. ether Rf= 0.71 Alternative Prep. 3 A mixture of the product of step (a) (150mg), 2-cyanobenzeneboronic acid (88mg), potassium phosphate (tribasic, 254mg) and tetrakis (triphenylphosphine)palladium(0) (5mg) in dry dioxan (2ml) was heated at 800 for 16h. The cooled mixture was partitioned between sodium carbonate (2N, 10my) and dichloromethane (3x20ml). The combined organic extracts were dried and evaporated to give a brown oil (163mg).

The crude material was purified by FCC eluting with petroleum ether:ether (7:3) to give the title compound as a pale yellow oil (47mg).

T.l.c. System A (6:4) Rf = 0.3 Alternative Prep. 4 n-Butyl lithium (1.57M; 0.95ml) was added dropwise to a solution of 2-bromobenzonitrile (271mg) in dry THF (5ml) at -75 to -70 under nitrogen. The mixture was stirred at -750 for 20min, then a solution of zinc chloride (1M; 1.5ml) in ether was added dropwise at -750. The mixture was stirred for 1 Omin, then tetrakis(triphenylphosphine)palladium (0) (18mg) and the product of step (a) in THF (2ml) were added sequentially.

The mixture was allowed to warm to room temperature and was then heated under reflux for 18h. The cooled mixture was partitioned between ether (3x15ml) and hydrochloric acid (0.1M; 15ml). The combined organic extracts were washed with brine (20mI) and dried. The solvent was evaporated and the residue was purified by FCC eluting with petroleum ether:ether (4:1) to give the title compound as a pale yellow oil (114mg).

T.l.c. System A (6:4) Rf = 0.3 The following preparations illustrate further modifications of the pyrazole compounds formed according to the process of the present invention in Examples 1 to 12 above: Preparation A (i) 3-ButvlA-FF2'-F(2-triphenylmethyl)-2H-tetrazol-5-ylj Fl .1 '-biphenyli-4- vll methyli-l -(i -methylethyl) -l H-pyrazole-5-carboxaldehyde A mixture of the product of Example 1 (4.39), manganese dioxide (5g) and freshly distilled THF (20ml) was heated at 50 C for 24h. Further manganese dioxide (59) was added and the mixture heated at 50"C for a further 24h. The mixture was filtered through hyflo and the filtrate concentrated in vacuo to give an off-white foam.Purification by FCC eluting with System A (1:2) gave the title compound as a white foam (2.8g).

T.l.c. System A (1:1) Rf=0.75 (ii) 3-Butyl-4-rt2'-r(2-triphenylmethyl)-2H-tetrazol-5-yll Fl I '-biphenyli-4- yli methyll -l -(1 -methylethyl) -l H-pyrazole-5-carboxylic acid A solution of sodium chlorite (80%, 4.47g) and sodium hydrogen orthophosphate (4.479) in water (50mI) was added to a stirred solution of the product of preparation A(i) (2.65g) in freshly distilled THF (50ml), t-butanol (50ml) and 2-methylbut-2-ene (24ml) and the mixture vigorously stirred overnight at room temperature. The mixture was concentrated in vacuo to 75ml, water (150ml) added and the mixture extracted with ethyl acetate (3x100ml).The combined extracts were washed with saturated brine (200ml), dried and concentrated in vacuo to afford the title compound as a white foam (3.0g).

n.m.r. (CDCl3) 6 0.84 (3H,t), 1.28 (2H,m), 1.41-1.6 (8H, d+m), 2.47 (2H,t), 4.0 (2H,s), 5.39 (1H,m), 6.85-7.5 (22H,m), 7.87 (1H,dd).

(iii) 3-Butyl-4-ff2'-(1 H-tetrazol-5-yl) [1.1'-biphenyl]-4-yl]methyl]-1 -(1 methylethyl)-1 H-pyrazole-5-carboxylic acid A solution of the product of preparation A (ii) (3.009) and conc.

hydrochloric acid (1 ml) in ethanol (25ml) was stirred at room temperature for 5h. 8% w/v Aqueous sodium hydrogen carbonate (100ml) was added and the mixture concentrated to 100ml. The mixture was extracted with ether (4x50ml) and the extracts discarded. The aqueous phase was acidified to pH2 with 2N hydrochloric acid and extracted with ethyl acetate (3x100ml). The combined extracts were washed with saturated brine (100ml), dried and concentrated in vacuo to give the title compound as a white powder (1.50g).

Assay Found: C,67.8; H,6.4; N,18.5; C25H28N602 requires: C,67.55; H,6.35; N,18.9% Preparation B (i) 1 .3-Dibutyl-4-FF2'-F(2-triphenylmethyl)-2H-tetrazol-5-yll Fl I '-biphenyll- 4-yfl methyll -i H-pvrazole-5-carboxaldehyde Prepared from the product of Example 2 according to the method of preparation A(i).

T.l.c. ether:petroleum ether (1:1) Rf=0.66 (ii) 1,3-Dibutyl-4-[[2'-[(triphenylmethyl)-2H-tetrazol-5-yl][1,1'-biphenyl]-4 ylmethyll-1 H-pyrazole-5-carboxylic acid Prepared from the product of preparation B(i) according to the method of preparation A(ii).

n.m.r. (CDCl3) 6 0.84 (3H,t), 0.92 (3H,t), 1.18-1.56(6H,m), 1.78 (2H,m), 2.46 (2H,t), 4.0 (2H,s), 4.48 (2H,t) 6.84-7.57 (22H,m), 7.87 (1H,dd).

(iii) 1.3-Dibutyl-4-[[2'-(1 H-tetrazol-5-yl) Fl.l '-bishenyl1-4-yllmethyll-1 H pyrazol e-5-carboxylic acid Prepared from the product of preparation B(ii) according to the method of preparation A(iii).

m.p. 180-1850C.

Preparation C 3-Butyl-4-[[2'-[(2-triphenylmethyl)-2H-tetrazol-5-yl Fl .1 '-biphenyll-4-yll methyll-l -methyl-I H-pyrazole-5-carboxaldehyde A suspension of manganese dioxide (750mg) in a solution of the product of Example 3 (300mg) in freshly distilled THF (10ml) was rapidly stirred at room temperature under nitrogen overnight. Further manganese dioxide (500mg) was added and the suspension stirred for another 6h. The mixture was filtered through hyflo and the filtrate concentrated in vacuo to give the title compound as a colourless foam (200mg).

T.l.c. ether Rf=0.65 Preparation D (i) 1-(1-Methylethyl)-3-propyl-4-[[2'-[(2-triphenylmethyl)-2H-tetrazol-5- yl][1/1'-biphenyl]-4-yl] methyl]-1H-pyrazole-5-carboxaldehyde Prepared from the product of Example 5 according to the method of preparation A(i).

T.l.c. System A (3:7) Rf=0.45 (ii) 1-(1-Methylethyl)-3-propyl-4-[[2'-[(2-triphenylmethyl)-2H-tetrazol-5- yll Fl I '-biphenyl]-4-yl]methyl]-1 H-pvrazole-5-carboxvlic acid Prepared from the product of preparation D(i) according to the method of preparation A(ii).

T.l.c. System A (1:1) Rf=0.5 (iii) 1 -(1 -Methylethyl)-3-propyl-4-[[2'-(1 H-tetrazol-5-vl) [1.1 '-biphenyli-4- yl]methyl]-1 H-pvrazole-5-carboxvlic acid Prepared from the product of preparation D(ii) according to the method of preparation A(iii).

Assay Found: C,67.3; H,6.2; N,19.5; C24H26N60 requires: C,67.0; H,6.1; N,19.5% Preparation E (i) 4'-[[3-Butyl-5-formyl-1-(1-methylethyl)-1 H-pyrazol-4-vll methyll Fl .1 '-biphenyll-2-carbonitrile Prepared from the product of Example 6 (5.0g) according to the method of preparation A(i) using manganese dioxide (6.5g) in a mixture of dichloromethane and dioxan (2:1) (150ml) to give the title compound as an orange oil (3.819).

T.l.c. System A (1:1) Rf = 0.61.

(ii) 3-ButyI-4-F(2'-cyano-Fl .1 '-biphenyll-4-yl)methyll-i -(1 -methylethyl)-1 Hpyrazole-5-carboxylic acid Prepared from the product of preparation E(i) (3.819) according to the method of preparation A(ii) using sodium chlorite (80%; 2.39), sodium dihydrogen orthophosphate (4.879), t-butanol (65ml) and 2-methylbut-2ene (4.219) to give the title compound as a yellow oil (3.629).

T.l.c. System A (1:1) Rf = 0.42 Preparation F (i) 3-Butyl-l -cyclopropylmethyl-4-FF2'-F2-(triphenyl meThyl) -2H- tetrazol-5-yl][1/1'-biphenyl]-4-yl]methyl]-1H-pyrazole-5-carboxaldehyde Prepared from the product of Example 8 (3.09) according to the method of preparation A(i) using manganese dioxide (9g) to give the title compound as a white foam (2.59).

T.l.c. System A (1 :1) Rf = 0.64 (ii) 3-Butyl-1-cyclopropylmethyl-4-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5- yll Fl ,1'-bi .1 '-biphenyll-4-yll methyll-1 H-pyrazole-5-carboxylic acid Prepared from the product of preparation F(i) (2.59) according to the method of preparation A(ii) using sodium chlorite (80%; 4.479), t-butanol (50ml), sodium dihydrogen orthophosphate (4.47g) and 2-methylbut-2-ene (24ml) to give the title compound as a white foam (2.4g).

T.I.c. System A (1:1) Rf 0.29 (iii) 3-Butyl-l -cyclopropylmethvl-4-FF2'-(l H-tetrazol-5-yl) Fl .1 '-biphenvll-4- yll methyll -l H -pyrazole-5-carboxvlic acid Prepared from the product of preparation F(ii) (2.3g) according to the method of preparation A(iii) using concentrated hydrochloric acid (1ml) to give the title compound as a white solid.

Assay Found: C,68.6; H,6.2; N,18.3; C26H28N602 requires C,68.4; H,6.2; N,18.4% Preparation G (i) 3-Butyl-1-propyl-4-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl][1,1' biphenyll -4-vIl methyli-l H-pvrazole-5-carboxaldehyde Prepared from the product of Example 9 (420mg) according to the method of preparation A(i) using manganese dioxide (1g) to give the title compound as a yellow oil (350mg).

T.l.c. System B (20:1) Rf = 0.88 (ii) 3-Butyl-1 -propyl-4-[[2'-[2-(triphenylmethyl)-2H-tetrazol-5-yl] Fl .1'- biphenyll-4-yll methyll-l H-pvrazole-5-carboxvlic acid Prepared from the product of preparation G(i) (350mg) according to the method of preparation A(ii) using sodium chlorite (80%; 465mg), t-butanol (5ml), sodium dihydrogen orthophosphate (465mg) and 2-methylbut-2-ene (3.2ml) to give the title compound as a white foam (380mg).

T.l.c. System B (20:1) Rf =0.34 (iii) 3-Butyl-1 -propyl-4-[[2'-(1 H-tetrazol-5-vl) Fl .1 '-b phenyll -4-yIl methyli- 1 H-pyrazole-5-carboxvlic acid Prepared from the product of preparation G(ii) (90mg) according to the method of preparation A(iii) using concentrated hydrochloric acid (0.1ml) to give the title compound as a white solid (46mg).

n.m.r. (CDCl3) # 0.86 and 0.90 (6H,t+t), 1.2-1.9 (6H,m), 2.49 (2H,m), 4.08 (2H,s), 4.47 (2H,m), 7.0-7.8 (8H, m).

Claims (10)

Claims

1. A compound of formula (IV)

wherein R1 represents a hydrogen atom or a group selected from C1 6alkyl or C2 6alkenyl; X represents a halogen atom or a group of the formula

R4 represents a group selected from -NH2, -CN, or a protected derivative of -C02H, a protected derivative of a C-linked tetrazolyl group.

2. A compound as claimed in Claim 1 wherein R1 represents a Cl,gaikyl group.

3. A compound as claimed in Claim 2 wherein the C1 5alkyl group is an ethyl, n-propyl or n-butyl group.

4. Use of a compound of formula (IV) as claimed in Claim 1 for the preparation of a compound of formula (la)

wherein R1 represents a hydrogen atom or a group selected from C1 6alkyl or C2 6alkenyl; R2a represents a hydrogen atom or a group selected from C1 6alkyl, C3jcycloalkyl, C3 7cycloalkylC1 4alkyl, C3 6alkenyl, fluoroC1-6alkyl, fluoroC3 6alkenyl; R3a represents a hydroxymethyl group; X represents a hydrogen atom or a halogen atom or a group of the formula

R4 represents a group selected from -NH2, -CN, or a protected derivative of -C02H, a protected derivative of -NH2 or an optionally protected C-linked tetrazolyl group.

5. A process for the preparation of a compound of formula (la)

wherein 91 represents a hydrogen atom or a group selected from C1 C1-6alkyl or C2 6alkenyl; R2a represents a hydrogen atom or a group selected from C1-6alkyl, C3jcycloalkyl1 C3-7cycloalkylC1-4alkyl, C3-6alkenyl, fluoroC1-6alkyl, fluoroC3 6alkenyl; R3a represents a hydroxymethyl group; X represents a hydrogen atom or a halogen atom or a group of the formula

R4 represents a group selected from -NH2, -CN, or a protected derivative of -C02H, a protected derivative of -NH2 or an optionally protected C-linked tetrazolyl group; which comprises: reacting a compound of formula (IV)

wherein R1 and X are as defined above, with a hydrazine of formula (III) R2NHNH2 (111) wherein R2 is as defined above.

6. A process as claimed in Claim 5 which comprises the reaction of a compound of formula (IV) wherein R1 represents a C1-5alkyl group, with a compound of formula (III) wherein R2 represents a C1 5alkyl group.

7. A process as claimed in Claim 6 wherein the C1-5alkyl group of R1 in the compound of formula (IV) is an ethyl, n-propyl or n-butyl group.

8. A process as claimed in Claim 6 wherein the C1 5alkyl group of R2 in the compound of formula (III) is an ethyl, isopropyl or n-butyl group.

9 A process as claimed in Claim 5 wherein R2 represents a C3 5cycloalkylC1 2alkyl group.

10. A process as claimed in Claim 9 wherein the C3 5cycloalkylC1 2alkyl group is a cyclopropylmethyl group.