The present invention concerns a process for the preparation of 3-methyl-l,2- dichloro-4-fluorobenzene.

3-Methyl-l,2-dichloro-4-fluorobenzene is useful in the preparation of modulators (for example antagonists) of CCR3 chemokine receptor activity. For example 3-methyl- l,2-dichloro-4-fluorobenzene is a useful pharmaceutical intermediate in the preparation of [(phenoxy)-[l,4']bipiperidinyl-r-yl] derivatives (see, for example, WO 03/004487, WO2004/099144 and WO2004/087659).

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

herein referred to as l,2-dichloro-4-fluoro-3-methylbenzene, the process comprising: a. reducing aldehyde of formula (III):

CHO

with an alkali metal borohydride (such as sodium borohydride) in ethanol to give compound of formula (IV):

b. halogenating a compound of formula (JV) with a halogenating agent to form a compound of formula (V):

(V)

wherein X is halogen (such as bromo or iodo); and, c. reducing compound or formula (V) with zinc and acetic acid to produce a compound of formula (I).

In one aspect the present invention provides a process for preparing a compound of formula (I), the process comprising: a. reacting a compound of formula (II):

with suitable strong base at a temperature in the range -80 to -30 ⁰ C in a suitable solvent to form a carbanion of a compound of formula (II); b. reacting the carbanion of a compound of formula (II) with a suitable formylating agent (such as N-methylformanilide or N,N-dimethylformamide) in a suitable solvent, and at a temperature in the range -80 to -30 ⁰ C (for example -50 to -30 ⁰ C) to give aldehyde of formula (III):

CHO

c. reducing the aldehyde of formula (III) with an alkali metal borohydride (such as sodium borohydride) in ethanol to give compound of formula (IV):

d. halogenating a compound of formula (IV) with a halogenating agent to form a compound of formula (V):

wherein X is halogen (such as bromo or iodo); and, e. reducing compound or formula (V) with zinc and acetic acid to produce a

compound of formula (I).

Suitable strong bases are, for example, C _1-1 O alkyl (for example Ci _-6 alkyl, such as C ₄ ) lithiums (such as «-butyl lithium or .sec-butyl lithium), a di-Ci _-10 alkyl (for example di- C _1-6 alkyl) lithium amide base (such as lithium diwo-propylamide), an aryl lithium (such as a phenyl lithium) or an arylalkyl lithium (such as a benzyl lithium).

In a still further aspect of the invention a suitable strong base is, for example a C _1-6 alkyl (such as a C _1-4 alkyl, for example a C ₄ ) lithium (such as «-butyl lithium or sec-butyl lithium) or a di-Ci _-6 alkyl lithium amide base (such as lithium diwo-propylamide). In another aspect of the invention the strong base is «-butyl lithium. A suitable solvent for formation of an aldehyde of formula (III) from a compound of formula (II) is an ether (for example tetrahydrofuran [THF], methyl fert-butyl ether or dioxan).

Suitable halogenating agents for the preparation of a compound of formula (V) include: trimethylsilyl iodide; triphenylphosphine and iodine (for example using acetonitrile as solvent); thionyl bromide; and, hydrogen bromide in acetic acid.

The reduction with zinc and acetic acid is suitably carried out by slowly (typically over 0.5 h) adding the compound of formula (V) to the mixture of zinc and acetic acid. When the halogenation of a compound of formula (IV) uses hydrogen bromide in acetic acid then the reduction with zinc and acetic acid can be conducted by adding the reaction mixture resulting from the halogenation reaction directly to zinc in acetic acid.

In another aspect of the invention the reduction with zinc and acetic acid is conducted at low concentration (for example by having a slow addition of the compound (V)) to minimise Wurtz-type coupling.

In a further aspect of the invention the compound of formula (V) is extracted from reaction mixture of the reduction with zinc and acetic acid by extraction of the reaction mixture with pentane and then evaporation of the pentane to leave the title compound. In a still further aspect the present invention provides a process as hereinbefore described wherein between 1 and 1.5 molar equivalents of strong base is used {for example between 1.3 equivalents of strong base}. In another aspect the present invention provides a process as hereinbefore described wherein between 0.3 and 0.6 molar equivalents (for example 0.35 to 0.45 molar equivalents) alkali metal borohydride are used.

The invention will now be illustrated by the following non-limiting Examples. In

the Examples the following apply, unless stated otherwise:

(i) when given, ¹ H NMR data is quoted and is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300MHz or 400MHz using perdeuterio DMSO-D6 (CD ₃ SOCD ₃ ) or CDCl ₃ as the solvent unless otherwise stated;

(ii) Reverse phase analytical HPLC was run on a Hewlett Packard Series 1100 using Waters "Symmetry" C8 column 3.5μm; 4.6 x 50mm column. The gradient was either:

"Standard" (0.1% Ammonium acetate/ Acetonitrile 75% to 5% in 3 min; 2 mL/min); Or,

"Fast" (0.1% Ammonium acetate/Acetonitrile 45% to 5% in 2.5 min; 2 mL/min); and, (iii) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionisation (CI) mode using a direct exposure probe; where values for m/z are given, generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion - (M+H) ⁺ .

EXAMPLE 1

This Example illustrates the preparation of l,2-dichloro-4-fluoro-3-methylbenzene. a) (2,3-Dichloro-6-fluorophenyl)methanol

A solution of 2,3-dichloro-6-fluoro-benzaldehyde (80 g) in ethanol (250 ml) was added dropwise to a stirred suspension of sodium borohydride (7.8 g) in ethanol (150 ml) at a rate that maintained the internal reaction temperature below 10 °C. After complete addition, approximately 20 minutes, the mixture was allowed to reach ambient temperature. The mixture was evaporated to -1/4 volume and brine (200 ml) plus acetic acid (5 ml) was added cautiously to the stirred mixture. The resulting solid was extracted into diethyl ether (3 x 300 ml). The organic solution was dried over magnesium sulfate, filtered and evaporated to leave a solid. This solid was stirred in isohexane : ethyl acetate mixture (100:1, 300 ml) for 16 hours. The resulting solid was filtered and dried to give the subtitle compound as an off white solid (60 g). Mpt 90-92 ⁰ C NMR δcDcis: 7.42 (dd, IH), 7.01 (t, IH), 4.88 (d, 2H), 2.04 (t, IH).

b) 2-Dichloro-4-fluoro-3 -(iodomethyl)benzene

Triphenylphosphine (3.22 g), imidazole (0.84 g) and iodine (3.12 g) were added, in that order, to acetonitrile (20 mL). A solution of (2,3-dichloro-6-fluorophenyl)methanol (2 g) in acetonitrile (10 mL) was added and the mixture was stirred at room temperature, under nitrogen, for 0.5 h. LC/MS showed that all of the starting alcohol had been consumed and a new peak, believed to be the benzyl iodide had appeared; retention time 2.71 minutes on standard gradient.

c) 1 ,2-Dichloro-4-fluoro-3-methylbenzene In an adjacent flask powdered zinc (3.27 g) was added to acetonitrile (10 mL) and to the suspension was added glacial acetic acid (10 mL). This was heated, under nitrogen, to 80 ⁰ C. The l,2-dichloro-4-fluoro-3-(iodomethyl)benzene solution, described above, was added dropwise over 0.5 hours to the hot zinc / acetic acid mixture. LC/MS showed that all of the starting benzyl iodide had been consumed and the required product had formed; retention time 2.63 minutes on standard gradient. The reaction mixture was allowed to cool to room temperature and filtered. The filtrate was extracted twice with pentane. The pentane was concentrated on a rotary evaporator with the bath at 40 ⁰ C but no vacuum applied to give the title compound (1.6 g; contains ca 10% acetonitrile by NMR).

¹ H NMR δ( _C Dci3): 2.34 (3H, d), 6.92 (IH, t), 7.24 - 7.30 (IH, m).

EXAMPLE 2 This Example illustrates the preparation of l,2-dichloro-4-fluoro-3-methylbenzene.

a) 1 ,2-Dichloro-4-fluoro-3-(bromomethyl)benzene 2,3-Dichloro-6-fluorophenyl)methanol (14.2 g) was dissolved in a solution of hydrogen bromide in acetic acid (140 mL) and the mixture was heated at 80 ⁰ C for 10 minutes. LC/MS showed that all of the starting material had been consumed and a new peak, corresponding to the required benzyl bromide, was visible; retention time 2.58 minutes on standard gradient. The reaction mixture was allowed to cool to room temperature.

b) l,2-dichloro-4-fluoro-3-methylbenzene

Powdered zinc (23.8 g) was added to acetonitrile (50 mL) and glacial acetic acid

(50 mL) and the suspension was heated, under nitrogen, to 80 ⁰ C. The reaction mixture containing l,2-dichloro-4-fluoro-3-(bromomethyl)benzene in acetic acid containing hydrogen bromide, described above, was added dropwise to the hot zinc / acetic acid mixture over approximately 1 hour. LC/MS showed that the desired product had formed; retention time 2.63 minutes on standard gradient. The reaction mixture was allowed to cool to room temperature then filtered to remove the zinc. The filtrate was extracted with pentane (six times) and the solvent was removed on a rotary evaporator with the water bath at 40 ⁰ C and no vacuum to give the title compound (10.4 g).

¹ H NMR δ ₍ cDci3): 2.34 (3H, d), 6.92 (IH, t), 7.24 - 7.30 (IH, m).