WO1995019967A1

WO1995019967A1 - A process for the preparation of 3-(substituted phenyl) pyrazole derivatives

Info

Publication number: WO1995019967A1
Application number: PCT/GB1995/000039
Authority: WO
Inventors: Harjinder Singh Bansal; Susan Patricia Barnett; Ewan James Turner Chrystal; Michael Louis Rogers
Original assignee: Zeneca Limited
Priority date: 1994-01-21
Filing date: 1995-01-10
Publication date: 1995-07-27
Also published as: GB9401136D0; IL112331A0; AU1389395A

Abstract

A process for the synthesis of a herbicide of general formula (I), wherein X is halogen or cyano; Y is H, alkyl, alkenyl or alkynyl, any of which may optionally be substituted, cyano, nitro, halogen, NR?10R11, OR10, SO¿pR10, CO2R?10, CONR10R11, NR10SO¿2R?11, COR10, C(NOR10)R11, OSO¿pR?10 or NR10COR11; R1¿ is hydrogen or alkyl, alkenyl, alkynyl, benzyl, cycloalkyl or cycloalkenyl, any of which may optionally be substituted; R2 is lower haloalkoxy; and R3 is halogen; from a compound of general formula (II), wherein X and Y are as defined above and R4 is lower alkyl; comprises the steps of: (i) reacting the compound of formula (II) with a hydrazine derivative; (ii) reacting the product with a compound R9-Z where R9 is a lower haloalkyl group and Z is a leaving group in the presence of a base; and (iii) halogenating the product to give a compound of formula (I).

Description

A PROCESS FOR THE PREPARATION OF 3-(SUBSTITUTED PHENYL) PYRAZOLE DERIVATIVES

The present invention relates to a process for making herbicidal pyrazole derivatives and intermediates used in that process.

A large number of herbicidal pyrazole derivatives are described in J0372460, EP-A-361114 and US Patent No. 5,032,165. Routes for the synthesis of the pyrazole derivatives are given in these documents but the suggested synthetic routes are complex and involve many steps and could not readily be undertaken on a commercial scale.

The present invention is particularly concerned with the synthesis of compounds of general formula I: wherein X is halogen or cyano;

Y is H, alkyl, alkenyl or alkynyl, any of which may optionally be substituted, cyano, nitro, halogen, NR¹⁰R^U, OR¹⁰, SO R¹⁰, CO-R¹⁰,

C0NR¹⁰R^U, NR¹⁰S0 R^U, COR¹⁰, C(N0R¹⁰)R^U, OSO R¹⁰ or NR¹⁰C0R ;

1 "

R is hydrogen or alkyl, alkenyl, alkynyl, benzyl, cycloalkyl or cycloalkenyl , any of which may optionally be substituted; R is lower haloalkoxy; and

3 R is halogen.

Compounds of general formula I are particularly active as herbicides but their synthesis is complex and expensive which makes it difficult to produce the compounds cost effectively.

A route for the synthesis «f compounds of general formula (I) is set out in J0322660 but this route is long and involves several purification steps. The present inventors therefore set out to simplify the synthesis.

In a first aspect of the invention there is provided a process for the synthesis of a compound of general formula (I) as defined above from a compound of general formula (II) wherein X and Y are as defined above for general formula (I) and R is lower alkyl; the process comprising the steps of:

(i) reacting the compound of formula (II) with a hydrazine of formula

(VI) where R is as defined above; to produce a compound of formula (VII) where X, Y and R are as defined above;

(ii) reacting the compound of formula (VII) with a compound of g formula (VIII) where R is a lower haloalkyl group and Z is a leaving group ; in the presence of a base to produce a compound of formula (IX) where R ,

R , X and Y are as defined above; and

(iii) halogenating the compound of formula (IX) to give a compound of formula (I) .

As used herein, the term "alkyl" refers to straight or branched alkyl chains having up to 10 carbon atoms. The terms "lower" used in relation to "alkyl" means that the chains have from 1 to 4 carbon atoms.

The term "halogen" used herein includes fluorine, chlorine, bromine and iodine.

Suitable optional substituents for alkyl groups described herein include halogen such as chlorine, fluorine and bromine; haloalkyl such as trifluoromethyl; haloalkoxy such as difluoromethoxy or trifluoromethoxy; aryl such as phenyl or naphthyl; cycloalkyl, containing, for example, up to 7 ring atoms; or heterocyclyl containing, for example, up to 10 ring atoms, up to three of which are selected from oxygen, nitrogen and sulphur, such as tetrahydrofuryl . Suitable optional substituents for pyridine groups described herein include dialkyl a ino groups. Optional substituents for imidazole groups are lower alkyl groups which may be attached at the nitrogen or a carbon atom in the imidazole ring.

In the compounds of general formula (I), it is greatly preferred that both X and Y are halogen and particularly chlorine or fluorine. Most preferably X is chlorine and Y is fluorine. 2 Preferably R is a halomethoxy group in particular a dihalomethoxy group such as dichloro ethoxy or difluoromethoxy, most preferably difluoromethoxy.

3 Preferred examples of R include chlorine or fluorine, particularly chlorine.

In the compounds of general formula (II), an especially suitable group R is ethyl since this has been found to improve the yield when compounds of general formula (II) are converted to compounds of general formula (I).

The route of the process of the present invention is shown in Scheme A. In the process of the invention, the compound of formula (II) is reacted with the compound of formula (VI) to produce a compound of formula (VII). The reaction is carried out in the presence or absence of solvent, and optionally in the presence of a catalyst at temperatures of from -10 to 150°C in particular the reflux temperature of any solvent present.

Suitable solvents are those which dissolve both reactants and include

4 alcohols, in particular the alcohol corresponding to the group R in the compound of formula (II). For instance, when R is ethyl, a preferred solvent would be ethanol .

The applicants have found that, in contrast to the recommendations of the prior art, the reaction is preferably carried out in the absence of any solvent. Thus the compound of formula (II) is reacted directly with a appropriate alkylhydrazine, such as ethylhydrazine, at elevated temperature, for example at about 70 C. This modification forms a further aspect of the invention.

The compounds of formula (VII) is then reacted with a compound of formula (VIII) in the presence of a base as described in the art. Examples of suitable leaving groups include chlorine. A particularly preferred compound of formula (VIII) is chlorodifluoromethane.

The reaction is suitably effected in the presence of a solvent or mixture of solvents, in the presence or absence of a base and optionally in the presence of a catalyst at a temperature between -10°C and 100°C.

The applicants have found that this reaction is preferably undertaken as a stirred biphasic phase transfer reaction in the presence of an organic solvent and and aqueous base solution in the presence of a phase transfer catalyst, preferably at room temperature. Suitable organic solvents are not miscible with water and include chlorinated solvents, for example, dichloromethane and chloroform, aromatic solvents, for example, toluene, ethers, for example, diethyl ether and esters, for example, ethyl acetate. Dichloromethane is a preferred solvent.

Suitable phase transfer _.catalysts include tetraalkylammonium or tetraalkylphosphonium salts, in particular tetrabutylphosphonium bromide. Suitable bases are water soluble and include, but are not limited to, alkali and alkaline earth carbonates, bicarbonates and hydroxides, for example, sodium hydroxide.

In particular, the compound of formula (VII) is dissolved in an organic solvent such as dichloromethane with the phase transfer catalyst and the solution is saturated with compound of formula (VIII), usually by bubbling this compound in the form of a gas through the solution. The reaction is then initiated by the addition of an aqueous solution of base such as a 50% solution of aqueous sodium hydroxide and the mixture stirred vigorously at room temperature. This modification forms a further aspect of the invention.

Finally the compound of formula (IX) is halogenated to give the desired compound of formula (I). This may be done using conventional techniques as described in the prior art. In particular the reaction may be effected in a solvent such as halogenated hydrocarbons such as dichloromethane, chloroform and carbon tetrachloride, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate, nitriles such as acetonitrile and benzonitrile, chain-like ethers such as diethyl ether and methylcellosolve, cyclic ethers such as dioxane and tetrahydrofuran, dimethylsulphoxide and dimethylforma ide.

These solvents may be used individually, or they can be used in the form of mixtures.

A particularly preferred solvent is acetonitrile.

Suitable halogenating agents include chlorinating agents such as chlorine, phosphorus trichloride, phosphorus pentachloride and sulphuryl chloride, as well as other halogenating agents such as bromine and iodine.

The reaction temperature should be selected in the range from -30 to 150°C, preferably from 10° to 25°C which may be maintained by either the controlled addition of the chlorinating agent or cooling or both.

When acetonitrile is employed as a solvent, the reaction is effected conveniently at ambient temperature and is completed within a shorter time scale than reported hitherto, for example within about one hour. This solvent has the advantage of being environmentally very safe and available to use on an industrial scale.

Specific examples of compounds of formula (I) are contained in Table I. TABLE I

Compound X Y Mpt NMR δH

1 l F 39-41°C 3.8(3H,s); 6.7(lH,t); 7.2(2H,m);

7.5(lH,m).

2 Cl Cl Oil 3.8(3H,s); 6.7(lH,t); 7.3(2H,m);

7.5(lH,d).

3 F F Oil 3.8(3H,s); 6.7(lH,t); 6.9(2H,m);

7.5(lH,m).

The compounds of general formula (II) may be prepared in a variety of ways, some of which may be found in the literature. In particular, compounds of general formula (II) may be prepared from the reaction of a compound of formula (III); wherein X and Y are as defined above and R is a hydroxy or a leaving group; with a compound of formula (IV);

6 4 7 where R is a group R as defined above, and R is an activating group; or

R and R together form a cyclic activating group.

Reactions for the preparation of β keto esters similar to those of general formula (II) are known. In particular, reactions in which an aromatic acyl halide reacts with a compound such as Meldrum's acid or a malonate half ester salt are known in the art, for example from US 5,077,429 and papers by Guilford e_t al (J. Aoric. Food Chem.. (1992), 40, 2026-2032), Clay et al (Synthesis. (1993) 3, 290-292) and Oikawa et al (- . Pro. Chem.. (1978), 43(10), 2087-2088.

In the compound of general formula (III), suitable leaving groups R include halogen, in particular chlorine.

As used herein, the term 'activating group' means a group which increases the acidity of the hydrogen atoms on the adjacent carbon and is removable by acid catalysed hydrolysis, or by base catalysed hydrolysis, or by alcholysis.

Examples of activating groups R include carboxylic ester groups in particular alkyl ester groups, salts of carboxylate groups, nitriles and optionally N-substituted amides. In particular R is either a carboxylate

8 - 9+ ester of formula C0 R or a carboxylate salt of formula C0₉ R . Suitable p. R groups R are optionally substituted alkyl groups such as ethyl, or R together with R may be joined to form a cyclic structure. Suitable

9+ 9+ cations for R are organic or inorganic cations. Preferably R is an inorganic cation such as an alkali metal cation, suitably potassium.

Particularly preferred compounds of formula (IV) are malonate half ester salts where R is lower alkyl in particular ethyl and R is a group CO ^"R

9+ where R is an inorganic cation, in particular potassium.

Examples of cyclic activating groups include compounds where R is a g o g group of formula C0_?R and R with R together form a group -^(CH- ^- In this case, the compound of formula (IV) is Meldru 's acid.

The reaction may be carried out in the presence or absence of solvents or mixtures of solvents. Suitable solvents include chlorinated solvents such as dichloromethane, aromatic solvents such as toluene, ether solvents such as diethylether and tetrahydrofuran or nitriles such as acetonitrile. A preferred solvent is acetonitrile.

Furthermore, the reaction is carried out optionally in the presence of a base, and in the presence or absence of a nucleophilic catalyst. An inert atmosphere such as nitrogen or argon may be employed. Temperatures of from -70° to 200°C, preferably from -10° to 100°C, and most preferably from 0 to 100°C, are suitably employed. The reaction conditions which give optimal results will vary depending upon the specific nature of the compounds of formulae (III) and (IV). However the skilled chemist would be able to determine these readily.

Suitable bases for use in the reaction include inorganic bases such as alkali or alkaline earth metal hydroxides, bicarbonates, carbonates, hydrides or alcholates, in particular potassium carbonate, sodium hydroxide or sodium ethoxide. Alternatively organic bases such as tertiary amines, pyridine, optionally substituted pyridines, Hunigs base and diazobicycloundecane may be used.

Suitable nucleophilic catalysts include pyridine, substituted pyridines, imidazole, substituted i idazoles, tertiary amines such as trialkylamines and N-hydroxysuccinimide.

The reaction may also require the presence of a non basic inorganic salt. Suitable salts include but are not limited to magnesium salts, in parti cul ar magnes i um hal i des such as magnes i um chl ori de . c

When R is hydroxy, (i.e. the compound of formula (III) is a compound of formula (V)), the compound of formula (II) is preferably prepared using a base mediated reaction as described above but additionally in the presence of a dehydrating agent such as carbonyldiimidazole or a carbodiimide, for example N,N'-dicyclohexylcarbodiimide. In this reaction, preferred temperatures are from -60 to 150°C, typically from 20 to 40 C; a preferred solvent is dichloromethane and a preferred base is triethylamine. Dimethylaminopyidine is a typical nucleophilic catalyst for this reaction.

When the compound of formula (IV) is Meldrum's acid, the reaction is suitably effected in the presence of a base and in particular Hunig's base. Temperatures of from -60 to 100°C and in particular about 0°C are preferred in these circumstances, and dichloromethane is a preferred solvent.

When the compound of formula (IV) is a malonate half ester salt, in particular potassium ethyl malonate, compound (III) is typically an acid chloride (i.e. R5 is chloride).

A typical process comprises the pre-formation of a slurry of the malonate half ester salt, a magnesium salt, preferably magnesium chloride, and a base preferably triethylamine. The process is effected in an inert solvent, preferably acetonitrile, under an inert atmosphere of, for example, nitrogen, with vigorous stirring and cooling typically to about 10°C. The reaction is typically initiated by the careful addition of the compound of formula (III) to the cooled reaction mixture, usually at about 0°C. The mixture is then stirred at a temperature between 0°C to 100°C, generally at room temperature, for an extended period, conveniently overnight.

Although half ester salts such as potassium ethyl malonate are particularly useful for synthesising β-keto esters of general formula (II), there have been some disadvantages with prior art methods. In particular, it has proved necessary to use at least two different reaction solvents at different stages of the process. Clearly, this is not particularly desirable, especially if the process is to be carried out on an industrial scale, and the present inventors have now devised a route which enables the use of a single solvent. Therefore a further aspect of the present invention provides a process for preparing a compound of formula (II) wherein X is halogen or cyano;

Y is H, alkyl, alkenyl or alkynyl, any of which may optionally be substituted, cyano, nitro, halogen, NR¹⁰Rⁿ, OR¹⁰, SO R¹⁰, CO-R¹⁰ _.

C0NR¹⁰R^U, NR¹⁰S0₉R^U, COR¹⁰, C(N0R¹⁰)R^U, OSO R¹⁰ or NR¹⁰C0R ,^• and

4 R is lower alkyl; which process comprises reacting a compound of formula

5

(III) wherein X and Y are as defined above and R is a hydroxy or a leaving group; with a alonic acid half ester salt; characterised in that the reaction is carried out in a single solvent.

Suitable single solvents are those which dissolve the organic reagents and permit the continuous and efficient stirring of the suspension of inorganic salts, without the formation of an intractable mass, in a minimum solvent volume. The solvent should also allow the formation of an appropriate anion to react with compounds of general formula (III) to give the compound of general formula (II). The chosen solvent will depend upon the nature of the reactants and may be determined by the skilled chemist. Esters have been found to be particularly suitable solvents for reactions of compounds of general formula (III) with malonate half ester salts with ethyl acetate being particularly appropriate.

As mentioned above, it is particularly advantageous to use a single solvent reaction when the process is carried out on a commercial scale. Another advantage of the use of the single solvent is that the amount of inorganic reagents such as magnesium chloride may be decreased without a detrimental effect on the yield of the reaction.

Compounds of formula (III) may be readily prepared by from the corresponding acid of formula (V) by conventional techniques. For example, the acid of formula (V) is reacted with thionyl chloride or oxalyl chloride in the presence or absence of a solvent or mixture of inert solvents, in the presence or absence of a base and in the presence or absence of an inert atmosphere such as nitrogen or argon. Reactions involving thionyl chloride will often be carried out at elevated temperature, for example from 30° to 100°C, typically at the reflux temperature of any solvent which may be used. When oxalyl chloride is used, the reaction temperature will generally be between 0 and 50 C, usually room temperature. Examples of solvents which can be employed include ethers such as diethylether, or aromatics such as toluene, or chlorinated solvents such as dichloromethane, or nitriles such as acetonitrile.

The invention will now be further illustrated by way of the following examples.

EXAMPLE 1 This Example illustrates the preparation of .Compound No. 1 in Table 1. Step A

Preparation of 4-chloro-6-fluorobenzoyl chloride.

4-Chloro-6-fluorobenzoic acid (20g) was added to thionyl chloride (200cm ) and the mixture refluxed for 3 hours. After cooling excess thionyl chloride was removed under reduced pressure to afford a light brown liquid (22.4g). This material was used crude in Step B.

Alternative Step A

Preparation of 4-chloro-6-fluorobenzoyl chloride.

4-Chloro-6-fluorobenzoic acid (50g, 0.29 mol) was suspended in dichloromethane (300ml) and oxalyl chloride (29 mol, 42.20g, 0.332 mol) was added dropwise over about 45 minutes. Rapid evolution of gas occurred and the mixture was left stirring at room temperature overnight. The solvent was removed under reduced pressure to yield the product as a green oil (55g) which was used unpurified in Step B.

Step B

Preparation of Ethyl 3-(4-chloro-6-fluorophenyl)-3-oxopropionate

Potassium ethyl malonate (6.28g) was added to acetonitrile (55cm ) and the mixture cooled to 10°C under_nitrogen. Triethylamine (3.68g) and then magnesium chloride (4.25g) were added with vigorous stirring. The mixture was allowed to warm up to room temperature and stirring continued for 2 hours. The resulting slurry was cooled to 0°C and 4-chloro-6-fluorobenzoyl chloride (3.47g) added dropwise over 15 minutes, following by further addition of triethylamine (360mg) . The mixture was stirred overnight (17 hours) .

3 The acetonitrile was removed under reduced pressure. Toluene (20cm ) was added and the mixture reconcentrated under vacuum. Further toluene

3 (30cm ) was added and the mixture cooled to 10°C. An aqueous solution of 13% HCl (25cm ) was added carefully maintaining the internal temperature at

3 25°C. Ethyl acetate (100cm ) was added and the two layers separated. The organic layer was washed with an aqueous solution of 13% HCl twice and water, dried over magnesium sulphate, then filtered. The filtrate concentrated in vacuo to afford a pale orange residue. The product was isolated by column chromatography on silica gel (Merck 60) eluting with hexane : ether (2:1) to give ethyl 3-(4-chloro-6-fluorophenyl)-3- oxopropionate as a pale yellow viscous liquid (1.75g, 40%). δH (CDC1₃): 1.3(3,t); 3.95(2H,d); 4.25(2H,m); 7.2(2H,m); 7.9(lH,m).

Although this method produces the required product, it is necessary to remove the reaction solvent (acetonitrile) part way through the reaction and replace it with a second solvent (toluene).

Alternative Step B (Single Solvent Method)

Preparation of Ethyl 3-(4-chloro-6-fluorophenyl)-3-oxopropionate

Potassium ethyl malonate (719g, 24.22 mol) was added to a stirred solution of ethyl acetate (11.31) at room temperature. The solution was cooled to between 0°C and 5°C, following which triethylamine (1465ml, 10.4 mol) was added portionwise. Magnesium chloride (486g) was added rapidly to the reaction vessel and the resultant white suspension was warmed to 35°C, stirred for 6 hours and then cooled to 0°C. 4-Chloro-6-fluorobenzoyl chloride (prepared as in Step A) (565g, 2.03 mol) was dissolved in ethyl acetate (200ml) and the solution was then added slowly to the cooled suspension containing potassium ethyl malonate. A further two 100ml portions of ethyl acetate were added and then the reaction mixture was warmed to room temperature and stirred overnight, after which a thick foam had formed. The reaction mixture was then cooled to between 0°C and 5°C and 2M HCl (11) was added slowly over about 1 hour giving rise to an exotherm. 21 of 5M HCl was then added slowly to the reaction mixture over the next 1-2 hours. After stirring for a further 30 minutes, 3 litres of water was added to the reaction mixture which was then allowed to warm to room temperature. The aqueous phase was separated and extracted with ethyl acetate (2 x 41) and toluene (1 x 31). The organic phases were combined and concentrated jn. vacuo. dried (MgSO.) and the remaining solvent removed j_n vacuo to yield ethyl 3-(4-chloro-6-fluorothienyl)-3- oxopropionate which was used without further purification. δH (CDC1₃): 1.3(3,t); 3.95(2H,d); 4.25(2H,m); 7.2(2H,m); 7.9(lH,m).

This method is useful because only one solvent is used. An additional advantage is that less magnesium chloride is necessary to give optimum results than for the method of Step B.

Step C

Preparation of l-Hethyl-3-(4-chloro-6-fluorophenyl)-5-hydroxypyrazole.

Ethyl 3-(4-chloro-6-fluorophenyl)-3-oxopropionate (29.75g) and methyl hydrazine (11-03g) were heated together in EtOH (50ml) at 70°C for 4 hours. After cooling the solvent was removed in vacuo to afford an organic brown residue. Dichloromethane was added. The precipitated solid was filtered, washed with dichloromethane and dried to afford a white solid (10.18g 37%). δH (D₆ DMSO) 3.7(3H,s); 5.85(lH,d); 7.4(lH,m); 7.55(lH,m); 8.0(lH,b).

Step D

Preparation of l-Methy1-2-(4-chloro-6-fluorophenyl)-5-difluoromethoxy- pyrazole. l-Methyl-3-(4-chloro-6-fluorophenyl)-3-hydroxypyrazole (3g) was dissolved in dichloromethane (40cm ) , and tetrabutylphosphoniu bromide (1.23g) added. Chlorodifluoromethane gas was bubbled through the solution until saturated. 50% aqueous sodium hydroxide (200cm ) was added dropwise with vigorous stirring. When addition was complete the mixture was stirred at room temperature for 1 hour.

The reaction mixture was diluted with water and the two layers separated. The aqueous layer was further extracted with dichloromethane.

The dichloromethane extracts were combined, dried over magnesium sulphate and filtered. The filtrate was concentrated in vacuo and the two layers separated. The aqueous layer was further extracted with dichloromethane.

The dichloromethane extracts were combined, dried over magnesium sulphate and filtered. The filtrate was concentrated in vacuo to afford a light brown residue. The product was isolated by column chromatography on silica gel (Merck 60) eluting with hexane : ethyl acetate (2:1). (2.12g, 58%). δH (CDC1₃): 3.8(3,s); 6.3(lH,s); 6.6(lH,t); 7.15(2H,m); 7.9(lH,m). Step E

Preparation of l-Methyl-3-(4-chloro-6-fluorophenyl)-4-chloro-5-difluoro- methoxypyrazole - Compound No. 1.

1-Methyl-3-(4-chloro-6-fluorophenyl-5-difluoromethoxypyrazole (1.7g)

3 was dissolved in acetonitrile (20cm ). Sulphuryl chloride (1.4cm ) was added dropwise, maintaining the internal temperature at 25°C. When addition was complete, the mixture was stirred at room temperature for 1 hour.

The reaction mixture was poured into saturated sodium bicarbonate

3 solution and extracted with ether (3x25cm ). The ether extracts were washed with saturated sodium bicarbonate solution, water, dried over magnesium sulphate and filtered. The filtrate was concentrated in vacuo to give a pale orange viscous, residue, which solidified on standing (1.74g

91%). M.Pt: 39-41°C. δH (CDCI3): 3.8(3H.s); 6.7(lH,t); 7.2(2H,m);

7.5(lH,m).

EXAMPLE 2

Preparation of l-Hethyl-3-(4,6-dichlorophenyl)-5-hydroxypyrazyole.

Ethyl 3-(4,6-dichlorophenyl)-3-oxopropionate (6.75g 0.026mol) and methyl hydrazine (1.31g, 0.029mol) were heated together at 70°C for 3 hours. After cooling, the volatiles were removed in vacuo. The residual solid was heated with hot ethyl acetate, filtered and dried (2.76g, 44%) M.Pt 216-218°C. δH (CDC1₃): 3.5(3H,s); 5.85(lH,s); 7.35(lH,m); 7.55(lH,d); 7.7(lH,d).

EXAMPLE 3 Preparation of Methyl 3-(4-chloro-2-fluorophenyl)-3-oxopropionate.

Hunigs base (13.42g; 0.04mol), DMAP (67.5mg; 0.00052mol), and Meldrum's acid (7.46g, 0.052mol) were dissolved in CH₂C1₂ (200ml) and the solution cooled to 0°C under N₂. 4-Chloro-2-fluorobenzoyl chloride (10g, 0.052mol) in CH₂C1₂ (30ml) was added dropwise. When addition was complete the mixture was stirred for a further 1 hour at 0°C, allowed to warm up to room temperature and stirring continued for 1 hour.

The reaction, mixture was washed with dilute HCl, H₂0, brine, and dried (MgSO . The solvent was removed in vacuo and the residue taken up in MeOH (100ml). The solution was refluxed for 17 hours. The solvent was removed in vacuo and the desired compound isolated from the residue by column chromatography on silica gel eluting with hexane:diethyl ether (2:1).

Yield: 6.26g (53%);

M.Pt 64-66°C; δH (CDC1₃): 3.85(3H,s); 4.08(2H,d); 7.28(2H,m); 7.9(lH,t); ms M/Z 230 (M+EI).

CHEMICAL FORMULAE (IN DESCRIPTION)

CHEMICAL FORMULAE (IN DESCRIPTION)

SCHEME A

I)

(IX)

hσlogenαtion

(I)

Claims

1. A process for the preparation of a compound of general formula (I)

wherein

X is halogen or cyano;

Y is H, alkyl, alkenyl or alkynyl, any of which may optionally be substituted, cyano, nitro, halogen, NR¹⁰Rⁿ, OR¹⁰, SO R¹⁰, C0₉R¹⁰,

C0NR¹⁰R^U, NR¹⁰S0 R^U, COR¹⁰, C(NOR¹⁰)R^U, OSO R¹⁰ or NR¹⁰C0R ,^•

R 1 is hydrogen or alkyl, alkenyl, alkynyl, ben"zyl, cycloalkyl or cycloalkenyl , any of which may optionally be substituted;

R ,

2 i .s lower haloalkoxy; and 3 R is halogen; from a compound of general formula (II)

wherein X and Y are as defined above for formula (I) and R is lower alkyl; the process comprising the steps of:

(i) reacting the compound of formula (II) with a hydrazine of formula

(VI): R^HNH, (VI) where R ,1 is as defined above; to produce a compound of formula (VII):

where X, Y and R are as defined above;

(ii) reacting the compound of formula (VII) with a compound of formula (VIII):

R⁹-Z (VIII)

where R is a lower haloalkyl group and Z is a leaving group; in the presence of a base to produce a compound of formula (IX)

(iii) halogenating the compound of formula (IX) to a compound of formula (I).

A process as claimed in claim 1 wherein, in step (i), the compounds of formulae (VI) and (IV) are reacted together in the absence of a solvent.

3. A process as claimed in claim 1 or claim 2 wherein, in step (iii), chlorination is effected in the presence of acetonitrile as solvent,

4. A process as claimed in any one of claims 1 to 3, wherein the compound of general formula (II) is prepared by a process comprising: reacting a compound of formula (III):

ς wherein X and Y are as defined above and R is a hydroxy or a leaving group, with a compound of formula (IV):

o

,C II OR⁶ (IV)

H₂C ^R⁷

where R 6 is a group R4 as defined above, and R7 is an activating group; or R and R together form a cyclic activating group.

5. A process as claimed in claim 4, wherein the compound of general formula (IV) is Meldrum's acid or a malonic acid half ester salt.

6. A process for the preparation of a compound of general formula (IX) as defined in claim 1, the process comprising saturating a solution of the compound of formula (VII) with gaseous compound of formula (VIII) and subsequently adding base.

7. A process as claimed in any one of claims 1 to 5, wherein step (ii) is carried out by a process as claimed in claim 6.

8. A process for preparing a compound of formula (II):

wherein

X is halogen or cyano;

Y is H, alkyl, alkenyl or alkynyl, any of which may optionally be substituted, cyano, nitro, halogen, NR¹⁰R^U, OR¹⁰, SO R¹⁰, C0_?R¹⁰,

C0NR¹⁰R^U, NR¹⁰S0₉R^U, COR¹⁰, C(N0R¹⁰)R^U, 0S0_nR¹⁰ or NR¹⁰C0R ,^• and

4 "

R is lower alkyl; which process comprises reacting a compound of formula (III):

5 wherein X and Y are as defined above and R is a hydroxy or a leaving group; with a malonate half ester salt, characterised in that the reaction is carried out in a single solvent.

9. A process as claimed in claim 8, wherein the single solvent used in the reaction is an ester such as ethyl acetate.

10. A process as claimed in any one of claims 1 to 5 or 7, wherein the compound of general formula (II) is prepared by a process as claimed in claim 8 or claim 9.