WO2007083090A2

WO2007083090A2 - Process for the preparation of uracil derivatives

Info

Publication number: WO2007083090A2
Application number: PCT/GB2007/000095
Authority: WO
Inventors: Renaud Beaudegnies; Jérôme Cassayre; Brian David Gott; David Anthony Jackson; Christoph Lüthy; Laura Quaranta; Thomas Vettiger; Jean Wenger; Martin Zeller
Original assignee: Syngenta Limited; Syngenta Participations Ag
Priority date: 2006-01-17
Filing date: 2007-01-15
Publication date: 2007-07-26
Also published as: WO2007083090A3; GB0600914D0

Abstract

A process of making a compound of formula (I); the process comprising reacting a compound of formula (II); with a compound of formula (III) in which R1 is Cl to C3 alkyl or Cl to C3 haloalkyl, R2 is Cl to C3 alkyl, X1 and X2 are halogen R3 is a C 1-6 alkanoic acid 1-6 alkyl ester residue R4 is C 1-6 straight or branched-chain alkyl, such as methyl, ethyl, propyl or butyl, preferably ethyl.

Description

Process

The present invention relates to processes for making certain uracil compounds, to novel intermediates for use in the process and to processes for making certain of these intermediates.

United States Patent US 6 537 948 discloses certain uracil compounds that are useful as herbicides. This patent discloses various processes by which these compounds can be made, but each of these processes suffers from one or more of the disadvantages of low yield, difficult reaction conditions, unwelcome levels of by-products or costly starting materials.

The present invention provides a convenient and simple process for making certain of these uracil compounds that avoids one or more of these disadvantages.

According to the present invention there is provided a process for making a compound of

Formula (I);

the process comprising reacting a compound of Formula (II);

with a compound of Formula (III) Formula (III)

in which R¹ is Cl to C3 alkyl or Cl to C3 haloalkyl. Preferably R¹ is methyl substituted with fluorine for example, trifluoromethyl, chlorodifluoromethyl, difluoromethyl or the like, or ethyl substituted with fluorine, for example, pentafluoroethyl, 1,1-difiuoroethyl. Most preferably R₁ is trifluoromethyl.

R² is Cl to C3 alkyl. Preferably R² is methyl or ethyl, more preferably methyl,

X¹ and X² are halogen, preferably chlorine or fluorine. Most preferably X¹ is fluorine. Most preferably X² is chlorine.

R³ is a Cl to C6 alkanoic acid Cl to C6 alkyl ester residue, in which the alkanoic acid can be for example ethanoic, propionic, pentanoic or hexanoic acid, preferably ethanoic acid, and in which the alkyl ester can be of ethanol, propanol, isopropanol, butanol, isobutanol, tertiary butanol, pentanol, isopentanol, hexanol, isohexanol, preferably ethanol. Most preferably R³ is -CH₂COOCH₂CH₃.

R₄ is Cl to C6 straight or branched-chain alkyl, such as methyl, ethyl, propyl or butyl, preferably ethyl .

The reaction can be carried out in a solvent. Preferably the solvent is a polar aprotic solvent, such as acetonitrile, tetrahydromran, dioxane, dimethylformamide, N- methylpyrrolidone or dimethylsulphoxide. Preferred solvents are tetrahydrofuran or acetonitrile, particularly tetrahydrofuran. The reaction can be carried out at a temperature of -30°C to 5O⁰C. The reaction can be carried out in two temperature steps, the first at -10 to 5°C and the second at 5 to 4O⁰C,. Preferably, the lower temperature first stage is carried out in less than 1 hour, and the second higher temperature stage for less than 6 hours

The reaction is preferably carried out in the presence of a base, for example sodium hydroxide, potassium hydroxide, sodium or potassium hydride, or a metal alkoxide. Hindered metal alkoxides are preferred, particularly potassium tertiary butoxide. The reaction can be carried out batchwise or as a continuous process.

The compound of Formula (II) can be made by reacting a compound of Formula (IV);

with COCl₂ (phosgene), diphosgene or triphosgene; in which X¹, X² and R³, including their preferred embodiments, are all as defined above with reference to the compound of Formula (I)

The reaction with phosgene can be carried out in a solvent. Suitable solvents are ester solvents such as Cl to C6 alkyl esters of Cl to C6 alkanoic acids, for example ethyl acetate, butyl acetate; or hydrocarbon solvents, such as xylene or toluene; or halogenated hydrocarbons such as dichloroethane, chlorobenzene or fluorobenzene. Ester solvents are preferred, particularly ethyl acetate.

The reaction can be carried out at a temperature of 0 to 130°C. The reaction can be carried out in two temperature stages, the first at 0 to 10⁰C, typically for between 2 and 4 hours and the second at 70 to 130⁰C, typically for between 30 minutes and 2 hours. Preferably 0.1 to 5 molar equivalents excess phosgene is used.

The compound of Formula (IV) can be made by the selective reduction of a compound of Formula (V);

in which X¹, X² and R³, including their preferred embodiments, are all as defined above with reference to the compound of Formula (I)

The selective reduction can be carried out by typical nitro reducing systems. Suitable reducing systems include; hydrogen with a supported metal catalyst, dissolving metal such as iron with acetic acid or aqueous acid, transfer hydrogenation using formate or hydrazine and a catalyst A preferred reducing system uses hydrogen with a supported metal catalyst. Preferred metals include nickel, palladium and platinum. The reaction can be carried out in a solvent. Suitable solvents are ester solvents such as Cl to C6 alkyl esters of Cl to C6 alkanoic acids, for example ethyl acetate, butyl acetate; or hydrocarbon solvents, such as xylene or toluene; or alcohols. Ester solvents are preferred, particularly ethyl acetate.

The reduction can be carried out at 10-δ0°C for between 30 minutes and 12 hours.

The compound of Formula (V) can be made by the selective nitration of a compound of Formula (VI) ;

The selective nitration can be carried out using nitric acid or a mixture of nitric acid and aqueous or anhydrous sulphuric acid. Preferably 50 to 100% concentrated nitric acid is used, in preferably 95 to 100% concentrated sulphuric acid.

Compound (VI) can be dissolved in sulphuric acid, and nitric acid can be added while the mixture is preferably held at -20 to +20°C, more preferably -10 to +5°C. The nitric acid can be added over a period of 15 minutes to 2 hours, and may be diluted with sulphuric acid.

The compound of formula (VI) can be made by a selective replacement reaction on a compound of formula (VII) with a halogen X¹.

In which X² and R³, including their preferred embodiments, are as defined above with reference to the compound of formula (I) The selective replacement reaction can be carried out by conversion of the amino group to a diazonium salt. For example the tetra fiuorborate salt. The salt can then be heated in an inert hydrocarbon solvent at 80-150⁰C. Examples of suitable solvents include xylene and toluene. Alternatively, the diazonium salt can be treated with hydrogen fluoride. The compounds of formula (VII) can be made by the selective reduction of a compound of formula (VIII)

The selective reduction can be carried out by typical nitro reducing systems. Suitable reducing systems include; hydrogen with a supported metal catalyst, dissolving metal such as iron with acetic acid or aqueous acid, transfer hydrogenation using formate or hydrazine and a catalyst A preferred reducing system uses hydrogen with a supported metal catalyst. Preferred metals include nickel, palladium and platinum. The reaction can be carried out in a solvent. Suitable solvents are ester solvents such as Cl to C6 alkyl esters of Cl to C6 alkanoic acids, for example ethyl acetate, butyl acetate; or hydrocarbon solvents, such as xylene or toluene; or alcohols. Ester solvents^' are preferred, particularly ethyl acetate.

The reduction can be carried out at 10-80⁰C for between 30 minutes and 12 hours. Compounds of formula (VIII) can be made by the reaction of a compound of formula (IX)

Formula (IX)

with a compound of formula (XIII) which is described below,in which X², including its preferred embodiments, are as defined above with reference to the compound of formula

(I)₅ in which X³ is a leaving group, such as halogen, preferably chlorine. The reaction can be carried out by mixing compounds of formula (IX) and (XIII) in the presence of a base and optionally a solvent. Preferably a dipolar aprotic solvent. More preferably; acetonitrile and N,N-dimethylformamide. Preferably the reaction is heated to 40400⁰C. .

Compound (IX) is available from Aldrich.

Alternatively, compounds of formula (VI) can be made by the selective halogenation of a compound of formula (X)

In which X¹, X² and R³, including their preferred embodiments, are as defined above with reference to the compound of formula (I).

The selective halogenation can be carried out by conversion of the amino group to a diazonium salt with in the presence of a source of chloride such as copper (I) or copper (II) chloride salts. Diazotisation can be carried out using a nitrite source such as nitrous acid, nitrosyl sulphuric acid or an alkylnitrite in a suitable solvent. Examples of suitable solvents include acetic acid, water, acetonitrile.

Compounds of formula (X) can be made by selective reduction of a compound of formula (XI);

In which X¹ and R³, including their preferred embodiments, are as defined above with reference to the compound of formula (I). The selective reduction can be carried out by typical nitro reducing systems. Suitable reducing systems include; hydrogen with a supported metal catalyst, dissolving metal such as iron with acetic acid or aqueous acid, transfer hydrogenation using formate or hydrazine and a catalyst A preferred reducing system uses hydrogen with a supported metal catalyst. Preferred metals include nickel, palladium and platinum. The reaction can be carried out in a solvent. Suitable solvents are ester solvents such as Cl to C6 alkyl esters of Cl to C6 alkanoic acids, for example ethyl acetate, butyl acetate; or hydrocarbon solvents, such as xylene or toluene; or alcohols. Ester solvents are preferred, particularly ethyl acetate.

The reduction can be carried out at 10-80°C for between 30 minutes and 12 hours. Compounds of formula (XI) can be made by reaction of a compound of formula (XII)

Formula (XII)

with a compound of formula (XIII) Formula (XIII)

In which R³ and X¹, including their preferred embodiments, are as defined above with reference to the compound of formula (I). X⁴ is a leaving group, preferably halogen, more preferably fluorine or bromine. Most preferably the compound of formula (XII) is 2,5-difluoronitrobenzene.

The reaction can be carried out by mixing compounds of formula (XII) and (XIII) in the presence of a base, such as sodium or potassium carbonate or sodium or potassium alkoxides, and optionally a solvent. Preferably a dipolar aprotic solvent. More preferably; acetonitrile and N,N-dimethylformamide. Preferably the reaction is heated to 40-100⁰C.

Compounds of formula (XIII) can be made by reacting a compound of formula (XIV);

Formula (XIV)

with a compound of formula ;

N₂R³ hi which R³, including its preferred embodiments, is as defined above with reference to the compound of formula (I). Compounds of formula N₂R³ are commercially available from Aldrich. Preferably it is ethyl diazoacetate.

The reaction can be carried out by mixing (XIV) and N₂R³ in the absence or presence of a suitable catalyst in an inert solvent. Suitable catalysts are rhodium II compounds, lewis acids for example boron or aluminium halides and Broensted acids. Preferred catalysts are dirhodium tri(fluoroacetate), boron trifluoride and trifluoromethyl sulphonic acid. Suitable solvents are hydrocarbons, such as toluene, xylene, halohydrocarbons such as fluorobenzene, chlorobenzene or dichloroethane.

The reaction can be carried out at a temperature of 20 to 130°C, preferably 40 to 100°C, for 1 to 20 hours, preferably 2 to 10 hours Compound of formula (XIV) is commercially available from Aldrich., Alternatively,

Compound of Formula (XIV) can be made from a compound of formula (XV) as described by Petersen, John Brammer; Lei, Joergen; Clauson-Kaas, Niels; Norris, Kjeld,

Matematisk-Fysiske Meddelelser - Kongelige Danske Videnskabernes Selskab (1967), 36(5), 23 pp.

( 7 ^0 Formula (XV) ^NL-0

Compound of formula (XV) is commercially available from Aldrich. Compounds of formula (XII) are commercially available from Aldrich. Compounds of formula (XII) can also be made by the selective nitration of a compound of formula (XVI);

Formula (XVI)

Compounds of formula (XVI) are available from Aldrich. Alternatively compounds of Formula (VI) can be made by reaction of a compound of Formula (XVII);

with a compound of formula N₂R³.

In which X¹, X² and R³, including their preferred embodiments, are all as defined above with reference to the compound of formula (I). The reaction can be carried out in the presence of a catalyst Suitable catalysts are rhodium II compounds, lewis acids for example boron or aluminium halides and Broensted acids. Preferred catalysts are dirhodium tri(fiuoroacetate), boron trifmoride and trifluoromethyl sulphonic acid.

The reaction can be carried out in the presence of a solvent. Suitable solvents are hydrocarbons, such as toluene, xylene, halohydrocarbons such as fluorobenzene, chlorobenzene or dichloroethane.

The reaction can be carried out at a temperature of 20 to 100°C, preferably 40 to 100°C, for 1 to 20 hours, preferably 2 to 10 hours.

Compounds of formula N₂R³ are commercially available from Aldrich. Preferably it is ethyl diazoacetate.

It is also recognised that the compound of formula (V) can be made by the following alternative sequence. Compound of formula (XVII) is selectively nitrated, using standard methods described earlier, to prepare a compound of formula (XXV), which then reacts with a compound of the formula N₂R³ to give compound of formula (V).

The compound of Formula (XVII) can be made by the reaction of compound of Formula (XVIII)

(XVIII)

With 1,13,3 methoxypropane.

In which X¹ and X² including their preferred embodiments, are as defined above with reference to the compound of Formula (I) The reaction can be carried out in the presence of an acid catalyst such as hydrogen bromide in acetic acid or sulphuric acid.

The reaction is preferably carried out at a temperature of 15 to 9O⁰C, more preferably 20 to 7O⁰C, for between 1 and 10 hours, more preferably 2 to 6 hours.

The compound of Formula (XVIII) can be made by reaction of a compound of formula (XIX) Formula (XIX)

With 2-chloroacetoacetaniide (CH₃.CO.CHC1.CO.NH₂ ), in which X¹ and X² including their preferred embodiments, are as defined above with reference to the compound of Formula (I). The reaction can be carried out in a solvent. Preferred solvents are toluene, acetonitrile, dioxane, t-butyl methyl ether, acetone, methyl isobutyl ketone, 1,2-dimethoxyethane and dimethylformamide of which t-butyl methyl ether, 1,2-dimethoxyethane and methyl isobutyl ketone are preferred.

The reaction can be carried out at a temperature of 30 to 100⁰C, preferably 60 to 90°C, for 3 to 24 hours, preferably 5 to 18 hours.

The reaction is preferably carried out in the presence of a base catalyst. Examples of base catalysts are sodium or potassium salts of hydroxides, carbonates, hydrogencarbonates, alkoxides or tertiary amines, alkaline earth oxides. A preferred catalyst is potassium carbonate. 2-Chloroacetoacetamide is prepared by procedures described in J. Org. Chem., (1978), 43, 3821-3824.

Compounds of Formula (XIX) are commercially available from Aldrich.. Their preparation is reported, for example in J.Am.Chem.Soc. (1959) ,8_1 94-101, or in German patent DE 3 507 960 (Ube 1985), or in European Patent EP 417 720 (1991). Alternatively, the compound of formula (XVII) can be made by hydrolysis of a compound of formula (XXI)

In which X and X including their preferred embodiments, are as defined above with reference to the compound of formula (I) and in which R⁵ is Cl-6 alkyl, preferably methyl or ethyl.

The compound of formula (XXI) can be made by the rearrangement of a compound of formula (XXII)

OCOFT

Formula (XXII)

In which X¹ and X² including their preferred embodiments, are as defined above with reference to the compound of formula (I)₃ and R⁵ is as defined above with reference to Formula (XXI)

The compound of formula (XXII) can be made by the addition of an alkanoic acid anhydride to a compound of formula (XXIII)

In which X¹ and X² including their preferred embodiments, are as defined above with reference to the compound of formula (I).

The steps of making a compound of formula (XVII) from a compound of formula (XXIII) can be carried out in a single reaction mixture without isolating the intermediate compounds.

The compound of formula (XXIII) can be made by the oxidation of a compound of formula (XXIV)

Formula (XXIV)

In which X¹ and X² including their preferred embodiments, are as defined above with reference to the compound of formula (I)

The oxidation can be carried out by treatment of compound (XXIV) with an oxidising agent. Examples of suitable oxidising agents include peracetic acid, m-chloroperbenzoic acid and hydrogen peroxide. The compound of formula (XXIV) can be made by the reaction of a compound of formula (XIX) with 3-halo-pyridine, particularly 3-chloropyridine and 3-bromopyridine.

The reaction can be carried out by heating compounds of formula (XIX) with 3-halo- pyridine in a dipolar aprotic solvent containing a suitable base and catalyst. Solvents include N,N-dimethylformamide, N₅N-dimethylacetamide, N-methylprrolidone, and acetonitrile. Suitable bases include sodium and potassium carbonate, sodium or potassium hydroxide, alkalie metal alkoxides and tertiary amines. Suitable catalysts are transition metals and their salts. For example copper and palladium. The reaction temperature can be 100-160⁰C. Preferred conditions use N,N-dimethylacetamide and potassium carbonate at 130-160⁰C.

Certain of the intermediates in these processes are novel. Accordingly the present invention provides compounds of formula (V), particularly in which X¹ is F, X² is Cl and R³ is -CH₂COOCH₂CH₃, Formula (VI), particularly in which X¹ is F and X² is Cl and R³ is -CH₂COOCH₂CH₃, Formula (VII), particularly in which X¹ is NH₂, X² is Cl and R³ is -CH₂COOCH₂CH₃, Formula (VIII), particularly in which X¹ is NO₂, X² is Cl and R³ is -CH₂COOCH₂CH₃, Formula (X), particularly in which X¹ is F, X² is NH₂, and R³ is -CH₂COOCH₂CH₃ Formula (XI), particularly in which X¹ is F, X² is NO₂ and R³ is -CH₂COOCH₂CH₃ Formula (XVIII), particularly in which X¹ is F and X² is Cl, Formula (XXIII), particularly in which X¹ is F and X² is Cl, Formula (XXIV), particularly in which X¹ is F and X² is Cl, all as defined above. The Invention will now be illustrated by the following examples; EXAMPLES

1. (3-Hydroxy-pyridin-2-yIoxy)-acetic acid ethyl ester

This reaction produces a compound of Formula (XIII) from a compound of Formula (XIV).

The 2,3-dihydroxypyridine was charged to a clean/dry reactor followed by 1,2- dichloroethane. The mixture was agitated and heated to 85°C and the boron trifluoride etherate (3.3gm) in 1,2-dichloroethane (lOgm) was then charged to the slurry. Ethyl diazoacetate (31.1gm) in dichloroethane (32gm) was then slowly charged to the slurry over ~5hrs. The reaction mass was sampled for GC analysis then agitated overnight and allowed to cool. The following day the reaction mass was filtered to remove the excess 2,3-dihydroxypyridine. The resultant filtrates were then washed with 15% sulphuric acid (66.6gm) for 30 minutes then separated. The organic phase was then washed with sodium bicarbonate solution (50ml) and separated. The organic phase was then removed on a rotary evaporator at 45°C to give a brown viscous oil (43.3gm) which solidified on standing. The crude oil was distilled, at 169°C and 4 mbar, to give a clear colourless product.

¹H NMR rCDCM: 1.08-1.17 (t, 3H), 4.15-4.32 (q, 2H), 4.89-5.02 (s, 2H), 6.23-6.44 (br s, IH, OH), 6.76-6.92 (q, IH, aryl), 7.11-7.23 (q, IH, aryl), 7.55-7.71 (q, IH, aryl). 2. Preparation of [3-(2-ChIoro-4-nitro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (VIII) from a compound of Formula (IX).

The (3-Hydroxy-pyridin-2-yloxy)-acetic acid ethyl ester was charged to a clean/dry reactor followed by dry DMF and the mixture stirred under nitrogen. Then 3,4- dichloronitrobenzene was charged followed by the anhydrous potassium carbonate. The slurry was heated to 50°C and agitated for 64 hours on temperature. The reaction was worked up by the addition of water (100ml) and extracted with ether (2 x 75ml and 2 x 100ml and 1 x 500ml). The ether phases were combined, washed with brine (100ml) and topped to produce a pale fawn/brown flaky solid (30.5gm).

¹H NMR (CDCl₁): 1.19-1.33 (t, 3H), 4.09-4.30 (q, 2H), 4.83-4.95 (s, 2H), 6.81-6.98 (d, IH, aryl), 6.99-7.11 (q, IH, aryl), 7.40-7.58 (q, IH, aryl), 7.97-8.14 (m, 2H, aryl), 8.26- 8.44 (d, IH, aryl).

3. Preparation of [3-(4-Amino-2-chloro-phenoxy)-pyridm-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (VII) from a compound of Formula (VIlI).

Palladium on carbon catalyst (0.4gm) was charged to ethyl acetate (20ml) in a 300ml pressure reactor configured for hydrogen reductions. The [3-(2-Chloro-4-nitro-phenoxy)- pyridin-2-yloxy]-acetic acid ethyl ester dissolved in ethyl acetate (100ml) was fed over 2 hours to the pressure reactor under hydrogen at 2-10 barg pressure. The pressure reactor was then agitated for a further 80 minutes before purging with nitrogen and relieving the pressure. The Pd/C catalyst was filtered off and the resultant ethyl acetate solution was removed under reduced pressure to give a solid (5.6gm).

¹H NMR rCDCl₂): 1.14-1.38 (m, 3H), 3.42-4.07 (br s, 2H, NH₂), 4.15-4.37 (m, 2H), 4.93-5.14 (s, 2H), 6.49-6.60 (m, IH, aryl), 6.84-6.94 (m, 2H, aryl), 7.71-7.82 (d, IH, aryl).

4. Preparation of [3-(2-Chloro-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (VI) from a compound of Formula (VII).

Preparation of tetrafluoroborate salt of the amine - To a 50 ml 3-necked round-bottomed flask equipped with a magnetic flea, teflon thermometer and air condenser was charged [3-(4-amino-2-chloro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester (4g) and then acetic acid (12ml). To the resulting solution mixture was charged tetrafluoroboric acid (1.5ml) keeping the temperature below 18°C during the addition. Isoamyl nitrite (1.7ml) was then charged slowly to the reaction mixture below 18°C. Precipitation was observed shortly after addition of nitrite was completed. After 1/2 hour, significant precipitation hindered agitation and at this point ethyl acetate (16ml) and diethyl ether (8ml) were added and the crude product was filtered and washed with diethyl ether (4 x 15ml). The product was dried under suction for 3 hours. Crude product was an off-white precipitate.

The tetrafluoroborate salt was heated in xylene in a glass reactor at 137-140°C at reflux for 2 hours. The mixture was then agitated and allowed to cool overnight. The reaction mixture was then worked up by decanting the xylene solution from the tar at the base of the reactor. The xylene solution was then washed with saturated sodium carbonate. Separated and dried with anhydrous sodium sulphate. The solvent was evaporated to give a crude brown product oil (l.lgm), and the tar was weighed (3.6gm).

Tetrafluorb orate salt:

¹H NMR TdO-DMSQ^: 1.03-1.24 (m, 3H), 4.03-4.21 (m, 2H), 4.88-5.00 (s, 2H), 7.15- 7.35 (m, 2H₅ aryl), 7.89-8.03 (m, IH, aryl), 8.12-8.28 (m, IH, aryl), 8.55-8.71 (m, IH, aryl), 8.94-9.10 (m, IH, aryl)

19F NMR fd6-DMSC0: -148.7 to -148.63 r3-f2-Chloro-4-fluoro-phenoxy)-pyridin-2-yloxy1-acetic acid ethyl ester:

¹H NMR (CDCl₃): 1.23-1.62 (m, 3H), 4.18-4.26 (m, 2H), 4.95-4.97 (s, 2H), 6.85-6.690 (m, IH, aryl), 6.90-6.93 (m, IH, aryl), 6.96-6.98 (m,lH, aryl), 7.06-7.10 (m, IH, aryl), 7.18-7.23 (m, IH, aryl), 7.80-7.89 (m, IH, aryl)

5. [3-(4-FIuoro-2-nitro-phenoxy)-pyridin-2-yIoxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (XI) from a compound of Formula (XII).

The reagents were agitated together under an inert atmosphere at 74-78⁰C for approximately 14 hours. The cooled reaction mass was diluted with water (12Og) and extracted with ethyl acetate. The combined extracts were dried over sodium sulphate and evaporated to dryness to a dark brown gum (6.3g). The predominant component was identified as [3-(4-Fluoro-2-nitro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester.

¹H NMR fCDCk): 1.25 (t, 3H), 4.2 (q, 2H), 4.9 (s 2H), 7.0, 7.1, 7.3, 7.4, 7.7, 8.0 each (br, s, IH, total 6H).

6. [3-(2-Amino-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (X) from a compound of Formula (XI).

To the iron, acetic acid and water at 4O⁰C was added drop wise over 30 minutes a solution of [3-(4-fluoro-2-nitro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester in acetic acid (16ml). After stirring at 40-45⁰C for 2 hours and overnight at ambient temperature, the mixture was diluted with ethyl acetate and washed with 20% brine and 5% sodium bicarbonate solution. The organic phase was dried over sodium sulphate and evaporated to a dark brown oil 4.5g, that contained 70-80% of [3-(2-amino-4-fluoro- phenoxy)-pyridin-2-yloxy] -acetic acid ethyl ester.

¹H NMR (CDCl₁ ^'): 1.3 (t, 3H), 4.2 (q, 2H), 4.0-4.5 (br sH), 5.0 (s 2H), 6.4, 6.5, 7.1, 7.8 each (br, s, IH, total 4H), 6.8-6.9 (m, 2H).

7. [3-(2-Chloro-4-fluoro-phenoxy)-pyridin-2-yIoxy]-acetic acid ethyl ester This reaction produces a compound of Formula (VI) from a compound of Formula (X).

[3-(2-Amino-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester, acetonitrile and copper chloride were stirred together at room temperature. A solution of isopentylnitrite in acetonitrile (3ml) was added drop wise over 10 minutes. A slight exotherm and gas evolution were observed. Afer stirring for 3 hours at ambient temperature the reaction mass was filtered and washed through with ethyl acetate. The organic mixture was washed with 25% aqueous ammonia and saturated brine, dried over sodium sulphate and evaporated to dryness. The residue was a black oil 4. Ig, containing ca. 60% of [3-(2- chloro-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester.

¹H NMR rCPClO: 1.3 (t, 3H), 4.2(q, 2H), 5.0 (s, 2H), 6.8-7.0 (m, 3H), 7.1 (m, IH), 7.2 (m, IH), 7.9 (m, IH).

8. [3-(2-Chloro-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (VI) from a compound of Formula (X).

[3-(2-Amino-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester in acetic acid (20ml) with concentrated hydrochloric acid (ImI) was cooled to 5⁰C. A solution of sodium nitrite in water (5ml) was added drop wise. After stirring at O⁰C for 1 hour, the copper salts were added with concentrated hydrochloric acid (2ml) in acetic acid (10ml). The mixture was allowed to warm to ambient over 90 minutes. The mixture was diluted with water (5Og) and 5% sodium bicarbonate solution (25Og), extracted with toluene, dried over sodium sulphate and evaporated to dryness. The residue was a black oil 3.5 g, containing ca. 60% of [3-(2-chloro-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester.

¹H NMR rCPCl₁): 1.3 (t, 3H), 4.2(q, 2H), 5.0 (s, 2H), 6.8-7.0 (m, 3H), 7.1 (m, IH), 7.2 (m, IH), 7.9 (m, IH). 9. 2-(2-Chloro-4-fluoro-phenoxy)-3-oxo-butyramide

This reaction produces a compound of Formula (XVIII) from a compound of Formula (XIX)

The 2-chloro-4-fluorophenol, TBME and potassium carbonate were charged to a reactor and heated to 55⁰C. 2-Chloroacetoacetamide was added. After stirring over night the mixture was cooled, acidified with aq.-HCl, diluted with water and filtered. The solid product 2-(2-chloro-4-fluoro-phenoxy)-3-oxo-butyramide, was washed well with water. Yield 60%.

'H NMR fdfi-DMSOV 2.3 (s, 3H), 5.3, ( s, 2H), 7.0 (br, IH), 7.1-7.2 (m, IH), 7.5 (br, IH), 7.1-7.3 (br, d, 2H).

10. 3-(2-Chloro-4-fluoro-phenoxy)-pyridin-2-ol

This reaction produces a compound of Formula (XVII) from a compound of Formula

(XVIII)

HBr in Acetic acid was added at room temperature to a stirred mixture of 2-(2-chloro-4- fluoro-phenoxy)-3-oxo~butyrarnide, acetic acid and TMP. After 1 hour the mixture was heated to 5O⁰C. After a further 2 hours the solvent was evaporated under reduced pressure, diluted with chloroform and washed with water and sodium hydrogencarbonate solution. The organic phase was evaporated and the residue crystallised from toluene/methanol to give 3-(2-chloro-4-fluoro-phenoxy)-pyridin-2-ol (5.5g).

¹H NMR fCDCU: 6.2 (br t, IH), 6.7 (d, IH), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H), 13.5 (br, IH).

11. [3-(2-Chloro-4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (VI) from a compound of Formula

(XVII)

To a mixture of 3-(2-chloro-4-fluoro-phenoxy)-pyridin-2-ol and boron trifluoride etherate and ehlorobenzene was added ethyl diazoac etate. The mixture was heated at 5O⁰C for 4 hours. The cooled reaction mixture was washed with aqueous sulphuric acid, dried and evaporated to dryness to give [3-(2-chloro-4-fluoro-phenoxy)-pyridin-2- yloxyj-acetic acid ethyl ester.

¹H NMR CCDCI₁): 1.3 (t, 3H), 4.2(q, 2H), 5.0 (s, 2H), 6.8-7.0 (m, 3H), 7.1 (m, IH), 7.2 (m, IH), 7.9 (m, IH).

12. [3-(2-Chloro-4-fluoro-5-nitro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (V) from a compound of Formula (VI)

The [3-(2-chloro-4-fluoro-phenoxy)-pyridm-2-yloxy]-acetic acid ethyl ester was dissolved in sulphuric acid (98%) and cooled to 0-5⁰C. Nitric acid (65% by weight aqueous solution) was added over 30 minutes maintaining the temperature <10°C. After stirring for 2 hours the mixture was poured on to ice and extracted with ethyl acetate. The organic solution was evaporated to dryness to give [3-(2-Chloro-4-fluoro-5-nitro- phenoxy)-pyridin-2-yloxy] -acetic acid ethyl ester.

¹H NAlR (CDCM: 1.2 (t, 3H), 4.2 (q, 2H), 4.9 (s, 2H), 7.0-7.1 (dd, IH), 7.4-7.5 (m, 2H), 7.5 (d, IH), 8.0 (dd, IH). It is preferred to minimise the contact between aqueous acid adduct and product, and to keep the temperature <10°C, in order to avoid hydrolysis of the ester group. In an alternative work-up, the nitration reaction mass can be thrown into ice/water, or ice/water/ethanol, and the product crystallises and can be filtered. Any carboxylic acid formed can be readily re-esterifϊed by heating in ethanol in the presence of a catalytic quantity of an appropriate acid, e.g. sulphuric acid. 13. [3-(5-Amino-2-chloro~4-fluoro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (IV) from a compound of Formula (V)

A solution of [3-(2-chloro-4-fluoro-5-nitro-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester in ethyl acetate was added over 45 minutes to the suspension of iron powder in aqueous acetic acid at 5O⁰C. After stirring for 1 hour the mixture was cooled to 25⁰C, diluted with water and extracted with ethyl acetate. The organic phase was dried and evaporated to give [3-(5-amino-2-chloro-4-fluoro-phenoxy)-pyridin-2-yloxy] -acetic acid ethyl ester.

'H NMR Cdg-DMSO): 1.2 (t, 3H), 4.1 (q, 2H), 4.9 (s, 2H)₅ 5.4 (br s, 2H), 6.4 (m, IH), 7.0(m, IH), 7.2-7.3 (m, 2H), 7.9 (m, IH).

14. [3-(2-Chloro-4-fluoro-5-isocyanato-phenoxy)-pyridin-2-yIoxy]-acetic acid ethyl ester

This reaction produces a compound of Formula (II) from a compound of Formula (IV).

To a solution of phosgene in ethyl acetate at 0-5⁰C, was added a solution of [3-(5-amino- 2-chloro-4-fiuoro-phenoxy)-pyridin-2-yloxy] -acetic acid ethyl ester in ethyl acetate. The mixture was maintained at 0-10⁰C for 3 hours and then heated to 9O⁰C. Argon was blown through for 1 hour and then the mixture was cooled to 25°C. The solvent was evaporated to give [3-(2-chloro-4-fluoro-5-isocyanato-phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester.

¹H NM[R (CD₁CN): 1.2 (t, 3H)₃ 4.2 (q, 2H), 4.9 (s, 2H), 6.8 (d, IH), 7.0 (dd, IH), 7.3 (dd, IH), 7.4 (d, IH), 7.9 (dd, IH).

15. {S-P-Chloro^-fluoro-S-CS-methyl-l^-dioxo-^trifluoromethyl-Sjo-dihydro- 2H-pyrimidin-l-yI)-phenoxy]-pyridin-2~yloxy}~acetic acid ethyl ester

This reaction produces a compound of Formula (I) from a compound of Formula (II).

To (Z)-4,4,4-trifluoro-3-methylamino-but-2-enoic acid ethyl ester in THF is added at 0- 5⁰C potassium tert-butoxide. After 30 minutes the [3-(2-chloro-4-fluoro-5-isocyanato- phenoxy)-pyridin-2-yloxy]-acetic acid ethyl ester was added. After stirring at 0-5⁰C for 1 hour, the mixture was warmed to 23⁰C. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate and washed with 10% aq.-acetic acid. The organic phase was dried and evaporated to give {3-[2-chloro-4-fluoro-5-(3-methyl- 2,6-dioxo-4-trifluoromethyl-3,6-dihydro-2H-pyrimidm-l-yl)-phenoxy]-pyridin-2- yloxy} -acetic acid ethyl ester which was recrystallised from ethanol.

¹H NMR rCDCl₁): 1.2 (t, 3H), 3.5 (br s, 3H), 4.2 (q, 2H), 4.9, (q, 2H), 6.3 (s, IH), 6.9- 7.0 (m, 2H), 7.3-7.5 (m, 2H), 7.9 (m, IH). 16. 3-(2-Chloro-4-fluoro-phenoxy)-pyridine

This reaction produces a compound of Formula (XXIV) from a compound of Formula (XDC).

2-Chloro-4-fluoro-phenol and 3-Bromo-pyridine were dissolved in DMA. Solid Potassium carbonate and copper(I)oxide were added in one portion. The in homogeneous reaction mixture was stirred at 155-160 ⁰C for 7-8 h. After cooling to room temperature the mixture was filtered through Hyflo and evaporated (80 °C / 10 mbar). The crude product was distilled (b.p. 110 °C /0.7 mbar). Yield 60%.

¹H NMR f CDCU): 7.0-7.3 (m, 5H), 8.3-8.4 (m, 2H).

17. 3-(2-ChIoro-4-fluoro-phenoxy)-pyridine 1-oxide

This reaction produces a compound of Formula (XXIII) from a compound of Formula (XXW).

0

A mixture of 3-(2-chloro-4-fluoro-phenoxy)-pyridine and hydrogenperoxide urea adduct in acetonitrile was cooled to 0-5 ⁰C. Trifluoracetic anhydride was added during 1-2 h. The reaction mixture was warmed and stirred at room temperature for 2 h. The reaction mixture was added to water (100 g) containing sodium thiosulfate. The mixture was 5 filtered through Hyflo and extracted with dichloromethane (3 x 60 g). The organic phase was evaporated and the residue crystallised from toluene to give 3-(2-chloro-4-fluoro- phenoxy)-pyridine 1-oxide in 50% yield.

¹H NMR (CDCl₁): 6.8 (br s, IH), 7.0-7.3 (m, 4H), 7.9 (s, IH), 8.0 (br s, IH). 0 18. 3-(2-ChIoro-4-fluoro-phenoxy)-pyridin-2~ol

This reaction produces a compound of Formula (XVII) from a compound of Formula (XXHI).

10

3-(2-chloro-4-fluoro-phenoxy)-pyridine 1 -oxide in acetic anhydride was held at for 4 h. Evaporation to dryness gave an oily residue that was taken into 37% hydrochloric acid and held at reflux (104 °C) for 2 h. After cooling the mixture was extracted with

15 dichloromethane. The organic phases are washed with sodium bicarbonate and evaporated. The residue was crystallised from toluene to give 3-(2-chloro-4-fluoro- phenoxy)-pyridin-2-ol in 61% yield.

¹H NMR (CDCM: 6.2 (br t, IH), 6.7 (d, IH), 7.0-7.1 (m, 2H), 7.2-7.3 (m, 2H), 13.5 (br, 20 IH).

Claims

1. A process of making a compound of formula (I);

the process comprising reacting a compound of formula (II);

with a compound of formula (III)

Formula (III)

in which R¹ is Cl to C3 alkyl or Cl to C3 haloalkyl, R² is Cl to C3 alkyl, X¹ and X² are halogen R₃ is a C 1-6 alkanoic acid 1-6 alkyl ester residue

R₄ is C 1-6 straight or branched-chain alkyl, such as methyl, ethyl, propyl or butyl, preferably ethyl.

2. A process as claimed in claim 1 in which R₁ is trifluoromethyl.

3. A process as claimed in claims 1 or 2 in which R² is methyl or ethyl

4. A Process as claimed in claim 3 in which R² is methyl.

5. A process as claimed in claims 1 to 4 in which X¹ is fluorine and X² is chlorine.

6. A Process as claimed in claims 1 to 5 in which R₃ is -CH₂COOCH₂CH₃.

7. A process as claimed in claims 1 to 6 in which the compound of formula (II) is made by reacting a compound of formula (IV);

with phosgene, diphosgene or triphosgene.

8. A process as claimed in claim 7 in which the compound of formula (IV) is made by selective reduction of a compound of formula (V);

9. A process as claimed in claim 8 in which the compound of formula (V) is made by selective nitration of a compound of Formula (VI) ;

10. A process as claimed in claim 9 in which the compound of formula (VI) is made by selective halogenation of a compound of formula (X)

11. A process as claimed in claim 10 in which the compound of formula (X) is made by selective reduction of a compound of formula (XI)

12. A process as claimed in claim 11 in which the compound of formula (XI) is made by the reaction of compound of formula (XIII) with 2,5-difluoronitrobenzene

13. A process as claimed in claim 12 in which the compound of formula (XHT) is made by the reaction of compound of formula (XIV) with an alkyl diazoacetate, especially ethyl diazoacetate.

14. A compound of formula (X) in which R is -Cl-Cβ-alkyl, -alkyl-COO-alkyl, or - CO.alkyl, X¹ Is F, Cl or Br.

15. A compound of formula (XI) in which R is -Cl-C6-alkyl, -alkyl-COO-alkyl, or - CO.alkyl, X¹ is F, Cl or Br.

16. A process as claimed in claim 9 in which the compound of formula (VI) is made by reaction of a compound of formula (XVII);

with a compound of formula N₂R³.

17. A process as claimed in claim 16 in which the compound of formula (XVII) is made by the reaction of compound of formula (XVIII)

(XVIII)

With 1,1,3,3 methoxypropane.

18. A process as claimed in claim 17 in which the compound of formula (XVIII) is made by reaction of a compound of formula (XIX) with 2-chloroacetoacetamide (CH3.CO.CHCl.CO.NH₂),

Formula (IX)

19. A compound of formula (V), particularly in which X¹ is F, X² is Cl and R³ is - Cl- C6-alkyl, or -CO.alkyl or -CO.-Oalkyl, or CH₂COOH, or CH₂COOCH₂CH₃,

20. A compound of Formula (VI), particularly in which X¹ is F and X² is Cl and R³ is Cl-C6-alkyl, or-CO.alkyl or -CO.-Oalkyl, or CH₂COOH, or CH₂COOCH₂CH₃

21. A compound of Formula (XVIII), particularly in which X¹ is F and X² is Cl,

(XVIII)

22. A process as claimed in claim 16 in which the compound of formula (XVII) is made by hydrolysis of compound- of formula (XXI)

23. A process as claimed in claim 22 in which the compound of formula (XXI) is made by rearrangenment of a compound of formula (XXII)

24. A process as claimed in claim 23 in which the compound of formula (XXII) is made by the addition of an alkanoic acid anhydride to a compound of formula (XXIII)

(XXIII)

25. A process as claimed in claim 24 in which the compound of formula (XXIII) is made by oxidation of a compound of formula (XXIV)

Formula (XXIV)

26. A process as claimed in claim 25 in which the compound of formula (XXIV) is made by the reaction of compound of formula (XIX) and 3-halopyridine.

27. A compound of formula (XXIII) in which X¹ and X² are halogen.

28. A compound of formula (XXIV) in which X¹ and X² are halogen.

29. A process as claimed in claim 9 in which the compound of formula (VI) is made by the reaction on a compound of formula (VII)

30. A process as claimed in claim 29 in which the compound of formula (VII) is made by the reaction of compound of formula (VIII)

31. A process as claimed in claim 30 in which the compound of formula (VIII) is made by the reaction of compound of formula (XIII) with 3,4 -dichloronitrobenzene

32. A compound of formula (VII).

33. A compound of formula (VIII).