Chemical process

Abstract

The present invention provides, inter alia, a process for preparing a compound of formula (I) wherein the process is as defined in claim 1.

Description

[0001]CHEMICAL PROCESS The present invention relates to a novel process for the synthesis of 2-(2-methoxyethoxymethyl)-6- (trifluoromethyl)pyridine-3-carbonyl chloride (a compound of formula (I)). This compound is a useful intermediate in the synthesis of the herbicidal compound bicyclopyrone (a compound of formula (IV)). The synthesis of 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride is known, see for example WO 01 / 94339, comprising the reaction of 2-methoxyethoxymethyl)-6- (trifluoromethyl)pyridine-3-carboxylic acid with oxalyl chloride in the presence of a catalytic amount of dimethylformamide (DMF). A similar process is also disclosed in WO 00 / 39094. Processes for the synthesis of a compound of formula (IV) are disclosed in WO 2005 / 105718 and WO 2005 / 105745. The use of DMF as a catalyst for the formation of 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine- 3-carbonyl chloride has the serious disadvantage of the formation of undesirable residues (particularly in the form of tars) in the reaction vessel. This means that there is a requirement to use a filter and extensively wash the reactor with excess solvent to avoid an accumulation of tars in between process batches, making the known process unfavourable for large scale production. Thus, there is the need for a new, more efficient synthesis method that also reduces the accumulation of tars and avoids the use of a filter and / or excess solvent washes. Surprisingly, we have now found that the present invention provides a process for the synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride which (i) reduces the accumulation of tars in the reaction vessel (ii) provides an improved yield over the known processes and (iii) increases the rate of reaction. Such a more efficient and sustainable process can be used to deliver the desired compound of formula (I) which in turn can be converted to bicyclopyrone or derivatives thereof. Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I), said process comprising: reacting a compound of formula (II), with a chlorinating reagent in the presence of a compound of formula (III), wherein R1is C1-C10alkyl or C3-C6cycloalkyl and R2is C2-C10alkyl or C3-C6cycloalkyl; to give a compound of formula (I). According to a second aspect of the invention, there is provided a composition comprising a compound of formula (I) (I), and a compound of formula (VII), In a third aspect of the invention, there is provided a composition comprising a compound of formula (IV), and a compound of formula (III), wherein R1and R2are as defined herein. As used herein, the term "C1-C10alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms, and which is attached to the rest of the molecule by a single bond. C2-C10alkyl, C1-C4alkyl and C2-C4alkyl are to be construed accordingly. Examples of C1-C10alkyl include, but are not limited to, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, and 1-dimethylethyl (t-butyl). As used herein, the term "C3-C6cycloalkyl" refers to a stable, monocyclic ring radical which is saturated and contains 3 to 6 carbon atoms. Examples of C3-C6cycloalkyl include, but are not limited to, cyclopropyl, cyclopentyl and cyclohexyl. As used herein, the term "chlorinating reagent" refers to any chemical reagent capable of introducing a chlorine atom in the target molecule by forming a carbon-chlorine bond. The following list provides definitions, including preferred definitions, for substituents R1and R2with reference to the process according to the invention. For any one of these substituents, any of the definitions given below may be combined with any definition of any other substituent given below or elsewhere in this document. R1is C1-C10alkyl or C3-C6cycloalkyl. Preferably, R1is C1-C10alkyl. More preferably, R1is C1-C6alkyl. Even more preferably, R1is C1-C4alkyl. Even more preferably still, R1is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl. Yet even more preferably still, R1is selected from the group consisting of ethyl, n-propyl, iso-propyl and n-butyl. Yet even further more preferably still, R1is selected from the group consisting of ethyl, n-propyl, and n-butyl. Most preferably, R1is n-butyl. R2is C2-C10alkyl or C3-C6cycloalkyl. Preferably, R2is C2-C10alkyl. More preferably, R2is C2-C6alkyl. Even more preferably, R2is C2-C4alkyl. Even more preferably still, R2is selected from the group consisting of ethyl, n-propyl, iso-propyl and n-butyl. Yet even more preferably still, R2is selected from the group consisting of ethyl, n-propyl and n-butyl. Most preferably, R2is n-butyl. In one embodiment R1and R2are each independently selected from the group consisting of ethyl, n- propyl, iso-propyl and n-butyl. Preferably, R1and R2are each independently selected from the group consisting of ethyl, n-propyl and n-butyl. More preferably, R1and R2are each independently selected from n-propyl or n-butyl. Most preferably, R1and R2are n-butyl. Schemes 1 to 3 below describes the reactions of the invention in more detail. The substituent definitions are as defined herein. Scheme 1: Typically, the process described in Scheme 1 may be carried out in the absence of additional solvent or in the presence of a solvent, or mixture of solvents. These include but are not limited to aliphatic, alicyclic and aromatic hydrocarbons such as but not limited to, hexane, heptane, octane, dodecane, cyclohexane, methylcyclohexane, decalin, benzene, methoxybenzene (anisole), toluene, xylene (including xylene iso-mix, p-xylene, o-xylene and m-xylene), ethylbenzene, cumene, isopropylbenzene, mesitylene; halogenated hydrocarbons such as chlorobenzene, dichlorobenzene, dichloromethane, chloroform, carbon tetrachloride, dichloroethane and trichloroethane; heteroaromatic solvents such as pyridine or a substituted pyridine, for example, 2,6-dimethylpyridine; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, tert-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, dimethoxymethane, dimethoxyethane, diethoxymethane, dipropoxy methane, 1,3-dioxolane and 1,4- dioxane; esters, such as methyl acetate, ethyl acetate, isopropyl acetate and dimethyl carbonate; nitriles, such as acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1,4- dicyanobenzene); and sulphones such as sulfolane. Preferably the process described in Scheme 1 is carried out in a solvent or mixture of solvents selected from the group consisting of toluene, xylene (including xylene iso-mix, p-xylene, o-xylene and m-xylene) cumene, isopropylbenzene, mesitylene, nitrobenzene and ethylbenzene. Most preferably, the solvent is xylene (including xylene iso-mix, p- xylene, o-xylene and m-xylene). Preferably, the chlorinating reagent in the process described in Scheme 1 is selected from the group consisting of oxalyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene and thionyl chloride. More preferably, the chlorinating reagent is selected from the group consisting of oxalyl chloride, phosgene, diphosgene, triphosgene and thionyl chloride. Even more preferably, the chlorinating reagent is selected from the group consisting of oxalyl chloride, phosgene, diphosgene and triphosgene. Even more preferably still, the chlorinating reagent is selected from the group consisting of phosgene, diphosgene and triphosgene Most preferably, the chlorinating reagent is phosgene. Typically, at least one (preferably, more than one) equivalent of chlorinating reagent is used based on a compound of formula (II). Preferably, from 1 to 3 equivalents of chlorinating reagent are used based on a compound of formula (II). More preferably, from 1.1 to 2 equivalents of chlorinating reagent are used based on a compound of formula (II). Even more preferably, from 1.1 to 1.8 equivalents of chlorinating reagent are used based on a compound of formula (II). Yet even more preferably, from 1.1 to 1.6 equivalents of chlorinating reagent are used based on a compound of formula (II). Yet even more preferably still, from 1.1 to 1.4 equivalents of chlorinating reagent are used based on a compound of formula (II). Typically, the chlorinating reagent may be added in any number of alternative ways, such as, but not limited to, a single charge, multiple charges over a period of time and / or continuously over a period of time. Preferably, the chlorinating reagent is added continuously over a period of time. In one embodiment the chlorinating reagent is added over a period of from 0.25 to 8 hours. More preferably, the chlorinating reagent is added over a period of from 0.5 to 5 hours. Even more preferably, the chlorinating reagent is added over a period of from 2 to 4 hours. The skilled person will appreciate that the period of time over which the chlorinating reagent is added will be dependent upon a number of different factors, such as, the scale of the reaction, the temperature of the reaction, the stirring speed, the wt% concentration of a compound of formula (II) and / or the wt% concentration the compound of formula (III) and the capacity to vent the generated off gases. Typically, the compound of formula (III) is present in a sub-stoichiometric amount. Preferably, the compound of formula (III) is present in an amount of from 0.01 mol% to 40 mol% based on a compound of formula (II). More preferably, the compound of formula (III) is present in an amount of from 0.1 mol% to 20 mol% based on a compound of formula (II). Even more preferably, the compound of formula (III) is present in an amount of from 0.5 mol% to 5 mol% based on a compound of formula (II). Typically, the process described in Scheme 1 can be carried out at a temperature of from 0 ºC to 120 ºC, preferably, from 5 °C to 70 °C, more preferably from from 20 °C to 50 °C. The skilled person would appreciate that the temperature of the process according to the invention can vary and this variability in temperature may also reflect the choice of solvent used. Typically, the process of the present invention is carried out under an atmosphere that excludes air and water. Preferably, the process of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. Scheme 2: 0-110°C The compound of formula (I) may be converted to a compound of formula (VI) via an esterification described in Scheme 2. Typically the esterification process described in Scheme 2 may be carried out in the presence of a solvent, or mixture of solvents, such as but not limited to a halogenated hydrocarbon, for example dichloromethane, a nitrile for example acetonitrile, or an aromatic hydrocarbon, for example toluene or xylene (including xylene iso-mix, p-xylene, o-xylene and m-xylene), and in the presence of a base, such as but not limited to an alkylamine, for example triethylamine, an aromatic amine, for example pyridine or 4-dimethylaminopyridine (DMAP). Typically, the process described in Scheme 2 can be carried out at a temperature of from 0 ºC to 110 ºC, preferably, from 0 °C to 25 °C, more preferably from from 0 °C to 10 °C. The skilled person would appreciate that the temperature of the process according to the invention can vary and this variability in temperature may also reflect the choice of solvent used. Scheme 3: Solvent e.g CH CN or xy (VI)3 lene (IV)The compound of formula (VI) may be converted to a compound of formula (IV) via an isomerisation process described in Scheme 3. The isomerisation described in Scheme 3 of the ester derivative of formula (VI) to a compound of formula (IV) (bicyclopyrone) can be carried out, for example, in the presence of a base such as an alkylamine, for example triethylamine, a carbonate, for example potassium carbonate, and a catalytic amount of DMAP or a source of cyanide, such as acetone cyanohydrin or potassium cyanide. Typically, the process described in Scheme 3 may be carried out in the presence of a solvent, or mixture of solvents, such as but not limited to a halogenated hydrocarbon, for example dichloromethane, a nitrile for example acetonitrile, or an aromatic hydrocarbon, for example toluene or xylene (including xylene iso-mix, p-xylene, o-xylene and m-xylene). Typically, the process described in Scheme 3 can be carried out at a temperature of from 0 ºC to 110 ºC, preferably, from 20 °C to 100 °C, more preferably from from 30 °C to 80 °C. The skilled person would appreciate that the temperature of the process according to the invention can vary and this variability in temperature may also reflect the choice of solvent used. In a preferred embodiment there is provided a process for the preparation of a compound of formula (I), said process comprising: reacting a compound of formula (II), with a chlorinating reagent selected from the group consisting of oxalyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene and thionyl chloride (preferably, oxalyl chloride, phosgene, diphosgene, triphosgene and thionyl chloride) in the presence of a compound of formula (III), wherein R1is C1-C6alkyl (preferably, R1is C1-C4alkyl) and R2is C2-C6alkyl (preferably, R2is C2-C4alkyl); to give a compound of formula (I). More preferably, there is provided a process for the preparation of a compound of formula (I), said process comprising: reacting a compound of formula (II), (II) with a chlorinating reagent selected from the group consisting of oxalyl chloride, phosgene, diphosgene and triphosgene (preferably, phosgene, diphosgene and triphosgene) in the presence of a compound of formula (III), wherein R1is C1-C4alkyl (preferably, methyl, ethyl, n-propyl, iso-propyl or n-butyl) and R2is C2-C4alkyl (preferably, ethyl, n-propyl, iso-propyl or n-butyl); and wherein the compound of formula (III) is present in an amount of from 0.01 mol% to 40 mol% based on a compound of formula (II); to give a compound of formula (I). Even more preferably, there is provided a process for the preparation of a compound of formula (I), said process comprising: reacting a compound of formula (II), with a chlorinating reagent selected from the group consisting of phosgene, diphosgene and triphosgene (preferably, phosgene) in the presence of a compound of formula (III), wherein R1is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl (preferably, ethyl, n-propyl and n-butyl) and R2is selected from the group consisting of ethyl, n-propyl, iso-propyl and n-butyl (preferably, ethyl, n-propyl and n-butyl); and wherein the compound of formula (III) is present in an amount of from 0.01 mol% to 20 mol% (preferably, 0.5 mol% to 5 mol%) based on a compound of formula (II) and the process is carried out in a solvent or mixture of solvents selected from the group consisting of toluene, xylene, cumene, isopropylbenzene, mesitylene, nitrobenzene and ethylbenzene; to give a compound of formula (I). In a further embodiment of the invention the process further comprises converting a compound of formula (I) to a compound of formula (IV) or a tautomer or a salt thereof, via the intermediate (VI), (VI). In a further embodiment of the invention the process further comprises converting a compound of formula (I) to a compound of formula (IV) or a tautomer or a salt thereof, wherein the conversion is performed by reacting a compound of formula (V) or a tautomer thereof or a salt thereof, with a compound of formula (I), to give a compound of formula (VI), followed by subsequent reaction to a compound of formula (IV) or a tautomer thereof or a salt thereof (preferably, wherein the process further comprises the steps as described on page 37 of WO 01 / 94339). Preferably, the process further comprises converting a compound of formula (I) to a compound of formula (IV) or a tautomer or a salt thereof, wherein the conversion is performed by reacting a compound of formula (V) or a tautomer thereof or a salt thereof, with a compound of formula (I), in the presence of a base (preferably, triethylamine) to give a compound of formula (VI), followed by a subsequent isomerisation reaction in the presence of a base and a catalytic amount (preferably, from 0.1 to 20 mol %) of dimethylaminopyridine (DMAP) or a source of cyanide (preferably, acetone cyanohydrin or potassium cyanide) to a compound of formula (IV) or a tautomer thereof or a salt thereof. The skilled person would appreciate that the process of converting a compound of formula (II) to a compound of formula (IV) can be carried out in separate process steps, wherein the intermediate compounds (a compound of formula (I) and / or a compound of formula (VI)) can be isolated at each stage. Alternatively, the process of converting a compound of formula (II) to a compound of formula (IV) can be carried out in a telescoped procedure wherein the intermediate compounds produced are not isolated. Thus, it is possible for the process of the present invention to be conducted in a batch wise, semi-batch wise or continuous fashion. The compound of formula (V) is a commercially available material and the compound of formula (II) can be prepared via the methods described in WO 01 / 094339 and WO 2004 / 078729. In a further embodiment of the invention there is also provided a composition comprising a compound of formula (I) (I), and a compound of formula (VII), (VII). Preferably, there is provided a composition comprising a compound of formula (I) (I), and a compound of formula (VII), wherein the composition comprises less than 1 % w / w (preferably less than 0.5 % w / w) of a compound of formula (VII). The skilled person will appreciate that the compound of formula (VII) may also exist as the compound of formula (VIII) under aqueous conditions (either under aqueous acidic or basic conditions) as shown below, The present invention for compositions comprising a compound of formula (I) and a compound of formula (VII) is intended to include a compound of formula (VIII) and mixtures thereof in all proportions. In another embodiment of the invention there is provided a composition comprising a compound of formula (IV) and a compound of formula (III), (III) wherein R1and R2are as defined herein. In a further emdodiment of the invention there is provided a composition comprising a compound of formula (IV), and a compound of formula (III), wherein R1and R2are as defined herein. Preferably, R1and R2are each independently selected from the group consisting of ethyl, n-propyl, iso-propyl and n-butyl. More preferably, R1and R2are each independently selected from the group consisting of ethyl, n-propyl and n-butyl. Even more preferably, R1and R2are each independently selected from n-propyl or n-butyl. Most preferably, R1and R2are n- butyl. Examples: The following examples further illustrate, but do not limit the invention. Those skilled in the art will promptly recognise appropriate variations from the procedures both as to the reactants and as to the reaction conditions and techniques. The following abbreviations are used: s = singlet; br s = broad singlet; d = doublet; dd = double doublet; dt = double triplet; t = triplet, tt = triple triplet, q = quartet, quin = quintuplet, sept = septet; m = multiplet; GC = gas chromatography, RT = retention time, Ti = internal temperature, MH+= molecular mass of the molecular cation, M = molar, Q1HNMR = quantitative1HNMR, RT = room temperature1H NMR spectra are recorded at either 300 MHz or 400 MHz and chemical shifts are recorded in ppm. Throughout this description, temperatures are given in degrees Celsius and “m.p.” means melting point. LC / MS means Liquid Chromatography Mass Spectroscopy and the description of the apparatus, and the methods is as described below. LC / MS analysis was perfomed on the methyl ester derivatives and the samples were derivatised using MeOH. The compounds found in the examples were characterized by coupled High Performance Liquid Chromatography with mass spectrometry (HPLC / MS) or by Nuclear Magnetic Resonance (NMR). Method A: Analytical HPLC column 1: Nucleodur C18 Gravity (from Macherey-Nagel, Germany). Elution water + 0.1% v / v TFA, methanol in a ratio from 70:30 to 10:90 to 70:30 in 17 min at 25 °C. MS-method: APCI positive Method B: NMR spectra were recorded on a Bruker Avance spectrometer. The chemical shifts ( ^) are given in parts per million (ppm) relative to CDCl3 (7.28 ppm for1H), and DMSO-d6 (2.51 ppm for1H). Comparative Example C1 – N,N-dimethylformamide (DMF) as a catalyst In a double jacketed 1L reactor, under N2 atmosphere, a 44.6% o-xylene solution of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (489 g, 0.78 mol, 1.0 eq.) was diluted with dry o-xylene (171 g) to reach a final concentration of 33% w / w. The reaction was heated to 30 °C and DMF (1.7 g, 0.02 mol, 0.03 eq.) was added in one portion while stirring, then phosgene (132 g, 1.34 mol, 1.72 eq.) was introduced over a period of 3 h. The dark-brown mixture was stirred for an additional 2 h until full conversion of 2-methoxyethoxymethyl)- 6-(trifluoromethyl)pyridine-3-carboxylic acid was reached. The excess of phosgene and residual gases were removed by bubbling nitrogen through the solution for 30 min, and by further distilling at 40 °C slowly lowering the pressure to 10 mbar. A total of 158 g were distilled out of the reactor and the desired 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride (505 g, 0.75 mol) was obtained as a 43.9% w / w dark-brown solution in o-xylene in 95.4% yield.1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1, 1H), 7.76 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.77 – 3.70 (m, 2H), 3.62 – 3.56 (m, 2H), 3.38 (s, 3H). LC-MS m / z [M+MeOH]+294; tR = 8.06 min. Example 1 - N,N-diethylformamide (DEF) as a catalyst In a double jacketed 1L reactor, under N2 atmosphere, a 39% o-xylene solution of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (358 g, 0.50 mol, 1.0 eq.) was diluted with dry o-xylene (66 g) to reach a final concentration of 33% w / w. The reaction was heated to 30 °C and DEF (1.5 g, 0.015 mol, 0.03 eq.) was added in one portion while stirring, then phosgene (92 g, 0.93 mol, 1.87 eq.) was introduced over a period of 3h 40 mins. The dark-brown mixture was stirred for an additional 40 min until full conversion of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid was reached. The excess of phosgene and residual gases were removed by bubbling nitrogen through the solution for 30 min, and by further distilling at 40 °C slowly lowering the pressure to 10 mbar. A total of 57 g were distilled out of the reactor and the desired 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride (368 g, 0.49 mol) was obtained as a 39% w / w dark-brown solution in o-xylene with 98% yield.1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1, 1H), 7.76 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.77 – 3.70 (m, 2H), 3.62 – 3.56 (m, 2H), 3.38 (s, 3H). LC-MS m / z [M+MeOH]+294; tR = 8.06 min. Example 2 – N,N-dibutylformamide (DBF) as a catalyst In a double jacketed 1L reactor, under N2 atmosphere, a 41% o-xylene solution of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (542 g, 0.8 mol, 1.0 eq.) was diluted with dry o-xylene (96 g) to reach a final concentration of 35% w / w. The reaction was heated to 35 °C and DBF (3.8 g, 0.02 mol, 0.03 eq.) was added in one portion while stirring, then phosgene (106 g, 1.07 mol, 1.34 eq.) was introduced over 3 h. The dark-brown mixture was stirred for an additional 2 h until full conversion of 2-methoxyethoxymethyl)- 6-(trifluoromethyl)pyridine-3-carboxylic acid was reached. The excess of phosgene and residual gases were removed by bubbling nitrogen through the solution for 30 min, and by further distilling at 40 °C slowly lowering the pressure to 10 mbar. A total of 87 g were distilled out of the reactor and the desired 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride (560 g, 0.77 mol) was obtained as a 41% w / w dark-brown solution in o-xylene with 96.5% yield.1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1, 1H), 7.76 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.77 – 3.70 (m, 2H), 3.62 – 3.56 (m, 2H), 3.38 (s, 3H). LC-MS m / z [M+MeOH]+294; tR = 8.06 min. Example 3 – N,N-diisopropylformamide (DIF) as a catalyst In a double jacketed 1L reactor, under N2 atmosphere, a 40.3% o-xylene solution of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (208 g, 0.30 mol, 1.0 eq.) was diluted with dry o-xylene (46 g) to reach a final concentration of 33% w / w. The reaction was heated to 30 °C and DIF (1.2 g, 0.009 mol, 0.03 eq.) was added in one portion while stirring, then phosgene (50 g, 0.50 mol, 1.68 eq.) was introduced over a period of 3h 20 mins. The dark-brown mixture was stirred for an additional 40 min until full conversion of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid was reached. The excess of phosgene and residual gases were removed by bubbling nitrogen through the solution for 30 min, and by further distilling at 40 °C slowly lowering the pressure to 10 mbar. A total of 38 g were distilled out of the reactor and the desired 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride (213 g, 0.287 mol) was obtained as a 40.1% w / w dark-brown solution in o-xylene with 95.6% yield.1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1, 1H), 7.76 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.77 – 3.70 (m, 2H), 3.62 – 3.56 (m, 2H), 3.38 (s, 3H). LC-MS m / z [M+MeOH]+294; tR = 8.06 min. Example 4 – N,N-dipropylformamide (DPF) as a catalyst In a double jacketed 1L reactor, under N2 atmosphere, a 57.8% o-xylene solution of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid (145 g, 0.30 mol, 1.0 eq.) was diluted with dry o-xylene (109 g) to reach a final concentration of 33% w / w. The reaction was heated to 30 °C and DPF (1.2 g, 0.009 mol, 0.03 eq.) was added in one portion while stirring, then phosgene (50 g, 0.50 mol, 1.68 eq.) was introduced over a period of 3h 20mins. The dark-brown mixture was stirred for an additional 40 min until full conversion of 2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid was reached. The excess of phosgene and residual gases were removed by bubbling nitrogen through the solution for 30 min, and by further distilling at 40 °C slowly lowering the pressure to 10 mbar. A total of 45 g were distilled out of the reactor and the desired 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride (210 g, 0.29 mol) was obtained as a 41.2% w / w dark-brown solution in o-xylene with 96.7% yield.1H NMR (300 MHz, CDCl3) δ 8.36 (d, J = 8.1, 1H), 7.76 (d, J = 8.1 Hz, 1H), 4.95 (s, 2H), 3.77 – 3.70 (m, 2H), 3.62 – 3.56 (m, 2H), 3.38 (s, 3H). LC-MS m / z [M+MeOH]+294; tR = 8.06 min. The reactions listed in Table 1 and Table 2 below were carried out using analagous procedures to those described in examples 1 to 4 described above. Table 1: Results for the synthesis of 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DBF as a catalyst Compound Compound Compound of formula of formula of formula Entry Catalyst COCl2equiv. Temp. Yield (I) final (II) final (VII) conc. conc. (%w / w) (%w / w) (%w / w) DBF 1 0.03 1.68 30°C 96.8% 41.78 0.23 0.48 equiv. DBF 2 0.02 1.69 30°C 95.7% 41.13 0.20 0.48 equiv. Table 2: Results for the synthesis of 2-(2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DBF as a catalyst at 35 °C and 0.8 mol scale Compound of formula (I Post DBF Entry I) Reaction Yield COCl2 starting conc. Catalyst (%)atime* (m (eq.) (%w / w) ol%) 1 35 1 h 40 min 3 96.5 1.34 2 35 2 h 45 min 2.5 96.0 1.34 3 35 50 min 4.0 97.6 1.34 4 35 1 h 40 min 2.5 97.5 1.50 5 35 45 min 3 97.0 1.34+640 1 h 15 min 3 96.5 1.34 *Post Reaction Time – The time for which the reaction is stirred once the COCl2 dosage is complete.+Phosgene dosage was carried out over a period of 5 h instead of 3 h. Example 5 - Analytical data for 2-(trifluoromethyl)-7H-furo[3,4-b]pyridin-5-one (a compound of formula 1H NMR (400 MHz, DMSO) δ 8.38 (d, J = 8.0 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 4.88 (2H). Brief Description of the Drawings Figure 1a – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DMF as a catalyst (run one) Figure 1b – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DMF as a catalyst (run two) Figure 2a – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DEF as a catalyst (run one) Figure 2b – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DEF as a catalyst (run two, reactor was not washed between figure 2a and 2b) Figure 3a – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DBF as a catalyst (run one) Figure 3b – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DBF as a catalyst (run two, reactor was not washed between figure 3a and 3b) Figure 4 – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DIF as a catalyst Figure 5 – Residues (including tars) left on reaction vessel after synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride using DPF as a catalyst Figure 6 – Comparison of reaction kinetics using DBF, DIP and DPF with DMF as a catalyst showing %conversion (to a compound of formula (I)) against reaction time. For all catalysts tested in comparison with DMF (Figures 1a and 1b) a clear reduction of the tars formed in the reaction vessel was visible (Figures 2a, 2b, 3a, 3b, 4 and 5) and the absence of washes between the two runs for DEF and DBF did not visibly increase the amount of tars (Figures 2a, 2b, 3a and 3b) . DBF (Figures 3a and 3b) and DPF (Figure 5) showed little to no visible sign of tars. Table 3 below summarises what is shown pictorially by figures 1 to 5, wherein a score can be given for the visual appearance of the reactor after the synthesis of 2-(2-methoxyethoxymethyl)-6- (trifluoromethyl)pyridine-3-carbonyl chloride with 1 being the best (least amount of residue) and 5 being the worst (most amount of residue). Table 3 – Visual inspection score for residues left in the reactor after the synthesis of 2-(2- methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carbonyl chloride Catalyst Score (1 best to 5 worse) DMF 5 DEF 3 DIF 4 DPF 2 DBF 1 The reactions shown in Figure 6 were carried out using analagous procedures to those in examples 1 to 4 described above and carried out at 30°C using 1.7 equivalents of phosgene and 3 mol% (0.03 equivalents) of a compound of formula (III) (DMF, DBF, DIP or DPF) based on a compound of formula (II) (2-methoxyethoxymethyl)-6-(trifluoromethyl)pyridine-3-carboxylic acid). All controls for %conversion (to a compound of formula (I)) were analysed by standard HPLC analysis taking a sample of the reaction mixture at various times. This graph demonstrates that with comparable molar catalyst loading the reactions performed with DBF, DIP and DPF were unexpectedly faster than with DMF as a catalyst.

Claims

CLAIMS:

1. A process for the preparation of a compound of formula (I),said process comprising: reacting a compound of formula (II),with a chlorinating reagent in the presence of a compound of formula (III),wherein R1is C1-C10alkyl or C3-C6cycloalkyl and R2is C2-C10alkyl or C3-C6cycloalkyl; to give a compound of formula (I).

2. A process according to claim 1, wherein R1is C1-C6alkyl.

3. A process according to claim 1 or claim 2, wherein R1is selected from the group consisting of methyl, ethyl, n-propyl, iso-propyl and n-butyl.

4. A process according to any one of claims 1 to 3, wherein R2is C2-C6alkyl.

5. A process according to any one of claims 1 to 4, wherein R2is selected from the group consisting of ethyl, n-propyl, iso-propyl and n-butyl.

6. A process according to any one of claims 1 to 5 wherein R1is n-butyl and R2is n-butyl, 7. A process according to any one of claims 1 to 6, wherein the chlorinating reagent is selected from the group consisting of oxalyl chloride, phosphoryl chloride, phosphorus trichloride, phosphorus pentachloride, phosgene, diphosgene, triphosgene and thionyl chloride.

8. A process according to any one of claims 1 to 7, wherein the chlorinating reagent is phosgene.

9. A process according to any one of claims 1 to 8, wherein the compound of formula (III) is present in an amount of from 0.1 to 20 mol% based on a compound of formula (II).

10. A process according to any one of claims 1 to 9, wherein the compound of formula (III) is present in an amount of from 0.5 to 5 mol% based on a compound of formula (II).

11. A process according to any one of claims 1 to 10, wherein the process is carried out in a solvent or mixture of solvents selected from the group consisting of toluene, xylene, cumene, isopropylbenzene, mesitylene, nitrobenzene and ethylbenzene.

12. A process according to claim 12, wherein the solvent is xylene.

13. A process according to any one of claims 1 to 12, wherein the process further comprises converting a compound of formula (I) to a compound of formula (IV) or a tautomer thereof or a salt thereof,via the intermediate (VI),(VI).

14. A composition comprising a compound of formula (I)(I), and a compound of formula (VII),(VII).

15. A composition comprising a compound of formula (IV)and a compound of formula (III),(III) wherein R1and R2are as defined in any one of claims 1 to 6.

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