Process for the preparation of intermediates for the preparation of azoxystrobin

Abstract

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

Description

[0001] CHEMICAL PROCESS

[0002] The present invention relates to a novel process for the synthesis of certain dimethoxy acetal or methoxy acrylate substituted chloropyrimidine compounds. Such compounds are useful intermediates in the synthesis of the fungicidal compound azoxystrobin (a compound of formula (Xb)).

[0003] The synthesis of dimethoxy acetal or methoxy acrylate substituted chloropyrimidine compounds is known, see for example WO 92 / 08703 and WO 98 / 07707, comprising the reaction of a benzofuranone with sodium methoxide followed by a nucleophilic aromatic substitution with a dichloropyrimidine.

[0004] Tertiary amines are known as catalysts for the nucleophilic aromatic substitutions, for example 1 ,4- diazabicyclo[2.2.2]octane (DABCO) is used to make azoxystrobin or derivatives thereof in the final step of the process, see for example WO 2006 / 114572 and WO 2008 / 043978.

[0005] Tertiary amines are also known as catalysts for the reaction of a benzofuranone with a dichloropyrimidine derivatve. EP 3 476 837 discloses a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone, dichloropyrimidine and trimethylamine. EP 3 042 896 discloses a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone, dichloropyrimidine and an azabicyclic tertiary amine including, 1 ,4- diazabicyclo[2.2.2]octane. WO 2020 / 097971 discloses a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone, dichloropyrimidine and a catalyst 2-carbonyl-1 ,4- diazabicyclo[2.2.1]heptane. WO 2020 / 212928 and WO 2020 / 212919 discloses a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone, dichloropyrimidine and the tertiary amine catalyst 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene or 1 ,5-diazabicyclo[4.3.0]non-5-ene.

[0006] WO 2013 / 026391 discloses a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone before the subsequent addition of dichloropyrimidine and 1 ,4- diazabicyclo[2.2.2]octane. CN114685376 discloses a two-step process whereby firstly sodium methoxide is added to a reaction mixture comprising a benzofuranone before, secondly, the subsequent addition of this reaction mixture to dichloropyrimidine and a catalyst, such as tetramethylethylenediamine, pentamethyldiethylenetriamine, N-methylmorpholine, N-methylpyrrolidine or 1 ,3,5-trimethyl-1 ,3,5-triazine. WO 2014 / 203270 and WO 2015 / 102016 disclose a process whereby sodium methoxide is added to a reaction mixture comprising a benzofuranone before the subsequent addition of dichloropyrimidine and the tertiary amine catalyst hexamethylenetetramine, quinuclidine, quinuclidine hydrochloride or quinuclidinol.

[0007] EP 3 770 147 discloses a process whereby 1 ,4-diazabicyclo[2.2.2]octane and dichloropyrimidine are added at the same time to a reaction mixture comprising a benzofuranone and sodium methoxide. However, these are either unsuitable for large scale production and / or have high yield losses and the need for additional purification of the product. For example, the process disclosed in WO 2013 / 026391 is particularly unsuited to large scale manufacture as the high heat released in the second step and high catalyst loading induce the exotherm to increase the temperature significantly giving rise to high levels of impurities such as those described in US 9,920,015. Thus, there is the need for a new, more efficient synthesis method utilising more favourable reaction conditions and avoiding the generation of undesirable by-products.

[0008] The present invention provides a process for the synthesis of certain methoxy acrylate or dimethoxy propanoate substituted chloro pyrimidine compounds which (i) provides an improved yield over the known processes and (ii) reduces waste by-products. Surprisingly, we have now found that an improved yield, more efficient and sustainable process to deliver the desired compound of formula (I) can be achieved in the process of the present invention which in turn can be converted to azoxystrobin or a derivative thereof.

[0009] Thus, according to the present invention there is provided a process for the preparation of a compound of formula (I), wherein,

[0010] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0011] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0012] (II) ;

[0013] (ii) subsequently adding methoxide; and,

[0014] (iii) subsequently adding a tertiary amine catalyst or salt thereof.

[0015] As used herein, the term "methoxide" refers to any metal salt with a OCH3 anion. As used herein, the term "tertiary amine" refers to tertiary amines or quaternary ammonium salts capable of releasing tertiary amines, examples include but are not limited to, trimethylamine (MesN), 1 ,4- diazobicyclo[2.2.2]octane (DABCO), 2-methyl-1 ,4-diazabicyclo[2.2.2]octane (Methyl-DABCO), 1- Azabicyclo[2.2.2]octane (quinuclidine), 3-hydroxy-1-azabicyclo[2.2.2]octane, N-methylpyrrolidine, acid salts of the above amines including, but not excluding other salts, hydrochloride, hydrobromide, hydroiodide, sulphate, bisulphate and phosphate.

[0016] As used herein, the term "catalyst" refers to any tertiary amine that is able to form a chemical intermediate in situ that facilitates a reaction and is used in sub-stoichiometric amounts based on the starting materials. At the completion of the desired reaction step, the tertiary amine is released unchanged and can then facilitate a further reaction in what is known as a catalytic cycle. The skilled person will appreciate that catalysts may also undergo reactions that cause loss of catalytic nature and, if the rate of removal is high, may need to be replenished or maintained during a reaction.

[0017] As used herein, the term "salt" in reference to the amine catalyst refers to a salt or quaternary ammonium salt capable of releasing a tertiary amine, examples include but are not limited to, trimethylammonium chloride (or other counter ions for example, bromide, iodide, sulphate, hydrogen sulphate, phosphate, acetate, propanoate,), 1 ,4-diazo[2.2.2]octane hydrochloride, (or other anions for example as above for trimethylamine), N-methylpyrrolidinium hydrochloride (and similar) or quinuclidinium hydrochloride (and similar anions).

[0018] Schemes 1 to 3 below describe the reactions of the invention in more detail. The substituent definitions are as defined herein and A represents a suitable salt (for example, but not limited to, an alkali metal such as sodium).

[0019] Scheme 1 : The compound of formula (II) (3-(Methoxymethylene)benzofuran-2-one) may react with an alkali metal methoxide (for example, but not limited to, sodium methoxide) and methanol to form the phenolate compound of formula (Illa) which in turn can interconvert in the presence of a proton donor (for example, but not limited to methanol) to methyl 2-(2-hydroxyphenyl)-3,3-dimethoxy-propanoate the compound of formula (III), which is further referred to herein as the ‘hydroxy acetal’. Elimination of methanol from a compound of formula (III) can further yield methyl 2-(2-hydroxyphenyl)-3-methoxy-prop-2-enoate, a compound of formula (IV), which may be described herein as the ‘hydroxy acrylate’. The compound of formula (IV) can further interconvert to a compound of formula (IVa), which may be described herein as the ‘hydroxy acrylate anion’.

[0020] Scheme 2:

[0021] The compound of formula (Illa) may react with 4,6-dichloropyrimidine to form the desired product, methyl 2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3,3-dimethoxy-propanoate, a compound of formula (la).

[0022] Scheme 3:

[0023] The compound of formula (IVa) may react with 4,6-dichloropyrimidine to also form the desired product, methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate, a compound of formula (lb).

[0024] The skilled person would appreciate that for example, the compounds of formula (lb) (II), (IV), (IVa) and (Xb) may exist as E and / or Z isomers. Moreover, the individual isomers, may inverconvert in solid state, in solution, or under exposure to light. This invention covers processes to prepare all such isomers and mixtures thereof in all proportions. Where a crossed bond is shown, for example, compounds of formula (II), (IV) and (IVa), the skilled person would appreciate that this indicates an unspecified mixture of E / Z isomers. As such the skilled person would also appreciate that a compound of formula (II) could be drawn as a compound of formula (Ila) or a compound of formula (lib) below:

[0025] Step (i) of the process:

[0026] 4,6-dichloropyrimidine may be combined with the compound of formula (II), in any number of alternative ways. For example (but not limited to) the 4,6-dichloropyrimidine can be added to the compound of formula (II) or the compound of formula (II) can be added to the 4,6- dichloropyrimidine. Typically, the 4,6-dichloropyrimidine is added in the form of a solution, melt or a solid to the compound of formula (II) in a solvent.

[0027] The process described in step (i) can be carried out in the presence of a solvent or mixture of solvents, such as but not limited to, methanol, tert-butanol, tetrahydrofuran, 2-methyltetrahydrofuran, tert- butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, methyl acetate, ethyl acetate, n- propyl acetate, / so-propyl acetate, n-butyl acetate, / so-butyl acetate, tert-butyl acetate, dimethoxymethane, diethoxymethane, dipropoxy methane, 1 ,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, / V, / V-dimethylformamide, / V, / V-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1 ,4- dicyanobenzene), 1 ,4-dioxane, sulfolane, toluene, xylene / so-mix, cumene, isopropylbenzene, p-xylene, mesitylene, nitrobenzene, o-xylene, m-xylene, ethylbenzene, hexane, heptane, cyclohexane, methylcyclohexane, methyl formate, ethyl formate, n-propyl formate, / so-propyl formate, n-butyl formate, / so-butyl formate or tert-butyl formate.

[0028] In a preferred embodiment, the process described in step (i) is carried out in the presence of a solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate.. Preferably, the process described in step (i) is carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate. Most preferably, the process described in step (i) is carried out in methyl formate.

[0029] Typically, the 4,6-dichloropyrimidine is present in an amount of from 1 to 1.5 equivalents based on a compound of formula (II). Preferably, the 4,6-dichloropyrimidine is present in an amount of from 1.1 to 1.4 equivalents based on a compound of formula (II). More preferably, the 4,6-dichloropyrimidine is present in an amount of from 1.1 to 1.2 equivalents based on a compound of formula (II).

[0030] Step (ii) of the process:

[0031] Typically, the methoxide is added as a solution in methanol (for example, but not limited to, a 30 wt% solution of sodium methoxide). Preferably, the methoxide is an alkali metal methoxide. More preferably, the alkali metal methoxide is sodium methoxide or potassium methoxide, most preferably, sodium methoxide.

[0032] The methoxide 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 methoxide is added continuously over a period of time.

[0033] Typically, the methoxide addition is controlled such that the concentration of methoxide in solution is kept low to avoid the formation of undesirable by-products, for example (but not limited to) the methoxide is added over a period of from 0.25 to 8 hours or the methoxide is added such that the temperature of the reaction does not exceed 30 °C. In a preferred embodiment the methoxide is added over a period of from, 0.5 to 8 hours, more preferably from 1 to 7 hours and even more preferably from 2 to 6 hours. In another preferred embodiment, the methoxide is added such that the temperature of the reaction does not exceed 25 °C. Preferably, the methoxide is added such that the process is carried out at a temperature of from 5 to 25 °C. More preferably, the methoxide is added such that the process is carried out at a temperature of from 10 to 20 °C.

[0034] The skilled person will appreciate that the period of time over which the methoxide is added will be dependent upon the observed temperature rise (exotherm) in the reactor and is defined by the rate at which heat can be removed from the reaction equipment. This observed temperature rise is dependent upon a number of different factors, such as, the material of construction and size of the reaction equipment, the scale of the reaction, the starting temperature of the reaction, the weight% (wt%) concentration of methoxide and / or the weight% concentration of the reactants (4,6-dichloropyrimidine and a compound of formula (II)) in the solvent system, viscosity of the mixture, reactor configuration (cooling surface / agitation) and the cooling capacity of the reactor system. Typically, the total methoxide is added in an amount of from 1 to 1 .5 equivalents based on a compound of formula (II). Preferably, the methoxide is added in an amount of from 1 .1 to 1 .4 equivalents based on a compound of formula (II). More preferably, the methoxide is added in an amount of from 1.1 to 1.2 equivalents based on a compound of formula (II).

[0035] The skilled person will recognise that if the number of moles of 4,6-dichloropyrimidine increases relative to the number of moles of a compound of formula (II), it may be necessary to increase the number of moles of methoxide.

[0036] Step (Hi) of the process

[0037] The tertiary amine catalyst 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 tertiary amine catalyst is added in multiple charges and / or continuously.

[0038] Typically, the tertiary amine catalyst addition is controlled such that the concentration of a compound of formula (Illa) and / or a compound of formula (IVa) remains high in solution until the compound of formula (II) has been consumed and the compounds of formula (lll) / (llla) and (IV) / (IVa) are consumed, for example (but not limited) the tertiary amine catalyst is added over a period of from 0.25 to 8 hours or the tertiary amine catalyst is added such that the temperature of the reaction does not exceed 30 °C. In a preferred embodiment the tertiary amine catalyst is added over a period of from, 0.5 to 8 hours, more preferably from 1 to 7 hours and even more preferably from 2 to 6 hours. In another preferred embodiment, the tertiary amine catalyst is added such that the temperature of the reaction does not exceed 25 °C. Preferably, the tertiary amine catalyst is added such that the process is carried out at a temperature of from 5 to 25 °C. More preferably, the tertiary amine catalyst is added such that the process is carried out at a temperature of from 10 to 20 °C.

[0039] The skilled person will appreciate that the period of time over which the tertiary amine catalyst is added will be dependent upon a number of different factors, such as, the scale of the reaction, the mol% based on a compound of formula (II) and / or the wt% concentration of the starting reagents, 4,6- dichloropyrimidine, a compound of formula (II) and the methoxide.

[0040] The skilled person will also appreciate that the tertiary amine catalysts or appropriate salts as described herein are solids and will recognise that these materials can be added as a solids, liquid or solution in an appropriate solvent (suitable solvents include solvents such as the reaction solvents and methanol).

[0041] Preferably, the tertiary amine catalyst used in step (iii) of the process is selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane (Methyl- DABCO), 2,6-dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,5-dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 1 ,5- diazabicyclo[3.2.2]-nonane, 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, quinuclidine, quinuclidine hydrochloride, quinuclidinol, hexamethylenetetramine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N- methylmorpholine, N-methylpyrrolidine, N-methylimidazole, 1 ,3,5-trimethyl-1 ,3,5-triazine, 1 ,4- dimethylpiperazine, N,N-dimethylcyclohexylamine and trimethylamine. More preferably, the tertiary amine catalyst is selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane, 2-methyl-1 ,4- diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N-methylpyrrolidine and trimethylamine. Even more preferably, the tertiary amine catalyst is 1 ,4-diazabicyclo[2.2.2]octane, N-methylpyrrolidine or trimethylamine. Most preferably, the tertiary amine catalyst is 1 ,4-diazabicyclo[2.2.2]octane.

[0042] In one embodiment the tertiary amine catalyst is an azabicyclic (including diazabicyclic) tertiary amine catalyst.

[0043] The tertiary amine catalysts used in the process of the invention are either commercially available or can be synthesized using methods known to the skilled person.

[0044] Typically, the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II). Preferably, the tertiary amine catalyst is present in an amount of from 0.05 mol% to 10 mol% based on a compound of formula (II). More preferably, the tertiary amine catalyst is present in an amount of from 0.05 mol% to 2 mol% based on a compound of formula (II). Even more preferably, the tertiary amine catalyst is present in an amount of from 0.1 mol% to 1 .5 mol% based on a compound of formula (II). Even more preferably still, the tertiary amine catalyst is present in an amount of from 0.2 mol% to 1.3 mol% based on a compound of formula (II).

[0045] The skilled person would appreciate that steps (ii) and (iii) can be carried out concurrently. Preferably step (iii) commences prior to the completion of step (ii). More preferably, step (iii) commences when from 10% to 80% of the total amount of methoxide (total volume of solution) has been added and / or concentrations (>2 area% by GC analysis) of compounds of formula (lll)Z(llla) are present in solution. Even more preferably, step (iii) commences when from 30% to 70% of the total amount of methoxide (total volume of solution) has been added and / or concentrations (>10 area% by GC analysis) of compounds of formula (III) / (Illa) are present in solution. Even more preferably still, step (iii) commences when from 50% to 70% of the total amount of methoxide (total volume of solution) has been added and / or concentrations (>10 area% by GC analysis) of compounds of formula (III) / (Illa) are present in solution.

[0046] In a preferred embodiment, the methoxide (step (ii)) and tertiary amine catalyst (step (iii)) are added over a period of from 0.25 to 8 hours. More preferably, the methoxide and tertiary amine catalyst are added over a period of from, 0.5 to 8 hours, more preferably from 1 to 7 hours and even more preferably from 2 to 6 hours.

[0047] In another preferred embodiment, the methoxide and tertiary amine catalyst are added such that the temperature of the reaction does not exceed 30 °C. Preferably, the methoxide and tertiary amine catalyst are added such that the temperature of the reaction does not exceed 25 °C. More preferably, the methoxide and tertiary amine catalyst are added such that the process is carried out at a temperature of from 5 to 25 °C. More preferably, the methoxide and tertiary amine catalyst are added such that the process is carried out at a temperature of from 10 to 20 °C.

[0048] Typically, the process of the invention (steps (i), (ii) and (iii)) is carried out in the presence of a suitable solvent or mixture of solvents, such as but not limited to, methanol, tert-butanol, tetrahydrofuran, 2- methyltetrahydrofuran, te / Y-butylmethylether, tert-amyl methyl ether, cyclopentyl methyl ether, methyl acetate, ethyl acetate, n-propyl acetate, / so-propyl acetate, n-butyl acetate, / so-butyl acetate, tert-butyl acetate, dimethoxymethane, diethoxymethane, dipropoxy methane, 1 ,3-dioxolane, dimethyl carbonate, dichloromethane, dichloroethane, / V, / V-dimethylformamide, / V, / V-dimethylacetamide, N-methyl pyrrolidone (NMP), acetonitrile, propionitrile, butyronitrile, benzonitrile (or derivative thereof e.g 1 ,4- dicyanobenzene), 1 ,4-dioxane, sulfolane, toluene, xylene / so-mix, cumene, isopropylbenzene, p-xylene, mesitylene, nitrobenzene, o-xylene, m-xylene, ethylbenzene, hexane, heptane, cyclohexane, methylcyclohexane, methyl formate, ethyl formate, n-propyl formate, / so-propyl formate, n-butyl formate, / so-butyl formate or tert-butyl formate. Preferably, the process of the invention is carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate. More preferably, the process of the invention is carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of tetrahydrofuran, methyltetrahydrofuran, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate. Most preferably, the process of the invention is carried out in methyl formate.

[0049] Typically, water is excluded from the process of the invention.

[0050] When carrying out the process of the invention, the reaction temperature can be varied within a relatively wide range. The skilled person would appreciate that the temperature chosen will depend on the nature of the solvent or diluent, for example on its boiling point and / or its effectiveness for promoting the desired reaction, and on the rate at which the reaction is to be carried out. In general the reaction may be carried out at a temperature of from -10 to 50 °C, preferably from -5 to 40 °C, more preferably from 0 to 30 °C, even more preferably from 5 to 25 °C and even more preferably still from 10 to 20 °C.

[0051] The process of the invention can be carried out at any reasonable pressure depending on the choice of solvent and reaction temperature. Preferably, the reaction may be carried out at a pressure of from 0.01 to 10 Bar, more preferably from 0.5 to 5 Bar, even more preferably from 0.8 to 2 Bar (for example at ambient pressure). The skilled person would also appreciate the reaction can be carried out under reduced pressure with an appropriate solvent and that distillation can aid in the removal of heat from the reaction system.

[0052] Preferably, the process of the present invention is carried out under an inert atmosphere, such as nitrogen or argon. Without wishing to be bound by theory, it is believed that the tertiary amine catalyst and 4,6- dichloropyrimidine react in the process of the invention to form a quaternary ammonium salt that facitilitates the conversion of a compound of formula (Illa) or (IVa) to a compound of formula (I). For example, when the tertiary amine catalyst is 1 ,4-diazabicyclo[2.2.2]octane (DABCO) a compound of formula (V) is formed,

[0053] (V).

[0054] Likewise, when the tertiary amine catalyst is trimethylamine a compound of formula (VI) is formed,

[0055] (VI).

[0056] In a preferred embodiment of the process the compound of formula (I) is further converted to a compound of formula (X), wherein,

[0057] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups. Preferably, the compound of formula (I) is further converted to a compound of formula (X) by reacting a compound of formula (I), with 2-cyanophenol, or a salt thereof; to give a compound of formula (X), wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups.

[0058] More preferably, the compound of formula (I) is further converted to a compound of formula (X) by reacting a compound of formula (I), with 2-cyanophenol, or a salt thereof in the presence of a tertiary amine catalyst; to give a compound of formula (X), wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups. Even more preferably, the compound of formula (I) is further converted to a compound of formula (X) by reacting a compound of formula (I), with 2-cyanophenol, or a salt thereof in the presence of a tertiary amine catalyst selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,6- dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,5-dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 1 ,5- diazabicyclo[3.2.2]-nonane, 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, quinuclidine, quinuclidine hydrochloride, quinuclidinol, hexamethylenetetramine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N- methylmorpholine, N-methylpyrrolidine, N-methylimidazole, 1 ,3,5-trimethyl-1 ,3,5-triazine, 1 ,4- dimethylpiperazine, N,N-dimethylcyclohexylamine, N,N-diisopropylethylamine, triethylamine and tri methylamine; to give a compound of formula (X), wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups.

[0059] Yet even more preferably, the compound of formula (I) is further converted to a compound of formula (X) by reacting a compound of formula (I), with 2-cyanophenol, or a salt thereof in the presence of a tertiary amine catalyst selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N-methylpyrrolidine and trimethylamine; to give a compound of formula (X), wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups.

[0060] Yet even more preferably still, the compound of formula (I) is further converted to a compound of formula (X) by reacting a compound of formula (I), with 2-cyanophenol, or a salt thereof in the presence of from 0.01 to 40 mol% (preferably, from 0.01 to 20 mol%, more preferably from 0.05 to 2 mol%) of a tertiary amine catalyst selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N-methylpyrrolidine and trimethylamine, based on the compound of formula (I); to give a compound of formula (X), wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups.

[0061] The skilled person will recognize that compounds of formula (I) or compounds of formula (X) wherein W is the methyl 2-(3,3-dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, can be readily converted into compounds of formula (I) or compounds of formula (X) wherein W is the methyl (E)-2-(3- methoxy)acrylate group C(CO2CH3)=CHOCH3 by known methods to eliminate methanol (such as those disclosed in WO 98 / 07707 or WO 92 / 08703). For example, methanol can be eliminated from a compound of formula (I) wherein W is the methyl 2-(3,3-dimethoxy)propanoate group CH(CO2CH3)CH(OCH3)2 (and which can be in admixture with a compound of formula (I) wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3) by heating said compound or mixture to a temperature in the range of from 60 to 300 °C, preferably in the presence of a suitable catalyst, preferably an acid catalayst (for example, but not limited to, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate), optionally under reduced pressure, optionally in the presence of an acid anhydride, an acid chloride or 2-acetoxybenzonitrile, and optionally in the presence of a suitable solvent which assists removal of methanol (such as, but not limited to, toluene or dimethyl formamide).

[0062] In a preferred embodiment of the invention there is provided a process forthe preparation of a compound of formula (I), wherein,

[0063] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0064] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0065] (II) ;

[0066] (ii) subsequently adding sodium or potassium methoxide; and,

[0067] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof; wherein step (iii) commences prior to the completion of step (ii) (preferably, steps (ii) and (iii) are carried out concurrently). Preferably, steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate).

[0068] In another preferred embodiment of the invention there is provided a process for the preparation of a compound of formula (I), wherein,

[0069] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0070] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0071] (ii) ;

[0072] (ii) subsequently adding sodium or potassium methoxide; and,

[0073] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof; wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II), and wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added (preferably, steps (ii) and (iii) are carried out concurrently). Preferably, steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p- xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate).

[0074] Preferably, there is provided a process for the preparation of a compound of formula (I), wherein, W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0075] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0076] (II) ;

[0077] (ii) subsequently adding sodium or potassium methoxide; and,

[0078] (iii) subsequently adding a tertiary amine catalyst, wherein the tertiary amine catalyst is 1 ,4- diazabicyclo[2.2.2]octane or trimethylamine, or salt thereof, in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added and wherein the addition in steps (ii) and (iii) is controlled (preferably, steps (ii) and (iii) are carried out concurrently, more preferably, the addition in steps (ii) and (iii) is controlled over a period of from 0.5 to 8 hours). Preferably, steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate.

[0079] In another embodiment, there is provided a process for the preparation of a compound of formula (I), wherein,

[0080] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0081] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0082] (II) ;

[0083] (ii) subsequently adding sodium or potassium methoxide; and,

[0084] (iii) subsequently adding a tertiary amine catalyst selected from 1 ,4-diazabicyclo[2.2.2]octane or trimethylamine, or salt thereof, in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount of methoxide has been added and wherein the addition in steps (ii) and (iii) is controlled such that the process is carried out at a temperature of from 5 to 25 °C (preferably, steps (ii) and (iii) are carried out concurrently). Preferably, steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p- xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate.

[0085] In another embodiment, there is provided a process for the preparation of a compound of formula (I), wherein,

[0086] W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;

[0087] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0088] (ii) ;

[0089] (ii) subsequently adding sodium or potassium methoxide; and, (iii) subsequently adding a tertiary amine catalyst selected from 1 ,4-diazabicyclo[2.2.2]octane or trimethylamine, or salt thereof, in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount of methoxide has been added and wherein the addition in steps (ii) and (iii) is continuous and controlled (preferably, the addition in steps (ii) and (iii) is controlled such that the process is carried out at a temperature of from 5 to 25 °C or the addition in steps (ii) and (iii) is controlled over a period of from 0.5 to 8 hours). Preferably, steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p- xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate.

[0090] In another embodiment, there is provided a process for the preparation of a compound of formula (lb), comprising the steps of;

[0091] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0092] (ii) ;

[0093] (ii) subsequently adding methoxide;

[0094] (iii) subsequently adding a tertiary amine catalyst or salt thereof;

[0095] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb).

[0096] Preferably, there is provided a process for the preparation of a compound of formula (lb), comprising the steps of;

[0097] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0098] (II) ;

[0099] (ii) subsequently adding sodium or potassium methoxide; and,

[0100] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof;

[0101] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb); wherein step (iii) commences prior to the completion of step (ii).

[0102] More preferably, there is provided a process for the preparation of a compound of formula (lb), comprising the steps of;

[0103] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0104] (ii) ;

[0105] (ii) subsequently adding sodium or potassium methoxide; and,

[0106] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof;

[0107] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb); wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II), and wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added.

[0108] Even more preferably, there is provided a process for the preparation of a compound of formula (lb), comprising the steps of;

[0109] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0110] (ii) ;

[0111] (ii) subsequently adding sodium or potassium methoxide; and, (iii) subsequently adding a tertiary amine catalyst, wherein the tertiary amine catalyst is 1 ,4- diazabicyclo[2.2.2]octane or trimethylamine, or salt thereof, in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II);

[0112] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added and wherein the addition in steps

[0113] (ii) and (iii) is controlled (preferably, over a period of from 0.5 to 8 hours).

[0114] In another embodiment, there is provided a process for the preparation of a compound of formula (Xb), comprising the steps of;

[0115] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0116] (ii) ;

[0117] (ii) subsequently adding methoxide;

[0118] (iii) subsequently adding a tertiary amine catalyst or salt thereof;

[0119] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb);

[0120] (v) subsequently reacting a compound of formula (lb) with 2-cyanophenol, or a salt thereof (preferably in the presence of a tertiary amine catalyst) to give a compound of formula (Xb).

[0121] Preferably, there is provided a process for the preparation of a compound of formula (Xb),

[0122] comprising the steps of;

[0123] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0124] (II) ;

[0125] (ii) subsequently adding sodium or potassium methoxide; and,

[0126] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof;

[0127] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb);

[0128] (v) subsequently reacting a compound of formula (lb) with 2-cyanophenol, or a salt thereof (preferably in the presence of a tertiary amine catalyst) to give a compound of formula (Xb); wherein step (iii) commences prior to the completion of step (ii).

[0129] More preferably, there is provided a process for the preparation of a compound of formula (Xb), comprising the steps of; (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0130] (II) ;

[0131] (ii) subsequently adding sodium or potassium methoxide; and,

[0132] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof, wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II);

[0133] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb);

[0134] (v) subsequently reacting a compound of formula (lb) with 2-cyanophenol, or a salt thereof in the presence of a tertiary amine catalyst selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane (DABCO), 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,6-dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,5- dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 1 ,5-diazabicyclo[3.2.2]-nonane, 1 ,5,7-triazabicyclo[4.4.0]dec- 5-ene, 1 ,8-diazabicyclo[5.4.0]undec-7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, quinuclidine, quinuclidine hydrochloride, quinuclidinol, hexamethylenetetramine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N-methylmorpholine, N-methylpyrrolidine, N-methylimidazole, 1 ,3,5- trimethyl-1 ,3,5-triazine, 1 ,4-dimethylpiperazine, N,N-dimethylcyclohexylamine, N,N- diisopropylethylamine, triethylamine and trimethylamine to give a compound of formula (Xb); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added.

[0135] Even more preferably, there is provided a process for the preparation of a compound of formula (Xb), comprising the steps of;

[0136] (i) combining 4,6-dichloropyrimidine and a compound of formula (II),

[0137] (ii) ;

[0138] (ii) subsequently adding sodium or potassium methoxide; and,

[0139] (iii) subsequently adding a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, or salt thereof, wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II);

[0140] (iv) subsequently reacting the product of step (iii) in the presence of an acid catalyst (preferably, methane sulfonic acid, chloro sulfonic acid, dimethyl sulfate, p-toluene sulfonic acid or potassium bisulfate) to give a compound of formula (lb);

[0141] (v) subsequently reacting a compound of formula (lb) with 2-cyanophenol, or a salt thereof in the presence of a tertiary amine catalyst selected from the group consisting of 1 ,4- diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N- methylpyrrolidine and trimethylamine, wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 40 mol% (preferably from 0.01 mol% to 20 mol%, more preferably from 0.05 mol% to 2 mol%) based on a compound of formula (lb), to give a compound of formula (Xb); wherein step (iii) commences when from 10% to 80% (preferably, 30% to 70%, more preferably 50% to 70%) of the total amount (total volume) of methoxide has been added and wherein the addition in steps (ii) and (iii) is controlled (preferably, over a period of from 0.5 to 8 hours).

[0142] Examples:

[0143] 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.

[0144] The following abbreviations are used: GC = gas chromatography, RT = retention time, Ti = internal temperature, MH+= molecular mass of the molecular cation, M = molar, RT = room temperature, UFLC = Ultra-fast liquid chromatography, DCP = 4,6-dichloropyrimidine, CMP = 4-chloro-6- methoxypyrimidine, HCI = hydrochloric acid, MCH = methylcyclohexane, THF = tetrahydrofuran.

[0145] Some chemical yields (Examples 1-3 and Comparative Examples CO and C1) have been calculated precisely using quantitative GC analysis against dipentyl phthalate as an internal standard.

[0146] In other cases (Example 4 and Comparative Examples C2a, C2b, C3, C4a, C4b), qualitative GC analysis at the end of reaction has been used to compare reaction performance. Those skilled in the art will recognise that qualitative analysis is typically useful for comparing reaction outcomes between different experiments but cannot be used for direct comparison against experiments for which there is only quantitative analysis. In cases where qualitative GC analysis has been used to compare reaction performance, an estimate of the combined yield of Compound (la) and Compound (lb) has been calculated according to the formula:

[0147] Example 1

[0148] 3-(Methoxymethylene)benzofuran-2-one (36.25g, 93.3 w / w%, 0.192 moles), 4,6-dichloropyrimidine (31 ,2g, 99 w / w%, 0.207 mol, 1 .08 Equivalents) and methyl formate (142.1g, 97 w / w%, 2.29 mol) were charged to a 500 ml reactor fitted with a condenser and a nitrogen blanket, and the mixture cooled to 5°C. A solution of sodium methoxide in methanol (37.05g, 30 w / w%, 0.21 mol) was added to the reaction mixture over 5 hours whilst maintaining the temperature at 5°C. After 30% of the sodium methoxide had been added (90 minutes), a solution of 0.215g DABCO (0.0019 mole, 1 mol% relative to 3- (Methoxymethylene)benzofuran-2-one) in Methanol 1.42g was added over the remaining 3.5 hours of the methoxide addition. After the complete addition of both components, the mixture was stirred for 1 hour at 5°C. GC analysis showed that the reaction was complete (<2% 4,6-dichloropyrimidine in the GC Area% chromatogram).

[0149] Water 1 .6 g was added, the agitator was stopped and mixture was held at 5°C overnight. The solvents were removed at atmospheric pressure and then under vacuum finishing at 50°C and 250 mBar. The residue was heated to 60°C and hot water (60°C, 40.1g) added. The mixture was stirred for 30 minutes at 60°C before methyl cyclohexane (71.1 g) and water (93.2 g) were added at 60°C and the mixture heated to 70°C and stirred for 30 minutes before settling (30 mins) and phase separation of the lower aqueous phase. Methylcyclohexane (13.4 g) and water (13.4 g) added, at 60°C, to the mixture and then, with the mixture at 70°C, potassium hydroxide (6.4g of 10 w / w% solution) was added over 30 minutes. The agitator was stopped and after 30 minutes, the lower aqueous phase was separated. An HCI solution (15.8g at 0.88 w / w% HCI) was added and the mixture stirred at 70°C for 30 minutes before separating. The upper layer mixture was cooled to ambient temperature and separated into two phases. The lower melt (62.2g, 67.4 w / w%, Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate (0.1 19 moles), 5.16 w / w% methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3- methoxy-prop-2-enoate (0.010 mols), 67.1 %) and the upper, mainly methyl cyclohexane phase (79.4g, 9.7 w / w%, Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate (0.021 moles), 0.33 w / w%, methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate (0.001 mols); 11 .77% (recovered by recycle into the next reaction). The total yield of products - methyl 2-[2-(6-chloro-

[0150] 4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl (E)-2-[2-(6-chloropyrimidin-4- yl)oxyphenyl]-3-methoxy-prop-2-enoate was 79.2%. Example 2

[0151] 3-(Methoxymethylene)benzofuran-2-one (226.7g, 94.0 w / w%, 1.21 moles), 4,6-dichloropyrimidine (200.3g, 99 w / w%, 1.33 mol, 1.10 equivalents) and methyl formate (480.2g, 97 w / w%, 7.76 mol) were charged to a 2 L reactor fitted with condenser and a nitrogen blanket, and the mixture cooled to 10°C. A solution of sodium methoxide in methanol (257.1g of 30 w / w%, 1.4 mol, 1.15 Equivalents) was added to the reaction mixture over 6 hours whilst maintaining the temperature at ca. 10°C. After 60% of the sodium methoxide had been added (216 minutes), a solution of DABCO in methanol (5.76 ml of a 38.7 w / w% solution in methanol) (0.015 moles, 1.25 mol% relative to 3-(Methoxymethylene)benzofuran-2- one) was added over the remaining 144 minutes of the methoxide addition. After the complete addition of both components, the mixture was stirred for 1 hour at 10°C. GC analysis showed that the reaction was complete (<2% 4,6-dichloropyrimidine in the GC Area% chromatogram).

[0152] Water 10 g was added, the agitator was stopped and mixture was held at 10-19°C overnight. The solvents were removed at atmospheric pressure and then under vacuum finishing at 50°C and 250 mBar. The residue was heated to 60°C and hot water (60°C, 254g) added. The mixture was stirred for 30 minutes at 60°C before methyl cyclohexane (450 g upper organic layer from a previous experiment Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate: 10.36 w / w%; methyl (E)-2- [2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate: 0.48 w / w%) = 0.14 mols) and water (590 g) were added at 60°C and the mixture heated to 70°C and stirred for 30 minutes before settling (30 mins) and phase separation of the lower aqueous phase. Fresh methylcyclohexane (85 g) was added, at 60°C, to the mixture and the organic layer was cooled to ambient temperature and separated into two phases. The lower melt (513.2g, 66.2 w / w% Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)- phenyl]3,3-dimethoxypropanoate (0.96 moles), 4.95 w / w% methyl (E)-2-[2-(6-chloropyrimidin-4- yl)oxyphenyl]-3-methoxy-prop-2-enoate (0.08 mols), 85.6 % of theory) and the upper, mainly methyl cyclohexane phase (464.8g, 10.39 w / w%, Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate (0.14 moles), 0.44 w / w% methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3- methoxy-prop-2-enoate (0.01 mols); 11.57% (recovered by recycle into the next reaction) and subtract the Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl (E)-2-[2-(6- chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate in the MCH added before separations (0.14 mol, 11.57%). The total yield of products - methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate and methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate was 86.6%.

[0153] Example 3

[0154] 3-(Methoxymethylene)benzofuran-2-one (226.7, 94.0 w / w%, 1.21 moles), 4,6-dichloropyrimidine (200.3g, 99 w / w%, 1.33 mol, 1.10 Equivalents) and methyl formate (480.2g, 97 w / w%, 7.76 mol) were charged to a 2 L reactor fitted with condenser and a nitrogen blanket, and the mixture cooled to 10°C. A solution of sodium methoxide in methanol (257.1g of 30 w / w%, 1.4 mol, 1.15 Equivalents) was added to the reaction mixture over 6 hours whilst maintaining the temperature at ca. 10°C. After 60% of the sodium methoxide had been added (216 minutes), a solution of trimethylamine in methanol (3.576g of 25 w / w%solution) (0.015 moles, 1.25 mol% relative to 3-(Methoxymethylene)benzofuran-2-one) was added over the remaining 144 minutes of the methoxide addition. After the complete addition of both components, the mixture was stirred for 1 hour at 10°C. GC analysis showed that the reaction was complete (<2% 4,6-dichloropyrimidine in the GC Area% chromatogram).

[0155] Water 10g was added, the agitator was stopped and mixture was held at 10-19°C overnight. The solvents were removed at atmospheric pressure and then under vacuum finishing at 50°C and 250 mBar. The residue was heated to 60°C and hot water (60°C, 254g) added. The mixture was stirred for 30 minutes at 60°C before methyl cyclohexane, both fresh 35.5g and recycled (414 g upper organic layer from a previous experiment Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate: 10.36 w / w%; methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy- prop-2-enoate: 0.48 w / w%) = 0.14 mols) and water (590 g) were added at 60°C and the mixture heated to 70°C and stirred for 30 minutes before settling (30 mins) and phase separation of the lower aqueous phase. Fresh methylcyclohexane (85 g) was added, at 60°C, to the mixture and the organic layer was cooled to 25°C over 1 hour, the agitator switched off and the mixture separated into two phases. The lower melt (528.5g, 67.1 w / w% Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate (1.005 moles), 4.39 w / w% methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3- methoxy-prop-2-enoate (0.072 mols), 89.0% of theory) and the upper, mainly methyl cyclohexane phase (456.3g, 10.46 w / w% Methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate (0.135 moles), 0.39 w / w% methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate (0.006 mols); 11 .7% (recovered by recycle into the next reaction) and subtract the Methyl 2-[2-(6-chloro- 4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl (E)-2-[2-(6-chloropyrimidin-4- yl)oxyphenyl]-3-methoxy-prop-2-enoate in the MCH added before separations (0.144 mol, 11 .9%). The total yield of products - methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate was 88.8%.

[0156] Example 4

[0157] The general procedure for the comparison of different catalysts, molar concentrations and timing of addition described in Table 1 below is as follows:

[0158] 3-(Methoxymethylene)benzofuran-2-one (about 200 mmol), and 4,6-dichloropyrimidine (Actual mmol of 3-(Methoxymethylene)benzofuran-2-one x the ‘equivalents’ defined in Table 1) and the solvent (e.g methyl formate, 80.9 ml at 97 w / w% strength) were charged to a jacketed reactor and the temperature adjusted to the temperature defined in Table 1. Sodium methoxide solution in methanol (equivalents as defined in Table 1 , 30 w / w%) was added in a continuous mode to the reactor over a period as defined in Table 1. After a period as defined in Table 1 , tertiary amine catalyst (generally a 25% solution in methanol) addition was started. Unless specified, the feed of catalyst continues until the end of the sodium methylate solution addition. The reaction mixture is left to stir at the defined temperature for 60 minutes and sampled for GC end of reaction analysis.

[0159] The results in the table describe the final area% of desired compounds of methyl 2-[2-(6-chloro-4- pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate (a compound of formula (la) - major compound) and methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2-enoate (a compound of formula (lb) - minor compound).

[0160] The skilled person will recognise that, for example, lower temperatures, different ‘tertiary amine catalysts’, different solvent systems and lower loadings of catalyst may affect reaction times.

[0161] Table 1 - Summary of different catalysts, molar concentrations and timing of addition a) Catalyst added in a single portion. b) Catalyst added portion-wise: 0.1 mol% added at 144 mins and a further 0.1% added at 288 mins. c) Mole ratios are as equivalents (Equiv) relative to the number of moles of 3- (methoxymethylene)benzofuran-2-one (a compound of formula (II)). d) Mol% is the percentage of moles of catalyst relative to the moles of compound of formula (II). (1 mol% = 0.01 equivalents) e) The total addition time of the sodium methoxide solution. f) The time after which the tertiary amine catalyst feed is initiated or when the first dose of tertiary amine is added (in brackets the percentage of the total NaOMe addition time (e)).

[0162] The skilled person will recognise that entry numbers 12, 14, 16, 18 and 20 all represent comparative examples where the catalyst is added in a single portion prior to the addition of sodium methoxide. As can be seen from Table 1 , all examples where the catalyst feed is initiated after sodium methoxide addition has started clearly demonstrate an improvement in yield of the desired product.

[0163] Additional comparative examples:

[0164] Comparative Uncatalysed Process CO:

[0165] 3-(Methoxymethylene)benzofuran-2-one (240g, 93 w / w%, 1.27 moles), 4,6-dichloropyrimidine (210g, 100 w / w%, 1 .41 mol, 1.11 equiv) and methyl formate (490.2g, 97 w / w%, 8.16 mol) were charged to a 2 litre reactor fitted with condenser and a nitrogen blanket, and the mixture stirred at 18°C until all was in solution. A solution of sodium methoxide in methanol (269.4g, 30 w / w%, 1.50 mol) was added to the reaction mixture over 7 hours and 55 min whilst maintaining the temperature at 18°C, and then stirred for 1 hour, left unstirred for ca. 16 hours before sampling for analysis for completion of reaction. Water (10 g) was added to the mixture and the solvents removed at atmospheric pressure and then under vacuum finishing at 50°C and 250 mBar. The residue was heated to 60°C and hot water (60°C, 254g) added. The mixture was stirred for 30 minutes at 60°C before methyl cyclohexane (450 g) and water (590 g) were added at 60°C and the mixture heated to 70°C and stirred for 30 minutes before settling (30 mins) and phase separation of the lower aqueous phase. Methylcyclohexane (85 g) and water (250 g) added, at 60°C, to the mixture and then, with the mixture at 70°C, potassium hydroxide (113g of 9.64 w / w% solution) was added over 30 minutes. The agitator was stopped and after 30 minutes, the lower aqueous phase was separated. An HCI solution (100g at 0.88 w / w% HCI) was added and the mixture stirred at 70°C for 30 minutes before separating. The upper layer mixture was cooled to ambient temperature and separated into two phases. The lower melt (388.5g, 61.0 w / w% Compound (la) and (lb), 0.67 mols, 63.8%) and the upper, mainly methyl cyclohexane phase (544.9g, Yielding Compound (la) and (lb) of 10.95%). Total yield of products 74.8 % as Methyl 2-[2-(6-chloro-4-pyrimidin- 4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3- methoxy-prop-2-enoate.

[0166] Comparative example C1 ;

[0167] The process described in EP 3 476 837, example 1 on page 2 was reproduced as follows:

[0168] A 2L jacketed glass vessel connected to an external chiller bath and equipped with overhead stirrer and reflux condenser was set up. 3-(Methoxymethylene)benzofuran-2-one (77.7 g, 411 mmol, 93.3 w / w%) and 4,6-dichloropyrimidine (66.9 g, 444 mmol, 99.0 w / w%) were charged as solids to the rig followed by toluene (304 g, 3300 mmol). 25% solution of trimethylamine in methanol (0.76 g, 3.2 mmol) was added and the mixture was cooled to 5°C (NB: When the mixture reached ~7°C a slurry formed.).

[0169] 30% Sodium methoxide solution in methanol (79.4 g, 1470 mmol) was charged via a syringe pump over 5 h. The temperature was maintained at 5°C for the duration of the reaction. As the addition continued the slurry thinned then became a homogenous solution again.

[0170] After the sodium methoxide addition was complete, the reaction was stirred for a further 1 h at 5°C. Analysis by GC showed that the reaction was incomplete with 8.6% DCP, 25.9% a compound of formula (I I l) / (l I la) (hydroxy acetal) and 3.4% 3-(Methoxymethylene)benzofuran-2-one remaining. The stirrerwas switched off and temperature maintained at 5°C overnight.

[0171] The next day the agitator was switched on and reaction mixture was sampled to evaluate any changes. GC analysis showed that the reaction is still not complete with 2.6% 4,6-dichloropyrimidine, 9.7% of a compound of formula (lll) / (llla) (hydroxy acetal) and 4.1 % 3-(Methoxymethylene)benzofuran-2-one remaining. The temperature was increased to 10°C and the reaction mixture stirred for 1 h. GC analysis showed little to no change. In order to drive the reaction to completion, 8 ml (144 mmol) more sodium methoxide solution in methanol (30%) was added over 30 min. The reaction mixture was stirred for further 30 min before testing by GC. Very little change was observed, thus the reaction was considered complete and moved onto the next steps.

[0172] HCI solution (135 g, 2 w / w%) was added in aliquots to the reaction until pH reached <1 . The resultant mixture was stirred at 20°C for 15 min then left to settle. The lower aqueous layer was removed.

[0173] Water (200 g) was charged and the mixture was stirred at 20°C for 30 min before allowing to separate. As the separation contained a greater quantity of stringy solids the agitation was restarted and heat was applied with the temperature increased to 40°C. An improvement was seen so the temperature was again raised to 60°C where the separation was concluded. The lower aqueous phase (208.8g) was removed.

[0174] A 2ndportion of water (200 g) was charged and the mixture was stirred at 60°C for 30 min before the agitation was stopped and the 2 layers allowed to settle. The lower aqueous (203.8g) was removed.

[0175] The toluene was then removed by vacuum distillation to end conditions of 25mbar and 80°C.

[0176] The resultant melt (147.4 g) contained methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3- dimethoxypropanoate and methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate with overall yield of 67.7 % (quantitative GC analysis) and a ratio of 95:5.

[0177] Comparative example C2;

[0178] The process described in EP 3 042 896 embodiment 1 on page 9 was reproduced as follows:

[0179] C2a

[0180] A 300ml jacketed glass vessel was equipped with chiller bath, overhead stirrer and condenser, and a nitrogen blanket was applied. Toluene (200 ml) was charged followed by 3-(methoxy- methylene)benzofuran-2-one (37.8 g, 200 mmol, 93.3 w / w%) and 4,6-dichloropyrimidine (31.0 g, 206 mmol, 99.0 w / w%) and the mixture was stirred to give a homogenous solution at 15°C. Dry potassium carbonate (4.15 g, 30.0 mmol) was then charged followed by methyl formate (24.8 g, 400.0 mmol) and solid DABCO (0.90 g, 8.0 mmol). The mixture was cooled to 5°C. Sodium methoxide solution in methanol (1 1 .6 ml, 62 mmol, 30 w / w%) was charged over 1 h using a syringe pump. The mixture was then stirred for a further 30 min at 5°C then sampled for analysis by GC. The combined yield of methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl 2-[2-(6- chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate by qualitative GC analysis was 9.7%.

[0181] C2b A second experiment was carried out as above in C2a with the difference that cooling was switched off when the methoxide feed started resulting in the reaction temperature raising from 5 to 19°C during the addition of sodium methoxide. The combined yield of methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)- phenyl]3,3-dimethoxypropanoate and methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3- methoxyacrylate by qualitative GC analysis was 13.0%.

[0182] Comparative example C3:

[0183] The process described in WO 2013 / 026391 A1 example 1 on page 5 and 6 was reproduced as follows:

[0184] A 300 ml Jacketed glass vessel was equipped with overhead stirrer, condenser and connected to external cooling bath. 3-(Methoxymethylene)benzofuran-2-one (18.7 g, 100 mmol, 94.0 w / w%) was charged to the rig followed by potassium carbonate (7.0 g, 50 mmol, 99 mass%) and toluene (80 ml). The agitator was switched on and the bath was set to obtain a temperature of 0°C in the vessel. Once 0°C was reached sodium methoxide (21 .2 g, 110 mmol, 28 w / w%) was added as a singular portion and the reaction mixture was held for 0.4 h. GC analysis showed that the solution contained 18.8 % unreacted starting 3-(Methoxymethylene)benzofuran-2-one and 75% of a compound of formula (lll)Z(llla) (hydroxy acetal). 4,6-Dichloropyrimidine (16.7 g, 110 mmol, 98 mass%) was added as a singular portion followed by DABCO (1 .7 g, 15 mmol). The resultant mixture was stirred with the bath set to maintain a temperature of 0°C for 1 h. The combined yield of methyl 2-[2-(6-chloro-4-pyrimidin-4- yloxy)-phenyl]3,3-dimethoxypropanoate and methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3- methoxyacrylate by qualitative GC analysis was 87.2%.

[0185] The contents of the vessel were discharged and filtered through grade 1 filter paper to remove the inorganic solids. The filtrates were then transferred and washed with water (100 g, 5.56 mol) using a separating funnel. The lower aqueous layer (110.7 g) was disposed of. Qualitative GC analysis was consistent with the end of reaction sample above (prior to work-up).

[0186] Comparative example C4:

[0187] The process described in WO 2013 / 026391 A1 example 1 on page 6 was reproduced as follows:

[0188] C4a

[0189] A 300 ml Jacketed glass vessel was equipped with overhead stirrer, condenser and connected to external cooling bath. 3-(Methoxymethylene)benzofuran-2-one (18.7 g, 100 mmol, 94.0 w / w%) was charged to the reactor followed by potassium carbonate (14.0 g, 100 mmol, 99 w / w%) and toluene (80 ml). The agitator was switched on and the bath was set to obtain a temperature of 5°C in the vessel. Once 5°C was reached sodium methoxide (21.2 g, 110.1 mmol, 28 w / w%) was charged in a singular portion and the reaction mixture was held for 0.5 h at 5°C. GC analysis showed that at this stage the solution contains 68.6% of a compound of formula (lll) / (llla) (hydroxy acetal) and 25.2% unreacted starting 3-(Methoxymethylene)benzofuran-2-one.

[0190] 4,6-Dichloropyrimidine (16.7 g, 110 mmol, 98 w / w%) was added followed by DABCO (1 .7 g, 15 mmol) and the resultant mixture was stirred with the bath set to maintain a temperature of 5°C for 1 .2 h. The combined yield of methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate and methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3-methoxyacrylate by qualitative GC analysis was 84.8%.

[0191] The content of the vessel was discharged and filtered through grade 1 filter paper to remove the inorganic solids. The filtrates were then transferred to a separating funnel and washed with water (100 g, 5.56 mol). The lower aqueous layer (108.9 g) was disposed of and the upper toluene phase (77.1 g) was discharged and analysed by GC (area%). Qualitative GC analysis was consistent with the end of reaction sample above (prior to work-up).

[0192] C4b

[0193] A 300 ml Jacketed glass vessel was equipped with overhead stirrer, condenser and connected to external cooling bath. 3-(Methoxymethylene)benzofuran-2-one (18.7 g, 100 mmol, 94.0 w / w%) was charged to the rig followed by potassium carbonate (14.0 g, 100 mmol, 99 w / w%) and toluene (80 ml). The agitator was switched on and the bath was set to obtain a temperature of 5°C in the vessel. Sodium methoxide (21.2 g, 110.1 mmol, 28 w / w%) was charged via syringe pump over 30 min and the temperature maintained at 5°C. After the addition was complete, GC analysis showed that the solution contained 67.2% of a compound of formula (lll) / (llla) (hydroxy acetal) and 25.4% unreacted starting 3- (Methoxymethylene)benzofuran-2-one.

[0194] 4,6-Dichloropyrimidine (16.7 g, 110 mmol, 98 w / w%) followed by DABCO (1.7 g, 15 mmol) were added and the mixture was stirred at 5°C for 1 .2 h. The combined yield of methyl 2-[2-(6-chloro-4-pyrimidin-4- yloxy)-phenyl]3,3-dimethoxypropanoate and methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3- methoxyacrylate by qualitative GC analysis was 82.6%.

[0195] The content of the vessel was discharged and filtered through grade 1 filter paper to remove the inorganic solids. The filtrates were then transferred to a separating funnel and washed with water (100 g, 5.56 mol). The lower aqueous layer (108.9 g) was disposed of and the upper layer containing product (77.1 g, 100 w / w%) was discharged and analysed by GC (area%). Qualitative GC analysis was consistent with the end of reaction sample above (prior to work-up). Table 2 - Summary of Comparative Results by Qualitative GC Analysis a) Catalyst added in a single portion. c) Mole ratios are as equivalents (Equiv) relative to the number of moles of 3- (methoxymethylene)benzofuran-2-one (compound of formula (II)). d) Mol% is the percentage of moles of catalyst relative to the moles of compound of formula (II). (1 mol% = 0.01 equivalents) e) The total addition time of the sodium methoxide solution. f) The time after which the tertiary amine catalyst feed is initiated or when the first dose of tertiary amine is added (in brackets the percentage of the total NaOMe addition time (e)).

[0196] Compound of formula (II) - 3-(Methoxymethylene)benzofuran-2-one

[0197] Compound of formula (la) - methyl 2-[2-(6-chloro-4-pyrimidin-4-yloxy)-phenyl]3,3-dimethoxypropanoate Compound of formula (lb) - methyl (E)-2-[2-(6-chloropyrimidin-4-yl)oxyphenyl]-3-methoxy-prop-2- enoate

[0198] From these comparative examples it can be seen that conversion of the compound of formula (II) to the compound of formula (la) and (lb) is inferior when the sodium methoxide is added to a reaction mixture comprising a benzofuranone, dichloropyrimidine and a tertiary amine catalyst (C1 , C2a, C2b). Likewise the conversion of the compound of formula (II) to the compound of formula (I) is also inferior when sodium methoxide is added to a reaction mixture comprising a benzofuranone before the subsequent addition of dichloropyrimidine and 1 ,4-diazabicyclo[2.2.2]octane.

Claims

CLAIMS:1 . A process for the preparation of a compound of formula (I),wherein,W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups, comprising the steps of;(i) combining 4,6-dichloropyrimidine and a compound of formula (II),(II) ;(ii) subsequently adding methoxide; and,(iii) subsequently adding a tertiary amine catalyst or salt thereof.

2. A process according to claim 1 , wherein the tertiary amine catalyst is selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,6- dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 2,5-dimethyl-1 ,4-diazabicyclo[2.2.2]-octane, 1 ,5- diazabicyclo[3.2.2]-nonane, 1 ,5,7-triazabicyclo[4.4.0]dec-5-ene, 1 ,8-diazabicyclo[5.4.0]undec- 7-ene, 1 ,5-diazabicyclo[4.3.0]non-5-ene, quinuclidine, quinuclidine hydrochloride, quinuclidinol, hexamethylenetetramine, tetramethylethylenediamine, pentamethyldiethylenetriamine, N- methylmorpholine, N-methylpyrrolidine, N-methylimidazole, 1 ,3,5-trimethyl-1 ,3,5-triazine, 1 ,4- dimethylpiperazine, N,N-dimethylcyclohexylamine and trimethylamine.

3. A process according to claim 1 or 2, wherein the tertiary amine catalyst is selected from the group consisting of 1 ,4-diazabicyclo[2.2.2]octane, 2-methyl-1 ,4-diazabicyclo[2.2.2]-octane, quinuclidine, quinuclidinol, N-methylpyrrolidine and trimethylamine.

4. A process according to any one of claims 1 to 3, wherein the tertiary amine catalyst is 1 ,4- diazabicyclo[2.2.2]octane.

5. A process according to any one of claims 1 to 4, wherein the tertiary amine catalyst is present in an amount of from 0.01 mol% to 20 mol% based on a compound of formula (II).

6. A process according to any one of claims 1 to 5, wherein the tertiary amine catalyst is present in an amount of from 0.05 mol% to 2 mol% based on a compound of formula (II).

7. A process according to any one of claims 1 to 6, wherein step (iii) commences prior to the completion of step (ii).

8. A process according to any one of claims 1 to 7, wherein step (iii) commences when from 10% to 80% of the total amount of methoxide has been added.

9. A process according to any one of claims 1 to 8, wherein step (iii) commences when from 30% to 70% of the total amount of methoxide has been added.

10. A process according to any one of claims 1 to 9, wherein the addition in steps (ii) and (iii) is controlled.

11. A process according to any one of claims 1 to 10, wherein the addition in steps (ii) and (iii) is controlled such that the process is carried out at a temperature of from 5 to 25 °C.

12. A process according to any one of claims 1 to 11 , wherein the addition in steps (ii) and (iii) is controlled over a period of from 0.5 to 8 hours.

13. A process according to any one of claims 1 to 12, wherein steps (i), (ii) and (iii) are carried out in the presence of a suitable solvent or mixture of solvents selected from the group consisting of methanol, tert-butanol, tetrahydrofuran, methyltetrahydrofuran, methyl acetate, toluene, xylene (including xylene / so-mix, p-xylene, o-xylene or m-xylene), methylcyclohexane and methyl formate.

14. A process according to any one of claims 1 to 13, wherein the methoxide is an alkali metal methoxide.

15. A process according to any one of claims 1 to 14, wherein the process further comprises converting a compound of formula (I) to a compound of formula (X),wherein,W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the methyl 2-(3,3- dimethoxy)propanoate group CH(CC>2CH3)CH(OCH3)2, or a mixture of the two groups.

16. A compound of formula (V),or a compound of formula (VI),(VI).

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