The present invention relates to a process for preparing the strobilurin fungicide methyl (E)-
2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate(azoxystrobin).
Methods for preparing azoxystrobin are described in WO 92/08703. In one method,
azoxystrobin is prepared by reacting 2-cyanophenol with methyl (£)-2-[2-(6-chloropyrimidin-
4-yloxy)phenyl]-3-methoxyacrylate. A high-yielding method for producing
asymmetrical 4,6-bis(aryloxy)pyrimidine derivatives is disclosed in WO 01/72719 in which a
6-chloro-4-aryloxypyrimidine is reacted with a phenol, optionally in the presence of a solvent
and/or a base, with the addition of from 2 to 40 mol % of l,4-diazabicyclo[2.2.2]octane
(DABCO). In addition, it has previously been found by the present inventors that even lower
concentrations of DABCO (for example, between 0.1 and 2 mol%) are also able to catalyse
this reaction.
The present invention is,based on the discovery that, when preparing azoxystrobin or an
acetal precursor of azoxystrobin using DABCO as a catalyst, the order of addition of the
reaction components has an effect on the yield and reaction rate.
20 Accordingly, the present invention provides a process for preparing a compound of formula
(I):
25
(I)
wherein W is the methyl (#)-2-(3-methoxy)acrylate group C(C02CH3)=CHOCH3 or the
methyl 2-(3,3-dimethoxy)propanoate group C(C02CH3)CH(OCH3)2, or a mixture of the two
groups, which comprises either
(a) reacting a compound of formula (II):
WO 2008/043978 PCT/GB2007/003735
W' N r ^
CI (II)
w
wherein W has the meaning given above, with 2-cyanophenol, or a salt thereof in the
presence of between 0.1 and 40 mol % of DABCO, or
(b) reacting the compound of formula (HI):
(IH)
with a compound of formula (IV):
HO (IV)
W
or a salt thereof, where W has the meaning given above, in the presence of between 0.1 and
40 mol % of DABCO and wherein DABCO is not mixed with the compound of formula (II)
10 or the compound of formula (HI) unless (i) 2-cyanophenol or the compound of formula (TV)
or a salt of 2-cyanophenol or the compound of formula (IV) is present; or (ii) DABCO is
present as an acid salt or (iii) conditions are such that DABCO and the compound of formula
(IT) or the compound of formula (HI) are not able to react with each other; with the proviso
that when between 0.1 and 2 mol% DABCO is used, the DABCO is not added last.
15
Conveniently, the process of the invention is carried out by mixing one of the components of
the reaction, preferably in the presence of a solvent or diluent with the other component, if
appropriate in the presence of a solvent or diluent. An acid acceptor is added at a convenient
point, as discussed below, and the mixture is stirred, normally at an elevated temperature.
20 After the reaction is judged to be complete, the reaction mixture is worked up and the
product is isolated using conventional techniques well known to a skilled chemist.
According to prior art methods, the DABCO catalyst may be added at any time to the
reaction mixture including (i) as the first reactant, (ii) to the first component alone or (iii)
WO 2008/043978 PCT/GB2007/003735
- 3 -
after the second component has been added. However, it has now been found that, in order
to promote higher product yields and a faster reaction rate, DABCO should not be allowed to
react with the compound of formula (II) or the compound of formula (HI) in the absence of 2-
cyanophenol or the compound of formula (IV), or a salt of 2-cyanophenol or the compound
5 of formula (TV). While not wanting to be bound by theory, it is believed that, in the absence
of 2-cyanophenol or the compound of formula (IV), DABCO and the compounds of formula
(II) or (IH) react and then the reaction product can further convert to give a non-active
species, thus reducing yield and available catalyst. It is also believed that the reaction
between the neutral DABCO molecule and the compounds of formula (II) or (III) is inhibited
10 in the presence of acid species. Therefore, if an acid salt of DABCO is added to the reaction
flask or generated in situ (by the addition of neutral DABCO to a mixture containing an acid)
and, provided that the acid acceptor is not present or not sufficiently soluble in the reaction
mixture to quickly deprotonate the DABCO acid salt, the reaction between DABCO and the
compounds of formula (II) or (HI) is inhibited. It is also believed that, in the presence of 2-
15 cyanophenol or the compound of formula (IV), the phenol can act as an acid source either
protonating the DABCO salt directly or, after reaction between the phenol and the
compounds of formula (II) or (HI), may act as a base and be protonated by the mole of
hydrochloric acid produced. Finally, in the presence of a salt of 2-cyanophenol or a salt of
the compound of formula (IV), the reaction product of DABCO and the compounds of
: 20 formula (II) or (HI) reacts with the salt of 2-cyanophenol or the compound of formula (IV) to
give the expected product of formula (1) and, concomitantly, regenerates the catalyst.
Thus, in particular, the process of the present invention may be carried out by, for example,
any one of the following methods:
25 i) adding 2-cyanophenol or the compound of formula (IV) to the compound of formula
(II) or the compound of formula (HI), and then adding DABCO;
ii) adding 2-cyanophenol or the compound of formula (IV) to DABCO and then adding
the compound of formula (H) or the compound of formula (HI);
iii) adding DABCO to 2-cyanophenol or the compound of formula (TV) and then adding
30 the compound of formula (H) or the compound of formula (HI);
iv) adding the compound of formula (II) or the compound of formula (IH) to 2-
cyanophenol or the compound of formula (TV) and then adding DABCO;
WO 2008/043978 PCT/GB2007/003735
. 4 .
v) providing a mix of the compound of fonnula (II) or the compound of formula (HI) with
2-cyanophenol or the compound of fonnula (IV) and then adding DABCO;
vi) providing a mix of DABCO with 2-cyanophenol or the compound of formula (IV) and
then adding the compound of formula (II) or the compound of formula (IH);
5 vii) adding a mix of 2-cyanophenol or the compound of formula (IV) and the compound of
formula (II) or the compound of formula (HI) to DABCO; or
viii) adding a mix of 2-cyanophenol or the compound of formula (TV) and DABCO to the
compound of formula (II) or the compound of formula (ITI);
ix) adding DABCO to an acidic, solution of the compound of formula (II) or the compound
10 of formula (HI) in which sufficient acid is present to convert all of the DABCO to a
salt, and then adding 2-cyanophenol or the compound of formula (IV) provided that the
acid acceptor is either not added before the 2-cyanophenol or the reaction between the
DABCO salt and the acid acceptor is slow; or t
x) mixing an acid salt of DABCO, either as a solid or a preformed salt by the reaction of
15 acid and DABCO, to the compound of formula (11) or the compound of formula (III)
and then adding 2-cyanophenol or the compound of formula (IV) provided that the base
is either not added before the 2-cyanophenol or the reaction between the DABCO salt
and the acid acceptor is slow.
20 Suitable acid salts of DABCO include, but are not limited to DABCOH+Cl", DABCOH+
(HS04)\ (DABCOH+)2S04
2" and DABCOH+(S03Me)Of course, if DABCO is not able to react with the compound of formula (II) or the compound
or formula (HI), for example, if both components are in a solid state or if one component is
25 insoluble (or perhaps only partially soluble) in the solvent/diluent used in the reaction, then
they can be mixed with impunity. However, in such a case, before the conditions are made
suitable for the reaction to take place, 2-cyanophenol or the compound of formula (IV), or a
salt of 2-cyanophenol or the compound of formula (IV) must be added.
30 Further mixing options are thus allowed if the components of the reaction are first mixed in
conditions under which they are not able to react. For example, a mix of the compound of
WO 2008/043978 PCT/GB2007/003735
- 5 -
fonnula (II) or the compound of formula (III) with DABCO may be provided and the reaction
not started until 2-cyanophenol or the compound of formula (IV) is added.
hi a particular embodiment, the process of invention comprises reacting a compound of
5 formula (II):
or — o y (n)
w
wherein W has the meaning given above, with 2-cyanophenol, or a salt thereof (suitably
potassium 2-cyanophenoxide) in the presence of between 0.1 and 40 mol % of DABCO.
10 When the process of the invention is carried out using a compound of formula (II) where W
is the methyl 2-(3,3-dimethoxy)propanoate group or using a compound of formula (IV)
where W is the methyl 2-(3,3-dimethoxy)propanoate group, the product obtained may
include a proportion of the compound of formula (I) where W is the methyl (E)-2-(3-
methoxy)acrylate group. This may happen because it is possible that methanol is eliminated
15 from the methyl 2-(3,3-dimethoxy)propanoate group under the conditions of the process. For
the same reason, if the process is carried out using a compound of formula (II) or a
compound of formula (IV) where W is a mixture of the methyl 2-(3,3-dimethoxy)propanoate
group and the methyl (£)-2-(3-methoxy)acrylate group (and the invention includes such a
process), the product obtained will be a compound of formula (I) where W is a mixture of the
20 methyl 2-(3,3-dimethoxy)propanoate group and the methyl (i^-2~(3-methoxy)acrylate group;
however, the product may have a higher proportion of the compound of formula (I) where W
is the methyl (£)-2-(3-methoxy)acrylate group than expected from the proportion of (£)-2-(3-
methoxy)acrylate group in the mixed starting material due to this potential elimination of
methanol. This is of no real consequence because it will normally be required to convert the
25 product of formula (I) where W is the methyl 2-(3,3-dimethoxy)propanoate group to the
compound of formula (I) where W is the group methyl (£)-2-(3-methoxy)acrylate group by
the elimination of methanol.
WO 2008/043978 PCT/GB2007/003735
- 6 -
Conveniently the process of the invention is carried out in a suitable inert solvent or diluent.
These include, for example, aliphatic, alicyclic and aromatic hydrocarbons, such as
petroleum ether, hexane, heptane, cyclohexane, methylcyclohexane, benzene, toluene, xylene
and decalin; halogenated hydrocarbons, such as chlorobenzene, dichlorobenzene,
5 dichloromethane, chloroform, carbon tetrachloride, dichloroethane and trichloroethane;
heteroaromatic solvents such as pyridine or a substituted pyridine, for example,
2,6-dimethylpyridine; ethers, such as diethyl ether, dizwpropylether, methyl-fert-butyl ether,
msthyl-tert-amyl ether, dioxane, tetrahydrofuran, 1,2-dimethoxyethane, 1,2-diethoxyethane
and anisole; ketones, such as acetone, butanone, methyl isobutyl ketone and cyclohexanone;
10 nitriles, such as acetonitrile, propionitrile, n- and i-butyronitrile and benzonitrile; amides,
such as TV^-dimethylformamide, A^iV-dimethylacetamide, TV-methylformamide, iV-methylpyrrolidone
and hexamethylphosphoric triamide; tertiary amines, in particular, amines of the
formula R]R2R3N where R1, R2 and R3 are each independently Cwo (especially Ci-s) alkyl,
C3.6 cycloalkyl, aryl (especially phenyl) or aryl(Ci-4)alkyl (especially benzyl); or two or three
15 of R , R and R join together with the nitrogen atom to which they are attached to form one,
two or three 5-, 6- or 7-membered alicyclic rings optionally fused and optionally containing a
second ring nitrogen atom, examples of suitable tertiary amines being N,N-diz'sopropylethylamine
(Hunig'sbase), 7ViiV-dimethylaniline, triethylamine, ^-butyldimethylamine,
A^A^diwopropylmethylamine, N,N-diisopropy[isdbutylamme, A/,A^diwopropyl-2-
20 ethylbutylamine, tri-72-butylamine, A^A'-dicyclohexylmethylamine, JV,iV-dicyclohexylethylamine,
A^tert-butylcyclohexylamine, iy,JV-dimethylcyclohexylamine, l,5-diazabicyclo[4.3.0]-
non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene or 2-dimethylaminopyridine; esters, such as
methyl acetate, ethyl acetate and isopropyl acetate; sulphoxides, such as dimethylsulphoxide;
sulphones, such as dimethylsulphone or sulpholane; and mixtures of such solvents and
25 diluents and mixtures of one or more of them with water. In addition, if the starting
compounds for the reaction or the product from the reaction are in the form of liquids or will
be liquid at the reaction temperature, they may act as diluent/solvent for the process of the
invention. In such a situation, additional diluent or solvent may not be required.
30 Particularly suitable diluents are ketones [such as methyl z'sobutyl ketone and
cyclohexanone], esters [such as isopropyl acetate], tertiary amines [such as [A^iV-diwopropylethylamine
(Hunig's base)], aromatic hydrocarbons [such as toluene or xylene
WO 2008/043978 PCT/GB2007/003735
- 7 -
(mixed isomers or single isomer)] and amides [such as 7V,JV-dimethylforniamide]. In a
particular aspect of the present invention, methyl z'sobutyl ketone is used as diluent. In a
further aspect of the present invention, cyclohexanone is used as diluent, hi a further aspect
of the present invention, isopropyl acetate is used as diluent. In a further aspect of the
5 present invention, 7V,7V-dimethylfonnamide is used as diluent, hi a further aspect of the
present invention, toluene is used as diluent. In a further aspect of the present invention, N,Ndiz'se>
propylethylamine (Hilnig's base) is used as diluent. Most suitably, the diluent used in
the present invention is TV, JV-dimethylformamide.
10 hi a further embodiment of the present invention, the process is carried out in an aqueous
organic solvent system. Suitably, in this embodiment, when the compound of formula (II) is
reacted with 2-cyanophenol, the 2-cyanophenol is present as a salt. This salt may either have
been added as is or be generated in situ from the neutral phenol and the acid acceptor (see
below). Suitably, the salt is a lithium, caesium, sodium, potassium, l,5-diazabicyclo[4.3.0]-
15 non-5-ene or l,8-diazabicyclo[5.4.0]undec-7-ene salt of 2-cyanophenol. More suitably, the
salt is the l,8-diazabicyclo[5.4.0]undec-7-ene, sodium or potassium salt of 2-cyanophenol.
Even more suitably, the salt is the sodium or potassium salt of 2-cyanophenol. Most suitably,
the salt is potassium 2-cyanophenoxide. Suitable co-solvents for use in such an aqueous
process are solvents which are at least partially water immiscible solvents such as
20 cyclohexanone, methyl isobutyl ketone and isopropyl acetate. Advantageously, the water is
removed throughout the reaction when these partially water immiscible solvents are used. In
addition, it has also been found that water miscible solvents may also be used in such an
aqueous process. Suitable water miscible solvents are A^A^dimethylformamide, N,Ndimethylacetamide,
iV-methylpyrrolidinone and dimethyl sulphoxide. hi one embodiment,
25 the water is removed throughout the reaction when the water miscible solvents are used.
Most suitably, when such aqueous systems are used, the salt of 2-cyanophenol is potassium
2-cyanophenoxide and the diluent is cyclohexanone, methyl wobutyl ketone, isopropyl
acetate or iV.A^dimethylformamide. It is noted that when the 2-cyanophenol is added to the
process as an aqueous solution of potassium 2-cyanophenoxide it is possible to reduce the
30 quantity of acid acceptor (see below) used.
WO 2008/043978 PCT/GB2007/003735
- 8 -
fh addition, the process of the invention is preferably carried out in the presence of at least
0.8 moles of an acid acceptor per mole of 2-cyanophenol or a compound of formula (IV).
Suitable acid acceptors are all customary inorganic and organic bases. These include, for
example, alkaline earth metal and alkali metal hydroxides, acetates, carbonates, bicarbonates,
5 phosphates, hydrogen phosphates and hydrides [such as sodium hydroxide, potassium
hydroxide, sodium acetate, potassium acetate, sodium carbonate, potassium carbonate,
sodium bicarbonate, potassium bicarbonate, potassium phosphate, potassium hydrogen
phosphate, sodium phosphate, potassium hydrogen phosphate, calcium hydride, sodium
hydride and potassium hydride], guanidines, phosphazines (see, for example, Liebigs Ann.
10 1996,1055-1081), prophosphatranes (see, for example, JACS 1990, 9421-9422), metal
dialkylamines [such as lithium di-zw-propylamide] and tertiary amines [such as those
described above as possible solvents or diluents]. Particularly suitable acid acceptors are the
alkaline earth metal and alkali metal carbonates, especially potassium carbonate and sodium
carbonate and l,5-diazabicyclo[4.3.0]non~5-ene and l,8-diazabicyclo[5.4.0]undec-7-ene.
15 More suitably, the acid acceptor is potassium carbonate. Most suitably, the present invention
is carried out in the presence of methyl z'sobutyl ketone, cyclohexanone, isopropyl acetate,
A^,JV-diwopropylethylamine (Hiinig's base) or A^A^-dimethylformamide with potassium
carbonate as the acid acceptor.
20 The time at which the acid acceptor is added may be important in some embodiments of the
invention. If the acid acceptor to be used is not added as an aqueous solution and will not
generate large (one mole of water per mole of phenol deprotonated) amounts of water, such
as l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7~ene, alkali metal
phosphate or hydrogen phosphate, greater than mole of alkali metal or alkaline earth
25 carbonate, then the acid acceptor can be added at any time in the process. Also, if the 2-
cyanophenol is the first reaction component added, any acid acceptor can be added at any
time and consideration of whether to remove any water generated by the 2-cyanophenol plus
acid acceptor reaction can be made. Where a compound of formula (IT) is charged first,
aqueous solutions of acid acceptors should not be added before the 2-cyanophenol is added to
30 the mixture. For a compound of foimula (IV) added first, preferably in the presence of a
diluent, it is advantageous to add the compound of formula (HI) before adding the acid
acceptor. For a compound of formula (HI) added first, preferably in the presence of a diluent,
WO 2008/043978
. 9 .
PCT/GB2007/003735
the acid acceptor can be added at any suitable time. While not wanting to be bound by theory,
strong bases in the presence of significant quantities of water can hydrolyse compounds of
formula (II) resulting in by-product formation and lower yields - the presence of 2-
cyanophenol or both components of the reaction will neutralise the strong bases and allow
5 the desired reaction to occur. Obviously, in selecting the amount of acid acceptor to be
added, consideration of effects of potential excesses of acid acceptors should be made and
normally, when using aqueous solutions of acid acceptors, or acid acceptor which generate a
mole of water per mole of phenol deprotonated such as alkali or alkaline earth metal
hydroxides or hydrogen carbonates, close to stoichiometric quantities of base should be used.
10
The process of the invention is carried out in the presence of between 0.1 and 40 mol% of
l,4-diazabicyclo[2.2.2]octane (DABCO). Suitably, it is carried out in the presence of
between 0.2 and 40 mol% of DABCO. More suitably, it is carried out in the presence of
between 0.5 and 10 mol %. Most suitably, it is carried out in the presence of between 0.5
15 and 5 mol% DABCO.
In a particular embodiment of the invention the process is carried out in the presence of about
1 mol% DABCO with methyl z'sobutyl ketone, cyclohexanone, isopropyl acetate, N,N~diiwpropylethylamine
(Hiinig's base), toluene, or iV.TV-dimethylformamide as diluent. More
20 suitably, the diluent is Af Af-dimethylformamide or isopropyl acetate. Most suitably, the
diluent is iV,iV-dimethylformamide. Suitably, the acid acceptor will be potassium carbonate.
When carrying out the process of the invention, the reaction temperature can be varied within
a relatively wide range. The temperature chosen will depend on the nature of the solvent or
25 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 any given solvent.or
diluent, the reaction will tend to progress more slowly at lower temperatures. In general, the
reaction may be carried out at a temperature of from 0 to 120°C, suitably at a temperature of
from 40 to 100°C, and typically at a temperature of from 45 to 95°C, for example, from 60 to
30 95°C.
WO 2008/043978 PCT/GB2007/003735
-10-
The process of the invention can be carried out at any reasonable pressure depending on the
solvent, base and reaction temperature. For low boiling diluents or reagents, higher
temperatures can be accessed at higher than atmospheric pressures, and reactions can be
carried out at atmospheric pressures or under vacuum if desired. Suitably, the reaction may
5 be carried out at a pressure of from 0.01 to 10 Bara, more suitably at a pressure of from 0.5 to
5 Bara and most suitable at a pressure of from 0.8 to 2 Bara, for example at ambient pressure.
For carrying out the process of the invention, suitably from 0.4 to 4 mol, more suitably from
0.95 to 1.5 mol and most suitably from 1 to 1.2 mol, of 2-cyanophenol is employed per mol
10 of a compound of formula (II); and similar amounts (0.4 to 4 mol, more suitably from 0.95 to
1.5 mol and most suitably from 1 to 1.2 mol) of a compound of formula (IV) are employed
per mole of the compound of formula (in).
2-Cyanophenol is a commercially available material.
15
The compound of formula (II), where W is the methyl (i?)-2-(3-methoxy)acrylate group
C(C02CH3)=CHOCH3, and the compound of formula (II) where W is the methyl
2-(3,3-dimethoxy)propanoate group C(C02CH3)CH(OCH3)2, may be prepared as described
in WO 92/08703 from the reaction of 3-(a-methoxy)methylenebenzofuran-2(3JH)-one
20 (derived from benzofuran-2(3i2)-one) with 4,6-dichloropyrimidine. The compound of
formula (IT), where W is the methyl (£)-2-(3-methoxy)acrylate group, may also be prepared
by eliminating methanol from (that is, by the demethanolysis of) the compound of formula
(II) where W is the methyl 2-(3,3-dimethoxy)propanoate group, as described in
WO 92/08703 or WO 98/07707. The compound of formula (H), where W is the methyl
25 2-(3,3-dimethoxy)propanoate group, may be prepared as described in GB-A-2291874 by
reacting a compound of formula (IV), where W is the methyl 2-(3,3-dimethoxy)propanoate
group, with 4,6-dichloropyrimidine. It may be purified before use by known techniques or
may be used in an unpurified state from a previous reaction, for example, in a 'one-pot'
reaction.
30
The compound of formula (TV), where W is the methyl 2-(3,3-dimethoxy)propanoate group,
may be prepared as described in GB-A-2291874 from 3-(a-methoxy)methylenebenzofuranWO
2008/043978 PCT/GB2007/003735
- 1 1 -
2(3H)-one. The compound of formula (IV), where W is the methyl (E)-2~(3-
methoxy)acrylate group, may be prepared by the procedure described in EP 0 242 081 or by
the demethanolysis of the compound of formula (IV) where W is the methyl 2-(3,3-
dimethoxy)propanoate group, hi this case, the phenolic group needs to be protected by, for
5 example, benzylation before demethanolysis and then de-protected afterwards.
The following Examples illustrate the invention. The examples are not intended as
necessarily representative of the overall testing performed and are not intended to limit the
invention in any way.
10
EXAMPLES
In these examples:
DABCO . = diazabicylclo[2.2.2]octane
15 MIBK = methylisobutylketone
DMF = AW-dimethylformamide
DBU = l,8-diazabicyclo[5.4.0]undec-7-ene
20 a) Conversion of methyl (J5r)-2-{2-[6-chloropvrimidin-4-vloxy]phenvl>-3-methoxyacrylate to
methyl (E)- 2-{2-[6-(2-cvanophenoxy)pyrimidin^4-vloxv]phenyl)-3-methoxyacrylate with
DABCO (2.6mol%) added before the 2-cyanophenol.
To a stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-
25 methoxyacrylate in DMF (207.3g at 46.4%, 0.3mols) at 50°C, was added potassium
carbonate (63.5g at 98%, 0.45mols) andDABCO (0.89g at 98%, 0.0078mols, 2.6mol%). The
mixture was allowed to stir for 5 minutes and then a solution of 2-cyanophenol in DMF
(78.5g at 50%, 0.33mols) was added. The mixture was heated to 65°C and held at that
temperature for 1 hour. The DMF was removed by vacuum distillation and then the residues
30 were dissolved in toluene (165.8g), heated to 80°C and washed with water (318.6g). The
toluene solution (301.7g) contained methyl (E)~ 2-{2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (37.0%w/w), 92% of theory.
WO 2008/043978 PCT/GB2007/003735
-12-
b) Conversion of methyl f£l)-2-{2-r6-chloropvrimidin-4-vloxv]phenvl)-3-methoxvacrvlateto
methyl (E)- 2-{2-[6-(2-cvanophenoxv)pvriimdm-4-yloxylphenyl}-3-methoxvacrylate with
DABCO ("2.6mol%>) added after the 2-cyanophenol.
To a stirred solution of methyl (JS)-2- {2-[6-chloropyrimidin-4-yloxy]phenyl} -3-
methoxyacrylate in DMF (207.3g at 46.4%, 0.3mols) at 48°C, was added potassium
carbonate (54.1g at 98%, 0,38mols).and a solution of 2-cyanophenol in DMF (78.5g at 50%,
0.33mols). DABCO (0.89g at 98%, 0.0078mols, 2.6mol %) was added and the mixture
10 heated to 65°C and held at that temperature for 1 hour. The DMF was removed by vacuum
distillation and then the residues were dissolved in toluene (165.8g), heated to 80°C and
washed with water (318.6g). The concentration of methyl (£)- 2-{2-[6-(2-
cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate in the toluene solution was
39.1%w/w.(98.6% of theory).
15
c) Conversion of methyl (^-2-(2-[6-cMoropyrimidin-4-yloxy|phenvl}-3-methoxyacrylate to
methyl (E)~ 2-j2-[6-("2-cyanophenoxv)pyrimidin-4-vloxy]phenvl|-3-methoxyacrylate with
DABCO (2.6mol%) added after the 2-cvanophenol.
20 To a stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-
methoxyacrylate in DMF (207.3g at 46.4%, 0.3mols) at 48°C, was added potassium
carbonate (54. lg at 98%, 0.38mols) and a solution of 2-cyanophenol in DMF (78.5g at 50%,
0.33mols). DABCO (0,89g at 98%w/w, 0.0078mols, 2.6mol %) was added and the mixture
heated to 65°C and held at that temperature for 1 hour. The DMF was removed by vacuum
25 distillation, to a final temperature of 100°C and then the residues were dissolved, while still
hot, in toluene (165.8g). Hot water (319g) was added and the mixture stirred at 80°C for 30
minutes before settling and separating the aqueous phase. The concentration of methyl (E)-2-
{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate in the toluene
solution (306.7g) was 39.3%w/w (99.7% of theory).
WO 2008/043978 PCT/GB2007/003735
- 1 3 -
d") Conversion of methyl (•g)-2-{2-|"6-chloropvrimidin-4-vloxv]phenyl}-3-methoxvacrylate to
methyl (E)- 2-{2-r6-(2-cvanophenoxv)pvrimidin-4-vloxy]phenyl|-3-methoxvacrvlate with
DABCQ (2.6mol%> added after the 2-cyanophenol.
5 To a stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-
methoxyacrylate in DMF (207.3g at 46.4%, 0.3mols) at 48°C, was added potassium •
carbonate (54. lg at 98%, 0.38mols) and a solution of 2-cyanophenol in DMF (78.5g at
50%w/w, 0.33mols). DABCO (0.89g at 98%w/w, 0.0078mols, 2.6mol %) was added and the
mixture heated to 65°C and held at that temperature for 1 hour. The DMF was removed by
10 vacuum distillation, to a final temperature of 100°C and then the residues were dissolved,
while still hot, in toluene (165.8g). Hot water (319g) was added and the mixture stirred at
80°C for 30 minutes before settling and separating the aqueous phase. The concentration of
methyl (£)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate in the
toluene solution (303.9g) was 39.1%w/w (98.3% of theory).
15
e) Coupling of methyl (E)-2- j2-|"6-chloropvrimidm-4-vloxv]phenvU-3-merhoxyacrylate with
2-cyanophenol in MIBK with 2mol% DABCO added after the 2-cyanophenol.
A slurry containing methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
20 (80.9g at 99%, 0.25mols), potassium carbonate (52.8g at 98%, 0.375mols) and 2-
cyanophenol (33.6g at 97.5%, 0.275mols) in MIBK (160mls) was heated to approximately
60°C. A solution of DABCO (0.56g, 0.005mols) in MIBK (lOmls) was added. The mixture
was heated to 80°C and held at this temperature for 200 minutes. Water (300mls) was
charged to the reaction, maintaining the temperature in the range 70-80°C. The mixture was
25 stirred for 40 minutes then settled and the lower aqueous phase separated. The MIBK
solution (238.6g) contained methyl (£)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (41.3%w/w) 97.8% of theory.
f) Coupling of methyl (•g)-2-{2-f6-chloropyrimidin-4-vloxy1phenvl)-3-methoxyacrylate with
30 2-cyanophenol in MIBK with 2mol% DABCO added before the 2-cyanophenol.
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To a slurry containing methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-
methoxyacrylate (80.9g at 99%, 0.25mols) and potassium carbonate (52.8g at 98%,
0.375mols) in MBK (160mls) was added a solution of DABCO (0.56g, O.OOSmols) in MIBK
(lOmls). The mixture was heated to approximately 60°C and then 2-cyanophenol (33.6g at
5 97.5%, 0.275mols) was charged. The mixture was heated to 80°C and held at this
temperature for 280 minutes. Water (300mls) was charged to the reaction, maintaining the
temperature in the range 70-80°C. The mixture was stirred for 40 minutes then settled and the
lower aqueous phase separated. The MIBK solution (237.0g) contained methyl (E)-2-{2-[6-
(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (40.2%w/w) 94.5% of
10 theory.
g) Coupling of methyl ('Jg)-2-(2-r6-chloroPvrimidin-4-vloxv1phenvl}-3-methoxvacrvlate with
2-cvanophenol in DMF with 5.0 mol% DABCO added after 2-cyanophenol.
15 A stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
(80.0g at 98.0%w/w, 0.245mols) in DMF (80g) was heated to 60°C. Potassium carbonate
(52.4g at 98%w/w, 0.37mols), a solution of 2-cyanophenol (33.3g at 97.5%w/w, 0.27mols)
in DMF (33.3g), and DABCO (1.43g at 97%w/w, 0.012mols) were added, with a 5 minute
interval between each addition. The mixture was heated to 80°C (exotherm raised
20 temperature to 89°C). The reaction was complete in 10 minutes. The DMF was removed
from the mixture by vacuum distillation to a maximum temperature of 100°C. After allowing
the distillation residues to cool slightly, toluene (137g) was added. The solution was stirred at
75-80°C for 5 minutes and then hot water (263.6g) was added, keeping the temperature of the
mixture above 70°C. The two phase mixture was stirred at 80°C for 30 minutes, then settled
25 and separated. The toluene solution (229.7g) contained methyl (E)-2-{2-[6-(2-
cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (42.0%w/w), 98.0% of theory.
h) Coupling of methyl (^-2-{2-["6-chloropyrimidin-4-yloxv]phenyl}-3-methoxyacrylate with
2-cyanophenol in DMF with 5.0 mol% DABCO added before 2-cyanophenol.
30
A stirred solution of methyl (JE)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
(80.0g at 98.0%w/w, 0.245mols) in DMF (80g) was heated to 60°C. Potassium carbonate
WO 2008/043978 PCT/GB2007/003735
-15-
(52.4g at 98%w/w, 0.37mols), DABCO (1.43g at 97%w/w, 0.012mols), and a solution of 2-
cyanophenol (33.3g at 97.5%w/w, 0.27mols) in DMF (33.3g) were added, with a 5 minute
interval between each addition. The mixture was heated to 80°C. The reaction was complete
after 360 minutes. The DMF was removed from the mixture by vacuum distillation to a
5 maximum temperature of 100°C. After allowing the distillation residues to cool slightly,
toluene (137g) was added. The solution was stirred at 75-80°C for 5 minutes and then hot
water (263.6g) was added, keeping the mixture temperature above 70°C. The two phase
mixture was stirred at 80°C for 30 minutes, then settled and separated. The toluene solution
(228.9g) contained methyl (£)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-
10 methoxyacrylate (37%%w/w), 86.1% of theory.
i) Coupling of methyl (£r)-2-{2-["6-chloropyrimidin-4-vloxv1phenvl)-3-methoxvacrylate with
2-cvanophenol in DMF with 5.0 mol% DABCO added after 2-cyanophenol and potassium
carbonate added last.
15
A stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
(80.0g at 98.0%w/w, 0.245mols) in DMF (80g) was heated to 60°C. A solution of 2-
cyanophenol (33.3g at 97.5%w/w, 0.27mols) in DMF (33.3g), DABCO (1.43g at 97%w/w,
0.012mols) and potassium carbonate (52.4g at 98%w/w, 0.37mols) were added, with a 5
20 minute interval between each addition. The mixture was heated to 80°C (exotherm raised
temperature to 89°C). The reaction was complete in approximately 10 minutes. The DMF was
removed from the mixture by vacuum distillation to a maximum temperature of 100°C. After
allowing the distillation residues to cool slightly, toluene (137g) was added. The solution was
stirred at 75-80°C for 5 minutes and then hot water (263.6g) was added, keeping the mixture
25 temperature above 70°C. The two phase mixture was stirred at 80°C for 30 minutes, then
settled and separated. The toluene solution (229.lg) contained methyl (E)-2-{2-[6-(2-
cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (41.7%w/w), 97.1% of theory.
i) Coupling of methyl r^)-2-{2-|"6-chloropvrimidin-4-vloxylphenvl}-3-methoxvacrvlate with
30 2-cvanophenol in DMF with 5.0 mol% DABCO added before 2-cyanophenol. Methyl (E)-2-
{2-r6-chloropvrimidin-4-yloxylphenvll-3-methoxyacrylate was added last.
WO 2008/043978 PCT/GB2007/003735
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A stirred suspension of potassium, carbonate (51.6g at 98%w/w, 0.37mols) and DMF (80g)
was heated to 60°C. DABCO (1.41g at 97%w/w, 0.012mols), a solution of 2-cyanophenol
(32.8g at 97.5%w/w, 0.27mols) in DMF (32.8g), and methyl (^)-2-{2-[6-chloropyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (80.0g at 98.0%w/w, 0.244mols) were added, with a 5
5 minute interval between each addition. The mixture was heated to 80°C (exotherm raised
temperature to 84°C). The reaction was complete in approximately 20 minutes. The DMF
was removed from the mixture by vacuum distillation to a maximum temperature of 100°C.
After allowing the distillation residues to cool slightly, toluene (134.8g) was added. The
solution was stirred at 75-80°C for 5 minutes and then hot water (259.4g) was added,
10 keeping the mixture temperature above 70°C. The two phase mixture was stirred at 80°C for
30 minutes, then settled and separated. The toluene solution (225.6g) contained methyl (E)-2-
{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (43.79%w/w), 100%
, of theory.
15 k) Coupling of methyl (^)-2-{2-[6-chloropyrimidin-4-yloxylphenyl|-3-methoxvacrylate with
2-cyanophenol in DMF with 5.0 mol% DABCO added before 2-cyanophenol. Potassium
carbonate was added last.
A stirred solution of methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
20 (80.0g at 98.0%w/w, 0.244mols) in DMF (80g) was heated to 60°C. DABCO (1.41g at
97%w/w, 0.012mols), a solution of 2-cyanophenol (32.8g at 97.5%w/w, 0.27mols) in DMF
(32.8g) and potassium carbonate (51.6g at 98%w/w, 0.37mols) were added, with a 5 minute
interval between each addition. The mixture was heated to 80°C. The reaction was complete
in 4 hours. The DMF was removed from the mixture by vacuum distillation to a maximum
25 temperature of 100°C. After allowing the distillation residues to cool slightly, toluene
(134.8g) was added. The solution was stirred at 75-80°C for 5 minutes and then hot water
(259.4g) was added, keeping the mixture temperature above 70°C. The two phase mixture
was stirred at 80°C for 30 minutes, then settled and separated. The toluene solution (226.6g)
contained methyl (E)-2- {2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl} -3-
30 methoxyacrylate (37.95%w/w), 87.4% of theory.
WO 2008/043978 PCT/GB2007/003735
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1) Coupling of methyl 151-2- {2-[6-chloropvrimidin-4-vloxylphenyl>-3-methoxvacrvlate with
2-cyanophenol in isopropyl acetate with 40.0 mol% DABCO added after 2-cyanophenol.
To isopropyl acetate (20.6g) at 40°C was added methyl (£)-2-{2-[6-chloropyrimidin-4-
5 yloxy]phenyl}-3-methoxyacrylate (32.8g at 98%w/w, 0.1 mols). After stirring for 10 minutes
potassium carbonate (14.1g at 98%w/w, 0.1 mols) was added. Further isopropyl acetate
(0.8g) was added (to mobilise the slurry). After stirring for a further 10 minutes at 40°C, 2-
cyanophenol (12.2g at 97.5%w/w, O.lmols) was added. 10 minutes later DABCO (4.61g at
97%w/w, 0.04 mols) was added. The mixture was stirred at 40°C (exotherm took the
10 temperature to 45°C). The reaction was complete after 30 minutes. The reaction mixture was
heated to 60°C and diluted with isopropyl acetate (13.7g) and toluene (24.5g). The
temperature was raised to 65°C and then hot water (106.2g) was added. The two phase
mixture was stirred at 75°C for 30 minutes and then settled and separated. The organic phase
(107.6g) contained methyl (£)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-
15 methoxyacrylate (36.5%w/w), 97.5% of theory.
m) Coupling of methyl (£')-2-{2-[6-chloropvrimidin-4-vloxvlphenvl}-3-methoxyacrvlate
with 2-cyanophenol in isopropyl acetate with 40.0 mol% DABCO added before 2-
cyanophenol.
20
To isopropyl acetate (20.6g) at 40°C, was added methyl (£)-2~{2-[6-chloropyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (32.8g at 98%w/w, 0.1 mols). After stirring for 10 minutes
potassium carbonate (14. lg at 98%w/w, 0.1 mols) was added along with a further charge of
isopropyl acetate (0.8g). After stirring for a further 10 minutes at 40°C, DABCO (4.61g at
25 97%w/w, 0.04 mols) was added and then, after 10 minutes, 2-cyanophenol (12.2g at
97.5%w/w, O.lmols) was charged. The mixture was stirred at 40°C (exotherm took the
temperature to 45°C). The reaction was complete after approximately 20-30 minutes.
Isopropyl acetate (13.7g) and toluene (24.5g) were added and the mixture heated to 60-65°C
before charging hot water (106.2g). The two phase mixture was stirred at 75°C for 30
30 minutes and then settled and separated. The organic phase (94.7g) contained methyl (-£)-2-
{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate(40.2%w/w), 94.5%
of theory.
WO 2008/043978 PCT/GB2007/003735
- 1 8 -
n) Coupling of methyl fE)-2-{2-[6-chloropvrimidin-4-yloxvlphenvl)-3-methoxyacrvlate with
2-cyanophenol in isopropyl acetate with 40.0 mol% DABCO and extra solvent added before
2-cyanophenol.
5
To isopropyl acetate (20.6g) at 40°C, was added methyl (£)-2-{2-[6-chloropyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (32.8g at 98%w/w, 0.1 mols). After stirring for 10 minutes
potassium carbonate (14.1g at 98%w/w, 0.1 mols) was added along with a further charge of
isopropyl acetate (0.8g). After stirring for a further 10 minutes at 40°C, DABCO (4.61g at
10 97%w/w, 0.04 mols) was added, followed by isopropyl acetate (30.9g) and then, after 10
minutes, 2-cyanophenol (12.2g at 97.5%w/w, O.lmols) was charged. The reaction was held at
40°C for 105 minutes at which time GC analysis showed that 62% by area of methyl (E)-2-
{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate remained. After stirring at
ambient temperature for 16 hours and then at 40°C for 105 minutes the reaction had stopped.
15 A further charge of potassium carbonate was made (7.04g at 98%w/w, 0.05 mols) and
stirring continued for 160 minutes, with very little further reaction taking place. GC analysis
showed that 40 area% methyl (£)-2-{2-[6-chloropyrimidin-4-yloxy]phenyl}-3-
methoxyacrylate remained.
20 o) Coupling of methyl (,£r)-2-{2-r6-chloropvrimidin-4-vloxv1rjhenyl|-3-methoxyacrvlate with
2-cyanophenol in cyclohexanone with 2.5mol% DABCO added after 2-cyanophenol but
before methyl (E)-2- {2-[6-chloropwimidin-4-yloxvlphenyl|-3-methoxyacrylate.
Cyclohexanone (198.2g) was heated to 100°C, with stirring, and 2-cyanophenol (24.4g at
25 97.5%w/w, 0.2mols) was added. After 10 minutes potassium carbonate (70.4g at 98%w/w,
0.5mols) was added. The mixture was stirred for 10 minutes during which time frothing and
gassing was observed. DABCO (0.289g at 97%w/w, 0.0025mols) and methyl (£)-2-{2-[6-
chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (32.8g at 98%w/w, O.lmols) were then
added at 10 minute intervals. The reaction was stirred at 100°C for 80 minutes. The
30 temperature was adjusted to 80°C and hot water (106.2g) was added keeping the temperature
above 70°C. The mixture was stirred at 75°C for 30 minutes, and then settled and the
aqueous phase separated. The cyclohexanone solution (255.3g) contained methyl (E)-2-{2-
WO 2008/043978 PCT/GB2007/003735
-19-
[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl} -3-methoxyacrylate (15.2%w/w), 96.3% of
theory.
p) Coupling of methyl (^-2-(2-r6-cMoropyrimidin-4-vloxvlphenvl}-3-methoxvacrvlate with
5 2-cyanoplienol in cyclohexanone with 2.5mol% DABCQ added before 2-cyanophenol but
after methyU^)-2-{2-("6-chloropyrimidin-4-vloxy]phenyU-3-methoxyacrvlate.
Cyclohexanone (198.2g) was heated to 100°C, with stirring, and methyl (£)-2-{2-[6-
chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate (32.8g at 98%w/w, O.lmols) was
10 added. After stirring for 10 minutes DABCO (0.289g at 97%w/w, 0.0025mols) was
introduced and stirring continued for 10 minutes before adding potassium carbonate (70.4g at
98%w/w, 0.5mols). After stirring for a further 10 minutes at 100°C, 2-cyanophenol (24.4g at
97.5%w/w, 0.2mols) was added. The reaction was stirred at 100°C for 15 hours. The
temperature was adjusted to 80°C and hot water (106.2g) was added keeping the temperature
15 above 70°C. The mixture was stirred at 75°C for 30 minutes, and then settled and the
aqueous phase separated. The cyclohexanone solution (256.5g) contained methyl (E)-2-{2-
[.6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyaciylate (11.8%w/w), 75.1% of
theory.
20 q) Coupling of methyl (^)-2-{2-r6-chloropvrimidin-4-vloxv]phenyll-3-methoxyacrylate with
2-cyanophenol in toluene with 10mol% DABCQ added after 2-cyanophenol and with DBU
as the base.
Toluene (40.8g) was stirred and heated to 70°C. DABCO (0.85g at 98%w/w, 0.007mols) and
25 2-cyanophenol (9.9g at 97.5%w/w, 0.08mols) were added at 10 minute intervals. After a
further 10 minutes DBU (13.8g at 98%w/w, 0.09mols) was added over 5 minutes (exotherm
to 74°C). After stirring for a further 10 minutes, methyl (£)-2-{2-[6-chloropyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (24.2g at 98%w/w, 0.074mols) was added and the reaction
stirred at 70°C for 60 minutes (reaction was complete in 30 minutes). Hot water (75°C)
30 (78.3g) was added and the mixture stirred for 15 minutes at 70-75°C, then settled and the
aqueous phase separated. A second, water wash (78.3g) was applied in the same way. The
WO 2008/043978 PCT/GB2007/003735
-20-
toluene phase (73, lg) contained methyl (^-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxyjphenyl}-3-methoxyacrylate (38.6%w/w), 94.7% of theory.
r) Coupling of methyl (•g)-2-{2-r6-chloropvrimidin-4-vloxvlphenvli-3-methoxvacrvlate with
5 2-cvanophenol in toluene with 10mol% DABCO added before 2-cvanophenol and with DBU
as the base.
Toluene (40.8g) was stirred and heated to 70°C. Methyl (jE>2-{2-[6-chloropyrimidin-4-
yloxyjphenyl}-3-methoxyacrylate (24.2g at 98%w/w, 0.074mols), DABCO (0.85g at
10 98%w/w, 0.007mols) and 2-cyanophenol (9.9g at 97.5%w/w, 0.08mols) were added at 10
minute intervals, maintaining the temperature at 70°C. After a further 10 minutes DBU ,
(13.8'g at 98%w/w, 0.09mols) was added over 5.5 minutes. During the addition the
temperature went up to 78°C and cooling was applied to maintain 70°C. The reaction
mixture was stirred at 70°C for 90 minutes (still 35.8 area% methyl (E}-2-{2-[6-
15 chloropyrimidin-4-yloxy]phenyl}-3-methoxyacrylate unreacted by GC analysis). The reaction
temperature was raised to 80°C and stirring continued for another 90 minutes at which time
the reaction was still not complete (14.2 area% methyl (E)-2- {2-[6-chloropyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate unreacted by GC analysis).The temperature was raised to
100°C and stirring continued for a further 60 minutes to complete the reaction. The reaction
20 mixture was cooled to 70°C before hot water (75°C) (78.3g) was added. The mixture was
stirred for 15 minutes at 70-75°C, then settled and the aqueous phase separated. A second
water wash (78.3g) was applied in the same way. The toluene phase (66.6g) contained methyl
(£)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate(32.8%w/w),
73.3% of theory.
25
It can be seen from the results above that, in all cases, where the DABCO is mixed with the
compound of formula II in the absence of 2-cyanophenol, the yield of product is decreased
and often the reaction time is increased when compared to a reaction carried out under the
same conditions but wherein the DABCO is not mixed with the compound of formula II in
30 the absence of 2-cyanophenol. Compare, for instance, example (a) with any of (b), (c) and
(d); example (f) with (e); examples (h) and (k) with any of (g), (i) and (j); example (m) with
(1); example (p) with (o); and example (r) with (q). In addition, the benefits of controlling the
WO 2008/043978 PCT/GB2007/003735
- 2 1 -
reaction conditions to physically prevent DABCO and the compound of formula II reacting
can also be seen. Compare, for example, (m) in which, although DABCO is added to the
compound of formula II in the absence of 2-cyanophenol, it is only able to react slowly with
the compound of formula II due to the low solubility of the system, with (n) in which the
5 solubility has been increased: in the latter, a significant proportion of the starting material is
unreacted after more than 16 hours.
Although the invention has been described with reference to preferred embodiments and
examples thereof, the scope of the present invention is not limited only to those described
10 embodiments. As will be apparent to persons skilled in the art, modifications and
adaptations to the above-described invention can be made without departing from the spirit
and scope of the invention, which is defined and circumscribed by the appended claims. All
publications cited herein are herby incorporated by reference in their entirety for all purposes
to the same extent as is each individual publication were specifically and individually
15 indicated to so incorporated by reference.

We Claim:
1. A process for preparing cyano-phenolic pyrimidine-based compound of formula ( I ):
which comprises
reacting a 2-(6-chloropyrimidin-4-yl) oxybenzonitrile of the formula ( I I I ):
with a compound of the formula (IV):
or a salt thereof, in the presence of between 0.1 and 40 mol % of 1,4-
diazabicyclo[2.2.2]octane;
wherein W is the methyl (E)-2-(3-methoxy)acrylate group C(CO2CH3)=CHOCH3 or the
methyl 2-(3,3-dimethoxy)propanoate group C(CO2CH3)CH(OCH3)2, or a mixture of the
two groups, and wherein 1,4-diazabicyclo[2.2.2]octane is not mixed with the compound
of formula (II) or the compound of formula (III) unless (i) 2-cyanophenol or the
compound of formula (IV) is present; or (ii) 1,4-diazabicyclo[2.2.2]octane is present as
an acid salt or (iii) conditions are such that 1,4-diazabicyclo[2.2.2]octane and the
compound of formula (II) or the compound of formula (III) are not able to react with
each other; with the proviso that when between 0.1 and 2 mol% 1,4-
diazabicyclo[2.2.2]octane is used, the 1,4-diazabicyclo[2.2.2]octane is not added last.
2. The process as claimed in claim 1 which is carried out in the presence of between 0.5
and 5 mol % of l,4-diazabicyclo[2.2.2]octane.
23
The process as claimed in claim 1 or 2 which is carried out in an inert solvent or diluent.
The process as claimed in claim 3 in which the inert solvent or diluent is methyl isobutyl
ketone, cyclohexanone, W,/\Adi/sopropylethylamine, toluene, isopropyl acetate or N,Ndimethyrformamide.
The process as claimed in claim 4 in which the inert solvent or diluent is N,Ndimethylformamide.
The process as claimed in any one of the preceding claims which is carried out in an
aqueous organic solvent system.
The process as claimed in claim 6, wherein the organic solvent is cyclohexanone, methyl
isobutyl ketone, isopropyl acetate, or W,/V-dimethylformamide.
The process as claimed in claim 6 or claim 7 wherein, as a salt of 2-cyanophenol,
potassium 2-cyanophenoxide is used.
The process as claimed in any one of the preceding claims which is carried out in the
presence of an acid acceptor.
The process as claimed in claim 9 in which the acid acceptor is potassium carbonate or
sodium carbonate.
The process as claimed in any one of the preceding claims which is carried out at a
temperature of from 0 to 120°C.