PROCESS FOR THE PREPARATION OF AZOXYSTROBIN AND ANALOGUES THEREOF
This invention relates to a process for the preparation of the agricultural fungicide
azoxystrobin and analogues thereof, and to chemical intermediates therefor. It also relates to
processes for making the chemical intermediates and to their use for making other chemical
5 compounds.
The strobilurin fungicide methyl (E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-
3-methoxyacrylate, known by the common name azoxystrobin, is a widely used
commercial agrochemical product. It is described in The Pesticide Manual published by the
British Crop Protection Council, 12th edition, pp 54-55 and in the proceedings of the
10 Brighton Crop Protection Conference (Pests and Diseases) 1992, Volume 1, S-6, pp 435-442.
It was first disclosed in EP-A-0382375 (compound 9, Example 3) along with methods for its
preparation.
There are many ways of making azoxystrobin. Generally, it is preferred to construct
the methyl a-phenyl-~-methoxyacrylate group at an early stage and then build on the central
15 pyrimidinyloxy and terminal cyanophenoxy rings. For example, (E)-methyl 2-(2-
hydroxyphenyl)-3-methoxyacrylate may be reacted with 4,6-dichloropyrimidine under
alkaline conditions in N,N-dimethylformamide to form (E)-methyl 2-[2-(6-chloropyrimidin-
4-yloxy)phenyl)-3-methoxyacrylate which is then reacted with 2-cyanophenol in an Ullmanntype
coupling process (see EP-A-0382375). The (E)-methyl2-(2-hydroxyphenyl)-3-
20 methoxyacrylate may be prepared by the formylation aqd subsequent methylation of methyl
2-benzyloxyphenylacetate followed by removal ofthe benzyl protecting group (see EP-A-
0242081). Formylation and methylation techniques for preparing the methyl a-phenyl-~methoxyacrylate
warhead are also described in WO 97/30020 and WO 97/01538.
One reason for constructing the methyl a-phenyl-~-methoxyacrylate group before
25 building on the central pyrimidinyloxy ring is that, with the pyrimidinyloxy ring in place,
methyl 2-(6-chloropyrimidin-4-yloxy)phenylacetate and methyl 2-[6-(2-cyanophenoxy)pyrimidin-
4-yloxy]phenylacetate are prone to undergo a Smiles-type intramolecular
rearrangement when the usual bases for conducting the formylation and methylation stages
are used to form the methyl methoxyacrylate group. Smiles rearrangements are discussed in
30 the textbook Advanced Organic Chemistry by Jerry March, 4th edition, pp 675-676,
published by John Wiley & Sons. In the case of the methyl2-[6-(2-cyanophenoxy)pyrimidin3
5
-4-yloxy]phenylacetate, the compound obtained as a result of a Smiles rearrangement has the
formula:
or its keto tautomeric form.
The present invention, which involves the use of a lithium base, provides a method of
10 constructing the methyl a.-phenyl-f3-methoxyacrylate group after building on the central
pyrimidinyloxy ring or the central pyrimidinyloxy ring and terminal cyanophenol ring. It
avoids a Smiles-type rearrangement and delivers the desired E-isomer.
It is known to use lithiated bases for the monoalkylation of 8-phenylmenthyl
phenylacetate (see J Org Chem, 1994, 59, 5343-5346). It is also known to prepare substituted
15 benzaldehydes by heating a substituted phenyl-lithium compound with ethyl orthoformate or
N-methylformanilde and hydrolysing with acid the intermediate compound so formed (see,
for example, Organic Chemistry, voll, by I L Finar, 3rd edition, 1959, p 629). There is no
indication, however, that lithiated bases could be successfully employed in the formylation
and subsequent methylation of 2-pyrimidinyloxy substituted phenyl acetates in order to
20 convert the acetate group to theE-isomer of methyl a.-phenyl-f3-methoxyacrylate group.
25
According to the present invention there is provided a process for the preparation of a
compound of the general formula (I):
(I)
wherein R1 is a 4-pyrimidinyl ring substituted at the 6-position by halo (especially chloro),
hydroxy, 2-cyanophenoxy, 2,6-difluorophenoxy, 2-nitrophenoxy or 2-thiocarboxamido-
30 phenoxy and R2 is any group which can be transesterified to form a methyl ester, which
comprises treating a compound of general formula (ll):
4
(IT)
5
wherein R1 and R2 have the meanings given above, with a formylating agent and
10 subsequently treating the formylated product with .a methylating agent.
The process is of particular interest where R1 is a 4-pyrimidinyl ring substituted at the
6-position by chloro or 2-cyanophenoxy.
The term halo includes fluoro, chloro, bromo and iodo. When used in the context of
the definition of R 1 as a substituent in the 6-position of a 4-pyrimidinyl ring, it is preferably
15 chloro.
The group R2 is suitably a C1_s alkyl group or a benzyl or phenyl group in which the
phenyl rings are unsubstituted or may carry one or more substituents compatible with the
susceptibility of the group to be transesterif.ied intn.a methyl group. Most conveniently R2 is,
methyl.
20 Except where otherwise stated, alkyl groups .will normally contain from 1 to 8,
typically from 1 to 6, for example 1 to 4, carbon atoms in the form of straight or branched
chains. Specific examples are methyl, ethyl, n-and iso-propyl, n-, sec-, iso- and tert-butyl, npentyl,
n-hexyl and n-octyl.
Suitable formylating agents include those of general formula R10-CHO, wherein R1
25 is an aliphatic group containing from 1 to 8 carbon atoms, typically a C1_4 alkyl group, or an
optionally substituted aromatic group, for example, an optionally substituted phenyl group
such as 4-nitrophenyl. Other suitable formylating agents include N-disubstituted formamides,
such as N-methylformanilide, and N-formylimidazole.
Suitable methylating agents are compounds of the general formula MeL wherein Me
30 is methyl and L is a good leaving group such as a halide. Methyl iodide is particularly
suitable.
5
The treatment is conveniently carried out in an organic solvent, suitably an aprotic
solvent, at a temperature between -80°C (ii!-pproximately the temperature achieved using qry
ice, i.e. solid carbon dioxide, for cooling) and 25°C (the upper end of the 'ambient
temperature' range). The formylation step is suitably carried out at a temperature between
5 -80°C and -40°C, preferably -78°C and -60°C. The methylation step can be carried out at
higher temperatures, suitably at a temperature between -20°C and 25°C, for example between
-1 0°C and 1 0°C, typically at about 0°C.
Examples of aprotic solvents are ethers such as diethyl ether, tetrahydrofuran, glyme
(1,2-dimethoxyethane) and diglyme (the dimethyl ether of diethylene glycol), 1-methyl-2-
10 pyrrolidinone, tetramethylenediamine and dimethylfonnamide. Tetrahydrofuran and glyme
are particularly suitable.
15
Because of the unsymmetically substituted double bond of its vinylic group, the
compound of general formula (ll) may exist in the form of a mixture of the (E) and {Z)
geometric isomers:
It may also exist iti the for.rrl of its tautomer:
It is believed that one of the (E)- and (Z)-isomers predominates greater than 90%, but
this invention embraces both the (E)- and (Z)-isomers, the tautomeric form and mixtures
20 thereof in all proportions, including those which consist substantially of the (E)-isomer and
those which consist substantially of the (Z)-isomer.
The general formula (IT) is, therefore, to be read as including the (E)- and (Z)-isomers
and the tautomer, either individually or as any mixtures thereof.
6
5
10
15
20
25
The compound of general formula (II), which is a novel compound and forms another
aspect of the present invention, may be prepared by treating a compound of general formula
(ill):
(III)
wherein R 1 and R2 have the meanings given above, with a lithium base.
Suitable lithium bases include those of general formula R'R"NLi wherein R' and R"
are independently an aliphatic group containing from 1 to 8 carbon atoms, typically a C1_4
alkyl group, or an optionally substituted aromatic group, for example, an optionally
substituted phenyl group. A particularly suitable lithium base of this type is lithium
diisopropylamide. Another suitable lithium base is lithium bis(trimethylsilyl)amide.
The compound of the general formula (III) may be prepared as described in EP-A-
0382375 and EP-A-0242081.
The treatment is conveniently carried out in an organic solvent, suitably an aprotic
solvent, at a temperature between -80°C and -40°C, preferably .-78°C and -60°C Examples.
of aprotic solvents are given above.
This process for preparing the compound of general formula Cm forms another aspect
• j ~ • ~
of the present invention.
Conveniently the two processes, viz. the formation of the lithium compound (IT) and
the conversion of compound em to the compound (I), can be carried out in a 'one pot'
process using the same solvent medium.
Typically, a solution of the 2-substituted phenylacetate {ill) in a dry aprotic solvent is
cooled to -78°C and the lithium base added with stirring. This is followed by addition ofthe
formylating agent and stirring is continued at around this temperature. After allowing the
temperature to rise to about 0°C, the methylating agent is added and the mixture stirred at
ambient temperature until no further reaction takes place. The product (compound (I)) may
30 be isolated by drowning the mixture into water and extracting the product with a solvent such
as dichloromethane. The extract is dried and the product isolated by removing the solvent by
evaporation.
7
5
Thus, according to another aspect of the invention, there is provided a process for the
preparation of a compound of the general formula (I):
(I)
wherein R1 is a 4-pyrimidinyl ring substituted at the 6-position by halo (especially chloro),
hydroxy, 2-cyanophenoxy, 2,6-difluorophenoxy, 2-nitrophenoxy or 2-thiocarboxamido-
10 phenoxy and R2 is any group which can be transesterified to form a methyl ester, which
comprises the steps:
(a) treating a compound of general formula (ill):
15 (III)
wherein R 1 and R 2 have the. meanings given above, with a lithium base; and
(b) treating the compound so formed with a formylating agent and subsequently treating the
20 formylated,.produGt with a .methylating agent.
The processes of the invention are useful for preparing the agricultural fungicide
azoxystrobin and analogues thereof and for preparing intermediate products for conversion
into azoxystrobin or analogues thereof. In the case where R2 is other than methyl, R2 may be
converted to methyl by standard transesterification techniques described in the chemical
25 literature.
As well as being useful as an intermediate for conversion to the compound (I), the
compound of general formula (IT) may also be used for conversion to related compounds by
reaction with other electrophiles.
Thus according to yet another aspect of the present invention, there is provided a
30 process for the preparation of a compound of general formula (IV):
8
5
(IV)
R3
wherein R1 is a 4-pyrimidinyl ring substituted at the 6-position by halo (especially chloro),
hydroxy, 2-cyanophenoxy, 2,6-difluorophenoxy, 2-nitrophenoxy or 2-thiocarboxamidophenoxy,
R2 is any group which can be transesterified to form a methyl ester and R3 is an
10 alkyl or acyl group, which comprises treating a compound of general formula (m:
(II)
wherein R1 ahd R2 have the meanings given above, with an alkylating or acylating agent.
Suitable alkylating agents include those compounds of the general formula R3X
15 wherein R3 is Cr.95%.
10
EXAMPLE3
This Example illustrates the preparation of methyl 2-[6-(2-cyanophenoxy)pyrimidin-
4-yloxy ]phenylacetoacetate
Anhydrous tetrahydrofuran (2 ml) was added to methyl2-[6-(2-cyanophenoxy)-
15 pyrimidin-4-yloxy]phenylacetate (O.lg at 94%w/w, 2.6x10-4mol; prepared as described in
Example 4) in a round-bottomed flask under a dry inert atmosphere. The solution was
agitated well and cooled to -78°C. A solution of lithium bis(trimethylsilyl)amide in
tetrahydrofuran (0.26ml, lmol/1, 2.6x10-4mol) was added followed by acetyl chloride'
(0.05ml, 7xl0-4mol). The mixture was stirred at -78°C for 1.5 hours then the solution was
, 20 . ·allowed to warm to room temperature overnight. The.reaction mixture was d{owned into:
saturated ammonium chloride (IOml) and extracted with dichloromethane (3x15m1). The
organic extracts were combined, dried over magnesium sulphate and concentrated by rotary
evaporation to give a yellow oily solid (O.lg at 49% purity). NMR and GC-MS spectra were
consistent with the product being methyl2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]-
25 phenylacetoacetate. Yield 44%.
EXAMPLE4
This Example illustrates the preparation of the methyl 2-[6-(2-
cyanophenoxy)pyrimidin-4-yloxy)phenylacetate used in Examples 1, 2 and 3.
Stage 1: Preparation of methyl 2-(6-chloropyrimidin-4-yloxy)phenyl acetate
30 Methyl2-hydroxyphenylacetate (54.7g, 0.3295mol) and 4,6 dichloropyrimidine
(50.0g at 97%w/w strength, 0.3295mol) were dissolved and stirred in dimethylformamide
(50ml) under a dry nitrogen atmosphere. Potassium carbonate (81.8g) was added and the
12
mixture was heated to 50°C and held for 2.5 hours. Completion of reaction was checked by
gas chromatography.
The reaction mixture was allowed to cool then filtered through a bed of pre-washed
celite. The celite was rinsed with dimethylfonnamide to remove residual product. A sample
5 was taken and partitioned between water and cyclohexane. The organic phase was dried over
magnesium sulphate and concentrated by rotary evaporation to give a pale yellow oil. The
oil was analysed by GC-MS and proton NMR.
10
The combined dimethylformamide solution of product was returned to the flask for
use in the next stage.
Stage 2: Preparation of methyl2-[6-(2-cyanophenoxy)pyrimidin-4-yloxylphenylacetate
2-Cyanophenol (43.1g, 0.3625mol) was added to the stirred solution of the Stage 1
product (91.4g, 0.3295mol) in dimethylfonnamide. Extra dimethylformamide (50ml) was
added followed by potassium carbonate (68.2g). The mixture was heated to l20°C, held for
15 20 minutes then cooled to 80°C.
Dimethylformamide was removed by vacuum distillation to a vacuum of 20rnmHg
and batch temperature of 100°C. The melt was cooled to 80°C before adding toluene
(210ml) followed by hot water (200ml). The mixture was re-heated to 80°C and stirred for
30 minutes. Agitation was then stopped and the mixture was allowed to stand for 30
· · 20 · '· minutes. The lower two layers were run from the vessel leaving the upper toluene phase ·
behind. Toluene was removed by vacuum distillation to a vacuum of 20mmHg and batch
temperature of 100°C. The residue was allowed to cool to <65°C.
The residue was refluxed in 120ml methanol to dissolve then allowed to cool to 40°C
and stirred for 4 hours before cooling to 0°C holding for 1 hour then leaving to stand for 64
25 hours at room temperature. The crystals were filtered, displacement washed with 2x25ml
methanol then pulled dry by vacuum. Product yield from methyl 2-hydroxyphenylacetate
was 23.7% theory. The product identity of the Stage 2 title product was confirmed by GCMS
and proton NMR spectroscopy.
30
13
5
EXAMPLES
This Example characterises and illustrates the stability of lithiated methyl
2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenylacetate (Compound ll where R 1 is
6-(2-cyanophenoxy)pyrimidin-4-yl and R2 is methyl)
Methyl2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenylacetate (17.2mg at
100%w/w, 4.76x10-5 mol; prepared as described in Example 4) was weighed into an NMR
tube and dissolved in tetrahydrofuran, d8 (0.75ml, anhydrous). The solution was cooled to
-70°C using an acetone/solid carbon dioxide bath. Lithium bis(trimethylsilyl)amide solution
(95J.tl of lmol/litre solution in hexanes, 9.53xl0-5mol) was added and the solution was well
10 mixed. Proton NMR spectra were taken periodically using a 500MHz instrument at -70°C
over 2 hours.
The solution was quenched at -70°C with glacial acetic acid (50~-tl, 8.3x10-4mol) and
mixed well. The quenched solution was mixed with 5ml water and extracted with
dichloromethane (2x10ml). The organics were combined, dried over magnesium sulphate
15 and concentrated by rotary evaporation. The residue was analysed by reverse phase HPLC
using UVNis detection and also by proton NMR. The proton NMR spectrum is shown in
Figure 1.
In Figure 1, signals at -0-2.5 are attributable to the lithium bis(trimethylsilyl)amide
and hexanes. Proton signals that correspond to the methoxy. and methylene groups in the
.20 neutral metl}yL2,..[6-:(2-c.yanophenoxy)pyrimidin-4-yloxy]ph~nylacet;:tte were, absent in all
spectra of the basic solution at -70°C. A singlet at b6.2 with an integral representing 1 proton
was observed and is consistent with the olefinic proton in the anionic species. Changes to all
the signals in the aromatic and aliphatic region were also evident. The ratio of both the
aromatic and aliphatic signals to the residual tetrahydrofuran signal (internal standard) was
25 constant throughout the two hour period. No other signals were formed or depleted
throughout the experiment suggesting the stability of the anion to be in excess of 2 hours at -
70°C.
30
HPLC and NMR data for the quenched material were consistent with methyl
2-[ 6-(2-cyanophenoxy )pyrimidin-4-yloxy ]phenylacetate (>97% ).
14
EXAMPLE6
This Example characterises lithiated methyl 2-[6-(2-cyanophenoxy)pyrimidin-
4-yloxy]phenylacetate (Compound II where R1 is 6-(2-cyanophenoxy)pyrimidin-4-yl and R2
is methyl) by its infra-red spectrum
5 Infra-red spectra in THF at -70°C were produced for methyl2-[6-(2-cyanophenoxy)-
pyrimidin-4-yloxy]phenylacetate before and after the addition of lithium
bis(trimethylsilyl)amide (see Figure 2).
In Figure 2, it can be seen that the carbonyl stretching band at 1740 cm-1 is not
present when methyl2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenylacetate is treated with
10 lithium bis(trimethylsilyl)amide.

We claim:
1. A compound of general formula (II)
wherein R1 is a 4-pyrimidinyl ring substituted at the 6-position by halo, hydroxy, 2-
cyanophenoxy, 2,6-difluorophenoxy, 2-nitrophenoxy or 2-thiocarboxamidophenoxy and
R2 is any group which can be transesterified to form a methyl ester.
2. A compound according to claim 1 wherein R1 is a 4-pyrimidinyl ring substituted at the 6-
position by 2-cyanophenoxy and R2 is methyl.
3. A process for the preparation of a compound of general formula (II) as defined in claim
1, which comprises treating a compound of general formula (III):
wherein R1 and R- have the meanings given in claim 1, with a lithium base.