FORM2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
[See Section 1 0 and Rule 13]
Title of the invention: PROCESS FOR PREPARATION OF
AZOXYSTROBIN
Name of the Applicant: UPL LIMITED
Nationality:
Address:
India
UPL R&D CENTRE, Plot Nos. B-20 & C,
12, Rd Number 16, Wagle Industrial Estate,
Thane West, Thane, Maharashtra 400604
India
The following specification particularly describes the invention and the manner in
which it is to be performed.
FIELD OF THE DISCLOSURE:
The present invention relates to a process for preparation of strobilurin compound.
More particularly the present invention relates to an improved process for
5 preparation of azoxystrobin.
BACKGROUND OF THE DISCLOSURE:
Strobilurins are broad spectrum fungicides and are widely used pesticides both in
foliar application and in seed treatment. Due to their wide spectrum activity profile,
strobilurins are important class of fungicides. Notable amongst this class of
10 compounds are azoxystrobin, trifloxystrobin, fluoxastrobin, and picoxystrobin.
15
EP 382375 discloses various derivatives of propenoic acid useful as fungicides,
including azoxystrobin. This patent also discloses process for preparation of
azoxystrobin and intermediates thereof.
US8552185 discloses a process for the preparation of azoxystrobin using 1,4-
diazabicyclo[2.2.2]octane (DABCO) as a catalyst, a base and various solvents.
W020 17060917 discloses a process for the preparation of azoxystrobin by reacting
cyanophenol with methyl 3- methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl)
20 acrylate in the presence of a catalyst selected from a group of crown ethers or
polyethylene glycol (PEG) and polar solvent such as dimethylacetamide, dimethyl
sulfoxide, dimethylformamide or N-methyl-2-pyrrolidone.
The prior art processes for the preparation of azoxystrobin involves use of polar
25 solvents like dimethylacetamide, dimethyl sulfoxide, dimethylformamide or Nmethyl-
2-pyrrolidone having boiling points above 150°C. Use of such solvents as
reaction solvent requires tedious workup procedures after completion of reaction
for removal of these solvents. Thereby, increasing the number of operations and
labour and hence increasing the cost of the process.
2
5
Furthermore, it is well known that during manufacture of azoxystrobin, its
undesired isomer is formed as an impurity. It is always desirable that the teclmical
grade active ingredient be relatively free of impurities.
The present inventors surprisingly found a process for preparation of azoxystrobin
that provides the desired compounds in higb yield and purity; wherein above
discussed problems are overcome.
10 OBJECTIVES OF THE DISCLOSURE:
It is an object of the present invention to provide a process for the preparation of
azoxystrobin.
It is an object of the present invention to provide an economic and eco-friendly
process for the preparation of azoxystrobin.
15 It is another object of the present invention to provide an efficient process for the
preparation of azoxystrobin substantially free of undesired isomer.
SUMMARY OF THE DISCLOSURE:
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-
20 yl)methanol or salts/derivatives thereof.
0
Formula (I)
3
5
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I) comprising a step of reacting a compound of formula
(IV) with a compound of formula (V) in presence of (1,4-Diazabicyclo[2.2.2]octan-
2-yl)methanol or salts/derivatives thereof;
HOJ?
CN
Formula (IV) Formula (V)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
dimethoxy) propanoate.
In an aspect of the present invention, there is provided a process for preparation of
10 a compound of formula (IV) comprising step of reacting a compound of formula
(II) with a compound of formula (III) in presence of (1 ,4-Diazabicyclo[2.2.2]octan-
2-yl)methanol or salts/derivatives thereof,
Formula (II)
CH3
I
0
0
Formula (IV)
Formula (Ill)
4
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
dimethoxy) propanoate.
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I)
5 comprising steps of
10
i) reacting a compound of formula (II) with a compound of formula (III)
in presence of ( 1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof to obtain a compound of formula (IV); and
ii) reacting the compound of formula (IV) with a compound of formula (V)
in presence of ( 1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof to obtain azoxystrobin of formula (I)
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I)
0
Formula (I}
0
'cH3
15 comprising a step of reacting a compound of formula (II) with a compound of
formula (VI) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof
5
0
Formula (II) Formula (VI)
DETAILED DESCRIPTION OF THE DISCLOSURE:
The present disclosure now will be described hereinafter with reference to the
accompanying examples, in which embodiments of the disclosure are shown. This
5 description is not intended to be a detailed catalogue of all the different ways in
which the disclosure may be implemented, or all the features that may be added to
the instant disclosure. For example, features illustrated with respect to one
embodiment may be incorporated into other embodiments, and features illustrated
with respect to a particular embodiment may be deleted from that embodiment.
10 Thus, the disclosure contemplates that in some embodiments of the disclosure, any
feature or combination of features set forth herein can be excluded or omitted. In
addition, numerous variations and additions to the various embodiments suggested
herein will be apparent to those skilled in the art in light of the instant disclosure,
which do not depart from the instant disclosure. Hence, the following descriptions
15 are intended to illustrate some particular embodiments of the disclosure, and not to
exhaustively specify all permutations, combinations and variations thereof.
Unless otherwise defined, all technical and scientific terms used herein have the
same meaning as commonly understood by one of ordinary skill in the art to which
20 this disclosure belongs. Although methods and materials similar or equivalent to
those described herein can be used in the practice or testing of the disclosure,
suitable methods and materials are described herein.
It must be noted that, as used in this specification, the singular forms "a", "an" and
25 ''the" include plural referents unless the content clearly dictates otherwise. The
6
t=s "preferred" and ''preferably" refer to embodiments of the disclosure that may
afford certain benefits, under certain circumstances.
As used herein, the terms "comprising", "including", "having", "containing",
5 "involving", and the like are to be understood to be open-ended i.e., to mean
including but not limited to.
As used herein, the t=s "about" or "approximately" are inclusive of the stated
value and means within an acceptable range of deviation for the particular value as
10 detennined by one of ordinary skill in the art, considering the measurement in
question and the error associated with measurement of the particular quantity (i.e.,
the limitations of the measurement system). For example, "about" can mean within
one or more standard deviations, or within ±10% or ±5% of the stated value.
15 Recitation of ranges of values are merely intended to serve as a shorthand method
of referring individually to each separate value falling within the range, unless
otherwise indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. The endpoints of all ranges
are included within the range and independently combinable. As used herein, all
20 numerical values or numerical ranges include integers within such ranges and
fractions of the values or the integers within ranges unless the context clearly
indicates otherwise. Thus, for example, reference to a range of 90- 100%, includes
91%, 92%, 93%, 94%, 95%, 95%, 97%, etc., as well as 91.1%, 91.2%, 91.3%,
91.4%, 91.5%, etc., 92.1%, 92.2%, 92.3%, 92.4%, 92.5%, etc., and so forth. All
25 methods described herein can be performed in a suitable order unless otherwise
indicated herein or otherwise clearly contradicted by context.
The use of any and all examples, or exemplary language (e.g., "such as"), is
intended merely to better illustrate the disclosure and does not pose a limitation on
30 the scope of the disclosure unless otherwise claimed. No language in the
7
specification should be construed as indicating any non -claimed element as
essential to the practice of the disclosure as used herein.
While the disclosure has been described with reference to an exemplary
5 embodiment, it will be understood by those skilled in the art that various changes
may be made, and equivalents may be substituted for elements thereof without
departing from the scope of the disclosure. In addition, many modifications may be
made to adapt a particular situation or material to the teachings of the disclosure
without departing from the essential scope thereof. Therefore, it is intended that the
10 disclosure is not limited to the particular embodiment disclosed as the best mode
contemplated for carrying out this disclosure, but that the disclosure will include all
embodiments falling within the scope of the appended claims.
As used herein, the term "agrochemical" is understood to denote an agricultural
15 chemical such as pesticides, fungicides, insecticides, acaricides, herbicides,
nematicides, plant growth regulators and can be used interchangeably.
20
As used herein, the term "fungicide" refers to the ability of a substance to decrease
or inhibit growth of fungi or oomycetes.
As described herein, the term "substantially free of undesired isomer" means
azoxystrobin having purity of more than 98% and comprises less than 2% of
undesired isomers, preferably less than 1%, more preferably less than 0.5%
As used herein, the term "compound of formula (II)" refers to 3-
25 (methoxymethylene) benzofuran-2(3H}-one and is used interchangeably
throughout the specification.
As used herein, the term "compound of formula (III)" refers to 4,6-
dichloropyrimidine and is used interchangeably throughout the specification.
As used herein, the term "compound of formula (V)" refers to 2-cyanophenol; and
30 is used interchangeably throughout the specification.
8
As used herein, the term "compound of formula (VI)" refers to 2-[(6-Chloro-4-
pyrimidinyl)oxy ]benzonitrile; and is used interchangeably throughout the
specification.
In an aspect of the present invention, there is provided a process for preparation of
5 azoxystrobin of formula (1) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-
yl)methanol or salts/derivatives thereof.
0
Formula (I}
In an embodiment, (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol is used as catalyst.
In another embodiment, salt of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol is
10 used as catalyst.
Salts of (1 ,4-Diazabicyclo[2.2.2]octan-2-yl)methanol include inorganic salts and
organic salts.
Inorganic salts include, but not limited to, hydrochloride, hydrobromide, sulphate,
nitrate and phosphate. Organic salts include, but not limited to, formate, acetate,
15 benzoate, trifluoroacetate, citrate, succinate, maleate, fumarate and oxalate.
20
In another embodiment, (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol derivatives
includes its stereoisomers.
In an embodiment, (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof is used in a catalytic amount.
In an embodiment, (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof is used in an amount ranging from about 0.01 mol% to
about 10 mol%.
9
In an embodiment, the catalyst (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof is used in an amount lesser than 8 mol%.
In an embodiment, the catalyst (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof is used in an amount from about 0.1 mol% to about 8 mol%,
5 preferably, from about 0.1 mol% to about 6 mol%. In an embodiment, (1,4-
Diazabicyclo[2.2.2]octan-2-yl)methanol is used in solid form or in form of a solution in
suitable solvent such as dipropyl glycol.
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I) comprising step of reacting a compound of formula (IV) with
10 compound of formula (V) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof;
HOY?
CN
Formula (IV) Formula (V)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
dimethoxy) propanoate.
15 In an embodiment, compound of formula (IV) is prepared by conventionally known
methods.
In an embodiment, compound of formula (V) is prepared by conventionally known
methods.
In an embodiment, said reaction of compound of formula (IV) with compound of formula
20 (V) is carried out in presence of a non-polar solvent selected hydrocarbons, aromatic
hydrocarbons, ethers or mixture thereof; and a base selected from aliphatic amines;
aromatic amines; hydroxides, carbonates, bicarbonates of alkali or alkaline earth metal;
or alkali metal alkoxides.
In an embodiment, the non-polar solvent used is selected from group comprising of
25 hydrocarbons such as pentane, hexane, heptane, etc.; aromatic hydrocarbons such
10
as benzene, toluene, xylene, ethylbenzene, tetralin etc.; ether such as
tetrahydrofuran, diethyl ether, or a mixture thereof.
In an embodiment, the non-polar solvent used is toluene.
In an embodiment, the reaction of compound of formula (IV) with compound of
5 formula (V) is carried out in presence of a base.
The base used is selected from organic or inorganic base. For example, the organic
base such as aliphatic or aromatic amines; and the inorganic base such as metal
hydroxides, carbonates or bicarbonates, or alkoxides are used. The metal of the
inorganic base can be an alkali or alkaline earth metal, for example alkali metals
10 such as lithium, sodium, potassium, etc.; and for example, alkaline earth metals
such as magnesium, calcium, strontium, barium, etc. In an embodiment, the reaction
of compound of formula (IV) with compound of formula (V) is carried out in
presence of potassium carbonate or sodium carbonate.
In an embodiment, the amount of base used with respect to compound of formula
15 (IV) is in the range from about 0.5 to 3 moles, preferably I to 2 moles.
In an embodiment, said reaction of compound of formula (IV) with compound of
formula (V) is carried out at temperature below 100°C.
In an embodiment, said reaction of compound of formula (IV) with compound of
formula (V) is carried out at temperature ranging from about 0 octo about 100°C.
20 In an embodiment, said reaction of compound of formula (IV) with compound of
formula (V) is carried out at temperature ranging from about 30 oc to about 95°C.
Preferably, said reaction of compound of formula (IV) with compound of formula
(V) is carried out at temperature ranging from about 40 oc to about 90°C.
Inventors of present invention observed that the processes provided in prior art
25 carried out at temperature of I 00°C or above it, leads to formation of undesired
isomer; and these prior art processes when carried out at lower temperature results
in incomplete reaction. To overcome these problems associated with prior art,
1 1
inventors of present invention have developed a process which can be carried at
temperature below 1 00°C and provides Azoxystrobin substantially undesired
tsomer.
In an embodiment, there is provided a process for preparation of azoxystrobin of
5 formula (I) comprising step of reacting a compound of formula (IV) with compound
of formula (V) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof; and toluene as solvent at temperature below 1 00°C;
HOY?
CN
Formula (IV) Formula (V)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
10 dimethoxy) propanoate.
In an aspect of the present invention, there is provided a process for preparation of
compound of formula (IV) comprising step of reacting compound of formula (II)
with compound of formula (III) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-
15 yl)methanol or salts/derivatives thereof,
12
Formula (II) Formula (Ill)
Formula (IV)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
dimethoxy) propanoate.
5 The reaction of compound of formula (II) with compound of formula (Ill) is carried
out in presence of a solvent selected from water, alcohols, glycolic solvents, esters,
amides, ethers, hydrocarbons or mixtures thereof and a suitable base selected from
the group of alkali metal alkoxides. The solvent used may be selected from, but not
limited to, water, alcohols like methanol, glycolic solvents like dipropylene glycol
10 esters like methyl formate, amides like dimethylformamide, ethers like
tetrahydrofuran, hydrocarbons like toluene, or mixtures thereof.
In an embodiment, the reaction of compound of formula (ll) with compound of
formula (ill) is carried out in presence of a mixture of methanol and methyl formate
as a solvent.
15 In an embodiment, the base selected from the group of alkali metal alkoxides such
as sodium methoxide.
In an embodiment, the reaction of compound of formula (ll) with compound of
formula (ill) results in compound of formula (Na); wherein Q is methyl (E)-2-(3-
methoxy) acrylate, and the formula is represented as below
13
Formula (IVa)
In an embodiment, the compound of formula (IVa) is (E)-methyl 2-[ 2-(6-
chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate.
In an embodiment, the reaction of compound of formula (II) with compound of formula
5 (III) results in compound of formula (IVb); wherein Q is methyl 2-(3,3-dimethoxy)
propanoate, and the formula is represented as below
Formula (IVb)
In an embodiment, the compound of formula (IVb) is methyl 2-[2-(6-chloropyrimidin-4-
yloxy)phenyl]-3,3-dimethoxypropanoate.
10 In an embodiment, the compound of formula (IV) is (E)-methyl2-[2-(6-chloropyrimidin-
4-yloxy) phenyl]-3-methoxypropenoate; methyl 2-[2-(6-chloropyrimidin-4-
yloxy)phenyl]-3,3-dimethoxypropanoate; or mixture thereof.
In an embodiment, the product obtained is mixture of compound of formula (IV a) and
(IVb).
15 The compound of formula (IVb) can be converted to compound of formula (IVa) by
known methods.
14
The compound of formula (IVb) in a mixture of compound of formula (IV a) and (IVb)
can be converted to compound of formula (IVa) by known methods.
The compound of formula (IVb) is converted to compound of formula (IVa) by reaction
with an acid catalyst like p-toluenesulphonic acid or potassium bisulphite; and an acid
5 anhydride like acetic anhydride. Said reaction is carried out in presence of non-polar
solvent and at a temperature ranging from 50 to 90°C.
The non-polar solvent is selected from group comprising of hydrocarbons such as
pentane, hexane, heptane, decalin, etc.; aromatic hydrocarbons such as benzene, toluene,
xylene, ethylbenzene, tetralin etc.; ether such as tetrahydrofuran, diethyl ether, or a
10 mixture thereof; preferably it is toluene.
ln an embodiment, said process for preparation of compound of formula (IV) is carried
out at temperature below 100°C.
ln an embodiment, said process for preparation of compound of formula (IV) is carried
out at temperature ranging from -10°C to 100°C.
15 ln an embodiment, said process for preparation of compound of formula (IV) is carried
out at temperature ranging from about 0°C to about 95°C
ln an embodiment, said process for preparation of compound of formula (IV) is carried
out at temperature ranging from about 0°C to about 90°C.
ln an embodiment, the compound of formula (IVa) is used in process for preparation of
20 azoxystrobin of Formula (I).
ln an embodiment, there is provided a process for preparation of azoxystrobin of formula
(I) comprising step of reacting a compound of formula (IV a) with compound of formula
(V) in presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or salts/derivatives
thereof as a catalyst.
25 ln an aspect of the present invention, there is provided a process for preparation of
azoxystrobin comprising steps of:
15
i) reacting compound of formula (II) with compound of formula (III) in presence of
(1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or salts/derivatives thereof to obtain
compound of formula (IV); and
ii) reacting a compound of formula (IV) with compound of formula (V) in presence of
5 (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or salts/derivatives thereof to obtain
azoxystrobin
In an embodiment, the compound of formula (IV) is the compound of formula (IVa) i.e.
(E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate; or
10 compound of formula (IVb) i.e. methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-
dimethoxypropanoate; or mixture thereof.
In an embodiment, the compound of formula (IV) obtained is (E)-methyl 2-[2-(6-
chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate.
15 In an embodiment, the step i) and step ii) of the process is carried out in presence of nonpolar
solvent selected from the group comprising of hydrocarbons, aromatic
hydrocarbons, ethers or mixture thereof.
In an embodiment, the non-polar solvent used is selected from group comprising of
hydrocarbons such as pentane, hexane, heptane, etc.; aromatic hydrocarbons such as
20 benzene, toluene, xylene, ethylbenzene, tetralin etc.; ether such as tetrahydrofuran,
diethyl ether, or a mixture thereof.
In an embodiment, the non-polar solvent used is toluene.
In an embodiment, the step i) and step ii) of the process is carried out at temperature
below 100°C.
25 In an embodiment, the step i) and step ii) of the process is carried out at temperature
ranging from about 0 octo about 100°C.
In an embodiment, the azoxystrobin of formula (I) obtained in step ii) is crystallized from
a solvent selected from an alcohol, for example methanol.
16
ln an embodiment, process according to present disclosure provides azoxystrobin of
Formula (I) in yield of more than 90%
ln an embodiment, process according to present disclosure provides azoxystrobin of
Formula (I) in yield of more than 95%, preferably more than 96%.
5 lnventors of present invention surprisingly found that said process for preparation of
azoxystrobin of formula (I) according to present invention when carried out at
temperature below 100°C results in highly pure azoxystrobin with substantially less
amount of undesired Z-isomer; and
ln an embodiment, the azoxystrobin of formula (I) obtained is substantially free of
10 undesired Z-isomer.
ln an embodiment, the azoxystrobin of formula (I) obtained has the undesired Z-isomer
less than about 2%, preferably less than 1%.
ln an embodiment, the azoxystrobin of formula (I) obtained has the undesired Z-isomer
less than about 0.5%.
15 ln an embodiment, there is provided a process for preparation of azoxystrobin of formula
(I) substantially free of the undesired Z-isomer,
20
comprising steps of
i) reacting compound of formula (IT) with compound of formula (ill) in
ii)
presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof to obtain compound of formula (IV); and
reacting a compound of formula (IV) with compound of formula (V) in
presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof to obtain azoxystrobin of formula (I);
wherein step i) and ii) are carried out using toluene as a solvent and at temperature
25 below 100°C.
ln an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of formula (I)
17
5
10
15
0
Formula (I)
comprising step of reacting compound of formula (II) with compound of formula
(VI) m presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof as a catalyst.
0
Formula (II) Formula (VI)
Advantages of the Invention
1. The present invention provides Azoxystrobin of formula (I) in high yield
and purity.
2. The present invention provides highly pure Azoxystrobin of formula (I),
substantially free of undesired isomer.
3. The present invention avoids use of large volumes of highly polar solvents
such as Dimethylacetarnide, Dimethyl sulfoxide, Dimethylformarnide and
N-methyl-2-pyrrolidone; and hence related tedious workup procedures.
4. The present invention provides an economical, simple and industrially
viable process for preparation of Azoxystrobin of formula (I).
18
EXAMPLES
The following examples are presented to provide what is believed to be the most
useful and readily understood description of procedures and conceptual aspects of
this invention. The examples provided below are merely illustrative of the invention
5 and are not intended to limit the same to disclosed embodiments. Variations and
changes obvious to one skilled in the art are intended to be within the scope and
nature of the invention.
Method of analysis:
High Performance Liquid Chromatography (HPLC):
10 Samples were analysed on high performance liquid chromatograph with UV
detector using ODS3, Inertsil (250 mm x 4.6 mm, 5 Jl).
Mobile Phase - Acetonitrile : 0.1% Ortho-phosphoric acid in water
Example 1: Process for preparation of (E) methyl 2-[2-(6-chloropyrimidin-4-
yloxy) phenyl]-3-methoxypropenoate i.e. compound of formula (IVa)
15 To a stirred mixture of 3-(methoxymethylene) benzofuran-2(3H)-one (95% pure,
93g, 0.5 mole), 4,6-dichloropyrimidine (92g, 0.6 mole) and methyl formate (285g)
was added 30% sodium methoxide in methanol (117g, 0.65 mole) followed by
addition of catalyst (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol (0.36g, 0.0025
mole, 0.5 mole%). The reaction mixture was then maintained at 0 to l0°C for 2-3
20 hour. Methyl formate was then distilled off from the mixture. Toluene (350 ml) and
water (200 ml) were added to the remaining residue and the mixture was stirred at
60-70°C. The mixture was cooled to room temperature and the organic layer was
separated. The organic layer was subjected to dehydration and subsequent
demethanolysis. After completion of reaction, the organic layer was the washed
25 with 5% sodium bicarbonate solution followed by distillation of toluene to obtain a
reaction mass. The reaction mass was then recrystallised using methanol to get 134g
of (E) methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate in
>95% purity and in 79% yield.
19
Example 2: Process for preparation of Azoxystrobin of formula (I)
Toluene (440ml), (E) methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-
methoxypropenoate (94.36% pure, 136g, 0.40 mole), 2-cyano phenol (53.5g, 0.44
mole) and potassium carbonate (83g, 0.6 mole) were charged in reaction vessel and
5 stirred for 5-10 minutes. To this mixture was added 33% solution of ( 1,4-
Diazabicyclo[2.2.2]octan-2-yl)methanol in dipropyl glycol (4.5g, 0.010 mole, 2.6
mol%) and at 28 -30°C under stirring. The reaction mass was then heated to 85-
900C and maintained for 8 hours. After completion of the reaction, the mixture was
cooled, and water (200 ml) was added. The reaction mass was then stirred, and
10 layers were allowed to separate. The organic layer obtained (undesired Z isomer
content: 0.29%) was then subjected to distillation under vacuum till dryness to
obtain a reaction mass. The reaction mass was then recrystallised with methanol to
obtain solid product. The solid product obtained was filtered out, and dried to
provide Azoxystrobin: 155g. Purity: 99.7%.
15 Example 3: Process for preparation of Azoxystrobin of formula (I)
Toluene (440ml), (E) methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-
methoxypropenoate (94.36% pure, 136g, 0.40 mole), 33% solution of (1,4-
Diazabicyclo[2.2.2]octan-2-yl)methanol in dipropyl glycol (4.5g, 0.010 mole, 2.6
mol%) and potassium carbonate (83g, 0.6 mole) were charged in reaction vessel
20 and stirred for 5-10 minutes. To this mixture was added 2-cyano phenol (53.5g,
0.44 mole), at 28 -30°C under stirring. The reaction mass was then heated to 85-
900C and maintained for 8 hours. After completion of the reaction, the mixture was
cooled, and water (200ml) was added. The reaction mass was then stirred, and
layers were allowed to separate. The organic layer obtained (undesired Z isomer
25 content: 0.30%) was then subjected to distillation under vacuum till dryness to
obtain a reaction mass. The reaction mass was then recrystallised with methanol to
obtain solid product. The solid product obtained was filtered out and dried to
provide Azoxystrobin: 156g. Purity: >98%.
20
Example 4: Process for preparation of Azoxystrobin of formula (1)- Insitu
To a stirred mixture of 3-(methoxymethylene) benzofuran-2(3H)-one (95% pure,
93g, 0.5 mole), 4,6-dichloropyrimidine (95g, 0.625 mole,) and methyl formate
(285g) was added and stirred for 10 minutes and added catalyst (1,4-
5 Diazabicyclo[2.2.2]octan-2-yl)methanol (1.08g, 0.0025 mole, 0.5 mole%) as 33%
solution in dipropyl glycol. Followed by addition of 30% sodium methoxide in
methanol (117g, 0.65 mole) at 0-3°C within 18-20h. After addition was over, the
reaction mass was maintained at 0 to l0°C for 2-3 hour. Methyl formate was then
distilled off from the mixture. Toluene (350 ml) and water (200 ml) were added to
10 the remaining residue and the mixture was stirred at 60-70°C. The organic layer
was separated. The organic layer was subjected to dehydration and subsequent
demethanolysis.
After completion of reaction, the organic layer was then washed with 5% sodium
bicarbonate solution and the organic layer containing (E) methyl 2-[2-(6-
15 chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate was obtained. To this
organic layer containing (E) methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-
methoxypropenoate was added 2-cyano phenol (58g, 0.482 mole), potassium
carbonate (90.0g, 0.645mole) and 33% solution of (1,4-Diazabicyclo[2.2.2]octan-
2-yl)methanol in dipropyl glycol (4.8g, 0.0118 mole, 2.6 mol%) at room
20 temperature under stirring. The reaction mass was then heated to 85-86°C and
maintained for 8 hours. After completion of the reaction, the mixture was cooled to
50-55°C and water (125ml) was added. The reaction mass was then stirred, and
layers were allowed to separate. The organic layer was then subjected to distillation
under vacuum till dryness to obtain a reaction mass. The reaction mass was then
25 recrystallised with methanol to obtain solid product. The solid product obtained was
filtered out, and dried to provide Azoxystrobin: 157g. Purity: >98.
Example 5: Comparative Example:
The process for preparation of azoxystrobin as described in US8552185 using 1,4-
Diazabicyclo[2.2.2]octane) was reproduced.
21
5
Comparison of azoxystrobin obtained in example I of present invention and that
obtained by using processes described in US8552185 using toluene as solvent is
provided in Table No. I for better demonstration of the advantages of present
invention and is not intended to limit the scope of invention in any way.
Table 1
Example 1 Comparative Comparative
of present Example 1 Example2
invention
2-cyanophenol 0.44 mole 0.432 mol 0.432 mol
methyl(E)-2-{2-[6- 0.40 mole 0.40 mol 0.40 mol
chloropyrimidin-4-
yloxy]phenyl}-3-
methoxyacrylate
(1,4- - !O mol % !O mol %
Diazabicyclo[2.2.2]octane)
(1,4- 2.6 mol% - -
Diazabicyclo[2.2.2]octan-
2-yl)methanol
Base Potassium 1,8- 1,8-
carbonate Diazabicyclo(5.4. Diazabicyclo(5.4.
O)undec-7 -ene O)undec-7 -ene
Solvent Toluene Toluene Toluene
Undesired Z-isomer 0.29% 0.50% 0.51%
22
5
10
15
20
We claim:
1. A process for preparation of azoxystrobin comprising a step of reacting a
compound of formula (IV) with a compound of formula (V) in presence of
( 1,4-Diazabicyc1o[2.2.2] octan-2-yl)methanol or salts/derivatives thereof;
Formula (IV)
HOi?
CN
Formula (V)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl
2-(3,3-dimethoxy) propanoate.
2. The process as claimed in claim 1, wherein the compound of formula (IV)
is (E)-methyl 2-[2-( 6-chloropyrimidin-4-yloxy) phenyl]-3-
methoxypropenoate; methyl 2-[2-( 6-chloropyrimidin-4-yloxy )phenyl]-3,3-
dimethoxypropanoate; or mixture thereof.
3. The process as claimed in claim 1, wherein the reaction is carried out in
presence of a non-polar solvent selected from the group comprising of
hydrocarbons, aromatic hydrocarbons, ethers or mixture thereof; and a base
selected from the group comprising of aliphatic amines; aromatic amines;
hydroxides, carbonates, bicarbonates of alkali or alkaline earth metal; or
alkali metal alkoxides.
4. The process as claimed in claim 3, wherein the non-polar solvent is toluene.
5. The process as claimed in claim 1, wherein the(1,4-
Diazabicyclo[2.2.2]octan-2-yl)methanol or salts/derivatives thereof is in
23
5
10
15
20
solid form or in form of a solution in suitable solvent such as dipropyl
glycol.
6. The process as claimed m claim 1, wherein the(1,4-
Diazabicyclo[2.2.2]octan-2-yl)methanol or salts/derivatives thereof is in an
amount from about 0.1 mol% to about 8 mol%.
7. The process as claimed in claim 1, wherein the reaction is carried out at
temperature ranging from about 0 °C to about 1 00°C.
8. A process for preparation of compound of formula (IV) comprising step of
reacting compound of formula (II) with compound of formula (Til) in
presence of (1,4-Diazabicyclo[2.2.2]octan-2-yl)methanol or
salts/derivatives thereof,
CH3 I
00:0
Formula (II)
Formula (IV)
Formula (Ill)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl
2-(3,3-dimethoxy) propanoate.
9. The process as claimed in claim 8, wherein the reaction is carried out in
presence of a solvent selected from group comprising of water, alcohols,
glycolic solvents, esters, amides, ethers, hydrocarbons or mixtures thereof;
and a base selected from alkali metal alk:oxide.
10. A process for preparation of azoxystrobin comprising steps of
24
i) lelldillg cowpouwl af fomlllla (Il) with compcnmd of iilJmula (ID) ia.
pzuei!C4 of (1,4-Diazabicydo(l.2.2]odan-2-yl)methanol or saltrl&rivatives
tbereofto oblainehl!iJ!