The following specification particularly describes the invention and the manner in
which it is to be performed.
1
FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
THE PATENT RULES, 2003
COMPLETE SPECIFICATION
[See Section 10 and Rule 13]
Title of the invention: PROCESS FOR PREPARATION OF
AZOXYSTROBIN
Name of the Applicant: UPL LIMITED
Nationality: India
Address: UPL R&D CENTRE, Plot Nos. B-20 & C,
12, Rd Number 16, Wagle Industrial Estate,
Thane West, Thane, Maharashtra 400604
India
2
FIELD OF THE DISCLOSURE:
The present invention relates to a process for preparation of a strobilurins. More
particularly the present invention relates to a process for preparation of
5 azoxystrobin in high yield and purity.
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,
10 strobilurins are important class of fungicides. Notable amongst this class of
compounds are azoxystrobin, trifloxystrobin, fluoxastrobin, and picoxystrobin.
EP 382375 discloses various derivatives of propenoic acid useful as fungicides,
including azoxystrobin. This patent also discloses process for preparation of
15 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.
Although DABCO as catalyst provides azoxystrobin in good yield, use of DABCO
20 is not recommended as it cannot be easily recycled and reused, and thus is not a
suitable catalyst.
WO2017060917 discloses a process for the preparation of azoxystrobin by reacting
cyanophenol with methyl 3- methoxy (2-(2-(6-chloropyrimidine)-4-yl) oxyphenyl)
acrylate in the presence of a catalyst selected form a group of crown ethers or
25 polyethylene glycol (PEG) and polar solvent such as dimethylacetamide, dimethyl
sulfoxide, dimethylformamide or N-methyl-2-pyrrolidone.
Most of the prior art processes for the preparation of azoxystrobin involves use of
polar solvents like dimethylacetamide, dimethyl sulfoxide, dimethylformamide or
N-methyl-2-pyrrolidone having boiling points above 150°C. Use of such solvents
3
as reaction solvent requires higher reaction temperatures and tedious workup
procedures for removal of these solvents after completion of reaction. Thereby,
increasing the cost of the process, number of operations and labour.
The present inventors surprisingly found a 5 process for preparation of azoxystrobin
that provides the desired compounds in high yield and purity; wherein above
discussed problems are overcome.
OBJECTIVES OF THE DISCLOSURE:
10 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.
It is another object of the present invention to provide an efficient process for the
15 preparation of azoxystrobin which significantly improve the yield of azoxystrobin.
SUMMARY OF THE DISCLOSURE:
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of Formula (I)
O
N N
O
CN O
CH3
O
O
H3C
Formula (I)
20 comprising step of
reacting a compound of formula (II) with compound of formula (III);
4
CN
OH
Formula (II)
N N
Cl O
Q
Formula (III)
wherein Q is selected from methyl 􀂼-2-(3-methoxy) acrylate, and methyl 2-(3,3-
dimethoxy) propanoate;
OR
5 reacting compound of formula (IV) with compound of formula (V)
O
O
O
CH3
Formula (IV)
Formula (V)
O
CN
N N
Cl
wherein said reactions are carried out in a non-polar solvent in presence of Nmethyl
pyrrolidine and a polarity enhancer.
10 In another aspect of the present invention, there is provided a process for
preparation of compound of Formula (I) comprising step of reacting compound of
formula (II) with compound of formula (III) in a non-polar solvent in presence of
N-methyl pyrrolidine and a polarity enhancer.
15 In another aspect of the present invention, there is provided a process for
preparation of azoxystrobin of Formula (I) comprising step of reacting compound
of formula (IV) with compound of formula (V) in a non-polar solvent in presence
of N-methyl pyrrolidine and a polarity enhancer.
5
In yet another aspect of the present invention, there is provided a process for
preparation of azoxystrobin of Formula (I) comprising step of
reacting compound of formula (II) with compound of formula (III);
OR
reacting a 5 compound of formula (IV) with compound of formula (V);
in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity enhancer
wherein the weight ratio of the polarity enhancer to non-polar solvent is in the range
of about 1:5 to about 1:20.
10 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
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
15 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.
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
20 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
are intended to illustrate some particular embodiments of the disclosure, and not to
exhaustively specify all permutations, combinations and variations thereof.
25
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
this disclosure belongs. Although methods and materials similar or equivalent to
6
those described herein can be used in the practice or testing of the disclosure,
suitable methods and materials are described herein.
􀀬􀁗􀀃􀁐􀁘􀁖􀁗􀀃􀁅􀁈􀀃􀁑􀁒􀁗􀁈􀁇􀀃􀁗􀁋􀁄􀁗􀀏􀀃􀁄􀁖􀀃􀁘􀁖􀁈􀁇􀀃􀁌􀁑􀀃􀁗􀁋􀁌􀁖􀀃􀁖􀁓􀁈􀁆􀁌􀁉􀁌􀁆􀁄􀁗􀁌􀁒􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁖􀁌􀁑􀁊􀁘􀁏􀁄􀁕􀀃􀁉􀁒􀁕􀁐􀁖􀀃􀂳􀁄􀂴􀀏􀀃􀂳􀁄􀁑􀂴􀀃􀁄􀁑􀁇􀀃
􀂳􀁗􀁋􀁈􀂴􀀃 􀁌􀁑􀁆􀁏􀁘􀁇􀁈􀀃 􀁓􀁏􀁘􀁕􀁄􀁏􀀃 5 􀁕􀁈􀁉􀁈􀁕􀁈􀁑􀁗􀁖􀀃 􀁘􀁑􀁏􀁈􀁖􀁖􀀃 􀁗􀁋􀁈􀀃 􀁆􀁒􀁑􀁗􀁈􀁑􀁗􀀃 􀁆􀁏􀁈􀁄􀁕􀁏􀁜􀀃 􀁇􀁌􀁆􀁗􀁄􀁗􀁈􀁖􀀃 􀁒􀁗􀁋􀁈􀁕􀁚􀁌􀁖􀁈􀀑􀀃 􀀷􀁋􀁈􀀃
􀁗􀁈􀁕􀁐􀁖􀀃􀂳􀁓􀁕􀁈􀁉􀁈􀁕􀁕􀁈􀁇􀂴􀀃􀁄􀁑􀁇􀀃􀂳􀁓􀁕􀁈􀁉􀁈􀁕􀁄􀁅􀁏􀁜􀂴􀀃􀁕􀁈􀁉􀁈􀁕􀀃􀁗􀁒􀀃􀁈􀁐􀁅􀁒􀁇􀁌􀁐􀁈􀁑􀁗􀁖􀀃􀁒􀁉􀀃􀁗􀁋􀁈􀀃􀁇􀁌􀁖􀁆􀁏􀁒􀁖􀁘􀁕􀁈􀀃􀁗􀁋􀁄􀁗􀀃􀁐􀁄􀁜􀀃
afford certain benefits, under certain circumstances.
􀀤􀁖􀀃 􀁘􀁖􀁈􀁇􀀃 􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃 􀁗􀁋􀁈􀀃 􀁗􀁈􀁕􀁐􀁖􀀃 􀂳􀁆􀁒􀁐􀁓􀁕􀁌􀁖􀁌􀁑􀁊􀂴􀀏􀀃 􀂳􀁌􀁑􀁆􀁏􀁘􀁇􀁌􀁑􀁊􀂴􀀏􀀃 􀂳􀁋􀁄􀁙􀁌􀁑􀁊􀂴􀀏􀀃 􀂳􀁆􀁒􀁑􀁗􀁄􀁌􀁑􀁌􀁑􀁊􀂴􀀏􀀃
10 􀂳􀁌􀁑􀁙􀁒􀁏􀁙􀁌􀁑􀁊􀂴􀀏􀀃 􀁄􀁑􀁇􀀃 􀁗􀁋􀁈􀀃 􀁏􀁌􀁎􀁈􀀃 􀁄􀁕􀁈􀀃 􀁗􀁒􀀃 􀁅􀁈􀀃 􀁘􀁑􀁇􀁈􀁕􀁖􀁗􀁒􀁒􀁇􀀃 􀁗􀁒􀀃 􀁅􀁈􀀃 􀁒􀁓􀁈􀁑-ended i.e., to mean
including but not limited to.
􀀤􀁖􀀃􀁘􀁖􀁈􀁇􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁗􀁈􀁕􀁐􀁖􀀃􀂳􀁄􀁅􀁒􀁘􀁗􀂴􀀃􀁒􀁕􀀃􀂳􀁄􀁓􀁓􀁕􀁒􀁛􀁌􀁐􀁄􀁗􀁈􀁏􀁜􀂴􀀃􀁄􀁕􀁈􀀃􀁌􀁑􀁆􀁏􀁘􀁖􀁌􀁙􀁈􀀃􀁒􀁉􀀃􀁗􀁋􀁈􀀃􀁖􀁗􀁄􀁗􀁈􀁇􀀃
value and means within an acceptable range of deviation for the particular value as
15 determined 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.,
􀁗􀁋􀁈􀀃􀁏􀁌􀁐􀁌􀁗􀁄􀁗􀁌􀁒􀁑􀁖􀀃􀁒􀁉􀀃􀁗􀁋􀁈􀀃􀁐􀁈􀁄􀁖􀁘􀁕􀁈􀁐􀁈􀁑􀁗􀀃􀁖􀁜􀁖􀁗􀁈􀁐􀀌􀀑􀀃􀀩􀁒􀁕􀀃􀁈􀁛􀁄􀁐􀁓􀁏􀁈􀀏􀀃􀂳􀁄􀁅􀁒􀁘􀁗􀂴􀀃􀁆􀁄􀁑􀀃􀁐􀁈􀁄􀁑􀀃􀁚􀁌􀁗􀁋􀁌􀁑􀀃
one or more standard deviations, or within ±10% or ±5% of the stated value.
20 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
25 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
30 methods described herein can be performed in a suitable order unless otherwise
indicated herein or otherwise clearly contradicted by context.
7
􀀷􀁋􀁈􀀃 􀁘􀁖􀁈􀀃 􀁒􀁉􀀃 􀁄􀁑􀁜􀀃 􀁄􀁑􀁇􀀃 􀁄􀁏􀁏􀀃 􀁈􀁛􀁄􀁐􀁓􀁏􀁈􀁖􀀏􀀃 􀁒􀁕􀀃 􀁈􀁛􀁈􀁐􀁓􀁏􀁄􀁕􀁜􀀃 􀁏􀁄􀁑􀁊􀁘􀁄􀁊􀁈􀀃 􀀋􀁈􀀑􀁊􀀑􀀏􀀃 􀂳􀁖􀁘􀁆􀁋􀀃 􀁄􀁖􀂴􀀌􀀏􀀃 􀁌􀁖􀀃
intended merely to better illustrate the disclosure and does not pose a limitation on
the scope of the disclosure unless otherwise claimed. No language in the
specification should be construed 5 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
embodiment, it will be understood by those skilled in the art that various changes
10 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
disclosure is not limited to the particular embodiment disclosed as the best mode
15 contemplated for carrying out this disclosure, but that the disclosure will include all
embodiments falling within the scope of the appended claims.
􀀤􀁖􀀃􀁘􀁖􀁈􀁇􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁗􀁈􀁕􀁐􀀃􀂳􀁄􀁊􀁕􀁒􀁆􀁋􀁈􀁐􀁌􀁆􀁄􀁏􀂴􀀃􀁌􀁖􀀃􀁘􀁑􀁇􀁈􀁕􀁖􀁗􀁒􀁒􀁇􀀃􀁗􀁒􀀃􀁇􀁈􀁑􀁒􀁗􀁈􀀃􀁄􀁑􀀃􀁄􀁊􀁕􀁌􀁆􀁘􀁏􀁗􀁘􀁕􀁄􀁏􀀃
chemical such as pesticides, fungicides, insecticides, acaricides, herbicides,
20 nematicides, plant growth regulators and can be used interchangeably.
􀀤􀁖􀀃􀁘􀁖􀁈􀁇􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁗􀁈􀁕􀁐􀀃􀂳􀁉􀁘􀁑􀁊􀁌􀁆􀁌􀁇􀁈􀂴􀀃􀁕􀁈􀁉􀁈􀁕􀁖􀀃􀁗􀁒􀀃􀁗􀁋􀁈􀀃􀁄􀁅􀁌􀁏􀁌􀁗􀁜􀀃􀁒􀁉􀀃􀁄􀀃􀁖􀁘􀁅􀁖􀁗􀁄􀁑􀁆􀁈􀀃􀁗􀁒􀀃􀁇􀁈􀁆􀁕􀁈􀁄􀁖􀁈􀀃
or inhibit growth of fungi or oomycetes.
25 􀀤􀁖􀀃􀁘􀁖􀁈􀁇􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁗􀁈􀁕􀁐􀀃􀂳􀁉􀁘􀁑􀁊􀁌􀁆􀁌􀁇􀁄􀁏􀁏􀁜􀀃􀁈􀁉􀁉􀁈􀁆􀁗􀁌􀁙􀁈􀀃􀁄􀁐􀁒􀁘􀁑􀁗􀂴􀀃􀁌􀁖􀀃􀁄􀁑􀀃􀁄􀁐􀁒􀁘􀁑􀁗􀀃􀁒􀁉􀀃􀁄􀁆􀁗􀁌􀁙􀁈􀀃
ingredient such as a fungicide which causes an adversely modifying effect and
includes deviations from natural development, killing, regulation, desiccation,
retardation, and the like.
30 􀀤􀁖􀀃􀁇􀁈􀁖􀁆􀁕􀁌􀁅􀁈􀁇􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀏􀀃􀁗􀁋􀁈􀀃􀁗􀁈􀁕􀁐􀀃􀂳high 􀁜􀁌􀁈􀁏􀁇􀂴􀀃􀁒􀁉􀀃compound means that the yield of a
product produced by a process is increased by a measurable amount over the yield
8
of the same product produced under the same conditions by another process, but
without the improvement in the process as described herein.
􀂳􀀳􀁒􀁏􀁄􀁕􀁌􀁗􀁜􀀃􀁈􀁑􀁋􀁄􀁑􀁆􀁈􀁕􀂴􀀃􀁄􀁖􀀃􀁘􀁖􀁈􀀃􀁋􀁈􀁕􀁈􀁌􀁑􀀃􀁕􀁈􀁉􀁈􀁕􀁖􀀃􀁗􀁒􀀃􀁄􀀃component that improves the polarity
of overall reaction system thereby facilitating 5 the completion of the reaction at
temperature below 100°C.
As used herein, the term 􀂳􀁆􀁒􀁐􀁓􀁒􀁘􀁑􀁇􀀃􀁒􀁉􀀃􀁉􀁒􀁕􀁐􀁘􀁏􀁄􀀃􀀋􀀬􀀬􀀌􀂴􀀃refers to 2-cyanophenol; and
is used interchangeably throughout the specification.
10 As used herein, the term 􀂳􀁆􀁒􀁐􀁓􀁒􀁘􀁑􀁇􀀃 􀁒􀁉􀀃 􀁉􀁒􀁕􀁐􀁘􀁏􀁄􀀃 􀀋􀀬V􀀌􀂴􀀃 refers to 3-
(methoxymethylene) benzofuran-2(3H)-one and is used interchangeably
throughout the specification.
As used herein, the term 􀂳􀁆􀁒􀁐􀁓􀁒􀁘􀁑􀁇􀀃 􀁒􀁉􀀃 􀁉􀁒􀁕􀁐􀁘􀁏􀁄􀀃 􀀋􀀹􀀌􀂴􀀃 refers to 2-[(6-Chloro-4-
pyrimidinyl)oxy]benzonitrile; and is used interchangeably throughout the
15 specification.
As used herein, the term 􀂳􀁆􀁒􀁐􀁓􀁒􀁘􀁑􀁇􀀃 􀁒􀁉􀀃 􀁉􀁒􀁕􀁐􀁘􀁏􀁄􀀃 􀀋􀀹􀀬􀀌􀂴􀀃 refers to 4,6-
dichloropyrimidine and is used interchangeably throughout the specification.
In an aspect of the present invention, there is provided a process for preparation of
azoxystrobin of Formula (I)
20
O
N N
O
CN O
CH3
O
O
H3C
Formula (I)
9
comprising step of reacting a compound of formula (II) with compound of formula
(III);
CN
OH
Formula (II)
N N
Cl O
Q
Formula (III)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
5 dimethoxy) propanoate;
OR
reacting compound of formula (IV) with compound of formula (V)
O
O
O
CH3
Formula (IV)
Formula (V)
O
CN
N N
Cl
wherein said reactions are carried out in non-polar solvent in presence of N-methyl
10 pyrrolidine and a polarity enhancer.
In an embodiment, the process for preparation of azoxystrobin of Formula (I)
O
N N
O
CN O
CH3
O
O
H3C
Formula (I)
10
comprising a step of reacting compound of formula (II) with compound of
formula (III)
CN
OH
Formula (II)
N N
Cl O
Q
Formula (III)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl 2-(3,3-
5 dimethoxy) propanoate;
in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity enhancer.
In an embodiment, the compound of formula (III) is compound of formula (IIIa) i.e. (E)-
methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-methoxypropenoate; or compound
of formula (IIIb) i.e. methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-
1d0im ethoxypropanoate; or mixture thereof.
N N
Cl O
H3COOC
OCH3
Formula (IIIa)
N N
Cl O
H3COOC CH(OCH3)2
Formula (IIIb)
In an embodiment, the compound of formula (III) is selected from (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
15 In an embodiment, reaction of compound of formula (II) with compound of formula
(III) is carried out at temperature below 100°C.
In an embodiment, reaction of compound of formula (II) with compound of formula
(III) is carried out at temperature ranging from about 0°C to about 100°C.
11
In an embodiment, said reaction of compound of formula (II) with compound of
formula (III) is carried out at temperature ranging from 40°C to 100°C.
In a preferred embodiment, said reaction of compound of formula (II) with
compound of formula (III) is carried out at temperature ranging from 50°C to 95°C.
In an embodiment, reaction of 5 compound of formula (II) with compound of formula
(III) is carried out in about 1 to 15 hours.
In an embodiment, reaction of compound of formula (II) with compound of formula
(III) is carried out in about 5 to 12 hours.
In an embodiment, the compound of formula (III) used is prepared by reacting
10 compound of formula (IV) with compound of formula (VI) in a non-polar solvent
in presence of N-methyl pyrrolidine and a polarity enhancer.
N N
Cl Cl
Formula (VI)
In another embodiment, the compound of formula (III) is prepared by
conventionally known methods.
15 In an embodiment, the process for preparation of azoxystrobin of Formula (I)
comprising step of reacting a compound of formula (IV) with compound of formula
(V) in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity
enhancer.
In an embodiment, the catalytic amount of N-methyl pyrrolidine is used.
20 In an embodiment, the amount of N-methyl pyrrolidine used is in the range of 0.01
to 0.1 moles with respect to compound of formula (III).
In an embodiment, the non-polar solvent used is selected from group comprising of
hydrocarbons such as pentane, hexane, heptane, decalin, etc.; aromatic
12
hydrocarbons such 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
polarity enhancer used is selected from, but not limited to, group comprising of
N,N-dimethyl formamide, l,8-5 diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-
diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO),
1,4-Diazabicyclo[2.2.2]octane-2-methanol (DABCO-methanol), l,5,7-
triazabicyclo[4.4.0]dec-5-ene (TABDE), triethylamine (TEA),
tetramethylenediamine, dimethyloctylamine, dimethylaminopolystyrene,
10 quinuclidine-based molecule such as quinuclidine hydrochloride, 3-quinuclidinone
hydrochloride, 3-quinuclidinol; or salts and/or derivatives thereof.
In an embodiment, the polarity enhancer used is N,N-dimethyl formamide.
In an embodiment, the amount of polarity enhancer used is in the range of about 0.5
moles to about 2 moles with respect to compound of formula (III), preferably from
15 about 1 mole to about 1.5 moles. In an embodiment, the weight ratio of the polarity
enhancer to non-polar solvent is in the range of about 1:5 to about 1:20.
In an embodiment, the weight ratio of the polarity enhancer to non-polar solvent is
in the range of from about 1:5 to about 1:15. The inventor of present invention
observed that presence of polarity enhancer ensures completion of reaction by
20 optimizing the overall polarity of reaction system even at lesser temperature and
provides final product in high yield and purity.
In an aspect of the present invention, there is provided a process for preparation of
compound of Formula (I) comprising step of reacting compound of formula (II)
with compound of formula (III) in a non-polar solvent in presence of N-methyl
25 pyrrolidine and a polarity enhancer.
In an embodiment, the reaction of compound of formula (II) with compound of
formula (III) is carried out in presence of a base.
The base used is selected from organic or inorganic base.
13
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 such as lithium, sodium, potassium, etc.; and for example
5 alkaline earth metals such as magnesium, calcium, strontium, barium, etc
In an embodiment, the reaction of compound of formula (II) with compound of
formula (III) is carried out in presence of inorganic base selected from hydroxides,
carbonates, bicarbonates, or alkoxides of alkali or alkaline earth metal.
In an embodiment, the reaction of compound of formula (II) with compound of
10 formula (III) is carried out in presence of potassium carbonate.
In an embodiment the present invention, there is provided a process for preparation
of azoxystrobin of Formula (I) comprising step of reacting compound of formula
(II) with compound of formula (III) in toluene in presence of N-methyl pyrrolidine
and N, N-dimethyl formamide.
15 In an embodiment the present invention, there is provided a process for preparation
of azoxystrobin of Formula (I) comprising a step of reacting compound of formula
(II) with compound of formula (III) in toluene in presence of N-methyl pyrrolidine
and N, N-dimethyl formamide at temperature below 100°C.
In an embodiment, the weight ratio of N, N-dimethyl formamide to toluene is in the
20 range from about 1:5 to about 1:20.
In an embodiment, the weight ratio of N, N-dimethyl formamide to toluene is in the
range of about 1:5 to about 1:15. In yet another aspect of the present invention, there
is provided a process for preparation of azoxystrobin of Formula (I) comprising step
of
25 reacting compound of formula (II) with compound of formula (III);
OR
reacting a compound of formula (IV) with compound of formula (V);
14
in a non-polar solvent in presence of N-methyl pyrrolidine and an polarity enhancer
wherein the weight ratio of the polarity enhancer to non-polar solvent is in the range
of about 1: 5 to about 1: 20.
In an embodiment, the non-polar solvent used is toluene.
In an embodiment, the 5 polarity enhancer used is N, N-dimethyl formamide.
In an embodiment, the weight ratio of the polarity enhancer to non-polar solvent is
in the range of about 1: 5 to about 1: 15.
In an embodiment, the weight ratio of N, N-dimethyl formamide to toluene is in the
range of about 1: 10 to about 1: 14. In an embodiment, process according to present
10 provides azoxystrobin of Formula (I) in yield of more than 90%.
In an embodiment, process according to present provides azoxystrobin of Formula
(I) in yield of more than 95%, preferably more than 96%.
In an embodiment, there is provided a process for preparation of azoxystrobin of
Formula (I) comprising step of reacting a compound of formula (IV) with
15 compound of formula (V)
O
O
O
CH3
Formula (IV)
Formula (V)
O
CN
N N
Cl
in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity
20 enhancer.
Advantages of the Invention
15
1. The present invention provides Azoxystrobin of formula (I) in high yield
and purity.
2. The present invention avoids use of large volumes of highly polar solvents
such as Dimethylacetamide, Dimethyl sulfoxide, Dimethylformamide and
N-methyl-5 2-pyrrolidone; and hence related tedious workup procedures.
3. The present invention provides a process for preparation of Azoxystrobin of
formula (I) at temperature below 100°C.
4. The present invention provides an economical, simple and industrially
viable process for preparation of Azoxystrobin of formula (I)
10
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
15 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.
Methods:
High Performance Liquid Chromatography (HPLC):
20 Samples were analysed on high performance liquid chromatograph with UV
detector using ODS3, Inertsil (250 mm x 4.6 mm, 5 μ).
Mobile Phase - Acetonitrile : 0.1% Ortho-phosphoric acid in water
Example 1: Preparation of Azoxystrobin
Toluene (550ml), methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-
25 methoxypropenoate (160.35g), potassium carbonate (103.5g) and 2-cyano phenol
(66.7g) were charged in a reaction vessel. To this mixture N-methyl pyrrolidine
(2.15g, 5 mol%) and N, N-dimethyl formamide (45g) were added. The reaction
mass was then heated to 80-85°C and maintained for 8 to 10 hours under stirring.
16
After completion of the reaction, water was added, mixture was stirred, and layers
were allowed to separate. The organic layer was washed with 4-5% hypochlorite
solution and then the organic layer was subjected to distillation under vacuum till
dryness and the crude product obtained was recrystallised with methanol to obtain
5 194g of Azoxystrobin ( Yield: 96.2%) having purity of 98.29% (w/w).
Comparative Example: Preparation of Azoxystrobin (without using polarity
enhancer)
The process for preparation of azoxystrobin as described in example 1 was
followed, in the absence of N, N-dimethyl formamide. The comparative results are
10 presented in Table 1
Table 1
Example 1 of
present invention
Comparative
Example
2-cyanophenol 0.55 mole 0.55 mole
methyl(E)-2-{2-[6-
chloropyrimidin-4-
yloxy]phenyl}-3-
methoxyacrylate
0.5 mole 0.5 mole
N-methyl pyrrolidine 5 mol% 5 mol%
Base
(Potassium carbonate)
0.75 mole 0.75 mole
Polarity Enhancer
(N, N-dimethyl formamide)
45g -
Solvent (Toluene) 550g 550g
Yield 96.2% 86%
17
We claim:
1. A process for preparation of azoxystrobin of Formula (I)
O
N N
O
CN O
CH3
O
O
H3C
Formula (I)
comprising a step of reacting compound of formula (II) with compound of
5 formula (III)
CN
HO
Formula (II)
N N
Cl O
Q
Formula (III)
wherein Q is selected from methyl (E)-2-(3-methoxy) acrylate, and methyl
2-(3,3-dimethoxy) propanoate;
in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity
10 enhancer.
2. The process as claimed in claim 1, wherein the compound of formula (III)
is selected from (E)-methyl 2-[2-(6-chloropyrimidin-4-yloxy) phenyl]-3-
methoxypropenoate; methyl 2-[2-(6-chloropyrimidin-4-yloxy)phenyl]-3,3-
15 dimethoxypropanoate; or mixture thereof.
3. The process as claimed in claim 1, wherein said reaction is carried out at
temperature ranging from about 0°C to about 100°C.
18
4. The process as claimed in claim 1, wherein said non-polar solvent is selected
from group comprising of hydrocarbons; aromatic hydrocarbons; ethers or
mixtures thereof.
5. The process as claimed in claim 4, 5 wherein said non-polar solvent is toluene.
6. The process as claimed in claim 1, wherein said polarity enhancer is selected
from the group comprising of N,N-dimethyl formamide, l,8-
diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene
10 (DBN), 1,4-diazabicyclo[2.2.2]octane (DABCO), 1,4-
Diazabicyclo[2.2.2]octane-2-methanol (DABCO-methanol), l,5,7-
triazabicyclo[4.4.0]dec-5-ene (TABDE), triethylamine (TEA),
tetramethylenediamine, dimethyloctylamine, dimethylaminopolystyrene,
quinuclidine hydrochloride, 3-quinuclidinone hydrochloride, 3-
15 quinuclidinol; or salts and/or derivatives thereof.
7. The process as claimed in claim 6, wherein said polarity enhancer is N,Ndimethyl
formamide.
20 8. The process as claimed in claim 1, wherein the weight ratio of the polarity
enhancer to non-polar solvent is in the range from about 1:5 to about 1:20.
9. The process as claimed in claim 1, wherein said reaction is carried out in
presence of a base selected from organic or inorganic base.
25
10. The process as claimed in claim 9, wherein said reaction is carried out in
presence of inorganic base selected from hydroxides, carbonates,
bicarbonates, or alkoxides of alkali or alkaline earth metal.
19
11. The process as claimed in claim 1, wherein the amount of N-methyl
pyrrolidine is in the range of 0.01 to 0.1 moles with respect to compound of
formula (III).
12. A process for preparation 5 of azoxystrobin of Formula (I) comprising a step
of reacting compound of formula (II) with compound of formula (III) in
toluene in presence of N-methyl pyrrolidine and N, N-dimethyl formamide
at temperature ranging from about 0°C to about 100°C.
10 13. A process for preparation of azoxystrobin of Formula (I)
O
N N
O
CN O
CH3
O
O
H3C
Formula (I)
comprising step of reacting a compound of formula (IV) with compound of
formula (V)
O
O
O
CH3
Formula (IV)
Formula (V)
O
CN
N N
Cl
15
in a non-polar solvent in presence of N-methyl pyrrolidine and a polarity
enhancer.