U.S. patent application number 13/905447 was filed with the patent office on 2013-10-03 for process for the preparation of substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate derivatives.
This patent application is currently assigned to MAKHTESHIM CHEMICAL WORKS, LTD.. The applicant listed for this patent is David LEONOV, David OVADIA, Raya STURKOVICH. Invention is credited to David LEONOV, David OVADIA, Raya STURKOVICH.
Application Number | 20130261303 13/905447 |
Document ID | / |
Family ID | 39323004 |
Filed Date | 2013-10-03 |
United States Patent
Application |
20130261303 |
Kind Code |
A1 |
OVADIA; David ; et
al. |
October 3, 2013 |
PROCESS FOR THE PREPARATION OF SUBSTITUTED
CYANOPHENOXY-PYRIMIDINYLOXY-PHENYL ACRYLATE DERIVATIVES
Abstract
The present invention provides a process for reacting between a
phenol derivative and an aromatic substrate under phenolate forming
conditions comprising the following steps: (a) reacting a phenol
derivative with a base in a polar organic solvent to obtain a
phenolate salt, wherein water is removed from the reaction mixture
during the reaction, (b) adding the aromatic substrate to the
reaction mixture obtained in step (a), (c) heating the reaction
mixture of step (b) to a temperature in the range of 80.degree. to
1300.degree. C., preferably, 90.degree. to 1000.degree. C. for 2 to
7 hours to obtain a phenoxy substituted aromatic substrate, (d)
removing the solvent from the mixture of step (c) and optionally
further isolating and purifying the phenoxy substituted aromatic
substrate. Optionally, the removal of water during step (a) is in
conjunction with partial removal of the organic solvent.
Inventors: |
OVADIA; David; (Omer,
IL) ; STURKOVICH; Raya; (Beer-Sheva, IL) ;
LEONOV; David; (Rehovot, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
OVADIA; David
STURKOVICH; Raya
LEONOV; David |
Omer
Beer-Sheva
Rehovot |
|
IL
IL
IL |
|
|
Assignee: |
MAKHTESHIM CHEMICAL WORKS,
LTD.
Beer-sheva
IL
|
Family ID: |
39323004 |
Appl. No.: |
13/905447 |
Filed: |
May 30, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12519436 |
Jun 16, 2009 |
8471013 |
|
|
PCT/IL2007/001551 |
Dec 16, 2007 |
|
|
|
13905447 |
|
|
|
|
Current U.S.
Class: |
544/319 |
Current CPC
Class: |
C07D 239/52 20130101;
C07D 239/54 20130101 |
Class at
Publication: |
544/319 |
International
Class: |
C07D 239/52 20060101
C07D239/52 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 17, 2006 |
IL |
180134 |
Claims
1. A process for reacting a phenol derivative and an aromatic
substrate under phenolate forming conditions comprising the
following steps: a) reacting a phenol derivative with a base in a
polar organic solvent to obtain a phenolate salt, wherein water is
removed from the reaction mixture during the reaction, b) adding
the aromatic substrate to the reaction mixture comprising the
phenolate salt obtained in step (a), c) heating the reaction
mixture of step (b) to a temperature in the range of 80.degree. to
130.degree. C. for 2 to 7 hours to obtain a phenoxy substituted
aromatic substrate, d) removing the solvent from the mixture of
step (c) comprising the phenoxy substituted aromatic substrate.
2. A process according to claim 1, wherein the removal of water
during step (a) is in conjunction with partial removal of the polar
organic solvent.
3. A process according to claim 1, wherein the mole ratio between
said phenol derivative and base is 1:1 to 1:1.5.
4. A process according to claim 1, wherein the time required for
step (a) to obtain conversion to the phenolate salt is 30 to 120
minutes at a temperature between 60.degree. C. to 80.degree. C.,
while partially removing solvent with water from the reaction
mixture by vacuum distillation.
5. A process according to claim 1, wherein the cyanophenol
derivative is phenol, a mono-substituted phenol or a
poly-substituted phenol.
6. A process according to claim 1, wherein said base is selected
from the group consisting of a hydroxide, a carbonate base, and a
combination thereof.
7. A process according to claim 1, wherein the polar organic
solvent is selected from the group consisting of dimethyl formamide
(DMF), dimethyl acetamide (DMAA), dimethyl sulphoxide (DMSO), and a
combination thereof, and further wherein the reagent/solvent ratio
is 0.1 mole/150 ml to 0.1 mole/350 ml.
8. A process according to claim 1, wherein said aromatic substrate
is added in step (b) together with a polar organic solvent.
9. A process according to claim 1, wherein the aromatic substrate
is added in an amount such that the mole ratio between the phenol
derivative and aromatic substrate is between 1:0.8 and 1:1.
10. A process according to claim 1, wherein the aromatic substrate
is selected from the group consisting of mono- and poly-substituted
pyridine, pyrimidine and phenyl groups.
11. A process according to claim 1, comprising heating the reaction
mixture of step (b) to a temperature in the range of 80.degree. to
130.degree. C. for 2 to 7 hours to obtain the phenoxy substituted
aromatic substrate.
12. A process according to claim 1 for the preparation of methyl
(E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
(azoxystrobin) comprising the following steps: a) reacting
2-cyanophenol with an alkali metal hydroxide or carbonate, in a
polar organic solvent, at a temperature between 60.degree. C. to
80.degree. C., for about 1 hour, while removing the water which is
formed during the reaction via distillation with the solvent under
reduced pressure, b) adding (E)-methyl
2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate of
formula (I) to the reaction mixture obtained in step (a),
##STR00003## c) heating the reaction mixture of step (b) to a
temperature in the range of 80.degree. to 130.degree. C., for 2 to
7 hours, to obtain azoxystrobin, d) removing the solvent from the
mixture of step (c) by distillation under reduced pressure to
obtain a crude azoxystrobin, e) extracting the crude azoxystrobin
with a non-polar organic solvent and water to obtain an organic and
aqueous phase, and f) crystallizing the azoxystrobin from the
organic phase by cooling the organic solvent, filtering the
precipitated solid and rinsing the precipitated solid with an
alcohol to obtain azoxystrobin with a purity of 98%-99%.
13. A process according to claim 12, wherein said base is sodium
hydroxide, potassium hydroxide, sodium carbonate or potassium
carbonate.
14. A process according to claim 12, wherein said polar organic
solvent is selected from the group consisting of dimethyl formamide
(DMF), dimethyl acetamide (DMAA), dimethyl sulphoxide (DMSO), and a
combination thereof.
15. A process according to claim 12, wherein removing the water
which is formed during the reaction of step (a) is via distillation
with the solvent under reduced pressure, wherein the mole ratio
between the 2-cyanophenol and the base is between 1:1 and
1:1.5.
16. A process according to claim 12, wherein said non-polar organic
solvent of step (e) is selected from the group consisting of
toluene, xylene, at least C.sub.4 acetate esters, and a combination
thereof.
17. A process according to claim 12, further comprising: a)
reacting the 2-cyanophenol with sodium hydroxide in DMAA, DMSO, or
a combination thereof, at a temperature between 60.degree. C. to
80.degree. C. for about 1 hour, while removing the water which is
formed during the reaction via distillation with the solvent under
a reduced pressure of about 20-30 mbar, wherein the mole ratio
between the 2-cyanophenol and the sodium hydroxide is between 1:1
and 1:1.5; b) adding (E)-methyl
2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate of
formula (I) as a solution in DMAA to the reaction mixture obtained
in step (a), ##STR00004## c) heating the reaction mixture of step
(b) to a temperature in the range of 90.degree. C. to 100.degree.
C. for 4 to 6 hours to obtain azoxystrobin, d) removing the solvent
from the mixture of step (c) by distillation under reduced pressure
to obtain a crude azoxystrobin, e) extracting the crude
azoxystrobin with butylacetate and water to obtain an organic and
aqueous phase, and f) crystallizing the azoxystrobin from the
organic phase by cooling the organic solvent, filtering the
precipitated solid and rinsing the precipitated solid with methanol
to obtain azoxystrobin with a purity of 98%-99%.
18. The process according to claim 5, wherein the phenol derivative
is 2-cyanophenol or 4-cyanophenol.
19. The process according to claim 6, wherein the base is selected
from the group consisting of including metal hydroxides, alkali
metal hydroxides, metal carbonates, alkali metal carbonates, and
mixtures thereof.
20. The process according to claim 10, wherein the aromatic
substrate is a chloro-pyrimidine derivative.
Description
CROSS REFERENCE TO RELATED APPLICATION
[0001] This application is a divisional application of U.S.
Nonprovisional patent application Ser. No. 12/519,436, filed Jun.
16, 2009, now allowed, which is a National Stage application under
35 U.S.C. .sctn.371 to International Application No.
PCT/IL2007/001551 having an International filing date of Dec. 16,
2007, which claims benefit of Israeli Patent Application No.
180134, filed on Dec. 17, 2006, all of the foregoing being
incorporated by reference in their entirety herein.
FIELD OF THE INVENTION
[0002] The present invention relates to the field of chemical
synthesis, particularly to improved processes for synthesizing
substituted cyanophenoxy-pyrimidinyloxy-phenyl acrylate
derivatives.
BACKGROUND OF THE INVENTION
[0003] In the field of industrial chemical synthesis, the
improvement of the yield and selectivity of chemical processes
bears considerable impact on the industry. Particularly, the focus
in said improvements is on lowering costs, simplifying unit
operations and environmental considerations. These three factors
are particularly important in the field of agrochemicals where the
volume of chemicals is large and the marginal profit is relatively
small.
[0004] Of the many agrochemical compounds which are synthesized by
multi-stage synthesis, methyl
(E)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-yloxy]phenyl}-3-methoxyacrylate
(chemical common name: azoxystrobin), particularly drew the
attention of the present inventors. Azoxystrobin, disclosed in U.S.
Pat. No. 5,395,837, is a plant protection fungicide with
protectant, curative, eradicant, translaminar and systemic
properties. The preparation of azoxystrobin as described in Example
3 of U.S. Pat. No. 5,395,837 involves an aromatic substitution
reaction between 2-cyanophenol and (E)-Methyl
2-[2-(6-chl.theta..phi.pyridimin-4-yloxy)phenyl]-3-methoxypropenoate
also known as
(E)-Methyl-2-[2-(6-chloropyrimidin-4-yloxy)-phenyl]-3-methoxyacr-
ylate, at temperatures at 95.degree. to 100.degree. C. in DMF in
the presence of stoichiometric amounts of potassium carbonate and a
catalytic amount of copper(I) chloride. The reported yield of
azoxystrobin is 65% wherein the product was found to have a melting
point of 110.degree. C.-111.degree. C., indicating a final product
of relatively low purity, which subsequently required further
purification. It has been suggested that reactions of 2-cyanophenol
or other isomers of cyanophenol or phenols in general under
conditions of temperatures of about 90.degree. C. and above, in the
presence of basic reagents which can promote the formation of
phenolate salts, may cause polymerization and the formation of
tars. This clearly is a highly undesirable side effect.
[0005] Accordingly there is an ongoing and long felt need for a
process for aromatic substitution reactions in the presence phenols
with improved yield and selectivity.
[0006] Thus, it is the objective of the present invention to
provide a process for reacting phenols under basic conditions in
which the yield and selectivity is improved.
[0007] Other objectives of the invention shall become apparent as
the description proceeds.
SUMMARY OF THE INVENTION
[0008] The present invention provides a process for reacting
between a phenol derivative and an aromatic substrate under
phenolate forming conditions comprising the following steps: [0009]
a) reacting a phenol derivative with a base in a polar organic
solvent to obtain a phenolate salt, wherein water is removed from
the reaction mixture during the reaction. [0010] b) adding the
aromatic substrate to the reaction mixture obtained in step (a),
[0011] c) heating the reaction mixture of step (b) to a temperature
in the range of 80.degree. to 130.degree. C., preferebly,
90-100.degree. C. for 2 to 7 hours to obtain a phenoxy substituted
aromatic substrate, [0012] d) removing the solvent from the mixture
of step (c) and further isolating and purifying the phenoxy
substituted aromatic substrate.
[0013] Optionally, the removal of water during step (a) is in
conjunction with partial removal of the organic solvent.
DETAILED DESCRIPTION OF THE INVENTION
[0014] The following description is illustrative of embodiments of
the invention. The following description is not to be construed as
limiting, it being understood that the skilled person may carry out
many obvious variations to the invention. Throughout the
specification the terms "phenols" and "phenol derivative" include
phenol and mono and poly-substituted phenols, including
2-cyanophenol and other cyanophenol isomers.
[0015] The present invention provides a process for reacting
between a phenol derivative and an aromatic substrate under
phenolate forming conditions wherein the formation of polymeric
by-products and tars are minimized. In minimizing said by-products
and tars formation, the present process provides improved yields
together with facilitation of product separation and purification.
The present process provides yields of 90% and greater, wherein
said yield is calculated on the basis of the aromatic substrate. It
has been surprisingly found that generating the phenolate salt
separately and subsequently reacting said phenolate salt with the
aromatic substrate, prevents the formation of undesirable
byproducts and tars.
[0016] The present process comprises the following steps: [0017] a)
reacting a phenol derivative with a base in a polar organic solvent
to obtain a phenolate salt, wherein water is removed from the
reaction mixture during the reaction.
[0018] Step (a) is conducted wherein the mole ratio between said
phenol derivative and base is preferably between 1:1 to 1:1.5,
preferably 1:1.125 to 1:1.15. The time required for step (a) to
obtain conversion to a phenolate salt is 30 to 120 minutes at a
temperature between 60.degree. C. to 80.degree. C., while partially
removing solvent with water from the reaction mixture by vacuum
distillation.
[0019] According to a preferred embodiment of the present invention
said phenol derivative may be phenol, mono-substituted phenol or
poly-substituted phenol, more preferably, cyanophenol derivatives,
including 2-cyanophenol and 4-cyanophenol.
[0020] Said base may be selected from among hydroxide and carbonate
bases, including but not limited to metal hydroxides, alkali metal
hydroxides, metal carbonates and alkali metal carbonates
preferably, sodium hydroxide or potassium hydroxide.
[0021] Non-limiting examples of preferred polar organic solvents
are dimethyl formamide (DMF), dimethyl acetamide (DMAA) and
dimethyl sulphoxide (DMSO) wherein, preferably the range of the
reagent/solvent ratio is 0.1 mole/150 ml-0.1 mole/350 ml.
[0022] According to a specific embodiment of the invention, the
phenolate salt is formed via partial removal of solvent with water
under reduced pressure conditions. [0023] b) adding the aromatic
substrate to the reaction mixture obtained in step (a).
[0024] According to a particular embodiment of the invention said
aromatic substrate may be added together with a polar organic
solvent selected from the afore-mentioned group of solvents. The
aromatic substrate is added in an amount such that the mole ratio
between the phenol derivative and aromatic substrate is between
1:0.8 and 1:1
[0025] In yet a further preferred embodiment of the invention, the
aromatic substrate is selected from among mono and poly-substituted
pyridine, pyrimidine and phenyl groups. Preferably, at least
mono-halo substituted and more preferably chloropyrimidine
derivatives. [0026] c) heating the reaction mixture of step (b) to
a temperature in the range of 80.degree. to 130.degree. C.,
preferably about 100.degree. C. for 2 to 7 hours, preferably about
5 hours to obtain a phenoxy substituted aromatic substrate, [0027]
d) removing the solvent from the mixture of step (c) and further
isolating and purifying the phenoxy substituted aromatic
substrate.
[0028] The operations of step (d) can be carried out according to
methods known to the skilled artisan. Said methods include; solvent
removal by distillation wherein said distillation may be carried
out under reduced pressure conditions, separation and purification
by washing, extraction and crystallization.
[0029] According to a specific preferred embodiment of the present
invention, there is provided a process for the preparation of
methyl (2T)-2-{2-[6-(2-cyanophenoxy)pyrimidin-4-
yloxy]phenyl}-3-methoxyacrylate (azoxystrobin) comprising of the
following steps: [0030] a) reacting 2-cyanophenol with an alkali
metal hydroxide or carbonate, preferably sodium hydroxide in a
polar organic solvent preferably selected from among DMF, DMAA and
DMSO, more preferably DMAA, at a temperature between 60.degree. C.
to 80.degree. C. , preferably between 60.degree. C. to 70.degree.
C. for about 1 hour, while removing the water which is formed
during the reaction via distillation with the solvent under reduced
pressure, preferably about 20-30 mbar. The mole ratio between
2-cyanophenol and alkali metal hydroxide is between 1:1 and 1:1.5.
[0031] b) adding the aromatic substrate which is (E)-Methyl
2-[2-(6-chloropyridimin-4-yloxy)phenyl]-3-methoxypropenoate
(Compound of formula (I) to the reaction mixture obtained in step
(a). Optionally. Compound (I) is added to the reaction mixture as a
solution in DMAA.
[0031] ##STR00001## [0032] c) heating the reaction mixture of step
(b) to a temperature in the range of 80.degree. to 130.degree. C.,
preferably 90.degree. C. to 100.degree. C. for 2 to 7 hours,
preferably 4 to 6 hours to obtain azoxystrobin, [0033] d) removing
the solvent from the mixture of step (c) by distillation under
reduced pressure; and further washing and extracting the reaction
mixture with a non- polar organic solvent, non-limiting examples
being toluene, xylene, at least C.sub.4 acetate esters, preferably,
butylacetate and adding water to obtain an organic and aqueous
phase, thereafter discarding the aqueous phase and crystallizing
the azoxystrobin from the organic phase by cooling the organic
solvent, filtering the precipitated solid and rinsing thereafter
with an alcohol, preferably methanol to obtain azoxystrobin with
purity of 98%-99%.
[0034] In yet a further specific embodiment of the present
invention azoxystrobin is prepared according to the following
process: [0035] a) reacting 2-cyanophenol with sodium hydroxide in
DMAA and DMSO, more preferably DMAA, at a temperature between
60.degree. C. to 80.degree. C. for about 1 hour, while removing the
water which is formed during the reaction via distillation with the
solvent under reduced pressure of about 20-30 mbar, wherein the
mole ratio between 2-cyanophenol and sodium hydroxide is between
1:1 and 1:1.5; [0036] b) adding the aromatic substrate which is
(E)-Methyl
2-[2-(6-chlorpyridimin-4-yloxy)phenyl]-3-methoxypropenoate
(Compound of formula (I) to the reaction mixture obtained in step
(a), wherein Compound (I) is added to the reaction mixture as a
solution in DMAA.
[0036] ##STR00002## [0037] c) heating the reaction mixture of step
(b) to a temperature in the range of 90.degree. C. to 100.degree.
C. for 4 to 6 hours to obtain azoxystrobin, [0038] d) removing the
solvent from the mixture of step (c) by distillation under reduced
pressure; and further washing and extracting the reaction mixture
with butylacetate and adding water to obtain an organic and aqueous
phase, thereafter discarding the aqueous phase and crystallizing
the azoxystrobin from the organic phase by cooling the organic
solvent, filtering the precipitated solid and rinsing thereafter
with methanol to obtain azoxystrobin with purity of 98%-99%.
[0039] The process for obtaining azoxystrobin according to the
present invention provided azoxystrobin with purity of 98%-99% and
a yield of above 90%. This is a significant improvement in
comparison to the prior art methods which describe a process with a
yield of 64%. Furthermore, no tars were detected in the reaction
mixture of the present invention unlike the prior art method which
generates tars which affect the purity of the final product. Hence
the process of the present invention is more economical, produces
less by-products and impurities and further generates considerably
less effluents as a result of the improved yield. Accordingly, the
work up according to the present process thus the process also
provides improvements in terms of environmental and working
safety.
EXAMPLES
Example I
Preparation of Azoxystrobin
[0040] Dimethylacetamide (DMAA, 400 ml), 2-Cyanophenol (0.2M, 28 g)
and NaOH (0.225M, 9 g) were placed at ambient temperature into the
three-necked IL flask equipped with stirrer, condenser and
thermometer. Half the amount of DMAA containing water traces was
distilled at vacuum 20 mbar/60-65.degree. C. and the mixture was
kept at vacuum 20 mbar/ room temperature for Ih. The same amount of
prime DMAA was added and Compound (I) (0.2M, 64 g) was fed into the
flask.
[0041] The reaction mixture was heated to 100.degree. C. and kept
at these conditions for 5 hours (monitored by HPLC--conversion of
Compound (I) to Azoxystrobin 98-99%).
[0042] DMAA was distilled at vacuum 20 mbar/65-70.degree. C. At the
end of the distillation the temperature can be increased up to
90-100.degree. C.
[0043] 400 g Butylacetate (BuAc) and 200 g water were added to the
reaction mixture at 50-60.degree. C., the temperature was increased
to 80.degree. C. and stirred 10-15 min. The water phase was
separated at 80.degree. C. to remove DMAA traces and inorganic
salts.
[0044] For crystallization the BuAc phase was slowly cooled from
80.degree. C. to -5.degree. C. Filtration was done using filter #2.
The cake was washed with 60 ml cooled Butylacetate or methanol and
further dried in oven at 80.degree. C. during 15 hours.
Azoxystrobin with purity 98-99% and a yield of 90-92% was
obtained.
[0045] While embodiments of the invention have been described by
way of illustration, it will be apparent that the invention may be
carried out with many modifications, variations and adaptations,
without departing from its spirit or exceeding the scope of the
claims.
* * * * *