U.S. patent application number 16/155905 was filed with the patent office on 2019-04-11 for method of preparation of florasulam.
This patent application is currently assigned to Dow AgroSciences LLC. The applicant listed for this patent is Dow AgroSciences LLC. Invention is credited to Justin A. Alberts, Michael Gullo, Jossian Oppenheimer, David E. Podhorez.
Application Number | 20190106428 16/155905 |
Document ID | / |
Family ID | 65992979 |
Filed Date | 2019-04-11 |
United States Patent
Application |
20190106428 |
Kind Code |
A1 |
Oppenheimer; Jossian ; et
al. |
April 11, 2019 |
METHOD OF PREPARATION OF FLORASULAM
Abstract
The present disclosure concerns a method for preparing
florasulam which involves treating a solution of
2,6-difluoroaniline in 1,2-propylene glycol with: a) sulfonyl
chloride III and then b) a base to provide, after workup and
isolation, florasulam (I) in yields of about 65-85%. The treatment
of 2,6-difluoroaniline with sulfonyl chloride III and the base are
conducted by controlled additions.
Inventors: |
Oppenheimer; Jossian;
(Midland, MI) ; Gullo; Michael; (Midland, MI)
; Podhorez; David E.; (Midland, MI) ; Alberts;
Justin A.; (Midland, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Dow AgroSciences LLC |
Indianapolis |
IN |
US |
|
|
Assignee: |
Dow AgroSciences LLC
Indianapolis
IN
|
Family ID: |
65992979 |
Appl. No.: |
16/155905 |
Filed: |
October 10, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
62570271 |
Oct 10, 2017 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 487/04
20130101 |
International
Class: |
C07D 487/04 20060101
C07D487/04 |
Claims
1. A method of preparing florasulam (compound I) ##STR00005##
comprising: a) adding sulfonyl chloride III ##STR00006## to
2,6-difluoroaniline to form a mixture; and b) adding a base to the
mixture formed in step a).
2. The method of claim 1, wherein the adding of sulfonyl chloride
III is done by controlled addition.
3. The method of claim 1, wherein the adding of a base to the
mixture formed in step a) is done by controlled addition.
4. The method of claim 1, further comprising combining the
2,6-difluoroaniline with a glycol solvent prior to adding the
sulfonyl chloride III.
5. The method of claim 4, wherein the glycol solvent is
1,2-propylene glycol.
6. The method of claim 1, wherein the mole ratio of
2,6-difluoroaniline to sulfonyl chloride II is from about 1:1 to
about 2:1.
7. The method of claim 1, wherein the mole ratio of the base to
sulfonyl chloride II is from about 0.5:1 to about 2:1.
8. The method of claim 1, wherein the base is selected from a
trialkylamine, or a heterocylic amine
9. The method of claim 8, wherein the trialkylamine is
triethylamine.
10. The method of claim 8, wherein the heterocylic amine is
pyridine.
11. A method of preparing florasulam (compound I) ##STR00007##
comprising: a) controlled adding of sulfonyl chloride III
##STR00008## to 2,6-difluoroaniline to form a mixture; and b)
controlled adding of a base to the mixture formed in step a).
12. The method of claim 11, further comprising combining the
2,6-difluoroaniline with 1,2-propylene glycol prior to adding the
sulfonyl chloride III.
13. The method of claim 11 wherein the mole ratio of
2,6-difluoroaniline to sulfonyl chloride II is from about 1:1 to
about 2:1.
14. The method of claim 13, wherein the mole ratio of the base to
sulfonyl chloride II is from about 0.5:1 to about 2:1.
15. The method of claim 11, wherein the base is selected from
triethylamine or pyridine.
16. A method of preparing florasulam (compound I) ##STR00009##
comprising: a) adding sulfonyl chloride III ##STR00010## to
2,6-difluoroaniline while maintaining a temperature during the
adding of 20-30.degree. C. to form a mixture; and b) adding a base
to the mixture formed in step a) while maintaining the temperature
during the adding of 20-30.degree. C.
17. The method of claim 16, further comprising combining the
2,6-difluoroaniline with 1,2-propylene glycol prior to adding the
sulfonyl chloride III.
18. The method of claim 16 wherein the mole ratio of
2,6-difluoroaniline to sulfonyl chloride II is from about 1:1 to
about 2:1.
19. The method of claim 16, wherein the mole ratio of the base to
sulfonyl chloride II is from about 0.5:1 to about 2:1.
20. The method of claim 16, wherein the base is selected from
triethylamine or pyridine.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application Ser. No. 62/570,271, filed on Oct. 10, 2017, the entire
disclosure of which is hereby expressly incorporated by
reference.
FIELD OF THE INVENTION
[0002] An improved method of preparing florasulam is described. The
method includes the use of modified reaction conditions for the
sulfonamide coupling reaction.
BACKGROUND OF THE INVENTION
[0003] Florasulam
(N-(2,6-difluorophenyl)-8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidin-
e-2-sulfonamide, I) is a herbicide marketed by Dow AgroSciences
LLC. The final step of the manufacturing process for florasulam, as
described in U.S. Pat. No. 5,959,106, involves the coupling of
2,6-difluoroaniline (II) with
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride (III) to afford the sulfonamide product florasulam (I) as
shown in Scheme 1.
##STR00001##
[0004] In order to obtain commercially acceptable yields, the molar
ratio of the difluoroaniline (II) to the sulfonyl chloride (III) in
the reaction is from about 2.2 to about 5, preferably from about 2
to about 3. However, the use of excess amounts of the costly
2,6-difluoroaniline (II) increases the cost of manufacturing
florasulam by this method.
[0005] Chinese Patent Application No. CN103509027A describes
methods for preparing florasulam. The reaction scheme is shown in
Scheme 2.
##STR00002##
[0006] The modified reaction conditions described therein involve a
one pot procedure using a base, such as triethylamine, to allegedly
reduce the amount of the costly 2,6-difluoroaniline (II) used in
the method to from about 1 to about 1.5 molar equivalents. However,
this method fails to provide florasulam in the high yields that are
reported as shown in the examples below.
[0007] It is highly desirable to have a method of preparing
florasulam that reduces the amount of 2,6-difluoroaniline used in
the coupling reaction while maintaining/improving commercially
acceptable yields. Such a method could decrease the cost of
manufacturing florasulam by reducing the use of an expensive raw
material.
SUMMARY
[0008] Described herein is an improved method of preparing
florasulam (I). The improved method involves coupling
2,6-difluoroaniline (II) with
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride (III) using conditions that provide florasulam in high
yield at a lower cost. The improved method uses less
2,6-difluoroaniline than previous methods and produces florasulam
in high yield. The coupling reaction employs from about 1 to about
2 molar equivalents of 2,6-difluoroaniline and from about 0.5 to
about 1.5 molar equivalents of a base, relative to the amount of
sulfonyl chloride III used.
[0009] The method involves treating a solution of
2,6-difluoroaniline in propylene glycol with: a) sulfonyl chloride
III and then b) a base to provide, after workup and isolation,
florasulam (I) in yields of about 65 to about 85%. The treatments
with sulfonyl chloride III and the base are conducted by controlled
additions.
[0010] For example, in one embodiment of the method,
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride is added to a mixture of 2,6-difluoroaniline and
1,2-propylene glycol, a base is then added to the resulting
mixture, and florasulam is isolated from the final mixture. In
another embodiment of the method,
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride is added in a controlled manner to a mixture of
2,6-difluoroaniline and 1,2-propylene glycol, a base is then added
to the resulting mixture, and florasulam is isolated from the final
mixture.
[0011] In another embodiment of the method,
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride is added to a mixture of 2,6-difluoroaniline and
1,2-propylene glycol, a base is then added to the resulting mixture
in a controlled manner, and florasulam is isolated from the final
mixture. In another embodiment of the new method,
8-fluoro-5-methoxy [1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride is added to a mixture of 2,6-difluoroaniline and
1,2-propylene glycol at between about 15.degree. C. to about
35.degree. C., a base is then added to the resulting mixture at
between about 15.degree. C. to about 35.degree. C., and florasulam
is isolated from the final mixture.
DETAILED DESCRIPTION
[0012] Improved methods of preparing florasulam (I) are described
herein. The improved method involves coupling 2,6-difluoroaniline
(II) with
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride (III) using conditions to provide florasulam in high yield
at a lower cost. The methods use less 2,6-difluoroaniline. The
coupling reaction employs from about 1 to about 2 molar equivalents
of 2,6-difluoroaniline and from about 0.5 to about 1.5 molar
equivalents of a base, relative to the amount of sulfonyl chloride
III used.
[0013] The improved method is shown in Scheme 3. Specifically, the
method involves treating a solution of 2,6-difluoroaniline II in
1,2-propylene glycol with: (a) sulfonyl chloride III followed by
(b) a base to provide, after workup and isolation, florasulam (I)
in yields of about 65-85%. The additions of sulfonyl chloride III
and the base are conducted by controlled addition.
##STR00003##
I. Definitions
[0014] "Controlled addition" or "controlled adding," as used
herein, refers to controlling the rate at which a chemical is added
to a reaction vessel containing other chemicals in order to achieve
temperature control, sufficient physical mixing, and/or efficient
reaction rates for the chemistry that is being conducted in the
reaction vessel. Controlled addition or adding is the opposite of
uncontrolled addition or adding such as the rapid contacting of
reactants. Controlled addition (or adding) may also be referred to
as slow addition, continuous addition (i.e., con-addition), metered
addition, portion-wise addition, addition in a controlled manner,
and the like.
[0015] In some embodiments, the controlled addition or controlled
adding of a reactant in the described method may be conducted over
a period of at least about 0.5 hours, at least about 0.75 hours, at
least about 1 hour, at least about 1.5 hours, at least about 2
hours, at least about 2.5 hours, at least about 3 hours, at least
about 3.5 hours, at least about 4 hours, at least about 4.5 hours,
or at least about 5 hours.
II. Process Variables
[0016] A. Order of controlled addition of reactants
[0017] In some embodiments, the order of addition of reactants and
the controlled additions of those reactants in the method are used
to obtain high yields of florasulam. Sulfonyl chloride III should
be added to a solution of 2,6-difluoroaniline (II) in the solvent
in a controlled manner to achieve high yields of florasulam. The
addition of the base to the mixture formed by adding III to II can
also be done by a controlled addition. Failure to follow the order
of addition and/or controlled additions of the reactants, and
instead use of rapid contacting/mixing of all reactants and the
solvent, can lead to poor yields of florasulam. In some
embodiments, the base may be combined with the solution of
2,6-difluoroaniline (II) and the solvent to form a mixture before
controlled addition of sulfonyl chloride III to the mixture. [0018]
B. Bases
[0019] Bases for use in the described method may be selected from
the group including organic bases, inorganic bases, partially
inorganic bases, and combinations thereof.
[0020] Suitable organic bases include, but are not limited to,
trialkylamines, such as triethylamine, aromatic amines such as
pyridine, heterocyclic amines such as imidazole, N-methylimidazole
and benzimidazole, and bicyclic amines such as
1,4-diazabicyclo[2.2.2]octane and
1,8-diazabicyclo[5.4.0]undec-7-ene.
[0021] Suitable inorganic and partially inorganic bases may
include, but are not limited to, monobasic salts of organic diacids
such as potassium hydrogen tartrate and potassium hydrogen
phthalate, carbonate and bicarbonate salts such as sodium and
potassium carbonate and sodium and potassium bicarbonate, and salts
of monoacids such as sodium and potassium acetate. [0022] C.
Solvents [0023] Solvents for use in the described method include
those of Formula IV
##STR00004##
[0023] wherein X represents fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
1,1-difluoroethyl, hydroxymethyl, 1-hydroxyethyl, methoxymethyl, or
cyanomethyl, and R represents hydrogen, methyl, or fluoromethyl.
1,2-Propanediol (1,2-propylene glycol), 1,2-ethanediol (ethylene
glycol), and 2,2,2-trifluoroethanol are often more preferred. In
some embodiments, the solvent is 1,2-Propanediol due to its
performance in the method, its low cost, and its low toxicity.
[0024] The alcohol of Formula IV employed can be used alone as the
organic solvent medium or can be part of an organic solvent medium
that includes other alcohols of Formula I and/or inert organic
solvents. Inert solvents that can be employed in conjunction with
the alcohols of Formula IV include chlorinated aliphatic solvents,
such as dichloromethane, 1,2-dichloroethane, tetrachloroethylene,
chloroform, and 1,1,1-trichloroethane; chlorinated aromatic
solvents, such as 1,2-dichlorobenzene; aromatic hydrocarbons, such
as benzene, toluene, and xylene; nitriles, such as acetonitrile;
esters, such as ethyl acetate; and ethers, such as
1,2-dimethoxyethane and tetrahydrofuran. Inert organic solvents in
which the
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride compound of Formula III are at least somewhat soluble are
generally preferred (when an inert organic solvent is used) and
dichloromethane is typically more preferred. It is often preferred
to carry out the method in the presence of the alcohol as the only
organic solvent in the medium; that is, without the addition of
other inert organic solvents.
[0025] The amount of organic solvent medium employed is an amount
that facilitates mixing and contact of the reagents as well as heat
transfer and that supplies an appropriate amount of the alcohol of
Formula IV in relationship with the amount of the
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride compound of Formula III being used in the method. An
amount of alcohol sufficient to give a suitably rapid reaction
rate, but not so much as to create a problem in product isolation
or extra cost in recycle efforts should be employed. The reaction
rate typically increases as the amount of alcohol in the system
increases, but recovery of the desired product becomes more
difficult and expensive. An appropriate amount of the alcohol of
Formula IV is generally from at least about 0.3 parts to about 5
parts by weight of alcohol per part of the
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride compound of compound of Formula III used. Amounts between
about 0.5 and about 3.0 are generally more preferred. [0026] D.
Molar Equivalents of Reactants
[0027] The ratio of molar equivalents of 2,6-difluoroaniline (II)
relative to
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-a]pyrimidine-2-sulfonyl
chloride (i.e., sulfonyl chloride III) used in the described method
may be from about 1:1 to about 2:1. This ratio may be about 1.1:1,
about 1.2:1, about 1.3:1, about 1.4:1, about 1.5:1, about 1.6:1,
about 1.7:1, about 1.8:1, or about 1.9:1.
[0028] The ratio of molar equivalents of the base relative to
8-fluoro-5-ethoxy[1,2,4]triazolo-[1,5-a]pyrimidine-2-sulfonyl
chloride (i.e., sulfonyl chloride III) used in the described method
may be from about 0.5:1 to about 1.5:1. This ratio may be about
0.6:1, about 0.7:1, about 0.8:1, about 0.9:1, about 1:1, about
1.1:1, about 1.2:1, about 1.3:1, or about 1.4:1. [0029] E.
Temperature
[0030] The temperature range to use in the described processes when
combining the reactants together is very important for obtaining
high yields of florasulam. Combining 2,6-difluoroaniline in
1,2-propylene glycol with: a) sulfonyl chloride III and then b) a
base must be conducted under very temperature controlled
conditions. The temperature range for use in the described
processes when combining the reactants together may range from
about 15.degree. C. to about 35.degree. C. In some embodiments of
the described processes, the temperature when combining the
reactants together may range from about 20.degree. C. to about
35.degree. C., from about 20.degree. C. to about 30.degree. C.,
from about 20.degree. C. to about 25.degree. C., or from about
25.degree. C. to about 35.degree. C.
[0031] The following Examples are presented to illustrate various
aspects of the methods described herein and should not be construed
as limitations to the claims.
EXAMPLES
Example 1. Comparative Method of Preparing Florasulam--One Pot
Process (1)
[0032] To a 1 L jacketed reactor equipped with condenser was added
sulfonyl chloride (SC) (577.08 g in methylene chloride at 14.13wt
%) followed by propylene glycol (PG, 23.2 g) and
2,6-difluoroaniline (2,6-DFA, 39.4 g, 1:1:1 equivalent ratio with
SC). Triethylamine (Et.sub.3N, 2:1 equivalent ratio with SC) was
added to the mixture via an addition funnel. The addition of
Et.sub.3N caused the solution to boil over and some of the solution
was lost. After the addition the mixture was heated to 40.degree.
C., stirred using an overhead stirrer (about 300 rpm) and allowed
to react for 6 hours. After 6 hour the mixture was cooled to
0.degree. C. Barely any solids were noted in the reaction mixture.
The solution was filtered using a coarse grain glass frit Buchner
funnel. Some solids were retained. The solids were washed with
methanol (9.5:1 equivalent ratio with SC). The mother liquor, wash
and product were weighed and retained. The mother liquor and wash
were analyzed for florasulam via HPLC. Overall, less than 1% yield
of the desired product was obtained. Significant amount of the
sulfonic acid was formed in the reaction.
Example 2. Comparative Method of Preparing Florasulam--One Pot
Process (2)
[0033] Example 1 was repeated, but the Et.sub.3N was added slowly
to avoid the large exotherm. Mainly sulfonic acid obtained. Less
than 1% yield of desired product detected.
Example 3. Method of Preparing Florasulam
[0034] To a solution of 3.87 grams (0.03 mol) of
2,6-difluoroaniline in 5.4 grams of propylene glycol was added a
solution of 5.73 grams (0.02 mol) of
8-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonyl
chloride (SC) in 7 grams of methylene chloride over 1 hour. The SC
solution was added in about 0.5 mL portions every 5-10 minutes. The
temperature of the resulting mixture was maintained at less than
25.degree. C. during the addition of the SC. After stirring the
reaction mixture for another 1 hour at room temperature, 2.20 grams
(0.02 mol) of triethylamine was added over 2.45 hours using a
syringe pump. The reaction mixture was stirred at room temperature
overnight and then was diluted with 5 g of water over 15 minutes.
The resulting mixture was cooled to about 5.degree. C. with an ice
bath and then filtered. The collected white solid was rinsed with
15 mL of 7:3 (v/v) methanol-water and then dried at 50.degree. C.
to provide 5.44 g (74%) of florasulam (97.7 wt %). An additional 5%
yield (total yield 79%) of florasulam was detected in the aqueous
filtrate.
* * * * *