U.S. patent application number 09/760111 was filed with the patent office on 2001-11-29 for 4-aminopicolinates and their use as herbicides.
Invention is credited to Alexander, Anita Lenora, Balko, Terry William, Bjelk, Leslie Anne, Buysse, Ann Marie, Fields, Stephen Craig, Keese, Renee Joan, Krumel, Karl Leopold, Lo, William Chi-Leung, Lowe, Christian Thomas, Richburg, John Sanders III, Ruiz, James Melvin.
Application Number | 20010047099 09/760111 |
Document ID | / |
Family ID | 26872524 |
Filed Date | 2001-11-29 |
United States Patent
Application |
20010047099 |
Kind Code |
A1 |
Fields, Stephen Craig ; et
al. |
November 29, 2001 |
4-aminopicolinates and their use as herbicides
Abstract
4-Aminopicolinic acids, having halogen, alkoxy, alkylthio,
aryloxy, heteroaryloxy or trifluoromethyl substituents in the 3-,
5- and 6-positions, and their amine and acid derivatives are potent
herbicides demonstrating a broad spectrum of weed control.
Inventors: |
Fields, Stephen Craig;
(Indianapolis, IN) ; Alexander, Anita Lenora;
(Indianapolis, IN) ; Balko, Terry William;
(Greenfield, IN) ; Bjelk, Leslie Anne;
(Indianapolis, IN) ; Buysse, Ann Marie; (Carmel,
IN) ; Keese, Renee Joan; (Carmel, IN) ;
Krumel, Karl Leopold; (Midland, MI) ; Lo, William
Chi-Leung; (Indianapolis, IN) ; Lowe, Christian
Thomas; (Indianapolis, IN) ; Richburg, John Sanders
III; (Westfield, IN) ; Ruiz, James Melvin;
(Zionsville, IN) |
Correspondence
Address: |
Kenneth L. Loertscher
Dow AgroSciences LLC
9330 Zionsville Road
Indianapolis
IN
46268
US
|
Family ID: |
26872524 |
Appl. No.: |
09/760111 |
Filed: |
January 12, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60176720 |
Jan 14, 2000 |
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Current U.S.
Class: |
546/297 ;
546/310 |
Current CPC
Class: |
C07D 213/79
20130101 |
Class at
Publication: |
546/297 ;
546/310 |
International
Class: |
C07D 213/72 |
Claims
What is claimed is:
1. A compound of Formula I: 6wherein X represents H, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy, nitro,
or trifluoromethyl; Y represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy, heteroaryloxy or
trifluoromethyl; z represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy or nitro; and W represents
--NO.sub.2, --N.sub.3, --NR.sub.1R.sub.2, --N.dbd.CR.sub.3R.sub.4
or --NHN.dbd.CR.sub.3R.sub.4 where R.sub.1 and R.sub.2
independently represent H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
alkenyl, C.sub.3-C.sub.6 alkynyl, aryl, heteroaryl, hydroxy,
C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6 alkylcarbamyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 trialkylsilyl or
C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated or
unsaturated ring which may contain additional O, S or N
heteroatoms; and R.sub.3 and R.sub.4 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl or heteroaryl or R.sub.3 and R.sub.4 taken together
with .dbd.C represent a 5- or 6-membered saturated ring; and
agriculturally acceptable derivatives of the carboxylic acid, with
the proviso that when X represents H or Cl, then Y and Z are not
both Cl.
2. A compound of claim 1 wherein: X represents H, halogen, or
trifluoromethyl; Y represents halogen, aryloxy, heteroaryloxy, or
trifluoromethyl; Z represents halogen; and W represents
--NR.sub.1R.sub.2 where R.sub.1 and R.sub.2 independently represent
H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl or R.sub.1 and R.sub.2 taken together with N represent a 5-
or 6-membered saturated ring which may contain additional O or N
heteroatoms; and agriculturally acceptable salts, esters or amides
of the carboxylic acid.
3. A compound of claim 1 wherein: X represents H or F; Y represents
F, Cl, Br or aryloxy; z represents Cl; and W represents
--NH.sub.2.
4. A compound of claim 1 wherein Y represents a phenoxy group
substituted with halogen or C.sub.1-C.sub.4 alkyl groups in the
3-position.
5. An herbicidal composition comprising an herbicidally effective
amount of a 4-aminopicolinate of Formula I: 7wherein X represents
H. halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio,
aryloxy, nitro or trifluoromethyl; Y represents halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy,
heteroaryloxy or trifluoromethyl; z represents halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy or
nitro; and W represents --NO.sub.2, --N.sub.3, --NR.sub.1R.sub.2,
--N.dbd.CR.sub.3R.sub.4 or --NHN.dbd.CR.sub.3R.sub.4 where R.sub.1
and R.sub.2 independently represent H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, aryl, heteroaryl,
hydroxy, C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6 alkylcarbamyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 trialkylsilyl or
C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated or
unsaturated ring which may contain additional O, S or N
heteroatoms; and R.sub.3 and R.sub.4 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl or heteroaryl or R.sub.3 and R.sub.4 taken together
with .dbd.C represent a 5- or 6-membered saturated ring; and
agriculturally acceptable derivatives of the carboxylic acid, with
the proviso that when X represents Cl, then Y and Z are not both
Cl, in admixture with an agriculturally acceptable adjuvant or
carrier.
6. An herbicidal composition of claim 5 wherein: X represents H,
halogen or trifluoromethyl; Y represents halogen, aryloxy,
heteroaryloxy or trifluoromethyl; Z represents halogen; and W
represents --NR.sub.1R.sub.2 where R.sub.1 and R.sub.2
independently represent H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
alkenyl, C.sub.3-C.sub.6 alkynyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated ring which
may contain additional O or N heteroatoms; and agriculturally
acceptable salts, esters or amides of the carboxylic acid.
7. An herbicidal composition of claim 5 wherein: X represents H or
F; Y represents F, Cl, Br or aryloxy; Z represents Cl; and W
represents --NH.sub.2.
8. An herbicidal composition of claim 5 wherein: Y represents a
phenoxy group substituted with halogen or C.sub.1-C.sub.4 alkyl
groups in the 3-position.
9. An herbicidal composition of claim 5 containing
4-amino-3,6-dichloropyr- idine-2-carboxylic acid or an
agriculturally acceptable salt, ester or amide thereof.
10. A method of controlling undesirable vegetation which comprises
contacting the vegetation or the locus thereof with or applying to
the soil to prevent the emergence of vegetation an herbicidally
effective amount of a 4-aminopicolinate of Formula I: 8wherein X
represents H, halogen, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylthio, aryloxy, nitro or trifluoromethyl; Y represents halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy,
heteroaryloxy or trifluoromethyl; Z represents halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy or
nitro; and W represents --NO.sub.2, --N.sub.3, --NR.sub.1R.sub.2,
--N.dbd.CR.sub.3R.sub.4 or --NHN.dbd.CR.sub.3R.sub.4 where R.sub.1
and R.sub.2 independently represent H, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6 alkynyl, aryl, heteroaryl,
hydroxy, C.sub.1-C.sub.6 alkoxy, amino, C.sub.1-C.sub.6 acyl,
C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6 alkylcarbamyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 trialkylsilyl or
C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and R.sub.2 taken
together with N represent a 5- or 6-membered saturated or
unsaturated ring which may contain additional O, S or N
heteroatoms; and R.sub.3 and R.sub.4 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl or heteroaryl or R.sub.3 and R.sub.4 taken together
with .dbd.C represent a 5- or 6-membered saturated ring; and
agriculturally acceptable derivatives of the carboxylic acid, with
the proviso that when X represents Cl, then Y and Z are not both
Cl.
11. A method of claim 10 wherein: X represents H, halogen or
trifluoromethyl; Y represents halogen, aryloxy, heteroaryloxy or
trifluoromethyl; Z represents halogen;; W represents
--NR.sub.1R.sub.2 where R.sub.1 and R.sub.2 independently represent
H, C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl or R.sub.1 and R.sub.2 taken together with N represent a 5-
or 6-membered saturated ring which may contain additional O or N
heteroatoms; and agriculturally acceptable salts, esters or amides
of the carboxylic acid.
12. A method of claim 10 wherein: X represents H or F; Y represents
F, Cl, Br or aryloxy; Z represents Cl; and W represents
--NH.sub.2.
13. A method of claim 10 wherein: Y represents a phenoxy group
substituted with halogen or C.sub.1-C.sub.4 alkyl groups in the
3-position.
14. A method of claim 10 which comprises contacting the vegetation
or the locus thereof with or applying to the soil to prevent the
emergence of vegetation an herbicidally effective amount of
4-amino-3,6-dichloropyridi- ne-2-carboxylic acid or an
agriculturally acceptable salt, ester or amide thereof.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to certain novel 4-aminopicolinates
and their derivatives and to the use of these compounds as
herbicides.
[0002] A number of picolinic acids and their pesticidal properties
have been described in the art. For example, U.S. Pat. No.
3,285,925 discloses 4-amino-3,5,6-trichloropicolinic acid
derivatives and their use as plant growth control agents and
herbicides. U.S. Pat. No. 3,325,272 discloses
4-amino-3,5-dichloropicolinic acid derivatives and their use for
the control of plant growth. U.S. Pat. No. 3,317,549 discloses
3,6-dichloropicolinic acid derivatives and their use as plant
growth control agents. U.S. Pat. No. 3,334,108 discloses
chlorinated dithiopicolinic acid derivatives and their use as
parasiticides. U.S. Pat. No. 3,234,229 discloses
4-amino-polychloro-2-trichloromethylpyridine- s and their use as
herbicides. In Applied and Environmental Microbiology, Vol. 59, No.
7, July 1993, pp. 2251-2256, 4-amino-3,6-dichloropicolinic acid is
identified as a product of the anaerobic degradation of
4-amino-3,5,6-trichloropicolinic acid, the commercially available
herbicide picloram.
[0003] While picloram is recommended for the control of woody
plants and broadleaf weeds in certain applications, its properties
are not ideal. It would be highly desirable to discover related
compounds that are more potent, more selective or of broader
spectrum in their herbicidal activity and/or that have improved
toxicological or environmental properties.
SUMMARY OF THE INVENTION
[0004] It has now been found that certain 4-aminopicolinic acids
and their derivatives having selected substituents in the 3-, 5-,
and 6-positions are potent herbicides with a broad spectrum of weed
control and excellent crop selectivity. The compounds further
possess excellent toxicological or environmental profiles.
[0005] The invention includes compounds of Formula 1
[0006] wherein
[0007] x represents H, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy, nitro or trifluoromethyl;
[0008] Y represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy, heteroaryloxy or
trifluoromethyl;
[0009] Z represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy or nitro; and
[0010] W represents --NO.sub.2, --N.sub.3, --NR.sub.1R.sub.2,
--N.dbd.CR.sub.3R.sub.4 or --NHN.dbd.CR.sub.3R.sub.4
[0011] where
[0012] R.sub.1 and R.sub.2 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl, heteroaryl, hydroxy, C.sub.1-C.sub.6 alkoxy, amino,
C.sub.1-C.sub.6 acyl, C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6
alkylcarbamyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
trialkylsilyl or C.sub.1-C.sub.6 dialkyl phosphonyl or R.sub.1 and
R.sub.2 taken together with N represent a 5- or 6-membered
saturated or unsaturated ring which may contain additional O, S or
N heteroatoms; and
[0013] R.sub.3 and R.sub.4 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl or heteroaryl or R.sub.3 and R.sub.4 taken together
with .dbd.C represent a 5- or 6-membered saturated ring; and
[0014] agriculturally acceptable derivatives of the carboxylic
acid, with the proviso that when X represents H or Cl, then Y and Z
are not both Cl.
[0015] Compounds of Formula I wherein X represents H or F, wherein
Y represents F, Cl, Br or aryloxy, wherein Z represents Cl and
wherein R, and R.sub.2 represent H are independently preferred.
[0016] The invention includes herbicidal compositions comprising a
herbicidally effective amount of a 4-amino-picolinate of Formula I:
2
[0017] wherein
[0018] X represents H, halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy, nitro or trifluoromethyl;
[0019] Y represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy, heteroaryloxy or
trifluoromethyl;
[0020] z represents halogen, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 alkylthio, aryloxy or nitro; and
[0021] W represents --NO.sub.2, --N.sub.3, --NR.sub.1R.sub.2,
--N.dbd.CR.sub.3R.sub.4 or --NHN.dbd.CR.sub.3R.sub.4
[0022] where
[0023] R.sub.1 and R.sub.2 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl, heteroaryl, hydroxy, C.sub.1-C.sub.6 alkoxy, amino,
C.sub.1-C.sub.6 acyl, C.sub.1-C.sub.6 carboalkoxy, C.sub.1-C.sub.6
alkylcarbamyl, C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6
trialkylsilyl or C.sub.1-C.sub.6 dialkyl phosphonyl or R, and
R.sub.2 taken together with N represent a 5- or 6-membered
saturated or unsaturated ring which may contain additional O, S or
N heteroatoms; and
[0024] R.sub.3 and R.sub.4 independently represent H,
C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6 alkenyl, C.sub.3-C.sub.6
alkynyl, aryl or heteroaryl or R.sub.3 and R.sub.4 taken together
with .dbd.C represent a 5- or 6-membered saturated ring; and
[0025] agriculturally acceptable derivatives of the carboxylic
acid, with the proviso that when X represents Cl, then Y and Z are
not both Cl in admixture with an agriculturally acceptable adjuvant
or carrier. The invention also includes a method of use of the
compounds and compositions of the present invention to kill or
control undesirable vegetation by application of an herbicidal
amount of the compound to the vegetation or to the locus of the
vegetation as well as to the soil prior to emergence of the
vegetation. The use of the compounds to kill or control woody
plants and broadleaf weeds in grass crops is a preferred utility
and post-emergent application of the compounds to the undesirable
vegetation is a preferred method of application.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The herbicidal compounds of the present invention are
derivatives of 4-aminopicolinic acids: 3
[0027] These compounds are characterized by possessing halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy or nitro
substituents in the 3-position with halogen being preferred and
chlorine being most preferred; by possessing hydrogen, halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy, nitro
or trifluoromethyl substituents in the 5-position with hydrogen and
fluorine being preferred; and by possessing halogen,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylthio, aryloxy,
heteroaryloxy or trifluoromethyl substituents in the 6-position
with fluorine, chlorine, bromine or aryloxy being preferred.
Preferred aryloxy groups in the 6-position are 3-substituted
phenoxy groups, most preferably phenoxy groups substituted with
halogen or C.sub.1-C.sub.4 alkyl groups in the 3-position.
[0028] The amino group at the 4-position can be unsubstituted or
substituted with one or more C.sub.1-C.sub.6 alkyl, C.sub.3-C.sub.6
alkenyl, C.sub.3-C.sub.6 alkynyl, aryl, heteroaryl, hydroxy,
C.sub.1-C.sub.6 alkoxy or amino substituents. The amino group can
be further derivatized as an amide, a carbamate, a urea, a
sulfonamide, a silylamine, a phosphoramidate, an imine or a
hydrazone. Such derivatives are capable of breaking down into the
amine. An unsubstituted amino group or one substituted with one or
more alkyl substituents is preferred.
[0029] The carboxylic acids of Formula I are believed to be the
compounds that actually kill or control undesirable vegetation and
are typically preferred. Analogs of these compounds in which the
acid or amine group of the picolinic acid is derivatized to form a
related substituent that can be transformed within plants or the
environment to a acid group possess essentially the same herbicidal
effect and are within the scope of the invention. Therefore, an
"agriculturally acceptable derivative", when used to describe the
carboxylic acid functionality at the 2-position, is defined as any
salt, ester, acylhydrazide, imidate, thioimidate, amidine, amide,
orthoester, acylcyanide, acyl halide, thioester, thionoester,
dithiolester, nitrile or any other acid derivative well known in
the art which (a) does not substantially affect the herbicidal
activity of the active ingredient, i.e., the 4-aminopicolinic acid,
and (b) is or can be hydrolyzed in plants or soil to the picolinic
acid of Formula I that, depending upon the pH, is in the
dissociated or the undissociated form. Likewise, an "agriculturally
acceptable derivative", when used to describe the amine
functionality at the 4-position, is defined as any salt,
silylamine, phosphorylamine, phosphinimine, phosphoramidate,
sulfonamide, sulfinimine, sulfoximine, aminal, hemiaminal, amide,
thioamide, carbamate, thiocarbamate, amidine, urea, imine, nitro,
nitroso, azide, or any other nitrogen containing derivative well
known in the art which (a) does not substantially affect the
herbicidal activity of the active ingredient, i.e., the
4-aminopicolinic acid, and (b) is or can be hydrolyzed in plants or
soil to a free amine of Formula I. N-Oxides which are also capable
of breaking into the parent pyridine of Formula I are also covered
by the scope of this invention.
[0030] Suitable salts include those derived from alkali or alkaline
earth metals and those derived from ammonia and amines. Preferred
cations include sodium, potassium, magnesium, and aminium cations
of the formula:
R.sub.5R.sub.6R.sub.7NH.sup.+
[0031] wherein R.sub.5, R.sub.6, and R.sub.7 each, independently
represents hydrogen or C.sub.1-C.sub.12 alkyl, C.sub.3-C.sub.12
alkenyl or C.sub.3-C.sub.12 alkynyl, each of which is optionally
substituted by one or more hydroxy, C.sub.1-C.sub.4 alkoxy,
C.sub.1-C.sub.4 alkylthio or phenyl groups, provided that R.sub.5,
R.sub.6, and R.sub.7 are sterically compatible. Additionally, any
two of R.sub.5, R.sub.6, and R.sub.7 together may represent an
aliphatic difunctional moiety containing 1 to 12 carbon atoms and
up to two oxygen or sulfur atoms. Salts of the compounds of Formula
I can be prepared by treatment of compounds of Formula I with a
metal hydroxide, such as sodium hydroxide, or an amine, such as
ammonia, trimethylamine, diethanolamine, 2-methylthiopropylamine,
bisallylamine, 2-butoxyethylamine, morpholine, cyclododecylamine,
or benzylamine. Amine salts are often preferred forms of the
compounds of Formula I because they are water-soluble and lend
themselves to the preparation of desirable aqueous based herbicidal
compositions.
[0032] Suitable esters include those derived from C.sub.1-Cl.sub.2
alkyl, C.sub.3-C.sub.12 alkenyl or C.sub.3-C.sub.12 alkynyl
alcohols, such as methanol, iso-propanol, butanol, 2-ethylhexanol,
butoxyethanol, methoxypropanol, allyl alcohol, propargyl alcohol or
cyclohexanol. Esters can be prepared by coupling of the picolinic
acid with the alcohol using any number of suitable activating
agents such as those used for peptide couplings such as
dicyclohexylcarbodiimide (DCC) or carbonyl diimidazole (CDI), by
reacting the corresponding acid chloride of a picolinic acid of
Formula I with an appropriate alcohol or by reacting the
corresponding picolinic acid of Formula I with an appropriate
alcohol in the presence of an acid catalyst. Suitable amides
include those derived from ammonia or from C.sub.1-C.sub.12 alkyl,
C.sub.3-C.sub.12 alkenyl or C.sub.3-C.sub.12 alkynyl mono- or
di-substituted amines, such as but not limited to dimethylamine,
diethanolamine, 2-methylthiopropylamine, bisallylamine,
2-butoxyethylamine, cyclododecylamine, benzylamine or cyclic or
aromatic amines with or without additional heteroatoms such as but
not limited to aziridine, azetidine, pyrrolidine, pyrrole,
imidazole, tetrazole or morpholine. Amides can be prepared by
reacting the corresponding picolinic acid chloride, mixed
anhydride, or carboxylic ester of Formula I with ammonia or an
appropriate amine.
[0033] The terms "alkyl", "alkenyl" and "alkynyl", as well as
derivative terms such as "alkoxy", "acyl", "alkylthio" and
"alkylsulfonyl", as used herein, include within their scope
straight chain, branched chain and cyclic moieties. Unless
specifically stated otherwise, each may be unsubstituted or
substituted with one or more substituents selected from but not
limited to halogen, hydroxy, alkoxy, alkylthio, C.sub.1-C.sub.6
acyl, formyl, cyano, aryloxy or aryl, provided that the
substituents are sterically compatible and the rules of chemical
bonding and strain energy are satisfied. The terms "alkenyl" and
"alkynyl" are intended to include one or more unsaturated
bonds.
[0034] The term "aryl", as well as derivative terms such as
"aryloxy", refers to a phenyl or naphthyl group. The term
"heteroaryl", as well as derivative terms such as "heteroaryloxy",
refers to a 5- or 6-membered aromatic ring containing one or more
heteroatoms, viz., N, O or S; these heteroaromatic rings may be
fused to other aromatic systems. The aryl or heteroaryl
substituents may be unsubstituted or substituted with one or more
substituents selected from halogen, hydroxy, nitro, cyano, aryloxy,
formyl, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, halogenated
C.sub.1-C.sub.6 alkyl, halogenated C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 acyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl, aryl,
C.sub.1-C.sub.6OC(O)alkyl, C.sub.1-C.sub.6 NHC(O)alkyl, C(O)OH,
C.sub.1-C.sub.6C(O)Oalkyl, C(O)NH.sub.2, C.sub.1-C.sub.6
C(O)NHalkyl, or C.sub.1-C.sub.6C(O)N(alkyl).sub.2, provided that
the substituents are sterically compatible and the rules of
chemical bonding and strain energy are satisfied.
[0035] Unless specifically limited otherwise, the term halogen
includes fluorine, chlorine, bromine, and iodine.
[0036] The compounds of Formula I can be made using well-known
chemical procedures. The required starting materials are
commercially available or readily synthesized utilizing standard
procedures.
[0037] In general, reduction of picolinate N-oxides can be used to
prepare the corresponding picolinates. Electrolytic dehalogenation
of 5-halogenated picolinates can be used to prepare the 5-H
(unsubstituted) picolinates, and hydrolysis of pyridines
substituted at the 2 position by nitriles, amides, esters and other
hydrolyzable functionalities can be used to prepare the desired
picolinates.
[0038] 4-N-amide, carbamate, urea, sulfonamide, silylamine and
phosphoramidate amino derivatives can be prepared by the reaction
of the free amino compound with, for example, a suitable acid
halide, chloroformate, carbamyl chloride, sulfonyl chloride, silyl
chloride or chlorophosphate. The imine or hydrazone can be prepared
by reaction of the free amine or hydrazine with a suitable aldehyde
or ketone.
[0039] 6-Bromo analogs can be prepared by the reduction of several
key intermediates, e.g., the corresponding 6-bromo-4-azido,
6-bromo-4-nitro, and 6-bromo-4-nitro pyridine N-oxide analogs.
These intermediates, in turn, can be prepared either by
nucleophilic displacement of 6-bromo-4-halo analogs with NaN.sub.3
or by electrophilic nitration of the corresponding
6-bromopyridine-N-oxides. Alternatively, such analogs can be
prepared by direct amination of the corresponding 4,6-dibromo
analogs.
[0040] 6-Fluoro analogs can be prepared by direct amination of the
corresponding 4,6-difluoro analog.
[0041] 3- and 5-Alkoxy and aryloxy analogs can be prepared by
reduction of the corresponding 4-azido derivatives, which in turn
can be prepared by nucleophilic displacement of the corresponding
4-bromopyridines with NaN.sub.3. The required 3- and
5-alkoxy-4-bromopyridines can be prepared according to literature
procedures.
[0042] 6-Alkoxy, alkylthio, aryloxy and heteroaryloxy analogs can
be prepared by nucleophilic displacement with alkoxide,
thioalkoxide, aryloxide or heteroaryloxide on the appropriate
6-halopyridine.
[0043] 3- and 5-Alkylthio analogs can be prepared by lithiation of
the appropriate chloropyridines at low temperature and sequential
treatment with alkyl disulfides and carbon dioxide. Reaction of the
resulting picolinic acids with ammonium hydroxide gave the desired
products. 6-Cyano analogs can be prepared by amination of the
appropriate 4-halo-6-cyanopicolinate. 4-Halo-6-cyanopicolinates can
be prepared by action of trimethylsilyl cyanide (TMSCN) on the
appropriate pyridine N-oxide, which can be prepared by hydrogen
peroxide mediated oxidation of the corresponding pyridine. 3- and
5-Cyano analogs can be prepared by action of KCN on the appropriate
fluoropyridine at high temperature. 3- and 5-Fluoro, bromo, iodo
and nitro analogs can be prepared by electrophilic reaction of the
unsubstituted precursor with positive halogen or nitro sources such
as fluorine gas, bromine, iodine and fuming nitric acid
respectively. 6-Trifluoromethyl analogs can be prepared by
amination of readily available methyl trifluoromethylpicolinate
(oxidative halogenation of the 4-position followed by displacement
with ammonia or an amine equivalent) followed by chlorination of
the 3- and 5-positions. 3- and 5-Trifluoromethyl analogs can be
prepared by standard manipulations known to those skilled in the
art starting from the known compounds
2-fluoro-3-chloro-5-trifluorometylpyridine and
2,5-dichloro-3-trifluoromethylpyridine.
[0044] Substituted 4-amino analogs can be prepared by reacting the
corresponding 4-halopyridine-2-carboxylate or any other
displaceable 4-substituent with the substituted amine.
[0045] The compounds of Formula I, obtained by any of these
processes, can be recovered by conventional means. Typically, the
reaction mixture is acidified with an aqueous acid, such as
hydrochloric acid, and extracted with an organic solvent, such as
ethyl acetate or dichloromethane. The organic solvent and other
volatiles can be removed by distillation or evaporation to obtain
the desired compound of Formula I, which can be purified by
standard procedures, such as by recrystallization or
chromatography.
[0046] The compounds of Formula I have been found to be useful
pre-emergence and post-emergence herbicides. They can be employed
at non-selective (higher) rates of application to control a broad
spectrum of the vegetation in an area or at lower rates of
application for the selective control of undesirable vegetation.
Areas of application include pasture and rangelands, roadsides and
rights of ways, and crops such as corn, rice and cereals. It is
usually preferred to employ the compounds post-emergence. It is
further usually preferred to use the compounds to control a wide
spectrum of broadleaf weeds, including Dock species (Rumex spp),
Canada thistle (Cirsium arvense), pigweed species (Amaranthus
spp.), Senna species (Cassia spp.), spurge species (Euphorbia spp),
ragweed species (Ambrosia spp.), Sida species (Sida spp.), field
bindweed (Convolvulus arvensis), and knapweed species(Centaurea
spp.), among others. Use of the compounds to control undesirable
vegetation in grassy areas is especially indicated. While each of
the 4-aminopicolinate compounds encompassed by Formula I is within
the scope of the invention, the degree of herbicidal activity, the
crop selectivity, and the spectrum of weed control obtained varies
depending upon the substituents present. An appropriate compound
for any specific herbicidal utility can be identified by using the
information presented herein and routine testing.
[0047] The term herbicide is used herein to mean an active
ingredient that kills, controls or otherwise adversely modifies the
growth of plants. An herbicidally effective or vegetation
controlling amount is an amount of active ingredient which causes
an adversely modifying effect and includes deviations from natural
development, killing, regulation, desiccation, retardation, and the
like. The terms plants and vegetation include germinant seeds,
emerging seedlings and established vegetation.
[0048] Herbicidal activity is exhibited by the compounds of the
present invention when they are applied directly to the plant or to
the locus of the plant at any stage of growth or before planting or
emergence. The effect observed depends upon the plant species to be
controlled, the stage of growth of the plant, the application
parameters of dilution and spray drop size, the particle size of
solid components, the environmental conditions at the time of use,
the specific compound employed, the specific adjuvants and carriers
employed, the soil type, and the like, as well as the amount of
chemical applied. These and other factors can be adjusted as is
known in the art to promote non-selective or selective herbicidal
action. Generally, it is preferred to apply the compounds of
Formula I postemergence to relatively immature undesirable
vegetation to achieve the maximum control of weeds.
[0049] Application rates of about 1 to about 500 g/Ha are generally
employed in postemergence operations; for preemergence
applications, rates of about 10 to about 1000 g/Ha are generally
employed. The higher rates designated generally give non-selective
control of a broad variety of undesirable vegetation. The lower
rates typically give selective control and can be employed in the
locus of crops.
[0050] The herbicidal compounds of the present invention are often
best applied in conjunction with one or more other herbicides to
obtain control of a wider variety of undesirable vegetation. When
used in conjunction with other herbicides, the presently claimed
compounds can be formulated with the other herbicide or herbicides,
tank mixed with the other herbicide or herbicides, or applied
sequentially with the other herbicide or herbicides. Some of the
herbicides that can be employed in conjunction with the compounds
of the present invention include sulfonamides such as metosulam,
flumetsulam, cloransulam-methyl, diclosulam and florasulam,
sulfonylureas such as chlorimuron, nicosulfuron and metsulfuron,
imidazolinones such as imazaquin, imazapic, imazethapyr and
imazamox, phenoxyalkanoic acids such as 2,4-D and MCPA,
pyridinyloxyacetic acids such as triclopyr and fluroxypyr,
carboxylic acids such as clopyralid and dicamba, dinitroanilines
such as trifluralin and pendimethalin, chloroacetanilides such as
alachlor, acetochlor and metolachlor and other common herbicides
including acifluorfen, bentazon, clomazone, fumiclorac,
fluometuron, fomesafen, lactofen, linuron, isoproturon, and
metribuzin. Particularly preferred combinations are those with
florasulam, 2,4-D and fluroxypyr, which, against some weed species,
may actually exhibit synergy. A synergistic response may also be
obtained with compounds of the present invention when mixed with
auxin transport inhibitors such as diflufenzopyr and chlorflurenol.
The herbicidal compounds of the present invention can, further, be
used in conjunction with glyphosate and glufosinate on
glyphosate-tolerant or glufosinate-tolerant crops. It is generally
preferred to use the compounds of the invention in combination with
herbicides that are selective for the crop being treated and which
complement the spectrum of weeds controlled by these compounds at
the application rate employed. It is further generally preferred to
apply the compounds of the invention and other complementary
herbicides at the same time, either as a combination formulation or
as a tank mix.
[0051] The compounds of the present invention can generally be
employed in combination with known herbicide safeners, such as
cloquintocet, furilazole, dichlormid, benoxacor, mefenpyr-ethyl,
fenclorazoleethyl, flurazole, and fluxofenim, to enhance their
selectivity. They can additionally be employed to control
undesirable vegetation in many crops that have been made tolerant
to or resistant to them or to other herbicides by genetic
manipulation or by mutation and selection. For example, corn,
wheat, rice, soybean, sugarbeet, cotton, canola, and other crops
that have been made tolerant or resistant to compounds that are
acetolactate synthase inhibitors in sensitive plants can be
treated. Many glyphosate and glufosinate tolerant crops can be
treated as well, alone or in combination with these herbicides.
Some crops (e.g. cotton) have been made tolerant to auxinic
herbicides such as 2,4-dichlorophenoxy-acet- ic acid. These
herbicides may be used to treat such resistant crops or other auxin
tolerant crops.
[0052] While it is possible to utilize the 4-aminopicolinate
compounds of Formula I directly as herbicides, it is preferable to
use them in mixtures containing a herbicidally effective amount of
the compound along with at least one agriculturally acceptable
adjuvant or carrier. Suitable adjuvants or carriers should not be
phytotoxic to valuable crops, particularly at the concentrations
employed in applying the compositions for selective weed control in
the presence of crops, and should not react chemically with the
compounds of Formula I or other composition ingredients. Such
mixtures can be designed for application directly to weeds or their
locus or can be concentrates or formulations that are normally
diluted with additional carriers and adjuvants before application.
They can be solids, such as, for example, dusts, granules, water
dispersible granules, or wettable powders, or liquids, such as, for
example, emulsifiable concentrates, solutions, emulsions or
suspensions.
[0053] Suitable agricultural adjuvants and carriers that are useful
in preparing the herbicidal mixtures of the invention are well
known to those skilled in the art.
[0054] Liquid carriers that can be employed include water, toluene,
xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone,
cyclohexanone, trichloroethylene, perchloroethylene, ethyl acetate,
amyl acetate, butyl acetate, propylene glycol monomethyl ether and
diethylene glycol monomethyl ether, methanol, ethanol, isopropanol,
amyl alcohol, ethylene glycol, propylene glycol, glycerine, and the
like. Water is generally the carrier of choice for the dilution of
concentrates.
[0055] Suitable solid carriers include talc, pyrophyllite clay,
silica, attapulgus clay, kaolin clay, kieselguhr, chalk,
diatomaceous earth, lime, calcium carbonate, bentonite clay,
Fuller's earth, cotton seed hulls, wheat flour, soybean flour,
pumice, wood flour, walnut shell flour, lignin, and the like.
[0056] It is usually desirable to incorporate one or more
surface-active agents into the compositions of the present
invention. Such surface-active agents are advantageously employed
in both solid and liquid compositions, especially those designed to
be diluted with carrier before application. The surface-active
agents can be anionic, cationic or nonionic in character and can be
employed as emulsifying agents, wetting agents, suspending agents,
or for other purposes. Typical surface-active agents include salts
of alkyl sulfates, such as diethanolammonium lauryl sulfate;
alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate;
alkylphenol-alkylene oxide addition products, such as
nonylphenol-C.sub.18 ethoxylate; alcohol-alkylene oxide addition
products, such as tridecyl alcohol-C.sub.16 ethoxylate; soaps, such
as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium
dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate
salts, such as sodium di(2-ethylhexyl) sulfosuccinate; sorbitol
esters, such as sorbitol oleate; quaternary amines, such as lauryl
trimethylammonium chloride; polyethylene glycol esters of fatty
acids, such as polyethylene glycol stearate; block copolymers of
ethylene oxide and propylene oxide; and salts of mono and dialkyl
phosphate esters.
[0057] Other adjuvants commonly used in agricultural compositions
include compatibilizing agents, antifoam agents, sequestering
agents, neutralizing agents and buffers, corrosion inhibitors,
dyes, odorants, spreading agents, penetration aids, sticking
agents, dispersing agents, thickening agents, freezing point
depressants, antimicrobial agents, and the like. The compositions
may also contain other compatible components, for example, other
herbicides, plant growth regulants, fungicides, insecticides, and
the like and can be formulated with liquid fertilizers or solid,
particulate fertilizer carriers such as ammonium nitrate, urea and
the like.
[0058] The concentration of the active ingredients in the
herbicidal compositions of this invention is generally from about
0.001 to about 98 percent by weight. Concentrations from about 0.01
to about 90 percent by weight are often employed. In compositions
designed to be employed as concentrates, the active ingredient is
generally present in a concentration from about 5 to about 98
weight percent, preferably about 10 to about 90 weight percent.
Such compositions are typically diluted with an inert carrier, such
as water, before application. The diluted compositions usually
applied to weeds or the locus of weeds generally contain about
0.0001 to about 1 weight percent active ingredient and preferably
contain about 0.001 to about 0.05 weight percent.
[0059] The present compositions can be applied to weeds or their
locus by the use of conventional ground or aerial dusters,
sprayers, and granule applicators, by addition to irrigation water,
and by other conventional means known to those skilled in the
art.
[0060] The following Examples are presented to illustrate the
various aspects of this invention and should not be construed as
limitations to the claims.
EXAMPLES
[0061] 1. Preparation of 4-Amino-3,6-dichloropyridine-2-carboxylic
acid (Compound 1)
[0062] In a 3-liter (L) beaker was added 2000 grams (g) of hot
water, 115.1 g of 50 percent by weight NaOH, and 200 g of wet
4-amino-3,5,6-trichloropyridine-2-carboxylic acid (79.4 percent).
The solution was stirred for 30 minutes (min), filtered through a
paper filter, and transferred to a 5-L feed/recirculation tank.
This solution weighed 2315 g and contained 6.8 percent
4-amino-3,5,6-trichloropyridine-- 2-carboxylic acid. This feed was
recirculated at a rate of about 9.46 L/min and a temperature of
30.degree. C. through an undivided electrochemical cell having a
Hastelloy C anode and an expanded silver mesh screen cathode. After
normal anodization at +0.7 volt (v), the polarity of the cell was
reversed and the electrolysis was started. The cathode working
potential was controlled at -1.1 to -1.4 v relative to an Ag/AgCl
(3.0 M Cl.sup.-) reference electrode. While recirculating the feed,
a solution of 50 percent NaOH is slowly pumped into the
recirculation tank to maintain the NaOH concentration at a 1.5 to
2.0 percent excess. After about 15 hours (hr), the electrolysis was
terminated and the cell effluent was filtered through a paper
filter. The solution was neutralized with concentrated HCl and
concentrated to about 750 g of crude concentrate. The concentrate
was warmed to 85.degree. C. with stirring and the pH was adjusted
to less than 1 with concentrated HCl over 30 min. The resulting
slurry was cooled to ambient temperature and filtered. The filter
cake was washed with 3.times.200 milliliter (mL) portions of water
and dried under vacuum at 80.degree. C. The dried product, 118.1 g
assayed at 90.6 percent desired product; gas chromatography (GC)
indicated about 4 percent 4-amino-3,5,6-trichloropyri-
dine-2-carboxylic acid remaining as an impurity. A purified sample
of 4-amino-3,6-dichloropyridine-2-carboxylic acid had a melting
point (mp) of 185-187.degree. C. (dec.); .sup.1H NMR
(DMSO-d.sub.6): .delta. 13.9 (br, 1H), 7.0 (br m, 2H), 6.8 (s,1H);
.sup.13C NMR {.sup.1H} (DMSO-d.sub.6): .delta. 165.4 (1C), 153.4
(1C), 149.5 (1C), 147.7 (1C), 111.0 (1C), 108.1 (1C).
[0063] 2. Preparation of 2-Ethylhexyl
4-amino-3,6-dichloropyridine-2-carbo- xylate (Compound 2)
[0064] To a solution of 2-ethylhexanol (10 mL) and sulfuric acid (1
mL) was added 4-amino-3,6-dichloropyridine-2-carboxylic acid
(0.0097 mol, 2.0 g). After heating the reaction to reflux
overnight, the reaction mixture was cooled, poured into water (75
mL), and extracted with ethyl acetate (75 mL). The organic phase
was washed with sodium bicarbonate (75 mL), dried
(Na.sub.2SO.sub.4), and concentrated. The resulting solid was
recrystallized out of dichloromethane and hexane and filtered to
give 2-ethylhexyl 4-amino-3,6-dichloropyridine-2-carboxylate
(0.0074 mol, 2.36 g) as a crystalline solid (mp 55.degree. C.).
.sup.1H NMR (CDCl.sub.3): .delta. 0.9 (7H, m), 1.3 (7H, m), 1.7
(1H, m), 4.3 (2H, d), 5.1 (2H, bs), 6.7 (1H, s).
[0065] The following esters of
4-amino-3,5,6-trichloro-pyridine-2-carboxyl- ic acid were prepared
according to the procedure of Example 2:
[0066] methyl 4-amino-3,6-dichloropyridine-2-carboxylate(Compound
3); mp 134-135.degree. C.
[0067] ethyl 4-amino-3,6-dichloropyridine-2-carboxylate(Compound
4); mp 98-99.degree. C.
[0068] n-propyl 4-amino-3,6-dichloropyridine-2-carboxylate(Compound
5); mp 94-95.degree. C.
[0069] i-propyl 4-amino-3,6-dichloropyridine-2-carboxylate(Compound
6); mp 114-115.degree. C.
[0070] n-butyl 4-amino-3,6-dichloropyridine-2-carboxylate(Compound
7); mp 78-79.degree. C.
[0071] n-pentyl 4-amino-3,6-dichloropyridine-2-carboxylate
(Compound 8); mp 71-73.degree. C.
[0072] n-hexyl 4-amino-3,6-dichloropyridine-2-carboxylate (Compound
9); mp 65-66.degree. C.
[0073] butoxyethyl 4-amino-3,6-dichloropyridine-2-carboxylate
(Compound 10); mp 64-7.degree. C. as the monohydrate.
[0074] 3. Preparation of 4-Amino-3,6-dichloropyridine-2-carboxamide
(Compound 11)
[0075] To a 250 mL three neck roundbottom flask fitted with a
mechanical stirrer were added methyl 750 (10.0 g, 45 mmol) and 28%
aq. NH.sub.4OH (35 mL) at 0.degree. C. The suspension was stirred
vigorously for 24 hr while warming gradually to 25.degree. C. The
suspension was suction filtered, and the filter cake was washed on
the filter with cold water (2.times.100 mL). After air drying on
the filter, the analytically pure white solid product was collected
to give 4-amino-3,6-dichloropyridine-2-- carboxamide 11 (8.58 g,
92% yield); mp 240-241.degree. C.
[0076] 4. Preparation of Methyl N-acetyl
4-amino-3,6-dichloropyridine-2-ca- rboxylate (Compound 12) and
N,N-diacetyl 4-amino-3,6-dichloropyridine-2-ca- rboxylate (Compound
13)
[0077] A solution of acetic anhydride (75 mL) and methyl
4-amino-3,6-dichlororpyridine-2-carboxylate (0.00904 mol, 2.0 g)
was stirred and heated to reflux overnight. The solution was
cooled, concentrated, taken up in ethyl acetate (100 mL), and
washed with water (100 mL). The organic phase was washed with
saturated sodium bicarbonate (100 mL), dried (Na.sub.2SO.sub.4),
and concentrated. The solution was purified by chromatography on
silica gel. The front running spot was isolated and gave a yellow
oil identified as the diacylated 4-amide Compound 13 (0.0023 mol,
0.700 g). .sup.1H NMR 2.2 (6H, s), 3.9 (3H, s), 7.3 (1H, s). The
second spot gave a yellow solid identified as the monoacylated
4-amide compound 12(0.0035 mol, 0.920 g); mp 102-103.degree. C.
[0078] 5. Preparation of
4-Amino-6-bromo-3-chloropyridine-2-carboxylic acid (Compound
14)
[0079] A. Methyl 6-bromo-3-chloropyridine-2-carboxylate,
N-oxide
[0080] To a solution of methyl
6-bromo-3-chloropyridine-2-carboxylate (0.13 mol, 32.1 g) in
trifluoroacetic acid (75 mL) and trifluoroacetic anhydride (40 mL)
was cautiously added 50% hydrogen peroxide (0.17 mol, 13 g). The
reaction exothermed to reflux. After stirring for 30 min, the
solution was poured into a mixture of ice and 10 percent sodium
bisulfite (150 mL). The resulting solid was collected and dried in
vacuo to give a white solid (0.08 mol, 21.4 g). .sup.1H NMR
(CDCl.sub.3): .delta. 4.1 (3H, s), 7.3 (1H, d), 7.7 (1H, d).
[0081] B. Methyl 6-bromo-3-chloro-4-nitropyridine-2-carboxylate,
N-oxide
[0082] To a solution of fuming nitric acid (10 ML) and fuming
sulfuric acid (10 mL) was added methyl
6-bromo-3-chloropyridine-2-carboxylate, N-oxide and the reaction
was heated to 70.degree. C. in an oil bath for 4 hr. The mixture
was poured over ice water (100 mL) and extracted with ethyl acetate
(3.times.75 mL) and the combined extracts were backwashed with
brine, dried (Na.sub.2SO.sub.4) and concentrated. The dark oil was
chromatographed over silica in 4:1 EtOAc/hexane to give methyl
6-bromo-3-chloro-4-nitropyridine-2-carboxylate, N-oxide (0.007 mol,
2.2 g). .sup.1H NMR (CDCl.sub.3): .delta. 4.1 (3H, s), 8.4 (1H,
s).
[0083] C. Methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate
[0084] To a solution of titanium tetrachloride (0.015 mol, 2.8 g)
in tetrahydrofuran (50 mL) was added lithium aluminum hydride
(0.0175 mol, 0.7 g). The black slurry was stirred 15 min before
adding methyl 6-bromo-3-chloro-4-nitropyridine-2-carboxylate,
N-oxide (0.007 mol, 2.3 g) in THF (25 mL). The solution was stirred
1 hr before pouring into 1:1 H.sub.2O/NH.sub.4OH and filtering. The
filtrate was extracted with EtOAc (2.times.75 mL). The organic
phase was dried (Na.sub.2SO.sub.4), and concentrated. The red solid
was chromatographed over silica in 4:1 EtOAc/hexane to give methyl
4-amino-6-bromo-3-chloropyridine-2-carboxylat- e (0.003 mol, 0.8
g); mp 194-5.degree. C. .sup.1H NMR(CDCl.sub.3): .delta. 3.95 (3H,
s), 5.3 (2H, bs), 6.9 (1H, s).
[0085] D. 4-Amino-6-bromo-3-chloropyridine-2-carboxylic acid
(Compound 14)
[0086] To methyl 4-amino-6-bromo-3-chloropyridine-2-carboxylate
(200 mg; 0.8 mmol) in 10 mL of methanol was added excess 2N NaOH
(10 mL). The mixture was stirred for 1 hr at ambient temperature
and then evaporated to dryness in vacuo. The residue was dissolved
in water and diethyl ether. After separation of the phases, the
aqueous layer was acidified with 1N HCl to a pH=2. The aqueous
layer was evaporated to dryness and the residue was dissolved in 50
mL of methanol and filtered. The filtrate was evaporated under
reduced pressure and the residue was triturated with 5 percent
diethyl ether in petroleum ether to give 70 mg of
4-amino-6-bromo-3-chloropyridine-2-carboxylic acid, mp
182-183.degree. C.
[0087] 6. Preparation of Methyl
4-amino-3-chloro-6-fluoropyridine-2-carbox- ylate (Compound 15)
[0088] A. Methyl 3-chloro-4,6-difluoropyridine-2-carboxylate
[0089] To a solution of methyl
3,4,6-trichloropyridine-2-carboxylate (0.010 mol, 2.4 g) in DMSO
(10 mL) was added cesium fluoride (0.038 mol, 3.8 g) and the
suspension was heated for 2 hr at 100.degree. C. The reaction
mixture was dissolved in dilute HCl and extracted with ethyl
acetate (EtOAc). The organic layer was treated with
(trimethylsilyl)diazomethane (TMSCHN.sub.2) to re-esterify any
hydrolyzed ester. The mixture was concentrated and the resultant
residue was chromatographed over silica with 10 percent
EtOAc/hexane to give methyl
3-chloro-4,6-difluoropyridine-2-carboxylate (0.0072 mol, 1.5 g).
.sup.1H NMR (CDCl.sub.3): .delta. 4.00 (3H, s ), 6.95-6.90 (1H, m).
.sup.19F NMR {(H}: 5-65.0 (d, J=17 Hz), 95.8 (d, J=17 Hz).
[0090] B. Methyl 4-amino-3-chloro-6-fluoropyridine-2-carboxylate
(Compound 15)
[0091] Sodium azide (0.0086 mol, 0.60 g) was added to a solution of
methyl 3-chloro-4,6-difluoropyridine-2-carboxylate (0.0072 mol, 1.5
g) in 15 mL dimethyl formamide (DMF). The solution was stirred 10
min at ambient temperature before pouring into 350 mL water and
extracting the aqueous mixture with EtOAc (2.times.100 mL). The
organic phase was dried (Na.sub.2SO.sub.4) and then treated with
excess NaBH.sub.4 for 30 min. The excess NaBH.sub.4 was quenched
with aqueous EtOH and the mixture was diluted with water (200 mL).
The organic layer was separated and the aqueous layer extracted
with EtOAc (2.times.200 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4) and concentrated to an off-white powder which
was purified by reversed-phase HPLC to give methyl
4-amino-3-chloro-6-fluoropyridine-2-carboxylate (0.0059 mol, 1.2
g). .sup.1H NMR(CDCl.sub.3): .delta. 3.95 (3H, s), 5.2-5.1 (2H,
bs), 6.36 (1H, s). .sup.19F NMR {.sup.1H}: 5-72.7.
[0092] 7. Preparation of
4-Amino-3,5-difluoro-6-bromopyridine-2-carboxylic acid (Compound
16)
[0093] A. Preparation of
4-Amino-3,5,6-trifluoro-2-cyanopyridine
[0094] To a solution of 3,4,5,6-tetrafluoro-2-cyanopyridine in DMF
(75 mL) at 0.degree. C. was slowly added concentrated ammonium
hydroxide (15 mL). The reaction was stirred and additional 15 min
and the solution was diluted with water (150 mL). The solid was
collected and air dried to give
4-amino-3,5,6-trifluoro-2-cyanopyridine (25.5 g, 0.16 mol, 92%); mp
291-30 C.
[0095] B. Preparation of Methyl,
4-amino-6-bromo-3,5-difluoropyridine-2-ca- rboxylate (Compound
16)
[0096] A solution of 4-amino-3,5,6-trifluoro-2-cyanopyridine (19 g,
0.12 mol) in thirty percent hydrogen bromide in acetic acid (150
mL) was place in a Paar bomb and heated to 110.degree. C. for 3 hr.
The reaction was diluted with water (300 ml) and the solid
(4-amino-6-chloro-3,5-difluorop- yridine-2-carboxyamide) was
collected. This material, without further purification, was
slurried in methanol (500 ml) and concentrated hydrochloric acid
added. The slurry was heated under reflux for 4 hr and, after
cooling to room temperature, diluted with water (1,000 mL) and the
solid collected and dried to give methyl
4-amino-6-bromo-3,5-difluoropyri- dine-2-carboxlate (9.6 g, 0.04
mol, 25%); mp 110-111.degree. C.
[0097] 8. Preparation of 4-Amino-3,6-dibromopyridine-2-carboxylic
acid (Compound 17)
[0098] 3,4,5,6-Tetrabromopyridine-2-carboxamide (5.0 g) was
selectively aminated with ammonia gas at RT in 100 mL methanol. The
resultant solution was concentrated to an off-white solid and
hydrolyzed with conc. sulfuric acid (25 mL) at 140.degree. C. for 3
hr. the mixture was made basic with NaOH, extracted with EtOAc
(2.times.100 mL), acidified and filtered to give 1.4 g of pure
4-amino-3,6-dibromopyridine-2-carboxylic acid; mp 205.degree. C.
dec.
[0099] 9. Preparation of Methyl
4-amino-3,5,6-tribromopyridine-2-carboxyla- te (Compound 18)
[0100] Methyl 4-amino-3,5,6-tribromopyridine-2-carboxylate was
prepared by amination of methyl
3,4,5,6-tetrabromopyridine-2-carboxylate following the procedure of
Example 6B. .sup.1H NMR(CDCl.sub.3): .delta. 3.95 (3H, s), 6.9-6.8
(2H, bs).
[0101] 10. Preparation of
4-Amino-3,6-dichloro-5-fluoropyridine-2-carboxyl- ic acid (Compound
19)
[0102] To a solution of 4-amino-3,6-dichloropyridine-2-carboxylate
(1.5 g, 6.8 mmol) in 20 mL of dry acetonitrile was added
1-(chloromethyl)-4-fluor- o-1,4-diazoniabicyclo[2.2.2]octane bis
(tetrafluoroborate) (Selectfluor.TM. from Aldrich Chemical Company,
Inc.; 2.9 g, 2.59 mmol [F+]/g). The resulting mixture was heated at
reflux for 3 hr, then allowed to cool to room temperature. This
material was taken up in Et.sub.2O and washed with H.sub.20. The
organic layer was dried over MgSO.sub.4, filtered and concentrated
to yield a brown oil. The crude product was purified via reverse
phase HPLC (50% acetonitrile/water) to give 0.37 g of white solid
which was stirred in 1N NaOH for 1 hr then made acidic with conc.
HCl. The precipitated white solid was collected with suction,
washed with H.sub.2O and dried under vacuum to give 170 mg of
4-amino-3,6-dichloro-5-fluoropyridine-2-carboxylic acid (11%
yield); mp 214.degree. C. dec.
[0103] 11. Preparation of
4-Amino-3,6-dichloro-5-bromopyridine-2-carboxyli- c acid (Compound
20)
[0104] To a solution of methyl
4-amino-3,6-dichloropyridine-2-carboxylate (18 g, 81 mmol) in 100
mL fuming sulfuric acid was added bromine (15 mL, excess). The
resulting mixture was heated to 70.degree. C. for 30 min, then
allowed to cool to room temperature. This material was poured into
ice water (1000 mL) and extracted with EtOAc (4.times.500 mL). The
combined organic extracts were dried (MgSO.sub.4), filtered and
concentrated to yield a brown solid. The crude product was purified
via reverse phase HPLC (50% acetonitrile/water) to give 21 g of
4-amino-3,6-dichloro-5-bromopyridine-2-carboxylic acid as a white
solid (91% yield); mp 201-202.degree. C.
[0105] 12. Preparation of
4-Amino-3,6-dichloro-5-trifluoromethylpyridine-2- -carboxylic acid
(Compound 21)
[0106] A solution of
4-amino-3,6-dichloro-5-trifluoromethyl-2-cyanopyridin- e (0.5 g,
1.96 mmol) in 10 mL of 85% H.sub.2SO.sub.4 was stirred at
140.degree. C. for 0.5 hr. The reaction mixture was allowed to cool
and added to ice. The precipitated white solid was collected with
suction, rinsed several more times with water and allowed to air
dry to give 0.33 g of product as a white solid (61.4% yield); mp
173.degree. C.
[0107] 13. Preparation of
4-Amino-3,6-dichloro-5-methoxypyridine-2-carboxy- lic acid
(Compound 22)
[0108] A. Methyl 3-chloro-5-methoxypyridine-2-carboxylate,
N-oxide
[0109] In a dry 3-neck round bottom flask was added methyl
3,5-dichloropyridine-2-carboxylate, N-oxide (5.0 g, 22.5 mmol) to
25 mL of methanol to give a slurry. A 25% solution of sodium
methoxide in methanol (5.40 mL, 23.62 mmol) was added and heated to
reflux for 1.5 h. The reaction mixture was diluted in ethyl acetate
and added to H.sub.2O. The layers were separated and the aqueous
layer was saturated with brine and extracted 2 more times in ethyl
acetate. The combined organic layers were dried (MgSO.sub.4) and
concentrated to give a white solid. Purification by column
chromatography (silica gel) using an eluent of 50%
Et.sub.2O/Petroleum ether (1.5 L) then 100% Et.sub.2O to give 1.76
g of a white solid; mp 154-156.degree. C.
[0110] B. Methyl 3-chloro-5-methoxy-4-nitropyridine-2-carboxylate,
N-oxide
[0111] To methyl 3-chloro-5-methoxypyridine-2-carboxylate, N-oxide
(1.41 g, 5.97 mmol) in H.sub.2SO.sub.4 cooled to 0.degree. C. was
slowly added a 50/50 mixture of 30% oleum and fuming HNO.sub.3.
Reaction mixture stirred for 30 min at room temperature and then
heated to 70.degree. C. for 3 days. The reaction mixture was
diluted with ethyl acetate and cooled to 0.degree. C. Saturated
sodium bicarbonate was carefully added and the layers were
separated. Aqueous layer was washed 2 more times with ethyl
acetate. The combined organic layers were dried (MgSO.sub.4) and
concentrated to dryness. Purification by column chromatography
(silica gel) using an eluent of 20% ethyl acetate/hexane gave 300
mg of a yellow solid; mp 160.degree. C.
[0112] C. Methyl
3,6-dichloro-5-methoxy-4-nitropyridine-2-carboxylate
[0113] To methyl 3-chloro-5-methoxy-4-nitropyridine-2-carboxylate,
N-oxide (0.300 g, 1.12 mmol) in 5 mL of chloroform was added
PCl.sub.3 (0.664 mL, 7.62 mmol). The reaction mixture was heated to
reflux for 8 hr and then concentrated to dryness in vacuo to give
300 mg of a white solid.
[0114] D. Methyl
4-amino-3,6-dichloro-5-methoxypyridine-2-carboxylate
[0115] To methyl
3,6-dichloro-5-methoxy-4-nitropyridine-2-carboxylate (0.300 g, 1.06
mmol) in 5 mL of ethyl acetate was added SnCl.sub.2.times.2H.sub.2O
(1.60 g, 7.1 mmol). The reaction mixture was heated to 70.degree.
C. for 30 min and then cooled to room temperature. Saturated sodium
bicarbonate and a saturated solution of KHF.sub.2 were added to
reaction mixture. The mixture was extracted with ethyl acetate and
the layers were separated. The aqueous layer was washed 2 more
times with ethyl acetate. The combined organic layers were dried
(MgSO.sub.4) and concentrated to dryness to give 0.250 g of a
yellow solid.
[0116] E. 4-Amino-3,6-dichloro-5-methoxypyridine-2-carboxylic acid
(Compound 22)
[0117] 4-Amino-3,6-dichloro-5-methoxypyridine-2-carboxylic acid was
prepared by saponification of the methyl ester according to the
procedure of Example 17(D); mp 154-156.degree. C.
[0118] 14. Preparation of
4-Amino-3,6-dichloro-5-methylthiopyridine-2-carb- oxylic acid
(Compound 23)
[0119] 4-Amino-3,6-dichloro-5-methylthiopyridine-2-carboxylic acid
was prepared by analogy to the preparation of
4-amino-3,6-dichloro-5-methoxyp- yridine-2-carboxylic acid
following the procedure of Example 13 using sodium thiomethoxide
instead of sodium methoxide; mp 160.degree. C. dec.
[0120] 15. Preparation of
4-Amino-3,6-dichloro-5-phenylthiopyridine-2-carb- oxylate (Compound
24)
[0121] 4-Amino-3,6-dichloro-5-phenylthiopyridine-2-carboxylic acid
was prepared by analogy to the preparation of
4-amino-3,6-dichloro-5-methoxyp- yridine-2-carboxylic acid
following the procedure of Example 13 using sodium thiophenoxide
instead of sodium methoxide; mp 160.degree. C. dec.
[0122] 16. Preparation of Methyl
4-amino-3,6-dichloro-5-nitropyridine-2-ca- rboxylate (Compound
25)
[0123] To a solution containing
4-amino-3,6-dichloropyridine-2-carboxylic acid (0.5 g, 2.43 mmol)
and 10 mL of conc. H.sub.2SO.sub.4 was added dropwise a mixture of
conc. HNO.sub.3/H.sub.2SO.sub.4 (1 mL/1 mL) at RT. After stirring
for 5 min, the reaction mixture was added to ice and the solid was
collected by vacuum filtration. The resulting solid was dissolved
in 20% MeOH/EtOAc and trimethylsilyl diazomethane (TMSCHN.sub.2)
was then added until reaction was complete. Reaction mixture was
concentrated under reduced pressure, taken up in Et.sub.2O and
washed with aqueous NaHCO.sub.3, dried over MgSO.sub.4, filtered
and concentrated to give a brown oil. The crude product was
purified by chromatography, eluting with 10% ethyl acetate-hexane
to give 80 mg of the methyl ester as a yellow solid; mp
127-8.degree. C.
[0124] 17. Preparation of
4-N-Methylamino-3,6-dichloropyridine-2-carboxyli- c acid (Compound
26)
[0125] A. Methyl 3,6-dichloropyridine-2-carboxylate
[0126] To a 3-neck round bottom flask equipped with a reflux
condenser was added 3,6-dichloropyridine-2-carboxylic acid (50.0 g,
260.42 mmol) in methanol (200 mL). HCl(g) was bubbled in until
solution became saturated and stirred at room temperature for 2 hr.
The solution was concentrated to dryness in vacuo. Diethyl ether
was added to make a slurry that was subsequently added to a flask
filled with a 1:1 mixture of saturated sodium bicarbonate/diethyl
ether and stirred for 10 min. The aqueous phase was extracted with
diethyl ether (3.times.300 mL). The combined extracts were dried
(MgSO.sub.4) and concentrated to give 46.6 g of a light yellow
solid. .sup.1H NMR(CDCl.sub.3): 67 4.00 (s, 3H); 7.41 (d, 1H); 7.80
(d, 1H).
[0127] B. Methyl 3,6-dichloropyridine-2-carboxylate, N-oxide
[0128] Methyl 3,6-dichloropicolinate (20.0 g, 97.07 mmol) was
dissolved in a minimum amount of trifluoroacetic acid (TFA). In a
separate flask was stirred trifluoroacetic anhydride (TFAA, 38 mL)
and 50% H.sub.2O.sub.2 (9.9 g, 145.61 mmol) which was added to the
TFA solution. The reaction mixture was stirred at reflux for 1 hr
and concentrated to dryness. The orange oil was dissolved in ethyl
acetate and saturated sodium bicarbonate. The phases were separated
and the aqueous phase was extracted with ethyl acetate (2.times.200
mL). The combined extracts were dried (MgSO.sub.4) and concentrated
to a yellow solid. Purification by column chromatography (silica
gel) using an eluent of 50% ethyl acetate/hexane gave 12.13 g of a
yellow solid. .sup.1H NMR (CDCl.sub.3): .delta. 4.00 (s, 3H); 7.25
(d, 1H); 7.50 (d, 1H).
[0129] C. Methyl 3,4,6-Trichloropyridine-2-carboxylate
[0130] To methyl 3,6-dichloropicolinate N-oxide (5.0 g, 22.52 mmol)
dissolved in 15 mL of acetonitrile was added POCl.sub.3 (4.20 mL,
45.04 mmol). The reaction mixture was stirred at reflux for 5 hr,
cooled to room temperature and concentrated to dryness in vacuo.
The resultant orange oil was dissolved in diethyl ether. Carefully,
saturated sodium bicarbonate was added and the aqueous phase was
extracted with diethyl ether (2.times.100 mL). The combined
extracts were dried (MgSO.sub.4) and concentrated to dryness.
Purification by column chromatography (silica gel) using an eluent
of 20% ethyl acetate/hexane gave 5.89 g of a light yellow solid.
.sup.1H NMR(CDCl.sub.3): .delta. 4.00 (s, 3H); 7.55 (s, 1H).
[0131] D. 3,4,6-Trichloropyridine-2-carboxylic acid
[0132] To methyl 3,4,6-Trichloropicolinate (3.57 g, 14.85 mmol) in
20 mL of methanol was added 1N NaOH (14.85 mL, 14.85 mmol). The
reaction mixture was stirred at room temperature for 1 hr and then
concentrated to dryness in vacuo. 100 mL each of diethyl ether and
H.sub.2O were added. Aqueous layer was acidified with 1N HCl until
pH=2. Methylene chloride was added and the aqueous phase was
extracted with additional CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined extracts were dried (MgSO.sub.4) and concentrated to give
3.13 g of a white solid. .sup.1H NMR(CDCl.sub.3): .delta. 7.50 (s,
1H).
[0133] E. 4-N-Methylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 26)
[0134] 3,4,6-Trichloropyridine-2-carboxylic acid (1.56 g, 6.89
mmol) was dissolved in methylamine and placed in a Parr bomb at
80.degree. C. for 2 days. The reaction mixture was cooled to room
temperature and diluted with ethyl acetate. 1N HCl was added until
pH=2. The aqueous phase was extracted with ethyl acetate
(2.times.50 mL) and the combined extracts were dried (MgSO.sub.4)
and concentrated to dryness. Desired product was triturated from 5%
diethyl ether/pet ether; the solid was filtered and dried to give
0.600 g of a light yellow solid. .sup.1H NMR(CDCl.sub.3): .delta.
2.75 (s, 3H); 5.70 (s, 1H); 6.30 (s, 1H); mp 170-172.degree. C.
[0135] The following N-alkyl analogs of 4-amino-3,
6-dichloropyridine-2-ca- rboxylic acid were prepared according to
the procedure of Example 17:
[0136] 4-N-ethylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 27); mp 136-137.degree. C.
[0137] 4-N-isopropylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 28); mp 146-147.degree. C.
[0138] 4-N-butylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 29); mp 96-97.degree. C.
[0139] 4-N-allylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 30); mp 128-131.degree. C.
[0140] 4-N-hydroxyethylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 31); mp 140-141.degree. C.
[0141] 4-N-methoxyethylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 32); mp 97-99.degree. C.
[0142] 4-N,N-dimethylamino-3,6-dichloropyridine-2-carboxylic acid
(Compound 33); mp 110.degree. C.
[0143] 4-N-hydroxy-N-methyl-amino-3,6-dichloropyridine-2-carboxylic
acid (Compound 34); mp 140-1.degree. C.
[0144] 4-N-methoxy-N-methyl-3,6-dichloropyridine-2-carboxylic acid
(Compound 35); mp 98-99.degree. C.
[0145] 4-pyrrolidino-3,6-dichloropyridine-2-carboxylic acid
(Compound 36); mp 153-5.degree. C.
[0146] 4-pyrrolo-3,6-Dichloropyridine-2-carboxylic acid (Compound
37); mp 155-156.degree. C.
[0147] 18. Preparation of Methyl
4-azido-6-bromo-3-chloropyridine-2-carbox- ylic acid (Compound
38)
[0148] To a solution of methyl
4,6-dibromo-3-chloropyridine-2-carboxylate (6.0 g 0.018 mol) in DMF
(50 mL) was added sodium azide (2.0 g 0.03 mol) and the solution
warmed to 50.degree. C. for 1 hr. The reaction was diluted with
water (200 mL) and cooled to 0.degree. C. for 1 hr. The solid was
collected to give methyl 4-azido-6-bromo-3-chloropyridine-2-car-
boxylate (4.4 g, 0.012 mol, 66%); mp 84-86.degree. C.
[0149] 19. Preparation of 4-Nitro-3,6-dichloropyridine-2-carboxylic
acid (Compound 39)
[0150] Methyl 3,6-dichloropyridine-2-carboxylate N-oxide (5.0 g,
22.52 mmol) was dissolved in a minimum amount of H.sub.2SO.sub.4.
The mixture was cooled in an ice/water bath and to it was slowly
added 30% oleum (9.6 mL) and fuming HNO.sub.3 (9.6 mL), gradually
heated to 65.degree. C. and stirred for 48 hr. The cooled reaction
mixture was diluted with ethyl acetate (200 mL) and to it was
carefully added saturated sodium bicarbonate. The product was
extracted with ethyl acetate (2.times.150 mL) and the combined
extracts were dried (MgSO.sub.4) and concentrated to give 0.10 g of
a yellow solid; mp 192-193.degree. C.
[0151] 20. Preparation of
4-N,N-Dimethylformamidino-3,6-dichloropyridine-2- -carboxylic acid
(Compound 40)
[0152] To a suspension of methyl
4-amino-3,6-dichloro-pyridine-2-carboxyli- c acid (2.07 g, 10.0
mmol)in THF (50 mL) was added 5.0 eq N,N-dimethylformamide dimethyl
acetal (50 mmol). The mixture was heated to 50.degree. C. for 1 hr
during which time the suspension became a homogeneous solution. The
cooled reaction mixture was concentrated in vacuo, triturated with
hexanes to a white amorphous solid and dried under high vacuum to
give 2.5 g of a highly hygroscopic white powder (95% yield);
.sup.1H NMR (DMSO) .delta. 8,21 (1H, s), 7.95 (1H, s), 3.25 (3H,
s), 3.17 (3H, s).
[0153] 21. Preparation of 4-Amino-6-bromo-3-methoxypyridine-2
-carboxylic acid (Compound 41)
[0154] A. Methyl 4,6-dibromo-3-methoxypyridine-2-carboxylate
[0155] To methyl 4,6-dibromo-3-hydroxypyridine-2-carboxylate 3.98 g
(3.98 g, 12.81 mmol) in 40 mL of acetone was added K.sub.2CO.sub.3
(2.0 g, 14.47 mmol) and dimethyl sulfate (1.20 mL, 12.37 mmol). The
reaction mixture was refluxed overnight and concentrated to
dryness. The residue was dissolved in ethyl acetate and saturated
sodium bicarbonate. The phases were separated and the aqueous phase
was extracted with ethyl acetate (3.times.100 mL). The combined
extracts were dried (MgSO.sub.4) and concentrated to dryness. The
residue was purified by chromatography (silica gel). Elution with
15% ethyl acetate/hexane gave 0.980 g, of a white solid. .sup.1H
NMR(CDCl.sub.3): .delta. 3.95 (s, 3H); 3.90 (s, 3H); 7.80 (s,
1H).
[0156] B. Methyl 4-azido-6-bromo-3-methoxypyridine-2-carboxylate
Methyl 4,6-dibromo-3-methoxypyridine-2-carboxylate (0.980 g, 3.02
mmol) was dissolved in a minimum amount of DMF. Slowly sodium azide
(0.216 g, 3.32 mmol) was added followed by H.sub.2O to form a
homogeneous solution. The reaction mixture was heated to 60.degree.
C. and stirred for 2 days. Reaction mixture added to a flask filled
with ice water and extracted with ethyl acetate (3.times.50 mL).
Extracts were combined and back washed with H.sub.2O, dried
(MgSO.sub.4) and concentrated to give 0.500 g of an orange oil.
.sup.1H NMR(CDCl.sub.3): .delta. 3.90 (s, 3H); 3.95 (s, 3H); 7.20
(s, 1H).
[0157] C. Methyl
4-amino-6-bromo-3-methoxypyridine-2-carboxylate
[0158] To methyl 4-azido-6-bromo-3-methoxypyridine-2-carboxylate
(0.500 g, 1.74 mmol) in 10 mL of methanol was added NaBH.sub.4
(0.046 g, 1.22 mmol). The reaction mixture was stirred at room
temperature for 10 min. Ethyl acetate and water were added and the
phases were separated. The organic phase was washed with H.sub.2O,
dried (MgSO.sub.4) and concentrated to dryness in vacuo. The
residue was purified by chromatography (silica gel). Elution with
100% ethyl acetate gave 0.300 g of a white solid. .sup.1H
NMR(CDCl.sub.3): .delta. 3.90 (s, 1H); 3.95 (s, 1H); 4.60 (s, 2H);
6.85 (s, 1H).
[0159] D. 4-Amino-6-bromo-3-methoxypyridine-2-carboxylic acid
(Compound 41)
[0160] To methyl 4-amino-6-bromo-3-methoxypyridine-2-carboxylate
(0.300 g, 1.15 mmol) in 10 mL of methanol was added 1N NaOH (1.15
mL, 1.15 mmol). The reaction mixture was stirred at room
temperature for 1 hr and concentrated to dryness in vacuo. Diethyl
ether and H.sub.2O were added. The aqueous layer was acidified with
1N HCl until pH=2 and concentrated to dryness. Methanol (50 mL) was
added to the white solid. The mixture was filtered and the filtrate
concentrated to dryness. Triturating with 5% diethyl ether/pet
ether gave 0.180 g of a light pink solid. .sup.1H NMR(DMSO):
.delta. 3.60 (s, 3H); 6.80 (s, 1H).
[0161] 22. Preparation of
4-Amino-6-bromo-5-chloro-3-methoxypyridine-2-car- boxylic acid
(Compound 42)
[0162] A. Methyl
4-amino-6-bromo-5-chloro-3-methoxypyridine-2-carboxylate
[0163] To methyl 4-amino-6-bromo-3-methoxypyridine-2-carboxylate
(1.45 g, 5.56 mmol) in 10 mL of acetonitrile was added sulfuryl
chloride, in excess, via pipette until the solution remained
yellow. The solution was heated to reflux for 5 min. The reaction
mixture was added to saturated sodium bicarbonate and aqueous phase
was extracted with diethyl ether (3 x). The combined organic
extracts were dried (MgSO.sub.4), filtered and concentrated in
vacuo to give a yellow solid. Solid was washed in 10% diethyl
ether/petroleum ether and solid filtered to give 0.580 g of a white
solid.
[0164] B. 4-Amino-6-bromo-5-chloro-3-methoxypyridine-2-carboxylic
acid (Compound 42)
[0165] To
methyl-4-amino-6-bromo-5-chloro-3-methoxypyridine-2-carboxylate
(0.300 g, 1.02 mmol) in 10 mL of methanol was added 1 N NaOH (1.10
mL, 1.10 mmol). The reaction mixture was stirred at room
temperature for 4 hr and was then concentrated to dryness in vacuo.
The resulting aqueous layer was acidified with concentrated HCl.
The white solid was collected by filtration and was rinsed with
H.sub.2O. The solid was dried at 50.degree. C. under vacuum to give
0.230 g of a white fluffy solid; mp 154-156.degree. C. 23.
Preparation of 4-Amino-5,6-dichloro-3-fluoropyridi- ne-2-carboxylic
acid (Compound 43)
[0166] A. 4-Amino-5,6-dichloro-2-trichloromethylpyridine
[0167] To a solution of 4,5,6-trichloro-2-trichloromethylpyridine
(2 g, 6.7 mmol) in aqueous DMF was added NaN.sub.3 (0.5 g, 7.7
mmol). The resulting mixture was heated at 70.degree. C. for 2 hr,
added to H.sub.2O and extracted (3.times.) with Et.sub.2O. Organic
layer was concentrated to yield a white solid, which was dissolved
in 10 mL of MeOH. Excess NaBH.sub.4 was added and the reaction
mixture was stirred at room temperature for 0.5 hr. This material
was added to H.sub.2O, extracted (3.times.) with Et.sub.2O, dried
over MgSO.sub.4 and concentrated in vacuo. The resulting solid was
washed several times with hexane to give 1.3 g of
4-amino-5,6-dichloro-2-trichloromethylpyridine.
[0168] B. 4-Amino-5,6-dichloro-3-fluoropyridine-2-carboxylic acid
(Compound 43)
[0169] To a solution of
4-amino-5,6-dichloro-2-trichloromethylpyridine (1.25 g, 4.46 mmol)
in 20 mL of dry acetonitrile was added Selectfluor.TM. (1.9 g, 2.59
mmol [F+]/g). The resulting mixture was heated at reflux for 72 hr,
then allowed to cool to room temperature. This material was taken
up in Et.sub.2O and washed with H.sub.2O. The organic layer was
dried over MgSO.sub.4, filtered and concentrated to yield a dark
oil. The crude product was purified via reverse phase HPLC (75%
acetonitrile/water) to give 0.2 g of white solid which was stirred
in 80% H.sub.2SO.sub.4 at 155.degree. C. for 0.5 hr. Reaction
mixture was allowed to cool and extracted several times with 10%
MeOH/CH.sub.2Cl.sub.2. Organic layer was dried over MgSO.sub.4,
filtered and concentrated to give a white solid which was washed
several times with hexane-diethyl ether to give 60 mg of
4-amino-5,6-dichloro-3-fluorop- yridine-2-carboxylic acid; mp
208.degree. C. dec.
[0170] 24. Preparation of
4-Amino-3-bromo-6-chloropyridine-2-carboxylic acid (Compound
44)
[0171] A. Methyl 3-bromo-4-chloropyridine-2-carboxylate To a
solution of 3-bromo-4-chloropyridine-2-carboxylic acid (1.75 g, 7.4
mmol) in MeOH was added anhydrous HCl. The resulting mixture was
stirred at room temperature for 18 hr. The reaction mixture was
concentrated to give a solid, which was partitioned between
Et.sub.2O and saturated NaHCO.sub.3. Organic layer was dried over
MgSO.sub.4, filtered and concentrated to give a brown residue. This
material was purified via flash column chromatography to yield 1.35
g of product as a pale yellow oil.
[0172] B. Methyl 3-bromo-4,6-dichloropyridine-2-carboxylate
[0173] To a solution of methyl
3-bromo-4-chloropyridine-2-carboxylate (1.35 g, 5.4 mmol) in 5 mL
of TFA was added 30% H.sub.2O.sub.2 (1 g, 9.8 mmol). The resulting
mixture was stirred at 75.degree. C. for 0.5 hr and allowed to cool
to room temperature. Et.sub.2O was added and the organic layer was
washed carefully with saturated NaHCO.sub.3, dried over MgSO.sub.4,
filtered and concentrated to give the corresponding N-Oxide
intermediate as a white solid. This material was taken up in
acetonitrile (5 mL), POCl.sub.3 (2-3 mL) and heated at reflux for 2
hr. The reaction mixture was allowed to cool, added to Et.sub.2O
and washed carefully with saturated NaHCO.sub.3, dried over
MgSO.sub.4, filtered and concentrated to give 0.9 g of product as a
light brown oil. This material was sufficiently pure to carry on to
the next step.
[0174] C. 4-Amino-3-bromo-6-chloropyridine-2-carboxylic acid
(Compound 44)
[0175] To a solution of methyl
3-bromo-4,6-dichloropyridine-2-carboxylate (0.9 g, 3.2 mmol) in
aqueous DMF was added NaN.sub.3 (0.25 g, 3.8 mmol). The resulting
mixture was heated at 60.degree. C. for 1 hr, added to H.sub.2O and
extracted (3.times.) with Et.sub.2O. Organic layer was concentrated
to yield a white solid, which was dissolved in 10 mL of MeOH.
Excess NaBH.sub.4 was added and the reaction mixture stirred at
room temperature for 0.5 hr. This material was added to H.sub.2O,
extracted (3.times.) with Et.sub.2O, dried over MgSO.sub.4 and
concentrated. The resulting solid was stirred in 1N NaOH for 1 hr,
made acidic with conc. HCl and concentrated to dryness. This
material was extracted with MeOH, concentrated to give 220 mg of
4-amino-3-bromo-6-chloropyridine-2-carboxylic acid; mp 175.degree.
C. dec.
[0176] 25. Preparation of
4-Amino-3,5-dichloro-6-trifluoromethylpyridine-2- -carboxylic acid
(Compound 45)
[0177] A. Methyl
4-chloro-6-trifluoromethylpyridine-2-carboxylate
[0178] To a solution of 6-trifluoromethylpicolinic acid (8.6 g, 45
mmol; prepared from the corresponding
6-trifluoromethyl-2-cyanopyridine) in 25 mL of TFA was added 30%
H.sub.2O.sub.2 (7.8 g, 67.5 mmol). Reaction mixture was stirred at
70.degree. C. for 18 h and concentrated to give 8.0 g of the
N-oxide. This material was stirred in HCl/MeOH solution for 18 hr.
The reaction mixture was concentrated to give an oily residue which
was partitioned between Et.sub.2O and saturated NaHCO.sub.3. The
organic layer was dried over MgSO.sub.4, filtered and concentrated
to give 5.0 g of a yellow oil. Neat POCl.sub.3 was added and
stirred at reflux for 2 hr. The mixture was allowed to cool, added
carefully to saturated NaHCO.sub.3 and extracted (3.times.) with
Et.sub.2O. The organic layer was dried over MgSO.sub.4, filtered
and concentrated to give a brown solid. This material was purified
via flash column chromatograph to give 2.64 g of product as a white
solid; mp 62-3.degree. C.
[0179] B. Methyl
4-amino-6-trifluoromethylpyridine-2-carboxylate
[0180] To a solution of methyl
4-chloro-6-trifluoromethylpyridine-2-carbox- ylate (2.44 g, 10.2
mmol) in aqueous DMF was added NaN.sub.3 (0.7 g, 10.8 mmol). The
resulting mixture was heated at 70.degree. C. for 18 hr, added to
H.sub.2O and extracted (3.times.) with Et.sub.2O. The organic layer
was concentrated to yield a white solid that was dissolved in 10 mL
of MeOH. Excess NaBH.sub.4 was added and the reaction mixture
stirred at RT for 0.5 hr. This material was added to H.sub.2O,
extracted (3.times.) with Et.sub.2O. The extract was dried over
MgSO.sub.4 and concentrated. The resulting residue was purified via
flash column chromatography to give 0.95 of product as a white
solid; mp 114.degree. C.
[0181] C. Methyl
4-amino-3-5-dichloro-6-trifluoromethylpyridine-2-carboxyl- ate
[0182] To a solution of methyl
4-amino-6-trifluoromethylpyridine-2-carboxy- late (0.75 g, 3.4
mmol) in 5 mL of dry acetonitrile was added SO.sub.2Cl.sub.2 (0.55
ml, 6.8 mmol). The resulting mixture was heated at reflux for 0.5
hr, then allowed to cool to room temperature. This material was
taken up in Et.sub.2O and washed with saturated NaHCO.sub.3. The
organic layer was dried over MgSO.sub.4, filtered and concentrated
to give solid. The crude material was purified via flash column
chromatography to yield 0.28 g of product as a white solid; mp
135-60C.
[0183] D. Preparation of
4-Amino-3,5-dichloro-6-trifluoromethylpyridine-2-- carboxylate
(Compound 45)
[0184] To a solution of methyl
4-amino-3-5-dichloro-6-trifluoromethylpyrid- ine-2-carboxylate
(0.16 g, 0.56 mmol) in 5 mL of MeOH was added excess 1N NaOH. The
resulting reaction mixture was stirred at room temperature for 1
hr, then made acidic with conc. HCl. The precipitated white solid
was collected with suction, washed with H.sub.2O and dried under
vacuum to give 80 mg of compound 45; mp 178.degree. C. dec.
[0185] 26. Preparation of
4-Amino-3-chloro-6-trifluoromethylpyridine-2-car- boxylic acid
(Compound 46)
[0186] To a solution containing
4-amino-6-trifluoromethylpyridine-2-carbox- ylic acid methyl ester
(0.75 g, 3.4 mmol) in 5 mL of CH.sub.3CN was added dropwise a
solution of sulfuryl chloride (0.27 mL, 3.4 mmol) in 1 mL of
CH.sub.3CN. After stirring at RT for 1 hr, reaction mixture was
added to 50 mL of Et.sub.2O and washed with aqueous NaHCO.sub.3,
dried over MgSO.sub.4, filtered and concentrated to give a solid.
The crude product was purified by chromatography, eluting with 10%
ethyl acetate-hexane to give 200 mg of product as a white solid; mp
131-3.degree. C.
[0187] 27. Preparation of
4-Amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine- -2-carboxylic
acid (Compound 47)
[0188] A. Preparation of Methyl
3-chloro-6-(3,5-dichlorophenoxy)pyridine-2- -carboxylate
N-oxide
[0189] To a dry 3-neck round bottom flask was added 60% NaH (0.432
g, 10.81 mmol), dry THF (30 mL) and 3,5-dichlorophenol (1.76 g,
10.81 mmol). The mixture was stirred until evolution of H.sub.2 (g)
ceased. Methyl 3,6-dichloropyridine-2-carboxylate N-oxide (2.0 g,
9.00 mmol) was added in one portion and stirred at RT for 3 hr,
diluted with ethyl acetate and 100 mL of water. The aqueous phase
was extracted with ethyl acetate (2.times.200 mL). The combined
extracts were dried (MgSO.sub.4) and concentrated to give 2.40 g of
white solid.
[0190] B. Preparation of Methyl
3,4-dichloro-6-(3,5-dichlorophenoxy)pyridi- ne-2-carboxylate
[0191] To Methyl
3-chloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxylic acid N-oxide
(2.40 g, 6.89 mmol) dissolved in 50 mL of acetonitrile was added
POCl.sub.3 (1.28 mL, 13.77 mmol). The mixture was stirred at reflux
overnight after which it was cooled to RT and concentrated to
dryness in vacuo. The resultant orange oil was dissolved in diethyl
ether and saturated sodium bicarbonate was added carefully. The
aqueous phase was extracted with diethyl ether (2.times.100 mL).
The combined organic extracts were dried (MgSO.sub.4) and
concentrated to dryness. Purification by column chromatography
(silica gel) using an eluent of 20% diethyl ether/hexane gave 1.93
g of white solid.
[0192] C. Preparation of Methyl
4-amino-3-chloro-6-(3,5-dichlorophenoxy)py-
ridine-2-carboxylate
[0193] Methyl
3,4-dichloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxylic acid
(1.93 g, 5.26 mmol) was dissolved in a minimum amount of DMF and to
it was carefully added NaN.sub.3 (0.444 g, 6.84 mmol) and water to
form a homogeneous mixture which was heated to 70.degree. C. and
stirred overnight. The reaction mixture was poured into a water-ice
mixture and the product was extracted with ethyl acetate
(3.times.100 mL). The combined extracts were washed with pet
ether/water (200 mL), dried (MgSO.sub.4) and concentrated to
dryness in vacuo. The resulting oil was dissolved in methanol and
to it was added NaBH.sub.4 (0.200 g, 5.26 mmol) and stirred at RT
for 1.5 hr. Ethyl acetate and water was added and the aqueous phase
was extracted with ethyl acetate (2.times.100 mL). The combined
extracts were dried (MgSO.sub.4) and concentrated to dryness.
Purification by column chromatography (silica gel) using an eluent
of 20% diethyl ether/hexane-50% diethyl ether/hexane to give 0.900
g of clear solid.
[0194] D. Preparation of
4-Amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine-- 2-carboxylic
acid (Compound 47)
[0195] To Methyl
4-amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine-2-carbox- ylic
acid (0.0.720 g, 2.07 mmol) in 20 mL of methanol was added lN NaOH
(2.07 mL) and stirred at RT for 1 hr. The reaction mixture was
concentrated to dryness in vacuo and 100 mL each of diethyl ether
and H.sub.2O added. The aqueous layer acidified with 1N HCl until
pH=2. methylene chloride was added and the aqueous phase was
extracted with additional CH.sub.2Cl.sub.2 (2.times.100 mL). The
combined extracts were dried (MgSO.sub.4) and concentrated to
dryness in vacuo to give 0.390 g of white solid
4-amino-3-chloro-6-(3,5-dichlorophenoxy)pyridine-2-carboxy- lic
acid (Compound 47); mp 196.degree. C.
[0196] The following 6-phenoxy analogs of
4-amino-3-chloropyridine-2-carbo- xylic acid were prepared
according to the procedure of Example 27:
[0197] 4-amino-3-chloro-6-phenoxypyridine-2-carboxylic acid
(Compound 48); mp 178.degree. C.
[0198] 4-amino-3-chloro-6-(4-methoxyphenoxy)-pyridine-2-carboxylic
acid (Compound 49); mp 174.degree. C.
[0199] 4-amino-3-chloro-6-(4-methylphenoxy)-pyridine-2-carboxylic
acid (Compound 50); mp 173.degree. C.
[0200]
4-amino-3-chloro-6-(3,4-dichlorophenoxy)-pyridine-2-carboxylic acid
(Compound 51); mp 186-187.degree. C.
[0201] 4-amino-3-chloro-6-(3-methylphenoxy)-pyridine-2-carboxylic
acid (Compound 52); mp 169.degree. C.
[0202] 4-amino-3-chloro-6-(3-chlorophenoxy)-pyridine-2-carboxylic
acid (Compound 53); mp 176.degree. C.
[0203] 28. Preparation of
4-Amino-3,5-dichloro-6-phenoxypyridine-2-carboxy- lic acid
(Compound 54)
[0204] A. Preparation of Methyl
4-amino-3,5-dichloro-6-phenoxypyridine-2-c- arboxylate
[0205] A solution of 4-amino-3,5,6-trichloropyridine-2-carboxylic
acid (7.2 g, 0.03 mol), phenol (3.0 g, 0.036 mol) and sodium
hydroxide (2.7 g 0.068 mol) in DMSO (60 mL) and water (9 mL) was
heated to 130.degree. C. for 18 hr. The reaction was diluted with
water (250 mL) and a tacky solid collected. This material was
dissolved in methanol (100 mL) and treated with TMSCHN.sub.2 (25 mL
2M in hexanes). The reaction was stirred 30 min and concentrated.
The resulting oil was chromatographed over silica gel (80% hexane
and 20% ethyl acetate) to give methyl 4-amino-3,5-dichloro-6--
phenoxypyridine-2-carboxylate (1.2, g, 14%); mp 88-90.degree.
C.
[0206] B. Preparation of
4-Amino-3,5-dichloro-6-phenoxypyridine-2-carboxyl- ic acid
(Compound 54)
[0207] To a solution of methyl
4-amino-3,5-dichloro-6-phenoxypyridine-2-ca- rboxylate in methanol
(10 mL) and water (100 mL) was added sodium hydroxide (0.5 g
excess) and the solution heated under reflux for 3 hr. The solution
was cooled and concentrated hydrochloric acid (2 mL) added. The
solid was collected to give
4-amino-3,5-dichloro-6-phenoxypyridine-2-- carboxylic acid (1.1 g,
90%); mp 158-60.degree. C.
[0208] 29. Preparation of
4-Amino-3-chloro-5-fluoro-6-(3,4-dichlorophenoxy-
)pyridine-2-carboxylic acid (Compound 55)
[0209]
4-Amino-3-chloro-6-(3,4-dichlorophenoxy)-pyridine-2-carboxylic acid
was fluorinated with
[1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo-[2.2.- 2]octane
bis(tetrafluoroborate)] (F-TEDA) in refluxing acetonitrile; mp
156-160.degree. C.
[0210] 30. Preparation of
4-Amino-3,5-dichloro-6-(2-methylpropoxy)pyridine- -2-carboxylic
acid (Compound 56)
[0211]
4-amino-3,5-dichloro-6-(2-methylpropoxy)-pyridine-2-carboxylic acid
(Compound 56) was prepared following the procedure of Example 27
using 2-methylpropanol instead of phenol; mp 104-6.degree. C.
[0212] 31. Preparation of Herbicidal Compositions
[0213] In the following illustrative compositions, parts and
percentages are by weight.
Emulsifiable Concentrates
[0214]
1 Formulation A WT % 4-Amino-3,6-dichloropicolinate, 26.2
2-butoxyethyl ester Polyglycol 26-3 5.2 Nonionic
emulsifier-(di-sec- butyl)phenylpoly(oxypropylene)b lock polymer
with oxyethylene). The polyoxyethelene content is about 12 moles.
Witconate P12-20 5.2 (Anionic emulsifier-calcium dodecylbenzene
sulfonate- 60 wt. % active) Aromatic 100 63.4 (Xylene range
aromatic solvent)
[0215]
2 Formulation B WT % 4-Amino-3,6-dichloropicolinate, 3.5
2-ethylhexyl ester Sunspray 11N (paraffin oil) 40.0 Polyglycol 26-3
19.0 Oleic acid 1.0 Xylene range aromatic solvent 36.5
[0216]
3 Formulation C WT % 4-Amino-3,6-dichloropicolinate, 13.2 n-butyl
ester Stepon C-65 25.7 Ethomeen T/25 7.7 Ethomeen T/15 18.0 Xylene
range aromatic solvent 35.4
[0217] These concentrates can be diluted with water to give
emulsions of suitable concentrations for controlling weeds.
Wettable Powders
[0218]
4 Formulation D WT % 4-Amino-3,6-dichloropicolinic 26.0 acid
Polyglycol 26-3 2.0 Polyfon H 4.0 Zeosyl 100 (Precipitated 17.0
hydrated SiO.sub.2) Barden clay + inerts 51.0
[0219]
5 Formulation E WT % 4-Amino-3,6-dichloropicolinic acid 62.4
Polyfon H (sodium salt of lignin 6.0 sulfonate) Sellogen HR (sodium
naphthalene 4.0 sulfonate) Zeosyl 100 27.6
[0220] The active ingredient is applied to the corresponding
carriers and then these are mixed and ground to yield wettable
powders of excellent wettability and suspension power. By diluting
these wettable powders with water it is possible to obtain
suspensions of suitable concentrations for controlling weeds.
Water Dispersible Granules
[0221]
6 Formulation F WT % 4-Amino-3,6-dichloropicolinic 26.0 acid
Sellogen HR 4.0 Polyfon H 5.0 Zeosyl 100 17.0 Kaolinite clay
48.0
[0222] The active ingredient is added to the hydrated silica, which
is then mixed with the other ingredients and ground to a powder.
The powder is agglomerated with water and sieved to provide
granules in the range of -10 to +60 mesh. By dispersing these
granules in water it is possible to obtain suspensions of suitable
concentrations for controlling weeds.
Granules
[0223]
7 Formulation G WT % 4-Amino-3,6-dichloropicolinic 5.0 acid Celetom
MP-88 95.0
[0224] The active ingredient is applied in a polar solvent such as
N-methyl-pyrollidinone, cyclohexanone, gamma-butyrolactone, etc. to
the Celetom MP 88 carrier or to other suitable carriers. The
resulting granules can be applied by hand, granule applicator,
airplane, etc. in order to control weeds.
8 Formulation H WT % 4-Amino-3,6-dichloropicolinic 1.0 acid Polyfon
H 8.0 Nekal BA 77 2.0 Zinc Stearate 2.0 Barden Clay 87.0
[0225] All materials are blended and ground to a powder then water
is added and the clay mixture is stirred until a paste is formed.
The mixture is extruded through a die to provide granules of proper
size.
Water Soluble Liquids
[0226]
9 Formulation I Wt % 4-Amino-3,6-dichloropicolinic acid 11.2 KOH
3.7 Water 85.1
[0227] 4-Amino-3,6-dichloropicolinic acid is dispersed in water.
KOH is slowly added to neutralize the acid to a pH of between 9-12.
A water-soluble surfactant may be added. Other aids may be
incorporated to improve physical, chemical and/or formulation
properties.
[0228] 32. Evaluation of Postemergence Herbicidal Activity
[0229] Seeds of the desired test plant species were planted in
Grace-Sierra MetroMix.RTM. 306 planting mixture, which typically
has a pH of 6.0 to 6.8 and an organic matter content of about 30
percent, in plastic pots with a surface area of 64 square
centimeters. When required to ensure good germination and healthy
plants, a fungicide treatment and/or other chemical or physical
treatment was applied. The plants were grown for 7-21 days in a
greenhouse with an approximate 15 hr photoperiod which was
maintained at about 23-29.degree. C. during the day and
22-28.degree. C. during the night. Nutrients and water were added
on a regular basis and supplemental lighting was provided with
overhead metal halide 1000-Watt lamps as necessary. The plants were
employed for testing when they reached the first or second true
leaf stage.
[0230] A weighed amount, determined by the highest rate to be
tested, of each test compound was placed in a 20 mL glass vial and
was dissolved in 4 mL of a 97:3 v/v (volume/volume) mixture of
acetone and dimethyl sulfoxide (DMSO) to obtain concentrated stock
solutions. If the test compound did not dissolve readily, the
mixture was warmed and/or sonicated. The concentrated stock
solutions obtained were diluted with an aqueous mixture containing
acetone, water, isopropyl alcohol, DMSO, Atplus 411F crop oil
concentrate, and Triton X-155 surfactant in a
48.5:39:10:1.5:1.0:0.02 v/v ratio to obtain spray solutions of
known concentration. The solutions containing the highest
concentration to be tested were prepared by diluting 2 mL aliquots
of the stock solution with 13 mL of the mixture and lower
concentrations were prepared by serial dilution of the stock
solution. Approximately 1.5 mL aliquots of each solution of known
concentration were sprayed evenly onto each of the test plant pots
using a DeVilbiss atomizer driven by compressed air pressure of 2
to 4 psi (140 to 280 kilopascals) to obtain thorough coverage of
each plant. Control plants were sprayed in the same manner with the
aqueous mixture. In this test an application rate of 1 ppm results
in the application of approximately 1 g/Ha.
[0231] The treated plants and control plants were placed in a
greenhouse as described above and watered by sub-irrigation to
prevent wash-off of the test compounds. After 2 weeks the condition
of the test plants as compared with that of the untreated plants
was determined visually and scored on a scale of 0 to 100 percent
where 0 corresponds to no injury and 100 corresponds to complete
kill.
[0232] By applying the well-accepted probit analysis as described
by J. Berkson in Journal of the American Statistical Society, 48,
565 (1953) and by D. Finney in "Probit Analysis" Cambridge
University Press (1952), the above data can be used to calculate
GR.sub.50 and GR.sub.80 values, which are defined as growth
reduction factors that correspond to the effective dose of
herbicide required to kill or control 50 percent or 80 percent,
respectively, of a target plant.
[0233] Some of the compounds tested, application rates employed,
plant species tested, and results are given in Tables 1-2.
Selectivity to rice, corn and wheat are illustrated in Tables
3-5.
10TABLE 1 Post-emergent % Control 4 % Control Rate # M W X Y Z
XANST STEME POLCO (ppm) 1 OH NH.sub.2 H Cl Cl 95 100 100 125 2
O-2-EH.sup.2 NH.sub.2 H Cl Cl 95 80 100 250 3 O--Me NH.sub.2 H Cl
Cl 100 100 100 125 4 O--Et NH.sub.2 H Cl Cl 100 100 100 125 5 O--Pr
NH.sub.2 H Cl Cl 100 100 100 125 6 O-i-Pr NH.sub.2 H Cl Cl 100 100
100 125 7 O--Bu NH.sub.2 H Cl Cl 100 100 100 250 8 O-pentyl
NH.sub.2 H Cl Cl 100 90 100 250 9 O-hexyl NH.sub.2 H Cl Cl 100 100
100 250 10 O-BE.sup.3 NH.sub.2 H Cl Cl 90 50 100 125 11 NH.sub.2
NH.sub.2 H Cl Cl 80 85 95 125 12 O--Me NHC(O)Me H Cl Cl 90 30 100
125 13 O--Me N(C(O)Me).sub.2 H Cl Cl 95 100 80 250 14 OH NH.sub.2 H
Br Cl 85 90 50 250 15 OH NH.sub.2 H F Cl 100 70 90 250 16 OH
NH.sub.2 F Br F 60 30 70 250 17 OH NH.sub.2 H Br Br 100 80 100 250
18 O--Me NH.sub.2 Br Br Br 85 90 75 250 19 OH NH.sub.2 F Cl Cl 95
95 100 125 20 OH NH.sub.2 Br Cl Cl 85 90 50 250 21 OH NH.sub.2
CF.sub.3 Cl Cl 70 20 20 250 22 OH NH.sub.2 O--Me Cl Cl 80 90 100
250 23 OH NH.sub.2 S--Et Cl Cl 90 90 98 125 24 OH NH.sub.2 S--Ph Cl
Cl 60 50 50 250 25 O--Me NH.sub.2 NO.sub.2 Cl Cl 60 50 50 250 26 OH
NHMe H Cl Cl 90 90 95 125 27 OH NHEt H Cl Cl 85 100 90 125 28 OH
NH-i-Pr H Cl Cl 95 90 95 250 29 OH NHBu H Cl Cl 95 90 90 250 30 OH
NH(allyl) H Cl Cl 100 80 100 250 31 OH NH(CH.sub.2).sub.2OH Cl Cl
Cl 40 30 70 250 32 OH NH(CH.sub.2).sub.2OMe H Cl Cl 80 20 100 250
33 OH NMe.sub.2 H Cl Cl 100 100 100 250 34 OH NMe(OH) H Cl Cl 100
70 100 125 35 OH NMe(OMe) H Cl Cl 90 60 100 125 36 OH pyrrolidine H
Cl Cl 50 40 80 125 37 OH pyrrole H Cl Cl 90 70 90 125 38 O--Me
N.sub.3 H Br Cl 90 50 90 125 39.sup.1 OH NO.sub.2 H Cl Cl 85 30 90
125 40 OH N.dbd.CH(NMe.sub.2) H Cl Cl 100 90 100 250 41 OH NH.sub.2
H Br O--Me 80 90 100 125 42 OH NH.sub.2 Cl Br O--Me 85 90 90 250 43
OH NH.sub.2 Cl Cl F 90 85 60 125 44 OH NH.sub.2 H Cl Br 90 90 95
125 45 O--Me NH.sub.2 Cl CF.sub.3 Cl 90 0 80 250 46 O--Me NH.sub.2
H CF.sub.3 Cl 90 60 100 250 47 OH NH.sub.2 H O-3,5-DCPh.sup.4 Cl
100 100 100 250 48 OH NH.sub.2 H O--Ph Cl 100 60 100 250 49 OH
NH.sub.2 H O-4-MeOPh.sup.5 Cl 60 0 70 250 50 OH NH.sub.2 H
O-4-MePh.sup.6 Cl 60 0 70 250 51 OH NH.sub.2 H O-3,4-DCPh.sup.7 Cl
100 70 100 250 52 OH NH.sub.2 H O-3-MePh.sup.8 Cl 70 20 90 250 53
OH NH.sub.2 H O-3-CPh.sup.9 Cl 100 100 100 250 54 OH NH.sub.2 Cl
O--Ph Cl 100 0 40 250 55 OH NH.sub.2 F O-3,4-DCPh.sup.7 Cl 100 95
100 250 56 OH NH.sub.2 Cl O-2-MP.sup.10 Cl 85 30 20 250
.sup.1Compound 39 is the pyridine N-oxide .sup.2O-2-EH =
O-2-ethylhexyl .sup.3O-BE = O-(CH.sub.2).sub.2OBu .sup.4O-3,5-DCPh
= O-3,5-DichloroC.sub.6H.s- ub.3 .sup.5O-4-MeOPh =
O-4-MethoxyC.sub.6H.sub.4 .sup.6O-4-MePh = O-4-MethylC.sub.6H.sub.4
.sup.7O-3,4-DCPh = O-3,4-DichloroC.sub.6H.sub.3 .sup.8O-3-MePh =
O-3-MethylC.sub.6H.sub.4 .sup.9O-3-CPh = O-3-ChloroC.sub.6H.sub.4
.sup.10O-2-NP = O-2-Methylpropyl NT = not tested XANST = cocklebur
(Xanthium strumarium) STEME = chickweed (Stellaria media) POLCO =
wild buckwheat (Polygonum convolvulus)
[0234]
11TABLE 2 POSTMERGENCE HERBICIDAL ACTIVITY % CONTROL Cpd. Rate, No.
ppm STEME XANST CHEAL AMARE ABUTH VIOTR POLCO ALOMY ECHCG DIGSA
SETFA SORBI AVEFA 1 125 90 100 100 95 70 80 100 50 45 60 75 50 50 4
125 70 100 100 100 70 70 100 40 50 70 75 40 40 14 125 65 100 95 90
85 75 100 50 65 65 65 60 40 19 125 60 95 95 60 50 50 100 20 10 30
20 10 20 STEME = chickweed (Stellaria media) XANST = cocklebur
(Xanthium strumarium) CHEAL = lambsquarters (Chenopodium album)
AMARE = pigweed (Amaranthus retroflexus) ABUTH = velvetleaf
(Abutillon theophrasti) VIOTR = viola (Viola tricolor) POLCO = wild
buckwheat (Polygonum convolvulus) ALOMY = blackgrass (Alopecurus
myosuroides) ECHCG = barnyardgrass (Echinochloa crus-galli) DIGSA =
crabgrass (Digitaria sanguinalis) SETFA = giant foxtail (Setaria
faberi) SORBI = Rox orange sorghum (sorghum bicolor) AVEFA = wild
oats (Avena fatua)
[0235]
12TABLE 3 Control of Several Key Weeds in Rice post emergent
evaluation - % control Rate cmpd# ORYZA ECHCG CYPES (ppm) 1 10 75
75 250 14 10 65 75 250 27 40 70 50 250 ORYZA = rice (Oryza sativa)
ECHCG = Barnyardgrass (Echinochloa crus-galli) CYPES = yellow
nutsedge (Cyperus esculentus)
[0236]
13TABLE 4 Control of Several Key Weeds in Corn Post-emergent
Evaluation - % control Rate cmpd # ZEAMX ABUTH AMARE XANST (ppm) 15
0 40 75 90 250 20 10 70 90 85 250 33 20 80 50 100 125 43 0 70 90 85
250 ZEAMX = corn (Zea mays) ABUTH = velvetleaf (Abutilion
theophrasti) AMARE = pigweed (Amaranthus retroflexus) XANST =
cocklebur (Xanthium strumarium)
[0237]
14TABLE 5 Control of Several Key Weeds in Wheat Post-emergent
Evaluation - % control Rate cmpd # TRZAS STEME CHEAL POLCO (ppm) 14
0 70 70 90 250 23 20 30 90 98 125 41 10 20 90 100 250 46 10 50 100
100 31 TRZAS = wheat (Triticum aestivum) STEME = chickweed
(Stellaria media) CHEAL = lambsquarters (Chenopodium album) POLCO =
wild buckwheat (Polygonum convolvulus)
[0238] 33. Evaluation of Preemergence Herbicidal Activity
[0239] Seeds of the desired test plant species were planted in a
soil matrix prepared by mixing a loam soil (43 percent silt, 19
percent clay, and 38 percent sand, with a pH of about 8.1 and an
organic matter content of bout 1.5 percent) and sand in a 70 to 30
ratio. The soil matrix was contained in plastic pots with a surface
area of 113 square centimeters. When required to ensure good
germination and healthy plants. a fungicide treatment and/or other
chemical or physical treatment was applied.
[0240] A weighed amount, determined by the highest rate to be
tested, of each test compound was placed in a 20 mL glass vial and
was dissolved in 4 mL of a 97:3 v/v (volume/volume) mixture of
acetone and dimethyl sulfoxide to obtain concentrated stock
solutions. If the test compound did not dissolve readily, the
mixture was warmed and/or sonicated. The stock solutions obtained
were diluted with a 99.9:0.1 mixture of water and Tween.RTM. 155
surfactant to obtain application solutions of known concentration.
The solutions containing the highest concentration to be tested
were prepared by diluting 2 mL aliquots of the stock solution with
15 mL of the mixture and lower concentrations were prepared by
serial dilution of the stock solution. A 2.5 mL aliquot of each
solution of known concentration was sprayed evenly onto the soil
surface (113 sq. cm) of each seeded pot using a Cornwall 5.0 mL
glass syringe fitted with a TeeJet TN-3 hollow cone nozzle to
obtain thorough coverage of the soil in each pot. Control pots were
sprayed in the same manner with the aqueous mixture.
[0241] The treated pots and control pots were placed in a
greenhouse maintained with an approximate 15 hr photoperiod and
temperatures of about 23-29.degree. C. during the day and
22-28.degree. C. during the night. Nutrients and water were added
on a regular basis and supplemental lighting was provided with
overhead metal halide 1000-Watt lamps as necessary. The water was
added by top-irrigation. After 3 weeks the condition of the test
plants that germinated and grew as compared with that of the
untreated plants that germinated and grew was determined visually
and scored on a scale of 0 to 100 percent where 0 corresponds to no
injury and 100 corresponds to complete kill or no germination. Some
of the compounds tested, application rates employed, plant species
tested, and results are given in Tables 6-7.
15TABLE 6 Post-emergent % Control 5 % Control Rate # M W X Y Z
IPOHE AMARE ABUTH (ppm) 1 OH NH.sub.2 H Cl Cl 100 100 100 280 2
O-2-EH.sup.2 NH.sub.2 H Cl Cl 100 100 100 280 3 O--Me NH.sub.2 H Cl
Cl 100 100 100 280 4 O--Et NH.sub.2 H Cl Cl 100 100 100 280 5 O--Pr
NH.sub.2 H Cl Cl 100 100 100 280 6 O-i-Pr NH.sub.2 H Cl Cl 100 100
100 280 7 O--Bu NH.sub.2 H Cl Cl 100 100 100 280 8 O-pentyl
NH.sub.2 H Cl Cl 100 100 100 280 9 O-hexyl NH.sub.2 H Cl Cl 100 98
100 280 10 O-BE.sup.3 NH.sub.2 H Cl Cl 100 100 100 280 11 NH.sub.2
NH.sub.2 H Cl Cl 85 0 85 560 12 O--Me NHC(O)Me H Cl Cl 100 100 95
560 13 O--Me N(C(O)Me).sub.2 H Cl Cl 95 100 95 560 14 OH NH.sub.2 H
Br Cl 100 90 100 560 15 OH NH.sub.2 H F Cl 100 100 100 560 16 OH
NH.sub.2 F Br F 80 70 0 560 17 OH NH.sub.2 H Br Br 100 100 100 560
18 O--Me NH.sub.2 Br Br Br 30 80 98 280 19 OH NH.sub.2 F Cl Cl 100
100 100 560 20 OH NH.sub.2 Br Cl Cl 100 100 100 560 21 OH NH.sub.2
CF.sub.3 Cl Cl 90 80 80 560 22 OH NH.sub.2 O--Me Cl Cl 100 100 100
560 23 OH NH.sub.2 S--Et Cl Cl 0 40 40 560 24 OH NH.sub.2 S--Ph Cl
Cl 30 20 50 560 25 O--Me NH.sub.2 NO.sub.2 Cl Cl nt nt nt 250 26 OH
NHMe H Cl Cl 100 100 100 560 27 OH NHEt H Cl Cl 100 100 100 560 28
OH NH-i-Pr H Cl Cl 100 100 100 560 29 OH NHBu H Cl Cl 100 100 100
560 30 OH NH(allyl) H Cl Cl 85 90 95 560 31 OH NH(CH.sub.2).sub.2OH
Cl Cl Cl 100 95 95 560 32 OH NH(CH.sub.2).sub.2OMe H Cl Cl 90 70 90
560 33 OH NMe.sub.2 H Cl Cl 100 100 98 560 34 OH NMe(OH) H Cl Cl 95
100 100 560 35 OH NMe(OMe) H Cl Cl 85 95 90 560 36 OH pyrrolidine H
Cl Cl 80 80 95 560 37 OH pyrrole H Cl Cl 95 100 100 560 38 O--Me N3
H Br Cl 100 100 100 560 39.sup.1 OH NO.sub.2 H Cl Cl 100 100 100
560 40 OH N.dbd.CH(NMe.sub.2) H Cl Cl 100 100 100 560 41 OH
NH.sub.2 H Br O--Me 85 40 90 280 42 OH NH.sub.2 Cl Br O--Me 100 100
100 560 43 OH NH.sub.2 Cl Cl F 70 30 80 140 44 OH NH.sub.2 H Cl Br
100 100 100 560 45 O--Me NH.sub.2 Cl CF.sub.3 Cl 100 100 90 125 46
O--Me NH.sub.2 H CF.sub.3 Cl 100 95 95 140 47 OH NH.sub.2 H
O-3,5-DCPh.sup.4 Cl 0 100 95 280 48 OH NH.sub.2 H O--Ph Cl 100 30
100 280 49 OH NH.sub.2 H O-4-MeOPh.sup.5 Cl 0 0 0 70 50 OH NH.sub.2
H O-4-MePh.sup.6 Cl 0 0 0 70 51 OH NH.sub.2 H O-3,4-DCPh.sup.7 Cl 0
98 80 280 52 OH NH.sub.2 H O-3-MePh.sup.8 Cl 70 20 50 560 53 OH
NH.sub.2 H O-3-CPh.sup.9 Cl 100 0 100 560 54 OH NH.sub.2 Cl O--Ph
Cl 41 10 50 280 55 OH NH.sub.2 F O-3,4-DCPh.sup.7 Cl 100 95 100 250
56 OH NH.sub.2 Cl O-2-MP.sup.10 Cl 0 0 40 560 .sup.1Compound 39 is
the pyridine N-oxide .sup.2O-2-EH = O-2-ethylhexyl .sup.3O-BE =
O-(CH.sub.2).sub.2OBu .sup.4O-3,5-DcPh =
O-3,5-DichloroC.sub.6H.sub.3 .sup.5O-4-MeOPh =
O-4-MethoxyC.sub.6H.sub.4 .sup.6O-4-MePh = O-4-MethylC.sub.6H.sub.-
4 .sup.7O-3,4-DCPh = O-3,4-DichloroC.sub.6H.sub.3 .sup.8O-3-MePh =
O-3-MethylC.sub.6H.sub.4 .sup.9O-3-CPh = O-3-ChloroC.sub.6H.sub.4
.sup.10O-2-MP = O-2-Methylpropyl NT = not tested IPOHE =
morningglory (Ipomoea hederacea) AMARE = pigweed (Amaranthus
retroflexus) ABUTH = velvetleaf (Abutilon theophrasti)
[0242]
16TABLE 7 PREEMERGENCE HERBICIDAL ACTIVITY % CONTROL Cpd. Rate, No.
g/Ha XANST CHEAL AMARE ABUTH EPHHL ALOMY ECHCG DIGSA SETFA SORBI
AVEFA 1 35 99 99 88 95 62 36 17 20 40 60 37 3 35 90 100 90 95 20 nt
20 40 40 30 10 14 35 100 100 100 100 70 60 40 80 98 50 40 42 35 98
90 60 80 40 30 30 30 30 20 30 nt = no test CHEAL = lambsquarters
(Chenopodium album) XANST = cocklebur (Xanthium strumarium) AMARE =
pigweed (Amaranthus retroflexus) ABUTH = velvetleaf (Abutilion
theophrasti) EPHHL = wild poinsettia (Euphorbia heterophylla) ALOMY
= blackgrass (Alopecurus myosuroides) ECHCG = barnyardgrass
(Echinochloa crus-galli) DIGSA = crabgrass (Digitaria sanguinalis)
SEFTA = giant foxtail (Setaria faberi) SORBI = Rox orange sorghum
(Sorghum bicolor) AVEFA = wild oats (Avena fatua)
[0243] 34. Range & Pasture Crop Testing
[0244] Rates are calculated based upon 5 doses being applied. The
high rate (X), followed by serial dilutions of 1/2.times.,
1/4.times., 1/8.times. and 1/16.times.. Compound requirements are
based upon the 187 L/ha carrier volume, specifications of the
delivery system (Mandel track sprayer) and generating 24 mL of
technical spray material to allow for the dilutions and overage in
the sprayer. 1 Rate g / ha 187 L / ha = X Mg 24 mL
Example
[0245]
17 Starting X rate (g/ha) mgs required 560 71.9 280 35.9 140 17.95
70 8.9
[0246] All technical materials were formulated in 97:3
(acetone:DMSO) with 0.25% X-77. The total volume of solvent is
maintained at less than 7%. An overhead Mandel track sprayer
calibrated to deliver 187 L/ha was used for all treatment
applications (postemergence). Picloram was included as a comparison
treatment.
[0247] Solutions were applied with a mechanized track-sprayer at
the following settings:
[0248] Nozzle: 8002E
[0249] Speed: 2 mph
[0250] Spray Pressure: 40 psi
[0251] Spray height: 17 inches above top of plants
[0252] This provides an application volume of 187 L/ha.
[0253] Percent weed control (burn down) was evaluated 3 weeks after
treatment. Visual control on a 0-100 linear scale was used, with 0
representing no control and 100 representing total control. Burn
down ratings were taken for annual and perennial weed species. Some
of the compounds tested, application rates employed, plant species
tested, and results are given in Tables 8-10.
18TABLE 8 Salts of Compound 1 Post-emergent GR.sub.80 g/Ha salt
CASOB CONAR CIRAR free acid 11 59 47 potassium salt <8.8 36 27
amine salt <8.8 34 37 dimethylamine 11.8 >140 43 salt
monoethanolamine 11 20 18 salt triethylamine <8.8 16 <8.8
salt triisopropanolamine 11 20 43 salt CASOB = sicklepod (Cassia
obtusifolia) CONAR = field bindweed (Convolvulus arvensis) CIRAR =
Canada thistle (Cirsium arvense), 3 week evaluation
[0254]
19TABLE 9 Control of Several Key Weeds in Pasture Post-emergent
Evaluation - % control Rate Cmpd # AGRCR CIRAR RUMOB AMBEL (g/Ha) 3
30 90 100 100 70 6 30 95 100 93 70 26 10 90 100 nt 70 23 30 80 100
85 70 AGRCR = crested wheatgrass (Agropyron cristatum) (grass crop)
CIRAR = Canada thistle (Cirsium arvense) RUMOB = broadleaf dock
(Rumex obtusifolia) AMBEL = common ragweed (Ambrosia
artemisiifolia) 3 week evaluation nt = not tested
[0255]
20TABLE 10 Control of Several Key Weeds in Clover Pasture g/ha
GR.sub.20 GR.sub.80 GR.sub.80 Cmpd TRFRE CONAR CIRAR 3 <17.5
127.7 <17.5 4 <17.5 59 <17.5 5 <17.5 140.1 <17.5 6
98.8 98.8 <17.5 7 15.3 116.6 17.3 9 20.7 66 20.7 TRFRE = White
Clover (Trifolium repens) CONAR = Field Bindweed (Convolvulus
arvensis) CIRAR = Canada thistle (Cirsium arvense)
* * * * *