AU3895001A - Cycloimido-substituted benzofused heterocyclic herbicides - Google Patents

Cycloimido-substituted benzofused heterocyclic herbicides Download PDF

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AU3895001A
AU3895001A AU38950/01A AU3895001A AU3895001A AU 3895001 A AU3895001 A AU 3895001A AU 38950/01 A AU38950/01 A AU 38950/01A AU 3895001 A AU3895001 A AU 3895001A AU 3895001 A AU3895001 A AU 3895001A
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alkyl
mole
grams
nch
chloro
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Scott D. Crawford
Benjamin Dugan
Lester L. Maravetz
George Theodoridis
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FMC Corp
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FMC Corp
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P/00/011 28/5/91 Regulation 3.2(2)
.AUSTRALIA
Patents Act 1990
ORIGINAL
COMPLETE SPECIFICATION STANDARD PATENT Application Number: Lodged: o 0 0 .0.00 :0..0 Invention Title: CYCLOIMIDO-SUBSTITUTED BENZOFUSED HETEROCYCLIC HERBICIDES The following statement is a full description of this invention, including the best method of performing it known to us 1 CYCLOIMIDO-SUBSTITUTED BENZOIFUSED HETEROCYCLIC HERBICIDES Cross Reference This application is a divisional of Australian Patent Application No.
66670/98.
Background of the Invention The present invention relates generally to novel herbicidal compounds and methods for their use in controlling unwanted plant species in agriculture. In particular, the present invention pertains to cycloimido-substituted benzofused heterocyclic herbicides, and more particularly it pertains to herbicides in which the benzofused heterocycle is a benzofuran, benzimidazole, a 2,3dihydrobenzimidazole, or indole having a cycloimido moiety which is a 1 -substituted-6-trifluoromethyl-2,4-pyrimidinedione-3-y, a 1 -substituted-6trifluoromethyl-1 ,3,5-triazine-2,4-dion- 1-yl, a 3,4,5,6-tetrahydrophthalimid- 1-yl, a 4-difluoromethyl-4,5-dihydro-3-methyl-1 ,2,4-trizol-5(1 H)-on- 1 -yl, a 5,6,7,8tetrahydro-1 H,3 H-[1,3,4]thiadiazolo[3,5-a]pyridazinei min- 1 -yl, or a 1,6,8triazabicyclo[4.3.0]-nonane-7,9-dion-8-y ring.
Summary of the Invention It has now been found that certain cycloimido-substituted benzofused heterocyclic compounds are useful as pre-emergent and post-emergent 20 lubricides.
***These compounds are represented by formula 1:
A
0. 10 where J is a 1 -substituted-6-trifluoromethyl-2,4-pyrimidinedione-3-y, a 1substituted-6-trifluoromethyl- 1,3,5-triazine-2 ,4-dion-1 -yl, a 3,4,5,6tetrahydrophthalimid- 1 -yl, a 4-difluoromethyl-4,5-dihydro-3-methyl- 1,2,4-trizol- 5(1H)-on-1-yI, a 5,6,7,8-tetrahydro-1 H,3H-[1 ,3,4]thiadiazolo[3,5-a]pyridazineiminl-yl, or a 1 ,6,8-triazabicyclo[4.3.0]-nonane-7,9-dion-8-yI ring attached at the 7 position of a benzofuran, benzoxazole, 2,3-dihydrobenzimidazole, indole or benzimidazole, and X is selected from hydrogen, halogen, cyano, nitro, alkyl, haloalkyl and amino. Preferred R groups are optionally substituted alkyl groups.
More particularly, substituents are as follows: A is nitrogen double bonded to position 2 and B is oxygen; A is oxygen and B is CR 1 double-bonded to position 2; A is NH and B is nitrogen double-bonded to position 2; A is nitrogen double-bonded to position 2 and B is NR 2 A is CH double-bonded to position 2 and B is NR 2 A is NH and B is CR 1 double-bonded to position 2; or A and B are NH.
R is hydrogen, hydroxy, mercapto, straight or branched chain lower alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxylalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, aminosulfonyl, alkylsulfonylamino, alkoxycarbonyloxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl, (aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynylalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy) (aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, alkylsufonyl, or haloalkylsulfonyl;
R
1 is hydrogen, lower alkyl, or haloalkyl; R' is hydrogen, alkyl, haloalkyl,C00 2 (alkyl), CH 2 00 2 (alkyl), OH 2 00NH-alkyl,
CH
2 00N(alkyl) 2 0H 2 00 2 H, OH 2 00H 3 S0 2 (alkyl), OH 2 CH=0H 2
OH
2
C=OH.
X is selected from hydrogen, F, CI, Br, alkyl, haloalkyl, ON, NO 2 and NH 2 n is 0-3; J is selected from and R 3 is selected from hydrogen, alkyl, haloalkyl, OH 2 CN, CH 2 OH=0H 2
OH
2 C=-OH, 0H 2 00 2 (alkyl), C 2 00H 3 and NH 2 Preferred compounds are those of formula I where R is OH 3 0H 2 0H 3 O(0H 3 2 0H, OH 2
OH
2 OH, OH(0H 3 2 t-butyl, OF 3 OH(F)0H 3 0F 2 0F 3 O(0H 3 2 0000H 3
O(OH)
3
NH
2 SO OH 2
C
3
C
2
HO
2
-=N
2 0H 2 0H 2 00 2
OH
3 and OON(0H 3 2 X is a chlorine, bromine or fluorine substituted in one or both of positions 4 and 6; J is and R 3 is CH 3 or NH 2 One aspect of the present invention relates to compounds of formula I in which A is nitrogen double-bonded to position 2 and B is oxygen, and R, R 3 J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is oxygen and B is CR 1 double-bonded to position 2, and R, R 3
J,
X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is NH and B is nitrogen double-bonded to position 2, and R, J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is nitrogen double-bonded to position 2 and B is NR 2 and R, R 2
R
3
J,
X and n are as described above.
Another aspect of the present invention relates to compounds of formula I in which A is CH double-bonded to position 2 and B is NR 2 and R, R 2
R
3 J, X and n are as described above.
0 20 Another aspect of the present invention relates to compounds of formula I in which A is NH and B is CR 1 double-bonded to position 2, and R, R 1
R
3 J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I o" in which A and B are NH and R, R 3 J, X and n are as described above.
Another aspect of the present invention relates to compounds of formula I where J is not n
N-R
3
CF
3 when: A is oxygen and B is CR 1 double-bonded to position 2; A is CH doublebonded to position 2 and B is NR 2 or A is NH and B is CR' double-bonded to position 2; and R, R 1
R
3 X, and n are as described above.
As shown in the specification a wide range of substituents is described for position B in compounds of formula I whereas position A is generally unsubstituted. It was found that some herbicidal activity is retained when a methyl substituent is placed at position A, but that substitution at that position generally causes a sharp decrease in activity.
Certain intermediates of the present invention are novel. These include compounds of formula II: Y Z
-J
X(n)
Z-
where X is selected from hydrogen, F, CI, Br, alkyl, haloalkyl, CN, NO 2 and
NH
2 15 Y is selected from NO 2 NH,, or-NHN=C(CH 3
)R;
Z is selected from hydrogen, F, NH,, OH; with the proviso that when Y is
NHN=C(CH
3 Z is hydrogen; n is 0-3; R is hydrogen, hydroxy, straight or branched chain lower alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxylalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, alkylcarboxyoxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl, (aryl) (alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynlalkylthio, arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, or alkylsulfonyl; 0 J is selected from
CF
3 and R' is selected from hydrogen, alkyl, haloalkyl, CH 2
CN,
CH
2
CH=CH
2
CH
2 C=CH, 0H 2 00 2 (alkyl), 0H 2 00H 3 and NH 2 6- Y Z X(n)b
II
where Y is NO 2 NH, or -NHN=C(CH JR; Z is hydrogen, F, NH ,or OH; and R, J, X, and n are as described above; with the proviso that when Y is
NHN=C(CH
3 Z is hydrogen.
As used in this specification and unless otherwise indicated, the terms "alkyl," "alkenyl," "alkynyl," "haloalkyl," and "alkoxy" used alone or as part of a larger moiety, includes straight or branched carbon chains of 1 to 6 carbon atoms.
"Halogen" refers to fluorine, bromine or chlorine. "THF" means tetrahydrofuran, o0 "DMF" means N,N-dimethylformamide, and "DBU" means 1,8diazabicyclo[5.4.0]undec-7-ene. When in is 2 or 3, the substituents X may be the same or different from one another.
7 Scheme 1 x a N.Co Q-NHCfl R
F
1
X
F
2
X
b,c 3. NCo OCH3 3 d
I
X
e -4a,
R
3
H
4b, R 3 CH3
X
0 N' /IIR3 0 0 1K ACF3 g
S
S.
S
X
iN N R 3 OH O
CF
3 x h I "k
R
3 R9
KF
3 a) 70% HNO 3
/H
2
SO
4 0-5 oC; NaOSi(CH 3 3 MeOH, dioxane; Fe, EtOH, acetic acid, HCI, heat; CF3C(NH 2
)=CO
2
CH
2
CH
5 NaOSi(CH 3 3 DBU, DMF; (e) CH31, KCO 3 DMF, 60-80 HCI, NaNO2 Nal, H P; BBr ,CH l 2 HC=CR, Pd(Ph 3 P) 2CI2, Cul, triethylamine.
Benzofurans of formula I, where A is oxygen and B is CH double bonded to position 2, may be generally prepared as shown in Scheme 1. Starting with an appropriately substituted fluoroaniline derivative 1, nitration provides intermediate 2. Displacement of the fluorine of 2 with a methoxy group as shown in step b, followed by reduction of the nitro group as shown in step c provide the methoxyaniline 3. The methoxyaniline 3 is a versatile intermediate from which a number of compounds of the present invention can be made by attachment of various J groups. For example, a uracil ring may be appended as shown in step d to give intermediate 4a. At this point, R 3 substituents other than H may be introduced, as shown for example in step e to provide 4b where R 3 is methyl.
*S S 8 Using diazotization conditions (step f) 4b is converted to the iodoanisole 5 which is then deprotected to give the iodophenol 6. Palladium-catalyzed acetylenic coupling and ring closure as shown in step h give benzofurans 7 of the present invention. To obtain benzofurans of formula I where the J group is other than uracil, approaches analogous to that outlined in Scheme 1 may be followed. Such approaches based on Scheme 1 would be known to one skilled in the art.
Scheme 2 x n, R 3 HO N N R 3 CF3 8 a x HO N N R3
NO
2 0 CF3 9 x R O 'CF 3 11 b 9 9 9 *999 9. 9 .9 .9 *9 .9 9 9 HO i N 3 c
NH
2 0
CF
3 10 e d
C-NF
3 0
F
.9 9* 12 a) 70% HNO 3 /H SO, 0-5 oC; Fe, aqueous acetic acid, 50 oC; RCOCI, 10 pyridinium p-toluenesulfonate, triethylamine, xylene; 1,1-carbonylimidazole, THF; R'-halide, Ag 2 O, CH 2
CI
2 (to give 11 where R=R'O).
Benzoxazoles of formula I, where A is nitrogen double bonded to position 2 and B is oxygen, may be prepared as shown in Scheme 2 above.
Starting with a phenol such as intermediate 8 nitration under standard conditions 9 gives the nitrophenol 9. Certain of the benzoxazoles 11 of the present invention may be obtained by reduction of 9 to the aniline 10 followed by treatment with an acid halide (such as shown in step Alternatively, other benzoxazoles 11 may be obtained by treating 10 with carbonyldiimidazole to give intermediate 12 which can be O-alkyated according to step e. The approach outlined in Scheme 2 can be adapted, in ways known to one skilled in the art, to obtain benzoxazoles of formula I where the J group is other than uracil.
Scheme 3 X
X
NCO
2 Et N 3
C
F
F
O CF3 13 14
X
X 0 C3 d N Sis 16 0 N N N NH OL C> .17 a) see steps and of Scheme 1; 70% HNO 2
/H
2
SO
4 0-5 NH 4 OAc, triethylamine, dioxane, heat; SnCI 2
H
2 0 or Fe, NH 4 CI, aqueous ethanol, heat; (e)
RCO
2 H, heat; RCO-halide, CH 2 ClIPyridine, then POCI 3 CH2CI2; alkoxycarbonyl isothiocyanate, HgC1 2 heat (where R is -NHCO 2 alkyl); or thiophosgene, EtOAC, heat (where R is -SH).
Benzimidazoles of formula 1, where A is NH and B is nitrogen double bonded to position 2, may be prepared as shown in Scheme 3 above. For example, intermediate 13 may be converted to the uracil 14 by the well-known chemistry previously described. Nitration of 14 followed by aminolysis of the fluorine group (steps b and c) provides the nitroaniline 15. The diamine 16 is obtained by reduction of 15 under standard conditions. Benzimidazoles 17 of the present invention are obtained by treatment of 16 with a carboxylic acid, an acid halide, an alkoxycarbonyl isothiocyanate, or thiophosgene according to step e. Other benzimidazoles 17 of the present invention are obtained by derivativization of benzimidazoles depicted in Scheme 3 using techniques known to one skilled in the art. The approach outlined in Scheme 3 can be adapted, in ways known also to one skilled in the art, to obtain benzimidazoles of formula I where the J group is other than uracil.
X
N N N NH
CF
R
17A Benzimidazoles of structure 17A where R 3 is NH 2 are prepared in a manner analogous to that depicted in Scheme 3, except the NH 2 group is attached following nitration of the phenyl ring. The 1-unsubstituted uracil ring is formed as previously described in step d of Scheme 1, followed by nitration of the phenyl ring (Scheme 3, step The uracil ring is then aminated in the 1-position by methods known in the art by treating it with 1-aminooxysulfonyl-2,4,6-trimethyibenzene. The 1-aminouracil is then subjected to aminolysis of the phenyl fluorine (step c) followed by reduction to the diamine (step d).
x NH O "CF3 17B 11 2,3-Benzimidazoles of formula I, where A and B are NH may be prepared from Intermediate 16 in Scheme 3 by heating it with an appropriately substituted acetaldehyde ethyl hemiacetal, affording compounds of Structure 17B.
Scheme 4 N' R o2 CH 3 3 HN 0 -N a
YN
-N /CF 3 X N cF 3 0 0 18 19
R
b 0 H3
N
N
CF
3 a) i. NaNO 2 HCI; ii. SnCI22HO; iii. RCOCH; polyphosphoric acid, 80 'C.
Indoles of formula I, where A is CH double bonded to position 2 and B is NR', may be prepared according to Scheme 4 above. Using a Fischer indole route the starting aniline 18 may be converted to the corresponding hydrazone 19 which in turn may be cyclized under acidic conditions such as is shown in step b.
The resulting indoles 20 of the present invention may be further derivatized by alkylation of the indole ring nitrogen to indoles of formula I where R 1 is other than hydrogen. The approach outlined in Scheme 4 can be adapted, in ways known to one skilled in the art, to obtain indoles of formula 1 where the J group is other than uracil.
12
R
NH2 O CH 3 3 NH CH 3 N CF 3 CF 3 0 0 21 22 Indoles of formula I, where A is NH and B is CR 1 double bonded to position 2, may be prepared by a Fischer indole synthesis analogous to that shown in Scheme 4 starting with aniline 21. Substitution at the 3 position of indoles such as 22 with R 1 groups is known to one skilled in the art.
Compounds of the present invention may also be prepared in accordance with the procedures shown in the Examples below, by procedures analogous to those shown in the Examples, or by other methods that are generally known or available to one skilled in the art.
o.
10 EXAMPLE 1 1-METHYL-6-TRIFLUOROMETHYL-3-[7-BROMO-5-FLUORO-2-( 2 METHYLCARBONYLOXYPROP-2-YL)BENZOXAZOL-4-YL]-2,4(1 H,3H)- PYRIMIDINEDIONE (COMPOUND 104) Step A 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxy-6nitrophenyl)-2,4(1 H,3H)-pyrimidinedione A stirred solution of 17.0 grams (0.044 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione and grams (0.050 mole) of sulfuric acid in 100 mL of glacial acetic acid was cooled to S. 15 and 3.2 grams (0.050 mole) of 70% nitric acid was added dropwise. The reaction mixture was then allowed to warm to ambient temperature where it stirred for two hours. The reaction mixture was poured into water and extracted with diethyl ether. The extract was concentrated under reduced pressure to a residue.
The residue was purified by column chromatography on silica gel, yielding 16.4 grams of title compound; mp 76-78 'C.
13 Step B 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5hydroxyphenyl)-2,4(1 H,3H)-pyrimidinedione A stirred solution of 16.0 grams (0.037 mole) of 1-methyl-6-trifluoromethyl-3-(4-bromo-2-fluoro-5-hyd roxy-6-nitrophenyl)-2,4(1 H,3H)-pyrimidinedione and 10 mL of water in 120 mL of glacial acetic acid was heated to 50 and 16.0 grams (excess) of iron dust was slowly added. The reaction mixture was then cooled to ambient temperature where it stirred for one hour. The reaction mixture was filtered through diatomaceous earth, and the filtrate was partitioned in a mixture of 150 mL portions each of water and ethyl acetate. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 12.0 grams of title compound; mp 98-100 'C.
Step C Compound 104 A stirred solution of 0.50 gram (0.0013 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.21 gram (0.0013 mole) of 1-chlorocarbonyl-l-methylethyl acetate, 0.14 gram (0.0014 mole) of triethylamine, and 0.16 gram (0.0006 mole) of pyridinium ptoluenesulfonate in 50 mL of xylene was heated at 150 'C for about 18 hours. The reaction mixture was then cooled to ambient temperature and taken up in ethyl acetate. The solution was washed with water and an aqueous solution saturated with sodium chloride; then it was dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.72 gram of Compound 104. The NMR spectrum was consistent with the proposed structure.
14 EXAMPLE 2 1-METHYL-6-TRIFLUOROMETHYL-3-(7-BROMO-5-FLUORO-2-METHOXY BENZOXAZOL-4-YL)-2,4(1H,3H)-PYRIMIDINEDIONE (COMPOUND 109) Step A 1-methyl-6-trifluoromethyl-3-(7-bromo-5-fluorobenzoxazol-2-on-4-yl)- 2,4(1 H,3H)-pyrimidinedione A stirred solution of 2.0 grams (0.005 mole) of 1-methyl-6trifluoromethyl-3-(6-amino-4-bromo-2-fluoro-5-hydroxyphenyl)-2, 4 1H,3H)pyrimidinedione and 1.2 grams (0.008 mole) of carbonylimidazole in 50 mL of THF was heated at reflux for three hours. The reaction mixture was cooled and lo concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 1.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B Compound 109 A mixture of 0.50 gram (0.001 mole) of 1-methyl-6-trifluoromethyl- 3 (7-bromo-5-f uorobenzoxazol-2-on-4-yl)-2,4(1H,3H)-pyrimidinedione 0.17 gram (0.001 mole) of methyl iodode, and 0.27 gram (0.001 mole) of silver(l) oxide in mL of methylene chloride was stirred at ambient temperature for two hours. The product was isolated from the reaction mixture by column chromatography on silica gel, yielding 0.28 gram of Compound 109. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 3 1 -MOROML-6-TRIFLUOROMETHYL-3-7-C HLOR o-5-FLUORO-2-( SMETHYLETHYL)BENZOXAZOL-4-YL]- 2 4 (i H,3H)-PYRIMIDINEDIONE (COMPOUND 28) 25 Step A 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxyphenyl)- 2,4(1H,3H)-pyrimidinedione A stirred solution of 18.2 grams (0.054 mole) of 1-methyl-6trifluoromethyl-3-(5-amino-4-chloro-2-fluorophenyl)-2,4( H,3H)-pyrimidinedione in 100 .mL of sulfuric acid was cooled to 5' C, and a solution of 3.7 grams (0.054 mole) of sodium nitrite in about 10 mL of water was added dropwise. The reaction mixture was then warmed to ambient temperature where it stirred for two hours.
15 In a separate reaction vessel, a stirred mixture of 242 grams (0.970 mole) of copper(ll) sulfate and 1.5 grams (0.005 mole) of iron(ll) sulfate heptahydrate in about 300 mL of water and 300 mL of xylene was heated to reflux, and the pyrimidinedione diazonium solution prepared above was added dropwise. The reaction mixture was stirred at reflux for two additional hours, then allowed to cool as it stirred for about 18 hours. The reaction mixture was poured into about 600 mL of water, and the aqueous/organic layers were separated. The aqueous layer was washed with ethyl acetate, and the wash was combined with the organic layer.
The combined organic material was washed with water, then with an aqueous io solution saturated with sodium chloride. The organic material was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding impure product. The product was dissolved in diethyl ether and washed with aqueous 10% hydrochloric acid, and with water. The diethyl ether solution was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 7.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step B 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5-hydroxy-6nitrophenyl)-2,4(1H,3H)-pyrimidinedione This compound was prepared in the manner of Step A of Example 1, using 3.8 grams (0.011 mole).of 1-methyl-6-trifluoromethyl-3-(4-chloro-2-fluoro-5hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 1.0 gram (0.011 mole) of 70% nitric acid, and 50 mL of sulfuric acid, yielding 1.5 grams of title compound. The NMR S spectrum was consistent with the proposed structure.
Step C 1-methyl-6-trifluoromethyl-3-(6-amino-4-chloro-2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione This compound was prepared in the manner of Step B of Example 1, 0 using 1.5 grams (0.004 mole) 1-methyl-6-trifluoromethyl-3-(4-chloro- 2 hydroxy-6-nitrophenyl)-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.054 mole) of iron dust, and 5 mL of water in 50 mL of glacial acetic acid, yielding 1.0 gram of title compound. The NMR spectrum was consistent with the proposed structure.
16 Step D Compound 28 This compound was prepared in the manner of Step C of Example 1, using 0.52 gram (0.0015 mole) of 1-methyl-6-trifluoromethyl-3-(6-amino-4-chloro- 2-fluoro-5-hydroxyphenyl)-2,4(1H,3H)-pyrimidinedione, 0.18 gram (0.0017 mole) of isobutyryl chloride, 0.24 gram (0.0017 mole) of triethylamine, and 0.09 gram (0.0004 mole) of pyridinium p-toluenesulfonate in 50 mL of xylene, yielding 0.22 gram of Compound 28. The NMR spectrum was consistent with the proposed structure.
EXAMPLE 4 o0 SYNTHESIS OF 3-(4-CHLORO-6-FLUORO-2-PHENYLBENZOFURAN-7-YL)-1- METHYL-6-TRIFLUOROMETHYL-2,4(1 H,3H)-PYRIMIDINEDIONE (Compound 280) Step A ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate A stirred solution of 23.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6- 15 difluorophenyl)carbamate in 125 mL of concentrated sulfuric acid was cooled to about 0 'C and 7.7 mL (0.123 mole) of 70% nitric acid was added dropwise at a rate to maintain the reaction temperature below 10 Upon completion of addition, the reaction mixture was stirred at 10 °C for 30 minutes and then allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was poured into 150 mL of ice-water. The resulting precipitate was collected by vacuum filtration and washed with water followed by petroleum ether. The precipitate was dried in a heated vacuum desicator, yielding 30.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
25 Step B ethyl N-(4-chloro-6-fluoro-2-methoxy-3-nitrophenyl)carbamate Under a nitrogen atmosphere, a solution of 30.6 grams (0.109 mole) of ethyl N-(4-chloro-2,6-difluoro-3-nitrophenyl)carbamate and 18 mL (0.449 mole) of methanol in 175 mL of dioxane was stirred and 218 mL (0.218 mole) of 1M sodium trimethylsilanoate (in tetrahydrofuran) was added dropwise during a 45 minute period.
Upon completion of addition, the reaction mixture was heated to 65 "C where it stirred for three hours. At the conclusion of this period, the reaction mixture was allowed to a 17 cool to ambient temperature where it stirred for about 18 hours. The reaction mixture was concentrated under reduced pressure to a residue. The residue was taken up in cold 3N hydrochloric acid. The resulting solid was collected by filtration, washed with petroleum ether, and heat dried under vacuum, yielding 21.3 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step C ethyl N-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)carbamate Under a nitrogen atmosphere, a stirred solution of 21.3 grams (0.072 mole) of ethyl N-(4-chloro-6-fluoro-2-methoxy-3-nitrophenyl)carbamate, 18.3 grams (0.328 mole) of iron powder, 50 mL of acetic acid, and 250 mL of ethanol was heated to 650 C where it stirred for two hours. At the conclusion of this time, 3 mL (0.036 mole) of 12M hydrochloric acid was added. Upon completion of addition, the reaction mixture was stirred for an additional two hours. After this time, the reaction mixture was concentrated under reduced pressure to yield a brown oil. The oil was then taken up in methylene chloride. The mixture was filtered through diatomaceous earth, and the filter cake was washed with water and an aqueous saturated sodium bicarbonate solution. The filtrate was stored over sodium sulfate for about 18 hours and then filtered. The solvent was removed under reduced pressure to yield a black oil. This oil was filtered through a silica gel pad, yielding 15.0 grams of ethyl N-(3amino-4-chloro-6-fluoro-2-methoxyphenyl)carbamate. The NMR spectrum was consistent with the proposed structure.
Step D 3-(3-amino-4-chloro-6-fluoro-2-methoxyphenyl)-6-trifluoromethyl-2,4- (1H,3H)-pyrimidinedione This compound was prepared using 4.0 grams (0.036 mole) of sodium trimethylsilanolate, 6.6 grams (0.036 mole) of ethyl 3-amino-4,4,4-trifluorocrotonate, 8.5 grams (0.032 mole) of ethyl N-(3-amino-4-chloro-6-fluoro-2methoxyphenyl)carbamate, and 2.2 grams (0.014 mole) of DBU in 75 mL of DMF.
This preparation differs from well-known literature preparations for pyrimidinedione rings in that sodium trimethylsilanolate and DBU were used rather than sodium hydride. The yield of title compound was 1.7 grams. The NMR spectrum was consistent with the proposed structure.
Step E 3 3 -amino-4-chloro-6-fluoro-2-methoxyphenyl)-1-methyl-6trifluoromethyl- 2 4 (1 H,3H)-pyrimidinedione 18 A solution of 7.5 grams (0.021 mole) of 3-(3-amino-4-chloro-6-fluoro-2methoxyphenyl)-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione, 3.4 grams (0.025 mole) of potassium carbonate, and 3.5 grams (0.025 mole) of methyl iodide in 200 mL of acetone was stirred at ambient temperature for about 18 hours. The reaction mixture was then concentrated under reduced pressure, and the residue was taken up in 200 mL of water. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined extracts were washed with two 50 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 6.9 grams of crude product. The dark oil was combined with 7.0 grams of crude product prepared by a similar route to yield a total of 13.9 grams of crude product. The crude product was purified by column chromatography on silica gel, yielding 10.0 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step F 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6trifluoromethyl-2,4(1H,3H)-pyrimidinedione A solution of 4.0 grams (0.011 mole) of 3-(3-amino-4-chloro-6-fluoro-2methoxyphenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)-pyrimidinedione in 25 mL (0.300 mole) of concentrated hydrochloric acid was stirred and cooled in an ice bath.
During a 15 minute period, 1.9 grams (0.013 mole) of sodium nitrite was added 20 dropwise at a rate to maintain the reaction temperature at 15 Upon completion of addition, the mixture was stirred for 20 minutes and then poured into 15.0 grams (0.090 mole) of potassium iodide. The reaction mixture was stirred for 30 minutes and then filtered. The filter cake was thoroughly washed with distilled water and then taken up in 150 mL of ethyl acetate. The resulting solution was dried with sodium 25 sulfate and filtered. The filtrate was concentrated under reduced pressure to yield a brown solid. The solid was subjected to column chromatography on silica gel.
Elution was accomplished using 5:1 heptane and ethyl acetate. The productcontaining fractions were combined and concentrated under reduced pressure, yielding 3.0 grams of title compound. The NMR spectrum was consistent with the 3o proposed structure.
Step G 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6trifluoromethyl-2,4(1 H,3H)-pyrimidinedione 19 Under a nitrogen atmosphere, a stirred solution of 3.0 grams (0.006 mole) of 3-(4-chloro-6-fluoro-3-iodo-2-methoxyphenyl)-1-methyl-6-trifluoromethyl- 2,4(1H,3H)-pyrimidinedione in 75 mL of methylene chloride was cooled in a dry ice/acetone bath and 22.0 mL (0.022 mole) of 1M boron tribromide (in methylene chloride) was added dropwise during a 20 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature were it stirred for about one hour. At the conclusion of this period, the reaction mixture was poured into 200 mL of water and extracted with two 50 mL portions of methylene chloride. The combined extracts were .washed with one 100 mL portion of an aqueous saturated sodium chloride solution, dried with sodium sulfate, and filtered.
The filtrate was concentrated under reduced pressure, yielding 2.6 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step H Compound 280 Under a nitrogen atmosphere, a solution of 1.5 grams (0.003 mole) of 3-(4-chloro-6-fluoro-2-hydroxy-3-iodophenyl)-1-methyl-6-trifluoromethyl-2,4(1 H,3H)pyrimidinedione, 0.41 gram (0.004 mole) of phenylacetylene, and 0.71 gram (0.007 mole) of triethylamine in 25 mL of DMF was stirred. To this was added 0.09 gram (0.00013 mole) of dichlorobis(triphenylphosphine)pallidium (II) and 0.05 gram (0.00026 mole) of copper iodide. Upon completion of addition, the reaction mixture was heated to 70 "C where it stirred for 2.5 hours. After this time, the reaction mixture was cooled to ambient temperature and then poured into 150 mL of an aqueous 10% ammonium chloride solution. The resulting precipitate was collected by filtration and washed with water. The precipitate was taken up in 120 mL of ethyl acetate. The resulting solution was dried with sodium sulfate and filtered.
The filtrate was concentrated under reduced pressure to a brown solid. The solid was recrystallized using 1:1 chloroform and petroleum ether, yielding 0.31 gram of Compound 280. The mother liquor was concentrated to a residue. The residue was recrystallized using petroleum ether to yield an additional 0.21 gram of Compound 280, m.p. 215-216 The NMR spectrum was consistent with the proposed structure.
20 EXAMPLE SYNTHESIS OF 3-(4-C H LORO-6-FLUORO-2- TRIFLUOROMETHYLBENZIMIDAZOL-7-YL)-1-METHYL-6-TRIFLUOROMETHYL- 2,4(1 H,3H)-PYRIMIDINEDIONE (Compound 365) A stirred solution of 3.0 grams (0.0085 mole) of 3-(5,6-diamino-4-chloro- 2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 15.0 mL of trifluoroacetic acid was heated to 65 °C where it stirred for one hour. At the conclusion of this period, the reaction mixture was analyzed by TLC, which indicated that the reaction was not complete. The reaction mixture was stirred at 65 °C for an additional two hours. After this time, the reaction mixture was again analyzed by TLC, which indicated that the reaction was complete. The reaction mixture was allowed to cool to ambient temperature and then poured into 200 mL of water. The resulting mixture was allowed to stand at ambient temperature for about 18 hours.
At the conclusion of this period, the resulting solid was collected by filtration and washed with water followed by heptane. The filter cake was dried under vacuum, yielding 3.6 grams of Compound 365, m.p. 130 The NMR spectrum was consistent with the proposed structure.
EXAMPLE 6 20 SYNTHESIS OF 3-(4-CHLORO-2-ETHYL-6-FLUOROBENZIMIDAZOL-7-YL)-1- METHYL-6-TRIFLUOROMETHYL-2,4(1 H,3H)-PYRIMIDINEDIONE (COMPOUND 367) Step A 3-(4-chloro-2,6-difluorophenyl)-1-methyl-6-trifluoromethyl-2,4-(1H,3H)pyrimidinedione 25 Under a nitrogen atmosphere, a solution of 32.0 grams (0.900 mole) of sodium hydride (60% by weight) in 250 mL of DMF was vigorously stirred and cooled in an ice bath. To this a solution of 133.0 grams (0.726 mole) of ethyl 3-amino-4,4,4trifluorocrotonate in 150 mL of DMF was added dropwise at a rate to maintain the reaction mixture temperature at about 5 Upon completion of addition, a solution of 156.3 grams (0.663 mole) of ethyl N-(4-chloro-2,6-difluorophenyl)carbamate in 250 mL of DMF was added dropwise. Upon completion of addition, the mixture was 21 removed from the ice bath and heated to 130 "C where it stirred for 3.5 hours. After this time, the mixture was analyzed by gas chromatography which indicated that only a slight amount of the starting material was left. The mixture was cooled to "C and 83.0 mL (1.333 moles) of methyl iodide was added dropwise at a rate to maintain the reaction mixture temperature below 20 Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure to yield a dark viscous oil. The oil was taken up in methylene chloride and washed with three 1000 mL portions of water followed by one 1000 mL portion of an aqueous saturated sodium chloride solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 223.8 grams of title compound. The NMR spectrum was consistent with the proposed structure.
S t e p B 3-(4-chloro-2,6-difJuoro-5-nitrophenyl)- -methyl-6-trifluoromethyl- 2,4(1 H,3H)-pyrimidinedione A stirred solution of 211.0 grams (0.619 mole) of 3-(4-chloro-2,6difluorophenyl)-1-methyl-6-trifluoromethyl-2, 4 (1H,3H)-pyrimidinedione in 600 mL of concentrated sulfuric acid was cooled to less than 10 and 44 mL (0.689 mole) of Saqueous 70% nitric acid was added dropwise at a rate to maintain the reaction 20 temperature below 10 Upon completion of addition, the reaction mixture was analyzed by GC, which indicated the reaction was incomplete. The reaction was allowed to warm to ambient temperature and an additional 5 mL (0.078 mole) of aqueous 70% nitric acid was added. The reaction mixture was again analyzed by GC, which indicated the reaction was complete. The reaction mixture was poured 25 into ice-water. The resulting solid was collected by filtration, washed with water, and then taken up in 600 mL of methylene chloride. The resulting solution was washed with two 600 mL portions of water, one 600 mL portion of an aqueous saturated sodium bicarbonate solution, and one 600 mL portion of an aqueous saturated sodium chloride solution. The organic layer was separated, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding a waxy tan solid. The solid was triturated with heptane and allowed to stand for about 72 hours. At the conclusion of this period, the solid was collected by filtration, 22 washed with heptane, and dried under reduced pressure, yielding 201.4 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step C 3-(6-amino-4-chloro-2-fluoro-5-nitrophenyl)-1 -methyl-6-trifluoromethyl- 2,4(1H,3H)-pyrimidinedione To stirred solution of 200 grams (0.519 mole) of 3-(4-chloro-2,6-difluoro- 5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1 H,3H)-pyrimidinedione in 1000 mL of dioxane was added 150 mL (1.091 moles) of triethylamine in one portion. Upon completion of addition, the mixture was vigorously stirred and 400 grams (5.189 moles) of ammonium acetate was added in one portion. The reaction mixture was heated to 90 °C where it stirred for two hours. The reaction mixture was allowed to cool to ambient temperature where it stirred for about 18 hours. The resulting suspension was collected by filtration and washed with dioxane. The filtrate was concentrated under reduced pressure to yield a viscous dark oil. The oil was poured into ice-water. The resulting solid was collected by filtration and washed with water.
The solid was dried under reduced pressure and then at ambient temperature for about 18 hours, yielding 195.1 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step D 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4- (1H,3H)-pyrimidinedione and 3-(5,6-diamino-4-chloro-2-fluorophenyl)-1- 20 methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione A solution of 278.0 grams (1.232.moles) of tin(ll) chloride dihydrate, 264.0 grams (4.936 moles) of ammonium chloride, 400 mL of water, and 800 mL of ethanol was vigorously stirred, and 157.4 grams (0.411 mole) of 3-(6-amino-4-chloro- 2-fluoro-5-nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione was added. Upon completion of addition, the reaction mixture was heated to 83-85 °C where it stirred for 18 hours. After this time the reaction mixture was allowed to cool to ambient temperature. The resultant solid by-product was collected by filtration and i' washed with ethanol. The combined filtrate and wash was concentrated under reduced pressure to yield a suspension of additional by-product. The suspension was taken up in ethyl acetate and the resultant emulsion was filtered through a pad of diatomaceous earth. The filter cake was washed with ethyl acetate, and the combined organics were washed with three 200 mL portions of water. The organic 23 layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure to a brown residue. The residue was triturated with heptane and allowed to stand for about-five days. The resultant solid was collected by filtration and dried, yielding 144.4 grams of crude product. The crude product was. combined with material prepared by a similar route, yielding a total of 157.8 grams of material. The combined product was subjected to column chromatography on silica gel, yielding 83.2 grams of an orange solid. The solid was slurried with warm ethyl acetate, and the insoluble product was collected by filtration. The product was washed with ethyl acetate, and the wash and filtrate from above were combined. The process of concentrating the filtrate, and slurrying the solid residue was repeated twice more, yielding a total of 51.9 grams of title compound. The NMR spectrum was consistent with the proposed structure.
An alternate method for preparing 3-(5,6-diamino-4-chloro-2fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione is the following: A solution of 19.2 grams (0.050 mole) of 3-(6-amino-4-chloro-2-fluoro-5nitrophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione, 3.0 grams (0.056 mole) of ammonium chloride, and 50 mL of water in 100 mL of ethanol was stirred, and 11.2 grams (0.201 mole) of iron powder (325 mesh) was added in one portion.
Upon completion of addition, the reaction mixture was heated at reflux for one hour.
20 The reaction mixture was allowed to cool to ambient temperature, then it was filtered through diatomaceous earth to remove the iron powder. The filter cake was washed with 200 mL of acetone, and the wash was combined with the filtrate. The combination was stirred with decolorizing carbon and filtered. The filtrate was concentrated under reduced pressure, yielding a dark brown oil. The oil was then 25 taken up in 200 mL of methylene chloride and washed with three 100 mL portions of an aqueous saturated sodium bicarbonate solution. The organic layer was dried with magnesium sulfate, filtered, and concentrated under reduced pressure, yielding 12.8 grams of title compound. The NMR spectrum was consistent with the proposed structure.
Step E Compound 367 A stirred solution of 1.0 grams (0.0028 mole) of 3-(5,6-diamino-4-chloro- 2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione and 0.28 mL 24 (0.0035 mole) of pyridine in 10 mL chloroform was cooled to 5 °C and 0.27 mL (0.0031 mole) of propionyl chloride was added dropwise. Upon completion of addition, the mixture was allowed to warm to ambient temperature were it stirred for about 18 hours. The mixture was cooled to 5 "C and 5.0 mL (0.054 mole) of phosphorous oxychloride was added in one portion. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it stirred for about 18 hours. At the conclusion of this period, the reaction mixture was poured into 200 mL of cold water, the resulting mixture was stirred for one hour, then it was extracted with three 50 mL portions of chloroform. The combined extracts were dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 0.15 gram of an orange residue. The aqueous layer was made basic with an aqueous saturated sodium bicarbonate solution to a pH of 3-4. The resulting mixture was extracted with three 50 mL portions of methylene chloride. The extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure, yielding 0.70 gram of a yellow residue. The yellow residue was triturated with hot heptane. The resulting solid was collected by filtration and washed with heptane, yielding 0.67 gram of Compound 367, m.p. 150- 155 The NMR spectrum was consistent with the proposed structure.
EXAMPLE 7 S 20 SYNTHESIS OF 3-(2-T-BUTYL-4-CHLORO-6-FLUOROBENZIMIDAZOL-7-YL)-1- MVETHYL-6-TRIFLUOROMETHYL-2,4(1 H,3H)-PYRIMIDINEDIONE (Compound 369) To a stirred solution of 1.0 grams (0.0028 mole) of 3-(5,6-diamino-4chloro-2-fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione 15.0 25 mL of ethanol, and 4 mL of 5M hydrochloric acid was added 1.2 mL (0.0057 mole) of 2,2,6,6-tetramethyl-3,5-heptanedione. Upon completion of addition, the reaction mixture was heated to reflux where it stirred for ten minutes. At the conclusion of this period, the reaction mixture was analyzed by TLC, which indicated that the reaction was not complete. The reaction mixture was stirred at reflux for an additional two hours. After this time, the reaction mixture was again analyzed by TLC, which again indicated that the reaction was still not complete. As a result, an additional 1.0 mL 25 (0.0048 mole) of 2,2,6,6-tetramethyl-3,5-heptanedione was added. Upon completion of addition, the reaction mixture was stirred at reflux for three days. At the conclusion of this period, more ethanol was added to replace that which evaporated, and the reaction mixture was analyzed by TLC for a third time. The reaction mixture was allowed to cool to ambient temperature, poured into 100 mL of an aqueous saturated sodium bicarbonate solution, and 100 mL of chloroform was added. The aqueous layer was separated and washed with two 100 mL portions of chloroform. The chloroform layer and washes were combined, dried with magnesium sulfate, and filtered. The filtrate was treated with decolorizing carbon and stirred. The mixture o1 was filtered and concentrated under reduced pressure to yield a red oil. The oil was taken up in heptane. The resulting solid was collected by filtration and washed with heptane to yield a tan solid. The solid was purified by column chromatography on silica gel, yielding 0.36 gram of Compound 369, m.p. 125-130 The NMR spectrum was consistent with the proposed structure.
EXAMPLE 8 SYNTHESIS OF 3-(7-CHLORO-5-FLUORO-2-TRIFLUOROMETHYLINDOL-4-YL)-1- METHYL-6-TRIFLUOROMETHYL-2,4(1H,3H)-PYRIMIDINEDIONE S(Compound 500) 20 Step A 3-[5-(1-trifluoromethylethylidenehydrazino)-4-chloro-2-fluorophenyl]-1methyl-6-trifluoromethyl-2,4(1 H,3H)-pyrimidinedione A solution of 3.37 grams (0.010 mole) of 3-(5-amino-4-chloro-2fluorophenyl)-1-methyl-6-trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 80 mL of concentrated hydrochloric acid was stirred at 25 °C for 20 minutes. After this time, 25 the solution was cooled to 10 "C and a solution of 0.69 gram 0.010 mole) of sodium nitrite in 10 mL of water was slowly added. Upon completion of addition, the mixture was stirred for one hour at 10 °C and then a solution of 5.64 grams (0.025 mole) of tin (II) chloride dihydrate in 40 mL of concentrated hydrochloric acid was slowly added. Upon completion of addition, the reaction mixture was warmed to 25 °C where it stirred for one hour. At the conclusion of this period, 1.12 grams (0.010 mole) of trifluoroacetone was added and the resulting solid was collected by filtration, 26 yielding 3.13 grams of title compound, m.p. 213-214 The NMR spectrum was consistent with the proposed structure.
Step B Compound 500 A stirred solution of 2.0 grams (0.0044 mole) of trifluoromethylethylidenehydrazino)-4-chloro-2-fluorophenyl]-1-methyl-6trifluoromethyl-2,4(1H,3H)-pyrimidinedione in 80 mL of polyphosphoric acid was heated at 80 "C for 20 minutes. After this time, the reaction mixture was allowed to cool to 25 "C where it was diluted with water. The resulting solid was collected by filtration, yielding 0.73 gram of Compound 500, m.p. 208-210 The NMR spectrum was consistent with the proposed structure.
EXAMPLE 9 SYNTHESIS OF 3-(7-CHLORO-2-ETHOXYCARBONYLINDOL-4-YL)-4,5,6,7- TETRAHYDRO-1 H-ISOINDOLE-1,3(2H)-DIONE (Compound 595) Step A 3-(1-ethoxycarbonylethylidenehydrazino)-4-chloronitrobenzene This compound was prepared in the manner of Step A, Example 1, using, 17.25 grams (0.10 mole) of 2-chloro-5-nitroaniline, 6.9 grams 0.10 mole) of sodium nitrite, 56.4 grams (0.25 mole) of tin (II) chloride dihydrate, 11.61 grams (0.10 mole) of ethyl pyruvate, 30 mL of water, and 100 mL of concentrated hydrochloric 20 acid. This preparation differs in that ethyl pyruvate was used rather than trifluoroacetone. The yield of title compound was 19.4 grams. The NMR spectrum was consistent with the proposed structure.
Step B 7-chloro-2-ethoxycarbonyl-4-nitroindole This compound was prepared in the manner of Step B, Example 8, 25 using 14.0 grams (0.050 mole) of 3-(1-ethoxycarbonylethylidenehydrazino)-4chloronitrobenzene in 100 mL of polyphosphoric acid. The yield of title compound was 0.4 gram. The NMR spectrum was consistent with the proposed structure.
Step C 7-amino-4-chloro-2-ethoxycarbonylindole A stirred solution of 2.68 grams (0.01 mole) of 4-chloro-2- 3 0 ethoxycarbonyl-7-nitroindole, 80 mL of acetic acid, and 15 mL of water was heated to 65 and 18.3 grams (0.048 mole) of iron powder was slowly added during a 27 minute period. Upon completion of addition, the reaction mixture was allowed to cool to 25 "C where it stirred for one hour. After this time, the reaction mixture was poured into water, and the resulting mixture was filtered through diatomaceous earth. The filter cake was washed thoroughly with ethyl acetate. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure a residue. The residue was purified by column chromatography, yielding 0.4 gram of title compound. The NMR spectrum was consistent with the proposed structure.
Step D Compound 595 A stirred solution of 0.4 gram (0.0016 mole) of 7-amino-4-chloro-2ethoxycarbonylindole and 0.26 gram (0.0016 mole) of 3,4,5,6-tetrahydrophhalic anhydride in 80 mL of acetic acid was heated at reflux for about 18 hours. After this time, the reaction mixture was extracted with several portions of diethyl ether. The organic extracts were combined, dried with magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel, yielding 0.47 gram of Compound 595. The NMR spectrum was consistent with the proposed structure.
28 Table 1 Benzoxazoles 4 3
B
Y~n) I> R
A
7i where A is nitrogen double bonded to position 2 and B is 0; J is 0 N 0 N N
CF
3 Compound No. X R R3 1 4-Cl, 6-F CH3
OH
3 2 4-Cl, 6-F CH3
C
2 1- 3 4-Cl, 6-F CH3
CH
2
CN
4 4-Cl, 6-F CH3 CH 2
CH=CH
2 .0 5 4-Cl, 6-F CH3 NH 2 00.06 4-Cl, 6-F CH3 CH 2
C=CH
8 4-01, 6-F 0H3 CH-,OCH 3 9 4-Cl, 6-F CH3 CH 2
CO
2
C
2
H
o o* -29 Table 2 4 3
B
>R
Xq7 1
J
o N 0
CF
3 J1 CF 3 J2
I
N
J4
N-
0 0 CH 3 J6 No. A 10 10 11 12 13 14 16 17 1s 19 20 21 22 23 24 26 27 28 29 Double Bond Posit'n 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 x 4-Cl 4-Cl 4-CI 4,6-C 2 4,6-Cl 2 4,6-C 2 4-Br. 6-F 4-C F,.6-F 4,6-F, 4-CN, 6-F 4-OCF 2 ,6-F 4-Br, 6-F 4-CN, 6-F 4-CN, 6-F 4-CH3, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F
R
CH3
CH,
C H(CH 2 2
CH,
CH,
CH,
CHI
CH,
CH3
CH,
CH
2
CH,
C
2 1-1
CH(CH,),
CH
3
CH,
CH
7
CH,
CH(CH,),
CH
2
CH(CH
2 2 a a N 0 1-2 4-Cl, 6-F i 31 N 0 1-2 4-Cl, 6-F phenyl ii 32 N 0 1-2 4-Cl, 6-F p henytmethyl i 33 N 0 1-2 4-Cl, 6-F CF 3 J1 34 N 0 1-2 4-Cl, 6-F CCI 2 J1 N 0 1-2 4-Cl, 6-F Cl i 36 N 0 1-2 4-Cl, 6-F OH i 37 N 0 1-2 4-Cl. Br JA 38 N 0 1-2 4-Cl, 6-F NH, i 39 N 0 1-2 4-Cl, 6-F NHCH, i N 0 1-2 4-Cl, 6-F N(CH 3 2 J1 41 N 0 1-2 4-Cl, 6-F NHCH 2 cO 2 CH, JA 42 N 0 1-2 4-Cl, 6-F NHSOCH 3 J1 43 N 0 1-2 4-Br, 6-F NHCOCH 3 i 44 N 0 1-2 4-Cl, 6-F morpholino JA N 0 1-2 4-Cl, 6-F NHSO 2
C
8 H, i 46 N 0 1-2 4-Cl, 6-F NHSOCHCH, i 47 N 0 1-2 4-Cl, 6-F N(CH 3 )SOCH, JA 48 N 0 1-2 4-Cl. 6-F NHPO(OCH 3 i 49 N 0 1-2 4-Br, 6-F CH 2
CO
2
CH
3 i N 0 1-2 4-Cl, 6-F CHC0,CH, i 51 N 0 1-2 4-Cl, 6-F CH=CHCO 2
CH
3
JA
52 N 0 1-2 4-Cl, 6-F CH=C(C)CO 2
CH
3
JA
53 N 0 1-2 4-Cl, 6-F CH 2
CH(CI)CO
2 CH, JA 54 N 0 1-2 4-Cl, 6-F 0CH 3
JA
N 0 1-2 4-Cl, 6-F OC 2 H. JA 56 N 0 1-2 4-Cl, 6-F OCH(CH 3 2 Ai 57 N 0 1-2 4-Cl, 6-F OCH 2
CH=CH
2 i N 0 1-2 4-Cl, 6-F OCH 2
C(CH
3 i 59 N 0 1-2 4-Cl, 6-F OCH 2 CCH JA N 0 1-2 4-Cl, 6-F OCH 2 Co 2 CH, JA *.61 N .0 1-2 4-Cl, 6-F OCH(CH 3
)CO
2 CH 3 Ji 62 N 0 1-2 4-Cl, 6-F OCH 2 CN JA 63 N 0 1-2 4-Cl, 6-F OCH 2
CONH
2
JA
35 64 N 0 1-2 4-.Cl. 6-F OCHC0NHCH, JA N 0 1-2 4-Cl, 6-F OCH(CH,)CONH 2
JA
66 N 0 1-2 4-Cl, 6-F 0CH(CH 3
)CONHCH
3
JA
67 N 0 1-2 4-Cl, 6-F OCH 2 COH J 68 N 0 1-2 4-Cl, 6-F phenoxy J 69 N 0 1-2 4-Cl, 6-F p-OCH,0CH(CH,)C0 7 CH, Ji N 0 1-2 4-Cl, 6-F 4-chioropheno xy JA 71 N 0 1-2 4-Cl, 6-F phenytmethoxy i 72 N 0 1-2 4-Cl, 6-F CN J *73 N 0 1-2 4-Cl, 6-F C0 2 CH 3
JA
74 N 0 1-2 4-Cl, 6-F CO 2 H JA N 0 1-2 4-Cl, 6-F CONa JA 76 N 0 1-2 4-Cl, 6-F CONH 2
JA
77 N 0 1-2 4-Cl, 6-F CONHCH, JA 78 N 0 1-2 4-Cl, 6-F CON(CH 3 2
JA
79 N 0 1-2 4-Cl, 6-F CONHSO 2
CH
3
JA
31 81 82 83 84 86 87 88 89 91 92 93 94 96 97 98 99 100 101 102 103 104 105 106 107 108 30 109 110 il1 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0* 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 .1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Br, 6-F 4-Cl, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Br, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl,.6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F
CO
2
NHOCH,
.SCH,
SCHCO
2
CH,
SCH
2
CONH
2
SO
2
CH,
SH
CHOH
CH(CH,)OH
C(CH,),0H CH,0H CHCH(CH,)0H CHC(CH,),0H C(CH,),0C0CH,
CH(CH
3 2
OCOCH,
CH(CH,)OC0CH, 1CHBr,
CHOCH,
CH
2
OCHCCH
NH
2 phenoxymethyl
N(COCH,),
CHOCOCH,
4-chlorophenoxymethyl CH(Ph)OCOCH 3
C(CH,),OCOCH,
C0 2
H
OCH
2
CCH
OCH (C H 3 2 NHS0 2
CH,
OCH,
OCHCH=CH,
(CH,)(CN)0H
CH,
n-CH, i-CH, t-CH9
CH,
CHC0 2
CH,
phenoxymethyl
CONHCH
3 C0N(CH 3 C0 2
CH,
Phenyl SCH3
CH
2 OCH3 Benzyl 4-chlorophenyimethyl S0 2
CH
3 CF,3 C (C H,),O0C 2 C H,
S.
S S S S. S S S
S.
*5 55 4 5.55
S*
32 130 131 132 133 134 135 136 137 138 139 140 141 142 143 144 145 146 147 148 149 150 151 152 153 154 155 156 157 158 30 159 160 161 162 163 35 164 165 166 167 168 169 170 171 172 173 174 175 176 177 178 179 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-C. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F
C(CH,),CHOH
CH,
n-C,H.
i-C,H 7 t-C,H,
CH,OH
CH
2
CHOH
C(CH,),OH
CONHCH,
CON(CH)
2
CO
2
CH,
Phenyl
SCH
3
CH
2
OCH
3 Benzyl 4-chlorophenylmethyl
SOCH
3
CF
3
C(CH
3 2 0C0 2
CH,
C(CH
3 2
CH
2
OH
C(CH,)
2
CHOCH,
C
2
H,
CONa
CONHSO
2
CH
3 OCH,C0 2
CH,
OCH(CH,)COCH,
OCH
2
CH=CH
2
OCH
2
CCH
OH
OCH
3
OCH(CH)
2
CH
3 n-C,H.
i-C,H, t-CH 9
CH
2 0H
CH
2
CH
2
OH
C(CH,)
2 0H
CONHCH,
CON(CH)
2
,O,CH,
Phenyl
SCH,
CH
2
OCH
Benzyl 4-chlorophenylmethyl S0 2
CH
3
CF,
C(CH
3 2 0C0 2
CH
3
C(CH)
2
CHOH
0SeS 0 00 SO 0 900 0 0000 S A 5S 5 0 0 S 55
S
0
C.
sOS.
55 S
S.
,-33 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195 196 197 198 199 200 201 202 203 204 205 206 207 208 3 0. 209 210 211 212 213 35 214 215 216 217 218 219 220 221 222 223 224 225 226 227 228 229 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 C H C H C H
CH
C H C H C H C H C H 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl 4-Cl, 6-F 4,6-F 2 4-Cl, 6-F
C(CH
3 2
CH
2
OCH,
*C
2
H
5 CONa CO NH S 2 C H
OCH
2
COCH,
OCH(CH,)COCH,
OCH H 2 CH=C H 2 OCH 2
CCH
OH
OCH,
OCH(CH,),
CH
3 n-CH, i-C 3
H,
t-CH,
CH
2 0H
CHCHOH
C(CH,),0H CO NHC H 3
CON(CH
3
COCH,
Phenyl
SCH,
CH
2
OCH
3 Benzyl 4-chlorophenylmethyl
SO
2
CH,
CF
3
C(CH,),OCOCH,
C(CH,),CHOH
C(CH 3 2
CHOCH,
c C 2 Hs C0 2 Na
CONHSOCH,
OCH
2
COCH,
OCH(CH,)CO
2
CH,
OCH
2
CH=CH
2 OCH 2
CCH
OH
OCH 3
OCH(CH
3 2
CH,
CH
3 n-propyl isopropyl n-butyl t-butyl t-butyl t-butyl
CH(CH,)C
3
H,
J4 J4 J4 J4 J4 J4 A4 J4 J4 J4 J4 i Ai
AI
Ai Ai
AI
34 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 30 259 260 261 262 263 35 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
OH
OH
OH
CH
OH
CH
CH
OH
OH
OH
CH
OH
OH
CH
OH
OH
OH
CH
CH
CH
CH
CH
OH
CH
CH
CH
OH
4-Cl, 6-F 4-Cl, 6-F 4-01 4-01 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-01 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl 4-Cl 4-Cl 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl 4-01
H
4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F
CH=CH
2
C(CH,)=CH,
CHBr CHBr 2
CH(CI)CH,
CH(F)CH
3
CHCH
2
CI
CHCH
2
F
CH
2 0H
CHCHOH
CH(CH,)OH
C(CH,),OH
C(CH
3 2 0H
CH
2
CH(CH,)OH
CH(CH,)OC(CH
3 3 CH(0O 2
H,)
2
CH(CH
3
)OCOCH
3
CH(CH
3
)OCOCH(CH
3 CH(CH,)OCOPh
CH(CH
3
)OCONHCH,
CH(CH,)OCONHCH
2 Ph C(CH,),00H,
C(CHI)
2 00H 2 00H,
C(CH
3 2
OCOCH.
3
C(CH
3 2
NH
2 C(CH,),NHS0 2
CH,
CH
2
CHCHCN
CH
2
N(C
2
H,)
2
CH=NOH
CH=NOCH,
CHCH,OCOCH,
CH
2 CH,OCONHCH3
CH
2
CH
2
CO
2
H
CH
2
CH
2 C0 2
CH,
Phenyl
CHO
C0 2
H
C0 2
C
2
H
C0 2
C
2
H,
CON H 2 CONH CH 3
CON(CH
3 2
NHCOC(CH
3 3
CONH
2 CONH(CH3)
CON(CH
32 C0 2
H
C0 2
CH
3 3,4-dimethoxyphenyt 35 280 281 282 283 284 285 286 287 288 289 290 291 292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315 316 317 318 319 320 321 322 323 324 325 326 327 328 329
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 .2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 4-Cl, 6-F 6-F 4-0, 6-F 4-01, 6-F 6-F 6-F 4-Cl, 6-F 6-F 6-F 6-F 4-Cl, 6-F 4-Cl, 6-F 6-F 6-F 4-Cl, 6-F 4-Cl, 6-F 6-F 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 6-F 4-Cl, 6-F 6-F 4-Cl. 6-F 6-F 6-F 6-F 6-F 4-Cl, 6-F 6-F 6-F 6-F 4-01, 6-F 6-F 6-F 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-C, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F Phenyl
CH
3 n-propyl isopropyl t-butyl
CH(CH
3
)C
H
CH=CH
2
C(CH)=CH
2
CH(CI)CH
3
CH(F)CH,
CH,CH
2
CI
CHCH
2
F
CH,CHOH
CH(CH,)OH
C(CH
3 2 0H
CH
2
H(CH
3
)OH
CH(CH,)OC(CH
33
CH(OC
2
H)
CH(CH
3
)OCOCH,
CH(CH,)OCOCH(CH)
2 CH(CH)OCOPh
CH(CH,)OCONHCH,
CH(CH
3
)OONHCH
2 Ph C(CH 2 0CH 2
OCH
3
C(CH,)OCOCH
3
C(CH
3 2
NH,
C(CH,),NHSO
2
CH,
CH
2
CH,CHCN
CH
2
CH,OCOCH,
CH
2
CH
2 0CONHCH 3
CH,CH
2
CO
2
H
CH
2
CH
2
C
2
OCH
3
CONH
2
CONH(CH,)
CON(CH)
2 C0 2
H
CO,CH
3
CHOH
3,4-dimethoxyphefyl Phenyl CH3 C2Hs CH(CI)CH3 OH(F)CH3
CHCH
2
CI
CH,CH
2
F
CH
2
CHOH
CH(CH
3
)OH
C(CH,),OH
C(CH
3 2 00H20H:3 Ji J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J2 J3 J3 J3 J3 J3 J3 J3 J3 J3 J3 -36 330 0 CH 2-3 4-Cl, 6-F C(CH3)2NHSO2CH3 J3 331 0 CH 2-3 4-Cl. 6-F CHCH 2 CHCN J3 332 0 CH 2-3 4-Cl, 6-F CH2CH2CO2CH3 J3 333 0 CH 2-3 4-Cl, 6-F C0N(CH3)2 J3 334 0 CH 2-3 4-Cl, 6-F CH3 J4 335 0 CH 2-3 4-Cl, 6-F C2H5 J4 336 0 CH 2-3 4-Cl, 6-F CH(Cl)CH3 J4 337 0 CH 2-3 4-Cl, 6-F CH(F)CH3 J4 338 0 CH 2-3 4-Cl, 6-F CHCHCI J4 339 0 CH 2-3 4-Cl, 6-F CH 2
CH
2 F J4 340 0 CH 2-3 4-Cl, 6-F CH 2 CH,OH J4 341 0 CH 2-3 4-Cl. 6-F CH(CH,)OH J4 342 0 CH 2-3 4-Cl, 6-F C(CH 3 ),OH J4 343 0 CH 2-3 4-Cl, 6-F C(CH3)20CH20CH3 J4 344 0 CH 2-3 4-Cl, 6-F C(CH3)2NHSO2CH3 J4 345 0 OH 2-3 4-Cl, 6-F CH 2
CH
2
CH
2 CN J4 346 0 CH 2-3 4-Cl. 6-F CH2CH2CO2CH3 J4 347 0 CH 2-3 4-Cl, 6-F C0N(CH3)2 J4 348 0 CH 2-3 4-Cl, 6-F CH3 349 0 CH 2-3 4-Cl, 6-F C2H5 350 0 CH 2-3 4-Cl, 6-F CH(CI)CH3 351 0 CH 2-3 4-Cl, 6-F CH(F)CH3 352 0 CH 2-3 4-Cl, 6-F CHCHCI 353 0 CH 2-3 4-Cl, 6-F CH 2
CH
2 F 354 0 CH 2-3 4-Cl, 6-F CHCH 2 OH 355 0 CH 2-3 4-Cl, 6-F CH(CH 3 )OH 356 0 CH 2-3 4-Cl, 6-F C(CH 3 ),OH 357 0 CH 2-3 4-Cl. 6-F C(CH3)20CH20CH3 358 0 CH 2-3 4-Cl, 6-F C(CH3)2NHS2OCH3 359 0 CH 2-3 4-Cl, 6-F CH 2
CHCH
2 CN 360 0 CH 2-3 4-Cl, 6-F CH2CH2CO2H3 361 0 CH 2-3 4-Cl, 6-F C0N(CH3)2 362 NH N 2-3 4-Cl, 6-F H Ji 363 NH N 2-3 4-Cl, 6-F CH 3 Ji 35 364 NH N 2-3 4-Cl, 6-F CHF 2 Ji 365 NH N 2-3 4-Cl, 6-F CF 3 Ji 366 NH N 2-3 4-Cl, 6-F CCIF 2
J
367 NH N 2-3 4-Cl, 6-F C 2 H, J 368 NH N 2-3 4-Cl, 6-F I-C 3 H, J 369 NH N 2-3 4-Cl, 6-F t-C,H, 1 370 NH N 2-3 4-Cl, 6-F CH,OCH 3
J
371 NH N 2-3 4-Cl, 6-F C(CH 3 2 0C(0)CH, Ji 372 NH N 2-3 4-Cl, 6-F C 2 HC0 2
C
2 H, J 0. 373 NH N 2-3 4-Cl, 6-F Cyciohexyl JA 374 NH N 2-3 4-Cl, 6-F Adamantyl JA 375 NH N 2-3 4-Cl, 6-F Phenyl Ji 376 NH N 2-3 4-Cl. 6-F Benzyl J 377 NH N 2-3 4-Cl, 6-F CH(CH,)C,Hs Ji 378 NH N 2-3 4-Cl, 6-F CH,OC,H, Ji 379 NH N 2-3 4-Cl, 6-F C 2 H C H, J 37 380 381 382 383 384 385 386 387 388 389 390 391 392 393 394 395 396 397 398 399 400 401 402 403 4G4 405 406 407 408 30 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428
NH
NH
NH
NH
NH
NH
N-H
NH
NH
N
N
N
N
IN
N
N
N
N
N
N
N
N
N
N
NH
N- HN-CH(CH,),
NCH
3
NCH,
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NH
NH
NH
NH
NH
NH
NCH
3
NCH
3
NCH,
NCH
3
NCH
3
NCH,
NCH,
NCH,
NC
2
H,
NH
N
N
NCH,
NCH,
NCH,
NC
2
H,
NC
4
H,
NCH,
NC
4
,H,
NC
4
H,
NCH,
NCH,
NCHOCH
3
NCHOCH
3
NCH
2
OCH,
NCHOCH,
NCHOCH,
NCH
2 0CF1 3
NCOCH
3
NCOCH
3
NCOCH,
NCOZCH
3
NCOCH,
NCOCH
3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 2-3 2-3 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, &-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F" 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-NO, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F
C
3
HC,,H,
2-chloraphenylmethy[ 3-chlorophe nylm ethyl 4-chlorophenylmethyl
CFCF
3 Furan-2-yl
CHCI
C(CH
3 2
CHCI
0CH,
CH,
C
2H isopropyl t-butyl
CF,
CF
2
CF,
CH
3
C
2
H,
isopropyl t-butyl
CF
3
CF
2
CF
3
COCHCH
3
CH,
C
2
H,
CF
3
CH,
CF
3 isopropyl t-butyl
CF
3 CF 2
CF
3
CH,
C
3
H,
isopropyl t-butyl
CF
3
CFCF
3
CH,
C
2
H
isopropyl t-butyl
CF
3 CF 2
CF
3
CH
3
C
2
H,
isopropyl t-butyl
CF,
CFCF
3 -38 429 N NSO 2 CH, 1-2 4-Cl, 6-F CH 3
J
430 N NSO 2 CH, 1-2 4-Cl, 6-r C 2
H
5
J
431 N NSO 2 CH, 1-2 4-Cl, 6-F isopropyl i 432 N NS0 2
CH
3 1-2 4-Cl, 6-F t-butyl i 433 N NSOCH, 1-2 4-Cl, 6-F CF, i 434 N NS0 2 CH, 1-2 4-Cl, 6-F CF 2 CF, i 435 N NCHCHCH, 1-2 4-Cl, 6-F CH 3
J
436 N NCH 2
CHCH
2 1-2 4-Cl, 6-F C 2
H
5 j 437 N NCHCHCH, 1-2 4-Cl, 6-F isopropyl i 438' N NCH 2 CHCH, 1-2 4-Cl, 6-F t-butyl i 439 N NCH 2
CHCH
2 1-2 4-Cl, 6-F CF 3
JA
440 N NCH 2
CHCH
2 1-2 4-Cl, 6-F JiCF 1 441 N NCHCCH 1-2 4-Cl, 6-F CH 3 i 442 N NCHCCH 1-2 4-Cl. 6-F CAH i 443 N NCH 2 CCH 1-2 4-Cl, 6-F isopropyl i 444 N NCH 2 CCH 1-2 4-ClI. 6-F t-butyl JA 445 N NCH 2 CCH 1-2 4-Cl, 6-F CF 3
JA
446 N NCH 2 CCH 1-2 4-Cl, 6-F CFCF, JA 447 N NCHCO 2 Me 1-2 4-Cl. 6-F CH, Ai 448 N NCH 2
CO
2 Me 1-2 4-Cl, 6-F C2H, i 449 N NCH 2 Co 2 Me 1-2 4-Cl, 6-F isopropyl JA 450 N NCHCO.Me 1-2 4-Cl. 6-F t-butyl i 451 N NCH 2
CQ
3 Me 1-2 4-Cl, 6-F CF 3
JA
452 N NCH 2
CO
2 Me 1-2 4-Cl, 6-F CF 2
CF
3
J
453 N NCF 3 1-2 4-Cl, 6-F CH, J 454 N NCF, 1-2 4-Cl, 6-F C 2
H
5
J
455 N NCH 2
CO
2 Me 1-2 4-Cl, 6-F isopropyl JA 456 N NCH 2
CO
2 Me 1-2 4-Cl, 6-F t-butyl i 457 N NCH 2 COMe 1-2 4-Cl, 6-F CF, JA 30 458 N NCF 3 1-2 4-Cl, 6-F CFCF 3
JA
459 NH N 2-3 4-Cl, 6-F CH 3 J2 460 NH N 2-3 4-Cl, 6-F C 2 HS J2 461 NH N 2-3 4-Cl, 6-F isopropyl J2 462 NH N 2-3 4-Cl, 6-F t-butyl J2 35 463 NH N 2-3 4-Cl, 6-F CF 3 J2 *464 NH N 2-3 4-Cl, 6-F CF 2
CF
3 J2 465 NH N 2-3 4-Cl, 6-F CH 3 J3 466 NH N 2-3 4-Cl, 6-F C 2 H, J3 467 NH N 2-3 4-Cl, 6-F isopropyl J3 2. 40 468 NH N 2-3 4-Cl, 6-F t-butyl J3 469 NH N 2-3 4-Cl, 6-F CF 3 J3 470 NH N 2-3 4-Cl, 6-F CF 2
CF
3 J3 471 N H N 2-3 4-Cl, 6-F CH 3 J4 *472 NH N 2-3 4-Cl, 6-F C 2
H
5 J4 473 NH N 2-3 4-Cl, 6-F isopropyl J4 474 NH N 2-3 4-Cl, 6-F t-butyl J4 475 NH' N 2-3 4-Cl, 6-F CF 3 J4 476 NH N 2-3 4-Cl, 6-F CFC3J4 477 NH N 2-3 .4-Cl, 6-F CH 3 478 NH N 2-3 4-Cl. 6-F CAH 39 479 480 481 482 483 484 485 486 487 488 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528
NH
NH
NH
NH
NH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
N
N
N
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NCH,
NCH,
NCH,
NCH,
NCH,
NCH
3
NCH
3
NCH,
NCH,
NCH
3
NCH
3
NCH,
NCH
3
NCH
3
NC,H,
NC,H,
NC
2
H,
NC
2
H,
NC,H,
NC H, 2-3 2-3 2-3 2-3 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 6-F isopropyl 6-F t-butyl 6-F CF 3 6-F CF,CF3 6-F CH 3 6-F n-C,H 7 6-F I-C 3
H,
6-F t-C,H, 4-01, 6-F CH,OH 6-F CH 2
CH,OH
6-F C(CH 3 )0H 4-O, 6-F CONHCH 3 4-Ct. 6-F CON(CH 3 2 6-F 00 2
CH
3 4-Cl, 6-F CO,CH,CH 3 6-F Phenyl 6-F CF 2
CF
3 4-0, 6-F CHOCH, 4-Cl, 6-F Benzy! 6-F 4-chlorophenylmethy! 4-Cl, 6-F S0 2
CH,
4-01, 6-F CF 3 4-Cl, 6-F C(CH) 2 0COCH 3 6-F C(CH.) CH OH 4-Cl, 6-F C(CH 3 2
CH
2
OCH
3 4-Cl, 6-F C 2
H,
6-F CONa 6-F CONHSO 2
CH
3 6-F CHFCH, 4-Cl, 6-F 0H 2
COCH
2
CH
3 6-F CH, 4-Cl. 6-F C,H, 6-F isopropy! 6-F t-buty! 40!, 6-F CF, 6-F CF 2
CF
3 4-Cl, 6-F CHFCH, 6-F CON(CH 3 2 4-Cl, 6-F CH 2
COC,H,
6-F CH 2
CH
2
CN
6-F C(0H 3 2 0H 6-F C(CH 3 2 0COCH, 4-Cl, 6-F C(CH,) 2
NHSO
2
CH,
6-F 00 2
CH
2
CH
3 6-F CH 3 6-F C 2
H,
6-F isopropy! 4-Cl, 6-F t-butyl 4-Cl, 6-F CF 3 4-0. 6-F C0 2
CH
3 529 530 531 532 533 534 535 536 537 538 539 540 541 542 543 544 545 546 547 548 549 550- 551 552 553 554' 555 556 557 30 558 559 560 561 562 35 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578
NCH,
NCH,
NC
4
,H,
NCH
9
NCH.
NCH,
NCH
2 0CH,
NCH
2 0 H 3
NCO
2
CH,
NCHO0H 3
NCH
2
OCH,
NCHOCH
3
NCOCH
3
NCOCH
3
NCOCH
3
NCOCH
3
NCOCH
3
NCOCH,
NSO
2
CH,
NS0 2
CH
3
NSO
2
CH,
NSO
2
CH
3
NSO
2
CH,
NS0 2
CH
3
NCH
2
CHCH
2
NCHCHCH,
NCH
2
CHCH,
NCH
2
CHCH
2
NCH
2
CHCH,
NCHCHCH,
NCHC=ECH
NCHC-=CH
NCH
2
C=SCH
NCH
2
C=-CH
NCHC-=CH
NCH
2
C=-CH
NCHCO
2 Me
NCH
2 COMe
NCHCO
2 Me
NCHCO
2 Me
NCH
2 COM e
NCHCO
2 Me
NCH
2
CHF,
NCHCHF
2
NCHCHF,
NCHCHF
2
NCH
2
CHF,
NCHCHF
2
NH
NH
4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-C0, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl,' 6-F 4-Cl, 6-F
CH
3
C
2
H,
isopropyl t-butyl
CF,
C0 2
CH
3
CH
3 C 2
H
isopropyl t-butyl
CF
3 C0 2
CH,
CH
3
C
2
H,
isopropyl t-butyl
CF
3 C0 2
CH,
CH
3
C
2
H,
isopropyl t-butyl
CF
3 C0 2
CH,
CH
3
C
2
H,
isopropyl t-butyl
CF
3
COCH,
CH,
C
2
H,
isopropyl t-butyl
CF,
COCH
3
CH
3 C2H, isopropyl t-butyl
CF
3
COCH
3
CH
3
C
2
H
isopropyl t-butyl
CF
3
CO
2
CH
3
CH,
C
2
H,
41 579 580 581 582 583 584 585 586 587 588 589 590 591 592 593 594 595 596 597 598 599 600 601 602 603 604 605 606 607 30 608 609 610 611 612 35 613 614 615 616 617 618 619 620 621 622 623 624 625 626 627 628
CH
OH
CH
OH
OH
OH
OH
OH
OH
OH
CH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
OH
OH
OH
OH
OH
CH
OH
CH
OH
OH
OH
OH
OH
OH
OH
CH
OH
CH
CH
OH
CH
CH
OH
OH
OH
OH
OH
1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 4-Cl, 6-F 4-Cl, 6 F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-01, 6-F 4-01, 6-F 4-Cl. 6-F 4-01, 6-F 4-01, 6-F 4-01, 6-F 4-01, 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-01, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F isopropyl t-butyl
CF
3 C0 2
CH
3
CH,
CH,
isopropyl t-butyl
OF
3
COCH
3
CH,
O
2
H,
isopropyl t-butyl
CF,
C0 2 0H 3
COCHCH,
CH,
CH,
isopropyl t-butyl.
CF,
C0 2
CH
3
OH
3 n-C 3
H,
i-C 3
H,
t-O 4
H,
CH
2 0H
CHCHOH
C(CH
3 2 0H
CONHCH,
CON(CH.).
CO
2
H,
Phenyl
CF
2
CF,
C
2 00H, Benzyl 4-chloropheflylmethyl
SOCH,
CF
3
C(CH)
2 0C00H 3
C(CH,)
2 CH,0H
C(CH
3 2
CH
2 0CH 2
C
2
H,
CONa CON HS0 2
CH,
OHFCH
3
CH
2 00 2
CH
2
CH
3
OH
3
CH,
a.
42 629 NH CH 2-3 4-Cl, E- F isopropyl J2 630 NH CH 2-3 4-Cl, 6-F: t-buiyl J2 631 NH CH 2-3 4-Cl, C- F CF 3 J2 632 N H C CH 2-3 4-Cl, 6-F C02 CH 3 J2 633 N H C H 2-3 4-Cl, 6-F CH, J3 634 NH C H 2-3 A-Cl. C 2
H
5 J3 635 NH CH 2-3 4-*Cl, 6-F isopropyl J3 636 NH CH 2-3 4-Cl, 6-F t-butyl J3 637 NH C H 2-3 4-Cl, ELF CF 3 J3 638 NH CH 2-3 4-Cl, 6-F C0 2
CH
3 J3 639 NH CH 2-3 4-Cl, 6-F CH 3 J4 640 NH CH 2-3 4-Cl, 6-F 2HSJ4 641 NH CH 2-3 4-Cl, 6-F isopropyl J4 642 NH CH 2-3 4-Cl, 6- F t-butyl J4 643 NH CH 2-3 4-Cl, 6-F- CF 3 J4 644 NH CH 2-3 4-Cl, 6-F C0 2 CH 3 J4 645 NH CH 2-3 4-Cl, 6-F CH 3 646 NH CH 2-3 4-Cl, 6-F C2 H, 647 NH CH 2-3 4-Cl, 6-F isopropyl 648 NH CH 2-3 4-Cl, 6-F t-butyl 649 NH CH 2-3 4-Cl, 6-F CF, 650 NH CH 2-3 4-Cl, 6-F. CO 2 CH, 651 'NH
CCH
3 2-3 4-Cl, 6-F CH 3 Ai 652 NH
CCH
3 2-3 4-Cl. 6-F- C 2 H, JA 653 NH
CCH
3 2-3 4-Cl, 6-F isopropyl Ai 654 NH
CCH
3 2-3 4-Cl. 6-F t-butyl JA 655 NH
CCH
3 2-3 4-Cl, E- F CF 3
JA
*656 NH CCH 3 2-3 4-Cl, 6FC0 2
H
3
J
657 NH CCHCH, 2-3 4-Cl. 6-F CH, J 30 658 NH
CCH
2
CH
3 2-3 4-Cl. 6-F CH, J .659 NH
CCH
2
CH
3 2-3 4-Cl. 6-F isopropyl
J
*660 NH CCHCH 3 2-3 4-Cl, 6-F t-butyl J 661 NH
CCH
2
CH
3 2-3 4-Cl. 6-F CF 3
JA
662 NH
CCHCH
3 2-3 4-Cl, 6-F COCH, i 35 663 NH CCH 2
CHF
2 2-3 4-Cl, 6-F CH 3
JA
66.4 NH CCH 2 CHF 2 2-3 4-Cl, ELF CAH JA 0665 NH CCH 2 cHF 2 2-3 4-Cl. 6-F isopropyl JA *666 NH
CCH
2
CHF
2 2-3 4-Cl. 6-F t-butyl J .*o667 NH CCHCHF, 2-3 4-Cl, 6-F CF 3
J
40 668 N H CCH 2 CHF 2 2-3 4-Cl, 6-F COC J 669 NH CH 2-3 4-Cl, 6-F CH 3 J2 670 NH CH 2-3 4-Cl, 6-F CH, J2 **671 NH CH 2-3 4-Cl, 6--F isopropyl J2 672 NH C2-3 4-Cl. 6-F t-butyl J2 673 NH CH 2-3 4C.6FC 3
J
674 NH CH 2-3 4-Cl. 6-F CFCH J2 675 NH CH 2-3 4-Cl, 6-FC CH 3 J2 676 NH CH 2-3 4-Cl, 6-F C 2 H, J3 677 NH CH 2-3 4-Cl. 6-F isopropyl J3 678 NH CH 2-3 4-Cl. C-F: t-butyl J3 43 679 680 681 682 683 684 685 686 687 688 689 690 691 692 693 694 695 696 697 698 699 700 701 702 703 704 705 706 707 30 708 709 710 711 712 35 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NCH,
NH
CH
CH
CH
CH
CH
CH
CH
CH
N
0
NH
NH
NH
NH
NH
NH
NCOCH,
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NCH
3
N
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
NH
NCHCH,
NCHP0 2
CH,
NCOCH,
NCH
2
CE=N
NH
NH
NH
0
CH
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NCH
3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 1-2 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 2-3 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl. 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4-Cl, 6-F 4,6-Cl 2 4.6-CI 2
CF,
*CO
2
CH,
CH
3
C
2
H
isopropyl t-butyl
CF,
C0 2
CH
3
CH,
C
2
H,
isopropyl t-butyl
CF,
C0 2
CH
3
CF,
CF
3
CF
3
CF,
CF,
CF
3
CF,
CF
3 C0 2
C
2
H,
C0 2
C
2
H
CH,
C(CH
3 2 0H
CF,
C(CH
3 3
CF,
CHC(CH
3 3 pyridin-2-yl
H
CHC1 2 NHC0 2
CH,
CH(CH
3
)NHCHCO
2
CH,
CH(CH
3
)OCOCH,
C(CH
3
)=CH
2
CH=C(CH,)
2 C H(Br)CH,
CF
3
CH=NC
6
,H,
CH
2 0CO CH 3
CH(OCH
3
)CH,
CH(OCOCH
3
)CH,
SCH
3
CAH
CF
3
CF
3 .9 .9 9 9 9* 9 .9 S44 729 NH NH 4-Cl, 6-F CF 3 Ai 730 NH N 2-3 4,6-Cl 2
CF
3 731 NH N 2-3 4-Cl, 6-F S0 2 CH, i 732 NH N 2-3 4-Br,6-F CF 3 J1 733 NH N 2-3 4-Br,6-F CH, JA 734 NH N 2-3 4-CI.6-F CH 2 0H JA 735 NH N 2-3 4-Cl,6-F C(CH 3 ),OH Ai 736 NH N 2-3 4-CI,6-F C(CH,)OCHCH, i 737 NH N 2-3 4-CI,6-F SH ii 738 NH N 2-3 4-Cl,6-F SCH(CH,)C=-N i 739 'NH N 2-3 4-CI,6-F SC 2 H, JA 740 NH N 2-3 4-CI,6-F SCHC-=CH i 741 NH N 2-3 4-CI,6-F SCH 2 CdH 5 Ai 742 NH N 2-3 4-CI,6-F SC=-N JA 743 NH N 2-3 4-CI,6-F C(CH 3
),CH
2 SC-=N JA 744 NH N 2-3 4-CI,6-F SCH(CH,)C0 2
C
2 H, JA 745 NH N 2-3 4-CI,6-F SCH(CH 3
)CON(CH
3 2 Ji 746 NH N 2-3 4-CI,6-F SCH 2 C-=CH 747 NH N 2-3 4-Cl,6-F SCH 2
CH=CH
2
JA
748 NH N 2-3 4-CI,6-F SCH 2
JA
749 NH N 2-3 4-CI,6-F SCH 2
C=-CCH
2 CI i 750 0 CH 2-3 4-Cl, 6-F CHOCONHCH, JA 751 0 CH 2-3 4-Cl. 6-F CH 2
NHCOCH
2
(CH
4
JA
2-NO 2 752 0 CH 2-3 4-Cl, 6-F C(CH 3 )(OH)CH, JA 753 0 CH 2-3 4-Cl. 6-F CH 2 NH, i 754 0 CH 2 -3 4-Cl. 6-F C(CH 3
)(OH)CH(CH
3 2 J1 755 0 C H 2-3 4=Cl, 6-F CHNHCOCH 3
JA
756 0 CH 2-3 4-Cl, 6-F CHNHSOCH 3
JA
S757 0 CH 2-3 4-Cl, 6-F C(CH 3 2 F JA 30 758 0 CH 2-3 4-Cl, 6-F CHCO 2 H JA *759 0 CH 2-3 4-Cl, 6-F CH 2
CON(CH,)
2 Ai 760 0 CH 2-3 4-Cl, 6-F CHCON(CH 3
,)(OCH
3
JA
9761 0 CH 2-3 4-Cl, 6-F CH 2
CONHCH
3
JA
762 0 CH 2-3 4-Cl, 6-F CH 2
CONH
2
JA
0: 35 763 0 C H 2-3 4-Cl, 6-F C 2
HCON(CH
3
JA
764 0 CH 2-3 4-Cl, 6-F CH 4 Co 2 CH, JA 765 0 CH 2-3 4-Cl. 6-F C 3 H,,OH Ai 766 0 CH 2-3 4-Cl, 6-F CHJCONHCH 3
JA
76 H 4C SF 767 NH N 2-3 4-Cl SCF 3
JA
768 NH N 2-3 4-Cl CF 3 J3 45 Table 3 Characterizing Data Melting Points or Physical States of Representative Compounds No. MP/State 1 OIL 16 70-72
OIL
26 OIL 28 OIL 30 OIL 38 246-9 42 >250 43 SOLID 49 OIL 96 OIL 98 >245 99 OIL 100 OIL 101 OIL 102 OIL 103 OIL 104 OIL 105 >250 106 OIL 25 107 OIL 108 >250 109 OIL 110 OIL 112 86-88 221 193.5-6 222 183-6 223 OIL 224 OIL 225 OIL 226 63-6 227 134-6 228 42-5 229 OIL 230 163-5 231 65-70 232 186-91 233 85-90 234 65-70 235 63-7 236 56-8 237 141-2 238 143-5 239 162-4 240 72-6 241 67-70 242 163-5 243 51-55 No.
246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 '262 263 264 265 266 267 268 269 270 271 272 273 274 275 276 277 278 279 280 362 363 364 365 366 367 368 369 370 371 372 373 MPIState 45-9 35-8 67-71 84-9 65-68 55-7
OIL
GLASS
71-5 134-8 145-7
OIL
232-40 165-9 55-8 65-7 75-7 >50 155-7 130-6 258-61 110-8 73-7 270-5 265-72 62-72
OIL
220-2.5 116 SOFTENS
OIL
145-53 179-82 189-92 197-8 215-6 152-8 >165
SOLID
172-7 130 150-5 87-93 125-30 130
SOLID
SOLID
160 190 No.
377 378 379 380 381 382 383 384 385 386 387 388 399 405 469 481 493 500 513 522 527 563 595 618 693 694 695 696 697 698 699 700 701 702 705 706 708 709 710 711 712 713 714 715 716 717 718 719 MP/State 122-30 200 C> 116-22 201-4 117-24 193-5 131-40 103-5 158-160 132-5 112-4 107-9 177.5-8.5 130 98-100
SOLID
187-8 208-10 178-181 78-80 152-154 165-166 >240 235-237.5 60-65 221.5-223 160-162 173-177 60-63 142-145.5 95-102 160-162 245-248 258-260 102-103 88-89 140 DEC >200 130 RESIN >200 93-98 RESIN 123-130 RESIN 160-165 RESIN 90-95 115-120 RESIN 120-125 110-116 120-125 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 No. MP/State 117-122 RESIN 107-112 RESIN 108-114 RESIN 135-140 RESIN >210 182-183 174-175 >205 >205 150-152 RESIN 195-200 >205
SOLID
118-121 RESIN 88-92 >200 133-135 130-132 178-180 118-121 RESIN 150-155
SOLID
160-162 >200 106-109 98-100 104-110 RESIN 155-158 RESIN 137-139 189-190 78-82 87-89 75-77 96-98 90-92 60-62 95-97 144-146 146-147 70-76 185-187 63-65
OIL
50-54 172-173 239-241 46 No. MP/State No. MPIState No. MP/State No. MP/State 244 OIL 375 >200 720 128-132 RESIN 245 OIL 376 142-8 721 145-150 Biological Testing The benzofused heterocyclic compounds of this invention were tested for pre- and postemergence herbicidal activity using a variety of crops and weeds.
The test plants included soybean (Glycine max var. Winchester), field corn (Zea mays var. Pioneer 3732), wheat (Triticum aestivum var. Lew), morningglory (Ipomea lacunosa or Ipomea hederacea), velvetleaf (Abutilon theophrasti), green foxtail (Setaria viridis), Johnsongrass (Sorghum halepense), blackgrass (Aloepecurus mvosuroides), common chickweed (Stellaria media), and common cocklebur (Xanthium'strumarium For preemergence testing, two disposable fiber flats (8 cm x 15 cm x 25 cm) for each rate of application of each candidate herbicide were filled to an approximate depth of 6.5 cm with steam-sterilized sandy loam soil. The soil was leveled and impressed with a template to provide five evenly spaced furrows 13 cm long and 0.5 cm deep in each flat. Seeds of soybean, wheat, corn, green foxtail, and johnsongrass were planted in the furrows of the first flat, and seeds of velvetleaf, morningglory, common chickweed, cocklebur, and blackgrass were planted in the furrows of the second flat. The five-row template was employed to firmly press the seeds into place. A topping soil of equal portions of sand and sandy loam soil was placed uniformly on top of each flat to a depth of approximately 0.5 cm. Flats for postemergence testing were prepared in the same manner 25 except that they were planted 9-14 days prior to the preemergence flats and were placed in a greenhouse and watered, thus allowing the seeds to germinate and the foliage to develop.
In both pre- and postemergence tests, a stock solution of the candidate herbicide was prepared by dissolving 0.27g of the compound in 20 mL of water/acetone (50/50) containing 0.5% v/v sorbitan monolaurate. For an application rate of 3000 g/ha of herbicide a 10 mL portion of the stock solution was diluted with water/acetone (50/50) to 45 mL. The volumes of stock solution and 47 diluent used to prepare solutions for lower application rates are shown in the following table: Application Volume of Volume of Total Volume Rate Stock Solution Acetone/Water of Spray Solution (Lgha) (mL) (mL) 3000 10 35 1000 3 42 300 1 44 100 0.3 45 45.3 30 0.1 45 45.1 0.03 45 45.03 3 0.01 45 45.01 The preemergence flats were initially subjected to a light water spray.
The four flats were placed two by two along a conveyor belt the two preemergence followed by the two postemergence flats). The conveyor belt fed under a spray nozzle mounted about ten inches above the postemergent foliage.
i The preemergent flats were elevated on the belt so that the soil surface was at the same level below the spray nozzle as the foliage canopy of the postemergent plants. The spray of herbicidal solution was commenced and once stabilized, the S 20 flats were passed under the spray at a speed to receive a coverage equivalent of 1000L/ha. At this coverage the application rates are those shown in the above table for the individual herbicidal solutions. The preemergence flats were watered immediately thereafter, placed in the greenhouse and watered regularly at the soil surface. The postemergence flats were immediately placed in the green-house 25 and not watered until 24 hours after treatment with the test solution. Thereafter they were regularly watered at ground level. After 12-17 days the plants were examined and the phytotoxicity data were recorded.
Herbicidal activity data at selected application rates are given for various compounds of this invention in Table 4 and Table 5. The test compounds 3 are identified by numbers which correspond to those in Tables 1 and 2.
Phytotoxicity data were taken as percent control. Percent control was determined by a method similar to the 0 to 100 rating system disclosed in 48 "Research Methods in Weed Science," 2nd ed., B. Truelove, Ed.; Southern Weed Science Society; Auburn University, Auburn, Alabama, 1977. The rating system is as follows: Herbicide Rating System Rating.
Percent Control Description of Main Categories Crop Description Weed Description No effect No crop reduction/injury No weed control 10 Slight effect Slight discoloration or stunting Some discoloration, stunting or stand loss Crop injury more pronounced but not lasting Very poor weed control Poor weed control Poor to deficient weed control 30 Moderate effect Moderate injury, crop usually recovers Crop injury more lasting, recovery doubtful Lasting crop injury, no recovery Deficient weed control Deficient to moderate weed control Moderate weed control Heavy injury and stand loss satisfactory Crop nearly destroyed a few survivors 80 Severe Control somewhat less than Satisfactory to weed control Very good to excellent control Complete weed destruction Only occasional live plants left 35 100 Complete effect Complete crop destruction Formulation The compounds of the present invention were tested in the laboratory as water/acetone (50/50) solutions containing 0.5% v/v sorbitan monolaurate .49 emulsifier. It is expected that all formulations normally employed in applications of herbicides would be usable with the compounds of the present invention. These include wettable powders, emulsifiable concentrates, water suspensions, flowable concentrates, and the like.
Table 4. PREEMERGENCE HERBICIDAL ACTIVITY
CONTROL)
CRN ABUTH IPOSS STM XAP ALOMY SEW~ SORHA No. SOY WHT 16 26 28 38 42 43 49 96 98 99 20 100 *101 102 103 10.4 25- 106 107 108 109 110 30 112 221 222 223 :224 35 225 226 227 228 229 230 231 232 233 234 100 100 100 100 100 100 60 0 50 95.
100 50 40 40 80 20 50 100 30 80 0 100 100 100 70 100 100 100 40 70 100 100 100 100 100 20 .40 100 85 70 100 90 100 100 50 10 40 50 90 40 50 30 70 30 50 100 40 60 0 100 50 100 60 70 50 80 20 50 80 80 70 40 80 30 30 100 90 90 100 90 95 95 80 0 80 80 95 80 60 80 100 10 80 100 70 90 10 90 70 100 85 90 80 90 30 70 90' 95 90 80 100 50 70 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 60 100 100 100 100 100 100 80 75 100 100 100 100 100 100 100 70 100 .100 100 100 100 .100 100 100 70 50 100 100 100 90 100 100 100 100 100 100 100 100 100 100 90 50 100 .90 100 100 100 100 100 100 100 100 100 100 90 80 100 95 100 100 100 100 100 100 100 100 0 30 10 20 100 70 100 20 95 100 40 100 100 100 80 100 100 100 70 90 100 100 100 100 100 20 20 100 100 90 95 100 100 90 70 20 90 60 80 50 70 100 60 40 10 100 40 100
ND
100 90 95 50 60
ND
90 95 100 100 10 20 100 90 100 80 100 90 100 95 100 100 100 100 100 30 75 50 30 60 70 100 90 100 10 30 60 100 60 50 80 100 90 100 90 100 100 100 70 90 75 100 50 50 100 100 80 100 100 100 ND 100 ND 100 ND .100 80 100 ND 100 ND 100 95 100 ND 100 80 100 80 100 90 100 ND 40 ND 60 80 100 100 100 100 100 0 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 s0 235 100 236 100 237 100 238 100 239 100 240 100 241 60 242 100 243 100 244 95 245 100 246 100 247 100 248 100 249 100 250 80 251 90 252 100 253 100 254 25 255 100 256 100 257 40 258 30 259 70 260 100 :261 100 *262 90 263 100 265 70 266 50 267 0 268 30 269 60 270 70 271 80 272 20 273 100 274 100 275 100 362 100 :363 100 *364 100 365 ND 366 10 37 100 368 100 369 100 370 100 371 100 372 100 s0 100 100 100 70 90 60 70 95 70 100 80 80 60 100 90 90 80 40 90 100 95 20 90 80 0 30 40 70 80 40 0 40 30 10 30 30 70 70 0 80 100 80 100 100 60 30 10 95 100 100 100 95 90 95 100 10.0 90 100 100 70 100 100 90 100 100 95 100 100 95 100 100 100 100 100 95 100 100 100 100 90 80 100 100 100 100 100 90 100 100 95 100 100 95 100 100 50 100 100 95 100 100 100 100 100 100 100 100 80 100 50 95 100 100 95 100 100 10 90 70 75 100 60 80 100 70 80 100 100 95 100 100 40 100 100 65 100 100 10 20 0 80 90 '100 60 40 70 20 10 10 50 100 95 80 100 100 90 100 100 90 100 100 20. 100 70 90 100 100 90 100 100 100 100 100 100 100 .100 100 100 100 80 100 100 30 100 100 0 70 20 .100 100 100 95 100 100 100 100 100 95 100 100 100 100 100 95 100 100 100 100 100 60 100 100 100 100 100 70 90 100 95 100 100
ND
95 100 100 30 100 100 0 0 100 100 100 100 100 20 20 0 0 20 100 No 100 100 100 90 100 100 100 100 100 0 100 100 100 100 100 100 100 100 100 80
ND
100 100 100 100 100 100 100 100 100 90 100 100
ND
ND
50 100
ND
20 60 55 100 90 100 95 30 70 0 50 0 100 60 100 20 100 100 100 100 100 100 100 10 100 100 100 100 100 100 80 100 80 100 100 100 50 90 ND 100 ND 100 ND 100 100 100 ND 100 70 100 70 100 100 100 85 100 95 100 80 10 60 100.
90 100 100 100 ND 100 60 100 ND 100 70 100 20 70 ND 40 ND 100 95 100 80 100 50 100 75 100 0 10 ND 80 ND 30 50 5 ND 60 70 100 65 100 80 100 70 90 90 100 95 100 80 100 100 100 100 100 80 100 60 75 0 50 90 100 95 100 100 100 90 100 100 100 80 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 0 100 100 100 100 100 100 100 100 100 100 373 374 375 376 377 378 379 380 381 382 383 399 493 500 522 595 100 30 80 50 100 90 100 80 100 60 80 95 80 95 90 10 51 100 100 100 95 100 80 100 100 100 100 100 100 100 100 100 100 100 100 100 70 100 60 100 95 100 100 100 100 100 100 60 50 100 80 80 100 100 100 100 80 100 60 70 70 70 100 50 20 70 100 40 100o6 80 100 100 100 100 100 80 100 80 100 90 100 90 100 90 80 60 100 75 100 75 100 75 100 ND 0 Rate of Application is 0.3 Kg/Ha. SOY is soybean; WHT is wheat; CRN is corn; ABUTH is velvetleaf: IPOSS is morningglory; STEME is chickweed: XANPE is cocklebur; ALOMY is blackgrass, SETVI is green foxtail; SORHA is johnsongrass Table 5. POSTEMERGENCE HERBICIDAL ACTIVITY
CONTROL)
20 No. SOY WHT CRN ABUTH IPOSS STEME XANPE ALOMY SETVI SORHA
S
1 95 65 80 16 95 60 80 100 80 90 25 26 96 60 80 28 100 80 80 95 80 90 38 70 35 60 42 65 30 60 43 80 30 70 49 95 70 80 96 100 90 90 98 40 10 50 99 80 40 80 100 85 40 60 101 95 50 80 102 80 30 75 103 90 50 80 104 100 100 100 106 80 30 75 107 95 40 100 108 50 20 60 100 100 100 100 100 100 100 100 100 100 100 100 100 100 90 60 100 100 100 100 100 100 60 20 100 100 90 100 100 100 100 100 100 80 100 100 100 100 100 100 20 60 90 70 100 80 100 100 0 70 40 100 5 95 50 100 0 100 95 100 100 90 100 45 50 50 30 100 20 70 50 80 10 80 80 100 100 100 100 40 100 50 100 *100 40 70 30 65 90 100 100 100 100 70 100 100 100 100 -52 109 90 90 80 110 80 40 50 112 100 100 100 221 95 50. 60 222 100 70 90 223 95 40 90 224 95 70 100 225 60 30 60 226 70 40 80 227 95 60. 90 228 90 50 80 229 95 60 80 230 95 40 80 231 100 70 100 232 75 50 30 233 90 30 60 234 100 100 100 235 100 100 100 236 100 75 90 237 100 95 100 238 80 30 70 239 95 60 80 240 95 95 100 241 90 60 70 242 .100 100 100 243 95 70 95 ::244 95 60 90 *245 85 40 75 246 95 100 100 30 247 95 80 100 248 80 50 95 249 95 80 100 250 95 50 80 251 95 70 90 35 252 95 90 100 253 95 100 100 254 95 40 80 255 100 100 100 256 100 80 90 257 70 20 70 258 80 30 60 259 80 35 75 *.260 90 80 70 21 95 80 100 262 95 60 80 263 95 80 90 264 50 20 50 265 70 40 60 266 60 40 60 267 50 15 50 268 70 40 60 269 90. 40 70 100 100 100 100 100 100 100 100 100 100 100 100.
100 100 100 75 100 95 100 100 100 100 100 100 100 100 100 100 100 80 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 70 100 100 100 100 100 60 80 70 100 90 100 100 100 100 100 100 100 100 40 40 100 100 50 60 80 40 50 90 100 80 100 100 100 100 100
ND
80 100 80 100 90 100 20 30 100 100 100
ND
ND
100 100 85 100 100 100 60 100 100 100 100 80 100 100 100
ND
100 100 30 5 30
ND
100 95 100 0 30 10 10 20 80 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100* 100 100 100 100 100 100 100
ND
-53 270 70 40 50 271 80 40 60 272 50 30 45 273 95 60. 95 274 95 60 95 275 100 70 90 362 100 100 100 363 100 100 100 364 95 40 80 365 100 40 70 366 70 30 80 367 100 100 100 368 100 100 100 369 100 80 100 370 100 95 100 371 95 100 100 372 100 100 100 373 100 80 100 374 80 25 30 375 95 40 90 376 90 50 95 377 95 80 100 378 90 40 90 379 95 80 100 25 380 95 30 95 :381 95 40 95 382- 80 40 100 :383 95 40 95 ***399 95 30 70 S 30 493 95 60 90 *500 95 65 95 522 90 45 90 595 50 10 60 100 60 100 100 100 60 100 100 100 100 100 100 100 100 100 100 100 100 100 100 95 80 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 95 100* 95 100 100 100 100 100 90 100 100 100 100 100 100 100 100 100 95 100 100 100 100 100 100 100 100 30 40
ND
ND
50 100 100 100
ND
100 100
ND
100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 20 50
ND
20 80 90 95 100 100
ND
70 30 100 100 100 100
ND
100 100 25 90 90 100 80 70 70 100 80 60 50 65 80 50 10 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 100 Rate of Application is 0.3 Kg/Na. SOY is soybean; WHT is wheat: CRN is corn; ABUTl- is velvetteaf: IPOSS is 3 5 momningglory; STEME is chickweed; XANPE is cocklebur; ALOMY is blackgrass, SETVI is green foxtail; SORHA is johnsongrass Herbicidal compositions are prepared by combining herbicidally :0 effective amounts of the active compounds with adjuvants and carriers normally :employed in the art for facilitating the dispersion of active ingredients for the particular utility desired, r ecognizing the fact that the formulation and mode of application of a toxicant may affect the activity of the material in a given application. Thus, for agricultural use the present herbicidal compounds may be formulated as granules of relatively large particle size, as water-soluble or water-dispersible granules, as powdery dusts, as wettable powders, as emulsifiable concentrates, as solutions, or S54 as any of several other known types of formulations, depending on the desired mode of application. It is to be understood that the amounts specified in this specification are intended to be- approximate only, as if the word "about" were placed in front of the amounts specified.
These herbicidal compositions may be applied either as waterdiluted sprays, or dusts, or granules to the areas in which suppression of vegetation is desired. These formulations may contain as little as 0.2% or 0.5% to as much as 95% or more by weight of active ingredient.
Dusts are free flowing admixtures of the active ingredient with finely l0 divided solids such as talc, natural clays, kieselguhr, flours such as walnut shell and cottonseed flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant; these finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein is one containing 1.0 part or less of the herbicidal compound and 99.0 parts of talc.
Wettable powders, also useful formulations for both pre- and postemergence herbicides, are in the form of finely divided particles which disperse readily in water or other dispersant. The wettable powder is ultimately applied to the soil either as a dry dust or as an emulsion in water or other liquid. Typical carriers for wettable powders include Fuller's earth, kaolin clays, silicas, and other highly 20 absorbent, readily wet inorganic diluents. Wettable powders normally are prepared to contain about 5-80% of active ingredient, depending on the absorbency of the carrier, and usually also contain a small amount of a wetting, dispersing or emulsifying agent to facilitate dispersion. For example, a useful wettable powder formulation contains 80.0 parts of the herbicidal compound, 17.9 parts of Palmetto 25 clay, and 1.0 part of sodium lignosulfonate and 0.3 part of sulfonated aliphatic polyester as wetting agents. Additional wetting agent and/or oil will frequently be added to the tank mix for post-emergence application to facilitate dispersion on the foliage and absorption by the plant.
Other useful formulations for herbicidal applications are emulsifiable concentrates (ECs) which are homogeneous liquid compositions dispersible in water or other dispersant, and may consist entirely of the herbicidal compound and a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy 55 aromatic naphthas, isphorone, or other non-volatile organic solvents. For herbicidal application these concentrates are dispersed in water or other liquid carrier and normally applied as a spray to the area to be treated. The percentage by weight of the essential active ingredient may vary according to the manner in which the composition is to be applied, but in general comprises 0.5 to 95% of active ingredient by weight of the herbicidal composition.
Flowable formulations are similar to ECs except that the active ingredient is suspended in a liquid carrier, generally water. Flowables, like ECs, may include a small amount of a surfactant, and will typically contain active ingredients in the range of 0.5 to 95%, frequently from 10 to 50%, by weight of the composition.
For application, flowables may be diluted in water or other liquid vehicle, and are normally applied as a spray to the area to be treated.
Typical wetting, dispersing or emulsifying agents used in agricultural formulations include, but are not limited.to, the alkyl and alkylaryl sulfonates and sulfates and their sodium salts; alkylaryl polyether alcohols; sulfated higher alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition product of long-chain mercaptans and ethylene oxide.
Many other types of useful surface-active agents are available in commerce.
Surface-active agents, when used, normally comprise 1 to 15% by weight of the composition.
Other useful formulations include suspensions of the active ingredient in a relatively non-volatile solvent. such as water, corn oil, kerosene, propylene glycol, or other suitable solvents.
Still other useful formulations for herbicidal applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the toxicant is carried on relative coarse particles, are of particular utility for aerial distribution or for penetration of cover crop canopy. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low boiling dispersant solvent carrier, such as the Freon fluorinated hydrocarbons, may 56 also be used. Water-soluble or water-dispersible granules are free-flowing, nondusty, and readily water-soluble or water-miscible. The soluble or dispersible granular formulations described in US 3,920,442 are useful herein with the present herbicidal compounds. In use by the farmer on the field, the granular formulations, emulsifiable concentrates, flowable concentrates, solutions, etc., may be diluted with water to give a concentration of active ingredient in the range of say 0.1% or 0.2% to 1.5% or 2%.
The active herbicidal compounds of this invention may be formulated and/or applied with insecticides, fungicides, nematicides, plant growth regulators, fertilizers, or other agricultural chemicals and may be used as effective soil sterilants as well as selective herbicides in agriculture. In applying an active compound of this invention, whether formulated alone or with other agricultural chemicals, an effective amount and concentration of the active compound is of course employed; the amount may be as low as, e.g. about 1 to 250 g/ha, preferably about 4 to 30 g/ha. For field use, where there are losses of herbicide, higher application rates four times the rates mentioned above) may be employed.
The active herbicidal compounds of the present invention may also be used in combination with other herbicides. Such herbicides include, for example: N-(phosphonomethyl) glycine ("glyphosate"); aryloxyalkanoic acids such as (2,4o" dichlorophenoxy)acetic acid (4-chloro-2-methylphenoxy)acetic acid (+/-)-2-(4-chloro-2-methylphenoxy)propanoic acid (MCPP); ureas such as N,N-dimethyl-N'-[4-(1-methylethyl)phenyl]urea ("isoproturon"); imidazolinones such a s 2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-3pyridinecarboxylic acid ("imazapyr"), a reaction product comprising dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1H-imidazol-2-yl]-4-methylbenzoic acid and (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1 methylbenzoic acid ("imazamethabenz"), (+/-)-2-[4,5-dihydro4-methyl-4-(1methylethyl)-5-oxo-1H-imidazol-2-yl]-5-ethyl-3-pyridinecarboxylic acid ("imazethapyr"), and (+/-)-2-[4,5-dihydro-4-methyl-4-(1-methylethyl)-5-oxo-1
H-
imidazol-2-yl]-3-quinolinecarboxylic acid ("imazaquin"); diphenyl ethers such as 5-[2chloro-4-(trifluoromethyl)phenoxy]-2-nitrobenzoic acid ("acifluorfen"), methyl 5-(2,4dichlorophenoxy)-2-nitrobenzoate ("bifenox"), and 5-[2-chloro-4-(trifluoro- 57 methyl)phen oxy]-N-(methylsufonyI-2n itrobe nza mid e ("fomasafen"); hydroxybenzonitriles such as 4-hydroxy-3,5-diodobeflzonitrile ("ioxynil') and 3, 5-dibromo-4hydroxybenzonitlle ("bromoxylil"); sulfonylureas such as 2-[l[[(4chloro-6-nmethoxy-2pyrimidinyl)aminolcarbonyllaminolsulfonyllbenzoic acid ("chlorimuron"), 2-chloro-N- [[(4-methoxy-6-mfethyl, 3 ,5-triazin-2-y)amino]carboflYIbenzenesulfonamide pyimdinyl)aminolcarbonylamnolsulfonyllmethylbenzoic acid ("bensulfuron"), 2imethoxy-2-pynimid ifyl)amin oca rb onyflam in no]su lfonyfl-l -m ethyl-i1 H-pyrazol- 4-carboxylic acid ("pyrazosulfuron"), 3-[[[[(4-methoxy-6-methyl- 3, 5-triazin-2io yl)aminolcarbonyl]amifl1ulfofylYI2thiophenecarboxylic acid ("thifensulfuron"), and 2 2 -chloroethoxy)N[(4methoxy-6methyl 2 yl) am ino]carboflyl]beflze nesulfona mid e ("triasulfuron'); 2-(4-aryloxyphefloxy)alkanoic acis schas +/)-2[4-(6chio2-bxazolal) oyIIpheloxAlpropanoic acid ("fenoxaprop"), ooehl--yiinyiloxylpherioxylp ropanoic acid is:~1 ("flu azifop"), (/)24(6clr--unxlnioypexyracid( acid ("quizaloTop"), and (+-7--24dclrpeoypeoypoaocai "iclofop"); benzothiadiaziflofesS uch as 3-(1 -methylethyl)-1 H-2,1 ,3-benzothiadiazifl-4(3H)-ofle 2,2-dioxide ("bentazone");, 2-chloroacetanilideS such as N-butoxymethyl)-2-chloro- 2',6'-diethylacetaflhlide ("butachlor"); 2-hooN(-ty--ehlhnl--2 :20 methoxy-1 -methylethyl)acetamlide ("metachbor"), 2-chloro-N-(ethoxymethyl)-N-( 2 ethyl-6-methylpheflyl)acetamide ("acetochior"), and 2-chIo ro-N -(ethoxym ethyl) N-(2-methoxy-1 -methylethyl)acetamide ("dimethenamide"); arenecarboxylic acids such as 3,6-dichloro-2-methoxybenzoic acid ("dicamba"); and pyridyloxyacetic acids such as [(4-amino-3,5-ihoo6fur--prdnioyaei acid ("fluroxypyr").
25 It is apparent that various modifications may be made in the *.:formulations and application of the compounds of the present invention without departing from the inventive concepts herein, as defined in the claims.

Claims (4)

1. A compound having the formula Y Z X(n) where X is selected from hydrogen, F, Cl, Br, alkyl, haloalkyl, ON, NO 2 and NH-
2 Y is selected from NO 2 NH 2 or -NHN=C(CH
3 )R; Z is selected from hydrogen, F, NH 2 OH; with the proviso that when Y is NHN=C(CH 3 Z is hydrogen; n is 0-3; R is hydrogen, hydroxy, straight or branched chain lower alkyl, cycloalkyl, alkoxy, aryl, heteroaryl, alkenyl, haloalkyl, hydroxyalkyl, haloaryl, alkoxyaryl, arylalkyl, ::aryloxyalkyl, haloarylalkyl, alkylthio, heterocyclyl, alkoxyalkyl, alkoxylalkyloxyalkyl, alkylcarbonyloxyalkyl, arylcarbonyloxyalkyl, aminocarbonyloxyalkyl, aminoalkyl, cyanoalkyl, aminoalkenyl, carboxy, carboxyalkyl, alkylcarboxy, alkylcarboxyalkyl, *formyl, aminocarbonyl, amino, oxygen, cyano, nitro, alkylsulfonyl, alkylcarboxyoxyalkyl, alkylcarboxylalkoxy, alkoxycarbonylamino, *Po alkoxycarbonylalkylaminoalkyl, aryliminoalkyl, (aryl)(alkoxy)alkyl, (aryl)(alkylcarbonyloxy)alkyl, arylalkoxyalkyl, cyanoalkylthio, alkynlalkylthio, .arylalkylthio, cyanothio, cyanothioalkyl, alkoxycarbonylalkylthio, aminocarbonylalkylthio, alkenylalkylthio, haloalkylalkynylalkylthio, aminocarbonyloxyalkyl, arylalkylcarbonylaminoalkyl, (hydroxy)(aryl)alkyl, alkylcarbonylaminoalkyl, alkylsulfonylaminoalkyl, aminocarbonylalkyl, alkoxycarbonyl, and alkenyloxy, where the amino group may be substituted with one or two substituents independently selected from alkyl, hydroxy, alkoxy, carboxy, aryl, or alkylsulfonyl; J is selected from S 5005 S. 0 0 OSOe OS OS S ec 0 I SS S. 55 S S S 4 0000 S and R 3 is selected from hydrogen, alkyl, haloalkyl, CH 2 CN, CH 2 CH=CH 2 CH 2 C =CH, CH 2 CO 2 (alkyl), CH 2 00H 3 and NH 2 DATED this 201h day of April, 2001 FMVC CORPORATION WATERMARK PATENT TRADEMARK ATTORNEYS
4 TH FLOOR 'DURACK CENTRE" 263 ADELAIDE TERRACE PERTH WA 6000 S. S **SS S 05 0e
AU38950/01A 1997-02-26 2001-04-27 Cycloimido-substituted benzofused heterocyclic herbicides Abandoned AU3895001A (en)

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