Note: Descriptions are shown in the official language in which they were submitted.
HER3ICIDAL ~-PHENYL-4-PIPERIDINONES
- AND -DIHYDROPYRIDINONES
This invention belongs to the field of agricultural
chemistry, and provides to the art new herbicides and herbi-
cidal methods.
It has long been established that herbicides are
necessary to the most economical and productive use of the
land. Herbicides are in demand for use in killing and con-
trolling weeds growing in cropland, and also for killing and
controlling unwanted vegetation of all kinds, such as in
fallow land and on industrial property~
Despite the great amount of research effort which
has been expended in agricultural chemistry, herbicides
closely related to the compounds of formula (I), (II) or
(III) have not been previously discovered. The polyhalo-
pyridinones, which have two or more chlorin~ atoms as well
as other alkyl and halo substituents on the pyridine rings,
are known herbicides, but are obviously ~uite distant from
the present novel compounds.
Organic chemists have explored the piperidinones
and dihydropyridinones to a degree. For example, Leonard et
al., J. Am. Chem. Soc. 79, 156-60 (1957), disclosed 3,5-
di(substituted-benzyl and benzylidene)-4-piperidinones,
which are not herbicides.
Settimj et al. have worked with piperidinones, and
have disclosed the unsubstituted 3,5-diphenyl-1-methyl-
4-piperidinone. Gazz. Chim. Ital. 96, 604-11 (1966), C.A. -
65, 8913g (1966); Gazz. Chim. Ital. 96, 311-24 (1966), C.A. - -
67, 64261b (1967); Gazz. Chim. Ital. 100, 703-25 (1970),
C.A. 74, 41752t (1971).
_
X-4427A -2-
3 ~ `
A series of l-substituted ~-phenyl-4-piperidinones
and -dihydropyridinones are herbicides active against a wide ~-
range of weeds. Many of the compounds are new and are here
disclosed for the first time. Herbicidal methods making use ~.
of the compounds, which are particularly useful in cotton
culture, are also disclosed. -
The novel compounds are of one of the general
formulae
:;:
R2
\ ~ / \ R~
\ / ,
R ' '~f,''` ,"
.' ..
(I) (II) ~,~ .
wherein R i; methyl or ethyl;
R is ~
hydrogen, .
phenoxy,
:
phenylthio, ~.-
Cl-C4 alkoxy, :~.
Cl-C4 alkylthio, ~.
Cl-C4 alkyl, :
phenyl or
phenyl monosubstituted with chloro or fluoro;
R2 is bromo, fluoro or trifluoromethyl;
R3 is Cl-C3 alkyl, C2-C3 alkenyl or propargyl;
X-4427A -3-
~88543
R4 is `~
hydrogen,
phenoxy,
phenylthio, ~`~
Cl-C4 alkyl, ~ ~:
Cl-C4 alkoxy,
Cl-C4 alkylthio,
phenyl or ;.
phenyl monosubstituted with - -
chloro, -~
bromo,
fluoro, . ~-
trifluoromethyl, :
Cl-C3 alkyl or ~'
Cl-C3 alkoxy;
chloro, ~ ;
bromo,
fluoro,
trifluoromethyl, .
Cl-C3 alkyl or .
Cl-C3 alkoxy;
either X and Xl combine to form a carbon-carbon bond and x2
and X3 are hydrogen atoms, or X and Xl are hydrogen atoms
and x2 and X3 combine to form a carbon-carbon bond.
: The novel compounds of formulae (I) and (II) are
prepared by reducing a compound of one of the general
formulae ~`
X-4427A -4-
'
3543 - ~:
;; A
R2 ~ x,,
~ \f \~R~ 15~.~ f~b
, .,~, .
i .~.. ~,.
.. . ~ . ...
(IV) (V) ~.
wherein the various symbols are defined as before with an
10 aluminium or boron hydride.
The herbicidal method for controlling noxious
vegetation comprises applying to an area containing said
noxious vegetation a compound of the general formula .
Re~ _ '
R ~.
wherein R6 is C}-C3 alkyl, C2-C3 alkenyl or propargyl; -~
:~ R is
hydrogen,
~: -.,, ?
phenoxy,
phenylthio, ..
Cl-C4 alkyl,
~........................................................................ . ..
Cl-C4 aIkoxy~
: Cl-C4 alkylthio,
phe-nyl or
X-4427A -5-
,. , . , ,, . _ .
10885~3 "
phenyl monosubstituted with
chloro,
bromo,
fluoro, `
trifluoromethyl, -
Cl-C3 alkyl or ~`.
Cl-C3 alkoxy;
R8 i5 ,.
chloro, -~
bromo,
fluoro, `~ .
trifluoromethyl, .. .
Cl-C3 alkyl or
Cl-C3 alkoxy; - :
. ~; .-. :
each of X4 and X5 is hydrogen, or X4 and ~ : .
XS combine to form a carbon-carbon bond;
each of x6 and X7 ls hydrogen, or x6 and ~ .
X7 comblne to form a carbon-carbon bonds
provlded that no more than one of ~X4 and
20 X5) and (X6 and X7) form a bond. ~- -
. In the above five formulae, the general
chemlcal terms are u~ed ln thelr usual mean~ngs ln the : s
organic chemical art~ For example, the terms Cl-C3 ..
Ii . I j ~ ~, . . alkoxy, Cl-C3 alkyl, Cl-C4 alkyl, Cl-C4 alkoxy~ Cl-C
alkylthio~and C2-C3 alkenyl refer to such groups as :-~
. methoxy, ethoxy, isopropoxy, methylthio, ethylthio,
propylthio, methyl, ethyl, propyl,
-6-
.
,~, ~ ... .. . .. . .. . . . . . . . . .
1~88$43
vinyl, allyl, l-propenyl, butyl, t-butyl, isobutyl, butoxy
and isobutylthio. ;-
Agricultural chemists will immediately under~tand ~-~
that the addition of commonly-used ~ubstituents to the -~
compounds of formula (I), (II) or (III) is e~pected to
produce active compounds equivalent to those explicitly
described herein. For example, such substituents as halogen `-
atoms, Cl-C3 alkoxy, alkylthio and alkyl groups, and tri-
fluoromethyl groups, as well as functional groups ~uch a~
hydroxy, alkoxycarbonyl and cyano groups, may be added to
the compound~. In particular, the phenoxy and phenylthio `
Rl, R4 and R7 groups may be ~ub~tituted with such group~
particularly with halogen atom~, methyl and methoxy group~ ~
and trifluoromethyl groups, with the expectation of pro- . -
ducing piperidinones and dihydropyridinones equivalent to
the other compounds described herein.
It will al~o be understood that acid addition ~ -
~alt~ of the compound~ of formulae ~I), tII) and (III) may
be made and u~ed for the control of weed~. For example,
20 ~uch salts as hydrochlorides, hydrobromides, hydrofluorides,
sulfate~, nitrate~, toluenesulfonates, methanesulfonatés,
trifluoromethanesulfonates and the like are often used in
agricultural chemistry. Salts of the compound~ of formulae
(I), (II) and (III) are made in the usual manner by simple
contact of the compound with the acid in a solvent ~uch a~ -
an aqueous alçohol.
`~ It will be understood that the present invention *
may be practiced in various ways, making use of different
~ .
:~ X-4427A _j_
~ `~ ' ' .
i~8~3
cla~ses of compounds of formula (I), (II) or (III). In
such manners of practicing the invention, variou~ classes of
compound~ may be u~ed in carrying out the herbicidal methods,
and making use of the herbicidal composition~, of thi~
invention. For example, the following cla~ses of compounds
are contemplated, as new compositions in the case of com-
pounds of formulae (I) and ~ , and for use in herbicidal
method~ and compositions in all cases.
l) Compounds of formula (I); .
2) compounds of formula (II);
compound~ of formula (I) wherein:
8) Rl iQ hydrogen, alkyl, phenyl or substituted
phenyl;
4) Rl is hydrogen, phenoxy, phenylthio, phenyl
or sub~tituted phenyl;
5) Rl is phenoxy, phenylthio, phenyl or sub-
stituted phenyl;
6) Rl i~ hydrogen, alkyl, alkoxy or alkylthio;
7) Rl i~ alkyl, alkoxy or alkylthio;
8) Rl is hydrogen, alkoxy, alkylthio, alkyl,
phenyl or sub~tituted phenyl;
compounds of formula (II) wherein: ~.
9) R is alkyl or alkenyl;
10) R3 is alkyl;
ll) R3 is alkenyl or propargyl;
12) R4 i~ slkyl, phenyl or ~ub~tituted phènyl;
13) R4 i8 hydrogen, phenoxy, phenylthio, phenyl ~:
or sub~tituted phenyl;
- -
X-4427A -8-
.
~ 35~3
14) R4 is phenoxy, phenylthio, phenyl or sub~
stituted phenyl;
15) R4 is hydrogen, alkyl, alkoxy or alkylthio;
16) R4 is alkyl, alkoxy or alkylthio;
17) R4 is hydrogen, alkyl, phenyl or phenyl ~;~
mono~ub~tituted with chloro, bromo, fluoro, ; :-
trifluoromethyl, methyl or methoxy;
18) RS is chloro, bromo, fluoro, trifluoromethyl, ~ :
methyl or methoxy;
19) the compounds as de~cribed by subparagraphs 9
and 12; ~ .
20) the compounds as described by ~ubparagraphs 9
and 13; -,~
.. I ~,
21) the compounds as described by ~ubparagraph~ 9 ...
and 14; ~~'
22) the compounds as described by subparagrapho 9
and 15; i .
23) the compound~ a~ de~cribed by subparagraph~ 9
and 16;
24) the compounds as described by subparagraphs 9
. and 17; .
25) the compounds a~ described by ~ubparagraph~
10 and 12; .:
: : :
~ 26) the compounds as described by subparagraphs
:: . 10 and 13; -.
27) the compounds aJ de~cribed by subparagr~phs
` ~ ` 10 and 14;
28) the compound~ as de-cribed by Jubparagraphs
. - . 10 and lS;
~:` ` X-4427A -9- :
,~
- '
1088~;43
29) the compounds as described by subparagraphs
10 and 16;
30) the compounds as described by subparagraphs
10 and 17;
31) the compounds as described by subparagraphs
11 and 12
32) the compounds as de~cribed by subparagraphs .
11 and 13;
33) the compounds as described by ~ubparagraph~
11 and 14; - .-
34) the compound6 a~ described by subparagraph~ ;
11 and 15;
35) the compounds a~ described by subparagraphs
11 and 16;
36) the compounds as de~cribed by subparagraphJ
11 and 17; . :~ -
37) the compounds as described by subparagraphs ~ ;
9, 12 and 18; :
38) the compounds as described by subparagraphs
9, 13 and 18; ~'
39) the compounds as described by ~ubparagraphs ~:~
9, 14 and 18;
40) the compounds as described by ~ubparagraph~ .
9, 15 and 18;
41) the compounds as described by subparagraphs --:`
9, 16 and 18; -
42) the compounds a~ described by subparagraphs
-~
~ 1 9, 17 and 18;
- :
, ~ . .
~ ~ X-4427A -10-
~: `
~ - -
.
~,
~88S43
43) the compounds a~ de~cribed by subparagraph~
10, 12 and 18;
- 44) the compounds a~ described by subparagraphs
10, 13 and 18;
45) the compounds as described by subparagraphs
10, 14 and 18;
46) the compounds as de~cribed by ~ubparagraphs
10, 15 and 18;
47) the compounds as described by subparagraphs < ~
10, 16 and 18; ~'
48) the compounds a~ described by subparagraphs
10, 17 and 18; ~:
49) the compounds as described by subparagraphs
11, 12 and 18; ~ .
50) the compounds as described by subparagraphs
11, 13 and 18;
.~
51) the compounds as described by ~ubparagraphs
11, 14 and 18;
52) the compounds as described by subparagraphs
11, 15 and 18;
53) the compound~ as desaribed by subparagraphs : .
11, 16 and 18;
54) the compounds as described by subparagraph~
11, 17 and 18;
h bicidal compositions u~ing compound~ of formula ~III)
wherein:
. 55) X4, X5, x6 and X7 all are hydrogen atoms;
56) one of (X4 and X5) and.(X6 and X7) forms a
: bond;
. ~ .
,
X-4427A
.; ~
.: . :
~ ' :
. , .
1~88543
57) R6 iq alkyl or alkenyl; ;`
58) R6 i~ alkenyl or propargyl;
59) R6 i8 alkyl:
60) R7 is hydrogen, alkyl, phenyl or substituted
phenyl;
61) R7 i~ hydrogen, alkyl, phenyl or phenyl
monosubstituted with chloro, bromo, fluoro,
trifluoromethyl, methyl or methoxy; .
62) R7 is hydrogen, phenoxy, phenylthio, phenyl
or substituted phenyl;
63) R7 is phenoxy, phenylthio, phenyl or sub-
stituted phenyl;
64) R7 i8 hydrogen, alkyl, alkoxy or alkylthio;
65) R7 i# alkyl, alkoxy or alkylthio; ~ :
66) R7 is alkyl, phenyl or phenyl substituted s
with chloro or fluoroi :
67) R8 i~ chloro, bromo, fluoro, trifluoromethyl,
methyl or methoxy; ~. `
68) the compound~ as described by subparagraphs r
55 and 57; ` :--
69) the compounds as describea by subparagraph~
55 and 58;
70) the compound~ as described by ~ubparagraph~
55 and 59; :
71) the compounds as described by subparagraphs ~.
56 and 57;
72) the compounds as described by subparaqraphs
.
` 56 and 58;
~ 73) the compounds as described by subparagraphs
: ~ 56 and 59;
X-4427A -12-
'
, ,
lG885~3
74) the compound.~ a~ described by ~ubparagraphs ~ e
55 and 67;
. ,
75) the compounds as described by subparagraphs
56 and 67;
76) the compounds as described by subparagraphs :- -
55 and 60~
77) the compounds as described by ~ubparagraphs
55 and 61; ,~ :.,
,, ~ .
78) the compounds as deJcribed by ~ubparagraphs .-~
55 and 62;
79) the compounds as described by 6ubparagraphJ
55 and 63;
80) the compound~ a~ described by ~ubparagraphs -~-
55 and 64;
81) the compound~ a~ de~crlbed by subparagraphs '~
55 and 65; ~ ~! S,i~.`
'.
82) the compound~ a~ described by ~ubparagraph-
55 and 665 ,~
83) the compound~ as de~cribed by ~ubparagraph~
56 and 60;
84) the compound~ as described by subparagraphs
~:: . 56 and 61; .:.
85) the compounds as described by ~ubparagraphs
56 and 62;
: ~ ,
~ 86) the co~pounds as described by ~ubparagraph~ ;
~ -
56 and 63; . . `.
. 87) the compounds a~ described by ~ubparagraphJ
56-a-nd. 64
X-4427A~ -13
lG13~5~3
88) the c~mpound~ a~ de~cribed by 6ubparagraphs
56 and 65:
89) the compound~ as described by subparagraph~
56 and 66;
90) the compounds as described by ~ubparagraphs
57 and 60; '
91) the compounds as described by subparagraphs
57 and 61; ~ -
9Z) the compound~ as described by subparagraphs ~ :
57 and 62; :.
93) the compounds as described by 8ubparagraphs
57 and 63; .
94) the compounds as described by subparagraphs
57 and 64; -~
95) the compounds as described by subparagraphs
57 and 65; .
96) the compounds as described by subparagraphs :'
57 and 66; `~
97) th~ compounds as described by subparagraphs
20. 58 and 60; .
98) the compounds a~ described by subparagraph~
58 and 61; -
.,.
99) the compound~ as de~cribed by subparagraphs ~ :~
58 and 62:
100) the compounds a~ described by subparagraphs
58 and 63;
.101) the co~pound~ as described by ~ubparagraphs
: 58 and 64; ~.
~: .
.~
X-4427A -14-
' .
.
..
~, .
~ 088S~13
102) the compound~ a~ deJcribed by subparagraphs
58 and 65; -
103) the compounds as described by subparagraph~ ;
58 and 66;
104) the compounds a~ described by ~ubparagraphs
59 and 60; ~ :
105) the compounds as de wribed by ~ubparagraphs
59 and 61;
106) the compounds as described by subparagraphs
59 and 62: ~ ;
107) the compounds as described by subparagraph~ ~ -
59 and 63; ~.
108) the compounds as de~cribed by ~ubparagraph~
59 and 64;
109) the compound~ a~ de~cribed by ~ubparagraphs
: 59 and 65; .
110) the compound~ as described by subparagraph~
59 and 66;
111) the ¢ompound~ as de~cribed by ~ubparagraphs
57 and 67;
112) the compound~ a~ described by ~ubparagrapb~
58 and 67;
113) the compound~ a~ described by ~ubparagraphs
~- 59 and 67;
114) the compound~ as de~cribed by ~ubparagraphs ~;-
60 and 67J :
- 115) the compounds as described by ~ubparagraph~
, . - .
:~ ~ ! - 61 and 67;
~ ~ ~ X-4427A . -15- :
. . . .
,
~, -
:
,
~', '
"_ ,
...... ,. .. ,,,,, , . .. ,.. ~, . ,.,., , . - , , , . . .-,,, ., ,. . . ,..... ,; , ,-, - -
3 ~ ~
116) the compounds as described by ~ubparagraphs -
62 and 67; ;
117) the compounds as described by subparagraphs . :~
63 and 67; ~r'
118) the compounds as de~cribed by subparagraphs
64 and 67; ~`
119) the compounds as described by subparagraphs
65 and 67;
120) the compounds as described by subparagraph~
66 and 67;
121) the compounds as described by subparagraphs
55, S7 and 60;
122) the compounds a~ described by ~ubparagraphs
SS, 57 and 61;
123) the compounds as described by 3ubparagraphs
55, 57 and 62;
124) the compounds as described by 3ubparagraphs
5S, 57 and 63;
125) the compounds as described by subparagraphs - :~
55, 57 and 64; . :
126) the compounds as described by subparagraphs
55, 57 and 65;
127) the compounds as described by ~ubparagraph~
55, 57 and 66;
128) the compounds as described by subparagraph~
55, 58 and 60;
129) the compounds a~ described by subparagraphs
- . . - .
55, 58 and 61; , .
: . -
: X-4427A -16-
1~85~3
130) the compounds a~ descrLbed by ~ubparagraphs
55, 58 and 62;
131) the compounds as described by subparagraph~
55, 58 and 63;
132) the compounds as described by subparagraphs
55, 58 and 64;
133) the compounds as described by ~ubparagraphs
55, 58 and 65;
134) the compounds as described by subparagraphs .
55, 58 and 66;
135) the compounds as described by subparagraphs
55, 59 and 60; -
136) the compounds as described by ~ubparagraphs
SS, 59 and 61;
137) the compounds as described by subparagraphs
55, 59 and 62; ~ ~
138) the compounds as described by ~ubparagraphs ~ -
SS, S9 and 63;
139) the compounds as described by ~ubparagraphs
55, 59 and 64; ~ . . .:
140) the compounds as described by subparagraphs
55, 59 and 65;
141) the compounds as described by ~ubparagraphs
55, 59 and 66;
142) the compounds as described by subparagraphs ~`:
56, S7 and 60; :
143) the compounds as described by ~ubparagraphs
56, 57 and 61:
~ '
~:~ X-4427A -17-
: ' ~
~ ' .
.
~ .
1~885~3
144) the compound~ as described by aubpara~raphs
56, 57 and 62; - .
145) the compounds as described by subparagraphs -~.
56, 57 and 63;
146) the compounds as described by 6ubparagraph~
56, 57 and 64; ~
147) the compounds a~ described by ~ubparagraphs : ~.
56, 57 and 65;
148) the compounds as de~cribed by ~ubparagraphs
56, 57 and 66; . :
149) the compounds as described by subparagraph~ - :
56, 58 and 60; . ~;
150) the compound~ aQ de~cribed by ~ubparagraphs
56, 58 and 61; . ;~
. .
151) the compounds as de~cribed by subparagraphs
56, 58 and 62; .
152) the compounds as described by ~ubparagraph~ -.
56, 58 and 63; `
153) the compounds as described by subparagraph~
56, 58 and 64;
154) thé compounds as described by ~ubparagraphs ~ - -
.,
S6, 58 and 65; ~ '
155) the compound~ as described by ~ubparagraph~
;;. .
56, 58 and 66;
156) the compounds as described by aubparagrapha ~;
56, 59 and 60; .,.. ~
:-;
157) the compounds as described by ~ubparagraphs ~ ~:
: 56, S9 and 61; -
~:~ X-4427A -18- - -.~
; . ~ ". .
~ -, ," '
:~ .
:.- ",
1i~88543
153) the compounds as described by ~ubparagraphs
56, S9 and 62;
159) the compounds as described by subparagraphs
56, 59 and 63; -
160) the compounds as described by subparagraphs
56, 59 and 64;
161) the compounds as described by subparagraphs
56, S9 and 65;
162) the compounds as described by subparagraphs
1056, 59 and 66;
163) the compounds as described by subparagraphs
S5, 57, 60 and 67;
164) the compounds as described by 3ubparagraphs
55, 57, 61 and 67;
165) the compounds as described by subparagraphs
55, 57, 62 and 67;
166) the compounds as described by subparagraphs
55, 57, 63 and 67;
167) the compounds as described by subparagraphs
2055, 57, 64 and 67;
168) the compounds as described by subparagraphs
55, 57, 65 and 67;
169) the compound~ as described by ~ubparagraphs
55, 57, 66 and 67; ;
170) the compounds as described by ~ubparagraph~ :
55, 58, 60 and 67;
171) the compounds as described by subparagraphs
55, 58, 61 and 67:
X-4427A -19- -.
1~88S43
172) the compounds as deqcribed by subparagraph~
55, 58, 62 and 67; ~~
173) the compounds as described by subparagraphs
55, 58, 63 and 67;
174~ the compounds as described by ~ubparagraphs
55, 58, 64 and 67;
175) the compounds as described by ~ubparagraphs
55, 58, 65 and 67; `
.
176) the compounds as described by subparagraphs
55, 58, 66 and 67;
177) the compounds as described by ~ubparagraphs
55, 59, 60 and 67; ~`
178) the compounds as described by ~ubparagraphs
55, 59, 61 and 67; `~
179) the compounds as described by subparagraph~
55, 59, 62 and 67; -
180) the compounds as described by subparagraph~
~ t
55, 59, 63 and 67; ,'~ .
181) the compound~ a~ described by ~ubparagraphs
55, 59, 64 and 67; .- ~
182) the compound~ as described by subparagraphs j ,-
55, 59, 65 and 67;
183) the compounds a~ described by subparagraph~ . .
SS, 59, 66 and 67;
184) the compounds a~ described by ~ubparagraph~
~,` :.. - .
!~' ' 56, 57, 60 and 67; .:
~: 185) the compounds as de~cribed by subparagraphs
56, 57, 61 and 67;
X-4427A -20-
'~ :
~ .
38543
186) the compounds as described by subparagraph~
56, 57, 62 and 67; ;:
187) the compounds as de~cribed by subparagraphs
56, 57, 63 and 67; -~
188) the compounds as described by ~ubparagraphs
56, 57, 64 and 67; ~-
189) the compounds as described by subparagraphs ;~
56, 57, 65 and 67;
190) the compounds as described by subparagraphs
1056, 57, 66 and 67;
191) the compounds as described by Qubparagraphs
56, 58, 60 and 67;
192) the compounds as described by subparagraph~ ;
56, 58, 61 and 67; - `
193) the compounds as described by subparagraphs
56, 58, 62 and 67;
194) the compounds as described by subparagraphs . :~
56, 58, 63 and 67; .
195) the compounds as described by subparagraphs .,:;
2056, 58, 64 and 67;
196) the compounds as described by eubparagraphs
56, 58, 65 and 67; :,
197~ the compounds as described by ~ubparagraph~
- 56, 58, 66 and 67;
198) the compounds as described by subparagraph~ -
56, 59, 60 and 67;
199) the compounds as described by eubparagraph~
56, 59, 61 and 67;
X-4427A -21-
:
1~88S43
200) the compounds as de~cribed by subparagraphs
56, 59, 62 and 67;
201) the compound~ as described by subparagraph~
56, 59, 63 and 67;
202) the compounds a~ described by subparagraphs
56, 59, 64 and 67;
203) the compounds as described by subparagraphs
., ~
56, 59, 65 and 67;
204) the compounds as described by subparagraphs
56, 59, 66 and 67. ~ ~ ;
In order to assure that agricultural chemi~ts ~ '
understand and can obtain the compounds of formula (I), (II) ~ ~
or (III), a number of typical compounds will be named. ~ .
2,3-dihydro-3-(3-methylphenyl)-5-phenyl-1-vinyl- . ~
; j~
4(lH)-pyridinone
2,3-dihydro-1-ethyl-3,5-bis(3-methylphenyl)- c,- .
4(lH)-pyridinone I . :
3-(2-chlorophenyl)-5-(3-chlorophenyl)-2,3-di- -
hydro-l-propargyl-4~lH)-pyridinone
2,3-dihydro-5-(3-fluorophenyl)-3-phenoxy-1-(1-
propenyl)-4(lH)-pyridinone -;-~
2,3-dihydro-3-~3-ethylphenyl)-1-i~opropyl-5-
phenylthio-4(lH)-pyridinone :~ .
2,3-dihydro-5-(4-methylphenyl)-1-propyl-3-(3- -.- .`
, . ,, ::.
trifluoromethylphenyl)-4(lH)-pyridinone . ~-
2,3-dihydro-3-methyl-5-~3-propoxyphenyl)-1- .
propyl-4(lH)-pyridinone . .. ~ :
2,3-dih~ydro-3-(3-methoxyphenyl)-5-methoxy-1- . -
methyl-4(1H)-pyridinone .
X-4:427A -22-
_ '
:. . .
8S43
5-~3-bromophenyl)-2,3-dihydro-1-ethyl-3-(4-
fluorophenyl)-4(1H)-pyridinone
l-allyl-2,3-dihydro-5-t3-ethoxyphenyl)-3-t2-
methylphenyl)-4(lH)-pyridinone
2,3-dihydro-5-ethoxy-1-ethyl-3-(3-propylphenyl)-
4(lH)-pyridinone
2,3-dihydro-5-t3-isopropylphenyl)-1-methyl-3-
propyl-4(lH)-pyridinone -:
5-(4-bromophenyl)-2,3-dihydro-3-(3-ethoxyphenyl)-
1-isopropenyl-4(lH)-pyridinone
5-~3-chlorophenyl)-2,3-dihydro-3-propoxy-1-
propyl-4(lH)-pyridinone
2,3-dihydro-5-(3-methoxyphenyl)-1-(1-propenyl)-
3-(2-propylphenyl)-4(lH)-pyridinone
2,3-dihydro-5-(3-fluorophenyl)-1-isopropyl-3-
(3-trifluoromethylphenyl)-4(lH)-pyridinone
2,3-dihydro-1-ethyl-5-propyl-3-t3-trifluoromethyl-
phenyl)-4tlH)-pyridinone
2,3-dihydro-3-ethylthio-1-propyl-5-(3-propyl-
phenyl)-4(lH)-pyridinone
l-allyl-2,3-dihydro-5-~4-ethylphenyl)-3-~3-i~o-
propoxyphenyl)-4tlH)-pyridinone
2,3-dihydro-5-(3-ethoxyphenyl)-3-(3-isopropyl-
phenyl)-l-vinyl-4(lH)-pyridinone
3-t3-bromophenyl)-2,3-dihydro-5-i~opropylthio-1-
propyl-4(lH)-pyridinone
3-(2-bromophenyl)-2,3-dihydro-5-(3-ethoxyphenyl)-
l-propargyl-4(lH)-pyridinone
. .
~ '
X-4427A -23-
las~s43
2,3-dihydro-1-methyl-3,5-bi~(3-trifluoromethyl-
phenyl)-4(lH)-pyridinone
l-propyl-3-phenyl-5-(3-trifluoromethylphenyl)-
4-piperidinone
3-(4-chlorophenyl)-1-ethyl-5-(3-fluorophenyl)-4- ~ -
piperidinone . - :
3-~3-fluorophenyl)-5-~2-fluorophenyl)-1-methyl- :- :
4-piperidinone
3-~3-bromophenyl)-1-ethyl-5-phenyl-4-piperidinone
3-(3-fluorophenyl)-1-methyl-5-phenoxy-4-piperi-
dinone ; -
3-(3-bromophenyl)-1-ethyl-5-phenylthio-4-piperi-
dinone -
3-methoxy-1-methyl-5-(3-trifluoromethylphenyl)-
4-piperidinone
3-~3-bromophenyl)-1-methyl-5-propylthio-4-
piperidinone
l-ethyl-3-~3-fluorophenyl)-4-piperidinone
3-(2-chlorophenyl)-5-(3-fluorophenyl)-1-methyl-
20 4-piperidinone .
3-(3-bromophenyl)-1-ethyl-5-propyl-4-piperidinone
3-(3-fluorophenyl)-S-methoxy-l-methyl-4-piperi- -
dinone
3-(3-bromophenyl)-1-methyl-4-piperidinone :~
3-~3-bromophenyl)-5-ethoxy-1-methyl-4-piperidinone
3-~3-fluorophenyl)-5-i~opropylthio-1-methyl-4-
piperidinone
3-(3-bromophenyl)-1,5-diethyl-4-piperidinone
~ . ''"''
X-4427A -24-
1~88S43
3-ethylthio-1-methyl-5-(3-trifluoromethylphenyl)-
4-piperidinone
3-(3-fluorophenyl)-1-methyl-5-methylthio-4-
piperidinone
3-(3-fluorophenyl)-1-methyl-5-propoxy-4-piperi-
dinone -
3-(3-fluorophenyl)-5-isopropoxy-1-methyl-4-
piperidinone ~
3-(3-chlorophenyl)-1-ethyl-5-(3-fluorophenyl)- . :
10 4-piperidinone '~- :
3-(3-fluorophenyl)-1-methyl-5-(3-trifluoromethyl-
phenyl)-4-piperidinone
3-(3-bromophenyl)-1-ethyl-5-isopropyl-4-piperi- :~
dinone
3-(3-fluorophenyl)-1,5-dimethyl-4-piperidinone
1,3-dimethyl-5-(3-trifluoromethylphenyl)-4-
piperidinone
3-(3-chlorophenyl)-5-(3-fluorophenyl)-1-methyl-
4-piperidinone ;
3-isopropyl-1-methyl-5-(3-trifluoromethylphenyl)-
4-piperidinone
l-ethyl-3-(4-fluorophenyl)-5-(3-trifluoromethyl-
phenyl)-4-piperidinone
3-(3-chlorophenyl)-5-(2-methylphenyl)-1-propyl-
4-piperidinone
3-(3-methoxyphenyl)-1-vinyl-4-piperidinone
3-~3-ethylphenyl)-1-i~opropyl-5-(4-propylphenyl1-
4-piperidinone
;~ ~ . .....
X-4427A -25-
: . , .
. ' .
io88s43 -
l-allyl-3-phenoxy-5-(3-propylphenyl)-4-piperi- ~ -
dinone
l-ethyl-3-(3-methoxyphenyl)-5-~3-methylphenyl)-
4-piperidinone - ,
3-(3-i~opropoxyphenyl)-S-methyl~hio-l-propargyl-
4-piperidinone .-'f .:
3-(4-bromophenyl)-5-(3-ethoxyphenyl)-1-(1-pro- : ~
penyl)-4-piperidinone --
3-(2-ethylphenyl)-5-(3-propoxyphenyl)-1-vinyl-4-
piperidinone
3-ethoxy-5-(3-methylphenyl)-1-propargyl-4-piperi~
dinone -~
3-i~opropyl-5-(3-isopropylphenyl)-1-(1-propenyl)- ~ -
4-piperidinone
3-(3-chlorophenyl)-5-phenylthio-1-~1-propenyl)-
4-piperidinone .
l-isopropenyl-3-methyl-5-(3-propylphenyl)-4- ,
piperidinone
l-i~opropyl-3-~3-isopropylphenyl)-5-phenyl-4- ~ .
20 piperidinone :.
. 3-(3-methoxyphenyl)-1-propyl-5-(2-trifluoromethyl-
phenyl)-4-piperidinone .
3-ethylthio-1-ethyl-5-~3-propoxyphenyl)-4-piper-
idinone
l-allyl-3-(3-ethylphenyl)-5-propoxy-4-pLperidinone . -
3-(3-i-opropoxyphenyl)-1-(1-propenyl)-4~piperi- :.
dinone .
3-(4-ethoxyphenyl)-5-(3-ethoxyphenyl)-1-isopro- ;~
penyl-4-piperidinone . - ~;
. ~: - ,
. .
~ - X-4427A -26- ~ ~
,
,
,, ~ .
'~ .. ' '
10~8S43
l-allyl-3-~3-methoxyphenyl)-5-propylthio-4-
piperidinone
3-(3-chlorophenyl)-1-methyl-5-(2-propoxyphenyl)-
4-piperidinone
3-~3-ethylphenyl)-1-vinyl-4-piperidinone
3-(3-i~opropoxyphenyl)-5-phenoxy-1-propyl-4- ;
piperidinone
3-(3-isopropoxyphenyl)-5-(3-propylphenyl)-1-
propargyl-4-piperidinone -
1-isopropenyl-3-(3-isopropylphenyl)-5-phenyl-4- ~'. -
piperidinone
3-ethyl-1-~1-propenyl)-5-~3-methylphenyl)-4-
piperidinone
2,3-dihydro-3-~3-ethylphenyl)-1-ethyl-4(lH)- -
pyridinone
2,3-dihydro-3-ethyl-5-~3-i~opropoxyphenyl)-1- :
(l-propenyl)-4~lH)-pyridinone .
2,3-dihydro-1-methyl-5-(3-methylphenyl)-3-~4-
propoxyphenyl)-4~lH)-pyridinone '
5-~3-bromophenyl)-2,3-dihydro-1-isopropyl-3-
(2-isopropylphenyl)-4~1H)-pyridinone
2,3-dihydro-5-~3-fluorophenyl)-1-vinyl-4~lH)-
pyridinone
2,3-dihydro-3-(3-ethylphenyl)-5-(3-methoxyphenyl)-
l-vinyl-4(1H)-pyridinone
2,3-dihydro-3-~4-i~opropoxyphenyl)-5-(3-trifluoro- ~-
methylphenyl)-l-propargyl-4(lH)-pyridinone
2,3-dihydro-1-isopropenyl-5-isopropyl-3-(3-iso-
propylphenyi)-4(1H)-pyridinone
.. : ' .
~ X-4427A -27-
- ' .
1~885~3
2,3-dihydro-1-ethyl-3-~4-trifluoromethylphenyl)- ~ -
5-(3-trifluoromethylphenyl)-4(lH)-pyridinone :
2,3-dihydro-3-ethyl-S-~3-methylphenyl)-1-(1-pro-
penyl)-4(lH)-pyridinone
l-allyl-2,3-dihydro-5-(3-propylphenyl)-4(lH)-
pyridinone ~:
3-(3-chlorophenyl)-2,3-dihydro-5-(2-ethoxyphenyl)- ~ .
l-vinyl-4(lH)-pyridinone `~
2,3-dihydro-S-(3-methoxyphenyl)-3-phenylthio~
10 propargyl-4(lH)-pyridinone u
2,3-dihydro-3-phenoxy-5-phenyl-1-(1-propenyl)- .
4(lH)-pyridinone
2,3-dihydro-5-phenyl-3-(3-trifluoromethylphenyl)-
l-vinyl-4(lH)-pyridinone
3-butoxy-1-methyl-5-(3-trifluoromethylphenyl)-4-
piperidinone :.
3-~utylthio-1-ethyl-5-(3-fluorophenyl)-4-piperi-
dinone
3-(t-butyl)-1-ethyl-5-(3-trifluoromethylphenyl)- :
20 4-piperidinone .: -
3-(3-bromophenyl)-5-isobutyl-1-propyl-4-piperi- -~ -
dinone
2,3-dihydro-3-isobutoxy-1-isopropyl-5-~3-methyl-
phenyl)-4(lH)-pyridinone :
5-butyl-2,3-dihydro-1-isopropyl-3-~3-propoxy- ,~
phenyl)-4(lB)-pyridinone
3-(3-ethoxyphenyl)-5-isobutylthio-1-vinyl-4-
: ;piperidinone
' ' .. :,
~ . , ' ' ',
, . .
X-4427A -28-
,:
88543
2,3-dihydro-5-(3-ethylphenyl)-3-i~obutylthio-1-
propargyl-4(lH)-pyridinone
l-allyl-3-(t-butoxy)-5-~3-chlorophenyl)-4- ;
piperidinone
S-(t-butylthio)-2,3-dihydro-1-propyl-3-(3-
propylphenyl)-4(lH)-pyridinone
3-butyl-1-ethyl-5-(3-isopropylphenyl)-4-piperi- - -
dinone
3-butoxy-2,3-dihydro-5-~3-chlorophenyl)-1-pro~
pargyl-4(lH)-pyridinone
The compound~ of formulaé (I), (II) and ~III) are
made by various known processe~. The piperidinones can be
made, a~ taught by Settimj et aI., Gazz. Chim. Ital. 96,
604-11 (1966), by the conden~ation of 1-ethoxycarbonyl-1,3-
diphenyl-2-propanone~ with formaldehyde and primary amines
to form the corresponding piperidinones. ~his proces~, of
course, i~ not usable to form the dihydropyridinones.
The piperidinones, particularly the 3,5-diphenyl-
piperidinones, may be made from correspondingly substituted
bi~pidinones. The reaction was explained by Gottarelli,
Tetrahedron Letters, 2813-16 (1965), who showed the prepara-
tion of piperidinones from bi~pidinone~ by ~imple reaction ;
with alkali or w~th ~odium sulfide.
Both the piperidinones and dihydropyridinone~ arebest made by the reduction of the corresponding 4~1H)-
pyridinones with lithium aluminum hydride. The reduction
wa~ described in general by Tamura et al., Chem. Ind.
(London), 168-69 (1972). -
,~, . . ..
~ X--427A -29- ~ -
, . '
~ 8543
The pyridinone starting compounds are prepared by -- -
processes which are, in general, presently known in the art.
Benary and Bitter, Ber. 61, 1058 (192~) taught the
synthesis of an intermediate disodium salt of l,S-dihydroxy- -
2,4-diphenyl-1,4-pentadien-3-one by the condensation of
1,3-diphenyl-2-propanone with ethyl formate in the pre~ence
of sodium methoxide. The intermediate pentadienone is
neutralized with strong acid to form 3,5-diphenyl-4-pyrone. `-
Reaction of the pyrone with ammonium acetate at an elevated
temperature produces 3,5-diphenyl-4(lH)-pyridinone.
Alternatively, 3,5-diphenyl-4(lH)-pyridinone- can
be prepared by the reaction of an appropriately ring-
~ubstituted 1,3-diphenyl-2-propanone with formamide and
formamidine acetate. Reaction at reflux temperature pro-
duces the corresponding 3,5-diphenyl-4(lH)-pyridinone, which
is reacted with a halide of the desired l-sub~tituent in the `~ ~-
presence of a suitable strong base to form the de~ired
~tartin~ compound.
The preferred synthesis of the pyridinones is
adapted from the method~ of Benary and Bitter and of El-
Kholy et al., J. Hetero. Chem. 10, 665-67 (1973). An
appropriately substituted 1-phenyl-2-propanone i~ formylated
at low temperature with sodium methoxide and ethyl formate
ln ether, and the product is treated with an amine sa}t of
the desired 1-substituent in aqueous medium. The resulting
intermediate is predominantly a 1-amino-2-phenyl-1-buten-3-
- one. Some pyridinone is also formed at this step, as re-
ported by El-Kholy et al. The butenone is reformylated a~
~' ~ ' ' '
:, ~
X-4427A -30-
,.
. , .
1~88543
before, and spontaneously cyclizes to form the l-substituted-
3-phenyl-4(1H)-pyridinone.
The starting 2-propanones may be prepared by
~yntheses in the literature. For example, see Coan et al.,
J. Am. Chem. Soc. 76, 501 (1954); Sullivan et al., ~Di~odium
Tetracarbonylferrate," American Laboratory 49-56 (June
1974); Collman et al., "Synthesis of Hemifluorinated Xetones
u~ing Disodium Tetracarbonylferrate," J. Am. Chem. Soc. 95,
2689-91 (1973); Collman et al., "Acyl and Alkyl Tetracar-
bonylferrate Complexes as Intermediates in the Synthe~is ofAldehydes and Ketones,~ J. Am. Chem. Soc. 94, 2516-18 (1972).
The general synthesis methods of the pyridinones
proceed from either ketone starting compounds or from car-
bonyl halides. The general process is the sæme, whichever ;~
starting compound is used. The general process will be
di~cussed fir~t, and reagents and reaction conditions will
then be explained in detail.
The synthesis proceeds through an intermediate ofthe formula
~ ~ ~ C - C - C - R (VI)
R1 o
wherein Ql and g2 independently are
2 hydrogen atom~,
= CHOH, or an ~lkali metal ~alt thereo~,
., .
= CNN(R )2 or
= CHNHR12, provided that only one of Ql and Q2
is = CHNHR12,
X-4427A -31-
1~88S~3
R i~ a R2, R5 or ~8 group
R~ a Rl, R4 or R7 group
R12 is a R, R3 or R6 group.
The R9 groups independently are Cl-C3 alkyl, or
the R qroup~ combine with the nitrogen atom to which they
are attached to form pyrrolidino, piperidino, morpholino, N-
methylpiperazino and the like.
The -CHOH group~, which may be in the form of
alkali metal ~alt~, are provided by reaction with formylating
agents which will be defined below. The =CHN~R9)2 groups
are provided by reaction with aminoformylating agents, and -
the -CHNHR12 group~ are provided by exchanging ~ither zCHOH -
group~ or ~CHN(R9)2 groups with amine~ of the formula
R12NH2 . .;,
The lntermediates de~cribed above are prepared
from either ketone~ or carbonyl halide~, a~ will be ex- ~,
plained below. When Ql and Q2 each are 2 hydrogen atom~
the pyridinone~ are prepared by either ~ -
1. reacting with a formylating or amino-
formylating agent; -~
2. roacting again with a formylating or amino-
for-ylating agent; and
3. reacting with an amine of the formula R12NH2;
or
1. reacting with a formylating or amino-
formylating agent;
- 2. reacting with an amine of the formula R12NH2; A,'
; and
3. reacting again with a formylating or amino-
~ ~ - formylating agent.
- ~ X-4427A -32-
.
~ ;
1~885~3
When one of Ql and Q2 is either =CHOH or =CHN~R9)2,
and the other i8 2 hydrogen atoms, the pyridinones are
prepared by either
1. reacting with a formylating or aminoformylating
agent; and
2. reacting with an amine of the formula R12NH2;
or
1. reacting with an amine of the formula R12NH2;
and
2. reacting with a formylating or aminoformylating
agent.
When each of Ql and Q2 are either =CHOH or =CHN(R9)2,
the pyridinones are prepared by reacting with an amine of
the formula R12NH2. -
The variations of the synthesis, and the prepa-
ration of the intermediate~, will be sketched below.
When the proce~s starts with a ketone of the
general formula
~ ~ ~ CH - C - CH2 - R -
~c- ,.
the first step is the formylation or aminoformylation of one
of the methylene qroups. If a formylating agent is u~ed, a ~,
ketone of the formula
B.
~ / ~ C - C - CH - R
R
is produced. Reaction with an aminoformylatinq agent pro-
,
duces an enaminoketone such as (C) below.
X-4427A -33_
,
- '
~88543
C. o
C- CH - R~
1 0~ tRe) 2NCH
R
Organic chemists will understand that, although - ~
the sketche~ above ~how the first formylation or amino- -
formylation a~ occurring on a certain side of the ketone, it
may in fact occur on either side of the ketone, depending on -~
the activating characteri~tics of R10 and Rll. The course
of the reaction i~, the ~,ame in either case. It will also ~e ~-
understood that, in many in~tances, the product of the
x - .
formylation or aminoformylation step will actually be a ~.
mixture containing the two posJible monosu~stituted com-
pounds and the di~ubstituted compound.
The monosubstituted product i~ formylated or :
aminoformylated again, and exchanged with an amine of the
formula R12NH2. ~he s,teps may be performed in either order. ~;
If the exchange is performed first, the intermediate product
i~, an en~minoketone of the formula
D. C ~ - C - CH2 - R1
, o~ R1 2HNCH
R
Elth-r formylation or aminoformylation of the above enamino-
ketone affords the pyridinone product, a~ the intermediate
- cyclize~ a8 ~oon as the second group is introduced on the
.. .
other methylene group. ~}
A~ternatively, either of compou~s ~B) or (C~ may
, . . .
~ be either formylated or aminoformylated to prov~de inter-
,
~ mediates of any of the formulae below.
, ~,, , "
~ X-4427A -34- ~
:, .
:
,
lQ885~3
C - C - C - R~ 1 '
C~/ " 11 . .: ~.
R10 HOCH HCOH
-C - C- C- R11
\, ~/ 11 11
~0/ HOCH HCN(RD)2 `
R . -.
C- C- C- R11 ~
_,/ 11 11 ~ ~
~0~ ~R~)2NCH HCN(R~)2
.,
It will be understood that the compound similar to ~F),
wherein the formyl and aminoformyl groups are reversed, i8
equivalent in all respects to compound (F). Pyridinone~ are 17 ~ .
formed from any of the above three intermediates by simple
contact of the intermediate with an amine of the formula
R12NH2 -
When the starting compound i8 a carbonyl halide, .;:.
~ .
the process proceeds essentially a~ described above, except ~. :.
for ~ fir~t tep performed as foll~ws: ~
O .',' ~:'
H. ~ I~
~ / --CHz --G--Halo I (R~)2NCH=CH - R11 _ .,.
R~ ~ . ~ .
O ,'' ~:
CH2 - C - C - R
~ HCN(R~)z
.
: It will be understood that reaction (H) can also be per-
formed in the opposite manner, a~ ~hown below:
~ ' ~ ` .. .
~ X-4427A - -35- .
- . .
- , :
1~88543
~ CHCCHN(R~)s ~ Halo - C - CHs - R11 -
R1o~ c . . I ; .
-C - C - CH2 - R11 ~ , ~
~)2NCH . , ,
It is al~o possible to form intermediates using ~ ;
pho~gene as the carbonyl halide when the 3- and 5-~ubsti-
tuents of the pyridinone are identical.
1 0 . :
~ -CH=CH-N(R~)2 CC 1 2
r~ c ~
10/ c ~R~ 2NCH HCN(R~)z ~R10
The enaminoketones formed in equation~ ~H), (I)
~ and ~J) above are identical to the intermediates de~cribed
-~ in ~C) and ~G) above, and are converted to the pyridinone~
~8 d-~¢ribed above.
Alternatively, it i~ po~Jible to prepare the 1-
un-ubJtituted pyridinones by using NH3 in p}ace of R12NH2
in the process, or by u~ing the proce~ of Benary and -
Bitter. The pyridinone is then alkylated at the l-po~ition
with a halide of R12 according to common procedures.
As a chomlst would expect, the amine~, R12NH2,
may be used in tho form of salt~, preferably hydrohalide
salt~,~including h~ rochlorides, hydrobromide~ and the like.
Such -alt~ are often more convenient than the free amines.
X-4427A -36-
, ~ ~
1088S43
The formylating agents u~ed in the process are
chosen from the common agents used for such reactions. The
preferred agents are esters of formic acid of the formulae
O . ~:
I l 0~ (C1 -C6 a l ky l ) or
c-/
Similar formylations are discussed in Organic -
SYntheses 300-02, Collective Vol. III ~1955).
The e~ters are used in the presence of strong
ba~es, of which alkali metal alkoxides are preferred, such
as sodium methoxide, potassium ethoxide and lithium pro- ~`
poxide. Other bases may also be used, including alkali
metal hydrides, alkali metal amides, and inorganic bases
including alkali metal carbonates and hydroxides. Such
strong organic ba~es as diazabicyclononane and diazabicy-
cloundecane are ~180 useful.
Rsactions with formylating agents are performed in
;'
aprotic solvents such as are regularly used in chemical
synthesis. Ethyl ether is usually the preferred solvent.
Ethers in general, including ~olvents ~uch a~ ethyl propyl
ether, ethyl butyl ether, 1,2-dimethoxyethane and tetra-
hydrofuran, aromatic solvents such as benzene and xylene,
and alksnes such as hexane and octane can be used as formyla-
tion ~olvents.
Because of the strong base~ used in the formyla-
tion reactions, low temperatures produce the best yields.
~' ' , ' ' ..
X-4427A _37_
.: . .
: .
- 10885~3
Reaction at temperatures in the range of from about -25C.
to about 10C. is preferred. The reaction mixture may be
allowed to warm to room temperature, however, after the
reaction has proceeded part way to completion. Reaction
times from about 1 to about 24 hours are adequate for -
economic yields in the formylation reaction~.
The aminoformylating agents used in these synthe-
~es may be any compounds capable of reacting with an active
methylene group to introduce a =CHN(R9)2 group, or its acid
addition salt. Such agents are chosen from among s-triazine,
the orthoformamides,
HClN(R )2]3
the formate ester aminals,
Q3 _ R13
HCIN~R )2]2
the formamide acetals
Q3 _ R13
HCN~R )2
13 R13
the tris~formylamino)methanes,
H
HC(NHCH)3
and the formiminium halides,
HC=N(R9)2Halo
Halo
Q3~in the ~tructures above represents oxygen or ~ulfur, and
R13 represents Cl-C6 alkyl or phenyl.
'
-- .
X-4427A -38-
1~88543
U~eful references on the aminoformylating agents
include DeWolfe, Carboxylic Acid Derivatives 420-506 (Academic
Press 1970), and Ulrich, Chemi~try of Imidoyl Halides 87-96
(Plenum Pre~s 1968). Bredereck et al. have written many
paper~ on such agents and reactions, of which the following
are typical. Ber. 101, 4048-56 (1968); Ber 104, 2709-26 ~.
(1971); Ber. 106, 3732-42 (1973); Ber. 97, 3397-406 (1964);
Ann. 762, 62-72 (1972); Ber. 97, 3407-17 (1964); Ber. 103~
210-21 (1970); Angew. Chem. 78, 147 (1966); Ber. 98, 2887-96
0 (1965); Ber. 96, 1505-14 (1963); Ber. 104, 3475-85 (1971); --
Ber. 101, 41-50 (1968); Ber. 106, 3725-31 (1973); and Angew.
Chem. Int'l. Ed. 5, 132 (1966) . Other notable papers on the
subject include Kreutzberger et al., Arch. der Pharm. 301,
881-96 (196g), and 302, 362-75 (1969), and Weingarten et
al., J. Org. Chem. 32, 3293-94 (1967).
Aminoformylations are usually carried out without
solvent, at elevated temperatures from about 50C. to about
200C. Solvents such as dimethylformamide are sometimes
u~ed, howevor, particularly when it is desirable to raise
the boiling point of the reaction mixture.
The exchange reaction~ with R12NH2 are best per-
form d in protic ~olvents of which allcanol~ are preferred
and ethanol iB most appropriate. ~emperatures from a~sout
-20C. to about 100C. can be used for the exchange re-
actions Room temperature is ~ati-factory and is preferred.
In general, intermediate compounds ln the ~yn-
thesi~ are not purified, but are simply used in~succe~sive
steps after separation by extraction, neutralization or
removal of exces~ solvent or reactant as appropriate.
~- X-4427A -39-
10885~3
The enamine acylation reactions, H-J, are per-
formed in the presence of bases such as tertiary amines,
alkali metal carbonates, magnesium oxide and the like, and
in aprotic solvents as described above.
In some instances, as organic chemi~ts will
understand, it is necessary to apply additional synthetic
steps after the pyridinone has been formed. For example, it
i8 convenient to form compounds having an alkoxy R5 or R8
substituent by first making the corresponding hydroxy-
sub~tituted compound, and then substituting on the oxygenatom.
The compounds of formula (I), ~II) or ~III) are
most efficiently formed from the corresponding 4(lH)-
pyridinones by reduction with lithium aluminum hydride. The
reaction i8 carried out by ~imple contact of the starting
compound with the reducing agent in a solvent. The reaction
may be performed at room temperature, or it may be accelerated
by heating the reaction mixture moderately. In general,
temperatures from about 0C. to about 50C. can be used. In
addition to lithium aluminium hydride other aluminium or
boron hydrides may be used, for example sodium borohydride,
sodium cyanoborohydride, lithium aluminium tri-t-butoxy-
hydride, sodium aluminium bis(methoxyethoxy)hydride and
lithium triethylborohydride.
Solvents for the reaction may be any of the
typical inert organic reaction solvents, of which diethyl
- ether i~ preferred. Other ethers, including tetrahydrofuran
~ and isopropyl ether, alkanes including hexane and octane,
:
~ X-4427A -40-
1~88543
and aromatics such a~ benzene and xylene, are also usable
solvents.
As one would of course expect, reduction of the
pyridinone~ produces a mixture of products. First one, and
then the other, of the two double bonds ln the pyridinone
ring are reduced ~y the reaction. Necessarily, the reaction
produce~ a proportion of the 2,3-dihydropyridinone, a pro-
portion of the 5,6-dihydropyridinone, and a proportion of ~- ~
the piperidinone. The products are readily separated ac- -
cording to the usual methods. Column chromatography is
u~ually the preferred method of separation.
It i~ believed that the above description of the
synthesis iB adequate to enable an organic chemist to
prepare any compound of formula (I), ~II) or (III). The
following specific examples are provided merely as as~i~tance
to the chemist, to assure that all of the compounds are ;-
accesQible.
In the examples below, the product~ were identi-
fied by elemental microanalysis, thin-layer chromatography,
nuclear magnetic resonance analysis, infrared analysi~
ultraviolet analysis, and mass spectroscopy as wa~ required
or convenient in each case.
All temperature~ in the example~ below are on the
Celsius scale.
Example 1 --
2,3-dihydro-1-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-
4(lH)-pyridinone
Example 2
2,3-dihydro-1-methyl-5-phenyl-3-(3-tri$1uoromethylphenyl)-
4(lH)-pyridinone
X-4427A -41-
.
.
~ .
1088543
Example 3
l-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-4-piperidinone
A 556 g~ portion of 1-phenyl-3-(3-trifluoromethyl-
phenyl)-2-propanone was added to 4000 ml. of tetrahydrofuran
containing 284 g. of sodium methoxide at 10-15. The
addition was carried out over a 20 minute period with
constant stirring while the temperature was held below 15,
and the mixture was then stirred for 15 minutes more. Then
370 g. of ethyl formate was added over a 30 minute period, - ;
and the complete mixture was stirred 1 hour more at 10-15.
A second portion of 296 g. of ethyl formate was then added
slowly and the mixture wa~ stirred overnight while it was
allowed to warm to room temperature.
A solut$on of 336 g. of methylamine hydrochloride -~
in 1300 ml. of water wa~ then added, and the mixture wa~ -
stirred for 1/2 hour more. The phases were then allowed to
separate, and the organic layer was concentrated under
vacuum. The re~idue was dissolved in methylene chloride,
dried over ~odium ~ulfate and concentrated to an oil, which
weighed 723 g.
The oil was added to 4000 ml. of tetrahydro~uran,
284 g. of sodium methoxide wa~ added, and the proce-s de-
scribed above wa~ repeated, using the ~ame weight~ of ethyl
formate and of méthylamine hydrochloride. The oily re~idue
obtained from evaporation of the reaction mixture was di~-
~olved in methylene ¢hloride, washed with water and dried
over sodium sulfate. The methylene chloride was evaporated
under vacuum, and the residue crystallized upon standinq. A
small amount of diethyl ether was added to form a thick
X-4427A -42-
~' ' ' '' .
.
,' ': .
.
lOB8543
slurry which was chilled overnight. Filtration of the
chilled slurry produced 430 g. of 1-methyl-3-phenyl-5-(3-
trifluoromethylphenyl)-4(lH)-pyridinone, m.p. 153. -
A 21 g. portion of the above intermediate was -~
di~olved in 500 ml. of diethyl ether and 5 g. of lithium
aluminum hydride was added. The mixture was ~tirred at
reflux temperature for 3 hours, and excess hydride was
decompo~ed by adding successively 5 ml. of water, 15 ml. of
15 percent -~odium hydroxide solution and 5 ml. more of
water. The react$on mixture wa~ then cooled and stirred
overnight, and filtered through anhydrous magnesium sulfate.
The filtrate wa~ concentrated under vacuum to produce an oil
which wa~ ~eparated by chromatography over a silica gel
column.
The various fractions were eluted with benzene-
ethyl acetate mixtures. The 5th and 6th fractions obtained
contained primaril~ the two dihydro compounds, which were
~ep~rated by additional ~tages of chromatography to obtain
about 4.3 g. of the compounds of Examples 1 and 2. The com~
pound~ were identified by nuclear magnetic resonance analysis
and by mas~ ~pectroscopy, which indicated a molecular weight
of 331 for each.
About 4.1 g. of the compound of Example 3, m.p.
86.5-87.5, was obtained from the 7th, 8th and 9th fraction~. -
Theoretical Found
C68.46~ 68.t9~
H5.44 5.49 ;
N4.20 4.37 - --
,
.:~ . ~ .
X-4427A -43-
~: -
'.
': . :...... '...
1~88543
Example 42,3-dihydro-1-methyl-3-~3-methylphenyl)-5-phenyl-4(lH)-
pyridinone
Example S
2,3-dihydro-1-methyl-5-(3-methylphenyl)-3-phenyl-4(lH)-
pyridinone
Example 6
l-methyl-3-(3-methylphenyl)-5-phenyl-4-piperidinone
A 22.8 g. portion of 1-(3-methylphenyl)-3-phenyl-
2-propanone was reacted with ethyl formate and methylamine
hydrochloride as de~cribed in Examples 1-3 to produce 7 g.
of l-methyl-3-(3-methylphenyl)-5-phenyl-4(lH)-pyridinone.
The above intermediate pyridinone was reduced with
2 g. of lithium aluminum hydride in 100 ml. of diethyl ether
as described in Examples 1-3.
The second fraction obtained by column chromato-
graphy on ~ilica gel with benzene-ethyl acetate was the
piperidinone of Example 6, m,p. 100-103, yield 1.5 g. -
Theoretical Found
C 81.10% 80.98
H 8.24 8.00
N 4.98 4.87
The first fractions off the column contained the
compounds of Examples 4 and 5, which were separated by
further stages of chromatography with benzene-ethyl acetate.
The yield of the compound of Example 4 was about 500 mg.,
and it wa~ identified by nuclear magnetic resonance analysi~
and ma-~ spectro-copy. About 750 mg. of the product of
':
X-4427A -44-
- ~88543
Example 5 was obtained. The product had a melting point of
72-76 and the elemental microanaly~is was as follows.
Theoretical Found
C82.28~ 82.Z3%
H6.90 7.00
N5.05 4.83
Example 7
3,5-bis(3-fluorophenyl)-1-methyl-4-piperidinone
A 10.5 g. portion of 1,3-bis(3-fluorophenyl)-2-
10 propanone wa~ mixed with 16.2 g. of formaldehyde and 8 g. of -
40 percent aqueou~ methylamine solution in 75 ml. of de-
natured ethanol. The mixture was stirred at reflux tem-
perature overnight, cooled and filtered. The recovered
solids were ~dentified as 13 g. of essentially pure 3,5-
bis~3-fluorophenyl)-N,N-dimethylbispidinone.
A 7.1 g. portion of the bispidinone was combined
with 2.8 g. of hydroxylamine hydrochloride and 3.3 g. of
sodium methoxide in 50 ml. of 75 percent aqueous acetic
acid. The mixture was stirred at reflux for 6 hours, cooled,
and partially evaporated under vacuum to remove most of the
acetic acid. The concentrated solution was poured into a
large amount of water and extracted with chloroform. The
organic extract wa~ dried over magnesium sulfate and con-
centrated under vacuum. The residue waQ made basic with
aqueous sodium hydroxide and extracted aqain with chloro-
form. Evaporat~on of the chloroform extract under vacuum ~ -
. , . produced 0.7 g. of 3,5-bis(3-~luorophenyl)-l-methy7-4-
piper-idinone, molecular weight 301 by mass spectro~copy. - -
';'' ~ -'; '~
' ,
X-4427A -45- -~
10885~3
Example 8
2,3-dihydro-3-(4-fluorophenyl)-1-methyl-5-(3-trifluoromethyl-
phenyl)-4(lH)-pyridinone
Example 9
2,3-dihydro-5-(4-fluorophenyl)-1-methyl-3-(3-trifluoromethyl-
phenyl)-4(lH)-pyridinone
Example 10
3-(4-fluorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-
4-piperidinone
A 28 g. portion of 1-~4-fluorophenyl)-3-(3-
trifluoromethylphenyl)-2-propanone was reacted with ethyl
formate and methylamine hydrochloride as described in
ExampleQ 1-3 to produce 10 g. of 3-(4-fluorophenyl)-1-
methyl-5-(3-trifluoromethylphenyl)-4(lH)-pyridinone.
The above pyridinone was reduced with 2 g. of
lithium aluminum hydride as described in Examples 1-3.
The various products were separated by chromatography as i-
described above to produce about 0.8 g. each of the three
compounds named in the heading, which were identified as
20 follows.
Example 8, m.p. 89-91.
Theoretical Found
C 65.33% 65.06
H 4.33 4.24
N 4.01 3.89
Exampl2 9, molecular weight 349 by mass ~pectroscopy.
X-4427A -46-
',
1~88543
Example 10, m.p. 84-85.
Theoretical Found
C 64.96% 65.18%
H 4.84 4.79
N 3.99 3.95
Example 11
3,5-bis~3-chlorophenyl)-2,3-dihydro-1-methyl-4(1H)-pyridinone
Example 12
3,5-bis~3-chlorophenyl)-1-methyl-4-piperidinone
A 10 g. portion of 1,3-bis(3-chlorophenyl)-2~
propanone was reacted with ethyl formate and methylamine
hydrochloride to produce 7 g. of 3,5-bi~(3-chlorophenyl)- ~
l-methyl-4(lH)-pyridinone. A 6.4 g. portion of the pyri- , ;
dinone was reduced with 2 g. of lithium aluminum hydride and
the products were sepa~ated by chromatography a~ described
in the examples above. The yields were about 0.8 g. of
Example 11, and 1.5 g. of Example 12. ~ ;
Example 11, m.p. 140.
Theoretical Found
20 C 64.49% 64.s8%
H 5.41 5.77
N 4.18 4.07 ,
Example 12, m.p. 79. ,-
~heoretical Found -
C 64.68% 64.94%
~ 5.13 5.25
-~ N 4.19 4.24
Example 13
5-~(3-bromophenyl)-2,3-dihydro-1-methyl-3-phenyl-4~lH)-
pyridinone
- X-4427A -47-
' ' ' ` '
1~88543
Example 13a
3-(3-bromophenyl)-2,3-dihydro-1-methyl-5-phenyl-4(lH)-
pyridinone
Example 14
3-(3-bromophenyl)-1-methyl-5-phenyl-4-piperidinone
A 10 g. portion of 3-(3-bromophenyl)-1-methyl-S-
phenyl-4(lH)-pyridinone was made from 22 g. of the cor-
responding 2-propanone as described in Examples 1-3. The
pyridinone was reduced with 2 g. of lithium aluminum hydride
as described in the examples above, and the reaction mixture
wa~ chromatographed as described above with benzene-ethyl
acetate mixture~. The combined yield of the compound~ of
Examples 13 and 13a was 4 g., molecular weight 341 by mass
spectroscopy. The yield of the compound of Example 14 was
O.S g., molecular weight by mass spectroscopy 343.
Example 15
5-(3-chlorophenyl)-3-(4-chlorophenyl)-2,3-dihydro-1-methyl-
4(1~)-pyridinone
Example 16
3-(3-chlorophenyl)-5-(4-chlorophenyl)-2,3-dihydro-1-methyl-
4(lH)-pyridinone
Example 17
3-(3-chlorophenyl)-5-(4-chlorophenyl)-1-methyl-4-piperidinone
A 10 g. portion of 3-(3-chlorophenyl)-5-(4-chloro-
phenyl)-l-methyl-4(1H)-pyridinone was made from 33.6 g. of
the corresponding 2-propanone by the procedures of Examples
1-3. The pyridinone was reduced with lithium aluminum
hydride and the reaction mixture was separated by chroma-
tography as described in the examples above. The products
X-4427A -48-
1~88543
of Examples 15 and 16 were obtained a~ a mixture containing
both, combined yield 2.1 g., m.p. 125.5.
Theoretical Found
C 65.00% 65.15%
H 4.55 4.65
N 4.22 4.31
The compound of Example 17 wa~ obtained in a yield of 1.8 g.
m.p. 118.5-126.5.
Theoretical Found
C64.68~ 64.45~
H 5.13 4.93 ~-
N 4.19 4.32
Example 18 ~~
5-(4-chlorophenyl)-2,3-dihydro-1-methyl-3-~3-trifluoromethyl-
phenyl)-4(lH)-pyridinone
Example 19
.: ,,
3-(4-chlorophenyl)-2,3-dihydro-1-methyl-5-~3-trifluoromethyl-
ph-nyl)-4(lH)-pyridinone ~,
Example 20 -
20 3-(4-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-4-
piperidinone
A 15 g. portion of 1-(4-chlorophenyl)-3-(3-
trifluoromethyIphenyl)-2-propanone waa reacted with ethyl
formate and methylamine hydrochloride to prepare 10 g. of
3-(4-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-
4(1H)-pyrldinone. The intermediate pyridinone was reduced
with lithium aluminum hydride. Column chromatographic
separation of the reaction mixture on a silica gel column as --
; ~ described in the examples above produced about 0.5 g. of the
,;~: -
~ X-4427~ _49_ -
. ~ ,
':
~88543
compound of Example 18, m.p. 122.5, about 1.1 g. of the
compound of Example 19, m.p. 113.5, and about 1.3 g. of the
compound of Example 20, m.p. 115.5.
Example 18
Theoretical Found
C 62.39% 62.68~ ~ -
H 4.13 4.10
N 3.83 3.75
Example 19
Theoretical Found
C 62.39% 62.11%
H 4.13 4.36
N 3.83 3.83
Example 20
Theoretical Found
C 62.05% 61.75% -
H 4.66 4.74
N 3.81 3.86
Examplé 21
20 3-(2-chlorophenyl)-2,3-dihydro-1-methyl-5-~3-trifluoro-
methylphenyl)-4~lH)-pyridinone
Example 22
5-(2-chlorophenyl)-2,3-dihydro-1-methyl-3-~3-trifluoro- -
methylphenyl)-4(lH)-pyridinone
Example 23
3-~2-chlorophenyl)-1-methyl-5-(3-trifluoromethylphenyl)-4-
piperidinone
Ten g. of 3-(2-chlorophenyl)-1-methyl-5-(3-tri-
fluoromethylphenyl)-4(lH)-pyridinone was prepared ~rom 35 q.
, .
~ X-442iA ~ -50-
1~}88543
of l-(2-chlorophenyl)-3-(3-trifluoromethylphenyl)-2-
propanone by reaction with ethyl formate and methylamine
hydrochloride as de~cribed in Examples 1-3. The pyridinone -
~wa~ reduced with 2 g. of lithium aluminum hydride and exces~
hydride was decomposed and the product worked up and chromato-
graphed as described in Examples 1-3. The recovered yield~
were about 1.3 g. of a mixture of the compounds of Examples
21 and 22, which were identified by mass spectroscopy with --
an indicated molecular weight of 365. About 2.1 g. of the
compound of Example 23 was recovered, m.p. 90-92. The
elemental analysis of Example 23 was as follows.
Theoretical Found ~
C62.0s% 62.06% ~;
H 4.66 4.68 ;~ -~
N 3.81 3.74
Example 24
2,3-dihydro-3-~3-methoxyphenyl)-1-methyl-5-phenyl-4(lH)-
pyridinone
Example 25
-- '... :
2,3-dihydro-5-(3-methoxyphenyl)-1-methyl-3-phenyl-4t-lH)-
pyridinone
Example 26
3-(3-methoxyphenyl)-1-methyl-5-phenyl-4-piperidinone
A 54 g. portion of 1-(3-methoxyphenyl)-3-phenyl-
2-propanone was reacted with ethyl formate and methylamine
hydrochloride as described in Examples 1-3 to prepare 10 g.
~- of 3-(3-methoxyphenyl)-1-methyl-5-phenyl-4(lH)-pyridinone,
:
~ which was reduced with 2 g. of lithium aluminum hydride.
-.
X-4427A -51-
.
1~88543
~he reaction mixture was worked up as in the examples abo~e
and chromatographed over a silica gel column. Aboùt 1.4 g.
of a mixture of the compoundQ of Examples 24 and 25 wa~
o~tained, an oil which was identified by mass spectroscopy --~
a~ having a molecular weight of 293. About 1.3 g. of the ~
piperidinone of Example 26 was recovered, which had an -~;
indicated molecular weight of 295 by mass ~pectroscopy. ~`
Example 27
2,3-dihydro-1-ethyl-3-phenyl-5-~3-trifluoromethylphenyl)-
4(lH)-pyridinone
Example 28
2,3-dihydro-1-ethyl-5-phenyl-3-(3-trifluoromethylphenyl)- ~ ~
. - . - - . .
4(lH)-pyridinone ! ~ -`
Example 29 -
l-ethyl-3-phenyl-5-(3-trifluoromethylphenyl)-4-piperidinone
.~,
An 11.5 g. portion of 1-phenyl-3-(3-trifluoro-
methylphenyl)-2-propanone was reacted with ethyl format~ and
ethylamine hydrochloride as described in Examples 1-3 to
produce 6.8 g. of 1-ethyl-3-phenyl-5-(3-trifluoromethyl- , -
phenyl)-4(1H)-pyridinone, which waQ reduced with 2 g. ~f
lithium aluminum hydride a~ described above. After column
chromatography as described in the examples above, the ;--
products of Examples 27 and 28 were recovered a~ a m.lxture.
., :- .,,
Mass spectroscopy of the mixture showed a molecular weight
of 345, and the yield was 1.2 g. The molecular weight o
the product of Example 29 wa- indicated a~ 347 by mas~ -
peC~ro-copy~ yi-ld 1.9 g.
~ ~ J ~
~ X-4427A ~ -52-
, . ..
10885~3
Example _
2,3-dihydro-5-ethyl-1-methyl-3-(3-trifluoromethylphenyl)-
411H)-pyridinone
Example 31
2,3-dihydro-3-ethyl-1-methyl-5-(3-trifluoromethylphenyl)-
4(lH)-pyridinone
Example 32
3-ethyl-1-methyl-5-(3-trifluoromethylphenyl)-4-piperidinone `
Seventy q. of l-piperidino-l-butene and 77 g. of
triethylamine were di~olved in 1500 ml. of diethyl ether at
0. A 112 g. portion of 3-trifluoromethylphenylacetyl
chloride dis,~olved in 700 ml. of diethyl ether was added
dropwis,e, and the mixture wa~, stirred for 2 hours at 0
after completion of the addition. The mixture was then
evaporated to dryness under vacuum, and the residue was
taken up in methylene chloride. The solution was wa~hed
with water, dried and evaporated to an oily residue.
The above residue was combined with 500 ml. of
dimethylformamide dimethyl acetal and heated at reflux
temperature for 12 hours. The mixture was then evaporated
under vacuum, and the residue was mixed with 700 ml. of
denatured othanol and 150 g. of methylamine hydrochloride. '
The ethanol ~olution was heated at reflux for 12 hours more
and evaporated to dryae~,~,. The residue was taken up in
methylene chloride, wa~hed with water, dried, and evaporated -
to drynes~ again. The res~due was slurriea in diethyl ether
and filtered. Separation of the ~olids by column chromato-
- gra~phy on ~,ilica gel produced 10"5 g. of 3-ethyl-1-methyl-
5-(3-trifluoromethylphenyl)-4l1H)-pyridinone.
~X-4427A -S3-
: -
.
1~?88543
The pyridinone intermediate wa~ reduced with 2 g.
of lithium aluminum hydride and worked up and chromato-
graphed as described in the examples above. The products of
Examples 30 and 31 were isolated as a mixture, with a com-
bined yield of 1.2 g. Mass spectroscopy of the product
showed an indicated molecular weight of 283. The product of
Example 32, 2.6 g., had a molecular weight of 285 by ma~s
spectroscopy.
Example 33
1-allyl-2,3-dihydro-5-phenyl-3-(3-trifluoromethylphenyl)-
4~lH)-pyridinone
Example 34
l-allyl-2,3-dihydro-3-phenyl-5-(3-trifluoromethylphenyl)-
4(lH)-pyridinone
Example 35
l-allyl-3-phenyl-5-(3-trifluoromethylphenyl)-4-piperidinone
Twenty g. of l-phenyl-3-(3-trifluoromethylphenyl)-
2-propanone wa8 reacted with ethyl formate and allylamine
hydrochloride a~ de~cribed in Examples 1-3 to obtain 10.8 g.
of 1-allyl-3-phenyl-5-(3-trifluoromethylphenyl)-4(lH)-
pyridinone, which wa~ reacted with 2 g. of lithium aluminum
hydride a~ described in Examples 1-3. The reaction mixture
was worked up and chromatographed as descr$bed in the
examples above to obtain 1.2 g. of the products of Examples
33 and 34 a8 a mixture. The compounds were identified by
mass spectroscopy, which showed an indicated molecular
~ weight of 357. A yield of 1. O g. of the compound of Example
; 35 was obtained, which 8hswed a mass spectroscopy molecular
. .
~ weight of 359.
; ' ~ '.-.X-4427A -54- ~
.
1088543
Example 36
2,3-dihydro-1-methyl-3-(3-trifluoromethylphenyl)-4(lH)-
pyridinone ;~
Example 36a
2,3-dihydro-1-methyl-5-(3-trifluoromethylphenyl)-4(1~
pyridinone `
Example 37
l-methyl-3-(3-trifluoromethylphenyl)-4-piperidinone
A mixture of 50 g. of 3-trifluoromethylphenyl
acetone and 100 ml. of dimethylformamide dimethyl acetal in
200 ml. of dimethylformamide was stirred at reflux tem-
perature for S days. ~he excess volatile ingredients were
then removed under vacuum and the re~idual oil was taken up
in 200 ml. of ethanol. One hundred g. of methylamine
hydrochloride was added and the mixture wa~ refluxed over-
night. After cooling, precipitated amine was filtered off
and the filtrate was evaporated under vacuum. The residual
oil was taken up in methylene chloride and wa~hed twice with
300 ml. portion~ of water and once with 400 ml. of saturated
NaCl solution. The organic solution was then dried over
magnesium sulfate and evaporated under vacuum to an oily
residue which was taken up in 400 ml. of diethyl ether,
cooled and filtered. The ~olids were recrystallized from
i~opropyl ether-methylene chloride to produce 10 g. of
l-methyl-3-~-trifluoromethylphenyl)-4~lH)-pyridinone.
The above pyridinone~was reduced with lithium
aluminum hydride and the reaction mixture wa~ worked up and
chromatographed as de~cribed in the examples above. About
~ ' ' .,'.
~ X-4427A -55-
1~88S43
l.S g. of the product of Example 36 was obtained, m.p.
64-65C.
TheoreticalFound
C 61.17% 60.96%
H 4.74 4.70
N 5.49 5.51
About l.S g. of the product of Example 37 was
obtained, and was found to have an indicated molecular
.
weight by ma~s ~pectroscopy of 257. The product of Example
36a was recovered ~n the amount of 0.15 g.
The compounds described above have been tested in
a number of herbicidal te~t ~ystem~ to determine the range
of their herbicidal efficacy. The results produced by the
compound~ in the repre~entative tests reported below are
exemplary of the outstanding activity of the compounds.
Compound application rate~ are expre~ed in kilo-
grams of the compound per hectare of land (kg./ha.) through-
out this specification and claim~.
Blank spaces in the table~ below indicate that the
compound Wa# not tested again~t the named specie~. In ~ome
~nstances, the results of testing a compound repeatedly -
agaln~t a plant pecies have been averaged.
~ ntreated control plant~ or plots were included in
all te~t~. Ratings of the control produced by the compound~
wer- made by comparison of the treated plant~ or plot~ with
the controls. -
~ ~ ,
~ .
..
~ ~ ~ ;X--4427A -56-
~ ' ' , .
1088543
Test I
broad ~pectrum greenhouse te~t
Square plastic pots were filled with a ~terilized
sandy loam soil and were planted to seeds of tomato, large
crabgrass and pigweed. Each pot was individually fertilized.
Test compounds were applied postemergence to ~ome
pots and preemergence to others. Postemergence application~ -
of the compounds were sprayed over the emerged plant~ about
12 days after the seeds were planted. Preemergence ap-
plication~ were sprayed on the ~oil the day after the seedswere planted.
Each test compound wa~ di~solved in 1:1 acetone:
ethanol at the rate of 2 g. per 100 ml. The ~olution also
contained about 2 g. per 100 ml. of an anionic-nonionic
surfactant blend. One ml. of the solution was diluted to 4
ml. with deionized water, and 1-1~2 ml. of the reaulting
solution was applied to each pot, resulting in an application
rate of 16.8 kg./ha. of test compound.
Ater the compounds were applied, the pots were
moved to the greenhouse, watered as nece~sary, and observed
and rated about 10-13 days after appl~cation of the com-
pounds. Untreated control plants were used a~ ~tandard- in
every test.
The table below reports results of testing typical
compound~ of formulae (I), (Ii) and (IIT). The compounds
are identified by their exampl- numbers above.
Herbicidal effect wa~ rated on a 1-5 scale, where
. . .
1 indicates normal plants, and 5 indicates death of the
~- plant- or no emergence.
,. . .
X-4427A -s7-
' , ~
,: :
~088543
. .
. ~
~1 '
.' '~
.~1 ",.
~ - .
~ X :'
~ ~ : .
~ ~ er
P. . .
E~ '"`' ~'
,, I ~ ~;,- .
~ . .
~1 ..
.,~ ~.
~ , -,
l ~,
' ~ X ~
Z ~ ~ o In u~ o~ o ~
.
^:` : X-4427A - . - -58-
-
. ~ :
~ '
1088543 - .
. , .
~' X ' `., ~
10 ~ ;
~ ~ ....
~1 o -
- 31
~ ~. ~ .
,.
,' ~ 20 ~ 3 ~ ~
4 4~2 7A ~ 5 9_ :
.
-
, .
- 1088543
Te~t 2
seven-species greenhouse test
The test was conducted in general like the test
described in Test 1. In this test, the seeds were planted
in flat metal trays, rather than in pots. The compounds
were formulated according to the procedure above, except
that about 6 g./100 ml. of the compound was dissolved in the
~urfactant-containing solvent, and about 1 part of the
organic ~olution was diluted with 12 parts of water before
application to the trays. The compounds were applied at the
rate of 9.0 ~g./ha., and the results of testing against the
species named below were as follows.
~!~
X-4427A -60-
1088543
eFUUFz ~ ,~
--~uFu~o~ ~ ~ ~ N ~ ~ ~ N
~ ~ea~ laA
~ IFelxO,
p;~a
~eq ~ ,~
u~o~ ~ ~ ~ ~ ~ ~ ~ ~ -. ;:
"~
'FUuFZ u~ ~ u~ ~ ~ ~ u~ In u~
~o~.6 , ,', .
--~U~U;IO~ u~
~ ~ Ta~ In ~ U~
~ ~ xo,~ u~ u u~
2 paa~ç~a u~ un In
6se~qel~
~6IB~
U100 m. ~ ~ ~ ~ ,~
.' -
~' ' , , ,~
X-442~7A : -61-
;
, ~ .
1088S43
e~uu~z N N N ~ N ~ N N t~ ~ -
~oTB -:
--6uFu~o~ N N N ~ ~ N N ~ N N
~3e~aATa~ ~ N ~ N ~ N ~ ~ N ~ :
~TF~xo-a N N N N ~'J N ~
p~a~6~d N N N N N N tr~ N N N
s~e~
aBteq N ~ ~ N N N N t~ ~ t~ .~ ~
u~o3 N ~ N ~ ~`J N ~1 N ~ ~ ~ -
~ ~,',',~",''
Nl B~uu~z N ~r N N _I N N ~
.9 ~oTB " .
_Bu~u~ N ~ ~ ~ _I N ~ ~1 It~ ~
~al~aATa~ .::
(I) ~ N u~
~ TF~xo~
p~a~B~a u~ N ~r In Ut In ~r `~
sse~qe~
aB~eq u~ u~ u~
u~o ~ . .-
~o o
~ ~ / \,~ / \ / '
X-4427A -62-
''' ,
lG88543
e~ruU~a N ~ 1 N N N_~ ~I X ~ ~
~lolfi ~1
O_~jU~UTo~l ~ N N N N N~1 N N O
, ~ N N N ~ ~ ~ N
0 0 ~ ,XO,! ~ N NN ~ I~ 1~ 1 N
P~ paa~c : N N NN ~ N N ~1 æ
~se~qe~ I
~f j~ , N N N 1~ ~~ t~ ~ o
U~O ~ N ~ ~ ~ ~N N ~i
.~ .
~ ,0 ,',,,
~ e~uu~z ~r N
~¦ --fjU~U,IOg; It~ N ~1 a
N ~
~ ~e~,xoJ ~ ~ "~
P~ d "~ N U~ n ~ o
se2fiqe2~ .
a62eq u~ u~ ~ u. ~
u~o,, X
~o
I ,~
I ~ u~ o
I N C~l N N N N ~ ~ 1
Pil
. X-4427A -63-
.
. ~ ,
1~88S43
Test 3
multiple-species greenhouse test
In general, the test method was the ~ame as the
method of the test above. Various compounds were tested
preemergence and postemergence at different application
rates which are indicated in the tables below. A number of
additional weed and crop species were used in the preemer-
gence tests as is shown in the table. Typical results were
as follows.
X-4427A -64-
1~88543
elUUFZ ~ ~ N N N ~ ~ N N _I `
~:I016fjUlUlOW ~:
1~ ~r N ~ N ~ ~ ~
p3~Muo8u~Fr ~ u. N ~r N ~ ~ t'~ I" N ~.
}1?3¦~3A¦a~ ~ u~ N
l eO PI ~M ~ ~ _I N N ~ ~ ~ ~ N ~ ~ `
~ ~el xo,~ ~
p33MfjFa ~ u~ n N u~) ~r N ~ ~
p~el sn~
~s~6qel~ , .. --
a6~e~l u~
~31 ~BT~ ~ U~ ~ ~ ~ N
sse~g
p~ u~ ~r u~ ~ ~ ~ u~ ~ ~ ~r
ol eluOL ~ ~ N ~ N 1~ ~ ~ N
~ . ,,
~1 ~~q~n;~n ) N ~ ~I N t~l ~ N N N _I :
¦ 3~ N ~ ~ N _I N ~
a~ ~6ns ~ u~ N
~T~T~ u~
~a~ ~ r ~ N ..
ueaq~oS ~r ~ N N ~ ~ ~ N N N
UO:1 ~0;)
u~o ~ ~ ~r ~ ~ N ~r ~ N ~ ~
'
1~ "
~ N ~1 U~ N In N
O ~ O N O N N _i O O
, ' ~ .
~,: 0~
C ~
-',:, ~ / \ / \
~- ~ ' ,
: ~ X-4427A -65- .
,:
1088~;43
e~uulz _I N
JS~ol66u Fu~OW
paaMuosul~r ~ ~ N ~ N
~all a~Ta~
o PI~M N
~e~xo,~
p~a~a ~r ~ ~ ~ u~ ~ u~ In ~ ; ~ ~
p~el 8nW ~ ~ N N N N N N N
~8B~fiqel~
0 a~q ~r ~ ~ u~ u~
~al ~enE~qu~ l ~ ~ ~ r~
p~B~SU~ ~
~1 o~e~o,l, "~ ~ N
~aq~n~n ~ ~ ~ ~ N
a~ ~ ~ ~
~aa8 ~6ns ~ ~ ~ ~ u~ ~ ~r ~ N "
~}le}TY N ~ ~1 ~ ~ ~ N ~ t~
~ ea~M N ~ N N N N ~ N
ueaq~oS N
U011;~ ~
U~O ~ ~J ~ ~ ~ ~ ~ ~ ~ ~ ' ~ ~;
'' ';.
O ~,~ .~
1~7 r-l N ~ N N N ~ N
O _i N O N ~ N O ~1
~ ~ ' ' Z . ' '- ;
,~ , ~ ~ ~ -.
2~ O .-1 ~ ~ ~ ~, U~ ~D ~ O~ O .~,,~ .-
,
X-4427A ~ 66- - -
..'
.. - .
1~88543
~UU~ Z
,~lo~6u~ulow ~ ~ ,~ ~ .
p;~aMuosWlr ~ ~ ~ ~ ~ ,~
~eal~a~lal~ u~
~eo Pl ~M x
I~B~XO~a ~ ~ ~ ~
. ' ~o , '.
paaM6~a
p~e~8nW ~ ~ ~ ~ ~ ~ O
88~6q~;) . ~,
,~; u~ ~ U
al lenE~sqwel u~
~e~g O
ple~ulea
~¦ oleWO,I, ~ "~
cU~ laqum~n~) ,~
5~ 7~~--f `d ." N _~ N N ~
~a~ ~e~nS
}le~lY N
~Ba~ N ~ ~ N N ~
ueaq~OS
UOl ~,0~ _1 N _I N ~1
U10~ ~ N N _~ 't ~1 8
, `. .,
o c:.c X X
I ~ ~ N r~ --I e
.
~t N _I N _1 _I 4 11
.
- ~} ~a ~ -
0 a~
/ ~ * ~ `
~ ~ . ~ .
X-4427A -67- .
1~88S43
31 N N N N ~
1 ,~ N ~1 N N
~ ' ~` :'
al
~ N r~
~ .,
_l
ti~ ~ N
P~ U~ , ~ .
2 0
~1 . ~`.
,~, , , ~ ,~, . ,
O ~ X ' ':
~ : E~
"' ~ , Id . ,.
o ~
~a
X-4427A I -68-
. , ~
1~88543
Test 4
-
yellow nut~edge test
Typical compounds were evaluated in the greenhouse
against yellow nut~edge in a te~t method which followed in
general the method of Test 1, except that the acetone-
ethanol ~olution contained about l.S g./100 ml. of the test
compound. Both preemergence and postemergence te~t~ of the
compounds were made, and rates of from 0.28 to 9.0 kg./ha.
were applied in some instance~. The 1-5 rating scale was
used in tests at 9.0 kg./ha., while tests at lower appli-
cation rates were rated in percent control of the weed. The
test compounds were incorporated in the soil for te~ting
preemergence at rates below 9.0 kg./ha. The results of
testing typical compounds are presented in the table below.
Table 5
Compound of Rate Pre- Post-
Experiment No. kg./ha. emergence emergence
1~ 9.0 5 4
2~ 2.2 100~ 75%
1~ 0.56 80% 40%
~*
2 0.28 70%
3 9.0 5 4
3 2.2 95~ 7~
3 0.56 80~ 40%
3 0.28 60%
6 9.0 2 2
7 9.0 5 4
* Tested as a mixtur-.
- :
X-4427A -69-
.
1~88543
Test 5
broadleaf weed test
A number of typical compounds were tested in the
greenhouse against broadleaf weeds which are repre~entative
of families of weeds which exhibit resi~tance to many known
herbicides. The te~t method was generally the ~ame as the
method of Test 4, except that only preemergence surface ap-
plications of the compounds were made. All compounds were
te~ted at 9.0 kg./ha. The 1-5 rating ~cale wa~ u~ed.
Table 6 ~- ;
Compound ~-
of Garden
Example Huckle- Sickle- Common Prickly ~-
NO. ~r~y__ pod Ragweed Sida
1~ - . ', ,-.
j 5 5
3 5 5 5 -
6 3 3 4 ~
7 5 5 5 -
* Te~ted a~ a mixtùre.
20 Test 6 ~ ;
fourteen-species test -
This greenhou~e te~t wa~ performed to evaluate
typical compounds of the invention against a number of crop
and weed pecie~. The compounds w-re test-d at variou~ -
rates as indicated in the table below. In all ca~es, the ~ -
compound~ were applie~ preemerqencé to the test plants and
were either incorporated in the soil before the seed~ were - ;~
planted, or ~urface-appl~ed aftér planting. In general, the
' ' ~ - .
X-4427A -70-
.
1~88543
formulation of the compounds and planting and observation of
the test plants proceeded according to the method of Test 4,
except that the compounds were di~solved in acetone-
ethanol at 1 g./100 ml. concentration. A 0-10 rating ~cale
was used, where 0 indicates normal plants, and 10 ind~cates
dead plants or no emergence.
,
~ , .
. .
X-4427A -71- -
.
1~88S43
paa~uosm~ co o ~ o ~ o
,~
~aq~ n;) N ~ O ~ N O
paaM~Ia .~ o o ~. CD o N 1` ..
.. '~ '
UOl~ ~ O O O O O O O O , .-'-
ep~S : ` :
FIa o o o~ o ~ ~ ~ ,~
0 ue8q~0S ~ ~ O ~D t` O ~
~ ~lfj r~ ~ O N u~ ~ O O ~ oo
_~u~uloW -
~ea lM ~ N C0 ' O 1~ O O 0~
s~elg ~
ple~U ~ea ~ C0 o ~ ~ H
oo m
8~ ~ O ~
1~0 PI~M
OD N ~ O~ O~ 1~ o ..
u~n~ os u~
u~19
la~l~W o o o o o~ o ao o
$elxo~a ~ "',",
u~ u~ ',,
U10 ) ~ 0 3
. X
~o ~ Cl~
O ,~; O ~1 O t~ O _I O N 11
~ . ;~' '.
'~ ~` ' O ~ . ~ : .
~ ~ ~I N ~ ~ ~
X . ~.
~, C.) ~il . ,~ .
~,
:~; X-4427A -72-
'
.
1~885~3
The broad-~pectrwm activity of the compounds of
formulae (I), (II) and (III) i8 clearly illu~trated by the
above examples. The test result~ point up the efficacy of
the compounds against annual grasses, the relatively easily-
controlled broadleaves such as pigweed, and the more re-
sistant broadleaves such as nightshades. Plant ~cientists
will recognize that the exemplified activity of the com-
pounds shows that the compounds are broadly effective
against herbaceous weeds.
As the above test results demonstrate, an im-
portant embodiment of this invention is a method of reducing
the vigor of unwanted herbaceous plants which compr1ses
contacting the plants with an herbicidally-effective amount
of one of the compounds described above. In ~ome instance~,
as is clear from the test results, the whole population of
the contacted plant ~8 killed. In other instances, part of
the plants are killed and part of them are in~ured, and in
st~ll other instances ~ none of the plant~ are kllled but are
merely injured by application of the compound. It will be
understood that reducing the vigor of the unwanted plant
population by injuring the indivtdual plants, or by Xilllnq
part and injuring part, is beneficial even though ~ome part
of the plant population survives application of the com-
pound. The plant~, the vigor o$ which has been reduced, are
unusually ~uscepti~le to the stresses, such a~ disea~e,
drought, lack of nutrients and 80 forth, which normally
afflict plants.
Thus, the treated plants, even though they surviv-
appIication of the compound, are likely to expire due to
.
X-4427A -73-
~88543
stress of the environment. Further, if the treated plants
are growing in cropland, the crop, growing normally, tends
to shade out the treated plants of reduced vigor. The crop,
therefore, has a great advantage over the treated unwanted
plants in the competition for nutrients and sunlight. Still t
further, when the treated plants are growing in fallow land,
or industrial property which is desired to be bare, the fact
that their vigor is reduced necessarily tends to minimize
the treated plants' consumption of water and nutrients, and ~ -
~
al~o minimizes the fire hazard and nuisance which the plantspresent.
~ he compounds are herbicidally effective when
applied both preemergence and postemergence. Thus, they can
be applied to the 80il to kill and injure weed~ by soil
contact when the weed seeds are germinating and emerging,
and can also be used to kill and injure growing weed~ by ~/ -
direct contact with the exposed portions of the weeds.
Preemergence application of the compounds, wherein the
unwanted herbaceous plants are contacted with the compound
through application to the ~oil, is preferred. Seeds of
unwanted plants, which are contacted with the compound~ by
soil application, are here regarded as plants.
Preemergence applications of the compounds are
effective, as the examples show, whether the compounds-are
applied to the ~urface of the ~oil or are incorporated in
the soil.
The preferred compounds, which are also the
compounds wlth which the herbicidal method is preferably
carried out, are the following.
~X-4427A -74-
1~88543
2,3-dihydro-1-methyl-3-(3-methylphenyl)-5-phenyl-
4(lH)-pyridinone.
2,3-dihydro-1-methyl-5-(3-methylphenyl)-3-phenyl-
4(lH)-pyridinone.
2,3-dihydro-1-methyl-3-phenyl-5-(3-trifluoro-
methylphenyl)-4(lH)-pyridinone.
2,3-dihydro-1-methyl-5-phenyl-3-(3-trifluoro-
methylphenyl)-4(lH)-pyridinone.
2,3-dihydro-3-(4-fluorophenyl)-1-methyl-S-(3-
trifluoromethylphenyl)-4(lH)-pyridinone.
2,3-dihydro-5-(4-fluorophenyl)-1-methyl-3-(3-
trifluoromethylphenyl)-4(lH)-pyridinone.
3-(4-chlorophenyl)-2,3-dihydro-1-methyl-5-(3-
trifluoromethylphenyl)-4(lH)-pyridinone.
l-methyl-3-phenyl-5-(3-trifluoromethylphenyl)-4-
piperidinone.
As the examples above illustrate, the compounds
are acceptably ~afe to a number of crops, such a~ peanut~,
soybean, sorghum, wheat and rice when applied at proper
rates and at appropriate times. It will be noted that the
compounds are particularly and notably harmle~s to cotton in
the exemplified experiments. Because of the safety with
which this crop may be treated with the compounds, the use
of the method to reduce the vigor of unwanted plants in
cotton cropland is a preferred embodiment of the invention.
The best application rate of a given compound of
formula ~III) for the control of a given plant varies, of
course, depending upon the method of compound application,
X-4427A -75-
~ 1~88S43
climate, soil texture, water and organic matter contents of
the ~oil and other factors known to those ~killed in plant
~cience. It will be found, however, that the optimum ap-
plication rate iB in the range of from about 0.25 to about
20 kg./ha. in virtually every case. The optimum rates will
usually be found to be within the preferred range of from
about 1 to about 10 kg./ha.
The time when the compounds should be applied to
the soil or the unwanted plants is widely variable, ~ince
the compound~ are effective both preemergence and post-
emergence. At lea~t some control will result from appli- ;~
cation of the compound~ at any time when plants are growing
or germinating. They may also be applied to the soil during
a dormant sea~on to kill weeds germinating during the
following warm season.
When the compounds are used for weed control in an
annual crop, it is usually be~t to apply a preemergence
application of the compound to the soil at the time the crop
is being planted. If the compound is to be soil incor- -
20 porated, it will usually be applied and incorporated im- -
mediately before planting. If it is to be surface applied,
it is usually simplest to apply the compound immediately
after planting.
~he compounds are applied to the soil or to .
emerged planta in the manners usual in agriculture. ~hey
may be applied to the soil in the form of either water-
dispersed or granular formulations, the preparation of
which will be discussed below. U~ually, water-disper~ed
.
., ~ .
~ X-4427A -76-
. ..
1~88543
formulations will be used for the application of the com-
pound~ to emerged weed~. The formulation~ are applied with
any of the many types of sprayers and granular applicator~
which are in wide use for the distribution of agricultural
chemicals over soil or ~tanding vegetation. When a compound
is to be soil-incorporated, any of the usual ~oil incorpora-
tion equipment, such a~ the di~c harrow, the power-driven
rotary hoe and the liko, are effective.
The compound~ are useful for the control of
aquatic weeds, as well a~ terrestrial unde~ired plants.
Such aquatic weeds a~ duckweed, water milfoil, hydrilla and
the like are controlied when the compound~ are disper-ed in
the infested water at concentrations in the r~nge of from
about 0.1 to about 10 p.p.m. by weight. The compound- are
applied to water in the form of thé ~ame type~ o herbicid~l
compositions used for other herbicidal uses.
The compound~ are normally uQed in the form of the
herbicidal compo~itions which are an important embodiment of
~he invention. An herbicidal composition comprise~ a
compound useful in controlling unwanted plant~ and an in~rt
carrier. In general, the compositions are formulated in the
manners uqual in agricultural chemistry, and are novel only
beaau~e of the vital presence of the herbicidal compound.
Very often, the compounds are formulated a~ con-
centrated compo~itions which are applied either to the ~oil
or the foliage in the form of water dispersions or emulsion~ -
containing in the range of from about 0.1 percent to about 5
percent of the compound. Water-dispersible or emul~ifiable
- ,~,
~ X-4427A -77-
.
1088543
compositions are either solids usually known as wettable
powders, or liquids usually known as emulsifiable concen-
trate~. Wettable powders comprise an intimate, finely-
divided mixture of the compound, an inert carrier and sur-
factants. The concentration of the compound is usually from
about 10 percent to about 90 percent. The inert carrier i8 `~ :
usually chosen from among the attapulgite clays, the kaolin
clays, the montmorillonite clays, the diatomaceous earths or
the purified silicates. Effective surfactants, comprising
from about 0.5 percent to about 10 percent of the wettable
powder, are found among the sulfonated lignins, the con-
densed naphthalenesulfonates, the naphthalenesulfonates, the ~-
alkylben2enesulfonates, the alkyl sulfates and nonionic -~
surfactants such as ethylene oxide adducts of phenol.
Typical emulsifiable concentrates of the compounds
comprise a convenient concentration of the compound, such as -
from about 100 to about 500 g. per liter of liquid, di~-
solved in an inert carrier whi¢h i~ a mixture of water-
immiscible solvent and emulsifiers. Useful organic ~olven*s
include the aromatics, especially the xylenes, and the
petroleum fractions, especially the high-boiling naphthalenic
and olefinic portions of petroleum. Many other organic
solvents may also be used such as the terpenic solYent~ ~ and
the complex alcohols such as 2-ethoxyethanol. Suitable
emulsifiers for emulsifiable concentrates are chosen from
the same types of surfactants used for wettable powders.
When a compound i~ to be applied to the soil, as
for a preemergence application of the compound, it i8 con-
- venient to use a granular formulation. Such a formulation
X-4427A -78-
.
1~88543 `-
typically eompri-o- the compound di-persed on a granular
inort earrier ~ueh as coarsely ground elay The particle
~ize of granules usually ranges from about 0 1 to about 3
mm The usual formulation proeo~ for granule~ eompri~o-
di~olving the eompound in an inexpon-ive olvont and
applying the ~olution to the carrier in an appropriato
solids mixer Somewhat le~ oeonomieally, the eo~pound may
be di~per~ed in a dough eomposed of damp elay or other inert
carrier, whieh i~ thon dried and eoar~ely ground to produe-
the de~ired granular produet
It ha- boeome eu-tom-ary in agrieultural ehemi-try
to apply two or even moro agrieultural ehamiealJ ~i~ul-
taneou~ly in ordor to eontrol weed~ of many diff-rent typ--,
or weods and other pest~, with a ingl- applieation of
ehemieals The eompound- of formula (III) lend them~elv -
well to eombination with othor agrieultural eh~miaal- and
may u-efully bo eombin-d with inseetieides, fungieide~,
nomatieide~ and other herbieido~ aJ may be dosirable ~nd
eonvonient
- ' .'
-~,
''.
X-4427A _79_ -
