Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
W O 93/19599 P~/GB93/00542
HE~BICIDES
This invention relates to chemical compounds useful as herbicides, to
processes for preparing them and to herbicidal composi~ions and processes
utilising them.
A number of derivatives of monic acid are known to have utility as
biologically active compounds for use in human and veterinary medicine.
Such compounds are described inter alia in GB 1587058.
Ue have now found that certain monic acid derivatives, including
es~ers, amides and salts have a novel and unexpected herbicidal activity.
According to the present invention there is provided a herbicidal
co~position comprising a compound of the formula ~I3 or (IA) or ~IB) in
admixeure with a herbicidally acceptable carrier or diluent, wherein Y
represents (IC) or (ID) or (~E~ and wherein R2 is a group Co-xR3 wherein X
is 0 or S and R3 is hydro~en or an agrochemically acceptable ester-forming
radical; or R2 is a group -R4 wherein R4 is an optionally substituted aryl
or heterocyclic group; or R2 is a group Co-NR5R6 wherein R5 and R6 are the
same or different and each represent an agrochemically acceptable
amide-forming radical; stereoisomers of the compounds of formula (I), (IA)
and (IB) and salts of the compound of formula (I), (IA) and (IB) wherein R2 ::
is ~oXR3, X is 0 and R3 is hydrogen.
According to a further aspect of the present invention there is
pro~ided a process of severely damagi~g or killing un~anted pla~ts, which
- comprises applying to the plants, or to the growth medium of the plants, a
herbicidally effec~ive amount of a compound of ~he formula (I) or (IA)
wherein Y represents ~IC) or (ID) or (IE~;
R2 is a group Co-XR3 wherein X is 0 or S and R3 i~ hydrogen or an
agrochemically accep~a~le es~er-forming radical; or
R2 is a group R4 wherein R4 is an optionally substituted he~erocyclic
group; or R i5 a group -C~-N~-CH2-CO-~ ~herein U is hydr~gen, optionally
subs~itu~ed phenyl, optionally substituted C1 to C2~ alkyl, optionally
substitu~ed C2 to CB alkenyl, optionally substitueed C2 ~o C8 al~ynyl,
optionally substituted heterocy~lyl or C3 to C7 cycloalkyl; or
R i5 a grsup -C0-NH-NH2 or -C0-N~-N~-C0-Y wherein Y is op~ionally
substituted C1 to C20 alkyl, optionally substitueed C2 to CB alkenyl,
optionally substltuted aryl, optionally substituted aralkyl or optionally
substituted heterocyclyl; or
R2 is a group co-NR5 R6 wherein R5 and R6 are the same or differen~ and
s~T~ B 9 ~ I O ~ 5 4.2
,~ sY 1~4
each represent (a) hydrogen, or (b) C1 20 alkyl, C2 8 alkenyl, either o~
which may be optionally substituted with C3 7 cycloalkyl, halogen, carboxy,
Cl ~ alkoxycarbonyl, carbamyl, aryl, heterocyclyl, hydroxy, C1 &
alkanoyloxy, amino, mono- or di-(C1 6)alkylamino; or (c) C3 7 cycloalkyl
optionally substituted with Cl 6 alkyl; or
(d) optionally substituted aryl; or
(e~ optionally substituted heterocyclyl; or
(f) R5 and R6 together with the nitrogen atom to which they are attached
represent an optionally substituted C5 7 heterocyclic ring; or
R2 is a group -C0-0-R wherein R is a C3 20 alkyl, C3 8 cycloalkyl, C4 20
alkenyl, aralkyl, cycloalkylalkyl, heterocyclyl or heterocyclylalkyl group
which group is substituted with a ketonic oxo group; or R7 is a group
-CH2-CoR13 wherein R13 is acyl, aralkyl, amino, ureido or carbamic acid
ester residue, :
and stereoisomers of the compound of formula (I) and salts of the compound
of formula (I) wherein X is 0 and R3 is hydrogen.
The term "aryl" as used herein includes phenyl, and naphthyl
optionally substituted with up to five substituents which may be
independently selected from halogen, C1 6alkyl, C1 6alkoxy, Cl 6alkylthio,
balo(Cl 6~alkyl, hydroxy(C1 ~)alkyl, halo(C1 6)alkoxy, C2 8 alkenyl, C2 8
alkeneoxy, C2 8 alkenylthio, ~ ~ alkynyl, C2 8 alkyneoxy, C2 8
alkynylthio, hydroxy, cyano, nitro, amino, mono- and di- C1 6 alkylamino,
Cl 6 alkanesulphinyl, C1 6 alkane sulphonyl, carboxy, C1 6alkoxycarbonyl,
and Cl ~alkoxycarbonyl(C1 6~alkyl groups.
The term "aralkyl" as used herein includes groups in which the aryl
~oiety is a phenyl group which may be optinnally substituted as
hereinbefore defined for aryl and in whish the alkylene radical has from 1
to 4 carbon atoms.
The term "heterocyclyl" as used herein includes aliphatic or aromatic
single or fused rings comprising up to four hetero atoms in the ring
selected from oxygen, nitrogen and sulphur and optionally substituted with
aryl, with another heterocyclic ring or with one or ~ore o~ those
substituents mentioned above as optional substituents for aryl.
When R2 is a group Co-XR3, X is preferably 0.
Suitable ester-forming radicals, R3, include optionally subst;tuted C
. " .,, " .. .. . .. . ... . .. .
C~ -'.sv3 ~ F~ ET~ T
9 3 1 0 0 5'~
t) ~ 3 a~ MAY 1994
- 2a -
to C20 alkyl, optionally substituted C2 to C20, for example C2 to C~
alkenyl, optionally substituted C2 to C20, for example C2 to C8 alkynyl,
.'.
_
;V3 ~ $~
' 7 ~ JQ~4
optionally substituted C3 to C7 cycloalkyl, optionally substituted aryl or
optionally substituted heterocyclyl.
Optional substituents which may be present in optionally substituted
alkyl, alkenyl or alkynyl groups, such as those represented by R3, include
C3_7 cycloalkyl, C1_l0 alkoxy, C1 l0 alkylthio, C2 8 alkenoxy, C2 8
alkenylthio, C2 8 alkyneoxy, C2 8 alkynylthio, halogen, halo-C1 10 alkoxy,
halo-C2 8alkeneoxy, halo-C2 8alkynoxy, carboxyl Cl 6alkoxycarbonyl,
carbamoylt optionally substituted aryl, optionally substituted
heterocyclyl, hydroxy, cyano, nitro, Cl 6alkanoyloxy, a~ino, mono- and
di-(Cl 6)alkylamino.
Optional substituents w~ich may be present in C3 7cyclo~1kyl groups, :::
such as those represented by R I include Cl 6alkyl halo-Cl 6alkyl, C1 10
alkoxy, C1 10 alkylthio, C2 8 alkenyl, C2 8 alkeneoxy, C2 B alkenylthio
C2 8 alkynyl, C2 8 alkyneoxy, C2 8 alkynylthio, halogen, carboxy, Cl 6
alkoxycarbonyl, carbamoyl, optionally substituted aryll optionally
substituted-heterocyclyll hydroxy, cyanol nitro, C1_6alkanoyloxyl amino, ~:
mono- and di-(Cl 6)alkylamino.
When R3 is alkyl, optionally substituted by aryl it may be regarded as ~-
an aralkyl group as defined above.
Suit~ble ester-forming radicals R3 also include Cl to C10 alkyl
optionally substituted by hydroxy, halogen, cyano. Suitable ester-forming
radicals R3 also include C2 to C10, for example C2 to C4 alkenyl, for
example vinyl, prop-2-ene-1-yl, and but-1-ene-4-yl which may be
unsubstituted or op~ionally substituted by hydroxy by halogen or by cyano
prsvided that the alkenyl group is not substituted by hydroxy when it is a
vinyl groupO
A further preferred group R3 is a C1 1~ alkyl group, and preferably a
C1 4 alkyl ~roup, substituted by a group -A-R wherein A is O or a group
S()x wherein x is O, 1 or 2 and R11 is an optionally substituted Cl to
C10, and preferably optionally substituted Cl_6, for example C1 to C4 alkyl
group, an optionally substituted C2 to C8, and preferably optionally
substitued C2 6~ for example C2 to C4 alkenyl group, an optionally
substitued C2 to C8, and preferably optionally substitued C2 6~ for example
C2 to C4 alkynyl group or an optionally substituted phenyl group, an
S~ E~
' J' ;:._atloil I
-
J ~ 0 5 ~`2
04 MAY t994
7 ~ ';3
- 3a - -
optionally substituted Cl 6 alkyl carbonyl group or an optionally
substituted C3 7 cycloalkyl group, for example an optivnally substituted
C3 6 cycJoalkyl group, or an optionally substitututed C3 7 heterocyclic
group, for example an optionally substituted aliphatic heterocyclic group,
for example an optionally substituted oxygen-sontaining al;phatic ~
heterocyclic group. An example of a group R3 having thi~ substitution is `
the group -~CH2)n,-A-CH-CH-R12 wherein n' is an integer from 1 to 4 and R12
is hydrogen or a C1 $o C4 alkyl group. A is preferably oxygen.
Optional substituents may be thosë indicated above for alkyl, alkenyl,
alkynyl and aryl respectively.
,. "; , . . - `,, C,',',;~2~ S~T
P~,T 1~ J. J;3cation
W O 93/lg~99 ~ ~ 3 2 ~ PCT/GB93/00542
-- 4 --
Unless otherwise specified, alkyl, alkenyl and alkynyl groups,
including for example those present in R3, may be straight or branched
chain groups.
Salts of the compound of formula (I) (IA) and (IB) wherein R2 is the
group co-xR3 and in which X is 0 and R3 is hydrogen include for example
metal salts, e.g. aluminium, alkali metal salts, such as sodium or
potassiu~ alkaline earth metal salts, such as calcium or magnesium, and
ammonium or substituted ammonium salts for example those with lower
alkyl-amino such as triethylamine, hydroxy-lower alkylamines such as
2-hydroxyethylamine, bis(2-hydroxyethyl)-amine, or
eri-(2-hydroxyethyl)-amine, cycloalkylamincs such as bicyclohexyl-amine, or
with pro~aine, dibenzylamine, N,N-dibenzyl-ethylenediamine,
Nethylpiperidine, N-benzyl-~-phenethyl-amine, dehydroabietylamine,
N,N'-bis-dehydroabietylethylenediamine, or bases of th~ pyridine type ~such
as pyridine, collidine, or quinoline) or trimethylsulphonium.
Uhen R2 is an optionally substituted heterocyclic group -R4, preferred
heterocyclic gruups R4 include groups of formula (II) wherein R14 and R15,
which may be the same or different, are independently selected from
hydr~gen, optionally substituted phenyl, optionally substituted C1 to C20
al~yl, optionally substi~uted C2 to C8 alkenyl, optionally substituted C2
t~ C8 alkynyl, optionally substituted heterocyclyl or C3 to C7 cycloalkyl
or from those general substituents for heterocyclyl listed above, X is a
divalent group, -Y'-C~C- and Y' is oxygen or sulphur.
Preferably R4 is an optionally substitu~ed heterocyclic ring of
formula (III) ~herein Y is 0 or S and R14 and R15 have the meanings given
previously. An especially preferred group R4 is an optionally subs~itueed
oxazol-Z-yl group, for example a group of formula (IV) ~herein R14 has the
meaning given previously.
Alternatively R4 may be a group of formula (IY) uherein R14 is itself
an optionally substituted heterocyrlic group, for example a group of the
formula (IVa), (IVb) or ~I~c) in which formulae R16, R17, and R18 may be
the same ~r different each is selected from hydrogen, halogen9 opeionally
substitueed (Cl 6~alkyl, aryl, aralkyl9 heterocyclyl, (Cl 6)alkoxy,
hydroxy, carboxy and salts thereof, (Cl 6)alkoxycarbonyl, carbamoyl, mono-
or di-(Cl 6)~1kylcarb~moyl, sulphamoyl, mono- and di-(C1_6)alkylsulphamoyl,
cyano~ nitro, amino, mono-and di-(Cl 6)alkylamino, acylamino, ureido,
~Cl 6)-alkoxycarbonylamino, (Cl 6)alkoxyimino,
2~2,2-trichloroethoxy~arbonylamino, acyl, (Cl 6)alkylthio, arylthio,
wo 93/lg599 ~ t ~ 2 7 t ~ PCT/GB93/00542
(C1 6~alkanesulphinyl, arysulphinyl, (Cl 6)alkanesulphonyl and
arylsulphonyl. .
Suitably, R14 is a group of formula (IVc) and R16, R17 and R18 are
preferably hydrogen.
A further suitable ester-forming radical R3 is a group R7 wherein R7
represents an optionally substituted C3 20 alkyl, for example C3 10 alkyl,
C3 8 cycloalkyl, C4 20 alkenyl, aralkyl, cycloalkylalkyl, he~erocyclyl or
heterocyclylalkyl group which group is additionally substitu~ed with a
ketonic oxo group.
Thus one sub class of the group R2 when it is a group -Co-oR7 is a
group of formula (V) wherein Z is an optionally substituted C to C12
a}kylene group (-(C~2)n~ ~ wherein n'' is from 1 to 12) and R~ represents a
Cl 10 alkyl, C3_8 ~ycloalkyl, C2 10 alkenyl, C2_10 alkynyl, aryl, aralkyl,
cycloalkylalkyl or heterocyclyl group, each of which may be optionally
substituted. Optional substituents may be those specified above for the
groups alkyl, cycloalkyl, alkenyl, aryl and heterocyclyl respectively.
A further sub-class of the group R2 is a group Co-~R7 and R7 is a ::~
group -C~2-Co-R13 wherein R13 is suitably a carbamic aeid ester residue.
By the term "carbamic acid:ester residue" is meant a group of general
formula -N(Rl9)-CO-NR20R21 wherein Rl9 is hydrogen or an optionally
~subs~t~itued Cl ~ alkyl group and R20 and R21 are ~ndependently selected from
hydrogen or any of the groups R5 and R6 give~ below.
As exampIes of suita~le agrochemically acceptable amide-forming
radicals R5 and R6, whi:ch:-may be the same or different, there may be
mentioned:
: (a) hydrogen or:
: :(b) ah optionally;substituted Cl 20 alkyl group, an optionally
substituted C2 20, for example C2 8 alkenyl group or an
optionally substituted C2 20? for example C2 8 alkynyl group or
(c) optionally substituted C3 to C7 cycloalkyl or
(d) optionally subs~ituted aryl or
~e) opt~onally substituted heterocyclyl; or
(f~ R5 ant R6 together with the nitrogen atom to which they are
attached represent an optionally substituted C5 7 heterocyclic
ri~g or
d d R6 is a group -NR22-N23R2 wherein R is
hydrogen or C1 6 alkyl are R23 and R24, which may be the same or
different, may independently take any of the meanings given for :
3 6 - PCT/GB93/flO542
R5 and R6 under (a)t (b), (c), (d), (e) and (f) above or
(h) R6 is a group -NR22_N=CR23R24 wherein R22, R23 and R have
the meanings given previousIy or
(i~ R is hydrogen and R6 is a group -CR25R26-Co-U or - NR27-Co-U
wherein W is optionally substitu~ed phenyl or optionally
substituted heterocyclyl, R25, R26 and R27 are indendently
hydrogen or optionally substitued C1 6 alkyl groups.
Preferred agrochemically acceptable amide-forming groups R5 and R6 are
those wherein R5 is hydrogen or a Cl 4 alkyl group and R6 is a Cl_4 alkyl
group, each of which alkyl groups may independently be optionally
substitute~ by C3 7 cycloalkyl, C1 4 alkoxy, halogen, carboxy, C1 6
alkoxycarbonyl, carba~yl, optionally substituted aryl, optionally
sub~tieuted heterscyclyl, hydroxy, C~ 6 alkanoyloxy, a~ino, mono- or
di-(Cl ~)alkylamino or wherein R5 and R6 together uith the nitrogen atom eo
which they are attached represent an optionally substituted C5 6 aliphatic
heterocyclic ring. As examples of suitable groups wherein R5 and R6
toge~her with-the nitrogen a~om to which they are attached form an
optionally substituted C5 6 het~rocyclic ring~ there may be mentioned
morpholinyl, piperidyl, piperazinyl, or pyrollidinyl, each of which may be
optio~ally substitu~ed by halogen or Cl 4 alkyl~
~ hen R5 is hyd~ogen and R6 is a group -CR25R26-Co-U or - NR27-CO-U,
R25, R26 and R27 are pref~rably hydrogen and U is preferably optionally
substituted phenyl or an~optionally substituted 5 or 6~membered
heterocyclic ri~g co~aini~g from 1 to 3 heteroatoms selected from oxygen,
ni:trogen and sulphur, for i~stance thienyl or furanyl.
Suitable substituents for ~ ~hen it is a phenyl or heterocyclyl group
include those men~ioned previously and especially halogen, Cl to C6 alkyl,
C~ to C6 alkoxy, hydroxy~ carboxy, Cl-C6 alkoxycarbonyl, carbamoyl, mo~o-
or di- (Cl to C~) albl car~amoyl, sulphamoyl, mono- and di-~Cl to C6)
sulphamoyl, cyano, for example m- or p- cyano, nitro, amino, mono- and di-
(C1 to C6) alkylaminot C1 to C6 acylamino9 ureido, Cl to C6
alkoxycarbonylamino, Z,2,2-trichloroethoxycarbonylamino, Cl to C6 alkan~yl,
C1 to C6 al~ylthiot Cl to C6 alkanesulphinyl, and Cl to C6 alkanesulphonyl
Certain compounds of for~ula (I), (IA~ or (IB) are novel.
According to a further aspect of the present invention there is
provided a compound of t~e formula (I) or (IA) or (IB3 above wherein R2 is
a group Co-xR3 x, is 9 or 5 and R3 is a C~ 10 alkyl group substituted by a
group ~A-R11 wherein A is O or a group S()X wherein x is 0, 1 or 2 and R
W O 93/1959g P&T/GB93/00~42
~ 7 .7~t 3 ?.7`i~ f!
is an op~ionally substituted ~1 to C10 ak~-l group, an optionally
sub~tituted -2 to C8 alkenyl group, an c icnally substitued C2 to C8
~ vnyl gro-~p, an optio~ally substitute ^~nyl group, an optionally
s~Dstituted C1 6 alkyl carbonyl group, optionally substituted C 7
cycloalkyl group or an optionally substituted C~ 7 heterocycli. group
provided that R3 is not a ~roup -(CH2)2- when R is ethyl-
Optional substituents may be those indicated previously as suitable
for alkyl, alk~nyl, alkynyl, phenyl, cycloalkyl or heterocyclyl ~::
retrospective~y. `~
Preferably, R3 is 2 1 4 alkyl group substituted by a group -A-R
wherein A is O or a group S()x wherein x is 0, 1 or 2 and R is an
optionally substituted Cl to C6 akyl group, an optionally substituted C2 to ~:
: C6 alkenyl group, an optionally substitued C2 to C6 alkynyl group, an
optionally substituted phenyl group, or a~ optionally substi~u~ed Cl-6
alkyl carbonyl group, an optlonally substitued C3 6 cycloalkyl group or an
optionally subs~ituted aliphatic C3 7 oxygen-conta~ning heterocyclic group,
provided that R is not a group -(C~2)2- when Rl1 is ethyl.
In one embodiment of the present invention9 R3 is the group
-(G~2)n,-A~CHSCB-Rl2 wherein n' is an integer from 1 to 4 A is O or a
group S(~x ~herein x is 0, 1 or 2 and R is hytrogen or a Cl to C4 alkyl
gro~p.
Compounds of formula (I) uherein R' is the group COO~ and wherein Y
:represents {IC~ or (ID) or ~IE) are disclosed in Uest German
O~fenlegungsschriften~No. 2726619, 2726618 and 2848687 and European Pazent
Application No 79300371.6. Such compounds having the tri-substitu~ed
double bond in the E-configuration are referred to as monic acid C, monic ::
a~id A and monic acid B respecti~ely. Pre$erably the compounds of the
prese~t invention are deri~atiYes of Monic acid A. ~owever, the compounds
o~ the present invention may exist in the ~ (natural~ and Z (or iso) :
geometrical forms in respect of the tri-substituted double bond. The
stereochemistry of ~he compound of formula (I) is thus preferably defined
such that the moiety (VI) is that moiety having the trivial name "normonyl"
(3-l~2S,3R,4R,5S)-5-{(2S,3: ~S,5S)-2,3-epox~-~-hydro~y-4-methylhexyl}-
-3,4-dihydroxytetrahydropyran-2-yll-2-methyl-l(E)-enyl radical) such that
when R2 is the group -COO~, the compound of for~ula (I) is monir acid A.
Compounds of formula ~I) may ~hus conveniently be named as (1-normonyl)
derivatives and esters of monic acid A are conveniently na~ed as monate A
esters. It uill be appreciated that in compounds of formula (I), the group
W 0 93/l9599 ~ PCT/GB93/00542
R may conta}n one or more chiral centres. The present invention
enrompasses all such resultant isomeric possibilities.
Particular examRles of compounds for use in the composition of the
invention are illustrated in Table 1 below wherein the compound is of
formula (I) and the stereochemistry of the moiety (VI) is that of the
"normonyl" radical as described ab~ve. Table 2 lists examples of compounds
for use in the composition of the present invention wherein the compound is
of formula (IB), being derivatives of pseudomonic acid. Table 3 lists
examples of compound for use in the composition of the present invention
wherein the compound is of formula (I) and Y is of formula (IC), being
derivatives of monic acid C.
I~ will be readily appreciated that compounds having values of R2
corresp~nding to those listed in Table 1 may be prepared wherein the
compound is of for~ula (I) and Y is of the formula (IC) (being derivatives
of monic acid C) and ~herein the compound is of formula ~IB) (being
derivaeives on pseudomQnic acid) and such compounds should be considered as
being specifically disc10sed herein. Corresponding derivatiYes of the
compounds of formula (IA) and of formula (I) wherein Y is of formula (ID)
and (IE~ may also b~ readily prepared and should similarly be considered as
being~specifically disclosed herein.
TABLE 1
- ~ 2
CO~POUND R
~U~BER
:
: 1 -COO~
2 C0 0 CH2 C~ C~2
3 -C0-0-CH2-C~2-OB
4 -C0-S-C~3
-C0-0-C~2c~2-~-c~H2
6 C0 ( 2)3 3
7 -co-o-~cH2)3-co-phenyl
8 -CO-O-C~2-CO-N~-CO-NH2
-CO-O-C~2CN
-C0-0-CH2-~3-cyanophenyl)
11 -C0-0-C~2-(3-bromophenyl)
12 -C0-0-CH2-(3-methylphenyl~
W O 93/19599 ~ ~3 ~ 7 ~-1 r~ PCT/GB93t~0542
_ 9 _
TABLE 1 (Continued)
COMPOUND R
NUMBER
. _ . . . .
13 -CO-O CH2-(4-hydroxy~ethylphenyl)
14 -CO-NH-C~2-CO-(4-cyanophenyl)
Structure YII
16 Structure VIII
17 -co-o-(cH2)8-Br
18 Structure IX
19 Structure X
-C0-0-(C~z)l5cH3
21 -CO-O-C~3
22 Structure XI
23 -CO-O-(C~2)2-~-C~2-C~C~2
24 _Co-o-cc~2)2-o-cH-~-c~3
_Co-o-(c~2)3-cH=c~2
26 _~o^o-(c~2)2-o-~2 ~ 3
27 -CO-O-(G~2)2-~-PhenYl
28 (CH2)2-O-(4-chlorophenyl)
29 -Co-o-(c3~)2 o_~o-c~3
(C~2)2-o-c~2-co-oc2Hs
31 -C--(C~2)3-C~C~
32 -Co-o-(c~2)4-o-c~c~2
33 -CO-O-(C~2)3-o-c~c~
34 -C~_o-(c~2)2-o-~E-cH-(c~2~3 C 3
-CO-O-C2~5
36 _CO-O-~B-~C~3)2
37 -CO-0~ 2)3-~3
3~ -CO-O-C~2-C(~3)3
39 -CO-O-(cyclohe~yl~
-CO-O-(cyclopropyl)
42 -CO-O-(C~2)2-0-(~H2)2-0-CH3
43 -C-~ 2)2- G~2
44 -CO-O-tC~2)2-0-CH2-~=C~Cl
~5 -co-o-~(c~3)-co-o-c2~5
W O 93/l9599 PCT/GB93/00542
TABLE 1 (Continued)
COMPOUND R2
NUMBER
46 -C--C~2-CQ-NH2
47 -CO-O-CHz-CH=C~Cl
48 -Co-o-c~ 3)-c~=c~2
49 CO O C~2 C~=C~C~3
-CO-O-phenyl
51 -CO-0-(4-chlorophenyl)
52 -CO-O-S3-nitrophenyl~
53 -CO-0-(4 methoxyphenyl~
54 -CO-0-(4-~methoxycarbonyl)-phenyl)
-CO-O-C~2-~4-methoxyphenyl)
56 -CO-O-C~2-tfuran-2-yl)
57 -CO-O-CH2-CH2Cl
- 58 -CO-NH-(2,:4-dichlorophenyl)
: 59 -C0-NH-~2~5-dichlorophenyl)
-CO-N(CB3)-(2,4-dichlorophenyl)
61 -CO-N~
62 -CO-NB-~2H5~
63 -CO-N~C2B5~2
~: 64 -CO-morpholin-N-yl
-CO-NB~2
6~ -CO-N~-CH2-CO-OC~H5
~ 67 -Co-o-(c~2)2-s-c~3c~2
: 68 -CO-~-(C~2)2-0-C~sC~2
69 -C~-0-~2-0-C~-
-CO-O-C~2-(3-nitrophenyl)
71 -CO-O-C~2-C~C~
72 -Co-o-cH2-co-o-c2~5
73 -~0-0-(C~z)gC~
74 -CO-S-phenyl
-~0-S-C~2-CO-0~3
76 -~0-0-CH2-0-C2~5
77 -CO-NH-(C~2)2-0~ ;
WO 93/19599 ~,~ A3 ~ 7 ~ ~ P~IGB93/00542
;Y 1994
TA~I,E 1 (Continued)
,
COMPOUND R -
NUMBER
.. . .
7~ -CO-N~- ( C~2 ) 2-0-C2~5
7 9 -CO-N( -C~2-C~=C~2 ) 2
Structure ~II
81 S~ructure ~III
82 -CO-NH-Nt CE~3 ) 2
83 -co-NEI-Nsc t C~3 ) 2
84 Structure XIV
St~ucture XV
86 -CO~ C~2-C~ .C~2
87 -CO-~(C~2-c~2-o~)2
8~ -C~-O (C~3)3S
93 -CO-O-CE~2-cyclopropyl
44 ~~ ~~ ( C~2 3 2-0-C~2-CE~ 2 C~2 3
-CO-O-(C~2)2-0-C H(C3~7)-CH=C~z
9~i, -CO-~ N~3-C~ 3 ) C~3
97 c~ o~ fN~ (c~ ~
99 -CO-O ~Na
100 -co~o~ 2-cH2 o-c~(c~3)-c~3
101 -CO-O-C~2-CZ~-O-C~3
10~ _~o-o-~H2-ca2-o-c~2-c~2 C~3
103 -CO-O-C~( C~3 ) -C~I2-0-C~I2-CE3
104 -~:o-O-~EI2-Ca2-0-~ ~y~l~pr~pYl )
105 -C~C~2-ç~( ~H3 ~ -0-C~52-C~I3
106 -CO-~OC~3~ ;
... .
. . ?;~ q~T
== i
W 0 93/lg599 P~T/GB93J00542
~3~ 6 12 -
TABLE 2
(Pseudomonic acid deriatives)
COMPOUND R2
NUMBF.R
. . _
-CO-O-C~2-c~2-o-~=c~2
-CO-~-~2~5
91 -CO-O- ( CH2 ) 2-OH
92 -CO-N(C2H5)2
98 -CO-O N~-~C2~5)3
.
TABLE 3
(monic acid ~ deriatives)
...._~
CO~POUND R
NUMBER
107 -CO-O~
108 -CO-O-C~2-C~2-O-c2H5
Compounds for use in ehe present invention are eieher kno~n compounds
or may be prepared by methods analogous to those used for ~he preparation
of corresp~nding known compounds.
The compounds may be regarded as derivat~ves of mo~ic acid which may
be prepared by the selective hydrolysis of pseudomo~ic acid. ~ further
useul starting material is the ketone ~hich may be obtained from
pseudomonic acid by ozonolysis a~ -50 to -BOC as described for example in
GB 1 587 060. Derivatives of pseudomonic acid may of course be prepared
directly for pseudomonic acid as starting material.
In general it is desirable to protect the hydroxy groups during
reactions of the the starting material surh as monic acid or derivatives
thereof or the corresponding ketone. A wide variety of suitable pr~tectin~
groups is known and examples, are described for example in EP O 399 645.
Partîcularly suitable protecting groups are silyl groups since these are
readily removed under mild conditions. Such groups are introduced by
conventional silylating agents, including halosilanes and silaæanes. The
W O 93/19599 PCT/GB93/00542
- 13 ~
hydroxyl-protecting groups may subse~uently be removed by methods known in
the art, including enzymatic ~ethods. For example silyl prote~ting groups
may generally be removed by mild ~cid hydrolysis followed by alkaline
hydrolysis as described for example by J P Clayton, K Luk and N H Rogers in
Chemistry of Pseuodomonic acid, Part II J.C.S. Perkin Trans I, 1979, 308.
The compound No 1 of Table 1 is a known compound and may be prepared
for example as described above. A more detailed preparation is given in
Examples 2~ 3, 4 and 6 of GB 1,587,058. Salts of the compound of formula
(I) wherein X is 0 and R3 is hydrogen (i.e. salts of Compound No 1 ~f
Table 1) may also be prepared from monic acid by routine methods as
described for example in GB 1,587,058. Typical processes include the
reaction of monic acid ~ith a base, for example a hydroxide, carbonate or
bicarbonate of the dQsired cation folloued by the removal of water; ion
exchange with an appropriate resin; and reaction with amines.
Compound No 2 and Compound No 21 of Table 1 are know~ compounds and
may be prepared for example as described in Examples 24 and 3 respectively
of GB 1,587,059. General methods of preparing compounds of formula (I)
wherein R2 is a group _coxR3 and X is 0 and R3 is an agrochemically
acceptable ester-forming radical are also disclosed ln GB 1,587,059.
Compound No 3 of Table 1 is a known compound and may be prepared for
ex~mple using the general methods described in GB 1,587,059 or as more
specifically described in J Antibiot. 1988 41(5).
Compound No 4 of Table 1 is a known compound and may be prepared for
example using the me~hods disclosed in EP 0 002 371 as more specifically
disclosed in Example 5 thereof. Co~pounds uherein R2 in the compound of
formula (I) is Co-xR3 and X is S may similarly be prepared using the
general methods disclosed in EP 0 002 371.
Co~pound Nos 6 and 7 of Table 1 are known compounds and may be
prepared for example as described in EP 0 025 288 and as more specifically
described in Examples 2 and 5 thereof. Compounds ~herein R2 in the
compound of formula (I) is a group of formula -Co-o-R7 and R7 is a C3 20
alkyl, C3 8 cycloalkyl, C4 20 alkenyl, aralkyl, cycloalkylalkyl~
heterocyclyl or heterocyclylalkyl group which group is substituted uith a
ketonic oxo group, may be prepared using the general methods described in
EP 0 025 288.
Compound No 8 of Table 1 is a kno~n compound and may be prepared for
examp1e using the methods disclosed in Japanese patent No 54-151132.
W O 93/l9599 P~T/GB93/~542
C ~ o~ùnd No 10 of Table 1 is a known compound and may be prepared for
example using the methods disclosed in EP 0 052 437, and as more
specifically described in Example 2 thereof. Compounds of formula (I?
wherein R2 is a group -Co-oR3 may also be prepared as described in ~apanese
Patent No 54-12376 or EP 0 052 437.
Compound No 14 of Table 1 is a known compound and may be prepared for
example using the methods disclosed in EP 0 087 953, and as more
spccifically described in Example 21 thereof. Compounds of formula (I)
wherein R2 is a group -CO-NH-C~2-CO-U as hereinbefore defined may be
prepared using the general me~hods set out in EP 0 087 953 where it is an
intermediate in the manufacture of the compounds ~herein R2 is a
heterocyclic group -R4 havi~g the formula (III) ab~ve which may similarly
be prepared as described in EP 0 087 953. Thus for example, Compound No 19
may be prepared using an analogous method to that described in Example 14
of EP 0 087 953 (5-methyl~ normon-2-yl)oxazole or as more specifically
described in J Chem Soc., Perkin Trans. I 1989 (11) 2059-63. Similarly,
Compound No 22 of Table 1 may be prepared as described in Example 10 of
EP 0 087 953.
Com~ound No 15~of Table 1 is a k~own compound and may be prepared for
example using the methods disclosed in EP Q 123 378, and as more ~:
sp~ ically disclosed in Example 8 thereof. Cvmpounds of general formula
wherein R2 is a group -CO-N~-N~2 or -C0-N~-N~-C0-U as hereinbefore
defined may be prepared using the general methods described in EP 0 123 378
~here such compound~ are in~ermediates to heterocyclic derivatives which ::
themselves provide further ex~mples of co~pounds of the general formula ~I)
herein R2 is a group -R4.
Co~psund No 18 of Table 1 is a ~nown compound and may be prepared for ::
examp}e using the methods disclosed in EP 0 3g9 645, and as more
specifically disclosed in Example 16 thereof. Compounds of general formula
~I) wherein R2 is a group -R4 having the for~ula (II) above may be prepared
using the general methods of EP 0 399 645.
Compound of for~ula (I), (IA) or ~IB) wherein R2 is a group of formula
CoNR5R~ may be prepared using the general methods described in
EP 0 001 914.
In general therefore, typical processes for the manufacture of
compounds of formula (I), (IA) or (IB) wherei~ R2 is the group -CooR3
include ~he reaction of a salt of monic acid (A, B or C~ or pseudomonic
acid, for example an alkali metal salt, with a compound R3-L wherein L is a
wo 93/19599 ~J ti '-? s.~ 7 ~ ~ P~r/GB93/005q2
15 -
leaving group such as halogen or mesolate to form an ester. The reaction
suitably takes place in a solvent such as dimethylformamide or
dimethylsulphoxide at a temperature in the range 10C to 100C and
optionally in the presence of a co-solvent such as
hexamethylenephosphonamide or N,N-dimethylpropyleneurea and optionally in
the presence of a catalyst, such as an iodide catatlyst. If desired the
salt of monic acid or pseudomonic acid may be prepared in situ, for example
by treatment of the acid uith the appropriate base such as the carbonate.
Alternatively, compounds of formula (I), (IA) or (IB) wherein R2 is
the group -CoxR3 or -CoNR5R6 may be prepared by the action of a compound
R3X~ or R5R6N~ on a monic or pseudomonic acid or a simple activated :-~
derivative thereof. Suitably the raction takes place in a solvent such as :~:
tetrahydrofuran, diethyl ether, dichloromethane or chloroform and at a
temperature in the range from -10C to 70C~
Other suitable methods of preparation of the compsunds for use in the
compo~ition of the present invention are described in the literature with -:
specific reference to the patents and papers cited above.
The compounds~for use in the compositions of the present invention are
ac~ive against a broad;range of weed species including monocotyledonous and
dicotyledonous species. Many compounds sho~ good selectivity in crops, :~
pa~ticularly wheat, barley, maize, oil seed rape, su~ar beet and rice. The
compoun~s for use in compositions of the present invention are preferably
: applied directly to unwanted plants (post-emergence application) but they
may also be applied:to the soil before the un~ansed plants emerge
(pre-emergence application).
Thus acording to a:~further aspect of the present inYention there is
provided a process of severely damaging or killing unwanted plants~ ~hich
~omprises applying to the plants or the the gro~th medium of the plan~s
herbicidally effectiYe amount of a compound of the formula (I) or tTA) or
(IB) as hereinbefor~ defined wherein R2 is as hereinbefore defined.
Novel compounds of the present invention are preferably used in the
form of a composition co~prising a compound of for~ula (I) in admixture
uith a carrier comprising a solid or liquid diluent.
Suitable compositions sf the present invention include both dilute
compositions, which are ready for immediate use, and concen~rated
compositions, which require to be diluted before use, usually with uater.
Preferably the compositions contain from 0.01~ to 90X by weigh~ of the
active ingredient. Dilute compositions ready for use preferably contain
W O 93/19~99 ~ PCT/GB93/00542
- 16 -
from 0.01 to 2% of active ingredient, uhile concentrated compositions may
contain from 20 to 90X of active ingredient, al~hough from 20 to 70~ is
usually preferred.
The solid compositions may be in the form of granules, or dusting
powders wherein the active ingredient is mixed with a finely divided solid
diluent, e.g. kaolin, bentonite, kieselguhr, dolomite, calcium carbonate,
talc, powdered magnesia, Fuller's earth and gypsum. They may also be in
the form of dispersible powders or grains, comprising a wetting agent to
facilitate the dispersion of the powder or grains in liquid. Solid
compositions in the form of a powder may be applied as foliar dusts.
Liquid compssitions may comprise a soIution or dispersion of an active
ingredient in ~ater optionally containing a surface-active agent, or may
comprise a solution or~dispersion of an active ingredient in a
water-immisc~ble organic solvent which is dispersed as droplets in water.
Surface-active agen~s ~ay be of ~he cationic, anionic, or non-ionic
type or mixtures thereof. The cationic agents are, for example, quaternary
ammonium compounds (e.g. cetyltrimethylammonium bromide~. Suitable anionic
agents are s~aps; salts of aliphatic mono ~ster of sulphuric acid, for
example sodium lauryl sulphate; and salts of sulphonated aromatic -~
co~pounds, for example sodium dodecylbenzenesulphonate, sodium,calciu~, and
a~onium lignosulphonate, butylnaphthalene sulphonate, and a mixture of the
sodium salts of diisopropy~ and triisopropylnaphthalenesulphonic acid.
Suitable ~on-ionic agents are the condensation products of ethylene oxide
with fa~ty alcohols such as oleyl alcohol and cetyl ~lcohol, or with
alkylphenols such as~octyl- or nonyl- phenol (e.g. Agral 90) or
octyl-cresol. Other non-ionic agents are the partial esters derived from
long chain fatty acids and hexitol anhydrides, for example sorbitan
monolaurate; the condensation products of the par~ial ester with ethylene
ox~de; the lecithi~s; and~silicone surface active agents ~wa~er soluble
surface active agents ha~ing a skeleton ~hich comprises a siloxane chain
e.g. Silwet L77). A suitable mixture in mineral oil is Atplus 411F.
The aqueous solutisns or dispersions may be prepared by dissolving the
active ingredient in uater or an organic solvent optionally containing
we~ting or dispexsing agent(s) and ehen, when organic solvents are used,
adding the mixture so obtained to water optionally containing wetting or
dispersing agent~). Suitable organic solvents include, for example,
ethylene di- hloride, isopropyl alcohol, propylene glycol, diacetone
93~19599 - 17 ~ ) 3 ~ 7 ~ o PCT/GB93/00542
alcohol, toluene, kerosene, ~ethylnaphthalene, the xylenes and
trichloroethylene.
The compositions for use in the form of aqueous solutions or
dispersions are generally supplied in the form of a concentrate containing
a high proportion of the active ingredient, and the concentrate is then
diluted with water before use. The concentrates are usually required to ~-
withstand storage for prolonged periods and after such storage, to be
capable of dilution with water to form aqueous preparations which remain
homogeneous for a sufficient time to enable them to be applied by
conventional spray equipment. Concentrates conveniently contain 20-90%,
preferably 20-70X, by weight of the active ingredient(s). Dilute
preparations ready for use may contain varying amounts of the active
ingredient(s) dependi~g upon the intended purpose; amounts of 0.01~ to
lO.OX and preferably O.lX to 2Z, by ueight of active ingredient(s) are
normally used.
A preférred form of concentrated composition comprises the active
ingredient wh$ch has been finely divided and which has been dispersed in
ater in the presence of a surface-active agent and a suspending agent. -`
Suitabl~ suspending agents are hydrophilic colloids and include, for ;~
exa~ple, polyvinylpyrrolidone and sodium carboxymethylcellulose, and the
vegetable gums, for example gum acacia and gum tragacanth. Preferred
suspending agents are those which impart thixotropic properties to, and
increase the viscosity of~the concentrate. Examples of preferred
suspending agents include hydrated colloidal mineral silicates, such as
montmorillonite, beidellite, nontronite, hectorite, saponite, and
saucorite. Beneonite is especially preferred. Other suspending agents
include cellulose deri~atives and polyvinyl alcohol.
~ The rate of application of the compounds of the invention will depend
on a number of factors including, for example, the compound chosen for use,
the identity of the plants whose growth is to be inhibited, the
formulations selected for use and whether the compound is to be applied for
foliage or root uptake.~ As a general guide, ho~ever, an applic~ion rate
of from 0.0001 to 20 kilograms per hectare is suitable while from 0.001 to
10, for example 0.001 to 2 kilograms per hectare may be preferred.
The compositions of the invention may comprise, in addition to one or
more compounds of the inven~ion, one or more compounds not of the invention
but which possess biological activity. Accordingly in yet a still further
embodiment the invention provides a herbicidal composition comprisin~ a
W O 93/19S99 ~31~ ~ PCT/&B93/00542
~ _ 18 -
mixture of at least one herbicidal compound of formula (I) (IA) or (IB~ as
hereinbefore defined with at least one other herbicide~
The other herbicide may be any herbicide not having the formula (I)
(IA) or (IB). It uill generally be a herbicide having a complementary
action in the particular application.
Examples of useful complementary herbicides include:
A. benzo-2,1,3-thiadiazin-4-one-2,2-dioxides such as bentazone;
B. hormone herbicides, particularly the phenoxy alkanoic acids such as
MCPA, MCPA-thioethyl, dichlorprop, 2,4,5-T, MCPB, 2,4-D, 2,4-DB,
mecoprop, trichlopyr, clopyralid, and their derivatives (eg. salts,
esters and amides);
C. 1,3 dimethylpyrazole derivatives such as pyrazoxyfen, pyrazolate and
benzofenap; :
D. Dinitrophenols and their derivatives (eg. acetates) such as dinoterb, ~;
dinoseb and its ester, dinoseb acetate;
E. dinitroaniline herbicides such as dinitramine, trifluralin,
ethalflurolin, pendimethalin, oryzalin;
F. arylurea herbicides such as diuron , flumeturon, metoxuron, neburon,
isoprot:uron , c~lorotoluron , chloroxuron, linuron, monolinuron,
chlorobromuron, dai~uron, methabenzthiazuron;
G.~ pbenylcarbamoyloxyphenylcarbamates such as phenmediph~ and
desmedipham;
H. 2-phenylpyridazin-3-ones such as chloridazon and norflura~sn;
I. uracil herbicides such as lenacil , bromacil and terbacil;
J. triazine h~rbicides such as a~razine , simazine, aziprotryne,
cyanazine, prO~etryD, dime~hametryn, simetryne~ and terbutryn;
K. phosphorothioate herbicides such as piperophos, bensulide, and
butamifos;
L. thiocarbamate herbicides such as cycloate, vernolate, molinate,
thiobencarb, butyla~e , EPTC , tri-allate, di-allate, esprocarb,
tiocarbazil, pyridaee, prosulfocarb and di~epiperate;
~. 1,2~4-triazin-5-one herbicides such as metamitron and metribuzin;
N. benzoic acid herbicides such as 2,3~6-TBA, dicamba and chloramben;
O. anilide herbicides such as pretilachlor, butachlor, alachlor,
propachlor, propanil, metazachlor, me~lachlor, acetochlor , and
dimetha~hlor;
P. dihalobenzonitrile herbicides such as dichlobenil, bromDxynil and
ioxynil;
:
W~ 93Jlg59~ ~ ~1 3 ~?~ 7 ~ 6 PCT~G~93/~0~42 - 19 -
Q. haloalkanoic herbicides such as dalapon, TCA and salts thereof;
R. diphenylether herbicides such as lact~fen9 fluroglycofen or salts or
ester thereof, nitrofen, bifenox, aciflurofen and salts and esters
thereof, oxyfluorfen, fomesafen, chlornitrofen and chlomethoxyfen;
S. phenoxyphenoxypropionate herbicides such as diclofop and esters
thereof such as the methyl ester, fluazifop and esters thereof,
haloxyfop and esters thereof, quizalofop and esters thereof and
fenoxaprop and esters thereof such as the ethyl ester;
T~ cyclohexanedione herbicides such as alloxydim and salts thereof,
sethoxydim, cycloxydim, tralkoxydim , and clethodim;
U~ sulfonyl urea herbicides such as chlorsulfuron, sulfometuron,
me~sulfuron and esters thereof; benzsulfuron and esters thereof such
as DPX-M6313, chlorimuron and esters such as the ethyl ester thereof
pirimisulfuron and esters such as the methyl ester thereof,
2-[3-(4-methoxy-6-methyl-1,3,5- triazin-zyl)-3-methylure~dosulphonyl)
benzoic acid esters such as the methyl ester thereof (DPX-LS300) and
pyrazosulfuron;
V~ imidazolidinone herbicides such as imazaquin, imazamethabenz, imazapyr
and isopropylammonium sal~s thereof, imazethapyr;
. arylanilide herbicides such as fl~mprop and e~ters thereof,
~ benzoylprop-ethyl9 difluf~nican
X. anino acid herbicides such as glyphosate and glufosinate and their
salts and esters , sulphosate (glyphosate trimesium) and
bialaphos;
Y. organoars~nical herbicides such as monosodium methanearsonate (MS~A);
Z. herbicidal amide deri~ative such as napropamide, propyzamide,
carbetamide, tebuta~t bromobutide, isoxaben~ naproanilide and
naptal~m;
M triketones such as ~ulcotrione;
BB. ~iscellaneous herbicides including ethofum*sate, cinmethylin,
d fenzoquat and salts thereof such as the methyl sulphate sal~,
clomazone, oxadiazon, bromofenoxim, barban, tridiphane,
flurochloridone, quin~hlorac and mefanacet;
CC. ~xa~ples of usefuI contact herbicides include:
bipyridylium herbicides such as those in which ~he active entity is
paraquat and those in ~hich ~he active en~ity is diquat;
* Thes2 compounds are preferably employed in combination uith a
W O 93/19599 0 PCT/GB93/00542
~ 20 -
safener such as dichlormid.
** These compounds have been demonstrated to exhibit additive andin several instances synergystic effects when applied in admixture with
compounds of the present invention.
It is an ad~antage of preferred compounds of the prPsent invention
that they are compatible with a wide range of co-herbicides such as those
listed above and may exhibit additive or synergystic effects in such
mixtures.
The invention is illustrated by the following Examples.
EXAMPLE 1
The compounds listed in Table 1 were characterised by their NMR
spectrum. In each case, the moiety derived from monic acid A (i.e. the
"normonyl" group of structure VI belou) ~as characterised by a complex but
readily identifiable spectrum which corresponded to tha~ of Compound No 1,
monic acid itself. Table II below lists the vis;ble characterising
features of the spectrum a~tributable to the different groups R2 although
key peaks derived from the monic acid moiety may be included for
comparative identificaeion. The solvent in which the spectrum was recorded
is also given.
TABLE II
Compound Solvent ~ NMR
Num~er
2 CDC13 5.9(1~9m); 5.2(2~ ; 4-6(2H,d)
3 d6-DNS0 4.0(2~,t); 3.5(2H,m~
4 C~C13 2.3(3~,s)
CDC13 6.5(1H,t); 4.3(2~,m); 3.9(2~,m); 3.8(2~,m~
6 CDC13 400(2~,t); 2.2~3H,s)
7 CDC13 8.0-7.5(5H~m~, 4.2~2H~t~; 2.2S2H,t)
8 d6-DMS0 4.6t2H,s)
9 CDC13 4.8(28,s~
CDC13 7.7-7.4(4~,m); 5.2(2~,s)
11 CDC13 7.6-7.2~4H,m); 5.1(2H,s)
12 CDC13 7.3-7.1(4~,m); 5.1(2~,s); 2.2(3~,s)
13 ~DC13 7.4(4H,s); 5.1~Z~s~; 4.7(2~,d~
W O 93/19~99 PCT/GB93/00542
21 - ~ , 7 ~ ~
TABLE II (Continued)
. ~
Compound So~ven~ 1~ NMR
Num~er
14 CDCl3 8.1-7.8(4H,m); 4.8(2H,d) `
d6-DMS0 10.2(1~,s); 9.8(1~,s); 7.9(1H,s); 7.2(1H,d);
6.6(1H~s)
16 CD~13 9.8(1H,s); 9.6(1H,s); 7.6(2H,d); 6.6(2~,d);
2.9(6~,s)
17 CD~13 4.1~2H,t); 3.4(2~,t)
18 CD~13 7.8(1~,s); 7.5(1H,s); 7~1~1H,d); 6.6(1R,s)
19 d6-~MS0 6.8(1~,s); 1.2(3H,t)
CDCl3 4.1t2~;t)
21 CDC13 3 7(3~S)
22 CDCl3 8.0(2H,d); 7.8(2~,d); 7.6(1H,s)
.
EXAMPLE 2
-
This Exa~ple illustrates ~he preparation of 2-Vinyloxye~hyl monate A
(Compound No 5 of Table 1).
~ Sodium monaee A (lg~ ~mH~ uas dissolved in dimethylform~mide (25ml)
and stirred ui~h 2-chloroethylvinyl e~her ~0.6ml9 6mM~, hexamethyl-
phosphoramide (3 drops) and sodium iodide (0.9g~ at 80C for 6 hours.
:~fter evaporation i~ vacuo ~he residue was partitioned between ethyl
acetate and bri~e, and the aqueous phase further extracted with ethyl
acetate (3x50ml). The combined organic fractions ~ere uashed with 10%
sodium thiosulpha~e solueion9 saturated sodiu~ bicarbo~ate solution and
brine~ dried ~MgS04) and evaporated in vacuo. Separation on silica (type
60, 20g) eluting ~ith 0 to 4Z me~hanol/CPOC13 gave the produc~, which
crystallised on sta~ding to give a solid of melting point 78-80~Co The NMR
spectrum was as indicated irO Exa~ple 1.
EYA~LE 3
This Example illustrates the preparation of cyanomethyl monate A
(Compound No 9 of Table 1)~
A solution containing sodium monate A (2.00g, 5.4~mol)~
chloroacetonitrile (0.35ml, 5.4m~ol) and dimethylforma~i~e (50ml~ was
stirred 1 hour at 80 and then evaporated in YacUO- The residue uas taken
up in ethyl aceta~e, which uas washed uith aqueous sodium bicarbona~e and
W O 93/19599 ~ 22 - PCT/GB93/~0542
then brine, dried (MgS04), evaporated in vacuo, and purified by
chromatography (O to 4% methanol in chloroform, 20g silica gel) to give the
desired product as a clear oil. The NMR spectrum ~as as indicated in
Example 1.
EXAMPLE 4
This Example illustrates the preparation of 3-bromobenzyl monate A
(Compound No 11 of Table 1).
A solution containing sodium monate A (l.lgm 3mmol), m-bromobenzyl
bromide (0.75g, 3mmol), and dimethylformamide (35ml) was stirred at 20C
for 5 hours and then evaporated in vacuo. The resiude was taken up in
ethyl acetate/brine, the organic layer washed with aqueous sodium
bicarbonate, then brine, dried (MgS04), evaporated in vacuo, a~d purified
by chromatography (O to 6% metha~ol in dichloromethane, 20g silica gel) to
give the desired product as a colourlass oil which solidified to yield
white powder of melting point 91C-92~C. The NMR spectrum was as indicated
in Example 1.
EXAMPLE 4
ThiS Example illustra~es the preparation of 3-methylbenzyl monate A
(Compound No 12 of Table l)o
A solution containing sodium monate A (0.73g, 2mmol), ~-bro~o-m-xylene
(0:37g, 2mmol) and dimethylformamide (25ml~ ~as stirred at 20C for
17 hours and then evaporated in vacuo. The residue was taken up in ethyl
acetate/brine, the organic phase washed with aqueous sodium bicarbonate and
then brine, dried (MgS04~ and evapora~ed in vacuo. The residual oil was
purified by chromatography (O to 4X ~ethanol in dichloromethane7 15g silica
gel) to yield the desired produc~ a3 a colourless oil. The N~R spectrum
uas as indieated in Ex~mple 1.
EXA~PLE 5 ~:
This Example illustrates the preparation of 4-hydroxymethylbenzyl
~onate A (Compound No 13 of Table 1). ::
~ -Toluic acid (13.6g, lOOmmol~ was refluxed in methanol t95ml) and
concentrated sulphuric acid (5ml~ for l~ hsurs. The reaction was
evaporated to half volume, poured into water, extraeted with ethyl acetate,
dried (M~S04), and eYaporated in vacuo. To the residue was added
N-brcmosucc~nimide (17.8g, lOOmmol), benzoyl peroxide (lOOmg~ and earbon
tetrachloride (50ml) and refluxed for 2* hours. The reaction was ~hen
filtered, and the filtrate evaporated in vacuo.
W O 93/19599 PCT/GB93/00542
- 23 - ~ ~3 7 ~ ~i
The product, methyl-4~bromomethylbenzoate (9.2g, 40mmol) in toluene
(80ml) was cooled to -303C and a solution of diisobutyl aluminium hydride
in toluene ~60ml, 25%, BOmmol) was added dropwise and stirred for 1 h~ur.
The solution was allowed to warm to room temperature and stirred a further
2 hours. The reaction was then quenched with methanol, filtered, and the
filtrate washed with aqueous sodium bicarbonate solution and then brine.
The orgnaic layer was dried (MgS04) and evaporated in vacuo to yield
4-bromomethylbenzyl alcohol.
A solution co~taining sodium monate A (4mmol) and 4-bromomethylbenzyl
alcohol (4mmol~ in dime~hylformamide (60ml) was stirred overnight at room
temperature, and then e~aporated in vacuo. The residue ~as taken up in
ethyl acetate/brine, ~ashed with aqueous sodium bicarbonate and then brine,
dried and evaporated. The residue was purified by chromatography, eluting
with methanol~dichlorometha~e ~ixtures to yield a colourless oil. The NMR
spec~rum was as indicated in Example 1.
EXAMPLE 6
This ~xample illustrates the preparation of 4-dimethylaminobenzoyl-
monhydrazide A (Compound No 16 of Table 1).
Monic acid A (3.44g, lOmmol~ ~as dissolved in tetrahydrofuran (lOOml)
a~d cooled to O~C. Triethylamine (1.5ml, ll~mol) and isobutylchloroformate
~,4ml, llmmol) ~ere added and -~tirred for 30 minutes~ Dimethylamino-
ben~ahydrazide ~1079g, ~Ommol~ ~as added and the reaction mixture stirred
for 5 hours. The reaction mixture was then filtered and evapora~ed under
reduced pressure. The residue was crystallised from ether to yield the
de~ir~d product as a white ~olid of melting point 116-118C. The NMR
spec~rum ~as as indicated in Ex~mple 1.
EXAMPLE 7
This ~xample illusta~es the preparation of l-bromo-8-octyl monate A
(Compound No 17 of Table 1~.
A solution containing sodium monate A (l.OgJ 2.7m~ol) and
1,8-dibromooctane (0.75g, 2.7mmol) in dimethylformamide ~5ml) was stirred
overnight at room temperature and then evaported under reduced pressure.
The residue was dissolved in ethyl acetate/~ater and the orga~ic layer
washed ~ith water, dried (MgS04) and evapora~ed under reduced pressureO
The resulting residue was purified by column chromatography (silica gel,
eluting uith O to 3X methanol in dichloromethane~ to yield the desired
product as an oil. The NMR spectrum uas as indicated in Example 1.
W O 93/lgS99 - PCT/GB93/00542
~ r~ 24 -
J EXAMPLE 8
The Example illustrates the preparation of cetyl monate A (Compound
No 20 of Table 1).
Monic acid A (25.8g, 75mmol), potassium carbonate ~10.5g, 76mmol),
sodium iodide (15.0g, lOOmmol) and cetyl bromide (45ml, 147mmol) were
stirred in dimethylformamide (750ml) and hexamethylphosphoramide (150
drops) for 24 hours. The mixture was diluted with ethyl acetate (1.51),
washed with water (4 x 0.51) and brine, dried and evaporated. The residue
~as purified on silica (1200g), eluting with 5~ methanol in chloroform, to
give a fine white powder. This was recrystallised from ethyl
acetate/hexane to give the desired product. The NMR spectrum was as
indicated in Example 1.
EXAMPLE 9
This Example illustrates the preparation of pent-4-enyl monate A
(Compound No 25 of Table I).
Sodium monate A (160mg, 0.44mM) was dissolved in dimethylformamide
(2ml) and stirred ui~h 1-bromopent-4-ene (131mg, 0.88~M~ and
N,N-dimethylpro wleneurea (0.38ml) at room te~perature for 4 hours and ehen
at 70C for 2 hours. Volatile components ~ere removed by evaporation in
vacuo. Separation on silica eluting with 55:45 acetoneJhexæne gave the
de~ired product as a colourless syrup.
1~ NMR ~tCDC13) 5.82~ m), 5.77 (lH, S)7 5.08 (1~, d), 5.00 (1~, d),
4.11 (2H~ t), 2.21 ~3~, s), 1.22 (3~, d~, 0.95 ~3~, d).
; EXAMPLES 10 T0 15
The following compounds were prepared using the general method of
Examplè 9:
4-Methoxybenzyl monate A (Compound ~o 55 of Table I~
NMR ~(CDC13) 7.3~ (2~, d), 6.88 (2HI d), 5.79 (lH, s), 5.07 (2H, s),
3.90 (3H, s)~ 2.21 (3~, s), 1.22 (3H, d3, 0.92 (3~, d).
3-Nitrobenzyl monate A (Compo~nd No 70 of Table I)
H NMR ~(CDC13) 8.28 (1~, s), 3.20 (lH, d~, 7.70 (1~, d~, 7.54 (lH, t),
5.80 ~2H, s), 2.22 (3~, s), 1.21 (3~, d), 0.93 (3~, d).
Propargyl monate A (Compound No 71 of Table I~
~ NMR ~(CDC13) 5.80 (lH, s), 4.71 (2H, s), 2.22 (3~, s)~ 1.21 (3~9 d),
0.94 (3H, d).
W O 93/195~9 ~ ~ 3 i 7 ~ ~ PCT/GB93/00542
- 25 -
Ethyl acet-2-yl monate ~ (Compound No 72 of Table ~)
-'~ NMR ~(CDCl3) 5.89 ~lH, s), 4.63 (2H, abq), 4.22 (2H, q), 2.22
i~, s), 1-29 (3~9 t), 1.22 (3~, d), 0.91 (3H, d).
Decyl monate A ~Compound No 73 of Table I)
1~ NMR ~(~DCl3) 5.78 (lH, s), 4.Q8 (2~, t), 2.21 (3H, s), 1.21 (3H, d),
0.95 (3H, d), 0.87 (3H, t).
2-Phenoxyethoxy monate A (Compound No 27 of Table 1)
1H NMR S(CDC13~ 7.29 (2~, t), 6.91 (3~, m), 5.81 (1~, s) 4.46 (3H, t),
4.19 (3H, t), 2.22 (3~, s), 1.21 (3H, d), 0~92 (3H, d).
EXAMPLE 16
This ~xa~ple illustrates the preparation of prop-2-yl monate A
(Compound No 36 of Table I).
Sodium monate ~ (200mg, 0.55mM) was dissolved in dimethylformamide
~2ml) and stirred with 2-bromopropane (136mg, l.llmM),
N~N-dimethylpr~pyleneurea (0.476g) and sodium iodide (166mg, l.llmM~ at
room ~emperature for 1.5 hours and then let to stand for 4 days. Volatile
components were re~oved by evaporation in vacuo. Separa~ion on silica
eluting ~ith 55:45 acetone/hexane ~ave the desired product as a colourless
sy~up.
1~ NMR ~(CDCl3) 5.72 (1~, s~, 5.02 ~1~, m), 2.21 (3H, s), 1.24 (6H, d),
1.22 ~3~, d), 0.94 (3~, d).
~n~s 17 ro 19
The following compounds ~ere prepared in a manner corresponding to
that to Example 16:-
2-E~boxye~hyl monate A (Compound No 26 of Ta~le I~
~ NMR ~(CDC13) 5.81 (1~, s), 4.26 (2H, t), 3~66 (2~, t), 3.54 (2~, t),
2.21 (3~, s), 1.22 (3~, m), 1.21 t3H, d), 0.94 ~3~, d).
Pent-4-ynyl monate A (Compound No 31 of Table I)
lH NMR ~CDCl3~ 5.78 (lH, s), 4.20 ~2H, t), 2.21 (3~, s)~ 1.22 (3~, d),
0.94 (3H, d3.
Ethyl propion-2-yl monate A (Compound No 45 of Table I~, obtained as a
mixture of diastereoisomers.
1~ NMR ~(CDCl3) 5.86 (1~, s), 5.09 (1~, m), 4.21 (2H, q), 2.21 (3H, s),
~ ~.3 ~ 26 - P~T/GB93/~0542
1.50 (3~, d), 1.25 (3H, t), 1.22 (3~, d), 0.92 (3~, d~.
EXAMPLE 20
This Example illustrates the preparation of 2-(4-chlorophenoxy)ethyl
monate A (Compound No 28 of Table I)
Monic acid A (200mg, 0.58mM) was dissolved in dimethylformamide (lml)
and stirred with 2-(4-chlorophenoxy)ethyl bromide (273mg, 1.16mM) and N,N-
dimethylpropyleneurea (510mg, 3.98mM). Potassium carbonate t120mg, 0.87~M)
was added and the mixture stirred at room temperature for 1 hour and at
80C for 1.5 hours. Volatile componenes were removed by evaporation in
vacuo. Separation on silica eluting with 55:45 acetone/hexane gave the
desired product as a gum.
B NMR ~(CDC13) 7 25 (2H, d), 6.82 (2H, d), 5.80 (lH, S)9 4.40 ~2H, m),
4.16 (2~,~m), 2.22 (3B, s), 1.21 (3H, d), 0.93 (3~, d).
E%AMPLES 21 T0 32
The following compounds were prepared using the general method of
Example 20:
2-((2-methoxy)ethoxy)ethyl monate A (Compound No 42 of Table I)
H NHR ~(CDCl3) 5.81 (1~, s), 4.27 (2~, t), 3.72 (2~, t), 3.65 (2~, m),
.
~ 3.55 (2H, m), 3.40 (3~, s), 2.21 (3~, s), 1.21 (3H, d), 0.95 (3H, d).
:
A ~1:4~ mixture of 1-methylprop-2-enyl mona~e A (Compound No 49 of Table I
- its~lf a mixture of diastereoisomers) and but-2-enyl monate A (Compound
~o 48 of Table I - itself a mixture of geometric~l isomers)
1-~ethylprop-2-enyl monate A
1~ N~R ~(CDCl3) 5.78 (lH, m), 5.39 ~1~, m), 5.25 ~1~, m), 5.15 (lH? m),
2.21 ~3~, s), 1.70 (3H, s), 1.21 ~3H, d), 0.99 and ~.80 (3~, 2xd).
But-2-enyl monate A
~ ~MR ~(CDC13~ 5.78 (lH, m), 5.60 (1~, m~, 4.63 and 4.52 (2~, 2xd),
2.21 (3H, s), 1.21 (3H, d), 0.95 (3~, d).
2-(Ethoxycarbonylmethoxy)ethyl monate A (Compound No 30 of Table 1)
lH NMR ~(CDCl3~ 5.80 (1~, s), 4.29 (2~, t), 4.23 (2H9 q), 4.14 (2~, s),
3.80 (2B, t), 2.23 (3H, s), 1.28 (3H, t), 1.23 (3~, d), 0.94 (3H, d~.
93~19~9g ~ 7 ~ PCT/GB93J00542
- 27 -
2-(Acetoxy)ethyl monate A (Compound No 29 of Table 1)
lH NMR ~(CDCl3) 5.78 (lH, s)? 4.28 (4H, s), 2.23 (3~, S)9 2.08 (3H, s),
1.22 (3~, d~, 0.94 (3H, dj.
2-(Car~amoylmethoxy)ethyl monate A (Compound No 46 of Table 1)
1~ NMR ~(C~C13) 6.65 (lH, s), 6.50 (lH, s), 5.86 (1~, d), 4.54 (2H, s),
2.22 (2H, s), 1.21 (3H, d), 0.92 (3~, d3.
3-Chloroprop-2-en-1-yl monate A (Compound No 47 of Table 1)
1~ NMR ~(CD~13) 6.37-5.91 (2H, m~, 5.79 (1~, s), 5.81 & 4.59 (2~, 2 x
d), 2.21 (3~, s), 1.22 (3~, d), 0.94 (3~, d).
Ethyl monate A ~Compound No 35 of Table 1)
NMR ~(CDCl3) 5.75 (lH, s), 4.12 (2H, q), 2.21 ~3H, s), 1.29 ~3H, t~,
1.21 (3~, d), 0.93 (3H, d).
Butyl monate A ~Compound No 37 of Table 1)
1~ NMR ~(CDC~3) 5.75 (1~, s), 4.10 (2~, t), 2.20 (3~, s), 1.65 (2~, m),
1.38 (2~, m), 1.21 t3~, d), 0.92 (6~, m).
~yelohexyl mona~e A (Compound Mo 39 of Table 1)
:: :
H NHR ~(CDCl3) 5.73 (1~, s), 4.78 (lH, m), 2.21 ~3~, s), 1.80-1.20 -~
~10~, s~ 22 (3~, d), 0.94 (3~, d).
~thoxy~ethyl monate ~ (Compound No 76 of Table 1).
1~ NMR ~(CDCl3) 5.79 (1~, s), 5.30 (2~, sj, 2.22 (3~, S)9 1.22 (3H, d),
0.92 (3B, d).
: EXAMPLE 33
This Example illustrates the preparatio~ of 2-(allyloxy)ethyl monate A
(Compound No 23 of Table I)
.
S~age 1 Preparation of l-Mesyloxy-2-allyloxyethane
2-Allyloxyethanol (5.0g, 49mM) uas stirred with trie~hy~amine (5.2g,
51mM) in dichloro~etha~e (25ml3 at 0C under nitrogen. Methanesulphonyl
rhloride (5.61g, 49mM) was added slowly with stirring. The cooling bath
was removed at the mixture stirred at room temperature for a further
1 hour. Yolatile components were removed by evaporation in vacuo. The
93/19599 ~, PCTJGB93/00542
~ 28 -
residue was partitioned between diethyl ether and water. The organic
fraction was washed twice with water and once uith brine, dried (MgS04) and
evaporated in vacuo. The product was a yellow oil.
Stage 2 Preparation of 2-(allyloxy)ethyl monate A
80dium monate A (165mg, 0.45mM) was dissolved in dimethylformamide
(2ml) and stirred with 1-mesyloxy-2-allyloxyethane (162mg, 0.90mM) and
N,N-dimethylpropyleneurea (0.39ml) at room temperature for 19 hours.
Volatile components were removed by evaporation in vacuo. Separation on
silica eluting with 55:45 acetone/hexane gave the desired product as a
colourless oil.
~ ~MR ~(CDC13) 5.gO (1~, m), 5.81 (1~, s), 5.27 (lH, d), 5.20 (lH, d),
4.27 (2~, t), 4.05 (2~, d), 3.75 (2~, t), 2.21 (3~, s), 1.22 (3H, d), 0.92
(3H, s)~
EXAMPLES 34 TO 37
The following compounds were prepared using ~he general method of
Example 33:-
3-Yinyloxypropyl ~onate A (Compound No 33 of Table 1)
1~ NMR ~(CD~13) 6.46 (lH, dd), 5.76 (lH, s), 4.19 (3H, m), 4.01
(1~, dd~, 3.79 (2~, t), 2.21 (3~, s3 ? 1.23 (3~, d), O.9S ~3H, d)~
2~(3-Chloroprop-2-en-1-yIoxy)ethyl monate A No 44 of Table l)
1~ NMR ~CDCl3) 6.20 ~1~, d), 5.95 (1~, q), 5.81 (1~, s), 4.27 (4~, m),
3.70 (2~, t~t 2.22 (3~, s), 1.22 (3H, d), 0.94 (3~, d3.
4-Vinyloxybut-1-yl monate A ~Compound No 32 of Table l)
lH ~M~ ~(CDCI3) 6.46 (1~, abq), 5.74 (1~, s), 4.11 (2L, m~, 2.21
(3~, s), 1.20 ~3Ht d)7 0.92 (3~9 d).
2-1prop-2-yn-1-yloxy)ethyl monate A (Compound No 43 of Table l)
~ R ~(CDCl3) 5.80 (1~, s), 4.28 ~2~, t), 4.21 (Z~, d), 3.79t2H, t)
2.48 (1~, t), 2.21 (3~, s), 1.21 (3L, d), 0.94 (3~, d~
EXAMPLE 38
This Example illustrates the prepara~ion of N,N-Die~hyl-monicamide A
(Compound No 63 of Table I)
Monic acid A (200mg, 0.58mM) was dissolved in tetrahydrofuran (5ml)
and cooled to -10C u~der nitrogen. Triethylamine (59mg, 0.58mM) and
i~obutylchloroformate (80mg, 0.58mM~ uere added and s~irred for 30 minutes.
93/19599 ~ 3 7 ~ g3
A solution of diethylamine (47mg, 0.58mM) in tetrahydrofuran (0.5 ml) was
added an the reaction mixture stirred for 1 hour and ~hen at room
temperature for 2 hours. The reaction mixture was filtered and evapora~ed
in vacuo. Thin layer chromatography indicated that the reaction was
incomplete so further diethylamine (20mg) in tetrahydrofuran (3ml) was
added and the mixture stood at room temperature overnight. Volatile
components were removed by evaporation in vacuo. The residue was taken up
in water (lOml) and extracted with chloroform (3xlOml). The combined
organic extracts were dried (HgS04) and evaporated in vacuo. The resulting
residue was purified by column chromatography (silica gel? eluting with
methanol/chloroform 1:9) to give the desired product as a colourless gu~.
H NMR ~(CDC13) 5.87 (1~, s), 1.91 (3~, s), 1.21 (3H, d), 1.12 (6H, m),
0.92 (3~, d).
EXAMPLES 39 TO 56
The following compound was prepared using the general method of
Example 38: -
Monic acid A morpholine amide (Compound No 64 of Table I)
H NMR 8(CDC13) 5.81 (1~, s), 3.67-3.47 (8H, m), 1.90 (3~, s), 1.21
(3~, d), 0.94 (3H, d).
N-C2,4-Dichlorophenyl)-N-methyl~onic amide A (Compound No 60 of Table 1)
H ~MR ~(CDC13) 7.50-7;.15 (3H, m), 5.49 (1~, s), 3.20 (3~, s), 2.18
(3~,~s), 1.22 ~3L, d),~O.95 (3H, d~. ;
N-(2-~ydroxyethyl)monica ide A (Co~pound No 77 of Table 1).
H NMR~ d6-DMSO) 7.89 (1~, t), 5.81 (1~9 5)9 4.51 (4H, m~, 2.21 (3H, s),
1.21 (3H, d), 0.95 (3H, d).
N-(2-Ethoxyethyl)monicamide A (Compound No 78 of Table 1).
1~ NMR ~(d6-DMSO) 6.21~(lH, ~), 5.68 (1~, s), 3.62-3.42 (6H, m), 2.20
(3H, s), 1.20 (6~, m), 0.92 (3H, d).
N-(Ethoxycarbonylmethyl)mo~icamide A (Compound No 66 of Table 1)
1~ NMR ~(CDC13) 6.24 ~lH, t), 5.73 (1~, s), 4.23 (2~, q), 4.06 (2~, d),
2.19 ~3H, s), 1.30 (3H, t), 1.22 (3H, d), 0.92 (3~, d).
Monicamide A (Compound No 61 of Table 1)
lH NMR ~(d4-MeO~) 5.93 (1~, s), 2.29 (3~, s), 1.35 (3~, d), 1.10 t3~, d).
W O 93/19599 - PCT/GB93/00542
~3~ 9 - 30 -
N-(2,4-Dichlorophenyl)monicamide A (Compound No 58 of Table 1)
lH NMR ~(d4-MeOH) 7.99 (lP., d), 7.63 (lH, d), 7.45 (1~ dd), 6.20 (lH, s~,
2.38 (3H, s), 1.33 (3H, d), 1.10 (3H, d).
N,N-bisallylmonicamide A (Compound No 79 of Table 1).
1~ NMR ~(CDC13) S.89 (~H, s), 5.76 (2H, m), 5.16 (4H, m), 1.97 (3H, s),
1.22 ~3~, d), 0.93 (3H, d).
Monic acid A piperidine amide (Compound No 80 of Table 13.
H NMR ~(CDC13) 5.81 (lH, s3, 3.50 (4H, m), 1.85 ~3H, s), 1.60 (6H, m),
1.21 t3H, d), 0.92 (3H, d).
. :.
Monic acid A N-methylpiperazine amide (Compound No 81 of Table 1).
H NMR ~(d4-MeO~) 5.99 (lH, s), 3.72 (4~, m), 2.56 ~4H, t), 2.44 (3H, s),
1.97 ~3H, s), 1.32 (3~, d), 1.06 (3H, d). ~:~
,,
NrN-Dimethylmonichydrazide A (Compound No 82 of Table 1).
1~ NMR ~(CD~13) 5.52 (lH, s), 2.40 (6~9 s), 2.04 (3H, s), 1.10 (3H, d), :::~0.83 (3H, d).
Mo~ichydrazide A (Compound No 65 of Table 1) -~
~: H N~R ~(d4-MeQH) 5.80 ~(lH, s), 2~28 (3~, s), 1.30 (3H, d), 1.04 (3H, d).
'::
N-(Prop-2~ylidiene)~onichydrazone A (Compound No ~3 of Table 1).
1~ NMR ~(d4-MeOH) 6.84 (1~, s), 5.76 ~lH, s), 2.33 (3H, s), 2.20 (3H, s),
2.12 (38, s), 1.35 (3~, d), lolO (3~, d).
: N-~2,5-Dichlorophenyl)monicamide A ~Compound No 59 of Table 1)
~H ~MR ~(d6-DMSO) 9.42 (lH, s), 7.86 (lH, d), 7.46 (lH, d), 7.18 (lH, dd), ::~
6.05 (1~, s~, 2.21 (3~, s), 1.02 (3H, d), 0.80 t3H, d).
Monic acid A pyrrolidine amide (Compound No 84 of Table 1).
H NMR ~(CD~13~ 5.8B (lH, s), 3.4~ (4~, m), 2.08 (3H, s), 1.90 ~4H, m),
1.21 (3H, d3, 0.92 (3~, d).
W O 93/1959g ~ 7 il ~ PCT/~B93/00542
Monic acid A 2,6-dimethylmorpholine amide (Compound No 85 of Table 1).
lH NMR ~(CDCl3) 5 80 (lH, s), 3.50 (6H-, m), 1.85 (3B, s), 1.20 (9H, m),
0.93 (3H, d).
N-Allylmonicamide A ~Compound No 86 of Table 1).
NMR ~(CDC13) 5.92-5.72 (2~, m), 5.68 (lH, s), 5.22-5.10 ~2~, m), 3.10
(2H, m), 2.18 (3~, s), 1.21 (3~ d), 0.92 (3H, d).
N,N-bis(2-hydroxyethyl)monicamide A (Compound No 87 of Table 1~.
H NMR ~(d6-DMS0) 5.90 (1~, s), 3.40 (4~, m), 3.30 (4~, m), 1.80 (3H, s),
1.10 ~3~, d), 0.78 ~3H, d)
EXAMPLE 57
This Example illustrates the prepara~ion of S-(carbometh~xymethyl)
thiomonate A (Compound No 75 of Table I).
ffonic acid A (80mg, 0.23mM) was dissolved in tetrahydrofuran ~3ml) and
cooled to -10C under nitrogen. Triethylamine (24mg, 0.23mM~ and a
solution of isobutylchloro~ormate (32mg, 0.232M) in tetrahydrofuran ~0.7ml)
were added and stirred for 20 minutes. A solution of me~hylthioglycolate
~25mg, 0.23mM~) in tetrahydrofuran (0.5 ml) was added an the reaction ~:
mixture stirred for 1 hour and then at room temperature ~cr 3 hours. The
. ,
reactlon mixture was evaporated in vacuo and the resulting residue stored
at room temperature for 7 days. The mixture was purified by column
chromatography ~silica gel, eluting ~ith methanol/chloroform 1:9) to give
the desired product as a colourless gum (67 m~, 67~
N~R ~CD~13) 6.10 ~ 9 S~ 4.76 ~3~, s), 4.74 (2~, s~ 2.21 (3~, s),
1.22 (3~, d), 0.93 (3~:d).
EgAHPLES 58 AND 59
The following compounds were prepared using the general method of
Example 57.
S-Phenylthiomonate A (Compound No 74 of Table 1~
1~ NMR ~(CDCl3~ 7.42 (~H, s3, 6.18 (l~ s), 2.20 (3~, S)7 1.22 (3~, d),
0.92 (3~, d).
S-(2-Yinyloxye~hyl)thiomonate A (Compound No 68 of Table 1~
1~ NMR ~(~D~13) 6.45 (1~, dd), 6.07 (1~, s), 5.80 (2H, s), 3.18 ~2a, t),
2.21 (3H, s), 1.73 (2~, t), 1.21 (3~, d), 0.95 (3~r d~.
W O 93/1g5g9 - PCTlGB93/00542
32 -
EXAMPLE 60
This Example illustrates the preparation of 3-Nitrophenyl monate A
(Compound No 52 of Table 1).
Monic acid A (200mg, 0.58mM) was dissolved in tetrahydrofuran ~5.5ml)
and cooled to -10C under nitrogen. Triethylamine ~59mg? 0.58mM) and
isobutylchloroformate (80mg, 0.58mM) were added and stirred for 10 minutes -
and then at room temperature for 1 hour. Solids were removed by filtration
and the filtrate con~entrated in vacuo. The residue was taken up in
dichloromethane (2.5ml) and 3-nitrophenol (323mg, 2.32mM) added. A
solution of pyridine (35mg) in dichloromethane (0.5ml~ was added to give a
clear homogeneous solution and the mixture was stirred at room temperature
overnight. Solvents were removed ~n vacuo and separated on silica elu~ing
with 55:45 acetoneJhexane to give the desired product.
,
'~ NMR ~(CDC13) 8.10 (lH, d~, 8.02 tlH, m), 7.54 (1~, t), 7.47 tlH, d),
6.02 (lH, S)9 2.19 (3~, s), 1.22 (3~, d), 0.95 (3H, d~. -
EXAMPLES 61 T0 67
The following compounnds ~ere preared using th~ general method of
~xample 60:
: : .:
Phenyl monate A (Compound No 50 of Table 1)
NHR~(CDC13) 7.~39 ~2~, t), 7.21 (lH, t37 7.10 (2H, d), 6.00 (lH, s),
2.28 (3~, s), 1.21 (3H, d), 0.93 (3~, d).
Purfuryl mon te A (CoMpo~nd No 56 of Table 1~
NMR ~(C~C13~ 7.42 (1~, s), 6.41 (1~, d)9 6.32 (1~, t), 5~79 (lH~ s),
5.08 (2~, s), 2.22 (3~, s)~ 1.21 (3~, d), 0.94 (3M, d).
Neopentyl monate A (Compound No 38 of Table 1)
NMR ~(CDC13) 5.78 ~lH, s), 3.79 (2H, s)y 2.21 (3H, s)~ 1.21 (3H, d),
0.95 (12~, m).
2-Chloroethyl monate A (Compound No 57 of Table 1)
H NMR ~(CD~13) 5.81 (1~, s), 4.37 (2H, t), 3.72 (2~, t~, 2.24 (3H, s),
1.22 (3H, d), 0.98 (3~9 d).
4-Methoxyphenyl monate A (Compound No 53 of Table 1~
H NMR ~(CDC13) 7.01 (2~, d), 6.88 (2H, d), 5.97 (lH, s), 3.80 (3H, s),
2.26 (3H, s), 1.22 (3~, d), 0.94 (3H, d).
W O 93/19599 PCT/GB93/00542
33 ~ ~ ~ 3 7 ~
4-Chlorophenyl monate A (Compound No 51 of Table 1)
lH NMR ~(CDC13) 7.28 (2H, d), 6.97 ~2~, d), 5.91 (lH, s), 2~20 (3H, s),
1.15 (2H, d), 0.88 (2H, d).
2-(Vinylthio)ethyl monate A (Compound No 67 of Table 1)
H NMR ~(CDC13) 6.33 (lH, dd), 5.78 (1~, s), 5.28 (1~, d), 5.20 (lH, d),
4.28 (2H, t), 2.95 (2~, t), 2.21 (3~, s), 1.21 (3~, d), 0.95 (3H, d).
EXAMPLE 68
The following Example illustrates the preparation of Monic acid A
trimethylsulphonium salt (Compound No 88 of Table 1).
Trimethylsulphonium iodide t59mg, 0.29mM) was dissolved in water (5ml)
and treated with Dowex lX2 (HO ) resin for 10 minutes. The solution was
filtered into a solution of monic acid A (lOOmg, 0.29 ~M) in water (lOml)~
The solution was freeze-dried to give the desired product.
lH NMR ~(D20) 5.70 ~1~, s), 2.83 (9~, s), 1.90 (1~, s), 1.16 (3H, d),
0.91 (3H, d~.-
EXAMPLE 69
The following Example illustrates the preparation of ~-
4-(Methoxycarbonyl~phenyl monate A (Compound No 54 of Table 1).
~ Monic ac~d A (250mg, 0.72mM) ~as dissolved in dichloromethane (3ml). A
solution of triethylamine~(74mg, 0.73mM) in dichloromethane (lml) was added
and the mixture stirred at room temperature for S minutes. The reaction
mixture was cooled in an ice/~ater bath and a solution of
isopreny}chloroformate (88mg, 0.73m~) in dichloromethane (lml) added slowly
and the ~ixture stirred~with cooling for a further 10 minutes.
4-~Methoxycarbonyl)phenol (166mg, 1.09mM) and N,N-dimethylaminopyridine
(9mg) were added and~the mixture stirred for a fur~her 2 hours with
cooling. The crude reaction mixture was separated on silica eluting with
55:45 acetone~hexane to give the desired product.
1~ NMR 8(CDC13) 8.08 (2~, d), 7.18 (2~, d), 5.99 (1~, s)~ 3.91 (3~, s),
2.27 (3~, s), 1.21 (3~, d), 0.93 (3H, d).
EXAMPLE 70
The ollowing Example illustrates the preparation of 2-Vinyloxyethyl
pseudomonate A (Compound No 89 of Table 1).
Pseudomonic acid A (200mg, 0.40mM) was dissolved în acetone (2ml) and
stirred with l-chloro-2vinyloxyethane (85mg, 0.60mM~ and sodium iodide
(132mg, 88mM). Potassium carbonate ~83mg, 0.60mM) ~as added and the
W O ~3/l9599 PCT/GBg3~00542
~ '`3
mixture stirred at room temperature for 2 hours and at reflux overnight.
Volatile components were removed by evaporation in vacuo. The residue was
taken up in dimethylformamide (lml) and N,N-dimethylpropyleneurea
(0.5ml) and heated at 80C for 4 hours. Further portions of
1-chloro-2-vinyloxyethane (85mg, 0.60mM) and sodium iodide ~120mg) were
added and heating continued for 8 hours. The reaction mixture was ~-
partitioned bet~een water and diethylether and the organic layer was washed
with water and brine and then dried over magnesium sulphate. Separation on
silica eluting with 55:45 acetone~hexane gave the desired product as a gum.
~ NMR ~(CDC13) 6.49 (lH, m), 5.76 (1~, s), 4.32 (2~, t), 4.20 (~, dd),
4.Q8 (2H, t), 2.32 ~2~, t), 2.20 (3~, s), 1.21 t3~, d), 0.95 (3~, d).
E ~ PLES 71 AND 72
The fsllowing compounds were prepared using the general method of
Example 7Q:
Ethyl pseudomonate A (Compound No 90 of Tab}e 1).
~ NMR ~(CDC13) 5.79 (lH, s), 4.15 (2~, q), 4.11 (2~, t), 2.28 (2~, t),
2~21 (3~, s), 0.95 (3~ d3.
2-~ydroxyethyl pseudo~onate A (Comp~und No 91 of Table 1).
~ NNR ~(CDC13) 5.78 (1~, s), 4.21 (2H, t~, 4.08 (2H, t), 2.32 (2H, t),
2.21 (3X, s~, 1.21 ~3H, d), 0.95 (3H, d).
E8AHPLE_73
The foll~wing Example illustrates the preparation of N,N-Diethyl
pseudomonicamide A (Compou~d No 92 of T ble 1).
Ps~udomonic acid A (200mg, 0.40mM~ ~as dissolved in tetrahydrofuran
(4ml) and cooled to -10C under nitrogen. Triethylamine (41mg, 0.40mM) and
isobutylchloroformate (5Smg, 0.40mM3 were added and stirred for 30 ~inutes.
A solu~ion of diethylamine ~32mg, 0.40mM) in tetrahydrofuran (2ml) was
added an the reaction ~ix~ure stirred for 30 minutes and then stood at room
temperature overnight. The reaction mixture was filtered and evaporated in
vacuo. The residue ~as taken up in water (lOml) and ex~rac~ed with
chloroform (3xlOml). The combined organic extraces were dried over
magnesium sulphate and evaporated in vacuo. The resulting residue was
purified by column chromaeography (silica gel, eluting with acetoneJhexane
55:45) to give the product as a colourless gum.
1~ NMR ~(CDC13) 5.78 (1~, s), 4.08 (2H, t~, 3.31 (4~, q), 2.28 (2~, t),
2.21 (3~, s), l.Z2 ~6~, t), 0.95 (3H, d).
W O 93/19599 ~ 7'1 ~; PCT/GB93/00542
- 35 _
EXAMPLE 74
This example illustrates the preparation of monic acid A .
isopropylamine salt (Compound No 96 of Table 1) ~`
Monic acid A (50mg, 0.15mM~ was dissolved in tetrahydrofuran (2ml3 and
was treated with isopropylamine (8.6mg, 0.15mM). After 20 minutes at room
temperature, a precipitate formed which was collected by filtration to give
the desired product.
lH NMR ~(CDCl3) 5.76 (1~, s), 2.21 (3H, s), 1.21 (3H9 d), 1.10 ~6~, d),
0.93 (3H, d)-
EXAMPLES 75 AND 76 .
.
The following compounds were prepared using the general method of
~Example 74: .
Monic acid A triethylamine salt (Compound No 97 of Table 1)
1~ NMR ~(CDC13) 5.B0 (lH, s), 2.88 (6H, q), 2.13 (3~, s3, 1.20 ~12H, m),
0.92 (3~, d).
Pseudomonic acid A triethylamine salt (Compound No 98 of Table 2) ~
H NMR ~(CDC13) 5.78 (lH, s), 4.08 ~2~t t), 3.00 (6~9 q), 2.21 (3H, s),
1.25 (9~t t), 0.94 (3H, d)~
XAMPLE 77
This Example illus~rates the preparation of Monic acid A sodium salt
(Compound No 99 of Table 1)
Monic acid A (1.2g, 3.48mM) was suspended in water (35~1) and was
treated ~ith an aqueous O.lM solution of sodium hytroxide (34r8ml, 3.48mN~.
The solution was freeze dried to give the desired produc~ as a white solid.
1~ N~R ~(D20) 5.69 (lH, s~, 1.85 (l~, s), 1~15 (3~, d), 0.90 (3H, d).
EXA~PLE 78
.
: This Example illustrates the preparation of 2-ethoxyethyl monate C
(Compound No la8 of Tab~e 3? from monic acid C (~ompound No 107 of Table 3)
~ onic acid C (1.62g, 0.49mM) was taken up in a mixture of
dimethylformamide (lml) and N,N-dimethylpropyleneurea (0.43ml). Potassium
ca~bona~e (0.102g, 0.74mM) was added and the reaction mixture stirred for 1
hour at 80-90CC. After cooling to room temperature, a solution of
2-chloroethylethylether (0.107g, O.99mM~ in dimethylformamide (0.5ml) was
added and the mixture stirred at room temperature for 19 hours, at 90C for
6 hours and then lef~ to stand at room temperature overnigh2. Volatile
components were remo~ed in ~acuo and the residue separated on silica1
~j~ 3 36 - PCT/GBg3/00542
eluting with acetone/hexane ~1:1) to give the desired product as a gum.
1~ NMR ~(CDCl3) 5.81 Sl~, s), 5.45 (2H, d), 4.25 (2H, t), 3.75 (2~, t),
2.22 (3H, s), 1.23 ~3H, t), 1.17 (3H, d), l.00 (3H, d).
E~AMPLES 79 T0 87
The fol~owing compounds ~ere prepared using the general me~hod of :
Example 20:-
2-(Hex-2-en-1-yl)ethyl monate A ~Compound No 94 of Table 1)
H NMR ~(~DC13) 5.80 (lH, s), 5.30-5.60 (2H, m), 4.22 (2~, t), 2.21
(3~, s), 1.21 (3~, d), 0.95 (6H, m).
~:
Cyclopropylmethyl monate A (Compound No 93 of Table 1) :~
1~ NMR ~C~Cl3) 5.80 (1~, s), 3~92 (2~, d), 2.23 (3~, .c), 1.23 (3H, d), .
0.94 (3~, d), 0.57 (2~, m~, 0.29 (2~, m).
(E/Z) 2-(Prop-1-en~l-yloxy)ethyl monate A (1:1) (Co~pound No 24 of Table 1
1~ NMR ~(CDC13) 6.24 and S.79 (1~, 2 x d), 5.80 S1~, s), 4.81 and 4.44
, 2 x m),4 26 (2~, m),:2.23 (3L, s), 1.23 (3d, d), 0.95 (3~, d)~
2-(Prop-2-yloxy)ethyl monate A ~239075) (Compound No 100 vf Table 1)
N~R~ ~CDCl3~ 5.Bl lld, s), 4.22 (2H, m), 3.63 (2H, t), 2.22 (3H, s),
1.:Z3 (3H, d), 1.18 (6B, d), 0.95 (3~, d).
2-Hethoxyethyl monate A (Co~pound No 101 of Table 1)
~ NMR ~(CDC133 5.83 (1~, s)~ 4.25 (2H, t), 3.60 (2B, t), 3.40 ~3H, s~,
2.22 (3~, s), 1.23 ~3H, d3, 0.95 (3~, d).
:: :
2-(Prop-1-yloxy)-ethyl monate A (Compound No 102 of Table 1), a mix~ure of
diastereo~somers
lH NMR ~(CDCl3) 5~80 (lH, s), 4.23 t2H, t), 3.65 (2~, t), 2~21 (3H, s~,
1.60 (2H, t), 1.21 (3~, d), 0.90 (6~, m).
2-Ethoxy-1-methylethyl monate A ~Compound No 103 of Table 1~ -
~ NMR ~(CDCl3) 5.78 (1~, s), 5.09 (lH, m), 2.21 ~3~ s~, 1.20 (9H, 0),
0.93 ~3H, d).
W O 93/19599 ~ PCT/GB93/00~42
2-Cyclopropyloxyethyl monate A (Compound No 104 of Table 1)
H NMR ~CDC13) 5.81 (lH, s), 4.21 (2~, t), 3.72 (2~, t), 2.21 (3H, s),
1.21 (3~, d), O.9S (3~, d), 0.60 (2~, m), 0.50 (2H, m).
2-Ethoxy-2-methylethyl monate A (Compound No 105 of Table 1), a mixture of
diastereoisomers. ~lH NMR ~(CDCl3) 5.68 (lB, s), 4.02 (2H, t), 2.21 (3H, s), 1.15 (6~7 m), ~:
0.88 (6~, m).
EXAMPLE 88
The follouing compounds were prepared using the general method of
Example 60.
A (5:2) mixture of
i) 2-(hex-1-en-1-yloxy)ethyl monate A (Compound No 34 of Table 1)
lH NMR ~CDGl3) 5.91 (1~, d), 5.79 (lH, s), 4.38 (lH, q), 2.20 (2H, s),
1.21 (3~, d), 0.92 (3~, d).
and
ii) 2~ (vinyl~-but-1-yloxy)ethyl monate A (Compound No 95 of Table 1)
: ~ N~R ~(CDC13) 5.79 (1~, s), 5062 (1~, m), 5.20 ~lH, d), 2.20 (2H, s),
1.21 ~3~, d), 0.92 (3H, d).
EXAMPLES 89 ~ND 90
: The follo~ing co~pounds ~ere prepared using the general method of
Example 38:
N-Methoxymnnicamide A (Compound No 106 of Table 1)
1~ NMR ~(d6-DMS0) 5.58 (1~, s), 3.70 (3H, s), 2.20 (3~, s), i.21 ~3~, d),
0.95 (3H, d).
N-Ethylmcnicamide A (Co~pound No 62 of Table 1)
H NMR S(CDC13~ 5.64 (1~, s), 5.54 (1~, t), 3.33 (2~, q), 2.18 (3~, s),
1.22 (3'~, d), 1.17 (3H, t), 0.~5 (3~, d).
EXAMPLE 91
This ~xample illustrates the herbicidal properties of compounds
according to the inven~ion.
The herbicidal activity of the compounds was tested as follows:
Each chemical was formulated by dissolving it in an appropriate amount,
dependent on the final spray volumef of a solvent/surfactant blend which
comprised 78.2 gm/litre of Tween 20 and 21.8 gm/litre of Span 80 adjusted ~:
W 0 93/1~599 ~ 38 - PCT/~B93/00542
to 1 litre using methylcyclohexanone. ~ween 20 is a Trade Mark for a
surface-active agent comprising a condensate of 20 molar proportions of
ethylene oxide with sorbitan laurate. Span 80 is a Trade Mark for a
surface-active agent comprising sorbitan mono-laurate. If the chemical did
not dissolve, the volume was made up to 5cm3 with water, glass beads were
added and this mixture was then shaken to effect dissolution or suspension
of the chemical, after which the beads were removed. In all cases, the
mixture was then diluted with water to the required spray volume. If
sprayed independently, volumes o~ 25cm3 and 30cm3 were required for
pre-emergence and post-emergence tests respectively; if sprayed together,
45cm was required. The sprayed aqueous emulsion contained 4X of the
~initial solvent/surfactant mix and the test chemical at an appropriate - concentration.
The spray compositions so prepared were sprayed onto young pot plants
(post-emergence test) at a spray volume equivalent to 1000 li~res per
hectare for Compound Numbers 1 to 22 and 400 litres per hectare for
Com~pound Numbers 23 to 94.~ Damage to plants was assessed 13 days after
; spraying~by comparison with untreated plants, on a scale ~f O to 9 where Ois O~damage, 1 is 1-5Z damage, 2 is 6-15X damage, 3 is 16-25Z damage, 4 is
26~3SX damage, 5 is 36-59% damage, 6 is 60-69% damage, 7 is 70-79% damage,
8~is 80-89Z damage and 9 is 90-lOOZ damage.
The~designation n_~ indicaees that a compound wàs not tested against
the~indicated species.
The~ rèsults of the tests are given in Table III below.
:
- .
WO 93/19599 PCI`/~1393/0~i42
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- 45 -
TABLE IV
Abbreviations used for Test Plants
_
BV - Sugar beet
BN - Rape
GM - Soybean
ZM - Maize
OS - Rice
TA - Winter wheat
PA - Polygonum aviculare
CA - Chenopodium album
`GA - Galium ~
AR - Amaranthus retroflexus
BP ~ ~
EH - llup rbi a he teropvl la
AT - Abutilon ~heophrasti
XT - Xanthium strumarium
AF - Avena fatua ~-
~M _ . Alopecurus osu~
GPY~n.~2~, "'
SH - Sor~hum
5V - Setaria viridis
DS - ~5
EC ~ Echinochloa ~E~
CE - ~ esculentus
MI - Matricaria per~orata
L~ - Lolium ~
PD - Paniucum di cotomi f i rum
WO 93J19599 PCl`/GB93/00542
- 46 -
C~EMICAL FORMULAE
( IN DESCRIPTION )
f~ :
E~ Q~c~ ~CE~C~2~ ~C~ 2
f (I~
c~3
Cl~33 110~ f~3~C~2~f~;c~3~1z
3 ~C~3C~3c;~c~3~c3~ce~c ~O C~3 (LO
0~1
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~I3C ~ CE~ ,,C~ ,~O ~ 3 O
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O
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~C / ~CE~ 1 ( IE )
WO 93/1~599 PCl/GB93/0054
-- 47 _
C~ ICAL FORMULAE
( IN l~ESCRIPTION ) ::
N,~<RX~4 ( II )
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o
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WO 93/19599 PCI`/GB93/00542
- 48 -
CHEMICAL FORMUI~
IN DESCRIPTION )
\C~C O (VII)
11 \~3 :
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N~CH3
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WO93/19~99 ~ ? 7 q ~ PCI`/GB93/00542
-- 49 -
CHEMICAL FOR~UI~E
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