U.S. patent application number 15/027768 was filed with the patent office on 2016-09-15 for herbicidal compounds.
This patent application is currently assigned to SYNGENTA PARTICIPATIONS AG. The applicant listed for this patent is SYNGENTA LIMITED, SYNGENTA PARTICIPATIONS AG. Invention is credited to Jutta Elisabeth BOEHMER, Timothy Robert DESSON, Jake GOODWIN-TINDALL, Alan Joseph Hennessy, Matthew Brian HOTSON, Kenneth LING, Adrian LONGSTAFF, James Alan Morris, Mangala PHADTE, Clarie Janet RUSSELL, Sally Elizabeth RUSSELL, Ravindra Sonawane.
Application Number | 20160264547 15/027768 |
Document ID | / |
Family ID | 51659651 |
Filed Date | 2016-09-15 |
United States Patent
Application |
20160264547 |
Kind Code |
A1 |
PHADTE; Mangala ; et
al. |
September 15, 2016 |
Herbicidal Compounds
Abstract
The invention relates to pyrrolone compounds of the formula (I),
wherein X, R.sup.1, R.sup.2, R.sup.3, R.sup.a, R.sup.b, R.sup.c and
R.sup.d are as defined in the specification. Furthermore, the
present invention relates to processes and intermediates for making
compounds of formula (I), to herbicidal compositions comprising
these compounds and to methods of using these compounds to control
plant growth. ##STR00001##
Inventors: |
PHADTE; Mangala; (Corlim,
IIhas, IN) ; Sonawane; Ravindra; (Corlim, IIhas,
IN) ; Morris; James Alan; (Bracknell, Berkshire,
GB) ; BOEHMER; Jutta Elisabeth; (Bracknell,
Berkshire, GB) ; DESSON; Timothy Robert; (Bracknell,
Berkshire, GB) ; RUSSELL; Sally Elizabeth;
(Bracknell, Berkshire, GB) ; LING; Kenneth;
(Bracknell, Berkshire, GB) ; Hennessy; Alan Joseph;
(Bracknell, Berkshire, GB) ; HOTSON; Matthew Brian;
(Bracknell, Berkshire, GB) ; LONGSTAFF; Adrian;
(Bracknell, Berkshire, GB) ; RUSSELL; Clarie Janet;
(Bracknell, Berkshire, GB) ; GOODWIN-TINDALL; Jake;
(Bracknell, Berkshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYNGENTA PARTICIPATIONS AG
SYNGENTA LIMITED |
Basel
Guildford Surrey |
|
CH
GB |
|
|
Assignee: |
SYNGENTA PARTICIPATIONS AG
Basel
CH
|
Family ID: |
51659651 |
Appl. No.: |
15/027768 |
Filed: |
October 2, 2014 |
PCT Filed: |
October 2, 2014 |
PCT NO: |
PCT/EP2014/071167 |
371 Date: |
April 7, 2016 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07D 401/04 20130101;
A01N 43/90 20130101; C07D 498/04 20130101; A01N 53/00 20130101;
C07D 405/14 20130101; C07D 487/04 20130101; A01N 43/54 20130101;
A01N 43/50 20130101; C07D 401/14 20130101 |
International
Class: |
C07D 401/04 20060101
C07D401/04; C07D 401/14 20060101 C07D401/14; C07D 405/14 20060101
C07D405/14; C07D 487/04 20060101 C07D487/04; A01N 43/90 20060101
A01N043/90; C07D 498/04 20060101 C07D498/04; A01N 43/50 20060101
A01N043/50; A01N 43/54 20060101 A01N043/54 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 7, 2013 |
IN |
2977/DEL/2013 |
Claims
1. A herbicidal compound of formula (I) ##STR00192## wherein X is
selected from S and O; R.sup.a is selected from hydrogen and
halogen; R.sup.b is selected from hydrogen, halogen,
C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl C.sub.1-C.sub.4
haloalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.4 alkenyloxy,
C.sub.2-C.sub.4 alkynyloxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.3
alkoxy-C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.4 alkylthio,
C.sub.1-C.sub.4 alkylsulfinyl, C.sub.1-C.sub.4 alkylsulfonyl, a
group R.sup.5R.sup.6N--, a group R.sup.5C(O)N(R.sup.6)--, a group
R.sup.5S(O.sub.2)N(R.sup.6)--, a group R.sup.5R.sup.6NSO.sub.2--, a
group R.sup.5R.sup.6NC(O)--, aryl optionally substituted by one or
more groups independently selected from halogen, nitro, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 haloalkoxy, aryloxy optionally
substituted by one or more groups independently selected from
halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy
and heteroaryl optionally substituted by one or more groups
independently selected from halogen, nitro, cyano, C.sub.1-C.sub.3
alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl and
C.sub.1-C.sub.3 haloalkoxy; R.sup.c is selected from hydrogen,
halogen, C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.6 cyanoalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.6 hydroxyalkyl, C.sub.2-C.sub.6 alkenyloxy
C.sub.1-C.sub.6 alkyl and C.sub.3-C.sub.6 cycloalkyl optionally
substituted by from 1 to 3 groups independently selected from
cyano, C.sub.1-C.sub.3 alkyl and C.sub.1-C.sub.3 alkoxy; R.sup.d is
selected from hydrogen, halogen, cyano, C.sub.1-C.sub.6 alkyl and
C.sub.1-C.sub.6 haloalkyl; R.sup.1 is selected from hydrogen,
hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.2-C.sub.4 alkynyl, C.sub.1-C.sub.4 cyanoalkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl and
R.sup.2 is selected from hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.2-C.sub.4 alkenyl, C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4
alkenyloxy, C.sub.2-C.sub.4 alkynyloxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 hydroxyalkyl,
C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.3 haloalkoxy and
C.sub.1-C.sub.4 cyanoalkyl, with the proviso that when R.sup.1 is
methyl, R.sup.2 is not H; or R.sup.1 and R.sup.2 together with the
nitrogen and carbon atoms to which they are attached form a 3-7
membered saturated or partially unsaturated ring optionally
comprising from 1 to 3 heteroatoms independently selected from S, O
and N and optionally substituted with from 1 to 3 groups
independently selected from hydroxyl, .dbd.O, C.sub.1-C.sub.6 alkyl
and C.sub.1-C.sub.6 haloalkyl. R.sup.3 is selected from halogen,
hydroxyl, --NR.sup.14R.sup.15, or any one of the following groups
##STR00193## R.sup.5 and R.sup.6 are independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, or R.sup.5 and R.sup.6 together with
the carbon atoms to which they are attached form a 3-6 membered
saturated or partially unsaturated ring optionally comprising from
1 to 3 heteroatoms independently selected from S, O and N and
optionally substituted with from 1 to 3 groups independently
selected from halogen and C.sub.1-C.sub.6 alkyl; R.sup.7 and
R.sup.8 are independently selected from hydrogen, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, a C.sub.3-C.sub.6 cycloalkyl group
optionally substituted with 1 to 3 groups independently selected
from C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.3 haloalkyl and C.sub.2-C.sub.4 haloalkenyl, a
C.sub.5-C.sub.10 heterocyclyl group which can be mono- or bicyclic
comprising from 1 to 4 heteroatoms independently selected from N, O
and S and optionally substituted with 1 to 3 groups independently
selected from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 alkoxy, a C.sub.5-C.sub.10 heteroaryl
group which can be mono- or bicyclic comprising from 1 to 4
heteroatoms independently selected from N, O and S and optionally
substituted with 1 to 3 groups independently selected from halogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 haloalkyl and
C.sub.1-C.sub.3 alkoxy, a C.sub.6-C.sub.10 aryl group optionally
substituted with 1 to 3 groups independently selected from halogen,
nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy, a
C.sub.6-C.sub.10 arylalkyl group optionally substituted with 1 to 3
groups independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl and the group
--OC(O)--C.sub.1-C.sub.4 alkyl, or R.sup.7 and R.sup.8 together
with the atoms to which they are attached form a 3-6 membered
saturated or partially unsaturated ring optionally comprising from
1 to 3 heteroatoms independently selected from S, O and N and
optionally substituted with from 1 to 3 groups independently
selected from halogen and C.sub.1-C.sub.6 alkyl; R.sup.9 is
selected from C.sub.1-C.sub.6 alkyl and benzyl optionally
substituted with 1 to 3 groups independently selected from halogen,
nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy; R.sup.14
and R.sup.15 are independently selected from hydrogen,
C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 haloalkyl,
C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 alkoxy-C.sub.1-C.sub.20
alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl and
benzyl, or R.sup.14 and R.sup.15 together with the carbon atoms to
which they are attached form a 3-6 membered saturated or partially
unsaturated ring optionally comprising from 1 to 3 heteroatoms
independently selected from S, O and N and optionally substituted
with from 1 to 3 groups independently selected from halogen and
C.sub.1-C.sub.6 alkyl; or an N-oxide or salt form thereof.
2. The compound of claim 1, wherein X is O.
3. The compound of claim, wherein R.sup.a is hydrogen.
4. The compound of claim 1, wherein R.sup.d is hydrogen.
5. The compound of claim 1, wherein R.sup.1 is selected from
C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4
haloalkyl.
6. (canceled)
7. (canceled)
8. The compound of claim 1, wherein R.sup.2 is selected from
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3
alkoxy-C.sub.1-C.sub.3 alkyl.
9. (canceled)
10. The compound of claim 1, wherein R.sup.3 is selected from
hydroxyl, halogen, C.sub.1-C.sub.6 alkylcarbonyloxy,
C.sub.1-C.sub.6 alkoxycarbonyloxy and aryloxycarbonyloxy wherein
the aryl group may be substituted with 1 to 3 groups independently
selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl and
C.sub.1-C.sub.3 haloalkoxy.
11. (canceled)
12. (canceled)
13. The compound of claim 1, wherein R.sup.b is selected from
hydrogen, halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.3 alkyl, heteroaryl
substituted by halogen or methoxy and aryl substituted by halogen
or methoxy.
14. (canceled)
15. (canceled)
16. The compound of claim 1, wherein R.sup.c is selected from
C.sub.1-C.sub.8 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.8
alkenyl, C.sub.1-C.sub.6 cyanoalkyl and C.sub.3-C.sub.6 cycloalkyl
optionally substituted by from 1 to 3 groups independently selected
from cyano and C.sub.1-C.sub.3 alkyl.
17. (canceled)
18. (canceled)
19. (canceled)
20. (canceled)
21. The compound of claim 1 wherein R.sup.b is selected from
R.sup.5R.sup.6NC(O)-- and R.sup.5C(O)N(R.sup.6)-- and R.sup.c is
selected from hydrogen, halo, C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.4 haloalkyl.
22. (canceled)
23. The compound of claim 1, wherein R.sup.b is selected from halo
and C.sub.1-C.sub.4 alkyl and R.sup.c is C.sub.1-C.sub.3
haloalkyl.
24. (canceled)
25. A herbicidal composition comprising a compound of formula I as
defined in claim 1 together with at least one agriculturally
acceptable adjuvant or diluent.
26. A composition according to claim 25 which comprises a further
herbicide in addition to the compound of formula I.
27. A composition according to claim 24 which comprises a
safener.
28. (canceled)
29. A method of controlling weeds in crops of useful plants,
comprising applying to said weeds or to the locus of said weeds, or
to said useful plants or to the locus of said useful plants, a
compound of formula I as defined in claim 1.
Description
[0001] The present invention relates to certain substituted
dihydro-hydantoin derivatives, to processes for their preparation,
herbicidal compositions comprising them, and their use in
controlling plants or inhibiting plant growth.
[0002] Herbicidal dihydro-hydantoins of the formula
##STR00002##
wherein A is a pyridine ring are taught in U.S. Pat. No. 4,600,430.
Similar compounds wherein A is a pyridazine ring are taught in U.S.
Pat. No. 4,604,127.
SUMMARY OF THE INVENTION
[0003] In a first aspect, the invention provides compounds of the
formula (I)
##STR00003##
wherein
[0004] X is selected from S and O;
[0005] R.sup.a is selected from hydrogen and halogen;
[0006] R.sup.b is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl C.sub.1-C.sub.4 haloalkyl,
C.sub.1-C.sub.6 alkoxy, C.sub.2-C.sub.4 alkenyloxy, C.sub.2-C.sub.4
alkynyloxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 haloalkoxy, C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.4 alkylthio, C.sub.1-C.sub.4 alkylsulfinyl,
C.sub.1-C.sub.4 alkylsulfonyl, a group R.sup.5R.sup.6N--, a group
R.sup.5C(O)N(R.sup.6)--, a group R.sup.5S(O.sub.2)N(R.sup.6)--, a
group R.sup.5R.sup.6NSO.sub.2--, a group R.sup.5R.sup.6NC(O)--,
aryl optionally substituted by one or more groups independently
selected from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl and
C.sub.1-C.sub.3 haloalkoxy, aryloxy optionally substituted by one
or more groups independently selected from halogen, nitro, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 haloalkoxy and heteroaryl optionally
substituted by one or more groups independently selected from
halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3
haloalkoxy;
[0007] R.sup.c is selected from hydrogen, halogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.4
alkoxy-C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.6 hydroxyalkyl,
C.sub.2-C.sub.6 alkenyloxy C.sub.1-C.sub.6 alkyl and
C.sub.3-C.sub.6 cycloalkyl optionally substituted by from 1 to 3
groups independently selected from cyano, C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy;
[0008] R.sup.d is selected from hydrogen, halogen, cyano,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 haloalkyl;
[0009] R.sup.1 is selected from hydrogen, hydroxyl, C.sub.1-C.sub.4
alkyl, C.sub.2-C.sub.4 alkenyl, C.sub.2-C.sub.4 alkynyl,
C.sub.1-C.sub.4 cyanoalkyl, C.sub.3-C.sub.6 cycloalkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl and C.sub.1-C.sub.4 haloalkyl and R.sup.2 is selected from
hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl, C.sub.2-C.sub.4 alkenyl,
C.sub.1-C.sub.4 alkoxy, C.sub.2-C.sub.4 alkenyloxy, C.sub.2-C.sub.4
alkynyloxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4
hydroxyalkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.3 haloalkoxy
and C.sub.1-C.sub.4 cyanoalkyl, with the proviso that when R.sup.1
is methyl, R.sup.2 is not H;
[0010] or R.sup.1 and R.sup.2 together with the nitrogen and carbon
atoms to which they are attached form a 3-7 membered saturated or
partially unsaturated ring optionally comprising from 1 to 3
heteroatoms independently selected from S, O and N and optionally
substituted with from 1 to 3 groups independently selected from
hydroxyl, .dbd.O, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
haloalkyl.
[0011] R.sup.3 is selected from halogen, hydroxyl,
--NR.sup.14R.sup.15, or any one of the following groups
##STR00004##
[0012] R.sup.5 and R.sup.6 are independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy and C.sub.1-C.sub.6
alkoxy-C.sub.1-C.sub.6 alkyl, or R.sup.5 and R.sup.6 together with
the carbon atoms to which they are attached form a 3-6 membered
saturated or partially unsaturated ring optionally comprising from
1 to 3 heteroatoms independently selected from S, O and N and
optionally substituted with from 1 to 3 groups independently
selected from halogen and C.sub.1-C.sub.6 alkyl;
[0013] R.sup.7 and R.sup.8 are independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, a C.sub.3-C.sub.6
cycloalkyl group optionally substituted with 1 to 3 groups
independently selected from C.sub.1-C.sub.3 alkyl, C.sub.2-C.sub.4
alkenyl, C.sub.1-C.sub.3 haloalkyl and C.sub.2-C.sub.4 haloalkenyl,
a C.sub.5-C.sub.10 heterocyclyl group which can be mono- or
bicyclic comprising from 1 to 4 heteroatoms independently selected
from N, O and S and optionally substituted with 1 to 3 groups
independently selected from halogen, C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 alkoxy, a
C.sub.5-C.sub.10 heteroaryl group which can be mono- or bicyclic
comprising from 1 to 4 heteroatoms independently selected from N, O
and S and optionally substituted with 1 to 3 groups independently
selected from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 alkoxy, a C.sub.6-C.sub.10 aryl group
optionally substituted with 1 to 3 groups independently selected
from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy, a
C.sub.6-C.sub.10 arylalkyl group optionally substituted with 1 to 3
groups independently selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3 haloalkyl and the group
--OC(O)--C.sub.1-C.sub.4 alkyl, or R.sup.7 and R.sup.8 together
with the atoms to which they are attached form a 3-6 membered
saturated or partially unsaturated ring optionally comprising from
1 to 3 heteroatoms independently selected from S, O and N and
optionally substituted with from 1 to 3 groups independently
selected from halogen and C.sub.1-C.sub.6 alkyl;
[0014] R.sup.9 is selected from C.sub.1-C.sub.6 alkyl and benzyl
optionally substituted with 1 to 3 groups independently selected
from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3
haloalkoxy;
[0015] R.sup.14 and R.sup.15 are, independently, selected from
hydrogen, C.sub.1-C.sub.20 alkyl, C.sub.1-C.sub.20 haloalkyl,
C.sub.1-C.sub.20 alkoxy, C.sub.1-C.sub.20 alkoxy-C.sub.1-C.sub.20
alkyl, C.sub.2-C.sub.20 alkenyl, C.sub.2-C.sub.20 alkynyl and
benzyl, or R.sup.14 and R.sup.15 together with the carbon atoms to
which they are attached form a 3-6 membered saturated or partially
unsaturated ring optionally comprising from 1 to 3 heteroatoms
independently selected from S, O and N and optionally substituted
with from 1 to 3 groups independently selected from halogen and
C.sub.1-C.sub.6 alkyl;
[0016] or an N-oxide or salt form thereof.
[0017] In a second aspect, the invention provides herbicidal
compositions comprising a compound of the invention together with
at least one agriculturally acceptable adjuvant or diluent.
[0018] In a third aspect, the invention provides the use of a
compound or a composition of the invention for use as a
herbicide.
[0019] In a fourth aspect, the invention provides a method of
controlling weeds in crops of useful plants, comprising applying to
said weeds or to the locus of said weeds, or to said useful crop
plants, a compound or a composition of the invention.
[0020] In a fifth aspect, the invention relates to processes useful
in the preparation of compounds of the invention.
[0021] In a sixth aspect, the invention relates to intermediates
useful in the preparation of compounds of the invention.
DETAILED DESCRIPTION
[0022] In particularly preferred embodiments of the invention, the
preferred groups for X, R.sup.a, R.sup.b R.sup.c, R.sup.d, R.sup.1,
R.sup.2 and R.sup.3, in any combination thereof, are as set out
below.
[0023] Preferably, X is O.
[0024] Preferably, R.sup.a is hydrogen.
[0025] Preferably, R.sup.d is hydrogen.
[0026] Preferably, R.sup.1 is selected from C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 haloalkyl. More
preferably, R.sup.1 is selected from C.sub.1-C.sub.4 alkyl and
C.sub.1-C.sub.4 alkoxy. Most preferably, R.sup.1 is selected from
methyl and methoxy.
[0027] Preferably, R.sup.2 is selected from C.sub.1-C.sub.3 alkyl,
C.sub.1-C.sub.3 alkoxy and C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.3
alkyl. More preferably, R.sup.2 is selected from methyl, ethyl,
methoxy, ethoxy and methoxymethyl. Even more preferably, R.sup.2 is
selected from methyl and ethoxy. Most preferably, R.sup.2 is
methyl.
[0028] Preferably, R.sup.3 is selected from hydroxyl, halogen,
C.sub.1-C.sub.6 alkylcarbonyloxy, C.sub.1-C.sub.6 alkoxycarbonyloxy
and aryloxycarbonyloxy wherein the aryl group may be substituted
with 1 to 3 groups independently selected from halogen, nitro,
cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy,
C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy. Even more
preferably, R.sup.3 is selected from hydroxyl and halogen. Most
preferably, R.sup.3 is hydroxyl.
[0029] In one embodiment, X, R.sup.a, R.sup.d, R.sup.1, R.sup.2 and
R.sup.3 are as described above in any combination and R.sup.b and
R.sup.c are as described below in any combination.
[0030] Preferably R.sup.b is selected from hydrogen, halogen,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
alkoxy-C.sub.1-C.sub.3 alkyl, heteroaryl substituted by halogen or
methoxy and aryl substituted by halogen or methoxy. More
preferably, R.sup.b is selected from hydrogen, halogen, methoxy,
heteroaryl substituted by halogen or methoxy and aryl substituted
by halogen or methoxy groups. Even more preferably, R.sup.b is
hydrogen.
[0031] Preferably, R.sup.c is selected from C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.6
cyanoalkyl and C.sub.3-C.sub.6 cycloalkyl optionally substituted by
from 1 to 3 groups independently selected from cyano and
C.sub.1-C.sub.3 alkyl.
[0032] Even more preferably, R.sup.c is selected from
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.6
cyanoalkyl and C.sub.3-C.sub.6 cycloalkyl optionally substituted by
from 1 to 3 groups independently selected from cyano and
C.sub.1-C.sub.3 alkyl.
[0033] Even more preferably R.sup.c is selected from methyl, ethyl,
iso-propyl, (2-methyl)-prop-1-yl, (1-methyl)-prop-1-yl, tert-butyl,
(1,1-dimethyl)-prop-1-yl, (1,1-dimethyl)-but-1-yl,
(1-methyl-1-ethyl)-prop-1-yl, cyclobutyl, cyclopropyl,
(1-methyl)cycloprop-1-yl, (1-methyl-1-cyano)-eth-1-yl,
(1-methyl-1-ethyl-2-cyano)-prop-1-yl,
(1,1-dimethyl-2-cyano)-prop-1-yl, 1-fluoroethyl, 1,1-difluoroethyl,
difluoromethyl, 1-fluoro-1-methylethyl and trifluoromethyl.
[0034] Even more preferably, R.sup.c is selected from tert-butyl,
(1-methyl-1-cyano)-eth-1-yl, 1,1-difluoroethyl,
1-fluoro-1-methylethyl and trifluoromethyl.
[0035] Most preferably, R.sup.c is trifluoromethyl.
[0036] In particular, the substituted pyridine may be
4-tert-butyl-pyrid-2-yl,
4-((1-methyl-1-cyano)-eth-1-yl)-pyrid-2-yl,
4-(1,1-difluoroethyl)-pyrid-2-yl,
4-(1-fluoro-1-methylethyl)-pyrid-2-yl or
4-(trifluoromethyl)-pyrid-2-yl.
[0037] In a further embodiment, X, R.sup.a, R.sup.d, R.sup.1,
R.sup.2 and R.sup.3 are as described above in any combination and
R.sup.b is selected from R.sup.5R.sup.6NC(O)-- and
R.sup.5C(O)N(R.sup.6)--, wherein R.sup.5 and R.sup.6 are as
described above, and R.sup.c is selected from hydrogen, halo,
C.sub.1-C.sub.4 alkyl and C.sub.1-C.sub.4 haloalkyl. More
preferably, R.sup.b is R.sup.5R.sup.6NC(O)--.
[0038] In a further embodiment, X, R.sup.a, R.sup.d, R.sup.1,
R.sup.2 and R.sup.3 are as described above in any combination and
R.sup.b is selected from halogen and C.sub.1-C.sub.4 alkyl and
R.sup.c is C.sub.1-C.sub.3 haloalkyl, preferably
trifluoromethyl.
[0039] In a further embodiment, the invention provides compounds of
the formula (I)
##STR00005##
wherein
[0040] X is selected from S and O;
[0041] R.sup.a is selected from hydrogen and halogen;
[0042] R.sup.b is selected from hydrogen, halogen, C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.3 alkoxy, a group
R.sup.5R.sup.6N--, a group R.sup.5C(O)N(R.sup.6)--, a group
R.sup.5S(O.sub.2)N(R.sup.6)--, a group R.sup.5R.sup.6NSO.sub.2--, a
group R.sup.5R.sup.6NC(O)--, aryl optionally substituted by one or
more groups independently selected from halogen, nitro, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 haloalkoxy, and heteroaryl optionally
substituted by one or more groups independently selected from
halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3
haloalkoxy;
[0043] R.sup.c is selected from hydrogen, halogen, C.sub.1-C.sub.8
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.8 alkenyl,
C.sub.1-C.sub.6 cyanoalkyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
hydroxyalkyl, C.sub.2-C.sub.6 alkenyloxy C.sub.1-C.sub.6 alkyl and
C.sub.3-C.sub.6 cycloalkyl optionally substituted by from 1 to 3
groups independently selected from cyano, C.sub.1-C.sub.3 alkyl and
C.sub.1-C.sub.3 alkoxy;
[0044] R.sup.d is selected from hydrogen, halogen, cyano,
C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6 haloalkyl;
[0045] R.sup.1 is selected from hydrogen, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy and C.sub.1-C.sub.4 haloalkyl and R.sup.2 is
selected from hydrogen, hydroxyl, C.sub.1-C.sub.4 alkyl,
C.sub.1-C.sub.4 alkoxy, C.sub.1-C.sub.4 alkoxy-C.sub.1-C.sub.4
alkyl, C.sub.1-C.sub.4 haloalkyl, C.sub.1-C.sub.3 haloalkoxy and
C.sub.1-C.sub.4 cyanoalkyl, with the proviso that when R.sup.1 is
methyl, R.sup.2 is not H;
[0046] or R.sup.1 and R.sup.2 together with the nitrogen and carbon
atoms to which they are attached form a 3-7 membered saturated or
partially unsaturated ring optionally comprising from 1 to 3
heteroatoms independently selected from S, O and N and optionally
substituted with from 1 to 3 groups independently selected from
hydroxyl, .dbd.O, C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6
haloalkyl.
[0047] R.sup.3 is selected from halogen, hydroxyl, and any one of
the following groups
##STR00006##
[0048] R.sup.5 and R.sup.6 are independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, or R.sup.5 and
R.sup.6 together with the carbon atoms to which they are attached
form a 3-6 membered saturated or partially unsaturated ring
optionally comprising from 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with from 1 to
3 groups independently selected from halogen and C.sub.1-C.sub.6
alkyl;
[0049] R.sup.7 and R.sup.8 are independently selected from
hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, a
C.sub.5-C.sub.10 heteroaryl group which can be mono- or bicyclic
comprising from 1 to 4 heteroatoms independently selected from N, O
and S and optionally substituted with 1 to 3 groups independently
selected from halogen, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 alkoxy, a C.sub.6-C.sub.10 aryl group
optionally substituted with 1 to 3 groups independently selected
from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3 haloalkoxy,
or R.sup.7 and R.sup.8 together with the atoms to which they are
attached form a 3-6 membered saturated or partially unsaturated
ring optionally comprising from 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with from 1 to
3 groups independently selected from halogen or C.sub.1-C.sub.6
alkyl;
[0050] R.sup.9 is selected from C.sub.1-C.sub.6 alkyl and benzyl
optionally substituted with 1 to 3 groups independently selected
from halogen, nitro, cyano, C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy, C.sub.1-C.sub.3 haloalkyl and C.sub.1-C.sub.3
haloalkoxy;
[0051] or an N-oxide or salt form thereof.
[0052] In this particular embodiment, the preferred groups for X,
R.sup.a, R.sup.b R.sup.c, R.sup.d, R.sup.1, R.sup.2 and R.sup.3, in
any combination thereof, are as set out below.
[0053] Preferably X is O.
[0054] Preferably R.sup.a is hydrogen.
[0055] Preferably, R.sup.d is hydrogen.
[0056] Preferably R.sup.1 is C.sub.1-C.sub.4 alkyl, C.sub.1-C.sub.4
alkoxy or C.sub.1-C.sub.4 haloalkyl. More preferably, R.sup.1 is
C.sub.1-C.sub.4 alkyl or C.sub.1-C.sub.4 alkoxy. Most preferably,
R.sup.1 is methyl or methoxy.
[0057] Preferably R.sup.2 is C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3
alkoxy or C.sub.1-C.sub.3 alkoxy-C.sub.1-C.sub.3 alkyl. More
preferably R.sup.2 is methyl, methoxy, ethoxy or methoxymethyl.
[0058] Preferably, R.sup.3 is hydroxyl, halogen, C.sub.1-C.sub.6
alkylcarbonyloxy, C.sub.1-C.sub.6 alkoxycarbonyloxy or
aryloxycarbonyloxy wherein the aryl group may be substituted with 1
to 3 groups independently selected from halogen, nitro, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkyl and C.sub.1-C.sub.3 haloalkoxy. Even more preferably,
R.sup.3 is hydroxyl or halogen. Most preferably, R.sup.3 is
hydroxyl.
[0059] In one embodiment of this embodiment, X, R.sup.a, R.sup.d,
R.sup.1, R.sup.2 and R.sup.3 are as described above in any
combination and R.sup.b and R.sup.c are as described below in any
combination.
[0060] Preferably R.sup.b is hydrogen, halogen, methoxy, heteroaryl
substituted by halogen or methoxy or aryl substituted by halogen or
methoxy groups.
[0061] Even more preferably, R.sup.b is hydrogen.
[0062] Preferably, R.sup.c is C.sub.1-C.sub.8 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.8 alkenyl, C.sub.1-C.sub.6
cyanoalkyl or C.sub.3-C.sub.6 cycloalkyl optionally substituted by
from 1 to 3 groups independently selected from cyano and
C.sub.1-C.sub.3 alkyl.
[0063] Even more preferably, R.sup.c is C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.3 haloalkyl, C.sub.1-C.sub.6 cyanoalkyl or
C.sub.3-C.sub.6 cycloalkyl optionally substituted by from 1 to 3
groups independently selected from cyano and C.sub.1-C.sub.3
alkyl.
[0064] Even more preferably R.sup.c is methyl, ethyl, iso-propyl,
(2-methyl)-prop-1-yl, (1-methyl)-prop-1-yl, tert-butyl,
(1,1-dimethyl)-prop-1-yl, (1,1-dimethyl)-but-1-yl,
(1-methyl-1-ethyl)-prop-1-yl, cyclobutyl, cyclopropyl,
(1-methyl)cycloprop-1-yl, (1-methyl-1-cyano)-eth-1-yl,
(1-methyl-1-ethyl-2-cyano)-prop-1-yl,
(1,1-dimethyl-2-cyano)-prop-1-yl, 1-fluoroethyl, 1,1-difluoroethyl,
difluoromethyl, 1-fluoro-1-methylethyl or trifluoromethyl.
[0065] Even more preferably, R.sup.c is tert-butyl,
(1-methyl-1-cyano)-eth-1-yl, 1,1-difluoroethyl,
1-fluoro-1-methylethyl or trifluoromethyl.
[0066] Most preferably, R.sup.c is trifluoromethyl.
[0067] In particular, the substituted pyridine may be
4-tert-butyl-pyrid-2-yl,
4-((1-methyl-1-cyano)-eth-1-yl)-pyrid-2-yl,
4-(1,1-difluoroethyl)-pyrid-2-yl,
4-(1-fluoro-1-methylethyl)-pyrid-2-yl or
4-(trifluoromethyl)-pyrid-2-yl.
[0068] In a further embodiment of this embodiment, X, R.sup.a,
R.sup.d, R.sup.1, R.sup.2 and R.sup.3 are as described above in any
combination and R.sup.b is R.sup.5R.sup.6NC(O)-- or
R.sup.5C(O)N(R.sup.6)--, wherein R.sup.5 and R.sup.6 are as
described above, and R.sup.c is hydrogen, halo, C.sub.1-C.sub.4
alkyl or C.sub.1-C.sub.4 haloalkyl. More preferably, R.sup.b is
R.sup.5R.sup.6NC(O)--.
[0069] In a further embodiment of this embodiment, X, R.sup.a,
R.sup.d, R.sup.1, R.sup.2 and R.sup.3 are as described above in any
combination and R.sup.b is halogen or C.sub.1-C.sub.4 alkyl and
R.sup.c is C.sub.1-C.sub.3 haloalkyl, preferably
trifluoromethyl.
[0070] The compounds of formula (I) may exist as different
geometric isomers, or in different tautomeric forms. This invention
covers all such isomers and tautomers, and mixtures thereof in all
proportions, as well as isotopic forms such as deuterated
compounds.
[0071] The compounds of this invention may contain one or more
asymmetric centers and may thus give rise to optical isomers and
diastereomers. While shown without respect to stereochemistry, the
present invention includes all such optical isomers and
diastereomers as well as the racemic and resolved, enantiomerically
pure R and S stereoisomers and other mixtures of the R and S
stereoisomers and agrochemically acceptable salts thereof. It is
recognized certain optical isomers or diastereomers may have
favorable properties over the other. Thus when disclosing and
claiming the invention, when a racemic mixture is disclosed, it is
clearly contemplated that both optical isomers, including
diastereomers, substantially free of the other, are disclosed and
claimed as well.
[0072] Alkyl, as used herein, refers to an aliphatic hydrocarbon
chain and includes straight and branched chains e.g. of 1 to 8
carbon atoms such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl,
n-hexyl, and isohexyl.
[0073] Alkenyl, as used herein, refers to an aliphatic hydrocarbon
chain having at least one double bond, and preferably one double
bond, and includes straight and branched chains e.g. of 2 to 8
carbon atoms such as ethenyl (vinyl), prop-1-enyl, prop-2-enyl
(allyl), isopropenyl, but-1-enyl, but-2-enyl, but-3-enyl,
2-methypropenyl.
[0074] Alkynyl, as used herein, refers to an aliphatic hydrocarbon
chain having at least one triple bond, and preferably one triple
bond, and includes straight and branched chains e.g. of 2 to 8
carbon atoms such as ethynyl, prop-1-ynyl, prop-2-ynyl (propargyl)
but-1-ynyl, but-2-ynyl and but-3-ynyl.
[0075] Cycloalkyl, as used herein, refers to a cyclic, saturated
hydrocarbon group having from 3 to 6 ring carbon atoms. Examples of
cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and
cyclohexyl.
[0076] Hydroxyalkyl, as used herein, refers to the group --ROH,
wherein R is alkyl as defined above.
[0077] Alkoxy, as used herein, refers to the group --OR, wherein R
is alkyl as defined above. Examples of alkoxy groups include
methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy,
sec-butoxy, t-butoxy, n-pentoxy, isopentoxy, neo-pentoxy,
n-hexyloxy, and isohexyloxy.
[0078] Alkenyloxy, as used herein, refers to the group --OR,
wherein R is alkenyl as defined above. Examples of alkenyloxy
groups are ethenyloxy, propenyloxy, isopropenyloxy, but-1-enyloxy,
but-2-enyloxy, but-3-enyloxy, 2-methypropenyloxy etc.
[0079] Alkynyloxy, as used herein, refers to the group --OR,
wherein R is alkynyl is as defined above. Examples of alkynyloxy
groups are ethynyloxy, propynyloxy, but-1-ynyloxy, but-2-ynyloxy
and but-3-ynyloxy.
[0080] Alkoxyalkyl, as used herein, refers to a group R,
substituted at any position with one or more groups --OR, wherein
each R is, independently, alkyl as defined herein.
[0081] Alkoxyalkoxy, as used herein, refers to the group --OROR,
wherein each R is, independently, an alkyl group as defined
above.
[0082] Alkenyloxyalkyl, as used herein, refers to the group --ROR',
wherein R is alkyl as used herein and R' is alkenyl as used
herein.
[0083] Cyanoalkyl, as used herein, refers to an alkyl group
substituted with one or more cyano groups.
[0084] Halogen, halide and halo, as used herein, refer to iodine,
bromine, chlorine and fluorine.
[0085] Haloalkyl, as used herein, refers to an alkyl group as
defined above wherein at least one hydrogen atom has been replaced
with a halogen atom as defined above. Examples of haloalkyl groups
include chloromethyl, dichloromethyl, trichloromethyl,
fluoromethyl, difluoromethyl and trifluoromethyl. Preferred
haloalkyl groups are fluoroalkyl groups {i.e. haloalkyl groups,
containing fluorine as the only halogen). More highly preferred
haloalkyl groups are perfluoroalkyl groups, i.e. alkyl groups
wherein all the hydrogen atoms are replaced with fluorine
atoms.
[0086] Haloalkenyl, as used herein, refers to an alkenyl group as
defined above wherein at least one hydrogen atom has been replaced
with a halogen atom as defined above.
[0087] Haloalkoxy, as used herein, refers to the group --OR,
wherein R is haloalkyl as defined above.
[0088] Alkylthio, as used herein, refers to the group --SR, wherein
R is an alkyl group as defined above. Alkylthio groups include, but
are not limited to, methylthio, ethylthio, propylthio,
tert-butylthio, and the like.
[0089] Alkylsulfinyl, as used herein, refers to the group --S(O)R,
wherein R is an alkyl group as defined above.
[0090] Alkylsulfonyl, as used herein, refers to the group
--S(O).sub.2R, wherein R is an alkyl group as defined above.
[0091] Alkylcarbonyloxy, as used herein, refers to the group
--OC(O)R, wherein R is alkyl as defined herein.
[0092] Alkoxycarbonyloxy, as used herein, refers to the group
--OC(O)OR, wherein R is an alkyl group as defined above. Examples
of alkoxycarbonyloxy groups are methoxycarbonyloxy,
ethoxycarbonyloxy, propoxycarbonyloxy, but-1-oxycarbonyloxy,
but-2-oxycarbonyloxy and but-3-oxycarbonyloxy.
[0093] Hydroxy or hydroxyl, as used herein, refers to the group
--OH.
[0094] Nitro, as used herein, refers to the group --NO.sub.2.
[0095] Cyano, as used herein, refers to the group --CN.
[0096] Aryl, as used herein, refers to an unsaturated aromatic
carbocyclic group of from 6 to 10 carbon atoms having a single ring
(e.g., phenyl) or multiple condensed (fused) rings, at least one of
which is aromatic (e.g., indanyl, naphthyl). Preferred aryl groups
include phenyl, naphthyl and the like. Most preferably, an aryl
group is a phenyl group.
[0097] Aryloxy, as used herein, refers to the group --O-aryl,
wherein aryl is as defined above. Preferred aryloxy groups include
phenoxy, naphthyloxy and the like.
[0098] Aryloxycarbonyloxy, as used herein, refers to the group
--OC(O)O-aryl wherein aryl is a as defined above.
[0099] Arylalkyl, as used herein, refers to a group R--Ar, wherein
R is alkyl as defined herein and Ar is aryl as defined herein.
Arylalkyl groups may be substituted on the alkyl linker or on the
ring. An example of an arylalkyl group is the benzyl group
(--CH.sub.2C.sub.6H.sub.5).
[0100] Heterocyclyl, as used herein, refers to a non-aromatic ring
system containing 3 to 10 ring atoms, at least one ring heteroatom
and consisting either of a single ring or of two or more fused
rings. Preferably, single rings will contain up to three and
bicyclic systems up to four heteroatoms which will preferably be
chosen from nitrogen, oxygen and sulfur. Examples of such groups
include pyrrolidinyl, imidazolinyl, pyrazolidinyl, piperidyl,
piperazinyl, quinuclidinyl, morpholinyl, together with unsaturated
or partially unsaturated analogues such as
4,5,6,7-tetrahydro-benzothiophenyl, chromen-4-onyl, 9H-fluorenyl,
3,4-dihydro-2H-benzo-1,4-dioxepinyl, 2,3-dihydro-benzofuranyl,
piperidinyl, 1,3-dioxolanyl, 1,3-dioxanyl, 4,5-dihydro-isoxazolyl,
tetrahydrofuranyl and morpholinyl.
[0101] Heteroaryl, as used herein, refers to a ring system
containing 5 to 10 ring atoms, 1 to 4 ring heteroatoms and
consisting either of a single aromatic ring or of two or more fused
rings, at least one of which is aromatic. Preferably, single rings
will contain up to three and bicyclic systems up to four
heteroatoms which will preferably be independently chosen from
nitrogen, oxygen and sulfur. Examples of such groups include
pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, furanyl,
thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl,
triazolyl and tetrazolyl. Examples of bicyclic groups are
benzothiophenyl, benzimidazolyl, benzothiadiazolyl, quinolinyl,
cinnolinyl, quinoxalinyl and pyrazolo[1,5-a]pyrimidinyl.
[0102] `Saturated ring`, as used herein, refers to a ring system in
which the atoms in the ring are linked by single bonds.
[0103] `Partially unsaturated ring`, as used herein, refers to a
ring system in which at least two atoms in the ring are linked by a
double bond. Partially unsaturated ring systems do not include
aromatic rings.
[0104] "Optionally substituted", as used herein, means the group
referred to can be substituted at one or more positions by any one
or any combination of the radicals listed thereafter. For most
groups, one or more hydrogen atoms are replaced by the radicals
listed thereafter. For halogenated groups, for example, haloalkyl
groups, one or more halogen atoms are replaced by the radicals
listed thereafter.
[0105] Suitable salts include those derived from alkali or alkaline
earth metals and those derived from ammonia and amines. Preferred
cations include sodium, potassium, magnesium, and ammonium cations
of the formula N+(R.sup.19R.sup.20R.sup.21R.sup.22) wherein
R.sup.19, R.sup.20, R.sup.21 and R.sup.22 are independently
selected from hydrogen, C.sub.1-C.sub.6 alkyl and C.sub.1-C.sub.6
hydroxyalkyl. Salts of the compounds of Formula I can be prepared
by treatment of compounds of Formula I with a metal hydroxide, such
as sodium hydroxide, or an amine, such as ammonia, trimethylamine,
diethanolamine, 2-methylthiopropylamine, bisallylamine,
2-butoxyethylamine, morpholine, cyclododecylamine, or benzylamine.
Amine salts are often preferred forms of the compounds of Formula I
because they are water-soluble and lend themselves to the
preparation of desirable aqueous based herbicidal compositions.
[0106] Acceptable salts can be formed from organic and inorganic
acids, for example, acetic, propionic, lactic, citric, tartaric,
succinic, fumaric, maleic, malonic, mandelic, malic, phthalic,
hydrochloric, hydrobromic, phosphoric, nitric, sulfuric,
methanesulfonic, naphthalenesulfonic, benzenesulfonic,
toluenesulfonic, camphorsulfonic, and similarly known acceptable
acids when a compound of this invention contains a basic
moiety.
[0107] In another aspect the present invention provides
intermediates useful in the preparation of compounds of the
invention.
[0108] In one embodiment, there are provided intermediates of the
formula (III) wherein X, R.sup.1, R.sup.2, R.sup.a, R.sup.b,
R.sup.c and R.sup.d are as defined above.
##STR00007##
[0109] In another embodiment, there are provided intermediates
shown below wherein X, R.sup.1, R.sup.2, R.sup.14, R.sup.15,
R.sup.a, R.sup.b, R.sup.c and R.sup.d are as defined above.
##STR00008##
[0110] Compounds of the invention may be prepared by techniques
known to the person skilled in the art of organic chemistry.
General methods for the production of compounds of formula (I) are
described below. Unless otherwise stated in the text, the
substituents X, R.sup.1, R.sup.2, R.sup.3, R.sup.a, R.sup.b,
R.sup.c and R.sup.d are as defined hereinbefore. The starting
materials used for the preparation of the compounds of the
invention may be purchased from usual commercial suppliers or may
be prepared by known methods. The starting materials as well as the
intermediates may be purified before use in the next step by state
of the art methodologies such as chromatography, crystallization,
distillation and filtration.
[0111] For example, compounds of formula (IX) wherein R.sup.1 is an
alkyl or alkoxy group and R.sup.2 is a hydrogen or alkyl group may
be prepared by reaction of amino-pyridine (IV) with
phenylchloroformate to give carbamate product (V). The subsequent
reaction with an appropriately substituted amino-ester (VI) gives
compounds of type (VII) and subsequent cyclisation gives compounds
of type (VIII) and reduction with e.g. with sodium borohydride
gives compounds of type (IX). The methyl amino-ester (VI) may also
be replaced by other amino esters or amino-acids. Phenyl
chloroformate may be replaced by other activating groups such as
phosgene or para-nitrophenyl chloroformate. The cyclisation to
(VIII) may occur in situ or require heating for carboxylic acids or
esters or treatment with a reagent such as thionyl chloride for
carboxylic acids. Compounds of type (VII) can be converted to
compounds of type (IX) directly by treatment with a reducing
reagent such as DIBAL-H or NaBH.sub.4. Esters of type (VII) may
also be reduced to their corresponding primary alcohols and then
such alcohols can be re-oxidised to compounds of type (IX) with
oxidants such as Dess-Martin periodinane.
##STR00009##
[0112] Alternatively, compounds of formula (IX) wherein R.sup.1 is
an alkyl group or alkoxy group and R.sup.2 is a hydrogen or alkyl
group may be prepared by Palladium catalysed reaction of
chloro-pyridine (X) with urea (XI) to give (XII) (for a reference
to a related reaction see WO2006048249, example 3.1) and then
subsequent cyclisation gives compounds of type (IX).
##STR00010##
Urea (XI) may be formed by reaction of ester (XII) with Grignard
reagents, reductive amination of the product ketone (XIV) with
amines and finally reaction of the subsequent product amine (XV)
with TMS-isocyanate to give compounds of type (XI). Alternatively
(XV) can be formed by a Grignard addition of type R.sub.2MgCl to
appropriate imines. Alternatively, a nitrile can replace the ester
group of (XIII) in the reaction with Grignard reagents.
##STR00011##
Alternatively, reaction of compounds of type (XIV) with
methoxylamine following by reduction of the oxime ether formed
gives compounds of type (XV) which can form compounds of type (XI)
where R.sup.1 is alkoxy. Alternatively, reaction of compounds of
type (XIV) where R.sup.2 is hydrogen with methoxylamine followed by
addition of Grignard reagents to the formed oxime also can give
compounds of type (XV).
##STR00012##
[0113] Compounds of formula (XVIII) wherein R.sup.2 is an hydroxy
group may be prepared by the Palladium catalysed reaction of
chloro-pyridine (X) with urea (XVI) to give urea (XVII) (for a
reference to a related reaction see WO2006048249, example 3.1),
which can react with aqueous glyoxal solution to give product
(XVIII). Compounds of formula (IX) where R.sup.2 is an alkoxy group
may be prepared by reacting compounds of formula (XVIII) with
alcohols of type R.sup.4--OH under acidic conditions.
##STR00013##
[0114] Alternatively, compounds of formula (V) may be reacted with
compounds of formula (XIX) wherein R.sup.2 is a hydrogen or alkyl
group to give products of type (XX). Cyclisation with a suitable
reagent such as thionyl chloride gives compounds of formula (XXI),
which can be alkylated with a suitable base such as LiHMDS and a
suitable alkylating agent such as methyl iodide (for R.sup.1=Me) to
give compound (VIII). Reduction as before gives compounds of type
(IX).
##STR00014##
Alternatively oxidative cleavage (using ozonolysis or
OsO.sub.4/NalO.sub.4 or similar conditions) of an appropriate vinyl
compound such as (XXII) or derivatives thereof and cyclisation
could give the desired product.
##STR00015##
Alternatively, compounds of type (XXIII) may be coupled with
compounds of type (X) under Palladium catalysed conditions to give
compounds of type (VIII) and then standard reduction with
NaBH.sub.4 for example gives products of type (IX).
##STR00016##
Amino and chloro-pyridines, where not commercially available, may
be made by literature routes such as below and as detailed in J.
March, Advanced Organic Chemistry, 4th ed. Wiley, New York,
1992.
##STR00017##
Suitable conditions for effecting these transformations are set out
in J. March, Advanced Organic Chemistry, 4th ed. Wiley, New York,
1992.
[0115] The compounds of formula (I) according to the invention can
be used as herbicides in unmodified form, as obtained in the
synthesis, but they are generally formulated into herbicidal
compositions in various ways using formulation adjuvants, such as
carriers, solvents and surface-active substances. Therefore, the
invention also relates to a herbicidal composition which comprises
a herbicidally effective amount of a compound of formula (I) in
addition to formulation adjuvants. The formulations can be in
various physical forms, e.g. in the form of dusting powders, gels,
wettable powders, water-dispersible granules, water-dispersible
tablets, effervescent pellets, emulsifiable concentrates,
microemulsifiable concentrates, oil-in-water emulsions,
oil-flowables, aqueous dispersions, oily dispersions,
suspo-emulsions, capsule suspensions, emulsifiable granules,
soluble liquids, water-soluble concentrates (with water or a
water-miscible organic solvent as carrier), impregnated polymer
films or in other forms known e.g. from the Manual on Development
and Use of FAO Specifications for Plant Protection Products, 5th
Edition, 1999. Such formulations can either be used directly or
they are diluted prior to use. The dilutions can be made, for
example, with water, liquid fertilizers, micronutrients, biological
organisms, oil or solvents.
[0116] The formulations can be prepared e.g. by mixing the active
ingredient with the formulation adjuvants in order to obtain
compositions in the form of finely divided solids, granules,
solutions, dispersions or emulsions. The active ingredients can
also be formulated with other adjuvants, such as finely divided
solids, mineral oils, oils of vegetable or animal origin, modified
oils of vegetable or animal origin, organic solvents, water,
surface-active substances or combinations thereof. The active
ingredients can also be contained in very fine microcapsules
consisting of a polymer. Microcapsules contain the active
ingredients in a porous carrier. This enables the active
ingredients to be released into the environment in controlled
amounts (e.g. slow-release). Microcapsules usually have a diameter
of from 0.1 to 500 microns. They contain active ingredients in an
amount of about from 25 to 95% by weight of the capsule weight. The
active ingredients can be in the form of a monolithic solid, in the
form of fine particles in solid or liquid dispersion or in the form
of a suitable solution. The encapsulating membranes comprise, for
example, natural or synthetic rubbers, cellulose, styrene/butadiene
copolymers, polyacrylonitrile, polyacrylate, polyesters,
polyamides, polyureas, polyurethane or chemically modified polymers
and starch xanthates or other polymers that are known to the person
skilled in the art in this connection. Alternatively, very fine
microcapsules can be formed in which the active ingredient is
contained in the form of finely divided particles in a solid matrix
of base substance, but the microcapsules are not themselves
encapsulated.
[0117] The formulation adjuvants that are suitable for the
preparation of the compositions according to the invention are
known per se. As liquid carriers there may be used: water, toluene,
xylene, petroleum ether, vegetable oils, acetone, methyl ethyl
ketone, cyclohexanone, acid anhydrides, acetonitrile, acetophenone,
amyl acetate, 2-butanone, butylene carbonate, chlorobenzene,
cyclohexane, cyclohexanol, alkyl esters of acetic acid, diacetone
alcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene,
diethylene glycol, diethylene glycol abietate, diethylene glycol
butyl ether, diethylene glycol ethyl ether, diethylene glycol
methyl ether, N,N-dimethylformamide, dimethyl sulfoxide,
1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether,
dipropylene glycol dibenzoate, diproxitol, alkylpyrrolidone, ethyl
acetate, 2-ethylhexanol, ethylene carbonate, 1,1,1-trichloroethane,
2-heptanone, alpha-pinene, d-limonene, ethyl lactate, ethylene
glycol, ethylene glycol butyl ether, ethylene glycol methyl ether,
gamma-butyrolactone, glycerol, glycerol acetate, glycerol
diacetate, glycerol triacetate, hexadecane, hexylene glycol,
isoamyl acetate, isobornyl acetate, isooctane, isophorone,
isopropylbenzene, isopropyl myristate, lactic acid, laurylamine,
mesityl oxide, methoxypropanol, methyl isoamyl ketone, methyl
isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate,
methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic
acid, octylamine acetate, oleic acid, oleylamine, o-xylene, phenol,
polyethylene glycol (PEG400), propionic acid, propyl lactate,
propylene carbonate, propylene glycol, propylene glycol methyl
ether, p-xylene, toluene, triethyl phosphate, triethylene glycol,
xylenesulfonic acid, paraffin, mineral oil, trichloroethylene,
perchloroethylene, ethyl acetate, amyl acetate, butyl acetate,
propylene glycol methyl ether, diethylene glycol methyl ether,
methanol, ethanol, isopropanol, and alcohols of higher molecular
weight, such as amyl alcohol, tetrahydro-furfuryl alcohol, hexanol,
octanol, ethylene glycol, propylene glycol, glycerol,
N-methyl-2-pyrrolidone and the like. Water is generally the carrier
of choice for diluting the concentrates. Suitable solid carriers
are, for example, talc, titanium dioxide, pyrophyllite clay,
silica, attapulgite clay, kieselguhr, limestone, calcium carbonate,
bentonite, calcium montmorillonite, cottonseed husks, wheat flour,
soybean flour, pumice, wood flour, ground walnut shells, lignin and
similar substances, as described, for example, in CFR 180.1001. (c)
& (d).
[0118] A large number of surface-active substances can
advantageously be used in both solid and liquid formulations,
especially in those formulations which can be diluted with a
carrier prior to use. Surface-active substances may be anionic,
cationic, non-ionic or polymeric and they can be used as
emulsifiers, wetting agents or suspending agents or for other
purposes. Typical surface-active substances include, for example,
salts of alkyl sulfates, such as diethanolammonium lauryl sulfate;
salts of alkylarylsulfonates, such as calcium
dodecyl-benzenesulfonate; alkylphenol/alkylene oxide addition
products, such as nonylphenol ethoxylate; alcohol/alkylene oxide
addition products, such as tridecylalcohol ethoxylate; soaps, such
as sodium stearate; salts of alkylnaphthalenesulfonates, such as
sodium dibutylnaphthalenesulfonate; dialkyl esters of
sulfosuccinate salts, such as sodium
di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol
oleate; quaternary amines, such as lauryltrimethylammonium
chloride, polyethylene glycol esters of fatty acids, such as
polyethylene glycol stearate; block copolymers of ethylene oxide
and propylene oxide; and salts of mono- and di-alkylphosphate
esters; and also further substances described e.g. in "McCutcheon's
Detergents and Emulsifiers Annual" MC Publishing Corp., Ridgewood
N.J., 1981.
[0119] Further adjuvants that can usually be used in pesticidal
formulations include crystallization inhibitors, viscosity
modifiers, suspending agents, dyes, anti-oxidants, foaming agents,
light absorbers, mixing auxiliaries, antifoams, complexing agents,
neutralizing or pH-modifying substances and buffers, corrosion
inhibitors, fragrances, wetting agents, take-up enhancers,
micronutrients, plasticisers, glidants, lubricants, dispersants,
thickeners, antifreezes, microbicides, and also liquid and solid
fertilizers.
[0120] The compositions according to the invention can additionally
include an additive comprising an oil of vegetable or animal
origin, a mineral oil, alkyl esters of such oils or mixtures of
such oils and oil derivatives. The amount of oil additive in the
composition according to the invention is generally from 0.01 to
10%, based on the spray mixture. For example, the oil additive can
be added to the spray tank in the desired concentration after the
spray mixture has been prepared. Preferred oil additives comprise
mineral oils or an oil of vegetable origin, for example rapeseed
oil, olive oil or sunflower oil, emulsified vegetable oil, such as
AMIGO.RTM. (Rhone-Poulenc Canada Inc.), alkyl esters of oils of
vegetable origin, for example the methyl derivatives, or an oil of
animal origin, such as fish oil or beef tallow. A preferred
additive contains, for example, as active components essentially
80% by weight alkyl esters of fish oils and 15% by weight
methylated rapeseed oil, and also 5% by weight of customary
emulsifiers and pH modifiers. Especially preferred oil additives
comprise alkyl esters of C.sub.8-C.sub.22 fatty acids, especially
the methyl derivatives of C.sub.12-C.sub.18 fatty acids, for
example the methyl esters of lauric acid, palmitic acid and oleic
acid, being of importance. Those esters are known as methyl laurate
(CAS-111-82-0), methyl palmitate (CAS-112-39-0) and methyl oleate
(CAS-112-62-9). A preferred fatty acid methyl ester derivative is
Emery.RTM. 2230 and 2231 (Cognis GmbH). Those and other oil
derivatives are also known from the Compendium of Herbicide
Adjuvants, 5th Edition, Southern Illinois University, 2000.
[0121] The application and action of the oil additives can be
further improved by combination with surface-active substances,
such as non-ionic, anionic or cationic surfactants. Examples of
suitable anionic, non-ionic and cationic surfactants are listed on
pages 7 and 8 of WO 97/34485. Preferred surface-active substances
are anionic surfactants of the dodecylbenzylsulfonate type,
especially the calcium salts thereof, and also non-ionic
surfactants of the fatty alcohol ethoxylate type. Special
preference is given to ethoxylated C.sub.12-C.sub.22 fatty alcohols
having a degree of ethoxylation of from 5 to 40. Examples of
commercially available surfactants are the Genapol types (Clariant
AG). Also preferred are silicone surfactants, especially
polyalkyl-oxide-modified heptamethyltriloxanes which are
commercially available e.g. as Silwet L-77.RTM., and also
perfluorinated surfactants. The concentration of the surface-active
substances in relation to the total additive is generally from 1 to
30% by weight. Examples of oil additives consisting of mixtures of
oil or mineral oils or derivatives thereof with surfactants are
Edenor ME SU.RTM., Turbocharge.RTM. (Syngenta AG, CH) or ActipronC
(BP Oil UK Limited, GB).
[0122] If desired, it is also possible for the mentioned
surface-active substances to be used in the formulations on their
own, that is to say, without oil additives.
[0123] Furthermore, the addition of an organic solvent to the oil
additive/surfactant mixture may contribute to an additional
enhancement of action. Suitable solvents are, for example,
Solvesso.RTM. (ESSO) or Aromatic Solvent.RTM. (Exxon Corporation).
The concentration of such solvents can be from 10 to 80% by weight
of the total weight. Oil additives that are present in admixture
with solvents are described, for example, in U.S. Pat. No.
4,834,908. A commercially available oil additive disclosed therein
is known by the name MERGE.RTM. (BASF Corporation). A further oil
additive that is preferred according to the invention is SCORE.RTM.
(Syngenta Crop Protection Canada).
[0124] In addition to the oil additives listed above, for the
purpose of enhancing the action of the compositions according to
the invention it is also possible for formulations of
alkylpyrrolidones (e.g. Agrimax.RTM.) to be added to the spray
mixture. Formulations of synthetic lattices, e.g. polyacrylamide,
polyvinyl compounds or poly-1-p-menthene (e.g. Bond.RTM.,
Courier.RTM. or Emerald.RTM.) may also be used. It is also possible
for solutions that contain propionic acid, for example Eurogkem
Pen-e-trate.RTM., to be added to the spray mixture as
action-enhancing agent.
[0125] The herbicidal compositions generally comprise from 0.1 to
99% by weight, especially from 0.1 to 95% by weight, compounds of
formula (I) and from 1 to 99.9% by weight of a formulation adjuvant
which preferably includes from 0 to 25% by weight of a
surface-active substance. Whereas commercial products will
preferably be formulated as concentrates, the end user will
normally employ dilute formulations.
[0126] The rates of application of compounds of formula (I) may
vary within wide limits and depend on the nature of the soil, the
method of application (pre- or post-emergence; seed dressing;
application to the seed furrow; no tillage application etc.), the
crop plant, the grass or weed to be controlled, the prevailing
climatic conditions, and other factors governed by the method of
application, the time of application and the target crop. The
compounds of formula (I) according to the invention are generally
applied at a rate of from 10 to 2000 g/ha, especially from 50 to
1000 g/ha.
[0127] Preferred formulations have especially the following
compositions (%=percent by weight):
Emulsifiable Concentrates:
[0128] active ingredient: 1 to 95%, preferably 60 to 90%
surface-active agent: 1 to 30%, preferably 5 to 20% liquid carrier:
1 to 80%, preferably 1 to 35%
Dusts:
[0129] active ingredient: 0.1 to 10%, preferably 0.1 to 5% solid
carrier: 99.9 to 90%, preferably 99.9 to 99%
Suspension Concentrates:
[0130] active ingredient: 5 to 75%, preferably 10 to 50% water: 94
to 24%, preferably 88 to 30% surface-active agent: 1 to 40%,
preferably 2 to 30%
Wettable Powders:
[0131] active ingredient: 0.5 to 90%, preferably 1 to 80%
surface-active agent: 0.5 to 20%, preferably 1 to 15% solid
carrier: 5 to 95%, preferably 15 to 90%
Granules:
[0132] active ingredient: 0.1 to 30%, preferably 0.1 to 15% solid
carrier: 99.5 to 70%, preferably 97 to 85% The following Examples
further illustrate, but do not limit, the invention.
Formulation Examples for Herbicides of Formula (I) (%=% by
Weight)
TABLE-US-00001 [0133] F1. Emulsifiable concentrates a) b) c) d)
active ingredient 5% 10% 25% 50% calcium dodecylbenzenesulfonate 6%
8% 6% 8% castor oil polyglycol ether 4% -- 4% 4% (36 mol of
ethylene oxide) octylphenol polyglycol ether -- 4% -- 2% (7-8 mol
of ethylene oxide) NMP -- -- 10% 20% arom. hydrocarbon mixture 85%
78% 55% 16% C.sub.9-C.sub.12
Emulsions of any desired concentration can be obtained from such
concentrates by dilution with water.
TABLE-US-00002 F2. Solutions a) b) c) d) active ingredient 5% 10%
50% 90% 1-methoxy-3-(3-methoxy- -- 20% 20% -- propoxy)-propane
polyethylene glycol MW 400 20% 10% -- -- NMP -- -- 30% 10% arom.
hydrocarbon mixture 75% 60% -- -- C.sub.9-C.sub.12
The solutions are suitable for use in the form of microdrops.
TABLE-US-00003 F3. Wettable powders a) b) c) d) active ingredient
5% 25% 50% 80% sodium lignosulfonate 4% -- 3% -- sodium lauryl
sulfate 2% 3% -- 4% sodium diisobutylnaphthalene- -- 6% 5% 6%
sulfonate octylphenol polyglycol ether -- 1% 2% -- (7-8 mol of
ethylene oxide) highly dispersed silicic acid 1% 3% 5% 10% kaolin
88% 62% 35% --
The active ingredient is mixed thoroughly with the adjuvants and
the mixture is thoroughly ground in a suitable mill, affording
wettable powders which can be diluted with water to give
suspensions of any desired concentration.
TABLE-US-00004 F4. Coated granules a) b) c) active ingredient 0.1%
5% 15% highly dispersed silicic acid 0.9% 2% 2% inorganic carrier
99.0% 93% 83% (diameter 0.1-1 mm) e.g. CaCO.sub.3 or SiO.sub.2
The active ingredient is dissolved in methylene chloride and
applied to the carrier by spraying, and the solvent is then
evaporated off in vacuo.
TABLE-US-00005 F5. Coated granules a) b) c) active ingredient 0.1%
5% 15% polyethylene glycol MW 200 1.0% 2% 3% highly dispersed
silicic acid 0.9% 1% 2% inorganic carrier 98.0% 92% 80% (diameter
0.1-1 mm) e.g. CaCO.sub.3 or SiO.sub.2
The finely ground active ingredient is uniformly applied, in a
mixer, to the carrier moistened with polyethylene glycol. Non-dusty
coated granules are obtained in this manner.
TABLE-US-00006 F6. Extruder granules a) b) c) d) active ingredient
0.1% 3% 5% 15% sodium lignosulfonate 1.5% 2% 3% 4%
carboxymethylcellulose 1.4% 2% 2% 2% kaolin 97.0% 93% 90% 79%
The active ingredient is mixed and ground with the adjuvants, and
the mixture is moistened with water. The mixture is extruded and
then dried in a stream of air.
TABLE-US-00007 F7. Dusts a) b) c) active ingredient 0.1% 1% 5%
talcum 39.9% 49% 35% kaolin 60.0% 50% 60%
Ready-to-use dusts are obtained by mixing the active ingredient
with the carriers and grinding the mixture in a suitable mill.
TABLE-US-00008 F8. Suspension concentrates a) b) c) d) active
ingredient 3% 10% 25% 50% ethylene glycol 5% 5% 5% 5% nonylphenol
polyglycol ether -- 1% 2% -- (15 mol of ethylene oxide) sodium
lignosulfonate 3% 3% 4% 5% carboxymethylcellulose 1% 1% 1% 1% 37%
aqueous formaldehyde 0.2% 0.2% 0.2% 0.2% solution silicone oil
emulsion 0.8% 0.8% 0.8% 0.8% water 87% 79% 62% 38%
The finely ground active ingredient is intimately mixed with the
adjuvants, giving a suspension concentrate from which suspensions
of any desired concentration can be obtained by dilution with
water.
[0134] The invention also provides a method of controlling plants
which comprises applying to the plants or to the locus thereof a
herbicidally effective amount of a compound of formula (I).
[0135] The invention also provides a method of inhibiting plant
growth which comprises applying to the plants or to the locus
thereof a herbicidally effective amount of a compound of formula
(I).
[0136] The invention also provides a method of controlling weeds in
crops of useful plants, comprising applying to said weeds or to the
locus of said weeds, or to said useful plants or to the locus of
said useful plants, a compound or a composition of the
invention.
[0137] The invention also provides a method of selectively
controlling grasses and/or weeds in crops of useful plants which
comprises applying to the useful plants or locus thereof or to the
area of cultivation a herbicidally effective amount of a compound
of formula (I).
[0138] The term "herbicide" as used herein means a compound that
controls or modifies the growth of plants. The term "herbicidally
effective amount" means the quantity of such a compound or
combination of such compounds that is capable of producing a
controlling or modifying effect on the growth of plants.
Controlling or modifying effects include all deviation from natural
development, for example: killing, retardation, leaf burn,
albinism, dwarfing and the like.
[0139] The term "plants" refers to all physical parts of a plant,
including seeds, seedlings, saplings, roots, tubers, stems, stalks,
foliage, and fruits. The term "locus" is intended to include soil,
seeds, and seedlings, as well as established vegetation and
includes not only areas where weeds may already be growing, but
also areas where weeds have yet to emerge, and also to areas under
cultivation with respect to crops of useful plants. "Areas under
cultivation" include land on which the crop plants are already
growing and land intended for cultivation with such crop plants.
The term "weeds" as used herein means any undesired plant, and thus
includes not only agronomically important weeds as described below,
but also volunteer crop plants.
[0140] The compounds of the invention can be applied before or
after planting of the crops, before weeds emerge (pre-emergence
application) or after weeds emerge (post-emergence application),
and are particularly effective when applied post-emergence to the
weeds.
[0141] Crops of useful plants in which the composition according to
the invention can be used include, but are not limited to,
perennial crops, such as citrus fruit, grapevines, nuts, oil palms,
olives, pome fruit, stone fruit and rubber, and annual arable
crops, such as cereals, for example barley and wheat, cotton,
oilseed rape, maize, rice, soy beans, sugar beet, sugar cane,
sunflowers, ornamentals, switchgrass, turf and vegetables,
especially cereals, maize and soy beans.
[0142] The grasses and weeds to be controlled may be both
monocotyledonous species, for example Agrostis, Alopecurus, Avena,
Brachiaria, Bromus, Cenchrus, Cyperus, Digitaria, Echinochloa,
Eriochloa, Lolium, Monochoria, Panicum, Poa, Rottboellia,
Sagittaria, Scirpus, Setaria, Sida and Sorghum, and dicotyledonous
species, for example Abutilon, Amaranthus, Chenopodium,
Chrysanthemum, Euphorbia, Galium, Ipomoea, Kochia, Nasturtium,
Polygonum, Sida, Sinapis, Solanum, Stellaria, Veronica, Viola and
Xanthium.
[0143] In all aspects of the invention, in a particular embodiment,
the weeds, e.g. to be controlled and/or growth-inhibited may be
monocotyledonous or dicotyledonous weeds, which are tolerant or
resistant to one or more other herbicides for example, HPPD
inhibitor herbicides such as mesotrione, PSII inhibitor herbicides
such as atrazine or EPSPS inhibitors such as glyphosate. Such weeds
include, but are not limited to resistant Amaranthus biotypes.
[0144] Crops are to be understood as also including those crops
which have been rendered tolerant to herbicides or classes of
herbicides (e.g. auxins or ALS-, EPSPS-, PPO- and HPPD-inhibitors)
by conventional methods of breeding or by genetic engineering. An
example of a crop that has been rendered tolerant to
imidazolinones, e.g. imazamox, by conventional methods of breeding
is Clearfield.RTM. summer rape (canola). Examples of crops that
have been rendered tolerant to herbicides by genetic engineering
methods include e.g. glyphosate- and glufosinate-resistant maize
varieties commercially available under the trade names
RoundupReady.RTM. and LibertyLink.RTM., respectively.
[0145] Crops are also to be understood as being those which have
been rendered resistant to harmful insects by genetic engineering
methods, for example Bt maize (resistant to European corn borer),
Bt cotton (resistant to cotton boll weevil) and also Bt potatoes
(resistant to Colorado beetle). Examples of Bt maize are the Bt 176
maize hybrids of NK.RTM. (Syngenta Seeds). The Bt toxin is a
protein that is formed naturally by Bacillus thuringiensis soil
bacteria. Examples of toxins, or transgenic plants able to
synthesize such toxins, are described in EP-A-451 878, EP-A-374
753, WO 93/07278, WO 95/34656, WO 03/052073 and EP-A-427 529.
Examples of transgenic plants comprising one or more genes that
code for an insecticidal resistance and express one or more toxins
are KnockOut.RTM. (maize), Yield Gard.RTM. (maize), NuCOTIN33B.RTM.
(cotton), Bollgard.RTM. (cotton), NewLeaf.RTM. (potatoes),
NatureGard.RTM. and Protexcta.RTM.. Plant crops or seed material
thereof can be both resistant to herbicides and, at the same time,
resistant to insect feeding ("stacked" transgenic events). For
example, seed can have the ability to express an insecticidal Cry3
protein while at the same time being tolerant to glyphosate.
[0146] Crops are also to be understood as being those which are
obtained by conventional methods of breeding or genetic engineering
and contain so-called output traits (e.g. improved storage
stability, higher nutritional value and improved flavor).
[0147] Any method of application to weeds/crop of useful plant, or
locus thereof, which is routinely used in agriculture may be used,
for example application by spray or broadcast method typically
after suitable dilution of a compound of formula (I) (whether said
compound is formulated and/or in combination with one or more
further active ingredients and/or safeners, as described
herein).
[0148] The compounds of formula (I) according to the invention can
also be used in combination with other active ingredients, e.g.
other herbicides, and/or insecticides, and/or acaricides, and/or
nematocides, and/or molluscicides, and/or fungicides, and/or plant
growth regulators. Such mixtures, and the use of such mixtures to
control weeds and/or undesired plant growth, form yet further
aspects of the invention. For the avoidance of doubt, mixtures of
invention also include mixtures of two or more different compounds
of formula (I). In particular, the present invention also relates
to a composition of the invention which comprises at least one
further herbicide in addition to the compound of formula (I).
When a compound of formula (I) is combined with at least one
additional herbicide, the following mixtures of the compound of
formula (I) are preferred. Compound of formula (I)+acetochlor,
compound of formula (I)+acifluorfen, compound of formula
(I)+acifluorfen-sodium, compound of formula (I)+aclonifen, compound
of formula (I)+acrolein, compound of formula (I)+alachlor, compound
of formula (I)+alloxydim, compound of formula (I)+allyl alcohol,
compound of formula (I)+ametryn, compound of formula
(I)+amicarbazone, compound of formula (I)+amidosulfuron, compound
of formula (I)+aminocyclopyrachlor, compound of formula
(I)+aminopyralid, compound of formula (I)+amitrole, compound of
formula (I)+ammonium sulfamate, compound of formula (I)+anilofos,
compound of formula (I)+asulam, compound of formula (I)+atrazine,
formula (I)+aviglycine, formula (I)+azafenidin, compound of formula
(I)+azimsulfuron, compound of formula (I)+BCPC, compound of formula
(I)+beflubutamid, compound of formula (I)+benazolin, formula
(I)+bencarbazone, compound of formula (I)+benfluralin, compound of
formula (I)+benfuresate, compound of formula (I)+bensulfuron,
compound of formula (I)+bensulfuron-methyl, compound of formula
(I)+bensulide, compound of formula (I)+bentazone, compound of
formula (I)+benzfendizone, compound of formula (I)+benzobicyclon,
compound of formula (I)+benzofenap, compound of formula
(I)+bicyclopyrone, compound of formula (I)+bifenox, compound of
formula (I)+bilanafos, compound of formula (I)+bispyribac, compound
of formula (I)+bispyribac-sodium, compound of formula (I)+borax,
compound of formula (I)+bromacil, compound of formula
(I)+bromobutide, formula (I)+bromophenoxim, compound of formula
(I)+bromoxynil, compound of formula (I)+butachlor, compound of
formula (I)+butafenacil, compound of formula (I)+butamifos,
compound of formula (I)+butralin, compound of formula
(I)+butroxydim, compound of formula (I)+butylate, compound of
formula (I)+cacodylic acid, compound of formula (I)+calcium
chlorate, compound of formula (I)+cafenstrole, compound of formula
(I)+carbetamide, compound of formula (I)+carfentrazone, compound of
formula (I)+carfentrazone-ethyl, compound of formula (I)+CDEA,
compound of formula (I)+CEPC, compound of formula
(I)+chlorflurenol, compound of formula (I)+chlorflurenol-methyl,
compound of formula (I)+chloridazon, compound of formula
(I)+chlorimuron, compound of formula (I)+chlorimuron-ethyl,
compound of formula (I)+chloroacetic acid, compound of formula
(I)+chlorotoluron, compound of formula (I)+chlorpropham, compound
of formula (I)+chlorsulfuron, compound of formula (I)+chlorthal,
compound of formula (I)+chlorthal-dimethyl, compound of formula
(I)+cinidon-ethyl, compound of formula (I)+cinmethylin, compound of
formula (I)+cinosulfuron, compound of formula (I)+cisanilide,
compound of formula (I)+clethodim, compound of formula
(I)+clodinafop, compound of formula (I)+clodinafop-propargyl,
compound of formula (I)+clomazone, compound of formula
(I)+clomeprop, compound of formula (I)+clopyralid, compound of
formula (I)+cloransulam, compound of formula
(I)+cloransulam-methyl, compound of formula (I)+CMA, compound of
formula (I)+4-CPB, compound of formula (I)+CPMF, compound of
formula (I)+4-CPP, compound of formula (I)+CPPC, compound of
formula (I)+cresol, compound of formula (I)+cumyluron, compound of
formula (I)+cyanamide, compound of formula (I)+cyanazine, compound
of formula (I)+cycloate, compound of formula (I)+cyclosulfamuron,
compound of formula (I)+cycloxydim, compound of formula
(I)+cyhalofop, compound of formula (I)+cyhalofop-butyl, compound of
formula (I)+2,4-D, compound of formula (I)+3,4-DA, compound of
formula (I)+daimuron, compound of formula (I)+dalapon, compound of
formula (I)+dazomet, compound of formula (I)+2,4-DB, compound of
formula (I)+3,4-DB, compound of formula (I)+2,4-DEB, compound of
formula (I)+desmedipham, formula (I)+desmetryn, compound of formula
(I)+dicamba, compound of formula (I)+dichlobenil, compound of
formula (I)+ortho-dichlorobenzene, compound of formula
(I)+para-dichlorobenzene, compound of formula (I)+dichlorprop,
compound of formula (I)+dichlorprop-P, compound of formula
(I)+diclofop, compound of formula (I)+diclofop-methyl, compound of
formula (I)+diclosulam, compound of formula (I)+difenzoquat,
compound of formula (I)+difenzoquat metilsulfate, compound of
formula (I)+diflufenican, compound of formula (I)+diflufenzopyr,
compound of formula (I)+dimefuron, compound of formula
(I)+dimepiperate, compound of formula (I)+dimethachlor, compound of
formula (I)+dimethametryn, compound of formula (I)+dimethenamid,
compound of formula (I)+dimethenamid-P, compound of formula
(I)+dimethipin, compound of formula (I)+dimethylarsinic acid,
compound of formula (I)+dinitramine, compound of formula
(I)+dinoterb, compound of formula (I)+diphenamid, formula
(I)+dipropetryn, compound of formula (I)+diquat, compound of
formula (I)+diquat dibromide, compound of formula (I)+dithiopyr,
compound of formula (I)+diuron, compound of formula (I)+DNOC,
compound of formula (I)+3,4-DP, compound of formula (I)+DSMA,
compound of formula (I)+EBEP, compound of formula (I)+endothal,
compound of formula (I)+EPTC, compound of formula (I)+esprocarb,
compound of formula (I)+ethalfluralin, compound of formula
(I)+ethametsulfuron, compound of formula
(I)+ethametsulfuron-methyl, formula (I)+ethephon, compound of
formula (I)+ethofumesate, compound of formula (I)+ethoxyfen,
compound of formula (I)+ethoxysulfuron, compound of formula
(I)+etobenzanid, compound of formual (I)+fenoxaprop, compound of
formula (I)+fenoxaprop-P, compound of formula (I)+fenoxaprop-ethyl,
compound of formula (I)+fenoxaprop-P-ethyl, compound of formula
(I)+fentrazamide, compound of formula (I)+ferrous sulfate, compound
of formula (I)+flamprop-M, compound of formula (I)+flazasulfuron,
compound of formula (I)+florasulam, compound of formula
(I)+fluazifop, compound of formula (I)+fluazifop-butyl, compound of
formula (I)+fluazifop-P, compound of formula (I)+fluazifop-P-butyl,
formula (I)+fluazolate, compound of formula (I)+flucarbazone,
compound of formula (I)+flucarbazone-sodium, compound of formula
(I)+flucetosulfuron, compound of formula (I)+fluchloralin, compound
of formula (I)+flufenacet, compound of formula (I)+flufenpyr,
compound of formula (I)+flufenpyr-ethyl, formula (I)+flumetralin,
compound of formula (I)+flumetsulam, compound of formula
(I)+flumiclorac, compound of formula (I)+flumiclorac-pentyl,
compound of formula (I)+flumioxazin, formula (I)+flumipropin,
compound of formula (I)+fluometuron, compound of formula
(I)+fluoroglycofen, compound of formula (I)+fluoroglycofen-ethyl,
formula (I)+fluoxaprop, formula (I)+flupoxam, formula
(I)+flupropacil, compound of formula (I)+flupropanate, compound of
formula (I)+flupyrsulfuron, compound of formula
(I)+flupyrsulfuron-methyl-sodium, compound of formula (I)+flurenol,
compound of formula (I)+fluridone, compound of formula
(I)+flurochloridone, compound of formula (I)+fluroxypyr, compound
of formula (I)+flurtamone, compound of formula (I)+fluthiacet,
compound of formula (I)+fluthiacet-methyl, compound of formula
(I)+fomesafen, compound of formula (I)+foramsulfuron, compound of
formula (I)+fosamine, compound of formula (I)+glufosinate, compound
of formula (I)+glufosinate-ammonium, compound of formula
(I)+glyphosate, compound of formula (I)+halauxifen, compound of
formula (I)+halauxifen-methyl, compound of formula
(I)+halosulfuron, compound of formula (I)+halosulfuron-methyl,
compound of formula (I)+haloxyfop, compound of formula
(I)+haloxyfop-P, compound of formula (I)+HC-252, compound of
formula (I)+hexazinone, compound of formula (I)+imazamethabenz,
compound of formula (I)+imazamethabenz-methyl, compound of formula
(I)+imazamox, compound of formula (I)+imazapic, compound of formula
(I)+imazapyr, compound of formula (I)+imazaquin, compound of
formula (I)+imazethapyr, compound of formula (I)+imazosulfuron,
compound of formula (I)+indanofan, compound of formula (I) and
indaziflam, compound of formula (I)+iodomethane, compound of
formula (I)+iodosulfuron, compound of formula
(I)+iodosulfuron-methyl-sodium, compound of formula (I)+ioxynil,
compound of formula (I) and ipfencarbazone, compound of formula
(I)+isoproturon, compound of formula (I)+isouron, compound of
formula (I)+isoxaben, compound of formula (I)+isoxachlortole,
compound of formula (I)+isoxaflutole, formula (I)+isoxapyrifop,
compound of formula (I)+karbutilate, compound of formula
(I)+lactofen, compound of formula (I)+lenacil, compound of formula
(I)+linuron, compound of formula (I)+MAA, compound of formula
(I)+MAMA, compound of formula (I)+MCPA, compound of formula
(I)+MCPA-thioethyl, compound of formula (I)+MCPB, compound of
formula (I)+mecoprop, compound of formula (I)+mecoprop-P, compound
of formula (I)+mefenacet, compound of formula (I)+mefluidide,
compound of formula (I)+mesosulfuron, compound of formula
(I)+mesosulfuron-methyl, compound of formula (I)+mesotrione,
compound of formula (I)+metam, compound of formula (I)+metamifop,
compound of formula (I)+metamitron, compound of formula
(I)+metazachlor, compound of formula (I) and metazosulfuron,
compound of formula (I)+methabenzthiazuron, formula (I)+methazole,
a compound of formula (I) and methiozolin, compound of formula
(I)+methylarsonic acid, compound of formula (I)+methyldymron,
compound of formula (I)+methyl isothiocyanate, compound of formula
(I)+metobenzuron, formula (I)+metobromuron, compound of formula
(I)+metolachlor, compound of formula (I)+S-metolachlor, compound of
formula (I)+metosulam, compound of formula (I)+metoxuron, compound
of formula (I)+metribuzin, compound of formula (I)+metsulfuron,
compound of formula (I)+metsulfuron-methyl, compound of formula
(I)+MK-616, compound of formula (I)+molinate, compound of formula
(I)+monolinuron, a compound of formula (I) and monosulfuron, a
compound of formula (I) and monosulfuron-ester compound of formula
(I)+MSMA, compound of formula (I)+naproanilide, compound of formula
(I)+napropamide, compound of formula (I)+naptalam, formula
(I)+NDA-402989, compound of formula (I)+neburon, compound of
formula (I)+nicosulfuron, formula (I)+nipyraclofen, formula
(I)+n-methyl glyphosate, compound of formula (I)+nonanoic acid,
compound of formula (I)+norflurazon, compound of formula (I)+oleic
acid (fatty acids), compound of formula (I)+orbencarb, compound of
formula (I)+orthosulfamuron, compound of formula (I)+oryzalin,
compound of formula (I)+oxadiargyl, compound of formula
(I)+oxadiazon, compound of formula (I)+oxasulfuron, compound of
formula (I)+oxaziclomefone, compound of formula (I)+oxyfluorfen,
compound of formula (I)+paraquat, compound of formula (I)+paraquat
dichloride, compound of formula (I)+pebulate, compound of formula
(I)+pendimethalin, compound of formula (I)+penoxsulam, compound of
formula (I)+pentachlorophenol, compound of formula
(I)+pentanochlor, compound of formula (I)+pentoxazone, compound of
formula (I)+pethoxamid, compound of formula (I)+petrolium oils,
compound of formula (I)+phenmedipham, compound of formula
(I)+phenmedipham-ethyl, compound of formula (I)+picloram, compound
of formula (I)+picolinafen, compound of formula (I)+pinoxaden,
compound of formula (I)+piperophos, compound of formula
(I)+potassium arsenite, compound of formula (I)+potassium azide,
compound of formula (I)+pretilachlor, compound of formula
(I)+primisulfuron, compound of formula (I)+primisulfuron-methyl,
compound of formula (I)+prodiamine, compound of formula
(I)+profluazol, compound of formula (I)+profoxydim, formula
(I)+prohexadione-calcium, compound of formula (I)+prometon,
compound of formula (I)+prometryn, compound of formula
(I)+propachlor, compound of formula (I)+propanil, compound of
formula (I)+propaquizafop, compound of formula (I)+propazine,
compound of formula (I)+propham, compound of formula
(I)+propisochlor, compound of formula (I)+propoxycarbazone,
compound of formula (I)+propoxycarbazone-sodium, compound of
formula (I)+propyzamide, compound of formula (I)+prosulfocarb,
compound of formula (I)+prosulfuron, compound of formula
(I)+pyraclonil, compound of formula (I)+pyraflufen, compound of
formula (I)+pyraflufen-ethyl, formula (I)+pyrasulfotole, compound
of formula (I)+pyrazolynate, compound of formula
(I)+pyrazosulfuron, compound of formula (I)+pyrazosulfuron-ethyl,
compound of formula (I)+pyrazoxyfen, compound of formula
(I)+pyribenzoxim, compound of formula (I)+pyributicarb, compound of
formula (I)+pyridafol, compound of formula (I)+pyridate, compound
of formula (I)+pyriftalid, compound of formula (I)+pyriminobac,
compound of formula (I)+pyriminobac-methyl, compound of formula
(I)+pyrimisulfan, compound of formula (I)+pyrithiobac, compound of
formula (I)+pyrithiobac-sodium, formula (I)+pyroxasulfone, formula
(I)+pyroxulam, compound of formula (I)+quinclorac, compound of
formula (I)+quinmerac, compound of formula (I)+quinoclamine,
compound of formula (I)+quizalofop, compound of formula
(I)+quizalofop-P, compound of formula (I)+quizalofop-ethyl,
compound of formula (I)+quizalofop-P-ethyl, compound of formula
(I)+rimsulfuron, compound of formula (I)+saflufenacil, compound of
formula (I)+sethoxydim, compound of formula (I)+siduron, compound
of formula (I)+simazine, compound of formula (I)+simetryn, compound
of formula (I)+SMA, compound of formula (I)+sodium arsenite,
compound of formula (I)+sodium azide, compound of formula
(I)+sodium chlorate, compound of formula (I)+sulcotrione, compound
of formula (I)+sulfentrazone, compound of formula (I)+sulfometuron,
compound of formula (I)+sulfometuron-methyl, compound of formula
(I)+sulfosate, compound of formula (I)+sulfosulfuron, compound of
formula (I)+sulfuric acid, compound of formula (I)+tar oils,
compound of formula (I)+2,3,6-TBA, compound of formula (I)+TCA,
compound of formula (I)+TCA-sodium, formula (I)+tebutam, compound
of formula (I)+tebuthiuron, formula (I)+tefuryltrione, compound of
formula 1+tembotrione, compound of formula (I)+tepraloxydim,
compound of formula (I)+terbacil, compound of formula
(I)+terbumeton, compound of formula (I)+terbuthylazine, compound of
formula (I)+terbutryn, compound of formula (I)+thenylchlor,
compound of formula (I)+thiazafluron, compound of formula
(I)+thiazopyr, compound of formula (I)+thifensulfuron, compound of
formula (I)+thiencarbazone, compound of formula
(I)+thifensulfuron-methyl, compound of formula (I)+thiobencarb,
compound of formula (I)+tiocarbazil, compound of formula
(I)+topramezone, compound of formula (I)+tralkoxydim, a compound of
formula (I) and triafamone compound of formula (I)+tri-allate,
compound of formula (I)+triasulfuron, compound of formula
(I)+triaziflam, compound of formula (I)+tribenuron, compound of
formula (I)+tribenuron-methyl, compound of formula (I)+tricamba,
compound of formula (I)+triclopyr, compound of formula
(I)+trietazine, compound of formula (I)+trifloxysulfuron, compound
of formula (I)+trifloxysulfuron-sodium, compound of formula
(I)+trifluralin, compound of formula (I)+triflusulfuron, compound
of formula (I)+triflusulfuron-methyl, compound of formula
(I)+trifop, compound of formula (I)+trifop-methyl, compound of
formula (I)+trihydroxytriazine, compound of formula
(I)+trinexapac-ethyl, compound of formula (I)+tritosulfuron,
compound of formula
(I)+[3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-
-tetrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl
ester (CAS RN 353292-31-6), compound of formula
(I)+2-[[8-chloro-3,4-dihydro-4-(4-methoxyphenyl)-3-oxo-2-quinoxalinyl]car-
bonyl-1,3-cyclohexanedione and the compound of formula
(I)+VX-573.
[0150] In particular, the following mixtures are important:
[0151] mixtures of a compound of formula (I) with an acetanilide
(e.g. compound of formula (I)+acetochlor, compound of formula
(I)+dimethenamid, compound of formula (I)+metolachlor, compound of
formula (I)+S-metolachlor, or compound of formula (I)+pretilachlor)
or with other inhibitors of VLCFAE (e.g. compound of formula
(I)+pyroxasulfone).
[0152] mixtures of a compound of formula (I) with an HPPD inhibitor
(e.g. compound of formula (I)+isoxaflutole, compound of formula
(I)+mesotrione, compound of formula (I)+pyrasulfotole, compound of
formula (I)+sulcotrione, compound of formula (I)+tembotrione,
compound of formula (I)+topramezone, compound of formula
(I)+bicyclopyrone;
[0153] mixtures of a compound of formula (I) with a triazine (e.g.
compound of formula (I)+atrazine, or compound of formula
(I)+terbuthylazine);
[0154] mixtures of a compound of formula (I) with glyphosate;
[0155] mixtures of a compound of formula (I) with
glufosinate-ammonium;
[0156] mixtures of a compound of formula (I) with a PPO inhibitor
(e.g. compound of formula (I)+acifluorfen-sodium, compound of
formula (I)+butafenacil, compound of formula
(I)+carfentrazone-ethyl, compound of formula (I)+cinidon-ethyl,
compound of formula (I)+flumioxazin, compound of formula
(I)+fomesafen, compound of formula (I)+lactofen, or compound of
formula (I)+SYN 523
([3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-te-
trahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl
ester) (CAS RN 353292-31-6)).
[0157] Whilst two-way mixtures of a compound of formula (I) and
another herbicide are explicitly disclosed above, the skilled man
will appreciate that the invention extends to three-way, and
further multiple combinations comprising the above two-way
mixtures. In particular, the invention extends to:
[0158] mixtures of a compound of formula (I) with a triazine and an
HPPD inhibitor (e.g. compound of formula (I)+triazine+isoxaflutole,
compound of formula (I)+triazine+mesotrione, compound of formula
(I)+triazine+pyrasulfotole, compound of formula
(I)+triazine+sulcotrione, compound of formula
(I)+triazine+tembotrione, compound of formula
(I)+triazine+topramezone, compound of formula
(I)+triazine+bicyclopyrone;
[0159] mixtures of a compound of formula (I) with glyphosate and an
HPPD inhibitor (e.g. compound of formula
(I)+glyphosate+isoxaflutole, compound of formula
(I)+glyphosate+mesotrione, compound of formula
(I)+glyphosate+pyrasulfotole, compound of formula
(I)+glyphosate+sulcotrione, compound of formula
(I)+glyphosate+tembotrione, compound of formula
(I)+glyphosate+topramezone, compound of formula
(I)+glyphosate+bicyclopyrone;
[0160] mixtures of a compound of formula (I) with
glufosinate-ammonium and an HPPD inhibitor (e.g. compound of
formula (I)+glufosinate-ammonium+isoxaflutole, compound of formula
(I)+glufosinate-ammonium+mesotrione, compound of formula
(I)+glufosinate-ammonium+pyrasulfotole, compound of formula
(I)+glufosinate-ammonium+sulcotrione, compound of formula
(I)+glufosinate-ammonium+tembotrione, compound of formula
(I)+glufosinate-ammonium+topramezone, compound of formula
(I)+glufosinate-ammonium+bicyclopyrone;
[0161] mixtures of a compound of formula (I) with a VLCFAE
inhibitor and an HPPD inhibitor (e.g. compound of formula
(I)+S-metolachlor+isoxaflutole, compound of formula
(I)+S-metolachlor+mesotrione, compound of formula
(I)+S-metolachlor+pyrasulfotole, compound of formula
(I)+S-metolachlor+sulcotrione, compound of formula
(I)+S-metolachlor+tembotrione, compound of formula
(I)+S-metolachlor+topramezone, compound of formula
(I)+S-metolachlor+bicyclopyrone, compound of formula
(I)+acetochlor+isoxaflutole, compound of formula
(I)+acetochlor+mesotrione, compound of formula
(I)+acetochlor+pyrasulfotole, compound of formula
(I)+acetochlor+sulcotrione, compound of formula
(I)+acetochlor+tembotrione, compound of formula
(I)+acetochlor+topramezone, compound of formula
(I)+acetochlor+bicyclopyrone, compound of formula
(I)+pyroxasulfone+isoxaflutole, compound of formula
(I)+pyroxasulfone+mesotrione, compound of formula
(I)+pyroxasulfone+pyrasulfotole, compound of formula
(I)+pyroxasulfone+sulcotrione, compound of formula
(I)+pyroxasulfone+tembotrione, compound of formula
(I)+pyroxasulfone+topramezone, compound of formula
(I)+pyroxasulfone+bicyclopyrone, compound of formula
(I)+S-metolachlor+mesotrione+bicyclopyrone.
[0162] mixtures of a compound of formula (I) with glyphosate and a
VLCFAE inhibitor (e.g. compound of formula
(I)+glyphosate+S-metolachlor, compound of formula
(I)+glyphosate+acetochlor, compound of formula
(I)+glyphosate+pyroxasulfone).
[0163] Particularly preferred are mixtures of the compound of
formula (I) with mesotrione, bicyclopyrone, isoxaflutole,
tembotrione, topramezone, sulcotrione, pyrasulfotole, metolachlor,
S-metolachlor, acetochlor, pyroxasulfone, P-dimethenamid,
dimethenamid, flufenacet, pethoxamid, atrazine, terbuthylazine,
bromoxynil, metribuzin, amicarbazone, bentazone, ametryn,
hexazinone, diuron, tebuthiuron, glyphosate, paraquat, diquat,
glufosinate, acifluorfen-sodium, butafenacil, carfentrazone-ethyl,
cinidon-ethyl, flumioxazin, fomesafen, lactofen,
[3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-tet-
rahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl
ester.
[0164] The mixing partners of the compound of formula (I) may also
be in the form of esters or salts, as mentioned e.g. in The
Pesticide Manual, 14th Edition (BCPC), 2006. The reference to
acifluorfen-sodium also applies to acifluorfen, the reference to
dimethenamid also applies to dimethenamid-P, the reference to
glufosinate-ammonium also applies to glufosinate, the reference to
bensulfuron-methyl also applies to bensulfuron, the reference to
cloransulam-methyl also applies to cloransulam, the reference to
flamprop-M also applies to flamprop, and the reference to
pyrithiobac-sodium also applies to pyrithiobac, etc.
[0165] The mixing ratio of the compound of formula (I) to the
mixing partner is preferably from 1:100 to 1000:1.
[0166] The mixtures can advantageously be used in the
above-mentioned formulations (in which case "active ingredient"
relates to the respective mixture of compound of formula (I) with
the mixing partner).
[0167] The compounds of formula (I) according to the invention can
also be used in combination with one or more safeners. Likewise,
mixtures of a compound of formula (I) according to the invention
with one or more further active ingredients, in particular with one
or more further herbicides, can also be used in combination with
one or more safeners. The term "safener" as used herein means a
chemical that when used in combination with a herbicide reduces the
undesirable effects of the herbicide on non-target organisms, for
example, a safener protects crops from injury by herbicides but
does not prevent the herbicide from killing the weeds. Where a
compound of formula (I) is combined with a safener, the following
combinations of the compound of formula (I) and the safener are
particularly preferred. Compound of formula (I)+AD 67 (MON 4660),
compound of formula (I)+benoxacor, compound of formula
(I)+cloquintocet-mexyl, compound of formula (I)+cyometrinil and a
compound of formula (I)+the corresponding (Z) isomer of
cyometrinil, compound of formula (I)+cyprosulfamide (CAS RN
221667-31-8), compound of formula (I)+dichlormid, compound of
formula (I) and dicyclonon, compound of formula (I) and dietholate,
compound of formula (I)+fenchlorazole-ethyl, compound of formula
(I)+fenclorim, compound of formula (I)+flurazole, compound of
formula (I)+fluxofenim, compound of formula (I)+furilazole and a
compound of formula (I)+the corresponding R isomer or furilazome,
compound of formula (I)+isoxadifen-ethyl, compound of formula
(I)+mefenpyr-diethyl, compound of formula (I) and mephenate,
compound of formula (I)+oxabetrinil, compound of formula
(I)+naphthalic anhydride (CAS RN 81-84-5), compound of formula (I)
and TI-35, compound of formula
(I)+N-isopropyl-4-(2-methoxy-benzoylsulfamoyl)-benzamide (CAS RN
221668-34-4) and a compound of formula
(I)+N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide-
. Particularly preferred are mixtures of a compound of formula (I)
with benoxacor, a compound of formula (I) with cloquintocet-mexyl,
a compound of formula (I)+cyprosulfamide and a compound of formula
(I) with
N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.
[0168] The safeners of the compound of formula (I) may also be in
the form of esters or salts, as mentioned e.g. in The Pesticide
Manual, 14th Edition (BCPC), 2006. The reference to
cloquintocet-mexyl also applies to cloquintocet and to a lithium,
sodium, potassium, calcium, magnesium, aluminium, iron, ammonium,
quaternary ammonium, sulfonium or phosphonium salt thereof as
disclosed in WO02/34048 and the reference to fenchlorazole-ethyl
also applies to fenchlorazole, etc.
[0169] Preferably the mixing ratio of compound of formula (I) to
safener is from 100:1 to 1:10, especially from 20:1 to 1:1.
[0170] The mixtures can advantageously be used in the
above-mentioned formulations (in which case "active ingredient"
relates to the respective mixture of compound of formula (I) and
any further active ingredient, in particular a further herbicide,
with the safener).
[0171] It is possible that the safener and a compound of formula
(I) and one or more additional herbicide(s), if any, are applied
simultaneously. For example, the safener, a compound of formula (I)
and one or more additional herbicide(s), if any, might be applied
to the locus pre-emergence or might be applied to the crop
post-emergence. It is also possible that the safener and a compound
of formula (I) and one or more additional herbicide(s), if any, are
applied sequentially. For example, the safener might be applied
before sowing the seeds as a seed treatment and a compound of
formula (I) and one or more additional herbicides, if any, might be
applied to the locus pre-emergence or might be applied to the crop
post-emergence.
[0172] Preferred mixtures of a compound of formula (I) with further
herbicides and safeners include:
[0173] Mixtures of a compound of formula (I) with S-metolachlor and
a safener, particularly benoxacor.
[0174] Mixtures of a compound of formula (I) with isoxaflutole and
a safener.
[0175] Mixtures of a compound of formula (I) with mesotrione and a
safener.
[0176] Mixtures of a compound of formula (I) with sulcotrione and a
safener.
[0177] Mixtures of a compound of formula (I) with tembotrione and a
safener.
[0178] Mixtures of a compound of formula (I) with topramezone and a
safener.
[0179] Mixtures of a compound of formula (I) with bicyclopyrone and
a safener.
[0180] Mixtures of a compound of formula (I) with a triazine and a
safener.
[0181] Mixtures of a compound of formula (I) with a triazine and
isoxaflutole and a safener.
[0182] Mixtures of a compound of formula (I) with a triazine and
mesotrione and a safener.
[0183] Mixtures of a compound of formula (I) with a triazine and
sulcotrione and a safener.
[0184] Mixtures of a compound of formula (I) with a triazine and
tembotrione and a safener.
[0185] Mixtures of a compound of formula (I) with a triazine and
topramezone and a safener.
[0186] Mixtures of a compound of formula (I) with a triazine and
bicyclopyrone and a safener.
[0187] Mixtures of a compound of formula (I) with glyphosate and a
safener.
[0188] Mixtures of a compound of formula (I) with glyphosate and
isoxaflutole and a safener.
[0189] Mixtures of a compound of formula (I) with glyphosate and
mesotrione and a safener.
[0190] Mixtures of a compound of formula (I) with glyphosate and
sulcotrione and a safener.
[0191] Mixtures of a compound of formula (I) with glyphosate and
tembotrione and a safener.
[0192] Mixtures of a compound of formula (I) with glyphosate and
topramezone and a safener.
[0193] Mixtures of a compound of formula (I) with glyphosate and
bicyclopyrone and a safener.
[0194] Mixtures of a compound of formula (I) with
glufosinate-ammonium and a safener.
[0195] Mixtures of a compound of formula (I) with
glufosinate-ammonium and isoxaflutole and a safener.
[0196] Mixtures of a compound of formula (I) with
glufosinate-ammonium and mesotrione and a safener.
[0197] Mixtures of a compound of formula (I) with
glufosinate-ammonium and sulcotrione and a safener.
[0198] Mixtures of a compound of formula (I) with
glufosinate-ammonium and tembotrione and a safener.
[0199] Mixtures of a compound of formula (I) with
glufosinate-ammonium and topramezone and a safener.
[0200] Mixtures of a compound of formula (I) with
glufosinate-ammonium and bicyclopyrone and a safener.
[0201] Mixtures of a compound of formula (I) with S-metolachlor and
a safener.
[0202] Mixtures of a compound of formula (I) with S-metolachlor and
isoxaflutole and a safener.
[0203] Mixtures of a compound of formula (I) with S-metolachlor and
mesotrione and a safener.
[0204] Mixtures of a compound of formula (I) with S-metolachlor and
sulcotrione and a safener.
[0205] Mixtures of a compound of formula (I) with S-metolachlor and
tembotrione and a safener.
[0206] Mixtures of a compound of formula (I) with S-metolachlor and
topramezone and a safener.
[0207] Mixtures of a compound of formula (I) with S-metolachlor and
bicyclopyrone and a safener
[0208] Mixtures of a compound of formula (I) with pyroxasulfone and
a safener.
[0209] Mixtures of a compound of formula (I) with pyroxasulfone and
isoxaflutole and a safener.
[0210] Mixtures of a compound of formula (I) with pyroxasulfone and
mesotrione and a safener.
[0211] Mixtures of a compound of formula (I) with pyroxasulfone and
sulcotrione and a safener.
[0212] Mixtures of a compound of formula (I) with pyroxasulfone and
tembotrione and a safener.
[0213] Mixtures of a compound of formula (I) with pyroxasulfone and
topramezone and a safener.
[0214] Mixtures of a compound of formula (I) with pyroxasulfone and
bicyclopyrone and a safener
[0215] Mixtures of a compound of formula (I) with acetochlor and a
safener.
[0216] Mixtures of a compound of formula (I) with acetochlor and
isoxaflutole and a safener.
[0217] Mixtures of a compound of formula (I) with acetochlor and
mesotrione and a safener.
[0218] Mixtures of a compound of formula (I) with acetochlor and
sulcotrione and a safener.
[0219] Mixtures of a compound of formula (I) with acetochlor and
tembotrione and a safener.
[0220] Mixtures of a compound of formula (I) with acetochlor and
topramezone and a safener.
[0221] Mixtures of a compound of formula (I) with acetochlor and
bicyclopyrone and a safener.
[0222] Mixtures of a compound of formula (I) with S-metolachlor and
mesotrione and bicyclopyrone and a safener.
[0223] Mixtures of a compound of formula (I) with S-metolachlor and
a triazine and mesotrione and bicyclopyrone and a safener.
[0224] Various aspects and embodiments of the present invention
will now be illustrated in more detail by way of example. It will
be appreciated that modification of detail may be made without
departing from the scope of the invention.
[0225] For the avoidance of doubt, where a literary reference,
patent application, or patent, is cited within the text of this
application, the entire text of said citation is herein
incorporated by reference.
EXAMPLES
Preparation Examples
[0226] The following abbreviations were used in this section:
s=singlet; bs=broad singlet; d=doublet; dd=double doublet;
dt=double triplet; t=triplet, tt=triple triplet, q=quartet,
sept=septet; m=multiplet; RT=retention time, MH.sup.+=molecular
mass of the molecular cation.
[0227] 1H NMR spectra were recorded at 400 MHz either on a Varian
Unity Inova instrument 400 MHz or on a Bruker AVANCE-II
instrument.
[0228] The compounds may exist in a mixture of diastereoisomers,
which may be observed by LC-MS and NMR. The stereochemistry of the
chiral centre at the carbon containing the R.sub.3 group was
generally found to interconvert at room temperature when R.sup.3 is
hydroxyl. Depending on the nature of R.sup.2 substitution and the
conditions for product synthesis, purification and analysis the
ratio of diastereomers may change.
Example 1
Preparation of
5-hydroxy-1-[5-iodo-4-(trifluoromethyl)-2-pyridyl]-3,4-dimethyl-imidazoli-
din-2-one (A25)
##STR00018##
[0229] Procedure for synthesis of
1-(2,2-dimethoxy-1-methyl-ethyl)-3-[5-iodo-4-(trifluoromethyl)-2-pyridyl]-
-1-methyl-urea (Step-1)
##STR00019##
[0231] 5-iodo-4-(trifluoromethyl)pyridin-2-amine (for a synthesis
see Bioorganic & Medicinal Chemistry Letters, 1994, 4(6),
835-8) (0.500 g, 1.74 mmol) was dissolved in DCM (5 mL) and then
carbonyl-diimidazole (1.06 g, 80% purity) was added. The reaction
mixture was heated at 105.degree. C. in a microwave vial for 15
minutes and then cooled to 10.degree. C.
1,1-dimethoxy-N-methyl-propan-2-amine (preparation as in example
13) (695 mg, 3 equiv.) was added and the reaction was stirred at
room temperature for 15 mins. The reaction was diluted with DCM (10
mL) and water (5 mL) was added. This mixture was filtered and the
aqueous layer extracted with further DCM (2.times.10 mL). The
combined organics were dried (Na.sub.2SO.sub.4), filtered and
evaporated and then chromatographed on silica eluting with 20-30%
EtOAc in isohexane. Fractions containing product were evaporated to
give desired product as an amber gum (326 mg, 42%).
[0232] LC-MS: (positive ES MH+ 448).
Procedure for synthesis of
5-hydroxy-1-[5-iodo-4-(trifluoromethyl)-2-pyridyl]-3,4-dimethyl-imidazoli-
din-2-one (Step-2)
##STR00020##
[0234]
1-(2,2-dimethoxy-1-methyl-ethyl)-3-[5-iodo-4-(trifluoromethyl)-2-py-
ridyl]-1-methyl-urea (260 mg, 0.581 mmol) was dissolved in acetic
acid (5.2 mL) and water (2.6 mL). The reaction mixture was stirred
at room temperature for 2 days. The reaction mixture was then
evaporated and dried (100 to 1 mBar at 20-35.degree. C.) for 2 h to
remove traces of acetic acid to give product as a lilac gum which
crystallised to give a solid (230 mg, 98%).
[0235] LC-MS: (positive ES MH+ 402).
[0236] .sup.1H NMR (CDCl.sub.3): Major diastereomer: 8.69 (s, 1H),
8.64 (s, 1H), 5.56 (m, 1H), 4.65 (very br s, 1H), 3.53 (m, 1H),
2.93 (s, 3H), 1.33 (d, 3H).
[0237] Minor diastereomer: 8.70 (s, 1H), 8.64 (s, 1H), 5.91 (d,
1H), 4.65 (very br s, 1H), 3.76 (m, 1H), 2.88 (s, 3H), 1.38 (d,
3H).
Example 2
Preparation of
5-hydroxy-1-[5-(4-methoxy-3-pyridyl)-4-(trifluoromethyl)-2-pyridyl]-3,4-d-
imethyl-imidazolidin-2-one (A24)
##STR00021##
[0239]
5-hydroxy-1-[5-iodo-4-(trifluoromethyl)-2-pyridyl]-3,4-dimethyl-imi-
dazolidin-2-one (50 mg, 1 equiv. 0.125 mmol),
(6-methyl-3-pyridyl)boronic acid (22 mg, 1.1 equiv.),
tricyclohexylphosphine (4 mg, 0.12 equiv.)
tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.05 equiv.), in
1,4-dioxane (0.5 mL) was treated with K.sub.2CO.sub.3 (38 mg) in
water (0.2 mL). The reaction was heated for 80 minutes at
100.degree. C., then treated with further
6-methyl-3-pyridyl)boronic acid (2.2 equiv.), tricyclohexyl
phosphine (4 mg, 0.12 equiv.),
tris(dibenzylideneacetone)dipalladium(0) (6 mg, 0.05 equiv),
K.sub.3PO.sub.4 (45 mg, 1.7 equiv.) and the reaction was then
heated for a further 75 minutes at 100.degree. C.
[0240] The reaction mixture was diluted with EtOAc (6 mL) then
filtered through celite, evaporated, then chromatographed on silica
eluting with 20-100% EtOAc in isohexane. Fractions containing
product were evaporated to give desired product as an amber gum (35
mg, 69%).
[0241] LC-MS: (positive ES MH+ 367).
[0242] .sup.1H NMR (CDCl.sub.3): Major diastereomer: 8.69 (s, 1H),
8.46 (s, 1H), 8.21 (m, 1H), 7.57 (dm, 1H), 7.25 (dm, 1H), 5.65 (m,
1H), 4.91 (br s, 1H), 3.56 (m, 1H), 2.95 (s, 3H), 2.64 (s, 3H),
1.36 (d, 3H).
[0243] Minor diastereomer: 8.69 (s, 1H), 8.46 (s, 1H), 8.21 (m,
1H), 7.57 (dm, 1H), 7.25 (dm, 1H), 6.00 (d, 1H), 4.78 (br s, 1H),
3.79 (m, 1H), 2.92 (s, 3H), 2.64 (s, 3H), 1.42 (d, 3H).
Example 3
Preparation of
5-hydroxy-1-[5-methoxy-4-(trifluoromethyl)-2-pyridyl]-3,4-dimethyl-imidaz-
olidin-2-one (A12)
##STR00022##
[0245] A mixture of
di-tert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phos-
phane (RockPhos) (11 mg, 4.5 mol %), allylpalladium(II) chloride
dimer (3 mg, 1.5 mol %) and Cs.sub.2CO.sub.3 (245 mg, 1.5 equiv.)
in toluene (0.8 mL) was degassed by bubbling N.sub.2 through the
reaction mixture for 5 mins. This mixture was then heated to
90.degree. C. for 3 mins then methanol (101 .mu.L, 5 equiv.) was
added, followed by
5-hydroxy-1-[5-iodo-4-(trifluoromethyl)-2-pyridyl]-3,4-dimethyl-imidazoli-
din-2-one (200 mg, 0.499 mmol, 1 equiv.). The reaction was then
heated in a sealed tube at 80.degree. C. for 1 h and 25 minutes.
Further
di-tert-butyl-[6-methoxy-3-methyl-2-(2,4,6-triisopropylphenyl)phenyl]phos-
phane (RockPhos) (11 mg, 4.5 mol %), allylpalladium(II) chloride
dimer (3 mg, 1.5 mol %) and methanol (40 .mu.L, 2 equiv.) was
added. The reaction was then heated in a sealed tube at 80.degree.
C. for a further 1 h. The reaction mixture was diluted with 4 ml
EtOAc, filtered through celite, then evaporated, then
chromatographed on silica eluting with 0-100% EtOAc in isohexane.
Fractions containing product were evaporated to give desired
product as a pale yellow solid (80 mg, 53%).
[0246] LC-MS: (positive ES MH+ 306).
[0247] .sup.1H NMR (CDCl.sub.3): Major diastereomer: 8.45 (s, 1H),
8.03 (s, 1H), 5.53 (m, 1H), 4.90 (br s, 1H), 3.95 (s, 3H), 3.50 (m,
1H), 2.91 (s, 3H), 1.33 (d, 3H).
[0248] Minor diastereomer: 8.44 (s, 1H), 8.05 (s, 1H), 5.88 (d,
1H), 4.75 (br s, 1H), 3.95 (s, 3H), 3.75 (m, 1H), 2.88 (s, 3H),
1.39 (d, 3H).
Example 4
Preparation of
4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidi-
n-2-one (A8)
##STR00023##
[0249] Procedure for synthesis of N,1,1-trimethoxypropan-2-imine
(Step-1)
##STR00024##
[0251] Methoxylamine hydrochloride (21.2 g) was suspended in
methanol (65 mL) then potassium acetate (50.4 g, quickly ground in
pestle and mortar to break up lumps) was added all at once and the
thick white suspension resulting was stirred at room temp for 15
mins then cooled to 15.degree. C. and then
1,1-dimethoxypropan-2-one (30 g) was added slowly over 25 mins. The
reaction was stirred at room temperature for 50 mins and then
diluted with 200 ml DCM, then 100 ml sat. NaHCO.sub.3 (aq) was
added cautiously over 15 mins. After effervescence subsided, the
layers were separated, extracted with further DCM (2.times.80 mL),
dried Na.sub.2SO.sub.4, filtered and concentrated at 220 mbar and
35.degree. C. (care as desired product is volatile) to give 37 g
amber liquid, which was used without further purification.
[0252] .sup.1H NMR (CDCl.sub.3) showed a 3:1 ratio of E:Z
isomers.
Procedure for synthesis of N,1,1-trimethoxypropan-2-amine
(Step-2)
##STR00025##
[0254] N,1,1-trimethoxypropan-2-imine (20 g) was dissolved in
acetic acid (80 mL) then was cooled to 13.degree. C. NaBH.sub.3CN
(9.82 g) was added portionwise over 10 mins. After 18 hrs at room
temperature, the reaction was concentrated to remove bulk of HOAc
then residue dissolved in DCM (300 mL) and satd. NaHCO.sub.3 (aq)
(300 mL) was added slowly with stirring. The mixture was stirred at
rt for 90 mins, and then 40% NaOH(aq) was added until the solution
reached pH 12. The layers were separated, extracted with further
DCM (3.times.100 mL). The combined DCM layers were dried
(Na.sub.2SO.sub.4), filtered and evaporated to give 16.4 g of crude
product as a pale amber oil, which was further purified by
Kugelrohr distillation (120.degree. C. at 70 mBar) to give product
(12.0 g, 59% yield) which was approximately 95% pure by NMR and
used without further purification.
Procedure for synthesis of
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-urea (Step-3)
##STR00026##
[0256] N,1,1-trimethoxypropan-2-amine (2.000 g, 13.41 mmol) was
dissolved in IPA (5 mL) and the mixture was cooled to 0.degree. C.
under N.sub.2, then trimethylsilyl isocyanate (commercially
available) (4.83 mL, 33.51 mmol) was added and the reaction was
allowed to warm to room temperature and was stirred at room
temperature for 24 h. The reaction mixture was worked up by adding
DCM (30 mL) and water (15 mL), extracting with further DCM
(2.times.15 mL), dried (Na.sub.2SO.sub.4), filtered and evaporated
then chromatographed on silica eluting with 50-100% EtOAc in
isohexane. Fractions containing product were evaporated to give the
desired product as a white solid (2.08 g, 81% yield).
[0257] .sup.1H NMR (CDCl.sub.3): 5.36 (br s, 2H), 4.47 (d, 1H),
4.32 (pentet, 1H), 3.75 (s, 3H), 3.37 (d, 6H), 1.24 (d, 3H).
Procedure for synthesis of
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-3-[4-(trifluoromethyl)-2-pyrid-
yl]urea (Step-4)
##STR00027##
[0259] 1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-urea (300 mg,
1.56 mmol), 2-chloro-4-(trifluoromethyl)pyridine (commercially
available) (312 mg, 1.1 equiv.), potassium carbonate (324 mg),
tris(dibenzylideneacetone)dipalladium(0) (30 mg),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (70 mg) were
suspended in 1-4-dioxane (4 mL) and the mixture was then heated at
105.degree. C. in a sealed vial for 2 h. The mixture was allowed to
cool to room temperature, diluted with EtOAc (6 mL), filtered, then
chromatographed on silica eluting with 0-100% EtOAc in isohexane.
Fractions containing product were evaporated to give the desired
product as a yellow gum (170 mg, 32%).
[0260] LC-MS: (positive ES MH+ 338).
Procedure for synthesis of
4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidi-
n-2-one (Step-5)
##STR00028##
[0262]
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methoxy-3-[4-(trifluoromethyl)-2-
-pyridyl]urea (155 mg, 0.459 mmol) was dissolved in acetic acid (1
mL) and water (0.5 mL) and stirred at room temperature for 25 mins
and then at 60.degree. C. for 2 h and 45 mins. The reaction was
left at room temperature for 18 h before heating again at
60.degree. C. for 2 h. Reaction mixture was evaporated and then
chromatographed on silica eluting with 0-24% EtOAc in isohexane.
Fractions containing product were evaporated to give the desired
product as a pale beige solid (101 mg, 75%).
[0263] NMR indicated a ratio of diastereoisomers in approximately a
2:1 ratio.
[0264] .sup.1H NMR (CDCl.sub.3): Major diastereomer: 8.55 (s, 1H),
8.43 (dd, 1H), 7.25 (d, 1H), 5.55 (m, 1H), 5.04 (very br s, 1H),
3.90 (s, 3H), 3.71 (m, 1H), 1.45 (d, 3H).
[0265] .sup.1H NMR (CDCl.sub.3): Minor diastereomer: 8.53 (s, 1H),
8.45 (dd, 1H), 7.24 (d, 1H), 5.87 (d, 1H), 4.60 (very br s, 1H),
3.93 (s, 3H), 3.80 (m, 1H), 1.50 (d, 3H).
[0266] LC-MS: (positive ES MH+ 292).
[0267] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 5
Preparation of
4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidi-
n-2-one (A8)--Alternative Synthesis
##STR00029##
[0269] Phenyl N-[4-(trifluoromethyl)-2-pyridyl]carbamate (for a
synthesis see WO 2007004749) (9.93 g, 1.05 equiv.) was suspended in
1,4-dioxane (25 mL) under a Nitrogen atmosphere and treated with
N,1,1-trimethoxypropan-2-amine (5.00 g, 22.51 mmol, 1 equiv.) and
the reaction was heated to reflux for 2.5 h. The reaction was
cooled to room temperature, then 2N aqueous HCl (30 mL) was added
to the reaction mixture and heated to 50.degree. C. for 25 minutes.
EtOAc (100 mL) and water (75 mL) was added and the aqueous layer
was further extracted EtOAc (2.times.75 mL). The combined organic
fractions were washed with satd NaHCO.sub.3 (aq), dried
(Na.sub.2SO.sub.4), filtered and then chromatographed on silica
eluting with 0-26% EtOAc in isohexane. Fractions containing product
were evaporated to give the desired product as a crystalline solid
(6.865 g).
[0270] LC-MS: (positive ES MH+ 292).
[0271] NMR and LC-MS data for A3 and A4 were consistant with A8
(example 4).
[0272] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 6
Preparation of
(4R,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one and
(4S,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one (A3)
and
Example 7
(4R,5R)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imid-
azolidin-2-one and
(4S,5R)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one (A4)
[0273] A sample of compound A8 was separated into two major
fractions by preparative chiral SFC (Lux Cellulose-4 column,
eluting with IPA (7%) with other fractions discarded. The analysis
could be performed by HPLC on a Lux Amylose-2 or WHELK-O1 column
eluting with heptane/IPA in a 70/30 ratio.
[0274] One fraction eluting from the SFC column was found to
equilibrate to
(4R,5R)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]-
imidazolidin-2-one and
(4S,5R)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one.
[0275] The absolute stereochemistry may be proven by synthesis (in
an analogous way to example 8-alternative synthesis below).
[0276] Another fraction eluting from the SFC column was found to
equilibrate to
(4R,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one and
(4S,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one.
[0277] The absolute stereochemistry could be proven by synthesis
(see Example 8--alternative synthesis below) and also by X-ray
crystallography after recrystallization of a sample from
DCM/isoHexane. NMR and LC-MS data for A3 and A4 were consistant
with A8 (example 4).
[0278] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 8
Preparation of
(4S,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one and
(4R,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one (A3)--Alternative Synthesis
Procedure for synthesis of methyl (2S)-2-(methoxyamino)propanoate
(Step-1)
##STR00030##
[0280] To a stirred solution of methyl (2R)-2-hydroxypropanoate
(16.5 g, 158 mmol, 15.1 mL) in DCM (475 mL) at 0.degree. C. was
added trifluoromethanesulfonic anhydride (49.7 g, 174 mmol)
followed after 5 mins by 2,6-dimethylpyridine (19.5 g, 182 mmol).
The resulting mixture was stirred at 0.degree. C. for 10 minutes to
give a solution of methyl
(2R)-2-(trifluoromethylsulfonyloxy)propanoate. Separately,
O-methylhydroxylamine hydrochloride (65.98 g, 790.0 mmol) was
dissolved in water (130 mL) then sodium hydroxide (50% aqueous)
(33.1 mL 632.0 mmol) was added. The solution of
O-methylhydroxylamine in water was added to the solution of methyl
(2R)-2-(trifluoromethylsulfonyloxy)propanoate in DCM, and the
mixture was stirred at room temperature for 30 minutes. The organic
layer was separated and chromatographed on silica eluting with
0-45% EtOAc in isohexane. Fractions containing product were
evaporated to give the desired product as a pale yellow oil (23.5
g). The product appears to have some volatility so caution was
taken with the evaporation step. The product was used without
further purification.
Procedure for synthesis of methyl
(2S)-2-[methoxy-[[4-(trifluoromethyl)-2-pyridyl]carbamoyl]amino]propanoat-
e (Step-2)
##STR00031##
[0281] Procedure as for Example 5 Alternative Synthesis
Procedure for synthesis of
(4S,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one and
(4R,5S)-4-hydroxy-1-methoxy-5-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imi-
dazolidin-2-one (A3) (Step-3)
##STR00032##
[0283] To a stirred solution of methyl
(2S)-2-[methoxy-[[4-(trifluoromethyl)-2-pyridyl]carbamoyl]amino]propanoat-
e (18.3 g, 57.0 mmol) in a mixture of tetrahydrofuran (103 mL) and
methanol (103 mL) at 5.degree. C. under nitrogen was added
NaBH.sub.4 (5.10 g, 2.25 equiv.) portionwise over 20 mins, keeping
the internal temperature below .about.6.5.degree. C. The mixture
was then stirred at 6.5.degree. C. for 1 h before the reaction was
quenched with acetone (50 mL) slowly over 45 minutes with external
cooling to keep the internal temperature below .about.6.5.degree.
C. Sat. aqueous NH.sub.4Cl solution (150 mL) was added followed by
water (150 mL). The reaction was stirred at 15.degree. C. for 10
mins, then extracted with DCM (4.times.400 mL and then 1.times.100
mL). Combined DCM fractions were washed with water (50 mL) dried
(Na.sub.2SO.sub.4), filtered and concentrated to .about.200 mL
volume, then chromatographed on silica eluting with 0-27% EtOAc in
isohexane. Fractions containing product were evaporated to give the
desired product as a white solid (5.65 g, 34%).
[0284] NMR and LC-MS data for A3 was consistant with A8 (example
4).
[0285] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Examples 9 and 10
Preparation of
4,5-dihydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (A7) and
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]im-
idazolidin-2-one (A6)
##STR00033##
[0286] Procedure for synthesis of 4
1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (Step-1)
##STR00034##
[0288] A mixture of tris(dibenzylideneacetone)dipalladium(0) (0.202
g, 0.220 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene
(0.493 g, 0.826 mmol), potassium carbonate (1.93 g, 13.8 mmol) and
methylurea (0.408 g, 5.51 mmol) in 1,4-dioxane (30 mL) was treated
with 2-chloro-4-(trifluoromethyl)pyridine (commercially available)
(1.0 g, 5.51 mmol), The mixture was warmed to 75-80.degree. C. with
stirring under a Nitrogen atmosphere for 3.5 h. The reaction
mixture was diluted with EtOAc (20 mL) and water (20 mL) and
filtered through a pad of celite, rinsing through with further
small portions of EtOAc and water. The organic phase was separated
and the aqueous further extracted with EtOAc (5 mL). The organic
extracts were combined, washed with brine (10 mL), dried over
MgSO.sub.4, filtered and the filtrate evaporated giving an orange
liquid. This was chromatographed (eluting with an EtOAc/iso-hexane
gradient) and fractions containing product were evaporated and
triturated with iso-hexane to give the desired product as a light
yellow powder (0.669 g, 55%).
[0289] .sup.1H NMR (CDCl.sub.3): 9.44 (br.s, 1H), 9.04 (br.s, 1H),
8.32 (d, 1H), 7.15 (s, 1H), 7.06 (d, 1H), 2.99 (d, 3H).
[0290] LC-MS: (positive ES MH+ 220).
Procedure for synthesis of
4,5-dihydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (A7) and
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]im-
idazolidin-2-one (A6) (Step-2)
##STR00035##
[0292] To 1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]urea (0.65 g,
3.0 mmol) in ethanol (20 mL) was added glyoxal (40% aqueous
solution) (2.6 g, 18 mmol, 2.0 mL) via syringe, the mixture then
being warmed and heated at reflux for 2 hours. The reaction mixture
was allowed to cool to room temperature and concentrated to give a
syrupy residue. This was dissolved in DCM (50 mL) and washed with
brine (2.times.5 mL). The organic phase was dried (MgSO.sub.4)
filtered and the filtrate concentrated giving the crude product as
a dark green gum (1.07 g). The crude product was dissolved in DCM
(20 mL) then chromatographed on silica eluting with EtOAc in
isohexane. Fractions containing product were evaporated to give
4,5-dihydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (0.562 g, 68%) and
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-
-2-one (0.11 g, 12%).
4,5-Dihydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-one
[0293] .sup.1H NMR (CDCl.sub.3): Major diastereoisomer: 8.35 (br.s,
1H), 8.32 (d, 1H), 7.12 (dd, 1H), 5.71 (d, 1H); 4.96 (m, 1H), 4.82
(m, 1H), 3.54 (d, 1H), 3.01 (s, 3H).
[0294] Minor diastereoisomer: 8.47 (br.s, 1H), 8.38 (d, 1H), 7.19
(dd, 1H), 5.89 (d, 1H), 5.15 (m, 1H), 5.12 (m, 1H), 3.82 (d, 1H),
2.97 (s, 3H).
[0295] LC-MS: (positive ES MH+ 278).
5-Ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin--
2-one (existing predominately as the trans diastereoisomer)
[0296] .sup.1H NMR (CDCl.sub.3): 8.46 (s, 1H), 8.38 (d, 1H), 7.18
(dd, 1H), 5.73 (d, 1H), 4.82 (d, 1H), 4.71 (s, 1H), 3.66 (m, 2H),
3.00 (s, 3H), 1.28 (t, 3H).
[0297] LC-MS: (positive ES MH+ 306).
Examples 11 and 12
Preparation of
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-
-2-one (Enantiomer 1, A34) and
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-
-2-one (Enantiomer 2, A35)
##STR00036##
[0299]
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidaz-
olidin-2-one (A6) was separated into individual enantiomers E1 and
E2 by preparative chiral HPLC (CHIRALPAK IC column, eluting with
isoHexane (containing 0.1% TFA) and IPA).
[0300] The first eluting enantiomer E1 was purified further by
chromatography on silica eluting with EtOAc in isohexane. Fractions
containing product were evaporated to give pure enantiomer E1
(A34). A34 could be assigned as
(5R)-5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazo-
lidin-2-one by inference from biological activity of related
compounds of known absolute configuration and comparison of elution
time from chiral HPLC.
[0301] Enantiomer E2 (A35) was sufficiently pure after the chiral
HPLC purification and could be assigned as
(5S)-5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazo-
lidin-2-one by inference from biological activity of related
compounds of known absolute configuration and comparison of elution
time from chiral HPLC.
[0302] NMR and LC-MS data was consistant with racemic
5-ethoxy-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-
-2-one (A6)--both enantiomers were of predominantly trans
configuration as determined by NMR.
Example 13
Preparation of
4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (A19)
##STR00037##
[0303] Procedure for synthesis of
1,1-dimethoxy-N-methyl-propan-2-amine (Step 1)
##STR00038##
[0305] Ti(O-iPr).sub.4 (34.3 g, 2 equiv.) was cooled to 10.degree.
C. under a nitrogen atmosphere then ethanol (89 mL) was added
followed by 1,1-dimethoxypropan-2-one (7.14 g, 1 equiv),
methylamine hydrochloride (8.16 g, 2 equiv.) and triethylamine
(16.8 mL, 2 equiv.). The reaction was stirred at room temperature
for 15 h. The reaction was cooled to 10.degree. C. and then
NaBH.sub.4 (3.43 g, 1.5 equiv.) was added and the reaction was
stirred at room temperature for 6 h. The reaction was cooled to
10.degree. C., then carefully over 10 minutes poured into ice cold
aqueous ammonia (180 mL, 2M). The mixture was filtered, washing
through with DCM (300 mL). The layers were separated and then the
aqueous layer was extracted with further DCM (3.times.100 mL). The
combined DCM layers were dried (Na.sub.2SO.sub.4), filtered and
evaporated with care as to not lose any of the volatile product.
This crude material was distilled on a Kugelrohr (70 to 110.degree.
C. 14 mBar) to give product (4.41 g) as a colourless oil, which was
used without further purification.
[0306] 1H NMR (CDCl.sub.3): 4.11 (d, 1H), 3.41 (s, 6H), 2.69
(pentet, 1H), 2.43 (s, 3H), 1.06 (d, 3H).
Procedure for synthesis of
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-urea (Step 2)
##STR00039##
[0308] 1,1-dimethoxy-N-methyl-propan-2-amine (1.0 g, 7.50 mmol) was
dissolved in CDCl.sub.3 (1.5 mL). Trimethylsilyl isocyanate
(commercially available) (2 equiv.) was added and the reaction was
stirred at room temp for 4 days. The reaction mixture heated to
reflux for 160 minutes while incrementally adding a further
trimethylsilyl isocyanate (1.5 equiv.) The reaction was evaporated
and treated with water (10 mL), stirred for 90 minutes, then
evaporated to give crude product (1.08 g) which was used without
further purification.
[0309] 1H NMR (CDCl.sub.3): 4.60 (br s, 2H), 4.30 (br s, 1H), 4.24
(d, 1H), 3.41 (s, 6H), 2.71 (s, 3H), 1.18 (d, 3H).
Procedure for synthesis of
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-3-[4-(trifluoromethyl)-2-pyridy-
l]urea (Step 3)
##STR00040##
[0311] 1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-urea (220 mg,
1.249 mmol), 2-chloro-4-(trifluoromethyl)pyridine (commercially
available) (272 mg, 1.2 equiv.), potassium carbonate (259 mg, 1.5
equiv.), tris(dibenzylideneacetone)dipalladium(0) (47 mg),
4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (111 mg) were
suspended in 1-4-dioxane (6 mL) and the mixture was then heated at
105.degree. C. in a sealed vial for 1 h. The mixture was allowed to
cool to room temperature, diluted with EtOAc (6 mL), filtered then
chromatographed on silica eluting with 0-100% EtOAc in isohexane.
Fractions containing product were evaporated to give the desired
product as a colourless gum (282 mg, 70%).
[0312] LC-MS: (positive ES MH+ 322).
Procedure for synthesis of
4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (A19) (Step 4)
##STR00041##
[0314]
1-(2,2-dimethoxy-1-methyl-ethyl)-1-methyl-3-[4-(trifluoromethyl)-2--
pyridyl]urea (240 mg, 0.787 mmol) was dissolved in acetic acid (6
mL), then water (3 mL) was added to give a homogeneous solution.
This was stirred at room temperature for 2 days and then at
60.degree. C. for 1 h. The reaction was evaporated (100 to 1 mBar
at 20-35.degree. C. for 2 h) to remove traces of HOAc to give
product (204 mg, 99%) as an amber gum.
[0315] 1H NMR (CDCl.sub.3): Major diastereomer: 8.54 (s, 1H), 8.37
(d, 1H), 7.16 (d, 1H), 5.61 (m, 1H), 4.95 (br s, 1H), 3.53 (m, 1H),
2.93 (s, 3H), 1.34 (d, 3H).
[0316] Minor diastereomer: 8.54 (s, 1H), 8.39 (m, 1H), 7.16 (d,
1H), 5.95 (d, 1H), 4.81 (br s, 1H), 3.76 (pentet, 1H), 2.89 (s,
3H), 1.40 (d, 3H).
[0317] LC-MS: (positive ES MH+ 276).
[0318] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 14
Preparation of
4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin-2-on-
e (A19)--Alternative Synthesis
##STR00042##
[0320] Phenyl N-[4-(trifluoromethyl)-2-pyridyl]carbamate (for a
synthesis see WO 2007004749) (4.54 g, 1.05 equiv.) was suspended in
1,4-dioxane (12 mL) under a Nitrogen atmosphere and then
1,1-dimethoxy-N-methyl-propan-2-amine (3.46 g, 15.3 mmol) was added
and the reaction was heated at 105.degree. C. for 25 mins. Aqueous
2N HCl (20 mL) was added to the reaction mixture and this was
heated to 32.degree. C. for 30 mins. EtOAc (5 mL) and water (50 mL)
were added and the aqueous phase was extracted with further EtOAc
(2.times.50 mL). The combined EtOAc layers were washed with sat.
aqueous NaHCO.sub.3 (5 mL), evaporated and then chromatographed on
silica eluting with 0-100% EtOAc in isohexane. Fractions containing
product were evaporated to give a colourless gum which slowly
crystallised to give product (3.80 g, 90%).
[0321] NMR and LC-MS consistant with A19 from example 13 above.
[0322] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 15
Preparation of
5-allyl-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin--
2-one (A32)
##STR00043##
[0323] Procedure for synthesis of methyl
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoate
(Step 1)
##STR00044##
[0325] To phenyl N-[4-(trifluoromethyl)-2-pyridyl]carbamate (for a
synthesis see WO 2007004749) (0.328 g, 1.16 mmol) dissolved in
1,4-dioxane (6 mL), under a Nitrogen atmosphere, was added methyl
2-aminopent-4-enoate (for a synthesis see WO2007137168) (0.150 g,
1.16 mmol). The mixture was then warmed to 80.degree. C. for 3 h.
The reaction temperature was then raised to 100.degree. C., and
heating continued for a further 1.5 h. The reaction mixture was
concentrated to remove the bulk of solvent, the oily residue being
taken up in EtOAc (20 mL) and washed with water (2.times.5 mL). The
organic phase was separated and dried over MgSO.sub.4, filtered and
then chromatographed on silica eluting with EtOAc in isohexane.
Fractions containing product were evaporated to give product as a
white solid (0.167 g, 45%)
[0326] LC-MS: (positive ES MH+ 318).
Procedure for synthesis of
5-allyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-dione
(Step 2)
##STR00045##
[0328] Methyl
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoate
(0.114 g, 0.359 mmol) was dissolved in 1,4-dioxane (4 mL) was
treated with 2N hydrochloric acid (4 mL) and the mixture was heated
at 60-70.degree. C. for 3 h. The reaction temp was raised to
85.degree. C. and heating continued for a further 1 h. The reaction
mixture then being allowed to cool to room temperature and then
concentrated. The residue was taken into DCM (15 mL) and the
organic phase separated. The aqueous was further extracted with DCM
(2.times.10 mL) and the DCM extracts combined, dried over
MgSO.sub.4, filtered and the filtrate concentrated giving crude
intermediate
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoic acid
as a white gum (47 mg). The aqueous phase was evaporated giving
further
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoic acid
as a white foam (73 mg). Both fractions of
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoic acid
were combined and used with further purification in the next step.
The crude
2-[[4-(trifluoromethyl)-2-pyridyl]carbamoylamino]pent-4-enoic acid
was taken into DCM (4 mL), then oxalyl chloride (0.0912 g, 0.719
mmol) was added to the fine slurry at room temperature. The
reaction mixture was stirred for 2 h and then allowed to stand
overnight. The reaction mixture was concentrated and the residue
taken into EtOAc (20 mL) and washed with water (5 mL). The organic
phase was separated, the aqueous being further extracted with EtOAc
(10 mL). The organic extracts were then combined, washed with water
(3 mL), dried over MgSO.sub.4, filtered and the filtrate
concentrated giving crude product as a light brown gum that began
to solidify on standing (141 mg). This was used in the next step
without further purification.
[0329] LC-MS: (positive ES MH+ 286).
Procedure for synthesis of
5-allyl-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-dione
(Step 3)
##STR00046##
[0331] A solution of
5-allyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-dione
(0.120 g, 0.421 mmol) in DMF (1.5 mL) was cooled to 0-5.degree. C.
in an ice bath was treated dropwise with LiHMDS (1.0M in THF, 0.442
mmol, 0.442 mL). The resultant solution was stirred 5 minutes, then
iodomethane (0.0717 g, 0.505 mmol) was added and stirring continued
for 40 minutes. The reaction mixture was concentrated and the oily
residue being taken up in EtOAc (15 mL) and washed with brine
(3.times.2 mL), dried over MgSO.sub.4, filtered and the filtrate
concentrated giving crude product, which was chromatographed on
silica eluting with EtOAc in isohexane. Fractions containing
product were evaporated to give product as a white solid (0.060 g,
48%).
[0332] LC-MS: (positive ES MH+ 300).
Procedure for synthesis of
5-allyl-4-hydroxy-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidin--
2-one (Step 4)
##STR00047##
[0334]
5-allyl-1-methyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-
-dione (0.057 g, 0.19 mmol) in methanol (10 mL) was cooled to
around -35.degree. C. (acetone/CO.sub.2 bath). NaBH.sub.4 (0.0073
g, 0.19 mmol) was added in a single portion and the reaction was
stirred for 30 minutes at between -30 and -40.degree. C. The
reaction mixture was allowed to warm slowly to room temperature.
Further NaBH.sub.4 (0.0073 g, 0.19 mmol) was added and the mixture
stirred at room temp for a further 30 minutes.
[0335] The reaction mixture was quenched by the careful addition of
water (2 mL), then concentrated and the residue being left to stand
at room temperature for 72 h. The mixture was diluted with EtOAc
(20 mL) and the organic phase separated. The aqueous phase was
further extracted with EtOAc (15 mL) and the organic extracts
combined, washed with water (5 mL), dried over MgSO.sub.4, filtered
and evaporated to give product as a light grey gum (56 mg,
98%).
[0336] LC-MS: (positive ES MH+ 302).
[0337] 1H NMR (CDCl.sub.3): Major diastereomer: 8.15 (s, 1H), 8.37
(d, 1H), 7.15 (dd, 1H), 5.75 (m, 1H), 5.70 (d, 1H), 5.23 (dd, 1H),
5.20 (dd, 1H), 4.90 (d, 1H), 3.54 (ddd, 1H), 2.96 (s, 3H), 2.55 (m,
1H), 2.53 (m, 1H).
[0338] 1H NMR (CDCl.sub.3): Minor diastereomer: 8.15 (s, 1H), 8.37
(d, 1H), 7.15 (dd, 1H), 5.98 (m, 1H), 5.70 (d, 1H), 5.26 (dd, 1H),
5.18 (d, 1H), 4.79 (br.s, 1H), 3.65 (ddd, 1H), 2.91 (s, 3H), 2.69
(m, 1H), 2.55 (m, 1H).
Example 16
Preparation of
4-hydroxy-1-methyl-5-(trifluoromethyl)-3-[4-(trifluoromethyl)-2-pyridyl]i-
midazolidin-2-one (A33)
##STR00048##
[0339] Procedure for synthesis of 2,2-dimethoxy-N-methyl-ethanimine
(Step 1)
##STR00049##
[0341] Methylamine hydrochloride (4.05 g, 1.05 equiv.) in DCM (60
mL) was cooled to 0.degree. C., then K.sub.2CO.sub.3 (5.53 g, 1
equiv.) was added over 5 minutes. Reaction was stirred at 0.degree.
C. for a further 10 minutes then 2,2-dimethoxyacetaldehyde (6.04
mL, 40 mmol) was added and the reaction was stirred vigorously at
0.degree. C. After 5 minutes at 0.degree. C., the reaction was
allowed to warm to room temperature. After 15 minutes at room
temperature, DCM was decanted off, solid was extracted with DCM
(2.times.15 mL). Combined DCM fractions were dried
(Na.sub.2SO.sub.4), filtered, and evaporated to give product which
was used without further purification (4.10 g, 87%).
Procedure for synthesis of
1,1,1-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (Step 2)
##STR00050##
[0343] KHF.sub.2 (2.01 g, 0.75 equiv.) was suspended in MeCN (69
mL) and DMF (8.0 mL) under Nitrogen, and cooled to 0.degree. C.
then 2,2-dimethoxy-N-methyl-ethanimine (4.02 g, 1 equiv.) was added
followed by dropwise addition of TFA (3.28 mL, 1.25 equiv.) over 2
minutes. Reaction was stirred at 0.degree. C. for 5 minutes, then
trimethyl(trifluoromethyl)silane (7.6 mL, 1.5 equiv.) was added
over 5 minutes and the reaction was stirred at 0.degree. C. for 3
h. Reaction was then treated with sat. aqueous NaHCO3 (50 mL) over
3 minutes The reaction mixture was then extracted with diethyl
ether (3.times.200 mL), dried (Na.sub.2SO.sub.4), filtered and
evaporated (care as product is volatile) to give product (14.1 g,
44%), which was used without further purification.
Procedure for synthesis of
1,1,1-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (Step 3)
##STR00051##
[0345] Crude 1,1,1-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine
(3.58 g, 1.2 equiv.) was dissolved in 1,4-dioxane (2.5 mL) and
treated with N-[4-(trifluoromethyl)-2-pyridyl]carbamate (for a
synthesis see WO 2007004749) (1.00 g, 3.19 mmol) and heated at
110.degree. C. for 2 h 15 minutes. Reaction mixture was then
evaporated and the residue chromatographed on silica eluting with
EtOAc in isohexane (0-35%). Fractions containing product were
evaporated to give product as a gum (0.40 g, 33%).
[0346] LC-MS: (positive ES MH+ 376).
Procedure for synthesis of
4-hydroxy-1-methyl-5-(trifluoromethyl)-3-[4-(trifluoromethyl)-2-pyridyl]i-
midazolidin-2-one (Step 4)
##STR00052##
[0348] 1,1,1-trifluoro-3,3-dimethoxy-N-methyl-propan-2-amine (0.377
g) was suspended in water (2 mL) and then treated with TFA (2 mL)
and the reaction mixture was then heated to 60.degree. C. for 1.5
h. The reaction was evaporated and treated with sat. aqueous
NaHCO.sub.3 (15 mL) and DCM (15 mL). The aqueous phase was further
extracted with DCM (2.times.10 mL) and then the combined DCM phases
were dried (Na.sub.2SO.sub.4), filtered and evaporated to give
product as a white solid (320 mg, 97%).
[0349] LC-MS: (positive ES MH+ 330).
[0350] 1H NMR (CDCl.sub.3): 8.48 (s, 1H), 8.42 (d, 1H), 7.25 (d,
1H), 6.02 (m, 1H), 5.01 (br s, 1H), 3.93 (m, 1H), 3.10 (s, 3H).
Example 17
Preparation of
(4R,5S)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one and
(4S,5S)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one (A37)
##STR00053##
[0351] Procedure for synthesis of (4-nitrophenyl)
N-[4-(trifluoromethyl)-2-pyridyl]carbamate (Step 1)
##STR00054##
[0353] To a stirred solution of 4-(trifluoromethyl)pyridin-2-amine
(5 g, 30.84 mmol) and pyridine (2.56 g, 32.38 mmol) in DCM (75 mL)
at 0.degree. C. (internal temp) was added (4-nitrophenyl)
carbonochloridate (6.22 g, 30.84 mmol) over 15 mins, keeping temp
at or below 8.degree. C., and the reaction mixture was then stirred
at 0.degree. C. for 1 h. After 90 mins at 0.degree. C., the
reaction was allowed to warm to room temperature, and stirred at
for 1 hr. Ice cold water (25 mL) was added. The biphasic mixture
was filtered and the precipitate washed with ice cold water (10 mL)
and DCM (2.times.10 mL). The precipitate was dried under vacuum to
give product as a white solid (7.60 g, 75%).
[0354] LC-MS: (positive ES MH+ 328).
Procedure for synthesis of
(5S)-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,4-dion-
e (Step 2)
##STR00055##
[0356] A mixture of (4-nitrophenyl)
N-[4-(trifluoromethyl)-2-pyridyl]carbamate (1.20 g, 3.67 mmol) and
1,4-dioxane (12 mL), under a nitrogen atmosphere, was treated with
(2S)-2-(methylamino)propanoic acid (commercially available) (0.416
g, 4.03 mmol, and the mixture was stirred at room temperature for 5
h then at 60.degree. C. for 1.5 h, left at room temperature
overnight, then heated at 80.degree. C. for 1.5 h and then left
over the weekend at rt. The reaction mixture was filtered rinsing
through with small portions of EtOAc, then the filtrate and
washings were combined and concentrated to give a deep yellow oily
residue. The oily residue was taken into EtOAc (25 mL) and washed
with saturated NaHCO.sub.3 solution (3.times.15 mL) and brine (10
mL). The organic phase was dried over MgSO.sub.4, filtered,
evaporated and the residue chromatographed on silica eluting with
EtOAc in isohexane. Fractions containing product were evaporated to
give product (0.675 g, 67%).
[0357] LC-MS: (positive ES MH+ 274).
Procedure for synthesis of
(4R,5S)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one and
(4S,5S)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one (A37) (Step 3)
##STR00056##
[0359]
(5S)-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazolidine-2,-
4-dione (0.660 g, 2.42 mmol) was stirred in methanol (20 mL) and
the solution was cooled to around -15.degree. C. (ice-salt bath).
Sodium borohydride (0.0933 g, 2.42 mmol) was added in a single
portion and the reaction was allowed to warm to 15.degree. C. over
1 h, and was then quenched by the careful addition of water (0.5
mL). After 5 minutes stirring the mixture was diluted further with
water (40 mL). A white precipitate formed, which was filtered off,
washed with water and dried under suction giving a white powder.
The combined filtrate and washings were extracted with DCM
(3.times.20 mL). The organic extracts were then combined, washed
with brine (2.times.20 mL), dried over MgSO.sub.4, filtered and the
filtrate concentrated giving a light grey gum, (0.367 g, 55%).
[0360] NMR and LC-MS consistant with example 13 (A19).
[0361] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
Example 18
Preparation of
(4R,5R)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one and
(4S,5R)-4-hydroxy-1,5-dimethyl-3-[4-(trifluoromethyl)-2-pyridyl]imidazoli-
din-2-one (A38)
##STR00057##
[0363] Method as for example 17 but using
(2R)-2-(methylamino)propanoic acid (commercially available).
[0364] NMR and LC-MS consistant with example 13 (A19).
[0365] The diastereomeric ratio was found to vary according to
conditions for product synthesis, purification and analysis. The
stereochemistry of the chiral centre at the carbon containing the
hydroxyl group was found to interconvert at room temperature.
[0366] Table 1 lists examples of compounds of the general formula
(I)
##STR00058##
wherein R.sup.a, R.sup.b, R.sup.c, R.sup.d, R.sup.1, R.sup.2,
R.sup.3 and X are as defined above.
[0367] These compounds were made by the general methods
described.
TABLE-US-00009 TABLE 1 1H NMR (measured in CDCl.sub.3 unless
otherwise Compound STRUCTURE indicated) .delta. LC-MS A1
##STR00059## 8.52 (s, 1H), 8.39 (d, 1H), 7.15 (d, 1H), 5.68 (m,
1H), 4.94 (br s, 1H), 3.40 (m, 1H), 2.92 (s, 3H), 1.85 (m, 1H),
1.55 (m, 1H), 0.98 (t, 3H). positive ES MH+ 290 A2 ##STR00060##
8.47 (s, 1H), 8.38 (d, 1H), 7.18 (dd, 1H), 5.72 (d, 1H), 4.81 (d,
1H), 4.71 (s, 1H), 3.54 (ddq, 2H), 3.00 (s, 3H), 1.65 (m, 2H), 0.96
(t, 3H). positive ES MH+ 320 A3 ##STR00061## As for A8 As for A8 A4
##STR00062## As for A8 As for A8 A5 ##STR00063## 8.46 (s, 1H), 8.39
(d, 1H), 7.19 (d, 1H), 5.74 (d, 1H), 4.82 (d, 1H), 4.67 (s, 1H),
3.43 (s, 3H), 3.01 (s, 3H). positive ES MH+ 292 A6 ##STR00064##
8.46 (s, 1H), 8.38 (d, 1H), 7.18 (dd, 1H), 5.73 (d, 1H), 4.82 (d,
1H), 4.71 (s, 1H), 3.66 (m, 2H), 3.00 (s, 3H), 1.28 (t, 3H).
positive ES MH+ 306 A7 ##STR00065## Major diastereoisomer: 8.35
(br.s, 1H), 8.32 (d, 1H), 7.12 (dd, 1H), 5.71 (d, 1H); 4.96 (m,
1H), 4.82 (m, 1H), 3.54 (d, 1H), 3.01 (s, 3H). Minor
diastereoisomer: 8.47 (br.s, 1H), 8.38 (d, 1H), 7.19 (dd, 1H), 5.89
(d, 1H), 5.15 (m, 1H), 5.12 (m, 1H), 3.82 (d, 1H), 2.97 (s, 3H).
positive ES MH+ 278 A8 ##STR00066## Major diastereomer: 8.55 (s,
1H), 8.43 (dd, 1H), 7.25 (d, 1H), 5.55 (m, 1H), 5.04 (very br s,
1H), 3.90 (s, 3H), 3.71 (m, 1H), 1.45 (d, 3H). Minor diastereomer:
8.53 (s, 1H), 8.45 (dd, 1H), 7.24 (d, 1H), 5.87 (d, 1H), 4.60 (very
br s, 1H), 3.93 (s, 3H), 3.80 (m, 1H), 1.50 (d, 3H). positive ES
MH+ 292 A9 ##STR00067## Major diastereomer: 8.72 (m, 1H), 8.67 (s,
1H), 8.42 (s, 1H), 7.78 (t, 1H), 7.45 (d, 1H), 7.35 (dd, 1H), 5.65
(s, 1H), 4.94 (s, 1H), 3.56 (m, 1H), 2.94 (s, 3H), 1.36 (d, 3H).
Minor diastereomer: 8.72 (m, 1H), 8.67 (s, 1H), 8.44 (s, 1H), 7.78
(t, 1H), 7.45 (d, 1H), 7.35 (dd, 1H), 5.99 (d, 1H), 4.77 (s, 1H),
3.79 (pentet, 1H), 2.95 (s, 3H), 1.41 (d, 3H). positive ES MH+ 353
A10 ##STR00068## 8.36 (s, 1H), 8.03 (s, 1H), 5.66 (s, 1H), 4.80 (br
s, 1H), 4.69 (s, 1H), 3.95 (s, 3H), 3.65 (m, 2H), 2.97 (s, 3H),
1.26 (t, 3H). positive ES MH+ 336 A11 ##STR00069## Major
diastereomer: 9.30 (s, 1H), 8.75 (s, 1H) 8.72 (s, 2H), 8.24 (s,
1H), 5.65 (m, 1H), 4.80 (m, 1H), 3.55 (m, 1H), 2.96 (s, 3H), 1.35
(d, 3H). Minor diastereomer: 9.30 (s, 1H), 8.75 (s, 1H) 8.72 (s,
2H), 8.24 (s, 1H), 6.00 (d, 1H), 4.65 (s, 1H), 3.85 (m, 1H), 2.92
(s, 3H), 1.42 (d, 3H). positive ES MH+ 354 A12 ##STR00070## Major
diastereomer: 8.45 (s, 1H), 8.03 (s, 1H), 5.53 (m, 1H), 4.90 (br s,
1H), 3.95 (s, 3H), 3.50 (m, 1H), 2.91 (s, 3H), 1.33 (d, 3H). Minor
diastereomer: 8.44 (s, 1H), 8.05 (s, 1H), 5.88 (d, 1H), 4.75 (br s,
1H), 3.95 (s, 3H), 3.75 (m, 1H), 2.88 (s, 3H), 1.39 (d, 3H).
positive ES MH+ 306 A13 ##STR00071## 8.56 (s, 1H), 8.23 (s, 1H),
7.44 (m, 3H), 7.32 (m, 2H), 5.77 (d, 1H), 4.81 (d, 1H), 4.74 (s,
1H), 3.66 (m, 2H), 3.03 (s, 3H), 1.28 (m, 3H). positive ES MH+ 382
A14 ##STR00072## 9.30 (s, 1H), 8.75 (s, 2H), 8.70 (s, 1H), 8.24 (s,
1H), 5.80 (d, 1H), 4.75 (s, 1H), 4.71 (d, 1H), 3.69 (m, 2H), 3.04
(s, 3H), 1.29 (t, 3H). positive ES MH+ 384 A15 ##STR00073## 9.30
(s, 1H), 8.75 (s, 2H), 8.70 (s, 1H), 8.25 (s, 1H), 5.81 (d, 1H),
4.71 (s, 1H), 4.70 (d, 1H), 3.46. (s, 3H), 3.05 (s, 3H). positive
ES MH+ 370 A16 ##STR00074## 8.70 (s, 1H), 8.58 (s, 1H), 5.70 (d,
1H), 4.71 (s, 1H), 4.54 (d, 1H), 3.66 (m, 2H), 3.00 (s, 3H), 1.27
(t, 3H). positive ES MH+ 432 A17 ##STR00075## 8.81 (s, 1H), 8.62
(s, 1H), 5.65 (d, 1H), 4.84 (d, 1H), 4.81 (d, 1H), 2.91 (s, 3H).
positive ES MH+ 404 A18 ##STR00076## 8.70 (s, 1H), 8.57 (s, 1H),
5.71 (d, 1H), 4.66 (s, 1H), 4.58 (d, 1H), 3.43 (s, 3H), 3.00 (s,
3H). positive ES MH+ 418 A19 ##STR00077## Major diastereomer: 8.54
(s, 1H), 8.37 (d, 1H), 7.16 (d, 1H), 5.61 (m, 1H), 4.95 (br s, 1H),
3.53 (m, 1H), 2.93 (s, 3H), 1.34 (d, 3H). Minor diastereomer: 8.54
(s, 1H), 8.39 (m, 1H), 7.16 (d, 1H), 5.95 (d, 1H), 4.81 (br s, 1H),
3.76 (pentet, 1H), 2.89 (s, 3H), 1.40 (d, 3H). positive ES MH+ 276
A20 ##STR00078## Major diastereomer: 8.70 (m, 1H), 8.48 (s, 1H),
8.25 (s, 1H), 8.20 (s, 1H), 7.18 (s, 1H), 5.62 (s, 1H), 4.92 (s,
1H), 3.90 (s, 3H), 3.55 (m, 1H), 2.94 (s, 3H), 1.36 (d, 3H).
positive ES MH+ 383 A21 ##STR00079## Major diastereomer: 8.65 (m,
1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.55 (s, 1H), 6.82 (s, 1H), 5.62
(s, 1H), 4.85 (s, 1H), 3.90 (s, 3H), 3.55 (m, 1H), 2.95 (s, 3H),
1.35 (d, 3H). positive ES MH+ 383 A22 ##STR00080## Major
diastereomer: 8.72 (s, 1H), 8.50 (s, 2H), 8.20 (s, 1H), 5.62 (s,
1H), 4.83 (s, 1H), 4.08 (s, 3H), 3.55 (m, 1H), 2.94 (s, 3H), 1.35
(d, 3H). positive ES MH+ 384 A23 ##STR00081## Major diastereomer:
8.68 (m, 1H), 8.55 (d, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 6.89 (d,
1H), 5.62 (s, 1H), 4.95 (br s, 1H), 3.70 (s, 3H), 3.54 (m, 1H),
2.95 (s, 3H), 1.35 (d, 3H). positive ES MH+ 383 A24 ##STR00082##
Major diastereomer: 8.69 (s, 1H), 8.46 (s, 1H), 8.21 (m, 1H), 7.57
(dm, 1H), 7.25 (dm, 1H), 5.65 (m, 1H), 4.91 (br s, 1H), 3.56 (m,
1H), 2.95 (s, 3H), 2.64 (s, 3H), 1.36 (d, 3H). Minor diastereomer:
8.69 (s, 1H), 8.46 (s, 1H), 8.21 (m, 1H), 7.57 (dm, 1H), 7.25 (dm,
1H), 6.00 (d, 1H), 4.78 (br s, 1H), 3.79 (m, 1H), 2.92 (s, 3H),
2.64 (s, 3H), 1.42 (d, 3H). positive ES MH+ 367 A25 ##STR00083##
Major diastereomer: 8.69 (s, 1H), 8.64 (s, 1H), 5.56 (m, 1H), 4.65
(very br s, 1H), 3.53 (m, 1H), 2.93 (s, 3H), 1.33 (d, 3H). Minor
diastereomer: 8.70 (s, 1H), 8.64 (s, 1H), 5.91 (d, 1H), 4.65 (very
br s, 1H), 3.76 (m, 1H), 2.88 (s, 3H), 1.38 (d, 3H). positive ES
MH+ 402 A26 ##STR00084## Major diastereomer 8.32 (s, 1H), 8.16 (d,
1H), 7.86 (d, 1H), 6.43 (d, 1H), 5.58 (d, 1H), 3.37 (m, 1H), 2.80
(s, 3H), 1.18 (d, 3H). Minor diastereomer 8.32 (s, 1H), 8.17 (d,
1H), 7.86 (d, 1H), 6.18 (d, 1H), 5.91 (d, 1H), 3.39 (m, 1H), 2.72
(s, 3H), 1.18 (d, 3H). Positive ES MH+ 242 A27 ##STR00085## Major
diastereomer 8.48 (s, 1H), 8.15 (d, 1H), 7.05 (d, 1H), 5.79 (d,
1H), 3.65 (m, 1H), 2.97 (s, 3H), 2.5(s, 3H), 1.4 (d, 3H). Minor
diastereomer 8.58 (s, 1H), 8.16 (d, 1H), 7.07 (d, 1H), 6.21 (d,
1H), 3.88 (m, 1H), 2.94 (s, 3H), 2.55(s, 3H), 1.45 (d, 3H).
Positive ES MH+ 222 A28 ##STR00086## Major diastereomer 8.55 (s,
1H), 8.43 (dd, 1H), 7.25 (d, 1H), 5.55 (d, 1H), 5.04 (very br s,
1H), 3.90 (s, 3H), 3.38 (d, 1H), 1.45 (d, 3H). Minor diastereomer
8.53 (s, 1H), 8.45 (dd, 1H), 7.24 (d, 1H), 5.87(d, 1H), 4.60 (very
br s, 1H), 3.93 (s, 3H), 3.71 (m, 1H), 1.50 (d, 3H). positive ES
MH+ 306 A29 ##STR00087## 8.46 (s, 1H), 8.38 (d, 1H), 7.18 (dd, 1H),
5.74 (d, 1H), 4.80 (d, 1H), 4.79 (s, 1H), 3.51-3.73 (m, 3H), 3.33
(m, 1H), 1.27 (t, 3H), 1.25 (t, 3H). positive ES MH+ 320 A30
##STR00088## Major diastereomer 8.17 (d, 1H), 8.04 (d, 1H), 6.91
(d, 1H), 5.50 (d, 1H), 3.41 (m, 1H), 2.84 (s, 3H), 1.31 (d, 3H),
1.24 (s, 9H). Minor diastereomers 8.17 (d, 1H), 8.05 (d, 1H), 6.92
(d, 1H), 5.85 (d, 1H), 3.63 (m, 1H), 2.80 (s, 3H), 1.31 (d, 3H),
1.27 (s, 9H). Positive ES MH+ 264 A31 ##STR00089## Major
diastereomer: 8.54 (s, 1H), 8.37 (d, 1H), 7.17 (m, 1H), 5.75 (ddd,
1H), 5.70 (d, 1H), 5.44 (m, 1H), 5.43 (m, 1H), 5.01 (br s, 1H),
3.89 (m, 1H), 2.89 (s, 3H). Minor diastereomer: 8.54 (s, 1H), 8.39
(m, 1H), 7.17 (m, 1H), 6.02 (m, 2H), 5.51 (m, 2H), 4.06 (m, 1H),
2.83 (s, 3H). positive ES MH+ 288 A32 ##STR00090## Major
diastereomer: 8.15 (s, 1H), 8.37 (d, 1H), 7.15 (dd, 1H), 5.75 (m,
1H), 5.70 (d, 1H), 5.23 (dd, 1H), 5.20 (dd, 1H), 4.90 (d, 1H), 3.54
(ddd, 1H), 2.96 (s, 3H), 2.55 (m, 1H), 2.53 (m, 1H). Minor
diastereomer: 8.15 (s, 1H), 8.37 (d, 1H), 7.15 (dd, 1H), 5.98 (m,
1H), 5.70 (d, 1H), 5.26 (dd, 1H), 5.18 (d, 1H), 4.79 (br.s, 1H),
3.65 (ddd, 1H), 2.91 (s, 3H), 2.69 (m, 1H), 2.55 (m, 1H). positive
ES MH+ 302 A33 ##STR00091## 8.48 (s, 1H), 8.42 (d, 1H), 7.25 (d,
1H), 6.02 (m, 1H), 5.01 (br s, 1H), 3.93 (m, 1H), 3.10 (s, 3H).
positive ES MH+ 330 A34 ##STR00092## As for A6 As for A6 A35
##STR00093## As for A6 As for A6 A36 ##STR00094## 8.54 (s, 1H),
8.45 (dd, 1H), 7.25 (d, 1H), 6.02 (m, 1H), 4.75 (very br s, 1H),
3.89 (s, 3H), 3.75 (m, 1H), 3.68 (m, 1H). positive ES MH+ 278 A37
##STR00095## As for A19 As for A19 A38 ##STR00096## As for A19 As
for A19 A39 ##STR00097## 8.44 (s, 1H), 8.40 (d, 1H), 7.22 (d, 1H),
5.77 (d, 1H), 4.86 (s, 1H), 4.85 (d, 1H), 3.99 (m, 2H), 3.03 (s,
3H). positive ES MH+ 360 A40 ##STR00098## (DMSO-d6): 8.57 (d, 1H),
8.47 (s, 1H), 7.75 (s, 1H), 7.36 (d, 1H), 6.46 (d, 1H), 5.68 (d,
1H), 3.43 (q, 1H), 1.15 (d, 3H). positive ES MH+ 262 A41
##STR00099## 8.46 (s, 1H), 8.38 (d, 1H), 7.19 (dd, 1H), 5.94 (m,
1H), 5.75 (d, 1H), 5.36 (dd, 1H), 5.26 (dd, 1H), 4.80 (d, 1H), 4.77
(s, 1H), 4.15 (m, 2H), 3.01 (s, 3H). positive ES MH+ 318 A42
##STR00100## 8.50 (s, 1H), 8.37 (d, 1H), 7.16 (d, 1H), 5.89 (s,
1H), 4.90 (s, 1H), 4.37 (d, 1H), 3.57 (m, 1H), 3.49 (d, 6H), 3.04
(s, 3H). positive ES MH+ 336 A43 ##STR00101## Major diastereomer:
8.50 (s, 1H), 8.37 (d, 1H), 7.16 (d, 1H), 5.89 (m, 1H), 5.03 (m,
1H), 3.91 (m, 1H), 3.82 (m, 1H), 3.51 (q, 1H), 2.96 (s, 3H), 2.36
(br m, 1H) Minor diastereomer: 8.55 (s, 1H), 8.37 (d, 1H), 7.18 (m,
1H), 5.89 (m, 1H), 5.46 (br s, 1H), 3.96 (m, 1H), 3.76 (m, 1H),
3.51 (q, 1H), 2.96 (s, 3H), 2.36 (br m, 1H) positive ES MH+ 292 A44
##STR00102## 8.44 (s, 1H), 8.38 (d, 1H), 7.19 (dd, 1H), 5.82 (d,
1H), 4.92 (s, 1H), 4.79 (d, 1H), 4.32 (d, 2H), 3.03 (s, 3H), 2.54
(t, 1H) positive ES MH+ 316 A45 ##STR00103## 8.45 (s, 1H), 8.38 (d,
1H), 7.18 (d, 1H), 5.77 (d, 1H), 4.80 (s, 1H), 4.78 (d, 1H), 3.74
(q, 2H), 3.58 (t, 2H), 3.39 (s, 3H), 3.01 (s, 3H). positive ES MH+
336 A46 ##STR00104## 8.62 (s, 1H), 8.42 (d, 1H), 7.20 (dd, 1H),
5.92 (t, 1H), 4.98 (d, 1H), 3.68-3.77 (m, 2H), 3.21-3.29 (m, 1H),
2.14-2.22 (m, 1H), 2.02-2.13 (m, 1H), 1.89- 2.02 (m, 1H), 1.36-1.49
(m, 1H). positive ES MH+ 288 A47 ##STR00105## As for A46 As for A46
A48 ##STR00106## 8.46 (s, 1H), 8.37 (d, 1H), 7.17 (d, 1H), 5.66 (d,
1H), 4.80 (d, 1H), 4.71 (s, 1H), 3.93 (dt, 1H), 2.96 (s, 3H), 1.27
(dd, 6H). positive ES MH+ 320 A49 ##STR00107## Major diastereomer:
8.64 (s, 1H), 8.33 (s, 1H), 5.56 (t, 1H), 4.63 (d, 1H), 3.52 (m,
1H), 2.93 (s, 3H), 1.34 (d, 3H). Minor diastereomer: 8.64 (s, 1H),
8.35 (s, 1H), 5.91 (dd, 1H), 4.46 (d, 1H), 3.76 (m, 1H), 2.89 (s,
3H), 1.39 (d, 3H). positive ES MH+ 310 A50 ##STR00108## Major
diastereomer: 8.64 (s, 1H), 8.38 (s, 1H), 5.51 (dd, 1H), 4.68 (d,
1H), 3.89 (s, 3H), 3.72 (m, 1H), 1.45 (d, 3H). Minor diastereomer:
8.62 (s, 1H), 8.40 (s, 1H), 5.83 (dd, 1H), 4.28 (d, 1H), 3.92 (s,
3H), 3.79 (m, 1H), 1.50 (d, 3H). positive ES MH+ 326 A51
##STR00109## Major diastereomer 8.48 (s, 1H), 8.15 (s, 1H), 5.56
(d, 1H), 4.98 (br s, 1H), 3.51 (dq, 1H), 2.92 (s, 3H), 2.40 (s,
3H), 1.33 (d, 3H). Minor diastereomer 8.47 (s, 1H), 8.17 (s, 1H),
5.91 (d, 1H), 4.83 (br s, 1H), 3.74 (pentet, 1H), 2.88 (s, 3H),
2.40 (s, 3H), 1.39 (d, 3H). positive ES MH+ 290 A52 ##STR00110##
8.41 (s, 1H), 8.17 (s, 1H), 5.70 (s, 1H), 4.70 (s, 1H), 3.64 (m,
2H), 3.00 (s, 3H), 2.40 (s, 3H), 1.27 (t, 3H). positive ES MH+ 320
A53 ##STR00111## 8.57 (s, 1H), 8.34 (s, 1H), 5.70 (d, 1H), 4.70 (s,
1H), 4.52 (d, 1H), 3.67 (m, 2H), 3.00 (s, 3H), 1.28 (t, 3H).
positive ES MH+ 340 A54 ##STR00112## 8.55 (s, 1H), 8.39 (d, 1H),
7.17 (d, 1H), 5.82 (s, 1H), 3.58 (br s, 3H), 3.39 (s, 3H), 2.98 (s,
3H). positive ES MH+ 306 A55 ##STR00113## Major diastereomer 8.63
(s, 1H), 8.54 (s, 1H), 5.83 (d, 1H), 4.30 (br s, 1H), 3.93 (s, 3H),
3.80 (m, 1H), 1.50 (d, 3H). Minor diastereomer 8.65 (s, 1H), 8.52
(s, 1H), 5.51 (d, 1H), 4.70 (br s, 1H), 3.90 (s, 3H), 3.72 (m, 1H),
1.45 (d, 3H). positive ES MH+ 370/372 A56 ##STR00114## Major
diastereomer 8.85 (s, 1H), 8.53 (s, 1H), 7.22 (br s, 1H), 5.60 (m,
1H), 4.84 (br s, 1H), 3.53 (m, 1H), 2.92 (s, 3H), 2.23 (s, 3H),
1.33 (d, 3H). Minor diastereomer 8.85 (s, 1H), 8.52 (s, 1H), 7.22
(br s, 1H), 5.93 (m, 1H), 4.70 (br s, 1H), 3.75 (m, 1H), 2.88
(s,
3H), 2.23 (s, 3H), 1.39 (d, 3H). positive ES MH+ 333 A57
##STR00115## Major diastereomer 8.95 (s, 1H), 8.53 (s, 1H), 7.48
(br s, 1H), 5.60 (m, 1H), 4.86 (m, 1H), 3.52 (m, 1H), 2.92 (s, 3H),
1.33 (d, 3H), 1.33 (s, 9H). Minor diastereomer 8.97 (s, 1H), 8.52
(s, 1H), 7.48 (br s, 1H), 5.94 (m, 1H), 4.71 (m, 1H), 3.75 (m, 1H),
2.88 (s, 3H), 1.39 (d, 3H), 1.33 (s, 9H). positive ES MH+ 375 A58
##STR00116## Major diastereomer 8.50 (s, 1H), 8.20 (s, 1H), 5.50
(m, 1H), 5.02 (m, 1H), 3.89 (s, 3H), 3.68 (m, 1H), 2.41 (s, 3H),
1.44 (d, 3H). Minor diastereomer 8.47 (s, 1H), 8.23 (s, 1H), 5.81
(m, 1H), 4.59 (m, 1H), 3.93 (s, 3H), 3.76 (quintet, 1H), 2.41 (s,
3H), 1.48 (d, 3H). positive ES MH+ 306 A59 ##STR00117## 8.28 (m,
2H), 7.10 (dd, 1H), 5.72 (d, 1H), 5.00 (d, 1H), 4.71(s, 1H), 3.66
(m, 2H), 2.99 (s, 3H), 1.91(t, 3H), 1.27(t, 3H). positive ES MH+
302 A60 ##STR00118## Major diastereomer: 8.36 (d, 1H), 8.30 (d,
1H), 7.09 (dd, 1H), 5.59 (m, 1H), 5.12 (d, 1H), 3.51 (m, 1H), 2.93
(s, 3H), 1.92 (t, 3H), 1.33 (d, 3H). Minor diastereomer: 8.36 (d,
1H), 8.30 (d, 1H), 7.09 (dd, 1H), 5.92 (m, 1H), 4.98 (d, 1H), 3.74
(m, 1H), 2.89 (s, 3H), 1.92 (t, 3H), 1.40 (d, 3H). positive ES MH+
272 A61 ##STR00119## 8.21 (d, 1H), 8.06 (m, 1H), 7.07 (dd, 1H),
5.71 (s, 1H), 5.19 (s, 1H), 4.70(s, 1H), 3.65 (m, 2H), 2.98 (s,
3H), 1.70(d, 3H), 1.63(d, 3H), 1.27(t, 3H). positive ES MH+ 298 A62
##STR00120## Major diastereomer: 8.51 (s, 1H), 8.50 (s, 1H), 6.93
(m, 1H), 5.71 (d, 1H), 5.60 (m, 1H), 5.42 (d, 1H), 4.91 (m, 1H),
3.53 (m, 1H), 2.93 (s, 3H), 1.33 (d, 3H). Minor diastereomer: 8.51
(s, 1H), 8.50 (s, 1H), 6.93 (m, 1H), 5.94 (m, 1H), 5.71 (d, 1H),
5.42 (d, 1H), 4.76 (m, 1H), 3.76 (m, 1H), 2.88 (s, 3H), 1.39 (d,
3H). positive ES MH+ 302 A63 ##STR00121## Major diastereomer 8.15
(d, 1H), 8.11 (m, 1H), 7.01 (dd, 1H), 5.54 (d, 1H), 3.46 (m, 1H),
2.88 (s, 3H), 1.66 (d, 3H), 1.60 (d, 3H), 1.28 (d, 3H). Minor
diastereomer 8.15 (d, 1H), 8.11 (m, 1H), 7.01 (dd, 1H), 5.88 (d,
1H), 3.68 (m, 1H), 2.83 (s, 3H), 1.66 (d, 3H), 1.60 (d, 3H), 1.34
(d, 3H). positive ES MH+ 268 A64 ##STR00122## Major diastereomer:
8.47 (s, 1H), 8.42 (d, 1H), 7.25 (m, 1H), 5.57 (d, 1H), 3.73 (m,
1H), 1.47 (d, 3H). Minor diastereomer: 8.44 (s, 1H), 8.35 (d, 1H),
7.27 (m, 1H), 5.94 (d, 1H), 3.86 (m, 1H), 1.48 (d, 3H). positive ES
MH+ 278 A65 ##STR00123## Major diastereomer: 8.58 (s, 1H), 8.46 (s,
1H), 5.63 (br.s., 1H), 4.77 (d, 1H), 4.12 (m, 1H), 3.54 (qd, 1H),
2.94 (s, 3H), 1.46 (s, 9H) 1.35 (d, 3H). Minor diastereomer: 8.58
(s, 1H), 8.46 (s, 1H), 5.95 (dd, 1H), 5.60 (t, 1H), 4.60 (d, 1H),
3.78 (t, 1H), 2.90 (s, 3H), 1.46 (s, 9H) 1.35 (d, 3H). positive ES
MH+ A66 ##STR00124## Major diastereomer: 8.65 (d, 1H), 8.26 (dd,
1H), 8.02 (t, 1H), 5.87 (br.s, 1H), 5.53 (d, 1H), 5.20 (br.s, 1H),
3.89 (s, 3H), 3.70 (m, 1H), 1.48 (s, 9H), 1.45 (d, 3H). Minor
diastereomer: 8.67 (d, 1H), 8.24 (dd, 1H), 8.00 (t, 1H), 5.87
(br.s, 1H), 5.85 (d, 1H), 4.75 (br.s, 1H), 3.92 (s, 3H), 3.78 (m,
1H), 1.50 (d, 3H), 1.48 (s, 9H). positive ES MH+ 323 A67
##STR00125## Major diastereomer: 8.62 (d, 1H), 8.25 (d, 1H), 7.96
(dd, 1H), 5.84 (br.s, 1H), 5.59 (t, 1H), 5.11 (d, 1H), 3.51 (ddd,
1H), 2.92 (s, 3H), 1.48 (s, 9H), 1.34 (d, 3H). Minor diastereomer:
8.62 (d, 1H), 8.25 (d, 1H); 7.96 (dd, 1H), 5.94 (dd, 1H), 5.84
(br.s, 1H), 4.96 (d, 1H), 3.75 (m, 1H), 2.88 (s, 3H), 1.48 (s, 9H),
1.38 (d, 3H). positive ES MH+ 307 A68 ##STR00126## Major
diastereomer: 8.44 (d, 1H), 7.98 (s, 1H), 7.26 (dd, 1H), 5.81 (m,
1H), 5.12 (d, 1H), 4.13 (m, 1H), 3.18 (d, 3H), 2.65-2.36 (m, 2H).
Minor diastereomer: 8.46 (d, 1H), 8.29 (s, 1H), 7.28 (dd, 1H), 5.72
(m, 1H), 5.40 (t, 1H), 4.00 (m, 1H), 3.18 (d, 3H), 2.65-2.36 (m,
2H). positive ES MH+ 344 A69 ##STR00127## 8.58 (s, 1H), 8.24 (s,
1H), 6.20 (brs, 1H), 5.71 (s, 1H), 4.79 (brs, 1H), 4.69 (s, 1H),
3.68 (m, 2H), 2.99 (s, 3H), 1.48 (s, 9H), 1.28 (t, 3H). positive ES
MH+ 371 A70 ##STR00128## Major diastereomer: 8.59 (s, 1H), 8.34 (s,
1H), 6.15 (s, 1H), 5.53 (d, 1H), 3.90 (s, 3H), 3.72 (m, 1H), 1.49
(s, 9H), 1.46 (d, 3H). Minor diastereomer: 8.59 (s, 1H), 8.34 (s,
1H), 6.15 (s, 1H), 5.85 (d, 1H), 3.93 (s, 3H), 3.79 (m, 1H), 1.49
(s, 9H), 1.46 (d, 3H). positive ES MH+ 357 A71 ##STR00129## Major
diastereomer: 8.52 (s, 1H), 8.27 (s, 1H), 6.28 (s, 1H), 5.56 (d,
1H), 4.98 (brs, 1H), 3.51 (m, 1H), 2.91 (s, 3H), 1.47 (s, 9H), 1.32
(d, 3H). Minor diastereomer: 8.52 (s, 1H), 8.27 (s, 1H), 6.28 (s,
1H), 5.91 (d, 1H), 4.80 (brs, 1H), 3.73 (m, 1H), 2.87 (s, 3H), 1.47
(s, 9H), 1.37 (d, 3H). positive ES MH+ 341 A72 ##STR00130## Major
diastereomer 8.37 (s, 1H), 8.30 (d, 1H), 7.11 (dd, 1H), 5.59 (d,
1H), 5.51 (brs, 1H), 3.53 (m, 1H), 2.93 (s, 3H), 1.33 (d, 3H).
Minor diastereomer 8.37 (s, 1H), 8.30 (d, 1H), 7.11 (dd, 1H), 5.93
(d, 1H), 5.51 (brs, 1H), 3.73 (m, 1H), 2.89 (s, 3H), 1.40 (d, 3H).
positive ES MH+ 326 A73 ##STR00131## Major diastereomer: 8.57 (s,
1H), 8.46 (d, 1H), 7.26 (m, 1H), 5.58 (d, 1H), 5.03 (brs, 1H), 3.92
(s, 3H), 3.74 (m, 1H), 1.47 (d, 3H). Minor diastereomer: 8.55 (s,
1H), 8.47 (d, 1H), 7.26 (m, 1H), 5.89 (d, 1H), 5.03 (brs, 1H), 3.95
(s, 3H), 3.81 (m, 1H), 1.51 (d, 3H). positive ES MH+ 342 A74
##STR00132## Major diastereomer: 8.49 (m, 1H), 8.36 (d, 1H), 7.88
(dd, 1H), 5.60 (d, 1H), 4.94 (br.s, 1H), 3.53 (ddd, 1H), 2.93 (s,
3H), 1.34 (d, 3H). Minor diastereomer: 8.49 (m, 1H), 8.36 (d, 1H),
7.88 (dd, 1H), 5.96 (d, 1H), 4.78 (br.s, 1H), 3.77 (pent, 1H), 2.89
(s, 3H), 1.40 (d, 3H). positive ES MH+ 276 A75 ##STR00133##
8.49-8.61 (m, 1H), 8.45 (d, 1H), 7.21-7.28 (m, 1H), 5.86-5.94 (m,
1H), 4.88-4.93 (m, 1H), 4.78- 4.86 (m, 1H), 3.86-4.08 (m, 3H),
3.29-3.42 (m, 1H). positive ES MH+ 290 A76 ##STR00134## Major
diastereomer: 8.50 (s, 1H), 8.36-8.44 (m, 1H), 7.21 (d, 1H),
5.60-5.67 (m, 1H), 4.92-4.98 (m, 1H), 4.58-4.92 (m, 2H), 3.67-3.79
(m, 1H), 3.32- 3.39 (m, 3H), 1.34-1.41 (m, 3H). Minor diastereomer:
8.50 (s, 1H), 8.36-8.44 (m, 1H), 7.21 (d, 1H), 5.97 (dd, 1H),
4.92-4.98 (m, 1H), 4.58-4.92 (m, 2H), 3.94- 4.06 (m, 1H), 3.40-3.52
(m, 3H) 1.41-1.47 (m, 3H). positive ES MH+ 306 A77 ##STR00135##
8.54 (s, 1H) 8.38 (d, 1H) 7.12-7.19 (m, 1H) 5.81 (s, 1H) 4.96 (d,
1H) 3.58 (s, 3H) 3.40 (s, 3H) 2.99 (s, 3H). positive ES MH+ 306 A78
##STR00136## As for A77 As for A77 A79 ##STR00137## Major
diastereomer: 8.48 (s, 1H), 8.25 (s, 1H), 6.80 (d, 1H), 5.61 (dd,
1H), 3.76 (s, 3H), 3.61 (dq, 1H), 2.39 (s, 3H), 1.27 (d, 3H). Minor
diastereomer: 8.49 (s, 1H), 8.33 (s, 1H), 6.56 (d, 1H), 5.92 (t,
1H), 3.77 (s, 3H), 3.70 (quin, 1H), 2.39 (s, 3H), 1.30 (d, 3H).
positive ES MH+ 306 A80 ##STR00138## Major diastereomer: 8.53 (m,
1H), 8.39 (d, 1H), 7.93 (dd, 1H), 5.55 (d, 1H), 5.00 (br.s, 1H),
3.90 (s, 3H), 3.72 (ddd, 1H), 1.45 (d, 3H). Minor diastereomer:
8.56 (m, 1H), 8.37 (d, 1H), 7.93 (dd, 1H), 5.87 (d, 1H), 4.56
(br.s, 1H), 3.93 (s, 3H), 3.80 (pent, 1H), 1.50 (d, 3H). positive
ES MH+ 292 A81 ##STR00139## 8.49 (d, 1H), 8.28 (d, 1H), 7.89 (dd,
1H), 5.73 (d, 1H), 5.00 (d, 1H), 4.79 (d, 1H), 3.02 (s, 3H), 2.74
(d, 1H). positive ES MH+ 278 A82 ##STR00140## 8.47 (s, 1H), 8.40
(d, 1H), 7.18 (d, 1H), 5.74 (s, 1H), 4.85 (brs, 1H), 4.71 (s, 1H),
3.67 (m, 2H), 3.00 (s, 3H), 1.28 (t, 3H). positive ES MH+ 356 A83
##STR00141## 8.50 (d, 1H), 8.30 (d, 1H), 7.89 (dd, 1H), 5.74 (d,
1H), 4.80 (d, 1H), 4.71 (s, 1H), 3.68 (m, 2H), 3.00 (s, 3H), 1.28
(t, 3H). positive ES MH+ 306 A84 ##STR00142## Major diastereomer:
8.35 (s, 1H), 8.32 (d, 1H), 7.11 (d, 1H), 6.60 (t, 1H), 5.59 (d,
1H), 5.10 (br.s., 1H), 3.51 (dq, 1H), 2.92 (s, 3H), 1.33 (d, 3H).
Minor diastereomer: 8.34 (s, 1H), 8.32 (d, 1H), 7.11 (d, 1H), 6.60
(t, 1H), 5.93 (d, 1H), 4.96 (br.s., 1H), 3.74 (pentet, 1H), 2.88
(s, 3H), 1.39 (d, 3H). positive ES MH+ 258 A85 ##STR00143## Major
diastereomer: 8.53 (d, 1H), 8.35 (d, 1H), 7.16 (dd, 1H), 5.59 (t,
1H), 4.97 (d, 1H), 3.53 (dq, 1H), 2.93 (s, 3H), 1.34 (d, 3H). Major
diastereomer: 8.53 (d, 1H), 8.36 (d, 1H), 7.16 (dd, 1H), 5.94 (dd,
1H), 4.83 (d, 1H), 3.75 (t, 1H), 2.89 (s, 3H), 1.39 (d, 3H).
positive ES MH+ 292 A86 ##STR00144## Major diastereomer: 8.31 (s,
1H), 7.12 (s, 1H), 6.57 (t, 1H), 5.59 (t, 1H), 4.61 (d, 1H), 3.53
(dq, 1H), 2.92 (s, 3H), 1.33 (d, 3H). Major diastereomer: 8.31 (s,
1H), 7.12 (s, 1H), 6.57 (t, 1H), 5.94 (dd, 1H), 4.45 (d, 1H), 3.75
(pentet, 1H), 2.88 (s, 3H), 1.39 (d, 3H). positive ES MH+ 292 A87
##STR00145## Major diastereomer: 8.45- 8.61 (m, 1H), 8.23-8.44 (m,
1H), 7.07-7.22 (m, 1H), 5.64-5.62 (m, 1H), 4.97-4.99 (m, 1H), 4.42
(dd, 1H), 3.92 (dd, 1H), 3.67-3.84 (m, 1H), 2.15- 2.33 (m, 1H),
1.34-1.46 ppm (m, 3H). Minor diastereomer: 8.45- 8.61 (m, 1H),
8.23-8.44 (m, 1H), 7.07-7.22 (m, 1H), 5.85-6.03 (m, 1H), 4.74 (d,
1H), 4.57 (dd, 1H), 4.02 (quin, 1H), 3.67- 3.84 (m, 1H), 2.15-2.33
(m, 1H), 1.34-1.46 ppm (m, 3H). positive ES MH+ 300 A88
##STR00146## Major diastereomer: 8.55 (s, 1H), 8.39 (d, 1H), 7.16
(d, 1H), 5.94 (d, 1H), 3.92 (m, 1H), 3.62 (m, 1H), 3.19 (m, 1H),
1.39 (d,3H), 1.18 (t, 3H). Minor diastereomer: 8.55 (s, 1H), 8.39
(d, 1H), 7.16 (d, 1H), 5.57 (d, 1H), 3.62(m, 2H), 3.19 (m, 1H),
1.35 (d, 3H), 1.20 (t, 3H). positive ES MH+ 290 A89 ##STR00147##
Major diastereomer: 8.19 (m, 2H), 7.09 (d, 1H), 5.59 (d, 1H), 3.50
(m, 1H), 3.13 (s, 3H), 2.92 (s, 3H), 1.52 (s, 6H), 1.33 (d, 3H).
Minor diastereomer: 8.19 (m, 2H), 7.09 (d, 1 H, 5.93 (d, 1H), 3.73
(m, 1H), 3.13 (s, 3H), 2.88(s, 3H), 1.52 (s, 6H), 1.40 (d, 3H).
positive ES MH+ 280 A90 ##STR00148## Major diastereomer: 8.54 (m,
1H), 8.39 (d, 1H), 7.26 (dd, 1H), 5.53 (dd, 1H), 5.03 (d, 1H), 3.90
(s, 3H), 3.71 (ddd, 1H), 1.45 (d, 3H). Minor diastereomer: 8.52 (m,
1H), 8.42 (d, 1H), 7.24 (dd, 1H), 5.85 (dd, 1H), 4.59 (d, 1H), 3.93
(s, 3H), 3.79 (pentet, 1H), 1.49 (d, 3H). positive ES MH+ 308 A91
##STR00149## Major diastereomer: 8.50 (s, 1H), 8.38 (d, 1H), 7.19
(dd, 1H), 5.86 (br s, 1H), 5.68 (m, 1H), 4.98 (d, 1H), 3.74 (m,
1H), 1.36 (d, 3H). Minor diastereomer: 8.46 (s, 1H), 8.36 (d, 1H) ,
7.12 (dd, 1H), 5.99 (d, 1H), 5.71 (br s, 1H), 4.88 (d, 1H), 4.04
(pentet, 1H), 1.39 (d, 3H). positive ES MH+ 278 A92 ##STR00150##
Major diastereomer: 8.28 (d, 1H), 8.10 (d, 1H), 6.96 (dd, 1H), 5.55
(t, 1H), 5.07 (d, 1H), 3.49 (ddd, 1H), 2.91 (s, 3H), 1.32 (d, 3H).
Minor diastereomer: 8.27 (d, 1H), 8.11 (d, 1H), 6.96 (dd, 1H), 5.89
(dd, 1H), 4.94 (d, 1H), 3.72 (m, 1H), 2.87 (s, 3H), 1.37 (d, 3H).
positive ES MH+ 242 A93 ##STR00151## Major diastereomer 8.36 (m,
2H), 7.18 (m, 1H), 5.52 (d, 1H), 4.47 (brs, 1H), 3.90 (s, 3H), 3.70
(m, 1H), 1.92 (t, 3H), 1.48 (d, 3H). Minor diastereomer 8.36 (m,
2H), 7.18 (m, 1H), 5.83 (d, 1H), 5.21 (brs, 1H), 3.93 (s, 3H), 3.77
(m, 1H), 1.92 (t, 3H), 1.49 (d, 3H). positive ES MH+ 288 A94
##STR00152## Major diastereomer 8.59 (s, 1H), 8.45 (d, 1H), 7.28
(dd, 1H), 5.97 (d, 1H), 5.39 (d, 1H), 5.03 (brs, 1H), 4.42 (m, 1H),
4.12 (m, 1H), 4.00 (m, 1H), 3.63 (m, 1H). Minor diastereomer 8.59
(s, 1H), 8.45 (d, 1H), 7.28 (dd, 1H), 6.17 (d, 1H), 5.39 (d, 1H),
5.24 (brs, 1H), 4.41 (m, 1H), 4.39 (m, 1H), 4.26 (m, 1H), 3.88 (m,
1H). positive ES MH+ 290 A95 ##STR00153## 8.55 (s, 1H), 8.39 (d,
1H), 7.17 (d, 1H), 6.07 (d, 1H), 5.0(br.s, 1H), 3.72 (m, 1H), 3.42
(m, 3H), 1.22 (t, 3H). positive ES MH+ 276 A96 ##STR00154## 8.57
(s, 1H), 8.40 (d, 1H), 7.17 (d, 1H), 6.90 (s, 1H), 4.62 (s, 1H),
3.87 (m, 1H), 3.64 (m, 1H), 2.99 (s, 3H), 2.07 (s, 3H), 1.27 (t,
3H). positive ES MH+ 348 A97 ##STR00155## positive ES MH+ 482 A98
##STR00156## positive ES MH+ 496/498 A99 ##STR00157## positive ES
MH+ 494 A100 ##STR00158## positive ES MH+ 404 A101 ##STR00159##
positive ES MH+ 396 A102 ##STR00160## 8.49 (s, 1H), 8.27 (d, 1H),
7.55 (d, 2H), 7.33-7.41 (m, 3H), 7.14 (dd, 1H), 7.10 (s, 1H), 4.70
(s, 1H), 3.92 (dq, 1H), 3.68 (dq, 1H), 3.39 (s, 3H), 3.00 (s, 3H),
1.30 (t, 3H). positive ES MH+ 522 A103 ##STR00161## 8.55 (s, 1H),
8.42 (d, 1H), 7.53 (d, 2H), 7.31-7.41 (m, 3H), 7.21 (dd, 1H), 7.11
(s, 1H), 4.51 (s, 1H), 3.91 (dq, 1H), 3.66 (dq, 1H), 3.46 (s, 3H),
2.92 (s, 3H), 1.30 (t, 3H). positive ES MH+ 522 A104 ##STR00162##
Major diastereomer: 8.50 (s, 1H), 8.40 (d, 1H), 7.28- 7.13 (m, 6H),
5.13 (d, 1H), 3.89 (s, 3H), 3.77-3.71 (m, 2H), 3.53 (d, 1H), 3.16
(br.s., 1H), 1.45 (d, 3H) Minor diastereomer: 8.57 (s, 1H), 8.40
(d, 1H), 7.28- 7.13 (m, 6H), 5.52 (d, 1H), 3.94 (s, 3H), 3.90-3.73
(m, 2H), 3.57 (d, 1H), 3.30 (very br.s., 1H), 1.53 (d, 3H).
positive ES MH+ 381 A105 ##STR00163## Major diastereomer: 8.53 (s,
1H), 8.46 (s, 1H), 5.59 (t, 1H), 4.97 (t, 1H), 4.57 (s, 2H), 3.52
(m, 1H), 3.45 (s, 3H), 2.92 (d, 3H), 1.33 (dd, 3H). Minor
diastereomer: 8.53 (s, 1H), 8.47 (s, 1H), 5.94
(dd, 1H), 4.82 (t, 1H), 4.57 (s, 2H), 3.75 (m, 1H), 3.45 (s, 3H),
2.88 (d, 3H), 1.39 (dd, 3H). positive ES MH+ 320 A106 ##STR00164##
Major diastereomer: 8.30- 8.56 (m, 2H), 7.27-7.32 (m, 1H),
6.80-7.23 (m, 1H), 5.59-5.75 (m, 1H), 4.80-4.97 (m, 1H), 3.83- 4.10
(m, 1H), 1.40-1.53 (m, 3H). Minor diastereomer: 8.30- 8.56 (m, 2H),
7.27-7.32 (m, 1H), 6.80-7.23 (m, 1H), 5.87-6.09 (m, 1H), 4.69-4.80
(m, 1H), 4.10- 4.35 (m, 1H), 1.53-1.60 (m, 3H). positive ES MH+ 312
A107 ##STR00165## Major diastereomer: 8.53 (s, 1H), 8.29-8.44 (m,
1H), 7.07-7.23 (m, 1H), 5.73- 5.89 (m, 1H), 5.62 (t, 1H), 5.17-5.36
(m, 2H), 4.92 (d, 1H), 4.15-4.33 (m, 1H), 3.51-3.77 (m, 2H),
1.24-1.34 (m, 3H). Minor diastereomer: 8.53 (s, 1H), 8.29-8.44 (m,
1H), 7.07-7.23 (m, 1H), 5.94 (dd, 1H), 5.73-5.89 (m, 1H), 5.17-5.36
(m, 2H), 4.80 (d, 1H), 4.15-4.33 (m, 1H), 3.89 (quin, 1H),
3.51-3.77 (m, 1H), 1.36 (d, 3H). positive ES MH+ 302 A108
##STR00166## Major diastereomer: 8.52 (s, 1H), 8.51 (s, 1H), 5.58
(t, 1H), 4.96 (br t, 1H), 4.69 (s, 2H), 3.69 (m, 2H), 3.60 (m, 2H),
3.52 (dq, 1H), 3.40 (d, 3H), 2.92 (d, 3H), 1.33 (dd, 3H). Minor
diastereomer: 8.52 (s, 1H), 8.51 (s, 1H), 5.93 (dd, 1H), 4.81 (dd,
1H), 4.69 (s, 2H), 3.75 (m, 1H), 3.69 (m, 2H), 3.60 (m, 2H), 3.40
(d, 3H), 2.88 (d, 3H), 1.38 (dd, 3H). positive ES MH+ 364 A109
##STR00167## 8.27 (d, 1H), 8.13 (s, 1H), 7.04 (d, 1H), 5.75 (s,
1H), 4.62 (s, 1H), 3.58 (m, 2H), 3.02 (s, 3H), 2.85 (s, 3H), 1.42
(s, 6H), 1.15 (t, 3H). positive ES MH+ 310 A110 ##STR00168## Major
diastereomer: 8.53 (s, 1H), 8.35-8.38 (m, 1H), 7.12-7.18 (m, 1H),
5.59- 5.65 (m, 1H), 4.96 (br.s., 1H), 3.54-3.63 (m, 2H), 3.02-3.17
(m, 1H), 1.45- 1.77 (m, 2H), 1.32 (d, 2H), 0.90-1.02 (m, 3H). Minor
diastereomer: 8.53 (s, 1H), 8.35-8.38 (m, 1H), 7.12-7.18 (m, 1H),
5.94 (d, 1H), 4.84 (br.s., 1H), 3.85-3.95 (m, 1H), 3.02- 3.17 (m,
1H), 1.45-1.77 (m, 2H), 1.38 (d, 1H), 0.90-1.02 (m, 3H). positive
ES MH+ 304 A111 ##STR00169## Major diastereomer: 8.50 (s, 1H), 8.42
(d, 1H), 7.17- 7.25 (m, 1H), 5.66-5.71 (m, 1H), 4.92 (br.s., 1H),
4.16-4.38 (m, 1H), 3.79 (qd, 1H), 3.53-3.74 (m, 1H), 1.38 (d, 3H).
Minor diasteromer: 8.48 (s, 1H), 8.42 (d, 1H), 7.17- 7.25 (m, 1H),
6.00 (d, 1H), 4.80 (br.s., 1H), 4.16- 4.38 (m, 1H), 3.99-4.08 (m,
1H), 3.53-3.74 (m, 1H), 1.41-1.47 (m, 3H). positive ES MH+ 344 A112
##STR00170## Major diastereomer: 8.47 (s, 1H), 8.36-8.43 (m, 1H),
7.20 (d, 1H), 5.79-6.15 (m, 1H), 5.61-5.69 (m, 1H), 4.92 (br.s.,
1H), 3.95-4.07 (m, 1H), 3.67- 3.78 (m, 1H), 3.38-3.56 (m, 1H), 1.36
(d, 3H). Minor diastereomer: 8.47 (s, 1H), 8.36-8.43 (m, 1H), 7.20
(d, 1H), 5.79-6.15 (m, 2H), 4.69-4.82 (m, 1H), 3.95-4.07 (m, 1H),
3.78-3.94 (m, 1H), 3.38- 3.56 (m, 1H), 1.39-1.44 (m, 3H). positive
ES MH+ 326 A113 ##STR00171## Major diastereomer: 8.44- 8.59 (m,
1H), 8.31-8.42 (m, 1H), 7.16 (d, 1H), 5.94 (d, 1H), 4.83 (br.s.,
1H), 3.83-3.96 (m, 1H), 3.17- 3.33 (m, 1H), 3.02 (dd, 1H),
1.83-2.13 (m, 1H), 1.38 (d, 3H), 0.87-1.05 (m, 6H) - Minor
diastereomer: 8.44- 8.59 (m, 1H), 8.31-8.42 (m, 1H), 7.16 (d, 1H),
5.61 (s, 1H), 4.87-5.00 (m, 1H), 3.52-3.69 (m, 1H), 3.33- 3.47 (m,
1H), 2.90 (dd, 1H), 1.83-2.13 (m, 1H), 1.31 (d, 3H), 0.87-1.05 (m,
6H). positive ES MH+ 318 A114 ##STR00172## Major diastereomer:
8.36- 8.49 (m, 2H), 7.25 (d, 1H), 5.69 (d, 1H), 4.32-4.47 (m, 1H),
4.16-4.28 (m, 1H), 3.66-3.84 (m, 1H), 1.40-1.50 (m, 3H). Minor
diastereomer: 8.36- 8.49 (m, 2H), 7.25 (d, 1H), 6.02 (d, 1H),
4.56-4.70 (m, 1H), 3.89-4.03 (m, 1H), 3.66-3.84 (m, 1H), 1.40-1.50
(m, 3H). positive ES MH+ 301 A115 ##STR00173## Major diastereomer:
8.48- 8.60 (m, 1H), 8.29-8.44 (m, 1H), 7.06-7.21 (m, 1H), 5.51-5.65
(m, 1H), 4.82 (br.s., 1H), 3.48- 3.57 (m, 1H), 2.48-2.58 (m, 1H),
1.33-1.41 (m, 3H), 0.59-1.06 (m, 4H). Minor diastereomer 8.48- 8.60
(m, 1H), 8.29-8.44 (m, 1H), 7.06-7.21 (m, 1H), 5.89 (d, 1H), 4.88-
4.99 (m, 1H), 3.76-3.88 (m, 1H), 2.36-2.47 (m, 1H), 1.42-1.50 (m,
3H), 0.59-1.06 (m, 4H). positive ES MH+ 302 A116 ##STR00174## Major
diastereomer 8.59 (s, 1H), 8.49 (d, 1H), 7.32 (d, 1H), 6.05 (s,
1H), 4.84 (brs, 1H), 4.18 (m, 1H), 3.98 (m, 1H), 3.91 (m, 1H), 2.68
(m, 1H), 2.13 (m, 1H). Minor diastereomer 8.59 (s, 1H), 8.46 (d,
1H), 7.32 (d, 1H), 6.15 (d, 1H), 5.39 (brs, 1H), 4.23 (m, 1H), 3.98
(m, 1H), 3.91 (m, 1H), 2.80 (m, 1H), 2.35 (m, 1H). positive ES MH+
290
Example 19
Preparation of 1,1,3-trimethoxy-N-methyl-propan-2-amine as used for
synthesis of examples of the type A54, A77 and A78 (chiral
preparative HPLC of racemic product A54 gave separated enantiomers
A77 and A78)
##STR00175##
[0368] Procedure for synthesis of
1,1,3-trimethoxy-N-methyl-propan-2-amine (Step 1)
##STR00176##
[0370] A solution of 2-bromo-1,1,3-trimethoxy-propane (commercially
available) (7 g, 32.85 mmol) in methylamine (40% aqueous solution)
(105 mL, 210 mmol) was divided into seven equal portions and these
were heated at 130.degree. C. for 1 h in a microwave. The combined
reaction mixtures were then concentrated and the residue obtained
was treated with toluene and evaporated again. The residue was then
stirred with DCM, filtered and evaporated to give the crude product
that was taken to next step without further purification.
Example 20
Preparation of 2-chloro-4-(1-fluoro-1-methyl-ethyl)pyridine as used
for synthesis of examples of the type A63
##STR00177##
[0371] Procedure for synthesis of
2-chloro-4-(1-fluoro-1-methyl-ethyl)pyridine (Step 1)
##STR00178##
[0373] 2-(2-chloro-4-pyridyl)propan-2-ol (commercially
available)(180 mg, 1.0 mmol) was dissolved in DCM and the resultant
mixture was cooled to 0.degree. C. Diethylaminosulfur trifluoride
(2.5 equiv., 5.2 mmol) was added dropwise such that the temperature
did not exceed 5.degree. C. After the addition the reaction was
allowed to warm to room temperature and was then added portionwise
with stirring to a mixture of ice (100 ml) and NaHCO.sub.3 in a
beaker (some effervescence), making sure that the pH of the
solution was >7 at all times. After .about.30 mins, the mixture
was diluted with DCM (30 mL) and water (20 mL) and transferred to a
sep funnel. The organic phase was separated. The aqueous phase was
further extracted with DCM (2.times.20 mL), the organic extracts
were then combined, washed with water (15 mL), dried over
MgSO.sub.4, filtered and the filtrate evaporated giving a
yellow-brown liquid. This was chromatographed on silica. Fractions
containing product were evaporated to give the desired product,
which was used without further purification.
[0374] LC-MS: (positive ES MH+ 174).
Example 21
Preparation of 4-(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine as
used for synthesis of examples of the type A72, A73
##STR00179##
[0375] Procedure for synthesis of
4-(1,1,2,2,2-pentafluoroethyl)pyridin-2-amine (Step 1)
##STR00180##
[0377] Prepared by analogy to the synthesis of
4-(trifluoromethyl)pyridin-2-amine (as described in EP2228366)
using
(E)-5-ethoxy-3-hydroxy-3-(1,1,2,2,2-pentafluoroethyl)pent-4-enenitrile
(for a synthesis see Martins et al, ARKIVOC Issue 13, pages
187-194) as starting material. This synthesis can be applied to the
synthesis of a range of related pyridine intermediates.
Example 22
Preparation of 2-chloro-4-[chloro(difluoro)methyl]pyridine as used
for synthesis of examples of the type A90, A91
##STR00181##
[0378] Procedure for synthesis of
2-chloro-4-[chloro(difluoro)methyl]pyridine (Step 1)
##STR00182##
[0380] 2-chloro-4-(difluoromethyl)pyridine (commercially available)
(0.950 g, 5.81 mmol) was suspended in CCl.sub.4 (3.3 ml), then
1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione (675 mg, 0.5 equiv.)
and benzoyl benzenecarboperoxoate (70 mg, 0.05 equiv.) were added
and the mixture was microwaved to 160.degree. C. for 30 mins.
Further benzoyl benzenecarboperoxoate (70 mg, 0.05 equiv.) was
added and the mixture was further microwaved to 180.degree. C. for
20 mins. Even further benzoyl benzenecarboperoxoate (70 mg, 0.05
equiv.) was added and the mixture was further microwaved at
180.degree. C. for 20 mins. The mixture was filtered through
celite, washed through with DCM then chromatographed eluting with
0-7% ethyl acetate in isohexane. Fractions contained product were
combined and evaporated to give product as a colourless oil (700
mg, 61% yield).
[0381] .sup.1H NMR: 8.58 (dd, 1H), 7.57 (d, 1H), 7.45 (dd, 1H).
Example 23
Preparation of 2-chloro-4-(1-methoxy-1-methyl-ethyl)pyridine as
used for synthesis of examples of the type A89
##STR00183##
[0382] Procedure for synthesis of
2-chloro-4-[chloro(difluoro)methyl]pyridine (Step 1)
##STR00184##
[0384] A mixture of 2-(2-chloro-4-pyridyl)propan-2-ol (commercially
available) (2.4 g, 14 mmol) in THF (120 mL) and methyl iodide (1.8
mL, 28 mmol) was treated with sodium hydride (0.71 g, 28 mmol). The
mixture was stirred for 16 h at rt. and then the reaction mix was
poured into water (500 mL), and extracted with ethyl acetate. The
combined organic layers were dried over sodium sulfate and
chromatographed. Fractions contained product were combined and
evaporated to give product as a colourless oil (2.31 g, 89%
yield).
[0385] LC-MS: (positive ES MH+ 186).
Example 24
Preparation of
N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl-propanamideas
used for synthesis of examples of the type A57
##STR00185##
[0386] Procedure for synthesis of
N-[6-chloro-4-(trifluoromethyl)-3-pyridyl]-2,2-dimethyl-propanamide
(Step 1)
##STR00186##
[0388] A mixture of 5-bromo-2-chloro-4-(trifluoromethyl)pyridine
(commercially available) (75 mg, 0.288 mmol),
2,2-dimethylpropanamide (32 mg, 0.317 mmol), XantPhos Pd G3
precatalyst (13 mg, 0.014 mmol), K.sub.2CO.sub.3 (79 mg, 0.57 mmol)
in 1,4-Dioxane (0.5 mL) was heated at 90.degree. C. for 0.5 h and
then 110.degree. C. for 2 h. Purification by reverse phase HPLC
delivered product (14 mg, 15%).
[0389] LC-MS: (positive ES MH+ 281).
Example 25
Preparation of
N-tert-butyl-6-chloro-4-(trifluoromethyl)pyridine-3-carboxamide as
used for synthesis of examples of the type A65
##STR00187##
[0390] Procedure for synthesis of
N-tert-butyl-6-chloro-4-(trifluoromethyl)pyridine-3-carboxamide
(Step 1)
##STR00188##
[0392] To a stirred solution of
6-chloro-4-(trifluoromethyl)pyridine-3-carboxylic acid (for a
synthesis see Tetrahedron, 2004, 60(51), pages 11869-11874) (3.87
g, 17.2 mmol) in DCM (8 mL) was added tert-butylamine (3.61 mL,
34.3 mmol) followed by DIPEA (3.59 mL, 20.6 mmol). The reaction
mixture was cooled to 0.degree. C. before the addition of HATU
(4.84 g, 20.6 mmol). The reaction was stirred for 10 mins at
0.degree. C., followed by stirring for 30 mins at room temperature.
The reaction was then quenched with water. The aqueous layer was
extracted with DCM, and the combined organic phases, dried
(MgSO.sub.4) and evaporated. Crude product was chromatographed
eluting with 3:1, iso-hexane/EtOAc, followed by recrystallisation
(Et.sub.2O/i-hexane) provided product (3.44 g, 12.3 mmol, 71%
yield).
[0393] LC-MS: (positive ES MH+ 281).
Example 26
Preparation of
2-chloro-5-(methoxymethyl)-4-(trifluoromethyl)pyridine as used for
synthesis of examples of the type A105
##STR00189##
[0394] Procedure for synthesis of
[6-chloro-4-(trifluoromethyl)-3-pyridyl]methanol (Step 1)
##STR00190##
[0396] Methyl 6-chloro-4-(trifluoromethyl)pyridine-3-carboxylate
(commercially available) (1.00 g) was dissolved in dry THF (12 mL)
under a N.sub.2 atmosphere and the reaction was cooled to
-60.degree. C. then LiAlH4 (163 mg) was added over 10 mins. The
reaction was stirred at -60.degree. C. for 25 mins and was then
treated with saturated NH.sub.4Cl (aq) (5 mL) and then EtOAc (60
mL). Filtration through celite and then evaporation gave a crude
oil which was dissolved in MeOH (5 mL), cooled to 0.degree. C. then
NaBH.sub.4 (53 mg) was added portionwise and the reaction was
stirred at 0.degree. C. The reaction was then concentrated, treated
with EtOAc (10 mL) and washed with 10% citric acid and then
saturated brine and finally the organic layer was dried
Na.sub.2SO.sub.4 and evaporated to give the desired product.
[0397] .sup.1H NMR: (400 MHz, Chloroform) .delta. 8.78 (s, 1H),
7.56 (s, 1H), 4.93 (s, 2H), 1.91 (very br s, 1H).
Procedure for synthesis of
2-chloro-5-(methoxymethyl)-4-(trifluoromethyl)pyridine (Step 2)
##STR00191##
[0399] [6-chloro-4-(trifluoromethyl)-3-pyridyl]methanol (655 mg)
was dissolved in dry THF (2 mL), cooled to 5.degree. C. under
N.sub.2 then KOtBu (1.65M in THF) (2.07 mL) was added over 1 min.
Then Mel (236 .mu.L) was added. The reaction was stirred for 3
minutes, then EtOAc (10 mL) and saturated brine (aqueous), was
added and the aqueous layer was extracted with further EtOAc
(2.times.20 mL). The combined organic layers were dried
(Na.sub.2SO.sub.4), filtered and evaporated to give amber oil,
which was chromatographed, eluting with 0-30% EtOAc in isohexane.
Fractions containing product were evaporated to give product as an
amber oil (332 mg, 48%).
[0400] .sup.1H NMR: (400 MHz, Chloroform) .delta. 8.70 (s, 1H),
7.56 (s, 1H), 4.63 (s, 2H), 3.48 (s, 3H).
[0401] LC-MS: (positive ES MH+ 226).
Example 27
Herbicidal Action
Example 27a
Pre-Emergence Herbicidal Activity
[0402] Seeds of a variety of test species were sown in standard
soil in pots. After cultivation for one day (pre-emergence) under
controlled conditions in a glasshouse (at 24/16.degree. C.,
day/night; 14 hours light; 65% humidity), the plants were sprayed
with an aqueous spray solution derived from the formulation of the
technical active ingredient in acetone/water (50:50) solution
containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate,
CAS RN 9005-64-5). The test plants were then grown in a glasshouse
under controlled conditions (at 24/16.degree. C., day/night; 14
hours light; 65% humidity) and watered twice daily. After 13 days,
the test was evaluated (5=total damage to plant; 0=no damage to
plant). Results are shown in Table 2.
TABLE-US-00010 TABLE 2 Application pre-emergence Compound Rate
number (g/Ha) AMARE ABUTH ECHCG SETFA ALOMY ZEAMX A1 1000 5 5 5 5 4
3 A2 1000 5 5 4 3 2 1 A3 1000 5 4 5 5 3 3 A4 1000 5 5 5 5 4 3 A5
1000 5 5 4 4 3 2 A6 1000 5 5 4 5 4 2 A7 1000 5 5 3 4 4 1 A8 1000 5
5 4 5 4 3 A9 1000 5 5 5 5 4 3 A10 1000 5 5 5 5 4 3 A11 1000 5 5 4 5
4 3 A12 1000 5 5 5 5 4 3 A13 1000 5 5 3 3 3 1 A14 1000 5 5 5 4 A15
1000 5 3 4 3 A16 1000 5 5 4 4 A17 1000 5 4 3 3 A18 1000 5 5 4 4 A19
1000 5 5 5 5 4 3 A20 1000 5 5 4 5 4 5 A21 1000 5 5 5 5 3 2 A22 1000
5 5 5 5 4 3 A23 1000 5 2 2 3 3 1 A24 1000 5 5 5 4 4 3 A25 1000 5 5
5 4 4 2 A26 1000 3 4 4 4 2 2 A27 1000 5 4 4 4 3 3 A28 1000 5 3 4 5
4 2 A29 1000 5 5 1 2 1 1 A30 1000 5 5 5 5 4 2 A31 1000 5 5 5 5 2
A32 1000 5 5 5 4 4 2 A33 1000 5 4 2 3 3 0 A34 1000 5 5 5 5 3 A35
1000 5 4 4 4 2 A36 1000 5 1 4 2 2 0 A37 1000 5 5 5 4 4 3 A38 1000 5
5 5 5 3 A39 1000 5 5 3 2 4 1 A40 1000 5 4 3 2 2 2 A41 1000 5 5 2 2
1 1 A42 1000 4 1 0 3 0 0 A43 1000 2 5 1 2 1 0 A44 1000 5 5 5 4 4 2
A45 1000 5 5 3 3 2 1 A46 1000 5 5 4 2 4 3 A47 1000 5 5 5 4 4 2 A48
1000 5 5 1 3 4 1 A49 1000 5 5 4 4 4 3 A50 1000 5 5 5 4 4 2 A51 1000
5 5 5 4 4 3 A52 1000 5 5 5 4 4 2 A53 1000 5 5 4 4 4 2 A54 1000 5 5
2 2 3 0 A55 1000 5 5 4 4 4 2 A56 1000 5 5 1 1 2 0 A57 1000 5 5 3 3
4 1 A58 1000 5 5 3 3 4 4 A59 1000 5 5 3 3 4 1 A60 1000 5 5 1 1 1 0
A61 1000 5 5 4 1 4 1 A62 1000 5 4 4 3 2 A64 1000 5 2 4 3 2 A65 1000
5 5 5 5 3 A66 1000 5 5 5 4 2 A67 1000 5 5 5 5 3 A68 1000 0 0 0 0 0
A69 1000 5 5 5 5 2 A70 1000 5 5 5 5 3 A71 1000 5 5 5 0 3 A72 1000 5
5 5 5 2 A73 1000 5 5 4 5 3 A74 1000 5 5 4 4 3 A75 1000 5 5 4 4 2
A76 1000 5 5 3 4 2 A77 1000 5 5 5 5 3 A78 1000 5 5 4 3 1 A79 1000 5
5 5 5 2 A80 1000 5 5 5 4 2 A81 1000 3 2 0 2 0 A82 1000 5 5 3 3 2
A83 1000 5 5 4 4 1 A84 1000 5 5 5 5 3 A85 1000 5 5 5 5 3 A86 1000 5
5 5 5 3 A87 1000 5 5 4 4 3 A88 1000 5 5 4 4 2 A89 1000 5 5 4 4 2
A90 1000 5 3 4 4 2 A91 1000 5 5 4 4 2 A92 1000 5 5 5 4 3 A93 1000 5
5 5 5 3 A94 1000 5 5 5 5 4 A95 1000 5 5 5 5 1 A96 1000 5 5 4 4 4 1
A97 1000 5 5 4 4 4 3 A98 1000 0 0 0 0 0 0 A99 1000 5 1 0 0 0 0 A100
1000 5 5 3 3 4 1 A101 1000 5 5 4 4 4 0 A102 1000 5 5 4 3 1 A103
1000 2 1 1 4 1 A104 1000 5 4 5 5 3 A105 1000 5 5 5 5 4 A106 1000 5
5 4 3 2 A107 1000 5 5 5 4 2 A108 1000 5 5 5 4 2
Example 27b
Post-Emergence Herbicidal Activity
[0403] Seeds of a variety of test species were sown in standard
soil in pots. After 8 days cultivation (post-emergence) under
controlled conditions in a glasshouse (at 24/16.degree. C.,
day/night; 14 hours light; 65% humidity), the plants were sprayed
with an aqueous spray solution derived from the formulation of the
technical active ingredient in acetone/water (50:50) solution
containing 0.5% Tween 20 (polyoxyethelyene sorbitan monolaurate,
CAS RN 9005-64-5). The test plants were then grown in a glasshouse
under controlled conditions (at 24/16.degree. C., day/night; 14
hours light; 65% humidity) and watered twice daily. After 13 days,
the test was evaluated (5=total damage to plant; 0=no damage to
plant). Results are shown in Table 3.
TABLE-US-00011 TABLE 3 Application post-emergence Compound Rate
number (g/Ha) ECHCG SETFA AMARE ABUTH ALOMY ZEAMX A1 1000 5 5 5 5 5
3 A2 1000 5 5 5 5 4 2 A3 1000 5 5 5 5 5 5 A4 1000 5 5 5 5 5 5 A5
1000 4 4 5 5 4 2 A6 1000 5 5 5 5 5 2 A7 1000 5 5 5 5 4 4 A8 1000 5
5 5 5 5 4 A9 1000 5 5 5 5 5 4 A10 1000 5 5 5 5 5 4 A11 1000 5 5 5 5
4 4 A12 1000 5 5 5 5 5 5 A13 1000 5 5 5 5 4 0 A14 1000 5 5 5 5 4 3
A15 1000 4 4 5 5 4 0 A16 1000 5 5 5 5 5 2 A17 1000 5 5 5 5 5 4 A18
1000 5 5 5 5 5 3 A19 1000 5 5 5 5 5 4 A20 1000 5 5 5 5 5 4 A21 1000
5 5 5 5 5 3 A22 1000 5 5 5 5 5 5 A23 1000 2 4 5 5 4 2 A24 1000 5 5
5 5 5 4 A25 1000 5 5 5 5 5 5 A26 1000 1 1 3 4 1 1 A27 1000 3 3 5 5
3 3 A28 1000 5 5 4 4 5 2 A29 1000 4 3 5 5 4 2 A30 1000 5 5 5 5 5 3
A31 1000 5 5 5 5 4 A32 1000 5 5 5 5 5 2 A33 1000 1 2 3 5 4 1 A34
1000 5 5 5 5 4 A35 1000 3 3 5 0 1 A36 1000 5 3 5 1 4 2 A37 1000 5 5
5 5 5 4 A38 1000 5 5 5 5 4 A39 1000 5 5 5 5 5 1 A40 1000 4 3 5 5 4
1 A41 1000 2 4 5 5 4 2 A42 1000 0 2 4 4 2 1 A43 1000 5 0 1 5 1 2
A44 1000 5 5 5 5 4 4 A45 1000 3 3 5 5 2 1 A46 1000 5 5 5 5 5 3 A47
1000 5 5 5 5 5 4 A48 1000 4 4 5 5 4 1 A49 1000 5 5 5 5 5 4 A50 1000
5 5 5 5 5 5 A51 1000 5 5 5 5 5 5 A52 1000 5 5 5 5 5 5 A53 1000 5 5
5 5 5 3 A54 1000 5 5 5 5 5 4 A55 1000 5 5 5 5 5 4 A56 1000 3 2 5 5
4 1 A57 1000 5 5 5 5 5 4 A58 1000 5 5 5 5 4 4 A59 1000 5 5 5 5 5 4
A60 1000 4 3 5 5 4 3 A61 1000 5 5 5 5 5 3 A62 1000 5 5 5 5 2 A64
1000 5 4 5 4 1 A65 1000 5 5 5 5 5 A66 1000 5 5 5 5 5 A67 1000 5 5 5
5 4 A68 1000 0 0 0 0 0 A69 1000 5 4 4 5 3 A70 1000 5 5 5 5 5 A71
1000 5 5 5 5 4 A72 1000 5 5 5 5 2 A73 1000 5 5 5 5 3 A74 1000 4 5 5
5 3 A75 1000 5 5 5 5 2 A76 1000 4 4 5 5 1 A77 1000 5 5 5 5 5 A78
1000 5 3 5 5 0 A79 1000 5 5 5 5 4 A80 1000 5 5 5 5 4 A81 1000 2 2 4
4 0 A82 1000 4 4 5 5 2 A83 1000 1 4 5 5 1 A84 1000 5 5 5 5 4 A85
1000 5 5 5 5 4 A86 1000 5 5 5 5 2 A87 1000 5 5 5 5 4 A88 1000 5 5 5
5 3 A89 1000 5 5 5 5 3 A90 1000 5 5 5 5 5 A91 1000 5 4 5 5 3 A92
1000 5 5 5 5 4 A93 1000 5 5 5 5 4 A94 1000 5 5 5 5 5 A95 1000 5 5 5
5 2 A96 1000 5 5 5 5 5 3 A97 1000 5 5 5 5 5 3 A98 1000 0 0 4 0 0 1
A99 1000 3 0 5 1 0 1 A100 1000 5 5 5 5 5 4 A101 1000 5 5 5 5 5 3
A102 1000 2 1 5 5 1 A103 1000 0 1 2 0 1 A104 1000 5 5 5 5 5 A105
1000 5 5 5 5 5 A106 1000 4 4 5 5 1 A107 1000 5 5 5 5 3 A108 1000 5
5 5 5 5 ABUTH = Abutilon theophrasti; AMARE = Amaranthus
retroflexus; SETFA = Setaria faberi; ALOMY = Alopecurus
myosuroides; ECHCG = Echinochloa crus-galli; ZEAMX = Zea mays.
* * * * *