U.S. patent application number 15/514048 was filed with the patent office on 2017-10-12 for herbicidal pyridino-/pyrimidino-thiazoles.
This patent application is currently assigned to Syngenta Participations AG. The applicant listed for this patent is SYNGENTA PARTICIPATIONS AG. Invention is credited to Neil Brian CARTER, Alison Clare ELLIOTT, Derek MCCORMACK, Matthew Murdoch MCLACHLAN, Anne Mary SEVILLE, Matthew John WEBBER.
Application Number | 20170290337 15/514048 |
Document ID | / |
Family ID | 54148515 |
Filed Date | 2017-10-12 |
United States Patent
Application |
20170290337 |
Kind Code |
A1 |
CARTER; Neil Brian ; et
al. |
October 12, 2017 |
Herbicidal Pyridino-/Pyrimidino-Thiazoles
Abstract
The present invention relates to herbicidally active
pyridino-/pyrimidino-thiazole derivatives, as well as to processes
and intermediates used for the preparation of such derivatives. The
invention further extends to herbicidal compositions comprising
such derivatives, as well as to the use of such compounds and
compositions in controlling undesirable plant growth: in particular
the use in controlling weeds, in crops of useful plants.
Inventors: |
CARTER; Neil Brian;
(Bracknell Berkshire, GB) ; MCCORMACK; Derek;
(Bracknell Berkshire, GB) ; SEVILLE; Anne Mary;
(Bracknell Berkshire, GB) ; WEBBER; Matthew John;
(Bracknell Berkshire, GB) ; MCLACHLAN; Matthew
Murdoch; (Bracknell Berkshire, GB) ; ELLIOTT; Alison
Clare; (Bracknell, Berkshire, GB) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
SYNGENTA PARTICIPATIONS AG |
Basel |
|
CH |
|
|
Assignee: |
Syngenta Participations AG
Basel
CH
|
Family ID: |
54148515 |
Appl. No.: |
15/514048 |
Filed: |
September 18, 2014 |
PCT Filed: |
September 18, 2014 |
PCT NO: |
PCT/EP2015/071419 |
371 Date: |
March 24, 2017 |
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A01N 43/78 20130101;
C07D 213/76 20130101; A01N 47/18 20130101; A01N 47/36 20130101;
C07D 277/44 20130101 |
International
Class: |
A01N 43/78 20060101
A01N043/78; C07D 213/76 20060101 C07D213/76; C07D 277/44 20060101
C07D277/44; A01N 47/18 20060101 A01N047/18; A01N 47/36 20060101
A01N047/36 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 24, 2014 |
GB |
1416840.5 |
Jul 8, 2015 |
GB |
1511932.4 |
Claims
1. A method of controlling unwanted plant growth, comprising
applying a compound of formula (I) ##STR00194## or a salt or
N-oxide thereof, wherein, X.sub.1 is N or CR.sup.1; R.sup.1 is
hydrogen, halogen, cyano, C.sub.1-C.sub.6alkyl,
C.sub.3-C.sub.6cycloalkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.1-C.sub.6alkoxy, --C(O)OR.sup.6 or
S(O).sub.n(C.sub.1-C.sub.6alkyl), formyl, hydroxyl,
--C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, benzyloxy, C.sub.1-C.sub.6
haloalkoxy, or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen,
halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6cycloalkyl, --C(O)OR.sup.6,
S(O).sub.n(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6 alkoxy, or
C.sub.1-C.sub.6 haloalkoxy; n is 0, 1, or 2; R.sup.3 is hydrogen,
cyano, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.3-C.sub.10cycloalkyl, NR.sup.6R.sup.7, R.sup.4 is O, S, or
N(C.sub.1-C.sub.6alkyl); X.sub.2 is O, S, or NR.sup.8; R.sup.5 is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy,
C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy,
C.sub.6-C.sub.10aryl or C.sub.6-C.sub.10aryl substituted by from 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;
C.sub.3-C.sub.10heterocylcyl or C.sub.3-C.sub.10heterocyclycl
substituted by from 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 NR.sup.6R.sup.7; or R.sup.3 and R.sup.5 together with X.sub.2
and the atoms to which they are attached, form a saturated or
partially unsaturated 5-9 membered ring system optionally
comprising 1 to 3 heteroatoms independently selected from S, O and
N and optionally substituted with 1 to 3 groups independently
selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.3 and
R.sup.8 together with the atoms to which they are attached form a
saturated or partially unsaturated 5-9 membered ring system
optionally comprising 1 to 3 heteroatoms independently selected
from S, O and N and optionally substituted with 1 to 3 groups
independently selected from halogen or C.sub.1-C.sub.6 alkyl;
R.sup.6 and R.sup.7 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, or R.sup.4 and R.sup.5
together with X.sub.2 and the atoms to which they are attached,
form a saturated or partially unsaturated 5-9 membered ring system
optionally comprising 1 to 3 heteroatoms independently selected
from S, O and N and optionally substituted with 1 to 3 groups
independently selected from halogen or C.sub.1-C.sub.6 alkyl; or
R.sup.6 and R.sup.7 together with the nitrogen atom to which they
are attached form a saturated or partially unsaturated 3-6 membered
ring optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl; R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy,
C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy; or
R.sup.7 and R.sup.8 together with the carbon atoms to which they
are attached form a saturated or partially unsaturated 3-9 membered
ring optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl, to the unwanted plants or to the locus thereof.
2. The method according to claim 1, wherein R.sup.1 is hydrogen,
halogen, formyl, cyano, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
alkylsulfonyl, C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6
haloalkoxy, --C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, or
C.sub.1-C.sub.6 haloalkyl
3. (canceled)
4. The method according to claim 1, wherein R.sup.2 is halogen,
cyano, nitro, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 alkenyl, C.sub.1-C.sub.6 alkylsulfinyl,
C.sub.1-C.sub.6 alkylsulfonyl, C.sub.1-C.sub.6 alkylthio,
--C(O)OR.sup.6, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.3-C.sub.6 cycloalkyl, or C.sub.2-C.sub.6 alkynyl
5. (canceled)
6. The method according to claim 1 wherein R.sup.3 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.2-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6 haloalkoxy,
C.sub.2-C.sub.6 alkenyloxy, C.sub.3-C.sub.10 cycloalkyl, or
NR.sup.6R.sup.7.
7. (canceled)
8. The method according to claim 1 wherein R.sup.5 is
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.1-C.sub.6 haloalkyl,
C.sub.2-C.sub.6 haloalkenyl, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.2-C.sub.6 alkenyloxy,
C.sub.2-C.sub.6 alkynyloxy, C.sub.3-C.sub.10 cycloalkyloxy,
C.sub.3-C.sub.10 cycloalkenyloxy, C.sub.2-C.sub.6 haloalkenyloxy,
C.sub.6-C.sub.20 aryl, C.sub.3-C.sub.20 heterocylcyl, or
NR.sup.6R.sup.7.
9. The method according to claim 1, wherein R.sup.3 and R.sup.5
together with X.sub.2 and the atoms to which they are attached,
form a ring system Q, selected from the group consisting of Q.sub.1
and Q.sub.2, ##STR00195## wherein X.sup.2 and R.sup.4 are as
defined in claim 1, and A denotes the point of attachment to the
pyridino/pyrimidino-thiazole moiety.
10. (canceled)
11. The method according to claim 1 wherein R.sup.4 is O.
12. The method according to claim 1 wherein X.sub.2 is O, or
NR.sup.8.
13. (canceled)
14. (canceled)
15. (canceled)
16. A herbicidal composition comprising from 0.1 to 99% by weight,
of a compound of Formula (I) as defined in claim 1, and from 1 to
99.9% by weight of a formulation adjuvant, wherein the formulation
adjuvant comprises from 0 to 25% by weight of a surface-active
substance.
17. (canceled)
18. The herbicidal composition of claim 16, further comprising at
least one additional pesticide selected from a herbicide or
herbicide safener.
19. (canceled)
20. (canceled)
21. A method of selectively controlling weeds at a locus comprising
crop plants and weeds, wherein the method comprises application to
the locus, of a weed-controlling amount of (i) a compound of
formula (I): ##STR00196## or a salt or N-oxide thereof, wherein,
X.sub.1 is N or CR.sup.1; R.sup.1 is hydrogen, halogen, cyano,
C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl,
C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl,
C.sub.1-C.sub.6alkoxy, --C(O)OR.sup.6 or
S(O).sub.n(C.sub.1-C.sub.6alkyl), formyl, hydroxyl,
--C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, benzyloxy, C.sub.1-C.sub.6
haloalkoxy, or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen,
halogen, cyano, nitro, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6haloalkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.6cycloalkyl, --C(O)OR.sup.6,
S(O).sub.n(C.sub.1-C.sub.6alkyl), C.sub.1-C.sub.6 alkoxy, or
C.sub.1-C.sub.6 haloalkoxy; n is 0, 1, or 2; R.sup.3 is hydrogen,
cyano, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6haloalkenyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.3-C.sub.10cycloalkyl, NR.sup.6R.sup.7, R.sup.4 is O, S, or
N(C.sub.1-C.sub.6alkyl); X.sub.2 is O, S, or NR.sup.8; R.sup.5 is
hydrogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl,
C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.10cycloalkyl,
C.sub.3-C.sub.10cycloalkenyl, C.sub.1-C.sub.6haloalkyl,
C.sub.2-C.sub.6haloalkenyl, C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy,
C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy,
C.sub.6-C.sub.10aryl or C.sub.6-C.sub.10aryl substituted by from 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;
C.sub.3-C.sub.10heterocylcyl or C.sub.3-C.sub.10heterocyclycl
substituted by from 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 NR.sup.6R.sup.7; or R.sup.3 and R.sup.5 together with X.sub.2
and the atoms to which they are attached, form a saturated or
partially unsaturated 5-9 membered ring system optionally
comprising 1 to 3 heteroatoms independently selected from S, O and
N and optionally substituted with 1 to 3 groups independently
selected from halogen or C.sub.1-C.sub.6 alkyl; or R.sup.3 and
R.sup.8 together with the atoms to which they are attached form a
saturated or partially unsaturated 5-9 membered ring system
optionally comprising 1 to 3 heteroatoms independently selected
from S, O and N and optionally substituted with 1 to 3 groups
independently selected from halogen or C.sub.1-C.sub.6 alkyl;
R.sup.6 and R.sup.7 are each independently hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, or C.sub.2-C.sub.6 alkynyl, or R.sup.4 and R.sup.5
together with X.sub.2 and the atoms to which they are attached,
form a saturated or partially unsaturated 5-9 membered ring system
optionally comprising 1 to 3 heteroatoms independently selected
from S, O and N and optionally substituted with 1 to 3 groups
independently selected from halogen or C.sub.1-C.sub.6 alkyl; or
R.sup.6 and R.sup.7 together with the nitrogen atom to which they
are attached form a saturated or partially unsaturated 3-6 membered
ring optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl; R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6alkoxy,
C.sub.1-C.sub.6haloalkoxy, C.sub.2-C.sub.6alkenyloxy,
C.sub.2-C.sub.6alkynyloxy, C.sub.3-C.sub.10cycloalkyloxy,
C.sub.3-C.sub.10cycloalkenyloxy, C.sub.2-C.sub.6haloalkenyloxy; or
R.sup.7 and R.sup.8 together with the carbon atoms to which they
are attached form a saturated or partially unsaturated 3-9 membered
ring optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl.
Description
[0001] The present invention relates to herbicidally active
pyridino-/pyrimidino-thiazole derivatives, as well as to processes
and intermediates used for the preparation of such derivatives. The
invention further extends to herbicidal compositions comprising
such derivatives, as well as to the use of such compounds and
compositions in controlling undesirable plant growth: in particular
the use in controlling weeds, in crops of useful plants.
[0002] Herbicidal pyrimidino-imidazoles are known from
WO2005/047281. Pyridino-/pyrimidino-thiazole derivatives, for use
as acaricidal/insecticidal/molluscicidal/nematicidal agents, or in
controlling invertebrate pests, are described in WO2010/129497,
WO2011/128304, WO2013/186089, and WO2014/007395.
[0003] The present invention is based on the finding that
pyridino-thiazole, and pyrimidino-thiazole, derivatives of formula
(I) as defined herein, exhibit surprisingly good herbicidal
activity.
[0004] Thus, in a first aspect of the invention there is provided
the use of a compound of formula (I)
##STR00001##
or a salt or N-oxide thereof, wherein, X.sub.1 is N or CR.sup.1;
R.sup.1 is hydrogen, halogen, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.3-C.sub.6 cycloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.1-C.sub.6 alkoxy, C(O)OR.sup.6 or
S(O).sub.n(C.sub.1-C.sub.6 alkyl), formyl, hydroxyl,
--C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, benzyloxy, C.sub.1-C.sub.6
haloalkoxy, or C.sub.1-C.sub.6 haloalkyl; R.sup.2 is hydrogen,
halogen, cyano, nitro, 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,
C.sub.3-C.sub.6 cycloalkyl, --C(O)OR.sup.6,
S(O).sub.n(C.sub.1-C.sub.6 alkyl), C.sub.1-C.sub.6 alkoxy, or
C.sub.1-C.sub.6 haloalkoxy; n is 0, 1, or 2; R.sup.3 is hydrogen,
cyano, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.3-C.sub.10
cycloalkyl, NR.sup.6R.sup.7, R.sup.4 is O, S, or N(C.sub.1-C.sub.6
alkyl); X.sub.2 is O, S, or NR.sup.8; R.sup.5 is hydrogen,
C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6
alkynyl, C.sub.3-C.sub.10 cycloalkyl, C.sub.3-C.sub.10
cycloalkenyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
haloalkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy,
C.sub.3-C.sub.10 cycloalkyloxy, C.sub.3-C.sub.10 cycloalkenyloxy,
C.sub.2-C.sub.6 haloalkenyloxy, C.sub.6-C.sub.10 aryl or
C.sub.6-C.sub.10 aryl substituted by from 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; C.sub.3-C.sub.10 heterocyclyl or
C.sub.3-C.sub.10 heterocyclyl substituted by from 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 NR.sup.6R.sup.7; or R.sup.3 and
R.sup.5 together with X.sub.2 and the atoms to which they are
attached, form a saturated or partially unsaturated 5-9 membered
ring system optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl; or R.sup.3 and R.sup.8 together with the atoms to which they
are attached form a saturated or partially unsaturated 5-9 membered
ring system optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl; or R.sup.4 and R.sup.5 together with X.sub.2 and the atoms
to which they are attached, form a saturated or partially
unsaturated 5-9 membered ring system optionally comprising 1 to 3
heteroatoms independently selected from S, O and N and optionally
substituted with 1 to 3 groups independently selected from halogen
or C.sub.1-C.sub.6 alkyl; R.sup.6 and R.sup.7 are each
independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6
haloalkyl, C.sub.2-C.sub.6 alkenyl, or C.sub.2-C.sub.6 alkynyl, or
R.sup.6 and R.sup.7 together with the nitrogen atom to which they
are attached form a saturated or partially unsaturated 3-6 membered
ring optionally comprising 1 to 3 heteroatoms independently
selected from S, O and N and optionally substituted with 1 to 3
groups independently selected from halogen or C.sub.1-C.sub.6
alkyl; R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6 alkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl; C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6
haloalkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.2-C.sub.6 alkynyloxy,
C.sub.3-C.sub.10 cycloalkyloxy, C.sub.3-C.sub.10 cycloalkenyloxy,
C.sub.2-C.sub.6 haloalkenyloxy; or R.sup.7 and R.sup.8 together
with the carbon atoms to which they are attached form a saturated
or partially unsaturated 3-9 membered ring optionally comprising 1
to 3 heteroatoms independently selected from S, O and N and
optionally substituted with 1 to 3 groups independently selected
from halogen or C.sub.1-C.sub.6 alkyl, as a herbicide.
[0005] Compounds of formula (I) may exist as different geometric
isomers, or in different tautomeric forms. This invention covers
the use of all such isomers and tautomers, and mixtures thereof in
all proportions, as well as isotopic forms such as deuterated
compounds.
[0006] It may be the case that compounds of formula (I) 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 the use of 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.
[0007] Each alkyl moiety either alone or as part of a larger group
(such as alkoxy, alkylthio, alkoxycarbonyl, alkylcarbonyl,
alkylaminocarbonyl, or dialkylaminocarbonyl, et al.) may be
straight-chained or branched. Typically, the alkyl is, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,
tert-butyl, n-pentyl, neopentyl, or n-hexyl. The alkyl groups are
generally C.sub.1-C.sub.6 alkyl groups (except where already
defined more narrowly), but are preferably C.sub.1-C.sub.4 alkyl or
C.sub.1-C.sub.3 alkyl groups, and, more preferably, are
C.sub.1-C.sub.2 alkyl groups (such as methyl).
[0008] Alkenyl and alkynyl moieties can be in the form of straight
or branched chains, and the alkenyl moieties, where appropriate,
can be of either the (E)- or (Z)-configuration. Alkenyl and alkynyl
moieties can contain one or more double and/or triple bonds in any
combination; but preferably contain only one double bond (for
alkenyl) or only one triple bond (for alkynyl).
[0009] The alkenyl or alkynyl moieties are typically
C.sub.2-C.sub.4 alkenyl or C.sub.2-C.sub.4 alkynyl, more
specifically ethenyl (vinyl), prop-2-enyl (allyl), ethynyl,
prop-2-ynyl (propargyl), or prop-1-ynyl.
[0010] Preferably, the term cycloalkyl refers to cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl.
[0011] In the context of the present specification the term "aryl"
preferably means phenyl.
[0012] Heterocyclyl groups and heterocyclic rings (either alone or
as part of a larger group, such as heterocyclyl-alkyl-) are ring
systems containing at least one heteroatom and can be in mono- or
bi-cyclic form. Preferably, heterocyclyl groups will contain up to
two heteroatoms which will preferably be chosen from nitrogen,
oxygen and sulfur. Examples of heterocyclic groups include
oxetanyl, thietanyl, azetidinyl and 7-oxa-bicyclo[2.2.1]hept-2-yl.
Heterocyclyl groups containing a single oxygen atom as heteroatom
are most preferred. The heterocyclyl groups are preferably 3- to
8-membered, more preferably 3- to 6-membered rings.
[0013] Halogen (or halo) encompasses fluorine, chlorine, bromine or
iodine. The same correspondingly applies to halogen in the context
of other definitions, such as haloalkyl or halophenyl.
[0014] Haloalkyl groups having a chain length of from 1 to 6 carbon
atoms are, for example, fluoromethyl, difluoromethyl,
trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,
2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,
pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl,
2,2,3,3-tetrafluoroethyl and 2,2,2-trichloroethyl,
heptafluoro-n-propyl and perfluoro-n-hexyl.
[0015] Alkoxy groups preferably have a chain length of from 1 to 6
carbon atoms. Alkoxy is, for example, methoxy, ethoxy, propoxy,
isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert-butoxy or a
pentyloxy or hexyloxy isomer, preferably methoxy and ethoxy. It
should also be appreciated that two alkoxy substituents may be
present on the same carbon atom.
[0016] Haloalkoxy is, for example, fluoromethoxy, difluoromethoxy,
trifluoromethoxy, 2,2,2-trifluoroethoxy, 1,1,2,2-tetrafluoroethoxy,
2-fluoroethoxy, 2-chloroethoxy, 2,2-difluoroethoxy or
2,2,2-trichloroethoxy, preferably difluoromethoxy, 2-chloroethoxy
or trifluoromethoxy.
[0017] C.sub.1-C.sub.6 alkyl-S-- (alkylthio) is, for example,
methylthio, ethylthio, propylthio, isopropylthio, n-butylthio,
isobutylthio, sec-butylthio or tert-butylthio, preferably
methylthio or ethylthio.
[0018] C.sub.1-C.sub.6 alkyl-S(O)-- (alkylsulfinyl) is, for
example, methylsulfinyl, ethylsulfinyl, propylsulfinyl,
isopropylsulfinyl, n-butylsulfinyl, isobutylsulfinyl,
sec-butylsulfinyl or tert-butylsulfinyl, preferably methylsulfinyl
or ethylsulfinyl.
[0019] C.sub.1-C.sub.6 alkyl-S(O).sub.2-- (alkylsulfonyl) is, for
example, methylsulfonyl, ethylsulfonyl, propylsulfonyl,
isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl,
sec-butylsulfonyl or tert-butylsulfonyl, preferably methylsulfonyl
or ethylsulfonyl.
[0020] Compounds of formula (I) may form, and/or be used as,
agronomically acceptable salts with amines (for example ammonia,
dimethylamine and triethylamine), alkali metal and alkaline earth
metal bases or quaternary ammonium bases. Among the alkali metal
and alkaline earth metal hydroxides, oxides, alkoxides and hydrogen
carbonates and carbonates used in salt formation, emphasis is to be
given to the hydroxides, alkoxides, oxides and carbonates of
lithium, sodium, potassium, magnesium and calcium, but especially
those of sodium, magnesium and calcium. The corresponding
trimethylsulfonium salt may also be used.
[0021] Compounds of formula (I) may also form (and/or be used as)
agronomically acceptable salts with various organic and/or
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 the compound of formula (I) contains a basic
moiety.
[0022] Compounds of formula (I) may also be in the form of/used as
hydrates which may be formed during the salt formation.
[0023] Preferred values of X.sub.1, X.sub.2, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7, R.sup.8, and n, are as
set out below, and a compound of formula (I) according to the
invention may comprise any combination of said values. The skilled
person will appreciate that values for any specified set of
embodiments may combined with values for any other set of
embodiments where such combinations are not mutually exclusive.
[0024] Preferably R.sup.1 is hydrogen, halogen, formyl, cyano,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylthio, C.sub.1-C.sub.6 haloalkoxy,
--C(O)NR.sup.6R.sup.7, NR.sup.6R.sup.7, or C.sub.1-C.sub.6
haloalkyl. More preferably R.sup.1 is hydrogen, fluorine, chlorine,
cyano, trifluoromethyl, methoxy, difluoromethoxy, formyl,
methanesulfonyl, carboxamide, methanethiol or amino.
[0025] Preferably R.sup.2 is halogen, cyano, nitro, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl,
C.sub.1-C.sub.6 alkylsulfinyl, C.sub.1-C.sub.6 alkylsulfonyl,
C.sub.1-C.sub.6 alkylthio, --C(O)OR.sup.6, C.sub.1-C.sub.6 alkoxy,
C.sub.1-C.sub.6 haloalkoxy, C.sub.3-C.sub.6 cycloalkyl, or
C.sub.2-C.sub.6 alkynyl. More preferably R.sup.2 is halogen, cyano,
C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6
alkenyl, C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy,
C.sub.3-C.sub.6 cycloalkyl, --C(O)OR.sup.6, or C.sub.2-C.sub.6
alkynyl. Even more preferably R.sup.2 is methyl, trifluoromethyl,
chloro, bromo, iodo, fluoro, vinyl, acetylenyl, methoxycarbonyl,
--CO.sub.2H, or cyclopropyl;
[0026] Preferably R.sup.3 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkyl, C.sub.1-C.sub.6
haloalkoxy, C.sub.2-C.sub.6 alkenyloxy, C.sub.3-C.sub.10
cycloalkyl, or NR.sup.6R.sup.7. More preferably R.sup.3 is
hydrogen, or C.sub.1-C.sub.3 alkyl. Even more preferably R.sup.3 is
methyl or ethyl.
[0027] Preferably R.sup.4 is O.
[0028] Preferably X.sub.2 is O, or NR.sup.8.
[0029] Preferably R.sup.5 is C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6
alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-C.sub.10 cycloalkyl,
C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 haloalkenyl,
C.sub.1-C.sub.6 alkoxy, C.sub.1-C.sub.6 haloalkoxy, C.sub.2-C.sub.6
alkenyloxy, C.sub.2-C.sub.6 alkynyloxy, C.sub.3-C.sub.10
cycloalkyloxy, C.sub.3-C.sub.10 cycloalkenyloxy, C.sub.2-C.sub.6
haloalkenyloxy, C.sub.6-C.sub.10 aryl, C.sub.6-C.sub.10 aryl
substituted by 1-3 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,
C.sub.3-C.sub.10 heterocyclyl, or NR.sup.6R.sup.7. In one set of
embodiments R.sup.5 is preferably methyl, ethyl, iso-propyl,
tert-butyl, or tert-butoxy. In a further set of embodiments,
R.sup.5 is preferably phenyl optionally substituted by 1-3 groups
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,
more preferably phenyl substituted once by halogen, nitro, cyano,
C.sub.1-C.sub.3 alkyl, C.sub.1-C.sub.3 alkoxy, C.sub.1-C.sub.3
haloalkyl, or C.sub.1-C.sub.3 haloalkoxy,
[0030] In a further set of embodiments R.sup.5 is preferably
C.sub.2-C.sub.6 alkynyl. Compounds of formula (I) where R.sup.5 is
C.sub.2-C.sub.6 alkynyl are novel and thus form a further aspect of
the invention.
[0031] Preferably R.sup.8 is hydrogen, cyano, C.sub.1-C.sub.6
alkyl, C.sub.1-C.sub.6 haloalkyl, C.sub.2-C.sub.6 alkenyl, or
C.sub.2-C.sub.6 alkynyl. More preferably R.sup.8 is hydrogen or
methyl. In one set of embodiment R.sup.8 is hydrogen. In a further
set of embodiments R.sup.8 is methyl.
[0032] In embodiments where R.sup.3 and R.sup.5 together with
X.sub.2 and the atoms to which they are attached, form a saturated
or partially unsaturated 5-9 membered ring system optionally
comprising 1 to 3 heteroatoms independently selected from S, O and
N and optionally substituted with 1 to 3 groups independently
selected from halogen or C.sub.1-C.sub.6 alkyl, it is preferred
that the following groups Q, are formed:
##STR00002##
wherein X.sup.2 and R.sup.4 are as defined herein, and A denotes
the point of attachment to the pyridino/pyrimidino-thiazole moiety.
Preferably in each of groups Q.sub.1 and Q.sub.2, R.sup.4 is O and
X.sub.2 is O or NR.sup.8. Even more preferably, R.sup.4 is O and
X.sub.2 is O or NR.sup.8 and R.sup.8 is methyl.
[0033] Tables 1 and 2 below provide 91 specific examples of
herbicidal compounds of formula (I) for use according to the
invention.
TABLE-US-00001 TABLE 1 Specific examples of compounds of formula
(I) Compound Structure A1 ##STR00003## A2 ##STR00004## A3
##STR00005## A4 ##STR00006## A5 ##STR00007## A6 ##STR00008## A7
##STR00009## A8 ##STR00010## A9 ##STR00011## A10 ##STR00012## A11
##STR00013## A12 ##STR00014## A13 ##STR00015## A14 ##STR00016## A15
##STR00017## A16 ##STR00018## A17 ##STR00019## A18 ##STR00020## A19
##STR00021## A20 ##STR00022## A21 ##STR00023## A22 ##STR00024## A23
##STR00025## A24 ##STR00026## A25 ##STR00027## A26 ##STR00028## A27
##STR00029## A28 ##STR00030## A29 ##STR00031## A30 ##STR00032## A31
##STR00033## A32 ##STR00034## A33 ##STR00035## A34 ##STR00036## A35
##STR00037## A38 ##STR00038## A39 ##STR00039## A40 ##STR00040## A41
##STR00041## A43 ##STR00042## A44 ##STR00043## A45 ##STR00044## A46
##STR00045## A47 ##STR00046## A48 ##STR00047## A49 ##STR00048## A50
##STR00049## A51 ##STR00050## A52 ##STR00051## A53 ##STR00052## A54
##STR00053## A55 ##STR00054## A56 ##STR00055## A57 ##STR00056## A58
##STR00057## A59 ##STR00058## A60 ##STR00059## A61 ##STR00060## A62
##STR00061## A63 ##STR00062##
[0034] As stated hereinbefore, compounds of formula (I) wherein
R.sup.5 is C.sub.2-C.sub.6 alkynyl are novel. Accordingly, the
invention also provided compounds of formula (I)-(i), which are
compounds of formula (I) as defined herein, wherein R.sup.5 is
C.sub.2-C.sub.6 alkynyl. In compounds of formula (I)-(i) the
preferred substituents for X.sub.1, X.sub.2, R.sup.1, R.sup.2,
R.sup.3, R.sup.4, R.sup.6, R.sup.7, R.sup.8 and n are as defined
hereinbefore, with respect to compounds of formula (I)
[0035] However, particularly preferred embodiments will have the
substituent preferences described below.
[0036] Where X.sub.1 is CR.sup.1, R.sup.1 is preferably halogen,
more preferably fluoro. R.sup.2 is preferably methyl,
trifluoromethyl, chloro, bromo, iodo, fluoro, vinyl, acetylenyl,
methoxycarbonyl, --CO.sub.2H, or cyclopropyl, more preferably
methyl. R.sup.3 is preferably hydrogen or C.sub.1-C.sub.3 alkyl,
more preferably methyl or ethyl, most preferably methyl. R.sup.4 is
preferably oxygen. X.sub.2 is preferably oxygen or NR.sup.8,
wherein R.sup.8 is preferably hydrogen. R.sup.5 is preferably
C.sub.3-C.sub.5 alkynyl.
[0037] In one particularly preferred set of embodiments, R.sup.5 is
selected from the group consisting of 1-methyl-prop-2-ynyl,
1,1-dimethylprop-2-ynyl, and prop-2-ynyl. Table 2 below provides 28
specific examples of compounds of formula (I)-(i) according to the
invention.
TABLE-US-00002 TABLE 2 Specific examples of compounds of formula
(I)-(i) Compound Structure B1 ##STR00063## B2 ##STR00064## B3
##STR00065## B4 ##STR00066## B5 ##STR00067## B6 ##STR00068## B7
##STR00069## B8 ##STR00070## B9 ##STR00071## B10 ##STR00072## B11
##STR00073## B12 ##STR00074## B13 ##STR00075## B14 ##STR00076## B15
##STR00077## B16 ##STR00078## B17 ##STR00079## B18 ##STR00080## B19
##STR00081## B20 ##STR00082## B21 ##STR00083## B22 ##STR00084## B23
##STR00085## B24 ##STR00086## B25 ##STR00087## B26 ##STR00088## B27
##STR00089## B28 ##STR00090##
[0038] Compounds of formula (I) may be prepared according to the
following schemes, in which the substituents X.sub.1, X.sub.2,
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and n, have (unless otherwise stated explicitly) the
definitions described hereinbefore, using 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 synthetic procedures are
derived from WO2013/186089 or W2010/129497. The starting materials
used for the preparation of the compounds of the invention may be
purchased from the 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.
[0039] Typical abbreviations used throughout are as follows:
Ac=acetyl Bn=benzyl Bu=butyl t-BuOH=tert-butanol
DMAP=4-dimethylaminopyridine
DMF=N, N-dimethylformamide
[0040] DMSO=dimethylsulfoxide DPPA=diphenylphosphoryl azide
Et.sub.3N=triethylamine Et.sub.2O=diethyl ether EtOAc=ethyl acetate
EtOH=ethanol mCPBA=meta-chloro-benzoic acid Me=methyl MeI=methyl
iodide MeCN=acetonitrile
NBS=N-bromosuccinimide
[0041] N-Boc=N-tert-butoxycarbony
NIS=N-odosuccnmde
[0042] Ph=phenyl TFA=trifluoroacetic acid THF=tetrahydrofuran
##STR00091##
[0043] As shown in Reaction Scheme 1, compounds of formula (I) can
be prepared via a three step sequence wherein a suitably
substituted 2-bromo-thiazole-5-carboxylic acid (II) can be reacted
to form an acyl azide with suitable reagents such as
diphenylphosphoryl azide (DPPA) which can be further converted
in-situ with a suitable alcohol, such as t-butanol (t-BuOH) to give
the carbamates of formula (III). This can be further substituted
with alkylating agents such as MeI under basic conditions (for
example using NaH) in a polar solvent (such as DMF) to give
compounds of formula (IV). These compounds can be converted to
products of formula (I) using palladium catalysed cross-coupling
between a suitable boronic acid derivative of formula (V) with a
palladium catalyst such as Pd(PPh.sub.3).sub.4, a base such as
potassium carbonate and a solvent which may be a mixed solvent
system such as ethanol, toluene and water.
[0044] Alternatively (as also shown in reaction scheme 1) compounds
of formula (I) can be prepared via variation of the three step
sequence wherein a suitably substituted
2-bromo-thiazole-5-carboxylic acid (II) can be reacted to form an
acyl azide with suitable reagents such as diphenylphosohoryl azide
(DPPA) which can be further converted in-situ with a suitable
alcohol, such as t-Butanol (t-BuOH) to give the carbamates of
formula (III).
[0045] These compounds can be converted to products of formula (Ia)
using palladium catalysed cross-coupling between a suitable boronic
acid derivative of formula (V) with a palladium catalyst such as
Pd(PPh.sub.3).sub.4, a base such as potassium carbonate and a
solvent which may be a mixed solvent system such as ethanol,
toluene and water. These materials can be further reacted with
alkylating agents such as MeI under basic conditions (for example
using NaH) with a polar solvent (such as DMF) to give compounds of
formula (I).
[0046] Compounds of formula (I) may also be prepared via
condensation of an appropriately substituted thioamide (VI) in the
presence of an appropriately substituted 2-halo .beta.-keto ester
(VII), for example where R.sup.2=alkyl or trifluoroalkyl, to give
compounds of formula (VIII) which can be further elaborated via
basic saponification, for example with NaOH, water and ethanol
mixtures. The resulting carboxylic acid (IX) can be reacted to form
an acyl azide with suitable reagents such as diphenylphosphoryl
azide (DPPA), which can be further converted in-situ with a
suitable alcohol, such as t-butanol (t-BuOH), to give the
carbamates of formula (Ia). These materials can be further reacted
with alkylating agents such as MeI under basic conditions, for
example using K.sub.2CO.sub.3 in a polar solvent (such as MeCN), to
give compounds of formula (I) (Reaction Scheme 2).
##STR00092##
##STR00093##
[0047] As shown in Reaction Scheme 3, when R.sup.4 is O, X.sub.2 is
O and R.sup.5 is t-Bu, the resulting N-Boc group may be removed
under mild acidic conditions, such as with HCl in ether, to afford
an amine salt, such as the HCl salt. Compounds of formula (X) may
then be further converted to compounds such as (Ic) by reaction
with a suitable chloroformate (such as ethyl chloroformate) and a
base such as pyridine.
[0048] Alternatively, compounds of formula (X) may then be further
converted to compounds such as (Id) by reaction with a suitable
isocyanate (such as t-butyl-isocyanate). Compounds of formula (Id)
may be further alkylated with a suitable electrophile and base
combination (for example MeI, K.sub.2CO.sub.3) to give compounds of
the type where X.sub.2=NR.sup.8 (Ie).
[0049] As a further alternative, compounds of formula (X) may then
be further converted to compounds of Formula (XI) by reaction with
a compound of Formula (XXX), where Lg is a suitable leaving group
(such as Cl); for example phosgene or a suitable phosgene
equivalent (such as carbonyldiimidazole or 4-nitrophenyl
chloroformate). This may be followed by reaction with an alcohol,
amine or thiol to afford compounds of formula (I).
##STR00094##
[0050] In cases where R.sup.2 is H, it is possible to convert
compounds of Formula (If) into compounds of Formula (Ig) by
alkylation of the nitrogen using a base, such as NaH, and an
electrophile, such as MeI, in a polar solvent, such as DMF. It is
then possible perform electrophilic substitution to introduce new
R.sup.2 substituents on compound (Ig). Electrophilic halogenation
reagents can be used to perform this transformation. For example
where R.sup.2 is I, N-iodosuccinimide in a solvent such as
acetonitrile are suitable conditions to give a compound of formula
(Ii). Where R.sup.2 is Br, N-bromosuccinimide in a solvent (e.g.
acetonitrile) is suitable to give a compound of formula (Ij), and
where R.sup.2 is Cl, N-chlorosuccinimide in a solvent (e.g.
acetonitrile) can be used to furnish a compound of formula (Ik).
Where R.sup.2 is F, Selectfluor.TM.
(1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane
ditetrafluoroborate) in acetonitrile is a typical set of reaction
conditions to perform the transformation to convert a compound of
formula (Ig) into a compound of formula (Ih) (Reaction Scheme 4,
above).
[0051] Compounds of formula (I) may also be prepared via
condensation of an appropriately substituted thioamide (VI) in the
presence of an appropriately substituted 2-halo ketone (XII) (e.g.
chloroacetone) to give compounds of formula (XIII), which can be
further elaborated via halogenation (for example with NBS) to
afford the bromo-thiazole (XIV).
##STR00095##
[0052] Reaction of compounds of this type with a nitrogen
containing heterocycle, such as a hydantoin of formula (XV), in the
presence of a copper catalyst (e.g. CuI) with a base (e.g.
K.sub.2CO.sub.3) with a ligand (e.g. N,N'-dimethylethylenediamine
(XVI)) in a suitable solvent (e.g. 1,4-dioxane) affords compounds
of formula (Im). This is shown schematically in Reaction Scheme 5
(above), and typical methods for such a transformation are taught,
for example, in WO2011/136292).
[0053] Compounds of formula (X) can be converted to a compound of
formula (In) by treatment with a bifuctional reagent (XVII) (such
as 1-chloro-2-isothiocyanoethane) in a solvent (such as dioxane) as
taught in WO2013/186089 (Reaction Scheme 6).
##STR00096##
[0054] Acylation of a compound of formula (Ia) with a bifuctional
reagent (XVIII) (e.g. chloroethyl chloroformate) with a base (e.g
sodium hydride) in an ethereal solvent (e.g. THF) affords compounds
of formula (Io). The N-Boc group can be removed under mild
conditions with reagents such as TFA in CH.sub.2Cl.sub.2 to give
(Ip).
##STR00097##
[0055] Further compounds of formula (Ip) can be cyclized by
deprotonation with a suitable base (such as NaH) in a polar solvent
(DMF is a suitable solvent for this step) to give compound of
formula (Iq) (Reaction Scheme 7).
[0056] Iodinated compounds of formula (Ir) can themselves be useful
building block to allow easy access to compounds of formulae
(Is)-(Ix) (Reaction Scheme 8). Compound (Is) can be prepared by
Iodine-Lithium exchange (using a reagent such as n-BuLi) followed
by quenching with CO.sub.2 in an ethereal solvent (such as
THF).
##STR00098##
[0057] Compounds of Formula (It) can be prepared by Iodine-Lithium
exchange (using a reagent such as n-BuLi) followed by quenching
with a chloroformate (such as methyl chloroformate) in an ethereal
solvent (such as THF).
[0058] Compounds of formula (Iu) can be made via a Stille
cross-coupling with a Pd catalyst (such as
Pd(PPh.sub.3).sub.2Cl.sub.2) in a suitable solvent (such as
1,4-dioxane) with a suitable stannane (such as (XIX)).
[0059] Compounds of formula (Iv) can be made via a Stille
cross-coupling with a Pd catalyst (such as
Pd(PPh.sub.3).sub.2Cl.sub.2) in a suitable solvent (such as
1,4-dioxane) with a suitable stannane (such as (XX)).
[0060] Compounds of formula (Iw) can be made via a Suzuki
cross-coupling with a Pd pre-catalyst (such as Pd(OAc).sub.2), with
a suitable ligand (such as P(c-hexyl).sub.3) and base (such as
K.sub.3PO.sub.4) in a suitable solvent such as 1,4-dioxane with a
suitable boronic acid (such as (XXI)).
[0061] Reaction of compounds of Formula (X) with carbon disulphide
in a solvent such as ethanol and a base such as K.sub.2CO.sub.3,
followed by addition of an electrophile such as an alkyl iodide
gives compounds of formula (Iaa) (Reaction Scheme 9).
##STR00099##
[0062] Compounds of formula (Iab) where X.sub.2 is O and R.sup.5 is
alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl or
haloalkenyl, can be made via in-situ generation of an isocyanate
from a hydroxamic acid anhydride (XXV) (for example N-boc-O-tosyl
hydroxylamine wherein R.sup.4 is O, X.sub.2 is O and R.sup.5 is
t-Bu) in the presence of a base (for example K.sub.2CO.sub.3) via a
Lossen rearrangement (as taught by Thambidurai et al., Tetrahedron
Letters, 2012, 53, 2292 and Tetrahedron Letters, 2014, 55, 2014)
which will then react with the amino-heterocycle of formula (X) to
form the substituted urea compound (Iab) (Reaction Scheme 10).
##STR00100##
[0063] Further, N-oxides of formula (Iac) may be prepared by
oxidation of (I) with an oxidising agent such as
meta-chloroperbenzoic acid (mCPBA) or other suitable oxidants, in a
suitable solvent (for example CH.sub.2Cl.sub.2) (Reaction Scheme
11).
##STR00101##
[0064] It can be seen from the general methods described above, as
well as from the specific examples, that certain compounds of
Formula (I) are not only useful as herbicides per se, but may also
be used as intermediates in the production of further herbicidal
compounds of formula (I). This is particularly the case for
compounds of formula (I) wherein R.sup.3 is hydrogen, and/or
R.sup.2 is iodo.
[0065] The compounds of Formula (I) as described herein may be used
as herbicides by themselves, but they are generally formulated into
herbicidal compositions using formulation adjuvants, such as
carriers, solvents and surface-active agents (SFAs). Thus, the
present invention further provides a herbicidal composition
comprising a herbicidal compound as described herein and an
agriculturally acceptable formulation adjuvant. The composition can
be in the form of concentrates which are diluted prior to use,
although ready-to-use compositions can also be made. The final
dilution is usually made with water, but can be made instead of, or
in addition to, water, with, for example, liquid fertilisers,
micronutrients, biological organisms, oil or solvents.
[0066] Such herbicidal compositions generally comprise from 0.1 to
99% by weight, especially from 0.1 to 95% by weight of 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.
[0067] The compositions can be chosen from a number of formulation
types, many of which are known from the Manual on Development and
Use of FAO Specifications for Plant Protection Products, 5th
Edition, 1999. These include dustable powders (DP), soluble powders
(SP), water soluble granules (SG), water dispersible granules (WG),
wettable powders (WP), granules (GR) (slow or fast release),
soluble concentrates (SL), oil miscible liquids (OL), ultra low
volume liquids (UL), emulsifiable concentrates (EC), dispersible
concentrates (DC), emulsions (both oil in water (EW) and water in
oil (EO)), micro-emulsions (ME), suspension concentrates (SC),
aerosols, capsule suspensions (CS) and seed treatment formulations.
The formulation type chosen in any instance will depend upon the
particular purpose envisaged and the physical, chemical and
biological properties of the compound of Formula (I).
[0068] Dustable powders (DP) may be prepared by mixing a compound
of Formula (I) with one or more solid diluents (for example natural
clays, kaolin, pyrophyllite, bentonite, alumina, montmorillonite,
kieselguhr, chalk, diatomaceous earths, calcium phosphates, calcium
and magnesium carbonates, sulphur, lime, flours, talc and other
organic and inorganic solid carriers) and mechanically grinding the
mixture to a fine powder.
[0069] Soluble powders (SP) may be prepared by mixing a compound of
Formula (I) with one or more water-soluble inorganic salts (such as
sodium bicarbonate, sodium carbonate or magnesium sulphate) or one
or more water-soluble organic solids (such as a polysaccharide)
and, optionally, one or more wetting agents, one or more dispersing
agents or a mixture of said agents to improve water
dispersibility/solubility. The mixture is then ground to a fine
powder. Similar compositions may also be granulated to form water
soluble granules (SG).
[0070] Wettable powders (WP) may be prepared by mixing a compound
of Formula (I) with one or more solid diluents or carriers, one or
more wetting agents and, preferably, one or more dispersing agents
and, optionally, one or more suspending agents to facilitate the
dispersion in liquids. The mixture is then ground to a fine powder.
Similar compositions may also be granulated to form water
dispersible granules (WG).
[0071] Granules (GR) may be formed either by granulating a mixture
of a compound of Formula (I) and one or more powdered solid
diluents or carriers, or from pre-formed blank granules by
absorbing a compound of Formula (I) (or a solution thereof, in a
suitable agent) in a porous granular material (such as pumice,
attapulgite clays, fuller's earth, kieselguhr, diatomaceous earths
or ground corn cobs) or by adsorbing a compound of Formula (I) (or
a solution thereof, in a suitable agent) on to a hard core material
(such as sands, silicates, mineral carbonates, sulphates or
phosphates) and drying if necessary. Agents which are commonly used
to aid absorption or adsorption include solvents (such as aliphatic
and aromatic petroleum solvents, alcohols, ethers, ketones and
esters) and sticking agents (such as polyvinyl acetates, polyvinyl
alcohols, dextrins, sugars and vegetable oils). One or more other
additives may also be included in granules (for example an
emulsifying agent, wetting agent or dispersing agent).
[0072] Dispersible Concentrates (DC) may be prepared by dissolving
a compound of Formula (I) in water or an organic solvent, such as a
ketone, alcohol or glycol ether. These solutions may contain a
surface active agent (for example to improve water dilution or
prevent crystallisation in a spray tank).
[0073] Emulsifiable concentrates (EC) or oil-in-water emulsions
(EW) may be prepared by dissolving a compound of Formula (I) in an
organic solvent (optionally containing one or more wetting agents,
one or more emulsifying agents or a mixture of said agents).
Suitable organic solvents for use in ECs include aromatic
hydrocarbons (such as alkylbenzenes or alkylnaphthalenes,
exemplified by SOLVESSO 100, SOLVESSO 150 and SOLVESSO 200;
SOLVESSO is a Registered Trade Mark), ketones (such as
cyclohexanone or methylcyclohexanone) and alcohols (such as benzyl
alcohol, furfuryl alcohol or butanol), N-alkylpyrrolidones (such as
N-methylpyrrolidone or N-octylpyrrolidone), dimethyl amides of
fatty acids (such as C.sub.8-C.sub.10 fatty acid dimethylamide) and
chlorinated hydrocarbons. An EC product may spontaneously emulsify
on addition to water, to produce an emulsion with sufficient
stability to allow spray application through appropriate
equipment.
[0074] Preparation of an EW involves obtaining a compound of
Formula (I) either as a liquid (if it is not a liquid at room
temperature, it may be melted at a reasonable temperature,
typically below 70.degree. C.) or in solution (by dissolving it in
an appropriate solvent) and then emulsifying the resultant liquid
or solution into water containing one or more SFAs, under high
shear, to produce an emulsion. Suitable solvents for use in EWs
include vegetable oils, chlorinated hydrocarbons (such as
chlorobenzenes), aromatic solvents (such as alkylbenzenes or
alkylnaphthalenes) and other appropriate organic solvents which
have a low solubility in water.
[0075] Microemulsions (ME) may be prepared by mixing water with a
blend of one or more solvents with one or more SFAs, to produce
spontaneously a thermodynamically stable isotropic liquid
formulation. A compound of Formula (I) is present initially in
either the water or the solvent/SFA blend. Suitable solvents for
use in MEs include those hereinbefore described for use in in ECs
or in EWs. An ME may be either an oil-in-water or a water-in-oil
system (which system is present may be determined by conductivity
measurements) and may be suitable for mixing water-soluble and
oil-soluble pesticides in the same formulation. An ME is suitable
for dilution into water, either remaining as a microemulsion or
forming a conventional oil-in-water emulsion.
[0076] Suspension concentrates (SC) may comprise aqueous or
non-aqueous suspensions of finely divided insoluble solid particles
of a compound of Formula (I). SCs may be prepared by ball or bead
milling the solid compound of Formula (I) in a suitable medium,
optionally with one or more dispersing agents, to produce a fine
particle suspension of the compound. One or more wetting agents may
be included in the composition and a suspending agent may be
included to reduce the rate at which the particles settle.
Alternatively, a compound of Formula (I) may be dry milled and
added to water, containing agents hereinbefore described, to
produce the desired end product.
[0077] Aerosol formulations comprise a compound of Formula (I) and
a suitable propellant (for example n-butane). A compound of Formula
(I) may also be dissolved or dispersed in a suitable medium (for
example water or a water miscible liquid, such as n-propanol) to
provide compositions for use in non-pressurised, hand-actuated
spray pumps.
[0078] Capsule suspensions (CS) may be prepared in a manner similar
to the preparation of EW formulations but with an additional
polymerisation stage such that an aqueous dispersion of oil
droplets is obtained, in which each oil droplet is encapsulated by
a polymeric shell and contains a compound of Formula (I) and,
optionally, a carrier or diluent therefor. The polymeric shell may
be produced by either an interfacial polycondensation reaction or
by a coacervation procedure. The compositions may provide for
controlled release of the compound of Formula (I) and they may be
used for seed treatment. A compound of Formula (I) may also be
formulated in a biodegradable polymeric matrix to provide a slow,
controlled release of the compound.
[0079] The composition may include one or more additives to improve
the biological performance of the composition, for example by
improving wetting, retention or distribution on surfaces;
resistance to rain on treated surfaces; or uptake or mobility of a
compound of Formula (I). Such additives include surface active
agents (SFAs), spray additives based on oils, for example certain
mineral oils or natural plant oils (such as soy bean and rape seed
oil), and blends of these with other bio-enhancing adjuvants
(ingredients which may aid or modify the action of a compound of
Formula (I)).
[0080] Wetting agents, dispersing agents and emulsifying agents may
be SFAs of the cationic, anionic, amphoteric or non-ionic type.
[0081] Suitable SFAs of the cationic type include quaternary
ammonium compounds (for example cetyltrimethyl ammonium bromide),
imidazolines and amine salts.
[0082] Suitable anionic SFAs include alkali metals salts of fatty
acids, salts of aliphatic monoesters of sulphuric acid (for example
sodium lauryl sulphate), salts of sulphonated aromatic compounds
(for example sodium dodecylbenzenesulphonate, calcium
dodecylbenzenesulphonate, butylnaphthalene sulphonate and mixtures
of sodium di-isopropyl- and tri-isopropyl-naphthalene sulphonates),
ether sulphates, alcohol ether sulphates (for example sodium
laureth-3-sulphate), ether carboxylates (for example sodium
laureth-3-carboxylate), phosphate esters (products from the
reaction between one or more fatty alcohols and phosphoric acid
(predominately mono-esters) or phosphorus pentoxide (predominately
di-esters), for example the reaction between lauryl alcohol and
tetraphosphoric acid; additionally these products may be
ethoxylated), sulphosuccinamates, paraffin or olefine sulphonates,
taurates and lignosulphonates.
[0083] Suitable SFAs of the amphoteric type include betaines,
propionates and glycinates.
[0084] Suitable SFAs of the non-ionic type include condensation
products of alkylene oxides, such as ethylene oxide, propylene
oxide, butylene oxide or mixtures thereof, with fatty alcohols
(such as oleyl alcohol or cetyl alcohol) or with alkylphenols (such
as octylphenol, nonylphenol or octylcresol); partial esters derived
from long chain fatty acids or hexitol anhydrides; condensation
products of said partial esters with ethylene oxide; block polymers
(comprising ethylene oxide and propylene oxide); alkanolamides;
simple esters (for example fatty acid polyethylene glycol esters);
amine oxides (for example lauryl dimethyl amine oxide); and
lecithins.
[0085] Suitable suspending agents include hydrophilic colloids
(such as polysaccharides, polyvinylpyrrolidone or sodium
carboxymethylcellulose) and swelling clays (such as bentonite or
attapulgite).
[0086] Herbicidal compositions as described herein may further
comprise at least one additional pesticide. For example, the
compounds of formula (I) can also be used in combination with other
herbicides or plant growth regulators. In a preferred embodiment
the additional pesticide is a herbicide and/or herbicide safener.
Examples of such mixtures are, in which `I` represents a compound
of Formula (I), I+acetochlor, I+acifluorfen, I+acifluorfen-sodium,
I+aclonifen, I+acrolein, I+alachlor, I+alloxydim, I+ametryn,
I+amicarbazone, I+amidosulfuron, I+aminopyralid, I+amitrole,
I+anilofos, I+asulam, I+atrazine, I+azafenidin, I+azimsulfuron,
I+BCPC, I+beflubutamid, I+benazolin, I+bencarbazone, I+benfluralin,
I+benfuresate, I+bensulfuron, I+bensulfuron-methyl, I+bensulide,
I+bentazone, I+benzfendizone, I+benzobicyclon, I+benzofenap,
I+bicyclopyrone, I+bifenox, I+bilanafos, I+bispyribac,
I+bispyribac-sodium, I+borax, I+bromacil, I+bromobutide,
I+bromoxynil, I+butachlor, I+butamifos, I+butralin, I+butroxydim,
I+butylate, I+cacodylic acid, I+calcium chlorate, I+cafenstrole,
I+carbetamide, I+carfentrazone, I+carfentrazone-ethyl,
I+chlorflurenol, I+chlorflurenol-methyl, I+chloridazon,
I+chlorimuron, I+chlorimuron-ethyl, I+chloroacetic acid,
I+chlorotoluron, I+chlorpropham, I+chlorsulfuron, I+chlorthal,
I+chlorthal-dimethyl, I+cinidon-ethyl, I+cinmethylin,
I+cinosulfuron, I+cisanilide, I+clethodim, I+clodinafop,
I+clodinafop-propargyl, I+clomazone, I+clomeprop, I+clopyralid,
I+cloransulam, I+cloransulam-methyl, I+cyanazine, I+cycloate,
I+cyclosulfamuron, I+cycloxydim, I+cyhalofop, I+cyhalofop-butyl,
I+2,4-D, I+daimuron, I+dalapon, I+dazomet, I+2,4-DB,
I+I+desmedipham, I+dicamba, I+dichlobenil, I+dichlorprop,
I+dichlorprop-P, I+diclofop, I+diclofop-methyl, I+diclosulam,
I+difenzoquat, I+difenzoquat metilsulfate, I+diflufenican,
I+diflufenzopyr, I+dimefuron, I+dimepiperate, I+dimethachlor,
I+dimethametryn, I+dimethenamid, I+dimethenamid-P, I+dimethipin,
I+dimethylarsinic acid, I+dinitramine, I+dinoterb, I+diphenamid,
I+dipropetryn, I+diquat, I+diquat dibromide, I+dithiopyr, I+diuron,
I+endothal, I+EPTC, I+esprocarb, I+ethalfluralin,
I+ethametsulfuron, I+ethametsulfuron-methyl, I+ethephon,
I+ethofumesate, I+ethoxyfen, I+ethoxysulfuron, I+etobenzanid,
I+fenoxaprop-P, I+fenoxaprop-P-ethyl, I+fentrazamide, I+ferrous
sulfate, I+flamprop-M, I+flazasulfuron, I+florasulam, I+fluazifop,
I+fluazifop-butyl, I+fluazifop-P, I+fluazifop-P-butyl,
I+fluazolate, I+flucarbazone, I+flucarbazone-sodium,
I+flucetosulfuron, I+fluchloralin, I+flufenacet, I+flufenpyr,
I+flufenpyr-ethyl, I+flumetralin, I+flumetsulam, I+flumiclorac,
I+flumiclorac-pentyl, I+flumioxazin, I+flumipropin, I+fluometuron,
I+fluoroglycofen, I+fluoroglycofen-ethyl, I+fluoxaprop, I+flupoxam,
I+flupropacil, I+flupropanate, I+flupyrsulfuron,
I+flupyrsulfuron-methyl-sodium, I+flurenol, I+fluridone,
I+flurochloridone, I+fluroxypyr, I+flurtamone, I+fluthiacet,
I+fluthiacet-methyl, I+fomesafen, I+foramsulfuron, I+fosamine,
I+glufosinate, I+glufosinate-ammonium, I+glyphosate, I+halauxifen,
I+halosulfuron, I+halosulfuron-methyl, I+haloxyfop, I+haloxyfop-P,
I+hexazinone, I+imazamethabenz, I+imazamethabenz-methyl,
I+imazamox, I+imazapic, I+imazapyr, I+imazaquin, I+imazethapyr,
I+imazosulfuron, I+indanofan, I+indaziflam, I+iodomethane,
I+iodosulfuron, I+iodosulfuron-methyl-sodium, I+ioxynil,
I+isoproturon, I+isouron, I+isoxaben, I+isoxachlortole,
I+isoxaflutole, I+isoxapyrifop, I+karbutilate, I+lactofen,
I+lenacil, I+linuron, I+mecoprop, I+mecoprop-P, I+mefenacet,
I+mefluidide, I+mesosulfuron, I+mesosulfuron-methyl, I+mesotrione,
I+metam, I+metamifop, I+metamitron, I+metazachlor,
I+methabenzthiazuron, I+methazole, I+methylarsonic acid,
I+methyldymron, I+methyl isothiocyanate, I+metolachlor,
I+S-metolachlor, I+metosulam, I+metoxuron, I+metribuzin,
I+metsulfuron, I+metsulfuron-methyl, I+molinate, I+monolinuron,
I+naproanilide, I+napropamide, I+naptalam, I+neburon,
I+nicosulfuron, I+n-methyl glyphosate, I+nonanoic acid,
I+norflurazon, I+oleic acid (fatty acids), I+orbencarb,
I+orthosulfamuron, I+oryzalin, I+oxadiargyl, I+oxadiazon,
I+oxasulfuron, I+oxaziclomefone, I+oxyfluorfen, I+paraquat,
I+paraquat dichloride, I+pebulate, I+pendimethalin, I+penoxsulam,
I+pentachlorophenol, I+pentanochlor, I+pentoxazone, I+pethoxamid,
I+phenmedipham, I+picloram, I+picolinafen, I+pinoxaden,
I+piperophos, I+pretilachlor, I+primisulfuron,
I+primisulfuron-methyl, I+prodiamine, I+profoxydim,
I+prohexadione-calcium, I+prometon, I+prometryn, I+propachlor,
I+propanil, I+propaquizafop, I+propazine, I+propham,
I+propisochlor, I+propoxycarbazone, I+propoxycarbazone-sodium,
I+propyzamide, I+prosulfocarb, I+prosulfuron, I+pyraclonil,
I+pyraflufen, I+pyraflufen-ethyl, I+pyrasulfotole, I+pyrazolynate,
I+pyrazosulfuron, I+pyrazosulfuron-ethyl, I+pyrazoxyfen,
I+pyribenzoxim, I+pyributicarb, I+pyridafol, I+pyridate,
I+pyriftalid, I+pyriminobac, I+pyriminobac-methyl, I+pyrimisulfan,
I+pyrithiobac, I+pyrithiobac-sodium, I+pyroxasulfone, I+pyroxsulam,
I+quinclorac, I+quinmerac, I+quinoclamine, I+quizalofop,
I+quizalofop-P, I+rimsulfuron, I+saflufenacil, I+sethoxydim,
I+siduron, I+simazine, I+simetryn, I+sodium chlorate,
I+sulcotrione, I+sulfentrazone, I+sulfometuron,
I+sulfometuron-methyl, I+sulfosate, I+sulfosulfuron, I+sulfuric
acid, I+tebuthiuron, I+tefuryltrione, I+tembotrione,
I+tepraloxydim, I+terbacil, I+terbumeton, I+terbuthylazine,
I+terbutryn, I+thenylchlor, I+thiazopyr, I+thifensulfuron,
I+thiencarbazone, I+thifensulfuron-methyl, I+thiobencarb,
I+topramezone, I+tralkoxydim, I+tri-allate, I+triasulfuron,
I+triaziflam, I+tribenuron, I+tribenuron-methyl, I+triclopyr,
I+trietazine, I+trifloxysulfuron, I+trifloxysulfuron-sodium,
I+trifluralin, I+triflusulfuron, I+triflusulfuron-methyl,
I+trihydroxytriazine, I+trinexapac-ethyl, I+tritosulfuron,
I+[3-[2-chloro-4-fluoro-5-(1-methyl-6-trifluoromethyl-2,4-dioxo-1,2,3,4-t-
etrahydropyrimidin-3-yl)phenoxy]-2-pyridyloxy]acetic acid ethyl
ester (CAS RN 353292-31-6). The compounds of formula (I) and/or
compositions of the present invention may also be combined with
herbicidal compounds disclosed in WO06/024820 and/or
WO07/096576.
[0087] 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, Sixteenth Edition, British Crop Protection
Council, 2012.
[0088] The compound of Formula (I) can also be used in mixtures
with other agrochemicals such as fungicides, nematicides or
insecticides, examples of which are given in The Pesticide Manual
(supra).
[0089] The mixing ratio of the compound of Formula (I) to the
mixing partner is preferably from 1:100 to 1000:1.
[0090] 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).
[0091] The compounds of Formula (I) as described herein can also be
used in combination with one or more safeners. Likewise, mixtures
of a compound of Formula (I) as described herein with one or more
further herbicides can also be used in combination with one or more
safeners. The safeners can be AD 67 (MON 4660), benoxacor,
cloquintocet-mexyl, cyprosulfamide (CAS RN 221667-31-8),
dichlormid, fenchlorazole-ethyl, fenclorim, fluxofenim, furilazole
and the corresponding R isomer, isoxadifen-ethyl, mefenpyr-diethyl,
oxabetrinil, N-isopropyl-4-(2-methoxy-benzoylsulfamoyl)-benzamide
(CAS RN 221668-34-4). Other possibilities include safener compounds
disclosed in, for example, EP0365484 e.g
N-(2-methoxybenzoyl)-4-[(methylaminocarbonyl)amino]benzenesulfonamide.
Particularly preferred are mixtures of a compound of Formula I with
cyprosulfamide, isoxadifen-ethyl, cloquintocet-mexyl and/or
N-(2-methoxybenzoyl)-4-[(methyl-aminocarbonyl)amino]benzenesulfonamide.
[0092] 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 (supra). The reference to cloquintocet-mexyl also applies to
a lithium, sodium, potassium, calcium, magnesium, aluminium, iron,
ammonium, quaternary ammonium, sulfonium or phosphonium salt
thereof as disclosed in WO 02/34048, and the reference to
fenchlorazole-ethyl also applies to fenchlorazole, etc.
[0093] 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.
[0094] 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 safener).
[0095] As described above, compounds of formula (I) and/or
compositions comprising such compounds may be used in methods of
controlling unwanted plant growth, and in particular in controlling
unwanted plant growth in crops of useful plants. Thus, the present
invention further provides a method of selectively controlling
weeds at a locus comprising crop plants and weeds, wherein the
method comprises application to the locus, of a weed-controlling
amount of a compound of formula (I), or a composition as described
herein. `Controlling` means killing, reducing or retarding growth
or preventing or reducing germination. Generally the plants to be
controlled are unwanted plants (weeds). `Locus` means the area in
which the plants are growing or will grow.
[0096] 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 weed(s) 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.
[0097] The application is generally made by spraying the
composition, typically by tractor mounted sprayer for large areas,
but other methods such as dusting (for powders), drip or drench can
also be used.
[0098] Useful plants in which the composition according to the
invention can be used include crops such as cereals, for example
barley and wheat, cotton, oilseed rape, sunflower, maize, rice,
soybeans, sugar beet, sugar cane and turf.
[0099] Crop plants can also include trees, such as fruit trees,
palm trees, coconut trees or other nuts. Also included are vines
such as grapes, fruit bushes, fruit plants and vegetables.
[0100] Crops are to be understood as also including those crops
which have been rendered tolerant to herbicides or classes of
herbicides (e.g. ALS-, GS-, EPSPS-, PPO-, ACCase- 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., as well as
those where the crop plant has been engineered to over-express
homogentisate solanesyltransferase as taught in, for example,
WO2010/029311.
[0101] 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
synthesise 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.
[0102] Crops are also to be understood to include 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 flavour).
[0103] Other useful plants include turf grass for example in
golf-courses, lawns, parks and roadsides, or grown commercially for
sod, and ornamental plants such as flowers or bushes.
[0104] The compositions can be used to control unwanted plants
(collectively, `weeds`). The weeds to be controlled include both
monocotyledonous (e.g. grassy) species, for example: Agrostis,
Alopecurus, Avena, Brachiaria, Bromus, Cenchrus, Cyperus,
Digitaria, Echinochloa, Eleusine, Lolium, Monochoria, Rottboellia,
Sagittaria, Scirpus, Setaria and Sorghum; and dicotyledonous
species, for example: Abutilon, Amaranthus, Ambrosia, Chenopodium,
Chrysanthemum, Conyza, Galium, Ipomoea, Kochia, Nasturtium,
Polygonum, Sida, Sinapis, Solanum, Stellaria, Veronica, Viola and
Xanthium. Weeds can also include plants which may be considered
crop plants but which are growing outside a crop area (`escapes`),
or which grow from seed left over from a previous planting of a
different crop (`volunteers`). Such volunteers or escapes may be
tolerant to certain other herbicides.
[0105] Preferably the weeds to be controlled and/or
growth-inhibited, include monocotyledonous weeds, more preferably
grassy monocotyledonous weeds, in particular those from the
following genus: Agrostis, Alopecurus, Apera, Avena, Brachiaria,
Bromus, Cenchrus, Cyperus (a genus of sedges), Digitaria,
Echinochloa, Eleusine, Eriochloa, Fimbristylis (a genus of sedges),
Juncus (a genus of rushes), Leptochloa, Lolium, Monochoria,
Ottochloa, Panicum, Pennisetum, Phalaris, Poa, Rottboellia,
Sagittaria, Scirpus (a genus of sedges), Setaria and/or Sorghum,
and/or volunteer corn (volunteer maize) weeds; in particular:
Alopecurus myosuroides (ALOMY, English name "blackgrass"), Apera
spica-venti, Avena fatua (AVEFA, English name "wild oats"), Avena
ludoviciana, Avena sterilis, Avena sativa (English name "oats"
(volunteer)), Brachiaria decumbens, Brachiaria plantaginea,
Brachiaria platyphylla (BRAPP), Bromus tectorum, Digitaria
horizontalis, Digitaria insularis, Digitaria sanguinalis (DIGSA),
Echinochloa crus-galli (English name "common barnyard grass",
ECHCG), Echinochloa oryzoides, Echinochloa colona or colonum,
Eleusine indica, Eriochloa villosa (English name "woolly
cupgrass"), Leptochloa chinensis, Leptochloa panicoides, Lolium
perenne (LOLPE, English name "perennial ryegrass"), Lolium
multiflorum (LOLMU, English name "Italian ryegrass"), Lolium
persicum (English name "Persian darnel"), Lolium rigidum, Panicum
dichotomiflorum (PANDI), Panicum miliaceum (English name "wild
proso millet"), Phalaris minor, Phalaris paradoxa, Poa annua
(POAAN, English name "annual bluegrass"), Scirpus maritimus,
Scirpus juncoides, Setaria viridis (SETVI, English name "green
foxtail"), Setaria faberi (SETFA, English name "giant foxtail"),
Setaria glauca, Setaria lutescens (English name "yellow foxtail"),
Sorghum bicolor, and/or Sorghum halepense (English name "Johnson
grass"), and/or Sorghum vulgare; and/or volunteer corn (volunteer
maize) weeds.
[0106] In one embodiment, grassy monocotyledonous weeds to be
controlled comprise weeds from the genus: Agrostis, Alopecurus,
Apera, Avena, Brachiaria, Bromus, Cenchrus, Digitaria, Echinochloa,
Eleusine, Eriochloa, Leptochloa, Lolium, Ottochloa, Panicum,
Pennisetum, Phalaris, Poa, Rottboellia, Setaria and/or Sorghum,
and/or volunteer corn (volunteer maize) weeds; in particular: weeds
from the genus Agrostis, Alopecurus, Apera, Avena, Brachiaria,
Bromus, Cenchrus, Digitaria, Echinochloa, Eleusine, Eriochloa,
Leptochloa, Lolium, Panicum, Phalaris, Poa, Rottboellia, Setaria,
and/or Sorghum, and/or volunteer corn (volunteer maize) weeds.
[0107] In a further embodiment, the grassy monocotyledonous weeds
are "warm-season" (warm climate) grassy weeds; in which case they
preferably comprise (e.g. are): weeds from the genus Brachiaria,
Cenchrus, Digitaria, Echinochloa, Eleusine, Eriochloa, Leptochloa,
Ottochloa, Panicum, Pennisetum, Phalaris, Rottboellia, Setaria
and/or Sorghum, and/or volunteer corn (volunteer maize) weeds. More
preferably, the grassy monocotyledonous weeds, e.g. to be
controlled and/or growth-inhibited, are "warm-season" (warm
climate) grassy weeds comprising (e.g. being): weeds from the genus
Brachiaria, Cenchrus, Digitaria, Echinochloa, Eleusine, Eriochloa,
Panicum, Setaria and/or Sorghum, and/or volunteer corn (volunteer
maize) weeds.
[0108] In another particular embodiment the grassy monocotyledonous
weeds, are "cool-season" (cool climate) grassy weeds; in which case
they typically comprise weeds from the genus Agrostis, Alopecurus,
Apera, Avena, Bromus, Lolium and/or Poa.
[0109] 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.
PREPARATION EXAMPLES
[0110] Throughout the following examples, 1H NMR spectra were
recorded at 400 MHz or 500 MHz, unless otherwise stated, either on
a Varian Unity Inova instrument or Bruker AVANCE-II instrument.
[0111] The following abbreviations are used: s=singlet; d=doublet;
dd=double doublet; t=triplet, q=quartet; m=multiplet. The term app.
is used for apparent and br. denotes a broader signal.
[0112] Molecules are given their known names or named according to
the naming programs within Accelrys Draw 4.0 or Symyx Notebook 6.6.
If such programs are unable to name a molecule, the molecule is
named using agreed naming conventions.
Example 1 Preparation of compound A1 (tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate)
1.1 Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate
ethyl ester (compound 1.1001)
##STR00102##
[0114] To a flask charged with thionicotinamide (10 g, 72.3 mmol)
was added ethyl-2-chloroacetoacetate (11.9 g, 72.4 mmol) and heated
at reflux in ethanol (100 mL) overnight. The next morning solvent
was removed in vacuo and the residue partitioned between EtOAc and
sat. aq. NaHCO.sub.3 solution. The aqueous phase was extracted with
two further portions of EtOAc. The combined organic extracts were
washed with brine then dried over MgSO.sub.4 and concentrated in
vacuo. The resulting mixture was purified via flash chromatography
on silica gel using an EtOAc/isohexane gradient to give the desired
compound (4-methyl-2-(3-pyridyl)thiazole-5-carboxylate ethyl ester,
11.9 g) as a pale brown oil which slowly solidified.
[0115] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.17 (1H, m), 8.69 (1H,
dd), 8.24 (1H, m), 7.40 (1H, m), 4.37 (2H, q), 2.80 (3H, s), 1.40
(3H, t)
1.2 Preparation of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid
(1.2001)
##STR00103##
[0117] A solution of 4-methyl-2-(3-pyridyl)thiazole-5-carboxylate
ethyl ester (compound 1.1001; 35.2 g, 142 mmol) in methanol (462
mL) was cooled in ice/water then a solution of NaOH (17.0 g, 425
mmol) in water (214 mL) was added slowly with stirring and stirred
without cooling for one hour.
[0118] 2M HCl (216 mL) was added slowly with stirring and ice/water
cooling. The mixture was stirred for a further 30 mins. The
resulting precipitate was filtered, washed with water and air-dried
to give the desired compound
(4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid, 28.1 g) as an
off white solid.
[0119] 1H NMR (400 MHz, d6-DMSO) .delta.=13.54 (1H, br. s.), 9.16
(1H, d), 8.72 (1H, dd), 8.35 (1H, m), 7.56 (1H, dd) 2.70 (3H,
s)
1.3 Preparation of tert-butyl
N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (1.3001)
##STR00104##
[0121] To a suspension of
4-methyl-2-(3-pyridyl)thiazole-5-carboxylic acid (compound 1.2001;
22.4 g, 101.7 mmol) in 2-methylpropan-2-ol (448 mL) and toluene
(448 mL) was added Et.sub.3N (14.2 mL, 101 mmol) and the reaction
stirred for five minutes at room temperature before DPPA (27.8 g,
101 mmol) was added slowly with stirring and cooling to maintain
the temperature below ambient. The reaction was heated gradually to
reflux for 3 hours, then allowed to cool overnight to room
temperature.
[0122] The solvent was removed in vacuo and the residue purified
via flash column chromatography on silica gel using an
EtOAc/isohexane gradient to give the desired compound (tert-butyl
N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.8 g) as a beige
solid.
[0123] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.09 (1H, s), 8.59 (1H,
d), 8.16 (1H, dd), 7.36 (1H, m), 6.72 (1H, br. s), 2.37 (3H, s),
1.49 (9H, br. s.)
1.4 Preparation of tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A1)
##STR00105##
[0125] A solution of tert-butyl
N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (compound 1.3001;
21.2 g, 72.7 mmol) in anhydrous DMF (245 mL) was cooled in
ice/water and NaH 60% w/w (3.49 g, 87.3 mmol) was added
portion-wise with stirring, then warmed to ambient over 5 minutes.
The mixture was re-cooled in ice/water and then a solution of MeI
(11.35 g, 80.0 mmol) in dry DMF (5 mL) was added dropwise with
stirring and cooling over 30 minutes. The reaction was stirred at
room temperature overnight and then cautiously quenched with water
(1000 mL) and 2M HCl (7.29 mL). The reaction mixture was extracted
three times with EtOAc, the combined organic extracts were washed
twice with brine then dried over MgSO.sub.4. The solvent was
removed in vacuo and the residue purified via flash chromatography
on silica gel using an EtOAc/isohexane gradient to give the desired
compound (tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 25.1 g)
as a beige solid.
[0126] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.63 (1H,
dd), 8.17 (1H, d), 7.36 (1H, dd), 3.22 (3H, s), 2.33 (3H, s), 1.44
(9H, br.s.)
Example 2 Preparation of tert-butyl
N-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate
(A2)
##STR00106##
[0128] To a flask charged with pyrimidin-5-ylboronic acid (150.0
mg, 1.21 mmol) was added EtOH (2.7 mL) and toluene (5.3 mL) then 2M
aq. K.sub.2CO.sub.3 (1.2 mL, 2.4 mmol) was added. The reaction was
set stirring and tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (409 mg, 1.33
mmol) was added, followed by Pd(PPh.sub.3).sub.4 (70 mg, 0.06
mmol). The mixture was heated at 90.degree. C. for two hours and
then allowed to cool overnight to ambient.
[0129] The mixture was diluted with EtOAc and washed twice with
brine. The combined aqueous washings were back-extracted with EtOAc
and the combined organic extracts were washed with brine and then
dried over MgSO.sub.4. The solvent was removed in vacuo and the
residue purified via flash column chromatography on silica gel
using an EtOAc/isohexane gradient to afford the desired compound
(tert-butyl
N-methyl-N-(4-methyl-2-pyrimidin-5-yl-thiazol-5-yl)carbamate, 170
mg) as a straw coloured gum.
[0130] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.23 (1H, s), 9.18 (2H,
s), 3.23 (3H, s), 2.35 (3H, s), 1.45 (9H, br.s.)
Example 3 Preparation of tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate
(A3)
##STR00107##
[0132] To a flask charged with tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (8.78 g, 27.8
mmol) and (5-fluoro-3-pyridyl)boronic acid (4.71 g, 33.4 mmol) was
added ethanol (55.7 mL) and toluene (111.6 mL). Pd(PPh.sub.3).sub.4
(1.50 g, 1.30 mmol) was added and the mixture stirred vigorously.
2M aq. K.sub.2CO.sub.3 (25.5 mL, 51.0 mmol) was added and the
reaction was heated to reflux for 7 hours, then left to cool to
ambient overnight.
[0133] Solvent was removed in vacuo and the crude material was
re-dissolved in CHC1.sub.3 and washed with water. The organic phase
was concentrated in vacuo and the residue purified via flash column
chromatography on silica gel using an EtOAc/isohexane gradient to
give the desired compound (tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate,
6.92 g) as a beige solid.
[0134] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.85-8.89 (1H, m), 8.49
(1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H,
br.s).
Example 4 Preparation of tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (A35)
4.1 Preparation of Compound A35
##STR00108##
[0136] To a flask charged with tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (11.31 g, 38.6 mmol) and
(5-fluoro-3-pyridyl)boronic acid (6.52 g, 46.3 mmol) was added
toluene (151 mL) and ethanol (75 mL). Pd(PPh.sub.3).sub.4 (2.20 g,
1.90 mmol) was added, followed by 2M aq K.sub.2CO.sub.3 (38.6 mL,
77.2 mmol). The reaction was heated to reflux for five and a half
hours. The reaction mixture was cooled to room temperature and
concentrated in vacuo to remove the organics. The mixture was
diluted with CHCl.sub.3 and washed with water. The organic phase
was concentrated in vacuo and the residue purified via flash column
chromatography on silica using an EtOAc/isohexane gradient to
afford the desired compound (tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 10.2 g)
as a beige solid.
[0137] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.87 (1H, m), 8.44 (1H,
d), 7.94-7.87 (1H, m), 6.73 (1H, br. s), 2.39 (3H, s), 1.55 (9H,
s)
4.2 Alternative preparation of tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate
(A3)
[0138] Compound A35 may also be used as an intermediate in an
alternative method of producing compound A3.
##STR00109##
[0139] To a round bottomed flask charged with tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg,
2.59 mmol) and K.sub.2CO.sub.3 (429 mg, 3.10 mmol) was added
iodomethane (807 mg, 5.69 mmol) as a solution in MeCN (20 mL) and
the mixture set vigorously stirring. After 5 minutes the reaction
was heated to reflux for 2 hours. Upon cooling the mixture was
filtered through celite and concentrated in vacuo. The resulting
semi-solid was purified via flash column chromatography on silica
gel using an EtOAc/isohexane gradient to afford the desired
compound (tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate,
449 mg) as a yellow gum.
[0140] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.85-8.89 (1H, m), 8.49
(1H, d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H,
br.s.)
Example 5 Preparation of tert-butyl
N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carb-
amate (A16)
5.1 Preparation of tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (compound 5.1001)
##STR00110##
[0142] To a flask charged with
2-bromo-4-methyl-thiazole-5-carboxylic acid (5.0 g, 22.5 mmol) and
Et.sub.3N (3.14 mL, 22.5 mmol) was added t-BuOH (193 mL) and the
mixture was heated to reflux. DPPA (4.89 mL, 22.5 mmol) was added
dropwise over ca. 15 mins, then stirred at reflux for a further 6.5
hours, then allowed to cool overnight.
[0143] The reaction mixture was concentrated in vacuo and the
residue was diluted with EtOAc (95 mL) and washed with water (140
mL). The aqueous phase was back-extracted twice more with EtOAc and
the combined organics were washed with brine and dried over
MgSO.sub.4. The solvent was removed in vacuo and the residue
purified via flash column chromatography on silica gel using an
EtOAc/isohexane gradient to afford the desired compound (tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)carbamate, 5.4 g) as an opaque
gum.
[0144] 1H NMR (400 MHz, CDCl.sub.3) 6.32 (1H, br. s), 2.29 (3H, s),
1.51 (9H, s)
5.2 Preparation of tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (5.2001)
##STR00111##
[0146] To a flask charged with tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)carbamate (32.0 g, 109.12 mmol)
was added DMF (130 mL), the reaction was cooled in an ice bath and
NaH 60% w/w (4.8 g, 120 mmol) added portion-wise with stirring and
cooling to maintain the temperature in the range 5-10.degree. C.
The mixture was stirred for 10 mins then allowed to warm to ambient
over ca. 40 mins. The reaction was cooled in an ice bath then
iodomethane (16.27 g, 114.6 mmol) in DMF (100 mL) was added slowly
with stirring and cooling to maintain the temperature in the range
5-10.degree. C. The reaction was allowed to warm to ambient and
stirred for a further 5 hours. The reaction mixture was cooled in
an ice bath and quenched by the cautious addition of water (920
mL).
[0147] The reaction mixture was extracted three times with EtOAc
and the combined organics washed with brine and dried over
MgSO.sub.4. The solvent was removed in vacuo and the residue
purified via flash column chromatography on silica gel eluting with
an EtOAc/isohexane gradient to afford the desired compound
(tert-butyl N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate,
33.2 g) as a colourless oil.
[0148] 1H NMR (400 MHz, CDCl.sub.3) .delta.=1.43 (9H, br. s.), 2.24
(3H, s), 3.16 (3H, s)
5.3 Preparation of
3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridi-
ne (5.3001)
##STR00112##
[0150] To a flask charged with 3-bromo-5-(difluoromethoxy)pyridine
(4.50 g, 20.1 mmol) was added bispinacolatodiboron (7.65 g, 30.1
mmol), [1,1'-bis(diphenylphosphino)-ferrocene]palladium(ii)
dichloride dichloromethane adduct (837 mg, 1.00 mmol) and KOAc (6.5
g, 64.0 mmol). 1,4-Dioxane (95 mL) was added and the mixture was
purged with dry N.sub.2 and heated at 100.degree. C. for 1
hour.
[0151] The reaction was cooled to ambient and concentrated in
vacuo. The residue was dissolved in CH.sub.2Cl.sub.2 and filtered
through celite. The filtrate was concentrated in vacuo to give a
thick black oil which was purified via flash column chromatography
on silica gel using an EtOAc/isohexane gradient to afford the
desired compound
(3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrid-
ine, 3.95 g) as a straw coloured oil which crystallized on
standing.
[0152] .sup.11H NMR (400 MHz, CDCl.sub.3) .delta.=8.80 (1H, d),
8.54 (1H, d), 7.82 (1H, m), 6.76-6.36 (1H, t), 1.36 (12H, s)
5.4 Preparation of tert-butyl
N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carb-
amate (A16)
##STR00113##
[0154] To a microwave vial charged with tert-butyl
N-(2-bromo-4-methyl-thiazol-5-yl)-N-methyl-carbamate (500 mg, 1.59
mmol) and
3-(difluoromethoxy)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)py-
ridine (430 mg, 1.59 mmol) was added EtOH (2 mL) and toluene (4
mL). Pd(PPh.sub.3).sub.4 (85.3 mg, 0.074 mmol) was added, followed
by 2M K.sub.2CO.sub.3 (1.45 mL, 2.90 mmol) and the tube sealed. The
mixture was heated to 130 C for 30 minutes under microwave
irradiation.
[0155] Upon cooling the solvent was removed in vacuo and residue
partitioned between CHCl.sub.3 and water. The organic phase was
concentrated in vacuo to give a black gum which was purified via
flash column chromatography on silica gel using a EtOAc/isohexane
gradient to afford impure tert-butyl
N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carb-
amate. This material was further purified via flash column
chromatography on a C.sub.18 reverse phase column using a water
(0.1% formic acid modifier)/MeCN (0.1% formic acid modifier)
gradient to afford the desired compound (tert-butyl
N-[2-[5-(difluoromethoxy)-3-pyridyl]-4-methyl-thiazol-5-yl]-N-methyl-carb-
amate, 352 mg).
[0156] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.91 (1H, d), 8.50 (1H,
d), 7.99 (1H, s), 6.82-6.41 (1H, t), 3.23 (3H, s), 2.33 (3H, s),
1.45 (9H, br. s)
Example 6 Preparation of ethyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A19)
##STR00114##
[0158] To a flask charged with
N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine (300.0 mg, 1.46 mmol)
dissolved in CH.sub.2Cl.sub.2 (4 mL) was added pyridine (173.4 mg,
2.192 mmol) and DMAP (17.9 mg, 0.147 mmol). The reaction mixture
was cooled in an ice bath and a solution of ethyl chloroformate
(206 mg, 1.90 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added drop-wise.
After one hour at ambient the solvent was removed in vacuo. The
residue was partitioned between water and EtOAc and the organic
phase washed once with brine then dried (MgSO.sub.4). The solvent
was removed in vacuo and the residue purified via flash column
chromatography on silica gel using an EtOAc/isohexane gradient as
eluent to afford the target compound (ethyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 280 mg)
as a straw coloured gum.
[0159] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.64 (1H,
dd), 8.17 (1H, m), 7.37 (1H, dd), 4.20 (2H, q), 3.27 (3H, s), 2.33
(3H, s), 1.24 (3H, app. br. s)
Example 7 Preparation of
3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea
(A21)
7.1 Preparation of
2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-amine hydrochloride
(7.1001)
##STR00115##
[0161] To a solution of tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate
(4.23 g, 13.1 mmol) in CH.sub.2Cl.sub.2 (66 mL), cooled with an ice
bath, was added 2M hydrogen chloride in Et.sub.2O (65.4 mL, 130.7
mmol) slowly with stirring. The mixture was stirred in the ice bath
for a further 5 minutes then allowed to stand overnight and stirred
at ambient for a further 2 days.
[0162] Concentration in vacuo yielded the desired compound
(2-(5-fluoro-3-pyridyl)-N,4-dimethyl-thiazol-5-amine hydrochloride,
3.84 g) as an orange solid.
[0163] 1H NMR (400 MHz, d6-DMSO) .delta.=8.79 (1H, m), 8.51 (1H,
d), 8.01 (1H, m), 2.85 (3H, s), 2.25 (3H, s)
7.2 Preparation of
3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea
(A21)
##STR00116##
[0165] A solution of N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine
hydrochloride (600.0 mg, 2.92 mmol) in CH.sub.2Cl.sub.2 (9 mL) was
cooled in an ice bath and a solution of t-butylisocyanate (348 mg,
3.51 mmol) in CH.sub.2Cl.sub.2 (1 mL) was added drop-wise. The
reaction was allowed to warm to ambient and allowed to stir for 3
days.
[0166] The solvent was removed in vacuo and the residue purified
via flash column chromatography on silica gel eluted with a
CH.sub.2Cl.sub.2/EtOAc gradient to afford the desired compound
(3-tert-butyl-1-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]urea,
300 mg) as a white solid.
[0167] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.12 (1H, d), 8.67 (1H,
dd), 8.19 (1H, m), 7.39 (1H, dd), 4.48 (1H, br. s), 3.20 (3H, s),
2.35 (3H, s), 1.30 (9H, br. s)
Example 8 Preparation of S-tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate
(A22)
##STR00117##
[0169] To a flask charged with
N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride (300.0 mg,
1.46 mmol) was added CH.sub.2Cl.sub.2 (4 mL), pyridine (173.4 mg,
2.19 mmol) and DMAP (17.9 mg, 0.15 mmol). The reaction mixture was
cooled in an ice bath and a solution of S-tert-butyl
chlorothioformate (290 mg, 1.90 mmol) in CH.sub.2Cl.sub.2 (1 mL)
was added drop-wise. The reaction was allowed to stir at ambient
for one hour.
[0170] The solvent was removed in vacuo and the residue partitioned
between water and EtOAc. The organic phase was washed with brine
then dried (MgSO.sub.4). Concentration in vacuo afforded a thick
residue which was purified via flash column chromatography on
silica gel using an EtOAc/isohexane gradient to afford the desired
compound (S-tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamothioate, 290
mg) as a pale yellow gum.
[0171] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.12 (1H, d), 8.66 (1H,
dd), 8.20 (1H, m), 7.38 (1H, dd), 3.25 (3H, s), 2.35 (3H, s), 1.47
(9H, m)
Example 9 Preparation of tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate
(A23)
##STR00118##
[0173] To a flask charged with
N,4-dimethyl-2-(3-pyridyl)thiazol-5-amine hydrochloride (300.0 mg,
1.47 mmol) was added EtOH (1.0 mL). The mixture was cooled in an
ice bath and carbon disulphide (127 .mu.L, 2.11 mmol) was added
followed by K.sub.2CO.sub.3 (235 mg, 1.68 mmol). The mixture was
allowed to warm gradually to ambient overnight.
[0174] 2-Iodo-2-methyl-propane (194 .mu.L, 1.47 mmol) was added and
the reaction stirred at ambient for three days. The solvent was
removed in vacuo and the residue was partitioned between water and
EtOAc. The organic phase was washed once with brine and
concentrated in vacuo and the residue purified via flash column
chromatography on silica gel using an EtOAc/isohexane gradient to
afford the desired compound (tert-butyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamodithioate, 37
mg) as a pale yellow gum.
[0175] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.14 (1H, d), 8.68 (1H,
dd), 8.25 (1H, m), 7.44 (1H, m), 3.65 (3H, s), 2.32 (3H, s), 1.59
(9H, s)
Example 10 Preparation of tert-butyl
N-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carb-
amate (A28)
##STR00119##
[0177] To a microwave tube charged with tert-butyl
N-[2-bromo-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carbamate (200
mg, 0.55 mmol) and
3-methoxy-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine
(131 mg, 0.56 mmol) was added ethanol (1.2 mL) and toluene (2.4 mL)
then 2M K.sub.2CO.sub.3 (549 .mu.L, 1.1 mmol) followed by
Pd(PPh.sub.3).sub.4 (33 mg, 0.03 mmol). The tube was sealed and the
reaction was heated to 130.degree. C. for 20 mins under microwave
irradiation.
[0178] Upon cooling the solvent was removed in vacuo and the
residue dissolved in CHCl.sub.3, and washed with water. The
reaction mixture was concentrated in vacuo to leave a dark brown
gum, which was purified via flash column chromatography on silica
gel using an EtOAc/isohexane gradient to afford the desired
compound (tert-butyl
N-[2-(5-methoxy-3-pyridyl)-4-(trifluoromethyl)thiazol-5-yl]-N-methyl-carb-
amate, 92 mg) as a beige solid.
[0179] 1H NMR (500 MHz, CDCl.sub.3) .delta.=8.64 (1H, d), 8.40 (1H,
d), 7.77 (1H, br. s), 3.95 (3H, s), 3.26 (3H, s), 1.43 (9H, br.
s)
Example 11 Preparation of of tert-butyl
N-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A30)
##STR00120##
[0181] To a flask charged with tert-butyl
N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.52 mmol)
was added MeCN (3.0 mL), the mixture was purged with dry N.sub.2
then NBS (183 mg, 1.03 mmol) was added in a single portion. The
mixture was stirred for an hour at ambient and then left to stand
for 4 days.
[0182] The reaction mixture was concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
eluting with a EtOAc/isohexane gradient to afford the desired
compound (tert-butyl
N-[4-bromo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 110 mg)
as colourless gum.
[0183] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.70-8.64
(1H, m), 8.20 (1H, m), 7.42-7.37 (1H, m), 3.25 (3H, s), 1.46 (9H,
br. s)
Example 12 Preparation of tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A31)
##STR00121##
[0185] To a flask charged with tert-butyl
N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (1.1 g, 3.8 mmol)
was added MeCN (33 mL), the reaction was cooled in ice, purged with
dry N.sub.2 then NIS (1.78 g, 7.91 mmol) was added in a single
portion. The mixture was allowed to warm to ambient and stirred for
a further 7 days.
[0186] The reaction mixture was concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
eluting with a EtOAc/isohexane gradient to afford the desired
compound (tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.02 g) as
a beige solid.
[0187] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.67 (1H,
dd), 8.22 (1H, m), 7.40 (1H, dd), 3.24 (3H, s), 1.46 (9H, br.
s)
Example 13 Preparation of tert-butyl
N-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (A32)
##STR00122##
[0189] To a flask charged with tert-butyl
N-methyl-N-[2-(3-pyridyl)thiazol-5-yl]carbamate (150 mg, 0.51
mmol), dissolved in MeCN (6.1 mL) and purged with dry N.sub.2 was
added SelectFluor.RTM. (364.7 mg, 1.03 mmol) in a single portion.
The reaction was again flushed with dry N.sub.2 then stirred
ambientfor 5 hours. Water (15 mL) added then the mixture was
extracted three times with EtOAc. The combined organics were dried
(MgSO.sub.4) and the solvent was concentrated in vacuo. The residue
was purified via flash column chromatography on silica gel eluting
with an EtOAc/isohexane gradient to afford the desired compound
(tert-butyl
N-[4-fluoro-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 60 mg)
as a straw coloured gum.
[0190] 1H NMR (500 MHz, CDCl.sub.3) .delta.=9.06 (1H, d), 8.65 (1H,
d), 8.13 (1H, d), 7.38 (1H, dd), 3.30 (3H, br. s), 1.50 (9H, br.
s)
Example 14 Preparation of
3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione
(A33)
14.1 Preparation of 4-methyl-2-(3-pyridyl)thiazole (14.1001)
##STR00123##
[0192] To a flask charged with thionicotinamide (50 g, 361.8 mmol)
was added EtOH (300 mL) followed by chloroacetone (40 g, 432.3
mmol) and the mixture was heated to reflux overnight.
[0193] Upon cooling the solvent was removed in vacuo and the
residue was dissolved in water (400 mL) and made basic with
NaHCO.sub.3. This mixture was extracted three times with EtOAc and
the combined organics washed once with brine then dried
(MgSO.sub.4). The organics were concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
using an EtOAc/isohexane gradient to give the desired compound
(4-methyl-2-(3-pyridyl)thiazole, 38.8 g) as a straw coloured
oil.
[0194] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.15 (1H, d), 8.63 (1H,
dd), 8.22 (1H, m), 7.36 (1H, m), 6.95 (1H, s), 2.53 (3H, s)
14.2 Preparation of 5-bromo-4-methyl-2-(3-pyridyl)thiazole
(14.2001)
##STR00124##
[0196] 4-Methyl-2-(3-pyridyl)thiazole (10.0 g, 56.7 mmol) was
dissolved in DMF (100 mL) and NBS (11.1 g, 62.4 mmol) was added
with cooling to keep the temperature at below ambient. The reaction
was heated at 50 C for ca. 3 hours and left to cool overnight.
[0197] The reaction was quenched with water (400 mL) and extracted
three times with EtOAc. The combined organics were washed three
times with brine and dried (MgSO.sub.4).
[0198] The reaction mixture was concentrated in vacuo and the
residue was purified via flash column chromatography on silica gel
using an EtOAc/isohexane gradient to give
5-bromo-4-methyl-2-(3-pyridyl)thiazole (13.24 g, 51.9 mmol) as a
beige solid.
[0199] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.06 (1H, m) 8.66 (1H,
dd) 8.15 (1H, s) 7.35-7.41 (1H, m) 2.48 (3H, s)
14.3 Preparation of
3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione
(A33)
##STR00125##
[0201] To a microwave tube charged with
5-bromo-4-methyl-2-(3-pyridyl)thiazole (136 mg, 0.53 mmol) was
added 3-methylimidazolidine-2,4-dione (121.6 mg, 1.07 mmol) and
N,N'-dimethylethylenediamine (4.7 mg, 0.05 mmol) dissolved in
1,4-dioxane (3.2 mL). CuI (10.2 mg, 0.05 mmol) and K.sub.2CO.sub.3
(295 mg, 2.13 mmol) were added, the tube was sealed the mixture was
heated at 160.degree. C. for 1 hour under microwave
irradiation.
[0202] The solvent was removed in vacuo and the residue partitioned
between water and EtOAc, filtered to remove residual solid and
partitioned. The aqueous phase was extracted with two further
portions of EtOAc. The combined organic extracts were washed with
brine, dried (MgSO.sub.4), and concentrated in vacuo. The residue
was purified via reverse phase flash chromatography a C.sub.18
column eluted with a water and MeCN gradient to give the desired
compound
(3-methyl-1-[4-methyl-2-(3-pyridyl)thiazol-5-yl]imidazolidine-2,4-dione,
21 mg) as a white solid.
[0203] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.66 (1H,
dd), 8.17 (1H, m), 7.39 (1H, m), 4.28 (2H, s), 3.15 (3H, s), 2.43
(3H, s)
Example 15 Preparation of
3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one
(A38)
15.1 Preparation of 2-chloroethyl
N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]car-
bamate (16.1001)
##STR00126##
[0205] To a flask charged with tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (800 mg,
2.59 mmol) was added dry THF (7 mL). The reaction was cooled in ice
then sodium hydride 60% w/w (114 mg, 2.85 mmol) was added
portionwise with stirring over 10 mins during which time the
reaction had set solid. After standing at ambient for 20 mins, a
solution of chloroethyl chloroformate (407 mg, 2.85 mmol) in THF
(0.3 mL) was added. After a further 10 minutes stirring a hazy
solution resulted, which was stirred for a further 3 hours at
ambient.
[0206] The reaction was quenched with water (1 mL) and 2M HCl (528
.mu.l) and then concentrated in vacuo, redissolved in CH.sub.3Cl
and partitioned with water. The organic solvent was concentrated in
vacuo to yield a pale orange gum which was purified via flash
column chromatography on silica gel using an EtOAc/isohexane
gradient to give the desired compound (2-chloroethyl
N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]car-
bamate, 520 mg) as a colourless gum.
[0207] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.90 (1H, m), 8.52 (1H,
d), 7.96 (1H, m), 4.46 (2H, m), 3.68 (2H, m), 2.33 (3H, s), 1.48
(9H, s)
15.2 Preparation of 2-chloroethyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate
(16.2001)
##STR00127##
[0209] A flask charged with 2-chloroethyl
N-tert-butoxycarbonyl-N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]car-
bamate (625 mg, 1.50 mmol) and CH.sub.2Cl.sub.2 (6 mL) was cooled
in an ice bath and TFA (3 mL) was added slowly with stirring for 5
minutes then left at ambient for 1 hour 45 minutes.
[0210] The solvent was removed in vacuo to leave a gum which was
dissolved in CHCl.sub.3, shaken with water and passed through a
hydrophobic phase separating cartridge. The aqueous phase was
neutralised with sat. aq. NaHCO.sub.3, extracted with CHCl.sub.3
and passed through a hydrophobic phase separating cartridge. The
combined organics were concentrated in vacuo to give the desired
compound (2-chloroethyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate, 393
mg).
[0211] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.88 (1H, m), 8.47 (1H,
d), 7.94 (1H, m), 6.93 (1H, br. s), 4.50 (2H, m), 3.77 (2H, m),
2.41 (3H, s)
15.3 Preparation of
3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one
(A38)
##STR00128##
[0213] A flask charged with 2-chloroethyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]carbamate (202 mg,
0.64 mmol) and DMF (1.45 mL) was cooled in a salt/ice bath then
sodium hydride 60% w/w (30.7 mg, 0.768 mmol) was added in one
portion. The reaction mixture was stirred with cooling for 20
minutes then at ambient for a further 3 hours.
[0214] The reaction was cooled in ice then quenched with water (5.8
mL) and 2M HCl (63 .mu.L). The reaction mixture was extracted three
times with EtOAc and the combined organics washed once with brine
and dried (MgSO.sub.4), then concentrated in vacuo. The residue was
purified via column chromatography on silica gel using an
EtOAc/isohexane gradient to afford the desired compound
(3-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]oxazolidin-2-one,
120 mg).
[0215] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.87 (1H, m), 8.51 (1H,
d), 7.96-7.90 (1H, m), 4.64-4.53 (2H, m), 4.06-3.97 (2H, m), 2.52
(3H, s)
Example 16 Preparation of methyl
5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate
(A39)
##STR00129##
[0217] To a flask charged with a solution of tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.19 g,
0.44 mmol) in THF (1 mL) cooled to -78.degree. C. was added n-BuLi
(1.6M) in hexanes (0.55 mL, 0.89 mmol) drop-wise over 5 min. After
30 min stirring at -78.degree. C., methyl chloroformate (0.07 mL,
0.89 mmol) was added. The mixture was stirred at -78.degree. C. for
one hour before being allowed to warm to ambient.
[0218] The reaction was quenched at room temperature by the
addition of sat. aq. NH.sub.4Cl solution and extracted with three
portions of CH.sub.2Cl.sub.2. The combined organic extracts were
dried (MgSO.sub.4) and concentrated in vacuo. The residue was
purified via flash column chromatography on silica gel eluted with
an EtOAc/isohexane gradient, followed by further purification with
reverse phase HPLC to give the desired compound (methyl
5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylate,
4.7 mg).
[0219] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.23 (1H, br. s), 8.80
(1H, d), 8.64 (1H, d), 7.74 (1H, dd), 3.98 (3H, s), 3.31 (3H, s),
1.65-1.32 (9H, br. s)
Example 17 Preparation of tert-butyl
N-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate (A40)
##STR00130##
[0221] To a microwave tube charged with tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (80 mg,
0.19 mmol), tributyl(vinyl)stannane (0.122 g, 0.38 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (0.14 mg, 0.02 mmol) was added
1,4-dioxane (1 mL). The tube was sealed and heated at 140.degree.
C. for 30 min under microwave irradiation.
[0222] The reaction mixture was concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
eluting with an EtOAc/isohexane gradient to give the desired
compound (tert-butyl
N-methyl-N-[2-(3-pyridyl)-4-vinyl-thiazol-5-yl]carbamate, 41.4 mg)
as a brown gum.
[0223] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08-9.01 (1H, m), 8.58
(1H, dd), 8.16 (1H, dd), 7.31 (1H, m), 6.50 (1H, dd), 6.16 (1H,
dd), 5.42 (1H, dd), 3.17 (3H, s), 1.36 (9H, br. s)
Example 18 Preparation of tert-butyl
N-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate
(A41)
##STR00131##
[0225] To a microwave tube charged with tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg,
0.24 mmol), tributyl(ethynyl)stannane (150 mg, 0.45 mmol) and
PdCl.sub.2(PPh.sub.3).sub.2 (17 mg, 0.024 mmol) was added
1,4-dioxane (2 mL) and the tube was sealed. The reaction was sealed
and heated to 140.degree. C. for 30 min under microwave
irradiation.
[0226] The reaction mixture was concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
eluting with an EtOAc/isohexane gradient to afford the desired
compound (tert-butyl
N-[4-ethynyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 37 mg)
as a brown gum.
[0227] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.09 (1H, d), 8.66 (1H,
dd), 8.22 (1H, m), 7.38 (1H, dd), 3.43 (3H, s), 1.81 (1H, s), 1.51
(9H, br. s)
Example 19 Preparation of tert-butyl
N-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate
(A43)
##STR00132##
[0229] To a microwave tube charged with tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (100 mg,
0.24 mmol), cyclopropylboronic acid (27 mg, 0.31 mmol),
tricyclohexylphosphine (6.7 mg, 0.024 mmol) and K.sub.3PO.sub.4
(180 mg, 0.84 mmol) was added toluene (0.72 mL) and water (50
.mu.L). The solution was degassed by vacuum and purged with Ar,
Pd(OAc).sub.2 (2.6 mg, 0.012 mmol) was added and the reaction was
sealed and heated to 120.degree. C. for 35 min under microwave
irradiation.
[0230] The reaction mixture was then diluted with water and
extracted with three portions of CH.sub.2Cl.sub.2. The combined
organics were dried (MgSO.sub.4) and concentrated in vacuo to give
a brown gum which was purified via preparative reverse phase HPLC
to afford the desired compound (tert-butyl
N-[4-cyclopropyl-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate, 1.6
mg).
[0231] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.01 (1H, s), 8.60 (1H,
d), 8.14 (1H, m), 7.32 (1H, dd), 3.20 (3H, s), 1.89-1.63 (5H, m),
1.39 (9H, br. s)
Example 20 Preparation of
5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylic
acid (A44)
##STR00133##
[0233] To a flask charged with tert-butyl
N-[4-iodo-2-(3-pyridyl)thiazol-5-yl]-N-methyl-carbamate (0.1 g,
0.24 mmol) was added THF (1 mL, 12.3 mmol) and the reaction cooled
to -78.degree. C. n-Butyllithium (1.6M) in hexanes (0.30 mL, 0.48
mmol) was then added dropwise over the course of 5 min. After 30
min stirring at -78.degree. C., carbon dioxide was bubbled through
the reaction mixture for 10 minutes from subliming dry ice. The
reaction was allowed to warm to room temperature then quenched by
the addition of sat. aqueous NH.sub.4Cl and the resulting mixture
was extracted with three portions CH.sub.2Cl.sub.2. The combined
organic phases were dried over MgSO.sub.4 and concentrated in vacuo
to give a brown gum which was purified via reverse phase HPLC to
give the desired compound
(5-[tert-butoxycarbonyl(methyl)amino]-2-(3-pyridyl)thiazole-4-carboxylic
acid, 5.9 mg).
[0234] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.37 (1H, app. br. s),
8.78 (1H, app. br.s), 8.43 (1H, d), 7.68 (1H, app. br. s), 3.37
(3H, s), 1.46 (9H, br.s)
Example 21 Preparation of
3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea
(A45)
##STR00134##
[0236] To a flask charged with tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate
(93 mg, 0.45 mmol) dissolved in DMF (2 mL) was added
K.sub.2CO.sub.3 (82.0 mg, 0.59 mmol) and the reaction mixture was
cooled to ca. 10.degree. C. Then
(tert-butoxycarbonylamino)-4-methylbenzenesulfonate (prepared
according to the procedure of Thambidurai et al., Synlett 2011,
1993) (156.2 mg, 0.54 mmol) was added The resulting orange reaction
was stirred for 3 days at ambient.
[0237] The solvent was removed in vacuo and the residue was
dissolved in EtOAc, washed with water and the aqueous phase
back-extracted three times with EtOAc. The combined organics were
dried (Na.sub.2SO.sub.4), concentrated in vacuo and the residue
purified via flash column chromatography on silica gel eluting with
a CH.sub.2Cl.sub.2/methanol gradient to afford the desired compound
(3-tert-butoxy-1-methyl-1-(4-methyl-2-(3-pyridyl)thiazol-5-yl)urea,
93 mg) as an orange solid.
[0238] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.12 (1H, s), 8.58 (1H,
d), 8.18 (1H, d), 7.43 (1H, dd), 6.96 (1H, br. s), 3.28 (3H, s),
2.41 (3H, s), 1.23 (9H, s)
Example 22 Preparation of (4-nitrophenyl)
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (A61)
##STR00135##
[0240] N,4-Dimethyl-2-(3-pyridyl)thiazol-5-amine (5.19 g, 23.0
mmol) and pyridine (2.73 g, 34.5 mmol) plus DMAP (287 mg, 2.30
mmol) were dissolved in CH.sub.2Cl.sub.2 (75 mL), cooled in an ice
bath and a solution of (4-nitrophenyl) chloroformate (6.03 g, 29.9
mmol) in CH.sub.2Cl.sub.2 (25 mL) was added drop-wise with
stirring. The flask was allowed to warm to ambient and stirred for
a further 2 days. The reaction mixture was concentrated in vacuo
and the residue partitioned between water and EtOAc. The aqueous
phase was back extracted with EtOAc. The combined organic extracts
were combined, washed once with brine, dried over MgSO.sub.4,
filtered and the filtrate concentrated in vacuo. The residue was
purified via flash column chromatography on silica gel and eluted
with a CH.sub.2Cl.sub.2/EtOAc gradient to afford the desired
compound
((4-nitrophenyl)-N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate-
, 7.51 g, ca. 92% purity) as a beige solid.
[0241] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.14 (1H, s), 8.67 (1H,
dd), 8.33-8.26 (3H, m), 7.39 (1H, dd), 7.23-2.33 (2H, m), 3.40 (3H,
s), 2.46 (3H, s)
Example 23 Preparation of 1,1-dimethylprop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B3)
##STR00136##
[0243] To a flask charged with 2-methylbut-3-yn-2-ol (84 mg, 1.00
mmol) dissolved in N,N-dimethylformamide (1.5 mL) and cooled in ice
was added sodium hydride (60% suspension in oil w/w) (44 mg, 1.10
mmol). The flask was removed from the ice bath and stirred for 15
mins then re-cooled in ice/water. (4-Nitrophenyl)
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg,
0.497 mmol) was added with stirring and cooling. The reaction was
warmed to room temperature and stirred for one further hour. The
reaction was quenched with water (6 mL), extracted three times with
EtOAc and the organic extracts washed with brine. The combined
organics extracts were dried over MgSO.sub.4 and solvent removed in
vacuo. The crude residue was purified via reverse phase flash
chromatography using a C.sub.18 silica column and a
water/acetonitrile gradient to afford the desired compound
(1,1-dimethylprop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 81
mg).
[0244] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.09 (1H, d), 8.64 (1H,
dd), 8.18 (1H, d), 7.37 (1H, dd), 3.27 (3H, s), 2.59 (1H, s), 2.5
(3H, s), 1.81-1.53 (6H, br. s)
Example 24 Preparation of 1-methylprop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B2)
##STR00137##
[0246] To a flask charged with but-3-yn-2-ol (70 mg, 1.00 mmol)
dissolved in N,N-dimethylformamide (1.5 mL) and cooled in ice was
added sodium hydride (60% suspension in oil w/w) (44 mg, 1.10
mmol). The flask was removed from the ice bath and stirred for 15
mins, then re-cooled with an ice bath. (4-Nitrophenyl)
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg,
0.50 mmol) was added with stirring and cooling. The reaction was
warmed to room temperature and stirred for one further hour.
[0247] The reaction was quenched with water (6 mL) and extracted
three times with EtOAc then the organic extracts washed with brine.
The combined organic extracts were dried over MgSO.sub.4 and
solvent removed in vacuo. The crude residue was purified via
reverse phase flash chromatography using a C.sub.18 silica column
and a water/acetonitrile gradient to afford the desired compound
(1-methylprop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 96 mg) as
a straw coloured gum.
[0248] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.09 (1H, d), 8.65 (1H,
dd), 8.18 (1H, d), 7.38 (1H, dd), 5.43 (1H, br.s), 3.30 (3H, s),
2.51 (1H, br. s), 2.35 (3H, s), 1.45 (3H, br. s)
Example 25 Preparation of prop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (B1)
##STR00138##
[0250] To a flask charged with propargyl alcohol (55.7 mg, 1.00
mmol) dissolved in N,N-dimethylformamide (1.5 mL), and cooled in
ice was added sodium hydride (60% suspension in oil w/w) (44 mg,
1.10 mmol). The flask was removed from the ice bath and stirred for
15 mins, then re-cooled with an ice bath. (4-Nitrophenyl)
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate (200 mg,
0.50 mmol) was added with stirring and cooling. The reaction was
warmed to room temperature and stirred for one further hour.
[0251] The reaction was quenched with water (6 mL) and extracted
three times with EtOAc then the organic extracts washed once with
brine. The combined organic extracts were dried over MgSO.sub.4,
filtered and solvent removed in vacuo. The crude residue was
purified via reverse phase flash chromatography using a C.sub.18
silica column and a water/acetonitrile gradient to afford the
desired compound (prop-2-ynyl
N-methyl-N-[4-methyl-2-(3-pyridyl)thiazol-5-yl]carbamate, 78 mg) as
a straw coloured gum.
[0252] 1H NMR (400 MHz, CDCl.sub.3) .delta.=9.08 (1H, d), 8.65 (1H,
dd), 8.18 (1H, m), 7.38 (1H, dd), 4.72 (2H, br. s), 3.31 (3H, s),
2.51 (1H, br. s), 2.35 (3H, s)
Example 26 Preparation of tert-butyl N-[2-(5-fluoro-3-pyridyl
N-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62)
##STR00139##
[0254] To a flask charged with tert-butyl
N-[2-(5-fluoro-3-pyridyl)-4-methyl-thiazol-5-yl]-N-methyl-carbamate
(A3) (250 mg, 0.77 mmol) was added CH.sub.2Cl.sub.2 (25 mL) and the
mixture stirred vigorously at 0.degree. C. (ice bath). mCPBA (382
mg, 1.55 mmol) was added as a single portion and mixture was
allowed to warm to ambient and left stirring overnight.
[0255] The reaction mixture was quenched by the addition of sodium
metabisulfite solution (10% w/w, 100 mL) and the phases separated.
The organic phase was tested for peroxide (Quantofix.RTM. Peroxide
100 test strips, manufactured by Machery-Nagel) and found to be
free of residual peroxide.
[0256] The reaction mixture was concentrated in vacuo and the
residue purified via flash column chromatography on silica gel
eluting with an EtOAc/isohexane gradient to give the desired
compound (tert-butyl N-[2-(5-fluoro-3-pyridyl
N-oxide)-4-methyl-thiazol-5-yl]-N-methyl-carbamate (A62), 14 mg) as
a colourless glass
[0257] 1H NMR (400 MHz, CDCl.sub.3) .delta.=8.55 (1H, s), 8.12 (1H,
d), 7.54 (1H, dd), 3.21 (3H, s), 2.32 (3H, s), 1.46 (9H, br. s)
[0258] Tables 3 and 4 below shows compound of formula (I) as made
using the methods described above, or in analogous manner to the
compounds described in Examples 1 to 25.
TABLE-US-00003 TABLE 3 Compounds of formula (I) Physical Data
(.sup.1H NMR, 400 MHz, CDCl.sub.3 unless Compound Structure stated)
A1 ##STR00140## 9.08 (1H, d), 8.63 (1H, dd), 8.17 (1H, d), 7.36
(1H, dd), 3.22 (3H, s), 2.33 (3H, s), 1.44 (9H, br.s.) A2
##STR00141## 9.23 (1H, s), 9.18 (2H, s), 3.23 (3H, s), 2.35 (3H,
s), 1.45 (9H, br.s.) A3 ##STR00142## 8.85-8.89 (1H, m), 8.49 (1H,
d), 7.93 (1H, dd), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br.s.) A4
##STR00143## 8.92 (1H, d), 8.58 (1H, d), 8.20 (1H, t), 3.23 (3H,
s), 2.33 (3H, s), 1.45 (9H, br.s.) A5 ##STR00144## 10.2 (1H, s),
9.32 (1H, s), 9.08 (1H, s), 8.58 (1H, s), 3.21 (3H, s), 2.35 (3H,
s), 1.44 (9H, br. s) A6 ##STR00145## 8.62 (1H, d), 8.33 (1H, d),
7.71 (1H, br. s), 3.92 (3H, s), 3.21 (3H, s), 2.32 (3H, s), 1.47
(9H, br. s) A7 ##STR00146## 9.23 (1H, d), 8.87 (1H, d), 8.47 (1H,
dd), 3.24 (3H, s), 2.34 (3H, s), 1.45 (9H, br. s) A8 ##STR00147##
(500 MHz, CDCl.sub.3) 9.19 (1H, s), 9.07 (1H, s), 8.59 (1H, s),
6.76 (1H, br. s), 6.42 (1H, br. s), 3.23 (3H, s), 2.33 (3H, s),
1.45 (9H, br. s) A9 ##STR00148## (500 MHz, CDCl.sub.3) 9.31 (1H,
d), 9.14 (1H, d), 8.69 (1H, m), 3.24 (3H, s), 3.18 (3H, s), 2.35
(3H, s), 1.46 (9H,br. s) A10 ##STR00149## (500 MHz, CDCl.sub.3)
9.23 (1H, d), 8.89 (1H, d), 8.44 (1H, s), 3.25 (3H, m), 2.36 (3H,
s), 1.46 (9H, br. s) A11 ##STR00150## (500 MHz, CDCl.sub.3) 8.42
(1H, d), 8.09 (1H, d), 7.49 (1H, s), 4.04 (2H, br. s), 3.21 (3H,
s), 2.31 (3H, s), 1.44 (9H, br. s) A12 ##STR00151## (500 MHz,
CDCl.sub.3) 8.79 (1H, d), 8.50 (1H, m), 8.05 (1H, m), 3.23 (3H, s),
2.57 (3H, s), 2.33 (3H, s), 1.59-1.32 (9H, br. s) A13 ##STR00152##
(500 MHz, CDCl.sub.3) 8.38 (1H, d), 8.15 (1H, d), 7.46 (1H, m),
3.22 (3H, s), 3.05 (6H, 2x s), 2.32 (3H, s), 1.44 (9H, br. s) A14
##STR00153## 8.66 (1H, d), 8.40 (1H, d), 7.80 (1H, dd), 7.48-7.33
(5H, m), 5.18 (2H, s), 3.22 (3H, s), 2.32 (3H, s), 1.44 (9H, br. s)
A15 ##STR00154## (400 MHz, DMSO-d6) 10.33 (1H, br. s), 8.50 (1H,
d), 8.20 (1H, d), 7.60-7.53 (1H, m), 3.15 (3H, s), 2.24 (3H, s),
1.39 (9H, s) A16 ##STR00155## 8.91 (1H, d), 8.50 (1H, d), 7.99 (1H,
s), 6.82-6.41 (1H, t), 3.23 (3H, s), 2.33 (3H, s), 1.45 (9H, br. s)
A17 ##STR00156## 9.18 (1H, d), 8.62 (1H, dd), 8.17 (1H, m), 7.38
(1H, m), 3.63 (2H, q), 2.32 (3H, s), 1.43 (9H, br. s), 1.18 (3H, t)
A18 ##STR00157## 9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, dt), 7.37
(1H, m), 3.74 (3H, br. s), 3.28 (3H, s), 2.33 (3H, s) A19
##STR00158## 9.08 (1H, d), 8.64 (1H, dd), 8.17 (1H, m), 7.37 (1H,
dd), 4.20 (2H, q), 3.27 (3H, s), 2.33 (3H, s), 1.24 (3H, app. br.
s) A20 ##STR00159## 9.09 (1H, d), 8.64 (1H, dd), 8.18 (1H, m), 7.37
(1H, dd), 4.98 (1H, m), 3.26 (3H, s), 2.33 (3H, s), 1.23 (6H, br.
d) A21 ##STR00160## 9.12 (1H, d), 8.67 (1H, dd), 8.19 (1H, m), 7.39
(1H, dd), 4.48 (1H, br. s), 3.20 (3H, s), 2.35 (3H, s), 1.30 (9H,
br. s) A22 ##STR00161## 9.12 (1H, d), 8.66 (1H, dd), 8.20 (1H, m),
7.38 (1H, dd), 3.25 (3H, s), 2.35 (3H, s), 1.47 (9H, m) A23
##STR00162## 9.14 (1H, d), 8.68 (1H, dd), 8.25 (1H, m), 7.44 (1H,
m), 3.65 (3H, s), 2.32 (3H, s), 1.59 (9H, s) A24 ##STR00163## 8.89
(1H, s), 8.57 (1H, d), 8.02 (1H, m), 3.27 (3H, s), 1.44 (9H, br. s)
A25 ##STR00164## 9.10 (1H, d), 8.71 (1H, dd), 8.25 (1H, d), 7.42
(1H, dd), 3.27 (3H, s), 1.44 (9H, br. s) A26 ##STR00165## (500 MHz,
CDCl.sub.3) 9.31 (1H, s), 9.23 (2H, s), 3.28 (3H, s), 1.44 (9H, br.
s) A27 ##STR00166## (500 MHz, CDCl.sub.3) 8.94 (1H, d), 8.66 (1H,
d), 8.28 (1H, t), 3.27 (3H, s), 1.57-1.33 (9H, br. s) A28
##STR00167## (500 MHz, CDCl.sub.3) 8.64 (1H, d), 8.40 (1H, d), 7.77
(1H, br. s), 3.95 (3H, s), 3.26 (3H, s), 1.43 (9H, br. s) A29
##STR00168## (300 MHz, CDCl.sub.3) 9.08 (1H, s), 8.67 (1H, d),
8.22-8.16 (1H, m), 7.39 (1H, dd), 3.26 (3H, s), 1.46 (9H, s) A30
##STR00169## 9.08 (1H, d), 8.70-8.64 (1H, m), 8.20 (1H, m), 7.42-
7.37 (1H, m), 3.25 (3H, s), 1.46 (9H, br. s) A31 ##STR00170## 9.08
(1H, d), 8.67 (1H, dd), 8.22 (1H, m), 7.40 (1H, dd), 3.24 (3H, s),
1.46 (9H, br. s) A32 ##STR00171## (500 MHz, CDCl.sub.3) 9.06 (1H,
d), 8.65 (1H, d), 8.13 (1H, d), 7.38 (1H, dd), 3.30 (3H, br. s),
1.50 (9H, br. s) A33 ##STR00172## 9.08 (1H, d), 8.66 (1H, dd), 8.17
(1H, m), 7.39 (1H, m), 4.28 (2H, s), 3.15 (3H, s), 2.43 (3H, s) A34
##STR00173## 9.07 (1H, d), 8.62 (1H, dd), 8.15 (1H, m), 7.35 (1H,
m), 3.77 (2H, m), 3.54 (2H, m), 2.91 (3H, s), 2.42 (3H, s) A35
##STR00174## 8.87 (1H, m), 8.44 (1H, d), 7.94-7.87 (1H, m), 6.73
(1H, br. s), 2.39 (3H, s), 1.55 (9H, s) A38 ##STR00175## 8.87 (1H,
m), 8.51 (1H, d), 7.96-7.90 (1H, m), 4.64- 4.53 (2H, m), 4.06-3.97
(2H, m), 2.52 (3H, s) A39 ##STR00176## 9.23 (1H, br. s), 8.80 (1H,
d), 8.64 (1H, d), 7.74 (1H, dd), 3.98 (3H, s), 3.31 (3H, s),
1.65-1.32 (9H, br. s) A40 ##STR00177## 9.08-9.01 (1H, m), 8.58 (1H,
dd), 8.16 (1H, dd), 7.31 (1H, m), 6.50 (1H, dd), 6.16 (1H, dd),
5.42 (1H, dd), 3.17 (3H, s), 1.36 (9H, br. s) A41 ##STR00178## 9.09
(1H, d), 8.66 (1H, dd), 8.22 (1H, m), 7.38 (1H, dd), 3.43 (3H, s),
1.81 (1H, s), 1.51 (9H, br. s) A43 ##STR00179## 9.01 (1H, s), 8.60
(1H, d), 8.14 (1H, m), 7.32 (1H, dd), 3.20 (3H, s), 1.89-1.63 (5H,
m), 1.39 (9H, br. s) A44 ##STR00180## 9.37 (1H, app. br. s), 8.78
(1H, app. br. s), 8.43 (1H, d), 7.68 (1H, app. br. s), 3.37 (3H,
s), 1.46 (9H, br. s) A45 ##STR00181## 9.12 (1H, s), 8.58 (1H, d),
8.18 (1H, d), 7.43 (1H, dd), 6.96 (1H, br. s), 3.28 (3H, s), 2.41
(3H, s), 1.23 (9H, s) A50 ##STR00182## 8.87 (1H, s), 8.54 (1H, d),
7.95 (1H, m), 3.27 (3H, s), 1.57-1.34 (9H, m) A51 ##STR00183## 8.88
(1H, br. s), 8.55 (1H, br. s), 8.06-7.82 (1H, m), 3.26 (3H, s),
1.46 (9H, br. s) A52 ##STR00184## 8.87 (s, 1H), 8.53 (1H, d), 7.97
(1H, m), 3.24 (3H, s), 1.46 (9H, br. s) A61 ##STR00185## 9.14 (1H,
s), 8.67 (1H, dd), 8.33-8.26 (3H, m), 7.39 (1H, dd), 7.23-2.33 (2H,
m), 3.40 (3H, s), 2.46 (3H, s) A62 ##STR00186## 8.55 (1H, s), 8.12
(1H, d), 7.54 (1H, dd), 3.21 (3H, s), 2.32 (3H, s), 1.46 (9H, br.
s) A63 ##STR00187## 8.57 (1H, s), 8.21 (1H, d), 7.63 (1H, d), 3.27
(3H, s), 1.44 (9H, s)
TABLE-US-00004 TABLE 4 Compounds of formula (I) Compound Structure
Physical Data B1 ##STR00188## 9.08 (1H, d), 8.65 (1H, dd), 8.18
(1H, m), 7.38 (1H, dd), 4.72 (2H, br. s), 3.31 (3H, s), 2.51 (1H,
br. s), 2.35 (3H, s) B2 ##STR00189## 9.09 (1H, d), 8.65 (1H, dd),
8.18 (1H, d), 7.38 (1H, dd), 5.43 (1H, br. s), 3.30 (3H, s), 2.51
(1H, br. s), 2.35 (3H, s), 1.45 (3H, br. s) B3 ##STR00190## 9.09
(1H, d), 8.64 (1H, dd), 8.18 (1H, d), 7.37 (1H, dd), 3.27 (3H, s),
2.59 (1H, s), 2.5 (3H, s), 1.81-1.53 (6H, br. s) B10 ##STR00191##
8.87 (1H, s), 8.50 (1H, d), 7.95 (1H, d), 3.28 (3H, s), 2.59 (1H,
s), 2.35 (3H, s), 1.64 (6H, br. s) B11 ##STR00192## 8.87 (1H, s),
8.51 (1H, d), 7.95 (1H, m), 4.73 (2H, br. s), 3.30 (3H, s), 2.51
(1H, br. s), 2.36 (3H, s) B12 ##STR00193## 8.87 (1H, s), 8.50 (1H,
d), 7.95 (1H, m), 4.70 (2H, br. s), 3.30 (3H, s), 2.35 (3H, s),
1.85 (3H, s)
BIOLOGICAL EXAMPLES
B1 Pre-Emergence Herbicidal Activity
[0259] Seeds of a variety of test species were sown in standard
soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA),
Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa
crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX),
Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and
Setaria faberi (SETFA). 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 Tables 5 and
6.
B2 Post-Emergence Herbicidal Activity
[0260] Seeds of a variety of test species were sown in standard
soil in pots: Triticum aestivium (TRZAW), Oryza sativa (ORYSA),
Avena fatua (AVEFA), Alopecurus myosuroides (ALOMY), Echinochloa
crus-galli (ECHCG), Lolium perenne (LOLPE), Zea Mays (ZEAMX),
Abutilon theophrasti (ABUTH), Amaranthus retroflexus (AMARE) and
Setaria faberi (SETFA). 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 Tables 7 and 8.
TABLE-US-00005 TABLE 5 Control of weed species by compound of
formula (I) after pre-emergence application at a rate of 1000 g/Ha
Com- pound ORYSA TRZAW ALOMY AVEFA LOLPE ECHCG A1 2 2 2 4 2 4 A2 1
0 0 3 2 5 A3 1 1 1 3 2 4 A4 0 0 1 4 2 4 A5 0 0 0 0 0 0 A6 1 0 1 0 1
2 A7 1 1 1 4 2 2 A8 0 0 0 0 0 0 A9 0 0 0 0 0 0 A10 1 1 0 1 1 1 A11
2 2 1 1 0 2 A12 0 0 0 3 1 3 A13 1 0 0 0 0 1 A14 0 1 0 0 1 0 A15 0 0
0 0 0 0 A16 1 3 0 3 4 4 A17 0 0 0 0 0 0 A18 0 1 1 2 2 5 A19 0 0 1 1
1 5 A20 0 0 0 2 2 5 A21 0 0 0 2 1 5 A22 0 0 0 0 0 0 A23 0 0 0 0 0 0
A24 0 1 2 4 3 4 A25 1 0 1 4 3 4 A26 1 0 2 4 3 4 A27 0 0 0 2 2 2 A28
0 0 0 1 2 3 A29 2 3 1 2 2 3 A30 1 0 1 3 2 4 A31 1 1 1 1 2 3 A32 2 0
0 1 1 2 A38 3 0 1 1 2 5 A45 2 1 2 3 2 3 A51 0 0 0 2 3 1 A52 1 0 0 3
3 2 A62 1 1 2 2 2 3 A63 0 0 0 1 1 1
TABLE-US-00006 TABLE 6 Control of weed species by compound of
formula (I)-(i) after pre-emergence application at a rate of 1000
g/Ha Com- pound ZEAMX ABUTH SETFA AMARE LOLPE ECHCG B1 5 2 5 2 3 2
B2 5 3 5 3 3 1 B3 5 4 4 3 3 3
TABLE-US-00007 TABLE 7 Control of weed species by compound of
formula (I) after post-emergence application at a rate of 1000 g/Ha
Com- pound TRZAW ORYSA AVEFA ALOMY ECHCG LOLPE A1 0 1 4 0 4 4 A2 1
1 5 1 5 3 A3 1 1 4 1 5 3 A4 1 1 5 0 4 2 A5 0 0 0 0 0 0 A6 1 0 2 1 4
2 A7 2 1 4 1 5 3 A8 2 1 2 1 3 0 A9 2 1 2 1 2 1 A10 1 1 2 0 4 0 A11
2 1 1 1 2 1 A12 2 1 2 0 4 3 A13 2 1 0 1 2 0 A14 0 0 0 0 1 0 A15 1 0
2 0 1 1 A16 4 0 5 3 5 4 A17 1 2 4 1 1 2 A18 1 0 3 1 5 2 A19 1 0 3 1
5 2 A20 1 0 3 1 5 3 A21 1 0 4 2 5 3 A22 0 0 2 0 2 2 A23 0 0 1 0 1 0
A24 1 2 4 0 5 4 A25 2 1 4 1 5 4 A26 1 2 5 0 5 4 A27 2 1 4 1 5 3 A28
1 1 2 1 4 3 A29 1 1 4 1 5 4 A30 2 1 4 1 5 4 A31 1 1 5 1 4 3 A32 0 1
3 1 3 2 A35 1 0 1 0 2 0 A38 1 0 4 1 5 3 A45 2 2 5 1 4 4 A51 0 0 4 0
4 2 A52 1 0 4 1 4 3 A61 1 0 2 0 1 1 A62 1 0 4 1 4 4 A63 0 0 3 1 5
2
TABLE-US-00008 TABLE 8 Control of weed species by compound of
formula (I)-(i) after post-emergence application at a rate of 1000
g/Ha Com- pound SETFA ZEAMX ECHCG LOLPE AMARE ABUTH B1 5 5 4 3 1 1
B2 5 4 2 4 2 2 B3 5 5 4 4 2 1
* * * * *