CINNOLINIUM COMPOUNDS FOR USE IN A METHOD OF CONTROLLING UNWANTED PLANT GROWTH
20220132847 · 2022-05-05
Assignee
Inventors
Cpc classification
C07F9/38
CHEMISTRY; METALLURGY
C07F9/30
CHEMISTRY; METALLURGY
International classification
C07F9/30
CHEMISTRY; METALLURGY
Abstract
The present invention relates to herbicidally active cinnolinium derivatives of formula (I), 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.
Claims
1. A compound of formula (I) or an agronomically acceptable salt or zwitterionic species thereof: ##STR00171## wherein R.sup.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.2-C.sub.6alkenyl, C.sub.2-C.sub.6alkynyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6haloalkyl, —OR.sup.7, —OR.sup.15a, —N(R.sup.6)S(O).sub.2R.sup.15, —N(R.sup.6)C(O)R.sup.15, —N(R.sup.6)C(O)OR.sup.15, —N(R.sup.6)C(O)NR.sup.16R.sup.17, —N(R.sup.6)CHO, —N(R.sup.7a).sub.2 and —S(O).sub.rR.sup.15; R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6haloalkyl; and wherein when R.sup.1 is selected from the group consisting of —OR.sup.7, —OR.sup.15a, —N(R.sup.6)S(O).sub.2R.sup.15, —N(R.sup.6)C(O)R.sup.15, —N(R.sup.6)C(O)OR.sup.15, —N(R.sup.6)C(O)NR.sup.16R.sup.17, —N(R.sup.6)CHO, —N(R.sup.7a).sub.2 and —S(O).sub.rR.sup.15, R.sup.2 is selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.1 and R.sup.2 together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; Q is (CR.sup.1aR.sup.2b).sub.m; m is 0, 1, 2 or 3; each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, —OH, —OR.sup.7, —OR.sup.15a, —NH.sub.2—NHR.sup.7, —NHR.sup.15a, —N(R.sup.6)CHO, —NR.sup.7bR.sup.7c and —S(O).sub.rR.sup.15; or each R.sup.1a and R.sup.2b together with the carbon atom to which they are attached form a C.sub.3-C.sub.6cycloalkyl ring or a 3- to 6-membered heterocyclyl, which comprises 1 or 2 heteroatoms individually selected from N and O; and R.sup.3 is selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O).sub.rR.sup.15, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6halooalkyl, C.sub.1-C.sub.6haloalkoxy, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.6cycloalkyl, —N(R.sup.6).sub.2, phenyl, a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl comprising 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R.sup.9 substituents; A is selected from the group consisting of: —C(O)OR.sup.410, —CHO, —C(O)R.sup.424, —C(O)NHOR.sup.411, —C(O)NHCN, —C(O)NHR.sup.425, —S(O).sub.2NHR.sup.425, —C(O)NHS(O).sub.2R.sup.414, —C(O)NR.sup.46(CR.sup.46.sub.2).sub.q—C(O)OR.sup.410, —C(O)NR.sup.46(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410, —C(O)NR.sup.46(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)OR.sup.410, —C(O)NR.sup.46S(O).sub.2(CR.sup.46.sub.2).sub.qC(O)OR.sup.410—(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410, —(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —OC(O)NHOR.sup.411—O(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —OC(O)NHCN, —O(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410—O(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —NR.sup.46C(O)NHOR.sup.411, —NR.sup.46C(O)NHCN, —C(O)NHS(O).sub.2R.sup.412, —OC(O)NHS(O).sub.2R.sup.412, —NR.sup.46C(O)NHS(O).sub.2R.sup.412, —S(O).sub.2OR.sup.410, —OS(O).sub.2OR.sup.410, —NR.sup.46S(O).sub.2OR.sup.410, —NR.sup.46S(O)OR.sup.410, —NHS(O).sub.2R.sup.414, —S(O)OR.sup.410, —S(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —S(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410, —S(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —OS(O).sub.2OR.sup.410—S(O).sub.2NHCN, —S(O).sub.2NHC(O)R.sup.418, —S(O).sub.2NHS(O).sub.2R.sup.412, —OS(O).sub.2NHCN, —OS(O).sub.2NHS(O).sub.2R.sup.412, —OS(O).sub.2NHC(O)R.sup.418, —NR.sup.46S(O).sub.2NHCN, —NR.sup.46S(O).sub.2NHC(O)R.sup.418, —N(OH)C(O)R.sup.415—ONHC(O)R.sup.415—NR.sup.46S(O).sub.2NHS(O).sub.2R.sup.412, —P(O)(R.sup.413)(OR.sup.410), —P(O)H(OR.sup.410), —OP(O)(R.sup.413)(OR.sup.410), —NR.sup.46P(O)(R.sup.413)(OR.sup.410) and tetrazole; each R.sup.46 is independently selected from hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.49 is independently selected from the group consisting of halogen, cyano, —OH, —N(R.sup.46).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; R.sup.410 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R.sup.49 substituents, which may be the same or different; R.sup.411 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, —C(O)OR.sup.410, and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.49 substituents, which may be the same or different; R.sup.412 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —OH, —N(R.sup.46).sub.2, phenyl, a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl comprising 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R.sup.420 substituents; R.sup.413 is selected from the group consisting of —OH, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy and phenyl; R.sup.414 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, and N(R.sup.46).sub.2; R.sup.415 is selected from the group consisting of C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.49 substituents, which may be the same or different; R.sup.418 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —N(R.sup.46).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.49 substituents, which may be the same or different; each R.sup.420 is independently C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6alkoxy, halogen, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6haloalkoxy, or C.sub.1-C.sub.3alkoxyC.sub.1-C.sub.3alkyl; R.sup.424 is a peptide moiety comprising 1, 2, or 3 amino acid moieties, each amino acid moiety independently selected from the group consisting of Ala, Cys, Asp, Glu, Phe, Gly, His, Ile, Lys, Leu, Met, Asn, Pro, Gln, Arg, Ser, Thr, Val, Trp and Tyr, wherein said peptide moiety is bonded to the rest of the molecule via a nitrogen atom in the amino acid moiety; R.sup.425 is phenyl optionally substituted by 1 or 2 R.sup.49 substituents, or a 5- or 6-membered heteroaryl comprising 1, 2, 3 or 4 heteroatoms individually selected from N, O and S and optionally substituted by 1 or 2 R.sup.49 substituents; q is an integer of 1, 2, or 3; each R.sup.5 is independently selected from the group consisting of hydrogen, halogen, cyano, nitro, —S(O).sub.rR.sup.15, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, C.sub.1-C.sub.6fluoroalkoxy, C.sub.1-C.sub.6alkoxy, C.sub.3-C.sub.6cycloalkyl and —N(R.sup.6).sub.2; k is an integer of 0, 1, 2, 3, or 4; each R.sup.6 is independently selected from hydrogen and C.sub.1-C.sub.6alkyl; each R.sup.7 is independently selected from the group consisting of C.sub.1-C.sub.6alkyl, —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15 and —C(O)NR.sup.16R.sup.17; each R.sup.7a is independently selected from the group consisting of —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15, —C(O)NR.sup.16R.sup.17 and —C(O)NR.sup.6R.sup.15a; R.sup.7b and R.sup.7c are independently selected from the group consisting of C.sub.1-C.sub.6alkyl, —S(O).sub.2R.sup.15, —C(O)R.sup.15, —C(O)OR.sup.15, —C(O)NR.sup.16R.sup.17 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; or R.sup.7b and R.sup.7c together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; X is selected from the group consisting of C.sub.3-C.sub.6cycloalkyl, phenyl, a 5- or 6-membered heteroaryl, which comprises 1, 2, 3 or 4 heteroatoms individually selected from N, O and S, and a 4- to 6-membered heterocyclyl, which comprises 1, 2 or 3 heteroatoms individually selected from N, O and S, and wherein said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties are optionally substituted by 1 or 2 R.sup.9 substituents, and wherein the aforementioned CR.sup.1R.sup.2, Q and Z moieties may be attached at any position of said cycloalkyl, phenyl, heteroaryl or heterocyclyl moieties; n is 0 or 1; each R.sup.9 is independently selected from the group consisting of halogen, cyano, —OH, —N(R.sup.6).sub.2, C.sub.1-C.sub.4alkyl, C.sub.1-C.sub.4alkoxy, C.sub.1-C.sub.4haloalkyl and C.sub.1-C.sub.4haloalkoxy; Z is selected from the group consisting of hydrogen, methoxy, —C(O)OR.sup.10, —CH.sub.2OH, —CHO, —C(O)NHOR.sup.11, —C(O)NHCN, —OC(O)NHOR.sup.11, —OC(O)NHCN, —NR.sup.6C(O)NHOR.sup.11, —NR.sup.6C(O)NHCN, —C(O)NHS(O).sub.2R.sup.12, —OC(O)NHS(O).sub.2R.sup.12, —NR.sup.6C(O)NHS(O).sub.2R.sup.12, —S(O).sub.2OR.sup.10, —OS(O).sub.2OR.sup.10, —NR.sup.6S(O).sub.2OR.sup.10, —NRS(O)OR.sup.10, —NHS(O).sub.2R.sup.14, —S(O)OR.sup.10, —OS(O)OR.sup.10, —S(O).sub.2NHCN, —S(O).sub.2NHC(O)R.sup.18, —S(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHCN, —OS(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHC(O)R.sup.18, —NR.sup.6S(O).sub.2NHCN, —NR.sup.6S(O).sub.2NHC(O)R.sup.18, —N(OH)C(O)R.sup.15, —ONHC(O)R.sup.15, —NR.sup.6S(O).sub.2NHS(O).sub.2R.sup.12, —P(O)(R.sup.13)(OR.sup.10), —P(O)H(OR.sup.10), —OP(O)(R.sup.13)(OR.sup.1), —NR.sup.6P(O)(R.sup.13)(OR.sup.10) and tetrazole; R.sup.10 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, phenyl and benzyl, and wherein said phenyl or benzyl are optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.11 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.12 is selected from the group consisting of C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —OH, —N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.13 is selected from the group consisting of —OH, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6alkoxy and phenyl; R.sup.14 is C.sub.1-C.sub.6haloalkyl; R.sup.15 is selected from the group consisting of C.sub.1-C.sub.6alkyl and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.15a is phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; R.sup.16 and R.sup.17 are independently selected from the group consisting of hydrogen and C.sub.1-C.sub.6alkyl; or R.sup.16 and R.sup.17 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl ring which optionally comprises one additional heteroatom individually selected from N, O and S; and R.sup.18 is selected from the group consisting of hydrogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6haloalkyl, C.sub.1-C.sub.6alkoxy, —N(R.sup.6).sub.2 and phenyl, and wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9 substituents, which may be the same or different; and, r is 0, 1 or 2, with the proviso that: (i) when A is —P(O)(OH)(OR.sup.410) and R.sup.410 is C.sub.1-C.sub.6alkyl, and R.sup.1 and R.sup.2 are both hydrogen, m is 0, and n is 0, then Z is not hydrogen, and (ii) the compound of formula (I) is not methyl 2,3-dimethylcinnolin-2-ium-4-carboxylate.
2. The compound according to claim 1, wherein k is 1 or 2, and each R.sup.5 is is independently selected from the group consisting of halogen, —OR.sup.7, C.sub.1-C.sub.3alkyl, C.sub.1-C.sub.3haloalkyl, C.sub.3-C.sub.6cycloalkyl, C.sub.1-C.sub.3haloalkoxy, C.sub.2-C.sub.4alkenyl, C.sub.2-C.sub.4alkynyl, C.sub.1-C.sub.3alkoxycarbonyl, C.sub.1-C.sub.3alkylaminocarbonyl, di-C.sub.1-C.sub.3alkylaminocarbonyl and phenyl, wherein said phenyl is optionally substituted by 1, 2 or 3 R.sup.9, which may be the same or different.
3. The compound according to claim 1, wherein R.sup.3 is selected from the group consisting of hydrogen, halogen and C.sub.1-C.sub.6alkyl, phenyl and thiazole, wherein said phenyl or thiazole is optionally substituted by 1 or 2 R.sup.9, which may be the same or different.
4. The compound according to claim 1, wherein n is 0.
5. The compound according to claim 1, wherein R.sup.1 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, —OR.sup.7, —NHS(O).sub.2R.sup.15, —NHC(O)R.sup.15, —NHC(O)OR.sup.15, —NHC(O)NR.sup.16R.sup.17, —N(R.sup.7a).sub.2 and —S(O).sub.rR.sup.15.
6. The compound according to claim 1, wherein R.sup.2 is selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl and C.sub.1-C.sub.6fluoroalkyl.
7. The compound according to claim 1, wherein m is 1, 2, or 3.
8. The compound according to claim 7, wherein each R.sup.1a and R.sup.2b are independently selected from the group consisting of hydrogen, halogen, C.sub.1-C.sub.6alkyl, C.sub.1-C.sub.6fluoroalkyl, —OH, —NH.sub.2, and NHR.sup.7.
9. The compound according to claim 1, wherein each R.sup.1a is hydrogen.
10. The compound according to claim 1, wherein each R.sup.2b is independently selected from the group consisting of hydrogen, chloro, fluoro, methyl, ethyl, n-propyl, n-butyl, n-pentyl or n-hexyl.
11. The compound according to claim 1, wherein m is 0,
12. The compound according to claim 1, wherein Z is selected from the group consisting of hydrogen, —CH.sub.2OH, and —OCH.sub.3.
13. The compound according to claim 12, wherein Z is hydrogen.
14. The compound according to claim 1, wherein Z is selected from the group consisting of —C(O)OR.sup.10, —CHO, —C(O)NHOR.sup.11, —C(O)NHCN, —OC(O)NHOR.sup.11, —OC(O)NHCN, —NR.sup.6C(O)NHOR.sup.11, —NR.sup.6C—(O)NHCN, —C(O)NHS(O).sub.2R.sup.12, —OC(O)NHS(O).sub.2R.sup.12, —NR.sup.6C(O)NHS(O).sub.2R.sup.12, —S(O).sub.2OR.sup.10, —OS—(O).sub.2OR.sup.10, —NR.sup.6S(O).sub.2OR.sup.10, —NR.sup.6S(O)OR.sup.10, —NHS(O).sub.2R.sup.14, —S(O)OR.sup.10, —OS(O)OR.sup.10, —S(O).sub.2NHCN, —S(O).sub.2NHC(O)R.sup.18, —S(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHCN, —OS(O).sub.2NHS(O).sub.2R.sup.12, —OS(O).sub.2NHC(O)R.sup.18, —NR.sup.6S(O).sub.2NHCN, —NR.sup.6S(O).sub.2NHC(O)R.sup.18, —N(OH)C(O)R.sup.15, —ONHC(O)R.sup.15, —NR.sup.6S(O).sub.2NHS(O).sub.2R.sup.12, —P(O)(R.sup.13)(OR.sup.10), —P(O)H(OR.sup.10), —OP(O)(R.sup.13)(OR.sup.10), —NR.sup.6P(O)(R.sup.13)(OR.sup.10) and tetrazole.
15. The compound according to claim 14, wherein Z is selected from the group consisting of —C(O)OR.sup.10, —CH.sub.2OH, —C(O)NHOR.sup.11, —C(O)NHS(O).sub.2R.sup.12, —S(O).sub.2OR.sup.10, —OS(O).sub.2OR.sup.10, —NR.sup.6S(O).sub.2OR.sup.10, —NHS(O).sub.2R.sup.14, —S(O)OR.sup.10, —P(O)(R.sup.13)(OR.sup.10) and tetrazole.
16. The compound according to claim 1, wherein A is selected from the group consisting of —C(O)OR.sup.410, —C(O)NHOR.sup.411, —C(O)NHR.sup.425, —S(O).sub.2NHR.sup.425, —C(O)NHS(O).sub.2R.sup.414—C(O)NR.sup.46(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —C(O)NR.sup.46S(O).sub.2(CR.sup.46.sub.2).sub.qC(O)OR.sup.410—(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —OC(O)NHOR.sup.411, —O(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —OC(O)NHCN, —O(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410, —O(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —S(O).sub.2OR.sup.410, —S(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —S(CR.sup.46.sub.2).sub.qS(O).sub.2OR.sup.410—P(O)(R.sup.413)(OR.sup.410), —P(O)H(OR.sup.410), —OP(O)(R.sup.413)(OR.sup.410) and —NR.sup.46P(O)(R.sup.413)(OR.sup.410).
17. The compound according claim 16, wherein A is selected from the group consisting of: —C(O)OR.sup.410, —C(O)NHOR.sup.411, —C(O)NHR.sup.425, —C(O)NHS(O).sub.2R.sup.414, —C(O)NR.sup.46(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —C(O)NR.sup.46S(O).sub.2(CR.sup.46.sub.2).sub.qC(O)—OR.sup.410, —(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, —(CR.sup.46.sub.2).sub.qP(O)(R.sup.413)(OR.sup.410), —S(O).sub.2OR.sup.410, —S(CR.sup.46.sub.2).sub.qC(O)OR.sup.410—O(CR.sup.46.sub.2).sub.qC(O)OR.sup.410, and —P(O)(R.sup.413)(OR.sup.410).
18. The compound according to claim 14, wherein A is selected from the group consisting of —C(O)OR.sup.410, —C(O)NHS(O).sub.2R.sup.414, —S(O).sub.2—OR.sup.10, and —P(O)(R.sup.413)(OR.sup.410).
19. An agrochemical composition comprising a herbicidally effective amount of a compound of formula (I) as defined in claim 1 and an agrochemically-acceptable diluent or carrier.
20. A method of controlling unwanted plant growth, comprising applying a compound of formula (I) as defined in claim 1 to the unwanted plants or to the locus thereof.
Description
EXAMPLES
Formulation Examples
[0230]
TABLE-US-00005 Wettable powders a) b) c) active ingredients 25% 50% 75% sodium lignosulfonate 5% 5% — sodium lauryl sulphate 3% — 5% sodium diisobutylnaphthalenesulfonate — 10% 6% phenol polyethylene glycol ether — 2% — (7-8 mol of ethylene oxide) highly dispersed silicic acid 5% 10% 10% Kaolin 62% 27% —
[0231] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording wettable powders that can be diluted with water to give suspensions of the desired concentration.
TABLE-US-00006 Powders for dry seed treatment a) b) c) active ingredients 25% 50% 75% light mineral oil 5% 5% 5% highly dispersed silicic acid 5% 5% — Kaolin 65% 40% — Talcum — 20
[0232] The combination is thoroughly mixed with the adjuvants and the mixture is thoroughly ground in a suitable mill, affording powders that can be used directly for seed treatment.
TABLE-US-00007 Emulsifiable concentrate active ingredients 10% octylphenol polyethylene glycol ether 3% (4-5 mol of ethylene oxide) calcium dodecylbenzenesulfonate 3% castor oil polyglycol ether (35 mol of ethylene oxide) 4% Cyclohexanone 30% xylene mixture 50%
[0233] Emulsions of any required dilution, which can be used in plant protection, can be obtained from this concentrate by dilution with water.
TABLE-US-00008 Dusts a) b) c) Active ingredients 5% 6% 4% Talcum 95% — — Kaolin — 94% — mineral filler — — 96%
[0234] Ready-for-use dusts are obtained by mixing the combination with the carrier and grinding the mixture in a suitable mill. Such powders can also be used for dry dressings for seed.
TABLE-US-00009 Extruded granules Active ingredients 15% sodium lignosulfonate 2% Carboxymethylcellulose 1% Kaolin 82%
[0235] The combination is mixed and ground with the adjuvants, and the mixture is moistened with water. The mixture is extruded and then dried in a stream of air.
TABLE-US-00010 Coated granules Active ingredients 8% polyethylene glycol (mol. wt. 200) 3% Kaolin 89%
[0236] The finely ground combination is uniformly applied, in a mixer, to the kaolin moistened with polyethylene glycol. Non-dusty coated granules are obtained in this manner.
TABLE-US-00011 Suspension concentrate active ingredients 40% propylene glycol 10% nonylphenol polyethylene glycol ether (15 mol of ethylene oxide) 6% Sodium lignosulfonate 10% Carboxymethylcellulose 1% silicone oil (in the form of a 75% emulsion in water) 1% Water 32%
[0237] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
TABLE-US-00012 Flowable concentrate for seed treatment active ingredients 40% propylene glycol 5% copolymer butanol PO/EO 2% Tristyrenephenole with 10-20 moles EO 2% 1,2-benzisothiazolin-3-one (in the form of a 20% solution 0.5% in water) monoazo-pigment calcium salt 5% Silicone oil (in the form of a 75% emulsion in water) 0.2% Water 45.3%
[0238] The finely ground combination is intimately mixed with the adjuvants, giving a suspension concentrate from which suspensions of any desired dilution can be obtained by dilution with water. Using such dilutions, living plants as well as plant propagation material can be treated and protected against infestation by microorganisms, by spraying, pouring or immersion.
Slow Release Capsule Suspension
[0239] 28 Parts of the combination are mixed with 2 parts of an aromatic solvent and 7 parts of toluene diisocyanate/polymethylene-polyphenylisocyanate-mixture (8:1). This mixture is emulsified in a mixture of 1.2 parts of polyvinylalcohol, 0.05 parts of a defoamer and 51.6 parts of water until the desired particle size is achieved. To this emulsion a mixture of 2.8 parts 1,6-diaminohexane in 5.3 parts of water is added. The mixture is agitated until the polymerization reaction is completed. The obtained capsule suspension is stabilized by adding 0.25 parts of a thickener and 3 parts of a dispersing agent. The capsule suspension formulation contains 28% of the active ingredients. The medium capsule diameter is 8-15 microns. The resulting formulation is applied to seeds as an aqueous suspension in an apparatus suitable for that purpose.
List of Abbreviations:
[0240] Boc=tert-butyloxycarbonyl
br=broad
CDCl.sub.3=chloroform-d
CD.sub.3OD=methanol-d
° C.=degrees Celsius
D.sub.2O=water-d
DCM=dichloromethane
d=doublet
dd=double doublet
dt=double triplet
DMSO=dimethylsulfoxide
EtOAc=ethyl acetate
h=hour(s)
HCl=hydrochloric acid
HPLC=high-performance liquid chromatography (description of the apparatus and the
methods used for HPLC are given below)
m=multiplet
M=molar
min=minutes
MHz=mega hertz
mL=millilitre
mp=melting point
ppm=parts per million
q=quartet
quin=quintet
rt=room temperature
s=singlet
t=triplet
THE=tetrahydrofuran
LC/MS=Liquid Chromatography Mass Spectrometry
Preparative Reverse Phase HPLC Method:
[0241] Compounds purified by mass directed preparative HPLC using ES+/ES− on a Waters FractionLynx Autopurification system comprising a 2767 injector/collector with a 2545 gradient pump, two 515 isocratic pumps, SFO, 2998 photodiode array (Wavelength range (nm): 210 to 400), 2424 ELSD and QDa mass spectrometer. A Waters Atlantis T3 5 micron 19×10 mm guard column was used with a Waters Atlantis T3 OBD, 5 micron 30×100 mm prep column.
Ionisation method: Electrospray positive and negative: Cone (V) 20.00, Source Temperature (° C.)
120, Cone Gas Flow (L/Hr.) 50
[0242] Mass range (Da): positive 100 to 800, negative 115 to 800.
[0243] The preparative HPLC was conducted using an 11.4 minute run time (not using at column dilution, bypassed with the column selector), according to the following gradient table:
TABLE-US-00013 Time (mins) Solvent A (%) Solvent B (%) Flow (ml/min) 0.00 100 0 35 2.00 100 0 35 2.01 100 0 35 7.0 90 10 35 7.3 0 100 35 9.2 0 100 35 9.8 99 1 35 11.35 99 1 35 11.40 99 1 35
515 pump 0 ml/min Acetonitrile (ACD)
515 pump 1 ml/min 90% Methanol/10% Water (make up pump)
Solvent A: Water with 0.05% Trifluoroacetic Acid
Solvent B: Acetonitrile with 0.05% Trifluoroacetic Acid
PREPARATION EXAMPLES
Example 1: Preparation of 2,3-dimethylcinnolin-2-ium-4-carboxylate A61
[0244] ##STR00026##
Step 1: Preparation of 3-methylcinnolin-4-ol
[0245] ##STR00027##
[0246] To a mixture of 1-(2-aminophenyl)propan-1-one (22 g) and glacial acetic acid (22 mL) was added 2M aqueous hydrochloric acid (66 mL) and water (22 mL). The mixture was cooled to 0° C. and a solution of sodium nitrite (11.192 g) in water (44 mL) was added slowly, keeping the temperature between 0° C. and 5° C. The mixture was stirred at 0° C. for one hour and urea (0.886 g) was added and stirred for another hour. To this was added a solution of sodium acetate (159.19 g) in water (440 mL) followed by dichloromethane (110 mL) at 0° C. and then the mixture was allowed to warm to room temperature and stirred for 15 hours. The reaction mass was filtered and the light brown solid was washed sequentially with water (50 mL), dichloromethane (20 mL) and hexane (20 mL) and dried to give 3-methylcinnolin-4-ol.
[0247] .sup.1H NMR (400 MHz, CDCl.sub.3) 12.50 (br. s., 1H) 8.15 (d, 1H) 7.48-7.60 (m, 1H) 7.39-7.47 (m, 1H) 7.19-7.31 (m, 1H) 2.34-2.35 (m, 3H) Step 2: Preparation of 4-chloro-3-methyl-cinnoline
##STR00028##
[0248] To a mixture of 3-methylcinnolin-4-ol (9 g) and chlorobenzene (90 mL), under a nitrogen atmosphere, was added 2-methylpyridine (1.0466 g) drop wise at room temperature. Phosphorus oxychloride (7.936 mL) was then added drop wise and the resulting mixture was heated at reflux for 2 hours. The reaction mass was poured cautiously into ice cold water and the resulting mixture was basified with saturated aqueous sodium carbonate solution. The reaction mass was extracted with dichloromethane (3×50 mL) and the combined organic layers were concentrated then purified by silica gel chromatography eluting with a 3:7 ration of ethyl acetate in iso-hexane to give 4-chloro-3-methyl-cinnoline.
[0249] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.48 (m, 1H), 8.12 (m, 1H), 7.74-7.84 (m, 2H), 3.03 (s, 3H) Step 3: Preparation of 3-methyl-4-(p-tolylsulfonyl)cinnoline
##STR00029##
[0250] A mixture of 4-chloro-3-methyl-cinnoline (0.5 g) and acetonitrile (6 mL), under a nitrogen atmosphere, was cooled to 0° C. and sodium p-toluenesulfinate (0.549 g) was added in one portion. The mixture was stirred cold for 1 hour and then allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between water and ethyl acetate (100 mL), then extracted further ethyl acetate (2×100 mL). The combined organic layers were dried over sodium sulphate and concentrated to give 3-methyl-4-(p-tolylsulfonyl)cinnoline.
[0251] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.15 (d, 1H), 8.62 (d, 1H), 7.81-7.92 (m, 4H), 7.32 (d, 2H), 3.35 (s, 3H), 2.41 (s, 3H)
Step 4: Preparation of 3-methylcinnoline-4-carbonitrile
[0252] ##STR00030##
[0253] To a solution of 3-methyl-4-(p-tolylsulfonyl)cinnoline (2.5 g) in N,N-dimethylformamide (25 mL), under a nitrogen atmosphere, was added sodium cyanide (1.7 g) at room temperature. The reaction mixture was stirred for 2 hours then quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulphate and concentrated to give crude 3-methylcinnoline-4-carbonitrile which was used without further purification.
Step 5: Preparation of 3-methylcinnoline-4-carboxylic Acid
[0254] ##STR00031##
[0255] To a mixture of crude 3-methylcinnoline-4-carbonitrile (1 g) and water (8 mL) was added concentrated sulfuric acid (8 mL) drop wise. The reaction mixture was heated at 80° C. for 10 days. The reaction mixture was diluted with water (20 mL), basified with aqueous 2M sodium hydroxide, washed with ethyl acetate (3×100 mL) and the aqueous phase was acidified with 2M aqueous hydrochloric acid. The crude product was extracted with ethyl acetate (3×100 mL) and the combined organic layers were concentrated to give 3-methylcinnoline-4-carboxylic acid.
[0256] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.49 (d, 1H) 8.09 (d, 1H) 7.95 (td, 2H) 2.99 (s, 3H) (CO.sub.2H proton missing)
Step 6: Preparation of 2,3-dimethylcinnolin-2-ium-4-carboxylate A61
[0257] To a solution of 3-methylcinnoline-4-carboxylic acid (300 mg) in tetrahydrofuran (9 mL) and 1,4-dioxane (9 mL) was added dimethyl sulphate (0.603 g) drop wise at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 50 hours then concentrated and washed sequentially with tert-butyl methyl ether (2×20 mL) and acetone (10 mL). The resulting solid was purified by preparative reverse phase HPLC to give 2,3-dimethylcinnolin-2-ium-4-carboxylate.
[0258] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.38-8.50 (m, 1H), 8.14-8.23 (m, 3H), 4.84 (s, 3H), 2.95-3.13 (m, 3H)
Example 2: Preparation of ethyl-(2-methylcinnolin-2-ium-4-yl)phosphinate A48
[0259] ##STR00032##
Step 1: Preparation of 4-(p-tolylsulfonyl)cinnoline
[0260] ##STR00033##
[0261] To a solution of 4-chloro-cinnoline (24 g) in N,N-dimethylformamide (200 mL) was added with sodium p-toluenesulfonate (31.2 g) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then quenched into ice water. The resulting solid was filtered and dried to afford 4-(p-tolylsulfonyl)cinnoline as a pale yellow solid.
[0262] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.75 (s, 1H), 8.74-8.67 (m, 2H), 7.94-7.92 (d, 4H), 7.36-7.34 (d, 2H), 2.41 (s, 3H)
Step 2: Preparation of 1-ethylphosphonoyloxyethane
[0263] ##STR00034##
[0264] To a solution of triethyl phosphite (10 g) in tetrahydrofuran (100 mL) was added ethyl magnesium bromide (1.8 mL, 1 M in tetrahydrofuran) at room temperature. The reaction mixture was heated at 80° C. for 16 hours then quenched with 2M aqueous hydrochloric acid (75 mL). The crude product was extracted with ethyl acetate (3×100 mL), dried over sodium sulfate then concentrated. Purification by silica gel chromatography eluting with 0-80% ethyl acetate in iso-hexane afforded 1-ethylphosphonoyloxyethane as a pale yellow oil.
[0265] .sup.1H NMR (400 MHz, CDCl.sub.3) 7.72 (s, 5H), 6.40 (s, 0.5H), 4.20-4.09 (m, 2H), 1.83-1.77 (m, 2H), 1.39-1.35 (t, 3H), 1.19-1.12 (m, 3H)
Step 3: Preparation of 4-[ethoxy(ethyl)phosphoryl]cinnoline
[0266] ##STR00035##
[0267] To a solution of 1-ethylphosphonoyloxyethane (1.28 g) in tetrahydrofuran (20 mL) at 78° C. was added lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran, 10.5 mL) under a nitrogen atmosphere. The mixture was stirred at −78° C. for 1 hour then a solution of 4-(p-tolylsulfonyl)cinnoline (1.00 g) in tetrahydrofuran (10.0 mL) was added to the reaction mixture drop wise at this temperature. The resulting reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (20.0 mL) and extracted with ethyl acetate (3×30 mL). The combined organic phase was dried over sodium sulfate, concentrated, then purified by silica gel chromatography eluting with 0-50% ethyl acetate in iso-hexane to give 4-[ethoxy(ethyl)phosphoryl]cinnoline as a yellow oil.
[0268] .sup.1H NMR (300 MHz, CDCl.sub.3) 9.59-9.56 (d, 1H), 8.70-8.66 (m, 2H), 7.98-7.87 (m, 2H), 4.30-3.99 (m, 2H), 2.18-1.96 (m, 2H), 1.41-1.36 (t, 3H), 1.19-1.07 (m, 3H)
Step 4: Preparation of 4-[ethoxy(ethyl)phosphoryl]-2-methyl-cinnolin-2-ium iodide
[0269] ##STR00036##
[0270] To a solution of 4-[ethoxy(ethyl)phosphoryl]cinnoline (0.65 g) in tetrahydrofuran (20 mL) was added iodomethane (0.49 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then concentrated and triturated with acetone to afford 4-[ethoxy(ethyl)phosphoryl]-2-methyl-cinnolin-2-ium iodide as a brown solid.
[0271] .sup.1H NMR (300 MHz, DMSO-d.sub.6) 9.94-9.91 (d, 1H), 8.94-8.91 (d, 1H), 8.78-8.75 (d, 1H), 8.54-8.42 (m, 2H), 4.95 (s, 3H), 4.24-3.97 (m, 2H), 2.39-2.16 (m, 2H), 1.31-1.27 (t, 3H), 1.10-1.04 (m, 3H)
Step 5: Preparation of ethyl-(2-methylcinnolin-2-ium-4-yl)phosphinate A48
[0272] A mixture of 4-[ethoxy(ethyl)phosphoryl]-2-methyl-cinnolin-2-ium iodide (0.78 g) and concentrated aqueous hydrochloric acid (15 mL) was heated at 100° C. for 16 hours. After cooling to room temperature solvents were removed in vacuo and the residue was concentrated and triturated with acetone (10 mL) to afford ethyl-(2-methylcinnolin-2-ium-4-yl)phosphinate as a black gum.
[0273] .sup.1H NMR (400 MHz, D.sub.2O) 9.38-9.36 (d, 1H), 8.79-8.77 (d, 1H), 8.50-8.47 (d, 1H), 8.27-8.18 (m, 2H), 4.79 (s, 3H), 1.88-1.83 (m, 2H), 0.91-0.82 (m, 3H)
Example 3: Preparation of 2-methylcinnolin-2-ium-4-carboxylic Acid Methyl Sulfate A3
[0274] ##STR00037##
[0275] To a solution of cinnoline-4-carboxylic acid (0.5 g) in toluene (9 mL) was added dimethyl sulfate (0.532 g) drop wise at room temperature under a nitrogen atmosphere. The mixture was heated at 110° C. for 2 hours then cooled to room temperature and concentrated. To this crude product was added acetone followed by heating at reflux for 5 minutes with vigorous stirring. After cooling the resulting precipitate was filtered and dried to give 2-methylcinnolin-2-ium-4-carboxylic acid methyl sulfate as a dark blue/green solid.
[0276] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.65 (d, 1H), 9.20 (d, 1H), 8.64-8.58 (m, 1H), 8.46-8.41 (m, 1H), 8.39-8.31 (m, 1H), 4.94 (s, 3H), 3.66 (s, 3H) (CO.sub.2H proton missing)
Example 4: Preparation of N-methoxy-2-methyl-cinnolin-2-ium-4-carboxamide 2,2,2-trifluoroacetate A4
[0277] ##STR00038##
Step 1: Preparation of N-methoxycinnoline-4-carboxamide
[0278] ##STR00039##
[0279] A mixture of cinnoline-4-carboxylic acid (0.5 g), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (1.03 g) and methoxyammonium chloride (0.264 g) was stirred in acetonitrile (14.4 mL) under a nitrogen atmosphere at room temperature. Triethylamine (0.734 g) was added and the reaction was stirred at room temperature for 3.5 hours. The reaction mixture was concentrated and the residue partitioned between 2M aqueous hydrochloric acid and dichloromethane. The aqueous layer was extracted with further dichloromethane and the combined organic phase was dried over magnesium sulfate and concentrated. The resulting solid was triturated with acetone, filtered then dried to give crude N-methoxycinnoline-4-carboxamide which was used without further purification.
Step 2: Preparation of N-methoxy-2-methyl-cinnolin-2-ium-4-carboxamide 2,2,2-trifluoroacetate A4
[0280] Crude N-methoxycinnoline-4-carboxamide from Step 1 was stirred in iodomethane (5.70 g) at room temperature for 16 hours. The reaction mixture was concentrated and the residue partitioned between water and dichloromethane. The aqueous layer was concentrated then purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give N-methoxy-2-methyl-cinnolin-2-ium-4-carboxamide 2,2,2-trifluoroacetate as a red/brown gum.
[0281] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.94 (s, 1H), 8.94 (br. s., 1H), 8.65 (d, 1H), 8.49-8.27 (m, 2H), 4.94 (s, 3H), 4.05 (s, 3H) (NH proton missing)
Example 5: Preparation of (2-methylcinnolin-2-ium-4-carbonyl)-methylsulfonyl-azanide
[0282] ##STR00040##
Step 1: N-methylsulfonylcinnoline-4-carboxamide
[0283] ##STR00041##
[0284] A mixture of cinnoline-4-carboxylic acid (0.3 g), N,N-dimethylaminopyridine (0.276 g), methanesulfonamide (0.217 g) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.438 g) was stirred in dichloromethane (12.1 mL) under a nitrogen atmosphere at room temperature for 19 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford N-methylsulfonylcinnoline-4-carboxamide as an orange gum.
[0285] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.43 (br s, 1H), 8.59-8.54 (m, 1H), 8.51-8.45 (m, 1H), 8.00-7.91 (m, 2H), 3.53 (s, 3H) (NH proton missing)
Step 2: Preparation of (2-methylcinnolin-2-ium-4-carbonyl)-methylsulfonyl-azanide A5
[0286] A mixture of N-methylsulfonylcinnoline-4-carboxamide (0.18 g) and iodomethane (3.42 g) was stirred at room temperature for 21 hours. The resulting solid was then filtered and dried to afford (2-methylcinnolin-2-ium-4-carbonyl)-methylsulfonyl-azanide as a brown solid.
[0287] 1H NMR (400 MHz, CD.sub.3OD) 9.87 (s, 1H), 9.24-9.11 (m, 1H), 8.63-8.55 (m, 1H), 8.39-8.26 (m, 2H), 4.84-4.77 (m, 3H), 3.24 (s, 3H)
Example 6: Preparation of 2-methylcinnolin-2-ium-4-sulfonate A6
[0288] ##STR00042##
Step 1: Preparation of cinnoline-4-sulfonic Acid
[0289] ##STR00043##
[0290] To a suspension of 4-chlorocinnoline (0.2 g) in water (4 mL) was added sodium sulfite (0.234 g) and the mixture was heated at 100° C. for 1 hour. The reaction mixture was concentrated to give cinnoline-4-sulfonic acid as a yellow solid.
[0291] .sup.1H NMR (400 MHz, D.sub.2O) 9.50 (s, 1H), 8.56-8.48 (m, 1H), 8.48-8.40 (m, 1H), 8.02-7.91 (m, 2H)
Step 2: Preparation of 2-methylcinnolin-2-ium-4-sulfonate A6
[0292] To a mixture of cinnoline-4-sulfonic acid (0.11 g) in toluene (2.62 mL) was added dimethyl sulfate (0.08 g) and the mixture was heated at 110° C. for 2 hours under a nitrogen atmosphere. The reaction mixture was concentrated then purified by preparative reverse phase HPLC to afford 2-methylcinnolin-2-ium-4-sulfonate as a beige solid.
[0293] .sup.1H NMR (400 MHz, D.sub.2O) 9.74 (s, 1H), 8.77 (d, 1H), 8.57 (d, 1H), 8.39-8.33 (m, 1H), 8.32-8.25 (m, 1H), 4.85 (s, 3H)
Example 7: Preparation of (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoic acid 2,2,2-trifluoroacetate A9
[0294] ##STR00044##
Step 1: Preparation of tert-butyl (2R)-2-(cinnoline-4-carbonylamino)propanoate
[0295] ##STR00045##
[0296] A mixture of cinnoline-4-carboxylic acid (0.5 g) and [(1S)-2-tert-butoxy-1-methyl-2-oxo-ethyl]ammonium chloride (0.574 g) in dichloromethane (14.4 mL) was cooled to 0° C. and pyridine (0.751 mL) was added drop wise, followed by the addition of dicyclohexylcarbodiimide (0.718 g) in one portion. The reaction mixture was allowed to warm to room temperature and stirred for 1 hour. The reaction mixture was filtered and the filtrate was concentrated and partitioned between water and ethyl acetate. The organic layer was washed sequentially with water, 0.1M aqueous hydrochloric acid and brine, then dried with magnesium sulfate and concentrated to give tert-butyl (2R)-2-(cinnoline-4-carbonylamino)propanoate as a dark red gum.
[0297] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.38 (s, 1H), 8.61 (dd, 1H), 8.39 (dd, 1H), 7.95-7.82 (m, 2H), 6.86 (d, 1H), 4.83-4.70 (m, 1H), 1.59 (d, 3H), 1.53 (s, 9H)
Step 2: Preparation of tert-butyl (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoate Iodide A8
[0298] ##STR00046##
[0299] A mixture of methyl iodide (1.33 mL) and tert-butyl (2R)-2-(cinnoline-4-carbonylamino)propanoate (0.2 g) were stirred at room temperature for 20 hours. The reaction mixture was concentrated and the residue was triturated with ethyl acetate to afford tert-butyl (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoate iodide as an orange solid.
[0300] .sup.1H NMR (400 MHz, D.sub.2O) 9.75 (s, 1H), 8.70-8.64 (m, 1H), 8.60-8.52 (m, 1H), 8.47-8.38 (m, 2H), 4.96 (s, 3H), 4.65 (d, 1H), 1.60-1.50 (m, 12H) (NH proton missing)
Step 3: Preparation of (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoic acid 2,2,2-trifluoroacetate A9
[0301] A mixture of tert-butyl (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoate iodide (0.14 g) and trifluoroacetic acid (0.947 mL) was stirred at room temperature for 2 hours. The reaction mixture was concentrated then recrystallised with ethyl acetate to afford (2R)-2-[(2-methylcinnolin-2-ium-4-carbonyl)amino]propanoic acid as an orange solid.
[0302] .sup.1H NMR (400 MHz, D.sub.2O) 9.77 (s, 1H), 8.71-8.64 (m, 1H), 8.60-8.50 (m, 1H), 8.48-8.33 (m, 2H), 4.95 (s, 3H), 1.61 (d, 3H) (one CH proton hidden underwater peak, NH and CO.sub.2H protons missing)
Example 8: Preparation of 2-methyl-N-(methylsulfamoyl)cinnolin-2-ium-4-carboxamide A10
[0303] ##STR00047##
Step 1: Preparation of N-(methylsulfamoyl)cinnoline-4-carboxamide
[0304] ##STR00048##
[0305] A mixture of cinnoline-4-carboxylic acid (0.3 g) and 1,1′-carbonyldiimidazole (0.342 g) was heated in tetrahydrofuran (8.61 mL) at 70° C. for 1 hour under a nitrogen atmosphere. The mixture was cooled to room temperature and (sulfamoylamino)methane (0.228 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.342 mL) were added sequentially. The reaction mixture was stirred at room temperature for 22 hours, concentrated, then purified by preparative reverse phase HPLC to afford N-(methylsulfamoyl)cinnoline-4-carboxamide as a pale yellow gum.
[0306] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.39 (s, 1H), 8.62 (d, 1H), 8.42 (d, 1H), 8.05-7.91 (m, 2H), 2.86 (s, 3H) (two NH protons missing)
Step 2: Preparation of 2-methyl-N-(methylsulfamoyl)cinnolin-2-ium-4-carboxamide A10
[0307] A mixture of methyl iodide (1.1 mL) and N-(methylsulfamoyl)cinnoline-4-carboxamide (0.06 g) were stirred at room temperature for 4 hours. The resulting solid was filtered then washed with acetone to afford 2-methyl-N-(methylsulfamoyl)cinnolin-2-ium-4-carboxamide iodide as a pale orange solid.
[0308] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.04 (s, 1H), 8.69 (dd, 2H), 8.56-8.37 (m, 2H), 4.97 (s, 3H), 2.85 (s, 3H) (NH proton missing)
Example 9: Preparation of [2-(2,2-difluoroethyl)cinnolin-2-ium-4-carbonyl]-methylsulfonyl-azanide A14
[0309] ##STR00049##
[0310] A mixture of 2,2-difluoroethyl trifluoromethanesulfonate (0.522 g) and N-methylsulfonylcinnoline-4-carboxamide (200 mg) in acetonitrile (5 mL) was heated at 80° C. overnight. The reaction mixture was cooled and the resulting solid was filtered and dried to give [2-(2,2-difluoroethyl)cinnolin-2-ium-4-carbonyl]-methylsulfonyl-azanide.
[0311] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.16 (s, 1H), 8.80-8.73 (m, 2H), 8.58-8.47 (m, 2H), 6.87-6.56 (m, 1H), 5.68 (dt, 2H), 3.52 (s, 3H)
Example 10: Preparation of 2-methyl-N-(2-methyl-1,2,4-triazol-3-yl)cinnolin-2-ium-4-carboxamide Iodide A25
[0312] ##STR00050##
Step 1: Preparation of N-(2-methyl-1,2,4-triazol-3-yl)cinnoline-4-carboxamide
[0313] ##STR00051##
[0314] A mixture of cinnoline-4-carboxylic acid (0.3 g), triethylamine (0.485 mL) and 1-methyl-1h-1,2,4-triazol-5-amine (0.203 g) was stirred in ethyl acetate (8.61 mL) at room temperature for 15 minutes. Propylphoshonic anhydride (2.05 mL) was added drop wise and the resulting mixture was stirred at room temperature for 20 hours. To this was added 0.5M aqueous hydrochloric acid (30 mL) followed by additional stirring for 2 hours. The resulting precipitate was filtered, washed with 0.5M aqueous hydrochloric acid then dried to afford N-(2-methyl-1,2,4-triazol-3-yl)cinnoline-4-carboxamide as a colourless solid.
[0315] .sup.1H NMR (400 MHz, DMSO-d.sub.6) 11.71 (br. s., 1H), 9.72 (br. s., 1H), 8.63 (d, 1H), 8.35 (br. s., 1H), 8.16-7.86 (m, 2H), 3.85 (br. s., 3H) (NH proton missing)
Step 2: Preparation of 2-methyl-N-(2-methyl-1,2,4-triazol-3-yl)cinnolin-2-ium-4-carboxamide Iodide A25
[0316] A mixture of methyl iodide (0.123 mL), N-(2-methyl-1,2,4-triazol-3-yl)cinnoline-4-carboxamide (0.1 g) and methanol (1.18 mL) was heated at 60° C. for 24 hours. The resulting precipitate was filtered, washed with acetone then dried to afford 2-methyl-N-(2-methyl-1,2,4-triazol-3-yl)cinnolin-2-ium-4-carboxamide iodide as an orange solid.
[0317] .sup.1H NMR (400 MHz, D.sub.2O) 9.78 (s, 1H), 8.89-8.78 (m, 1H), 8.57-8.49 (m, 1H), 8.31-8.22 (m, 2H), 8.20 (s, 1H), 4.85 (s, 3H), 3.76 (s, 3H) (NH proton missing)
Example 11: Preparation of ethoxy-[(2-methylcinnolin-2-ium-4-yl)methyl]phosphinic Acid A51
[0318] ##STR00052##
Step 1: Preparation of ethyl 2-cinnolin-4-yl-2-diethoxyphosphoryl-acetate
[0319] ##STR00053##
[0320] To a suspension of 4-(p-tolylsulfonyl)cinnoline (1 g) and caesium carbonate (5.74 g) in N,N-dimethylformamide (35.2 mL) was added ethyl 2-diethoxyphosphorylacetate (0.863 mL) and the reaction mixture was stirred at room temperature for 72 hours. The reaction mixture was partitioned between water (50 mL) and dichloromethane (200 mL). The organic phase was washed with water (5×50 mL), dried with sodium sulfate, concentrated then purified by silica gel chromatography eluting with 0 to 100% ethyl acetate in iso-hexane to give ethyl 2-cinnolin-4-yl-2-diethoxyphosphoryl-acetate as an orange oil.
[0321] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.60 (d, 1H), 8.49-8.53 (m, 1H), 8.36-8.39 (m, 1H), 7.93-8.03 (m, 2H), 3.93-4.37 (m, 7H), 1.21-1.30 (m, 6H), 1.09 (t, 3H)
Step 2: Preparation of cinnolin-4-ylmethyl(ethoxy)phosphinic Acid
[0322] ##STR00054##
[0323] A mixture of ethyl 2-cinnolin-4-yl-2-diethoxyphosphoryl-acetate (300 mg) and 2.5M aqueous sodium hydroxide (2 mL) was heated at reflux for 2 hours. The reaction mixture was neutralised with saturated aqueous ammonium chloride and washed with dichloromethane. The aqueous layer was concentrated, stirred in acetone, filtered then dried to give cinnolin-4-ylmethyl(ethoxy)phosphinic acid as a green oil.
[0324] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.27 (d, 1H), 8.42-8.33 (m, 2H), 8.00-7.88 (m, 2H), 3.91-3.81 (m, 2H), 3.62-3.51 (m, 2H), 1.14 (t, 3H) (POH proton missing)
Step 3: Preparation of ethoxy-[(2-methylcinnolin-2-ium-4-yl)methyl]phosphinic Acid A51
[0325] To a mixture of cinnolin-4-ylmethyl(ethoxy)phosphinic acid (220 mg), acetone (2 mL) and iodomethane (0.543 mL) was added a minimum amount of methanol. The solution was stirred at room temperature overnight, concentrated, then purified by preparative reverse phase HPLC to afford ethoxy-[(2-methylcinnolin-2-ium-4-yl)methyl]phosphinic acid.
[0326] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.57 (d, 1H), 8.60-8.68 (m, 1H), 8.48-8.57 (m, 1H), 8.27-8.35 (m, 2H), 4.89 (s, 3H), 4.00 (quin, 2H), 3.82-3.93 (m, 2H), 1.21 (t, 3H) (Some exchange of CH.sub.2 protons)
Example 12: Preparation of (2-methylcinnolin-2-ium-4-yl)methylphosphonic Acid A50
[0327] ##STR00055##
Step 1: Preparation of 4-(diethoxyphosphorylmethyl)cinnoline
[0328] ##STR00056##
[0329] A mixture of ethyl 2-cinnolin-4-yl-2-diethoxyphosphoryl-acetate (250 mg) and 0.5M aqueous sodium hydroxide (1 mL) was heated at 60° C. for 90 minutes. The reaction mixture was neutralised with saturated aqueous ammonium chloride and washed with dichloromethane. The organic layer was concentrated then purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to give 4-(diethoxyphosphorylmethyl)cinnoline.
[0330] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.27 (d, 1H), 8.39-8.48 (m, 1H), 8.31 (d, 1H), 7.85-8.01 (m, 2H), 4.09 (q, 4H), 3.90 (d, 2H), 1.22 (q, 6H)
Step 2: Preparation of 4-(diethoxyphosphorylmethyl)-2-methyl-cinnolin-2-ium iodide A47
[0331] ##STR00057##
[0332] A mixture of 4-(diethoxyphosphorylmethyl)cinnoline (125 mg), acetone (2 mL) and iodomethane (0.139 mL) was stirred at room temperature overnight. The resulting precipitate was then filtered to afford 4-(diethoxyphosphorylmethyl)-2-methyl-cinnolin-2-ium iodide as a brown solid.
[0333] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.69 (d, 1H), 8.59-8.68 (m, 2H), 8.33-8.42 (m, 2H), 4.93 (s, 3H), 4.07-4.25 (m, 4H), 1.27 (t, 6H). (Note: benzylic protons exchanged in the deuterated solvent)
Step 3: Preparation of (2-methylcinnolin-2-ium-4-yl)methylphosphonic Acid A50
[0334] A mixture of 4-(diethoxyphosphorylmethyl)-2-methyl-cinnolin-2-ium (100 mg) and concentrated hydrochloric acid (1 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC to afford (2-methylcinnolin-2-ium-4-yl)methylphosphonic acid.
[0335] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.59 (d, 1H), 8.59-8.67 (m, 1H), 8.48-8.57 (m, 1H), 8.25-8.34 (m, 2H), 4.88 (s, 3H), 3.91 (d, 1H) (partial exchange of CH.sub.2 at 3.91, POH proton missing)
Example 13: Preparation of ethoxy-[2-(2-methylcinnolin-2-ium-4-yl)ethyl]phosphinic Acid 2,2,2-trifluoroacetate A54
[0336] ##STR00058##
Step 1: Preparation of 4-(2-diethoxyphosphorylethyl)cinnoline
[0337] ##STR00059##
[0338] A microwave vial was charged with 4-chlorocinnoline (0.5 g), 1-[ethoxy(vinyl)phosphoryl]oxyethane (0.934 mL), palladium (II) acetate (0.0341 g), tris-o-tolylphosphane (0.102 g), triethylamine (1.27 mL) and N,N-dimethylformamide (9.87 mL), purged with nitrogen then heated at 150° C. under microwave irradiation for 30 minutes. The reaction mixture was diluted with dichloromethane, concentrated, then purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to give 4-(2-diethoxyphosphorylethyl)cinnoline as an orange gum.
[0339] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.21 (s, 1H), 8.58-8.51 (m, 1H), 8.10-8.03 (m, 1H), 7.91-7.78 (m, 2H), 4.22-4.07 (m, 4H), 3.45-3.34 (m, 2H), 2.27-2.14 (m, 2H), 1.36-1.31 (m, 6H)
Step 2: Preparation of 4-(2-diethoxyphosphorylethyl)-2-methyl-cinnolin-2-ium iodide
[0340] ##STR00060##
[0341] To a solution of 4-(2-diethoxyphosphorylethyl)cinnoline (0.129 g) in acetone (2.19 mL) was added iodomethane (0.273 mL) and lithium chloride (0.002 g). The reaction mixture was heated at 40° C. for 6 hours then left to stand overnight. The reaction mixture was concentrated to give 4-(2-diethoxyphosphorylethyl)-2-methyl-cinnolin-2-ium iodide as a brown gum, which was used without further purification.
[0342] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.88 (s, 1H), 8.61-8.53 (m, 2H), 8.44-8.32 (m, 2H), 4.96 (s, 3H), 4.28-4.12 (m, 4H), 3.77-3.68 (m, 2H), 2.65-2.53 (m, 2H), 1.37-1.31 (m, 6H)
Step 3: Preparation of ethoxy-[2-(2-methylcinnolin-2-ium-4-yl)ethyl]phosphinic acid 2,2,2-trifluoroacetate A54
[0343] A mixture of 4-(2-diethoxyphosphorylethyl)-2-methyl-cinnolin-2-ium iodide (0.19 g) and concentrated hydrochloric acid (1.74 mL) was heated at reflux for 3 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to afford ethoxy-[2-(2-methylcinnolin-2-ium-4-yl)ethyl]phosphinic acid 2,2,2-trifluoroacetate as a yellow gum.
[0344] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.67 (s, 1H), 8.62-8.54 (m, 2H), 8.39-8.30 (m, 2H), 4.90 (s, 3H), 4.11-4.02 (m, 2H), 3.67 (ddd, 2H), 2.36-2.25 (m, 2H), 1.28 (t, 3H) (POH proton missing)
Example 14: Preparation of 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetic Acid Chloride
[0345] ##STR00061##
Step 1: Preparation of methyl 2-cinnolin-4-ylsulfanylacetate
[0346] ##STR00062##
[0347] A mixture of methyl 2-sulfanylacetate (0.14 g), potassium carbonate (0.267 g), 4-(p-tolylsulfonyl)cinnoline (250 mg) and acetone (8.8 mL) was heated at reflux for 5 hours. The reaction mixture was filtered and concentrated to give methyl 2-cinnolin-4-ylsulfanylacetate as a yellow solid, which was used without further purification.
Step 2: Preparation of methyl 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetate Iodide
[0348] ##STR00063##
[0349] To a mixture of methyl 2-cinnolin-4-ylsulfanylacetate (194 mg), acetone (8.28 mL) and iodomethane (0.515 mL) was added a minimum amount of methanol. The solution was stirred at room temperature overnight, concentrated, then purified by preparative reverse phase HPLC to afford methyl 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetate iodide as an off white solid.
[0350] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.59 (s, 1H), 8.50-8.55 (m, 1H), 8.43-8.48 (m, 1H), 8.26-8.34 (m, 2H), 4.85 (s, 3H), 4.50 (s, 2H), 3.83 (s, 3H)
Step 3: Preparation of 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetic Acid Chloride A57
[0351] A mixture of methyl 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetate iodide (0.1 g) and concentrated hydrochloric acid (2 mL) was heated at 70° C. for 2 hours. The reaction mixture was concentrated to afford 2-(2-methylcinnolin-2-ium-4-yl)sulfanylacetic acid chloride.
[0352] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.62 (s, 1H), 8.53-8.48 (m, 1H), 8.48-8.42 (m, 1H), 8.34-8.25 (m, 2H), 4.87 (s, 3H), 4.49 (s, 2H) (CO.sub.2H proton missing)
Example 15: Preparation of [2-[2-(methanesulfonamido)-2-oxo-ethyl]cinnolin-2-ium-4-yl]-methoxy-phosphinate A63
[0353] ##STR00064##
Step 1: Preparation of 2-bromo-N-methylsulfonyl-acetamide
[0354] ##STR00065##
[0355] To a solution of methanesulfonamide (1 g) in toluene (63 mL) was added 2-bromoacetyl bromide (3.7 mL) drop wise at room temperature. The reaction was heated at 70° C. for 5 hours then cooled to room temperature. After further cooling over ice and the resulting precipitate was filtered, washed with cold toluene then dried to give 2-bromo-N-methylsulfonyl-acetamide as a pale yellow solid.
[0356] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.81 (br s, 1H), 3.95 (s, 2H), 3.35 (s, 3H)
Step 2: Preparation of [2-[2-(methanesulfonamido)-2-oxo-ethyl]cinnolin-2-ium-4-yl]-methoxy-phosphinate A63
[0357] To a mixture of 4-dimethoxyphosphorylcinnoline (200 mg) in acetone (2 mL) was added 2-bromo-N-methylsulfonyl-acetamide (362 mg) over 10 minutes. The mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between water and dichloromethane.
[0358] The aqueous layer was concentrated and purified by preparative reverse phase HPLC to give [2-[2-(methanesulfonamido)-2-oxo-ethyl]cinnolin-2-ium-4-yl]-methoxy-phosphinate as a brown foamy solid.
[0359] .sup.1H NMR (400 MHz, D.sub.2O) 9.46-9.56 (m, 1H) 8.75 (d, 1H) 8.55 (d, 1H) 8.22-8.41 (m, 2H) 5.91-5.99 (m, 2H) 3.51 (s, 3H) 3.17 (s, 3H) (NH proton missing)
Example 16: Preparation of (2-tert-butylcinnolin-2-ium-4-yl)-ethoxy-phosphinate A75
[0360] ##STR00066##
Step 1: Preparation of 4-diethoxyphosphorylcinnoline
[0361] ##STR00067##
[0362] To a stirred suspension of sodium hydride (0.106 g, 60% in mineral oil) in tetrahydrofuran (17.6 mL) was added diethyl phosphite (0.364 g) at 0° C. under a nitrogen atmosphere, followed by stirring for 30 minutes. This mixture was then added dropwise to an ice cold solution of 4-(p-tolylsulfonyl)cinnoline (0.5 g) in tetrahydrofuran (4.8 mL). After warming to room temperature the combined mixture was stirred for a further 2 hours then left to stand overnight. After dilution with water (50 mL) and extraction with dichloromethane (3×) the organic phase was washed sequentially with water and brine, then dried over magnesium sulfate and concentrated to give 4-diethoxyphosphorylcinnoline as a yellow gum.
[0363] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.64 (d, 1H), 8.69-8.62 (m, 1H), 8.55-8.49 (m, 1H), 7.98-7.86 (m, 2H), 4.37-4.16 (m, 4H), 1.37 (t, 6H)
Step 2: Preparation of 2-tert-butyl-4-diethoxyphosphoryl-cinnolin-2-ium perchlorate A73
[0364] ##STR00068##
[0365] To a stirred solution of 4-diethoxyphosphorylcinnoline (0.6 g) in tert-butylacetate (10 mL) was added perchloric acid (1.06 mL) at room temperature. The reaction mixture was stirred at room temperature for 16 hours then quenched with ice, diluted with water (100 mL) and extracted with ethyl acetate (2×75 mL). The combined organic phase was dried over sodium sulfate then concentrated to give 2-tert-butyl-4-diethoxyphosphoryl-cinnolin-2-ium perchlorate as a brown liquid.
[0366] .sup.1H NMR (400 MHz, D.sub.2O) 9.65-9.63 (d, 1H), 8.69-8.67 (d, 1H), 8.61-8.59 (d, 1H), 8.40-8.29 (m, 2H), 4.34-4.18 (m, 4H), 1.90 (s, 9H), 1.28-1.26 (t, 6H)
Step 3: Preparation of (2-tert-butylcinnolin-2-ium-4-yl)-ethoxy-phosphinate A73
[0367] A solution of 2-tert-butyl-4-diethoxyphosphoryl-cinnolin-2-ium perchlorate (0.3 g) in concentrated hydrochloric acid (10 mL) was stirred at room temperature for 72 hours. The reaction mixture was concentrated then purified by preparative reverse phase HPLC to give (2-tert-butylcinnolin-2-ium-4-yl)-ethoxy-phosphinate as a brown liquid.
[0368] .sup.1H NMR (400 MHz, D.sub.2O) 9.57-9.55 (d, 1H), 8.69-8.67 (d, 1H), 8.58-8.56 (d, 1H), 8.29-8.20 (m, 2H), 3.85-3.78 (m, 2H), 1.87 (s, 9H), 1.11-1.07 (t, 3H)
Example 17: Preparation of isopropoxy-(2-isopropylcinnolin-2-ium-4-yl)phosphinate A74
[0369] ##STR00069##
[0370] A mixture of 4-di-isopropylphosphorylcinnoline (0.4 g) and 2-iodopropane (6.46 mL) was heated for 1 hour at 100° C. under microwave irradiation. The reaction mixture was then filtered through diatomaceous earth, concentrated and purified by preparative reverse phase HPLC to give isopropoxy-(2-isopropylcinnolin-2-ium-4-yl)phosphinate as a light brown solid.
[0371] .sup.1H NMR (400 MHz, D.sub.2O) 9.46-9.43 (d, 1H), 8.70-8.68 (d, 1H), 8.54-8.52 (d, 1H), 8.28-8.19 (m, 2H), 5.46-5.39 (m, 1H), 4.45-4.37 (m, 1H), 1.72-1.70 (d, 6H), 1.08-1.07 (d, 6H)
Example 18: Preparation of [2-(2-hydroxyethyl)cinnolin-2-ium-4-yl]-methoxy-phosphinate A68
[0372] ##STR00070##
Step 1: Preparation of cinnolin-4-yl(methoxy)phosphinic Acid
[0373] ##STR00071##
[0374] To mixture of 4-dimethoxyphosphorylcinnoline (3.41 g) and 1,4-dioxane (100 mL) was added aqueous 3M sodium hydroxide (24 mL) drop wise and the resulting mixture was stirred for 2 hours at room temperature. The reaction mixture was concentrated then partitioned between water and dichloromethane. The aqueous layer was acidified to pH 3 with concentrated hydrochloric acid, concentrated and the residue was stirred in methanol. After filtration the filtrate was concentrated then purified by preparative reverse phase HPLC to give cinnolin-4-yl(methoxy)phosphinic acid.
[0375] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.58 (d, 1H), 8.87-8.82 (m, 1H), 8.64-8.59 (m, 1H), 8.23-8.17 (m, 2H), 3.67 (d, 3H) (POH proton missing)
Step 2: Preparation of [2-(2-hydroxyethyl)cinnolin-2-ium-4-yl]-methoxy-phosphinate A68
[0376] A mixture of 1,3,2-dioxathiolane 2,2-dioxide (161 mg), cinnolin-4-yl(methoxy)phosphinic acid (290 mg) and 1,2-dichloroethane (5 mL) was heated at 85° C. overnight. The reaction mixture was concentrated and partitioned between water and dichloromethane. The aqueous layer was concentrated and purified by preparative reverse phase HPLC to give [2-(2-hydroxyethyl)cinnolin-2-ium-4-yl]-methoxy-phosphinate as a brown gum.
[0377] .sup.1H NMR (400 MHz, D.sub.2O) 9.45-9.51 (m, 1H) 8.71 (d, 1H) 8.51-8.57 (m, 1H) 8.20-8.33 (m, 2H) 5.15 (dd, 2H) 4.17-4.25 (m, 2H) 3.47-3.57 (m, 3H) (OH proton missing) Also isolated from this reaction was hydroxy-[2-(2-hydroxyethyl)cinnolin-2-ium-4-yl]phosphinate A67 as a brown gum.
##STR00072##
[0378] .sup.1H NMR (400 MHz, D.sub.2O) 9.45-9.51 (m, 1H) 8.68-8.74 (m, 1H) 8.47-8.51 (m, 1H) 8.46 (s, 1H) 8.15-8.29 (m, 2H) 5.12 (dd, 2H) 4.14-4.26 (m, 2H) (OH or POH proton missing).
Example 19: Preparation of hydroxy-(2-methylcinnolin-2-ium-4-yl)phosphinate A78
[0379] ##STR00073##
[0380] To a suspension of methoxy-(2-methylcinnolin-2-ium-4-yl)phosphinate (0.2 g) in dichloromethane (2 mL) was added bromotrimethylsilane (0.394 g) at room temperature. The reaction mixture was stirred for 5 hours then concentrated, triturated with acetone and dried to give hydroxy-(2-methylcinnolin-2-ium-4-yl)phosphinate as a pale brown solid.
[0381] .sup.1H NMR (400 MHz, D.sub.2O) 9.46 (d, 1H), 8.72 (d, 1H), 8.49 (d, 1H), 8.31-8.17 (m, 2H), 4.81 (s, 3H) (POH proton missing)
Example 20: Preparation of [2-(2-methoxy-2-oxo-ethyl)cinnolin-2-ium-4-carbonyl]-methylsulfonyl-azanide A15
[0382] ##STR00074##
[0383] A mixture of methyl 2-bromoacetate (0.23 mL) and N-methylsulfonylcinnoline-4-carboxamide (0.2 g) in acetonitrile (5 mL) was heated at 80° C. overnight. The reaction mixture was concentrated and the residue partitioned between dichloromethane and water. The aqueous phase was concentrated and purified by preparative reverse phase HPLC to give [2-(2-methoxy-2-oxo-ethyl)cinnolin-2-ium-4-carbonyl]-methylsulfonyl-azanide, .sup.1H NMR (400 MHz, CD.sub.3OD) 10.01 (s, 1H), 9.27-9.21 (m, 1H), 8.62-8.57 (m, 1H), 8.42-8.31 (m, 2H), 6.11-6.06 (m, 1H), 3.87 (s, 3H), 3.22 (s, 3H) (One proton at 6.11-6.06 exchanged out)
Example 21: Preparation of cyclopropylsulfonyl-[2-(3-methoxy-3-oxo-propyl)cinnolin-2-ium-4-carbonyl]azanide A19
[0384] ##STR00075##
[0385] A mixture of methyl 3-bromopropanoate (0.18 mL) and N-cyclopropylsulfonylcinnoline-4-carboxamide (0.15 g) in acetonitrile (4 mL) was heated at 80° C. overnight. A further aliquot of methyl 3-bromopropanoate (0.18 mL) was added and heating continued again overnight. The reaction mixture was concentrated and the residue partitioned between dichloromethane and water. The aqueous phase was concentrated and purified by preparative reverse phase HPLC to give cyclopropylsulfonyl-[2-(3-methoxy-3-oxo-propyl)cinnolin-2-ium-4-carbonyl]azanide.
[0386] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.04 (s, 1H), 9.01-8.95 (m, 1H), 8.64-8.57 (m, 1H), 8.40-8.32 (m, 2H), 5.41 (t, 2H), 3.69 (s, 3H), 3.40 (t, 2H), 3.15-3.08 (m, 1H), 1.32-1.19 (m, 2H), 1.16-1.04 (m, 2H) [2-(2-carboxyethyl)cinnolin-2-ium-4-carbonyl]-cyclopropylsulfonyl-azanide A20, was also isolated from this reaction mixture
##STR00076##
[0387] .sup.1H NMR (400 MHz, CD.sub.3OD) 10.07 (s, 1H), 8.90-8.84 (m, 1H), 8.67-8.58 (m, 1H), 8.41-8.32 (m, 2H), 5.40 (t, 2H), 3.38 (t, 2H), 3.12 (tt, 1H), 1.30-1.23 (m, 2H), 1.16-1.08 (m, 2H) (CO.sub.2H proton missing)
Example 22: Preparation of 2-(carboxymethyl)cinnolin-2-ium-4-carboxylate A23
[0388] ##STR00077##
[0389] A mixture of [2-(2-methoxy-2-oxo-ethyl)cinnolin-2-ium-4-carbonyl]-methylsulfonyl-azanide (0.25 g) and aqueous 2M hydrochloric acid (4 mL) was heated at 80° C. for 2 hours. The mixture was concentrated and triturated with acetone to give 2-(carboxymethyl)cinnolin-2-ium-4-carboxylate as a brown solid.
[0390] .sup.1H NMR (400 MHz, D.sub.2O) 9.68 (s, 1H), 8.77-8.73 (m, 1H), 8.53-8.48 (m, 1H), 8.32-8.21 (m, 2H), 5.85 (s, 2H) (CO.sub.2H proton missing)
Example 23: Preparation of 2-(4-carboxycinnolin-2-ium-2-yl)ethyl sulfate A28
[0391] ##STR00078##
[0392] To a mixture of cinnoline-4-carboxylic acid (0.4 g) and 1,2-dichloroethane (8 mL) was added 1,3,2-dioxathiolane 2,2-dioxide (0.312 g) and the mixture was heated at 85° C. overnight. The resulting precipitate was filtered off, washed with acetone and The reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was concentrated 2-(4-carboxycinnolin-2-ium-2-yl)ethyl sulfate as a yellow solid.
[0393] .sup.1H NMR (400 MHz, D.sub.2O) 9.67 (s, 1H) 8.64-8.76 (m, 1H) 8.47-8.58 (m, 1H) 8.15-8.33 (m, 2H) 5.29-5.37 (m, 2H) 4.62-4.76 (m, 2H) (CH.sub.2 underwater peak, CO.sub.2H proton missing)
Example 24: Preparation of 3-(2-methylcinnolin-2-ium-4-yl)propanoic Acid Chloride A55
[0394] ##STR00079##
Step 1: Preparation of methyl 3-cinnolin-4-ylpropanoate
[0395] ##STR00080##
[0396] A microwave vial was charged with 4-chlorocinnoline (0.5 g), methyl acrylate (0.547 mL), palladium (II) acetate (0.034 g), tris-o-tolylphosphane (0.102 g), triethylamine (1.27 mL) and N,N-dimethylformamide (9.87 mL), purged with nitrogen then heated at 150° C. under microwave irradiation for 30 minutes. The reaction mixture was diluted with dichloromethane and washed with water (3×). The organic phase was concentrated, then purified by silica gel chromatography eluting with 0 to 10% methanol in dichloromethane to give methyl 3-cinnolin-4-ylpropanoate as a brown gum.
[0397] .sup.1H NMR (400 MHz, CDCl.sub.3) 9.20 (s, 1H), 8.56 (d, 1H), 8.08-8.00 (m, 1H), 7.90-7.76 (m, 2H), 3.71 (s, 3H), 3.43 (t, 2H), 2.82 (t, 2H)
Step 2: Preparation of methyl 3-(2-methylcinnolin-2-ium-4-yl)propanoate Iodide A81
[0398] ##STR00081##
[0399] To a stirred solution of methyl 3-cinnolin-4-ylpropanoate (0.503 g) in acetone (9.89 mL) was added iodomethane (1.23 mL) and lithium chloride (0.008 g). The reaction mixture was heated at 40° C. for 6 hours. The reaction mixture was cooled to room temperature and allowed to stand overnight. The reaction mixture was concentrated to give methyl 3-(2-methylcinnolin-2-ium-4-yl)propanoate iodide which was used without further purification.
[0400] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.69 (s, 1H), 8.63-8.55 (m, 2H), 8.38-8.29 (m, 2H), 4.89 (s, 3H), 3.75-3.65 (m, 5H), 3.05-3.00 (m, 2H)
Step 3: Preparation of 3-(2-methylcinnolin-2-ium-4-yl)propanoic acid 2,2,2-trifluoroacetate A56
[0401] ##STR00082##
[0402] A mixture of methyl 3-(2-methylcinnolin-2-ium-4-yl)propanoate iodide (0.723 g) and aqueous 2M hydrochloric acid (16.1 mL) was heated at 60° C. for 2.5 hours. The reaction mixture was cooled to room temperature and allowed to stand for 72 hours. The reaction mixture was concentrated and purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give 3-(2-methylcinnolin-2-ium-4-yl)propanoic acid 2,2,2-trifluoroacetate.
[0403] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.66 (s, 1H), 8.64-8.54 (m, 2H), 8.38-8.28 (m, 2H), 4.91 (s, 3H), 3.69 (t, 2H), 2.97 (t, 2H) (CO.sub.2H proton missing)
Step 4: Preparation of 3-(2-methylcinnolin-2-ium-4-yl)propanoic Acid Chloride A55
[0404] A column was packed with Discovery DSC-SCX ion exchange resin (2 g). It was washed with methanol (3 column volumes). To this was added 3-(2-methylcinnolin-2-ium-4-yl)propanoic acid 2,2,2-trifluoroacetate (0.11 g) dissolved in a minimum amount of methanol. The column was eluted with methanol (3 column volumes) and then eluted with 3M hydrogen chloride in methanol (3 column volumes). The methanolic hydrogen chloride fractions were combined and concentrated to give 3-(2-methylcinnolin-2-ium-4-yl)propanoic acid chloride as a green gum.
[0405] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.73 (s, 1H), 8.65-8.54 (m, 2H), 8.41-8.28 (m, 2H), 4.93 (s, 3H), 3.78-3.70 (m, 2H), 3.04 (t, 2H) (CO.sub.2H proton missing)
Example 25: Preparation of (2-ethylcinnolin-2-ium-4-carbonyl)-methylsulfonyl-azanide A22
[0406] ##STR00083##
[0407] A mixture of iodoethane (0.2 mL) and N-methylsulfonylcinnoline-4-carboxamide (0.2 g) in acetonitrile (5 mL) was heated at 80° C. overnight. A further aliquot of iodoethane (0.2 mL) was added and heating continued again overnight. A third aliquot of iodoethane (0.2 mL) was added and heating continued again overnight. The reaction mixture was concentrated and the residue partitioned between dichloromethane and water. The aqueous phase was concentrated and purified by preparative reverse phase HPLC to give (2-ethylcinnolin-2-ium-4-carbonyl)-methylsulfonyl-azanide.
[0408] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.99 (s, 1H), 8.98-8.92 (m, 1H), 8.68-8.60 (m, 1H), 8.40-8.32 (m, 2H), 5.19 (q, 2H), 3.34-3.32 (m, 3H), 1.84 (t, 3H)
Example 26: Preparation of ethyl 2-(2-methylcinnolin-2-ium-4-yl)acetate 2,2,2-trifluoroacetate A52
[0409] ##STR00084##
Step 1: Preparation of diethyl 2-cinnolin-4-ylpropanedioate
[0410] ##STR00085##
[0411] To a suspension of 4-(p-tolylsulfonyl)cinnoline (1 g) and dicesium carbonate (5.74 g) in N,N-dimethylformamide (35.17 mL) was added diethyl propanedioate (0.854 g). The mixture was stirred at room temperature for 72 hours. and the reaction stirred at room temperature over the weekend. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with water (5×), concentrated then purified by silica gel chromatography eluting with a mixture of methanol and dichloromethane to give diethyl 2-cinnolin-4-ylpropanedioate.
[0412] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.36 (s, 1H), 8.49-8.57 (m, 1H), 8.22 (d, 1H), 7.88-8.05 (m, 2H), 5.49 (s, 1H), 4.27 (dd, 4H), 1.25 (s, 6H)
Step 2: Preparation of ethyl 2-cinnolin-4-ylacetate
[0413] ##STR00086##
[0414] To a solution of diethyl 2-cinnolin-4-ylpropanedioate (0.2 g) in DMSO (6.94 mL) was added a solution of sodium chloride (0.049 g) in water (0.5 mL). The mixture was heated at 150° C. for 3 hours. The mixture was concentrated and purified by silica gel chromatography eluting with a mixture of ethyl acetate and iso-hexane to give ethyl 2-cinnolin-4-ylacetate, which was used without purification in the next step.
Step 3: Preparation of ethyl 2-(2-methylcinnolin-2-ium-4-yl)acetate 2,2,2-trifluoroacetate A52
[0415] A mixture of ethyl 2-cinnolin-4-ylacetate (0.04 g) and iodomethane (0.115 mL) in acetone (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated then purified by preparative reverse phase HPLC (trifluoroacetic acid was present in the eluent) to give ethyl 2-(2-methylcinnolin-2-ium-4-yl)acetate 2,2,2-trifluoroacetate.
[0416] .sup.1H NMR (400 MHz, CD.sub.3OD) 9.72 (s, 1H), 8.66-8.57 (m, 1H), 8.56-8.48 (m, 1H), 8.40-8.31 (m, 2H), 4.92 (s, 3H), 4.23 (q, 2H), 1.28 (t, 3H) (CH.sub.2 exchanged)
Example 27: Preparation of 3-[2-(3-phosphonopropyl)cinnolin-2-ium-4-yl]propylphosphonic Acid Chloride A82
[0417] ##STR00087##
Step 1: Preparation of 2,4-bis(3-diethoxyphosphorylpropyl)cinnolin-2-ium bromide
[0418] ##STR00088##
[0419] To a solution of 1-bromo-3-diethoxyphosphoryl-propane (1.9 g) in N,N-dimethylformamide (5 mL) was added cinnoline (0.5 g) and sodium iodide (catalytic) at room temperature. The reaction mixture was heated at 100° C. for 4 hours. The reaction mixture was concentrated to afford crude 2,4-bis(3-diethoxyphosphorylpropyl)cinnolin-2-ium bromide as a dark brown liquid, which was used without further purification.
Step 2: Preparation of 3-[2-(3-phosphonopropyl)cinnolin-2-ium-4-yl]propylphosphonic Acid Chloride A82
[0420] A solution of 2,4-bis(3-diethoxyphosphorylpropyl)cinnolin-2-ium bromide (0.75 g) in conc. hydrochloric acid (10 mL) was heated at 100° C. for 16 hours. The reaction mixture was cooled to room temperature, concentrated and purified by preparative reverse phase HPLC 3-[2-(3-phosphonopropyl)cinnolin-2-ium-4-yl]propylphosphonic acid chloride as a pale yellow liquid.
[0421] .sup.1H NMR (300 MHz, D.sub.2O) 9.45 (s, 1H), 8.49-8.41 (m, 2H), 8.22-8.20 (m, 2H), 5.07-5.02 (t, 2H), 3.45-3.40 (t, 2H), 2.43-2.32 (m, 2H), 2.06-2.01 (m, 2H), 1.82-1.65 (m, 4H) (POH protons missing)
[0422] Additional compounds in Table A were prepared by analogous procedures, from appropriate starting materials.
TABLE-US-00014 TABLE A Physical data for compounds of the invention Compound Number Structure .sup.1H NMR A1
BIOLOGICAL EXAMPLES
Post-Emergence Efficacy
[0423] Seeds of a variety of test species were sown in standard soil in pots. After cultivation for 14 days (post-emergence) under controlled conditions in a glasshouse (at 24/16° C., day/night; 14 hours light; 65% humidity), the plants were sprayed with an aqueous spray solution derived from the dissolution of the technical active ingredient formula (I) in a small amount of acetone and a special solvent and emulsifier mixture referred to as IF50 (11.12% Emulsogen EL360™+44.44% N-methylpyrrolidone+44.44% Dowanol DPM glycol ether), to create a 50 g/l solution which was then diluted to required concentration using 0.25% or 1% Empicol ESC70 (Sodium lauryl ether sulphate)+1% ammonium sulphate in water as diluent.
[0424] The test plants were then grown in a glasshouse under controlled conditions (at 24/16° C., day/night; 14 hours light; 65% humidity) and watered twice daily. After 13 days the test was evaluated (100=total damage to plant; 0=no damage to plant).
The results are shown in Table B (below). A value of n/a indicates that this combination of weed and test compound was not tested/assessed.
Test Plants:
[0425] Ipomoea hederacea (IPOHE), Euphorbia heterophylla (EPHHL), Chenopodium album (CHEAL), Amaranthus palmeri (AMAPA), Lolium perenne (LOLPE), Digitaria sanguinalis (DIGSA), Eleusine indica (ELEIN), Echinochloa crus-galli (ECHCG), Setaria faberi (SETFA)
TABLE-US-00015 TABLE B Control of weed species by compounds of formula (I) after post-emergence application Compound Application No. Rate g/Ha AMAPA CHEAL EPHHL IPOHE ELEIN LOLPE DIGSA SETFA ECHCG A1 1000 100 100 70 70 100 50 90 30 20 A2 1000 100 70 70 70 70 30 60 60 30 A3 1000 20 20 30 20 60 20 50 10 30 A4 1000 10 40 50 20 20 0 0 10 10 A5 1000 100 90 90 90 90 50 90 70 50 A6 1000 10 60 60 0 10 10 10 10 10 A7 1000 100 100 90 70 80 40 100 70 70 A8 1000 20 30 30 10 10 20 20 10 20 A9 1000 50 50 50 50 40 10 40 30 20 A10 1000 80 70 70 30 60 30 70 50 50 A11 1000 40 60 70 60 30 20 40 50 50 A12 1000 60 60 70 70 30 40 20 60 30 A13 1000 0 0 10 10 10 10 10 10 10 A14 1000 20 20 40 40 30 0 40 30 20 A15 1000 50 30 30 10 0 10 0 10 20 A16 1000 50 60 30 40 0 10 0 10 20 A17 1000 50 30 20 40 20 10 10 10 0 A18 1000 10 10 10 20 20 0 30 10 20 A19 500 30 60 40 30 50 20 40 0 60 A20 1000 50 30 20 10 0 0 0 0 10 A21 1000 90 70 80 80 80 60 70 90 50 A22 1000 70 70 60 90 70 60 80 70 50 A23 1000 50 50 20 20 40 10 70 30 30 A24 1000 70 70 40 60 50 20 40 50 50 A25 1000 50 50 20 30 10 10 10 20 10 A26 1000 20 40 20 30 20 10 0 10 20 A27 1000 100 100 100 100 70 80 80 80 40 A28 1000 90 70 30 20 40 50 70 40 20 A29 1000 90 90 80 80 20 40 30 50 40 A30 1000 100 100 100 100 80 40 90 70 50 A31 1000 100 80 100 90 100 70 100 90 60 A33 1000 40 40 80 60 70 40 80 40 20 A34 1000 20 50 60 50 40 0 30 60 20 A35 1000 20 0 40 20 0 0 10 10 0 A36 1000 40 30 20 30 30 0 10 30 10 A37 1000 100 80 90 80 70 40 80 60 40 A38 1000 60 50 60 20 90 0 30 40 20 A39 1000 80 30 20 30 10 0 10 30 20 A40 1000 90 70 30 10 10 20 20 40 20 A41 1000 80 60 100 80 30 30 40 40 20 A42 1000 70 60 60 40 80 10 60 40 20 A43 1000 60 30 90 80 90 20 70 50 30 A44 1000 80 40 30 20 0 0 0 20 20 A45 1000 100 90 100 90 100 50 90 90 70 A46 1000 100 100 100 100 100 60 100 90 90 A47 1000 60 70 30 20 50 10 40 40 30 A48 1000 100 100 100 70 100 40 70 100 80 A49 1000 100 90 100 90 100 30 100 90 70 A50 1000 60 30 20 20 30 0 20 10 20 A51 1000 90 60 90 60 80 20 90 90 70 A52 500 50 60 40 20 70 10 30 10 10 A53 1000 100 70 100 100 100 30 90 90 80 A54 500 30 20 80 20 30 20 40 30 30 A55 1000 90 100 70 70 100 20 100 30 90 A56 500 100 90 40 30 70 10 100 60 70 A57 1000 40 40 20 10 40 10 30 30 10 A58 1000 80 70 20 20 30 0 70 60 10 A60 1000 100 100 100 100 100 40 90 70 50 A61 1000 100 100 70 100 90 10 70 40 50 A63 1000 30 30 70 30 50 10 70 60 50 A64 1000 20 20 70 70 50 10 50 50 50 A65 1000 90 90 100 70 80 40 90 80 50 A66 1000 40 30 80 60 70 10 90 70 60 A67 1000 30 60 30 30 10 0 90 50 20 A68 1000 100 100 100 100 100 40 100 90 60 A69 500 100 90 100 90 90 40 100 90 70 A70 1000 50 60 60 30 80 10 70 20 70 A71 1000 100 90 100 80 90 40 90 100 30 A74 500 100 60 50 50 60 30 20 20 10 A75 500 50 50 30 30 70 30 30 30 70 A76 500 100 90 100 90 100 50 80 80 70 A77 500 100 90 80 90 100 30 90 90 50 A78 1000 30 10 70 10 40 10 50 40 50 A82 1000 30 0 20 10 10 10 10 0 20