US20120289707A1 - Process for the preparation of amides - Google Patents
Process for the preparation of amides Download PDFInfo
- Publication number
- US20120289707A1 US20120289707A1 US13/556,904 US201213556904A US2012289707A1 US 20120289707 A1 US20120289707 A1 US 20120289707A1 US 201213556904 A US201213556904 A US 201213556904A US 2012289707 A1 US2012289707 A1 US 2012289707A1
- Authority
- US
- United States
- Prior art keywords
- alkyl
- hydrogen
- independently
- formula
- acid
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 238000000034 method Methods 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 16
- 150000001408 amides Chemical class 0.000 title description 6
- 239000003054 catalyst Substances 0.000 claims abstract description 83
- PAYRUJLWNCNPSJ-UHFFFAOYSA-N Aniline Chemical compound NC1=CC=CC=C1 PAYRUJLWNCNPSJ-UHFFFAOYSA-N 0.000 claims abstract description 68
- 229910052787 antimony Inorganic materials 0.000 claims abstract description 36
- WATWJIUSRGPENY-UHFFFAOYSA-N antimony atom Chemical compound [Sb] WATWJIUSRGPENY-UHFFFAOYSA-N 0.000 claims abstract description 33
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 26
- ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims abstract description 23
- 239000003377 acid catalyst Substances 0.000 claims abstract description 21
- 150000001875 compounds Chemical class 0.000 claims abstract description 19
- 229910052739 hydrogen Inorganic materials 0.000 claims description 110
- 239000001257 hydrogen Substances 0.000 claims description 109
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 82
- -1 bromo, hydroxy Chemical group 0.000 claims description 66
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 50
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 46
- 229910052736 halogen Inorganic materials 0.000 claims description 43
- 150000002367 halogens Chemical class 0.000 claims description 39
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 29
- 125000001153 fluoro group Chemical group F* 0.000 claims description 29
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 27
- 125000001424 substituent group Chemical group 0.000 claims description 26
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 25
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 21
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 20
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 20
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 20
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 claims description 20
- JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 19
- 239000004327 boric acid Substances 0.000 claims description 19
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 18
- VUDCTLOJEPCNRS-UHFFFAOYSA-N [2-[(dimethylamino)methyl]phenyl]boronic acid Chemical group CN(C)CC1=CC=CC=C1B(O)O VUDCTLOJEPCNRS-UHFFFAOYSA-N 0.000 claims description 16
- 125000004414 alkyl thio group Chemical group 0.000 claims description 16
- 125000004995 haloalkylthio group Chemical group 0.000 claims description 16
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 15
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 14
- 239000002253 acid Substances 0.000 claims description 13
- 125000001246 bromo group Chemical group Br* 0.000 claims description 13
- 125000002947 alkylene group Chemical group 0.000 claims description 12
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 12
- 125000003226 pyrazolyl group Chemical group 0.000 claims description 12
- 125000003342 alkenyl group Chemical group 0.000 claims description 11
- 125000000304 alkynyl group Chemical group 0.000 claims description 10
- 125000000168 pyrrolyl group Chemical group 0.000 claims description 10
- JGOJQVLHSPGMOC-UHFFFAOYSA-N triethyl stiborite Chemical group [Sb+3].CC[O-].CC[O-].CC[O-] JGOJQVLHSPGMOC-UHFFFAOYSA-N 0.000 claims description 10
- 150000001543 aryl boronic acids Chemical group 0.000 claims description 8
- 229910052799 carbon Inorganic materials 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 7
- 125000000335 thiazolyl group Chemical group 0.000 claims description 7
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 6
- 101150065749 Churc1 gene Proteins 0.000 claims description 5
- 102100038239 Protein Churchill Human genes 0.000 claims description 5
- 125000006652 (C3-C12) cycloalkyl group Chemical group 0.000 claims description 4
- 125000001118 alkylidene group Chemical group 0.000 claims description 4
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 3
- 125000006274 (C1-C3)alkoxy group Chemical group 0.000 claims description 3
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 3
- 125000004849 alkoxymethyl group Chemical group 0.000 claims description 3
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 3
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 claims description 3
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 3
- 150000002431 hydrogen Chemical class 0.000 claims 7
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 150000001412 amines Chemical class 0.000 abstract description 4
- 230000008878 coupling Effects 0.000 abstract description 2
- 238000010168 coupling process Methods 0.000 abstract description 2
- 238000005859 coupling reaction Methods 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 51
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 38
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 25
- 0 CC(=O)O.I.II.I[IH]I.[1*]N(C(C)=O)C1=CC=CC2=C1C1([4*])[Y]C2([5*])C([7*])CC1[6*].[1*]NC1=CC=CC2=C1C1([4*])[Y]C2([5*])C([7*])CC1[6*].[2*]C.[2*]C.[3*]C.[3*]C Chemical compound CC(=O)O.I.II.I[IH]I.[1*]N(C(C)=O)C1=CC=CC2=C1C1([4*])[Y]C2([5*])C([7*])CC1[6*].[1*]NC1=CC=CC2=C1C1([4*])[Y]C2([5*])C([7*])CC1[6*].[2*]C.[2*]C.[3*]C.[3*]C 0.000 description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 24
- 150000001735 carboxylic acids Chemical class 0.000 description 20
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 20
- 229910052757 nitrogen Inorganic materials 0.000 description 19
- 239000008096 xylene Substances 0.000 description 15
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 14
- 238000010992 reflux Methods 0.000 description 13
- BPTABBGLHGBJQR-UHFFFAOYSA-N [3,5-bis(trifluoromethyl)phenyl]boronic acid Chemical compound OB(O)C1=CC(C(F)(F)F)=CC(C(F)(F)F)=C1 BPTABBGLHGBJQR-UHFFFAOYSA-N 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 12
- VUWZPRWSIVNGKG-UHFFFAOYSA-N fluoromethane Chemical compound F[CH2] VUWZPRWSIVNGKG-UHFFFAOYSA-N 0.000 description 11
- 239000000460 chlorine Substances 0.000 description 10
- 125000005843 halogen group Chemical group 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 239000002904 solvent Substances 0.000 description 7
- VPLCSAACLVZROJ-UHFFFAOYSA-N CN1C=C(C(=O)O)C([H]C(F)F)=N1 Chemical compound CN1C=C(C(=O)O)C([H]C(F)F)=N1 VPLCSAACLVZROJ-UHFFFAOYSA-N 0.000 description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- 208000033962 Fontaine progeroid syndrome Diseases 0.000 description 6
- 150000004703 alkoxides Chemical class 0.000 description 6
- 125000003118 aryl group Chemical group 0.000 description 6
- 125000005842 heteroatom Chemical group 0.000 description 6
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 6
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 6
- 229910052717 sulfur Inorganic materials 0.000 description 6
- YHOQMAJZIIUYAZ-UHFFFAOYSA-N C1=CC=C(N)C2=C1C1C(C(C)C)C2CC1 Chemical compound C1=CC=C(N)C2=C1C1C(C(C)C)C2CC1 YHOQMAJZIIUYAZ-UHFFFAOYSA-N 0.000 description 5
- 125000002573 ethenylidene group Chemical group [*]=C=C([H])[H] 0.000 description 5
- QUPDWYMUPZLYJZ-UHFFFAOYSA-N ethyl Chemical compound C[CH2] QUPDWYMUPZLYJZ-UHFFFAOYSA-N 0.000 description 5
- 239000000463 material Substances 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 239000000376 reactant Substances 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N CC(=O)O Chemical compound CC(=O)O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 239000008346 aqueous phase Substances 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 125000005620 boronic acid group Chemical group 0.000 description 4
- 150000001721 carbon Chemical group 0.000 description 4
- 125000000753 cycloalkyl group Chemical group 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 125000004076 pyridyl group Chemical group 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- NRIYPIBRPGAWDD-UHFFFAOYSA-N (5-methylthiophen-2-yl)boronic acid Chemical compound CC1=CC=C(B(O)O)S1 NRIYPIBRPGAWDD-UHFFFAOYSA-N 0.000 description 3
- 238000004293 19F NMR spectroscopy Methods 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- RLOHOBNEYHBZID-UHFFFAOYSA-N 3-(difluoromethyl)-1-methylpyrazole-4-carboxylic acid Chemical compound CN1C=C(C(O)=O)C(C(F)F)=N1 RLOHOBNEYHBZID-UHFFFAOYSA-N 0.000 description 3
- 125000002373 5 membered heterocyclic group Chemical group 0.000 description 3
- 125000004070 6 membered heterocyclic group Chemical group 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- FMOQDENZICAHFK-UHFFFAOYSA-N CC(C)C1C2CCC1C1=C2/C=C\C=C/1N.CC(C)C1C2CCC1C1=C2/C=C\C=C/1NC(=O)C1=CN(C)N=C1C(F)F.CN1C=C(C(=O)O)C(C(F)F)=N1 Chemical compound CC(C)C1C2CCC1C1=C2/C=C\C=C/1N.CC(C)C1C2CCC1C1=C2/C=C\C=C/1NC(=O)C1=CN(C)N=C1C(F)F.CN1C=C(C(=O)O)C(C(F)F)=N1 FMOQDENZICAHFK-UHFFFAOYSA-N 0.000 description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 3
- 239000005864 Sulphur Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 description 3
- 125000002541 furyl group Chemical group 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 125000006412 propinylene group Chemical group [H]C#CC([H])([H])* 0.000 description 3
- 229920006395 saturated elastomer Polymers 0.000 description 3
- 125000001544 thienyl group Chemical group 0.000 description 3
- 238000010626 work up procedure Methods 0.000 description 3
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- ALAZJIDJYQDZPN-UHFFFAOYSA-N C.CI.CI.CN1C=C(C(=O)NC2=CC=CC=C2C2CC2C2CC2)C([H]C(F)F)=N1.CN1C=C(C(=O)O)C([H]C(F)F)=N1.NC1=CC=CC=C1C1CC1C1CC1 Chemical compound C.CI.CI.CN1C=C(C(=O)NC2=CC=CC=C2C2CC2C2CC2)C([H]C(F)F)=N1.CN1C=C(C(=O)O)C([H]C(F)F)=N1.NC1=CC=CC=C1C1CC1C1CC1 ALAZJIDJYQDZPN-UHFFFAOYSA-N 0.000 description 2
- HPEQRZYPGWFZRU-UHFFFAOYSA-N CC(C)C1C2CCC1C1=C2C=CC=C1NC(=O)C1=CN(C)N=C1[H]C(F)F Chemical compound CC(C)C1C2CCC1C1=C2C=CC=C1NC(=O)C1=CN(C)N=C1[H]C(F)F HPEQRZYPGWFZRU-UHFFFAOYSA-N 0.000 description 2
- RWILWCKEBRTORG-UHFFFAOYSA-H CN1C=C(C(=O)N/C2=C/C=C\C3=C2C2CCC3C2=C(Cl)Cl)C([H]C(F)F)=N1.CN1C=C(C(=O)O)C([H]C(F)F)=N1.I[V](I)I.I[V]I.N/C1=C/C=C\C2=C1C1CCC2C1=C(Cl)Cl.[V]I Chemical compound CN1C=C(C(=O)N/C2=C/C=C\C3=C2C2CCC3C2=C(Cl)Cl)C([H]C(F)F)=N1.CN1C=C(C(=O)O)C([H]C(F)F)=N1.I[V](I)I.I[V]I.N/C1=C/C=C\C2=C1C1CCC2C1=C(Cl)Cl.[V]I RWILWCKEBRTORG-UHFFFAOYSA-H 0.000 description 2
- CERSACOSWWTXDV-UHFFFAOYSA-N CN1C=C(C(=O)NC2=CC=CC3=C2C2CCC3C2=C(Cl)Cl)C([H]C(F)F)=N1 Chemical compound CN1C=C(C(=O)NC2=CC=CC3=C2C2CCC3C2=C(Cl)Cl)C([H]C(F)F)=N1 CERSACOSWWTXDV-UHFFFAOYSA-N 0.000 description 2
- UEXJQNSMMJXIHQ-UHFFFAOYSA-N CN1C=C(C(=O)NC2=CC=CC=C2C2CC2C2CC2)C([H]C(F)F)=N1 Chemical compound CN1C=C(C(=O)NC2=CC=CC=C2C2CC2C2CC2)C([H]C(F)F)=N1 UEXJQNSMMJXIHQ-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- VLBAAZYGJAXMBQ-UHFFFAOYSA-N N/C1=C/C=C\C2=C1C1CCC2C1=C(Cl)Cl Chemical compound N/C1=C/C=C\C2=C1C1CCC2C1=C(Cl)Cl VLBAAZYGJAXMBQ-UHFFFAOYSA-N 0.000 description 2
- WRBFUJVNYHEZAL-UHFFFAOYSA-N NC1=CC=CC=C1C1CC1C1CC1 Chemical compound NC1=CC=CC=C1C1CC1C1CC1 WRBFUJVNYHEZAL-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 150000001448 anilines Chemical class 0.000 description 2
- 229910000410 antimony oxide Inorganic materials 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 238000010533 azeotropic distillation Methods 0.000 description 2
- 238000006555 catalytic reaction Methods 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- 239000010432 diamond Substances 0.000 description 2
- 125000006222 dimethylaminomethyl group Chemical group [H]C([H])([H])N(C([H])([H])[H])C([H])([H])* 0.000 description 2
- IPZJQDSFZGZEOY-UHFFFAOYSA-N dimethylmethylene Chemical compound C[C]C IPZJQDSFZGZEOY-UHFFFAOYSA-N 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 230000000855 fungicidal effect Effects 0.000 description 2
- 125000001188 haloalkyl group Chemical group 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 2
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 125000002971 oxazolyl group Chemical group 0.000 description 2
- VTRUBDSFZJNXHI-UHFFFAOYSA-N oxoantimony Chemical class [Sb]=O VTRUBDSFZJNXHI-UHFFFAOYSA-N 0.000 description 2
- 125000000714 pyrimidinyl group Chemical group 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 2
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 2
- ZYYANAWVBDFAHY-UHFFFAOYSA-N (2,3-dimethylphenyl)boronic acid Chemical compound CC1=CC=CC(B(O)O)=C1C ZYYANAWVBDFAHY-UHFFFAOYSA-N 0.000 description 1
- QQLRSCZSKQTFGY-UHFFFAOYSA-N (2,4-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(F)C=C1F QQLRSCZSKQTFGY-UHFFFAOYSA-N 0.000 description 1
- SQTUYFKNCCBFRR-UHFFFAOYSA-N (2,4-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C(OC)=C1 SQTUYFKNCCBFRR-UHFFFAOYSA-N 0.000 description 1
- KTOJGSDLJNUAEP-UHFFFAOYSA-N (2,5-difluorophenyl)boronic acid Chemical compound OB(O)C1=CC(F)=CC=C1F KTOJGSDLJNUAEP-UHFFFAOYSA-N 0.000 description 1
- QOZLFNQLIKOGDR-UHFFFAOYSA-N (2,5-dimethoxyphenyl)boronic acid Chemical compound COC1=CC=C(OC)C(B(O)O)=C1 QOZLFNQLIKOGDR-UHFFFAOYSA-N 0.000 description 1
- OOMZKLJLVGQZGV-UHFFFAOYSA-N (2,5-dimethylphenyl)boronic acid Chemical compound CC1=CC=C(C)C(B(O)O)=C1 OOMZKLJLVGQZGV-UHFFFAOYSA-N 0.000 description 1
- NPLZNDDFVCGRAG-UHFFFAOYSA-N (2-cyanophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C#N NPLZNDDFVCGRAG-UHFFFAOYSA-N 0.000 description 1
- DGFCTCGCMKEILT-UHFFFAOYSA-N (2-ethoxyphenyl)boronic acid Chemical compound CCOC1=CC=CC=C1B(O)O DGFCTCGCMKEILT-UHFFFAOYSA-N 0.000 description 1
- QSSPYZOSTJDTTL-UHFFFAOYSA-N (2-ethylphenyl)boronic acid Chemical compound CCC1=CC=CC=C1B(O)O QSSPYZOSTJDTTL-UHFFFAOYSA-N 0.000 description 1
- QCSLIRFWJPOENV-UHFFFAOYSA-N (2-fluorophenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1F QCSLIRFWJPOENV-UHFFFAOYSA-N 0.000 description 1
- DGUWACLYDSWXRZ-UHFFFAOYSA-N (2-formylphenyl)boronic acid Chemical compound OB(O)C1=CC=CC=C1C=O DGUWACLYDSWXRZ-UHFFFAOYSA-N 0.000 description 1
- ROEQGIFOWRQYHD-UHFFFAOYSA-N (2-methoxyphenyl)boronic acid Chemical compound COC1=CC=CC=C1B(O)O ROEQGIFOWRQYHD-UHFFFAOYSA-N 0.000 description 1
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- ABMYEXAYWZJVOV-UHFFFAOYSA-N pyridin-3-ylboronic acid Chemical compound OB(O)C1=CC=CN=C1 ABMYEXAYWZJVOV-UHFFFAOYSA-N 0.000 description 1
- QLULGIRFKAWHOJ-UHFFFAOYSA-N pyridin-4-ylboronic acid Chemical compound OB(O)C1=CC=NC=C1 QLULGIRFKAWHOJ-UHFFFAOYSA-N 0.000 description 1
- KXJJSKYICDAICD-UHFFFAOYSA-N quinolin-8-ylboronic acid Chemical compound C1=CN=C2C(B(O)O)=CC=CC2=C1 KXJJSKYICDAICD-UHFFFAOYSA-N 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000005346 substituted cycloalkyl group Chemical group 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000004305 thiazinyl group Chemical group S1NC(=CC=C1)* 0.000 description 1
- ARYHTUPFQTUBBG-UHFFFAOYSA-N thiophen-2-ylboronic acid Chemical compound OB(O)C1=CC=CS1 ARYHTUPFQTUBBG-UHFFFAOYSA-N 0.000 description 1
- QNMBSXGYAQZCTN-UHFFFAOYSA-N thiophen-3-ylboronic acid Chemical compound OB(O)C=1C=CSC=1 QNMBSXGYAQZCTN-UHFFFAOYSA-N 0.000 description 1
- 125000004306 triazinyl group Chemical group 0.000 description 1
- ZBZJXHCVGLJWFG-UHFFFAOYSA-N trichloromethyl(.) Chemical compound Cl[C](Cl)Cl ZBZJXHCVGLJWFG-UHFFFAOYSA-N 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
The invention relates to a process for the preparation of fungicidally active compounds such as tricyclic amine derivatives (I). The process involves coupling of a carboxylic acid e.g. a compound of formula (II) with an aniline, e.g. a compound of formula (III) in the presence of a boronic acid catalyst or an antimony catalyst
wherein R1, R2, R3, R4, R5, R6, R7, X, Y and Het are defined in the specification.
Description
- The present invention relates to a process for the preparation of certain fungicidally active tricyclic amine derivatives and to certain fungicidally active ortho-substituted-cyclopropyl-azolcarboxamides.
- Tricyclic amine derivatives having fungicidal activity are disclosed in WO/2004/035589 and WO 2007/048556. Ortho-substituted-cyclopropyl-azolcarboxamides of the formula (IA) are disclosed in WO03/074491
- wherein
Heta is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a;
R1a is hydrogen or halo;
R2a is hydrogen or halo;
R3a is optionally substituted C2-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and
R4a, R5a and R6a are independently selected from hydrogen, halo, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4) alkyl and C1-4 haloalkoxy(C1-4) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen. - The compounds disclosed in WO03/074491 have microbiocidal activity, in particular fungicidal activity.
- A variety of methods for the preparation of the above compounds have been described in WO2004/035589, WO 2007/048556, and WO 2003/074491.
- It has now been surprisingly found that these compounds may be advantageously obtained by coupling the respective amine and carboxylic acid in the presence of a boronic acid catalyst or an antimony catalyst.
- The present invention relates to a process for the preparation of compounds of the formula (I)
- wherein
where Het is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, provided that the ring is not 1,2,3-triazole, the ring being substituted by groups R8, R9 and R10;
X is a single or double bond;
Y is O, S, N(R11), (CR12R13)(CR14R15)m(CR16R17)n or C═C(A)Z in which A and Z are independently C1-6 alkyl or halogen;
m is 0 or 1; n is 0 or 1;
R1 is hydrogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, CH2C≡CR18, CH2CR19═CHR20, CH═C═CH2 or COR21;
R2 and R3 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or C1-4 haloalkoxy;
R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, hydroxymethyl, C1-4 alkoxymethyl, C(O)CH3 or C(O)OCH3;
R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4)alkylene or C1-4 haloalkoxy(C1-4)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen;
R11 is hydrogen, C1-4 alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy), formyl, C(O)C1-4 alkyl (optionally substituted by halogen or C1-4 alkoxy), C(═O)O—C1-6 alkyl (optionally substituted by halogen, C1-4 alkoxy or cyano) or C1-4 alkoxy (C1-4) alkylene;
R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, halogen, in hydroxy, C1-6 alkyl, C2-6 alkenyl [both optionally substituted by halogen, hydroxy, C1-4 alkoxy, ═O, aryl or O—C(O)—C1-4 alkyl or a 3-7 membered carboxylic ring (itself optionally substituted by up to three methyl groups)], a 3-7 membered saturated ring (optionally substituted by up to three methyl groups and optionally containing one heteroatom selected from nitrogen and oxygen) or C1-4 alkoxy; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring (optionally substituted by up to three methyl groups and optionally with up to 2 heteroatoms each independently selected from O and N); or R12 and R13 together form a C1-6 alkylidene (optionally substituted by up to three methyl groups) or a C3-6 cycloalkylidene group (optionally substituted by up to three methyl groups);
R18, R19 and R20 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl or C1-4 alkoxy(C1-4)alkylene; and
R21 is hydrogen, C1-6 alkyl, C1-6 haloalkyl, C1-4 alkoxy (C1-4) alkylene, C1-4 alkyl-S—(C1-4) alkylene, C1-4 alkoxy or aryl;
comprising the step of reacting a carboxylic acid of formula (II) - wherein Het is as defined above
with an aniline of the formula (III) - wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined above;
in the presence of a boronic acid catalyst or an antimony catalyst. - Halogen is fluoro, chloro, bromo or iodo; preferably fluoro, chloro or bromo.
- Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, sec-butyl, iso-butyl, tert-butyl, neo-pentyl, n-heptyl, 1,3-dimethylbutyl, 1,3-dimethylpentyl,1-methyl-3-ethyl-butyl or 1,3,3-trimethylbutyl. Likewise, each alkylene moiety is a straight or branched chain.
- Haloalkyl moieties are alkyl moieties which are substituted by one or more of the same or different halogen atoms and are, for example, CF3, CF2Cl, CHF2, CH2F, CCl3, CF3CH2, CHF2CH2, CH2FCH2, CH3CHF or CH3CF2.
- Alkenyl and alkynyl moieties can be in the form of straight or branched chains.
- Each alkenyl moiety, where appropriate, may be of either the (E)- or (Z)-configuration.
- A 3-5 membered carbocyclic ring includes a spiro-three or five membered ring.
- Aryl includes phenyl, naphthyl, anthracyl, fluorenyl and indanyl but is preferably phenyl.
- Alkyliden moieties may be in the form of straight or branched chains. Alkyliden includes methylidene[CH2═], ethylidene [CH3C(H)═], n-propylidene, i-propylidene [(CH3)2C═], n-butylidene, i-butylidene, 2-butylidene, n-pentylidene, i-pentylidene, neo-pentylidene, 2-pentylidene, n-hexylidene, 2-hexylidene, 3-hexylidene, i-hexylidene and neo-hexylidene.
- Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
- Cycloalkenyl includes cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
- Cycloalkylidene includes cyclopropylidene [c(C3H4)═], cyclobutylidene, cyclopentylidene and cyclohexylidene.
- In one aspect of the invention, R11 is hydrogen, C1-4 alkyl, benzyl (in which the phenyl group is optionally substituted with up to three substituents, each independently selected from halogen, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy), formyl, C(O)C1-4 alkyl or C1-4 alkoxy (C1-4) alkylene.
- In another aspect of the invention, R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, C1-4 alkyl or C1-4 alkoxy.
- Het is preferably pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl, pyrimidyl, pyridazinyl, 2,3-hydro-[1, 4] oxathiine-6-yl, oxazinyl, thiazinyl or triazinyl.
- Het is more preferably pyrrolyl, pyrazolyl, thiazolyl, oxazolyl, pyridinyl or 2,3-dihydro-[1, 4] oxathiine-yl.
- Het is even more preferably pyrrolyl, pyrazolyl, thiazolyl or pyridinyl.
- Het is most preferably pyrrolyl or pyrazolyl.
- Preferably X is a single bond.
- In one aspect, Y is O, S, N(R11), CH2, CH2CH2, CH2CH2CH2, C(CH3)2, CH(CH3), CH C2H5), C(CH3)(C2H5), CH(OCH3) or C(OCH3)2; more preferably N(R11), O, S, CH2, CH2CH2, CH2CH2CH2, C(CH3)2, CH(CH3) or CH(C2H5); even more preferably N(R11), O, S, CH2 or CH2CH2; and still more preferably O, CH2 or N(R11). Preferably Y is O, N(R11) or (CR12R13)(CR14R15)m(CR16R17)n. More preferably Y is O or (CR12R13)(CR14R15)m(CR16R17)n. Even more preferably Y is (CR12R13)(CR14R15)m(CR16R17)n. Still more preferably Y is (CR12R13), e.g. CHCH(CH3)CH3.
- In a further aspect, Y is C═C(A)Z in which A and Z are independently C1-6 alkyl or halogen. Preferably A and Z are independently halogen, more preferably both A and Z are chlorine.
- Preferably n is 0.
- Preferably m is 0.
- Preferably R1 is hydrogen, CH2C≡CR18, CH═C═CH2 or COR21.
- More preferably R1 is hydrogen, CH2C≡CH, CH═C═CH2, C(O)H or C(O)CH3.
- Yet more preferably R1 is hydrogen, CH2C≡CH, CH═C═CH2 or C(O)CH3.
- Even more preferably R1 is hydrogen, CH2C≡CH or CH═C═CH2.
- Most preferably R1 is hydrogen.
- Preferably R2 is hydrogen, halogen or C1-4 alkyl.
- More preferably R2 is hydrogen or halogen.
- Most preferably R2 is hydrogen.
- Preferably R3 is hydrogen or methyl.
- More preferably R3 is hydrogen.
- Preferably R4 is hydrogen, C1-4 alkyl, halogen, C1-4 haloalkyl, C1-4 alkoxy, C(O)CH3 or C(O)OCH3.
- More preferably R4 is hydrogen, C1-2 alkyl, halogen, CF3, methoxy, C(O)CH3 or C(O)OCH3.
- Even more preferably R4 is hydrogen, methyl, chlorine, CF3 or methoxy.
- Most preferably R4 is hydrogen or methyl.
- Preferably R5 is hydrogen, C1-4 alkyl, halogen, C1-4 haloalkyl, C1-4 alkoxy, C(O)CH3 or C(O)OCH3.
- More preferably R5 is hydrogen, C1-2 alkyl, chlorine, CF3, methoxy, C(O)CH3 or C(O)OCH3.
- Most preferably R5 is hydrogen or methyl.
- Preferably R6 is hydrogen, C1-4 alkyl, C1-4 alkoxy or C(O)CH3.
- More preferably R6 is hydrogen, methyl, methoxy or C(O)CH3.
- Most preferably R6 is hydrogen or methyl.
- Preferably R7 is hydrogen, C1-4 alkyl, C1-4 alkoxy or C(O)CH3.
- More preferably R7 is hydrogen, methyl, methoxy or C(O)CH3.
- Most preferably R7 is hydrogen or methyl.
- Preferably R8 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl or methoxymethylene.
- More preferably R8 is hydrogen, chloro, fluoro, bromo, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Even more preferably R8 is hydrogen, chloro, fluoro, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Most preferably R8 is hydrogen, chloro, fluoro, methyl, CF3, CHF2 or CH2F.
- Preferably R9 is hydrogen, halogen, C1-4 alkyl or C1-4 haloalkyl or methoxymethylene.
- More preferably R9 is hydrogen, chloro, fluoro, bromo, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Even more preferably R9 is hydrogen, chloro, fluoro, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Most preferably R9 is hydrogen, chloro, fluoro, methyl, CF3, CHF2 or CH2F.
- Preferably R10 is hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl or methoxymethylene.
- More preferably R10 is hydrogen, chloro, fluoro, bromo, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Even more preferably R10 is hydrogen, chloro, fluoro, C1-2 alkyl, CF3, CF2Cl, CHF2, CH2F or methoxymethylene.
- Most preferably R10 is hydrogen, chloro, fluoro, methyl, CF3, CHF2 or CH2F.
- In one aspect of the invention R11 is hydrogen, C1-4 alkyl, benzyl, formyl, C(O)CH3 or C(O)OC(CH3)3; more preferably hydrogen or C1-2 alkyl.
- Preferably R11 is C1-4 alkyl, formyl, C(O)CH3 or C(O)OC1-6 alkyl (optionally substituted by halogen, CN or C1-4 alkoxy).
- More preferably R11 is C(O)OC1-4 alkyl.
- In one aspect of the invention R12, R13, R14, R15, R16 and R17 are each, independently, hydrogen, C1-2 alkyl or methoxy.
- Preferably R12 and R13 are each, independently, hydrogen, halogen, C1-5 alkyl, C1-3 alkoxy, CH2OH, CH(O), C3-6 cycloalkyl, CH2O—C(═O)CH3, CH2—C3-6 cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring; or R12 and R13 together form C1-5 alkylidene or C3-6 cycloalkylidene.
- More preferably R12 and R13 are, independently, H, CH3, C2H5, n-C3H7, i-C3H7, n-C4H9, sec-C4H9, i-C4H9, CH(C2H5)2, CH2-cyclopropyl or cyclopentyl; or R12 and R13 together with the carbon atom to which they are attached form a 3-membered or 5-membered carbocyclic ring.
- Preferably R14 is H or CH3.
- Preferably R15 is H or CH3.
- Preferably R16 is H or CH3.
- Preferably R17 is H or CH3.
- Preferably R18 is hydrogen, chloro, bromo, methyl or methoxy.
- More preferably R18 is hydrogen, chloro or methyl.
- Most preferably R18 is hydrogen.
- Preferably R19 is hydrogen, chloro, bromo, methyl or methoxy.
- More preferably R19 is hydrogen, chloro or methyl.
- Most preferably R19 is hydrogen.
- Preferably R20 is hydrogen, chloro, bromo, methyl or methoxy.
- More preferably R20 is hydrogen, chloro or methyl.
- Most preferably R20 is hydrogen.
- Preferably R21 is hydrogen, methyl, OC(CH3)3 or CH3OCH2.
- For example,
- Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and R10;
- X is a single bond;
- Y is (CR12R13)(CR14R15)m(CR16R17)n or C═C(A)Z in which A and Z are independently C1-6 alkyl or halogen;
- m is 0 or 1;
- n is 0 or 1;
- R1 is hydrogen;
- R2 and R3 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or C1-4 haloalkoxy;
- R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, hydroxymethyl, C1-4 alkoxymethyl, C(O)CH3 or C(O)OCH3;
- R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4)alkylene or C1-4 haloalkoxy(C1-4)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen;
- R12 and R13 are each, independently, hydrogen, halogen, C1-5 alkyl, C1-3 alkoxy, CH2OH, CH(O), C3-6 cycloalkyl, CH2O—C(═O)CH3, CH2—C3-6 cycloalkyl or benzyl; or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring;
- or R12 and R13 together form C1-5 alkylidene or C3-6 cycloalkylidene; and
- R14, R15, R16 and R17 are each, independently, H or CH3.
- Preferably, R8, R9 and R10 are each, independently, hydrogen, chloro, fluoro, methyl, CF3, CHF2 or CH2F, provided that at least one of R8, R9 and R10 is not hydrogen.
- Preferably, n is 0 and m is 0. Preferably, R12 and R13 are each, independently, hydrogen, C1-4 alkyl or C1-4 alkoxy. Preferably, R2 is hydrogen, halogen or C1-4 alkyl.
- Preferably, R3 is hydrogen or methyl. Preferably Het is pyrazolyl.
- Preferably Het is a group of formula (VIIA)
- in which R7a is selected from CF3 and CHF2;
- Preferably, R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen.
- Preferably, X is a single bond;
- Preferably, Y is C═CCl2 or CHCH(CH3)CH3.
- For example, in one embodiment:
- Het is a group of formula (VIIA)
- in which R7a is selected from CF3 and CHF2;
- R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen;
- X is a single bond;
- Y is CHCH(CH3)CH3; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)3.
- For example, in further embodiment:
- Het is a group of formula (VIIA)
- in which R7a is selected from CF3 and CHF2;
R1, R2, R3, R4, R5, R6, R7 are each independently hydrogen;
X is a single bond;
Y is C═C(A)Z in which A and Z are, independently fluoro, chloro or bromo, preferably chloro;
and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid. - According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (VI)
- comprising reacting a carboxylic acid of formula (IV)
- with an aniline of formula (V)
- in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be 3,5-bis-(trifluoromethyl)-phenylboronic acid or Sb(OEt)3.
- According to a further highly preferred embodiment of the invention, the invention relates to a process for the preparation of a compound of formula (VIII)
- comprising reacting a carboxylic acid of formula (IV)
- with an aniline of formula (VII)
- in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.
- In a further embodiment, the present invention provides a process for the preparation of compounds of formula (IA)
- wherein
Heta is a 5- or 6-membered heterocyclic ring containing one to three heteroatoms, each independently selected from oxygen, nitrogen and sulphur, the ring being substituted by groups R4a, R5a and R6a;
R1a is hydrogen or halogen;
R2a is hydrogen or halogen;
R3a is optionally substituted C2-12 alkyl, optionally substituted C2-12 alkenyl, optionally substituted C2-12 alkynyl, optionally substituted C3-12 cycloalkyl, optionally substituted phenyl or optionally substituted heterocyclyl; and
R4a, R5a and R6a are independently selected from hydrogen, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4) alkyl and C1-4 haloalkoxy(C1-4) alkyl, provided that at least one of R4a, R5a and R6a is not hydrogen
comprising reacting a carboxylic acid of formula (IIA) - with an aniline of the formula (IIIA)
- in the presence of a boronic acid catalyst or an antimony catalyst.
- Halogen is fluoro, chloro or bromo.
- Each alkyl moiety is a straight or branched chain and is, for example, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl or neo-pentyl.
- When present, each optional substituent on an alkyl moiety is, independently, selected from halogen, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); where R′ and R″ are, independently, hydrogen or C1-4 alkyl.
- Alkenyl and alkynyl moieties can be in the form of straight or branched chains.
- The alkenyl moieties, where appropriate, can be of either the (E)- or (Z)-configuration. Examples are vinyl, allyl and propargyl.
- When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from those optional substituents given above for an alkyl moiety.
- Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- When present, each optional substituent on cycloalkyl is, independently, selected from C1-3 alkyl and those optional substituents given above for an alkyl moiety.
- The term heterocyclyl refers to a non-aromatic or aromatic ring containing up to 10 atoms including one or more (preferably one or two) heteroatoms selected, each independently, from O, S and N. Examples of such rings include 1,3-dioxolanyl, tetrahydrofuranyl, morpholinyl, thienyl and furyl.
- When present, each optional substituent on phenyl or on heterocyclyl is, independently, selected from C1-6 alkyl and those optional substituents given above for an alkyl moiety. When present, there are up to four optional substituents on phenyl, each independently selected.
- When present, each optional substituent on an alkyl moiety is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy, cyano and nitro.
- When present, each optional substituent on alkenyl or on alkynyl is, independently, selected from the preferred list of halogen and cyano.
- When present, each optional substituent on cycloalkyl is, independently, selected from the preferred list of methyl, ethyl, trifluoromethyl, methoxy, trifluoromethoxy and cyano.
- When present, each optional substituent on phenyl or on a heterocyclyl group is, independently, selected from the preferred list of halo, hydroxy, methoxy, trifluoromethoxy, difluoromethoxy and cyano.
- It is preferred that Heta is pyrrolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, thiophenyl, furyl, isothiazolyl or isoxazolyl (more preferably pyrrolyl, pyrazolyl or thiazolyl), each being substituted by groups R4a, R5a and R6a.
- Preferably
- Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a;
R1a is hydrogen, fluoro, chloro or bromo;
R2a is hydrogen, fluoro, chloro or bromo;
R3a is optionally substituted C2-12 alkyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C2-12 alkenyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C2-12 alkynyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted C3-12 cycloalkyl, wherein, when present, each optional substituent is, independently, selected from C1-3 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from C1-6 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from C1-6 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N; R′ and R″ are, independently, hydrogen or C1-4 alkyl; and
R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4)alkyl and C1-4 haloalkoxy(C1-4)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen. - Preferably R1a and R2a are, independently, hydrogen or fluoro.
- Preferably R3a is C2-6 alkyl, optionally substituted C3-8 cycloalkyl, phenyl, thienyl or furyl.
- Preferably R4a, R5a and R6a are, independently, selected from hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl and C1-4 alkoxy(C1-4)alkyl; provided that at least one of R4a, R5a and R6a is not hydrogen. More preferably R4a, R5a, and R6a are, independently, selected from hydrogen, halogen, methyl, C1-2 haloalkyl and methoxymethyl; provided that at least one of R4a, R5a and R6a is not hydrogen.
- Preferably, Heta is pyrazolyl. More preferably, Heta is pyrazol-4-yl. More preferably, Heta is a group of formula (VIIA)
- wherein R7a is selected from CF3 and CHF2. Preferably, R7a is CHF2.
- Preferably, R1a is hydrogen. Preferably, R2a is hydrogen. More preferably, R1a and R2a are hydrogen.
- Preferably, R3a is optionally substituted cycloalkyl. More preferably, R3a is optionally substituted cyclopropyl. More preferably, R3a is a group of the formula (VIIIA)
- wherein R8a is H or C1-6 alkyl. Preferably, R8a is H or Methyl. More preferably, R8a is H.
- For example,
- Heta is a group of formula (VIIA)
- wherein R7a is selected from CF3 and CHF2;
R1a is R2a, and R3a are hydrogen;
R3a is a group of the formula (VIIIA) - wherein R8a is H or C1-4 alkyl, preferably H or Methyl, more preferably H; and the catalyst is a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.
- According to a very highly preferred embodiment, the invention relates to a process for the preparation of a compound of formula (IXA)
- comprising reacting an acid of formula (XA)
- with an aniline of formula (XIA)
- in the presence of a boronic acid catalyst or an antimony catalyst, e.g. boric acid or an aryl boronic acid such as 3,5-bis-(trifluoromethyl)-phenylboronic acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid, or an antimony III alkoxide such as Sb(OEt)3. For example, the catalyst may be boric acid or 2-(N,N-dimethylaminomethyl)phenylboronic acid.
- Preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 10:1 to 1:10. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 5:1 to 1:5. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 2:1 to 1:2. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 1.2:1 to 1:1.2. More preferably, the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 1.1:1 to 1:1.1.
- The reaction of the invention is optionally (and preferably) conducted in a suitable solvent. Suitable solvents include, but are not limited to, linear, branched or cyclic aliphatic hydrocarbons, such as ligroin or cyclohexane, pentane, hexane, heptane, octane, as well as aromatic solvents, such as benzene, toluene, xylene, monochlorobenzene, dichlorobenzene, trichlorobenzene.
- A preferred solvent is xylene.
- The reaction of the invention may be carried out at a temperature such that an acceptable rate of reaction is attained. Preferably, the reaction is conducted at a temperature of from 0° C. to 200° C. More preferably, the reaction is conducted at a temperature of from 50° C. to 180° C. More preferably, the reaction is conducted at a temperature of from 100° C. to 170° C. More preferably, the reaction is conducted at a temperature of from 130° C. to 150° C.
- Preferably, provision is made for removal of water from the reaction mixture, e.g. removal of water prior to completion of the reaction. Water may be removed from the reaction continuously. A suitable method is azeotropic removal of water. Suitable apparatus for conducting azeotropic removal of water will be known to those skilled in the art. We have found that removal of water is highly desirable in order to achieve a commercially useful conversion to product.
- Examples of the boronic acids include boric acid, phenylboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, 2,3-dimethylphenylboronic acid, 4-dimethylphenylboronic acid, 2,5-dimethylphenylboronic acid, 2-ethylphenylboronic acid, 4-n-propylphenylboronic acid, 4-isopropylphenylboronic acid, 4-n-butylphenylboronic acid, 4-tert-butylphenylboronic acid, 1-naphthylboronic acid, 2-naphthylboronic acid, 2-biphenylboronic acid, 3-biphenylboronic acid, 4-biphenylboronic acid, 2-fluoro-4-biphenylboronic acid, 2-fluorenylboronic acid, 9-fluorenylboronic acid, 9-phenanthrenylboronic acid, 9-anthracenylboronic acid, 1-pyrenylboronic acid, 2-trifluoromethylphenylboronic acid, 3-trifluoromethylphenylboronic acid, 4-trifluorophenylboronic acid, 3,5-bis(trifluoromethyl)phenylboronic acid, 2-methoxyphenylboronic acid, 3-methoxyphenylboronic acid, 4-methoxyphenylboronic acid, 2,5-dimethoxyphenylboronic acid, 4,5-dimethoxyphenylboronic acid, 2,4-dimethoxyphenylboronic acid, 2-ethoxyphenylboronic acid, 3-ethoxyphenylboronic acid, 4-ethoxyphenylboronic acid, 4-phenoxyboronic acid, 4-methylenedioxyphenylboronic acid, 2-fluorophenylboronic acid, 3-fluorophenylboronic acid, 4-fluorophenylboronic acid, 2,4-difluorophenylboronic acid, 2,5-difluorophenylboronic acid, 4,5-difluorophenylboronic acid, 3,5-difluorophenylboronic acid, 2-formylphenylboronic acid, 3-formylphenylboronic acid, 4-formylphenylboronic acid, 3-formyl-4-methoxyphenylboronic acid, 2-cyanophenylboronic acid, 3-cyanophenylboronic acid, 4-cyanophenylboronic acid, 3-nitrophenylboronic acid, 3-acetylphenylboronic acid, 4-acetylphenylboronic acid, 3-trifluoroacetylphenylboronic acid, 4-trifluoroacetylphenylboronic acid, 4-methylthiophenylboronic acid, 4-vinylphenylboronic acid, 3-carboxyphenylboronic acid, 4-carboxyphenylboronic acid, 3-aminophenylboronic acid, 2-(N,N-dimethylamino)phenylboronic acid, 3-(N,N-dimethylamino)phenylboronic acid, 4-(N,N-dimethylamino)phenylboronic acid, 2-(N,N-diethylamino)phenylboronic acid, 3-(N,N-diethylamino)phenylboronic acid, 4-(N,N-diethylamino)phenylboronic acid, 2-(N,N-dimethylaminomethyl)phenylboronic acid, furan-2-boronic acid, furan-3-boronic acid, 4-formyl-2-furanboronic acid, dibenzofuran-4-boronic acid, benzofuran-2-boronic acid, thiophene-2-boronic acid, thiophene-3-boronic acid, 5-methylthiophene-2-boronic acid, 5-chlorothiophene-2-boronic acid, 4-methylthiophene-2-boronic acid, 5-methylthiophene-2-boronic acid, 2-acetylthiophene-5-boronic acid, 5-methylthiophene-2-boronic acid, benzothiophene-2-boronic acid, dibenzothiophene-4-boronic acid, pyridine-3-boronic acid, pyridine-4-boronic acid, pyrimidine-5-boronic acid, quinoline-8-boronic acid, isoquinoline-4-boronic acid, 4-benzenebis(boronic acid), phenylboronic acid-pinacol ester, and 4-cyanophenylboronic acid-pinacol ester.
- A preferred class of boronic acids are aryl boronic acids. Most preferred is 2-(N,N-dimethylaminomethyl)phenylboronic acid and 3,5-trifluoromethylphenylboronic acid.
- An alternative preferred boronic acid is boric acid.
- Antimony for use as a catalyst in the present invention may be, for example, antimony III or antimony V.
- Examples of antimony for use as a catalyst include antimony complexes, e.g. organo antimony complexes such as aryl antimony complexes and saturated and unsaturated carbon chain antimony complexes, with the ligand complexed to the antimony with a suitable coordination atom, e.g. selected from O, S or N. Example of suitable antimony catalysts include:
- antimony halides, e.g. SbCl3,
antimony oxides, e.g. Sb2C3,
antimony alkoxides, e.g. Sb(ORx)3 in which Rx is alkyl, alkenyl, alkynyl, e.g. C1-C4 alkyl, C2-C4 alkenyl, e.g. C3-C4 alkynyl, in particular Sb(OEt)3,
antimony carboxylic acids, e.g. Sb(C2CRx)3 in which Rx is as defined above, in particular Sb(Ac)3. - Examples of antimony V catalysts include aryl antimony complexes, such as those mentioned in Nomura et al., Chemistry Letters, The Chemical Society of Japan, 1986, pages 1901-1904. These include antimony complexed with aryl groups and carboxylates, e.g. Ph3Sb(C2CRx)2 in which Rx is as defined above, particularly Ph3Sb(OAc)2, and antimony oxides complexed with aryl groups, e.g. Ph3SbO.
- Preferably the catalyst is recycled, e.g. by extracting the catalyst from the reaction solution into the aqueous phase. Extraction of the catalyst may be achieved by changing the pH of the reaction solution, e.g. to alkaline pH, so that the catalyst transfers from the organic phase to the aqueous phase. The catalyst may subsequently be transferred from the aqueous phase to fresh reactant solution by changing the pH, e.g. to acidic pH.
- Boronic acid catalysts, such as 3,5-bis-(trifluoromethyl)-phenylboronic acid, are particularly suitable for catalyst recycle by extracting the catalyst from the reactant solution to aqueous phase.
- Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of carboxylic acid (II) or (IIA).
- Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of carboxylic acid (II) or (IIA).
- Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 0.1 and 25 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of carboxylic acid (II) or (IIA). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of carboxylic acid (II) or (IIA).
- Preferably, the amount of catalyst employed is up to 50 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is up to 25 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is up to 15 mol % based on the amount of aniline (III) or (IIIA).
- Preferably, the amount of catalyst employed is at least 0.01 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is at least 0.1 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is at least 1 mol % based on the amount of aniline (III) or (IIIA).
- Preferably, the amount of catalyst employed is between 0.01 and 50 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 0.1 and 25 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 1 and 15 mol % based on the amount of aniline (III) or (IIIA). More preferably, the amount of catalyst employed is between 8 and 12 mol % based on the amount of aniline (III) or (IIIA).
- Usually one type of catalyst will be used in a reaction. However, the invention also covers reactions in which more than one type of catalyst is used, e.g. either separately, sequentially or simultaneously. For example, more than one type of boronic catalyst or antimony catalyst may be used or a boronic acid catalyst and an antimony catalyst may be used.
- Suitable methods for the preparation of carboxylic acids (II) and anilines (III) are disclosed in WO04/035589 and WO 2007/048556. Suitable methods for the preparation of carboxylic acids (IIA) and anilines (IIIA) are disclosed in WO03/074491. Other methods will be apparent to those skilled in the art.
- Workup of the reaction mixture is achieved according to well known procedures of synthetic organic chemistry. For example, an aqueous workup may be achieved by the addition of water (or other aqueous solution), and extraction of the desired product with a suitable organic solvent.
- Alternatively, the product may be isolated by removing any solvent present by distillation, e.g. under reduced pressure.
- Purification of the product may be achieved by any one of a number of methods, e.g. distillation, recrystallization and chromatography.
- The present invention will now be described by way of the following non-limiting examples. Those skilled in the art will promptly recognize appropriate variations from the procedures both as to reactants and as to reaction conditions and techniques.
- All references mentioned herein are incorporated by reference in their entirety. All aspects and preferred features of the invention may be combined with each other, except where this is evidently not possible.
-
FIG. 1 -
FIG. 1 shows the reaction profile of the boronic acid catalysed reaction of Example 2: - using 10 mole % catalyst, under azeotropic reflux in toluene. The X axis indicates time in hours and the Y axis indicates mole fraction. Triangles represent the acid reactant, diamonds represent the aniline reactant, circles represent product.
-
FIG. 2 -
FIG. 2 shows a profile of mole fraction of 3,5-bis-(trifluoromethyl)-phenylboronic acid catalyst in the organic phase (toluene) versus pH. Circles represent modelled data, diamonds represent experimental data. -
- An oven-dried round bottomed flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves, and this was connected to the nitrogen line. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by anhydrous toluene (2 mL) via syringe. The mixture was azeotropically refluxed overnight, under nitrogen. After this time, the solution was cooled and concentrated in vacuo to give a pale brown solid. 1H and 19F NMR and GC analyses showed only 5% conversion to amide product.
-
- An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by 3,5-bis-(trifluoromethyl)-phenylboronic acid (26 mg, 5 mol %) and anhydrous toluene (4 mL). The mixture was heated to reflux and was azeotropically refluxed overnight under nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was cooled, and quenched with saturated aqueous solutions of sodium hydrogencarbonate (10 mL) and ammonium chloride (10 mL).
- The aqueous layer was extracted with ethyl acetate (3×10 mL). Combined organic extracts were washed with water (10 mL), dried with MgSC4 and concentrated in vacuo to give a brown solid which was identified as the amide product by 1H and 19F NMR, and GC-MS (0.55 g, 76%).
- The boronic acid catalysed reaction was profiled using 10 mole % catalyst, under azeotropic reflux in toluene. The removal of water by azeotropic reflux appears to be advantageous, since without these conditions, reactions were not complete after 18 hours. See
FIG. 1 . - Recycling of the catalyst was by extracting the boronic acid from the reaction mass with strong aqueous alkali, acidifying and then re-extracting into toluene ready for the next batch was investigated. The phase partition was modelled using the calculated Log P (3.013) and pKa (6.57) and the experimental values are close although show a slight tail at the higher pH possibly due to the high ionic strength. See
FIG. 2 . - Catalyst recycle would significantly reduce the cost contribution of catalyst to the product.
-
- An oven-dried flask was evacuated and refilled with nitrogen three times. The flask was fitted with a dropping funnel containing charged 3 Å molecular sieves. 3-Difluoromethyl-1-methyl-1H-pyrazole-4-carboxylic acid (0.36 g, 2 mmol), 9-Isopropyl-1,2,3,4-tetrahydro-1,4-methano-naphthalen-5-ylamine (0.4 g, 2 mmol) were added to the flask, followed by antimony (III) ethoxide (34 μL, 5 mol %) and anhydrous toluene (4 mL). The reaction was refluxed azeotropically overnight, under an atmosphere of nitrogen. A sample was analysed by GC which indicated quantitative conversion to the amide and so the solution was quenched with methanol (5 mL), and a solid crashed out of the resulting solution. This suspension was filtered through a pad of Celite, washing with 50/50 ethyl acetate/acetone (10 mL). The resulting solution was concentrated in vacuo to yield a yellow solid which was identified by 1H and 19F NMR, and GCMS analyses as the amide product (0.53 g, 73%).
-
-
Actual Strength 100% Mol Mol. Materials Wt (g) (%) Wt. (g) Wt. mmol. Ratio DF-Pyrazole 0.41 95.9 0.393 176 2.2 1.0 acid (IV) Aniline (VII) 0.52 95 0.494 239 2.2 1.0 Boric acid 0.0142 98 0.0139 61.8 0.23 0.1 Xylene 15 ml 99 — — — — - A 50 ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3A molecular sieves 8-12 mesh (with 10 ml xylene). The system was purged with nitrogen and vented to atmosphere.
- DF-Pyrazole acid (compound IV) (0.41 g), aniline (compound VII) (0.56 g), xylene (15 ml) and boric acid catalyst (14.2 mg) were charged to the flask. The mixture was heated to reflux (˜144 deg C.) and held on temperature for 8 hrs. Reaction was monitored via GCMS.
-
- GC/MS Details: The product had the same retention time, molecular ion (M+331) and fragmentation pattern as found with the authentic compound.
- NMR: NMR spectrum of product was consistent with that for authentic material.
-
- A selection of catalysts (10 mol %) were screened. The procedure in Example 4 was repeated varying the catalyst employed.
-
Catalyst Solvent Connditions Results None Xylene Vigorous reflux 2% conversion to with Dean & desired product Stark set-up Relatively clean 5 hr reaction B(OH)3 Xylene Vigorous reflux 55% conversion with Dean & to desired product Stark set-up Relatively clean 8 hr reaction Xylene Vigorous reflux with Dean & Stark set-up. 8 hr 55% conversion to the desired product - Conversions were determined by GCMS analysis. The results presented in the table are based on consumption of the aniline component. Conversions based on carboxylic acid consumption are different, presumably due to response factor differences. NMR analysis has shown that monitoring aniline consumption gives the best measure of reaction conversion.
- Desired product was formed in all cases, but reaction rate was very slow without catalyst present. Reasonably good rates were achieved with both of the boron-based catalysts tried. Interestingly, a synthetically advantageous rate was achieved with cheap boric acid catalyst (55% conversion in 8 hr), The product was isolated and its structure confirmed by NMR analysis.
-
-
Mo- Actual Strength 100% lecular Molar Materials Weight % Weight weight Mmol Ratio DF-Pyrazole 0.5 93.0 0.465 176 2.6 1.0 acid (X) BiCP Aniline 0.94 48.7 0.458 173 2.6 1.0 (XI) 2-(N,N- 0.047 98 0.046 179 0.26 0.1 dimethyl- aminomethyl) phenylboronic acid Xylene 20 ml 99 17.2 106 162 62.4 - A 50 ml three neck round bottom flask was fitted with a magnetic flea, thermometer, oil bath, condenser, and Dean & Stark apparatus filled with 3 Å molecular sieves 8-12 mesh (with 10 ml xylene). The system was purged with nitrogen and vented to the atmosphere.
- DF-pyrazole acid X (0.5 g), BiCP-aniline XI (0.94 g), xylene (20 ml) and 2-(N,N-dimethyl aminomethyl)phenylboronic acid catalyst (47 mg) were charged to the flask. The mixture was heated to reflux (˜143° C.) and held at this temperature for 10 hours.
- The reaction was monitored via HPLC; 45% conversion being achieved after 5 hours, and 58% after 10 hours.
- Product identity was confirmed by HPLC and GCMS comparison with authentic material.
-
- The procedure of Example 6 was repeated varying the catalyst employed.
-
Solvent Conditions Time Catalyst Conversion Xylene Reflux, Dean 5 hours None <1% and Stark Xylene Reflux, Dean 5 hours 2-(N,N- 45% and Stark dimethylaminomethyl) phenylboronic acid (10 Mol %) Xylene Reflux, Dean 5 hours Boric Acid 25% and Stark (10 Mol %) Xylene Reflux, Dean 20 hours Boric Acid 50% and Stark (10 Mol %) - These results show that in the absence of catalysts, virtually no reaction occurred after 5 hours at 140° C.
- Addition of catalyst, however, had a dramatic effect on reaction rate—45% conversion being achieved after 5 hours with 10% of 2-(N,N-dimethylaminomethyl) phenylboronic acid. Boric acid catalyst was less effective, but still generated a useful reaction rate (25% conversion after 5 hours). Product identity was confirmed by GCMS comparison with authentic material.
Claims (15)
1-16. (canceled)
17. A process for (a) the preparation of compounds of the formula (I)
wherein
Het is pyrrolyl or pyrazolyl, either being substituted by groups R8, R9 and R10;
X is a single bond;
Y is (CR12R13)(CR14R15)m(CR16R17)n or C═C(A)Z in which A and Z are independently C1-6 alkyl or halogen;
m is 0 or 1;
n is 0 or 1;
R1 is hydrogen;
R2 and R3 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 alkoxy or C1-4 haloalkoxy;
R4, R5, R6 and R7 are each, independently, hydrogen, halogen, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, hydroxymethyl, C1-4 alkoxymethyl, C(O)CH3 or C(O)OCH3;
R8, R9 and R10 are each, independently, hydrogen, halogen, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4)alkylene or C1-4 haloalkoxy(C1-4)alkylene, provided that at least one of R8, R9 and R10 is not hydrogen;
R12 and R13 are each, independently, hydrogen, halogen, C1-5 alkyl, C1-3 alkoxy, CH2OH, CH(O), C3-6 cycloalkyl, CH2O—C(═O)CH3, CH2—C3-6 cycloalkyl or benzyl;
or R12 and R13 together with the carbon atom to which they are attached form the group C═O or a 3-5 membered carbocyclic ring;
or R12 and R13 together form C1-5 alkylidene or C3-6 cycloalkylidene; and
R14, R15, R16 and R17 are each, independently, H or CH3;
comprising the step of reacting a carboxylic acid of formula (II)
wherein R1, R2, R3, R4, R5, R6, R7, X and Y are as defined above;
in the presence of a boronic acid catalyst or an antimony catalyst;
or (b) the preparation of compounds of the formula (IA)
wherein
Heta is pyrrolyl, pyrazolyl or thiazolyl, each being substituted by groups R4a, R5a, R6a;
R1a is hydrogen, fluoro, chloro or bromo;
R2a is hydrogen, fluoro, chloro or bromo;
R3a is optionally substituted C2-12 alkyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H);
optionally substituted C2-12 alkenyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4-alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H);
optionally substituted C2-12 alkynyl, wherein, when present, each optional substituent is, independently, selected from fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H);
optionally substituted C3-12 cycloalkyl, wherein, when present, each optional substituent is, independently, selected from C1-3 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); optionally substituted phenyl, wherein, when present, each optional substituent is, independently, selected from C1-6 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N and R′R″NN═C(H); or optionally substituted heterocyclyl, wherein, when present, each optional substituent is, independently, selected from C1-6 alkyl, fluoro, chloro, bromo, hydroxy, cyano, C1-4 alkoxyC(═O), formyl, nitro, C1-4 alkoxy, C1-4 haloalkoxy, C1-4 alkylthio, C1-4 haloalkylthio, HC(OR′)═N;
R′ and R″ are, independently, hydrogen or C1-4 alkyl; and
R4a, R5a, and R6a are, independently, selected from hydrogen, fluoro, chloro, bromo, cyano, nitro, C1-4 alkyl, C1-4 haloalkyl, C1-4 alkoxy(C1-4)alkyl and C1-4 haloalkoxy(C1-4)alkyl, provided that at least one of R4a, R5a, and R6a is not hydrogen.
comprising reacting a carboxylic acid of formula (IIA)
18. The process according to claim 1 wherein the boronic acid catalyst is an aryl boronic acid.
19. The process according to claim 1 wherein the boronic acid catalyst is 2-(N,N-dimethylaminomethyl)phenylboronic acid, boric acid or 3,5-trifluoromethylphenyl boronic acid.
20. The process according to claim 1 wherein the antimony catalyst is Sb(OEt)3.
21. The process according to claim 1 wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of carboxylic acid (II) or (IIA).
22. The process according to claim 1 wherein the catalyst is employed in an amount of between 1 and 15 mol % based on the amount of aniline (III) or (IIIA).
23. The process according to claim 1 wherein the molar ratio of acid (II) or (IIA):aniline (III) or (IIIA) is in the range of from 2:1 to 1:2.
25. The process according to claim 1 wherein Y is CHCH(CH3)CH3.
26. The process according to claim 1 wherein Y is C═CCl2.
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US13/556,904 US20120289707A1 (en) | 2008-05-14 | 2012-07-24 | Process for the preparation of amides |
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GB0808772A GB0808772D0 (en) | 2008-05-14 | 2008-05-14 | Process |
GB0808766.0 | 2008-05-14 | ||
GB0808766A GB0808766D0 (en) | 2008-05-14 | 2008-05-14 | Process |
GB0808772.8 | 2008-05-14 | ||
PCT/EP2009/055651 WO2009138375A1 (en) | 2008-05-14 | 2009-05-11 | Process for the preparation of amides |
US99278111A | 2011-02-21 | 2011-02-21 | |
US13/556,904 US20120289707A1 (en) | 2008-05-14 | 2012-07-24 | Process for the preparation of amides |
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PCT/EP2009/055651 Continuation WO2009138375A1 (en) | 2008-05-14 | 2009-05-11 | Process for the preparation of amides |
US99278111A Continuation | 2008-05-14 | 2011-02-21 |
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BR (1) | BRPI0912558A2 (en) |
IL (1) | IL208792A0 (en) |
MX (1) | MX2010011790A (en) |
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EP2181087B1 (en) | 2007-08-16 | 2015-10-14 | Solvay Sa | Process for the preparation of esters of 4-fluorosubstituted 3-oxo-alcanoic acids |
GB201004301D0 (en) * | 2010-03-15 | 2010-04-28 | Syngenta Participations Ag | Process |
EP2560960B1 (en) * | 2010-04-20 | 2014-02-26 | Syngenta Participations AG | Process for the preparation of pyrazole carboxylic acid amides |
US8987470B2 (en) | 2010-10-27 | 2015-03-24 | Solvay Sa | Process for the preparation of pyrazole-4-carboxamides |
TWI534126B (en) * | 2011-01-25 | 2016-05-21 | 先正達合夥公司 | Process for the preparation of pyrazole carboxylic acid amides |
EP2675816A4 (en) * | 2011-02-14 | 2014-08-13 | Univ Alberta | Boronic acid catalysts and methods of use thereof for activation and transformation of carboxylic acids |
WO2013118130A1 (en) * | 2012-02-06 | 2013-08-15 | Symed Labs Limited | A process for the preparation of 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide |
CN105557722A (en) * | 2014-10-15 | 2016-05-11 | 陕西美邦农药有限公司 | Pesticide composition containing benzovindiflupyr |
WO2017054112A1 (en) * | 2015-09-28 | 2017-04-06 | 常州市卜弋科研化工有限公司 | Method of preparing 3-fluoroalkyl-1-methylpyrazole-4-carboxylic acid |
CN106588745B (en) * | 2016-12-02 | 2019-06-14 | 杭州百昂锐地科技有限公司 | A kind of intermediate and its preparation method and application of benzo alkene fluorine bacterium azoles |
CN115947688B (en) * | 2023-03-15 | 2023-05-16 | 佛山职业技术学院 | Pyrazolonamine hapten, antigen, antibody, detection device and preparation and application thereof |
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WO2009138375A1 (en) | 2009-11-19 |
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US20110178310A1 (en) | 2011-07-21 |
BRPI0912558A2 (en) | 2015-07-28 |
US8227619B2 (en) | 2012-07-24 |
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EP2280944A1 (en) | 2011-02-09 |
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