WO2014018506A1 - Fluoropicolinoyl fluorides and processes for their preparation - Google Patents
Fluoropicolinoyl fluorides and processes for their preparation Download PDFInfo
- Publication number
- WO2014018506A1 WO2014018506A1 PCT/US2013/051629 US2013051629W WO2014018506A1 WO 2014018506 A1 WO2014018506 A1 WO 2014018506A1 US 2013051629 W US2013051629 W US 2013051629W WO 2014018506 A1 WO2014018506 A1 WO 2014018506A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- compound
- formula
- alkoxy
- group
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 25
- 150000002222 fluorine compounds Chemical class 0.000 title abstract description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 69
- 150000001875 compounds Chemical class 0.000 claims description 44
- 125000005843 halogen group Chemical group 0.000 claims description 34
- 125000001424 substituent group Chemical group 0.000 claims description 32
- -1 phosphonium halide Chemical class 0.000 claims description 29
- NROKBHXJSPEDAR-UHFFFAOYSA-M potassium fluoride Chemical compound [F-].[K+] NROKBHXJSPEDAR-UHFFFAOYSA-M 0.000 claims description 29
- 239000002904 solvent Substances 0.000 claims description 28
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 23
- 125000003545 alkoxy group Chemical group 0.000 claims description 23
- 125000004767 (C1-C4) haloalkoxy group Chemical group 0.000 claims description 21
- 125000004765 (C1-C4) haloalkyl group Chemical group 0.000 claims description 21
- 125000000229 (C1-C4)alkoxy group Chemical group 0.000 claims description 21
- 239000011698 potassium fluoride Substances 0.000 claims description 21
- 125000000217 alkyl group Chemical group 0.000 claims description 20
- 125000003342 alkenyl group Chemical group 0.000 claims description 19
- 125000000304 alkynyl group Chemical group 0.000 claims description 19
- HXJUTPCZVOIRIF-UHFFFAOYSA-N sulfolane Chemical compound O=S1(=O)CCCC1 HXJUTPCZVOIRIF-UHFFFAOYSA-N 0.000 claims description 19
- XJHCXCQVJFPJIK-UHFFFAOYSA-M caesium fluoride Chemical compound [F-].[Cs+] XJHCXCQVJFPJIK-UHFFFAOYSA-M 0.000 claims description 18
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 15
- 235000003270 potassium fluoride Nutrition 0.000 claims description 14
- 239000003054 catalyst Substances 0.000 claims description 13
- PUZPDOWCWNUUKD-UHFFFAOYSA-M sodium fluoride Chemical compound [F-].[Na+] PUZPDOWCWNUUKD-UHFFFAOYSA-M 0.000 claims description 13
- 150000003983 crown ethers Chemical class 0.000 claims description 11
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 claims description 10
- 229910001512 metal fluoride Inorganic materials 0.000 claims description 10
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 7
- 150000002367 halogens Chemical group 0.000 claims description 7
- 239000011775 sodium fluoride Substances 0.000 claims description 6
- 235000013024 sodium fluoride Nutrition 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 5
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 4
- 229920000570 polyether Polymers 0.000 claims description 4
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 3
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 claims description 3
- 150000003990 18-crown-6 derivatives Chemical group 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 125000004438 haloalkoxy group Chemical group 0.000 claims 4
- 125000001188 haloalkyl group Chemical group 0.000 claims 4
- ZAFLZRNJFHWOQQ-UHFFFAOYSA-N 3-chloropyridine-2-carbonyl chloride Chemical class ClC(=O)C1=NC=CC=C1Cl ZAFLZRNJFHWOQQ-UHFFFAOYSA-N 0.000 abstract description 4
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 44
- 239000000203 mixture Substances 0.000 description 42
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 39
- 239000007787 solid Substances 0.000 description 39
- 238000006243 chemical reaction Methods 0.000 description 35
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 31
- 239000011541 reaction mixture Substances 0.000 description 28
- 238000004293 19F NMR spectroscopy Methods 0.000 description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 21
- 238000003756 stirring Methods 0.000 description 21
- 238000005160 1H NMR spectroscopy Methods 0.000 description 20
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 14
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 14
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 235000019439 ethyl acetate Nutrition 0.000 description 11
- 238000010438 heat treatment Methods 0.000 description 11
- 239000000126 substance Substances 0.000 description 11
- 238000004821 distillation Methods 0.000 description 10
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 10
- 239000000741 silica gel Substances 0.000 description 10
- 229910002027 silica gel Inorganic materials 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 9
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 9
- 238000004458 analytical method Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 229940086542 triethylamine Drugs 0.000 description 8
- XEZNGIUYQVAUSS-UHFFFAOYSA-N 18-crown-6 Chemical compound C1COCCOCCOCCOCCOCCO1 XEZNGIUYQVAUSS-UHFFFAOYSA-N 0.000 description 7
- 239000000460 chlorine Substances 0.000 description 7
- 239000012043 crude product Substances 0.000 description 7
- 239000007858 starting material Substances 0.000 description 7
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 6
- 125000004414 alkyl thio group Chemical group 0.000 description 6
- 125000004432 carbon atom Chemical group C* 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- 239000000543 intermediate Substances 0.000 description 6
- 239000000725 suspension Substances 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 239000003480 eluent Substances 0.000 description 5
- 150000004673 fluoride salts Chemical class 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- LJANYXUDWCCLMQ-UHFFFAOYSA-N pyridine-2-carbonyl fluoride Chemical class FC(=O)C1=CC=CC=N1 LJANYXUDWCCLMQ-UHFFFAOYSA-N 0.000 description 5
- OSTNSZKOBGVNID-UHFFFAOYSA-N 3,4,5,6-tetrafluoropyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=NC(F)=C(F)C(F)=C1F OSTNSZKOBGVNID-UHFFFAOYSA-N 0.000 description 4
- QERMRZQVBGYSFJ-UHFFFAOYSA-N 4,5,6-trifluoropyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=CC(F)=C(F)C(F)=N1 QERMRZQVBGYSFJ-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-FIBGUPNXSA-N acetonitrile-d3 Chemical compound [2H]C([2H])([2H])C#N WEVYAHXRMPXWCK-FIBGUPNXSA-N 0.000 description 4
- 125000002252 acyl group Chemical group 0.000 description 4
- 229910001515 alkali metal fluoride Inorganic materials 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 150000002148 esters Chemical class 0.000 description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000002808 molecular sieve Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 239000012044 organic layer Substances 0.000 description 4
- 239000012074 organic phase Substances 0.000 description 4
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- PJAIMBYNTXNOCN-UHFFFAOYSA-N 3,6-dibromo-1h-indole Chemical compound BrC1=CC=C2C(Br)=CNC2=C1 PJAIMBYNTXNOCN-UHFFFAOYSA-N 0.000 description 3
- BASWDJWLHQQKAU-UHFFFAOYSA-N 4,5-dichloro-6-(4-chlorophenyl)pyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC(Cl)=CC=2)=N1 BASWDJWLHQQKAU-UHFFFAOYSA-N 0.000 description 3
- AHDFCMPBXDNBBR-UHFFFAOYSA-N 4,5-dichloro-6-(4-chlorophenyl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC(Cl)=CC=2)=N1 AHDFCMPBXDNBBR-UHFFFAOYSA-N 0.000 description 3
- YRUPBIPDCOEFHZ-UHFFFAOYSA-N 4,5-dichloro-6-(4-methoxyphenyl)pyridine-2-carbonyl chloride Chemical compound C1=CC(OC)=CC=C1C1=NC(C(Cl)=O)=CC(Cl)=C1Cl YRUPBIPDCOEFHZ-UHFFFAOYSA-N 0.000 description 3
- BNQYSFWLVLAPPF-UHFFFAOYSA-N 4,5-dichloro-6-(4-methoxyphenyl)pyridine-2-carboxylic acid Chemical compound C1=CC(OC)=CC=C1C1=NC(C(O)=O)=CC(Cl)=C1Cl BNQYSFWLVLAPPF-UHFFFAOYSA-N 0.000 description 3
- XQZXNWKQNTWHOZ-UHFFFAOYSA-N 4,5-dichloro-6-phenylpyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC=CC=2)=N1 XQZXNWKQNTWHOZ-UHFFFAOYSA-N 0.000 description 3
- HBPSHBLIEQWDMD-UHFFFAOYSA-N 4,5-dichloro-6-phenylpyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC=CC=2)=N1 HBPSHBLIEQWDMD-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 3
- 150000001805 chlorine compounds Chemical class 0.000 description 3
- 125000004093 cyano group Chemical group *C#N 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 239000004009 herbicide Substances 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 238000012544 monitoring process Methods 0.000 description 3
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- XDHYNPMDFIFHFL-UHFFFAOYSA-N propan-2-yl 3,4,5,6-tetrafluoropyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=NC(F)=C(F)C(F)=C1F XDHYNPMDFIFHFL-UHFFFAOYSA-N 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 0 *c1cccc(C(Cl)=O)n1 Chemical compound *c1cccc(C(Cl)=O)n1 0.000 description 2
- RPBUWNXYNYVENO-UHFFFAOYSA-N 3,4,5,6-tetrachloropyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=NC(Cl)=C(Cl)C(Cl)=C1Cl RPBUWNXYNYVENO-UHFFFAOYSA-N 0.000 description 2
- GNLWWMULFXGGJU-UHFFFAOYSA-N 3,6-difluoropyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=NC(F)=CC=C1F GNLWWMULFXGGJU-UHFFFAOYSA-N 0.000 description 2
- WABXFXHAELFJJG-UHFFFAOYSA-N 5-fluoropyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=CC=C(F)C=N1 WABXFXHAELFJJG-UHFFFAOYSA-N 0.000 description 2
- 101150041968 CDC13 gene Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000004817 gas chromatography Methods 0.000 description 2
- ODRFMIJNQNBMMJ-UHFFFAOYSA-N methyl 6-(4-chloro-2-fluoro-3-methoxyphenyl)-4,5-difluoropyridine-2-carboxylate Chemical compound COC(=O)C1=CC(F)=C(F)C(C=2C(=C(OC)C(Cl)=CC=2)F)=N1 ODRFMIJNQNBMMJ-UHFFFAOYSA-N 0.000 description 2
- 150000004702 methyl esters Chemical class 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 description 2
- DAWMZTDNNVXXNS-UHFFFAOYSA-N propan-2-yl 3,6-difluoropyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=NC(F)=CC=C1F DAWMZTDNNVXXNS-UHFFFAOYSA-N 0.000 description 2
- GVTNRGPDFNRZDX-UHFFFAOYSA-N propan-2-yl 4,5-dichloro-6-(4-chlorophenyl)pyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC(Cl)=CC=2)=N1 GVTNRGPDFNRZDX-UHFFFAOYSA-N 0.000 description 2
- UEMMMVIJKLOXHJ-UHFFFAOYSA-N propan-2-yl 4,5-dichloro-6-(4-methoxyphenyl)pyridine-2-carboxylate Chemical compound C1=CC(OC)=CC=C1C1=NC(C(=O)OC(C)C)=CC(Cl)=C1Cl UEMMMVIJKLOXHJ-UHFFFAOYSA-N 0.000 description 2
- FWPXDYCSECBKSZ-UHFFFAOYSA-N propan-2-yl 6-(4-chlorophenyl)-4,5-difluoropyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=CC(F)=C(F)C(C=2C=CC(Cl)=CC=2)=N1 FWPXDYCSECBKSZ-UHFFFAOYSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 2
- YXFVVABEGXRONW-JGUCLWPXSA-N toluene-d8 Chemical compound [2H]C1=C([2H])C([2H])=C(C([2H])([2H])[2H])C([2H])=C1[2H] YXFVVABEGXRONW-JGUCLWPXSA-N 0.000 description 2
- 238000003828 vacuum filtration Methods 0.000 description 2
- CAYQIZIAYYNFCS-UHFFFAOYSA-N (4-chlorophenyl)boronic acid Chemical compound OB(O)C1=CC=C(Cl)C=C1 CAYQIZIAYYNFCS-UHFFFAOYSA-N 0.000 description 1
- VOAAEKKFGLPLLU-UHFFFAOYSA-N (4-methoxyphenyl)boronic acid Chemical compound COC1=CC=C(B(O)O)C=C1 VOAAEKKFGLPLLU-UHFFFAOYSA-N 0.000 description 1
- ZQGDSZPGKPJABN-UHFFFAOYSA-N 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane Chemical compound C1C[N+]2(CCl)CC[N+]1(F)CC2 ZQGDSZPGKPJABN-UHFFFAOYSA-N 0.000 description 1
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 1
- DYKPANQCIFHPMI-UHFFFAOYSA-N 3,6-dichloropyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=NC(Cl)=CC=C1Cl DYKPANQCIFHPMI-UHFFFAOYSA-N 0.000 description 1
- XTMUXJBJCMRWPG-UHFFFAOYSA-N 3-chloropyridine-2-carboxylic acid Chemical class OC(=O)C1=NC=CC=C1Cl XTMUXJBJCMRWPG-UHFFFAOYSA-N 0.000 description 1
- LPLSXEQPNFWFFS-UHFFFAOYSA-N 4,5,6-trichloropyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC(Cl)=C(Cl)C(Cl)=N1 LPLSXEQPNFWFFS-UHFFFAOYSA-N 0.000 description 1
- YTCQTRRFYKVAMD-UHFFFAOYSA-N 4,5,6-trifluoropyridine-2-carboxylic acid Chemical compound OC(=O)C1=CC(F)=C(F)C(F)=N1 YTCQTRRFYKVAMD-UHFFFAOYSA-N 0.000 description 1
- ZHWBNBHTQZRIQD-UHFFFAOYSA-N 4,5-dichloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carbonyl chloride Chemical compound COC1=C(Cl)C=CC(C=2C(=C(Cl)C=C(N=2)C(Cl)=O)Cl)=C1F ZHWBNBHTQZRIQD-UHFFFAOYSA-N 0.000 description 1
- ZAYTUZJMFVYJSU-UHFFFAOYSA-N 4,5-dichloro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid Chemical compound COC1=C(Cl)C=CC(C=2C(=C(Cl)C=C(N=2)C(O)=O)Cl)=C1F ZAYTUZJMFVYJSU-UHFFFAOYSA-N 0.000 description 1
- VSTZSOOOFVIGJA-UHFFFAOYSA-N 4,5-difluoro-6-(4-methoxyphenyl)pyridine-2-carbonyl fluoride Chemical compound C1=CC(OC)=CC=C1C1=NC(C(F)=O)=CC(F)=C1F VSTZSOOOFVIGJA-UHFFFAOYSA-N 0.000 description 1
- MQYKRYOZJUIWOY-UHFFFAOYSA-N 4,5-difluoro-6-phenylpyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=CC(F)=C(F)C(C=2C=CC=CC=2)=N1 MQYKRYOZJUIWOY-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- WRHDYOGDDZYNMT-UHFFFAOYSA-N 4-amino-3-chloro-5-fluoropyridine-2-carboxylic acid Chemical compound NC1=C(F)C=NC(C(O)=O)=C1Cl WRHDYOGDDZYNMT-UHFFFAOYSA-N 0.000 description 1
- JRIASDXJZYOBCA-UHFFFAOYSA-N 5-chloropyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=C(Cl)C=N1 JRIASDXJZYOBCA-UHFFFAOYSA-N 0.000 description 1
- WFGXOXOHPSVPTI-UHFFFAOYSA-N 6-(4-chlorophenyl)-4,5-difluoropyridine-2-carbonyl fluoride Chemical compound FC(=O)C1=CC(F)=C(F)C(C=2C=CC(Cl)=CC=2)=N1 WFGXOXOHPSVPTI-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WAIPAZQMEIHHTJ-UHFFFAOYSA-N [Cr].[Co] Chemical compound [Cr].[Co] WAIPAZQMEIHHTJ-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000012455 biphasic mixture Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001735 carboxylic acids Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 230000000875 corresponding effect Effects 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 1
- 229960001826 dimethylphthalate Drugs 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- XFZUQTKDBCOXPP-UHFFFAOYSA-N florpyrauxifen Chemical compound COC1=C(Cl)C=CC(C=2C(=C(N)C(Cl)=C(C(O)=O)N=2)F)=C1F XFZUQTKDBCOXPP-UHFFFAOYSA-N 0.000 description 1
- 238000003682 fluorination reaction Methods 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-M picolinate Chemical compound [O-]C(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-M 0.000 description 1
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical class OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- WDBVGEMYQHJBDA-UHFFFAOYSA-N propan-2-yl 4,5-dichloro-6-phenylpyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=CC(Cl)=C(Cl)C(C=2C=CC=CC=2)=N1 WDBVGEMYQHJBDA-UHFFFAOYSA-N 0.000 description 1
- CUCADYTVGOVTKY-UHFFFAOYSA-N propan-2-yl 4,5-difluoro-6-(4-methoxyphenyl)pyridine-2-carboxylate Chemical compound C1=CC(OC)=CC=C1C1=NC(C(=O)OC(C)C)=CC(F)=C1F CUCADYTVGOVTKY-UHFFFAOYSA-N 0.000 description 1
- PCHKPGRAPBRHIZ-UHFFFAOYSA-N propan-2-yl 4,5-difluoro-6-phenylpyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=CC(F)=C(F)C(C=2C=CC=CC=2)=N1 PCHKPGRAPBRHIZ-UHFFFAOYSA-N 0.000 description 1
- WHVLRUBYLHVRPJ-UHFFFAOYSA-N propan-2-yl 5-fluoropyridine-2-carboxylate Chemical compound CC(C)OC(=O)C1=CC=C(F)C=N1 WHVLRUBYLHVRPJ-UHFFFAOYSA-N 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- PSAYJRPASWETSH-UHFFFAOYSA-N pyridine-2-carbonyl chloride Chemical compound ClC(=O)C1=CC=CC=N1 PSAYJRPASWETSH-UHFFFAOYSA-N 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 239000012429 reaction media Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 125000000547 substituted alkyl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000005809 transesterification reaction Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/55—Acids; Esters
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/34—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom
- A01N43/40—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one nitrogen atom as the only ring hetero atom six-membered rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
- C07D213/807—Processes of preparation by oxidation of pyridines or condensed pyridines
Definitions
- fluoropicolinoyl fluorides and processes for their preparation.
- a process for the preparation of 5-fluoro-6-aryl- picolinoyl fluorides from chloropicolinoyl chlorides is provided herein.
- U.S. Patent 6,297,197 Bl describes inter alia certain 6-(alkoxy or aryloxy)-4- amino-3-chloro-5-fluoropicolinate compounds and their use as herbicides.
- U.S. Patents 6,784,137 B2 and 7,314,849 B2 describe inter alia certain 6-(aryl)-4-amino-3-chloro-5- fluoropicolinate compounds and their use as herbicides.
- U.S. Patent 7,432,227 B2 describes inter alia certain 6-(alkyl)-4-amino-3-chloro-5-fluoropicolinate compounds and their use as herbicides.
- fluoropicolinoyl fluorides and processes for their preparation.
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; m is 0, 1, 2 or 3; and n is 1, 2, 3 or 4; wherein the sum of m and n is less than or equal to 4; which comprises fluorinating a compound of Formula A:
- R, m and n are as previously defined; with a source of fluoride ion to produce the compound of the Formula I.
- Fluoropicolinoyl fluorides provided herein may be prepared from chloropicolinoyl chlorides as shown in Scheme 1 below.
- M-F represents a metal fluoride salt, including but not limited to, sodium fluoride, potassium fluoride or cesium fluoride.
- the solvent is sulfolane or acetonitrile.
- M-F represents a metal fluoride salt, including but not limited to, sodium fluoride, potassium fluoride or cesium fluoride.
- the solvent is sulfolane or acetonitrile.
- Ar represents an aryl group.
- fluoropicolinoyl fluorides and processes for their preparation.
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; m is 0, 1, 2 or 3; and n is 1, 2, 3 or 4; wherein the sum of m and n is less than or equal to 4; which comprises fluorinating a compound of Formula A:
- R, m and n are as previously defined; with a source of fluoride ion to produce the compound of the Formula I.
- provided herein is a process for the preparation of compound of the Formula I, wherein m is 0. In other embodiments, m is 1.
- n 1, 2 or 3. In some embodiments, n is 2 or 3 other embodiments, n is 2. In other embodiments, n is 3.
- the compound of Formula I is: wherein R is aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; and n is 1, 2 or 3.
- the compound of Formula I is:
- the process includes a catalyst selected from a crown ether, a phosphonium halide, a polyether, a phosphazenium salt, and a tetra-substituted ammonium halide.
- the catalyst is a crown ether.
- the crown ether is 18-crown-6.
- the source of fluoride ion is a metal fluoride.
- the metal fluoride is selected from sodium fluoride, potassium fluoride and cesium fluoride. In one embodiment, the metal fluoride is potassium fluoride.
- the process includes a solvent.
- the solvent is selected from an alkyl nitrile or an alkyl sulfone.
- the solvent is acetonitrile or sulfolane.
- R is phenyl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; and n is 1 or 2; which comprises reacting a compound of Formula A: wherein R is phenyl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; and n is 1 or 2; with potassium fluoride in the presence of a crown ether and a solvent.
- the solvent is acetonitrile or sulfolane.
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; wherein the sum of m and n is between 1 and 4.
- n is 1, 2, 3 or 4.
- the compound is of the formula:
- the compound is of the formula: wherein R is aryl substituted with from 0 to 5 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; and n is 1, 2 or 3. In one embodiment, n is 1 or 2.
- the compound is of the formula: wherein
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy;
- R 1 is selected from the group consisting of H; alkyl; cycloalkyl; alkenyl; alkynyl; and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy and C 1 -C 4 haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; wherein the sum of m and n is between 1 and 4; which comprises (a) fluorinating a compound of Formula A:
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; which further comprises (b) reacting a compound for Formula I with a source of R OH to produce a compound of Formula II.
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy;
- R 1 is selected from the group consisting of H; alkyl; cycloalkyl; alkenyl; alkynyl; unsubstituted or substituted C7-C11 arylalkyl; and aryl substituted with from 0 to 5 substituents independently selected from halo, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 alkoxy and C1-C4 haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; wherein the sum of m and n is between 1 and 4; which comprises (a) fluorinating a compound of Formula A:
- R is selected from the group consisting of halo; alkyl; cycloalkyl; alkenyl; alkynyl; alkoxy and aryl substituted with from 0 to 5 substituents independently selected from halo, C 1 -C4 alkyl, C 1 -C4 haloalkyl, C 1 -C4 alkoxy and C 1 -C4 haloalkoxy; m is 0, 1, 2 or 3; and n is 0, 1, 2, 3 or 4; which further comprises (b) reacting a compound for Formula I with a source of R OH to produce a compound of Formula II.
- the reaction of step (b) further comprises a base.
- the base is a trialkyl amine base, e.g., triethylamine.
- Fluoropicolinoyl fluorides provided herein may be prepared from chloropicolinoyl chlorides as shown in Scheme 1 below.
- M-F represents a metal fluoride salt, including but not limited to, sodium fluoride, potassium fluoride or cesium fluoride.
- the solvent is sulfolane or acetonitrile.
- n 1 to 3
- M-F represents a metal fluoride salt, including but not limited to, sodium fluoride, potassium fluoride or cesium fluoride.
- the solvent is sulfolane or acetonitrile.
- Ar represents an aryl group.
- the fluoropicolinoyl fluorides provided herein may be used as intermediates in the preparation of picolinate acids and esters, which in turn may be used as intermediates in the preparation of 4-amino-5-fluoro-3-halo-6-aryl-picolinates such as 4-amino-3-chloro-5- fluoro-6-(4-chloro-2-fluoro-3-methoxyphenyl)pyridine-2-carboxylic acid.
- Schemes 3 and 4 are non-limiting examples of the processes provided herein.
- Carboxylic acid or ester derivatives of the picolinoyl fluorides provided herein may be prepared according to Schemes 3 and 4 as desired products, or to further characterize the picolinoyl fluorides, as in some instances, the picolinoyl fluorides are not stable to certain conventional purification methods.
- the picolinoyl fluorides were characterized by GC/MS and 19 F NMR analysis without purification.
- 4,5,6-trifluoropicolinoyl fluoride was isolated by distillation and characterized by GC/MS and NMR techniques.
- the esters and carboxylic acids provided below were purified and characterized by GC/MS and NMR techniques.
- Schemes 3 and 4 provide direct access to di-, tri- and tetra-fluoropicolinoyl fluorides in good yields. Previous methods, as illustrated in Scheme 5, resulted in complex mixtures of undesired products. Thus, the processes provided herein represent and improved process for access to di-, tri- and tetra-fluoropicolinates.
- the mono-, di-, tri, and tetra-chloropicolinoyl chloride and/or 6-aryl-picolinoyl chloride starting materials provided herein are known compounds, and/or may be prepared from known chloropicolinates using routine techniques known in the art. See, e.g., U.S. Patent 6,784,137 B2. Higher esters, including unsubstituted or substituted C 7 -Cn arylalkyl esters, can be prepared by direct esterification or transesterification reactions using techniques which are well known in the art. An exemplary scheme for the preparation of a 6- aryl-picolinoyl chloride is shown below:
- Fluoride ion sources which may be used in processes provided herein include alkali metal fluorides (“M-F”), which include sodium fluoride (NaF), potassium fluoride (KF) and cesium fluoride (CsF). Fluoride salts such as tetrabutylammonium fluoride (n- Bu 4 NF) may also be used.
- M-F alkali metal fluorides
- NaF sodium fluoride
- KF potassium fluoride
- CsF cesium fluoride
- Fluoride salts such as tetrabutylammonium fluoride (n- Bu 4 NF) may also be used.
- the reactions are carried out in a solvent or reaction medium such as, acetonitrile, sulfolane, alkyl nitriles, polyethers, or alkyl sulfones, including mixtures thereof.
- a solvent or reaction medium such as, acetonitrile, sulfolane, alkyl nitriles, polyethers, or alkyl sulfones, including mixtures thereof.
- the solvent used is an alkyl nitrile or an alkyl sulfone.
- the solvent used is acetonitrile or sulfolane.
- Catalysts such as crown ethers or phase transfer agents which are known to increase the rate of fluoride exchange may also be used.
- the catalyst is a crown ether, a phosphonium halide, a polyether, a phosphazenium salt, or a tetra- substituted ammonium halide.
- the catalyst is a crown ether, e.g., 18- crown-6.
- the temperature at which the reaction is conducted is not critical. In certain embodiments, the temperature is from about 50 °C to about 200 °C, and in some
- the reaction neither the rate, nor the order, of addition of the reactants is critical.
- the solvent and alkali metal fluoride, and optionally, the catalyst are mixed before the picolinoyl chloride is added to the reaction mixture.
- the reaction requires from about 2 to about 100 hours and is conducted at ambient atmospheric pressure. In some embodiments, the reaction is conducted at a pressure up to and including 500 psi.
- an amount of alkali metal fluoride is provided which will supply at least about an equimolar amount of fluorine atoms based on the number of chlorine atoms to be exchanged in the starting material, i.e., at least an equimolar amount of alkali metal fluoride.
- the products obtained by any of the processes provided herein may be recovered by conventional means, such as evaporation or extraction, and may be purified by standard procedures, such as distillation, recrystallization or chromatography.
- alkyl alkenyl and “alkynyl,” as well as derivative terms such as “alkoxy,” “acyl,” “alkylthio” and “alkylsulfonyl” as used herein, include within their scope straight chain, branched chain and cyclic moieties, and include moieties having one to twelve carbon atoms. In certain embodiments, “alkyl,” “alkoxy,” “acyl,” “alkylthio” and
- alkylsulfonyl each contain one to six carbon atoms or alternatively, one to four carbon atoms.
- alkenyl and alkynyl each contain two to six carbon atoms or alternatively, two to four carbon atoms.
- alkyl alkenyl and “alkynyl,” as well as derivative terms such as “alkoxy,” “acyl,” “alkylthio” and “alkylsulfonyl” may be unsubstituted or substituted with one or more substituents selected from but not limited to halogen, hydroxy, Ci-C 6 alkoxy, Ci-C 6 alkylthio, Ci-C 6 acyl, formyl, cyano, aryloxy or aryl, provided that the substituents are sterically compatible and the rules of chemical bonding and strain energy are satisfied.
- the terms “alkenyl” and “alkynyl” are intended to include one or more unsaturated bonds.
- aryl refers to a 6-14 membered aromatic carbocylic group, e.g., phenyl or naphthyl.
- arylalkyl refers to a phenyl substituted alkyl group having a total of 7 to 11 carbon atoms, such as benzyl (-CH 2 C 6 H 5 ), 2-methylnaphthyl (- CH 2 C 10 H 7 ) and 1- or 2-phenethyl (-CH 2 CH 2 C 6 H 5 or -CH(CH 3 )C 6 H 5 ).
- substituents independently selected from halogen, nitro, cyano, Ci-C 6 alkyl, Ci-C 6 alkoxy, halogenated Ci-C 6 alkyl, halogenated Ci-C 6 alkoxy, Ci-C 6 alkylthio, C(0)OCi-C 6 alkyl, or where two adjacent substituents are taken together as -0(CH 2 )
- 6-Aryl groups provided herein may be substituted with from 1 to 4 substituents independently selected from halogen, C 1 -C 4 alkyl, C 1 -C 4 haloalkyl, C 1 -C 4 alkoxy or C 1 -C 4 haloalkoxy.
- the substitution pattern is selected from 4-substituted phenyl, 2,4-disubstituted phenyl, 2,3,4-trisubstituted phenyl, 2,4,5-trisubstituted phenyl, and 2,3,4,6-tetrasubstituted phenyl.
- halogen refers to fluorine, chlorine, bromine and iodine.
- the flask was fitted with a thermometer, magnetic stir bar and the same distillation set up described above. This distillation system could vent to vacuum or N 2 . Vacuum (ca. 70 mmHg) was established and then heating of the distillation vessel commenced. The product was collected as a clear colorless liquid (6.7 g, bp 55-60 °C @ 55-60 mmHg).
- the reaction was carried out in a nitrogen atmosphere glove box. To a glass jar equipped with a stir bar was added 5-chloropicolinoyl chloride (0.704 g, 4 mmol), 18-crown- 6 (0.106 g, 0.4 mmol), KF (0.744 g, 12.8 mmol) and sulfolane (pre-dried, 8 g). The mixture was heated to 130 °C on a heating block for 19 hours. A sample was taken and analyzed by GC. The results showed that the reaction was not complete, therefore additional KF (0.232 g, 4 mmol) was added and the mixture was heated to 130 °C for additional 22 hours. A sample was analyzed by GC, GC/MS and 19 F NMR. GC showed this reaction was complete.
- the reaction mixture was extracted with methyl tert- butyl ether (MTBE, 2 x 50 mL).
- MTBE methyl tert- butyl ether
- the combined organic extracts were washed with water (3 x 50 mL) and saturated aqueous NaCl solution (50 mL) and concentrated under reduced pressure to provide a brown oil.
- the crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane 20% hexane/ethyl acetate) to provide 0.93 g (48% yield) of isopropyl 6-(4-chlorophenyl)-4,5-difluoropicolinate as a white solid.
- the reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2 x 50 mL). The combined organic extracts were washed with water (3 x 50 mL) and saturated NaCl (50 mL) and concentrated under reduced pressure to provide a brown oil.
- the crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane -> 20%> hexane/ethyl acetate) to provide 1.2 g (70%> yield) of isopropyl 4,5- difiuoro-6-phenyl-picolinate as a yellow oil.
- the reaction mixture was extracted with methyl tert-butyl ether (MTBE, 2 x 75 mL). The combined organic extracts were washed with water (3 x 75 mL) and saturated NaCl (75 mL) and concentrated under reduced pressure to provide a brown oil.
- the crude product oil was purified by silica gel flash chromatography (hexane/ethyl acetate gradient, 100% hexane 20%) hexane/ethyl acetate) to provide 0.60 g (25% yield) of isopropyl 4,5-difluoro-6-(4- methoxyphenyl)-picolinate as a pale yellow solid.
- This solid was dissolved in 3 mL of acetonitrile, cooled in a refrigerator, filtered and rinsed with 0.5 mL of cold acetonitrile to give 529 mg of a white solid, mp 134- 134 °C, 97 area% purity by LC analysis.
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Abstract
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Priority Applications (16)
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RU2015106018A RU2627659C2 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and methods of their production |
KR1020157004098A KR101946680B1 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
EP13750414.8A EP2877452B1 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
BR112015001445A BR112015001445B8 (en) | 2012-07-24 | 2013-07-23 | FLUORIDE-PICOLINOYL FLUORIDES AND THEIR PREPARATION PROCESSES |
ES13750414.8T ES2641724T3 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and procedures for their preparation |
AU2013293204A AU2013293204B2 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
MX2015001138A MX351309B (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation. |
IN1482DEN2015 IN2015DN01482A (en) | 2012-07-24 | 2013-07-23 | |
PL13750414T PL2877452T3 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
JP2015524381A JP6062050B2 (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluoride and methods for their preparation |
CA2879518A CA2879518C (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
NZ704104A NZ704104A (en) | 2012-07-24 | 2013-07-23 | Fluoropicolinoyl fluorides and processes for their preparation |
CN201380042976.9A CN104583183B (en) | 2012-07-24 | 2013-07-23 | Fluorine picolinoyl fluoride and preparation method thereof |
IL236817A IL236817B (en) | 2012-07-24 | 2015-01-20 | Fluoropicolinoyl fluorides and processes for their preparation |
ZA2015/00601A ZA201500601B (en) | 2012-07-24 | 2015-01-27 | Fluoropicolinoyl fluorides and processes for their preparation |
HK15111202.4A HK1210465A1 (en) | 2012-07-24 | 2015-11-13 | Fluoropicolinoyl fluorides and processes for their preparation |
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US201261675229P | 2012-07-24 | 2012-07-24 | |
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EP (1) | EP2877452B1 (en) |
JP (1) | JP6062050B2 (en) |
KR (1) | KR101946680B1 (en) |
CN (1) | CN104583183B (en) |
AR (1) | AR092355A1 (en) |
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CO (1) | CO7200264A2 (en) |
ES (1) | ES2641724T3 (en) |
HK (1) | HK1210465A1 (en) |
IL (1) | IL236817B (en) |
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MX (1) | MX351309B (en) |
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PL (1) | PL2877452T3 (en) |
RU (1) | RU2627659C2 (en) |
TW (1) | TWI586650B (en) |
UY (1) | UY34945A (en) |
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TW201609651A (en) | 2013-11-12 | 2016-03-16 | 陶氏農業科學公司 | Process for fluorinating compounds |
BR102014028164A2 (en) * | 2013-11-12 | 2015-09-08 | Dow Agrosciences Llc | process for fluorination of compounds |
TW201609652A (en) | 2013-11-12 | 2016-03-16 | 陶氏農業科學公司 | Process for fluorinating compounds |
TWI726900B (en) | 2015-08-04 | 2021-05-11 | 美商陶氏農業科學公司 | Process for fluorinating compounds |
CN113233974A (en) * | 2021-04-09 | 2021-08-10 | 山东领海生物科技有限公司 | Synthesis method of acyl fluoride |
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