JP2016500060A - 2−トリフルオロメチルイソニコチン酸及びエステルの調製方法 - Google Patents
2−トリフルオロメチルイソニコチン酸及びエステルの調製方法 Download PDFInfo
- Publication number
- JP2016500060A JP2016500060A JP2015542256A JP2015542256A JP2016500060A JP 2016500060 A JP2016500060 A JP 2016500060A JP 2015542256 A JP2015542256 A JP 2015542256A JP 2015542256 A JP2015542256 A JP 2015542256A JP 2016500060 A JP2016500060 A JP 2016500060A
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- Prior art keywords
- formula
- bis
- diphenylphosphino
- chloride
- palladium
- 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.)
- Granted
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- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- BZFGKBQHQJVAHS-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carboxylic acid Chemical compound OC(=O)C1=CC=NC(C(F)(F)F)=C1 BZFGKBQHQJVAHS-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 150000002148 esters Chemical class 0.000 title claims abstract description 13
- 239000001257 hydrogen Substances 0.000 claims abstract description 9
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 9
- 239000000556 agonist Substances 0.000 claims abstract description 5
- 101000890887 Homo sapiens Trace amine-associated receptor 1 Proteins 0.000 claims abstract description 4
- 102100040114 Trace amine-associated receptor 1 Human genes 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 18
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 18
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 17
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 17
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 17
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 17
- KZPYGQFFRCFCPP-UHFFFAOYSA-N 1,1'-bis(diphenylphosphino)ferrocene Chemical compound [Fe+2].C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=C[C-]1P(C=1C=CC=CC=1)C1=CC=CC=C1 KZPYGQFFRCFCPP-UHFFFAOYSA-N 0.000 claims description 13
- CYPYTURSJDMMMP-WVCUSYJESA-N (1e,4e)-1,5-diphenylpenta-1,4-dien-3-one;palladium Chemical compound [Pd].[Pd].C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1.C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 CYPYTURSJDMMMP-WVCUSYJESA-N 0.000 claims description 12
- 150000002825 nitriles Chemical class 0.000 claims description 10
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-Bis(diphenylphosphino)propane Substances C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 claims description 9
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 claims description 9
- NXQGGXCHGDYOHB-UHFFFAOYSA-L cyclopenta-1,4-dien-1-yl(diphenyl)phosphane;dichloropalladium;iron(2+) Chemical compound [Fe+2].Cl[Pd]Cl.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1.[CH-]1C=CC(P(C=2C=CC=CC=2)C=2C=CC=CC=2)=C1 NXQGGXCHGDYOHB-UHFFFAOYSA-L 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 238000010992 reflux Methods 0.000 claims description 8
- -1 2-trifluoromethylisonicotinic acid ester Chemical class 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 239000002585 base Substances 0.000 claims description 7
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 claims description 6
- 239000012346 acetyl chloride Substances 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000000460 chlorine Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- 230000009466 transformation Effects 0.000 claims description 6
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 claims description 6
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- XGCDBGRZEKYHNV-UHFFFAOYSA-N 1,1-bis(diphenylphosphino)methane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CP(C=1C=CC=CC=1)C1=CC=CC=C1 XGCDBGRZEKYHNV-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 4
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-UHFFFAOYSA-N 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 230000032050 esterification Effects 0.000 claims description 4
- 238000005886 esterification reaction Methods 0.000 claims description 4
- 230000007062 hydrolysis Effects 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- 239000011541 reaction mixture Substances 0.000 claims description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims description 4
- CXNIUSPIQKWYAI-UHFFFAOYSA-N xantphos Chemical compound C=12OC3=C(P(C=4C=CC=CC=4)C=4C=CC=CC=4)C=CC=C3C(C)(C)C2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 CXNIUSPIQKWYAI-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical group BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 239000007789 gas Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 claims description 2
- UAXNXOMKCGKNCI-UHFFFAOYSA-N 1-diphenylphosphanylethyl(diphenyl)phosphane Chemical group C=1C=CC=CC=1P(C=1C=CC=CC=1)C(C)P(C=1C=CC=CC=1)C1=CC=CC=C1 UAXNXOMKCGKNCI-UHFFFAOYSA-N 0.000 claims description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 229910001854 alkali hydroxide Inorganic materials 0.000 claims description 2
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000011630 iodine Chemical group 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 229910021645 metal ion Inorganic materials 0.000 claims description 2
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 claims description 2
- LXNAVEXFUKBNMK-UHFFFAOYSA-N palladium(II) acetate Substances [Pd].CC(O)=O.CC(O)=O LXNAVEXFUKBNMK-UHFFFAOYSA-N 0.000 claims description 2
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 claims description 2
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 2
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 claims 1
- KXZJHVJKXJLBKO-UHFFFAOYSA-N chembl1408157 Chemical compound N=1C2=CC=CC=C2C(C(=O)O)=CC=1C1=CC=C(O)C=C1 KXZJHVJKXJLBKO-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 239000013543 active substance Substances 0.000 abstract description 2
- 239000000543 intermediate Substances 0.000 abstract description 2
- 239000000575 pesticide Substances 0.000 abstract description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 230000006315 carbonylation Effects 0.000 abstract 1
- 238000005810 carbonylation reaction Methods 0.000 abstract 1
- 238000007333 cyanation reaction Methods 0.000 abstract 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- 239000012044 organic layer Substances 0.000 description 18
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 13
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 12
- XQCJUIRPIWHLLS-UHFFFAOYSA-N methyl 2-(trifluoromethyl)pyridine-4-carboxylate Chemical compound COC(=O)C1=CC=NC(C(F)(F)F)=C1 XQCJUIRPIWHLLS-UHFFFAOYSA-N 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 11
- 239000011734 sodium Substances 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000007788 liquid Substances 0.000 description 9
- FZINIBTZNSPWQR-UHFFFAOYSA-N 4-chloro-2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC(Cl)=CC=N1 FZINIBTZNSPWQR-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 7
- 239000002253 acid Substances 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- 239000000706 filtrate Substances 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- MLFFNKLBERSEPF-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine-4-carbonitrile Chemical compound FC(F)(F)C1=CC(C#N)=CC=N1 MLFFNKLBERSEPF-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 0 *c1cc(C(F)(F)F)ncc1 Chemical compound *c1cc(C(F)(F)F)ncc1 0.000 description 4
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 4
- DDCHYZRDWLPNRF-UHFFFAOYSA-N ethyl 2-(trifluoromethyl)pyridine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC(C(F)(F)F)=C1 DDCHYZRDWLPNRF-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- ABCYVXOLXFNJBA-UHFFFAOYSA-N [2-(trifluoromethyl)pyridin-4-yl] trifluoromethanesulfonate Chemical compound FC(F)(F)C1=CC(OS(=O)(=O)C(F)(F)F)=CC=N1 ABCYVXOLXFNJBA-UHFFFAOYSA-N 0.000 description 3
- 150000001298 alcohols Chemical class 0.000 description 3
- 125000003118 aryl group Chemical group 0.000 description 3
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 229910052757 nitrogen Inorganic materials 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical compound CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 2
- LDFBXJODFADZBN-UHFFFAOYSA-L 3-diphenylphosphanylpropyl(diphenyl)phosphane;palladium(2+);dichloride Chemical compound Cl[Pd]Cl.C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LDFBXJODFADZBN-UHFFFAOYSA-L 0.000 description 2
- OYQSAEIWDLIZHC-UHFFFAOYSA-N 4-iodo-2-(trifluoromethyl)pyridine Chemical compound FC(F)(F)C1=CC(I)=CC=N1 OYQSAEIWDLIZHC-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 2
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 2
- 150000007530 organic bases Chemical class 0.000 description 2
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- NASUJCGZBMBQAM-UHFFFAOYSA-N propan-2-yl 2-(trifluoromethyl)pyridine-4-carboxylate Chemical compound CC(C)OC(=O)C1=CC=NC(C(F)(F)F)=C1 NASUJCGZBMBQAM-UHFFFAOYSA-N 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical compound CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- ZDZHCHYQNPQSGG-UHFFFAOYSA-N 1-naphthalen-1-ylnaphthalene Chemical group C1=CC=C2C(C=3C4=CC=CC=C4C=CC=3)=CC=CC2=C1 ZDZHCHYQNPQSGG-UHFFFAOYSA-N 0.000 description 1
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-Tetramethylpiperidine Substances CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 1
- UJJMLGJZQGGQAZ-UHFFFAOYSA-N 2-(fluoromethyl)pyridine Chemical compound FCC1=CC=CC=N1 UJJMLGJZQGGQAZ-UHFFFAOYSA-N 0.000 description 1
- LKHCWMQMRXAPHX-UHFFFAOYSA-N 2-(trifluoromethyl)-1h-pyridin-4-one Chemical compound OC1=CC=NC(C(F)(F)F)=C1 LKHCWMQMRXAPHX-UHFFFAOYSA-N 0.000 description 1
- LBLYYCQCTBFVLH-UHFFFAOYSA-N 2-Methylbenzenesulfonic acid Chemical compound CC1=CC=CC=C1S(O)(=O)=O LBLYYCQCTBFVLH-UHFFFAOYSA-N 0.000 description 1
- BSKHPKMHTQYZBB-UHFFFAOYSA-N 2-methylpyridine Chemical compound CC1=CC=CC=N1 BSKHPKMHTQYZBB-UHFFFAOYSA-N 0.000 description 1
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- XVEXNWJBZDKDBQ-UHFFFAOYSA-N 4-bromo-2-(trifluoromethyl)pyridine;hydrobromide Chemical compound Br.FC(F)(F)C1=CC(Br)=CC=N1 XVEXNWJBZDKDBQ-UHFFFAOYSA-N 0.000 description 1
- UWDMKTDPDJCJOP-UHFFFAOYSA-N 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-ium-4-carboxylate Chemical compound CC1(C)CC(O)(C(O)=O)CC(C)(C)N1 UWDMKTDPDJCJOP-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- PFQKECNHHBOXHX-UHFFFAOYSA-N Br.FC(F)(F)C1=NC=CC=C1.CO Chemical compound Br.FC(F)(F)C1=NC=CC=C1.CO PFQKECNHHBOXHX-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- LELOWRISYMNNSU-UHFFFAOYSA-N Hydrocyanic acid Natural products N#C LELOWRISYMNNSU-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 101150003085 Pdcl gene Proteins 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 102000011829 Trace amine associated receptor Human genes 0.000 description 1
- 108050002178 Trace amine associated receptor Proteins 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 230000021523 carboxylation Effects 0.000 description 1
- 238000006473 carboxylation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- WMKGGPCROCCUDY-PHEQNACWSA-N dibenzylideneacetone Chemical compound C=1C=CC=CC=1\C=C\C(=O)\C=C\C1=CC=CC=C1 WMKGGPCROCCUDY-PHEQNACWSA-N 0.000 description 1
- AAXGWYDSLJUQLN-UHFFFAOYSA-N diphenyl(propyl)phosphane Chemical compound C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 AAXGWYDSLJUQLN-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010952 in-situ formation Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 230000026045 iodination Effects 0.000 description 1
- 238000006192 iodination reaction Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052744 lithium Inorganic materials 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- YSWGDPAVEHLSSK-UHFFFAOYSA-N methanol [2-(trifluoromethyl)pyridin-4-yl] methanesulfonate Chemical compound FC(C1=NC=CC(=C1)OS(=O)(=O)C)(F)F.CO YSWGDPAVEHLSSK-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000001301 oxygen Chemical group 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000020477 pH reduction Effects 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 125000004193 piperazinyl group Chemical group 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229910000404 tripotassium phosphate Inorganic materials 0.000 description 1
- 235000019798 tripotassium phosphate Nutrition 0.000 description 1
- 238000005292 vacuum distillation Methods 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
- C07D213/60—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
- C07D213/84—Nitriles
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- 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
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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- 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
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- Plural Heterocyclic Compounds (AREA)
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- Catalysts (AREA)
Abstract
Description
[式中、
R2は、C1−6−アルキル、ヒドロキシ、ハロゲンによって、又は−(CH2)p−アリールによって場合により置換されている、(CH2)n−(O)o−ヘテロシクロアルキルであり;
nは、0、1、2であり;
oは、0、1であり;
pは、0、1、2である]
で表されるTAAR1作動薬又はその薬学的に好適な酸付加塩の調製方法のための、本発明の方法の使用に関する。
[式中、R1は、水素又はC1−6−アルキルである]
で表される2−トリフルオロメチルイソニコチン酸及びエステルの調製方法であって、パラジウム錯体触媒の存在下での、式:
[式中、Xは、ハロゲン又は−OSO2CY3であり、ここで、Yは、ハロゲンである]で表される2−トリフルオロメチルピリジン誘導体の変換を含む方法。
で表されるニトリルを形成するための式Iの2−トリフルオロメチルピリジン誘導体と金属シアン化物MCN(式中、Mは、金属イオンを表す)との反応、ならびに式Iの2−トリフルオロメチルイソニコチン酸及びエステルを形成するためのさらなる加水分解又はエステル化を含む。
[式中、
R2は、C1−6−アルキル、ヒドロキシ、ハロゲンによって、又は−(CH2)p−アリールによって場合により置換されている、(CH2)n−(O)o−ヘテロシクロアルキルであり;
nは、0、1、2であり;
oは、0、1であり;
pは、0、1、2である]
で表されるTAAR1作動薬又はその薬学的に好適な酸付加塩の調製方法における、本発明の方法の使用をさらに含む。
で表される場合により保護されたアリールアミンとを反応させることによって調製され得る。
4−クロロ−2−トリフルオロメチル−ピリジンの調製
還流冷却器、マグネチックスターラー及び不活性ガス供給路を備えた25mlの丸底フラスコ中、1.63g(10.0mmol)の4−ヒドロキシ−2−トリフルオロメチル−ピリジンを、室温で、4.9mlのシクロヘキサン及び0.077mlのDMFで処理し、2.19ml(25.0mmol)の塩化オキサリルを加え、混合物を3時間加熱還流し、室温まで冷まし、18mlの水をゆっくり(ガス発生)滴下し、混合物を18mlのMTBEで抽出し、分離した有機層を1M NaHCO3で洗浄し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させ、黒色の粗液体を12mlのn−ヘキサンで処理し、室温で5分間撹拌し、濾過し、減圧下で蒸発させて、0.9gの4−クロロ−2−トリフルオロメチルピリジンを黄色の液体として得た。
GC−EI−MS: M 181+/M 183+。
4−クロロ−2−トリフルオロメチルピリジンからの2−トリフルオロメチル−イソニコチン酸メチルエステルの調製
792mlのメタノール中の76.8g(423mmol)の4−クロロ−2−トリフルオロメチル−ピリジン、7.67g(7.67mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び88.4ml(635mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌した。粗混合物(約30%の酸を含有する)を減圧下で約20%の混合物まで濃縮し、30.9ml(423mmol)の塩化チオニルでゆっくり処理し、1時間還流した。混合物を減圧下で蒸発させ、残渣を450mlの水及び450mlのMTBEで処理し、生じた懸濁液を濾過した。濾液から有機層を分離し、225mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸メチルエステルを得て、これを約20mmbar/bp97〜99℃で蒸留して、80.7gの2−トリフルオロメチル−イソニコチン酸メチルエステル を無色の液体として得た。
GC−EI−MS: M 205+。
4−クロロ−2−トリフルオロメチルピリジンからの2−トリフルオロメチル−イソニコチン酸エチルエステルの調製
3.0mlのエタノール中の182mg(1.0mmol)の4−クロロ−2−トリフルオロメチルピリジン、18.2mg(0.022mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び0.21ml(1.50mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌し、粗混合物を減圧下で蒸発させ、残渣を4.0mlの0.5M HCl及び4.0mlのMTBEで処理し、生じた懸濁液を濾過し、有機層を分離し、2.0mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸エチルエステルを得て、これを2.0mlのシクロヘキサンと共に室温で10分間撹拌し、濁った明褐色の溶液を濾過し、濾液を減圧下で蒸発させて、113mgの2−トリフルオロメチル−イソニコチン酸エチルエステルを明褐色の液体として得た。
GC−EI−MS: M 219+。
4−クロロ−2−トリフルオロメチルピリジンからの2−トリフルオロメチル−イソニコチン酸イソプロピルエステルの調製
3.0mlの2−プロパノール中の182mg(1.0mmol)の4−クロロ−2−トリフルオロメチルピリジン、18.2mg(0.022mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び0.21ml(1.5mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌し、粗混合物を減圧下で蒸発させ、残渣を4.0mlの0.5M HCl及び4.0mlのMTBEで処理し、生じた懸濁液を濾過し、有機層を分離し、2.0mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸エチルエステルを得て、これを2.0mlのシクロヘキサンと共に室温で10分間撹拌し、濁った明褐色の溶液を濾過し、濾液を減圧下で蒸発させて、134mgの2−トリフルオロメチル−イソニコチン酸イソプロピルエステルを明褐色の液体として得た。
GC−EI−MS: M 233+。
トリフルオロ−メタンスルホン酸2−トリフルオロメチル−ピリジン−4−イルエステルの調製
マグネチックスターラー及び不活性ガス供給路を備えた25mlの丸底フラスコ中、1.63g(10.0mmol)の2−トリフルオロメチル−ピリジン−4−オールを8.15mlのジクロロメタンに溶解し、2.04ml(12.0mmol)のN−エチルジイソプロピルアミンを加え、溶液を0〜5℃まで冷却し、1.86ml(11.0mmol)のトリフルオロメタンスルホン酸無水物を滴下し、混合物を0〜5℃で1時間撹拌し、混合物を10mlの0.5M HClで抽出し、分離した有機層を無水Na2SO4で乾燥させ、減圧下で蒸発させた。残渣を、シクロヘキサン/MTBEを用いて15gシリカで精製して、1.58gのトリフルオロ−メタンスルホン酸2−トリフルオロメチル−ピリジン−4−イルエステルを明黄色の油状物として得た。
GC−EI−MS: M 295+。
トリフルオロ−メタンスルホン酸2−トリフルオロメチル−ピリジン−4−イルエステルからの2−トリフルオロメチル−イソニコチン酸メチルエステルの調製
4.0mlのメタノール中の295mg(1.0mmol)のトリフルオロ−メタンスルホン酸2−トリフルオロメチル−ピリジン−4−イルエステル、18.1mg(0.022mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び0.21ml(1.5mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌し、粗混合物(約30%の酸を含有する)を0.073ml(1.0mmol)の塩化チオニルで処理し、1時間還流し、混合物を減圧下で蒸発させ、残渣を4.0mlの水及び4.0mlのMTBEで処理し、生じた懸濁液を濾過し、分離した有機層を4.0mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸メチルエステルを得て、これを2.0mlのシクロヘキサンで処理し、混合物を濾過し、減圧下で蒸発させて、136mgの2−トリフルオロメチル−イソニコチン酸メチルエステルを明黄色の液体として得た。
GC−EI−MS: M 205+。
4−ブロモ−2−トリフルオロメチルピリジン臭化水素酸塩からの2−トリフルオロメチル−イソニコチン酸メチルエステルの調製
4.0mlのメタノール中の307mg(1.0mmol)の4−ブロモ−2−トリフルオロメチルピリジン臭化水素酸塩、18.1mg(0.022mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び0.35ml(2.5mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌し、粗混合物(約30%の酸を含有する)を0.073ml(1.0mmol)の塩化チオニルで処理し、1時間還流し、混合物を減圧下で蒸発させ、残渣を4.0mlの水及び4.0mlのMTBEで処理し、生じた懸濁液を濾過し、分離した有機層を2.0mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸メチルエステルを得て、これを2.0mlのシクロヘキサンと共に15分間撹拌し、濾過し、減圧下で蒸発させて、112mgの2−トリフルオロメチル−イソニコチン酸メチルエステルを無色の液体として得た。
GC−EI−MS: M 205+。
4−ヨード−2−トリフルオロメチルピリジンからの2−トリフルオロメチル−イソニコチン酸メチルエステルの調製
3.0mlのメタノール中の165mg(0.60mmol)の4−ヨード−2−トリフルオロメチルピリジン、16.5mg(0.020mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体及び0.126ml(0.907mmol)のトリエチルアミンの混合物を、70barのCO下、130℃で18時間撹拌し、粗混合物を0.044ml(1.0mmol)の塩化チオニルで処理し、1時間還流し、減圧下で蒸発させ、残渣を2.0mlの水及び2.0mlのMTBEで処理し、生じた懸濁液を濾過し、有機層を分離し、2.0mlの1M NaHCO3で抽出し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、粗2−トリフルオロメチル−イソニコチン酸エチルエステルを得て、これを2.0mlのシクロヘキサンと共に室温で10分間撹拌し、明褐色の懸濁液を濾過し、濾液を減圧下で蒸発させて、104mgの2−トリフルオロメチル−イソニコチン酸メチルエステルを明褐色の液体として得た。GC−EI−MS: M 205+。
4−クロロ−2−トリフルオロメチルピリジンからの2−トリフルオロメチル−イソニコチン酸の調製
1.5mlのTHF及び1.5mlの水中の182mg(1.0mmol)の4−クロロ−2−トリフルオロメチルピリジン、18.0mgのPdCl2(dppp)及び210mgの炭酸水素ナトリウムの混合物を、70barのCO下、120℃で20時間撹拌し、THFを減圧下で除去し、0.5mlの2M NaOHを加え、懸濁液を濾過した。清澄な溶液を0.52mlの25%塩酸で処理し、室温で1時間撹拌し、濾過し、白色の結晶を40℃で乾燥させて、146mgの2−トリフルオロメチル−イソニコチン酸を得た。GC−EI−MS: M 191+。
4−クロロ−2−トリフルオロメチルピリジンからの2−(トリフルオロメチル)ピリジン−4−カルボニトリルの調製
40.0mlのDMF中の4.0g(22.0mmol)の4−クロロ−2−トリフルオロメチルピリジンの混合物をアルゴンでフラッシュし、0.98g(1.76mmol)の1,1’−ビス(ジフェニルホスフィノ)フェロセン(CAS: 12150-46-8)、1.01g(1.10mmol)のトリス(ジベンジリデンアセトン)ジパラジウム(0)(CAS: 51364-51-3)及び2.59g(22.0mmol)のシアン化亜鉛を加えた。混合物をアルゴンでフラッシュし、85〜90℃で15時間撹拌し、黒色の混合物を5〜10℃まで冷却し、110mlの水及び110mlのMTBEを加え、室温で30分間撹拌し、次に、ガラス繊維フィルターで濾過し、フィルターケーキを15mlのMTBEで洗浄し、濾液から有機層を分離し、110mlの水で2回洗浄し、分離した有機層を無水Na2SO4で乾燥させ、濾過し、減圧下で蒸発させて、4.20gの粗2−(トリフルオロメチル)ピリジン−4−カルボニトリルを得たが、これは不純物としてジベンジリデンアセトンを含有した。粗生成物を8.40mlのMTBEで処理し、生じた懸濁液を室温で15分間撹拌し、次に、濾過し、フィルターケーキを4.0mlのMTBEで洗浄した。褐色の濾液を減圧下で蒸発させて、3.60gの標記生成物を褐色の油状物として得て、これを10mbar/b.p.58〜60℃で蒸留して、2.75gの2−(トリフルオロメチル)ピリジン−4−カルボニトリルを無色の液体として得た。
GC−EI−MS: M 172+。
2−(トリフルオロメチル)ピリジン−4−カルボニトリルからの2−トリフルオロメチル−イソニコチン酸の調製
0.86mlのエタノール中の172mg(1.0mmol)の2−(トリフルオロメチル)ピリジン−4−カルボニトリルの混合物を、0.20g(5.0mmol)の水酸化ナトリウムで処理した。混合物を1.5時間還流し、室温まで冷まし、黄色の懸濁液を室温まで冷まし、3.0mlの水及び0.65mlの塩酸を加えた。懸濁液を30分間0〜5℃まで冷却し、濾過し、2.0mlの水で洗浄した。ベージュ色の結晶を40℃/15mbar/2時間で乾燥させ、0.15gの2−トリフルオロメチル−イソニコチン酸を得た。GC−EI−MS: M 191+。
2−(トリフルオロメチル)ピリジン−4−カルボニトリルからの2−トリフルオロメチル−イソニコチン酸メチルエステルの調製
1.70mlのメタノール中の172mg(1.0mmol)の2−(トリフルオロメチル)ピリジン−4−カルボニトリルの混合物を、氷冷下、0.71mlの塩化アセチルで処理し(塩化水素のインサイチュー生成)、溶液を4時間還流し、室温まで冷まし、減圧下で蒸発させ、残渣を1.0mlのMTBEで処理し、1.0mlの1M NaHCO3で抽出し、分離した有機層をNa2SO4で乾燥させ、濾過し、減圧下で蒸発させて、0.16gの2−トリフルオロメチル−イソニコチン酸メチルエステルを得た。
GC−EI−MS: M 205+。
Claims (23)
- 変換が、反応体R1OH(式中、R1は、上記のとおりである)の存在下での、一酸化炭素(CO)との反応を含む、請求項1に記載の方法。
- パラジウム錯体触媒が、1,1−ビス(ジフェニルホスフィノ)エタン(dppe)、1,1’−ビス−(ジフェニルホスフィノ)フェロセン(dppf)、ビス(ジフェニルホスフィノ)メタン(dppm)、1,3−ビス(ジフェニルホスフィノ)プロパン(dppp)、4,5−ビス(ジフェニルホスフィノ)9,9−ジメチルキサンテンからか又はトリフェニルホスファンから選択される配位子との、塩化ビス(ベンゾニトリル)パラジウム(II)、トリス(ジベンジリデンアセトン)ジパラジウム(0)、酢酸パラジウム(II)又は塩化パラジウム(II)から選択される、請求項1〜3のいずれか一項に記載の方法。
- パラジウム錯体触媒が、配位子1,1’−ビス(ジフェニルホスフィノ)フェロセン(dppf)又は1,3−ビス(ジフェニルホスフィノ)プロパン(dppp)との塩化パラジウム(II)から選択される、請求項2又は4に記載の方法。
- 変換が、5bar〜100barのCO圧下で実施される、請求項2、4及び5のいずれか一項に記載の方法。
- 変換が、塩基の存在下で実施される、請求項2及び4〜6のいずれか一項に記載の方法。
- 変換が、50℃〜170℃の間の反応温度で実施される、請求項2及び4〜7のいずれか一項に記載の方法。
- 反応体R1OH(式中、R1は、C1−6−アルキルである)を用いた変換の場合、一酸化炭素を用いた変換に続き、塩化水素生成剤で処理する、請求項2及び4〜8のいずれか一項に記載の方法。
- 塩化水素生成剤が、塩化チオニル又は塩化アセチルから選択される、請求項9に記載の方法。
- 塩化水素生成剤での処理が、反応混合物の還流条件で実施される、請求項9又は10に記載の方法。
- パラジウム錯体触媒が、配位子1,1’−ビス(ジフェニルホスフィノ)フェロセン(dppf)又はrac−2−(ジ−tert.−ブチルホスフィノ)−1,1−ビナフチルとの、Pd(PPh3)4(0)、1,1’−ビス(ジフェニルホスフィノ)フェロセン−パラジウム(II)ジクロリドジクロロメタン付加体、Pd(P−tert−Bu3)2、トリス(ジベンジリデンアセトン)ジパラジウム(0)又はPd(TFA)2から選択される、請求項3に記載の方法。
- 金属シアン化物MCNが、シアン化亜鉛、あるいはシアン化亜鉛とシアン化ナトリウム又はシアン化カリウムとの混合物である、請求項3又は12に記載の方法。
- 変換が、50℃〜120℃の間の反応温度で実施される、請求項3、12及び13のいずれか一項に記載の方法。
- 式IVのニトリルから式I(式中、R1=水素)の2−トリフルオロメチルイソニコチン酸への加水分解が、塩基を用いて実施される、請求項3に記載の方法。
- 塩基が、アルカリ水酸化物である、請求項15に記載の方法。
- 式IVのニトリルから式I(式中、R1=C1−6−アルキル)の2−トリフルオロメチルイソニコチン酸エステルへのエステル化が、塩化水素ガス又は塩化水素生成剤の存在下、アルコールR1OH(式中、R1は、C1−6−アルキルである)を用いて実施される、請求項3に記載の方法。
- 塩化水素生成剤が、塩化チオニル又は塩化アセチルから選択される、請求項17に記載の方法。
- R1が、水素、メチル、エチル又はi−プロピルである、請求項1〜18のいずれか一項に記載の方法。
- R1が、水素又はメチルである、請求項1〜19のいずれか一項に記載の方法。
- Xが、フッ素、塩素、臭素、ヨウ素又はトリフルオロメタンスルホニルである、請求項1〜20のいずれか一項に記載の方法。
- Xが、塩素である、請求項1〜21のいずれか一項に記載の方法。
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AU2013346882A1 (en) | 2015-04-02 |
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RU2015119876A (ru) | 2017-01-10 |
MX362274B (es) | 2019-01-10 |
RU2654486C2 (ru) | 2018-05-21 |
SG11201503573WA (en) | 2015-06-29 |
EP2920150B1 (en) | 2017-07-19 |
ES2641376T3 (es) | 2017-11-08 |
SI2920150T1 (sl) | 2017-10-30 |
MY170491A (en) | 2019-08-08 |
NZ706266A (en) | 2019-10-25 |
CN104781236A (zh) | 2015-07-15 |
US9481650B2 (en) | 2016-11-01 |
WO2014076127A1 (en) | 2014-05-22 |
IL237904A (en) | 2017-10-31 |
CN104781236B (zh) | 2018-04-24 |
CA2885155A1 (en) | 2014-05-22 |
EP2920150A1 (en) | 2015-09-23 |
AU2013346882B2 (en) | 2017-05-04 |
KR20150083864A (ko) | 2015-07-20 |
US20150291530A1 (en) | 2015-10-15 |
BR112015010120A2 (pt) | 2017-07-11 |
PL2920150T3 (pl) | 2017-11-30 |
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