CN104781236B - 制备2-三氟甲基异烟酸和酯的方法 - Google Patents
制备2-三氟甲基异烟酸和酯的方法 Download PDFInfo
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- CN104781236B CN104781236B CN201380059373.XA CN201380059373A CN104781236B CN 104781236 B CN104781236 B CN 104781236B CN 201380059373 A CN201380059373 A CN 201380059373A CN 104781236 B CN104781236 B CN 104781236B
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- palladium
- trifluoromethyls
- double
- acid
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- 238000000034 method Methods 0.000 title claims abstract description 34
- 150000002148 esters Chemical class 0.000 title claims abstract description 16
- TWBYWOBDOCUKOW-UHFFFAOYSA-N isonicotinic acid Chemical compound OC(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-N 0.000 title claims description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims abstract description 35
- 229910052763 palladium Inorganic materials 0.000 claims abstract description 16
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 10
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000012190 activator Substances 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 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 27
- 238000006243 chemical reaction Methods 0.000 claims description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 claims description 16
- 229910002091 carbon monoxide Inorganic materials 0.000 claims description 16
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical group ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 15
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 15
- 239000002585 base Substances 0.000 claims description 13
- 239000002253 acid Substances 0.000 claims description 10
- ATRQECRSCHYSNP-UHFFFAOYSA-N 2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=CC=CC=N1 ATRQECRSCHYSNP-UHFFFAOYSA-N 0.000 claims description 9
- 229910052736 halogen Inorganic materials 0.000 claims description 9
- 150000002367 halogens Chemical group 0.000 claims description 9
- 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 7
- 239000003054 catalyst Substances 0.000 claims description 7
- 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 6
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 6
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000003446 ligand Substances 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 5
- 239000000376 reactant Substances 0.000 claims description 5
- 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 claims description 4
- AAXGWYDSLJUQLN-UHFFFAOYSA-N diphenyl(propyl)phosphane Chemical compound C=1C=CC=CC=1P(CCC)C1=CC=CC=C1 AAXGWYDSLJUQLN-UHFFFAOYSA-N 0.000 claims description 4
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical class C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 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
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 3
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 239000011737 fluorine Substances 0.000 claims description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 3
- 239000011541 reaction mixture Substances 0.000 claims description 3
- 238000006467 substitution reaction Methods 0.000 claims description 3
- 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 2
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- WUOIAOOSKMHJOV-UHFFFAOYSA-N ethyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(CC)C1=CC=CC=C1 WUOIAOOSKMHJOV-UHFFFAOYSA-N 0.000 claims description 2
- 239000011630 iodine Substances 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
- UJNZOIKQAUQOCN-UHFFFAOYSA-N methyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C)C1=CC=CC=C1 UJNZOIKQAUQOCN-UHFFFAOYSA-N 0.000 claims description 2
- XSXHWVKGUXMUQE-UHFFFAOYSA-N osmium dioxide Inorganic materials O=[Os]=O XSXHWVKGUXMUQE-UHFFFAOYSA-N 0.000 claims description 2
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 2
- HAKVNWBUOCSHTR-UHFFFAOYSA-N (9,9-dimethylxanthen-1-yl)-diphenylphosphane Chemical class C=12C(C)(C)C3=CC=CC=C3OC2=CC=CC=1P(C=1C=CC=CC=1)C1=CC=CC=C1 HAKVNWBUOCSHTR-UHFFFAOYSA-N 0.000 claims 1
- 150000002431 hydrogen Chemical group 0.000 claims 1
- 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 abstract description 3
- 239000013543 active substance Substances 0.000 abstract description 2
- 239000003905 agrochemical Substances 0.000 abstract description 2
- 230000006315 carbonylation Effects 0.000 abstract 1
- 238000005810 carbonylation reaction Methods 0.000 abstract 1
- 238000007333 cyanation reaction Methods 0.000 abstract 1
- 239000000543 intermediate Substances 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 28
- YNBADRVTZLEFNH-UHFFFAOYSA-N methyl nicotinate Chemical compound COC(=O)C1=CC=CN=C1 YNBADRVTZLEFNH-UHFFFAOYSA-N 0.000 description 24
- 239000012044 organic layer Substances 0.000 description 19
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 15
- -1 2- trifluoromethyl pyridines Trifluoromethyl -4- picolinic acids Chemical class 0.000 description 13
- IJOSVNBGIKAARU-UHFFFAOYSA-N 3-chloro-2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=NC=CC=C1Cl IJOSVNBGIKAARU-UHFFFAOYSA-N 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 12
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 12
- 229960001238 methylnicotinate Drugs 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 11
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 239000007832 Na2SO4 Substances 0.000 description 10
- 229910052938 sodium sulfate Inorganic materials 0.000 description 10
- 238000003756 stirring Methods 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 9
- XBLVHTDFJBKJLG-UHFFFAOYSA-N Ethyl nicotinate Chemical compound CCOC(=O)C1=CC=CN=C1 XBLVHTDFJBKJLG-UHFFFAOYSA-N 0.000 description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 8
- XLQDQRMFMXYSQS-UHFFFAOYSA-N dichloromethane;hydrochloride Chemical compound Cl.ClCCl XLQDQRMFMXYSQS-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 8
- 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 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 7
- 238000000605 extraction Methods 0.000 description 7
- 150000002825 nitriles Chemical class 0.000 description 7
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 6
- 239000000706 filtrate Substances 0.000 description 6
- 125000004836 hexamethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[*:1] 0.000 description 6
- 239000003513 alkali Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 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
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- BTANRVKWQNVYAZ-UHFFFAOYSA-N butan-2-ol Chemical compound CCC(C)O BTANRVKWQNVYAZ-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- 229940064982 ethylnicotinate Drugs 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- GTLDTDOJJJZVBW-UHFFFAOYSA-N zinc cyanide Chemical compound [Zn+2].N#[C-].N#[C-] GTLDTDOJJJZVBW-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 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
- 238000001035 drying Methods 0.000 description 3
- 239000000284 extract Substances 0.000 description 3
- 150000007524 organic acids Chemical class 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000011282 treatment Methods 0.000 description 3
- CXBDYQVECUFKRK-UHFFFAOYSA-N 1-methoxybutane Chemical group CCCCOC CXBDYQVECUFKRK-UHFFFAOYSA-N 0.000 description 2
- AXIRKFLGSOEBGV-UHFFFAOYSA-N 3-iodo-2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=NC=CC=C1I AXIRKFLGSOEBGV-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 206010013786 Dry skin Diseases 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
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 229910002666 PdCl2 Inorganic materials 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000007789 gas Substances 0.000 description 2
- 239000011261 inert gas Substances 0.000 description 2
- 150000007529 inorganic bases Chemical class 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 238000002156 mixing Methods 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
- MUJIDPITZJWBSW-UHFFFAOYSA-N palladium(2+) Chemical compound [Pd+2] MUJIDPITZJWBSW-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 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
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- ZFPGARUNNKGOBB-UHFFFAOYSA-N 1-Ethyl-2-pyrrolidinone Chemical class CCN1CCCC1=O ZFPGARUNNKGOBB-UHFFFAOYSA-N 0.000 description 1
- SMZAZDGFGOHROS-UHFFFAOYSA-N 3-bromo-2-(trifluoromethyl)pyridine Chemical class FC(F)(F)C1=NC=CC=C1Br SMZAZDGFGOHROS-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
- MTVNAPYHLASOSX-UHFFFAOYSA-N 9,9-dimethylxanthene Chemical class C1=CC=C2C(C)(C)C3=CC=CC=C3OC2=C1 MTVNAPYHLASOSX-UHFFFAOYSA-N 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 0 C=N*(C1)C1C(F)(F)F Chemical compound C=N*(C1)C1C(F)(F)F 0.000 description 1
- XFXPMWWXUTWYJX-UHFFFAOYSA-N Cyanide Chemical compound N#[C-] XFXPMWWXUTWYJX-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
- 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
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical class 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
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 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
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 150000004982 aromatic amines Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 150000004649 carbonic acid derivatives Chemical class 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
- 125000000058 cyclopentadienyl group Chemical group C1(=CC=CC1)* 0.000 description 1
- 125000003963 dichloro group Chemical group Cl* 0.000 description 1
- ONDPGJBEBGWAKI-UHFFFAOYSA-N diphenylphosphane;propane Chemical compound CCC.C=1C=CC=CC=1PC1=CC=CC=C1 ONDPGJBEBGWAKI-UHFFFAOYSA-N 0.000 description 1
- ZSWFCLXCOIISFI-UHFFFAOYSA-N endo-cyclopentadiene Natural products C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 1
- 230000032050 esterification Effects 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 239000003365 glass fiber Substances 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 125000004415 heterocyclylalkyl group 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
- 238000011065 in-situ storage Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052742 iron Inorganic materials 0.000 description 1
- SORXVYYPMXPIFD-UHFFFAOYSA-N iron palladium Chemical compound [Fe].[Pd] SORXVYYPMXPIFD-UHFFFAOYSA-N 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 150000002576 ketones Chemical class 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
- 238000004519 manufacturing process Methods 0.000 description 1
- 229910021645 metal ion Inorganic materials 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 125000002757 morpholinyl group Chemical group 0.000 description 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical class CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 150000002790 naphthalenes Chemical class 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen(.) Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 125000005936 piperidyl group Chemical group 0.000 description 1
- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
- 239000012286 potassium permanganate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 235000021003 saturated fats Nutrition 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
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- MNWBNISUBARLIT-UHFFFAOYSA-N sodium cyanide Chemical compound [Na+].N#[C-] MNWBNISUBARLIT-UHFFFAOYSA-N 0.000 description 1
- 229960005137 succinic acid Drugs 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
- WHRNULOCNSKMGB-UHFFFAOYSA-N tetrahydrofuran thf Chemical compound C1CCOC1.C1CCOC1 WHRNULOCNSKMGB-UHFFFAOYSA-N 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 125000005270 trialkylamine group Chemical group 0.000 description 1
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 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
- C07D213/79—Acids; Esters
- C07D213/803—Processes of preparation
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- 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
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- 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
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Abstract
本发明包括一种制备式I的2‑三氟甲基异烟酸和酯的新方法,其中R1是氢或C1‑6‑烷基,所述方法包括钯催化的羰基化或氰化步骤。式I的2‑三氟甲基异烟酸和酯是用于制备活性药剂和农用化学剂比如例如式III的TAAR1激动剂的多用途中间体。
Description
本发明涉及制备式I的2-三氟甲基异烟酸和酯的新方法
其中R1是氢或C1-6-烷基。
式I的2-三氟甲基异烟酸和酯是用于制备活性药剂和农用化学剂的多用途中间体(例如Manfred Schlosser等人,Eur.J.Org.Chem.2003,1559-1568)。
本发明还涉及本发明的方法用于制备式III的TAAR1激动剂或其药用酸加成盐的方法的用途
其中
R2是任选地被C1-6-烷基、羟基、卤素、或-(CH2)p-芳基取代的(CH2)n-(O)o-杂环烷基;
n是0、1、2;
o是0、1;
p是0、1、2。
式III的TAAR激动剂已经在PCT公开WO 2012/016879中公开。
现有技术中描述了多种合成。
例如Chikara Fukaya等人,Chem.Pharm.Bull.38(9)2446-2458(1990)提议首先用三甲基铝甲基化4-氯-2-三氟甲基吡啶并且随后用KMnO4氧化甲基基团。所得的收率低并且该方法不可应用于工业规模。
Manfred Schlosser等人,Eur.J.Org.Chem.2003,1559-1568)描述了通过最初去质子化、接着在3-位碘化,然后卤素迁移并最后羧化,以45%的总收率从2-三氟吡啶制备2-三氟甲基-4-吡啶羧酸。同样该合成不可应用于工业规模。
Manfred Schlosser等人,Eur.J.Org.Chem.2003,1569-1575描述了从2-三氟甲基吡啶开始的合成,将2-三氟甲基吡啶在负70℃用酰胺碱LITMP(Li-2,2,5,5-四甲基哌啶)处理,接着用二氧化碳处理。该合成显示对所需2-三氟甲基异烟酸的选择性低,应用了昂贵的酰胺碱并且也难以在工业规模上操作。
因此,本发明的目的是找到一种方法,所述方法能够克服从本领域中已知方法知晓的缺点的方法,并且所述方法能够以工业规模进行。
发现该目的可以以下文概述的方法完成。
制备式I的2-三氟甲基异烟酸和酯的方法
其中R1是氢或C1-6-烷基,所述方法包括在钯配合物催化剂的存在下转化式II的2-三氟甲基吡啶衍生物
其中X是卤素或-OSO2CY3,其中Y是卤素。
阐述以下定义以说明和定义用于描述本文中发明的不同术语的意义和范围。
术语“C1-6-烷基”涉及一至六个碳原子,优选一至四个,更优选一至两个碳原子的支或直链单价饱和脂肪烃基。该术语进一步的实例为如甲基、乙基、正丙基、异丙基、正丁基、仲-丁基或叔丁基、戊基和其异构体以及己基和其异构体之类的基团。
术语“卤素”是指氟、氯、溴或碘,而且特别是氯。
术语“芳基”,涉及芳香碳环,比如涉及苯或萘环,优选苯环。
术语“杂环烷基”是指可以包含1,2或3个选自氮、氧和/或硫的杂原子的非芳香的5至6元单环,比如哌嗪基、哌啶基、吗啉基、吡咯烷基或硫代吗啉基。
术语“药用酸加成盐”包括无机和有机酸的盐,所述酸比如盐酸、硝酸、硫酸、磷酸、柠檬酸、甲酸、富马酸、马来酸、乙酸、琥珀酸、酒石酸、甲磺酸、对甲苯磺酸等。
式II的2-三氟甲基吡啶衍生物可市购。它们可以备选地根据PCT国际公开WO2011/161612或其中引用的文献的教导来合成。
合适的式II的2-三氟甲基吡啶衍生物是其中X是氟、氯、溴、碘或三氟甲磺酰基的那些。尤其使用4-氯-2-三氟吡啶(X=氯)。
合适的钯配合物催化剂是可市购的或可以按照本领域技术人员已知的方法原位制备。
它们可以选自具有选自1,1-双(二苯基膦基)乙烷(dppe),1,1′-双(二苯基膦基)二茂铁(dppf),双(二苯基膦基)甲烷(dppm),1,3-双(二苯基膦基)丙烷(dppp),4,5-双(二苯基膦基)9,9-二甲基呫吨或选自三苯基膦的配体的双(苄腈)氯化钯(II)(CAS No.14220-64-5),三(二亚苄基丙酮)二钯(0)(CAS:51364-51-3),(醋酸钯(II)(CAS No.3375-31-3)或氯化钯(II)CAS No.7647-10-1。
在一个实施方案中,所述转化包括在反应物R1OH(其中R1如上所定义)的存在下将式II的2-三氟甲基吡啶衍生物与一氧化碳(CO)的反应。
特别选择的用于该转化的钯配合物催化剂是具有配体1,1′-双(二苯基膦基)二茂铁(dppf)或1,3-双(二苯基膦基)丙烷(dppp)的氯化钯(II),优选其可市购的形式1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物(CAS No.95464-05-4)和(1,3-双(二苯基膦基)丙烷)-氯化钯(II)(CAS No.59831-02-6)。
所述转化可以在5巴至100巴,更特别是60巴至70巴的CO压力下进行。
反应温度通常选自50℃和170℃之间,特别是120℃和140℃之间。
有利地,存在碱,其可以选自有机碱,比如叔胺或选自无机碱,比如碱性的碳酸氢盐或碱性的磷酸盐。有机碱的合适代表是三烷基胺,如三乙胺,并且无机碱的合适代表是例如碳酸氢钠或磷酸三钾。
反应物R1OH是水(R1=H)以提供2-三氟甲基异烟酸或是C1-6-醇(R1=C1-6-烷基)以提供各自的2-三氟甲基异烟酸酯。
特别地,使用C1-4-醇比如甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇或叔丁醇,更特别地,使用甲醇、乙醇或异丙醇,并且甚至更特别地,使用甲醇。
在用水转化的情况下,可以加入选自醚比如二烷或四氢呋喃或低级醇如甲醇、乙醇或异丙醇的有机溶剂。发现四氢呋喃是特别合适的。
在用C1-6-醇转化的情况下,用一氧化碳的起始转化可以接着用氯化氢生产剂处理,以促进完全的酯形成。
合适的氯化氢产生剂可以选自无机酸氯化物,如氯化氢,或选自有机酸氯化物比如亚硫酰氯或乙酰氯。发现亚硫酰氯最合适。
用氢产生剂处理通常在反应混合物的回流条件下进行。
在进一步的实施方案中,所述转化包括式I的2-三氟甲基吡啶衍生物与金属氰化物MCN(其中M表示金属离子)的反应,形成式IV的腈
并且进一步水解或酯化,形成式I的2-三氟甲基异烟酸和酯。
选择用于该转化的钯配合物催化剂通常是Pd(PPh3)4(0),1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物(CAS No.95464-05-4),Pd(P-叔-Bu3)2,三(二亚苄基丙酮)二钯(0)或Pd(TFA)2,其配体为1,1′-双(二苯基膦基)二茂铁(dppf)或外消旋-2-(二-叔丁基膦基)-1,1-联萘。
合适的金属氰化物MCN是氰化锌,或与氰化钠或氰化钾混合的氰化锌,而且特别是氰化锌。
反应温度通常在50℃和120℃之间选择。
反应在合适的有机溶剂比如在N,N,-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基-2-吡咯烷酮、N-乙基-2-吡咯烷酮中发生,而且优选在N,N-二甲基甲酰胺中发生。
可以例如通过用合适的溶剂比如叔甲基丁醚萃取并蒸发溶剂的方式从反应混合物中分离式IV的腈。粗制腈的真空蒸馏可以提供高纯度腈。
在合适的碱存在下,将式IV的腈水解为式I的2-三氟甲基异烟酸(R1=氢)进行,所述碱可以选自碱金属氢氧化物比如氢氧化钠、氢氧化钾或氢氧化锂。
通常,反应在合适的溶剂比如在低级醇比如甲醇,乙醇,1-丙醇,2-丙醇中在回流条件下发生。
产物的分离可以在用盐酸水溶液酸化后通过过滤来进行。
式IV的腈向式I的2-三氟甲基异烟酸酯(R1=C1-6-烷基)的酯化利用醇R1OH(其中R1是C1-6-烷基),在氯化氢气体或氯化氢产生剂的存在下进行。
特别地,使用C1-4-醇比如甲醇、乙醇、正丙醇、异丙醇、正丁醇、仲丁醇或叔丁醇,更特别地,使用甲醇、乙醇、或异丙醇,并且甚至更特别地,使用甲醇。
合适的氯化氢产生剂可以选自无机酸氯化物,比如氯化氢或选自有机酸氯化物比如亚硫酰氯或乙酰氯。发现乙酰氯是最合适的。
通常反应在相应醇的回流条件下进行。
相应酯的分离可以通过用合适的溶剂比如叔甲基丁醚从中和的反应混合物中萃取出和通过之后蒸发有机溶剂来进行。
优选包括在反应物R1OH(其中R1如上所定义)的存在下,用一氧化碳(CO)转化式II的2-三氟甲基吡啶衍生物的实施方案。
如上所述,本发明还包括在制备式III的TAAR1激动剂或其药用酸加成盐的方法中使用本发明的方法
其中
R2是任选地被C1-6-烷基、羟基、卤素或-(CH2)p-芳基取代的(CH2)n-(O)o-杂环烷基;
n是0、1、2;
o是0、1;
p是0、1、2。
式III的化合物可以例如根据PCT公开WO 2012/016879,通过将式I的2-三氟甲基异烟酸和酯与式IV的任选被保护的芳胺反应来制备
在上述情况中,任选被保护的,意为杂环烷基部分R2的氮杂原子用常见氨基保护基团比如例如Boc保护。在该情况下,所述方法还包括例如在酸性条件下去除氨基保护基团。
实施例
缩写:
DMF | N,N’-二甲基甲酰胺 |
MTBE | 甲基叔丁醚 |
PdCl2(dppp) | 二氯(二苯基膦-丙烷)钯(II) |
r.t. | 室温 |
THF | 四氢呋喃 |
实施例1
4-氯-2-三氟甲基-吡啶的制备
在25ml装有回流冷凝器、磁力搅拌器和惰性气体供给物的圆底烧瓶中,将1.63g(10.0mmol)4-羟基-2-三氟甲基-吡啶用4.9ml环己烷和0.077ml DMF处理,在室温加入2.19ml(25.0mmol)草酰氯,将混合物加热至回流3小时,冷却至室温,逐滴缓慢(气体放出)加入18ml水,将混合物用18ml MTBE萃取,将分离的有机层用1M NaHCO3洗涤并且将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,将粗制黑色液体用12ml正己烷处理,在室温搅拌5min,在减压下过滤并蒸发,获得0.9g 4-氯-2-三氟甲基吡啶,为黄色液体。
GC-EI-MS:M 181+/M 183+。
实施例2
从4-氯-2-三氟甲基吡啶制备2-三氟甲基-异烟酸甲酯
将76.8g(423mmol)4-氯-2-三氟甲基-吡啶,7.67g(7.67mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和88.4ml(635mmol)三乙胺在792ml甲醇中的混合物在70巴CO下于130℃搅拌18小时。将粗制混合物(含~30%酸),在减压下浓缩至~20%混合物,用30.9ml(423mmol)亚硫酰氯缓慢处理并回流一小时。将混合物在减压下蒸发,用450ml水和450ml MTBE处理残留物,并过滤所形成的悬浮液。从滤液中分离有机层并用225ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸甲酯,将其在~20mmbar/bp 97-99℃蒸馏,获得80.7g 2-三氟甲基-异烟酸甲酯,为无色液体。
GC-EI-MS:M 205+。
实施例3
从4-氯-2-三氟甲基吡啶制备2-三氟甲基-异烟酸乙酯
将182mg(1.0mmol)4-氯-2-三氟甲基吡啶,18.2mg(0.022mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和0.21ml(1.50mmol)三乙胺在3.0ml乙醇中的混合物在70巴CO下于130℃搅拌18小时,将粗制混合物在减压下蒸发,将残留物用4.0ml 0.5MHCl和4.0ml MTBE处理,过滤所形成的悬浮液,将有机层分离并用2.0ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸乙酯,将其与2.0ml环己烷在室温搅拌10min,将浅的混浊的棕色溶液过滤并将滤液在减压下蒸发,获得113mg 2-三氟甲基-异烟酸乙酯,为浅棕色液体。
GC-EI-MS:M 219+。
实施例4
从4-氯-2-三氟甲基吡啶制备2-三氟甲基-异烟酸异丙酯
将182mg(1.0mmol)4-氯-2-三氟甲基吡啶,18.2mg(0.022mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和0.21ml(1.5mmol)三乙胺在3.0ml 2-丙醇中的混合物在70巴CO下于130℃搅拌18小时,将粗制混合物在减压下蒸发,将残留物用4.0ml0.5M HCl和4.0ml MTBE处理,过滤所形成的悬浮液,分离有机层并用2.0ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸乙酯,将其与2.0ml环己烷在室温搅拌10min,将浅的混浊棕色溶液过滤并将滤液在减压下蒸发,获得134mg 2-三氟甲基-异烟酸异丙酯,为浅棕色液体。
GC-EI-MS:M 233+.
实施例5
三氟-甲磺酸2-三氟甲基-吡啶-4-基酯的制备
在装有磁力搅拌器和惰性气体供给物的25ml圆底烧瓶中,将1.63g(10.0mmol)2-三氟甲基-吡啶-4-醇溶解在8.15ml二氯甲烷中,加入2.04ml(12.0mmol)N-乙基二异丙胺并且将溶液冷却至0-5℃并逐滴加入1.86ml(11.0mmol)三氟甲磺酸酐,将混合物在0-5℃搅拌1小时,将混合物用10ml 0.5M HCl萃取,将分离的有机层用无水Na2SO4干燥并在减压下蒸发。将残留物经15g二氧化硅用环己烷/MTBE纯化,获得1.58g三氟-甲磺酸2-三氟甲基-吡啶-4-基酯,为浅黄色油状物。
GC-EI-MS:M 295+。
实施例6
从三氟-甲磺酸2-三氟甲基-吡啶-4-基酯制备2-三氟甲基-异烟酸甲酯
将295mg(1.0mmol)三氟-甲磺酸2-三氟甲基-吡啶-4-基酯、18.1mg(0.022mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和0.21ml(1.5mmol)三乙胺在4.0ml甲醇中的混合物在70巴CO下在130℃搅拌18小时,将粗制混合物(含~30%酸)用0.073ml(1.0mmol)亚硫酰氯处理,回流一小时,将混合物在减压下蒸发,将残留物用4.0ml水和4.0ml MTBE处理,将形成的悬浮液过滤,将分离的有机层用4.0ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸甲酯,将其用2.0ml环己烷处理,将混合物在减压下过滤并蒸发,获得136mg 2-三氟甲基-异烟酸甲酯,为浅黄色液体。
GC-EI-MS:M 205+。
实施例7
从4-溴-2-三氟甲基吡啶氢溴酸盐制备2-三氟甲基-异烟酸甲酯
将307mg(1.0mmol)4-溴-2-三氟甲基吡啶氢溴化物,18.1mg(0.022mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和0.35ml(2.5mmol)三乙胺在4.0ml甲醇中的混合物在70巴CO下在130℃搅拌18小时,将粗制混合物(含~30%酸)用0.073ml(1.0mmol)亚硫酰氯处理,回流一小时,将混合物在减压下蒸发,将残留物用4.0ml水和4.0ml MTBE处理,将形成的悬浮液过滤,将分离的有机层用2.0ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸甲酯,将其与2.0ml环己烷搅拌15min,在减压下过滤并蒸发,获得112mg 2-三氟甲基-异烟酸甲酯,为无色液体。
GC-EI-MS:M 205+。
实施例8
从4-碘-2-三氟甲基吡啶制备2-三氟甲基-异烟酸甲酯
将165mg(0.60mmol)4-碘-2-三氟甲基吡啶,16.5mg(0.020mmol)1,1’-双(二苯基膦基)二茂铁-二氯化钯(II)二氯甲烷加合物和0.126ml(0.907mmol)三乙胺在3.0ml甲醇中的混合物在70巴CO下于130℃搅拌18小时,将粗制混合物用0.044ml(1.0mmol)亚硫酰氯处理并回流一小时,在减压下蒸发,将残留物用2.0ml水和2.0ml MTBE处理,将形成的悬浮液过滤,分离有机层并用2.0ml 1M NaHCO3萃取,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制2-三氟甲基-异烟酸乙酯,将其与2.0ml环己烷在室温搅拌10min,将浅棕色悬浮液过滤并将滤液在减压下蒸发,获得104mg 2-三氟甲基-异烟酸甲酯,为浅棕色液体。GC-EI-MS:M 205+。
实施例9
从4-氯-2-三氟甲基吡啶制备2-三氟甲基-异烟酸
将182mg(1.0mmol)4-氯-2-三氟甲基吡啶,18.0mg PdCl2(dPPP)和210mg碳酸氢钠在1.5ml THF和1.5ml水中的混合物在70巴CO下于120℃搅拌20小时,在减压下去除THF,加入0.5ml 2M NaOH并将悬浮液过滤。将澄清溶液用0.52ml 25%盐酸处理,在室温搅拌1h,过滤并将白色晶体在40℃干燥,获得146mg 2-三氟甲基-异烟酸。GC-EI-MS:M 191+。
实施例10
从4-氯-2-三氟甲基吡啶制备2-(三氟甲基)吡啶-4-甲腈
将4.0g(22.0mmol)4-氯-2-三氟甲基吡啶在40.0ml DMF中的混合物用氩冲洗,加入0.98g(1.76mmol)1,1’-双(二苯基膦基)二茂铁(CAS:12150-46-8),1.01g(1.10mmol)三(二亚苄基丙酮)二钯(0)(CAS:51364-51-3)和2.59g(22.0mmol)氰化锌。将混合物用氩冲洗并在85-90℃搅拌15小时,将黑色混合物冷却至5-10℃,加入110ml水和110ml MTBE,在室温搅拌半小时,然后经玻璃纤维滤器过滤,将滤饼用15ml MTBE洗涤,从滤液分离有机层,并用110ml水洗涤有机层两次,将分离的有机层用无水Na2SO4干燥,在减压下过滤并蒸发,获得粗制4.20g 2-(三氟甲基)吡啶-4-甲腈,其含有杂质二亚苄基丙酮。将粗制产物用8.40mlMTBE处理,并将所形成的悬浮液在室温搅拌15min,然后过滤,并将滤饼用4.0ml MTBE洗涤。将棕色滤液在减压下蒸发,获得3.60g的标题产物,为棕色油状物,将其在10mbar/b.p.58-60℃蒸馏,获得2.75g 2-(三氟甲基)吡啶-4-甲腈,为无色液体。
GC-EI-MS:M 172+。
实施例11
从2-(三氟甲基)吡啶-4-甲腈制备2-三氟甲基-异烟酸
将172mg(1.0mmol)2-(三氟甲基)吡啶-4-甲腈在0.86ml乙醇中的混合物用0.20g(5.0mmol)氢氧化钠处理。将混合物回流1.5小时,冷却至室温并且将黄色悬浮液冷却至室温,加入3.0ml水和0.65ml盐酸。将悬浮液冷却至0-5℃达30min.,过滤并用2.0ml水洗涤。将米黄色晶体在40℃/15mbar干燥2小时,获得0.15g 2-三氟甲基-异烟酸。GC-EI-MS:M191+。
实施例12
从2-(三氟甲基)吡啶-4-甲腈制备2-三氟甲基-异烟酸甲酯
将172mg(1.0mmol)2-(三氟甲基)吡啶-4-甲腈在1.70ml甲醇中的混合物在冰冷却下用0.71ml乙酰氯(原位产生氯化氢)处理,将溶液回流4小时,冷却至室温并在减压下蒸发,将残留物用1.0ml MTBE处理并用1.0ml 1M NaHCO3萃取,将分离的有机层用Na2SO4干燥,在减压下过滤并蒸发,获得0.16g 2-三氟甲基-异烟酸甲酯。
GC-EI-MS:M 205+。
Claims (13)
1.制备式I的2-三氟甲基异烟酸和酯的方法,
其中R1是氢或C1-6-烷基,所述方法包括在反应物R1OH存在下和在钯配合物催化剂存在下,用一氧化碳(CO)对式II的2-三氟甲基吡啶衍生物的转化,其中R1如上所定义,所述钯配合物催化剂选自具有配体的双(苄腈)氯化钯(II)、三(二亚苄基丙酮)二钯(O)、醋酸钯(II)、或氯化钯(II),所述配体选自1,1-双(二苯基膦基)乙烷(dppe)、1,1′-双-(二苯基膦基)二茂铁(dppf)、双(二苯基膦基)甲烷(dppm)、1,3-双(二苯基膦基)丙烷(dppp)、4,5-双(二苯基膦基)9,9-二甲基呫吨或选自三苯基膦,
其中X是卤素或-OSO2CY3,其中Y是卤素。
2.权利要求1所述的方法,其中所述钯配合物催化剂选自具有配体1,1′-双(二苯基膦基)二茂铁(dppf)或1,3-双(二苯基膦基)丙烷(dppp)的氯化钯(II)。
3.权利要求1或2所述的方法,其中所述转化在5巴至100巴的CO压力下进行。
4.权利要求1或2所述的方法,其中所述转化在碱的存在下进行。
5.权利要求1或2所述的方法,其中所述转化在50℃至170℃之间的反应温度进行。
6.权利要求1或2所述的方法,其中在采用其中R1是C1-6-烷基的反应物R1OH转化的情况下,与一氧化碳的转化之后是用氯化氢产生剂的处理。
7.权利要求6所述的方法,其中所述氯化氢产生剂选自亚硫酰氯或乙酰氯。
8.权利要求6所述的方法,其中用氯化氢产生剂的处理在反应混合物的回流条件下进行。
9.权利要求1或2所述的方法,其中R1是氢、甲基、乙基或异丙基。
10.权利要求1或2所述的方法,其中R1是氢或甲基。
11.权利要求1或2所述的方法,其中X是氟、氯、溴、碘或三氟甲磺酸基。
12.权利要求1或2所述的方法,其中X是氯。
13.权利要求1至12中任一项所述的方法用于制备式III的TAAR1激动剂或其药用酸加成盐的用途,
其中
R2是任选被C1-6-烷基、羟基、卤素、或-(CH2)p-芳基取代的(CH2)n-(O)o-杂环烷基;
n是0、1、2;
o是0、1;
p是0、1、2。
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AU2013346882B2 (en) | 2017-05-04 |
ZA201503201B (en) | 2016-09-28 |
JP2016500060A (ja) | 2016-01-07 |
ES2641376T3 (es) | 2017-11-08 |
SI2920150T1 (sl) | 2017-10-30 |
MX362274B (es) | 2019-01-10 |
EP2920150A1 (en) | 2015-09-23 |
KR20150083864A (ko) | 2015-07-20 |
WO2014076127A1 (en) | 2014-05-22 |
CA2885155C (en) | 2021-02-16 |
NZ706266A (en) | 2019-10-25 |
RU2015119876A (ru) | 2017-01-10 |
CA2885155A1 (en) | 2014-05-22 |
PL2920150T3 (pl) | 2017-11-30 |
MX2015005376A (es) | 2015-07-21 |
RU2654486C2 (ru) | 2018-05-21 |
CN104781236A (zh) | 2015-07-15 |
IL237904A (en) | 2017-10-31 |
AU2013346882A1 (en) | 2015-04-02 |
HRP20171346T1 (hr) | 2017-10-20 |
EP2920150B1 (en) | 2017-07-19 |
HK1207377A1 (zh) | 2016-01-29 |
SG11201503573WA (en) | 2015-06-29 |
US20150291530A1 (en) | 2015-10-15 |
MY170491A (en) | 2019-08-08 |
JP6267221B2 (ja) | 2018-01-24 |
BR112015010120A2 (pt) | 2017-07-11 |
US9481650B2 (en) | 2016-11-01 |
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