CN1506347A - 氟化的苯甲醛 - Google Patents
氟化的苯甲醛 Download PDFInfo
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- CN1506347A CN1506347A CNA2003101202233A CN200310120223A CN1506347A CN 1506347 A CN1506347 A CN 1506347A CN A2003101202233 A CNA2003101202233 A CN A2003101202233A CN 200310120223 A CN200310120223 A CN 200310120223A CN 1506347 A CN1506347 A CN 1506347A
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- Prior art keywords
- formula
- alkyl
- compound
- fluoroalkyl
- acid
- Prior art date
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- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 title 2
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 9
- 150000001875 compounds Chemical class 0.000 claims description 52
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 35
- -1 fluoro-2-hydroxy-3-methyl phenyl aldehydes Chemical class 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 23
- 229910052731 fluorine Inorganic materials 0.000 claims description 19
- 239000002253 acid Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 16
- 239000011737 fluorine Substances 0.000 claims description 14
- 229910052799 carbon Inorganic materials 0.000 claims description 13
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 12
- 229910052739 hydrogen Inorganic materials 0.000 claims description 12
- 239000001257 hydrogen Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 10
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- XXBDWLFCJWSEKW-UHFFFAOYSA-N dimethylbenzylamine Chemical compound CN(C)CC1=CC=CC=C1 XXBDWLFCJWSEKW-UHFFFAOYSA-N 0.000 claims description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 6
- 239000005864 Sulphur Substances 0.000 claims description 6
- VKYKSIONXSXAKP-UHFFFAOYSA-N hexamethylenetetramine Chemical compound C1N(C2)CN3CN1CN2C3 VKYKSIONXSXAKP-UHFFFAOYSA-N 0.000 claims description 6
- 229910052763 palladium Inorganic materials 0.000 claims description 6
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 5
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 5
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 5
- 229910052794 bromium Inorganic materials 0.000 claims description 5
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 5
- 229910052760 oxygen Inorganic materials 0.000 claims description 5
- 239000001301 oxygen Substances 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000000470 constituent Substances 0.000 claims description 4
- 238000005984 hydrogenation reaction Methods 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 4
- 125000000467 secondary amino group Chemical class [H]N([*:1])[*:2] 0.000 claims description 4
- GKQDDKKGDIVDAG-UHFFFAOYSA-N 4-fluoro-2-methylphenol Chemical compound CC1=CC(F)=CC=C1O GKQDDKKGDIVDAG-UHFFFAOYSA-N 0.000 claims description 3
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 3
- 229910000042 hydrogen bromide Inorganic materials 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 2
- KJTLSVCANCCWHF-UHFFFAOYSA-N Ruthenium Chemical compound [Ru] KJTLSVCANCCWHF-UHFFFAOYSA-N 0.000 claims description 2
- ABDBNWQRPYOPDF-UHFFFAOYSA-N carbonofluoridic acid Chemical compound OC(F)=O ABDBNWQRPYOPDF-UHFFFAOYSA-N 0.000 claims description 2
- 229910017052 cobalt Inorganic materials 0.000 claims description 2
- 239000010941 cobalt Substances 0.000 claims description 2
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 229940071870 hydroiodic acid Drugs 0.000 claims description 2
- 229910000765 intermetallic Inorganic materials 0.000 claims description 2
- 229910052741 iridium Inorganic materials 0.000 claims description 2
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims description 2
- 235000011007 phosphoric acid Nutrition 0.000 claims description 2
- 229910052697 platinum Inorganic materials 0.000 claims description 2
- 229910052703 rhodium Inorganic materials 0.000 claims description 2
- 239000010948 rhodium Substances 0.000 claims description 2
- MHOVAHRLVXNVSD-UHFFFAOYSA-N rhodium atom Chemical compound [Rh] MHOVAHRLVXNVSD-UHFFFAOYSA-N 0.000 claims description 2
- 229910052707 ruthenium Inorganic materials 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 6
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims 5
- 239000003905 agrochemical Substances 0.000 abstract description 3
- 150000003935 benzaldehydes Chemical class 0.000 abstract 2
- 239000004480 active ingredient Substances 0.000 abstract 1
- 238000004519 manufacturing process Methods 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 26
- 239000002904 solvent Substances 0.000 description 17
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 16
- 239000000203 mixture Substances 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 14
- 239000012074 organic phase Substances 0.000 description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 10
- 239000007788 liquid Substances 0.000 description 10
- 238000002835 absorbance Methods 0.000 description 8
- 238000001816 cooling Methods 0.000 description 8
- 239000012043 crude product Substances 0.000 description 8
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 7
- 238000009835 boiling Methods 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000005194 fractionation Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 5
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- 150000003335 secondary amines Chemical class 0.000 description 5
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- SNRUBQQJIBEYMU-UHFFFAOYSA-N Dodecane Natural products CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 3
- 125000006340 pentafluoro ethyl group Chemical group FC(F)(F)C(F)(F)* 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 2
- OMGVVVBQKWNRQA-UHFFFAOYSA-N 3-fluoro-2-methylphenol Chemical class CC1=C(O)C=CC=C1F OMGVVVBQKWNRQA-UHFFFAOYSA-N 0.000 description 2
- FDUBQNUDZOGOFE-UHFFFAOYSA-N 5-fluoro-2-hydroxybenzaldehyde Chemical compound OC1=CC=C(F)C=C1C=O FDUBQNUDZOGOFE-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 125000003545 alkoxy group Chemical group 0.000 description 2
- 125000001118 alkylidene group Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- RWRIWBAIICGTTQ-UHFFFAOYSA-N difluoromethane Chemical compound FCF RWRIWBAIICGTTQ-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 125000002769 thiazolinyl group Chemical group 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- SYYSBZOSEAUMEY-UHFFFAOYSA-N 1,1,1-trifluoro-2-$l^{1}-sulfanylethane Chemical compound FC(F)(F)C[S] SYYSBZOSEAUMEY-UHFFFAOYSA-N 0.000 description 1
- 125000005918 1,2-dimethylbutyl group Chemical group 0.000 description 1
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- OCJBOOLMMGQPQU-UHFFFAOYSA-N 1,4-dichlorobenzene Chemical compound ClC1=CC=C(Cl)C=C1 OCJBOOLMMGQPQU-UHFFFAOYSA-N 0.000 description 1
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000006176 2-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(C([H])([H])*)C([H])([H])C([H])([H])[H] 0.000 description 1
- QMIXWHAIFDQEDH-UHFFFAOYSA-N 2-methyl-4-(trifluoromethoxy)phenol Chemical compound CC1=CC(OC(F)(F)F)=CC=C1O QMIXWHAIFDQEDH-UHFFFAOYSA-N 0.000 description 1
- 125000004493 2-methylbut-1-yl group Chemical group CC(C*)CC 0.000 description 1
- QTWJRLJHJPIABL-UHFFFAOYSA-N 2-methylphenol;3-methylphenol;4-methylphenol Chemical compound CC1=CC=C(O)C=C1.CC1=CC=CC(O)=C1.CC1=CC=CC=C1O QTWJRLJHJPIABL-UHFFFAOYSA-N 0.000 description 1
- UGEJOEBBMPOJMT-UHFFFAOYSA-N 3-(trifluoromethyl)phenol Chemical compound OC1=CC=CC(C(F)(F)F)=C1 UGEJOEBBMPOJMT-UHFFFAOYSA-N 0.000 description 1
- 125000003542 3-methylbutan-2-yl group Chemical group [H]C([H])([H])C([H])(*)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WDRJNKMAZMEYOF-UHFFFAOYSA-N 4-(trifluoromethoxy)phenol Chemical compound OC1=CC=C(OC(F)(F)F)C=C1 WDRJNKMAZMEYOF-UHFFFAOYSA-N 0.000 description 1
- RHMPLDJJXGPMEX-UHFFFAOYSA-N 4-fluorophenol Chemical compound OC1=CC=C(F)C=C1 RHMPLDJJXGPMEX-UHFFFAOYSA-N 0.000 description 1
- COVZYZSDYWQREU-UHFFFAOYSA-N Busulfan Chemical compound CS(=O)(=O)OCCCCOS(C)(=O)=O COVZYZSDYWQREU-UHFFFAOYSA-N 0.000 description 1
- NDUJQDZEJYRLRB-UHFFFAOYSA-N C(CCCC)OCC(C(OOCCC(C)C)(OCC(CC)C)OC(CCC)C)(C)C Chemical compound C(CCCC)OCC(C(OOCCC(C)C)(OCC(CC)C)OC(CCC)C)(C)C NDUJQDZEJYRLRB-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- XRPXWFFKDYYBCN-UHFFFAOYSA-N FC(F)(F)CSCl Chemical compound FC(F)(F)CSCl XRPXWFFKDYYBCN-UHFFFAOYSA-N 0.000 description 1
- LSRGXLRLWFDKNR-UHFFFAOYSA-N FC(F)(F)[S] Chemical compound FC(F)(F)[S] LSRGXLRLWFDKNR-UHFFFAOYSA-N 0.000 description 1
- RPKRIOYUXBSZHT-UHFFFAOYSA-N FC(F)C(F)(F)[S] Chemical compound FC(F)C(F)(F)[S] RPKRIOYUXBSZHT-UHFFFAOYSA-N 0.000 description 1
- ADNSNMKLBNWLAA-UHFFFAOYSA-N FC(F)[S] Chemical compound FC(F)[S] ADNSNMKLBNWLAA-UHFFFAOYSA-N 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 239000007868 Raney catalyst Substances 0.000 description 1
- 229910000564 Raney nickel Inorganic materials 0.000 description 1
- ZKBNUNIVNISNDB-UHFFFAOYSA-N [Cl].FC Chemical compound [Cl].FC ZKBNUNIVNISNDB-UHFFFAOYSA-N 0.000 description 1
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 1
- 125000002723 alicyclic group Chemical group 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 229910045601 alloy Inorganic materials 0.000 description 1
- 239000000956 alloy Substances 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940117389 dichlorobenzene Drugs 0.000 description 1
- 125000004786 difluoromethoxy group Chemical group [H]C(F)(F)O* 0.000 description 1
- 125000001028 difluoromethyl group Chemical group [H]C(F)(F)* 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- VLABHYACZYHUKA-UHFFFAOYSA-N ethyl thiohypofluorite Chemical compound CCSF VLABHYACZYHUKA-UHFFFAOYSA-N 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000003709 fluoroalkyl group Chemical group 0.000 description 1
- 230000022244 formylation Effects 0.000 description 1
- 238000006170 formylation reaction Methods 0.000 description 1
- 150000005826 halohydrocarbons Chemical class 0.000 description 1
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 1
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000006608 n-octyloxy group Chemical group 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
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000011541 reaction mixture Substances 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
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
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Abstract
本发明涉及氟化的苯甲醛,其制备方法以及氟化的苯甲醛用于制备活性成分,特别是药物与农用化学品中活性成分的用途。
Description
本发明涉及氟化的苯甲醛,其制备方法以及氟化的苯甲醛用于制备活性成分,特别是药物与农用化学品中活性成分的用途。
氟化的苯甲醛,如氟化的2-羟基和2-烷氧基苯甲醛是药物及农用化学品中活性成分的有价值原料,因为氟和氟化的取代基会增加亲油性并因此增加整个活性成分分子通过膜的能力。例如,如5-氟-2-羟基苯甲醛适合于作为原材料用于制备治疗心血管疾病所用的药物(也参见WO-A-01/19780,81页)。
5-氟-2-羟基苯甲醛可以,例如通过4-氟苯酚的甲酰化来制备(Suzuki等,Chem.Pharm.Bull.,1963,31(5),1751-1753)。但是,收率低于理论收率的20%是不可接受的。
因此仍然需要提供氟化的2-羟基-3-甲基苯甲醛及其有效的制备方法。
现在已经发现制备如下式(I)化合物的方法:
其中
R1在各种情况下独立地为C1-C12烷基,氯或溴或如下式(IIa)或(IIb)的基团:
A-B-D-E (IIa)
A-E (IIb)
其中,各自独立地
A不存在或是C1-C8亚烷基,
B不存在或是氧,硫或是NR2,其中R2是氢或C1-C8烷基,
D是羰基,
E是C1-C8烷基,C1-C8烷氧基,NH(C1-C8烷基)或N(C1-C8烷基)2
或者是含有4-12个碳原子环状氨基,
n是0至3-m的整数,
RF是氟、C1-C12氟烷基,-O(C1-C12氟烷基)或-S(C1-C12氟烷基),和
m是1-3的整数,
其特征在于式(II)的化合物
其中,R1和RF以及n和m定义如上,
●在乌洛托品的存在下
●在酸的存在下
转化为式(I)的化合物。
在本发明的范围内,在上文中和下文所列全部的基团定义,参数和说明,一般说来或在优选范围内,即特定范围和优选范围,均可以依照要求组合。
烷基,亚烷基,烷氧基和烯基在各种情况下独立地分别为直链、环状、支链或无支链的烷基,亚烷基,烷氧基或烯基。上述情况也适用于芳烷基的非芳香性片断。
C1-C4烷基是,例如甲基,乙基,正丙基,异丙基,正丁基,仲丁基和叔丁基,C1-C8烷基另外是,例如正戊基,1-甲基丁基,2-甲基丁基,3-甲基丁基,新戊基,1-乙基丙基,环己基,环戊基,正己基,1,1-二甲丙基,1,2-二甲丙基,1-甲基戊基,2-甲基戊基,3-甲基戊基,4-甲基戊基,1,1-二甲基丁基,1,2-二甲基丁基,1,3-二甲基丁基,2,2-二甲基丁基,2,3-二甲基丁基,3,3-二甲基丁基,1-乙基丁基,2-乙基丁基,1,1,2-三甲基丙基,1,2,2-三甲基丙基,1-乙基-1-甲丙基,1-乙基-2-甲丙基,1-乙基-2-甲丙基,正庚基和正辛基,C1-C12烷基还另外是,例如金刚烷基,正壬基,正癸基和正十二烷基。
C1-C8烷氧基是,例如甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,仲丁氧基和叔丁氧基,正戊氧基,1-甲基丁氧基,2-甲基丁氧基,3-甲基丁氧基,新戊氧基,1-乙基丙氧基,环己氧基,环戊氧基,正己氧基和正辛氧基。
氟烷基在各种情况下独立地为被至少一个氟原子和任选还被氯原子和/或溴原子取代的直链、环状、支链或无支链的烷基。
C1-C12多氟烷基是,例如三氟甲基,氯氟甲基,二氟甲基,二氟氯甲基,1,1,2,2-四氟-1-乙基,2-氯-2,1,1-三氟-1-乙基,2,2,2-三氟乙基,五氟乙基,1,1-二氯-2,2,2-三氟乙基,七氟异丙基,正九氟丁基,全氟环戊基,全氟环己基和全氟十二烷基。
对于式(I)和(II)的化合物来说优选的取代方式定义如下:
R1优选在各种情况下独立地为C1-4烷基或氯,更优选甲基。
n优选为0或1,更优选0。
RF优选为氟,C1-C4氟烷基,-O(C1-C4氟烷基)或-S(C1-C4氟烷基),更优选三氟甲基,三氟甲基硫,三氟甲氧基,氯氟甲基,氯氟甲基硫,氯氟甲氧基,二氟甲氧基,二氟甲基,二氟甲基硫,二氟甲氧基,二氟氯甲基,二氟氯甲基硫,二氟氯甲氧基,1,1,2,2-四氟-1-乙基,1,1,2,2-四氟-1-乙基硫,1,1,2,2-四氟-1-乙氧基,2-氯-2,1,1-三氟-1-乙基,2-氯-2,1,1-三氟-1-乙基硫,2-氯-2,1,1-三氟-1-乙氧基,2,2,2-三氟乙基,2,2,2-三氟乙基硫,2,2,2-三氟乙氧基,五氟乙基,五氟乙基硫,五氟乙氧基,1,1-二氯-2,2,2-三氟乙基,1,1-二氯-2,2,2-三氟乙基硫,1,1-二氯-2,2,2-三氟乙氧基,七氟异丙基,正九氟丁基,全氟环戊基,全氟环己基和全氟十二烷基。
m,在所有的RF均为氟的情况下为1-3,否则为1或2,优选1。
式(II)的化合物在乌洛托品的存在下和在酸的存在下转化为式(I)的化合物。
式(II)化合物与乌洛托品的摩尔比可以是,例如1∶1-10∶1,优选1∶1-5∶1,更优选1.5∶1-2.5∶1。
式(II)化合物与酸的摩尔比可以是,例如1∶1-100∶1,优选3∶1-10∶1。
使用的酸优选为,以水参考***为基础,在25℃下pKa值为3或以下的酸。
特别优选的酸是全氟烷基羧酸,正磷酸和多磷酸,有机磺酸,任选溶解于乙酸中的盐酸、氢溴酸或氢碘酸,硫酸氢盐或硫酸,更优选处于乙酸中的氢溴酸,多磷酸,甲烷磺酸和三氟乙酸,更优选三氟乙酸。
任选,也可以向反应混合物中加入有机溶剂,只要它们在所述的反应条件下基本上是惰性的即可。
优选在使用的酸中进行反应。
反应温度可以是,例如0℃-150℃,优选30℃-150℃,更优选70℃-110℃。
反应压力可以是,例如0.5-100巴,尽管优选环境压力。
转化式(II)化合物的程序是,例如首先加入式(II)化合物与酸,紧接着加入乌洛托品。
式(I)的化合物可以通过本身已知的方式,通过萃取和随后进行蒸馏,或者在式(I)化合物在30℃下固化的情况下通过重结晶进行加工。
式(I)的化合物同样也包括包括在本发明中,以上说明类似地适用于优选的范围。
特别优选的单个式(I)化合物包括:
5-氟-2-羟基-3-甲基苯甲醛,5,6-二氟-2-羟基-3-甲基苯甲醛和2-羟基-3-甲基-5-(三氟甲氧基)苯甲醛。
优选,例如通过将式(III)化合物转化来制备式(I)化合物,
其中:R1、RF和m具有上述定义和优选范围,n是0至3-m之间的整数,
a)-在甲醛的存在下和
-在式(IV)仲胺的存在下
HNR3R4 (IV)
其中,R3和R4各自独立地为C1-8烷基或者NR3R4作为一个整体为总共含有4-12个碳原子的环状氨基,
式(III)化合物转化为式(V)化合物,
其中,R3、R4和RF以及n和m各自具有上述定义和优选范围,和
b)将式(V)化合物还原为式(II)化合物。
作为重要的中间体,式(II)的化合物也同样包括在本发明中,除了2-甲基-4-氟苯酚之外。上述说明类似地适用于优选范围。
作为重要的中间体,式(V)的化合物也另外地包括在本发明中,除了5-氟-2-羟基-N,N-二甲基苄基胺之外。上述说明类似地适用于优选范围。
在步骤a)中,式(III)的化合物在甲醛的存在下和在式(IV)仲胺的存在下转化为式(V)的化合物。
甲醛与式(III)化合物的摩尔比可以是,例如0.8-10,优选1.0-10,更优选1.2-3.6。
式(IV)的仲胺与式(III)化合物的摩尔比可以是,例如0.8-10,优选1.0-10,更优选1.05-3.15。
甲醛可以,例如以多聚甲醛的形式和/或以水溶液的形式使用,优选以32-40wt%的溶液形式使用。
式(IV)的仲胺可以以,例如没有溶剂的形式,或者可能的话,以水溶液的形式使用。特别优选使用呈水溶液形式的二甲胺。
反应温度可以是,例如-40℃-120℃,优选-10℃-40℃,更优选-5℃-10℃。
反应压力可以是,例如,0.5-100巴,尽管优选环境压力。
反应时间可以是10分钟-72小时,优选3小时-24小时。
对于反应来说合理的程序实例是首先加入式(III)的化合物和式(IV)的仲胺,接着加入甲醛。
式(V)的化合物可以通过本身已知的方式,通过萃取和随后进行蒸馏,或者在式(V)化合物在30℃下固化的情况下通过重结晶进行加工。
根据步骤b)的还原可以有利地在氢和加氢催化剂的存在下进行。
优选的加氢催化剂是,例如镍、钯、铂、钴、铑、铱和钌的金属或金属化合物,如盐或络合物,尽管优选金属,如镍或钯。优选使用细分散形式的金属,如作为阮内金属或施涂于载体上的形式。
特别优选用氢和阮内镍和/或载于碳上的钯进行还原。
还原可以,例如在反应温度为20℃-200℃下进行,优选50-180℃,更优选80-150℃。
还原中氢的分压可以是,例如0.1-180巴,优选10-150巴,更优选40-120巴。
任选并优选,反应可以在溶剂的存在下进行,只要它在选定的反应条件下基本上惰性即可。
适合的溶剂是,例如,脂肪族、脂环族或芳族烃,任选卤代烃,例如汽油馏分,苯,甲苯,二甲苯,氯苯,二氯苯,石油醚,己烷,环己烷,二氯甲烷,氯仿或四氯化碳;醚,例如***,二异丙醚,二氧六环,四氢呋喃或乙二醇二甲基或二乙基醚;醇,如甲醇,乙醇和异丙醇;羧酸,如乙酸;或溶剂的混合物。
还原反应时间可以是10分钟-200小时,优选5-100小时。
在特别优选的实施方案中,还原在载于活性碳上的钯和乙酸的存在下,在氢分压为40-120巴下进行。
可根据本发明得到的式(I)和(II)的化合物特别适合用于制备活性成分,例如药物的活性成分。优选的药物活性成分是用于治疗心血管疾病的那些。特别是,在WO-A-01/19780中描述的那些。
本发明实质的优点是它们可以周容易得到的反应物以简单的方法制备式(I)和(II)的化合物。此外,本发明式(I)和(II)的化合物构成制备活性成分,特别是药物活性成分的有价值原料。
实施例
实施例1:5-氟-2-羟基-3-甲基苯甲醛的制备
将84g 4-氟-2-甲基苯酚溶于512ml三氟乙酸中并分几次与181g六亚甲基四胺混合。在加料结束后,将反应溶液加热到100℃,加热5小时。冷却之后,首先滴加80ml 50%的硫酸,然后滴加480ml水,之后将溶液在室温下再搅拌3小时。用二氟甲烷将反应溶液萃取3次。将合并的萃取液用水洗涤1次并干燥,减压蒸除溶剂。残余物用正己烷重复萃取,合并萃取液并减压蒸除溶剂。接着将粗产物分馏。得到25g(理论收率的25%)亮黄色固体,熔点为49-52℃,7毫巴下的沸点为70-72℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):1.08(s,1H,OH);9.83(s,1H,CHO);7.14,7.07(2×dd,2H,H-4,H-6);2.28(s,3H,CH3)。
实施例2:5,6-二氟-2-羟基-3-甲基苯甲醛的制备
将30g 4,5-二氟-2-甲基苯酚溶于180ml三氟乙酸中并分几次与57.2g六亚甲基四胺混合。在加料结束后,将反应溶液加热到97-100℃,加热4小时。冷却之后,首先滴加60ml 50%的硫酸,然后滴加300ml水,之后将溶液在室温下再搅拌2小时。用甲基叔丁基醚将反应溶液萃取3次。将合并的萃取液用水洗涤1次并干燥,减压蒸除溶剂。残余物用正己烷重复萃取,合并萃取液并减压蒸除溶剂。得到12.5g(理论收率的33%)亮黄色固体,熔点为53-56℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):11.39(bs,1H,OH);10.24(s,1H,CHO);7.23(m,1H,H-4);2.22(s,3H,CH3)。
利用GC-MS得到以下图谱(EI,70eV,I/%):172(100,M+)。
实施例3:2-羟基-3-甲基-5-(三氟甲氧基)苯甲醛的制备
将100g 2-甲基-4-(三氟甲氧基)苯酚溶于600ml三氟乙酸中并分几次与144g六亚甲基四胺混合。在加料结束后,将反应溶液加热到100℃,加热16小时。冷却之后,首先滴加200ml 50%的硫酸,然后滴加700ml水,之后将溶液在室温下再搅拌3小时。用甲基叔丁基醚进行3次萃取,将合并的有机相用水洗涤1次并干燥,减压蒸除溶剂。残余物用正己烷重复萃取,合并萃取液并减压蒸除溶剂。得到40g(理论收率的34%)浅黄色液体,4毫巴下的沸点为65-67℃。
1H NMR谱包含以下特征吸收:(DMSO-d6,δ/ppm):11.03(bs,1H,OH);10.12(s,1H,CHO);7.59,7.48(2×m,2H,H-4,H-6);2.26(s,3H,CH3)。
通过GC-MS得到以下图谱(EI,70eV,I/%):220(100,M+)。
实施例4:4,5-二氟-2-羟基-N,N-二甲基苄基胺的制备
首先将400g 3,4-二氟苯酚加到408ml 40%的二甲胺水溶液中并冷却到0℃。在0-5℃下,在60分钟内滴加276ml 37%的甲醛水溶液。混合物在5-10℃下保持2小时,接着在室温下搅拌20小时。将混合物与600ml水混合,除去有机相,用二氯甲烷萃取水相,将合并的有机相干燥并减压蒸除溶剂。粗产物随后减压分馏。得到395g(理论收率的65%)无色液体,16毫巴下的沸点为93℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):11.32(s,1H,OH);7.77,7.60(2m,2H,H-3,H-6);3.57(s,2H,CH2);2.32(s,6H,N(CH3)2)。
通过GC-MS得到以下图谱(EI,70eV,I/%):187(100,M+);143(36,(M-N(CH3)2)+)。
实施例5:2-羟基-5-(三氟甲氧基)-N,N-二甲基苄基胺的制备
首先将130g 4-三氟甲氧基苯酚加到97ml 40%的二甲胺水溶液中并冷却到3℃。在0-5℃下,在45分钟内滴加66ml 37%的甲醛水溶液。混合物在5-10℃下另外保持2小时,接着在室温下搅拌19小时。将混合物再次冷却到0℃,加入4.9ml 40%的二甲胺水溶液,随后滴加3.3ml37%的甲醛水溶液。混合物在室温下另外搅拌3小时。将混合物与100ml水混合,除去有机相,用二氯甲烷萃取水相,将合并的有机相干燥并减压蒸除溶剂。粗产物随后减压分馏。得到118g(理论收率的69%)浅黄色液体,18毫巴下的沸点为110-112℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):11.08(bs,1H,OH);7.03(dd,1H,JH4-H3=8.9Hz,JH-4-H6=2.4Hz,H-4);6.84(d,1H,JH-6,H4=2.3Hz,H-6);6.80(d,1H,JH3-H4=8.8Hz,H-3);3.62(s,2H,CH2);2.32(s,3H,CH3)。
通过GC-MS得到以下图谱(EI,70eV,I/%):235(100,M+);191(19,(M-N(CH3)2)+)。
实施例6:6-羟基-2,3,4-三氟-N,N-二甲基苄基胺的制备
首先将400g 3,4,5-三氟苯酚加到359ml 40%的二甲胺水溶液中并冷却到0℃。在0-5℃下,在90分钟内滴加243ml 37%的甲醛水溶液。随后将混合物在室温下搅拌20小时。将混合物与600ml水和500ml二氯甲烷混合,除去有机相,水相用二氯甲烷萃取一次,将合并的有机相干燥并减压蒸除溶剂。粗产物吸收在500ml水中并在冰浴冷却下用稀盐酸调节至pH为1-2。用二氯甲烷将酸溶液萃取一次,并随后在冰浴冷却下用稀氢氧化钠溶液调节至pH为8-9。将碱性反应液用二氯甲烷萃取3次,合并的有机相用水洗涤1次并干燥,减压除去溶剂,粗产物随后减压分馏。得到305g(理论收率的55%)浅黄色液体,10毫巴下的沸点为96℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):11.70(s,1H,OH);6.41(m,1H,H-5);3.71(s,2H,CH2);2.37(s,6H,N(CH3)2)。
实施例7:2-羟基-4-(三氟甲基)-N,N-二甲基苄基胺的制备
首先将195g 3-三氟甲基苯酚加到160ml 40%的二甲胺水溶液中并冷却到15℃。在155℃下,在40分钟内滴加108ml 37%的甲醛水溶液。随后将混合物在室温下搅拌20小时。将混合物再次冷却到15℃,与8ml 40%的二甲胺水溶液混合并滴加5.5ml 37%的甲醛水溶液。随后,反应物在室温下再搅拌4.5小时。将混合物再次冷却到15℃,与32ml40%的二甲胺水溶液混合并滴加21ml 37%的甲醛水溶液。随后,继续在室温下搅拌17小时。将混合物与150ml水混合,除去有机相,水相用二氯甲烷萃取两次,将合并的有机相用水洗涤1次并减压蒸除溶剂。粗产物吸收在250ml水中并在冰浴冷却下用稀盐酸调节至pH为1-2。用二氯甲烷将酸溶液萃取一次,并随后在冰浴冷却下用稀氢氧化钠溶液调节至pH为11。将碱性反应液用二氯甲烷萃取2次,合并的有机相用水洗涤1次并干燥,之后减压除去溶剂,粗产物随后减压分馏。得到186g(理论收率的71%)浅黄色液体,14毫巴下的沸点为91℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):7.08-6.98(m,3H,H-3,H-5,H-6);3.67(s,2H,CH2);2.32(s,6H,N(CH3)2)。
实施例8:4,5-二氟-2-甲基苯酚的制备
首先将214g 4,5-二氟-2-羟基-N,N-二甲基苄基胺加入到处于高压釜中的700ml乙酸中,与50g钯/活性碳(5%)混合并与70巴的氢气加热到100℃,加热26小时。将高压釜冷却并减压。滤除催化剂并用乙酸洗涤,将滤液与3000ml水混合。水溶液用甲基叔丁基醚萃取3次。合并的有机相用水洗涤1次并干燥,且减压蒸除溶剂。粗产物随后减压分馏。馏出物通过结晶进一步纯化,得到98g(理论收率的58%)无色固体,熔点为68-70℃,13毫巴下的沸点为78-80℃。
1H NMR谱包含以下特征吸收:(CDCl3,δ/ppm):6.92,6.62(2m,2H,H-3,H-6);4.82(s,1H,OH);2.19(2,3H,CH3)。
通过GC-MS得到以下图谱(EI,70eV,I/%):144(100,M+);126(21,(M-F+H)+)。
Claims (21)
1.一种制备如下式(I)化合物的方法:
其中
R1在各种情况下独立地为C1-C12烷基,氯或溴或如下式(IIa)或(IIb)的基团:
A-B-D-E (IIa)
A-E (IIb)
其中,各自独立地
A不存在或是C1-C8亚烷基,
B不存在或是氧,硫或是NR2,其中R2是氢或C1-C8烷基,
D是羰基,
E是C1-C8烷基,C1-C8烷氧基,NH(C1-C8烷基)或N(C1-C8烷基)2
或者是含有4-12个碳原子环状氨基,
n是0至3-m的整数,
RF是氟、C1-C12氟烷基,-O(C1-C12氟烷基)或-S(C1-C12氟烷基),和
m是1-3的整数,
其特征在于式(II)的化合物
其中,R1和RF以及n和m定义如上,
●在乌洛托品的存在下和
●在酸的存在下
转化为式(I)的化合物。
2.根据权利要求1的方法,其特征在于R1在各种情况下独立地为C1-C4烷基或氯。
3.根据权利要求1-2中至少一项的方法,其特征在于n为0或1。
4.根据权利要求1-3中至少一项的方法,其特征在于RF为氟,C1-C4氟烷基,-O(C1-C4氟烷基)或-S(C1-C4氟烷基)。
5.根据权利要求1-4中至少一项的方法,其特征在于乌洛托品与式(II)化合物的摩尔比为1∶1-10∶1。
6.根据权利要求1-5中至少一项的方法,其特征在于酸与式(II)化合物的摩尔比为1∶1-100∶1。
7.根据权利要求1-6中至少一项的方法,其特征在于使用的酸为,以水参考***为基础,在25℃下pKa值为3或以下的酸。
8.根据权利要求1-7中至少一项的方法,其特征在于使用的酸为全氟烷基羧酸,正磷酸和多磷酸,有机磺酸,任选溶解于乙酸中的盐酸、氢溴酸或氢碘酸,硫酸氢盐或硫酸。
10.根据权利要求9的方法,其特征在于步骤a)中甲醛与式(III)化合物的摩尔比为0.8-10。
11.根据权利要求9-10中至少一项的方法,其特征在于步骤a)中式(IV)的仲胺与式(III)化合物的摩尔比为0.8-10。
12.根据权利要求9-11中至少一项的方法,其特征在于步骤b)在氢气与加氢催化剂的存在下进行。
13.根据权利要求12的方法,其特征在于使用的加氢催化剂是镍、钯、铂、钴、铑、铱和钌的金属或金属化合物,如盐或络合物。
14.根据权利要求12-13中至少一项的方法,其特征在于步骤b)中的还原在反应温度为20℃-200℃,氢分压为0.1-180巴下进行。
16.5-氟-2-羟基-3-甲基苯甲醛,5,6-二氟-2-羟基-3-甲基苯甲醛和2-羟基-3-甲基-5-(三氟甲氧基)苯甲醛。
17.式(II)的化合物
其中
R1在各种情况下独立地为C1-C12烷基,氯或溴或如下式(IIa)或(IIb)的基团:
A-B-D-E (IIa)
A-E (IIb)
其中,各自独立地
A不存在或是C1-C8亚烷基,
B不存在或是氧,硫或是NR2,其中R2是氢或C1-C8烷基,
D是羰基,
E是C1-C8烷基,C1-C8烷氧基,NH(C1-C8烷基)或N(C1-C8烷基)2
或者是含有4-12个碳原子环状氨基,
n是0至3-m的整数,
RF是氟、C1-C12氟烷基,-O(C1-C12氟烷基)或-S(C1-C12氟烷基),和
m是1-3的整数,
除了4-氟-2-甲基苯酚之外。
18.式(V)的化合物
其中
R1在各种情况下独立地为C1-C12烷基,氯或溴或如下式(IIa)或(IIb)的基团:
A-B-D-E (IIa)
A-E (IIb)
其中,各自独立地
A不存在或是C1-C8亚烷基,
B不存在或是氧,硫或是NR2,其中R2是氢或C1-C8烷基,
D是羰基,
E是C1-C8烷基,C1-C8烷氧基,NH(C1-C8烷基)或N(C1-C8烷基)2或者是含有4-12个碳原子环状氨基,
n是0至3-m的整数,
RF是氟、C1-C12氟烷基,-O(C1-C12氟烷基)或-S(C1-C12氟烷基),和
m是1-3的整数,和
R3和R4各种独立地为C1-C8烷基或NR3R4作为一个整体为总共具有4-12个碳原子的环状氨基,
除了5-氟-2-羟基-N,N-二甲基苄基胺之外。
19.4,5-二氟-2-羟基-N,N-二甲基苄基胺,2-羟基-5-(三氟甲氧基)-N,N-二甲基苄基胺,6-羟基-2,3,4-三氟-N,N-二甲基苄基胺和2-羟基-4-(三氟甲基)-N,N-二甲基苄基胺。
20.权利要求15-19中至少一项的化合物或者根据权利要求1-14中至少一项原方法制备的化合物在制备药物活性成分方面的用途。
21.根据权利要求20的用途,其特征在于药物活性成分是用于治疗心血管疾病的那些。
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CN114702370A (zh) * | 2022-04-14 | 2022-07-05 | 北京化工大学 | 一种利用镍基催化剂制备邻位甲基化酚类化合物的方法 |
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US8525131B2 (en) | 2009-11-25 | 2013-09-03 | The Regents Of The University Of Michigan | Phosphorescent organic compounds |
CN114163316B (zh) * | 2021-11-19 | 2024-06-21 | 爱斯特(成都)生物制药股份有限公司 | 一种制备4-溴-2-甲氧基-5-三氟甲基苯甲醛的方法 |
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GB1420572A (en) * | 1974-02-21 | 1976-01-07 | Merck & Co Inc | 2-amino-methylphonol derivatives |
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DE3304202A1 (de) * | 1983-02-08 | 1984-08-09 | Bayer Ag, 5090 Leverkusen | Verfahren zur herstellung von aromatischen aldehyden |
DE3836161A1 (de) | 1988-10-24 | 1990-04-26 | Bayer Ag | Schaedlingsbekaempfungsmittel auf basis von substituierten aminothiazolen |
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CN114702370A (zh) * | 2022-04-14 | 2022-07-05 | 北京化工大学 | 一种利用镍基催化剂制备邻位甲基化酚类化合物的方法 |
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