CN1049663A - 吡咯并喹啉类化合物 - Google Patents
吡咯并喹啉类化合物 Download PDFInfo
- Publication number
- CN1049663A CN1049663A CN90107135A CN90107135A CN1049663A CN 1049663 A CN1049663 A CN 1049663A CN 90107135 A CN90107135 A CN 90107135A CN 90107135 A CN90107135 A CN 90107135A CN 1049663 A CN1049663 A CN 1049663A
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- Prior art keywords
- compound
- salt
- group
- nmr
- phenyl
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- SLHCMPVPVQSTBV-UHFFFAOYSA-N C1=CNC2=C3C=CN=C3C=CC2=C1 Chemical class C1=CNC2=C3C=CN=C3C=CC2=C1 SLHCMPVPVQSTBV-UHFFFAOYSA-N 0.000 title abstract description 10
- 150000003839 salts Chemical class 0.000 claims abstract description 103
- 238000000034 method Methods 0.000 claims abstract description 66
- 239000000203 mixture Substances 0.000 claims abstract description 37
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 8
- 208000035150 Hypercholesterolemia Diseases 0.000 claims abstract description 7
- 208000031226 Hyperlipidaemia Diseases 0.000 claims abstract description 7
- 208000020346 hyperlipoproteinemia Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims description 138
- -1 4Be hydrogen Chemical class 0.000 claims description 117
- 125000000217 alkyl group Chemical group 0.000 claims description 48
- 239000002253 acid Substances 0.000 claims description 43
- 125000003118 aryl group Chemical group 0.000 claims description 26
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 25
- 229910052736 halogen Inorganic materials 0.000 claims description 25
- 238000002360 preparation method Methods 0.000 claims description 23
- 150000002367 halogens Chemical class 0.000 claims description 22
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 22
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 19
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000001624 naphthyl group Chemical group 0.000 claims description 13
- 125000001424 substituent group Chemical group 0.000 claims description 13
- 125000000623 heterocyclic group Chemical group 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 11
- 125000003282 alkyl amino group Chemical group 0.000 claims description 10
- 239000000460 chlorine Substances 0.000 claims description 9
- 239000001301 oxygen Substances 0.000 claims description 9
- 229910052760 oxygen Inorganic materials 0.000 claims description 9
- 125000003545 alkoxy group Chemical group 0.000 claims description 8
- 238000006460 hydrolysis reaction Methods 0.000 claims description 8
- 125000001544 thienyl group Chemical group 0.000 claims description 8
- 125000005023 xylyl group Chemical group 0.000 claims description 8
- 230000032050 esterification Effects 0.000 claims description 7
- 238000005886 esterification reaction Methods 0.000 claims description 7
- 125000003944 tolyl group Chemical group 0.000 claims description 7
- 150000003973 alkyl amines Chemical class 0.000 claims description 6
- 125000004390 alkyl sulfonyl group Chemical group 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 125000002592 cumenyl group Chemical group C1(=C(C=CC=C1)*)C(C)C 0.000 claims description 6
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 6
- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 claims description 6
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 5
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 5
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 4
- 241001465754 Metazoa Species 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 4
- 125000005678 ethenylene group Chemical group [H]C([*:1])=C([H])[*:2] 0.000 claims description 4
- 239000011737 fluorine Substances 0.000 claims description 4
- 229910052731 fluorine Inorganic materials 0.000 claims description 4
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 4
- LSNNMFCWUKXFEE-UHFFFAOYSA-M Bisulfite Chemical compound OS([O-])=O LSNNMFCWUKXFEE-UHFFFAOYSA-M 0.000 claims description 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical group C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- 239000005977 Ethylene Chemical group 0.000 claims description 3
- 241000534944 Thia Species 0.000 claims description 3
- 125000004453 alkoxycarbonyl group Chemical group 0.000 claims description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 3
- 239000000470 constituent Substances 0.000 claims description 3
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 239000003112 inhibitor Substances 0.000 claims description 3
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 3
- 239000000376 reactant Substances 0.000 claims description 3
- 238000007363 ring formation reaction Methods 0.000 claims description 3
- 238000006884 silylation reaction Methods 0.000 claims description 3
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 2
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 2
- KXDHJXZQYSOELW-UHFFFAOYSA-N Carbamic acid Chemical compound NC(O)=O KXDHJXZQYSOELW-UHFFFAOYSA-N 0.000 claims description 2
- 125000004104 aryloxy group Chemical group 0.000 claims description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 2
- 125000004212 difluorophenyl group Chemical group 0.000 claims description 2
- 230000003647 oxidation Effects 0.000 claims description 2
- 238000007254 oxidation reaction Methods 0.000 claims description 2
- 159000000000 sodium salts Chemical class 0.000 claims description 2
- 125000001475 halogen functional group Chemical group 0.000 claims 6
- LQYDVZGVUPXQRB-UHFFFAOYSA-N C(C)(C)C1=CC=CC=C1.[O] Chemical compound C(C)(C)C1=CC=CC=C1.[O] LQYDVZGVUPXQRB-UHFFFAOYSA-N 0.000 claims 1
- 150000001555 benzenes Chemical class 0.000 claims 1
- 125000001207 fluorophenyl group Chemical group 0.000 claims 1
- 150000002431 hydrogen Chemical class 0.000 claims 1
- 125000005186 naphthyloxy group Chemical group C1(=CC=CC2=CC=CC=C12)O* 0.000 claims 1
- 125000003808 silyl group Chemical group [H][Si]([H])([H])[*] 0.000 claims 1
- 229910052717 sulfur Inorganic materials 0.000 claims 1
- 125000004434 sulfur atom Chemical group 0.000 claims 1
- 150000003577 thiophenes Chemical class 0.000 claims 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 abstract description 6
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 abstract 2
- 235000002639 sodium chloride Nutrition 0.000 description 78
- 238000006243 chemical reaction Methods 0.000 description 76
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 63
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 38
- 239000000243 solution Substances 0.000 description 33
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 30
- 150000002148 esters Chemical group 0.000 description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 23
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 21
- 239000011541 reaction mixture Substances 0.000 description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 19
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 18
- 230000002829 reductive effect Effects 0.000 description 18
- 239000002904 solvent Substances 0.000 description 17
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical class C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000007788 liquid Substances 0.000 description 15
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 15
- 238000012360 testing method Methods 0.000 description 15
- 238000000605 extraction Methods 0.000 description 13
- 238000001819 mass spectrum Methods 0.000 description 12
- DYLIWHYUXAJDOJ-OWOJBTEDSA-N (e)-4-(6-aminopurin-9-yl)but-2-en-1-ol Chemical compound NC1=NC=NC2=C1N=CN2C\C=C\CO DYLIWHYUXAJDOJ-OWOJBTEDSA-N 0.000 description 11
- 229960004756 ethanol Drugs 0.000 description 11
- 230000009931 harmful effect Effects 0.000 description 11
- 239000012046 mixed solvent Substances 0.000 description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 10
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 10
- 229910001873 dinitrogen Inorganic materials 0.000 description 10
- 239000011259 mixed solution Substances 0.000 description 10
- 229910052697 platinum Inorganic materials 0.000 description 10
- 239000006188 syrup Substances 0.000 description 10
- 235000020357 syrup Nutrition 0.000 description 10
- 238000009834 vaporization Methods 0.000 description 10
- 239000003513 alkali Substances 0.000 description 9
- 239000002585 base Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 9
- 238000001035 drying Methods 0.000 description 9
- 238000010438 heat treatment Methods 0.000 description 9
- 229910052763 palladium Inorganic materials 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 8
- 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 8
- 125000005907 alkyl ester group Chemical group 0.000 description 8
- 239000007864 aqueous solution Substances 0.000 description 8
- 235000010290 biphenyl Nutrition 0.000 description 8
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 8
- 238000001704 evaporation Methods 0.000 description 8
- 230000008020 evaporation Effects 0.000 description 8
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 8
- 239000000047 product Substances 0.000 description 8
- 239000011734 sodium Substances 0.000 description 8
- 229910052708 sodium Inorganic materials 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000003981 vehicle Substances 0.000 description 8
- 229920002554 vinyl polymer Polymers 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 7
- 239000004305 biphenyl Substances 0.000 description 7
- 239000000284 extract Substances 0.000 description 7
- 230000007062 hydrolysis Effects 0.000 description 7
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 7
- 238000006722 reduction reaction Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000000741 silica gel Substances 0.000 description 6
- 229910002027 silica gel Inorganic materials 0.000 description 6
- 229960001866 silicon dioxide Drugs 0.000 description 6
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 6
- 239000000126 substance Substances 0.000 description 6
- 229910052725 zinc Inorganic materials 0.000 description 6
- 239000011701 zinc Substances 0.000 description 6
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 description 5
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 description 5
- RKOTXQYWCBGZLP-UHFFFAOYSA-N N-[(2,4-difluorophenyl)methyl]-2-ethyl-9-hydroxy-3-methoxy-1,8-dioxospiro[3H-pyrido[1,2-a]pyrazine-4,3'-oxolane]-7-carboxamide Chemical compound CCN1C(OC)C2(CCOC2)N2C=C(C(=O)NCC3=C(F)C=C(F)C=C3)C(=O)C(O)=C2C1=O RKOTXQYWCBGZLP-UHFFFAOYSA-N 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 5
- 229910052783 alkali metal Inorganic materials 0.000 description 5
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 5
- 238000003810 ethyl acetate extraction Methods 0.000 description 5
- 125000004494 ethyl ester group Chemical group 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 150000007524 organic acids Chemical class 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 238000010898 silica gel chromatography Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 4
- WWSJZGAPAVMETJ-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-3-ethoxypyrazol-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C=1C(=NN(C=1)CC(=O)N1CC2=C(CC1)NN=N2)OCC WWSJZGAPAVMETJ-UHFFFAOYSA-N 0.000 description 4
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 4
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 4
- 150000001340 alkali metals Chemical class 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
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- 238000004587 chromatography analysis Methods 0.000 description 4
- 238000004440 column chromatography Methods 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- 229910052759 nickel Inorganic materials 0.000 description 4
- 125000006239 protecting group Chemical group 0.000 description 4
- 210000002966 serum Anatomy 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 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 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- BZFBDUQOBQHBSZ-DLCQERRASA-N (3s,8r,9s,10r,13s,14s,17s)-17-[3-(dimethylamino)propyl-methylamino]-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-ol;dihydrochloride Chemical compound Cl.Cl.C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](N(C)CCCN(C)C)[C@@]1(C)CC2 BZFBDUQOBQHBSZ-DLCQERRASA-N 0.000 description 3
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 102100029077 3-hydroxy-3-methylglutaryl-coenzyme A reductase Human genes 0.000 description 3
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 3
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- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 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
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229920001567 vinyl ester resin Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
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Abstract
本发明涉及对3-羟基-3-甲基-戊二酰基-辅酶
A还原酶(HMG-COA-还原酶)具有抑制作用的新
的吡咯并喹啉类化合物及其药学上适用的盐,制备它
们的方法,含有它们的药用组合物,它们作为药物的
应用,以及治疗血胆甾醇过多、血脂蛋白过多和有关
疾病的方法。
Description
本发明涉及新的吡咯并喹啉类化合物及其药学上适用的盐。
更具体地说,本发明涉及对3-羟基-3-甲基-戊二酰基-辅酶A还原酶(HMG-CoA-还原酶)具有抑制作用的新的吡咯并喹啉类化合物及其药学上适用的盐,制备它们的方法,含有它们的药用组合物,它们作为药物的应用,以及治疗血胆甾醇过多、血脂蛋白过多和有关疾病的方法。
因此,本发明的一个目的是提供吡咯并喹啉类化合物及其药学上适用的盐,通过抑制HMG-CoA还原酶的活性而限制生物合成,从而显示抗血胆甾醇过多剂或抗血脂蛋白过多剂的作用,因此可以降低血清胆甾醇浓度和血脂浓度。
本发明的另一目的是提供制备吡咯并喹啉类化合物及其药学上适用的盐的方法。
本发明的又一目的是提供含有上述吡咯并喹啉类化合物及其药学上适用的盐作为有效成分的药用组合物。
本发明的再一目的是提供上述吡咯并喹啉类化合物及其药学上适用的盐作为药物的应用,以及治疗人或动物的血胆甾醇过多、血脂蛋白过多和有关疾病的方法。
高浓度的血液胆甾醇和血脂引起动脉硬化。已知HMG-CoA还原酶抑制剂可以有效地降低血浆胆甾醇〔尤其是低密度脂蛋白胆甾醇(LDL-C)〕的浓度。现已确定,降低LDL-C浓度能够产生保护作用,免得冠状心脏疾病、大脑梗塞等。
本发明的吡咯并喹啉类化合物可以抑制HMG-CoA还原酶,因此可以抑制胆甾醇生物合成。它们可以降低血中胆甾醇的浓度。因此,它们可用于治疗血胆甾醇过多和血脂蛋白过多(如动脉粥样硬化),有关疾病(如绞痛、心肌梗塞、大脑血管闭塞、动脉瘤、外周血管疾病、再发胰腺炎和黄瘤),糖尿病患者肾病等。
本发明的吡咯并喹啉类目的化合物或其药学上适用的盐是新的,可用以下通式表示,
其中R1和R2各自为氢或低级烷基,
R3为可以由1个或多个合适取代基取代的芳基或杂环基团,
R4为氢、卤素或低级烷基,
A为亚甲基、次甲基、氧杂、硫杂、亚磺酰基或磺酰基
Y为1,2-亚乙烯基或1,2-亚乙基,
Z为下式基团,
其中R5为羧基或受保护的羧基,
R6为氢或羟基保护基,
目的化合物(Ⅰ)合适的药学上适用的盐是普通无毒的盐,可以包括与碱生成的盐,如无机碱盐,例如碱金属盐(如钠盐、钾盐等),碱土金属盐(如钙盐、镁盐等);铵盐;有机碱盐,例如有机胺盐(如三乙胺盐、吡啶盐、甲基吡啶盐、乙醇胺盐、三乙醇胺盐、二环己胺盐、N,N-二苄基乙二胺盐等);与碱性氨基酸(如精氨酸等)生成的盐;与酸,如与无机酸生成的无机酸加成盐(例如盐酸盐、氢溴酸盐、硫酸盐、磷酸盐等),与有机酸生成的有机酸加成盐(例如甲酸盐、乙酸盐、三氟乙酸盐、马来酸盐、酒石酸盐、甲磺酸盐、苯磺酸盐等);与酸性氨基酸(如天冬氨酸、谷氨酸等)生成的盐等。
在目的化合物(Ⅰ)和下面提到的中间化合物中,应该理解,由于不对称碳原子和/或双键的存在,因此可以有1个或多个立体异构体,例如旋光异构体和/或几何异构体,这些异构体也包括在本发明的范围内。
本发明的目的化合物(Ⅰ)或其药学上适用的盐可以按照下述反应路线所述的方法制备。
方法9:
其中R1、R2、R3、R4、R5、A、Y、Z和 各自的定义同上,
R5 a为受保护的羧基,
R5 b为酯化的羧基,
R5 c为N-〔芳基(低级)烷基〕甲酰氨基,
R6 a为羟基保护基,
Aa为亚磺酰基和磺酰基。
用于方法1的化合物(Ⅱ)是新的,例如可以按照下述方法或者按常规的方法进行制备。
方法A:
R6和R7各自为低级烷基,
X为卤素。
在本发明说明书以上和下面的叙述中,本发明范围内所包括的合适实例和各种定义详细说明如下。
除非另有说明,术语“低级的”是指1~6个碳原子。
合适的“低级烷基”可以包括直链或支链的烷基,如甲基、乙基、丙基、异丙基、丁基、叔丁基、戊基、己基等,其中较好的例子可以是C1~C4烷基,最好的例子是甲基。
合适的“芳基”可以包括苯基、甲苯基、二甲苯基、枯烯基、 基、萘基等,其中较好的例子是苯基和萘基。
其中上述芳基可以由1个或多个(最好是1~3个)合适的取代基取代,例如
如下面所述的卤素,例如氯、氟等;
羟基;
如上面所述的低级烷基,例如甲基、叔丁基等;
芳氧基,其中芳基部分如以上所述,例如苯氧基等;
如下面所述的三卤代(低级)烷基,例如三氟甲基等;
如下面所述的低级烷氧基,例如甲氧基等;
如下面所述的单或二(低级)烷氨基,例如二甲氨基等。
上面所述“可以由1个或多个合适取代基取代的芳基”较好的例子有苯基或萘基,苯基或萘基各自可以由1~3个选自以下一组合适的取代基取代:卤素、羟基、C1~C4烷基、苯氧基、三卤素(C1~C4)烷基、C1~C4烷氧基和二(C1~C4)烷氨基,并且更好的例子可以是:
苯基;
单或二或三卤素苯基,如2-(或3-或4)-氟苯基,2,4-(或3,4)二氟苯基,4-氯苯基,3,4-二氯苯基,2-氯-4-氟苯基,2,4,6-三氟苯基等;
单或二(C1~C4)烷基苯基,如间-甲苯基,2,4-(或3,4-或3,5-)二甲苯基等;
〔单或二(C1~C4)烷基〕(卤素)苯基,如4-氟-2-(或3-)甲基苯基,4-氟-3,5-二甲基苯基等;
苯氧基苯基,如4-苯氧基苯基等;
萘基,如2-萘基等;
三卤素(C1~C4)烷基苯基,如3-三氟甲基苯基等;
〔二(C1~C4)烷氨基〕苯基,如4-二甲氨基苯基等;
〔单或二(C1~C4)烷基〕(羟基)苯基,如3,5-二叔丁基-4-羟基苯基等;
〔(C1~C4)烷氧基〕(卤素)苯基,如2-甲氧基-4-氟苯基等。
“可以被一个或几个合适取代基取代的杂环基团”中合适的杂环基团部分,包括含有至少1个杂原子(如氧、硫或氮原子)的不饱和单环或多环杂环基团。
较好的不饱和杂环基团可以是含有硫原子的不饱和三~八元,最好是五~六元杂环,如噻吩基等;
其中上述杂环基团可以由1个或几个,最好是1~3个合适的取代基取代,例如在说明中所提到的“可以由1个或几个合适取代基取代的芳基”。
上面所述“可以由1个或几个合适取代基取代的杂环基团”较好的例子有噻吩基,噻吩基可以由选自C1~C4烷基和卤素的1或2个合适的取代基取代,其中较好的例子是噻吩基、C1~C4烷基噻吩基和卤素噻吩基,最好的例子是5-甲基-2-噻吩基和5-氯-噻吩基。
合适的“受保护的羧基”可以包括酯化的羧基和酰胺化的羧基,其中“酯化的羧基”和“酰胺化的羧基”可以用下面所述的例子表示。
“酯化的羧基”的酯部分的合适例子有例如低级烷基酯(如甲基酯、乙基酯、丙基酯、异丙基酯、丁基酯、异丁基酯、叔丁基酯、戊基酯、己基酯等),它们至少有1个合适的取代基,例如低级链烷酰氧基(低级)烷基酯,如乙酰氧基甲基酯、丙酰氧基甲基酯、丁酰氧基甲基酯、戊酰氧基甲基酯、新戊酰氧基甲基酯、己酰氧基甲基酯、1-(或2-)乙酰氧基乙基酯、1-(或2-或3-)乙酰氧基丙基酯、1-(或2-或3-或4-)乙酰氧基丁基酯、1-(或2-)丙酰氧基乙基酯、1-(或2-或3-)丙酰氧基丙基酯、1-(或2-)丁酰氧基乙基酯、1-(或2-)异丁酰氧基乙基酯、1-(或2-)新戊酰氧基乙基酯、1-(或2-)己酰氧基乙基酯、异丁酰氧基甲基酯、2-乙基丁酰氧基甲基酯、3,3-二甲基丁酰氧基甲基酯、1-(或2-)戊酰氧基乙基酯等;低级链烷磺酰基(低级)烷基酯,如2-甲磺酰基乙基酯等;单(或二或三)卤素(低级)烷基酯,如2-碘乙基酯、2,2,2-三氯乙基酯等;低级烷氧基羰氧基(低级)烷基酯,如甲氧基羰氧基甲基酯、乙氧基羰氧基甲基酯、丙氧基羰氧基甲基酯、叔丁氧基羰氧基甲基酯、1-(或2-)甲氧基羰氧基乙基酯、1-(或2-)乙氧基羰氧基乙基酯、1-(或2-)异丙氧基羰氧基乙基酯等;苯并〔C〕呋喃酮亚基(低级)烷基酯;(5-低级烷基-2-氧-1,3-二氧戊环-4-基)(低级)烷基酯,如(5-甲基-2-氧-1,3-二氧戊环-4-基)甲基酯、(5-乙基-2-氧-1,3-二氧戊环-4-基)甲基酯、(5-丙基-2-氧-1,3-二氧戊环-4-基)乙基酯等;低级链烯基酯,如乙烯基酯、烯丙基酯等;低级炔基酯,如乙炔基酯、丙炔基酯等;至少可以有1个合适取代基的芳基(低级)烷基酯,如苄基酯、4-甲基苄基酯、4-硝基苄基酯、苯乙基酯、三苯甲基酯、二苯甲基酯、双(甲氧基苯基)甲基酯、3,4-二甲氧基苄基酯、4-羟基-3,5-二-叔丁基苄基酯等;至少可以有1个合适取代基的芳基酯,如苯基酯、4-氯苯基酯、甲苯基酯、叔丁基苯基酯、二甲苯基酯、 基酯、枯烯基酯等;2-苯并〔C〕呋喃酮基酯等。
上面所述“酯化的羧基”更好的例子可以是C1~C4烷氧基羰基,最好的例子是甲氧基羰基。
“酰胺化的羧基”合适的例子可以包括下面所述的N-〔芳基(低级)烷基〕甲酰氨基,其中更好的例子是N-〔苯基(C1~C4)烷基〕甲酰氨基,最好的例子是N-(1-苯乙基)甲酰氨基。
合适的“卤素”包括氯、溴、碘和氟,其中对于R4更好的例子是氯和氟,对于X更好的例子是溴。
合适的“三卤素(低级)烷基”可以包括直链或支链的,如三氟甲基、三氟乙基、三氯甲基、三氯乙基等,其中更好的例子是三卤素(C1~C4)烷基,最好的例子是三氟甲基。
合适的“低级烷氧基”可以包括直链或支链的,如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、叔丁氧基、戊氧基、己氧基等,其中更好的例子是C1~C4烷氧基,最好的例子是甲氧基。
合适的“单或二(低级)烷氧基”包括直链或支链的,如甲氨基、二甲氨基、乙氨基、二乙氨基、N-甲基-N-乙氨基、丙氨基、二丙氨基、异丙氨基、丁氨基、戊氨基、己氨基等。所述单或二(低级)烷氨基更好的例子是二(C1~C4)烷氨基,最好的例子是二甲氨基。
合适的“羟基保护基”包括三取代的甲硅烷基,如由低级烷基、芳基和芳基(低级)烷基取代的甲硅烷基,如三甲基甲硅烷基、三乙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基、二异丙基甲基甲硅烷基、三苯基甲硅烷基、三苄基甲硅烷基、叔丁基二苯基甲硅烷基等;酰基,如氨基甲酰基、脂肪族酰基、芳香族酰基、杂环酰基、带有芳香族基团和杂环基团的脂肪族酰基,该酰基系由羧酸、碳酸、磺酸和氨基甲酸衍生得到;其中更好的例子是〔(C1~C4)烷基〕二苯基甲硅烷基,最好的例子是叔丁基二苯基甲硅烷基。
N-〔芳基(低级)烷基〕甲酰胺和“芳基(低级)烷胺”合适的“芳基(低级)烷基”部分,可以是由芳基(如苯基、甲苯基、二甲苯基、枯烯基、 基、萘基等)取代的直链或支链低级烷基,如苯甲基、苯乙基、苯丙基、1-甲基-2-苯基乙基、苯丁基、苯戊基、苯己基等,其中更好的例子是苯基(C1~C4)烷基,最好的例子是1-苯基乙基。
下面详细叙述制备本发明的目的化合物(Ⅰ)的方法:
(1)方法1:
将化合物(Ⅱ)或其盐还原,可以制得化合物(Ⅰ-a)或其盐。
化合物(Ⅰ-a)和(Ⅱ)合适的盐可以与化合物(Ⅰ)的盐相同。
适用于该步脱去保护基反应的还原方法可以包括如下,例如应用金属(如锌、锌汞合金等)或铬化物的盐(如氯化亚铬、乙酸亚铬等)和有机或无机酸(如乙酸、丙酸、盐酸、硫酸等)组成的组合物进行还原反应;在普通的金属催化剂,如钯催化剂(例如海绵状钯、钯黑、氧化钯、钯-碳、胶态钯、钯-硫酸钡、钯-碳酸钡、氢氧化钯-碳等),镍催化剂(例如还原镍、氧化镍、阮内镍等),铂催化剂(例如铂片、海绵状铂、铂黑、胶态铂、氧化铂、铂丝等),硼氢化钠,三(低级)烷基甲硼烷与硼氢化钠的组合物等存在下进行常规的催化还原,其中更好的方法是应用三(低级)烷基甲硼烷和硼氢化钠的组合物。
该步反应通常在对反应无有害影响的一般溶液中进行,常用的一般溶剂有水、醇(如甲醇、乙醇、丙醇等)、二噁烷、四氢呋喃、乙酸、缓冲溶液(如磷酸盐缓冲液、乙酸盐缓冲液等)及其类似物,或者为它们的混合溶剂。
反应温度不是严格的,反应通常可以在冷却至温热条件下进行。
(2)方法2:
使化合物(Ⅰ-b)或其盐脱去R5 a上的羧基保护基,可以制得化合物(Ⅰ-C)或其盐。
化合物(Ⅰ-C)合适的盐可以与化合物(Ⅰ)的盐相同。
化合物(Ⅰ-b)合适的盐可以是与例如化合物(Ⅰ)成盐中所用的酸生成的盐。
本反应通常可以用普通的方法(如水解、还原等)完成。
(1)水解:
最好在碱或酸存在下进行水解。合适的碱包括碱金属氢氧化物(如氢氧化钠、氢氧化钾等),碱土金属氢氧化物(如氢氧化镁、氢氧化钙等),碱金属氢化物(如氢化钠、氢化钾等),碱土金属氢化物(如氢化钙等),碱金属醇盐(如甲醇钠、乙醇钠、叔丁醇钾等),碱金属碳酸盐(如碳酸钠、碳酸钾等),碱土金属碳酸盐(如碳酸镁、碳酸钙等),碱金属碳酸氢盐(如碳酸氢钠、碳酸氢钾等)及其类似物。
合适的酸包括有机酸,如甲酸、乙酸、丙酸、三氟乙酸、苯磺酸、对甲苯磺酸等,无机酸,如盐酸,氢溴酸,硫酸,磷酸等,应用三氟乙酸进行酸性水解时,加入阳离子捕集剂(如苯酚、苯甲醚等)通常可以使酸性水解加速。
在羟基保护基是三(低级)烷基甲硅烷基时,可以在三(低级)烷基卤化铵(如三丁基氟化铵等)存在下进行水解。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有例如水、二氯甲烷、醇(如甲醇、乙醇等)、四氢呋喃、二噁烷、丙酮等或它们的混合溶剂。液体的碱或酸也可以用作为溶剂。
反应温度不是严格的,反应通常在从冷却到加热条件下进行。
(2)还原:
适用于该步脱去保护基反应的还原方法包括如下,例如用金属(如锌、锌汞合金等)或铬化合物的盐(如氯化亚铬、乙酸亚铬等)和有机酸或无机酸(如乙酸、丙酸、盐酸、硫酸等)组成的组合物进行还原反应;在普通的金属催化剂,如钯催化剂(例如海绵状钯、钯黑、氧化钯、钯碳、胶态钯、钯硫酸钡、钯-碳酸钡、氢氧化钯-碳等),镍催化剂(如还原镍、氧化镍、阮内镍等),铂催化剂(如铂片、海绵状铂、铂-黑、胶态铂、氧化铂、铂丝等)及其类似物存在下进行常规的催化还原。
该步反应通常在对反应无有害影响的一般溶剂中进行,常用的溶剂有水、醇(如甲醇、乙醇、丙醇等)、二噁烷、四氢呋喃、乙酸、缓冲溶液(如磷酸盐缓冲液、乙酸盐缓冲液等)及其类似物,或者为它们的混合溶剂。
反应温度不是严格的,反应通常在冷却至温热条件下进行。
在羧基保护基为烯丙基时,可以应用钯化合物通过氢解进行去保护。
用于该反应合适的钯化合物可以是钯-碳、氢氧化钯-碳、氯化钯、钯-配位体复合物(如四(三苯基膦)钯(O),双(二亚苄基丙酮)钯(O),二〔1,2-双(二苯基膦)乙烷〕钯(O),四(亚磷酸三苯基酯)钯(O),四(亚磷酸三乙基酯)钯(O)等)。
反应最好在应有的烯丙基消除剂存在下进行,烯丙基消除剂有例如胺(如吗啉、N-甲基苯胺等),活性亚甲基化合物(如双甲酮、乙酸苯酰、2-甲基-3-氧戊酸等),氰醇化合物(如α-四氢吡喃基氧基苄基氰等),低级链烷酸或其盐(如甲酸、乙酸、甲酸铵、乙酸钠等),N-羟基琥珀酰亚胺等。
该步反应可以在碱如低级烷基胺(如丁胺、三乙胺等)、吡啶等存在下进行。
当在该步反应中应用钯-配位体复合物时,反应最好在相应的配位体(如三苯基膦、亚磷酸三苯基酯、亚磷酸三乙基酯等)存在下进行。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有水、甲醇、乙醇、丙醇、二噁烷、四氢呋喃、乙腈、氯仿、二氯甲烷、二氯乙烷、乙酸乙酯等,或者它们的混合溶剂。
按照需要脱去的羧基保护基的种类,选择脱去保护基的反应。
(3)方法3:
使化合物(Ⅰ-c)或其盐环合,可以制得化合物(Ⅰ-d)或其盐。
化合物(Ⅰ-d)合适的盐可以与化合物(Ⅰ-b)的盐相同。
该步反应通常用常规的方法(如加热)进行,或者在缩合剂存在下进行。
较好的缩合剂有例如碳化二亚胺化合物或其盐,如N,N′-二乙基碳化二亚胺、N,N′-二异丙基碳化二亚胺,N,N′-二环己基碳化二亚胺、N-环己基-N′-吗啉代乙基碳化二亚胺、N-环己基-N′-(4-二乙基-氨基环己基)碳化二亚胺、N-乙基-N′-(3-二甲氨基丙基)碳化二亚胺或其盐酸盐等;N,N′-羰基二咪唑,N,N′-羰基双(2-甲基咪唑);烯酮亚胺化合物,如五亚甲基烯酮-N-环己基亚胺、二苯基烯酮-N-环己基亚胺等;乙氧基乙炔;1-烷氧基-1-氯乙烯;聚磷酸乙酯;聚磷酸异丙酯;磷酰氯;三氯化磷;亚硫酰氯;草酰氯;三苯基膦与四氯化碳或二氮烯二羧酸酯的组合物;2-乙基-7-羟基苯并异噁唑鎓盐;2-乙基-5-(间-磺苯基)-异噁唑鎓氢氧化物分子内盐;1-(对-氯苯磺酰氧基)-6-氯-1H-苯并三唑;1-羟基苯并三唑;由N,N-二甲基甲酰胺与亚硫酰氯、光气、磷酰氯等反应制得的所谓Vilsmeier试剂等。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有二氯甲烷、甲醇、乙醇、丙醇、乙腈、吡啶、N,N-二甲基甲酰胺、4-甲基-2-戊酮、四氢呋喃、苯、甲苯、二甲苯等,或它们的混合溶剂。
该步反应的反应温度不是严格的,反应通常在冷却至加热条件下进行。
(4)方法4:
将化合物(Ⅰ-e)或其盐还原,可以制得化合物(Ⅰ-f)或其盐。
化合物(Ⅰ-e)和(Ⅰ-f)合适的盐可以与化合物(Ⅰ)的盐相同。
还原方法和反应条件(如反应温度、溶剂等)与以上方法(2)所述脱去化合物(Ⅰ-b)的羧基保护基的反应实质上是相同的,因此可以参照以上的叙述。
(5)方法5:
将羟基保护基引入化合物(Ⅰ-a)或其盐中,可以制得化合物(Ⅰ-g)或其盐。
化合物(Ⅰ-g)合适的盐可以与化合物(Ⅰ)的盐相同。
用于该步反应合适的羟基保护基引入剂可以是普通的甲硅烷基化剂(如以上“羟基保护基”所述,它能够引入三取代的甲硅烷基,如三取代的甲硅烷基卤化物,例如三取代的甲硅烷基氯等);酰化剂(如以上“羟基保护基”所述,它能够引入酰基,如羧酸、碳酸、磺酸及其反应衍生物,例如酰卤、酸酐、活性酰胺、活性酯等)及其类似物。
(6)方法6:
将化合物(Ⅰ-h)或其盐氧化,可以制得化合物(Ⅰ-i)或其盐。
化合物(Ⅰ-h)和(Ⅰ-i)合适的盐可以与化合物(Ⅰ)的盐相同。
用于该步反应中甲酰基的合适氧化剂是能够使硫基转变成亚磺酰基或磺酰基的普通氧化剂,例如高锰酸钾,铬化合物(如三氧化铬、铬酸、铬酸钠、重铬酸、重铬酸钠、重铬酸吡啶鎓等),卤素过苯甲酸(如间-氯过苯甲酸等)及其类似物。
反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有例如水、丙酮、二噁烷、二甲基甲酰胺、二氯甲烷、吡啶等,或者为它们的混合溶剂。
反应温度不是严格的,反应通常在冷却至温热条件下进行。
(7)方法7:
使化合物(Ⅰ-j)或其盐进行脱去保护反应(脱去羟基保护基Ra 6),可以制得化合物(Ⅰ-a)或其盐。
化合物(Ⅰ-j)合适的盐可以与化合物(Ⅰ)的盐相同。
反应通常用常规的方法(如水解、还原等)进行。
水解和还原的方法以及反应条件(如反应温度、溶剂等)与以上方法2所述脱去化合物(Ⅰ-b)羧基保护基的反应实质上是相同的,因此可以参照以上所述。
在羟基保护基是三取代的甲硅烷基时,脱去该保护基的反应还可以在四(低级)烷基氟化铵(如四丁基氟化铵等)存在下进行。
(8)方法8:
使化合物(Ⅰ-k)或其盐与芳基(低级)烷基胺或其盐反应,可以制得化合物(Ⅰ-l)或其盐。
化合物(Ⅰ-k)和(Ⅰ-l)合适的盐可以与化合物(Ⅰ-b)的盐相同。
芳基(低级)烷基胺合适的盐可以与化合物(Ⅰ-b)的盐相同。
通常在有或者没有对反应无有害影响的普通溶剂如水、醇(例如甲醇、乙醇、丙醇等)、二噁烷、四氢呋喃、苯、甲苯、二甲苯等,或它们的混合溶剂存在下,通过加热化合物(Ⅰ-k)和芳基(低级)烷基胺进行该步反应。
反应温度不是严格的,反应通常在温热至加热条件下进行。
在具有光学活性的苯基(低级)烷基胺用于该步反应时,可以通过普通的方法(例如萃取、沉淀、分级结晶、重结晶、层析、高效液相色谱等)将目的化合物(Ⅰ-b)的非对映体进行分离,以便得到具有光学活性的非对映体。
(9)方法9:
使化合物(Ⅰ-l)或其盐的N-〔芳基(低级)烷基〕甲酰氨基R5 c进行水解,可以制得化合物(Ⅰ-c)或其盐。
水解的方法和反应条件(如反应温度、溶剂等)与以上方法2中所述脱去化合物(Ⅰ-b)的羧基保护基的反应实质上是相同的,因此可以参照以上所述。
按方法1~9得到的目的化合物(Ⅰ)可以用常规的方法例如萃取、沉淀、分级结晶、重结晶、层析高效液相色谱法等进行分离和纯化。
下面详细叙述制备新的起始化合物(Ⅱ)或其盐的方法A~D。
(A)方法A
使化合物(Ⅲ)或其盐与化合物(Ⅳ)反应,可以制得化合物(Ⅴ)。
化合物(Ⅲ)合适的盐可以与化合物(Ⅰ)的盐相同。
该方法中某些起始化合物(Ⅲ)是新的化合物,可以按照已知的方法(如J.Org.Chem.27,4713(1962)等)制备。
该步反应可以在碱,如方法2中所述碱的存在下进行。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有二氯甲烷、甲醇、乙醇、丙醇、吡啶、N,N-二甲基甲酰胺、4-甲基-2-戊酮、四氢呋喃等,或者它们的混合溶剂。
反应温度不是严格的,反应通常在温热至加热条件下进行。
(B)方法B
使化合物(Ⅴ)环合,可以制得化合物(Ⅵ)。
该步反应通常在(称为)路易斯酸的存在下进行,路易斯酸有例如卤化锌(如氯化锌等)、三卤化硼(如三氯化硼、三氟化硼等)、四卤化钛(如四氯化钛、四溴化钛等)、四卤化锡(如四氯化锡、四溴化锡等)、卤化铝(如氯化铝、溴化铝等)、三卤乙酸(如三氯乙酸、三氟乙酸等),其中卤化锌是较好的。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有二氯甲烷、甲醇、乙醇、丙醇、吡啶、N,N-二甲基甲酰胺、4-甲基-2-戊酮、四氢呋喃等,或者是它们的混合溶剂。
反应温度不是严格的,反应通常在温热至加热条件下进行。
(C)方法C
在三卤氧化磷存在下使化合物(Ⅵ)与化合物(Ⅶ)反应,可以制得化合物(Ⅷ)。
用于该步反应较好的三卤氧化磷可以是磷酰氯等。
该步反应通常在对反应无有害影响的普通溶剂中进行,常用的溶剂有二氯甲烷、甲醇、乙醇、丙醇、乙腈、吡啶、N,N-二甲基甲酰胺、4-甲基-2-戊酮、四氢呋喃等,或者是它们的混合溶剂。
反应温度不是严格的,反应通常在冷却至加热条件下进行。
(D)方法D
使化合物(Ⅷ)与化合物(Ⅸ)或其盐反应,可以制得化合物(Ⅱ)或其盐。
该步反应可以在碱存在下进行,所用的碱有碱金属氢氧化物(如氢氧化钠、氢氧化钾等碱土金属氢氧化钠(如氢氧化镁、氢氧化钙等),碱金属氢化物(如氢化钠、氢化钾等),碱土金属氢化物(如氢化钙等),碱金属醇盐(如甲醇钠、乙醇钠、叔丁醇钾等),碱金属碳酸盐(如碳酸钠、碳酸钾等),碱土金属碳酸盐(如碳酸镁、碳酸钙等),碱金属碳酸氢盐(如碳酸氢钠、碳酸氢钾等),低级烷基锂(如正丁基锂等),及其类似物,其中应用碱金属氢化物和低级烷基锂是较好的。
反应通常在对反应无有害影响的溶剂中进行,常用的溶剂有二氯甲烷、甲醇、乙醇、丙醇、吡啶、N,N-二甲基甲酰胺、4-甲基-2-戊酮、四氢呋喃、己烷等,或是它们的混合溶剂。
反应温度不是严格的,反应通常在冷却至温热条件下进行。
本发明的目的化合物及其药学上适用的盐是有效的HMG-CoA抑制剂,可以降低血清胆甾醇浓度和血脂浓度,因此尤其可用作胆甾醇生物合成的抑制剂。
在本发明中,具有更有效作用的目的化合物(Ⅰ)或其药学上适用的盐可以用下式表示,
Za为下式
根据J.Med.Chem.29,170(1986)的X-衍射结晶学类推,可以预计(3R,5S)-化合物可能是活性最高的化合物。
为了表明目的化合物(Ⅰ)的用途,下面叙述本发明化合物(Ⅰ)的代表性化合物抑制HMG-CoA作用和抑制胆甾醇生物合成作用的试验数据。试验化合物
(A)化合物A:实例2-25化合物
(B)化合物B:实例13-2化合物
(1)试验1〔对大鼠肝3-羟基-3-甲基戊二酰辅酶A还原酶活性影响的试验(在体外)〕
试验1方法:
将从大鼠肝微粒体溶出并经第二次硫酸铵沉淀步骤纯化的3-羟基-3-甲基-戊二酰辅酶A还原酶溶液5μl,加到35μl反应混合液中,该反应混合液中含有1.11KBq(=0.03μci)3-羟基-3-甲基〔3-14C〕戊二酰辅酶A,100mM磷酸钾缓冲液,PH7.4,10mM乙二胺四乙酸(EDTA),10mM二硫苏糖醇,并含或不含不同浓度的试验化合物。加入10μl 25mM还原型β-烟酰胺腺嘌嘌吟磷酸二核苷酸(NADPH)使反应开始。将反应混合液置于37℃孵育20分钟。加入10μl 2N盐酸终止反应。于37℃继续保温15分钟后,从反应液中取出20μl等分试样加到硅胶板上(60F-254Merck公司产品)。以苯/丙酮(1∶1)为展开剂进行层析分离。将薄板上分布有麦沃内酯的各部分刮下来,并作放射性计数。
试验1结果:
试验化合物 | 半数抑制浓度(μg/ml) |
化合物A化合物B | 0.0250.012 |
(2)试验2〔对大鼠甾醇合成影响的试验(体内试验)〕
试验2方法:
用插管灌饲法给雄性SD品系大鼠口服试验化合物。灌服化合物后1小时,给大鼠腹腔注射剂量为3.7MBq/kg(=100μci/kg)的〔1-MC〕乙酸钠。50分钟后在短暂乙醚麻醉下,作心脏穿刺取血样2.5ml。离心分离出的血浆进行水解,并用石油醚抽提非皂化脂类。以毛地黄皂苷化物形式从这些提取物中分离出甾醇,溶于1ml甲醇中,并作放射性计数。
试验2结果:
试验化合物 | 剂量(mg/kg) | 抑制百分率(%) |
化合物A | 10.0 | 95.7 |
为了治疗给药,本发明的目的化合物(Ⅰ)及其药学上适用的盐,可以按普通的药物制剂形式应用,该制剂中含有上述化合物作为有效成分,并与药学上适用的载体进行混合,合适的载体有例如适用于口服、非经胃肠道给药和外用剂型的有机或无机的固体或液体赋形剂。
药物制剂可以是固体形式,如片剂、颗粒剂、粉剂、胶囊剂,或为液体形式,如溶液、混悬液、糖浆、乳剂、柠檬汁等。
如果需要,可以将辅助剂、稳定剂、湿润剂和其他常用的添加剂,如乳糖、硬脂酸、硬脂酸镁、石膏粉、蔗糖、玉米淀粉、滑石、明胶、琼脂、果胶、花生油、橄榄油、可可脂、乙二醇、酒石酸、柠檬酸、富马酸等包括在上述制剂中。
化合物(Ⅰ)的剂量可以不同,这主要取决于患者的年龄、病情、疾病的种类、所应用的化合物(Ⅰ)的种类等。一般来讲,患者每天应用的剂量约为0.1mg~约1000mg或以上,最好为1mg~200mg。本发明目的化合物(Ⅰ)的平均单次剂量约为0.1mg、1mg、10mg、20mg、30mg、50mg、100mg、200mg、250mg,可以用于治疗血胆甾醇过多和血脂蛋白过多症及有关的疾病。
下面叙述制备例和实例,以便详细地说明本发明。
制备例1-1)
将2,2-二甲基-1,2,3,4-四氢喹啉(4.69g)和2-溴-4′-氟苯乙酮(3.17g)在无水N,N-二甲基甲酰胺(6ml)中的混合物,在氮气流和搅拌下,于70~80℃加热5小时。将反应混合物倒入冰水(50ml)中。生成的胶状产物与乙醚一起研磨,得淡黄色结晶。收集结晶并用甲醇洗涤,得到N-(4-氟苯甲酰基甲基)-2,2-二甲基-1,2,3,4-四氢喹啉(3.7g)。
MS(m/e):297(M+)
NMR(CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6Hz),2.83(2H,t,J=6Hz),4.68(2H,s),6.06(1H,d,J=8Hz),6.57(1H,t,J=8Hz),6.9-7.01(2H,m),7.12-7.25(2H,m),7.99-8.13(2H,m)
按制备例1-1)基本上相同的方法制备表A化合物。
*该反应在N,N-二异丙基-N-乙胺存在下进行。
表A化合物的物理化学数据
产物的制备例号 数据
1-2) IR(薄膜):1710,1600,1495,1325,1070,740cm-1
NMR(90MHz,CDCl3,δ):1.26(6H,s),1.90(2H,t,J=6Hz),2.43(3H,s),2.83(2H,t,J=6Hz),4.68(2H,s),6.07(1H,d,J=8Hz),6.58(1H,m),6.82-7.07(2H,m),7.33-7.49(2H,m),7.7-7.93(2H,m)
1-3) IR(薄膜):2940,1700,1600,1500cm-1
NMR(200MHz,CDCl3,δ):1.17(3H,d, J=6.4Hz),1.7-2.2(2H,m),2.7-3.0(2H,m),3.5-3.6(1H,m),4.55(1H,d,J=18.0Hz),4.78(1H,d,J=18.0Hz),6.2-8.1(8H,m)
1-4) IR(薄膜):2940,1700,1600,1580,1490,1460,1360,1310,1235,1210,1160,1110,980,860,810,740cm-1
NMR(200MHz,CDCl3,δ):1.24(6H,s),1.91(2H,t,J=6.7Hz),2.51(3H,s),2.82(2H,t,J=6.7Hz),4.54(2H,s),6.11(1H,d,J=8.0Hz),6.5-6.7(1H,m),6.9-7.1(4H,m),7.7-7.9(1H,m)
1-5) IR(薄膜):2940,1695,1605,1490cm-1
NMR(200MHz,CDCl3,δ):1.25(6H,s),1.69(2H,t,J=6.7Hz),2.40(6H,s),2.83(2H,t,J=6.7Hz),4.69(2H,s),6.0-7.7(7H,m)
1-6) IR(薄膜):2970,2940,1700,1600,1490cm-1
NMR(200MHz,CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6.7Hz),2.33(6H,s),2.83(2H,t),4.66(2H,s),6.06(1H,d,J=8.1Hz),6.57(1H,t,J=8Hz),6.8-7.0(2H,m),7.75(1H,d,J=6.9Hz)
1-7) mp:110-120℃
IR(液体石蜡):1680,1600cm-1
NMR(200MHz,CDCl3,δ):1.29(6H,s),1.95(2H,t,J=6.7Hz),2.85(2H,t,J=6.7Hz),4.86(2H,s),6.14(1H,d,J=8.0Hz),6.61(1H,t,J=8.0Hz),6.8-7.0(2H,m),7.5-7.7(2H,m),7.8-8.2(4H,m),8.61(1H,s)
1-8) IR(纯的):2920,1690,1600,735cm-1
NMR(CDCl3,δ):1.30(6H,s),1.92(2H,t,J=7.5Hz),2.85(2H,t,J=7.5Hz),4.70(2H,s),6.08(1H,d,J=8Hz),6.61(1H,t,J=8.7Hz),6.8-7.1(2H,m),7.5-8.5(4H,m)
1-9) IR(液体石蜡),1680,1235,740cm-1
NMR(200MHz,CDCl3,δ):1.26(6H,s),1.92(2H,t,J=6Hz),2.53(3H,s),2.83(2H,t,J=6Hz),4.48(2H,s),6.24(1H,d,J=8Hz),6.60(1H,d,J=6Hz),6.81(1H,d,J=4Hz),6.92-7.01(2H,m),7.75(1H,d,J=4Hz)
1-10) IR(液体石蜡):1690,1605,1490,1240,1165,740cm-1
NMR(200MHz,CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6Hz),2.35(6H,s),2.83(2H,t,J=6Hz),4.69(2H,s),6.08(1H,d,J=8Hz),6.56(1H,t,J=7Hz),6.88-6.99(2H,m),7.26(1H,d,J=6Hz),7.81(1H,d,J=6Hz),7.83(1H,s)
1-11) IR(液体石蜡):1710,1600,1460,1200,740cm-1
NMR(200MHz,CDCl3,δ):1.24(6H,s),1.91(2H,t,J=6Hz),2.83(2H,t,J=6Hz),4.65(2H,s),6.03(1H,d,J=8Hz),6.59(1H,t,J=6Hz),6.91-7.01(2H,m),7.59(1H,d,J=8Hz),7.89(1H,dd,J=2Hz,8Hz),8.14(1H,d,J=2Hz)
1-12) IR(液体石蜡):1700,1490,1250,1160,735cm-1
NMR(200MHz,CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6Hz),2.83(2H,t,J=6Hz),4.69(2H,s),6.06(1H,d,J=8Hz),6.55(1H,t,J=7Hz),6.91-7.01(2H,m),7.31-7.37(1H,m),7.48-7.53(1H,m),7.70-7.88(2H,m)
1-13) IR(液体石蜡):1700,1612,1195,1160,732cm-1
NMR(CDCl3,δ):1.25(6H,s),1.91(2H,t,J=6.5Hz),2.82(2H,t,J=6.5Hz),4.59(2H,s),6.05(1H,d,J=8.1Hz),6.58(1H,t,J=7.2Hz),6.89-7.07(4H,m),8.01(1H,m)
1-14) mp:92-103℃
IR(液体石蜡):1693,1494,1155,1128,740cm-1
NMR(CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6.5Hz),2.35(3H,s),2.83(2H,t,J=6.5Hz),4.67(2H,s),6.06(1H,d,J=8.0Hz),6.57(1H,t,J=6.8Hz),6.89-7.16(3H,m),7.86-7.94(2H,m)
1-15) mp:88-93℃
IR(液体石蜡):1698,1587,1490,739cm-1
NMR(CDCl3,δ):1.24(6H,s),1.91(2H,t,J=6.5Hz),2.83(2H,t,J=6.5Hz),4.68(2H,s),6.05(1H,d,J=8.1Hz),6.58(1H,t,J=7.7Hz),6.95(2H,m),7.49(2H,d,J=8.6Hz),8.00(2H,d,J=8.6Hz)
1-16) IR(纯的):1702,1610,1160,739cm-1
NMR(CDCl3,δ):1.25(6H,s),1.91(2H,t,J=6.5Hz),2.83(2H,t,J=6.5Hz),4.63(2H,s),6.08(1H,d,J=8.2Hz),6.56(1H,m),6.91-7.33(4H,m),7.58(1H,m),7.94(1H,m)
1-17) IR(纯的):1705,1605,1155,740cm-1
NMR(CDCl3,δ):1.24(6H,s),1.92(2H,t,J=6.5Hz),2.83(2H,t,J=6.5Hz),4.66(2H,s),6.04(1H,d,J=8.1Hz),6.59(1H,t,J=7.7Hz),6.90-7.36(3H,m),7.82-7.95(2H,m)
1-18) IR(液体石蜡):1700,1600,1580,1220,749cm-1
NMR(CDCl3,δ):1.25(6H,s),1.91(2H,t,J=6.5Hz),2.83(2H,t,J=6.5Hz),4.68(2H,s),6.09(1H,d,J=8.2Hz),6.57(1H,t,J=8Hz),6.90-7.45(9H,m),8.05(2H,d,J=10Hz)
1-19) IR(薄膜):1695,1605,740cm-1
NMR(CDCl3,δ):1.25(6H,s),1.91(2H,t,J=6.5Hz),2.37(3H,s),2.50(3H,s),2.82(2H,t,J=6.5Hz),4.56(2H,s),6.11(1H,d,J=8Hz),6.5-7.2(5H,m),7.94(1H,d,J=8Hz)
1-20) 质谱m/e:269(M+),146
NMR(CDCl3,δ):2.00(2H,m),2.81(2H,m),3.36(2H,m),4.63(2H,s),6.29(1H,d,J=8Hz),6.58(1H,t,J=6.8Hz),6.9-7.2(4H,m),7.98(2H,m)
1-21) mp:114-115℃
1-22) mp:104-107℃
IR(液体石蜡):1690,1608,1510,745cm-1
NMR(CDCl3,δ):2.02(2H,m),2.33(6H,s),2.82(2H,t,J=6.3Hz),3.39(2H,t,J=5.7Hz),4.66(2H,s),6.29(1H,d,J=8.0Hz),6.57(1H,t,J=7.3Hz),6.94(2H,m),7.23(1H,d,J=6.0Hz),7.74(1H,d,J=9.3Hz),7.76(1H,s)
1-23) mp:105-107℃
IR(液体石蜡):1702,1600,1580,745cm-1
NMR(CDCl3,δ):2.02(2H,m),2.82(2H,t,J=6.4Hz),3.37(2H,t,J=5.7Hz),4.62(2H,s),6.27(1H,d,J=7.9Hz),6.61(1H,t,J=7.3Hz),6.96(2H,m),7.44(1H,d,J=8.3Hz),7.81(1H,d,J=8.5Hz),8.06(1H,s)
1-24) mp:77.0-78.5℃
IR(液体石蜡):1690,1600,1160,1114,738cm-1
NMR(CDCl3,δ):2.02(2H,m),2.33(3H,s),2.83(2H,t,J=6.3Hz),3.38(2H,t,J=5.7Hz),4.65(2H,s),6.28(1H,d,J=7.9Hz),6.59(1H,t,J=7.0Hz),6.91-7.13(3H,m),7.86(2H,m)
1-25) IR(薄膜):1690,1605,1595,1280,835,740cm-1
NMR(200MHz,CDCl3,δ):1.24(6H,s),1.90(2H,t,J=6Hz),2.81(2H,t,J=6Hz),3.96(3H,s),4.62(2H,s),6.08-7.9(6H,m)
1-26) IR(薄膜):1710,1640,1600,740cm-1
NMR(200MHz,CDCl3,δ):1.24(6H,s),1.89(2H,t,J=6Hz),2.81(2H,t,J=6Hz),4.47(2H,s),6.2-7.1(5H,m)
1-27) NMR(CDCl3,δ):1.23(6H,s),1.89(2H,t,J=6Hz),2.21(3H,s),2.80(2H,t,J=6Hz),4.65(2H,s),5.98(1H,d,J=10Hz),6.8-7.2(4H,m),8.10(2H,m)
1-28) NMR(CDCl3,δ):1.25(6H,s),1.87(2H,t,J=6.3Hz),2.78(2H,t,J=6.3Hz),4.65(2H,s),5.95(1H,d,J=9.0Hz),6.7-7.3(4H,m),7.9-8.3(2H,m)
1-29) NMR(CDCl3,δ):1.23(6H,s),1.90(2H,t,J=6Hz),2.80(2H,t,J=6Hz),4.65(2H,s),5.95(1H,m),6.3-6.7(2H,m),7.1-7.2(2H,m),8.0-8.1(2H,m)
1-30) mp:121-124℃
IR(液体石蜡):1703,1602,1500,738cm-1
NMR(CDCl3,δ):1.25(6H,s),1.92(2H,t,J=6.5Hz),2.83(2H,t,J=6.5Hz),4.72(2H,s),6.09(1H,d,J=8.2Hz),6.57(1H,t,J=7.3Hz),6.90-7.00(2H,m),7.47-7.66(3H,m),8.04-8.08(2H,m)
1-31) mp:172-177℃
IR(液体石蜡):1676,1600,1188,743cm-1
NMR(CDCl3,δ):1.16(6H,s),1.83(2H,t,J=6.6Hz),2.73(2H,t,J=6.1Hz),2.97(6H,s),4.53(2H,s),6.04(1H,d,J=7.8Hz),6.30-7.00(5H,m),7.92(2H,d,J=8.4Hz)
1-32) IR(液体石蜡):1690,1600,1505cm-1
NMR(CDCl3,δ):3.43(2H,t,J=5Hz),4.28(2H,t,J=5Hz),6.3-6.9(4H,m),7.13(2H,t,J=8Hz),8.00(2H,dd,J=6 and 8Hz)
1-33) IR(液体石蜡):1695,1600cm-1
NMR(CDCl3,δ):3.10(2H,t,J=5.2Hz),3.72(2H,t,J=5.2Hz),4.72(2H,s),6.32(1H,d,J=8.2Hz),6.63(1H,t,J=8.2Hz),6.90(1H,t,J=8.2Hz),7.06-7.26(3H,m),8.00-8.07(2H,m)
1-34) IR(纯的):1710,1600,1220,740cm-1
NMR(CDCl3,δ):1.23(6H,s),1.87(2H,t,J=6.5Hz),2.80(2H,t,J=6.5Hz),4.58(2H,s),6.20(1H,d,J=8.3Hz),6.62(1H,t,J=6.8Hz),7.01-7.55(5H,m)
1-35) mp:95-98℃
IR(液体石蜡):1690,1598,1227,1154,737cm-1
NMR(CDCl3,δ):1.37(6H,s),4.69(2H,s),5.41(1H,d,J=9.8Hz),5.99(1H,d,J=8.1Hz),6.28(1H,d,J=9.8Hz),6.54(1H,t,J=7.3Hz),6.85-6.95(2H,m),7.18(2H,t,J=8.7Hz),8.05-8.14(2H,m)
1-36) mp:78-83℃
IR(液体石蜡):1679,1603,1280,1155,750cm-1
NMR(CDCl3,δ):2.00(2H,quintet,J=5.8Hz),2.81(2H,t,J=6.3Hz),3.39(2H,t,J=5.7Hz),3.95(3H,s),4.60(2H,s),6.26(1H,d,J=7.8Hz),6.52-7.06(5H,m),7.85(1H,m)
1-37) IR(纯的):3620,2940,1690,1600,1490cm-1
NMR(CDCl3,δ):1.26(6H,s),1.49(18H,s),1.91(2H,t,J=6.7Hz),2.83(2H,t,J=6.7Hz),4.68(2H,s),5.77(1H,s),6.12(1H,d,J=7.8Hz),6.5-7.0(3H,m),7.95(2H,s)
1-38) mp:74-84℃
IR(液体石蜡):1700,1600cm-1
NMR(CDCl3,δ):1.25(6H,s),1.75(2H,t,J=6.8Hz),2.83(2H,t,J=6.8Hz),3.87(3H,s),4.71(2H,s),6.09(1H,d,J=8.0Hz),6.57(1H,t,J=7.3Hz),6.9-7.0(2H,m),7.16(1H,m),7.42(1H,t,J=8.0Hz),7.57(1H,t,J=1.5Hz),7.66(1H,d,J=7.3Hz)
1-39) IR(薄膜):1675,1410,1220,1010,745cm-1
NMR(200MHz,CDCl3,δ):1.26(6H,s),1.95(2H,t,J=6Hz),2.85(2H,t,J=6Hz),4.38(2H,s),6.26(1H,d,J=8Hz),6.65(1H,t,J=7Hz),6.94-7.04(3H,m),7.74(1H,d,J=4Hz)
制备例 2-1)
将N-(4-氟苯甲酰基甲基)-2,2-二甲基-1,2,3,4-四氢喹啉(3.96g)和氯化锌(12.7g)在无水乙醇(20ml)中的混合物回流1.5小时。反应混合物倒入冷的2N盐酸溶液(50ml)中,并用乙酸乙酯萃取。萃取液用饱和碳酸氢钠水溶液洗涤,并过滤。滤液在减压下蒸发。残余物经硅胶(40g)柱层析,用正己烷和乙酸乙酯(20∶1,V/V)的混合液洗脱。收集含目的化合物的部分,并在减压下浓缩,得到5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉(3.72g),为无色糖浆状物。
IR(纯的):1540,1450,1220,1185,745cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6Hz),3.05(2H,t,J=6Hz),6.97-7.24(4H,m),7.39(1H,s),7.59-7.71(3H,m)
MS(m/e):279(M+)
按制备例2-1)基本上相同的方法制备表B化合物。
表B化合物的物理化学数据
产物的制备例号 数据
2-2) IR(薄膜):1610,1450,1180,745cm-1
NMR(200MHz,CDCl3,δ):1.57(6H,s),2.08(2H,t,J=6Hz),2.42(3H,s),3.06(2H,t,J=6Hz),6.97-7.78(8H,m)
2-3) IR(薄膜):3050,2980,2940,1615,1540,1500cm-1
NMR(200MHz,CDCl3,δ):1.58(3H,d,J=6.5Hz),1.9-2.4(2H,m),3.04(2H,t,J=6.1Hz),4.2-4.5(1H,m),6.97(1H,d,J=7.0Hz),7.0-7.2(3H,m),7.32(1H,s),7.5-7.7(3H,m)
2-4) IR(薄膜):3050,2980,2940,1615,1585,1540cm-1
NMR(200MHz,CDCl3,δ):1.56(6H,s),2.0-2.2(2H,m),2.33(3H,s),3.07(2H,t,J=6.5Hz),6.8-7.4(7H,m)
2-5) IR(液体石蜡):1600,1530cm-1
NMR(200MHz,CDCl3,δ):1.56(6H,s),2.07(2H,t,J=6.5Hz),2.38(6H,s),3.05(2H,t,J=6.5Hz),6.89(1H,s),6.98(1H,d,J=7.0Hz),7.10(1H,t,J=7.0Hz),7.32(2H,s),7.43(1H,s),7.77(1H,d,J=7.0Hz)
2-6) IR(薄膜):3050,2980,2940,1615,1535cm-1
NMR(200MHz,CDCl3,δ):1.55(6H,s),2.07(2H,t,J=6.2Hz),2.32(6H,d,J=2.1Hz),3.05(2H,t,J=6.2Hz),6.98(1H,d,J=7.0Hz),7.10(1H,t,J=7.0Hz),7.30(2H,d,J=6.9Hz),7.36(1H,s),7.70(1H,d,J=7.0Hz)
2-7) IR(薄膜):3050,2980,2940,1630,1600,1530cm-1
NMR(200MHz,CDCl3,δ):1.59(6H,s),2.10(2H,t,J=4.9Hz),3.07(2H,t,J=4.9Hz),7.02(1H,d,J=7.0Hz),7.1-7.5(4H,m),7.57(1H,s),7.8-8.0(4H,m),8.15(1H,s)
2-8) IR(纯的):2970,1613,1535,745cm-1
NMR(CDCl3,δ):1.58(6H,s),2.09(2H,t,J=6Hz),3.06(2H,t,J=6Hz),7.0-7.2(2H,m),7.4-7.6(3H,m),7.7-7.9(3H,m)
2-9) IR(薄膜):1670,1445,1180,785,740cm-1
NMR(200MHz,CDCl3,δ):1.54(6H,s),2.06(2H,t,J=6Hz),2.51(3H,s),3.03(2H,t,J=6Hz),6.72(1H,m),6.96-7.14(3H,m),7.40(1H,s),7.73(1H,d,J=8Hz)
2-10) IR(薄膜):1615,1540,1185,740cm-1
NMR(200MHz,CDCl3,δ):1.55(6H,s),2.07(2H,t,J=6Hz),2.30(3H,s),2.33(3H,s),3.05(2H,t,J=6Hz),6.96-7.22(3H,m),7.37(1H,s),7.41-7.47(2H,m),7.75(1H,d,J=8Hz)
2-11) IR(薄膜):1590,1530,1450,1350,1180,740cm1
NMR(200MHz,CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6Hz),3.05(2H,t,J=6Hz),6.99-7.77(7H,m)
2-12) IR(薄膜):1610,1450,1180,745cm-1
NMR(200MHz,CDCl3,δ):1.57(6H,s),2.08(2H,t,J=6Hz),3.06(2H,t,J=6Hz),6.91-7.49(7H,m),7.73-7.77(1H,m)
2-13) mp:73.5-74.5℃
IR(液体石蜡):1590,1535,1188,1140,750cm-1
NMR(CDCl3,δ):1.57(6H,s),2.09(2H,t,J=6.4Hz),3.06(2H,t,J=6.4Hz),6.89-7.24(4H,m),7.52-7.77(3H,m)
2-14) IR(纯的):1612,1534,1180,1113,736cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.4Hz),2.34(3H,s),3.05(2H,t,J=6.4Hz),6.97-7.72(7H,m)
2-15 mp:68-71℃
IR(纯的):1615,1598,1535,743cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.4Hz),3.05(2H,t,J=6.4Hz),6.98-7.72(8H,m)
2-16) IR(纯的):1615,1536,1185,745cm-1
NMR(CDCl3,δ):1.57(6H,s),2.09(2H,t,J=6.4Hz),3.06(2H,t,J=6.4Hz),6.99-7.83(8H,m)
2-17) IR(纯的):1600,1540,1500,770,743cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.4Hz),3.05(2H,t,J=6.4Hz),6.99-7.70(7H,m)
2-18) IR(纯的):1538,1448,1230,745cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.4Hz),3.05(2H,t,J=6.4Hz),7.01-7.75(13H,m)
2-19) mp:98-99℃
IR(液体石蜡):1610,1535,1182,750cm-1
NMR(CDCl3,δ):1.55(6H,s),2.10(2H,t,J=6.4Hz),2.33(3H,s),2.37(3H,s),3.06(2H,t,J=6.4Hz),6.95-7.39(7H,m)
2-20) IR(纯的):2930,1540,746cm-1
NMR(CDCl3,δ):2.20(2H,m),2.96(2H,m),4.09(2H,m),6.9-7.2(4H,m),7.5-7.7(3H,m)
质谱(m/e):251(M+)
2-21) mp:91-92℃
IR(液体石蜡):1613,1595,1545,1166,750cm-1
NMR(CDCl3,δ):2.27(2H,m),3.02(2H,t,J=6.1Hz),4.20(2H,t,J=5.7Hz),6.87-7.77(2H,m)
2-22) mp:74-77℃
IR(液体石蜡):1614,1538,742cm-1
NMR(CDCl3,δ):2.26(2H,m),2.29(3H,s),2.33(3H,s),3.01(2H,t,J=6.1Hz),4.17(2H,t,J=5.7Hz),6.92-7.77(7H,m)
2-23) mp:103-104.5℃
IR(液体石蜡):1590,1530,743cm-1
NMR(CDCl3,δ):2.26(2H,m),3.02(2H,t,J=6.1Hz),4.19(2H,t,J=5.7Hz),6.96-7.75(7H,m)
2-24) mp:96-98.5℃
IR(液体石蜡):1610,1540,1170,1114,744cm-1
NMR(CDCl3,δ):2.26(2H,m),2.33(3H,s),3.02(2H,t,J=6.1Hz),4.19(2H,t,J=5.7Hz),6.94-7.71(7H,m)
2-25) IR(薄膜):1600,1450,1280,1185,1035,745cm-1
NMR(200MHz,CDCl3,δ):1.57(6H,s),2.08(2H,t,J=6Hz),3.05(2H,t,J=6Hz),3.85(3H,s),6.7-7.6(6H,m)
2-26) IR(薄膜):1595,1445,1115,1025,740cm-1
NMR(200MHz,CDCl3,δ):1.57(6H,s),2.10(2H,t,J=6Hz),3.07(2H,t,J=6Hz),6.7-7.6(5H,m)
2-27) NMR(CDCl3,δ):1.54(6H,s),2.06(2H,t,J=6Hz),2.46(3H,s),3.01(2H,t,J=6Hz),6.84(1H,s),7.10(2H,m),7.34(1H,s),7.47(1H,s),7.62(2H,m)
2-28) NMR(CDCl3,δ):1.55(6H,s),2.06(2H,t,J=8Hz),3.01(2H,t,J=8Hz),6.9-7.2(3H,m),7.39(1H,s),7.5-7.7(3H,m)
2-29) NMR(CDCl3,δ):1.55(6H,s),2.07(2H,t,J=6Hz),3.02(2H,t,J=6Hz),6.78(1H,d,J=10Hz),7.0-7.4(3H,m),7.41(1H,s),7.59(2H,m)
2-30) IR(纯的):1603,1538,1450,1183,743cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.4Hz),3.05(2H,t,J=6.4Hz),6.97-7.78(9H,m)
2-31) IR(纯的):2900,1610,1223,740cm-1
NMR(CDCl3,δ):1.55(6H,s),2.07(2H,t,J=6.4Hz),3.01(6H,brs),3.04(2H,t,J=6.4Hz),6.83-7.75(8H,m)
2-32) IR(液体石蜡):1630,1580,1540,1500cm-1
NMR(CDCl3,δ):4.29(2H,dd,J=4.4 and 5.8Hz),4.53(2H,dd,J=4.4 and 5.8Hz),6.71(1H,d,J=7.6Hz),7.01-7.18(3H,m),7.20(1H,s),7.43(1H,d,J=8.1Hz),7.56-7.65(2H,m)
2-33) mp:98-99℃
IR(液体石蜡):1600,1540,1500cm-1
NMR(CDCl3,δ):3.29(2H,t,J=5.0Hz),4.46(2H,t,J=5.0Hz),7.0-7.2(5H,m),7.5-7.7(3H,m)
2-34) IR(纯的):1603,1535,1230,744cm-1
NMR(CDCl3,δ):1.57(6H,s),2.11(2H,t,J=6.4Hz),3.07(2H,t,J=6.4Hz),6.98-7.28(4H,m),7.42-7.60(3H,m)
2-35) IR(薄膜):1539,1220,1183,742cm-1
NMR(CDCl3,δ):1.65(6H,s),5.71(1H,d,J=9.9Hz),6.58(1H,d,J=9.9Hz),7.00-7.35(5H,m),7.57-7.66(3H,m)
2-36) mp:128-129℃
IR(液体石蜡):1601,1494,1277,1152,746cm-1
NMR(CDCl3,δ):2.26(2H,quint,J=5.9Hz),3.01(2H,t,J=6.1Hz),3.85(3H,s),4.20(2H,t,J=5.7Hz),6.71-6.79(2H,m),6.93(1H,d,J=7.0Hz),7.05(1H,t,J=7.5Hz),7.38(1H,s),7.53-7.62(2H,m)
2-37) IR(纯的):3640,2960,1610,1530cm-1
NMR(CDCl3,δ):1.51(18H,s),1.56(6H,s),2.08(2H,t,J=6.2Hz),3.05(2H,t,J=6.2Hz),5.13(1H,s),6.9-7.3(2H,m),7.33(1H,s),7.49(2H,s),7.68(1H,d,J=7.9Hz)
2-38) IR(纯的):2970,2940,1605,1575,1535cm-1
NMR(CDCl3,δ):1.56(6H,s),2.08(2H,t,J=6.2Hz),3.05(2H,t,J=6.2Hz),3.87(3H,s),6.80(1H,m),6.99(1H,d,J=7.1Hz),7.0-7.4(4H,m),7.44(1H,s),7.76(1H,d,J=7.9Hz)
2-39) IR(液体石蜡):2980,2940,1560cm-1
NMR(200MHz,CDCl3,δ):1.54(6H,s),2.06(2H,t,J=6.5Hz),3.04(2H,t,J=6.5Hz),6.87(1H,d,J=3.8Hz),6.98(1H,d,J=3.8Hz),7.01(1H,d,J=7.9Hz),7.12 (1H,t,J=7.9Hz),7.40(1H,s),7.68(1H,d,J=7.9Hz)
制备例3-1)
在氮气流和搅拌下,于0°~10℃向磷酰氯(6.07g)的无水乙腈(10ml)溶液中缓慢地加入3-二甲氨基丙烯醛(3.68g)在无水乙腈(10ml)中的溶液,在30分钟内加完。在相同温度下向反应混合物中缓慢地加入5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉(3.70g)在无水乙腈(9ml)中的溶液。在氮气流下将反应混合物回流7小时,冷却至室温,并在搅拌下缓慢地倒入冷的氢氧化钠(6.34g)水(130ml)溶液中。反应混合物用甲苯萃取2次,合并萃取液并用饱和的氯化钠水溶液洗涤,经无水硫酸镁干燥,在减压下蒸发。残余物经硅胶柱层析,用正己烷和乙酸乙酯(5∶1,V/V)的混合液洗脱。收集含目的化合物的部分并在减压下蒸发。将残余的油状物与正己烷一起研磨,得到(E)-3-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕丙烯醛(3.11g),为黄色结晶。
mp:157.5-160.5℃
IR(液体石蜡):1665,1660,1540,1220,1120cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6Hz),3.03(2H,t,J=6Hz),6.14(1H,dd,J=8 and 16Hz),6.98-7.38(7H,m),7.81(1H,d,J=16Hz),9.55(1H,d,J=8Hz)
按制备例3-1)基本上相同的方法制备表C化合物。
表C
表C化合物的物理化学数据
产物的制备例号 数据
3-2) IR(薄膜):1675,1605,1120,740cm-1
NMR(90MHz,CDCl3,δ):1.72(6H,s),2.14(2H,t,J=6Hz),2.37(3H,s),3.03(2H,t,J=6Hz),6.16(1H,dd,J=6.9 and 15.6Hz),6.90-7.30(7H,m),7.76(1H,d,J=15.6Hz),9.50(1H,d,J=6.9Hz)
3-3) mp:121-123℃
IR(液体石蜡):1670,1610,1520cm-1
NMR(90MHz,CDCl3,δ):1.47(3H,d,J=6Hz),2.1-2.4(2H,m),2.9-3.3(2H,m),4.7-5.1(1H,m),6.58(1H,dd,J=16 and 7.0Hz),7.0-7.7(8H,m),9.58(1H,d,J=7Hz)
3-4) IR(薄膜):2940,1670,1600,1530cm-1
NMR(200MHz,CDCl3,δ):1.77(6H,s),2.06(3H,s),2.17(2H,t,J=6.4Hz),3.04(2H,t,J=6.4Hz),5.87(1H,dd,J=7.6 and 15.8Hz),6.9-7.4(6H,m),7.81(1H,d,J=15.8Hz),9.50(1H,d,J=7.6Hz)
3-5) IR(薄膜):2980,2940,1770,1605,1520cm-1
NMR(200MHz,CDCl3,δ):1.74(6H,s),2.14(2H,t,J=6.6Hz),2.33(6H,s),3.01(2H,t,J=6.6Hz),6.22(1H,dd,J=7.6 and 15.8Hz),6.9-7.5(6H,m),7.81(1H,d,J=15.8Hz),9.54(1H,d,J=7.7Hz)
3-6) IR(薄膜):2940,1675,1615,1520cm-1
NMR(200MHz,CDCl3,δ):1.74(6H,s),2.14(2H,t,J=6.6Hz),2.28(6H,s),3.02(2H,t,J=6.6Hz),6.19(1H,dd,J=7.6 and 15.8Hz),6.9-7.3(5H,m),7.80(1H,d,J=15.8Hz),9.55(1H,d,J=7.6Hz)
3-7) IR(薄膜):1670,1600cm-1
NMR(200MHz,CDCl3,δ):1.76(6H,s),2.16(2H,t,J=6.6Hz),3.04(2H,t,J=6.6Hz),6.18(1H,dd,J=7.5 and 15.8Hz),7.0-8.0(10H,m),9.54(1H,d,J=7.5Hz)
3-8) IR(CH2Cl2):1676,1320,1120,733cm-1
NMR(CDCl3,δ):1.71(6H,s),2.15(2H,t,J=6.6Hz),3.02(2H,t,J=6.6Hz),6.05(1H,dd,J=16.5 and 6.6Hz),6.9-7.8(7H,m),7.80(1H,d,J=16.5Hz),9.57(1H,d,J=6.6Hz)
3-9) IR(薄膜):1670,1605,1110,730cm-1
NMR(200MHz,CDCl3,δ):1.59(6H,s),2.11(2H,t,J=6Hz),2.51(3H,s),3.08(2H,t,J=6Hz),6.49(1H,dd,J=8Hz,16Hz),7.02-7.60(6H,m),9.50(1H,d,J=8Hz)
3-10) IR(薄膜):1670,1610,1530,1150,1125,730cm-1
NMR(200MHz,CDCl3,δ):1.74(6H,s),2.14(2H,t,J=6Hz),2.25(3H,s),2.28(3,s),3.02(2H,t,J=6Hz),6.24(1H,dd,J=8Hz,16Hz),6.99-7.30(6H,m),7.82(1H,d,J=16Hz),9.54(1H,d,J=8Hz)
3-11) IR(薄膜):1680,1110,735cm-1
NMR(200MHz,CDCl3,δ):1.73(6H,s),2.15(2H,t,J=6Hz),3.03(2H,t,J=6Hz),6.17(1H,dd,J=7Hz,16Hz),7.04-7.52(7H,m),7.81(1H,d,J=16Hz),9.60(1H,d,J=7Hz)
3-12) IR(液体石蜡):1665,1610,1125,790,745cm-1
NMR(200MHz,CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6Hz),3.03(2H,t,J=6Hz),6.16(1H,dd,J=8Hz,16Hz),6.99-7.49(8H,m),7.82(1H,d,J=16Hz),9.58(1H,d,J=8Hz)
3-13) IR(纯的):1670,1603,1180,1117,728cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.4Hz),3.03(2H,t,J=6.4Hz),6.08(1H,dd,J=7.6 and 15.8Hz),6.88-7.30(6H,m),7.83(1H,d,J=15.8Hz),9.59(1H,d,J=7.6Hz)
3-14) IR(薄膜):1675,1610,1174,1118,745cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),2.31(3H,s),3.02(2H,t,J=6.3Hz),6.17(1H,dd,J=7.6 and 15.9Hz),6.97-7.26(6H,m),7.81(1H,d,J=15.9Hz),9.55(1H,d,J=7.6Hz)
3-15) IR(薄膜):1675,1603,1521,742cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),3.03(2H,t,J=6.3Hz),6.17(1H,dd,J=7.5 and 15.9Hz),6.9-7.4(7H,m),7.81(1H,d,J=15.9Hz),9.57(1H,d,J=7.5Hz)
3-16) IR(薄膜):1673,1608,1120,746cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),3.03(2H,t,J=6.3Hz),6.10(1H,dd,J=7.6 and 15.9Hz),7.02-7.43(7H,m),7.84(1H,d,J=15.9Hz),9.58(1H,d,J=7.6Hz)
3-17) IR(薄膜):1675,1603,1537,1120,748cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),3.03(2H,t,J=6.3Hz),6.13(1H,dd,J=7.5 and 15.9Hz),6.75-7.30(6H,m),7.81(1H,d,J=15.9Hz),9.68(1H,d,J=7.5Hz)
3-18) IR(薄膜):1675,1615,1235,748cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),3.02(2H,t,J=6.3Hz),6.24(1H,dd,J=7.6 and 15.9Hz),6.98-7.43(12H,m),7.82(1H,d,J=15.9Hz),9.56(1H,d,J=7.6Hz)
3-19) IR(薄膜):1670,1602,750cm-1
NMR(CDCl3,δ):1.77(6H,s),2.04(3H,s),2.17(2H,t,J=6.3Hz),2.38(3H,s),3.03(2H,t,J=6.3Hz),5.93(1H,dd,J=7.6 and 15.7Hz),6.93-7.19(6H,m),7.81(1H,d,J=15.7Hz),9.49(1H,d,J=7.6Hz)
3-20) IR(液体石蜡):1685,1670,1610,740cm-1
NMR(CDCl3,δ):2.29(2H,m),3.02(2H,m),4.36(2H,m),6.58(1H,dd,J=7.5 and 16.2Hz),7.0-7.6(7H,m),9.54(1H,d,J=7.5Hz)
3-21) IR(液体石蜡):1658,1610,1522,1153,1115,741cm-1
NMR(CDCl3,δ):2.31(2H,m),3.03(2H,t,J=6.1Hz),4.37(2H,t,J=5.6Hz),6.53(1H,dd,J=7.6 and 16.3Hz),6.97-7.48(7H,m),9.55(1H,d,J=7.6Hz)
3-22) IR(液体石蜡):1670,1610,1500,744cm-1
NMR(CDCl3,δ):3.02(2H,t,J=6.1Hz),2.31(2H,m),2.35(6H,s),4.37(2H,t,J=5.8Hz),6.60(1H,dd,J=7.7 and 16.3Hz)7.00-7.66(7H,m),9.54(1H,d,J=7.7Hz)
3-23) IR(液体石蜡):1673,1612,745cm-1
NMR(CDCl3,δ):2.31(2H,m),3.04(2H,t,J=6.1Hz),4.38(2H,t,J=5.8Hz),6.61(1H,dd,J=7.6 and 16.3Hz),7.08-7.59(7H,m),9.58(1H,d,J=7.6Hz)
3-24) mp:140-141℃
IR(液体石蜡):1683,1670,1613,1143,1111,740cm-1
NMR(CDCl3,δ):2.26(2H,m),2.35(3H,s),3.03(2H,t,J=6.1Hz),4.37(2H,t,J=5.8Hz),6.59(1H,dd,J=7.6 and 16.3Hz),7.01-7.60(7H,m),9.55(1H,d,J=7.6Hz)
3-25) IR(薄膜):1670,1600,1530,1280,1150,1120,735cm-1
NMR(200MHz,CDCl3,δ):1.72(3H,s),1.77(3H,s),2.15(2H,t,J=6Hz),3.02(2H,t,J=6Hz),3.70(3H,s),6.07(1H,quartet,J=8Hz),6.7-7.25(6H,m),7.80(1H,d,J=16Hz),9.54(1H,d,J=8Hz)
3-26) IR(薄膜):1670,1600,1120,730cm-1
NMR(200MHz,CDCl3,δ):1.59(3H,s),1.74(3H,s),2.16(2H,t,J=6Hz),3.04(2H,t,J=6Hz),6.08(1H,quartet,J=8Hz),6.7-7.6(6H,m),7.83(1H,d,J=16Hz),9.62(1H,d,J=8Hz)
3-27) NMR(CDCl3,δ):1.70(6H,s),2.10(2H,t,J=6Hz),2.35(3H,s),2.95(2H,t,J=6Hz),6.08(1H,dd,J=16.8 and 9.0Hz),6.8-7.5(6H,m),7.80(1H,d,J=16.8Hz),9.50(1H,d,J=9.0Hz)
3-28) NMR(CDCl3,δ):1.72(6H,s),2.13(2H,t,J=8Hz),3.00(2H,t,J=8Hz),6.13(1H,dd,J=6 and 17Hz),7.0-7.3(6H,m),7.76(1H,d,J=17Hz),9.56(1H,d,J=6Hz)
3-29) NMR(CDCl3,δ):1.73(6H,s),2.14(2H,t,J=6Hz),3.00(2H,t,J=6Hz),6.12(1H,dd,J=15 and 8Hz),6.7-7.5(6H,m),7.78(1H,d,J=15Hz),9.56(1H,d,J=8Hz)
3-30) IR(液体石蜡):1664,1620,1130,745cm-1
NMR(CDCl3,δ):1.74(6H,s),2.15(2H,t,J=6.3Hz),3.03(2H,t,J=6.3Hz),6.17(1H,dd,J=7.6 and 15.9Hz),7.01-7.47(8H,m),7.82(1H,d,J=15.8Hz),9.54(1H,d,J=7.6Hz)
3-31) IR(液体石蜡):1679,1610,1121,745cm-1
NMR(CDCl3,δ):1.74(6H,s),2.13(2H,t,J=6.3Hz),3.01(8H,m),6.35(1H,dd,J=7.7 and 15.8Hz),6.72-7.35(7H,m),7.82(1H,d,J=15.8Hz),9.54(1H,d,J=7.7Hz)
3-32) mp:165-170℃
IR(液体石蜡):1670,1610,1500cm-1
NMR(CDCl3,δ):4.4-4.7(4H,m),6.56(1H,dd,J=7.6 and 17.2Hz),6.18(1H,d,J=7.5Hz),6.9-7.6(7H,m),9.56(1H,d,J=7.6Hz)
3-33) mp:177-179℃
IR(液体石蜡):1675,1610,1520cm-1
NMR(CDCl3,δ):3.28(2H,t,J=5Hz),4.62(2H,t,J=5Hz),6.47(1H,dd,J=7 and 16Hz),6.95-7.65(8H,m),9.56(1H,d,J=7Hz)
3-34) IR(纯的):1670,1600,1244,743cm-1
NMR(CDCl3,δ):1.73(3H,s),1.76(3H,s),2.17(2H,t,J=7.1Hz),3.04(2H,t,J=6.3Hz),5.91(1H,dd,J=7.6 and 15.8Hz),7.03-7.57(6H,m),7.80(1H,d,J=15.8Hz),9.56(1H,d,J=7.6Hz)
3-35) IR(薄膜):1675,1535,1120,745cm-1
NMR(CDCl3,δ):1.84(6H,s),5.66(1H,d,J=9.9Hz),6.17(1H,dd,J=7.5 and 15.8Hz),6.55(1H,d,J=9.9Hz),6.83-7.41(7H,m),7.84(1H,d,J=15.8Hz),9.54(1H,d,J=7.5Hz)
3-36) mp:170-173.5℃
IR(液体石蜡):1680,1620,1276,740cm-1
NMR(CDCl3,δ):2.31(2H,quint,J=6.0Hz),3.02(2H,t,J=6.1Hz),3.76(3H,s),4.37(2H,t,J=5.8Hz),6.49(1H,dd,J=7.6 and 16.3Hz),6.74-6.83(2H,m),6.97-7.05(2H,m),7.16-7.29(2H,m),7.43(1H,d,J=16.3Hz),9.51(1H,d,J=7.6Hz)
3-37) IR(纯的):3650,2960,1670,1600cm-1
NMR(CDCl3,δ):1.45(18H,s),1.75(6H,s),2.14(2H,t,J=6.0Hz),3.02(2H,t,J=6.0Hz),5.24(1H,s),6.32(1H,dd,J=7.7 and 15.9Hz),7.0-7.5(5H,m),7.82(1H,d,J=15.9Hz),9.57(1H,d,J=7.7Hz)
MASS m/z:443
3-38) IR(纯的):2980,1670,1600cm-1
NMR(CDCl3,δ):1.59(6H,s),2.13(2H,t,J=6.2Hz),3.06(2H,t,J=6.2Hz),3.81(3H,s),6.22(1H,dd,J=7.6 and 15.8Hz),6.9-8.0(8H,m),9.55(1H,d,J=7.6Hz)
3-39) IR(液体石蜡):2980,2940,1670,1610,1535cm-1
NMR(CDCl3,δ):1.59(6H,s),2.12(2H,t,J=6.2Hz),3.08(2H,t,J=6.2Hz),6.46(1H,dd,J=7.8 and 15.8Hz),7.0-7.7(6H,m),9.51(1H,d,J=7.8Hz)
制备例4-1)
将60%氢化钠/矿物油(0.63g)用正己烷(3ml×2)洗涤2次,剩余的粉末状氢化钠悬浮在无水四氢呋喃(24ml)中。在氮气流下将悬浮液冷却至-20℃。在氮气流和搅拌下,于-20℃~-15℃向悬浮液中滴入乙酰乙酸甲酯(1.6g)在无水四氢呋喃(8ml)中的溶液。反应混合物于-20℃~-15℃搅拌30分钟,并在氮气流和搅拌下于-20℃~-15℃滴入1.6M正丁基锂/己烷溶液(8.6ml)。反应混合物于-20℃~-15℃搅拌30分钟。在氮气流下于-20℃~-15℃向混合物中滴入(E)-3-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕丙烯醛(3.07g)在无水四氢呋喃中的溶液,在30分钟内滴完。反应混合物于-20~-15℃搅拌1小时,用饱和氯化铵水溶液使反应混合物冷至-10℃~0℃。在减压下蒸除四氢呋喃,残余物用乙酸乙酯萃取。萃取液用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥,过滤并在减压下蒸发。残余物经“硅酸镁载体”(florisil)(商标,由floridin公司生产)(120g)层析,用正己烷和乙酸乙酯(5∶2,V/V)的混合液洗脱。将含目的化合物的部分合并,并在减压下浓缩,得到甲基(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-5-羟基-3-氧庚-6-烯酸酯(2.60g)。
IR(纯的):3500,2900,1740,1720,1535,1440,1230,1155,830,745cm-1
NMR(CDCl3,δ):1.63(6H,s),2.10(2H,t,J=6Hz),2.59(2H,d,J=6Hz),2.84(1H,d,J=4Hz),3.00(2H,t,J=6Hz),3.44(2H,s),3.75(3H,s),4.60-4.68(1H,m),5.52(1H,dd,J=5 and 16Hz),6.87(1H,dd,J=1.5 and 16Hz),6.9-7.4(7H,m)
按制备例4-1)基本上相同的方法制备表D化合物。
表D
表D化合物的物理化学数据
产物的制备例号 数据
4-2) IR(薄膜):3490,1738,1720,1605,1042,746cm-1
NMR(200MHz,CDCl3,δ):1.63(6H,s),2.10(2H,t,J=6.4Hz),2.38(3H,s),2.57(2H,d,J=6.1Hz),2.74(1H,d,J=4.0Hz),3.00(2H,t,J=6.3Hz),3.42(2H,s),3.75(3H,s),4.95(1H,m),5.54(1H,dd,J=5.5 and 15.8Hz),6.88(1H,d,J=15.8Hz),6.95-7.39(7H,m)
4-3) IR(薄膜):3450,2950,1745,1710,1640,1530,1500cm-1
NMR(200MHz,CDCl3,δ):1.38(3H,d,J=6.6Hz),2.1-2.3(2H,m),2.76(2H,d,J=6.0Hz),2.84(1H,br s),2.9-3.2(2H,m),3.49(2H,s),3.74(3H,s),4.6-4.9(2H,m),5.96(1H,dd,J=5.7 and 16.2Hz),6.74(1H,d,J=16.2Hz),6.9-7.5(7H,m)
4-4) IR(薄膜):3460,2940,1745,1710,1610,1535cm-1
NMR(200MHz,CDCl3,δ):1.64(6H,s),2.0-2.2(5H,m),3.02(2H,t,J=6.2Hz),3.41(2H,s),3.75(3H,s),4.5-4.6(1H,m),5.30(1H,dd,J=5.4 and 15.7Hz),6.84(1H,d,J=15.7Hz),6.9-7.3(6H,m)
4-5) IR(薄膜):3500,2940,1740,1710,1600cm-1
NMR(200MHz,CDCl3,δ):1.62(6H,s),2.09(2H,t,J=6.1Hz),2.34(6H,s),2.57(2H,d,J=5.6Hz),2.74(1H,d,J=3.9Hz),3.00(2H,t,J=6.1Hz),3.43(2H,s),3.74(3H,s),4.66(1H,m),5.56(1H,dd,J=5.5 and 15.8Hz),6.8-7.4(7H,m)
4-6) IR(薄膜):3450,2940,1740,1710cm-1
NMR(200MHz,CDCl3,δ):1.62(6H,s),2.09(2H,t,J=6.1Hz),2.29(6H,s),2.58(2H,d,J=6.0Hz),2.78(1H,d,J=3.9Hz),3.00(2H,t,J=6.1Hz),3.44(2H,s),3.74(3H,s),4.66(1H,m),5.55(1H,dd,J=5.4 and 15.8Hz),6.86(1H,dd,J=1.5 and 15.8Hz),6.9-7.1(4H,m),7.32(1H,d,J=6.4Hz)
4-7) IR(薄膜):3500,2980,2940,1745,1715,1630,1600,1530cm-1
NMR(200MHz,CDCl3,δ):1.66(6H,s),2.12(2H,t,J=6.4Hz),2.44(2H,d,J=5.4Hz),2.76(1H,d,J=4.1Hz),3.02(2H,t,J=6.4Hz),3.25(2H,s),3.68(3H,s),4.59(1H,m),5.52(1H,dd,J=5.3 and 15.8Hz),6.9-8.0(11H,m)
4-8) IR(CH2Cl2):1745,1712,1320,730cm-1
NMR(CDCl3,δ):1.63(6H,s),2.11(2H,m),2.55(2H,d,J=6Hz),2.86(1H,d,J=4Hz),3.01(2H,m),3.46(2H,s),3.73(3H,s),4.66(1H,m),5.51(1H,dd,J=15 and 6Hz),6.8-7.6(8H,m)
4-9) IR(薄膜):3500,1745,1715,1440,1180,730cm-1
NMR(200MHz,CDCl3,δ):1.57(6H,s),2.09(2H,t,J=6Hz),2.27(1H,s),2.48(3H,s),2.54-2.83(2H,m),3.05(2H,t,J=6Hz),3.48(2H,s),3.71(3H,s),4.66(1H,m),5.98(1H,dd,J=7Hz,16Hz),6.68(1H,d,J=16Hz),6.93-7.53(5H,m)
4-10) IR(薄膜):3505,1745,1715,1440,730cm-1
NMR(200MHz,CDCl3,δ):1.62(6H,s),2.09(2H,t,J=6Hz),2.27(1H,s),2.29(3H,s),2.30(3H,s),2.58-2.72(2H,m),3.00(2H,t,J=6Hz),3.42(2H,s),3.74(3H,s),4.65(1H,m),5.57(1H,dd,J=6Hz,16Hz),6.86(1H,dd,J=1Hz,16Hz),6.90-7.39(6H,m)
4-11) IR(薄膜):3500,1740,1715,1440,735cm-1
NMR(200MHz,CDCl3,δ):1.62(6H,s),2.10(2H,t,J=6Hz),2.63-2.96(2H,m),3.00(2H,t,J=6Hz),3.47(2H,s),3.73(1H,s),3.76(3H,s),4.69(1H,m),5.56(1H,dd,J=5Hz,16Hz),6.89(1H,dd,J=2Hz and J=16Hz),6.9-7.08(2H,m),7.29-7.53(4H,m)
4-12) IR(薄膜):3500,1740,1710,1610,1580,1440,1150,730cm-1
NMR(200MHz,CDCl3,δ):1.63(6H,s),2.10(2H,t,J=6Hz),2.27(1H,s),2.61(2H,d,J=6Hz),2.85(1H,d,J=4Hz),3.01(2H,t,J=6Hz),3.45(2H,s),3.75(3H,s),4.67(1H,m),5.55(1H,dd,J=5Hz and J=16Hz),6.84-7.40(8H,m)
4-13) IR(薄膜):3450,1740,1710,1155,1135,744cm-1
NMR(CDCl3,δ):1.63(6H,s),2.11(2H,t,J=6.3Hz),2.59(2H,d,J=6.0Hz),2.8(1H,d,J=4.0Hz),3.01(2H,t,J=6.3Hz),3.46(2H,s),3.75(3H,s),4.65(1H,m),5.50(1H,dd,J=5.5Hz and 15.8Hz),6.84-7.45(7H,m)
4-14) IR(薄膜):3450,1743,1712,1174,1116,745cm-1
NMR(CDCl3,δ):1.62(6H,s),2.10(2H,m),2.30(3H,s),2.59(2H,d,J=6.0Hz),2.81(1H,d,J=4.0Hz),3.00(2H,m),3.44(2H,s),3.75(3H,s),4.65(1H,m),5.53(1H,dd,J=5.3Hz and 15.8Hz),6.82-7.34(7H,m)
4-15) IR(薄膜):3450,1744,1712,1525,743cm-1
NMR(CDCl3,δ):1.62(6H,s),2.10(2H,t,J=6.3Hz),2.61(2H,d,J=6.0Hz),2.85(1H,d,J=4.2Hz),3.00(2H,t,J=6.3Hz),3.44(2H,s),3.75(3H,s),4.65(1H,m),5.53(1H,dd,J=5.1 and 15.8Hz),6.84-7.43(8H,m)
4-16) IR(薄膜):3450,1743,1715,1670,1154,745cm-1
NMR(CDCl3,δ):1.64(6H,s),2.12(2H,m),2.55(2H,d,J=6.0Hz),2.70(1H,d,J=3.9Hz),3.01(2H,t,J=5.8Hz),3.43(2H,s),3.74(3H,s),4.64(1H,m),5.50(1H,dd,J=5.6Hz and 15.8Hz),6.86-7.43(8H,m)
4-17) IR(薄膜):3450,1745,1712,1185,745cm-1
NMR(CDCl3,δ):1.62(6H,s),2.07-2.27(4H,m),2.63(1H,m),3.01(2H,m),3.46(2H,s),3.75(3H,s),4.68(1H,m),5.55(1H,dd,J=5.1 and 15.8Hz),6.92-7.35(7H,m)
4-18) IR(薄膜):3500,1746,1714,1235,748cm-1
NMR(CDCl3,δ):1.63(6H,s),2.10(2H,t,J=6.3Hz),2.61(2H,d,J=6.0Hz),2.78(1H,d,J=4.0Hz),3.00(2H,t,J=6.0Hz),3.44(2H,s),3.73(3H,s),4.67(1H,m),5.58(1H,dd,J=5.4Hz and 15.8Hz),6.84-7.41(13H,m)
4-19) IR(薄膜):3500,1745,1713,748cm-1
NMR(CDCl3,δ):1.64(6H,s),2.03-2.15(5H,m),2.37(3H,s),2.45(2H,m),2.63(1H,m),3.01(2H,t,J=6.2Hz),3.38(2H,s),3.74(3H,s),4.56(1H,m),5.34(1H,dd,J=5.6Hz and 15.7Hz),6.80-7.25(7H,m)
4-20) IR(纯的):3500(br),1700-1760(br),745cm-1
NMR(CDCl3,δ):2.24(2H,m),2.81(1H,d,J=5.8Hz),2.88(1H,d,J=4Hz),2.96(2H,t,J=6Hz),3.50(2H,s),3.73(3H,s),4.24(2H,t,J=6Hz),4.72(1H,m),5.99(1H,dd,J=6Hz and 16Hz),6.72(1H,d,J=16Hz),6.9-7.2(4H,m),7.3-7.5(3H,m)
4-21) IR(纯的):3495,1745,1712,1610,1138,743,730cm-1
NMR(CDCl3,δ):2.27(2H,m),2.80(3H,m),3.00(2H,t,J=6.0Hz),3.49(2H,s),3.74(3H,s),4.24(2H,t,J=5.8Hz),4.71(1H,m),5.93(1H,dd,J=6.0Hz and16.3Hz),6.67(1H,d,J=16.3Hz),6.89-7.43(6H,m)
4-22) IR(纯的):3470,1743,1713,1610,729cm-1
NMR(CDCl3,δ):2.24(2H,m),2.32(6H,s),2.76-2.84(3H,m),2.99(2H,t,J=6Hz),3.50(2H,s),3.73(3H,s),4.26(2H,t,J=5.8Hz),4.72(1H,m),6.03(1H,dd,J=6.2Hz and 16.4Hz),6.77(1H,d,J=16.4Hz),6.92-7.47(6H,m)
4-23) IR(纯的):3490,1742,1711,743,728cm-1
NMR(CDCl3,δ):2.25(2H,m),2.83(2H,d,J=6Hz),2.92(1H,d,J=4Hz),3.0(2H,t,J=6Hz),3.52(2H,s),3.74(3H,s),4.23(2H,t,J=5.8Hz),6.02(1H,dd,J=5.7Hz and 16.3Hz),6.72(1H,d,J=16.13Hz),6.95-7.60(6H,m)
4-24) IR(纯的):3450,1740,1710,1650,1165,1115,742cm-1
NMR(DMSO-d6,δ):2.25(2H,m),2.33(3H,s),2.81(2H,d,J=6Hz),3.00(2H,t,J=6Hz),3.50(2H,s),3.74(3H,s),4.25(2H,t,J=5.8Hz),4.73(1H,m),6.00(1H,dd,J=6.0Hz and 16.4Hz),6.73(1H,d,J=16.4Hz),6.93-7.41(6H,m)
4-25) IR(薄膜):3450,1745,1720,740cm-1
NMR(200MHz,CDCl3,δ):1.63(6H,broad s),2.10(2H,broad t,J=ca.6Hz),2.51-2.68(2H,m),3.00(2H,t,J=6Hz),3.42(2H,s),3.75(3H,s),4.60(1H,m),5.45(1H,dd,J=6Hz,16Hz),6.7-7.2(7H,m)
4-26) IR(薄膜):3450,1740,1720,1440,735cm-1
NMR(200MHz,CDCl3,δ):1.63(6H,s),2.11(2H,t,J=6Hz),2.59(2H,d,J=6Hz),3.00(2H,t,J=6Hz),3.45(2H,s),3.75(3H,s),4.66(1H,m),5.54(1H,dd,J=5Hz and 16Hz),6.8-7.4(6H,m)
4-27) IR(纯的):3450,1740,1710,837,750cm-1
NMR(CDCl3,δ):1.73(6H,s),2.08(2H,t,J=6.3Hz),2.39(3H,s),2.59(2H,d,J=6.0Hz),2.78(1H,m),2.96(2H,t,J=6.2Hz),3.44(2H,s),3.75(3H,s),4.64(1H,m),5.50(1H,dd,J=5.3 and 15.8Hz),6.80-7.40(7H,m)
4-28) NMR(CDCl3,δ):1.57(3H,s),1.63(3H,s),2.11(2H,t,J=6Hz),2.58(2H,d,J=6Hz),2.80(1H,d,J=3.6Hz),2.96(2H,t,J=6Hz),3.40(2H,s),3.72(3H,s),4.60(1H,m),5.50(1H,dd,J=16Hz and 5.7Hz),6.6-7.5(7H,m)
4-29) NMR(CDCl3,δ):1.61(6H,s),2.09(2H,t,J=6Hz),2.58(2H,d,J=6Hz),2.86(1H,d,J=4Hz),2.97(2H,t,J=6Hz),3.44(2H,s),3.74(3H,s),4.64(1H,m),5.51(1H,dd,J=16Hz and 6Hz),6.6-7.4(7H,m)
4-30) IR(薄膜):3500,1740,1710,1602,745cm-1
NMR(CDCl3,δ):1.63(6H,s),2.10(2H,t,J=6.3Hz),2.56(2H,d,J=5.9Hz),2.76(1H,d,J=4.0Hz),3.00(2H,t,J=6.3Hz),3.42(2H,s),3.74(3H,s),4.63(1H,m),5.52(1H,dd,J=5.4 and 15.8Hz),6.87(1H,d,J=15.9Hz),6.96-7.44(8H,m)
4-31) mp:128-130℃
IR(液体石蜡):3500,1747,1716,1150,742cm-1
NMR(CDCl3,δ):1.62(6H,s),2.09(2H,t,J=6.4Hz),2.63(2H,d,J=6.0Hz),2.67(1H,d,J=4.1Hz),2.98(8H,m),3.43(2H,s),3.73(3H,s),4.65(1H,br),5.61(1H,dd,J=5.5Hz and 15.8Hz),6.77-7.02(4H,m),7.25-7.39(3H,m)
4-32) IR(纯的):3500,2950,1745,1715,1630cm-1
NMR(CDCl3,δ):2.8-2.9(3H,m),3.47(2H,s),3.74(3H,s),4.3-4.6(4H,m),4.7-4.8(1H,m),6.03(1H,dd,J=5.9 and 16.4Hz),6.73(1H,d,J=16.4Hz),6.70(1H,d,J=7.6Hz),7.03(1H,t,J=7.6Hz),7.1-7.5(5H,m)
4-33) IR(纯的):3450,2950,1740,1710,1640,1530cm-1
NMR(CDCl3,δ):2.80(2H,d,J=6.0Hz),2.94(1H,d,J=4.0Hz),3.26(2H,t,J=5.2Hz),3.49(2H,s),3.74(3H,s),4.51(2H,t,J=5.2Hz),5.91(1H,dd,J=5.6 and 16.3Hz),6.71(1H,dd,J=1.5 and 16.3Hz),7.0-7.5(7H,m)
4-34) IR(薄膜):3450,1745,1711,1604,1153,745cm-1
NMR(CDCl3,δ):1.62(6H,s),2.12(2H,br),2.52(2H,d,J=6.0Hz),2.72(1H,m),3.01(2H,m),3.43(2H,s),3.75(3H,s),4.60(1H,br),5.38(1H,dd,J=5.4Hz and 15.7Hz),6.80-7.46(7H,m)
4-35) IR(纯的):3475,1742,1712,1643,1219,742cm-1
NMR(CDCl3,δ):1.74(6H,s),2.59(2H,d,J=6.0Hz),2.83(1H,d,J=4.1Hz),3.44(2H,s),3.75(3H,s),4.63(1H,m),5.56(1H,dd,J=5.3Hz and 15.9Hz),5.58(1H,d,J=9.8Hz),6.50(1H,d,J=9.8Hz),6.76-7.43(8H,m)
4-36) IR(液体石蜡):3500,1742,1710,1602,1150,745cm-1
NMR(CDCl3,δ):2.27(3H,m),2.75(2H,d,J=5.9Hz),2.99(2H,t,J=5.9Hz),3.48(2H,s),3.73(3H,s),3.76(3H,s),4.24(2H,t,J=5.7Hz),4.67(1H,br),5.89(1H,dd,J=6.1Hz and 16.3Hz),6.64(1H,d,J=16.4Hz),6.72-7.28(6H,m)
4-37) IR(纯的):3650,3500,2950,1745,1710,1640,1530cm-1
NMR(CDCl3,δ):1.46(18H,s),1.63(6H,s),2.10(2H,t,J=6.6Hz),2.5-2.8(2H,m),3.00(2H,t,J=6.6Hz),3.42(2H,s),3.72(3H,s),4.65(1H,m),5.12(1H,s),5.62(1H,dd,J=5.4 and 15.8Hz),6.9-7.1(2H,m),7.22(2H,s),7.35(1H,d,J=7.6Hz)
4-38) IR(纯的):3400,2950,1740,1710,1600cm-1
4-39) IR(纯的):3450,2940,1740,1710,1640,1545cm-1
NMR(CDCl3,δ):1.57(6H,s),2.09(2H,t,J=7.5Hz),2.63(1H,d,J=3.9Hz),2.7-3.0(2H,m),3.05(2H,t,J=7.5Hz),3.47(2H,s),3.72(3H,s),4.66(1H,m),5.98(1H,dd,J=6.5Hz and 16.0Hz),6.65(1H,d,J=16.0Hz),6.9-7.6(5H,m)
实例1-1)
在氮气流下,于室温将1M三乙基甲硼烷/正己烷(12.0ml)和新戊酸(0.06g)的混合物搅拌2小时。向混合物中加入甲基(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-5-羟基-3-氧庚-6-烯酸酯(2.57g)在无水四氢呋喃(25ml)中的溶液。2小时后将反应混合物冷却至-78℃,并向其中滴入甲醇(12ml)。在氮气流下,于-75℃~-70℃将硼氢化钠(0.54g)小心地分次加入。在相同温度下搅拌1小时后,用0.5M柠檬酸水溶液使反应混合物冷至-10℃~0℃,温热至室温并用乙醚萃取。萃取液用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥并在减压下蒸发。残余物溶于温热至40℃~45℃的甲醇(30ml)中,在减压下蒸发。上述步骤后再重复2次,残余物经硅胶柱层析,用正己烷和乙酸乙酯(2∶1,V/V)的混合液洗脱。收集含目的化合物的部分,并在减压下浓缩,得到甲基(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸酯(1.84g),为白色结晶。
mp:108.5-109.5℃
IR(液体石蜡):3500,3450,1740,1440,1210cm-1
NMR(CDCl3,δ):1.38-1.6(2H,m),1.64(6H,s),2.10(2H,t,J=6Hz),2.45(2H,d,J=6Hz),3.00(2H,t,J=6Hz),3.36(1H,br s),3.66(1H,d,J=4Hz),3.73(3H,s),4.1-4.2(1H,m),4.4-4.5(1H,m),5.56(1H,dd,J=6 and 16Hz),6.85(1H,dd,J=1.5Hz and 16Hz),6.9-7.4(7H,m)
按实例1-1)基本上相同的方法制备表1化合物。
表1
表1化合物的物理化学数据
产物的
实例号 数据
1-2) IR(薄膜):3420,1720,1605,1053,742cm-1
NMR(200MHz,CDCl3,δ):1.3-1.7(2H,m),1.64(6H,s),2.10(2H,t,J=6.3Hz),2.36(3H,s),2.44(2H,d,J=5.3Hz),3.00(2H,t,J=6.3Hz),3.21(1H,br s),3.64(1H,br s),3.72(3H,s),4.14(1H,m),4.45(1H,m),5.59(1H,dd,J=5.5Hz and 15.8Hz),6.84(1H,d,J=15.8Hz),6.91-7.39(7H,m)
1-3) IR(薄膜):3400,2940,1725,1610,1530,1500cm-1
NMR(200MHz,CDCl3,δ):1.38(3H,d,J=6.6Hz),1.5-1.8(2H,m),2.0-2.3(2H,m),2.49(2H,d,J=6.7Hz),2.8-3.2(4H,m),3.72(3H,s),4.2-5.0(3H,m),5.98(1H,dd,J=5.9Hz and 16.2Hz),6.72(1H,d,J=16.2Hz),6.9-7.5(7H,m)
质谱m/z:437(M+),419(M+-H2O),343,317,278
1-4) IR(薄膜):3450,2950,1730,1610,1585,1535cm-1
质谱m/z:465(M+),447(M+-H2O),429,371,345
1-5) IR(薄膜):3430,2440,1730,1600cm-1
NMR(200MHz,CDCl3,δ):1.63(6H,s),2.09(2H,t,J=6.1Hz),2.32(6H,s),1.3-1.6(2H,m),2.44(2H,d,J=7Hz),3.00(2H,t,J=6.1Hz),3.26(1H,s),3.68(1H,s),3.72(3H,s),4.16 and 4.46(2H,each m),5.60(1H,dd,J=5.5 and 15.8Hz),6.73(1H,d,J=15.7Hz),6.90-7.40(6H,m)
质谱m/z:461(M+),341
1-6) IR(薄膜):3400,2940,1725,1610,1530cm-1
NMR(200MHz,CDCl3,δ):1.3-1.6(2H,m),1.63(6H,s),2.09(2H,t,J=6.2Hz),2.26(6H,s),2.46(2H,d,J=5.3Hz),2.99(2H,t,J=6.2Hz),3.36(1H,s),3.71(1H,s),3.72(3H,s),4.17(1H,m),4.46(1H,m),5.59(1H,dd,J=5.4Hz and 15.8Hz),6.83(1H,dd,J=1.4 and 15.8Hz),6.9-7.4(5H,m)
质谱m/z:479(M+),461(M+-H2O),359
1-7) IR(薄膜):3420,2940,1725,1630,1600cm-1
NMR(200MHz,CDCl3,δ):1.2-1.5(2H,m),1.66(6H,s),2.12(2H,t,J=6.3Hz),2.2-2.4(2H,m),3.02(2H,t,J=6.3Hz),3.28 and 3.58(2H,each s),3.68(3H,s),4.03(1H,m),4.40(1H,m),5.57(1H,dd,J=5.3 and 15.8Hz),6.8-8.0(11H,m)
质谱m/z:483(M+),363,336
1-8) IR(CH2Cl2):3450,1730,1320,735cm-1
NMR(CDCl3,δ):1.3-1.6(2H,m),1.65(6H,s),2.10(2H,t,J=6Hz),2.43(2H,d,J=6Hz),3.01(2H,t,J=6Hz),3.57(1H,s),3.72(3H,s),4.13(1H,m),4.45(1H,m),5.55(1H,dd,J=16 and 6Hz),6.8-7.7(8H,m)
1-9) IR(薄膜):3400,1730,1440,1180,730cm-1
NMR(200MHz,CDCl3,δ):1.5-1.87(2H,m),1.56(6H,s),2.10(2H,t,J=6Hz),2.48(3H,s),2.49(2H,d,J=6Hz),2.8(1H,broad s),3.05(2H,t,J=6Hz),3.7(1H,broad s),3.70(3H,s),4.25(1H,m),4.44(1H,m),6.00(1H,dd,J=7Hz,16Hz),6.64(1H,d,J=16Hz),6.95-7.11(3H,m),7.27(1H,d,J=6Hz),7.51(1H,d,J=4Hz)
1-10) IR(薄膜):3450,1730,1440,730cm-1
NMR(200MHz,CDCl3,δ):1.40-1.6(2H,m),1.63(6H,s),2.09(2H,t,J=6Hz),2.27(3H,s),2.28(3H,s),2.43-2.47(2H,m),3.00(2H,t,J=6Hz),3.14(1H,broad s),3.63(1H,broad s),3.72(3H,s),4.16(1H,m),4.46(1H,m),5.62(1H,dd,J=6Hz,16Hz),6.84(1H,dd,J=1Hz and 16Hz),6.91-7.39(6H,m)
1-11) IR(薄膜):3450,1730,1440,735cm-1
NMR(200MHz,CDCl3,δ):1.4-1.6(2H,m),1.62(3H,s),1.63(3H,s),2.10(2H,t,J=6Hz),2.50(2H,d,J=6Hz),3.00(2H,t,J=6Hz),3.63(1H,d,J=1Hz),3.73(4H,s),4.23(1H,m),4.50(1H,m),5.61(1H,dd,J=5Hz,16Hz),6.86(1H,dd,J=2Hz,16Hz),6.94-7.08(2H,m),7.31-7.53(4H,m)
1-12) IR(薄膜):3450,1725,1610,1440,740cm-1
NMR(200MHz,CDCl3,δ):1.40-1.6(2H,m),1.64(6H,s),2.10(2H,t,J=6Hz),2.46(2H,d,J=6Hz),3.01(2H,t,J=6Hz),3.41(1H,broad s),3.68(1H,broad s),3.73(3H,s),4.17(1H,m),4.48(1H,m),5.59(1H,dd,J=5Hz,16Hz),6.81-7.40(8H,m)
1-13) IR(薄膜):3400,1725,1155,1135,741cm-1
NMR(CDCl3,δ):1.32-1.64(2H,m),1.64(6H,s),2.11(2H,t,J=6.3Hz),2.46(2H,d,J=5.5Hz),3.01(2H,t,J=6.3Hz),3.29(1H,m),3.66(1H,m),3.73(3H,s),4.13(1H,m),4.45(1H,m),5.53(1H,dd,J=5.6 and 15.8Hz),6.82-7.44(7H,m)
1-14) IR(薄膜):3400,1730,1532,1172,1116,744cm-1
NMR(DMSO-d6,δ):1.26-1.57(2H,m),1.59(6H,s),2.05(2H,m),2.30(3H,s),2.50(2H,m),2.94(2H,m),3.58(3H,s),3.81(1H,m),4.21(1H,m),4.78(1H,d,J=5.4Hz),4.96(1H,d,J=4.9Hz),5.58(1H,dd,J=5.4 and 15.9Hz),6.74-7.29(7H,m)
1-15) IR(液体石蜡):3400,1725,1525,745cm-1
NMR(DMSO-d6,δ):1.30-1.50(2H,m),1.59(6H,s),2.05(2H,m),2.50(2H,m),2.94(2H,m),3.58(3H,s),3.81(1H,m),4.20(1H,m),4.78(1H,d,J=5.5Hz),4.97(1H,d,J=4.9Hz),5.59(1H,dd,J=5.5 and 15.9Hz),6.79(1H,d,J=15.9Hz),6.9-7.4(7H,m)
1-16) IR(纯的):3450,1738,1720,1153,745cm-1
NMR(DMSO-d6,δ):1.20-1.50(2H,m),1.61(6H,s),2.07(2H,m),2.1-2.5(2H,m),2.95(2H,m),3.58(3H,s),3.75(1H,m),4.16(1H,m),4.75(1H,d,J=5.4Hz),4.93(1H,d,J=4.8Hz),5.48(1H,dd,J=5.5 and 15.8Hz),6.79(1H,d,J=15.8Hz),6.89-7.41(7H,m)
1-17) IR(液体石蜡):3440,1728,1602,1182,750cm-1
NMR(DMSO-d6,δ):1.30-1.57(2H,m),1.58(6H,s),2.05(2H,m),2.20-2.38(2H,m),2.94(2H,m),3.58(3H,s),3.78(1H,m),4.22(1H,d,J=4Hz),4.78(1H,d,J=4Hz),4.99(1H,m),5.62(1H,dd,J=5.3 and 15.9Hz),6.79(1H,d,J=15.9Hz),6.93-7.49(6H,m)
1-18) IR(薄膜):3450,1730,1590,1232,748cm-1
NMR(DMSO-d6,δ):1.30-1.52(2H,m),1.59(6H,s),2.05(2H,m),2.2-2.5(2H,m),2.94(2H,m),3.55(3H,s),3.90(1H,m),4.21(1H,m),4.78(1H,d,J=6Hz),4.94(1H,d,J=4Hz),5.59(1H,dd,J=5.6 and 15.8Hz),6.74-7.44(13H,m)
19) IR(薄膜):3450,1740,1725,745cm-1
NMR(DMSO-d6,δ):1.10-1.40(2H,m),1.57(6H,s),1.93-2.10(5H,m),2.25(3H,s),2.47(2H,m),2.90(2H,m),3.53(3H,s),4.07(2H,m),4.60(1H,d,J=3.0Hz),4.76(1H,d,J=3.0Hz),5.13-5.45(1H,m),6.60-7.11(7H,m)
1-20) NMR(CDCl3,δ):1.6-1.8(2H,m),2.25(2H,m),2.52(2H,d,J=6Hz),3.0(2H,t,J=6Hz),3.40(1H,s),3.70(1H,s),3.72(3H,s),4.26(3H,m),4.53(1H,m),6.01(1H,dd,J=8 and 17Hz),6.71(1H,d,J=17Hz),6.9-7.2(4H,m),7.3-7.5(3H,m)
1-21) IR(薄膜):3400,1730,1611,1588,1135,742cm-1
NMR(DMSO-d6,δ):1.56(2H,m),2.18(2H,m),2.50(2H,m),2.93(2H,m),3.58(3H,s),4.01(1H,m),4.25(3H,m),4.80(1H,d,J=5.5Hz),4.98(1H,d,J=4.5Hz),6.00(1H,dd,J=5.9 and 16.3Hz),6.57(1H,d,J=16.3Hz),6.88-7.47(6H,m)
1-22) IR(薄膜):3400,1730,1612,745cm-1
NMR(DMSO-d6,δ):1.66(2H,m),2.16(2H,m),2.26(6H,s),2.43(2H,m),2.94(2H,m),3.31(2H,m),3.58(3H,s),4.01(1H,m),4.26(3H,m),4.81(1H,d,J=5.6Hz),4.98(1H,d,J=4.4Hz),6.10(1H,dd,J=6.1 and 16.4Hz),6.64(1H,d,J=16.4Hz),6.87-7.33(6H,m)
1-23) IR(薄膜):3420,1730,743cm-1
NMR(DMSO-d6,δ):1.61(2H,m),2.16(2H,m),2.3-2.5(2H,m),2.95(2H,m),3.58(3H,s),4.01(1H,m),4.24(3H,m),4.80(1H,m),5.04(1H,m),6.15(1H,dd,J=5.8 and 16.4Hz),6.65(1H,d,J=16.4Hz),6.91-7.71(6H,m)
1-24) IR(纯的):3430,1730,1610,1160,744cm-1
NMR(DMSO-d6,δ):1.60(2H,m),2.16(2H,m),2.30(3H,s),2.49(2H,m),2.95(2H,m),3.58(3H,s),4.01(1H,m),4.25(3H,m),4.80(1H,m),4.95(1H,m),6.04-6.17(1H,m),6.63(1H,d,J=16.4Hz),6.87-7.36(6H,m)
1-25) IR(薄膜):3450,1730,1440,735cm-1
NMR(200MHz,CDCl3,δ):1.19-1.5(2H,m),1.62(3H,s),1.65(3H,s),2.10(2H,broad t,J=ca.6Hz),2.42-2.45(2H,m),3.00(2H,t,J=6Hz),3.06(1H,broad s),3.64(1H,broad s),3.73(6H,s),4.10(1H,m),4.41(1H,m),5.49(1H,dd,J=6Hz,16Hz),6.6-7.2(7H,m)
1-26) IR(薄膜):3400,1725,1590,1435,750cm-1
NMR(200MHz,CDCl3,δ):1.2-1.6(2H,m),1.64(6H,s),2.09(2H,t,J=6Hz),2.4-2.5(2H,m),3.01(2H,t,J=6Hz),3.30(1H,broad s),3.70(1H,broad s),3.73(3H,s),4.17(1H,m),4.46(1H,m),5.56(1H,dd,J=6 and J=16Hz),6.7-7.4(6H,m)
1-27) IR(液体石蜡):3450,1732,1530,1213,838cm-1
NMR(DMSO-d6,δ):1.36(2H,t,J=5.8Hz),1.57(6H,s),2.03(2H,t,J=8.0Hz),2.31-2.50(5H,m),2.89(2H,m),3.58(3H,s),3.82(1H,m),4.04(1H,m),4.77(1H,d,J=5.5Hz),4.93(1H,d,J=4.8Hz),5.55(1H,dd,J=5.5 and15.9Hz),6.72-7.46(7H,m)
1-28) IR(薄膜):3400,1725,1440,730cm-1
NMR(CDCl3,δ):1.2-1.7(2H,m),1.63(6H,s),2.10(2H,t,J=6Hz),2.3-2.5(2H,m),2.97(2H,t,J=6Hz),3.71(3H,s),4.1(1H,m),4.4(1H,m),5.4-5.8(1H,m),6.6-7.6(7H,m)
1-29) IR(薄膜):3400,1730,1440,730cm-1
NMR(CDCl3,δ):1.3-1.5(2H,m),1.62(6H,s),2.09(2H,t,J=6Hz),2.45(2H,d,J=6Hz),2.97(2H,t,J=6Hz),3.41(1H,s),3.64(1H,m),3.73(3H,s),4.10(1H,m),4.45(1H,m),5.55(1H,dd,J=15 and 6Hz),6.6-7.4(7H,m)
1-30) IR(薄膜):3430,1723,1603,743cm-1
NMR(DMSO-d6,δ):1.25-1.53(2H,m),1.60(6H,s),2.06(2H,t,J=5.9Hz),2.28-2.50(2H,m),2.94(2H,m),3.58(3H,s),3.84(1H,m),4.19(1H,m),4.77(1H,d,J=5.4Hz),4.95(1H,d,J=4.9Hz),5.56(1H,dd,J=5.5 and 15.9Hz),6.79(1H,d,J=15.9Hz),6.87-6.97(2H,m),7.19-7.40(6H,m)
1-31) IR(薄膜):3410,1730,1611,1160,743cm-1
NMR(DMSO-d6,δ):1.00-1.47(2H,m),1.53(6H,s),2.00(2H,t,J=6.3Hz),2.28(2H,m),2.85(8H,m),3.52(3H,s),3.70-4.22(2H,m),4.66(1H,d,J=4.2Hz),4.81(1H,d,J=4.8Hz),5.57(1H,dd,J=6.0 and 15.3Hz),6.62-7.20(8H,m)
1-32) IR(纯的):3450,2950,1730,1630,1585cm-1
NMR(CDCl3,δ):1.6-1.9(2H,m),2.51(2H,d,J=6.2Hz),3.58(1H,s),3.72(3H,s),3.75(1H,s),4.3-4.6(6H,m),6.02(1H,dd,J=6.1 and 16.4Hz),6.70(1H,d,J=16.4Hz),6.70(1H,d,J=7.5Hz),6.98(1H,t,J=7.5Hz),7.09-7.19(3H,m),7.42-7.49(2H,m)
MASS m/z:425,407,304
1-33) mp:148-150℃
IR(液体石蜡):3490,1735,1540,1500cm-1
NMR(CDCl3,δ):1.5-1.8(2H,m),2.51(2H,d,J=6.2Hz),3.2-3.3(2H,m),3.4-3.8(2H,m),3.73(3H,s),4.2-4.5(1H,m),4.5-4.6(3H,m),5.93(1H,dd,J=5.8Hz and 16.3Hz),6.69(1H,dd,J=1.4 and 16.3Hz),6.9-7.5(7H,m)
1-34) NMR(CDCl3,δ):1.37-1.53(2H,m),1.60(3H,s),1.63(3H,s),2.08(2H,t,J=6.6Hz),2.40(2H,d,J=6.0Hz),2.98(2H,t,J=6.6Hz),3.68(3H,s),4.00-4.47(2H,m),5.35(1H,dd,J=6.0Hz and 15.0Hz),6.64-7.37(7H,m)
MASS m/z:449,485
1-35) IR(薄膜):3400,1724,1218,740cm-1
NMR(DMSO-d6,δ):1.29-1.61(2H,m),1.71(6H,s),2.21-2.40(2H,m),3.58(3H,s),3.80(1H,m),4.20(1H,m),4.78(1H,d,J=5.5Hz),4.98(1H,d,J=4.9Hz),5.62(1H,dd,J=5.5 and 15.8Hz),5.78(1H,d,J=9.9Hz),6.56(1H,d,J=9.9Hz),6.82-6.94(3H,m),7.17-7.27(3H,m),7.40-7.47(2H,m)
1-36) IR(薄膜):3400,1726,1600,1150,744cm-1
NMR(DMSO-d6,δ):1.43-1.71(2H,m),2.18(2H,br),2.29-2.5(2H,m),2.94(2H,br),3.58(3H,s),3.71(3H,s),3.96(1H,m),4.24(3H,br),4.78(1H,d,J=5.5Hz),4.91(1H,d,J=4.4Hz),5.92(1H,dd,J=6.1 and 16.3Hz),6.50(1H,d,J=16.3Hz),6.78-7.25(6H,m)
1-37) IR(液体石蜡):3650,3400,2950,1720cm-1
NMR(CDCl3,δ):1.45(18H,s),1.45-1.63(2H,m),1.64(6H,s),2.09(2H,t,J=6.2Hz),2.40-2.60(2H,m),3.00(2H,t,J=6.2Hz),3.24(1H,s),3.71(4H,s),4.23(1H,m),4.47(1H,m),5.10(1H,s),5.66(1H,dd,J=5.5 and 15.8Hz),6.86(1H,dd,J=1.5 and 15.8Hz),6.93-7.03(2H,m),7.22(2H,s),7.35(1H,d,J=7.5Hz)
质谱 m/z:561,525,441
1-38) IR(纯的):3400,2940,1730,1605cm-1
质谱m/z:463
1-39) IR(纯的):3420,2950,1730,1615,1550cm-1
NMR(CDCl3,δ):1.57(6H,s),1.4-1.8(2H,m),2.09(2H,t,J=6.4Hz),2.4-2.7(2H,m),3.06(2H,t,J=6.4Hz),3.68(3H,s),4.1-4.6(2H,m),5.98(1H,dd,J=6.8Hz and 15.9Hz),6.61(1H,d,J=15.9Hz),7.0-7.6(5H,m)
质谱m/z:473(M+),455,437(碱基)
实例2-1)
在冰冷却下,向甲基(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸酯(1.6g)的甲醇(15ml)溶液中滴入1N氢氧化钠水溶液(3.54ml)。将反应混合物温热至室温,并在相同温度下搅拌3小时。在减压下蒸发溶剂,残余物溶于水(10ml)中,过滤并冷冻干燥,得到(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(1.53g),为淡黄色粉末。
IR(液体石蜡):3300,1565,1220cm-1
NMR(DMSO-d6,δ):1.16-1.52(2H,m),1.58(6H,s),1.79-2.10(4H,m),2.93(2H,m),3.63(1H,m),4.22(1H,m),5.16(1H,br s),5.56(1H,dd,J=6Hz and 16Hz),6.75(1H,d,J=16Hz),6.86-6.97(2H,m),7.07(1H,br s),7.15-7.24(3H,m),7.37-7.44(2H,m)
按实例2-1)基本上相同的方法制备表2化合物。
表2化合物的物理化学数据
产物的
实例号 数据
2-2) IR(液体石蜡):3350,1565,742cm-1
NMR(200MHz,DMSO-d6,δ):1.16-1.48(2H,m),1.59(6H,s),1.75-1.87(4H,m),2.32(3H,s),2.93(2H,br s),3.56(1H,m),4.20(1H,m),5.12(1H,br s),5.57(1H,dd,J=5.1 and 15.9Hz),6.75(1H,d,J=15.9Hz),6.85-7.30(7H,m)
2-3) IR(液体石蜡):3330,1570,1220,835,740cm-1
NMR(200MHz,CD3OD,δ):1.35 and 1.36(3H,each d,J=6.5Hz),1.5-1.8(2H,m),2.1-2.3(2H,m),2.3-2.5(2H,m),2.8-3.1(2H,m),3.9-4.2(1H,m),4.3-4.5(7H,m),5.9-6.1(1H,m),6.73(1H,d,J=16.3Hz),6.8-7.5(7H,m)
元素分析 C25H25FNO4Na·1.5H2O:
计算值: C63.55,H5.97,N2.96
测定值: C63.49,H5.76,N2.79
2-4) IR(液体石蜡):3350,1565cm-1
NMR(200MHz,DMSO-d6,δ):1.2-1.5(2H,m),1.60(6H,s),1.65-2.10(7H,m),2.8-3.0(2H,m),3.47(1H,m),4.13(1H,br s),5.06(1H,br s),5.33(1H,dd,J=4.1 and 15.7Hz),6.73(1H,d,J=15.7Hz),6.8-7.3(6H,m)
2-5) IR(液体石蜡):3300,1570,740cm-1
NMR(200MHz,CD3OD,δ):1.3-1.6(2H,m),1.64(6H,s),2.08(2H,t,J=6.1Hz),2.1-2.3(2H,m),2.32(6H,s),2.97(2H,t,J=6.1Hz),3.82(1H,m),4.36(1H,m),5.60(1H,dd,J=5.9 and 15.8Hz),6.7-7.3(7H,m)
2-6) IR(液体石蜡):3350,1565,1180,740cm-1
NMR(90MHz,DMSO-d6,δ):1.0-1.5(2H,m),1.56(6H,s),1.7-2.1(4H,m),2.21(6H,s),2.7-3.0(2H,m),3.4-3.8(1H,m),4.0-4.4(1H,m),4.4-5.3(2H,br s),5.57(1H,dd,J=5 and 16Hz),6.6-7.3(6H,m)
2-7) IR(液体石蜡):3300,1565,1150,740cm-1
NMR(200MHz,DMSO-d6,δ):1.1-1.5(2H,m),1.62(6H,s),1.7-2.0(2H,m),2.07(2H,br s),2.50(2H,br s),3.60(1H,m),4.18(1H,m),5.12(1H,br s),5.59(1H,dd,J=5.2 and 15.9Hz),6.85(1H,d,J=15.8Hz),6.9-7.0(2H,m),7.14(1H,br s),7.33(1H,d,J=7.2Hz),7.4-7.5(2H,m),7.55(1H,d,J=8.5Hz),7.8-8.0(4H,m)
2-8) IR(液体石蜡):3350,1570,1120,740cm-1
NMR(DMSO-d6,δ):1.2-1.4(2H,m),1.59(6H,s),1.6-2.2(4H,m),2.95(2H,m),3.57(1H,m),4.24(1H,m),5.19(1H,br s),5.58(1H,dd,J=16 and 4Hz),6.81(1H,d,J=16Hz),6.9-7.75(7H,m)
2-9) IR(薄膜):3350,1570cm-1
NMR(200MHz,DMSO-d6,δ):1.2-1.6(2H,m),1.53(6H,s),1.79-2.03(4H,m),2.43(3H,s),2.98(2H,m),3.72(1H,m),4.17(1H,m),4.86(1H,broad s),6.03(1H,dd,J=6Hz,16Hz),6.50(1H,d,J=16Hz),6.92-7.05(3H,m),7.20(1H,broad s),7.38(1H,d,J=8Hz),7.56(1H,s)
2-10) IR(液体石蜡):3350,1570,740cm-1
NMR(200MHz,DMSO-d6,δ):1.23-1.5(2H,m),1.58(6H,s),1.74-2.0(4H,m),2.23(6H,s),2.93(2H,m),3.56(1H,m),4.20(1H,m),5.08(1H,broad s),5.59(1H,dd,J=5 and 16Hz),6.74(1H,d,J=16Hz),6.87-7.30(7H,m)
2-11) IR(液体石蜡):3350,1570,740cm-1
NMR(200MHz,CD3OD,δ):1.43-1.74(2H,m),1.63(6H,s),2.08(2H,t,J=6Hz),2.19-2.43(2H,m),2.98(2H,t,J=6Hz),3.95(1H,m),4.40(1H,quartet,J=6Hz),5.63(1H,dd,J=6Hz,16Hz),6.83-7.00(3H,m),7.22-7.55(4H,m)
NMR(200MHz,DMSO-d6,δ):1.24-1.6(2H,m),1.58(6H,s),1.79-2.11(4H,m),2.94(2H,broad t),3.62(1H,m),4.24(1H,m),5.21(1H,broad s),5.61(1H,dd,J=5 and 16Hz),6.79(1H,d,J=16Hz),6.90-7.01(2H,m),7.24-7.64(4H,m)
2-12) IR(液体石蜡):3350,1575cm-1
NMR(200MHz,CD3OD,δ):1.37-1.7(2H,m),1.63(6H,s),2.08(2H,t,J=6Hz),2.1-2.38(2H,m),2.97(2H,t,J=6Hz),3.87(1H,m),4.37(1H,dd,J=6Hz,13Hz),5.61(1H,dd,J=6 and 16Hz),6.83-7.43(8H,m)
NMR(200MHz,DMSO-d6,δ):1.15-1.67(2H,m),1.58(6H,s),1.77-2.08(4H,m),2.94(2H,m),3.59(1H,m),4.23(1H,m),5.19(1H,broad s),5.60(1H,dd,J=5 and 16Hz),6.78(1H,d,J=16Hz),6.88-7.47(8H,m)
2-13) NMR(DMSO-d6,δ):1.36-1.59(2H,m),1.59(6H,s),1.74-2.06(4H,m),2.95(2H,m),3.54(1H,m),4.19(1H,m),5.13(1H,br s),5.48(1H,dd,J=5.20 and 15.8Hz),6.74(1H,d,J=15.8Hz),6.89-7.42(6H,m)
2-14) NMR(DMSO-d6,δ):1.10-1.58(2H,m),1.58(6H,s),1.77-2.10(4H,m),2.25(3H,s),2.93(2H,m),3.36(1H,s),3.62(1H,m),4.22(1H,m),5.14(1H,br s),5.57(1H,dd,J=5.2 and 15.9Hz),6.71-7.28(7H,m)
2-15) NMR(DMSO-d6,δ):1.10-1.58(2H,m),1.58(6H,s),1.78-2.08(4H,m),2.94(2H,m),3.63(1H,m),4.21(1H,m),5.17(1H,br s),5.57(1H,dd,J=5.1 and 15.9Hz),6.76(1H,d,J=15.8Hz),6.88-7.41(7H,m)
2-16) NMR(DMSO-d6,δ):1.10-1.59(2H,m),1.59(6H,s),1.70-2.10(4H,m),2.95(2H,m),3.48(1H,m),4.15(1H,m),5.08(1H,br s),5.48(1H,dd,J=5.0 and 15.8Hz),6.75(1H,d,J=15.8Hz),6.89-7.39(7H,m)
2-17) NMR(DMSO-d6,δ):1.20-1.57(2H,m),1.57(6H,s),1.76-2.07(4H,m),2.94(2H,m),3.34(3H,s),3.61(1H,m),4.22(1H,m),5.17(1H,br s),5.60(1H,dd,J=5.0 and 15.9Hz),6.76(1H,d,J=15.9Hz),6.88-7.49(6H,m)
2-18) NMR(DMSO-d6,δ):1.20-1.51(2H,m),1.59(6H,s),1.78-2.08(4H,m),2.94(2H,m),3.35(1H,s),3.67(1H,br s),4.24(1H,br s),5.15(1H,br s),5.55(1H,dd,J=5.0 and 15.9Hz),6.71-7.46(13H,m)
2-19) NMR(DMSO-d6,δ):0.80-1.32(2H,m),1.60(6H,s),1.67-2.07(7H,m),2.32(3H,s),2.94(2H,m),3.35(2H,m),4.12(1H,br s),5.00(1H,br s),5.36(1H,dd,J=5.0 and 15.8Hz),6.68-7.23(7H,m)
2-20) NMR(CD3OD,δ):1.6-1.8(2H,m),2.21(2H,m),2.36(2H,m),2.96(2H,t,J=6Hz),4.07(1H,m),4.28(2H,t,J=6Hz),4.42(1H,m),6.06(1H,dd,J=6 and 16Hz),6.70(1H,d,J=16Hz),6.8-7.5(7H,m)
2-21) NMR(CD3OD,δ):1.57-1.79(2H,m),2.23-2.40(4H,m),2.96(2H,m),4.03(1H,m),4.26(2H,m),4.38(1H,m),5.98(1H,dd,J=6.6 and 16.3Hz),6.64(1H,d,J=16.3Hz),6.84-7.48(6H,m)
2-22) NMR(C3OD,δ):1.73(2H,m),2.1-2.5(4H,m),2.30(6H,s),2.93(2H,m),3.90-4.63(4H,m),6.03(1H,dd,J=6.8Hz and 16.2Hz),6.62-7.33(7H,m)
2-23) NMR(CD3OD,δ):1.72(2H,m),2.20(2H,m),2.36(2H,m),2.97(2H,m),4.03(1H,m),4.26(2H,m),4.43(1H,m),6.10(1H,m),6.70(1H,d,J=16.3Hz),6.91-7.61(6H,m)
2-24) NMR(CD3OD,δ):1.77(2H,m),2.20(2H,m),2.30(3H,s),2.34(2H,m),2.93(2H,m),4.10(1H,m),4.26(2H,m),4.43(1H,m),6.00-6.16(1H,m),6.70(1H,d,J=16Hz),6.8-7.4(6H,m)
2-25) IR(液体石蜡):3350,1565cm-1
NMR(200MHz,DMSO-d6,δ):1.02-1.5(2H,m),1.58(6H,s),1.72-2.05(4H,m),2.93(2H,broad t,J=ca.6Hz),3.51(1H,m),3.69(3H,s),4.16(1H,m),5.02(1H,broad s),5.43(1H,dd,J=5 and 16Hz),6.63-7.17(8H,m)
NMR(200MHz,CD3OD,δ):1.22-1.6(2H,m),1.64(6H,broad s),2.06-2.34(4H,m),2.98(2H,t,J=6Hz),3.72(3H,s),3.7(1H,m),4.32(1H,m),5.49(1H,dd,J=6 and 16Hz),6.67-7.2(7H,m)
2-26) IR(液体石蜡):3350,1590cm-1
NMR(200MHz,CD3OD,δ):1.28-1.6(2H,m),1.65(6H,s),2.11(2H,t,J=6Hz),2.21-2.37(2H,m),3.00(2H,t,J=6Hz),3.86(1H,m),4.36(1H,m),5.55(1H,dd,J=6 and 16Hz),6.67(1H,d,J=16Hz),6.8-7.4(5H,m)
2-27) NMR(DMSO-d6,δ):1.10-1.55(2H,m),1.56(6H,s),1.76-2.08(4H,m),2.31(3H,s),2.89(2H,m),3.35(1H,m),3.61(1H,m),4.21(1H,m),5.12(1H,m),5.53(1H,dd,J=5.2 and 15.9Hz),6.69-7.42(8H,m)
2-28) NMR(DMSO-d6,δ):1.1-1.6(2H,m),1.57(6H,s),1.7-2.2(4H,m),2.93(2H,m),4.22(1H,m),5.59(1H,m),6.73(1H,d,J=16Hz),6.8-7.5(6H,m)
2-29) NMR(DMSO-d6,δ):1.1-1.6(2H,m),1.57(6H,s),1.78-2.07(4H,m),2.94(2H,br s),3.61(1H,m),4.21(1H,m),5.18(1H,br s),5.56(1H,dd,J=16 and 6Hz),6.7-7.5(7H,m)
2-30) NMR(DMSO-d6,δ):1.16-1.53(2H,m),1.59(6H,s),1.76-2.08(4H,m),2.94(2H,m),3.40(1H,br),3.59(1H,m),4.20(1H,m),5.57(1H,dd,J=5.1 and 15.8Hz),6.76(1H,d,J=14.8Hz),6.86-6.96(2H,m),7.19-7.39(6H,m)
2-31) NMR(DMSO-d6,δ):1.20-1.52(2H,m),1.58(6H,s),1.76-2.07(4H,m),2.91(8H,br),3.35(1H,br),3.65(1H,m),4.21(1H,m),5.08(1H,br),5.61(1H,dd,J=5.2 and 15.9Hz),6.68-6.92(4H,m),7.16-7.23(4H,m)
2-32) IR(液体石蜡):3320,1570cm-1
NMR(CD3OD,δ):1.6-1.9(2H,m),2.2-2.5(2H,m),4.09(1H,m),4.3-4.5(5H,m),6.13(1H,dd,J=6.6 and 16.4Hz),6.59(1H,d,J=7.5Hz),6.70(1H,d,J=16.4Hz),6.90(1H,t,J=7.5Hz),7.09(1H,d,J=7.5Hz),7.17(2H,m),7.51(2H,m)
2-33) IR(液体石蜡):3300,1565cm-1
NMR(CD3OD,δ):1.5-2.0(2H,m),2.32(2H,d,J=6Hz),3.1-3.3(2H,m),3.8-4.2(1H,m),4.2-4.6(3H,m),5.95(1H,dd,J=6Hz and 16Hz),6.63(1H,d,J=16Hz),6.8-7.5(7H,m)
2-34) IR(液体石蜡):3350,1570cm-1
NMR(CD3OD,δ):1.6-1.8(2H,m),2.3-2.5(2H,m),3.0-3.8(2H,m),4.0-4.5(2H,m),4.5-4.9(2H,m),6.18(1H,dd,J=6.5 and 16.3Hz),6.77(1H,d,J=16.3Hz),7.1-7.8(7H,m)
2-35) IR(纯的):3350,1570cm-1
NMR(CD3OD,δ):1.6-1.9(2H,m),2.35(2H,d,J=5.5Hz),4.06(1H,m),4.45(1H,m),4.7-5.0(4H,m),6.13(1H,dd,J=6.3Hz and 16.3Hz),6.71(1H,d,J=16.3Hz),7.1-7.8(7H,m)
2-36) NMR(CD3OD,δ):1.2-1.5(2H,m),1.64(3H,s),1.67(3H,s),2.11(2H,t,J=6.3Hz),2.22-2.27(2H,m),3.00(2H,t,J=6.3Hz),3.77(1H,m),4.31(1H,m),5.44(1H,dd,J=6.2 and 15.8Hz),6.80-7.55(7H,m)
2-37) NMR(DMSO-d6,δ):1.14-1.53(2H,m),1.70(6H,s),1.80-2.08(2H,m),3.59(1H,br),4.20(1H,br),5.17(1H,br),5.61(1H,dd,J=5.1 and 15.8Hz),5.77(1H,d,J=9.8Hz),6.55(1H,d,J=9.8Hz),6.81-6.93(3H,m),7.17-7.26(4H,m),7.39-7.46(2H,m)
2-38) IR(液体石蜡):3300,1563,1150,740cm-1
NMR(DMSO-d6,δ):1.32-1.63(2H,m),1.81-2.17(4H,m),2.93(2H,br),3.70(3H,s),3.70(1H,m),4.22(3H,m),5.05(1H,br),5.93(1H,dd,J=5.8 and 16.3Hz),6.48(1H,d,J=16.4Hz),6.79-7.24(7H,m)
2-39) IR(液体石蜡):3350,1570cm-1
NMR(CD3OD,δ):1.46(18H,s),1.64(6H,s),1.2-1.6(2H,m),2.08(2H,t,J=6.3Hz),2.2-2.4(2H,m),2.97(2H,t,J=6.3Hz),3.98(1H,m),4.38(1H,m),5.70(1H,dd,J=5.6 and 15.8Hz),6.7-7.1(4H,m),7.18(1H,d,J=7.3Hz),7.19(2H,s)
2-40) IR(液体石蜡):3350,1570,740cm-1
NMR(200MHz,CDCl3,δ):1.3-2.0(8H,m),2.0-2.4(4H,m),2.9-3.1(2H,m),3.81(3H,s),4.0-4.5(2H,m),5.63(1H,dd,J=5.9 and 15.9Hz),6.7-7.7(8H,m)
2-41) IR(液体石蜡):3300,1570cm-1
NMR(CD3OD,δ):1.56(6H,s),1.6-1.9(2H,m),2.07(2H,t,J=6.2Hz),2.2-2.4(2H,m),3.03(2H,t,J=6.2Hz),3.9-4.1(1H,m),4.2-4.4(1H,m),6.07(1H,dd,J=6.9 and 15.8Hz),6.64(1H,d,J=15.8Hz),6.95(1H,d,J=6.9Hz),7.04(1H,t,J=6.9Hz),7.22(1H,s),7.42( H,d,J=6.9Hz),7.48(1H,s)
实例3-1)
在冰冷却下,向(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(23mg)的水(0.7ml)溶液中加入1N盐酸(0.05ml)。反应混合物用乙醚萃取。萃取液用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥并在减压下蒸发。残余物溶于干燥二氯甲烷(1ml)中。在室温下向该溶液中加入N-乙基-N’-(3-二甲氨基丙基)碳化二亚胺盐酸盐(9.6mg)。反应混合物在室温下搅拌4小时,然后用二氯甲烷萃取。萃取液经无水硫酸镁干燥,过滤并在减压下蒸发。得到的油状物经硅胶柱层析纯化,用正己烷和乙酸乙酯(1∶1,V/V)的混合液洗脱,得到(±)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(含微量顺式异构体的反式异构体)(10mg)。
IR(液体石蜡):3450,1730,1540,1500,1450,1370,1230,1160,1040,730cm-1
实例3-2)
在冰冷却下,向(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(770mg)的水(23ml)溶液中滴入1N盐酸(1.8ml)。反应混合物用乙酸乙酯萃取。萃取液用饱和氯化钠水溶液洗涤,经无水硫酸镁干燥并在减压下蒸发。残余物溶于无水甲苯(25ml)中,将该溶液置于迪安-斯达克装置中加热回流。3.5小时后在真空下除去甲苯。残余的糖浆状物经硅胶(27g)柱层析,用正己烷和乙酸乙酯(1∶1,V/V)的混合液洗脱,得到2个部分。前一部分为(±)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.28g)。
mp:165.5~166.5℃(用二氯甲烷-二异丙醚重结晶)。
IR(液体石蜡):3450,1730,1540,1500,1450,1370,1230,1160,1040,730cm-1
NMR(CDCl3,δ):1.54-1.91(2H,m),1.63(6H,s),2.10(3H,m),2.60(1H,m,J=1,4 and 17Hz),2.73(1H,dd,J=4 and 17Hz),3.01(2H,t,J=6Hz),4.29(1H,br s),5.22(1H,m),5.55(1H,dd,J=6 and 16Hz),6.89(1H,dd,J=1 and 16Hz),6.95-7.14(4H,m),7.25-7.41(3H,m)
第二部分为反式异构体和顺式异构体的外消旋混合物(0.35g)。
实例4
将(±)-赤-(E)-7-〔5,6-二氢-1-(4-氟苯基)-4-甲基-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(0.50g)在甲醇(10ml)中的混合物在10%钯-碳(0.1g)存在下于室温氢化4小时。过滤反应混合物,滤液经蒸发。残余物溶于蒸馏水中并冷冻干燥,得到(±)-赤-(E)-7-〔5,6-二氢-1-(4-氟苯基)-4-甲基-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚酸钠(0.49g)。
IR(液体石蜡):3380,1580cm-1
NMR(CD3OD,δ):1.33(3H,d,J=6Hz),1.4-2.4(8H,m),2.7-3.2(4H,m),3.6-4.2(2H,m),4.70(1H,m),6.8-7.6(7H,m)
实例5
在氮气流和搅拌下,于室温向甲基(±)-赤-(E)-7-〔2,3-二氢-6-(4-氟苯基)吡咯并〔1,2,3-de〕〔1,4〕-苯并噻嗪-5-基〕-3,5-二羟基庚-6-烯酸酯(2.71g)和咪唑(2.09g)的N,N-二甲基甲酰胺(30ml)溶液中滴入叔丁基氯二苯基硅烷(3.71g)。混合物在相同温度下搅拌24小时,然后倒入水(70ml)中。混合物用乙酸乙酯(60ml)萃取,萃取液用盐水洗涤,干燥和蒸发。糖浆状残余物经硅胶(100g)柱层析,用己烷-乙酸乙酯(20∶1,V/V)洗脱,得到甲基(±)-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)-7-〔2,3-二氢-6-(4-氟苯基)吡咯并〔1,2,3-de〕〔1,4〕-苯并噻嗪-5-基〕庚-6-烯酸酯(5.05g)。
IR(纯的):2950,1735,1530cm-1
NMR(CDCl3,δ):0.90(9H,s),0.96(9H,s),1.69-1.96(2H,m),2.40-2.68(2H,m),2.9-3.1(2H,m),3.57(3H,s),3.8-4.0(2H,m),4.2-4.5(2H,m),5.38(1H,dd,J=6.5 and 16.4Hz),6.07(1H,d,J=16.4Hz),7.0-7.8(27H,m)
质谱 m/z:917
实例6-1)
在-20℃以下向甲基(±)-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)-7-〔2,3-二氢-6-(4-氟苯基)吡咯并〔1,2,3-de〕〔1,4〕苯并噻嗪-5-基〕庚-6-烯酸酯(2.20g)的二氯甲烷(25ml)溶液中加入间氯过苯甲酸(80%,0.57g)。混合物在相同温度下搅拌45分钟。加入5%亚硫酸氢钠水溶液(10ml)和饱和碳酸氢钠水溶液(25ml)后,混合物用二氯甲烷(30ml×3)萃取。合并萃取液,干燥并蒸发。糖浆状残余物经硅胶柱层析,用甲苯-乙酸乙酯(4∶1,V/V)洗脱,得到甲基(±)-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)-7-〔2,3-二氢-6-(4-氟苯基)-1-氧吡咯并〔1,2,3-de〕〔1,4〕苯并噻嗪-5-基〕庚-6-烯酸酯(1.88g)。
IR(纯的):2950,2860,1735,1535cm-1
NMR(CDCl3,δ):0.88(9H,s),0.98(9H,s),1.6-2.0(2H,m),2.4-2.8(2H,m),3.2-3.4(2H,m),3.56 and 3.60(3H,each s),3.8-4.5(4H,m),5.3-5.7(1H,m),6.08(1H,d,J=16Hz),7.0-7.8(27H,m)
实例6-2)
在搅拌和5℃以下,向甲基-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)-7-〔2,3-二氢-6-(4-氟苯基)吡咯并〔1,2,3-de〕〔1,4〕苯并噻嗪-5-基〕庚-6-烯酸酯(2.30g)的二氯甲烷(20ml)溶液中加入间氯过苯甲酸(80%,1.2g)。混合物于00℃搅拌2小时。加入5%亚硫酸氢钠水溶液(10ml)和饱和碳酸氢钠水溶液(25ml)以后,混合物用二氯甲烷(50ml)萃取。萃取液用盐水洗涤,干燥并蒸发得到糖浆状残余物,经硅胶(50g)柱层析,用甲苯-乙酸乙酯洗脱,得到甲基(±)-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)-7-〔2,3-二氢-6-(4-氟苯基)-1,1-二氧吡咯并〔1,2,3-de〕〔1,4〕-苯并噻嗪-5-基〕庚-6-烯酸酯(1.29g)。
IR(纯的):3050,2940,2860,1735,1535,1500cm-1
NMR(CDCl3,δ):0.88(9H,s),0.97(9H,s),1.7-2.0(2H,m),2.4-2.8(2H,m),3.2-3.3(2H,m),3.59(3H,s),4.0-4.3(3H,m),4.4-4.5(1H,m),5.37(1H,dd,J=6.2 and 16.4Hz),6.05(1H,d,J=16.4Hz),7.0-7.8(27H,m)
质谱 m/z:949
实例7-1)
在冰冷却下向1N氟化四丁铵的四氢呋喃(40ml)溶液中滴入乙酸(2.4ml),然后在冰冷却下将混合物加到甲基(±)-赤-(E)-3,5-双(叔丁基二苯基甲硅烷氧基)7-〔2,3-二氢-6-(4-氟苯基)-1-氧吡咯并〔1,2,3-de〕〔1,4〕苯并噻嗪-5-基〕庚-6-烯酸酯(1.99g)的四氢呋喃(10ml)溶液中。所得的混合物在室温下搅拌40小时并用乙酸乙酯(100ml)稀释。溶液用盐水洗涤3次,干燥并蒸发得到糖浆状残余物。残余物经硅胶柱层析,用乙酸乙酯-甲醇(40∶1,V/V)洗涤,得到甲基(±)-赤-(E)-7-〔2,3-二氢-6-(4-氟苯基)-1-氧吡咯并〔1,2,3-de〕〔1,4〕苯并噻嗪-5-基〕-3,5-二羟基庚-6-烯酸酯(0.69g)。
IR(纯的):3370,3000,2950,1730,1530,1500cm-1
NMR(CDCl3,δ):1.5-1.8(2H,m),2.50(2H,d,J=5.9Hz),2.8-3.0(1H,m),3.5-3.7(1H,m),3.72(3H,s),4.2-4.8(4H,m),6.04(1H,dd,J=5.5 and 16Hz),6.70(1H,d,J=16Hz),7.0-7.8(7H,m)
实例7-2)
按实例7-1)基本上相同的方法制得甲基(±)-赤-(E)-7-〔2,3-二氢-6-(4-氟苯基)-1,1-二氧吡咯并〔1,2,3,-de〕〔1,4〕苯并噻嗪-5-基〕-3,5-二氢庚-6-烯酸酯(0.44g)。
IR(纯的):3450,1730,1535,1500cm-1
NMR(CDCl3,δ):1.6-1.8(2H,m),2.51(2H,d,J=6.2Hz),3.5-3.7(2H,m),3.73(3H,s),3.76(1H,s),3.82(1H,s),4.2-4.7(2H,m),4.8-4.9(2H,m),5.90(1H,dd,J=5.3 and 16.2Hz),6.70(1H,d,J=16.2Hz),7.1-7.8(7H,m)
实例8
将甲基(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸酯(1.0g)和(S)-(-)-1-苯基乙胺(1.34g)的混合物于90℃搅拌6小时,然后冷却至室温。反应混合物用乙酸乙酯稀释并倒入稀盐酸中。混合物用乙酸乙酯萃取,萃取液依次用饱和碳酸氢钠水溶液和盐水洗涤。有机层经干燥和蒸发,得到N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺(1.27g)的非对映混合物。该非对映混合物在硅胶柱上经中压层析分离,用己烷和乙酸乙酯(2∶3,V/V)的混合液洗脱,得到非对映体A,N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺(0.43g),为糖浆状物。
[α]26 D-15.6°(C1.0,CHCl3)
IR(薄膜):3320,2990,2950,1640,1535,1500cm-1
NMR(CDCl3,δ):1.38-1.57(2H,m),1.49(3H,d,J=7.0Hz),1.62(6H,s),2.09(2H,t,J=6.2Hz),2.20-2.40(2H,m),3.00(2H,t,J=6.2Hz),4.13(1H,m),4.45(1H,m),5.11(1H,m),5.54(1H,dd,J=5.3 and 15.8Hz),6.09(1H,bd,J=7.9Hz),6.83(1H,dd,J=1.5 and 15.8Hz),6.90-7.40(12H,m)
继续用己烷和乙酸乙酯(1∶2,V/V)的混合液洗脱,得到它的非对映体B(0.49g),为糖浆状物,用己烷和乙酸乙酯混合液结晶,得到无色针状物(0.34g)。
[α]26 D-36.3°(C1.0,CHCl3)
mp:133-135℃
IR(液体石蜡):3420,3200,1650,1530,1500cm-1
NMR(CDCl3,δ):1.25-1.54(2H,m),1.49(3H,d,J=7.0Hz),1.62(6H,s),2.09(2H,t,J=6.2Hz),2.20-2.40(2H,m),3.00(2H,t,J=6.2Hz),4.13(1H,m),4.44(1H,m),5.11(1H,m),5.53(1H,dd,J=5.3 and 15.8Hz),6.06(1H,bd,J=7.8Hz),6.82(1H,dd,J=1.3 and 15.8Hz),6.87-7.41(12H,m)
实例9-1)
将N-(S)-(1-苯基乙基)-赤-(E)-7-(5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体A(0.37g)溶于含1N氢氧化钠(3.4ml)的乙醇(4ml)中,并回流15小时。在真空下除去溶剂得到残余物,残余物与水(10ml)混合并用1N盐酸(4.4ml)酸化。所得的混合物用乙酸乙酯萃取。萃取液用盐水洗涤2次,经干燥并蒸发得到赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸,是非对映体A的酸,为黄色糖浆状物。将此糖浆状物的四氢呋喃(2ml)溶液冷却,并向其中加入1-羟基苯并三唑(0.046g)和N-(3-二甲氨基丙基)-N′-乙基碳化二亚胺(0.11g),溶液在室温下静置过夜。反应混合物用乙酸乙酯稀释,所得的悬浮液依次用饱和碳酸氢钠水溶液和盐水洗涤。有机层经干燥和蒸发得到浆状物(0.33g)。该糖浆状物用乙酸乙酯和异丙醚的混合液结晶,得到(-)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.19g)。
[α]24 D-6.1°(C1.0,丙酮)
mp:171-173℃(分解)
IR(液体石蜡):3500,1735,1535,1500cm-1
NMR(丙酮 -d6,δ):1.66(6H,s),1.70-2.00(2H,m),2.12(2H,t,J=6.9Hz),2.45-2.76(2H,m),3.00(2H,t,J=6.9Hz),4.31(1H,m),4.42(1H,d,J=3.1Hz),5.30(1H,m),5.65(1H,dd,J=6.4 and 15.8Hz),6.90-7.51(8H,m)
实例9-2)
将N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体B(0.28g)水解,所得的非对映体B的酸按实例9-1)基本上相同的方法进行内酯化,得到(+)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.18g),为结晶状。
[α]26 D+6.2°(C1.0,丙酮)
mp:170-172℃(分解)
IR(液体石蜡):3500,1735,1535,1500cm-1
NMR(Acetone-d6,δ):1.66(6H,s),1.70-2.00(2H,m),2.12(2H,t,J=6.9Hz),2.45-2.76(2H,m),3.00(2H,t,J=6.9Hz),4.31(1H,m),4.42(1H,d,J=3.1Hz),5.30(1H,m),5.65(1H,dd,J=6.4 and 15.8Hz),6.90-7.51(8H,m)
实例10-1)
将(-)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.12g)在甲醇中的悬浮液用冰冷却,并向其中滴入1N氢氧化钠溶液(0.29ml)。混合物在室温下搅拌1小时。在真空下除去溶液,残余物溶于水(7ml)中并冷冻干燥,得到(-)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(0.13g),为淡黄色粉末。
[α]29 D-27.4°(C0.5,甲醇)
NMR(CD3OD,δ):1.36-1.71(2H,m),1.64(6H,s),2.09(2H,t,J=6.2Hz),2.16-2.38(2H,m),2.98(2H,t,J=6.2Hz),3.91(1H,m),4.35(1H,m),5.57(1H,dd,J=6.1 and 15.9Hz),6.81-7.42(8H,m)
实例10-2)
按实例10-1)基本上相同的方法将(+)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.09g)水解,得到(+)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(0.10g),为淡黄色粉末。
[α]29 D+27.6°(C0.5,甲醇)
NMR(CD3OD,δ):1.36-1.71(2H,m),1.64(6H,s),2.09(2H,t,J=6.2Hz),2.16-2.38(2H,m),2.98(2H,t,J=6.2Hz),3.91(1H,m),4.35(1H,m),5.57(1H,dd,J=6.1 and 15.9Hz),6.81-7.42(8H,m)
实例11
将甲基(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸酯(2.0g)和(S)-(-)-1-苯基乙胺(2.5g)进行缩合,按实例8基本上相同的方法将所得的非对映的酰胺进行分离,得到N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体A(0.71g),为糖浆状物。
[α]26 D-24.8°(C1.0,CHCl3)
IR(薄膜):3320,2990,2950,1640,1600,1535cm-1
NMR(CDCl3,δ):1.30-1.60(2H,m),1.50(3H,d,J=6.9Hz),1.64(6H,s),2.10(2H,t,J=5.9Hz),2.20-2.40(2H,m),2.99(2H,t,J=5.9Hz),3.71(3H,s),4.10(1H,m),4.41(1H,m),5.12(1H,m),5.48(1H,dd,J=5.8 and 15.7Hz),6.11(1H,bd,J=7.6Hz),6.60-7.40(12H,m)
按实例8基本上相同的方法制得N-(S)-1-(1-苯基乙基)-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体B(0.68g),为糖浆状物。
[α]26 D-23.9°(C1.0,CHCl3)
IR(薄膜):3320,2990,2950,1645,1605,1540cm-1
NMR(CDCl3,δ):1.30-1.60(2H,m),1.50(3H,d,J=6.9Hz),1.63(6H,s),2.09(2H,t,J=6.2Hz),2.20-2.40(2H,m),2.99(2H,t,J=6.2Hz),3.71(3H,s),4.10(1H,m),4.40(1H,m),5.11(1H,m),5.46(1H,dd,J=5.7 and 15.7Hz),6.09(1H,d,J=7.8Hz),6.50-7.40(12H,m)
实例12-1)
将N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体A(0.50g)进行水解,所得的对映体A的酸按实例9-1)基本上相同的方法进行内酯化,得到(-)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.24g),为结晶状。
[α]24 D-12.2°(C1.0,丙酮)
mp:144-146℃(dec.)
IR(液体石蜡):3450,1720,1605,1540,1500cm-1
NMR(丙酮 -d6,δ):1.57-1.90(2H,m),1.65(6H,s),2.12(2H,t,J=6.4Hz),2.41-2.72(2H,m),2.99(2H,t,J=6.4Hz),3.76(3H,s),4.24(1H,m),4.37(1H,d,J=3.2Hz),5.22(1H,m),5.54(1H,dd,J=6.6 and 15.7Hz),6.71-7.30(7H,m)
实例12-2)
按实例9-1)所述的方法将N-(S)-(1-苯基乙基)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酰胺的非对映体B(0.50g)进行水解,并将所得的酸进行内酯化,得到(+)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.25g),为结晶体。
[α]24 D+14.3°(C1.0,丙酮)
mp:152-153.5℃(分解)
IR(液体石蜡):3450,1720,1605,1540,1500cm-1
NMR(丙酮 -d6,δ):1.57-1.90(2H,m),1.65(6H,s),2.12(2H,t,J=6.4Hz),2.41-2.72(2H,m),2.99(2H,t,J=6.4Hz),3.76(3H,s),4.24(1H,m),4.37(1H,d,J=3.2Hz),5.22(1H,m),5.54(1H,dd,J=6.6 and 15.7Hz),6.71-7.30(7H,m)
实例13-1)
按实例10-1)所述的方法将(-)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.15g)进行水解,得到(-)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(0.16g),为淡黄色粉末。
[α]24 D-43.6°(C1.0,甲醇)
NMR(CD3OD,δ):1.14-1.58(2H,m),1.65(6H,s),2.09(2H,t,J=6.4Hz),2.11-2.34(2H,m),2.98(2H,t,J=6.4Hz),3.72(3H,s),3.79(1H,m),4.31(1H,m),5.49(1H,dd,J=6.3 and 15.7Hz),6.65-7.20(7H,m)
实例13-2)
按实例10-1)所述方法将(+)-(E)-6-〔2-{5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基}乙烯基〕-4-羟基-3,4,5,6-四氢-2H-吡喃-2-酮(反式异构体)(0.15g)进行水解,得到(+)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸钠(0.16g)。
[α]24 D+43.5°(C1.0,甲醇)
NMR(CD3OD,δ):1.14-1.58(2H,m),1.65(6H,s),2.09(2H,t,J=6.4Hz),2.11-2.34(2H,m),2.98(2H,t,J=6.4Hz),3.72(3H,s),3.79(1H,m),4.31(1H,m),5.49(1H,dd,J=6.3 and 15.7Hz),6.65-7.20(7H,m)
Claims (18)
2、权利要求1所述的化合物,其中
R3为苯基、甲苯基、二甲苯基、枯烯基、 基、萘基或含硫原子的五或六元不饱和的杂环基团,上述各个基团可以由1个或多个选自以下一组的取代基取代:卤素、羟基、低级烷基、芳氧基、三卤代(低级)烷基、低级烷氧基和单或二(低级)烷氨基,
R5为羧基、酯化的羧基或酰胺化的羧基,以及
R6为氢、三取代的甲硅烷基或酰基。
3、权利要求2所述的化合物,其中
R3为苯基、甲苯基、二甲苯基、枯烯基、 基、萘基或噻吩基,各个基团可以由1至3个选自以下一组的取代基取代:卤素、羟基、低级烷基、苯氧基、甲苯氧基、二甲苯氧基、枯烯氧基、 氧基、萘氧基、三卤代(低级)烷基、低级烷氧基和单或二(低级)烷氨基,
4、权利要求3所述的化合物,其中
R3为苯基、萘基或噻吩基,它们各自由1至3个选自以下一组的取代基取代:卤素、羟基、低级烷基、苯氧基、三卤代(低级)烷基、低级烷氧基和单或二(低级)烷氨基,
R5为羧基、低级烷氧羰基或N-〔苯基(低级)烷基〕甲酰氨基,以及
R6为氢或(低级烷基)二苯基甲硅烷基。
5、权利要求4所述的化合物,其中
R1和R2各自为氢或C1~C4烷基,
R3为苯基、萘基或噻吩基,它们各自由1至3个选自以下一组的取代基取代:卤素、羟基、C1~C4烷基、苯氧基、三卤素(C1~C4)烷基、C1~C4烷氧基和单或二(C1~C4)烷氨基,
R4为氢、卤素或C1~C4烷基,
R5为羧基、C1~C4烷氧基羰基或N-〔苯基(C1~C4)烷基〕甲酰氨基,以及
R6为氢或(C1~C4烷基)二苯基甲硅烷基。
6、权利要求5所述的化合物,其中Y为1,2-亚乙烯基。
7、权利要求6所述的化合物,其中A为亚甲基或次甲基。
9、权利要求8所述的化合物,其中R5为羧基,R6为氢。
10、权利要求9所述的化合物,其中
R1和R2各自为氢或甲基,
R3为苯基、2-(或3-或4-)氟苯基、2,4-(或3,4-)二氟苯基、4-氯苯基、3,4-二氯苯基、2-氯-4-氟苯基、2,4,6-三氟苯基、间甲苯基、2,4-(或3,4-或3,5-)二甲苯基、4-氟-2-(或3-)甲基苯基、4-氟-3,5-二甲基苯基、4-苯氧基苯基、2-萘基、3-三氟甲基苯基、4-二甲氨基苯基、3,5-二叔丁基-4-羟基苯基、2-甲氧基-4-氟苯基、5-甲基-2-噻吩基或5-氯,-2-噻吩基,
R4为氢、氯、氟或甲基。
11、权利要求10所述的化合物,它们是下述化合物或其钠盐,
(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸,
(±)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸,
(+)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟苯基)-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸,或
(+)-赤-(E)-7-〔5,6-二氢-4,4-二甲基-1-(4-氟-2-甲氧基苯基〕-4H-吡咯并〔3,2,1-ij〕喹啉-2-基〕-3,5-二羟基庚-6-烯酸。
12、一种制备下式化合物或其药学上适用的盐的方法,
其中R1和R2各自为氢或低级烷基,
R3为芳基或杂环基,它们各自可以由1个或几个合适的取代基取代,
R4为氢、卤素或低级烷基,
A为亚甲基、次甲基、氧杂、硫杂、亚磺酰基或磺酰基,
Y为1,2-亚乙烯基或1,2-亚乙基,
Z为下式基团,
其中R5为羧基或受保护的羧基,
R6为氢或羟基保护基,以及
该方法包括
(a)使下式化合物或其盐还原,
(b)使下式化合物或其盐脱去R5 a上的羧基保护基,
其中R1、R2、R3、R4、A、Y和 各自的定义同上,R5 a为受保护的羧基,
得到下式化合物或其盐,
(c)使下式化合物或其盐环合,
(d)使下式化合物或其盐还原,
(e)将羟基保护基引入到下式化合物或其盐中,
其中R1R2R3R4R5A、Y和 各自的定义同上,R6 a为羟基保护基,
(f)使下式化合物或其盐氧化,
其中R1、R2、R3、R4、R5、R6 a和Y各自的定义同上,得到下式化合物或其盐,
其中R1、R2、R3、R4、R5、R6 a和Y各自的定义同上,Aa为亚磺酰基或磺酰基,
(g)使下式化合物或其盐脱去羟基保护基R6 a,
其中R1、R2、R3、R4、R5、R6 a、A、Y和 各自的定义同上,得到下式化合物或其盐,
(h)使下式化合物或其盐与芳基(低级)烷基胺或其盐反应,
得到下式化合物或其盐,
其中R1、R2、R3、R4、A、Y和 各自的定义同上,R5 c为N-〔芳基(低级)烷基〕甲酰氨基,
(i)使下式化合物或其盐的N-〔芳基(低级)烷基〕甲酰氨基R5 c水解,
其中R1、R2、R3、R4、R5 c、A、Y和 各自的定义同上,得到下式化合物或其盐,
13、含有权利要求1所述化合物或其可药用盐作为有效成分,与药学上适用的载体或赋形剂混合得到的药用组合物。
14、用作药物的权利要求1化合物或其药学上适用的盐。
15、用作3-羟基-3-甲基戊二酰基-辅酶A还原酶抑制剂的权利要求1化合物或其药学上适用的盐。
16、应用权利要求1所述的化合物或其药学上适用的盐配制治疗人或动物中血胆甾醇过多和血脂蛋白过多症及其有关的疾病。
17、一种治疗血胆甾醇过多和血脂蛋白过多症及其有关疾病的方法,该方法包括给人或动物服用权利要求1所述化合物或其药学上适用的盐。
18、一种配制药用组合物的方法,该方法包括将权利要求1所述化合物或其药学上适用的盐与药学上适用的载体或赋形剂混合。
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JPH0565748U (ja) * | 1992-02-21 | 1993-08-31 | 株式会社ユニシアジェックス | 後輪操舵装置 |
WO1999020632A1 (fr) * | 1997-10-23 | 1999-04-29 | Takeda Chemical Industries, Ltd. | Derives d'imidazopyridine condenses, leur procede de production et preparations les renfermant |
KR100385673B1 (ko) * | 2001-08-17 | 2003-06-02 | 신의승 | 회전추를 이용한 휴대가 간편한 원판 운동기구 |
WO2011082266A2 (en) | 2009-12-30 | 2011-07-07 | Arqule, Inc. | Substituted heterocyclic compounds |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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HU204253B (en) * | 1982-11-22 | 1991-12-30 | Sandoz Ag | Process for producing mevalonolactone analogues and derivatives and pharmaceutical compositions containing them |
US4739073A (en) * | 1983-11-04 | 1988-04-19 | Sandoz Pharmaceuticals Corp. | Intermediates in the synthesis of indole analogs of mevalonolactone and derivatives thereof |
-
1989
- 1989-08-22 GB GB898919091A patent/GB8919091D0/en active Pending
-
1990
- 1990-02-13 GB GB909003252A patent/GB9003252D0/en active Pending
- 1990-07-13 US US07/552,127 patent/US5164400A/en not_active Expired - Fee Related
- 1990-07-15 IL IL9095088A patent/IL95088A0/xx unknown
- 1990-07-16 IE IE259090A patent/IE902590A1/en unknown
- 1990-07-31 AU AU60012/90A patent/AU6001290A/en not_active Abandoned
- 1990-08-02 ZA ZA906102A patent/ZA906102B/xx unknown
- 1990-08-04 EP EP19900115042 patent/EP0414023A3/en not_active Withdrawn
- 1990-08-21 PT PT95052A patent/PT95052A/pt not_active Application Discontinuation
- 1990-08-21 CN CN90107135A patent/CN1049663A/zh active Pending
- 1990-08-21 KR KR1019900013035A patent/KR910004636A/ko not_active Application Discontinuation
- 1990-08-21 FI FI904138A patent/FI904138A0/fi not_active Application Discontinuation
- 1990-08-21 HU HU905089A patent/HUT55015A/hu unknown
- 1990-08-21 NO NO90903666A patent/NO903666L/no unknown
- 1990-08-21 CA CA002023726A patent/CA2023726A1/en not_active Abandoned
- 1990-08-22 JP JP2221750A patent/JPH0386882A/ja active Pending
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108752340A (zh) * | 2018-07-18 | 2018-11-06 | 吕烨 | 吡咯并喹啉衍生物及其在治疗心律失常中的用途 |
Also Published As
Publication number | Publication date |
---|---|
ZA906102B (en) | 1991-05-29 |
AU6001290A (en) | 1991-02-28 |
EP0414023A2 (en) | 1991-02-27 |
NO903666D0 (no) | 1990-08-21 |
GB8919091D0 (en) | 1989-10-04 |
EP0414023A3 (en) | 1991-11-06 |
US5164400A (en) | 1992-11-17 |
IE902590A1 (en) | 1991-02-27 |
CA2023726A1 (en) | 1991-02-23 |
PT95052A (pt) | 1991-04-18 |
KR910004636A (ko) | 1991-03-29 |
JPH0386882A (ja) | 1991-04-11 |
HUT55015A (en) | 1991-04-29 |
HU905089D0 (en) | 1991-01-28 |
IL95088A0 (en) | 1991-06-10 |
NO903666L (no) | 1991-02-25 |
GB9003252D0 (en) | 1990-04-11 |
FI904138A0 (fi) | 1990-08-21 |
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