CN1055684C - 取代的吡啶化合物的制备方法 - Google Patents
取代的吡啶化合物的制备方法 Download PDFInfo
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- CN1055684C CN1055684C CN89100326A CN89100326A CN1055684C CN 1055684 C CN1055684 C CN 1055684C CN 89100326 A CN89100326 A CN 89100326A CN 89100326 A CN89100326 A CN 89100326A CN 1055684 C CN1055684 C CN 1055684C
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- group
- propyl
- methyl
- fluorophenyl
- yield
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- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims description 37
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims description 20
- 150000003222 pyridines Chemical class 0.000 title abstract description 14
- 238000004519 manufacturing process Methods 0.000 title 1
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 17
- 230000007062 hydrolysis Effects 0.000 claims abstract description 13
- -1 azido- Chemical class 0.000 claims description 310
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 168
- 125000000217 alkyl group Chemical group 0.000 claims description 104
- 238000000034 method Methods 0.000 claims description 97
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 66
- 239000001257 hydrogen Substances 0.000 claims description 62
- 229910052739 hydrogen Inorganic materials 0.000 claims description 62
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 57
- 239000002585 base Substances 0.000 claims description 54
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 54
- 238000006243 chemical reaction Methods 0.000 claims description 53
- 125000003545 alkoxy group Chemical group 0.000 claims description 52
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 52
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 51
- 150000002431 hydrogen Chemical class 0.000 claims description 48
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 41
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 34
- 229910052736 halogen Inorganic materials 0.000 claims description 27
- 150000002367 halogens Chemical class 0.000 claims description 27
- 239000002253 acid Substances 0.000 claims description 24
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 23
- 150000002148 esters Chemical class 0.000 claims description 16
- 230000002829 reductive effect Effects 0.000 claims description 15
- 239000003513 alkali Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 238000006722 reduction reaction Methods 0.000 claims description 13
- 239000012442 inert solvent Substances 0.000 claims description 11
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 9
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims description 9
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 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 claims description 5
- 239000011591 potassium Substances 0.000 claims description 5
- 229910052700 potassium Inorganic materials 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 4
- 150000007513 acids Chemical class 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- 239000011575 calcium Substances 0.000 claims description 3
- 229910052791 calcium Inorganic materials 0.000 claims description 3
- JLVVSXFLKOJNIY-UHFFFAOYSA-N Magnesium ion Chemical compound [Mg+2] JLVVSXFLKOJNIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000001207 fluorophenyl group Chemical group 0.000 claims description 2
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- HCXJFMDOHDNDCC-UHFFFAOYSA-N 5-$l^{1}-oxidanyl-3,4-dihydropyrrol-2-one Chemical group O=C1CCC(=O)[N]1 HCXJFMDOHDNDCC-UHFFFAOYSA-N 0.000 claims 2
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims 2
- 125000004916 (C1-C6) alkylcarbonyl group Chemical group 0.000 claims 1
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims 1
- BRDWIEOJOWJCLU-LTGWCKQJSA-N GS-441524 Chemical compound C=1C=C2C(N)=NC=NN2C=1[C@]1(C#N)O[C@H](CO)[C@@H](O)[C@H]1O BRDWIEOJOWJCLU-LTGWCKQJSA-N 0.000 claims 1
- 235000019439 ethyl acetate Nutrition 0.000 claims 1
- 229910001425 magnesium ion Inorganic materials 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 220
- 239000003814 drug Substances 0.000 abstract description 5
- 230000009467 reduction Effects 0.000 abstract description 5
- 238000005984 hydrogenation reaction Methods 0.000 abstract description 3
- 239000013543 active substance Substances 0.000 abstract 1
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 162
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 161
- 238000005160 1H NMR spectroscopy Methods 0.000 description 132
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 111
- 239000000203 mixture Substances 0.000 description 108
- YMWUJEATGCHHMB-UHFFFAOYSA-N dichloromethane Natural products ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 101
- 239000000243 solution Substances 0.000 description 86
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 81
- 229910052731 fluorine Inorganic materials 0.000 description 62
- 239000011737 fluorine Substances 0.000 description 62
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 61
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 61
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 60
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 60
- 239000000460 chlorine Substances 0.000 description 60
- 229910052801 chlorine Inorganic materials 0.000 description 60
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 57
- 125000003118 aryl group Chemical group 0.000 description 45
- 239000012074 organic phase Substances 0.000 description 45
- 229910052760 oxygen Inorganic materials 0.000 description 45
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 43
- 238000003756 stirring Methods 0.000 description 43
- 239000001301 oxygen Substances 0.000 description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 38
- 239000000741 silica gel Substances 0.000 description 36
- 229910002027 silica gel Inorganic materials 0.000 description 36
- 229960001866 silicon dioxide Drugs 0.000 description 36
- 125000001544 thienyl group Chemical group 0.000 description 36
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 35
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 35
- 229910052794 bromium Inorganic materials 0.000 description 35
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 33
- 238000005406 washing Methods 0.000 description 32
- 239000000047 product Substances 0.000 description 31
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 30
- 239000003921 oil Substances 0.000 description 29
- 235000019198 oils Nutrition 0.000 description 29
- 239000003208 petroleum Substances 0.000 description 29
- 125000002541 furyl group Chemical group 0.000 description 28
- 238000010992 reflux Methods 0.000 description 28
- 125000004414 alkyl thio group Chemical group 0.000 description 27
- 238000004440 column chromatography Methods 0.000 description 27
- 239000007788 liquid Substances 0.000 description 27
- 239000012043 crude product Substances 0.000 description 26
- 125000004076 pyridyl group Chemical group 0.000 description 26
- 125000000714 pyrimidinyl group Chemical group 0.000 description 26
- 125000005493 quinolyl group Chemical group 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 24
- 125000004390 alkyl sulfonyl group Chemical group 0.000 description 24
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 23
- 125000005956 isoquinolyl group Chemical group 0.000 description 23
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 description 23
- 239000002904 solvent Substances 0.000 description 23
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 22
- 125000003710 aryl alkyl group Chemical group 0.000 description 22
- 125000001072 heteroaryl group Chemical group 0.000 description 22
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 21
- 229910052799 carbon Inorganic materials 0.000 description 21
- 125000004432 carbon atom Chemical group C* 0.000 description 21
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 20
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 19
- 239000013078 crystal Substances 0.000 description 18
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 18
- 239000012299 nitrogen atmosphere Substances 0.000 description 18
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 18
- 150000001721 carbon Chemical group 0.000 description 17
- 125000004494 ethyl ester group Chemical group 0.000 description 17
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 16
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 15
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 15
- 239000007864 aqueous solution Substances 0.000 description 15
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 15
- 238000001035 drying Methods 0.000 description 15
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 15
- 239000012312 sodium hydride Substances 0.000 description 15
- 229910000104 sodium hydride Inorganic materials 0.000 description 15
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 14
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 14
- 125000004453 alkoxycarbonyl group Chemical group 0.000 description 14
- 125000004104 aryloxy group Chemical group 0.000 description 14
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 14
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 13
- 125000006125 ethylsulfonyl group Chemical group 0.000 description 13
- VMJNTFXCTXAXTC-UHFFFAOYSA-N 2,2-difluoro-1,3-benzodioxole-5-carbonitrile Chemical group C1=C(C#N)C=C2OC(F)(F)OC2=C1 VMJNTFXCTXAXTC-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 12
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 12
- 125000004391 aryl sulfonyl group Chemical group 0.000 description 12
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 description 12
- 239000003795 chemical substances by application Substances 0.000 description 12
- 229960004756 ethanol Drugs 0.000 description 12
- 238000003810 ethyl acetate extraction Methods 0.000 description 12
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 12
- 125000000335 thiazolyl group Chemical group 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 11
- 150000001299 aldehydes Chemical class 0.000 description 11
- 125000005110 aryl thio group Chemical group 0.000 description 11
- 125000004541 benzoxazolyl group Chemical group O1C(=NC2=C1C=CC=C2)* 0.000 description 11
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 11
- 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 11
- 125000001786 isothiazolyl group Chemical group 0.000 description 11
- 125000000842 isoxazolyl group Chemical group 0.000 description 11
- 150000004702 methyl esters Chemical class 0.000 description 11
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 11
- 125000003373 pyrazinyl group Chemical group 0.000 description 11
- 125000002098 pyridazinyl group Chemical group 0.000 description 11
- 238000010898 silica gel chromatography Methods 0.000 description 11
- 229910052938 sodium sulfate Inorganic materials 0.000 description 11
- 235000011152 sodium sulphate Nutrition 0.000 description 11
- 238000000967 suction filtration Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 11
- 125000005034 trifluormethylthio group Chemical group FC(S*)(F)F 0.000 description 11
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 10
- 238000009835 boiling Methods 0.000 description 10
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 10
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 10
- 125000002971 oxazolyl group Chemical group 0.000 description 10
- 150000003053 piperidines Chemical class 0.000 description 10
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 9
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 description 9
- JDCBWJCUHSVVMN-UHFFFAOYSA-N but-3-en-2-amine Chemical compound CC(N)C=C JDCBWJCUHSVVMN-UHFFFAOYSA-N 0.000 description 9
- 238000000605 extraction Methods 0.000 description 9
- 235000002639 sodium chloride Nutrition 0.000 description 9
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 125000004397 aminosulfonyl group Chemical group NS(=O)(=O)* 0.000 description 8
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 150000002576 ketones Chemical class 0.000 description 8
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 8
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 8
- 229910052757 nitrogen Inorganic materials 0.000 description 8
- 239000003960 organic solvent Substances 0.000 description 8
- 239000002994 raw material Substances 0.000 description 8
- 238000010572 single replacement reaction Methods 0.000 description 8
- 239000012279 sodium borohydride Substances 0.000 description 8
- 229910000033 sodium borohydride Inorganic materials 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- JSLZUBLGGPEVQN-DIPNUNPCSA-N (2r)-4-methyl-2-propan-2-yl-2-[2-[4-[4-[2-(3,4,5-trimethoxyphenyl)ethyl]piperazin-1-yl]butoxy]phenyl]-1,4-benzothiazin-3-one Chemical compound COC1=C(OC)C(OC)=CC(CCN2CCN(CCCCOC=3C(=CC=CC=3)[C@@]3(C(N(C)C4=CC=CC=C4S3)=O)C(C)C)CC2)=C1 JSLZUBLGGPEVQN-DIPNUNPCSA-N 0.000 description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 7
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 7
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 7
- 125000002252 acyl group Chemical group 0.000 description 7
- 150000001408 amides Chemical class 0.000 description 7
- 150000002170 ethers Chemical class 0.000 description 7
- AEXYGJRYLCZIJM-ALCCZGGFSA-N ethyl (z)-3-amino-4-methylpent-2-enoate Chemical compound CCOC(=O)\C=C(/N)C(C)C AEXYGJRYLCZIJM-ALCCZGGFSA-N 0.000 description 7
- 229930195733 hydrocarbon Natural products 0.000 description 7
- 150000002500 ions Chemical class 0.000 description 7
- 229950001891 iprotiazem Drugs 0.000 description 7
- 230000003647 oxidation Effects 0.000 description 7
- 238000007254 oxidation reaction Methods 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 235000015424 sodium Nutrition 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 229910052783 alkali metal Inorganic materials 0.000 description 6
- 125000003282 alkyl amino group Chemical group 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 230000008859 change Effects 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 238000002425 crystallisation Methods 0.000 description 6
- 230000008025 crystallization Effects 0.000 description 6
- 125000000753 cycloalkyl group Chemical group 0.000 description 6
- 125000002147 dimethylamino group Chemical group [H]C([H])([H])N(*)C([H])([H])[H] 0.000 description 6
- 150000002430 hydrocarbons Chemical class 0.000 description 6
- 125000002883 imidazolyl group Chemical group 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- 125000001624 naphthyl group Chemical group 0.000 description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 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
- 125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 description 6
- GVNVAWHJIKLAGL-UHFFFAOYSA-N 2-(cyclohexen-1-yl)cyclohexan-1-one Chemical compound O=C1CCCCC1C1=CCCCC1 GVNVAWHJIKLAGL-UHFFFAOYSA-N 0.000 description 5
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 5
- 101150065749 Churc1 gene Proteins 0.000 description 5
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 5
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 5
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- 235000020357 syrup Nutrition 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- CXWXQJXEFPUFDZ-UHFFFAOYSA-N tetralin Substances C1=CC=C2CCCCC2=C1 CXWXQJXEFPUFDZ-UHFFFAOYSA-N 0.000 description 1
- VSAISIQCTGDGPU-UHFFFAOYSA-N tetraphosphorus hexaoxide Chemical compound O1P(O2)OP3OP1OP2O3 VSAISIQCTGDGPU-UHFFFAOYSA-N 0.000 description 1
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 description 1
- 150000003613 toluenes Chemical class 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- 125000002306 tributylsilyl group Chemical group C(CCC)[Si](CCCC)(CCCC)* 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- YFNKIDBQEZZDLK-UHFFFAOYSA-N triglyme Chemical compound COCCOCCOCCOC YFNKIDBQEZZDLK-UHFFFAOYSA-N 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- HRXKRNGNAMMEHJ-UHFFFAOYSA-K trisodium citrate Chemical compound [Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O HRXKRNGNAMMEHJ-UHFFFAOYSA-K 0.000 description 1
- 229940038773 trisodium citrate Drugs 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
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Abstract
本发明涉及一类新的取代吡啶的方法,其中通过还原取代吡啶的酮基,接着水解,环化或氢化来完成。这类新化合物能用作药剂的活性化合物。
Description
本发明涉及取代吡啶,用于制备它们的中间体,它们的制备方法及其在药剂中的用途。
人们已经知道从霉菌培养基分离得到的内酯衍生物是3-羟基-3-甲基-戊二酰基辅酶A还原酶(HMG-CoA还原酶)的抑制剂,〔mevinolin,EP-A22,478;US4,231,938〕。此外,某些吲哚衍生物或吡唑衍生物也是HMG-CoA还原酶的抑制剂〔EP-A1,114,027;美国专利4,613,610〕。
A代表由下列相同或不同取代基单取代、二取代或三取代的杂芳基,所述取代基为卤素,烷基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷氧羰基或式-NR1R2基团,其中R1和R2可相同或不同,表示烷基,芳基,芳烷基,酰基,烷基磺酰基或芳基磺酰基,或
A代表由相同或不同烷基单取代至五取代的芳基,其中烷基可以任意由羟基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷基,芳烷氧基,芳烷硫基,芳烷基磺酰基,卤素,氰基,硝基,三氟甲基,三氟甲氧基,三氟甲硫基,烷氧羰基,氨磺酰基,二烷基氨磺酰基,氨基甲酰基,二烷基氨基甲酰基或式-NR1R2基团所取代,其中R1和R2定义如前,
A代表直链或支链烷基,
B代表环烷基,或能由卤素,氰基,烷氧基,烷硫基,烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基,三氟甲基磺酰基,烷氧羰基,酰基或式-NR1R2基团取代的烷基,其中R1和R2可相同或不同,表示烷基,芳基,芳烷基,酰基,烷基磺酰基或芳基磺酰基,或
B代表由氨基甲酰基,二烷基氨基甲酰基,氨磺酰基,二烷基氨酰基,杂芳基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷氧基,芳烷硫基或芳烷基磺酰基取代的烷基,其中提到的杂芳基和芳基取代基可由下列相同或不同取代基单取代,二取代或三取代,所述取代基为卤素,氰基,三氟甲基,三氟甲氧基,烷基,烷氧基,烷硫基或烷基磺酰基,
D和E可相同或不同,代表氢,CN或NO2,环烷基或能由叠氮基,卤素,羟基,氰基,烷氧基,烷硫基,烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基,三氟甲基磺酰基,烷氧羰基,酰基或式-NR1R2基团(R1、R2定义如前)取代的直链或支链烷基,或由氨基甲酰基,二烷基氨基甲酰基,氨磺酰基,二烷基氨磺酰基,杂芳基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷氧基,芳烷硫基或芳烷基磺酰基取代的直链或支链的烷基,其中杂芳基和芳基能由相同或不同的卤素、氰基,三氟甲基,三氟甲氧基,烷基,烷氧基,烷硫基或烷基磺酰基单取代,二取代或三取代,或
D和E代表由下列相同或不同取代基单取代,二取代或三取代的杂芳基,所述取代基为卤素,烷基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基或烷氧羰基,或式-NR1R2基团,其中R1和R2定义如前,或
D和E代表能由下列相同或不同烷基所单取代至五取代的芳基,其中烷基能任意由羟基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷基,芳烷氧基,芳烷硫基,芳烷基磺酰基,卤素,氰基,硝基,三氟甲基,三氟甲氧基,三氟甲硫基,烷氧羰基,氨磺酰基,二烷基氨磺酰基,氨基甲酰基或二烷基氨基甲酰基,或式-NR1R2基团所取代,其中R1和R2定义如前,或
D或E代表式-NR3R4,-COR5或-CR11R12-Y基团,基中R3和R4可相同或不同,表示氢,或表示烷基,芳基或芳烷基,或表示式-COR6或-SO2R7基团,或R3和R4一起形成亚烷基链,该链能由N,O,S和/或N-烷基,N-芳基,N-氨基甲酰基或N-烷氧羰基阻断,
R6表示氢,或表示-NHR8基团,或表示烷氧基或表示烷基,芳基,芳氧基,芳烷基,芳烷氧基或杂芳基,其中所提到的这些基团能由下列相同或不同取代基所单取代,二取代或三取代,该取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,
R7表示环烷基,或表示能由氰基,卤素,三氟甲基,三氟甲氧基或烷氧羰基所取代的烷基,或表示芳基,芳烷基或杂芳基,其中这些基团能由下列相同或不同取代基所单取代,二取代或三取代,所述取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,
R8表示氢,环烷基,或任意由氰基,卤素,三氟甲基或三氟甲氧基取代的烷基,或
R8表示芳基,芳烷基或杂芳基,其中所提到的基团能由下列相同或不同取代基所单取代,二取代或三取代,所述取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,
R5表示氢,环烷基,羟基,烷氧基,三甲基甲硅烷基烷氧基,芳氧基或芳烷氧基,或为式-NR9R10基团,其中
R9和R10可相同或不同,表示氢,烷基,芳基或芳烷基,或任意取代的通过氮原子键合的杂环基,包括来自吡咯烷,哌啶,吗啉,硫代吗啉或哌嗪的杂环基,
R11和R12可相同或不同,表示氢或由羟基,卤素,烷氧基或烷氧羰基任意取代的烷基,或表示环烷基,或R11和R12一起形成可多达6个碳原子的饱和或不饱和碳环或杂环,
Y表示式-NR13R14,-COR15,-S-R16,-SO-R16,-SO2-R16,-OR17或-N3基团,其中
R13和R14可相同或不同,表示氢,烷基,芳基或芳烷基,其中芳基能由卤,氰基,烷基,烷氧基或三氟甲基所取代,或表示式-COR15或-SO2R16基团,或R13和R14一起形成亚烷基链,该链能由N,O,S和/或N-烷基,N-芳基,N-芳烷基,N-氰基甲酰基或N-烷氧羰基所阻断,
R15表示氢,式-NR18R19基团,烷基或烷氧基,或表示芳基,芳氧基,芳烷基,芳烷氧基或杂芳基,其中这些基团能由下列相同或不同取代基所单取代,二取代或三取代,所述取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,
R16表示环烷基,由氰基,卤素,三氟甲基,三氟甲氧基或烷氧羰基任意取代的直链或支链烷基,或
R16表示芳基,芳烷基或杂芳基,这些基团能由下列相同或不相同取代基所单取代,二取代或三取代,所述取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,或
R16表示三甲基甲硅烷基或二甲基乙基甲硅烷基,或-NR9R10,其中R9和R10定义如前,
R17表示氢,环烷基或能由卤素,氰基,烷氧基,烷硫基,烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基,三氟甲基磺酰基,烷氧羰基或酰基或式-NR1R2基团取代的烷基,其中R1和R2定义如前,或
R17表示能由氨基甲酰基,二烷基氨基甲酰基,氨磺酰基,二烷基氨磺酰基,杂芳基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷氧基,芳烷硫基或芳烷基磺酰基取代的烷基,这里杂芳基和芳基能由下列相同或不同的卤素,氰基,三氟甲基,三氟甲氧基,烷基,烷氧基,烷硫基或烷基磺酰基所单取代,双取代或三取代,或
R17表示由下列相同或不同取代基单取代,取代或三取代的杂芳基,所述取代基为卤素,烷基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,三氟甲基,三氟甲氧基,三氟甲硫基,烷氧羰基或式-NR1R2基团,其中R1和R2定义同前,或
R17表示能由下列相同或不同取代基所单取代至五取代的芳基,所述取代基为烷基,烷氧基,烷硫基,烷基磺酰基,芳基,芳氧基,芳硫基,芳基磺酰基,芳烷基,芳烷氧基,芳烷硫基,芳烷基磺酰基,卤素,氰基,硝基,三氟甲基,三氟甲氧基,三氟甲硫基,烷氧羰基,氨磺酰基,二烷基氨磺酰基,氨基甲酰基,二烷基氨基甲酰基或式-NR1R2基团,其中R1和R2定义如前,或R17表示2,5-二氧代-四氢吡咯基,四氢吡喃基,三烷基甲硅烷基或COR16基团,其中R16定义如前,
R18和R19可相同或不同,表示氢,环烷基或由氰基,卤素,三氟甲基或三氟甲氧基任意取代的烷基,或表示由下列相同或不取代基单取代,二取代或三取代的芳基,芳烷基或杂芳基,所述取代基为烷基,烷氧基,烷硫基,卤素,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,氨基,烷基氨基或二烷基氨基,或
E和D一起代表下式基团并形成一个环:或
式中W表示式或-CHOH基团,m表示数1,2或3,Z表示O,S,CH2或N-R20,R13和R14定义如前,R20表示氢,烷基,芳基,芳烷基,氨基甲酰基或烷氧羰基,在D和E为相邻位置情况下,X代表式-CH2-CH2-或-CH=CH-基团,
对本发明通式(I)化合物的氧化产物能理解为吡啶N-氧化物的相应产物。
令人惊奇的是,本发明的取代吡啶显示出对HMG-CoA还原酶(3-羟基-3-甲基-戊二酰基辅酶A还原酶)具有极佳的抑制性。
环烷基通常是指具有3至8个碳原子的环烃基,就选环丙基,环戊基和环己基环。可提到的例子有环丙基,环戊基,环己基和环辛基。
烷基通常是指含有1至12个碳原子的直链或支链烃基,较好为1至6个碳原子的低级烷基。可提到的例子有甲基,乙基,丙基,异丙基,丁基,异丁基,戊基,异戊基,己基,异己基,庚基,异庚基,辛基和异辛基。
烷氧基通常是指含有1至12个碳原子,并且通过氧原子键合的直链或支链烃基,较好是含1至约6个碳原子的低级烷氧基,最好是含1至4个碳原子的烷氧基。可提到的例子有甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,戊氧基,异戊氧基,己氧基,异己氧基,庚氧基,异庚氧基,辛氧基或异辛氧基。
烷硫基通常指含有1至12个碳原子,并通过硫原子键合的直链或支链烃基,较好是含1至约6个碳原子的低级烷硫基,最好是含1至4个碳原子的烷硫基、可提到的例子有甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,戊硫基,异戊硫基,己硫基,异己硫基,庚硫基,异庚硫基,辛硫基或异辛硫基。
烷基磺酰基通常指含有1至12个碳原子,并通过SO2基团键合的直链或支链烃基,较佳是含有1至约6个碳原子的低级烷基磺酰基。可提到的例子有:甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,丁基磺酰基,异丁基磺酰基,戊基磺酰基,异戊基磺酰基,己基磺酰基,异己基磺酰基。
氨磺酰基(氨基磺酰基)表示-SO2-NH2。
芳基通常指含有6至约12个碳原子的芳族基团,较佳芳基是苯基,萘基和联苯基。
芳氧基通常指含有6至约12个碳原子,并通过氧原子键合的芳族基团,较佳芳氧基为苯氧基或萘氧基。
芳硫基通常指含有6至约12个碳原子,并通过硫原子键合的芳族基团,较佳芳硫基为苯硫基或萘硫基。
芳基磺酰基通常指含有6至约12个碳原子,并通过SO2基团键合的芳族基团,可提到的例子有苯磺酰基,萘磺酰基和联苯磺酰基。
芳烷基通常指含有7至14个碳原子,并通过亚烷基链键合的芳基,脂族部分含1至6个碳原子和芳族部分含6至12碳原子的芳烷基较好。可提到的例子有苄基,萘甲基,苯乙基和苯丙基。
芳烷氧基通常指含有7至14个碳原子,并且其中亚烷基通过氧原子键合的芳烷基,脂族部分含有1至6个碳原子和芳族部分含有6至12个碳原子的芳烷氧基较好。可提到的例子有苄氧基,萘基甲氧基,苯乙氧基和苯丙氧基。
芳烷硫基通常指含有7至约14个碳原子,并且其中烷基链通过硫原子键合的芳烷基。脂族部分含有1至6个碳原子和芳族部分含有6至12个碳原子的芳烷硫基较好。它们可以是下列芳烷硫基:苄硫基,萘甲硫基,苯乙硫基和苯丙硫基。
芳烷基磺酰基通常指含有7至约14个碳原子,并且烷基通过SO2链键合的芳烷基。脂族部分含有1至6个碳原子和芳族部分含6至12个碳原子的芳烷基磺酰基较佳。它们可以是苄基磺酰基,萘甲基磺酰基,苯乙基磺酰基苯丙基磺酰基。
烷氧羰基例如能由下式表示在这里,烷基表示含有1至12个碳原子的直链或支链烃基。烷基部分含有1至约6个碳原子的低级烷氧羰基较好,烷基部分含有1至4个碳原子的烷氧羰基最好。它们的例子可以是甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基或异丁氧羰基。
酰基通常指,通过羰基键合的苯基或含有1至约6个碳原子的直链或支链低级烷基。较佳是苯基和含有至4个碳原子的烷基。它们可以是苯甲酰基,乙酰基,乙基碳酰,丙基碳酰,异丙基碳酰,丁基碳酰和异丁基碳酰。
卤素通常是指氟,氯,溴或碘,较好是氟,氯或溴,最好是氟或氯。
杂芳基通常指含有杂原子如氧,硫和/或氮原子,并能与其他芳环进一步稠合的5至6元芳环。含有一个氧,一个硫和/或可达2个氮原子,并任选与苯稠合的5和6元芳环较好,杂芳基最好的例子有噻吩基,呋喃基,吡咯基,吡唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,喹唑啉基,喹喔啉基,2,3-二氮杂萘基,噌啉基,噻唑基,苯并噻唑基,异噻唑基,噁唑基,苯并噁唑基,异噁唑基,咪唑基,苯并咪唑基,吲哚基和异吲哚基。
如果R22为酯基时,则优选的生理上可耐受的酯基要求在体内易水解成游离羧酸和相应的生理上可耐受的醇。例子包括烷基(C1-C4)酯和芳烷基(C7-C10)酯,较佳是低级烷基酯和苄酯,尤其是下列酯类:甲酯,乙酯,丙酯,苄酯。
如R22表示阳离子,则优选生理上可耐受的金属阳离子或铵离子。在这里,较佳的为硷金属阳离子或硷土金属阳离子例如钠阳离子,钾阳离子,镁阳离子或钙阳离子,从胺得到的非毒性取代铵阳离子,例如得自二低级烷胺,三低级烷胺,普鲁卡因,二苄胺,N,N′-二苄基-1,2-乙二胺,N-苄基-β-苯乙胺,N-甲基吗啉或N-乙基吗啉,1-ephenamine,二氢枞酸基胺,N,N′-双-二氢枞酸基-1,2-乙二胺,N-低级烷基哌啶和其它能用来形成盐的胺类。
在通式(I)中,通式(Ia)和(Ib)化合物较佳。
A代表噻吩基,呋喃基,噻唑基,异噻唑基,噁唑基,异噁唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,吲哚基,异吲哚基,喹啉基,异喹啉基,2,3-二氮杂萘基,喹喔啉基,喹唑啉基,噌啉基,苯并噻唑基,苯并噁唑基或苯并咪唑基,其中每个都能由下列相同或不同取代基所单取代或二取代,所述取代基为氟,氯,溴,低级烷基,低级烷氧基,苯基,苯氧基,三氟甲基,三氟甲氧基或低级烷氧羰基,或
A代表各自能被相同或不同低级烷基单取代至四取代的苯基或萘基,并且所述烷基可任意由羟基,低级烷氧基,低级烷硫基,低级烷基磺酰基,苯基,苯氧基,苯硫基,苯基磺酰基,苄基,苄氧基,苄硫基,苄基磺酰基,苯乙基,苯乙氧基,苯乙硫基,苯乙基磺酰基,氟,氯,溴或氰基取代,
R1和R2可相同或不同,表示低级烷基,苯基,苄基,乙酰基,苯甲酰基,苯基磺酰基或低级烷基磺酰基,或
A代表直链或支链的低级烷基,
B代表环丙基,环戊基或环己基,或代表能由氟,氯,溴,氰基,低级烷氧基,低级烷硫基,低级烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲基磺酰基,低级烷氧羰基,苯甲酰基,低级烷基羰基或式-NR1R2基团取代的低级烷基,式中R1和R2定义如前,或
B代表由吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,吡咯基,吲哚基,噻吩基,呋喃基,咪唑基,噁唑基,噁唑基,噻唑基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基,苄基磺酰基,苯乙氧基,苯乙硫基或苯乙基磺酰基取代的低级烷基,本处提到的杂芳基和芳基能由相同或不同的氟,氯,溴,低级烷基,低级烷氧基,三氟甲基或三氟甲氧基所单取代或二取代,
D和E可相同或不同,代表氢,CN,NO2,环丙基,环戊基或环己基,或能由叠氮基,氟,氯,溴,氰基,羟基,低级烷氧基,低级烷硫基,低级烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲基磺酰基,低级烷氧羰基,苯甲酰基或低级烷基羰基,或式-NR1R2基团取代的直链或支链低级烷基,其中R1和R2定义如前,或
D和E代表由吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,吡咯基,吲哚基,噻吩基,呋喃基,咪唑基,噁唑基,噻唑基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基,苄基磺酰基,苯乙氧基,苯乙硫基或苯乙基磺酰基取代的直链或支链低级烷基,本处的杂芳基和芳基能由相同或不同的氟,氯,溴,低级烷基,低级烷氧基,三氟甲基或三氟甲氧基所单取代或二取代,或
E和D代表噻吩基,呋喃基,噻唑基,四唑基,异噻唑基,噁唑基,异噁唑基,吡啶基,嘧啶基,吡嗪基,哒嗪基,吲哚基,异吲哚基,喹啉基,异喹啉基,2,3-二氮杂萘基,喹喔啉基,喹唑啉基,噌啉基,苯并噻唑基,苯并噁唑基或苯并咪唑基,其中每个相能由相同或不同的氟,氯,溴,低级烷基,低级烷氧基,苯基,苯氧基,三氟甲基,三氟甲氧基或低级烷氧羰基所单取代或二取代,或
E和D代表由相同或不同低级烷基所单取代至四取代的苯基或萘基,其中低级烷基可任选由羟基,低级烷氧基,低级烷硫基,低级烷基磺酰基,苯基,苯氧基,苯硫基,苯基磺酰基,苄基,苄氧基,苄硫基,苄基磺酰基,苯乙基,苯乙氧基,苯乙硫基,苯乙基磺酰基,氟,氯,溴,溴,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,低级烷氧羰基或式-NR1R2基团所取代,其中R1和R2定义如前,或
E和D代表式-NR3R4,-COR5或-CR11R12-Y基团,其中R3和R4可相同或不同,表示氢,低级烷基,苯基或苄基,或式-COR6或-SO2R7基团,其中
R6表示氢,-NHR8基团或低级烷氧基,或表示由低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基任意取代的低级烷基,苯基,苄基,苄氧基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,
R7表示环丙基,环戊基或环己基,或由氰基,氟,氯,溴,三氟甲基或低级烷氧羰基任意取代的低级烷基,或表示由低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基任意取代的苯基,苄基,噻吩基,呋喃基,嘧啶基,吡啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,
R8表示氢或由氰基,氟,氯或溴任意取代的低级烷基,或由低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基任意取代的苯基,苄基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,
R5表示氢,环己基,羟基,低级烷氧基,三甲基甲硅烷基低级烷氧基或苄氧基,或为式-NR9R10基团,其中
R9和R10可相同或不同,表示氢,低级烷基或苯基,或表示包括来自吡咯烷,哌啶,哌嗪,N-烷基哌嗪,N-芳基哌嗪,N-苄基哌嗪,N-氨基甲酰基哌嗪或N-烷氧羰基哌嗪的杂环,
R11和R12可相同或不同,表示氢或由羟基,氟,氯,低级烷氧基或低级烷氧羰基任意取代的低级烷基,或为环丙基,环戊基或环己基,或R11和R12一起形成具有6个碳原子的饱和或不饱和碳环或杂环,
Y表示式-NR13R14,-COR15,-S-R16,SO-R16,-SO2R16,-OR17或N3基团,其中
R13和R14可相同或不同,表示氢,能由氟,氯,溴,低级烷基,低级烷氧基或三氟甲基所取代的低级烷基,苯基或苄基或表示式-COR15,-SO2R16基团或R13和R14一起组成由O,N,S,N-低级烷基,N-苄基,N-苯基,N-氨基甲酰基或N-低级烷氧羰基阻断的亚烷基键,
R15表示-NR18R19基团,低级烷基,低级烷氧基或由低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基任意取代的苯基,苄基,苄氧基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,
R16表示环丙基,环戊基,环己基或由氰基,氟,氯,溴,三氟甲基或低级烷氧羰基任意取代的直链或支链低级烷基,或表示由下列相同或不同取代基任意单取代或多取代的苯基,萘基,苄基,噻吩基,呋喃基,嘧啶基,吡啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,所述取代基为低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基,或表示三甲基甲硅烷基,二甲基乙基甲硅烷基或-NR4R10基团,其中R17和R10定义如前,
R17表示氢,环丙基,环戊基,环己基或由氟,氯,溴,氰基,低级烷氧基,低级烷硫基,低级烷基磺酰基,三氟甲基,三氟甲氧基,三氟甲基磺酰基,低级烷氧羰基,苯甲酰基,低级烷基羰基或式-NR1R2基团取代的低级烷基,其中R1和R2定义如前,或
R17表示由吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,吡咯基,吲哚基,噻吩基,呋喃基,咪唑基,噁唑基,噻唑基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基,苄基磺酰基,苯乙氧基,苯乙硫基或苯乙基磺酰基取代的低级烷基,这里的杂芳基和芳基能由下列相同或不取代基单取代或二取代,所述取代基为氟,氯,溴,低级烷基,低级烷氧基,三氟甲基或三氟甲氧基,或
R17表示噻吩基,呋喃基,噻唑基,异噻唑基,噁唑基,异噁唑基,吡啶基,咪啶基,吡嗪基,哒嗪基,吲哚基,异吲哚基,喹啉基,异喹啉基,2,3-二氮杂萘基,喹喔啉基,喹唑啉基,噌啉基,苯并噻唑基,苯并噁唑基或苯并咪唑基,它们每一个能由相同或不同的氟,氯,溴,低级烷基,低级烷氧基,苯基,苯氧基,三氟甲基,三氟甲氧基或低级烷氧羰基所取代,或
R17表示由下列相同或不同取代基所单取代至四取代的苄基,苯基或萘基,所述取代基为低级烷基,低级烷氧基,低级烷硫基,低级烷基磺酰基,苯基,苯氧基,苯硫基,苯基磺酰基,苄基,苄氧基,苄硫基,苄基磺酰基,苯乙基,苯乙氧基,苯乙硫基,苯乙基磺酰基,氟,氯,溴,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,低级烷氧羰基或式-NR1R2基团,其中R1和R2定义如前,或
R17表示2,5-二氧代-四氢吡咯基,四氢吡喃基,二甲基叔丁基甲硅烷基,三丙基甲硅烷基,三丁基甲硅烷基或式COR16基团,式中R16定义如前,和
R18和R19可相同或不同,表示氢,或任意由氰基,氟,氯或溴取代的低级烷基或由低级烷基,低级烷氧基,氟,氯,溴,三氟甲基,二甲氨基或二乙氨基任意取代的苯基,苄基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噻唑基,苯并噁唑基,噻唑基,噁唑基,异噁唑基或异噻唑基,或
z表示O,CH2或NHR20,
R13和R14定义如前,和
R20表示氢,低级烷基,苯基,苄基,氨基甲酰基或低级烷氧羰基,在E和D处于邻位的情况下,
X代表式-CH=CH-基团,
具有下面通式(Ia)和(Ib)的那些化合物和它们的氧化产物是最佳化合物其中:
A代表能由氟,氯,甲基,甲氧基或三氟甲基取代的噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基或异喹啉基,或由下列相同或不同取代基单取代,二取代或三取代的苯基,所述取代基为甲基,羟甲基,乙基,丙基,异丙基,羟乙基,羟丙基,丁基,异丁基,甲氧甲基,乙氧甲基,丙氧甲基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,苯基,苯氧基,苄基,苄氧基,氟,氯,溴,氰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,异丁氧羰基或叔丁氧羰基,或A代表甲基,乙基,丙基,异丙基,丁基或叔丁基,
B代表环丙基,环戊基或环己基,或代表能由叠氮基、氟,氯,溴,氰基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,仲丁氧基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,丁氧羰基,异丁氧羰基,叔丁氧羰基,苯甲酰基,乙酰基,吡啶基,嘧啶基,噻吩基,呋喃基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基或苯甲基磺酰基取代的甲基,乙基,丙基,异丙基,丁基,仲丁基或叔丁基,
D和E可相同或不同,代表CN,NO2,氢,环丙基,环戊基,环己基或能由下列取代基取代的甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基或异己基,所述取代基为氟,氯,溴,碘,氰基,羟基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,叔丁硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,丁基磺酰基,异丁基磺酰基,叔丁基磺酰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,异丁氧羰基,叔丁氧羰基,苯甲酰基,乙酰基,乙基羰基或-NR1R2基团,其中R1和R2可相同或不同,表示甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,苯基,苄基,乙酰基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基或苯基磺酰基,或所述取代基可以为吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,噻吩基,呋喃基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基或苄基磺酰基,这里的杂芳基或芳基能由氟,氯,溴,甲基,乙基,丙基,异丙基,异丁基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,三氟甲基或三氟甲氧基所取代,或
E和D代表噻吩基,呋喃基,吡啶基,嘧啶基,吡嗪基,四唑基,哒嗪基,噁唑基,异噁唑基,咪唑基,吡唑基,噻唑基,异噻唑基,喹啉基,异喹啉基,苯并噁唑基,苯并咪唑基或苯并噻唑基,这些基团能由氟,氯,甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,苯基,苯氧基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,异丙氧羰基,丙氧羰基,丁氧羰基,异丁氧羰基或叔丁氧羰基所取代,或
E和D代表能由下列相同或不同取代基单取代,二取代或三取代的苯基,所述取代基为甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基,羟甲基,羟乙基,羟丙基,异己基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,甲氧甲基,乙氧甲基,丙氧甲基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,叔丁硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,丁基磺酰基,异丁基磺酰基,叔丁基磺酰基,苯基,苯氧基,苯硫基,苯基磺酰基,苄基,苄氧基,苄硫基,苄基磺酰基,氟,氯,溴,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,异丁氧羰基,叔丁氧羰基或-NR1R2基团,其中R1和R2定义如前,或
E和D代表式-NR3R4,-COR5或-CR11R12-Y基团,其中R3和R4可相同或不同,表示氢,甲基,乙基,丙基,异丙基,叔丁基,戊基,异戊基,己基,异己基,苯基,苄基,式-COR6或-SO2R7基团,其中
R6表示氢,-NHR8基团,甲氧基,乙氧基,丙氧基,异丙氧基,甲基,乙基,丙基,异丙基,丁基或由甲基,甲氧基,氟或氯任意取代的苯基,苄基,苄氧基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基或异喹啉基,
R7表示由氟,氯,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基或异丁氧羰基任意取代的乙基,丙基,异丙基,丁基,异丁基,或由甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基或异丙氧基,氟或氯任意取代的苯基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基或异喹啉基,
R8表示氢,由氟或氯任意取代的甲基,乙基,丙基,异丙基,丁基,异丁基,戊基,异戊基,己基或异己基,或表示能由氟,氯,甲基或甲氧基取代的苯基,
R5表示氢,环己基,羟基,甲氧基,乙氧基,丙氧基,丁氧基,异丙氧基,异丁氧基或三甲基甲硅烷基乙氧基,或表示NR9R10基团,其中
R9和10可相同或不同,表示氢,甲基,乙基,丙基,异丙基,丁基,异丁基或苯基,或表示包括哌啶,N-甲基哌嗪,N-乙基哌嗪,N-苄基哌嗪或吗啉系列的杂环,
R11和R12可相同或不同,表示氢或由羟基,氟,氯,甲氧基,乙氧基,甲氧羰基或乙氧羰基任意取代的甲基,乙基,丙基或异丙基,或表示环丙基,环戊基或环己基,或R和R一起表示环丙基,环戊基或环己基,
Y表示式-NR13R14,-COR5,-SR16,-SO-R10,-SO2R16,-OR17或-N3基团,其中
R13和R14可相同或不同,表示氢,甲基,乙基,丙基,异丙基,丁基,异丁基或由氟,氯,甲基或甲氧基任意取代的苯基,或表示-COR15或-SO2R16基团,或R13和R14与氮原子一起形成包括哌啶,哌嗪,吗啉,吗啉-N-氧化物,N-低级烷基哌嗪,苯甲基哌嗪或苯基哌嗪系列的环,
R15表示氢,-NR18R19基团,甲基,乙基,丙基,异丙基,甲氧基,乙氧基,丙氧基,异丙氧基或由甲基,甲氧基,氟或氯任意取代的苯基,苄基,苄氧基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基或异喹啉基,
R16表示由氟,氯,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基或异丁氧羰基任意取代的甲基,乙基,丙基,异丙基,丁基,异丁基或异戊基,或表示由相同或不同的甲基,乙基,丙基,异丙基,甲氧基,氟和氯任意单取代或多取代的苄基,苯基,萘基,噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基或异喹啉基,或表示三甲基甲硅烷基,二甲基乙基甲硅烷基或-NR9R10基团,其中R9和R10定义如前,
R17表示氢,环丙基,环戊基,环己基或能由下列取代基取代的甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基或异己基,所述取代基为氟,氯,溴,氰基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,叔丁硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺基,丁基磺酰基,异丁基磺酰基,叔丁基磺酰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,异丁氧羰基,叔丁氧羰基,苯甲酰基,乙酰基,乙基羰基或-NR1R2基团,其中R1和R2可相同或不同,表示甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,苯基,苄基,乙酰基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基或苯基磺酰基,或者所述取代基为吡啶基,嘧啶基,吡嗪基,哒嗪基,喹啉基,异喹啉基,噻吩基,呋喃基,苯基,苯氧基,苯硫基,苯基磺酰基,苄氧基,苄硫基或苄基磺酰基,这里所提的杂芳基和芳基能被氟,氯,甲基,乙基,丙基,异丙基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,三氟甲基或三氟甲氧基的取代,或
R17表示噻吩基,呋喃基,吡啶基,嘧啶基,吡嗪基,哒嗪基,噁唑基,异噁唑基,咪唑基,吡唑基,噻唑基,异噻唑基,喹啉基,异喹啉基,苯并噁唑基,苯并咪唑基或苯并噻唑基,这些基团能被氟,氯,甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,苯基,苯氧基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基,异丙氧羰基,丙氧羰基,丁氧羰基,异丁氧碳基或叔丁氧羰基所取代,或
R17表示苄基或苯基,它们可由下列相同或不同取代基所单取代,二取代或三取代,所述取代基为甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基,异己基,甲氧基,乙氧基,丙氧基,异丙氧基,丁氧基,异丁氧基,叔丁氧基,甲硫基,乙硫基,丙硫基,异丙硫基,丁硫基,异丁硫基,叔丁硫基,甲基磺酰基,乙基磺酰基,丙基磺酰基,异丙基磺酰基,丁基磺酰基,异丁基磺酰基,叔丁基磺酰基,苯基,苯氧基,苯硫基,苯基磺酰基,苄基,苄氧基,苄硫基,苄基磺酰基,氟,氯,溴,氰基,三氟甲基,三氟甲氧基,三氟甲硫基,甲氧羰基,乙氧羰基,丙氧羰基,异丙氧羰基,丁氧羰基,异丁氧羰基,叔丁氧羰基或-NR1R2基团,其中R1和R2定义如前,或
R17表示2,5-二氧代-四氢吡咯基,四氢吡喃基,三甲基叔丁基甲硅烷基,三甲基甲硅烷基或-COR16基团,其中R16定义如前,
R18和R19可相同或不同,表示氢或由氟或氯任意取代的甲基,乙基,丙基,异丙基,丁基,异丁基,戊基,异戊基,己基或异己基,或表示由氟,氯,甲基或甲氧基任意取代的苯基,或
X表示下式基团
-CH=CH-
特别优选的化合物为通式(Ia)和(I)的下述化合物和它们的氧化产物,其中
A代表噻吩基或呋喃基,由下列相同或不同取代基单取代或二取代的苯基,所述取代基为甲基,羟甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,甲氧基,乙氧基,丙氧基,异丙氧基,苯氧基,苄氧基,氟,氯或三氟甲基,或A代表甲基,乙基,丙基或异丙基,
B代表可以由氟,氯,甲氧基,苯基或苯氧基取代的环丙基,甲基,乙基,丙基,异丙基,丁基,异醒基或叔丁基,
D和E可相同或不同,代表氢,CN,NO2,环丙基,环戊基或环己基,或
D和E代表能由下列取基取代的甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基或异己基,所述取代基为叠氮基,氟,氯,碘,甲氧基,乙氧基,丙氧基,异丙氧基,甲硫基,乙硫基,甲基磺酰基,乙基磺酰基,乙氧羰基,丙氧羰基,异丙氧羰基或式NR1R2基团,其中R1和R2可相同或不同,表示氢,甲基,乙基,丙基,异丙基,苯基或苄基,或所述取代基为可以由氟,氯,甲基,甲氧基,三氟甲基或三氟甲氧基任意取代的毗啶基,嘧啶基,喹啉基,噻吩基,呋喃基,苯基,苯氧基,苯基磺酰基或苄氧基,或
D和E代表可任意由氟,氯,甲基,乙基,丙基,异丙基,甲氧基,苯基,甲氧羰基或乙氧羰基取代的噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噁唑基,四唑基,苯并噻唑基或苯并咪唑基,或
D和E代表能由下列相同或不同取代基单取代或二取代的苯基,所述取代基为甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁氧基,甲氧基,乙氧基,丙氧基,异丙氧基,甲硫基,乙硫基,甲基磺酰基,乙基磺酰基,苯基,苯氧基,苯基磺酰基,苄氧基,氟,氧,溴,氰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基或式-NR1R2基团,其中R1和R2定义如前,或
D和E代表式-NR3R4,-COR5或-CR11R12-Y,其中
R3表示氢,
R4表示氢,甲基,乙基,丙基或式-COR6或-SO2R7基团,其中
R6表示氢,-NHR8,甲氧基,乙氧基,甲基,乙基,丙基或异丙基,
R7表示三氟甲基,苯基或甲苯基,
R8表示氢,甲基,乙基,丙基,异丙基,丁基或苯基,
R5表示氢,环己基,羟基,氨基,甲氨基,二甲氨基,甲氧基,乙氧基,三甲基甲硅烷基,乙氧基或基团NR9R10,其中
R9和R10可相同或不同,表示氢,甲基,乙基,丙基或苯基,或R9和R10一起组成吗啉环,
R11和R12表示氢,甲基或乙基,
Y表示式-NR13R14,-COR15,-S-R10,-SO-R16,-SO2R16或-OR17基团,其中
R13和R14可相同或不同,表示氢,甲基,乙基,丙基或-COR15或-SO2R16基团,或R13和R14与氮原子一起形成包括吗啉或吗啉N-氧化物系列的环,
R15表示氢,甲基,-NR18R19基团,甲基,乙基,丙基,甲氧基或乙氧基,
R16表示三氟甲基,甲基,乙基,丙基,异丙基,丁基,异丁基,异戊基或苄基,或表示可任意由一个或多个甲基或氯取代的苯基或萘基,或表示三甲基甲硅烷基,二甲基乙基甲硅烷基或-NR9R10基团,其中R9和R10定义如前,
R17表示氢,环丙基,环戊基,环己基或能任意由下列取代基氟,氯,甲氧基,乙氧基,丙氧基,异丙氧基,甲硫基,乙硫基,甲基磺酰基,乙基磺酰基,乙氧羰基,丙氧羰基,异丙氧羰基或式NR1R2取代的甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁基,戊基,异戊基,己基或异己基,其中R1和R2可相同或不同,代表氢,甲基,乙基,丙基,异丙基,苯基或苄基,所述取代基还可为由氟,氯,甲基,甲氧基,三氟甲基,三氧甲氧基任意取代的吡啶基,嘧啶基,喹啉基,噻吩基,呋喃基,苯氧基,苯基磺酰或苄氧基,或
R17表示噻吩基,呋喃基,吡啶基,嘧啶基,喹啉基,异喹啉基,苯并噁唑基,苯并噻唑基或苯并咪唑基,它们可任意由氟,氯,甲基,乙基,丙基,异丙基,甲氧基,苯基,甲氧羰基或乙氧羰基取代,或
R17表示能由下列相同或不同取代基单取代或二取代的苄基或苯基,所述取代基为甲基,乙基,丙基,异丙基,丁基,异丁基,叔丁氧基,甲氧基,乙氧基,丙氧基,异丙基,甲硫基,乙硫基,甲基磺酰基,乙基磺酰基,苯基,苯氧基,苯基磺酰基,苄氧基,氟,氯,溴,氰基,三氟甲基,三氟甲氧基,甲氧羰基,乙氧羰基或式-NR1R2基团,其中R1和R2定义如前,或
R17表示2,5-二氧代-四氢吡咯基,四氢毗喃基,二甲基叔丁基甲硅烷基,三甲基甲硅烷基或-COR16基团,其中R16定义如前,
R18和R19可相同或不同,表示氢,甲基,乙基,丙基,异丙基,丁基,异丁基或苯基,或
其中R21表示氢,R22表示氢,甲基或乙基,或钠或钾离子。
本发明通式(I)取代吡啶具有几个不对称碳原子,因此存在各种立体化学形式的异构体。本发明不仅涉及个别异构体,而且涉及它们的混合物。
随基团X或R定义的不同,可得到不同的立体异构体,下面更详细地进行描述:
优选式(I)化合物是具有E构型(II)的那些化合物。
b)如果基团-R-代表下式基团那么通式(I)化合物至少具有二个不对称碳原子,即键连有羟基的那二个碳原子。按照这些羟基之间的互相位置关系,本发明化合物能以赤式构型(IV)或苏式构型(V)存在。赤型(IV)苏型(V)
在每种情况下赤式和苏式构型的化合物还存在二种对映体,即3R,5S-异构体或3S,5R-异构体(赤型)和3R,5R-异构体和3S,5R-异构体(苏型)。
在上面情况中,具有赤式构型的异构体较好,最好是3R,5S-异构体和3R,5S-3S,5R-外消旋体。
c)如果基团-R-表示下式基团则取代吡啶至少具有二个不对称碳原子,即键连有羟基的碳原子和链连有下式基团的碳原子根据内酯环上羟基相对自由价的位置不同,取代吡啶能以顺-内酯(VI)或反-内酯(VII)形式存在。 顺-内酯(VI) 反-内酯(VII)
在每种情况下上述顺-内酯和反-内酯还存在二种异构体,即4R,6R-异构体或4S,6S-异构体(顺-内酯)和4R,6S-异构体或4S,6R-异构体(反-丙酯)。较佳异构体是反-内酯类。这里最佳异构体为4R,6S-异构体(反式)和4R,6S-4S,6R-外消旋体。
对于酸类来说,可通过酯的水解制得,
对于内酯类来说,可通过羧酸的环化制得,
对于盐类来说,可通过酯或内酯的水解制得,
对于亚乙基化合物(X=-CH2-CH2-)来说,可用常规方法氢化乙烯化合物(X=-CH=CH-)制得,如需要可解析异构体。
上述还原反应能使用常规的还原剂来进行,较好使用适合于将酮类还原成羟基化合物的那类还原剂,尤其适合的还原剂为惰性溶剂中的金属氢化物或配位金属氢化物,如合适的话,可有三烷基甲硼烷存在。最好使用配位金属氢化合物例如氢硼化锂,氢硼化钠,氢硼化钾,氢硼化锌,三烷基氢硼化锂,三烷基氢硼化钠,氰基氢硼化钠或氢化铝锂进行还原反应。在三乙基甲硼烷存在下使用氢硼化钠进行还原反应最佳。
还原反应的合适溶剂为反应条件下不发生变化的常规有机溶剂。较佳溶剂包括醚例如***,二噁烷,四氢呋喃或二甲氧乙烷,囟代烃例如二氯甲烷,三氯甲烷,四氯化碳,1,2-二氯乙烷或烃类例如苯,甲苯或二甲苯。也可以采用这些溶剂的混合物。
最好在这样的条件下进行羰基还原成羟基的反应,即不引起其余官能团如烷氧羰基发生变化的条件。在有三乙基甲硼烷存在下,采用于惰性溶剂如较佳的醚类中的氢硼化钠为还原剂是最适合的。
通常在-80℃至30℃的温度范围内进行还原反应,较佳范围为-78℃至0℃。
本发明方法通常在常压下进行,但也可能在减压或高压下来进行(例如在0.5至5巴的范围)。
相对于1摩尔酮类化合物来说,通常采用1至2摩尓,最好1至1.5摩尔的还原剂。
在上面所述的还原条件下,通常只将羰基还原成羟基,而不会引起将双键还原成单键。
在制备X为亚乙基的通式(I)化合物时,可采用同时将羰基和双键还原的条件进行酮类(III)的还原反应。
另外,分二步进行羰基和双键的还原操作也是可行的。
通式(I)中的羧酸酯类的通式如下:式中A,B,D,E和R21定义如前,R23为烷基。
通过用常规方法,对通式(Id)羧酸酯或通式(If)内酯进行水解能制得通式(Ic)羧酸。水解反应通常是在惰性溶剂中,用常规的碱处理酯或内酯来实现,一般来说,首先形成通式(Ie)盐类,然后第二步是用酸处理,将其转化成通式(Ic)的游离酸类。
适合于水解反应的硷类为常规的碱。优选硷金属氢氧化物或碱土金属氢氧化物例如,氢氧化钠,氢氧化钾或氢氧化钡,或硷金属碳酸化物如碳酸钠或碳酸钾或碳酸氢钠,或烷氧基硷金属如乙醇钠,甲醇钠,甲醇钾,乙醇钾或叔丁醇钾。最佳的硷为氢氧化钠或氢氧化钾。
水解的合适溶剂为水或常规用于水解的有机溶剂。优选醇类如甲醇,乙醇,丙醇,异丙醇或丁醇,或醚类如四氢呋喃或二噁烷,二甲基甲酰胺或二甲基亚砜。最佳是醇类如甲醇,乙醇,丙醇或异丙醇。也可以采用这些溶剂的混合物。
通常在0℃至100℃的温度范围,较好在20℃至80℃的范围进行水解反应。
水解反应一般是在常压下进行,但是在低压或高压下进行也是可行的(例如0.5巴至5巴)。
水解反应中,通常每摩尔酯或内酯采用1至3摩尔,较好1至1.5摩尔的硷。最佳采用等摩尔量的反应试剂。
在上述反应中,第一步首先形成本发明盐类化合物(Ie),作为中间体能分离出来。经常规的无机酸处理所得的盐(Ie)能得到本发明的酸(Ic),较佳的酸包括无机酸如盐酸,氢溴酸,硫酸或磷酸。现已证明,在制备羧酸(Ic)中,对水解第二步所得的硷性反应混合物不进行盐的分离,而直接进行酸化是有利的。然后用常规方法分离所得酸类。
通常可通过常规方法环化本发明的羧酸(Ic)制备得到本发明的式(If)内酯,例如在惰性溶剂中加热相应的酸,如果合适的话,可存在有分子筛。
合适的溶剂有烃类如苯,甲苯,二甲苯,矿物油馏份,1,2,3,4-四氢化萘或二甘醇二甲醚或三甘醇二甲醚。优先采用苯,甲苯或二甲苯。同样也可以使用这些溶剂的混合物。最好在分子筛存在下使用烃类,尤其是甲苯。
通常在-40℃至200℃,较佳在-25℃至50℃的温度范围进行环化反应。
通常于常压下进行环化,但在低压或高压(例如0.5至5巴)也是可行的。
此外,借助于环化剂或水消除剂,也能在惰性有机溶剂中进行环化反应。较佳的水消除剂为碳化二亚胺类,优选的碳化二亚胺类为N,N′-二环己基碳化二亚胺对甲苯磺酸酯,N-环己基-N′-〔2-(N″-甲基吗啉)乙基〕碳化二亚胺或N-(3-二甲氨基丙基)-N′-乙基碳化二亚胺盐酸盐。
环化反应的合适溶剂是常规的有机溶剂。较佳溶剂包括醚类如***,四氢呋喃或二噁烷,或氯代烃类如二氯甲烷,氯仿或四氯化碳,或烃类如苯,甲苯,二甲苯或矿物油馏份。最佳溶剂是氯代烃类如二氯甲烷,氯仿或四氯化碳,或烃类如苯,甲苯,二甲苯或矿物油馏份。最佳是使用氯代烃类如二氯甲烷,氯仿或四氯化碳。
通常在0℃至80℃,较佳在10℃至50℃的温度范围内进行反应。
已证明,使用碳化二亚胺类作为脱水剂的环化操作是有利的。
一般,可使用常规方法(如E.L.Eliel,“碳化合物的立体化学”,McGraw Hill,1962,所述)将异构体拆分成均匀立体异构体组分。对拆分来说,较好是在外消旋酯这步进行。尤其是使用常规方法,通过D-(+)或L-(-)-α-甲基苄胺处理,将反-内酯类(VII)的外消旋混合物转化成下式(Ig)非对映的二羟酰胺,紧接着用常规方法如色谱法或结晶法将其拆分成各自的非对映体。然后按常规方法水解纯的非对映的酰胺,例如在水和/或有机溶剂如醇类(例如甲醇,乙醇,丙醇或异丙醇)中,用无机硷如氢氧化钠或氢氧化钾处理上述非对映的酰胺得到相应的纯对映体的二羟酸(Ic),所述二羟酸(Ic)再通过上面所描述的环化反应被转化成纯对映体内酯。概括地说,在用上面方法制备纯对映体形式的本发明通式(I)化合物时,所得的最终产物的构型是取决于起始原料的构型。
用作起始原料的酮(VIII)是新化合物。
反应中所用的合适碱为常规强碱性化合物。优选的硷包括有机锂化合物例如正丁基锂,仲丁基锂,叔丁基锂或苯基锂,或酰胺例如二异丙基酰胺锂,酰胺钠或酰胺钾,六甲基二甲硅烷酰胺锂,或硷金属氢化物例如氢化钠或氢化钾。同样,也可采用这些硷的混合物。最佳的碱为丁基锂,氢化钠或它们的混合物。
该反应的合适溶剂为反应条件下不发生变化的常规有机溶剂,优选的溶剂包括醚类如***,四氢呋喃,二噁烷或二甲氧乙烷,或烃类如苯,甲苯,二甲苯,环己烷,己烷或碱物油馏份。同样也可采用这些溶剂的混合物。最佳溶剂是醚类如***或四氢呋喃。
通常在-80℃至50℃,较好在-20℃至室温的温度范围内进行反应。
一般是在常压进行反应,但在低压和高压下进行也是可行的(例如0.5至5巴)。
在进行该反应时,通常相对每摩尔醛采用1至2,较好1至1.5摩尔的乙酰乙酸酯。
起始原料的式(X)乙酰乙酸酯是已知的,并能按已知方法制备〔Beilstein′s Handbuch der Organischem Chemie(Beilstein′s有机化学手册)III,632;438〕。
用于在本发明方法的可提到的乙酰乙酸酯例子有乙酰乙酸甲酯,乙酰乙酸乙酯,乙酰乙酸丙酯,乙酰乙酸异丙酯。
通过式(Ia)化合物的实施例来说明作为起始原料的通式(IX)醛类的制备。
按照路线A,第一步〔1〕还原反应操作如下:在惰性溶剂如醚类,例如***,四氢呋喃或二噁烷,最好在四氢呋喃中,使用金属氢化物作还原剂,例如氢化铝锂,氰基氢硼化钠,氢化铝钠,氢化二异丁基铝或双-(2-甲氧基乙氧基)-二氢铝酸钠,并且按所用的还原剂,选择反应温度范围在-70℃至100℃,较好-70℃至室温或室温至70℃下,将其中R24示1至4个碳原子的烷基的式(X)吡啶还原成羟甲基化合物(XI)。较好在室温至80℃下,使用混于四氢呋喃中的氢化铝锂进行还原反应。在第二步〔2〕中使用常规方法将羟甲基化合物(XI)氧化成醛(VII)。该氧化反应例如可以采用氯代铬酸吡啶鎓,如合适的话,可以有铝存在下,在惰性溶剂如氯化烃,最好在二氯甲烷中和0℃至60℃温度范围,优选为室温下来进行,也可以按Swern氢化反应的常规方法,使用三氟乙酸/二甲基亚砜来进行。在第三步〔3〕中,于氢比化钠存在下,2-(环己氨基)乙烯基磷酸二乙酯与醛(XII)反应得到醛(IX),反应条件为有惰性溶剂如醚类,例如***,四氢呋喃或二噁烷,较好是四氢呋喃存在,温度范围为-20℃至40℃,较好为-5℃至室温。
这里用作为起始原料的式(X)化合物通常能按路线B经氧化二氢吡啶(XIII)得到,其中二氢吡啶(XIII)也按基团D的定义通过改变相应的官能团制得。用作为起始原料的二氢吡啶是已知化合物,能用已知方法〔EP-A88,276,DE-A2,847,236〕制备。把二氢吡啶(XIII)氧化成吡啶(X)的操作可如下进行,例如在-20℃至150℃温度范围,较好在回流温度下使用混于冰酯酸中的氧化铬,或在0℃至100℃温度范围,较佳于室温下,使用混于惰性溶剂如氯化烃,较佳在二氯甲烷中的2,3-二氯-5,6-二氰基-对苯醌作为氧化剂。下面的所应式用来描述改变基团D的一些实例:
水解二氢吡啶(XIV)可得到二氢吡啶羧酸(XV),例如通过与混于二甲氧基乙烷中的硷金属氢氧化物在室温下反应来完成。将上述二氢吡啶羧酸(XV)脱羧得到二氢吡啶(XVI),例如在二甘醇中加热到200℃。另外,通过已知方法能将二氢吡啶羧酸(XV)进行反应得到二氢吡啶羧酸酰胺(XVII),例如与二环己基碳化二亚胺反应。
使用常规的还原剂,例如混于四氢呋喃中的氢化铝锂,在室温或沸点温度下能将二氢吡啶(XVIII)还原成二氢吡啶(XIV)。
由上述方法氧化二氢吡啶(XVIII)制得的吡啶(XX)能用合适的还原剂,例如氢化铝锂,氢化二异丁基铝或双-(2-甲氧基乙氧基)二氢铝酸钠在惰性溶剂如四氢呋喃中经还原制得式(XXI)的吡啶。
吡啶(XXI)能用已知方法还原成式(XXII)吡啶,例如在有硷如氢化钠存在下与烷基囟或苄基卤反应,或在有硷例如咪唑,吡啶或三乙胺存在下,与三烷基甲硅烷基卤或酰基卤反应。吡啶(XXI)的羟基能用已知方法转化成离去基团,例如在硷存在下,与三氟甲烷磺酸酐,亚硫酰氯或甲烷磺酰氯反应。然后用已知方法将离去基团交换成亲核基团。
本发明式(I)化合物具有有效的药理学性质,能用作为药物。具体地说,它们是3-羟基-3-甲基-戊二酰基辅酶A(HGM-CoA)还原酶的抑制剂,因此也是胆甾醇生物合成的抑制剂,能用于血脂蛋白过高,血脂蛋白或动脉硬化的治疗。本发明活性化合物另外还能降低血液中的胆甾醇含量。
使用惰性、非毒性、适于药用的赋形剂或溶到,按已知方式能将这类新的活性化合物制成常规制剂,例如片剂,包衣片剂,丸剂,胶囊,烟雾剂,糖浆,乳剂,悬浮液和溶液剂。在这些配方中,治疗活性化合物的浓度应约为总混合物的0.5至98%(重量),较好1至90%(重量),也就是说该量要足以达到指定的剂量范围。
利用溶剂和/或赋形剂分散活性化合物,制得制剂,如合适的话,可使用乳化剂和/或分散剂,例如在采用水为稀释剂的情况下,如合适,可使用有机溶剂作为辅助溶剂。
辅助溶剂的例子有:水,非毒性有机溶剂如石蜡(例如矿物油馏份),植物油(例如花生油/芝麻油),醇(例如乙醇,丙三醇),赋形剂如磨碎的天然矿物(例如高岭土,泥质土,滑石,白垩),磨碎的合成矿物(例如高分散性硅石,硅酸盐),糖(例如蔗糖,乳糖,葡萄糖),乳化剂(例如聚氧乙烯脂肪酸酯,聚氧乙烯脂肪醇醚,烷基磺酸酯和芳基磺酸酯),分散剂(例如本素亚硫酸酯废液,甲基纤维素,淀粉和聚乙烯基吡咯烷酮)和润滑剂(例如硬脂酸镁,滑石,硬脂酸和月桂基硫酸钠)。
可按常规方式给药,较好为口服,非肠胃给药,经舌或静脉内给药。如口服给药,则所采用片剂还可含有添加剂如柠檬酸钠,碳酸钙和磷酸钙以及各种添加物,如淀粉,较好是山芋淀粉,明胶等,以及上面所提的赋形剂。另外,润滑剂如硬脂酸镁,月桂基硫酸钠和滑石能辅助性地用于制备片剂。对于水悬浮液来说,在活性化合物中可加各种矫味剂或着色剂以及上面所提的辅助剂。
在非肠胃给药时,使用合适的液体赋形剂制备活性化合物的溶液。
一般来说,对于静脉内给药已证明给药量在约0.001至1mg/kg(体重)能获得有效的结果,较好为约0.01至0.5mg/kg(体重),对于口服给药来说,剂量约0.01至20mg/kg,较好为0.1至10mg/kg(体重)。
尽管如此,仍可以根据被治疗者的体重或给药的途径,各自对药物的反应,制剂的形式和给药时间间隔而可以变动上面提到的剂量。
因此,在某些情况里,用少于上面所提的最低剂量能满足治疗目的,同样在有些情况中,会使用超过上面的最高限量。对于较大用量给药来说,建议一天分成几次用药。
制备实施例
实施例1
将62g(0.5mol)4-氟苯甲醛和79g(0.5mol)异丁酰乙酸乙酯加到300ml异丙醇中,然后加入2.81ml(28mmol)哌啶和1.66ml(29mmol)乙酸和40ml异丙醇的混合物。于室温搅拌混合物48小时,真空浓缩,高真空蒸馏剩余物。
沸点(0.5mm):127℃
得率:108.7g(82.3%理论得率)
实施例2
1,4-二氢-2,6-二异丙基-4-(4-氯苯基)吡啶-3,5-二甲酸二乙酯
将98g(0.371mol)实施例1所得化合物与58.3g(0.371mmol)3-氨基-4-甲基-2-戊烯酸乙酯在300ml乙醇中加热回流18小时。所得混合物冷却至室温,真空蒸去溶剂,在130℃和高真空下蒸馏除去末反应的起始原料。在余下的浆液中加入正己烷并搅拌,抽滤出沉淀物,用正己烷洗涤和经干燥器干燥,得率:35g(23.4%,理论得率)1H-NMR(CDCl3):=1.1-1.3(m,18H);4.05-4.25
(m,6H);5.0(s,1H);6.13(s,
1H);6.88(m,2H);7.2(m,2H)
ppm.
实施例3
在6.6g(16.4mmol)实施例2所得化合物的200ml二氯甲烷(p.a.)溶液中加入3.8g(16.4mmol)2,3-二氯-5,6-二氰基-对苯醌,并于室温搅拌混合物1小时,然后经硅藻土抽滤,二氯甲烷相用水萃取三次(每次100ml),用硫酸镁干燥。经真空浓缩后,剩余物进行柱色谱(100g硅胶,70-230目,3.5cm,乙酸乙酯/石油醚1∶9洗脱)分离。
得率:5.8g(87.9%,理论得率)1H-NMR(CDCl3):=0.98(t,6H);1.41(d,12H);3.1(m,
2H);4.11(q,4H);7.04(m,2H);
7.25(m,2H)ppm.
实施例4
在氮气氛和-10℃至-5℃下,将21ml(80.5mmol)双(2-甲氧基乙氧基)-二氢铝酸钠的3.5M甲苯溶液加入到9.2g(23mmol)实施例3所得化合物的100ml干燥四氢呋喃溶液,于室温搅拌混合物5小时。冷却至0℃,小心滴加100ml水,然后混合物用乙酸乙酯萃取三次,每次用100ml。合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥和真空蒸发。剩余物经柱色谱(200g硅胶,70-230目,4.5cm.乙酸乙酯/石油醚3∶7)纯化。
得率:7.2g(87.2%,理论得率)1H-NMR(CDCl3):=0.95(t,3H);1.31(m;12H);3.05
(m,1H);3.48(m,1H),3.95(q,
2H);4.93(d,2H);7.05-7.31
(m,4H)ppm.
实施例5
5-(叔丁基二甲基甲硅烷氧甲基)-2,6-二异丙基-4-(4-氟苯基)吡啶-3-甲酸乙酯
在室温下,将2.1(13.8mmol)叔丁基二甲基甲硅烷基氯,1.8g(27.5mmol)咪唑和0.05g 4-二甲氨基吡啶加入4.5g(12.5mmol)实施例4所得化合物的50ml二甲基甲酰胺的溶液中,于室温搅拌混合物过夜,加入200ml水,用1N盐酸调节混合物的pH至3。混合物用醚萃取三次,每次用100ml。合并有机相,用饱和氯化钠洗涤,硫酸镁干燥和真空浓缩。剩余物经柱色谱(150g硅胶,70-230目,4cm.乙酸乙酯/石油醚1∶9)纯化。
得率:4.2g(73.7%,理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.9(s,9H);1.02(t,
3H);1.35(m,12H);3.1(m,1H);
3.47(m,1H);4.03(q,2H);4.4
(s,2H);7.05-7.40(m,4H)ppm.
实施例6
3-(叔丁基二甲基甲硅烷氧甲基)-2,6-二异丙基-4-(4-氟苯基)-5-羟甲基吡啶
在0℃和氮气氛下,将9.2ml(32.2mmol)双(2-甲氧基乙氧基)二氢铝酸钠的3.5M甲苯溶液加到4.2g(9.2mmol)实施例5所得化合物的100ml干燥四氢呋喃溶液中,于室温搅拌混合物过夜,然后冷却至0℃,小心滴加100ml水,混合物用乙酸乙酯萃取三次,每次用100ml。合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥和真空浓缩。剩余物用柱色谱(100g硅胶,70-230目,3.5cm,乙酸乙酯/石油醚2∶8)纯化。
得率:2.4g(60%,理论得率)1H-NMR(CDCl3):=0.2(s,6H);1.11(s,9H);1.6(m,
12H);3.7(m,2H);4.55(s,2H);
4.65(d,2H);7.35-7.55(m,4H)
ppm.
实施例7
将1.24g(12.4mmol)中性氧化铝和2.7g(12.4mmol)氯化铬酸吡啶鎓加到2.7g(6.2mmol)实施例6所得化合物的50ml二氯甲烷溶液中,于室温搅拌混合物1小时,经硅藻土过滤后,甲200ml二氯甲烷洗涤。真空浓缩二氯甲烷相,剩余物用柱色谱(100g硅胶,70-230目,3.5cm,乙酸乙酯/石油醚1∶9)纯化。
得率:2g(77%理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.9(s,9H);1.35(m,
12H);3.5(m,1H);3.9(m,1H);
4.38(s,2H);7.15-7.35(m,4H);
9.8(s,1H)ppm.实施例8
在-5℃和氮气氛下,向180mg(6mmol)80%浓氢化钠的15ml干燥四氢呋喃悬浮液中滴加1.6g(6mmol)2-(环己氨基)乙烯基磷酸二乙酯溶于30ml干燥四氢呋喃的溶液。30分钟后,于上述同样温度下,滴加实施例7所得化合物的40ml干燥四氢呋喃液,温热混合物至回流,历时3小时,混合物经冷却至室温后,分批加入200ml的冰水中,用乙酸乙酯萃取三次,每次用100ml,合并有机相,用饱和氯化钠洗涤和硫酸镁干燥,然后真空浓缩,剩余物溶于70ml甲苯,加入0.9g(7mmol)草酸二水合物的30ml水溶液,并加热回流混合物30分钟。再冷却至室温,分离各相,有机相用饱和氯化钠溶液洗涤,硫酸镁干燥和真空浓缩,剩余物用柱色谱(100g硅胶,07-230目,3.5cm,乙酸乙酯/石油醚1∶9)纯化。
得率:2g(95%理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.9(s,9H);1.38(m,
12H);3.36(m,1H);3.48(m,1H);
4.48(s,2H);6.03(dd,1H);7.12
-7.35(m,5H);9.45(d,1H)ppm.
实施例9
在-5℃和氮气下,将1.02g(8.8mmol)乙酸甲酯的5ml干燥四氢呋喃液滴加入330mg(11mmol)80%浓氢化钠的30ml干燥四氢呋喃悬浮液中。15分钟后,于相同温度滴加入5.5ml(8.8mmol)15%浓丁基锂的正己烷溶液,并搅拌15分钟。接着再滴加入溶于20ml干燥四氢呋喃的2g(4.4mmol)实施例8所得化合物,混合物于-5℃搅拌30分钟。向该反应溶液中小心地加入3ml的50%浓乙酸,用100ml水稀释该混合物,并用醚萃取三次,每次100ml。合并有机相,用饱和碳酸氢钠溶液洗涤二次,饱和氯化钠溶液洗涤一次,硫酸镁干燥和真空浓缩。剩余物用柱色谱(100g硅胶,70-230目,3cm,乙酸乙酯/石油醚3∶7)纯化。
得率:1.9g(84%理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.9(s,9H);1.35(m,
12H);2.5(m,2H);3.32(m,1H);
3.45(m,1H);3.48(s,2H);3.81
(s,3H);4.35(s,2H);4.55(m,1H);
5.32(dd,1H);6.42(d,1H);7.15
(m,4H)ppm.
实施例10
把4.5ml(4.5mmol)三乙基硼烷的1M四氢呋喃溶液在室温加到1.9g(3.7mmol)实施例9所得化合物的40ml干燥四氢呋喃溶液中,通入空气5分钟,将内部温度冷却至-30℃,然后慢慢加入160mg(4.5mmol)氢硼化钠和3ml甲醇,于-30℃搅拌该混合物30分钟,然后加入12ml 30%浓过氧化氢和25ml水的混合物。在此期间,让温度升至0℃,再搅拌30分钟。萃取混合物三次,每次用70ml乙酸乙酯,合并有机相,依次用饱和碳酸氢钠溶液和饱和氯化钠溶液各洗涤一次,硫酸镁干燥和真空蒸发。剩余物用柱色谱(80g硅胶,230-400目,2.5cm,乙酸乙酯/石油醚4∶6)纯化。
得率:1.5g(78.9%理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.9(s,9H);1.35(m,
12H);1.5(m,2H);2.5(m,2H);
3.35(m,1H);3.45(m,1H);3.8
(s,3H);4.15(m,1H);4.45(m,
3H);5.32(dd,1H);6.38(d,1H)
7.05-7.25(m,4H)ppm.
实施例11
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-羟甲基-吡啶-3基〕-3,5-二羟基-6-庚烯酸甲酯
将15ml 0.1N盐酸加到8.4g(14.6mmol)实施例10所得化合物的135ml甲醇溶液,于室温搅拌该混合物4天,并真空浓缩,将剩余物溶于二氯甲烷,用饱和碳酸氢钠溶液洗涤几次。有机相用硫酸镁干燥和真空蒸发,剩余物用柱色谱(硅胶,70-230目,乙酸乙酯/石油醚4∶6)纯化。
得率:3.6g(52.5%,理论得率)1H-NMR(CDCl3):=1.25(m,6H);1.33(d,6H);1.40(m,
2H);2.41(m,2H);3.30(m,1H);
3.45(m,1H);3.71(s,3H);4.07
(m,1H);4.28(m,1H);4.39(d,2H);
5.25(dd,1H);6.30(d,1H);7.08
(m,4H)ppm.
实施例12
0℃和氮气氛下,将4.5g(12.5mmol)实施例4所得化合物的50ml二甲基甲酰胺液滴加入414mg(13.8mmol)80%浓氢化钠的20ml二甲基甲酰胺悬浮液中,相同温度下搅拌30分钟。接着滴加入1.65ml(13.8mmol)苄基溴的二甲基甲酰胺液,于室温搅拌混合物3小时,然后将其注入到0℃的300ml水中,用醚萃取三次,每次150ml。合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥和真空浓缩。剩余物用柱色谱(100g硅胶,70-230目,3.5cm,乙酸乙酯/石油醚1∶10)纯化。
得率:2.6g(46.4%理论得率)1H-NMR(CDCl3):=0.95(t,3H);1.3(m,12H);3.05
(m,1H);3.38(m,1H);3.97(q,
2H);4.2(s,2H);4.38(s,2H);
7.02(m,2H);7.25(m,7H)ppm.
实施例13
按实施例6相似的方法,使2.5g(5.5mmol)实施例12所得化合物进行反应。
得率:1.5g(68%理论得率)1H-NMR(CDCl3):=1.3(m,12H);3.35(m,1H);3.45
(m,1H);4.13(s,2H);4.35(m,
4H);7.08(m,2H);7.25(m,7H)
ppm.
实施例14
按实施例7相似的方法,使1.5g93.6mmol)实施例13所得化合物进行反应。
得率:1.1g(75.9%理论得率)1H-NMR(CDCl3):=1.3(m,12H);3.4(m,1H);3.85
(m,1H);4.18(s,2H);4.38(s,
2H);7.05-7.35(m,9H);9.75
(s,1H)ppm.
实施例15
按实施例8类似的方法,使1.1g(2.7mmol)实施例14所得化合物进行反应。
得率:450mg(38.8%理论得率)1H-NMR(CDCl3):=1.35(m,12H);3.35(m,1H);3.42
(m,1H);4.21(s,2H);4.41(s,
2H);6.0(dd,1H);7.05-7.4(m,
10H);9.38(d,1H)ppm.
实施例16
按实施例9相似的方法,使431mg(1mmol)实施例15所得化合物进行反应。
得率:300mg(54.8%理论得率)
实施例17
按实施例10相似的方法,使300mg(0.55mmol)实施例16所得化合物进行反应。
得率:180mg(59.6%理论得率)1H-NMR(CDCl3):=1.2-1.35(m,12H);1.4(m,2H);
2.41(m,2H);3.3(m,2H);3.73
(s,3H);4.05(m,1H);4.15(s,
2H);4.28(m,1H);4.35(s,2H);
5.25(dd,1H);6.3(d,1H);6.95
-7.35(m,9H)ppm.
实施例18
15g(56.8mmol)实施例1所得化合物和.65g(56.8mol)3-氨基丁烯酸甲酯在150ml乙醇中加热回流20小时。冷却混合物,过滤和真空浓缩,剩余物用柱色谱(250g硅胶,70-230目,4.5cm,乙酸乙酯/石油醚3∶7)纯化。
得率:13.6g(66.3%理论得率)1H-NMR(CDCl3):=1.2(m,9H);2.35(s,3H);3.65
(s,3H);4.12(m,3H);4.98(s,
1H);5.75(s,1H);6.88(m,2H);
7.25(m,2H)ppm.
实施例19
4-(4-氟苯基)-2-异丙基-6-甲基吡啶-3,5-二甲酸3-乙酯5-甲酯
按实施例3相似的方法,使13.5g(37.4mmol)实施例18所得化合物进行反应。
得率:9.5g(70.9%理论得率)1H-NMR(CDCl3):=0.98(t,3H);1.31(d,6H);2.6
(s,3H);3.11(m,1H);3.56(s,
3H);4.03(q,2H);7.07(m,2H);
7.25(m,2H)ppm.
实施例20
在0℃和氮气氛下,将26.5ml(92.75mmol)双(2-甲氧基乙氧基)-二氢铝酸钠的3.5M甲苯溶液加到9.5g(26.5mmol)实施例19所得化合物的200ml无水四氢呋喃溶液中,于室温搅拌质混合物30分钟。再冷却至0℃,小心滴加入200ml水,然后用乙酸乙酯萃取三次,每次150ml。合并有机相,用饱和氯化钠溶液洗涤一次,硫酸镁干燥和真空浓缩,剩余物用柱色谱(200g硅胶,70-230目,4.5cm,乙酸乙酯/石油醚2∶8)纯化。
得率:4.2g(48.2%理论得率)1H-NMR(CDCl3):=0.98(t,3H);1.3(d,6H);2.73
(s,3H);3.05(m,1H);3.98(q,
2H);4.45(d,2H);7.1(m,2H);
7.25(m,2H)ppm.
实施例21
首先将49g(0.31mol)异丁酰乙酸乙酯和67g(0.31mol)3-苯氧基-4-氟苯甲醛加到300ml异丙醇中,接着加入1.81ml(18mmol)哌啶和1.061(18.6mmol)乙酸在30ml异丙醇中的混合物。于室温搅拌该混合物过夜,然后真空浓缩和高真空干燥。
得率:110g(无需纯化就能用于实施例22)。
实施例22
30g(84.3mmol)实施例21所得化合物和13.2g(84.3mmol)3-氨基-4-甲基-2-戊烯酸乙酯在150ml乙醇中加热回流过夜,该混合物冷却至0℃,滤出沉淀物,用石油醚洗涤和干燥器干燥。
得率:18.4g(44.2%理论得率)1H-NMR(CDCl3):δ=1.05-1.25(m,18H);4.05-4.2
(m,6H);4.95(s,1H);6.03(s,
1H);6.85-7.1(m,6H);7.3(m,
2H)ppm.
实施例23
按实施例3相似的方法,使18.4g(37.2mmol)实施例22所得化合物进行反应。
得率:17.6g(96%理论得率)1H-NMR(CDCl3):=1.05(t,6H);1.29(d,12H);3.08
(m,2H);4.05(q,4H);6.95-
7.35(m,8H)ppm.
实施例24
2,6-二异丙基-4-(4-氟-3-苯氧基苯基)-5-羟甲基-吡啶-3-甲酸乙酯
按实施例4相似的方法,使10g(20.3mmol)实施例23所得的化合物进行反应。
得率:4.9g(59.0%理论得率)1H-NMR(CDCl3):=1.07(t,3H);1.3(m,12H);3.04
(m,1H);3.47(m,1H);4.05(m,
2H);4.45(s,2H);6.95-7.4
(m,8H)ppm.
实施例25
1,4-二氢-2,6-二甲基-4-(4-氟苯基)-吡啶-3,5-二甲酸甲酯·2-氰基乙酯
15.4g(0.1mol)3-氨基丁烯酸2-氰基乙酯,12.4g(0.1mol)对氟苯甲醛和11.6g乙酰乙酸甲酯在150ml乙醇中加热回流过夜。用旋转蒸发器除去溶剂,将剩余物溶于乙酸乙酯,水洗,干燥,真空除去溶剂后得33.8g粗产品。
粗产品得率:94.4%理论得率1H-NMR(DMSO):=1.15(tr,3H,CH3);2.3(m,6H,CH3);
2.75(m,2H,CH2CN);3.55(s,3H,
OCH3);4.15(m,2H,OCH2);4.9(m,
1H,p-FC6H4-CH);6.9-7.3(m,4H,
芳香-H);8.8,9.0(2s,1H,NH)
ppm.
实施例26
将33.8g实施例26的粗产品加到12g(0.3mol)氢氧化钠的300ml水/150ml 1,2-二甲氧基乙烷的溶液中,该悬浮液变热成为澄清的溶液。在25℃搅拌过夜,加入100ml水,用二氯甲烷洗涤混合物三次,稀盐酸调节pH至1,二氯甲烷萃取出粘的沉淀产物。干燥和真空浓缩溶剂,得到25.8g粗产品。
粗产品得率:84.5%理论得率1H-NMR(DMSO):=2.25(s,6H,CH3);3.55(s,3H,
OCH3);4.85(broad s,1H,FC6H4-CH
);6.9-7.3(m,4H,芳香(c-H);
8.85(宽s,1H,NH);1.7(宽,
1H,COOH)ppm.
实施例27
将悬浮于90ml双(2-羟乙基)***(二醇)的12.g(41mmol)实施例26的粗制产品加热至200℃的浴温,冒出大量的气体。气体冒出后,快速冷却澄清的溶液,用500ml水/500ml***洗涤,水相用***洗涤二次,合并醚相并用水,1N氢氧化钠溶液洗涤,并干燥。经旋转蒸发器除去溶剂后,得到8.7g粗制产物。
粗得率:81.2%理论得率
实施例28
2,6-二甲基-4-(4-氟苯基)-吡啶-3-甲酸甲酯
8.6g(33mmol)粗制的实施例27化合物和3.3g氧化铬(VI)在90ml冰醋酸中加热回流1小时,然后用旋转蒸发器除去溶剂,向剩余物中加入乙酸乙酯/石油醚(1∶1),抽滤滤除不溶物。真空浓缩母液和色谱纯化(500g硅胶,乙酸乙酯/石油醚1∶1)。
得率:1.45g(16.3%理论得率)1H-NMR(CDCl3):=2.6(s,6H,CH3);3.65(s,3H,
OCH3);7.0(s,1H,吡啶-H);
7.1-7.4(m,4H,芳香-H)
ppm.
实施例29
在-78℃和氮气氛下,将5.3ml二异丁基氢化铝(1M,于甲苯中)加到1.35g(5.2mmol)实施例28所得化合物的25ml无水四氢呋喃溶液中,温热至25℃,用20%的浓氢氧化钾溶液水解该混合物,乙酸乙酯洗涤水相,然后合并有机相并干燥。真空蒸发得1.12g粗制产品。
得率:93%理论得率1H-NMR(CD3OD):=2.5(s,3H,CH3);2.7(s,3H,
CH3);4.5(s,2H,CH2OH);4.6(s,
OH);7.0(s,1H,吡啶:-H);7.1
-7.6(m,4H,芳香-H)ppm.
实施例30
在1.0g(4.3mmol)实施例29所得化合物的20ml二氯甲烷中分批加入1.5g(7mmol)二铬酸吡啶鎓盐,25℃搅拌混合物2小时,经色谱(150g硅胶,二氯甲烷/甲醇10∶1)浓缩得0.71g产物。
得率:72%理论得率1H-NMR(DMSO):=2.5(s,3H,CH3);2.7(s,3H,CH3);
7.2(s,1H,吡啶-H);7.3-7.6
(m,4H,芳香-H);9.95(s,1H,
CHO)ppm.
实施例31
在0℃和氮气氛下,将778mg(3.2mmol)〔2-(环己氨基)乙烯基〕磷酸二乙酯的3ml四氢呋喃液于15分钟加入75.5mg(3.2mmol)氢化钠的3ml无水四氢呋喃液中,0℃搅拌混合物15分钟,然后滴加入0.6g(2.6mmol)实施例30所得化合物的3ml乙腈/3ml二甲基甲酰胺的溶液。混合物于0℃和250℃分别搅拌1小时和30分钟,用50ml水进行水解,然后用***(3×50ml)洗涤,对有机相干燥和真空浓缩后,用8ml甲苯溶液解,并在60°-80℃和氮气氛下于1.2g(13.5mmol)草酸/20ml水中搅拌1.5小时。冷却混合物,用2N氢氧化钠溶液将pH调节至10,然后用醚洗涤四次,干燥醚相,真空浓缩和色谱(100g硅胶,二氯甲烷/甲醇30∶1)纯化。
得率:0.3g(45%理论得率)1H-NMR(CDCl3):=2.6(s,6H,CH3);6.2(dd,1H,
CH-CHO);6.9-7.4(m,5H,
芳香-H);7.45(d,1H,CH=CH-CHO);
9.5(d,1H,CHO)ppm.
实施例32
在0℃和氮气氛下,把82.2μl(0.76mmol)乙酰乙酸甲酯滴加到18.5mg(0.8mmol)氢化钠的1ml四氢呋喃液中。15分钟后,于0℃滴加入0.55ml(0.77mmol)正丁基锂(1.5M于己烷中),0℃搅拌混合物15分钟后,再滴加入180mg(0.7mmol)实施例31化合物的3ml四氢呋喃液。1小时后,用饱和氯化铵溶液水解混合物,用二氯甲烷洗涤三次,干燥有机相。真空除去溶剂得0.25g油状物。
粗得率:95%理论得率1H-NMR(CDCl3):=2.55,2.58(2s,6H,CH3);2.6
(2H,CH2);3.45(s,2H,CH2CO2);
3.75(s,3H,OCH3);4.6(m,1H,
CHOH);5.45(dd,1H,CH-CHOH);6.5
(d,1H,CH=CH-CHOH);6.9(s,1H,
吡啶-H);7.0-7.4(m,4H,
芳香-H)ppm.
实施例33
向0.25g(0.67mmol)实施例32化合物和0.81ml(0.81mmol)三乙基硼烷(1M,于四氢呋喃中)溶液通入空气5分钟,于-30℃慢慢加入30.6mg(0.81mol)氢硼化钠和0.55ml甲醇,并于-30℃搅拌30分钟,控制温度不超过0℃情况,加入4.7ml水和2.16ml的30%浓过氧化氢液液的混液,30分钟后用水稀释,并用乙酸乙酯洗涤三次,有机相用碳酸氢钠溶液洗涤,然后干燥,真空除去溶剂,剩余物经75g硅胶色谱纯化,乙酸乙酯洗脱得0.11产物。
得率:43.7%理论得率1H-NMR(CDCl3):δ=2.45(m,2H,CH2CO2);2.5,2.58
(2s,6H,CH3);3.75(s,3H,OCH3);
4.2,4.4(2m,2H,CHOH);5.45
(dd,1H,CH-CHOH);6.55(d,1H,
CH=CH-OH);6.4(s,1H,吡啶-
H);7.0-7.4(m,4H,芳香-H)
ppm.
实施例34
5-(2-氰乙基)-3-乙基-1,4-二氢-2-(4-氟苯基)-4-异丙基-6-甲基-吡啶-3,5-二甲酸酯
按实施例25相似方法,由2.75g(0.1mol)异亚丙基-4-氟苯甲酰乙酸乙酯和15.4g(0.1mol)3-氨基丁烯酸2-氰基乙酯制得32.6g粗产物。
粗产物得率:93.5%理论得率1H-NMR(CDCl3):δ=0.7-1.3(m,9H,CH3);2.3,2.35
(2s,3H,CH3);2.75(m,2H,
CH2CN);3.9-4.4(m,5H,
CHCH3,CH2O);5.6,5.7,6.1,
6.2(4s,1H,CH);7.0-8.0(m,
4H,芳香-H)ppm.
实施例35
1,4-二氢-2-(4-氟苯基)-4-异丙基-6-甲基-吡啶-3,5-二甲酸3-乙酯
按实施例26相似方法,由36g(93.2mmol)实施例34化合物制得7.17g粗产物。
粗产物得率:22.2%理论得率1H-NMR(DMSO):=0.8(m,9H,CH3);1.6(m,1H,
CHCH3);2.2,2.25(2s,3H,CH3);
3.8(m,3H,CH2O,CH);7.2-7.5
(m,4H,芳香-H)ppm.
实施例36
按实施例27的相似方法,由11.3g(32.6mmol)实施例35化合物制得7.15g粗产物。
粗产物得率:7.25%理论得率1H-NMR(CDCl3):=0.8-1.3(m,9H,CH3);2.5,2.6
(2s,3H,CH3);3.1(m,1H,
CHCH3);3.8-4.2(m,2H,CH2O);
4.55,5.2(br,1H,CH);6.8(s,
1H,CH);6.9-8.0(m,4H,
芳香-H)ppm.
实施例37
按实施例28相似方法,由6.95g(22.9mmol)实施例36化合物经色谱纯化(硅胶,甲苯/乙醇95∶5)得2.82g产物。
得率:41%理论得率1H-NMR(CDCl3):=1.0(tr,3H,CH3);1.3(d,6H,
CH3CH);2.6(S,3H,CH3);3.1
(sept,1H,CH);4.1(q,2H,CH2O);
7.0(s,1H,吡啶-H);7.1-
7.6(m,4H,芳香-H)ppm.
实施例38
按实施例29相似方法,使5.5g(18.3mmol)实施例37化合物进行反应,经干燥器干燥后,得到4.24g粗产物。
得率:89%理论得率1H-NMR(CDCl3):=1.3(d,6H);2.55(s,3H);3.36
(m,1H);4.49(s,2H);7.09(m,
3H);7.53(m,2H)ppm.
实施例39
按实施例30相似方法使4.1g(15.85mmol)实施例38化合物进行反应。
得率:2.23g(54.7%理论得率)1H-NMR(CDCl3):=1.3(d,6H);2.65(s,3H);3.91
(m,1H);7.10-7.28(m,3H);
7.5(m,2H);9.91(s,1H)ppm.
实施例40
2.13g(0.3mmol)实施例39化合物按实施例38相似方法进行反应。
得率:1.34g粗产物(57%理论得率)1H-NMR(CDCl3):=12.8(d,6H);2.6(s,3H);3.27
(m,1H);6.11(dd,1H);7.05-
7.55(m,6H);9.55(d,1H)ppm.
实施例41
1.07g(3.78mmol)实施例40化合物按实施例32相似方法进行反应。
得率:0.34g粗产物(22.5%理论得率)1H-NMR(CDCl3):=1.25(d,6H);2.5(m,2H);2.57
(s,3H);3.2(m,1H);3.42(s,
2H);3.75(s,3H);4.45(m,1H);
5.3(dd,1H);6.6(d,1H);7.05
(m,3H);7.43(m,2H)ppm.
实施例42
赤-(E)-7-〔2-(4-氟苯基)-2-异丙基-6-甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
200mg(0.5mmol)实施例41化合物按实施例33相似方法进行反应。
得率:21.5mg(10.7%理论得率)1H-NMR(CDCl3):=1.23(d,6H);1.5(m,2H);2.45
(m,2H);2.58(s,3H);3.21(m,
1H);3.72(s,3H);4.11(m,1H);
4.38(m,1H);5.31(dd,1H);6.55
(d,1H);7.05(m,3H);7.4(m,
2H)ppm.
实施例43
按实施例25相似方法,由26.4g(0.1mol)4-氟亚苄基-2-丁酰乙酸乙酯和15.4g(0.1mol)3-氨基丁烯酸2-氰基乙酯制得44.6g粗产物。
粗产物得率:100%理论得率1H-NMR(DMSO):δ=1.15(m,9H,CH3-CH2,CH3-CH-CH3);
2.3(s,3H,CH3);2.45(m,2H,
CH2-CN);4.0(q,2H,CH2O);4.1(m,
1H,CHCH3);4.15(m,2H,CH2O);
4.4(s,1H,p-FC6H4CH);6.9-7.3
(m,4H,芳香-H);8.3(s,1H,NH)
ppm.
实施例44
按实施例26相似方法,由10.2g(25.6mmol)实施例43化合物制得8.5g粗产物。
粗产物得率:95%理论得率1H-NMR(DMSO):=1.15(m,9H,CH3CH2,CH3CHCH3);
2.25,2.3(2s,3H,CH3);4.0(m,
3H,CH2O,CH3CH);4.85,6.3(2s,1H,
FC6H4-CH);6.9-7.3(m,4H,
芳香-H);8.1(s,1H,NH);10.9
(s,1H,COOH)ppm.
实施例45
按实施例27相似方法,由实施例44化合物获得5.6g粗产物。
粒产物得率:77%理论得率1H-NMR(CDCl3):=1.2(m,9H,CH3CH2,CH3CHCH3);
2.6(s,3H,CH3);4.1(m,CHCH3,
CH2O);4.5,4.6(2d,1H,
FC6H4CH);5.3(s,1H,NH);
6.9-7.4(m,>5H,芳香-H)
ppm.
实施例46
按实施例37相似的方法,由5.5g(18.2mmol)实施例45化合物经硅胶柱色谱(二氯甲烷)得2.9g红色油状物。
得率:53%理论得率1H-NMR(CDCl3):=1.05(tr,3H,CH3CH2);1.35(d,
6H,CH3CH);2.6(s,3H,CH3);
3.15(sept.,1H,CH);4.1(q,2H,
CH2);6.95(s,1H,吡啶-H);
7.1-7.4(m,4H,芳香-H)ppm.
实施例47
按实施例29相似的方法,由2.8g(9.3mmol)实施例46化合物获得2.19g产物。
得率:91%理论得率1H-NMR(CDCl3):=1.3(d,6H,CH3CH);1.5(br,1H,
0H);2.5(s,3H,CH3);3.5(七,
1H,CH);4.6(s,2H,CH2);6.9
(s,1H,吡啶-H);7.1-7.5(m,
4H,芳香-H)ppm.
实施例48
按实施例30相似方法,由实施例47化合物获得0.56g产物
得率:28.3%理论得率1H-NMR(CDCl3):=1.3(d,6H,CH3CH);2.6(s,3H,
CH3);3.6(七,1H,CH);1,0
(s,1H,吡啶-H);7.1-7.4
(m,4H,芳香-H);10.0(s,1H,
CHO)ppm.
实施例49
(E)-3-〔4-(4-氟苯基)-2-异丙基-6-甲基-吡啶-3-基〕-2-丙烯醛
按实施例31相似方法,由0.51g(1.99mmol)实施例48化合物获得0.48g产物。
得率:85.5%理论得率1H-NMR(CDCl3):=1.2(d,6H,CH3CH);2.5(s,3H,
CH3);3.3(七,1H,CH);6.0
(dd,1H,CHCHO);6.9(s,1H,
吡啶-H);7.0-7.3(m,4H,
芳香-H);7.5(d,1H,CH);9.5
(d,1H,CHO)ppm.
实施例50
按实施例32相似方法,由0.41g(1.44mmol)实施例49化合物获得0.22g产物。
得率:38.2%理论得率1H-NMR(CDCl3):=1.3(d,6H,CH3CH);2.5(s,3H,
CH3);3.3(七,1H,CH);3.5
(s,2H,CH2);3.25(s,3H,
OCH3);4.6(m,1H;CHOH);5.3
(dd,1H,CH);6.6(d,1H,CH);
6.9(s,1H,吡啶-H);7.0-
7.3(m,4H,芳香:-H)ppm.
实施例51
赤-(E)-7-〔4-(4-氟苯基)-2-异丙基-6-甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
1.2g(3.01mmol)实施例50化合物按实施例33相似方法进行反应。
得率:320mg(26.6%理论得率)1H-NMR(CDCl3):=1.28(d,6H);1.40(m,2H);2.45
(m,2H);2.55(s,3H);3.35(m,
1H);3.72(s,3H);4.15(m,1H);
4.39(m,1H);5.30(dd,1H);6.55
(d,1H);6.88(s,1H);7.0-7.30
(m,4H)ppm.
实施例52
1,4-二氢-3,6-二甲基-4-(4-氟苯基)-5-苯基-吡啶-3-甲酸甲酯
24.0g(0.1mol)1-(4-氟苯基)-2-苯基-丁烯-3-酮,23g(0.2mol)3-氨基丁烯酸甲酯和6ml(0.1mol)冰酯酸在150ml乙醇中加热回流过夜,然后加入11.5g(0.1mol)3-氨基丁烯酸甲酯和3ml冰醋酸并加热回流18小时,接着再加入11.5g(0.1mol)3-氨基丁烯酸甲酯和3ml冰醋酸并加热回流18小时。真空除去溶剂,剩余物中加入80ml甲醇,抽滤除去不溶物,真空浓缩该甲醇化溶液并在73℃-90℃/18毫巴下从剩余物中蒸馏去除过量的氨基丁烯酸酯,得到37.5g脆性熔融物的粗产物。
粗产物得率:大于100%理论得率1H-NMR(CDCl3):=1.85(s,3H,CH3);2.85(s,3H,
CH3);3.6(s,3H,CH3);4.65,
5.4(2br,s,1H,CH);6.7-7.4
(m,9H,芳香-H)ppm.
实施例53
按实施例37相似方法,由37.3g(0.1mol,粗)实施例52化合物获得20.4g固体产物。
得率:49.4%理论得率1H-NMR(CDCl3):δ=2.45(s,3H,CH3);2.6(s,3H,
CH3);3.5(s,3H,CH3);6.7-
7.4(m,9H,芳香-H)ppm.
实施例54
按实施例29相似方法,由20.2g(60mmol)实施例53化合物制得12.4g粗产物。
得率:67%理论得率1H-NMR(CDCl3):δ=2.0(br,s,1H,OH);2.3(s,3H,
CH3);2.75(s,3H,CH3);4.45
(s,2H,CH2);6.8-7.3(m,9H,
芳香-H)ppm.
实施例55
按实施例30相似方法,将6.0g(19.5mmol)得自实施例54的化合物经硅胶(二氯甲烷)色谱纯化,得3.8g固体。
得率:64%理论得率1H-NMR(CDCl3):=2.4(s,3H,CH3);2.9(s,3H,
CH3);6.8-7.3(m,9H,
芳香-H)9.8(s,1H,CHO)ppm.
实施例56
按实施例31相似方法,由3.1g(10mmol)实施例55化合物获得2.0g粗产物。
得率:60%理论得率1H-NMR(CDCl3):=2.4(s,3H,CH3); 2.75(s,3H,
CH3);6.15(dd,1H,CHCHO);6.85
(d,1H,CH);6.9-7.3(m,9H,
芳香-H);9.4(d,1H,CHO)
ppm.
实施例57
按实施例32相似方法,由2.0g(6mmol)实施例56化合物获得2.4g粗产物。
粗产物得率:89%理论得率1H-NMR(CDCl3):=2.3(s,3H,CH3);2.6(s,3H,
CH3);2.7(m,2H,CH2);3.45
(d,2H,CH2);3.75(2s,3H,
OCH3);4.5(m,1H,CH);5.4
(dd,1H,CHCHO);6.3(2d,1H,CH);
6.7-7.3(m,9H,芳香-H)ppm.
实施例58
赤-(E)-7-〔2,6-二甲基-4-(4-氟苯基)-5-苯基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例33相似的方法,2.4g(5.3mmol)实施例57化合物经硅胶色谱(乙酸乙酯)得550mg产物。
得率:23.1%理论得率1H-NMR(CDCl3):=1.7(br,s,2H,OH);2.3(s,3H,
CH3);2.4-2.6(m,2H,CH2);
2.65(s,3H,CH3);3.7(s,3H,
OCH3);4.1(m,1H,CHOH);4.45
(m,1H,CHOH);5.4(dd,1H,
CHCHOH);6.3(d,1H,CH);6.7-
7.3(m 9H,芳香-H)ppm.
实施例59
在-50℃和氮气氛下,把0.57ml(9.2mmol)甲基碘和327mg(10.9mmol)80%浓氢化钠加到3g(8.4mmol)实施例4化合物的100ml干燥四氢呋喃液中,搅拌混合物2小时让温度上升到25℃。然后小心加入水,醚萃取几次,硫酸钠干燥有机相和真空浓缩。
得率:2.9g(92.7%理论得率)1H-NMR(CDCl3):=0.97(t,3H);1.3(m,12H);3.05
(m,1H);3.21(s,3H);3.38(m,
1H);3.96(q,2H);4.1(s,2H);
7.08(m,2H);7.25(m,2H)ppm.
实施例60
在60℃和氮气氛下,将溶解于30ml无水四氢呋喃的2.85g(7.6mmol)实施例59化合物滴加入0.5g(13.2mmol)氢化铝锂的20ml无水四氢呋喃液中。混合物加热回流1小时,接着冷却至0℃,然后小心滴加入1.5ml水和0.3ml 15%的浓氢氧化钾溶液。从沉淀物中抽滤出溶液,沉淀物用***蒸煮几次。合并有机相,硫酸镁干燥和真空浓缩。剩余物经柱色谱(硅胶,70-230目,乙酸乙酯/石油醚1∶9)纯化。
得率:1.9g(74.8%理论得率)1H-NMR(CDCl3):=1.3(m,12H);3.17(s,3H);3.35
(m,1H);3.43(m,1H);4.02(s,
2H);4.35(d,2H);7.12(m,2H);
7.25(m,2H)ppm.
实施例61
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-甲氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按类似于实施例7、8、9和10的反应由得自实施例60的化合物制备实施例61的化合物。1H-NMR(CDCl3):δ=1.23(m,6H);1.32(d,6H);1.40
(m,2H);2.43(m,2H);3.18(s,
3H);3.32(m,2H);3.73(s,3H);
4.05(s,2H);4.08(m,1H);4.29
(m,1H);5.23(dd,1H);6.31(d,
1H);7.0-7.20(m,4H)ppm.
实施例62
按类似于实施例5,6,7,8,10,11和12的反应,由实施例20化合物合成上述化合物。1H-NMR(CDCl3):δ=0.0(s,6H);0.82(s,9H);1.22
(d,6H);1.40(m,2H);2.42(m,
2H);2.65(s,3H);3.28(m,1H);
3.70(s,3H);4.08(m,1H);4.26
(m,1H);4.29(s,2H);5.22(dd,
1H);6.30(d,1H);7.0-7.20
(m,4H)ppm.
实施例63
按实施例5,6,7,8,9,10,11和12相似方法,由实施例20化合物合成上面化合物。1H-NMR(CDCl3):=1.22(d,6H);1.30-1.60(m,2H);
2.43(m,2H);2.69(s,3H);3.32
(m,1H);3.72(s,3H);4.07(m,
1H);4.30(m,1H);4.41(s,2H);
5.25(dd,1H);6.31(d,1H);
7.11(m,4H)ppm.
实施例64
赤-(E)-7-〔3-苄氧甲基-4-(4-氟苯基)-1-异丙基-6-甲基-吡啶-5-基〕-3,5-二羟基-6-庚烯酸甲酯
按类似实施例5,6,7,8,9,10,11和12的反应,由实施例20化合物合成上面化合物。1H-NMR(CDCl3):=1.23(d,6H);1.40(m,2H);2.42
(m,2H);2.63(s,3H);3.30(m,
1H);3.72(s,3H);4.10(m,1H);
4.15(s,2H);4.32(m,1H);4.38
(S,2H);5.20(dd,1H);6.31(d,
1H);7.0-7.40(m,9H)ppm.
实施例65
0℃下,把865mg(3.3mmol)三苯基膦,0.41ml(3.3mmol)2,2-二甲基丁酸和0.52ml(3.3mmol)偶氮二羧酸二乙酯依次加到1.29g(3mmol)实施例6化合物的50ml无水四氢呋喃溶液中,于室温搅拌混合物过夜。真空浓缩混合物,剩余物经柱色谱(硅胶,70-230目,乙酸乙酯/石油醚1∶9)纯化。
得率:1.32g(87%理论得率)1H-NMR(CDCl3):=0.01(s,6H);0.86(t,3H);0.91
(s,9H);1.2(s,6H);1.39(m,
12H);1.6(q,2H);3.24(m,1H);
3.48(m,1H);4.38(s,2H);4.79
(s,2H);7.05-7.35(m,4H)ppm.
实施例66
把2.6ml(2.6mmol)四丁基氟化铵的1M四氢呋喃溶液加到溶于20ml无水四氢呋喃中的1.3g(2.6mmol)实施例65化合物中,室温搅拌混合物1小时。混合物中加入饱和碳酸氢钠溶液,然后用二氯甲烷萃取数次。硫酸镁干燥有机相并真空浓缩,剩余物经柱色谱(硅胶,70-230目,乙酸乙酸/石油醚1∶9洗脱)纯化。
得率:1g(95.2%理论得率)1H-NMR(CDCl3):=0.71(t,3H);1.02(s,6H);1.21
(d,6H);1.25(d,6H);1.43(q,
2H);3.09(m,1H);3.38(m,1H);
4.3(d,2H);4.61(s,2H);6.95-
7.18(m,4H)ppm.
实施例67
2,6-二异丙基-5-(2,2-二甲基丁酰氧甲基)-4-(4-氟苯基)-吡啶-3-甲醛
按实施例7相似方法,使1g(2.5mmol)实施例66化合物进行反应。
得率:890mg(86.4%理论得率)1H-NMR(CDCl3):=0.82(t,3H);1.25(s,6H);1.32
(m,12H);1.55(q,2H);3.26(m,
1H);3.88(m,1H);4.77(s,2H);
7.09-7.27(m,4H);9.77(s,1H)
ppm.
实施例68
(E)-3-〔2,6-二异丙基-5-(2,2-二甲基丁酰氧甲基)-4-(4-氟苯基)-吡啶-3-基〕-2-丙烯醛
使860mg(2.1mol)实施例67化合物进行与实施例8相似的反应。
得率:420mg(45.6%理论得率)1H-NMR(CDCl3):=0.82(t,3H);1.14(s,6H);1.31
(m,12H);1.53(q,2H);3.22(m,
1H);3.33(m,1H);4.75(s,2H);
5.99(dd,1H);7.05-7.29(m,
5H);9.4(d,1H)ppm.
实施例69
在-5℃和氮气氛下,将0.15ml(1.4mmol)乙酰乙酸甲酯的2ml无水四氢呋喃液滴加入54.6mg(1.82mmol)80%浓氢化钠的5ml无水四氢呋喃悬浮液中,15分钟后,在相同的温度下滴加入0.89ml(1.4mmol)15%浓丁基锂的正己烷液,并且15分钟后再加入408mg(1.8mmol)干燥溴化锌的5ml无水四氢呋喃液。于-5℃搅拌混合物15分钟,加入溶于10ml干燥四氢呋喃中的400mg(0.91mmol)实施例68化合物,并且搅拌混合物过夜。然后加入饱和氯化铵溶液并用醚萃取数次,有机相经硫酸镁干燥和真空浓缩后,所得剩余物用柱色谱(硅胶,70-230目,乙酸乙酯/石油醚3∶7)纯化。
得率:200mg(38.5%理论得率)1H-NMR(CDCl3):=0.8(t,3H);1.12(s,6H);1.27
(d,6H);1.32(d,6H);1.53(q,
2H);2.45(m,2H);3.18(m,1H);
3.27(m,1H);3.43(s,2H);3.74
(s,3H),4.50(m,1H);4.73(s,
2H);5.28(dd,1H);6.38(d,1H);
7.0-7.10(m,4H)ppm.
实施例70
赤-(E)-7-〔2,6-二异丙基-5-(2,2-二甲基丁酰氧甲基)-4-(4-氟苯基)-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例10相似方法使180mg(0.32mmol)实施例化合物进行反应。
得率:138mg(77.5%理论得率)1H-NMR(CDCl3):=0.81(t,3H);1.12(s,6H);1.28
(m,6H);1.40(m,2H);1.53(q,
2H);2.43(m,2H);3.17(m,1H);
3.32(m,1H);3.73(s,3H);4.08
(m,1H);4.31(m,1H);4.75(s,
2H);5.28(dd,1H);6.32(d,1H);
7.0-7.1(m,4H)ppm.
实施例71
赤-(E)-7-〔5-苯甲酰氧甲基-2,6-二异丙基-4-(4-氟苯基)-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例65,66,67,68,69和70相似的反应,由实施例6化合物合成上式化合物。1H-NMR(CDCl3):=1.31(m,6H);1.40(m,2H);2.43
(m,2H);3.32(m,2H);3.73(s,
3H);4.07(m,1H);4.32(m,1H);
5.07(s,2H);5.30(dd,1H);
6.32(d,1H);6.90-7.20(m,4H);
7.42(m,2H);7.55(m,1H);8.02
(m,2H)ppm.
实施例72
按实施例65,66,67,68,69和70相类似的反应,由实施例6所得的化合物合成上式化合物。1H-NMR(CDCl3):=1.25(m,12H);1.40(m,2H);2.02
(s,3H);2.43(m,3H);3.20(m,
1H);3.32(m,1H);3.72(s,3H);
4.07(m,1H);4.29(m,1H);4.81
(S,2H);5.28(dd,1H);6.30(d,
1H);7.0-7.1(m,4H)ppm.
实施例73
(E/Z)-3-羧甲基-4-(4-氟苯基)-3-丁烯-2-酮
在300ml异丙醇中加入62g(0.5mol)4-氟苯甲醛和53.9ml(0.5ml)乙酰乙酸甲酯,然后加入2.81ml(28mmol)哌啶和1.66ml(29mmol)乙酸在40ml异丙醇中混合物,于室温搅拌48小时,真空浓缩混合物,再高真空蒸馏剩余物。
沸点(0.5mm):135℃
得率:50.5g(45.5%,理论得率)
实施例74
1,4-二氢-2,6-二甲基-4-(4-氟苯基)-吡啶-3,5-二甲酸二甲酯
将33.3g(0.15mol)实施例73化合物与17.3g(0.15mol)3-氨基丁烯酸甲酯的150ml乙醇液加热回流4小时。冷却至0℃,抽滤得到析出的沉淀物,经少量石油醚洗涤并用干燥器干燥。
得率:32g(66.8%理论得率)1H-NMR(CDCl3):=2.33(s,6H);3.65(s,6H);4.99
(s,1H);5.77(s,1H);6.89(m,
2H);7.22(m,2H)ppm.
实施例75
使32g(0.1mol)实施例74化合物进行实施例3相似的反应。
得率:27.2g(87%理论得率)1H-NMR(CDCl3):=2.59(s,6H);3.56(s,6H);7.08
(m,2H);7.25(m,2H)ppm.
实施例76
2,6-二甲基-4-(4-氟苯基)-5-羟甲基吡啶-3-甲酸甲酯
在-10℃至-5℃和氮气氛下,将40.3ml(141mmol)2-双(2-甲氧乙氧基)二氢铝酸钠的3.5M甲苯溶液加入14.9g(47mmol)实施例75化合物的300ml干燥四氢呋喃溶液中,于室温搅拌混合物30分钟。冷却至0℃后,向混合物中小心滴加入150ml水,并用乙酸乙酯萃取数次。合并有机相,用饱和氯化钠溶液洗涤,硫酸镁干燥和真空浓缩,剩余物用醚/石油醚结晶后,经干燥器干燥得7.5g(55.2%理论得率)。1H-NMR(CDCl3):=2.52(s,3H);2.7(s,3H);3.52
(s,3H);4.45(s,2H);7.05-7.3
(m,4H)ppm.
实施例77
按实施例5,6,7,8,9和10的相似反应,由实施例76化合物制得实施例77化合物。1H-NMR(CDCl3):=0.01(s,6H);0.92(s,9H);1.40
(m,2H);2.49(m,2H);2.62(s,
3H);2.71(s,3H);3.80(s,3H);
4.17(m,1H);4.36(s,2H);4.38
(m,1H);5.42(dd,1H);6.31(d,
1H);7.10-7.20(m,4H)ppm.
实施例78
赤-(E)-7-〔2,6-二甲基-4-(4-氟苯基)-5-羟甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按相似于实施例11的方法,由实施例77所得化合物制得实施例78化合物。
实施例79
在150ml干燥异丙醇中加入39g(0.25mol)环丙基碳酰乙酸乙酯和31g(0.25mol)4-氟苯甲醛,再加入1.4ml(14mmol)吡啶和0.83ml(14.5mmol)乙酸在20ml异丙醇中的混合物,于室温搅拌混合物48小时,然后真空浓缩,对所得剩余物进行高真空蒸馏。
沸点(0.5mm):140℃
得率:52.3g(78.8%理论得率)
实施例80
将39.3g(0.15mol)实施例79化合物和23.6g(0.15mol)3-氨基-4-甲基-2-戊烯酸乙酯在150ml乙二醇中加热回流过夜。混合物冷却至室温后,用醚萃取数次,合并有机相,用10%浓盐酸洗涤3次,水和饱和碳酸氢钠各洗涤1次,硫酸镁干燥和真空浓缩。剩余物于石油醚/***中搅拌,抽吸过滤和干燥器干燥。
得率:22.8g(37.8%理论得率)1H-NMR(CDCl3):=0.65(m,2H);1.03(m,2H);1.15
(m,13H);2.78(m,1H);4.15(m,
4H);5.03(s,1H);5.72(s,1H);
6.90(m,2H);7.22(m,2H)ppm.
实施例81
使19.1g(47mmol)实施例80化合物进行实施例3的相似反应。
得率:9.8g(52.5%理论得率)1H-NMR(CDCl3):=0.97(m,8H);1.25(m,8H);2.09
(m,1H);3.06(m,1h);4.02(m,
4H);7.06(m,2H);7.26(m,2H)
ppm.
实施例82
6-环丙基-4-(4-氟苯基)-5-羟甲基-2-异丙基-吡啶-3-甲酸乙酯
使6g(15mmol)实施例81化合物进行实施例4相似的反应。
得率:31.g(57.9%理论得率)1H-NMR(CDCl3):=0.97(t,3H);1.03(m,2H);1.22
(m,8H),2.38(m,1H);3.03(m,
1H);4.0(q,2H);4.58(s,2H);
7.1(m,2H);7.25(m,2H)ppm.
实施例83
6-环丙基-4-(4-氟苯基)-2-异丙基-5-甲氧甲基-吡啶-3-甲酸乙酯
使2.9g(8mmol)实施例82化合物进行实施例59相似的反应。
得率:2g(67.4%理论得率)1H-NMR(CDCl3):=0.93(t,3H);0.98(m,2H);1.22
(d,6H);1.24(m,2H);2.32(m,
1H);3.03(m,1H);3.28(s,3H);
3.97(q,2H);4.25(s,2H);7.08
(m,2H);7.25(m,2H)ppm.
实施例84
6-环丙基-4-(4-氟苯基)-3-羟甲基-2-异丙基-5-甲氧甲基吡啶
在氮气氛下,在1.9g(5mmol)实施例83化合物的50ml干燥四氢呋喃溶液中加入44.3ml(15mmol)2-甲氧乙氧基)二氢铝酸钠的3.5M甲苯溶液,于室温搅拌混合2小时和加热回流1小时。混合物冷却至0℃后,小心滴加入50ml水,然后用乙酸乙酯萃取数次。合并乙酸乙酯相,用饱和氯化钠洗涤,硫酸镁干燥和真空浓缩。
得率,1.6g(97%理论得率)1H-NMR(CDCl3):=0.89(m,2H),1.17(d,6H);1.19
(m,2H);2.20(s,1H);3.13(s,
3H);3.32(m,1H);4.07(s,2H);
4.26(s,2H);7.05(m,2H);7.16
(m,2H)ppm.
实施例85
按实施例7,8,9和10相似的反应,由实施例84化合物制得实施例85化合物。1H-NMR(CDCl3):=0.95(m,2H);1.17(m,6H);1.22
(m,2H);1.40(m,2H);2.25(m,
1H);2.44(m,2H);3.22(s,3H);
3.23(m,1H);3.73(s,3H);4.07
(m,1H);4.18(s,2H);4.28(m,
1H);5.22(dd,1H);6.30(d,1H);
7.0-7.20(m,4H)ppm.
实施例86
在-5℃下,在溶于100ml干燥四氢呋喃中的5g(13.9mmol)实施例4化合物中依次加入1.69ml(20.9mmol)吡啶和1/5(20.9mmol)亚硫酰氯,于室温搅拌混合物15分钟,混合物经乙酸乙酯稀释和用饱和碳酸氢钠萃取数次,有机相用硫酸镁干燥和真空浓缩。剩余物经柱色谱(硅胶,70-230目,石油醚/乙酸乙酯95∶5)。
得率:3.2g(65.2%理论得率)1H-NMR(CDCl3):=0.98(t,3H);1.30(d,6H);1.35
(d,6H);3.05(m,1H);3.45(m,
1H);3.98(q,2H);4.38(s,2H);
7.13(m,2H);7.31(m,2H)ppm.
实施例87
于0℃,将溶解于50ml无水四氢呋喃中的3.22g(9.1mmol)实施例86化合物滴加到2.11g(18.2mmol)酚钠的50ml无水四氢呋喃溶液中,加热回流该混合物4天。混合物经冷却至室温后,用150ml水稀释和***萃取数次。合并有机相,硫酸镁干燥和真空浓缩,剩余物经柱色谱(硅胶,70-230目,石油醚/乙酸乙酯95∶5)纯化。
得率:3.2g(80.8%理论得率)1H-NMR(CDCl3):=0.97(t,3H);1.3(d,6H);1.33
(d,6H);3.1(m,1H);3.32(m,
1H);4.0(q,2H);4.7(s,2H);
6.78-7.31(m,9H)ppm.
实施例88
使3.25g(7.5mmol)实施例87化合物进行实施例60相似的反应。
得率:2.75g(93.2%理论得率)1H-NMR(CDCl3):=1.35(m,12H);3.30(m,1H);3.48
(m,1H);4.42(d,2H);4.62(s,
2H);6.75-7.30(m,9H)ppm.
实施例89
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-苯氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例7,8,9和10相似的方法,由实施例88化合物制得实施例89化合物。1H-NMR(CDCl3):=1.28(m,6H);1.31(d,6H);1.43
(m,2H);2.41(m,2H);3.30(m,
2H);3.71(s,3H);4.08(m,1H);
4.30(m,1H);4.65(s,2H);5.28
(dd,1H);6.35(d,1H);6.75-
7.30(m,9H)ppm.
实施例90
将1.88g(22.4mmol)二氢呋喃和0.525g(1.49mmol)对甲苯磺酸吡啶鎓加到5.36g(14.9mmol)实施例4化合物的100ml干燥二氯甲烷溶液中,加热回流该混合物48小时。混合物经冷却至室温后,用二氯甲烷稀释和水萃取数次。有机相用硫酸镁干燥和真空浓缩,剩余物经柱色谱(硅胶,70-230目,二氯甲烷)纯化。
得率:4.4g(66.7%理论得率)1H-NMR(CDCl3):=0.98(t,3H);1.31(m,12H);
1.40-1.80(m,6H);3.05(m,1H);
3.43(m,2H);3.61(m,1H);3.98
(q,2H);4.05(d,1H);4.45(m,
1H);4.55(d,1H);7.05(m,2H);
7.25(m,2H)ppm.
实施例91
2,6-二异丙基-4-(4-氟苯基)-3-羟甲基-5-(四氢吡喃-2-基-氧甲基)吡啶
使4.4g(9.9mmol)实施例90化合物进行实施例60相似反应。
得率:2.5g(63.5%理论得率)1H-NMR(CDCl3):=1.32(m,12H);1.40-1.80(m,
6H);3.40(m,3H);3.57(m,1H);
3.95(d,1H);4.35(m,3H);4.5
(d,1H);7.11(m,2H);7.25(m,
2H)ppm.
实施例92
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-(四氢吡喃-2-基-氧甲基)-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例7,8,9和10的相似反应,由实施例91所得化合物制得实施例92化合物。1H-NMR(CDCl3):δ=1.20-1.80(m,20H);2.43(m,
2H);3.32(m,1H);3.41(m,2H);
3.58(m,1H);3.72(s,3H);3.98
(d,1H);4.08(m,1H);4.29(m,
1H);4.43(m,1H);4.54(d,1H);
5.28(dd,1H);6.31(d,1H);7.10
(m,4H)ppm.
实施例93
3-氨基-4-甲基-2-戊烯酸2-(三甲基甲硅烷基)乙酯
将3g对甲苯磺酸加到150g(0.65mol)异丁酰乙酸2-(三甲基甲硅烷基)乙酯的700ml甲苯液中,于室温用氨气饱和上述混合物,然后静置过夜,接着加热回流8小时,继续通入氨气。混合物经冷却至室温后,进行过滤,用水萃取该甲苯溶液数次,硫酸镁干燥和真空浓缩。得率:134g(90%理论得率)1H-NMR(CDCl3):=0.21(s,9H);1.15(m,2H);1.30
(m,6H);2.48(m,1H);4.31(m,
2H);4.71(s,1H)ppm.
实施例94
将52.7g(90.2mol)实施例1化合物加到45.8g(0.2mol)实施例93化合物的100ml乙二醇溶液中,并加热回流过夜。冷却该混合物,加入5ml浓盐酸,再加热至100℃维持30分钟。冷却混合物至室温,进行真空浓缩,剩余物溶于乙酸乙酯后,用稀盐酸萃取数次。有机相依次用饱和碳酸氢钠溶液和氯化钠洗涤各一次,硫酸镁干燥和真空浓缩。剩余物经柱色谱(硅胶,70-230目,二氯甲烷)纯化。
得率:39.2g(41.3%理论得率)1H-NMR(CDCl3):=0.01(s,9H);0.95(m,2H);1.18
(m,12H);1.22(t,3H);4.10(m,
6H);4.97(s,1H);6.10(s,1H);
6.85(m,2H);7.18(m,2H)ppm.
实施例95
将83.3ml(83.3mmol)四丁基氯化铵的1M四氢呋喃溶液加到38.9g(81.8mmol)实施例94化合物的300ml干燥四氢呋喃溶液中,于室温搅拌该混合物48小时,然后真空浓缩,把剩余物溶于***,依次用稀氢氧化钠溶液和稀硫酸洗涤各三次。用硫酸镁干燥有机相并真空浓缩。
得率:29g(94.5%理论得率)1H-NMR(CDCl3):=1.09-1.3(m,15H);4.02(q,
2H);4.08(m 2H);4.18(m,1H);
4.89(s,1H);7.03(m,2H);7.12
(m,2H)ppm.
实施例96
按实施例27,3,29,7,8,9和10的相似反应,由实施例95化合物制得实施例96化合物。1H-NMR(CDCl3):=1.28(m,12H);1.50(m,2H);
2.47(m,2H);3.05(m,1H);3.35
(m,1H);3.72(s,3H);4.13(m,
1H);4.38(m,1H);5.31(dd,1H);
6.55(d,1H);6.85(s,1H);7.05
(m,2H);7.25(m,2H)ppm.
实施例97
将0.9ml哌啶加到24.8g(0.2mol)4-氟苯甲醛和32.4g(0.2mol)苄基异丙基酮的150ml甲苯液中,并加热回流过夜。混合物经冷却至室温后,用水萃取数次,硫酸镁干燥有机相和真空浓缩。对剩余物初级蒸馏,一直至浴温为150℃和0.1毫巴的高真空条件,得到43.8g粗产物。
得率:81%理论得率
实施例98
将2.86ml(50mmol)冰醋酸加到13.45g(50mmol)实施例97化合物和17.4g(100ml)3-氨基-4-甲基-2-戊烯酸乙酯的80ml乙二醇液中,混合物加热回流过夜,经冷却至室温后,进行真空浓缩。将剩余物溶于二氯甲烷,并用水萃取几次。硫酸镁干燥有机相和真空浓缩,剩余物被溶于乙酸乙酯后,用10%浓盐酸,水和饱和碳酸氢钠溶液液涤。再干燥有机相和浓缩,剩余物经柱色谱(硅胶,70-230目,乙酸乙酯/石油醚)纯化。
得率:2.3g(11.3%理论得率)1H-NMR(CDCl3):=1.1(m,9H);1.25(m,6H);2.70
(m,1H);3.90-4.40(m,3H);
4.55(s,1H);5.75(s,1H);6.80
-7.30(m,9H)ppm.
实施例99
按实施例3,29,7,8,9和10相似的反应,由实施例98化合物制得实施例99化合物。1H-NMR(CDCl3):δ=1.18(d,6H);1.32(m,6H);1.42
(m,2H);2.40(m,2H);2.70(d,
1H);2.88(m,1H);3.38(m,1H);
3.48(d,1H);3.71(s,3H);4.05
(m,1H);4.30(m,1H);5.30(dd,
1H);6.39(d,1H);6.70-7.20
(m,9H)ppm.
实施例100
按实施例7,8,69和10的相似反应,由实施例4所得化合物制得实施例100化合物。1H-NMR(CDCl3):δ=0.98(t,3H);1.25(m,6H;1.32
(d,6H);1.45(m,2H);2.42(m,
2H);3.05(m,1H);3.32(m,1H);
3.72(s,3H);3.98(q,2H);4.10
(m,1H);4.32(m,1H);5.29(dd,
1H);6.38(d,1H);7.02(m,2H);
7.12(m,2H)ppm.
实施例101
1,4-二氢-2,6-二异丙基-4-(4-氟苯基)-5-吗啉代羰基-吡啶-3-甲酸乙酯
在氮气氛下,将1.05g(6.5mmol)N,N-羰基咪唑加到溶于20ml干燥四氢呋喃中的1.875g(5mmol)实施例95化合物中,于室温搅拌混合物30分钟,然后加热回流30分钟,并加入0.87ml(10mmol)吗啉的5ml干燥四氢呋喃溶液,接着再加热至沸并维持2小时。将混合物冷却至室温,进行真空浓缩,把剩余物溶于二氯甲烷并依次用1N盐酸,1N氢氧化钠溶液和水洗涤。硫酸镁干燥有机相并真空浓缩,剩余物经结晶和干燥器干燥。
得率:1.96g(88%理论得率)1H-NMR(CDCl3):δ=1.0-1.28(m,15H);3.20-4.40
(配位区,12H);4.70(s,
1H);5.50(s,1H);6.90(m,2H);
7.20(m,2H)ppm.
实施例102
按实施例3的相似反应,从9g(21.5mmol)实施例101化合物制得上式化合物。
得率:7.6g(80%理论得率)1H-NMR(CDCl3):=0.95(t,3H);1.25(m,6H);1.35
(m,6H);2.70-3.80(
配位区,10H);4.0(m,2H);7.0-
7.50(m,4H)ppm.
实施例103
按实施例29,7,8,9和10的相似反应,从实施例102化合物制得实施例103化合物。1H-NMR(CDCl3):=1.10-1.50(配位区,
14H);2.40(m,2H);2.80-3.65
(配位区,10H);3.75(s,
3H);4.10(m,1H);4.35(m,1H);
5.25(m,1H);6.45(dd,1H);
6.95-7.50(m,4H)ppm.
实施例104
在氮气氛和-78℃下,将20.6ml(31mmol)二异丁基氢化铝(1M,于甲苯中)加到溶干30ml干燥甲苯中的1.37g(3.1mmol)实施例102化合物中,该温度下搅拌1小时,接着于室温搅拌48小时。用20%浓氢氧化钾溶液于冰冷却下将其水解,并用甲苯萃取数次。硫酸镁干燥有机相,真空浓缩和干燥器干燥。得率:104g(87%理论得率)1H-NMR(CDCl3):=1.28(d,6H);1.32(d,6H);2.15
(m,4H);3.18(s,2H);3.45(m,
2H);3.52(m,4H);4.32(d,2H);
7.05-7.20(m,4H)ppm.
实施例105
按实施例7,8,9和10的相似反应,从实施例104化合物制得上式化合物1H-NMR(CDCl3):=1.25(m,12H);1.40(m,2H);2.20
(m,4H);2.45(m,2H);3.20(s,
2H);3.30(m,1H);3.45(m,1H);
3.55(m,4H);3.75(s,3H);4.10
(m,1H);4.30(m,1H);5.30(dd,
1H);6.25(d,1H);7.0-7.20(m,
4H)ppm.
实施例106
赤-(E)-7-〔(2,6-二异丙基)-4-(4-氟苯基)-5-碘代甲基-吡啶-3-基)-3,5-二羟基-6-庚烯酸甲酯
将80mg(0.1514mmol)实施例105化合物溶于5ml甲基碘中,混合物在30℃搅拌3小时和60℃搅拌过夜(无光下)。真空浓缩混合物和在干燥器中用五氧化磷干燥,得到120mg粗产物。1H-NMR(CDCl3):=1.20-1.70(配位区,14H);
2.45(m,2H);3.30(m,2H);3.75
(s,3H);4.05(m,1H);4.20(s,
2H);4.30(m,1H);5.30(dd,1H);
6.25(d,1H);7.0-7.25(m,4H)
ppm.
实施例107
氮气氛下,依次将22.3μl(0.19mmol)苄硫醇和32.7μl(0.237mmol)三乙胺加到溶于2ml干燥二氯甲烷中的90mg(0.158mmol)实施例106化合物中,并于室温搅拌过夜。混合物用二氯甲烷稀释,并用水萃取数次。硫酸镁干燥有机相并真合浓缩后,剩余物经柱色谱(硅胶,70-230目,乙酸乙酯/石油醚1∶1)纯化。
得率:20mg(22.4%理论得率)1H-NMR(CDCl3):=1.23(m,12H);1.4(m,2H);2.40
(m,2H);3.20(m,2H);3.28(s,
2H);3.55(s,2H);3.73(s,3H);
4.05(m,1H);4.25(m,1H);5.25
(dd,1H);6.25(d,1H);6.90-
7.28(m,9H)ppm.
实施例108
将52mg(0.303mmol)间氯过苯甲酸加到80mg(0.1515mmol)实施例105化合物的3ml干燥二氯甲烷液中,于室温搅拌1小时。混合物依次用碘化钾溶液,硫代硫酸钠溶液和碳酸氢钠溶液洗涤,有机相用硫酸镁干燥和真空浓缩。
得率:60mg(73%理论得率)1H-NMR(CDCl3):=1.10-1.55(配位区,
14H);2.45(m,2H);2.70-3.70
(配位区,10H);3.75(s,
3H);4.0(m,1H);4.10(m,1H);
4.30(m,2H);5.25(dd,1H);6.25
(d,1H);7.0-7.30(m,4H)ppm.
实施例109
将210g(1mol)4-氟苯甲酰乙酸乙酯和144g(2mol)2-甲基丙醛的溶液与7ml哌啶和5ml乙酸的100ml异丙醇液一起于50℃搅拌过夜。在约15乇分批浓缩得到粗产物(无需纯化)(270g,约85%)。
实施例110
3-乙氧羰基-2-(4-氟苯基)-14,-二氢-4-异丙基-6-甲基-5-甲氧羰基吡啶
将62.9g(0.2mol)实施例109化合物和21.9g(0.19mol)3-氨基丁烯酸甲酯于200ml乙二醇中加热回流过夜。***萃取混合物3次,合并有机相,然后用2N盐酸和饱和氯化钠溶液萃取,硫酸镁干燥和浓缩至干。所得剩余物分二部分经色谱(750g硅胶,230-400目,柱直径为7.5cm),用石油醚/***乙酯10∶1至5∶1进行洗脱)纯化。
得率:21.5g(31%),黄色晶体
熔点:109℃
实施例111
按实施例3的相似方法,由14.9g(14.5mmol)实施例110化合物制得实施例111化合物。
得率:15.2g(102%)粗产物,无色油(无需纯化就能用于反应)。1H-NMR(CDCl3):=1.02(t,3H,CH2CH3);1.33(d,
6H,CH(CH3)2);2.55(S,3H,6-
CH3);3.15(七,1H,CH(CH3)2);
3.95(s,3H,O-CH3);4.08(q,
2H,CH2-CH3);7.1(m,2H,3′-H);
7.55(m,2H,2′-H);ppm.
实施例112
按实施例4的相似方法,由10g(27.8mmol)实施例111化合物制得上式化合物。
得率:4.53g(49%理论得率),淡黄色晶体
熔点:113℃
实施例113
按相似实施例5,6,7,8,9和10的所应,由实施例112化合物制得无色泡沫状的上式化合物。1H-NMR(CDCl3):δ=0.2(s,6H,Si(CH3)2);9.13
(s,9H,Si-C(CH3)3);1.3(m,
8H,CH(CH3)2+CH(OH)-CH2-CH(OH))
;2.4(m,2H,CH2-COOCH3);
2.65(s,3H,6′-CH3);3.1(b,1H,
OH);3.65(b,1H,OH);3.7(s,3H,
O-CH3);4.1(m,1H,CH-OH);
4.35(m,1H,CH-OH);4.8(s,2H,
5′-CH2);5.15(dd,1H,6-H);
6.7(d,1H,7-H);7.0(m,2H,
3″-H);7.35(m,2H,2″-H)ppm.
实施例114
将223g(0.4mmol)实施例113化合物和0.5ml 1N盐酸在5ml乙醇溶液中于室温搅拌2天。然后进行浓缩和柱色谱(18g硅胶,230-400目,柱径2cm,氯仿/甲醇10∶1)纯化,得到100mg(57%理论得率)无色泡沫体。1H-NMR(CDCl3):δ=1.2-1.45(m,8H,CH(CH3)2+
CH(OH)-CH2-CH(OH));2.4(m,2H,
CH2-COOCH3);2.7(s,3H,6′-Ch3);
3.1(b,1H,OH);3.6(m,2H,
CH(CH3)2+OH);3.7(s,3H,
O-CH3);4.1(m,1H,CHOH);4.35
(m,1H,CH-OH);4.88(s,2H,5′-
CH2);5.18(dd,1H,6′-H);6.7
(d,1H,7-H);7.03(m,2H,3″-
H);7.38(m,2H,2″-H)ppm.
实施例115
赤-(E)-7-〔5-苄氧甲基-2-(4-氟苯基)-4-异丙基-6-甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按相似于实施例12,6,7,8,9和10的反应,由实施例112化合物制得上式化合物。1H-NMR(CDCl3):=1.2-1.45(m,8H,CH(CH3)2+
CH(OH)-CH2-CH(OH);2.4(m,2H,
CH2-COOCH3);2.6(s,3H,6′-
CH3);3.05(b,1H,OH);3.5(m,
2H,CH(CH3)2+OH);3.72(s,
3H,O-CH3);4.1(m,1H,CH-OH);
4.35(m,1H,CHOH);4.62(s,2H,
O-CH2);4.66(s,2H,OCH2);5.15
(dd,7H,6-H);6.2(d,1H,7-H);
7.12(m,2H,3″-H);7.3-7.45
(m,7H,芳香-H)ppm.
实施例116
按相似于实施例59,6,7,8,9和10的反应,由实施例112化合物制得无色泡沫体的上式化合物。1H-NMR(CDCl3):=1.2-1.45(m,8H,CH(CH3)2+
CH(OH)-CH2-CH(OH);2.4(m,2H,
CH2-COOCH3);2.63(s,3H,66′-
CH3);3.15(b,1H,OH);3.5(m,
4H,O-CH3+CH(CH3)2);3.62
(b,1H,OH);3.71(s,3H,COOCH3);
4.1(m,1H,CH-OH);4.35(m,1H,
CH-OH);4.55(s,2H,O-CH2);5.15
(dd,1H,6-H);6.65(d,1H,7-H);
7.0(m,2H,3″-H);7.35(m,2H,
2″-H)ppm.
实施例117
将863gm(4mmol)80%浓间氯过苯甲酸加到溶于10ml二氯甲烷中的实施例64化合物中,室温搅拌过夜。然后真空浓缩,剩余物经柱色谱(硅胶,70-230目,二氯甲烷/甲醇96∶4)纯化。
得率:107mg(50%理论得率)1H-NMR(CDCl3):=1.20-1.60(m,2H);1.45(d,6H);
2.40(m,2H);2.58(s,3H);3.62
(m,1H);3.72(s,3H);4.08(m,
1H);4.12(s,2H);4.30(m,1H);
4.38(s,2H);5.23(dd,1H);6.28
(d,1H);7.00-7.40(m,9H)ppm.
实施例118
3-氨基-4′-氟代肉桂腈
在室温和搅拌下,将41g(1mol)乙腈,135g(1.1mol)4-氟苄腈和7.4g(0.1mol)叔丁醇的300ml四氢呋喃溶液滴加到30g氢化钠的300ml纯而无水的四氢呋喃悬浮液中,约30℃加热混合物直至反应开始。然后在外部冷却下维持35-40℃,继续滴加,接着将混合物加热回流30分钟,再小心滴加入500ml水。水相用乙酸乙酯萃取二次,合并有机相,硫酸钠干燥。汽提除去溶剂,所得晶体于***中搅拌和抽吸过滤(65.1g)。用旋转蒸发器将滤液浓缩至干,使用甲苯于300g硅胶柱上进行过滤和用***结晶(46.3g)。
得率:111.4g(69%理论得率),无色晶体
熔点:108℃
实施例119
E/Z-4-乙氧羰基-2,6-二甲基--4庚烯-3-酮
将158g(1mol)异丁酰乙酸乙酯,108g(1.5mol)异丁醛,8.75ml哌啶和6.25ml乙酸于400ml异丙醇中50℃搅拌20小时。于水泵真空条件下汽提除去挥发性组分,剩余物高真空蒸馏。
得率:145g(68%理论得率),无色油,
熔点(0.2毫巴)60℃。
实施例120
在200℃浴温下,加热26.7g(165mmol)实施例118化合物和35g(165mmol)实施例119的E/Z-4-乙氧羰基-2,6-二甲基-4-庚烯-3-酮4小时,然后再加入17g后一种组分并加热混合过夜。剩余物经450g碳胶(230-400目),31甲苯/石油醚(1∶),31甲苯和21甲苯/乙酸乙酯(10∶1)洗脱纯化,经浓缩滤液和***重结晶得5.7g(9.7%)淡黄色晶体(熔点:140℃)。滤液再经750g硅胶柱色谱,石油醚/乙酸乙酯910∶1)洗脱,得到二个色区:
1. 7.4g副产物,无色晶体(***/石油醚),熔点141℃。
2. 3,5-双氰基-2,6-双-4-氟苯基-1,4-二氢-4-异丙基吡啶〔2.2g(3.7%)浅黄色晶体,熔点:227-228℃(***/石油醚)〕。
总得率:13.1g(22%理论得率)1H-NMR(CDCl3):=0.93(d,3H);1.02(d,3H);1.2
(m,6H);1.3(t,3H);1.8(m,1H);
3.6(d,1H);4.2(m,2H);6.15(b,
1H);7.2(t,2H);7.53(m,2H)
ppm.
实施例121
按实施例3的相似方法,由16.0g(45mmol)实施例120化合物制得上式化合物。
得率:14.5g(91%理论得率)
熔点:82℃
实施例122
在-78℃至-75℃和氮气氛下,将110ml(165mmol)二异丁基氢化铝的1.5M甲苯溶液滴加到14.5g(41mmol)实施例121化合物的320ml甲苯(无水)溶液中,并且于该温下搅拌2小时,然后在-20℃时搅拌1,小时。向混合物中滴加入350ml水和250ml乙酸乙酯,然后经硅藻土抽滤,乙酸乙酯洗涤,水相再用300ml乙酸乙酯萃取。合并有机相,氯化钠溶液洗涤,硫酸钠干燥和浓缩。剩余物经500g硅胶(230-400目)柱色谱,石油醚/乙酸乙酯(5∶1)洗脱以及乙酯/石油醚重结晶得浅黄色晶体5.4g(42%理论得率),熔点:147℃。
实施例123
按实施例8的相似方法,由200gm(6.6mmol)80%的纯氢化钠,0.86g(3.3mmol)2-(环己氨基)乙烯基磷酸二乙酯和0.94g(3mmol)实施例122化合物进行制备。
得率:0.46g(45%理论得率)
熔点:210℃
实施例124
(E)-7-〔2-(4-氟苯基)-5-羟甲基-4,6-二异丙基-吡啶-3-基〕-5-羟基-3-氧代-6-庚烯酸甲酯
在0℃至5℃和氢气下,将0.5ml(4.5mmol)乙酰乙酸甲酯滴加到0.15g(5mmol)80%的纯氢化钠的6.5ml四氢呋喃(纯而无水)悬浮液中,15分钟后,于0℃滴加3.65ml(6mmol)的15%浓丁基锂的己烷液10分钟,15分钟后,再加入1.01g(4.5mmol)干燥溴化锌的4.5ml四氢呋喃溶液,最后加入0.51g(1.5mmol)实施例123化合物。室温搅拌混合物过夜,慢慢加入饱和氯化铵溶液,水相用乙酸乙酯萃取,合并有机相,饱和氯化钠洗涤,硫酸钠干燥和进行浓缩。剩余物径20g硅胶(230-400目)柱(3cm)色谱,石油醚-乙酸乙酯(1∶1)洗脱得0.17g(25%理论得率)浅黄色油。
Rf=0.35(石油醚-乙酸乙酯(1∶1))。
实施例125
赤-(E)-7-〔2-(4-氟苯基)-5-羟甲基-4,6-二异丙基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例10相似的方法,由0.15g(0.33mmol)实施例124化合物进行制备。
得率:85mg(56%理论得率)1H-NMR(CDCl3):δ=1.25-1.6(m,14H,CH(OH)-CH2-CH(OH)
+CH(CH3)2);2.45(m,2H,
CH2-COOCH3);3.1(b,1H,OH);
3.45-3.7(m,3H,CH(CH3)2+
OH);3.7(s,3H,OCH3);4.1(m,
1H,CH(OH);4.35(m,1H,CH(OH);
4.85(s,2H,CH2-OH);5.7(dd,
1H,6-H);6.25(d,1H,7-H);7.05
(t,2H,3″-H);7.45(m,2H,2″-
H)ppm.
实施例126
按实施例122相似的方法,将3.5g(10mmol)实施例121化合物和35ml的1M二异丁基氢化铝的甲苯溶液在-75℃下保持1.5小时,然后混合物升温至-30℃并加入水来进行制备。
得率:0.8g(22%理论得率)无色晶体
熔点:88℃(石油醚)
实施例127
由1.25g(3.5mmol)实施例126化合物按实施例8相似的方法进行制备。
得率:0.17g(72%理论得率)无色油
Rf=0.35(石油醚-乙酸乙酯(5∶1))。
实施例128
由0.95g(2.48mmol)实施例127化合物按实施例123的相似方法进行制备。
得率:0.83g(67%理论得率)无色油
Rf=0.27(石油醚-乙酸乙酯(2∶1))。
实施例129
赤-(E)-7-〔5-乙氧羰基-2-(4-氟苯基)-4,6-二异丙基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
由0.89g(1.66mmol)实施例128化合物按实施例10的相似方法进行制备
得率:0.65g(78%理论得率)无色油1H-NMR(CDCl3):δ=1.25-1.5(m,17H,CH(CH3)2+
CH2-CH3+CH(OH)-CH2);2.42
(m,2H,CH2-COOCH3);2.95(m,
1H,CH(CH3)2);3.15(b,1H,
OH);3.2(m 1H,CH(CH3)2);3.6
(b,1H,OH);3.7(s,3H,O-CH3);
4.1(m,1H,CH-OH);4.4(m,3H,
CH-OH+O-CH2-CH3);5.2(dd,
1H,6-H);6.75(d,1H,7-H);7.05
(t,2H,3″-H);7.45(m,2H,2″-
实施例130 H)ppm.
将67mg(0.15mmol)实施例116化合物和54mg(0.17mmol)55%浓间氯苯甲酸在6ml二氯甲烷中室温搅拌2小时,汽提除去溶剂,将剩余物溶于20ml乙酸乙酯,4知用20ml饱和的碳酸氢钠溶液洗涤。水相用20ml乙酸乙酯洗涤,合并有机相,并用硫酸镁干燥,经10g硅胶(230-400目)柱(2cm)色谱用乙酸乙酯以及乙酸乙酯/甲醇(10∶1)洗脱。
得率:57mg(82%理论得率)非晶形固体1H-NMR(CDCl3):=1.1-1.3(m,2H,CH(OH)-CH2-CH(OH))
;1.35(d,6H,CH(CH3)2);
2.38(m,2H,CH2-COOCH3);2.6
(s,3H,6′-CH3);3.4(b,1H,OH);
3.5(m,4H,CH(CH3)2+CH2-O-CH3
);3.28(b,1H,OH);3.72(s,
3H,COOCH3);4.05(m,1H,HO-C-H);
4.28(m,1H,HO-C-H);4.55(s,2H,
O-CH2);5.12(dd,1H,6-H);6.38
(d,1H,7-H);7.05-7.25(m,4H,
芳香-H)ppm.
实施例131
2-(4-氟苯基)-3-甲酰-4,6-二异丙基-5-甲氧甲基吡啶
按实施例59的相似方法,由3.15g(10mmol)实施例122化合物制得3.15g(96%理论得率)无色晶体的上式化合物,熔点为77℃(甲醇)。
实施例132
赤-(E)-7-〔2-(4-氟苯基)-4,6-二异丙基-5-甲氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例8,9和10相似方法,由实施例131化合物获得熔点为92℃(***/石油醚)的无色晶体。1H-NMR(CDCl3):δ=1.3(m,14H,CH(CH3)2+4-H);
2.4(m,2H,2-H);3.05(b,1H,OH)
3.3-3.57(m,5H,O-CH3+
CH(CH3)2);3.62(b,1H,OH);
3.72(s,3H,COOCH3);4.1(m,1H
CH-OH)4.35(m,1H,CH-OH);4.55
(s,2H,O-CH2);5.15(dd,1H,
6-H);6.75(d,1H,7-H);7.0(t,
2H,3″H);7.45(m,2H,2″-H).
实施例133
将17.4g(0.2mol)3-氨基丁酰腈和56g(0.2mol)实施例109化合物在800ml乙醇中加热回流过夜。汽提除去溶剂,剩余物经硅胶柱色谱用石油醚/乙酸乙酯(20∶1)洗脱。
得率:14.9g(21%理论得率)1H-NMR(CDCl3):=1.0(m,9H);1.9(m,1H);2.2(m,
3H);3.6(d,1H);3.9(m,2H);
5.75(b,1H);7.1(t,2H);7.25
(m,2H).
实施例134
5-氰基-3-乙氧羰基-2-(4-氟苯基)-4-异丙基-6-甲基吡啶
9.8g(30mol)实施例1 33化合物按实施例3进行操作得上式化合物。
得率:9.4g(96%理论得率)熔点:76℃。
实施例135
在-75℃和氩气下,将50ml(60mmol)1.2M二异丁基氢化铝的甲苯溶液于1.5小时内加入到9.8g(30mmol)实施例134化合物的150ml甲苯(纯而无水)溶液中,继续搅拌30分钟。然后-30℃下小心地滴加入280ml水,硅藻土抽滤混合物,用乙酸乙酯洗涤,水相用乙酸乙酯萃取,合并有机相,用饱和的氯化钠溶液洗涤,硫酸钠干燥和浓缩。剩余物经柱色谱(400g硅胶,230-400目,6cm,石油醚/乙酸乙酯10∶1)纯化得3个色段:
2. 2.1g(25%理论得率)标题化合物(实施例135)熔点:157℃(***/石油醚)
实施例136
-75℃下,将2.2g(10.5mmol)三氟乙酸酐的10ml二氯甲烷液滴加到1.1g(14mmol)DMSO的8ml二氯甲烷液中,-70℃搅拌该混合物10分钟,然后滴加入2.0g(7mmol)实施例135化合物的50ml二氯甲烷溶液,再将混合物于-70℃搅拌1小时。在这悬浮液中滴加入2.1ml(21mmol)三乙胺,混合物于-65℃搅拌10分钟。将混合物升温至室温,用饱和氯化钠溶液洗涤,硫酸钠干燥和浓缩。
粗得率:2.0g(100%理论得率),熔点:109℃。1H-NMR(CDCl3):=1.52(d,6H,CH(CH3)2);2.9
(s,3H,6-CH3);4.0(七.1H,
CH(CH3)2);7.2(m,2H,3′-H);
7.5(m,2H,2′H);9.95(s,1H,
CHO).
实施例137
按实施例8的相似方法由1.9g实施例136化合物进行制备。
得率:0.6g(28%理论得率),熔点:112℃(***-石油醚)。
实施例138
按实施例9相似方法,由0.52g(1.7mmol)实施例137化合物进行制备。
得率:0.32g(44%理论得率)浅黄色油。
实施例139
按实施例10相似的方法,由0.32g实施例138化合物进行制备。
得率:0.15g(47%理论得率)浅黄色油。1H-NMR(CDCl3):=1.35(m,2H,CH(OH)CH2-CH(OH);
1.45(d,6H,CH(CH3)2);2.42(m,
2H,CH2-COOCH3);2.7(s,3H,6-CH3);
3.55(m,2H,CH(CH3)2+OH);3.68
(b,1H,OH);3.72(s,3H,O-CH3);
4.13(m,1H,CH(OH)),4.4(m,1H,
CH(OH));5.32,(dd,1H,olefin-
H);6.6(d,1H,olefin-H);7.08
(m,2H,3″-H);7.45(m,2H,2″-H).
实施例140
将21.7g(0.72mol)氢化钠(80%浓度,20%矿物油)加入到11***(纯而无水)中,接着加入85.5g(127ml,0.72mol)碳酸二乙酯(UK22-010)。在沸点温度下干4小时内向该溶液中滴加入100g(0.72mol)4-氟乙酰苯的300ml***溶液(需剧烈地机械搅拌,形成粘性浆料)然后再加热回流混合物1小时,接着冷却至约5℃,在此温度和氮气下,滴加入50ml乙酸的100ml Et2O溶液,接着滴加入约500ml水,分离有机相,所得水相再用Et2O(2×400ml)萃取。把醚相合并,NaHCO3洗涤,MgSO4干燥和浓缩。剩余物用维格罗分馏柱进行分馏。
得率:93%(60%),沸点(0.4MM):99-102℃。
实施例141
将52.8g(0.2mol)实施例1化合物和16.4g(0.2mol)3-氨基丁酰腈在200ml乙二醇中加热回流2小时,然后冷却,除去沉积出的油后,用***萃取三次。醚相用水洗涤,干燥和浓缩,剩余物和前面分离得到的油用***结晶。
得率:31.4g(48%),熔点:168℃。
实施例142
5-氰基-3-乙氧羰基-4-(4-氟苯基)-2-异丙基-6-甲基吡啶
按实施例3的相似方式,使14.8g(45mmol)实施例141化合物进行反应。
得率:13.7g(93%理论得率)无色晶体
熔点:95℃。
实施例143
5-氰基-4-(4-氟苯基)-5-羟基亚氨基甲基-3-羟甲基-2-异丙基-6-甲基吡啶化合物2
在-78℃和氩气下,将83.3ml(0.1mol)1.2M二异丁基氢化铝甲苯溶液于3小时内滴加到16.3g(50mmol)实施例142化合物的240ml甲苯(纯,无水)中,温度始终维持低于-75℃。-75℃继继搅拌混合物30分钟后升温至-30℃,接着小心加入300ml水和160ml乙酸乙酯。用硅藻土抽滤混合物和乙酸乙酯洗涤。乙酸乙酯萃取水相三次,然后合并有机相,用饱和氯化钠溶液洗涤,硫酸钠干燥和浓缩。经二次硅胶柱色谱,使用甲苯/乙酸乙酯(5∶1)或石油醚/乙酸乙酯(5∶1)洗脱得3.4g Rf为0.2(石油醚/乙酸乙酯5∶1)的5-氰基-4-(4-氟苯基)-3-羟甲基-2-异丙基-6-甲基吡啶和4-(4-氟苯基)-5-甲酰-3-羟基-2-异丙基-6-甲基吡啶的混合物。
3.16g上述混合物溶干10ml甲醇,并加入到1.22g(17.6mol)盐酸羟胺和1.22g(14.9mmol)醋酸钠的10ml水溶液中,于室温搅拌3小时。经旋转蒸发器除去甲醇,再加入少量水,用乙酸乙酯萃取混合物三次。所得有机相用饱和氯化钠溶液洗涤,硫酸钠干燥和浓缩。剩余物经柱色谱(100g硅胶,230-400目,4cm,石油醚/乙酸乙酯5∶1)纯化得二种馏份:
化合物1∶5-氰基-4-(4-氟苯基)-3-羟甲基-2-异丙基-6-甲基吡啶,
0.65g(4.9%)无色晶体,熔点:132℃。1H-NMR(CDCl3):=1.32(d,6H,,CH(CH3)2);1.6
(b,1H,OH);2.7(s,3H,6-CH3);
3.5(七,1H,CH(CH3)2);4.5
(d,2H,CH2-OH);7.15-7.35(m,
4H,aromatic-H).
化合物2:5-氰基-4-(4-氟苯基)-5-羟基亚氨基甲基-3-羟甲基-2-
异丙基-6-甲基吡啶,
2.15g(15.3%)非晶形固体,1H-NMR(CFCl3):=1.33(d,6H,CH(CH3)2);
1.4(b,1H,-OH);
2.7(s,3H,6-CH3);
3.48(m,1H,CH(CH3)2);
4.4(d,2H,CH2-OH);
7.15(m,4H,芳香H);
7.77(s,1H,CH=N-);
8.08(s,1H,=N-OH).
实施例144
5-氰基-4-(4-氟苯基)-3-甲酰-2-异丙基-6-甲基吡啶
A)使0.63g(2.2mmol)实施例144化合物进行实施例136相似的所应。
得率:0.6g(97%)
B)-78℃下,将4.4g(21mmol)三氟乙酸酐的15ml二氯甲烷液滴加到1.1g(14mmol)DMSO的18ml二氯甲烷(纯,无水)液中,-70℃搅拌混合物10分钟。把2.1g(7mmol)实施例143化合物2加到50ml二氯甲烷中,-70℃搅拌混合物1小时,此时加入5.8ml(42mmol)三乙胺,于室温下再搅拌混合物4小时。然后经饱和氯化钠溶液洗涤,浓缩,100g硅胶柱色谱(230-400目,4cm,石油醚/乙酸乙酯10∶1)纯化和乙酸乙酯/石油醚重结晶。
得率:0.31g(16%),熔点:82℃1H-NMR(CDCl3):=1.32(d,6H,CH(CH3)2);2.78(s,
3H,6-CH3);3.77(m,1H,
CH(CH3)2);7.23(m,2H,3′-H);
7.36(m,2H,2′-H);9.86(s,1H,
CHO).
实施例145
按实施例8,9和10相似的反应,使实施例144化合物进行反应,得到无色固体,熔点:124℃。1H-NMR(CDCl3):δ=1.3(m,8H,CH(CH3)2+
CH(OH)-CH2-CH(OH));2.4(m,2H,
CH2-COOCH3);2.75(s,3H,6-CH3);
3.35(m,2H,CH(CH3)+OH);3.6
(b,1H,OH);3.7(s,3HO-CH3);
4.1(m,1H,CH-OH);4.35(m,1H,
CH-OH);5.3(dd,1H,6-H);6.4
(d,1H,7-H);7.05-7.3(m,4H,
Ar-H).
实施例146
5-(叔丁基二甲基甲硅烷氧甲基)-6-环丙基-4-(4-氟苯基)-2-异丙基-吡啶-3-甲酸乙酯
使15g(42mmol)实施例82化合物进行实施例5相似的反应。
得率:16.9g(85%理论得率)。
实施例147
3-(叔丁基二甲基甲硅烷氧甲基)-2-环丙基-4-(4-氟苯基)-5-羟甲基-6-异丙基吡啶
使16.9g(35.8mmol)实施例146化合物进行实施例6的相似反应。
得率:12.3g(80%理论得率)。
实施例148
3-(叔丁基二甲基甲硅烷氧甲基)-2-环丙基-4-(4-氟苯基)-6-异丙基-5-甲氧甲基吡啶
使5.5g(12.8mmol)实施例147化合物进行实施例59的相似反应。
得率:5.7g粗产物。
实施例149
将5.7g(12.8mmol)实施例148的粗产物溶于无水四氢呋喃中,加入12.8ml四丁基氟化铵溶液(1M,于THF中),并于室温搅拌混合物过夜。然后加入50ml饱和的碳酸氢钠溶液,用二氯甲烷萃取数次。合并有机相,硫酸钠干燥,浓缩和硅胶柱色谱(洗脱液:石油醚/乙酸乙酯7∶3)纯化。
得率:3.9g(94%理论得率)1H-NMR(CDCl3):=0.0(s,6H);0.87(s,9H);0.8-
1.0(m,2H);1.22(d,6H);1.10-
1.30(m,2H);2.31(m,1H);3.12
(s,3H);3.30(m,1H);3.98(s,
2H);4.47(m,2H);7.0-7.3(m,
4H)ppm.
实施例150
按实施例7,8,9和10的相似反应,由实施例149化合物制得实施例150化合物。1H-NMR(CDCl3):=0.89(m,2H);1.18(m,2H);1.26
(d,6H);1.40(m,2H);2.24(m,
1H);2.44(m,2H);3.17(s,3H);
3.30(m,1H);3.72(s,3H);4.03
(s,2H);4.12(m,1H);4.32(m,
1H);5.51(d,d,1H);6.32(d,1H);
7.10(m,4H)ppm.
实施例151
与1.1g对甲苯磺酸加到49.9g(0.32mol)环丙基碳酰乙酸乙酯的200ml干燥甲苯液中,干室温和搅拌下,通入氨气饱和该混合物。然后静置过夜,于水分离器中加热回流混合物8小时,加热时不断地通入氨气。将混合物冷却过夜后,过滤,真空浓缩甲苯溶液,以及高真空加热至65℃,蒸馏移去未反应的起始原料,得到剩余物。
得率:11.9g(24%理论得率)
实施例152
将6.2g(40mmol)实施例151化合物和10.5g(40mmol)实施例79化合物溶于100ml乙二醇中,并加热回流过夜。然后冷却至室温,用***萃取混合物数次。有机相依次用10%浓盐酸和饱和碳酸氢钠溶液各洗涤一次,硫酸镁干燥和真空浓缩。
得率:10.4g(65.1%理论得率)1H-NMR(CDCl3):δ=0.60(m,4H);0.95(m,4H);1.23
(t,6H);2.72(m,2H);4.12(m,
4H);5.02(s,1H);5.40(s,1H);
6.88(m,2H);7.20(m,2H)ppm.
实施例153
按实施例3,4,59,60,7,8,9和10的相似反应,由实施例152化合物制备上式化合物。1H-NMR(CDCl3):=0.89(m,4H);1.08(m,4H);1.40
(m,2H);2.21(m,2H);2.43(m,
2H);3.21(s,3H);3.72(s,3H);
4.11(m,1H);4.15(s,2H);4.30
(m,1H);5.47(dd,1H);6.30(d,
1H);7.10(m,4H)ppm.
实施例154
2,6-二异丙基-5-乙氧甲基-4-(4-氟苯基)-吡啶-3-甲酸乙基
室温下,将4.4ml(76mmol)无水乙醇滴加到2.29g(76mmol)氢化钠(80%浓度)的30ml无水四氢呋喃悬浮液中,并搅拌30分钟。然后滴加入2.7g(7.6mmol)实施例86化合物的20ml无水四氢呋喃溶液,并且加热回流过夜。分批将反应液注入冰水中,将pH调节到8后,用***萃取数次。所得有机相用氯化钠溶液洗涤,硫酸钠干燥,浓缩和硅胶柱色谱(用乙酸乙酯/石油醚5∶95进行洗脱)纯化。
得率:1.07g(36.4%理论得率)1H-NMR(CDCl3):=0.95(t,3H);1.13(t,3H);1.31
(m,6H);3.05(m,1H);3.32(q,
2H);3.41(m,1H);3.97(q,2H);
4.18(d,2H);7.08(m,2H);7.27
m,2H)ppm.
实施例155
按实施例60,7,8,9和10的相似方法,由实施例154化合物获得实施例155化合物。1H-NMR(CDCl3):6=1.13(t.3H);1.20-1.50(m,8H);
2.43(m,2H);3.30(m,3H);3.72
(s,3H);4.08(m,1H);4.12(s,
2H);4.29(m,1H);5.25(dd,1H);
6.30(d,1H);7.0-7.2(m,4H)ppm.
按实施例155的相似方法,由实施例86获得下列化合物:
实施例156
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-丙氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯。
实施例157
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-异丙氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯。
实施例158
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-丁氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯。
实施例159
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-戊氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯。
实施例160
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-己氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯。
实施例161
在10ml四氢呋喃中溶入487mg(1mmol)实施例155化合物并加入10ml的0.1N氢氧化钠溶液。1小时后,真空汽提移去四氢呋喃,冻干含水剩余物。
得率:490mg(99%理论得率)
反-(E)-6-〔2-(3-苄氧甲基-2,6-二异丙基-4-(4-氟苯基)-吡啶-5-基)-乙烯基〕-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮
将5.5g(10mmol)实施例17的产物溶于100ml四氢呋喃,加入100ml的0.1N氢氧化钠溶液,然后于室温搅拌1小时。接着加入100ml水稀释该溶液,用1N HCl调节pH至4.4,接着用二氯甲烷萃取。将二氯甲烷相干燥和真空浓缩。所得剩余物溶于100ml无水甲苯,并加入40g 4埃的分子筛和加热回流过夜。然后用分子滤器进行分离,真空浓缩,对剩余物进行石油醚结晶。
得率:4.3(83.2%理论得率)1H-NMR(CDCl3):
1.22(d,6H);1.32(d,6H);1.40-1.80(m,2H);
2.45-2.70(m,2H);3.30(m,2H);4.12(m,1H);
4.14(s,2H);4.45(s,2H);5.04(m,1H);5.28
(dd,1H);6.39(d,1H);6.95-7,40(m,9H)ppm.
实施例163
反-(E)-6-〔2-(2,6-二异丙基-4-(4-氟苯基)-5-苯氧甲基-吡啶-3-基)-乙烯基〕-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮
按实施例162相似的方法,由540mg(1mmol)实施例89的产物制得450mg(89.4%理论得率)上式产物。1H-NMR(CDCl3):
=1.25(d,6H);1.30(d,6H);1.40-1.70(m,2H);
2.60(m,2H);3.30(m,2H);4.18(m,1H);4.65
(s,2H);5.08(m,1H);5.30(dd,1H);6.42
(d,1H);6.70-7.30(m,9H)ppm.
赤-(E)-〔3-叠氮甲基-2,6-二异丙基-4-(4-氟苯基)-吡啶-5-基)-3,5-二羟基-6-庚烯酸甲酯
将459mg(1mmol)实施例11的产物和320mg(1.1mmol)三苯基膦溶于10ml无水四氢呋喃,加入3.2ml 0.48M HN3甲苯溶液,然后冰浴冷却,并加入173ml(1.1mmol)偶氮二甲酸二乙酯。于室温搅拌溶液过夜后,进行真空浓缩。剩余物经硅胶色谱(流动相:乙酸乙酯-石油醚1∶1)。
得率:260mg(53.7%理论得率)1H-NMR(CDCl3):
=1.30(d,6H);1.39(d,6H);1.25-1.60(m,2H);
2.50(m,2H);3.37(m,2H);3.80(s,3H);4.15
(s,1H);4.18(s,2H);4.36(m,1H);5.36
(dd,1H);6.36(d,1H);7.15(m,4H)ppm.
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-琥珀酰亚胺氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例164相似的方法,由实施例11的产物和N-羟基琥珀酰亚胺进行制备。1H-NMR(CDCl3):?=
1.28(d,6H);1.37(d,6H);1.2-1.5(m,2H);
2.43(m,2H);2.66(s,4H);3.32(七,1H);
3.72(s,3H);3.78(七,1H);4.08(m,1H);
4.31(m,1H);4.86(s,2H);5.28(dd,1H);6.33
(d,1H);7.0-7.4(m,4H)ppm.
赤-(E)-7-〔2,6-二异丙基-4-(4-氟苯基)-5-琥珀酰亚胺基甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例164的相似方法,使用实施例11的产物和琥珀酰亚胺进行制备。1H-NMR(CDCl3):?=
1.23(m,12H);1.25-1.50(m,2H);2.43(m,2H);
2.51(s,4H);3.16(m,1H);3.28(m,1H);3.73
(s,3H);4.07(m,1H);4.26(m,1H);4.52
(s,2H);5.25(dd,1H);6.20(d,1H);7.0-7.2
(m,4H)ppm.
实施例167
赤-(E)-7-〔2,6-二异丙基-3-(4-氟苄氧甲基)-4-(4-氟苯基)-吡啶-5-基)-3,5-二羟基-6-庚烯酸甲酯
按实施例12-17的相似方法,由实施例4的产物和4-氟苄基溴制得上式化合物。1H-NMR(CDCl3):=
1.25(m,6H);1.32(d,6H);1.21-1.5(m,2H);
2.42(m,2H);3.30(m,2H);3.72(s,3H);4.07
(m,1H);4.13(s,2H);4.28(m,1H);4.30
(s,2H);5.22(dd,1H);6.30(d,1H);6.90-7.30
(m,8H)ppm.
反-(E)-6-〔2-(2,6-二异丙基-3-(4-氟苄氧甲基)-4-(4-氟苯基)-吡啶-5-基)乙烯基-3,4,5,6-四氢-4-羟基-2H-吡喃-2-酮
按实施例164的相似方法,用实施例167的产物进行制备1H-NMR(CDCl3):=
1.23(d,6H);1.32(d,6H);1.40-1.80(m,2H);
2.40(m,2H);3.30(m,2H);4.13(s,2H);4.16
(m,1H);4.30(s,2H);5.05(m,1H);5.28
(dd,1H);6.37(d,1H);6.9-7.3(m,8H)ppm.
(E/Z)-2-乙氧羰基-4-甲基-1-(噻吩-2-基)戊烯-3-酮
按实施例1的相似方法,从异丁酰乙酸乙酯和噻吩-2-甲醛制备上面化合物
得率:86%,黄色油,沸点145℃(1.5毫巴)。
(E/Z)-2-乙氧羰基-1-(呋喃-2-基)-4-甲基-戊烯-3-酮
按实施例1的相似方法,从呋喃-2-甲醛和异丁酰乙酸乙酯制备上式化合物。
得率:93%,黄色油,沸点130℃(0.5毫巴)。
2,6-二异丙基-4-(噻吩-2-基)-1,4-二氢吡啶-3,5-二甲酸二乙酯
将10g(0.28mol)实施例169产物和44g(0.28mol)3-氨基-4-甲基-2-戊烯酸乙酯在160℃加热24小时,然后用乙酸乙酯溶解,用6N盐酸洗涤三次,水和饱和碳酸氢钠溶液各洗涤二次,有机相用硫酸钠干燥,真空浓缩,剩余物经400g硅胶色谱,用石油醚-二氯甲烷(2∶1)洗脱。
得率:50g(46%)无色晶体,熔点为72℃。
实施例172
赤-(E)-7-〔2,6-二异丙基-5-甲氧甲基-4-(噻吩-2-基)-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例3,4,59,6,7,8,9和10的相似方法,由实施例171化合物制备上式化合物。
无色晶体,熔点为94℃。
4-(呋喃-2-基)-3,5-双(羟乙基)-2,6-二异丙基-吡啶
按实施例171,3和122的相似方法,由实施例170化合物和3-氨基-4-甲基-2-戊烯酸乙酯制备上式化合物。
无色晶体,熔点为212℃。
实施例174
3-甲酰-4-(呋喃-2-基)-5-羟甲基-2,6-二异丙基吡啶
按实施例7的相似方法,从32g(0.11mol)实施例173的化合物和28.6g(0.13mol)氯代铬酸吡啶鎓制得上式化合物。
得率:14.6g(46%)无色晶体,熔点:113℃。
实施例175
赤-(E)-7-〔4-(呋喃-2-基)-5-羟甲基-2,6-二异丙基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例123,124和125的相似方法,从实施例174化合物制得上式化合物。
无色晶体,熔点:86℃。
赤-(E)-7-〔2,4,6-三异丙基-5-甲氧甲基-吡啶-3-基〕-3,5-二羟基-6-庚烯酸甲酯
按实施例171,3,4,59,6,7,8,9和10的相似方法,使用实施例119化合物和3-氨基-4-甲基-2-戊烯酸乙酯合成上式化合物。无色油。1H-NMR(CDCl3):?=1.1-1.35(m,18H,异丙基-H)
1.65-1.85(m,2H,4-H)
2.55(d,2H,2-H),3.2-3.45(m,7H,
异丙基-H,OH,CH3-O-CH2)
3,7(m,4H,OH,COOCH3)
4.35(m,1H,HO-CH) 4.45(s,2H,CH3-O-CH2
)4.62(m,1H,HO-CH)5.55
(da,1H,6-H)6.73(d,1H,7-H)
应用实施例
实施例177
按G.C Ness等人在Archives of Brochemistry and Biophysics,197,493-499(1979)上的改进方法测定酶的活性。用Altromin粉状饲料喂雄性Rico鼠(体重300-400g)11天,其中每公斤饲料中加入40gcolestyramine。将鼠杀死后,取出肝并置于冰上,将其揭碎并在盛有于三倍体积的0.1M蔗糖,0.05M KCl,0.04MKxHy磷酸盐,0.03M乙二胺四乙酸,0.002M二硫苏糖醇(SPE)缓冲剂(pH7.2)的特波-Elvejem匀浆器中匀化3次。接着在15000*g的条件下,离心混合物15分钟,除去沉淀物。在100,000g下沉淀上层清液75分钟。将小糖丸溶于1/4体积的SPE缓冲剂中,再一次均化和在100,000g条件下离心60分钟。用为小糖丸5倍体积量的SPE缓冲剂溶解小糖丸,并进行均化,冷冻和-78℃贮藏(酶溶液)。
对试验来说,将试验化合物(或作为参比物质的mevinolin)溶于加有5%(体积)的1N N3OH的二甲基甲酰胺中,然后将10μl各种浓度的上述溶液用于酶试验。化合物经酶在37℃预培养20分钟后,开始试验。每批试验物为0.380ml,其含有4μmol 6-磷酸葡萄糖,1.1mg牛血清白蛋白,2.1μmol二硫苏糖醇,0.35μmol NADP,1单位6-磷酸葡萄糖脱氢酶的35μml KxHy磷酸盐(pH为7.2),20μl酶制剂和56nmol 3X羟基-3-甲基-戊二酰基辅酶A(戊二酰基-3-14C)100,000dpm。
于37℃培养60分钟后,进行离心操作,所得600μl上层清液注入到装填有5-氯化物100-200目(阴离子交换)的柱(0.7×4cm)上,用2ml蒸馏水冲洗,并且将3ml磺化蓖麻油加到流动的阳性洗涤水中,然后经LKB闪烁计数器计数。通过绘出对试验化合物浓度的抑制百分数曲线,用内插法(intragrolation)确定出IC50值。为测定相对抑制能力,将对照物mevinolin的IC50值定值为100,并与同时测得的试验化合物的IC50值进行比较。
实施例178
通过持续几周的喂食实验,测试本发明化合物对狗体内血胆固醇值的亚慢性活性。在持续的几周时间里,将需研究的物质以胶囊的形式,与饲料一起每天一次喂给键康的警狗。在整个喂料实验期间,即在试验物质给药前,期间以后的时间里,在饲料中额外还掺有用作为没食子酸螯合剂的Colestyramine(4g/100g饲料)。每周抽二次狗的静脉血,并使用商业化的试验装置来测定血清胆固醇。把给药期间的血清胆固醇数值与给药前(对照)的血清胆固醇进行比较。
从而得到,经每天口服给药8mg/kg二周后,本发明化合物能降低血清中胆固醇量的66%。
可以理解到本发明的实施例是用于描述而非限制本发明,在此基础上可作出的各种改进和变化,它们仍属于本发明的基本精袖和范围。
Claims (4)
A代表氟代苯基或C1-C4烷基;
B与E相同或互异,并代表C1-C4烷基或C3-C6环烷基;
D代表氢、氰基、苯基、羟基、C1-C6烷氧基、取代的C1-C6烷基、其取代基可为卤素、羟基、叠氮基、吗啉代基、氧代吗啉代基、苄硫基、琥珀酰亚氨基;或代表R24-O-CH2-基其中R24代表C1-C6烷基、苯基、任选卤代的苄基、C1-C6烷基羰基、苯基羰基、三(C1-C4烷基)甲硅烷基、四氢吡喃基、琥珀酰亚氨基;或代表R5-CO-基,其中R5代表C1-C6烷氧基、吗啉代基;
X代表-CH=CH-,
对于酸类来说,可通过酯的水解制备,
对于酯的盐类来说,可通过酯的水解制得。
2.按权利要求1的方法,其特征在于所述的还原反应是在-80至+30℃温度范围进行的。
4.按权利要求3的方法,其特征在于该反应是在-80℃至+50℃温度范围进行的。
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DE3801406A DE3801406A1 (de) | 1988-01-20 | 1988-01-20 | Substituierte pyridine |
DEP3801406.8 | 1988-01-20 | ||
IT21317/A88 | 1988-07-11 | ||
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