CN1102644A - Condensed pyridine type mevalonolactone intermediate and process for its production - Google Patents
Condensed pyridine type mevalonolactone intermediate and process for its production Download PDFInfo
- Publication number
- CN1102644A CN1102644A CN 93114352 CN93114352A CN1102644A CN 1102644 A CN1102644 A CN 1102644A CN 93114352 CN93114352 CN 93114352 CN 93114352 A CN93114352 A CN 93114352A CN 1102644 A CN1102644 A CN 1102644A
- Authority
- CN
- China
- Prior art keywords
- phenyl
- methyl
- hydrogen
- group
- alkyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 title claims abstract description 47
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 title claims abstract description 23
- JYVXNLLUYHCIIH-ZCFIWIBFSA-N R-mevalonolactone, (-)- Chemical compound C[C@@]1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-ZCFIWIBFSA-N 0.000 title claims description 15
- JYVXNLLUYHCIIH-UHFFFAOYSA-N (+/-)-mevalonolactone Natural products CC1(O)CCOC(=O)C1 JYVXNLLUYHCIIH-UHFFFAOYSA-N 0.000 title claims description 11
- 229940057061 mevalonolactone Drugs 0.000 title claims description 11
- 238000000034 method Methods 0.000 title description 16
- 238000004519 manufacturing process Methods 0.000 title description 2
- -1 butoxy, isobutoxy, sec-butoxy Chemical group 0.000 claims description 359
- 229910052739 hydrogen Inorganic materials 0.000 claims description 103
- 239000001257 hydrogen Substances 0.000 claims description 103
- 239000000460 chlorine Substances 0.000 claims description 66
- 229910052801 chlorine Inorganic materials 0.000 claims description 66
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 63
- 239000002585 base Substances 0.000 claims description 54
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 54
- 229910052794 bromium Inorganic materials 0.000 claims description 54
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 45
- 229910052731 fluorine Inorganic materials 0.000 claims description 45
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 45
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical class OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 44
- 239000011737 fluorine Substances 0.000 claims description 42
- 150000002431 hydrogen Chemical class 0.000 claims description 40
- 150000001875 compounds Chemical class 0.000 claims description 39
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 34
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 33
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 33
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 30
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 29
- 238000002360 preparation method Methods 0.000 claims description 29
- 239000000543 intermediate Substances 0.000 claims description 28
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 26
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 26
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 26
- 125000006272 (C3-C7) cycloalkyl group Chemical group 0.000 claims description 24
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 claims description 23
- 229910052760 oxygen Inorganic materials 0.000 claims description 22
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 20
- 229910001882 dioxygen Inorganic materials 0.000 claims description 19
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 17
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 16
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 15
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 claims description 14
- 125000004469 siloxy group Chemical group [SiH3]O* 0.000 claims description 14
- 229920002554 vinyl polymer Polymers 0.000 claims description 14
- 239000003513 alkali Substances 0.000 claims description 13
- 239000000377 silicon dioxide Substances 0.000 claims description 13
- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims description 12
- 125000000339 4-pyridyl group Chemical group N1=C([H])C([H])=C([*])C([H])=C1[H] 0.000 claims description 12
- 150000002500 ions Chemical class 0.000 claims description 12
- AMFYRKOUWBAGHV-UHFFFAOYSA-N 1h-pyrazolo[4,3-b]pyridine Chemical compound C1=CN=C2C=NNC2=C1 AMFYRKOUWBAGHV-UHFFFAOYSA-N 0.000 claims description 11
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 11
- 238000009833 condensation Methods 0.000 claims description 11
- 230000005494 condensation Effects 0.000 claims description 11
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 11
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 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 claims 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 claims description 11
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000006034 1,2-dimethyl-1-propenyl group Chemical group 0.000 claims description 10
- 125000004806 1-methylethylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 10
- 125000006017 1-propenyl group Chemical group 0.000 claims description 10
- 125000004189 3,4-dichlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(Cl)C([H])=C1* 0.000 claims description 10
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229940073608 benzyl chloride Drugs 0.000 claims description 10
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 10
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 claims description 10
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 9
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000003682 3-furyl group Chemical group O1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 9
- 125000001541 3-thienyl group Chemical group S1C([H])=C([*])C([H])=C1[H] 0.000 claims description 9
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 9
- 125000004206 2,2,2-trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 claims description 8
- 125000004198 2-fluorophenyl group Chemical group [H]C1=C([H])C(F)=C(*)C([H])=C1[H] 0.000 claims description 8
- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 8
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 8
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000006432 1-methyl cyclopropyl group Chemical group [H]C([H])([H])C1(*)C([H])([H])C1([H])[H] 0.000 claims description 7
- 125000004182 2-chlorophenyl group Chemical group [H]C1=C([H])C(Cl)=C(*)C([H])=C1[H] 0.000 claims description 7
- 125000004179 3-chlorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(Cl)=C1[H] 0.000 claims description 7
- 125000004207 3-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(OC([H])([H])[H])=C1[H] 0.000 claims description 7
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 claims description 7
- JIQNWFBLYKVZFY-UHFFFAOYSA-N methoxycyclohexatriene Chemical group COC1=C[C]=CC=C1 JIQNWFBLYKVZFY-UHFFFAOYSA-N 0.000 claims description 7
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims description 7
- 125000004455 (C1-C3) alkylthio group Chemical group 0.000 claims description 6
- ZPQOPVIELGIULI-UHFFFAOYSA-N 1,3-dichlorobenzene Chemical compound ClC1=CC=CC(Cl)=C1 ZPQOPVIELGIULI-UHFFFAOYSA-N 0.000 claims description 6
- 125000006276 2-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C(*)C([H])=C1[H] 0.000 claims description 6
- 125000006275 3-bromophenyl group Chemical group [H]C1=C([H])C(Br)=C([H])C(*)=C1[H] 0.000 claims description 6
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 claims description 6
- PXLAFWIVWICIRK-UHFFFAOYSA-N [difluoro(trifluoromethoxy)methyl] hypofluorite Chemical compound FOC(F)(F)OC(F)(F)F PXLAFWIVWICIRK-UHFFFAOYSA-N 0.000 claims description 6
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 6
- 125000000040 m-tolyl group Chemical group [H]C1=C([H])C(*)=C([H])C(=C1[H])C([H])([H])[H] 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N monobenzene Natural products C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- 125000003261 o-tolyl group Chemical group [H]C1=C([H])C(*)=C(C([H])=C1[H])C([H])([H])[H] 0.000 claims description 6
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 claims description 6
- 150000005229 pyrazolopyridines Chemical class 0.000 claims description 6
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 claims description 6
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 6
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 claims description 6
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 6
- 125000005808 2,4,6-trimethoxyphenyl group Chemical group [H][#6]-1=[#6](-[#8]C([H])([H])[H])-[#6](-*)=[#6](-[#8]C([H])([H])[H])-[#6]([H])=[#6]-1-[#8]C([H])([H])[H] 0.000 claims description 5
- 125000001340 2-chloroethyl group Chemical group [H]C([H])(Cl)C([H])([H])* 0.000 claims description 5
- 239000005591 Pendimethalin Substances 0.000 claims description 5
- OCKPCBLVNKHBMX-UHFFFAOYSA-N butylbenzene Chemical compound CCCCC1=CC=CC=C1 OCKPCBLVNKHBMX-UHFFFAOYSA-N 0.000 claims description 5
- 125000001624 naphthyl group Chemical group 0.000 claims description 5
- 125000003944 tolyl group Chemical group 0.000 claims description 5
- KJTLQQUUPVSXIM-UHFFFAOYSA-N DL-mevalonic acid Natural products OCCC(O)(C)CC(O)=O KJTLQQUUPVSXIM-UHFFFAOYSA-N 0.000 claims description 4
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 150000003222 pyridines Chemical class 0.000 claims description 4
- 229940125670 thienopyridine Drugs 0.000 claims description 4
- 239000002175 thienopyridine Substances 0.000 claims description 4
- UEMGWPRHOOEKTA-UHFFFAOYSA-N 1,3-difluorobenzene Chemical compound FC1=CC=CC(F)=C1 UEMGWPRHOOEKTA-UHFFFAOYSA-N 0.000 claims description 3
- 125000006036 1-ethyl-1-propenyl group Chemical group 0.000 claims description 3
- 125000006037 1-ethyl-2-propenyl group Chemical group 0.000 claims description 3
- 125000006021 1-methyl-2-propenyl group Chemical group 0.000 claims description 3
- 125000000954 2-hydroxyethyl group Chemical group [H]C([*])([H])C([H])([H])O[H] 0.000 claims description 3
- 125000006022 2-methyl-2-propenyl group Chemical group 0.000 claims description 3
- WWUVJRULCWHUSA-UHFFFAOYSA-N 2MP Natural products CCCC(C)=C WWUVJRULCWHUSA-UHFFFAOYSA-N 0.000 claims description 3
- YHQXBTXEYZIYOV-UHFFFAOYSA-N 3-methylbut-1-ene Chemical group CC(C)C=C YHQXBTXEYZIYOV-UHFFFAOYSA-N 0.000 claims description 3
- XQNVDQZWOBPLQZ-UHFFFAOYSA-N 4-(trifluoromethoxy)benzaldehyde Chemical compound FC(F)(F)OC1=CC=C(C=O)C=C1 XQNVDQZWOBPLQZ-UHFFFAOYSA-N 0.000 claims description 3
- 125000004199 4-trifluoromethylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C(F)(F)F 0.000 claims description 3
- JNYLMODTPLSLIF-UHFFFAOYSA-N 6-(trifluoromethyl)pyridine-3-carboxylic acid Chemical group OC(=O)C1=CC=C(C(F)(F)F)N=C1 JNYLMODTPLSLIF-UHFFFAOYSA-N 0.000 claims description 3
- HOSGXJWQVBHGLT-UHFFFAOYSA-N 6-hydroxy-3,4-dihydro-1h-quinolin-2-one Chemical group N1C(=O)CCC2=CC(O)=CC=C21 HOSGXJWQVBHGLT-UHFFFAOYSA-N 0.000 claims description 3
- JRLTTZUODKEYDH-UHFFFAOYSA-N 8-methylquinoline Chemical group C1=CN=C2C(C)=CC=CC2=C1 JRLTTZUODKEYDH-UHFFFAOYSA-N 0.000 claims description 3
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims description 3
- 125000001118 alkylidene group Chemical group 0.000 claims description 3
- 150000001555 benzenes Chemical group 0.000 claims description 3
- 125000000649 benzylidene group Chemical group [H]C(=[*])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 3
- 125000004956 cyclohexylene group Chemical group 0.000 claims description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 3
- 125000004186 cyclopropylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C1([H])[H] 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 125000001072 heteroaryl group Chemical group 0.000 claims description 3
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- MHNNAWXXUZQSNM-UHFFFAOYSA-N methylethylethylene Natural products CCC(C)=C MHNNAWXXUZQSNM-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- QMMOXUPEWRXHJS-UHFFFAOYSA-N pent-2-ene Chemical compound CCC=CC QMMOXUPEWRXHJS-UHFFFAOYSA-N 0.000 claims description 3
- 125000000538 pentafluorophenyl group Chemical group FC1=C(F)C(F)=C(*)C(F)=C1F 0.000 claims description 3
- RFPMGSKVEAUNMZ-UHFFFAOYSA-N pentylidene Chemical group [CH2+]CCC[CH-] RFPMGSKVEAUNMZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000012797 qualification Methods 0.000 claims description 3
- 150000003527 tetrahydropyrans Chemical class 0.000 claims description 3
- 125000006035 1,2-dimethyl-2-propenyl group Chemical group 0.000 claims description 2
- 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
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000000051 benzyloxy group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])O* 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 150000002367 halogens Chemical class 0.000 claims description 2
- 239000011630 iodine Substances 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- FHSAZOGISLHXPK-UHFFFAOYSA-N 3-hydroxyoxan-2-one Chemical compound OC1CCCOC1=O FHSAZOGISLHXPK-UHFFFAOYSA-N 0.000 claims 6
- FZWLAAWBMGSTSO-UHFFFAOYSA-N Thiazole Chemical compound C1=CSC=N1 FZWLAAWBMGSTSO-UHFFFAOYSA-N 0.000 claims 6
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 claims 4
- 230000015572 biosynthetic process Effects 0.000 claims 2
- KJTLQQUUPVSXIM-ZCFIWIBFSA-M (R)-mevalonate Chemical compound OCC[C@](O)(C)CC([O-])=O KJTLQQUUPVSXIM-ZCFIWIBFSA-M 0.000 claims 1
- 125000005810 2,5-xylyl group Chemical group [H]C1=C([H])C(=C(*)C([H])=C1C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims 1
- 125000004211 3,5-difluorophenyl group Chemical group [H]C1=C(F)C([H])=C(*)C([H])=C1F 0.000 claims 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 claims 1
- 150000002596 lactones Chemical class 0.000 claims 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 150000003217 pyrazoles Chemical class 0.000 claims 1
- 125000005920 sec-butoxy group Chemical group 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 abstract description 2
- MISJRAXTGWOCLJ-UHFFFAOYSA-N 3-hydroxy-3-methyloxan-2-one Chemical compound CC1(O)CCCOC1=O MISJRAXTGWOCLJ-UHFFFAOYSA-N 0.000 abstract 1
- OZJPLYNZGCXSJM-UHFFFAOYSA-N 5-valerolactone Chemical compound O=C1CCCCO1 OZJPLYNZGCXSJM-UHFFFAOYSA-N 0.000 abstract 1
- 229940123934 Reductase inhibitor Drugs 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 81
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 75
- 239000000243 solution Substances 0.000 description 37
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 18
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000011541 reaction mixture Substances 0.000 description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 7
- 238000002425 crystallisation Methods 0.000 description 7
- 230000008025 crystallization Effects 0.000 description 7
- RKMGAJGJIURJSJ-UHFFFAOYSA-N 2,2,6,6-tetramethylpiperidine Chemical compound CC1(C)CCCC(C)(C)N1 RKMGAJGJIURJSJ-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 6
- 238000004587 chromatography analysis Methods 0.000 description 6
- 239000012230 colorless oil Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 5
- 239000013078 crystal Substances 0.000 description 5
- 239000000284 extract Substances 0.000 description 5
- 230000003647 oxidation Effects 0.000 description 5
- 238000007254 oxidation reaction Methods 0.000 description 5
- SPPOMCVKLNYEIZ-UHFFFAOYSA-N tert-butyl 5-ethenyl-6-methyl-2,3-dioxohept-5-enoate Chemical compound C(C)(C)(C)OC(C(C(CC(C=C)=C(C)C)=O)=O)=O SPPOMCVKLNYEIZ-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 4
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 239000010410 layer Substances 0.000 description 4
- CDXVUROVRIFQMV-UHFFFAOYSA-N oxo(diphenoxy)phosphanium Chemical compound C=1C=CC=CC=1O[P+](=O)OC1=CC=CC=C1 CDXVUROVRIFQMV-UHFFFAOYSA-N 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- KJTLQQUUPVSXIM-ZCFIWIBFSA-N (R)-mevalonic acid Chemical compound OCC[C@](O)(C)CC(O)=O KJTLQQUUPVSXIM-ZCFIWIBFSA-N 0.000 description 3
- 206010003210 Arteriosclerosis Diseases 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 208000011775 arteriosclerosis disease Diseases 0.000 description 3
- 238000011097 chromatography purification Methods 0.000 description 3
- 230000006837 decompression Effects 0.000 description 3
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical compound CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 3
- 239000007789 gas Substances 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 238000010992 reflux Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- SPEUIVXLLWOEMJ-UHFFFAOYSA-N 1,1-dimethoxyethane Chemical compound COC(C)OC SPEUIVXLLWOEMJ-UHFFFAOYSA-N 0.000 description 2
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 2
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 2
- UFWIBTONFRDIAS-UHFFFAOYSA-N Naphthalene Chemical compound C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 238000006482 condensation reaction Methods 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000012442 inert solvent Substances 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 150000002642 lithium compounds Chemical class 0.000 description 2
- 229940050176 methyl chloride Drugs 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 150000004714 phosphonium salts Chemical class 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- 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 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 1
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- HEWZVZIVELJPQZ-UHFFFAOYSA-N 2,2-dimethoxypropane Chemical compound COC(C)(C)OC HEWZVZIVELJPQZ-UHFFFAOYSA-N 0.000 description 1
- JFVAZAQELKYEFZ-UHFFFAOYSA-N 2-cyclopropyl-4-(4-fluorophenyl)quinoline Chemical group C1=CC(F)=CC=C1C1=CC(C2CC2)=NC2=CC=CC=C12 JFVAZAQELKYEFZ-UHFFFAOYSA-N 0.000 description 1
- KBTAFGCGWQASQZ-UHFFFAOYSA-N C(C)(C)OCCCCOF Chemical compound C(C)(C)OCCCCOF KBTAFGCGWQASQZ-UHFFFAOYSA-N 0.000 description 1
- XBPCUCUWBYBCDP-UHFFFAOYSA-N Dicyclohexylamine Chemical compound C1CCCCC1NC1CCCCC1 XBPCUCUWBYBCDP-UHFFFAOYSA-N 0.000 description 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 1
- OTMSDBZUPAUEDD-UHFFFAOYSA-N Ethane Chemical compound CC OTMSDBZUPAUEDD-UHFFFAOYSA-N 0.000 description 1
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- FIZDBNPUFMDGFZ-UHFFFAOYSA-N [2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]methanol Chemical compound OCC1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 FIZDBNPUFMDGFZ-UHFFFAOYSA-N 0.000 description 1
- XMGRDYSKQTVPOH-UHFFFAOYSA-N [Br-].[PH4+].C1=CC=CC=C1 Chemical class [Br-].[PH4+].C1=CC=CC=C1 XMGRDYSKQTVPOH-UHFFFAOYSA-N 0.000 description 1
- KCZCBAKVZPEDHY-UHFFFAOYSA-N [O].O=C1C=CC=CO1 Chemical compound [O].O=C1C=CC=CO1 KCZCBAKVZPEDHY-UHFFFAOYSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 229940111121 antirheumatic drug quinolines Drugs 0.000 description 1
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 229910000085 borane Inorganic materials 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- FESAXEDIWWXCNG-UHFFFAOYSA-N diethyl(methoxy)borane Chemical compound CCB(CC)OC FESAXEDIWWXCNG-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 125000001207 fluorophenyl group Chemical group 0.000 description 1
- 230000002140 halogenating effect Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- JCIVHYBIFRUGKO-UHFFFAOYSA-N lithium;2,2,6,6-tetramethylpiperidine Chemical compound [Li].CC1(C)CCCC(C)(C)N1 JCIVHYBIFRUGKO-UHFFFAOYSA-N 0.000 description 1
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 description 1
- LANOKECRDQDWOU-BQYQJAHWSA-N methyl (E)-3,5-dioxo-7-phenylhept-6-enoate Chemical class COC(=O)CC(=O)CC(=O)\C=C\c1ccccc1 LANOKECRDQDWOU-BQYQJAHWSA-N 0.000 description 1
- VCNWJEZPTFGKLI-FVWNJDPFSA-N methyl (E,3S,5R)-3,5-dihydroxy-7-phenylhept-6-enoate Chemical class COC(=O)C[C@@H](O)C[C@@H](O)\C=C\c1ccccc1 VCNWJEZPTFGKLI-FVWNJDPFSA-N 0.000 description 1
- VCNWJEZPTFGKLI-BQYQJAHWSA-N methyl (e)-3,5-dihydroxy-7-phenylhept-6-enoate Chemical class COC(=O)CC(O)CC(O)\C=C\C1=CC=CC=C1 VCNWJEZPTFGKLI-BQYQJAHWSA-N 0.000 description 1
- VCNWJEZPTFGKLI-UHFFFAOYSA-N methyl 3,5-dihydroxy-7-phenylhept-6-enoate Chemical class COC(=O)CC(O)CC(O)C=CC1=CC=CC=C1 VCNWJEZPTFGKLI-UHFFFAOYSA-N 0.000 description 1
- 150000004702 methyl esters Chemical class 0.000 description 1
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N methylimidazole Natural products CC1=CNC=N1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 1
- 238000005192 partition Methods 0.000 description 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 description 1
- REPWBKQJAMXHFL-UHFFFAOYSA-N phenylphosphane;hydrobromide Chemical class [Br-].[PH3+]C1=CC=CC=C1 REPWBKQJAMXHFL-UHFFFAOYSA-N 0.000 description 1
- 150000003009 phosphonic acids Chemical class 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 150000003112 potassium compounds Chemical class 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 150000003248 quinolines Chemical class 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- ODZPKZBBUMBTMG-UHFFFAOYSA-N sodium amide Chemical compound [NH2-].[Na+] ODZPKZBBUMBTMG-UHFFFAOYSA-N 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 150000003388 sodium compounds Chemical class 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- 125000004205 trifluoroethyl group Chemical group [H]C([H])(*)C(F)(F)F 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
Landscapes
- Pyridine Compounds (AREA)
Abstract
The synthetic condensed pyridine type of methylhydroxy valerolactone intermediate may be used to prepare position-7 substitutional (E, 3R, 5S)-3,5-dihydroxyl-6-heptenoic acid or its 1,5-valerolactone, antimer with the activity of HMG-10A reductase inhibitor, which are used to prepare medicine to cure hypercholesterolemia.
Description
The present invention relates to a kind of new intermediate in order to condensed pyridine type mevalonolactone derivative, it is that a kind of HMGCoA reductase inhibitor and it are to be used as too high therapeutical agent of blood cholesterol or arteriosclerosis therapeutical agent, with and preparation method thereof and as the new condensed pyridine derivative of raw material.
Before this, condensed pyridine type list hydroxyl valeric acid lactone derivatives is by synthesizing as the side chain that progressively extends the condensed pyridine ring structure that is disclosed in European patent 535548 or the Japanese patent application 257870/1991.(scheme 1)
This method provide each rapid step by step in goodish productive rate, but shake such as being included in some steps because of there being some to lack, make troubles, specific conditions (extremely low temperature, borane reagent) also needs to control the sterie configuration (cis-structure has high activity) of two hydroxyls, because side chain progressively extends, and need highly most advanced and sophisticated asymmetric synthetic method or carry out, the optically active form partition of weak effect is to obtain optically active material ((3R, 5S)-structure is highly active).
The invention provides a kind of novel method, solved the difficult problem in the method and the new intermediate that is used for this method.
The condensed pyridine type mevalonolactone intermediate of formula I:
Wherein encircling X is phenyl ring, the hetero-aromatic ring that substituted benzene ring or 5-or 6-position replace;
R
1And R
2Be hydrogen independently respectively, C
1-8Alkyl, C
3-7Cycloalkyl, C
1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, R
20R
21-(R wherein
20And R
21Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) eOR
22(R wherein
22Be hydrogen or C
1-3Alkyl and e are 1,2 or 3); Or R
1And R
2Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;
R
3Last hydrogen, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
5-7Cycloalkenyl group or
(R wherein
7Be hydrogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine, hydrogen be for methyl, trichloromethyl, trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol); Or by one
(R wherein
7Be as above to limit) and 01 or two C
1-3The C that alkyl replaced
1-3Alkyl.
(R
9aAnd R
9bRepresentative is protected the group of hydroxyl and is methoxymethyl independently, 2-methoxy (ethoxy) methyl, tetrahydropyrans respectively; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; contraposition-methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R
9aAnd R
9bBe associated in and constitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With
R
10Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, the silica-based or tertiary butyl dimethylamino benzophenone alcohol radical of trimethylammonium first), but the thing pyridine derivate reaction of contracting of through type (2) makes:
Wherein encircle X, R
1, R
2And R
3As above limit:
Y is P
+R
11R
12R
13Hal
-Or P(W) R
14R
15(R wherein
11, R
12And R
13Be methyl independently respectively, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, five oxygen phenyl or benzyls, R
14And R
15Be respectively methyl independently, ethyl, propyl group, sec.-propyl, butyl, the 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group, benzyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2-trifluoro ethoxy, phenoxy group, methoxy phenoxy, methylphenoxy, penta fluoro benzene oxygen base or benzyloxy, or R
14And R
15Be associated in and constitute 5-or 6-unit ring together, halogen is a chlorine, and bromine or iodine and W are O or S, connect and compose negatively charged ion with alkali, it again with formula (3) compound condensation:
R wherein
9a, R
9bAnd R
10As above limit.
Distinguishingly, Y is P(O in formula (2)) ph
2, the productive rate of condensation reaction and stereoisomerism selectivity (trans selectivity) are fabulous, and can obtain good yield and highly purified formula I compound.(scheme 2)
Scheme 2
The formula I intermediate is a kind of new compound; and be a kind of useful as intermediates; it can form is the condensed pyridine type mevalonolactone derivative (I) of HMG-CoA reductase inhibitor and is used as the hypercholesterolemia therapeutical agent or the arteriosclerosis therapeutical agent, by the R of an one-step hydrolysis for the protection oh group
9aAnd R
9bAnd be the R of ester
10(in the formula, (I-1) represents the condensed pyridine type mevalonate, and (I-2) represents the condensed pyridine type mevalonic acid, and on behalf of the pharmacy acceptable salt of condensed pyridine type mevalonic acid and (I-3), (I-5) represent the condensed pyridine type mevalonolactone.) (scheme 3)
These compounds four kinds of steric isomers are arranged, and they can make by the inventive method according to the spatial disposition of the hydroxyl of used formula (3) compound.
Formula (2) compound also is new, and it obtains by the relevant intermediate in the scheme is synthetic.
The hydroxyl of formula VI compound and halogenating agent such as PBr
3Reaction obtains halogenated formula (IX) compound.As halogenated compound and PR
11R
12R
13(R wherein
11, R
12And R
13As above limit) reaction, can De (wherein Y is P Dao phosphonium salt
+R
11R
12R
13Hal
-Formula (2) compound).When halogenated compound by with PR
14R
15(WR
16) Arbusow reaction, (R wherein
14, R
15As above limit with W, and R
16Be methyl, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group or benzyl), perhaps Shang Shu phosphonium salt is hydrolyzed, can make formula (2) compound, wherein Y is P(W) R
14R
15(R wherein
14, R
15As above limit with W).
Formula (3) compound is synthetic by the method for scheme 5.
The condensation reaction of formula (2) condensed pyridine derivative and formula (3) aldehyde compound be by in the taking-up formula (2) adjacent to the hydrogen atom of Y, its method is to utilize to handle with salt in anhydrous inert solvent, constitute negatively charged ion, and then with the aldehyde compound reaction of formula (3).
Inert solvent can be, for example aliphatic hydrocrbon, aromatic hydrocarbon or ether solvent.Be preferably ether solvent such as diethyl ether, 1,2-diethoxyethane, 1,2-glycol dimethyl ether or tetrahydrofuran (THF).Further, as needs, available anionic stablizer, polar solvent such as hexamethyl phosphoric triamide, methyl-sulphoxide or the methylimidazole alkane ketone stablized.
Alkali can be: for example, sodium compound such as sodium hydride or sodium amide, potassium compound such as tert.-butoxy potassium, lithium compound such as butyllithium or phenyl lithium, or the baseization lithium compound is as 2,2,6,6-tetramethyl piperidine lithium.
Temperature of reaction changes according to response matrix.But the temperature when adding alkali between-78 to 30 ℃, and with the reflux temperature of temperature from-70 ℃ to solvent of aldehyde reaction.
Synthetic formula I compound can be made condensed pyridine type mevalonolactone derivative (I) according to the method for such scheme 3 like this.Condensed pyridine type mevalonolactone intermediate as the formula I of The compounds of this invention comprises formula (1a), (1b) and compound (1c)
Further, comprise formula (2a) as the condensed pyridine type mevalonolactone of the formula (2) of The compounds of this invention, (2b) and compound (2c):
Mentioned the as above substituent of compound below.In arbitrary compound, substituent R
1, R
2, R
3, Z and Y as above limit.
R
1And R
2Be hydrogen preferably respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclohexyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol.
R
3Be hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.
In formula (1a) and quinolines (2a), R
4a, R
5aAnd R
6aBe hydrogen independently respectively, C
1-6Alkyl, C
3-7Cycloalkyl C
1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, R
26R
27N-(is R wherein
26And R
27Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) mOR
28(R wherein
28Be hydrogen or C
1-3Alkyl and m are 1,2 or 3); Or
R
4aAnd R
5aFormation-CH=CH-CH=CH-connects together; Or
R
4aAnd R
5aFormation-OC(R connects together
29) (R
30) O-(R wherein
29And R
30Be respectively hydrogen or C
1-3Alkyl) when they is the ortho position mutually.
The following R that mentioned
4a, R
5aAnd R
5aAnd R
6aSubstituting group preferably,
That is, work as R
5aAnd R
6aWhen being hydrogen simultaneously, R
4aBe hydrogen preferably, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino.
Work as R
6aDuring for hydrogen, R
4aAnd R
5aCan connect together and represent 6-chloro-8-methyl, 6-bromo-7-methoxyl group, 6-methyl-7-chlorine, 6-chloro-8-hydroxyl, 5-methyl-2-hydroxyl, 6-methoxy-7-chlorine, 6-chloro-7-methoxyl group, 6-hydroxyl-7-chlorine, 6-oxygen-7-hydroxyl, 6-chloro-8-bromine, 5-chloro-6-hydroxyl, 6-bromo-8-chlorine, 6-bromo-8-hydroxyl, 5-methyl-8-chlorine, 7-hydroxyl-8-chlorine, 6-bromo-8-hydroxyl, 6-methoxyl group-7-methyl, 6-chloro-8-bromine, 6-methyl-8-bromine, 6, the 7-difluoro, 6,8-difluoro, 6,7-methylene radical dioxygen base, 6,8-dichloro, 5, the 8-dimethyl, 6,8-dimethyl, 6, the 7-dimethoxy, 6, the 7-diethoxy, 6,7-dibromo or 6,8-dibromo.
Further, R
4a, R
5a, R
6aCan represent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.
Be preferably formula (1a) and quinoline compound (2a), wherein R
1Be contraposition chlorine, R
2, R
4a, R
5aAnd R
6aBe respectively hydrogen, and R
3Be cyclopropyl.
In formula (1b) and Pyrazolopyridine type compound (2b), R
4bBe hydrogen, C
1-8Alkyl, C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Alkenyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, fluorine, chlorine, bromine,
(wherein, R
6b, R
7bAnd R
8bBe hydrogen independently respectively, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine ,-NR
31R
32(R wherein
31And R
32Be C independently respectively
1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, three silyloxies, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) nOR
33(R wherein
33Be hydrogen or C
1-3Alkyl and n are 1,2 or 3), or
Work as R
8bWhen being hydrogen, R
6bAnd R
7bAs they formation-OC(R that links together during mutually at the ortho position
34) (R
35) O-(R wherein
34And R
35Be hydrogen or C independently respectively
1-3Alkyl), or
Work as R
7bAnd R
8bWhen being hydrogen simultaneously, R
6bBe
(R wherein
3bBe hydrogen, C
1-4Alkyl, C
1-3Alkoxyl group, trifluoromethyl, chlorine, bromine or fluorine), phenyl-C
2-3Alkenyl wherein phenyl can be by C
1-4Alkyl, C
1-3Alkoxyl group, oxygen, chlorine or bromine replaces, or can be selected from C by one
1-3Alkoxyl group, naphthyl and
(R wherein
6b, R
7bAnd R
B6As above limit) and zero, one or two C
1-8The C that alkyl replaces
1-3Alkyl;
R
5bBe to be connected on the hydrogen atom of the 1-of Pyrazolopyridine ring or 2-position, and R
5bBe hydrogen, C
1-8Alkyl is replaced C by 1-3 fluorine atom
1-3Alkyl, C
3-7Cycloalkyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl or
(R wherein
6bAnd R
8bAs above limit), or
Be selected from C by one
1-3Alkoxyl group, hydroxyl, naphthalene and
(R wherein
6b, R
7bAnd R
8bAs above limit) and zero, one or two C
1-8The C that alkyl is got
1-3Alkyl replaces.
R
1, R
2, R
3With Z be qualification about formula (1).
Following substituting group has been mentioned R preferably
4bAnd R
5bSubstituting group
That is R,
4bBe hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2,3-4-tolyl, 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-trifluoromethyl, 2-, 3-or 4-chloromethyl phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2, the 6-difluorophenyl, 2,3-difluorophenyl, 3, the 5-difluorophenyl, 2,5-difluorophenyl, 3, the 4-difluorophenyl, 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,3-dichlorophenyl, 2, the 5-dichlorophenyl, 3,5-dichlorophenyl, 3, the 4-dichlorophenyl, 2,3-xylyl, 2, the 5-xylyl, 2,6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2,4-dimethoxy phenyl, 3, the 4-dimethoxy phenyl, 3,5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;
R
5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring preferably and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, the ring ethyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, 2-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.
Formula (1b) and Pyrazolopyridine compound (2b) be R wherein
1Be the contraposition fluorine, R
2Be hydrogen, R
4bAnd R
5bBe respectively methyl and R
3Being cyclopropyl, is preferably.
In formula (1c) and Pyrazolopyridine type compound (2c), R
4cAnd R
5cBe hydrogen independently respectively, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
1-6Alkoxyl group, fluorine, chlorine, bromine,
(R wherein
6c, R
7cAnd R
8cBe hydrogen independently respectively, C
1-4Alkyl, C
1-3Alkoxyl group, C
3-7Cycloalkyl, trifluoromethyl, fluorine, chlorine and bromine), 2-, 3-or 4-pyridyl, 2-or 5-pyrimidyl, 2-or 3-thienyl, 2-or 3-furyl,
(R wherein
6cAs above limit) ,-NR
37And R
38(R wherein
37And R
38Be hydrogen independently respectively, C
1-4Alkyl,
(wherein j is 1,2 or 3, and R
6cAs above limit), or R
37And R
38Formation-(CH together
2) k-(wherein k be 3,4 or 5), quilt
(R wherein
6cAs above limit) and zero, one or two C
1-3Alkyl or α-or C that β-naphthalene replaced
1-3Alkyl, or
R
4cAnd R
5cConnect together and constitute C
2-6Zero to three substituting groups of alkylidene group and quilt replace, and substituting group is selected from C
1-4Alkyl, C
3-7Cycloalkyl, fluorine, zero to one substituting group of chlorine and bromine and quilt replaces, and substituting group is selected from
(R wherein
6cAs above limit), or-(CHR
39) P-A-(CHR
40) q-(wherein p and q be respectively 0,1,2 or 3, A is-(CR
41)=(CR
42)-(be R wherein
41And R
42Be respectively hydrogen or C
1-3Alkyl) ,-O-;-S-or-N(R
43Be hydrogen, C
1-4Alkyl, or
(R wherein
6cAs above limit with j)), and R
39And R
40Be hydrogen or C independently respectively
1-4Alkyl) or-CH=CH-CH=CH-
Following substituting group has been mentioned R
4cAnd R
5cSubstituting group preferably.
That is: R preferably
4cAnd R
5cBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, the 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, the 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or
R
4cAnd R
5cConstitute ethene together, trimethylene, tetramethylene, 1-two pentylidene, methyl tetramethylene, oxo tetramethylene or benzene tetramethylene.
Be preferably formula (1c) and (2c) Thienopyridines, wherein R
1Be to aim at fluorine, R
2Be hydrogen, R
4cBe ethyl, R
5cBe methyl and R
3It is cyclopropyl.
Reference example 1
(3R
*, 5S
*, 6E)-and 7-phenyl-3, the preparation of 5-dihydroxy-6-heptenoic acid methyl esters
Under-78 ℃, with diethyl methoxy borane (1.07ml, 8.13mmol) join (E)-7-phenyl-3,5-dioxo-6-heptenoic acid methyl esters (2.00g, 8.12mmol) THF(20mol)/methyl alcohol (5.0mol) solution in, miscellany is stirred made in 15 minutes then and reaches room temperature, miscellany is cooled to-78 ℃ again, add therein then sodium borohydride (1.54g, 40.7mmol).Reaction mixture stirred 4 hours down at-78 ℃, stirred 8 hours under room temperature from-78 ℃ again.Add acetic acid (2.0ml) with termination reaction, again reaction mixture is poured in the saturated sodium bicarbonate aqueous solution, extract with diethyl ether again.Organic layer washs with saturated nacl aqueous solution, again through dried over sodium sulfate and concentrated.Resistates is dissolved in the methyl alcohol (10mol), concentrates then.This operation repeats 10 times, decomposes behind organoboron compound through distilling again, and product is through the chromatography (hexane: ethyl acetate=2: 1), obtain (3R of purifying
*, 5S
*, 6E)-and 7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (1.16g, 56%).
Rf=0.08(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：3475，3005，1720，1490，1435，1205，1110，1070，1030，775，730cm
-1.
1H-NMR（CDCl
3）：δ7.38（d，J＝7.2Hz，2H），7.31（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.62（d，J＝15.7Hz，1H），6.21（dd，J＝15.7，6.4Hz，1H），4.59（m，1H），4.43（m，1H），3.74（s，1H），3.72（s，3H），3.24（s，1H），2.54（dd，J＝19.8，16.5Hz，1H），2.52（dd，J＝17.4，16.5Hz，1H），1.80（dt，J＝14.3，9.4Hz，1H），1.73（dt，J＝14.3，3.1Hz，1H）.
MS（m/z）250（M
+，2.5），232（M
+-H
2O，3.5），218（4），215（4），200（15），158（60），104（100）.
Reference example 2
(3R
*, 5S
*, 6E)-and 7-phenyl-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters
(the 3R that obtains in the reference example 1
*, 5S
*, 6E)-7-phenyl-3,5-dihydroxy-6-heptenoic acid methyl esters (1.10g, 4.39mmol) and tosic acid (50mg, catalytic amount) be dissolved in the dimethyl-acetal acetone (10.0ml), then reaction mixture was at room temperature stirred 2 hours.Miscellany dilutes with diethyl ether, and organic layer is with saturated sodium bicarbonate solution and sodium chloride solution washing, then through anhydrous magnesium sulfate drying and concentrated.Product is through chromatography (hexane: ethyl acetate=10: 1), obtain (3R
*, 5S
*, 6E)-and 7-phenyl-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (1.17g, 92%) is colorless oil.
Rf=0.08(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：3000，1735，1440，1380，1200，1160，1085，1030，770，740cm
-1.
1H-NMR（CDCl
3）：δ7.37（d，J＝7.2Hz，2H），7.29（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.60（d，J＝15.9Hz，1H），6.16（dd，J＝15.9，6.2Hz，1H），4.57（m，1H），4.40（m，1H），3.70（s，3H），2.60（dd，J＝15.6，6.9Hz，1H），2.52（dd，J＝15.6，6.2Hz，1H），1.74（dt，J＝12.3，2.5Hz，1H），1.54（s，3H），1.45（s，3H），1.40（dd，J＝11.4，10.2Hz，1H）.
MS（m/z）290（M
+，3），232（M
+-CO
2Me，4），215（15），158（50），104（100）.
Reference example 3
(3R
*, 5S
*)-6-oxo-3, the producing of 5-isopropylidene dioxo-6-heptenoic acid methyl esters
With (the 3R that obtains in the reference example 2
*, 5S
*, 6E)-and 7-phenyl-5, (340mg 1.17mmol) is dissolved in the methyl alcohol (50ml) 5-isopropylidene dioxo-6-heptenoic acid methyl esters, solution is cooled to-78 ℃ again.The mixed gas of receiving ozone that ozonizer provides and oxygen fed wherein change blueness into up to reaction soln.Then, feed nitrogen to remove excessive ozone gas.Add methyl-sulfide (1.0mol) then therein.Reaction mixture at room temperature stirred 12 hours and concentrated.Product is through chromatography purification (hexane: ethyl acetate=3: 1), obtain (3R
*, 5S
*)-6-oxo-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (210mg, 83%) is colourless crystallization.
Rf=0.14(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：2950，1735，1435，1380，1080，1030，775，730cm
-1.
1H-NMR（CDCl
3）：δ9.58（s，1H），4.38（m，1H），3.70（s，3H），2.58（dd，J＝15.8，7.0Hz，1H），2.44（dd，J＝15.8，6.0Hz，1H），1.86（dt，J＝12.9，2.7Hz，1H），1.50（s，3H），1.46（s，3H），1.35（dd，J＝12.0，12.0Hz，1H）.
MS（m/z）201（M
+-Me，24），129（31），97（36），59（100）.
Reference example 4
(3R, 5S, 6E)-and 7-phenyl-3, the preparation of 5-dihydroxyl-6-heptenoic acid methyl esters
Will be according to document (J.Org.Chem., 56,5752(1991)) (3S, the 5R of preparation, 6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid (4S)-4,7,7-trimethylammonium-3-replace (1-naphthyl) two rings (2 outward, 2,1) (210mg 0.42mmol) is dissolved in the methyl alcohol the outer substituting group ester of heptane-2, and adds 1M aqueous sodium hydroxide solution (0.2ml) therein.Mixture was at room temperature stirred 12 hours.Methyl alcohol is removed in decompression then.The residue dilute with water, and (4S)-4,7,7-trimethylammonium-3-replaces outward-and the outer substituted alcohols of (1-naphthyl) two ring (2,2,1) heptane-2-extracts with diethyl ether, the water layer hcl acidifying, and extract carboxylic acid with diethyl ether, the diethyl ether solution reaction of organic layer and diazomethane is to form methyl esters.Add the excessive diazomethane of acetic acid consumption, organic layer washs with saturated sodium bicarbonate aqueous solution, then through dried over mgso and concentrated.Product is through the silica gel column chromatography (hexane: ethyl acetate=2: 1), obtain that (6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (92mg, 87%) is colorless oil for 3S, 5R of purifying.
Rf=0.08(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：3475，3005，1720，1490，1435，1205，1110，1070，1030，775，730cm
-1.
1H-NMR（CDCl
3）：δ7.38（d，J＝7.2Hz，2H），7.31（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.62（d，J＝15.7Hz，1H），6.21（dd，J＝15.7，6.4Hz，1H），4.59（m，1H），4.43（m，1H），3.74（s，1H），3.72（s，3H），3.24（s，1H），2.54（dd，J＝19.8，16.5Hz，1H），2.52（dd，J＝17.4，16.5Hz，1H），1.80（dt，J＝14.3，9.4Hz，1H），1.73（dt，J＝14.3，3.1Hz，1H）.
MS （m/z）250（M
+，2.5），232（M
+-H
2O，3.5），218（4），215（4），200（15），158（60），104（100）.
HRMS Calcd.for C
14H
18O
4;M
+250.1222，found m/z250.1224.
[α]
20
D+8.23°（c1.19，CHCl
3）
Reference example 5
(3S, 6R, 6E)-and 7-phenyl-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters
With reference example 4 obtain (3S, 5R, 6E)-7-phenyl-3,5-dihydroxyl-6-heptenoic acid methyl esters (90mg, 0.36mmol) and tosic acid (5mg, catalytic amount) be dissolved in acetone dimethyl-acetal (1.0ml).Reaction mixture at room temperature stirred 6 hours, then miscellany is released with ether alkene, and organic layer was with saturated sodium bicarbonate aqueous solution and sodium chloride solution washing, then through anhydrous magnesium sulfate drying and concentrated.Product is analysed purification (hexane: obtain ethyl acetate=10: 1) that (6E)-7-phenyl-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (97mg, 92%) is colorless oil for 3S, 5R layer by layer through silica gel chromatography.
Rf=0.78(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：3000，1735，1440，1380，1200，1160，1085，1030，770，740cm
-1.
1H-NMR（CDCl
3）：δ7.37（d，J＝7.2Hz，2H），7.29（t，J＝7.2Hz，2H），7.24（tt，J＝7.2，1.3Hz，1H），6.60（d，J＝15.9Hz，1H），6.16（dd，J＝15.9，6.2Hz，1H），4.57（m，1H），4.40（m，1H），3.70（s，3H），2.60（dd，J＝15.6，6.9Hz，1H），2.52（dd，J＝15.6，6.2Hz，1H），1.74（dt，J＝12.3，2.5Hz，1H），1.54（s，3H），1.45（s，3H），1.40（dd，J＝11.4，10.2Hz，1H）.
MS（m/z）290（M
+，3），232（M
+-CO
2Me，4），215（15），158（50），104（100）.Milli MS Calcd.for C
17H
22O
4M
+;290，1498，found m/z;290，1496.
[α]
20
D+6.66°（c1.11，CHCl
3）
Reference example 6
(3S, 5R)-6-oxo-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters
With reference example 5 obtain (6E)-7-phenyl-3, (120mg 0.41mmol) is dissolved in the methyl alcohol (20ml) 5-isopropylidene dioxo-6-heptenoic acid methyl esters, then solution is cooled to-78 ℃ for 3S, 5R.The ozone that the adding ozonizer obtains and the gas mixture of oxygen become blue up to reaction soln.Pour nitrogen then to remove excessive ozone, add methyl-sulfide (0.5ml) again.Reaction mixture at room temperature stirred 12 hours and concentrated.Product is through the chromatography (hexane: obtain ethyl acetate=3: 1) that (3S, 5R)-6-oxo-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (49mg, 90%) is a colorless oil of purifying.
Rf=0.14(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：2950，1735，1435，1380，1080，1030，775，730cm
-1.
1H-NMR（CDCl
3）：δ9.58（s，1H），4.38（m，1H），3.70（s，3H），2.58（dd，J＝15.8，7.0，1H），2.44（dd，J＝15.8，6.0，1H），1.86（dt，J＝12.9，2.7，1H），1.50（s，3H），1.46（s，3H），1.35（dt，J＝12.0，12.0，1H）.
MS（m/z）201（M
+-Me，24），129（31），97（36），59（100）.
[α]
20
D+20.00°（c 1.03，CHCl
3）
Reference example 7
3-brooethyl-2-cyclopropyl-4-(4-fluorophenyl) preparation of quinoline
At room temperature (6.0g is in toluene 20.5mmol) (40ml)-methylene dichloride (20ml) solution with phosphorus tribromide (4.0ml 42.1mmol) joins 2-cyclopropyl-3-methylol-4-(4-fluorophenyl) quinoline.Reaction mixture at room temperature stirs 3 hours, yet pours termination reaction in the sodium bicarbonate aqueous solution into.The miscellany ethyl acetate extraction, organic layer is through anhydrous magnesium sulfate drying and concentrated.Resistates is through chromatography (hexane: chloroform=3: 1) purify that to obtain required product (6.54g, 89%) be white crystals.
Fusing point: 140 ℃
1H-NMR（CDCl
3）：δ7.97（d，J＝8.9，1H），7.62（dd，J＝6.8，1.6Hz，1H），7.40（m，6H），4.59（s，2H），2.51（m，1H），1.41-1.37（m，2H），1.16-1.12（m，2H）.
Embodiment 1
(4.00g is in toluene solution 10.2mmol) (50mol), with miscellany reflux 5 hours with triphenyl phosphine (2.81g 10.7mmol) joins 3-brooethyl-2-cyclopropyl-4-(4-fluorobenzene that reference example 7 obtains) quinoline.Filter and collect the gained solid, and dry again with toluene wash, obtain 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl } methyl three benzene phosphonium bromides (680g, quantitative yield), be white powder.
Fusing point: 245 ℃ (decomposition)
IR（CHCl
3）：3300，3050，1600，1520，1495，1440，1320，1220，1150，920，840cm
-1.
1H-NMR（CDCl
3）：δ0.3-0.7（m，2H），1.2-0.9（m，2H），2.5-2.0（m，1H），5.5（d，2H，14.4Hz），8.0-6.8（m，23H）.
Embodiment 2
The preparation of { 2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl } methyl-phosphorous acid diethyl ester
With triethyl-phosphite (3.50ml, 20.4mmol) join 3-brooethyl-2-cyclopropyl-4-(4-fluorophenyl that reference example 7 obtains) quinoline (4.00g, 10.2mmol) toluene solution (30ml) in, reaction mixture was refluxed 12 hours under heating, removal of solvent under reduced pressure, product is purified through chromatography then, and (hexane: ethyl acetate=2: 1) obtaining { 2-cyclopropyl-4-(4-fluorobenzene yl-quinoline-3-yl } methyl-phosphorous acid diethyl ester (4.14g, quantitative yield) is white crystals.
Fusing point: 89 ℃
Rf=0.09(hexane: ethyl acetate=5: 1)
IR（CHCl
3）：2950，1600，1510，1490，1435，1240，1145，1020，970，830cm
-1.
1H-NMR（CDCl
3）：δ8.95（d，J＝8.4Hz，1H），7.59（dt，7.0，1.2Hz，1H），7.35-7.17（m，6H），4.01-3.84（m，4H），3.43（d，J＝22.5Hz，2H），2.67-2.61（m，1H），1.33-1.29（m，2H），1.19（t，J＝7.0Hz，6H），1.09（dd，J＝8.0，3.1Hz，2H）.
MS（m/z）413（M
+，63），385（4），356（4），328（5），276（100）.
Embodiment 3
The preparation of { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester
3-brooethyl-2-cyclopropyl-4-(4-the fluorophenyl that obtains in reference example 7) quinoline (1.00g, 2.80mmol) toluene solution (20ml) in add the positive phosphorus (1.30g of hexichol oxyethyl group, 5.65mmol), then with reaction mixture reflux 12 hours.Solvent decompression is removed, and product is through chromatography (hexane: ethyl acetate=1: 1), obtain { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl of purifying } phosphine oxide diphenyl phthalate (1.38g, quantitative yield) is colourless crystallization.
Fusing point: 170 ℃
Rf=0.11(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：2950，1605，1510，1490，1435，1210，1110，1025，830cm
-1.
1H-NMR（CDCl
3）：δ7.95（d，J＝8.3Hz，1H），7.57（t，J＝7.2Hz，1H），7.51-7.33（m，1H），7.24（td，J＝7.0，1.2Hz，1H），7.05（d，J＝8.4Hz，1H），6.99（d，J＝8.7Hz，1H），6.97（d，J＝8.7Hz，1H），6.80（d，J＝5.5Hz，1H），6.78（d，J＝5.5Hz，1H），4.04（d，J＝14.0Hz，2H），2.61-2.55（m，1H），1.24-1.20（m，2H），0.89（dd，J＝8.8，3.1Hz，2H）.
MS（m/z）477（M
+，3），449（0.1），352（4），246（8），201（50），124（25），77（100）.
Embodiment 4
(3R
*, 5S
*)-7-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid methyl esters
With tert-butyl lithium (0.15ml, 1.60M pentane solution, 0.24mmol) at-78 ° of (join down embodiment 2 obtains { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl methyl-phosphorous acid diethyl ester (100mg, 0.24mmol) THF solution (3.0ml) in, miscellany was stirred 30 minutes down (the 3R that reference example 3 is obtained at-78 ℃
*, 5S
*)-6-oxo-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (50mg, 0.23mmol) THF solution (2.0ml) add wherein down at-78 ℃, reaction mixture stirred 3 hours down at-78 ℃ to 0 ℃ then, at room temperature restir is 2 hours, add the saturated sodium bicarbonate solution termination reaction, use the extracted with diethyl ether reaction mixture.Organic layer washs with sodium chloride solution, again through anhydrous magnesium sulfate drying and concentrated.Resistates is through chromatography purification (hexane: ethyl acetate=10: 1), obtain (3R
*, 5S
*, 6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (14mg, 12%), for colourless crystallization and (6E)-and structure (31mg, 29%), be colourless crystallization.
The 6Z-structure
Rf=0.40(hexane: ethyl acetate=5: 1)
IR（CHCl
3）：3000，1730，1600，1510，1490，1380，1230，1160，1090，840cm
-1.
1H-NMR（CDCl
3）：δ7.96（d，J＝8.2Hz，1H），7.62（dd，J＝6.7，1.5Hz，1H），7.37-7.15（m，6H），6.42（d，J＝11.4Hz，1H），5.61（dd，J＝11.4，8.2Hz，1H），4.38-4.30（m，1H），4.13-4.06（m，1H），3.64（s，3H），2.48（dd，J＝15.5，6.8Hz，1H），2.46-2.41（m，1H），2.29（dd，J＝15.5，6.3Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.
MS（m/z）475（M
+，6），416（8），400（5），344（21），288（100），275（43）.
The 6E-structure
Fusing point: 133 ℃
Rf=0.33(hexane: ethyl acetate=5: 1)
IR（CHCl
3）：3000，1730，1605，1510，1490，1380，1230，1160，1090，840cm
-1.
1H-NMR（CDCl
3）：δ7.95（d，J＝8.4Hz，1H），7.58（dd，J＝6.6，1.6Hz，1H），7.37-7.15（m，6H），6.55（dd，J＝16.3，1.2Hz，1H），5.57（dd，J＝16.3，6.1Hz，1H），4.38-4.33（m，1H），4.32-4.25（m，1H），3.71（s，3H），2.54（dd，J＝15.5，6.7Hz，1H），2.43（m，1H），2.35（dd，J＝15.6，6.4Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.
MS（m/z）475（M
+，6），416（8），400（5），344（21），288（100），275（43）.
Embodiment 5
(3R
*, 5S
*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters
With { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acids of obtaining among the embodiment 3, (115mg, THF solution (6ml) 0.24mmol) is cooled to-78 ℃ to diphenyl ester.Then, (0.16ml 0.26mmol), stirs miscellany 30 minutes then to add butyllithium therein.Add (the 3R that obtains in the reference example 3
*, 5S
*)-6-oxidation-3,5-isopropylidene dioxo-6-heptenoic acid methyl esters (50mg, THF solution 12.0ml 0.23mmol)) stirred 4 hours down at-78 ℃, then temperature was risen to stirred overnight at room temperature.Miscellany obtains (3R according to same procedure reaction among the embodiment 4
*, 5S
*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (71mg, 64%) is colourless crystallization.
1It is 99: 1 that H-NMR records the E/Z ratio.
Fusing point, R
f, IR,
1The 6E-structure of HMR and MS such as embodiment 4.
Embodiment 6
(3R
*, 5S
*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters
Under-78 ℃, with butyllithium (0.16ml, 1.62M hexane solution, 0.06mmol) join 2,2,6,6-tetramethyl piperidine (37mg, 0.26mmol) THF solution (2.0ml) in, miscellany stirred 15 minutes down at-78 ℃, under-78 ℃, add therein that embodiment 3 obtains 2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester (115mg, 0.24mmol) THF solution (4.0ml), miscellany at room temperature stirred 30 minutes then.(the 3R that obtains in the reference example 3
*, 5S
*)-6-oxo-3, (50mg, THF solution (2.0ml) 0.23mmol) at room temperature adds wherein 5-isopropylidene dioxygen generation-6-heptenoic acid methyl esters, then reaction mixture is at room temperature stirred 3 hours.Miscellany is according to the same procedure among the embodiment 4 reaction, obtains (6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3, and 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (84mg, 76%) is colourless crystallization.Warp
1The ratio that H-NMR records E/Z is 98.2.
Fusing point, R
f, IR,
HThe 6E-structure of NMRtMs such as embodiment 4.
Embodiment 7-10
Below with 2,2,6 in the amine alternate embodiment 6,6-tetramethyl piperidine.Reaction obtains following result by the same procedure operation.
| Embodiment | Amine | The productive rate of structure | E/Z |
| 7 8 9 10 | Two different third hexahydroaniline of trimethylammonium first silicon amine dicyclohexyl amine of Diisopropylamine | 54 47 60 64 | 98：2 98：2 97：3 95：5 |
Embodiment 11
(3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters
Under-78 ℃, with butyllithium (0.125ml, 1.62M hexane solution, 0.06mmol) join 2,2,6,6-tetramethyl piperidine (29mg, 0.20mmol) THF solution (2.0ml) in, miscellany stirred 15 minutes down at-78 ℃, under-78 ℃, add therein that embodiment 3 obtains 2-cyclopropyl-4-(4-fluorophenyl) and isoquinoline 99.9-3-yl } methyl oxidation phosphonic acid diphenyl ester (98mg, 0.20mmol) THF solution (4.0ml), miscellany at room temperature stirred 30 minutes then.Obtain in the reference example 6 (3S, 5R)-6-oxo-3, (38mg, THF solution (2.0ml) 0.18mmol) at room temperature adds wherein 5-isopropylidene dioxo-6-heptenoic acid methyl esters, then reaction mixture is at room temperature stirred 3 hours.Add the saturated sodium bicarbonate solution termination reaction then, miscellany extracts with diether.Organic layer washs with sodium chloride solution, then through anhydrous magnesium sulfate drying and spissated product, chromatography purification (hexane: ethyl acetate=5: 1), obtain (6E)-7-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl }-3,5-isopropylidene dioxygen base-6-heptenoic acid methyl esters (62mg, 74%), is colorless oil.Warp
1The ratio that H-NMR records E/Z is 98.2.
1H-NMR
〔α〕
20 D＝19.16°（c0.96，CHCl
3）
Rf=0.33(hexane: ethyl acetate=5: 1)
IR（CHCl
3）：3000，1730，1605，1510，1490，1380，1230，1160，1090，840cm
-1.
1H-NMR（CDCl
3）：δ7.95（d，J＝8.4Hz，1H），7.58（dd，J＝6.6，1.6Hz，1H），7.37-7.15（m，6H），6.55（dd，J＝16.3，1.2Hz，1H），5.57（dd，J＝16.3，6.1Hz，1H），4.38-4.33（m，1H），4.32-4.25（m，1H），3.71（s，3H），2.54（dd，J＝15.6，6.7Hz，1H），2.43（m，1H），2.35（dd，J＝15.6，6.4Hz，1H），1.46（s，3H），1.40-1.35（m，4H），1.37（s，3H），1.31-1.25（m，2H），1.04（dd，J＝8.1，3.3Hz，2H）.
MS（m/z）475（M
+，6），416（8），400（5），344（21），288（100），275（43）.
HRMS（Calcd.for C
29H
30O
4NF;M
+475.2149，found m/z 475，2157.
Embodiment 12
(3R, 5S)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene
Under-70 ℃, (miscellany stirred 30 minutes down at-78 ℃ then for 0.42ml, the THF solution (15ml) of { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } the first base three phenyl phosphonium bromides that 0.67mmol) join that embodiment 1 obtains with butyllithium.Under-78 ℃, add again separately preparation (3R, 5S)-6-oxo-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (208mg, 0.78mmol) THF solution (5ml), miscellany stirred 2 hours down at-78 ℃ then, the limit is warming up to the room temperature limit and spends the night again.Miscellany is according to reaction of embodiment 4 same procedure and purification, obtain (3R, 5S, 6Z)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (40mg, 40%), is the 6E-structure (200mg, 58%) of colorless oil and colourless crystallization.
The 6E-structure
Rf=0.40(hexane: ethyl acetate=5: 1)
IR（CHCl
3）：3450，3000，1720，1595，1560，1510，1490，1380，1310，1260，1220，1200，1160，1100，1030，970，950，920，840cm
-1.
1H-NMR（CDCl
3）：δ7.0-8.1（m，8H），6.4（d，J＝11Hz，1H），5.6（dd，J＝11，8Hz，1H），3.7-4.2（m，2H），2.1-2.7（m，3H），0.8-1.7（m，21H）.
MS（m/z）518（M
+H，100），462，404，386，344，316，288，274，262，220，173，154，136.
The 6E-structure
Fusing point: 46 ℃
［α］
25
D＝＋10.4°（c 1.0,CHCl
3)
The Rf=0.33(hexane: ethyl acetate=5:1)
IR（KBr）：3450，3000，1720，1595，1560，1510，1490，1380，1310，1260，1220，1200，1160，1100，1030，970，950，920，840cm
-1.
1H-NMR（CDCl
3）：60MHz,δ7-8(m,8H),6.5(d,J=16Hz,1H)5.5(dd,J=16,6Hz,1H)4.0-4.5(m,2H),2.2-2.6(m,3H),0.85-1.7(m,21H).
MS（m/z）518（M
+H，100），462，404，386，344，316，288，274，262，220，173，154，136.
Embodiment 13
(3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the preparation of 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester
Under 0 ℃, (1.24ml 2.0mmol) joins 2,2,6, and (161mg in the THF solution (5ml) 1.1mmol), stirs miscellany 15 minutes the 6-tetramethyl piperidine then with butyllithium.Again miscellany is cooled to-78 ℃, then, add { 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl } methyl oxidation phosphonic acid diphenyl ester (419mg that obtains among the embodiment therein, 0.86mmol) THF solution (5ml), then miscellany was stirred 30 minutes, add the separately (3R of preparation more therein, 5S)-6-oxo-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (294mg, 1.1mmol) THF solution (5ml), then miscellany was stirred 4 hours down at-78 ℃, at room temperature spend the night again.Miscellany is handled according to same procedure among the embodiment 6, obtain (3R, 5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-isopropylidene dioxo-6-heptenoic acid tert-butyl ester (378mg, 83%) is white crystals.High performance liquid chromatography confirms that the E/Z ratio is 95: 5.
Fusing point, (α)
25 D, R
f, IR,
1H-NMR and MS conform to 6E-structure among the embodiment 12.
Reference example 8
(4R
*, 6S
*)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5, the preparation of 6-four oxygen-2H-pyran-2-one
(170mg, methyl chloride solution (2ml) 1.5mmol) joins (3R that obtains among the embodiment 5 with trifluoro ethyl ester
*, 5S
*, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, (48mg in dichloromethane solution 0.1mmol) (5ml), at room temperature stirred miscellany 24 hours 5-isopropylidene dioxygen base-6-heptenoic acid methyl esters.The reaction soln water cooling adds 5% sodium hydrogen carbonate solution then, and miscellany extracts with methyl chloride.Then, organic layer is with the saturated nacl aqueous solution washing and through anhydrous sodium sulfate drying.Solvent steams through decompression, and resistates is through chromatogram layer utmost point purification (ethane: ethyl acetate=5: 1), obtain (4R then
*, 6S
*)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-pyran-2-one (30mg, 75%) is white crystals.
Fusing point: 201 ℃
IR（CHCl
3）：3440，3005，1730，1600，1560，1510，1490，1410，1230，1155，1060，970，830，730cm
-1.
1H-NMR（CDCl
3）：δ1.03-1.08（m，2H），1.30-1.40（m，2H），1.56-1.60（m，1H），1.78（m，1H），2.38（m，1H），2.60（ddd，J＝7.4，4.0，1.5Hz，1H），2.70（dd，J＝1.30，4.8Hz，1H），4.25（m，1H），5.18 and 4.66（m，1H，ratio 64∶36），5.62（dd，J＝16.1，6.2Hz，1H），6.72（dd，J＝16.1，1.4Hz，1H），7.17-7.25（m，4H），7.30-7.37（m，2H），7.61（dd，J＝6.1，2.1Hz，1H），7.96（d，J＝8.3Hz，1H）.
MS（m/z）403（M
+，9），316（11），288（100），274（12）.
Reference example 9
(4R, 6S)-6-2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5, the preparation of 6-tetrahydrochysene-2H-pyran-2-one
(the 3R that mentions among the embodiment 13,5S, 6E)-7-2-cyclopropyl-4-(4-fluorophenyl) and quinoline-3-yl }-3, the 5-oxo isopropylidene-6-heptenoic acid tert-butyl ester (259mg, 0.5mmol) according to visit method reaction identical among the embodiment 8 obtain (4R, 6S)-6-{ 2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-base-E-vinyl }-4-hydroxyl-3,4,5,6-tetrahydrochysene-2H-pyran-2-one (151mg, 75%) is a white crystals.
Fusing point: 139 ℃
[α]
20
D＝+9.0°（c1.0，CHCl
3）
Rf=0.19(hexane: ethyl acetate=2: 1)
IR（CHCl
3）：3440，3005，1730，1600，1560，1510，1490，1410，1230，1155，1060，970，830，730cm
-1.
1H-NMR（CDCl
3）：δ1.03-1.08（m，2H），1.30-1.40（m，2H），1.56-1.60（m，1H），1.78（m，1H），2.38（m，1H），2.60（ddd，J＝7.4，4.0，1.5Hz，1H），2.70（dd，J＝1.30，4.8Hz，1H），4.25（m，1H），5.18 and 4.66（m，1H，ratio 64∶36），5.62（dd，J＝16.1，6.2Hz，1H），6.72（dd，J＝16.1，1.4Hz，1H），7.17-7.25（m，4H），7.30-7.37（m，2H），7.61（dd，J＝6.1，2.1Hz，1H），7.96（d，J＝8.3Hz，1H）.
MS（m/z）403（M
+，9），316（11），288（100），274（12）.
The invention provides a kind of new intermediate that is used for condensed pyridine type mevalonolactone derivative, this derivative is that a kind of HMG-CoA reductase inhibitor and it are used as too high therapeutical agent of blood cholesterol or arteriosclerosis therapeutical agent, with and preparation method thereof and as the new condensed pyridine derivative of its raw material.
Claims (30)
1, the condensed pyridine type first hydroxyl of formula I or acid lactone intermediate:
Wherein encircling X is phenyl ring, the replacement hetero-aromatic ring of substituted benzene ring or 5-or 6-unit;
R
1And R
2Be hydrogen independently respectively, C
1-8Alkyl, C
3-7Cycloalkyl, C
1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, R
20R
21-(R wherein
20And R
21Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O (CH
2) eOR
22(R wherein
22Be hydrogen or C
1-3Alkyl and e are 1,2 or 3); Or R
1And R
2Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;
R
3Be hydrogen, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
5-7Cycloalkenyl group or
(R wherein
7Be hydrogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine, chloro methyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol); Or by one
(R wherein
7Be as above to limit) and zero, one or two C
1-3The C that alkyl replaced
1-3Alkyl; Z is
(R
9aAnd R
9bRepresentative is protected the group of hydroxyl and is methoxyl methyl independently, 2-methoxy (ethoxy) methyl, tetrahydropyrans respectively; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; to methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R
9aAnd R
9bBe associated in and constitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With
R
10Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, trimethyl silicon based or tertiary butyl dimethyl methyl is silica-based).
2, a kind of intermediate as claimed in claim 1, it be formula (I quinoline type mevalonolactone intermediate a):
Wherein work as R
4a, R
5aAnd R
6aBe hydrogen independently respectively, C
1-6Alkyl, C
3-7Cycloalkyl, C
1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, R
26R
27N-(is R wherein
26And R
27Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) mOR
28(R wherein
28Be hydrogen or, C
1-3Alkyl and m are 1,2 or 3); Or
R
4aAnd R
5aFormation-CH=CH-CH=CH-connects together; Or
R
4aAnd R
5aFormation-OC(R connects together
29) (R
30) O-(R wherein
29And R
30Be respectively hydrogen or, C
1-3Alkyl) when they is the ortho position mutually; With
R
1, R
2, R
3With Z as limiting in the formula I.
3, intermediate as claimed in claim 1 is the Pyrazolopyridine type mevalonolactone intermediate of formula (1b):
R wherein
4bBe hydrogen, C
1-8Alkyl, C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Alkenyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, fluorine, chlorine, bromine,
(R wherein
6b, R
7bAnd R
8bBe hydrogen independently respectively, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine ,-NR
31R
32(R wherein
31And R
32Be C independently respectively
1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) nOR
33(wherein be hydrogen or C
1-3Alkyl and n are 1,2 or 3), or
Work as R
8bWhen being hydrogen, R
6bAnd R
7bAs they (R wherein that links together during mutually at the ortho position
34And R
35Be hydrogen or C independently respectively
1-3Alkyl), or
Work as R
7bAnd R
8bWhen being hydrogen simultaneously, R
6bBe
(R wherein
3bBe hydrogen, C
1-4Alkyl, C
1-3Alkoxyl group, trifluoromethyl, chlorine, bromine or fluorine), phenyl-C
2-3Alkenyl wherein phenyl can be by C
1-4Alkyl, C
1-3Alkoxyl group, oxygen, chlorine or bromine replaces or can be selected from C by one
1-3Alkoxyl group, naphthyl and
(R wherein
6b, R
7bAnd R
B6As above limit) and zero, one or two C
1-8The C that alkyl replaces
1-3Alkyl replaces
R
5bBe to be connected on the hydrogen atom of the 1-of Pyrazolopyridine ring or 2-position, and R
5bBe hydrogen, C
1-8Alkyl is replaced C by 1-3 fluorine atom
1-3Alkyl, C
3-7Cycloalkyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl or
(R wherein
6bAnd R
8bAs above limit), or
Be selected from C by one
1-3Alkoxyl group, hydroxyl, naphthyl and
(R wherein
6b, R
7bAnd R
8bAs above limit) and zero, one or two C
1-8The C that alkyl is got
1-3Alkyl and
R
1, R
2, R
3With Z be about the qualification in the formula (1).
4, intermediate as claimed in claim 1 is a kind of formula (1c) thienopyridine type mevalonolactone intermediate:
R wherein
4cAnd R
5cBe hydrogen independently respectively, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
1-6Alkoxyl group, fluorine, chlorine, bromine,
(R wherein
6c, R
7cAnd R
8cBe hydrogen independently respectively, C
1-4Alkyl, C
1-3Alkoxyl group, C
3-7Cycloalkyl, trifluoromethyl, fluorine, chlorine and bromine), 2-, 3-or 4-pyridyl, 2-or 5-pyrimidyl, 2-or 3-thienyl, 2-or 3-furyl,
(R wherein
6cAs above limit) ,-NR
37And R
38(R wherein
37And R
38Be hydrogen independently respectively, C
1-4Alkyl,
(wherein j is 1,2 or 3, and R
6cAs above limit), or R
37And R
38Formation-C(CH together
2)
k-(wherein k is 3,4 or 5), quilt
(R wherein
6cAs above limit) and zero, one or two C
1-3Alkyl or α-or C that β-naphthalene replaced
1-3Alkyl, or
R
4cAnd R
5cConnect together and constitute C
2-6Zero to three substituting groups of alkylidene group and quilt replace, and substituting group is selected from C
1-4Alkyl, C
3-7Cycloalkyl, fluorine, zero to one substituting group of chlorine and bromine and quilt replaces, and substituting group is selected from
(R wherein
6cAs above limit), or-(CHR
39) P-A-(CHR
40) q-(wherein p and q be respectively 0,1,2 or 3, A is-(CR
41)=(CR
42)-(be R wherein
41And R
42Be respectively hydrogen or C
1-3Alkyl) ,-O-;-S-or-N(R
43Be hydrogen, C
1-4Alkyl, or
(R wherein
6cAs above limit with j)), and R
39And R
40Be hydrogen or C independently respectively
1-4Alkyl) or-CH=CH-CH=CH-; And
R
1, R
2, R
3Defined in Z such as formula I.
5, quinoline type monohydroxy valeric acid lactone intermediate as claimed in claim 2, wherein in formula (1a),
R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1, the 2-pendimethalin base, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.
Work as R
5aAnd R
6aWhen being hydrogen simultaneously, R
4aBe hydrogen preferably, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, the 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino; Or
Work as R
6aDuring for hydrogen, R
4aAnd R
5aRepresent 6-chloro-8-methyl, 6-bromo-7-methoxyl group, 6-methyl-7-chlorine, 6-chloro-8-hydroxyl together, 5-methyl-2-hydroxyl, 6-methoxy-7-chlorine, 6-chloro-7-methoxyl group, 6-hydroxyl-7-chlorine, 6-oxygen-7-hydroxyl, 6-chloro-8-bromine, 5-chloro-6-hydroxyl, 6-bromo-8-chlorine, 6-bromo-8-hydroxyl, 5-methyl-8-chlorine, 7-hydroxyl-8-chlorine, 6-bromo-8-hydroxyl, 6-methoxyl group-7-methyl, 6-chloro-8-bromine, 6-methyl-8-bromine, 6, the 7-difluoro, 6,8-difluoro, 6,7-methylene radical dioxygen base, 6,8-dichloro, 5, the 8-dimethyl, 6,8-dimethyl, 6, the 7-dimethoxy, 6, the 7-diethoxy, 6,7-dibromo or 6,8-dibromo; Or
R
4a, R
5a, R
6aRepresent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.
6, Pyrazolopyridine type mevalonate intermediate as claimed in claim 3, wherein in formula (1b),
R
3Be hydrogen, methyl, ethyl, propyl group, and propyl group, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;
R
4bBe hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-tolyl; 2-, 3-or 4-tolyl; 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-methoxyphenyl, 2-, 3-or 4-trifluoromethyl, 2-, 3-or 4-chloromethyl phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, the 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2,6-difluorophenyl, 2,3-difluorophenyl, 3,5-difluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 2,4 dichloro benzene base, 2,6-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl, 3,5-dichlorophenyl, 3,4-dichlorophenyl, 2,3-xylyl, 2,5-xylyl, 2, the 6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2, the 4-dimethoxy phenyl, 3,4-dimethoxy phenyl, 3, the 5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4, the 6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;
R
5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, the ring ethyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, Alpha-Naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.
7, the thienopyridine type first hydroxy pentane ester lactone intermediate described in claim 4, wherein in formula (1c),
R
3Be hydrogen preferably, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;
R
4cAnd R
5aBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methyl ring nonyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, the 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, the 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or
R
4cAnd R
5cThe formation that connects together ethene, trimethylene, tetramethylene, 1,5 pentylidene, methyl tetramethylene, chlorine tetramethylene or benzene tetramethylene.
8, quinoline type mevalonolactone intermediate as claimed in claim 2, wherein in formula (1a), R
1Be the contraposition fluorine, R
2, R
4a, R
5a, and R
6aBe respectively hydrogen, and R
3Be cyclopropyl.
9, Pyrazolopyridine type mevalonolactones intermediate as claimed in claim 3, wherein in formula (1b), R
1Be to fluorine, R
2Be hydrogen R
4bAnd R
5bBe respectively methyl, and R
3Be cyclopropyl.
10, thienopyridine type mevalonolactone intermediate as claimed in claim 4, wherein in formula (1c), R
1Be to fluorine, R
2Be hydrogen, R
4cBe ethyl, R
5cBe methyl, and R
3It is cyclopropyl.
11, a kind of formula (2) condensed pyridine derivative:
Wherein encircling X is phenyl ring, the replacement hetero-aromatic ring of substituted benzene ring or 5-or 6-unit;
R
1And R
2Be hydrogen independently respectively, C
1-8Alkyl, C
3-7Cycloalkyl, C
1-3Alkoxyl group, butoxy, different oxygen base, sec-butoxy, tert.-butoxy, R
20R
21-(R wherein
20And R
21Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) eOR
22(R wherein
22Be hydrogen or C
1-3Alkyl and e are 1,2 or 3); Or R
1And R
2Be associated in formation-CH=CH-CH=CH-or methylene radical dioxygen base together, when their difference are mutually on the ortho position;
R
3Be hydrogen, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
5-7Cycloalkenyl group or
(R wherein
7Be hydrogen, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine, hydrogen be for methyl, trichloromethyl, trifluoromethoxy, trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy or methylol); Or by one
(R wherein
7Be as above to limit) and zero, one or two C
1-3The C that alkyl replaced
1-3Alkyl;
Y is P
+R
11R
12R
13Hal or P(W) R
14R
15(R wherein
11, R
12And R
13Be methyl independently respectively, ethyl, propyl group, sec.-propyl, butyl, 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, five oxygen phenyl or benzyls, R
14And R
15Be respectively methyl independently, ethyl, propyl group, sec.-propyl, butyl, the 2-chloroethyl, 2,2,2-trifluoroethyl, phenyl, methoxyphenyl, tolyl, pentafluorophenyl group, benzyl, methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, 2-chloroethoxy, 2,2,2-trifluoro ethoxy, phenoxy group, methoxy phenoxy, methoxy phenoxy, penta fluoro benzene oxygen base or benzyloxy, or R
14And R
15Be associated in and constitute 5-or 6-unit ring together, halogen is a chlorine, and bromine or iodine and W are O or S.
12, derivative as claimed in claim 11 wherein is the quinoline of formula (2a):
Wherein work as R
4a, R
5aAnd R
6aBe hydrogen independently respectively, C
1-6Alkyl, C
3-7Cycloalkyl, C
1-3Alkoxyl group, butoxy, isobutoxy, sec-butoxy, R
26R
27N-(is R wherein
26And R
27Be hydrogen or C independently respectively
1-3Alkyl), trifluoromethyl, trifluoromethoxy, difluoro-methoxy, fluorine, chlorine, bromine, phenyl, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) mOR
28(R wherein
28Be hydrogen or, C
1-3Alkyl and m are 1,2 or 3); Or
R
4aAnd R
5aFormation-CH=CH-CH=CH-connects together; Or
R
4aAnd R
5aFormation-OC(R connects together
29) (R
30) O-(R wherein
29And R
30Be respectively hydrogen or, C
1-3Alkyl) when they is the ortho position mutually; And
R
1, R
2, R
3With Y suc as formula defined in (2).
13, derivative as claimed in claim 11 is the ratio azoles and the pyridine derivate of formula (2b):
R wherein
4bBe hydrogen, C
1-8Alkyl, C
1-6Alkoxyl group, C
3-7Cycloalkyl, C
2-6Alkenyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl, fluorine, chlorine, bromine,
(R wherein
6b, R
7bAnd R
8bBe hydrogen independently respectively, C
1-8Alkyl, C
1-8Alkoxyl group, C
1-3Alkylthio, chlorine, bromine, fluorine ,-NR
31R
32(R wherein
31And R
32Be C independently respectively
1-3Alkyl), chloromethyl, trichloromethyl, trifluoromethyl, trifluoromethoxy, the trichlorine methoxyl group, difluoro-methoxy, phenoxy group, benzyloxy, hydroxyl, the trimethylammonium silyloxy, phenylbenzene-uncle's fourth siloxy, methylol or-O(CH
2) nOR
33(R wherein
33Be hydrogen or, C
1-3Alkyl and n are 1,2 or 3), or
Work as R
8bWhen being hydrogen, R
6bAnd R
7bWhen linking together during mutually at the ortho position, they form OC(R
34) (R
35) O-(R wherein
34And R
35Be hydrogen or C independently respectively
1-3Or work as R alkyl),
7bAnd R
8bWhen being hydrogen simultaneously, R
6bBe
(R wherein
3bBe hydrogen, C
1-4Alkyl, C
1-3Alkoxyl group, trifluoromethyl, chlorine, bromine or fluorine), phenyl-C
2-3Alkenyl wherein phenyl can be by C
1-4Alkyl, C
1-3Alkoxyl group, oxygen, chlorine or bromine replaces or can be selected from C by one
1-3Alkoxyl group, naphthyl and
(R wherein
6b, R
7bAnd R
6bAs above limit) and zero, one or two C
1-8The C that alkyl replaces
1-3Alkyl replaces
R
5bBe to be connected on the hydrogen atom of the 1-of Pyrazolopyridine ring or 2-position, and R
5bBe hydrogen, C
1-8Alkyl is replaced C by 1-3 fluorine atom
1-3Alkyl, C
3-7Cycloalkyl, α-or betanaphthyl, 2-, 3-or 4-pyridyl, 2-or 3-thienyl, 2-or 3-furyl or
(R wherein
6bAnd R
8bAs above limit) or
Be selected from C by one
1-3Alkoxyl group, hydroxyl, naphthyl and
(R wherein
6b, R
7bAnd R
8bAs above limit) and zero, one or two C
1-8The C that alkyl replaced
1-3Alkyl and
R
1, R
2, R
3With Z be about the qualification in the formula (1).
14, derivative as claimed in claim 11 is the thienopyridine derivative of formula (2c):
R wherein
4cAnd R
5cBe hydrogen independently respectively, C
1-8Alkyl, C
2-6Alkenyl, C
3-7Cycloalkyl, C
1-6Alkoxyl group, fluorine, chlorine, bromine,
(R wherein
6c, R
7cAnd R
8cBe hydrogen independently respectively, C
1-4Alkyl, C
1-3Alkoxyl group, C
3-7Cycloalkyl, trifluoromethyl, fluorine, chlorine and bromine), 2-, 3-or 4-pyridyl, 2-or 5-pyrimidyl, 2-or 3-thienyl, 2-or 3-furyl,
(R wherein
6cAs above limit) ,-NR
37And R
38(R wherein
37And R
38Be hydrogen independently respectively, C
1-4Alkyl,
(wherein j is 1,2 or 3, and R
6cAs above limit), or R
37And R
38Formation-C(CH together
2)
k-(wherein k is 3,4 or 5), quilt
(R wherein
6cAs above limit) and zero, one or two C
1-3Alkyl or α-or C that β-naphthalene replaced
1-3Alkyl, or
R
4cAnd R
5cConnect together and constitute C
2-6Zero to three substituting groups of alkylidene group and quilt replace, and substituting group is selected from C
1-4Alkyl, C
3-7Cycloalkyl, fluorine, zero to one substituting group of chlorine and bromine and quilt replaces, and substituting group is selected from
(R wherein
6cAs above limit), or-(CHR
39) P-A-(CHR
40) q-(wherein p and q be respectively 0,1,2 or 3, A is-(CR
41)=(CR
42)-(be R wherein
41And R
42Be respectively hydrogen or C
1-3Alkyl) ,-O-;-S-or-N(R
43)-(be R wherein
43Be hydrogen, C
1-4Alkyl, or
(R wherein
6cAs above limit with j)), and R
39And R
40Be hydrogen or C independently respectively
1-4Alkyl) or-CH=CH-CH=CH-; And
R
1, R
2, R
3Defined in Y such as formula I.
15, the quinoline described in claim 12, wherein in formula (2a),
R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1, the 2-3,5-dimethylphenyl, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-two basic phenyl, 3,4-diformazan chloro-phenyl-, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.
Work as R
5aAnd R
6aWhen being hydrogen simultaneously, R
4aBe hydrogen, 5-fluorine, 6-fluorine, 7-fluorine, 8-fluorine, 5-chlorine, 6-chlorine, 7-chlorine, 8-chlorine, 5-bromine, 6-bromine, 7-bromine, the 8-bromine, 5-methyl, 6-methyl, 7-methyl, 8-methyl, 5-methoxyl group, the 6-methoxyl group, 7-methoxyl group, 8-methoxyl group, 5-trifluoromethyl, 6-trifluoromethyl, 7-trifluoromethyl, the 8-trifluoromethyl, 6-trifluoromethoxy, 6-difluoro-methoxy, 8-hydroxyethyl, 5-hydroxyl, the 6-hydroxyl, 7-hydroxyl, 8-hydroxyl, 6-ethyl, 6-butyl or 7-dimethylamino; Or
Work as R
6aDuring for hydrogen, R
4aAnd R
5aRepresent 6-chloro-8-methyl, 6-bromo-7-methoxyl group, 6-methyl-7-chlorine, 6-chloro-8-hydroxyl together, 5-methyl-2-hydroxyl, 6-methoxy-7-chlorine, 6-chloro-7-methoxyl group, 6-hydroxyl-7-chlorine, 6-oxygen-7-hydroxyl, 6-chloro-8-bromine, 5-chloro-6-hydroxyl, 6-bromo-8-chlorine, 6-bromo-8-hydroxyl, 5-methyl-8-chlorine, 7-hydroxyl-8-chlorine, 6-bromo-8-hydroxyl, 6-methoxyl group-7-methyl, 6-chloro-8-bromine, 6-methyl-8-bromine, 6, the 7-difluoro, 6,8-difluoro, 6,7-methylene radical dioxygen base, 6,8-dichloro, 5, the 8-dimethyl, 6,8-dimethyl, 6, the 7-dimethoxy, 6, the 7-diethoxy, 6,7-dibromo or 6,8-dibromo; Or
R
4a, R
5aAnd R
6aRepresent 5,7-dimethoxy-8-hydroxyl, 5,8-two chloro-6-hydroxyls, 6,7,8-trimethoxy, 6,7,8-trimethylammonium, 6,7,8-trichlorine, 5-fluoro-6,8-dibromo or 5-chloro-6,8-dibromo together.
16, pyrazolo pyridine derivatives as claimed in claim 13, wherein in formula (2b),
R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1,2-dimethyl amyl group, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl;
R
4bBe hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, cyclopropyl, cyclohexyl, phenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-methoxyphenyl 2-, 3-or 4-trichlorophenyl, 2-, 3-or 4-fluorine add basic phenyl, 3-or 4-phenelyl, 4-(2-first butyl) phenyl, 4-heptyl phenyl, the hot phenyl of 4-, 4-penta phenyl, the own phenyl of 4-, 4-propyl phenyl, 4-butylbenzene base, 4-butylbenzene base, 4-trimethylphenylmethane base, 4-butoxyphenyl, 4-penta oxygen phenyl, the own oxygen phenyl of 4-, 4-oxygen in heptan phenyl, the hot oxygen phenyl of 4-, 4-Phenoxyphenyl, 4-biphenylyl, 4-trichloroanisole base, 2,4 difluorobenzene base, 2, the 6-difluorophenyl, 2,3-difluorophenyl, 3, the 5-difluorophenyl, 2,5-difluorophenyl, 3, the 4-difluorophenyl, 2,4 dichloro benzene base, 2, the 6-dichlorophenyl, 2,3-dichlorophenyl, 2, the 5-dichlorophenyl, 3,5-dichlorophenyl, 3, the 4-dichlorophenyl, 2,3-xylyl, 2, the 5-xylyl, 2,6-xylyl, 3, the 4-xylyl, 2,5-dimethoxy phenyl, 2, the 6-dimethoxy phenyl, 2,4-dimethoxy phenyl, 3, the 4-dimethoxy phenyl, 3,5-dimethoxy phenyl, 3, two (trifluoromethyl) phenyl of 5-, 3,4-methylene radical dioxygen phenyl, 2,4,6-trimethoxyphenyl, 3,4-methylene radical dioxo phenyl, 2,4,6-trimethoxyphenyl, 3,4,5-trimethylphenyl or 2,4,6-triisopropyl phenyl;
R
5bBe on the nitrogen-atoms that is attached on 1 of Pyrazolopyridine ring and be methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, 2,2,2-trifluoroethyl, 2-hydroxyethyl, cyclohexyl, benzyl, 2-benzyl chloride base, 2-acrinyl, 3-fluoroform benzyl, 2-styroyl, phenyl, 2-, 3-or 4-chloro-phenyl-, 2-, 3-or 4-bromophenyl, 2-, 3-or 4-fluorophenyl, 2-, 3-or 4-tolyl, 2-, 3-or 4-trifluoromethyl, 3-or 4-methoxyphenyl, 2-hydroxyphenyl, 4-cumyl, the 4-tert-butyl-phenyl, 4-trifluoromethoxy benzaldehyde base, 2,3-dichlorophenyl, the 2,4 dichloro benzene base, 2, the 5-dichlorophenyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,4,6-trichlorophenyl, 2,3,4-trifluorophenyl, 2, the 4-difluorophenyl, 3, two (trifluoromethyl) phenyl of 5-, 3-chloro-4-tolyl, 3-chloro-6-tolyl, 4-chloro-2-tolyl, 2-chloro-6-tolyl, 2-chloro-6-fluorophenyl, 2-chloro-5-fluoroform phenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-chloro-phenyl-, 2-chloro-4-fluoroform phenyl, 3-fluoro-6-tolyl, 2-naphthyl, 2-pyridyl, 3-methyl-5-trifluoromethyl-2-pyridyl, 4-pyridyl or 2,6-two chloro-4-pyridyl.
17, thiazole as claimed in claim 14 and pyridine derivate, wherein in formula (2c),
R
3Be hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, isopentyl, 1, the 2-pendimethalin base, hexyl, heptyl, octyl group, vinyl, 1-propenyl, 1-methyl ethylene, 1-methyl isophthalic acid-propenyl, 2-methyl isophthalic acid-propenyl, 1,2-dimethyl-1-propenyl, cyclopropyl, cyclobutyl, cyclohexyl, 1-methyl cyclopropyl, 2-methyl cyclopropyl, phenyl, 2-aminomethyl phenyl, 3-aminomethyl phenyl, 4-aminomethyl phenyl, the 2-chloro-phenyl-, 3-chloro-phenyl-, 4-chloro-phenyl-, 2-methoxyphenyl, the 3-methoxyphenyl, 4-methoxyphenyl, 3,4-3,5-dimethylphenyl, 3,4-dichlorophenyl, 3-fluoroform phenyl, benzyl, 4-benzyl chloride base, 4-xylyl, 4-methoxybenzyl, 2-styroyl or 1-xylyl.
R
4cAnd R
5cBe hydrogen independently respectively, methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group, 1,2-pendimethalin base, hexyl, heptyl, octyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-methylcyclohexyl, suberyl, cyclopropyl methyl, vinyl, 1-methyl ethylene, the 1-propenyl, allyl group, 1-methyl isophthalic acid-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, crotyl, 1-ethyl vinyl, 1,2-dimethyl-1-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl, 1-methyl isophthalic acid-butenyl, 1-methyl-2-butene base, 2-methyl-1-butene thiazolinyl, 1-isopropyl-ethylene base, 1-methyl-1-pentene thiazolinyl or phenyl; Or
R
4cAnd R
5cThe formation that connects together ethene, trimethylene tetramethylene, 1,5 pentylidene, methyl tetramethylene, chlorine tetramethylene or benzene tetramethylene.
18, quinoline as claimed in claim 12, in its Chinese style (2a), R
1Be contraposition-fluorine, R
2, R
4a, R
5aAnd R
6aBe respectively hydrogen, and R
3Be cyclopropyl.
19, pyrazolo pyridine derivatives as claimed in claim 13, wherein in formula (2b), R
1Be contraposition-fluorine, R
2Be hydrogen, R
4bAnd R
5bBe respectively methyl, and R
3It is cyclopropyl.
20, thiazole as claimed in claim 14 and pyridine derivate, wherein in formula (2c), R
1Be contraposition-fluorine, R
2Be hydrogen, R
4cBe ethyl, R
5cBe methyl, and R
3It is cyclopropyl.
21, a kind of compound for preparing the formula (1) that claim 1 limits comprising as formula (2) compound and alkali reaction that claim 11 limited, forms negatively charged ion, and then with formula (3) compound condensation:
R wherein
9aAnd R
9bBe respectively to protect the group of hydroxyl and be methoxyl methyl, 2-methoxy (ethoxy) methyl, tetrahydropyrans independently; 4-methoxy THP trtrahydropyranyl; the 1-ethoxyethyl, 1-methyl isophthalic acid-methoxyethyl, allyl group; benzyl; to methoxybenzyl, trityl, the trimethylammonium first is silica-based; tertiary butyl dimethyl methyl is silica-based or tertiary butyl hexichol is silica-based, or R
9aAnd R
9bConstitute isopropylidene together, ring pentylidene, cyclohexylene or benzylidene; With
R
10Be methyl, ethyl, propyl group, sec.-propyl, the tertiary butyl, THP trtrahydropyranyl, allyl group, benzyl, trityl group, the trimethylammonium first is silica-based or tertiary butyl dimethyl methyl is silica-based.
22, as the preparation method of formula (1a) compound that claim 2 limited, comprise formula (2a) compound and the alkali reaction that limit as claim 10, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
23, as the preparation method of formula (1b) compound that claim 3 limited, comprise formula (2b) compound and the alkali reaction that limit as claim 13, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
24, as the preparation method of formula (1c) compound that claim 4 limited, comprise formula (2c) compound and the alkali reaction that limit as claim 14, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
25, as the quinoline type first hydroxyl valerolactone intermediates preparation that claim 5 limited, comprise the quinoline and the alkali reaction that limit as claim 15, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
26, as Pyrazolopyridine type first hydroxyl valerolactone intermediates preparation that claim 6 limited, comprise the pyrazolo pyridine derivatives and the alkali reaction that limit as claim 16, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
27, as thiazole and pyridine type first hydroxyl valerolactone intermediates preparation that claim 7 limited, comprise the thiazole and pyrazole derivatives and the alkali reaction that limit as claim 17, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
28, as the quinoline type first hydroxyl valerolactone intermediates preparation that claim 8 limited, comprise the quinoline and the alkali reaction that limit as claim 18, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
29, as Pyrazolopyridine first hydroxyl valerolactone intermediates preparation that claim 9 limited, comprise the pyrazolo pyridine derivatives and the alkali reaction that limit as claim 19, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
30, as thiazole and pyridine type first hydroxyl valerolactone intermediates preparation that claim 10 limited, comprise the thiazole and pyridine derivate and the alkali reaction that limit as claim 20, form negatively charged ion, again formula (3) compound condensation that is limited with claim 21.
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| CN 93114352 CN1102644A (en) | 1993-11-11 | 1993-11-11 | Condensed pyridine type mevalonolactone intermediate and process for its production |
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| CN 93114352 CN1102644A (en) | 1993-11-11 | 1993-11-11 | Condensed pyridine type mevalonolactone intermediate and process for its production |
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100445267C (en) * | 2005-10-21 | 2008-12-24 | 上海医药工业研究院 | Process for preparing 4-(4-fluoro-phenyl)-3- hydroxymethyl-2- cyclopropyl-quinoline |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
| CN103508946A (en) * | 2012-06-20 | 2014-01-15 | 徐州万邦金桥制药有限公司 | Preparation method of pitavastatin calcium |
| US9156845B2 (en) | 2012-06-29 | 2015-10-13 | Pfizer Inc. | 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors |
| CN106749403A (en) * | 2016-12-08 | 2017-05-31 | 广东省测试分析研究所（中国广州分析测试中心） | A kind of flame-retardant luminous bifunctional material of difluorophenyl quinoline phosphine oxide and preparation method thereof |
| US9695171B2 (en) | 2013-12-17 | 2017-07-04 | Pfizer Inc. | 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors |
| US10039753B2 (en) | 2015-09-14 | 2018-08-07 | Pfizer Inc. | Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors |
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1993
- 1993-11-11 CN CN 93114352 patent/CN1102644A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100445267C (en) * | 2005-10-21 | 2008-12-24 | 上海医药工业研究院 | Process for preparing 4-(4-fluoro-phenyl)-3- hydroxymethyl-2- cyclopropyl-quinoline |
| CN102174039A (en) * | 2011-03-10 | 2011-09-07 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
| CN102174039B (en) * | 2011-03-10 | 2013-11-06 | 上海交通大学 | Preparation method of high-optical-purity pitavastatin calcium key intermediate |
| CN103508946A (en) * | 2012-06-20 | 2014-01-15 | 徐州万邦金桥制药有限公司 | Preparation method of pitavastatin calcium |
| CN103508946B (en) * | 2012-06-20 | 2016-06-29 | 徐州万邦金桥制药有限公司 | The preparation method of Pitavastatin Calcium |
| US9156845B2 (en) | 2012-06-29 | 2015-10-13 | Pfizer Inc. | 4-(substituted amino)-7H-pyrrolo[2,3-d] pyrimidines as LRRK2 inhibitors |
| US9642855B2 (en) | 2012-06-29 | 2017-05-09 | Pfizer Inc. | Substituted pyrrolo[2,3-d]pyrimidines as LRRK2 inhibitors |
| US9695171B2 (en) | 2013-12-17 | 2017-07-04 | Pfizer Inc. | 3,4-disubstituted-1 H-pyrrolo[2,3-b]pyridines and 4,5-disubstituted-7H-pyrrolo[2,3-c]pyridazines as LRRK2 inhibitors |
| US10039753B2 (en) | 2015-09-14 | 2018-08-07 | Pfizer Inc. | Imidazo[4,5-c]quinoline and imidazo[4,5-c][1,5]naphthyridine derivatives as LRRK2 inhibitors |
| CN106749403A (en) * | 2016-12-08 | 2017-05-31 | 广东省测试分析研究所（中国广州分析测试中心） | A kind of flame-retardant luminous bifunctional material of difluorophenyl quinoline phosphine oxide and preparation method thereof |
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