CN1069976A - 环己烷和四氢吡喃衍生物 - Google Patents
环己烷和四氢吡喃衍生物 Download PDFInfo
- Publication number
- CN1069976A CN1069976A CN92108659A CN92108659A CN1069976A CN 1069976 A CN1069976 A CN 1069976A CN 92108659 A CN92108659 A CN 92108659A CN 92108659 A CN92108659 A CN 92108659A CN 1069976 A CN1069976 A CN 1069976A
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- CN
- China
- Prior art keywords
- methyl
- methoxyl group
- dimethyl
- base
- pyrans
- Prior art date
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- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 title claims description 11
- 150000003527 tetrahydropyrans Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 99
- 239000002585 base Substances 0.000 claims description 267
- JRZJOMJEPLMPRA-UHFFFAOYSA-N 1-nonene Chemical compound CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims description 184
- 239000000203 mixture Substances 0.000 claims description 130
- -1 (glycyl) amino Chemical group 0.000 claims description 122
- 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 88
- DHMQDGOQFOQNFH-UHFFFAOYSA-M Aminoacetate Chemical compound NCC([O-])=O DHMQDGOQFOQNFH-UHFFFAOYSA-M 0.000 claims description 72
- 238000002360 preparation method Methods 0.000 claims description 72
- 238000000034 method Methods 0.000 claims description 61
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 50
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 47
- 238000006243 chemical reaction Methods 0.000 claims description 42
- SNTWKPAKVQFCCF-UHFFFAOYSA-N 2,3-dihydro-1h-triazole Chemical compound N1NC=CN1 SNTWKPAKVQFCCF-UHFFFAOYSA-N 0.000 claims description 41
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 claims description 41
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 29
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 28
- RAXXELZNTBOGNW-UHFFFAOYSA-N 1H-imidazole Chemical class C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims description 26
- 125000003282 alkyl amino group Chemical group 0.000 claims description 24
- 229910021529 ammonia Inorganic materials 0.000 claims description 22
- KXDAEFPNCMNJSK-UHFFFAOYSA-N Benzamide Chemical compound NC(=O)C1=CC=CC=C1 KXDAEFPNCMNJSK-UHFFFAOYSA-N 0.000 claims description 21
- 239000001301 oxygen Substances 0.000 claims description 20
- 229910052760 oxygen Inorganic materials 0.000 claims description 20
- 125000000217 alkyl group Chemical group 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 239000001257 hydrogen Substances 0.000 claims description 18
- 229910052739 hydrogen Inorganic materials 0.000 claims description 18
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 15
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 14
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 14
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 14
- 150000002148 esters Chemical class 0.000 claims description 13
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 12
- 150000003839 salts Chemical class 0.000 claims description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 11
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052783 alkali metal Inorganic materials 0.000 claims description 8
- 125000004414 alkyl thio group Chemical group 0.000 claims description 8
- JMANVNJQNLATNU-UHFFFAOYSA-N oxalonitrile Chemical compound N#CC#N JMANVNJQNLATNU-UHFFFAOYSA-N 0.000 claims description 8
- 125000006239 protecting group Chemical group 0.000 claims description 8
- MGRVRXRGTBOSHW-UHFFFAOYSA-N (aminomethyl)phosphonic acid Chemical class NCP(O)(O)=O MGRVRXRGTBOSHW-UHFFFAOYSA-N 0.000 claims description 7
- 239000004471 Glycine Substances 0.000 claims description 7
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 150000002460 imidazoles Chemical class 0.000 claims description 7
- 241000233866 Fungi Species 0.000 claims description 6
- 125000001539 acetonyl group Chemical group [H]C([H])([H])C(=O)C([H])([H])* 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 6
- AFFLGGQVNFXPEV-UHFFFAOYSA-N 1-decene Chemical compound CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 claims description 5
- DXGMMGATZRQTEO-UHFFFAOYSA-N 2-amino-1-$l^{1}-oxidanylethanone Chemical compound NCC([O])=O DXGMMGATZRQTEO-UHFFFAOYSA-N 0.000 claims description 5
- 238000007126 N-alkylation reaction Methods 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 5
- 125000002947 alkylene group Chemical group 0.000 claims description 5
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 4
- 206010061217 Infestation Diseases 0.000 claims description 4
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 claims description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
- 125000002252 acyl group Chemical group 0.000 claims description 3
- 239000004599 antimicrobial Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical group [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 3
- 125000004076 pyridyl group Chemical group 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-M methanesulfonate group Chemical class CS(=O)(=O)[O-] AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 2
- 125000001624 naphthyl group Chemical group 0.000 claims description 2
- 125000005493 quinolyl group Chemical group 0.000 claims description 2
- 125000001567 quinoxalinyl group Chemical group N1=C(C=NC2=CC=CC=C12)* 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- WJKHJLXJJJATHN-UHFFFAOYSA-N triflic anhydride Chemical compound FC(F)(F)S(=O)(=O)OS(=O)(=O)C(F)(F)F WJKHJLXJJJATHN-UHFFFAOYSA-N 0.000 claims description 2
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 3
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical class C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 claims 1
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 claims 1
- 150000001350 alkyl halides Chemical class 0.000 claims 1
- 150000003851 azoles Chemical class 0.000 claims 1
- 239000000470 constituent Substances 0.000 claims 1
- 125000000951 phenoxy group Chemical group [H]C1=C([H])C([H])=C(O*)C([H])=C1[H] 0.000 claims 1
- 150000003008 phosphonic acid esters Chemical class 0.000 claims 1
- 150000003852 triazoles Chemical class 0.000 claims 1
- 230000001857 anti-mycotic effect Effects 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 210
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 153
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 131
- 238000005160 1H NMR spectroscopy Methods 0.000 description 115
- 238000002451 electron ionisation mass spectrometry Methods 0.000 description 104
- 239000000243 solution Substances 0.000 description 104
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 88
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 80
- 238000003756 stirring Methods 0.000 description 65
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 58
- 238000005406 washing Methods 0.000 description 48
- 238000001035 drying Methods 0.000 description 44
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 43
- 239000012230 colorless oil Substances 0.000 description 41
- 235000019439 ethyl acetate Nutrition 0.000 description 39
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 38
- 239000012141 concentrate Substances 0.000 description 36
- 238000000605 extraction Methods 0.000 description 34
- 239000003480 eluent Substances 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 31
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 31
- 238000010898 silica gel chromatography Methods 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 230000006837 decompression Effects 0.000 description 22
- 239000010410 layer Substances 0.000 description 22
- 238000000746 purification Methods 0.000 description 21
- FOEYMRPOKBCNCR-UHFFFAOYSA-N spiro[2.5]octane Chemical compound C1CC11CCCCC1 FOEYMRPOKBCNCR-UHFFFAOYSA-N 0.000 description 18
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 17
- 235000002639 sodium chloride Nutrition 0.000 description 17
- 229920002554 vinyl polymer Polymers 0.000 description 17
- 239000012044 organic layer Substances 0.000 description 16
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonium chloride Substances [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 15
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 15
- 239000012043 crude product Substances 0.000 description 15
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 14
- 239000000706 filtrate Substances 0.000 description 14
- 238000004809 thin layer chromatography Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 12
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 12
- 239000002904 solvent Substances 0.000 description 12
- 229920006395 saturated elastomer Polymers 0.000 description 11
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 10
- 239000002253 acid Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 10
- GQKZBCPTCWJTAS-UHFFFAOYSA-N methoxymethylbenzene Chemical compound COCC1=CC=CC=C1 GQKZBCPTCWJTAS-UHFFFAOYSA-N 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 229910000104 sodium hydride Inorganic materials 0.000 description 10
- 239000000725 suspension Substances 0.000 description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 9
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 9
- 235000014347 soups Nutrition 0.000 description 9
- 238000009834 vaporization Methods 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 8
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 8
- 239000007788 liquid Substances 0.000 description 8
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 8
- 239000000741 silica gel Substances 0.000 description 8
- 229910002027 silica gel Inorganic materials 0.000 description 8
- 229960001866 silicon dioxide Drugs 0.000 description 8
- 239000012312 sodium hydride Substances 0.000 description 8
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 7
- IKHGUXGNUITLKF-XPULMUKRSA-N acetaldehyde Chemical compound [14CH]([14CH3])=O IKHGUXGNUITLKF-XPULMUKRSA-N 0.000 description 7
- 235000019270 ammonium chloride Nutrition 0.000 description 7
- 230000000845 anti-microbial effect Effects 0.000 description 7
- 238000004587 chromatography analysis Methods 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 7
- 150000002431 hydrogen Chemical class 0.000 description 7
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 6
- 150000001721 carbon Chemical group 0.000 description 6
- 239000006185 dispersion Substances 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 6
- 239000012280 lithium aluminium hydride Substances 0.000 description 6
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 description 6
- UAYWVJHJZHQCIE-UHFFFAOYSA-L zinc iodide Chemical compound I[Zn]I UAYWVJHJZHQCIE-UHFFFAOYSA-L 0.000 description 6
- 239000003054 catalyst Substances 0.000 description 5
- 230000008030 elimination Effects 0.000 description 5
- 238000003379 elimination reaction Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 238000003818 flash chromatography Methods 0.000 description 5
- 150000002576 ketones Chemical class 0.000 description 5
- 239000002609 medium Substances 0.000 description 5
- 230000004048 modification Effects 0.000 description 5
- 238000012986 modification Methods 0.000 description 5
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 229910052938 sodium sulfate Inorganic materials 0.000 description 5
- 235000011152 sodium sulphate Nutrition 0.000 description 5
- 239000003826 tablet Substances 0.000 description 5
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Natural products C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 5
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 4
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 description 4
- YXHKONLOYHBTNS-UHFFFAOYSA-N Diazomethane Chemical compound C=[N+]=[N-] YXHKONLOYHBTNS-UHFFFAOYSA-N 0.000 description 4
- 241000406668 Loxodonta cyclotis Species 0.000 description 4
- PCLIMKBDDGJMGD-UHFFFAOYSA-N N-bromosuccinimide Chemical compound BrN1C(=O)CCC1=O PCLIMKBDDGJMGD-UHFFFAOYSA-N 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 4
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 4
- 239000002775 capsule Substances 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 description 4
- 239000002244 precipitate Substances 0.000 description 4
- 150000003222 pyridines Chemical class 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical compound [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 description 4
- WMZNGTSLFSJHMZ-UHFFFAOYSA-N 3-methoxycarbonylbenzoic acid Chemical compound COC(=O)C1=CC=CC(C(O)=O)=C1 WMZNGTSLFSJHMZ-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 3
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 238000010934 O-alkylation reaction Methods 0.000 description 3
- KKMYOXXLGLLLOY-VANKVMQKSA-N O[C@@H]1CO[C@@H](C#N)[C@H](O)[C@H]1O Chemical compound O[C@@H]1CO[C@@H](C#N)[C@H](O)[C@H]1O KKMYOXXLGLLLOY-VANKVMQKSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- UCTLHLZWKJIXJI-LXIBVNSESA-N [(3s,8r,9s,10r,13s,14s)-17-chloro-16-formyl-10,13-dimethyl-2,3,4,7,8,9,11,12,14,15-decahydro-1h-cyclopenta[a]phenanthren-3-yl] acetate Chemical compound C([C@@H]12)C[C@]3(C)C(Cl)=C(C=O)C[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)C)C1 UCTLHLZWKJIXJI-LXIBVNSESA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N acetone Substances CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 230000007059 acute toxicity Effects 0.000 description 3
- 231100000403 acute toxicity Toxicity 0.000 description 3
- 125000003710 aryl alkyl group Chemical group 0.000 description 3
- JXLHNMVSKXFWAO-UHFFFAOYSA-N azane;7-fluoro-2,1,3-benzoxadiazole-4-sulfonic acid Chemical compound N.OS(=O)(=O)C1=CC=C(F)C2=NON=C12 JXLHNMVSKXFWAO-UHFFFAOYSA-N 0.000 description 3
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 3
- SRBFZHDQGSBBOR-KKQCNMDGSA-N beta-D-xylose Chemical compound O[C@@H]1CO[C@@H](O)[C@H](O)[C@H]1O SRBFZHDQGSBBOR-KKQCNMDGSA-N 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
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- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
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- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
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- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
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- CXHHBNMLPJOKQD-UHFFFAOYSA-M methyl carbonate Chemical compound COC([O-])=O CXHHBNMLPJOKQD-UHFFFAOYSA-M 0.000 description 1
- RDOXTESZEPMUJZ-UHFFFAOYSA-N methyl phenyl ether Natural products COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 description 1
- 230000001035 methylating effect Effects 0.000 description 1
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 1
- 239000011785 micronutrient Substances 0.000 description 1
- 235000013369 micronutrients Nutrition 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
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- DEDOPGXGGQYYMW-UHFFFAOYSA-N molinate Chemical compound CCSC(=O)N1CCCCCC1 DEDOPGXGGQYYMW-UHFFFAOYSA-N 0.000 description 1
- 125000005322 morpholin-1-yl group Chemical group 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- UJQMLHKSZKBMMO-UHFFFAOYSA-N n,n-diethylethanamine;pyridine Chemical compound C1=CC=NC=C1.CCN(CC)CC UJQMLHKSZKBMMO-UHFFFAOYSA-N 0.000 description 1
- OKDQKPLMQBXTNH-UHFFFAOYSA-N n,n-dimethyl-2h-pyridin-1-amine Chemical compound CN(C)N1CC=CC=C1 OKDQKPLMQBXTNH-UHFFFAOYSA-N 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- ONDXXAPHPJPFKQ-UHFFFAOYSA-N n-[bis(dimethylamino)phosphoryl]-n-methylmethanamine;oxolane Chemical compound C1CCOC1.CN(C)P(=O)(N(C)C)N(C)C ONDXXAPHPJPFKQ-UHFFFAOYSA-N 0.000 description 1
- 125000003136 n-heptyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 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 description 1
- 239000012434 nucleophilic reagent Substances 0.000 description 1
- 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 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
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- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000033116 oxidation-reduction process Effects 0.000 description 1
- 125000001037 p-tolyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-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
- PMOIAJVKYNVHQE-UHFFFAOYSA-N phosphanium;bromide Chemical compound [PH4+].[Br-] PMOIAJVKYNVHQE-UHFFFAOYSA-N 0.000 description 1
- 125000000612 phthaloyl group Chemical group C(C=1C(C(=O)*)=CC=CC1)(=O)* 0.000 description 1
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- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005344 pyridylmethyl group Chemical group [H]C1=C([H])C([H])=C([H])C(=N1)C([H])([H])* 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 210000000664 rectum Anatomy 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910001925 ruthenium oxide Inorganic materials 0.000 description 1
- WOCIAKWEIIZHES-UHFFFAOYSA-N ruthenium(iv) oxide Chemical compound O=[Ru]=O WOCIAKWEIIZHES-UHFFFAOYSA-N 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
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- 239000007929 subcutaneous injection Substances 0.000 description 1
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- 238000005694 sulfonylation reaction Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- IBOQFKOBXMBSIQ-UHFFFAOYSA-N tert-butyl (4,6-dimethylpyridin-2-yl)sulfanylformate Chemical compound CC1=CC(C)=NC(SC(=O)OC(C)(C)C)=C1 IBOQFKOBXMBSIQ-UHFFFAOYSA-N 0.000 description 1
- RUPAXCPQAAOIPB-UHFFFAOYSA-N tert-butyl formate Chemical group CC(C)(C)OC=O RUPAXCPQAAOIPB-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229950004288 tosilate Drugs 0.000 description 1
- 239000012745 toughening agent Substances 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- RSJKGSCJYJTIGS-UHFFFAOYSA-N undecane Chemical compound CCCCCCCCCCC RSJKGSCJYJTIGS-UHFFFAOYSA-N 0.000 description 1
- 239000006216 vaginal suppository Substances 0.000 description 1
- 229940120293 vaginal suppository Drugs 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000009333 weeding Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/02—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms
- A01N43/04—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom
- A01N43/14—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings
- A01N43/16—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with one or more oxygen or sulfur atoms as the only ring hetero atoms with one hetero atom six-membered rings with oxygen as the ring hetero atom
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/64—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with three nitrogen atoms as the only ring hetero atoms
- A01N43/647—Triazoles; Hydrogenated triazoles
- A01N43/653—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/90—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having two or more relevant hetero rings, condensed among themselves or with a common carbocyclic ring system
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N49/00—Biocides, pest repellants or attractants, or plant growth regulators, containing compounds containing the group, wherein m+n>=1, both X together may also mean —Y— or a direct carbon-to-carbon bond, and the carbon atoms marked with an asterisk are not part of any ring system other than that which may be formed by the atoms X, the carbon atoms in square brackets being part of any acyclic or cyclic structure, or the group, wherein A means a carbon atom or Y, n>=0, and not more than one of these carbon atoms being a member of the same ring system, e.g. juvenile insect hormones or mimics thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
- C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
-
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Abstract
式(I)中其符号具有在说明书中给定含义的化
合物具有抗真菌活性。
Description
本发明叙及新颖的环己烷及四氢吡喃衍生物以及它们的制备工艺、含这些化合物的抗菌组合物以及在抗菌方面的应用。
已知由青霉属培养产生的3-四氢吡喃基的酯具有杀菌活性(美国专利No.4,952,604)。然而已知的3-四氢吡喃酯以杀菌活性和稳定性来看作为杀菌剂并不是十分满意的。
说得更详细些,本发明叙及的是由通式(1)代表的新化合物,
式中X是-O-或-CH2-;
R1是-Y-烷基,-Y-芳烷基,或-Y-芳基〔Y代表-O-,-CONH-,-NHCO-,-(CH=CH)n-,(n代表0,1,2,或3),-C≡C-,-CH2O-,或-CH2S-〕;
R2代表氢或羟基;
R3代表能与血红素配位的基团;
R4和R5分别代表氢,低级烷基,烷氧基或烷硫基,或者R4和R5与相邻的碳原子一起可以形成5-或6-员缩酮环;
R6代表氢,低级烷基,烷氧基或烷硫基,氨基,低级烷基氨基或二低级烷基氨基;
R7代表氢,羟基,低级烷基,烷氧基或烷硫基,它们可以任意被氢,酰基或芳基取代;或者代表5-或6-员杂环,它们含有一个或多个氮原子,此外还可以含有氧或硫原子;或者
R6和R7与相邻的碳原子一起可以形成5-或6-员缩酮环;或者
R2和R4可以在一起形成单键以及形成药学上适合的盐,及其式(Ⅰ)所示化合物的水合物或溶剂化物或者由它们形成的盐。
这里所使用的术语“低级的”,除非另加说明,意指含有直至7个碳的碳链,包括7个碳的碳链。
“烷基”系指具有1至15个碳原子的直链或支链烷基,如象甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,正戊基,异戊基,正己基,异己基,正庚基,正辛基,正壬基,4,8-二甲壬基,正癸基,正十一烷基,正十二烷基,正十三烷基,正十四烷基,正十五烷基,
“芳烷基”系指在Y和芳基之间的亚烃基含有1至5个碳原子的芳烷基,如象苄基,苯乙基,3-苯丙基,4-苯丁基,5-苯戊基,吡啶基甲基,2-吡啶基乙基,3-吡啶基丙基,4-吡啶基丁基,5-吡啶基戊基,β-萘甲基,2-(β-萘基)乙基,3-(β-萘基)丙基,4-(β-萘基)丁基,5-(β-萘基)戊基,2-喹啉基甲基,3-喹啉基甲基,2-(2-喹啉基)乙基,2-(3-喹啉基)乙基,3-(2-喹啉基)丙基,3-(3-喹啉基)丙基,2-喹喔啉基甲基,2-(2-喹喔啉基)乙基,3-(2-喹喔啉基)丙基。这些芳烷基的芳环上可以任意取代有1或2个卤原子,羟基,二低级烷基氨基,1-四氢吡咯基,1-哌啶基,1-哌嗪基,4-吗啉基,低级烷基或烷氧基,其中的烷基可以被任意取代有一个或多个卤原子。特别优选的烷基是苄基,4-氯苄基,4-氟苄基,2,4-二氯苄基,2,4-二氟苄基,4-甲基苄基,4-乙基苄基,4-丙基苄基,4-叔丁基苄基,苯乙基,2-(4-氯苯基)乙基,2-(4-氟苯基)乙基,2-(2,4-二氯苯基)乙基,2-(4-甲基苯基)乙基,2-(4-乙基苯基)乙基,2-(4-正丙基苯基)乙基,3-苯基丙基,3-(4-氯苯基)丙基,3-(4-氟苯基)丙基,3-(2,4-二氯苯基)丙基,3-(2,4-二氟苯基)丙基,3-(4-甲基苯基)丙基,3-(4-乙基苯基)丙基,3-(4-正丙基苯基)丙基,4-苯基丁基,4-(4-氯苯基)丁基,4-(4-氟苯基)丁基,4-(2,4-二氯苯基)丁基,4-(2,4-二氟苯基)丁基,4-(4-甲基苯基)丁基,4-(4-乙基苯基)丁基,4-(4-正丙基苯基)丁基,5-苯基戊基,5-(4-氯苯基)戊基,5-(4-甲基苯基)戊基,β-萘甲基,2-(β-萘基)乙基,3-(β-萘基)丙基,4-(β-萘基)丁基,5-(β-萘基)戊基和2-喹啉基甲基。
“芳基”特别系指苯基,萘基,吡啶基,喹啉基,或喹喔啉基,它们可以取代有1个至多个卤原子,羟基,低级烷基,卤烷基,烷氧基,氨基或二低级烷基氨基,如象苯基,4-氯苯基,4-氟苯基,2,4-二氯苯基,2,4-二氟苯基,4-三氟甲基苯基,2-氟-4-三氟甲基苯基,4-甲苯基,4-乙基苯基,4-丙基苯基,4-叔丁基苯基,吡啶基,2-萘基,2-喹啉基,3-喹啉基,2-喹唑啉基。
能够与血红素配位的基团是,例如氨基,含1至3个碳原子的低级烷基氨基,1H-咪唑-1-基甲基,1H-1,2,4-三唑-1-基甲基,氨基乙酰氧基,氨基乙酰氨基,(低级烷基氨基)乙酰氨基,(二低级烷基氨基)乙酰氨基,(氨甲基)羟基磷酰氧基,〔(低级烷基氨基)甲基〕羟基磷酰氧基,0-甲基(氨基甲基)羟基磷酰氧基,0-甲基(低级烷基氨基)羟基磷酰氧基,3-氨基-2-氧代丙基,3-氨基-2-羟基丙基,3-(低级烷基氨基)-2-氧代丙基,3-(二低级烷基氨基)-2-氧代丙基,3-(低级烷基氨基)-2-羟基丙基,3-(二低级烷基氨基)-2-羟基丙基,1,3-噁唑-5-基甲基,在这些基团中,特别优选的是1H咪唑-1-基甲基,1H-1,2,4-三唑-1-基甲基,氨基乙酰氧基,(氨基乙酰)氨基,(氨基甲基)羟基磷酰氧基,0-甲基(氨基甲基)羟基磷酰氧基,3-氨基-2-氧代丙基,3-氨基-2-羟基丙基,1,3-噁唑-5-基甲基。
“低级烷基”的实例是甲基,乙基,正丙基,异丙基,正丁基,异丁基,仲丁基,正戊基,异戊基,正己基,异己基。
“低级烷氧基”的实例是甲氧基,乙氧基,正丙氧基,异丙氧基,正丁氧基,异丁氧基,仲丁氧基,正戊氧基,异戊氧基,正己氧基,异己氧基,
低级烷硫基或烷硫基的实例有甲硫基,乙硫基,正丙硫基,异丙硫基,正丁硫基,
5-或6-员缩酮环的实例有1,3-二嗪茂烷,1,3-二噁茂烷或1,3-二噁烷。
低级烷基氨基的实例有甲氨基,乙氨基,正丙氨基,异丙氨基。
二低级烷基氨基的实例有二甲氨基,二乙氨基,N-乙基甲氨基。
“酰基”系指脂肪族或芳香族酰基,优选具有1至4个碳原子的脂肪族酰基,如乙酰基,丙酰基。
术语“含有一个或多个氮原子及其还可能含有氧或硫原子的5-或6-员杂环“尤指1-吗啉基,1-硫吗啉基,4-甲基哌嗪基,咪唑-1-基,1H-1,2,4-三唑-1-基,
式(1)所示的新化合物可由下述方法制备。
方法A
R2是氢,R3是氨基乙酰氧基或(氨基乙酰)氨基而R1,R4,R5,R6,R7和X如前述定义的式(Ⅰ)所示的化合物可以通过用N-保护的甘氨酸或它的活泼酯来酰化式(Ⅱ)所示化合物然后除去保护基的方法来制备。
式中R31为羟基或氨基,而R1,R4,R5,R6,R7和X如前述定义。
方法B
式(Ⅰ)所示化合物〔式中R2为氢原子,R3是(氨基甲基)羟基磷氧基或0-甲基(氨基甲基)羟基磷酰氧基,而R1,R4,R5,R6,R7和X与前述定义相同〕可以由式(Ⅱ)所示化合物〔式中R31是羟基,而R1,R4,R5,R6,R7和X如前述定义〕与N-保护的(氨基甲基)膦酸反应来制备,如果需要的话,生成的磷酸酯再0-甲基化,然后除去保护基。
方法C
式(Ⅰ)所示化合物〔式中R2代表氢原子,R3是(低级烷基氨基)酰氨基,(二低级烷基)酰氨基,((低级烷基氨基)甲基)羟基磷酰氧基,0-甲基((低级烷基氨基)甲基)羟基磷酰氧基,3-(低级烷基氨基)-2-氧代丙基,3-(二低级烷基氨基)-2-氧代丙基,3-(低级烷基氨基)-2-羟基丙基,3-(二低级烷基氨基)-2-羟基丙基以及R1,R4,R5,R6,R7和X如前述所定义〕可以通过式(Ⅲ)所示化合物〔式中Z为-NHCOCH2-,-O-PO(OH)CH2-,-O-PO(OCH3)CH2-,-CH2CH(OH)CH2-或-CH2COCH2-,R32为一个氢原子或N-保护基团,而R1,R4,R5,R6,R7和X如前述定义〕的N-烷基化来制备,需要时接着除去N-保护基。
方法D
式(Ⅰ)所示化合物(式中R2为羟基,R3为1-唑基甲基,而R1,R4,R5,R6,R7和X同前述定义〕可以通过式(Ⅳ)所示化合物〔式中R1,R4,R5,R6,R7和X同前述定义〕与咪唑或1H-1,2,4-三唑的碱金属盐的反应来制备。
方法E
式(Ⅰ)所示化合物〔式中R3为1H-咪唑-1-基甲基或1H-1,2,4-三唑-1-基甲基,而R1,R2,R4,R5,R6,R7和X同前述定义〕可以通过由式(Ⅴ)所示化合物〔式中R2代表氢,或R2和R4形成一个单键,而R1,R4,R5,R6,R7和X同前述定义〕与甲磺酰氯,对甲苯磺酰氯或三氟甲磺酸酐反应,接着用咪唑或1H-1,2,4-三唑的碱金属盐处理形成的甲磺酸酯,对甲苯磺酸酯或三氟甲磺酸酯来制备。
方法F
式(Ⅰ)所示化合物(式中X代表亚甲基,R2为氢原子,R3代表3-氨基-2-羟基丙基,R6为甲基,而R1,R4,R5如前述定义)可以通过式(Ⅵ)所示的化合物(式中R1,R4,R5和R7如前述定义)与三甲基硅氰的反应,接着将形成的O-保护的氰醇还原成β-氨基醇来制备。
下面,将对本发明的式(Ⅰ)所示的6-员环化合物的制备过程作更详细的说明。
方法A
通式(Ⅱ)所代表的化合物的具体实例包括:
(2S,3R,5R)-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-5-甲基-2-〔(Z)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-5-甲基-2-〔(E)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-乙氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-5-甲基-2-壬基-4-丙氧基四氢-2H-吡喃-3-醇,
(2S,3R,4R,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-甲氧基-5-甲基-〔(E)-癸烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-(4,8-二甲壬基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-丁氧基-4-甲氧基-2-〔(E)-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-苄氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-乙氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-(2,4-二氟苄氧基)-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(9S,10R,11R)-11-甲氧基-9-〔(E)-1-壬烯基〕-8-氧杂-1,5-二硫螺〔5,5〕十一烷-10-醇,
(2S,3R,4R,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-4,5-二甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-2-(4-丙基苯基)乙烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔2-(4-丙基苯基)乙基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-〔2-(4-氯苯基)乙基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-(2-萘乙基)四氢-2H-吡喃-3-醇,
(2R,3R,4S,5S)-2-〔(4-氯苯硫基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔4-(4-甲苯基)丁基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-辛烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-十一碳烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-〔(E)-2-(4-氯苯基)乙烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-2-萘乙烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-4-甲氧基-2-壬基-5-(3-苯丙氧基)四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-(4-叔丁基苄氧基)-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4R,5R)-5-(2-羟基乙氧基)-4-甲氧基-2-壬基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-(1-壬炔基)四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-〔(E)-1-庚烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-(庚氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2R,3R,4S,5S)-N-庚基-3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲酰胺,
(2S,3R,4S,5S)-2-〔(Z)-(4-氯苯基)乙烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-(苄氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-〔(1E,3E)-4,8-二甲基-1,3,7-壬三烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-2-〔(1Z,3E)-4,8-二甲基-1,3,7-壬三烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-2-(4-丙苯基)乙烯基〕四氢-2H-吡喃-3-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇,
(6S,7S,10S)-10-甲基-7-〔(E)-1-壬烯基〕-1,4,8-三氧杂螺〔4,5〕癸-6-醇,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-乙氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-5-甲基-2-〔(E)-1-壬烯基〕-4-丙氧四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-5-甲基-2-〔(Z)-1-壬烯基〕-4-丙氧四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-5-甲基-2-壬基-3-丙氧四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-2-(庚氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-胺,
(2R,3R,4S,5S)-3-氨基-N-庚基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲酰胺,
(2S,3R,4R,5R)-5-丁氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4R,5R)-5-苄氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-2-萘乙烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-(2-萘乙基)四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-辛烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-十一碳烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5S)-2-〔(E)-1-庚烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-胺,
(2S,3R,4R,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-胺,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-胺,
(1S,2S,6S)-2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己胺,
(1S,2S,6S)-2-甲氧基-3,3-二甲基-6-〔(Z)-1-壬烯基〕环己胺,
(1S,2S,6R)-2-甲氧基-3,3-二甲基-6-壬基-环己胺,
(1R,2S,6R)-6-辛氧基-2-甲氧基-3,3-二甲基环己胺,
(1R*,2R*)-2-辛氧基-5,5-二甲基环己胺,
(1R*,2S*)-2-〔(E)-1-壬烯基〕-5,5-二甲基环己胺,以及
(1R*,2R*)-5,5-二甲基-2-壬基环己基胺。
用于甘氨酸的N-保护基团的实例在多肽化学中是已知的,如叔丁氧羰基,苄氧羰基,和邻苯二甲酰基。
酰化是在碱性催化剂如4-(二甲氨基)吡啶或4-四氢吡咯基吡啶或4-四氢吡咯基吡啶的存在下通过用脱水剂来处理通式(Ⅱ)所示的化合物和N-保护的甘氨酸来完成的,所用脱水剂有二环己基碳二亚胺,1-环己基-3-〔2-(N-甲基吗啉-1-基)乙基〕碳二亚胺对甲苯磺酸盐,1-乙基-3-(3-二甲氨基丙基)碳二亚胺盐酸盐,或2,4,6-三异丙基苯磺酰氯。
反应在溶剂中进行,如氯仿,二氯甲烷,乙腈,二甲基甲酰胺,吡啶,等等,反应温度在0°和60℃之间,优选0和25℃之间。
N-保护甘氨酸的活泼酯的实例有N-羟基丁二酰亚胺的酯,1-羟基苯并三唑的酯,N-羟基邻苯二甲酰亚胺的酯或N-羟基-5-降冰片烯-2,3-二羰基化合物的酯。
在碱性催化剂如象4-(二甲氨基)吡啶或4-四氢吡咯基吡啶的存在下,在上述提到的同样的溶剂和反应温度下,或者在没有碱性催化剂的存在下,处理式(Ⅱ)所示化合物和活泼酯来进行酰化。
N-保护基可以用文献中已知的方法来除去。
方法B:
在这些方法中,可以采用与上述方法A描述的相同的N-保护基,优选叔丁氧羰基。
在4-二甲氨基吡啶或4-四氢吡咯基吡啶的存在下,用方法A叙述的同样的脱水剂或用活化剂如2,4,6-三异丙基苯磺酰氯等处理式(Ⅱ)所示化合物和N-保护的(氨甲基)膦酸来进行反应。
反应在有机溶剂如二氯甲烷,氯仿,二甲基甲酰胺,吡啶等中,在0至60℃的温度下,优选0至40℃的温度下进行,N-保护基团文献中已知的程序除去。
形成的磷酸酯与甲基化试剂如象重氮甲烷,三甲基硅基重氮甲烷,碘甲烷等反应来进行磷酸酯的0-甲基化。反应在有机溶剂如象乙醚,四氢呋喃,二氧六环,甲醇或乙醇中进行,也可使用两种或多种溶剂的混合物。使用碘甲烷时反应可以在缚酸剂如碱金属碳酸盐的存在下进行。
方法C:
在这一方法中,使用与方法A定义的同样的N-保护基。
N-烷基化可以在Lenckart条件下或催化氢化的条件下用烷基化试剂或用低级烷基醛来进行。
用烷基化试剂如象碘甲烷或碘乙烷进行的反应在缚酸剂如象碱金属氢化物,碱金属碳酸盐或二异丙基乙基胺的存在下,在溶剂如二氯甲烷,氯仿,四氢呋喃等中进行。反应温度在-20至30℃之间,优选0至25℃。N-保护基可以由文献中已知的程序除去。
在Lenckart条件下的还原N-烷基化可以用“有机反应,卷V,第7章301-330(1949)”描述的程序进行。
在催化氢化条件下的还原N-烷基化在溶剂如象甲醇,乙醇等中,室温下进行。
方法D
通式(Ⅳ)所示的化合物的具体实例包括:
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-壬基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(Z)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-乙氧基-7-甲基-4-〔(Z)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-7-甲基-4-〔(E)-1-壬烯基〕-8-丙氧基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-7-甲基-4-〔(Z)-1-壬烯基〕-8-丙氧基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-7-甲基-4-壬基-8-丙氧基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7R,8S)-7-丁氧基-8-甲氧基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7R,8S)-7-苄氧基-8-甲氧基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-2-萘乙烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-(2-萘乙基)-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-1-辛烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-1-十一碳烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8S)-4-〔(E)-1-庚烯基〕-8-甲氧基-7-甲基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7S,8R)-8-甲氧基-7-甲基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7R,8S)-8-甲氧基-7-甲基-4-壬基-1,5-二氧杂螺〔2,5〕辛烷,
(3S,4S,7R,8S)-8-甲氧基-7-甲基-4-〔(Z)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷,和
(3S,4R,7S,8S)-8-甲氧基-7-甲基-4-(庚氨基羰基)-1,5-二氧杂螺〔2,5〕辛烷,
上述反应可以在溶剂如N,N-二甲基甲酰胺,或二甲亚砜中进行,反应温度-10°至60℃,优选0至25℃,咪唑或1H-1,2,4-三唑的碱金属盐的量通常为环氧化物的1至10当量,优选3至5当量。
方法E
通式(Ⅴ)所示化合物的具体实例包括:
(2S,5R)-〔5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲醇,
(2S,5R)-〔5,6-二氢-5-甲基-2-〔(E)-1-壬烯基〕-2H-吡喃-3-基〕甲醇,
(2S,5R)-〔5,6-二氢-5-甲基-2-〔(E)-2-萘乙烯基〕-2H-吡喃-3-基〕甲醇,
(2S,5R)-〔5,6-二氢-5-甲基-2-(2-萘乙基)-2H-吡喃-3-基〕甲醇,
(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-壬基环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲氧基-6-辛氧基环己基〕甲醇,
(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(Z)-1-壬烯基〕环己基〕甲醇,
(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-2-萘乙烯基〕环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(2-萘乙基)环己基〕甲醇,
(1R*,6S*)-〔3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇,
(1R*,6R*)-〔3,3-二甲基-6-壬基环己基〕甲醇,
(1S*,6R*)-〔3,3-二甲基-6-辛氧基环己基〕甲醇,
(1R*,6S*)-〔3,3-二甲基-6-〔(Z)-1-壬烯基〕环己基〕甲醇,
(1R*,6S*)-〔3,3-二甲基-6-〔(E)-2-萘乙烯基〕环己基〕甲醇,
(1R*,6S*)-〔3,3-二甲基-6-(2-萘乙基)环己基〕甲醇,
(1R,2R,6S)-〔2-乙氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇,
(1R,2R,6S)-〔2-乙氧基-3,3-二甲基-6-〔(E)-2-萘乙烯基〕环己基〕甲醇,
(1R,2R,6R)-〔3,3-二甲基-6-壬基-2-丙氧基环己基〕甲醇,
(1R,2R,6R)-〔3,3-二甲基-6-(2-萘乙基)-2-丙氧基环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(萘甲氧基)环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(2-萘己氧基)环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(喹啉甲氧基)环己基〕甲醇,
(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(2-喹啉乙氧基)环己基〕甲醇,
(1S*,6R*)-〔3,3-二甲基-6-(萘甲氧基)环己基〕甲醇,
(1S*,6R*)-〔3,3-二甲基-6-(2-萘乙氧基)环己基〕甲醇,
(1S*,6R*)-〔3,3-二甲基-6-(喹啉甲氧基)环己基〕甲醇,和
(1S*,6R*)-〔3,3-二甲基-6-(2-喹啉基乙氧基)环己基〕甲醇,
上述磺酰化可以在干燥有机溶剂中如象在二氯甲烷,氯仿,乙醚,四氢呋喃中及其在缚酸剂如三乙胺吡啶存在下进行,反应温度在-10至40℃之间,优选0至25℃。
相继的取代反应可以N,N-二甲基甲酰胺这样的溶剂中进行,反应温度在0°和60℃之间,优选15和25℃之间。咪唑或1H-1,2,4-三唑的碱金属盐的量通常是磺酸酯衍生物的1至10当量,优选3至5当量。
方法F
由通式(Ⅵ)所示化合物的具体实例包括:
〔(1S*,2R*)-2-辛氧基-5,5-二甲基环己基〕乙醛,
〔(1S,2R,6R)-6-辛氧基-2-甲氧基-3,3-二甲基环己基〕乙醛,
〔(1S*,2R*)-5,5-二甲基-2-壬基环己基〕乙醛,
〔(1R,2R,6R)-1-甲氧基-3,3-二甲基-6-壬基环己基〕乙醛,
〔(1R,2R,6R)-2-乙氧基-3,3-二甲基-6-壬基环己基〕乙醛,
〔(1S*,2R*)-5,5-二甲基-2-(萘甲氧基)环己基〕乙醛,
〔(1S*,2R*)-5,5-二甲基-2-(2-萘乙氧基)环己基〕乙醛,
〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(萘甲氧基)环己基〕乙醛,和
〔(1R,2R,6R)-2-甲氧基-3-二甲基-6-(2-萘乙氧基)环己基〕乙醛。
在催化量的Lewis酸如象氯化锌,碘化锌,等,优选碘化锌,的存在下,用三甲基硅氰处理由通式(Ⅵ)所示的化合物,可以将它们的醛基转化为0-三甲基硅基-氰醇。
反应在溶剂如象苯,甲苯,二甲苯等中进行,反应温度在0至60℃之间,优选0至25℃之间。
采用碱金属氢化物如氢化锂铝等可将形成的氰醇衍生物还原成相应的β-氨基醇衍生物。
反应在一个溶剂如乙醚,四氢呋喃等中进行,反应温度在25至100℃之间,优选50至80℃之间。
用实际上是形成盐的常规程序,用酸处理通式(Ⅰ)所示化合物的游离碱可以将其制备成药学上适合的酸加成盐。在上述过程中,治疗上适合而有用的酸有无机酸(例如盐酸,氢溴酸,磷酸,硝酸,硫酸)和有机酸(例如草酸,乙酸,甲酸,三氟甲酸,马来酸,琥珀酸,富马酸,酒石酸,柠檬酸,水杨酸,山梨酸,乳酸)。
起始物的合成
式Ⅱ,Ⅳ,Ⅴ和Ⅵ的起始物都是新化合物,可以按照下述图1、2、3、4、5和6的程序制备:
a)通式(Ⅱ)所示化合物(式中X为氧原子,R2为氢原子,R3为羟基而R1,R4,R5,R6和R7如前述定义)由流程1的方法制备如下:
流程1(1) (R为低级烷基 P1为羟基保护基)
流程1(2)
(P2为羟基保护基)
b)通式(Ⅱ)所示化合物(式中X为氧原子,R2为氢原子,R3为氨基,而R4,R5,R6和R7如前述定义)是新化合物,可以按流程2制备如下:
流程2
c)通式(Ⅳ)所示化合物(式中X为氧原子,而R1,R4,R5,R6和R7与前述定义相同)可按流程3制备如下:
d)通式(Ⅴ)所示化合物(式中X为氧原子,R2和R4形成一个单键,R6和R7同前述定义)可按流程4所示制备如下:
e)通式(Ⅴ)所示化合物(式中X为亚甲基,R6为甲基,而R2,R3,R4,R5和R7与前述定义相同)可以按流程5制备:
(P3是羟基保护基)
流程5(2)
(P3是羟基保护基)
f)通式(Ⅵ)所示化合物(式中R1,R4,R5和R7与前述定义同)按流程6制备如下:
流程6
在流程1中术语“C3-OH的修饰”(反应程序(3)→(4))或“C4-OH的修饰”(反应程序(8)→(9))系指,例如,O-烷基化,仲羟基的氧化,相应氧代衍生物的Wittig烯化或缩酮化,还原除去相应的硫代氨基甲酸酯或乙酸酯,或者是通过氧化-还原程序使仲-OH发生立体化学的翻转等。
术语“C-1侧链的修饰”(反应程序(12)→(Ⅱa))系指,例如,用各种亲核试剂如烷硫醇的碱金属盐,芳烷硫醇的碱金属盐等进行的溴化物(12)的取代反应,或者是通过脱溴化氢,形成的烯醇醚的臭氧化,接着将内酯还原成本缩醛,然后成苷化等将溴化物(12)转化成苷(Ⅱa)。
术语“C-1侧链的修饰”(反应(13)→(Ⅱa))意指,例如,伯羟基的O-烷基化或氧化成为羧酸,然后转化成为相应的酯,接着用胺进行胺解等。
在流程5中,术语“羰基的修饰”(反应程序(16)→(17))意指,例如,酮还原为醇接着O-烷基化或还原除去形成的醇羟基,或者是酮的Wittig烯化或缩酮化等。
本发明提供的化合物对各种真菌显示了广泛的抗菌活性,能够用作处理和预防真菌感染的疾病的药剂,本发明的化合物的离体抗菌活性和急性毒性说明如下:
1.离体抗菌活性
本发明的代表性化合物的离体抗菌活性是测定在未观察到真菌生长时最小抑制浓度(MIC),即抗真菌浓度。
MICs的测定是按NCCLS的微量培养液稀释法
(microbroth dilution procedure)加以较小的改变进行的(Galgiani等,Antimicrob Agents Chemother.,33,731(1989))。介质用0.2%的低熔点琼脂糖固化,用0.25%K2HPO4(于酵母氮基质中)缓冲至PH7.0(Difco Lab)。接种物为1×105个细胞/ml,在27℃下保温3天。其MICs(μg/ml)示于表1。参考化合物为美国专利No.4,952,604的化合物(IA)。所用化合物是参考其制备实例鉴定的。
通过测定小抑制浓度(MIC:方法A)或80%生长抑制浓度(IC80:方法B)测量了表1和表2中本发明的代表性化合物的离体抗菌活性。MIC定义为不能观察到真菌生长时抗菌剂的浓度,而IC80则是由OD630测量的细胞浊度减少80%时的浓度。
使用精密试验培养皿,按照NCCLS的规定而仅作少量的改进(Galgiani et al.,Antimicrob Agents Chemother 33,731(1989)),用方法A或方法B测定了抗菌活性。
(方法A)介质用0.2%的低熔点琼脂糖固化并且用0.25%K2HPO4的酵母氮基缓冲液处理到PH7.0。接种物的大小是1×105个细胞/mL。且在27℃保温3天。它们的MIC(μg/mL)列于表1中,参考化合物是美国专利No.4,952,604上的化合物(IA)。
(方法B)酵母用的介质用0.25%K2HPO4酵母氮基缓冲液调至PH7.0,用于丝状真菌时,将0.2%的低熔点琼脂补加到上述介质中,接种物的大小是1×104个细胞/ml,并且在27℃保温1-2天,Fluconazole(Pfizer)用作参比。
2。急性毒性
本发明的代表性化合物(实例4,21,60和69)的急性毒性(LD50)由老鼠口服测定。上述提到的实例4,21,60和69中获得的化合物的LD50值均大于500mg/kg。
因而,式(Ⅰ)所示化合物及其药学上适宜的盐是非常有效的抗真菌剂,它们对各种菌种包括白假丝酵母,新型隐球酵母,烟曲霉,发癣菌属,小孢霉属,Exophiala spp.,芽酵母属,和荚膜组织孢浆菌都是有活性的。
这样,本发明的化合物对于局部治疗和内吸治疗动物及人类的真菌病都是有效的。例如,在不同的种类中,治疗由假丝酵母属,发癣菌属,或小孢霉属引起的局部和粘膜真菌感染,它们是有效的,它们也用于,例如用于治疗由假丝酵母属,隐球酵母属,曲霉属,Paracoccidiodes,Sporotrix,Exophiala,芽酵母属,或组织孢浆菌属引起的内吸真菌感染。
对于临床应用,抗菌剂(Ⅰ)或盐的形式可以单独服用,但通常是通过混入赋形剂,粘着剂,润滑剂,崩解剂,涂盖物,乳化剂,悬浮剂,溶剂,稳定剂,吸附增强剂,和/或软膏基而加工成适于特殊用途和需要的目的的药学混合物来使用。该混合物可口服,注射,直肠或局部使用。
口服药用制剂可以是粒剂,片剂,糖衣片,胶囊,丸,悬浮剂或乳化剂。对于不经肠注射,例如静脉,肌内或皮下注射,制剂的形式可以是含有其它物质,例如盐或葡萄糖以使溶液具有等渗性的无菌水溶液。本发明的抗菌剂的使用形式也可以是栓剂或阴道药栓,或它们部分地以洗液,溶液,乳剂,软膏或粉剂的形式被应用。
式(Ⅰ)的抗真菌化合物的日剂量为0.1-50mg/kg(一次或分次服用),口服或非肠道使用。因此片剂或胶囊含有5mg至0.5g的活性化合物,在适合的时候一次或二次或多次服用。总之,实际用量由医生决定,可因年龄、体重和病人的反应而有不同。
此外,式(Ⅰ)的化合物和它们的盐对于各种植物病原菌也有活性,这些病原菌的例子有Pyricularia oryzae,瓜果腐霉,交链孢属,和拟青霉。
因而,它们特别以加工成适于特殊应用和需要的目的的组合物的形式应用于农业和园艺目的,这些组合物的例子有粉剂,或粒剂,种衣剂,水溶液,分散剂或乳剂,浸渍液,喷雾剂或气雾剂。这种组合物可以含有常用的在农业和园艺上已知和可接受的载体,稀释剂或辅剂。
其它具有除草,或杀虫活性,或别的抗菌活性的化合物可以结合到组合物中去,可以有各种方式施用这些化合物和组合物。例如它们可以直接施用于植物叶片、茎、枝、种子或根,或直接施用于土壤或其它生长介质,以及它们不仅用于治疗疾病,也可用于预防植物或种子受到侵袭。
下面的例子说明了制备本发明的化合物的优选方法,但并不意味着限制了这个发明的范围。
起始物质的制备
参考实例1
(2R,3R,4S,5S)-3-叔丁基二甲基硅氧基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲醛的制备
(a)甲基2,4-二-O-苄基-β-D吡喃木糖苷的制备
向甲基3-O-苯基氨基甲酰基-β-D-吡喃木糖苷(73.6克,0.26摩尔)在DMF(300ml)的溶液中分批加入60%NaH-油悬浮液(36.0克,0.9摩尔)。室温搅拌30分钟后,向此反应混合液中滴加溴化苄(113ml,0.95摩尔),加完后继续搅拌3小时,减压下蒸发反应混合物,所得油状物在乙醚(500ml)和水(500ml)之间分配,醚层经无水硫酸钠干燥后,减压下蒸发至干,将得到的琥珀色粘稠状油(150g)溶于28%NaOMe-MeOH(750ml)溶液中并且回流加热19小时,减压下将反应混合物蒸发至干,油状剩余物在乙醚(500ml)和水(500ml)之间分配,醚层用水(250ml×2)洗后,减压下蒸发至干,剩余物在硅胶柱上层析,CH2Cl2/AcOEt(95∶5)为洗提剂,得到甲基2,4-二-O-苄基-β-D-吡喃木糖苷(80.5g,收率90%),呈无定形粉末状; EI-MS:m/z 344(M+);1H-NMR(CDCl3)δ:2.54(1H,d,J=2.5Hz),3.21(1H,dd,J=7.5&9Hz),3.22(1H,dd,J=10&12Hz),3.52(3H,s),3.49(1H,m),3.68(1H,t,J=9Hz),3.93(1H,dd,J=6&12Hz),4.25(1H,d,J=7.5Hz),4.63(1H,d,J=12Hz),4.66(1H,d,J=11.5Hz),4.75(1H,d,J=12Hz),4.90(1H,d,J=12Hz),7.31(10H,br.s).
(b)甲基2,4-二-O-苄基-3-O-甲基-β-D-吡喃木糖苷的制备
向甲基2,4-二-O-苄基-β-D-吡喃木糖苷(38g,0.11摩尔)在干DMF(500ml)中的溶液加入60%NaH的油悬浮液,在0℃搅拌30分钟后,加入碘甲烷(17g,0.12摩尔)然后将反应混合物温热至室温。溶液继续搅拌1小时然后在减压下蒸发至干,所得油状剩余物在乙醚(300ml)和水(300ml)之间分配,醚层用无水硫酸钠干燥,减压下蒸发至干得甲基2,4-二-O-苄基-3-O-甲基-β-D-吡喃木糖苷(39.4g,收率100%)为无色的油状物;
EI-MS:m/z 358(M+),254(M+-Bn);1H-NMR(CDCl3)δ:3.18(1H,dd,J=10&12Hz),3.24(1H,dd,J=7.5&9Hz),3.29(1H,t,J=9Hz),3.50(1H,m),3.52(3H,s),3.65(3H,s),3.9(1H,dd,J=5.9&12Hz),4.21(1H,d,J=7.5Hz),4.62(1H,d,J=12Hz),4.69(1H,d,J=11Hz),4.75(1H,d,J=12Hz),4.85(1H,d,11Hz),7.35(10br.s).
(c)2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基乙酸酯的制备
甲基2,4-二-O-苄基-3-O-甲基-β-D-吡喃木糖苷(30g,0.084摩尔)在AcOH(250ml)和2NH2SO4(100ml)中的悬浮液在100℃下加热3小时,在减压下将得到的清澈溶液浓缩至一半体积然后在乙醚和水(各400ml)之间分配。醚层相继用水(100ml×2),5%碳酸氢钠水溶液(200ml)和水(100ml×2)洗涤,醚层用无水硫酸钠干燥后在减压下蒸发至干,得到一个相应的半缩醛衍生物的异构体混合物(25克),呈泡沫状。
上述半缩醛衍生物(25克),三乙胺(10g,0.1摩尔)和催化量的N,N-二甲氨基吡啶在干燥二氯甲烷中的溶液用乙酰氯(7.1g,0.09摩尔)处理,并在室温下搅拌3小时。
上述溶液在减压下蒸发至干并且在乙醚(200ml)和水(200ml)之间分配,醚层用水(50ml×2)洗后,在减压下蒸发至干,剩余物在硅胶柱上层析,AcOEt/正己烷(2∶8)作为洗脱剂,得到2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基乙酸酯(22.8g,收率70%)为两种异构体混合物,呈无定形粉末状。
EI-MS:m/z 386(M+),343(M+-Ac),295(M+-Bn);1H-NMR(CDCl3)δ:2.04(1.5H,s),2.13(1.5H,s),3.3~3.6(4H,m),3.66(1.5H,s),3.69(1.5H,s),3.70(0.5H,dd,J=5&12Hz),3.90(0.5H,dd,J=5&12Hz),4.61~4.80(4H,m),5.51(0.5H,d,J=8.0Hz),6.15(0.5H,d,J=3.9Hz),7.34(10H,br.s).
(d)2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基甲腈
室温搅拌下,向2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基乙酸酯(20g,0.052摩尔)和Me3SiCN(20ml,0.16摩尔)在无水硝基甲烷(300ml)中的溶液里加入三氟化硼乙醚络合物(1.0g,0.007摩尔),混合物在室温搅拌30分钟后,减压下蒸发至干,剩余物在硅胶柱上层析,CH2Cl2/AcOEt(99∶1)作为洗脱液,得到2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基甲腈,为无色油状物(13.0g,收率71%);
EI-MS:m/z 353(M+),262(M+-Bn);1H-NMR(β-氰基异构体)(CDCl3)δ;3.15(1H,dd,J=10,11Hz),3.23(1H,t,J=10Hz),3.49(1H,m),3.59(1H,t,J=10Hz),3.66(3H,s),3.96(1H,dd,J=5&11Hz),3.97(1H,d,J=10Hz),4.61(1H,d,J=12Hz),4.73(1H,d,J=12Hz),4.84(1H,d,J=11Hz),4.88(1H,d,J=11Hz),7.29~7.42(10H,m).
(e)2,4-二-O-苄基-3-O-甲基-1,5-脱水-L-木糖醇
2,4-二-O-苄基-3-O-甲基-α,β-D-吡喃木糖基甲腈(13.0g,0.037摩尔)的乙醇(100ml)和2.5N NaOH水溶液(50ml)的溶液在室温下搅拌两天。将上述清澈的溶液浓缩至原体积的1/3,并用1N HCl调节至PH4,然后在乙醚(300ml)和水(100ml)之间分配,醚层用水(100ml×2)洗,硫酸镁干燥,减压下蒸发至干。
在氮气流下,0℃(冰浴)向上述剩余物(8.9g,24毫摩尔)滴加2.0M甲硼烷-硫甲醚的THF溶液(55.7ml,4.6当量)。加完后,移去冰浴,溶液在室温下搅拌21小时,然后在40℃搅拌4小时,将反应混合物仔细地倾入水(200ml)中,用AcOEt(70ml×3)提取,结合AcOEt层用饱和食盐水洗涤,无水MgSO4干燥,滤去MgSO4,减压下除去溶剂,获得粗产物(大约10g),为无色粘稠油,粗品在硅胶柱上层析,(SiO2大约250g,洗脱液:正己烷/AcOEt=2∶1,然后1∶1)得2,4-二-O-苄基-3-O-甲基-1,5-脱水-L-木糖醇。(5.42g,0.015摩尔)和它的C-5差向异构体(1.04g,3毫摩尔),前者为无色针状结晶,后者为无色粘稠状油,收率分别为63.0%和12.1%。
EI-MS:m/z 358(M+),267(M+-Bn);1H-NMR(CDCl3)δ:1.82(1H,br.s),3.18(1H,dd,J=11Hz),3.24(1H,m),3.37(1H,m),3.48(1H,m),3.63(1H,m),3.71(3H,s),3.80(1H,br.d,J=12Hz),3.95(1H,dd,J=6&11Hz),4.62(1H,d,J=11Hz),4.65(1H,d,J=11Hz),4.74(1H,d,J=11Hz),4.87(1H,d,J=11Hz),7.27~7.38(10H,m).
(f)3-O-甲基-1,5-脱水-L-木糖醇
氮气流中,-78℃,及在强烈搅拌下,将2,4-二-O-苄基-3-O-甲基-1,5-脱水-L-木糖醇(41.18g,115毫摩尔)的干燥乙醚(80ml)溶液加到金属钠(15.8g,3.0当量)的液氨溶液中。在液氨沸点(-33℃)反应4小时后,慢慢地加入甲醇直至兰色消失以停止兰色反应混合物的反应,蒸出液氨后,加入水-甲醇(1∶1)混合物(500ml),形成的溶液通过一个Dowax 50W×8柱(大约500ml)使其中和,用水-甲醇(1∶1)混合物(500ml)彻底冲洗该柱,合并水-甲醇溶液,减压下蒸发,得到棕色油状粗品(38g),棕色油经硅胶柱层析纯化(SiO2大约1kg),CHCl3/MeOH(4∶1)作洗脱剂,得3-O-甲基-1,5-脱水-L-木糖醇(16.09g,90.4毫摩尔),为黄色粘稠状油,收率78.6%。
FAB-MS:m/z 179(MH+);1H-NMR(CDCl3)δ:1.95(1H,t,J=6Hz),2.10(1H,d,J=4Hz),2.45(1H,d,J=4Hz),3.13(1H,t,J=9Hz),3.28(1H,t,J=10Hz),3.31(1H,ddd,J=4,5&9Hz),3.54(1H,dt,J=4&9Hz),3.69(3H,s),3.66~3.80(2H,m),3.90(1H,m),4.0(1H,dd,J=5.5&10Hz).
(g)4,6-O-苄叉-3-O-甲基-1,5-脱水-L-木糖醇的制备
搅拌下,向3-O-甲基-1,5-脱水-L-木糖醇(0.1g,5.6×10-4摩尔)的苯甲醛溶液中加入无水氯化锌(0.05g,3×10-4摩尔),所得混合物在室温下搅拌2小时,减压下将混合物蒸发至干,然后在乙酸乙酯(50ml)和10%碳酸钠(50ml)之间分配。乙酸乙酯层用饱和食盐水(20ml×2)洗涤,无水硫酸钠干燥,然后蒸发至干得到无色油状粗品(0.14g)。将此油状物与正己烷(5.0ml)一起研磨,得无色无定形粉末状的4,6-O-苄叉-3-O-甲基-1,5-脱水-L-木糖醇(0.127g,85%)。
EI-MS:m/z 266(M+);1H-NMR(CDCl3)δ:2.44(1H,br.s),3.33(1H,dd,J=10Hz),3.34(1H,t,J=11Hz),3.40(1H,dt,J=5&10Hz),3.57(1H,t,J=10Hz),3.68(3H,s),3.71(1H,t,J=10Hz),3.71(1H,m),4.06(1H,dd,J=5.7&11Hz),4.32(1H,dd,J=5&10Hz),5.55(1H,s),7.36~7.39(3H,m),7.47~7.50(2H,m).
(h)4,6-O-苄叉-2-脱氧-3-O-甲基-2-氧代-1,5-脱水-L-木糖醇的制备
在-78℃,5分钟内,向草酰氯(0.136ml,1.58毫摩尔)的干燥CH2Cl2(1。0ml)溶液中滴加干燥DMSO(0.197ml,2。78毫摩尔)的干燥CH2Cl2(1.0ml)溶液。在-78℃搅拌10分钟后,在5分钟后,-78℃下,向上述奶状悬浮液中滴加4,6-O-苄叉-3-O-甲基-1,5-脱水-L-木糖醇(0.35g,1.32毫摩尔)的干燥CH2Cl2(1.0ml)溶液,在-78℃搅拌15分钟后,在3分钟内,向此反应混合物滴加三乙胺(0.921ml,6.6毫摩尔),在-78°下继续搅拌30分钟,将反应混合物逐渐温热到室温,并用CH2Cl2(20ml)和水(20ml)分配,二氯甲烷溶液用饱和食盐水(10ml×2)洗涤后,用无水硫酸钠干燥,然后蒸发至干,剩余物用硅胶柱层析,CH2Cl2/AcOEt(9∶1)作洗脱剂,得到无色无定形粉末状的4,6-O-苄叉-2-脱氧-3-O-甲基-2-氧代-1,5-脱水-L-木糖醇,(0.301g,86%);
EI-MS:m/z 264(M+);1H-NMR(DMSO)δ:3.45(3H,s),3.65(1H,m),3.70(1H,t,J=10Hz),3.81(1H,t,J=10Hz),3.90(1H,dd,J=4&10Hz),4.01(1H,d,J=14Hz),4.14(1H,d,J=10Hz),4.18(1H,d,J=14Hz),5.54(1H,s),7.35~7.41(3H,m),7.48~7.52(2H,m).
(i)4,6-O-苄叉-2-脱氧-3-O-甲基-2-亚甲基-1,5-脱水-L-木糖醇的制备
将油中的KH(17.2g,0.15摩尔)放置在一个三颈烧瓶(500ml)中;用正己烷(×3)洗去油,向干燥的KH中加入90ml四氢呋喃(以LAH上新蒸馏的),接着在冷却(20℃)和猛烈搅拌下加入30ml六甲基二硅氨烷。形成的混合物用声波处理30分钟,此时最初的灰色悬浮液转变成白色,然后一次将53.6克甲基三苯基溴化(0.15摩尔,由二氯甲烷-乙醚重结晶)加到上述混合物中。此时内部温度升至35-40℃,形成的深黄色悬浮液搅拌20分钟,然后将反应混合物冷却至-40℃,在10分钟内,将4,6-O-苄叉-2-脱氧-3-O-甲基-2-氧代-1,5-脱水-L-木糖醇(9.0g,0.034摩尔)的THF-HMPA(9∶1,50ml)溶液滴入上述冷却的混合物中,在1小时内,将反应混合物温热至室温,然后用水和乙醚分配,合并有机层,用无水硫酸镁干燥,蒸发至干后得到油状的环外亚甲基衍生物粗品,粗产物用快速柱色谱纯化,(洗提剂:正己烷-乙酸乙酯=4∶1)得无色结晶的4,6-O-苄叉-2-脱氧-3-O-甲基-2-亚甲基-1,5-脱水-L-木糖醇(6.36g,收率71.2%);
EI-MS:m/z 262(M+);1H-NMR(CDCl3)δ:3.53(2H,m),3.64(3H,s),3.70(1H,dd,J=10Hz),3.95(1H,m),4.07(1H,d,11Hz),4.29(1H,d,11Hz),4.30(1H,m),5.10(1H,s),5.33(1H,s),5.56(1H,s),7.33~7.40(3H,m),7.49~7.52(2H,m).
(j)(2S,3R,4S,5S)-(3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-基〕甲醇的制备
4,6-O-苄叉基-2-脱氧-3-O-甲基-2-亚甲基-1,5-脱水-L-木糖醇(1.0g,3.8毫摩尔)的甲醇(10ml)溶液,在室温,氢气中,Pd/炭黑催化剂的存在下搅拌12小时,过滤除去催化剂,并用甲醇(10ml×2)洗涤催化剂,合并滤液和洗涤液,然后在减压下蒸发至干,得到(2S,3R,4S,5S)-〔3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-基〕甲醇(0.668g,100%,为一无色油。
EI-MS:m/z 176(M+),145(M+-CH2OH);1H-NMR(CDCl3)δ:1.00(3H,d,7Hz),2.05(1H,br.s),2.21(1H,m),2.42(1H,br.s),3.24(2H,m),3.38(3H,s),3.60(2H,m),3.74(1H,dd,J=6&12Hz),3.83(1H,dd,J=2&12Hz),3.89(1H,dd,J=3.5&12Hz).
(k)(2S,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-2-〔(叔丁基二甲基硅氧基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃的制备
叔丁基二甲基氯硅烷被加到(2S,3R,4S,5S)-(3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-基)甲醇(1g,5。68毫摩尔)和咪唑(1.93g,28。4毫摩尔)的干燥DMF(5ml)溶液中,在室温搅拌12小时后,减压下将反应混合物蒸发至干所得粘稠剩余物用乙醚(25ml)和水(25ml)分配。醚层用水(20ml×2)洗,无水硫酸钠干燥并在减压下蒸发至干,剩余物用硅胶柱层析,洗脱剂为AcOEt/正己烷(1∶100),得到无色油状的(2S,3R,4S,5S)-3-(叔丁基二甲基硅氧基)2-〔(叔丁基二甲基硅氧基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃(1.84g,80%收率);
EI-MS:m/z 404(M+);1H-NMR(CDCl3)δ:0.79(9H,s),0.80(9H,s),1.1(3H,d,J=7Hz),2.20(1H,m),2.93(1H,dd,J=3.5&9Hz),3.15(1H,dd,J=4&11Hz),3.19(1H,m),3.45(3H,s),3.55(2H,m),3.65(1H,dd,J=5.5&11Hz),3.75(1H,dd,J=4.5&11Hz).
(l)(2S,3R,4S,5S)-〔3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃-2-基〕甲醇的制备
在5℃和猛烈的搅拌下,将三氟乙酸(3.28ml)和水(6.43ml)的混合物加到(2S,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-2-〔(叔丁基二甲基硅氧基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃(1.0g,2.48毫摩尔)的干燥THF(6.43ml)的溶液中,在5℃猛烈搅拌25分钟后,通过加入冷的饱和碳酸氢钠水溶液(30ml)仔细地使反应混合物的反应停止。形成的乳状液在乙醚(50ml)和水(50ml)之间分配,醚层用水(20ml×2)洗涤,无水硫酸钠干燥,减压下蒸发至干,剩余物用硅胶柱层析,洗脱剂为AcOEt-正己烷(2∶8),获得无色油状的(2S,3R,4S,5S)-〔3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃-2-基〕甲醇(0.595g,83%收率);
EI-MS:m/z 290(M+);1H-NMR(CDCl3)δ:0.87(9H,s),0.97(3H,d,J=7Hz),1.92(1H,br.s),2.2(1H,m),3.14(2H,m),3.28(3H,s),3.56(1H,t,J=9Hz),3.57(1H,dd,J=3&11.5Hz),3.65(1H,br.dd,J=6&11Hz),3.78(1H,dd,J=2&11.5Hz),3.84(1H,br.dd,J=2&11Hz).
(m)(2R,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲醛的制备
在-78℃,5分钟内,向草酰氯(0.036ml,0.42毫摩尔)的干燥CH2Cl2(0.5ml)溶液中滴加干燥DMSO(0.049ml,0。69毫摩尔)的干燥CH2Cl2(0.1ml)溶液,在-78℃搅拌10分钟后,在-78℃,5分钟内向形成的奶状悬浮液滴加(2S,3R,4S,5S)-〔3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃-2-基〕甲醇(0.1g,0.345毫摩尔)的干燥CH2Cl2(0.1ml)溶液,在-78℃搅拌15分钟后在3分钟内向反应混合物滴加三乙胺(0.24ml,1.73毫摩尔),在-78℃继续搅拌30分钟,然后将反应混合物逐渐温热到室温,并在CH2Cl2(10ml)和水(10ml)之间分配,二氯甲烷层用饱和食盐水(5ml×2)洗涤,无水硫酸钠干燥,减压下蒸发至干,剩余物在硅胶柱上层析,洗脱剂为AcOEt/正己烷(1∶9),得到无色油状的(2R,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲醛(0.085g,86%收率);
EI-MS:m/z 288(M+);1H-NMR(CDCl3)δ:0.85(3H,d,J=7Hz),0.87(9H,s),2.28(1H,m),3.12(1H,dd,J=4&5Hz),3.28(3H,s),3.59(1H,dd,J=5&11.5Hz),3.81(1H,d,J=4Hz),3.81(1H,dd,J=9&11.5Hz),4.08(1H,dd,J=4&5Hz),9.80(1H,s).
参考实例2
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-壬烯基〕四氢-2H-吡喃-3-醇的制备
(a)0℃,搅拌下,将正丁基锂(4.0ml,正己烷中1.6M)加入到正-辛基三苯基溴化膦(2124mg)的干燥THF(10ml)和干燥HMPA(5ml)的溶液中,混合物在0℃搅拌30分钟后,向形成的橙色溶液中加入(2S,3R,4S,5S)-4-甲氧基-5-甲基-3-(叔丁基二甲基硅氧基)四氢-2H-吡喃-2-甲醛(497mg)的干燥THF(3ml)溶液。混合物在0℃搅拌30分钟,然后在室温搅拌2小时,通过加入饱和氯化铵水溶液使反应停止,混合物用乙醚提取,合并醚层并用饱和食盐水洗涤,硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化,获得(2S,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃(602mg,72%收率)。
(b)将上述硅醚(400mg)的干燥THF(5.5ml)溶液加入到四正丁基氟化铵的THF(1。0M,4.2ml)溶液中,室温下搅拌2小时后,反应用水停止,混合物用乙醚提取,醚提取液用饱和食盐水洗涤,硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化后得到无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基四氢-2H-吡喃-3-醇(233mg,83%收率);
EI-MS:m/z 270(M+);1H-NMR(CDCl3)δ:0.98(3H,d,J=7Hz),1.2~1.4(12H,m),2.0~2.3(2H,m),3.13(1H,dd,J=6&9Hz),3.34(3H,s),3.43(1H,t,J=9Hz),3.56(1H,dd,J=2&12Hz),3.75(1H,dd,J=2&12Hz),3.80(1H,dt,J=1&9Hz),5.36(1H,ddt,J=10,11&2Hz),5.65(1H,dt,J=11&7Hz).
参考实例3:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇的制备
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇(23mg)和二苯基二硫化物(15mg)的环己烷(1ml)溶液用中压汞灯,在室温下照射1小时,除去溶剂后得到粗产物,经制备级薄层色谱纯化(用正己烷∶乙酸乙酯=5∶1展开三次),得到无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(20mg,87%收率);
EI-MS:m/z 270(M+);1H-NMR(CDCl3)δ:0.83(3H,t,J=7Hz),1.03(3H,d,J=7Hz),1.2~1.5(10H,m),2.2(1H,m),2.3(2H,m),3.29(1H,dd,J=5&9Hz),3.36(3H,S),3.4~3.5(2H,m),3.59(1H,dd,J=2&12Hz),3.82(1H,dd,J=1&12Hz),5.54(1H,ddt,J=7,16&2Hz),5.87(1H,dt,J=16&7Hz).
参考实例4:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇的制备
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇(5。0mg)于甲醇(1ml)中,以5%pd/c(10mg)为催化剂氢化1小时,过滤混合物,滤饼用甲醇洗涤,合并滤液,蒸发,获得无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇(4。8mg,96%收率);
EI-MS:m/z 272(M+);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.00(3H,d,J=7Hz),1.2~1.5(16H,m),2.2(1H,m),3.09(1H,m),3.21(1H,dd,J=5&10Hz),3.35(3H,s),3.39(1H,t,J=10Hz),3.52(1H,dd,J=2&12Hz),3.79(1H,dd,J=2&12Hz).
参考实例5:
(2S,3R,4S,5S)-2-(庚氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇的制备
(a)在0℃,将(2S,3R,4S,5S)-(3-苄氧基-4-甲氧基-5-甲基四氢-2H-吡喃-2-基)甲醇(30mg,0.11毫摩尔)的干燥THF(1ml)溶液加到NaH(6mg,0.150毫摩尔)的干燥THF(0.5ml)悬浮液中,20分钟后,在0℃,将溴代正庚烷(22μl,0.14毫摩尔)和碘化钾(22mg,0.13毫摩尔)加到上述混合物中,反应混合物在室温搅拌12小时,然后回流12小时,反应用水停止,并用二氯甲烷提取(2次),合并有机层并用水洗,MgSO4干燥,然后浓缩,剩余的油状物用硅胶柱层析纯化(洗脱液为正己烷∶乙酸乙酯=3∶1),得无色油状的(2S,3R,4S,5S)-3-苄氧基-2-(庚氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃(23mg,56%);EI-MS:m/z 364(M+)
(b)上述醚衍生物(19mg,0.05毫摩尔)和钯炭(5mg)在乙酸乙酯(0.8ml)中的混合物在氢气中搅拌过夜。过滤除去催化剂,并用二氯甲烷洗涤,滤液用硫酸镁干燥,过滤后浓缩。剩余物用硅胶柱层析纯化,洗脱剂为正己烷:AcOEt(1∶1),得无色油状的(2S,3R,4S,5S)-2-(庚氧基甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇(10mg,71%收率);
CI-MS:m/z 275(MH+);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.00(3H,d,J=7Hz),1.27~1.33(7H,m),1.56~1.61(3H,m),2.19(1H,m),2.71(1H,s),3.24(1H,dd,J=9&5Hz),3.32(1H,ddd,J=10,6&4Hz),3.39(3H,s),3.48(1H,dt,J=7&3Hz),3.58(1H,dd,J=12&2Hz),3.58(1H,t,J=9Hz),3.62(1H,dd,J=10&6Hz),3.68(1H,dd,J=10&4Hz),3.82(1H,dd,J=12&2Hz).
参考实例6:
(2S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-酮
在-26℃,将(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(53mg)的干燥甲苯(0.3ml)溶液加入到N-氯代〕二酰亚胺(78mg)和甲硫醚(44μl)的干燥甲苯(2ml)溶液中,所得混合物在-26℃搅拌1小时,将三乙胺(0.1ml)加入到形成的混合物中,在-26℃15分钟后,让混合物温热至室温,然后继续搅拌1小时,反应混合物用乙醚(2ml)稀释,并加入水,混合物用乙醚提取,合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用快速柱色谱纯化(正己烷∶乙酸乙酯=10∶1),得无色油状的(2S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-壬烯基〕四氢-2H-吡喃-3-酮(41mg,78%收率);
EI-MS:m/z 267(M+-H);1H-NMR(CDCl3)δ:0.87(3H,d,J=7Hz),1.02(3H,d,J=7Hz),1.2~1.5(10H,m),2.09(2H,m),2.61(1H,m),3.44(3H,s),3.90(1H,dd,J=3&12Hz),3.97(1H,dd,J=2&12Hz),3.98(1H,dd,J=1&7Hz),4.21(1H,d,J=7Hz),5.64(1H,ddt,J=7,16&2Hz),5.79(1H,dt,J=16&6Hz).
参考实例7:
(2R,3S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺
(a)参考实例6中的酮(41mg)溶解在甲醇(0.5ml)中并冷却到0℃,将硼氢化钠(5.6mg)加到这个溶液中,在0℃搅拌30分钟后,加入水使反应停止,用0.1N盐酸将混合物调节至PH7,混合物用乙醚提取,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶色谱纯化(正己烷∶乙酸乙酯=5∶1),得(2S,3S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(37mg,89%收率)。
(b)在0℃向(2S,3S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(30mg)和2,6-二叔丁基吡啶(27μl)的干燥二氯甲烷(0.5ml)中加入三氟甲磺酸酐(21μl),混合物在0℃搅拌20分钟,然后在0℃用饱和碳酸氢钠水溶液中止反应,形成的混合物用二氯甲烷提取,合并有机提取物用冰冷却的饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,用快速柱色谱纯化剩余物(正己烷∶乙酸乙酯=10∶1)得(2S,3S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基三氟甲磺酸酯(29mg,64%收率),并立即用于下步反应。
(c)将上述磺酸酯(29mg)溶于N,N-二甲基甲酰胺(0。9ml)中并冷却到0℃,将叠氮锂加入到此溶液中,在0℃搅拌15分钟后,用水(2ml)稀释反应混合物,并用乙醚提取。合并醚层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(正己烷∶乙酸乙酯=10∶1)得(2S,3R,4S,5S)-3-叠氮基-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃(9mg,43%收率)。
(d)上述叠氮化物(9mg)和氢化锂铝(2mg)在干燥乙醚(1。5ml)中的混合物回流1小时,将混合物冷却到0℃后,相继向混合物中滴加2μl水,2μl15%氢氧化钠溶液和6μl水,滤去形成的晶状白色沉淀,浓缩滤液得到粗产物,粗产物用制备极薄层色谱纯化(乙酸乙酯为洗脱剂)得无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺(6.8mg,83%收率);
EI-MS:m/z 269(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.03(3H,d,J=8Hz),1.2~1.4(10H,m),2.04(2H,m),2.16(1H,m),3.19(1H,dd,J=5&10Hz),3.36(3H,s),3.46(1H,t,J=10Hz),3.61(1H,dd,J=4&12Hz),3.82(1H,dd,J=4&12Hz),5.42(1H,dd,J=8&16Hz),5.82(1H,dt,J=16&6Hz).
参考实例8:
(2S,3R,4S,5S)-5-甲基-4-甲氧基-2-(1-壬炔基)四氢-2H-吡喃-3-醇的制备
(a)室温下,向三苯膦(136mg)和四溴化碳(172mg)的干燥二氯甲烷(2ml)溶液加入(2S,3R,4S,5S)-4-甲氧基-5-甲基-3-(叔丁基二甲基硅氧基)四氢-2H-吡喃-2-甲醛(50mg)的干燥二氯甲烷(0.5ml)溶液。室温下搅拌1小时后,过滤混合物,并蒸发滤液,剩余物用硅胶柱色谱纯化,得到(2S,3R,4S,5S)-2-(2,2-二溴乙烯基)-3-叔丁基二甲基硅氧基)-4-甲氧基-5-甲基四氢-2H-吡喃(70mg,91%收率)。
(b)在-78℃,上述二溴化物(70mg)的干燥四氢呋喃溶液用正丁基锂(0.19ml的1.65摩尔正己烷溶液)处理,在-78℃搅拌1小时后,将反应混合物温热至室温并继续搅拌1小时,加入饱和氯化铵水溶液使反应中止,混合物用乙醚提取,合并醚提取液并用饱和和食盐水洗涤,无水硫酸钠干燥,浓缩,剩余物用硅胶柱色谱纯化(洗脱液为正己烷∶乙酸乙酯=20∶1),得无色油状的(2S,3R,4S,5S)-S-(叔丁基二甲基硅氧基)-2-乙炔基-4-甲氧基-5-甲基四氢-2H-吡喃(23mg,51%收率);
EI-MS:m/z 284(M+).1H-NMR(CDCl3)δ:0.10(3H,s),0.12(3H,s),0.89(9H,s),0.99(3H,d,J=7Hz),2.20(1H,m),2.42(1H,d,J=2Hz),3.07(1H,dd,J=5&8Hz),3.31(3H,s),3.50(1H,dd,J=3&12Hz),3.67(1H,t,J=8Hz),3.79(1H,dd,J=3&12Hz),3.86(1H,dd,J=2&8Hz).
(c)在-78℃,用正丁基锂(59μl1.65M的正己烷溶液)处理上述乙炔衍生物(23mg)的干燥四氢呋喃溶液,在0℃搅拌30分钟后,加入正溴庚烷(38μl),将混合物温热到室温并继续搅拌1小时,加入饱和氯化铵水溶液使反应中止,混合物用乙醚提取。合并醚提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用薄层色谱纯化,得(2S,3R,4S,5S)-3-(叔丁基二甲基硅氧基)-4-甲氧基-5-甲基-2-(1-壬炔基)四氢-2H-吡喃(10mg,32%收率),按照与参考实例2-b类似的方法,由上述化合物获得了(2S,3R,4S,5S)-5-甲基-4-甲氧基-2-(1-壬炔基)四氢-2H-吡喃-3-醇,为无色油状物;
EI-MS:m/z 268(M+);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.04(3H,d,J=8Hz),1.2~1.4(10H,m),2.2(3H,m),3.21(1H,dd,J=5&9Hz),3.40(3H,s),3.55(1H,dd,J=3&12Hz),3.62(1H,t,J=9Hz),3.82(2H,m).
参考实例9:
(2S,3R,4S,5S)-N-庚基-3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲酰胺的制备
(a)在猛烈搅拌下,将高碘酸钠(0。05g,0.234毫摩尔)和氧化钌(0。02g,0.15毫摩尔)加到(2S,3R,4S,5S)-(3-苄氧基-4-甲氧基-5-甲基四氢-2H-吡喃-2-基)甲醇(0.02g,0.075毫摩尔)的乙腈(2ml),四氯化碳(2ml)和水(ml)的混合溶液中,搅拌12小时后,用0。1N盐酸将反应混合物调节到PH2然后用乙醚(20ml)和水(10ml)分配,醚层用无水硫酸镁干燥,减压下蒸发至干。向所得粗酸的乙醚(5ml)和MeoH(1ml)混合溶液中加入10%的三甲基硅基重氮甲烷的正己烷溶液(0.5g 0.44毫摩尔),混合物在室温搅拌10分钟,在减压下将溶液蒸发至干,剩余物用硅胶柱层析,洗脱液为AcDEt/正己烷(2∶8),得油状的(2R,3R,4S,5S)-3-苄氧基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲酸甲酯(6.6mg,30%收率);
EI-MS m/z 294(M+);
1H-NMR(CDCl3)δ:1.0(3H,d,J=7.2Hz),2.2(1H,m),3.20(1H,dd,J=5&11Hz),3.35(1H,dd,J=4&9Hz),3.6(1H,t,J=9Hz),3.65(3H,s),3.7(3H,s),3.8(1H,d,J=9Hz),4.0(1H,dd,J=4&11Hz),4.59(1H,d,J=12Hz),4.62(1H,d,J=12Hz),7.3(5H,m).
(b)(2R,3R,4S,5S)-3-苄氧基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲甲酸甲酯(7mg,0.024毫摩尔)和庚胺(0.1ml,0.68毫摩尔)的混合物在90℃加热3小时,用0。1N盐酸将反应混合物的PH调至了,并且用乙醚(10ml)和水(10ml)分配,醚层用无水硫酸镁干燥,减压下蒸发至干,形成的粗酰胺的甲醇(5ml)溶液在Pd/C(5mg)存在下,氢气中,室温下搅拌12小时,过滤除去催化剂,并用甲醇(2ml×2)洗涤催化剂。合并滤液和洗涤液,减压下蒸发至干。剩余物在硅胶柱上层析。洗脱液为AcOEt/正己烷(4∶6)。得油状的(2R,3R,4S,5S)-N-庚基-3-羟基-4-甲氧基-5-甲基四氢-2H-吡喃-2-甲酰胺(3.4mg,50%收率)
FAB-MS:m/z 288(MH+).1H-NMR(CDCl3)δ:
0.91(3H,t,J=6.5Hz),1.05(3H,d,J=7Hz),1.25(10H,br.s),2.2(1H,m),3.10~3.6(7H,br.m),3.3(3H,s),3.81(1H,dd,J=2.5&12Hz),8.0(1H,br.s).
参考实例10:
(3S,4S,7S,8S,)-8-甲氧基-7-甲基-4-〔(E)-1-乇烯基〕-1,5-二氧杂螺〔2。5〕辛烷的制备
将三甲基氧化锍的碘化物(74mg)加到氢化钠(14mg,60%油悬浮液)的干燥二甲基硫代酰胺(1ml)的悬浮液中。混合物在室温下搅拌1小时,然后滴加(2S,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-酮(30mg)的干燥四氢呋喃(0。2ml)溶液。在室温搅拌2小时后,加入饱和氯化铵水溶液使反应终止。混合物用乙醚提取,合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,用制备级薄层色谱纯化剩余物(正己烷∶乙酸乙酯=10∶1),得无色油状的(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷;
EI-MS:m/z 282(M+);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.10(1H,d,J=7Hz),1.2~1.4(10H,m),2.0(2H,m),2.2(1H,m),2.43(1H,d,J=5Hz),2.80(1H,d,J=5Hz),3.37(3H,s),3.52(1H,d,J=3Hz),3.66(1H,dd,J=3&12Hz),3.90(1H,dd,J=4&12Hz),3.94(1H,d,J=8Hz),5.56(1H,dd,J=8&15Hz),5.71(1H,m).
参考实例11:
(2S,5R)-(5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基)甲醇的制备
(a)根据参考实例6类似的方法由(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-醇获得(2S,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-酮
(b)0℃,搅拌下,向甲氧基甲基氯化鏻(1,130mg)的干燥四氢呋喃(3ml)悬浮液中加入正丁基锂(1。9ml,1。6M正己烷溶液),混合物在0℃搅拌30分钟后,向形成的深橙色溶液加入(2S,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-酮(273mg)的干燥四氢呋喃(3ml)溶液。30分钟后,让混合物温热至室温,再搅拌2小时加入饱和氯化铵水溶液使反应中止。混合物用乙醚提取,合并有机提抽液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。剩余物用硅胶柱层析纯化(洗脱液为正己烷∶乙酸乙酯=10∶1)。得(2S,4S,5S)-4-甲氧基-5-甲基-3-甲氧甲叉基-2-壬基四氢-2H-吡喃(249mg,83%收率)。
(c)将上述烯醇醚(249mg)和对甲苯磺酸(5。3mg)的二氯甲烷(5ml)溶液搅拌1小时,然后反应混合物用饱和碳酸氢钠水溶液和二氯甲烷分配。有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化,得(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-甲醛(141mg,67%收率)。
(d)室温下,将硼氢化钠加到(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-2-甲醛(141mg)的甲醇(1ml)溶液中。混合物被搅拌30分钟后,加水使反应中止。用0.1N盐酸将混合物的PH调到7,混合物用乙醚提取。合并有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。剩余物用制备级薄层色谱纯化(洗脱剂为正己烷∶乙酸乙酯=5∶1),得无色油状的(2S,5R)-(5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基)甲醇(142mg,100%收率);
EI-MS:m/z254(M+);1H-NMR(CDCl3)δ:0.81(3H,t,J=7Hz),0.94(3H,d,J=8Hz),1.20(14H,br.s),1.36(2H,m),1.48(1H,m),3.39(1H,dd,J=5&11Hz),3.61(1H,dd,J=5&11Hz),3.93(1H,d,J=12Hz),4.01(1H,d,J=12Hz),4.09(1H,d,J=7Hz),5.69(1H,d,J=3Hz).
参考实例12:
(1R,2S,3R)-2-苄氧甲基-3-甲氧基-4,4-二甲基-环己醇的制备
(a)(1S,6R)-3,3-二甲基-6-(1-甲基乙烯基)-2-氧代环己烷-1-甲酸甲酯的制备
氩气中,80-85℃(浴温)及搅拌下,向氢化钠(162mg)和碳酸二甲酯(850μl)的干燥吡啶(1ml)混合物中滴加1-甲基-1,6-二氢香芹酮(335mg)的干吡啶(1.5ml)溶液。混合物在80-85℃搅拌3小时后,用冰浴冷却,反应混合物用乙酸中和并用水稀释,然后用乙醚提取。合并有机提取液并用饱和碳酸氢钠水溶液和饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱色谱纯化(洗脱剂为正己烷∶乙酸乙酯=20∶1),得(1S,6R)-3,3-二甲基-6-(1-甲基乙烯基)-2-氧代环己烷-1-甲酸甲酯(361mg,80%收率)。
(b)(1S,2R,6R)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己烷-1-甲酸甲酯的制备
0℃,将硼氢化钠(217mg)加到(1S,6R)-3,3-二甲基-6-(1-甲基乙烯基)-2-氧代环己烷-1-甲酸甲酯(1。38g)和氯化铈(Ⅱ)t水合物(2.14g)的甲醇(10ml)混合物中,混合物在室温下搅拌1小时,然后加入水中止反应。用0.1N盐酸调节混合物的PH到7,混合物用乙醚提取合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用快速柱色谱纯化(洗脱剂为正己烷∶乙酸乙酯=20∶1),得(1S,2R,6R)-2-羟基-3,3-二甲基-6-(1-甲基乙烯基)环己烷-1-甲酸甲酯(1。15g,83%收率)。
上述醇(1。15g)和氢化钠(230mg,60%油的分散液),碘甲烷(0。6ml)在干N,N-二甲基甲酰胺中的混合物在室温下搅拌3小时。将混合物冷却到0℃,加水中止反应。用0.1N盐酸调节混合物的PH到7,混合物用乙醚提取,合并有机层并用饱和食盐水洗涤,硫酸钠干燥,过滤,浓缩,得(1S,2R,6R)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己烷-1-甲酸甲酯(1。12g,92%收率)。
(c)〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己基〕甲基苄基醚的制备
0℃,分小批向(1S,2R,6R)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己烷-1-甲酸甲酯(1.03g)的干乙醚(10ml)溶液加入氢化锂铝(92mg)室温下将混合物搅拌1小时,混合物冷却到0℃后,相继滴入92μl水,92μl15%氢氧化钠溶液和276μl水,滤去生成的晶状白色沉淀,浓缩滤液得(1R,2R,6R)-〔2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己基〕甲醇(784mg,91%收率)
上述醇(621g)和氢化钠(141mg,60%油中分散液)及溴化苄(0.41ml)的干N,N-二甲基甲酰胺(2.5ml)混合物在室温搅拌10小时,将混合物冷却到0℃后,加水中止反应,用0。1N盐酸调节混合物的PH到7,混合物用乙醚提取合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用快速柱色谱纯化。(洗脱剂为正己烷∶乙酸乙酯=20∶1)得〔(1S,2R,6R)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己基〕甲基苄基醚。(726mg,83%收率)。
(d)〔(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己基〕-1-乙酮的制备
-78℃下,臭氧流鼓泡通过上述烯(600mg)的甲醇(5ml)溶液直玉兰色不消失。N2鼓泡通过上述溶液,加入甲硫醚(1。45ml),撤去冷浴,混合物在室温搅拌2小时,浓缩反应混合物,剩余物用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=10∶1),得〔(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己基〕-1-乙酮(450mg,75%收率)。
(e)(1R,2S,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己醇的制备
在猛烈搅拌下,1小时内,向冰冷却的30%过氧化氢(0。46ml)和二氯甲烷(2.5ml)的混合物中滴加三氟乙酸酐(0。8ml)的二氯甲烷(0.5ml)溶液。滴加完毕后,加入〔(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己基〕-1-乙酮(440mg)的二氯甲烷(0.5ml)溶液。添加在20分钟内进行,形成的混合物在室温搅拌20小时。然后缓慢加入10%亚硫酸钠水溶液。并且继续搅拌15分钟,分离有机相,水相用二氯甲烷提取。合并有机提取液并依次用水,2N碳酸氢钾溶液和饱和食盐水洗涤,最后用无水硫酸钠干燥真空中蒸去溶剂。剩余物在硅胶柱上层析(洗脱剂为正己烷∶乙酸乙酯=20∶1),得(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己基乙酸酯(161mg)和(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己醇(128mg)
乙酸酯衍生物按如下程序转化为醇衍生物:
0℃,向上述乙酸酯(161mg)的干乙醚(2ml)溶液,分小批加入氢化锂铝(10mg),混合物在室温下搅拌30分钟,混合物冷却到0℃后,依次滴入10μl水,10ml15%的氢化钠溶液和30μl水。滤去形成的晶状沉淀,浓缩滤液得(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己醇(128mg,总收率92%);为一无色的油;
EI-MS:m/z 278(M+);1H-NMR(CDCl3)δ:0.90(3H,s),0.98(3H,s),1.1~1.9(5H,m),2.80(1H,d,J=11Hz),3.40(3H,s),3.62(2H,m),3.95(1H,dd,J=3&9Hz),4.53(1H,d,J=12Hz),4.57(1H,d,J=12Hz),7.33(5H,m).
参考实例13:
(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己烷-1-甲醛的制备。
(a)-26℃,向N-氯代丁二酰亚胺(216mg)和甲硫醚(119μl)的干甲苯(3ml)混合物加入(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己醇(150mg)的干甲苯(0.5ml)溶液。然后混合物在-26℃搅拌1小时。向形成的混合物中加入三乙胺(0.37ml)。在-26℃15分钟后,让其混合物温热至室温再继续搅拌1小时用乙醚稀释反应混合物并加入水。用乙醚提取,合并醚相并用饱和食盐水洗涤,无水硫酸钠干燥并浓缩。剩余物用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=10∶1),得(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基-1-环己酮(125mg,83%收率)。
(b)0℃,搅拌下,向甲氧甲基三苯基氯化鏻(460mg)的干四氢呋喃(2ml)悬浮液加入正丁基锂(0.83ml,1.60M的正己烷溶液)。混合物在0℃搅拌30分钟后,向形成的深橙色溶液加入前述酮(125mg)的干四氢呋喃(0.5ml)溶液。30分钟后,混合物让其温热至室温,再搅拌2.5小时。加入饱和氯化铵水溶液中止反应。混合物用乙醚提取,合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=5∶1),得〔(1R,2R)-2-甲氧基-6-(甲氧甲叉)-3,3-二甲基环己基〕甲基苄基醚(99mg,72%收率)。
(c)上述烯醇醚(99mg)和对甲苯磺酸(2.0mg)的二氯甲烷混合物在室温下搅拌1小时。反应混合物用饱和碳酸氢钠水溶液和二氯甲烷分配。有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,并浓缩。剩余物用硅胶柱层析纯化,得无色油状的(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己烷-1-甲醛(68mg,73%收率);
EI-MS:m/z 290(M+);1H-NMR(CDCl3)δ:0.89(3H,s),1.02(3H,s),1.2~1.6(3H,m),2.05(1H,m),2.43(1H,m),2.80(1H,d,J=11Hz),3.42(3H,s),3.54(1H,dd,J=5&9Hz),3.63(1H,dd,J=3&9Hz),4.43(1H,d,J=12Hz),4.47(1H,d,J=12Hz),7.3(5H,m),9.55
参考实例14:
(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇的制备
(a)0℃,搅拌下,向正辛基三苯基溴化鏻(313mg)的干四氢呋喃(0。5ml)和干HMPA(0.5ml)溶液中加入正丁基锂(0.44ml,1.6M的正己烷溶液。混合物在0℃搅拌30分钟后,向形成的橙色溶液加入(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己烷-1-甲醛(68mg)的干四氢呋喃(0。5ml)溶液,混合物在0℃搅拌30分钟,在室温搅拌2小时,加入饱和氯化铵水溶液中止反应。混合物用乙醚提取,合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤浓缩。剩余物在硅胶柱上层析(洗脱剂为正己烷∶乙酸乙酯=10∶1),得〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲基苄基醚(54mg,61%)。
(b)将上述苄醚(54mg)的干四氢呋喃溶液迅速加到搅拌良好的钠(50mg)-液氨(1ml)溶液中,混合物在-33℃搅拌10分钟,加入甲醇中止反应,氨让其蒸发,剩余物用水稀释并用乙醚提取。有机提取物用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。剩余物用制备级薄层色谱纯化(洗脱剂为正己烷∶乙酸乙酯=5∶1)。得无色油状的(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇(33mg,79%收率);
EI-MS:m/z 296(M+);
1H-NMR(CDCl3)δ:0.88(3H,t,J=6Hz),0.90(3H,s),1.03(3H,s),1.2~1.5(15H,m),2.0(2H,m),2.15(1H,m),2.87(1H,d,J=11Hz),3.55(3H,s),3.60(1H,dd,J=7&11Hz),3.73(1H,dd,J=3&11Hz),5.18(1H,dt,J=11&8Hz),5.39(1H,tt,J=1&11Hz)
参考实例15:
(1R,2R,6R)-(2-甲氧基-3,3-二甲基-6-苄氧基环己基)甲醇的制备
(a)(1R,2R,3R)-2-(苄氧甲基)-3-甲氧基-4,4-二甲基环己醇(7mg)和氢化钠(5mg,60%的油分散液)及溴代正辛烷(20μl)的干N,N-二甲基甲酰胺(0.3ml)的混合物在室温搅拌2小时。将混合物冷却到0℃,加加入水中止反应,用0。1N盐酸调节混合物的pH到7,混合物用乙醚提取,合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(洗脱剂为正己烷∶乙酸乙酯=10∶1)得〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-辛基环己基〕甲基苄基醚(8mg,83%)。
(b)上述苄基醚(8mg)在甲醇(0。5ml)中,10%Pd/C存在下,氢解13小时,过滤混合物,滤饼用甲醇洗涤,合并滤液,蒸发得无色油状的(1R,2R,6R)-(2-甲氧基-3,3-二甲基-6-辛氧基环己基)甲醇(5.5mg,89%收率);
EI-MS:m/z 300(M+);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),0.89(3H,s),0.92(3H,s),1.2~1.4(14H,m),1.7(1H,m),1.7~1.9(2H,m),2.52(1H,d,J=11Hz),2.73(1H,dt,J=4&11Hz),3.1~3.5(4H,m),3.55(3H,s).
参考实例16:
1)(1R*,2R*)-4,4-二甲基-2-(2-丙烯基)环己醇的制备
(a)将4,4-二甲基-2-环己烯-1-酮(500mg)的干四氢呋喃(2ml)溶液加到良好搅拌的锂(141mg)-液氨(5ml)溶液中,混合物在-33℃搅拌1小时。然后加入烯丙基溴(2。4g),搅拌30分钟,加入甲醇中止反应,氨让其蒸发,剩余物用水稀释,乙醚提取,有机提取液用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=30∶1),得无水油状的4,4-二甲基-2-(2-丙烯基)环己酮(345mg,52%收率)。
(b)0℃,向三(叔丁氧基)氢化锂铝(460mg)的干四氢呋喃(3。5ml)溶液加入4,4-二甲基-2-(2-丙烯基)环己酮(250mg),混合物在室温下搅拌2小时,加水中止反应,用0.1N盐酸调节混合物的PH到7,乙醚提取,合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩。剩余物用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=20∶1),得无色油状的(1R*,2R*)-4,4-二甲基-2-(2-丙烯基)环己醇(185mg,73%收率);
EI-MS:m/z 168(M+);1H-NMR(CDCl3)δ:0.90(3H,s),0.93(3H,s),1.2~1.8(7H,m),1.95(1H,m),2.46(1H,m),3.23(1H,dt,J=5&11Hz),5.02(1H,br.d,J=10Hz),5.06(1H,br.d,J=17Hz),5.85(1H,m).
2)(1R*,2R*)-5,5-二甲基-2-辛氧基环己-1-基乙醛的制备
(a)(1R*,2R*)-4,4-二甲基-2-(2-丙烯基)环己醇(150mg),氢化钠(43mg,60%的油分散液)和溴代正辛烷(180μl)在干N,N-二甲基甲酰胺(1ml)中的混合物在室温搅拌3小时,混合物让其冷却至0℃,然后加水中止反应。用0.1N盐酸调节混合物的PH到7,乙醚提取,合并有机提取液用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用硅胶柱层析纯化,得无色油状的(1R*,2R*)-4,4-二甲基-2-(2-丙烯基)环己基辛基醚(222mg,89%收率)
(b)在-78℃,臭氧流鼓泡通过(1R*,2R*)-4,4-二甲基-2-(2-丙烯基)环己基辛基醚(200mg)的甲醇(2.5ml)溶液直至兰色不消失。N2鼓泡通过上述系统,并加入甲硫醚(1ml),撤去冷浴,混合物在室温搅拌2小时,将混合物浓缩,剩余物用硅胶柱层析纯化(洗脱剂正己烷∶乙酸乙酯=10∶1),得无色油状的〔(1R*,2R*)-5,5-二甲基-2-辛氧环己-1-基〕乙醛(151mg,15%收率);
EI-MS:m/z 282(M+);1H-NMR(CDCl3)δ:0.90(3H,s),0.92(3H,t,J=7Hz),0.99(3H,s),1.2~1.7(18H,m),1.82(1H,m),2.14(1H,m),2.25(1H,m),2.75(1H,m),3.20(1H,m),3.52(1H,dt,J=5&12Hz),9.68(1H,t,J=2Hz).
参考实例17:(2R,3R,4S,5S)-2-〔(4-氯苯硫基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇的制备
(a)4,6-0-苄叉-2-脱氧-2-甲基-3-0-甲基-1,5-脱水-L-甘露糖醇(400mg),NBS(345mg)(N-溴代丁二酰亚胺),碳酸钡(185mg)在四氢化碳10ml)和1.1,2.2-四氯乙烷中的混合物回流2小时,混合物趁热过滤,滤饼用四氢化碳洗涤,合并滤液,减压下蒸发得粗产物。并用硅胶柱层析纯化(洗脱剂为正己烷∶乙酸乙酯=10∶1)得无色油状的(2R,3R,4S,5R)-2-(溴甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-基苯甲酸酯(231mg 42%收率)。
(b)上述溴化物(20mg),对一氯硫酚(17mg氢化钠(5mg,60%的油中分散液),碘化钾(14mg)在干四氢呋喃(0。5ml)中的混合物在室温搅拌13小时,混合物用水稀释,用0。1N盐酸调节它的PH到7,混合物用二氯甲烷提取。合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(洗脱剂为正己烷∶乙酸乙酯=10∶1),得无色油状的(2R,3R,4S,5S)-2-〔(4-氯苯硫基)甲基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-醇(13mg,75%收率);
EI-MS:m/z 303(M+);1H-NMR(CDCl3)δ:0.97(3H,d,J=6Hz),2.25(1H,m),2.62(1H,m),2.71(1H,m),3.13(1H,m),3.25(3H,s),3.3~3.6(3H,m),7.08(2H,d,J=8Hz),7.25(2H,d,J=8Hz).
实例1:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐的制备
(a)(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-醇(9.0mg),N-(叔丁氧羰基)甘氨酸(17.5mg),4-二甲氨基吡啶(12.0mg)和二环己基碳二亚胺(21。0mg)在于二氯甲烷(0.5ml)中的混合物于室温下搅拌3小时,反应混合物中加入水,混合物在水和二氯乙烷之间分配,有机层用饱和食盐水洗涤。硫酸钠干燥,过滤,浓缩,剩余物用制备极薄层色谱纯化,得(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基,N-(叔丁氧羰基)甘氨酸酯(12.8mg,收率91%);EI-MS:M/Z427(M+)
(b)上述酯(12.8mg)和三氟乙酸(50μl)在干二氯甲烷(0.5ml)中的混合物于室温下搅拌1小时,在减压下蒸发混合物,得无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐(12.0mg,92%收率);
EI-MS:m/z 327(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.89(3H,t,J=7Hz),1.05(3H,d,J=8Hz),1.28(10H,m),1.97(1H,m),2.10(1H,m),2.26(1H,m),3.28(3H,s),3.39(1H,dd,J=5&9Hz),3.57(1H,dd,J=2&12Hz),3.65(1H,br.d,J=17Hz),3.80(1H,dd,J=2&12Hz),3.84(1H,br.d,J=17Hz),4.00(1H,t,J=10Hz),4.93(1H,t,J=9Hz),5.29(1H,t,J=10Hz),5.66(1H,dt,J=8&10Hz)
下述实例2-51的化合物以类似于实例1的方法获得,如无另外说明则均为无色油状物:
实例2:
(2S,3R,4S,5S)-2-〔(E)-1-庚烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 299(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.04(3H,d,J=8Hz),1.2-1.4(6H,m),1.99(2H,m),2.26(1H,m),3.28(3H,s),3.35(1H,dd,J=5&9Hz),3.56(1H,dd,J=2&12Hz),3.64(1H,t,J=8Hz),3.73(1H,br.d,J=17Hz),3.82(1H,dd,J=2&12Hz),3.85(1H,br.d,J=17Hz),4.90(1H,t,J=9Hz),5.38(1H,dd,J=8&16Hz),5.77(1H,dt,J=7&16Hz)
实例3:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-辛烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 313(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.05(3H,d,J=8Hz),1.2-1.4(8H,m),2.00(2H,m),2.71(1H,m),3.29(3H,s),3.36(1H,m),3.56(1H,d,J=12Hz),3.61(1H,t,J=8Hz),3.6-3.9(2H,br),3.80(1H,d,J=12Hz),4.91(1H,t,J=9Hz),5.39(1H,dd,J=7&16Hz),5.77(1H,dt,J=16&7Hz).
实例4:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z327(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=6Hz),1.04(3H,d,J=7Hz),1.24(br.s,10H),2.0(2H,m),2.2(1H,br),3.28(3H,s),3.35(1H,dd,J=5&9Hz),3.56(1H,br.d,J=11Hz),3.62(1H,brt,J=9Hz),3.7-3.9(3H,m),4.90(1H,t,J=9Hz),5.38(1H,dd,J=15&8Hz),5.76(1H,dt,J=15&6Hz)
实例5:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬烯基四氢-2H-吡喃-3-基甘氨酸酯甲酸盐;
EI-MS:m/z 329(M+-HCO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=6.5Hz),1.03(3H,d,J=7Hz),1.25(12H,br.s),1.45(2H,m),1.7(2H,m),2.23(1H,m),3.18(1H,m),3.28(1H,dd,J=4.5&9.8Hz),3.3(3H,s),3.5(1H,dd,J=2.2&12Hz),3.55(2H,br.s),3.78(1H,dd,J=2&12Hz),4.8(3H,br.s),4.87(1H,dd,J=9.8Hz),8.23(1H,br.s).
实例6:
(2S,3R,4S,5S)-2-〔(E)-1-癸烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 341(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.05(3H,d,J=7Hz),1.2-1.4(12H,m),1.98(2H,m),2.26(1H,m),3.29(3H,s),3.35(1H,dd,J=5&9Hz),3.56(1H,dd,J=2&12Hz),3.62(1H,t,J=8Hz),3.6-3.9(2H,br),3.81(1H,dd,J=2&12Hz),4.90(1H,t,J=9Hz),5.39(1H,dd,J=8&16Hz),5.77(1H,dt,16&7Hz).
实例7:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-十一碳烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 355(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.04(3H,d,J=8Hz),1.25-1.3(14H,m),1.99(2H,m),2.26(1H,m),3.28(3H,s),3.36(1H,dd,J=5&9Hz),3.56(1H,br.d,J=12Hz),3.62(1H,t,J=8Hz),3.7-3.9(2H,br),3.81(1H,br.d,J=12Hz),4.90(1H,t,J=9Hz),5.38(1H,dd,J=8&16Hz),5.77(1H,dt,J=16&7Hz).
实例8:
(2S,3R,4S,5S)-2-(4,8-二甲基壬基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 357(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.8-0.9(12H,m),1.0-1.6(14H,m),2.03(1H,m),3.24(1H,m),3.40(1H,t,J=11Hz),3.43(3H,s),3.5-3.8(4H,m),4.91(1H,t,J=9Hz).
实例9:
(2S,3R,4S,5S)-2-〔(1E,3E)-4,8-二甲基-1,3,7-壬三烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 351(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.08(3H,d,J=7Hz),1.46(3H,s),1.67(3H,s),1.73(3H,s),2.04 4H,m)2.71(1H,m),3.25(3H,s),3.3-3.9(6H,m),4.95(1H,t,J=9Hz),5.48(2H,m),5.79(1H,br.d,J=11Hz),6.47(1H,dd,J=11&16Hz).
实例10:
(2S,3R,4S,5S)-2-〔(1Z,3E)-4,8-二甲基-1,3,7-壬三烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 351(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,d,J=8Hz),1.22(3H,s),1.47(3H,s),1.75(3H,s),2.10(5H,m),3.2-3.7(6H,m),3.53(3H,s),4.94(1H,t,J=9Hz),5.30(2H,m),6.05(1H,d,J=2Hz),6.33(1H,5,J=11Hz)
实例11:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1E,3E,5E)-1,3,5-壬三烯〕四氢-2H-吡喃-3-基甘氨酸酯甲酸盐,无色形粉末;
EI-MS:m/z 323(M+-HCO2H);1H-NMR(CDCl3)δ:0.90(3H,t,J=6.5Hz),1.07(3H,d,J=6.7Hz),1.40(2H,m),2.07(2H,dd,J=6.5&14Hz),2.27(1H,m),3.32(3H,s),3.47-3.71(5H,m),3.83(1H,dd,J=2.5&12Hz),4.93(1H,t,J=8.1Hz),5.54(4H,br.m),5.73(1H,m),6.0-6.25(4H,m),8.24(1H,br.s).
实例12:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1Z,3E,5E)-1,3,5-壬三烯〕四氢-2H-吡喃-3-基甘氨酸酯甲酸盐;
EI-MS:m/z 323(M+-HCO2H);1H-NMR(CDCl3)δ:0.91(3H,t,J=6.5Hz),1.08(3H,d,J=6.5Hz),1.43(2H,m),2.09(2H,dd,J=6.5&14Hz),2.28(1H,m),3.36(3H,s),3.41(1H,dd,J=5&8.3Hz),3.4(1H,m),3.50(1H,m),3.57(1H,dd,J=2.5&12Hz),3.82(1H,dd,J=2.3&12Hz),4.15(1H,dd,J=8.3Hz),4.95(1H,dd,J=8.3Hz),5.31(1H,dd,J=8.3&10Hz),5.80(4H,br.m),6.06-6.31(4H,m),8.2(1H,br.s).
实例13:
(2S,3R,4S,5S)-2-〔(E)-2-(4-氯苯基)乙烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 340(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.04(3H,d,J=7Hz),2.27(1H,m),3.42(3H,s),3.39(1H,m),3.61(1H,d,J=11Hz),3.6-3.9(3H,m),3.85(1H,d,J=11Hz),4.95(1H,t,J=9Hz),6.08(1H,dd,J=6&16Hz),6.59(1H,d,J=16Hz),7.23(4H,s).
实例14:
(2S,3R,4S,5S)-2-〔(Z)-2-(4-氯苯基)乙烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:340(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.05(3H,d,J=7Hz),2.29(1H,m),3.27(3H,s),3.35(1H,dd,J=5&9Hz),3.60(1H,d,J=11Hz),3.6-3.8(2H,m),3.85(1H,d,J=11Hz),4.02(1H,t,J=9Hz),5.05(1H,t,J=9Hz),5.61(1H,t,J=10Hz),6.69(1H,d,J=11Hz),7.23(2H,d,J=8Hz),7.31(2H,d,J=8Hz).
实例15:
(2S,3R,4S,5S)-2-〔2-(4-氯苯基)乙基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 342(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.00(3H,d,J=7Hz),2.23(1H,m),2.99(1H,dd,J=8&14Hz),3.10(1H,dd,J=3&14Hz),3.26(3H,s),3.30(1H,dd,J=5&9Hz),3.49(1H,m),3.78(1H,dd,J=3&12Hz),3.85(2H,br.s),5.06(1H,t,J=9Hz),7.20(2H,d,J=9Hz),7.27(2H,d,J=9Hz)
实例16:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-2-萘乙烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 355(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.12(1H,d,J=7Hz),2.31(1H,m),3.44(1H,dd,J=5&9Hz),3.66(1H,dd,J=2&12Hz),3.90(2H,m),5.05(1H,t,J=9Hz),6.25(1H,dd,J=7&16Hz),6.78(1H,d,J=16Hz),7.45(2H,m),7.56(1H,dd,J=2&8Hz),7.7-7.8(4H,m).
实例17:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-(2-萘乙基)四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 357(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.07(3H,d,J=7Hz),1.86(2H,m),2.24(1H,m),2.80(1H,m),3.00(1H,m),3.22(1H,m),3.28(1H,dd,J=5&10Hz),3.29(3H,s),3.52(1H,dd,J=2&12Hz),3.84(1H,dd,J=2&12Hz),3.90(2H,m),4.94(1H,t,J=9Hz),7.32(1H,m),7.42(2H,m),7.44(1H,br.s),7.77(3H,m).
实例18:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔4-(4-甲基苯基)丁基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 361(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.03(3H,d,J=7Hz),1.1-1.51(6H,m),2.22(1H,m),2.55(2H,m),3.16(1H,m),3.28(1H,dd,J=5&9Hz),3.30(3H,s),3.48(1H,dd,J=2&12Hz),3.76(1H,dd,J=2&12Hz),3.91(2H,m),4.86(1H,t,J=9Hz),7.60(4H,m).
实例19:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-(1-壬炔基)四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 325(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.00(3H,d,J=7Hz),1.2-1.6(10H,m),2.18(3H,m),3.30(1H,m),3.34(3H,s),3.48(1H,d,J=12Hz),3.84(3H,m),4.16(1H,d,J=7Hz),5.09(1H,t,J=7Hz).
实例20:
(2R,3R,4S,5S)-2-(4-氯苯硫基)甲基-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 360(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.99(3H,d,J=6Hz),2.22(1H,m),2.61(1H,m),2.74(1H,m),3.13(1H,m),3.25(3H,s),3.27(1H,m),3.49(1H,d,J=12Hz),3.7-3.9(2H,m),3.80(1H,d,J=12Hz),7.07(2H,d,J=8Hz),7.20(2H,d,J=8Hz).
实例21:
(2S,3R,4S,5S)-5-甲基-2-〔(E)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 355(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(6H,t,J=6Hz),1.04(3H,d,J=6Hz),1.26(10H,br.s),1.53(2H,m),2.00(2H,m),2.22(1H,br.s),3.28(1H,m),3.45(2H,m),3.55(1H,d,J=11Hz),3.69(1H,t,J=8Hz),3.79(3H,m),4.92(1H,t,J=8Hz),5.45(1H,dd,J=15&7Hz),5.77(1H,dt,J=15&6Hz).
实例22:
(2S,3R,4S,5S)-5-甲基-2-〔(Z)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 355(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(6H,m),1.05(3H,d,J=7Hz),1.26(10H,br.s),1.52(2H,dq,J=14&7Hz),1.96(1H,m),2.11(1H,m),2.22(1H,m),3.28(1H,dt,J=10&6Hz),3.44-3.49(2H,m),3.57(1H,d,J=10Hz),3.68-3.81(3H,m),4.04(1H,t,J=9Hz),4.95(1H,t,J=9Hz),5.36(1H,t,J=9Hz),5.66(1H,dt,J=9&8Hz).
实例23:
(2S,3R,4S,5S)-5-甲基-2-壬基-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 327(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.84-0.89(6H,m)1.01(3H,d,J=7Hz),1.25(14H,br.s),1.46-1.56(4H,m),2.19(1H,m),3.25(2H,m),3.39(1H,dd,J=5&9Hz),3.45(2H,m),3.75(1H,dd,J=3&12Hz),3.81-3.93(2H,m),4.87(1H,t,J=9Hz).
实例24:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 327(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),0.98(3H,d,J=7Hz),1.27(10H,br.s),2.02-2.11(3H,m),3.25(1H,dd,J=8&3Hz),3.34(3H,s),3.41(1H,dd,J=12&8Hz),3.74(1H,dd,J=12&4Hz),3.81-3.91(2H,m),4.33(1H,br.t,J=6Hz)5.16(1H,m),5.41(1H,dd,J=15&6Hz),5,80(1H,dt,J=15&7Hz)
实例25:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 327(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.02(3H,d,J=6Hz),1.27-1.36(10H,m),2.02-2.18(3H,m),3.30(1H,br.d,J=5Hz),3.35(3H,s),3.42(1H,dd,J=12&6Hz),3.78(3H,m),4.61(1H,br.接近t),5.09(1H,br.接近d,5.37(1H,t,J=9Hz),5.68(1H,dt,J=10&8Hz)
实例26:
(2S,3R,4R,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 329(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.01(3H,d,J=7Hz),1.26(14H,br.s),1.45-1.52(2H,m),2.07(1H,m),3.29(1H,dd,J=7&3Hz),3.36(3H,s),3.37(1H,m)3.73(1H,dd,J=12&4Hz),3.79(1H,br接近t,3.88(2H,br.s),5.03(1H,m)
实例27:
(2S,3R,4S,5S)-4-乙氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 341(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.81(3H,t,J=7Hz),0.98(3H,d,J=7Hz),1.07(3H,t,J=7Hz),1.20(10H,br.s),1.90(1H,m),2.05(1H,m),2.16(1H,m),3.32(1H,t,J=9Hz),3.41(1H,dd,J=9&5Hz),3.50(2H,d,J=10Hz),3.59-3.63(2H,m),3.71(1H,d,J=10Hz),3.96(1H,t,J=9Hz),4.88(1H,t,J=9Hz),5.29(1H,t,J=10Hz),5.58(1H,dt,J=9&8Hz)
实例28:
(2S,3R,5R)-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 297(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.01(3H,d,J=7Hz),1.25-1.35(10H,m),1.76(2H,m),2.03-2.10(3H,m),3.51-3.61(4H,m),3.88(1H,t,J=7Hz),4.91(1H,m),5.46(1H,dd,J=16&7Hz),5.76(1H,dt,J=16&7Hz)
实例29:
(2S,3R,4S,5R)-4,5-二甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 343(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.25-1.30(10H,m),1.98(2H,m),3.16(1H,t,J=11Hz),3.26(1H,t,J=9Hz),3.36(1H,dd,J=10&5Hz),3.47-3.53(8H,m),3.64(1H,t,J=9Hz),4.08(1H,dd,J=11&5Hz),4.76(1H,t,J=10Hz),5.28(1H,dd,J=15&7Hz),5.78(1H,dt,J=15&7Hz)
实例30:
(2S,3R,4S,5R)-5-乙氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 357(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.18-1.32(13H,m),1.98(2H,m),3.18(1H,t,J=11Hz),3.25(1H,t,J=9Hz),3.46(1H,dt,J=10&4Hz),3.50(3H,s),3.61-3.68(5H,m),4.04(1H,dd,J=11&5Hz),4.75(1H,t,J=10Hz),5.28(1H,dd,J=15&7Hz),5.78(1H,dt,J=15&7Hz)
实例31:
(2S,3R,4S,5R)-5-苄氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 419(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.23-1.29(10H,m),1.97(2H,m),3.21(1H,t,J=11Hz),3.34(1H,t,J=9Hz),3.52(3H,s),3.57(1H,dd,J=10&4Hz),3.61-3.66(3H,m),3.98(1H,dd,J=11&5Hz),4.59(1H,d,J=11Hz),4.69(1H,d,J=11Hz),4.77(1H,t,J=10Hz),5.27(1H,dd,J=15&7Hz),5.77(1H,dt,J=15&7Hz),7.27-7.35(5H,m)
实例32:
(2S,3R,4S,5R)-4-甲氧基-2-壬基-5-(3-苯丙氧基)四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 449(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.24-1.37(15H,m),1.42(1H,m),1.86(2H,m),2.66(2H,t,J=8Hz),3.09(1H,t,J=11Hz),3.17-3.23(2H,m),3.39(1H,m),3.50(3H,s),3.56(2H,t,J=7Hz),3.86(1H,br.s),4.01(1H,dd,J=11&5Hz),4.70(1H,t,J=10Hz),7.15-7.19(2H,m),7.25-7.19(3H,m)
实例33:
(2S,3R,4S,5R)-5-(4-叔丁基苄氧基)-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 475(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.23(10H,br.s),1.30(9H,s),1.97(2H,m),3.19(1H,t,J=11Hz),3.34(1H,t,J=9Hz),3.54(3H,s),3.58(1H,dd,J=10&6Hz),3.63(1H,t,J=9Hz),3.72(1H,d,J=18Hz),3.84(1H,d,J=18Hz),3.97(1H,dd,J=12&6Hz),4.55(1H,d,J=11Hz),4.68(1H,d,J=11Hz),4.77(1H,t,J=10Hz),5.27(1H,dd,J=15&7Hz),5.77(1H,dt,J=15&7Hz),7.25(2H,d,J=8Hz),7.36(2H,d,J=8Hz)
实例34:
(2S,3R,4S,5R)-5-(2,4-二氟苄氧基)-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 455(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.86(3H,t,J=7Hz),1.23-1.31(10H,m),1.97(2H,m),3.21(1H,t,J=11Hz),3.31(1H,t,J=9Hz),3.49(3H,s),3.57-3.66(2H,m),3.75-3.86(2H,m),4.02(1H,dd,J=11&5Hz),4.62(1H,d,J=12Hz),4.69(1H,d,J=12Hz),4.77(1H,t,J=9Hz),5.27(1H,dd,J=15&7Hz),5.77(1H,dt,J=15&7Hz),6.79(1h,dt,J=10&2Hz),6.86(1H,dt,J=8&2Hz),7.34(1H,dt,J=8&7Hz).
实例35:
(2S,3R,4S,5R)-5-丁氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 385(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),0.92(3H,t,J=7Hz),1.24-1.39(12H,m),1.52(2H,m),1.98(2H,m),3.17(1H,t,J=11Hz),3.24(1H,t,J=9Hz),3.43(1H,dt,J=10&4Hz),3.50(3H,s),3.58(1H,t,J=7Hz),3.63(1H,t,J=8Hz),3.71(1H,d,J=18Hz),3.84(1H,d,J=18Hz),4.04(1H,dd,J=12&6Hz),4.74(1H,t,J=10Hz),5.28(1H,dd,J=15&8Hz),5.77(1H,dt,J=15&7Hz).
实例36:
(2S,3R,4S,5R)-5-(2-羟基乙氧基)-4-甲氧基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 375(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.25(12H,br.s),1.31-1.45(2H,m),2.07(2H,br.s),3.11-3.28(3H,m),3.48-3.54(6H,m),3.68-3.77(4H,m),4.03(1H,dd,J=12&5Hz),4.77(1H,t,J=9Hz).
实例37:
(2S,3R,4S,5R)-5-(2-羟基-2-甲基丙氧基)-4-甲氧基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 404(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.21(3H,s),1.24(17H,s),1.40(2H,m),3.17(1H,t,J=12Hz),3.28(1H,br.t,J=9Hz),3.35(1H,t,J=9Hz),3.39(1H,d,J=10Hz),3.47-3.54(2H,m),3.48(3H,s),3.95(2H,br.s),4.04(1H,dd,J=12&5Hz),4.76(1H,t,J=9Hz),6.47(1H,br.s).
实例38:
(2S,3R,4S,5R)-4-甲氧基-2-壬基-5-(2-氧丙氧基)四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 388(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.24-1.43(16H,m),2.12(3H,s),3.21(1H,t,J=11Hz),3.26(1H,t,J=9Hz),3.35(1H,t,J=9Hz),3.43-3.53(1H,m),3.48(3H,s),3.94(2H,br.s),4.08(1H,dd,J=11&4Hz),4.28(2H,s),4.71(1H,t,J=9Hz).
实例39:
(2S,3R,4S,5R)-4-甲氧基-2-壬基-5-〔2-(1H-1,2,4-三唑-1-基)乙氧基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 426(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.24-1.60(14H,m),1.95(2H,br.s),3.00(1H,t,J=11Hz),3.13(1H,t,J=9Hz),3.32(3H,s),3.35-3.44(1H,m),3.48(1H,br.s),3.87(1H,dd,J=11&5Hz),3.92-4.05(2H,m),4.33(2H,m),4.70(1H,t,J=10Hz),7.94(1H,s),8.13(1H,s).
实例40:
(2S,3R,4S,5S)-2-庚基氨基甲酰基-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯甲酸盐;
EI-MS:m/z 344(M+-HCO2H);1H-NMR(CDCl3)δ:0.90(3H,t,J=6.5Hz),1.10(3H,d,J=7Hz),1.23(10H,br.s),2.3(1H,m),3.2-3.55(7H,br.m),3.3(3H,s),3.8(1H,dd,J=2.5&12Hz),4.9(1H,t,J=9.9Hz),5.0(3H,br.s),8.0(2H,br.s).
实例41:
(2S,3R,4S,5S)-2-(庚氧甲基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 331(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.04(3H,d,J=7Hz),1.26(10H,m),2.24(1H,m),3.32(3H,s),3.33(1H,dd,J=9&5Hz),3.39-3.48(7H,m),3.55(1H,dd,J=12&2Hz),3.83(1H,dd,J=12&2Hz),4.97(1H,t,J=9Hz).
实例42:
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 328(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=6Hz),0.97(3H,d,J=6Hz),1.27(10H,br.s),1.95(2H,m),2.12(1H,m),3.02(1H,t,J=10Hz),3.13(1H,t,J=12Hz),3.40(3H,s),3.66(1H,br.d,J=18Hz),3.84(2H,m),4.02(1H,t,J=10Hz),4.85(1H,t,J=10Hz),5.24(1H,t,J=10Hz),5.67(1H,dd,J=10&15Hz).
实例43:
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 330(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),0.94(3H,d,J=7Hz),1.25(14H,br.s),1.43(2H,m),1.89(1H,m),2.95(1H,t,J=10Hz),3.03(1H,t,J=12Hz),3.21(1H,t,J=10Hz),3.38(3H,s),3.81(1H,dd,J=5&12Hz),3.86(2H,s),4.77(1H,t,J=10Hz).
实例44:
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 328(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=6Hz),0.95(3H,d,J=6Hz),1.26(10H,br.s),1.97(3H,m),3.00(1H,t,J=10Hz),3.10(1H,t,J=12Hz),3.38(3H,s),3.65(1H,t,J=8Hz),3.71(1H,br.d,J=17Hz),3.83(2H,m),4.81(1H,t,J=10Hz),5.33(1H,dd,J=8&15Hz),5.76(1H,dt,J=8&15Hz).
实例45:
(9S,10R,11R)-11-甲氧基-9-〔(E)-1-壬烯基〕-8-氧杂-1,5-二硫杂螺〔5,5〕十一-10-基甘氨酸酯甲酸盐;
EI-MS:m/z 417(M+-HCO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.25(10H,m),1.97(4H,m),2.72(1H,m),2.88(1H,m),3.00(1H,m),3.13(1H,m),3.43(1H,d,J=9Hz),3.49(2H,d,J=12Hz),3,58(3H,s),3.63(1H,t,J=9Hz),4.22(1H,d,J=12Hz),5.27(1H,t,J=9Hz),5.41(1H,dd,J=8&16Hz),5.74(1H,dt,J=6&16Hz).
实例46:
(6S,7S,10S)-10-甲基-7-〔(E)-1-壬烯基〕-1,4,8-三氧杂螺〔4,5〕癸-6-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 356(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=6.6Hz),1.07(3H,d,J=6.8Hz),1.26-1.44(10H,br.m),2.0(3H,br.m),3.65(1H,dd,J=3.7&11.7Hz),3.78-4.05(11H,br.m),4.98(1H,d,J=8.1Hz),5.47(1H,dd,J=7.3&15.4Hz),5.78(1H,dt,J=7.3&15.4Hz).
实例47:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1E,3E)-1,3-壬二烯基〕四氢-2H-吡喃-3-基甘氨酸酯甲酸盐;
EI-MS:m/z 325(M+-HCO2H);1H-NMR(CDCl3)δ:0.88(3H,t,J=6.5Hz),1.07(3H,d,J=6.5Hz),1.24-1.38(6H,br.m),2.04(2H,q,J=6.5Hz),2.26(1H,m),3.32(3H,s),3.34(1H,dd,J=3.8&9Hz),3.43(1H,d,J=15.0Hz),3.53(1H,d,J=15.0Hz),3,58(1H,dd,J=2.5&10.0Hz),3.65(1H,dd,J=7.5&9.0Hz),3.82(1H,dd,J=2.1&10.0Hz),4.93(1H,t,J=9.0Hz),5.01(3H,br.s),5.47(1H,dd,J=7.5&15.0Hz),5.71(1H,dt,J=6.5&15.0Hz),6.0(1H,dd,J=10.0&15.0Hz),6.21(1H,dd,J=10.0&15Hz),8.08(1H,s).
实例48:
(2S,3R,4S)-4-甲氧基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
FAB-MS:m/z 314(MH+-CF3CO2H);1H-NMR(CDCl3)δ:0.88(3H,br.t),1.27(10H,br.s),1.67(1H,br.m),1.99(1H,br.m),2.14(2H,br.m),3.34(3H,s),3.36-3.49(5H,br.m),3.67(1H,br.m),3.88(1H,br.m),4.03(2H,br.m),4.80(1H,br.m),5.28(1H,br.m),5,68(1H,br.m).
实例49:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-2-(4-丙基苯基)乙烯基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 347(M+-CF3CO2H);1H-NMR(CDCl3)δ:1.03(3H,d,J=7Hz),1.06(3H,t,J=8Hz),1.72(2H,m),2.1-2.3(3H,m),3.42(3H,s),3.40(1H,m),3.62(1H,d,J=12Hz),3.6-3.9(3H,m),3.89(1H,d,J=12Hz),4.96(1H,t,J=9Hz),6.09(1H,dd,J=6&16Hz),6.60(1H,d,J=16Hz),7.26(4H,s).
实例50:
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔2-(4-丙基苯基)乙基〕四氢-2H-吡喃-3-基甘氨酸酯三氟乙酸盐;
EI-MS:m/z 349(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.97(3H,d,J=7Hz),1.03(3H,t,J=8Hz),1.82(4H,m),2.1-2.4(5H,m),3.10(1H,m),3.30(3H,s),3.36(1H,m),3.48(1H,d,J=12Hz),3.6-3.8(2H,m),3.82(1H,d,J=12Hz),4.92(1H,t,J=9Hz),7.23(4H,s)
实例51:
(2S,3R,4S,5R)-4-甲氧基-5-〔2-(吗啉基)乙氧基〕-2-壬基四氢-2H-吡喃-3-基甘氨酸酯二(三氟乙酸)盐;
FAB-MS:m/z 445(MH+-2CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.20-1.43(16H,m),2.95-3.34(6H,m),3.43(3H,s),3.46-3.70(3H,m),3.94-4.04(12H,m),4.74(1H,t,J=8Hz).
实例52:
(2S,3R,4S,5S)-3-〔(氨乙酰基)氨基〕-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃三氟乙酸盐的制备;
(a)(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-胺(5.2mg),N-(叔丁氧羰基)甘氨酸(10.1mg),4-二甲氨基吡啶(7.0mg)和二环己基碳二亚胺(12.0mg)在二氯甲烷(0.5ml)中的混合物在室温搅拌2小时,加水中止反应,混合物用二氯甲烷提取,有机层用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备极薄层色谱纯化(乙酸乙酯为洗脱剂),得(2S,3R,4S,5S)-3-〔〔(叔丁氧羰基氨基)乙酰基〕氨基〕-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃(6.3mg,收率79%)。
(b)上述酰胺(6.0mg)和三氟乙酸(30μl)在干二氯甲烷(0.3ml)中的混合物在室温搅拌1小时,减压下蒸去溶剂,得无色油状的(2S,3R,4S,5S)-3-〔(氨乙酰基)氨基〕-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃三氟乙酸盐(5.6mg,收率83%);
EI-MS:m/z 340(M+-CF3CO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7Hz),1.10(3H,d,J=8Hz),1.1-1.3(10H,m),1.95(2H,m),2.21(1H,m),3.0-3.8(7H,m),3.27(3H,s),5.42(1H,m),5.7(1H,m).
下述实例53-55中的化合物用类似实例52的方法获得。
实例53:
(2S,3R,4S,5S)-3-〔(氨乙酰基)氨基〕-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃甲酸盐;
FAB-MS:m/z 328(MH+-HCO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7.3Hz),1.01(3H,d,J=6.9Hz),1.24(12H,br.s),1.46-1.49(4H,br.m),2.18(1H,m),3.11(1H,m),3.21-3.30(4H,br.m),3.48(1H,br.d,J=11.7Hz),3.76-4.05(4H,br.m),7.05(3H,br.s),7.99(1H,br.m).
实例54:
(1R,2S,3S)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-3-甲氧基-1-辛氧基环己烷三氟乙酸盐;粘稠浆状物;
FAB-MS:m/z 343(MH+-CF3COOH);1H-NMR(CDCl3+D2O)d:0.85(3H,s),0.85(3H,t,J=7Hz),0.95(3H,s),1.1-1.6(12H,m)1.90(2H,m)2.85(1H,d,J)=11Hz),3.17(1H,m),3.3-3,6(2H,m),3.43(3H,s),3.7-4.0(2H,m).
实例55:
(1R,2S,3S)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-3-甲氧基-1-〔2-(4-甲氧苯基)乙基〕环己烷三氟乙酸盐,粘稠浆状物;
EI-MS:m/z 348(M+-CF3COOH);1H-NMR(CDCl3+D2O)δ 0.77(3H,s),0.90(3H,s),1.0-1.35(4H,m),1.7-1.8(2H,m),2.35(1H,m),2.67(1H,d,J=10Hz),2.65(1H,m)3.32(3H,s),3.69(3H,s),3.6-3.9(3H,m),6.75(2H,d,J=8Hz),7.00(2H,d,J=8Hz)
由式(Ⅱ)的化合物(式中R31为氨基)起始的下列化合物也能以类似实例52的方法获得:
(1S,2S,3S)-2-〔(氨基乙酰基)氨基〕-3-甲氧基-4,4-二甲基-1-〔(E)-1-壬烯基〕环己烷,
(1R,2S,3S)-2-〔(氨基乙酰基)氨基〕-3-甲氧基-4,4-二甲基-1-壬基环己烷,
(1S*,2R)-2-〔(氨基乙酰基)氨基〕-4,4-二甲基-1-〔(E)-1-壬烯基〕环己烷,
(1S*,2R*)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-1-壬基环己烷,
(1R*,2R*)-2-〔(氨乙酰基)氨基〕-1-辛氧基-4,4-二甲基环己烷,
实例56:
(2S,3R,4S,5S)-3-〔〔(二甲氨基)乙酰基〕氨基〕-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃的制备
向(2S,3R,4S,5S)-3-〔(氨基乙酰基)氨基〕-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃甲酸盐(10mg)和碳酸钾(15mg)在DMF(1.0ml)中的悬浮液中加入碘甲烷(5μl),在室温搅拌14小时后,反应混合物在减压下蒸发,油状剩余物在乙醚(2ml)和水(2ml)之间分配,醚层用水(1ml)洗涤,减压下蒸发至干,剩余物在硅胶柱上层析,洗脱剂为CH2Cl2/MeOH(8∶2),得粗产物,粗产物进一步用制备极薄层色谱纯化,洗脱剂为AcOEt/i-PrOH,得(2S,3R,4S,5S)-〔〔(二甲氨基)乙酰基〕氨基〕-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃(2mg,21%收率),为一油状物;
FAB-MS:m/z 357(MH+-HCO2H);1H-NMR(CDCl3)δ:0.87(3H,t,J=7.3Hz),1.00(3H,d,J=7.3Hz),1.25(12H,br.s),1.45(2H,m),1.69(2H,m),2.15(1H,m),2.2(3H,br.s),2.25(3H,br.s),3.0(1H,m),3.1(1H,m),3.25-3.7(5H,br.m),3.36(3H,s),7.3(1H,br.s).
实例57:
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甲基氨基甲基膦酸酯的制备
(a)向(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(0.5g),二甲氨基吡啶(0.03g)和(N-苯酯基氨基)甲基膦酸(0.7g)的干吡啶(30ml)溶液加入2,4,6-三(异丙基)苯磺酰氯(0.74g),反应混合物在室温下搅拌12小时,减压下蒸发至干,剩余物在乙醚(50ml)和0.1N盐酸(50ml)之间分配,醚层用无水硫酸钠干燥,减压下蒸发至干,将形成的黄色油溶解在乙醚(30ml)和甲醇(5ml)中,将10%三甲基硅基重氮甲烷的己烷溶液加到上述溶液中直至停止释放气体,将反应混合物蒸发至干,并用硅胶柱层析纯化,洗脱剂为CH2Cl2/AcOEt(7∶3),得无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甲基(苄氧羰氨基)甲基膦酸酯(0.8g,84%收率),EI-MS:m/z 511(M+)
(b)(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甲基(苄氧羰基氨基)甲基膦酸酯(0.8g)的甲醇(20ml)溶液在氢气中,钯黑(50mg)存在下,于室温搅拌4小时,过滤除去催化剂,并用甲醇(10ml×2)洗涤,合并滤液和洗涤液并在减压下蒸发至干,得无色油状的(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-基甲基(氨甲基)膦酸酯(0.534g,90%收率)。
FAB-MS:m/z 380(MH+);1H-NMR(CDCl3)δ:0.88(3H,t,J=6Hz),1.0(3H,d,J=6.3Hz),1.24(14H,br.s),1.54(1H,m),1.7(1H,m),2.31(1H,m),3.1-3.3(5H,br.m),3.37(1.5H,s),3.40(1.5H,s),3.47-3.54(2H,m),3.79(1H,m),3.85(1.5H,d,J=12Hz),3.91(1.5H,d,J=12Hz),4.2(1H,m).
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基(氨甲基)膦酸酯可由与实例57相同的方法但不O-甲基化来获得。
实例58:
(2S,3S,4S,5S)-S-(1H-咪唑-1-基甲基)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇的制备
(3S,4S,7S,8S)-8-甲氧基-7-甲基-4-〔(E)-1-壬烯基〕-1,5-二氧杂螺〔2,5〕辛烷(4.2mg)和咪唑钠衍生物(14.0mg)的干N,N-二甲基甲酰胺(0.5ml)混合物在室温搅拌15小时,反应混合物用水稀释,乙醚提取,合并乙醚提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(乙酸乙酯为洗脱剂)得无水油状的(2S,3S,4S,5S)-3-(1H-咪唑-1-基甲基)-4-甲氧基-S-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-醇(4.1mg,79%收率);
EI-MS:m/z 351(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=8Hz),1.10(3H,d,J=7Hz),1.2-1.5(10H,m),2.1(3H,m),2.39(1H,br.s,-OH),2.93(1H,d,J=5Hz),3.39(3H,s),3.40(1H,dd,J=3&12Hz),3.61(1H,d,J=8Hz),3.76(1H,dd,J=4&12Hz),3.96(1H,d,J=14Hz),4.13(1H,d,J=14Hz),5.87(2H,m),6.91(1H,s),7.14(1H,s),7.46(1H,s).
实例59:
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲基〕-1H-咪唑的制备
(a)0℃,向(2S,5R)-(5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基)甲醇(10mg)和三乙胺(17μl)的干二氯甲烷(0。5ml)混合物中加入甲磺酰氯(10μl),让混合物温热至室温并搅拌30分钟,加入饱和碳酸氢钠水溶液中止反应,形成的混合物用二氯甲烷提取,合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化,得(2S,5R)-(5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基)甲基甲磺酸酯(10.0mg)。
(b)上述磺酸酯(10.0mg)和咪唑钠衍生物(27mg)在干N,N-二甲基甲酰胺(0.5ml)中的混合物在室温下搅拌13小时,加水稀释反应混合物,并用乙醚提取,醚提取物用饱和食盐水洗涤,无水磺酸钠干燥,过滤,浓缩,剩余物在减压下,60℃加热得粗产物,薄层色谱纯化(洗脱剂为乙酸乙酯∶甲醇=10∶1),得无色油状的1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲基〕-1H-咪唑(8.3mg,91%收率);
EI-MS:m/z 304(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.00(3H,d,J=7Hz),1.26(14H,br.s),1.40(2H,m),1.56(1H,m),3.45(1H,dd,J=5&12Hz),3.65(1H,dd,J=4&12Hz),3.90(1H,d,J=7Hz),4.40(1H,d,J=16Hz),4.49(1H,d,J=16Hz),5.56(1H,d,J=4Hz),6.91(1H,s),7.10(1H,s),7.57(1H,s).
下述实例60-62中的化合物由类似实例59的方法获得。
实例60:
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2〔(E)-1-壬烯基〕-2H-吡喃-3-基〕甲基〕-1H-咪唑;无色油状物;
EI-MS:m/z 302(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.01(3H,d,J=7Hz),1.1-1.6(10H,m),2.06(2H,m),2.33(1H,m),3.46(1H,dd,J=6&8Hz),3.70(1H,dd,J=5&11Hz),4.24(1H,d,J=8Hz),4.38(1H,d,J=16Hz),4.47(1H,d,J=16Hz),5.45(1H,dd,J=8&16Hz),5.69(2H,m),6.90(1H,s),7.14(1H,s),7.66(1H,s).
实例61:
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲基〕-1H-1,2,4-三唑;无色无定形粉末;
EI-MS:m/z 305(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),1.02(3H,d,J=7Hz),1.26(14H,br.s),1.40(2H,m),1.56(1H,m),3.47(1H,dd,J=5&12Hz),3.67(1H,dd,J=4&11Hz),3.93(1H,t,J=6Hz),4.64(1H,d,J=16Hz),4.76(1H,d,J=16Hz),5.66(1H,d,J=4Hz),7.98(1H,s),8.20(1H,s).
实例62:
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-(2-萘乙基)-2H-吡喃-3-基〕甲基〕-1H-1,2,4-三唑,无色油状物;
EI-MS:m/z 333(M+);1H-NMR(CDCl3)δ:1.06(3H,d,J=8Hz),2.00(2H,m),2.34(1H,br),2.92(2H,m),3.54(1H,dd,J=5&12Hz),3.74(1H,dd,J=4&12Hz),3.98(1H,br.s),4.63(1H,d,J=16Hz),4.75(1H,d,J=15Hz),5.69(1H,br.s),7.36(1H,d,J=1Hz),7.44(2H,m),7.63(1H,s),7.79(3H,m),7.93(1H,s),8.26(1H,s).
实例63:
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲基-1H-咪唑的制备
(a)0℃,向(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲醇(5mg)和三乙胺(10μl)在干二氯甲烷(0.5ml)中的混合物加入甲磺酰氯(4μl),将混合物温热至室温并搅拌1小时,加入饱和碳酸氢钠水溶液中止反应,形成的混合物用二氯甲烷提取,合并有机层并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(正己烷∶乙酸乙酯=10∶1为洗脱剂),得(1R,2R,6S)-〔2-甲氧基-3,3-二甲基-6-〔(E)-壬烯基〕环己基〕甲基甲磺酸酯(5.5mg,85%收率)。
(b)上述磺酸酯(5.5mg)和咪唑钠衍生物(13mg)在干N,N-二甲基甲酰胺(0.3ml)中的混合物在室温搅拌6小时,反应混合物用水稀释,并用乙醚提取,合并有机提取液并用饱和食盐水洗涤,无水硫酸钠干燥,过滤,浓缩,剩余物用制备级薄层色谱纯化(乙酸乙酯为洗脱剂)得无色油状的1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲基〕-1H-咪唑(3.8mg,78%收率);
EI-MS:m/z 346(M+);1H-NMR(CDCl3)δ:0.78(3H,t,J=7Hz),0.89(3H,s),1.05(3H,s),1.2-1.4(15H,m),1.7-2.0(3H,m),2.58(1H,d,J=13Hz),3.57(3H,s),4.07(1H,d,J=14Hz),4.16(1H,dd,J=3&14Hz),5.16(1H,dd,J=9&15Hz),5.51(1H,dd,J=15&7Hz),7.15(1H,s),7.22(1H,s),7.80(1H,s).
下述实例64-83中的化合物由类似实例63的方法制备。
实例64:
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(Z)-1-壬烯基〕环己基〕甲基〕-1H-咪唑,无色油状物;
EI-MS:m/z 346(M+);1H-NMR(CDCl3)δ:0.88(3H,t,J=7Hz),0.90(3H,s),1.05(3H,s),1.2-1.5(14H,m),1.63(1H,m),2.0-2.2(3H,m),2.64(1H,d,J=10Hz),3.59(3H,s),3.98(1H,dd,J=4&15Hz),4.07(1H,dd,J=4&15Hz),5.15(1H,dd,J=9&11Hz),5.43(1H,dt,J=11&7Hz),6.93(1H,s),7.05(1H,s),7.53(1H,s).
实例65:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-壬基环己基〕甲基〕-1H-1,2,4-三唑,无色油状物;
EI-MS:m/z 349(M+);1H-NMR(CDCl3)δ:0.86(3H,s),0.88(3H,t,J=8Hz),1.04(3H,s),1.1-1.91(22H,m),2.87(1H,d,J=10Hz),3.63(3H,s),4.29(1H,dd,J=4&14Hz),4.52(1H,d,J=14Hz),8.05(1H,m),8.24(1H,m).
实例66:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-壬基环己基〕甲基〕-1H-咪唑,无色油状物;
EI-MS:m/z 348(M+);1H-NMR(CDCl3)δ:0.87(3H,t,J=8Hz),0.87(3H,s),1.03(3H,s),1.1-1.4(20H),1.8-2.0(2H,m),2.56(1H,d,J=9Hz),3.58(3H,s),4.07(1H,dd,J=3&14Hz),4.19(1H,dd,J=3&14Hz),6.97(1H,s),7.10(1H,s),7.65(1H,s).
实例67:
(1R,2R,6S)-1-〔3,3-二甲基-2-甲氧基-6-(1-甲基乙烯基)〕环己烷-1-基甲基-1H-咪唑,无色油状物;
EI-MS:m/z 262(M+);1H-NMR(CDCl3)δ:0.92(3H,s),1.05(3H,s),1.2-1.6(4H,m),1.56(3H,s),1.9(2H,m),2.63(1H,d,J=10Hz),3.59(3H,s),3.93(1H,dd,J=2&14Hz),4.08(1H,dd,J=3&14Hz),4.84(1H,br.s),4.87(1H,br.s),6.94(1H,s),7.01(1H,s),7.45(1H,s).
实例68:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-辛氧基环己基〕甲基〕-1H-咪唑,无色油状物;
EI-MS:m/z 350(M+);1H-NMR(CDCl3)δ:0.81(3H,t,J=10Hz),0.83(3H,s),0.96(3H,s),1.2-1.4(14H,m),1.6(1H,m),1.7-1.9(2H,m),2.49(1H,d,J=11Hz),2.72(1H,dt,J=4&11Hz),3.14(1H,dd,J=7&16Hz),3.52(1H,m),3.55(3H,s),4.15(1H,dd,J=3&14Hz),4.21(1H,dd,J=4&14Hz),6.90(1H,s),7.03(1H,s),7.55(1H,s).
实例69:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-辛氧基环己基〕甲基〕-1H-1,2,4-三唑,无色油状物;
EI-MS:m/z 351(M+);1H-NMR(CDCl3)δ:0.92(3H,t,J=10Hz),0.95(3H,s),1.07(3H,s),1.3-1.5(14H,m),1.7(1H,m),1.9(2H,m),2.64(1H,dt,J=4&11Hz),2.92(1H,d,J=11Hz)3.14(1H,dd,J=7&16Hz),3.58(1H,dd,J=6&15Hz),3.72(3H,s),4.52(1H,d,J=14Hz),4.58(1H,dd,J=4&14Hz),8.06(1H,br.s),8.23(1H,br.s).
实例70:
4-三氟甲基-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-咪唑-1-基甲基)环己基〕苯甲酰胺:无色油状物;
EI-MS:m/z 409(M+);1H-NMR(CDCl3)δ:1.04(3H,s),1.09(3H,s),1.35(1H,m),1.47(1H,m),1.74~2.0(3H,m),2.71(1H,br.s),3.55(3H,s),4.11(1H,m),4.22(2H,s),6.86(1H,s),7.00(1H,s),7.58(2H,d,J=7.3Hz),8.04(2H,d,J=7.3Hz),8.04(1H,d,J=7.3Hz),8.66(1H,s).
实例71:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-〔4-N,N-二甲氧基)苯基〕乙基〕环己基〕甲基〕-1H-1,2,4-三唑;无色粘稠浆状物;
EI-MS:m/z 370(M+);1H-NMR(C6D6)δ:0.91(3H,S),0.95(3H,s),0.87-1.00(3H,m),1.11-1.32(2H,m)1.40-1.47(2H,m),1.76-1.86(1H,m),2.23-2.32(1H,m),2.51-2.58(1H,m),2.59(6H,s)2.88(1H,d,J=10.3Hz),3.51(3H,s),3.69(1H,dd,J=4.0&14.7Hz),4.21(1H,dd,J=2.2&14.7Hz),6.72(2H,d,J=8Hz),7.10(2H,d,J=8Hz),7.57(1H,s),7.99(1H,s).
实例72:
1-〔〔(1R,2R,6R)-6-〔2-〔4-氯苯基)乙基〕-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,无色粘稠浆状物;
EI-MS:m/z 361(M+);H-NMR(CDCl3)δ:0.89(3H,s),1.05(3H,s),1.00-1.28(3H,m),1.33-1.40(1H,m)1.41-1.52(1H,m),1.59-1.70(2H,m),190-2.00(1H,m),2.35-2.46(1H,m),2.60-2.70(1H,m),2.86(1H,d,J=11.0Hz),3.63(3H,s),4.28(1H,dd,J=4.4&14.7Hz),4.48(1H,dd,J=2.2&14.7Hz),7.09(2H,d,J=8.1Hz),7.25(2H,d),7.96(1H,s),8.10(1H s)
实例73:
1-〔〔(1R,2R,6R)-6-〔(4-氯苯硫基)甲基〕-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,无色粘稠浆状物;
EI-MS m/z 379(M+);1H-NMR(CDCl3)δ:0′.91(3H,s),1.04(3H,s),1.10-1.49(3H,m),1.57-1.69(2H,m),1.93(1H,m),2.75(1H,d,J=11Hz),3.05/(1H,dd,J=7.4&12.5Hz),3.26(1H,dd,J=3&12.5Hz),3.59(3H,s),4.25(1H,dd,J=3.7&14.7Hz),4.50(1H,dd,J=2.9&14.7Hz),7.26(4H,m),7.97(1H,s),8.24(1H,s).
实例74:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-(4-甲苯基)乙基)环己基〕-1H-1,2,4-三唑,无色粘稠浆状物;
EI-MS:m/z 341(M+);1N-NMR(CDCl3)δ:0.89(3H,s),1.05(3H,s),1.00-1.28(3H,m),1.33-1.40(1H,m),1.42-1.55(1H,m),1.60-1-70(2H,m),1.91-2.01(1H,m),2.33(3H,s),2.33-2.44(1H,m),2.61-2.71(1H,m),2.99(1H,d,J=10.3Hz),3.64(3H,s),4.27(1H,dd,J=4.0&14.3Hz),4.49(1H,dd,J=2.6&14.3Hz),7.04-7.14(4H,m),7.95(1H,s).
实例75:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(2-β-萘乙基)环己基〕甲基〕-1H-1,2,4-三唑,无色粘稠浆状物;
EI-MS:m/z 377(M+);1H-NMR(CDCl3)δ:0.91(3H,s),1.05(3H,s),1.08-1.42(3H,m),1.35-1.42(1H,m),1.54-1.65(1H,m),1.65-1.75(2H,m),2.04-2.15(1H,m),2.54-2.65(1H,m),2.80-2.89(1H,m),2.89(1H,d,J=10.7Hz),3.63(3H,s),4.29(1H,dd,J=4.4&14.6Hz)4.50(1H,dd,J=2.4&14.6Hz),7.31(1H,d,J=8.3Hz),7.39.749(2H,m),7.59(1H,s),7.76-7.84(3H,m),7.94(1H,s)8.09(1H,s)
实例76:
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-(2-喹啉-2-基乙基)环己基〕甲基〕-1H-1,2,4-三唑,无色固体;
EI-MS:m/z 378(M+);1H-NMR(CDCl3)d.0.90(3H,s),1.04(3H,s),1.08-1.40(4H,m),1.50-1.83(3H,m),2.30-2.38(1H,m),2.88(1H,d,J=10Hz),2.80-2.97(1H,m),3.05-3.18(1H,m),3.65(3H,s),4.38(1H,bd),4.55(1H,dd,J=2&14.8Hz),7.30(1H,m),7.53(1H,m),7.82(1H,m),7.77-7.84(1H,m),7.94(1H,s),8.00-8.22(2H,m),8.21(1H,s).
实例77:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-(4-三氟甲基苯基)乙基〕环己基〕甲基〕-1H-1,2,4-三唑,无色固体;
EI-MS:m/z 395(M+);1H(CDCl3)δ0.90(3H,s),1.96(3H,s),1.06-1.29(3H,m),1.36-1.42(1H,m),1.46-1.57(1H,m),1.61-1.72(2H,m),1.98-2.08(1H,m),2.45-2.56(1H,m),2.68-2.80(1H,m),2.86(1H,d,J=11Hz),3.63(3H,s),4.29(1H,dd,J=4.4&14.7Hz),4.49(1H,dd,J=2.9&14.7Hz),7.28(2H,d,J=8,OHz)7.54(2H,d,J=8.0Hz)7,96(1H,s),8.13(1H,s).
实例78:
1-〔〔(1R,2R,6R)-6-(对-三氟甲氧基苯乙基)-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑;无色结晶;
FAB-MS:m/z 412(MH+);1H-NMR(CDCl3)δ 0.89(3H,s),1.06(3H,s),1.1-1.3(2H,m),1.38(1H,m),1.49(1H,m)1.6-1.8(2H,m),1.9-2.1(2H,m)2.44(1H,m),2.69(1H,m),2.87(1H,d,J=11Hz),3.64(3H,s),4.29(1H,dd,J=4&15Hz),4.93(1H,dd,J=2&15Hz),7.27(2H,d,J=9Hz),7.17(2H,d,J=9Hz),7.96(1H,s),8.13,(1H,s).
实例79:
1-〔〔(1R,2R,6R)-2-甲氧基-6-(对-甲氧基苯乙基)-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,无色结晶;
EI-MS:;m/z 357(M+);1H-NMR(CDCl3)δ:0.89(3H,s),1.04,3H,s),1.1-1.3(2H,m)1.36(1H,m)1.48(1H,m),1.6-1.7(2H,m)1.8-2.0(2H,m),2.37(1H,m),2.66(1H,m),2.89(1H,d,J=11Hz),3.64(3H,s),3.79(3H,s),4.27(1H,dd,J=4&15Hz),4.49(1H,dd,J=3&15Hz,),6.83(2H,d,J=9Hz),7.08(2H,d,J=9Hz),7.94(1H,s),8.01(1H,s).
实例80:
1-〔〔(1R,2R,6S)-6-(2,4-二氟苯乙基)-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,无色结晶;
EI-MS:m/z 363(M+);1H-NMR(CDCl3)δ:0.89(3H,s),1.06(3H,s),1.1-1.5(6H,m),1.8-2.0(2H,m),2.4-2.5(1H,m),2.6-2.7(1H,m),2.93,(1H,d,J=11Hz),3.66(3H,s),4.29(1H,dd,J=4&15Hz),4.51(1H,d,J=15Hz),6.7-6.9(2H,m),7.0-7.2(1H,m),7.93(1H,s).
实例81:
1-〔〔(1R,2R,6R)-6-(4-乙苯基)乙基-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,无色形粉末;
EI-MS:m/z 355(M+);1H-NMR(CDCl3)δ:0.89(3H,s),1.05(3H,s),1.13(1H,m),1.22(3H,t,J=7Hz),1.23(1H,m)1.37(1H,dd,J=3&13Hz),1.51(1H,m),1.63-1.70(2H,m),1.98(1H,m),2.18(1H,m),2.42(1H,m),2.63(2H,q,J=8Hz),2.69(1H,m),2.88(1H,d,J=10Hz),3.63(3H,s),4.27(1H,dd,J=4&14hz),4.50(1H,dd,J=2&15Hz),7.08(2H,d,J=8Hz),7.13(2H,d,J=8Hz),8.00(1H,s),8.14(1H,s).
实例82:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-(4-吡咯烷基苯基)乙基〕环己基〕甲基〕-1H-1,2,4-三唑,无色粘稠浆状物;
EI-MS:m/z 396(M+)1H-NMR(C6D6)δ:0.77-1.02(3H,m),0.91(3H,s),0.94(3H,s),1.11-1.34(2H,m),1.40-1.57(6H,m),1.78-1.89(1H,m),2.28-2.38(1H,m),2.55-2.66(1H,m),2.88(1H,d,J=11.2Hz),2,98-3.06(4H,m),3.51(3H,s),3.70(1H,brd,J=14Hz),4.21(1H,brd,J=14Hz),6.60(2H,d,J=8Hz),7.12-7.21(2H),7.59(1H,s),7.99(1H,s).
实例83:
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(4-乙基苯氧基)甲基〕甲基〕-1H-1,2,4-三唑,粘稠浆状物;
EI-MS:m/z 357(M+);1H-NMR(CDCl3)δ:0.94(3H,s)1.06(3H,s),1.21(3H,t,J=8Hz),1.4-1.75(5H,m),2.59(2H,q,J=8Hz),2.87(1H,d,J=11Hz),3.64(3H,s),3.92(1H,dd,J=4&10Hz),4.08,(1H,dd,J=4&10Hz),4.36(1H,dd,J=4&14Hz),4.59(1H,dd,J=3&14Hz,6.81(2H,d,J=9Hz),7.11(2H,d,J=9Hz,7.96.(1H,s),8.26(1H,s).
由式(Ⅴ)所示化合物起始,由类似实例61的方法获得下述化合物:
(1R,2R,6R)-1-〔〔2-甲氧基-3,3-二甲基-6-(萘甲氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R,2R,6R)-1-〔〔2-甲氧基-3,3-二甲基-6-(2-萘乙氧基)环己基〕甲基〕-1H-咪唑;
(1R,2R,6R)-1-〔〔2-甲氧基-3,3-二甲基-6-(2-萘乙氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R*,2S*)-1-〔〔5,5-二甲基-2-〔(E)-1-壬烯基〕环己基〕甲基〕-1H-咪唑;
(1R*,2S*)-1-〔〔5,5-二甲基-2-〔(E)-1-壬烯基〕环己基〕甲基〕-1H-1,2,4-三唑;
(1R*,2R*)-1-〔〔5,5-二甲基-2-壬基环己基〕甲基〕-1H-咪唑;
(1R*,2R*)-1-〔〔5,5-二甲基-2-壬基环己基〕甲基〕-1H-1,2,4-三唑;
(1S*,2R*)-1-〔〔5,5-二甲基-2-辛氧基环己基〕甲基〕-1H-咪唑;
(1S*,2R*)-1-〔〔5,5-二甲基-2-辛氧基环己基〕甲基〕-1H-1,2,4-三唑;
(1R*,2S*)-〔〔5,5-二甲基-2-〔(Z)-1-壬烯基〕环己基〕甲基〕-1H-咪唑;
(1R*,2S*)-〔〔5,5-二甲基-2-〔(Z)-1-壬烯基〕环己基〕甲基〕-1H-1,2,4-三唑;
(1R*,2S*)-〔〔5,5-二甲基-2-〔(E)-2-萘乙烯基〕环己基〕甲基〕-1H-咪唑;
(1R*,2S*)-〔〔5,5-二甲基-2-〔(E)-2-萘乙烯基〕环己基〕甲基〕-1H-1,2,4-三唑;
(1R*,2S*)-〔〔5,5-二甲基-2-(2-萘乙基)环己基〕甲基〕-1H-咪唑;
(1R*,2S*)-〔〔5,5-二甲基-2-(2-萘乙基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(萘甲氧基)环己基〕甲基〕-1H-咪唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(萘甲氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(2-萘乙氧基)环己基〕甲基〕-1H-咪唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(2-萘乙氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(喹啉基甲氧基)环己基〕甲基〕-1H-咪唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(喹啉基甲氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(2-喹啉基乙氧基)环己基〕甲基〕-1H-咪唑;
(1R,2R,6R)-〔〔2-甲氧基-3,3-二甲基-6-(2-喹啉基乙氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(萘甲氧基)环己基〕甲基〕-1H-咪唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(萘甲氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(2-萘乙氧基)环己基〕甲基〕-1H-咪唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(2-萘乙基)环己基〕甲基〕-1H-1,2,4-三唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(喹啉基甲氧基)环己基〕甲基〕-1H-咪唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(喹啉基甲氧基)环己基〕甲基〕-1H-1,2,4-三唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(2-喹啉基乙氧基)环己基〕甲基〕-1H-咪唑;
(1S*,2R*)-〔〔5,5-二甲基-2-(2-喹啉基乙氧基)环己基〕甲基〕-1H-1,2,4-三唑;
2-氟-4-三氟甲基-N-〔(1R,2R,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺;
2,4-二氟-N-〔(1R,2R,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺;
2,4-二氯-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺;
4-三氟甲基-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺。
实例84:
1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕-3-氨基-2-丙醇的制备
(a)(1R*,2R*)-5,5-二甲基-2-辛氧基环己烷-1-基乙醛(50mg),三甲基硅氰(35mg)和碘化锌(5mg)在干苯(1ml)中的混合物于室温下搅拌1小时,过滤反应混合物,浓缩滤液,得粗产物直接用于下步反应;
(b)上述三甲基硅基氰醇(25mg)和氢化锂铝(5mg)在干四氢呋喃(0。5ml)的混合物回流1小时,将混合物冷却到0℃,依次滴入5μl水,5μl15%氢氧化钠溶液,和15μl水,滤去形成的晶状沉淀,浓缩滤液得粗产物,用制备级薄层色谱纯化(展开液为乙酸乙酯∶甲醇=10∶1)得无色液体1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕-3-氨基-2-丙醇(13mg,63%收率);
FAB-MS:m/z313(MH+);1H-NMR(CDCl3)δ:0.88(3H,t,J=10Hz),0.92(3H,s),0.94(3H,s),1.2-1.7(20H,m),1.95(1H,m),2.80(2H,br.m),3.2-3.4(2H,m),3.4(2H,m).
由式(Ⅵ)所示的化合物起始,用类似实例84的方法,获得下列化合物:
3-氨基-1-〔(1S*,2R*)-5,5-二甲基-2-苯丙氧基)环己基〕丙-2-醇,
3-氨基-1-〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-辛氧基环己基〕丙-2-醇,
3-氨基-1-〔(1S,2R,6R)-2-甲氧基-3,3-二甲基-6-壬基环己基〕丙-2-醇,
3-氨基-1-〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(3-苯丙氧基)环己基〕丙-2-醇。
实例85:
3-氨基-1-〔(1S*,2S*)-5,5-二甲基-2-辛氧基环己基〕-2-丙酮的制备
(a)3-氨基-1-〔(1S*,2S*)-5,5-二甲基-2-辛氧基环己基〕-2-丙醇(50mg),S-叔丁氧羰基-4,6-二甲基-2-巯基吡啶(46mg)和三乙胺(20μl)在甲醇(1。5ml)中的混合物于室温下搅拌2小时。混合物中加入水,让其在水和乙醚之间分配,有机层用饱和食盐水洗涤,硫酸钠干燥,过滤,浓缩。剩余物用硅胶柱色谱纯化(洗脱剂为正己烷∶乙酸乙酯=5∶1)。得3-〔(叔丁氧羰基)氨基〕-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕-2-丙醇(55mg,83%收率);EI-MS:m/z395(M+-H2O)。
(b)上述醇(10mg)和吡啶-铬酸盐(120mg)在二氯甲烷(2ml)中的混合物于室温下搅拌20小时,用乙醚稀释反应混合物,混合物通过填充有硅胶的漏斗过滤,滤饼用乙醚洗涤,合并滤液并蒸发,得3-〔(叔丁氧羰基)氨基〕-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕-2-丙酮(7.9mg,80%收率),FAB-MS:m/z412(MH+)。
(c)上述酮(6mg)和三氟乙酸(100μl)在二氯甲烷(0.5ml)中的混合物于室温下搅拌1小时,减压下蒸发混合物得无色油状的3-氨基-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕-2-丙酮三氟乙酸盐(4.4mg,71%收率);
EI-MS:m/z 311(M+-CF3CO2H);1H-NMR(CDCl3)δ;0.87(3H,t,,J=7Hz),0.89(3H,s),0.96(3H,s),1.2~1.6(18H,m),1.9~2.3(3H,m),2.80(1H,m),3.19(1H,m),3.50(1H,m),3.92(1H,br.d,J=12Hz),4.05(1H,br.d,J=12Hz).
实例A
按常规方法制造了每个含下述成份的硬质明胶胶囊:
1-[[(1R,2R,6R)-2-甲氧基
-3,3一二甲基-6-辛氧基环已基]甲基]
-1H-咪唑 100mg
乳糖 56mg
结晶纤维素 30mg
硅酸,疏松无水 10mg
滑石 3mg
硬脂酸镁
1mg
共计 200mg
实例B:
按常规方法制造了每片含下述成份的片剂:
1-[[(1R,2R,6R)-2-甲氧基
-3,3一二甲基-6-辛氧基环已基]甲基]
-1H-咪唑 100mg
乳糖 60mg
玉米淀粉 20mg
乙二醇化的淀粉的钠盐 10mg
聚乙烯基吡咯烷酮 6mg
滑石 3mg
硬脂酸镁
1mg
共计 200mg
Claims (13)
1、制备式(Ⅰ)所示化合物和药学上适宜的盐,以及式(Ⅰ)所示化合物的水合物或溶剂化物和它们的盐的方法
式中,X为-O-或-CH2-;
R′为-Y-烷基,-Y-芳烷基或-Y-芳基[其中Y代表-O-,-CONH-,-NHCO-,-(CH=CH)n-(其中n代表0,1,2或3),-C≡C-,-CH2O-或-CH2S-];
R2为氢或羟基;
R3是一个能与血红素配位的基团;
R4和R5分别为氢,低级烷基,烷氧基或烷硫基,或R4和R5一起与相邻碳原子相连而形成5-或6-负缩酮环;
R6为氢,低级烷基,烷氧基或烷硫基,氨基,低级烷基氨基,或二低级烷基氨基;
R7为氢,羟基,低级烷基,烷氧基或烷硫基,它们可以任意取代有一个羟基,酰基或芳基,或含有一个或多个氮原子的5-或6-负杂环,这些杂环还可能含有1个氧或硫原子;或者
R6和R7共同与相邻碳原子相连形成5-或6-负缩酮环;或者
R2和R4相互连接形成一个单键。
其方法包括
(A)用N-保护甘氨酸或它的活泼酯来酰化式(Ⅱ)所示化合物,然后再除去保护基,以制
(式中R31为羟基或氨基,向R1,R4,R5,R6,R7和X与前述定义同)
备式(Ⅰ)所示化合物(式中R2为氢原子,R3为氨基乙酰氧基或(氨基乙酰)氨基,而R1,R4,R5,R6,R7和X与前述定义同),或者
(B)让式(Ⅱ)所代表的化合物(式中R31为羟基而R1,R4,R5,R6,R7和X与前述定义同)与N-保护的(氨甲基)膦酸反应,接着如果需要的话生成的膦酸酯发生O-甲基化,然后除去保护基以制备式(Ⅰ)所示化合物,(式中R2为氢原子,R3为(氨甲基)羟基膦酰氧基或O-甲基-(氨甲基)羟基膦酰氧基,而R1,R4,R5,R6,R7和X同前述定义。或者
(C)N-烷基化式(Ⅲ)所代表的化合物,如果
(式中Z为-NHCOCH2-,-O-PO(OH)CH2-,-O-PO(OCH3)CH2-,-CH2CH(OH)CH2-,或
-CH2COCH2-,R32为氢或N-保护的基团,向R1,R4,R5,R6,R7和X同前述定义)
需要的话,接着除去N-保护基,从而制备式(Ⅰ)所示的化合物(式中R2为氢原子,R3为[(低级烷基氨基)乙酰基]氨基,
[(二低级烷基)乙酰基]氨基,[(低级烷基氨基)甲基]羟基膦酰氧基,O-甲基[(低级烷基氨基)甲基]羟基膦酰氧基,3-(低级烷基氨基)-a-氧代丙基,3-(二低级烷基氨基)-a-氧代丙基,3-(低级烷基氨基)-a-羟基丙基,或3-(二低级烷基氨基)-a-羟基丙基,而R1,R4,R5,R6,R7和X同前述定义),或
(D)式(Ⅳ)所代表的化合物与咪唑或1H-1,2,4-
(式中R1,R4,R5,R6,R7和X同前述)三唑的碱金属盐反应来制备通式(Ⅰ)所代表的化合物(式中R2为羟基,R3为唑系-1-基甲基而R1,R4,R5,R6,R7和X同前述定义。或
(E)式(Ⅴ)所代表的化合物与甲磺酰氯,
(式中R2为氢或R2和R4共同形成一个键,而R1,R4,R5,R6,R7和X同前述定义)
对甲苯磺酰氯或三氟甲磺酸酐反应,接着形成的甲磺酸酯,对甲苯磺酸酯或三氟甲磺酸酯用咪唑或1H-1,2,4-三唑的碱金属盐处理,以制备式(Ⅰ)所代表的化合物(式中R3为1H-咪唑-1-基甲基或1H-1,2,4-三唑-1-基甲基,而R1,R4,R5,R6,R7和X同前述定义),或
(F)式(Ⅵ)所代表的化合物与三甲基硅氰反
(式中R1,R4,R5和R7同前述定义)
应,接着将形成的O-保护的氰醇还原为β-氨基醇,从而制备式(Ⅰ)所代表的化合物(式中X为亚甲基,R2为氢原子,R3是3-氨基-2-羟基丙基,R6是甲基,而R1,R4,R5和R7同前述定义)。
2、按权项要求1制备式Ⅰ所示化合物的方法,式中-Y-烷基部分中的烷基是具有1到15个碳原子的直链或支链烷基;在式子Y-芳烷基中Y和芳基之间的亚烃基是具有1至5个碳原子的亚烃基,在式子-Y-芳基和-Y-芳烷基中的芳基是苯基,萘基,吡啶基,喹啉基,喹喔啉基,它们可以取代有一个或多个卤原子,羟基,低级烷基,卤代低级烷基,低级烷氧基,氨基,或二低级烷基氨基,能与血红素配位的基团是氨基,或具有1至3个碳原子的氨基-低级烷基,或1H-咪唑-1-基甲基,1H-1,2,4-三唑-1-基甲基,氨基乙酰氧基,(氨基乙酰)氨基,〔(低级烷基氨基)乙酰〕氨基,〔(二低级烷基氨基)乙酰〕氨基,(氨甲基)羟基膦酰氧基,〔(低级烷基氨基)甲基〕羟基膦酰氧基,O-甲基-(氨甲基)羟基膦酰氧基,O-甲基-〔(低级烷基氨基)甲基羟基膦酰氧基,3-氨基-2-氧代丙基,3-氨基-2-羟基丙基,3-(低级烷基氨基)-2-氧代丙基,3-(二低级烷基氨基)-2-氧代丙基,3-(低级烷基氨基)-2-羟基丙基,3-(二低级烷基氨基)-2-羟基丙基,或1,3-氧杂唑系-5-基甲基。
3、按权项要求1制备下列化合物的方法(2S,3R,4S,5S)-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯;
(2S,3R,4S,5S)-4-乙氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-5-甲基-2-〔(E)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-5-甲基-2-〔(Z)-1-壬烯基〕-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-5-甲基-2-壬基-4-丙氧基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-2-〔(E)-1-癸烯基〕-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-2-(4,8-二甲基壬基)-4-甲氧基-5-甲基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1E,3E,5E)-1,3,5-壬三烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1Z,3E,5E)-1,3,5-壬三烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5R)-5-丁氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5R)-5-苄氧基-4-甲氧基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甘氨酸酯,
(2S,3R,4S,5R)-4-甲氧基-5-甲基-2-〔(Z)-1-壬烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6R)-2-甲氧氨-3,3-二甲基-6-辛氧基环己基〕甲基〕-1H-咪唑,
(6S,7S,10S)-10-甲基-7-〔(E)-1-壬烯基〕-1,4,8-三氧杂螺〔4,5〕癸烷-6-基甘氨酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-〔(1E,3E)-1,3-壬二烯基〕四氢-2H-吡喃-3-基甘氨酸酯,
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-〔(E)-1-壬烯基〕-2H-吡喃-3-基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-(1-甲基乙烯基)环己基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(Z)-1-壬烯基〕环己基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-〔(E)-1-壬烯基〕环己基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-壬基环己基〕甲基〕-1H-咪唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-辛氧基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-壬基-2H-吡喃-3-基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(2S,5R)-5,6-二氢-5-甲基-2-(2-萘乙基)-2H-吡喃-3-基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-66壬基环己基〕甲基〕-1H-1,2,4-三唑,
(2S,3R,4S,5S)-3-〔(氨乙酰基)氨基〕-4-甲氧基-5-甲基-2-〔(E)-1-壬烯基〕四氢-2H-吡喃,
(2S,3R,4S,5S)-3-〔(氨乙酰基)氨基〕-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基甲基氨甲基膦酸酯,
(2S,3R,4S,5S)-4-甲氧基-5-甲基-2-壬基四氢-2H-吡喃-3-基氨甲基膦酸酯,
(1S,2S,3S)-2-〔(氨乙酰基)氨基〕-3-甲氧基-4,4-二甲基-1-〔(E)-1-壬烯基〕环己烷,
(1R,2S,3S)-2-〔(氨乙酰基)氨基〕-3-甲氧基-4,4-二甲基-1-壬基环己烷,
(1S*,2R*)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-1-〔(E)-1-壬烯基〕环己烷,
(1R*,2R*)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-1-壬基环己烷,
(1R*,2R*)-2-〔(氨乙酰基)氨基〕-1-辛氧基-4,4-二甲基环己烷,
3-氨基-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕丙-2-醇,
3-(甲氨基)-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕丙-2-醇,
3-氨基-1-〔(1R,2R,6R)-3,3-二甲基-2-甲氧基-6-辛氧基环己基〕丙-2-醇,
3-氨基-1-〔(1R,2R,6R)-3,3-二甲基-2-甲氧基-6-壬基环己基〕丙-2-醇,
3-氨基-1-〔(1S*,2R*)-5,5-二甲基-2-(3-苯丙氧基)环己基〕丙-2-醇,或
3-氨基-1-〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(3-苯丙氧基)环己基〕丙-2-醇,
3-氨基-1-〔(1S*,2R*)-5,5-二甲基-2-辛氧基环己基〕丙-2-酮,
2-氟-4-三氟甲基-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺,
2,4-二氟-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基〕环己基〕苯甲酰胺,
2,4-二氯-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺,
2,4-二氟-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺,
4-三氟甲基-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H,-1,2,4-三唑-1-基甲基)环己基〕苯甲酰胺,以及
4-三氟甲基-N-〔(1R,2S,3R)-3-甲氧基-4,4-二甲基-2-(1H-咪唑-1-基甲基)环己基〕苯甲酰胺,及其这些化合物的在药学上是适宜的盐,以及这些化合物的水合物,溶剂化物及其盐的制备方法。
4、根据权项要求1,制备下列化合物的方法:
(1R,2S,3S)-2-〔(氨乙酰基)氨基〕-4,4-二甲基-3-甲氧基-1-辛氧基环己烷三氟乙酸盐,
(1R,2S,3S)-2〔(氨乙酰基)氨基〕-4,4-二甲基-3-甲氧基-1-〔2-(4-甲氧苯基)乙基〕环己烷三氟乙酸盐,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-〔4-(N,N-二甲氨基)苯基〕乙基〕环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-6-〔2-(4-氯苯基)乙基〕-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-6-〔(4-氯苯硫基甲基〕-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-(4-甲苯基)乙基〕环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(2-β-萘乙基)环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6S)-2-甲氧基-3,3-二甲基-6-(2-喹啉-2-基乙基)环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-〔4-三氟甲基苯基〕乙基〕环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-6-(对-三氟甲氧基苯乙基)-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-6-(对-甲氧苯乙基)-3,3-二甲基-环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6S)-6-(2,4-二氟苯乙基)-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-6-(4-乙基苯基)乙基-2-甲氧基-3,3-二甲基环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-〔2-(4-吡咯烷基苯基)乙基〕环己基〕甲基〕-1H-1,2,4-三唑,
1-〔〔(1R,2R,6R)-2-甲氧基-3,3-二甲基-6-(4-乙苯氧基)甲基〕甲基〕-1H-1,2,4-三唑,
5、制造抗菌组合物的方法,这种组合物含有权项要求1-4任一项中的化合物及其通常在这样的组合物中使用的载体。
6、抗菌组合物,它们含有作为活性组份的有效量的权项要求1-4中任一项的化合物,及其这样的组合物通常使用的载体。
7、权项要求1-4中任一项的化合物用于生产处治或预防真菌感染的疾病的药物。
8、权项要求1-4中任一项的化合物,它们或者由权项要求10的方法制备或者由明显的化学等价物制备。
9、上文,特别是有关实施所描述的发明。
13、式(Ⅵ)所示的化合物
式中R1,R4,R5和R7同权项要求1的定义。
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CN1626492B (zh) * | 2003-08-18 | 2010-05-26 | 默克专利股份有限公司 | 氢化方法 |
CN113444003A (zh) * | 2021-05-25 | 2021-09-28 | 浙江工业大学 | 井冈羟胺a酯类衍生物及其制备和应用 |
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WO1996037479A1 (en) * | 1995-05-26 | 1996-11-28 | F. Hoffmann La Roche Ag | Cyclohexanone oxime derivatives |
BR9803596A (pt) * | 1997-09-23 | 2000-04-25 | Pfizer Prod Inc | Derivados do resorcinol. |
US6878381B2 (en) | 1999-03-22 | 2005-04-12 | Pfizer, Inc | Resorcinol composition |
US6828460B2 (en) | 1999-03-22 | 2004-12-07 | Pfizer Inc. | Resorcinol derivatives |
US7138531B2 (en) * | 2001-10-15 | 2006-11-21 | Kemin Pharma B.V.B.A. | Preparation and use of carbohydrate-based bicyclic ring structures with antimicrobial and cytostatic activity |
CA2512713C (en) * | 2003-01-07 | 2012-03-13 | Kemin Pharma Europe, B.V.B.A. | Bicyclic carbohydrate compounds useful in the treatment of infections caused by flaviviridae sp., such as hepatitis c and bovine viral diarrhea viruses |
KR101451979B1 (ko) * | 2005-05-25 | 2014-10-21 | 메르크 파텐트 게엠베하 | 테트라하이드로피란-3-온으로부터 테트라하이드로피란의제조 방법 |
US8273900B2 (en) | 2008-08-07 | 2012-09-25 | Novartis Ag | Organic compounds |
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DE2132547C2 (de) * | 1971-06-30 | 1982-11-11 | Basf Ag, 6700 Ludwigshafen | Verfahren zur Hydrierung ein- oder mehrkerniger aromatischer Diamine zu den entsprechenden cycloaliphatischen Aminen |
US4252742A (en) * | 1979-07-13 | 1981-02-24 | Ciba-Geigy Corporation | Chemical process for the preparation of 2,6-dialkylcyclohexylamines from 2,6-dialkylphenols |
US4351839A (en) * | 1981-03-30 | 1982-09-28 | Rohm And Haas Company | Fungicidal 2-aryl-2-1-H-azoyl-(alkyl)-gamma-butyrolactones |
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JPH0739396B2 (ja) * | 1988-01-14 | 1995-05-01 | 呉羽化学工業株式会社 | 新規アゾール置換シクロアルカノール誘導体、その製造法及び該誘導体の農園芸用殺菌剤としての利用 |
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US4952604A (en) * | 1989-05-03 | 1990-08-28 | Merck & Co., Inc. | Antifungal agent |
JP2637824B2 (ja) * | 1989-08-15 | 1997-08-06 | 呉羽化学工業株式会社 | 新規アゾール置換シクロアルカノール誘導体、その製造法及び該誘導体の農園芸用殺菌剤 |
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CN1626492B (zh) * | 2003-08-18 | 2010-05-26 | 默克专利股份有限公司 | 氢化方法 |
CN113444003A (zh) * | 2021-05-25 | 2021-09-28 | 浙江工业大学 | 井冈羟胺a酯类衍生物及其制备和应用 |
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HUT64031A (en) | 1993-11-29 |
IL102552A0 (en) | 1993-01-14 |
NO922934L (no) | 1993-01-25 |
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AU653043B2 (en) | 1994-09-15 |
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AU8040494A (en) | 1995-02-16 |
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HU9202394D0 (en) | 1992-10-28 |
PL295382A2 (en) | 1993-04-05 |
RU2084439C1 (ru) | 1997-07-20 |
IS3888A (is) | 1993-01-25 |
BG61033B1 (bg) | 1996-09-30 |
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ZA925386B (en) | 1993-03-31 |
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