CN1234392A - 旋光性β－氨基醇化合物及其用途 - Google Patents
旋光性β－氨基醇化合物及其用途 Download PDFInfo
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- CN1234392A CN1234392A CN99105088A CN99105088A CN1234392A CN 1234392 A CN1234392 A CN 1234392A CN 99105088 A CN99105088 A CN 99105088A CN 99105088 A CN99105088 A CN 99105088A CN 1234392 A CN1234392 A CN 1234392A
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- Prior art keywords
- compound
- optically active
- methyl
- borane
- phenyl
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 49
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 26
- 239000001257 hydrogen Substances 0.000 claims abstract description 26
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 20
- 125000001624 naphthyl group Chemical group 0.000 claims abstract description 6
- 125000005428 anthryl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C3C(*)=C([H])C([H])=C([H])C3=C([H])C2=C1[H] 0.000 claims abstract description 5
- 125000005561 phenanthryl group Chemical group 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims abstract 3
- -1 IV Chemical class 0.000 claims description 197
- UORVGPXVDQYIDP-UHFFFAOYSA-N borane Chemical compound B UORVGPXVDQYIDP-UHFFFAOYSA-N 0.000 claims description 108
- 229910000085 borane Inorganic materials 0.000 claims description 61
- 239000003153 chemical reaction reagent Substances 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 38
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 17
- 239000000460 chlorine Substances 0.000 claims description 9
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 8
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 8
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims description 8
- 229910052794 bromium Inorganic materials 0.000 claims description 8
- 229910052801 chlorine Inorganic materials 0.000 claims description 8
- 239000011737 fluorine Substances 0.000 claims description 8
- 229910052731 fluorine Inorganic materials 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 239000000463 material Substances 0.000 claims description 3
- 125000005466 alkylenyl group Chemical group 0.000 claims 1
- 125000000217 alkyl group Chemical group 0.000 abstract description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 94
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 82
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 50
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 45
- 239000002585 base Substances 0.000 description 35
- 238000006243 chemical reaction Methods 0.000 description 35
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 31
- 238000006722 reduction reaction Methods 0.000 description 25
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 24
- 239000002904 solvent Substances 0.000 description 22
- 150000002431 hydrogen Chemical class 0.000 description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 18
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 18
- 230000009467 reduction Effects 0.000 description 18
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 16
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 14
- RWRDLPDLKQPQOW-UHFFFAOYSA-N tetrahydropyrrole Substances C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 14
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 13
- 239000000203 mixture Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 12
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000001931 aliphatic group Chemical group 0.000 description 12
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical compound C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 12
- 229910052760 oxygen Inorganic materials 0.000 description 10
- 230000035484 reaction time Effects 0.000 description 10
- 230000002829 reductive effect Effects 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 239000003795 chemical substances by application Substances 0.000 description 9
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 9
- 125000006178 methyl benzyl group Chemical group 0.000 description 9
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 9
- 239000001301 oxygen Substances 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 9
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 8
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 7
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 7
- UWTDFICHZKXYAC-UHFFFAOYSA-N boron;oxolane Chemical compound [B].C1CCOC1 UWTDFICHZKXYAC-UHFFFAOYSA-N 0.000 description 7
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 7
- 229910052751 metal Inorganic materials 0.000 description 7
- 239000002184 metal Substances 0.000 description 7
- 239000011591 potassium Substances 0.000 description 7
- 229910052700 potassium Inorganic materials 0.000 description 7
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 229910052791 calcium Inorganic materials 0.000 description 6
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 5
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- ATJFFYVFTNAWJD-UHFFFAOYSA-N Tin Chemical compound [Sn] ATJFFYVFTNAWJD-UHFFFAOYSA-N 0.000 description 5
- 150000001298 alcohols Chemical class 0.000 description 5
- 229910052782 aluminium Inorganic materials 0.000 description 5
- SMZOGRDCAXLAAR-UHFFFAOYSA-N aluminium isopropoxide Chemical compound [Al+3].CC(C)[O-].CC(C)[O-].CC(C)[O-] SMZOGRDCAXLAAR-UHFFFAOYSA-N 0.000 description 5
- 235000010290 biphenyl Nutrition 0.000 description 5
- 238000005810 carbonylation reaction Methods 0.000 description 5
- 230000003197 catalytic effect Effects 0.000 description 5
- 239000007810 chemical reaction solvent Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000011630 iodine Substances 0.000 description 5
- 229910052740 iodine Inorganic materials 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000011734 sodium Substances 0.000 description 5
- 229910052708 sodium Inorganic materials 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 125000006729 (C2-C5) alkenyl group Chemical group 0.000 description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 4
- JRZJOMJEPLMPRA-UHFFFAOYSA-N 1-nonene Chemical compound CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 4
- QQZOPKMRPOGIEB-UHFFFAOYSA-N 2-Oxohexane Chemical compound CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 4
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 description 4
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 description 4
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 description 4
- BLRPTPMANUNPDV-UHFFFAOYSA-N Silane Chemical compound [SiH4] BLRPTPMANUNPDV-UHFFFAOYSA-N 0.000 description 4
- 229910021529 ammonia Inorganic materials 0.000 description 4
- 125000003118 aryl group Chemical group 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 4
- 238000002329 infrared spectrum Methods 0.000 description 4
- 229910052744 lithium Inorganic materials 0.000 description 4
- 239000012280 lithium aluminium hydride Substances 0.000 description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 4
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 4
- 239000002798 polar solvent Substances 0.000 description 4
- 229920002223 polystyrene Polymers 0.000 description 4
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- 239000011701 zinc Substances 0.000 description 4
- 229910052725 zinc Inorganic materials 0.000 description 4
- 125000006717 (C3-C10) cycloalkenyl group Chemical group 0.000 description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 3
- 125000000590 4-methylphenyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1*)C([H])([H])[H] 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 125000006374 C2-C10 alkenyl group Chemical group 0.000 description 3
- 125000005865 C2-C10alkynyl group Chemical group 0.000 description 3
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 description 3
- 239000004793 Polystyrene Substances 0.000 description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 description 3
- 125000003545 alkoxy group Chemical group 0.000 description 3
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 3
- 239000004411 aluminium Substances 0.000 description 3
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 3
- GIXWDMTZECRIJT-UHFFFAOYSA-N aurintricarboxylic acid Chemical compound C1=CC(=O)C(C(=O)O)=CC1=C(C=1C=C(C(O)=CC=1)C(O)=O)C1=CC=C(O)C(C(O)=O)=C1 GIXWDMTZECRIJT-UHFFFAOYSA-N 0.000 description 3
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 3
- NGPGYVQZGRJHFJ-UHFFFAOYSA-N chembl1604790 Chemical compound OC1=CC(O)=CC=C1N=NC1=CC=C([N+]([O-])=O)C=C1 NGPGYVQZGRJHFJ-UHFFFAOYSA-N 0.000 description 3
- BGTOWKSIORTVQH-UHFFFAOYSA-N cyclo-pentanone Natural products O=C1CCCC1 BGTOWKSIORTVQH-UHFFFAOYSA-N 0.000 description 3
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 3
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 3
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 3
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 3
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 3
- 229910000077 silane Inorganic materials 0.000 description 3
- 239000012279 sodium borohydride Substances 0.000 description 3
- 229910000033 sodium borohydride Inorganic materials 0.000 description 3
- LLZRNZOLAXHGLL-UHFFFAOYSA-J titanic acid Chemical compound O[Ti](O)(O)O LLZRNZOLAXHGLL-UHFFFAOYSA-J 0.000 description 3
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 3
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 3
- 229920002554 vinyl polymer Polymers 0.000 description 3
- QZJHKLLXBFHIOL-IBGZPJMESA-N (2r)-2-(naphthalen-2-ylmethylamino)-2-phenylethanol Chemical compound C1([C@@H](NCC=2C=C3C=CC=CC3=CC=2)CO)=CC=CC=C1 QZJHKLLXBFHIOL-IBGZPJMESA-N 0.000 description 2
- AFFLGGQVNFXPEV-UHFFFAOYSA-N 1-decene Chemical compound CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 description 2
- OWQUYBAASOSGNO-CDNKMLFNSA-N 2-[[(Z)-N-(2-hydroxy-5-sulfoanilino)-C-phenylcarbonimidoyl]diazenyl]benzoic acid Chemical compound C1=CC=C(C=C1)/C(=N/NC2=C(C=CC(=C2)S(=O)(=O)O)O)/N=NC3=CC=CC=C3C(=O)O OWQUYBAASOSGNO-CDNKMLFNSA-N 0.000 description 2
- PJKVFARRVXDXAD-UHFFFAOYSA-N 2-naphthaldehyde Chemical compound C1=CC=CC2=CC(C=O)=CC=C21 PJKVFARRVXDXAD-UHFFFAOYSA-N 0.000 description 2
- HVCNXQOWACZAFN-UHFFFAOYSA-N 4-ethylmorpholine Chemical compound CCN1CCOCC1 HVCNXQOWACZAFN-UHFFFAOYSA-N 0.000 description 2
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 2
- 101100132433 Arabidopsis thaliana VIII-1 gene Proteins 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BZKFMUIJRXWWQK-UHFFFAOYSA-N Cyclopentenone Chemical compound O=C1CCC=C1 BZKFMUIJRXWWQK-UHFFFAOYSA-N 0.000 description 2
- 239000005977 Ethylene Substances 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000031226 Hyperlipidaemia Diseases 0.000 description 2
- 239000012448 Lithium borohydride Substances 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 2
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- ISWQCIVKKSOKNN-UHFFFAOYSA-L Tiron Chemical compound [Na+].[Na+].OC1=CC(S([O-])(=O)=O)=CC(S([O-])(=O)=O)=C1O ISWQCIVKKSOKNN-UHFFFAOYSA-L 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- YCNZFPXXIWEFCF-UHFFFAOYSA-N alumane;sodium Chemical compound [Na].[AlH3] YCNZFPXXIWEFCF-UHFFFAOYSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000006615 aromatic heterocyclic group Chemical group 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- AZWXAPCAJCYGIA-UHFFFAOYSA-N bis(2-methylpropyl)alumane Chemical compound CC(C)C[AlH]CC(C)C AZWXAPCAJCYGIA-UHFFFAOYSA-N 0.000 description 2
- UORVGPXVDQYIDP-BJUDXGSMSA-N borane Chemical class [10BH3] UORVGPXVDQYIDP-BJUDXGSMSA-N 0.000 description 2
- MCQRPQCQMGVWIQ-UHFFFAOYSA-N boron;methylsulfanylmethane Chemical compound [B].CSC MCQRPQCQMGVWIQ-UHFFFAOYSA-N 0.000 description 2
- LRJRPHROCLHMHK-UHFFFAOYSA-N boron;n,n-dimethylmethanamine Chemical compound [B].CN(C)C LRJRPHROCLHMHK-UHFFFAOYSA-N 0.000 description 2
- BYKCUMSOQIPHSR-UHFFFAOYSA-N boron;n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound [B].CCN(C(C)C)C(C)C BYKCUMSOQIPHSR-UHFFFAOYSA-N 0.000 description 2
- RJTANRZEWTUVMA-UHFFFAOYSA-N boron;n-methylmethanamine Chemical compound [B].CNC RJTANRZEWTUVMA-UHFFFAOYSA-N 0.000 description 2
- NNTOJPXOCKCMKR-UHFFFAOYSA-N boron;pyridine Chemical compound [B].C1=CC=NC=C1 NNTOJPXOCKCMKR-UHFFFAOYSA-N 0.000 description 2
- KDKYADYSIPSCCQ-UHFFFAOYSA-N but-1-yne Chemical group CCC#C KDKYADYSIPSCCQ-UHFFFAOYSA-N 0.000 description 2
- 125000002837 carbocyclic group Chemical group 0.000 description 2
- 125000004452 carbocyclyl group Chemical group 0.000 description 2
- 229910002091 carbon monoxide Inorganic materials 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 125000004122 cyclic group Chemical group 0.000 description 2
- 230000006837 decompression Effects 0.000 description 2
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 2
- GGSUCNLOZRCGPQ-UHFFFAOYSA-N diethylphenylamine Natural products CCN(CC)C1=CC=CC=C1 GGSUCNLOZRCGPQ-UHFFFAOYSA-N 0.000 description 2
- SIPUZPBQZHNSDW-UHFFFAOYSA-N diisobutylaluminium hydride Substances CC(C)C[Al]CC(C)C SIPUZPBQZHNSDW-UHFFFAOYSA-N 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 235000015177 dried meat Nutrition 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 150000002148 esters Chemical group 0.000 description 2
- QPNJHVDIRZNKOX-LURJTMIESA-N ethyl (2s)-pyrrolidine-2-carboxylate Chemical compound CCOC(=O)[C@@H]1CCCN1 QPNJHVDIRZNKOX-LURJTMIESA-N 0.000 description 2
- 238000003810 ethyl acetate extraction Methods 0.000 description 2
- 125000001207 fluorophenyl group Chemical group 0.000 description 2
- 125000003707 hexyloxy group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])O* 0.000 description 2
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- ZZNQQQWFKKTOSD-UHFFFAOYSA-N diethoxy(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](OCC)(OCC)C1=CC=CC=C1 ZZNQQQWFKKTOSD-UHFFFAOYSA-N 0.000 description 1
- SOGIFFQYRAXTDR-UHFFFAOYSA-N diethoxy(methyl)silane Chemical compound CCO[SiH](C)OCC SOGIFFQYRAXTDR-UHFFFAOYSA-N 0.000 description 1
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- ICIUAVWMRLXFDX-UHFFFAOYSA-N diethyl(dimethoxy)stannane Chemical compound [O-]C.[O-]C.CC[Sn+2]CC ICIUAVWMRLXFDX-UHFFFAOYSA-N 0.000 description 1
- HQWPLXHWEZZGKY-UHFFFAOYSA-N diethylzinc Chemical group CC[Zn]CC HQWPLXHWEZZGKY-UHFFFAOYSA-N 0.000 description 1
- OLLFKUHHDPMQFR-UHFFFAOYSA-N dihydroxy(diphenyl)silane Chemical compound C=1C=CC=CC=1[Si](O)(O)C1=CC=CC=C1 OLLFKUHHDPMQFR-UHFFFAOYSA-N 0.000 description 1
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- ZXWUGCNBZZSJJN-UHFFFAOYSA-N dihydroxy-di(propan-2-yl)silane Chemical compound CC(C)[Si](O)(O)C(C)C ZXWUGCNBZZSJJN-UHFFFAOYSA-N 0.000 description 1
- 125000001891 dimethoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- JJQZDUKDJDQPMQ-UHFFFAOYSA-N dimethoxy(dimethyl)silane Chemical compound CO[Si](C)(C)OC JJQZDUKDJDQPMQ-UHFFFAOYSA-N 0.000 description 1
- KNUZJYUHBCEOAS-UHFFFAOYSA-N dimethoxy-di(propan-2-yl)stannane Chemical compound CO[Sn](OC)(C(C)C)C(C)C KNUZJYUHBCEOAS-UHFFFAOYSA-N 0.000 description 1
- XCLIHDJZGPCUBT-UHFFFAOYSA-N dimethylsilanediol Chemical compound C[Si](C)(O)O XCLIHDJZGPCUBT-UHFFFAOYSA-N 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- QZDTWEBSDXQIDB-UHFFFAOYSA-N ditert-butyl(dimethoxy)stannane Chemical compound CO[Sn](OC)(C(C)(C)C)C(C)(C)C QZDTWEBSDXQIDB-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 125000004185 ester group Chemical group 0.000 description 1
- JREARPFWSGLDLG-UHFFFAOYSA-N ethenyl(dimethyl)silane Chemical class C[SiH](C)C=C JREARPFWSGLDLG-UHFFFAOYSA-N 0.000 description 1
- FWDBOZPQNFPOLF-UHFFFAOYSA-N ethenyl(triethoxy)silane Chemical compound CCO[Si](OCC)(OCC)C=C FWDBOZPQNFPOLF-UHFFFAOYSA-N 0.000 description 1
- MBGQQKKTDDNCSG-UHFFFAOYSA-N ethenyl-diethoxy-methylsilane Chemical class CCO[Si](C)(C=C)OCC MBGQQKKTDDNCSG-UHFFFAOYSA-N 0.000 description 1
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- AITHNFWLLMAZEN-UHFFFAOYSA-N ethyl 3,5-dihydroxyhept-6-ynoate Chemical compound CCOC(=O)CC(O)CC(O)C#C AITHNFWLLMAZEN-UHFFFAOYSA-N 0.000 description 1
- WDSYXFUBVPLPJX-UHFFFAOYSA-N ethyl 3,5-dioxohept-6-ynoate Chemical compound CCOC(=O)CC(=O)CC(=O)C#C WDSYXFUBVPLPJX-UHFFFAOYSA-N 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 244000231310 firewheel Species 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
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- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
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- PCZOHLXUXFIOCF-BXMDZJJMSA-N lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 description 1
- QLJODMDSTUBWDW-UHFFFAOYSA-N lovastatin hydroxy acid Natural products C1=CC(C)C(CCC(O)CC(O)CC(O)=O)C2C(OC(=O)C(C)CC)CC(C)C=C21 QLJODMDSTUBWDW-UHFFFAOYSA-N 0.000 description 1
- ORPJQHHQRCLVIC-UHFFFAOYSA-N magnesium;propan-2-olate Chemical class CC(C)O[Mg]OC(C)C ORPJQHHQRCLVIC-UHFFFAOYSA-N 0.000 description 1
- LGRLWUINFJPLSH-UHFFFAOYSA-N methanide Chemical compound [CH3-] LGRLWUINFJPLSH-UHFFFAOYSA-N 0.000 description 1
- UISUQHKSYTZXSF-UHFFFAOYSA-N methanolate;tin(2+) Chemical compound [Sn+2].[O-]C.[O-]C UISUQHKSYTZXSF-UHFFFAOYSA-N 0.000 description 1
- POPACFLNWGUDSR-UHFFFAOYSA-N methoxy(trimethyl)silane Chemical compound CO[Si](C)(C)C POPACFLNWGUDSR-UHFFFAOYSA-N 0.000 description 1
- BFXIKLCIZHOAAZ-UHFFFAOYSA-N methyltrimethoxysilane Chemical compound CO[Si](C)(OC)OC BFXIKLCIZHOAAZ-UHFFFAOYSA-N 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- SCKOUBDZKROGNS-UHFFFAOYSA-N n,n-dimethylformamide;methoxymethane Chemical compound COC.CN(C)C=O SCKOUBDZKROGNS-UHFFFAOYSA-N 0.000 description 1
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- 125000000587 piperidin-1-yl group Chemical group [H]C1([H])N(*)C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 1
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- 238000000711 polarimetry Methods 0.000 description 1
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- TUZYXOIXSAXUGO-PZAWKZKUSA-N pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 description 1
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- DZUXGQBLFALXCR-CDIPTNKSSA-N prostaglandin F1alpha Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)C[C@H](O)[C@@H]1CCCCCCC(O)=O DZUXGQBLFALXCR-CDIPTNKSSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 125000000714 pyrimidinyl group Chemical group 0.000 description 1
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- 238000001953 recrystallisation Methods 0.000 description 1
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- 238000000926 separation method Methods 0.000 description 1
- VGKDLMBJGBXTGI-SJCJKPOMSA-N sertraline Chemical compound C1([C@@H]2CC[C@@H](C3=CC=CC=C32)NC)=CC=C(Cl)C(Cl)=C1 VGKDLMBJGBXTGI-SJCJKPOMSA-N 0.000 description 1
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- 150000004354 sesquiterpene derivatives Chemical class 0.000 description 1
- KCIKCCHXZMLVDE-UHFFFAOYSA-N silanediol Chemical compound O[SiH2]O KCIKCCHXZMLVDE-UHFFFAOYSA-N 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
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- 238000001228 spectrum Methods 0.000 description 1
- 238000011916 stereoselective reduction Methods 0.000 description 1
- 229930002534 steroid glycoside Natural products 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
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- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 125000001712 tetrahydronaphthyl group Chemical group C1(CCCC2=CC=CC=C12)* 0.000 description 1
- 125000000383 tetramethylene group Chemical group [H]C([H])([*:1])C([H])([H])C([H])([H])C([H])([H])[*:2] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- DBDCNCCRPKTRSD-UHFFFAOYSA-N thieno[3,2-b]pyridine Chemical compound C1=CC=C2SC=CC2=N1 DBDCNCCRPKTRSD-UHFFFAOYSA-N 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- XTTGYFREQJCEML-UHFFFAOYSA-N tributyl phosphite Chemical compound CCCCOP(OCCCC)OCCCC XTTGYFREQJCEML-UHFFFAOYSA-N 0.000 description 1
- CMHHITPYCHHOGT-UHFFFAOYSA-N tributylborane Chemical compound CCCCB(CCCC)CCCC CMHHITPYCHHOGT-UHFFFAOYSA-N 0.000 description 1
- PWBHRVGYSMBMIO-UHFFFAOYSA-M tributylstannanylium;acetate Chemical compound CCCC[Sn](CCCC)(CCCC)OC(C)=O PWBHRVGYSMBMIO-UHFFFAOYSA-M 0.000 description 1
- CPUDPFPXCZDNGI-UHFFFAOYSA-N triethoxy(methyl)silane Chemical compound CCO[Si](C)(OCC)OCC CPUDPFPXCZDNGI-UHFFFAOYSA-N 0.000 description 1
- JCVQKRGIASEUKR-UHFFFAOYSA-N triethoxy(phenyl)silane Chemical compound CCO[Si](OCC)(OCC)C1=CC=CC=C1 JCVQKRGIASEUKR-UHFFFAOYSA-N 0.000 description 1
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 description 1
- ZMANZCXQSJIPKH-UHFFFAOYSA-O triethylammonium ion Chemical compound CC[NH+](CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-O 0.000 description 1
- LALRXNPLTWZJIJ-UHFFFAOYSA-N triethylborane Chemical compound CCB(CC)CC LALRXNPLTWZJIJ-UHFFFAOYSA-N 0.000 description 1
- ITMCEJHCFYSIIV-UHFFFAOYSA-M triflate Chemical compound [O-]S(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-M 0.000 description 1
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 1
- ZNOCGWVLWPVKAO-UHFFFAOYSA-N trimethoxy(phenyl)silane Chemical compound CO[Si](OC)(OC)C1=CC=CC=C1 ZNOCGWVLWPVKAO-UHFFFAOYSA-N 0.000 description 1
- WRECIMRULFAWHA-UHFFFAOYSA-N trimethyl borate Chemical compound COB(OC)OC WRECIMRULFAWHA-UHFFFAOYSA-N 0.000 description 1
- CYTQBVOFDCPGCX-UHFFFAOYSA-N trimethyl phosphite Chemical compound COP(OC)OC CYTQBVOFDCPGCX-UHFFFAOYSA-N 0.000 description 1
- 125000003258 trimethylene group Chemical group [H]C([H])([*:2])C([H])([H])C([H])([H])[*:1] 0.000 description 1
- ODHXBMXNKOYIBV-UHFFFAOYSA-O triphenylazanium Chemical compound C1=CC=CC=C1[NH+](C=1C=CC=CC=1)C1=CC=CC=C1 ODHXBMXNKOYIBV-UHFFFAOYSA-O 0.000 description 1
- MXSVLWZRHLXFKH-UHFFFAOYSA-N triphenylborane Chemical compound C1=CC=CC=C1B(C=1C=CC=CC=1)C1=CC=CC=C1 MXSVLWZRHLXFKH-UHFFFAOYSA-N 0.000 description 1
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
- 239000004246 zinc acetate Substances 0.000 description 1
- 229940102001 zinc bromide Drugs 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- JDLYKQWJXAQNNS-UHFFFAOYSA-L zinc;dibenzoate Chemical compound [Zn+2].[O-]C(=O)C1=CC=CC=C1.[O-]C(=O)C1=CC=CC=C1 JDLYKQWJXAQNNS-UHFFFAOYSA-L 0.000 description 1
- XDWXRAYGALQIFG-UHFFFAOYSA-L zinc;propanoate Chemical compound [Zn+2].CCC([O-])=O.CCC([O-])=O XDWXRAYGALQIFG-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B53/00—Asymmetric syntheses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
- C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
- C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/143—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of ketones
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D215/14—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/022—Boron compounds without C-boron linkages
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
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- C07C2603/04—Ortho- or ortho- and peri-condensed systems containing three rings
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Abstract
本发明涉及式(Ⅱ)β－氨基醇化合物，其中,R1为苯基,R2是氢,或者R1和R2一起构成(CH2)n,其中n为3或4,和Ar为萘基,蒽基或菲基。本发明还涉及该化合物的用途。
Description
本申请是中国专利申请No.94190966.2的分案申请。
本发明涉及新的β-氨基醇化合物及其用途、新的旋光性β-氨烷氧基甲硼烷配合物和生产旋光性醇的方法，在该方法中将β-氨基醇化合物和甲硼烷试剂作为还原剂施用于羰基化合物。此外，本发明还涉及还原1,3-二羰基化合物以生产旋光性1,3-顺-二醇化合物的方法。
许多供药物、农用药品或化妆品用的生理活性物质具有1,2-或1,3-顺-二醇结构。例如，作为一类抗高脂血剂的一系列HMG-CoA还原酶抑制剂，在其甲瓦龙酸链部分中都有1,3-顺-二醇作为共同的局部结构，它是抑制还原酶活性的必要结构。
此外，在天然生理活性物质中，有许多物质具有1,3-顺-二醇结构。可以提及的有，例如具有催产作用或血管加压作用的前列腺素F1α和F2α、戊霉素(一种多烯大环内酯抗生素)，二性霉素B(一种多烯型抗霉菌剂)，misaquinolide A(一种大环内酯抗肿瘤剂)，G-strophatine(一种强心苷)和pulkerine(一种印度天人菊Gaillardia pulchella中含有的倍半萜烯)。
在此之前，通过化学技术已经开发出了多种制备1,3-顺-二醇的方法(Tetrahedron Lett.,28,155(1987),Tetrahedron Lett.,26,2951(1985))但是，这些方法需要许多步骤。因为要先引入第一手性中心，然后在第一手性中心的基础上构建第二手性中心。而且需要极低的温度作为反应条件以便以高光学产率和高顺式选择性地获得所需的1,3-顺-二醇。因此，存在许多工业上的局限性。
在此之前，已知有许多通过使用旋光性试剂不对称地还原羰基化合物而生产旋光性醇的方法。可以提及的有许多方法，包括，例如，Corey等人的采用旋光性甲硼烷配合物的方法(E.J.Corey and A.V.Gavai,Tetrahedron Lett.,29,3201(1988)),Meerwein-Pon-ndolf-Verley(MPV)型不对称还原法(M.M.Midland,D.C.Mc-Dowell and Gabriel,J.Org.Chem.,54,159(1989))和采用酶或微生物的方法(G.Frater,Helv.Chim.Acta,62,2815,2829(1979))。
对于不对称地还原芳族羰基化合物,已开发了多种选择性高的试剂。但是，即使使用这些试剂，据认为仍难以达到不对称还原二烷基羰基的高选择性。而且最好也只能使不对称产率达到50％ee(异构体过量)。通常，芳族羰基化合物的不饱和基团的高电子密度据信会在过渡状态中为不对称还原提供实质性的电子效应。而对于没有这种实质性的电子效应的二烷基羰基而言，则需要一种能够识别位阻效应的差别的试剂(Organic Synthetic Chemistry,Vol.45,No.2,p.101(1987))。因此，在底物为2-己酮等时，已知没有一种还原剂能充分提供这种能力。上述的用于不对称还原反应的试剂都是只能用于单羰基化合物的不对称还原，而且已知应用于二羰基化合物者几乎没有。
另一方面，已知有一种Yamazaki等人的采用旋光性甲硼烷配合物的方法，(日本未审查的专利版号No.146786/1982)。即该方法使用由(S)-1-苄基-2-吡咯烷甲醇和甲硼烷制得的旋光性甲硼烷，对乙基苯基酮进行不对称还原。但是，可获得的旋光性纯度最多仅为67％，而且要花约60小时。因此，不能认为该方法是一种实用的方法。It-suno等人尝试用一种甲硼烷配合物对羰基化合物进行不对称还原，该配合物具有引入到(S)-1-苄基-2-吡咯烷甲醇的苄基部分上的聚苯乙烯(S.Itsuno,K.Ito,T.Maruyama,A.Hirao and S.Naka-hama,Bul.Chem.Soc.Jpn.,59,3329(1986))。但是不能获得满意的旋光纯度。Yamazaki等人的方法和Itsuno等人的方法已用于还原单羰基化合物，但没有用于还原二羰基化合物。已知Noyori等人采用BINAP-Ru配合物的方法是应用于二羰基化合物的(RyojiNoyori and Hidemasa Takaya,Chemistry,43,146(1988)和R.Noyori,chem,Soc.Rev.,18,187(1988)，而且该方法也应用于直接还原1,2-二羰基和1,3-二羰基化合物。但在任何情况下，得到的旋光性二醇是反式的。
根据Hiyama等人的最近的采用旋光性甲硼烷试剂直接不对称还原具有引入的不对称酯基的1,3-二羰基化合物(欧洲专利No.475627)或不对称还原1,3-二羰基化合物的方法(Tetrahedron,Lett.,29,6467(1988))，用所期望的顺式选择性的不对称还原反应可以获得1,3-顺-二醇，但是没有获得足够的不对称产率。因此，目前为止还未建立一种直接还原二羰基化合物以获得旋光性顺式二醇化合物的方法。
本发明的目的是通过不对称还原羰基化合物从而以高不对称产率获得旋光性醇，尤其是通过同时还原二羰基化合物的二个羰基基团从而在高顺式形成速度下以高不对称产率获得旋光性1,3-顺式二醇化合物。目的还在于提供能实现该目的的出色的还原催化剂以及通过使用该催化剂而提供一种旋光性1,3-顺式二醇化合物。
发明者们已进行了广泛的研究，其目标是开发一种还原剂，它能提供高不对称产率和高顺式选择性并且能在广泛的反应条件范围内使用，以及开发一种生产旋光性1,3-顺式二醇化合物的方法。结果，发现有可能以最高不对称产率100％ee和99％的高顺式选择性生产旋光性1,3-顺式二醇化合物，其办法是使用由旋光性β-(N-萘甲基)氨基醇化合物和甲硼烷制得的旋光性β-(N-萘甲基)氨烷氧基甲硼烷配合物来还原1,3-二羰基化合物。本发明是在该发现的基础上加以完成的。
因此，本发明提供了式(Ⅰ)旋光性β-氨烷氧基配合物：
(Ⅰ)其中，R1为C1-C8烷基，C3-C7环烷基，C7-C11芳烷基或C6-C10芳基，R2是氢，C1-C8烷基，C3-C7环烷基或C7-C11芳烷基，或者R1和R2一起构成(CH2)n，其中n为3或4，且Ar为可能被1-3个下列取代基取代的萘基，蒽基或菲基：卤素，硝基，C1-C6烷基，C3-C7环烷基，C2-C6链烯基，C2-C6炔基，C7-C11芳烷基，C6-C10芳基，C1-C6烷氧基和聚苯乙烯等取代基。
本发明还提供式(Ⅱ)旋光性β-氨基醇化合物： (Ⅱ)其中，R1为C1-C8烷基，C3-C7环烷基，C7-C11芳烷基或C6-C10芳基，R2是氢，C1-C8烷基或C7-C11芳烷基，或者R1和R2一起构成(CH2)n，其中n为3或4，和Ar为可被1-3个下列取代基取代的萘基，蒽基或菲基；卤素，硝基，C1-C6烷基，C3-C7环烷基，C2-C6链烯基，C2-C6炔基，C7-C11芳烷基，C6-C10芳基，C1-C6烷氧基和聚苯乙烯等取代基。
此外，本发明提供了一种生产式(Ⅳ)旋光性醇化合物的方法：
(Ⅳ)其中，R3和R4不同，各自为C1-C10烷基，C3-C10环烷基，C2-C10链烯基，C2-C10炔基，C3-C10环烯基，C7-C11芳烷基，或C6-C14芳基，或者R3和R4一起构成环结构，和*表示旋光性活性中心，它包括用上述的旋光性β-氨烷氧基甲硼烷配合物还原式(Ⅲ)羰基化合物： (Ⅲ)其中R3和R4的定义如上。
此外，本发明提供了一种生产式(Ⅵ)化合物的方法： (Ⅵ)其中当X为键时，R5为CHO,CH(OR9)(OR10)(其中R9和R10各自独立，可为氢或C1-C3烷基，或者R9和R10一起构成C2-C5亚烷基)，CH2OR11(其中R11为氢，C1-C3烷基，可能被甲基或甲氧基取代的苄基，三苯甲基，四氢吡喃基，甲氧甲基，三甲基甲硅烷基，二甲基叔丁基甲硅烷基或二苯基叔丁基甲硅烷基)，CH2R12(R12为氟，氯，溴或碘)，CN,CO2R13(R13为氢，C1-C4烷基或可能被甲基或甲氧基取代的苄基)，或CONR14R15(其中R14和R15各自独立，可为氢，C1-C3烷基，苄基，1-甲基苄基，或可能被甲基或甲氧基取代的苯基)，以及当X为-CH2-,-CH2CH2-,-CH=CH-,-(CH3)C=CH-,-CH=C(CH3)-或-C≡C-时，R5是氢，三烷基甲硅烷基，碳环脂族基，碳环芳族基，杂环芳族基，稠合杂环芳族基，链状不饱和脂族基，或环状不饱和脂族基，和R6为羟基，C1-C10烷氧基，OM(M为锂，钠，钾，钙，NHR′3(其中R′为氢，C1-C3烷基，C3-C7环烷基，C2-C5链烯基，苯基或苄基)或C0-C7氨基，以及*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，该方法包括用上述的旋光性β-氨烷氧基甲硼烷配合物还原式(Ⅴ)羰基化合物： (Ⅴ)其中R5,R6和X如上所述，而且Y和Z各自独立，为-CO-或-CH(OH)-，只要Y和Z不同时为-CH(OH)-。
此外，本发明还提供了一种生产式(Ⅵ-1)化合物的方法：
(Ⅵ-1)其中R6为羟基，C1-C10烷氧基，OM(M为锂，钠，钾，钙，NHR′3(其中R′为氢，C1-C3烷基，C3-C7环烷基，C2-C5链烯基，苯基或苄基))或C0-C7氨基，R7为C1-C7烷基或C3-C7环烷基，R8为可能被C1-C7烷基，氟，氯或溴取代的苯基，*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，该方法包括用上述的旋光性β-氨烷氧基甲硼烷配合物还原式(Ⅴ-1)1,3-二羰基化合物：
(Ⅴ-1)其中R6,R7和R8的定义如上。
此外，本发明提供了一种生产式(Ⅵ-2)旋光活性1,3-顺-二醇化合物的方法：
(Ⅵ-2)其中R5为氢，三烷基甲硅烷基，碳环脂族基，碳环芳族基，杂环芳族基，稠合杂环芳族基，链状不饱和脂族基或环状不饱和脂族基，R6为羟基，C1-C10烷氧基，OM(M为锂，钠，钾，钙，NHR′3(其中R′为氢，C1-C3烷基，C3-C7环烷基，C2-C5链烯基，苯基或苄基)或C0-C7氨基，以及*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，该方法包括用上述的旋光性β-氨烷氧基甲硼烷配合物还原式(Ⅴ-2)1,3-二羰基化合物：
(Ⅴ-2)其中R5和R6的定义如上。
在该说明书中，n代表“正”，i代表“异”，sec代表“仲”，text代表“叔”，Me代表“甲基”，Et代表“乙基”，Bu代表“丁基”，Ph代表“苯基”和THF代表“四氢呋喃”。
现在，详细描述本发明的化合物。作为式(Ⅰ)和(Ⅱ)中的R1的取代基，可以提及下列取代基：
C1-C8烷基包括，例如，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，正己基，正庚基和正辛基。
C3-C7环烷基包括，例如，环丙基，环丁基，环戊基，环己基和环庚基。
C7-C11芳烷基包括，例如，苄基，邻甲基苄基，间甲基苄基，对甲基苄基，对氯苄基，1-甲基苄基，苯乙基，邻甲基苯乙基，间甲基苯乙基，对甲基苯乙基，3-苯基丙基，3-(邻甲基苯基)丙基，3-(间甲基苯基)丙基，3-(对甲基苯基)丙基，4-苯基丁基，α-萘甲基和β-萘甲基。
C6-C10芳基包括，例如，苯基，邻甲苯基，间甲苯基，对甲苯基，2,3-二甲基苯基，2,4-二甲基苯基，2,5-二甲基苯基，2,6-二甲基苯基，3,4-二甲基苯基，3,5-二甲基苯基，2,3,4-三甲基苯基，2,3,5-三甲基苯基，2,3,6-三甲基苯基，3,4,5-三甲基苯基，3,4,6-三甲基苯基，2,4,6-三甲基苯基，α-萘基和β-萘基。
作为R2取代基的C1-C8烷基，C3-C7环烷基和C7-C11芳烷基与对应的R1取代基相同。
Ar为萘基，蒽基或菲基，它可任意地被1-3个下列取代基取代：卤素，硝基，C1-C6烷基，C3-C7环烷基，C2-C6链烯基，C2-C6炔基，C7-C11芳烷基，C6-C10芳基，C1-C6烷氧基和聚苯乙烯取代基。各取代基在下面加以描述。
卤素包括氟，氯，溴和碘。
C1-C6烷基包括，例如甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基和正己基。
C3-C7环烷基与相应的R1取代基相同。
C2-C6链烯基包括，例如，乙烯基，2-丙烯基，3-丁烯基，4-戊烯基和5-己烯基。
C2-C6炔基包括，例如，乙炔基，2-丙炔基，3-丁炔基，4-戊炔基和5-己炔基。
C1-C6烷氧基包括，例如甲氧基，乙氧基，正丙氧基，异丙氧基，正丁氧基，异丁氧基，仲丁氧基，叔丁氧基，正戊氧基和正己氧基。
本发明的式(Ⅰ)和(Ⅱ)化合物包括，例如，表1中所列的化合物。但是，应理解，本发明的化合物并不局限于这些具体实施例。此处，Me为甲基，t-Bu为叔丁基和Ph为苯基。表1
(Ⅰ)
(Ⅱ)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)表1(续)
表1(续)
表1(续)
表1(续)表1(续)表1(续)表1(续)表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)
表1(续)表1(续)
表1(续)
表1(续)
表1(续)
表1(续)表1(续)表1(续)
现在，详细描述甲硼烷配合物(Ⅰ)的合成的以及使用该甲硼烷配合物的羰基化合物的不对称反应。
使用旋光性β-氨基醇(Ⅷ)作为原料采用已知方法可以高产率地分两步或三步方便地制取本发明的旋光性的β-氨基醇化合物(Ⅱ)及其甲硼烷配合物(Ⅰ)，而旋光性β-氨基醇又可方便地从氨基酸酯获得(JIKKEN KAGAKU KOZA 17,YUKI KAGOBUTSU NOHANNO(GE)P.25,P.Karrer,P.Portmann and M.Suter,Helv.Chim,Acta,31,1617(1948)；P.Karrer and P.Port-mann,ibid.,32,1034(1949)；P.Karrer,P.Portmann and M.Suter,ibid.,32,1156(1949)；R.R.Gebhard and P.Karrer,ibid.,38,915(1955)；Synthetic Methods of Organic ChemistryVol.11,52；H.Bauer,E.Adams and H.Tabor,Biochem.Prep.4,46(1955))。
下面的反应图式表示了旋光性的式(Ⅰ)β-氨氧基甲硼烷配合物和旋光性的式(Ⅱ)β-氨基醇化合物的合成路线。在下式中，R1,R2和Ar的定义如上。
步骤A是将氨基酸酯(Ⅶ)的酯部分还原成醇(Ⅷ)的还原反应。作为还原剂，可以使用例如氢化铝锂，氢化二异丁基铝，氢化二烷氧基铝钠或氢化硼锂。较佳的是，采用氢化铝锂。作为反应溶剂，可以使用醚型溶剂如二乙基醚，二正丙基醚，四氢呋喃，1,3-或1,4-二噁烷。反应可以在-78℃-60℃，较佳的为-10℃-20℃之间进行。
步骤B为通过步骤A中所获得的β-氨基醇(Ⅷ)和芳香醛的脱水缩合反应而形成噁唑烷环的反应。反应溶剂可以是例如醇溶剂如甲醇，乙醇，正丙醇或异丙醇，极性溶液如乙腈，二甲基甲酰胺或二甲基亚砜，卤素型溶剂如二氯甲烷，1,1-或1,2-二氯乙烷，氯仿或四氯化碳，或醚型溶剂如二乙基醚，二正丙基醚，四氢呋喃，1,3-或1,4-二噁烷。较佳的是使用甲醇，乙腈或四氢呋喃。反应在-78℃-60℃，较佳的是在-10℃-30℃之间进行。
步骤C是通过使步骤B中获得的噁唑烷化合物(Ⅸ)还原开环而制得N-(芳基)甲基-β-氨基醇化合物的反应。作为还原剂，可以使用例如氢化铝锂，氢化二异丁基铝，氢化二烷氧基铝钠，氢化硼锂，氢化硼钾或氢化硼钠。较佳的是使用氢化硼钾或氢化硼钠。反应溶剂可以是例如醇型溶剂如甲醇，乙醇，正丙醇或异丙醇，或醚型溶剂如二乙基醚，二正丙基醚，四氢呋喃，1,3-或1,4-二噁烷。较佳的是使用甲醇，乙腈或四氢呋喃。反应在-78℃-60℃，较佳的是在-10℃-20℃之间进行。
步骤D是N-(芳基)甲基-β-氨基醇化合物(Ⅱ)的另一合成途径，即通过β-氨基醇化合物(Ⅷ)和相应的磺酸的芳基甲基酯的反应而制取N-(芳基)甲基-β-氨基醇化合物(Ⅱ)。
作为含有芳基甲基基团的磺酸酯，可以使用例如甲基化产物，苯磺酸酯，对氯苯磺酸酯，对甲苯磺酸酯，对硝基苯磺酸酯或三氟甲磺酸酯。优选使用甲基化产物。作为碱，可以使用叔胺或不饱和胺如三乙胺，三甲胺，吡啶，DBU(1,8-二氮杂二环[5.4.0]-7-十一烯)或DBU(1,5-二氮杂二环[4.3.0]-5-壬烯)。优选使用三乙胺。反应溶剂可以是，例如，醚型溶剂如二乙基醚，二正丙基醚，四氢呋喃，1,3-或1,4-二噁烷，极性溶剂如乙腈，二甲基甲酰胺或二甲基亚砜，卤素型溶剂如二氯甲烷，1,1-或1,2-二氯乙烷，氯仿或四氯化碳。较佳的是采用二氯甲烷或氯仿，更佳的是采用二氯甲烷。反应在-78℃-60℃，更佳的是在-10℃-30℃之间。
步骤E是通过步骤C或D中获得的N-(芳基)甲基-β-氨基醇化合物(Ⅱ)与甲硼烷试剂的反应而合成β-氨烷氧基甲硼烷配合物(Ⅰ)的反应。作为甲硼烷试剂，可以使用，例如甲硼烷·四氢呋喃配合物，甲硼烷·二乙基醚配合物，甲硼烷·吡啶配合物，甲硼烷·氨配合物，甲硼烷·叔丁胺配合物，甲硼烷·N,N-二乙基苯胺配合物，甲硼烷·N,N-二异丙基乙胺配合物，甲硼烷·二甲胺配合物，甲硼烷·4-二甲基氨吡啶配合物，甲硼烷·4-乙基吗啉配合物，甲硼烷·二甲硫配合物，甲硼烷·三甲胺配合物，甲硼烷·三苯膦配合物或甲硼烷·亚磷酸三苯基酯配合物。较佳的是使用甲硼烷·四氢呋喃配合物或甲硼烷·二乙基醚配合物。更佳的是使用甲硼烷·四氢呋喃配合物。反应溶剂可以是例如醇溶剂如甲醇，乙醇，正丙醇或异丙醇，极性溶剂如乙腈，二甲基甲酰胺或二甲基亚砜，卤素型溶剂如二氯甲烷，1,1-或1,2-二氯乙烷，氯仿或四氯化碳，或醚型溶剂如二乙基醚，二正丙基醚，四氯呋喃，1,3-或1,4-二噁烷。较佳的是使用甲醇，二氯甲烷，二乙基醚或四氢呋喃。更佳的是使用四氢呋喃。反应在-100℃-80℃，较佳的是在-78℃-40℃之间进行。
β-氨烷氧基甲硼烷配合物(Ⅰ)对光、水和热是稳定的，而且能溶于各种不同的溶剂，它因而具有在实验中非常便于操作的优点。
此外，在某些情况下，β-氨烷氧基甲硼烷配合物(Ⅰ)可以如下地在反应体系中形成而不必将其分离以供使用：即在羰基化合物的还原反应时，将N-(芳基)甲基-β-氨基醇化合物(Ⅱ)和甲硼烷试剂加入到反应体系中。
羰基化合物(Ⅲ)或(Ⅴ)被步骤E中获得的旋光性β-氨烷氧基甲硼烷配合物(Ⅰ)立体选择性地还原，从而获得相应的旋光性醇化合物(Ⅳ)或(Ⅵ)。
下面将描述式(Ⅲ),(Ⅳ),(Ⅴ)和(Ⅵ)化合物的各个取代基。
R3和R4不同，各自为C1-C10烷基，C3-C10环烷基，C2-C10链烯基，C2-C10炔基，C3-C10环烯基，C7-C11芳烷基，或C6-C14芳基，否则，R3和R4可一起构成环结构。
C1-C10烷基包括，例如，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，正己基，正庚基，正辛基。正壬基和正癸基。
C3-C10环烷基包括，例如，环丙基，环丁基，环戊基，环己基，环庚基，环辛基，环壬基和环癸基。
C2-C10链烯基包括，例如，乙烯基，1-丙烯基，1-甲基乙烯基，2-丙烯基，1,2-二甲基-1-丙烯基，1-丁烯基，1-戊烯基，1-壬烯基，1-庚烯基，1-辛烯基，1-壬烯基和1-癸烯基。
C2-C10炔基包括：例如，乙炔基，1-丙炔基，2-丙烯基，1-丁炔基，3-甲基-1-丁炔基，1-戊炔基，1-己炔基，1-庚炔基，1-辛炔基，1-壬炔基和1-癸炔基。
C3-C10环烯基包括，例如，2-环丙烯基，1-环丁烯基，3-环戊烯基，1-环己烯基，2-环己烯基和3-环己烯基。
C7-C11芳烷基与对应的R1的取代基相同。
C6-C14芳基包括，例如，苯基，邻甲苯基，间甲苯基，对甲苯基，2,3-二甲基苯基，2,4-二甲基苯基，2,5-二甲基苯基，2,6-二甲基苯基，3,4-二甲基苯基，3,5-二甲基苯基，2,3,4-三甲基苯基，3,4,6-三甲基苯基，2,4,6-三甲基苯基，2-氯苯基，3-氯苯基，4-氯苯基，3,4-二氯苯基，2-甲氧苯基，3-甲氧苯基，4-甲氧苯基，3,4-二甲氧苯基，3-硝基苯基，α-萘基，β-萘基，(2-甲基)-2-萘基，(3-甲基)-1-萘基，(4-甲基)-1-萘基，(5-甲基)-1-萘基，(6-甲基)-1-萘基，(7-甲基)-1-萘基，(8-甲基)-1-萘基，(1-甲基)-2-萘基，(3-甲基)-2-萘基，(4-甲基)-2-萘基，(5-甲基)-2-萘基，(6-甲基)-2-萘基，(7-甲基)-2-萘基，(8-甲基)-2-萘基，(2-乙基)-1-萘基，(3-乙基)-1-萘基，(4-乙基)-1-萘基，(5-乙基)-1-萘基，(6-乙基)-1-萘基，(7-乙基)-1-萘基，(8-乙基)-1-萘基，(1-乙基)-2-萘基，(3-乙基)-2-萘基，(4-乙基)-2-萘基，(5-乙基)-2-萘基，(6-乙基)-2-萘基，(7-乙基)-2-萘基，(8-乙基)-2-萘基，(2-丙基)-1-萘基，(3-丙基)-1-萘基，(4-丙基)-1-萘基，(5-丙基)-1-萘基，(6-丙基)-1-萘基，(7-丙基)-1-萘基，(8-丙基)-1-萘基，(1-丙基)-2-萘基，(3-丙基)-2-萘基，(4-丙基)-2-萘基，(5-丙基)-2-萘基，(6-丙基)-2-萘基，(7-丙基)-2-萘基，(8-丙基)-2-萘基，1-蒽基，2-蒽基，9-蒽基，1-菲基，3-菲基，4-菲基和9-菲基。
R3和R4一起构成的环结构包括，例如，
1-甲基环丁酮，2,2-二甲基环丁酮，2,2-二乙基环丁酮，2,2-二正丙基环丁酮，2,2-二异丙基环丁酮，2,2-二正丁基环丁酮，2,2-二异丁基环丁酮，2,2-二仲丁基环丁酮，2,2-二叔丁基环丁酮，2,2-二正戊基环丁酮，2,2-二正己基环丁酮，1-甲基环戊酮，2,2-二甲基环戊酮，2,2-二乙基环戊酮，2,2-二正丙基环戊酮，2,2-二异丙基环戊酮，2,2-二正丁基环戊酮，2,2-二异丁基环戊酮，2,2-二仲丁基环戊酮，2,2-二叔丁基环戊酮，2,2-二正戊基环戊酮，2,2-二正己基环戊酮，三甲基环己酮，2,2-二甲基环己酮，2,2-二乙基环己酮，2,2-二正丙基环己酮，2,2-二异丙基环己酮，2,2-二正丁基环己酮，2,2-二异丁基环己酮，2,2-二仲丁基环己酮，2,2-二叔丁基环己酮，2,2-二正戊基环己酮，2,2-二正己基环己酮，环丁烯酮，2-环戊烯酮，2-环己烯酮，2,3-二氢-2-茚酮和1-四氢萘酮。
X为键，-CH2-,-CH2CH2-,-CH=CH-,-(CH3)C=CH-,-CH=C(CH3)-或-C≡C-。
当X为键时，R5为CHO,CH(OR9)(OR10)(其中R9和R10各自独立，可为氢或C1-C3烷基，或者R9和R10一起构成C2-C5亚烷基)，CH2OR11(其中R11为氢，C1-C3烷基，可能被甲基或甲氧基取代的苄基，三苯甲基，四氢吡喃基，甲氧甲基，三甲基甲硅烷基，二甲基叔丁基甲硅烷基或二苯基叔丁基甲硅烷基)，CH2R12(R12为氟，氯，溴或碘)，CN,CO2R13(R13为氢，C1-C4烷基或可能被甲基或甲氧基取代的苄基)，或CONR14R15(其中R14和R15各自独立，分别为氢，C1-C3烷基，苄基，1-甲基苄基，或可能被甲基或甲氧基取代的苯基。
R9和R10各自独立，可以是氢，甲基，乙基，正丙基或异丙基，或者R9和R10一起构成1,2-亚乙基，1,3-亚丙基，或2,2-二甲基-1,3-亚丙基。
R11可能是氢，甲基，乙基，正丙基，异丙基，邻甲基苄基，间甲基苄基，对甲基苄基，邻甲氧基苄基，间甲氧基苄基，对甲氧基苄基，三苯甲基，四氢吡喃基，甲氧甲基，三甲基甲硅烷基，二甲基叔丁基甲硅烷基或二苯基叔丁基甲硅烷基。
R12为氟，氯，溴或碘。
R13可以是氢，甲基，乙基，正丙基，异丙基，正丁基，异丁基，叔丁基，邻甲基苄基，间甲基苄基，对甲基苄基，邻甲氧基苄基，间甲氧基苄基或对甲氧基苄基。
R14和R15各自独立，可以是氢，甲基，乙基，正丙基，异丙基，苄基，1-甲基苄基，邻甲基苯基，间甲基苯基，对甲基苯基，邻甲氧基苯基，间甲氧基苯基或对甲氧基苯基。
X为-CH2-,-CH2CH2-,-CH=CH-,-(CH3)C=CH-,-CH=C(CH2)-或-C≡C-时，R5是氢，三烷基甲硅烷基，脂族碳环基，芳族碳环基，芳族杂环基，芳族稠合杂环基，脂族链状不饱和基，或脂族环状不饱和基。
三烷基甲硅烷基包括，例如，三甲基甲硅烷基，三乙基甲硅烷基，三正丙基甲硅烷基，三异丙基甲硅烷基，三正丁基甲硅烷基，三异丁基甲硅烷基，三正己基甲硅烷基，二甲基乙基甲硅烷基，二甲基正丙基甲硅烷基，二甲基正丁基甲硅烷基，二甲基异丁基甲硅烷基，二甲基叔丁基甲硅烷基，二甲基正戊基甲硅烷基，二甲基正辛基甲硅烷基，二甲基环己基甲硅烷基，二甲基己基甲硅烷基，二甲基-2,3-二甲基丙基甲硅烷基，二甲基-2-(二环庚基)甲硅烷基，二甲基苄基甲硅烷基，二甲基苯基甲硅烷基，二甲基对甲苯基甲硅烷基，二甲基六氟苯基甲硅烷基，甲基二苯基甲硅烷基，三苯基甲硅烷基，二苯基叔丁基甲硅烷基，三苄基甲硅烷基，二苯基乙烯基甲硅烷，二苯基正丁基甲硅烷基和苯基甲基乙烯基甲硅烷基。
脂族碳环基可以是，例如，可被一个或多个选自R7,C2-C6酰氧基和羟基取代的六氢化萘基或四氢化萘基，较佳的是下列基团：
芳族碳环基可以是，例如，可被1-3个选自R7和/或1或2个选自R8的取代基取代的苯基或萘基，较佳的为下列基团： 
芳族杂环基可以是，例如，可被1-3个选自R7,C1-C3烷氧基甲基，苯基氨基甲酰基和/或1或2个选自R8的取代基所取代的吡啶基，嘧啶基，吡唑基，咪唑基，吡咯基，噻吩基或呋喃基。较佳的是下列基团：
稠合的芳族杂环基可以是，例如，吲哚基，喹啉基，吡唑并吡啶基，噻吩并吡啶基，吡咯并吡啶基或异喹啉基，它可被1-3个选自R7,C1-C3烷氧基甲基，苯基氨基甲酰基的取代基和/或1或2个选自R8的取代基所取代，较佳的是下列基团：
脂族链状不饱和基可以是，例如，乙烯基或乙炔基，它可被1个选自R7,1个或2个选自R8的取代基和/或四唑基所取代，较佳的为下列基团：
脂族环状不饱和基可以是，例如，环己烯基，它可被1-4个选自R7和/或1或2个选自R8的取代基所取代，较佳的是为下列基团：
(W=O,S,CH2)Y和Z各自独立，为-CO-或-CH(OH)-，只要Y和Z不同时为-CH(OH)-。
R6为羟基，C1-C10烷氧基，金属氧基或C0-C7氨基。
C1-C10烷氧基包括，例如，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，叔丁氧基，正戊氧基，正己氧基，正庚氧基，正辛氧基，正壬氧基，正癸氧基，环丙氧基，环丁氧基，环戊氧基，环己氧基，环庚氧基，环辛氧基，环壬氧基，环癸氧基，2-丙烯氧基，顺-2-丁烯氧基，反-2-丁烯氧基，β-甲基丙烯氧基，苄氧基，邻甲基苄氧基，间甲基苄氧基，对甲基苄氧基，苯氧基，邻甲基苯氧基，间甲基苯氧基，对甲基苯氧基，2,3-二甲基苯氧基，2,4-二甲基苯氧基，2,5-二甲基苯氧基，2,6-二甲基苯氧基，3,4-二甲基苯氧基，3,5-二甲基苯氧基，α-萘氧基和β-萘氧基。
OM为羧酸盐基团，而M为锂，钠，钾，钙或NHR′3(其中R′为氢，C1-C3烷基，C3-C7环烷基，C2-C5链烯基，苯基或苄基)，较佳的为钠，钾，铵，三甲基铵，三乙基铵，三正丙基铵，三苄基铵，三苯基铵，三环己基铵或三乙烯基铵。
C0-C7氨基包括，例如，氨基，甲氨基，乙氨基，二甲氨基，正丙基氨基，异丙基氨基，甲氨基，正丁基氨基，异丁基氨基，仲丁基氨基，叔丁基氨基，甲基正丙基氨基，甲基异丙基氨基，二乙氨基，正戊基氨基，甲基正丁基氨基，甲基异丁基氨基，甲基仲丁基氨基，甲基叔丁基氨基，乙基正丙基氨基，乙基异丙基氨基，正己基氨基，甲基正戊基氨基，乙基正丁基氨基，乙基异丁基氨基，乙基仲丁基氨基，乙基叔丁基氨基，二正丙基氨基，正丙基异丙基氨基，二异丙基氨基，环丙基氨基，环丁基氨基，环戊基氨基，环己基氨基，二环己基氨基，N-甲基-N-苯基氨基，α-甲基苄基氨基，1-吖丙啶基，1-吖丁啶基，1-吡咯烷基，1-哌啶基和1-吡咯基。
R7为C1-C8烷基或C3-C7环烷基。C1-C8烷基包括，例如，甲基，乙基，正丙基，异丙基，正丁基，异丁基，仲丁基，叔丁基，正戊基，正己基和正庚基。C3-C7环烷基包括，例如，环丙基，环丁基，环戊基，环己基和环庚基。
R8是可能被C1-C7烷基，氟，氯，溴或碘取代的苯基。它可以是，例如，苯基，3-甲基苯基，4-甲基苯基，3,5-二甲基苯基，3-乙基苯基，4-乙基苯基，3,5-二乙基苯基，3-甲基-5-乙基苯基，3-正丙基苯基，4-正丙基苯基，3,5-二正丙基苯基，3-异丙基苯基，4-异丙基苯基，3,5-二异丙基苯基，3-氟苯基，4-氟苯基，3,5-二氟苯基，3-氯苯基，4-氯苯基，3,5-二氯苯基，3-氟-4-氯苯基，3-溴苯基，4-溴苯基或3,5-二溴苯基。
用于该反应的溶剂可以是例如醇型溶剂如甲醇，乙醇，正丙醇或异丙醇，极性溶剂如乙腈，二甲基甲酰胺或二甲基亚砜，卤素型溶剂如二氯甲烷，1,1-或1,2-二氯乙烷，氯仿或四氯化碳，或醚型溶剂如二乙基醚，二正丙基醚，四氢呋喃，1,3-或1,4-二噁烷。较佳的是使用甲醇，二氯甲烷，二乙基醚或四氢呋喃。更佳的是使用四氢呋喃。反应在-78℃-40℃，较佳的是在-10℃-30℃之间进行。
为了化学计量式地进行该反应，β-氨烷氧基甲硼烷配合物(Ⅰ)的用量为羰基化合物(Ⅲ)的1-2当量，或化合物(Ⅴ)的2-3当量。另一方面，以催化剂方式进行该反应时，β-氨基醇(Ⅱ)的用量为0.1-20mol％，更佳的为1-10mol％，而甲硼烷试剂可以是，例如，甲硼烷·四氢呋喃配合物，甲硼烷·二乙基醚配合物，甲硼烷·吡啶配合物，甲硼烷·氨配合物，甲硼烷·叔丁胺配合物，甲硼烷·N,N-二乙基苯胺配合物，甲硼烷·N,N-二异丙基乙胺配合物，甲硼烷·二甲胺配合物，甲硼烷·4-二甲基氨吡啶配合物，甲硼烷·4-乙基吗啉配合物，甲硼烷·二甲硫配合物，甲硼烷·三甲胺配合物，甲硼烷·三苯膦配合物或甲硼烷·亚磷酸三苯基酯配合物。较佳的是使用甲硼烷·四氢呋喃配合物或甲硼烷·二乙基醚配合物。更佳的是使用甲硼烷·四氢呋喃配合物。此外，为使催化反应更易进行，最好使用用量为3-10当量，更佳的是3-6当量的醇型溶剂，如甲醇，乙醇，正丙醇或异丙醇，较佳的为甲醇或乙醇，更佳的为甲醇。
为了提高1,3-二羰基化合物的不对称还原反应的顺式选择性，可以使用金属试剂如甲硼烷试剂，铝试剂，硅试剂，锡试剂，磷试剂，钛试剂，锌试剂，镁试剂或钙试剂。
甲硼烷试剂可以是，例如，烷氧甲硼烷试剂如二乙基甲氧基甲硼烷，三甲氧基甲硼烷，三正丁氧基甲硼烷，或儿茶酚硼烷，三烷基甲硼烷试剂如三乙基甲硼烷，三苯基甲硼烷，三正丁基甲硼烷，三仲丁基甲硼烷，或三叔丁基甲硼烷，或二烷基甲硼烷试剂如氰白甲硼烷(cyamelborane)，或二环[3.3.1]壬-9-甲硼烷(9-BBN)。
铝试剂可以是例如，三醇铝试剂如三异丙醇铝，三乙醇铝，三正丁醇铝或三仲丁醇铝，或者烷基铝的醇盐试剂如乙醇二乙基铝，乙醇二正丙基铝或乙醇二异丙基铝。
硅试剂可以是，例如，四烷氧基硅烷试剂如四甲氧基硅烷，四乙氧基硅烷，或四苯氧基硅烷，三烷氧基硅烷试剂如三甲氧基(甲基)硅烷，三乙氧基(甲基)硅烷，三甲氧基(苯基)硅烷，三乙氧基(苯基)硅烷，三乙氧基(乙烯基)硅烷或γ-氯代丙基三甲氧基硅烷，二烷氧基硅烷试剂如二甲氧基二甲基硅烷，二乙氧基二乙基硅烷，二甲氧基(甲基)乙烯基硅烷，二乙氧基(甲基)硅烷，二甲氧基(乙基)乙烯基硅烷，二乙氧基(甲基)乙烯基硅烷，二甲氧基二苯基乙烯基硅烷，或二乙氧基二苯基硅烷，单烷氧基硅烷试剂，如甲氧基三甲基硅烷，乙氧基三甲基硅烷，甲氧基(二甲基)乙烯基硅烷，或乙氧基(二甲基)乙烯基硅烷，或者二羟基硅烷试剂如二羟基二甲基硅烷，二羟基二乙基硅烷，二羟基二正丙基硅烷，二羟基二异丙基硅烷，或二羟基二苯基硅烷。
锡试剂可以是，例如，乙酸烷基(锡)试剂如乙酸三正丁基锡，二乙酸二正丁基锡，或二乙酸二辛基锡，或者烷基(烷氧基)锡试剂如二甲基二甲氧基锡，二乙基二甲氧基锡，二正丙基二甲氧基锡，二异丙基二甲氧基锡，二正丁基二甲氧基锡，二异丁基二甲基氧锡，二仲丁基二甲氧基锡，或二叔丁基二甲氧基锡。
磷试剂可以是，例如，亚磷酸三酯如亚磷酸三甲酯，亚磷酸三乙酯，亚磷酸三异丙酯，亚磷酸三正丁酯或亚磷酸三苯酯。
钛试剂可以是，例如，醇钛如原钛酸四乙酯，原钛酸三氯代异丙酯，原钛酸四正丙酯，四丙氧基钛或四丁氧基钛。
锌试剂可以是，例如，羧酸锌如乙酸锌，丙酸锌，或苯甲酸锌，卤化锌例如氟化锌，氯化锌，溴化锌或碘化锌，或烷基锌试剂如二甲基锌，二乙基锌，二正丙基锌或二异丙基锌。
镁试剂可以是，例如，醇镁试剂如二甲醇镁，二乙醇镁，二正丙醇镁或异丙醇镁。
钙试剂可以是，例如，醇钙试剂如二甲醇钙，二乙醇钙，二正丙醇钙或异丙醇钙。
在这些金属试剂中，优选的是二乙基甲氧基硼烷，三异丙醇铝和原钛酸三氯化异丙基酯，更优选的是二乙基甲氧基硼烷和三异丙醇铝。
金属试剂的用量为1,3-二羰基化合物的1-3当量，较佳的为1-1.2当量。
根据本发明，通过使用旋光性的式(Ⅰ)β-氨烷氧基甲硼烷配合物对式(Ⅴ)1,3-二羰基化合物进行还原的简便操作可以高产率地和高选择性地合成所需的旋光性的式(Ⅵ)1,3-顺-二醇化合物。旋光性1,3-顺-二醇构成了抗高脂血治疗剂(HMG-CoA还原酶抑制剂)的重要的局部结构。因此，本发明的旋光性β-氨烷氧基甲硼烷配合物(Ⅰ)能用于生产典型的HMG-CoA还原酶抑制剂如Lovastatin,Simvastatin或Pravastatin。此外，本发明的化合物能应用于各种羰基化合物(式(Ⅲ))，以高的不对称产率生产成旋光性醇(式(Ⅳ))。
现在，结合实施例更详细地描述本发明，但应理解，本发明决非局限于这些具体实施例。实施例1旋光性β-氨基醇化合物(Ⅱ)(步骤A,B和D)的制备(S)-N-(β-萘基)甲基-2-吡咯烷甲醇((S)-Ⅱ-1)的制备步骤A
可商购的脯氨酸乙酯(Ⅶ-1)用氢化铝锂在用冰冷却的乙醚中还原，获得脯氨醇(prolinol)(Ⅷ-1)。使用旋光性的原料，分别获得对应的旋光性脯氨醇(Ⅷ-1)。步骤B和C
将1.000g(9.89mmol)(S)-脯氨醇((S)-Ⅷ-1)溶于25ml干乙腈，再搅拌加入1.545g(9.89mmol)β-萘甲醛。混合物搅拌24小时。然后减压蒸馏除去乙腈，定量地获得噁唑烷化合物((S)-Ⅸ-1)(粗产品：2.55g)。然后，将噁唑烷化合物溶于20ml甲醇中，并用冰冷却。然后加入374mg(9.89mmol)硼氢化钠，搅拌混合物4小时。减压蒸去甲醇，残留物用氯仿重结晶，定量地获得S-N-(β-萘基)甲基-2-吡咯烷甲醇((S)-Ⅱ-1)(2.40g)。 ((S)-Ⅱ-1 )[α]D20-49.8°(C=0.1,CH3OH)IR光谱(KBr)νmaxcm-1:3200,3030,2950,2850,1600,1580,1420,1340,1180,1020,850,820,7401H-NMR(CDCl3)δppm:7.30-7.83(7H,m，芳香-H)，2.28-4.23(8H,m，其他-H)，1.66-1.90(4H,m,C-CH2CH2-C)(R)-N-(β-萘基)甲基-2-吡咯烷甲醇((R)-Ⅱ-1)的制备
使用(R)-脯氨醇((R)-Ⅷ-1)为原料，进行类似的操作，获得(R)-N-(β-萘基)甲基-2-吡咯烷甲醇((R)-Ⅱ-1)。
((R)-Ⅱ-1)[α]D20+50.7°(C=0.1,CH3OH)IR光谱(KBr)νmaxcm-1:3200,3030,2950,2850,1600,1580,1420,1340,1180,1020,850,820,7401H-NMR(CDCl3)δppm:7.30-7.83(7H,m，芳香-H)，2.28-4.23(8H,m，其他-H)，1.66-1.90(4H,m,C-CH2CH2-C)(S)-N-(α-萘基)甲基-2-吡咯烷甲醇((S)-Ⅱ-2)的制备
使用(S)-脯氧醇((S)-Ⅷ-1)和α-萘甲醛为原料，进行类似的操作，获得(S)-N-(α-萘基)甲基-2-吡咯烷甲醇((S)-Ⅱ-2)。
((S)-Ⅱ-2 )[α]D20-65.6°(C=0.16,CH3OH)IR光谱(NaCl)νmaxcm-1:3400,3040,2950,2870,1600,1500,1460,1350,1170,1040,800,790,7801H-NMR(CDCl3)δppm:7.25-8.30(7H,m，芳香-H)，2.60-4.55(7H,m，其他-H)，2.35(1H,br,OH),1.65-2.01(4H,m,C-CH2CH2-C)(R)-N-(β-萘基)甲基-2-苯基甘氨醇((R)-Ⅱ-3)的制备
使用1.00g(7.29mmol)(R)-苯基甘氨醇((R)-Ⅷ-2)和β-萘甲醛，进行类似的操作，定量地获得(R)-N-(β-萘基)甲基-2-苯基甘氨醇(2.01g)((R)-Ⅱ-3)。 ((R)-Ⅱ-3)[α]D20+3.1°(C=0.1,CH3OH)1H-NMR(CDCl3)δppm:7.30-7.80(12H,m，芳香-H)，3.50-4.30(5H,m，其他-H),2.30(1H,br,OH),2.02(1H,br s,NH)实施例2旋光性β-氨基烷氧基甲硼烷配合物(Ⅰ)的制备(步骤E)(S)-N-(β-萘基)甲基-2-吡咯烷甲氧基甲硼烷((S)-Ⅰ-1)的制备
将2.41g(10mmol)(S)-N-(β-萘基)甲基-2-吡咯烷甲醇((S)-Ⅱ-1)溶于50ml干THF中，再搅拌滴加10ml含有1.0M甲硼烷·四氢呋喃配合物的四氢呋喃溶液(以下简称BH3·THF溶液)。氢气的发生结束后，再搅拌混合物10分钟。以THF溶液形式使用该甲硼烷配合物以还原羰基化合物。然后，于室温减压蒸去THF，得2.53g(100％)所需物质，为粘性油状物。该物质的物理性能数值如下：IR光谱(KBr)νmaxcm-1:3030,2950,2850,2350(B-H),1600,1450,1420,1360,1280,1180,1030,850,820,7501H-NMR(CDCl3)δppm:7.30-7.83(7H,m，芳香-H),1.00-5.80(13H,m，其他-H)，
使用化合物((R)-Ⅱ-1),((S)-Ⅱ-2)和((R)-Ⅱ-3)作为原料，进行类似的操作，获得表2所示的旋光性β-氨基烷氧基甲硼烷配合物(Ⅰ)。
表2
参考例1(E)7-[2′-环丙基-4′-(对氟苯基)喹啉-3′-基]-3,5-二氧代-6-庚烯酸乙酯的制备
在氮气流中，将2.35g(63.1mmol)60％氢化钠悬浮于300ml干THF中，搅拌悬浮液5分钟，然后用冰冷却，然后用注射器逐渐滴加7.47g(57.4mmol)乙酰乙酸乙酯，在氢气的发生结束后，再搅拌混合物15分钟。然后，用注射器逐渐滴加37.8ml(60.3mmol)1.6M正丁基锂，搅拌混合物15分钟。在确认反应溶液的颜色变为黄色至橙红色之后，将6.00g(15.9mmol)(E)-3-[2′-环丙基-4′-(对氟苯基)喹啉-3′-基]-2-丙烯酸-N-甲基-N-甲氧基酰胺(G.B.Reddy,T.Mina-mi,T.Hanamoto,T.Hiyama,J.Org.Chem.,56.,5754,1991)溶于100ml干THF中，然后将该溶液滴加入反应溶液。然后，将反应温度升至室温，再搅拌混合物24小时。用冰冷却反应溶液，再加入200ml 1M乙酸水溶液以结束反应。分离出水相并用200ml乙酸乙酯萃取二次。将萃取物加入有机层，用饱和NaCl水溶液洗得混合物二次，用无水MgSO4干燥，然后减压蒸去溶剂。残留物用硅胶柱色谱法纯化(展开溶剂：己烷/乙酸乙酯=10/1)，然后用乙酸乙酯重结晶，得3.11g目的化合物。MS光谱(El)m/e445(M+),400,358,330,316,2881H-NMR(CDCl3)δppm:7.97-7.19(8H,m，芳香-H),7.71(1H,d,J=16Hz,COCH=c),6.03(1H,d,J=16Hz,COC=CH),5.51(1H,s，烯醇-烯键-H)，4.21(2H,q,J=7Hz,COOCH2),3.40(2H,s,COCH2COO),2.35-2.40(1H,m,CH-c-丙基)，1.39-1.41,1.07-1.09(4H,m,-CH2CH2-),1.28(3H,t,J=7Hz,COOCCH3)。实施例3用旋光性N-萘基甲基-2-吡咯烷甲醇(化合物(Ⅱ)/BH3)催化不对称还原单羰基化合物
将羰基化合物(1mmol)溶于5mlTHF中，再加入192mg(6mmol)甲醇和23mg(0.1mmol)旋光性N-萘基甲基-2-吡咯烷甲醇(化合物(Ⅱ))。然后，加入3ml或10ml(3mmol或10mmol)1MBH3·THF溶液，在20℃或30℃下搅拌混合物6-19小时。向反应溶液中加入13ml 1N HCl进行盐析，再用100ml乙酸乙酯萃取。然后，用10ml饱和NaCl水溶液洗涤萃取物，再用无水MgSO4干燥。然后，减压蒸去溶剂，得到的液体用薄层色谱法分离纯化，定量地获得所需的旋光性醇。
表3显示了用旋光性N-萘基甲基-2-吡咯烷甲醇(化合物(Ⅱ-1)或化合物(Ⅱ-2)不对称还原各种不同单羰基化合物的结果。所得到的醇的不对称产率和绝对构象是通过与旋光性标准产物的比较而确定的，即将醇产物转化成氨基甲酸酯非对映异构体，然后根据DaicelChemical Industries,Ltd.的使用CHIRALCEL OD柱的高效液相色谱分析法，或者根据Lamed等人的方法(E.Keinan,E.K.Hafeli,K.K.Seth,and R.Lamed,J.Am.Chem.Soc.,108,162(1986))用硅胶进行高效液相色谱法分析。
表3 
a)反应温度：30℃，反应时间：6小时，BH3·THF:10mmolb)反应温度：20℃，反应时间：19小时，BH3·THF:3mmol在单羰基化合物(Ⅲ)的不对称还原反应中，催化量的本发明的化合物(Ⅰ)即能达到高的不对称产率；化合物(Ⅰ)无需分离，亦即可由化合物(Ⅱ)在反应体系中就地加以形成。在传统的使用2-己酮作为底物的不对称还原反应中(J.Chem.Soc.Perkin Trans.I.2887(1984),J.Org.Chem.49,555(1984))，即使用化学计算量的甲硼烷配合物时，不对称产率也仅为25％ee(在(S)-脯氨酸的氮原子上具有被引入的聚合物取代基的一种甲硼烷配合物)或55％ee(一种(S)-2-氨基-3-甲基-1,1-二苯基丁-1-醇甲硼烷配合物)。因此，证明了本发明的化合物的优越性。实施例4各种旋光性β-氨烷氧基甲硼烷配合物(Ⅰ)不对称还原1,3-二羰基化合物(Ⅴ)。
将1mmol(445.5mg)1,3-二羰基化合物(Ⅴ)溶于30ml THF，搅拌下加入1M二乙甲氧基甲硼烷·THF的THF溶液1ml或1mmol(204.3mg)三异丙醇铝。在氮气流下调节混合物温度至-78℃或20℃。
在该1,3-二羰基化合物(Ⅴ)溶液中滴加实施例2中获得的(S)-N-(β-萘基)甲基-2-吡咯烷甲氧基甲硼烷配合物(S)-Ⅰ-1)，搅拌混合物3小时。或者，为了在反应体系中形成甲硼烷配合物，将2-10ml(2-10mmol)1.0M BH3·THF溶液滴加入实施例1中获得的(S)-N-(β-萘基)甲基-2-吡咯烷甲醇((S)-Ⅰ-1)或各种旋光性β-氨基醇的THF溶液(0.1-3mmol)中。将该溶液滴加入上述的1,3-二羰基化合物(Ⅴ)中，搅拌混合物3-28小时。当使用催化量的β-氨基醇时，再加入192mg(6mmol)甲醇。
然后，在反应溶液中加入乙酸(9mmol,540.5mg)，用300ml乙酸乙酯稀释混合物，用20ml饱和的NaCl水溶液洗涤，并用无水硫酸钠干燥。减压馏去溶剂，在得到的橙红色液体中加入1升甲醇，在50-60℃加热混合物1小时。然后，减压馏去甲醇。得到的黄色液体用硅酸柱色谱纯化，得所需的旋光性1,3-顺-二醇化合物(Ⅵ-1)。采用Daicel Chemical Industries,Ltd.生产的CHIRALCEL OD柱，通过高效液相色谱法确定不对称产率(％ee)。
就表4中所示的还原剂而言，在测试号No.1-3中使用的是β-氨烷氧基甲硼烷配合物((S)-Ⅰ-1)。在测试号No.4-9中，使用的是在反应体系中由β-氨基醇形成的氨基烷氧基甲硼烷配合物。在测试号No.5和6中，使用的是催化量的β-氨基醇((S)-Ⅱ-1)。此外，在测试号No.6中，用二氯甲烷为溶剂。
表4
a)反应温度：-78℃，反应时间：3小时，b)反应温度：20℃，反应时间：3小时，c)反应温度：20℃，反应时间：28小时，d)反应温度：-78℃，反应时间：23小时，CH2Cl2溶剂e)反应温度：-78℃，反应时间：5小时，f)反应温度：20℃，反应时间：20小时。对比例1
| 编号 | 还原剂 | 金属试剂 | 化学产率(％) | 顺式形成速率(％)顺式/顺式+反式 | 不对称产率(％ee) | 绝对构象 |
| 7 | 〔(R)-Ⅱ-3〕+BH3各2摩尔倍数 | Et2BOMe | 19a) | 100 | 24 | 3R,5S |
| 8 | 〔(R)-Ⅱ-1〕+BH3各2摩尔倍数 | Al(OPr-i)3 | 15e) | 99 | 100 | 3R,5S |
| 9 | 〔(R)-Ⅱ-1〕+BH3各3摩尔倍数 | Al(OPr-i)3 | 74f) | 99 | 100 | 3R,5S |
使用传统的甲硼烷配合物，按实施例4同样方式进行操作。结果列于表5。
表5
a)反应温度：-78℃，反应时间：3小时，b)反应温度：20℃，反应时间：3小时。实施例5
将50mg(0.27mmol)3,5-二氧代-6-庚炔酸乙酯溶于5ml THF和52ml甲醇中。然后，加入或不加入三异丙醇铝作为金属试剂，使用5.4ml 1.0M BH3·THF溶液和6.2mg(0.027mmol)实施例1中获得的(S)-N-(β-萘基)甲基-2-吡咯烷甲醇(化合物(S)-Ⅱ-1)，在20℃进行反应20小时，以获得所需的产物3,5-二羟基-6-庚炔酸乙酯(Ⅵ-2)。1H-NMR(CDCl3)δppm:4.81(1H,br,≡-CH-OH),4.17(2H,q,J=7Hz,COOCH2),3.60(1H,m,C-CH(OH)-C),3.04(1H,s,C≡C-H),1.50-1.65(6H,m，其它-H)，1.3(3H,t,J=7Hz,COOCH2CH3)。IR(NaCl)cm-1:3400(OH),2220(C≡C),1720(C=O)。
表6
| 编号 | 金属试剂 | 化学产率(％) | 顺式形成速率(％)顺式/顺式+反式 | 不对称产率(％ee) | 绝对构象 |
| 12 | -Al(OPr3 -i) | 9091 | 9999 | 82100 | 3R,5S3R,5S |
催化量的本发明的化合物在不对称还原1,3-二羰基化合物(Ⅴ-1)和(Ⅴ-2)中，表现出比传统的甲硼烷配合物催化剂更高的不对称产率和更高的非对映异构体选择性(更高的顺式形成速率)。
Claims (5)
1．一种式(Ⅱ)旋光性β-氨基醇化合物：
(Ⅱ)其特征在于，其中，R1为苯基，R2是氢，或者R1和R2一起构成(CH2)n，其中n为3或4，和Ar为萘基，蒽基或菲基。
2．一种生产式(Ⅳ)旋光性醇化合物的方法： (Ⅳ)其中，R3和R4不同，各自为C1-C6烷基或苯基，和*表示旋光活性中心，或者该化合物是
或
其特征在于，它包括用权利要求1中所述的式(Ⅱ)旋光性β-氨基醇化合物和甲硼烷试剂，来还原式(Ⅲ)羰基化合物：
(Ⅲ)其中R3和R4如上所述，或者来还原下列物质：
或
3．一种生产式(Ⅵ)化合物的方法：
(Ⅵ)其中X为-CH=CH-,R6为羟基或C1-C4烷氧基，R7为C3-C5环烷基，R8为可被氟、氯或溴取代的苯基，以及*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，其特征在于，该方法包括用权利要求1所述的式(Ⅱ)旋光性β-氨基醇化合物和甲硼烷试剂，来还原式(Ⅴ)羰基化合物： (Ⅴ)其中R6,R7和R8如上所述，而且Y和Z各自独立，为-CO-或-CH(OH)-，只要Y和Z不同时为-CH(OH)-。
4．一种生产式(Ⅵ-1)化合物的方法： (Ⅵ-1)其中R6为羟基或C1-C4烷氧基，R7为C3-C5环烷基，R8为可被氟、氯或溴取代的苯基，*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，其特征在于，该方法包括用权利要求1所述的式(Ⅱ)旋光性β-氨基醇化合物和甲硼烷试剂，来还原式(Ⅴ-1)1,3-二羰基化合物： (Ⅴ-1)其中R6,R7和R8的定义如上。
5．一种生产式(Ⅵ-2)旋光活性1,3-顺-二醇化合物的方法：
(Ⅵ-2)其中R5为氢，R6为羟基或C1-C4烷氧基，以及*为旋光活性中心，只要二个旋光活性中心互相呈顺式构象，其特征在于，该方法包括用权利要求1所述的式(Ⅱ)旋光性β-氨基醇化合物和甲硼烷试剂，来还原式(Ⅴ-2)1,3-二羰基化合物：
(Ⅴ-2)其中R5和R6的定义如上。
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| JPH06329679A (ja) * | 1993-01-20 | 1994-11-29 | Nissan Chem Ind Ltd | 光学活性β−アミノアルコキシボラン錯体 |
| US5831132A (en) * | 1994-10-28 | 1998-11-03 | Sumika Fine Chemicals Company, Ltd. | Process for producing optically active carbinols |
| US6262283B1 (en) | 1996-12-06 | 2001-07-17 | Magainin Pharmaceuticals Inc. | Stereoselective synthesis of 24-hydroxylated compounds useful for the preparation of aminosterols, vitamin D analogs, and other compounds |
| CA2406847C (en) | 2000-04-12 | 2009-11-17 | Genaera Corporation | Regioselective and stereoselective oxidation of fused ring systems useful for the preparation of aminosterols |
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| US7153889B2 (en) | 2002-11-12 | 2006-12-26 | Abbott Laboratories | Bicyclic-substituted amines as histamine-3 receptor ligands |
| US7098222B2 (en) | 2004-05-12 | 2006-08-29 | Abbott Laboratories | Bicyclic-substituted amines having cyclic-substituted monocyclic substituents |
| US7205316B2 (en) | 2004-05-12 | 2007-04-17 | Abbott Laboratories | Tri- and bi-cyclic heteroaryl histamine-3 receptor ligands |
| US7145005B2 (en) | 2004-05-12 | 2006-12-05 | Abbott Laboratories | 2-(6-{2-[(2R)-2-Methyl-1-pyrrolidin-1-yl]-ethyl}-2-naphthalen-2-yl)-2H-pyridazin-3-one salts and their preparation |
| TWI504394B (zh) | 2011-04-29 | 2015-10-21 | Ind Tech Res Inst | 安托芬之製備方法 |
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| CA772624A (en) * | 1967-11-28 | F. Crowther Albert | Substituted oxazolidines | |
| US2573606A (en) * | 1946-12-02 | 1951-10-30 | Parke Davis & Co | Lower alkyl and alkenyl n-(1-naphthyl methyl) n-hydroxyethyl amines |
| JPS57146786A (en) * | 1981-03-09 | 1982-09-10 | Kyowa Hakko Kogyo Co Ltd | Optically active borane compound and preparation of optically active compound using the same |
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| US5157129A (en) * | 1990-04-18 | 1992-10-20 | Merck & Co., Inc. | Enantiospecific synthesis of s-(+)-5,6-dihydro-4-(r-amino)-4h-thieno(2,3-b)thiopyran-2-sulfonamide-7,7-dioxide |
| ATE146790T1 (de) * | 1992-05-14 | 1997-01-15 | Pfizer | Enantioselektive katalysatoren aus oxazaborolidin |
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