CN1069028A - 红豆杉醇侧链的不对称合成 - Google Patents
红豆杉醇侧链的不对称合成 Download PDFInfo
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- CN1069028A CN1069028A CN92105923A CN92105923A CN1069028A CN 1069028 A CN1069028 A CN 1069028A CN 92105923 A CN92105923 A CN 92105923A CN 92105923 A CN92105923 A CN 92105923A CN 1069028 A CN1069028 A CN 1069028A
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- HYJVYOWKYPNSTK-UONOGXRCSA-N (2r,3s)-3-benzamido-2-hydroxy-3-phenylpropanoic acid Chemical compound N([C@H]([C@@H](O)C(O)=O)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 HYJVYOWKYPNSTK-UONOGXRCSA-N 0.000 title description 4
- 238000011914 asymmetric synthesis Methods 0.000 title description 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 33
- 239000001257 hydrogen Substances 0.000 claims abstract description 29
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 29
- 238000002360 preparation method Methods 0.000 claims abstract description 22
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims abstract description 20
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 15
- 125000002252 acyl group Chemical group 0.000 claims abstract description 14
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 14
- 125000005587 carbonate group Chemical group 0.000 claims abstract description 13
- 150000002431 hydrogen Chemical class 0.000 claims abstract description 9
- -1 t-butyldiphenylsilyl Chemical group 0.000 claims description 71
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 25
- 238000006243 chemical reaction Methods 0.000 claims description 22
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical class O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims description 21
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 13
- 125000006502 nitrobenzyl group Chemical group 0.000 claims description 12
- 238000006884 silylation reaction Methods 0.000 claims description 10
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical class C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 claims description 8
- 239000003513 alkali Substances 0.000 claims description 8
- 150000002466 imines Chemical class 0.000 claims description 8
- 239000003960 organic solvent Substances 0.000 claims description 8
- 239000004473 Threonine Substances 0.000 claims description 7
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 6
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 150000002367 halogens Chemical group 0.000 claims description 5
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 claims description 4
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 claims 1
- 238000000354 decomposition reaction Methods 0.000 claims 1
- 238000006073 displacement reaction Methods 0.000 claims 1
- 125000002485 formyl group Chemical class [H]C(*)=O 0.000 claims 1
- 125000001273 sulfonato group Chemical class [O-]S(*)(=O)=O 0.000 claims 1
- OVMSOCFBDVBLFW-VHLOTGQHSA-N 5beta,20-epoxy-1,7beta,13alpha-trihydroxy-9-oxotax-11-ene-2alpha,4alpha,10beta-triyl 4,10-diacetate 2-benzoate Chemical compound O([C@@H]1[C@@]2(C[C@H](O)C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)O)C(=O)C1=CC=CC=C1 OVMSOCFBDVBLFW-VHLOTGQHSA-N 0.000 abstract description 11
- 229930012538 Paclitaxel Natural products 0.000 abstract description 11
- 229960001592 paclitaxel Drugs 0.000 abstract description 11
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 abstract description 11
- 239000000543 intermediate Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- INIGTCHMPNFSAM-UHFFFAOYSA-N 4-hydroxy-3-phenylazetidin-2-one Chemical class C1=CC=C(C=C1)C2C(NC2=O)O INIGTCHMPNFSAM-UHFFFAOYSA-N 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 26
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 24
- 239000000203 mixture Substances 0.000 description 19
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 18
- 239000000460 chlorine Substances 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 13
- 235000019439 ethyl acetate Nutrition 0.000 description 12
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 11
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 10
- 125000006239 protecting group Chemical group 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 8
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 8
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 8
- 229960003328 benzoyl peroxide Drugs 0.000 description 8
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 125000000217 alkyl group Chemical group 0.000 description 7
- 238000013375 chromatographic separation Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- 235000010290 biphenyl Nutrition 0.000 description 6
- 229940126214 compound 3 Drugs 0.000 description 6
- 150000003839 salts Chemical class 0.000 description 6
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 6
- FBZSDKXFQUKDLD-JGVFFNPUSA-N (3r,4s)-3-hydroxy-4-phenylazetidin-2-one Chemical compound N1C(=O)[C@H](O)[C@@H]1C1=CC=CC=C1 FBZSDKXFQUKDLD-JGVFFNPUSA-N 0.000 description 5
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 5
- 239000002808 molecular sieve Substances 0.000 description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 5
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 5
- 238000005406 washing Methods 0.000 description 5
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 4
- 125000002603 chloroethyl group Chemical group [H]C([*])([H])C([H])([H])Cl 0.000 description 4
- 229940125904 compound 1 Drugs 0.000 description 4
- 229940125898 compound 5 Drugs 0.000 description 4
- 238000001704 evaporation Methods 0.000 description 4
- 230000008020 evaporation Effects 0.000 description 4
- 150000002460 imidazoles Chemical class 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 4
- 235000003140 Panax quinquefolius Nutrition 0.000 description 3
- 240000005373 Panax quinquefolius Species 0.000 description 3
- 241001116498 Taxus baccata Species 0.000 description 3
- 239000012346 acetyl chloride Substances 0.000 description 3
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 229940125773 compound 10 Drugs 0.000 description 3
- 229940125782 compound 2 Drugs 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 239000000039 congener Substances 0.000 description 3
- 239000012043 crude product Substances 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000003818 flash chromatography Methods 0.000 description 3
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 description 3
- QARBMVPHQWIHKH-UHFFFAOYSA-N methanesulfonyl chloride Chemical compound CS(Cl)(=O)=O QARBMVPHQWIHKH-UHFFFAOYSA-N 0.000 description 3
- TVHCXXXXQNWQLP-DMTCNVIQSA-N methyl (2s,3r)-2-amino-3-hydroxybutanoate Chemical compound COC(=O)[C@@H](N)[C@@H](C)O TVHCXXXXQNWQLP-DMTCNVIQSA-N 0.000 description 3
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 3
- WURFKUQACINBSI-UHFFFAOYSA-M ozonide Chemical compound [O]O[O-] WURFKUQACINBSI-UHFFFAOYSA-M 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 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 3
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 description 2
- SUHXTVABLHHRST-UHFFFAOYSA-N 2-azidoacetyl chloride Chemical compound ClC(=O)CN=[N+]=[N-] SUHXTVABLHHRST-UHFFFAOYSA-N 0.000 description 2
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-UHFFFAOYSA-N 0.000 description 2
- 125000002774 3,4-dimethoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C(OC([H])([H])[H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 2
- FBZSDKXFQUKDLD-UHFFFAOYSA-N 3-hydroxy-4-phenylazetidin-2-one Chemical compound N1C(=O)C(O)C1C1=CC=CC=C1 FBZSDKXFQUKDLD-UHFFFAOYSA-N 0.000 description 2
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 2
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 229930182822 D-threonine Natural products 0.000 description 2
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical compound CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001336 alkenes Chemical class 0.000 description 2
- 150000001350 alkyl halides Chemical class 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 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 2
- 229930014667 baccatin III Natural products 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 229910052794 bromium Inorganic materials 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 229910052801 chlorine Inorganic materials 0.000 description 2
- 125000004218 chloromethyl group Chemical group [H]C([H])(Cl)* 0.000 description 2
- 238000004587 chromatography analysis Methods 0.000 description 2
- 125000000490 cinnamyl group Chemical group C(C=CC1=CC=CC=C1)* 0.000 description 2
- 238000003381 deacetylation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 125000004772 dichloromethyl group Chemical group [H]C(Cl)(Cl)* 0.000 description 2
- 125000005982 diphenylmethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])(*)C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 2
- GNTDGMZSJNCJKK-UHFFFAOYSA-N divanadium pentaoxide Chemical compound O=[V](=O)O[V](=O)=O GNTDGMZSJNCJKK-UHFFFAOYSA-N 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 125000004969 haloethyl group Chemical group 0.000 description 2
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- HRDXJKGNWSUIBT-UHFFFAOYSA-N methoxybenzene Chemical group [CH2]OC1=CC=CC=C1 HRDXJKGNWSUIBT-UHFFFAOYSA-N 0.000 description 2
- FXKJJLARAQPLMG-APWZRJJASA-N methyl (2s,3r)-2-amino-3-[tert-butyl(diphenyl)silyl]oxybutanoate Chemical class C=1C=CC=CC=1[Si](C(C)(C)C)(O[C@H](C)[C@H](N)C(=O)OC)C1=CC=CC=C1 FXKJJLARAQPLMG-APWZRJJASA-N 0.000 description 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical group [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 description 2
- 125000004368 propenyl group Chemical group C(=CC)* 0.000 description 2
- GRJJQCWNZGRKAU-UHFFFAOYSA-N pyridin-1-ium;fluoride Chemical compound F.C1=CC=NC=C1 GRJJQCWNZGRKAU-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000007363 ring formation reaction Methods 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 125000003866 trichloromethyl group Chemical group ClC(Cl)(Cl)* 0.000 description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical compound CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 2
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 2
- 229920002554 vinyl polymer Polymers 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- NHOWDZOIZKMVAI-UHFFFAOYSA-N (2-chlorophenyl)(4-chlorophenyl)pyrimidin-5-ylmethanol Chemical group C=1N=CN=CC=1C(C=1C(=CC=CC=1)Cl)(O)C1=CC=C(Cl)C=C1 NHOWDZOIZKMVAI-UHFFFAOYSA-N 0.000 description 1
- VWWPJZHACDRSFD-QAPCUYQASA-N (2S,3R)-2-amino-3-[tert-butyl(diphenyl)silyl]oxybutanoic acid Chemical compound C=1C=CC=CC=1[Si](C(C)(C)C)(O[C@H](C)[C@H](N)C(O)=O)C1=CC=CC=C1 VWWPJZHACDRSFD-QAPCUYQASA-N 0.000 description 1
- XSYLUBKWRZCOQP-CXRLMVSZSA-N (3r,4s)-1-benzoyl-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1([C@H]([C@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)C1=CC=CC=C1 XSYLUBKWRZCOQP-CXRLMVSZSA-N 0.000 description 1
- XYWGQFNRQIIWIV-UHFFFAOYSA-N 1-benzoyl-3-hydroxy-4-phenylazetidin-2-one Chemical compound O=C1C(O)C(C=2C=CC=CC=2)N1C(=O)C1=CC=CC=C1 XYWGQFNRQIIWIV-UHFFFAOYSA-N 0.000 description 1
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Abstract
本发明涉及从浆果赤霉素III合成红豆杉醇过程
中的有用中间体即(3R,4S)-3-羟基-4-苯基-2-氮
杂环丁酮衍生物的制备方法,并涉及用所述方法产生
的式(Ⅲ)化合物,式中Ar是苯基;R1是氢、羧酸中的
酰基、或碳酸酯基;R2是氢或羧基保护基;R3是氢或
羧基保护基。
Description
本发明涉及红豆杉醇侧链的新型手性中间体,并涉及用于制备这些中间体的新方法。
红豆杉醇(Ⅰ)是一种天然产物,已发现它在体内和体外都显示出优异的抗肿瘤活性。最近的研究已阐明了它的独特作用方式,这包括微管蛋白的异常聚合和有丝分裂的破坏。它目前正在美国和法国进行临床试验,初步结果已经证实它是一种最有前景的化学治疗剂。
红豆杉醇的临床成功已引起人们对其供应的颇大关注。红豆杉醇是用难度大、收率低的分离方法,从缓慢生长的紫杉树的皮中提取的,需要收获大批紫杉树,这也已引起生态问题。一种相关物质即10-脱乙酰浆果赤霉素Ⅲ(Ⅱ)大量存在于浆果紫杉(Taxus baccata)的叶中,这一观察已导致几支研究队伍设计了从10-脱乙酰浆果赤霉素Ⅲ出发制备红豆杉醇的半合成路线。
Ⅱ:Ra=H;Rb=H
Denis等人的美国专利4,924,011公开了制备红豆杉醇的方法,该方法是使7-(三乙基甲硅烷基)浆果赤霉素Ⅲ与(2R,3S)-N-苯甲酰-O-(1-乙氧基乙基)-3-苯基异丝氨酸反应,随后脱除保护基。在Denis等人,J.Org.Chem.,1990,55:1957-1959中,报导了手性3-苯基异丝氨酸化合物的一种改进合成方法。
Holton在1990年12月5日公开的欧洲申请400,971中公开了把羟基保护的1-苯甲酰-3-羟基-4-苯基-2-氮杂环丁酮作为红豆杉醇的C-13侧链用于受保护浆果赤霉素Ⅲ的酰化。氮杂环丁酮是由酰氧基乙酰氯和N-亚苄基-对甲氧基苯胺缩合生成的;然而,这样生成的产物是一种外消旋混合物,需要进行拆分才能获得所希望的对映体。Palomo等人在Tet.Lett.,1990,31:6529-6432中也报导了用上述方法进行所述氮杂环丁酮的合成。
Ojima等人在J.Org.Chem.,1991,56:1681-1683中报导了带有手性侧链的(甲硅烷氧基)乙酸酯与N-(三甲基甲硅烷基)亚胺缩合,生成高对映体纯度的3-羟基-4-芳基-2-氮杂环丁酮。然而,手性(甲硅烷氧基)乙酸酯既没有市售,也不能廉价地进行所要求的酶促拆分。
2-氮杂环丁酮的手性合成在医药化学的其它领域也具有重要意义,在β-内酰胺类抗生素领域最为显著。Bose等人在J.Org.Chem.,1982,47:4075-4081中报导了叠氮基乙酰氯与一种N-(苯基亚丙烯基)-D-苏氨酸酯缩合,生成对应取代的顺式-2-氮杂环丁酮,它是一种1∶1非对映体混合物。Tenneson和Belleau在Can.J.Chem.,1980,58:1605-1607中报导,当N-(苯基亚丙烯基)-D-苏氨酸酯的羟基用叔丁基二甲基甲硅烷基保护时,产物顺式-2-氮杂环丁酮是以9∶1非对映体比例获得的。Wagle等人在J.Org.Chem.,1988,53:4227-4236中提到一个类似反应,其中使用三苯基甲硅烷基作为羟基保护基团,生成95∶5非对映体混合物。
尽管所报道的利用从羟基保护的D-苏氨酸衍生的亚胺和叠氮基乙酰氯进行的环化缩合反应导致高度非对映体选择性,但这样的有利结果不能外推到带有其它取代基的反应物,因为已知这种类型的反应对于两个反应物中所使用的取代基的类型都是敏感的。例如,Wharton等人在J.Chem.Soc.Perkin Trans.I,1984,29-39中报道了N-亚苄基-L-丙氨酸-L-脯氨酸叔丁酯与(尤其是)苯氧乙酰氯或苄氧乙酰氯的环化缩合。然而,产物得率非常低,而且实际上没有非对映体选择性。
按我们自己的经验,我们发现,苄氧乙酰氯与N-亚苄基-O-(二苯基·叔丁基甲硅烷基)-(L)-苏氨酸对硝基苄酯的反应产生氮杂环丁酮的2∶1非对映体混合物;而且当使用叔丁基二苯基甲硅烷氧基乙酰氯时,没有分离出任何氮杂环丁酮。因此,意外的是,在环化缩合中使用一种酰氧乙酰氯会生成氮杂环丁酮的一种有利于所要非对映体的优于10∶1的非对映体混合物。
本发明提供具有式(Ⅲ)的(3R,4S)-2-氮杂环丁酮衍生物:
式中Ar是苯基;R1是氢、羧酸中的酰基、或碳酸酯基;R2是氢或羧基保护基;R3是氢或羟基保护基。
本发明的另一方面提供一种用于制备式(Ⅲa)化合物的方法
它包括下列步骤:(a)在惰性有机溶剂中,在碱存在下,使式(Ⅳ)的(L)-苏氨酸的亚胺衍生物与式(Ⅴ)的乙酰卤反应
式中Ar是苯基,R2a是羧基保护基,R3a是羟基保护基;
式中R1a是羧酸中的酰基或碳酸酯基;X是卤素;
(b)分离出所希望的非对映体。亚胺最好通过羟基保护的(L)苏氨酸与苯甲醛反应就地产生。
本发明的另一方面提供一种用于制备具有式(Ⅵ)的(3R,4S)-2-氮杂环丁酮衍生物的方法
式中Ar是苯基,R1a是羧酸中的酰基或碳酸酯基;所述方法包括下列步骤:(a)在惰性有机溶剂中,在碱存在下,使式(Ⅳ)的(L)-苏氨酸的亚胺衍生物与式(Ⅴ)的乙酰卤反应;(b)分离出所希望的非对映体;(c)脱除(L)-苏氨酸手性模(chiral template)。亚胺最好通过羟基保护的(L)-苏氨酸与苯甲醛反应就地产生。
本发明的中间体和方法,为从浆果赤霉素Ⅲ进行红豆杉醇或其衍生物合成中的关键化合物,即(3R,4S)-3-羟基-4-苯基-2-氮杂环丁酮及其羟基保护的同类物,提供了一条经济、高效的制备路线。
本发明提供一种具有式(Ⅲ)的(3R,4S)-2-氮杂环丁酮衍生物
式中Ar是苯基;R1是氢、羧酸中的酰基、或碳酸酯基;R2是氢或羧基保护基;R3是氢或羟基保护基。式(Ⅲ)的化合物可以进一步改性,以提供化合物(3R,4S)-3-羟基-4-苯基-2-氮杂环丁酮及其羟基保护的同类物,这些同类物是从浆果赤霉素Ⅲ合成红豆杉醇及其衍生物的过程中的有用中间体。
除非另外指明,本文中所使用的“低级烷基”代表具有1~5个碳原子的直碳链或支化碳链。“低级烯基”代表具有至少一个碳-碳双键并具有2~5个碳原子的直碳链或支化碳链。“卤素”包括氟、氯、溴和碘。由于从R1、R2、R3、R1a、R2a和R3a的定义显而易见,R1也可以定义为是氢或R1a,R2也可以定义为是氢或R2a,R3也可以定义为是氢或R3a,所以这种较简单的术语将使用于整个说明书。
“羧酸中的酰基”系指酯基Rc-CO-,其中Rc可以是(但不限于)氢;低级烷基,如甲基、乙基、丙基、异丙基等;卤代低级烷基,如氯甲基、二氯甲基、三氯甲基、三氟甲基;取代的甲基,如甲氧甲基、三苯甲氧甲基、苯氧甲基、对氯苯氧甲基;苯基和取代的苯基,如2,4,6-三甲基苯基、邻甲氧羰基苯基;苯乙基和丙烯基。“碳酸酯基”系指碳酸酯Rd-O-CO-,其中Rd可以是(但不限于)低级烷基,如甲基、乙基、丙基、异丁基,取代的乙基,如2,2,2-三卤乙基(如2,2,2-三氯乙基)、2-(三甲基甲硅烷基)乙基、2-(苯磺酰基)乙基;低级烯基,如乙烯基和烯丙基;肉桂基;对硝基苯基;苄基和取代的苄基,如3,4-二甲氧基苄基、对甲氧基苄基、邻硝基苄基和对硝基苄基。
“羟基保护基”可以是通常用来封闭羟基的任何基团。羟基保护基的实例包括碳酸酯Rc-O-CO-,其中Rc可以是(但不限于)低级烷基,如甲基、乙基、丙基、异丁基;取代的乙基,如2,2,2-三卤乙基(如2,2,2-三氯乙基)、2-(三甲基甲硅烷基)乙基、2-(苯磺酰基)乙基;低级烯基,如乙烯基和烯丙基;肉桂基;对硝基苯基;苄基和取代的苄基,如3,4-二甲氧基苄基、对甲氧基苄基、邻硝基苄基和对硝基苄基;酯Rd-CO-,其中Rd可以是(但不限于)氢;低级烷基,如甲基、乙基、丙基等;卤代低级烷基,如氯甲基、二氯甲基、三氯甲基、三氟甲基;取代的甲基,如甲氧甲基、三苯甲氧甲基、苯氧甲基、对氯苯氧甲基;苯基和取代的苯基,如2,4,6-三甲基苯基、邻甲氧羰基苯基;苯乙基和丙烯基;醚Re,其中Re可以是(但不限于)甲氧甲基、四氢吡喃基、四氢呋喃基、苄氧甲基、叔丁氧甲基、2-甲氧基乙氧基甲基、2,2,2-三氯乙氧甲基、乙氧乙基、2,2,2-三氯乙基、叔丁基、烯丙基、对氯苯基、苄基、对甲氧基苄基、邻硝基苄基、对硝基苄基、对氯苄基、对氰基苄基、二苯基甲基、三苯基甲基、或三有机甲硅烷基,例如,三甲基甲硅烷基、三乙基甲硅烷基、异丙基二甲基甲硅烷基、叔丁基二甲基甲硅烷基、(三苯基甲基)二甲基甲硅烷基、叔丁基二苯基甲硅烷基、甲基二异丙基甲硅烷基、叔丁氧基二苯基甲硅烷基和三苯基甲硅烷基。
“羧基保护基”包括(但不限于)低级烷基,如甲基、乙基、丙基和叔丁基;取代的低级烷基,如9-芴基甲基、甲氧甲基、甲氧基乙氧甲基、苄氧甲基、苯甲酰甲基、对溴苯甲酰甲基、α-甲基苯甲酰甲基、2,2,2-三氯乙基、2-卤乙基、2-(三甲基甲硅烷基)乙基;烯丙基;苯基;苄基;取代的苄基,如三苯基甲基、二苯基甲基、2,4,6-三甲基苄基、对溴苄基、邻硝基苄基、对硝基苄基、对甲氧基苄基、2,6-二甲氧基苄基;三有机甲硅烷基,如三甲基甲硅烷基、三乙基甲硅烷基、叔丁基二甲基甲硅烷基、异丙基二甲基甲硅烷基、苯基二甲基甲硅烷基和二叔丁基甲基甲硅烷基。
保护基的另一些实例以及用于引入和脱除保护基的方法,可参阅一些常规教科书,如Green和Wutz,Protective Groups in Organic Synthesis,2d Edition,John Wiley & Sons,Inc.,1991。
在一个优选实施方案中,R1是羧酸中的酰基,优选低级链烷酰基;最优选的是,R1是乙酰基。在另一个优选实施方案中,R3是一个庞大的三有机甲硅烷基,优选叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基;最优选的是,R3是叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基。在另一个优选实施方案中,R2选自甲基、乙基、烯丙基和对硝基苄基;最优选的是,R2是对硝基苄基或甲基。特别优选的实施方案是如下式(Ⅲ)化合物,其中R1是乙酰基、R2是甲基或对硝基苄基,R3是叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基。
R1是R1a,R2是R2a,R3是R3a(Ⅲa)的式(Ⅲ)化合物,是按方案Ⅰ中所示,使式(Ⅳ)的羟基和羧基保护的N-亚苄基-(L)-苏氨酸与式(Ⅴ)的乙酰卤反应制备的。
方案Ⅰ
在方案Ⅰ中,Ar、R1a、R2a和R3a如前面所限定;X是卤素,如氯、溴和碘。环化缩合反应在一种惰性有机溶剂如二氯甲烷、氯仿、四氢呋喃等中进行,并在碱存在下进行,所述碱优选叔胺碱,如三乙胺、三甲胺、二异丙基乙基胺等,反应温度低于0℃,如约-5℃~约-40℃。所得到的产物是一种比例至少为10∶1,有利于所希望的(3R,4S)-氮杂环丁酮(Ⅲa)的非对映体混合物。这种非对映体混合物可以用常规方法如重结晶或色谱法分离;但更为有利的是,可利用简单的重结晶法,大规模分离所希望的非对映体。这些非对映体的分离,既可以在刚刚形成氮杂环丁烷环之后进行,也可以在一个或多个保护基脱除之后进行。
上述反应的起始原料可以从容易得到的试剂制备。例如,式(Ⅳ)的亚胺可按照已知方法从(L)-苏氨酸和苯甲醛制备;式(Ⅴ)化合物可从乙醇酸和适当的酰化剂制备。
在一种优选方法中,亚胺是在惰性有机溶剂如二氯甲烷、氯仿、四氢呋喃等中使羟基和羧基保护的(L)-苏氨酸与苯甲醛反应就地产生的。这个反应优选在水清除剂如分子筛的存在下,在有利于生成亚胺的温度如常温下进行。这样生成的产物,即式(Ⅳ)化合物,不需分离就可用于上述环化缩合反应。
式(Ⅲa)化合物可被转化成式(Ⅲ)化合物,其中R1、R2或R3中至少有一个是氢。于是,式(Ⅲa)化合物的R1a、R2a或R3a中至少有一个利用常规脱保护方法用氢置换,所用方法的选择将取决于保护基的特性。给定了保护基,本领域技术人员就能够选择合适的脱保护方法。例如,可以利用碱水解脱除羧基保护基R2a,在R1a是链烷酰基的情况下脱除R1a;在R1a是2,2,2-三氯乙氧羰基的情况下,可用诸如锌/乙酸将其脱除;在R3是叔丁基二苯基甲硅烷基的情况下,可用氟化氢/吡啶将其脱除,而在R3是叔丁氧基二苯基甲硅烷基的情况下,可用氟化四丁铵/乙酸将其脱除。进一步的实例可参阅Green和Wutz,Protective Groups in Organic Synthesis,2d Edition,John Wiley & Sons,Inc.,1991。
式(Ⅲa)化合物上的(L)-苏氨酸手性模,可用方案Ⅱ中所示的三步法脱除。
方案Ⅱ
首先脱除羟基保护基R3。如上所述,可以用不同的方法进行脱保护,这取决于所选择的保护基。例如,叔丁基二苯基甲硅烷基保护基可用氟化氢/吡啶脱除,而叔丁氧基二苯基甲硅烷基保护基可用氟化四丁铵/乙酸脱除。
第二步涉及醇(Ⅶ)脱水,生成对应的丙烯酸酯衍生物(Ⅷ)。脱水可以用各种各样的方法进行,例如,用碘、五氧化二磷、亚硫酰氯、亚硫酰溴或Ph3P(OSO2CF3)2处理。一种方便的方法是使羟基转化成磺酸酯,例如,在低温如-78℃下,在碱如三乙胺存在下,使它与甲苯磺酰氯、甲苯磺酸酐、甲磺酸酐或甲磺酰氯反应,在(例如)室温将反应温合物保持几小时,使磺酸酯消除,生成烯烃(Ⅷ)。
第三步涉及烯烃(Ⅷ)的臭氧分解,生成氮杂环丁酮(Ⅵ)。臭氧分解是在有机溶剂如二氯甲烷和甲醇的混合物中,在低温如约-78℃下进行的。这样生成的臭氧化物用合适的试剂分解;合适试剂的实例包括锌/乙酸、催化加氢、亚磷酸三甲酯、硫脲、三苯膦和二甲硫醚。优选使用二甲硫醚。使反应液温热至室温,产生所希望的氮杂环丁酮(Ⅵ)。已经注意到,在R2a是甲基的情况下,优选在臭氧化物分解和温热之后,将所形成的固体物溶于惰性有机溶剂如四氢呋喃中,并在-78℃下用水合肼处理,得到氮杂环丁酮(Ⅵ)。
式(Ⅵ)化合物可以通过脱除R1a基团转化成化合物(3R,4S)-3-羟基-4-苯基-2-氮杂环丁酮(Ⅸ)。这种解封反应可以用本领域公知的方法进行。例如,在R1是乙酰基的情况下,可以通过碱水解将其脱除。化合物(Ⅸ)可以进一步加工,得到羟基保护的(3R,4S)-1-苯甲酰-3-羟基-4-苯基-2-氮杂环丁酮,然后可将其用于使浆果赤霉素Ⅲ酰化,以生成红豆杉醇。例如,按照欧洲专利申请400,971中公开的方法,将化合物(Ⅸ)用乙基乙烯基醚和催化量的甲磺酸处理,得到(3R,4S)-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮。然后将后者用正丁基锂处理,随后再用苯甲酰氯处理,得到产物(3R,4S)-1-苯甲酰-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮。然后,在吡啶中,在二甲氨基吡啶存在下,使该产物与7-O-三乙基甲硅烷基浆果赤霉素Ⅲ反应,在三乙基甲硅烷基保护基脱除后生成红豆杉醇。
此外,也可以如Ojima等人J.Org.Chem.,1991,56:1681-1683中所述,把化合物(Ⅸ)转化成(2R,3S)-N-苯甲酰基苯基异丝氨酸,然后用适当羟基保护的(2R,3S)-N-苯甲酰基苯基异丝氨酸,按照美国专利4,924,011中所述的步骤,使7-O-三乙基甲硅烷基浆果赤霉素Ⅲ酰化。
以下实施例对这里所公开并请求保护的发明予以更充分的说明;它们决不应被误认为是要限制本发明的范围,本发明的范围只由所附的权利要求书加以限定。
实施例1 3-乙酰氧基-α-〔〔(1-叔丁基二苯基甲硅烷基)氧〕乙基〕-2-氧代-4-苯基-1-氮杂环丁烷乙酸对硝基苄酯(化合物1)的制备
(a)O-叔丁基二苯基甲硅烷基-(L)-苏氨酸对硝基苄酯(化合物2)
将无水CH2Cl2(100毫升)中的(L)-苏氨酸对硝苄酯甲苯磺酸盐(10.0克,0.0234摩尔)(按照Bose,A.K.等人,J.Org.Chem.,1982,47:4075-4081中报道的步骤制备),在咪唑(3.130克,0.0468摩尔)和二苯基叔丁基甲硅烷基氯(6.70毫升,0.0257摩尔)存在下,在室温下搅拌16小时。过滤除去固体物。把产物分配于CH2Cl2和水之间,随后用5%碳酸氢盐水溶液和水洗涤有机物,干燥和蒸发,得到一种粗制油状物。经闪式色谱法分离(己烷中的65%乙酸乙酯)得到油状化合物2(9.60克,83%)。
NMR(CDCl3)δ8.13(d,J=8.7Hz,2H) 7.58-7.24(m,12H) 5.15(d,J=13.3Hz,1H) 4.93(d,J=13.3Hz,1H) 4.34(m,1H) 3.34(d,J=2.5Hz,1H) 1.12(d,J=6.4Hz,3H) 0.98(s,9H).HRMS,对于C27H33N2O5Si,计算值为493.2159,实测值为493.2150。
(b)化合物1的制备
化合物2(1.473克,2.980毫摩尔)与苯甲醛(0.60毫升,5.97毫摩尔)在无水CH2Cl2(10毫升)中,在分子筛存在下,在室温下搅拌16小时。将溶液冷却到-30℃,加入三乙胺(0.789毫升,5.662毫摩尔),随后在20分钟内以CH2Cl2溶液(5毫升)形式加入乙酰氧基乙酰氯(0.609毫升,5.662毫摩尔)。让混合物达到室温过夜,随后分配于CH2Cl2和水之间。有机物进一步用0.1N HCl、5%碳酸氢盐和盐水洗涤,然后用硫酸镁干燥。闪式色谱法分离后得到化合物1的非对映体混合物(1.710克,84%)〔(3R,4S)∶(3S,4R)=91∶9,用NMR测定〕。
NMR(CDCl3)δ8.22-8.19(m,2H) 7.60-7.08(m,17H) 5.93(d,J=5.2Hz,1H主要产物 ) 5.79(d,J=5.0Hz,1H次要产物) 5.43(d,J=5.2Hz,1H主要) 5.27(d,J=13.2Hz,1H主要) 5.04(d,J=5Hz,1H次要) 4.98(d,J=13.2Hz,1H主要) 4.84(d,J=13.2Hz,1H次要) 4.57(d,J=13.2Hz,1H次要) 4.45(m,1H) 4.30(m,1H) 1.64(s,3H) 1.15(d,J=6.2Hz,3H次要) 0.99(d,J=6.2Hz,3H主要) 0.88(s,9H).
HRMS:C38H41N2O8Si(M+H)的计算值为681.2632,实测值为681.2639。
实施例2 3-乙酰氧基-α-〔〔(叔丁基二苯基甲硅烷基)氧〕乙基〕-2-氧代-4-苯基-1-氮杂环丁烷乙酸甲酯(化合物3)的制备
(a)O-叔丁基二苯基甲硅烷基-(L)-苏氨酸甲酯(化合物4)
(L)-苏氨酸甲酯盐酸盐(Sigma化学公司,1.190克,7.020毫摩尔)于无水CH2Cl2(10毫升)中,与咪唑(955毫克,14.03毫摩尔)和二苯基叔丁基甲硅烷基氯(2.0毫升,7.720毫摩尔)一起在室温下搅拌16小时。后处理和色谱分离同实施例1(a),得到稠油状化合物4(1.740克,67%)。
NMR(CDCl3δ7.65-7.33(m,10H) 4.32(m,1H) 3.59(s,3H) 3.25(d,J=2.5Hz,1H) 1.09(d,J=6.2Hz,3H) 0.99(s,9H).
(b)化合物3的制备
化合物4(472毫克,1.270毫摩尔)于CH2Cl2(5毫升)中,在分子筛存在下,在室温下用苯甲醛(0.235毫升,2.310毫摩尔)处理过夜。当冷却到-30℃时,加入三乙胺(0.336毫升,2.40毫摩尔),随后在10分钟内加入乙酰氧基乙酰氯(0.258毫升,2.40毫摩尔)。让混合物在6小时内达到室温。后处理和色谱分离同实施例1(b),得到化合物3的非对映体混合物(464毫克,65%)。〔(3R,4S)∶(3S,4R)=95∶5,用NMR测定〕。
NMR(CDCl3)δ7.60-7.01(m,15H) 5.97(d,J=5Hz,1H主要) 5.81(d,J=5Hz,1H次要) 5.45(d,J=5Hz,1H主要) 5.04(d,J=5Hz,1H次要) 4.40(d,J=3Hz,1H) 4.27(m,1H) 3.69(s,3H主要) 3.22(s,3H,次要) 0.94(d,J=6.2Hz,3H) 0.88(s,9H).HRMS,C32H38NO6Si的计算值为560.2468,实测值为560.2487。
实施例3 不分离中间体而制备化合物3
(L)-苏氨酸甲酯盐酸盐(20.73克,0.122摩尔)在无水CH3Cl2(200毫升)中,在咪唑(16.61克,0.244摩尔)、二苯基叔丁基甲硅烷基氯(35.0毫升,0.134摩尔)和4-二甲氨基吡啶(5~10毫克)存在下搅拌16小时。将固体过滤,滤液用5%碳酸氢盐水溶液和水洗涤,然后用硫酸镁干燥。过滤后,溶液在分子筛(约10毫升)存在下,在室温下用苯甲醛(25.0毫升,0.244摩尔)处理18小时。当冷却到-40℃时,溶液用三乙胺(32毫升,0.232摩尔)处理,随后在40分钟内用乙酰氧基乙酰氯(25毫升,0.232摩尔)在CH2Cl2(25毫升)中的溶液处理。让溶液在5小时内达到0℃。后处理同实施例2(b),得到一种粗制油状物,将其和乙醚一起研制,得到纯(3R,4S)化合物3(19.13克,三步产率为28%),没有(3S,4R)非对映体的痕迹。可以从母液中得到具有较低纯度的第二批产品。
实施例4 3-乙酰氧基-α-〔〔(叔丁氧基二苯基甲硅烷基)氧〕乙基〕-2-氧代-4-苯基-1-氮杂环丁烷乙酸甲酯(化合物5)的制备
(a)O-叔丁氧基二苯基甲硅烷基-(L)-苏氨酸甲酯(化合物6)
(L)-苏氨酸甲酯盐酸盐(1.2625克,7.444毫摩尔)于无水CH2Cl2(15毫升)中,与咪唑(1.010克,14.89毫摩尔)和叔丁氧基二苯基甲硅烷基氯(2.274克,7.816毫摩尔)一起,在室温下搅拌16小时。后处理同实施例1(a),得到稠油状化合物6(2.881克,99%)。此产品原样用于下一步骤。
NMR(CDCl3)δ7.70-7.25(m,10H) 4.44(m,1H) 3.62(s,3H) 3.31(d,J=3Hz,1H) 2.12(br,s 2H) 1.3-1.15(m,12H).
(b)化合物5的制备
化合物6(548毫克,1.414毫摩尔)于CH2Cl2(10毫升)中,在分子筛存在下,在室温下用苯甲醛(0.158毫升,1.55毫摩尔)处理过夜。当冷却到-40℃时,加入三乙胺(0.20毫升,1.698毫摩尔),随后在10分钟内加入乙酰氧基乙酰氯(0.182毫升,1.698毫摩尔)。让混合物在4小时内达到室温。后处理和色谱分离同实施例1(b),得到化合物5的非对映体混合物〔(3R,4S)∶(3S,4R)=93∶7,用NMR测定〕。
NMR(CDCl3)δ7.42-7.20(m,15H) 5.90(d,J=5.1Hz,1H主要) 5.68(d,J=5Hz,1H次要) 5.39(d,J=5.1Hz,1H主要) 4.96(d,J=5Hz,1H次要) 4.58(m,1H) 4.40(br d,1H) 3.68(s,3H主要) 3.25(s,3H次要) 1.14(s,9H) 1.07(d,J=6.6Hz,3H).
实施例5 从化合物1制备(3R,4S)-3-乙酰氧基-α-(1-羟基乙基)-2-氧-4-苯基-1-氮杂环丁烷乙酸对硝基苄酯(化合物7)
实施例1的非对映体混合物(155.6毫克,0.228毫摩尔)于无水四氢呋喃(1毫升)中与HF/吡啶(4.4M,0.52毫升,2.28毫摩尔HF)一起在室温下搅拌3天。溶液用乙酸乙酯稀释,并迅速倾入5%碳酸氢钠中停止反应。有机层用更多的碳酸氢钠、水和盐水洗涤。干燥和蒸发,得到一种粗产物,在二氧化硅上用30%乙酸乙酯/己烷对其进行色谱分离,得到标题化合物(75.7毫克)。
NMR(CDCl3)δ8.19(d,J=8.4Hz,2H) 7.67-7.24(m,7H) 5.89(d,J=4.8Hz,1H) 5.22(s,2H) 5.07(d,J=4.8Hz,1H) 4.36(m,1H) 4.01(d,J=4.2Hz,1H) 3.05(d,J=9.3Hz,1H) 1.72(s,3H) 1.23(d,J=6.5Hz,3H).HRMS,C22H23N2O8的计算值为443.1454,实测值为443.1470。
实施例6 从化合物3制备(3R,4S)-3-乙酰氧基-α-(1-羟基乙基)-2-氧代-4-苯基-1-氮杂环丁烷乙酸甲酯(化合物8)
实施例2的非对映体混合物(444毫克,0.793毫摩尔)于无水四氢呋喃(4毫升)中,在室温下用HF/吡啶(4.4M,1.80毫升,7.93毫摩尔)处理5天。快速终止反应和后处理同上述实施例5,随后进行色谱分离(40%乙酸乙酯/己烷),得到白色固体状标题化合物(139毫克,54%)。
NMR(CDCl3)δ7.42-7.25(m,5H) 5.90(d,J=4.8Hz,1H) 5.09(d,J=4.8Hz,1H) 4.28(m,1H) 4.01(d,J=4.8Hz,1H) 3.70(s,3H) 1.73(s,3H) 1.19(d,J=6.6Hz,3H).
实施例7 从化合物5制备化合物8
实施例4的非对映体混合物(245.1毫克,0.414毫摩尔)于无水四氢呋喃(2毫升)中,先用乙酸(0.15毫升)、后用氟化四丁铵(1M四氢呋喃溶液,1.20毫升,3当量)处理。溶液在室温下搅拌14小时,然后分配于5%碳酸氢钠水溶液和乙酸乙酯之间。色谱分离同实施例6,得到化合物8(66毫克,50%)。NMR谱与实施例6中所报道的相吻合。
实施例8 (3R,4S)-3-乙酰氧基-4-苯基-2-氮杂环丁酮(化合物9)的制备
(a)(3R,4S)-3-乙酰氧基-α-亚乙基-4-苯基-2-氧代-1-氮杂环丁烷乙酸对硝基苄酯(化合物10)
将化合物7(75毫克,0.169毫摩尔)于-78℃下溶解于CH2Cl2中,加入甲磺酰氯(0.013毫升,0.170毫摩尔),随后加入三乙胺(0.047毫升,0.338毫摩尔)。让反应混合物达到0℃,并监测起始原料的消失(TLC)。按如上所述再加入2份甲磺酰氯和三乙胺,并将混合物在室温下搅拌4小时。分配于水和乙酸乙酯之间,随后用稀碳酸氢盐、稀HCl和盐水洗涤有机物,干燥,得到一种粗产物,用闪式色谱法(28%乙酸乙酯/己烷)将其纯化,得到油状化合物10(62.9毫克,88%)。
NMR(CDCl3)δ8.19(d,J=8.6Hz,2H) 7.44(d,J=8.6Hz,2H) 7.34-7.21(m,5H) 6.95(q,J=7.3Hz,1H) 5.92(d,J=4.2Hz,1H) 5.64(d,J=4.2Hz,1H) 5.28(d,J=13.3Hz,1H) 5.18(d,J=13.3Hz,1H) 2.08(d,J=7.3Hz,3H) 1.71(s,3H). HRMS:C22H21N2O7(M+H)的计算值为425.1349,实测值为425.1363。
(b)化合物9的制备
化合物10(41毫克,0.0966毫摩尔)于CH2Cl2/MeOH(各3毫升)中,在-78℃下用臭氧气流处理,直至蓝色持久不变。溶液用氮气吹扫,臭氧化物用甲硫醚(0.5毫升)分解。让溶液达到室温,并搅拌48小时。产物用蒸发和色谱法(30%乙酸乙酯/己烷)分离,得到白色固体状化合物9(20毫克,100%)。
NMR(CDCl3)δ7.38-7.24(m,5H) 6.31(br s,1H) 5.87(br m,1H) 5.04(d,J=4.8Hz,1H) 1.67(s,3H).
实施例9 从化合物8制备化合物9
使用化合物8代替化合物7,重复实施例8(a)中所述的步骤,得到(3R,4S)-3-乙酰氧基-α-亚乙基-4-苯基-2-氧代-1-氮杂环丁烷乙酸甲酯(化合物11)。
将所得到的粗制化合物11(6.2克)溶解于二氯甲烷中,并在-78℃下进行臭氧化处理。用甲硫醚(5毫升)迅速停止反应,随后温热至室温并蒸发,得到一种白色固体。将这种固体溶解于四氢呋喃(150毫升)中,冷却至-78℃。加入两份等量的水合肼(总量为2.4毫升),混合物在-78℃放置2小时后进行后处理。在分配于乙酸乙酯和水之间及干燥之后,粗产物进行色谱分离(40%乙酸乙酯/己烷),得到无色固体状化合物9(2.13克,总得率54%)。
Claims (9)
2、权利要求1的化合物,其中R1是乙酰基。
3、权利要求1的化合物,其中R3是叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基。
4、权利要求1的化合物,其中R1是乙酰基;R3是叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基。
5、权利要求1的化合物,其中R1是乙酰基;R3是叔丁基二苯基甲硅烷基或叔丁氧基二苯基甲硅烷基;R2是甲基或对硝基苄基。
9、按照权利要求8的方法,其中所述(L)-苏氨酸基团的脱除包括:(a)消除α-氢原子和羟基或其磺酸酯衍生物,生成丙烯酸酯;(b)使步骤(a)的产物进行臭氧分解。
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