CN1067682C - 抗肿瘤化合物、药物组合物、其制备方法以及其用于治疗的方法 - Google Patents
抗肿瘤化合物、药物组合物、其制备方法以及其用于治疗的方法 Download PDFInfo
- Publication number
- CN1067682C CN1067682C CN94192117A CN94192117A CN1067682C CN 1067682 C CN1067682 C CN 1067682C CN 94192117 A CN94192117 A CN 94192117A CN 94192117 A CN94192117 A CN 94192117A CN 1067682 C CN1067682 C CN 1067682C
- Authority
- CN
- China
- Prior art keywords
- phenyl
- group
- amino
- methyl
- silyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
- 150000001875 compounds Chemical class 0.000 title claims abstract description 50
- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000011282 treatment Methods 0.000 title claims abstract description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title claims description 29
- 230000000259 anti-tumor effect Effects 0.000 title claims description 9
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 12
- -1 4-p-methoxy-phenyl Chemical group 0.000 claims description 247
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 56
- 239000002585 base Substances 0.000 claims description 35
- 229910052739 hydrogen Inorganic materials 0.000 claims description 35
- 239000001257 hydrogen Substances 0.000 claims description 33
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 claims description 28
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 28
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 24
- 238000006243 chemical reaction Methods 0.000 claims description 23
- 239000003513 alkali Substances 0.000 claims description 18
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 18
- 239000011734 sodium Substances 0.000 claims description 14
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 13
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 9
- HZVOZRGWRWCICA-UHFFFAOYSA-N methanediyl Chemical compound [CH2] HZVOZRGWRWCICA-UHFFFAOYSA-N 0.000 claims description 9
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 9
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 8
- 150000002431 hydrogen Chemical class 0.000 claims description 8
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 8
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 7
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical compound [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- 125000004369 butenyl group Chemical group C(=CCC)* 0.000 claims description 7
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 7
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 7
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 7
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 7
- 229910052708 sodium Inorganic materials 0.000 claims description 7
- 125000001255 4-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1F 0.000 claims description 6
- 125000004210 cyclohexylmethyl group Chemical group [H]C([H])(*)C1([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- 229910052744 lithium Inorganic materials 0.000 claims description 6
- 125000003944 tolyl group Chemical group 0.000 claims description 6
- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000001622 2-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C([H])=C(*)C([H])=C([H])C2=C1[H] 0.000 claims description 5
- 125000002541 furyl group Chemical group 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 125000004044 trifluoroacetyl group Chemical group FC(C(=O)*)(F)F 0.000 claims 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 claims description 4
- 230000000903 blocking effect Effects 0.000 claims description 4
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 4
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 claims description 4
- 125000001972 isopentyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 claims description 4
- 125000003762 3,4-dimethoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C(OC([H])([H])[H])C([H])=C1* 0.000 claims description 3
- JNRLEMMIVRBKJE-UHFFFAOYSA-N 4,4'-Methylenebis(N,N-dimethylaniline) Chemical class C1=CC(N(C)C)=CC=C1CC1=CC=C(N(C)C)C=C1 JNRLEMMIVRBKJE-UHFFFAOYSA-N 0.000 claims description 3
- NABHJQWQMBODEZ-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[K] Chemical compound C(C)(C)N(C(C)C)CC[K] NABHJQWQMBODEZ-UHFFFAOYSA-N 0.000 claims description 3
- WOWJWPXBKOURTA-UHFFFAOYSA-N C(C)(C)N(C(C)C)CC[Na] Chemical compound C(C)(C)N(C(C)C)CC[Na] WOWJWPXBKOURTA-UHFFFAOYSA-N 0.000 claims description 3
- 206010009944 Colon cancer Diseases 0.000 claims description 3
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 3
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 3
- DHXVGJBLRPWPCS-UHFFFAOYSA-N Tetrahydropyran Chemical compound C1CCOCC1 DHXVGJBLRPWPCS-UHFFFAOYSA-N 0.000 claims description 3
- 210000005075 mammary gland Anatomy 0.000 claims description 3
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 claims description 3
- 210000001672 ovary Anatomy 0.000 claims description 3
- 229910052700 potassium Inorganic materials 0.000 claims description 3
- 239000011591 potassium Substances 0.000 claims description 3
- 125000001501 propionyl group Chemical group O=C([*])C([H])([H])C([H])([H])[H] 0.000 claims description 3
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 claims description 3
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 3
- 239000012312 sodium hydride Substances 0.000 claims description 3
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 3
- 125000001544 thienyl group Chemical group 0.000 claims description 3
- WIHIUTUAHOZVLE-UHFFFAOYSA-N 1,3-diethoxypropan-2-ol Chemical compound CCOCC(O)COCC WIHIUTUAHOZVLE-UHFFFAOYSA-N 0.000 claims description 2
- OXHNLMTVIGZXSG-UHFFFAOYSA-N 1-Methylpyrrole Chemical compound CN1C=CC=C1 OXHNLMTVIGZXSG-UHFFFAOYSA-N 0.000 claims description 2
- 125000000094 2-phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000004203 4-hydroxyphenyl group Chemical group [H]OC1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001584 benzyloxycarbonyl group Chemical group C(=O)(OCC1=CC=CC=C1)* 0.000 claims description 2
- 125000000031 ethylamino group Chemical group [H]C([H])([H])C([H])([H])N([H])[*] 0.000 claims description 2
- 208000002154 non-small cell lung carcinoma Diseases 0.000 claims description 2
- 125000000286 phenylethyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])([H])* 0.000 claims description 2
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 claims description 2
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 claims description 2
- 229910000105 potassium hydride Inorganic materials 0.000 claims description 2
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical group C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 claims description 2
- 125000006255 cyclopropyl carbonyl group Chemical group [H]C1([H])C([H])([H])C1([H])C(*)=O 0.000 claims 2
- 208000001333 Colorectal Neoplasms Diseases 0.000 claims 1
- 201000010989 colorectal carcinoma Diseases 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 229910000103 lithium hydride Inorganic materials 0.000 claims 1
- IHLVCKWPAMTVTG-UHFFFAOYSA-N lithium;carbanide Chemical compound [Li+].[CH3-] IHLVCKWPAMTVTG-UHFFFAOYSA-N 0.000 claims 1
- RSHAOIXHUHAZPM-UHFFFAOYSA-N magnesium hydride Chemical compound [MgH2] RSHAOIXHUHAZPM-UHFFFAOYSA-N 0.000 claims 1
- 229910012375 magnesium hydride Inorganic materials 0.000 claims 1
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims 1
- 229940123237 Taxane Drugs 0.000 abstract description 18
- 238000005859 coupling reaction Methods 0.000 abstract description 13
- 229930190007 Baccatin Natural products 0.000 abstract description 8
- 239000002246 antineoplastic agent Substances 0.000 abstract description 8
- 239000002243 precursor Substances 0.000 abstract description 5
- 230000008569 process Effects 0.000 abstract description 3
- 229940127089 cytotoxic agent Drugs 0.000 abstract 1
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 72
- 238000005160 1H NMR spectroscopy Methods 0.000 description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 55
- 238000004458 analytical method Methods 0.000 description 43
- 239000000243 solution Substances 0.000 description 43
- 239000007787 solid Substances 0.000 description 39
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 38
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 37
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 33
- 239000011541 reaction mixture Substances 0.000 description 31
- 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 description 28
- 239000012043 crude product Substances 0.000 description 26
- 235000019439 ethyl acetate Nutrition 0.000 description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 23
- 150000003839 salts Chemical class 0.000 description 23
- 229930012538 Paclitaxel Natural products 0.000 description 20
- 239000000203 mixture Substances 0.000 description 20
- 229960001592 paclitaxel Drugs 0.000 description 20
- 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 description 20
- LJCZNYWLQZZIOS-UHFFFAOYSA-N 2,2,2-trichlorethoxycarbonyl chloride Chemical compound ClC(=O)OCC(Cl)(Cl)Cl LJCZNYWLQZZIOS-UHFFFAOYSA-N 0.000 description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 19
- 239000003480 eluent Substances 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- 238000010898 silica gel chromatography Methods 0.000 description 18
- 238000001035 drying Methods 0.000 description 17
- 229910052799 carbon Inorganic materials 0.000 description 16
- 125000004432 carbon atom Chemical group C* 0.000 description 16
- 239000000460 chlorine Substances 0.000 description 15
- 238000000605 extraction Methods 0.000 description 15
- 125000000217 alkyl group Chemical group 0.000 description 14
- 125000001072 heteroaryl group Chemical group 0.000 description 14
- 239000003921 oil Substances 0.000 description 14
- 125000003118 aryl group Chemical group 0.000 description 13
- 238000003381 deacetylation reaction Methods 0.000 description 13
- 150000003952 β-lactams Chemical class 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 125000003342 alkenyl group Chemical group 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- ZDZOTLJHXYCWBA-VCVYQWHSSA-N N-debenzoyl-N-(tert-butoxycarbonyl)-10-deacetyltaxol Chemical compound O([C@H]1[C@H]2[C@@](C([C@H](O)C3=C(C)[C@@H](OC(=O)[C@H](O)[C@@H](NC(=O)OC(C)(C)C)C=4C=CC=CC=4)C[C@]1(O)C3(C)C)=O)(C)[C@@H](O)C[C@H]1OC[C@]12OC(=O)C)C(=O)C1=CC=CC=C1 ZDZOTLJHXYCWBA-VCVYQWHSSA-N 0.000 description 11
- 125000000304 alkynyl group Chemical group 0.000 description 11
- 229930014667 baccatin III Natural products 0.000 description 11
- 125000000392 cycloalkenyl group Chemical group 0.000 description 11
- 125000004366 heterocycloalkenyl group Chemical group 0.000 description 11
- 125000004415 heterocyclylalkyl group Chemical group 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- 238000005406 washing Methods 0.000 description 11
- 125000002252 acyl group Chemical group 0.000 description 10
- 229940063683 taxotere Drugs 0.000 description 10
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 9
- 239000012141 concentrate Substances 0.000 description 9
- 229920006395 saturated elastomer Polymers 0.000 description 9
- XMPZTFVPEKAKFH-UHFFFAOYSA-P ceric ammonium nitrate Chemical compound [NH4+].[NH4+].[Ce+4].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O XMPZTFVPEKAKFH-UHFFFAOYSA-P 0.000 description 8
- 239000012230 colorless oil Substances 0.000 description 8
- 150000002466 imines Chemical class 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 238000003756 stirring Methods 0.000 description 8
- 239000011701 zinc Substances 0.000 description 8
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 6
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 238000001704 evaporation Methods 0.000 description 6
- 230000004224 protection Effects 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 229940034982 antineoplastic agent Drugs 0.000 description 5
- 125000000753 cycloalkyl group Chemical group 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 229910052757 nitrogen Inorganic materials 0.000 description 5
- 239000003960 organic solvent Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 229930191978 Gibberellin Natural products 0.000 description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 4
- 201000011510 cancer Diseases 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 230000008878 coupling Effects 0.000 description 4
- 238000010168 coupling process Methods 0.000 description 4
- UAOMVDZJSHZZME-UHFFFAOYSA-N diisopropylamine Chemical class CC(C)NC(C)C UAOMVDZJSHZZME-UHFFFAOYSA-N 0.000 description 4
- 239000000284 extract Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- IXORZMNAPKEEDV-UHFFFAOYSA-N gibberellic acid GA3 Natural products OC(=O)C1C2(C3)CC(=C)C3(O)CCC2C2(C=CC3O)C1C3(C)C(=O)O2 IXORZMNAPKEEDV-UHFFFAOYSA-N 0.000 description 4
- 239000003448 gibberellin Substances 0.000 description 4
- 231100000252 nontoxic Toxicity 0.000 description 4
- 230000003000 nontoxic effect Effects 0.000 description 4
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 4
- 239000000825 pharmaceutical preparation Substances 0.000 description 4
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- WRIKHQLVHPKCJU-UHFFFAOYSA-N sodium bis(trimethylsilyl)amide Chemical compound C[Si](C)(C)N([Na])[Si](C)(C)C WRIKHQLVHPKCJU-UHFFFAOYSA-N 0.000 description 4
- 125000000025 triisopropylsilyl group Chemical group C(C)(C)[Si](C(C)C)(C(C)C)* 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 206010033128 Ovarian cancer Diseases 0.000 description 3
- 206010061535 Ovarian neoplasm Diseases 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 230000005540 biological transmission Effects 0.000 description 3
- 238000006482 condensation reaction Methods 0.000 description 3
- 238000010511 deprotection reaction Methods 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
- 239000012895 dilution Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 239000011737 fluorine Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000006872 improvement Effects 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 239000001301 oxygen Substances 0.000 description 3
- 125000005936 piperidyl group Chemical group 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 239000000376 reactant Substances 0.000 description 3
- 238000000926 separation method Methods 0.000 description 3
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 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
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- JKTCBAGSMQIFNL-UHFFFAOYSA-N 2,3-dihydrofuran Chemical compound C1CC=CO1 JKTCBAGSMQIFNL-UHFFFAOYSA-N 0.000 description 2
- 125000001494 2-propynyl group Chemical group [H]C#CC([H])([H])* 0.000 description 2
- RSEBUVRVKCANEP-UHFFFAOYSA-N 2-pyrroline Chemical compound C1CC=CN1 RSEBUVRVKCANEP-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 241000202349 Taxus brevifolia Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- VYWQTJWGWLKBQA-UHFFFAOYSA-N [amino(hydroxy)methylidene]azanium;chloride Chemical class Cl.NC(N)=O VYWQTJWGWLKBQA-UHFFFAOYSA-N 0.000 description 2
- 125000005073 adamantyl group Chemical group C12(CC3CC(CC(C1)C3)C2)* 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 150000001340 alkali metals Chemical class 0.000 description 2
- 150000004703 alkoxides Chemical class 0.000 description 2
- NWDNGTNUGMYFEQ-AOWWOYQVSA-N benzyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound N1([C@H]([C@H](C1=O)OC(C)OCC)C=1C=CC=CC=1)C(=O)OCC1=CC=CC=C1 NWDNGTNUGMYFEQ-AOWWOYQVSA-N 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- KQIADDMXRMTWHZ-UHFFFAOYSA-N chloro-tri(propan-2-yl)silane Chemical compound CC(C)[Si](Cl)(C(C)C)C(C)C KQIADDMXRMTWHZ-UHFFFAOYSA-N 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001162 cycloheptenyl group Chemical group C1(=CCCCCC1)* 0.000 description 2
- 125000000596 cyclohexenyl group Chemical group C1(=CCCCC1)* 0.000 description 2
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 2
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 125000005043 dihydropyranyl group Chemical group O1C(CCC=C1)* 0.000 description 2
- FJKIXWOMBXYWOQ-UHFFFAOYSA-N ethenoxyethane Chemical compound CCOC=C FJKIXWOMBXYWOQ-UHFFFAOYSA-N 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Natural products O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 2
- 238000005984 hydrogenation reaction Methods 0.000 description 2
- 229910052738 indium Inorganic materials 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000012544 monitoring process Methods 0.000 description 2
- 125000001624 naphthyl group Chemical group 0.000 description 2
- 229930014626 natural product Natural products 0.000 description 2
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 description 2
- 239000003375 plant hormone Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- 125000002112 pyrrolidino group Chemical group [*]N1C([H])([H])C([H])([H])C([H])([H])C1([H])[H] 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000012266 salt solution Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000010561 standard procedure Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- DKPFODGZWDEEBT-QFIAKTPHSA-N taxane Chemical class C([C@]1(C)CCC[C@@H](C)[C@H]1C1)C[C@H]2[C@H](C)CC[C@@H]1C2(C)C DKPFODGZWDEEBT-QFIAKTPHSA-N 0.000 description 2
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 description 2
- PVNIQBQSYATKKL-UHFFFAOYSA-N tripalmitin Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCC PVNIQBQSYATKKL-UHFFFAOYSA-N 0.000 description 2
- HQMAQPXSVTZAMU-SBKAZOPESA-N (3r,4s)-3-(1-ethoxyethoxy)-4-(2-phenylethenyl)azetidin-2-one Chemical compound N1C(=O)[C@H](OC(C)OCC)[C@@H]1C=CC1=CC=CC=C1 HQMAQPXSVTZAMU-SBKAZOPESA-N 0.000 description 1
- LUYQINUDJUXWNB-CLGJWYQZSA-N (3r,4s)-3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1=CC=CC=C1 LUYQINUDJUXWNB-CLGJWYQZSA-N 0.000 description 1
- AWKAUVRITIXXDS-VHSXEESVSA-N (3r,4s)-3-hydroxy-4-(2-phenylethenyl)azetidin-2-one Chemical compound N1C(=O)[C@H](O)[C@@H]1C=CC1=CC=CC=C1 AWKAUVRITIXXDS-VHSXEESVSA-N 0.000 description 1
- CCUIHLAXXUSXHL-HEVMSJOKSA-N (3r,4s)-4-(cyclohexylmethyl)-3-(1-ethoxyethoxy)azetidin-2-one Chemical compound N1C(=O)[C@H](OC(C)OCC)[C@@H]1CC1CCCCC1 CCUIHLAXXUSXHL-HEVMSJOKSA-N 0.000 description 1
- DWUPUUWHHUPUAI-DTWKUNHWSA-N (3r,4s)-4-(cyclohexylmethyl)-3-hydroxyazetidin-2-one Chemical compound N1C(=O)[C@H](O)[C@@H]1CC1CCCCC1 DWUPUUWHHUPUAI-DTWKUNHWSA-N 0.000 description 1
- HEXRCFLQWXZCKV-CLGJWYQZSA-N (3r,4s)-4-cyclohexyl-3-(1-ethoxyethoxy)azetidin-2-one Chemical compound N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1CCCCC1 HEXRCFLQWXZCKV-CLGJWYQZSA-N 0.000 description 1
- JHTSLEYVTKBQTI-JGVFFNPUSA-N (3r,4s)-4-cyclohexyl-3-hydroxyazetidin-2-one Chemical compound N1C(=O)[C@H](O)[C@@H]1C1CCCCC1 JHTSLEYVTKBQTI-JGVFFNPUSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- FJTRNRFAIZEJJJ-UHFFFAOYSA-N 1,1-dimethoxyethene Chemical compound COC(=C)OC FJTRNRFAIZEJJJ-UHFFFAOYSA-N 0.000 description 1
- CDPKQEKZWDVJBH-UHFFFAOYSA-N 1-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound C1C(=O)N(OC(C)OCC)C1C1=CC=CC=C1 CDPKQEKZWDVJBH-UHFFFAOYSA-N 0.000 description 1
- AVCSTMXZMIAZIL-UHFFFAOYSA-N 1-benzoyl-3-(2-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound O=C1C(OCCOCC)C(C=2C=CC=CC=2)N1C(=O)C1=CC=CC=C1 AVCSTMXZMIAZIL-UHFFFAOYSA-N 0.000 description 1
- KWVPFECTOKLOBL-KTKRTIGZSA-N 2-[(z)-octadec-9-enoxy]ethanol Chemical compound CCCCCCCC\C=C/CCCCCCCCOCCO KWVPFECTOKLOBL-KTKRTIGZSA-N 0.000 description 1
- QISAUDWTBBNJIR-UHFFFAOYSA-N 2-phenylmethoxyacetyl chloride Chemical compound ClC(=O)COCC1=CC=CC=C1 QISAUDWTBBNJIR-UHFFFAOYSA-N 0.000 description 1
- LUYQINUDJUXWNB-UHFFFAOYSA-N 3-(1-ethoxyethoxy)-4-phenylazetidin-2-one Chemical compound N1C(=O)C(OC(C)OCC)C1C1=CC=CC=C1 LUYQINUDJUXWNB-UHFFFAOYSA-N 0.000 description 1
- HOJZAHQWDXAPDJ-UHFFFAOYSA-N 3-anilino-2-hydroxypropanoic acid Chemical group OC(=O)C(O)CNC1=CC=CC=C1 HOJZAHQWDXAPDJ-UHFFFAOYSA-N 0.000 description 1
- 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 1
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 description 1
- HIQIXEFWDLTDED-UHFFFAOYSA-N 4-hydroxy-1-piperidin-4-ylpyrrolidin-2-one Chemical compound O=C1CC(O)CN1C1CCNCC1 HIQIXEFWDLTDED-UHFFFAOYSA-N 0.000 description 1
- MWKMQPSNTJCASD-UHFFFAOYSA-N 4-phenylazetidin-2-one Chemical compound N1C(=O)CC1C1=CC=CC=C1 MWKMQPSNTJCASD-UHFFFAOYSA-N 0.000 description 1
- FCSKOFQQCWLGMV-UHFFFAOYSA-N 5-{5-[2-chloro-4-(4,5-dihydro-1,3-oxazol-2-yl)phenoxy]pentyl}-3-methylisoxazole Chemical compound O1N=C(C)C=C1CCCCCOC1=CC=C(C=2OCCN=2)C=C1Cl FCSKOFQQCWLGMV-UHFFFAOYSA-N 0.000 description 1
- XZIIFPSPUDAGJM-UHFFFAOYSA-N 6-chloro-2-n,2-n-diethylpyrimidine-2,4-diamine Chemical compound CCN(CC)C1=NC(N)=CC(Cl)=N1 XZIIFPSPUDAGJM-UHFFFAOYSA-N 0.000 description 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- NOWKCMXCCJGMRR-UHFFFAOYSA-N Aziridine Chemical compound C1CN1 NOWKCMXCCJGMRR-UHFFFAOYSA-N 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- QBXHBXUMFIUNPO-UHFFFAOYSA-N CCOC(C=C=O)OC1C(NC1=O)C2=CC=CC=C2 Chemical compound CCOC(C=C=O)OC1C(NC1=O)C2=CC=CC=C2 QBXHBXUMFIUNPO-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- OIFBSDVPJOWBCH-UHFFFAOYSA-N Diethyl carbonate Chemical group CCOC(=O)OCC OIFBSDVPJOWBCH-UHFFFAOYSA-N 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N Furaldehyde Natural products O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920001503 Glucan Polymers 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N Methyl ethyl ketone Natural products CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 1
- 208000000112 Myalgia Diseases 0.000 description 1
- 208000028389 Nerve injury Diseases 0.000 description 1
- 229920002701 Polyoxyl 40 Stearate Polymers 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 235000002595 Solanum tuberosum Nutrition 0.000 description 1
- 244000061456 Solanum tuberosum Species 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 241001116500 Taxus Species 0.000 description 1
- 241001330449 Taxus wallichiana Species 0.000 description 1
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 description 1
- WDLUEZJSSHTKAP-UHFFFAOYSA-N acetaldehyde;1,1-diethoxyethane Chemical compound CC=O.CCOC(C)OCC WDLUEZJSSHTKAP-UHFFFAOYSA-N 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- KXKVLQRXCPHEJC-UHFFFAOYSA-N acetic acid trimethyl ester Natural products COC(C)=O KXKVLQRXCPHEJC-UHFFFAOYSA-N 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 238000010306 acid treatment Methods 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000005907 alkyl ester group Chemical group 0.000 description 1
- 125000004414 alkyl thio group Chemical group 0.000 description 1
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 125000005161 aryl oxy carbonyl group Chemical group 0.000 description 1
- 125000005110 aryl thio group Chemical group 0.000 description 1
- 125000004104 aryloxy group Chemical group 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- HONIICLYMWZJFZ-UHFFFAOYSA-N azetidine Chemical compound C1CNC1 HONIICLYMWZJFZ-UHFFFAOYSA-N 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 239000012267 brine Substances 0.000 description 1
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000004744 butyloxycarbonyl group Chemical group 0.000 description 1
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N butyric aldehyde Natural products CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 238000001311 chemical methods and process Methods 0.000 description 1
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 125000004093 cyano group Chemical group *C#N 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 125000003074 decanoyl 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(*)=O 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000006837 decompression Effects 0.000 description 1
- HCFAJYNVAYBARA-UHFFFAOYSA-N di-n-propyl ketone Natural products CCCC(=O)CCC HCFAJYNVAYBARA-UHFFFAOYSA-N 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- SBZXBUIDTXKZTM-UHFFFAOYSA-N diglyme Chemical compound COCCOCCOC SBZXBUIDTXKZTM-UHFFFAOYSA-N 0.000 description 1
- 229940043279 diisopropylamine Drugs 0.000 description 1
- FDPIMTJIUBPUKL-UHFFFAOYSA-N dimethylacetone Natural products CCC(=O)CC FDPIMTJIUBPUKL-UHFFFAOYSA-N 0.000 description 1
- 238000007599 discharging Methods 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229930004069 diterpene Natural products 0.000 description 1
- 150000004141 diterpene derivatives Chemical class 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000005886 esterification reaction Methods 0.000 description 1
- 125000003754 ethoxycarbonyl group Chemical group C(=O)(OCC)* 0.000 description 1
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 1
- 238000003810 ethyl acetate extraction Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 125000005226 heteroaryloxycarbonyl group Chemical group 0.000 description 1
- 125000005368 heteroarylthio group Chemical group 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000007327 hydrogenolysis reaction Methods 0.000 description 1
- 150000002460 imidazoles Chemical class 0.000 description 1
- 230000000266 injurious effect Effects 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 235000012204 lemonade/lime carbonate Nutrition 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- YNESATAKKCNGOF-UHFFFAOYSA-N lithium bis(trimethylsilyl)amide Chemical compound [Li+].C[Si](C)(C)[N-][Si](C)(C)C YNESATAKKCNGOF-UHFFFAOYSA-N 0.000 description 1
- 201000005202 lung cancer Diseases 0.000 description 1
- 208000020816 lung neoplasm Diseases 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 1
- PZOYNGVBODHSLH-HEVMSJOKSA-N methyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound COC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1=CC=CC=C1 PZOYNGVBODHSLH-HEVMSJOKSA-N 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- QQZOPKMRPOGIEB-UHFFFAOYSA-N n-butyl methyl ketone Natural products CCCCC(C)=O QQZOPKMRPOGIEB-UHFFFAOYSA-N 0.000 description 1
- UFWIBTONFRDIAS-UHFFFAOYSA-N naphthalene-acid Natural products C1=CC=CC2=CC=CC=C21 UFWIBTONFRDIAS-UHFFFAOYSA-N 0.000 description 1
- 230000008764 nerve damage Effects 0.000 description 1
- 125000001402 nonanoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002801 octanoyl group Chemical group C(CCCCCCC)(=O)* 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920001515 polyalkylene glycol Polymers 0.000 description 1
- 229940099429 polyoxyl 40 stearate Drugs 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- NBBJYMSMWIIQGU-UHFFFAOYSA-N propionic aldehyde Natural products CCC=O NBBJYMSMWIIQGU-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 238000007363 ring formation reaction 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
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- MLHHOBIEJBNONR-GSTZGWFYSA-N tert-butyl (2s,3r)-2-cyclohexyl-3-(1-ethoxyethoxy)-3-methyl-4-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@@](OC(C)OCC)(C)[C@@H]1C1CCCCC1 MLHHOBIEJBNONR-GSTZGWFYSA-N 0.000 description 1
- PLAUIGSDHJXQIK-JQXSQYPDSA-N tert-butyl (2s,3r)-2-cyclohexyl-3-(1-ethoxyethoxy)-4-oxoazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1CCCCC1 PLAUIGSDHJXQIK-JQXSQYPDSA-N 0.000 description 1
- WBVQQBOHJVFBFQ-MWSTZMHHSA-N tert-butyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-(2-phenylethenyl)azetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C=CC1=CC=CC=C1 WBVQQBOHJVFBFQ-MWSTZMHHSA-N 0.000 description 1
- CZTZICYNMYGUNU-JQXSQYPDSA-N tert-butyl (3r,4s)-3-(1-ethoxyethoxy)-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@H](OC(C)OCC)[C@@H]1C1=CC=CC=C1 CZTZICYNMYGUNU-JQXSQYPDSA-N 0.000 description 1
- PDBCRPKYNWQALZ-QWHCGFSZSA-N tert-butyl (3r,4s)-3-acetyl-2-oxo-4-phenylazetidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1C(=O)[C@@H](C(=O)C)[C@H]1C1=CC=CC=C1 PDBCRPKYNWQALZ-QWHCGFSZSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960001947 tripalmitin Drugs 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 125000000297 undecanoyl group Chemical group O=C([*])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])[H] 0.000 description 1
- HGBOYTHUEUWSSQ-UHFFFAOYSA-N valeric aldehyde Natural products CCCCC=O HGBOYTHUEUWSSQ-UHFFFAOYSA-N 0.000 description 1
- 125000003774 valeryl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D305/00—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms
- C07D305/14—Heterocyclic compounds containing four-membered rings having one oxygen atom as the only ring hetero atoms condensed with carbocyclic rings or ring systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D205/00—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom
- C07D205/02—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings
- C07D205/06—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D205/08—Heterocyclic compounds containing four-membered rings with one nitrogen atom as the only ring hetero atom not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with one oxygen atom directly attached in position 2, e.g. beta-lactams
-
- 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
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Animal Behavior & Ethology (AREA)
- General Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Epoxy Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明涉及用作化学治疗剂的新的紫杉烷类化合物或其前体。用于制备新的紫杉烷类化合物的方法包括在碱存在下,使式(Ⅲ)或(Ⅳ)浆果赤霉素与式(Ⅴ)β-内酰胺类化合物发生的偶合反应。本发明还提供了包括所述新的紫杉烷类化合物的药物组合物,以及用这些新化合物治疗某些癌症的方法。
Description
本发明的背景
本工作部分也由National Institute of Health的拨款(GM42798)赞助。
本发明涉及具有强抗肿瘤活性的新的紫杉烷类化合物(taxanes)、这些化合物的前体、包括这些化合物的组合物、以及合成这些化合物的方法和使用这些新化合物治疗肿瘤的方法。
紫杉醇(Taxol)目前被认为是癌症化学疗法中最令人兴奋的“导向”化合物。紫杉醇是从Taxus Brevifolia(Pacific Yew)树皮中分离出的一种复杂的二萜。紫杉醇具有高的细胞毒性和对抗不同癌症的强抗肿瘤活性,这些癌症由现有抗肿瘤药物并未得到有效地治疗。例如,紫杉醇曾于1992年底由FDA批准同意用于治疗晚期卵巢癌,目前正用于乳腺癌和肺癌的Ⅱ期临床试验中。
尽管紫杉醇是癌症化学疗法中的一个重要的“导向”化合物,但是紫杉醇在水介质中有限的溶解度导致了其应用的严重局限性。而且,众所周知,较好的药物可以由天然存在的“导向”化合物衍生得到。事实上,法国研究人员已经发现了通过修饰紫杉醇的C-13侧链而得到一种新的抗癌药剂。这种称作“Taxotère”的非天然化合物在C-13位的(2R,3S)-苯基异丝氨酸部分的氨基上不具有苯甲酰基而具有叔丁氧羰基,并且在C-10位不是乙酰氧基而是羟基。与紫杉醇相比,Taxotère具有更好的抗肿瘤活性和更好的生物利用度。目前,Taxotère正在美国、欧洲和日本进行Ⅱ期临床试验。
最近报道紫杉醇和Taxotère的临床试验揭示了紫杉醇具有副作用,例如神经损伤、肌肉疼痛或心律失调。Taxotère也具有副作用。例如,Taxotère引起口腔溃疡和白血细胞计数下降。这两种药物还有其他较小的副作用。
紫杉醇较差的水溶性在其药物应用中引起实际问题。例如,含有紫杉醇的药物制剂可能需要特别的载体。紫杉醇药物的最大剂量也受紫杉醇溶解度的限制。
另一方面,Taxotère在某种程度上改善了水溶性,因此与紫杉醇相比,它具有较好的药理学性质,但是,该抗肿瘤剂仍具有溶解度问题。
14-羟基-10-脱乙酰基浆果赤霉素Ⅲ比通常的10-脱乙酰基浆果赤霉素Ⅲ具有更高的水溶性。10-脱乙酰基浆果赤霉素Ⅲ目前被用于制备紫杉醇和Taxotère。14-OH-DAB的这种较高的溶解度是由于在C-14位上额外的羟基所致。因此,由14-OH-DAB所衍生的新的抗肿瘤剂紫杉烷类化合物作为治疗剂可望具有显著改进的水溶性和药理学性质。据信所述改进的药理学性质与抵抗不同种类癌症的毒性和活性谱的改进有关。
因此,本发明的目的是开发新的紫杉醇或Taxotère类抗肿瘤剂,它们具有显著的结构差异,并提高溶解度。
本发明的另一个目的是提供一系列由14-OH-DAB衍生的新的紫杉烷类化合物,它们具有强的抗肿瘤活性和更好的治疗谱。本发明的另一个目的是以高产率和最少数目的合成步骤合成新的紫杉烷类化合物。
在这些化合物中,R1代表未取代或取代的直链或支链烷基、链烯基或炔基,未取代或取代的芳基或杂芳基,未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基;
R2为未取代或取代的直链或支链烷基、链烯基或炔基、环烷基、杂环烷基、环烯基、杂环烯基、芳基或杂芳基;
或者R2也可为RO-、RS-或RR′N-,其中R代表未取代或取代的直链或支链烷基、链烯基或炔基、环烷基、杂环烷基、环烯基、杂环烯基、芳基或杂芳基;R′为氢或如上所定义的R;R和R′可以连接起来形成环状结构;
R3代表氢或酰基或烷基或链烯基或炔基、或未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基、未取代或取代的芳基或杂芳基或羟基保护基;
R4代表氢或酰基或烷基、链烯基或炔基、未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基、未取代或取代的芳基或杂芳基或羟基保护基;
R5代表氢或酰基或烷基、链烯基或炔基、未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基、未取代或取代的芳基或杂芳基或羟基保护基;
R6代表氢或酰基或烷基、链烯基或炔基、未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基、未取代或取代的芳基或杂芳基或羟基保护基;
R5和R6以连接起来形成环状结构;
R7代表酰基;
R8代表氢或羟基保护基。
新的紫杉烷类化合物(Ⅰ)和(Ⅱ)可通过下述方法合成:包括在碱存在下,使式(Ⅲ)或式(Ⅳ)浆果赤霉素与式(Ⅴ)β-内酰类发生偶合反应:其中G1、G2、G3和G4代表羟基保护基或酰基或烷基或链烯基或炔基、或未取代或取代的环烷基、杂环烷基、环烯基或杂环烯基、或未取代或取代的芳基或杂芳基;G3和G4可以连接起来形成环状结构;R6如上所定义;其中G1、G2、G4、和R6如上所定义:
其中G为羟基保护基,例如乙氧基乙基(EE)、三乙基甲硅烷基(TES)、和二甲基(叔丁基)甲硅烷基(TBDMS),且R1和R2如上所定义。
本发明新的紫杉烷类化合物显示出对人乳腺、非小细胞肺(non-small cell lung)、卵巢、和结肠癌细胞具有强的抗肿瘤活性。因此,开发具有较小不希望有的副作用、具有较好的药理学性质和/或具有抗各种类型肿瘤活性谱的、不同于紫杉醇和Taxotère的新的抗癌药物是非常重要的。
为了更好地理解本发明、以及其他和进一步的目的,可参考下列描述,而且本发明的范围在所附的权利要求书中指出。
本发明的详细描述
如上所示,新的式(Ⅰ)或(Ⅱ)的紫杉烷类化合物或其前体可用作抗肿瘤剂。本发明的紫杉烷类化合物对人乳腺、非小细胞肺、卵巢和结肠癌细胞具有强的抗肿瘤活性。
新的式(Ⅰ)紫杉烷类化合物可通过修饰式(Ⅲ)浆果赤霉素来合成,
其中G1、G2、G3、G4和R7如上所定义。
新的式(Ⅱ)紫杉烷类化合物可通过修饰式(Ⅳ)浆果赤霉素来合成,其中G1、G2、G4和R7如上所定义。前体(Ⅲ)和(Ⅳ)易于获得。浆果赤霉素类化合物(Ⅲ)和(Ⅳ)均可通过化学修饰14β-羟基-10-脱乙酰基浆果赤霉素(14-OH-DAB),即一种天然存在于Himalayan Yew中的化合物进行制备。14-OH-DAB的分离方法由Appendino等人叙述,“14β-羟基-10-脱乙酰基浆果赤霉素Ⅲ,一种来源于Himalayan Yew的新的紫杉烷”,J.Chem.Soc.Perkin Trans I,2525-2529(1992),这里将该文献的内容并入本文作为参考。
其中G、R1和R2如上所定义。
β-内酰胺类化合物(Ⅴ)易于从β-内酰胺类化合物(Ⅵ)来制备,(Ⅵ)易于通过在本发明人实验室中研究的、如路线1中所示的手性烯醇化物(enolate)-亚胺环化缩合法来获得。所述环化缩合反应由Ojima等人,Tetrahedron,1992,48,6985:Ojima,I.等人,J.Org.Chem.,56,1681(1991),及美国专利申请No.07/842,444(于1992年2月27日提交)叙述,这里将上述文献的全部内容并入本文作为参考。在该制备中,β-内酰胺类化合物(Ⅵ)可以高产率和极高的对映体纯度获得。路线1说明了手性β-内酰胺的合成。在路线1中,R*为手性辅助基部分,该手性辅助基部分可以为(-)-反式-2-苯基-1-环己基、(-)-10-二环己基氨磺酰基-D-异冰片基或(-)-基;TMS为三甲基甲硅烷基;所述的碱为二异丙基氨基锂或六甲基二硅氮烷基锂(Lithium hexamethyldisilazide);且G和R1如上所定义。从化合物(Ⅵ′)的N-位置上除去4-甲氧基苯基以制得β-内酰胺类化合物(Ⅵ)可以通过用硝酸铈铵(CAN)处理来完成。
路线Ⅰ
现在参照路线2,其中G为三异丙基甲硅烷基(TIPS)的β-内酰胺类化合物(Ⅵa)可被转化为3-羟基-β-内酰胺类化合物(Ⅶ),接着用基团例如乙氧基乙基(EE)或三乙基甲硅烷基(TES)保护,生成β-内酰胺类化合物(Ⅵ)。所述保护基团可以通过用本领域技术人员一般已知的方法连接到β-内酰胺类化合物(Ⅵ)的羟基上。其中G为(叔丁基)二甲基甲硅烷基(TBDMS)的β-内酰胺类化合物(Ⅵ)可以按上述的手性烯醇化物-亚胺环化缩合反应直接得到。β-内酰胺类化合物(Ⅵ)可以在碱存在下与酰氯类、氯甲酸酯类和氨基甲酰氯类化合物反应,生成β-内酰胺类化合物(Ⅴ)。β-内酰胺类化合物(Ⅴ)可以与浆果赤霉素(Ⅲ)或(Ⅳ)偶合。
路线3和4说明了在碱存在下β-内酰胺类化合物(Ⅴ)与浆果赤霉素类(Ⅲ)或(Ⅳ)的偶合,接着脱保护,分别以高产率得到新的紫杉烷类化合物(Ⅰ)或(Ⅱ)。
路线4
如此制得的紫杉烷类化合物由上述式Ⅰ和Ⅱ来表示。R1至R8如上述一般所定义。R1、R2和R各自独立地为含有1-10个碳原子的直链或支链烷基、含有2-10个碳原子的直链或支链链烯基、或含有2-10个碳原子的直链或支链炔基、含有3-10个碳原子的环烷基、含有3-10个碳原子的杂环烷基、含有3-10个碳原子的环烯基、含有3-10个碳原子的杂环烯基、含有6-20个碳原子的多环烷基、含有6-20个碳原子的芳基、含有3-15个碳原子的杂芳基;
或者R2也可以为RO-、RS-或RR′N-基团,其中R如上所定义;
R′为氢或者也可以为上述所定义的R;R和R′可以连接起来形成具有2-10个碳原子的环状结构;
R3、R4、R5或R6各自独立地为氢或具有1-20个碳原子的酰基,或者如上所定义的R或羟基保护基:
R7为具有1-20个碳原子的酰基;
R8为氢或羟基保护基。
杂芳族基团还可以包括氧、氮和硫原子。此外,关于上述式(Ⅰ)和(Ⅱ),R3也可以为氢或G1;R4也可以为氢或G2;R5也可以是氢或G3;R6也可以为氢或G4;且R6也可以为氢或G,其中G、G1、G2、G3和G4如前所定义。
如上所定义的R1、R2和R中的每个基团可任选被下列一个或多个基团取代:卤素、羟基、氨基、巯基、氰基、羧基、烷氧基、烷氨基、二烷氨基、烷硫基、烷氧羰基,其中所述烷基部分具有1-15个碳原子,芳氧基、芳硫基、芳氧羰基,其中所述芳基部分具有6-20个碳原子,或杂芳硫基、杂芳氧基羰基,其中所述杂芳基部分具有3-15个碳原子。
在一个实施方案中,R1也可以为选自下列基团的烷基:甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、庚基、异庚基、辛基、异辛基、环己基甲基、环己基乙基、苄基、苯乙基、环丙基、环丁基、环戊基、环己基、环庚基、环辛基和金刚烷基;或者为选自下列基团的链烯基:乙烯基、烯丙基、2-苯基乙烯基、2-呋喃基乙烯基、2-吡咯基-乙烯基、2-吡啶基乙烯基、2-噻吩基乙基;或者为选自乙炔基和炔丙基的未取代或取代的炔基:或为选自下列基团的芳基:苯基、甲苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-氟苯基、4-三氟甲基苯基、4-氯苯基和萘基;或者为选自下列基团的杂芳基:呋喃基、吡咯基和吡啶基;或选自环戊烯基、环己烯基和环庚烯基的环烯基;或选自环氧乙烷基、吡咯烷基、哌啶基、四氢呋喃基和四氢吡喃基的杂环烷基;或选自二氢呋喃基、二氢吡咯基、二氢吡喃基(dihydropiranyl)和二氢吡啶基的杂环烯基;
R2是未取代或取代的烷基、链烯基、炔基、选自下列基团的芳基或杂芳基:苯基、甲苯基、4-氟苯基、4-氯苯基、4-甲氧基苯基、联苯基、1-萘基、2-萘基、异丙基、异丁基、新戊基、己基、庚基、环己基、环己基甲基、苄基、苯乙基、苯基乙烯基、丁烯基、烯丙基、乙烯基、炔丙基、吡啶基、呋喃基、噻吩基、吡咯烷基和哌啶基;
或者R2为RO-、RS-、或RR′N-,其中R为选自下列基团的未取代或取代的烷基:甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、庚基、异庚基、辛基、异辛基、环丙基、环丁基、环戊基、环己基、环庚基、环辛基和金刚烷基;或者选自下列基团的链烯基:乙烯基和烯丙基;或者选自苯基和萘基的芳基;或者选自呋喃基、吡咯基和吡啶基的杂芳基;或者选自环戊烯基、环己烯基和环庚烯基的环烯基;或者选自环氧乙烷基、四氢呋喃基、吡咯烷基、哌啶基和四氢吡喃基(tetrahydropiranyl)的杂环烷基;或者选自二氢呋喃基、二氢吡咯基、二氢吡喃基(dihydropiranyl)、二氢吡啶基的杂环烯基;R′为氢或者为如上所定义的R;环状RR′N-为包括吖丙啶子基(aziridino)、氮杂环丁烷子基(azetidino)、吡咯烷子基(pyrrolidino)、哌啶子基或吗啉代的基团;
其中所述羟基保护基团选自甲氧基甲基、甲氧基乙基、1-乙氧基乙基、苄氧基甲基、(β-三甲基甲硅烷基乙氧基)甲基、四氢吡喃基、2,2,2-三氯乙氧羰基、苄氧羰基、叔丁氧羰基、9-芴基甲氧羰基、2,2,2-三氯乙氧基甲基、三甲基甲硅烷基、三乙基甲硅烷基、三丙基甲硅烷基、二甲基乙基甲硅烷基、二甲基(叔丁基)甲硅烷基、二乙基甲基甲硅烷基、二甲基苯基甲硅烷基和二苯基甲基甲硅烷基;
所述酰基选自乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基和三氟乙酰基、丙酰基、丁酰基、戊酰基、己酰基、庚酰基、环己烷羰基、辛酰基、壬酰基、癸酰基、十一烷酰基、十二烷酰基、苯甲酰基、苯乙酰基、萘羰基、吲哚乙酰基、甲氧羰基、乙氧羰基、丙氧羰基、和丁氧羰基;和
R5和R6与所述紫杉烷骨架的两个氧原子一起形成环状结构,其中所述环状结构选自碳酸酯、甲醛缩醇(methylacetal)、乙醛缩醇(ethylacetal)、丙醛缩醇(propylacetal)、丁醛缩醇(butylacetal)、苯甲醛缩醇(phenylacetal)、二甲酮缩醇(dimethylketal)、二乙酮缩醇(diethylketal)、二丙酮缩醇(dipropylketal)、和二丁酮缩醇(dibutylketal)。
在另一实施方案中,R1可以为苯基、甲苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-氟苯基、4-三氟甲基苯基、4-羟基苯基、1-萘基、2-萘基、吡啶基、呋喃基、噻吩基、吡咯基、N-甲基吡咯基、2-苯基乙烯基、2-呋喃基乙烯基、2-吡啶基乙烯基、2-噻吩基乙烯基、2-苯基乙基、2-环己基乙基、环己基甲基、异丁基或环己基;
R2选自下列基团:苯基、甲苯基、4-氟苯基、4-氯苯基、4-甲氧基苯基、联苯基、1-萘基、2-萘基、异丙基、异丁基、新戊基、己基、庚基、环己基、环己基甲基、苄基、苯基乙基和苯基乙烯基;
或者R2为RO-,其中R选自下列基团:甲基、乙基、丙基、异丙基、丁基、异丁基、权丁基、戊基、异戊基、新戊基、己基、异己基、环己基、苯基、苄基和9-芴基甲基;
或者R2为RR′N-,并选自下列基团:甲氨基、乙氨基、丙氨基、异丙氨基、丁氨基、异丁氨基、叔丁氨基、新戊氨基、环己基氨基、苯氨基或苄氨基、二甲氨基、二乙氨基、二丙氨基、二丁氨基、二戊氨基、二己氨基、二环己基氨基、甲基(叔丁基)氨基、环己基(甲基)氨基、甲基(苯基)氨基、吡咯烷子基(Pyrrolidiono)、哌啶子基、或吗啉代基团;
R3和R4选自下列基团:氢、乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基和三氟乙酰基、苯甲酰基、苯乙酰基、丙烯酰基、和丁烯基、肉桂酰基、烯丙基、苄基、甲氧基甲基、甲氧基乙基、1-乙氧基乙基、四氢吡喃基、2,2,2-三氯乙氧羰基、苄氧基羰基、叔丁氧羰基、9-芴基甲氧羰基、三甲基甲硅烷基、三乙基甲硅烷基、(叔丁基)二甲基甲硅烷基;
R5选自氢、乙酰基、氯乙酰基、烯丙基、苄基、丙烯酰基、丁烯基、和肉桂酰基,且R6为氢;其中R5和R6连接起来形成一个选自下列基团的环状结构:羰基、亚丙基、亚丁基、亚戊基、苯基亚甲基、二甲基亚甲基、二乙基亚甲基、二丙基亚甲基、二丁基亚甲基、甲氧基亚甲基、乙氧基亚甲基、亚甲基、1,2-亚乙基和1,2-亚丙基;
R7选自苯甲酰基、和环己烷羰基:
R8选自氢、1-乙氧基乙基、2,2,2-三氯乙氧羰基、三甲基甲硅烷基、三乙基甲硅烷基和叔丁基二甲基甲硅烷基。
代表性的羟基保护基包括甲氧基甲基(MOM)、甲氧基乙基(MEM)、1-乙氧基乙基(EE)、苄氧基甲基、(β-三甲基甲硅烷基乙氧基)甲基、四氢吡喃基、2,2,2-三氯乙氧羰基(Troc)、苄氧羰基(CBZ)、叔丁氧羰基(t-BOC)、9-芴基甲氧羰基(Fmoc)、2,2,2-三氯乙氧基甲基、三甲基甲硅烷基、三乙基甲硅烷基、三丙基甲硅烷基、二甲基乙基甲硅烷基、二甲基(叔丁基)甲硅烷基、二乙基甲基甲硅烷基、二甲基苯基甲硅烷基和二苯基甲基甲硅烷基、乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基或三氟乙酰基。
浆果赤霉素(Ⅲ)或(Ⅳ)与β-内酰胺(Ⅴ)的偶合反应,如路线3和4所示,发生在位于浆果赤霉素(Ⅲ)的C-13羟基或位于浆果赤霉素(Ⅳ)的C-14羟基上的碱金属醇盐上。所述醇盐可以容易地通过使浆果赤霉素与碱金属碱反应来生成。
代表性的烷基金属碱(alkyl metal base)包括:在无水非质子传递有机溶剂中的六甲基二硅氮烷基钠、六甲基二硅氮烷基钾、六甲基二硅氮烷基锂、二异丙基氨基钠、二异丙基氨基钾、二异丙基氨基锂、氢化钠。四氢呋喃(THF)、二噁烷、乙醚、二甲氧基乙烷(DME)、二甘醇二甲醚、二甲基甲酰胺(DMF)或这些溶剂与己烷、甲苯和二甲苯的混合物是有用的非质子传递有机溶剂。所述偶合反应优选在约-100℃至约50℃,更优选约-50℃至约25℃的温度范围内进行。
所述偶合反应也优选在惰性气氛例如氮和氩气氛中进行。当使用可溶性碱例如六甲基二硅氮烷基钠、六甲基二硅氮烷基钾、六甲基二硅氮烷基锂、二异丙基氨基钠、二异丙基氨基钾、二异丙基氨基锂时,用于反应中的碱的量优选与浆果赤霉素的量大致相当。应用稍微过量的碱对该反应没有有害的影响。当使用异种碱例如氢化钠和氢化钾时,优选使用为浆果赤霉素的量5-10倍当量的碱。
在浆果赤霉素的金属醇盐上发生的偶合反应一般优选在约-100℃至50℃,更优选约-50℃至25℃温度范围内,通过加入上述β-内酰胺的无水非质子传递有机溶剂的溶液来进行。将反应物混合物搅拌15分钟至24小时,并且反应进程和完全程度可以用已知方法例如薄层色谱法(TLC)监测。当有限的反应物完全耗尽时,反应通过加入冷的盐水溶液而中止。粗的反应混合物用标准的(一般为本领域技术人员所公知的)分离方法来处理,得到相应的紫杉烷。β-内酰胺与浆果赤霉素的比率为2∶1至1∶2 。更优选地以约1∶1的比率进行,以更加经济和有效,但是该比率对反应而言不是关键性的。处理是指用于从反应混合物中得到产物的任何常规的分离方法。
然后,羟基保护基团可以用一般为本领域技术人员所公知的标准方法来脱去,以得到所需的紫杉烷衍生物。例如,1-乙氧基乙基和三乙基甲硅烷基可以通过在室温下加入0.5 N HCl达36小时来脱去。Troc基团可以通过在60℃加入在甲醇中的锌和乙酸达1小时来脱去,而不影响紫杉烷上的其他官能团或骨架。另一种脱去保护方法是用氟化物离子处理三异丙基甲硅烷基(TIPS)或(权丁基)二甲基甲硅烷基(TBDMS)。
本发明化合物可以配制成药物制剂或配制成其可药用的盐,特别是无毒的可药用的酸加成盐或无毒的可药用的碱式盐形式。这些盐可以按常规化学方法从本发明化合物制得。
一般地,所述盐是通过在适宜的溶剂或溶剂的各种组合形式中使游离碱或酸与形成所需盐的化学计算用量的或过量的无机或有机酸反应来制备。例如,可以将游离碱溶于适宜酸的水溶液中,并用标准技术例如通过蒸发溶液来得到盐。另一种可选择的方法是,可以将游离碱溶于有机溶剂例如低级链烷醇、醚、烷基酯、或其混合液(例如溶于甲醇、乙醇、乙醚、乙酸乙酯、乙酸乙酯-乙醚溶液等)中,之后将其用适宜的酸处理形成相应的盐。所述盐是通过标准回收技术得到的,例如通过从溶液中过滤自发分离出的所需要的盐,或者可以通过加入该盐不溶于其中的一种溶剂使其沉淀,并从该溶剂中将其回收。
由于本发明紫杉烷化合物具有抗肿瘤活性,因此可以利用它们治疗癌症。所述的新化合物可以以片剂、丸剂、粉剂混合物、胶囊剂、注射剂、溶液剂、栓剂、乳剂、分散体、食品预混剂(food premix)和以其他适宜形式给药。含有所述化合物的药物制剂可方便地与无毒的药用有机载体混合,所述化合物通常为每剂量单位约0.01mg直至2500mg,或更高,优选50-500mg。典型的可药用载体为例如:甘露糖醇、脲、葡聚糖类、乳糖、马铃薯和玉米淀粉、硬脂酸镁、滑石、植物油、聚(亚烷基)二醇、乙基纤维素、聚(乙烯吡咯烷酮)、碳酸钙、油酸乙酯、肉豆蔻酸异丙酯、苯甲酸苄酯、碳酸钠、明胶、碳酸钾、硅酸和其他常规使用的可接受的载体。所述药物制剂也可以含有无毒的辅助物质,例如乳化剂、防腐剂、润湿剂等,例如脱水山梨糖醇单月桂酸酯、三乙醇胺油酸酯、聚氧乙烯单硬脂酸酯、三棕榈酸甘油酯、硫代琥珀酸二辛基钠等。
本发明化合物也可以进行冷冻干燥,并且如果必要,与其他可药用的赋形剂混合,以制备适于胃肠外、注射给药的制剂。就所述给药而言,所述制剂可以在水(生理盐水)、或水与有机溶剂例如丙二醇、乙醇等的混合物中配制。
当然给药的剂量,不论是单次剂量、多次剂量或日剂量随所用的本发明具体化合物而改变,因为所述化合物的效力、所选的给药途径、受治疗者的身材、患者症状的性质不同。给药剂量并不受制于有限的范围,但通常是一种有效量或相当量,按从一剂型经由活性药物代谢释放而产生的生理活性的游离形式的摩尔量为准计,从而达到其所需的药理和生理作用。
下列非限制实施例用于说明本发明。本发明的全部范围在说明书之后的权利要求书中指明。
实施例
β-内酰胺类(Ⅵ)是按路线1所示、通过手性烯醇化物-亚胺环化缩合方法制得的,其中使甲硅烷氧基乙酸酯类化合物(A)与亚胺类化合物或醛亚胺类化合物(B)和(B′)在碱例如二异丙基氨基锂、或六甲基二硅氮烷基锂存在下发生反应。获得起始化合物(A)和(B)或(B′)的方法描述于实施例1-12中。在实施例1-12中用制备物质(A)、(B)、和(B′)的物质易于商购得到。
实施例1
三异丙基甲硅烷氧基乙酸(-)-(1R,2S)-2-苯基-1-环己基酯(A)的制备
羟基乙酸(-)-(1R,2S)-2-苯基-1-环己基酯(851mg,3.63mmol)的溶液是通过(-)-(1R,2S)-2-苯基-1-环己醇与苄氧基乙酰氯的酯化,并接着进行氢解制得。然后,将三异丙基甲硅烷基氯(840mg,4.36mmol)和咪唑(618mg,9.08mmol)在二甲基甲酰胺(DMF)(1.7ml)中于室温搅拌12-20小时。将混合物倾入戊烷(25ml)中,用水和盐水洗涤。合并的有机层用无水MgSO4干燥,并真空浓缩。粗产物在一短硅胶柱上纯化,用己烷/氯仿(3/1)作洗脱剂,得到纯的三异丙基甲硅烷氧基乙酸(-)-(1R,2S)-2-苯基-1-环己基酯(1.35g,95%产率),为无色油状物。
上述三异丙基甲硅烷氧基-乙酸酯的鉴定效据如下所示:
[α]D 20-17.1°(c 3.15,CHCl3);IR(净样)1759,1730(′CO)cm-1;1H NMR(CDCl3)δ0.93-0.99(m,21H),1.30-1.62(m,4H),1.72-2.0(m,3H),2.10-2.19(m,1H),2.66(dt,J=11.5,4.0 Hz,1H),3.90(d,J=16.6 Hz,1H),4.07(d,J=16.6Hz,1H),5.07(dt,J=10.6,4.0 Hz,1H),7.16-7.30(m,5H). 元素分析计算值C23H38O3Si:c,70.72;H,9.81. 实测值:C,70.79;H,9.85.
实施例2-4
N-三甲基甲硅烷基亚胺类化合物(B)的制备
用于环化缩合法中的N-三甲基甲硅烷基醛亚胺类化合物可以容易地通过六甲基二硅氮烷基锂与醛类反应制得。制备N-三甲基甲硅烷基苯甲醛亚胺的典型方法描述如下。
在0℃于氮气氛下,向75ml无水THF中加入17.29ml(75mmol)六甲基二硅氮烷和30ml(75mmol)正丁基锂(2.5M的己烷溶液)。搅拌1小时后,在室温下加入7.65ml(75mmol)苯甲醛,并使混合物回流3小时。然后,用注射器加入9.52ml(75mmol)新蒸的三甲基甲硅烷基氯。将混合物回流2小时。在此过程中,形成白色沉淀。然后,将反应混合物冷却至室温,在氮气氛下将液体层用注射器转移到蒸馏瓶中。真空蒸发溶剂,油状残余物减压(68℃/1mmHg)蒸馏,得到纯的N-三甲基甲硅烷基苯甲醛亚胺,为浅黄色油状物(10.6 g,80%),它具有以下鉴定数据:
1H NMR(CDCl3)δ0.18(s,9H),7.33-7.36(m,3H),7.72-7.75(m,2H),8.89(s,1H);13c NMR(CDCl3)δ-1.25,128.34,128.39,131.96,138.70,168.32
以相同的方式,分别以4-甲氧基苯甲醛和3,4-二甲氧基-苯甲醛为原料制备N-三甲基甲硅烷基(4-甲氧基)苯甲醒亚胺和N-三甲基甲硅烷基-(3,4-二甲氧基)苯甲醛亚胺,产率为78-82%。所述亚胺类各个化合物的鉴定数据阐述如下。
实施例3
N-三甲基甲硅烷基(4-甲氧基)苯甲醛亚胺
浅黄色油状物; bp 105℃/0.4 mmHg;1H NMR(CDCl3)δ0.00(s,9H),3.60(s,3H),6.69(d,J=8.7 Hz,2H),7.50(d,J=8.7 Hz,2H),8.66(s,1H).
实施例4
N-三甲基甲硅烷基-(3,4-二甲氧基)苯甲醛亚胺
无色油状物; bp 140℃/0.2 mmHg;1H NMRδ0.00(s,9H),3.67(s,3H),3.71(s,3H),6.65(d,J=8.2 Hz,1H),7.01(dd,J=8.2,1.8 Hz,1H),7.22(d,J=1.8 Hz,1H),8.63(s,1H).
实施例5-12
N-(4-甲氧基苯基)醛亚胺类化合物(B′)的制备
制备该类化合物的典型方法,以N-(4-甲氧基苯基)(4-氟)苯甲醛亚胺的制备为例叙述如下。向4.81g(39mmol)对甲氧基苯胺的60ml二氯甲烷溶液中加入4.85g(39mmol)4-氟苯甲醛。将该混合物在室温下与无水硫酸镁搅拌15小时。滤出脱水剂,真空浓缩滤波,得到亚胺粗品。亚胺粗品用己烷/二氯甲烷重结晶,得到7.69g(86%)纯的N-(4-甲氧基苯基)(4-氟)苯甲醛亚胺,为白色针状体。
该亚胺的鉴定效据如下:
Mp 99℃;1H NMR(CDCl3)δ3.82(s,3H),6.92(d,J=8.7 Hz,2H),7.13(t,J =8.6 Hz,2H),7.21(d,J=8.7Hz,2H),7.88(dd,J=8.6,5.7 Hz,2H),8.39(s,1H).
其他N-(4-甲氧基苯基)醛亚胺类化合物以相同方式、以高产率制备。这些亚胺类各个化合物的鉴定数据见下面。
实施例6
N-(4-甲氧基苯基)苯甲醛亚胺
白色固体;mp 71-72℃;1H NMR(CDCl3)δ3.93(s,3H),6.93(d,J=8.8 Hz,2H),7.23(d,J=8.8 Hz,2H),7.46(m,2H),7.87(m,2H),8.48(s,1H).
实施例7N-(4-甲氧基苯基)(4-三氟甲基)苯甲醛亚胺
白色针状体;mp 124℃;1H NMR(CDCl3)δ3.81(s,3H),6.91(d,J=8.8 Hz,2H),7.15(d,J=8.8 Hz,2H),7.75(d,J=8.5 Hz,2H),8.10(d,J=8.6 Hz,2H),8.39(s,1H).
实施例8
N-(4-甲氧基苯基)糠醛亚胺
黄色丸状物;mp 68-70℃;1H NMR(CDCl3)δ3.82(s,3H),6.54(dd,J=3.5,1.8 Hz,1H),6.90(d,J=3.5 Hz,1H),6.92(d,J=8.9 Hz,2H),7.26(d,J=8.9 Hz,2H),7.59(d,J=1.8 Hz,1H),8.31(s,1H).
实施例9
N-(4-甲氧基苯基)-3-苯基丙烯醛亚胺
黄色薄片;mp 119-121℃;1H NMR(CDCl3)δ3.8l(s,3H),6.90-7.60(m,7H),8.28(m,1H)(约.1∶1立体异构体混合物)。
实施例10
N-(4-甲氧基苯基)-3-(2-呋喃基)丙烯醛亚胺
黄色针状体;mp 71-73℃;1H NMR(CDCl3)δ3.78(s,3H),6.45(dd,J=3.4,1.6 Hz,1H),6.52(d,J=3.4 Hz,1H),6.87(d,J=15.8 Hz,1H),6.90(d,J=8.9 Hz,2H),6.98(dd,J=15.8,8.7 Hz,1H),7.18(d,J=8.9 Hz,2H),7.46(d,J=1.6 Hz,1H),8.20(d,J=8.7 Hz,1H).
实施例11
N-(4-甲氧基苯基)-3-甲基丁醛亚胺
黄色油状物;1H NMR(CDCl3)δ1.02(d,J=6.7 Hz,6H),2.03(m,1H),2.33(dd,J=6.9,5.3 Hz,2H),3.78(s,3H),6.86(d,J=8.8 Hz,2H),7.03(d,J=8.8 Hz,2H),7.86(t,J=5.3 Hz,1H).
实施例12
N-(4-甲氧基苯基)环己基乙醛亚胺
黄色油状物;1H NMR(CDCl3)δ1.00-1.80(m,11H),2.34(dd,J=6.7,5.4 Hz,2H),3.79(s,3H),6.86(d,J=8.9 Hz,2H),7.02(d,J=8.9 Hz,2H),7.86(t,J=5.4Hz,1H);IR(neat)3033-2849,1505,1244,1038,803 cm-1.
如路线1所示,进行手性烯醇化物-亚胺环化缩合反应,得到4-取代的-2-氮杂环丁酮类化合物(Ⅵ)和(Ⅵ′)。其他具有不同R1取代基的氮杂环丁酮类化合物按实施例13和15中所述相同的下列方法制备。所述氮杂环丁酮类化合物的鉴定数据分别示于实施例14和16-20中。
实施例13-14
(3R,4S)-3-甲硅烷氧基-4-取代的-2-氮杂环丁酮类化合物(Ⅵ)的制备
制备该类化合物的典型方法,以(3R,4S)-3-三异丙基甲硅烷氧基-4-苯基-2-氮杂环丁酮(Ⅵa)的制备为例叙述如下。在0℃向645μl(4.6mmol)二异丙胺的10ml THF溶液中加入1.85ml(4.6mmol,2.5M)正丁基锂。将溶液在0℃搅拌1小时,接着在-78℃在1小时时间内(用套管)加入在15ml THF中的1.5g(3.8mmol)(-)TIPS酯。将反应物在该温度下搅拌2小时,接着在-95℃在2小时时间内加入在15ml THF中的817mg(4.6mmol)N-三甲基甲硅烷基苯甲醛亚胺。将反应物在此温度下搅拌过夜,并使其缓慢升至室温。反应经加入饱和NH4Cl而中止。水层用乙醚萃取,有机层用3%HCl和盐水洗涤,用MgSO4干燥,并浓缩。油状物粗品用硅胶色谱法纯化,用1:5 EtOAc/己烷作洗脱剂,得到1.03g(84%)(3R,4S)-3-三异丙基甲硅烷氧基-4-苯基-2-氮杂环丁酮(Ⅵa),为白色固体。
Ⅵa的鉴定数据如下:
Mp 76-77℃;[α]D 20+52.7°(c 1.00,CHCl3);1H NMR(300MHz,CDCl3)δ0.86-0.93(m,21H),4.8l(d,J=4.7 Hz,1H),5.17(dd,J=4.7,2.6 Hz,1H),6.18(bs,1H),7.17-7.35(m,5H);-13c NMR(75 MHz,CDCl3)δ11.8,17.4,17.5,59.6,79.9,127.9,128.0,128.1,136.4,170.0;IR(KBr)3234,2946-2866,1760,1458 cm-1. 元素分析计算值C18H29NO2Si c 67.66;H 9.15;N 4.38. 实测值:C 67.64;H9.25;N 4.44.
实施例14
(3R,4S)-3-三异丙基甲硅烷氧基-4-(2-苯基乙烯基)-2-氮杂环丁酮(Ⅵb)
72%;无色液体;1H NMR(300 MHz,CDCl3)δ0.98-1.02(m,21H),4.36(dd,J=4.6,8.3 Hz,1H),5.09(dd,J=2.3,4.6 Hz,1H),6.29(dd,J=8.3,16.0 Hz,1H),6.59(d,J=16.0 Hz,1H),6.83,(bs,1H),7.23-7.39(m,5H);13C NMR(75 MHz,CDCl3)δ11.79,17.61,17.66,58.34,79.86,126.05,126.45,127.90,128.56,134.41,136.30,169.69;IR(净样)3262,3032,2944,2865,1748,1672,1623 cm-1. 元素分析计算值 C20H31NO2Si: C,69.52;H,9.04;N,4.05. 实测值:C,69.75;H,9.02;N,3.89.
实施例15-20
(3R,4S)-1-(4-甲氧基苯基)-3-甲硅烷氧基-4-取代的-2-氮杂环丁酮类化合物(Ⅵ′)的制备
在-10℃下向2.51mmol的二异丙胺的15ml THF溶液中加入2.51ml正丁基锂(2.5M的THF溶液)。30分钟后,产生二异丙基氨基锂(LDA),并将溶液冷却至-95℃,加入2.17mmol手性酯的5mlTHF溶液。1小时后,加入2.5mmol适宜亚胺的3ml THF溶液。将该混合物在-95℃搅拌过夜,反应进程用TLC或1H NMR监测。反应用饱和NH4Cl中止,并且THF用旋转蒸发仪除去。加入乙醚(10ml)。水层用乙醚(10ml×3)萃取。干燥并除去溶剂,得到粗产物,将其经硅胶柱色谱法纯化(己烷/乙酸乙酯=10∶1),得到相应的纯β-内酰胺。对映体过量是用HPLC(使用CHIRALCEL OD柱、采用正己烷/异丙醇(i-PrOH)(90/10)作洗脱剂)来测定的。
实施例15
(3R,4S)-4-(异丁基)-1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-2-氮杂环丁酮(Ⅵ′-c)
87%;浅黄色固体;mp 59-60℃;[α]D 20+60.46°(c 1.26,CHCl3);1H NMR(300 MHz,CDCl3)δ0.96(d,J=6.4Hz,3H),1.03(d,J=6.4 H2,3H),1.10-1.30(m,21H),1.60-1.68(m,1H),1.70-1.92(m,2H),3.75(s,3H),4.16-4.22(m,1H),5.06(d,J=5.1 Hz,1H),6.86(d,J=9.0Hz,2H),7.32(d,J=9.0 Hz,2H);13C NMR(75 MHz,CDCl3)δ12.34,17.82,17.91,22.18,23.37,25.34,35.89,55.50,57.33,76.34,114.52,118.73,131.00,156.29,165.58;IR(KBr)2946,1742,1513,1458,1249 cm1. 元素分析计算值C23H39NO3Si: C,68.10;H,9.70;N,3.45. 实测值:C,68.26;H,9.85;N.3.35.
实施例16
(3R,4S)-4-(环己基甲基)-1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-2-氮杂环丁酮(Ⅵ′-d)
83%;低熔点固体;[α]D 20+43.7°(c 0.92,CHCl3);1H NMR(300 MHz,CDCl3)δ0.85-1.95(m,34H),3.78(s,3H),4.19-4.25(m,1H),5.05(d,J=5.1 Hz,1H),6.86(d,J=9.0 Hz,2H),7.32(d,J=9.0 Hz,2H);13CNMR(75 MHz,CDCl3)δ12.15,17.76,17.83,26.12,26.22,26.47,32.84,34.22,34.51,55.36,56.41,76.13,114.30,118.45,130.81,155.99,165.55;IR(净样)2925-2865,1749,1513,1464,1448,1389,1246,1174,1145,1128,939,882,828,684 cm-1. 元素分析计算值C26H43NO3Si:C,70.06;H,9.72;N,3.14. 实测值:C,69.91;H,9.71;N,3.02.
实施例17
1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-4-(4-氟苯基)-2-氮杂环丁酮(Ⅵ′-f)
白色固体;mp 121-122℃;[α]D 20+82.5°(c 0.724,CHCl3);1H NMR(CDCl3)δ0.82-0.84(m,18H),0.86-1.01(m,3H),3.62(s,3H),5.02(d,J=4.9 Hz,1H),5.11(d,J=4.9 Hz,1H),6.68(d,J=6.9 Hz,2H),6.96-7.25(m,6H);IR(CHCl3)3050,2974,2868,1748 cm-1. 元素分析计算值C25H34NO3FSi:C,67.69;H,7.72;N,3.16. 实测值:C,67.77;H,7.83;N.3.19.
实施例18
1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-4-(4-三氟甲基苯基)-2-氮杂环丁酮(Ⅵ′-g)
白色固体;mp 132-133℃;[α]D 20+89.7°(c 0.925,CHCl3);1H NMR(CDCl3)δ0.87-1.15(m,21H),3.74(s,3H),5.21(d,J=4.9 Hz,1H),5.27(d,J=4.9 Hz,1H),6.79(d,J=8.0 Hz,2H),7.25(d,J=8.0 Hz,2H),7.46(d,J=8.0 Hz,2H),7.60(d,J=8.0 Hz,2H);IR(CHCl3)3050,2975,2868,1750,878 cm-1. 元素分析计算值C26H34NO3F3Si:C,63.26;H,6.94;N,2.84. 实测值:C,63.36;H,7.13;N,2.88.
实施例19
1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-4-(2-呋喃基)-2-氮杂环丁酮(Ⅵ′-h)
白色固体;mp 109-110℃;[α]D 20-86.2°(c 1.4,CHCl3);1H NMR(CDCl3)δ0.98-1.10(m,21H),3.75(s,3H),5.20(d,J=4.9 Hz,1H),5.24(d,J=4.9 Hz,1H),6.35-6.40(m,2H),6.81(d,J=9.0 Hz,2H),7.30(d,J=9.0Hz,2H),7.42(m,1H);13C NMR(CDCl3)δ11.96,17.52,17.57,55.43,57.19,78.13,110.23,110.63,114.44,118.55,131.08,142.80,148.51,156.45,165.27. 元素分析
计算值C23H33NO4Si:C,66.47;H,8.00;N,3.37. 实测值:C,66.56;H,8.13;N,3.30.
实施例20
1-(4-甲氧基苯基)-3-三异丙基甲硅烷氧基-4-{2(2-呋喃基)乙烯基)-2-氮杂环丁酮(Ⅵ′-i)
白色固体;mp 103.5-105.5℃;[α]D 20-128.4°(c2.8,CHCl3);1H NMR(CDCl3)δ1.05-1.09(m,21H),3.76(s,3H),4.69(dd,J=4.9,8.6 Hz,1H),5.15 (d.J=4.9 Hz,1H),6.25(dd,J=8.6,16.0 Hz,1H),6.29(d,J=3.3Hz,1H),6.37(dd,J=1.8,3.3 Hz,1H),6.57(d,J=16.0 Hz,1H),6.83(m,2H),7.34-7.41(m,3H);13C NMR(CDCl3)δ12.11,17.70,17.74,55.54,61.94,77.18,78.45,107.88,108.42,111.26,114.54,118.70,123.46,123.82,142.46,190.99;IR(KBr)2948,2866,1743,1513,1389,1246,1181,1120 cm-1. 元素分析计算值C25H35NO4Si:C,67.99;H,7.99;N,3.17. 实测值:C,68.07;H,7.94;N,3.10.
如路线1中所示,将β-内酰胺中间体(Ⅵ′)转化成β-内酰胺类化合物(Ⅵ)的反应是按实施例21-23所述方法完成的。以这种方式获得的氮杂环丁酮类化合物(Ⅵc)至(Ⅵj)举例说明了各种R1基团。(Ⅵc)至(Ⅵj)的鉴定数据在每一化合物之后列出。
实施例21-23
N-(4-甲氧基苯基)-β-内酰胺类化合物(Ⅵ′)转化成β-内酰胺类化合物(Ⅵ)的反应
在-15℃下于20分钟内,向0.24mmol 1-(4-甲氧基苯基)-β-内酰胺的MeCN(20ml)溶液中加入0.65mmol硝酸铈铵(CAN)的10ml CH3CN和20ml水的混合物。搅拌1小时后,用水(20ml)稀释,然后用乙酸乙酯(15ml×2)萃取该混合物。合并的有机层依次用水(7ml)、5% Na2SO4(10ml×2)、5% Na2CO3(10ml.)和盐水(5ml)洗涤。干燥、真空除去溶剂,接着用活性炭脱色,得到粗产物。该粗产物用硅胶柱色谱法进一步纯化,用己烷/乙酸乙酯(3/1)作洗脱剂,得到N-脱保护的β-内酰胺。
实施例21
(3R,4S)-4-(异丁基)-3-三异丙基甲硅烷氧基-2-氮杂环丁酮(Ⅵc)83%;黄色油状物;[α]D 20+35.45°(c 1.33,CHCl3);1H NMR(300 MHz,CDCl3)δ0.93(d,J=6.6 Hz,3H),0.96(d,J=6.5 Hz,3H),1.05-1.25(m,22H),1.52(m,1H),1.67(m,1H),3.78(m,1H),4.96(dd,J=4.8,2.4 Hz,1H),6.02(bs,1H);13C NMR(75 MHz,CDCl3)δ12.12,17.72,17.80,22.29,23.08,25.35,39.08,54.45,78.04,170.00;IR(净样)3238,1759,1465,1184 cm-1. 元素分析计算值C16H33NO2Si:C,64.16;H,11.1;N,4.68. 实测值:C,64.17;
实施例22
(3R,4S)-4-(环己基甲基)-3-三异丙基甲硅烷氧基-2-氮杂环丁酮(Ⅵd)85%;黄色油状物;[α]D 20+12.44°(c 1.46,CHCl3);1H NMR(300MHz,CDCl3)δ0,97-1.25(m,32H),1.40-1.70(m,2H),3.80(dt,J=8.4,4.8 Hz,1H),4.95(dd,J=4.8,2.4 Hz,1H),6.05(bs,1H);13C NMR(75 MHz,CDCl3)δ12.06,17.77,17.82,26.16,26.25,26.46,33.15,33.82,34.85,37.72,53.89,77.98,169.98;IR(neat)3238,1759,1465,1184 cm- 1. 元素分析计算值C19H37NO2Si:C,67.20;H,10.98;N,4.12. 实测值:C,67.40;H,10.79;N,3.98.
实施例23
(3R,4S)-3-三异丙基甲硅烷氧基-4-(2-环己基乙基)-2-氮杂环丁酮(Ⅵj)的制备
在50℃和800psi氢气氛下,将(Ⅵb)(100mg,0.29mmol)的甲醇(10ml)混合物用5%Rh-C催化剂(10mg)氢化20小时。滤出催化剂后,真空蒸发溶剂,残余物在短的硅胶柱上纯化,用己烷/乙酸乙酯(5/1)作洗脱剂,得到95mg(93%产率)Ⅵj,为无色液体:[α]D 20-162.3°(c 1.46,CHCl3);1H NMR(CDCl3)δ1.07-1.72(m,36H),3.61-3.57(m,1H),4.94(dd,J=2.4,4.8 Hz,1H),6.42(bs,1H);13C NMR(CDCl3)δ12.02,17.79,26.31,26.60,27.54,33.19,33.39,33.54,37.71,56.44,77.74,170.15;IR(净样)3236(′NH),2925,2866,1760(′CO),1464,1451,1384,1348,1244 cm-1. 元素分析计算值C27H39NO3Si:C,71.48;H,8.66;N,3.09. 实测值:C,7l.35;H,8.66;N,3.01.
如路线2所示,将3-TIPSO-4-取代的-2-氮杂环丁酮类化合物或β-内酰胺类化合物Ⅵ转化成β-内酰胺类化合物Ⅶ的反应按实施例24-28所述制备方法完成。对于每一个β-内酰胺(Ⅶa)-(Ⅶe)的鉴定数据在每一化合物之后列出。
实施例24-28
3-羟基-4-取代的-2-氮杂环丁酮类化合物(Ⅶ)的制备
在室温下,向2.6mmol 3-三异丙基甲硅烷氧基-4-取代的-2-氮杂环丁酮的20ml THF溶液中加入3.1mmol(1M的THF溶液)正丁基氟(NBu4 F)。5小时后,蒸发溶剂,粗油状物直接用硅胶色谱法纯化,用5∶1 EtOAc/己烷洗脱,得到3-羟基-4-取代的-2-氮杂环丁酮:
实施例24
(3R,4S)-3-羟基-4-苯基-2-氮杂环丁酮(Ⅶa)
100%;白色固体;mp 189-190℃;[α]D 20+181.6°(c0.5,CH3OH);1H NHR(300 MHz,CD3OD)δ4.84(d,J=4.7 Hz,1H),5.04(d,J=4.7 Hz,1H),7.25-7.35(m,5H);IR(KBr)3373,3252,1732,1494 cm-1. 元素分析计算值 C9H9NO2:C 66.25%,H 5.56%,N 8.58%. 实测值:C 66.42%,H 5.74%,N8.62%.
实施例25
(3R,4S)-3-羟基-4-(2-苯基乙烯基)-2-氮杂环丁酮(Ⅶb)
82%;白色固体;mp 143-144℃;[α]D 20+21.9°(c 1.05,MeOH);1H NMR(300 MHz,CD3OD)δ4.35(ddd,J=0.8,4.7,7.7 Hz,1H),4.93(d,J=4.7 Hz,1H),6.28(dd,J=7.7,16.0 Hz,1H),7.18-7.43(m,5H);13C NMR(75 MHz,CD3OD)δ58.95,79.63,126.83,127.58,128.88,129.61,135.28,137.96,172.79;IR(KBr)3320,3276,1754,1464 cm-1.元素分析计算值 C11H11NO2:C,69.83;H,5.86;N,7.40.实测值:C,69.72;H,5.92;N,7.24.
实施例26
(3R,4S)-3-羟基-4-(异丁基)-2-氮杂环丁酮(Ⅶc)
94%;白色固体;mp 141-142℃;[α]D 20+26.6°(c 0.70,MeOH);1H NMR(300 MHz,MeOH-d4)δ0.94(d,J=6.8 Hz,3H),0.97(d,J=6.8 Hz,3H),1.45(m,2H),1.71(七重峰,J=6.6 Hz,1H),3.75(m,1H),4.79(d,J=4.7 Hz,1H);13C NMR(75 MHz,MeOH-d4)δ22.62,23.48,26.53,39.90,55.47,77.76,173.18;IR(KBr)3274,3178,1762,1685,1155 cm-1. 元素分析计算值 C7H13NO2:C,58.72;H,9.15;N,9.78. 实测值:C,58.55;H,9.41;N,9.69.
实施例27
(3R,4S)-4-(环己基甲基)-3-羟基-2-氮杂环丁酮(Ⅶd)
92%;白色固体;mp 147-148℃;[α]D 20+8.73°(c,0.573,CH3OH);1H NMR(300 MHz,MeOH-d4)δ0.88-1.82(m,13H),3.78(m,1H),4.79(d,J=4.7 Hz,1H);1H NMR(300MHz,DMSO-d6)δ0.86-1.72(m,13H),3.58(m,1H),4.63(m,1H),5.82(d,J=7.6 Hz,1H),8.13(d,J=5.6,1H);13CNMR(75 MHz,MeOH-d4)δ27.29,27.41,27.48,34.07,35.06,36.11,38.52,55.02,77.65,173.22;IR(KBr)3301,3219,2915,2847,1754,1694,1168 cm-1. 元素分析计算值 C10H17NO2:C,65.54,H,9.35,N,7.64. 实测值:C,65.72,H,9.46,N,7.42.
实施例28
(3R,4S)-4-环己基-3-羟基-2-氮杂环丁酮(Ⅶe)
在90℃和在800psi的条件下,于高压釜中将500mg(3.06mmol)4-苯基-3-羟基-2-氮杂环丁酮Ⅵa和15mg Rh-C在10ml甲醇中的悬浮液加热。5天后,释放掉氢气压力,并将催化剂经硅藻土过滤。蒸发溶剂,得到一固体,将其用乙酸乙酯重结晶,得到440mg(85%)Ⅶe,为白色固体:白色固体;mp 140-140.5℃;[α]D 20+65.1°(c 0.66,CH3OH);1H NMR(250 MHz,MeOH-d4)δ0.75-1.10(m,2H),1.12-1.35(m,3H),1.40-2.00(m,6H),3.28(dd,J=9.7,4.6 Hz,1H),4.81(d,J=4.6 Hz,1H);1HNMR(250 MHz,DMSO-d6)δ0.75-1.00(m,2H),1.10-1.35(m,3H),1.37-1.55(m,1H),1.58-1.85(m,5H),3.10(dd,J=9.6,4.7 Hz,1H),4.67(m,1H),5.87(d,J=7.8 Hz,1H),8.21(bs,1H);13C NMR(63 MHz,DMSO-d6)δ25.08,25.36,26.07,28.83,29.17,37.51,59.04,76.41,170.21;IR(KBr)3312,3219,2928,1726 cm-1. 元素分析计算值C9H15NO2:C,63.88,H,8.93,N,8.28. 实测值:C,63.70,H,9.00,N,8.06.
一经形成,β-内酰胺类化合物(Ⅶ)便需要保护羟基。保护基团是按实施例29-33所述方法连接上的,得到β-内酰胺类化合物(Ⅵ)。用不同G基团保护的β-内酰胺类化合物(Ⅵ)的鉴定数据在每一化合物(Ⅵa-EE)至(Ⅵe-EE)之后列出。
实施例29-33
3-(羟基被保护的)-4-取代的-2-氮杂环丁酮类化合物(Ⅵ)的制备
在0℃下,向1.9mmol 3-羟基-4-取代的-2-氮杂环丁酮的20ml THF溶液中加入3.9mmol乙基乙烯基醚。2小时后,在0℃下,该反应混合物用乙醚稀释,并用饱和NaHCO3洗涤。有机层用Na2CO3干燥,过滤,并浓缩。得到3-(1-乙氧基乙氧基)-4-取代的-2-氮杂环丁酮:
实施例29
(3R,4S)-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅵa-EE)
100%;白色固体;mp 78-80℃;1H NMRδ(CDCl3)[0.98(d,J=5.4 Hz),1.05(d,J=5.4 Hz),3H],[1.11(t,J=7.1 Hz),1.12(t,J=7.1 Hz),3H],[3.16-3.26(m),3.31-3.42(m),3.59-3.69(m),2H],[4.47(q,J=5.4 Hz),4.68(q,J=5.4 Hz),1H],[4.82(d,J=4.7 Hz),4.85(d,J=4.7 Hz),1H],5.17-5.21(m,1H),6.42(bd,1H),7.35(m,5H);IR(KBr)3214,2983,2933,1753,1718,1456 cm-1.
元素分析计算值 C13H17NO3:C,66.36;H,7.28;N,5.95.实测值:C,66.46;H,7.11;N,5.88.
实施例30
(3R,4S)-3-(1-乙氧基乙氧基)-4-(2-苯基乙烯基)-2-氮杂环丁酮(Ⅵb-EE)
98%;白色固体;mp 98-99℃;1H NMR(300 MHz,CDCl3)δ[1.17(t,J=7.1 Hz),1.18(t,J=7.1 Hz),3H],[1.26(d,J=5.4 Hz),1.35(d,J=5.4 Hz),3H],[3.44-3.52(m),3.60-3.68(m),3.75-3.82(m),2H],4.41(dd,J=4.9,8.5 Hz,1H),[4.81(q,J=5.4 Hz),4.90(q,J=5.4Hz),1H],[5.11(d,J=4.9 Hz),5.11(d,J=4.9 Hz),1H],6.01(bs,1H),[6.27(dd,J=8.5,15.9 Hz),6.28(dd,J=8.5,15.9 Hz),1H],[6.61(d,J=15.9 Hz),6.63(d,J=15.9 Hz),1H],7.27-7.42(m,5H);13C NMR(75MHz,CDCl3)δ15.04,20.37,20.42,57.22,57.81,61.23,62.22,78.77,79.29,99.50,99.82,125.56,125.79,126.59,128.12,128.65,134.47,134.58,136.15,168.59,168.77;IR(KBr)3310,3030,2963,1770 cm-1. 元素分析计算值
C15H19NO3:C,68.94;H,7.33;N,5.36. 实测值:C,69.13;H,7.44;N,5.16.
实施例31
(3R,4S)-3-(1-乙氧基乙氧基)-4-(异丁基)-2-氮杂环丁酮(Ⅵc-EE)
100%;无色油状物:[α]D 20+20.93°(c 1.72,CHCl3);1H NMR(300 MHz,CDCl3)δ0.86(d,J=6.5 Hz,3H),0.92(d,J=6.5 Hz,3H),1.17(t,J=7.0 Hz,3H),[1.29(d,J=5.3 Hz),1.34(d,J=5.3 Hz),3H],1.46(m,2H),1.62(m,1H),[3.49(m),3.69(m),2H)],3.80(m,1H),(4.79(q,J=5.4 Hz),4.90(q,J=5,4 Hz),1H],4.87(m,1H),6.78(bs,1H);13C NMR(75 MHz,CDCl3)δ15.08,20.42,(21.98,22.06),(23.15,23.22),25.35,(39.01,39.10),(53.35,53.69),(61.24,62.24),(77.79,77.92),(99.75,100.05),(169.56,169.65);IR(净样)3269,2956,2871,1758,1468,1382,1340,1152,1115,1083,1052,936,893 cm-1.
实施例32
(3R,4S)-4-(环己基甲基)-3-(1-乙氧基乙氧基)-2-氮杂环丁酮(Ⅵd-EE)
100%;无色油状物;[α]D 20+10.92°(c 1.42,CHCl3);1H NMR(300 MHz,CDCl3)δ0.84-1.71(m,13H),1.16(t,J=7.0 Hz,3H),[1.28(d,J=5.3 Hz),1.33(d,J=5.3 Hz),3H],3.48(m,1H),[3.72(m),3.8(m),2H],[4.78(q,J=5.4 Hz),4.85(q,J=5.4 Hz),1H],4.82(m,1H),6.76(bs,1H);13C NMR(75 MHz,CDCl3)δ14.37,19.72,25.30,25.44,25.63,(32.02,32.13),(33.09,33.17),(34.03,34.07),(38.98,37.07),(52.15,52.49),(60.49,61.52),(75.97,76.39),(99.00,99.35),(168.98,169.05);IR(净样)3278,2924,2852,1758,1448,1382,1150,1114,1086,938,886cm-1. 元素分析计算值 C14H25NO3:C,65.85;H,9.87;N,5.49.实测值:C,66.03;H,9.71;N,5.30.
实施例33
(3R,4S)-4-环己基-3-(1-乙氧基乙氧基)-2-氮杂环丁酮(Ⅵe-EE)
100%;白色固体;mp 87-89℃;[α]D 20+83°(c 0.76,CH3OH);1H NMRδ(250 MHz,CDCl3)0.84(m,2H),1.07-1.34(m,9H),1.66(m,6H),3.32(m,1H),[3.42(q,J=7.7Hz),3.54(q,J=7.7 Hz),3.65(q,J=7.7 Hz),3.74(q,J=7.7 Hz),2H],4.81(m,1H),[4.80(m),4.90(q,J=5.2 Hz),1H],6.92(bs,1H);IR(CHCl3)3412,2989,2931,1760,1443,1155,1114 cm-1. 元素分析计算值C13H27NO3:C,64.70;H,9.61;N,5.80. 实测值:C,64.82;H,9.66;N,5.64.
按照实施例34至52所述的制备方法,使其中G代表说明书中另外保护基的被保护的β-内酰胺类化合物(Ⅵ)与酰基氯类、氯甲酸酯类或氨基甲酰氯类在碱的存在下进行反应。实施例34至52中所得的β-内酰胺类化合物示于路线2中。其中G代表各种保护基团的β-内酰胺类化合物(Ⅴa)至(Ⅴd)的鉴定数据在每一实施例之后的各β-内酰胺后列出。
实施例34
1-酰基-3-(羟基被保护的)-4-取代的-2-氮杂环丁酮类化合物(Ⅴa)的制备
制备该类化合物的典型方法,以(3R,4S)-1-苯甲酰基-3-(乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴa-EE)的制备为例叙述如下。在0℃下、于搅拌下,向Ⅵa-EE(460mg,1.9mmol)、4-(二甲氨基)吡啶DMAP(5mg)和三乙胺(542ml,3.9mmol)的20ml二氯甲烷溶液中滴加苯甲酰氯(340ml,2.9mmol)。撤去冷却浴,将混合物在25℃搅拌2小时。反应混合物用饱和NH4Cl水溶液和盐水洗涤,用无水Na2CO3干燥,真空浓缩,得到油状粗产物。粗产物用短硅胶柱纯化(洗脱剂∶EtOAc/己烷=1/5),得到纯Ⅴa-EE(611mg,92%),为无色油状物:IR(净样)3064-2933,1798,1682,1450 cm-1;1H NMR(CDCl3)δ[1.04(d,J=5.4 Hz),1.14(d,J=5.4 Hz)](3H),1.11-1.17(m,3H),3.23-3.74(m,2H),[4.57(q,J=5.4 Hz),4.76(q,J=5.4 Hz)](1H),5.28(d,J=6.2 Hz,1H),[5.43(d,J=6.2 Hz),5.46(d,J=6.2 Hz)](1H),7.30-7.65(m,8H).
实施例35-46
1-烷氧基-和1-芳氧基-羰基-3-(羟基被保护的)-4-取代的-2-氮杂环丁酮类化合物(Ⅴb)的制备
在0℃下,向2.2mmol 3-(1-乙氧基乙氧基)-4-取代的-2-氮杂环丁酮、5mg DMAP、4.5mmol三乙胺的20ml二氯甲烷溶液中滴加3.3mmol溶于5ml二氯甲烷中的氯甲酸烷基酯。将反应混合物在室温下搅拌过夜。有机层用盐水洗涤几次,用Na2CO3干燥,并浓缩。粗固体经硅胶色谱法纯化,得到N-保护的β-内酰胺:
实施例35
(3R,4S)-1-甲氧羰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-a-EE)
62%;浅黄色油状物;[α]D 20+98.2°(c 1.1,CHCl3);1HNMR(250 MHz,CDCl3)δ[0.97(d,J=5.4 Hz),1.08(d,J=5.4 Hz),3H],1.10(bt,J=7.3 Hz,3H),[3.21(dq,J=9.5,7.1 Hz),3.32(q,J=7.1 Hz),3.64(dq,J=9.5,7.1 Hz),2H],[3.76(s),3.77(s),3H],[4.48(q,J=5.4Hz),4.69(q,J=5.4 Hz),1H],[5.11(d,J=5.9 Hz),5.14(d,J=5.9 Hz),1H],5.23(d,J=5.9 Hz,1H),7.34(m,5H);13C NMR(63 MHz,CDCl3)δ(14.96,15.07),(19.84,20.69),53.59,(60.74,62.36),(61.14,61.92),(76.21,77.21),(99.16,99.56),(127.73,128.03,128.31,128.36,128.62,128.85),(133.41,133.58),(149.51,149.57),(165.21,165.67);IR(neat)3033,2979,2957,1821,1738,1654,1440,1336,1101 cm-1. 元素分析计算值 C15H19NO5:C,61.42;H,6.53;N,4.78. 实测值:C,61.55;H,6.51;N,4.90.
实施例36
(3R,4S)-1-乙氧羧基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-b-EE)
82%;无色油状物;[α]D 20+100.9°(c 1.08,CHCl3);1HNMR(250 MHz,CDCl3)δ[0.95(d,J=5.4 Hz),1.06(d,J=5.4 Hz),3H],1.08(bt,J=7.3 Hz,2H),[1.19(t,J=7.1 Hz),1.20(t,J=7.1 Hz),3H],[3.20(dq,J=9.4,7.1 Hz),3.31(q,J=7.1 Hz),3.32(q,J=7.1 Hz),3.63(dq,J=9.4,7.1 Hz),2H],[4.18(q,J=7.1 Hz),4.19(q,J=7.1 Hz),2H],[4.47(q,J=5.4 Hz),4.67(q,J=5.4 Hz),1H],[5.09(d,J=5.8 Hz),5.13(d,J=5.8Hz),1H],5.21(d,J=5.8 Hz,1H),7.30(m,5H);13C NMR(62 MHz,CDCl3)δ14.14,(14.95,15.07),(19.86,20.05),(60.76,62.35),62.36,(61.14,61.90),(76.18,77.20),(99.17,99.53),(127.73,128.02,128.25,128.30,128.50,128.63),(133.59,133.77),(148.99,149.05),(165.33,165.79);IR(挣样)2978,2934,1814,1731,1646,1540,1456,1323,1175,1096 cm-1. 元素分析计算值 C16H21NO5:C,62.53;H,6.89;N,4.56. 实测值:C,62.45;H,6.63;N,4.83.
实施例37
(3R,4S)-1-正丁氧羰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-c-EE)
83%;无色油状物;[α]D 20+70.4°(c 1.25,CHCl3);1HNMR(250 MHz,CDCl3)δ0.79(t,J=7.3 Hz,3H),[0.94(d,J=5.1 Hz),1.07(d,J=5.1 Hz),3H],1.07(t,J=7.4Hz,2H),1.20(m,2H),1.51(五重峰,J=6.7 Hz,2H),[3.21(m),3.30(q,J=7.1 Hz),3.61(m),2H],4.09(m,2H),[4.46(q,J=5.2 Hz),4.66(q,J=5.2 Hz),1H],[5.07(d,J=5.8 Hz),5.11(d,J=5.8 Hz),1H],5.19(d,J=5.8 Hz,1H),7.28(m,5H);13C NMR(63 MHz,CDCl3)δ13.50,(14.95,15.29),18.71,(19.84,20.05),30.42,(60.77,62.33),(61.25,62.02),66.51,(76.24,77.26),(99.17,99.52),(127.76,128.03,128.22,128.27,128.50,128.60),(133.61,133.80),(148.96,149.02),(165.40,165.85);IR(净样)2961,2933,1817,1732,1653,1456,1394,1250,1099 cm-1. 元素分析计算值:C18H25NO5:C,64.46;H,7.51;N,4.18. 实测值:C,64.44;H,7.57;N,4.24.
实施例38
(3R,4S)-1-叔丁氧羰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-d-EE)
83%;白色固体;mp 90-91℃;[α]D 20+70.4°(c 1.25,CHCl3);1H NMR(250 MHz,CDCl3)δ[0.96(d,J=5.4 Hz),1.08(d,J=5.4 Hz),3H],[1.09(t,J=7.0 Hz),1.10(t,J=7.0 Hz),3H],(1.36(s),1.37(s),9H],[3.23(dq,J=9.5,7.1 Hz),3.32(q,J=7.1 Hz),3.65(dq,J=9.5,7.1 Hz),2H],[4.48(q,J=5.4 Hz),4.69(q,J=5.4 Hz),1H],[ 5.03(d,J=5.8 Hz),5.07(d,J=5.8Hz),1H],5.18(d,J=5.8 Hz,1H),7.31(m,5H);13C NMR(63 MHz,CDCl3)δ(14.98,15.08),(19.89,20.10),27.84,(60.74,62.32),(61.28,62.08),(75.91,76.54),(99.10,99.41),(127.76,128.07,128.20,128.42,128.85),(133.98,134.16),147.56,(165.61,166.04);IR(CHCl3)3025,2982,2932,1809,1725,1601,1497,1331,1256,1152 cm-1. 元素分析计算值C18H25NO5:C,64.46;H,7.51;N,4.18. 实测值:C,64.50;H,7.41;N,4.17.
实施例39
(3R,4S)-3-(1-乙氧基乙氧基)-1-苯氧羰基-4-苯基-2-氮杂环丁酮(Ⅴb-e-EE)
79%;白色固体;mp 50-52℃;[α]D 20+64.9°(c 0.94,CHCl3);1H NMR(250 MHz,CDCl3)δ[1.00(d,J=5.3 Hz),1.11(m),3H],[1.14(m),3H],[3.27(m),3.35(q,J=7.1 Hz),3.70(m),2H],[4.54(q,J=5.3 Hz),4.74(q,J=5.3 Hz),1H],[5.25(d,J=5.8 Hz),5.29 (d,J=5.8Hz),1H],5.34(d,J=5.8 Hz,1H),7.03-7.39(m,10H);IR(CHCl3)3028,2981,2934,1815,1744,1591,1486,1327,1192 cm-1. 元素分析计算值 C20H21NO5:C,67.59;H,5.96;N,3.94. 实测值:C,67.33;H,6.06;N,3.75.
实施例40
(3R,4S)-3-(1-乙氧基乙氧基)-4-苯基-1-苯基甲氧羰基-2-氮杂环丁酮(Ⅴb-f-EE)
44%;白色固体;mp 58-60℃;[α]D 20+91.4°(c 1.16,CHCl3);1H NMR(250 MHz,CDCl3)δ[0.97(d,J=5.3 Hz),1.09(d,J=5.3 Hz),3H],[1.10(t,J=7.0 Hz),1.11(t,J=7.0 Hz),3H],[3.23(dq,J=9.5,7.1 Hz),3.33(q,J=7.1 Hz),3.66(dq,J=9.5,7.1 Hz),2H],[4.50(q,J=5.4 Hz),4.70(q,J=5.4 Hz),1H],[5.13(d,J=5.6 Hz),5.15(d,J=5.6 Hz),1H],[5.19(s),5.20(s),2H],5.23(d,J=5.6 Hz,1H),7.21(m,2H),7.26-7.37(m,8H);13C NMR(63 MHz,CDCl3)δ(14.99,15.10),(19.90,20.10),(60.83,62.41),(61.64,62.14),68.01,(76.31,77.28),(99.19,99.53),(127.37,127.86,128.07,128.16,128.36,128.52,128.63,128.85),(133.49,13 3.68),134.89,(148.72,148.78),(165.37,165.81);IR(CHCl3)3028,2981,2934,1815,1733,1604,1450,1380,1004 cm-1.元素分析计算值 C21H23NO5:C,68.28;H,6.28;N,3.79.实测值:C,68.07;H,6.43;N,3.72.
实施例41
(3R,4S)-1-叔丁氧羰基-4-环己基-3-(1-乙氧基乙氧基)-2-氮杂环丁酮(Ⅴb-g-EE)
91%;无色油状物;[α]D 20+62.5°(c 1.12,CHCl3);1HNMR(250 MHz,CDCl3)δ1.10-1.28(m,6H),1.15(t,J=7.0Hz,3H),[1.27(d,J=5.4 Hz),1.31(d,J=5.4 Hz),3H],[1.45(s),1.46(s),9H],1.63-1.70(m,5H),[3.43(dq,J=9.2,7.0 Hz),3.62(m),3.75(d,J=7.0 Hz),3.78(d,J=7.0 Hz),2H],3.85(t,J=6.1 Hz,1H),[4.78(q,J=5.4 Hz),4.88(m),1H],[4.85(d,J=6.1Hz),4.86(d,J=6.1 Hz),1H];13C NMR(63 MHz,CDCl3)δ15.07,(20.25,20.37),(26.05,26.14),26.26,(27.33,27.95),(29.05,29.20),(30.04,30.23),(37.54,37.64),(61.19,62.53),(62.06,62.32),(75.42,75.85),83.06,100.11,148.72,(166.70,166.76);IR(净样)2980,2931,2854,1807,1725,1450,1370,1329,1212,1118 cm-1.元素分析计算值 C18H31NO5:C,63.32;H,9.15;N,4.10.实测值:C,63.15;H,8.97;N,3.96.
实施例42
(3R,4S)-1-叔丁氧羰基-3-(1-乙氧基乙氧基)-4-(2-苯基乙烯基)-2-氮杂环丁酮(Ⅴb-h-EE)
86%;白色固体;mp 69-73℃;1H NMR(300 MHz,CDCl3)δ[1.16(t,J=7.1 Hz),1.18(t,J=7.1 Hz),3H],[1.25(d,J=5.4 Hz),1.36(d,J=5.4 Hz),3H],1.48(s,9H),[3.47(m),3.62(m),3.80(m),2H],4.68(dd,J=5.8,8.8 Hz,1H),[4.82(q,J=5.4 Hz),4.91(q,5.4Hz),1H],[5.09(d,J=5.8 Hz),5.11(d,J=5.8 Hz),1H],[6.23(dd,J=8.8,15.8 Hz),6.25(dd,J=8.8,15.8 Hz),1H],[6.72(d,J=15.8 Hz),6.73(d,J=15.8H2),1H],7.27-7.44(m,5H);13C NMR(75 MHz,CDCl3)δ14.98,20.31,27.98,60.24,60.85,61.46,62.36,63.58,83.38,99.63,99.87,122.45,122.63,126.69,128.20,128.61,136.15,136.34,136.38,147.74,147.79,165.33,165.53;IR(KBr)3027,3020,2984,2933,1809,1723 cm-1.元素分析计算值 C20H27NO5:C,66.46;H,7.53;N,3.88.实测值:C,66.60;H,7.50;N,3.87.
实施例43
(3R,4S)-1-叔丁氧羰基-3-(1-乙氧基乙氧基)-4-(异丁基)-2-氮杂环丁酮(Ⅴb-i-EE)
80%;黄色油状物;[α]D 20+77.45°(c 0.216,CHCl3);1HNMR(300 MHz,CDCl3)δ0.89(d,J=5.7 Hz,6H),1.41(t,J=7.1 Hz,3H),[1.25(d,J=5.3 Hz),1.31(d,J=5.3Hz),3H],1.45(s,9H),1.51-1.67(m,3H),[3.48(dq,J=9.3,7.1 Hz),3.55-3.71(m,1H),3.80(dq,J=9.3,7.1Hz),2H],4.08(q,J=6.1 Hz,1H),[4.70(q,J=5.3 Hz),4.90(q,J=5.3 Hz),1H],4.85(d,J=6.1 Hz,1H);13C NMR(75 MHz,CDCl3)δ14.95,(20.11,20.28),(22.42,22.59),22.70,(24.89,25.07),27.83,(37.03,37.31),(56.14,56.38),(61.07,62.27),(75.65,75.92),82.98,99.91,148.1,(166.1,165.9);IR(净样)293l,2960,2872,(1790,1807),(1708,1726),(1454,1465),1332,1256,1048,1158,996,955,857,834,770 cm-1.元素分析计算值C16H29NO5:C,60.93;H,9.27;N,4.44.实测值:C,61.19;H,9.41;N,4.37.
实施例44
(3R,4S)-1-叔丁氧羰基-4-环己基甲基-3-(1-乙氧基乙氧基)-2-氮杂环丁酮(Ⅴb-j-EE)
93%;黄色油状物;[α]D 20+75.64°(c 0.78,CHCl3);1HNMR(300 MHz,CDCl3)δ0.81-1.74(m,13H),1.19(t,J=7.1 Hz,3H),1.48(s,9H),[1.30(d,J=5.3 Hz),1.35(d,J=5.3 Hz),3H],[3.45(dq,J=9.3,7.1 Hz),3.62-3.71(m),3.78(dq,J=9.3,7.1Hz),2H],4.01(m,1H),[4.81(q,J=5.3 Hz),4.91(q,J=5.3 Hz),1H],[4.86(d,J=6.1 Hz),4.87(d,J=6.1 Hz),1H];13C NMR(75MHz,CDCl3)δ15.03,20.19,20.36,26.10,26.36,27.91,(33.17,33.31),(33.35,33.49),(34.33,34.58),(35.39,35.68),(55.77,55.99),(61.14,62.21),(75.74,75.90),82.96,(99.86,99.95),147.96,166.13;IR(净样)2979,2923,2850,1719,1807,1449,1336,1154 cm-1.元素分析
计算值 C19H33NO5:C,64.20;H,9.36;N,3.94.实测值:C,64.00;H,9.17;N,4.02.
实施例45-50
1-(N-单取代的-氨基甲酰基)-3-(羟基被保护的)-4-取代的-2-氮杂环丁酮类化合物(Ⅴd)的制备
在-78℃下,向0.5mmol 3-(1-羟基被保护的)-4-取代的-2-氮杂环丁酮(Ⅵ)的6ml四氢呋喃溶液中滴加0.6mmol正丁基锂(n-BuLi)。5分钟后,加入1mmol异氰酸酯。反应混合物在-78℃搅拌30分钟,加入2ml饱和NH4Cl溶液使反应中止。反应混合物用30ml乙醚稀释,有机层用盐水洗几次,用Na2CO3干燥,并浓缩。粗固体用硅胶色谱法纯化,得到相应的N-氨基甲酰基β-内酰胺(Ⅴd)。
实施例45
(3R,4S)-3-(1-乙氧基乙氧基)-1-苯基氨基甲酰基-4-苯基-2-氮杂环丁酮(Ⅴd-a-EE)
66%;浅黄色固体;mp 152-155℃;[α]D 20+87.8°(c .9,CHCl3);1H NMR(250 MHz,CDCl3)δ[1.07(d,J=5.4Hz),1.13(d,J=5.4 Hz),3H],1.16(t,J=7.1 Hz,3H),[3.26(dq,J=9.5,7.1 Hz),3.37(q,J=7.1 Hz),3.39(q,J=7.1 Hz),3.67(dq,J=9.5,7.1 Hz),2H],[4.53(q,J=5.4 Hz),4.72(q,J=5.4 Hz),1H],5.28(m,2H),[6.59(bs),6.60(bs),1H],7.10-7.55(m,10H),8.68(bs,1H);13C NMR(63 MHz,CDCl3))δ(15.04,15.16),(19.98,20.11),(60.99,62.53),61.80,(76.05,76.66),(99.34,99.70),(119.63,120.69,124.37,127.67,127.95,128.40,128.45,128.67,128.85,129.04,129.12,130.49),133.48,(137.03,137.28),(147.23,147.29),(168.12,168.52);IR(CHCl3)3342,3017,2982,2932,1773,1719,1602,1548,1445,1312,1224,1210 cm-1.元素分析计算值 C20H22N2O4:C,67.78;H,6.26;N,7.90.实测值:C,67.92;H,5.98;N,8.17.
实施例46
(3R,4S)-1-叔丁氧羰基-4-苯基-3-(1,1,1-三氯乙氧羰基)-2-氮杂环丁酮(Ⅴb-a-Troc)
白色固体;mp 122-124℃;[α]D 20+28°(c 0.5,CHCl3);1H NHR(250 MHz,CDCl3)δ1.39(s,9H),4.43(d,J=11.7Hz,1H),4.55(d,J=11.7 Hz,1H),5.28(d,J=5.5 Hz,1H),5.76(d,J=5.5 Hz,1H),7.30(m,5H);13C NMR(63MHz,CDCl3)δ27.81,60.80,77.03,78.76,84.40,127.73,128.58,129.09,131.55,147.71,152.17,160.34;IR(CHCl3)3016,2976,1819,1771,1732,1683,1244 cm-1.元素分析计算值 C17H18Cl3NO6:C,46.54;H,4.14;N,3.19.实测值:C,46.33;H,4.34;N,3.33.
实施例47
(3R,4S)-3-乙酰基-1-叔丁氧羰基-4-苯基-2-氮杂环丁酮(Ⅴb-a-Ac)
白色固体;mp 63-64℃;[α]D 20+32.1°(c 0.81,CHCl3);1H NMR(250 MHz,CDCl3)δ1.37(s,9H),1.65(s,3H),5.22(d,J=5.5 Hz,1H),5.83(d,J=5.5 Hz,1H),7.23-7.33(m,5H);3C NMR(63 MHz,CDCl3)δ19.71,27.81,60.84,75.94,84.07,127.43,128.31,128.67,132.44,147.25,162.39,168.83;1R(CHCl3)3026,2984,1815,1752,1731,1497,1371,1286,1224,1152,1024 cm-1.元素分析
计算值 C6H19NO5:C,62.94;H,6.27;N,4.59.实测值:C,63.17;H,6.14;N,4.52.
实施例48
(3R,4S)-1-叔丁基氨基甲酰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-b-EE)
74%;浅黄色粘稠油状物;[α]D 20+144.3°(c.7,CHCl3);1H NMR(250 MHz,CDCl3)δ[0.96(d,J=5.3 Hz),1.05(d,J=5.3 Hz),3H],1.10(t,J=7.1 Hz,3H),[1.33(s),1.34(s),9H],[3.21(dq,J=9.3,7.0 Hz),3.30(q,J=7.0 Hz),3.33(q,J=7.1 Hz),3.62(dq,J=9.1,7.0 Hz),2H],[4.46(q,J=5.4 Hz),4.66(q,J=5.4 Hz),1H],5.10-5.19(m,2H),[6.59(bs),6.60(bs),1H],7.23-7.36(m,5H);13C NMR(63 MHz,CDCl3)δ(14.86,14.99),(19.75,19.95),(28.81,29.30),(60.62,61.20),(60.80,62.29),(75.57,76.76),(98.91,99.34),(127.07,127.40,127.70,128.17,128.29,128.53),(133.71,133.86),(148.54,148.59),(167.67,168.13);IR(CHCl3)3362,3035,2977,2932,1767,1710,1605,1537,1457,1366,1320,1282,1217,1100 cm-1.元素分析计算值C18H26N2O4:C,64.65;H,7.84;N,8.38.实测值:C,64.46;H,7.75;N,8.39.
实施例49
(3R,4S)-1-苄基氨基甲酰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴb-c-EE)
50%;浅黄色粘稠油状物;[α]D 20+66.2°(c.8,CHCl3);1H NMR(250 MHz,CDCl3)δ[0.99(d,J=5.5 Hz),1.08(d,J=5.5 Hz),3H],1.12(m,3H),[3.16-3.40(m),3.63(m),2H],[4.35-4.55(m),4.69(q,J=5.5 Hz),3H],5.21(m,2H),[7.03(bs),7.05(bs),1H],7.32(m,10H);13C NMR(63 MHz,CDCl3)δ(15.01,15.14),(19.90,20.11),43.83,(60.66,62.44),(60.75,61.54),(75.93,77.04),(99.16,99.56),(127.25,127.64,127.69,128.17,127.93,128.35,128.55,128.64,128.74),(133.59,133.76),137.80,150.02,(167.73,168.19);IR(CHCl3)3379,3090,3033,2980,2930,1773,1707,1604,1536,1455,1319,1270,908 cm-1.元素分析计算值 C21H24N2O4:C,68.46;H,6.57;N,7.60.实测值:C,68.30;H,6.66;N,7.51.
实施例50
(3R,4S)-3-(1-乙氧基乙氧基)-1-乙基氨基甲酰基-4-苯基-2-氮杂环丁酮(Ⅴd-d-EE)
63%;浅黄色油状物;[α]D 20+96.7°(c.9,CHCl3);1HNMR(250 MHz,CDCl3)δ[0.96(d,J=5.3 Hz),1.04(d,J=5.3 Hz),3H],1.05-1.18(m,3H),[3.13-3.39(m),3.59(m),4H],[4.45(q,J=5.3 Hz),4.65(q,J=5.3 Hz),1H],5.16(m,2H),[6.60(bs),6.62(bs),1H],7.27(m,5H);13C NMR(63 MHz,CDCl3)δ14.98,(19.84,29.93),34.79,(60.56,61.35),(60.72,62.35),(75.91,77.03),(99.14,99.54),(127.28,127.55,127.85,128.27,128.40),(133.74,13 3.89),(149.87,149.93),(167.62,168.07);IR(CHCl3)3378,3035,2980,2934,1774,1704,1537,1455,1321,1271,1112,1025 cm-1.
实施例51-52
1-(N, N-二取代的-氨基甲酰基)-3-(羟基被保护的)-4-取代的-2-氮杂环丁酮类化合物(Ⅴd)的制备
制备该类化合物的典型方法,以(3R,4S)-(-)-1-吗啉羰基-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴc-b)的制备为例叙述如下。在室温下,向30mg(0.13mmol)3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮Ⅵa-EE的2mlCH2Cl2溶液中加入2mg DMAP和0.05ml三乙胺。5分钟后,加入22.9mg(0.15mmol)吗啉羰基氯。反应混合物在室温搅拌2小时。反应混合物用20ml CH2Cl2稀释,有机层用盐水洗涤两次,用Na2CO3干燥,并浓缩。固体粗产物经硅胶色谱法纯化,得到纯的Ⅴc-b;87%;浅黄色油状物:1H NMR(250 MHz,CDCl3)δ[0.90(d,J=5.3 Hz),1.01(d,J=5.3 Hz)](3H),[1.04(t,J=7.1 Hz),1.18(t,J=7.1Hz)](3H),3.20(m,4H),[3.28(m),3.53(m),3.67(m)](2H),3.60(m,4H),[4.41(q,J=5.3 Hz),4.63(q,J=5.3 Hz)](1H), [5.07(d,J=5.8 Hz),5.08(d,J=5.8 Hz)](1H),[5.29(d,J=5.8 Hz),5.32(a,J=5.8 Hz)](1H),7.23-7.27(m,5H).
实施例52
(3R,4S)-(-)-1-(N,N-二甲基氨基甲酰基)-3-(1-乙氧基乙氧基)-4-苯基-2-氮杂环丁酮(Ⅴc-a)
55%;无色液体;1H NMR(250 MHz,CDCl3)δ[0.98(d,J=5.4 Hz),1.10(d,J=5.4 Hz)](3H),1.12(t,J=7.1 Hz),1.13(t,J=7.1 Hz),3H],3.16(bs,6H),[3.37(m),3.67(m)](2H),[4.47(q,J=5.4 Hz),4.71(q,J=5.4 Hz)](1H),[5.11(d,J=5.7 Hz),5.12(d,J=5.7 Hz)](1H),5.34(t,J=5.7 Hz,1H),7.34(m,5H).
下列实施例53-56提供了通过使用14-OH-DAB,即一种可从市场上获得的天然化合物,制备浆果赤霉素类化合物(Ⅲ)和(Ⅳ)的方法。浆果赤霉素类化合物(Ⅲa)、(Ⅲb)、(Ⅲ-b)和(Ⅳa)的鉴定数据示于这些实施例之后。
实施例53
7,10-二TroC-14-羟基-10-脱乙酰基浆果赤霉素-Ⅲ-1,14-碳酸酯(Ⅲa)的制备
将14-羟基-10-脱乙酰基浆果赤霉素Ⅲ(14-OH-DAB)(910mg,1.63mmol)溶于18ml无水吡啶中。该溶液在80℃加热,并加入1ml氯甲酸三氯乙酯。搅拌5分钟后,再加入0.4ml氯甲酸三氯乙酯,并将该混合物(氯甲酸三氯乙酯的总量:1.4ml,2.15g,9.71mmol,约6倍相当量)搅拌30秒。从油浴中移出反应烧瓶,反应混合物用薄层色谱法(TLC)检验,以确证反应的完全程度。然后,加入几滴甲醇和一块冰,以除去过量的氯甲酸酯。反应混合物用氯仿萃取,萃取液用0.1 N盐酸和饱和盐水洗涤。用无水MgSO4干燥后,除去溶剂,残余物经硅胶柱色谱法纯化,用EtOAc/己烷(1∶1)作洗脱剂,得到1.16g(75%)白色固体状Ⅲa。Ⅲa的鉴定数据如下:1H NMR (CDCl3)δ1.20(s,3H,H17),1.28(s,3H,H16),1.88(s,3H,H19),2.08(m,1H,H6β),2.18(s,3H,H18),2.33,(s,3H,4-OAc),2.63(m,1H,H6α),3.75(bs,1H,H14),3.82(d,J=7.1 Hz,1H,H3),4.20(d,J=8.4Hz,1H,H20β),4.34(d,J=8.4Hz,1H,H20α),4.61(d,J=11.8Hz,1H,Troc),4.79(s,2H,Troc),4.91(d,J=11.8Hz,1H,Troc),4.97(bs,1H,H5),5.01(bs,1H,OH),5.01(bs,1H,H13),5.59,(dd,J=7.2,10.6Hz,1H,H7),6.10(d,J=7.1Hz,1H,H2),6.25(s,1H;H10),7.50(m,2H),7.65(m,1H),8.03(d,2H);13C NMR(CDC13)δ10.80,15.22,21.56,22.21,25.63,33.05,41.28,46.71,56.44,68.93,71.79,75.78,76.00,76.54,77.56,79.03,79.91,83.49,84.09,88.25,94.10,127.87,129.01,129.86,130.92,134.38,144.81,152.76,153.12,153.18,164.73,170.64,199.97.
实施例54
14-乙酰基-7,10-二Troc-14-羟基DAB(Ⅲb)的制备
在-10℃下,向594mg(0.654mmol)7,10-二Troc-14-羟基-10-脱乙酰基浆果赤霉素Ⅲ(Ⅲa)的30ml吡啶溶液中加入230ml(3.27mmol,5倍相当量)乙酰氯。将反应混合物在-10℃搅拌24小时。反应混合物用EtOAc萃取,用0.1N盐酸和盐水洗涤。萃取液用无水MgSO4干燥,真空浓缩,得到粗产物。粗产物用硅胶快速柱色谱法纯化,用EtOAc/己烷(1∶1)作洗脱剂,得到402mg(65%)Ⅲb,为白色固体,它具有下列鉴定数据:mp 225-226℃;1H NMR(CDCl3)δ1.10(s,3H),1.21(s,3H),1.88(s,3H),2.02(s,3H),2.05(m,1H,H6β),2.19(s,3H),2.38(s,3H),2.64(m,1H,H6α),2.74(s,1H,OH),3.19(bs,1H,OH),3.98(d,J=7.3 Hz,1H,H3),4.23(d,J=8.4 Hz,1H,H20α),4.30(d,J=8.4 Hz,1H,H20β),4.61(d,J=11.8Hz,1H,TROC),4.72(m,1H,H13),4.77(d,J=7.1 Hz,1H,TROC),4.91(d,J=11.8 Hz,1H,TROC),4.98(m,1H,H5),5.39(d,J=5.4 Hz,1H,H14),5.62(dd,J=7.1,10.5 Hz,1H,H7),5.84(d,J=7.3 Hz,1H,H2),6.30(s,1H,H10),7.44-7.62(m,2H),8.03-8.06(m,2H).元素分析计算值 C37H40Cl6O16:C,46.61;H,4.23.实测值:C,46.80;H,4.39.
实施例55
14-羟基-2-环己基羰基-2-脱苯甲酰基-10-脱乙酰基浆果赤霉素Ⅲ(Ⅲ-B)的制备
将14-羟基-10-脱乙酰基浆果赤霉素Ⅲ(500mg,0.899mmol)和5%Rh-C催化剂(50mg)在甲醇(8ml)和Et0Ac(2ml)中的悬浮液于50℃和900psi氢气压力下氢化36小时。将反应混合物冷却至室温后释放出氢气,滤出催化剂,真空蒸发溶剂,得到粗产物。粗产物用硅胶柱色谱法纯化,用EtOAc/己烷(1∶1)作洗脱剂,得到498mg(98%)Ⅲ-B,为白色固体,它具有下列鉴定数据:1H NMR(DMSO-d6)δ0.88(s,6H),1.46(s,3H),1.86(s,3H),2.14(s,3H),1.12-2.24(m,13H),3.59(m,2H),3.93(d,J=8.0 Hz,1H),3.99(d,J=7.0 Hz,1H),4.25(d,J=8.0 Hz,1H),4.36(m,1H),4.39(s,1H),4.76(d,J=2.0 Hz,1H),4.88(bd,J=9.1 Hz,1H),4.96(d,J=7.1 Hz,1H),5.08(d,J=2.0 Hz,1H),5.29(d,J=7.1 Hz,1H),5.45(d,J=5.2 Hz,1H),6.64(d,J=6.3Hz,1H);13C NMR (DMSO-d6)δ9.36,14.51,21.14,22.05,24.82,25.04,25.23,26.40,28.11,28.44,36.41,42.04,42.56,45.78,57.17,70.70,72.21,73.22,74.08,74.54,75.05,75.39,79.80,83.58,135.15,139.11,169.52,174.62,209.87.
实施例56
7,10-二TroC-14-羟基-10-脱乙酰基浆果赤霉素Ⅲ(Ⅳa)的制备
将14-羟基-10-脱乙酰基浆果赤霉素Ⅲ(14-OH-DAB)(900mg,1.61mmol)溶于18ml无水吡啶中。将溶液在80℃加热,并加入0.92ml(1.42g,6.44mmol,4倍相当量)氯甲酸三氯乙酯。搅拌5分钟后,从油浴中撤出反应瓶,反应混合物用薄层色谱法(TLC)检查,以确证反应完全程度。然后,加入几滴甲醇和一块冰,以便除去过量的氯甲酸酯。反应混合物用CHCl3萃取,萃取液用0.1N盐酸和饱和盐水洗涤。用无水MgSO4干燥,并除去溶剂,残余物用硅胶柱色谱法纯化,用EtOAc/己烷(1∶1)作洗脱剂,得到808mg(55%)Ⅳa,为白色固体:1H NMR(CDCl3)δ1.10(s,3H,H17),1.18(s,3H,H16),1.83(s,3H,H19),2.02(m,1H,H6β),2.14(s,3H,H18),2.30(s,3H,4-OAc),2.61(m,1H,H6α),3.22(m,1H,OH),3.61(s,1H,OH),3.66(m,1H,OH),3.89(d,J=7.1 Hz,H3),4.01(m,1H,H14),4.18(d,J=8.4 Hz,1H,H20β),4.28(d,J=8.4Hz,1H,H20α),4.60(d,J=11.9 Hz,1H,Troc),4.73(m,1H,H13),4.77(s,2H,Troc),4.83(d,J=11.9 Hz,1H,Troc),4.95(m,1H,H5),5.57(dd,J=7.1,10.6 Hz,1H,H7),5.79(d,J=7.1 Hz,1H,H2),6.24(s,1H,H10),7.40-7.60(m,3H),8.02(bd,2H).
实施例57-62描述了通过前述实施例中所制备的β-内酰胺类化合物(Ⅴ)和浆果赤霉素类化合物(Ⅲ)和(Ⅳ)进行偶合来合成本发明的紫杉烷类化合物。所述偶合反应在碱存在下、按路线3和4中所示方法进行。在实施例57中,在C7和C10位的羟基被保护,但是,脱去保护是在实施例58中进行。在实施例59中,进行了偶合反应与脱去保护反应,以合成紫杉烷类化合物Ⅰb和Ⅰc。
实施例57-62
7,10-二Troc-10-脱乙酰基-14-羟基-紫杉醇-1,14-碳酸酯(Ⅰa-diTroc)的合成
在-40℃下,于30分钟内,向浆果赤霉素Ⅲa(86.9mg,0.093mmol)和N-苯甲酰基-β-内酰胺Ⅴa-a-EE(47.3mg,0.14mmol)的3.0ml THF溶液中加入六甲基二硅氮烷基钠(NaHMDS)0.13ml(1.2eq,0.85M的THF溶液)。对反应混合物进行TLC分析表明,浆果赤霉素Ⅲa完全耗尽。反应混合物用10ml饱和NH4Cl溶液处理。反应混合物用乙醚(10ml×3)萃取,然后用二氯甲烷(10ml)萃取,合并的萃取液用盐水洗涤,用无水硫酸钠干燥,并浓缩,得到粗产物。该粗产物用柱色谱法纯化,用EtOAc/己烷(1/2)作洗脱剂,得到95.9mg 2′-EE-7,10-二Troc-10-脱乙酰基-14-羟基-紫杉醇-1,14-碳酸酯,为白色固体。该化合物用0.5N盐酸的THF溶液在室温下处理1小时。将反应混合物干燥,用硅胶色谱法纯化,用EtOAc/己烷(2/3)作洗脱剂,得到65.5mg(75%总产率)紫杉烷Ⅰa-diTroc,为白色固体,它具有下列鉴定数据:mp 178-180℃;[α]D 20-5.9°(c 0.85,CHCl3);1H NMR(CDCl3)δ1.30(s,6H,H16,H17),1.89 (s,3H,H19),1.92,(s,3H,H18),2.08(m,1H,H6β),2.56(s,3H,4-OAC),2.62(m,1H,H6α),3.81(d,J=7.4Hz,1H,H3),4.09(bs,1H,2′-OH),4.24(d,J=8.5Hz,1H,H20β),4.31,(d,J=8.5Hz,1H,H20α),4.60(d,J=11.9Hz,1H,Troc),4.76(s,2H,Troc),4.87-4.94(m,4H,Troc,H5,H2′,H14),5.55(dd,J=7.1,10.5Hz,1H,H7),5.93(dd,J=2.8,8.9Hz,1H,H3′),6.11(d,J=7.4Hz,1H,H2),6.19(s,1H,H10),6.47(d,J=6.2Hz,1H,H13),7.21(d,J=8.9Hz,1H,NH),7.31-7.64(m,11H),7.75(d,J=7.4Hz,2H),8.12(d,J=7.4Hz,2H);13C NMR(CDCl3)δ10.93,14.63,22.39,22.51.25.39,33.07,41.64,46.39,54.92,56.47,68.88,73.87,74.42,75.78,75.88,77.22,77.45,78.29,79.61,80.17,83.59,88.01,94.02,94.07,126.80,127.31,127.73,128.34,128.64,129.07(2),130.16,132.04,132.46,133.44,134.35,137.53,139.71,151.63,153.06,153.15,164.79,167.69,171.37,172.03,199.33;IR(CHCl3)3038,2951,1820,1761,1737,1667,1479,1379,1250,1220;元素分析计算值 C52H49NCl6O19:C,51.85;H,4.10;N,1.16.实测值:C,51.67;H,3.86;N,1.13.
实施例58
10-脱乙酰基-14-羟基-紫杉醇-1,14-碳酸酯(Ⅰa)的合成
将紫杉烷Ⅰa-diTroC(100mg)用Zn粉(200mg)在乙酸中于40℃处理几小时。反应混合物用玻璃滤器过滤,滤液经真空浓缩。残余物溶于CH2Cl2中,Zn盐经过滤除去,得到粗产物。该粗产物经EtOAc/己烷(3∶1)重结晶,得到纯的紫杉烷Ⅰa(48mg,72%),为白包粉末:1H NMR(CDCl3)δ1.21(s,3H),1.27(s,3H),1.78(s,3H),1.85(m,1H,H6β),2.04(s,3H),2.54(s,3H,4-OAc),2.56(m,1H,H6α),3.80(d,J=7.6 Hz,1H,H3),3.93(d,J=4.4Hz,1H,2′-OH),4.28(m,4H,H20,H7,OH),4.88(m,3H,H5,H14,H2′),5.16(s,1H,H10),5.93(m,1H,H3′),6.07(d,J=7.6 Hz,1H,H2),6.44(d,J=5.8 Hz,1H,H13),7.23-7.60(m,12H),7.73(bd,2H),8.14(bd,2H);13C NMR(CDCl3)δ10.10,14.22,14.39,21.11,22.17,22.61,25.57,36.67,41.62,45.97,54.71,57.86,60.47,69.43,71.63,73.82,73.99,74.66,76.18,77.27,79.76,80.43,84.13,88.37,126.79,127.40,127.91,128.28,128.59,129.07,130.22,131.98,133.56,134.25,135.76,136.22,137.67,151.89,165.02,167.67,171.09,172.06,209.76.
实施例59
13-[(2R,3S)-3-(叔丁氧羰基)氨基-2-羟基-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素-Ⅲ-1,14-碳酸酯(Ⅰb)的合成
在-30℃下于10分钟内,向浆果赤霉素Ⅲa(100mg,0.107mmol)和N-t-BOC-β-内酰胺Ⅴb-d-EE(52mg,0.155mmol)的3.0mlTHF溶液中加入NaHMDS 0.12ml(1.1eq,1.0M THF溶液)。反应混合物经TLC分析表明,浆果赤霉素Ⅲa完全耗尽。将反应混合物倾入盛有10ml饱和NH4Cl溶液的100ml烧杯中,以使反应中止。反应混合物用乙醚(10ml×3)萃取,然后用二氯甲烷(10ml)萃取,合并的萃取液用盐水洗涤,用无水硫酸钠干燥,并浓缩,得到浅黄色固体(170mg)。粗产物经硅胶柱色谱法纯化,用EtOAc/己烷(1/1)作洗脱剂,得到紫杉烷13-[(2R,3S)-3-(叔丁氧羰基)氨基-2-EEO-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素-Ⅲ-1,14-碳酸酯(Ⅰc-EE)(118mg.88%),为白色固体。该产物直接用于下一步骤中,以便同时脱去EE和Troc保护基。
粗紫杉烷Ⅰc-EE(157mg)用Zn粉(480mg)在2ml冰醋酸中于室温下处理8小时,然后将温度升至50℃,并在此温度下维持4小时。过滤溶液,将滤液倾入到冰冷的、饱和碳酸氢钠溶液(20ml)中。溶液用二氯甲烷(20ml)萃取,萃取液用无水MgSO4干燥,并浓缩,得到白色固体,将其经硅胶柱色谱法进一步纯化,用EtOAc/己烷(2/1)作洗脱剂,得到紫杉烷Ⅰc(63mg,总产率70%,按浆果赤霉素Ⅲa计),其具有下列鉴定数据:mp 190℃(分解.);[α]D 20 -22.83°(c,0.193,CHCl3);1H NMR(300 MHz,CDCl3)δ1.36(s,9H,t-Boc),1,77(s,3H,H19),1.82(m,1H,H6b),1.87(s,3H,H18),2.43(bs,3H,4-OAc),2.55(m,1H,H6a),3.69(bs,1H,OH),3.80(d,J=7.5 Hz,H3),4.20-4.30(m,3H,H20,H5),4.69(s,1H,OH),4.75(d,J=6.7 Hz,H14),4.92(d,J=8.5 Hz,1H,H7),5.19(s,1H,H10),5.30(m,1H,H3),5.62(d,J=8.6 Hz,1H,Hr),6.01(d,J=7.5 Hz,1H,H2),6.45(d,J=5.9Hz,1H,H13),7.51-7.64(m,8H),8.02(d,J=7.3 Hz);13CNMR(75 MHz,CDCl3)δ9.97,14.37,21.98,22.52,25.69,28.24,29.68,36.74,41.67,45.94,57.91,69.36,71.65,74.09,74.31,74.82,76.09,79.64,80.58,83.98,88.09,126.61,128.13,128.96,129.93,134.18,135.82,136.52,138.00,151.87,155.70,164.78,170.64,171.89,209.69;IR(净样)3403,2931,1817(amide),1734,1715,1703,1242,1085.元素分析计算值 C4H51NO16:C,62.18;H,6.05;N,1.65.实测值:C,61.91;H,6.33;N,1.61.
实施例60
14-[(2R,3S)-3-(N-苯甲酰基)氨基-2-羟基-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素Ⅲ(Ⅱa)的合成
在-40℃于30分钟内,向浆果赤霉素Ⅳa(79.6mg,0.09mmol)和N-苯甲酰基-β-内酰胺Ⅴa-a-EE(45.8mg,0.14mmol)的3.0ml THF溶液中加入NaHMDS 0.13ml(1.2eq,0.85M的THF溶液)。反应混合物经TLC分析表明,浆果赤霉素Ⅲa完全耗尽。反应混合物用10ml饱和NH4Cl溶液处理。反应混合物用乙醚(10ml×3)萃取,然后用二氯甲烷(10ml)萃取,合并的萃取液用盐水洗涤,用无水硫酸钠干燥,并浓缩,得到粗产物。该粗产物经硅胶柱色谱法纯化,用EtOAc/己烷(1∶3)作洗脱剂,得到90.2mg(82%)14-[(2R,3S)-3-(N-苯甲酰基)氨基-2-EEO-3-苯基丙酰基]-10-脱乙酰基-14-羟基-浆果赤霉素Ⅲ(Ⅱa-EE),为白色固体。该被保护的紫杉烷Ⅱa-EE用Zn在乙酸中于60℃处理9小时。反应混合物经玻璃滤器过滤,滤液经真空浓缩。残余物再溶于CH2Cl2中,Zn盐经过滤除去,得到粗产物。该粗产物经EtOAc/己烷(3∶1)作洗脱剂的硅胶柱色谱法纯化,得到33.7mg(75%)紫杉烷Ⅱa,为白色粉末,其具有下列鉴定数据:mp 198-202℃;[α]D 20-13.2(c 0.38,MeOH);1H NMR(CDCl3)δ1.17(s,3H),1.20(s,3H),1.74(s,3H,H19),1.84(m,1H,H6b),2.14(s,3H,H18),2.17(s,3H,4-OAc),2.60,(m,1H,H6a),3/07(bs,1H,2′-OH),4.03(d,J=6.6 Hz,1H,H3),4.14(d,J=8.4 Hz,1H,H20),4.27(m,3H,H20,H7,10-OH),4.55(m,1H,H2′),4.99(bd,1H,H5),5.07(m,1H,H13),5.17(d,J=5.8Hz,1H),5.34(s,1H,H10),5.65(d,J=5.7 Hz,1H,H14),5.83(bd,2H,H2,H3′),6.91(d,J=9.4 Hz,1H,NH),7.36-7.59(m,11H),7.77(bd,2H),8.15(bd,2H);13C NMR (CDCl3)δ9.53,15.32,20.66,22.08,26.03,29.69,37.06,42.85,46.50,54.68,58.00,71.63,72.06,73.60,75.03,76.60,77.12,78.82,80.31,83.98,127.10,127.24,128.25,128.42,128.84,129.04,130.62,132.51,133.59,135.04,137.89,140.68,166.49,168.13,170.86,172.12,211.58;IR(CHCl3)n 3632,3434,3026,3016,2943,2838,1724,1648;元素分析计算值 C25H49NO14:C,65.29;H,5.97;N,1.69.实测值:C,65.15;H,6.01;N,1.79.
该实施例包括脱去保护步骤,以得到紫杉烷(Ⅱa),如路线4所示。
实施例61
7,10-二Troc-14-[(2R,3S)-3-(叔丁氧羰基)氨基-2-羟基-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素Ⅲ(Ⅱb-diTroc)的合成
在-40℃于10分钟内,向50mg(0.055mmol)浆果赤霉素Ⅳa的10ml THF溶液中加入0.06ml(0.06mmol)NaHMDS。在-40℃加入25mg(0.083mmol)N-t-BOC-β-内酰胺Ⅴb-d-EE的THF溶液,并搅拌1小时。在-40℃加入饱和NH4Cl中止反应。分离有机层,水层用乙酸乙酯萃取。合并的有机萃取液用无水Na2CO3干燥,并真空浓缩。粗产物经硅胶柱色谱法纯化,用EtOAc/己烷(1∶3)作洗脱剂,得到54.2mg(82%)7,10-二Troc-14-[(2R,3S)-3-(叔丁氧羰基)氨基-2-EEO-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素Ⅲ(Ⅱb-diTroc-EE),为白色固体。该被保护的紫杉烷Ⅱb-diTroc-EE用0.5N HCl在THF中于室温下处理1小时。反应混合物用无水Na2CO3干燥,用硅胶柱色谱法纯化,用EtOAc,己烷(1∶3)作洗脱剂,得到40.0mg(81%)紫杉烷Ⅱb-diTroc,为白色粉末:1H NMR(CDCl3)δ1.19(s,3H,H17),1.24(s,3H,H16),1.45(s,9H),1.85(s,3H),2.03(m,1H,H6b),2.24(s,3H,H18),2.37(s,3H,4-OAC),2.65(m,1H,H6a),3/01(d,J=5.7 Hz,1H,OH),4.01(d,J=6.8 Hz,1H,H3),4.15(d,J=8.4 Hz,1H,H20),4.32(d,J=8.4 Hz,1H,H20),4.36(d,J=5.6Hz,1H,NH),4.62(d,J=11.8 Hz,1H),4.79(s,2H),4.92(d,J=11.8 Hz,1H),4.95-5.02(m,3H,H2′,H5,OH),5.18(d,J=9.5 Hz,1H,H13),5.34(d,J=9.5 Hz,1H,H14),5.63(dd,J=7.2,10.5 Hz,1H,H7),5.71(d,J=5.1 Hz,1H,H3′),5.84(d,J=6.8 Hz,1H,H2),6.34(s,1H,H10),7.29-7.60(m,8H),8.12(bd,2H);13C NMR(CDCl3)δ15.33,22.25,28.11,28.17,28.30,28.45,28.50,33.26,42.85,46.82,55.98,56.51,71.88,73.05,73.60,76.22,76.57,77.61,77.67,77.88,79.65,80.01,81.31,83.54,83.60,94.21,126.97,128.29,128.37,128.74,128.92,130.48,131.21,133.67,138.55,144.71,153.07,153.22,156.23,166.22,171.04,171.97,200.88;
该实施例表明,只有浆果赤霉素(Ⅳa)与用EE保护的β-内酰胺类化合物(Ⅴb-d)的偶合反应才能得到被保护的紫杉烷,如路线4所示。在本实施例中,所得到的紫杉烷是Ⅱb-diTroc。
实施例62
14-[(2R,3S)-3-(叔丁氧羧基)氨基-2-羟基-3-苯基丙酰基]-10-脱乙酰基-14-羟基浆果赤霉素Ⅲ(Ⅱb)的合成
在室温下向108mg(0.09mmol)Ⅱb-diTroc的2ml乙酸和3ml甲醇的溶液中加入240mg Zn(活化的)。将反应温度升至60℃,并搅拌混合物2小时。反应混合物经玻璃滤器过滤,滤液真空浓缩。残余物再溶于CH2Cl2中,过滤去除Zn盐,得到116mg粗产物。该粗产物经硅胶柱色谱法纯化,用EtOAc/己烷(4∶1)作洗脱剂,得到48.8mg(70%)紫杉烷Ⅱb,为白色粉末:1HNMR(CDCl3)δ1.15(s,3H),1.16(s,3H),1.45(s,9H),1.73(s,3H),1.81(m,1H,H6b),2.13(s,3H),2.36(s,3H),2.60(m,1H,H6a),3/03(d,J=5.7 Hz,1H,OH),4.02(d,J=6.9 Hz,1H,H3),4.17(d,J=8.5 Hz,1H,H20),4.25-4.34(m,4H,H2O,H7),4.83(d,J=6.0 Hz,1H),4.99(m,2H,H2′,H5),5.18(d,J=9.5 Hz,1H,H13),5.31(s,1H,H10),5.37(d,J=9.5 Hz,1H,H14),5.67(d,J=6.0 Hz,1H,H3′),5.83(d,J=6.9 Hz,1H,H2),7.31-7.56(m,8H),8.12(bd,2H);
本实施例说明Ⅱb-diTroc经脱保护步骤得到紫杉烷Ⅱb,如路线4所示。
上述方法描述了一种用于治疗癌症的、明显提高了效果的化合物的成熟和精致的制备方法。
因此,尽管已描述了目前所认为的本发明的优选实施方案,但是本领域技术人员将认识到,也可对本发明实施其他的进一步的改进,而不偏离本发明的真正精神实质,所述进一步的其他改进包括在本文的所附权利要求书范围内。
Claims (8)
1.下式(Ⅰ)或(Ⅱ)的化合物: 其中:
R1为苯基、甲苯基、4-甲氧基苯基、3,4-二甲氧基苯基、4-氟苯基、4-三氟甲基苯基、4-羟基苯基、1-萘基、2-萘基、吡啶基、呋喃基、噻吩基、吡咯基、N-甲基吡咯基、2-苯基乙烯基、2-呋喃基乙烯基、2-吡啶基乙烯基、2-噻吩基乙烯基、2-苯基乙基、2-环己基乙基、环己基甲基、丙基、异丙基、异丁基、叔丁基、异丁烯基、丁烯基、或环己基;
R2选自下列基团:苯基、甲苯基、4-氟苯基、4-氯苯基、4-甲氧基苯基、联苯基、1-萘基、2-萘基、异丙基、异丁基、新戊基、己基、庚基、环己基、环己基甲基、苄基、苯基乙基和苯基乙烯基;
或者R2为RO-,其中R选自下列基团:甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、异戊基、新戊基、己基、异己基、环己基、苯基、苄基和9-芴基甲基;
或者R2为RR’N-,并选自下列基团:甲氨基、乙氨基、丙氨基、异丙氨基、丁氨基、异丁氨基、叔丁氨基、新戊氨基、环己基氨基、苯氨基或苄氨基、二甲氨基、二乙氨基、二丙氨基、二丁氨基、二戊氨基、二己氨基、二环己基氨基、甲基(叔丁基)氨基、环己基(甲基)氨基、甲基(苯基)氨基、吡咯烷子基(pyrrolidiono)、哌啶子基、或吗啉代基团;
R3和R4选自下列基团:氢、乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基和三氟乙酰基、苯甲酰基、苯乙酰基、丙酰基、环丙基羰基、丙烯酰基、和丁烯基、肉桂酰基、烯丙基、苄基、甲氧基甲基、甲氧基乙基、1-乙氧基乙基、四氢吡喃基、2,2,2-三氯乙氧羰基、苄氧基羰基、叔丁氧羰基、9-芴基甲氧羰基、三甲基甲硅烷基、三乙基甲硅烷基、(叔丁基)二甲基甲硅烷基;
R5选自氢、乙酰基、氯乙酰基、烯丙基、苄基、丙烯酰基、丁烯基、和肉桂酰基,和
R6为氢;
或者,R5和R6连接起来形成的环状结构且连接起来的R5-R6选自下列基团:羰基、亚丙基、亚丁基、亚戊基、苯基亚甲基、二甲基亚甲基、二乙基亚甲基、二丙基亚甲基、二丁基亚甲基、甲氧基亚甲基、乙氧基亚甲基、亚甲基、1,2-亚乙基和1,2-亚丙基;
R7选自苯甲酰基和环己烷羰基;和
R8选自氢、1-乙氧基乙基、2,2,2-三氯乙氧羰基、三甲基甲硅烷基、三乙基甲硅烷基和叔丁基二甲基甲硅烷基。
2.权利要求1的化合物,其中:
R1为苯基、异丁基、异丁烯基或丁烯基;
R2为氢、苯基或叔丁氧基;
R3为氢、三乙基甲硅烷基或2,2,2-三氯乙氧羰基;
R4为氢、乙酰基、丙酰基或环丙基羰基;
R5和R6连接起来形成的环状结构且连接起来的R5-R6选自下列基团:羰基、亚丙基、亚丁基、亚戊基、苯基亚甲基、二甲基亚甲基、二乙基亚甲基、二丙基亚甲基、二丁基亚甲基、甲氧基亚甲基、乙氧基亚甲基、亚甲基、1,2-亚乙基和1,2-亚丙基;
R7为苯甲酰基;和
R8为氢或1-乙氧基乙基。
3.权利要求1的化合物,其中:
R1是苯基或异丁基;
R2是苯基或叔丁氧基;
R3是氢;
R4是氢或乙酰基;
R5和R6连接起来形成羰基;
R7是苯甲酰基;和
R8是氢。
4.权利要求3的化合物,其中:
R1是异丁基;
R2是叔丁氧基;
R4是乙酰基;
并且R3、R5、R6、R7和R8的定义与权利要求3中的定义相同。
其中R1、R2、R3、R4、R5、R6、R7和R8的定义同权利要求1,
该方法的特征在于:
(a)在碱存在下,使式(Ⅲ)或(Ⅳ)的浆果赤霉素与式(Ⅴ)的β-内酰胺类化合物反应: 其中:
G1是权利要求1中定义的R3或者是一个羟基保护基团;
G2是权利要求1中定义的R4或者是一个羟基保护基团;
G3是权利要求1中定义的R5或者是一个羟基保护基团;
G4是权利要求1中定义的R6或者是一个羟基保护基团;和
R7的定义同权利要求1中定义;
上述的羟保护基团选自:甲氧基甲基、甲氧基乙基、1-乙氧基乙基、苄氧基甲基、(β-三甲基甲硅烷基乙氧基)甲基、四氢呋喃基、2,2,2-三氯乙氧羰基、苄氧羰基、叔丁氧羰基、9-芴基甲氧羰基、2,2,2-三氯乙氧基甲基、三甲基甲硅烷基、三乙基甲硅烷基、三丙基甲硅烷基、二甲基乙基甲硅烷基、二甲基(叔丁基)甲硅烷基、二乙基甲基甲硅烷基、二甲基苯基甲硅烷基和二苯基甲基甲硅烷基;
其中G为选自下列的羟基保护基团:甲氧基甲基、甲氧基乙基、1-乙氧基乙基、苄氧基甲基、(β-三甲基甲硅烷基乙氧基)甲基、四氢呋喃基、2,2,2-三氯乙氧羰基、苄氧羰基、叔丁氧羰基、9-芴基甲氧羰基、2,2,2-三氯乙氧基甲基、三甲基甲硅烷基、三乙基甲硅烷基、三丙基甲硅烷基、二甲基乙基甲硅烷基、二甲基(叔丁基)甲硅烷基、二乙基甲基甲硅烷基、二甲基苯基甲硅烷基、二苯基甲基甲硅烷基、乙酰基、氯乙酰基、二氯乙酰基、三氯乙酰基和三氟乙酰基;
R1和R2的定义同权利要求1中定义;
其中所述碱选自:六甲基二硅氮烷基钠、六甲基二硅氮烷基钾、六甲基二硅氮烷基锂、二异丙基氨基钠、二异丙基氨基钾、二异丙基氨基锂、氢化钠、氢化钾、氢化锂、氢化钙、氢化镁、苯基锂、甲基锂、和丁基锂;和
(b)脱去所述羟基保护基团;并且任选地将得到的其中R3、R4、R5、R6和R8是氢原子的式(Ⅰ)或(Ⅱ)的化合物相互转换以形成其中R3、R4、R5、R和R8如权利要求1中定义的式(Ⅰ)或(Ⅱ)化合物。
6.一种具有抗肿瘤活性的药物组合物,其特征在于它包含权利要求1-4中任一项所述的化合物和可药用的载体。
7.权利要求1-4中任一项所述的化合物在制备用于治疗肿瘤的药物中的应用。
8.权利要求7的应用,其中所述的肿瘤选自卵巢、乳腺、非小细胞肺和结肠癌。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/040,189 | 1993-03-26 | ||
US08/040,189 US5475011A (en) | 1993-03-26 | 1993-03-26 | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1123547A CN1123547A (zh) | 1996-05-29 |
CN1067682C true CN1067682C (zh) | 2001-06-27 |
Family
ID=21909617
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN94192117A Expired - Fee Related CN1067682C (zh) | 1993-03-26 | 1994-03-24 | 抗肿瘤化合物、药物组合物、其制备方法以及其用于治疗的方法 |
Country Status (19)
Country | Link |
---|---|
US (3) | US5475011A (zh) |
EP (1) | EP0690856B1 (zh) |
JP (2) | JP3157165B2 (zh) |
KR (1) | KR100223720B1 (zh) |
CN (1) | CN1067682C (zh) |
AT (1) | ATE229018T1 (zh) |
AU (1) | AU676041B2 (zh) |
CA (1) | CA2158147C (zh) |
CZ (1) | CZ288924B6 (zh) |
DE (1) | DE69431833T2 (zh) |
DK (1) | DK0690856T3 (zh) |
ES (1) | ES2190440T3 (zh) |
HU (1) | HUT73848A (zh) |
NO (1) | NO311722B1 (zh) |
PL (2) | PL179587B1 (zh) |
PT (1) | PT690856E (zh) |
RU (1) | RU2137764C1 (zh) |
SK (1) | SK282317B6 (zh) |
WO (1) | WO1994022856A1 (zh) |
Families Citing this family (71)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6335362B1 (en) * | 1991-09-23 | 2002-01-01 | Florida State University | Taxanes having an alkyl substituted side-chain and pharmaceutical compositions containing them |
US5475011A (en) * | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
US6005120A (en) | 1993-07-20 | 1999-12-21 | Florida State University | Tricyclic and tetracyclic taxanes |
FR2718137B1 (fr) * | 1994-04-05 | 1996-04-26 | Rhone Poulenc Rorer Sa | Procédé de préparation de trialcoylsilyl-7 baccatine III. |
US5763477A (en) * | 1994-07-22 | 1998-06-09 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III |
IT1275936B1 (it) * | 1995-03-17 | 1997-10-24 | Indena Spa | Derivati della 10-deacetilbaccatina iii e della 10-deacetil-14b- idrossibaccatina iii loro metodo di preparazione e formulazioni |
BR9608040B1 (pt) | 1995-04-28 | 2010-02-23 | composto taxàide pentacÍclico. | |
IT1275435B (it) * | 1995-05-19 | 1997-08-07 | Indena Spa | Derivati della 10-desacetil-14beta-idrossibaccatina iii,loro metodo di preparazione e formulazioni che li contengono |
EP0747372A1 (en) * | 1995-06-06 | 1996-12-11 | Dr. Reddy's Research Foundation | Taxane derivatives from 14-beta-hydroxy-10 deacetybaccatin III |
US5840748A (en) * | 1995-10-02 | 1998-11-24 | Xechem International, Inc. | Dihalocephalomannine and methods of use therefor |
US5654448A (en) * | 1995-10-02 | 1997-08-05 | Xechem International, Inc. | Isolation and purification of paclitaxel from organic matter containing paclitaxel, cephalomannine and other related taxanes |
US5854278A (en) * | 1995-12-13 | 1998-12-29 | Xechem International, Inc. | Preparation of chlorinated paclitaxel analogues and use thereof as antitumor agents |
US6177456B1 (en) | 1995-10-02 | 2001-01-23 | Xechem International, Inc. | Monohalocephalomannines having anticancer and antileukemic activity and method of preparation therefor |
US5807888A (en) * | 1995-12-13 | 1998-09-15 | Xechem International, Inc. | Preparation of brominated paclitaxel analogues and their use as effective antitumor agents |
US5688977A (en) * | 1996-02-29 | 1997-11-18 | Napro Biotherapeutics, Inc. | Method for docetaxel synthesis |
DK0914102T3 (da) | 1996-05-24 | 2006-01-09 | Angiotech Pharm Inc | Præparater og fremgangsmåder til behandling eller forebyggelse af syddomme i legemskanaler |
WO1998000419A1 (en) * | 1996-07-02 | 1998-01-08 | Bristol-Myers Squibb Company | Ortho-ester analogs of paclitaxel |
KR100225535B1 (ko) * | 1996-08-27 | 1999-10-15 | 정지석 | 파클리탁셀의 제조방법 |
EP0868422A1 (de) * | 1996-09-24 | 1998-10-07 | Marigen S.A. | Ultramikroemulsionen aus spontan dispergierbaren konzentraten mit antitumoral und antiviral wirksamen estern von baccatin-iii-verbindungen |
US6515016B2 (en) * | 1996-12-02 | 2003-02-04 | Angiotech Pharmaceuticals, Inc. | Composition and methods of paclitaxel for treating psoriasis |
US5811452A (en) * | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
US7288665B1 (en) | 1997-08-18 | 2007-10-30 | Florida State University | Process for selective derivatization of taxanes |
WO1999008986A1 (en) * | 1997-08-21 | 1999-02-25 | Florida State University | Method for the synthesis of taxanes |
US6235776B1 (en) | 1998-11-12 | 2001-05-22 | Cell Pathways, Inc. | Method for treating a patient with neoplasia by treatment with a paclitaxel derivative |
US6235782B1 (en) | 1998-11-12 | 2001-05-22 | Rifat Pamukcu | Method for treating a patient with neoplasia by treatment with a platinum coordination complex |
ITMI991483A1 (it) * | 1999-07-06 | 2001-01-06 | Indena Spa | Derivati tassanici e procedimenti per la loro preparazione |
WO2001024763A2 (en) | 1999-10-01 | 2001-04-12 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
ATE349438T1 (de) * | 1999-11-24 | 2007-01-15 | Immunogen Inc | Cytotoxische wirkstoffe enthaltend taxane und deren therapeutische anwendung |
GEP20043239B (en) | 2000-02-02 | 2004-05-25 | Florida State Univ Research Foundation Us | C10 Carbonate Substituted Taxanes as Antitumor Agents |
US6649632B2 (en) | 2000-02-02 | 2003-11-18 | Fsu Research Foundation, Inc. | C10 ester substituted taxanes |
MXPA01009906A (es) * | 2000-02-02 | 2003-07-28 | Univ Florida State Res Found | Taxanos sustituidos con carbonato en c7 como agentes. |
US6916942B2 (en) * | 2000-02-03 | 2005-07-12 | Bristol-Myers Squibb Company | Process for the preparation of C-4 carbonate taxanes |
US6449899B1 (en) * | 2001-03-08 | 2002-09-17 | Council Of Scientific And Industrial Research | Method for inducing improved seed germination in Podophyllum hexandrum Royle |
ITMI20012186A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
MXPA05001390A (es) * | 2002-08-02 | 2005-07-29 | Immunogen Inc | Agentes citotoxicos que contienen taxanos potentes novedosos y su uso terapeutico. |
US7390898B2 (en) * | 2002-08-02 | 2008-06-24 | Immunogen Inc. | Cytotoxic agents containing novel potent taxanes and their therapeutic use |
ITMI20021921A1 (it) * | 2002-09-10 | 2004-03-11 | Indena Spa | Funzionalizzazione della posizione 14 dei nuclei tassanici e sintesi di nuovi derivati antitumorali. |
CA2501805C (en) * | 2002-10-09 | 2012-05-22 | Phytogen Life Sciences, Inc. | Novel taxanes and methods related to use and preparation thereof |
US7064980B2 (en) * | 2003-09-17 | 2006-06-20 | Sandisk Corporation | Non-volatile memory and method with bit line coupled compensation |
US7202370B2 (en) * | 2003-10-27 | 2007-04-10 | Conor Medsystems, Inc. | Semi-synthesis of taxane intermediates from 9-dihydro-13-acetylbaccatin III |
HN2005000054A (es) * | 2004-02-13 | 2009-02-18 | Florida State University Foundation Inc | Taxanos sustituidos con esteres de ciclopentilo en c10 |
TW200533339A (en) * | 2004-03-16 | 2005-10-16 | Bristol Myers Squibb Co | Therapeutic synergy of anti-cancer compounds |
US20060045877A1 (en) * | 2004-08-30 | 2006-03-02 | Goldmakher Viktor S | Immunoconjugates targeting syndecan-1 expressing cells and use thereof |
MX2007009748A (es) * | 2005-02-14 | 2007-09-26 | Univ Florida State Res Found | Composiciones de taxano sustituidas con esteres ciclopropilicos en c10. |
RS52438B (en) * | 2005-03-31 | 2013-02-28 | Accord Healthcare Inc. | PREPARATION OF 9-DIHYDRO-13-ACETYLBACCATINE TAXAN III |
EP2647641A1 (en) * | 2005-11-04 | 2013-10-09 | Accord Healthcare Inc. | New methods for the preparation of taxanes using chiral auxiliaries |
US7615653B2 (en) * | 2006-03-15 | 2009-11-10 | The Research Foundation Of State University Of New York | Anti-tuberculosis taxane compounds |
WO2008106491A2 (en) * | 2007-02-27 | 2008-09-04 | University Of Utah Research Foundation | Peptides that interact with topoisomerase i and methods thereof |
AR069979A1 (es) * | 2007-12-26 | 2010-03-03 | Biotest Ag | Metodo para disminuir los efectos secundarios citotoxicos y mejorar la eficacia de los inmunoconjugados |
PL2242772T3 (pl) * | 2007-12-26 | 2015-05-29 | Biotest Ag | Immunokonjugaty nakierowane na CD138 i ich zastosowanie |
ES2543201T3 (es) * | 2007-12-26 | 2015-08-17 | Biotest Ag | Métodos y agentes que mejoran la dirección a las células tumorales que expresan CD138 |
PT2238168E (pt) * | 2007-12-26 | 2014-07-18 | Biotest Ag | Agentes visando cd138 e suas utilizações |
DK2080764T3 (da) | 2008-01-18 | 2012-09-24 | Indena Spa | Faste former af ortataxel |
EP2080763A1 (en) * | 2008-01-18 | 2009-07-22 | INDENA S.p.A. | Crystalline form I of ortataxel |
US8242166B2 (en) * | 2008-03-31 | 2012-08-14 | Florida State University Research Foundation, Inc. | C(10) ethyl ester and C(10) cyclopropyl ester substituted taxanes |
KR101764081B1 (ko) | 2008-04-30 | 2017-08-01 | 이뮤노젠 아이엔씨 | 가교제 및 그 용도 |
CA2725535C (en) | 2008-05-23 | 2016-01-05 | The University Of British Columbia | Modified drugs for use in liposomal nanoparticles |
CN101838281B (zh) * | 2010-05-20 | 2015-02-18 | 上海博速医药科技有限公司 | 一种多西他赛手性侧链中间体的制备方法 |
TW201316990A (zh) | 2011-08-02 | 2013-05-01 | Astellas Pharma Inc | 藥劑併用之癌治療方法 |
CN104302324A (zh) | 2011-12-08 | 2015-01-21 | 生物测试股份公司 | 靶向cd138的免疫偶联物的用途 |
CN105849086B (zh) | 2012-11-24 | 2018-07-31 | 杭州多禧生物科技有限公司 | 亲水性链接体及其在药物分子和细胞结合分子共轭反应上的应用 |
JP6100627B2 (ja) * | 2013-06-24 | 2017-03-22 | 株式会社パイロットコーポレーション | 熱消色性筆記具インキ組成物及びそれを内蔵した筆記具 |
CN104650109B (zh) * | 2013-11-22 | 2019-01-01 | 江苏天士力帝益药业有限公司 | 紫杉烷类化合物 |
US10464955B2 (en) | 2014-02-28 | 2019-11-05 | Hangzhou Dac Biotech Co., Ltd. | Charged linkers and their uses for conjugation |
US9557445B2 (en) | 2015-02-24 | 2017-01-31 | Arkema France | Optical diffusion blend materials for LED lighting |
AU2015242213A1 (en) | 2015-07-12 | 2018-03-08 | Hangzhou Dac Biotech Co., Ltd | Bridge linkers for conjugation of cell-binding molecules |
US9839687B2 (en) | 2015-07-15 | 2017-12-12 | Suzhou M-Conj Biotech Co., Ltd. | Acetylenedicarboxyl linkers and their uses in specific conjugation of a cell-binding molecule |
US20210308277A1 (en) | 2016-11-14 | 2021-10-07 | Hangzhou Dac Biotech Co., Ltd. | Conjugation linkers, cell binding molecule-drug conjugates containing the linkers, methods of making and uses such conjugates with the linkers |
CA3092037A1 (en) | 2018-02-21 | 2019-08-29 | Celgene Corporation | Bcma-binding antibodies and uses thereof |
CN109485593A (zh) * | 2018-12-12 | 2019-03-19 | 福建紫杉园生物有限公司 | 一种拉洛他赛手性侧链的合成工艺 |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2629819B1 (fr) * | 1988-04-06 | 1990-11-16 | Rhone Poulenc Sante | Procede de preparation de derives de la baccatine iii et de la desacetyl-10 baccatine iii |
US4960790A (en) * | 1989-03-09 | 1990-10-02 | University Of Kansas | Derivatives of taxol, pharmaceutical compositions thereof and methods for the preparation thereof |
US5175315A (en) * | 1989-05-31 | 1992-12-29 | Florida State University | Method for preparation of taxol using β-lactam |
US5015744A (en) * | 1989-11-14 | 1991-05-14 | Florida State University | Method for preparation of taxol using an oxazinone |
US5015722A (en) * | 1990-04-04 | 1991-05-14 | Hoechst Celanese Corporation | Melt-processable polyester capable of forming an anisotropic melt which exhibits a highly attractive balance between its molding and heat deflection temperatures |
MX9102128A (es) * | 1990-11-23 | 1992-07-08 | Rhone Poulenc Rorer Sa | Derivados de taxano,procedimiento para su preparacion y composicion farmaceutica que los contiene |
IT1254517B (it) * | 1992-03-06 | 1995-09-25 | Indena Spa | 14-beta idrossi-10-deacetil-baccatina iii, suoi derivati, loro prepazione ed impiego terapeutico |
FR2698363B1 (fr) * | 1992-11-23 | 1994-12-30 | Rhone Poulenc Rorer Sa | Nouveaux dérivés du taxane, leur préparation et les compositions qui les contiennent. |
US5475011A (en) * | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
-
1993
- 1993-03-26 US US08/040,189 patent/US5475011A/en not_active Expired - Lifetime
-
1994
- 1994-03-24 KR KR1019950704147A patent/KR100223720B1/ko not_active IP Right Cessation
- 1994-03-24 PT PT94912300T patent/PT690856E/pt unknown
- 1994-03-24 RU RU95122773A patent/RU2137764C1/ru not_active IP Right Cessation
- 1994-03-24 CZ CZ19952480A patent/CZ288924B6/cs not_active IP Right Cessation
- 1994-03-24 CN CN94192117A patent/CN1067682C/zh not_active Expired - Fee Related
- 1994-03-24 DE DE69431833T patent/DE69431833T2/de not_active Expired - Lifetime
- 1994-03-24 SK SK1183-95A patent/SK282317B6/sk not_active IP Right Cessation
- 1994-03-24 DK DK94912300T patent/DK0690856T3/da active
- 1994-03-24 PL PL94310827A patent/PL179587B1/pl not_active IP Right Cessation
- 1994-03-24 JP JP52219294A patent/JP3157165B2/ja not_active Expired - Fee Related
- 1994-03-24 PL PL94338693A patent/PL180708B1/pl not_active IP Right Cessation
- 1994-03-24 ES ES94912300T patent/ES2190440T3/es not_active Expired - Lifetime
- 1994-03-24 CA CA002158147A patent/CA2158147C/en not_active Expired - Fee Related
- 1994-03-24 WO PCT/US1994/003215 patent/WO1994022856A1/en active IP Right Grant
- 1994-03-24 HU HU9502642A patent/HUT73848A/hu not_active Application Discontinuation
- 1994-03-24 EP EP94912300A patent/EP0690856B1/en not_active Expired - Lifetime
- 1994-03-24 AU AU64916/94A patent/AU676041B2/en not_active Ceased
- 1994-03-24 AT AT94912300T patent/ATE229018T1/de active
-
1995
- 1995-06-05 US US08/461,730 patent/US5599820A/en not_active Expired - Lifetime
- 1995-09-25 NO NO19953796A patent/NO311722B1/no not_active IP Right Cessation
- 1995-10-13 US US08/542,537 patent/US5705508A/en not_active Expired - Lifetime
-
1999
- 1999-04-09 JP JP10293599A patent/JP3145993B2/ja not_active Expired - Fee Related
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4876399A (en) * | 1987-11-02 | 1989-10-24 | Research Corporation Technologies, Inc. | Taxols, their preparation and intermediates thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1067682C (zh) | 抗肿瘤化合物、药物组合物、其制备方法以及其用于治疗的方法 | |
CN100351246C (zh) | 选择性衍生紫杉烷的方法 | |
CN1085553A (zh) | 脱氧红豆杉醇 | |
CN1080256C (zh) | 新的β-内酰胺类及制备紫杉烷的方法 | |
CN1102829A (zh) | 紫杉酚、紫杉酚类似物及其中间体的合成及它的组合物 | |
CN1261072A (zh) | 7-卤代和7β,8β-亚甲基-紫杉醇,抗肿瘤用途以及含其药物组合物 | |
CN101048394A (zh) | 太平洋紫杉醇向多烯紫杉醇的半合成转化 | |
CN1942460A (zh) | 紫杉烷衍生物的一锅合成及其向太平洋紫杉醇和多烯紫杉醇的转化 | |
CN1200731A (zh) | 半合成塔三烷用的中间体及其制备方法 | |
CN1151740A (zh) | 7-醚-紫杉酚类似物、抗肿瘤药物用途及含有它们的药物组合物 | |
CN1703409A (zh) | 新紫杉烷和用途及制备方法 | |
CN1286823C (zh) | 用于制备紫杉烷的噁唑烷中间体 | |
CN1205184C (zh) | β-内酰胺 | |
CN1082541A (zh) | 氟代红豆杉醇 | |
CN1856486A (zh) | 取代的内酰胺和它们作为抗癌剂的用途 | |
CN1075066C (zh) | 带烷基取代的侧链的紫杉烷及含该化合物的药物组合物 | |
CN1221539C (zh) | 紫杉烷衍生物 | |
CN1179955C (zh) | 制备紫杉醇及其衍生物的方法 | |
CN1098415A (zh) | 亚水杨基氨基过渡金属配合物及其制法 | |
CN1101346A (zh) | 碳2塔三烷衍生物和含有该衍生物的药物组合物 | |
CN1942473A (zh) | 生产五环紫杉烷的方法 | |
CN1244569C (zh) | C-10位紫杉烷衍生物及其药物组合物 | |
CN1129217A (zh) | 浆果赤霉素衍生物及其制备方法 | |
CN1468218A (zh) | 双环化合物的制备方法和及其中间体 | |
CN1681799A (zh) | 14位官能化的紫杉烷衍生物及其制备方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
C17 | Cessation of patent right | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20010627 Termination date: 20130324 |