CN1037774C - 紫杉烷的膦酰氧甲基醚衍生物 - Google Patents
紫杉烷的膦酰氧甲基醚衍生物 Download PDFInfo
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- CN1037774C CN1037774C CN93121100A CN93121100A CN1037774C CN 1037774 C CN1037774 C CN 1037774C CN 93121100 A CN93121100 A CN 93121100A CN 93121100 A CN93121100 A CN 93121100A CN 1037774 C CN1037774 C CN 1037774C
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- Prior art keywords
- compound
- och
- salt
- hydroxyl
- taxol
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- 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 title abstract description 32
- VBKBIDUVUIYPEC-UHFFFAOYSA-N phosphonooxymethoxymethyl dihydrogen phosphate Chemical class OP(O)(=O)OCOCOP(O)(O)=O VBKBIDUVUIYPEC-UHFFFAOYSA-N 0.000 title abstract description 10
- 150000001875 compounds Chemical class 0.000 claims abstract description 252
- 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 claims description 201
- 229930012538 Paclitaxel Natural products 0.000 claims description 196
- 229960001592 paclitaxel Drugs 0.000 claims description 188
- 229910052739 hydrogen Inorganic materials 0.000 claims description 168
- -1 acetoxyl group Chemical group 0.000 claims description 143
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 114
- 150000003839 salts Chemical class 0.000 claims description 60
- 239000001257 hydrogen Substances 0.000 claims description 59
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 42
- 239000001301 oxygen Substances 0.000 claims description 38
- 229910052760 oxygen Inorganic materials 0.000 claims description 38
- 125000002941 2-furyl group Chemical group O1C([*])=C([H])C([H])=C1[H] 0.000 claims description 34
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 28
- OMPJBNCRMGITSC-UHFFFAOYSA-N Benzoylperoxide Chemical group C=1C=CC=CC=1C(=O)OOC(=O)C1=CC=CC=C1 OMPJBNCRMGITSC-UHFFFAOYSA-N 0.000 claims description 27
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 27
- 229960003328 benzoyl peroxide Drugs 0.000 claims description 27
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical class OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 claims description 26
- 229910052731 fluorine Inorganic materials 0.000 claims description 26
- 239000011737 fluorine Substances 0.000 claims description 24
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical class CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 20
- 159000000000 sodium salts Chemical class 0.000 claims description 19
- 229910052799 carbon Inorganic materials 0.000 claims description 18
- 125000006239 protecting group Chemical group 0.000 claims description 18
- WSDQIHATCCOMLH-UHFFFAOYSA-N phenyl n-(3,5-dichlorophenyl)carbamate Chemical compound ClC1=CC(Cl)=CC(NC(=O)OC=2C=CC=CC=2)=C1 WSDQIHATCCOMLH-UHFFFAOYSA-N 0.000 claims description 16
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 15
- 150000001721 carbon Chemical group 0.000 claims description 14
- 125000001072 heteroaryl group Chemical group 0.000 claims description 14
- 230000004224 protection Effects 0.000 claims description 14
- 125000001476 phosphono group Chemical group [H]OP(*)(=O)O[H] 0.000 claims description 11
- 125000000882 C2-C6 alkenyl group Chemical group 0.000 claims description 10
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 claims description 9
- 150000004579 taxol derivatives Chemical class 0.000 claims description 9
- BMFMQGXDDJALKQ-BYPYZUCNSA-N Argininic acid Chemical class NC(N)=NCCC[C@H](O)C(O)=O BMFMQGXDDJALKQ-BYPYZUCNSA-N 0.000 claims description 8
- OBSLWIKITOYASJ-YDEIVXIUSA-N (3r,4r,5s,6r)-6-(hydroxymethyl)-3-(methylamino)oxane-2,4,5-triol Chemical class CN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O OBSLWIKITOYASJ-YDEIVXIUSA-N 0.000 claims description 7
- 125000005913 (C3-C6) cycloalkyl group Chemical group 0.000 claims description 6
- 150000002169 ethanolamines Chemical class 0.000 claims description 6
- 125000000175 2-thienyl group Chemical group S1C([*])=C([H])C([H])=C1[H] 0.000 claims description 5
- 239000005864 Sulphur Substances 0.000 claims description 5
- 229910052736 halogen Inorganic materials 0.000 claims description 5
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- 150000002367 halogens Chemical class 0.000 claims description 4
- 125000005843 halogen group Chemical group 0.000 claims description 3
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 2
- 125000003368 amide group Chemical group 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims 14
- 125000004890 (C1-C6) alkylamino group Chemical group 0.000 claims 1
- 125000003601 C2-C6 alkynyl group Chemical group 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 4
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 469
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 239
- 239000000243 solution Substances 0.000 description 171
- 235000019439 ethyl acetate Nutrition 0.000 description 156
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 118
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 109
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 107
- 238000000034 method Methods 0.000 description 97
- 238000006243 chemical reaction Methods 0.000 description 96
- 238000002360 preparation method Methods 0.000 description 94
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 89
- 238000003756 stirring Methods 0.000 description 87
- 239000000203 mixture Substances 0.000 description 78
- 238000005406 washing Methods 0.000 description 71
- 239000000047 product Substances 0.000 description 69
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 67
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 64
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 64
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 59
- 239000011541 reaction mixture Substances 0.000 description 51
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 50
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 45
- 238000005160 1H NMR spectroscopy Methods 0.000 description 42
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 40
- 239000011734 sodium Substances 0.000 description 39
- 238000004128 high performance liquid chromatography Methods 0.000 description 38
- 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 37
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 36
- 239000007789 gas Substances 0.000 description 36
- 238000010898 silica gel chromatography Methods 0.000 description 35
- 239000007787 solid Substances 0.000 description 35
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 33
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 32
- 239000002904 solvent Substances 0.000 description 31
- 239000000741 silica gel Substances 0.000 description 30
- 229910002027 silica gel Inorganic materials 0.000 description 30
- 229960001866 silicon dioxide Drugs 0.000 description 30
- 239000000706 filtrate Substances 0.000 description 28
- 238000001704 evaporation Methods 0.000 description 27
- 238000001035 drying Methods 0.000 description 26
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 25
- 229910052786 argon Inorganic materials 0.000 description 25
- 238000001914 filtration Methods 0.000 description 25
- 239000003999 initiator Substances 0.000 description 25
- 239000007864 aqueous solution Substances 0.000 description 24
- 229920006395 saturated elastomer Polymers 0.000 description 24
- 238000001816 cooling Methods 0.000 description 23
- LQZMLBORDGWNPD-UHFFFAOYSA-N N-iodosuccinimide Chemical compound IN1C(=O)CCC1=O LQZMLBORDGWNPD-UHFFFAOYSA-N 0.000 description 22
- 206010028980 Neoplasm Diseases 0.000 description 22
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 22
- 239000012044 organic layer Substances 0.000 description 22
- 239000002585 base Substances 0.000 description 21
- 239000000725 suspension Substances 0.000 description 21
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 19
- 239000000460 chlorine Substances 0.000 description 19
- 239000012141 concentrate Substances 0.000 description 19
- 238000003818 flash chromatography Methods 0.000 description 19
- CPZBTYRIGVOOMI-UHFFFAOYSA-N methylsulfanyl(methylsulfanylmethoxy)methane Chemical compound CSCOCSC CPZBTYRIGVOOMI-UHFFFAOYSA-N 0.000 description 19
- 239000012266 salt solution Substances 0.000 description 19
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 18
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 description 18
- 238000010265 fast atom bombardment Methods 0.000 description 18
- 239000012043 crude product Substances 0.000 description 17
- FPENSXCWDDOFJI-UHFFFAOYSA-N dihydroxidodioxidophosphorus(.) Chemical compound [O]P(O)(O)=O FPENSXCWDDOFJI-UHFFFAOYSA-N 0.000 description 17
- 239000003814 drug Substances 0.000 description 17
- 239000002808 molecular sieve Substances 0.000 description 17
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 17
- QMMFVYPAHWMCMS-UHFFFAOYSA-N Dimethyl sulfide Chemical compound CSC QMMFVYPAHWMCMS-UHFFFAOYSA-N 0.000 description 16
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 description 16
- 239000006260 foam Substances 0.000 description 16
- 125000004423 acyloxy group Chemical group 0.000 description 15
- 125000003118 aryl group Chemical group 0.000 description 15
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 15
- 238000001819 mass spectrum Methods 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 235000009518 sodium iodide Nutrition 0.000 description 15
- 239000004342 Benzoyl peroxide Substances 0.000 description 14
- 241000699666 Mus <mouse, genus> Species 0.000 description 14
- 229940123237 Taxane Drugs 0.000 description 14
- 239000002253 acid Substances 0.000 description 14
- 235000019400 benzoyl peroxide Nutrition 0.000 description 14
- 238000010790 dilution Methods 0.000 description 14
- 239000012895 dilution Substances 0.000 description 14
- 238000005984 hydrogenation reaction Methods 0.000 description 14
- 125000002816 methylsulfanyl group Chemical group [H]C([H])([H])S[*] 0.000 description 14
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- 229910052751 metal Inorganic materials 0.000 description 12
- 239000002184 metal Substances 0.000 description 12
- KZNICNPSHKQLFF-UHFFFAOYSA-N succinimide Chemical compound O=C1CCC(=O)N1 KZNICNPSHKQLFF-UHFFFAOYSA-N 0.000 description 12
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 12
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 11
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 11
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical group [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 11
- 210000004027 cell Anatomy 0.000 description 11
- DCFKHNIGBAHNSS-UHFFFAOYSA-N chloro(triethyl)silane Chemical compound CC[Si](Cl)(CC)CC DCFKHNIGBAHNSS-UHFFFAOYSA-N 0.000 description 11
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- HDFFVHSMHLDSLO-UHFFFAOYSA-N Dibenzyl phosphate Chemical compound C=1C=CC=CC=1COP(=O)(O)OCC1=CC=CC=C1 HDFFVHSMHLDSLO-UHFFFAOYSA-N 0.000 description 9
- 241001274216 Naso Species 0.000 description 9
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- 238000013019 agitation Methods 0.000 description 8
- 238000000354 decomposition reaction Methods 0.000 description 8
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 8
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 7
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 7
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- 230000003197 catalytic effect Effects 0.000 description 7
- CZKMPDNXOGQMFW-UHFFFAOYSA-N chloro(triethyl)germane Chemical compound CC[Ge](Cl)(CC)CC CZKMPDNXOGQMFW-UHFFFAOYSA-N 0.000 description 7
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- 229910052740 iodine Inorganic materials 0.000 description 7
- 239000011630 iodine Substances 0.000 description 7
- 229910052744 lithium Inorganic materials 0.000 description 7
- 125000004092 methylthiomethyl group Chemical group [H]C([H])([H])SC([H])([H])* 0.000 description 7
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- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 6
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- QHOINBKBMJLHPY-UHFFFAOYSA-N 2-chloroethyl formate Chemical compound ClCCOC=O QHOINBKBMJLHPY-UHFFFAOYSA-N 0.000 description 4
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- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
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Abstract
本发明涉及一种新的水溶性塔三烷膦酰氧甲基醚衍生物,它们作为抗肿瘤剂的应用以及含有该新化合物的药物组合物。
Description
本申请是我们1993年8月17日递交的共同未决申请08/108,015的部分继续申请,而后者是1992年12月24日递交,现已放弃的美国专利申请U.S.S.No7/996,455的部分继续申请。U.S.S.No8/108,015在这里全部加到本文中以作参考。
本发明涉及抗肿瘤化合物。更具体地说,本发明提供了新的紫杉烷衍生物、其药物组合物以及它们作为抗肿瘤剂的应用。
Taxol_(紫杉酚)是一种从太平洋紫杉树(Taxusbrevifolia)的树皮中提取的天然产物。在体内动物模型中它已显示出良好的抗肿瘤活性,最近的研究己阐明了其独特的作用模式,它包括微管蛋白的异常聚合和有丝分裂的破坏。最近,美国和法国正在对该产物的抗卵巢癌、乳腺癌和其它癌症的作用进行临床试验,并且初步结果已证实它是最有希望的化学治疗剂。Rowinsky和Donehower对紫杉酚 临床研究的结果进行了综述(见“TheClinical Pharmacology and Use of AnumicrotubuleAgents in Cancer Chemotherapeutics”,Phermac、Ther,52:35-84,1991。
最近已发现称作Taxotere_的紫杉酚的半合成类似物在动物模型中也具有良好的抗肿瘤活性。Taxotere_也已在欧洲和美国进行临床试验。紫杉酚和Taxotere_的结构显示如下,其中给出了紫杉酚分子的常规编号系统:
Taxol_:R=PH;R′=乙酰基
Taxotere_:R=叔丁氧基;R′=氢
紫杉酚的一个缺点是其水溶性极低,因此需要将它配制在非水溶性药物载体中。一种常用的载体是Cremophor EL,该载体本身对人有不良副作用。为此,大量的研究小组已制备出紫杉酚的水溶性衍生物,这些衍生公开在如下文献中:
(a)Haugwitz等人,美国专利4,942,184;
(b)Kingston等人,美国专利5,059,699;
(c)Stella等人,美国专利4,960,790 ;
(d)1993年9月8日公开的欧洲专利申请0,558,959A1,
(e)Vyas等人,Bioorganic & Medicnal ChemcstryLetter,1993,3:1357-1360;
(f)Nicolaou等人,Nature,1993,364:464-466。
本发明的化合物是紫杉烷的膦酰氧甲基醚衍生物及其可作药物的盐。该盐的水溶性有助于制备药物配方。
本发明涉及式(A)的塔三烷衍生物或其可作药物的盐: 其中T为在C13碳原子上带有取代3-氨基-2-羟基丙酰氧基的塔三烷;n为1、2或3;m为0或1-6的整数。
另一方面,本发明提供了具有式(B)的紫杉烷衍生物: 其中T′为其中非反应性羟基被封阻的T,m和n的定义同式(A)。
本发明也提供了具有式(C)的中间产物: 其中T′、m和n的定义同式(A),且RY为膦酰基保护基。
本发明也提供式(D)的化合物: 其中m和n的定义同上;txn为紫杉烷残基;或其C13金属醇盐。
本发明还提供了一种在哺乳动物宿主中抑制肿瘤的方法,它包括给该哺乳动物服用抗肿瘤有效量的式(A)化合物。
本发明还提供了一种药物组合物,它包括抗肿瘤有效量的式(A)化合物和可作药物的载体。
除非特别说明,以下定义适用于整个申请文本。
“烷基”指具有1-6个碳原子的直链或支链饱和碳链;其例子包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、正戊基、仲戊基、异戊基和正己基。“链烯基”指具有至少一个碳-碳双键且具有2-6个碳原子的直链或支链碳链;其例子包括乙烯基、丙烯基、异丙烯基、丁烯基、异丁烯基、戊烯基和己烯基。“炔基”指具有至少一个碳-碳三键且具有2-6个碳原子的直链或支链碳链;其例子包括乙炔基、丙炔基、丁炔基和己炔基。
“芳基”指具有6-10个碳原子的芳香烃;其例子包括苯基和萘基。“取代芳基”指被选自C1-6烷酰氧基、羟基、卤素、C1-6烷基、三氟甲基、C1-6烷氧基、芳基、C2-6链烯基、C1-6烷酰基、硝基、氨基和酰氨基的至少一个基团取代的芳基。“卤素”指氟、氯、溴和碘。
“膦酰基”指基团-P(O)(OH)2,“膦酰氧甲氧基”或“膦酰氧甲基醚”一般指基团-OCH2(OCH2)mOP(O)(OH)2。“(甲硫基)硫代羰基”指基团-C(S)SCH3。“甲硫基甲基”(也缩写为MTM)一般指基团-CH2SCH3。
“紫杉烷部分”(也缩写为txn)代表含有如下所示结构式及绝对构型的20个碳原子塔三烷核心骨架的部分:上面所示的编号系统是常规紫杉烷命名中所使用的系统,在整个申请文本中均使用这一系统。例如,符号C1指标记为“1”的碳原子;C5-C20氧环杂丁烷指通过标记为4、5和20的碳原子与氧原子形成的氧杂环丁烷环;C9氧指与标记为“9”的碳原子相连的氧原子;所述氧原子可以是氧代基团、α-或β-羟基,或α-或β-酰氧基。
“紫杉烷衍生物”(缩写为T)指带有C13侧链的紫杉烷部分的化合物。
“杂芳基”指含有至少一个、至多四个选自氧、硫和氮的非碳原子的五元或六元芳香环。杂芳基的例子包括噻吩基、呋喃基、吡咯基、咪唑基、吡唑基、噻唑基、异噻唑基、噁唑基、异噁唑基、三唑基、噻二唑基、噁二唑基、四唑基、噻三唑基、噁三唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、三嗪基、四嗪基等。
“膦酰基保护基”指用以封阻或保护膦酰官能基团的基团;优选的这类保护基是能够利用不显著影响分子其余部分的方法除去的基团。合适的膦酰基保护基是本领域熟练技术人员熟知的,其例子包括苄基和烯丙基。
“羟基保护基”包括,但不限于:成醚类,如甲基、叔丁基、苄基、对-甲氧基苄基、对-硝基苄基、烯丙基、三苯甲基、甲氧甲基、甲氧乙基甲基、乙氧乙基、四氢吡喃基、四氢硫代吡喃基和三烷基甲硅烷基,如三甲基甲硅烷基和叔丁基二甲基甲硅烷基;成酯类,如苯甲酰基、乙酰基、苯乙酰基、甲酰基、单-、二-和三卤乙酰基(如氯代乙酰基、二氯乙酰基、三氯乙酰基、三氟乙酰基);成碳酸酯类。如甲基、乙基、2,2,2-三氯乙基、烯丙基、苄基和对-硝基苯基。
羟基和膦酰基保护基的其它例子可从例如下列普通参考著作中找到:Greene和Wuts,Protective Groups in OrganicSynthesis,2d,Ed.,1991,John Wiley & Sons,以及McOmie,Protctcie Groups in Organic Chemistry,1975,Plenum Press。从这类参考书中也可找到加入和除去保护基的方法。
“可作药用的盐”指酸性膦酰基团的金属盐或胺盐,其中阳离子对活化化合物的毒性或生物活性无显著作用。合适的金属盐包括锂盐、钠盐、钾盐、钙盐、钡盐、镁盐、锌盐和铝盐。优选的金属盐是钠盐和钾盐。合适胺盐的例子有:氨、三甲醇氨基甲(TRIS)、三乙胺、普鲁卡因、苯乍生、二苄基胺、氯普鲁卡因,胆碱、二乙醇胺、三乙醇胺、乙二胺、葡糖胺、N-甲基葡糖胺、赖氨酸、精氨酸、乙醇胺等。优选的胺盐是赖氨酸盐、精氨酸盐和N-甲基葡糖胺盐。
在本说明书及权利要求书中,术语-OCH2(OCH2)mOP(O)(OH)2总包括游离酸及其可作药物的盐,除非明确提到指游离酸。
一方面,本发明提供了式(A)的紫杉烷衍生物或其可作药用的盐: 其中T为在C13碳原子上带有取代的3-氨基-2-羟基丙酰氧基的塔三烷基团;n为1、2或3;m为0或1-6的整数。
在一实施方案中,紫杉烷残基至少含有以下官能基:C1-羟基、C2-苯甲酰氧基、C4-乙酰氧基、C5-C20氧杂环丁烷、C9-氧和C11-C12双键。
在一优选实施方案中,紫杉烷残基得自下式残基:其中R2e′为氢原子,且R2e为氢原子、羟基、OC(O)Rx或-OC(O)ORx;或R2e为氢原子,且R2e′为氟原子;R3e为氢原子、羟基、OC(O)Rx、C1-6烷氧基或-OC(O)ORx;R6e和R7e之一为氢原子,且另一个为羟基或-OC(O)Rx;或R6e和R7e共同形成氧代基团;Rx的定义同下。
在另一实施方案中,C13侧链得自下式残基:其中R1e为氢原子或-C(O)Rx、-C(O)ORx;R4和R5独立地为C1-6烷基、C2-6链烯基、C1-2链炔基或-Z-R6;Z为一直接键、C1-6烷基或C2-6链烯基;R6为芳基、取代芳基、C3-6环烷基或杂芳基;Rx为被1-6个相同或不同的卤原子非限制性地取代的C1-6烷基、C3-6环烷基、C2-6链烯基或下式残基:其中D为一键或C1-6烷基;Ra、Rb和Rc独立地为氢原子、氨基、C1-6烷氨基、二-C1-6烷氨基、卤原子、C1-6烷基或C1-6烷氧基;P为0或1。
在一优选实施方案中,R4为C1-6烷基且P为1,或R4为-Z-R6且P为0。更优选的是R4(O)p为叔丁氧基、苯基、异丙氧基、正丙氧基或正丁氧基
在另一优选实施方案中,R5为C2-6链烯基或-Z-R6,且Z和R6的定义同前。更优选的是,R5为苯基、2-呋喃基、2-噻吩基、异丁烯基、2-丙烯基或C3-6环烷基。
在另一实施方案中,式(A)化合物可更具体地由下式或其可作药物的盐表示:其中R1为羟基、-OCH2(OCH2)mOP(O)(OH)2、-OC(O)Rx或-OC(O)ORx;R2′为氢原子,且R2为氢原子、羟基、-OCH2(OCH2)mOP(O)(OH)2或-OC(O)ORx;或R2′为氟原子,且R2为氢原子;R3为氢原子、羟基、乙酰氧基、-OCH2(OCH2)mOP(O)(OH)2或-OC(O)ORx;R6和R7之一为氢原子,且另一个为羟基、C1-6烷酰氧基或-OCH2(OCH2)mOP(O)(OH)2;或R6和R7共同形成氧代基;条件是R1、R2、R3、R6或R7中至少一个为-OCH2(OCH2)mOP(O)(OH)2;R4、R5、Rx、m和P的定义同前。
式(I)化合物中,Rx的例子包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、氯代甲基、2,2,2-三氯乙基、环丙基、环丁基、环戊基、环己基、乙烯基、2-丙烯基、苯基、苄基、溴代苯基、4-氨基苯基、4-甲氨基苯基、4-甲基苯基、4-甲氧基苯基等。R4和R5的例子包括2-丙烯基、异丁烯基、3-呋喃基、3-噻吩基、苯基、萘基、4-羟基苯基、4-甲氧基苯基、4-氟苯基、4-三氟甲基苯基、甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、乙烯基、2-丙烯基、2-丙炔基、苄基、苯乙基、苯基乙烯基、3,4-二甲氧基苯基、2-呋喃基、2-噻吩基、2-(2-呋喃基)乙烯基、2-甲基丙基、环丙基、环丁基、环戊基、环己基、环己基甲基、环己基乙基等。
在一优选实施方案中,本发明提供了其中R5为C2-6链烯基或-Z-R6且Z和R6的定义同前的式(I)化合物。更优选的是,R5为苯基、3-呋喃基、3-噻吩基、2-丙烯基、异丁烯基、2-呋喃基、2-噻吩基或C3-6环烷基。
在另一优选实施方案中,式(I)化合物中的R4为C1-6烷基,在此情况下P为1;或R4为-Z-R6且Z和R6的定义同前,在此情况下P为0。更优选的是R4(O)p-为叔丁氧基、苯基、异丙氧基、正丙氧基、正丁氧基。
在另一优选实施方案中,本发明提供了其中R1为-OCH2(OCH2)mOP(O)(OH)2的式(I)化合物。在一更优选的实施方案中,R2为羟基、-OCH2(OCH2)mOP(O)(OH)2或-OC(O)Rx,且Rx优选为C1-6烷基。在另一更优选的实施方案中,R3为羟基或乙酰氧基。
在另一优选实施方案中,本发明提供了其中R2为-OCH2(OCH2)mOP(O)(OH)2;R1为羟基或-OC(O)ORx;R3为氢原子、羟基、乙酰氧基、-OCH2(OCH2)mOP(O)(OH)2或-OC(O)ORx且Rx的定义同前的式(I)化合物。在一更优选的实施方案中,R1为羟基-OC(O)ORx,且Rx优选为C1-6烷基;R3为羟基或乙酰氧基。
在另一优选实施方案中,本发明提供了其中R3为-OCH2(OCH2)mOP(O)(OH)2;R1为羟基或-OC(O)ORx;R2′为氢原子,且R2为氢原子、羟基或-OC(O)ORx;或R2′为氟且R2为氢原子;且Rx的定义同前的式(I)化合物。在一更优选的实施方案中,R1为羟基或-OC(O)ORx,且Rx优选为C1-6烷基。在另一更优选实施方案中R2为羟基。
在另一优选实施方案中,当膦酰氧甲氧基存在于塔三烷残基的C7上时m为0或1。
优选的式(A)化合物的可作药物的盐是碱金属盐,包括锂盐、钠盐和钾盐;胺盐,包括三乙胺盐、三乙醇胺盐、乙醇胺盐、精氨酸盐、赖氨酸盐和N-甲基葡糖胺盐。更优选的盐是精氨酸盐、赖氨酸盐和N-甲基葡糖胺盐。
式(A)塔三烷衍生物的最优选实施方案包括如下化合物:(1)7-O-膦酰氧甲基紫杉酚;(2)2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚;(3)2′-O-膦酰氧甲基紫杉酚;(4)2′,7-双-O-(膦酰氧甲基)紫杉酚;(5)3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚;(6)3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚;(7)10-脱乙酰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(膦酰氧甲基)紫杉酚;(8)2′-O-膦酰氧甲氧甲基紫杉酚;以及它们各自的可作药物的盐,尤其是钠盐、钾盐、精氨酸盐、赖氨酸盐、N-甲基葡糖胺盐、乙醇胺盐、三乙胺盐和三乙醇胺盐。
由塔三烷衍生物起始物T-〔OH〕n(其中T和n的定义同前)可制备出式(A)化合物。T-〔OH〕n的身分无特殊限制,只要它们在紫杉烷残基上或在C13侧链上存在至少一个反应性羟基,以便形成膦酰氧甲基醚连接键。应当理解的是,反应性羟基可直接连接于C13丙酰氧主链上(如紫杉酚的2′-羟基)或连接于紫杉烷核心骨架上(如紫杉酚的7-羟基);或者它存在于C13侧链取代基或紫杉烷核心上的取代基上。反应流程I所示的反应秩序可用于制备式(A)化合物:反应流程I
反应流程I中T′为其中非反应性羟基已被保护的紫杉烷衍生物;Ry为膦酰基保护基;n和m的定义同前。这样,被适当保护的、带有一个或多个反应性羟基的T′首先被转化为式(B)的相应甲硫基甲基醚。以紫杉酚举例,T′可以是紫杉酚本身(以影响2′,7-双甲硫基甲基化)、7-O-三乙基甲硅烷基紫杉酚或2′-O-乙氧羰基紫杉酚。用二甲基亚砜/乙酸酐或用二甲硫和一种有机过氧化物处理T′-〔OH〕n可制备出其中m为0的式(B)化合物。这些反应将在后继部分更详细地讨论。带有一个间隔亚甲氧基单元的MTM醚(即m=1的式(B)化合物)可通过多种可能的途径制得。一种途径是将m=0的式(B)化合物与碘代琥珀酰亚氨(NIS)和甲硫基甲醇反应,致使该链延长一个亚甲氧基单元:
甲硫基甲醇化合物及其制备方法在Syn.Comm.,1986,16(13):1607-1610中已有报道。
在另一替代方法中,是用正丁基锂、二异丙基氨化锂或六甲基二硅叠氮化锂等碱处理式(Aa)化合物,得到T-醇盐(Ad),然后将Ad与氯甲基甲硫基甲基醚反应,得到其中m=1的式(B)化合物。
化合物(Ae)是通过甲硫基甲醇盐(由甲硫基甲醇与正丁基锂、二异丙基氨化锂或六甲基二硅叠氮化锂反应得到)与氯碘甲烷反应制得。化合物(Ae)也可通过用化学计算量或更少量(如约0.8当量)碘化钠处理1,1′-二氯二甲基醚(ClCH2OCH2Cl),然后再用硫代甲醇钠处理而制得。1,1′-二氯二甲基醚在Ind.J.Chem.,1989,28B,pp.454-456中已有报道。
在另一方法中,是将式(Aa)化合物与双(MTM)醚、CH3SCH2OCH2SCH3和NIS反应,得到其中m=1的式(B)化合物。
双(MTM)醚是通过用碘化钠及硫代甲醇钠处理1,1′-二氯二甲基醚制得。
可将上述使用甲硫基甲醇和NIS的方法应用于具有MTM基团的任何试剂,使其链一次延长一个亚甲氧单元。例如,可将其中m=1的式(B)化合物与甲硫基甲醇和NIS反应,得到其中m=2的式(B)化合物。重复该方法可得到其中m为3、4、5或6的式(B)化合物。
在反应流程I所示的第二步骤中,甲硫基甲基醚被转化成相应的被保护的膦酰氧甲基醚。它是通过用NIS和被保护的磷酸酯HOP(O)(ORy)2处理MTM醚而完成的。在第三步骤中,膦胺基保护基和所有羟基保护基均被除去,得到式(A)化合物。例如,合适的膦酰基保护基苄基可通过催化氢解除去,羟基保护基如三烷基甲硅烷基可用氟化物离子除去,三氯乙氧羰基可用锌除去。除去保护基的方法可从下列教科书中查到:Green和Wuts,ProtectiveGroups in Organic Synthesis,John Wiley &Sons,1991;和Mc Omie,Proteitive in OrganicChemistry,Plenum Press 11973。上述两个步骤将在说明书的后继部分详细讨论。
反应流程II中,式(Aa)化合物与式(Ca)化合物和NIS反应,得到式(C)化合物,然后经脱保护得到式(A)化合物。其中m为0的式(Ca)化合物可通过首先用六甲基二硅叠氮化钠、锂或钾等碱处理甲硫基甲醇,然后将所得到的甲硫基甲醇与被保护的氯代磷酸酯(如氯代磷酸二苄基酯)反应而制得。其中m为1的式(Ca)化合物可通过用双保护的磷酸酯盐(如磷酸二苄基酯的钠盐、钾盐、四(正丁基)铵盐)处理CH3SCH2OCH2Cl制得;或者通过首先用碘化钠将CH3SCH2OCH2Cl转化为相应的碘代化合物,然后与磷酸酯盐反应制得。或者,其中m为1的式(Ca)化合物可通过用碘化钠和硫代甲醇钠处理ClCH2OCH2Cl;然后用NIS和双保护的磷酸酯(如磷酸二苄基酯)处理CH3SCH2OCH2SCH3而制得。任何带有MTM基团的前述试剂可通过与甲硫基甲醇和NIS反应而一次延长一个亚甲氧单元。
反应流程III中,碘代磷酸酯化合物是通过将ClCH2(OCH2)mCl与双保护的磷酸酯盐反应,然后将所产生的ClCH2(OCH2)mOP(O)(ORy)2与碘化钠反应而得到。
反应流程IV显示了另一种合用于制备一小类式(A)化合物的方法,其中至少一个膦酰氧甲氧基与塔三烷残基相连。反应流程IV
反应流程IV中,m和n的定义同前;X为非氢基团,P为羟基保护基;txn为塔三烷残基。式(D)化合物是具有13α-羟基和一个或多个直接或间接与塔三烷核心相连的甲硫基甲基醚的塔三烷;且也包括式(D)的C13金属醇盐。式(D)化合物的例子是7-O-甲硫基甲基浆果赤霉素III:
塔三烷(D)与氮杂环丁酮的偶联反应与反应流程VI中所示的类似;因此其中所示的用以制备式(Id)化合物的方法也可应用于制备式(Ba)化合物〔即其中至少一个MTM基团直接或间接与紫杉烷残基相连的式(B)化合物〕,只要将式(D)化合物代替反应流程VI中的式(II)化合物。塔三烷(D)优选首先被转化为C13金属醇盐,如醇钠、醇钾或醇锂;优选醇锂。氮杂环丁酮是用作C13侧链的前体。与紫杉烷偶联后,除去羟基保护基P,并根据需要将侧链上的游离羟基转化为MTM醚,或如下面所述衍生为酯或碳酸酯。
氮杂环丁酮可用后面所述方法制备,该方法也是本领域普通方法。利用合适保护的紫杉烷,通过上面所述的制备(B)的一般方法可制备出式(D)化合物。但更方便的是,通过用氢硼化物(如氢硼化钠或氢硼化四丁铵)断裂13-侧链可由式(Ba)化合物得到式(D)化合物;例如,用氢硼化四丁铵处理7-O-MTM,可得到7-O-MTM浆果赤霉素III。
反应流程V更具体地说明了反应流程I中制备式(A)化合物的一般方法,它说明的是式(I′)化合物(即其中m为0的式(I)化合物)的制备方法。这一合成次序中使用的方法可通用于未由式(I)具体包括的其它塔三烷衍生物。而且,本领域技术人员可依照这里所公开的内容对反应流程(V)的方法进行改进,以获得其中m为1或2的式(A)塔三烷衍生物。
应当知道,反应流程V及说明书其它各处的术语“羟基保护基”可包括碳酸酯基(-OC(O)ORx);因此,当利用碳酸酯基作为羟基保护基时,应在后继步骤中将其除去,以产生游离羟基,否则碳酸酯残基将成为终产物的一部分。反应流数V
反应流程V中,R1a为羟基、被保护羟基、-OC(O)Rx或-OC(O)ORx;R2′为氢原子,且R2a为氢原子、羟基、被保护羟基或-OC(O)ORx;或R2′为氟,且R2a为氢原子;R3a为氢原子、羟基、被保护羟基、乙酰氧基或-OC(O)ORx;R6a和R7a之一为氢原子,且另一个为羟基、被保护羟基或C1-6烷酰氧基;或R6a和R7a共同形成一氧代基团;条件是R1a、R2a或R3a、R6a或R7a中至少一个为羟基。R16为羟基、被保护羟基、-OCH2SCH3;-OC(O)Rx或
-OC(O)ORx;R2′为氢原子,且R2b为氢原子、羟基、被保护羟基、-OCH2SCH3或-OC(O)ORx;或R2′为氟,且R2b为氢原子;R3b为氢原子、羟基、被保护羟基、乙酰氧基、-OCH2SCH3或-OC(O)ORx;R6b和R7b之一为氢原子且另一个为羟基、被保护羟基、C1-6烷酰氧或-OCH2SCH3;或R6b和R7b共同形成一氧代基团;条件是R1b、R2b、R3b、R6b和R7b中至少一个为-OCH2SCH3。R1c为羟基、被保护羟基、-OCH2OP(O)(ORy)2、-OC(O)Rx或-OC(O)ORx;R2′为氢原子,R2c为氢原子、羟基、被保护羟基、-OCH2OP(O)(ORy)2或-OC(O)ORx;或R2′为氟,且R2c为氢原子;R3c为氢原子、羟基、被保护羟基、乙酰氧基、-OCH2OP(O)(ORy)2或-OC(O)ORx;R6c或R7c之一为氢原子且另一个为羟基、被保护羟基、C1-6烷酰氧基或-OCH2OP(O)(ORy)2;条件是R1c、R2c、R3c、R6c和R7c中至少一个为-OCH2OP(O)(ORy)2。R1′为羟基、-OCH2OP(O)(OH)2、-OC(O)ORx或-OC(O)ORx;R2_为氢;且R2″为氢原子、羟基、-OCH2OP(O)(OH)2或-OC(O)ORx;或R2_为氟,且R2_为氢原子;R3′为氢原子、羟基、乙酰氧基、-OCH2OP(O)(OH)2或-OC(O)ORx;R6′和R7′之一为氢原子,另一个为羟基、C1-6烷酰氧基或-OCH2P(O)(OH)2;条件是R1′、R2″、R3′、R6′和R7′中至少一个为-OCH2OP(O)(OH)2、R4、R5和Rx的定义同前,且Ry为膦酰基保护基。
在第一步骤中,式(Ia)化合物的游离羟基被转化成相应的甲硫基甲基醚(-OCH2SCH3)基团。这一转化可通过方法1a(二甲硫法)或方法1b(二甲亚砜法)完成。将醇转化为甲硫基甲基醚的二甲硫法在Medina等人,Tet.Lett.,1988,pp 3773-3776中已有报道,其相应部分并入本文以作参考。二甲亚砜法是广泛熟悉的Pummerer反应。
应当注意,羟基的反应性随其在式(Ia)紫杉烷衍生物起始物中的位置不同而变化。虽然一般来说,2′-羟基在酰化反应中比7-羟基更易反应,而7-羟基则比10-羟基更易反应。但现已惊奇地发现,7-羟基比2′-羟基更易于转化为甲硫基甲基醚。C-1上的叔羟基一般反应性最低。羟基反应性上的差异可被用于控制甲硫基甲基化的位点和程度。
因此,利用其中R1a和R2a均为羟基的式(Ia)化合物所获得的主要甲硫基甲基化产物是相应的7-O-甲硫基甲基醚。为了获得其中R16为甲硫基甲氧基的式(Ib)化合物,若7-羟基存在而又未转化为甲硫基甲基醚,则可用常规的羟基保护基(如三乙基甲硅烷氧基)保护7-羟基。同样,当用相同或不同的羟基保护基保护可能存在的、又未被转化的7-和/或2′-羟基时,可得到10-甲硫基甲基醚。尽管7-羟基是优选的甲硫基甲基化位点,但如果所需产物是7-单甲硫基甲基醚,仍优选保护2′-羟基。
而且,可对反应条件进行控制,以有利于双-或三-甲硫基甲基醚紫杉烷衍生物的形成。例如,在紫杉酚的情况下,提高反应时间或使用较大过量的甲硫基甲基化试剂可导致产物混合物中2′,7-双(甲硫基甲基)醚紫杉酚比率较高。
现在回到反应流程V。在方法(Ia)中,用二甲硫和有机过氧化物(如过氧化苯甲酰)处理式(Ia)化合物。反应是在有利于产物形成的温度下于惰性有机溶剂(如乙腈、二氯甲烷等)中进行;通常是在-40℃至室温的温度范围内进行。二甲硫和过氧化苯甲酰相应于塔三烷衍生物起始物(Ia)过量使用,且二甲硫相对于过氧化苯甲酰过量使用。
所用起始物的相对量取决于所要达到的甲硫基甲基化程度。因此,当要将紫杉烷衍生物起始物(Ia)的一个游离羟基转化为甲硫基甲基醚时,二甲硫和过氧化苯甲酰相对于紫杉烷衍生物(Ia)最高达10倍过量地使用;且优选以2-3倍过量于过氧化苯甲酰的量使用二甲硫。在起始物(Ia)具有2′-和7-羟基的情况下,所得2′,7-双(甲硫基甲基)醚的量随二甲硫和过氧化苯甲酰相对量的增加而增加。当所需产物为2′,7-双(甲硫基甲基)醚时,优选使用15-20倍过量于紫杉烷衍生物起始物的二甲硫;且使用约5-10倍过量于紫杉烷衍生物起始物的过氧化苯甲酰。
也可通过将式(Ia)化合物与二甲亚砜和乙酸酐反应制备式(Ib)化合物(方法1b)。该方法适用于将非-2′-羟基衍生为其甲硫基甲基醚。本方法(1b)中,式(Ia)化合物被溶于二甲亚砜,并向溶液中加入乙酸酐。该反应通常在室温下进行18-24小时,得到单甲硫基甲基醚。
在该反应流程的第二步,甲硫基甲基醚被转化为相应的被保护膦酰氧甲基醚。可利用Veenemen等人,Tetrahedren,1991,V47,pp 1547-1562中所述的一般方法完成由甲硫基甲基到被保护的膦酰氧基甲基的转化,该文献的有关部分并入本文以作参考。因此,用N-碘琥珀酰亚胺和被保护的磷酸(如磷酸二苄酯)处理带有至少一个甲硫基甲基醚的式(Ib)化合物。该反应于惰性有机溶剂,如四氢呋喃或卤代烃(如1,2-二氯乙烷或二氯乙烷)中进行,且根据需要在脱水剂(如分子筛)存在下进行。为加速反应,也可加入催化剂,如三氟甲磺酸银。反应温度为0℃至室温,优选室温。N-碘琥珀酰亚胺和被保护磷酸是以约与甲硫基甲基醚(Ib)相等的摩尔当量使用,但优选它们被轻微过量服用,例如约1.3-1.5当量于式(Ib)化合物。
在该反应流程的第三步,可能存在的膦酰基保护基和羟基保护基被除去。去保护可利用本领域熟知的常规方法完成,如酸-或碱-催化的水解、氢解、还原等。例如,可利用催化氢解除去苄基膦酰基保护基和苄氧羰基羟基保护基。去保护的方法可从Greene和Wutz或McOmie(出处同前)等教科书中查到。
式(I)化合物的碱盐可通过常规技术形成,它包括将式(I)游离酸化合物与金属碱或与胺接触。合适的金属碱包括:钠、钾、锂、钙、钡、镁、锌和铝的氢氧化物、碳酸盐和碳酸氢盐;合适的胺包括:三乙胺、氨、赖氨酸、精氨酸、N-甲基葡糖胺、乙醇胺、普鲁卡因、苯乍生、二苄基胺、三甲醇氨基甲、氯普鲁卡因、胆碱、二乙醇胺、三乙醇胺等。通过层析后冷却干燥或结晶可进一步纯化碱盐。
以上所述的方法可应用于任何式T-〔OH〕n的紫杉烷衍生物,形成式(A)化合物。文献中所报导的许多T-〔OH〕n可举例如下:(a)紫杉酚;(b)Taxotere_;(c)10-去乙酰基紫杉酚;(d)PCT申请93/106079(1993年4月1日公开)中公开的具有下式的紫杉烷衍生物:其中R1为-OR6、-SR7或-NR8R9;R2为氢原子、烷基、链烯基、炔基、芳基或杂芳基;R3和R4独自为氢原子、烷基、链烯基、链炔基、芳基、杂芳基或酰,但条件是R3和R4不都为酰基;R5为-COR10、-COOR10、-COSR10、-CONR8R10、-SO2R11或-POR12R13;R6为氢原子、烷基、链烯基、链炔基、芳基、杂芳基、羟基保护基或增加紫杉烷衍生物水溶性的官能团;R7为烷基、链烯基、链炔基、芳基、杂芳基或巯基保护基;R8为氢原子、烷基、链烯基、链炔基、芳基、杂芳基;R9为氨基保护基;R10为烷基、链烯基、链炔基、芳基、杂芳基;R11为烷基、链烯基、链炔基、芳基、杂芳基、-OR10或-NR8R14;R12和R13独自为烷基、链烯基、链炔基、芳基、杂芳基、-OR10或-NR8R14;R14为氢原子、烷基、链烯基、链炔基、芳基、杂芳基;R15和R16独自为氢原子、羟基、低级烷酰氧基、链烯酰氧基、链炔酰氧基、芳酰氧基或R15和R16共同形成一氧代基;R17和R18独自为氢原子、羟基、低级烷酰氧基、链烯酰氧基、链炔酰氧基、芳酰氧基或R17和R18共同形成一氧代基;R19和R20独自为氢或羟基或低级烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基;R21和R22独自为氢或低级烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基,或R21和R22共同形成一氧代基;R24为氢、羟基、低级烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基;或R23和R24共同形成一氧代基或亚甲基,或R23和R24共同与它们所连接的碳原子一起形成环氧乙烷环,或R23和R22共同与它们所连接的碳原子一起形成氧杂环丁烷环;R25为氢、羟基、或低级烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基;或R26为氢、羟基或低级链烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基;或R26和R25共同形成一氧代基;R27为氢、羟基或低级烷氧基、烷酰氧基、链烯酰氧基、链炔酰氧基或芳酰氧基;(e)美国专利5,227,400公开的紫杉烷衍生物,紫杉酚的3′-去苯基-3′-(2-呋喃基)或3′-(2-噻吩基)衍生物,Taxotere_:(f)EP534,709(1993年3月31日公开)中公开的紫杉烷衍生物(其中侧链苯基被萘基、苯乙烯基或取代苯基独立取代的紫杉酚)。也见1992年6月11日公开的PCT92/09589;(g)EP534,707(1993年3月31日公开)中公开的紫杉烷衍生物(其中3′-N-苯甲酰基被乙氧羰基或甲氧羰基取代的紫杉酚衍生物);(h)1993年4月1日公开的PCT申请93/06093中所公开的紫杉酚和Taxotere_的10-去乙酸基衍生物;(i)1993年1月20日公开的EP524,093中所公开的10-、7-或10-双-O-(N-取代基氨基甲酰基紫杉烷衍生物);(j)Klein,“Synthesis of 9-Dihydrotaxol:A NewBivactive Taxane”,Tetrahedron Letters,1993,34(13):2047-2050中所公开的紫杉酚的9-α-羟基类似物;(k)在205th ACS National Meetiny inColirado,1993上公开由14β-羟基-10-去乙酰基浆果赤霉素III制得的紫杉酚和Taxotere_的14-β-羟基类似物(Ned.Chem.Division,Abstract No.28);和(1)其它紫杉烷,如在我们1993年5月20日递交的共同未决美国专利申请U.S.S.N.08/062,687中所公开的C7-氟紫杉烷和各种C10-取代的紫杉烷,该专利申请全部并入本文以作参考。
紫杉烷衍生物中的游离羟基可利用常规方法转化为相应的酯或碳酸酯;例如,在式(Ia)化合物中R1a、R2a和R3a之一为-OC(O)Rx或-OC(O)ORx,且Rx的定义同前。因此,可在叔胺等碱存在下将塔三烷衍生物T-OH与式L-C(O)ORx化合物(L为离去基团)(如氯甲酸酯)反应,得到相应的碳酸酯;例如,在二异丙基乙基胺存在下将紫杉酚与氯甲酸乙酯反应,得到2′-O-乙氧羰基紫杉酚。也可将T-OH与羧酸RxCO2H或其酯化等价物(如酐、活性酯或酰基卤)反应,得到相应的酯。
或者,通过用适当取代的3-氨基-2-羟基丙酸、其酰化等价物或其前体酰化具有C13-羟基的紫杉烷残基来制备紫杉烷衍生物T-〔OH〕n。取代的3-氨基-2-羟基-丙酸的适当前体的例子如式(III)的氮杂环丁酮。该酰化反应的例子有偶联羟基保护的浆果赤霉素III或羟基保护的10-脱乙酰基浆果赤霉素III与苯基异丝氨酸衍生物以得到紫杉酚衍生物(Denis等人,美国专利4,924,011和4,924,012)以及偶联被保护浆果赤霉素III与氮杂环丁酮以得到紫杉酚及其衍生物(1990年12月5日公开的欧洲专利甲请400,971(现在的美国专利5,175,315)和美国专利5,229,526。
EP400,971中所公开的方法(Holton法)包括在N,N-二甲基氨基吡啶和吡啶存在下将1-苯甲酰基-3-(1-乙氧基)乙氧基-4-苯基-2-氮杂环丁酮与7-O-三乙基甲硅烷基浆果赤霉素III反应12小时;在除去各种羟基保护基后得到紫杉酚。Ojima等人在“New and Efficient Approaches tothe Semisynthesis of Taxol and its C-13 SideChain Analogs ty Means of β-Lactam Method”Tetrahedron,1992,48(34):6985-7012中报导了一种改进的Holton方法。Ojima的方法包括:首先利用氢化钠产生7-三乙基甲硅烷基浆果赤霉素III的钠盐,然后将该盐与手性1-苯甲酰基-3-(1-乙氧基)乙氧基-4-苯基-2-氮杂环丁酮反应并除去羟基保护基,得到紫杉酚。在U.S.5,229,526中,Holton提到将偶联浆果赤霉素III或其衍生物的金属醇盐和2-氮杂环丁酮反应得到带有C13侧链的紫杉烷。据说该方法具有很高的非对映选择性;因此可使用侧链前体2-氮杂环丁酮的外消旋混合物。最近,Ojima等人在“A Highly Efficient Ronte toTaxotere by the β-Lactam Synthon Method”,Tetrahedren Lettecs,1993,34(26):4149-4152中报导,将7,10-双-O-(三氯乙氧羰基)-10-去乙酰基浆果赤霉素III的金属醇盐与手性1-(叔-丁氧羰基)-4-苯基-3-(被保护羟基)-2-氮杂环丁酮偶联,并在去保护后得到Taxotere_。该文献有关部分并入本文以作参考。
其中,R2′为氢,且R2d为氢、被保护羟基或-OC(O)ORx;或R2′为氟,且R2d为氢;R3d为氢、乙酸基、被保护羟基或-OC(O)ORx;R6d和R7d之一为氢,且另一个为羟基、被保护羟基或C1-6链烷酰氧基;或R6d和R7d共同形成氧代基;P为羟基保护基;M为氢或IA族金属,如锂、钠或钾;且P、R4、R5和Rx的定义司前。反应可按EP400,971中所述方法进行,其中,M为氢的式(II)浆果赤霉素III衍生物在有机碱(如N,N-二甲基氨基吡啶)存在下与式(III)氮杂环丁酮反应。但优选如美国专利5,229,526和Ojima的文章(出处同前)中所公开的那样首先用强碱(如IA族金属的氢化物、烷基氨化物和双(三烷基甲硅烷基)氨化物)将浆果赤霉素III衍生物转化为13-醇盐。更优选的是,13-醇盐为醇锂。锂盐可通过将其中M为氢的式(II)化合物与强金属碱(如二异丙基氨化锂、C1-6烷基锂、双(三甲基甲硅烷基)氨化锂、苯基锂、氢化锂)反应形成。
式(II)塔三烷与式(III)氮杂环丁酮的偶联反应是在惰性有机溶剂(如四氢呋喃)中于0℃至-78℃的降低温度下进行。式(III)氮杂环丁酮可作为外消旋混合物去偶联其中M为IA族金属的紫杉烷金属醇盐;在此情况下,氮杂环丁酮试剂优选以至少2当量于紫杉烷试剂的量使用。更优选约3-6当量。也可使用手性氮杂环丁酮,在此情况下1当量于紫杉烷的氮杂环丁酮就足够了,但优选稍微过量地使用氮杂环丁酮,例如最高达1.5当量。
羟基保护基可相同或可按以下方式进行选择:能够选择性地除去一个或多个保护基而基本上不影响其它保护基;例如在式(Id)化合物中R2d和PO可均为三乙基甲硅烷氧基,且R3d可为苄氧羰基;在钯-碳存在下催化氢解可除去苄氧羰基保护基,而不除去三乙基甲硅烷基。因此,可选择性地除去式(Id)化合物中的羟基保护基,得到式(Ia)化合物。
式(II)化合物或者是文献中已知的,如浆果赤霉素III、10-脱乙酰基浆果赤霉素III及其羟基被保护的衍生物,或者可通过常规方法制得,例如将羟基转化为碳酸酯。其它式(II)化合物可按照下面“起始物的制备”部分中所述的方法制备。
可按照EP400,971和Ojima等人,Tetrahedron,48:6985-7012,1992中所述的一般方法,由式(IIIa)化合物制备式(III)化合物。因此,首先用正丁基锂或三乙胺等碱处理式(IIIa)化合物,然后再用式R4(O)PCO-L化合物(其中L为离去基团)处理,即得到式(III)化合物。
式(IIIa)化合物可按照EP400,971中所公开的一般方法通过中间体化合物3-乙酸基-4-取代的-2-氮杂环丁酮(IIIb)制得,或者可按照US5,229,526公开的方法通过中间体化合物3-三乙基甲硅烷氧基-4-取代的-2-氮杂环丁酮制得。在一改进方法中,可通过用联亚胺缩合乙酰氧基乙酰氯,然后通过氢解或酸裂解除去N-亚胺基而得到化合物(IIIb);该方法示于下面的反应流程中,其中R5′为非限制性取代的芳基或杂芳基,如呋喃基或噻吩基。该方法公开于1993年4月23日递交的共同未决申请U.S.S.N08/052,434,该申请文献并入本文以作参考。
由这些环化加成反应得到的产物(IIIb)通常是两种顺式-氮杂环丁酮的外消旋混合物。该外消旋混合物可通过常规方法解析,例如通过转化为非对映体、在填充了手性吸附剂的柱上的差异吸附或酶解。例如,可将式(IIIb)化合物的外消旋混合物与催化酯水解的酶(如酯酶或脂酶)接触,以选择性地除去一个对映体的3-酰基而不影响其它基团(见Brieva等人,J.Org.Chem,1993,58:1068-1075;也是1993年7月14日递交的共同未决申请U.S.S.No92,170,1993年7月29日公开的欧洲专利申请552041)。或者,首先对外消旋混合物进行碱催化水解以除去3-酰基并产生相应3-羟基β-内酰胺的外消旋混合物;然后将3-羟基β-内酰胺的外消旋混合物与一种能够催化羟基酰化的酶接触以选择性地酰化一对映体上的羟基而不影响其它基团。或者用手性羧酸酰化3-羟基β-内酰胺的外消旋混合物,并利用已知方法分离所产生的非对映体混合物,最后除去手性辅助配合剂,得到所需对映体。
Ojima等人在J.Org.Chem.56:1681-1683,1991;Tet.Lett.,33:5737-5740,1992;和Tetrahedron,48:4985-7012,1992中报导了大量手性式(IIIa)氮杂环丁酮和/或相应的N-(P-甲氧苯基)同族物的合成;其中P为羟基保护基三异丙基甲硅烷基;R5为4-甲氧苯基、3,4-二甲氧苯基、苯基、4-氟苯基、4-三氟甲基苯基、2-呋喃基、2-苯乙烯基、2-(2-呋喃基)乙烯基、2-甲基丙基、环己基甲基、异丙基、苯乙基、2-环己基乙基或正丙基。以上文献的相关部分均并入本文以作参考。属于式(III)定义内但未在上述文献中具体公开的其它氮杂环丁酮可由本领域熟练技术人员按已知方法制备。生物学评估
本发明化合物为新的抗肿瘤剂;已在体外细胞毒性试验和体内动物肿瘤模型中对代表性的式(A)化合物进行了评估。体外细胞毒性数据
本发明化合物显示出抗结肠癌细胞HCT-116和HCT-116/VM46的体外细胞毒性活性。HCT-116/VM46细胞是已预先进行了替尼泊甙抗性选择并表达多药物抗性表型(包括抗紫杉酚)的细胞。按照D.A.Scudiero等人在“Evaluat-ion of soluble tetrazolium/formazan assayfor cell growth and drug sensitivity in cultwreusing humen and other tumor cell lines,”Cancer.Res.48:4827-4833,1988中所述的XTT(2,3-双(2-甲氧基-4-硝基-5-硫代苯基)-5-〔(苯氨基)羰基〕2H-氢氧化四唑鎓)检测法,在HCT-116人结肠癌细胞上进行细胞毒性检测。将细胞按4000细胞/孔的量加到96孔微量滴定板上,24小时加入药物并系列稀释。于37℃培养72小时,此时加入四唑鎓染料XTT。活细胞中的脱氢酶将XTT还原为在450nm处吸光的形式,它可通过分光光度计定量测定。吸收值越大,则活细胞的数目越大。结果以IC50表示,它为抑制细胞繁殖(EP450nm处吸收)至未处理对照细胞的50%所需的药物浓度。表I给出了该检测中所评估化合物的IC50值。表I 抗人结肠癌细胞体外细胞毒性数据
化合物 | IC50(μM) | |
HCT-116 | HCT-116/VM461 | |
Taxotere_紫杉酚实施例1″ 3″ 4 | 0.0040.0040.0200.2660.044 | 0.213(53)0.44(124)1.30(66)6.67(25)5.36(122) |
括号中的数字是与HCT-116细胞相比的抗性倍数。
也对化合物7-O-甲硫基甲基紫杉酚(实例1(a))的细胞毒性进行了试验,结果是它的抗HCT-116IC50为0.003μM,抗HCT-116/VM46的IC50为0.025μM。体内抗肿瘤活性
在Balb/C×DBA2F1(CDF1)杂交小鼠皮下(SC)植入0.1ml 2%(W/V)M109肺癌浆液(如W.Rose“Evaluation of Madison 109 Lung Carcimoma asa Model fos Screening Antitumoz Drugs,”CancerTreatment Reports,65,No.3-4 pp.299-312(1981))。通过静脉给各组小鼠服用试验化合物和对照药物紫杉酚;每组小鼠接受不同剂量水平的化合物,对每一化合物评估三或四种不同剂量水平。每天观察小鼠的存活情况,直到首先出现死亡或植入肿瘤后75天为止。每次实验中保留一组小鼠不处理,作为对照。每周一次或两次测定肿瘤,并按照公开的方法(出处同前)利用mm表示的大小来估计肿瘤的重量。
将化合物处理(T)小鼠的中间存活时间与对照(O)小鼠的中间存活时间进行比较。将化合物处理的每组小鼠的两值之比乘以100,并以百分数(即%T/C)表示于表II中。另外,表II也以T-C值(天)表示了处理值和对照组肿瘤长至1g的中间时间差。T-C值越大,初级肿瘤生长的推迟越大。显示出%T/C≥125%和/或T-C≥4.0(天)的化合物被认为在M109SC模型中具有活性。
表II
a化合物在植入肿瘤后第4、5、6、7和8天通过静脉服用,每日一次。b化合物在植入肿瘤后第5、6、7、8和9天通过静脉服用,每日一次。c较高剂量达到寿命的最大增加;
化合物 | 最大效果 | 最佳剂量 | |
%T/C | T-C(days) | (mg/kg/inj;) | |
实施例1紫杉酚 | 131134 | 14.014 | 45a48/24a,c |
实施例3紫杉酚 | 160151 | 18.815 | 24b18b |
较低剂量与引起肿瘤生长的最大推迟有关。
作为阳性对照,在鼠和人异种移植肿瘤模型(M109,A2780/CDDP-抗顺氯氨铂人卵巢癌和HCT-116-人结肠癌)中对实施例3化合物(三乙醇胺盐形式)的抗紫杉酚活性进一步进行了评估。A2780/CDDP模型公开于Rose和Basler,lnVivo,1990,4:391-396;HCT-116模型公开于Rose和Basler,ln Vivo,1989,3:249-254。M109每两周在Balb/c小鼠在皮下传代,并皮入植入CDF1小鼠以进行抗肿瘤评估。将A2780/CDDP和HCT-116在无胸腺小鼠中培养,以便传代(每两至三周)和治疗实验。实例3化合物可溶于水中通过静脉服用,或溶于带有几滴Tween80的水中口服,而紫杉酚既可悬浮于加Tween80的水中,也可溶于Cremophore/乙醇(50%/50%)并用盐水稀释。SCM109肿瘤试验的治疗方案是自肿瘤植入后的第4天开始每日一次,连续进行5天。对于人肿瘤异种移植试验,是自肿瘤达到50-100mg开始每隔一天服用一次化合物,共服用5次。
在一个M109实验中,静脉注射实施例3化合物时,在36mg/Kg/inj时达到最大%T/C值155(T-C为19天)(参见36或18mg/kg/inj时紫杉酚的最大%T/C值132(T-C为13天)。在同一实验中,以160mg/kg/adm的剂量口服实施例3化合物时达到的最大%T/C值是158(T-C为22.8天),而悬浮于水和Tween80中的同样剂量(最高试验剂量)的紫杉酚不显示活性。在另一M109实验中,以48mg/kg/inj的剂量静脉注射实例3化合物时产生的最大%T/C为170(T-C为17天)(比较48或36mg/kg/inj剂量时紫杉酚的最大%T-C167(T-C:14天))。在同一实验中以200mg/kg/adm的剂量口服实例3化合物所产生的最大%T/C为172(T-C为17天),而溶于Cremophore/乙醇/盐水的紫杉酚在60mg/kg/inj剂量时未显示出活性。在这一实验中,由于溶解性和毒性限制,溶于Cremophore/乙醇/盐水的紫杉酚不可能以大于60mg/kg/inj的剂量服用。
在A2780/CDDP实验中,以36mg/kg/inj的剂量静脉注射实例3化合物所产生的最大T-C值为29.8天(参见36/mg/kg/inj剂量时紫杉酚的最大T-C值26.3)。以160mg/kg/adm的剂量口服实例3化合物所产生的最大T-C值为20天。在HCT-116实验中,用24或36mg/kg/inj剂量的紫杉酚进行静脉注射治疗时7个处理小鼠中的6个或8个处理小鼠中的6个得到治愈,而以160或240mg/kg/adm的剂量口服实例3化合物时分别使8个处理小鼠中的6个或7个得到治愈。治愈指植入肿瘤后80天肿瘤消失。
本发明化合物是塔三烷衍生物的膦酰氧甲基醚。其可作药物的盐与紫杉酚相比显示出更好的水溶性,从而更便于药物配制。不受理论束缚,据信本发明膦酰氧甲基醚是紫杉酚或其衍生物的前药;膦酰氧甲基残基是在体内与磷酸酶接触时被除去,产生母本化合物。如上所示,本发明化合物是有效的肿瘤抑制剂。因此,本发明涉及的另一个方面是一种抑制哺乳动物肿瘤的方法。它包括给携带肿瘤的宿主服用抗肿瘤有效量的式(A)化合物。
本发明化合物可按与紫杉酚类似的方式使用;因此,熟悉癌症治疗的肿瘤专家不经过度实验就能够确定服用本发明化合物的合适治疗方案。本发明化合物的剂量、给药途径和程序等无特别限制,且随所使用的具体化合物而变。因此,本发明化合物可通过任何适当的给药途径服用,优选非肠道途径;剂量为,例如1-100mg/kg体重,或20-50mg/m2式。(A)化合物也可口服;口服剂量为5-500mg/kg体重。所用实际剂量可根据所配制的具体组合物、给药途径和具体部位、所要治疗的宿主和肿瘤类型而改变。在决定剂量时要考虑到影响药物作用的许多因素,其中包括患者年龄、体重、性别、饮食和身体状况。
本发明也提供了含有抗肿瘤有效量的式(A)化合物及一种或多种可作药物的载体、赋形剂、稀释剂或辅助剂的药物组合物。配制紫杉酚或其衍生物的实例可从如美国专利4,960,790和4,814,470中查到。例如,可将本发明化合物配制成片剂、丸剂、粉末混合物、胶囊剂、注射剂、溶液、栓剂、乳液、分散液、食品预混物及其它合适形式。也可将它们制成无菌固体组合物,如冻干产品,并根据需要与其它可作药用的赋形剂结合。也可在非肠道给药之前用无菌水、生理盐水、水和有机溶剂(如丙二醇、乙醇)的混合物或某些其它无菌注射介质重组该固体组合物。
可作药用的载体的典型例子有甘露醇、脲、葡聚糖、乳糖、马铃薯或玉米淀粉、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、十四烷酸异丙酯、苯甲酸苄基酯、碳酸钠、明胶、碳酸钾、硅酸。药物制剂也可含有无毒性辅助物质,如乳化剂、防腐剂、湿润剂等,例如脱水山梨醇单月桂酸酯、三乙醇胺油酸酯、聚氧乙烯单硬脂酸酯、甘油三棕榈酸酯、二苯基钠硫代琥珀酸酯。
在以下实验方法中,在未具体指出时所有温度应被理解为摄氏度(C)。核磁共振(NMR)光谱特征指以四甲基甲硅烷(TMS)作为参比标准用%百分比(ppm)表示的化学位移(δ),质子NMR光谱数据中各个位移的相对面积对应于分子中特定官能基的氢原子数。位移的多重性以宽单峰(bs)、宽双峰(bd)、宽三峰(bt)、宽四峰(bq)、单峰(s)、多重峰(m)、双峰(d)、四重峰、三峰、双双峰(dd)、双三重峰(dt)和双四重峰(dq)。用于吸收NMR光谱的溶剂是丙酮-d6(氘化丙酮)、DMSO-d6(全氘化二甲亚砜)、D2O(重水)、CDCl3(含氘氯仿)和其它常规氘化溶剂。红外(IR)光谱仅包括具有官能基鉴定值吸收波数(cm-1)。
Celite是Johns-Manville产品公司登记用于硅藻上的商标。
本文中所使用的缩写是本领域广泛使用的,其部分例子有:MS(质谱);HRMS(高分辨质谱);Ac(乙酰基);Ph(苯基);V/V(体积/体积);FAB(快速原子轰击);NOBA(间-硝基苄基醇);min(分钟);h或hr(小时);NIS(N-碘琥珀酰亚胺);BOC(叔丁氧羰基);CBZ(苄氧羰基);Bn(苄基);Bz(苯甲酰基);TES(三乙基甲硅烷基);DMSO(二甲亚砜);THF(四氢呋喃);HMDS(六甲基二硅氮烷)。制备起始物
于0℃用吡啶(0.028ml,0.346mmol)和三氯乙基氯甲酸酯(0.0724ml,0.260mmol)处理10-去乙酰基紫杉酚(140mg,0.173mmol)的无水二氯甲烷(3.5ml)溶液。维持该温度1h后,撒掉冷浴,于室温下过夜搅拌混合物。蒸发溶剂,残余物在硅胶上色谱(30-50%乙酸乙酯的己烷溶液),得到泡沫状标题化合物(92.3mg,46%)。进一步洗脱后得到未反应的起始物(35mg,25%)和2′,10-O-双(2,2,2-三氯乙氧羰基)-10-去乙酰基紫杉酚(产率为16%)。(b)2′,7-O-双(2,2,2-三氯乙氧羰基)-10-去乙酸基-11,12-二氢紫杉酚-10,12(18)-二烯
于室温下用1,1,2-三氟-2-氯三胺(0.0384ml,0.238mmol)处理步骤(a)产物(92.3mg,0.079mmol)的无水二氯甲烷(2ml)溶液。过夜搅拌后蒸发溶剂,通过柱色谱(25%乙酸乙酯的己烷)纯化残余物,得到白色粉末状标题化合物(42.8mg,47.3%)。
(c)10-去乙酸基-11,12-二氢紫杉酚-10,12(18)-二烯
将步骤(b)产物(39mg,0.034mmol)溶于甲醇(0.5ml)和乙酸(0.5ml)并用酸洗过的锌粉(66.4mg,1.020mmol)处理。浆液于40℃加热1h,过滤并蒸发滤液。用60%乙酸乙酯/己烷色谱残余物后得到泡沫状标题化合物(22mg,81%)。(d)10-去乙酸基紫杉酚
在钯-碳(10%,14.7mg,0.014mmol pd)存在下,在大气压下氢化步骤(c)产物(22mg,0.028mmol)的乙酸乙酯(0.7ml)溶液。室温下5.5h后过滤(用乙酸乙酯浸渍),蒸发并层析(60%乙酸乙酯的己烷),得到白色泡沫状标题化合物(15.0mg,68%)。制备例2 7-脱氧-7α-氟紫杉酚(a)2′-O-苄氧羰基-7-脱氧-7α-氟紫杉酚
将三氟化二乙基氨基硫(DAST,18.7μl,0.141mmol)溶于无水二氯甲烷(0.5ml),并将该溶液冷却至0℃。加入2′-O-(苄氧羰基)紫杉酚(71mg,0.072mmol)的二氯甲烷(1ml)溶液,所得溶液于0℃保温30min,并于室温保持4h。然后向反应混合物中加水(0.15ml)以终止反应,浓缩所得混合物,留下的残余物经硅胶柱层析(用40%乙酸乙酯的己烷洗脱)后产生61mg(Y:85.7%)标题化合物和2′-O-苄氧羰基-8-去甲基-7,8-环丙基紫杉酚。(b)7-脱氧-7α-氟紫杉酚
将步骤(a)所得产物(89mg)溶于乙酸乙酯(3ml),并在披钯炭(10%pd,29mg,0.027mmol)存在下,于一个氢气压下轻微搅拌混合物。12h后,除去溶剂,残余物通过硅胶层析纯化(用40%乙酸乙酯的己烷洗脱),得到67.7mg标题化合物及8-去甲基-7,8-环丙基紫杉酚。
以下HPLC法可用于分离7-脱氧-7α-氟紫杉酚和8-脱甲基-7,8-环丙基紫杉酚。
装置
泵:PE4系列
柱:Shandon Hypercarb(石墨化碳),7u,100×
4.6mm,#59864750(有关制备性尺寸柱的资料可从
Keystone Scientific,Bellefonate,PA得
到)
注射器:PEISS-100
探测器:HP-1040M
条件
流动相:85∶15二氯甲烷∶己烷
以80∶19∶1二氯甲烷∶己烷∶异丙醇不丧失分离
流速:2.5ml/min
检测器:254nm
稀释剂:溶于二氯甲烷的样品制备例3 7-脱氧-7α-氟浆果赤霉素III
向干燥环境下的无水烧瓶中加入2′-O-(苄氧羰基)紫杉酚(4g,4mmol)和无水甲苯(80ml)。于室温下搅拌所产生的浆液,同时滴入无水四氢呋喃(16ml),直至产生无色溶液。在干冰/丙酮浴上冷却该溶液至-78℃,然后用三氟化二乙基氨基硫(DAST,1.2ml,2.5当量)。搅拌反应混合物16h,使它逐步升至室温。过滤所得悬液,液滤(用乙酸乙酯(30ml)稀释)用碳酸氢钠饱和水溶液和盐水依次洗涤。干燥(MgSO4)并浓缩有机相,得到粗产物,为白色泡沫状。通过硅胶柱层析(用10%CH2CN的CH2Cl2洗脱)分批纯化粗产物,得到1.45g 2′-O-(苄氧羰基)-7-脱氧-7α-氟紫杉酚和2′-O-(苄氧羰基)-8-脱甲基-7,8-环丙基紫杉酚(经1H-NMR测得为82∶18混合物)。
将上述混合物(1.45g)溶于乙酸乙酯(60ml)并用披钯碳(300mg)处理。于50psi氢气压力下振荡4h后,排空反应,通过一短硅胶塞过滤并浓缩,得到所需产物混合物7-脱氧-7α-氟紫杉酚和8-脱基-7,8-环丙基紫杉酚,为白色泡沫(1.24g,Y:99%,经1H-NMR测得为90∶10混合物)。将该混合物加至无水二氯甲烷(30ml)中,用氢硼化四丁基铵(745mg,2.9mmol,2eq)处理,并搅拌6h,然后用乙酸(1ml)终止反应,用另外30ml二氯甲烷稀释,并用碳酸氢钠饱和水溶液洗涤。干燥(MgSO4)并浓缩有机相。所得取代的塔三烷核心混合物粗品通过硅胶柱层析(用10%CH3CN的CH2Cl2洗脱)部分纯化,得到7-脱氧-7α-氟浆果赤霉素III和8-脱甲基-7,8-环丙基浆果赤霉素III的90∶10(通过1H-NMR测得)混合物(510mg,60%),为白色泡沫。经热的异丙醇结晶后,得到7-脱氧-7α-氟浆果赤霉素III(为白色小针状物,Y:410mg);m.p.234-236℃(水解)。制备例4 10-脱乙酸基-7-脱氧-7α-氟紫杉酚(a)2′-O-苄氧羰基-10-脱乙酸基紫杉酚
依次用氯甲酸苄酯(0.0146ml,0.102mmol)和二异丙基乙胺(0.0177ml,0.102mmol)处理10-脱乙酸基紫杉酚(27mg,0.034mmol)的二氯甲烷(1ml)溶液。于0℃搅拌反应混合物45min,再于室温搅拌12h。经蒸发溶剂和硅胶层析(用40%乙酸乙酯的己烷洗脱)后得到25.5mg(Y:81%)泡沫状标题化合物。(b)10-脱乙酸基-7-脱氧-7α-氟紫杉酚
于0℃用DAST(0.0071ml,0.055mmol)处理步骤(a)所得产物(25.5mg,0.028mmol)的二氯甲烷(0.8ml)溶液。0℃进行45min后,该反应于室温进行5h。蒸发溶剂及层析后得到粗泡沫状2′-O-苄氧羰基-7-脱氧-7α-氟紫杉酚。将该化合物溶于乙酸乙酯(1ml),于披钯炭(10%,8.9mg)存在下,于室温及1个氢气压下轻微搅拌12h。过滤除去催化剂,并对产物进行硅胶层析,得到10mg(Y:40%)标题化合物的泡沫。制备例5 10-脱乙酰基-7-脱氧-7α-氟紫杉酚
将2′,10-O-双(2,2,2-三氯乙氧羰基)-10-脱乙酰基紫杉酚(120mg,0.013mmol)的二氯甲烷(2ml)溶液冷却至0℃,并用DAST(0.0266ml,0.207mmol)处理。溶液于0℃搅拌30min及于室温搅拌4h。加水(0.05ml)终止反应。浓缩反应混合物且残余物通过硅胶层析(用30%乙酸乙酯的己烷洗脱)纯化,得到81mg(Y:68%)2′,10-O-双(2,2,2-三氯乙氧羰基)-7-脱氧-7α-氟紫杉酚的泡沫。将该化合物(63mg,0.054mmol)溶于甲醇(0.5ml)和乙酸(0.5ml),并于45℃用锌粉(104mg,1.62mmol)处理90min。过滤混合物并浓缩滤液,残余物经硅胶层析(用40%己烷的60%乙酸乙酯洗脱)后得到38mg(Y:86%)标题化合物,为白色固体。制备例6 7-脱氧浆果赤霉素III(a)7-O-〔(甲硫基)硫代羰基〕浆果赤霉素III
将浆果赤霉素III(750mg,1.278mmol)溶于无水四氢呋喃(20ml),并一次性加入咪唑(8.7mg,0.128mmol)。于室温下加入氢化钠(50%于矿物油中,77mg,1.597mmol)。当气体挥发停止时(10min),一次性加入二硫化碳(4.6ml)。室温下3h后,用甲基碘(0.238ml,3.835mmol)处理该黄色溶液并搅拌过夜。经乙酸乙酯和水处理后得到标题化合物,为粗油状物。替代方法:
将浆果赤霉素III(394mg,0.672mmol)溶于四氢呋喃(5ml)和二硫化碳(1ml),向该溶液中加入氢化钠(40.3mg,60%,1.009mmol),并加入催化量咪唑。室温下搅拌反应混合物1.5h,然后加入甲基碘(122.8μl,2.016mmol)。40min后,真空除去溶剂,残余物进行硅胶层析(用20%-50%-60%乙酸乙酯的己烷洗脱),得到标题化合物(260mg,Y:57.2%)和7-表浆果赤霉素(98.5mg,25%)。(b)7-O-〔(甲硫基)硫代羰基〕-13-O-三乙基甲硅烷基浆果赤霉素III
将得自步骤(a)的粗油产物溶于无水二甲基甲酰胺(5ml),并于室温下用咪唑(870mg,12.78mmol)和三乙基甲硅烷基氯(2.10ml,12.78mmol)处理15h。加水并用乙酸乙酯萃取。用水充分洗涤有机层,然后干燥。经硅胶快速层析(用20%乙酸乙酯的己烷洗脱)后得到标题化合物,为透明状固体(Y:209mg,两步总产率为20%)。替代方法:
将步骤(a)产物(193.4mg,0.286mmol)溶于无水二甲基甲酰胺(2.86ml)。向该溶液中加入咪唑(77.9mg,1.14mmol)后再加入三乙基甲硅烷基氯(192μl,1.14mmol)。于室温后过夜搅拌反应混合物。12h后,用乙酸乙酯(150ml)稀释反应混合物。用水(3×10ml)和盐水(1×10ml)洗涤有机层,并真空浓缩。残余物经硅胶层析(用20%乙酸乙酯的己烷洗脱)后得到标题产物(163mg.Y:72.0%)。(c)7-脱氧-13-O-三乙基甲硅烷基浆果赤霉素III
于三丁基氢化锡(0.310ml,1.150mmol)和2,2′-偶氮二异丁腈(AIBN,10mg)存在下,将步骤(b)产物(182mg,0.230mmol)的无水苯(5ml)加热至80℃。3h后冷却溶液,真空蒸发溶剂,残余物经硅胶层析(用20%乙酸乙酯的己烷洗脱)后得到油状标题化合物。(d)7-脱氧浆果赤霉素III
将步骤(c)产物溶于四氢呋喃(5ml),并于室温下用四丁基氟化铵(1M于四氢呋喃,0.50ml,0.50mmol)处理2h。用乙酸乙酯稀释,用水和盐水洗涤,再经硅胶层析(用1∶1乙酸乙酯/己烷洗脱)后得到标题化合物,为透明状固体(63mg,两步总产率:58%)。制备例7 10-脱乙酸基浆果赤霉素III(a)10-脱乙酰基-10-O-(五氟苯氧基)硫代羰基-7-O-三乙基甲硅烷基浆果赤霉素III
将7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素III(见Greene等人,J.Am.Chem.Soc.,110,P5917,1988)(319mg,0.485mmol)溶于无水四氢呋喃(5ml),冷却至-40℃,并用正丁基锂(1.58M于己烷,0.384ml,0.606mmol)处理。维持该温度40min后,利用注射器均匀加入氯硫甲酸五氟苯基酯(0.086ml,0.536mmol)。于-20℃搅拌反应混合物90min,用饱和氯化铵溶液终止反应,并用乙酸乙酯萃取。干燥并浓缩乙酸乙酯层,残余物经硅胶层析纯化(用40%乙酸乙酯的己烷洗脱)后得到泡沫状标题化合物(320mg,Y:74%)。(b)10-脱乙酸基-7-O-三乙基甲硅烷基浆果赤霉素III
将步骤(a)产物(119mg,0.135mmol)溶于无水甲苯(3ml),并用AIBN(2mg)处理。用无水氮气使溶液脱气,然后加入三丁基氢化锡(0.055ml,0.202mmol)。溶液于90℃加热1h,蒸发溶剂并对残余物进行硅胶层析(用40%乙酸乙酯的己烷洗脱)后,得到无色泡沫状标题化合物(87mg,Y:99%)。(c)10-脱乙酸基浆果赤霉素III
将步骤(b)的产物(120mg,0.187mmol)溶于乙腈(3.5ml),并冷却溶液至-10℃。加入浓HCl(36%,0.060ml),搅拌溶液30min。用乙酸乙酯(75ml)稀释混合物,并用饱和碳酸氢钠水溶液和盐水洗涤,然后干燥及浓缩。通过快速硅胶层析(用70%乙酸乙酯的己烷洗脱)纯化残余物后得到泡沫状10-脱乙酸基浆果赤霉素III(75mg,Y:76%)。制备例8 10-脱乙酸基-7-脱氧浆果赤霉素III(a)7-O-〔(甲硫基)硫代羰基〕-10-脱乙酸基浆果赤霉素III
将10-脱乙酸基浆果赤霉素III(75mg,0.142mmol)溶于无水四氢呋喃(2ml)和二硫代碳(0.5ml),然后加入氢化钠(60%于矿物油中,8.5mg,0.213mmol),并将混合物于室温下搅拌2h。加入碘甲烷(0.026ml,0.426mmol),该反应过夜进行,除去溶剂并通过硅胶层析(用50-70%乙酸乙酯的己烷洗脱)纯化残余物后,得到泡沫状标题化合物(46.4mg,Y:53%)。(b)10-脱乙酸基-7-脱氧-浆果赤霉素III
在AIBN(2mg)和三丁基氢化锡(0.079ml,0.290mmol)存在下及在氩气环境下,将步骤(a)产物(30mg,0.058mmol)在苯(1ml)中回流3h。浓缩反应混合物,并快速硅胶层析残余物(用40%乙酸乙酯的己烷洗脱),接着通过HPLC(高压液相层析)与其它成分分离后,得到泡沫状标题化合物(16.8mg,Y:56%)。替代方法:
向7-O-〔(甲硫基)硫代羰基〕-13-O-三乙基甲硅烷基浆果赤霉素III(制备例1步骤(b)的产物,416.3mg,0.527mmol)的无水甲苯(10.5ml)溶液中加入催化量AIBN,并用无水N2使所得溶液脱氢5min。加入三丁基氢化锡(708.7μl,2.63mmol),并将反应混合物于100℃加热2h,然后再加入三丁基氢化锡(425.3μl,1.581mmol),于100℃加热5.5h后冷却至室温。经硅胶层析(用20%乙酸乙酯的己烷洗脱)后得到7-脱氧-10-脱乙酸基-13-O-(三乙基甲硅烷基)浆果赤霉素III(320mg,Y:97%)。
于室温下向上一步骤产物(160mg,0.255mmol)的无水四氢呋喃(2ml)溶液中加入四丁基氟化铵(766μl,1M,0.766mmol),于室温下搅拌反应混合物1h。除去溶剂,对残余物进行硅胶层析(用50-70%乙酸乙酯的己烷洗脱)后,得到所需标题产物(115mg,Y:87.9%)。制备例9 (3R,4S)-1-叔丁氧羰基-4-苯基-3-三乙基甲硅烷氧基-2-氮杂环丁酮于0℃及氩气环境下向(3R,4S)-4-苯基-3-三乙基甲硅烷氧基-2-氮杂环丁酮(2.200g,7.92mmol)的无水四氢呋喃(25ml)搅拌溶液中加入N,N-二异丙基乙胺(1.65ml,9.510mmol,1.2equiv)。搅拌5min后,加入二-叔丁基碳酸酯(2.080g,9.510mmol,1.2equiv)和4-二甲氨基吡啶(193.6mg,1.581mmol,0.20equiv)。于0℃搅拌反应混合物60min,然后用乙酸乙酯(25ml)稀释。所得溶液依次用盐水、10%NaHCO3和10%HCl溶液洗涤,用MgSO4干燥,浓缩后得到粗产物(油),通过硅胶快速层析(用15%乙酸乙酯的己烷洗脱)进一步纯化该化合物后得到标题化合物(2.4g,Y:83%),为白色固体。制备例10 (±)-顺-3-乙酸基-4-苯基氮杂环丁-2-酮(a)向装有温度计、磁力搅拌器和滴液漏斗的1L三颈圆底烧瓶中加入氢化苯酰胺(30.00g,100.5mmol)和乙酸乙酯(150ml)。在搅拌及氩气覆盖条件下将反应混合物冷却至5℃,并加入三乙胺(16.8ml,121mmol),然后在90min内滴加完乙酸基乙酰氯(12.4ml,116mmol)的乙酸乙酯(300ml)溶液。维持该温度16h后,将反应混合物温热至20℃(1.5h),并转移至分离漏斗,有机层依次用NH4Cl饱和水溶液(150ml,100ml)、NaHCO3饱和水溶液(120ml)和盐水(120ml)洗涤。为了进行鉴定,在这一阶段通过于MgSO4上干燥有机相、过夜和真空除去溶剂分离出标题化合物,以定量粗品产率得到(±)顺-3-乙酸基-1-〔(苯基)(亚苄亚氨基)甲基〕-4-苯基氮杂环丁-2-酮,为红色玻璃。(b)于氩气流下将(a)中获得的化合物的乙酸乙酯(500ml)溶液小心地转移至2.0L帕尔烧瓶中,其中含有10%披钯活性炭(6.00g)。用氢气(4atm)处理该混合物20h,然后通过Celite填塞过滤除去催化剂。液饼在乙酸乙酯(200ml)中浆化,搅拌(10min)并过滤,滤饼用乙酸乙酯(100ml)浸渍,并合并滤液。用10%HCl(300ml)洗涤有机层,两层均通过多孔玻璃漏斗过滤以除去白色沉淀(二苄基胺·HCl),将其用乙酸乙酯(100ml)浸渍。分离各相,并用另一份10%HCl(200ml)洗涤有机相。用乙酸乙酯(200ml)再萃取公开的10%HCl溶液,并用NaHCO3饱和水溶液(300ml)和盐水(250ml)洗涤合并的有机层。有机层经MgSO4干燥、过夜及真空浓缩后产生75ml终体积。冷却该混合物至4℃,并过滤分离沉淀产物。用己烷(200ml)洗涤滤饼后得到16.12g(自氢化苯酰胺的总产率为78.1%)白色针状标题化合物。mp=150-151℃。制备例11 (±)-顺-3-三乙基甲硅烷氧基-4-(2-呋喃基)-N-叔丁氧羰基氮杂环丁-2-酮(a)基本按制备例10(a)所述方法进行,所不同的是用糠醛胺〔即2-呋喃基-CH-(N=CH-2-呋喃基)2〕代替了氢化苯酰胺,并反应规模为18.6mmol而不是100mmol。即由糠醛胺(5.00g,18.6mmol)、三乙胺(3.11ml,22.3mmol)和乙酸基乙酰氯(2.30ml,21.4mmol)得到6.192g(Y:90.4%)(±)-顺-3-乙酸基-1-〔(2-呋喃基)(2-呋喃亚甲亚氨基)甲基〕-4-(2-呋喃基)氮杂环丁-2-酮,为浅红色浆液。(b)基本按照制备例10(b)所述的方法,所不同的是产物是通过制备性TLC分离,且以糠醛胺起始量计的反应规模为2.7mmol。即将上述(a)得到的粗产物再溶于乙酸乙酯(50ml),并加至10%披钯活性炭(150mg)上。通过制备性TLC(2mm硅胶,用1∶1乙酸乙酯/己烷洗脱)纯化粗固体后得到386mg(自糠醛胺核心的总产率为65.8%)(±)-顺-3-(乙酸基)-4-(2-呋喃基)氮杂环丁-2-酮的黄色固体。用乙酸乙酯/己烷重结晶。m.p.=118-119℃(c)将上面(b)得到的化合物(3.78g,19.4mmol)的60ml甲醇溶液与K2CO3(20mg,0.14mmol)一起搅拌90min,用Dowex 50W-X8中和溶液并过滤。浓缩滤液,残余物溶于80ml无水THF,并与咪唑(1.44g,21.2mmol)和TESCl(3.4ml,20.2mmol)一起搅拌30min。用乙酸乙酯稀释溶液,并用盐水洗涤,用MgSO4干燥,并浓缩。经硅胶层析残余物(用3∶1己烷/乙酸乙酯洗脱)后得到4.47g(Y:86%)(±)-顺-3-三乙基甲硅烷氧基-4-(2-呋喃基)-氮杂环丁-2-酮,为无色油状物。(d)于0℃将(c)的产物(2.05g,7.7mmol)的30ml二氯甲烷溶液与二异丙基乙胺(1.5ml,8.6mmol)、碳酸二叔丁酯(2.0g,9.2mmol)和催化量二甲氨基吡啶(DMAP)一起搅拌。用二氯甲烷稀释溶液,并用盐水洗涤,用MgSO4干燥,并浓缩,再经硅胶层析残余物(用8∶1己烷/乙酸乙酯洗脱)后得到2.0g(Y:70%)标题化合物,为蜡质固体。
利用如得自假单孢属的PS-30(Amano lnternationalCo.)的脂酶,对(b)中得到的外消旋混合物进行酶促水解,得到(3R,4R)-3-羟基-4-(2-呋喃基)-氮杂环丁-二-酮。使用脂酶P17-30和其它酶的酶促方法公开于我们1993年7月14日递交的共同未决申请U.S.S.N.092,170中,该文献并入本文以作参考。
按照(c)和(d)所述方法,由(3R,4R)-3-羟基-4-(2-呋喃基)-氮杂环丁-2-酮得到(3R,4R)-N-(叔丁氧羰基)-3-三乙基甲硅烷氧基-4-(2-呋喃基)氮杂环丁-2-酮。制备例12 (±)-顺-3-三乙基甲硅烷氧基-4-(2-噻吩基)-N-叔丁氧羰基氮杂环丁-2-酮(a)基本按照制备例10(a)所述的方法,所不同的是用氢化噻吩酰胺〔即2-噻吩基-CH-(N=CH-2-噻吩基)2〕代替氢化苯酰胺。即,由氢化噻吩酰胺(30g,94.7mmol)、噻吩乙胺(15.84ml,114mmol)和乙酸基乙酰氯(11.6ml,108mmol)反应得到(±)-顺-3-乙酸基-1-〔(2-噻吩基)(2-三亚乙基四氨基亚甲亚氨基)甲基〕-4-(2-噻吩基)氮杂环丁-2-酮,为粘性油状物。(b)于25℃向(a)中所得产物(0.431g,1.03mmol)于二氯甲烷(2.93ml)的搅拌溶液中一次性加入70%乙酸溶液(0.35ml冰醋酸和0.15ml水)。回流反应混合物,并搅拌2.5h。用50ml二氯甲烷稀释反应混合物,然后用两份75ml碳酸氢钠饱和水溶液和一份50ml饱和盐水洗涤。真空浓缩有机萃取物至一棕色油状物,溶于微量二氯甲烷,并置于4″×0.5″的硅胶柱上。用10-60%EtOAe于己烷中的梯度溶液洗脱后,得到少极性的副产物和(±)-顺-3-乙酸基-4-(2-噻吩基)氮杂环丁-2-酮(0.154g,Y:75%),为白色固体。(c)将(b)中得到的产物(2.5g,11.8mmol)溶于甲醇(10ml),并用碳酸氢钠饱和水溶液(10ml)处理,于室温下搅拌所得浆液3h。用乙酸乙酯(20ml)稀释反应,并水(15ml)洗、水相用乙酸乙酯反萃取数次,合并的有机相经MgSO4干燥和浓缩后,产生黄色固体(Y:1.7g)。将该粗产物溶于无水四氢呋喃(20ml),并在冰/水浴上冷却溶液至5℃。加入咪唑(752mg,1.1eq),搅拌5min后,滴加三乙基氯代硅烷(1.85ml,1.1eq)。所得悬浮液于该温度下搅拌3h;过滤除去固体,水洗(2×20ml)有机相,然后用MgSO4干燥并浓缩,通过硅胶柱层析纯化粗产物(用己烷/乙酸乙酯7∶3)后得到(±)-顺-3-三乙基甲硅烷氧基-4-(2-噻吩基)-氮杂环丁-2-酮(1.5g,Y:45%),为无色固体,m.p.70-71℃。替代方法
将(b)的产物(2.0g,9.37mmol)的40ml甲醇溶液与K2CO3(60mg,0.43mmol)一起搅拌30min,用Dowex50W-X8中和溶液并过滤。浓缩滤液并将残余物溶于50ml无水THF,于0℃与咪唑(0.85g,11.3mmol)和TESCl(1.9ml,12.5mmol)一起搅拌30min。用乙酸乙酯稀释溶液,用盐水洗涤,用MgSO4干燥,并浓缩。再经硅胶层析残余物(用3∶1己烷/乙酸乙酯洗脱)后得到2.13g(Y:86%)无色油状标题化合物。(d)将(c)所得产物(425.7mg,1.48mmol)溶液溶于二氯甲烷(10ml),并在冰/水浴上冷却至5℃。依次用催化量DMAP、二异丙基乙胺(TESCl,0.25ml,1.0eq)及二-叔丁基碳酸酯(388.4mg,1.2eq)处理反应,于该温度搅拌2h后,用碳酸氢钠饱和水溶液终止反应,水洗(5ml)有机相,用MgSO4干燥,通过一短硅胶塞,并浓缩,得到无色油状所需产物(525.3mg,Y:93%)。
可采用制备9、11(d)和12(d)所述方法制备其它可用于制备本发明化合物的N-取代的氮杂环丁酮。下表列出了一些这类氮杂环丁酮的例子。P为羟基保护基,如三乙基甲硅烷基、三异丙氧甲硅烷基和乙氧乙基。
制备例13 10-脱氧taxotere
L | R4(O)p | R5 |
Cl | Ph | 4-CH3O-Ph-3,4-diCH3O-Ph-Ph-4-F-Ph-4-CF3-Ph-2-呋喃基2-噻吩基PhCH=CH-2-呋喃基-CH=CH-(CH3)2CHCH2-C6H11-CH2-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2-CH3CH2CH2-4-Cl-Ph2-F-Ph3-F-Ph4-CH3-Ph |
Cl | 4-CH3O-Ph- | 3,4-diCH3O-Ph-4-CF3-Ph-2-呋喃基PhCH=CH-(CH3)2CHCH2-C6H11-CH2-PhCH2CH2- |
L | R4(O)p | R6 |
(CH3)3CO- | (CH3)3CO- | 4-CH3O-Ph-4-F-Ph-4-CF3-Ph-PhCH=CH-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2-CH3CH2CH2- |
Cl | CH3- | 4-CH3O-Ph-Ph-4-F-Ph-2-呋喃基2-呋喃基-CH=CH-PhCH2CH2-C6H11-CH2CH2-CH3CH2CH2- |
于氩气环境下将10-脱乙酸基-7-O-三乙基甲硅烷基浆果赤霉素III(100mg,0.156mmol)置于烧瓶中并溶于无水四氢呋喃(1.5ml)。冷却至-40℃,滴加正丁基锂(1.45M于己烷,0.119ml,0.170mmol),然后在2min内加入(3R,4S)-1-叔丁氧羰基-4-苯基-3-三乙基甲硅烷氧基-2-氮杂环丁酮(94.2mg,0.25mmol)的四氢呋喃(0.5ml)溶液,立即加热混合物至0℃并搅拌45min,然后用饱和氯化铵(3ml)终止反应。混合物用乙酸乙酯萃取,干燥并浓缩。硅胶层析(用30%乙酸乙酯的己烷洗脱)后得别10-脱氧-2′,7-双-O-(三乙基甲硅烷基)taxotere泡沫(125mg,Y:76%)。将该化合物(100mg,0.098mmol)立即于-5℃溶于乙腈(2ml),并用盐酸(0.037ml,36%,12M)处理。于-5℃搅拌2h,用碳酸氢钠水溶液终止反应,用乙酸乙酯萃取,并干燥。蒸发溶剂并进行硅胶层析(用75%乙酸乙酯的己烷洗脱)后,得到泡沫状标题化合物(80.5mg,Y:80%)。
按照制备例13提供的一般方法,利用合适的浆果赤霉素III成分和氮杂环丁酮成分作为起始物,可制备出其它式(Ia)化合物;下表中列出了其它式(Ia)化合物的例子。应当理解,尽管下面所示的化合物带有游离羟基,通过适当选择各种羟基保护基,2′-、7-或10-位的任何保护基可被选择性除去而不影响其它保护基。
制备例14 双(甲硫甲基)醚
R2 | R2a | R3a | H4(O)p | R5 |
H | OH | AcO | Ph | 4-CH3O-Ph-3,4-diCH3O-Ph-Ph-4-F-Ph-4-CF3-Ph-2-呋喃基2-噻吩基PhCH=CH-2-呋喃基-CH=CH-(CH3)2CHCH2-C6H11-CH2-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2-CH2CH2CH2-4-Cl-Ph2-F-Ph3-F-Ph4-CH3-Ph |
R2 | R2a | R3a | R4(O)p | R5 |
H | OH | OH | (CH3)3CO | 4-CH3O-Ph-Ph4-F-Ph-4-CF3-Ph-2-呋喃基2-噻吩基PhCH=CH-C6H11-CH2-(CH3)2CH-PhCH2CH2- |
OH | H | Ph | 4-CH3O-Ph-3,4-diCH3O-Ph-4-F-Ph-4-CF3-Ph-2-呋喃基2-噻吩基PhCH=CH-2-呋喃基-CH=CH-(CH3)2CHCH2-C6H11-CH2-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2-CH3CH2CH2- |
R2 | R2a | R3a | R4(O)p | R5 |
H | H | (CH3)3CO | 4-CH3O-Ph-3,4-diCH3O-Ph-Ph-4-F-Ph-4-CF3-Ph-2-呋喃基2-噻吩基PhCH=CH-2-furanyl-CH=CH-(CH3)2CHCH2-C6H11-CH2-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2-CH3CH2CH2- | |
H | OH | AcO | 2-萘基4-OH-Ph4-CH3O-Ph4-F-Ph(CH3)3CO-CH3-(CH3)2CH-CH2=CHCH2-4-Cl-Ph | Ph |
F | H | AcO | (CH3)3CO- | Ph |
F | H | OH | Ph | Ph |
R2 | R2a | R3a | R4(O)p | R5 |
H | H | AcO | Ph | 4-CH3O-Ph-3,4-diCH3O-Ph-Ph-4-F-Ph-4-CF3-Ph-2-呋喃基21噻吩基PhCH=CH-2-呋喃基-CH=CH-(CH3)2CHCH2-C6H11-CH2-(CH3)2CH-PhCH2CH2-C6H11-CH2CH2CH3CH2CH2- |
CH3SCH2OCH2SCH3
于0℃,将碘化钠(8.23g,55.23mmol),加至1,1′-二氯二甲基醚(3.0g,26.3mmol)的丙酮(100ml)溶液中,并于该温度下搅拌20min。然后将硫代甲醇钠(1.84g,5.23mmol)分四次加入,所得溶液再搅拌1h。通过Celite填塞过滤异源溶液,滤液真空浓缩,残余油在乙酸乙酯和碳酸氢钠饱和水溶液之间分配,除去水层并用乙酸乙酯进一步萃取。合并后的有机相用饱和碳酸氢钠水溶液和5%硫代硫酸钠水溶液的1∶1(V/V)混合物处理。有机相用盐水洗涤,用NaSO4干燥并真空浓缩。通过快速层析(30∶1,己烷∶乙酸乙酯)纯化残余物后得到1.9g黄色油状物,经用Kugelrhor装置(120-130℃,20mmHg)蒸馏后得到1.5g无色油状标题化合物:1H NMR(300MHz,CDCl3)δ4.73(4H,s),2.15(6H,s).制备例15 二苄基甲硫基甲基磷酸酯
CH3SCH2OP(O)(OBu)2
于室温下向双(甲硫基甲基)醚(30mg,2.34mmol)和分子筛(300mg)的THF(100ml)溶液中加入磷酸二苄酯(2.74g,9.85mmol)和N-碘琥珀酰亚胺(608mg,2.71mmol),搅拌溶液4h。用乙酸乙酯稀释反应混合物,并通过Celite过滤。用碳酸氢钠饱和水溶液和5%硫代硫酸钠水溶液的1∶1(V∶V)混合物处理滤液。无色有机萃取物用盐水洗涤,NaSO4干燥,并真空浓缩,得到600mg(69%)标题化合物:1H NMR(300MHz,CDCl3)δ7.35(10H,s),5.29(2H,d,J=12.2Hz),5.08(4H,dd,J=8.0,1.0Hz),4.68(2H,s),2.10(3H,s)。
提供以下实施例是为了说明本发明代表性化合物的合成,而不要以为是以任何方式限定本发明的范围。本发明技术人员利用这些方法,不经过过分实验就可合成属于本发明但未具体公开的化合物。实施例1 7-O-膦酰氧甲基紫杉酚及其单钠盐(a)制备7-O-甲硫基甲基紫杉酚
于0℃,向剧烈搅拌的紫杉酚(0.85g,1mmol)和二甲硫(0.72ml,8mmol)于无水乙腈(10ml)中的混合物中加入过氧化苯甲酰(0.98g,4mmol)。搅拌于0℃继续进行2.5h。通过甲苯∶丙酮(2∶1,V/V)溶剂系统(Rftax=0.38,Rfprod=0.64)中的硅胶TLC监测反应进程,当观察到高极性产物的形成时,通过利用Rotavapor,于30℃蒸发溶剂终止反应。对反应混合物进行TLO分析发现存在部分未反应的紫杉酚和2′,7-O-双(甲硫基甲基)紫杉酚。在硅胶60(40-63μm)EM Science(100ml)〔柱直径:2in.,利用乙酸乙酯∶己烷(1∶1,V/V)溶剂系统(Rfprod=0.34)〕上通过快速柱层析从反应混合物中分离出标题化合物。从级分12-18(每一级分约20ml)中回收产物(552mg,Y:60%)。MS(FAB/matrix NOBA,NaI,KT):[M+H]+,m/z 914;[M+Na]+,m/z 936;[M+K]+,m/z 952Elemental Analysis:C:64.28(calc.64.39),H:5.85(calc.6.07),N:1.46(calc.1.53)UV(MeOH):λmax=226nm,E(1%/1cm)=150,A=0.2653IR(KBr):3432,3066,2940,1726,1668,1602,1582,1514,1484,1452,1372,1242,1178,1142,1108,1068,1026,990,916,884,852,802,774,710,608,570,538,482cm-1.1H-NMR(CDCl3)δ:1.15(3H,s),1.19(3H,s),1.73(3H,s),1.79(H,s),1.90(3H,d),2.09(3H,s),2.16(3H,s),2.29(2H,d),2.35(3H,s),2.77(H,m),3.70(H,d),3.83(H,d),4.17(H,d),4.26(H,m,overlapswith H,d),4.63(2H,t),4.77(H,dd),4.91(H,d),5.65(H,d),5.77(H,dd),6.16(H,dd),6.48(H,s),7.07(H,d),7.29-7.50(10H,m),7.57(H,m),7.73(2H,d),8.08(2H,d).(b)制备7-O-二苄基膦酰氧甲基紫杉酚
将N-碘琥珀酰亚胺(45mg,0.2mM)和磷酸二苄酯(55mg,0.2mM)的无水四氢呋喃(4ml)溶液加到7-O-甲硫甲基紫杉酚(119mg,0.13mM)和粉化分子筛4_(约120mg)的无水1,2-二氯乙烷(5ml)混合物中。于室温下搅拌反应混合物16h,在甲苯∶丙酮(2∶1,V/V)系统(Rfprod=0.48)中通过TLC监测反应进程。通过Celite545过滤掉分子筛,并用二氯甲烷(100ml)萃取滤液。用1%硫代硫酸钠溶液(约100ml)、0.5M碳酸氢钠(100ml)及盐水洗涤有机层。通过Whatman相分离器过滤萃取物,并蒸发溶剂。在硅胶60快速层析柱上纯化(二氯甲烷∶乙酸乙酯,2∶1(V/V))后得到7-O-二苄基膦酰氧甲基紫杉酚(41.5mg)。(c)制备7-O-膦酰氧甲基紫杉酚及其单钠盐
将7-O-二苄基膦酰氧甲基紫杉酚(41.5mg)溶于乙酸乙酯(5ml),并加入10%披钯炭(20mg)。于室温及40PSI(275KPa)下氢化1h。于氯仿∶甲醇∶水(120∶45∶8,V/V)中通过TLC监测反应进程。通过制备性TLC(20×20×0.05cm硅胶板于分析系统中)纯化后得到7-O-膦酰氧甲基紫杉酚(26mg,75%)。
由于在硅胶纯化过程中观察到7-O-二苄基膦酰氧甲基紫杉酚的分解,已对氢化方法进行了改进。即,将7-O-二苄基膦酰氧甲基紫杉酚粗提物不经任何纯化进行氢化。粗提物的氢化于60PSI(400KPa)进行24h。
将7-O-膦酰氧甲基紫杉酚(70mg)溶于5ml丙酮-水(1∶1)溶液中,并用水稀释至50ml。加入无水碳酸氢钠(18mg,1.2eq.),于室温下利用Rotavapor蒸发丙酮,并冷却干燥剩余的水溶液。于水∶乙腈(70∶30,V/V)系统中通过C18逆相柱层析纯化7-O-膦酰氧甲基紫杉酚单钠盐粗品。在乙腈:0.05M乙酸铵缓冲液〔45∶55,V/V,PH=7,Rt=2.09min〕中通过分析性HPLC(15Cm,jones C18柱,1ml/min,l=230/270nm)监测洗脱液。合并含有所需产物的级分,蒸发乙腈,并冷冻干燥剩余水溶液,得到7-O-膦酰氧甲基紫杉酚单钠盐(112mg)。MS(FAB):[M+H]+,m/z 986;[M+Na]+,m/z 1008UV(MeOH):λmax=230nm,E(1%/1cm)=248IR(KBr):3430,3066,2948,1724,1652,1602,1580,1518,1486,1452,1372,1316,1246,1178,1154,1108,1070,1000,982,946,856,802,776,710,628,538cm-1.1H-NMR(acetone-d6/D2O)δ:8.05(2H,d),7.92(2H,d),7.65(1H,dd),7.58-7.35(9H,m,overlap),7.23(1H,dd),6.38(1H,s),6.08(1H,t),5.65(1H,d),5.60(1H,d),5.10(1H,br.s),4.99(1H,d),4.97(1H,br.s),4.80(1H,d),4.28(1H,dd),4.11(2H,s),3.79(1H,d),2.94(1H,m),2.35(3H,s),2.35-2.10(1H,m),2.13(3H,s),1.95(3H,s),1.84(1H,m),1.67(3H,s),1.13(6H,s,overlap).实施例2 制备7-O-膦酰氧甲基紫杉酚的替代方法(a)制备2′-O-(苄氧羰基)紫杉酚
于室温下,向紫杉酚(150mg,0.176mmol)、N,N-二异丙基乙胺(93μl,0.534mmol,3eq.)及无水二氯甲烷(4ml)的搅拌溶液中加入氯代苯甲酸苄基酯(75μl,0.525mmol,3eq.)。于室温搅拌反应混合物3h,浓缩至2ml,并在硅胶柱上纯化(利用1∶1的乙酸乙酯/己烷作为洗脱剂),得到白色粉末状标题化合物(150mg,Y:86%)。MP140-150℃(分解)。(b)制备2′-O-(苄氧羰基)-7-O-甲硫甲基紫杉酚
向2′-O-(苄氧羰基)紫杉酚(4.935g;5.0mmol)的无水乙腈(80ml)冷冻溶液(干冰-CCl4;-30℃浴温)中依次加入二甲硫(3.6ml;40mmol)和过氧化苯甲酰(4.9g;20.247mmol)。于-30℃维持10min后移去冷浴,并将反应混合物于室温下剧烈搅拌2h。然后用乙酸乙酯稀释混合物至200ml,并用水和盐水洗涤。MgSO4干燥有机层,蒸发溶剂后的残余物于真空下维持18h,以除去作为反应前产物存在的任何二甲亚砜。在硅胶柱上纯化残余物,首先用乙酸乙酯∶己烷(1∶2)作为洗脱剂以除去少极性杂质,然后以乙酸乙酯∶己烷(1∶1)作为第二洗脱剂以得到泡沫状所需标题化合物。经用无水乙醚研磨和过滤后,得到标题化合物的松散固体(5.0g,95%)。MP120-122℃。MS(FAB):[MH]+,m/z 1048;[M+Na]+,m/z 1070;[M+K]+,m/z 108IR(KBr):3440,3066,1750,1722,1664,1602,1583,1538cm-1.NMR(CDCl3)δ:1.177(3H,s)1.236(3H,s)1.745(3H,s)2.023(3H,s)2.121(3H s)2.162(3H,s)2.436(3H,s)3.887(H,d)4.134(H,d)4.197(H,d)4.295(H,m)4.964(H,d)5.161(2H,d)5.450(H,d)5.703(H,d)5.981(H,dd)6.257(H,t)6.541(H,s)6.920(H,d,NH)7.322-8.22(15H,m).
该标题化合物也可通过下面的替代方法制备:
向2′-O-(苄氧羰基)紫杉酚(2.0g;2.0263mmol)的无水二甲亚砜(10ml)溶液中滴加乙酸酐(10ml)。于室温及N2环境下搅拌所得反应混合物18h,用乙酸乙酯(100ml)稀释,并小心地用冷6%碳酸氢钠溶液(6×30ml)、冷水(6×30ml)和盐水洗涤。干燥有机层(MgSO4)并蒸发溶剂后得到残余物,通过硅胶柱层析纯化,并用二氯甲烷、二氯甲烷-5%乙腈和二氯甲烷-10%乙腈洗脱后得到所需标题化合物(1.86g,87.7%)。该化合物与通过上述二甲硫/过氧化苯甲酰法获得的产物相同。(c)制备2′-O-(苄氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚
向2′-O-(苄氧羰基)-7-O-甲硫甲基紫杉酚(5.0g;5.5396mmol)的元水1,2-二氯乙烷(120ml)溶液中加入活化的粉状4_分子筛(5.0),于室温下向该混合物中滴加N-碘琥珀酰亚胺(1.61g,7.1632mmol)和磷酸二苄基酯(1.97g;7.1632mmol)的混合物于无水四氢呋喃(90ml)中的溶液。于室温下剧烈搅拌30min后,在Celite上过滤反应混合物,将滤液蒸发至干,得到红色残余物。将其溶于乙酸乙酯(100ml),用6%冷NaHSO3溶液(2×50ml)、6%冷NaHCO3溶液(2×50ml)和盐水(1×50ml)洗涤。干燥有机层(MgSO4),蒸发溶剂后得到一固体,再经用无水乙醚研磨和过滤后得到象牙色固体状标题化合物(5.9g,97%)。MP124-127℃。MS(FAB):[MH]+,m/z 1278;[M+Na]+,m/z 1301;[M+K]+,m/z 1316IR(KBr):3430,3066,3032,1750,1726,1664,1582,1532cm-1NMR(CDCl3)δ:1.160(3H,s)1.703(3H,s)1.985(3H,s)2.164(3H,s)2.420(3H,s)3.854(H,d)4.151(H,d)4.216(H,m)4.298(H,d)4.873(H,d)5.043(6H,m)5.140(2H,d)5.417(H,d)5.670(H,d)5.971(H,dd)6.241(H,t)6.317(H,s)6.912(H,d,NH)7.280-8.115(25H,m).(d)制备7-O-膦酰氧甲基紫杉酚
向2′-O-(苄氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(6.0g,4.7095mmol)的乙酸乙酯(120ml)溶液中加入10%pd/c(6.0g),并将混合物于60psi(400KPa)氢化24h。通过Celite过滤反应混合物并蒸发溶剂后,得到4.07g粗残余物。经-短硅胶柱纯化(依次用氯仿:10%、20%和40%甲醇洗脱)后得到白色固体状标题化合物(3.2g,71%),MP155-158℃。
该产物与可靠样品具有同样的Rf(TLC)和同样的保留时间(HPLC)。MS(FAB):[MH]+,m/z 964;[M+Na]+,m/z 986;[M+K]+,m/z1002;[M+K++Na+-H]+,m/z 1024;[M+2K-H]+,m/z 1040UV(MeOH):λmax=230nm,E(1%/1cm)=252.5IR(KBr):3432,3066,2992,1722,1648,1602,1580,1522,1488,1452,1372,1316,1246,1178,1154,1110,1070,1000,980,946,854,802,776,710,628,538cm-1.1NMR(acetone-d6/D2O),δ:1.08(3H,s),1.10(3H,s),1.63(3H,s),1.88(3H,s),1.96(H,m),2.13(3H,s),2.32(3H,s),2.89(H,m),3.76(H,d),4.19(H,m),4.89(H,dd),5.09(H,dd),5.55-5.60(2H,overlapping d′s),6.04(H,t),6.32(H,s),720(H,t),7.34-7.67(10H,overlapping m′s),7.87(2H,dd),8.02(2H,dd).实施例3 2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚(a)制备2′-O-(乙氧羰基)紫杉酚
向紫杉酚(4.35g,5.1mmol)的无水二氯甲烷(51ml)溶液中加入N,N-二异丙基乙胺(2.67ml,15.3mmol)以及氯代甲酸乙酯(1.46ml,15.3mmol),该反应混合物于0℃搅拌2h,再于室温继续搅拌1h。用乙酸乙酯(400ml)稀释反应混合物后,用NaHCO3饱和溶液(2×30ml)及盐水(30ml)洗涤有机相。所得有机相经MgSO4干燥后产生粗标题化合物(93%),它不经进一步纯化而直接用于下一步骤。MS(FAB/NOBA,NaI,KI):[M+H]+,m/z 926;[M+Na]+,m/z 948;[M+K ]+,m/z 964HRMS(FAB/NOBA,CsI/Gly external reference):[M+H]+m/z 926.3588 observed,C50H56NO16,calculated value:926.3599(deviation Δ=1.2ppm)1HNMR(CDCl3):δ1.13(3H,s),1.23(3H,s),1.30(3H,t),1.67(3H,s),1.92(3H,s),2.21(3H,s),2.37(H,d),2.45(3H,s),2.54(H,m),3.80(H,d),4.15-4.32(4H,m′s overlapping),4.43(H,dd),4.96(H,d),5.42(H,d),5.68(H,d),5.98(H,dd),6.28(2H,m′s,overlapping),7.00(H,d),7.34-7.59(11H,m′soverlapping),7.74(2H,d),8.12(2H,d).替代方法:
将紫杉酚(5.40g,6.324mmol)的无水二氯甲烷(63ml)溶液冷却至0℃,并用净N,N-二异丙基乙胺(3.30ml,3equiv)处理,然后在5min内滴加净氯代甲酸乙酯(1.81ml,3equiv)。利用TLC(50%乙酸乙酯的己烷)监测反应,0℃2h及室温16h后,反应完毕,用乙酸乙酯(300ml)稀释桔黄色溶液,并用NaHCO3饱和水溶液(3×75ml)和盐水(75ml)洗涤。干燥(MgSO4)及蒸发后,得到粗标题化合物,它通过沉淀纯化:加入二氯甲烷(约100ml),冷却,加入己烷(约60ml)至混浊点。在水中冷却数小时后,过滤收集固体。产率5.17g(88%)。替代方法:
于氩气环境下在火焰干燥的单颈3L烧瓶中将紫杉酚(99.0g,115.9mmol)溶于1.350ml无水二氯甲烷。冷却溶液至-10℃,缓慢加入N,N-二异丙基乙胺(52.4g,405.7mmol)(加入时间约3min),接着加入ClCO2Et(31.45g,289.8mmol;加入时间约15min)。于-4℃搅拌所得混合物。通过TLC判断反应未完全,加入另一份N,N-二异丙基乙胺(2.62g,20.28mmol)及ClCO2Et(2.20g,20.28mmol),并于-4℃继续搅拌3h。通过TLC来测出起始物。用乙酸乙酯(1.5l)稀释该冷混合物,并转移至一分离漏斗,依次用5%KHSO4(2×500ml)、水(1×500ml)、5%KHSO4(1×500ml)、水(1×500ml)、饱和NaHCO3(2×500ml)和盐水(2×500ml)洗涤,再经干燥(MgSO4)和真空除去溶剂后,得到147g粗产物。将其溶于热的二氯甲烷(800ml,浴温42℃)并在搅拌下滴加己烷(530ml),同时维持该温度。于室温下结晶混合物3h,然后于冷室(0℃)中过夜。过滤收集重的白色结晶,并用己烷/CH2Cl21∶1(V/V)(2×200ml)。于吸滤器上干燥1h后,真空过夜干燥(约1.0mmHg),得到95.7g(89%)标题化合物(通过HPLC测得的均一性指数为98.5%)。(b)制备2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚
向2′-O-(乙氧羰基)紫杉酚(4.38g,7.7mmol)的无水二甲亚砜(12.5ml)溶液中加入乙酸酐(12.5ml)。于室温下搅拌反应混合物24h,然后用乙酸乙酯(500ml)稀释,用NaHCO3饱和水溶液(3×40ml)和水(2×40ml)洗涤所得有机层于MgSO4上干燥,真空蒸发溶剂至干燥。通过硅胶层析(40%乙酸乙酯的己烷)纯化残余物后,得到所需标题化合物(4.39g,94%)。MS(FAB/NOBA,NaI,KI):[M+H]+,m/z 986;[M+Na]+,m/z 1008;[M+K]+,m/z 1024HRMS(FAB/NOBA,CsI/Gly external reference):[M+H]+m/z 986.3646(calculated value:986.3633,deviation Δ=1.3ppm)1HNMR(CDCl3)δ:1.18(3H,s),1.20(3H,s),1.30(3H,s),1.75(3H,s),1.84(H,m),2.09(3H,s),2.11(3H,s),2.16(3H,s),2.24(H,d),2.37(H,d),2.45(3H,s),2.80(H,m),3.68(H,d),4.08-4.33(5H,m,overlapping),4.65(2H,s),4.96(H,d),5.43(H,d),5.69(H,d),5.98(H,dd),6.26(H,t),6.55(H,s),7.00(H,d),7.32-7.61(11H,m,overlapping),7.73(2H,dd),8.11(2H,dd).替代方法:
将2′-O-(乙氧羰基)紫杉酚(2.260g,2.4406mmol)溶于无水二甲亚砜(6ml),并于室温下一次性加入乙酸酐(6ml)。通过HPLC(C18分析柱;60%乙腈-40%10mM磷酸铵缓冲液,PH6)监测反应。30h后,用乙酸乙酯(250ml)稀释溶液,并用NaHCO3水溶液(3次)、水和盐水洗涤。MgSO4干燥及过滤后,将粗产物在硅胶上层析(40%乙酸乙酯的己烷),得到白色泡沫状标题化合物(2.030g,91%),通过HPLC测得的纯度为90%。将部分通过第二柱(5%乙腈的二氯甲烷)纯化后得到纯度为97%(HPLC)的物质。制备2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚的替代方法
于-40℃将2′-O-(乙氧羰基)紫杉酚(4.170g,4.503mmol)溶于无水乙腈(68ml),加入二甲硫(3.2ml,44.10mmol)及过氧化苯甲酰(4.400g,18.24mmol)。将该混合物于冰浴上,并于0℃搅拌,通过TLC(40%乙酸乙酯的己烷)监测反应进程。3h后检测不到起始物,加入乙酸乙酯(250ml)和碳酸氢钠饱和水溶液(100ml)。有机相用碳酸氢钠、水和盐水进一步洗涤,然后在MgSO4上干燥并过滤。通过硅胶快速层析(4%乙腈的二氯甲烷)纯化残基物后,得到白色泡沫状标题化合物(2.571g,58%)。通过HPLC测得的纯度大于97%。NMR光谱与上面报导的相同。制备2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚的替代方法
将2′-O-(乙氧羰基)紫杉酚(49.3g,53.2mmol)置于火焰干燥的1L单颈烧瓶中,并于室温下溶于无水乙腈(500ml)。利用注射器快速加入甲基硫(39.1ml,0.532mol)。于冰/盐浴上冷却搅拌的反应混合物至-16℃,一次性加入固体过氧化苯甲酰(51.6g,0.213mol)(反应完全需要整整4个当量)。继续搅拌30分钟,其间温度升至约-10℃。在此期间反应介质保持异相(过氧化苯甲酰未全部溶解)。将冷却浴改为冰/水,温度升至0℃,且剩余的过氧化苯甲酰在升温后约5min溶解。于0℃搅拌另2.5h后通过TLC判定反应完全。通过旋转蒸发除去溶剂后溶液体积减至约200ml,将其转移至分离漏斗中,用庚烷(5×500ml)洗涤用乙酸乙酯(1.5l)稀释乙腈层,并依次用3∶1的饱和NaHCO3/5%K2CO3(V/V)混合物(2×500ml)、饱和NaHCO3(2×500ml)、半饱和盐水(1×500ml)和盐水(1×500ml)洗涤,干燥(MgSO4)并真空除去溶剂后,得到67.0g粗产物。将其溶于丙酮(200ml)、于水浴中加热至40℃,在搅拌下滴加己烷,直至观察到混浊(400ml)。结晶混合物于室温下放置3h,然后转移至冷室(0℃)放置过夜(16h)。形成厚饼,过滤收集固体,并用己烷/丙酮3∶1(V/V)(2×50ml)。所得白色结晶在吸滤器上干燥1h,然后真空(~0.5mmHg)过夜,得到47.5g(Y:91%)标题化合物(通过HPLC测得的均一性指数=94.8%)。(c)制备2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚
于室温下将N-碘代琥珀酰亚胺(1.953g,8.65mmo1)和磷酸二苄基酯(2.41g,8.65mmol)的四氢呋喃溶液加至2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚(5.677g,5.76mmol)和4_分子筛(5.7g)于二氯甲烷(100ml)的混合物中。于室温下搅拌反应混合物40min。之后通过TLC测得反应完全。通过Celite过滤反应混合物,经真空过滤后得到一棕色残余物,将其用乙酸乙酯(800ml)稀释,用1%Na2SO4(2×80ml)及5%盐水(2×50ml)洗涤有机层。真空浓缩并干燥有机相。经层析所得残余物(50-60%乙酸乙酯的己烷)后得到所需标题化合物。MS(FAB/NOBA,NaI,KI):[M+Na]+,m/z 1238;[M+K]+,m/z 1254HRMS(FAB/NOBA,CsI/Gly external reference):[M+Na]+m/z 1216.4291(C65H71NO20P calculated value:1216.4307;deviation Δ=1.3ppm)1HNMR(CDCl3),δ:1.18(3H,s),1.21(3H,s),1.30(3H,t),1.67(6H,s),1.80(H,s),1.93(H,m),1.99(3H,d),2.18(3H,s),2.23(H,m),2.38(H,m),2.45(3H,s),2.80(H,m),3.86(H,d),4.14-4.32(5H,m′s,overlapping),4.88(H,d),5.00-5.07(4H,m′s,overlapping),5.42(H,d),5.68(H,d),5.96(H,dd),6.26(H,t),6.33(H,s),6.95(H,d),7.30-7.61(11H,m′s overlapping),7.75(2H,dd),8.12(2H,dd).替代方法:
向2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚(350mg,0.355mmol)的无水四氢呋喃(8ml)溶液中加入N-碘代琥珀酰亚胺(120mg,0.532mmol)和磷酸二苄基酯(148mg,0.532mmol)的无水四氢呋喃(5ml)溶液。利用HPLC(C18柱;70%乙腈,30%10mM磷酸铵,PH6)。2h后,测得的起始物少于5%,反应终止。用乙酸乙酯(75ml)稀释溶液,用1%二硫化钠水溶液(2×50ml)和盐水(50ml)洗涤。于MgSO4上快速干燥并过滤后,蒸发溶剂。经硅胶快速层析(45%乙酸乙酯/己烷)后得到白色泡沫状标题化合物(281mg,65%)。HPLC分析测得的纯度约为95%。替代方法:
将粉碎的4_分子筛置于火焰干燥的1L-颈烧瓶中,然后将其与-真空管(约0.5mmHg)相连。用加热枪加热分子筛始10min,同时用手振荡。真空冷却后,向瓶中通气氩气,并加入2′-O-(乙氧羰基)-7-O-甲硫甲基紫杉酚(37.5g,38.03mmol),接着加入磷酸二苄基酯(14.8g,53.24mmol)和THF(400ml)。于室温下用磁力搅拌器剧烈搅拌非均质混合物15min。在另一火焰干燥烧瓶中,于氩气下将N-碘代琥珀酰亚胺(10.7g,47.54mmol)溶于THF(50ml)(在制备NIS溶液过程中,转移液体,并在反应过程中用铝箔盖住容器以避光),然后用注射器将其缓慢(10min)加至反应混合物中,用5ml THF洗涤含有NIS的烧瓶,并转移至反应混合物中,室温下搅拌2h。TLC分析证实无起始物存在。深红色溶液经CeliteR填塞直接过滤到剧烈搅拌的两相混合物中,其中含有乙酸乙酯(500ml)、10%硫代硫酸钠(300ml)和饱和碳酸氢钠(200ml)。几分钟后红色消失,产生无色溶液,用EtoAc(~100ml)洗涤CeliteR塞,并将两液体层转移至分离漏斗。用1L EtoAc稀释有机层,分离各层,并用饱和NaHCO3和5%K2CO3的混合物(3∶1V/V,2×500ml)、饱和NaHCO3(2×500ml)、半饱和盐水(1×500ml)和盐水(1×500ml)洗涤有机层。萃取物用无水MgSO4干燥并过滤。通过搅拌于室温下用5.0g中性Norit(活性炭)处理15min。经CeliteR过滤及减压除去溶剂后得到52g粗产物。将其溶于甲苯/二氯甲烷(280ml/25ml),并滴加己烷(20ml)。室温放置3h后,结晶混合物于0℃放置过夜。烧瓶壁上形成浅黄色固体。弃去母液后,用甲苯(50ml)研磨残余物,过滤,用甲苯洗涤,并抽滤干燥30min,然后转移至装有Drieri-teR的干燥器中,并进一步真空(20.5mmHg)干燥4h,得到24.4g(Y:53%)标题化合物(通过HPLC测得均一性指数=95.9%)。母液蒸发干燥,用甲苯(100ml)研磨,过滤,用甲苯洗涤,并在吸滤器上干燥30min。于上述干燥器上干燥后得到12.5g(Y:27%)相同产物,(通过HPLC测得均一性指数=97.1%)。(d)制备2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚;其单钠盐,单钾盐,三乙胺盐,精氨酸盐,赖氨酸盐,乙醇胺盐,N-甲基葡聚胺盐和三乙醇胺盐
向2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(1.23g,1.01mmol)的无水乙酸乙酯(40ml)溶液中加入10%披钯炭(428mg,10%,0.404mmol)。在连续振荡条件下氢化(60psi=400KPa)24h,通过Celite过滤固体,然后用乙酸乙酯数次浸泡Celite。浓缩滤液后得到游离酸形式标题化合物(1.01g,通过HPLC判定纯度为80%)。下-步通过制备性C-18柱层析除去杂质。MS(FAB/NOBA,NaI,KI):[M+Na]+,m/z 1058;[M+K]+,m/z 1074;[M+2Na-H]+,m/z 1080;[M+Na+K-H]+,m/z 1096;[M+2K-H]+,m/z 1112HR-MS(FAB/NOBA,CsI/Gly,external reference):[M+Na]+,m/z 1058.3163(C51H58NO20PNa calculated value:1058.3188;deviation Δ=2.3ppm)1H NMR(acetone-d6/D2O)δ:1.13(3H,s),1.21(3H,s),1.66(3H,s),1.87(H,m),1.93(3H,s),2.14(3H,s),2.18(H,m),2.44(3H,s),2.95(H,m),3.81(H,d),4.12(2H,s),4.15-4.27(3H,m′s overlapping),4.92-4.99(2H,br.m′s overlapping),5.15(H,br.s),5.48(H,d),5.61(H,d),5.84(H,dd),6.07(H,t),6.36(H,s),7.25(H,t),7.28-7.69(10H,m′soverlapping),7.89(2H,dd),8.08(2H,dd),8.86(H,d).替代方法:
在披钯炭(10%W/W,150mg)存在下于60psi(400KPa)帕氏振荡器中氢化2′-O-(乙氧羰基)-7-O-(二苄基膦酰氧甲基)紫杉酚(490mg,0.402mmol)的乙酸乙酯(20ml)溶液。通过TLC和HPLC监测反应进程,当检测不到任何起始物或中间产物(推测为磷酸-苄基酯)时(26h),通过Celite过滤悬浮液,并蒸发干燥。HPLC分析测得的纯度为88-92%。替代方法:
于0℃搅拌条件下将下面所述的2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚三乙胺盐(5.4g,4.75mmol)在EtoAc(100ml)和5%NaHSO4(45ml)之间剧烈分配30min。分离出水层,用EtoAc(20ml)萃取。合并后的EtoAc层用半盐水(25ml)和盐水(25ml×2)洗涤,经MgSO4干燥和过滤后,得到酸(~4.75mmol)的EtoAc(~150ml)溶液。然后在旋转蒸发器上干燥该EtoAc溶液后得到3.75g(Y:95%)游离酸形式的标题化合物。经HPLC分析测得的均一性指数为96.1%。单钠盐制备如下:
利用声波将2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚样品(1.6g,1.55mmol)溶于乙腈(30ml)。用水(30ml)稀释该溶液,并加入1.1M NaHCO3溶液(2.11ml,2.32mmol),振荡和声波交替处理后得到一溶液(5-20min)。将该部分乳状溶液加到C-18柱上,用2柱体积的水洗涤,然后用25%乙腈/水洗脱单钠盐。收集合适的级分,蒸发乙腈并冷冻干燥水相,得到标题化合物的单钠盐(850mg,约50%),HPLC纯度为97%。MS(FAB/NOBA,NaI,KI):[M+Na]+,m/z 1180HR-MS(FAB/NOBA,CsI/Gly external reference):[M+Na]+,m/z 1080.2968(C51H57NO20PNa2 calculated value:1080.3007;deviation D=3.6ppm)Elemental analysis:C:52.65(calc.56.72),H:5.06(calc.5.23),N:1.20(calc.1.30),Na:2.74(calc.2.12)IR(KBr):3430,3066,2988,1746,1722,1660,1602,1582,1526,1488,1452,1374,1246,1178,1150,1108,1070,1052,1026,1002,966,912,834,792,776,710,628,538cm-1.1H-NMR(DMSO-d6,D2O,acetone-d6)δ:1.10(6H,s),1.23(3H,t),1.64(3H,s),1.70(H,m),1.90(3H,s),1.99(H,m),2.14(3H,s),2.37(3H,s),2.98(H,m),3.74(H,d),4.07(2H,s),4.13-4.26(3H,m,overlapping),4.80(H,br.dd),4.97(H,d),5.09(H,br.t),5.44(H,d),5.55(H,d),5.99(H,t),6.34(H,s),7.22(H,t),7.4 3-7.69(10H,m,overlapping),7.92(2H,dd),8.06(2H,dd).钠盐也可通过如下方法制备:
于室温搅拌条件下用乙基己醇钠(87.5mM于EtoAc,1.0ml,0.0875mmol)溶液处理2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚粗品(89%;70mg,0.060mmol)的EtoAc(2ml)。室温下搅拌1h后,加入己烷(1.2ml)至混浊点,于-20℃保存2h,通过精细滤纸过滤细无孔粉末(有一定困难,很慢),得到45mg(70%)钠盐。通过HPLC测得的纯度为95.2%,它含有少量乙基己酸(NMR)。三乙醇胺盐按下法制备:
将得自氢化的粗品(89%,HPLC)2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚(0.69g,0.593mmol,校正杂质后)溶于乙酸乙酯(10ml),并缓慢搅拌,同时滴加三乙醇胺溶液(0.11M于EtoAc,使用5.1ml,0.95eq)。40℃消化所得乳状溶液2h,然后在精细滤纸上过滤,用冷EtoAc浸泡。产生:499mg(80%)无孔、细粉、无静电粉末,于真空过夜干燥。HPLC纯度为96.6%(C-18,45%5mM Q12+10mM磷酸铵,PH6,55%乙腈)。NMR光谱(D2O/丙酮/DMSO)显示出乙酸乙酯轨迹,且无其它净切割杂质,分析为2-3X水合物。
由另一实验中附带得到的三乙醇胺盐通过以下步骤进一步纯化。将三乙醇胺盐(约2g)溶于30%乙腈/水。在轻微的氮气压力下通过C18柱(Bakerbend)洗脱该溶液,该柱具有20%-40%乙腈于水的梯度。收集含有所需三乙醇胺盐的级分;通过减压旋转蒸发除去乙腈。冷冻水溶液,过夜冻干后得到1.4g三乙醇胺盐,纯度为97.5%。
于0℃剧烈搅拌条件下,将2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚三乙胺盐(3.0g,2.64nnol)在EtoAc(60ml)和5%NaHSO4(30ml)之间分配15min。分离水层并用EtoAc(10ml)萃取、用盐水(15ml)洗涤合并的EtoAc后,Na2SO4干燥,过滤,得到酸(~2.64mmol)的EtoAc(~70ml)溶液。于室温剧烈搅拌下,在5分钟内向该EtoAc溶液中滴加N(CH2CH2OH)3(0.35ml,2.64mmol)。所得悬浮液再搅拌1h后过滤,用EtoAc(15ml×2)洗涤,真空干燥,得到2.8g三乙醇胺盐(89%)。HPLC分析显示其均一性指数为98.7%;m.p.:>157℃(分解)。Elemental analysis calculated for C56H73N2O23P.2.0 H2O.0.3EtOAc:C,55.60;H,6.48;N,2.27;KF(H2O),2.92.Found:55.94;H,6.59;N,2.43;KF(H2O),3.50.三乙胺盐制备如下:
于室温下向2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(10g,8.23mmol)的EtoAc(350ml)溶液中加入10%披钯碳(2g,20%)。通过抽空气及通入氩气使所得悬浮液脱气。重复该方法两次。然后以氢气代替氩气进行同样的脱气步骤。于室温及气球氢气压力(每平方英寸2-3磅)下剧烈搅拌所得悬浮液16h。抽掉氢气,按同样方法用氩气脱气三次。所得悬浮液通过Celite填空过滤。在剧烈搅拌下向该均匀滤液中于5min内缓慢加入Et3N(8.23mmol,1.14ml),所得白色细悬液再搅拌30min,用孔径为E600漏斗过滤,真空(1mmHg)干燥滤饼16h后得到8.22g标题三乙胺盐(Y:88%),HPLC分析显示的均一性指数为97.4%;m.p.>178℃(分解)。Elemental analysis calculated for C57H73N2O20P·4.5 H2O:C,56.19;H,6.79;N,2.30;KF(H2O),6.65.Found:56.33;H,6.87;N,2.32;KF(H2O),7.96.制备三乙胺盐的替代方法:
将2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(5.67g,4.66mmol)加至250ml烧瓶中,并溶于乙酸乙酯(150ml)。该烧瓶装有一三相阀,一个与真空相连,一个与氩气相连。利用该阀,将该烧瓶部分抽真空,然后泵入氩气。再重复该方法两次。向烧瓶中加入披钯活性碳(10%pd)(0.85g),用填充氢气的气球代替与一三相阀相连的氩气管。利用该阀,将烧瓶部分抽真空并通入氢气,再重复该方法四次。在氢气球压力下于室温过夜搅拌所得混合物。在首次暴露于氢气后17h,经TLC分析显示起始物消失。用氩气管取代与三相阀相连的氢气球。利用该阀,使烧瓶部分抽真空,然后通入氩气。再重复该方法两次。通过Celite真空过滤烧瓶内容物,用乙酸乙酯(2×10ml)浸泡Celite。向搅拌滤液中加入NEt3(0.650ml,4.66mmol)。于室温搅拌所得悬浮2h,通过旋转蒸发使其体积降至约150ml。过滤固体,用乙酸乙酯(2×10ml)洗涤及真空干燥后,得到4.76g(90%产率)白色粉末状标题三乙胺盐(通过HPLC分析测得均一性指数为96.6%)。制备三乙胺盐的替代方法:
将2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(5.17g,4.25mmol)加到250ml烧瓶中并溶于乙酸乙酯(150ml)。该烧瓶装有一三相阀,一个与室里真空相连,一个与氩气相连。利用该阀,将烧瓶部分抽真空,然后通入氩气。重复该方法两次。向烧瓶中加入披钯活性碳(10%pd)(0.86g)。用填充氢气的气球取代与三相阀相连的氩气管,利用该阀,使烧瓶部分抽真空,然后通入氢气。重复该方法五次,于室温氢气球压力下搅拌所得混合物过夜。在首次暴露于氢气16h后,通过TLC分析发现起始物已消失。用氩气管取代与三相阀相连的氢气球,利用该阀,将烧瓶部分抽真空,然后通入氩气。重复该方法两次。在Celite填塞上真空过滤烧瓶内容物。用乙酸乙酯(4×10ml)浸泡Celite,向所得滤液中加入NEt3(0.590ml,4.25mmol)。所得悬浮液于室温搅拌1h,通过旋转蒸发使体积减至约140ml。过滤固体,用乙酸乙酯(10ml)洗涤,并真空干燥,得到4.46g(Y:92%)白色固体状标题三乙胺盐(通过HPLC分析测得均一性指数为96.7%)。赖氨酸盐制备如下:
于0℃将2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(15.0g,12.34mmol)分批加到10%披钯碳(20%负荷,3g)的EtOH(600ml,200标准强度)悬浮液中。通过抽真空及通入氩气使所得悬液脱气。重复该方法两次。然后用氢气取代氩气,在剧烈搅拌下进行同样的脱气处理。所得混合物于0℃搅拌2h。除去冷却浴,于室温下搅拌反应溶液4-1/2h。通过三次抽氢气及通入氩气使反应混合物脱气。氩气下通过Celite塞过滤,在剧烈搅拌条件下,在5min内向所得滤液中缓慢加入赖氨酸(1.63g,0.49eq)于H2O/EtOH的1∶1混合物(200标准强度)(20ml)的溶液中。向所得白色悬液中加入蒸馏水(110ml)并搅拌30min。温热至约55℃。所得均匀溶液于50℃油浴中放置,并缓慢冷却至室温放置16h,及4℃放置3h。过滤并抽干16h后,得到11.8g(产率约80%)赖氨酸盐,通过HPLC测得均一性指数为99.0%;m.p.:>170℃(分解)。Elemental analysis calculated for C57H72N3O22P·8.0 H2O:C,51.62;H,6.69;N,3.17;KF(H2O),10.87.Found:51.76;H,6.57;N,3.48;KF(H2O),11.42.乙醇胺盐的制备方法如下:
于0℃剧烈搅拌下将2′-O-(乙氧羰基)-7-O-膦酰氧甲基紫杉酚三乙胺盐(3.0g,2.64mmol)在EtoAc(60ml)和5%NaHSO4(30ml)之间分配15min。分离水层并用EtoAc(15ml)萃取。合并EtoAc层,用盐水(15ml)洗涤,Na2SO4干燥及过滤后,得到游离酸(约2.64mmol)的EtoAc(~70ml)溶液。于室温剧烈搅拌条件下,在5min内向该EtoAc溶液中滴加H2NCH2CH2OH(0.15ml,2.64mmol)的EtoAc(5ml)溶液。所得悬浮液再搅拌1h,然后过滤,用EtoAc(15ml×2)洗涤,并真空干燥,得到2.6g标题乙醇胺盐(Y:89%)。通过HPLC测得均一性指数为97.8%;m.p.:>130℃(分解)。Elemental analysis calculated for C53H65N2O21P·2.5 H2O:C,55.73;H,6.18;N,2.45;KF(H2O),3.94.Found:C,55.76;H,6.39;N,2.45;KF(H2O),6.00.精氨酸盐的制备方法如下:
于0℃将2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(30.0g,24.69mmol)分批加到10%披钯碳(20%负荷,6g)的EtOH(900ml,200标准强度)的悬浮液中。通过抽真空及通入氩气使所得悬浮液脱气。重复该方法2次,然后用氢气取代氩气进行上述脱气,同时剧烈搅拌。所得混合物于0℃搅拌2h。除去冷却浴,于室温下搅拌反应溶液24h。按照上述方法通过抽氢气及通氩气使反应混合物三次脱气。氩气下通过Celite塞过滤,将滤液分为两等份,向每份中加入EtOH(190ml,200标准强度)。在剧烈搅拌下,在5min内向其中一份中缓慢加入精氨酸(2.0g,0.94eq)于H2O∶EtOH(200标准强度)的2∶1混合物(20ml)中的溶液,向所得白色悬浮液中加入蒸馏水(100ml)并搅拌30min,然后温热至约60℃。热过滤,并将滤液放置在于50℃油浴中,让其冷却至室温,于室温放置2h,4℃放置2h。过滤,用3%H2O于EtOH的冷溶液(100ml)洗涤,抽干16h后得到12.95g Y:~86%)标题精氨酸盐,均一性指数为96.7%。
于55℃将该物质(12.95g)溶于15%H2O于EtOH的混合物(2700ml)中。冷却溶液,于30℃放置3-1/2h,室温放置16,及4℃放置3h。过滤所得结晶,用2%H2O的EtOH冷溶液(50ml×2)洗涤,抽干4h,然后真空(1mmHg)干燥16h,得到10.2g(Y:~80%)标题精氨酸盐(均一性指数98.5);m.p.:>176℃(分解)。Elemental analysis calculated for C57H72N5O22P·6.4 H2O:C,51.65;H,6.45;N,5.28;KF(H2O),8.7.Found:C,51.86;H,6.65;N,5.53;KF(H2O),8.72.N-甲基葡糖胺盐的制备方法如下:
于0℃将2′-O-(乙氧羰基)-7-O-二苄基膦酰氧甲基紫杉酚(30.0g,24.69mmol)分批加到10%披钯碳(20%负荷,6g)的EtOH(900ml,200标准强度)悬液中。通过抽空气及通入氩气使所得悬浮液脱气。重复该方法2次,然后用氢气代替氩气进行上述脱气,同时剧烈搅拌。所得混合物于0℃搅拌2h,除去冷却浴,于室温继续搅拌反应溶液24h。通过抽氢气及通入氩气使反应混合物脱气三次。于氩气下通过Celite塞过滤,将滤液分成两等份,并向每一份中加入EtOH(190ml,200标准强度)。在剧烈搅拌情况下,于5分钟内向一份(约630ml)中缓慢加入N-甲基葡糖胺(2.24g,0.94eq)于H2O∶EtOH(200标准强度)的1∶1混合物中的溶液(20ml)。向所得白色悬浮液中加入蒸馏水(100ml),搅拌悬浮液30min,然后温热至49℃。将清晰的均质溶液放置在50℃油浴中,让其冷却至室温,并于室温放置2h,于4℃放置1-1/2h。过滤,用3%H2O的EtOH溶液(100ml)洗涤,于室温吸干16h,得到9.65g(Y:64%)标题N-甲基葡糖胺盐,其均一性指数为96.4%。
于52℃将该物质(9.65g)溶于15%H2O的EtOH溶液(~450ml)中,冷却溶液,于28℃放置3-1/2h,室温放置16h,4℃放置3h。过滤所得结晶,用冷的2%H2O的EtOH溶液(50ml×2)洗涤,吸干4h,真空(1mmHg)干燥16h,得到7.5g(Y:~80%)标题N-甲基葡糖胺盐(通过HPLC测得的均一性指数为98.6%);m.p.>154℃(分解)。Elemental analysiscalculated for C58H75N2O25P·5.0 H2O:C,52.72;H,6.48;N,2.12;KF(H2O),6.82.Found:C,53.09;H,6.50;N,2.08;KF(H2O),7.12.实施例4 2′-O-(膦酰氧甲基)紫杉酚(a)制备2′-O-(甲硫甲基)-7-O-(三乙基甲硅烷基)紫杉酚
向7-O-(三乙基甲硅烷基)紫杉酚(2.46g,2.5439mmol)于无水乙腈(100ml)中的冷却(0至-5℃)溶液中加入二甲硫(1.348g;1.59ml;21.6976mmol),接着再加入过氧化苯甲酰(2.628g;10.8488mmol)。于0℃搅拌该异质混合物1h,并于5℃放置18h,观察了黄色溶液。将其蒸发干燥并通过硅胶柱纯化(用乙酸乙酯∶己烷,1∶4,1∶3和1∶2洗脱),得到标题化合物(1.0g,38%),它被直接用于下一步骤。(b)制备2′-O-(甲硫甲基)紫杉酚
向步骤(a)产物(1.0g;0.9737mmol)的无水乙腈(30ml)冷却(-15℃)溶液中滴加0.5N HCl(3ml)。所得溶液于-15℃搅拌1h,5℃搅拌18h,然后用乙酸乙酯(30ml)稀释,用6%NaHCO3冷溶液和盐水洗涤。于MgSO4上干燥后蒸发至干,再经硅胶板纯化(二氯甲烷:15%乙腈)后得到纯标题化合物(280mg,31.4%)。IR(KBr):3446,3064,2940,1726,1666,1582,1516,1486.NMR(CDCl3):δ1.118(s,3H),1.229(s,3H),1.662(s,3H),1.689(s,3H),1.871(s,3H),2.209(s,3H),2.450(s,3H),3.800(d,H),4.119(d,H),4.305(d,H),4.413(m,H),4.563(d,H),4.703(d,H),4.940(d,H),4.958(dd,H),5.667(d,H),5.822(dd,H),6.263(m,2H),7.019(d,NH),7.293-8.127(m,15H).MS:[M+H]+,914;[M+Na]+,936;[M+K]+,952HRMS:MH+:914.3394(calculated=914.3422)(c)制备2′-O-(二苄基膦酰氧甲基)紫杉酚
向步骤(b)产物的无水1,2-二氯乙烷(12ml)溶液中加入粉化的4_分子筛(1.0g),接着滴加N-碘代琥珀酰亚胺(0.33g;1.4622mmol)和磷酸二苄基酯(0.41g;1.4622mmol)的无水四氢呋喃(8ml)溶液混合物。于室温下搅拌所得混合物1h,然后通过Celite过滤,滤液蒸发至干燥,红色残余物溶于乙酸乙酯(50ml),用冷的6%NaHSO3、冷的6%NaHCO3和盐水洗涤,MgSO4干燥和蒸发后得到一泡沫。通过硅胶板纯化(二氯甲烷:20%乙腈)后,得到纯产物(0.77g,69%)。IR(KBr):3854,3744,3362,3066,1960,1722,1602,1580.NMR(CDCl3):δ1.075(s,3H),1.167(s,3H),1.651(s,3H),1.799(s,3H),2.209(s,3H),2.296(s,3H),2.464(m,H),3.686(d,H),4.121(d,H),4.240(d,H),4.293(m,H),4.808-4.957,(m,6H),5.006(m,H),5.565-5.649(m,2H),6.034(t,H),6.194(3,H),7.100-8.132,(m,26H).MS:[M+H]+,1144;[M+Na]+,1166;[M+K]+,1182(d)制备2′-O-(膦酰氧甲基)紫杉酚
于60psi(400kpa)下将步骤(c)产物(0.9g0.7874mmol)、10%pd/c(1.0g)及乙酸乙酯(20ml)的混合物氢化24h。通过Celite过滤反应混合物,滤液蒸发干燥。通过硅胶板纯化残余物(二氯甲烷∶40%甲醇)后得到标题产物(0.254g,33.4%)Mp202-205℃(d)。IR(KBr):3438,3066,2942,1722,1652,1602cm-1.NMR(acetone-d6/D2O):δ1.081(s,6H),1.571(s,3H),1.847(s,3H),2.115(s,3H),2.357(s,3H),3.707(d,H),4.08(m,2H),4.275(m,H),4.941-5.085(m,4H),5.231(t,H),5.430(d,H),5.544(d,H),5.970(t,H),6.376(s,H),6.961-8.017(m,16H).MS:[M+Na]+,986;[M+K]+,1002;[M+2Na-H]+,1008;[M+Na+K-H]+,1024;[M+2K-H]+,1040HRMS:MNa+,986.2955(Calculated=986.2976)实施例5 2′,7-O-双(膦酰氧甲基)紫杉酚钠盐(a)制备2′,7-O-双(甲硫甲基)紫杉酚
于0℃将固体过氧化苯甲酰(1.995g,8mmol)加至紫杉酚(0.853g,1mmol)和二甲硫(1.465g,20mmo l)的乙腈(20ml)搅拌溶液中。于0℃剧烈搅拌反应混合物3h。通过TLC在己烷∶乙酸乙酯(1∶1,V/V,Rf紫杉酚=0.24,Rf产物=0.60)中监测反应进程。当起始物消失(约3h)后,通过于25℃用真空蒸发溶剂干燥终止反应,用硅胶析(EMScience,40-63μm,100ml干硅胶,柱径:Ф=3/4in.,溶剂系统∶己烷∶乙酸乙酯(3∶2,V/V),每一级分的体积约25ml)分离干残余物。从级分15-19回收标题化合物。MS(FAB/mattix NOBA,NaI KI):[M+H]+,m/z 974;[M+Na]+,m/z 996;[M+K]+,m/z 1012UV(MeOH):λmax=204nm,E(1%/1cm)=243.45;λmax=228nm,E(1%/1cm)=313.99IR(KBr):3440,3064,2926,1724,1668,1602,1582,1514,1484,1452,1372,1314,1266,1242,1178,1142,1068,1026,990,916,886,848,800,774,710,646,606,570,540,480cm-1.1H-NMR(CDCl3)δ:1.17(3H,s),1.20(3H,s),1.68(3H,s),1.74(3H,s),1.84(H,dd),2.04(3H,d),2.09(3H,s),2.15(3H,s)overlaps with(H,m),2.37(H,dd),2.51(3H,s),2.79(H,ddd),3.78(H,d),4.18(H,d),4.28(H,m),4.31(H,d),4.53-4.74(4H,two overlapping AB m),4.93(H,d),4.95(H,d),5.68(H,d),5.82(H,dd),6.24(H,dd),6.54(H,s),7.05(H,d),7.28-7.59(10H,overlapping m),7.57(H,m),7.76(2H,d),8.09(2H,d).(b)制备2′,7-O-双(二苄基膦酰氧甲基)紫杉酚
于室温下将N-碘代琥珀酰亚胺(135mg,0.5mmol)和磷酸二苄基酯(167mg,0.5mmol)的无水四氢呋喃(8ml)溶液加到2′,7-O-双(甲硫甲基)紫杉酚(198mg,0.2mmol)、5_分子筛(约200mg)及二氯甲烷(12ml)的混合物中。搅拌反应混合物1.5h,在Celite上过滤掉分子筛,用二氯甲烷(10ml)洗涤,于室温下利用真空蒸发溶剂至干燥。将残余物溶于乙酸乙酯(100ml),并在分离漏斗中用1%硫代硫酸钠(50ml)、0.5mNaHCO3(50ml)及水(2×50ml)洗涤有机相在MgSO4上干燥,蒸发至干,并重溶于乙酸乙酯(1ml)。用50ml乙醚∶己烷(1∶1)沉淀产物,并用同一溶剂系统(2×50ml)洗涤两次,得到粗产物(218mg,74%)。通过将其二氯甲烷(3ml)溶液加至硅胶(Ф=3/4in.×L=1in.)并用50ml二氯甲烷∶乙酸乙酯(3∶1)溶剂系统洗脱,纯化该产物,得到标题化合物(172.7mg,59.3%)。MS(FAB,matrix NOBA/NaI,KI):[M+Na]+,m/z 1456;[M+K]+,m/z 1472UV(MeCN):λmax=194nm,E(1%/1cm)=1078.36;λmax=228nm,E(1%/1cm)=311.95IR(KBr):3430,3066,3032,2958,1744,1726,1664,1602,1582,1532,1488,1456,1372,1270,1244,1158,1108,1068,1016,1000,952,886,800,776,738,698,604,498cm-1.1H-NMR(CDCl3)δ:1.12(3H,s),1.14(3H,s),1.56(H,m),1.67(3H,s),1.84(3H,d),1.90(H,m),2.17(3H,s),2.29(3H,s),2.73(H,m),3.73(H,d),4.08(H,d),4.15(H,m),4.20(H,d),4.77(H,m),4.79(H,d),4.91-5.04(10H overlapping m),5.25(H,dd),5.38(H,dd),5.54-5.64(2H,overlapping m),5.99(H,br.dd),6.25(H,s),7.11-7.14(2H,m),7.24-7.64(28H,overlapping m),7.94(2H,dd),8.04(2H,dd),8.30(H,d).(c)制备2′,7-O-双(膦酰氧甲基)紫杉酚钠盐
将2′,7-O-双(二苄基膦酰氧甲基)紫杉酚样品(112mg,0.078mmol)溶于乙酸乙酯(7ml),并于室温、60psi(400kpa)下在10%披钯木炭(50mg)上氢化2h。在Celite上过滤掉催化剂,用乙酸乙酯(10ml)浸泡Celite,用固体NaHCO3(20g,3eq.)处理滤液,然后蒸发溶剂至干燥。残余物再溶于5ml水∶丙酮(4∶1,V/V)并通过C-18逆相柱层析纯化(55-105μC-18,水,50ml干C-18,Ф=3/4in.,于水∶丙酮(4∶1,V/V)。在加入Q12离子对鸡尾酒(Regis)的乙腈∶磷酸缓冲液(PH6,50/50,V/V)中的分析值HPLC Jones C-18柱(15Cm,1ml/min,λ=230mn)监测洗脱液,Rt=4.7min。合并含有标题化合物的级分,于20℃真空蒸发丙酮,并冷冻干燥溶液,得到标题化合物(44.2mg,58.8%)。MS(FAB,matrix NOBA/NaI,KI):[M+H]+,m/z 1118;[M+Na]+,m/z 1140UV(MeCN):λmax=192nm,E(1%/1cm)=129.73;λmax=230nm,E(1%/1cm)=26.43IR(KBr):3430,3066,2956,1724,1658,1604,1582,1520,1486,1452,1374,1316,1256,1152,1110,1070,1026,966,914,802,772,710,538cm-1.1H-NMR(acetone-d6/D2O)δ:0.97(3H,s),1.02(3H,s),1.47(H,m),1.54(3H,s),1.70(H,m),1.75(3H,s),1.85(H,m),2.11(3H,s),2.30(3H,s),2.88(H,m),3.64(H,d),4.03(H,m),4.06(H,d),4.16(H,d),4.74(H,m),4.86(H,m),5.11(H,br.t),5.22(H,d),5.42(H,d),5.90(H,br.t),6.21(H,s),7.06(H,br.t),7.32-7.69(10H,ovelapping m),7.80(2H,d),7.93(2H,d).实施例6 7-O-甲硫甲基浆果赤霉素III
向2′-O-乙氧羰基-7-O-甲硫甲基紫杉酚(实施例3(b)化合物,27g,27.4mmol)于100ml THF和500ml甲醇的溶液中加入刚粉碎的K2CO3(2.7g,19mmol)。搅拌溶液30分钟,并用IR-120(H+)树脂中和,过滤并浓缩。将粗滤液溶于200ml二氯甲烷,并与氢硼化四丁基铵(10g)。用二氯甲烷稀释溶液,用水、饱和碳酸氢钠和盐水洗涤。有机层于MgSO4上干燥并浓缩。经硅胶层析残余物(1∶1己烷/乙酸乙酯)后得到9.4g标题化合物(53%),熔点269℃。FABMS(NOBA)M+H calcd for C33H43SO11:647.Found:647.IR(KBr)3474,1746,1724,1712,1270,1240,1070cm-11H NMR(CDCl3,300MHz)δ8.08(d,J=7.1Hz,2H),7.58(t,J=7.5Hz,1H),7.45(t,J=7.8Hz,2H),6.55(s,1H),4.94(d,J=8.1Hz,1H),4.83(brq,J=5.1Hz,1H),4.66(ABq,J=14.7,12.3Hz,2H),4.30(m,2H),4.13(d,J=8.4Hz,1H),3.91(d,J=6.6Hz,1H),2.79(m,1H),2.27(s,3H),2.25(m,2H),2.19(s,aH),2.16(s,3H),2.10(s,4H),1.81(m,1H),1.72(s,3H),1.61(m,2H),1.16(s,3H),1.03(s,3H).13C NMR(CDCl3,75.5Hz)δ202.3,170.8,169.3,167.0,144.2,132.6,132.1,130.1,129.4,128.6,83.9,80.9,78.7,75.7,74.5,73.9,67.9,57.6,47.6,42.7,38.3,26.7,22.6,21.0,20.1,15.2,15.0,10.8.实施例7 3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚三乙醇胺盐(a)制备3′-N-脱苯甲酰-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-7-O-甲硫甲基紫杉酚
向HMDS(0.40ml,1.90mmol)的15ml THF溶液中加入n-BuLi(0.75ml,2.5M于己烷,1.88mmol),并于-55℃搅拌5min。向该溶液中加入7-MTM浆果赤霉素III(实例6化合物,1.03g,1.59mmol)的10ml THF溶液,搅拌10min,然后加入10ml(3R,4R)-1-(叔丁氧羰基)-4-(2-呋喃基)-3-(三乙基甲硅烷氧基)-2-氮杂环丁酮(883mg,2.40mmol)溶液,移去冷却浴,并用0℃浴代替,搅拌反应混合物30min,用乙酸乙酯稀释溶液,并用饱和NH4Cl溶液洗涤,于MgSO4上干燥并浓缩。在硅胶上层析残余物(2.5∶1己烷/乙酸乙酯)后,得到1.5g偶联产物3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-7-O-甲硫甲基-2′-O-三乙基甲硅烷基紫杉酚(93%)。FABMS(NOBA)M+Na calcd for C50H71NSSiO16:1036.Found:1036.IR(film)3446(s),1720,1368,1242,1166,1144,1124,1066cm-1 1H NMR(CDCl3,300MHz)δ 8.07(d,J=7.2Hz,2H),7.56(m,1H),7.46(t,J=7.5Hz,2H),7.36(m,1H),6.56(s,1H),6.33(m,1H),6.20(m,2H),5.67(d,J=6.9Hz,1H),5.29(brs,2H),4.94(d,J=7.8Hz,1H),4.75(s,1H),4.65(s,2H),4.28(m,2H),4.16(d,J=8.1Hz,1H),3.89(d,J=6.9Hz,1H),2.80(m,1H),2.46(s,3H),2.37(m,1H),2.22(m,1H),2.16(s,3H),2.10(s,3H),2.04(s,3H),1.84(m,1H),1.74(s,3H),1.65(m,1H),1.33(s,9H),1.20(s,3H),1.19(s,3H),0.81(t,J=7.8Hz,9H),0.47(m,6H).13C NMR(CDCl3,75.5Hz)δ202.0,171.2,170.3,169.3,167.1,155.3,152.0,141.9,141.0,133.6,132.9,130.2,129.2,128.7,110.7,107.3,84.0,81.1,80.2,78.7,76.1,75.7,74.7,74.1,72.4,71.1,57.4,52.8,47.1,43.3,35.2,33.0,28.1,26.3,22.9,21.2,21.0,15.0,14.5,10.9,6.5,4.3.
向上面得到的2′-三乙基甲硅烷基醚(330mg,0.32mmol)的7ml THF溶液中加入氟化四丁铵(0.35ml,1.0)M于THF,0.35mmol),并搅拌10min。用乙酸乙酯稀释溶液并用盐水洗涤,经MgSO4干燥、浓缩及硅胶层析残余物(2∶1己烷/乙酸乙酯)后,得到301mg标题化合物(95%)。FABMS(NOBA)M+H calcd for C45H58NO16S:900.Found:900.IR(film)3442,1720,1242,1066,1026cm-1 1H NMR(CDCl3,300MHz)δ8.07(d,J=7.3Hz,2H),7.57(t,J=7.3Hz,1H),7.45(t,J=7.8Hz,2H),7.38(s,1H),6.53(s,1H),6.34(d,J=3.2Hz,1H),6.29(d,J=3.2Hz,1H),6.17(t,J=8.1Hz,1H),5.65(d,J=6.9Hz,1H),5.29(m,2H),4.92(d,J=8.0Hz,1H),4.70(m,1H),4.64(d,J=4.6Hz,2H),4.29(m,2H),4.14(d,J=8.3Hz,1H),3.86(d,J=6.8Hz,1H),3.37(d,J=5.8Hz,1H),2.77(m,1H),2.38(s,3H),2.32(m,2H),2.16(s,3H),2.10(s,3H),2.02(s,3H),1.77(m,3H),1.73(s,3H),1.33(s,9H),1.17(s,3H),1.12(s,3H).13C NMR(CDCl3,75.5Hz)δ202.0,172.6,170.3,169.2,167.0,155.2,151.3,142.4,140.4,133.7,133.2,130.2,129.1,128.7,110.7,107.4,83.9,81.2,80.5,78.6,76.5,76.1,75.4,74.6,74.0,72.5,71.8,57.4,51.7,47.2,43.2,35.2,32.8,28.1,26.4,22.6,20.9,15.2,14.6,10.9,8.3.(b)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-甲硫甲基紫杉酚
于0℃向步骤(a)产物(864mg,0.96mmol)的50ml二氯甲烷溶液中加入二异丙基乙胺(2.0ml,11.5mmol)和氯代甲酸乙酯(0.50ml,5.25mmol)并搅拌4h。用二氯甲烷稀释溶液,并用饱和碳酸氢盐洗涤,用MgSO4干燥,并浓缩。经硅胶层析残余物(1∶1己烷/乙酸乙酯)后,得到884mg2′碳酸乙酯标题化合物(95%)。FABMS(NOBA)M+H calcd for C48H62NO18S 972.3688.Found:972.3654.IR(film)1752,1720,1370,1244,1196,1176,1064cm-1 1H NMR(CDCl3,300MHz)δ8.09(d,J=7.8Hz,2H),7.57(t,J=7.5Hz,1H),7.46(t,J=7.8Hz,2H),7.38(s,1H),6.55(s,1H),6.35(m,1H),6.27(m,1H),6.22(t,J=7.8Hz,1H),5.67(d,J=7.2Hz,1H),5.51(d,J=9.9Hz,1H),5.34(d,J=2.4Hz,1H),5.25(d,J=10.2Hz,1H),4.95(d,J=8.1Hz,1H),4.65(s,2H),4.30(m,2H),4.22(m,2H),3.88(d,J=7.2Hz,1H),2.81(m,1H),2.41(s,3H),2.36-2.21(m,2H),2.16(s,3H),2.11(s,3H),2.09(s,3H),1.83(m,1H),1.74(s,3H),1.67(s,1H),1.59(s,1H),1.34(s,9H),1.29(t,J=7.2Hz,3H),1.20(s,3H),1.18(s,3H).13C NMR(CDCl3,75.5Hz)δ202.1,169.9,169.1,167.6,167.0,154.0,150.1,142.6,141.0,133.6,132.9,130.2,129.2,128.7,110.7,107.5,83.9,81.1,80.7,78.7,76.0,75.7,75.1,74.7,74.2,71.8,65.1,57.4,49.7,47.1,43.2,35.0,33.0,28.1,26.3,22.6,21.1,20.9,15.1,14.5,14.1,10.9.(c)制备3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-二苄基膦酰氧甲基紫杉酚
向步骤(b)产物(230mg,0.236mmol)的10ml无水THF溶液中加入300mg4_分子筛、磷酸二苄酯(270mg,0.98mmol)和重结晶的NIS(62mg,0.28mmol)。向该溶液中加入三氟甲磺酸银(45mg,0.17mmol)并搅拌溶液3h。通过Celite过滤溶液,并用乙酸乙酯稀释,用10%NaS2O3、饱和碳酸氢盐和盐水洗涤,于MgSO4上干燥,并浓缩。硅胶层析残余物(15%乙腈/氯仿)后得到219mg磷酸二苄酯标题化合物(77%)。FABMS(NOBA)M+Na calcd for C61H72NPO22Na 1224.Found:1224.IR(film)3422(br),1750,1722,1370,1244,1160,1036,1016,1000,976,944cm-1 1H NMR(CDCl3,300MHz)δ8.08(d,J=6.9Hz,2H),7.58(t,J=7.2Hz,1H),7.46(t,J=7.8Hz,2H),7.39(s,1H),7.31(m,10),6.35(m,2H),6.28(s,1H),6.21(t,J=7.8Hz,1H),5.64(d,J=6.9Hz,1H),5.50(d,J=10.5Hz,1H),5.39(d,J=6.6Hz,1H),5.32(d,J=2.4Hz,1H),5.25(d,J=9.9Hz,1H),5.01(dd,J=8.1,6.3Hz,5H),4.86(d,J=8.4Hz,1H),4.29-4.09(m,4H),3.85(d,J=6.9Hz,1H),2.77(m,1H),2.40(s,3H),2.30(m,2H),2.16(s,3H),1.99(s,3H),1.94(m,1H),1.70(s,3H),1.67(s,1H),1.54(s,1H),1.34(s,9H),1.28(t,J=7.2Hz,3H),1.20(s,3H),1.17(s,3H).13C NMR(CDCl3,75.5Hz)δ201.8,169.9,169.2,167.7,167.0,155.1,154.0,150.0,142.74,141.1,133.7,132.9,130.2,129.1,128.7,128.5,128.4,128.0,110.7,107.6,93.8,84.1,81.6,80.8,80.7,78.8,76.3,75.1,74.6,71.8,69.3,69.2,65.1,57.0,49.7,46.7,43.2,35.0,28.1,26.4,22.6,21.2,20.8,14.6,14.1.10.5.(d)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚三乙醇胺盐
向步骤(c)产物(311mg,0.25mmol)的25ml乙酸乙酯溶液中加入60mg披钯碳(10%),并在H2环境下搅拌溶液30min。通过Celite滤掉催化剂,并真空浓缩滤液。残余物溶于3ml乙酸乙酯并加入三乙醇胺(2.3ml,0.1M于乙酸乙酯,0.23mmol)。浓缩溶液,在C18柱上层析残余物(40%乙腈/水)并冻干后,得到205mg磷酸酯三乙醇胺盐(67%)。FABMS(NOBA)M+Na calcd for C47H60HPO22Na 1044.Found:1044.IR(film)3432(br),1752,1722,1372,1246,1158,1108,1096,1070,1002cm-1 1H NMR(d6 acetone/D2O,300MHz)δ8.09(d,J=7.2Hz,2H),7.62(m,2H),7.52(t,J=7.5Hz,2H),6.48(d,J=3.3Hz,1H),6.42(m,2H),6.16(t,J=8.7Hz,1H),5.65(d,J=6.9Hz,1H),5.46(d,J=3.6Hz,1H),5.30(d,J=3.6Hz,1H),5.17(brs,1H),5.01(brd,J=9.0Hz,1H),4.19(brs,1H),4.18(m,5H),3.95(m,6H),3.87(d,J=6.9Hz,1H),3.68(s,7H),3.50(brt,J=4.8Hz,6H),2.95(m,1H),2.44(s,3H),2.41(m,2H),2.16(s,3H),1.9(s,3H),1.94(m,1H),1.68(s,3H),1.34(s,9H),1.24(t,J=6.9Hz,3H),1.17(s,6H).实施例8 3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚三乙醇胺盐(a)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-7-O-甲硫甲基紫杉酚
于-55℃向HMDS(0.5ml,2.4mmol)的18ml THF溶液中加入n-BuLi(0.85ml,2.5M于己烷,2.1mmol)。10min后,滴加7-MTM浆果赤霉素III(1.15g,1.78mmol)的18ml THF溶液,并冷却搅拌10min。加入(±)顺-1-(叔-丁氧羰基)-4-(2-噻吩基)-3-(三乙基甲硅烷氧基)-2-氮杂环丁酮(2.80g,7.3mmol)的18ml THF溶液,并在30分钟内使冷却浴缓慢升温至0℃。用乙酸乙酯稀释溶液,并用饱和NH4Cl溶液洗涤,MgSO4干燥,并浓缩。硅胶层析残余物(5∶1己烷/乙酸乙酯),得到1.87g回收的内酰胺(3∶1己烷/乙酸乙酯),得到1.44g偶联产物3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-7-O-甲硫甲基-2′-O-三乙基甲硅烷基紫杉酚(78%)。FABMS(NOBA)M+Na calcd for C51H71NO15S2SiNa 1052.Found:1052.IR(film)3442(br),1720,1490,1368,1270,1242,1162,1110,1064,1024,984,754cm-1 1H NMR(CDCl3,300MHz)δ8.09(d,J=7.2Hz,2H),7.57(t,J=7.6Hz,1H),7.47(t,J=7.8Hz,2H),7.22(m,1H),6.95(m,2H),6.55(s,1H),6.21(t,J=9.3Hz,1H),5.68(d,J=6.9Hz,1H),5.49(brd,1H),5.39(brd,J=9.6Hz,1H),4.94(d,J=7.8Hz,1H),4.65(s,2H),4.57(s,1H),4.28(m,2H),4.17(d,J=8.4Hz,1H),3.88(d,J=6.9Hz,1H),2.80(m,1H),2.46(s,3H),2.37(m,1H),2.20(m,1H),2.17(s,3H),2.10(s,3H),2.03(s,3H),1.84(m,1H),1.74(s,3H),1.68(s,1H),1.62(s,1H),1.31(s,9H),1.20(s,6H),0.84(t,J=7.8Hz,9H),0.50(m,6H).13C NMR(CDCl3,75.5Hz)δ201.9,171.1,170.7,170.1,169.3,167.0,155.1,142.8,140.9,133.6,132.9,130.2,129.2,128.7,126.9,124.6,83.9,81.2,80.1,78.8,77.4,76.0,75.7,75.2,74.8,74.1,71.3,57.4,53.8,47.0,43.3,35.3,33.3,28.1,26.3,23.0,21.3,20.9,14.9,14.4,10.9,6.6,4.5.
向上面获得的2′-三乙基甲硅烷基醚(1.41g,1.37mmol)的14ml THF溶液中加入氟化四丁铵(1.4ml,1.0M于THF,1.40mmol)。搅拌溶液30min,用乙酸乙酯稀释,并用盐水洗涤,于MgSO4上干燥,并浓缩。经硅胶层析残余物(1∶1己烷/乙酸乙酯)后得到1.16g标题化合物(92%)。FABMS(NOBA)M+Na calcd for C45H57NO15S2Na 938.Found:938.IR(film)3440(br),1720,1368,1242,1168,1106,1066,710cm-1 1H NMR(CDCl3,300MHz)δ8.08(d,J=7.2Hz,2H),7.59(m,1H),7.47(t,J=7.8Hz,2H),7.24(m,1H),7.07(m,1H),6.99(m,1H),6.53(s,1H),6.18(t,J=8.1Hz,1H),5.66(d,J=6.9Hz,1H),5.49(d,J=9.6Hz,1H),5.32(d,J=9.6Hz,1H),4.92(d,J=7.8Hz,1H),4.63(m,3H),4.28(m,2H),4.15(d,J=8.4Hz,1H),3.86(d,J=6.9Hz,1H),2.80(m,1H),3.47(d,J=5.4Hz,1H),2.78(m,1H),2.36(s,3H),2.34(,2H),2.17(s,3H),2.10(s,3H),2.00(s,3H),1.83(m,1H),1.74(s,3H),1.72(s,1H),1.61(s,1H),1.33(s,9H),1.21(s,3H),1.18(s,3H).13C NMR(CDCl3,75.5Hz)δ201.9,172.3,170.3,169.2,167.0,154.0,141.5,140.2,133.7,133.3,130.2,129.1,128.7,127.0,125.4,125.4,83.9,81.3,80.4,78.6,76.1,75.4,74.5,74.0,73.4,72.5,57.5,52.8,47.2,43.2,35.3,32.9,28.2,26.4,22.6,20.9,15.1,14.7,10.8.(b)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-甲硫甲基紫杉酚于0℃向步骤(a)产物(621mg,0.677mmol)的35ml二氯甲烷溶液中加入二异丙基乙胺(1.20ml,6.89mmol)和氯代甲酸乙酯(0.35ml,3.7mmol)并搅拌1h。移去冷却浴,搅拌溶液2h,用二氯甲烷稀释,并用饱和碳酸氢盐洗涤,于MgSO4上干燥,并浓缩。经硅胶层析残余物(1∶1己烷/乙酸乙酯)后得到528mg标题化合物(79%)。FABMS(NOBA)M+Na calcd for C48H61NO17S2Na 1010.Found:1010.IR(film)3510,3440,1752,1720,1370,1244,1198,1170,1026,988,756cm-1 1H NMR(CDCl3,300MHz)δ8.09(d,J=7.2Hz,2H),7.58(m,1H),7.48(t,J=7.8Hz,2H),7.26(m,1H),6.99(,2H),6.55(s,1H),6.23(t,J=9.0Hz,1H),5.68(d,J=6.9Hz,2H),5.33(d,J=9.9Hz,1H),5.25(d,J=2.4Hz,1H),4.94(d,J=7.8Hz,1H),4.65(s,2H),4.33-4.08(m,5H),3.88(d,J=6.9Hz,1H),2.80(m,1H),2.40(s,3H),2.40-2.20(m,2H),2.16(s,3H),2.11(s,3H),2.07(s,3H),1.83(m,1H),1.74(s,3H),1.69(s,1H),1.60(s,1H),1.33(s,9H),1.31(t,J=7.2Hz,3H),1.20(s,3H),1.19(s,3H).13C NMR(CDCl3,75.5Hz)δ202.0,169.7,169.1,167.5,167.1,154.0,140.9,133.6,132.9,130.2,129.2,128.7,127.2,125.4,125.3,83.9,81.2,80.6,78.8,76.9,76.0,75.7,74.7,74.2,72.8,72.0,65.2,57.4,50.9,47.1,43.3,35.1,33.0,28.1,26.4,22.7,21.2,20.9,15.1,14.5,14.1,10.9.(c)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-二苄基膦酰氧甲基紫杉酚
向步骤(b)产物(516mg,0.522mmol)的15ml无水THF溶液中加入530mg4_分子筛、磷酸二苄酯(576mg,2.09mmol)和重结晶NIS(136mg,0.604mmol)。向该溶液中加入三氟甲磺酸银(50mg,0.194mmol)并搅拌溶液1h。通过Celite过滤溶液,用乙酸乙酯稀释,用10%NaS2O3、饱和碳酸氢盐和盐水洗涤,于MgSO4上干燥并浓缩。通过硅胶层析残余物(15%乙腈/氯仿)后得到535mg标题化合物(84%)。FABMS(NOBA)M+Na calcd for C61H72NO21PSNa 1240.Found:1240.IR(film)3424(br),1750,1722,1370,1244,1016,1000,944cm-1 1H NMR(CDCl3,300MHz)δ8.08(d,J=7.0Hz,2H),7.58(m,1H),7.47(t,J=7.5Hz,2H),7.28(m,11H),6.99(m,2H),6.33(s,1H),6.22(t,J=7.8Hz,1H),5.66(m,2H),5.39(t,J=6.6Hz,1H),5.34(d,J=12Hz,1H),5.22(d,J=2.4Hz,1H),5.01(dd,J=8.1,6.0Hz,5H),4.86(d,J=7.8Hz,1H),4.29-4.08(m,5H),3.85(d,J=6.6Hz,1H),2.76(m,1H),2.39(s,3H),2.35-2.18(m,2H),2.16(s,3H),1.97(s,4H),1.69(s,4H),1.33(s,9H),1.30(t,J=7.2Hz,3H),1.20(s,3H),1.17(s,3H).13C NMR(CDCl3,75.5Hz)δ197.4,165.4,164.9,163.3,162.7,150.6,149.7,136.7,136.0,129.4,128.6,125.9,124.7,124.3,124.2,124.1,123.6,122.9,121.1,121.0,89.4,79.8,77.3,76.5,76.3,74.4,72.0,70.7,70.3,67.7,64.9,64.9,60.9,52.7,46.5,42.3,38.9,30.7,23.8,22.0,18.3,17.0,16.4,10.3,9.8,6.2.(d)制备3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚三乙醇胺盘
向步骤(c)产物(512mg,0.42mmol)的30ml乙酸乙酯溶液中加入53mg Pd/C(10%),并在H2环境下搅拌溶液3h。通过Celite过滤掉催化剂,并真空浓缩滤液。残余物溶于2ml乙酸乙酯,并加入三乙醇胺(4.0ml,0.1M于乙酸乙酯,0.40mmol)。浓缩溶液,在C18上层析残余物(40%乙腈/水)并冻干,得到280mg磷酸酯的三乙醇胺盐(56%)。HPLC分析测得该盐的纯度为96%。FABMS(NOBA)M+Na calcd for C47H60NO21PS 1060. Found:1060.IR(KBr)3422(br),1750,1720,1372,1246,1162,1096,1068,1000cm-1 1H NMR(d6acetone/D2O,300MHz)δ8.06(d,J=7.2Hz,2H),7.63(t,J=7.2Hz,1H),7.52(t,J=7.8Hz,2H),7.38(d,J=4.2Hz,1H),7.16(d,J=3.5Hz,1H),7.01(dd,J=5.1,3.6Hz,1H),6.37(s,1H),6.11(t,J=8.7Hz,1H),5.61(d,J=6.9Hz,1H),5.60(s,1H),5.26(d,J=4.5Hz,1H),5.14(d,J=6.6Hz,1H),5.00(d,J=8.4Hz,1H),4.86(dd,J=12.0,6.3Hz,1H),4.17(m,5H),4.00(s,7H),3.92(t,J=4.8Hz,6H),3.84(d,J=6.9Hz,1H),3.48(t,J=5.4Hz,6H),2.94(m,1H),2.42(s,3H),2.36(m,1H),2.27(m,1H),2.15(s,3H),1.95(s,4H),1.66(s,3H),1.30(s,9H),1.23(t,J=7.2Hz,3H),1.14(s,6H).实施例9 10-脱乙酰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(膦酰氧甲基)紫杉酚(a)制备10-脱乙酰基-10-O-苄氧羰基-7-O-三乙基甲硅烷基浆果赤霉素III
在氩气环境下向含有7-O-三乙基甲硅烷基-10-脱乙酰基浆果赤霉素III(2.093g,3.177mmol)的干燥烧瓶中加入无水THF(30ml),并冷却至-70℃。向其中滴加1.6M正丁基锂(2.38ml,3.81mmol)。搅拌15min后,滴加氯代甲酸苄酯(0.91ml,6.35mmol)。搅拌混合物3h,并逐步温热至室温。用25ml饱和NH4Cl终止反应,用盐水洗涤,并用MgSO4干燥。经快速层析(硅胶,30-45%乙酸乙酯/己烷)后,得到2.24g(89%)白色泡沫状标题化合物。1H NMR(300MHz,CDCl3)δ8.10(d,J=8.0,2H);7.63-7.58(m,1H)7.47(t,J=8.0,2H);7.41-7.26(m,5H);6.29(s,1H);5.61(d,J=7.0,1H);5.20(q,J=12.2,2H);4.96(d,J=9.0,1H);4.87-4.84(m,1H);4.48(dd,J=6.7,J=10.4,1H);4.30(d,J=8.5,1H);4.14(d,J=8.5,1H);3.84(d,J=7.0,1H);2.58-2.48(m,1H);2.29(m,4H);2.20(s,3H);2.03(d,J=5.0,1H);1.92-1.83(m,1H);1.68(s,3H);1.17(s,3H);1.04(s,3H);0.91(t,J=7.5,9H);0.57(q,J=7.4,6H).(b)制备10-脱乙酰基-10-O-苄氧羰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-2′,7-双-O-三乙基甲硅烷基紫杉酚
向含有步骤(a)产物(3.50g,4.42mmol)的干燥烧瓶中加入少量甲苯。然后真空浓缩溶液。将烧瓶置于氩气环境下,并加入100ml THF。冷却烧瓶至-70℃,并滴加1.0M六甲基二硅叠氮化锂(6.19ml,6.19mmol),搅拌20min,滴加(3R,4S)-1-(叔丁氧羰基)-4-苯基-3-三乙基甲硅烷氧基-2-氮杂环丁酮(2.58g,7.07mmol)的10ml无水THF溶液。搅拌反应混合物3.5h,逐步升至室温。然后用70ml饱和NH4Cl终止反应用盐水洗涤,并用MgSO4干燥。经快速层析(硅胶,5-15%乙酸乙酯/己烷)后得到5.12g(98%)白色泡沫状标题化合物。1H NMR(300MHz,CDCL3)δ8.11(d,J=8.0,2H);7.60-7.58(m,1H);7.48(t,J=8.0,2H);7.24-7.26(m,10H);6.32-6.26(m,2H);5.69(d,J=7.0,1H);5.47(bd,J=9.7,1H);5.31-5.10(m,3H);4.94(d,J=8.5,1H);4.56(s,1H);4.46(dd,J=6.9,J=10.6,1H);4.31(d,J=8.3,1H);4.17(d,J=8.3,1H);3.81(d,J=7.0,1H);2.53(s,3H);2.48-2.33(m,1H);2.22-2.17(m,1H);2.09(s,3H);1.95-1.86(m,1H);1.70(s,3H);1.65(s,1H);1.52(s,1H);1.30(s,9H);1.26-1.19(m,6H);0.94-0.87(m.9H);0.80-0.75(m,9H);0.61-0.53(m,6H);0.48-0.30(m,6H).(c)制备10-脱乙酰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-7-O-三乙基甲硅烷基紫杉酚
将步骤(b)产物(5.12g,4.40mmol)溶于100ml乙酸乙酯,转移至帕尔瓶中,并置于氩气环境下。向其中加入10%披钯碳(2.4g),并将反应混合物置于帕尔氢化装置(55psi)中氢化8h。通过Celite塞过滤混合物并浓缩。经快速层析(硅胶,15-20%乙酸乙酯/己烷)后得到3.24g(79%)白色泡沫状标题化合物,帕尔装置中所出现的酸性残余物是步骤(b)产物的2′-三乙基甲硅烷基水解的结果。1H NMR(300MHz,CDCl3)δ8.10(d,J=8.0,2H);7.63-7.58(m,1H);7.49(d,J=8.0,2H);7.39-7.26(m.5H);6.27-6.17(m,1H);5.64(d,J=7.2);5.42(d,J=9.4,1H);5.28-5.25(m,1H);5.12(s,1H);4.92(d,J=8.6,1H);4.62(bs,1H);4.38-4.2 8(m,3H);4.17(d,J=8.5,1H);3.85(d,J=6.7,1H);3.36(d,J=5.3,1H);2.49-2.40(m,1H);2.36(s,3H);2.25(bd,J=8.7,2H);1.99-1.91(m,1H);1.85(s,3H);1.74(s,3H);1.69(s,1H),1.67(s,1H);1.35(s,9H);1.22(s,3H);1.11(s,3H);0.93(t,J=7.59H);0.61-0.49(m.6H).(d)制备10-脱乙酰-2′-O-苄氧羰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-7-O-三乙基甲硅烷基紫杉酚
向含有步骤(c)产物(3.24g,3.51mmol)的烧瓶中加入30ml无水二氯甲烷,将烧瓶置于氩气环境下并冷却至0℃。向混合物中加入N,N-二异丙基乙胺(1.22ml,7.02mmol),然后滴加氯代甲酸苄酯(1.00ml,7.02mmol),15min后,移去冷却浴,于室温下搅拌反应7h。用30ml饱和NH4Cl终止反应,用盐水洗涤并用MgSO4干燥。经快速层析(硅胶,7-20%乙酸乙酯/己烷)后得到3.24g(89%)标题化合物,为白色固体。1H NMR(300MHz,CDCl3)δ8.10(d,J=8.0,2H);7.62-7.57(m,1H);7.48(t,J=8.0,2H);7.40-7.26(m,10H);6.33-6.27(m,1H);5.66(d,J=7.0,1H);5.49-5.42(m,2H);5.31(s,1H);5.22-5.13(m,3H);4.93(d,J-9.4,1H);4.38(dd,J=6.5,J=10.7,1H);4.34-4.28(m.2H);4.18(d J=8.3,1H);3.90(d,J=6.7,1H);2.52-2.30(m,4H);2.24-2.20(m,1H);1.97-1.87(m,3H);1.74(s,3H);1.59(s,3H);1.32(s,9H);1.26,(s,3H);1.11(s,3H);0.96-0.88(m,9H);0.61-0.48(m,6H).(e)制备10-脱乙酰基-2′-O-苄氧羰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(二苄基膦酰氧甲基)-7-O-三乙基甲硅烷基紫杉酚
将步骤(d)产物溶于13.5ml(5 4%)DMSO、8.75ml(35%)乙酸酐和2.75ml(11%)冰醋酸中,并置于氩气环境下。搅拌反应混合物56h,用乙酸乙酯稀释至体积60ml。用饱和NaHCO3洗涤,直至用PH试纸测得为中性,然后用盐水洗涤。用MgSO4干燥有机层并浓缩。用15-20%EtoAc/己烷快速层析后得到3.12g粗白色泡沫,通过NMR测得其中70%为所需硫代甲基乙缩醛产物(即10-脱乙酰基-2′-O-苄氧羰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(甲硫甲基)-7-O-三乙基甲硅烷基紫杉酚
将上述粗混合物(3.12g)溶于1,2-二氯乙烷(61ml)并置于氩气环境下。加入4_粉化分子筛(3.12g)并剧烈搅拌所产生的异质混合物,通过套管加入重结晶N-碘代琥珀酰亚胺(0.830g,3.69mmol)和磷酸二苄酯(1.027g,3.69mmol)的无水THF(46ml)溶液。搅拌所得混合物5h,通过Celite过滤,用乙酸乙酯稀释至250ml。依次用(2×125ml)冷2%NaHSO3、冷6%NaHCO3(2×125ml)和盐水洗涤,用MgSO4干燥并浓缩。经快速层析(硅胶,25-35%乙酸乙酯/己烷)后得到1.52g(40%)标题化合物,为白色固体。1H NMR(CDCl3,300MHz)δ8.08(d,J=7.0,2H);7.59-7.55(m,1H);7.46(t,J=7.2,2H);7.38-7.25(m,20H);6.30(t,J=8.5,1H);5.65(d,J=6.8,1H);5.49-5.39(m,4H);5.32(s,1H);5.18-4.19(m,4H);4.93(d,J=9.2,1H);4.44(dd,J=6.6,J=10.2,1H);4.31(d,J=8.4,1H);4.16(d,J=8.5,1H);3.80(d,J=6.9,1H);2.69-2.39,(m,4H),2.33-2.23(m,3H);2.03(s,3H);1.90(t,J=12.6,1H);1.68-1.63(m,6H);1.28(s,9H);1.16-1.10(m,6H);0.93(t,J=7.4,9H);0.55(q,J=7.8,6H).13C NMR(CDCl3,75.5MHz)δ204.1,169.7,167.9,167.1,151.1,140.7,135.7,133.6,130.2,129.2,128.9,128.8,128.7,128.6,128.5,128.4,128.3,128.2,128.0,127.8,126.4,90.4,84.2,81.1,80.4,79.3,78.8,74.9,72.8,72.0,70.5,69.2,69.1,69.0,58.1,46.8,43.2,37.1,35.0,28.1,26.5,22.8,21.0,14.1,10.0,6.9,5.5.M.S.(FAB)m/z+:1345(f)制备10-脱乙酰基-2′-O-苄氧羰基-3′-N-脱苯甲酰基-3 ′-N-(叔丁氧羰基)-10-O-(二苄基膦酰氧甲基)紫杉酚
将步骤(e)产物(50.8mg,0.038mmol)的无水THF(2.5ml)溶液于氩气环境下冷却至-40℃。向其中滴加氟化四丁铵(0.057ml,0.057mmol)的THF(1.0M)溶液,搅拌反应混合物1.5h,同时逐步升至-20℃。用15ml饱和NH4Cl终止反应,并用30ml EtOAc稀释。有机层用2×15ml NaHCO3和盐水洗涤。然后用MgSO4干燥并浓缩、经制备性层析(硅胶,50%乙酸乙酯/己烷)得到36mg(77%)标题化合物,它为白色粉未。1H NMR(CDCl3,300MHz)δ 8.10(d,J=8.5,2H);7.60-7.55(m,1H);7.49-7.44(m,2H);7.36-7.18(m,20H);6.27-6.22(m,1H);5.78(s,1H);5.67(d,J=7.0,1H);5.44-5.34(m,3H);5.27(d,J=2.2,1H);5.24-5.05(m,4H);5.01-4.91(m,4H);4.39-4.28(m,2H);4.17(d,J=8.2,1H);3.87(d,J=7.0,1H);2.58-2.51(m,1H);2.41(s,3H);2.40-2.18(m,H),2.00-1.87(m,5H);1.73-1.69(m,4H);1.30(s,9H);1.22-1.15(m,6H).M.S.(FAB)m/z+:1231(g)制备10-脱乙酰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(膦酰氧甲基)紫杉酚三乙醇胺盐
将500ml帕尔瓶中加入10-脱乙酰基-2′-O-苄氧羰基-3 ′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(二苄基膦酰氧甲基)紫杉酚(264.9mg,0.215mmol)和乙酸乙酯(20ml)。用氩气洗涤烧瓶,并加入10%pd/c(318mg),所得混合物置于具有55磅/平方英寸(psi)氢气压力的帕尔瓶中。通过HPLC(70∶30CH3CN/Q8缓冲液,PH6.0,1.00ml/min,Zorbax C-18柱,25.0Cm,λ=230nm)监测反应,直至起始物消失(12.5h)。经Celite塞过滤混合物,用乙酸乙酯及少量二氯甲烷洗涤。浓缩所得滤液,并将残余物溶于二氯甲烷(5ml)。加入己烷,引起白色沉淀形成,从中分离出140.3mg游离酸(通过HPLC测得的纯度为80%),为白色固体。将该物质直接用于下一步骤。
向含有上述游离酸(140mg,0.153mmol)的烧瓶中加入二氯甲烷(10ml)。用0.100M三乙醇胺的乙酸乙酯(1.16ml,0.116mmol)溶液处理所得溶液,使溶液变浑浊。加入约2ml己烷。将混合物于-20℃放置过夜。经4.0-5.5μm熔结玻璃漏斗过滤所产生的沉淀。取出固体,于真空下放置4h,得到69.9mg(42%)标题三乙醇胺盐,为灰白粉末,通过HPLC分析测得其纯度为95-96%(TR=2.05min,70∶30CH3CN/Q8缓冲液PH6.0,1.00ml/min,Zorbax C-18 25.0Cm,λ=230nm)。1H-NMR(d6-acetone/D2O,300MHz):δ8.03(d,J=7.4,2H);7.65(t,J=7.3,1H);7.54(t,J=7.6,2H);7.42-7.33(m,5H);7.21(t,J=7.0,1H);6.09(t,J=9.0,1H);5.81(s,1H);5.59(d,J=7.0,1H);5.12(bs,2H);4.93(d,J=8.4,2H),4.56(d,J=4.9,1H);4.31-4.26(m,1H);4.11(s,2H);3.41-3.37(m,6H);2.42-2.32(m,5H);2.15(bs,1H);1.97(s,3H);1.77-1.64(m,2H);1.58(s,3H);1.13(s,9H);1.15-1.07(m,6H).13C NMR(d6-acetone,D2O,75.6MHz):δ171.6,166.9,156.6,141.8,135.1,134.2,131.0,130.7,129.4,129.3,128.4,128.1,88.3,85.4,81.9,79.7,78.6,78.1,76.8,76.0,74.8,71.9,71.2,47.4,44.0,37.1,36.3,28.5,27.0,23.1,22.0,14.7,10.4.HRMS:MNa+,940.3142(Calculated for C44H56NO18PNa=940.3133)实施例10 2′-O-膦酰氧甲氧甲基紫杉酚(a)制备2′-O-(甲硫甲氧甲基)-7-O-三乙基甲硅烷基紫杉酚
于室温下向7-O-三乙基甲硅烷基紫杉酚(70.0mg,72.2mmol)、双(甲硫甲基)醚(90g,72.2mmol)、分子筛(70mg)和N-碘代琥珀酰亚胺(160mg,72.2mmol)的THF(2.0ml)溶液中加入三氟甲磺酸银(5.0mg,19.5mmol),并将所得溶液搅拌2h。然后用乙酸乙酯稀释反应混合物,并通过Celite过滤。滤液依次用饱和碳酸氢钠水溶液、饱和碳酸氢钠水溶液和5%硫代硫酸钠水溶液的1∶1(V∶V)混合物及盐水洗涤。在NaSO4上干燥有机相,并真空浓缩。经快速层析(3∶1,己烷∶乙酸乙酯)纯化残余油,得到22.0mg(29%)标题化合物,为白色固体:1H NMR(300MHz,CDCl3)δ8.12-7.20(15H,m),7.04(1H,d,J=8.9Hz),6.41(1H,s),6.25(1H,m),5.81(1H,dd,J=8.9,2.4Hz),5.68(1H,d,J=7.0Hz),4.93(1H,d,8.0Hz),4.79(2H,m),4.71(1H,d,2.4Hz),4.45(1H,dd,J=10.5,6.6Hz),4.30(1H,d,J=8.3Hz),4.28(1H,d,J=11.7Hz),4.17(1H,d,J=8.3Hz),4.04(1H,d,J=11.7Hz),3.80(1H,d,J=6.9Hz),2.48-1.13(25H,m,incl.singlets at 2.51,2.13,2.05,2.01,1.69,1.19,1.16),0.98-0.85(9H,m),0.65-0.50(6H,m).(b)制备2′-O-(二苄基膦酰氧甲氧甲基)-7-三乙基甲硅烷基紫杉酚
于室温下向步骤(a)产物(15mg,0.014mmol)和分子筛(15mg)的THF(0.5ml)溶液中加入磷酸二苄酯(20.0mg,0.089mmol)及N-碘代琥珀酰亚胺(4.2mg,0.0187mmol),搅拌溶液1h。此时通过TLC分析反应混合物发现仅存在起始物。在2h内分三次加入三氟甲磺酸银(5.0mg,0.019mmol),并搅拌反应1h。用乙酸乙酯稀释反应混合物,所得溶液经Celite塞过滤。滤液用饱和碳酸氢钠和5%硫代硫酸钠水溶液的1∶1(V∶V)混合溶液处理。然后用盐水洗涤有机萃取物,于NaSO4上干燥,并真空浓缩。经快速层析纯化残余油(1∶1,己烷∶乙酸乙酯),得到5.0mg(33%)标题化合物:1H NMR(300MHz,CDCl3)δ8.08-7.16(25H,m),7.18(1H,d,J=8.8Hz),6.41(1H,s),6.21(1H,m),5.82(1H,dd,J=9.0,3.1Hz),5.66(1H,d,7.0Hz),5.01-4.65(10H,m),4.56(1H,dd,J=14.7,5.6Hz),4.43(1H,dd,J=10.4,6.7Hz),4.29(1H,d,J=8.3Hz),4.16(1H,d,J=8.3Hz),3.78(1H,d,J=7.0Hz),2.60-1.13(22H,m,incl.singlets at 2.49,2.15,1.93,1.66,1.15,1.13,3H each),0.95-0.84(9H,m),0.63-0.45(6H,m).(c)制备2′-O-膦酰氧甲氧甲基紫杉酚
按照实例9(f)的方法,用氟化四丁铵处理步骤(b)产物以除去7-O-三乙基甲硅烷基保护基。按前面实例所述方法对所得化合物进行催化氢化后得到标题化合物。实施例11 2′-O-膦酰氧甲氧甲基紫杉酚(替代途径)(a)制备2′-O-三乙基甲硅烷基紫杉酚
于0℃向紫杉酚(20.0g,0.0234mmol)和咪唑(3.5g,0.052mmol)的150ml DMF(二甲基甲酰胺)溶液中加入三乙基甲硅烷基氯(6.0ml,0.053mol),每次2.0ml,在20min内加完。然后于0℃搅拌1h。用乙酸乙酯及饱和氯化铵水溶液稀释反应混合物。除去有机层,用盐水洗涤,用NaSO4干燥,并真空浓缩,得到黄色油状物。经快速层析(己烷∶乙酸乙酯,1∶3,1∶1)纯化后得到21.07g(Y:98%)所需标题化合物,为无色白色固体。1H-NMR(300MHz,CDCl3)δ8.15(2H,m),7.70(2H,m),7.65-7.30(11H,m)7.15(1H,d,J=8.9Hz),6.30(1H,s),6.25(1H,m),6.70-6.10(2H,m),4.94(1H,d,J=7.9Hz),4.67(1H,d,2.0Hz),4.40(1H,m),4.29(1H,d,J=8.4Hz),4.18(1H,d,J=8.4Hz),3.81(1H,d,J=7.1Hz),2.65-1.10(22H,including singlets at2.55,2.20,1.88,1.69,1.22,1.13,3H each).(b)制备2 ′-O-三乙基甲硅烷基-7-O-苄氧羰基紫杉酚
在10min内将丁基锂(1.6M于己烷,12.9ml,8.06mmol)滴加至冷却至-50℃的2′-O-三乙基甲硅烷基紫杉酚(22.3g,24.1mmol)的THF(250ml)溶液中。搅拌所得溶液20min,并将温度维持在-50℃至-35℃。然后冷却混合物至-50℃,在5min内滴加氯代甲酸苄酯(5.08ml,29.8mmol)。将反应混合物于-40℃维持30min,然后在约30min内平衡至0℃。用乙酸乙酯及饱和氯化铵水溶液稀释混合物,用盐水洗涤有机层,于NaSO4上干燥并真空浓缩。对粗产物进行1H-NMR分析,发现存在所需的2′-O-三乙基甲硅烷基-7-O-苄氧羰基紫杉酚和2′-O-三乙基甲硅烷基-7-表羟基紫杉酚(3∶1)。该产物混合物不经纯化直接用于下一步骤,并随后分离异构体,通过快速层析纯化主要产物2′-O-三乙基甲硅烷基-7-O-苄氧羰基紫杉酚的分析性样品;
1H-NMR(300MHz,CDCl3)δ8.12(2H,m),7.72(1H,m),7.65-7.27(1H,d,J=8.8Hz),6.41(1H,m),6.20(1H,m),5.72-5.65(2H,m),5.52(1H,m),5.24(1H,d,J=12.3Hz),5.16(1H,d,J=12.3Hz),4.95(1H,d,J=8.7Hz),4.69(1H,s),4.35(1H,d,J=8.3Hz),4.25(1H,d,J=8.3Hz),3.94(1H,d,J=6.8Hz),2.70-1.12(22H,including singlets at2.54,2.14,2.01,1.80,1.20,1.15,3H each),0.81-0.73(9H,m),0.55-0.31(6H,m).(c)制备7-O-苄氧羰基紫杉酚
将盐酸(6N,1.0ml,6.0mmol)加至冷却至0℃的步骤(b)产物(24.0g,22.6mmol)的乙腈(250ml)溶液中,10min后TLC分析(己烷∶乙酸乙酯,1∶1)证实反应完全。用饱和碳酸氢钠水溶液及乙酸乙酯稀释反应混合物,除去有机层,用盐水洗涤,用NaSO4干燥,并真空浓缩。经快速层析(己烷∶乙酸乙酯,1∶3,然后1∶1)纯化残余油状物,得到11.4g(48%)标题化合物和4.8g(70%)7-表羟基紫杉酚。1H-NMR(300MHz,CDCl3)δ8.09(2H,m),7.71(2H,m),7.65-7.27(16H,m),7.10(1H,d,8.9Hz),6.39(1H,s),6.16(1H,m),5.81(1H,d,J=8.9,2.4Hz),5.65(1H,d,J=6.9Hz),5.49(1H,dd,J=10.6,7.2Hz),5.20(1H,d,J=11.9Hz),5.12(1H,d,J=11.9),4.91(1H,d,J=8.4Hz),4.78(1H,m),4.30(1H,d,J=8.4Hz),4.15(1H,d,J=8.4Hz),3.91(1H,d,J=6.8Hz),3.69(1H,d,J=4.9Hz),2.65-1.10(22H,including singlets at 2.39,2.18,1.81,1.75,1.21,1.15,3H each).(d)制备2′-O-(甲硫甲氧甲基)-7-O-苄氧羰基紫杉酚
于室温下将三氟甲磺酸银(300mg,1.17mmol)加至7-O-苄氧羰基紫杉酚(5.53g,5.71mmol)、1,1′-二硫甲基二甲基醚(7.8g,57.1mmol)、N-碘代琥珀酰亚胺(6.35g,28.3mmol)及炉干燥的粉化分子筛(5.0g)的THF(110ml)溶液中。20min后通过TLC分析(己烷∶乙酸乙酯,1∶1)发现约40%起始物转化为跑得更快的产物。然后加入三氟甲磺酸银(150mg,0.585mmol),约30min后通过TLC测得反应约65%完全、用乙酸乙酯(100ml)稀释混合物,用Celite塞过滤并将滤液倒入含有200ml饱和碳酸氢钠水溶液和50ml 5%硫代硫酸钠水溶液的分离漏斗中。取出有机层,用盐水洗涤,于NaSO4上干燥并真空浓缩。通过快速层析(己烷∶乙酸乙酯,梯度洗脱4∶1-3∶2)纯化残余油状物,得到3.0g(54%)标题化合物,为浅黄色固体。1H-NMR(300MHz,CDCL3)δ8.10(2H,m),7.74(2H,m),7.66-7.25(18H,m),7.05(1H,d,J=8.9Hz),6.40(1H,s),6.26(1H,m),5.77(1H,dd,J=8.8,2.5Hz),5.71(1H,d,J=6.9Hz),5.51(1H,dd,J=10.6,7.1Hz),5.21(1H,d,J=11.9Hz),5.14(1H,d,J=11.9Hz),4.92(1H,m),4.79(2H,m),4.68(1H,d,J=2.5Hz),4.31(1H,d,J=11.8Hz),4.30(1H,d,J=8.5Hz),4.16(1H,d,J=8.5Hz),4.10(1H,d,J=11.8Hz),3.93(1H,d,J=6.9Hz),2.65-1.10(25Hincluding singlets at 2.50,2.15,2.05,1.74,1.72,1.20,1.15,3H each).(e)制备2′-O-(二苄基膦酰氧甲氧甲基)-7-O-苄氧羰基紫杉酚
于室温下,向2′-O-(甲硫甲氧甲基)-7-O-苄氧羰基紫杉酚(1.06g,1.07mmol)和炉干粉化分子筛(1.0g)的THF(20ml)溶液中加入磷酸二苄酯(1.49g,5.30mmol),紧接着加入N-碘代琥珀酰亚胺(2.65g,1.18mmol)。2.5h后通过TLC分析(己烷∶乙酸乙酯,1∶1),发现反应完成60%。加入N-碘代琥珀酰亚胺(175mg,0.78mmol),搅拌30min,再通过TLC分析发现反应完全。用乙酸乙酯(50ml)稀释反应混合物,并用Celite塞过滤。将滤液倒入含有100ml饱和碳酸氢钠水溶液和20ml 5%硫代硫酸钠水溶液的分离漏斗中,取出有机层,用盐水洗涤,用NaSO4干燥,并真空浓缩。利用快速层析(己烷∶乙酸乙酯,梯度洗脱,3∶1-1∶1)纯化残余油状物,得到750mg(62%)所需标题化合物,为白色固体。1H-NMR(360MHz,CDCl3)δ8.10(2H,m),7.79(2H,m),7.65-7.24(26H,m),7.10(1H,m),6.41(1H,s),6.20(1H,m),5.79(1H,dd,J=8.8,3.6Hz),5.65(1H,d,J=7.0Hz),5.52(1H,m),5.20(1H,d,J=11.8Hz),5.11(1H,d,J=11.8Hz),5.04-4.85(6H,m),4.75-4.60(4H,m),4.30(1H,d,8.4Hz),4.15(1H,d,J=8.4Hz),3.92(1H,d,J=7.0Hz)2.65-1.10(22Hincluding singlets at 2.48,2.19,1.95,1.80,1.20,1.10,3H each).(f)制备2′-O-膦酰氧甲氧甲基紫杉酚三乙醇胺盐
向放置在帕尔瓶中的2′-O-(二苄基膦酰氧甲氧甲基)-7-O-苄氧羰基紫杉酚(500mg,0.382mmol)的乙酸乙酯(40ml)溶液中加入Pd-C(10%)。将该容器固定在帕尔装置上,将混合物通过50psi氢气、振荡混合物6.5h,然后用熔结玻璃漏斗过滤,向滤液中加入三乙醇胺(0.1N于乙酸乙酯,4.0ml),真空浓缩所得溶液。粗产物悬浮于5.0ml乙酸乙酯中,并弃掉溶剂。重复该法三次,得到标题三乙醇胺盐(300mg),经HPLC分析测得的纯度为87%。通过C18层柱(水∶乙腈,3∶1)进一步纯化该化合物后,得到所需标题化合物(120mg,34%),HPLC测得纯度为95%。1H-NMR(300MHz,CD3COCD3,D2O)δ9.05(1H,d,J=8.7Hz),8.15-7.12(21H,m),6.40(1H,m),6.05(1H,m),5.69-5.55(2H,m),5.01-4.85(6H,m),4.35(1H,m),4.14(2H,m),3.96-3.85(6H,m),3.25(1H,d,J=7.1Hz),3.30-3.15(6H,m)2.50-1.04(22H,includingsinglets at 2.49,2.15,2.05,1.81,1.60,3H each).附加实施例
按照上面提供的一般方法,制备出下列属于本发明式(A)范围内的化合物:
*“c”表示环
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OP(O)(OH)2 | AcO | Ph | 4-F-Ph-4-CH3-Ph2-呋喃基2-噻吩基(CH3)2CH-异丁烯基(2-甲基-1-丙烯基)c-C3H6-3-呋喃基3-噻吩基2-丙烯基 |
RI-OCH2OP(O)(OH)2 | RII′H | RIIOH | RIIIAcO | RIVPh | RV4-CF3-Ph-2-呋喃基(CH3)2CH-2-噻吩基异丁烯基环丙基3-噻吩基3-呋喃基2-丙烯基异丙基 |
CH3CH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | Ph | 4-F-Ph-2-噻吩基异丙基2-丙烯基异丁烯基环丙基2-呋喃基3-呋喃基3-噻吩基 |
-OCH2OP(O)(OH)2 | H | OHHCH3CH2OC(O)O- | OH | (CH3)3CO- | Ph |
RI | RII′ | RII | RIII | RIV | RV |
OHCH3CH2OC(O)O- | H | -OCH2OP(O)(OH)2 | OH | (CH3)3CO- | Ph |
-OCH2OP(O)(OH)2 | H | HCH3CH2OC(O)O- | AcO | Ph | Ph |
OHCH3OC(O)O-CH3CH2OC(O)O-CH3(CH2)2OC(O)O-CH3(CH2)3OC(O)O-CCl3CH2OC(O)O-CH3C(O)O-CH3CH2(O)O-CH3(CH2)2C(O)O-CH3(CH2)3C(O)O-PhC(O)O-PhOC(O)O-CH2=CHCH2OC(O)O-PhCH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | Ph | Ph |
OH | H | OH | -OCH2OP(O)(OH)2 | Ph | Ph |
OH | H | H | -OCH2OP(O)(OH)2 | Ph | Ph |
-OCH2OP(O)(OH)2 | H | H | H | (CH3)3CO- | 4-CH3O-Ph |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
CH3OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
CH3CH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
CH3(CH2)2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
CH3(CH2)3OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
CCl3CH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
CH3C(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
CH3CH2(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
CH3(CH2)2C(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
CH3(CH2)3C(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
PhC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
PhOC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
CH2=CHCH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
PhCH2OC(O)O- | H | -OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 异丁烯基2-丙烯基环丙基3-呋喃基3-噻吩基异丙基环丁基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | AcO | CH3CH2CH2CH2O- | 2-呋喃基3-呋喃基异丁烯基2-丙烯基环丙基环丁基3-噻吩基2-噻吩基异丙基 |
OH | H | -OCH2OP(O)(OH)2 | AcO | CH3CH2CH2CH2O- | 2-呋喃基3-呋喃基异丁烯基2-丙烯基环丙基环丁基3-噻吩基2-噻吩基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | AcO | isopropyloxy | 2-呋喃基3-呋喃基2-噻吩基异丁烯基2-丙烯基环丙基环丁基3-噻吩基异丙基 |
OH | H | -OCH2OP(O)(OH)2 | AcO | isopropyloxy | 2-呋喃基3-呋喃基2-噻吩基异丁烯基2-丙烯基环丙基环丁基3-噻吩基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
OHCH3OC(O)O-CH3CH2OC(O)O-CH3(CH2)2OC(O)O-CH3(CH2)3OC(O)O-CC(3CH2OC(O)O-CH3C(O)O-CH3CH2(O)O-CH3(CH2)2C(O)O-CH3(CH2)3C(O)O-PhC(O)O-PhOC(O)O-CH2=CHCH2OC(O)O-PhCH2OC(O)O- | H | -OCH2OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 3-呋喃基异丁烯基2-丙烯基2-噻吩基3-噻吩基环丙基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OCH2OP(O)(OH)2 | AcO | (CH3)3CO- | 2-呋喃基异丁烯基2-噻吩基2-丙烯基异丙基环丙基3-噻吩基3-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | AcO | CH3CH2CH2CH2O- | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | AcO | isopropyloxy | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | OMe | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OP(O)(OH)2 | OMe | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO- | 2-呋喃基3-呋喃基3-噻吩基异丙基环丙基异丁烯基2-噻吩基2-丙烯基 |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | -OCO2CH3 | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
OH | H | -OCH2OP(O)(OH)2 | -OCO2CH3 | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | OMe | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
OH | H | -OCH2OP(O)(OH)2 | OMe | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCO2CH2CH3 | H | -OCH2OP(O)(OH)2 | -OC(O)Ph | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
OH | H | -OCH2OP(O)(OH)2 | -OC(O)Ph | PhCH3CH2CH2CH2O-isopropyloxy | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
OH | H | -OCH2OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | OMe | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
OH | H | -OCH2OCH2OP(O)(OH)2 | OMe | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
RI | RII′ | RII | RIII | RIV | RV |
OH | H | -OCH2OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO-isopropyloxyCH3CH2CH2CH2O- | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO- | 异丁烯基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | OMe | (CH3)3CO- | 异丁烯基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO- | 异丁烯基 |
OH | H | -OCH2OCH2OP(O)(OH)2 | -OCO2CH3 | Ph | 2-呋喃基 |
OH | H | -OCH2OCH2OP(O)(OH)2 | OMe | Ph | 2-呋喃基 |
OH | H | -OCH2OCH2OP(O)(OH)2 | -OC(O)Ph | Ph | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OCO2CH3 | (CH3)3CO- | 2-丙烯基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | OMe | (CH3)3CO- | 2-丙烯基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | -OC(O)Ph | (CH3)3CO- | 2-丙烯基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCH2OCH2OP(O)(OH)2 | H | OH | AcO | (CH3)3CO- | 2-呋喃基2-噻吩基3-呋喃基3-噻吩基异丁烯基2-丙烯基环丙基 |
-OCH2OCH2OP(O)(OH)2 | H | OH | AcO | CH3CH2CH2CH2O-isopropyloxy(CH3)3CO- | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | H | OH | -OCO2CH3 | (CH3)3CO-Phisopropyloxy | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | H | OH | OMe | (CH3)3CO-Phisopropyloxy | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | H | OH | -OC(O)Ph | (CH3)3CO-Phisopropyloxy | 2-呋喃基 |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | AcO | Ph | Ph |
RI | RII′ | RII | RIII | RIV | RV |
OH | F | H | -OCH2OP(O)(OH)2 | (CH3)3CO-Ph | Ph |
-OCO2CH2CH3 | F | H | -OCH2OP(O)(OH)2 | (CH3)3CO-Ph | Ph |
-OCH2OP(O)(OH)2 | F | H | AcO | Ph | 2-呋喃基异丁烯基3-呋喃基2-噻吩基2-丙烯基环丙基3-噻吩基异丙基 |
-OCH2OCH2OP(O)(OH)2 | F | H | AcO | Ph | 2-呋喃基异丙烯基3-呋喃基2-噻吩基2-丙烯基环丙基3-噻吩基异丙基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCH2OP(O)(OH)2 | F | H | AcO | (CH3)3CO- | 2-呋喃基3-噻吩基异丁烯基3-呋喃基环丙基2-噻吩基Ph2-丙烯基 |
-OCH2OCH2OP(O)(OH)2 | F | H | AcO | (CH3)3CO- | 2-呋喃基3-噻吩基异丁烯基3-呋喃基环丙基2-噻吩基Ph2-丙烯基 |
-OCH2OP(O)(OH)2 | F | H | -OCO2CH3 | (CH3)3CO- | 2-呋喃基 |
-OCH2OP(O)(OH)2 | F | H | OMe | (CH3)3CO- | 2-呋喃基 |
-OCH2OP(O)(OH)2 | F | H | -OC(O)Ph | (CH3)3CO- | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | F | H | -OCO2CH3 | (CH3)3CO- | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | F | H | OMe | (CH3)3CO- | 2-呋喃基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCH2OCH2OP(O)(OH)2 | F | H | -OC(O)Ph | (CH3)3CO- | 2-呋喃基 |
-OCH2OCH2OP(O)(OH)2 | H | OH | OH | (CH3)3CO- | Ph |
OH | H | -OCH2OCH2OP(O)(OH)2 | OH | (CH3)3CO- | Ph |
-OCO2CH2CH3 | H | -OCH2OCH2OP(O)(OH)2 | OH | (CH2)3CO- | Ph |
OH | H | OH | -OCH2OCH2OP(O)(OH)2 | (CH3)3CO- | Ph |
-OCO2CH2CH3 | H | OH | -OCH2OCH2OP(O)(OH)2 | (CH3)3CO- | Ph |
OH | F | H | -OCH2OCH2OP(O)(OH)2 | (CH3)3CO- | Ph2-呋喃基3-呋喃基2-噻吩基3-噻吩基异丁烯基环丙基2-丙烯基 |
RI | RII′ | RII | RIII | RIV | RV |
-OCO2CH2CH3 | F | H | -OCH2OCH2OP(O)(OH)2 | (CH3)3CO- | Ph2-呋喃基3-呋喃基2-噻吩基3-噻吩基异丁烯基环丙基2-丙烯基 |
Claims (38)
R1为羟基、-OCH2(OCH2)mOP(O)(OH)2、-OC(O)Rx或-OC(O)ORx;
R2′为氢,且R2为氢、羟基、-OCH2(OCH2)mOP(O)(OH)2或-OC(O)ORx;或R2′为氟,且R2为氢;
R3为氢、羟基、乙酰氧基、-OCH2(OCH2)mOP(O)OH2或-OC(O)ORx;
R6和R7之一为氢,另一个为羟基、C1-6烷酰氧基或-OCH2(OCH2)mOP(O)(OH)2;或R6和R7共同形成一氧代基;条件是R1、R2、R3、R6或R7中至少一个为-OCH2(OCH2)mOP(O)(OH)2;
m为0、1或2;
R4和R5独立地为C1-6烷基、C2-6链烯基、C2-6链炔基或-Z-R6;
Z为一直接键、C1-6烷基或C2-6链烯基;
R6为C6-10芳基;被至少一个选自C1-6烷酰氧基、羟基、卤素、C1-6烷基、三氟甲基、C1-6烷氧基、C6-10芳基、C2 -6链烯基、C1-6烷酰基、硝基、氨基和酰氨基取代的C6-10芳基;C3-6环烷基或含有至少一个、至多4个选自氧、硫和氮的非碳原子的五元或六元杂芳基;
P为0或1;且
Rx为非限制性地被1-6个相同或不同卤原子取代的C1-6烷基、C3-6环烷基、C2-6链烯基或下式残基
其中D为-键或C1-6亚烷基;且Ra、Rb和Rc独立为氢、氨基、C1-6烷氨基、二-C1-6烷氨基、卤素、C1-6烷基或C1 -6烷氧基。
2.根据权利要求1的化合物或其可作药用的盐,其中R2′为氢,且R2为-OCH2OP(O)(OH)2。
3.根据权利要求2的化合物,其中R′为羟基或-OC(O)ORx;且Rx的定义同前。
4.根据权利要求3的化合物,其中Rx为C1-6烷基。
5.根据权利要求3的化合物,其中R3为氢、羟基或乙酸基。
6.根据权利要求3的化合物,其中R4(O)p为苯基或叔丁氧基。
7.根据权利要求3的化合物,其中R5为苯基、2-呋喃基或2-噻吩基。
8.根据权利要求1的化合物或其可作药用的盐,它为2′-O-(乙氧羰基)-7-O-(膦酰氧甲基)紫杉酚。
9.权利要求8化合物的钠盐。
10.权利要求8化合物的三乙醇胺盐。
11.权利要求8化合物的三乙胺盐。
12.权利要求8化合物的精氨酸盐。
13.权利要求8化合物的赖氨酸盐。
14.权利要求8化合物的乙醇胺盐。
15.权利要求8化合物的N-甲基葡糖胺盐。
16.根据权利要求1的化合物或其可作药用的盐,它为7-O-(膦酰氧甲基)紫杉酚。
17.权利要求16化合物的钠盐。
18.根据权利要求1的化合物或其可作药用的盐,它为3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-呋喃基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚。
19.权利要求18化合物的三乙醇胺盐。
20.根据权利要求1的化合物或其可作药用的盐,它为3′-N-脱苯甲酰基-3′-脱苯基-3′-N-(叔丁氧羰基)-3′-(2-噻吩基)-2′-O-乙氧羰基-7-O-膦酰氧甲基紫杉酚。
21.权利要求20化合物的三乙醇胺盐。
22.根据权利要求1的化合物或其可作药用的盐,其中R′为-OCH2OP(O)(OH)2。
23.根据权利要求22的化合物,其中R2′为氢,R2为氢、羟基或-OC(O)ORx,且Rx的定义同权利要求1。
24.权利要求23的化合物,其中R3为氢、羟基或乙酸基。
25.根据权利要求23的化合物,其中R4(O)p为苯基或叔丁氧基。
26.根据权利要求23的化合物,其中R5为苯基。
27.根据权利要求1的化合物或其可作药用的盐,它为2′-O-(膦酰氧甲基)紫杉酚。
28.根据权利要求1的化合物或其可作药用的盐,其中R1和R2均为-OCH2OP(O)(OH)2。
29.根据权利要求1的化合物或其可作药用的盐,它为2′,7-O-双(膦酰氧甲基)紫杉酚。
30.权利要求29化合物的钠盐。
31.根据权利要求1的化合物或其可作药用的盐,其中R′为-OCH2OCH2OP(O)(OH)2。
32.根据权利要求1的化合物或其可作药用的盐,它为2′-O-膦酰氧甲氧甲基紫杉酚。
33.权利要求32化合物的三乙醇胺盐。
34.根据权利要求1的化合物或其可作药用的盐,其中R3为-OCH2OP(O)(OH)2。
35.根据权利要求1的化合物或其可作药用的盐,它为10-脱乙酰基-3′-N-脱苯甲酰基-3′-N-(叔丁氧羰基)-10-O-(膦酰氧甲基)紫杉酚。
36.权利要求35化合物的三乙醇胺盐。
37.下式化合物其中R1c为羟基、保护羟基、-OCH2OP(O)(OCH2Ry)2或-OC(O)ORx;R2′为氢,R2c为氢、羟基、保护羟基、-OCH2OP(O)(OCH2Ry)2或-OC(O)ORx;或R2′为氟,R2c为氢;R3c为氢、羟基、保护羟基、乙酸基、-OCH2OP(O)(OCH2Ry)2或-OC(O)ORx;R6c或R7c之一为氢,且另一个为羟基、保护羟基、C1-6烷酰氧基或-OCH2OP(O)(ORy)2;或R6c和R7c共同形成一氧代基;条件是R1b、R2b、R3b、R6c或R7c中至少一个为-OCH2OP(O)(OCH2Ry)2;Ry为膦酰基保护基;且P、R4、R5和Rx的定义同前。
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US99645592A | 1992-12-24 | 1992-12-24 | |
US996455 | 1992-12-24 | ||
US10801593A | 1993-08-17 | 1993-08-17 | |
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US15484093A | 1993-11-24 | 1993-11-24 | |
US154840 | 1993-11-24 | ||
US108,015 | 1993-11-24 | ||
US996,455 | 1993-11-24 | ||
US154,840 | 1993-11-24 |
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CN93121100A Expired - Fee Related CN1037774C (zh) | 1992-12-24 | 1993-12-24 | 紫杉烷的膦酰氧甲基醚衍生物 |
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JP (1) | JP3189140B2 (zh) |
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