CN1230437C - 海鞘素及其结构类似化合物的中间体的合成方法 - Google Patents
海鞘素及其结构类似化合物的中间体的合成方法 Download PDFInfo
- Publication number
- CN1230437C CN1230437C CNB018070973A CN01807097A CN1230437C CN 1230437 C CN1230437 C CN 1230437C CN B018070973 A CNB018070973 A CN B018070973A CN 01807097 A CN01807097 A CN 01807097A CN 1230437 C CN1230437 C CN 1230437C
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- Prior art keywords
- compound
- obtains
- amino
- rings
- ecteinascidin
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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- 238000000034 method Methods 0.000 title claims abstract description 11
- PKVRCIRHQMSYJX-AIFWHQITSA-N trabectedin Chemical compound C([C@@]1(C(OC2)=O)NCCC3=C1C=C(C(=C3)O)OC)S[C@@H]1C3=C(OC(C)=O)C(C)=C4OCOC4=C3[C@H]2N2[C@@H](O)[C@H](CC=3C4=C(O)C(OC)=C(C)C=3)N(C)[C@H]4[C@@H]21 PKVRCIRHQMSYJX-AIFWHQITSA-N 0.000 title claims abstract description 11
- 229960000977 trabectedin Drugs 0.000 title claims abstract description 7
- 150000001875 compounds Chemical class 0.000 title claims description 12
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 21
- 150000001408 amides Chemical class 0.000 claims description 11
- -1 amino lactone Chemical class 0.000 claims description 7
- 235000019439 ethyl acetate Nutrition 0.000 claims description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 229940125898 compound 5 Drugs 0.000 claims description 5
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 3
- 238000005828 desilylation reaction Methods 0.000 claims description 3
- 230000002829 reductive effect Effects 0.000 claims description 3
- FANCTJAFZSYTIS-IQUVVAJASA-N (1r,3s,5z)-5-[(2e)-2-[(1r,3as,7ar)-7a-methyl-1-[(2r)-4-(phenylsulfonimidoyl)butan-2-yl]-2,3,3a,5,6,7-hexahydro-1h-inden-4-ylidene]ethylidene]-4-methylidenecyclohexane-1,3-diol Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)CS(=N)(=O)C1=CC=CC=C1 FANCTJAFZSYTIS-IQUVVAJASA-N 0.000 claims description 2
- 238000003776 cleavage reaction Methods 0.000 claims description 2
- 238000005336 cracking Methods 0.000 claims description 2
- 238000006073 displacement reaction Methods 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- NSPJNIDYTSSIIY-UHFFFAOYSA-N methoxy(methoxymethoxy)methane Chemical compound COCOCOC NSPJNIDYTSSIIY-UHFFFAOYSA-N 0.000 claims description 2
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims description 2
- XKJCHHZQLQNZHY-UHFFFAOYSA-N phthalimide Chemical compound C1=CC=C2C(=O)NC(=O)C2=C1 XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 claims description 2
- 230000007017 scission Effects 0.000 claims description 2
- 150000003335 secondary amines Chemical class 0.000 claims description 2
- QFLWZFQWSBQYPS-AWRAUJHKSA-N (3S)-3-[[(2S)-2-[[(2S)-2-[5-[(3aS,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-4-[1-bis(4-chlorophenoxy)phosphorylbutylamino]-4-oxobutanoic acid Chemical compound CCCC(NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)[C@@H](NC(=O)CCCCC1SC[C@@H]2NC(=O)N[C@H]12)C(C)C)P(=O)(Oc1ccc(Cl)cc1)Oc1ccc(Cl)cc1 QFLWZFQWSBQYPS-AWRAUJHKSA-N 0.000 claims 3
- 125000005219 aminonitrile group Chemical group 0.000 claims 3
- AOSZTAHDEDLTLQ-AZKQZHLXSA-N (1S,2S,4R,8S,9S,11S,12R,13S,19S)-6-[(3-chlorophenyl)methyl]-12,19-difluoro-11-hydroxy-8-(2-hydroxyacetyl)-9,13-dimethyl-6-azapentacyclo[10.8.0.02,9.04,8.013,18]icosa-14,17-dien-16-one Chemical compound C([C@@H]1C[C@H]2[C@H]3[C@]([C@]4(C=CC(=O)C=C4[C@@H](F)C3)C)(F)[C@@H](O)C[C@@]2([C@@]1(C1)C(=O)CO)C)N1CC1=CC=CC(Cl)=C1 AOSZTAHDEDLTLQ-AZKQZHLXSA-N 0.000 claims 2
- GLGNXYJARSMNGJ-VKTIVEEGSA-N (1s,2s,3r,4r)-3-[[5-chloro-2-[(1-ethyl-6-methoxy-2-oxo-4,5-dihydro-3h-1-benzazepin-7-yl)amino]pyrimidin-4-yl]amino]bicyclo[2.2.1]hept-5-ene-2-carboxamide Chemical compound CCN1C(=O)CCCC2=C(OC)C(NC=3N=C(C(=CN=3)Cl)N[C@H]3[C@H]([C@@]4([H])C[C@@]3(C=C4)[H])C(N)=O)=CC=C21 GLGNXYJARSMNGJ-VKTIVEEGSA-N 0.000 claims 2
- IWZSHWBGHQBIML-ZGGLMWTQSA-N (3S,8S,10R,13S,14S,17S)-17-isoquinolin-7-yl-N,N,10,13-tetramethyl-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1H-cyclopenta[a]phenanthren-3-amine Chemical compound CN(C)[C@H]1CC[C@]2(C)C3CC[C@@]4(C)[C@@H](CC[C@@H]4c4ccc5ccncc5c4)[C@@H]3CC=C2C1 IWZSHWBGHQBIML-ZGGLMWTQSA-N 0.000 claims 2
- 229940126657 Compound 17 Drugs 0.000 claims 2
- 229940125773 compound 10 Drugs 0.000 claims 2
- 229940125758 compound 15 Drugs 0.000 claims 2
- ZLVXBBHTMQJRSX-VMGNSXQWSA-N jdtic Chemical compound C1([C@]2(C)CCN(C[C@@H]2C)C[C@H](C(C)C)NC(=O)[C@@H]2NCC3=CC(O)=CC=C3C2)=CC=CC(O)=C1 ZLVXBBHTMQJRSX-VMGNSXQWSA-N 0.000 claims 2
- SZUVGFMDDVSKSI-WIFOCOSTSA-N (1s,2s,3s,5r)-1-(carboxymethyl)-3,5-bis[(4-phenoxyphenyl)methyl-propylcarbamoyl]cyclopentane-1,2-dicarboxylic acid Chemical compound O=C([C@@H]1[C@@H]([C@](CC(O)=O)([C@H](C(=O)N(CCC)CC=2C=CC(OC=3C=CC=CC=3)=CC=2)C1)C(O)=O)C(O)=O)N(CCC)CC(C=C1)=CC=C1OC1=CC=CC=C1 SZUVGFMDDVSKSI-WIFOCOSTSA-N 0.000 claims 1
- GHYOCDFICYLMRF-UTIIJYGPSA-N (2S,3R)-N-[(2S)-3-(cyclopenten-1-yl)-1-[(2R)-2-methyloxiran-2-yl]-1-oxopropan-2-yl]-3-hydroxy-3-(4-methoxyphenyl)-2-[[(2S)-2-[(2-morpholin-4-ylacetyl)amino]propanoyl]amino]propanamide Chemical compound C1(=CCCC1)C[C@@H](C(=O)[C@@]1(OC1)C)NC([C@H]([C@@H](C1=CC=C(C=C1)OC)O)NC([C@H](C)NC(CN1CCOCC1)=O)=O)=O GHYOCDFICYLMRF-UTIIJYGPSA-N 0.000 claims 1
- ONBQEOIKXPHGMB-VBSBHUPXSA-N 1-[2-[(2s,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]oxy-4,6-dihydroxyphenyl]-3-(4-hydroxyphenyl)propan-1-one Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=CC(O)=C1C(=O)CCC1=CC=C(O)C=C1 ONBQEOIKXPHGMB-VBSBHUPXSA-N 0.000 claims 1
- RRSNDVCODIMOFX-MPKOGUQCSA-N Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O Chemical compound Fc1c(Cl)cccc1[C@H]1[C@@H](NC2(CCCCC2)[C@@]11C(=O)Nc2cc(Cl)ccc12)C(=O)Nc1ccc(cc1)C(=O)NCCCCCc1cccc2C(=O)N(Cc12)C1CCC(=O)NC1=O RRSNDVCODIMOFX-MPKOGUQCSA-N 0.000 claims 1
- LNUFLCYMSVYYNW-ZPJMAFJPSA-N [(2r,3r,4s,5r,6r)-2-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[(2r,3r,4s,5r,6r)-6-[[(3s,5s,8r,9s,10s,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-3-yl]oxy]-4,5-disulfo Chemical compound O([C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1[C@@H](COS(O)(=O)=O)O[C@H]([C@@H]([C@H]1OS(O)(=O)=O)OS(O)(=O)=O)O[C@@H]1C[C@@H]2CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)[C@H]1O[C@H](COS(O)(=O)=O)[C@@H](OS(O)(=O)=O)[C@H](OS(O)(=O)=O)[C@H]1OS(O)(=O)=O LNUFLCYMSVYYNW-ZPJMAFJPSA-N 0.000 claims 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 claims 1
- 230000021736 acetylation Effects 0.000 claims 1
- 238000006640 acetylation reaction Methods 0.000 claims 1
- OSVHLUXLWQLPIY-KBAYOESNSA-N butyl 2-[(6aR,9R,10aR)-1-hydroxy-9-(hydroxymethyl)-6,6-dimethyl-6a,7,8,9,10,10a-hexahydrobenzo[c]chromen-3-yl]-2-methylpropanoate Chemical compound C(CCC)OC(C(C)(C)C1=CC(=C2[C@H]3[C@H](C(OC2=C1)(C)C)CC[C@H](C3)CO)O)=O OSVHLUXLWQLPIY-KBAYOESNSA-N 0.000 claims 1
- 229940125797 compound 12 Drugs 0.000 claims 1
- 229940126543 compound 14 Drugs 0.000 claims 1
- 229940126142 compound 16 Drugs 0.000 claims 1
- FGTJJHCZWOVVNH-UHFFFAOYSA-N tert-butyl-[tert-butyl(dimethyl)silyl]oxy-dimethylsilane Chemical compound CC(C)(C)[Si](C)(C)O[Si](C)(C)C(C)(C)C FGTJJHCZWOVVNH-UHFFFAOYSA-N 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 239000002246 antineoplastic agent Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 2
- 230000003389 potentiating effect Effects 0.000 abstract 1
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 23
- 239000000243 solution Substances 0.000 description 23
- 239000000203 mixture Substances 0.000 description 19
- OAYLNYINCPYISS-UHFFFAOYSA-N ethyl acetate;hexane Chemical compound CCCCCC.CCOC(C)=O OAYLNYINCPYISS-UHFFFAOYSA-N 0.000 description 15
- KXDHJXZQYSOELW-UHFFFAOYSA-M Carbamate Chemical compound NC([O-])=O KXDHJXZQYSOELW-UHFFFAOYSA-M 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 12
- 239000012141 concentrate Substances 0.000 description 11
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- 229910002027 silica gel Inorganic materials 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 10
- 239000000376 reactant Substances 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000001035 drying Methods 0.000 description 8
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 7
- 238000005160 1H NMR spectroscopy Methods 0.000 description 7
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- 238000007701 flash-distillation Methods 0.000 description 7
- 229910052938 sodium sulfate Inorganic materials 0.000 description 7
- 235000011152 sodium sulphate Nutrition 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- 229910052757 nitrogen Inorganic materials 0.000 description 6
- 239000007864 aqueous solution Substances 0.000 description 5
- 238000000605 extraction Methods 0.000 description 5
- 238000010189 synthetic method Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- XPDWGBQVDMORPB-UHFFFAOYSA-N Fluoroform Chemical compound FC(F)F XPDWGBQVDMORPB-UHFFFAOYSA-N 0.000 description 4
- 229910010082 LiAlH Inorganic materials 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 238000010790 dilution Methods 0.000 description 3
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- 150000002596 lactones Chemical group 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
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- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
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- QRUDEWIWKLJBPS-UHFFFAOYSA-N benzotriazole Chemical compound C1=CC=C2N[N][N]C2=C1 QRUDEWIWKLJBPS-UHFFFAOYSA-N 0.000 description 2
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- 238000004293 19F NMR spectroscopy Methods 0.000 description 1
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- NNFCIKHAZHQZJG-UHFFFAOYSA-N potassium cyanide Chemical compound [K+].N#[C-] NNFCIKHAZHQZJG-UHFFFAOYSA-N 0.000 description 1
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- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
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- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
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Abstract
本发明描述了一种用于合成化合物5的有效方法,5是从易于获得的结构单元3b和4合成的强效抗癌剂海鞘素(ecteinascidin)(1)及其结构类似物phthalascidin(2)的关键中间体。
Description
发明背景
海鞘素743(1,Et743)是一种非常有效的海生抗肿瘤剂1,目前用其对各种临床病人进行了研究2。因为这些化合物从天然原料(被囊动物的Ecteinascidia turbinata)不能充足地获得,所以其通过在1996年报导的完全合成路线在工业上生产3。近年来,已经找到了一种与Et 743的类似结构的化合物2(phthalascidin,Pt 650),其显示出实际上与1难以区分的抗癌的活性4。
1和2均用由结构单元3和43经普通的五环中间体5合成。
5的合成最初由构造化合物3a和4在六个步骤中完成,总产率为35%(每步骤的平均收率大约84%)3。因为1和/或2的工业合成从经济上考虑最终必须以数千克的规模生产,所以我们探索发现了一种从2和3到5的更有效的和可重复的另一路线。
发明概述
因此,本发明的一个实施方案是涉及一种新的合成方法,用于中间体化合物5的制备,该方法比原来的方法更容易进行,在六个步骤中由3b3+4至5进行生产,总产率为57%(每步平均收率接近92%)。用于合成五环的5的优选方法总结于下面的方案15中。
方案1
本发明的第二个优选实施方案是用于将五环化合物5转化为phthalascidin 2的新的合成方法,其平稳地进行并且产率极好(每步平均收率90.8%)。该方法在下面的方案2中描述。
方案2
优选实施方案的详细说明
如上述方案1中说明的,将共沸干燥的(C7H8-THF)氨基内酯4在0℃的四氢呋喃中的溶液逐滴地用由酸3b3(1.03当量)制备的酰化试剂、1-羟基-7-氮杂苯并***(HOAT,1.08当量)、2-氯-1,3-二甲基咪唑鎓六氟磷酸盐(CIP1.03当量)和三乙胺(2.06当量)在CH2Cl2中的溶液在0℃进行处理。
由萃取处理得到的耦合产品6不经进一步纯化,通过在DMF溶液中在23℃用过量的烯丙基溴和1.09当量的Cs2CO3处理进行烯丙基化,在硅胶上进行闪蒸色谱之后从3a和4以81%的总产率得到酰胺7。
7的内酯官能团选择性还原为相应的内半缩醛(8)是通过与1.1当量氢化二乙氧基铝锂(LiAlH2(OEt)2)在***中在-78度反应15min,产率95%。8至9的7,8脱甲硅烷基作用和使用0.6M三氟甲磺酸在3∶2H2O-CF3CH2OH中在45℃反应7小时的9的环化(不经纯化),以89%的总产率从8生成五环产品10。
最后,10的内酰胺官能团可以通过用4当量LiAlH2(OEt)2在THF在0℃处理35min完全还原成相应的环缩醛胺,其暴露在HCN下从10得到五环的氨基腈5,在硅胶上进行闪蒸色谱后,得到87%的总产率。
方案1和上文说明的5的合成相对于最初使用的合成路线3是有利的,不仅因为实质上更大的总产率(57对35%),而且因为各个步骤简单和可重现,特别是酰胺耦合(2a+3→6)和内部的Pictet-Spengler环化(9→10)。另外,在产品纯化或者按比例放大方面没有遇到困难。
方案1所示程序的成功关键因素是用于两个还原步骤8→9和10→5的LiAlH2(OEt)2的高效性和选择性,这表示该试剂在合成方法中所体现的效益常常比以前更大。
在方案2,五环三醇5首先通过用1.1当量的PhNTf2(McMurry试剂)、2当量的Et3N和0.2当量的4-二甲基-氨基吡啶在CH2Cl2中在30℃下处理38小时转化为单三氟甲磺酸酚酯11(未显示)(74%)。11转化为单叔丁基二甲基甲硅烷(TBS)醚12和用甲氧基甲基氯化物(MOMCl)醚化以高产率生成23。
在13中的N-烯丙氧基羰基和O-烯丙基的裂解得到仲胺14(94%),其进行N-甲基化得到15,以及进行C-甲基化得到16。酚16的乙酰化生成相应的乙酸酯17,其基于脱甲硅基作用形成伯醇18。18的伯羟基的Mitsunobu置换生成了酞酰亚胺19,其基于甲氧基甲基醚的酸催化裂解得到phthalascidin 2。
因为Et 743(1)最初的合成路线已经被证明大规模合成是可接受的,我们的期望是在此描述的改进方法将更为有效,并成为合成phthalascidin(2)4的新途径。因为phthalascidin比海鞘素743更稳定并且更加容易产生,可以证明它是一种更实用的治疗剂。
本发明将参考下面的实施例进一步说明,这些实施例用于帮助理解本发明,但不认为是对本发明的限制。在此所有记录的百分比除非另作说明均为重量百分数。所有温度用摄氏温度表示。
实施例1
酸(224mg,0.400mmol)溶于蒸馏的乙酸(5.0mL)和0.2N HCl(1.5mL)并且加热到110℃。5.5小时后,反应物在真空中浓缩并通过反复与甲苯(3×10mL)在真空中共沸浓缩进行干燥然后溶于DMF(1.0mL)。叔丁基二甲基甲硅烷基氯化物(304mg,2.03mmol)和咪唑(152mg,2.24mmol)作为固体加入,混合物在23℃搅拌2小时。反应用2∶1乙酸-水(1.5mL)猝灭并且搅拌30分钟。反应物倾入0.5M草酸水溶液中(100mL)并且用3∶7的乙酸乙酯-己烷(2×100mL)萃取。合并的有机层用饱和氯化钠水溶液(100mL)洗涤,用硫酸钠干燥,过滤并在真空中浓缩。残余物通过闪蒸柱色谱法(100mL硅胶,梯度1∶1乙酸乙酯-己烷至0.1%乙酸-乙酸乙酯),得到实质上纯净的所需产品,澄清的粘性油(204.6mg,95%)。
Rf0.10(乙酸乙酯);1H NMR(400MHz,CDCl3)δ25(br s,1H),6.32(s,2H),5.90(ddt,J=17.0,10.6,5.4Hz,1H),5.28(d,J=17.1Hz,1H),5.20(d,J=10.4Hz,1H),5.11(d,J=8.0Hz,1H),4.61-4.57(m,1H),4.55(d,J=5.5Hz,2H),3.70(s,3H),3.04(dd,J=14.0,5.1Hz,1H),2.93(dd,J=14.0,6.4Hz,1H),0.99(s,18H),0.15(s,12H);13C NMR(101MHz,CDCl3)δ176.3,155.7,149.9,142.2,132.5,130.5,118.0,115.6,66.1,60.0,54.5,37.2,25.8,18.4,-4.6;FTIR(neat)3438(m),3331(m),3088(m v br),2956(s),2931(s),2894(s),2863(s),1719(s),1578(s),1496(s),1435(s),1361(s),1253(s),1231(s),1093(s);1010(m),938(w),831(s)cm-1;使用重氮甲烷生成甲酯的衍生之后进行HPLC分析(ChiralPak AD,1%在己烷中的异丙醇,流速:1.0mL/min,λ=226nm),96%ee,Ry=11.1min(主),9.2min(次);HRMS(FAB),[m+H]/z,C26H46O7NSi2计算值:540.2813,实验值540.2823;[α]D 23+18.8°(c1.0,二氯甲烷)。
实施例2
将胺(100.0mg,0.380mmol)通过在真空中用2∶3THF-甲苯(5mL)共沸浓缩进行干燥,然后溶于THF(1.5mL)并且冷却至0℃。在另一个烧瓶中,将酸(211.7mg,0.392mmol)和1-羟基-7-氮杂苯并***(55.8mg,0.410mmol)通过在真空中用2∶3THF-甲苯(5mL)共沸浓缩进行干燥,然后溶于二氯甲烷(1.5mL)。向该烧瓶加入固体的2-氯-1,3-二甲基咪唑啉鎓六氟磷酸盐(109.3mg,0.392mmol),然后通过注射器加入三乙胺(109μL,0.782mmol),得到澄清的暗黄色溶液。该混合物在23℃搅拌3分钟,然后冷却至0℃,将导管***装有胺的烧瓶中。用二氯甲烷(1.5mL)转移该烧瓶中的内容物。金黄的溶液在0℃搅拌18小时,温热至23℃,并再搅拌6小时。该反应物用乙酸乙酯(6mL)稀释,然后在真空中部分浓缩,除去二氯甲烷。将溶液倾入0.5M乙酸水溶液(100mL)中,用3∶7乙酸乙酯-己烷(,100mL)萃取,用饱和的碳酸氢钠水溶液洗涤(100mL)。水层用3∶7乙酸乙酯-己烷(100mL)再萃取,合并的有机层用硫酸钠干燥,过滤并在真空中浓缩,得到透明的薄膜(约300mg)。该残余物不进一步纯化就可使用。该物质可用闪蒸柱色谱(100mL硅胶,梯度1∶3至2∶3乙酸乙酯-己烷)提纯,但是只得到50%产率,大概是由于硅胶促进了分解。
Rf0.36(2∶3乙酸乙酯-己烷);1H NMR(400MHz,CDCl3)δ(氨基甲酸酯和酰胺旋转异构体的混合物)6.35(s,1H),6.20(s,1H),5.91-5.81(m,3H),5.94-5.59(m,1.5H),5.42(d,J=3.3Hz,0.5H),5.30-5.03(m,3H),4.74-4.63(m,1H),4.60(dd,J=10.8,3.1Hz,0.5H),4.53(br s,1H),4.45(d,J=5.1Hz,1H),4.36(d,J=10.6Hz,0.5H),4.19(d,J=10.6Hz,0.5H),3.68(s,1.5H),3.61(s,1.5H),3.56(d,J=8.4Hz,0.5H),3.03-2.90(m,3H),2.79(dd,J=13.0,4.6Hz,0.5H),2.24(d,J=16.0Hz,0.5H),2.06(br s,3H),0.99(s,9H),0.91(s,9H),0.15(s,6H),0.06(s,6H);13C NMR(101MHz,CDCl3)δ(氨基甲酸酯和酰胺旋转异构体的混合物)169.2,169.0,167.9,167.5,155.6,155.2,150.1,149.7,146.9,146.5,145.1,145.0,142.1,141.7,136.8,136.2,132.4,132.3,130.7,130.3,117.9,117.8,115.5,115.3,111.3,110.9,110.5,108.1,107.8,101.4,73.0,66.1,65.9,60.0,59.9,54.7,52.2,51.9,51.0,47.6,43.2,39.6,38.5,29.1,27.4,25.8,25.7,18.4,18.3,8.9,-4.53,-4.56,-4.65,-4.74;FTIR(纯)3406(w br),3319(w br),2956(m),2931(m),2894(w),2856(m),1725(m),1644(m),1575(m),1494(m),1463(m),1431(s),1356(w),1231(s),1163(w),1094(s),1044(m),1013(m),831(s)cm-1;HRMS(ESI),[m+H]/z,C39H57O11N2Si2计算值:785.3501,实验值:785.3469;[α]D 24+20.5°(c 1.0,氟仿)。
实施例3:
酚(约300mg,0.380mmol)在真空中用甲苯(5mL)共沸浓缩进行干燥,然后溶于DMF(15mL)。用注射器加入烯丙基溴(330pL,3.82mmol),然后,加入在真空中用温和火焰干燥的固体碳酸铯(134.7mg,0.413mmol),反应物在23℃搅拌2小时。将反应物倾入水中(300mL),用1∶4乙酸乙酯-己烷(2×150mL)萃取,用饱和氯化钠水溶液洗涤(100mL),用硫酸钠干燥,过滤,在真空中浓缩。用闪蒸柱色谱提纯残留物(75mL硅胶,梯度1∶4to3∶7乙酸乙酯-己烷),得到所需的产物,基本上纯净的透明膜(252.9mg,经两个步骤后81%)。还发现该物质对硅胶不稳定,因此为了得到所述的产率,要求进行快速色谱。
Rf0.47(2∶3乙酸乙酯-己烷);1H NMR(400MHz,CDCl3)δ(氨基甲酸酯和酰胺旋转异构体的混合物)6.35(s,1H),6.20(s,1H),6.03-5.78(m,5H),5.52-5.44(m,1.4H),5.38-5.33(m,1H),5.31-5.13(m,3.6H),4.73-4.59(m,1.4H),4.55(d,J=5.1Hz,1H),4.48(d,J=5.1Hz,1H),4.34(d,J=10.6Hz,0.6H),4.244.04(m,3H),3.68(s,1.5H),3.60(s,1.5H),3.54(d,J=8.8Hz,0.4H),3.15-2.90(m,2.6H),2.77(dd,J=12.8,4.8Hz,0.6H),2.34(m,0.4H),2.12(s,1.5H),2.09(s,1.5H),0.99(s,9H),0.92(s,9H),0.16(s,6H),0.07(s,3H),0.05(s,3H);13C NMR(101MHz,CDCl3)δ(氨基甲酸酯和酰胺旋转异构体的混合物)169.2.168.8,167.4,167.1,155.5,155.1,150.2,150.0,149.8,145.5,145.3,142.2,141.9,139.2,138.8,133.4,133.2,132.4,130.6,130.2,118.3,118.0,117.9,117.8,117.7,117.2,115.5,115.2,114.3,113.9,111.1,110.9,101.8,101.7,73.8,73.7,72.8,66.1,65.9,60.04,59.99,54.9,52.1,51.9,51.1,47.7,43.3,39.8,38.5,29.6,27.9,25.8,25.7,18.4,18.3,9.6,9.4,-4.51,-4.54,-4.6,-4.7;FTIR(纯)3306(w br),2956(m),2931(m),2898(m),2856(m),1750(m),1719(m),1650(m),1575(m),1494(m),1431(s),1363(m),1250(m),1231(m),1163(w),1094(s),1044(m),1013(m),944(w),919(w),831(s)cm-1;HRMS(ESI),[m+H]/z,C42H61O11N2Si2计算值:825.3814,实验值825.3788;[α]D 24+21.7°(c1.0,氯仿)。
实施例4:
将内酯(3.54.1mg,0.429mmol)在真空中用甲苯(10mL)共沸浓缩进行干燥,然后溶于***(8.0mL)并在干冰-丙酮浴中冷却至-78℃。沿着烧瓶侧壁用2分钟滴加0.10M的LiAlH2(OEt)2(4.7mL,0.47mmol)11的溶液。反应物在-78℃搅拌15分钟,然后将浅黄色溶液倾入0℃的0.1N HCl(50mL)中,同时快速搅拌。用***(2×75mL)萃取该溶液,用饱和氯化钠水溶液洗涤(50mL),用硫酸钠干燥,过滤并在真空中浓缩。残留物用闪蒸柱色谱提纯(150mL硅胶,梯度3∶7至2∶3至to1∶1乙酸乙酯-己烷),得到需要的产物,基本上纯净的透明膜(339.0mg,95%)。
Rf0.20(2∶3乙酸乙酯-己烷);1H NMR(400MHz,CDCl3)δ(端基异构体、氨基甲酸酯和酰胺旋转异构体的混合物)6.43(s,0.2H),6.37(s,0.2H),6.16(s,1.4H),6.15(s,0.2H),6.05-5.80(m,4.4H),5.82-5.59(m,1.2H),5.41-5.14(m,3.8H),5.07-4.95(m,1.5H),4.85-4.76(m,1.6H),4.61-4.46(m,2.2H),4.26-4.41(m,3.8H),4.10-3.75(m,0.5H),3.68(s,0.3H),3.66(s,0.3H),3.63(s,2.4H),3.37(d,J=11.0Hz,0.8H),3.33-2.94(m,0.7H),2.90-2.65(m,2.8H),2.35(dd,J=17.7,7.5Hz,0.7H),2.12(s,0.3H),2.11(s,0.3H),2.09(s,2.4H),1.05(s,4.5H),0.92(s,13.5H),0.16(s,3H),0.07(s,4.5H),0.04(s,4.5H);13C NMR(101MHz,CDCl3)δ(端基异构体、氨基甲酸酯和酰胺旋转异构体的混合物)169.8,156.1,149.6,149.2,144.6,141.7,138.3,133.8,132.2,130.2,118.9,118.0,116.7,115.1,113.4,112.5,101.3,93.4,73.2,66.2,62.4,60.1,53.6,51.4,44.6,38.5,26.5,25.9,25.8,18.5,18.3,9.5,-4.56,-4.59;FTIR(纯)3406(m br),3325(m br),2956(m),2931(m),2894(m),2856(m),1714(m),1644(m),1578(m),1496(m),1433(s),1360(m),1255(m),1234(m),1095(s),1044(m),1013(m),941(w),830(s)cm-1;HRMS(ESI),[m+H]/z,C42H63O11N2Si2计算值:827.3970,实验值:827.4009;
[α]D 25-1.5°(c1.0,氟仿)。
实施例5:
将内半缩醛(316.3mg,0.382mmol)溶于被氮气净化的甲醇(3.8mL)中。无水氟化钾(110.3mg,1.90mmol)以固体加入,用氮气抽吸/净化容器。反应物在23℃搅拌30分钟,用甲苯(5mL)稀释浅粉色的混合物并在真空中浓缩。残留物溶于被氮气净化的2,2,2-三氟乙醇(15mL),丁基化的羟基甲苯(4.3mg,0.02mmol)以固体加入。向烧瓶中加入1.0M三氟甲磺酸12水溶液(23mL),容器再次用氮气进行抽吸/净化。溶液在油浴中在45℃搅拌7小时。混合物在真空中部分浓缩,除去醇,然后倾入到80%饱和氯化钠水溶液(100mL)中,用乙酸乙酯萃取(2×100mL),用饱和氯化钠水溶液洗涤(50mL),用硫酸钠干燥,过滤,然后在真空中浓缩。残留物通过闪蒸柱色谱提纯(100mL硅胶,5∶95甲醇-二氯甲烷),得到需要的产物,基本上纯争的白色固体(198.5mg,89%)。从甲苯中得到晶体。
M.p.:130℃(dec.);Rf(5∶95甲醇-二氯甲烷);1H NMR(400MHz,丙酮-d6)δ(氨基甲酸酯旋转异构体的混合物)8.34(br s,1H),8.32(br s,1H),6.31(d,J=4.4Hz,1H),6.14(m,1H),5.97(s,1H),5.97-5.90(m,1H),5.90(s,1H),5.68(m,1H),5.42-5.37(m,2H),5.31-5.22(m,2H),5.18-5.12(m,1H),4.85(d,J=6.6Hz,1H),4.65-4.55(m,2H),4.38-4.34(m,1H),4.26-4.22(m,1H),3.89-3.86(m,1H),3.77(s,3H),3.71(m,1H),3.57(d,J=15.0Hz,1H),3.48-3.43(m,1H),3.25-3.13(m,2H),3.00(d,J=16.8Hz,1H),2.34(m,1H),2.11(s,3H);13C NMR(101MHz,丙酮-d6)δ(氨基甲酸酯旋转异构体的混合物)169.4,169.2,153.8,153.7,150.6,149.3,148.2,148.0,145.5,141.0,135.1,134.5,133.9,130.2,130.1,122.4,117.9,117.8,117.7,117.5,114.2,112.7,111.0,110.8,108.4,108.3,102.1,75.4,66.74,66.69,65.6,61.6,61.2,60.9,54.3,53.5,52.9,50.1,49.3,34.1,33.6,27.5,9.7;FTIR(KBr)3400(s br),2944(m),2881(m),1700(s),1639(s),1501(w),1463(s),1435(s),1356(m),1320(m),1288(m),1269(m),1238(m),1213(m),1166(m),1102(s),1065(s),1030(m),999(m),938(m),807(w)cm-1;HRMS(ESI),[m+H]/z,C30H33O10N2计算值:581.2135,实验值581.2112;[α]D 25-27.2°(c 0.50,甲醇)。
实施例6
将酰胺(198.0mg,0.341mmol)在真空中用甲苯(10mL)共沸浓缩进行干燥,溶于THF(10mL)然后冷却至0℃。用10分钟滴加0.20MLiAlH2(OEt)2(6.8mL,1.36mmol)13。反应物在0℃搅拌35分钟,得到甲醇胺。Rf0.59(4∶1乙酸乙酯-己烷)。首先加入乙酸(425pL,7.44mmol)以淬灭反应。然后加入4.8M***水溶液(4251L,2.04mmol)、无水硫酸钠(2.5g,17.6mmol)和Celite_(6mL),进行氨基→腈的转化并沉淀出电铝盐。观察到气泡,5分钟后,反应物温热至23℃并搅拌7小时。用Celite_过滤悬浮液,用乙酸乙酯(100mL稀释。该溶液在真空中浓缩,用闪蒸柱色谱提纯(100mL硅胶,2∶1乙酸乙酸-己烷),得到需要的产物,基本上纯净的白色泡沫(175.6mg,87%)。
Rf0.31(4∶1乙酸乙酯-己烷);1H NMR(400MHz,CDCL3)δ((氨基甲酸酯旋转异构体的混合物)6.43(br s,0.6H),6.26(s,0.4H),6.24(s,0.6H),6.20(s,0.4H),6.07-6.00(m,1H),5.97-5.82(m,4H),5.61(s,0.6H),5.52(si 0.4H),5.37-5.17(m,3H),4.90(d,J=7.8Hz,0.4H),4.84(d,J=8.3Hz,0.6H),4.73-4.60(m,2H),4.16-4.08(m,2.6H),3.97-3.94(m,1.4H),3.77(s,1.2H),3.68-3.61(m,1H),3.62(s,1.8H),3.49-3.36(m,1H),3.29-3.19(m,3H),2.76-2.69(m,1H),2.11(s,1.8H),2.08(s,1.2H),2.00-1.83(m,2H);13C NMR(101MHz,CDCl3)δ(氨基甲酸酯旋转异构体的混合物)154.3,153.8,148.4,148.34,148.26,146.2,145.9,144.3,138.8,133.62,133.56,132.7,132.2,130.7,130.3,120.5,120.3,117.9,117.8,117.4,117.2,116.3,112.6,112.5,112.1,111.9,107.2,106.4,101.1,74.5,74.0,66.7,66.5,64.5,64.3,60.8,60.5,59.1,58.9,58.0,56.7,56.6;49.9,49.4,48.9,48.7,31.2,30.5,29.7,25.9,9.43,9.35;FVrIR(纯)3369(m br),2931(mbr),1688(m),1500(w),1463(m)1431(s),1375(m),1325(m),1294(m),1269(m),1106(s),1063(m),994(m),956(w)cm-1;HRMS(ESI),[m+H]/z,C31H34O9N3计算值:592.2295,实验值:592.2316;[α]D 25+30.4°(c1.0,氯仿)。
实施例7
将酚(170.0mg,0.287mmol)在真空下用甲苯(10mL)共沸浓缩进行干燥,然后溶于二氯甲烷中(3.0mL)。加入三乙胺(80μL,0.574mmol)和4-二甲基氨基吡啶(7.0mg,0.0574mmol),溶液在干冰-乙腈浴中冷却到-30℃,N-苯基三氟甲磺酰亚胺(113.5mg,0.318mmol)以固体加入,反应物在-30℃在Cryobath_中搅拌38小时。混合物倾入1∶1饱和碳酸氢钠水溶液-饱和氯化钠水溶液中(100mL),用二氯甲烷萃取(2×75mL),用硫酸钠干燥,过滤并在真空中浓缩。残留物用闪蒸柱色谱提纯(100mL硅胶,梯度2∶3至3∶4乙酸乙酯-己烷),得到需要的产物,基本上纯净的澄清的膜(153.4mg,74%)。
Rf0.18(2∶3乙酸乙酯-己烷);1H NMR(400MHz,CDCl3)δ(氨基甲酸酯旋转异构体的混合物)7.16(s,0.6H),6.63(s,0.4H),6.60(s,0.6H),6.45(s,0.4H),6.08-5.86(m,4H),5.74(m,0.6H),5.59(m,0.4H),5.40-5.16(m,4H),4.96-4.89(m,1H),4.74-4.60(m,3H),4.26(m,1H),4.19-4.15(m,2H),4.00(m,1H),3.89(s,1.2H),3.83(s,1.8H),3.66-3.64(m,1H),3.39-3.24(m,4H),2.91-2.83(m,1H),2.11(s,1.2H),2.05(s,1.8H),1.86-1.78(m,1H);13C NMR(101MHz,CDCl3)δ(氨基甲酸酯旋转异构体的混合物)154.0,153.9,148.6,148.4,147.3,146.6,144.7,144.5,141.3,141.0,139.1,138.9,136.9,136.7,133.7,132.2,132.1,131.6,129.4,127.0,123.0,121.5,121.3,119.9,118.5(q,J=321Hz,CF3),118.2,117.7,117.6,117.4,116.3,116.1,112.6,112.3,112.1,112.0,101.3,101.2,74.5,66.9,66.7,65.7,65.5,62.0,61.9,59.54,59.48,58.6,56.5,49.8,49.3,49.0,48.4,31.0,30.4,26.1,26.0,9.5,9.4;19F NMR(376MHz,BF3·OEt2在-153.0PPm标准设置,CDCl3)δ(氨基甲酸酯旋转异构体的混合物)-74.02,-74.01;FTIR(neat)3325(w br),2949(w br),1688(m),1588(w),1500(m),1425(s),1319(m),1288(m),1256(m),1213(s),1138(s),1106(m),1038(m),988(m),875(w)cm-1;HRMS(ESI),[m+H1/z C32H33O11N3SF3计算值:724.1788,实验值:724.1803;[α]D 26+34.3°(c1.0,氯仿)。
附注:
下述公开文献提供了背景信息,引用在此作为参考。
(1)在该领域的最早研究始于Prof.Kenneth.L.Rnehart和他的小组。参见,
(a)Rinehart,K.L.;Shield,L.S.“药物科学概论”(Topics in PharmaceuticalSciences),eds.Breimer,D.D.;Crommelin,D.J.A.;Midha,K.K.(AmsterdamMedical Press,Noordwijk,The Netherlands),1989,pp.613.
(b)Rinehart,K.L.;Holt,T.G.;Fregeau,N.L.;Keifer,P.A.;Wilson,G.R.;Perun,T.J.,Jr.;Sakai,R.;Thompson,A.G.;Stroh,J.G.;Shield,L.S.;Seigler,D.S.;Li,L.H.;Martin,D.G.;Grimmelikhuijzen,C.J.P.;Gade,G.J.Nat.Prod.1990,53,771.
(c)Rinehart,K.L.;Sakai,R;Holt,T.G.;Fregeau,N.L.;Perun,T.J.,Jr.;Seigler,D.S.;Wilson,G.R.;Shield,L.S.PureAppl.CherrL 1990,62,1277.
(d)Rinehart,K.L.;Holt,T.G.;Fregeau,N.L.;Stroh,J.G.;Keifer,P.A.;Sun,F.;Li,L.H.;Matin,D.G.J.Org.Chem.1990,55,4512.
(e)Wright,A.E.;Forleo,D.A.;Gunawardana,G.P.;Gunasekera,S.P.;Koehn,F.E.;McConnell,O.J.J.Org.Chem..1990,55,4508.Sakai,R.;Rinehart,K.L.;Guan,Y.;Wang,H.J.Proe.Natl.Acad.Sci.USA 1992,89,11456.
(2)(a)Business Week,13September 1999,p.22..(b)“科学”(Science)1994,266,1324.
(3)Corey,E.J.;Gin,D.Y.;Kania,R.美国化学学报(J.Am.Chem.Soc.)1996,118,9202.
(4)Martinez,E.J.;Owa,T.;Schreiber,S.L.;Corey,E.J.Proc.Natl.Acad.Sci.USA 1999,96,3496.
(5)参见Myers,A.G.;Kung,D.W.J.Am.Chem.Soc.1999,121,10828,另一种合成诸如5的结构的方法。
(6)用CIP进行羧酸-胺耦合的方法,参见:
(a)Akaji,K.;Kuriyama,N.;Kimura,T.;Fujiwara,Y.;Kiso,Y.“四面体通讯”(Tetrahedron Lett.)1992,33,3177.
(b)Akaji,K.;Kuriyama,N.;Kiso,Y.Tetrahedron Lett.1994,35,3315.
(c)Akaji,K.;Kuriyama,N.;Kiso,Y.有机化学杂志(J.Org.Chem.).1996,61,3350.
(7)反应剂LiAIH2(OEt)2通过在使用前将1.0MLiAlH4在醚中的溶液加入到0℃的1当量乙酸乙酯溶液中并在0℃搅拌2小时进行制备;参见:Brown,H.C.;Tsukamoto,A.J.Am.Chem Soc.1964,86,1089.
(8)对于内酯类还原的一般性回顾,参见:
(a)Brown,H.C.;Krishnamurthy,S.Tetrahedron,1979,35,567.
(b)Cha,J.S.Org.Prep.Proc.Int.,1989,21(4),451.
(c)Seyden-Penne,J.Reduction by the Alumino-and Borohydndes in OrganicSynthesis;2nd Ed.;Wiley-VCH:New York,1997;Section 3.2.5.
(9)对于用氢化反应剂进行酰胺还原的一般性参考,参见ref.7以及Myers,A.G.;Yang,B.H.;Chen,H.;Gleason,J.L.J.Am.Chem.Soc.1994,116,9361.
(10)由氮气清洁的水制备。
(11)该反应剂通过将1.0M氢化锂铝在Et2O(1当量)中的溶液加入到0℃的乙酸乙酯(1当量)在Et2O中的溶液中制备。混合物在0℃搅拌2小时,一部分溶液用于还原内半缩醛。Brown,H.C.;Tsukamoto,A.J AnL Chenz.Soc.1964,86,1089.
(12)由氮气清洁的水制备。
(13)参见脚注11所引用的参考文献。
前面已经描述了本发明的细节,包括其优选的实施方案。但是,本领域的技术人员应认识到根据本发明探索的思路可在所附权利要求书列出的本发明的范围和构思内对本发明进行许多饰修和/或改进。
Claims (4)
1、一种从化合物11制备海鞘素结构类似物化合物2的方法,包括以下步骤:
(a)将化合物11:
转化为单叔丁基二甲基甲硅烷基醚,化合物12:
(b)用甲氧基甲基氯化物醚化,生成化合物13:
(c)裂解13中的N-烯丙氧基羰基和O-烯丙基基团,得到仲胺,化合物14:
(d)化合物14N-甲基化,得到化合物15:
(e)化合物15的C-甲基化,得到化合物16:
(f)酚16乙酰化,得到相应的乙酸酯,化合物17:
(g)化合物17脱甲硅烷基生成伯醇,化合物18:
(h)18的伯羟基的Mitsunobu置换生成酞酰亚胺,化合物19:
(i)酸催化裂解化合物19的甲氧基甲基醚,生成海鞘素结构类似物化合物2:
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