CN101029072A - 一类5,6-双氢-胆甾化合物 - Google Patents
一类5,6-双氢-胆甾化合物 Download PDFInfo
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- CN101029072A CN101029072A CN 200710039216 CN200710039216A CN101029072A CN 101029072 A CN101029072 A CN 101029072A CN 200710039216 CN200710039216 CN 200710039216 CN 200710039216 A CN200710039216 A CN 200710039216A CN 101029072 A CN101029072 A CN 101029072A
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- 150000001875 compounds Chemical class 0.000 title claims abstract description 35
- 238000000034 method Methods 0.000 claims abstract description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 27
- 238000006243 chemical reaction Methods 0.000 claims description 26
- -1 steroid compound Chemical class 0.000 claims description 14
- MPXTYZZFIJTPPA-JOQRFCRPSA-N [(2s,3r,4s,5r)-2-[(2s,3r,4s,5s)-3-acetyloxy-2-[[(3r,8s,9r,10r,13s,14r,16r,17s)-3,17-dihydroxy-10,13-dimethyl-17-[(2s)-6-methyl-3-oxoheptan-2-yl]-1,2,3,4,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthren-16-yl]oxy]-5-hydroxyoxan-4-yl]oxy-4,5-dihydro Chemical class C1=CC(OC)=CC=C1C(=O)O[C@H]1[C@H](O[C@@H]2[C@H]([C@H](O[C@H]3[C@]([C@@]4(C)CC[C@H]5[C@@]6(C)CC[C@@H](O)CC6=CC[C@@H]5[C@H]4C3)(O)[C@H](C)C(=O)CCC(C)C)OC[C@@H]2O)OC(C)=O)OC[C@@H](O)[C@@H]1O MPXTYZZFIJTPPA-JOQRFCRPSA-N 0.000 claims description 13
- 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 description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 9
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 claims description 8
- 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 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 7
- 229940125797 compound 12 Drugs 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- 230000003637 steroidlike Effects 0.000 claims description 6
- UNILWMWFPHPYOR-KXEYIPSPSA-M 1-[6-[2-[3-[3-[3-[2-[2-[3-[[2-[2-[[(2r)-1-[[2-[[(2r)-1-[3-[2-[2-[3-[[2-(2-amino-2-oxoethoxy)acetyl]amino]propoxy]ethoxy]ethoxy]propylamino]-3-hydroxy-1-oxopropan-2-yl]amino]-2-oxoethyl]amino]-3-[(2r)-2,3-di(hexadecanoyloxy)propyl]sulfanyl-1-oxopropan-2-yl Chemical compound O=C1C(SCCC(=O)NCCCOCCOCCOCCCNC(=O)COCC(=O)N[C@@H](CSC[C@@H](COC(=O)CCCCCCCCCCCCCCC)OC(=O)CCCCCCCCCCCCCCC)C(=O)NCC(=O)N[C@H](CO)C(=O)NCCCOCCOCCOCCCNC(=O)COCC(N)=O)CC(=O)N1CCNC(=O)CCCCCN\1C2=CC=C(S([O-])(=O)=O)C=C2CC/1=C/C=C/C=C/C1=[N+](CC)C2=CC=C(S([O-])(=O)=O)C=C2C1 UNILWMWFPHPYOR-KXEYIPSPSA-M 0.000 claims description 5
- 125000000037 tert-butyldiphenylsilyl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1[Si]([H])([*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims description 5
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 3
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 claims description 3
- 239000000203 mixture Substances 0.000 claims description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 2
- YQTCQNIPQMJNTI-UHFFFAOYSA-N 2,2-dimethylpropan-1-one Chemical group CC(C)(C)[C]=O YQTCQNIPQMJNTI-UHFFFAOYSA-N 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- DNJIEGIFACGWOD-UHFFFAOYSA-N ethanethiol Chemical compound CCS DNJIEGIFACGWOD-UHFFFAOYSA-N 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 5
- 229910052739 hydrogen Inorganic materials 0.000 claims 5
- 239000001257 hydrogen Substances 0.000 claims 5
- 238000010189 synthetic method Methods 0.000 claims 4
- 239000000377 silicon dioxide Substances 0.000 claims 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims 2
- VYMPLPIFKRHAAC-UHFFFAOYSA-N 1,2-ethanedithiol Chemical compound SCCS VYMPLPIFKRHAAC-UHFFFAOYSA-N 0.000 claims 1
- DCERHCFNWRGHLK-UHFFFAOYSA-N C[Si](C)C Chemical compound C[Si](C)C DCERHCFNWRGHLK-UHFFFAOYSA-N 0.000 claims 1
- 235000010290 biphenyl Nutrition 0.000 claims 1
- 239000004305 biphenyl Substances 0.000 claims 1
- QTZUMCMRRPENJM-LJQANCHMSA-N n-[(1s)-1-(3-chloro-4-fluorophenyl)-2-hydroxyethyl]-2-(oxan-4-ylamino)-6,8-dihydro-5h-pyrido[3,4-d]pyrimidine-7-carboxamide Chemical compound N([C@H](CO)C=1C=C(Cl)C(F)=CC=1)C(=O)N(CC1=N2)CCC1=CN=C2NC1CCOCC1 QTZUMCMRRPENJM-LJQANCHMSA-N 0.000 claims 1
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims 1
- HMPSOEYFMTWOFC-UHFFFAOYSA-N propane-2,2-dithiol Chemical compound CC(C)(S)S HMPSOEYFMTWOFC-UHFFFAOYSA-N 0.000 claims 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 claims 1
- 230000002194 synthesizing effect Effects 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 description 26
- 230000015572 biosynthetic process Effects 0.000 description 25
- 238000005160 1H NMR spectroscopy Methods 0.000 description 22
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 18
- 239000002994 raw material Substances 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 16
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 15
- 239000012074 organic phase Substances 0.000 description 15
- 239000007787 solid Substances 0.000 description 14
- 238000003756 stirring Methods 0.000 description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 12
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 11
- MPXTYZZFIJTPPA-UHFFFAOYSA-N 3beta,16beta,17alpha-trihydroxycholest-5-en-22-one 16-O-(2-O-(4-methoxybenzoyl)-beta-D-xylopyranosyl)-(1-3)-(2-O-acetyl-alpha-arabinopyranoside) Natural products C1=CC(OC)=CC=C1C(=O)OC1C(OC2C(C(OC3C(C4(C)CCC5C6(C)CCC(O)CC6=CCC5C4C3)(O)C(C)C(=O)CCC(C)C)OCC2O)OC(C)=O)OCC(O)C1O MPXTYZZFIJTPPA-UHFFFAOYSA-N 0.000 description 10
- MAGWLGAJMLWPLZ-UHFFFAOYSA-N OSW-1 Natural products COc1ccc(cc1)C(=O)OC2C(O)C(O)COC2OC3C(O)COC(OC4CC5C6CC=C7CC(O)CCC7(C)C6CCC5(C)C4(O)OC(C)C(=O)CCC(C)C)C3OC(=O)C MAGWLGAJMLWPLZ-UHFFFAOYSA-N 0.000 description 10
- 229910052786 argon Inorganic materials 0.000 description 9
- 239000007864 aqueous solution Substances 0.000 description 8
- 239000003054 catalyst Substances 0.000 description 7
- HPKJGHVHQWJOOT-ZJOUEHCJSA-N N-[(2S)-3-cyclohexyl-1-oxo-1-({(2S)-1-oxo-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}amino)propan-2-yl]-1H-indole-2-carboxamide Chemical compound C1C(CCCC1)C[C@H](NC(=O)C=1NC2=CC=CC=C2C=1)C(=O)N[C@@H](C[C@H]1C(=O)NCC1)C=O HPKJGHVHQWJOOT-ZJOUEHCJSA-N 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
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- 238000010791 quenching Methods 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- AEVBPXDFDKBGLT-YOUFYPILSA-N (2s,3s,4r,5r)-n-[2-[4-(diethoxyphosphorylmethyl)anilino]-2-oxoethyl]-5-(2,4-dioxopyrimidin-1-yl)-3,4-dihydroxyoxolane-2-carboxamide Chemical compound C1=CC(CP(=O)(OCC)OCC)=CC=C1NC(=O)CNC(=O)[C@@H]1[C@@H](O)[C@@H](O)[C@H](N2C(NC(=O)C=C2)=O)O1 AEVBPXDFDKBGLT-YOUFYPILSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- WCDLCPLAAKUJNY-UHFFFAOYSA-N 4-[4-[3-(1h-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidin-6-yl]phenyl]morpholine Chemical compound C1COCCN1C1=CC=C(C2=CN3N=CC(=C3N=C2)C2=CNN=C2)C=C1 WCDLCPLAAKUJNY-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 239000000010 aprotic solvent Substances 0.000 description 4
- WQLVFSAGQJTQCK-UHFFFAOYSA-N diosgenin Natural products CC1C(C2(CCC3C4(C)CCC(O)CC4=CCC3C2C2)C)C2OC11CCC(C)CO1 WQLVFSAGQJTQCK-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 238000000921 elemental analysis Methods 0.000 description 4
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- INLFWQCRAJUDCR-IQVMEADQSA-N (1R,2S,4S,5'S,6R,7S,8R,9S,12S,13S)-5',7,9,13-tetramethylspiro[5-oxapentacyclo[10.8.0.02,9.04,8.013,18]icosane-6,2'-oxane] Chemical compound O([C@@H]1[C@@H]([C@]2(CC[C@@H]3[C@@]4(C)CCCCC4CC[C@H]3[C@@H]2C1)C)[C@@H]1C)[C@]11CC[C@H](C)CO1 INLFWQCRAJUDCR-IQVMEADQSA-N 0.000 description 3
- 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 description 3
- 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 description 3
- WWTBZEKOSBFBEM-SPWPXUSOSA-N (2s)-2-[[2-benzyl-3-[hydroxy-[(1r)-2-phenyl-1-(phenylmethoxycarbonylamino)ethyl]phosphoryl]propanoyl]amino]-3-(1h-indol-3-yl)propanoic acid Chemical compound N([C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)O)C(=O)C(CP(O)(=O)[C@H](CC=1C=CC=CC=1)NC(=O)OCC=1C=CC=CC=1)CC1=CC=CC=C1 WWTBZEKOSBFBEM-SPWPXUSOSA-N 0.000 description 3
- VSWICNJIUPRZIK-YFVHKJHSSA-N 1,2,2,3,3,4-hexadeuterio-4H-pyridine Chemical compound N1(C(C(C(C=C1)[2H])([2H])[2H])([2H])[2H])[2H] VSWICNJIUPRZIK-YFVHKJHSSA-N 0.000 description 3
- 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 description 3
- KUZSBKJSGSKPJH-VXGBXAGGSA-N 5-[(9R)-6-[(3R)-3-methylmorpholin-4-yl]-11-oxa-1,3,5-triazatricyclo[7.4.0.02,7]trideca-2,4,6-trien-4-yl]pyrazin-2-amine Chemical compound C[C@@H]1COCCN1c1nc(nc2N3CCOC[C@H]3Cc12)-c1cnc(N)cn1 KUZSBKJSGSKPJH-VXGBXAGGSA-N 0.000 description 3
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- 239000005909 Kieselgur Substances 0.000 description 3
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 2
- CODBZFJPKJDNDT-UHFFFAOYSA-N 2-[[5-[3-(dimethylamino)propyl]-2-methylpyridin-3-yl]amino]-9-(trifluoromethyl)-5,7-dihydropyrimido[5,4-d][1]benzazepine-6-thione Chemical compound CN(C)CCCC1=CN=C(C)C(NC=2N=C3C4=CC=C(C=C4NC(=S)CC3=CN=2)C(F)(F)F)=C1 CODBZFJPKJDNDT-UHFFFAOYSA-N 0.000 description 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 2
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Abstract
本发明涉及一类结构新颖的具有5,6-双氢-胆固醇骨架的甾体分子以及它们的合成方法,这类化合物可以用来合成OSW-1类似物5,6-双氢-OSW-1。该5,6-双氢-胆甾化合物的结构式如图,利用本发明所述的方法合成5,6-双氢-OSW-1,操作简便,更加具有原子经济性。
Description
技术领域
本发明涉及一类结构新颖的具有5,6-双氢-胆固醇骨架的甾体分子以及它们的合成方法,这类化合物可以用来合成OSW-1类似物5,6-双氢-OSW-1。利用本发明所述的方法合成5,6-双氢-OSW-1,操作简便,更加具有原子经济性。
技术背景
1992年,东京大学医药学院的Y.Sashida研究小组从一种原产于南非的常绿观赏植物Ornithogalum saunderside的地下球茎中分离出一系列具有胆固醇骨架的皂甙,它们只是在甙元的3-位和二糖配基的2”-位上略有不同,均具有极强的抗肿瘤活性,作为主要提取物的虎眼万年青皂甙(OSW-1,化合物1)对多种恶性肿瘤细胞具有极强的杀伤力,比目前临床所使用的几种抗癌药物如丝裂霉素(Mitomycin)、阿霉素(Adriamycin)、紫杉醇(Taxol)等的效力高出10-100倍。更为重要的是,虽然OSW-1对多种恶性肿瘤细胞都具有很好的活性,但是它对人的正常肺细胞的毒害却很小(IC501500nM)(参见Phytochemistry,1992,31,3969;Bioorg.&Med.Chem.Lett.,1997,7,633),其具体结构如下:
由于OSW-1所具有的极强的抗癌活性以及其独特的化学结构,并且含该化合物的植物资源较少,所以这一类化合物的化学合成已经引起了广泛关注。目前,已有五个小组完成了OSW-1及其甙元的合成(P.L.Fuchs小组:参见Tetra.Lett.,1998,39,1099;惠永正小组:参见J.Org.Chem.,1999,64,202;Z.D.Jin小组:参见J.Am.Chem.Soc.,2002,124,6576;J.W.Morzycki小组:参见Carbohydrate Res.,2002,337,1269和田伟生小组:参见Tetra.Lett.,2003,44,9375)。
为了更加深入地研究结构和活性之间的关系,许多OSW-1及其甙元类似物被合成出来,但是其中许多类似物没有活性或者活性很弱。俞飚小组发现:16α-羟基-OSW-1(化合物2)的抗肿瘤活性很弱,23-氧杂-OSW-1(化合物3)的生物活性比OSW-1高100倍,5,6-双氢-OSW-1(化合物4)、22-去氧-OSW-1(化合物5)和26,27-去甲基-OSW-1(化合物6)的生物活性也高于OSW-1:
其中,Ac是乙酰基,MBz是对甲氧基苯甲酰基。
俞飚小组以去氢表雄酮8为起始原料,通过氢化还原5,6-双键得到表雄酮9,然后采用类似合成OSW-1的方法,用15步以3.8%的总收率合成了5,6-双氢-OSW-1(参见Chin.J.Chem.2004,22,994):
而去氢表雄酮8则由天然的薯蓣皂甙元(diosgenin)经六步反应降解而来,总收率在25-50%之间(参见J.Am.Chem.Soc.,1940,62,3350;J.Org.Chem.,1956,21,520):
a,Ac2O,200℃;b,CrO3;c,NaOAc;d,盐酸羟胺;e,对乙酰氨基苯磺酰氯;f,K2CO3,MeOH。
显然,这种利用甾体皂甙元的合成策略有很多缺点,比如降解工艺陈旧、操作步骤繁琐、环境污染严重等等,更重要的是甾体皂甙元的碳骨架及其官能团未能得到充分利用,这必然造成资源的极大浪费。
田伟生等人长期致力于资源性化合物的合理利用研究,特别是甾体皂甙元的合理利用,他们发展了一种直接利用薯蓣皂甙元完整骨架合成OSW-1甙元的方法(CN02145066.8);他们还发展了一种高效的合成26-溴代-16,22-二氧代-胆甾醇化合物的方法(参见CN 200610029252.2)。在此基础上,本发明遵照原子经济性的原则进行资源性化合物的化学转化,以剑麻皂甙元(tigogenin)为原料,利用其完整骨架和既有官能团合成了一系列具有5,6-双氢-胆固醇骨架的C-27甾体分子,这些化合物可以进一步用来合成5,6-双氢-OSW-1。
发明内容
本发明的目的是提供一类5,6-双氢-胆甾化合物。
本发明的另一目的是提供合成上述5,6-双氢-胆甾化合物的方法。
本发明的目的还提供一种上述5,6-双氢-胆甾化合物的用途,用于合成OSW-1类似物5,6-双氢-OSW-1。
本发明所述的5,6-双氢-胆甾化合物的结构如下:
R1为H、MOM、Bn、PMB、THP、Tr、Ac、Bz、Piv、TMS、TES、TBS或者TBDPS;R2为H或者与R4成16,17-双键;R3为SMe、SEt、SPh、SCH2Ph、S(CH2)nSAc或者与R4成S(CH2)nS;R4为SMe、SEt、SPh、SCH2Ph、与R3成S(CH2)nS或者与R2成16,17-双键;n=2或3;
其中,Me是甲基,Et是乙基,Ph是苯基,MOM是甲氧亚甲基,Bn是苄基,PMB是对甲氧基苄基,THP是四氢吡喃基,Tr是三苯甲基,Ac是乙酰基,Bz是苯甲酰基,Piv是特戊酰基,TMS是三甲基硅基,TES是三乙基硅基,TBS是叔丁基二甲基硅基,TBDPS是叔丁基二苯基硅基。
上述甾体化合物可以进一步描述为如下结构:
其中,R5为SMe、SEt、SPh、SCH2Ph或者S(CH2)nS;R6为SMe、SEt、SPh、SCH2Ph或者S(CH2)nSAc;R1和各基团的定义如前所述。
本发明所述的5,6-双氢-胆甾化合物通过方法1)、方法2)、方法3)或者方法1)~2)合成:
方法1):在非质子性溶剂中,化合物11、硫醇和催化剂在0~50℃反应0.1~20小时,得到化合物12;化合物11与硫醇及催化剂的摩尔比是1∶1~5∶0.01~5;
方法2):在非质子性溶剂中,化合物12、催化剂和醋酐在0~50℃反应5分钟~20小时,得到化合物13;化合物12、醋酐与催化剂的摩尔比是1∶1~50∶0.01~5;
方法3):在非质子性溶剂中,化合物11、硫醇和催化剂,在0~50℃反应0.1~20小时,然后直接向体系中加入醋酐,反应5分钟~20小时,得到化合物13;化合物11、硫醇、醋酐及催化剂的摩尔比是1∶1~5∶1~50∶0.01~5;
上述反应中所述的非质子性溶剂是CH2Cl2、CHCl3、CCl4、1,2-二氯乙烷、THF、乙醚或者它们的混合物;所述的催化剂是AlCl3、BF3·Et2O、TiCl4或HClO4;所述的硫醇是MeSH、EtSH、PhCH2SH、PhSH、乙二硫醇或者丙二硫醇;
上述反应中化合物11参照文献的方法合成(CN 200610029252.2),其结构为:
其中,R1的定义如前所述。
本发明所述的5,6-双氢-胆甾化合物参照文献的方法可以合成5,6-双氢-OSW-14(参见Chin.J.Chem.2004,22,994;Tetra.Lett.,2003,44,9375;CN 02145066.8;CN200610026473.4)。
直接以天然的剑麻皂甙元为基本原料,通过14步反应以3.6%的总收率得到了OSW-1类似物5,6-双氢-OSW-1。这种合成策略充分利用了天然的甾体皂甙元tigogenin:利用其碳骨架合成侧链,利用其官能团进行进一步转化。这比先将其降解成表雄酮然后再引入碳链的策略更为经济合理。
具体实施方法
通过以下具体实施方法将有助于理解本发明,但并不限制本发明的内容。
化合物11a、11c~11e参照文献的方法合成(CN 200610029252.2)。
实施例1 化合物14的合成
将10g Tigogenin溶于25ml Py中,加入6ml Ac2O(2.5eq)40℃反应2.5h,原料消失,停止加热,室温冷却,向其中加入冰水,搅拌使Ac2O完全分解,抽滤得10.89g白色固体14(99%)。
化合物14:C29H46O4;FW 458;m.p 187-190℃;[α]D 25-146.96°(c 0.98,CHCl3);
1H-NMR(300MHz,CDCl3):δ4.68(1H,m,3-H),4.40-4.37(1H,q,16-H),3.46-3.37(2H,dd,26-H),2.02(3H,s,CH3CO),0.97(3H,d,J=7.2Hz,21-CH3),0.83(3H,s,19-CH3),0.79(3H,d,J=6.8Hz,27-CH3),0.0.76(3H,s,18-CH3)
实施例2 化合物15的合成
将11g化合物14溶于50ml DCM中,加入150ml丙酮,50ml 4×10-4mol/L的EDTA-Na2溶液,冰水浴条件下分多次加入88g Oxone·和47g NaHCO3的混合物,反应6天,原料消失,过滤,无机盐用DCM洗涤几次,蒸干有机溶剂,有机物用热水洗涤,得到白色固体15,收率约为80%。
化合物15:C29H46O5;FW 474;mp 170-171℃;[α]D 25-46.97°(c 0.98,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.68(1H,m,3-H),3.58-3.56(2H,dd,26-H),2.06(3H,s,CH3CO),2.03(3H,s,CH3CO),1.25(3H,s,19-CH3),1.02(3H,d,J=6.4Hz,21-CH3),0.81(3H,d,J=6.8Hz,27-CH3),0.73(3H,s,18-CH3)
实施例3 化合物16的合成
将1.205g化合物15用20ml干燥的DCM溶解,氩气保护下室温滴加0.32ml 30%的HBr/HOAc溶液,室温搅拌反应18h无原料,加入饱和NaHCO3水溶液淬灭反应,DCM萃取,合并有机相,有机相用饱和食盐水洗涤两次,无水MgSO4干燥,旋干,柱层析分离(PE∶EA=20∶1),得到1.209g白色固体16(88.9%)。
化合物16:C29H45BrO4;FW 537;mp 144-145℃;[α]D 25-134.5°(c 0.965,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.70(1H,m,3-H),3.45-3.44(2H,d,26-H),2.03(3H,s,CH3CO),1.06(3H,d,J=6.4Hz,21-CH3),1.03(3H,d,J=6.8Hz,27-CH3),0.85(3H,s,19-CH3),0.77(3H,s,18-CH3);
13C-NMR(75MHz,CDCl3)δ218.24,213.07,73.35,66.34,53.66,50.85,44.36,43.21,41.89,39.35,38.64,37.09,36.26,35.45,34.30,33.98,31.82,28.13,28.06,27.23,21.36,20.55,18.73,15.28,13.08,12.08;
MS(Madal):537(M+),561(M+23+1).
IR(KBr):2974,2944,1735,1723,1247,1023.
实施例4 化合物11a的合成
将149mg化合物16用20ml EtOH溶解,加入39mgNH4Cl和45mg Zn粉,回流反应30min无原料,硅藻土过滤Zn粉,滤渣用乙醇充分洗涤,蒸干有机溶剂,直接柱层析分离(PE∶EA=20∶1),得到118mg白色固体11a(92.9%)。
化合物11a:C29H46O4;FW458;mp 148-154℃;[α]D 25-136.35°(c 1.045,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.70(1H,m,3-H),2.03(3H,s,CH3CO),1.06(3H,d,J=6.4Hz,21-CH3),1.02(3H,s,19-CH3),1.00(3H,d,J=6.8Hz,26-CH3),0.92(3H,d,J=6.8Hz,27-CH3),0.80(3H,s,18-CH3)
实施例5 化合物13a的合成
将6.336g化合物11a溶于干燥的DCM中,氩气保护下室温滴加2.1ml(1.2eq)BF3.Et2O,2.9ml(2eq)PhSH,2.9ml(2.2eq)Ac2O,反应30min无原料,加入饱和NaHCO3水溶液淬灭反应,DCM萃取,合并有机相,有机相用饱和食盐水洗涤两次,无水MgSO4干燥,旋干有机溶剂,柱层析分离(PE∶EA=20∶1),得到5.417g淡黄色油状物13a(71.2%)。
化合物13a:C35H50O3S;FW 550;
1H-NMR(300MHz,CDCl3)δ7.31-7.19(5H,m,Ph-H),4.70(1H,m,3-H),3.80(2H,q,20-H),2.02(3H,s,CH3CO),1.26(3H,d,J=6.4Hz,21-CH3),0.98(3H,s,19-CH3),0.87(3H,d,J=6.8Hz,26-CH3),0.85(3H,d,J=6.8Hz,27-CH3),0.82(3H,s,18-CH3)
实施例6 化合物10的合成
方法一:由13a合成
将2.109g化合物13a溶于60ml EtOH中,加入7ml W-2型Raney-Ni,回流反应24h,点板无原料,硅藻土过滤,滤渣用乙醇充分洗涤,旋干有机溶剂,直接柱层析(PE∶EA=20∶1)得到1.601g无色油状物10(94.45%)。
方法二:由13b合成
将4.995g化合物13b用100ml EtOH溶解,加入30ml W-2型Raney-Ni室温搅拌反应2d,点板无原料,硅藻土过滤,滤渣用乙醇充分洗涤,旋干溶剂,柱层析分离(PE∶EA=30∶1),得到3.00g无色油状物10(99.0%)。
化合物10:C29H46O3;FW 442;
1H-NMR(300MHz,CDCl3)δ5.48(0.3H,s,16-H),5.34(0.65H,s,16-H),4.72-4.65(1H,m,3-H),3.19(1H,q,20-H),2.03(3H,s,CH3CO),1.23(1.5H,d,J=6.4Hz,21-CH3),1.21(2.0H,d,J=6.4Hz,21-CH3),0.88-0.84(9H,27-CH3,26-CH3,19-CH3),0.81(1.91H,s,18-CH3),0.76(1.02H,s,18-CH3)
实施例7 化合物12b的合成
将904mg化合物11a用50ml干燥的DCM溶解,氩气保护下加入300μl(1.2eq)BF3.Et2O,335μl(2eq)HSCH2CH2SH,室温搅拌反应30min无原料,加入饱和食盐水淬灭反应,DCM萃取,合并有机相,无水MgSO4干燥,旋干,柱层析分离(PE∶EA=10∶1),得到1.036g淡黄色固体12b(98.3%)。
化合物12b:C31H50O3S2;FW 534;m.p 213-216℃;[α]D 25-35.45°(c 1.035,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.70(1H,m,3-H),2.66-2.23(4H,dq,-SCH2CH2S-),2.02(3H,s,CH3CO),1.10(3H,d,J=6.4Hz,21-CH3),0.89(3H,s,19-CH3),0.87(3H,d,J=6.8Hz,26-CH3),0.82(3H,d,J=6.8Hz,27-CH3),0.81(3H,s,18-CH3);
EI(m/z):535(M++1)
实施例8 化合物13b的合成
方法一:由12b合成
将6.446g化合物12b用50ml DCM溶解,加入23ml(20eq)Ac2O,滴加3滴HClO4,室温搅拌反应1h,点板无原料,加入饱和NaHCO3水溶液搅拌1h,DCM萃取,饱和食盐水洗至中性,无水MgSO4干燥,旋干,柱层析分离(PE∶EA=30∶1),得到4.726g淡黄色油状物13b(68.0%)。
方法二:由11a一锅法合成
将100mg化合物11a用5ml DCM溶解,氩气保护下加入1.2eq.BF3.Et2O和2.0eq.)HSCH2CH2SH,室温搅拌30min,化合物11a转化完全。然后直接向体系中加入20eq.醋酐,室温搅拌反应1h,加入饱和NaHCO3水溶液搅拌1h,DCM萃取,饱和食盐水洗至中性,无水MgSO4干燥,旋干,柱层析分离,得到82mg淡黄色油状物13b(65.2%)。
化合物13b:C31H50O3S2;FW 534;
1H-NMR(300MHz,CDCl3)δ4.70(1H,m,3-H),3.68(2H,q,20-H),2.99-2.80(4H,dq,-SCH2CH2SAc),2.78(3H,s,CH3CO),2.02(3H,s,CH3CO),1.22(3H,d,J=6.4Hz,21-CH3),0.94(3H,s,19-CH3),0.88(3H,d,J=6.8Hz,26-CH3),0.86(3H,d,J=6.8Hz,27-CH3),0.84(3H,s,18-CH3)
实施例9 化合物18的合成
将175mg化合物10溶于干燥的DCM中,氩气保护下加入75μl(1.5eq)BF3.Et2O,2.6ml(40eq)HC(OEt)3和0.23.ml(10eq)HOCH2CH2OH,室温搅拌24h,点板无原料,加入饱和NaHCO3水溶液淬灭反应,DCM萃取,合并有机相,有机相用饱和食盐水洗涤,无水MgSO4干燥,旋干,柱层析分离,得到156mg无色油状物18(81.1%),经过重结晶,分得化合物18α和18β。
化合物18α:C31H50O4;FW 486;m.p 150-154℃;[α]D 25+0.2063°(c 1.115,CHCl3);
1H-NMR(300MHz,CDCl3)δ5.65(1H,s,16-H),4.70(1H,m,3-H),3.96(4H,s,-CH2CH2-),2.42(1H,q,20-H),2.03(3H,s,CH3CO),1.03(3H,d,J=6.4Hz,21-CH3),0.88(3H,s,19-CH3),0.87(3H,d,J=6.8Hz,26-CH3),0.85(3H,d.J=6.8Hz,27-CH3),0.77(3H,s,18-CH3);
IR(KBr):2931,2844,1733,1247;
元素分析:计算值C%:76.50 H%:10.35
实测值C%:76.32 H%:10.16
化合物18β:C31H50O4;FW 486;
1H-NMR(300MHz,CDCl3)δ5.55(1H,s,16-H),4.70(1H,m,3-H),3.96(4H,s,-CH2CH2-),2.42(1H,q,20-H),2.03(3H,s,CH3CO),1.03(3H,d,J=6.4Hz,21-CH3),0.88(3H,s,19-CH3),0.87(3H,d,J=6.8Hz,26-CH3),0.85(3H,d,J=6.8Hz,27-CH3),0.77(3H,s,18-CH3)
实施例10 化合物19a的合成
将135mg化合物18α溶于10ml甲醇中,加入19mg K2CO3回流反应1.5h后,点板无原料,蒸掉甲醇,DCM萃取,无水MgSO4干燥,旋干,柱层析分离,得到128mg白色固体19a(大于99%)。
化合物19a:C29H48O3;FW 444;
1H-NMR(300MHz,CDCl3)δ5.65(1H,s,16-H),5.31(1H,s,-OH),3.97(4H,s,-CH2CH2-),3.71(1H,m,3-H),2.48(1H,q,20-H),1.04(3H,d,J=6.4Hz,21-CH3),0.87(3H,d,J=6.8Hz,26-CH3),0.85(3H,d,J=6.8Hz,27-CH3),0.84(3H,s,19-CH3),0.78(3H,s,18-CH3)
实施例11 化合物19b的合成
将1.103g化合物19a,152mg(0.5eq)DMAP和507mg(3.0eq)imid.用10ml DMF溶解,室温下加入670mg(1.8eq)TBSCl,2min时出现白色固体,搅拌反应2h,点板无原料,加水淬灭反应,DCM萃取,合并有机相,有机相用饱和食盐水洗涤,无水MgSO4干燥,旋干,柱层析分离,得到1.382g白色固体19b(99.7%)。
化合物19b:C35H62O3Si;FW 558;m.p 91-93℃;[α]D 25+4.04°(c 1.100,CHCl3);
1H-NMR(300MHz,CDCl3)δ5.65(1H,s,16-H),3.96(4H,s,-OCH2CH2O-),3.55(1H,m,3-H),2.42(1H,q,20-H),1.03(3H,d,J=6.4Hz,21-CH3),0.88(9H,s,-SiC(CH3)3),0.86(3H,d,J=6.8Hz,26-CH3),0.84(3H,d,J=6.8Hz,27-CH3),0.83(3H,s,19-CH3),0.77(3H,s,18-CH3),0.04(6H,s,-Si(CH3)2);
IR(KBr):2961,2932,2860,1088
实施例12 化合物19c的合成
将128mg化合物19a,18mg(0.5eq)DMAP用5ml干燥的DCM溶解,室温滴加300μl(10eq)Py和91μl(1.2eq)TBDPSCl,搅拌反应28h,点板还有少量原料,加水淬灭反应,DCM萃取,合并有机相,有机相用饱和食盐水洗涤,无水MgSO4干燥,旋干,柱层析分离,得到156mg白色固体19c(81.6%)。
化合物19c:C45H66O3Si;FW 683;
1H-NMR(300MHz,CDCl3)δ5.65(1H,s,16-H),3.96(4H,s,-OCH2CH2O-),3.55(1H,m,3-H),2.42(1H,q,20-H),1.03(3H,d,J=6.4Hz,21-CH3),0.88(9H,s,-SiC(CH3)3),0.86(3H,d,J=6.8Hz,26-CH3),0.84(3H,d,J=6.8Hz,27-CH3),0.83(3H,s,19-CH3),0.77(3H,s,18-CH3),0.04(6H,s,-Si(CH3)2)
实施例13 化合物20的合成
将989mg化合物19b用无水乙醚溶解,室温下滴加1.15ml(8eq)Py,加入0.5g(1.1eq)的OsO4,搅拌反应20h,点板无原料,通入大大过量的H2S气体,柱层析分离,得到609mg白色固体20(58.1%)。
化合物20:C35H64O5Si;FW 592;m.p 238-239℃;[α]D 25-25.984°(c 1.100,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.26(1H,m,16-H),4.04(1H,d,16-OH),3.96(4H,s,-OCH2CH2O-),3.55(1H,m,3-H),3.10(1H,s,17-OH),1.12(3H,d,J=6.4Hz,21-CH3),0.88(9H,s,-SiC(CH3)3),0.86(3H,d,J=6.8Hz,26-CH3),0.85(3H,d,J=6.8Hz,27-CH3),0.78(3H,s,19-CH3),0.75(3H,s,18-CH3),0.05(6H,s,-Si(CH3)2);
IR(KBr):3475,2931,1091;
元素分析:计算值C%:70.89 H%:10.88
实测值C%:70.95 H%:11.06
实施例14 化合物21的合成
-78℃下,把58μl(4.0eq.)DMSO的1ml DCM溶液滴入71μl(4.0eq.)(COCl)2的1ml DCM溶液中,15min后,滴加121mg化合物53(1.0eq.)的3ml DCM溶液,反应20min,再滴加227μl(8.0eq.)Et3N,反应40min后撤去低温,自然升至室温并继续反应20min,乙酸乙酯稀释,有机相用饱和NaCl水溶液洗涤三次,无水MgSO4干燥,过滤,减压蒸去溶剂,在粗品中加入几滴Et3N,快速柱层析分离(PE∶EA=50∶1),回收原料2010mg(回收率9.1%),分得化合物21的白色固体106mg(87.9%,95.5%based on reacted 20)。
化合物21:C35H62O5Si;FW 590;m.p 199-200℃;[α]D 25-149.25°(c 0.64,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.75(1H,s,17-OH),4.00(4H,s,-OCH2CH2O-),3.56(1H,m,3-H),2.74(1H,q,20-H),1.03(3H,d,J=6.4Hz,21-CH3),0.91(9H,s,-SiC(CH3)3),0.89(3H,d,J=6.8Hz,26-CH3),0.88(3H,d,J=6.8Hz,27-CH3),0.85(3H,s,19-CH3),0.83(3H,s,18-CH3),0.06(6H,s,-Si(CH3)2)
IR(KBr):3462,2955,2931,1749,1380,1250
ESI(MS):592(M+),591(M+-1);
元素分析:计算值C%:71.14 H%:10.57
实测值C%:71.17 H%:10.67
实施例15 化合物22的合成
将105mg化合物21溶于5ml THF中,在-78℃下分多次少量加入27mg(4.0eq.)LiAlH4,控制在-78℃反应,反应完毕后加水搅拌,乙醚萃取,有机相用饱和NaCl水溶液洗涤,无水MgSO4干燥,过滤,减压蒸去有机溶剂,快速柱层析分离(PE∶EA=20∶1),得化合物22白色固体74mg(70.2%)。
化合物22:C35H64O5Si;FW 592;m.p 176-178℃;[α]D 25-15.25°(c 0.865,CHCl3);
1H-NMR(300MHz,CDCl3)δ4.12(1H,s,16-H),4.05(4H,d,-OCH2CH2O-),3.90(1H,m,16-OH),3.54(1H,m,3-H),2.59(1H,q,20-H),1.19(3H,d,J=6.4Hz,21-CH3),0.89(3H,d,J=6.8Hz,26-CH3),0.88(3H,d,J=6.8Hz,27-CH3),0.87(9H,s,-SiC(CH3)3),0.85(3H,s,19-CH3),0.79(3H,s,18-CH3),0.04(6H,s,-Si(CH3)2);
IR(KBr):3469,2956,2929,2858,1467,1383,1255;
元素分析:计算值C%:70.89 H%:10.89
实测值C%:70.26 H%:10.20
实施例16 化合物23的合成
将200mg 4MS加入100ml蛋形瓶中,用火烤瓶,冷却至室温后在氩气保护下将163mg二糖亚胺酯24的3ml DCM溶液、26mg(1.0eq)保护的OSW-1甙元22的3ml DCM溶液加入到干燥的蛋形瓶中搅拌15min,然后在-10℃下滴加0.5mlTMSOTf溶液(0.005M in DCM,0.05eq.),反应1h,点板无原料,加入Et3N淬灭反应,过滤,滤液旋干,快速柱层析分离(PE∶EA=20∶1),得到化合物2348mg(80.0%)。
化合物23:C73H130O16Si4;FW 1374;m.p 83-85℃;
1H-NMR:8.06(2H,d,J=9.0Hz,Ar),6.90(2H,d,J=9.0,Ar),5.09(1H,s),4.97(1H,br s),4.91(1H,br s),4.55(1H,br s),4.49(1H,br s),4.03-4.93(4H,m),3.87(3H,s,OMe),3.76-3.70(2H,m),3.51(2H,br s),3.32(2H,br s),2.66(1H,q,J=7.2Hz,20-H),2.02(3H,s,-OAc),1.10(3H,d,J=7.2Hz,21-Me),1.06(3H,s,19-Me),1.00-0.86(45H,m),0.68-0.53(18H,m),0.06(6H,s,Me-Si).
实施例17 5,6-双氢-OSW-1化合物4的合成
化合物2313mg溶于2.2ml醋酸和0.9ml水中,75℃反应3h,原料消失,直接减压蒸除溶剂,快速柱层析分离(DCM∶MeOH=20∶1),分得最终目标化合物5,6-双氢-OSW-15mg(60.2%)。
化合物4:C47H70O15;FW 874;m.p 138-139℃;[α]D 25-18.3°(c 0.385,MeOH);
1H-NMR(300MHz,pyridine-d6):8.09(2H,d,J=9.0Hz,Ar),6.98(2H,d,J=9.0,Ar),5.40(1H,t,J=7.6Hz),5.27(1H,t,J=7.6Hz),4.81(1H,d,J=7.8Hz),4.51(1H,s),4.27(1H,d,J=6.0Hz),4.10(1H,s),3.96-3.82(6H,m),3.52-3.48(3H,m),3.41(3H,s,OMe),2.85(1H,q,J=6.9Hz,20-H),1.83(3H,s,OAc),1.25(3H,s),1.04(3H,d,J=6.3Hz),1.02(3H,s),0.79(6H,m);
1H-NMR(500MHz,pyridine-d6):8.41(2H,d,J=9.0Hz,Ar),7.16(2H,d,J=9.0Hz,Ar),5.76(1H,t like,J=9.0Hz,2”-H),5.64(1H,t like,J=7.2Hz,2’-H),5.38(1H,br d,J=4.2Hz,6-H),5.20(1H,d,J=7.8Hz,1”-H),4.87(1H,s),4.67(1H,d,J=6.0Hz,1’-H),4.87(1H,s),4.33(1H,dd,J=5.4Hz and 11.4Hz),4.31(1H,brs),4.27-4.22(4H,m),3.92(1H,m,3-H),3.82(3H,s,OMe),3.82-3.80(2H,m),3.38(1H,q,J=7.2Hz,20-H),2.06(3H,s,OAc),1.36(3H,d,J=7.2Hz,21-Me),1.05(3H,s,19-Me),0.96 and 0.93(each 3H,d,J=6.0Hz,26-or 27-Me),0.91(3H,s,18-Me);
13C-NMR(75MHz,pyridine-d6):δ219.05,169.38,165.55,164.01,132.54,114.37,114.24,103.79,100.95,88.51,85.78,81.10,76.46,75.25,72.18,70.83,70.76,67.16,55.61,54.31,48.27,47.00,46.45,45.29,39.44,39.38,37.57,35.90,35.64,33.07,32.81,32.61,29.22,27.84,22.93,22.59,21.01,14.03,12.61,11.95;
MS(ESI)::897(M+Na+),874(M+);
IR(KBr):3500,2960,1732,1453,1279,1069,711.
实施例18 化合物12c的合成
将987mg化合物11c用50ml干燥的DCM溶解,氩气保护下加入300μl(1.2eq)BF3.Et2O和2.5eq.HSCH2CH2CH2SH,室温搅拌1小时,反应结束。加入饱和食盐水淬灭反应,DCM萃取,合并有机相,无水MgSO4干燥,旋干,柱层析分离,得到1.051g淡黄色固体12c(90.2%)。
化合物12c:C35H58O3S2;FW 590;
1H-NMR(300MHz,CDCl3)δ4.94(1H,m),3.62(2H,m),2.85(1H,m,3-H),2.51(4H,m,-SCH2);
ESI(m/z):591(M++1)
实施例19 化合物12d的合成
将991mg化合物11d用50ml干燥的DCM溶解,氩气保护下加入300μl(1.2eq)BF3.Et2O和2.5eq.HSCH2CH2SH,室温搅拌1小时,反应结束。加入饱和食盐水淬灭反应,DCM萃取,合并有机相,无水MgSO4干燥,旋干,柱层析分离,得到1.032g淡黄色固体12d(89.4%)。
化合物12d:C31H52O3S2;FW 536;
1H-NMR(300MHz,CDCl3)δ4.68(s,2H,3-O
CH 2
OCH3),3.75(m,1H,3-H),3.35(s,3H,3-OCH2O
CH 3
),2.80(4H,m,-SCH2);
ESI(m/z):537(M++1)
实施例20 化合物13e的合成
将500mg化合物11e溶于10mL干燥的DCM中,氩气保护下加入1.2eq.BF3.Et2O和2.0eq.PhSH,然后滴加2.9ml(2.2eq)Ac2O,反应30min,反应结束。加入饱和NaHCO3水溶液淬灭反应,DCM萃取,合并的有机相用饱和食盐水洗涤两次,无水MgSO4干燥,旋干有机溶剂,柱层析分离,得到358mg淡黄色油状物13e(62.8%)。
化合物13a:C49H66O2SSi;FW 746;
1H-NMR(300MHz,CDCl3)δ7.67-7.19(15H,m,Ph-H),3,39(1H,m,3-H),1.07(9H,s,t-Bu);
ESI(m/z):745(M++1)
Claims (7)
1、一类5,6-双氢-胆甾化合物,其特征是具有如下结构:
R1为H、MOM、Bn、PMB、THP、Tr、Ac、Bz、Piv、TMS、TES、TBS或者TBDPS;R2为H或者与R4成16,17-双键;R3为SMe、SEt、SPh、SCH2Ph、S(CH2)nSAc或者与R4成S(CH2)nS;R4为SMe、SEt、SPh、SCH2Ph、与R3成S(CH2)nS或者与R2成16,17-双键;n=2或3;
其中,Me是甲基,Et是乙基,Ph是苯基,MOM是甲氧亚甲基,Bn是苄基,PMB是对甲氧基苄基,THP是四氢吡喃基,Tr是三苯甲基,Ac是乙酰基,Bz是苯甲酰基,Piv是特戊酰基,TMS是三甲基硅基,TES是三乙基硅基,TBS是叔丁基二甲基硅基,TBDPS是叔丁基二苯基硅基。
3、如权利要求1所述的5,6-双氢-胆甾化合物的合成方法,其特征是通过方法1)、方法2)、方法3)或者方法1)~2)合成:
方法1):在非质子性溶剂中,化合物11、硫醇和催化剂在0~50℃反应0.1~20小时,得到化合物12;化合物11与硫醇及催化剂的摩尔比是1∶1~5∶0.01~5;
方法2):在非质子性溶剂中,化合物12、催化剂和醋酐在0~50℃反应5分钟~20小时,得到化合物13;化合物12、醋酐与催化剂的摩尔比是1∶1~50∶0.01~5;
方法3):在非质子性溶剂中,化合物11、硫醇和催化剂,在0~50℃反应0.1~20小时,然后直接向体系中加入醋酐,反应5分钟~20小时,得到化合物13;化合物11、硫醇、醋酐及催化剂的摩尔比是1∶1~5∶1~50∶0.01~5;
上述反应中,化合物12和13的结构如权利要求2所示;化合物11的结构为:
其中,R1的定义如权利要求1所述。
4、如权利要求3所述的甾体化合物的合成方法,其特征是所述的非质子性溶剂是CH2Cl2、CHCl3、CCl4、1,2-二氯乙烷、四氢呋喃、乙醚或者它们的混合物。
5、如权利要求3所述的甾体化合物的合成方法,其特征是所述的催化剂是AlCl3、BF3Et2O、TiCl4或HClO4。
6、如权利要求3所述的甾体化合物的合成方法,其特征是所述的硫醇是MeSH、EtSH、PhCH2SH、PhSH、乙二硫醇或者丙二硫醇。
7、如权利要求1所述的5,6-双氢-胆甾化合物的用途,其特征是所述5,6-双氢-胆甾化合物用于合成OSW-1类似物5,6-双氢-OSW-1。
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