CN1887900A - 一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法 - Google Patents
一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法 Download PDFInfo
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- CN1887900A CN1887900A CN 200610029252 CN200610029252A CN1887900A CN 1887900 A CN1887900 A CN 1887900A CN 200610029252 CN200610029252 CN 200610029252 CN 200610029252 A CN200610029252 A CN 200610029252A CN 1887900 A CN1887900 A CN 1887900A
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- compound
- oac
- acetic acid
- hydrogen bromide
- acid solution
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- 238000003786 synthesis reaction Methods 0.000 title abstract description 21
- 230000015572 biosynthetic process Effects 0.000 title abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 13
- 150000003431 steroids Chemical class 0.000 claims abstract description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 19
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 19
- -1 26-bromo-16, 22-dioxo-cholesterol compound Chemical class 0.000 claims description 18
- MNZMECMQTYGSOI-UHFFFAOYSA-N acetic acid;hydron;bromide Chemical compound Br.CC(O)=O MNZMECMQTYGSOI-UHFFFAOYSA-N 0.000 claims description 13
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- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 10
- 229940125782 compound 2 Drugs 0.000 claims description 10
- 230000003647 oxidation Effects 0.000 claims description 8
- 238000007254 oxidation reaction Methods 0.000 claims description 8
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
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- 230000002194 synthesizing effect Effects 0.000 claims description 6
- WIERHVRLMSNHPH-NOIOWZGKSA-N (3S,8S,9S,10R,13S,14S,17R)-17-[(2S)-7-bromo-6-methyl-3-oxoheptan-2-yl]-3-hydroxy-10,13-dimethyl-1,2,3,4,7,8,9,11,12,14,15,17-dodecahydrocyclopenta[a]phenanthren-16-one Chemical compound BrCC(CCC([C@H]([C@H]1C(C[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)=O)C)=O)C WIERHVRLMSNHPH-NOIOWZGKSA-N 0.000 claims description 5
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- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 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
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- 125000005843 halogen group Chemical group 0.000 claims 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 abstract description 17
- 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 abstract description 10
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- 238000009776 industrial production Methods 0.000 abstract description 2
- MPXTYZZFIJTPPA-MKQTXCTDSA-N [(2s,3r,4s,5r)-2-[(2s,3r,4s,5s)-3-acetyloxy-2-[[(3s,8r,9s,10r,13s,14s,16s,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 compound 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-MKQTXCTDSA-N 0.000 abstract 1
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Abstract
本发明涉及一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法,即在溴化氢-乙酸溶液作用下,甾体E/F缩酮螺环发生开环反应并且26-位溴代,得到26-溴代-16,22-二氧代-胆甾醇化合物,脱溴后即可得到胆甾类化合物,胆甾类化合物可用来合成OSW-1甙元及其类似物。该反应过程如图中公式,本发明的方法不仅操作简便,而且适合工业化生产。
Description
技术领域
本发明涉及一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法,即甾体皂甙元或其衍生物的16-位氧化产物和溴化氢-乙酸溶液反应,得到了一系列甾体E/F环开环的26-溴代化合物;这类化合物脱溴后即得到16,22-二氧代-胆甾醇化合物,可以进一步合成OSW-1及其类似物。
技术背景
虎眼万年青皂甙(OSW-1)是一种从原产于南非的常绿观赏植物Ornithogalumsaunderside的地下球茎中分离出的具有胆固醇骨架的皂甙,它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(IC50 1500nM)(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。但是多数研究小组以去氢表雄酮为起始原料来合成OSW-1甙元(参见Tetra.Lett.,1998,39,1099;J.Org.Chem.,1999,64,202;J.Arm.Chem.Soc.,2002,124,6576;CarbohydrateRes.,2002,337),而去氢表雄酮是由天然的薯蓣皂甙元(Diosgenin)经六步反应降解得来的,总收率在25-50%之间(参见J.Am.Chem.Soc.,1940,62,3350;J.Org.Chem.,1956,21,520)。
田伟生等人以薯蓣皂甙元(diosgenin)为起始原料,充分利用甾体皂甙元的完整碳骨架,分别合成了虎眼万年青皂甙(OSW-1)(参见CN 02145066.8;Tetra.Lett.,2003,44,9375;CN 200610026473.4)和偏诺皂甙元(pennogenin,参见CN 02150907.7;Chinese Science in China Ser.B Chemistry,2004,47,142),报道的合成路线如下:
OSW-1的合成:
Pennogenin的合成:
由上述合成路线可以看出,从diosgenin合成双酮化合物A需要先还原打开F环然后再氧化打开E环,而合成双酮化合物B仅仅需要氧化打开E/F环;并且合成双酮化合物A操作较为繁琐,需要重复氧化和分离才能转化较为完全,而双酮化合物B可以从diosgenin以大于70%的总产率获得;为了更加高效地合成OSW-1和pennogenin两个天然产物,田伟生等人把两条合成路线进行了整合,把易于大量制备的双酮B的衍生物化合物D转化为较难于大量制备的双酮A的衍生物化合物C(参见CN 200610025917.2):
但是,上述路线较长,操作也比较繁琐,总收率较低,不利于化合物C的大量制备。
田伟生等人也报道了26-溴代-16,22-二氧代-胆甾醇化合物的合成,但是效率比较低下(参见CN 02150907.7):
26-溴代-16,22-二氧代-胆甾醇化合物可以参照文献的方法脱除26-溴,得到胆甾类化合物A及其类似物(参见J.Med.Chem.,1984,27,1690;Tetra.Lett.,1994,35,935)。
本发明从甾体皂甙元或其衍生物的16-位氧化产物出发,非常方便地制备了26-溴代-16,22-二氧代-胆甾醇化合物,并可以进一步用来合成化合物A及其类似物,从而实现了合成OSW-1路线中关键化合物的量的积累。
发明内容
本发明的目的是提供一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法。
本发明所述的26-溴代-16,22-二氧代-胆甾醇化合物的合成方法如下:
甾体皂甙元或其衍生物的16-位氧化产物1溶解在非质子性溶剂、乙酸或它们的混合溶剂中,加入溴化氢-乙酸溶液,混合物在-20℃~回流温度下搅拌0.5~24h,得到26-溴代-16,22-二氧代-胆甾醇化合物2,化合物1与溴化氢的摩尔比是1∶1-10;所述的溴化氢-乙酸溶液是含1~50%溴化氢的乙酸溶液;所述的非质子性溶剂是二氯甲烷、三氯甲烷、四氯化碳、二氯乙烷、乙醚、四氢呋喃(THF)、1,4-二噁烷(dioxane)、苯、甲苯、乙腈或它们的混合溶剂;
所述的化合物1和2的结构式如下所示:
代表朝上或者朝下;R1为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R2成羰基;R2为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R1成羰基;R3为H或者C1~4的烃基;R4为OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS;R5为H、OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS;R6为H、OH、OAc、OTMS、X或者与R7成5,6-双键或5,6-环氧;R7为H、OH、OAc、OTMS、X或者与R6成5,6-双键或5,6-环氧;
其中,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,X是卤素。
化合物2可以参照文献的方法合成胆甾类化合物A及其类似物(参见J.Med.Chem.,1984,27,1690;Tetra.Lett.,1994,35,935),从而实现了合成OSW-1路线中关键化合物的量的积累。。
本发明从甾体皂甙元或其衍生物的16-位氧化产物出发,非常方便地制备了26-溴代-16,22-二氧代-胆甾醇化合物,不仅操作简便,而且适合工业化生产,比已有的方法具有很大的优越性。参照文献的方法可以方便地合成OSW-1甙元及其类似物(参见CN 02145066.8;CN 200610025917.2;CN 200610026473.4)。
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。
本发明的化合物1a、1d、1e、1f、1g参照文献的方法合成(参见CN 02150907.7;Tetra.Lett.,1994,35,935)。
实施例1 化合物1b和1c的合成
1.861g化合物1a溶于50ml无水乙醇中,加入0.411g NH4Cl(2.6eq.)和0.966g锌粉(5.0eq.),回流0.5h,荧光点消失,反应良好。硅藻土过滤,滤饼用无水乙醇洗涤,滤液旋干,快速柱层析分离(PE∶EA=40∶1-10∶1),分得化合物1b0.139g(10.0%)和化合物1c 1.314g(89.0%)。
化合物1b:C29H44O4;FW 472;mp 150℃;
1H-NMR(CDCl3,300MHz)δ:5.39(1H,d,J=4.8Hz,6-H),4.63-4.57(1H,m,3-H),3.61-3.56(3H,m,26-H and 16-OH),1.03(3H,s,19-Me),1.01(3H,d,J=6.9Hz,21-Me),0.83(3H,d,J=6.3Hz,27-Me),0.76(3H,s,18-Me);
MS(EI):454(M+-18,11.1%),43(100%).
化合物1c:C31H48O5;FW 500;mp 145-148℃;
1H-NMR(CDCl3,300MHz)δ:5.38(1H,d,J=4.8Hz,6-H),4.62-4.50(1H,m,3-H),3.70-3.36(4H,m,26-H and 16-OCH2CH3),2.03(3H,s,OAc),1.21(3H,t,J=7.2Hz,16-OCH2CH3),1.03(3H,s,19-Me),1.01(3H,d,J=6.6Hz,21-Me),0.81(3H,d,J=7.8Hz,27-Me),0.78(3H,s,18-Me).
实施例2 化合物2a的合成
取0.5g化合物1a,用5ml CH2Cl2溶解,加入0.2ml 30%溴化氢-乙酸溶液,室温下反应,TLC跟踪至反应完成,约需2h,用饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离得化合物2a 0.415g(产率76%)。
化合物2a:C29H43Br3O4;FW 692;
1H-NMR(CDCl3,300MHz)δ:5.50(1H,t,J=5.4Hz,6-H),4.83(1H,m,3-H),3.43(2H,d,J=5.2Hz,26-H),2.03(3H,s,OAc),1.04(6H,S,18,19-CH3);
IR v:2946,1736,1377,1242,1029cm-1.
实施例3 化合物2b的合成
方法一:由化合物1b合成化合物2b
0.299g化合物1b溶于5ml CH2Cl2,加入0.20ml 33%溴化氢-乙酸溶液,室温下反应1.5h,反应完成,饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离,得化合物2b 0.314g(产率92.8%)。
方法二:由化合物1c合成化合物2b
0.316g化合物1c溶于5ml CH2Cl2,加入0.30ml 33%溴化氢-乙酸溶液,室温下反应3.0h,反应完成,饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离,得化合物2b 0.295g(产率87.4%)。
化合物2b:C29H43BrO4;FW 534;
1H-NMR(CDCl3,300MHz)δ:5.38(1H,t,J=4.4Hz,6-H),4.62(1H,m,3-H),3.45(2H,d,J=5.2Hz,26-H),2.17(3H,s,OAc),1.04(6H,s,18,19-CH3);
MS(ESI):536(M++2);
IR v:2960,1728,1456,1375,1247,1021cm-1;
元素分析 理论值C 65.04%,H 8.09%,
测量值C 65.46%,H 8.42%.
实施例4 化合物2d的合成
取0.3g化合物1d,用10ml CH2Cl2溶解,加入0.22ml 33%溴化氢-乙酸溶液(2.0eq.),室温下反应,TLC跟踪至反应完成,约需1.5h,用饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离(PE∶EA=16∶1),得化合物2d 0.306g(产率89%)。
化合物2d:C29H45BrO4;FW 536;
1HNMR(CDCl3,300MHz)δ:4.67(1H,m,3-H),3.34(1H,m,26-H),2.77(1H,m,20-H),2.03(3H,s,OAc),1.13(3H,d,J=6.4Hz,21-CH3),0.91(3H,d,J=6.8Hz,27-CH3),0.85(3H,s,19-CH3),0.77(3H,s,18-CH3);
MS(ESI):538(M++2);
IR v:2960,1728,1020cm-1;
元素分析 理论值C 64.79%,H 8.44%,
测量值C 64.76%,H 8.49%.
实施例5 化合物2e的合成
0.433g化合物1e溶于5ml CH2Cl2,加入0.15ml 37%溴化氢-乙酸溶液,室温下反应,TLC跟踪至反应完成,饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离,得化合物2e 0.357g(产率75.6%)。
化合物2e:C43H59BrO4Si;FW 746;
1HNMR(CDCl3,300MHz)δ:7.69-7.65and 7.40-7.36(10H,m,Ar),3.49(1H,m,3-H),3.31(m,2H,26-H),1.06(9H,s,t-Bu),1.10(d,3H,J=6.9Hz,21-H),0.96(d,3H,J=5.4Hz,27-Me),0.86(s,3H,18-Me),0.85(s,3H,19-Me);
MS(ESI):748(M++2);
元素分析 理论值C 69.05%,H 7.95%,
测量值C 68.83%,H 8.07%.
实施例6 化合物2f的合成
取0.339g化合物1f,用5ml CH2Cl2溶解,加入0.35ml 33%溴化氢-乙酸溶液,室温下反应,TLC跟踪至反应完成,饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离,得化合物2f0.194g(产率51.3%)。
化合物2f:C31H51BrO6;FW 598;
1HNMR(CDCl3,300MHz)δ:4.75-4.71(m,2H,12-OCH2OCH3),4.68(s,2H,3-OCH2OCH3),3.75(m,2H,3-H,12-H),3.37(s,3H,12-OCH2OCH3),3.35(s,3H,3-OCH2OCH3),3.30(m,2H,26-H),1.04(d,J=6.6Hz,3H,21-CH3),0.96(d,3H,J=5.4Hz,27-Me),0.87(s,3H,18-CH3),0.85(s,3H,19-CH3);
MS(ESI):600(M++2);
元素分析 理论值C 62.09%,H 8.57%,
测量值C 62.40%,H 8.49%.
实施例7 化合物2g的合成
取0.424g化合物1g,用5ml CH2Cl2溶解,加入0.20ml 30%溴化氢-乙酸溶液,室温反应,TLC跟踪至反应完成,饱和NaHCO3溶液淬灭,水相用CH2Cl2萃取,合并的有机相用饱和食盐水洗,无水Na2SO4干燥,过滤,浓缩所得粗产物经柱层析分离,得化合物2g 0.187g(产率40.4%)。
化合物2g:C41H49BrO7;FW 732;
1HNMR(CDCl3,300MHz)δ:8.03-7.46(10H,m,Ar),3.99(m,2H,1-H and 3-H),3.44(1H,m,26-H),3.04(m,1H,6-H),1.18(d,3H,J=6.9Hz,21-H),1.00(3H,s,19-Me),0.95(3H,s,18-Me),0.89(3H,d,J=6.3Hz,27-Me);
MS(ESI):734(M++2);
元素分析 理论值C 67.11%,H 6.73%,
测量值C 67.02%,H 6.54%.
实施例8 化合物3a的合成
将200mg化合物2a溶于5ml乙醇中,加入180mg(10.0eq.)锌粉和38mgNH4Cl(2.5eq.),加热回流10h,反应完全,过滤除去固体,将乙醇旋干,所得残留物用乙酸乙酯溶解,饱和食盐水洗涤,无水硫酸钠干燥后,浓缩得反应粗产物,快速柱层析得化合物3a 90mg(产率68.3%)。
化合物3a:C29H44O4;FW 456;
1H-NMR(CDCl3,300MHz)δ:5.37(1H,d,J=5.1Hz,6-H),4.62(1H,m,3-H),2.04(3H,s,OAc),1.06(3H,d,J=6.0Hz,21-Me),1.05(3H,s,19-Me),0.91(6H,d,J=6.0Hz,26,27-Me),0.81(3H,s,18-Me);
MS(EI):441(M+-15,5.4%),397(11.5%),340(100%);
IR v:1732,1712cm-1.
实施例9 化合物3d的合成
将1.072g化合物2d溶于50mL乙醇中,加入0.65g(5.0eq)锌粉和0.268gNH4Cl(2.5eq),加热回流4h,反应完全,过滤除去固体,将乙醇旋干,所得残留物用乙酸乙酯溶解,饱和食盐水洗涤,无水硫酸钠干燥后,浓缩得反应粗产物,快速柱层析得化合物3d 0.805mg(产率87.9%)。
化合物3d:C29H46O4;FW 458;
1H-NMR(CDCl3,300MHz)δ:4.61(1H,m,3-H),2.04(3H,s,OAc),1.06(3H,d,J=6.0Hz,21-Me),0.91(6H,d,J=6.0Hz,26,27-Me),0.85(3H,s,19-Me),0.79(3H,s,18-Me);
元素分析 理论值C 75.94%,H 10.11%,
测量值C 75.82%,H 9.87%.
实施例10 化合物4的合成
化合物3a 2.290g溶于35ml HOAc,加入1.06ml HSCH2CH2SH(2.5eq.),然后滴加1.3ml BF3·Et2O(2.0eq.),室温反应2.5h,原料消失。再加入20ml Ac2O,混合物立即由白色浑浊变为橙红色透明,反应20min,反应结束。加入饱和NaHCO3溶液,然后加固体NaHCO3至无气泡冒出,乙酸乙酯萃取,有机相分别用NaHCO3溶液和饱和NaCl溶液洗涤,MgSO4干燥,过滤,减压蒸去溶剂,快速柱层析分离(PE∶EA=40∶1),得化合物4的浅黄色粘稠油状物1.830g(63.5%)。
化合物4:C33H50O4S2;FW 574;[α]D 28=21.4°(C=0.433,CHCl3);
1H-NMR(CDCl3,300MHz)δ:5.40(1H,d,J=3.9Hz,6-H),4.61(1H,m,3-H),3.68(1H,q,J=6.9Hz,20-H),2.98 and 2.81(4H,m,SCH2CH2S),2.35(3H,s,SAc),2.04(3H,s,OAc),1.22(3H,d,J=7.2Hz,21-Me),1.05(3H,s,19-Me),0.98(3H,s,18-Me),0.87(6H,d,J=5.7Hz,26,27-Me);
13C-NMR(CDCl3,75MHz)δ:210.98,195.10,170.51,153.39,139.92,131.03,122.11,73.79,56.49,50.09,48.87,46.84,38.58,38.04,36.74,36.71,35.07,34.39,32.98,31.25,30.59,30.07,29.75,27.62,22.43,22.35,21.39,20.42,19.15,17.14,14.34;
MS(EI):574(M+,1.2%),475(M+-99,100%);
HRMS(MALDI):计算值C33H50O4S2Na:597.3040;测量值:597.3043;
IR v:1734,1713,1696cm-1。
实施例11 化合物5的合成
将930mg化合物4溶于30ml无水乙醇中,加入W-2型瑞尼镍约3.5g,室温反应0.5h,原料消失,过滤,残渣用无水乙醇充分洗涤,滤液旋干,快速柱层析分离(PE∶EA=20∶1),得化合物5白色固体641mg(90%)。
化合物5:C29H44O3;FW 440;
1H-NMR(CDCl3,300MHz)δ:5.37(2H,br s,6-H and 16-H),4.61(1H,m,3-H),3.20(1H,q,J=6.9Hz,20-H),2.04(3H,s,OAc),1.16(3H,d,J=6.6Hz,21-Me),1.06(3H,s,19-Me),0.87(6H,d,J=6.0Hz,26,27-Me),0.85(3H,s,18-Me);
MS(ESI):441(M++1,100%);
IR v:1735,1714,1244cm-1。
Claims (3)
1,一类26-溴代-16,22-二氧代-胆甾醇化合物的合成方法,其特征是所述的合成方法如下:
在非质子性溶剂、乙酸或它们的混合溶剂中,甾体皂甙元或其衍生物的16-位氧化产物1和溴化氢-乙酸溶液,在-20℃~回流温度下搅拌0.5~24h,得到26-溴代-16,22-二氧代-胆甾醇化合物2,化合物1与溴化氢的摩尔比是1∶1-10;所述的溴化氢-乙酸溶液是含1~50%溴化氢的乙酸溶液;
所述的化合物1与化合物2的结构式如下所示:
其中,
代表朝上或者朝下;R1为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R2成羰基;R2为H、OH、OMOM、OTHP、OTr、OAc、OBz、OPiv、OTES、OTBS、OTBDPS或者与R1成羰基;R3为H或者C1~4的烃基;R4为OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS;R5为H、OH、OMOM、OBn、OPMB、OTHP、OTr、OAc、OBz、OPiv、OTMS、OTES、OTBS或者OTBDPS;R6为H、OH、OAc、OTMS、X或者与R7成5,6-双键或5,6-环氧;R7为H、OH、OAc、OTMS、X或者与R6成5,6-双键或5,6-环氧;
所述的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,X是卤素。
2,一种如权利要求1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二氯甲烷、三氯甲烷、四氯化碳、二氯乙烷、乙醚、四氢呋喃、1,4-二噁烷、苯、甲苯、乙腈或它们的混合溶剂。
3,一种如权利要求1所述的甾体化合物的合成方法,其特征是所述的溴化氢-乙酸溶液是含1~50%溴化氢的乙酸溶液。
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CN104530179A (zh) * | 2014-12-15 | 2015-04-22 | 中国科学院上海有机化学研究所 | 一种26-卤代呋甾化合物、合成方法及其用途 |
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