CN1571779A - 制备14β-羟基-浆果赤霉素Ⅲ-1,14-碳酸酯的方法 - Google Patents
制备14β-羟基-浆果赤霉素Ⅲ-1,14-碳酸酯的方法 Download PDFInfo
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Abstract
用于制备新的具有抗肿瘤活性的紫杉烷衍生物的14β-羟基-浆果赤霉素III-1,14-碳酸酯的制备方法。
Description
本发明涉及制备14β-羟基-1,14-碳酸酯-浆果赤霉素III的方法。用本发明的方法获得的产物可用于制备新的具有抗肿瘤活性的紫杉烷衍生物。
紫杉烷类是近年来开发的最重要的抗肿瘤剂种类之一。紫杉醇是从短叶红豆杉(Taxus brevifolia)的树皮中获得的二萜络合物,被视为治疗癌症的主要药物之一。目前,人们正在广泛寻找具有更高药理活性和改进的药动学曲线的新的紫杉烷衍生物。一个具体的方法涉及对母体结构进行各种修饰的浆果赤霉素III衍生物。所述化合物的例子以US 5705508、WO97/43291、WO 96/36622中公开的14β-羟基浆果赤霉素III衍生物为代表。目前,14β-羟基-去乙酰浆果赤霉素III 1,14-碳酸酯衍生物是从前体14β-羟基-去乙酰浆果赤霉素III起始制备的,如EP 559 019中所述,该前体为通过提取西藏红豆杉(Taxus wallichiana)树叶可少量获得的天然化合物。非常需要容易、有效地制备大量14β-羟基-1,14-碳酸酯-浆果赤霉素III,从而制备大量其衍生物的新方法。
现已发现14β-羟基-浆果赤霉素III-1,14-碳酸酯可以通过由13-酮基浆果赤霉素III起始的方法进行制备,由10-去乙酰浆果赤霉素III可以容易地获得该化合物,而10-去乙酰浆果赤霉素III,与14β-羟基-浆果赤霉素III相反,可以从欧洲红豆杉(Taxus baccata)的树叶中很容易地大量分离。
因此,本发明涉及制备14β-羟基-浆果赤霉素III-1,14-碳酸酯的方法,其包括以下步骤:
a.用适宜的碱和氧化剂处理下式的7-三乙基甲硅烷基-13-酮基浆果赤霉素III,
生成7-三乙基甲硅烷基-13-酮基-14-羟基-浆果赤霉素III:
b.将1和14位的羟基碳酸化生成14β-羟基-7-三乙基甲硅烷基-13-酮基-浆果赤霉素III-1,14-碳酸酯:
c.将13位的酮还原,并将7位的保护基裂解。
用适宜的保护基,优选选自甲硅烷基醚类(优选三乙基甲硅烷基醚),在7位方便地保护起始的13-酮基浆果赤霉素III。用适宜的碱,特别是叔丁醇钾(t-BuOK)或二(三甲基甲硅烷基)氨基钾(KHMDS)处理进行步骤a)。可以在-40至-78℃下进行反应。该反应的适宜溶剂为醚类,如四氢呋喃或乙醚,特别是与六甲基磷酰胺(HMPA)或1,3-二甲基-3,4,5,6-四氢-2(1H)嘧啶酮(DMPU)混合的醚。然后用氧化剂,如氧氮杂环丙烷(oxaziridine)衍生物(特别是N-苯磺酰基苯基氧氮杂环丙烷、N-苯磺酰基间硝基苯基氧氮杂环丙烷和樟脑磺酰基氧氮杂环丙烷)处理烯醇化物以提供7-保护的13-酮基-14-羟基-浆果赤霉素III衍生物。
然后,通过在文献通常所述的条件下用羰基化试剂(例如羰基二咪唑或光气)处理进行步骤b),以提供1,14-碳酸酯衍生物。在从-40℃至室温范围内的温度下,于碱(优选吡啶或三乙胺)存在下,在惰性溶剂、优选醚或氯化溶剂中,可以方便地进行反应。既可以用纯的起始原料也可以用前一步骤的粗品进行反应。
在通常为-20至-50℃范围内的温度下,于乙醇中,用硼氢化钠容易地完成步骤c)中13位羰基的还原,反应在2-6小时内完成。也可以在甲醇、异丙醇,或在甲醇和四氢呋喃的混合物中进行反应。虽然优选使用过量的氢化物,但是可以按化学计算量使用还原剂。在本领域已知的条件下,也可以用其它氢化物实现还原,优选硼氢化四丁基铵、硼氢化锂、三乙酰氧基硼氢化钠。
根据所用的保护基,在不同条件下除去7位的保护。例如,如果7位的保护基为三乙基甲硅烷基醚,可以成功地使用用盐酸在甲醇中或氢氟酸和吡啶在乙腈中进行的水解。
通过氧化浆果赤霉素III可以方便地制备13-酮基-浆果赤霉素III。可以用臭氧,或用二氧化锰在非质子溶剂如二氯甲烷、四氢呋喃、丙酮、乙酸乙酯中进行浆果赤霉素III的氧化。可以在0℃-60℃,更优选在室温下进行反应。
在以下图式中概述了本发明的方法:
以下实施例进一步阐述了本发明。
所用的缩略语如下:
AcOEt=乙酸乙酯;TES=三乙基甲硅烷基;TESCl=三乙基氯硅烷;DCM=二氯甲烷;THF=四氢呋喃。
实施例
a)13-酮基-浆果赤霉素III
将浆果赤霉素III(150g,0.25mol)溶于丙酮(1.43L)。剧烈搅拌下分三份加入市售二氧化锰(450g)。起始产物消失后(4小时),将混悬液过滤并蒸除溶剂。将粗品混悬于AcOEt(100ml)中并回流1小时,然后加入环己烷(100ml)。蒸除溶剂后,从母液中获得标题化合物,为白色固体(140g,95%)。
b)7-TES-13-酮基-浆果赤霉素III
将13-酮基-浆果赤霉素III(5g,8.5mmol)、TESCl(3.6mL,21.4mmol,2.5当量)和N-甲基咪唑(2.73mL,34.3mmol,4当量)溶于无水DCM(25ml)中。在搅拌下将溶液放置1.5小时,之后将其缓慢倒入2M NaHSO4(25ml)中终止反应。用DCM(2×10ml)洗涤、萃取水层,并用盐水(2×20ml)萃取合并的有机层。用硫酸钠干燥有机溶液,得到4.7g标题化合物,其纯度足够用于随后的步骤。M.p.:212℃。TLC:cHex-AcOEt 1∶1,Rf=0.57。1H-NMR(200MHz,CDCl3)δ0.58-0.66(m,6H,Si-CH2);0.90-0.98(t,J=8.4,9H,CH2CH3);1.21(s,3H,17-Me);1.27(s,3H,16-Me);1.69(s,3H,19-Me);1.83-1.96(m,1H,6-H);2.20(s,3H,18-Me);2.21(s,3H,10-OAc);2.25(s,3H,4-OAc);2.48-2.65(m,1H,6-H);2.81(ABq,2H,14-H);3.93(d,J=6.6,1H,3-H);4.25(ABq,2H,20-H);4.51(dd,J=10.6,7.0,1H,7-H);4.94(d,J=7.7,1H,5-H);5.72(d,J=7.0,1H,2-H);6.61(s,1H,10-H);7.52(t,J=6.2,2H,Bz);7.64(t,J=6.2,1H,Bz);8.10(dd,J=7.4,1.1,2H,Bz)。
c)14-羟基-7-TES-13-酮基-浆果赤霉素III
在N2下,将7-TES-13-酮基-浆果赤霉素III(670mg,0.96mmol)溶于无水THF(9ml)和DMPU(2ml)的混合物中,并冷却至-60℃。向其中滴加预先冷却至-50℃的1 M的t-BuOK的THF溶液(2.5ml,0.86mmol)。将该溶液在-60℃下搅拌45分钟,然后逐滴加入溶于无水THF(2ml)的(±)-樟脑磺酰基-氧氮杂环丙烷(440mg,2mmol)。将反应混合物在-60℃下搅拌3小时,之后用10%AcOH的无水THF溶液(2ml)终止反应。然后在室温下放置混合物使其变暖,之后用DCM(2×10ml)萃取。用水、NaCl饱和水溶液(15ml)洗涤合并的有机层,并用Na2SO4干燥。用快速色谱法(硅胶,cHex-AcOEt,8∶2)纯化标题化合物,产率79%。或者,不进一步纯化该化合物,在随后的步骤中直接使用。M.p.:94-98℃。TLC:cHex-AcOEt1∶1,Rf=0.5。1H-NMR(200 MHz,CDCl3)δ0.58-0.66(m,6H,Si-CH2);0.91-0.99(t,J=8.7,9H,CH2CH3);1.24(s,3H,17-Me);1.28(s,3H,16-Me);1.75(s,3H,19-Me);1.83-2.05(m,1H,6-H);2.14(s,3H,18-Me);2.24(s,3H,10-OAc);2.26(s,3H,4-OAc);2.46-2.61(m,1H,6-H);3.64(s,1H,1-OH);3.73(d,J=1.8,1H,14-OH);3.87(d,J=6.9,1H,3-H);4.14(d,J=1.8,1H,14-H);4.31(s,2H,20-H);4.49(dd,J=10.7,6.6,1H,7-H);4.93(d,J=7.3,1H,5-H);5.89(d,J=7.0,1H,2-H);6.53(s,1H,10-H);7.46-7.66(m,3H,Bz);8.08(dd,J=7.0,1.5,2H,Bz)。
d)14β-羟基-7-TES-13-酮基-浆果赤霉素III 1,14-碳酸酯
在-10℃下,将14β-羟基-7-TES-13-酮基-浆果赤霉素(12.2g)于无水DCM(50ml)和吡啶(16ml)中的溶液滴加入20%的光气的DCM溶液(45mL,5当量)中。2小时后,向反应中逐滴加入5%NaHCO3水溶液(100ml)。用DCM(3×50ml)洗涤水层,并用快速色谱法(硅胶,DCM-AcOEt=50∶1)纯化粗品,得到标题化合物,产率95%。M.p.:97-99℃。TLC:cHex-AcOEt 1∶1,Rf=0.64。1H-NMR(200 MHz,CDCl3)δ 0.58-0.66(m,6H,Si-CH2);0.91-0.99(t,J=8.7,9H,CH2CH3);1.21(s,3H,17-Me);1.39(s,3H,16-Me);1.75(s,3H,19-Me);1.86-2.13(m,1H,6-H);2.22(s,3H,18-Me);2.25(s,3H,10-OAc);2.26(s,3H,4-OAc);2.48-2.63(m,1H,6-H);3.83(d,J=7.0,1H,3-H);4.30(ABq,2H,20-H);4.49(dd,J=11.0,7.0,1H,7-H);4.81(s,1H,14-H);4.93(d,J=7.3,1H,5-H);6.15(d,J=7.0,1H,2-H);6.54(s,1H,10-H);7.51(t,2H,Bz);7.62-7.70(m,1H,Bz);8.01(dd,J=7.0,1.9,2H,Bz)。
e)14β-羟基-7-TES-浆果赤霉素III 1,14-碳酸酯
将NaBH4(0.5g)的无水乙醇(10ml)混悬液冷却至-50℃,并加入冷却的14-羟基-7-TES-13-酮基-浆果赤霉素III 1,14-β-碳酸酯(0.5g,0.6mmol)的无水乙醇(10ml)溶液。起始产物消失后(8小时),用柠檬酸终止反应,并用AcOEt萃取。用硫酸钠干燥合并的有机层,并蒸除溶剂。色谱法后获得标题化合物,为白色固体,产率85%。M.p.:134-137℃。TLC:cHex-AcOEt1∶1,Rf=0.46。1H-NMR(200MHz,CDCl3)δ0.58-0.66(m,6H,Si-CH2);0.91-0.99(t,J=8.7,9H,CH2CH3);1.16(s,3H,17-Me);1.28(s,3H,16-Me);1.74(s,3H,19-Me);1.85-2.14(m,1H,6-H);2.06(s,3H,18-Me);2.21(s,3H,10-OAc);2.33(s,3H,4-OAc);2.47-2.65(m,1H,6-H);3.74(d,J=7.4,1H,3-H);4.12-4.35(m,2H,20-H);4.49(dd,J=10.3,6.6,1H,7-H);4.82(d,1H,14-H);4.99(d,J=7.3,1H,5-H);5.00-5.03(m,1H,13-H);6.11(d,J=7.4,1H,2-H);6.45(s,1H,10-H);7.50(t,2H,Bz);7.60-7.68(m,1H,Bz);8.04(dd,J=7.0,1.5,2H,Bz)。
f)14β-羟基-浆果赤霉素III 1,14-碳酸酯
将14-羟基-7-TES-浆果赤霉素III 1,14-β-碳酸酯(9.6g,1.3mmol)溶于冷却至0℃的乙腈(5.4ml)和吡啶(6.4ml)的混合物中。在15分钟内滴加入70%的HF的吡啶溶液(0.95ml),并将溶液在室温下搅拌过夜。然后将反应混合物倒入20mL冰中,并在搅拌下放置1小时,然后用DCM(3×10ml)萃取,并用10%NaHSO4(至pH=2)、5%NaHCO3(2×10ml)和盐水(2×10ml)洗涤合并的有机层。蒸除溶剂后,获得标题化合物,为白色固体,产率96%。
Claims (10)
2.权利要求1的方法,其中通过在从-40至-78℃的温度下,于氧氮杂环丙烷衍生物存在下,在与六甲基磷酰胺(HMPA)或1,3-二甲基-3,4,5,6-四氢-2(1H)嘧啶酮(DMPU)混合的醚中,用叔丁醇钾或二(三甲基甲硅烷基)氨基钾处理进行步骤a)。
3.权利要求2的方法,其中氧氮杂环丙烷衍生物选自N-苯磺酰基苯基氧氮杂环丙烷、N-苯磺酰基间硝基苯基氧氮杂环丙烷和樟脑磺酰基氧氮杂环丙烷。
4.权利要求1至3中任一项的方法,其中通过在从-40℃至室温范围内的温度下,于碱存在下,在氯化溶剂中,用羰基二咪唑或光气处理进行步骤b)。
5.权利要求1至4中任一项的方法,其中通过在从-20至-50℃的温度下用氢化物处理进行步骤c)。
6.权利要求5的方法,其中氢化物选自硼氢化钠、硼氢化锂、三乙酰氧基硼氢化钠,且在乙醇、甲醇、异丙醇,或在甲醇和四氢呋喃混合物中进行反应。
7.权利要求1至6中任一项的方法,其中通过10位羟基的选择性乙酰化,然后是13位羟基的氧化和7位羟基的保护制备7位羟基保护的13-酮基-浆果赤霉素III。
8.权利要求7的方法,其中通过用乙酐在10位对去乙酰浆果赤霉素III选择性乙酰化,然后于0℃-60℃下在非质子溶剂中用二氧化锰氧化获得13-酮基-浆果赤霉素III。
9.作为新的中间体的下式化合物7-三乙基甲硅烷基-13-酮基-14-羟基-浆果赤霉素III:
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IT2001MI002186A ITMI20012186A1 (it) | 2001-10-19 | 2001-10-19 | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
ITMI2001A002186 | 2001-10-19 |
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CA (1) | CA2463915C (zh) |
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HK (1) | HK1069170A1 (zh) |
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CN103450118A (zh) * | 2013-09-18 | 2013-12-18 | 江苏红豆杉药业有限公司 | 一种半合成法制备紫杉醇的方法 |
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ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20021921A1 (it) * | 2002-09-10 | 2004-03-11 | Indena Spa | Funzionalizzazione della posizione 14 dei nuclei tassanici e sintesi di nuovi derivati antitumorali. |
DK2080764T3 (da) | 2008-01-18 | 2012-09-24 | Indena Spa | Faste former af ortataxel |
Family Cites Families (10)
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IT1254517B (it) | 1992-03-06 | 1995-09-25 | Indena Spa | 14-beta idrossi-10-deacetil-baccatina iii, suoi derivati, loro prepazione ed impiego terapeutico |
US5475011A (en) * | 1993-03-26 | 1995-12-12 | The Research Foundation Of State University Of New York | Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment |
IT1275936B1 (it) * | 1995-03-17 | 1997-10-24 | Indena Spa | Derivati della 10-deacetilbaccatina iii e della 10-deacetil-14b- idrossibaccatina iii loro metodo di preparazione e formulazioni |
FR2732341A1 (fr) * | 1995-03-27 | 1996-10-04 | Rhone Poulenc Rorer Sa | Nouveaux taxoides, leur preparation et les compositions pharmaceutiques qui les contiennent |
IT1275435B (it) * | 1995-05-19 | 1997-08-07 | Indena Spa | Derivati della 10-desacetil-14beta-idrossibaccatina iii,loro metodo di preparazione e formulazioni che li contengono |
IT1283633B1 (it) * | 1996-05-10 | 1998-04-23 | Indena Spa | Derivati tassanici loro sintesi e formulazioni che li contengono |
US5811452A (en) * | 1997-01-08 | 1998-09-22 | The Research Foundation Of State University Of New York | Taxoid reversal agents for drug-resistance in cancer chemotherapy and pharmaceutical compositions thereof |
IT1318678B1 (it) * | 2000-08-10 | 2003-08-27 | Indena Spa | Procedimento per la preparazione di derivati della baccatina iii. |
IT1320107B1 (it) * | 2000-11-28 | 2003-11-18 | Indena Spa | Procedimento per la preparazione di derivati tassanici. |
ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN103450118A (zh) * | 2013-09-18 | 2013-12-18 | 江苏红豆杉药业有限公司 | 一种半合成法制备紫杉醇的方法 |
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KR20040045023A (ko) | 2004-05-31 |
JP4454310B2 (ja) | 2010-04-21 |
NO20041537L (no) | 2004-04-15 |
BR0213360A (pt) | 2004-10-26 |
ES2376162T3 (es) | 2012-03-09 |
IL161443A0 (en) | 2004-09-27 |
BR0213360B1 (pt) | 2014-04-15 |
CA2463915A1 (en) | 2003-05-01 |
WO2003035633A1 (en) | 2003-05-01 |
EP1436277B1 (en) | 2011-12-14 |
ATE537160T1 (de) | 2011-12-15 |
US7078432B2 (en) | 2006-07-18 |
CA2463915C (en) | 2009-11-24 |
KR100896542B1 (ko) | 2009-05-07 |
MXPA04003519A (es) | 2004-07-23 |
EP1436277A1 (en) | 2004-07-14 |
DK1436277T3 (da) | 2012-01-23 |
CN1271061C (zh) | 2006-08-23 |
PL368122A1 (en) | 2005-03-21 |
RU2291866C2 (ru) | 2007-01-20 |
HUP0401989A2 (hu) | 2005-01-28 |
HK1069170A1 (en) | 2005-05-13 |
HUP0401989A3 (en) | 2007-05-29 |
US20040266859A1 (en) | 2004-12-30 |
AU2002328918B2 (en) | 2008-09-04 |
ITMI20012186A1 (it) | 2003-04-19 |
RU2004111669A (ru) | 2005-04-20 |
JP2005512977A (ja) | 2005-05-12 |
NO328562B1 (no) | 2010-03-22 |
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