CN1688563A - 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 559019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-Boc-13-酮基浆果赤霉素III,
生成7-Boc-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-Boc-13-酮基-浆果赤霉素III-1,14-碳酸酯:
c.将13位的酮还原然后将7位的保护基裂解,反之亦然。
用适宜的保护基,优选叔丁氧基羰基(Boc),在7位方便地保护起始的13-酮基浆果赤霉素III。通过用适宜的碱,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,用硼氢化四丁基铵容易地完成步骤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。在本技术的已知条件下,也可以用其它氢化物实现还原,优选硼氢化锂、硼氢化钠、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位的保护基为叔丁氧基羰基,用甲酸可以成功地进行水解。
按照以下两种方法之一,可以快捷地制备起始的13-酮基浆果赤霉素III。
用臭氧在13位选择性地氧化10-去乙酰-浆果赤霉素III生成13-酮基-10-去乙酰浆果赤霉素III。可以在从-78℃至室温范围内的温度下,于醇或氯化溶剂,特别是甲醇或二氯甲烷中进行氧化。然后,将13-酮基-10-去乙酰-浆果赤霉素III进行区域选择性乙酰化,生成13-酮基-浆果赤霉素III。
或者,可以通过氧化浆果赤霉素III获得13-酮基-浆果赤霉素III,浆果赤霉素III可以是天然的或经区域选择性乙酰化10-去乙酰浆果赤霉素III获得的。氧化可以用臭氧,或者用二氧化锰在非质子溶剂如二氯甲烷中、在从0℃至60℃范围内的温度下、更优选在室温下进行。
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,HMPA=六甲基磷酰胺,DMPU=1,3-二甲基-3,4,5,6-四氢-2(1H)嘧啶酮。
实施例1
10-去乙酰-13-酮基-浆果赤霉素III
将10-去乙酰-浆果赤霉素III(3g,5mmol)溶于DCM-MeOH 1∶1(250ml)中并冷却至-78℃。向溶液中通入臭氧气流直至起始原料消失(2小时)。用氮气代替臭氧气流。然后用二甲基硫醚(1ml)和吡啶(1ml)处理溶液,蒸除溶剂,将粗品溶于EtOAc(100ml)并用0.1N HCl和冰洗涤。蒸除溶剂后,获得标题产物,产率90%。
实施例2
13-酮基-浆果赤霉素III
将浆果赤霉素III(150g,0.25mol)溶于丙酮(1.43升)。剧烈搅拌下分三份加入市售可得的二氧化锰(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EtOAc(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%)。
实施例3
7-Boc-13-酮基-浆果赤霉素III
在室温下,将13-酮基-浆果赤霉素III(1.1g,1.9mmol)的二氯甲烷(0.5ml)溶液溶于四氯化碳(14ml)。然后在剧烈搅拌下加入1-甲基咪唑(35ml,0.282mmol)和Boc2O(1.026g,4.7mmol)。搅拌下,将溶液于20℃放置18小时。之后,用丙酮(5ml)替换溶剂,将溶液倒入水(5ml)中并搅拌过夜。用布氏漏斗收集沉淀物,用正戊烷洗涤并干燥,得到1.1g标题产物(1.78mmol,94%)。
实施例4
14-羟基-7-Boc-13-酮基浆果赤霉素III
在-60℃、搅拌下,将7-Boc-13-酮基-浆果赤霉素III(0.65g,0.95mmol)的THF-DMPU 8∶2(10ml)溶液加入t-BuOK(0.425g,3.79mmol)的无水THF(10ml)溶液中。15分钟后,加入樟脑磺酰基氧氮杂环丙烷(2.63mmol)的THF-DMPU 8∶2(10ml)溶液。起始原料消失后(45分钟),用冰醋酸(0.4ml)终止反应并用10%的NH4Cl水溶液(25ml)稀释混合物。将有机层用水洗涤,用硫酸钠干燥并在减压下蒸发。产物不经纯化直接用于用于随后的步骤。
实施例5
14β-羟基-7-Boc-13-酮基浆果赤霉素III 1,14-碳酸酯
将14-羟基-7-Boc-13-酮基浆果赤霉素III(2.0g)和羰基二咪唑(0.65g,4.0mmol)溶于甲苯(11ml)并在搅拌下于75℃加热90分钟。将溶液冷却至室温并用0.2N HCl(5ml)处理。将有机层用EtOAc(15ml)稀释、用水洗涤、干燥,蒸除溶剂。通过快速色谱法(硅胶,cHex/DCM/Et2O,14∶3.5∶2.5)获得标题化合物,为白色固体(0.87g,1.20mmol,两步的产率82%)。
实施例6
14β-羟基-7-Boc-浆果赤霉素III 1,14-碳酸酯
在惰性气氛下,于-50℃将14β-羟基-7-Boc-13-酮基浆果赤霉素III 1,14-碳酸酯的THF溶液(3ml)加入硼氢化四丁基铵(1.29g)的干燥甲醇(11ml)溶液中。4小时后,用柠檬酸(1.5g)的水(5ml)溶液终止反应。用乙酸乙酯萃取混合物。有机相用硫酸镁干燥并在减压下蒸发。用柱色谱法纯化粗品,得到14β-羟基-7-Boc-浆果赤霉素III 1,14-碳酸酯(68%)和13-表-14β-羟基-7-Boc-浆果赤霉素III 1,14-碳酸酯(28%),转化产率70%。
实施例7
14β-羟基-浆果赤霉素III 1,14-碳酸酯
在-8℃下,将97%的甲酸溶液(5ml)加入14β-羟基-7-Boc-浆果赤霉素III 1,14-碳酸酯(0.50g,0.68mol)的二氯甲烷(3ml)溶液中。搅拌下保持反应5天,之后用2N氨中和。用乙酸乙酯萃取有机相,干燥并在减压下蒸发。经硅胶色谱法(己烷-乙酸乙酯=1.0∶1.3)得到产物,为白色固体,产率65%。
Claims (11)
2.权利要求1所述的方法,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所述的方法,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中任一项所述的方法,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中任一项所述的方法,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所述的方法,其中氢化物选自硼氢化四丁基铵、硼氢化四乙基铵、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中任一项所述的方法,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所述的方法,其中通过用乙酐在10位选择性乙酰化去乙酰浆果赤霉素III,然后于0℃-60℃下用二氧化锰在非质子溶剂中氧化,或通过用臭氧氧化浆果赤霉素III获得13-酮基-浆果赤霉素III。
9.作为新的中间体的下式的化合物7-Boc-13-酮基-14-羟基-浆果赤霉素III:
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IT2001MI002185A ITMI20012185A1 (it) | 2001-10-19 | 2001-10-19 | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
ITMI2001A002185 | 2001-10-19 |
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CN1688563A true CN1688563A (zh) | 2005-10-26 |
CN100338049C CN100338049C (zh) | 2007-09-19 |
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US (1) | US7317113B2 (zh) |
EP (1) | EP1436278B1 (zh) |
JP (2) | JP4467976B2 (zh) |
KR (1) | KR100896543B1 (zh) |
CN (1) | CN100338049C (zh) |
AT (1) | ATE466847T1 (zh) |
AU (1) | AU2002363080B2 (zh) |
BR (1) | BR0213329A (zh) |
CA (1) | CA2464336C (zh) |
DE (1) | DE60236303D1 (zh) |
DK (1) | DK1436278T3 (zh) |
ES (1) | ES2341611T3 (zh) |
HK (1) | HK1080475A1 (zh) |
HU (1) | HU229256B1 (zh) |
IL (4) | IL161444A0 (zh) |
IT (1) | ITMI20012185A1 (zh) |
MX (1) | MXPA04003517A (zh) |
NO (1) | NO328534B1 (zh) |
PL (1) | PL207878B1 (zh) |
PT (1) | PT1436278E (zh) |
RU (1) | RU2285000C2 (zh) |
SI (1) | SI1436278T1 (zh) |
WO (1) | WO2003035634A1 (zh) |
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ITMI20012186A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
ITMI20012185A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14beta-idrossi-baccatina iii-1,14-carbonato |
EP1547239A1 (en) * | 2002-09-16 | 2005-06-29 | Nokia Corporation | Direct conversion receiver and receiving method |
EP2080764B1 (en) | 2008-01-18 | 2012-08-22 | INDENA S.p.A. | Solid forms of ortataxel |
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JPH0620877A (ja) * | 1992-03-02 | 1994-01-28 | Du Pont Japan Ltd | タンタル固体電解コンデンサ |
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 |
US5917062A (en) * | 1997-11-21 | 1999-06-29 | Indena S.P.A | Intermediates and methods useful in the semisynthesis of paclitaxel and analogs |
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. |
IT1319682B1 (it) * | 2000-12-06 | 2003-10-23 | Indena Spa | Procedimento di sintesi del paclitaxel. |
ITMI20012186A1 (it) * | 2001-10-19 | 2003-04-19 | Indena Spa | Procedimento per la preparazione della 14-beta-idrossi-baccatina iii-1,14-carbonato |
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. |
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