CN100545155C - 紫杉醇和多烯紫杉醇侧链及其衍生物的合成方法 - Google Patents
紫杉醇和多烯紫杉醇侧链及其衍生物的合成方法 Download PDFInfo
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- C07C233/87—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明公开了一种紫杉醇和多烯紫杉醇新式侧链及其衍生物的合成方法，该合成方法是以取代的R-苯乙胺拆分环氧酸，然后经酯化羧基，氨解，盐酸水解等反应得到紫杉醇新式侧链及衍生物。
Description
技术领域
本发明涉及医药合成领域，具体地说涉及一种紫杉醇和多烯紫杉醇新式侧链及其衍生物的合成方法。
背景技术
紫杉醇是从红豆杉属植物中提取出来的。由于其含量很低且所提取的植物属于国家保护植物，从植物中提取紫杉醇已无法进行。多烯紫杉醇(docetaxel)是在紫杉醇(paclitael)的基础上进行结构改造而得到的，具有广谱的抗白血病和抗实体肿瘤活性，其抗癌活性是紫杉醇的1.3-12倍。紫杉醇和多烯紫杉醇都被认为是迄今疗效最显著的抗癌药物。紫杉醇和多烯紫杉醇结构复杂，全合成路线长，产率低。而其半合成则相对容易的多。开展紫杉醇和多烯紫杉醇的化学半合成方法，不仅有利于保护稀缺的植物资源，而且对扩大其在临床的运用，降低治疗成本都有重大意义和巨大的经济效益。
现有的紫杉醇和多烯紫杉醇的半合成文献和专利都主要采用10-脱乙酰巴卡亭III和C13侧链为原料。其中C13位的侧链无论是消旋的还是手性的均采用和紫杉醇、多烯紫杉醇相同的syn结构。syn结构的侧链由于其结构特殊：羟基和胺基处于syn位置，合成尤其是手性合成很困难，因而价格十分昂贵。
发明内容
本发明所要解决的技术问题在于提供一种紫杉醇和多烯紫杉醇新式手性侧链及其衍生物的合成方法，以解决现有技术的缺陷。
本发明所提供的合成结构式(I)的紫杉醇和多烯紫杉醇新式侧链及其衍生物的方法的具体步骤依次为：
①以结构式(II)的取代的R-苯乙胺拆分环氧酸：拆分的溶剂为乙酸乙酯、二氯甲烷、乙醚、四氢呋喃、氯仿、甲醇、乙醇或丙酮；
②酯化羧基：其中酯化反应的试剂为DCC(二环己基羰二酰亚胺)、硫酸二甲酯、氯化亚砜或卤代烷烃；反应得到的酯是1-6个碳的烷基或苄基；酯化反应的温度为-30℃-90℃；
③氨解或氢化：氨解反应是在氨水或氨的醇溶液中进行，反应温度为-20℃-100℃；氢化是常压氢化；
④盐酸水解；
⑤分别保护氨基，羟基和羧基；
其中结构式(I)为：
其中：R1为H、TBS(叔丁基二甲基硅)、TES(三乙基硅)、EE(乙氧基乙基)、THP(四氢吡喃基)、Troc(三氯乙基氧羰基)、MOM(甲氧甲基)、Ac(乙酰基)或PhCO(苯甲酰基)；
R2为氢；
R3为苯基或叔丁氧基；
R4为氢、1-5个碳的烷基、苄基、琥珀酰亚胺基或其它用于酯化的基团。
其中结构式(II)为：
其中：X为氢、1-5个碳的烷基、卤素、羟基、烷氧基、硝基或保护的胺基。
具体的反应式如下：
其余未说明之处为本领域技术人员根据该说明书可以实现的。
本发明在于提供了紫杉醇和多烯紫杉醇新式手性侧链及其衍生物的合成方法，应用简单的反应和价格低廉的原料，为紫杉醇和多烯紫杉醇的合成提供了廉价的手性侧链，使紫杉醇和多烯紫杉醇的半合成成本大大降低，有利于这两种抗癌药物的工业化生产，使其可以为更多的患者使用。
以下的实施例只是用于说明本发明，而非限制本发明。
实施例1
步骤一：
将trans环氧苯丙酸164克溶于1000毫升乙酸乙酯中，慢慢滴加R-苯乙胺121克，加毕慢慢加热回流2小时，然后慢慢冷至0度，有大量白色固体析出，抽滤，丙酮洗涤，干燥后得到白色固体128克。将该固体溶于1000毫升冰水中，小心滴加6N盐酸100毫升，有固体析出，用乙酸乙酯萃取，干燥后旋去溶剂，得到白色固体65克。得率：79.3％。
步骤二：
将步骤一得到的产物65克溶于无水二氯甲烷500毫升中，然后加入二氯亚砜60克。加热回流至无氯化氢气体放出，冷却至-30度，加入无水甲醇50毫升，滴加三乙胺120毫升，搅拌过夜，用水洗涤，有机相无水硫酸钠干燥，旋去溶剂后减压蒸馏，得到无色液体65克，得率：92.1％。
1H NMR(500MHz，CDCl3)δ：7.16-7.50(m，5H)，4.10(d，J＝1.7Hz，1H)，3.80(s ，3H)，3.50(d，J＝1.7Hz，1H).
步骤三：
将步骤二得到的无色液体溶于1000毫升无水甲醇中，冰水浴冷却下通入干燥的氨气至饱和，搅拌3天后旋去甲醇，得到白色固体40克。得率：79.1％。该粗产品可以直接用于下一步反应。
步骤四：
将步骤三得到的产物40克溶于500毫升6N的盐酸中，加热回流至原料消失，冷却后乙酸乙酯萃取，水相蒸干，用无水甲醇溶解，蒸去甲醇，得到白色固体48克。得率：100％。
1H NMR(500MHz，DMSO)δ：8.68(brs，2H)，7.50-7.54(m，2H)，7.34-7.40(m，3H)，4.70(d，J＝3.5Hz，1H)，4.54(d，J＝3.5Hz，1H).
步骤五：
将步骤四得到的产物40克溶于500毫升无水甲醇中，降温到0度，滴加二氯亚砜30毫升，加毕室温反应过夜，旋去溶剂，剩余物溶于1升二氯甲烷中，加水100毫升，搅拌下加入100克NaHCO3和苯甲酰氯31克，搅拌过夜，常规后处理得到白色固体50克。得率：90.7％。
1H NMR(500MHz，CDCl3)δ：7.75-7.85(m，2H)，7.37-7.56(m，3H)，7.25-7.36(m，5H)，5.61(dd，J＝8.5，3.8Hz，1H)，4.70(dd，J＝6.5，3.8Hz，1H)，3.71(s，3H).
步骤六：
将步骤五得到的产物40克悬浮于干燥的甲苯中，加入对茴香醛甲缩醛40毫升和5克PPTS，加热回流至原料反应完全，常规后处理得到白色固体50克，将得到的固体溶于1000毫升甲醇中，滴加200毫升2N的氢氧化锂溶液，反应完全后旋去甲醇，加入500毫升去离子水，用2N盐酸调pH至4-5，有固体析出，抽滤，干燥得白色固体40克，得率71.7％。
实施例2
步骤一：
将trans环氧苯丙酸164克溶于1000毫升乙酸乙酯中，慢慢滴加R-苯乙胺121克，加毕慢慢加热回流2小时，然后慢慢冷至0度，有大量白色固体析出，抽滤，丙酮洗涤，干燥后得到白色固体128克。将该固体悬浮于1000毫升无水乙醇中，滴加34克KOH溶于500毫升无水乙醇的溶液，加毕搅拌1小时后抽滤，固体用无水乙醇洗涤，干燥得到白色固体90克，得率：86.1％。
步骤二：
将步骤一得到的白色固体90克(R＝K+)悬浮于500毫升二氯甲烷中，加入硫酸二甲酯和催化剂，室温搅拌至原料消失，加入饱和NaHCO3溶液搅拌半小时，常规后处理，得到无色液体70克，得率：91.3％。
实施例3
步骤一：
将实施例2步骤二得到的无色液体70克溶于200毫升丙酮和50毫升水中，加入叠氮化钠50克和氯化铵25克，加热回流过夜，除去丙酮，剩余物用乙酸乙酯萃取，干燥后除去溶剂，得到淡黄色液体65克。得率：74.8％。
步骤二：
将步骤一得到的淡黄色液体65克溶于500毫升甲醇中，加入5％的Pd/C10克，常压氢化完全后抽滤，除去甲醇后加入6N盐酸加热回流2小时，除去溶剂，得到白色固体60克。得率：93.8％。
实施例4
步骤一：
将实施例3步骤二得到的产物40克溶于500毫升无水甲醇中，降温到0度，滴加二氯亚砜30毫升，加毕室温反应过夜，旋去溶剂，剩余物溶于1升二氯甲烷中，搅拌下加入100克NaHCO3和50克Boc酸酐，搅拌过夜，常规后处理得到白色固体50克。得率：91.9％。
步骤二：
将步骤一得到的产物40克悬浮于干燥的甲苯中，加入对茴香醛甲缩醛40毫升和5克PPTS，加热回流至原料反应完全，常规后处理得到白色固体50克，将得到的固体溶于1000毫升甲醇中，滴加200毫升2N的氢氧化锂溶液，反应完全后旋去甲醇，加入500毫升去离子水，用2N盐酸调pH至4-5，有固体析出，抽滤，干燥得白色固体42克，得率75.0％。
步骤三
将步骤二得到的产物40克溶于500毫升二氯甲烷中，加入N-羟基琥珀酰亚胺13.5克、2克DMAP和30克DCC，室温搅拌至原料消失，加入去离子水，搅拌30分钟，常规后处理得到白色固体45克，得率：91.2％。
Claims (1)
1.一种合成结构式(I)的紫杉醇和多烯紫杉醇侧链的方法，其特征在于该方法的具体步骤依次为：
①以结构式(II)的取代的R-苯乙胺拆分环氧酸：拆分的溶剂为乙酸乙酯、二氯甲烷、乙醚、四氢呋喃、氯仿、甲醇、乙醇或丙酮；
②酯化羧基：其中酯化反应的试剂为二环己基羰二酰亚胺、硫酸二甲酯、氯化亚砜或卤代烷烃；反应得到的酯是1-6个碳的烷基酯或苄基酯；酯化反应的温度为-30℃-90℃；
③氨解：氨解反应是在氨水或氨的醇溶液中进行，反应温度为-20℃-100℃；
④盐酸水解；
⑤分别保护氨基、羟基和羧基；
其中结构式(I)为：
其中：R1为H、叔丁基二甲基硅、三乙基硅、乙氧基乙基、四氢吡喃基、三氯乙基氧羰基、甲氧甲基、乙酰基或苯甲酰基；
R2为氢；
R3为苯基或叔丁氧基；
R4为氢、1-5个碳的烷基、苄基或琥珀酰亚胺基；
其中结构式(II)为：
其中：X为氢、1-5个碳的烷基、卤素、羟基或硝基。
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| CNB2007100364898A CN100545155C (zh) | 2007-01-16 | 2007-01-16 | 紫杉醇和多烯紫杉醇侧链及其衍生物的合成方法 |
| PCT/CN2007/000316 WO2008086661A1 (fr) | 2007-01-16 | 2007-01-29 | Procédé de synthétisation de chaîne latérale atypique de taxol ou de docétaxel et ses dérivés |
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| CN112574134A (zh) * | 2020-12-30 | 2021-03-30 | 重庆市碚圣医药科技股份有限公司 | 一种多西紫杉醇侧链的合成方法 |
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Non-Patent Citations (8)
| Title |
|---|
| (2S,3S)和(2R,3R)紫杉醇侧链异构体的合成. 余广鳌等.华中理工大学学报，第27卷第12期. 1999 |
| (2S,3S)和(2R,3R)紫杉醇侧链异构体的合成. 余广鳌等.华中理工大学学报，第27卷第12期. 1999 * |
| 立体选择性合成紫杉醇C-13侧链. 周忠强等.现代化工，第25卷第1期. 2005 |
| 立体选择性合成紫杉醇C-13侧链. 周忠强等.现代化工，第25卷第1期. 2005 * |
| 紫杉醇C13边链的合成. 赵亚婷等.中国药科大学学报，第37卷第3期. 2006 |
| 紫杉醇C13边链的合成. 赵亚婷等.中国药科大学学报，第37卷第3期. 2006 * |
| 苏型-N-苯甲酰基-3-苯基异丝氨酸甲酯的合成. 周忠强等.应用化学，第18卷第4期. 2001 |
| 苏型-N-苯甲酰基-3-苯基异丝氨酸甲酯的合成. 周忠强等.应用化学，第18卷第4期. 2001 * |
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| WO2008086661A1 (fr) | 2008-07-24 |
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