CN107011399B - β构型地西他滨前体的制备方法 - Google Patents
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Abstract
本发明提供了β构型地西他滨前体的制备方法，包括，在路易斯酸催化剂作用下，将结构为1‑烯基甲氧基‑2‑脱氧‑3，5‑二‑O‑乙酰基‑D‑呋喃核糖的酰化糖，与5‑氮杂胞嘧啶的硅醚化物直接进行偶合反应，得到β构型的1‑(2‑脱氧‑3，5‑二‑O‑乙酰基‑D‑核糖)‑4‑氨基‑1，3，5‑均三嗪‑2‑酮。本发明选择性高，重复性好，产物的摩尔收率和纯度均很高。
Description
技术领域
本发明涉及一种地西他滨前体的制备方法。
背景技术
地西他滨的制备工艺在很多文献中公开，大致分成异氰酸酯法、阿扎胞苷脱氧法、糖苷化法三类，其中糖苷化法的特点是将嘧啶部分与核糖部分进行偶合，偶合反应得到的产物为羟基保护的地西他滨(本申请称为地西他滨前体)，最后经脱保护(通常为水解)得到地西他滨。众所周知，地西他滨是一个β型异构体，但在制备时通常得到的是α、β的混旋体,显然，产物中β型的地西他滨的含量比例及其纯化繁简程度均直接受水解前地西他滨前体中β型的比例的影响。
在偶合前，需将核糖进行一系列处理，包括先将核糖醚化，再对糖的羟基进行保护，比如使用酰基保护得到本申请所称的酰化糖，然后，糖C1位的取代基通常必须转成卤素或酰基后才能进行偶合反应。
本领域人将C1位基团转换正是为了保证地西他滨前体中β型的比例，在数以百计的文献中，仅有几篇公开了不转换即进行偶合，其效果均不稳定且β∶α型的比例通常小于1。比如，CN101821278公开了使用了酰化糖，如1-甲氧基-2-脱氧-3，5-二-O-芴甲氧羰酰基-D-呋喃型核糖或对应使用对甲基苯甲酰基进行保护的酰化糖，直接进行偶合，所得到的产物均是α∶β＞3∶2。同样使用该法的US20120046457，产物中β型约占一半且不稳定，实施例5中β型仅占47.37％。上海清松制药有限公司的CN101560233仅在1个实施例后的色谱实验(说明书上标第6页)中α型占39.7％，披露β型占59.7％，但此比例与本发明人重复该偶合反应的直接产物中β∶α的比例迥异(操作及结果见本申请的对比例)，经分析，该专利色谱实验所用样品并非其偶合反应直接所得的产物，其样品纯度大于99％，而该实施例的偶合反应是直接延续硅烷化反应后的体系进行，硅烷化反应中六甲基二硅胺烷远远过量，偶合反应原料亦不可能被100％耗掉，偶合反应后用碱脱掉产物上的硅保护基亦将产生杂质。CN101560233偶合反应的原料与US20120046457完全相同，条件亦基本相同，该实施例仅通过简单的分液，而非前述CN101821278、US20120046457的复杂后处理过程，显然不可能得到纯度大于99％的产物，产物中β∶α亦不可与前述专利迥异，事实上，WO2008101448、论文《地西他滨α型异构体的制备》(2012年)均明确将该法直接用于制备α型前体，WO2008101448说明书第5页第8行更是指出该法形成α型是有“非常高”的选择性的，CN101560233通篇均未提及β∶α的问题，也不可能在偶合反应直接得到高β比例的产物。
上述直接偶合的文献，均采用C1位为甲氧基的酰化糖进行，CN106046089亦明确指出其α型杂质比例过高，CN106046089采用卤糖进行偶合，选择性好，使工艺产率高达89％。采用卤糖的CN101570559，β前体含量大于50％，采用卤糖的US20100249394中，β∶α可达2.5，
总之，直接使用甲氧基直接偶合的现有技术均教导不利于富集β型产物，多数文献均是将C1位基团进行转换，通常转为卤素或酰基再进行偶合。
发明内容
本发明克服了现有技术的偏见，提供一种新的制备地西他滨前体的方法，产物中β构型比例非常高。
本发明的地西他滨前体的制备方法，包括在路易斯酸催化剂的作用下，将结构为1-烯基甲氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖的酰化糖，与5-氮杂胞嘧啶的硅醚化物偶合，得到β构型富集的偶合产物1-(2-脱氧-3，5-二-O-乙酰基-D-核糖)-4-氨基-1，3，5-均三嗪-2-酮，该偶合产物即地西他滨前体。反应完成后，可通过常规方法淬灭反应，通过重结晶法纯化产物，重结晶溶剂可为甲苯。
任选地，所述偶合反应的溶剂为水溶性非质子溶剂，如乙腈。
任选地，所述偶合反应的温度为-5℃～5℃，如0℃。
任选地，所述酰化糖结构中的所述烯基为乙烯基或丙烯基，即用乙烯基C＝C-或丙烯基C-C＝C-进一步取代C1位甲氧基上的甲基，也可命为1-烯丙基氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖(酰化糖结构中的所述烯基为乙烯基)、1-(2-丁烯基)氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖(酰化糖结构中的所述烯基为丙烯基)。酰化糖可通过本领域常规方法将1位羟基被醚化的2-脱氧-D-呋喃核糖与羟基保护剂反应制得。
任选地，所述硅醚化物为2，4-二-(三甲基硅)-5-氮杂胞嘧啶，所述酰化糖与该硅醚化物的摩尔比为1:1.2-1.8，如为1:1.5。
任选地，所述催化剂为三氟甲磺酸。
任选地，所述催化剂与式I原料的摩尔比为0.2:1。
本发明的有益效果是：
本发明克服了现有技术的偏见，意外发现偶合反应前无需将C1位的甲氧基转化为其他基团，仅需用烯基进一步取代其甲基，偶合产物中β构型：α构型比值即稳定在2.5以上，相比现有技术中本类反应β∶α小于1来说，这是非常惊人的，本发明还优化了原料、配比条件，进一步提高了反应的选择性等；本发明步骤少，后处理简单，重复性好，产物的摩尔收率稳定在85％以上，纯度亦稳定在90％以上，非常利于后续制备地西他滨。
具体实施方式
实施例1：
60mmol的2，4-二-(三甲基硅)-5-氮杂胞嘧啶与50mmol的1-(2-丁烯基)氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖溶于500mL乙腈，控温至0℃，加入10mmol的三氟甲磺酸，继续保持0℃，搅拌反应2小时，HPLC监测反应完成。用500mL饱和碳酸氢钠水溶液快速淬灭反应及洗涤反应混合液，分离出有机层，在真空下将其蒸发至干燥，然后用甲苯重结晶，获得固体14.75g，经鉴定为1-(2-脱氧-3，5-二-O-乙酰基-D-核糖)-4-氨基-1，3，5-均三嗪-2-酮，HPLC检测其纯度为90％，其中β构型与α构型的含量比为2.5。
1H-NMR(DMSO-d6)δ：2.0(s,6H),2.2-3.0(m,2H),4.1(m,1H)，4.3(m,1H),4.8(m,1H),5.2(m,1H),6.1(m,1H),7.5(s,1H)，7.6(s,1H),8.4(s,1H)
实施例2-4：
用1-烯丙基氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖直接进行偶合反应，各条件参照实施例胞嘧啶原料1，2，4-二-(三甲基硅)-5-氮杂胞嘧啶用量不同，结果汇总如下：
对比例：
CN101560233实施例5亦未将C1位的甲氧基转为其他基团，而直接进行偶合反应，其催化剂与本申请最接近，下面完全重复该实施例，并对应检测分析其产物。
反应操作原文引述如下：
1000ml三颈瓶中加入5-氮杂胞嘧啶(50.7g，452.1mmol)，六甲基二硅胺烷(500ml，2.4mol)，硫酸铵(2g)，氮气下加热回流至澄清，减压蒸掉溶剂，溶于二氯甲烷(250ml)中，冷至5℃，滴加三甲基硅三氟甲磺酸酯(TMSOTf)(140ml，770mmol)。然后滴加式III(100g，430.6mmol)的二氯甲烷(500ml)溶液，室温搅拌过夜。滴加饱和碳酸氢钠溶液洗至中性，抽滤，滤液用饱和碳酸氢钠溶液(500ml)洗涤，分液，有机相用无水硫酸钠干燥，过滤蒸干溶剂得到式V。
注：根据专利说明书，式V指3′，5′-二乙酰氧基-5-氮杂-2′-脱氧胞苷，完全同本申请的地西他滨前体；式III指1-甲基-3，5-二乙酰氧基-2-脱氧-D-核糖，对应于本申请的酰化糖。
经测量，反应得到的地西他滨前体共90g，其纯度为75％，其中β：α＝0.9，计算得摩尔收率为50％，显然，其选择性、收率均远低于本发明。
Claims (6)
1.β构型地西他滨前体的制备方法，其特征是，在路易斯酸催化剂作用下，将1-烯基甲氧基-2-脱氧-3，5-二-O-乙酰基-D-呋喃核糖，与5-氮杂胞嘧啶的硅醚化物直接进行偶合反应，得到β构型的1-(2-脱氧-3，5-二-O-乙酰基-D-核糖)-4-氨基-1，3，5-均三嗪-2-酮；所述烯基为乙烯基或丙烯基。
2.根据权利要求1所述的制备方法，其特征是，所述偶合反应的溶剂为水溶性非质子溶剂。
3.根据权利要求1所述的制备方法，其特征是，所述偶合反应的温度为-5℃～5℃。
4.根据权利要求1所述的制备方法，其特征是，所述偶合反应的温度为0℃。
5.根据权利要求1所述的制备方法，其特征是，所述硅醚化物为2，4-二-(三甲基硅)-5-氮杂胞嘧啶。
6.根据权利要求1所述的制备方法，其特征是，所述催化剂为三氟甲磺酸。
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