CN1067681C - (s)-(+)-n,n-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺的制备方法 - Google Patents
(s)-(+)-n,n-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺的制备方法 Download PDFInfo
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Abstract
本发明提供了一种合成(S)-(+)-N,N-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺的立体专一性方法。所述化合物是制备度洛西丁的关键中间体。
Description
本发明涉及药物化学和合成有机化学领域,并提供了一种制备度洛西丁(duloxetine),即(+)-N-甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺盐酸盐的关键中间体的不对称合成方法。
度洛西丁是一种现在正在开发的抗抑郁症药物。它抑制去甲肾上腺素和血清素两者的摄入,并且目前正在进行临床评估。这种化合物被Robertson等人公开在美国专利5,023,269和4,956,388中,而其合成由Deeter等人在Tetrahedron hetters,31(49),7101~04(1990)中进行了更详细的讨论。制备度洛西丁的方法概述如下:
上述D步骤的产物,当其以盐酸盐的形式存在时,即是度洛西丁。
本发明提供了上述反应式中进行C步骤的改进条件,使步骤C的产物比以前以更好的纯度和产率更快地获得。
本发明也提供了分离中间体的特别有用的盐。
本发明提供了一种制备(S)-(+)-N,N-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺的方法,它包括在有机溶剂中使(S)-(-)-N,N-二甲基-3-(2-噻吩基)-3-羟基丙胺与氢化钠、苯甲酸钾或醋酸钾以及1-氟萦反应,如果需要,并将该产物转化为其磷酸盐而获得。该磷酸盐也是本发明的一方面和具体实例。
本发明提供了一种制备上述反应式中C步骤产物的特定对映体的不对称合成方法。该对映体被命名为(S)-(+)对映体,该命名将一直在本文中使用。本发明方法的原料(即上述的羟基丙胺)被命名为(S)-(-)对映体。
完成本发明的优选溶剂是二甲基亚砜。其它溶剂如二甲基甲酰胺、吡啶等,也可以使用。本方法在不常用的高浓度(如大约0.5~1.0摩尔,优选0.6~0.9摩尔)下可以有效地进行。然而浓度并不严重影响反应的速率和收率,当然只要不超过溶解度的限制就行。
反应物化合的顺序和方式并不重要且可以改变。反应物可以以固体加至反应混合物中,或可以分别溶解后以溶液形式混合。进一步地,任何反应物可以组合一起溶解,然后将这些组合溶解的溶液以任何顺序再混合。
实现本发明的优选的方法是将起始原料和氢化钠一起溶解,再加入钾盐化合物,然后加入1-氟萘,这一实施例将在下面更详细地描述。
当起始原料溶解后,最好在室温例如大约10℃至大约35℃下,加入氢化钠部分。氢化钠的量是起始原料的等摩尔量,使用过量的氢化钠设有发现有特别好的效果。然后将反应物搅拌一段时间,例如大约5至大约60分钟,然后再与苯甲酸钾或醋酸钾和1-氟萘混合。
只需要少量钾盐化合物,大约0.05至大约l当量。通常,当仅使用约0.1至大约0.3当量的钾盐化合物时,本发明的优点能最好地实现。除了明显的费用外,使用更多的钾盐化合物没有不利的影响。
加入钾盐化合物后再搅拌一段时间,然后再加入1-氟萘。稍过量的1-氟萘,如过量大约1%至大约25%,可以有益地用来避免价格更贵的噻吩起始原料的耗费。
加入氟萘以后,最好将反应混合物升温至大约40℃至大约75℃的温度,优选大约45℃至大约70℃,最好大约60℃至大约65℃。并将混合物再搅拌短时间,如大约1至大约5小时,最好大约1.5至大约4小时。
然后用常规的萃取和过滤方法分离所需产物,而且如果需要,通过在有机溶剂如乙酸乙酯中与磷酸反应,将所得产物有益地转化为磷酸盐。
如上所述本发明的优点在于在短时间内能以95%的产率制备所需产物,只有极少量外消旋化产物。
根据现有技术的教导能够得到用作本发明方法起始原料的羟基丙胺,提供下面的制备1以保证本申请的读者能够获得该起始原料。
本方法的产物二甲基化合物,通过去甲基化作用被转化为度洛西丁,得所需的甲基药物,并转化为盐酸盐。制备2说明了这种转化,同羟基起始原料的制备一样,该转化从现有技术中就能获得,而不构成本发明的部分。
制备1
(S)-(-)-N,N-二甲基-3-羟基-3-(2-噻吩基)-丙胺
将8.18g 2-乙酰基噻吩、6.66克二甲胺盐酸盐、2.9g仲用醛和在20ml异丙醇中的0.31g浓盐酸的混合物加热至回流并搅拌6小时。然后将混合物冷却至0℃再搅拌1小时。将浆状物过滤,并用冷的乙醇洗涤固体。在50℃下将洗涤过的固体干燥16小时,得到12.5g白色固体2-噻吩基-2-二甲基氢基乙基酮盐酸盐。在室温下,将12.0g部分中间产物在40ml乙醇中搅拌,缓慢加入氢氧化钠使溶液pH值升至11~12。加入1.03g硼氢化钠部分,将混合物在室温下搅拌4小时。然后加入7.5ml丙酮,将混合物再搅拌20分钟。然后通过蒸发将混合物浓缩,得白色浆状物,并加入120ml甲基叔丁基醚。加入浓盐酸将混合物酸化至pH 1~1.5,并将溶液搅拌10分钟。然后缓慢加入氢氧化钠使溶液呈酸性至pH 12。
然后分离各层溶液,水相用30ml甲基叔丁基醚萃取,合并有机相并用50ml水洗涤一次。通过蒸发将有机相浓缩至118ml,并加热至50℃。
在一个分开的容器中,在50℃将4.18g(S)-(+)酸溶解在12ml中,并将扁桃酸溶液缓慢加入到先前得到的溶液中。然后将得到的浆状物加热至回流并搅拌45分钟。然后将其冷却至室温再搅拌1小时,过滤,并用甲基叔丁基醚洗涤固体。然后在50℃真空下干燥固体,得到7.29g预期产物的扁桃酸盐,将其溶于水中,用氢氧化钠溶液碱化,萃取至有机溶剂中,并蒸发除去有机溶液,分离得到游离胺。
实施例1
(S)-(+)-N,N-二甲基-3-(1-萘氧基)-3-(2-噻吩基)丙胺磷酸盐
在25℃将13.5g(S)-(-)-N,N-二甲基-3-羟基-3-(2-噻吩基)丙胺溶解在80ml二甲基亚砜中。剧烈搅拌下向溶液中缓慢加入含3g氢化钠的60%矿物油分散液。搅拌15分钟后,加入1.17g苯甲酸钾,并继续在大约恒温下再搅拌15分钟。然后向反应混合物中缓慢加入12.8g 1-氟萘,加完之后,在60-65℃将混合物加热并搅拌2.5小时。然后将混合物缓慢倒入190ml冷水中,并加入乙酸将pH调至4.8。将混合物温度升至25℃,加入75ml己烷并继续搅拌10分钟。分离各层,再加入75ml己烷搅拌水相,并分离各相。加入氢氧化钠水溶液将水相pH值调至10.2并加入75ml乙酸乙酯。在25℃将混合物搅拌15分钟,通过助滤垫将两相混合物减压滤。使滤液相分离,并用75ml乙酸乙酯萃取水柑。萃取液与先前的乙酸乙酯层合并,并用100ml水洗涤混合物。在25℃下搅拌有机层,向其中滴加7g 85%的磷酸,滴加完后,将混合物再搅拌20分钟,然后冷却至0℃搅拌1小时。然后将浆状物过滤,每次用20ml冷的乙酸乙酯将固体物质洗涤3次。在60℃下干燥固体物质得24.19g白色固体标题化合物(98.1%效力),校正产率79.6%,91%EE。分析方法
用高效液相色谱分析实施例的产物,使用带有SP 4400积分仪和一个Spectroflow检测器的Spectra Physics SP 8800仪器,在230nm处,检测灵敏度是0.5个吸收单位,1秒钟过滤提升时间。所用柱子是Dupont Zorbax Rx(8,4.6mm×25cm。洗脱剂是71%乙腈,30%pH 6的0.01M磷酸盐缓冲液,流出速度是1.0ml一分钟,注射体积是20微升。通过用1∶1乙腈∶水将0.1至0.3g反应混合物或提取物稀释至50ml制备样品。产物峰在13-17分钟流出;起始原料在6-8分钟流出;氟萘在5-6分钟流出;二甲基亚砜在2-3分钟流出;苯甲酸钾在2-2.5分流出。
·在进行手性分析时,使用相同仪器,在280nm处测定,灵敏度为0.1个吸收单位,使用了Chiralce OD柱。用于手性分析的洗脱液组成是2%异丙酮、0.2%二乙胺和97.8%己烷。使用相同的注射和流出指数。用二氯甲烷将0.1~0.3g反应混合物或提取物稀释至5ml,用大约5ml水洗涤混合物,用硫酸钠干燥有机相。将所得溶液过滤并用洗脱剂稀释至25ml。在5~5.5分中时流出所需对映体,不想要的对映体在6-6.5分流出,氟萘在3-4分钟流出。
实施例2
(S)-(+)-N,N-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺
在室温下将1.60g(S)-(-)-N,N-二甲基-3-羟基-3-(2-噻吩基)丙胺溶解在8ml二甲基亚砜中,剧烈搅拌下向其中加入0.35g 60%氢化钠的矿物油分散液。搅拌30分钟后,加入0.28g苯甲酸钾,搅拌再持续10多分钟。加入1.52g 1-氟萘,然后在50℃下将混合物搅拌8小时。将反应混合物缓慢倒入30ml冷水中,加入醋酸将pH调至4.8。加入15m1己烷,将混合物搅拌10分钟,分离各层。向水相再加入15ml己烷搅拌并进行相分离。加入氢氧化钠水溶液将水相pH调至12.5,并加入15ml乙酸乙酯。将碱性混合物在室温下搅拌10分钟,分离各相。用另外15ml乙酸乙酯部分萃取水相,合并有机萃取物,用30ml水洗涤一次,并硫酸镁干燥。真空下除去溶剂得到红棕色油状物,将其溶解在少量1∶1的乙酸乙酯∶乙烷中。将该溶液通过硅胶层,用乙酸乙酯∶己烷∶甲醇∶氢氧化铵(47∶47∶5.8∶0.2)作为洗脱液。在真空下蒸发含产物能分,得所需琥珀色油状产物2.3g。
制备2
(S)-(+)-N-甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺盐酸盐。
在40℃下在40ml甲苯和40ml水的混合物中搅拌5g实施例1的产物,并加入2.5ml 30%氢氧化铵溶液。在恒温下将混合物搅拌10分钟,并分离各相。用水洗涤有机相,用硫酸镁干燥并过滤。在真空下将滤液浓缩至一半体积并加热至55℃。然后加入0.16g二异丙基乙胺,然后滴加2.39g氯代甲酸苯酯。在55℃将混合物搅拌1.25小时,加入50ml 1%碳酸氢钠溶液。并混合物在40-50℃下搅拌10分钟,分离各相。有机相用0.5N盐酸洗涤两次,然后用1%碳酸氢钠溶液洗涤。将洗涤过的有机相分为两等份,其中的一等份在真空下蒸发并向残余物中加入26ml二甲基亚砜。将混合物加热至45℃,滴加1g氢氧化钠和6ml水。在50℃下将碱性混合物搅拌18小时,用17ml水稀释,并用乙酸酸化至pH5.0-5.5。然后加入20ml己烷,将混合物搅拌10分钟,进行相分离。通过加入50%氢氧化钠水溶液将水相碱化为pH10.5,并加入17ml乙酸乙酯。搅拌10分钟后进行相分离,并用另外的17ml乙酸乙酯萃取水层。用水洗涤合并的有机萃取液,并在真空下浓缩至10ml。向残余物中加入0.46g浓盐酸,然后加入晶种和另外的10ml乙酸乙酯。将混合物再搅拌30分钟,并在真空下将溶液浓缩至10ml。将残余物在室温下搅拌1小时,并在0℃下搅拌1小时得到浆状物,将其过滤,用冷却的乙酸乙酯洗涤固体得1.32 g所需产物,即效力99.8%的白色固体度洛西丁。
上面实施例说明了本方法的方便和极好的结果。
Claims (4)
1.一种制备(S)-(+)-N,N-二甲基-3-(1-萘基氧基)-3-(2-噻吩基)丙胺的方法,它包括在有机溶剂中使(S)-(-)-N,N-二甲基-3-(2-噻吩基)-3-羟丙胺与氢化钠、选自苯甲酸钾或醋酸钾中的一种钾盐化合物和1-氟萘反应。
2.权利要求1的方法,其中使(S)-(-)-N,N-二甲基-3-(2-噻吩基)-3-羟丙胺与氢化钠一起溶解在有机溶剂中,然后搅拌下加入钾盐化合物,最后再在搅拌下加入1-氟萘。
3.权利要求1的方法,其中所述的钾盐化合物是苯甲酸钾。
4.权利要求2的方法,其中所述的钾盐化合物是苯甲酸钾。
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