CN1121386C - 还原1－取代－3－羟甲基－4－(4－氟苯基)四氢吡啶的化学方法 - Google Patents

还原1－取代－3－羟甲基－4－(4－氟苯基)四氢吡啶的化学方法 Download PDF

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CN1121386C
CN1121386C CN98805113A CN98805113A CN1121386C CN 1121386 C CN1121386 C CN 1121386C CN 98805113 A CN98805113 A CN 98805113A CN 98805113 A CN98805113 A CN 98805113A CN 1121386 C CN1121386 C CN 1121386C
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J·P·布伦南
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Abstract

本发明涉及制备式(I)化合物的方法，其中R1表示胺保护基团，该方法包括在稀释剂中于无机盐存在下，用金属氢化物还原式(II)化合物，其中R1如上文定义。

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还原1-取代-3-羟甲基-4-(4-氟苯基)四氢吡啶的化学方法
本发明涉及制备(-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶的方法，其中该化合物是制备氟苯哌苯醚的有用中间体。
美国专利4,007,196公开了具有抗抑郁活性的化合物。公开在该专利中的一个特殊化合物称作氟苯哌苯醚，具有下列结构A：人们已经发现该化合物可特别地用于治疗抑郁症，还公开了制备该重要化合物的几种方法。
WO 96/36636(在此引作参考)公开了一种这类方法。该申请权利要求1中的步骤C描述了还原式B化合物，
Figure C9880511300042
可得到式C化合物，其中X为卤素，优选F，R1为C2-5烷基、苯基C1-5烷基或取代苯基C1-5烷基。该还原反应可采用金属氢化物进行，根据权利要求4，该氢化物优选LiAlH4或NaAlH4。该申请中只给出了一个实施例与式B化合物有关，其中X为F，R1为乙基，利用氢化钠和氢化铝锂的混合物还原式B化合物。
当在WO 96/36636中描述的条件下进行反应且X为F和R1为苄基时，人们发现该反应产生了无法接受的脱氟水平。该杂质很难在该步骤中从所需产物分离出去，导致了在最终产物中存在氟苯哌苯醚脱氟类似物。再者，人们很难将氟苯哌苯醚类似物从氟苯哌苯醚中分离出去。其结果导致分离过程非常费时，而且浪费材料且成本昂贵。
令人惊奇的是，本发明发现了一种方法，该方法在还原步骤中只产生极少量的脱氟反应。本发明提供了制备式I化合物的方法，
Figure C9880511300052
其中R1表示胺保护基团，该方法包括在稀释剂中于无机盐存在下，用金属氢化物还原式II化合物，
Figure C9880511300061
其中R1如上文定义。合适的胺保护基团为不能被金属氢化物还原的基团。所述胺保护基团优选地选自a)烯丙基，b)二苯甲基，c)甲氧基甲基，d)苄氧基甲基，e)四氢吡喃基，f)任意取代的苄基，g)二(对甲氧基苯基)甲基，h)三苯基甲基，i)(对-甲氧基苯基)二苯基甲基，j)二苯基-4-吡啶基甲基，k)2，4，6-三甲基苯磺酰基，l)甲苯磺酰基，m)苄基磺酰基，n)C1-6炕基，o)三氟C1-4烷基，p)炔基或q)对甲氧基苄基或任意取代铵。更优选的胺保护基团为在苯环上被一个或多个下列基团任意取代的苄基：C1-4烷基、C1-4烷氧基、卤素或硝基。最优选R1表示苄基。
合适的金属氢化物为氢化钠、氢化钾、氢化镁、氢化钙、硼氢化钠、硼氢化钾、硼氢化锂、氢化铝锂、氢化铝钠、氢化铝、氢化双(2-甲氧基乙氧基)铝钠、氢化一-(C1-4烷氧基)铝锂、氢化二(C1-4烷氧基)铝锂或氢化二乙基铝钠或其混合物。优选的金属氢化物为氢化铝锂或氢化铝钠。更优选的金属氢化物为氢化铝锂。
相对于所使用的式II化合物量，金属氢化物的用量宜为0.5-5摩尔当量。金属氢化物的优选用量为0.75-1.25摩尔当量。更优选的金属氢化物用量为0.90-1.10摩尔当量。
适合的无机盐为锂盐、钠盐、镁盐、钙盐、锌盐、镧盐或铁盐或其混合物。优选的无机盐为卤化锂、卤化钠、卤化钙、卤化锌、卤化镁、卤化镧或卤化铁或其混合物。更优选的无机盐选自氯化锂、氯化钠、氯化钙、氯化锌、氯化铁(II)、氯化铁(III)、氯化镧、氯化镁、氟化镁、溴化镁或碘化镁或其混合物。最优选的无机盐为氯化镁、溴化镁或碘化镁。特别优选的盐为氯化镁。
该方法的机理还未详细研究。本领域技术人员将会理解，通过将起先使用的金属氢化物与无机盐反应，可形成活性还原剂。例如，在氢化铝锂和氯化镁情况下，活性物种可以是氢化镁、氢化铝氯镁、氢化铝镁或氢化铝镁锂或氯化镁和氢化铝锂的配合物中的一种或多种。人们应当可以理解，该方法包括了所有这类等同物。
相对于所使用的式II化合物的量，无机盐的用量宜为0.25摩尔当量至5摩尔当量。无机盐的优选用量为0.5-1.5摩尔当量。相对于所使用的式II化合物的量，无机盐的更优选的用量为0.75-1.25摩尔当量。
适合的稀释剂为相对于所使用的金属氢化物为惰性的有机液体，优选为式II化合物的溶剂。优选的稀释剂为醚或烃或其混合物。更优选的稀释剂选自四氢呋喃、甲苯、二噁烷、二乙基醚、二异丙基醚、叔丁基甲基醚、乙二醇二甲基醚或其混合物。最优选的稀释剂为四氢呋喃。
相对于所使用的式II化合物，稀释剂的适合用量为1-100份重量。优选的稀释剂量为相对于所使用的式II化合物用2-50份重量。更优选的稀释剂量为相对于所使用的式II化合物用3-10份重量。
该方法适宜在-70℃至所使用的稀释剂的沸点之间进行。优选在0-150℃温度范围下进行。更优选在0-100℃温度范围下进行。该方法最优选在50-70℃温度范围下进行。
所得到的脱氟化合物量宜为0.001％至1％。该百分数是指在实施例中所描述的HPLC得到的结果。所得到的脱氟化合物量优选为0.001％至0.5％。所得到的脱氟化合物量更优选为0.001％至0.2％。
由于本发明方法提供了制备氟苯哌苯醚的纯前体，所以具有其优点。通过下述方法，由式I化合物可得到纯形式的氟苯哌苯醚：a)将羟基基团转变成离去基团，如卤素或甲苯磺酰氧基，b)与芝麻酚或其盐反应，c)除去保护基团R1，以及任意地d)成盐，如无水或半水形式的盐酸盐。
通过下列实施例来阐述本发明，这些实施例仅仅作为实例。这些实施例的最终产物通过下列一种或多种方法确定：气-液色谱法、高效液相色谱法、元素分析、核磁共振光谱法和红外光谱法。
脱氟化合物为(-)-反式-苄基-3-羟甲基-4-苯基哌啶。
                        实施例 实施例1   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，将于THF中的氢化铝锂(2.0ml 1M溶液)小心地加入到基本上不含水的氯化镁(0.19g，1.5％H2O)中。搅拌混合物，加热至50℃，然后大约在2分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(0.60g，按WO 96/36636制得)的THF(1.7ml)溶液。搅拌反应混合物并在回流条件下沸腾4.2小时。冷却混合物至环境温度，然后在冰/水浴中搅拌，同时先加入水(0.1ml)，再加入5M氢氧化钠溶液(0.1ml)和水(0.1ml)。利用THF(5ml)稀释悬浮液并过滤混合物。利用THF(3×5ml)洗涤残留物，将合并的滤液和洗涤液减压蒸发，得到黄色油状物(0.49g)。通过GLC、手性HPLC和1H NMR分析该油状物。GLC条件：柱：DB1 1.5μm 15m×0.53mm载气(B)流量：4.5mls/min.，起始温度：40℃，1分钟升温直线：5℃/分钟至300℃，7分钟HPLC条件：柱：15cm长，内径4.6mm，包含二氧化硅颗粒，其表面已通过化学键合辛基甲硅烷基修饰；粒径＝5μm，柱温度为35℃。检测波长：214nm。流动相：15％(v/v)乙腈，0.1％(v/v)正磷酸(SG 1.69)和0.1％(w/v)丁烷磺酸钠水溶液。
产物归一化纯度为98.7％，HPLC表明包含0.3％脱氟化合物。实施例2   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，将于THF中的氢化铝锂(16.7ml 1M溶液)小心地加入到基本上不含水的氯化镁(1.58g，1.5％H2O)中。搅拌混合物，加热至50℃，然后大约在5分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(5.0g)的THF(14.2ml)溶液。搅拌反应混合物并在回流条件下沸腾6小时。冷却混合物至环境温度，然后在冰/水浴中搅拌，同时先加入水(0.8ml)，再加入5M氢氧化钠溶液(0.8ml)和水(0.8ml)。利用THF(5ml)稀释悬浮液并过滤混合物。利用THF(3×10ml)洗涤残留物，将合并的滤液和洗涤液减压蒸发，得到黄色油状物(3.3g)。采用上述条件，通过GLC、手性HPLC和1H NMR分析该油状物。产物归一化纯度为97.0％，HPLC表明包含0.2％脱氟化合物。实施例3至8
利用表1中描述的条件，根据与实施例1类似的方法进行实施例3-8。表1中使用了下述缩略语：M equiv II表示相对于所使用的式II化合物量的摩尔当量；GLC＝气液色谱法；HPLC＝高效液相色谱法；％(-F)＝脱氯化合物的百分数；这些栏目中的数据是指归一化百分数。
                           表1
实施例No.   IIG   THFml   LiAlH4M equiv II   MgCl2M equiv II 时间h   ％IIGLC ％(-F)HPLC
    3   0.60   1.7     1.0     0.5     3   0.1   0.3
    4   2.56   5.12     0.9     1.0     4   0   0.2
    5   0.48   1.0     0.75     1.0     5   2.9   0.4
    6   0.50   1.0     0.75     0.75     4   2.6   0.4
    7   0.60   1.7     1.0     1.5     5   4.2   0.2
    8   1.99   4.0     1.0     0.8     4   0.1   0.22
实施例9   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，将于THF中的氢化铝锂(2.0ml 1M溶液)小心地加入到基本上不含水的氯化镁(0.19g，1.5％H2O)中。搅拌混合物，加热至50℃，然后大约在2分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(0.60g)的THF(1.7ml)溶液。搅拌反应混合物并在回流条件下沸腾4小时。冷却混合物至环境温度，然后在冰/水浴中搅拌，同时先加入水(0.1ml)，再加入5M氢氧化钠溶液(0.1ml)和水(0.1ml)。利用THF(5ml)稀释悬浮液并过滤混合物。利用THF(3×5ml)洗涤残留物并将合并的滤液与洗涤液减压蒸发，得到黄色油状物(0.49g)。采用上述条件，通过GLC、手性HPLC和1HNMR分析该油状物。通过GLC分析，产物中仍然包含13.2％起始原料。通过HPLC测定的脱氟化合物量小于0.1％。实施例10   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，将于THF中的氢化铝锂(2.0ml 1M溶液)和甲苯(0.69ml)同时小心地加入到基本上不含水的氯化镁(0.53g，1.5％H2O)中。搅拌混合物，加热至50℃，然后大约在5分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(2.60g，可按照WO96/36636中所述制得)的THF(3.6ml)和甲苯(0.4ml)溶液。搅拌反应混合物并在回流条件下沸腾3.5小时。冷却混合物至环境温度，然后在冰/水浴中搅拌，同时加入0.5M氢氧化钠溶液(4.1ml)。利用THF(10ml)稀释悬浮液并过滤混合物。利用THF(10ml)洗涤残留物并将合并的滤液和洗涤液减压蒸发，得到黄色油状物(1.83g)。通过GLC、手性HPLC和1H NMR分析该油状物。标题化合物包含0.24％脱氟化合物。实施例11   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，将于THF中的氢化铝锂(3.76ml 1M溶液)小心地加入到基本上不含水的溴化镁(0.55g)中。搅拌混合物，加热至50℃，然后大约在5分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(1.12g)的THF(2.2ml)溶液。搅拌反应混合物并在回流条件下沸腾4.2小时。冷却混合物至环境温度，然后在冰/水浴中搅拌，同时加入0.5M氢氧化钠溶液(2ml)和水(0.1ml)。利用THF(7ml)稀释悬浮液并过滤混合物。利用THF(7ml)洗涤残留物并将合并的滤液和洗涤液减压蒸发，得到黄色油状物(0.99g)。通过GLC、手性HPLC和1H NMR分析该油状物。标题化合物包含0.18％脱氟化合物。实施例12   (-)-反式-1-苄基-3-羟甲基-4-(4-氟苯基)哌啶
在氮气气氛下，保持温度低于20℃，在搅拌条件下，将于THF中的氢化铝锂(7.24ml 1M溶液)小心地加入到于THF(32ml)中的基本上不含水的氯化镁(0.698g)中。搅拌混合物，加热至50℃，然后大约在30分钟内，滴加(+)-1-苄基-3-羟甲基-4-(4-氟苯基)-1，2，3，6-四氢吡啶(2.1 5g，可按照WO96/36636中所述制得)的THF(3.92ml)和甲苯(2.32ml)溶液。搅拌反应混合物并在回流条件下沸腾4.0小时。在冰/水浴中冷却混合物至0-5℃，同时加入氢氧化钠溶液(2.48g，5％w/w)。过滤悬浮液，利用THF(8ml)洗涤残留物并将合并的滤液和洗涤液减压蒸发，得到黄色油状物。通过GLC、手性HPLC和1H NMR分析该油状物。标题化合物包含0.24％脱氟化合物。实施例13&14：
根据与实施例12类似的方法进行实施例13和14，只是利用表2所示的摩尔当量金属盐替代氯化镁。
                           表2
实施例No. 金属盐 搅拌时间小时   ％产物GLC     ％SMGLC    ％脱氟HPLC
    13   MgCl2     1     96.4     0.0     0.13
    14   MgBr2     1     97.8     0.55     0.21
                             SM＝起始原料实施例15
根据与实施例12类似的方法进行该实施例，只是利用甲苯作为溶剂替代THF且混合物在110℃下加热搅拌2小时。该步骤得到产物(GLC纯度为93.7％)，HPLC表明包含1.07％脱氟化合物。比较实施例
在不存在无机盐的比较反应中，得到的脱氟化合物量为2-4％数量级，而且已经被证明很难除去。

Claims (5)

1.制备式I化合物的方法，
Figure C9880511300021
其中R1表示胺保护基团，该方法包括在选自醚、烃和其混合物的稀释剂中，于选自氯化镁、溴化镁或碘化镁的无机盐存在下，用金属氢化物还原式II化合物，
Figure C9880511300022
其中R1如上文定义。
2.根据权利要求1的方法，其中胺保护基团选自a)烯丙基，b)二苯甲基，c)甲氧基甲基，d)苄氧基甲基，e)四氢吡喃基，f)任选取代的苄基，g)二(对甲氧基苯基)甲基，h)三苯基甲基，i)(对-甲氧基苯基)二苯基甲基，j)二苯基-4-吡啶基甲基，k)2，4，6-三甲基苯磺酰基，1)甲苯磺酰基，m)苄基磺酰基，n)C1-6烷基，o)三氟C1-4烷基，p)炔基或q)对甲氧基苄基或任选取代铵。
3.根据权利要求2的方法，其中R1表示苄基。
4.根据权利要求1的方法，其中金属氢化物为氢化钠、氢化钾、氢化镁、氢化钙、硼氢化钠、硼氢化钾、硼氢化锂、氢化铝锂、氢化铝钠、氢化铝、氢化双(2-甲氧基乙氧基)铝钠、氢化一(C1-4烷氧基)铝锂、氢化二(C1-4烷氧基)铝锂或氢化二乙基铝钠或其混合物。
5.根据权利要求4的方法，其中金属氢化物为氢化铝锂或氢化铝钠。
CN98805113A 1997-05-17 1998-05-13 还原1－取代－3－羟甲基－4－(4－氟苯基)四氢吡啶的化学方法 Expired - Fee Related CN1121386C (zh)

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