CN109317203B - 一种治疗绝经后妇女骨质疏松症用药物中间体的制备方法 - Google Patents
一种治疗绝经后妇女骨质疏松症用药物中间体的制备方法 Download PDFInfo
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Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/0277—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature
- B01J31/0292—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature immobilised on a substrate
- B01J31/0295—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides comprising ionic liquids, as components in catalyst systems or catalysts per se, the ionic liquid compounds being used in the molten state at the respective reaction temperature immobilised on a substrate by covalent attachment to the substrate, e.g. silica
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
- B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
- B01J31/06—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides containing polymers
- B01J31/069—Hybrid organic-inorganic polymers, e.g. silica derivatized with organic groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
- C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
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Abstract
本发明属于化学制药技术领域，具体涉及一种治疗绝经后妇女骨质疏松症用药物中间体1‑[2‑(4‑溴苯氧基)乙基]吡咯烷的制备方法。本发明以1‑乙烯基咪唑为原料分别与1‑碘辛烷和1,8‑二碘辛烷反应制备出单体和交联剂，在自由基引发剂的作用下单体和交联剂在载体蒙脱土K10上反应形成聚合物，最后经过氢氧化钠水溶液处理得负载型碱性离子液体聚合物；本发明制备的负载型碱性离子液体聚合物可催化对溴苯酚和N‑(2‑氯乙基)吡咯烷盐酸盐反应制备治疗绝经后妇女骨质疏松症用药物中间体1‑[2‑(4‑溴苯氧基)乙基]吡咯烷，该催化体系反应时间短、收率高，且可经过简单处理后回收套用。
Description
技术领域
本发明属于化学制药技术领域，具体涉及一种治疗绝经后妇女骨质疏松症用药物中间体的制备方法。
背景技术
酒石酸拉索昔芬(lasofoxifene tartrate)，化学名为(5R,6S)-5,6,7,8-四氢-6-苯基-5-[4-[2-(1-吡咯烷基)乙氧基]苯基]-2-萘酚(2S,3S)-酒石酸盐，是美国辉瑞公司研发的选择性雌激素受体调节剂，2009年4月在欧洲批准上市，其片剂商品名为Fablyn。本品在不同的雌激素靶组织内呈现选择性激动或拮抗作用，对雌激素受体ERα和ERβ具有高度的亲和性，临床用于治疗绝经后妇女骨质疏松症。
目前有多种路线可制备出拉索昔芬原料药(参见：文献1、中国医药工业杂志，2010年第41卷第6期，468-471页和文献2、中国医药工业杂志，2011年第42卷第7期，481-483页)。拉索昔芬大多数制备路线中存在一个通用中间体1-[2-(4-溴苯氧基)乙基]吡咯烷，如Scheme 1所示：
1-[2-(4-溴苯氧基)乙基]吡咯烷是由对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐在碱性条件下发生Williamson醚化反应，反应式如Scheme2所示：
文献Organic Process Research&Development 2001,5,479-490中对此步反应进行了详尽的描述；以对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐为原料，采用乙醇钠/乙醇体系回流反应60h进行实验室规模制备，收率为74％；采用碳酸钾作为碱在甲基异丁基酮中在80-87℃下进行规模放大，反应8h；虽然反应时间大大缩短，但后处理采用氯化锌水溶液去除反应中生成的二胺副产物(Organic Process Research&Development 2001,5,479-490文献中化合物24)，且碳酸钾用量过多(约为对溴苯酚摩尔量的5.0倍)，导致最终收率为65％。
现有技术中对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐进行Williamson醚化反应收率低、且后处理繁琐；所以对该步反应进行优化提高收率、制备出高质量1-[2-(4-溴苯氧基)乙基]吡咯烷是决定酒石酸拉索昔芬能否实现GMP生产的关键。
发明内容
本发明的目的是克服现有技术中的不足，提供一种治疗绝经后妇女骨质疏松症用药物中间体的制备方法，所述药物中间体为1-[2-(4-溴苯氧基)乙基]吡咯烷；本发明以1-乙烯基咪唑为原料分别与1-碘辛烷和1,8-二碘辛烷反应制备出单体和交联剂，在自由基引发剂的作用下单体和交联剂在载体蒙脱土K10上反应形成聚合物，最后经过氢氧化钠水溶液处理得负载型碱性离子液体聚合物；本发明制备的负载型碱性离子液体聚合物可催化对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐反应制备治疗绝经后妇女骨质疏松症用药物中间体1-[2-(4-溴苯氧基)乙基]吡咯烷，该催化体系反应时间短、收率高，且可经过简单处理后回收套用。
根据本发明的一个方面，本发明提供了一种负载型碱性离子液体聚合物的制备方法，以1-乙烯基咪唑为原料分别与1-碘辛烷和1,8-二碘辛烷在甲醇中反应制备出单体和交联剂，在自由基引发剂的作用下单体和交联剂在甲苯中与载体蒙脱土K10进行聚合反应，聚合反应结束后经过氢氧化钠水溶液处理得负载型碱性离子液体聚合物；
具体包括如下步骤：
1)单体的制备：将等摩尔量的1-乙烯基咪唑和1-碘辛烷溶于甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得单体粗品，将单体粗品置于正庚烷超声后过滤、减压干燥得单体；
2)交联剂的制备：将1-乙烯基咪唑和1,8-二碘辛烷溶于甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得交联剂粗品，将交联剂粗品置于正庚烷超声后过滤、减压干燥得交联剂；所述1-乙烯基咪唑与1,8-二碘辛烷的用量按摩尔比计算为2：1；
3)离子液体的聚合与负载：将10.0g蒙脱土K10置于500ml甲苯中回流反应2-3h后降温至50-60℃加入单体1.0g、交联剂0.3-0.5g和自由基引发剂0.1-0.2g搅拌反应10h以上，然后降温至室温，过滤、将滤饼置于50mmol的氢氧化钠水溶液中超声2-3h后离心、水洗、干燥得负载型碱性离子液体聚合物。
优选的，所述自由基引发剂为偶氮二异丁腈(AIBN)或过氧化二苯甲酰(BPO)。
根据本发明的另一个方面，本发明提供了一种负载型碱性离子液体聚合物的用途，在溶剂和碱的存在下，用于催化对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐缩合反应制备治疗绝经后妇女骨质疏松症用药物中间体1-[2-(4-溴苯氧基)乙基]吡咯烷；具体包括如下步骤：
1)反应器中加入溶剂和碱开启搅拌器进行搅拌，然后将对溴苯酚、N-(2-氯乙基)吡咯烷盐酸盐和负载型碱性离子液体聚合物依次加入到反应器中进行缩合反应；
2)HPLC检测反应液中对溴苯酚浓度不再下降后，停止反应，降温至室温，过滤去除负载型碱性离子液体聚合物得滤液；
3)对滤液进行后处理纯化得1-[2-(4-溴苯氧基)乙基]吡咯烷。
优选的，所述溶剂为极性非质子溶剂，所述极性非质子溶剂为乙腈、丙酮、丁酮、甲基异丁基酮、二甲基亚砜、二甲基甲酰胺，进一步优选为二甲基亚砜；
优选的，所述碱为碳酸钠、碳酸钾或碳酸锂中的一种；按摩尔比甲酸，所述碱的摩尔用量为对溴苯酚摩尔量的2.0-2.5倍；
优选的，步骤1)所述缩合反应温度为80-100℃；
优选的，按照重量百分比计算，步骤1)所述负载型碱性离子液体聚合物的加入量为对溴苯酚的0.5wt％-20wt％；
优选的，按摩尔比计算，步骤1)所述对溴苯酚：N-(2-氯乙基)吡咯烷盐酸盐＝1:1.0-1.2。
本发明采用1-乙烯基咪唑为原料分别与1-碘辛烷和1,8-二碘辛烷在甲醇中反应制备出单体和交联剂，在自由基引发剂的作用下单体和交联剂在甲苯中与载体蒙脱土K10进行聚合反应制备出负载型碱性离子液体聚合物，技术原理如Scheme 3所示：
与现有技术相比，本发明具有如下优点：
1)本发明负载型碱性离子液体聚合物的原料易得、制备方法简便，无需特殊设备即可实现生产；
2)本发明制备的负载型碱性离子液体聚合物作为添加剂催化对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐缩合反应制备1-[2-(4-溴苯氧基)乙基]吡咯烷提高了反应收率，缩短了反应时间；
3)本发明制备的负载型碱性离子液体聚合物可通过简单过滤从反应体系中分离，且能够通过溶剂超声洗涤晾干后重复使用；
4)本发明通过优化催化反应后处理，采用成盐的方法对1-[2-(4-溴苯氧基)乙基]吡咯烷纯化，避免了繁琐的精馏操作，纯度高达99.9％以上。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明了，下面结合具体实施方式，对本发明进一步详细说明。应该理解，这些描述只是示例性的，而并非要限制本发明的范围。
蒙脱土K10来自于西格玛奥德里奇(上海)贸易有限公司，比表面积为260m2/g；
HPLC检测方法：色谱柱C18(3.5μm；50mm×2.1mm)，柱温为40℃；检测波长210nm；流动相为纯化水/乙腈/三氟乙酸/氨水＝65/35/0.25/0.2(体积比)，流速为0.8ml/min，时间为10min。
实施例1
按如下步骤制备负载型碱性离子液体聚合物：
1)单体的制备：将20mmol 1-乙烯基咪唑和20mmol 1-碘辛烷溶于100ml甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得单体粗品，将单体粗品置于80ml正庚烷在40-45℃超声2h后过滤、40℃下减压干燥得单体；
2)交联剂的制备：将40mmol 1-乙烯基咪唑和20mmol 1,8-二碘辛烷溶于100ml甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得交联剂粗品，将交联剂粗品置于100ml正庚烷在40-45℃超声2h后过滤、40℃下减压干燥得交联剂；
3)离子液体的聚合与负载：将10.0g蒙脱土K10置于500ml甲苯中回流反应2-3h后降温至50-60℃加入单体1.0g、交联剂0.4g和0.2g自由基引发剂AIBN搅拌反应16h，然后降温至室温，过滤、将滤饼置于100ml浓度为50mmol的氢氧化钠水溶液中超声2-3h后离心、水洗、干燥得负载型碱性离子液体聚合物(以下简写为K@PIL)。
实施例2
对实施例1制备的负载型碱性离子液体聚合物(K@PIL)作为催化剂催化对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐缩合反应制备1-[2-(4-溴苯氧基)乙基]吡咯烷，方法如下：
在氮气氛围下将对溴苯酚(10mmol，1.73g)和N-(2-氯乙基)吡咯烷盐酸盐(10mmol，1.70g)、碳酸钾(20mmol，2.76g)和负载型碱性离子液体聚合物(K@PIL)(0.17g，～10wt％)置于50ml甲基异丁基酮中在83±2℃下搅拌反应，HPLC检测反应液中对溴苯酚浓度不再变化时，停止反应，记录反应时间，反应液中底物对溴苯酚、产物1-[2-(4-溴苯氧基)乙基]吡咯烷和总杂质的面积百分比；作为对比，本发明研究了不添加催化剂K@PIL反应体系和不添加催化剂K@PIL、同时把碳酸钾用量提高至50mmol；其反应结果如表1所示：
表1 K@PIL催化效果
注：序列1为加入负载型碱性离子液体聚合物(K@PIL)作为催化剂的反应效果；序列2中未加入催化剂K@PIL；序列3中未加入催化剂K@PIL，且碳酸钾用量为50mmol(模拟Organic Process Research&Development 2001,5,479-490中反应条件)；总杂包括二胺副产等所有已知杂质及其其它所有未知杂质。
试验结果表明，加入负载型碱性离子液体聚合物(K@PIL)作为催化剂可加快反应速率、避免杂质的生成(序列1和2对比)；虽然不添加K@PIL作为催化剂、提高碳酸钾用量(序列1和3对比)可提高转化率，但是杂质大大增加，加大了分离难度，所以导致放大收率仅为65％。
实施例3
本发明对催化反应溶剂和碱的种类、负载型碱性离子液体聚合物(K@PIL)用量、N-(2-氯乙基)吡咯烷盐酸盐摩尔用量进行了进一步优化，方法如下：
在氮气氛围下将对溴苯酚(10mmol，1.73g)和N-(2-氯乙基)吡咯烷盐酸盐(10-15mmol，1.0-1.5eq)、碱(21mmol)和负载型碱性离子液体聚合物(K@PIL)(1.7mg-519mg，0.1wt％～30wt％)置于50ml溶剂中在83±2℃下搅拌反应，HPLC检测反应液中对溴苯酚浓度不再变化时，停止反应，记录反应时间，反应液中底物对溴苯酚、产物1-[2-(4-溴苯氧基)乙基]吡咯烷和总杂的面积百分比；其反应结果如表2所示：
表2反应条件优化
注：1)沸点小于80℃的溶剂是在回流条件下反应；2)ND是指未检测出或者小于0.1％.
试验结果表明，溶剂对反应影响较大，其中极性非质子溶剂可提高对溴苯酚反应转化率，以DMSO效果最好；碱的种类对反应影响不大，碳酸锂优于碳酸钾和碳酸钠，碱选择碳酸锂为易；综合反应转化率和目标产物的选择性，选择DMSO作为溶剂、碳酸锂作为碱、催化剂K@PIL用量为对溴苯酚重量的15wt％，N-(2-氯乙基)吡咯烷盐酸盐摩尔用量为对溴苯酚的1.2倍。
实施例4
采用最优工艺条件进行公斤级放大研究：
1)30L双层玻璃反应釜中加入15L DMSO和碳酸锂(776g，10.5mol)开启机械搅拌器进行搅拌，然后将对溴苯酚(865g，5mol)、N-(2-氯乙基)吡咯烷盐酸盐(1020g，6mol)和负载型碱性离子液体聚合物(K@PIL)(130g，15wt％)依次加入到反应器中，升温至90-100℃进行缩合反应；
2)4h后取反应液HPLC检测(面积百分比：对溴苯酚0.2％，1-[2-(4-溴苯氧基)乙基]吡咯烷99.1％，总杂0.7％)，降温至室温，过滤去除负载型碱性离子液体聚合物得滤液；
3)对滤液按重量平均分成5份，分别命名为W-A，W-B，W-C，W-D和W-E，采用不同后处理方法对滤液进行后处理，其中W-A为直接浓缩，W-B至W-E为采用不同酸进行成盐，以期能够与目标产物中吡咯烷的氮成盐在DMSO中析出起到纯化的目的，对成盐后的产品采取氢氧化钠的水溶液进行解盐，二氯甲烷萃取浓缩得1-[2-(4-溴苯氧基)乙基]吡咯烷；
具体成盐&解盐方法如下：将W-B至W-F滤液升温至40-45℃，然后滴加含有4mol酸的乙醇溶液，搅拌20-30min，然后降温至室温，观察是否有沉淀析出；将析出的沉淀加入到氢氧化钠的水溶液中溶解，二氯甲烷萃取浓缩得1-[2-(4-溴苯氧基)乙基]吡咯烷；直接浓缩和成盐&解盐后所获得产品收率(理论收率按照1-[2-(4-溴苯氧基)乙基]吡咯烷每份为1mol)和含量见表3；
表3不同后处理方法处理结果
注：NA是指不适用。
对W-C后处理方法制备出的1-[2-(4-溴苯氧基)乙基]吡咯烷进行结构表征1H-NMR(CDCl3,400MHz)7.40-7.32(2H,m),6.82-6.75(2H,m),4.07(2H,t),2.89(2H,t),2.66-2.58(4H,m),1.86-1.74(4H,m)；MSm/z270[M+1]+(丰度值98),272[M+1]+(丰度值100)。
实施例5
对实施例4放大分离出的催化剂(K@PIL)采用DMSO超声洗涤后晾干回收套用，对溴苯酚的转化率为98.9％，基本与新鲜制备的催化剂活性相当，所以可对其进行回收套用，降低生产成本。
尽管已经详细描述了本发明的实施方式，但是应该理解的是，在不偏离本发明的精神和范围的情况下，可以对本发明的实施方式做出各种改变、替换和变更。
Claims (9)
1.一种负载型碱性离子液体聚合物的制备方法，其特征在于：以1-乙烯基咪唑为原料分别与1-碘辛烷和1,8-二碘辛烷在甲醇中反应制备出单体和交联剂，在自由基引发剂的作用下单体和交联剂在甲苯中与载体蒙脱土K10进行聚合反应，聚合反应结束后经过氢氧化钠水溶液处理得负载型碱性离子液体聚合物；
具体包括如下步骤：
1）单体的制备：将等摩尔量的1-乙烯基咪唑和1-碘辛烷溶于甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得单体粗品，将单体粗品置于正庚烷超声后过滤、减压干燥得单体；
2）交联剂的制备：将1-乙烯基咪唑和1,8-二碘辛烷溶于甲醇中回流反应2-3天，然后减压蒸馏去除甲醇得交联剂粗品，将交联剂粗品置于正庚烷超声后过滤、减压干燥得交联剂；所述1-乙烯基咪唑与1,8-二碘辛烷的用量按摩尔比计算为2：1；
3）离子液体的聚合与负载：将10.0g蒙脱土K10置于500ml甲苯中回流反应2-3h后降温至50-60℃加入单体1.0g、交联剂0.3-0.5g和自由基引发剂0.1-0.2g搅拌反应10h以上，然后降温至室温，过滤、将滤饼置于50mmol的氢氧化钠水溶液中超声2-3h后离心、水洗、干燥得负载型碱性离子液体聚合物；
步骤3）所述自由基引发剂为偶氮二异丁腈或过氧化二苯甲酰。
2.一种权利要求1所述制备方法制备的负载型碱性离子液体聚合物的用途，其特征在于：在溶剂和碱的存在下，用于催化对溴苯酚和N-(2-氯乙基)吡咯烷盐酸盐缩合反应制备1-[2-(4-溴苯氧基)乙基]吡咯烷。
3.根据权利要求2所述的用途，其特征在于：包括如下步骤：
1）反应器中加入溶剂和碱开启搅拌器进行搅拌，然后将对溴苯酚、N-(2-氯乙基)吡咯烷盐酸盐和负载型碱性离子液体聚合物依次加入到反应器中进行缩合反应；
2）HPLC检测反应液中对溴苯酚浓度不再下降后，停止反应，降温至室温，过滤去除负载型碱性离子液体聚合物得滤液；
3）对滤液进行后处理纯化得1-[2-(4-溴苯氧基)乙基]吡咯烷。
4.根据权利要求3所述的用途，其特征在于：所述溶剂为极性非质子溶剂。
5.根据权利要求4所述的用途，其特征在于：所述极性非质子溶剂为乙腈、丙酮、丁酮、甲基异丁基酮、二甲基亚砜、二甲基甲酰胺。
6.根据权利要求5所述的用途，其特征在于：所述极性非质子溶剂为二甲基亚砜。
7.根据权利要求3所述的用途，其特征在于：所述碱为碳酸钠、碳酸钾或碳酸锂中的一种；所述碱的摩尔用量为对溴苯酚摩尔量的2.0-2.5倍。
8.根据权利要求3所述的用途，其特征在于：按照重量百分比计算，步骤1）所述负载型碱性离子液体聚合物的加入量为对溴苯酚的0.5wt%-20wt%。
9.根据权利要求3所述的用途，其特征在于：按摩尔比计算，步骤1）所述对溴苯酚：N-(2-氯乙基)吡咯烷盐酸盐=1:1.0-1.2。
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