CN105541680B - 一种比卡鲁胺的合成方法 - Google Patents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract
本发明公开了一种比卡鲁胺的合成方法，该方法以N‑(4‑氰基‑3‑三氟甲基苯基)‑3‑(4‑氟苯硫基)‑2‑甲基‑2‑羟基丙酰胺为原料，以具有反应控制相特点的磷钨杂多酸季铵盐为催化剂，以二氯甲烷为溶剂，在15‑30℃的反应温度下，使用过氧化氢氧化N‑(4‑氰基‑3‑三氟甲基苯基)‑3‑(4‑氟苯硫基)‑2‑甲基‑2‑羟基丙酰胺生成比卡鲁胺。本发明方法具有反应条件温和，反应收率高，催化效率高，催化剂和反应溶剂可回收循环使用的优点。
Description
技术领域
本发明涉及有机化合物的制备工艺，更具体的说是涉及药物比卡鲁胺的合成。
背景技术
目前前列腺癌在全世界范围内发病率较高，并因其发病时对病体造成的痛苦较大治疗困，现在前列腺癌是男性第二大致死性恶性肿瘤。前列腺癌和雄性激素有关，降低体内雄性激素的含量水平，是治疗前列腺癌的常用方法。许多非甾体类的抗雄激素药物在临床上用于治疗前列腺癌的治疗，其中比卡鲁胺是全世界范围内应用最广泛的抗雄激素药物，尤其是用于前列腺癌的治疗上。比卡鲁胺是Astra Zeneca公司抗雄激素药品康士得的通名，比卡鲁胺的化学名为：2-羟基-2-甲基-N-[4-氰基-3-(三氟甲基)苯基]-3-[(4-三氟苯基)硫砜]丙酰胺，英文名为：N-[4-cyano-3-(trifluoromethyl)phenyl]-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2methyl-propanamide比卡鲁胺的结构式为：。
文献报道的比卡鲁胺的合成方法是由比卡鲁胺硫醚中间体氧化制成的，比卡鲁胺中间体的化学名称为N-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺，其化学结构如下：，其氧化生成比卡鲁胺的过程，众多文献和专利都有报道：例如US2004176638A1， WO2009087666A1，WO2007039127A1，US2008177109A11，US2007149800A1，WO2007013094A2。所报道的方法中采用了间氯过氧苯甲酸作为氧化剂，氧化剂用量过大，且反应要用到大量的溶剂。氧化硫醚成砜的方法多采用有机过氧酸，如过氧乙酸，过氧苯甲酸等，这些氧化剂易产生大量的固体废弃物，造成极大的环境污染，并且过氧酸具有爆炸性，使用不安全，造成操作困难。高锰酸钾是强氧化剂，在使用时存在锰金属的残留问题以及氧化操作时易出现危险失控的问题，此类氧化剂在氧化时后处理也复杂，生产成本相对较高，对环境的污染也不可忽视。CN1458148A公开了采用过氧化氢作为氧化剂的氧化方法，过氧化氢是一种工业常用的氧化剂，其价格低廉，反应后产生水，不产生废弃物，不会造成污染；由于没有其他有机物产生，产品纯化简单，但所采用的催化体系为非均相体系。本发明旨在改善对双氧水的催化体系，寻找一种均相催化氧化制备比卡鲁胺的方法。
现代化工生产中，均相体系因具有反应条件温和，高活性、高选择性等诸多优点而被广泛采用，但最后产物的分离与提纯及催化剂回收带来工程上的困难，同时也有可能产生大量废液而对环境造成污染，为解决这些问题而采用的均相催化多相化方法原则上分为两大类，一类是将催化剂静态固定在有机高分子或无机载体上的均相催化剂固载化，另一类是将均相催化剂动态担载与产物互不相溶的液相而实施的液/液两相催化。而液/液两相催化体系既保留了均相催化反应条件温和、催化活性高、选择型好的优点，又具有多项催化工艺简单、催化剂易于产物分离的特点，呈现出良好的应用前景。专利CN1660498A，公开了一种乳液催化体系，使用过氧化氢做氧化剂，季铵盐杂多化合物为催化剂的催化氧化体系；该乳液体系能够在较温和的条件下，高效的选择催化氧化醇，有机硫化物，烯烃，烯丙醇，有机硫化物等多类有机分子。鉴于该催化体系的上述优点，因此本发明开发了以乳液催化体系催化氧化制备比卡鲁胺的方法。
发明内容
本发明的目的是克服现有技术的不足，提供一种乳液催化体系中动态均相催化氧化制备比卡鲁胺的方法，以提高催化效率、反应收率、并对反应溶剂和催化剂实现循环使用。
本发明制备比卡鲁胺的技术方案如下:
该方法以N-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺(硫醚中间体I)为原料，以具有反应控制相特点的磷钨杂多酸季铵盐为催化剂，以二氯甲烷为溶剂，在15-30℃的反应温度下，使用过氧化氢氧化硫醚中间体(I)生成比卡鲁胺。
所用的催化剂为具有反应控制相转移特点的磷钨杂多酸季铵盐，所述的磷钨杂多酸季铵盐选自十八烷基三甲基磷钨杂多酸盐([(C18H37)3N+(CH3)]3[PW12O40])或双十八烷基二甲基磷钨杂多酸盐([(C18H37)2N+(CH3)2]3[PW12O40])中的一种。
所述过氧化氢的浓度为20%-30%。
过氧化氢与硫醚中间体I的摩尔比为：1.5-2:1。
催化剂的用量为硫醚中间体I质量的1%-2%。
反应时间20-30分钟。
本发明方法具有反应条件温和，反应收率高，催化效率高，催化剂和反应溶剂可回收循环使用的优点。
具体实施方式
实施例1
制备催化剂：参考专利CN1660498A
催化剂A：[(C18H37)2N+(CH3)2]3[PW12O40]可按如下方法制备：将3.05克双十八烷基氯化铵加入盛有150毫升去离子水的烧杯中加热至30℃，在剧烈搅拌下，向该烧杯滴加有5克H3PW12O40的10毫升水溶液，立即生成白色沉淀，再连续搅拌3-4小时后，白色浆状液经过滤，去离子水洗涤，真空干燥得到白色固体6.7克，收率约为85%。
并以类似的方法制备得到催化剂B：[(C18H37)3N+(CH3)]3[PW12O40]
实施例2
取硫醚中间体(I)40克(约0.1mol)溶于40毫升二氯甲烷中，加入催化剂A 0.4克，并于室温(约25℃)滴加30%的过氧化氢15ml，搅拌反应25分钟，然后静置，分液，过滤回收催化剂，取上层有机层浓缩，干燥得到白色比卡鲁胺固体42.7克，回收溶剂二氯甲烷，产品收率为99.1%，HPLC含量98.9%，熔点192~194℃。
实施例3
取硫醚中间体(I)40克(约0.1mol)溶于40毫升二氯甲烷中，加入催化剂B 0.4克，并于室温(约25℃)滴加30%的过氧化氢15ml，搅拌反应25分钟，然后静置，分液，过滤回收催化剂，取上层有机层浓缩，干燥得到白色比卡鲁胺固体41.8克，回收溶剂二氯甲烷，反应收率42.6克，产品收率为97.2%，HPLC含量98.3%。
实施例4
取硫醚中间体(I)20克(约0.05mol)溶于20毫升二氯甲烷中，加入催化剂A 0.4克，并于室温(约25℃)滴加30%的过氧化氢11ml，搅拌反应30分钟，然后静置，分液，过滤回收催化剂，取上层有机层浓缩，干燥得到白色比卡鲁胺固体41.8克，回收溶剂二氯甲烷，反应收率21.3克，产品收率为99.1%，HPLC含量98.9%。
实施例5
取硫醚中间体(I)20克(约0.05mol)溶于40毫升二氯甲烷中，加入催化剂B 0.4克，并于20℃滴加30%的过氧化氢15ml，搅拌反应30分钟，然后静置，分液，过滤回收催化剂，取上层有机层浓缩，干燥得到白色比卡鲁胺固体41.8克，回收溶剂二氯甲烷，反应收率20.8克，产品收率为96.7%，HPLC含量98.5%。
实施例6
按照实施例2的相同条件，对催化剂A进行循环利用的催化活性考察
| 循环次数 | 反应收率 |
| 1 | 99.1% |
| 2 | 93% |
| 3 | 86% |
由于在实验操作过程中，存在催化剂的收集即转移损失，进而导致产品收率有所降低。
Claims (1)
1.一种比卡鲁胺的合成方法，其特征在于：以N-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺为原料，以磷钨杂多酸季铵盐为催化剂，以二氯甲烷为溶剂，在15-30℃的反应温度下，过氧化氢为氧化剂，催化氧化制备比卡鲁胺；所述过氧化氢的浓度为20%-30%，过氧化氢与N-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺的摩尔比为：1 .5-2:1；催化剂的用量为N-(4-氰基-3-三氟甲基苯基)-3-(4-氟苯硫基)-2-甲基-2-羟基丙酰胺质量的1%-2%；反应时间20-30分钟；所述磷钨杂多酸季铵盐的结构为[(C18H37)2N+(CH3)2]3[PW12O40]。
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