CN102241729B - 3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成方法 - Google Patents
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Abstract
本发明公开了一种3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成方法，包括如下步骤：将3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯于溶剂中，在金属催化剂存在下，与机胺甲酸盐反应，然后从反应产物中收集目标产物3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯。本发明的方法，反应条件温和，反应比较完全，经简单纯化后其纯度可达到99％以上。在整个反应中所使用的试剂都是易得的，同时反应收率高，反应条件温和，溶剂能回收利用，因而便于工业化实施。
Description
技术领域
本发明涉及一种制备非那甾胺重要中间体3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成方法。
背景技术
非那甾胺(finasteride，商品名Proscar，代号MK-906)是美国默克公司开发研制的良性前列腺增生症的治疗药物，已于1992年上市。良性前列腺增生症(BPH)是老年男性的常见疾病，也是导致男性排尿困难最常见的病因。研究发现二氢睾酮含量的升高是引起BPH的原因。5α-还原酶抑制剂可抑制睾酮转化为二氢睾酮而达到治疗BPH的目的。使增生的前列腺得不到双氢睾酮而萎缩，从而显示疗效。此药疗效确切，副作用小。其结构式如下：
目前，已有的技术中，均涉及到重用中间体3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成，反应式如下：
如药学实践杂志2007 25(5)310-312提供了一种制备非那甾胺的方法，在其关键步骤3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯氢化获得3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的过程中时，使用价格昂贵的Pd/C作为催化剂，冰醋酸为溶剂以85％的收率获得目标产物。该方法立体选择性差，获得产物的同时获得5-β构型的光学异构体(4)。其结构式如下：
利用该方法，经HPLC测定在产物中混有15-20％不等的β异构体，该异构体性质与产物接近，不易纯化分离，需通过多次重结晶去除造成了产物收率的降低，同时大量使用了贵金属催化剂Pd/C以及该异构体无法回收套用等问题造成了产品成本上升，限制了其工业化生产。
发明内容
本发明的目的是提供一种3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成方法，以克服现有技术存在的上述缺陷。
本方法的方法包括如下步骤：
将3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯于溶剂中，在金属催化剂存在下，与机胺甲酸盐反应2～24h，反应温度为20～100℃，然后从反应产物中收集目标产物3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯，立体选择性大于95％，收率为95～99.5％，反应方程式如下：
所述的金属催化剂为Raney-Ni或Ni(acac)2等；
所述的有机胺为三乙胺、三丁胺、三甲胺、三辛胺或吡啶等；
所述的酸优选为三乙胺；
所述的溶剂为甲醇、乙醇、冰醋酸、丙酮、四氢呋喃、乙醚、2-甲基呋喃、异丙醚、1，4-二氧六环、乙二醇二甲醚、一缩二乙二醇二甲醚、二氯甲烷、1，2-二氯乙烷、正戊烷、正己烷、石油醚、正庚烷、甲苯或二甲苯的一种以上；
3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯、金属催化剂和有机胺甲酸盐的质量比为1∶0.01-0.1∶1-3；
化合物(2)可根据文献J.Med.Chem.，1984，27，1690有详细报道，此处不再赘述，有机胺甲酸盐为市售化学品(美国Aldrich公司)。
本发明能以较高收率及高立体选择性得到纯度较高产物，另我们惊奇的是使用有机胺甲酸盐代替氢气作为供氢体后，产物的立体选择性大大提高，其立体选择性达到95％以上。同时该方法避免使用价格昂贵Pd/C催化剂，以便宜易得的催化剂Raney-Ni催化该反应。所使用的方法简单，安全，绿色环保。本方明所报道的方法避免了该类化合物传统合成工艺中所遇到的立体选择性差、收率低，所使用试剂价格昂贵等问题、大大降低了生产成本。同时避免了使用较为危险的氢气在中高压力反应的苛刻反应条件问题。其生产工艺中“三废”排放大幅度降低。这是其他方法无法达到的。以本发明所述及的方法制备得到的3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯由于其反应条件温和，反应比较完全，经简单纯化后其纯度可达到99％以上。在整个反应中所使用的试剂都是易得的，同时反应收率高，反应条件温和，溶剂能回收利用，因而便于工业化实施。
具体实施方式
通过以下具体实施方法将有助于理解本发明，但并不限制本发明的内容。
实施例1
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备：
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL乙醇及3.31gRaney-Ni。之后加入60g三乙胺甲酸盐。体系在回流情况下继续搅拌2h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞99∶1，产物中随后该产物经溶剂重结晶获得目标产物31.67g，yield：95％，HPLC含量大于99％。
实施例2
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL甲醇及3.31gRaney-Ni。之后加入60g三乙胺甲酸盐。体系在回流情况下继续搅拌5h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞98∶2，产物中随后该产物经溶剂重结晶获得目标产物31.67g，yield：95％，HPLC含量大于99％。
实施例3
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL甲醇及0.33gRaney-Ni。之后加入35g三乙胺甲酸盐。体系在回流情况下继续搅拌24h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞97∶3，产物中随后该产物经溶剂重结晶获得目标产物31.67g，yield：95％，HPLC含量大于99％。
实施例4
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL醋酸及0.33gRaney-Ni。之后加入60g三甲胺甲酸盐。体系在回流情况下继续搅拌2h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞99∶1，产物中随后该产物经溶剂重结晶获得目标产物32.68g，yield：98％，HPLC含量大于99％。
实施例5
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL醋酸及0.33gRaney-Ni。之后加入60g三乙胺甲酸盐。体系在回流情况下继续搅拌2h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞99∶1，产物中随后该产物经溶剂重结晶获得目标产物33.02g，yield：99％，HPLC含量大于99％。
实施例6
3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的制备
在一干燥充满氮气的装配有温度计、回流冷凝管、磁力搅拌的250mL三口瓶中依次加入3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯(33.14g；Fw：331.45；100mmol)，随后加入200mL四氢呋喃及3.3gRaney-Ni。之后加入60g三乙胺甲酸盐。体系在回流情况下继续搅拌24h。反应完毕后待体系冷却至室温后，过滤除去固体，将滤液蒸干，加入冰水后用二氯甲烷萃取，萃取液洗涤干燥，蒸干得粗产物，经HPLC分析粗产品中α异构体：β异构体＞97∶3，产物中随后该产物经溶剂重结晶获得目标产物31.68g，yield：95％，HPLC含量大于99％。
Claims (2)
1.3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯的合成方法，其特征在于，包括如下步骤：
将3-羰基-4-氮杂-5-雄甾烯-17β-羧酸甲酯于溶剂中，在金属催化剂存在下，与有机胺甲酸盐反应，然后从反应产物中收集目标产物3-羰基-4-氮杂-5α-雄甾-17β-羧酸甲酯；
反应时间为2～24h，反应温度为20～100°C；
所述的金属催化剂为Raney-Ni或Ni(acac)2，所述的有机胺为三乙胺、三丁胺、三甲胺、三辛胺或吡啶。
2.根据权利要求1所述的方法，其特征在于，所述的溶剂为甲醇、乙醇、冰醋酸、丙酮、四氢呋喃、乙醚、2-甲基呋喃、异丙醚、1，4-二氧六环、乙二醇二甲醚、一缩二乙二醇二甲醚、二氯甲烷、1，2-二氯乙烷、正戊烷、正己烷、石油醚、正庚烷、甲苯或二甲苯的一种以上。
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