CN108558745A - 一种帕博西林中间体的合成方法 - Google Patents
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- C—CHEMISTRY; METALLURGY
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/61—Halogen atoms or nitro radicals
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Abstract
本发明提供一种帕博西林中间体的合成方法，具体涉及药物合成技术领域，本发明的帕博西林中间体是指4‑(6‑氨基吡啶‑3‑基)哌嗪‑1‑甲酸叔丁酯，以2‑氨基‑5‑溴吡啶为起始原料，通过氧化、偶联、还原得到目的产物的工艺路线，对反应的影响因素进行了系统的实验研究，与传统的制备工艺相比，本发明的工艺路线在生产成本、工艺操作、产品收率和纯度以及环境保护上都有了明显的提高和改善。
Description
技术领域
本发明属于药物合成领域技术领域，具体涉及一种帕博西林中间体的合成方法。
背景技术
帕博西林(Palbociclib)是一种新型口服细胞周期蛋白依赖性激酶4/6(CDK4/6)抑制剂。主要通过调节细胞周期发挥作用，通过抑制CDK4/6活性来阻止细胞由G1期到S 期进而抑制DNA的合成。由美国辉瑞公司研制，并于2015年2月3日由FDA经加速批准途径批准在美国上市，临床上用来与来曲唑联合用于治疗绝经后雌激素受体(ER)阳性、人表皮生长因子受体2(HER2)阴性的晚期乳腺癌患者转移性疾病的初始内分泌治疗。 PalbociclibⅢ期试验PALOMA-3的研究将palbociclib加入标准氟维司群方案治疗经治的HR+/HER2-患者能获得超过两倍的无进展生存改善，Palbociclib将疾病进展时间推迟了将近5个月。因此，对帕博西林中间体的研究也就具有重要意义，现有帕博西林中间体4-(6-氨基吡啶-3-基)哌嗪-1-甲酸叔丁酯其现有的合成方式如：
辉瑞公司专利WO2014128588中公开了一种合成的方法下所示，该路线以1-叔丁氧羧基哌嗪、2-硝基-5-溴吡啶为起始原料，经偶联、还原两步反应制得目标产品。
该方法的优点为反应副产物少，收率较高，两步的总收率为89％，催化加氢还原反应绿色环保，但偶联用到的溶剂二甲基亚砜不便于回收，产物获得过程复杂，加氢反应的产品提取、纯化复杂，需要进一步进行优化研究。
因此，需要一种工艺路线在生产成本、工艺操作、产品收率和纯度以及环境保护上都有了明显的提高和改善的帕博西林中间体的合成方法。
发明内容
本发明的目的是提供一种帕博西林中间体的合成方法，工艺路线在生产成本、工艺操作、产品收率和纯度以及环境保护上都有了明显的提高和改善。
本发明提供了如下的技术方案：
一种帕博西林中间体的合成方法，具体步骤如下：
S1：2-硝基-5-溴吡啶(II)的合成：先分别在低温条件下配制溶液A和溶液B，溶液A为一定量的30％双氧水和一定量98％的浓硫酸的混合物，溶液B为一定量的98％浓硫酸和2-氨基-5-溴吡啶的混合物，在低温条件下将溶液B分批加入到溶液A中，升高温度反应一段时间，得到粗产品，加水搅拌降温再加入碱液搅拌，抽滤，重复加碱液调节PH，然后抽滤得到产物，具体反应式如下：
S2、4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(III)的合成：加入一定量乙腈后，依次加入2-硝基-5-溴吡啶、1-叔丁氧羧基哌嗪、氯化锂，系统进行氮气置换，并加装干燥管，加入三乙胺，然后行加热，缓慢升温，反应一段时间后降温，减压蒸去溶剂，然后加水过滤，得到粗品，再使用溶剂进行重结晶，然后抽滤得到产品，具体反应式如下：
S3、4-(6-氨基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(III)的合成：在反应釜中加入甲醇、10％钯碳分散均匀，加入4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯，系统封闭，充氮气至0.3MPa，置换两次，通入H2至反应釜压力0.3MPa，置换一次，然后常温开始反应，反应一段时间后，抽滤减压旋蒸，得到产品，具体反应式如下：
优选的，步骤S1中的配制溶液A和溶液B的温度条件为5-15℃，溶液A中2-氨基 -5-溴吡啶在98％浓硫酸中的比例为372-378g/L，溶液B中30％双氧水和98％浓硫酸的体积比为0.9-1.1：2，溶液B分批加到溶液A中，且混合后的溶液A和溶液B中，溶液A 中的浓硫酸和溶液B中浓硫酸的含量相同。
优选的，步骤S1中的溶液A和溶液B在50℃下反应至少3小时，以达到TLC分析原料点消失。
优选的，步骤S1中的步骤S1中所述的pH为7。
优选的，步骤S2中的反应条件为控制温度在70-73℃，反应32小时，通过TLC检测反应液显示原料点消失，反应结束后，降温至40℃，减压蒸去溶剂，向烧瓶内加水 30ml，控温40-50℃，加热30分钟，之后热过滤。
优选的，步骤S2中的重结晶使用的溶剂为乙酸乙酯，粗品占乙酸乙酯的比例为110-120g/L。
本发明的有益效果是：本发明的工艺路线在生产成本、工艺操作、产品收率和纯度以及环境保护上都有了明显的提高和改善。
具体实施方式
通过以下三步合成所需的产品，具体如下：
1、2-硝基-5-溴吡啶(II)的合成
于1000ml的三口反应瓶中加到160ml30％双氧水，利用低温反应浴降温至15℃以内，用恒压滴液漏斗将320ml98％浓硫酸滴入反应瓶内的双氧水中，瓶内溶液温度控制在5-15℃范围内，滴加完毕得溶液B。同时在另一个1000ml的三口反应瓶中加入160ml98％浓硫酸，利用低温反应浴降温，将60.00g2-氨基-5-溴吡啶分批加入，温度控制在5-15℃范围内，加料完毕得溶液A。
A、B溶液均配制完毕，用恒压滴液漏斗将溶液B分批滴加到溶液A中，仍利用低温反应浴控制反应瓶温度在0-10℃范围内，最佳温度为5℃，温度变化值不大于3℃，滴加完毕，反应液缓慢升温至50℃，继续反应3小时，取样进行TLC分析原料点消失。
向5000ml的三口反应瓶中加入5000ml水，降温至15℃以内，将上述反应液在搅拌的情况下用恒压滴液漏斗加入到水中，温度控制在-15℃范围内，滴加完毕后，继续搅拌18-20分钟。在5-15℃条件下，加入720g30％的液碱，加完继续搅拌0.5小时然后减压抽滤，加100ml水洗涤，滤饼用稀碱搅洗中和至pH＝7，再次抽滤，所得固体用甲醇重结晶，热过滤，干燥得到浅黄色固体51.13g产品，收率73.4％，产品液相色谱纯度大于99％。
2、4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(III)的合成
在干燥的100ml四口反应瓶中，加入96-100ml乙腈，依次加入2-硝基-5-溴吡啶16.00g、1-叔丁氧羧基哌嗪28g、氯化锂0.80g，系统进行氮气置换，并加装干燥管，加入三乙胺5g，然后用油浴进行加热，缓慢升温，控制温度在70-73℃，反应32小时，通过TLC检测反应液显示原料点消失。
反应结束后，降温至40℃，减压蒸去溶剂，向烧瓶内加水60ml，控温40-50℃，加热30分钟，之后热过滤。滤饼干燥后得到粗品23g，用200ml乙酸乙酯重结晶，溶液自然降温至10℃，抽滤得19.55g，收率85％，产品液相色谱纯度99.1％。
3、4-(6-氨基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(IV)的合成
在100ml反应釜中加入30ml甲醇、0.10g10％钯碳分散均匀，加入1.8g4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯，系统封闭，充氮气至0.3MPa，置换两次，通入H2 至反应釜压力0.3MPa，置换一次，然后常温开始反应，反应12h，HPLC分析反应液，原料含量低于0.5％。反应液通过0.45um的有机滤膜减压抽滤，抽滤减压旋蒸，得到白色固体1.71g，产品收率95％，纯度大于99％。
以上仅为本发明的优选实施例而已，并不用于限制本发明，尽管参照前述实施例对本发明进行了详细的说明，对于本领域的技术人员来说，其依然可以对前述各实施例所记载的技术方案进行修改，或者对其中部分技术特征进行等同替换。凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (6)
1.一种帕博西林中间体的合成方法，其特征在于，具体步骤如下：
S1：2-硝基-5-溴吡啶(II)的合成：先分别在低温条件下配制溶液A和溶液B，溶液A为一定量的30％双氧水和一定量98％的浓硫酸的混合物，溶液B为一定量的98％浓硫酸和2-氨基-5-溴吡啶的混合物，在低温条件下将溶液B分批加入到溶液A中，升高温度反应一段时间，得到粗产品，加水搅拌降温再加入碱液搅拌，抽滤，重复加碱液调节PH，然后抽滤得到产物，具体反应式如下：
S2、4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(III)的合成：加入一定量乙腈后，依次加入2-硝基-5-溴吡啶、1-叔丁氧羧基哌嗪、氯化锂，系统进行氮气置换，并加装干燥管，加入三乙胺，然后进行加热，缓慢升温，反应一段时间后降温，减压蒸去溶剂，然后加水过滤，得到粗品，再使用溶剂进行重结晶，然后抽滤得到产品，具体反应式如下：
S3、4-(6-氨基吡啶-3-基)-哌嗪-1-甲酸叔丁酯(III)的合成：在反应釜中加入甲醇、10％钯碳分散均匀，加入4-(6-硝基吡啶-3-基)-哌嗪-1-甲酸叔丁酯，系统封闭，充氮气至0.3MPa，置换两次，通入H2至反应釜压力0.3MPa，置换一次，然后常温开始反应，反应一段时间后，抽滤减压旋蒸，得到产品，具体反应式如下：
2.根据权利要求1所述的帕博西林中间体的合成方法，其特征在于，步骤S1中的配制溶液A和溶液B的温度条件为5-15℃，溶液A中2-氨基-5-溴吡啶在98％浓硫酸中的比例为372-378g/L，溶液B中30％双氧水和98％浓硫酸的体积比为0.9-1.1：2，溶液B分批加到溶液A中，且混合后的溶液A和溶液B中，溶液A中的浓硫酸和溶液B中浓硫酸的含量相同。
3.根据权利要求1所述的帕博西林中间体的合成方法，其特征在于，步骤S1中的溶液A和溶液B在50℃下反应至少3小时，以达到TLC分析原料点消失。
4.根据权利要求1所述的帕博西林中间体的合成方法，其特征在于，步骤S1中所述的pH为7。
5.根据权利要求1所述的帕博西林中间体的合成方法，其特征在于，步骤S2中的反应条件为控制温度在70-73℃，反应32小时，通过TLC检测反应液显示原料点消失，反应结束后，降温至40℃，减压蒸去溶剂，向烧瓶内加水30ml，控温40-50℃，加热30分钟，之后热过滤。
6.根据权利要求1所述的帕博西林中间体的合成方法，其特征在于，步骤S2中的重结晶使用的溶剂为乙酸乙酯，粗品占乙酸乙酯的比例为110-120g/L。
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