CN112321497A - 一种4-氨基吡啶类化合物的制备方法 - Google Patents
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Classifications
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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
- C07D213/72—Nitrogen atoms
- C07D213/73—Unsubstituted amino or imino radicals
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- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
本发明公开了一种4‑氨基吡啶类化合物的制备方法，包括：将4‑氨基‑3‑氯吡啶类化合物或4‑氨基‑3,5‑二氯吡啶类化合物、磷酸钾和催化剂加入到溶剂中，在0～10MPa、0～100℃下反应4～12h。本发明的4‑氨基吡啶类化合物制备方法，所涉及的原料易得或容易自制，成本低廉，本发明的制备方法简单，反应效率高，原料成本低，副产物具有经济价值；同时，本发明所涉及的反应对官能团具有很好的普适性和容忍性。
Description
技术领域
本发明涉及有机化合物制备技术领域，具体涉及一种4-氨基吡啶类化合物的制备方法。
背景技术
4-氨基吡啶类化合物是一类非常重要的化工原料，被广泛的应用科学研究、合成农药和医药产品的生产中。在科学研究中，这类化合物可通过参与种类繁多的有机化学反应来构建较为复杂的目标化合物。
目前已知的合成方法中，3-或3,5-具有氢原子的取代4-氨基吡啶类化合物大部分都是通过以下两种方法来制备的：一、使用相应的4-卤代吡啶类化合物在高压条件下与氨发生反应制得；二、分别用具有3-氯代或3,5-二氯代的4-氨基吡啶类化合物经过氢化脱氯制得。第一种方法需要逐个分别制得各种卤代吡啶，再进行高压氨化反应，反应操作复杂，收率较低；第二种方法通过取代的4-氨基吡啶类化合物在三乙胺存在下进行氢化脱氯制得，但所用试剂复杂，对环境不友好，操作复杂。
发明内容
因此，本发明要解决的技术问题在于克服现有技术中的4-氨基吡啶类化合物制备效率低、操作复杂的缺陷，从而提供一种4-氨基吡啶类化合物的制备方法，通过简单的操作方法，制备得到收率高、纯度高的4-氨基吡啶类化合物。
为此,本发明提供了一种4-氨基吡啶类化合物制备方法，包括如下步骤：
将4-氨基-3-氯吡啶类化合物或4-氨基-3,5-二氯吡啶类化合物、磷酸钾和催化剂加入到溶剂中，在0～10MPa、0～100℃下反应4～12h；
反应过程为：
优选地，所述取代基R选自烷基、烷氧基、酰胺基、酯基、酮羰基或卤素中的一种或多种。
优选地，所述R为多个取代基，相邻两个取代基相互独立或成环。
优选地，所述溶剂为苯、甲苯、二甲苯、甲醇、乙醇、异丙醇、正丙醇、叔丁醇、异丁醇、正丁醇、二氯甲烷、1,2-二氯乙烷、四氢呋喃或1,4-二氧六环中的至少一种。
优选地，所述催化剂为5％钯碳催化剂、10％钯碳催化剂、20％氧化钯碳催化剂或RaneyNi催化剂中的一种。
优选地，所述反应温度为20～70℃，所述反应压力为0.3～1MPa。
优选地，还包括反应后对反应产物进行后处理。
优选地，所述后处理包括浓缩和纯化，所述纯化为重结晶。
本发明技术方案，具有如下优点：
1.本发明提供的4-氨基吡啶类化合物制备方法，所涉及的原料易得或容易自制，成本低廉，反应条件温和，可适用于工业化大规模生产；
2.本发明提供的4-氨基吡啶类化合物的制备方法简单，反应效率高，原料成本低，副产物具有经济价值；同时，本发明所涉及的反应对官能团具有很好的普适性和容忍性。
具体实施方式
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
实施例1
4-氨基-3-氯-2,6-二氟吡啶的制备方法
3,5-二氯-2,4,6-三氟吡啶的合成：将250g五氯吡啶、190g无水氟化钾与600mL环丁砜混合，于150℃搅拌反应2h，降至室温，取样监测原料转化完全，将反应液倾倒在3L冰水中，用二氯甲烷萃取。有机相依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的粗品经过精馏纯化得到174.5g无色液体，为3,5-二氯-2,4,6-三氟吡啶，GC检测含量98.7％，收率87％。
4-氨基-3,5-二氯-2,6-二氟吡啶的合成：将500mL25％氨水冷却到0℃，向其中慢慢滴加100g3,5-二氯-2,4,6-三氟吡啶，反应液中逐渐析出白色固体。滴加结束后将反应液加热到60℃保温反应2.5h，降至室温。反应液抽滤，滤饼充分水洗，干燥，得到95g白色固体，为4-氨基-3,5-二氯-2,6-二氟吡啶，HPLC含量99％，收率96％。
4-氨基-3-氯-2,6-二氟吡啶的合成：将40g4-氨基-3,5-二氯-2,6-二氟吡啶、43g磷酸钾、2g10％钯碳催化剂(含水率54％)和200mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于0.5MPa氢气压力，50℃搅拌反应2h，降至室温，减压蒸除大部分溶剂，析出大量固体，加100mL水稀释，抽滤，滤饼充分水洗，然后用20mL50％乙醇水溶液重结晶，得到23.6g白色针状固体，为4-氨基-3-氯-2,6-二氟吡啶，HPLC含量98.5％，收率72％。
实施例2
4-氨基-2,6-二氟吡啶的制备方法
将40g4-氨基-3,5-二氯-2,6-二氟吡啶、86g磷酸钾、4g10％钯碳催化剂(含水率54％)和300mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于0.5MPa氢气压力，65℃搅拌反应8h，降至室温，减压蒸除大部分溶剂，然后加150mL水稀释，抽滤，滤饼充分水洗，然后用15mL50％乙醇水溶液重结晶，得到24g白色片状固体，为4-氨基-2,6-二氟吡啶，HPLC含量98.5％，收率92％。
实施例3
4-氨基-2,5,6-三氟吡啶的制备方法
3-氯-2,4,5,6-四氟吡啶的合成：将70g3,5-二氯-2,4,6-三氟吡啶、22g无水氟化钾与150mL环丁砜混合，于180℃搅拌反应2.5h，降至室温，取样监测原料转化完全，将反应液倾倒在1L冰水中，用二氯甲烷萃取。有机相依次用水、饱和氯化钠溶液洗涤，无水硫酸钠干燥，减压浓缩，得到的粗品经过精馏纯化得到46.5g无色液体，为3-氯-2,4,5,6-四氟吡啶，GC含量98.3％，收率72％。
4-氨基3-氯-2,5,6-三氟吡啶的合成：将200mL25％氨水冷却到0℃，向其中慢慢滴加40g3-氯-2,4,5,6-四氟吡啶，反应液中逐渐析出白色固体。滴加结束后将反应液加热到60℃保温反应2.5h，降至室温。反应液抽滤，滤饼充分水洗，干燥，得到35.8g白色固体，为4-氨基3-氯-2,5,6-三氟吡啶，HPLC含量99％，收率91％。
4-氨基-2,5,6-三氟吡啶的合成：将30g4-氨基3-氯-2,5,6-三氟吡啶、33g磷酸钾、3g10％钯碳催化剂(含水率54％)和150mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于0.5MPa氢气压力，65℃搅拌反应8h，降至室温，减压蒸除大部分溶剂，然后加100mL水稀释，抽滤，滤饼充分水洗，然后用10mL50％乙醇水溶液重结晶，得到21g白色羽毛片状固体，为4-氨基-2,5,6-三氟吡啶，HPLC含量98.5％，收率86％。
实施例4
4-氨基-2,6-二氟吡啶的制备方法
将40g4-氨基-3,5-二氯-2,6-二氟吡啶、86g磷酸钾、4g5％钯碳催化剂(含水率54％)和300mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于1MPa氢气压力，70℃搅拌反应12h，降至室温，减压蒸除大部分溶剂，然后加150mL水稀释，抽滤，滤饼充分水洗，然后用15mL50％乙醇水溶液重结晶，得到23.48g白色片状固体，为4-氨基-2,6-二氟吡啶，HPLC含量98.0％，收率90％。
实施例5
4-氨基-2,6-二氟吡啶的制备方法
将40g4-氨基-3,5-二氯-2,6-二氟吡啶、86g磷酸钾、4g20％钯碳催化剂(含水率54％)和300mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于0.3MP氢气压力，60℃搅拌反应4h，降至室温，减压蒸除大部分溶剂，然后加150mL水稀释，抽滤，滤饼充分水洗，然后用15mL50％乙醇水溶液重结晶，得到23.69g白色片状固体，为4-氨基-2,6-二氟吡啶，HPLC含量98.3％，收率90.8％。
实施例6
4-氨基-2,6-二氟吡啶的制备方法
将40g4-氨基-3,5-二氯-2,6-二氟吡啶、86g磷酸钾、4gRaneyNi催化剂和300mL50％乙醇水溶液加入到氢化釜中，依次用氮气、氢气置换，然后于1MPa氢气压力，70℃搅拌反应12h，降至室温，减压蒸除大部分溶剂，然后加150mL水稀释，抽滤，滤饼充分水洗，然后用15mL50％乙醇水溶液重结晶，得到23.36g白色片状固体，为4-氨基-2,6-二氟吡啶，HPLC含量98.4％，收率89.5％。
显然，上述实施例仅仅是为清楚地说明所作的举例，而并非对实施方式的限定。对于所属领域的普通技术人员来说，在上述说明的基础上还可以做出其它不同形式的变化或变动。这里无需也无法对所有的实施方式予以穷举。而由此所引伸出的显而易见的变化或变动仍处于本发明创造的保护范围之中。
Claims (8)
1.一种4-氨基吡啶类化合物的制备方法，其特征在于，包括如下步骤：
将4-氨基-3-氯吡啶类化合物或4-氨基-3,5-二氯吡啶类化合物、磷酸钾和催化剂加入到溶剂中，在0～10MPa、0～100℃下反应4～12h；
反应过程为：
2.根据权利要求1所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述取代基R选自烷基、烷氧基、酰胺基、酯基、酮羰基或卤素中的一种或多种。
3.根据权利要求2所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述R为多个取代基，相邻两个取代基相互独立或成环。
4.根据权利要求1所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述溶剂为苯、甲苯、二甲苯、甲醇、乙醇、异丙醇、正丙醇、叔丁醇、异丁醇、正丁醇、二氯甲烷、1,2-二氯乙烷、四氢呋喃或1,4-二氧六环中的至少一种。
5.根据权利要求1或2所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述催化剂为5％钯碳催化剂、10％钯碳催化剂、20％氧化钯碳催化剂或RaneyNi催化剂中的一种。
6.根据权利要求1所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述反应温度为20～70℃，所述反应压力为0.3～1MPa。
7.根据权利要求1～6任一项所述的4-氨基吡啶类化合物的制备方法，其特征在于，还包括反应后对反应产物进行后处理。
8.根据权利要求7所述的4-氨基吡啶类化合物的制备方法，其特征在于，所述后处理包括浓缩和纯化，所述纯化为重结晶。
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