CN104016914A - 一种酰胺化合物的制备方法 - Google Patents
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- 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
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- 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
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Abstract
本发明公开了一种酰胺化合物的制备方法，具体包括如下步骤：空气氛围中，在碱存在下，以氰基化合物、硼酸化合物为原料，以质子性溶剂以及非质子性溶剂的混合溶剂为反应介质，以钯化合物为催化剂，加热下通过氰基水解反应与碳碳偶联反应制备得到酰胺化合物。本发明公开的新的制备酰胺化合物的方法避免了现有技术中氧化剂的使用，从而有效抑制了氰基的过度水解，避免了酰胺进一步水解为羧酸的现象，极大提高了酰胺化合物的反应产率；并且此方法可与碳碳偶联反应同时进行，制备更多酰胺化合物，对于酰胺化合物的工业化生成具有重要的市场价值和经济效益。
Description
技术领域
本发明属于有机化合物制备领域，具体涉及一种酰胺化合物的制备方法。
背景技术
酰胺化合物是一类重要的化工原材料，在生物、医学、制药等领域有着广泛的应用。现有技术中制备酰胺化合物的方式有两种：一种是通过羧基与氨基的缩合反应来制备得到酰胺，但该反应通常需要对原料进行活化处理，反应条件通常比较苛刻。
另外则是通过氰基水解方式制备酰胺化合物，主要分为在酸性条件或者碱性条件下水解氰基。在碱性条件下，利用过氧化氢氧化的方法可在室温下短时间内水解腈为酰胺；但该方法通常不容易控制反应的进度，而使氰基完全水解成羧酸。
因此寻找新的高效、可控制备酰胺化合物的合成方法具有十分重要的意义。
发明内容
本发明的目的是提供一种酰胺化合物的制备方法。
为达到上述发明目的，本发明采用的技术方案是：一种酰胺化合物的制备方法，包括如下步骤：空气氛围中，在碱存在下，以氰基化合物、硼酸化合物为原料，以质子性溶剂以及非质子性溶剂的混合溶剂为反应介质，以钯化合物为催化剂，于40-100℃下通过氰基水解反应与碳碳偶联反应制备得到酰胺化合物；
所述氰基化合物的结构式为 ，式中Ar1为苯基或者吡啶基，X为卤素；
所述硼酸化合物的结构式为，式中Ar2为，其中，R1、R2、R3、R4、R5独立的选自H、CH3、OMe、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、F、Cl、Br、SCH3、CF3、OCF3、COCH3、NO2或者NH2；
所述酰胺化合物的结构式为
。
上述技术方案中，所述非质子性溶剂为甲苯、二甲苯、四氢呋喃、丙酮、N，N-二甲基甲酰胺、N，N-二甲基亚砜中的一种或一种以上混合物；所述质子性溶剂是水、乙醇、乙二醇乙醚、乙二醇甲醚中的一种或一种以上混合物。
上述技术方案中，所述碱为碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾、甲醇钠、甲醇钾、氢氧化钠、氢氧化钾、浓氨水、吡啶或者1,8-二氮杂二环十一碳-7-烯。
上述技术方案中，氰基水解反应与碳碳偶联反应的时间为0.5-48h。
上述技术方案中，所述氰基化合物与硼酸化合物的摩尔比为1-1.4∶1；碱与硼酸化合物的摩尔比为0.01-0.2∶1。
上述技术方案中，钯化合物作为催化剂，一般选用有机钯化合物，本发明优选四三苯基磷钯；其用量0. 1%-10%。
上述技术方案中，浓氨水的质量浓度为22-25%；1,8-二氮杂二环十一碳-7-烯又称DBU，其结构式为：
。
优选的技术方案中，所述氰基水解反应与碳碳偶联反应的温度为回流温度。
上述技术方案还包括提纯步骤，具体为反应结束后，利用二氯甲烷洗反应液，然后收集有机相，最后利用硅胶柱层析进行纯化分离后得到产物酰胺化合物。
本发明中质子溶剂和非质子溶剂的混合可以提高反应的效率；加热克服了反应的活化能，有利于反应的顺利进行。
以2-溴-5-氰基吡啶与苯硼酸制备2-苯基-5-酰胺基吡啶为例，本发明可表示如下：
由于上述技术方案运用，本发明与现有技术相比具有下列优点:
1．本发明公开的新的制备酰胺化合物的方法避免了现有技术中氧化剂的使用，从而有效抑制了氰基的过度水解，避免了酰胺进一步水解为羧酸的现象，极大提高了酰胺化合物的反应产率；
2．本发明公开的氰基水解制备酰胺化合物的方法可与碳碳偶联反应同时进行，制备更多酰胺化合物，对于酰胺化合物的工业化生成具有重要的市场价值和经济效益；
3. 本发明公开的制备酰胺化合物的合成路线短，只需一步；制备过程简单可控，效率高，环保，易于产业化。
具体实施方式
下面结合具体实施例对本发明作进一步描述：
实施例1
将2-溴-5-氰基吡啶 (10 mmol, 1.83g)，2,4-二氟苯硼酸(10 mmol，1.58 g)，Na2CO3 (0.5 mmol, 57 mg) ，四三苯基磷钯（0.1 mmol，115mg）溶于甲苯/乙醇/水（V:V:V=5:2:1）的混合溶剂中，回流反应24小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体 2-(2’,4’-二氟苯基)-5-酰胺吡啶2.1 g (产率：89%)；Ms(M/Z):234.1 (M+)；1H NMR (DMSO-d 6 , 400 MHz), δppm:9.15 (s, 1 H), 8.33 (dd, J=8 Hz, 2 Hz,1H), 8.22(s, 1H), 8.06 (m, 1H), 7.88(m, 1H), 7.66 (s, 1H), 7.44 (m, 1H), 7.27 (m, 1H)。
实施例2
将2-溴-5-氰基吡啶 (1 mmol, 0.183 g)，苯硼酸 (1 mmol, 0.122 g), K2CO3 (0.1 mmol, 13.8 mg) ，四三苯基磷钯（0.01 mmol，11.5 mg）溶于四氢呋喃/水（V:V=3:1）的混合溶剂中，回流反应12小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体2-苯基-5-酰胺基吡啶0.12 g (产率：60%)；Ms(M/Z):198.2 (M+)。
实施例3
将2-溴-5-氰基吡啶 (1 mmol, 0.183 g)，3-甲氧基-苯硼酸(1 mmol, 0.152 g), Na2CO3 (0.1 mmol, 11.4 mg) ，四三苯基磷钯（0.1 mmol，11.5 mg）溶于甲苯/水（V:V=2:1）的混合溶剂中，回流反应36小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体 2-(3’-甲氧基苯基)-5-酰胺基吡啶0.19 g (产率：83%)；Ms(M/Z):228.0 (M+)。
实施例4
将3-溴-5-氰基吡啶 (1 mmol, 0.183 g)，苯硼酸 (1 mmol, 0.122 g)，吡啶 (1 mL) ,四三苯基磷钯（0.01 mmol，11.5 mg）溶于甲苯/乙醇（V:V=3:1）的混合溶剂中，回流反应20小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体3-苯基-5-酰胺基吡啶0.11 g (产率：56%)；Ms(M/Z):198.2 (M+)。
实施例5
将3-溴-6-氰基吡啶 (1 mmol, 0.183 g)，苯硼酸 (1 mmol, 0.122 g), K2CO3 (0.05 mmol, 6.9 mg) ，四三苯基磷钯（0.01 mmol，11.5 mg）溶于甲苯/水 (V:V=3:1）的混合溶剂中，回流反应12小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体3-苯基-6-酰胺基吡啶0.15 g (产率：76%)；Ms(M/Z):198.2 (M+)。
实施例6
将2-溴-6-氰基吡啶 (1 mmol, 0.183 g)，苯硼酸(1 mmol, 0.122 g), K2CO3 (0.1 mmol, 13.8 mg) ，四三苯基磷钯（0.01 mmol，11.5 mg）溶于甲苯/水（V:V=3:1）的混合溶剂中，回流反应36小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体3-苯基-6-酰胺基吡啶0.17 g (产率：86%)；Ms(M/Z):198.2 (M+)。
实施例7
将3-溴-2-氰基吡啶 (1 mmol, 0.183 g)，苯硼酸(1 mmol, 0.122 g), K2CO3 (0.1 mmol, 13.8 mg) ，四三苯基磷钯（0.01 mmol，11.5 mg）溶于THF/H2O（V:V=3:1）的混合溶剂中，回流反应24小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体3-苯基-2-酰胺基吡啶0.17 g (产率：86%)；Ms(M/Z):198.2 (M+)。
实施例8
将2-溴-5-氰基吡啶 (1 mmol, 0.183g)，2-乙基-苯硼酸(1 mmol, 0.150 g), Na2CO3 (0.1 mmol, 11.4 mg) ，四三苯基磷钯（0.1 mmol，11.5 mg）溶于甲苯/水（V:V=1:1）的混合溶剂中，回流反应36小时后，停止反应，静置室温后，利用二氯甲烷进行水洗后，收集有机相，然后利用硅胶柱层析进行纯化分离后得到白色固体 2-(2’-乙基苯基)-5-酰胺基吡啶0.15 g (产率：66%)；Ms(M/Z):226.1 (M+)。
Claims (8)
1.一种酰胺化合物的制备方法，其特征在于，包括如下步骤：空气氛围中，在碱存在下，以氰基化合物、硼酸化合物为原料，以质子性溶剂以及非质子性溶剂的混合溶剂为反应介质，以钯化合物为催化剂，于40-150℃下通过氰基水解反应与碳碳偶联反应制备得到酰胺化合物；
所述氰基化合物的结构式为 ，式中Ar1为苯基或者吡啶基，X为卤素；
所述硼酸化合物的结构式为，式中Ar2为，其中，R1、R2、R3、R4、R5独立的选自H、CH3、OMe、CH2CH3、CH2CH2CH3、CH2CH2CH2CH3、F、Cl、Br、SCH3、CF3、OCF3、COCH3、NO2或者NH2；
所述酰胺化合物的结构式为
。
2.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述非质子性溶剂为甲苯、二甲苯、四氢呋喃、丙酮、N，N-二甲基甲酰胺、N，N-二甲基亚砜中的一种或一种以上混合物；所述质子性溶剂是水、乙醇、乙二醇乙醚、乙二醇甲醚中的一种或一种以上混合物。
3.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述碱为碳酸钠、碳酸钾、叔丁醇钠、叔丁醇钾、甲醇钠、甲醇钾、氢氧化钠、氢氧化钾、浓氨水、吡啶或者1,8-二氮杂二环十一碳-7-烯。
4.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述氰基水解反应与碳碳偶联反应的温度为回流温度。
5.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述氰基水解反应与碳碳偶联反应的时间为0.5-48h。
6.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述氰基化合物与硼酸化合物的摩尔比为(1-1.4)∶1；碱与硼酸化合物的摩尔比为(0.01-0.2)∶1。
7.根据权利要求1所述酰胺化合物的制备方法，其特征在于：所述钯化合物为四三苯基磷钯。
8.根据权利要求1所述酰胺化合物的制备方法，其特征在于：还包括提纯步骤，具体为反应结束后，利用二氯甲烷洗反应液，然后收集有机相，最后利用硅胶柱层析进行纯化分离后得到产物酰胺化合物。
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