CN116063163A - 7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法 - Google Patents
7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法 Download PDFInfo
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Abstract
本发明公开了一种7‑(苄氧基)‑2,4,5,6‑四氢‑1H‑环丁二烯[f]茚‑1‑酮的制备方法,该方法采用稳定易得的氯乙醛缩乙二醇与4‑(苄氧基)‑5‑溴‑2,3‑二氢‑1H‑茚作为原料,在碱的作用下进行高活性反应,以理想的反应收率制得7‑(苄氧基)‑2,4,5,6‑四氢‑1H‑环丁二烯[f]茚‑1‑酮。本发明通过采用氯乙醛缩乙二醇替代现有技术中的1,1‑二乙氧基乙烯作为原料,避免危险试剂如氨基钠的使用,提高反应的整体安全性,解决现有技术中所用原料稳定性差导致整体收率低的问题,还将两步反应变为一锅法,操作简便,更适宜放大生产。
Description
技术领域
本发明涉及医药合成中间体领域,具体涉及一种7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法。
背景技术
由于自身的结构特性,苯并环丁烯酮及其衍生物表现出独特的反应性,可以多种方式打开四元环进行反应,其开环反应范围较广,在有机合成、热固性聚合物等领域均有应用。近年来过渡金属催化的开发揭示了更为新颖的四元环开环模式,为苯并环丁烯酮及其衍生物提供一条新的合成路线循环骨架,由此开发更为方便的合成方法来制备具有广泛官能团耐受性的苯并环丁烯酮较为迫切。7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮作为苯并环丁烯酮衍生物中的一种,其不仅拥有苯并环丁烯酮衍生物的一般特性,还可作为NLRP3(NOD样受体家族,含吡啶结构域的蛋白3,其是多发性硬化、2型糖尿病、阿尔茨海默病和动脉粥样硬化的致病因素)激动抑制剂的关键原料,应用于相关疾病的治疗,极具市场应用前景。
现有技术中,采用4-(苄氧基)-5-溴-2,3-二氢-1H-茚作为原料在氨基钠作用下,与1,1-二乙氧基乙烯进行反应,构建环丁烯酮,以28%的收率得到7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮(WO 2021/150574),技术路线如下式所示:
上述技术路线存在一定的弊端:首先,反应原料1,1-二乙氧基乙烯稳定性差,易变质,从而导致反应整体收率较低;其次,反应中用到的氨基钠不仅在空气中不稳定,且与水可剧烈反应,有致爆危险,存在潜在的安全隐患,从而阻碍了该化合物的发展。
发明内容
本发明针对现有技术中7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法存在原料不稳定、反应收率低以及所用试剂安全隐患较高的问题,提出一种7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,操作简便,所用试剂及原料安全稳定,反应收率理想。
为实现上述目的,本发明采用如下技术方案:
本发明提供一种7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其技术路线如下式所示:
包括以下步骤:
步骤1:在惰性气体保护下,将化合物1溶于有机溶剂1中,加入碱,然后加入化合物2,升温至30~150℃反应1~4h;
步骤2:将步骤1得到的反应液倒入冰水中,用酸液调节pH至1~4,再经有机溶剂2萃取三次;
步骤3:将步骤2得到的萃取混合液分液,所得有机相用饱和食盐水反洗;再次分液,所得有机相用无水硫酸钠干燥,过滤,滤液浓缩物经有机溶剂3重结晶,得到目标化合物3。
进一步,所述有机溶剂1选自N,N-二甲基甲酰胺、无水四氢呋喃、乙醚、二甲基亚砜中的一种或多种,进一步优选为无水四氢呋喃。
进一步,步骤1中,所述碱选自甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠中的一种或多种,进一步优选为叔丁醇钾。
进一步,步骤1中,所述化合物1与碱、化合物2的摩尔比为1:2~5:1.5~2.5,并进一步优选为1:4:2。
进一步,步骤1中,所述化合物1与有机溶剂1的固液比为1:5~15g/mL。
进一步,步骤1中,反应温度为70℃,反应时间为2h。
进一步,步骤2中,所述酸液为3~6N的盐酸溶液,进一步优选为4N的盐酸水溶液。
进一步,所述有机溶剂2选自乙酸乙酯、醋酸异丙酯、二氯甲烷中的一种或多种。
进一步,所述有机溶剂3选自石油醚、正己烷、庚烷、环己烷、四氯化碳中的一种或多种。
进一步,步骤3中,所述化合物1与有机溶剂3的固液比为1:0.7~1.5g/mL,进一步优选为1:1g/mL。
与现有技术相比,本发明中7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法具有如下有益效果:
1.所用试剂低毒易得,避免使用危险试剂如氨基钠,有效避免了反应过程中存在的潜在安全隐患。
2.采用氯乙醛缩乙二醇替代1,1-二乙氧基乙烯作为原料,解决现有技术中由于所用原料1,1-二乙氧基乙烯稳定性差导致整体收率偏低的问题。
3.本发明将两步反应变为一锅法,反应完成后经简单后处理即可得到纯品,操作简便,适宜放大生产,减少中间步骤的处理和损失,从而提高目标产物的收率;同时,原料反应活性高,优化条件下目标产物的反应收率高达76.7%,为制备环丁酮类似物提供了可靠参考。
附图说明
图1为实施例中7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的核磁氢谱图。
图2为实施例中7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备反应式。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将结合本发明实施例的附图对本发明实施例的技术方案进行清楚、完整地描述。显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例。基于所描述的本发明的实施例,本领域普通技术人员在无需创造性劳动的前提下所获得的所有其它实施例,都属于本发明保护的范围。
实施例1
将1000g化合物1(97%,3.2mol)加入5L无水四氢呋喃中,氩气保护下,缓慢加入1465g叔丁醇钾(99%,12.93mol),滴入808g化合物2(97%,6.4mol),滴加完成后,升至70℃反应2h。将反应液倒入冰水中,4N盐酸调节pH=2~3,搅拌0.5h后,EA萃取(1L×3),饱和食盐水反洗,无水硫酸钠干燥,旋干后粗品用石油醚(1L)结晶得到645g化合物3,收率76.57%,纯度99.0%。
为进一步获得最佳碱种类及用量,实施例2-7采用不同碱的种类以及用量对验证本发明上述反应的影响(表1),除变量外,其他步骤与实施例1相同。
表1
由表1可知,叔丁醇钾对反应的促进作用优于甲醇钠、乙醇钠及叔丁醇钠,进一步,4eq的碱为最适宜的用量,在此基础上降低其用量将延缓反应进度,收率有所降低,而增加其用量,促进了副反应的进行,同样使反应收率有所降低。
实施例8
将100g化合物1(97%,0.32mol)加入500mLN,N-二甲基甲酰胺中,氩气保护下,缓慢加入145.0g叔丁醇钾(99%,1.28mol),滴入80.85g化合物2(97%,0.64mol),滴加完成后,升至150℃反应1h。将反应液倒入冰水中,4N盐酸调节pH=2~3,搅拌0.5h后,EA萃取(100mL×3),饱和食盐水反洗,无水硫酸钠干燥,旋干后粗品用石油醚(100mL)结晶得到48.57g化合物3,收率56.51%,纯度98.4%。
实施例9
将100g化合物1(97%,0.32mol)加入500mL无水四氢呋喃中,氩气保护下,缓慢加入145.2g叔丁醇钾(99%,1.28mol),滴入60.65g化合物2(97%,0.48mol),滴加完成后,升至70℃反应2h。将反应液倒入冰水中,4N盐酸调节pH=2~3,搅拌0.5h后,EA萃取(100mL×3),饱和食盐水反洗,无水硫酸钠干燥,旋干后粗品用石油醚(100mL)结晶得到53.69g化合物3,收率62.59%,纯度98.6%。
实施例10
将100g化合物1(97%,0.32mol)加入500mL无水四氢呋喃中,氩气保护下,缓慢加入145.2g叔丁醇钾(99%,1.28mol),滴入101.07g化合物2(97%,0.8mol),滴加完成后,升至70℃反应1.5h。将反应液倒入冰水中,4N盐酸调节pH=2~3,搅拌0.5h后,EA萃取(100mL×3),饱和食盐水反洗,无水硫酸钠干燥,旋干后粗品用石油醚(100mL)结晶得到58.05g化合物3,收率67.26%,纯度98.0%。
上述对实施例的描述是为了便于该技术领域的普通技术人员能理解和使用本发明。熟悉本领域技术人员显然可以容易的对这些实施例做出各种修改,并把在此说明的一般原理应用到其他实施例中,而不必经过创造性的劳动。因此,本发明不限于上述实施例。本领域技术人员根据本发明的原理,不脱离本发明的范畴所做出的改进和修改都应该在本发明的保护范围之内。
Claims (10)
2.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,所述有机溶剂1选自N,N-二甲基甲酰胺、无水四氢呋喃、乙醚、二甲基亚砜中的一种或多种。
3.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤1中,所述碱选自甲醇钠、乙醇钠、叔丁醇钾、叔丁醇钠中的一种或多种。
4.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤1中,所述化合物1与碱、化合物2的摩尔比为1:2~5:1.5~2.5。
5.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤1中,所述化合物1与有机溶剂1的固液比为1:5~15g/mL。
6.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤1中,反应温度为70℃,反应时间为2h。
7.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤2中,所述酸液为3~6N的盐酸溶液。
8.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,所述有机溶剂2选自乙酸乙酯、醋酸异丙酯、二氯甲烷中的一种或多种;所述有机溶剂3选自石油醚、正己烷、庚烷、环己烷、四氯化碳中的一种或多种。
9.根据权利要求1所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,步骤3中,所述化合物1与有机溶剂3的固液比为1:0.7~1.5g/mL。
10.根据权利要求1至9任一项所述7-(苄氧基)-2,4,5,6-四氢-1H-环丁二烯[f]茚-1-酮的制备方法,其特征在于,所述有机溶剂1为无水四氢呋喃;
和/或步骤1中,所述碱为叔丁醇钾;
和/或步骤1中,所述化合物1与碱、化合物2的摩尔比为1:4:2;
和/或步骤2中,所述酸液为4N的盐酸水溶液;
和/或步骤3中,所述化合物1与有机溶剂3的固液比为1:1g/mL。
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