CN114031538A - 一种3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备方法 - Google Patents
一种3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备方法 Download PDFInfo
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- C—CHEMISTRY; METALLURGY
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- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/44—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members
- C07D207/444—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5
- C07D207/456—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having three double bonds between ring members or between ring members and non-ring members having two doubly-bound oxygen atoms directly attached in positions 2 and 5 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 other ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
- C07B59/002—Heterocyclic compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
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Abstract
本发明涉及一种3‑氘代甲硒基‑4‑吗啉基马来酰亚胺化合物的制备方法,在有机溶剂中,氧气条件下,氘代甲硒基布恩特盐、吗啉和N‑苯基马来酰亚胺在铜催化作用下进行氧化胺化/硒化串联反应得到3‑氘代甲硒基‑4‑吗啉基马来酰亚胺化合物。所述方法反应条件简单、产物的产率和纯度高,为3‑氘代甲硒基‑4‑吗啉基马来酰亚胺化合物的制备开拓了新的合成路线和方法,具有良好的应用潜力和研究价值。
Description
技术领域
本发明属于有机化合物合成技术领域,尤其是涉及一种3-氘代甲硒基4-吗啉基马来酰亚胺化合物的制备方法。
背景技术
氘为氢在自然界中的一种稳定形态的非放射性同位素,由于具有比氢更大的原子质量使得C-D键比C-H键更加稳定(6-9倍)(International Journal of Cancer,2012,131,2411-2419;Space Science Reviews,2000,92,201-224)。将药物分子中的氢用氘取代后,可能封闭代谢位点、减少有毒代谢物的生成,此外,氘代可以减缓系统清除速率从而延长药物在体内的半衰期(Journal of Medicinal Chemistry,2014,57,3595-3611.)。因此,可以通过降低单次给药剂量,同时在不影响药物的药理活性情况下实现降低药物的毒副作用的目标。例如:2017年,SD-809作为全球首个氘代药物获FDA批准用于治疗亨廷顿舞蹈症引发的异常不自主运动(HD),商品名为AUSTEDOTM。与未氘代的四苯喹嗪相比,AUSTEDO能够显著减慢代谢过程,其半衰期接近非氘代四苯喹嗪的2倍(化工设计通讯,2016,42,199-199)。CTP-656是氘代依伐卡托,它的半衰期是15小时,而依伐卡托的半衰期为12小时,半衰期的延长使药物的服用频次可以从每日两次降低到每日一次,更为重要的是,CTP-656不需要与脂肪类饮食同服以增强药物的吸收。苏州泽璟开发的氘代药物多纳非尼获得国家重大专项和特殊审批资格,目前,正在进行III和I期临床试验。成都海创开发的HC-1119属于恩杂鲁胺的氘代产品,用于去势抵抗性前列腺癌的治疗,目前正在华西医院进行临床I/II期试验。
有机硒化合物常见于抗炎,抗氧化活性分子,且有大量文献报道在有机小分子骨架上引入硒甲基官能团,研究表明在含氮杂环骨架上引入硒醚基团,不仅可以改善氮杂环化合物的生理活性和理化性质,还有可能使其获得新的性质。硒甲基官能团在强效细胞毒剂、(Bioorg.Med.Chem.Lett.,2007,17,6853-6859)放射增敏剂、(Bioorg.Med.Chem.Lett.,2011,21,1151-1154)选择性抗肿瘤剂和自由基清除剂中发挥着独特而重要的作用(Eur.J.Med.Chem.,2018,157,14-27.)。因此,快速高效地在有价值的有机骨架上引入硒甲基官能团一直是整个药物化学中一项重要而具有挑战性的任务(Chem.Rev.,2001,101,2125-2180)。例如,抗肿瘤药物的后期硒甲基化修饰可以显著提高人类癌细胞的增殖活性并抑制微管蛋白聚合(Eur.J.Med.Chem.,2014,83,674-684;J.Med.Chem.,2017,60,7300-7314;Eur.J.Med.Chem.,2019,182,111670)。虽然现有技术可以实现简单的硒甲基化反应,但是未见氘代硒甲基化的技术报道。因此,开发新颖的、可储存的和易于操作的氘代硒甲基化试剂,实现有机小分子的氘代硒甲基化技术,有助于开发含硒氘代药物分子,这也是本发明得以完成的基础和动力所在。
发明内容
本发明所要解决的技术问题是提供一种3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备方法,该制备方法所用的反应试剂和催化剂容易获得,操作简单。
为解决以上技术问题,本发明提供下述技术方案:
一种3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备方法,在有机溶剂中,氧气条件下,氘代甲硒基布恩特盐、吗啉和N-苯基马来酰亚胺在铜催化作用下进行氧化胺化/硒化串联反应得到3-氘代甲硒基-4-吗啉基马来酰亚胺化合物。
上述的反应过程,可用下述的反应式表示:
所述氘代甲硒基布恩特盐、吗啉和N-苯基马来酰亚胺的摩尔比为3∶3∶1。
(1)过渡金属催化剂铜
本发明中的过渡金属催化剂铜是碘化亚铜、溴化亚铜、氯化亚铜、醋酸铜、氟化铜、氯化铜或溴化铜,优选为溴化亚铜,以摩尔量计,所述溴化亚铜的用量与所述N-苯基马来酰亚胺用量的10%。
(2)有机溶剂
本发明中的反应溶剂为有机溶剂,所述有机溶剂为二甲基亚砜、1,2-二氯乙烷、乙腈、苯和甲苯中的至少一种,优选甲苯。
(3)反应温度
本发明的制备方法中,反应温度为90-110℃,非限定性地例如可为90℃、100℃和110℃,反应温度优选100℃。
(4)反应时间
在本发明的制备方法中,反应时间并无特别的限定,例如可通过液相色谱仪检测目标产物或原料的残留百分比而确定合适的反应时间,其通常为20-24小时,非限定性例如为20小时、21小时、22小时、23小时或24小时,反应时间优选24小时。
(5)分离纯化
在一种优选的实施方式中,反应结束后的后处理步骤可为如下方法:反应结束后,将反应液冷却后加入乙酸乙酯稀释,用硅胶粉过滤,然后旋掉溶剂,将浓缩物通过柱色谱分离,以石油醚和乙酸乙酯混合液为洗脱剂,收集洗脱液,浓缩后得到目标产物。
本发明提供的3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备方法具有如下有益效果:
a)反应高效率、高收率、后处理简便;
b)利用氘代甲硒基布恩特盐作为硒基化试剂参与三组分的串联反应;
c)利用廉价易的铜/氧气作为催化体系;
本发明以氘代甲硒基布恩特盐、吗啉和N-苯基马来酰亚胺为反应原料,在过渡金属铜催化剂催化作用下,通过三组分串联反应得到3-氘代甲硒基-4-吗啉基马来酰亚胺化合物。本发明反应原料廉价易得、产物的产率和纯度高,为3-氘代甲硒基-4-吗啉基马来酰亚胺化合物的制备开拓了合成路线和方法,为小分子高效引入氘代甲硒基官能团提供新思路,具有重要的社会意义和经济意义。
附图说明
图1为本发明实施例1中氘代甲硒基布恩特盐原料的核磁碳谱图;
图2为本发明实施例1中氘代甲硒基布恩特盐原料的高分辨质谱图;
图3为本发明实施例1中3-氘代甲硒基-4-吗啉基马来酰亚胺产物的核磁氢谱图;
图4为本发明实施例1中3-氘代甲硒基-4-吗啉基马来酰亚胺产物的核磁碳谱图;
图5为本发明实施例1中3-氘代甲硒基-4-吗啉基马来酰亚胺产物的高分辨质谱图。
具体实施方式
下面通过具体的实施例对本发明进行详细说明,但这些例举性实施方式的用途和目的仅用来例举本发明,并非对本发明的实际保护范围构成任何形式的任何限定,更非将本发明的保护范围局限于此。
以下实施例所给出的新化合物的数据和纯度均通过核磁共振鉴定。
实施1:
3-氘代甲硒基4-吗啉基马来酰亚胺化合物的合成
在室温下,将氘代甲硒基布恩特盐(0.6mmol,3equiv)、吗啉(0.6mmol,3equiv)、N-苯基马来酰亚胺(0.2mmol,1equiv)、溴化亚铜(0.02mmol,0.1equiv)和2mL甲苯加入到反应管中,然后充入氧气,并且置换三次,在100℃反应温度下搅24h。将反应混合物冷却,然后加入乙酸乙酯进行稀释,用硅胶粉过滤,然后旋掉溶剂,经柱层析分离得到产物(洗脱剂:石油醚∶乙醚=9∶1),产物为黄色固体,熔点为107-108℃,收率77%,产物重量为54mg。
所得产物的核磁共振氢谱的数据如下:
1H NMR(400MHz,CDCl3):δ7.49-7.45(m,2H),7.38-7.34(m,3H),4.20(t,J=4.72Hz,4H),3.87(t,J=4.80Hz,4H);
所得产物的核磁共振碳谱的数据如下:
13C NMR(100MHz,CDCl3):δ169.0,165.6,148.4,131.9,128.9,127.7,126.3,90.6,67.1,48.9;
HRMS(ESI):calcd for C15H13D3N2O3NaSe[M+Na]+378.0412,found 378.0415.
由上述实施例可看出,当采用本发明的所述方法时,能够以高产率、高纯度得到3-氘代甲硒基-4-吗啉基马来酰亚胺化合物。
实施例2-7
除将其中的过渡金属催化剂溴化亚铜分别替换为如下的铜盐外,与实施例1相同的方式而分别实施了实施例2-7,所使用铜盐化合物和相应产物的收率如下表1所示。
表1
编号 | 过渡金属铜催化剂 | 反应产率(%) |
实施例2 | 碘化亚铜 | 42 |
实施例3 | 氯化亚铜 | 25 |
实施例4 | 醋酸铜 | 0 |
实施例5 | 氟化铜 | 0 |
实施例6 | 氯化铜 | 0 |
实施例7 | 溴化铜 | 0 |
由上表1可看出,当使用其它铜盐时,均不能够使得反应顺利进行,由此证明了溴化亚铜是该反应成功的关键因素,且对该反应体系最为有效。
实施例8-11
除将其中的有机溶剂甲苯分别替换为如下的有机溶剂外,以与实施例1相同的方式而分别实施了实施8-11,所使用有机溶剂和相应产物的收率如下表2所示。
表2
由上表2可看出,当使用其它有机溶剂时,除了在二氯乙烷和苯能发生反应,但产率降低;而在强极性溶剂二甲亚砜溶剂条件下没有任何产物。这证明了有机溶剂的合适选择对反应能否进行有着显著的,甚至是决定性的影响。
综上所述,由上述所有实施例可明确看出,当采用本发明的方法使用过渡金属催化剂(尤其是溴化亚铜)和合适的有机溶剂(尤其是甲苯)所组成的复合反应体系时,能够使氘代甲硒基布恩特盐、吗啉和N-苯基马来酰亚胺,在氧气条件下,通过三组分串联反应以高产率和高纯度合成得到3-氘代甲硒基-4-吗啉基马来酰亚胺化合物,为该类化合物的高效快捷合成提供了新策略。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然科研对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (5)
2.根据权利要求1所述的制备方法,其特征在于,所述氘代甲硒基布恩特盐、吗啉和N-苯基马来酰亚胺的摩尔比为3∶3∶1。
3.根据权利要求1所述的制备方法,其特征在于,以摩尔量计,所述铜催化剂的用量为所述N-苯基马来酰亚胺用量的10%。
4.根据权利要求1所述的制备方法,其特征在于,反应温度为90-110℃。
5.根据权利要求1所述的制备方法,其特征在于,反应时间为20-24h。
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