CN105753903A - 一种新型缩合剂及其制备方法 - Google Patents
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- C07F9/6527—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having nitrogen and oxygen atoms as the only ring hetero atoms
- C07F9/6533—Six-membered rings
- C07F9/65335—Six-membered rings condensed with carbocyclic rings or carbocyclic ring systems
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- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
- C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
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- C08G73/00—Macromolecular compounds obtained by reactions forming a linkage containing nitrogen with or without oxygen or carbon in the main chain of the macromolecule, not provided for in groups C08G12/00 - C08G71/00
- C08G73/06—Polycondensates having nitrogen-containing heterocyclic rings in the main chain of the macromolecule
- C08G73/10—Polyimides; Polyester-imides; Polyamide-imides; Polyamide acids or similar polyimide precursors
- C08G73/1067—Wholly aromatic polyimides, i.e. having both tetracarboxylic and diamino moieties aromatically bound
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Abstract
本发明公开了一种新型缩合剂及其制备方法,属于化学技术领域。其具有如下结构:
Description
技术领域
本发明涉及一种新型缩合剂及其制备方法,属于化学技术领域。
背景技术
羧酸与伯胺缩合制备酰胺为一类常见的单元反应,该类型单元反应已被用于众多领域。通过该单元反应制备得到的聚酰亚胺,具有极高的耐热性、良好的化学稳定性及优秀的导电性,已成为了有机高分子材料中综合性能最好的材料之一,目前在薄膜、复合材料、粘合剂和功能性材料等各领域得到广泛的应用。另外,通过该单元反应修饰蛋白质结构中氨基酸上的羧基,从而改变酶活性,进而在酶工程领域及医药领域得到广泛应用。但该单元反应会因与羧基或伯胺相连基团的不同导致分子化学性质及空间结构发生改变,影响反应活性,导致较难甚至无法得到相应的酰胺产物。为解决以上问题,世界发明专利申请公布号为WO9005739A1的《carboxylterminalpeptideandproteinsequencing》,采用了以下类型的缩合剂:
中国发明专利申请公布号为CN103765304A的《包含聚酰胺酸酯的液晶取向剂、液晶取向膜及液晶显示元件》,采用了以下类型的缩合剂:
通过采用以上文献报道的缩合剂,增大了羧酸与伯胺进行缩合反应的活性,使反应平衡趋向于目标产物,从而使底物能够或更易于发生转化,降低能耗,提高产率。这些种类缩合剂的出现,拓宽了该类型单元反应的应用范围,具有较大的实际应用价值及良好的市场前景。但同时,这些种类缩合剂仍存在上升空间,值得优化改进:因活性过于活泼,容易分解变质不便储存;对官能团的选择性较差,生成副产物增多;催化性能仍可提高,进一步缩短反应时间。
发明内容
本发明的目的之一,是提供一种新型缩合剂。本发明的新型缩合剂,应用于化学领域,可以显著提高羧酸与伯胺进行缩合反应的选择性和活性,使得底物能够或更易于发生转化,从而得到相应的酰胺产物。
本发明解决上述技术问题的技术方案如下:一种新型缩合剂,具有如下结构:
上述结构式中,R1、R2各自独立,相同或不同;
R1和R2代表如下结构:
X为氢、卤素、硝基、C1~C2烷基、C1~C2烷氧基或三氟甲基。
本发明的目的之二,是提供上述新型缩合剂的制备方法。本发明的制备方法,以仲胺与磷酰氯进行取代反应制得磷酰胺,配以碱性缚酸剂,工艺简单,操作方便,原料来源广泛,条件温和,不需要特殊的反应条件,适合规模化生产。
本发明解决上述技术问题的技术方案如下:一种新型缩合剂的制备方法,包括如下步骤:将化合物1,与化合物2按摩尔比1:1混合,在有机溶剂中发生取代反应,以相当于化合物1摩尔量1~1.5倍的碱性试剂作为缚酸剂,反应温度0~120℃,反应时间2~10小时,反应毕,浓缩反应液得到粗品,经重结晶精制,即得到所述新型缩合剂,其中,化合物1的结构式为化合物2的结构式为
上述制备方法中制备过程中的主要反应方程式为:
在上述技术方案的基础上,本发明还可以做如下改进。
进一步,所述有机溶剂为乙腈、苯、甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、乙醚、甲基叔丁基醚、环己烷、正己烷、正庚烷、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种。
进一步,所述碱性试剂为吡啶、三乙胺、N-甲基吗啉、N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾中的一种。
本发明通过上述方法制备得到的新型缩合剂料,具有良好催化活性的。本发明选取化合物3-26作为优选结构,其结构式如下:
本发明的有益效果是:
(1)相对于目前常用的缩合剂DMT-MM(即4-(4,6-二甲氧基三嗪-2-基)-4-甲基吗啉盐酸盐)和DBOP(即(2,3-二氢-2-硫酮-3-苯并噁唑)磷酸二苯酯),本发明的新型缩合剂,作为催化羧酸与伯胺缩合的缩合剂,展示了较好的性能,极大地提高了羧酸与伯胺缩合的选择性和活性,使其能够或更易于进行缩合反应,提升底物转化速率幅度更大,缩短反应时间、降低反应能耗,具有实际应用价值。
(2)本发明的制备方法,以仲胺与磷酰氯进行取代反应制得磷酰胺,且工艺简单,操作方便,原料来源广泛,条件温和,不需要特殊的反应条件,回收套用率高,对环境影响小,市场前景广阔,适合规模化生产。
(3)本发明的新型缩合剂,因结构中具有四氢噁嗪酮而使得在接触质子性溶剂及空气时性质较为稳定,便于储存及运输。
具体实施方式
以下结合具体实施例对本发明的原理和特征进行描述,所举实例只用于解释本发明,并非用于限定本发明的范围。
实施例1
一种如化合物3的新型缩合剂,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸二苯酯
氮氛下,250mL三颈瓶,加入4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪(25.0g,0.14mol)、氯膦酸二苯酯(37.9g,0.14mol)、四氢呋喃100mL,混合均匀后,滴入三乙胺(21.4g,0.21mol),滴毕,于40~60℃搅拌6小时,浓缩反应液,残留物加入200mL正己烷,加热至回流30分钟,趁热过滤,逐渐降低滤液温度至0℃,搅拌1小时,过滤得到无色晶体45.8g,收率为79.3%,HPLC检测主峰面积为99.7%。
1H-NMR(CDCl3-d1):δ1.78(s,6H),7.24(m,5H),7.36(m,8H),7.59(m,1H)。
实施例2
一种如化合物4的新型缩合剂,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸-二-(2-氧代-4,5-二氢-噁唑烷酮-1-基)-酯
氮氛下,250mL三颈瓶,加入4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪(25.0g,0.14mol),氯膦酸-二-(2-氧代-4,5-二氢-噁唑烷酮-1-基)酯(35.9g,0.14mol),N,N-二甲基甲酰胺100mL,混合均匀后,滴入三乙胺(21.4g,0.21mol),滴毕,于100~140℃搅拌12小时,浓缩反应液,残留物加入200mL正己烷,加热至回流30分钟,趁热过滤,逐渐降低滤液温度至0℃,搅拌1小时,过滤得到无色晶体39.6g,收率为71.0%,HPLC检测主峰面积为99.6%。
1H-NMR(CDCl3-d1):δ1.77(s,6H),3.32(t,4H),4.42(t,4H),7.21(m,3H),7.34(m,1H)。
实施例3
一种如化合物5的新型缩合剂,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸二丁酯
氮氛下,250mL三颈瓶,加入4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪(25.0g,0.14mol),氯膦酸二丁酯(32.0g,0.14mol),N,N-二甲基甲酰胺100mL,混合均匀后,滴入N,N-二异丙基乙胺(21.4g,0.21mol),滴毕,于100~140℃搅拌12小时,浓缩反应液,残留物加入250mL正己烷,加热至回流30分钟,趁热过滤,逐渐降低滤液温度至0℃,搅拌1小时,过滤得到无色晶体42.5g,收率为81.5%,HPLC检测主峰面积为99.8%。
1H-NMR(CDCl3-d1):δ1.08(t,6H),1.25(m,4H),1.54(m,4H),1.80(s,6H),3.61(m,4H),7.22(m,3H),7.39(m,1H)。
实施例4
一种如化合物6的新型缩合剂,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸-二-(4-氯-苯-1-基)酯
氮氛下,250mL三颈瓶,加入4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪(25g,0.14mol),氯膦酸-二-(4-氯-苯-1-基)酯(47.3g,0.14mol),二氯甲烷100mL,混合均匀后,滴入N,N-二异丙基乙胺(21.4g,0.21mol),滴毕,于0~25℃搅拌4小时,浓缩反应液,残留物加入200mL正己烷,加热至回流30分钟,趁热过滤,逐渐降低滤液温度至0℃,搅拌1小时,过滤得到无色晶体53.7g,收率为80.2%,HPLC检测主峰面积为99.8%。
1H-NMR(CDCl3-d1):δ1.75(s,6H),7.26(m,3H),7.41(m,8H),7.50(m,1H)。
缩合剂性能测试:
以化合物27与化合物28为底物进行取代反应,测试缩合剂性能。
实验例1
化合物3,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸二苯酯的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入化合物3(106.4g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时1小时,目标产物峰面积98.7%。
实验例2
化合物4,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸-二-(2-氧代-4,5-二氢-噁唑烷酮-1-基)-酯的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入化合物4(102.8g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时1小时,目标产物峰面积99.0%。
实验例3
化合物5,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸二丁酯的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入化合物5(102.8g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时1小时,目标产物峰面积99.1%。
实验例4
化合物6,即4,4-二甲基-2-氧代-4氢-苯并[e]噁嗪-1-基)-膦酸-二-(4-氯-苯-1-基)酯的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入化合物6(102.8g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时1小时,目标产物峰面积98.9%。
对比例:
分别使用DMT-MM和DBOP作为缩合剂,作用于相同反应底物,仅作为对比,用以说明本发明中优选缩合剂的有益效果。
对比例1:氯化4-(4,6-二甲氧基-1,3,5-三嗪-2-基)-4-甲基吗啉鎓(DMT-MM)的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入DMT-MM(62.7g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时4小时。
对比例2:(2,3-二氢-2-硫代-3-苯并噁唑)磷酸二苯酯(DBOP)的缩合性能实验
500mL三颈瓶,加入化合物27(28.2g,0.10mol),化合物28(24.0g,0.12mol),N-甲基-2-吡咯烷酮300mL,混合均匀后,加入DBOP(99.7g,0.26mol),加毕开始计时,于15~30℃搅拌,HPLC跟踪反应进程,当化合物27转化完全,耗时3.5小时。
通过比较缩合剂性能实施例与对比例结果,可见以相同反应底物,即化合物27与化合物28进行取代反应,化合物3-6与DMT-MM,DBOP参与反应得到产物的HPLC纯度相近,但耗时更短,说明本发明提供的缩合剂性能良好。
以上所述仅为本发明的较佳实施例,并不用以限制本发明,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 (4)
1.一种新型缩合剂,其特征在于,具有如下结构:
上述结构式中,R1、R2各自独立,相同或不同;
R1和R2代表如下结构:
X为氢、卤素、硝基、C1~C2烷基、C1~C2烷氧基或三氟甲基。
2.一种新型缩合剂的制备方法,其特征在于,包括如下步骤:将化合物1,与化合物2按摩尔比1:1混合,在有机溶剂中发生取代反应,以相当于化合物1摩尔量1~1.5倍的碱性试剂作为缚酸剂,反应温度0~120℃,反应时间2~10小时,反应毕,浓缩反应液得到粗品,经重结晶精制,即得到所述新型缩合剂,其中,化合物1的结构式为化合物2的结构式为
3.根据权利要求2所述的一种新型缩合剂的制备方法,其特征在于,所述有机溶剂为乙腈、苯、甲苯、二氯甲烷、1,2-二氯乙烷、氯仿、乙醚、甲基叔丁基醚、环己烷、正己烷、正庚烷、四氢呋喃、N,N-二甲基甲酰胺或N,N-二甲基乙酰胺中的一种。
4.根据权利要求2所述的一种新型缩合剂的制备方法,其特征在于,所述碱性试剂为吡啶、三乙胺、N-甲基吗啉、N,N-二异丙基乙胺、氢氧化钠、氢氧化钾、碳酸钠或碳酸钾中的一种。
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