CN112028814A - 基于新型催化Curtius重排反应制备胺类化合物的方法 - Google Patents
基于新型催化Curtius重排反应制备胺类化合物的方法 Download PDFInfo
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- CN112028814A CN112028814A CN202011058956.9A CN202011058956A CN112028814A CN 112028814 A CN112028814 A CN 112028814A CN 202011058956 A CN202011058956 A CN 202011058956A CN 112028814 A CN112028814 A CN 112028814A
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- reaction
- curtius rearrangement
- carboxylic acid
- azide
- oac
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- -1 amine compound Chemical class 0.000 title claims abstract description 51
- 230000003197 catalytic effect Effects 0.000 title claims abstract description 28
- 238000000034 method Methods 0.000 title claims abstract description 28
- 238000006969 Curtius rearrangement reaction Methods 0.000 title claims abstract description 15
- 238000006243 chemical reaction Methods 0.000 claims abstract description 80
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- 229960000549 4-dimethylaminophenol Drugs 0.000 claims abstract description 25
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-dimethylaminopyridine Substances CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims abstract description 25
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 23
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- 150000004982 aromatic amines Chemical class 0.000 claims abstract description 10
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- 239000007789 gas Substances 0.000 claims abstract description 4
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- OHXPGWPVLFPUSM-KLRNGDHRSA-N 3,7,12-trioxo-5beta-cholanic acid Chemical compound C1CC(=O)C[C@H]2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)C(=O)C[C@@H]3[C@]21C OHXPGWPVLFPUSM-KLRNGDHRSA-N 0.000 description 2
- PPHHAZOVVZBSCM-UHFFFAOYSA-N 4-chloro-3-(trifluoromethyl)benzoic acid Chemical compound OC(=O)C1=CC=C(Cl)C(C(F)(F)F)=C1 PPHHAZOVVZBSCM-UHFFFAOYSA-N 0.000 description 2
- 125000000242 4-chlorobenzoyl group Chemical group ClC1=CC=C(C(=O)*)C=C1 0.000 description 2
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Abstract
本发明基于新型催化Curtius重排反应制备胺类化合物。过渡金属催化sp2 C‑N键的形成是合成芳基胺的有效方法，催化sp3 C‑N键的偶联反应也时有报道，但同时实现sp2和sp3 C‑N键生成的方法相对未被充分发展。本发明使用资源丰富的有机羧酸作为碳源，易于制备的烷/芳氧基酰基叠氮作为氮源，在低至0.1mol％的DMAP和Cu(OAc)2催化下，以气体N2和CO2作为唯一副产物，一锅法生成保护的烷基、烯基和芳基胺类化合物。反应可应用于天然产物和药物分子的后期功能化，手性烷基胺的合成，以及不同的脲和伯胺的快速构建。机理研究表明，该反应通过级联羧酸活化、叠氮化、Curtius重排和亲核加成反应进行。
Description
技术领域
本发明涉及C-N键构建，具体涉及基于催化脱羧构建C-N键生成烷基、烯基和芳基胺的方法。
背景技术
含氮化合物广泛存在于生物碱、氨基酸、功能材料和天然产物中，与生命科学、材料科学及人类健康密切相关，因此C-N键的构建在有机合成中至关重要。
自1990年以来，在过渡金属催化C-N键偶联领域取得了重大进展，如铜催化的Ullmann反应、钯催化的Buchwald-Hartwig氨基化反应和Chan-Lam氨基化反应等，但这些反应一般局限于sp2 C-N键的构建。而sp3 C-N键的构建主要依赖于传统方法，如氮亲核取代，醇的Mitsunobu反应、羰基化合物的还原胺化以及烯烃的氢胺化反应等，这类反应主要应用于sp3C-N键的构建。因此开发同时适用于sp2和sp3 C-N键构建的方法具有挑战性。
有机羧酸对空气或水分稳定，一般无毒。在催化脱羧交叉偶联反应中，通常作为碳源，应用于C-C键的形成，但是很少应用于C-N键的形成。另外有机叠氮化合物由于制备简便，与各种官能团相容性好，作为亲电氮源在胺化反应中也得到了广泛的应用。因此，本发明探索了有机羧酸和有机叠氮化物之间的催化C-N键形成反应，从而实现sp2和sp3 C-N键的高效构建。
发明内容
过渡金属催化sp2 C-N键的形成是合成芳基胺的有效方法，催化sp3 C-N键的反应也时有报道，但同时实现sp2和sp3 C-N键生成的方法相对未被探索。
本发明以广泛存在的羧酸和易于制备的烷/芳氧基酰基叠氮为底物，以价格低廉的DMAP和Cu(OAc)2为催化剂，通过级联羧酸活化、叠氮化、Curtius重排和亲核加成反应，一步生成烷基、烯基和芳基胺，反应过程中气体N2和CO2作为唯一副产物，可同时适用于构建sp2和sp3 C-N键。此反应可应用于天然产物和药物分子的后期功能化，手性烷基胺的高效合成，以及脲和伯胺的快速构建。
为达到上述目的，本发明提供的技术方案是：
以有机羧酸作为碳源，以烷/芳氧基酰基叠氮作为氮源，在DMAP和Cu(OAc)2的催化下，通过一锅法催化生成烷基、烯基和芳基胺类化合物。在该反应中，N2和CO2是仅有的副产物。
其制备方法包括以下反应过程及后处理步骤：
将有机羧酸、DMAP和Cu(OAc)2加入带有磁力搅拌子的反应瓶中，DMAP与Cu(OAc)2的摩尔比为1：1；DMAP与有机羧酸的摩尔比为1：20–1：1000；用一半溶剂冲洗内壁后加入烷/芳氧基酰基叠氮，烷/芳氧基酰基叠氮与有机羧酸的摩尔比为1：1-1.5：1；加入剩余一半溶剂，升温下反应，通过薄层色谱监测反应。反应结束后，通过柱层析或者重结晶纯化。
其中，所述溶剂为乙腈或者DMASO中的一种。通过一锅法催化的Curtius重排构建C—N键。所述升温温度为80℃～120℃。
本发明还阐述了烷/芳氧基酰基叠氮的合成方法，合成路线为：
具体步骤为：将叠氮化钠的丙酮悬浮液加入带磁力搅拌子的圆底烧瓶中，将烷/芳氧基酰氯在室温下缓慢滴加。然后在不透光的条件下搅拌过夜。反应后用硅藻土过滤，乙酸乙酯洗涤，滤液真空浓缩，柱层析纯化，得到相应的烷/芳氧基酰基叠氮。
采用的烷/芳氧基酰基叠氮包括：
实验的最初，我们设想脱羧C-N键的构建是否可以通过亲电氮源和羧酸来实现。有机叠氮化合物由于制备简便，与各种官能团相容性好，作为亲电氮源在胺化反应中得到了广泛的应用。如方案1所示，我们设想通过有机羧酸和有机叠氮化物之间催化脱羧C-N键偶联反应从而生成烷基、烯基和芳基胺类化合物。我们希望发展一个在中性反应条件下，N2和CO2作为副产物的清洁反应，并能够有效构建sp2和sp3 C-N键。
方案1催化脱羧构建C-N键生成烷基、烯基和芳基胺类化合物
基于以上设想，我们以1-[(4-甲苯基)磺酰基]-4-哌啶甲酸为底物与2,2,2-三氯乙氧基酰基叠氮(TrocN3)为底物，CH3CN为溶剂，80℃条件下反应3h，当催化量的DMAP和Cu(OAc)2存在时，表现出显著的反应活性(方案2)。使用0.3mol％的DMAP和Cu(OAc)2作为催化剂时，反应收率可达到99％。没有催化剂，或者以吡啶代替DMAP存在时，反应不能顺利进行。没有Cu(OAc)2存在时，收率会大大降低。DMSO也是该反应的良溶剂，且DMSO良好的溶解性可进一步扩大反应的适用性。增加催化剂的量，反应可以在短时间内完成，且几乎可以实现当量转化。芳基有机羧酸可能由于具有更稳定的化学结构，反应需要在N2保护下进行，同时适当提高反应温度并延长反应时间。
方案2催化脱羧构建C-N键条件筛选
[a]0.1mmol of 1a.[b]Yield determined by crude NMR with CH2Br2 asstandard
在最优条件后，我们对底物范围进行了拓展，检验该催化脱羧构建C-N键生成烷基、烯基和芳基胺方法的普适性。如方案3所示，杂环(3a)、六元(3b-3d)、七元(3e)、四元(3f、3g)和螺环(3h)羧酸都是可行的底物，产率为94％-99％。对于直链和支链的烷基羧酸，可以获得较高的一级和二级烷基胺的产率(3i-3x)。由于空间位阻作用，三级羧酸的反应性比伯烷基和仲烷基羧酸差，但仍能以中等以上收率得到三级烷基胺(3y、3z)。对取代苯基(3j-3l)、烯基(3x)、溴(3p)、氟(3c,3g)、羰基(3f和3h)、酰胺(3r)等官能团均有耐受。甲基可以显著改变药物分子的生物活性，与亲电性的MeI或亲核性甲基金属化合物等常用的甲基化试剂相比，醋酸是最稳定、最便宜的甲基化试剂。因此，我们通过醋酸、氘代醋酸与烷氧基酰基叠氮反应，可以成功在分子中引入甲基和氘代甲基(3a'、3b'、4f)。
然后，我们测试了氮源烷/芳氧基酰基叠氮的底物范围。芳氧基酰基叠氮是有效的氮源，可以与1a偶联，生成所需的产物4a和4b。烷氧基酰基叠氮也可以使用，具有吸电子基团(3a)的叠氮甲酸酯比具有供电子基团(4c和4d)的叠氮甲酸酯具有更好的反应性。使用含有空间位阻的烷氧基酰基叠氮时也可以顺利的进行脱羧催化C-N的偶联(4e)。环己烯羧酸与苯氧基或苄氧基酰基叠氮的脱羧胺化反应，得到了较好的胺化产物(4g、4h)。这些底物证明了该方法的通用性和高效性。
以药物分子和天然产物羧酸进行反应时，该体系在后期功能化修饰中体现了巨大的潜力。以鹅去氧胆酸(5a)，去氢胆酸(5b)或油酸(5c)为例，含有裸露的羟基、羰基和顺式烯烃基团的天然产物在不需要保护官能团的情况下可以实现脱羧偶联反应。硫辛酸(5d)在CH3CN中溶解性较差，且含有不稳定的二硫官能团，我们使用CH3CN和DMSO的混合溶剂(1:1)，也能以中等以上收率得到胺类化学物(5d)。非甾体类抗炎药物如洛昔洛芬(5e)、氟比洛芬(5f)、酮基洛芬(5g)、布洛芬(5h)、伊索克酸(5i)和萘普生(5j)可以作为理想的底物，生成相应的胺类衍生物，产率为80-99％。含有杂芳环的药物，如吲哚(5k、5l)或恶唑(5m)均反应良好。尽管存在空间位阻，但抗炎药物依托度酸转化为胺化产物5l的收率也较优。烯丙基羧酸，如药物舒林酸，含有氧化敏感的亚砜基和共轭烯烃结构也是合适的底物，高收率的生成烯丙基胺衍生物5n。由雌酚酮衍生的芳氧基酰基叠氮与1-[(4-甲苯基)磺酰基]-4-哌啶甲酸反应时，5o产率为83％。当催化剂加量为5mol％Cu(OAc)2和10mol％DMAP时(注b)，反应在25min内完成，所需产物(3h、3l、3p、3r、3x、3a'、5a、5c、5e、5f和5k)的产率至少为95％。
方案3烷基羧酸和酰基叠氮普适性研究
a General conditions：Carboxylic acid(0.20mmol)，azidoformate(0.24mmol)，CH3CN(4mL)，DMAP(0.3mol％)，Cu(OAc)2(0.3mol％)，80℃，air，3h.b DMAP(10mol％)，Cu(OAc)2(5mol％)，80℃，air，10-25min，see Supplementary lnformationfor details.c DMAP(1mol％)，Cu(OAc)2(1mol％)，0.5h.d DMAP(0.5mol％)，Cu(OAc)2(0.5mol％)，N2，15h.e DMSO/CH3CN(1/1)，N2.
由于芳基羧酸具有更稳定的结构，因此我们对合成芳胺的条件优化后，适当增加催化剂的量，升高反应温度，延长反应时间，可以取得比较满意的收率(方案4)。苯环上含有吸电子和供电子取代基的一系列芳基羧酸都能得到较优的收率(6a-6p)。苯环上的官能团如氰基(6b)、三氟甲基(6c-6e)、硝基(6i)、甲氧基(6i、6j)、氨基(6k)、卤素(61-6p)均可耐受。苯环上的取代基位置对催化脱羧C-N构建没有影响，即使存在邻位取代基(6b、6c、6g、6i、6j、61和6m)的芳香族羧酸也能获得较高产率。含有杂芳环的羧酸，如吡啶(7a)、噻吩(7b)、呋喃(7c)、苯并噻吩(7d和7e)和苯并呋喃(7f)在此体系中耐受，也能顺利进行催化脱羧C-N构建杂芳胺。除芳基羧酸和杂芳基羧酸外，对环(8a)、末端(8b)、共轭(8c)和三取代(8d)烯烃羧酸进行了测试，均获得了理想的烯基胺。反应体系中，只分离到烯基胺的单一异构体(8c和8d)，但可以观察到了一些明显的副产物，可能是由于烯胺的不稳定性造成的。药物分子舒林酸和阿达帕林也能在CH3CN或DMSO中反应，顺利进行药物分子的后期修饰。
方案4(杂)芳基羧酸和烯基羧酸普适性研究
a General conditions：Carboxylic acid(0.20mmol)，TrocN3(0.3mmol)，CH3CN(4mL)，DMAP(1mol％)，Cu(OAc)2(0.5mol％)，100℃，N2，6h.b Cu(OAc)2(1mol％)，3h.c Cu(OAc)2(1mol％)，80℃，1h.d DMSO instead of CH3CN.
最后，我们研究了该反应的合成应用(方案5A)。由于氨基甲酸酯具有稳定的化学结构，且能够渗透细胞膜，在药物化学中通常用作肽键的替代。该发明是构建氨基甲酸酯的有效策略，我们将该方法应用于以氨基甲酸酯为连接的两个复杂分子的偶联。比如吲哚美辛和雌酚酮衍生的叠氮偶联，生成了含有两个复杂分子偶联的产物(5p)，证明该方法在药物化学研究中的潜力。
以一系列手性分子为例进行反应，研究催化脱羧C-N键构建在立体化学中的应用价值(方案5B)。将对映体纯药物(S)-布洛芬和(S)-萘普生用于反应，分别以高产率和99％ee得到了预期的胺化产物(S)-5h和(S)-5j。X射线晶体学分析(CCDC 1982345)证实了(S)-5j的绝对构型。以手性环羧酸为底物进行反应，定量得到手性环胺5q作为单一非对映异构体。从手性羧酸的反应中，也得到了单异构体的手性胺5r，收率为99％。这些结果表明在催化过程中有完全的手性转移。
脲的结构存在于许多生物活性化合物中，包括临床批准的药物，如索拉非尼、利修来得、卡瑞嗪和利托那韦，因此我们开发了几种方便的途径合成不同尿素(方案5C)。在反应溶剂CH3CN中加入少量水(CH3CN:H2O＝5:1)，可以以91％的产率生成对称脲结构10a。以氨基酸为原料，通过催化脱羧C-N偶联和分子内氮亲核取代反应，一步制得五元环脲结构10b。另外，研究发展了合成不对称脲的两步一锅反应。例如，在DMSO溶剂中进行化脱羧C-N偶联，再加入(S)-1-苯基乙胺进行二次取代反应，合成总收率为94％的不对称二烷基脲10c。采用类似的两步一锅合成工艺，以4-氯-3-(三氟甲基)苯甲酸和4-(4-氨基苯氧基)-N-甲基吡啶酰胺为原料，84％的总收率制备了二苯脲药物分子索拉非尼10d，进一步证明了该反应的合成应用。
具有重要伯胺片段的苯胺11a和手性烷基胺11b等化合物，通过新开发的一锅工艺，可获得高产率且保留手性中心(方案5D)。如在DMSO溶剂中反应，经过催化脱羧C-N偶联生成芳基胺，直接加入K2CO3水解可以87％收率得到芳基伯胺类化合物11a。以(S)-手性萘普生为例，CH3CN为溶剂反应时，由于水和CH3CN互溶，催化脱羧C-N偶联后经过水的水解作用，两步一锅构建烷基伯胺类化合物(s)-11b，可实现手性中心的完全保留。
当进行克级制备时，催化剂负载可进一步降低至0.1mol％的DMAP和Cu(OAc)2，并可使用一当量烷氧基酰基叠氮(方案5E)。由于该反应体系干净，监测反应完成后，可直接用稀盐酸洗涤，去除微量催化剂，通过重结晶工艺获得98％产率的胺类产物，证明了该方法的实用性。
方案5衍生应用及潜在价值
有益效果：
本发明开发了一种实现催化脱羧C-N生成的通用方法。本文所引用的羧酸均为稳定羧酸，并可在市场上获得。该方案可容忍多种官能团，具有良好的普适性。所有84例平均收率为87％，体现该发明的高效性。反应具有立体专一性，可由手性羧酸合成手性胺。反应在氧化还原中性反应条件下完成，操作简单，可适用于天然产物和药物分子后期修饰。本发明仅以廉价和低负载的商业化DMAP和Cu(OAc)2作为催化剂，反应过程中气体N2和CO2作为唯一的副产物，成本低廉，原子经济性高，符合绿色化学的理念。
该反应可应用于天然产物和药物分子的后期功能化，手性烷基胺的立体定向合成，以及脲和伯胺的快速构建。机理研究表明，该反应通过级联羧酸活化、酰基叠氮化、Curtius重排和亲核加成反应进行。
本发明发展了一系列便捷合成脲和伯胺的一锅法快速构建工艺，适用于放大反应。本发明基于基于新型催化Curtius重排反应制备胺类化合物的方法，在化工、药物化学和天然产物合成方面具有巨大的发展潜力。
附图说明
图1：本发明基于新型催化Curtius重排反应制备胺类化合物的方案。
具体实施方式
下面结合具体实施例对本发明作进一步说明。
1)反应过程及后处理
将羧酸(0.4mmmol)、DMAP(0.3mol％)和Cu(OAc)2(0.3mol％)加入带有磁力搅拌子的反应管中，用2mL CH3CN冲洗内壁后加入芳/烷氧基酰基叠氮(0.48mmol)，通过注射器加入剩余的2mL CH3CN，并在80℃下反应3h。反应结束后，粗产品通过柱层析或者重结晶纯化。
实施例1
制备2,2,2-三氯乙基-((1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-)甲基)氨基甲酸酯
目标产物通过反应过程及后处理。通过柱层析纯化得到94.0mg的目标产品(93％分离收率)。
1H NMR(400MHz,Chloroform-d)δ7.64(d,J＝8.5Hz,2H),7.49(d,J＝8.4Hz,2H),7.03(d,J＝2.5Hz,1H),6.81(d,J＝9.0Hz,1H),6.66(dd,J＝9.1,2.6Hz,1H),5.25(t,J＝5.5Hz,1H),4.76(s,2H),4.53(d,J＝5.5Hz,2H),3.81(s,3H),2.42(s,3H)；13C NMR(101MHz,Chloroform-d)δ168.4,156.2,154.7,139.6,136.5,133.7,131.3,131.0,129.9,129.3,115.6,115.1,112.1,101.3,95.7,74.7,55.8,35.4,13.2；IR(neat)v 3344,2929,1732,1682,1591,1478,1221,1045,811,721cm-1；HRMS(ESI)Calcd.for C21H18Cl4N2O4Na[M+Na]+524.9913,found 524.9908.
实施例2
制备2,2,2-三氯乙基((R)-3-((3R,7R,8R,9S,10S,13R,14S,17R)-3,7-二羟基-10,13-二甲基十六氢-1H-环戊[a]菲蒽-17-)丁基)氨基甲酸酯
目标产物通过反应过程及后处理。通过柱层析纯化得到93.2mg的目标产品(87％分离收率)。
1H NMR(400MHz,Chloroform-d)δ4.95(t,J＝6.1Hz,1H),4.72(s,2H),3.84(q,J＝3.0Hz,1H),3.49–3.42(m,1H),3.34–3.26(m,1H),3.21–3.12(m,1H),2.19(q,J＝12.7Hz,1H),2.00–1.94(m,2H),1.92–1.86(m,1H),1.84–1.78(m,2H),1.72–1.59(m,4H),1.52–1.45(m,6H),1.41–1.33(m,3H),1.31–1.09(m,7H),0.97(d,J＝6.6Hz,4H),0.90(s,3H),0.65(s,3H)；13C NMR(101MHz,Chloroform-d)δ154.6,95.9,74.6,72.1,68.6,56.1,50.6,42.9,41.6,40.0,39.7,39.5,39.0,36.0,35.4,35.2,34.8,33.9,32.9,30.8,28.5,23.8,22.9,20.7,18.7,11.9；IR(neat)v3445,3347,2932,2867,2133,1715,1520,1251,1141,731cm-1；HRMS(ESI)Calcd.for C26H42Cl3NO4Na[M+Na]+560.2071,found 560.2075.
实施例3
制备2,2,2-三氯乙基(4-(N,N-二丙基氨磺酰基)苯基)氨基甲酸酯
目标产物通过反应过程及后处理。通过柱层析纯化得到67.8mg的目标产品(79％分离收率)。1H NMR(400MHz,Chloroform-d)δ7.77(d,J＝8.7Hz,2H),7.57(d,J＝8.7Hz,2H),7.29(brs,1H),4.84(s,2H),3.08–3.04(m,4H),1.59–1.50(m,4H),0.86(t,J＝7.4Hz,6H)；13C NMR(101MHz,Chloroform-d)δ151.4,140.9,135.3,128.6,118.6,95.1,74.8,50.2,22.1,11.3；IR(neat)v3319,2966,1751,1596,1533,1207,1151,590cm-1；HRMS(ESI)Calcd.for C15H22Cl3N2O4S[M+H]+431.0361,found 431.0362.
实施例4
制备(2,2,2-三氯乙基)叔丁基((2R,4R)-1-([[1,1'-联苯]-4-)戊烷-2,4-)二氨基甲酸酯
目标产物通过反应过程及后处理。通过柱层析纯化得到52.5mg的目标产品(99％分离收率)。
1H NMR(400MHz,Chloroform-d)δ7.56(d,J＝7.6Hz,2H),7.51(d,J＝7.9Hz,2H),7.41(t,J＝7.5Hz,2H),7.31(t,J＝7.3Hz,1H),7.22(d,J＝7.6Hz,2H),5.05(d,J＝8.2Hz,1H),4.69(q,J＝11.9Hz,2H),4.53(d,J＝8.6Hz,1H),3.89–3.79(m,2H),2.92–2.71(m,2H),1.72–1.61(m,2H),1.39(s,9H),1.20(d,J＝6.7Hz,3H)；13C NMR(101MHz,Chloroform-d)δ155.5,154.0,141.0,139.5,137.1,130.0,128.9,127.29,127.27,127.1,95.9,79.5,74.4,49.1,45.1,41.0,40.7,28.5,21.2；IR(neat)v 3347,2974,1716,1514,1169,1114,733,698cm-1；HRMS(ESI)Calcd.for C25H31Cl3N2O4Na[M+Na]+551.1242,found 551.1247.
实施例5
制备(8R,9S,13S,14S)-13-甲基-17-氧代-7,8,9,11,12,13,14,15,16,17-十氢-6H-环戊[a]菲蒽-3-((1-(4-氯苯甲酰基)-5-甲氧基-2-甲基-1H-吲哚-3-)甲基)氨基甲酸酯
目标产物通过反应过程及后处理。通过柱层析纯化得到105.0mg的目标产品(84％分离收率)。
1H NMR(400MHz,Chloroform-d)δ7.66(d,J＝8.5Hz,2H),7.47(d,J＝8.5Hz,2H),7.27–7.24(m,1H),7.08(d,J＝2.4Hz,1H),6.90–6.85(m,3H),6.69(dd,J＝9.0,2.6Hz,1H),5.26(t,J＝5.5Hz,1H),4.55(d,J＝5.5Hz,2H),3.83(s,3H),2.92–2.87(m,2H),2.54–2.47(m,1H),2.44–2.37(m,4H),2.30–2.27(m,1H),2.19–2.12(m,1H),2.05–1.95(m,3H),1.68–1.57(m,3H),1.52–1.46(m,3H),0.90(s,3H)；13C NMR(101MHz,Chloroform-d)δ220.9,168.5,156.3,155.1,149.0,139.6,138.0,137.1,136.5,133.8,131.3,131.1,130.1,129.3,126.4,121.8,118.9,115.9,115.2,112.1,101.3,55.9,50.6,48.1,44.3,38.2,36.0,35.3,31.7,29.5,26.5,25.9,21.7,13.9,13.2；IR(neat)v 3348,2930,1736,1685,1489,1223,1088,1045,754cm-1；HRMS(ESI)Calcd.for C37H38ClN2O5[M+H]+625.2464,found625.2455
一种不对称脲的结构的合成方法，合成路线为：
具体步骤为：将羧酸(0.4mmol)、DMAP(1.0mol％)和Cu(OAc)2(1.0mol％)加入带有磁力搅拌子的反应瓶中，用2mL DMSO冲洗内壁后加入酰基叠氮，通过注射器加入2mL DMSO，加热升温至100℃下反应6h。反应完全后通过注射器加入胺类化合物(0.48mmol)和DIPEA(0.6mmol)，然后在100℃下反应24h，反应结束后粗产品通过乙酸乙酯和饱和食盐水萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化。
实施例6
本发明合成的不对称脲
制备4-(4-(3-(4-氯-3-(三氟甲基)苯基)脲基)苯氧基)-N-甲基吡啶啉酰胺(索拉菲尼)
氮气条件下，将4-氯-3-(三氟甲基)苯甲酸(44.9mg,0.2mmol)、DMAP(10μL,0.1Min CH3CN)和Cu(OAc)2(20μL,0.1M in CH3CN)加入带有磁力搅拌子的反应管中，用2mL DMSO冲洗内壁后加入2,2,2-三氯乙氧基酰基叠氮(65.5mg,0.30mmol)，通过注射器加入2mLDMSO溶解，之后封闭反应管，并在100℃下反应6h，反应完全后通过注射器加入4-(4-氨基苯氧基)-N-甲基-2-吡啶甲酰胺(58.4mg,0.24mmol)和DIPEA (38.8mg,0.3mmol)，封闭反应管，并在100℃下反应24h，反应结束后粗产品通过乙酸乙酯和饱和食盐水萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化。
1H NMR(400MHz,DMSO-d6)δ9.22–9.21(m,1H),9.00–8.99(m,1H),8.77–8.73(m,1H),8.52–8.49(m,1H),8.13–8.11(m,1H),7.68–7.58(m,4H),7.40–7.38(m,1H),7.19–7.13(m,3H),2.80–2.78(m,3H)；13C NMR(101MHz,DMSO-d6)δ165.9,163.8,152.5,150.3,147.9,139.3,137.0,132.0,126.7(q,J＝30.7Hz),124.2,123.1,122.3,121.4,120.5,118.7,116.8(q,J＝5.8Hz),114.0,108.7,26.0；19F NMR(376MHz,DMSO-d6)δ-61.46；IR(neat)v3566,2924,1828,1800,1549,1543,1417,1199cm-1；HRMS(ESI)Calcd.for C21H17ClF3N4O3[M+H]+465.0936,found 465.0932.
一种伯胺的结构的合成方法，合成路线为：
具体步骤为：将羧酸、DMAP和Cu(OAc)2加入带有磁力搅拌子的反应管中，用2mLCH3CN冲洗内壁后加入芳/烷氧基酰基叠氮，通过注射器加入2mL CH3CN，之后封闭反应管，并在80℃下反应3h，反应完全后通过注射器加入一水合氢氧化锂和去离子水，封闭反应管，并在50℃下反应3h，反应结束后粗产品通过乙酸乙酯和饱和食盐水萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化。
实施例7
制备(S)-1-(6-甲氧基萘-2-基)乙烷-1-胺
空气条件下，将(S)-萘普生(46.1mg,0.2mmol)、DMAP(6μL,0.1M in CH3CN)和Cu(OAc)2(6μL,0.1M in CH3CN)加入带有磁力搅拌子的反应管中，用2mL CH3CN冲洗内壁后加入2,2,2-三氯乙氧基酰基叠氮(52.4mg,0.24mmol)，通过注射器加入2mL CH3CN，之后封闭反应管，并在80℃下反应3h，反应完全后通过注射器加入一水合氢氧化锂(41.9mg,1.0mmol)和4mL去离子水，封闭反应管，并在50℃下反应3h，反应结束后粗产品通过乙酸乙酯和饱和食盐水萃取，有机相用无水硫酸钠干燥，过滤后减压浓缩，柱层析纯化。
以上所述，仅是本发明的较佳实施例，并非对本发明作任何形式上的限制，任何熟悉本专业的技术人员，在不脱离本发明技术方案范围内，依据本发明的技术实质，对以上实施例所作的任何简单的修改、等同替换与改进等，均仍属于本发明技术方案的保护范围之内。
Claims (6)
1.基于新型催化Curtius重排反应制备胺类化合物的方法，其特征在于：以有机羧酸作为碳源，以烷/芳氧基酰基叠氮作为氮源，在DMAP和Cu(OAc)2的催化下，以气体N2和CO2作为仅有的副产物，通过一锅法催化脱羧生成烷基、烯基和芳基胺类化合物。
2.根据权利要求1所述的基于新型催化Curtius重排反应制备胺类化合物的方法，其特征在于：其制备方法包括以下反应过程及后处理步骤：
将有机羧酸、DMAP和Cu(OAc)2加入带有磁力搅拌子的反应瓶中，DMAP与Cu(OAc) 2的摩尔比为1：1；DMAP与有机羧酸的摩尔比为1：20–1：1000；用一半溶剂冲洗内壁后加入烷/芳氧基酰基叠氮，烷/芳氧基酰基叠氮与有机羧酸的摩尔比为1：1-1.5：1；然后加入剩余一半溶剂，升温下反应，并通过薄层色谱监测反应。反应结束后，通过柱层析纯化或者重结晶纯化。
3.根据权利要求2所述的基于新型催化Curtius重排反应制备胺类化合物的方法，其特征在于：步骤(2)中所述溶剂为乙腈或者DMASO中的一种。
4.根据权利要求2所述的基于新型催化Curtius重排反应制备胺类化合物的方法，其特征在于：通过一锅法催化的Curtius重排构建C—N键。
5.根据权利要求2所述的基于新型催化Curtius重排反应制备胺类化合物的方法，其特征在于：所述升温温度为80℃～120℃。
6.根据权利要求2所述的基于催化脱羧构建C-N键生成烷基、烯基和芳基胺的方法，其特征在于：烷/芳氧基酰基叠氮的合成路线为：
反应步骤为：将叠氮化钠的丙酮悬浮液加入带磁力搅拌子的圆底烧瓶中，将酰氯在室温下缓慢滴加；然后将烧瓶密封，在不透光的条件下搅拌过夜；反应后用硅藻土过滤，乙酸乙酯洗涤，滤液真空浓缩，柱层析纯化，得到相应的烷/芳氧基酰基叠氮。其特征在于：采用的烷/芳氧基叠氮包括：
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| CN113493387A (zh) * | 2021-07-07 | 2021-10-12 | 上海库曜新材料有限公司 | 一种耐候性环氧树脂固化剂的合成方法 |
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| CN113143936A (zh) * | 2021-02-10 | 2021-07-23 | 北京蕴汇医药科技有限公司 | 鹅去氧胆酸或其衍生物在制备egfr和/或stat3的抑制剂中的用途 |
| CN113143936B (zh) * | 2021-02-10 | 2022-03-25 | 北京蕴汇医药科技有限公司 | 鹅去氧胆酸或其衍生物在制备egfr和/或stat3的抑制剂中的用途 |
| CN113248407A (zh) * | 2021-05-20 | 2021-08-13 | 中南民族大学 | 一种多功能芳香胺类化合物及其制备方法和应用 |
| CN113493387A (zh) * | 2021-07-07 | 2021-10-12 | 上海库曜新材料有限公司 | 一种耐候性环氧树脂固化剂的合成方法 |
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