CN112300047B - 一种串联还原胺化合成手性内酰胺的方法 - Google Patents

一种串联还原胺化合成手性内酰胺的方法 Download PDF

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CN112300047B
CN112300047B CN201910715880.3A CN201910715880A CN112300047B CN 112300047 B CN112300047 B CN 112300047B CN 201910715880 A CN201910715880 A CN 201910715880A CN 112300047 B CN112300047 B CN 112300047B
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高爽
丁小兵
邵攀霖
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Abstract

本发明属于化学合成制备技术领域，具体涉及一种串联还原胺化合成手性内酰胺的方法，所述方法以酮酸和酮酯的底物，成功实现了钌催化的不对称还原胺化/环化串联反应高效构建手性内酰胺。

Description

一种串联还原胺化合成手性内酰胺的方法
技术领域
本发明属于化学合成制备技术领域，涉及化合物的不对称催化，具体涉及一 种串联还原胺化合成手性内酰胺的方法。
背景技术
手性内酰胺及其衍生的环胺化合物广泛存在于生物活性分子和药物中间体 中，在医药制剂、农药生产等领域有着重要的应用。它们大多都能表现出一定的 生理活性，因而经常出现在各种潜在靶向药物的结构片段中。
Figure BDA0002152873230000011
目前大致分为两种：(1)分步合成手性内酰胺，即对还原胺化的芳基亚胺 中间体还原后再经脱保护关环得到内酰胺；(2)直接还原胺化和环化串联一步 合成内酰胺。
(1)Stepwise synthesis of chiral lactams
Figure BDA0002152873230000012
(2)Cascade reductive amination and cyclization to prepare actams
Figure BDA0002152873230000013
前述工艺路线不仅制备过程复杂，而且手性控制和催化效率不够理想。
本发明以芳香酮酸和酮酯的底物，成功实现了钌催化的不对称还原胺化/环 化串联反应高效构建手性内酰胺，表现出优异的反应性和立体选择性。
发明内容
鉴于现有技术存在的技术问题，本发明以酮酸和酮酯的底物，成功实现了钌 催化的不对称还原胺化/环化串联反应高效构建手性内酰胺。
本发明通过以下技术方案来实现，一种串联还原胺化合成手性内酰胺的方法， 包括以下步骤：
Figure BDA0002152873230000021
其中，R选自卤素、C1-4的烷基、C1-4的烷氧基、苯基取代或者未取代的C5-20的芳环或者杂芳环，R1选自氢、C1-4的烷基，X选自C1-4的羧酸，Ru catalyst选 自：
Figure BDA0002152873230000022
作为本发明的一种优选技术方案，所述卤素选自氟、氯、溴、碘。
作为本发明的一种优选技术方案，所述C1-4的烷基选自甲基、乙基、丙基、 异丙基、正丁基、异丁基、仲丁基、叔丁基。
作为本发明的一种优选技术方案，C1-4的烷氧基选自甲氧基、乙氧基、丙氧 基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基、叔丁氧基。
作为本发明的一种优选技术方案，C5-20的芳环选自苯环或者萘环；C5-20的杂 芳环选自呋喃、噻吩、吡咯、噻唑、咪唑、吡啶、吡嗪、嘧啶、哒嗪。
作为本发明的一种优选技术方案，R选自苯基、4-氟苯基、4-叔丁基苯基、 4-苯基取代苯基。
作为本发明的一种优选技术方案，R1选自tBu。
作为本发明的一种优选技术方案，所述反应在含有三氟乙醇的溶剂中进行。
作为本发明的一种优选技术方案，所述Ru catalyst选自
Figure BDA0002152873230000031
作为本发明的一种优选技术方案，所述NH4X为醋酸铵。
作为本发明的一种优选技术方案，当底物为0.2mmol时，用0.4mmol醋酸 铵为氨源，以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL三氟乙醇，氢气 的压力为50bar，在90℃下反应24h。
本发明相对于现有技术具有以下有益效果：
(1)本发明成功发展了钌催化的简单酮和普通氨源(铵盐)的不对称还原 胺化反应，并用于制备各种重要的手性伯胺片段，该反应的底物适用范围广，而 且有优异的立体控制，对映选择性最高达98％，S/C高达500。
(2)通过大量的实验研究发现，用三氟乙醇作溶剂时，有非常优异的反应 活性和选择性。
(3)本发明优选以芳香酮酸和酮酯的底物，成功实现了钌催化的不对称还 原胺化/环化串联反应高效构建手性内酰胺。
(4)该反应底物简单易得，底物适用范围广，对映选择性高达99％，仅需 一步反应就可以合成各种手性内酰胺。
具体实施方式
下面结合具体实施例对本发明做进一步的说明，但本发明不局限于此。
总实施例
Figure BDA0002152873230000032
其中，R1选自tBu；所述反应在含有三氟乙醇的溶剂中进行；所述Ru catalyst 选自
Figure BDA0002152873230000041
实施例1
Figure BDA0002152873230000042
反应条件为：芳香酮叔丁酯底物为0.2mmol时，用0.4mmol醋酸铵为氨源， 以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL三氟乙醇，氢气的压力为50 bar，在90℃下反应24h。
99％yield，94％ee，白色固体；1H NMR(400MHz，CDCl3)δ7.41-7.35(m，2H)， 7.34-7.28(m，3H)，5.93(s，1H)，4.76(t，J＝7.1Hz，1H)，2.64-2.52(m，1H)，2.51-2.37 (m，2H)，2.07-1.92(m，1H).13C NMR{1H}(101MHz，CDCl3)δ178.67，142.48， 128.92，127.93，125.64，58.13，31.37，30.33.
异构体通过HPLC法测定：Chiralpak IA柱，正己烷/异丙醇＝90/10，流速＝0.8mL/min，紫外检测λ＝210nm，tR＝12.7min(次峰)，13.9min(主峰).
实施例2-13
参照实施例1的制备反应路线，反应条件为：芳香酮叔丁酯底物为0.2mmol 时，用0.4mmol醋酸铵为氨源，以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4 mL三氟乙醇，氢气的压力为50bar，在90℃下反应24h。
目标化合物2-13的结构及结果如下：
Figure BDA0002152873230000051
反应条件为：芳香酮叔丁酯底物为0.2mmol时，用0.4mmol醋酸铵为氨源， 以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL三氟乙醇，氢气的压力为50 bar，在90℃下反应24h。
实施例2结果：白色固体；1H NMR(400MHz，CDCl3)1H NMR(400MHz， CDCl3)1H NMR(400MHz，CDCl3)δ7.42-7.26(m，5H)，5.90(s，1H)，4.55(dd，J＝ 9.1，4.6Hz，1H)，2.56-2.36(m，2H)，2.16-2.08(m，1H)，1.98-1.87(m，1H)，1.86 -1.61(m，2H).13C NMR(101MHz，CDCl3)δ172.35，142.51，128.86，127.99， 126.08，57.84，32.20，31.31，19.72.
异构体通过HPLC法测定：Chiralpak IA柱，正己烷/异丙醇＝90/10，流速＝0.8mL/min，紫外检测λ＝210nm，tR＝18.9min(主峰)，22.0min(次峰).
实施例3结果：白色固体；1H NMR(600MHz，CDCl3)δ7.37-7.29(m，1H)， 7.08(d，J＝7.7Hz，1H)，7.03-6.96(m，2H)，6.53(s，1H)，4.76(t，J＝7.1Hz，1H)， 2.64-2.54(m，1H)，2.52-2.37(m，2H)，2.01-1.91(m，1H).13C NMR{1H}(151MHz， CDCl3)δ178.59，163.15(d，J＝247.3Hz)，145.24(d，J＝6.8Hz)，130.56(d，J＝8.2 Hz)，121.16(d，J＝2.9Hz)，114.84(d，J＝21.2Hz)，112.62(d，J＝22.0Hz)，57.61， 31.18，30.10.
异构体通过HPLC法测定：Chiralpak AD-3柱，正己烷/异丙醇＝90/10，流 速＝0.8mL/min,紫外检测λ＝210nm,tR＝13.0min(次峰),13.8min(主峰).
实施例4结果：白色固体；1H NMR(400MHz,CDCl3)δ7.31-7.22(m,2H), 7.11-7.00(m,2H),6.48(s,1H),4.75(t,J＝7.1Hz,1H),2.63-2.53(m,1H),2.53-2.34 (m,2H),2.01-1.86(m,1H).13C NMR{1H}(101MHz,CDCl3)δ178.52,162.36(d,J ＝246.3Hz),138.19(d,J＝3.0Hz),127.32(d,J＝8.1Hz),115.81(d,J＝21.5Hz), 57.53,31.49,30.30.
异构体通过HPLC法测定：Chiralpak AD-3柱,正己烷/异丙醇＝90/10,流 速＝0.8mL/min,紫外检测λ＝210nm,tR＝13.0min(次峰),13.7min(主峰)
实施例5结果：白色固体；1H NMR(400MHz,CDCl3)δ7.39-7.30(m,2H), 7.27-7.22(m,2H),6.20(s,1H),4.74(t,J＝7.1Hz,1H),2.65-2.52(m,1H),2.52-2.33 (m,2H),2.00-1.86(m,1H).13C NMR{1H}(101MHz,CDCl3)δ178.36,140.99, 133.73,129.11,127.03,57.47,31.40,30.16.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝14.1min(主峰),15.3min(次峰).
实施例6结果：白色固体；1H NMR(400MHz,CDCl3)δ7.53-7.42(m,2H), 7.25-7.13(m,2H),6.85(s,1H),4.72(t,J＝7.1Hz,1H),2.64-2.51(m,1H),2.51-2.33 (m,2H),2.00-1.84(m,1H).13C NMR{1H}(101MHz,CDCl3)δ178.27,141.48, 132.07,127.36,121.79,57.48,31.35,30.09.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝14.7min(主峰),16.1min(次峰).
实施例7结果：白色固体；1H NMR(400MHz,CDCl3)δ7.30-7.21(m,1H), 7.15-7.04(m,3H),5.95(s,1H),4.72(t,J＝7.1Hz,1H),2.62-2.51(m,1H),2.50-2.37 (m,2H),2.36(s,3H),2.07-1.90(m,1H).13C NMR{1H}(101MHz,CDCl3)δ178.37, 142.45,138.72,128.83,128.71,126.30,122.73,58.02,31.43,30.27,21.45.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝10.9min(次峰),12.1min(主峰).
实施例8结果：白色固体；1H NMR(600MHz,CDCl3)δ7.21-7.15(m,4H),5.89 (s,1H),4.72(t,J＝7.2Hz,1H),2.60-2.52(m,1H),2.50-2.39(m,2H),2.35(s,3H), 2.01-1.92(m,1H).13C NMR{1H}(151MHz,CDCl3)δ178.31,139.40,137.79, 129.58,125.62,57.87,31.53,30.31,21.07.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝13.2min(次峰),13.8min(主峰).
实施例9结果：白色固体；1H NMR(400MHz,CDCl3)δ7.44-7.36(m,2H), 7.29-7.19(m,3H),5.80(s,1H),4.73(t,J＝7.2Hz,1H),2.62-2.51(m,1H),2.50-2.35 (m,2H),2.06-1.92(m,1H),1.32(s,9H).13C NMR{1H}(101MHz,CDCl3)δ178.20, 151.13,139.31,125.84,125.45,57.78,34.58,31.47,31.32,30.32.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝9.7min(主峰),10.1min(次峰).
实施例10结果：白色固体；1H NMR(400MHz,CDCl3)δ7.25-7.18(m,2H), 6.94-6.85(m,2H),6.22(s,1H),4.71(t,J＝7.2Hz,1H),3.81(s,2H),2.60-2.50(m, 1H),2.48-2.34(m,2H),2.02-1.88(m,1H).13C NMR{1H}(101MHz,CDCl3)δ 177.24,158.32,133.34,125.89,113.24,56.63,54.33,30.57,29.39.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝18.5min(次峰),19.8min(主峰).
实施例11结果：白色固体；1H NMR(400MHz,CDCl3)δ7.63-7.54(m,4H), 7.49-7.40(m,2H),7.40-7.31(m,3H),6.31(s,1H),4.80(t,J＝7.1Hz,1H),2.66-2.53 (m,1H),2.53-2.37(m,2H),2.09-1.95(m,1H).13C NMR{1H}(101MHz,CDCl3)δ 178.52,141.46,140.99,140.51,128.85,127.66,127.48,127.08,126.14,57.86,31.44, 30.34.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝21.1min(主峰),21.8min(次峰).
实施例12结果：白色固体；1H NMR(400MHz,CDCl3)δ7.90-7.79(m,3H), 7.74(s,1H),7.56-7.45(m,2H),7.44-7.37(m,1H),6.08(s,1H),4.92(t,J＝7.0Hz, 1H),2.72-2.59(m,1H),2.59-2.39(m,2H),2.14-2.00(m,1H).13C NMR{1H}(101 MHz,CDCl3)δ178.43,139.74,133.25,133.04,129.04,127.83,127.74,126.59, 126.22,124.33,123.59,58.13,31.23,30.18.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝16.0min(次峰),17.0min(主峰).
实施例13结果：白色固体；1H NMR(400MHz,CDCl3)δ7.40-7.35(m,1H), 6.65(s,1H),6.36-6.29(m,1H),6.22(d,J＝3.2Hz,1H),4.78(dd,J＝7.3,5.1Hz, 1H),2.58-2.42(m,2H),2.42-2.33(m,1H),2.31-2.17(m,1H).13C NMR{1H}(101 MHz,CDCl3)δ178.29,154.38,142.51,110.29,106.05,51.52,29.69,26.95.
异构体通过HPLC法测定：Chiralpak IA柱,正己烷/异丙醇＝90/10,流速＝0.8mL/min,紫外检测λ＝210nm,tR＝14.7min(次峰),16.7min(主峰).
对比实施例1
以3-苯甲酰丙酸甲酯4.1为模板底物，以醋酸铵作为氨源，用金属钌络合物 Ru(3.3e)(OAc)2作为催化剂，在90℃、50bar H2的条件下反应。
反应条件为：芳香酮叔丁酯底物为0.2mmol时，用0.4mmol醋酸铵为氨源， 以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL溶剂，氢气的压力为50bar， 在90℃下反应24h。异构体通过前述HPLC法测定。
结果发现，采用其他溶剂结果明显不及本发明选择三氟乙醇作为溶剂的方案， 如表1所示。
表1
Figure BDA0002152873230000081
Figure BDA0002152873230000082
对比实施例2
采用不同的酯取代基，如Me、Et、iPr、tBu进行反应，反应条件为：芳香 酮叔丁酯底物为0.2mmol时，用0.4mmol醋酸铵为氨源，以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL三氟乙醇作为溶剂，氢气的压力为50bar， 在90℃下反应24h。异构体通过前述HPLC法测定。
实验结果表明，用叔丁基取代的芳香酮酯作为底物是较好的选择，如表2 所示。
表2
Figure BDA0002152873230000091
Figure BDA0002152873230000092
对比实施例3
采用不同的金属钌络合物前体用于实验，结果发现采用金属络合物 Ru(3.3e)(OAc)2反应的化学选择性很好，优于其他金属络合物，反应式如下，结 果如表3所示。
Figure BDA0002152873230000093
Figure BDA0002152873230000094
表3
Figure BDA0002152873230000101
a芳香酮叔丁酯底物为0.2mmol时，用0.4mmol醋酸铵为氨源，以1mol％ 的金属络合物为催化剂，加入0.4mL三氟乙醇作为溶剂，氢气的压力为50bar， 在90℃下反应24h；
b化合物结构确认通过1H NMR分析；
cee值测定通过HPLC法；
d分离得到的值；
e与a反应条件不同的是：采用2当量的苯甲酸胺作为氨源；
f与a反应条件不同的是：采用氢气的压力为40bar；
g与a反应条件不同的是：采用1.2当量的醋酸铵为氨源。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施 例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替 代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (1)

1.一种串联还原胺化合成手性内酰胺的方法，其特征在于，
Figure FDA0003994099480000011
其中，R1选自tBu；所述Ru catalyst选自Ru(3.3e)(OAc)2，其中3.3e的结构式如下：
Figure FDA0003994099480000012
Ar＝4-MeO-3,5-tBu2C6H3，NH4X选自醋酸铵；
反应条件为：底物为0.2mmol，用0.4mmol醋酸铵为氨源，以1mol％的Ru(3.3e)(OAc)2为催化剂，加入0.4mL三氟乙醇，氢气的压力为50bar，在90℃下反应24h；
Figure FDA0003994099480000013
选自结构为2-13的化合物：
Figure FDA0003994099480000014
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1315941A (zh) * 1998-09-03 2001-10-03 Dsm有限公司 连续制备ε－己内酰胺与ε－己内酰胺前体的含水混合物的方法
CN1764449A (zh) * 2003-03-24 2006-04-26 纳幕尔杜邦公司 通过用芳基胺还原胺化乙酰丙酸制备5－甲基－n－芳基－2－吡咯烷酮和5－甲基－n－环烷基－2－吡咯烷酮的方法
CN1764379A (zh) * 2003-03-24 2006-04-26 纳幕尔杜邦公司 5－甲基－n－芳基－2－吡咯烷酮和5－甲基－n－烷基－2－吡咯烷酮的生产
CN103274982A (zh) * 2013-06-24 2013-09-04 陕西师范大学 乙酰丙酸转化生成内酰胺的方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1315941A (zh) * 1998-09-03 2001-10-03 Dsm有限公司 连续制备ε－己内酰胺与ε－己内酰胺前体的含水混合物的方法
CN1764449A (zh) * 2003-03-24 2006-04-26 纳幕尔杜邦公司 通过用芳基胺还原胺化乙酰丙酸制备5－甲基－n－芳基－2－吡咯烷酮和5－甲基－n－环烷基－2－吡咯烷酮的方法
CN1764379A (zh) * 2003-03-24 2006-04-26 纳幕尔杜邦公司 5－甲基－n－芳基－2－吡咯烷酮和5－甲基－n－烷基－2－吡咯烷酮的生产
CN103274982A (zh) * 2013-06-24 2013-09-04 陕西师范大学 乙酰丙酸转化生成内酰胺的方法

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Ruthenium-Catalyzed Conversion of Levulinic Acid to Pyrrolidines by Reductive Amination;Yao-Bing Huang, et al;《ChemSusChem》;20110916;第4卷;第1578-1581页 *
Selective and Efficient Iridium Catalyst for the Reductive Amination of Levulinic Acid into Pyrrolidones;Shengdong Wang, et al;《ChemSusChem》;20170905;第10卷;第4150-4154页 *

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