CN105712812A - 利用不对称还原胺化反应制备的手性β-芳基胺类化合物及其方法 - Google Patents
利用不对称还原胺化反应制备的手性β-芳基胺类化合物及其方法 Download PDFInfo
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- CN105712812A CN105712812A CN201610046962.XA CN201610046962A CN105712812A CN 105712812 A CN105712812 A CN 105712812A CN 201610046962 A CN201610046962 A CN 201610046962A CN 105712812 A CN105712812 A CN 105712812A
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- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 6
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
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- WZCZNEGTXVXAAS-UHFFFAOYSA-N trifluoromethanol Chemical compound OC(F)(F)F WZCZNEGTXVXAAS-UHFFFAOYSA-N 0.000 claims description 6
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- 229940013007 vyvanse Drugs 0.000 description 1
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- C07C209/26—Preparation of compounds containing amino groups bound to a carbon skeleton by reductive alkylation of ammonia, amines or compounds having groups reducible to amino groups, with carbonyl compounds by reduction with hydrogen
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Abstract
本发明涉及利用不对称还原胺化反应制备的手性β?芳基胺类化合物及其方法,基于α?芳基酮和二苯甲胺在手性催化剂催化下加氢发生不对称还原胺化的方法制备手性β?芳基胺类化合物。利用该合成方法,催化剂用量可以降低到十万分之五,同时产物的对映选择性可以达到98%,反应制得的N?二芳基甲基?β?芳基胺可以在温和的条件下脱除二芳基甲基,最终得到一级的β?芳基胺,解决了手性β?芳基胺类化合物的合成难题,同时相应原料非常廉价,因此具有很高的工业应用潜力。
Description
技术领域
本发明涉及手性胺类化合物,具体涉及一种利用不对称还原胺化反应制备的手性β-芳基胺类化合物及其方法。
背景技术
β-芳基胺是许多重要药物的药效基团。比如英国Shire公司治疗神经系统疾病的药物Vyvanse和Adderall XR,英国阿斯利康制药有限公司治疗哮喘的药物Symbicort,美国百时美施贵宝制药有限公司治疗艾滋病的药物Reyataz,美国艾伯维制药有限公司治疗艾滋病的药物Norvir和日本安斯泰来制药有限公司治疗前列腺增生的药物Flomax,它们的主要药效基团都是手性β-芳基胺。因此,研究和开发制备手性β-芳基胺类化合物的反应具有重要的意义。
不对称还原胺化是一种绿色高效的制备手性胺类化合物的方法。不对称还原胺化以简单廉价的酮和胺为原料,在手性催化剂作用下经过一步反应就可以得到手性胺。到目前为止,不对称还原胺化发展比较缓慢,并且没有工业化的实例,主要是由于该反应产率不高、手性控制困难以及催化剂催化效率低下而导致的成本过高。
发明内容
本发明的目的是提供一种利用不对称还原胺化反应制备的手性β-芳基胺类化合物及其方法,该方法利用不对称还原胺化反应,在万分之一催化剂用量的条件下高效、高立体选择性地合成手性β-芳基胺。
本发明所采用的技术方案为:
利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
所述合成方法基于不对称还原胺化反应:
其中:
M为金属铱或者金属铑的盐;
L为手性单膦、二膦或者膦氮配体;
Additives为添加剂组合;
Solvent为反应溶剂;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基;
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3,5-二甲氧基苯基或3,5-二甲苯基。
金属铱盐包括 (1,5-环辛二烯)二氯化铱(I)二聚体、氯二(环辛烯)铱(I)二聚体、1,5-环辛二烯双(甲基联苯基磷化氢)铱(I)六氟化磷盐、甲氧基(环辛二烯)铱(I)二聚体、双(1,5-环辛二烯)铱(I)六氟化锑盐、双(1,5-环辛二烯)铱(I)四氟硼酸盐、双1,5-环辛二烯铱(I)四(3,5-二(三氟甲基)苯基)硼酸盐;
金属铑盐包括双(降冰片二烯)铑(I) 四氟硼酸盐、双(降冰片二烯)铑(I) 六氟化锑盐、(降冰片二烯)二氯化铑(I)二聚体、(1,5-环辛二烯)二氯化铑(I)二聚体、双(1,5-环辛二烯)铑(I) 四氟化硼盐、氯二(环辛烯)铑(I)二聚体、(乙酰丙酮)(降冰片二烯)合铑(I)、双(1,5-环辛二烯)铑(I)六氟化锑盐。
L为手性单膦、二膦或者膦氮配体,具体包括以下配体:
。
Additives为添加剂组合,包括以下一种化合物或者多种化合物的组合使用:
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋。
Solvent为反应溶剂,包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷。
L1、L2和L3中,Ar为芳基取代基,包括苯基、2-甲基苯基、4-甲基苯基、4-甲氧基苯基、2,6-二甲基苯基、2,6-二叔丁基苯基、2,6-二异丙基苯基、2,6-叔丁基-4-甲氧基苯基、2,6-二异丙基-4-甲氧基苯基、3,5-二(三氟甲基)苯基、3,5-二氟苯基、3,5-二叔丁基苯基;
L4中, R为烷基取代基,包括甲基、乙基、异丙基、叔丁基、正丁基、异丁基;
L5中,R1和R2为相同或不同的烷基、环烷基、杂环取代基或芳环取代基;
L6、L7和L8中,R3和R4为是相同或不同的烷基或者环烷基,或者R3和R4与相连的氮组成五元或六元含氮杂环。
如所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法制备的手性β-芳基胺类化合物。
所述β-芳基胺类化合物脱除二芳基甲基后制取了一级手性β-芳基胺:
其中:
Solvent为反应溶剂,包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷;
反应的催化剂是钯/碳或者氢氧化钯/碳;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基。
本发明具有以下优点:
本发明所涉及的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,首先催化剂催化效率高,可以达到十万分之五的催化剂用量。其次,本发明利用还原胺化这一绿色反应制备手性胺,反应所需步骤少,反应原料简单廉价。该方法具有操作简单和易于规模生产的优点。
具体实施方式
下面结合具体实施方式对本发明进行详细的说明。
本发明涉及的手性β-芳基胺类化合物的合成方法,基于不对称还原胺化反应,利用α-芳基酮与二芳基甲胺在金属铱或铑催化剂作用下加氢,一步得到目标产物即手性β-芳基胺类化合物。
具体反应如下:
其中:
M为金属铱或者金属铑的盐;
L为手性单膦、二膦或者膦氮配体;
Additives为添加剂组合;
Solvent为反应溶剂;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基;
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3,5-二甲氧基苯基或3,5-二甲苯基。
金属铱盐包括但不局限于 (1,5-环辛二烯)二氯化铱(I)二聚体、氯二(环辛烯)铱(I)二聚体、1,5-环辛二烯双(甲基联苯基磷化氢)铱(I)六氟化磷盐、甲氧基(环辛二烯)铱(I)二聚体、双(1,5-环辛二烯)铱(I)六氟化锑盐、双(1,5-环辛二烯)铱(I)四氟硼酸盐、双1,5-环辛二烯铱(I)四(3,5-二(三氟甲基)苯基)硼酸盐;
金属铑盐包括但不局限于双(降冰片二烯)铑(I) 四氟硼酸盐、双(降冰片二烯)铑(I) 六氟化锑盐、(降冰片二烯)二氯化铑(I)二聚体、(1,5-环辛二烯)二氯化铑(I)二聚体、双(1,5-环辛二烯)铑(I) 四氟化硼盐、氯二(环辛烯)铑(I)二聚体、(乙酰丙酮)(降冰片二烯)合铑(I)、双(1,5-环辛二烯)铑(I)六氟化锑盐。
L为手性单膦、二膦或者膦氮配体,具体包括但不局限于以下配体:
L1(BINAP系列)、L2(SEGPHOS系列)和L3中,Ar为芳基取代基,包括但不局限于苯基、2-甲基苯基、4-甲基苯基、4-甲氧基苯基、2,6-二甲基苯基、2,6-二叔丁基苯基、2,6-二异丙基苯基、2,6-叔丁基-4-甲氧基苯基、2,6-二异丙基-4-甲氧基苯基、3,5-二(三氟甲基)苯基、3,5-二氟苯基、3,5-二叔丁基苯基;
L4(DuPhos)中, R为烷基取代基,包括但不局限于甲基、乙基、异丙基、叔丁基、正丁基、异丁基;
L5(Josiphos)中,R1和R2为相同或不同的烷基、环烷基、杂环取代基或芳环取代基。
L6、L7和L8中,R3和R4为是相同或不同的烷基或者环烷基,或者R3和R4与相连的氮组成五元或六元含氮杂环。
Additives为添加剂组合,包括但不局限于以下一种化合物或者多种化合物的组合使用:
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋。
Solvent为反应溶剂,包括但不局限于甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷。
上述合成方法合成的手性β-芳基胺类化合物,其芳基包括但不局限于取代苯、取代萘、取代吡啶、取代呋喃、取代噻吩或者取代吡咯。手性β-芳基胺是许多上市药物的药效基团,应用于但不局限于下列药物的合成:Dextroamphetamine、Lisdexamfetamine、(R,R)-Formoterol、(R)-Tamsulosin、Ritonavir或Darunavir。
利用上述合成方法,所使用的二芳基甲胺可以降低对反应催化剂活性的抑制作用,所使用的添加剂组合可以提高反应活性,催化剂用量可以降低到十万分之五,同时产物的对映选择性可以达到98%。
上述β-芳基胺类化合物可通过脱除二芳基甲基制取一级手性β-芳基胺:
其中:
Solvent为反应溶剂,包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷;
反应的催化剂是钯/碳或者氢氧化钯/碳;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基。
一、N-二苯甲基-1-(4-甲氧基苯基)丙-2-胺的制备:
通用制备方法一:在5 mL反应瓶中,加入32.8 mg (0.2 mmol)的1-(4-甲氧基苯基)-丙-2-酮、0.2 mmol二苯甲胺、2 mL二氯甲烷、0.1g 4A 分子筛、 56mg(0.04 mmol)四异丙基氧钛、68mg(0.04 mmol)六氟锑酸银、5mg(0.02 mmol)分子碘、5.5mg(0.05 mmol)三氟乙酸和万分之一的铱与L7(NR3R4=3,5-二甲基哌啶)络合制得的催化剂。将反应瓶置于高压反应釜,并用氢气置换2次后,将氢气加压至50大气压反应14小时,TLC显示反应完全。加入饱和碳酸氢钠水溶液,分离有机相。有机相减压蒸馏后得到粗产品N-二苯甲基-1-(4-甲氧基苯基)丙-2-胺的制备。产品经手性高效液相色谱分析,其立体选择性为98%。
通用制备方法二:在5 mL反应瓶中,加入32.8 mg (0.2 mmol)的1-(4-甲氧基苯基)-丙-2-酮、0.2 mmol二苯甲胺、2 mL二氯甲烷、0.1g 4A 分子筛、 56mg(0.04 mmol)四异丙基氧钛、5.5mg(0.05 mmol)三氟乙酸和万分之一的铱与L7(NR3R4=3,5-二甲基哌啶)络合制得的催化剂。将反应瓶置于高压反应釜,并用氢气置换2次后,将氢气加压至50大气压反应14小时,TLC显示反应完全。加入饱和碳酸氢钠水溶液,分离有机相。有机相减压蒸馏后得到粗产品N-二苯甲基-1-(4-甲氧基苯基)丙-2-胺的制备。产品经手性高效液相色谱分析,其立体选择性为97%。
以下是采用上述方法一或者二合成的5个N-二苯甲基-1-芳基丙-2-胺的名称、编号、产率、立体选择性、颜色、物态、核磁数据和质谱数据。
N-二苯甲基-1-(4-甲氧基苯基)丙-2-胺(1-1):产率95%;对映选择性98%;淡黄色粉末; 1H NMR (500
MHz, CDCl3):δ 7.28-7.48 (10H, m), 7.16 (2H, d,J = 8.6 Hz), 6.92
(2H, d,J = 8.6 Hz)), 5.08 (1H, s), 3.88 (3H, s), 2.92 (1H,m), 2.68-2.88
(2H, m), 1.68 (1H, bs),1.18 (3H, d,J = 6.2 Hz);ESI-MSm/z: 331.19 [M]+。
5-(2-(二苯甲胺基)丙级)-2-甲氧基-苯磺酰胺(1-2):产率78%;对映选择性85%;白色粉末; 1H NMR (500 MHz, CDCl3):δ 7.74 (1H, s), 7.20-7.7.40 (11H, m),
7.00 (1H, d,J = 8.5 Hz), 5.34 (1H, s), 4.04 (3H, s), 2.88 (1H,m),
2.62-2.84 (2H, m), 1.50 (1H, bs),1.10 (3H, d,J = 6.3 Hz);ESI-MSm/z: 410.17
[M]+。
N-二苯甲基-1-苯基-丙-2-胺(1-3):产率93%;对映选择性96%;无色液体; 1H NMR (500
MHz, CDCl3): δ7.17-7.44 (m, 15H), 5.05
(s, 1H), 2.84-2.92 (m, 2H), 2.72 (dd, J = 6.2 Hz, 6.2 Hz, 1H), 1.68 (bs, 1H),
1.18 (d, J = 6.2 Hz, 3H); ESI-MS m/z: 301.17 [M]+。
N-二苯甲基-1-(4-甲基苯基)丙-2-胺(1-4):产率90%;对映选择性95%;淡黄色粉末; 1H NMR (500 MHz, CDCl3):
δ 7.28-7.48 (m, 10H), 7.16
(d, J = 8.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H)), 5.08 (s, 1H), 3.88 (s, 3H),
2.92 (m, 1H), 2.68-2.88 (m, 2H), 1.68 (bs, 1H), 1.18 (d, J = 6.2 Hz, 3H);
ESI-MS m/z: 315.20 [M]+。
N-二苯甲基-1-(3-甲氧基苯基)丙-2-胺(1-5):产率94%;对映选择性98%;淡黄色粉末; 1H NMR (500 MHz, CDCl3):
δ7.44 (d,J = 8.3
Hz, 2H), 7.41 (d,J = 7.5 Hz, 2H), 7.24-7.38 (m, 8H), 7.05 (d,J
= 8.3 Hz, 2H)), 5.04 (s, 1H), 2.88 (m, 1H), 2.82 (dd,J = 7.0 Hz, 6.7
Hz, 1H), 2.68 (dd,J = 6.3 Hz, 6.3 Hz, 1H), 2.37(s, 3H), 1.70 (bs, 1H),
1.16 (d,J = 6.2Hz, 3H);;ESI-MS m/z: 331.21 [M]+。
二、N-二芳基甲基的脱除:
通用方法一:在20 mL反应瓶中,加入0.5 mmol的N-二苯甲基-1-芳基丙-2-胺、15 mg 10% 钯碳、10 mL甲醇和5滴乙酸。将反应瓶置于高压反应釜,并用氢气置换2次后,将氢气加压至15大气压35摄氏度下反应14小时,TLC显示反应完全。减压除去有机溶剂,加入饱和碳酸氢钠水溶液和二氯甲烷,分离有机相。有机相减压蒸馏后得到1-芳基丙-2-胺的粗产品。产品经乙酰化后手性高效液相色谱分析,其立体选择性与N-二苯甲基脱除前相比没有明显变化。
通用方法二:在20 mL反应瓶中,加入0.5 mmol的N-二苯甲基-1-芳基丙-2-胺、15 mg 10% 氢氧化钯/碳、10 mL甲醇和5滴乙酸。将反应瓶置于高压反应釜,并用氢气置换2次后,将氢气加压至15大气压35摄氏度下反应14小时,TLC显示反应完全。减压除去有机溶剂,加入饱和碳酸氢钠水溶液和二氯甲烷,分离有机相。有机相减压蒸馏后得到1-芳基丙-2-胺的粗产品。产品经乙酰化后手性高效液相色谱分析,其立体选择性与N-二苯甲基脱除前相比没有明显变化。
以下是采用上述方法合成的1-(4-甲氧基苯基)丙-2-胺的颜色、物态、核磁数据和质谱数据。
1-(4-甲氧基苯基)丙-2-胺(2-1):产率98%;对映选择性98%;无色固体;1H NMR (500 MHz, CDCl3):δ7.08 (d, J=8.7 Hz, 2H); 6.8 (d, J=8.4
Hz, 2H); 3.76 (s, 3H); 3.10 (m, 1H); 2.70 (dd, J1=6.0 Hz, J2=15.0 Hz, 1H); 2.49
(dd, J1=9.0 Hz, J2=12.0 Hz, 1H); 1.20 (bs, 2H); 1.13 (d, J=6.3 Hz, 3H);ESI-MSm/z: 165.11
[M]+。
1-苯基丙-2-胺(2-2):产率96%;对映选择性94%;黄色固体;1H NMR (500 MHz, CDCl3):δ7.10–7.24 (5H, m),3.07–3.15 (1H, m), 2.64 (1H,
dd, J 13.2, J 5.2), 2.48 (1H, dd, J 13.2, J 8.0), 1.06 (3H, d, J 6.0);ESI-MSm/z: 135.10
[M]+。
本发明的内容不限于实施例所列举,本领域普通技术人员通过阅读本发明说明书而对本发明技术方案采取的任何等效的变换,均为本发明的权利要求所涵盖。
Claims (8)
1.利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
所述合成方法基于不对称还原胺化反应:
其中:
M为金属铱或者金属铑的盐;
L为手性单膦、二膦或者膦氮配体;
Additives为添加剂组合;
Solvent为反应溶剂;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基;
Ar为苯基、2-甲苯基、4-甲苯基、4-甲氧基苯基、3,5-二甲氧基苯基或3,5-二甲苯基。
2.根据权利要求1所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
金属铱盐包括 (1,5-环辛二烯)二氯化铱(I)二聚体、氯二(环辛烯)铱(I)二聚体、1,5-环辛二烯双(甲基联苯基磷化氢)铱(I)六氟化磷盐、甲氧基(环辛二烯)铱(I)二聚体、双(1,5-环辛二烯)铱(I)六氟化锑盐、双(1,5-环辛二烯)铱(I)四氟硼酸盐、双1,5-环辛二烯铱(I)四(3,5-二(三氟甲基)苯基)硼酸盐;
金属铑盐包括双(降冰片二烯)铑(I) 四氟硼酸盐、双(降冰片二烯)铑(I) 六氟化锑盐、(降冰片二烯)二氯化铑(I)二聚体、(1,5-环辛二烯)二氯化铑(I)二聚体、双(1,5-环辛二烯)铑(I) 四氟化硼盐、氯二(环辛烯)铑(I)二聚体、(乙酰丙酮)(降冰片二烯)合铑(I)、双(1,5-环辛二烯)铑(I)六氟化锑盐。
3.根据权利要求1所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
L为手性单膦、二膦或者膦氮配体,具体包括以下配体:
。
4.根据权利要求1所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
Additives为添加剂组合,包括以下一种化合物或者多种化合物的组合使用:
分子筛、四异丙基氧钛、四甲基氧钛、四已基氧钛、四丙基氧钛、四丁基氧钛、甲酸、乙酸、丙酸、苯甲酸、对甲基苯甲酸、苯磺酸、对甲基苯磺酸、三氟乙酸、三氟甲磺酸、氢氯酸、氢溴酸、氢碘酸、甲磺酸、六氟锑酸银、六氟磷酸银、四(3,5-二(三氟甲基)苯基)硼酸银、六氟锑酸纳、分子碘、碘化铵、四丁基碘化铵、碘化铋。
5.根据权利要求1所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
Solvent为反应溶剂,包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷。
6.根据权利要求3所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法,其特征在于:
L1、L2和L3中,Ar为芳基取代基,包括苯基、2-甲基苯基、4-甲基苯基、4-甲氧基苯基、2,6-二甲基苯基、2,6-二叔丁基苯基、2,6-二异丙基苯基、2,6-叔丁基-4-甲氧基苯基、2,6-二异丙基-4-甲氧基苯基、3,5-二(三氟甲基)苯基、3,5-二氟苯基、3,5-二叔丁基苯基;
L4中, R为烷基取代基,包括甲基、乙基、异丙基、叔丁基、正丁基、异丁基;
L5中,R1和R2为相同或不同的烷基、环烷基、杂环取代基或芳环取代基;
L6、L7和L8中,R3和R4为是相同或不同的烷基或者环烷基,或者R3和R4与相连的氮组成五元或六元含氮杂环。
7.如权利要求1所述的利用不对称还原胺化反应制备手性β-芳基胺类化合物的方法制备的手性β-芳基胺类化合物。
8.根据权利要求7所述的手性β-芳基胺类化合物,其特征在于:
所述β-芳基胺类化合物脱除二芳基甲基后制取了一级手性β-芳基胺:
其中:
Solvent为反应溶剂,包括甲醇、乙醇、异丙醇、三氟甲醇、二氯甲烷、氯仿、1,2-二氯乙烷、氯苯、苯、甲苯、二甲苯、四氢呋喃、2-甲基四氢呋喃、乙醚、乙酸乙酯、甲酸乙酯、乙酸甲酯、1,4-二氧六环、乙腈、N,N-二甲基甲酰胺、己烷;
反应的催化剂是钯/碳或者氢氧化钯/碳;
R6是烷基、芳基、酯基、酰胺基或羧酸基;
R1、R2、R3、R4、R5是相同或不同的氢、烷基、环烷基、链烯基、链炔基、不饱和的单环烃基、烷氧基、卤素、羟基、硝基、氰基、三氟甲基、杂环取代基、酯基、酰胺基、酰基、醛基或磺酰胺基。
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CN109734611B (zh) * | 2019-01-23 | 2021-12-07 | 西北农林科技大学 | 一种手性三级胺类化合物的合成方法及其用途 |
CN110668976A (zh) * | 2019-10-21 | 2020-01-10 | 山东师范大学 | 卡巴拉汀光学异构中间体及(r)-卡巴拉汀的合成方法 |
CN110862324A (zh) * | 2019-11-14 | 2020-03-06 | 西北农林科技大学 | 一种手性二级胺类化合物的直接合成方法 |
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