CN114736134B - 一种(R)-β-羟基芳基丙酰胺类衍生物及制备方法 - Google Patents

一种(R)-β-羟基芳基丙酰胺类衍生物及制备方法 Download PDF

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CN114736134B
CN114736134B CN202210387626.7A CN202210387626A CN114736134B CN 114736134 B CN114736134 B CN 114736134B CN 202210387626 A CN202210387626 A CN 202210387626A CN 114736134 B CN114736134 B CN 114736134B
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钟为慧
赵向华
凌飞
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Taizhou Research Institute of Zhejiang University of Technology
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Abstract

本发明公开了一种(R)‑β‑羟基芳基丙酰胺类衍生物及其制备方法，所述的制备方法为：在氩气氛围及20～40℃下，将金属Ir络合物与手性配体加入到溶剂A中，搅拌反应0.5～2小时，制得金属Ir催化剂的溶剂A溶液；氮气保护下，往高压釜中依次加入β‑氧代丙酰胺类衍生物、上述制备的金属Ir催化剂、溶剂B及碱A，于30～80℃温度和3.0～8.0MPa的氢气压力下反应6～30小时，反应结束后，减压浓缩除去溶剂，残留物经柱层析分离，得到(R)‑β‑羟基芳基丙酰胺类衍生物。本发明方法得到的(R)‑β‑羟基芳基丙酰胺类衍生物，反应收率高达99％，对映选择性高达99％；与现有技术相比，本发明具有原子经济性高、绿色污染小、易于工业化等特点。

Description

一种(R)-β-羟基芳基丙酰胺类衍生物及制备方法
技术领域
本发明涉及一种以β-氧代丙酰胺类衍生物原料发生不对称氢化反应得到的(R)-β-羟基芳基丙酰胺类衍生物的制备方法。
背景技术
β-羟基酰胺及其衍生物是构建多种药物、天然产物以及生物活性分子的重要结构单元，例如抗菌类药物亚胺培南(Imipenem)和氯碳头孢(Loracarbef)，抗抑郁类药物托莫西汀(Tomoxetine)、度洛西汀(Duloxetine)、氟西汀(Fluoxetine)和尼索西汀(Nisoxetine)，抗艾滋病药物洛匹那韦(Lopinavir)和利托那韦(Ritonavir)等。
目前，获得手性β-羟基酰胺及其衍生物的方法主要有：(1)生物催化的不对称还原；(2)高价金属氧化物与硼烷的不对称还原；(3)α，β-不饱和酰胺的不对称硼化反应；(4)不对称催化加氢；(5)手性α，β-环氧酰胺的开环。近年来，金属催化的不对称催化氢化反应，蓬勃发展，具有原子经济性高，实用性强等特点，是一种获得手性醇的重要方法。
1997年，Gotor等人利用生物酶以82％～86％的产率和43％～92％的ee实现了(S)-β-羟基酰胺的不对称还原(Tetrahedron:Asymmetry,1997,8,3035-3038.)。2004年，Rhibasaki等使用红铝、15冠醚作为分子内氢化物转移试剂，实现了手性α，β-环氧酰胺的选择性开环，以优异的选择性得到了手性β-羟基酰胺(Angew.Chem.Int.Ed.2004,43,317–320.)。但是该反应不对称环氧化所需的催化剂用量较大，反应时间长，同时开环所需温度很低。2009年，Nishiyama等人利用双噁唑啉基苯基催化剂Rh(Phebox)实现了α，β-不饱和酯和酰胺的不对称硼化反应，再经由过硼酸钠还原，分别以19％～91％的产率，41％～97％的ee值获得手性β-羟基酯，以70％～74％的产率，93％～97％的ee值获得手性β-羟基酰胺(Chem.Commun.,2009,5987-5989.)。2013年，张绪穆小组利用Ir/f-amphox以优异的产率和对映选择性合成了一系列手性羟基酰胺(Org.Chem.Front.,2018,5,2000-2003.)。该体系对于手性α，γ等氧代酰胺都能以>99％的转化率和>99％的ee值得到相应的(S)-羟基酰胺，但对于β-氧代酰胺，转化率和对映选择性都大大降低。2020年，Yu等以高价手性氧化钒(V)络合物为催化剂，叔丁醇为添加剂，HBPin为还原剂，实现了N-苄基-β-酮酰胺的不对称硼烷还原，以18％～92％的收率，11-99％ee取得相应(S)-醇(J.Org.Chem.2020,85,6408–6419.)，但酰胺上取代基增加会大幅降低产物的收率，略微降低其对映选择性。
发明内容
针对现有技术存在的上述技术问题，本发明的目的在于提供一种通过β-氧代丙酰胺类衍生物的不对称氢化反应，高效制备(R)-β-羟基芳基丙酰胺类衍生物的方法。
本发明限定的一种(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其结构式如式(I)所示，其特征在于所述制备方法包括如下过程：
1)在氩气氛围及20～40℃下，将金属Ir络合物与如式(Ⅲ)所示的手性配体依次加入到溶剂A中，搅拌反应0.5～2小时，制得金属Ir催化剂；
2)将如式(Ⅱ)所示的β-氧代芳基丙酰胺类衍生物、步骤1)所得金属Ir催化剂、溶剂B及碱A依次加入到高压釜中，于30～80℃温度及3.0～8.0MPa的氢气压力下反应6～30小时，再减压浓缩除去溶剂，残留物经柱层析分离，得到如式(I)所示的(R)-β-羟基芳基丙酰胺类衍生物；
具体反应路线如下：
Figure BDA0003595539530000031
通式(I)、(Ⅱ)中，其中R1为取代芳基、杂环芳基、联苯基、萘基；R2和R3各自独立的选自氢、C1～C6直链或支链的烷基、苯基、苄基；
手性配体(Ⅲ)中，R4和R5各自独立的选自C1～C6直链或支链的烷基、C3～C6的环烷基、取代芳基或杂环芳基；R6为取代芳基、杂环芳基或C1～C6的烷基；
取代芳基中的取代基包括氢、卤素、C1～C6直链或支链的烷基、C1～C6烷氧基；杂环芳基包括吡啶基、呋喃基、噻吩基。
进一步，所述手性配体(Ⅲ)的结构式为如式L1～L7中所示的任意一种：
Figure BDA0003595539530000032
进一步地，本发明还限定了步骤1)中反应温度为30～80℃，金属Ir络合物为[Ir(NBD)2Cl]2、Ir(NBD)2)X、[Ir(COD)Cl]2或[Ir(COD)2]X其中的一种，X为阴离子，具体为BF4-、ClO4-、SbF6-、PF6-、CF3SO3-或B(Ar)4-，Ar为二(三氟甲基)苯或氟苯；手性配体(III)与金属Ir络合物的投料摩尔比为1.0～2.5:1，优选为2:1。
进一步地，本发明还限定了步骤2)中，碱A碱选自叔丁醇锂、叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、甲酸钠、乙酸钠、乙酸钾、碳酸氢钠、碳酸氢钾、甲醇钠、甲醇锂、氢氧化钠、氢氧化钾中的一种或两种以上混合物。
进一步地，本发明还限定了步骤(1)中的溶剂A和步骤(2)中的溶剂B各自独立地选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、甲苯、甲醇、乙醇、异丙醇、乙酸乙酯、1,4-二氧六环、六氟异丙醇中的一种或两种以上混合溶剂，所述溶剂A和溶剂B相同或不同，所述溶剂与相应物质的质量比为30:1～200:1。
进一步地，本发明还限定了步骤(1)中的金属Ir催化剂、碱A、β-氧代芳基丙酰胺类衍生物的投料摩尔比为1:2～100:100～100000。
进一步地，本发明还限定了还限定了所述制备方法制备得到的(R)-β-羟基芳基丙酰胺类衍生物。
本发明通过采用上述技术，与现有技术相比，本发明的有益效果如下：
本发明通过采用限定的制备方法，可以专一高效制得(R)-β-羟基芳基丙酰胺类衍生物，反应收率高达99％，对映选择性高达99％，与现有技术相比，本发明方法具有原子经济性高、绿色污染小、易于工业化等特点。本发明将在新型药物的发现，现有药物的结构修饰和天然产物全合成中，起到重要作用。
具体实施方式
以下通过具体的实施例对本发明的内容作进一步的详细说明，但本发明不局限于实施例。
实施例1：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000051
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯:正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为99％。
Ia的结构表征：[α]20 D＝+96.2(c＝0.76,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝92:8；flow rate＝1mL/min；UVdetection at 254nm；25℃；tR(R)＝16.118min(major),tR(S)＝17.681min(minor).1H NMR(400MHz,CDCl3)δ7.47-7.39(m,4H),7.34(d,J＝6.8Hz,1H),5.19(dd,J1＝9.2Hz,J2＝2.8Hz,1H),4.01(s,1H),3.03(s,3H),2.99(s,3H),2.77-2.64(m,2H).13C NMR(100MHz,CDCl3)δ172.3,143.1,128.5,127.5,125.8,70.4,41.9,37.1,35.3.HRMS(ESI)calcd forC11H16NO2[M+H]+:194.1176,found:194.1164.
实施例2：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000061
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和乙酸乙酯(2mL)，30℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(5MPa)，40℃下反应18h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：92％，ee值为98％。
实施例3：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000062
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和乙酸乙酯(2mL)，25℃下搅拌0.5h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(8MPa)，60℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为96％。
实施例4：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000071
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和乙酸乙酯(2mL)，30℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钾(5.6mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(3MPa)，40℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为94％。
实施例5：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000072
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，40℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、叔丁醇钠(9.6mg,0.10mmol)和异丙醇(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，40℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为95％。
实施例6：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000081
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、叔丁醇锂(8.0mg,0.10mmol)和异丙醇(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，40℃下反应8h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：82％，ee值为95％。
实施例7：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000082
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和四氢呋喃(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和四氢呋喃(4mL)，再把样品瓶放入高压釜中，充入H2(5MPa)，40℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为95％。
实施例8：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000091
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和1,4-二氧六环(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、甲醇锂(3.8mg,0.10mmol)和1,4-二氧六环(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，40℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为85％。
实施例9：(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)的制备
Figure BDA0003595539530000092
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和甲苯(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱa)(191.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、醋酸钠(8.0mg,0.10mmol)和甲苯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，40℃下反应30h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)，转化率：99％，ee值为75％。
实施例10：(R)-3-羟基-N,N-二甲基-3-(邻甲苯基)丙酰胺(Ib)的制备
Figure BDA0003595539530000101
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和乙酸乙酯(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱb)(205.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(邻甲苯基)丙酰胺(Ib)，转化率：99％，ee值为93％。
Ib的结构表征：[α]20 D＝+58.7(c＝0.88,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UVdetection at 254nm；25℃；tR(R)＝15.602min(major),tR(S)＝22.734min(minor).1H NMR(400MHz,CDCl3)δ7.23(d,J＝6.8Hz,2H),7.17(d,J＝7.6Hz,1H),7.09(d,J＝7.2,1H),5.10(dd,J1＝9.2Hz,J2＝2.8Hz),3.43(s,1H),2.98(s,3H),2.94(s,3H),2.71-2.58(m,2H),2.36(s,3H).13C NMR(100MHz,CDCl3)δ143.0,138.2,128.4,128.3,126.4,122.8,70.4,42.0,37.1,35.3,21.5.HRMS(ESI)calcd for C12h18NO2[M+H]+:208.1332,found:208.1345.
实施例11：(R)-3-羟基-N,N-二甲基-3-(间甲苯基)丙酰胺(Ic)的制备
Figure BDA0003595539530000111
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱc)(205.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(间甲苯基)丙酰胺(Ic)，转化率：99％，ee值为>99％。
Ic的结构表征：[α]20 D＝+70.2(c＝0.86,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UVdetection at 254nm；25℃；tR(R)＝18.013min(major),tR(S)＝19.446min(minor).1H NMR(400MHz,CDCl3)δ7.23(d,J＝6.8Hz,2H),7.17(d,J＝7.6Hz,1H),7.09(d,J＝7.2,1H),5.10(dd,J1＝9.2Hz,J2＝2.8Hz),3.43(s,1H),2.98(s,3H),2.94(s,3H),2.71-2.58(m,2H),2.36(s,3H).13C NMR(100MHz,CDCl3)δ143.0,138.2,128.4,128.3,126.4,122.8,70.4,42.0,37.1,35.3,21.5.HRMS(ESI)calcd for C12h18NO2[M+H]+:208.1332,found:208.1323.
实施例12：(R)-3-羟基-N,N-二甲基-3-(对甲苯基)丙酰胺(Id)的制备
Figure BDA0003595539530000121
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱd)(205.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(对甲苯基)丙酰胺(Id)，转化率：99％，ee值为98％。
Id的结构表征：mp 80-81℃,[α]20 D＝+104.9(c＝0.70,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝18.416min(major),tR(S)＝21.172min(minor).1H NMR(400MHz,CDCl3)δ7.28(t,J＝8Hz,2H),7.16(d,J＝8Hz,2H),5.11(dd,J1＝9.2Hz,J2＝3.2Hz,1H),3.85(s,1H),2.97(s,3H),2.93(s,3H),2.70-2.57(m,2H),2.34(s,3H).13C NMR(100MHz,CDCl3)δ172.4,140.1,137.2,129.1,125.7,70.2,42.0,37.1,35.3,21.1.HRMS(ESI)calcd for C12 h18NO2[M+H]+:208.1332,found:208.1321.
实施例13：(R)-3-(4-氯苯基)-3-羟基-N,N-二甲基丙酰胺(Ie)的制备
Figure BDA0003595539530000131
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱe)(225.7mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(4-氯苯基)-3-羟基-N,N-二甲基丙酰胺(Ie)，转化率：99％，ee值为99％。
Ie的结构表征：mp94-95℃,[α]20 D＝+89.5(c＝0.82,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝25.587min(major),tR(S)＝28.004min(minor).1H NMR(400MHz,CDCl3)δ7.45-7.32(m,4H),5.15(dd,J1＝9.6Hz,J2＝2.4Hz,1H),3.90(s,1H),3.02(s,3H),2.99(s,3H),2.76-2.58(m,2H).13C NMR(100MHz,CDCl3)δ172.1,141.6,133.2,128.6,127.2,69.8,41.7,37.1,35.3.HRMS(ESI)calcd for C11H15ClNO2[M+H]+:228.0786,found:228.0768.
实施例14：(R)-3-(4-氟苯基)-3-羟基-N,N-二甲基丙酰胺(If)的制备
Figure BDA0003595539530000132
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱf)(209.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(4-氟苯基)-3-羟基-N,N-二甲基丙酰胺(If)，转化率：99％，ee值为99％。
If的结构表征：mp79-80℃,[α]20 D＝+104.1(c＝0.54,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝22.451min(major),tR(S)＝23.900min(minor).1H NMR(400MHz,CDCl3)δ7.42-7.39(m,2H),7.08(t,J＝8.8Hz,2H),5.16(dd,J1＝9.2Hz,J2＝2.8Hz,1H),4.36(s,1H),3.02(s,3H),2.99(s,3H),2.73-2.59(m,2H).13C NMR(100MHz,CDCl3)δ172.2,161.0,138.9,127.4(d,3JC-F＝8.1),115.3(d,2JC-F＝21.1),69.9,41.9,37.1,35.3.HRMS(ESI)calcd for C11H15FNO2[M+H]+:212.1081,found:212.1065.
实施例15：(R)-3-(4-溴苯基)-3-羟基-N,N-二甲基丙酰胺(Ig)的制备
Figure BDA0003595539530000141
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱg)(270.1mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(4-溴苯基)-3-羟基-N,N-二甲基丙酰胺(Ig)，转化率：99％，ee值为>99％。
Ig的结构表征：mp103-104℃,[α]20 D＝+58.5(c＝1.06,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝20.439min(major),tR(S)＝21.930min(minor).1H NMR(400MHz,CDCl3)δ7.48(d,J＝8.4Hz,2H),7.28(d,J＝7.6Hz,2H),5.09(dt,J1＝9.2Hz,J2＝2.8Hz,1H),4.86(d,J＝2.8Hz,1H),2.98(s,3H),2.94(s,3H),2.69-2.53(m,2H).13C NMR(100MHz,CDCl3)δ172.0,142.1,131.5,127.5,121.2,69.8,41.7,37.1,35.3.HRMS(ESI)calcd for C11H15BrNO2[M+H]+:272.0281,found:272.0295.
实施例16：(R)-3-(3-溴苯基)-3-羟基-N,N-二甲基丙酰胺(Ih)的制备
Figure BDA0003595539530000151
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱh)(270.1mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(3-溴苯基)-3-羟基-N,N-二甲基丙酰胺(Ih)，转化率：99％，ee值为99％。
Ih的结构表征：mp54-55℃,[α]20 D＝+83.9(c＝0.62,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝18.077min(major),tR(S)＝20.244min(minor).1H NMR(600MHz,CDCl3)δ7.56(s,1H),7.40(d,J＝7.8Hz,1H),7.31(d,J＝7.8Hz,1H),7.22(t,J＝7.8Hz,1H),5.09(dd,J1＝9.6Hz,J2＝2.4Hz,1H),3.80(s,1H),2.97(s,3H),2.95(s,3H),2.68-2.55(m,2H).13C NMR(150MHz,CDCl3)δ171.9,145.4,130.5,130.0,128.9,124.4,122.6,69.8,41.7,37.1,35.3.HRMS(ESI)calcd for C11H15BrNO2[M+H]+:272.0281,found:272.0292.
实施例17：(R)-3-(4-甲氧基苯基)-3-羟基-N,N-二甲基丙酰胺(Ii)的制备
Figure BDA0003595539530000161
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(IIi)(221.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(4-甲氧基苯基)-3-羟基-N,N-二甲基丙酰胺(Ii)，转化率：99％，ee值为99％。
Ii的结构表征：mp66-68℃,[α]20 D＝+75.6(c＝0.86,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝31.166min(major),tR(S)＝37.081min(minor).1H NMR(400MHz,CDCl3)δ7.34(d,J＝8Hz,2H),6.91(d,J＝8.4Hz,2H),5.10(dd,J1＝8.8Hz,J2＝3.6Hz,1H),4.04(s,1H),3.82(s,3H),2.99(s,3H),2.96(s,3H),2.71-2.59(m,2H).13C NMR(100MHz,CDCl3)δ172.4,159.1,135.4,127.1,113.9,70.1,55.4,42.0,37.2,35.3.HRMS(ESI)calcd for C12 h18NO3[M+H]+:224.1281,found:224.1265.
实施例18：(R)-3-羟基-N,N-二甲基-3-(萘-2-基)丙酰胺(Ij)的制备
Figure BDA0003595539530000171
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱj)(241.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(萘-2-基)丙酰胺(Ij)，转化率：99％，ee值为98％。
Ij的结构表征：mp106-107℃,[α]20 D＝+81.5(c＝0.78,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝92:8；flow rate＝1mL/min；UV detection at 254nm；25℃；tR(R)＝23.257min(major),tR(S)＝31.132min(minor).1H NMR(400MHz,CDCl3)δ7.93(s,1H),7.89(d,J＝7.6Hz,3H),7.56-7.50(m,3H),5.36(d,J＝9.6Hz,1H),4.15(s,1H),3.04(s,1H),2.98(s,1H),2.85-2.70(m,2H).13C NMR(100MHz,CDCl3)δ172.3,140.5,133.4,133.0,128.2,128.0,127.7,126.1,125.8,124.4,124.0,70.5,41.9,37.1,35.3.HRMS(ESI)calcd for C15H18NO2[M+H]+:244.1332,found:244.1346.
实施例19：(R)-3-羟基-N,N-二甲基-3-(吡啶-4-基)丙酰胺(Ik)的制备
Figure BDA0003595539530000181
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱk)(192.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应30h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(吡啶-4-基)丙酰胺(Ik)，转化率：99％，ee值为95％。
Ik的结构表征：[α]20 D＝+4.4(c＝0.24,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UVdetection at 254nm；25℃；tR(S)＝44.245min(minor),tR(R)＝51.036min(major).1H NMR(400MHz,CDCl3)δ8.58(d,J＝6Hz,2H),7.58(d,J＝6Hz,2H),5.25(dd,J1＝9.2Hz,J2＝2.8Hz,1H),5.20(s,1H),3.02(s,3H),3.01(s,3H),2.82-2.57(m,2H).13C NMR(100MHz,CDCl3)δ170.9,156.2,147.4,122.3,68.7,40.6,37.1,35.4.HRMS(ESI)calcd forC10H15N2O2[M+H]+:195.1128,found:195.1120.
实施例20：(R)-N,N-二乙基-3-羟基-3-苯丙酰胺(Il)的制备
Figure BDA0003595539530000191
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱl)(219.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、叔丁醇锂(8.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-N,N-二乙基-3-羟基-3-苯丙酰胺(Il)，转化率：99％，ee值为98％。
Il的结构表征：[α]20 D＝+92.3(c＝0.72,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝92:8；flow rate＝1mL/min；UVdetection at 254nm；25℃；tR(R)＝12.519min(major),tR(S)＝14.407min(minor).1H NMR(400MHz,CDCl3)δ7.45-7.30(m,5H),5.18(dd,J1＝9.6Hz,J2＝2.8Hz,1H),3.52-3.38(m,2H),3.32-3.21(m,2H),2.75-2.61(m,2H),1.19(d,J＝7.2Hz,3H),1.15(d,J＝7.6Hz,3H).13C NMR(100MHz,CDCl3)δ171.5,143.2,128.5,127.5,125.8,70.6,42.0,41.5,40.3,14.1,13.0.HRMS(ESI)calcd for C13H20NO2[M+H]+:221.1489,found:221.1475.
实施例21：(R)-3-羟基-N,N-二甲基-3-(4-(三氟甲基)苯基)丙酰胺(Im)的制备
Figure BDA0003595539530000201
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱm)(259.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(4-(三氟甲基)苯基)丙酰胺(Im)，转化率：99％，ee值为87％。
Im的结构表征：mp 112-113℃,[α]20 D＝+61.5(c＝1.20,CHCl3).The eewasdetermined by HPLC on ChiralpakOD-H column,hexane:isopropanol＝90:10；flowrate＝1mL/min；UV detection at 254nm；25℃；tR(S)＝9.609min(minor),tR(R)＝12.390min(major).1H NMR(600MHz,CDCl3)δ7.61(d,J＝8.4Hz,2H),7.52(d,J＝8.4Hz,2H),5.19(dd,J1＝9.6Hz,J2＝2.4Hz,1H),4.3(s,1H),2.98(s,3H),2.95(s,3H),2.72-2.57(m,2H).13C NMR(150MHz,CDCl3)δ171.9,147.1,129.7(q,2JC-F＝32.1Hz),126.1,125.4(q,4JC-F＝3.75Hz),124.2(q,1JC-F＝270.3Hz),69.9,41.6,37.1,35.3.HRMS(ESI)calcd forC12h15F3NO2[M+H]+:262.1049,found:262.1062.
实施例22：(R)-3-([1,1'-联苯]-4-基)-3-羟基-N,N-二甲基丙酰胺(In)的制备
Figure BDA0003595539530000211
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱn)(267.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-([1,1'-联苯]-4-基)-3-羟基-N,N-二甲基丙酰胺(In)，转化率：99％，ee值为92％。
In的结构表征：mp111-112℃,[α]20 D＝+54.4(c＝0.72,CHCl3).The eewasdetermined by HPLC on ChiralpakOD-H column,hexane:isopropanol＝94:6；flow rate＝0.8mL/min；UV detection at 254nm；25℃；tR(S)＝36.842min(minor),tR(R)＝41.535min(major).1H NMR(600MHz,CDCl3)δ7.58(d,J＝8.4Hz,4H),7.47(d,J＝7.8Hz,2H),7.43(t,J＝7.8Hz,2H),7.33(t,J＝7.8Hz,1H),5.18(dt,J1＝9.6Hz,J2＝2.4Hz,1H),4.85(s,1H),2.98(s,3H),2.94(s,3H),2.74-2.63(m.2H).13C NMR(150MHz,CDCl3)δ172.3,142.2,140.9,140.5,128.8,127.3,127.2,127.1,126.2,70.2,41.9,37.1,35.3.HRMS(ESI)calcd for C17H20NO2[M+H]+:270.1489,found:270.1475.
实施例23：(R)-3-(呋喃-2-基)-3-羟基-N,N-二甲基丙酰胺(Io)的制备
Figure BDA0003595539530000221
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱo)(181.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-(呋喃-2-基)-3-羟基-N,N-二甲基丙酰胺(Io)，转化率：99％，ee值为92％。
Io的结构表征：mp67-69℃,[α]20 D＝+61.3(c＝0.48,CHCl3).The eewasdetermined by HPLC on ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UV detection at 220nm；25℃；tR(R)＝21.733min(major),tR(S)＝24.460min(minor).1H NMR(600MHz,CDCl3)δ7.37(s,1H),6.34-6.33(m,1H),6.29(d,J＝3.6Hz,1H),5.15(dt,J1＝9.6Hz,J2＝3Hz,1H),4.76(d,J＝3.6Hz,1H),3.00(s,3H),2.98(s,3H),2.87-2.76(m,2H).13C NMR(150MHz,CDCl3)δ171.8,155.3,141.9,110.3,106.1,64.5,37.9,37.1,35.2.HRMS(ESI)calcd for C9H14NO3[M+H]+:184.0968,found:184.0959.
实施例24：(R)-3-羟基-N,N-二甲基-3-(噻吩-2-基)丙酰胺(Ip)的制备
Figure BDA0003595539530000231
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱp)(197.3mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应12h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(噻吩-2-基)丙酰胺(Ip)，转化率：99％，ee值为99％。
Ip的结构表征：[α]20 D＝+59.6(c＝0.52,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝94:6；flow rate＝1mL/min；UVdetection at 220nm；25℃；tR(R)＝20.167min(major),tR(S)＝22.265min(minor).1H NMR(400MHz,CDCl3)δ7.15(dd,J1＝4.4Hz,J2＝1.6Hz,1H),6.89-6.87(m,2H),5.28(dd,J1＝8Hz,J2＝3.2Hz,1H),5.03(s,1H),2.883(s,3H),2.875(s,3H),2.73-2.63(m,2H).13C NMR(100MHz,CDCl3)δ170.7,146.0,125.6,123.4,122.2,65.8,40.7,36.1,34.2.HRMS(ESI)calcd for C9H14NO2S[M+H]+:200.0740,found:200.0729.
实施例25：(R)-3-羟基-N,N-二甲基-3-(吡啶-3-基)丙酰胺(Iq)的制备
Figure BDA0003595539530000241
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱk)(192.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、氢氧化钠(4.0mg,0.10mmol)和乙酸乙酯(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应24h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N,N-二甲基-3-(吡啶-3-基)丙酰胺(Iq)，转化率：99％，ee值为95％。
Ik的结构表征：[α]20 D＝+1.7(c＝0.46,CHCl3).The eewas determined by HPLCon ChiralpakOJ-H column,hexane:isopropanol＝94:6；flow rate＝0.8mL/min；UVdetection at 254nm；25℃；tR(S)＝29.541min(minor),tR(R)＝32.545min(major).1H NMR(400MHz,CDCl3)δ8.62(s,1H),8.54(d,J＝4.4Hz,1H),7.81(dt,J1＝8Hz,J2＝2Hz,1H),7.32(dd,J1＝7.6Hz,J2＝4.8Hz,1H),5.24-5.18(m,2H),3.00(s,3H),2.98(s,3H),2.75-2.60(m,2H).13C NMR(100MHz,CDCl3)δ171.8,148.8,147.5,133.8,125.1,123.6,68.3,41.5,37.1,35.3.HRMS(ESI)calcd for C10H15N2O2[M+H]+:195.1128,found:195.1136.
实施例26：(R)-3-羟基-N-甲基-3-苯基丙酰胺(Ir)的制备
Figure BDA0003595539530000251
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱr)(177.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、乙酸钠(8.2mg,0.10mmol)和四氢呋喃(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应24h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N-甲基-3-苯基丙酰胺(Ir)，转化率：99％，ee值为95％。
Ir的结构表征：[α]20 D＝+28.3(c＝0.52,CH3OH).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝92:8；flow rate＝1mL/min；UVdetection at 220nm；25℃；tR(R)＝11.462min(major),tR(S)＝14.040min(minor).1H NMR(600MHz,CDCl3)δ7.38-7.34(m,4H),7.30-7.28(m,1H),6.00(s,1H),5.10(dd,J1＝9Hz,J2＝3Hz,1H),3.45(s,1H),2.82(d,J＝4.8Hz,3H),2.60-2.52(m,2H).13C NMR(150MHz,CDCl3)δ172.5,143.1,128.5,127.7,125.6,70.9,44.6,26.2.HRMS(ESI)calcd for C10H14NO2[M+H]+:180.1019,found:180.1009.
实施例27：(R)-3-羟基-N-甲基-3-(噻吩-2-基)丙酰胺(Is)的制备
Figure BDA0003595539530000252
(1)在氩气气氛下往10mL烧瓶中加入[Ir(COD)Cl]2(3.36mg,0.5mmol％)，配体L2(7.47mg,1.05mmol％)和异丙醇(2mL)，25℃下搅拌1h，得到橙黄色溶液，直接用于下一步催化反应；
(2)往10mL的样品瓶中依次加入(Ⅱs)(183.2mg,1.0mmol)，步骤(1)所制备的金属Ir催化剂(1.05mmol％)、乙酸钠(8.2mg,0.10mmol)和四氢呋喃(4mL)，再把样品瓶放入高压釜中，充入H2(4MPa)，50℃下反应24h，反应结束后，减压浓缩回收溶剂，残留物经柱层析分离(乙酸乙酯：正己烷＝1:1)，制得(R)-3-羟基-N-甲基-3-(噻吩-2-基)丙酰胺(Is)，转化率：99％，ee值为90％。
Is的结构表征：[α]20 D＝+20.8(c＝0.52,CHCl3).The eewas determined by HPLCon ChiralpakAD-H column,hexane:isopropanol＝92:8；flow rate＝1mL/min；UVdetection at 220nm；25℃；tR(R)＝10.437min(major),tR(S)＝17.674min(minor).1H NMR(400MHz,CDCl3)δ7.25-7.24(m,1H),6.97-6.95(m,2H),5.96(s,1H),5.35(t,J＝6Hz,1H),3.69(s,1H),2.82(d,J＝4.8Hz,3H),2.68(s,1H),2.67(s,1H).13C NMR(100MHz,CDCl3)δ172.1,126.7,124.7,123.5,67.2,44.4,26.3.HRMS(ESI)calcd for C8H12NO2S[M+H]+:186.0583,found:186.0580.
实施例28：(R)-氟西汀的制备
Figure BDA0003595539530000261
(1)在氩气气氛下往25mL两口烧瓶中加入(R)-3-羟基-N-甲基-3-苯基丙酰胺(Ir)(896.1mg)，四氢呋喃(20mL)，分批次加入四氢铝锂(208.7mg)，70℃回流4h后，加入水和氢氧化钠(aq)溶液淬灭，过滤，并用乙酸乙酯萃取，分出的有机层经盐水洗涤、真空浓缩、柱色谱纯化，制得白色固体(740.2mg,89％，ee95％)，用于下一步反应；
Figure BDA0003595539530000271
(2)在氩气氛围下往25mL两口烧瓶中依次加入(R)-3-(甲基氨基)-1-苯基丙-1-醇(740.2mg)，DMAC(20mL),氢化钠(128.2mg)，在50℃下反应2h后，加入对氯三氟甲苯(1.2mL)，在80℃反应3h后，加入甲苯和水，用甲苯萃取水相，有机相经盐水洗涤、真空浓缩、柱色谱纯化后，得到氟西汀(963.6mg，70％，ee95％)。
实施例29：(R)-氟西汀的制备
Figure BDA0003595539530000272
(1)在氩气气氛下往25mL两口烧瓶中加入(R)-3-羟基-N,N-二甲基-3-苯丙酰胺(Ia)(966.3mg)，四氢呋喃(20mL)，分批次加入四氢铝锂(208.7mg)，70℃回流4h后，加入水和氢氧化钠(aq)溶液淬灭，过滤，并用乙酸乙酯萃取，分出的有机层经盐水洗涤、真空浓缩、柱色谱纯化，制得白色固体(R)-3-(二甲氨基)-1-苯基丙-1-醇(806.7mg)，收率为90％，ee值99％；
Figure BDA0003595539530000273
(2)在氩气氛围下往25mL两口烧瓶中依次加入(R)-3-(二甲氨基)-1-苯基丙-1-醇(806.7mg)，DMAC(20mL),氢化钠(128.2mg)，在50℃下反应2h后，加入对氯三氟甲苯(1.2mL)，在80℃反应3h后，加入甲苯和水，用甲苯萃取水相，有机相经盐水洗涤、真空浓缩、柱色谱纯化后，得到黄色液体(963.6mg，70％，ee95％)。
Figure BDA0003595539530000281
(3)在氩气氛围下往25mL两口烧瓶中依次加入(R)-N,N-二甲基-3-苯基-3-(4-(三氟甲基)苯氧基)丙-1-胺(963.6mg)，甲苯(10mL),三乙胺(3滴)，升至55℃加入氯甲酸苄酯(0.49mL)，反应5h后，加入1％碳酸氢钠溶液(30mL)，水(30mL)洗涤，所得有机相用无水硫酸镁干燥，减压蒸馏后，加入DMSO(10mL)溶解，后加入氢氧化钠(1.1g)，缓慢加入水(1mL)，50℃反应10h，加10mL水稀释，加醋酸调ph至5，石油醚(15*2mL)洗涤，在水层中加5mol/L氢氧化钠溶液调ph至12，乙酸乙酯萃取，有机相经盐水洗涤、真空浓缩、柱色谱纯化后，得到(R)-氟西汀(737.4mg,80％,ee 99％)。

Claims (7)

1.一种(R)-β-羟基芳基丙酰胺类衍生物的制备方法，所述(R)-β-羟基芳基丙酰胺类衍生物的结构式如式(I)所示，其特征在于所述制备方法包括如下过程：
1)在氩气氛围及20～40℃下，将金属Ir络合物与手性配体依次加入到溶剂A中，搅拌反应0.5～2小时，制得金属Ir催化剂，金属Ir络合物为[Ir(COD)Cl]2；
2)将如式(Ⅱ)所示的β-氧代芳基丙酰胺类衍生物、步骤1)所得金属Ir催化剂、溶剂B及碱A依次加入到高压釜中，于30～80℃温度及3.0～8.0MPa的氢气压力下反应6～30小时，再减压浓缩除去溶剂，残留物经柱层析分离，得到如式(I)所示的(R)-β-羟基芳基丙酰胺类衍生物；
具体反应路线如下：
Figure FDA0004175479540000011
通式(I)、(Ⅱ)中，其中R1为取代芳基、杂环芳基；R2和R3各自独立的选自氢、C1～C6直链或支链的烷基；
取代芳基中的取代基为氢、卤素、C1～C6直链或支链的烷基、C1～C6烷氧基；杂环芳基为吡啶基、呋喃基或噻吩基；
步骤1)中手性配体结构式为如式(SC,RFC,S,S)-L1、(SC,RFC,S,S)-L2、(SC,RFC,S,S)-L3、(SC,RFC,S,S)-L4、(SC,RFC,S,S)-L5、(SC,RFC,S,S)-L6中所示的任意一种：
Figure FDA0004175479540000021
2.根据权利要求1所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于步骤1)中的手性配体与金属Ir络合物的投料摩尔比为1.0～2.5:1。
3.根据权利要求1所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于步骤1)中的手性配体与金属Ir络合物的投料摩尔比为2:1。
4.根据权利要求1所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于步骤1)中的溶剂A和步骤2)中的溶剂B各自独立地选自二氯甲烷、四氢呋喃、2-甲基四氢呋喃、甲基叔丁基醚、甲苯、甲醇、乙醇、异丙醇、乙酸乙酯、1,4-二氧六环、六氟异丙醇中的一种或两种以上混合溶剂，所述溶剂A和溶剂B相同或不同。
5.根据权利要求1所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于步骤2)中的金属Ir催化剂、碱A、β-氧代芳基丙酰胺类衍生物的投料摩尔比为1:2～100:100～100000。
6.根据权利要求1所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于步骤2)中，碱A选自叔丁醇锂、叔丁醇钠、叔丁醇钾、碳酸钠、碳酸钾、甲酸钠、乙酸钠、乙酸钾、碳酸氢钠、碳酸氢钾、甲醇钠、甲醇锂、氢氧化钠、氢氧化钾中的一种或两种以上混合物。
7.根据权利要求6所述的(R)-β-羟基芳基丙酰胺类衍生物的制备方法，其特征在于碱A与β-氧代芳基丙酰胺类衍生物的投料摩尔比为0.01～0.1:1。
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