CN116444412A - 一种含手性三氟甲基氮杂环化合物的制备方法 - Google Patents

一种含手性三氟甲基氮杂环化合物的制备方法 Download PDF

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CN116444412A
CN116444412A CN202310413066.2A CN202310413066A CN116444412A CN 116444412 A CN116444412 A CN 116444412A CN 202310413066 A CN202310413066 A CN 202310413066A CN 116444412 A CN116444412 A CN 116444412A
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heterocyclic compound
chiral
nitrogen
trifluoromethyl
nitrogen heterocyclic
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侯国华
谢超超
郭倩伶
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Beijing Normal University
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Abstract

本发明公开了一种含手性三氟甲基氮杂环化合物的制备方法，包括以下步骤：将含不饱和氮杂环化合物Ⅰ在氢气氛围和铑手性催化剂的催化作用下进行反应，然后纯化，得到含手性三氟甲基氮杂环化合物Ⅱ，其中，所述含不饱和氮杂环化合物Ⅰ的结构式为式Ⅰ所示，所述含手性三氟甲基氮杂环化合物Ⅱ的结构式为式Ⅱ所示。本发明利用铑金属前体和手性双膦配体为原料自制了铑手性催化剂，该铑手性催化剂具有低毒、原子经济性高和对环境友好的优点；通过将含不饱和氮杂环化合物Ⅰ在氢气氛围和该自制的铑手性催化剂的催化作用下进行反应，成功地制备了含手性三氟甲基氮杂环化合物。本发明制备方法具有操作简便实用、产率高和ee值高的优点。

Description

一种含手性三氟甲基氮杂环化合物的制备方法
技术领域
本发明属于化学合成技术领域，特别涉及一种含手性三氟甲基氮杂环化合物的制备方法。
背景技术
光学纯的三氟甲基氮杂环是许多药物活性分子(例如抗癌药、抗疟药、抗病毒药、抗菌药、抗抑郁药)的重要结构单元，因此开发一种高效高对映选择性合成手性三氟甲基氮杂环的方法是十分重要的。
不对称催化氢化由于其高效，环境友好，原子经济等特点，一直是合成手性化合物的一种重要的方法。例如手性三氟甲基化合物以及手性氮杂环的合成虽然已经有文献的报道。Kuiling Ding等在“Catalytic Asymmetric Hydrogenation ofα-CF3-orβ-CF3-Substituted Acrylic Acids using Rhodium(I)Complexes with aCombination ofChiral and Achiral Ligands”.《Angew.Chem.Int.Ed.》.2013，第52期，第14191-14195页，公开了α-CF3-和β-CF3-取代的丙烯酸化合物经Rh和手性SPO配体以及三苯基膦原位生成催化剂进行不对称氢化反应生成含手性三氟甲基的酸。Xumu Zhang等在“Highly EfficientSynthesis of ChiralαCF3 Amines via Rh-Catalyzed Asymmetric Hydrogenation”.《Org.Lett.》.2015，第17期，第1154-1156页，公开了三氟甲基烯酰胺，经手性Rh-DuanPhos络合物催化作用进行不对称氢化反应生成手性α CF3胺。Wanbin Zhang等在“Mechanism ofthe Asymmetric Hydrogenation of Exocyclicα,β-Unsaturated Carbonyl Compoundswith an Iridium/BiphPhox Catalyst:NMR and DFT Studies”.《Angew.Chem.Int.Ed.》.2014，第53期，第1901-1905页，公开了不饱和氮杂环经过手性Iridium/BiphPhox催化剂催化作用进行不对称氢化反应生成手性吡咯烷酮。
但是含手性三氟甲基氮杂环底物(化合物)的制备却尚未见报道，由于手性三氟甲基氮杂环化合物是许多药物活性分子的结构单元，因此找到制备含手性三氟甲基氮杂环化合物的方法十分重要。
发明内容
针对上述现有技术存在的问题，本发明的目的在于提供了一种含手性三氟甲基氮杂环化合物的制备方法。该制备方法具有高效、环境友好的特点。
为了实现上述目的，本发明采用了如下技术方案：
一种含手性三氟甲基氮杂环化合物的制备方法，包括以下步骤：将含不饱和氮杂环化合物Ⅰ在氢气氛围和铑手性催化剂的催化作用下进行反应，然后纯化，得到含手性三氟甲基氮杂环化合物Ⅱ，其中，所述含不饱和氮杂环化合物Ⅰ的结构式为下式Ⅰ所示，所述含手性三氟甲基氮杂环化合物Ⅱ的结构式为下式Ⅱ所示：
其中，R选自C1-C20烷基、取代C1-C20烷基、苯基、萘基或取代苯基；
所述取代C1-C20烷基为C1-C20烷基上的1个或1个以上的H被取代基A取代的C1-C20烷基；所述取代苯基为苯基上的1个或1个以上的H被取代基A取代的苯基；所述取代基A选自：卤素、-CF3、C1-C3烷基、C1-C3烷氧基或苯基。
优选地，所述铑手性催化剂通过在氮气氛围下，将铑金属前体和手性双膦配体加入有机溶剂中，于15～35℃下搅拌反应0.5～1h得到。
优选地，所述铑金属前体为环辛二烯氯化铑二聚体；所述手性双膦配体为(R)-Monophos、(R)-MeDuPhos、(S,S)-f-Binaphane、(S)-DTBM-SegPhos、(R)-DM-SegPhos、(R)-Segphos或(R,R)-f-spiroPhos中的任意一种，进一步优选为(R,R)-f-spiroPhos。
优选地，所述有机溶剂为二氯甲烷、乙醚、甲苯、1,4-二氧六环、四氢呋喃和甲醇中的一种或者两种以上的组合，进一步优选为甲醇。
优选地，所述铑金属前体和含不饱和氮杂环化合物Ⅰ的摩尔比为0.5：50～120；例如，所述铑金属前体和不饱和氮杂环的摩尔比可选自：0.5：50、0.5：60、0.5：70、0.5：80、0.5：90、0.5：100、0.5：110或0.5：120；进一步优选为0.5：100。
优选地，所述反应时间为1～24h；例如，反应时间选自1h、4h、6h、8h、12h、14h、16h、18h、20h、22h或24h；进一步优选为1h；
优选地，所述反应温度为20～70℃；例如，反应温度选自：20℃、30℃、40℃、50℃、60℃或70℃；进一步优选为30℃。
优选地，所述反应时的氢气压力为100～1200psi；例如，反应压力选自100psi、140psi、300psi、500psi、700psi或1200psi；进一步优选为140psi。
优选地，所述含不饱和氮杂环化合物Ⅰ选自选自以下化合物1、和化合物18-35中的一种：
与现有技术相比，本发明具备如下有益效果：
本发明利用铑金属前体和手性双膦配体为原料自制了铑手性催化剂，该铑手性催化剂具有低毒、原子经济性高和对环境友好的优点；通过将含不饱和氮杂环化合物Ⅰ在氢气氛围和该自制的铑手性催化剂的催化作用下进行反应，成功地制备了含手性三氟甲基氮杂环化合物。本发明制备方法具有操作简便实用、产率高和ee值高的优点。
附图说明
为了更清楚地说明本发明实施例中的技术方案，下面将对实施例中所需要使用的附图作简单地介绍，显而易见地，下面描述中的附图仅仅是本发明的一些实施例，对于本领域普通技术人员来讲，在不付出创造性劳动的前提下，还可以根据这些附图获得其他的附图。
图1为本发明提供的含手性三氟甲基氮杂环化合物合成路线图；
图2为本发明中典型手性膦配体的化学结构式；
图3为本发明中典型的含不饱和氮杂环化合物Ⅰ的化学结构式。
具体实施方式
以下描述中，为了说明而不是为了限定，提出了诸如特定系统结构、技术之类的具体细节，以便透彻理解本发明实施例。然而，本领域的技术人员应当清楚，在没有这些具体细节的其它实施例中也可以实现本发明。
实施例1
参照图1的含手性三氟甲基氮杂环化合物的合成路线图：
制备(S)-1-苯基-3-(2,2,2-三氟乙基)吡咯烷-2-酮，其化学式如下：
具体步骤：在干燥的反应瓶中加入环辛二烯氯化铑二聚体(环辛二烯氯化铑二聚体与(E)-1-苯基-3-(2,2,2-三氟亚乙基)吡咯烷-2-酮(化合物1)的摩尔比为0.5:100)和(R,R)-f-spiroPhos(环辛二烯氯化铑二聚体与(R,R)-f-spiroPhos的摩尔比为0.5：1.1)，氮气置换后加入1.0mL甲醇，25℃下搅拌反应0.5h；然后用1.0mL甲醇将此溶液转到预先加入不饱和氮杂环底物1a(30.1mg,0.125mmol)，并将反应瓶移至反应釜中，通入氢气，设置氢气压力为140psi，25℃下反应24h；释放氢气，将反应混合物经过硅胶柱过滤，滤除催化剂和添加剂后即可得到目标产物，即(S)-1-苯基-3-(2,2,2-三氟乙基)吡咯烷-2-酮，为白色固体；30.0mg,yield:99％；97％ee；[α]D 25＝+28.4(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝3:97,2.0mL/min,230nm；tR＝6.5min(minor),tR＝7.1min(major)；1H NMR(CDCl3,400MHz)δ:7.51(d,J＝8.3Hz,2H),7.28(t,J＝7.8Hz,2H),7.07(t,J＝7.5Hz,1H),3.79–3.67(m,2H),2.91–2.78(m,2H),2.48–2.42(m,1H),2.12–2.00(m,1H),1.91–1.81(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.7,139.1,128.9,126.9(d,J＝276.5Hz),124.9,119.8,46.7,38.3(q,J＝2.5Hz),35.6(q,J＝29.3Hz),25.8；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.8Hz,3F)；TOF-HRMS Calcd.for C12H13NOF3[M+H+]:244.0943,found 244.0941.
实施例2
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(R)-Monophos。
实施例3
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(R)-MeDuPhos。
实施例4
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(S,S)-f-Binaphane。
实施例5
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(S)-DTBM-SegPhos。
实施例6
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(R)-DM-SegPhos。
实施例7
与实施例1的步骤基本相同，不同之处在于：使用的手性膦配体不同，本实施例中使用的手性膦配体为(R)-Segphos。
上述实施例1-7制备得到的目标产物、收率以及ee值结果如下表1所示。
表1.不同手性膦配体条件下制备得到的目标产物、收率以及ee值结果
手性膦配体 2a/3a 收率(％) ee.(％)
实施例1 (R,R)-f-spiroPhos 4:1 72 95
实施例2 (R)-Monophos 1:1 trace ND
实施例3 (R)-MeDuPhos 1:1 trace ND
实施例4 (S,S)-f-Binaphane 11:8 11 86
实施例5 (S)-DTBM-SegPhos 21:13 21 35
实施例6 (R)-DM-SegPhos 2:1 12 39
实施例7 (R)-Segphos 3:1 trace ND
由上述表1结果可知，当使用的手性膦配体为(R,R)-f-spiroPhos时(实施例1)，得到的目标产物即含手性三氟甲基氮杂环化合物2a的收率最高，并且含手性三氟甲基氮杂环化合物2a的对映体过量(enantiomeric excess)值即ee值最高。
实施例8
与实施例1的步骤基本相同，不同之处在于：使用的溶剂不同，本实施例中使用的溶剂为二氯甲烷。
实施例9
与实施例1的步骤基本相同，不同之处在于：使用的溶剂不同，本实施例中使用的溶剂为乙醚。
实施例10
与实施例1的步骤基本相同，不同之处在于：使用的溶剂不同，本实施例中使用的溶剂为甲苯。
实施例11
与实施例1的步骤基本相同，不同之处在于：使用的溶剂不同，本实施例中使用的溶剂为1,4-二氧六环。
实施例12
与实施例1的步骤基本相同，不同之处在于：使用的溶剂不同，本实施例中使用的溶剂为四氢呋喃。
上述实施例1与实施例8-12制备得到的目标产物、收率以及ee值结果如下表2所示。
表2.不同溶剂下制备得到的目标产物、收率以及ee值结果
溶剂 2a/3a 收率(％) ee.(％)
实施例1 甲醇 >99:1 99 99
实施例8 二氯甲烷 4:1 72 95
实施例9 乙醚 13:1 93 87
实施例10 甲苯 32:1 97 91
实施例11 1,4-二氧六环 32:1 97 93
实施例12 四氢呋喃 49:1 98 92
由上述表2结果可知，当使用的有机溶剂为甲醇时(实施例1)，反应只有单一产物即含手性三氟甲基氮杂环化合物2a，并且含手性三氟甲基氮杂环化合物2a的收率和ee值最高。
实施例13
与实施例1的步骤基本相同，不同之处在于：氢气压力不同，本实施例中的氢气压力为100psi。
实施例14
与实施例1的步骤基本相同，不同之处在于：氢气压力不同，本实施例中的氢气压力为300psi。
实施例15
与实施例1的步骤基本相同，不同之处在于：氢气压力不同，本实施例中的氢气压力为600psi。
实施例16
与实施例1的步骤基本相同，不同之处在于：氢气压力不同，本实施例中的氢气压力为900psi。
实施例17
与实施例1的步骤基本相同，不同之处在于：氢气压力不同，本实施例中的氢气压力为1200psi。
表3.不同氢气压力条件下制备得到的目标产物、收率以及ee值结果
氢气压力(psi) 2a/2a’ 收率(％) ee.(％)
实施例1 140 >99:1 >99 97
实施例13 100 >99:1 85 97
实施例14 300 >99:1 >99 97
实施例15 600 >99:1 >99 97
实施例16 900 >99:1 >99 97
实施例17 1200 >99:1 >99 97
由上述表3结果可知，当氢气压力140psi时(实施例1)，反应只有单一产物2a，并且含手性三氟甲基氮杂环化合物2a的收率和ee值最高。
实施例18
制备(S)-1-(间甲苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物18代替，最终得到白色固体；31.8mg,yield:99％；99.9％ee；[α]D 25＝+26.4(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,230nm；tR＝2.2min(minor),tR＝2.4min(major)；1H NMR(CDCl3,400MHz)δ:7.44(s,1H),7.36(d,J＝8.0Hz,1H),7.28–7.23(m,1H),6.98(d,J＝7.5Hz,1H),3.86–3.75(m,2H),3.03–2.85(m,2H),2.56–2.49(m,1H),2.36(s,3H),2.20–2.08(m,1H),1.98–1.86(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.8,139.1138.9,128.8,127.2(q,J＝275Hz),125.7,120.76,117.1,46.9,38.4(q,J＝2.7Hz),35.6(q,J＝29.0Hz),25.9,21.7；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.7Hz,3F)；TOF-HRMS Calcd.for C13H14NOF3Na[M+Na+]:280.0919,found 280.0918.
实施例19
制备(S)-1-(3-甲氧基苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物19代替，最终得到白色固体；33.4mg,yield:98％；99.9％ee；[α]D 25＝+11.1(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,254nm；tR＝2.8min(minor),tR＝3.0min(major)；1H NMR(CDCl3,400MHz)δ:7.48(d,J＝8.5Hz,2H),6.90(d,J＝8.7Hz,2H),3.84–3.71(m,2H),3.79(s,3H),3.03–2.84(m,2H),2.55–2.48(m,1H),2.19–2.08(m,1H),1.99–1.89(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.5,156.9,132.4,127.0(q,J＝279.6Hz),121.7,114.2,55.6,47.2,38.2,35.7(q,J＝29.0Hz),26.0；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.7Hz,3F)；TOF-HRMS Calcd.for C13H15NO2F3[M+H+]:274.1049,found 274.1052.
实施例20
制备(S)-1-(3-氟苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物20代替，最终得到白色固体；32.2mg,yield:99％；99.9％ee；[α]D 25＝+15.9(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,210nm；tR＝2.6min(major),tR＝2.8min(minor)；1H NMR(CDCl3,400MHz)δ:7.51(dt,J＝11.3,2.3Hz,1H),7.35–7.31(m,2H),6.89–6.84(m,1H),3.85–3.77(m,2H),3.03–2.87(m,2H),2.58–2.51(m,1H),2.21–2.09(m,1H),2.01–1.90(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:173.0,163.0(d,J＝245.1Hz),140.6(d,J＝10.5Hz),130.1(d,J＝9.3Hz),126.9(q,J＝276.5Hz),114.8(d,J＝3.1Hz),111.6(d,J＝21.2Hz),107.2(d,J＝26.3Hz),46.7,38.5(q,J＝2.7Hz),35.5(q,J＝29.2Hz),25.7；19F NMR(CDCl3,376MHz)δ:-64.9(t,J＝11.3Hz,3F),-111.16(s,1F)；TOF-HRMS Calcd.for C12H12NOF4[M+H+]:262.0849,found 262.0847.
实施例21
制备(S)-1-(3-溴苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物21代替，最终得到白色固体；39.3mg,yield:98％；99.9％ee；[α]D 25＝+21.7(c＝1.0,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,230nm；tR＝2.9min(minor),tR＝3.1min(major)；1H NMR(CDCl3,400MHz)δ:7.80(t,J＝2.0Hz,1H),7.58(ddd,J＝8.1,2.1,1.1Hz,1H),7.31–7.27(ddd,J＝8.0,1.7,1.2Hz,1H),7.22(t,J＝8.0Hz,1H),3.85–3.74(m,2H),3.02–2.86(m,2H),2.58–2.51(m,1H),2.20–2.06(m,1H),2.00–1.89(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.9,140.3,130.2,126.8(q,J＝277.8Hz),127.8,122.7,122.5,118.1,46.6,38.3(q,J＝2.6Hz),35.4(q,J＝29.1Hz),25.7；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.6Hz,3F)；TOF-HRMS Calcd.for C12H12NOF3Br[M+H+]:322.0048,found322.0046.
实施例22
制备(S)-1-(4-氟苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物22代替，最终得到白色固体；31.9mg,yield:98％；96％ee；[α]D 25＝+25.2(c＝0.5,CHCl2)；HPLC condition:Lux 5uCellulose-2(250×4.60mm),ipa:hex＝10:90,1.0mL/min,210nm；tR＝8.5min(major),tR＝8.9min(minor)；1H NMR(CDCl3,400MHz)δ:7.56(dd,J＝9.0,4.8Hz,2H),7.06(t,J＝8.6Hz,2H),3.86–3.78(m,2H),3.03–2.85(m,2H),2.57–2.50(m,1H),2.20–2.06(m,1H),2.00–1.90(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:171.8,158.8(q,J＝245.4Hz),134.3(d,J＝2.9Hz),125.9(q,J＝276.4Hz),120.7(d,J＝7.9Hz),114.7(d,J＝22.4Hz),46.0,37.2(q,J＝2.6Hz),34.6(q,J＝29.0Hz),24.8；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.6Hz,3F),-113.28–-126.39(m,1F)；TOF-HRMS Calcd.for C12H12NOF4[M+H+]:262.0849,found262.0847.
实施例23
制备(S)-1-(4-(叔丁基)苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物23代替，最终得到白色固体；36.6mg,yield:98％；99％ee；[α]D 25＝+15.7(c＝1.0,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,254nm；tR＝2.0min(minor),tR＝2.1min(major)；1H NMR(CDCl3,400MHz)δ:7.46(d,J＝8.6Hz,2H),7.33(d,J＝8.5Hz,2H),3.81–3.70(m,2H),2.94–2.79(m,2H),2.48–2.45(m,1H),2.11–2.03(m,1H),1.93–1.83(m,1H),1.25(s,9H)；13C{1H}NMR(CDCl3,101MHz)δ:172.65,147.95,136.44,127.06(q,J＝278.8Hz),125.82,119.65,46.76,38.24(q,J＝3.0Hz),35.57(q,J＝28.9Hz),34.42,31.31,25.87；19F NMR(CDCl3,376MHz)δ:-64.9(t,J＝10.7Hz,3F)；TOF-HRMS Calcd.forC16H21NOF3[M+H+]:300.1569,found 300.1564.
实施例24
制备(S)-1-(3-硝基苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物24代替，最终得到白色固体；35.6mg,yield:99％；99.7％ee；[α]D 25＝+20.3(c＝0.5,CHCl2)；SFC condition:Lux 5uAmylose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,254nm；tR＝5.0min(major),tR＝6.5min(minor)；1H NMR(CDCl3,400MHz)δ:8.38(t,J＝2.0Hz,1H),8.17(d,J＝8.2Hz,1H),8.02(d,J＝8.2Hz,1H),7.55(t,J＝8.2Hz,1H),3.93–3.85(m,1H),3.01–2.92(m,2H),2.65–2.58(dt,J＝14.1,7.2Hz),2.24–2.09(m,1H),2.06–1,96(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:173.4,148.6,140.2,129.9,126.8(q,J＝277.8Hz),125.3,119.3,113.9,38.4(q,J＝2.9Hz),35.4(q,J＝29.5Hz),25.6；19F NMR(CDCl3,376MHz)δ:-64.7(t,J＝10.2Hz,3F)；TOF-HRMS Calcd.for C12H12N2O3F4[M+H+]:289.0794,found 289.0798.
实施例25
制备(S)-1-(3,5-二甲基苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
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实验条件同实施例1，将实施例1中的化合物1用化合物25代替，最终得到白色固体；33.5mg,yield:99％；99.9％ee；[α]D 25＝+21.2(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,254nm；tR＝2.0min(minor),tR＝2.5min(major)；1H NMR(CDCl3,400MHz)δ:7.20(s,2H),6.81(s,1H),3.85–3.73(m,2H),3.06–2.74(m,2H),2.54–2.47(m,1H),2.31(s,6H),2.19–2.05(m,2H)1.97–1.87(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.8,139.1,138.7,127.0(q,J＝277.8Hz),126.8,118.0,47.1,38.4(q,J＝3.0Hz),35.6(q,J＝29.3Hz),26.0,21.5；19F NMR(CDCl3,376MHz)δ:-64.9(t,J＝10.7Hz,3F)；TOF-HRMS Calcd.for C14H17NOF3[M+H+]:272.1256,found272.1262.
实施例26
制备(S)-1-(3,4-二甲基苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物26代替，最终得到白色固体；33.5 mg,yield:99％；99％ee；[α]D 25＝+22.4(c＝1.0,CHCl2)；SFCcondition:Lux 5uCellulose-1(250×4.60 mm),MeOH:CO2＝10:90,3.0 mL/min,254 nm；tR＝2.2 min(minor),tR＝2.5 min(major)；1H NMR(CDCl3,400 MHz)δ:7.38(s,1H),7.27(d,J＝8.2 Hz,1H),7.11(d,J＝8.2 Hz,1H),3.84–3.72(m,2H),3.03–2.83(m,2H),2.54–2.48(m,1H),2.26(s,3H),2.23(s,3H),2.16–2.07(m,1H),1.98–1.87(m,1H)；13C{1H}NMR(CDCl3,101 MHz)δ:172.7,137.3,136.9,133.6,130.0,127.0(q,J＝276.6 Hz),121.5,117.6,47.1,38.3(q,J＝2.1 Hz),35.7(q,J＝29.0 Hz),26.0,20.1,19.3；19F NMR(CDCl3,377 MHz)δ:-64.9(t,J＝10.8 Hz,3F)；TOF-HRMS Calcd.for C14H17NOF3[M+H+]:272.1256,found 272.1262.
实施例27
制备(S)-1-(3,5-二甲氧基苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
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实验条件同实施例1，将实施例1中的化合物1用化合物27代替，最终得到白色固体；37.1 mg,yield:98％；99.9％ee；[α]D 25＝+3.5(c＝0.5,CHCl2)；SFCcondition:Lux 5uCellulose-1(250×4.60 mm),MeOH:CO2＝5:95,2.0 mL/min,254 nm；tR＝9.7min(minor),tR＝10.1 min(major)；1H NMR(CDCl3,400 MHz)δ:7.53(t,J＝1.3Hz,1H),6.84(d,J＝1.3Hz,2H),3.89(s,3H),3.86(s,3H),3.89–3.74(m,2H),3.03–2.86(m,2H),2.56–2.49(m,1H),2.18–2.08(m,1H),2.00–1.89(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:172.6,149.1,146.5,132.9,127.0(q,J＝282.7Hz),111.6,111.1,105.1,56.2,56.1,47.2,38.4,35.7(q,J＝29.0Hz),25.8；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.6Hz,3F).
实施例28
制备(S)-1-(3,5-二氯苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物28代替，最终得到白色固体；38.0mg,yield:98％；97％ee；[α]D 25＝+18.3(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,230nm；tR＝2.9min(minor),tR＝3.0min(major)；1H NMR(CDCl3,400MHz)δ:7.59(s,2H),7.15(s,1H),3.81–3.76(m,2H),2.98–2.90(m,2H),2.60–2.52(m,1H),2.20–2.10(m,1H),2.06–1.93(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:173.2,140.9,135.4,126.8(d,J＝276.4Hz),124.7,117.8,46.6,38.4(q,J＝2.7Hz),35.4(q,J＝29.3Hz),25.6；19F NMR(CDCl3,376MHz)δ:-64.7–-64.9(m,3F)；TOF-HRMS Calcd.for C12H11NOF3Cl2[M+H+]:312.0164,found 312.0165.
实施例29
(S)-1-(3,4-二氯苯基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮的制备：
实验条件同实施例1，将实施例1中的化合物1用化合物29代替，最终得到白色固体；38.0mg,yield:98％；98％ee；[α]D 25＝+20.4(c＝1.0,CHCl2)；SFC condition:Lux 5uAmylose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,254nm；tR＝4.7min(major),tR＝5.7min(minor)；1H NMR(CDCl3,400MHz)δ:7.78(s,1H),7.52(d,J＝8.9Hz,1H),7.42(d,J＝8.9Hz,1H)3.81–3.76(m,2H),3.03–2.81(m,2H),2.67–2.46(m,1H),2.21–2.05(m,1H),2.04–1.87(m,1H)；13C{1H}NMR(CDCl3,101MHz)δ:173.1,138.6,132.9,130.5,128.2,126.8(q,J＝277.8Hz),121.2,118.8,46.6,38.4(q,2.0Hz),35.5(q,J＝29.3Hz),25.6；19F NMR(CDCl3,377MHz)δ:-64.9(t,J＝10.5Hz,3F)；TOF-HRMS Calcd.for C12H11NOF3Cl2[M+H+]:312.0164,found 312.0165.
实施例30
制备(S)-1-(萘-1-基)-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物30代替，最终得到白色固体；35.1mg,yield:96％；99.9％ee；[α]D 25＝+23.4(c＝0.5,CHCl2)；SFC condition:Lux 5uCellulose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,230nm；tR＝4.6min(major),tR＝5.8min(minor)；1H NMR(CDCl3,400MHz)δ:7.91–7.84(m,2H),7.66–7.63(m,1H),7.54–7.47(m,3H),7.36(dd,J＝7.3,1.0Hz,1H),3.94–3.87(m,1H),3.80–3.74(m,1H),3.10–2.97(m,2H),2.70–2.62(m,1H),2.32–2.14(m,2H)；13C{1H}NMR(CDCl3,101MHz)δ:174.0,135.2,134.7,129.6,129.2(q,J＝157.6Hz),128.8,128.8,127,0,126.6,125.7,124.7,122.4,49.9,37.4(q,J＝2.2Hz),35.8(q,J＝29.3Hz),27.2；19F NMR(CDCl3,565MHz)δ:-64.7(s,3F)；TOF-HRMS Calcd.for C16H15NOF3[M+H+]:294.1100,found 294.1103.
实施例31
制备(S)-1-苯基-3-(2,2,2-三氟乙基)哌啶-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物31代替，最终得到白色固体和无色油；31.5mg,yield:96％；96％ee；[α]D 25＝-26.7(c＝1.0,CHCl2)；SFC condition:Lux 5u Amylose-1(250×4.60mm),MeOH:CO2＝20:80,3.0mL/min,210nm；tR＝2.4min(major),tR＝3.2min(minor)；1H NMR(600MHz,Chloroform-d)δ7.38(tt,J＝7.49,1.15Hz,2H),7.25(ddq,J＝7.06,5.93,1.18Hz,1H),7.21(dt,J＝8.46,1.18Hz,2H),3.76–3.67(m,1H),3.63(dddt,J＝12.17,5.44,4.19,1.27Hz,1H),3.22–3.07(m,1H),2.84–2.70(m,1H),2.38–2.29(m,1H),2.28–2.17(m,1H),2.09–1.92(m,2H),1.75(qd,J＝11.59,4.31Hz,1H).13C NMR(151MHz,Chloroform-d)δ170.0,143.2,129.3,127.3(q,J＝276.33Hz),127.0,126.1,51.4,37.4,35.2(q,J＝28.45Hz),26.9,22.5.19F NMR(CDCl3,565MHz)δ:-63.3(s,3F)；TOF-HRMS Calcd.for C13H15F3NO+[M+H+]:258.1100,found258.1098.
实施例32
制备(S)-1-(间甲苯基)-3-(2,2,2-三氟乙基)哌啶-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物32代替，最终得到白色固体：无色油；33.2mg,yield:98％；94％ee；[α]D 25＝-33.6(c＝1.0,CHCl2)；SFC condition:Lux 5u Amylose-1(250×4.60mm),MeOH:CO2＝20:80,3.0mL/min,210nm；tR＝1.7min(major),tR＝1.9min(minor)；1H NMR(600MHz,Chloroform-d)δ7.29–7.24(m,1H),7.07(ddt,J＝7.68,1.81,0.93Hz,1H),7.03(d,J＝1.87Hz,1H),7.02–6.98(m,1H),3.69(ddd,J＝12.29,9.94,4.91Hz,1H),3.61(dddt,J＝12.09,5.33,4.16,1.20Hz,1H),3.22–3.06(m,1H),2.77(tdd,J＝9.78,5.99,3.03Hz,1H),2.34(s,3H),2.33–2.27(m,1H),2.27–2.17(m,1H),2.09–2.01(m,1H),2.00–1.92(m,1H),1.80–1.72(m,1H).13C NMR(151MHz,Chloroform-d)δ170.0,143.2,139.2,129.1,127.8,127.3(q,J＝277.84Hz),126.9,123.0,37.4,35.2(q,J＝28.41Hz),26.9,22.5,21.4.19F NMR(565MHz,Chloroform-d)δ-63.38(s,3F)；TOF-HRMS Calcd.for C14H17F3NO+[M+H+]:272.1257,found 272.1257.
实施例33
制备(S)-1-(3-氟苯基)-3-(2,2,2-三氟乙基)哌啶-2-酮：
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实验条件同实施例1，将实施例1中的化合物1用化合物33代替，最终得到白色固体；34.04mg,yield:99％；98％ee；[α]D 25＝-24.8(c＝1.0,CHCl2)；SFC condition:Lux 5uAmylose-1(250×4.60mm),MeOH:CO2＝20:80,3.0mL/min,210nm；tR＝2.5min(major),tR＝3.2min(minor)；1H NMR(400MHz,Chloroform-d)δ7.33(td,J＝8.05,6.39Hz,1H),7.08–6.90(m,3H),3.79–3.54(m,2H),3.11(dqd,J＝15.18,12.15,3.07Hz,1H),2.77(dddd,J＝12.27,9.61,6.06,3.13Hz,1H),2.41–2.14(m,2H),2.01(dtq,J＝29.69,9.35,4.86Hz,2H),1.74(qd,J＝11.49,4.61Hz,1H).13C NMR(101MHz,Chloroform-d)δ170.11,162.93(d,J＝247.06Hz),144.60(d,J＝9.62Hz),130.29(d,J＝9.14Hz),128.58,125.82,121.62(d,J＝3.27Hz).19F NMR(565MHz,Chloroform-d)δ-63.40(s,3F),-111.57(s,F).；TOF-HRMSCalcd.for C13H14F4NO+[M+H+]:276.1006,found 276.1000.
实施例34
制备(S)-1-(4-甲氧基苯基)-3-(2,2,2-三氟乙基)哌啶-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物34代替，最终得到白色固体；34.4mg,yield:96％；93％ee；[α]D 25＝-36.3(c＝1.0,CHCl2)；SFC condition:Lux 5uAmylose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,210nm；tR＝5.2min(major),tR＝7.5min(minor)；1H NMR(400MHz,Chloroform-d)δ7.16–7.07(m,2H),6.96–6.83(m,2H),3.78(s,3H),3.71–3.54(m,2H),3.11(dtd,J＝15.29,12.27,3.01Hz,1H),2.75(tdd,J＝9.71,5.99,3.02Hz,1H),2.38–2.13(m,2H),2.08–1.88(m,2H),1.73(dtd,J＝13.34,11.23,4.27Hz,1H).13C NMR(101MHz,Chloroform-d)δ158.3,136.1,127.3(q,J＝287.73Hz)127.2,114.5,55.5,51.7,37.,35.29(q,J＝28.53Hz),26.9,22.5.19F NMR(376MHz,Chloroform-d)δ-63.37(s,3F)；TOF-HRMS Calcd.for C14H17F3NO2 +[M+H+]:288.1206,found 288.1213.
实施例35
制备(S)-1-苄基-3-(2,2,2-三氟乙基)吡咯烷-2-酮：
实验条件同实施例1，将实施例1中的化合物1用化合物35代替，最终得到白色固体；30.2mg,yield:96％；99.9％ee；[α]D 20＝4.6(c＝0.5,CH2Cl2)；SFC condition:Lux 5uAmylose-1(250×4.60mm),MeOH:CO2＝10:90,3.0mL/min,210nm；tR＝3.5min(major),tR＝3.7min(minor)；1H NMR(600MHz,Chloroform-d)δ7.34–7.30(m,2H),7.30–7.25(m,1H),7.23–7.18(m,2H),4.46(s,2H),3.28–3.14(m,2H),2.93(dqd,J＝14.50,11.75,2.63Hz,1H),2.73(tdd,J＝11.12,8.41,2.67Hz,1H),2.40–2.30(m,1H),2.04(ddq,J＝15.07,11.60,10.27Hz,1H),1.77(dq,J＝12.84,9.64Hz,1H).13C NMR(151MHz,Chloroform-d)δ173.6,136.2,128.8,128.2,127.8,127.0(q,J＝276.3Hz),47.1,44.8,36.9(d,J＝2.9Hz),35.7(q,J＝29.0Hz),25.9.19F NMR(CDCl3,377 MHz)δ:-64.8(s,3F)；TOF-HRMS Calcd.forC13H15F3NO+[M+H+]:258.1100,found 258.1103.
根据已知文献报道，化合物35可转化为一种手性3-(2,2,2-三氟乙基)-吡咯烷盐酸盐，该物质为重要的药物合成中间体。
本发明不局限于上述具体的实施方式，本领域的普通技术人员从上述构思出发，不经过创造性的劳动，所做出的种种变换，均落在本发明的保护范围之内。

Claims (8)

1.一种含手性三氟甲基氮杂环化合物的制备方法，其特征在于，包括以下步骤：将含不饱和氮杂环化合物Ⅰ在氢气氛围和铑手性催化剂的催化作用下进行反应，然后纯化，得到含手性三氟甲基氮杂环化合物Ⅱ，其中，所述含不饱和氮杂环化合物Ⅰ的结构式为下式Ⅰ所示，所述含手性三氟甲基氮杂环化合物Ⅱ的结构式为下式Ⅱ所示：
其中，R选自C1-C20烷基、取代基A取代的C1-C20烷基、苯基、萘基或取代基A取代的苯基；所述取代基A选自卤素、-CF3、C1-C3烷基、C1-C3烷氧基或苯基。
2.根据权利要求1所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述铑手性催化剂通过在氮气氛围下，将铑金属前体和手性双膦配体加入有机溶剂中，于15～35℃下搅拌反应0.5～1h得到。
3.根据权利要求2所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述铑金属前体为环辛二烯氯化铑二聚体；所述手性双膦配体为(R)-Monophos、(R)-MeDuPhos、(S,S)-f-Binaphane、(S)-DTBM-SegPhos、(R)-DM-SegPhos、(R)-Segphos或(R,R)-f-spiroPhos中的任意一种。
4.根据权利要求2所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述铑金属前体和含不饱和氮杂环化合物Ⅰ的摩尔比为0.5：50～120。
5.根据权利要求2所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述有机溶剂为二氯甲烷、乙醚、甲苯、1,4-二氧六环、四氢呋喃和甲醇中的一种或者两种以上的组合。
6.根据权利要求1所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述反应时间为1～24h，反应温度为20～70℃。
7.根据权利要求1所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述反应时的氢气压力为100～1200psi。
8.根据权利要求1所述的含手性三氟甲基氮杂环化合物的制备方法，其特征在于，所述含不饱和氮杂环化合物Ⅰ选自以下化合物1、和化合物18-35中的一种：
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CN117142918A (zh) * 2022-12-30 2023-12-01 北京师范大学 一种含手性三氟甲基氮杂环化合物的制备方法

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