CN105541695B - 一种2‑芳基氟代哌啶衍生物及其制备方法 - Google Patents

一种2‑芳基氟代哌啶衍生物及其制备方法 Download PDF

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CN105541695B
CN105541695B CN201610021947.XA CN201610021947A CN105541695B CN 105541695 B CN105541695 B CN 105541695B CN 201610021947 A CN201610021947 A CN 201610021947A CN 105541695 B CN105541695 B CN 105541695B
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piperidine derivative
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胡祥国
严楠
刘清泉
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芮培欣
涂媛鸿
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Jiangxi Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
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Abstract

本发明公开了一种2‑芳基氟代哌啶衍生物及其制备方法，以2‑芳基环氧哌啶化合物或2‑芳基哌啶溴醇化合物为底物，在四烷基氟化铵/氟氢化钾复合氟化剂作用下进行反应，即得；该反应操作简单、反应条件温和、成本低、副产物少、收率高，得到的2‑芳基氟代哌啶衍生物为药物筛选和新药创制提供原料来源。

Description

一种2-芳基氟代哌啶衍生物及其制备方法
技术领域
本发明涉及一种2-芳基氟代哌啶衍生物，及高选择性制备2-芳基氟代哌啶衍生物的方法，属于药物中间体合成技术领域。
背景技术
哌啶环作为重要的药效团存在于许多药物之中。例如：多羟基的哌啶衍生物米格列醇(Miglitol)作为α-葡萄糖苷酶的抑制剂，是治疗糖尿病的一线药物。含芳基的哌啶衍生物帕罗西汀(paroxetine)作为5-羟色胺再吸收选择性制剂是重要治疗抑郁症的药物。爱维莫潘(Alvimopan)作为μ型阿片受体的激活剂，用于治疗胃肠功能紊乱，在2012年高居美国前200个畅销零售药物的第三十七位。
目前大多数的具有潜在药用价值的该类化合物一般都是官能化氟代哌啶，即在氟原子的邻位有羟基或者氨基官能团。如东华大学的卿凤翎教授合成的系列isofagomine的类似物，该类多羟基氟代哌啶一般具有优异的糖苷酶抑制活性[(a)Li,R.-J.；Bols,M.；Rousseau,C.；Zhang,X.-G.；Wang,R.-W.；Qing,F.-L.Tetrahedron,2009,65,3717–3727l；(b)Yang,Y.；Zheng,F.；Bols M.；Marinescu,L.G.；Qing,F.-L.J.Fluorine Chem.2011,838–845.]，对酶的抑制是一种新颖的治疗癌症的策略。MK-0731是该类酶的抑制剂，目前已经作为治疗taxanerefractory solid tumors进入了临床一期研究。3是高效的血小板衍生生长因子受体的抑制剂，该类抑制剂可以用于癌症等重大疾病的治疗。而4则作为5-HT1A的激动剂，具有抗抑郁和镇痛的潜在用途。
氟代哌啶具有优异的生物活性和潜在的药用价值，氟代哌啶环的合成已经成为有机合成中的热点之一。根据氟的来源，氟代哌啶的合成主要有以下两种方法(1)利用亲核氟化试剂DAST，DeoxyFluor，Olah试剂，NEt3.3HF等制备；[(a)Al-Maharik,N.；O’Hagan,D.Aldrichimica Acta 2011,44,65–75；(b)Déchamps,I.；Gomez Pardo,D.；Cossy,J.Synlett 2007,263–267；(c)Huang,H.T.；Lacy,T.C.；Blachut,B.；Ortiz,G.X.Org Lett2013,15,1818-1821；(d)Launay,G.G.；Slawin,A.M.Z.；O'Hagan,D.Beilstein J Org Chem2010,6；(e)Kishi,Y.；Inagi,S.；Fuchigami,T.Eur J Org Chem 2009,103-109；(f)Kishi,Y.；Nagura,H.；Inagi,S.；Fuchigami,T.Chem Commun 2008,3876-3878；(g)Okoromoba,O.E.；Hammond,G.B.；Xu,B.Org.Lett.2015,17,3975-3977].(2)利用亲电氟化试剂，进行分子内胺氟化反应制备；[(a)Wu,T.；Yin,G.Y.；Liu,G.S.J.Am.Chem.Soc.2009,131,16354；(b)Li,Z.D.；Song,L.Y.；Li,C.Z.J Am Chem Soc 2013,135,4640-4643；(c)Kong,W.Q.；Feige,P.；de Haro,T.；Nevado,C.Angew Chem Int Edit 2013,52,2469-2473.]
氟代哌啶在癌症、抑郁症和糖尿病等严重威胁人类身心健康疾病治疗的新药创制中已经显示了重要的应用前景，缺乏高效合成方法是制约该类化合物新药创制的瓶颈。由于传统的直接氟化试如：Py·HF、Et2NSF3(DAST)和NEt3.3HF等大都比较活泼，反应较剧烈，存在反应选择性差、原子经济性一般、产物光学纯度低、官能团的兼容性较差等缺陷，因此亟需发展一种高效制备方法提供更多含氟哌啶衍生物。
发明内容
针对现有技术存在的缺陷，本发明的第一个目的在于提供一种具有全新结构的2-芳基氟代哌啶衍生物，构建含新型2-芳基氟代哌啶化合物库，为药物筛选和新药合成提供原料来源。
针对现有的氟代哌啶的合成存在副反应高，氟化试剂昂贵、且稳定性差，氟化效率低、反应条件苛刻等缺陷，本发明的另一个目的是在于提供一种操作简单、反应条件温和、成本低、副产物少、收率高制备所述2-芳基氟代哌啶衍生物的方法。
为了实现上述技术目的，本发明提供了一种2-芳基氟代哌啶衍生物，其具有式1结构：
其中，
R1为氢原子、硝基、氰基、卤素原子、C1～C4的烷基、C1～C4的卤代烷基或C1～C4的烷氧基；
R2选自苄氧羰基、乙酰基、叔丁氧羰基或氢原子；
X1和X2各自独立选自氢原子或氟原子。
优选的方案，R1为氢原子、氯原子、甲基、乙基、甲氧基或乙氧基。
本发明还提供了一种制备所述的2-芳基氟代哌啶衍生物的方法，该方法是
以式2结构2-芳基环氧哌啶化合物为底物，在四烷基氟化铵/氟氢化钾复合氟化剂作用下，进行SN2开环反应，即得；
或者，以式3结构2-芳基哌啶溴醇化合物为底物，在四烷基氟化铵/氟氢化钾复合氟化剂作用下，进行闭环-SN2开环反应，即得；
其中，
R1为氢原子、硝基、氰基、卤素原子、C1～C4的烷基、C1～C4的卤代烷基或C1～C4的烷氧基；
R3选自苄氧羰基、乙酰基、芴甲氧羰酰基、叔丁氧羰基或氢原子；
R4为芴甲氧羰酰基。
本发明采用的式2结构的2-芳基环氧哌啶化合物具有两种顺反异构体：包括式4和式5两种结构：
其中，
R1为氢原子、硝基、氰基、卤素原子、C1～C4的烷基、C1～C4的卤代烷基或C1～C4的烷氧基；
R3选自苄氧羰基、叔丁氧羰基、芴甲氧羰酰基、乙酰基或氢原子。
优选的方案，四烷基氟化铵、氟氢化钾与式2结构的2-芳基环氧哌啶化合物或式3结构的2-芳基哌啶溴醇化合物的摩尔量比为1～4:1:1；最优选为2:1:1。
较优选的方案，四烷基氟化铵为四甲基氟化铵、四乙基氟化铵或四丁基氟化铵。
最优选的方案，四烷基氟化铵为四丁基氟化铵。
优选的方案，SN2开环反应或者闭环-开环反应是在80～130℃下反应2～6h；式4结构2-芳基环氧哌啶化合物最佳反应温度为85～95℃，可以获得较高收率；式5结构2-芳基环氧哌啶化合物最佳反应温度为115～125℃，可以获得较高收率；式3结构2-芳基哌啶溴醇化合物最佳反应温度为95～105℃，可获得较高收率。
本发明最优选的2-芳基氟代哌啶衍生物包括式1～32化合物中的任意一种：
其中，2-芳基氟代哌啶衍生物17～32以盐酸盐形式保存。
本发明的2-芳基氟代哌啶衍生物的具体制备方法如下：将式2结构的2-芳基环氧哌啶化合物或式3结构的2-芳基哌啶溴醇化合物、四烷基氟化铵、氟氢化钾，在隔绝空气条件下，加入反应釜中；然后将反应釜放入油浴中在80～130℃下反应2～6h；反应结束后，将反应液冷却至室温，以乙酸乙酯稀释，再用饱和碳酸氢钠和水洗；有机层干燥，过滤，滤液减压蒸馏后经硅胶柱层析分离，即得。
本发明制备2-芳基氟代哌啶化合物合成路线如下：
(1)、反式2-芳基环氧哌啶化合物，在120℃左右温度下进行开环反应，得到2,4-cis产物为主，与2,5-cis产物的摩尔比为3.6～5:1(Ar为苯基或者取代苯基，R3选至苄氧羰基、叔丁氧羰基、乙酰基或氢原子时)；
当R3选至芴甲氧羰酰基、氢原子任意一种，进行开环反应时，主要为2,5-cis单一产物，与2,4-cis产物的摩尔比为大于20:1。
(2)、顺式2-芳基环氧哌啶化合物，在90℃左右温度下进行开环反应，得到2,5-trans产物和2,4-trans产物的摩尔比为1～1.3:1(Ar为苯或者取代苯基)；
(3)、2-芳基哌啶溴醇化合物，在100℃左右进行闭环-开环反应，主要得到2,4-trans单一产物，与2,5-trans产物的摩尔比为大于20:1(Ar为苯或者取代苯基)；
相对现有技术，本发明的技术方案带来的有益技术效果：
1、本发明的技术方案中采用的复合氟化试剂相对稳定、价格便宜，且氟化效果高、适应的反应条件温和。
2、本发明的2-芳基氟代哌啶衍生物的合成通过一锅法即可实现，方法简单，且副反应少，具有较高选择性，氟化产物收率高，反应条件温和。
3、本发明的2-芳基氟代哌啶衍生物为哌啶类药物提供了新的原料途径，具有广泛的应用价值。
说明书附图
【图1】为化合物1和化合物3的单晶结构图。
具体实施方式
下列实施例旨在进一步说明本发明内容，而不是限制本发明权利要求的保护范围。
下列实施案例中所用原料2-芳基环氧哌啶化合物(2aa-ad，2ba-bd，3ba-bd)和所示的化合物按照文献Coombs,T.C.；Lushington,G.H.；Douglas,J.；Aubé,J.Angew.Chem.Int.Edit.2011,50,2734.如下合成路线。
按照以下合成路线可制备，可以制备化合物1～8(5ba-bd和6ba-bd)。
实施例1
将TBAF·3H2O(1.26g,4mmol,2equiv),KHF2(156mg,2mmol,1equiv),2-芳基环氧化合物2ba(618mg,2mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在120℃下反应3h；用乙酸乙酯(60mL)稀释，再用饱和碳酸氢钠(15mL)和水(5mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物1(451.4mg,1.37mmol)和化合物5(92.6mg,0.28mmol)。
化合物1
1H NMR(400MHz,CDCl3):δ7.31–7.29(m,2H,HAr),7.20–7.18(m,2H,HAr),5.31(t,J＝5.2Hz,1H,H2),4.71(dddd,J＝3.2,3.2,6.8,47.0Hz,1H,H4),4.11(bd,J＝14.7Hz,1H,H6),3.90–3.86(m,1H,H5),3.31(bs,1H,OH),3.25(ddd,J＝2.0,2.0,14.7Hz,1H,H6),2.50–2.43(m,1H,H3e),2.41(dddd,J＝2.9,6.8,15.3,43.8Hz,1H,H3a),1.43(s,9H)；13C NMR(100MHz,CDCl3):δ156.4(C7),139.1(CAr),132.5(CAr),128.5(CAr),127.4(CAr),127.4(CAr),98.7(d,J＝174.3Hz,C4),80.9(C8),66.4(d,J＝28.1Hz,C5),51.4(d,J＝1.7Hz,C2),41.9(C6),28.6(d,J＝19.9Hz,C3),28.2(C9,10,11)；19F NMR(376MHz,CDCl3):δ-184.3(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-184.3(s,1F)；HRMS(ESI):calcd.for C16H21ClFNNaO3+[M+Na]+352.1086,found 352.1092.
化合物5
1H NMR(400MHz,CDCl3):δ7.36–7.33(m,2H,HAr),7.17(d,J＝8.4Hz,2H,HAr),5.49(bs,1H,H2),4.44–4.25(m,2H,H5and H6e),3.82–3.73(m,1H,1H,H4),2.71–2.58(m,2H,H3eand H6a),2.50(bs,1H,OH),1.91(ddd,J＝5.7,12.8,12.9Hz,1H,H3a),1.49(s,9H)；13C NMR(100MHz,CDCl3):δ154.8(C7),137.0(CAr),133.1(CAr),129.1(CAr),127.4(CAr),92.3(d,J＝178.0Hz,C5),81.4(C8),68.7(d,J＝18.8Hz,C4),51.9(C2),41.2(C6),33.3(C3),28.3(C9,10,11)；19F NMR(376MHz,CDCl3):δ-192.4(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-192.4(s,1F)；HRMS(ESI):calcd.for C16H21ClFNNaO3+[M+Na]+352.1086,found 352.1095.
实施例2
将TBAF·3H2O(945mg,3mmol,2equiv),KHF2(117mg,1.5mmol,1equiv),2-芳基环氧化合物2bb(413mg,1.5mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在115℃下反应4h；用乙酸乙酯(45mL)稀释，再用饱和碳酸氢钠(15mL)和水(5mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物2(301.3mg,1.02mmol)和化合物6(96.2mg,0.33mmol)。
化合物2
1H NMR(400MHz,CDCl3):δ7.35–7.31(m,2H,HAr),7.28–7.21(m,3H,HAr),5.34(t,J＝5.3Hz,1H,H2),4.71(dddd,J＝3.4,3.4,7.3,47.0Hz,1H,H4),4.12(bd,J＝14.4Hz,1H,H6),3.92–3.89(m,1H,H5),3.32(ddd,J＝2.1,2.1,14.7Hz,1H,H6),3.17(bs,1H,OH),2.49(dddd,J＝4.2,4.2,12.4,15.7Hz,1H,H3e),2.52–2.48(m,1H,H3a),1.43(s,9H,CH3).13C NMR(100MHz,CDCl3):δ156.5(C7),140.5(CAr),128.3(CAr),126.6(CAr),125.9(CAr),89.1(d,J＝178.2Hz,C4,),80.6(C8),67.4(d,J＝28.1Hz,C5),52.3(d,J＝2.0Hz,C2),42.2(C6),28.8(d,J＝18.9Hz,C3),28.3(C9,10,11)；19F NMR(376MHz,CDCl3):δ-184.1(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-184.1(s,1F)；HRMS(ESI):calcd.for C16H22FNNaO3 +[M+Na]+318.1476,found 318.1486.
化合物6
1H NMR(400MHz,CDCl3):δ7.39–7.23(m,5H,HAr),5.53(bs,1H,H2),4.45–4.26(m,2H,H6e,H5),3.81(dddd,J＝4.7,4.7,12.7,18.6Hz,1H,H4),2.75–2.63(m,2H,H3e and H6a),2.49(bs,1H,OH),1.91(ddd,J＝5.7,12.8,12.9Hz,1H,H3a),1.49(s,9H)；13C NMR(100MHz,CDCl3):δ155.0(C7),138.3(CAr),128.9(CAr),127.1(CAr),125.9(CAr),92.5(d,J＝176.5Hz,C5),80.9(C8),68.8(d,J＝18.8Hz,C4),52.7(C2),41.6(C6),33.3(C3),28.3(C9,10,11)；19FNMR(376MHz,CDCl3):δ-192.4(d,J＝49.6Hz,1F)；19F{1H}NMR(376MHz,CDCl3):δ-192.4(s,1F)；HRMS(ESI):calcd.for C16H22FNNaO3 +[M+Na]+318.1476,found 318.1481.
实施例3
将TBAF·3H2O(0.63g,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基环氧化合物2bc(289mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在115℃下反应4h；用乙酸乙酯(40mL)稀释，再用饱和碳酸氢钠(10mL)和水(3mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物3(210.1mg,0.680mmol)和化合物7(58.4mg,0.189mmol)。
化合物3
1H NMR(400MHz,CDCl3):δ7.17–7.12(m,4H,HAr),5.34(dd,J＝3.3,6.9Hz,1H,H2),4.71(dddd,J＝3.5,3.5,7.6,47.2Hz,1H,H4),4.10(bd,J＝14.4Hz,1H,H6),3.90–3.87(m,1H,H5),3.30(ddd,J＝2.2,2.2,14.4Hz,1H,H6),2.53–2.47(m,2H,H3e and OH),2.46(dddd,J＝3.3,6.9,15.6,43.8Hz,1H,H3a),1.43(s,9H,CH3).13C NMR(100MHz,CDCl3):δ156.6(C7),137.2(CAr),136.3(CAr),125.9(CAr),125.9(CAr),88.9(d,J＝174.7Hz,C4),80.6(C8),67.4(d,J＝28.6Hz,C5),51.7(d,J＝1.8Hz,C2),42.0(C6),28.6(d,J＝18.6Hz,C3),28.4(C9,10,11),21.0(CH3)；19F NMR(376MHz,CDCl3):δ-184.3(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-184.3(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO3 +[M+Na]+332.1632,found332.1644.
化合物7
1H NMR(400MHz,CDCl3):δ7.26–7.10(m,4H,HAr),5.49(bs,1H,H2),4.44–4.25(m,2H,H6e,H5),3.86–3.78(m,1H,H4),2.74–2.63(m,2H,H3e,H6a),2.46(bs,1H,OH),2.34(s,CH3),1.89(ddd,J＝6.1,12.9,12.9Hz,1H,H3a),1.49(s,9H)；13C NMR(100MHz,CDCl3):δ155.0(C7),136.8(CAr),135.2(CAr),129.6(CAr),125.8(CAr),92.6(d,J＝177.8Hz,C5),80.8(C8),68.8(d,J＝18.5Hz,C4),52.0(C2),41.6(C6),33.3(C3),28.3(CH3),20.9(C9,10,11)；19FNMR(376MHz,CDCl3):δ-192.4(s,1F)；19F{1H}NMR(376MHz,CDCl3):δ-192.4(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO3 +[M+Na]+332.1632,found 332.1640.
实施例4
将TBAF·3H2O(0.63g,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基环氧化合物2bd(305mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在115℃下反应5h；用乙酸乙酯(45mL)稀释，再用饱和碳酸氢钠(15mL)和水(5mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物3(216.7mg,0.667mmol)和化合物7(54.3mg,0.167mmol)。
化合物4
1H NMR(400MHz,CDCl3):δ7.22–7.18(m,2H,HAr),6.89–6.85(m,2H,HAr),5.33(dd,J＝3.5,6.3Hz,1H,H2),4.72(dddd,J＝3.7,3.7,6.9,47.0Hz,1H,H4),4.09(dd,J＝1.4,14.7Hz,1H,H6),3.94–3.87(m,1H,H5),3.80(s,3H,OCH3),3.28(ddd,J＝2.0,2.0,14.7Hz,1H,H6),2.68(bs,1H,OH),2.53–2.45(m,1H,H3a),2.42(dddd,J＝3.3,6.8,15.6,43.5Hz,1H,H3a),1.45(s,9H)；13C NMR(100MHz,CDCl3):δ158.4(C7),156.6(CAr),132.2(CAr),127.3(CAr),113.7(CAr),88.9(d,J＝174.1Hz,C4),80.6(C8),66.9(d,J＝28.5Hz,C5),55.2(OCH3),51.4(C2),41.8(C6),28.5(d,J＝18.7Hz,C3),28.4(C9,10,11)；19F NMR(376MHz,CDCl3):δ-183.9(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-183.9(s,1F)；HRMS(ESI):calcd.forC17H24FNNaO4+[M+Na]+348.1582,found 348.1589.
化合物8
1H NMR(400MHz,CDCl3):δ7.17–7.14(m,2H,HAr),6.90(d,J＝8.8Hz,2H,HAr),5.48(bs,1H,H2),4.41-4.28(m,2H,H5,H6e),3.86-3.79(m,4H,H4and OCH3),2.70-2.61(m,2H,H6aand H3e),2.38(s,1H,OH),1.88(ddd,J＝5.8,12.8,12.9Hz,1H,H3a),1.49(s,9H)；13C NMR(100MHz,CDCl3):δ158.6(C7),154.9(CAr),130.2(CAr),127.1(CAr),114.3(CAr),92.6(d,J＝179.6Hz,C5),80.8(C8),68.8(d,J＝18.4Hz,C4),55.3(OCH3),52.2(C2),41.6(C6),33.3(C3),28.3(C9,10,11)；19F NMR(376MHz,CDCl3):δ-192.4(d,J＝49.5Hz,1F)；19F{1H}NMR(376MHz,CDCl3):δ-192.4(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO4+[M+Na]+348.1582,found348.1586.
对比实施例1
其它条件都和实施例4一样，不同之处将反应釜放入油浴中在60℃下反应2h；最终得目标产物化合物3(126.8mg,0.39mmol)和化合物7(35.8mg,0.11mmol)，产率仅50％,回收2-芳基环氧化合物2bd(106.8mg,0.35mmol)。
对比实施例2
其它条件都和实施例4一样，不同之处将KHF2代替四丁基氟化铵/氟氢化钾复合氟化剂，将反应釜放入油浴中在115℃下反应5h；无目标产物化合物3生成，回收原料(2755mg)。
按照以下合成路线可制备，可以制备化合物9～16(7ba-bd和8ba-bd)。
实施例5
将TBAF·3H2O(756mg,2.4mmol,2equiv),KHF2(93.6mg,1.2mmol,1equiv),2-芳基环氧化合物2aa(370.8mg,1.2mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在90℃下反应3h；用乙酸乙酯(65mL)稀释，再用饱和碳酸氢钠(15mL)和水(6mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物9(140.8mg,0.428mmol)和化合物13(183.0mg,0.556mmol)。
化合物9
1H NMR(400MHz,CDCl3):δ7.34(d,J＝8.5Hz,2H,HAr),7.17(d,J＝8.2Hz,2H,HAr),5.55(bs,1H,H2),4.41(dddd,J＝4.7,8.8,12.6,50.6Hz,1H,H4),4.28(ddd,J＝5.0,5.0,11.4Hz,1H,H6e),3.83–3.74(m,1H,H5),2.72(dddd,J＝2.5,4.7,7.0,13.8Hz,1H,H3e),2.60(bs,1H,OH),2.56(dd,J＝11.4,13.2Hz,1H,H6a),2.04(dddd,J＝6.0,8.8,13.8,20.1Hz,1H,H3a),1.48(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ154.9(C7,C＝O),136.9(CAr),133.2(CAr),129.1(CAr),127.4(CAr),92.3(d,J＝176.3Hz,C4),81.1(C8),70.7(d,J＝18.5Hz,C5),52.5(d,J＝11.1Hz,C2),43.3(d,J＝8.5Hz,C6),32.0(d,J＝18.5Hz,C3),28.3(C9,10,11)；19F NMR(376MHz,CDCl3):δ-187.5(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-187.5(s,1F)；HRMS(ESI):calcd.for C16H21ClFNNaO3+[M+Na]+352.1086,found 352.1090.
化合物13
1H NMR(400MHz,CDCl3):δ7.30(d,J＝8.5Hz,2H,HAr),7.15(d,J＝8.4Hz,2H,HAr),5.18(t,J＝7.0Hz,1H,H2),4.54(dddd,J＝2.4,2.4,3.9,48.0Hz,1H,H5),4.37(t,J＝15.4Hz,1H,H6e),4.04(dddd,J＝3.9,3.9,7.0,14.4Hz,1H,H4),3.41(ddd,J＝2.4,15.4,39.8Hz,1H,H6a),2.33(dddd,J＝3.3,3.3,6.9,13.9Hz,1H,H3),2.19(bs,1H,OH),2.06(ddd,J＝7.0,7.0,13.9Hz,1H,H3),1.48(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ155.5(C7,C＝O),140.4(CAr),132.6(CAr),128.8(CAr),126.8(CAr),90.9(d,J＝179.4Hz,C5),80.7(C8),67.8(d,J＝27.6Hz,C4),52.0(C2),41.7(d,J＝22.9Hz,C6),32.7(d,J＝2.5Hz,C3),28.2(C9,10,11,CH3)；19F NMR(367MHz,CDCl3):δ-187.4(bs,1F)；19F{1H}NMR(367MHz,CDCl3):δ-185.4(s,1F)；HRMS(ESI):calcd.for C16H21ClFNNaO3+[M+Na]+352.1086,found 352.1096.
实施例6
将TBAF·3H2O(630.0mg,2.0mmol,2equiv),KHF2(78.0mg,1mmol,1equiv),2-芳基环氧化合物2ab(275.0mg,1.0mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在90℃下反应3h；用乙酸乙酯(80mL)稀释，再用饱和碳酸氢钠(15mL)和水(10mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物10(112.6mg,0.382mmol)和化合物14(135.2mg,0.458mmol)。
化合物10
1H NMR(400MHz,CDCl3):δ7.39–7.31(m,2H,HAr),7.29–7.23(m,3H,HAr),5.60(bs,1H，H2),4.45(dddd,J＝4.8,8.8,13.2,51.2Hz,1H,H4),4.28(ddd,J＝5.4,5.4,11.4Hz,1H,H6e),3.78(dddd,J＝5.6,8.7,12.8,19.2Hz,1H,H5),2.78(dddd,J＝2.4,4.8,6.9,13.6Hz,1H,H3e),2.60(dd,J＝11.4,13.2Hz,1H,H6a),2.39(bs,1H,OH),2.04(dddd,J＝6.0,8.8,13.6,20.8Hz,H3a),1.49(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ155.0(C7,C＝O),138.2(CAr),129.0(CAr),127.2(CAr),125.9(CAr),92.5(d,J＝176.4Hz,C4),80.8(C8),70.7(d,J＝18.3Hz,C5),52.9(d,J＝13.5Hz,C2),43.4(d,J＝8.4Hz,C6),32.0(d,J＝18.4Hz,C3),28.4(C9,10,11)；19F NMR(376MHz,CDCl3):δ-187.8(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-187.8(s,1F)；HRMS(ESI):calcd.for C16H22FNNaO3 +[M+Na]+318.1476,found 318.1486.
化合物14
1H NMR(400MHz,CDCl3):δ7.36–7.33(m,2H,HAr),7.24–7.21(m,3H,HAr),5.25(t,J＝6.6Hz,1H,H2),4.54(dddd,J＝2.5,2.5,4.2,48.0Hz,1H,H5),4.40(t,J＝15.3Hz,1H,H6e),4.05(dddd,J＝3.7,3,7,7.1,13.9Hz,1H,H4),3.46(ddd,J＝2.5,15.3,40.0Hz,1H,H6a),2.37(dddd,J＝3.6,3.6,6.6,14.3Hz,1H,H3),2.04(ddd,J＝6.6,6.6,14.3Hz,1H,H3),1.83(bs,1H,OH),1.39(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ155.6(C7,C＝O),141.5(CAr),128.8(CAr),127.0(CAr),125.3(CAr),90.8(d,J＝179.2Hz,C5),80.5(C8),67.9(d,J＝18.3Hz,C4),52.3(C2),41.6(d,J＝22.4Hz,C6),32.6(d,J＝2.8Hz,C3),28.3(C9,10,11)；19FNMR(376MHz,CDCl3):δ-185.7(bs,1F)；19F{1H}NMR(376MHz,CDCl3):δ-185.7(s,1F)；HRMS(ESI):calcd.for C16H22FNNaO3 +[M+Na]+318.1476,found 318.1482.
按实施例6的操作步骤，将TBAF·3H2O(1.26g,4.0mmol,4equiv),KHF2(78.0mg,1.0mmol,1equiv)，2-芳基环氧化合物2ab(275.0mg,1.0mmol,1equiv)在密闭环境下加入反应釜反应，最终得目标产物化合物10(104.0mg,0.352mmol)和化合物14(114.3mg,0.388mmol)，产率74％。
实施例7
将TBAF·3H2O(756mg,2.4mmol,2equiv),KHF2(93.6mg,1.2mmol,1equiv),2-芳基环氧化合物2ac(346.8mg,1.2mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在90℃下反应3h；用乙酸乙酯(65mL)稀释，再用饱和碳酸氢钠(15mL)和水(6mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物11(138.6mg,0.449mmol)和化合物15(180.4mg,0.584mmol)。
化合物11
1H NMR(400MHz,CDCl3):δ7.18–7.10(m,4H,HAr),5.56(bs,1H,H2),4.46(dddd,J＝4.9,8.5,11.7,51.4Hz,1H,H4),4.27(ddd,J＝5.6,5.6,11.4Hz,1H,H6e),3.78(dddd,J＝5.6,8.5,13.2,19.4Hz,1H,H5),2.76(dddd,J＝2.3,4.9,7.0,13.6Hz,1H,H3e),2.59(dd,J＝11.4,13.2Hz,1H,H6a),2.34(s,3H,CH3),2.02(dddd,J＝5.8,8.5,11.7,13.6Hz,2H,H3a andOH),1.49(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ155.0(C7,C＝O),136.9(CAr),135.0(CAr),129.6(CAr),125.8(CAr),92.7(d,J＝176.4Hz,C4),80.7(C8),70.9(d,J＝18.7Hz,C5),52.7(d,J＝13.1Hz,C2),,43.4(d,J＝13.1Hz,C6),32.2(d,J＝18.2Hz,C3),28.4(C9,10,11),20.9(CH3)；19F NMR(376MHz,CDCl3):δ-188.3(m,1F)；19F{1H}NMR(376MHz,CDCl3):δ-188.3(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO3 +[M+Na]+332.1632,found 332.1640.
化合物15
1H NMR(400MHz,CDCl3):δ7.17–7.10(m,4H,HAr),5.28(t,J＝6.2Hz,1H,H2),4.53(dddd,J＝2.4,2.4,3.9,47.5Hz,1H,H5),4.40(t,J＝15.4Hz,1H,H6e),4.04(dddd,J＝3.9,3.9,7.0,15.2Hz,1H,H4),3.44(ddd,J＝2.4,15.4,40.3Hz,1H,H6a),2.38(dddd,J＝3.3,3.3,6.8,14.6Hz,1H,H3),2.33(s,CH3),2.21(ddd,J＝6.2,6.2,14.6Hz,1H,H3),1.41(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ155.6(C7,C＝O),138.0(CAr),136.6(CAr),129.6(CAr),125.3(CAr),89.0(d,J＝179.2Hz,C5),80.4(C8),67.7(d,J＝27.6Hz,C4),51.7(C2),41.2(d,J＝22.0Hz,C6),32.0(d,J＝2.5Hz,C3),28.3(C9,10,11,CH3),21.0(CH3),；19F NMR(376MHz,CDCl3):δ-186.5(bs,1F)；19F{1H}NMR(376MHz,CDCl3):δ-186.5(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO3 +[M+Na]+332.1632,found 332.1640.
实施例8
将TBAF·3H2O(630mg,2.0mmol,2equiv),KHF2(78mg,1.0mmol,1equiv),2-芳基环氧化合物2ad(305mg,1.0mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在85℃下反应5h；用乙酸乙酯(60mL)稀释，再用饱和碳酸氢钠(10mL)和水(6mL)洗。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物12(120.7mg,0.371mmol)和化合物16(132.6mg,0.408mmol)。
化合物12
1H NMR(400MHz,CDCl3):δ7.15(d,J＝8.8Hz,2H,HAr),6.89(d,J＝8.8Hz,2H,HAr),5.55(bs,1H,H2),4.48(dddd,J＝5.1,8.8,13.2,51.4Hz,1H,H4),4.25(ddd,J＝5.1,5.1,11.5Hz,1H,H6e),3.81(s,3H,OCH3),3.79–3.72(m,1H,H5),2.74(dddd,J＝2.3,5.1,6.8,13.7Hz,1H,H3e),2.58(dd,J＝11.3,13.3Hz,1H,H6a),2.53(bs,1H,OH),2.01(dddd,J＝5.8,8.8,13.7,21.0Hz,1H,H3a),1.49(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ158.7(C7,C＝O),154.9(CAr),130.0(CAr),127.1(CAr),114.3(CAr),92.1(d,J＝177.1Hz,C4),80.7(C8),70.9(d,J＝18.2Hz,C5),55.3(OCH3),52.4(d,J＝12.8Hz,C2),43.1(d,J＝8.5Hz,C6),32.1(d,J＝18.4Hz,C3),28.4(C9,10,11)；19F NMR(376MHz,CDCl3):δ＝-188.3(s,1F)；19F{1H}NMR(376MHz,CDCl3):δ＝-188.3(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO4+[M+Na]+348.1582,found 348.1586.
化合物16
1H NMR(400MHz,CDCl3):δ7.15(d,J＝8.6Hz,2H,HAr),6.88(d,J＝8.6Hz,2H,HAr),5.26(t,J＝6.0Hz,1H,H2),4.54(dddd,J＝2.4,2.4,4.4,48.8Hz,1H,H5),4.44–4.36(m,1H,H6e),4.05(dddd,J＝3.8,3.8,6.7,15.1Hz,1H,H4),3.80(s,3H,OCH3),3.43(ddd,J＝2.4,15.3,40.3Hz,1H,H6a),2.37(dddd,J＝3.4,3.4,6.7,14.7Hz,1H,H3),2.19(ddd,J＝6.0,6.0,14.6Hz,1H,H3),1.41(s,9H,HCH3)；13C NMR(100MHz,CDCl3):δ158.6(C7,C＝O),155.6(CAr),133.1(CAr),126.6(CAr),114.3(CAr),90.5(d,J＝180.1Hz,C5),80.4(C8),67.8(d,J＝28.9Hz,C4),55.3(OCH3),51.6(C2),41.2(d,J＝21.4Hz,C6),32.1(C3),28.3(C9,10,11,CH3)；19F NMR(376MHz,CDCl3):δ＝-186.2(d,J＝46.1Hz,1F)；19F{1H}NMR(376MHz,CDCl3):δ＝-186.2(s,1F)；HRMS(ESI):calcd.for C17H24FNNaO4+[M+Na]+348.1582,found348.1588.
按照以下合成路线可制备，可以制备化合物17～20(7a-d)。
实施例9
将TBAF·3H2O(63.0mg,0.2mmol,2equiv),KHF2(7.8mg,0.1mmol,1equiv),2-芳基哌啶溴醇化合物4ba(51.1mg,0.1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在95℃下反应4h；用乙酸乙酯(30mL)稀释，再用饱和碳酸氢钠(5mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物17(10.3mg,0.045mmol)。将化合物17加入2N盐酸(2mL)和甲醇(4mL)混合体系中，反应2小时，即得目标产物。
化合物17
1H NMR(400MHz,MeOD):δ7.57–7.51(m,4H,HAr),4.92(bd,J＝46.5Hz,1H,H4),4.56(dd,J＝2.9,13.2Hz,1H,H2),4.17(bs,1H,H5),3.58(ddd,J＝2.0,2.0,13.4Hz,1H,H6),3.37(bd,J＝14.2Hz,1H,H6),2.66(dddd,J＝1.5,13.2,14.8,42.2Hz,1H,H3a),2.34–2.26(m,1H,H3e)；13C NMR(100MHz,MeOD):δ135.5(CAr),133.9(CAr),129.3(CAr),129.1(CAr),86.3(d,J＝174.9Hz,C4),61.4(d,J＝27.4Hz,C5),53.8(C2),46.3(C6),29.2(d,J＝20.2Hz,C3)；HRMS(ESI):calcd.for C11H14ClFNO+[M+H]+230.0742,found 230.0750.
实施例10
将TBAF·3H2O(630mg,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基哌啶溴醇化合物4bb(478mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在85℃下反应5h；用乙酸乙酯(50mL)稀释，再用饱和碳酸氢钠(10mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物18(80.0mg,0.41mmol)。将化合物18加入2N盐酸(3mL)和甲醇(8mL)混合体系中，反应2小时，即得目标产物。
化合物18
1H NMR(400MHz,D2O):δ7.46–7.42(m,5H,HAr),4.94(dddd,J＝1.5,3.6,5.2,45.3Hz,1H,H4),4.53(dd,J＝3.2,13.4Hz,1H,H2),4.23–4.19(m,1H,H5),3.53(ddd,J＝2.2,2.2,13.6Hz,1H,H6),3.35(ddd,J＝1.5,13.6Hz,1H,H6),2.57(dddd,J＝2.0,13.4,15.3,43.8Hz,1H,H3a),2.34–2.26(m,1H,H3e)；13C NMR(100MHz,D2O):δ134.7(CAr),130.0(CAr),129.4(CAr),127.5(CAr),125.9(CAr),86.3(d,J＝172.4Hz,C4),61.6(d,J＝28.6Hz,C5),54.5(C2),45.9(C6),28.9(d,J＝19.7Hz,C3)；HRMS(ESI):calcd.for C11H15FNO+[M+H]+196.1132,found 196.1141.
实施例11
将TBAF·3H2O(630mg,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基哌啶溴醇化合物4bc(492mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在105℃下反应2h；用乙酸乙酯(50mL)稀释，再用饱和碳酸氢钠(10mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物19(96.1mg,0.46mmol)。将化合物19加入2N盐酸(4mL)和甲醇(8mL)混合体系中，反应2小时，即得目标产物。
化合物19
1H NMR(400MHz,D2O):δ7.38(d,J＝8.9Hz,2H,HAr),6.98(d,J＝8.9Hz,2H,HAr),4.92(bd,J＝46.1Hz,1H,H4),4.47(dd,J＝3.0,13.2Hz,1H,H2),4.18(bs,1H,H5),3.50(ddd,J＝2.3,2.3,13.6Hz,1H,H6),3.32(bd,J＝13.6Hz,H6),2.68(dddd,J＝2.3,13.2,15.2,42.8Hz,1H,H3a),2.30–2.21(m,1H,H3e),2.26(s,3H,CH3)；13C NMR(100MHz,D2O):δ140.5(CAr),131.7(CAr),129.9(CAr),127.5(CAr),83.3(d,J＝174.4Hz,C4),61.5(d,J＝28.7Hz,C5),54.2(C2),45.8(C6),28.8(d,J＝19.3Hz,C3),20.2(CH3)；HRMS(ESI):calcd.forC12H17FNO+[M+H]+210.1289,found 210.1298.
实施例12
将TBAF·3H2O(630mg,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基哌啶溴醇化合物4bd(507mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在90℃下反应3h；用乙酸乙酯(70mL)稀释，再用饱和碳酸氢钠(15mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物20(94.5mg,0.42mmol)。将化合物20加入2N盐酸(5mL)和甲醇(10mL)混合体系中，反应2小时，即得目标产物。
化合物20
1H NMR(400MHz,D2O):δ7.38(d,J＝8.9Hz,2H,HAr),6.98(d,J＝8.9Hz2H,HAr),4.92(bd,J＝46.1Hz,1H,H4),4.47(dd,J＝3.0,13.2Hz,1H,H2),4.18(bs,1H,H5),3.76(s,3H,OCH3),3.50(ddd,J＝2.3,2.3,13.8Hz,1H,H6),3.32(d,J＝13.8Hz,H6),2.68(dddd,J＝2.3,13.2,15.2,42.8Hz,1H,H3a),2.28–2.20(m,1H,H3e)；13C NMR(100MHz,CD3OD):δ160.9(CAr),128.9(CAr),127.0(CAr),114.2(CAr),86.5(d,J＝176.6Hz,C4),61.5(d,J＝28.5Hz,C5),54.5(OCH3),54.1(C2),46.2(C6),29.3(d,J＝19.9Hz,C3)；HRMS(ESI):calcd.for C12H17FNO2 +[M+H]+226.1238,found 226.1243.
按实施例12的操作步骤，将四甲基氟化氨代替四丁基氟化氨，即得目标产物化合物20(83.3mg,0.32mmol)。
按照以下合成路线可制备，可以制备化合物21～24(6a-d)。
实施例13
将TBAF·3H2O(630mg,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基哌啶溴醇化合物3ba(432mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在110℃下反应5h；用乙酸乙酯(90mL)稀释，再用饱和碳酸氢钠(18mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物21(114.5mg,0.50mmol)。将化合物21加入2N盐酸(3mL)和甲醇(6mL)混合体系中，反应2小时，即得目标产物。
化合物21
1H NMR(400MHz,CD3OD):δ7.53(q,J＝8.5Hz,4H,HAr),4.84(bd,J＝47.3Hz,1H,H5),4.68(dd,J＝2.0,12.7Hz,1H,H2),4.28(bs,1H,H4),3.75(dd,J＝13.8,40.4Hz,1H,H6a),3.60(t,J＝13.8Hz,1H,H6e),2.49(dddd,J＝3.0,3.0,12.7,15.6Hz,1H,H3),2.11(bd,J＝15.6Hz,1H,H3)；13C NMR(100MHz,CD3OD):δ139.4(CAr),138.2(CAr),133.2(CAr),133.1(CAr),89.0(d,J＝175.7Hz,C5),66.3(d,J＝27.3Hz,C4),57.2(C2),47.7(J＝20.3Hz,C6),35.2(C3)；HRMS(ESI):calcd.for C11H14ClFNO+[M+H]+230.0742,found 230.0752.
实施例14
将TBAF·3H2O(630mg,2mmol,2equiv),KHF2(78mg,1mmol,1equiv),2-芳基哌啶溴醇化合物3bb(397mg,1mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在120℃下反应3h；用乙酸乙酯(90mL)稀释，再用饱和碳酸氢钠(18mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物21(101.4mg,0.52mmol)。将化合物21加入2N盐酸(3mL)和甲醇(6mL)混合体系中，反应2小时，即得目标产物。
化合物22
1H NMR(400MHz,D2O):δ7.97(bs,5H,HAr),5.39(bd,J＝43.4Hz,1H,H5),5.09(dd,J＝3.0,13.1Hz,1H,H2),4.84–4.81(m,1H,H4),4.26–4.17(m,1H,H6a),4.13(bs,1H,H6e),3.00(dddd,J＝3.0,3.0,13.0,15.6Hz,1H,H3),2.63(bd,J＝15.6Hz,1H,H3)；13C NMR(100MHz,MeOD):δ135.6(CAr),129.5(CAr),129.0(CAr),127.4(CAr),85.1(d,J＝175.8Hz,C5),62.4(d,J＝27.3Hz,C4),54.0(C2),43.7(d,J＝20.7Hz,C6),31.5(C3)；HRMS(ESI):calcd.forC11H15FNO+[M+H]+196.1132,found 196.1137.
实施例15
将TBAF·3H2O(378mg,1.2mmol,2equiv),KHF2(46.8mg,0.6mmol,1equiv),2-芳基哌啶溴醇化合物3bc(246.6mg,0.6mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在120℃下反应2.5h；用乙酸乙酯(65mL)稀释，再用饱和碳酸氢钠(10mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物23(67.7mg,0.324mmol)。将化合物23加入2N盐酸(3mL)和甲醇(6mL)混合体系中，反应2小时，即得目标产物。
化合物23
1H NMR(400MHz,D2O):δ7.56–7.48(m,4H,HAr),5.07(bd,J＝43.7Hz,1H,H5),4.75–4.74(m,1H,H2),4.52(bs,1H,H4),3.93–3.84(m,1H,H6a),3.78(bs,1H,H6e),2.69(dddd,J＝3.2,3.2,12.7,15.6Hz,1H,H3),2.50(s,3H,CH3),2.28(bd,J＝15.6Hz,1H,H3)；13C NMR(100MHz,D2O):δ140.4(CAr),132.0(CAr),129.9(CAr),127.4(CAr),84.8(d,J＝173.7Hz,C5),62.6(d,J＝28.5Hz,C4),53.7(C2),43.5(J＝19.8Hz,C6),30.6(C3),20.2(CH3)；HRMS(ESI):calcd.for C12H17FNO+[M+H]+210.1289,found 210.1296.
实施例16
将TBAF·3H2O(1.008g,3.2mmol,2equiv),KHF2(124.8mg,1.6mmol,1equiv),2-芳基哌啶溴醇化合物3bd(683.2mg,1.6mmol,1equiv)在密闭环境下加入反应釜中；然后将反应釜放入油浴中在120℃下反应3h；用乙酸乙酯(80mL)稀释，再用饱和碳酸氢钠(10mL)洗涤。有机层用无水硫酸钠干燥，过滤，滤液减压蒸馏后经硅胶快速柱层析分离，滤液减压蒸馏后经硅胶快速柱层析分离,即得目标产物化合物24(183.6mg,0.816mmol)。将化合物24加入2N盐酸(10mL)和甲醇(20mL)混合体系中，反应2小时，即得目标产物。
化合物24
1H NMR(400MHz,D2O):δ7.37(d,J＝8.6Hz,2H,HAr),6.98(d,J＝8.6Hz,2H,HAr),4.82(bd,J＝44.8Hz,1H,H5),4.49(dd,J＝2.4,12.8Hz,1H,H2),4.29–4.24(m,1H,H4),3.75(s,3H,OCH3),3.66(dd,J＝14.2,40.6Hz,1H,H6a),3.55–3.53(m,1H,H6e),2.51(dddd,J＝2.9,2.9,13.0,15.6Hz,1H,H3),2.04(bd,J＝15.6Hz,1H,H3)；13C NMR(100MHz,CD3OD):δ160.8(CAr),128.9(CAr),127.3(CAr),114.3(CAr),85.1(d,J＝175.9Hz,C5),62.6(d,J＝27.0Hz,C4),54.5(OCH3),53.5(C2),43.6(d,J＝19.5Hz,C6),31.3(C3)；HRMS(ESI):calcd.for C12H17FNO2 +[M+H]+226.1238,found 226.1239.
对比实施例3
按实施例16的操作步骤，将TBABF(TBABF·HF)氟化试剂(与底物摩尔比1:1)代替TBAF/KHF2复合氟化剂，即得目标产物化合物24(136.8mg,0.61mmol)，产率38％。
实施例17～24
化合物1～4和13～16，分别将化合物加入2N盐酸和甲醇混合体系中，反应2小时，即得目标产物25～28和29～32。
化合物25
1H NMR(400MHz,CD3OD):δ7.57–7.51(m,4H,HAr),4.69(dddd,J＝5.1,9.1,13.5,49.5Hz,1H,H4),4.53(bd,J＝13.1Hz,1H,H2),4.10(dddd,J＝5.4,9.1,11.9,17.2Hz,1H,H5),3.53(ddd,J＝4.9,4.9,12.1Hz,1H,H6e),3.08(t,J＝12.1Hz,1H,H6a),2.58–2.52(m,1H,H3e),2.35–2.26(m,1H,H3a)；HRMS(ESI):calcd.for C11H14ClFNO+[M+H]+230.0742,found230.0750.
化合物26
1H NMR(400MHz,D2O):δ7.61–7.60(m,5H,HAr),4.91(dddd,J＝5.1,9.2,13.6,49.7Hz,1H,H4),4.60(bd,J＝13.1Hz,1H,H2),4.27(dddd,J＝5.5,9.5,12.1,17.5Hz,1H,H5),3.73(ddd,J＝5.2,5.2,11.9Hz,1H,H6e),3.22(bd,J＝11.9Hz,1H,H6a),2.77–2.70(m,1H,H3e),2.52–2.40(m,1H,H3a)；HRMS(ESI):calcd.for C11H15FNO+[M+H]+196.1132,found196.1137.
化合物27
1H NMR(400MHz,D2O):δ7.49–7.42(m,4H,HAr),4.90(dddd,J＝5.1,9.3,13.4,49.6Hz,1H,H4),4.56(bd,J＝12.9Hz,1H,H2),4.25(dddd,J＝5.8,9.3,12.1,17.5Hz,1H,H5),3.72(dddd,J＝1.5,5.0,6.8,12.4Hz,1H,H6e),3.20(t,J＝12.4Hz,1H,H6a),2.73–2.67(m,1H,H3e),2.50–2.38(m,4H,H3a and CH3)；HRMS(ESI):calcd.for C12H17FNO+[M+H]+210.1289,found 210.1296.
化合物28
1H NMR(400MHz,D2O):δ7.61–7.21(m,2H,HAr),4.95(dddd,J＝5.1,9.3,12.8,49.9Hz,1H,H4),4.60(bd,J＝13.0Hz,1H,H2),4.35–4.24(m,1H,H5a),3.99(s,3H,OCH3),3.75(ddd,J＝5.3,5.3,12.5Hz,1H,H6e),3.25(t,J＝12.5Hz,1H,H6a),2.79–2.72(m,1H,H3e),2.56–2.44(m,1H,H3a)；HRMS(ESI):calcd.for C12H17FNO2 +[M+H]+226.1238,found226.1243.
化合物29
1H NMR(400MHz,D2O):δ7.58–7.52(m,4H,HAr),4.87(dddd,J＝5.4,9.0,14.4,48.4Hz,1H,H5),4.65(dd,J＝2.7,12.9Hz,1H,H2),4.26(dddd,J＝5.1,9.1,13.6,20.3Hz,1H,H4),3.88(ddd,J＝2.2,5.7,12.4Hz,1H,H6e),3.40(ddd,J＝6.0,11.8,14.4Hz,1H,H6a),2.52(dddd,J＝2.8,5.1,8.2,13.6Hz,1H,H3e),2.23(q,J＝12.8Hz,H3a)；HRMS(ESI):calcd.for C11H14ClFNO+[M+H]+230.0742,found230.0748.
化合物30
1H NMR(400MHz,D2O):δ7.33–7.26(m,5H,HAr),4.38(dddd,J＝5.3,8.6,14.3,50.8Hz,1H,H5),3.87(dddd,J＝5.0,8.7,13.8,20.3Hz,1H,H4),3.73(dd,J＝2.5,12.0Hz,1H,H2),3.28(ddd,J＝2.5,5.4,12.0Hz,1H,H6e),2.68(ddd,J＝5.3,10.8,16.1Hz,1H,H6a),2.12(dddd,J＝2.5,5.2,7.8,13.0Hz,1H,H3e),1.58(q,J＝13.0Hz,1H,H3a)；HRMS(ESI):calcd.for C11H15FNO+[M+H]+196.1132,found196.1138.
化合物31
1H NMR(400MHz,D2O):δ7.50(q,J＝8.1Hz,4H,HAr),4.93(dddd,J＝5.3,9.3,14.6,48.4Hz,1H,H5),4.61(dd,J＝2.9,12.9Hz,1H,H2),4.37–4.28(m,1H,H4),3.93(ddd,J＝2.1,5.5,12.5Hz,1H,H6e),3.49–3.42(m,1H,H6a),2.59(ddd,J＝2.9,5.5,8.5,13.9Hz,1H,H3e),2.49(s,3H,CH3),2.30(q,J＝13.9Hz,1H,H3a)；HRMS(ESI):calcd.for C12H17FNO+[M+H]+210.1289,found 210.1296.
化合物32
1H NMR(400MHz,CD3OD):δ7.45(d,J＝9.1Hz,2H,HAr),7.02(d,J＝9.1Hz,2H,HAr),4.67(dddd,J＝5.8,8.9,14.4,49.3Hz,1H,H5),4.39(dd,J＝2.8,12.7Hz,1H,H2),4.05(dddd,J＝5.4,8.9,13.7,20.1Hz,1H,H4),3.83(s,3H,OCH3),3.65(ddd,J＝2.2,5.4,12.3Hz,1H,H6e),3.23(ddd,J＝5.8,12.3,14.4Hz,1H,H6a),2.31(dddd,J＝2.9,5.2,8.0,13.7Hz,1H,H3e),2.08(q,J＝13.7Hz,1H,H3a)；HRMS(ESI):calcd.for C12H17FNO2 +[M+H]+226.1238,found 226.1240。

Claims (7)

1.制备2-芳基氟代哌啶衍生物的方法，其特征在于：以式3结构2-芳基哌啶溴醇化合物为底物，在四烷基氟化铵/氟氢化钾复合氟化剂作用下，进行闭环-SN2开环反应，即得式1结构2-芳基氟代哌啶衍生物；
其中，
R1为氢原子、硝基、氰基、卤素原子、C1～C4的烷基、C1～C4的卤代烷基或C1～C4的烷氧基；
R4为芴甲氧羰酰基；
R2选自氢原子；
X1为羟基或氟原子，且X1为羟基时X2为氟原子，X1为氟原子时X2为羟基；
所述2-芳基氟代哌啶衍生物中氟原子取代基相对芳基取代基为反式结构。
2.根据权利要求1所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：R1为氢原子、氯原子、甲基、乙基、甲氧基或乙氧基。
3.根据权利要求1所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：四烷基氟化铵、氟氢化钾与式3结构的2-芳基哌啶溴醇化合物的摩尔量比为1～4:1:1。
4.根据权利要求3所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：四烷基氟化铵、氟氢化钾与式3结构的2-芳基哌啶溴醇化合物的摩尔量比为2:1:1。
5.根据权利要求4所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：所述的四烷基氟化铵为四甲基氟化铵、四乙基氟化铵或四丁基氟化铵。
6.根据权利要求5所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：所述的四烷基氟化铵为四丁基氟化铵。
7.根据权利要求1所述的制备2-芳基氟代哌啶衍生物的方法，其特征在于：所述的闭环-SN2开环反应是在80～130℃下反应2～6h。
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