CN116535397A - 异苯并呋喃-1(3h)-酮类化合物及其制备方法、药物组合物和用途 - Google Patents
异苯并呋喃-1(3h)-酮类化合物及其制备方法、药物组合物和用途 Download PDFInfo
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- CN116535397A CN116535397A CN202210085074.4A CN202210085074A CN116535397A CN 116535397 A CN116535397 A CN 116535397A CN 202210085074 A CN202210085074 A CN 202210085074A CN 116535397 A CN116535397 A CN 116535397A
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Abstract
本发明属于医药技术领域，公开了异苯并呋喃‑1(3H)‑酮类化合物及其制备方法、药物组合物和用途。具体涉及式I所示的异苯并呋喃‑1(3H)‑酮类化合物，其可药用盐，及其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在制备单胺氧化酶B(MAO‑B)抑制剂、在制备治疗MAO‑B有关的疾病及在制备预防和/或治疗神经精神系统疾病药物中的用途。
Description
技术领域
本发明属于医药技术领域，涉及式I所示的新结构的异苯并呋喃-1(3H)-酮类化合物，其可药用盐，及其制备方法，含有一个或多个该类化合物的组合物，和该类化合物在抑制单胺氧化酶B(MAO-B)与治疗MAO-B有关的疾病，及在制备预防和/或治疗神经精神系统疾病药物中的用途。
背景技术
单胺氧化酶(MAOs)是以黄素腺嘌呤二核苷酸FAD为辅酶的黄素酶，位于线粒体外膜上，可催化内源性(神经递质)和外源性单胺类物质的氧化脱氨反应[Advances inExperimental Medicine and Biology,1982,148:141-153]。单胺氧化酶包含两种同工酶，单胺氧化酶A(MAO-A)和单胺氧化酶B(MAO-B)，它们的组织分布和底物特异性具有差异[JNucl Med,1995,36(7):1255-1262]。在组织分布上，MAO-B主要存在于5-羟色胺能神经元和星形胶质细胞中，而MAO-A主要位于儿茶酚胺能神经元中[Proc Natl AcadSci USA,1982,79(20):6385-6389]。在底物特异性上，MAO-A对去甲肾上腺素和5-羟色胺的亲和力高于MAO-B，而MAO-B对苯乙胺和苄胺类物质的亲和力更高[Annu Rev Neurosci,1999,22:197-217；Neurology,2003,61(11suppl 6):S62]。儿茶酚胺类神经递质(如：肾上腺素、去甲肾上腺素、多巴胺、酪胺和色胺)则是两种同工酶的共同底物。MAO-B不仅是调控脑内多巴胺和其他单胺类神经递质水平的关键酶，而且MAO-B催化单胺类物质发生的氧化反应，会产生过氧化氢和其他活性氧物质，进而导致氧化应激和细胞损伤[Chem Res Toxicol,2008,21(1):172-188]。许多研究表明，帕金森疾病主要的病理改变是脑黑质中多巴胺能神经元显著缺失，纹状体内多巴胺含量明显下降，另外，帕金森患者脑黑质中MAO-B的活性显著增强。而脑黑质中多巴胺的代谢主要是由星形胶质细胞中的MAO-B负责[J Nucl Med,1995,36(7):1255-1262；Neurotoxicology,2004,25(1):155-165]。因此，抑制MAO-B的活性，可以减少多巴胺的代谢，提高患者脑内多巴胺含量，改善帕金森症状，同时可以减少MAO-B催化的氧化反应产生的活性氧物质损伤细胞，具有潜在的神经保护作用[Advanced drug deliveryreviews,2008,60(13-14):1527-1533]。对于该靶点的调控有助于帕金森和老年痴呆等多种常见疑难病的研究和治疗，所以MAO-B的作用机制及其调控的研究具有非常重要的意义。
目前，非选择性MAO抑制剂和MAO-A选择性抑制剂主要作为三线药物，治疗抑郁症和情绪紊乱，如反苯环丙胺、氯吉兰和吗氯贝胺[Current Medicinal Chemistry,2004,11(15):2033-2043]。MAO-B选择性抑制剂主要作为辅助药物，与多巴胺前药左旋多巴或多巴胺激动剂联合使用，治疗帕金森疾病。到目前为止，已经有3种MAO-B选择性抑制剂在临床用于治疗帕金森，包括司来吉兰[Advances in biochemical psychopharmacology,1972,5:393-408]、雷沙吉兰[Molecular neurodegeneration,2007,2:13-13]和沙芬酰胺[Pharmacological Research,2004,50(1):77-85]。但是，应用不可逆MAO抑制剂(如苯乙肼、反苯环丙胺)，会产生严重的副作用“芝士效应”[Journal of Medicinal Chemistry,2004,47(7):1760-1766]。“芝士效应”副作用是由于药物对MAO-A的不可逆抑制造成。目前上市的不可逆MAO-B选择性抑制剂也具有一定缺陷，例如，雷沙吉兰具有拟交感神经副作用、司来吉兰会导致高血压。因此，新结构的可逆的MAO-B抑制剂具有重要的临床意义，有可能获得新的治疗帕金森和老年痴呆等神经精神疾病的药物。
本专利设计合成了新结构的异苯并呋喃-1(3H)-酮类MAO-B抑制剂，旨在为治疗与MAO-B相关的疾病提供全新的物质基础。
发明内容
本发明解决的技术问题在于提供式I所示的含有异苯并呋喃-1(3H)-酮类衍生物、其制备方法、药物组合物、及其在制备MAO-B抑制剂及其潜在的药物中的用途、在制备治疗神经精神疾病药物中的用途。
为解决本发明的技术问题，本发明提供了如下技术方案：
本发明技术方案的第一方面是提供了如通式I所示的异苯并呋喃-1(3H)-酮类衍生物及其药用盐：
在式I中，
R1、R2和R3独立地选自如下原子或基团或结构片断，包括：
H、F、Cl、Br、CN、甲基、乙基、三氟甲基、三氟乙基、CHF2、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3；
R4选自如下结构片断：
选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自H、F、Cl、Br、CN、NO2、甲基、乙基、三氟甲基、三氟乙基、三氟甲氧基、CHF2、OH、OCH3、OC2H5、亚甲二氧基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个氮原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S。
为完成本发明的目的，优选的化合物包括但不限定于：
本发明技术方案的第二方面是提供了第一方面所述化合物的制备方法，采用的技术方案包括以下步骤：
异苯并呋喃-1(3H)-酮类化合物(通式I所示)的合成是以3-氧代-1,3-二氢异苯并呋喃-1-膦酸二甲酯I为起始原料，通过硝化反应，在异苯并呋喃-1(3H)-酮6-位引入硝基，得到中间体II。II与包含R4取代基的芳醛发生Wittig-Horner反应，得到中间体III。然后利用催化氢化将硝基和碳碳双键还原，制备化合物IV。通过Sandermayer反应引入卤素，制备关键中间体V。从关键中间体V出发，与(R)-3-吡咯烷醇进行偶联反应，得到目标化合物。
试剂及反应条件：(a)硝酸钾，浓硫酸，0℃；(b)取代的醛，三乙胺，四氢呋喃，0℃，氩气；(c)钯碳，氢气，甲醇或三氟乙醇，室温；(d)三甲基溴硅烷，亚硝酸钠，三乙基苄基氯化铵，乙腈，0℃；(e)醋酸钯，(R)-3-吡咯烷醇，Xphos或Sphos，碳酸铯，1,4-二氧六环，90-100℃，氩气。
其中所述的R1、R2、R3和R4的定义如本发明技术方案第一方面所述。
另外，上述反应中的起始原料及中间体容易得到，各步反应可依据已报道的文献或对本领域熟练技术人员来说可以用有机合成中的常规方法很容易合成。通式I所述化合物可以溶剂化物或非溶剂化物的形式存在，利用不同的溶剂进行结晶可能得到不同的溶剂化物。通式I所述药学上可接受的盐包括不同酸的盐，如下列无机酸或有机酸的盐：盐酸，氢溴酸，磷酸，硫酸，甲磺酸，对甲苯磺酸，三氟乙酸，枸杞酸，马来酸，酒石酸，富马酸，柠檬酸，乳酸。在本发明范围内的所有这些盐都可采用常规方法制备。
本发明技术方案的第三方面是提供了一种药物组合物，所述药物组合物包括作为本发明技术方案第一方面所述的化合物或其可药用盐和药学上的常用载体。
该组合物包括本发明中至少一种化合物和在药学上可接受的载体。所述的药物组合物选自片剂、胶囊、丸剂、注射剂、缓释制剂、控释制剂或各种微粒给药系统。该药物组合物可根据本领域公知的方法制备。可通过将本发明化合物与一种或多种药学上可接受的固体或液体赋形剂和/或辅剂结合，制成适于人或动物使用的任何剂型。本发明化合物在其药物组合物中的含量通常为0.1-95重量％。
本发明化合物或含有它的药物组合物可以单位剂量形式给药，给药途径可为肠道或非肠道，如口服、静脉注射、肌肉注射、皮下注射、鼻腔、口腔粘膜、眼、肺和呼吸道、皮肤、阴道、直肠等。
给药剂型可以是液体剂型、固体剂型或半固体剂型。液体剂型可以是溶液剂(包括真溶液和胶体溶液)、乳剂(包括o/w型、w/o型和复乳)、混悬剂、注射剂(包括水针剂、粉针剂和输液)、滴眼剂、滴鼻剂、洗剂和搽剂等；固体剂型可以是片剂(包括普通片、肠溶片、含片、分散片、咀嚼片、泡腾片、口腔崩解片)、胶囊剂(包括硬胶囊、软胶囊、肠溶胶囊)、颗粒剂、散剂、微丸、滴丸、栓剂、膜剂、贴片、气(粉)雾剂、喷雾剂等；半固体剂型可以是软膏剂、凝胶剂、糊剂等。
本发明化合物可以制成普通制剂、也可以制成缓释制剂、控释制剂、靶向制剂及各种微粒给药系统。
这些制剂是按照本领域的技术人员所熟知的方法制备的。为制造片剂、胶囊剂、包衣剂所用的辅料是常规用的助剂，例如淀粉，明胶，阿拉伯胶，硅石，聚乙二醇，液体剂型所用的溶剂例如有水，乙醇，丙二醇，植物油类如玉米油，花生油，橄榄油等。含有本发明化合物的制剂中还可有其他助剂，例如表面活性剂，润滑剂，崩解剂，防腐剂，矫味剂，色素等。
为了将本发明化合物制成片剂，可以广泛使用本领域公知的各种赋形剂，包括稀释剂、黏合剂、润湿剂、崩解剂、润滑剂、助流剂。稀释剂可以是淀粉、糊精、蔗糖、葡萄糖、乳糖、甘露醇、山梨醇、木糖醇、微晶纤维素、硫酸钙、磷酸氢钙、碳酸钙等；湿润剂可以是水、乙醇、异丙醇等；粘合剂可以是淀粉浆、糊精、糖浆、蜂蜜、葡萄糖溶液、微晶纤维素、阿拉伯胶浆、明胶浆、羧甲基纤维素钠、甲基纤维素、羟丙基甲基纤维素、乙基纤维素、丙烯酸树脂、卡波姆、聚乙烯吡咯烷酮、聚乙二醇等；崩解剂可以是干淀粉、微晶纤维素、低取代羟丙基纤维素、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、羧甲基淀粉钠、碳酸氢钠与枸橼酸、聚氧乙烯山梨糖醇脂肪酸酯、十二烷基磺酸钠等；润滑剂和助流剂可以是滑石粉、二氧化硅、硬脂酸盐、酒石酸、液体石蜡、聚乙二醇等。
还可以将片剂进一步制成包衣片，例如糖包衣片、薄膜包衣片、肠溶包衣片，或双层片和多层片。
为了将给药单元制成胶囊剂，可以将有效成分本发明化合物与稀释剂、助流剂混合，将混合物直接置于硬胶囊或软胶囊中。也可将有效成分本发明化合物先与稀释剂、黏合剂、崩解剂制成颗粒或微丸，再置于硬胶囊或软胶囊中。用于制备本发明化合物片剂的各稀释剂、黏合剂、润湿剂、崩解剂、助流剂品种也可用于制备本发明化合物的胶囊剂。
为将本发明化合物制成注射剂，可以用水、乙醇、异丙醇、丙二醇或它们的混合物作溶剂并加入适量本领域常用的增溶剂、助溶剂、pH调剂剂、渗透压调节剂。增溶剂或助溶剂可以是泊洛沙姆、卵磷脂、羟丙基-β-环糊精等；pH调剂剂可以是磷酸盐、醋酸盐、盐酸、氢氧化钠等；渗透压调节剂可以是氯化钠、甘露醇、葡萄糖、磷酸盐、醋酸盐等。如制备冻干粉针剂，还可加入甘露醇、葡萄糖等作为支撑剂。
此外，如需要，也可以向药物制剂中添加着色剂、防腐剂、香料、矫味剂或其它添加剂。
为达到用药目的，增强治疗效果，本发明的药物或药物组合物可用任何公知的给药方法给药。
本发明化合物药物组合物的给药剂量依照所要预防或治疗疾病的性质和严重程度，患者或动物的个体情况，给药途径和剂型等可以有较大范围的变化。一般来讲，本发明化合物每天的合适剂量范围为0.1-1000mg/Kg体重，优选为1-500mg/Kg体重。上述剂量可以一个剂量单位或分成几个剂量单位给药，这取决于医生的临床经验以及包括运用其它治疗手段的给药方案。
本发明的化合物或组合物可单独服用，或与其他治疗药物或对症药物合并使用。当本发明的化合物与其它治疗药物存在协同作用时，应根据实际情况调整剂量。
本发明技术方案的第四方面是提供了本发明第一方面所述的化合物及其药用盐在制备MAO-B抑制剂中的应用、在制备预防和/或治疗与MAO-B有关的疾病的药物中的应用、在制备治疗神经精神疾病药物中的应用、在制备与阿尔茨海默症、帕金森、抑郁焦虑等疾病有关药物中的作用。
有益技术效果：
该专利申请的异苯并呋喃-1(3H)-酮类化合物是全新结构的MAO-B抑制剂。
具体实施方式
以下将结合实施例对发明做进一步说明，但并不限制本发明的范围。
化合物的结构是通过核磁共振(NMR)或高分辨质谱(HRMS)来确定的。NMR的测定是用Varian mercury 400或者Varian mercury 500，测定溶剂为CDCl3、DMSO-d6、Acetone-d6、MeOD，内标为TMS，化学位移是以ppm作为单位给出。m.p.是以℃给出的熔点，温度未加校正。硅胶柱层析一般使用200-300目硅胶为载体。缩写列表：
KNO3：硝酸钾；Na2CO3：碳酸钠；Cs2CO3：碳酸铯
H2SO4：硫酸；HCl：盐酸；TFA：三氟乙酸
NaCl：氯化钠；TEA：三乙胺
DMF：N,N-二甲基甲酰胺；DME：N,N-二甲基乙酰胺
THF：四氢呋喃；PE：石油醚；EA：乙酸乙酯；Acetone：丙酮
DCM：二氯甲烷；MeOH：甲醇
min：分钟；r.t.：室温；h：小时；Ar：氩气
Xphos：2-二环己基膦-2,4,6-三异丙基联苯
Sphos：2-双环己基膦-2,6-二甲氧基联苯
CDCl3：氘代氯仿；DMSO-d6：氘代二甲基亚砜；Acetone-d6：氘代丙酮
实施例1：
6-((R)-3-羟基吡咯烷-1-基)-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(5-硝基-3-氧代-1,3-二氢异苯并呋喃-1-基)膦酸二甲酯(中间体1)的合成
将KNO3(835mg，8.26mmol)溶于浓H2SO4(7mL)中，冰浴搅拌20min，缓慢加入(3-氧代-1,3-二氢异苯并呋喃-1-基)膦酸二甲酯(2g，8.26mmol)，冰浴搅拌4h，原料消失。将反应液倾倒入冰水中，搅拌30min，析出白色固体，过滤，将滤液溶剂旋干，乙醇热重结晶，得白色固体，与滤饼合并，干燥，共得白色固体2.09g，产率88％，熔点：138-139℃。
1H NMR(400MHz,CDCl3)δ(ppm):8.78(s,1H),8.61(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.98–7.95(m,1H),5.81(d,J＝12.8Hz,1H),3.97(d,J＝11.2Hz,3H),3.71(d,J＝10.4Hz,3H).
(2)(Z)-3-(2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体2)的合成
将中间体1(2.76g，9.6mmol)和邻甲基苯甲醛(1.15g，9.6mmol)溶于无水THF(40mL)中，缓慢滴加TEA(1.07g，10.56mmol)的THF溶液(10mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出亮黄色固体，过滤，水洗，干燥，得黄色固体2.5g，产率92.6％，熔点：>250℃。
1H NMR(400MHz,CDCl3)δ(ppm):8.80(d,J＝2.0Hz,1H),8.59(dd,J1＝8.8Hz,2.0Hz,1H),8.19(dd,J1＝6.8Hz,J2＝2.0Hz,1H),7.98(d,J＝8.8Hz,1H),7.35–7.25(m,3H),6.86(s,1H),2.51(s,3H).
(3)6-氨基-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体3)的合成
将中间体2(2.5g，8.9mmol)溶于三氟乙醇(50mL)中，加入钯碳(500mg)，室温催化氢化2h，原料消失。过滤，滤液浓缩，EA/THF(1/1)(90mL×3)萃取，合并有机层，有机相浓缩，柱层析(PE/EA＝5/1-3/1)得白色固体1.58g，产率70.4％，熔点：161-162℃。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.20–7.09(m,5H),6.92(dd,J1＝8.0Hz,J2＝2.4Hz,1H),6.85(d,J＝2.0Hz,1H),5.66(dd,J1＝8.0Hz,J2＝4.8Hz,1H),5.56(brs,2H),3.23(dd,J1＝14.4Hz,J2＝4.8Hz,1H),2.93(dd,J1＝14.4Hz,J2＝8.0Hz,1H),2.27(s,3H).
(4)6-溴-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体4)的合成
取亚硝酸钠(1.01g，14.7mmol)、三乙基苄基氯化铵(223mg，0.98mmol)和三甲基溴硅烷(2.25g，14.7mmol)溶于乙腈8mL，冰水浴中搅拌30min。将中间体3(1.24g，4.9mmol)溶于8mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌8h。加入30mL乙酸乙酯，用饱和NaCl(50mL×2)洗，无水硫酸镁干燥，浓缩，柱层析(0-1％Acetone/PE)，得白色固体632mg，产率41％，熔点：160-161℃。
1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J＝2.0Hz,1H),7.68(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.22–7.13(m,4H),6.89(dd,J1＝8.0Hz,J2＝0.8Hz,1H),5.63(t,J＝7.2Hz,1H),3.34(dd,J1＝14.0Hz,J2＝6.8Hz,1H),3.07(dd,J1＝14.0Hz,J2＝7.2Hz,1H),2.30(s,3H).
(5)6-((R)-3-羟基吡咯烷-1-基)-3-(2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例1)的合成
将中间体4(300mg，0.95mmol)、(R)-3-吡咯烷醇(120mg，1.4mmol)、醋酸钯(20mg，0.095mmol)、Sphos(60mg，0.14mmo)和碳酸铯(600mg，1.8mmol)加入到100mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热10h。硅藻土助滤，滤掉不溶物，EA洗。中压制备27％EAin PE，得浅黄色油状物233mg，产率76％。加入1.5mL HCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得类白色固体207mg，产率80％。
1H NMR(500MHz,DMSO-d6)δ(ppm):7.27(dd,J1＝8.5Hz,J2＝3.5Hz,1H),7.20–7.09(m,4H),6.91(dd,J1＝8.5Hz,J2＝2.5Hz,1H),6.70(d,J＝2.0Hz,1H),5.73(dd,J1＝8.0Hz,J2＝5.5Hz,1H),4.81(brs,1H),4.41(t,J＝3.0Hz,1H),3.45(dd,J1＝10.0Hz,J2＝5.0Hz,1H),3.36(dd,J1＝17.0Hz,J2＝9.0Hz,1H),3.33–3.29(m,1H),3.25(dd,J1＝14.5Hz,J2＝5.0Hz,1H),3.10(d,J＝10.0Hz,1H),2.98(ddd,J1＝14.5Hz,J2＝7.5Hz,J3＝2.5Hz,1H),2.28(s,3H),2.08–2.01(m,1H),1.94–1.88(m,1H)；HRMS(ESI):m/z,Calcd.for C20H22O3N[M+H]+:324.1594,Found 324.1589.
实施例2：
3-(3-氟苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮的合成
(1)(Z)-3-(3-氟亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体5)的合成
将中间体1(4.00g，14.0mmol)、3-氟苯甲醛(1.74g，14.0mmol)加入到无水THF(40mL)中，冰浴，恒压滴液漏斗缓慢滴加TEA(1.55g，15.3mmol)的无水THF(20mL)，Ar保护继续反应8h，反应完毕，旋干溶剂，加入冰水搅拌60min，析出浅黄色固体，过滤，水洗，干燥，得浅黄色固体3.88g，产率98％。
1H NMR(400MHz,CDCl3)δ(ppm):8.80(dd,J1＝2.0Hz,J2＝0.8Hz,1H),8.60(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.95(dd,J1＝8.8Hz,J2＝0.8Hz,1H),7.65(dt,J1＝10.0Hz,J2＝2.0Hz,1H),7.61(dt,J1＝8.0Hz,J2＝1.6Hz,1H),7.41(td,J1＝8.0Hz,J2＝6.0Hz,1H),7.70(tdd,J1＝8.4Hz,J2＝2.4Hz,J3＝0.8Hz,1H),6.60(s,1H).
(2)6-氨基-3-(3-氟苄基)异苯并呋喃-1(3H)-酮(中间体6)的合成
将中间体5(3.76g，13.2mmol)溶于THF(50mL)与MeOH(50mL)的溶液中，加入钯碳(700mg)，室温催化氢化反应6h，原料消失。过滤，滤液浓缩，柱层析(40g柱，15-60％EA/PE)，浓缩得白色固体，正己烷洗，得白色固体3.06g，收率90％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.98–7.96(m,2H),7.56(dt,J1＝8.0Hz,J2＝0.8Hz,1H),7.20–7.09(m,4H),5.89(dd,J1＝8.0Hz,J2＝4.8Hz,1H),3.37(dd,J1＝14.4Hz,J2＝4.4Hz,1H),3.06(dd,J1＝14.8Hz,J2＝8.4Hz,1H).
(3)6-溴-3-(3-氟苄基)异苯并呋喃-1(3H)-酮(中间体7)的合成
取亚硝酸钠(2.01g，29.1mmol)、三乙基苄基氯化铵(442mg，1.94mmol)和三甲基溴硅烷(4.45g，29.1mmol)溶于乙腈40mL，冰浴下搅拌15min后将中间体6(2.5g，9.7mmol)溶于20mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入80mL水，EA萃取(30mL×3)，无水硫酸镁干燥，浓缩，柱层析(40g柱，0-10％EA/PE)，得白色固体1.53g，产率50％。
(4)3-(3-氟苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮(实施例2)的合成
将中间体7(300mg，0.94mmol)、(R)-3-吡咯烷醇(163mg，1.88mmol)、醋酸钯(21.0mg，0.094mmol)、Sphos(77mg，0.19mmol)和碳酸铯(612mg，1.88mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液柱层析(20g柱，25-50％EA/PE，40％出峰)，得白色固体204mg，产率66％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.27(dd,J1＝8.4Hz,J2＝2.8Hz,1H),7.21–7.09(m,4H),6.91(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.70(d,J＝2.0Hz,1H),5.72(dd,J1＝8.0Hz,J2＝5.2Hz,1H),4.99(brs,1H),4.41(t,J＝3.2Hz,1H),3.45(dd,J1＝10.4Hz,J2＝4.8Hz,1H),3.41–3.33(m,2H),3.25(dd,J1＝14.4Hz,J2＝5.2Hz,1H),3.11(d,J＝10.4Hz,1H),2.98(ddd,J1＝14.4Hz,J2＝7.6Hz,J3＝2.0Hz,1H),2.28(s,3H),2.09–1.99(m,1H),1.94–1.89(m,1H)；HRMS(ESI):m/z,Calcd.for C19H19O3NF[M+H]+:328.1343,Found 328.1347.
实施例3：
6-((R)-3-羟基吡咯烷-1-基)-3-(4-氟苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(4-氟亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体8)的合成
将中间体1(1.5g，5.22mmol)和4-氟苯甲醛(816mg，5.75mmol)溶于无水THF(16mL)中，缓慢滴加TEA(634mg，6.26mmol)的THF溶液(4mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体1.40g，产率93.9％。
(核磁显示Z/E＝0.6/0.4)
1H NMR(400MHz,CDCl3)δ(ppm):8.80(dd,J1＝2.0Hz,J2＝0.4Hz,0.6H),8.76(dd,J1＝2.0Hz,J2＝0.4Hz,0.4H),8.60(dd,J1＝8.4Hz,J2＝2.0Hz,0.6H),8.37(dd,J1＝8.8Hz,J2＝2.0Hz,0.4H),7.93(dd,J1＝8.4Hz,J2＝0.8Hz,0.6H),7.92–7.86(m,1.2H),7.60(d,J＝8.8Hz,0.4H),7.48–7.44(m,0.8H),7.24–7.19(m,0.8H),7.18–7.13(m,1.2H),7.09(s,0.4H),6.61(s,0.6H).
(2)6-氨基-3-(4-氟苄基)异苯并呋喃-1(3H)-酮(中间体9)的合成
将中间体8(1.3g，4.56mmol)溶于三氟乙醇(20mL)，加入钯碳(150mg)，50℃催化氢化12h，原料消失。过滤，除去钯碳，滤液浓缩，正己烷洗，得白色固体1.01g，产率86.3％。
1H NMR(400MHz,MeOD)δ(ppm):7.18(d,J＝2.4Hz,1H),7.16(dd,J1＝4.8Hz,J2＝4.0Hz,2H),7.01(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.96–6.90(m,3H),5.66(t,J＝5.6Hz,1H),3.27(dd,J1＝14.4Hz,J2＝4.8Hz,1H),3.09(dd,J1＝14.4Hz,J2＝6.4Hz,1H).
(3)6-溴-3-(4-氟苄基)异苯并呋喃-1(3H)-酮(中间体10)的合成
取亚硝酸钠(483mg，7.00mmol)、三乙基苄基氯化铵(106mg，0.47mmol)和三甲基溴硅烷(1.07g，7.00mmol)溶于乙腈10mL，冰水浴中搅拌20min。将中间体9(600mg，2.21mmol)溶于5mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入80mL乙酸乙酯，用饱和NaCl(60mL×3)洗，无水硫酸镁干燥，浓缩，Flash柱层析(30g柱，3-8％EA/PE)，得白色固体664mg，产率88.9％。
1H NMR(500MHz,CDCl3)δ(ppm):7.96(s,1H),7.72(d,J＝8.5Hz,1H),7.14(dd,J1＝7.5Hz,J2＝6.0Hz,2H),7.07(d,J＝8.0Hz,1H),6.97(t,J＝8.5Hz,2H),5.63(t,J＝6.0Hz,1H),3.23(dd,J1＝14.5Hz,J2＝6.5Hz,1H),3.16(dd,J1＝14.5Hz,J2＝6.0Hz,1H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(4-氟苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例3)的合成
将中间体10(300mg，0.94mmol)、(R)-3-吡咯烷醇(163mg，1.88mmol)、醋酸钯(21mg，0.094mmol)、Xphos(90mg，0.188mmol)和碳酸铯(613mg，1.88mmol)加入到100mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热10h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(30g柱，6-59％EA/PE)，得浅粉色油状物195mg，产率63.6％。加入10mLHCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得白色固体136mg。
1H NMR(400MHz,MeOD)δ(ppm):7.45(d,J＝8.4Hz,1H),7.33(dd,J1＝8.4Hz,J2＝2.4Hz,1H),7.22(d,J＝2.4Hz,1H),7.17(dd,J1＝8.8Hz,J2＝5.6Hz,2H),6.93(tt,J1＝8.8Hz,J2＝2.8Hz,2H),5.77(t,J＝5.2Hz,1H),4.61(tt,J1＝4.4Hz,J2＝2.4Hz,1H),3.69–3.63(m,2H),3.57(td,J1＝8.8Hz,J2＝3.2Hz,1H),3.41(d,J＝11.2Hz,1H),3.36(dd,J1＝14.4Hz,J2＝9.6Hz,1H),3.16(dd,J1＝14.4Hz,J2＝6.4Hz,1H),2.32–2.23(m,1H),2.16–2.10(m,1H)；HRMS(ESI):m/z,Calcd.for C19H19O3NF[M+H]+:328.1343,Found 328.1346.
实施例4：
6-((R)-3-羟基吡咯烷-1-基)-3-(4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮的合成
(1)(Z)-3-(4-(三氟甲基))-6-硝基异苯并呋喃-1(3H)-酮(中间体11)的合成
将中间体1(6.00g，20.9mmol)、4-三氟甲基苯甲醛(3.64g，20.9mmol)加入到无水THF(60mL)中，冰浴，恒压滴液漏斗缓慢滴加TEA(2.33g，23.0mmol)的无水THF(20mL)，Ar保护继续反应8h，反应完毕。旋干溶剂，加入冰水搅拌60min，析出浅黄色固体，过滤，水洗，干燥，得浅黄色固体6.85g，产率98％。
1H NMR(400MHz,CDCl3)δ(ppm):8.82(d,J＝2.0Hz,1H),8.62(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.99(d,J＝8.0Hz,2H),7.98(dd,J1＝8.4Hz,J2＝0.8Hz,1H),7.70(d,J＝8.4Hz,2H),6.65(s,1H).
(2)6-氨基-3-(4-(三氟甲基))异苯并呋喃-1(3H)-酮(中间体12)的合成
将中间体11(6g，17.9mmol)溶于THF(70mL)与MeOH(70mL)的溶液中，加入钯碳(1.2g)，室温催化氢化反应6h，原料消失。过滤，滤液浓缩，Flash柱层析(80g柱，15-40％EA/PE，35％出峰)，过滤，正己烷洗，得白色固体4.24g，收率77％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.63(d,J＝8.0Hz,2H),7.43(d,J＝8.0Hz,2H),7.28(d,J＝8.0Hz,1H),6.94(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.80(d,J＝2.0Hz,1H),5.73(dd,J1＝7.2Hz,J2＝4.0Hz,1H),5.57(brs,2H),3.42(dd,J1＝14.4Hz,J2＝4.4Hz,1H),3.05(dd,J1＝14.4Hz,J2＝7.6Hz,1H).
(3)6-溴-3-(4-(三氟甲基)异苯并呋喃-1(3H)-酮(中间体13)的合成
取亚硝酸钠(2.69g，39.0mmol)、三乙基苄基氯化铵(593mg，39.0mmol)和三甲基溴硅烷(5.97g，39.0mmol)溶于乙腈100mL，冰浴下搅拌15min后将中间体12(4.0g，13.0mmol)溶于40mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入80mL水，EA萃取(40mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(40g柱，0-20％EA/PE)，得白色固体3.87g，产率80％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.99(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.96(d,J＝2.0Hz,1H),7.69(d,J＝8.4Hz,1H),7.65(d,J＝8.0Hz,2H),7.46(d,J＝8.0Hz,2H),5.95(dd,J1＝7.6Hz,J2＝4.4Hz,1H),3.56(dd,J1＝14.4Hz,J2＝4.4Hz,1H),3.19(dd,J1＝14.4Hz,J2＝7.6Hz,1H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(4-(三氟甲基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例4)的合成
将中间体13(400mg，1.08mmol)、(R)-3-吡咯烷醇(188mg，2.16mmol)、醋酸钯(25mg，0.11mmol)、Sphos(89mg，0.22mmol)和碳酸铯(704mg，2.16mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(20g柱，25-50％EA/PE)，得白色固体211mg，产率52％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.59(d,J＝8.0Hz,2H),7.40(d,J＝7.6Hz,2H),7.36(d,J＝8.4Hz,1H),6.89(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.62(d,J＝2.4Hz,1H),5.74(dd,J1＝7.2Hz,J2＝4.4Hz,1H),4.38–4.33(m,1H),3.46(t,J＝5.6Hz,1H),3.42–3.37(m,2H),3.34–3.25(m,2H),3.08–3.04(m,2H),2.04–1.94(m,1H),1.89–1.82(m,1H)；HRMS(ESI):m/z,Calcd.for C20H19O3NF3[M+H]+:378.1311,Found 378.1308.
实施例5：
6-((R)-3-羟基吡咯烷-1-基)-3-(4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z)-3-(4-(三氟甲氧基))-6-硝基异苯并呋喃-1(3H)-酮(中间体14)的合成
将中间体1(4.00g，14.0mmol)、4-三氟甲氧基苯甲醛(2.66g，14.0mmol)加入到无水THF(40mL)中，冰浴，恒压滴液漏斗缓慢滴加TEA(1.55g，15.3mmol)的无水THF(20mL)，Ar保护继续反应8h，反应完毕，旋干溶剂，加入冰水搅拌60min，析出浅黄色固体，过滤，水洗，干燥，得浅黄色固体3.88g，产率98％。
1H NMR(400MHz,CDCl3)δ(ppm):8.81(dd,J1＝2.0Hz,J2＝0.8Hz,1H),8.61(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.95(dd,J1＝8.4Hz,J2＝0.8Hz,1H),7.92(dt,J1＝8.8Hz,J2＝2.0Hz,2H),7.30(d,J＝7.6Hz,2H),6.61(s,1H).
(2)6-氨基-3-(4-(三氟甲氧基))异苯并呋喃-1(3H)-酮(中间体15)的合成
将中间体14(4.00g，11.4mmol)溶于THF(50mL)与MeOH(50mL)的溶液中，加入钯碳(0.8g)，室温催化氢化反应6h，原料消失。过滤，滤液浓缩，Flash柱层析(40g柱，15-60％EA/PE，40％出峰)，过滤，正己烷洗，得白色固体3.5g，收率95％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.33(d,J＝8.8Hz,2H),7.27(d,J＝4.8Hz,2H),7.24(d,J＝4.8Hz,1H),6.93(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.81(d,J＝2.0Hz,1H),5.68(dd,J1＝7.6Hz,J2＝4.4Hz,1H),5.57(brs,2H),3.34(dd,J1＝14.4Hz,J2＝4.4Hz,1H),2.98(dd,J1＝14.4Hz,J2＝7.6Hz,1H).
(3)6-溴-3-(4-(三氟甲氧基))异苯并呋喃-1(3H)-酮(中间体16)的合成
取亚硝酸钠(2.50g，36.2mmol)、三乙基苄基氯化铵(547mg，2.40mmol)和三甲基溴硅烷(5.41g，36.2mmol)溶于乙腈60mL，冰浴下搅拌15min后，将中间体15(3.9g，12.0mmol)溶于20mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入80mL水，EA萃取(50mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(40g柱，9-30％EA/PE，10％出柱)，得白色固体3.10g，产率67％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.98(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.95(d,J＝1.6Hz,1H),7.67(dt,J1＝8.0Hz,J2＝0.8Hz,1H),7.37–7.34(m,2H),7.29–7.27(m,2H),5.91(dd,J1＝7.6Hz,J2＝4.4Hz,1H),3.48(dd,J1＝14.4Hz,J2＝4.4Hz,1H),3.12(dd,J1＝14.4Hz,J2＝7.6Hz,1H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例5)的合成
将中间体16(400mg，1.04mmol)、(R)-3-吡咯烷醇(181mg，2.07mmol)、醋酸钯(25.0mg，0.11mmol)、Sphos(85mg，0.21mmol)和碳酸铯(677mg，2.08mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(20g柱，25-60％EA/PE，50％出峰)，得红色油状物，加入3mL(4M)盐酸的乙酸乙酯溶液，冰浴搅拌30min，析出固体，过滤，无水乙醚洗，得浅紫色固体200mg，产率60％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.38(d,J＝8.4Hz,1H),7.36–7.33(m,2H),7.27(d,J＝8.4Hz,2H),6.94(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.80(brs,1H),6.68(d,J＝2.4Hz,1H),5.75(dd,J1＝7.6Hz,J2＝4.8Hz,1H),4.43–4.39(m,1H),3.44(ddd,J1＝10.0Hz,J2＝4.8Hz,J3＝1.2Hz,1H),3.39–3.28(m,3H),3.10(d,J＝10.4Hz,1H),3.02(ddd,J1＝14.4Hz,J2＝7.6Hz,J3＝1.2Hz,1H),2.09–1.99(m,1H),1.94–1.88(m,1H)；HRMS(ESI):m/z,Calcd.for C20H19O4NF3[M+H]+:394.1260,Found 394.1265.
实施例6：
3-(4-氯苄基)-6-((R)-3-氨基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-(4-((5-硝基-3-氧代异苯并呋喃-1(3H)-亚烷基)甲基)苯基)氨基甲酸叔丁酯(中间体17)的合成
将中间体1(2.60g，9.0mmol)、4-Boc氨基苯甲醛(2g，9.0mmol)加入到无水THF(30mL)中，冰浴，恒压滴液漏斗缓慢滴加TEA(1.09g，10.8mmol)的无水THF(5mL)，Ar保护继续反应8h，反应完毕，旋干溶剂，加入冰水搅拌60min，析出桔黄色固体，过滤，水洗，干燥，得桔黄色固体3.3g，产率95％。(核磁显示Z/E＝1/0.1)
1H NMR(400MHz,CDCl3)δ(ppm):9.89(s,0.1H),8.78(d,J＝2.0Hz,0.9H),8.75(d,J＝2.0Hz,0.1H),8.56(dd,J1＝8.4Hz,J2＝2.0Hz,0.9H),8.35(dd,J1＝8.8Hz,J2＝2.0Hz,0.1H),7.89(d,J＝8.8Hz,0.9H),7.83(d,J＝8.8Hz,1.8H),7.78(d,J＝8.8Hz,0.1H),7.52(dd,J1＝8.4Hz,J2＝6.8Hz,0.2H),7.46(d,J＝8.8Hz,1.8H),7.41(d,J＝8.4Hz,0.2H),7.09(s,0.1H),6.64(s,0.9H),6.59(s,0.9H),1.56(s,0.9H),1.54(s,8.1H).
(2)叔丁基(4-((5-氨基-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)氨基甲酸酯(中间体18)的合成
将中间体17(3.3g，8.6mmol)溶于DCM(40mL)与MeOH(40mL)的溶液中，加入钯碳(660mg)，室温催化氢化反应16h。过滤，滤液浓缩，Flash柱层析(45g柱，6-40％EA/PE)，过滤，正己烷洗，得白色固体2.30g，收率75％。
1H NMR(400MHz,CDCl3)δ(ppm):7.27(d,J＝8.0Hz,2H),7.11(d,J＝8.8Hz,2H),7.03(d,J＝2.0Hz,1H),6.89(d,J＝8.0Hz,1H),6.86(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.44(brs,1H),5.54(t,J＝6.4Hz,1H),3.89(brs,2H),3.19(dd,J1＝14.0Hz,J2＝6.4Hz,1H),3.01(dd,J1＝14.0Hz,J2＝6.4Hz,1H),1.51(s,9H).
(3)叔丁基(4-((5-溴-3-氧代-1,3-二氢异苯并呋喃-1-基)甲基)苯基)氨基甲酸酯(中间体19)的合成
取亚硝酸钠(174mg，2.52mmol)、三乙基苄基氯化铵(38mg，0.17mmol)和三甲基溴硅烷(390mg，2.55mmol)溶于乙腈10mL，冰浴下搅拌15min后将中间体18(300mg，0.85mmol)溶于5mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入40mL水，EA萃取(30mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(30g柱，2-7％Acetone/PE)，得白色固体206mg，产率58％。
1H NMR(400MHz,CDCl3)δ(ppm):7.95(d,J＝2.0Hz,1H),7.68(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.29(d,J＝8.8Hz,2H),7.09(dt,J1＝8.4Hz,J2＝2.4Hz,2H),6.99(dt,J1＝8.0Hz,J2＝0.8Hz,1H),6.46(s,1H),5.61(t,J＝6.4Hz,1H),3.27(dd,J1＝14.4Hz,J2＝6.4Hz,1H),3.05(dd,J1＝14.4Hz,J2＝6.8Hz,1H),1.52(s,9H).
(4)3-(4-氨基苄基)-6-溴异苯并呋喃-1(3H)-酮(中间体20)的合成
将中间体19(1.07g，2.56mmol)溶于HCl的1M EA溶液10mL中，室温搅拌12h，加入饱和碳酸氢钠溶液至不再产生气泡，DCM萃取(30mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(45g柱，6-36％EA/PE)，得黄色固体763mg，产率94.1％。
1H NMR(400MHz,CDCl3)δ(ppm):7.95(d,J＝2.0Hz,1H),7.67(dd,J1＝8.0Hz,J2＝1.6Hz,1H),6.96(d,J＝8.8Hz,1H),6.96–6.93(m,2H),6.61(dt,J1＝8.4Hz,J2＝2.0Hz,2H),5.58(t,J＝6.4Hz,1H),3.65(brs,2H),3.25(dd,J1＝14.0Hz,J2＝6.0Hz,1H),2.96(dd,J1＝14.4Hz,J2＝7.2Hz,1H).
(5)6-溴-3-(4-氯苄基)异苯并呋喃-1(3H)-酮(中间体21)的合成
取氯化亚铜(134mg，0.10mmol)和亚硝酸叔丁酯(120mg，1.17mmol)溶于乙腈5mL，冰浴下搅拌15min后，将中间体20(300mg，0.83mmol)溶于3mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入1N盐酸4mL，搅拌30min，加入40mL水，EA萃取(30mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(45g柱，4-15％EA/PE)，得黄色固体180mg，产率64.5％。
1H NMR(400MHz,CDCl3)δ(ppm):7.97(d,J＝2.0Hz,1H),7.73(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.28–7.24(m,2H),7.11(dt,J1＝8.8Hz,J2＝2.4Hz,2H),7.09(d,J＝8.0Hz,1H),5.63(t,J＝6.4Hz,1H),3.22(dd,J1＝14.0Hz,J2＝6.4Hz,1H),3.16(dd,J1＝14.0Hz,J2＝6.0Hz,1H).
(6)3-(4-氯苄基)-6-((R)-3-氨基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐(实施例6)的合成
将中间体21(106mg，0.32mmol)、(R)-3-吡咯烷醇(55mg，0.63mmol)、醋酸钯(7.2mg，0.032mmol)、Xphos(31mg，0.064mmol)和碳酸铯(209mg，0.64mmol)加入到50mL三颈瓶中，加入1,4-二氧六环1mL，氩气保护，微波90℃加热40min。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(30g柱，4-51％EA/PE)，加入5mL HCl的EA溶液(1M)，搅拌2h，析出固体，过滤，无水乙醚洗，得白色固体22mg，产率20.4％。
1H NMR(400MHz,MeOD)δ(ppm):7.41(d,J＝8.4Hz,1H),7.22–7.19(m,3H),7.14(dt,J1＝8.4Hz,J2＝2.4Hz,2H),7.08(d,J＝2.4Hz,1H),5.76(t,J＝5.2Hz,1H),4.59(tt,J1＝4.4Hz,J2＝2.4Hz,1H),3.62(dd,J1＝10.8Hz,J2＝4.4Hz,1H),3.62–3.57(m,1H),3.50(td,J1＝8.8Hz,J2＝3.6Hz,1H),3.37–3.33(m,2H),3.14(dd,J1＝14.4Hz,J2＝6.4Hz,1H),2.29–2.20(m,1H),2.12–2.07(m,1H)；HRMS(ESI):m/z,Calcd.for C19H19O3NCl[M+H]+:344.1048,Found 344.1054.
实施例7：
3-(3-氟-4-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮的合成
(1)(Z/E)-3-(4-(3-氟-4-甲基苄基))-6-硝基异苯并呋喃-1(3H)-酮(中间体22)的合成
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将中间体1(3.50g，12.2mmol)、3-氟-4-甲基苯甲醛(1.68g，12.2mmol)加入到无水THF(40mL)中，冰浴，分液漏斗缓慢滴加TEA(1.36g，13.4mmol)的无水THF(20mL)，Ar保护继续反应6h，反应完毕，旋干溶剂，加入冰水搅拌60min，析出浅黄色固体，过滤，水洗，干燥，得浅黄色固体3.50g，产率95％。(核磁显示Z/E＝0.7/0.3)
1H NMR(400MHz,CDCl3)δ(ppm):8.80–8.78(m,0.7H),8.76–8.75(m,0.3H),8.59(dd,J1＝8.4Hz,J2＝2.0Hz,0.7H),8.39(dd,J1＝8.8Hz,J2＝2.0Hz,0.3H),7.92(dd,J1＝8.8Hz,J2＝0.8Hz,0.7H),7.70(d,J＝8.8Hz,0.3H),7.60(dd,J1＝10.8Hz,J2＝1.6Hz,0.7H),7.50(dd,J1＝7.6Hz,J2＝1.6Hz,0.7H),7.31(t,J＝7.6Hz,0.3H),7.25(t,J＝8.0Hz,0.7H),7.16(d,J＝7.6Hz,0.3H),7.12(t,J＝10.0Hz,0.3H),7.06(s,0.3H),6.56(s,0.7H),2.37(d,J＝2.0Hz,0.9H),2.33(d,J＝2.0Hz,2.1H).
(2)6-氨基-3-(3-氟-4-甲基苄基)异苯并呋喃-1(3H)-酮(中间体23)的合成
将中间体22(3.00g，9.96mmol)溶于THF(40mL)与MeOH(40mL)的溶液中，加入钯碳(600mg)，室温催化氢化反应6h，原料消失。过滤，滤液浓缩，Flash柱层析(40g柱，20-80％EA/PE)，过滤，正己烷洗，得白色固体2.3g，收率85％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.16(d,J＝8.4Hz,1H),7.09(t,J＝8.0Hz,1H),6.91(d,J＝10.8Hz,1H),6.88(dd,J1＝6.0Hz,J2＝2.0Hz,1H),6.85(d,J＝3.6Hz,1H),6.75(d,J＝2.0Hz,1H),5.62(dd,J1＝6.8Hz,J2＝4.4Hz,1H),5.50(brs,2H),3.20(dd,J1＝14.0Hz,J2＝4.4Hz,1H),2.92(dd,J1＝14.4Hz,J2＝7.2Hz,1H),2.12(s,3H).
(3)6-溴-3-(3-氟-4-甲基苄基)异苯并呋喃-1(3H)-酮(中间体24)的合成
取亚硝酸钠(1.63g，23.7mmol)、三乙基苄基氯化铵(359mg，1.58mmol)和三甲基溴硅烷(3.63g，23.7mmol)溶于乙腈60mL，冰浴下搅拌15min后将中间体22(2.14g，7.90mmol)溶于20mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入60mL水，EA萃取(40mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(40g柱，10-30％EA/PE，20％出柱)，得白色固体1.20g，产率45％。
1H NMR(400MHz,Acetone-d6)δ(ppm):7.91(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.89(d,J＝1.6Hz,1H),7.59(d,J＝8.0Hz,1H),7.14(t,J＝8.0Hz,1H),6.98(dd,J1＝8.4Hz,J2＝1.6Hz,1H),6.96(dd,J1＝4.8Hz,J2＝1.6Hz,1H),5.86(dd,J1＝6.8Hz,J2＝4.8Hz,1H),3.42(dd,J1＝14.4Hz,J2＝4.8Hz,1H),3.21(dd,J1＝14.4Hz,J2＝6.8Hz,1H),3.19(d,J＝2.0Hz,3H).
(4)3-(3-氟-4-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮(实施例7)的合成
将中间体24(400mg，1.19mmol)、(R)-3-吡咯烷醇(209mg，2.39mmol)、醋酸钯(26.7mg，0.12mmol)、Sphos(98mg，0.24mmol)和碳酸铯(775mg，2.38mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(20g柱，20-60％EA/PE，51％出峰)，得类白色固体267mg，产率65％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.34(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.15(t,J＝8.4Hz,1H),6.98(dd,J1＝11.2Hz,J2＝1.6Hz,1H),6.91(dd,J1＝8.4Hz,J2＝2.0Hz,2H),6.66(d,J＝2.4Hz,1H),5.74(dd,J1＝6.8Hz,J2＝4.4Hz,1H),4.97(brs,1H),4.42–4.39(m,1H),3.44(ddd,J1＝10.4Hz,J2＝4.8Hz,J3＝1.6Hz,1H),3.39–3.29(m,2H),3.27(dd,J1＝14.0Hz,J2＝4.8Hz,1H),3.09(d,J＝10.0Hz,1H),3.02(dd,J1＝14.0Hz,J2＝6.4Hz,1H),2.17(d,J＝2.0Hz,3H),2.08–1.99(m,1H),1.94–1.88(m,1H)；HRMS(ESI):m/z,Calcd.forC20H21O3NF[M+H]+:342.1500,Found 342.1487.
实施例8：
3-(5-氟-2-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(5-氟-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体25)的合成
将中间体1(1.5g，5.22mmol)和2-甲基-5-氟苯甲醛(722mg，5.22mmol)溶于无水THF(16mL)中，冰浴下，缓慢滴加TEA(630mg，6.26mmol)的THF溶液(4mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体1.45g，产率92.9％。
(核磁显示Z/E＝0.8/0.2)
1H NMR(400MHz,CDCl3)δ(ppm):8.81(d,J＝2.0Hz,0.8H),8.76(d,J＝2.4Hz,0.2H),8.60(dd,J1＝8.4Hz,J2＝2.0Hz,0.8H),8.36(dd,J1＝8.4Hz,J2＝2.4Hz,0.2H),7.98(d,J＝8.4Hz,0.8H),7.91(dd,J1＝10.4Hz,J2＝3.2Hz,0.8H),7.35(d,J＝8.4Hz,0.2H),7.33–7.28(m,0.2H),7.21(dd,J1＝8.8Hz,J2＝6.0Hz,0.8H),7.12–7.08(m,0.4H),7.03(s,0.2H),6.99(td,J1＝8.4Hz,J2＝2.8Hz,0.8H),6.78(s,0.8H),2.47(s,2.4H),2.29(s,0.6H).
(2)6-氨基-3-(5-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体26)的合成
将中间体25(1.44g，4.82mmol)溶于三氟乙醇(20mL)，加入钯碳(300mg)，50℃催化氢化12h，原料消失。过滤，除去钯碳，滤液浓缩，正己烷洗，得白色固体1.17g，产率90.3％。
1H NMR(400MHz,MeOD)δ(ppm):7.14(dd,J1＝8.4Hz,J2＝6.0Hz,1H),7.13(d,J＝8.0Hz,1H),7.02(dd,J1＝8.0Hz,J2＝2.4Hz,1H),7.00(d,J＝2.0Hz,1H),6.92(dd,J1＝10.0Hz,J2＝2.8Hz,1H),6.85(td,J1＝8.4Hz,J2＝2.4Hz,1H),5.67(dd,J1＝7.6Hz,J2＝5.2Hz,1H),3.27(dd,J1＝14.4Hz,J2＝5.2Hz,1H),3.06(dd,J1＝14.4Hz,J2＝7.6Hz,1H),2.27(s,3H).
(3)6-溴-3-(5-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体27)的合成
取亚硝酸钠(457mg，6.63mmol)、三乙基苄基氯化铵(101mg，0.44mmol)和三甲基溴硅烷(1.01g，6.63mmol)溶于乙腈10mL，冰水浴中搅拌20min。将中间体26(600mg，2.21mmol)溶于3mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入30mL乙酸乙酯，用饱和NaCl(30mL×2)洗，无水硫酸镁干燥，浓缩，Flash柱层析(45g柱，2-12％EA/PE)，得白色固体632mg，产率85.5％。
1H NMR(400MHz,CDCl3)δ(ppm):8.03(d,J＝1.6Hz,1H),7.73(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.15(dd,J1＝8.4Hz,J2＝6.0Hz,1H),7.00(d,J＝8.4Hz,1H),6.93–6.88(m,2H),5.62(t,J＝7.2Hz,1H),3.24(dd,J1＝14.4Hz,J2＝7.6Hz,1H),3.09(dd,J1＝14.4Hz,J2＝6.8Hz,1H),2.26(s,3H).
(4)3-(5-氟-2-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐(实施例8)的合成
将中间体27(350mg，1.05mmol)、(R)-3-吡咯烷醇(182.6mg，2.10mmol)、醋酸钯(24mg，0.105mmol)、Sphos(86mg，0.21mmol)和碳酸铯(684mg，2.1mmol)加入到100mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热10h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(30g柱，12-60％EA/PE)，得浅粉色油状物182mg，产率51.0％。加入6mL HCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得浅粉色固体165mg。
1H NMR(400MHz,MeOD)δ(ppm):7.36(d,J＝8.4Hz,1H),7.26(dd,J1＝8.4Hz,J2＝2.4Hz,1H),7.21(d,J＝2.4Hz,1H),7.12(dd,J1＝8.4Hz,J2＝6.0Hz,1H),6.89(dd,J1＝10.0Hz,J2＝2.8Hz,1H),6.83(td,J1＝8.8Hz,J2＝2.8Hz,1H),5.74(dd,J1＝7.2Hz,J2＝5.2Hz,1H),4.59(tt,J1＝4.8Hz,J2＝2.4Hz,1H),3.64(dd,J1＝10.8Hz,J2＝4.4Hz,1H),3.64–3.59(m,1H),3.57–3.51(m,1H),3.38(ddd,J1＝11.2Hz,J2＝3.6Hz,J2＝2.0Hz,1H),3.32–3.27(m,1H),3.09(dd,J1＝14.8Hz,J2＝7.6Hz,1H),2.29–2.20(m,1H),2.26(s,3H),2.13–2.06(m,1H)；HRMS(ESI):m/z,Calcd for C20H21O3NF[M+H]+:342.1500,Found342.1506.
实施例9：
6-((R)-3-羟基吡咯烷-1-基)-3-(3-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(3-氟-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体28)的合成
将中间体1(1.2g，4.183mmol)和2-甲基-3-氟苯甲醛(577mg，4.18mmol)溶于无水THF(15mL)中，缓慢滴加TEA(510mg，5.0mmol)的THF溶液(5mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体1.21g，产率96.8％。
(核磁显示Z/E＝0.6/0.4)
1H NMR(500MHz,CDCl3)δ(ppm):8.81(d,J＝2.0Hz,0.6H),8.76(d,J＝2.0Hz,0.4H),8.61(dd,J1＝8.5Hz,J2＝2.0Hz,0.6H),8.33(dd,J1＝9.0Hz,J2＝2.0Hz,0.4H),7.99(d,J＝8.5Hz,0.6H),7.96(d,J＝8.0Hz,0.6H),7.33(d,J＝9.0Hz,0.4H),7.30–7.27(m,1H),7.19(d,J＝8.0Hz,0.6H),7.16(d,J＝9.0Hz,0.4H),7.08(d,J＝8.0Hz,0.4H),7.06(s,0.4H),6.82(s,0.6H),2.41(s,1.8H),2.26(s,1.2H).
(2)6-氨基-3-(3-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体29)的合成
将中间体28(1.15g，3.8mmol)溶于三氟乙醇(20mL)，加入钯碳(240mg)，50℃催化氢化12h，原料消失。过滤，除去钯碳，滤液浓缩，正己烷洗，得白色固体1.04g，产率100％。
1H NMR(500MHz,DMSO-d6)δ(ppm):7.21(d,J＝8.5Hz,1H),7.14(dd,J1＝14.5Hz,J2＝7.5Hz,1H),7.04(d,J＝7.5Hz,1H),7.01(d,J＝8.0Hz,1H),6.93(d,J＝8.0Hz,1H),6.84(s,1H),5.66(dd,J1＝8.0Hz,J2＝4.5Hz,1H),5.59(brs,2H),3.32(dd,J1＝14.5Hz,J2＝4.5Hz,1H),2.98(dd,J1＝14.5Hz,J2＝8.0Hz,1H),2.18(s,3H).
(3)6-溴-3-((3-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体30)的合成
取亚硝酸钠(522mg，7.57mmol)、三乙基苄基氯化铵(115mg，0.50mmol)和三甲基溴硅烷(1.16g，7.57mmol)溶于乙腈10mL，冰水浴中搅拌20min。将中间体29(684mg，2.52mmol)溶于5mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入50mL乙酸乙酯，用饱和NaCl(50mL×3)洗，无水硫酸镁干燥，浓缩，Flash柱层析(45g柱，0-4％EA/PE)，得白色固体625mg，产率74.1％。
1H NMR(400MHz,CDCl3)δ(ppm):8.01(d,J＝1.6Hz,1H),7.71(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.11(dd,J1＝8.0Hz,J2＝5.6Hz,1H),6.98–6.94(m,3H),5.62(t,J＝6.8Hz,1H),3.31(dd,J1＝14.4Hz,J2＝7.2Hz,1H),3.12(dd,J1＝14.4Hz,J2＝6.8Hz,1H),2.23(s,3H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(3-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例9)的合成
将中间体30(350mg，1.05mmol)、(R)-3-吡咯烷醇(183mg，2.10mmol)、醋酸钯(24.7mg，0.11mmol)、Sphos(86mg，0.21mmol)和碳酸铯(684mg，2.18mmol)加入到100mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热10h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(30g柱，12-59％EA/PE)，得浅粉色油状物178mg，产率49.9％。加入10mLHCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得白色固体141mg。
1H NMR(500MHz,MeOD)δ(ppm):7.33(d,J＝8.5Hz,1H),7.21(dd,J1＝8.5Hz,J2＝2.5Hz,1H),7.14(d,J＝2.5Hz,1H),7.08(dd,J1＝13.5Hz,J2＝3.0Hz,1H),6.97(d,J＝7.5Hz,1H),6.92(t,J＝9.0Hz,1H),5.75(dd,J1＝7.0Hz,J2＝5.5Hz,1H),4.60(tt,J1＝4.5Hz,J2＝2.5Hz,1H),3.66–3.60(m,2H),3.54–3.51(m,1H),3.39–3.33(m,2H),3.19(dd,J1＝14.5Hz,J2＝7.0Hz,1H),2.28–2.22(m,1H),2.22(d,J＝2.5Hz,3H),2.13–2.09(m,1H)；HRMS(ESI):m/z,Calcd.for C20H21O3NF[M+H]+:342.1500,Found 342.1501.
实施例10：
3-(4-氟-2-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(4-氟-2-甲基苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体31)的合成
将中间体1(2.00g，10.4mmol)、2-甲基-4-氟苯甲醛(1.44g，10.4mmol)加入到无水THF(30mL)中，冰浴，恒压滴液漏斗缓慢滴加TEA(1.16g，11.4mmol)的无水THF(20mL)，Ar保护继续反应8h，反应完毕。旋干溶剂，加入冰水搅拌60min，析出黄色固体，过滤，水洗，干燥，得黄色固体2.49g，产率80％。(核磁显示Z/E＝0.6/0.4)
1H NMR(400MHz,CDCl3)δ(ppm):8.80(d,J＝2.0Hz,0.4H),8.76(d,J＝2.4Hz,0.6H),8.59(dd,J1＝8.4Hz,J2＝2.0Hz,0.4H),8.34(dd,J1＝8.8Hz,J2＝2.0Hz,0.6H),8.20(dd,J1＝8.8Hz,J2＝6.0Hz,0.4H),7.97(d,J＝8.8Hz,0.4H),7.36(dd,J1＝8.4Hz,J2＝5.6Hz,0.6H),7.33(d,J＝8.8Hz,0.6H),7.09–7.07(m,0.6H),7.03(s,0.6H),7.01–6.96(m,1.4H),6.78(s,0.4H),2.51(s,1.2H),2.34(s,1.8H).
(2)6-氨基-3-(3-氟-4-甲基苄基)异苯并呋喃-1(3H)-酮(中间体32)的合成
将中间体31(1.6g，5.35mmol)溶于DCM(20mL)与MeOH(20mL)的溶液中，加入钯碳(300mg)，室温催化氢化反应16h，原料消失。过滤，滤液浓缩，Flash柱层析(45g柱，6-100％EA/PE)，过滤，正己烷洗，得白色固体1.13g，收率78％。
1H NMR(500MHz,MeOD)δ(ppm):8.28(d,J＝5.0Hz,1H),7.94(s,1H),7.91(d,J＝8.0Hz,1H),7.60(d,J＝8.0Hz,1H),7.57(d,J＝8.5Hz,1H),7.17(dd,J1＝8.0Hz,J2＝5.0Hz,1H),5.86(dd,J1＝7.5Hz,J2＝4.5Hz,1H),3.51(dd,J1＝15.0Hz,J2＝4.5Hz,1H),3.16(dd,J1＝15.0Hz,J2＝7.5Hz,1H),2.57(s,3H).
(3)6-溴-3-(4-氟-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体33)的合成
取亚硝酸钠(1.50g，9.79mmol)、三乙基苄基氯化铵(149mg，0.65mmol)和三甲基溴硅烷(1.50g，9.79mmol)溶于乙腈50mL，冰浴下搅拌15min后将中间体32(885mg，3.26mmol)溶于20mL乙腈，滴入反应瓶中，继续冰浴搅拌12h。加入50mL水，EA萃取(30mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(30g柱，4-13％EA/PE)，得白色固体927mg，产率85％。
1H NMR(400MHz,MeOD)δ(ppm):7.94(d,J＝1.6Hz,1H),7.87(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.39(dt,J1＝8.0Hz,J2＝0.8Hz,1H),7.11(dd,J1＝8.8Hz,J2＝6.0Hz,1H),6.91(dt,J1＝9.6Hz,J2＝2.8Hz,1H),6.80(td,J1＝8.4Hz,J2＝2.8Hz,1H),5.79(ddd,J1＝7.6Hz,J2＝5.6Hz,J3＝0.8Hz,1H),3.34(dd,J1＝14.4Hz,J2＝5.2Hz,1H),3.17(dd,J1＝14.8Hz,J2＝7.2Hz,1H),2.33(s,3H).
(4)3-(4-氟-2-甲基苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮盐酸盐(实施例10)的合成
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将中间体33(150mg，0.45mmol)、(R)-3-吡咯烷醇(78mg，0.90mmol)、醋酸钯(10mg，0.045mmol)、Sphos(37mg，0.09mmo)和碳酸铯(293mg，0.90mmol)加入到50mL三颈瓶中，加入1,4-二氧六环8mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(20g柱，6-52％EA/PE)，得无色油状物106mg，产率69％。加入2mL HCl的EA溶液(1M)，搅拌1h，析出固体，过滤，无水乙醚洗，得白色固体95mg，产率90％。
1H NMR(400MHz,MeOD)δ(ppm):7.35(d,J＝8.4Hz,1H),7.26(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.21(s,1H),7.12(dd,J1＝8.4Hz,J2＝6.0Hz,1H),6.90(dd,J1＝10.0Hz,J2＝2.8Hz,1H),6.79(td,J1＝8.4Hz,J2＝2.8Hz,1H),5.74(t,J＝6.4Hz,1H),4.61(tt,J1＝4.8Hz,J2＝2.0Hz,1H),3.68–3.62(m,2H),3.55(td,J1＝8.8Hz,J2＝3.2Hz,1H),3.39(ddd,J1＝10.8Hz,J2＝3.2Hz,J3＝1.6Hz,1H),3.31–3.27(m,1H),3.13(dd,J1＝14.4Hz,J2＝6.8Hz,1H),2.32(s,3H),2.30–2.22(m,1H),2.15–2.09(m,1H)；HRMS(ESI):m/z,Calcd.forC20H21O3NF[M+H]+:342.1500,Found 342.1502.
实施例11：
6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)2-甲基-4-(三氟甲氧基)苯甲醛(中间体34)的合成
氩气保护下，将N,N,N'-三甲基乙二胺(8.00g，78.9mmol)溶于超干THF 100mL，0℃下加入32mL2.5M的正丁基锂的环己烷溶液，搅拌30min，冷却至-40℃，加入对三氟甲氧基苯甲醛(5.00g，26.3mmol)的超干THF溶液20mL，搅拌30min，加入32mL 2.5M的正丁基锂的环己烷溶液，搅拌3h，加入碘甲烷(30g，210mmol)的超干THF溶液20mL，升温至室温，搅拌1h，倾倒入1N盐酸中。DCM萃取(200mL×3)，柱层析P-P/A＝100/1-50/1，得浅无色油状物2.8g，产率52％。
(2)(Z)-3-(2-甲基-4-(三氟甲氧基)亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体35)的合成
将中间体1(6.77g，23.6mmol)溶于无水THF(60mL)中，加入中间体34(5.79g，28.4mmol)，冰浴下，滴入TEA(3.13g，31.0mmol)的无水THF(40mL)，Ar保护下冰浴搅拌30min，转移至室温反应8h，将反应液倾倒入冰水中，搅拌60min，析出固体，过滤，水洗，氯仿洗，无水乙醚洗，干燥，得黄色固体6.0g,产率70％。
1H NMR(400MHz,CDCl3)δ(ppm):8.80(d,J＝2.0Hz,1H),8.61(dd,J1＝8.8Hz,J2＝2.0Hz,1H),8.21(d,J＝8.8Hz,1H),7.98(d,J＝8.8Hz,1H),7.16(d,J＝8.8Hz,1H),7.11(s,1H),6.18(s,1H),2.52(s,3H).
(3)6-氨基-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体36)的合成
将中间体35(1.53g，4.2mmol)加入到EA(5mL)、MeOH(5mL)与THF(10mL)的混合溶液中，加入钯碳(300mg)，室温催化氢化8h，原料消失。过滤，滤液浓缩，柱层析(P/E＝3/1-2/1)，得白色固体940mg，产率77％。
(4)6-溴-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮(中间体37)的合成
取亚硝酸钠(553mg，8.01mmol)、三乙基苄基氯化铵(122mg，0.54mmol)和三甲基溴硅烷(1.23g，8.01mmol)溶于乙腈25mL，在冰水浴下搅拌30min后将中间体36(900mg，2.67mmol)溶于25mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入水100mL，EA萃取(50mL×3)洗，柱层析(PE-P/A＝100:1)，得白色固体740mg，产率69.2％。
1H NMR(400MHz,DMSO-d6)δ(ppm):8.01–7.99(m,2H),7.67(d,J＝8.8Hz,1H),7.34(d,J＝8.4Hz,1H),7.20(s,1H),7.14(d,J＝8.4Hz,1H),5.90(dd,J1＝8.4Hz,J2＝4.0Hz,1H),3.44(dd,J1＝14.8Hz,J2＝4.4Hz,1H),3.03(dd,J1＝14.8Hz,J2＝8.4Hz,1H),2.34(s,3H).
(5)6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-(三氟甲氧基)苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例11)的合成
将中间体37(50mg，0.13mmol)、(R)-3-吡咯烷醇(22mg，0.25mmol)、醋酸钯(2.8mg，0.013mmol)、Sphos(10mg，0.025mmol)和碳酸铯(81mg，0.25mmol)加入到50mL三颈瓶中，加入1,4-二氧六环3mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液Flash柱层析(20g柱，12-65％EA/PE)，得无色油状物39mg。加入2mL HCl的EA溶液(1M)，搅拌1h，析出固体，过滤，无水乙醚洗，得浅粉色固体26mg，产率47％。
1H NMR(400MHz,MeOD)δ(ppm):7.38(d,J＝8.4Hz,1H),7.26–7.23(m,1H),7.24(d,J＝8.4Hz,1H),7.17(d,J＝2.4Hz,1H),7.07(s,1H),6.98(d,J＝8.0Hz,1H),5.76(dd,J1＝7.2Hz,J2＝5.2Hz,1H),4.60(tt,J1＝4.8Hz,J2＝2.0Hz,1H),3.65(dd,J1＝10.8Hz,J2＝4.4Hz,1H),3.62(dd,J1＝9.6Hz,J2＝7.2Hz,1H),3.54(td,J1＝8.8Hz,J2＝3.2Hz,1H),3.39–3.37(m,1H),3.36(dd,J1＝14.4Hz,J2＝5.2Hz,1H),3.13(dd,J1＝14.4Hz,J2＝7.2Hz,1H),2.36(s,3H),2.30–2.21(m,1H),2.14–2.09(m,1H),HRMS(ESI):m/z,Calcd.forC21H20O4NF3Na[M+H]+:430.1250,Found 430.1250.
实施例12：
6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-甲氧基苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(4-甲氧基-2-甲基亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体38)的合成
Ar保护下，将中间体1(5g，17.4mmol)、2-甲基-4-甲氧基苯甲醛(2.60g，17.4mmol)加入到无水THF(50mL)中，冰浴，向上述溶液中滴加TEA(1.94g，19.1mmol)的无水THF(20mL)溶液，继续搅拌6h，浓缩，加入冰水60mL，搅拌60min，析出黄色固体，过滤，水洗，干燥，得桔红色固体5.3g，产率98％。(核磁显示Z/E＝0.6/0.4)
1H NMR(400MHz,CDCl3)δ(ppm):8.78(d,J＝2.0Hz,0.4H),8.75(d,J＝2.4Hz,0.6H),8.56(dd,J1＝8.8Hz,J2＝2.0Hz,0.4H),8.32(dd,J1＝8.8Hz,J2＝2.4Hz,0.6H),8.23(d,J＝8.8Hz,0.4H),7.93(d,J＝8.8Hz,0.4H),7.47(d,J＝8.8Hz,0.6H),7.32(d,J＝8.4Hz,0.6H),7.07(s,0.6H),6.89(d,J＝2.4Hz,0.6H),6.86(dd,J1＝8.8Hz,J2＝2.4Hz,0.4H),6.82(dd,J1＝8.0Hz,J2＝2.4Hz,0.6H),6.81(s,0.4H),6.79(d,J＝2.8Hz,0.4H),3.88(s,1.8H),3.86(s,1.2H),2.50(s,1.2H),2.32(s,1.8H).
(2)6-氨基-3-(4-甲氧基-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体39)的合成
将中间体38(5.3g，17.0mmol)溶于MeOH(60mL)和DCM(80mL)的溶液中，加入钯碳(1g)，室温催化氢化反应24h，原料消失。过滤，滤液浓缩，柱层析(0-5％EA/DCM)，过滤，正己烷洗，得白色固体2.10g，产率44％。
1H NMR(400MHz,CDCl3)δ7.08–7.06(m,2H),6.86(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.80(d,J＝4.0Hz,1H),6.73(d,J＝2.4Hz,1H),6.69(dd,J1＝8.0Hz,J2＝2.8Hz,1H),5.52(t,J＝6.8Hz,1H),3.80(s,3H),3.20(dd,J1＝14.4Hz,J2＝6.8Hz,1H),2.97(dd,J1＝14.4Hz,J2＝7.2Hz,1H),2.27(s,3H).
(3)6-溴-3-(4-甲氧基-2-甲基苄基)异苯并呋喃-1(3H)-酮(中间体40)的合成
取亚硝酸钠(919mg，13.3mmol)、三乙基苄基氯化铵(2.04g，13.3mmol)和三甲基溴硅烷(2.04g，13.3mmol)溶于乙腈30mL，冰浴下搅拌15min，将中间体39(1.26g，4.44mmol)溶于20mL乙腈，滴入反应瓶中，继续冰水浴搅拌18h。加入40mL水，EA萃取(40mL×3)，无水硫酸镁干燥，浓缩，柱层析(4-10％EA/PE)，得类白色固体1.11g，产率72％。
1H NMR(400MHz,CDCl3)δ(ppm):8.00(s,1H),7.67(dd,J1＝8.4Hz,J2＝1.6Hz,1H),7.02(d,J＝8.4Hz,1H),6.89(d,J＝8.0Hz,1H),6.75(t,J＝2.8Hz,1H),6.70(dd,J1＝8.4Hz,J2＝2.8Hz,1H),5.58(t,J＝7.2Hz,1H),3.80(s,3H),3.29(dd,J1＝14.0Hz,J2＝6.4Hz,1H),3.00(dd,J1＝14.4Hz,J2＝7.6Hz,1H),2.27(s,3H).
(4)6-((R)-3-氨基吡咯烷-1-基)-3-(2-甲基-4-甲氧基苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例12)的合成
将中间体40(150mg，0.43mmol)、(R)-3-吡咯烷醇(75.5mg，0.87mmol)、醋酸钯(9.7mg，0.043mmol)、Sphos(35.3mg，0.086mmol)和碳酸铯(280mg，0.86mmol))加入到50mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。滤液浓缩，Flash柱层析(30g柱，12-58％EA/PE)，得无色油状物102mg。加入6mLHCl的EA溶液(1M)，搅拌1h，析出固体，过滤，无水乙醚洗，得浅粉色固体102mg，两步产率61％。
1H NMR(400MHz,MeOD)δ(ppm):7.23(d,J＝8.4Hz,1H),7.20(dd,J1＝8.4Hz,J2＝2.0Hz,1H),7.16(s,1H),7.01(d,J＝8.4Hz,1H),6.72(d,J＝2.8Hz,1H),6.64(dd,J1＝8.4Hz,J2＝2.8Hz,1H),5.70(t,J＝6.4Hz,1H),4.57(tt,J1＝4.8Hz,J2＝2.0Hz,1H),3.74(s,3H),3.66–3.59(m,2H),3.53(td,J1＝9.2Hz,J2＝3.2Hz,1H),3.38(dd,J1＝10.8Hz,J2＝2.0Hz,1H),3.18(dd,J1＝14.4Hz,J2＝6.0Hz,1H),3.10(dd,J1＝14.4Hz,J2＝6.4Hz,1H),2.32–2.21(m,1H),2.24(s,3H),2.14–2.08(m,1H)；HRMS(ESI):m/z,Calcd.for C21H23O4NNa[M+Na]+:376.1519,Found 376.1534.
实施例13：
6-((R)-3-羟基吡咯烷-1-基)-3-(2,5-二氟苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z/E)-3-(2,5-二氟亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体41)的合成
将中间体1(1.3g，4.53mmol)和2,5-二氟苯甲醛(710mg，4.98mmol)溶于无水THF(15mL)中，缓慢滴加TEA(550mg，5.44mmol)的THF溶液(5mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体1.33g，产率97.0％。
(核磁显示Z/E＝0.8/0.2)
1H NMR(500MHz,CDCl3)δ(ppm):8.82(d,J＝2.0Hz,0.8H),8.78(s,0.2H),8.62(dd,J1＝9.0Hz,J2＝2.5Hz,0.8H),8.45(dd,J1＝9.0Hz,J2＝1.0Hz,0.2H),8.06–8.03(m,0.8H),8.00(d,J＝9.0Hz,0.8H),7.60(d,J＝8.5Hz,0.2H),7.23–7.18(m,0.6H),7.13–7.04(m,1.6H),6.91(s,0.2H),6.87(s,0.8H).
(2)6-氨基-3-(2,5-二氟苄基)异苯并呋喃-1(3H)-酮(中间体42)的合成
将中间体41(1.2g，3.96mmol)溶于三氟乙醇(10mL)，加入钯碳(240mg)，50℃催化氢化12h，原料消失。过滤，除去钯碳，滤液浓缩，正己烷洗，得白色固体1.06g，产率97.2％。
1H NMR(400MHz,MeOD)δ(ppm):7.20(d,J＝8.0Hz,1H),7.05–6.93(m,5H),5.69(dd,J1＝6.8Hz,J2＝4.8Hz,1H),3.33(dd,J1＝14.4Hz,J2＝4.8Hz,1H),3.11(dd,J1＝14.4Hz,J2＝6.8Hz,1H)。
(3)6-溴-3-(2,5-二氟苄基)异苯并呋喃-1(3H)-酮(中间体43)的合成
取亚硝酸钠(451mg，6.54mmol)、三乙基苄基氯化铵(100mg，0.44mmol)和三甲基溴硅烷(1.0g，6.54mmol)溶于乙腈10mL，冰水浴中搅拌20min。将中间体42(600mg，2.18mmol)溶于5mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入50mL乙酸乙酯，用饱和NaCl(50mL×3)洗，无水硫酸镁干燥，浓缩，Flash柱层析(30g柱，3-6％EA/PE)，得白色固体660mg，产率89.6％。
1H NMR(400MHz,CDCl3)δ(ppm):7.99(d,J＝2.0Hz,1H),7.76(dd,J1＝8.0Hz,J2＝1.6Hz,1H),7.20(dd,J1＝8.0Hz,J2＝0.8Hz,1H),7.02–6.91(m,3H),5.67(dd,J1＝7.2Hz,J2＝5.2Hz,1H),3.26(ddd,J1＝14.0Hz,J2＝5.2Hz,J3＝1.2Hz,1H),3.18(ddd,J1＝14.4Hz,J2＝7.2Hz,J3＝1.2Hz,1H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(2,5-二氟苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例13)的合成
将中间体43(350mg，1.04mmol)、(R)-3-吡咯烷醇(180mg，2.07mmol)、醋酸钯(23.3mg，0.104mmol)、Xphos(100mg，0.218mmol)和碳酸铯(678mg，2.08mmol)加入到100mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热10h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(30g柱，12-43％EA/PE)，得浅粉色油状物158mg，产率44.3％。加入10mL HCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得白色固体137mg。
1H NMR(500MHz,MeOD)δ(ppm):7.44(d,J＝8.5Hz,1H),7.24(dd,J1＝8.5Hz,J2＝2.5Hz,1H),7.14(s,1H),7.05–7.00(m,2H),6.99–6.94(m,1H),5.79(t,J＝5.5Hz,1H),4.61–4.59(m,1H),3.66–3.60(m,2H),3.53(t,J＝9.0Hz,1H),3.39–3.36(m,2H),3.19(dd,J1＝14.5Hz,J2＝7.0Hz,1H),2.29–2.22(m,1H),2.13–2.09(m,1H)；HRMS(ESI):m/z,Calcd.for C19H18O3NF2[M+H]+:346.1249,Found 346.1263.
实施例14：
6-((R)-3-羟基吡咯烷-1-基)-3-(3,5-二氟苄基)异苯并呋喃-1(3H)-酮盐酸盐的合成
(1)(Z)-3-(3,5-二氟亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体44)的合成
将中间体1(1.62g，5.63mmol)和3,5-二氟苯甲醛(800mg，5.63mmol)加入到无水THF(16mL)中，冰浴，缓慢滴加TEA(684mg，6.76mmol)的无水THF溶液(4mL)，Ar保护下室温反应5h。将反应液倾倒入冰水中，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体1.61g，产率94.0％。
1H NMR(500MHz,CDCl3)δ(ppm):8.81(s,1H),8.62(d,J＝8.5Hz,1H),7.95(d,J＝8.5Hz,1H),7.41(d,J＝7.0Hz,2H),6.85(t,J＝8.5Hz,1H),6.53(s,1H).
(2)6-氨基-3-(3,5-二氟苄基)异苯并呋喃-1(3H)-酮(中间体45)的合成
将中间体44(1.51g，4.98mmol)溶于三氟乙醇(20mL)中，加入钯碳(300mg)，40℃催化氢化1天，原料消失。过滤，除去钯碳，滤液浓缩，正己烷洗，得白色固体1.19g，产率86.9％。
1H NMR(400MHz,CDCl3)δ(ppm):7.06(d,J＝2.0Hz,1H),7.03(d,J＝8.0Hz,1H),6.93(dd,J1＝8.0Hz,J2＝2.0Hz,1H),6.78–6.73(m,2H),6.69(tt,J1＝8.8Hz,J2＝2.4Hz,1H),5.56(dd,J1＝7.2Hz,J2＝5.6Hz,1H),3.95(brs,2H),3.16(dd,J1＝14.4Hz,J2＝5.2Hz,1H),3.10(dd,J1＝14.4Hz,J2＝6.8Hz,1H).
(3)6-溴-3-(3,5-二氟苄基)异苯并呋喃-1(3H)-酮(中间体46)的合成
取亚硝酸钠(526mg，7.63mmol)、三乙基苄基氯化铵(116mg，0.51mmol)和三甲基溴硅烷(1.17g，7.63mmol)溶于乙腈16mL，冰水浴中搅拌30min。将中间体45(700mg，2.54mmol)溶于8mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌12h。加入60mL乙酸乙酯，用饱和NaCl(60mL×2)洗，无水硫酸镁干燥，浓缩，Flash柱层析(30g柱，2-8％EA/PE)，得白色固体550mg，产率64.2％。
1H NMR(400MHz,CDCl3)δ(ppm):8.00(d,J＝2.0Hz,1H),7.77(dd,J1＝8.0Hz,J2＝2.0Hz,1H),7.17(d,J＝8.4Hz,1H),6.78–6.73(m,2H),6.72(tt,J1＝8.8Hz,J2＝2.4Hz,1H),5.63(t,J＝6.4Hz,1H),3.21(dd,J1＝14.4Hz,J2＝5.6Hz,1H),3.16(dd,J1＝14.4Hz,J2＝6.8Hz,1H).
(4)6-((R)-3-羟基吡咯烷-1-基)-3-(3,5-二氟苄基)异苯并呋喃-1(3H)-酮盐酸盐(实施例14)的合成
将中间体46(300mg，0.89mmol)、(R)-3-吡咯烷醇(155mg，1.78mmol)、醋酸钯(20mg，0.089mmol)、Sphos(74mg，0.18mmol)和碳酸铯(600mg，1.8mmol)加入到100mL三颈瓶中，加入1,4-二氧六环5mL，氩气保护，90℃加热10h。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(30g柱，12-52％EA/PE)，得浅粉色油状物178mg，产率58.2％。加入5mL HCl的4M 1,4-二氧六环溶液，室温搅拌2h，析出固体，过滤，无水乙醚洗，干燥，得类浅粉色固体113mg。
1H NMR(500MHz,MeOD)δ(ppm):7.46(d,J＝8.5Hz,1H),7.22(dd,J1＝8.5Hz,J2＝2.5Hz,1H),7.10(d,J＝2.5Hz,1H),6.82(dd,J1＝8.5Hz,J2＝2.0Hz,2H),6.77(tt,J1＝9.0Hz,J2＝2.5Hz,1H),5.77(dd,J1＝6.5Hz,J2＝4.5Hz,1H),4.59(tt,J1＝5.0Hz,J2＝2.5Hz,1H),3.64–3.58(m,2H),3.51(t,J＝8.5Hz,1H),3.40(dd,J1＝14.5Hz,J2＝4.5Hz,1H),3.36(dd,J1＝10.0Hz,J2＝2.5Hz,1H),3.13(dd,J1＝14.5Hz,J2＝6.5Hz,1H),2.28–2.21(m,1H),2.12–2.08(m,1H)；HRMS(ESI):m/z,Calcd.for C19H18O3NF2[M+H]+:346.1249,Found 346.1265.
实施例15：
3-(3,4-二氟苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮的合成
(1)(Z)-3-(3,4-二氟亚苄基)-6-硝基异苯并呋喃-1(3H)-酮(中间体47)的合成
将中间体1(6.00g，20.9mmol)、3,4-二氟苯甲醛(2.97g，20.9mmol)加入到无水THF(60mL)中，冰浴，滴加TEA(2.33g，23.0mmol)的无水THF(20mL)，Ar保护继续反应8h，反应完毕，旋除溶剂，加入冰水，搅拌20min，析出黄色固体，过滤，水洗，干燥，得黄色固体6.0g，产率95％。
1H NMR(400MHz,CDCl3)δ(ppm):8.81(d,J＝2.0Hz,1H),8.60(dd,J1＝8.8Hz,J2＝2.0Hz,1H),7.93(d,J＝8.4Hz,1H),7.80(ddd,J1＝11.2Hz,J2＝7.6Hz,J3＝2.0Hz,1H),7.59–7.55(m,1H),7.27–7.21(m,1H),6.54(s,1H).
(2)6-氨基-3-(3,4-二氟苄基)异苯并呋喃-1(3H)-酮(中间体48)的合成
将中间体47(5.9g，19.5mmol)溶于THF(70mL)与MeOH(70mL)的溶液中，加入钯碳(1.2g)，室温催化氢化反应6h，原料消失。过滤，滤液浓缩，Flash柱层析(40g柱，50％EA/PE)，过滤，正己烷洗，得白色固体2.68g，产率50％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.36–7.25(m,2H),7.22(d,J＝8.4Hz,1H),7.06–7.02(m,1H),6.93(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.81(d,J＝2.0Hz,1H),5.69(dd,J1＝7.2Hz,J2＝4.4Hz,1H),5.55(brs,2H),3.29(dd,J1＝14.0Hz,J2＝4.4Hz,1H),2.98(dd,J1＝14.0Hz,J2＝7.2Hz,1H).
(3)6-溴-3-(3,4-二氟苄基)异苯并呋喃-1(3H)-酮(中间体49)的合成
取亚硝酸钠(1.94g，28.1mmol)、三乙基苄基氯化铵(428mg，1.88mmol)和三甲基溴硅烷(4.3g，28.1mmol)溶于乙腈100mL，在冰浴下搅拌15min后将中间体48(2.58g，9.38mmol)溶于20mL乙腈，在冰浴下滴加入反应瓶中，继续冰水浴搅拌8h。加入80mL水，EA萃取(40mL×3)，无水硫酸镁干燥，浓缩，Flash柱层析(40g柱，10-25％EA/PE)，得白色固体1.21g，产率38％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.99–7.96(m,2H),7.62(dt,J1＝8.0Hz,J2＝0.8Hz,1H),7.37–7.28(m,2H),7.07–7.03(m,1H),5.90(dd,J1＝7.2Hz,J2＝4.8Hz,1H),3.42(dd,J1＝14.4Hz,J2＝4.4Hz,1H),3.10(dd,J1＝14.4Hz,J2＝7.2Hz,1H).
(4)3-(3,4-二氟苄基)-6-((R)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮(实施例15)的合成
将中间体49(400mg，1.18mmol)、(R)-3-吡咯烷醇(206mg，2.37mmol)、醋酸钯(27mg，0.12mmol)、Sphos(96mg，0.24mmol)和碳酸铯(769mg，2.36mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(20g柱，15-50％EA/PE，39％出峰)，得白色固体202mg，产率50％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.36(d,J＝8.4Hz,1H),7.36–7.27(m,2H),7.06–7.03(m,1H),6.92(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.67(d,J＝2.0Hz,1H),5.75(dd,J1＝7.2Hz,J2＝4.8Hz,1H),4.97(brs,1H),4.42–4.39(m,1H),3.44(dd,J1＝10.0Hz,J2＝4.8Hz,1H),3.39–3.28(m,3H),3.09(d,J＝10.8Hz,1H),3.02(dd,J1＝14.4Hz,J2＝7.2Hz,1H),2.08–1.99(m,1H),1.94–1.87(m,1H)；HRMS(ESI):m/z,Calcd.for C19H18O3NF2[M+H]+:346.1249,Found 346.1265.
实施例16和实施例17:
将实施例15用IG手性半制备柱(10mm I.D.×250mmL)进行手性拆分：
拆分条件：50％异丙醇–正己烷，流速：3mL/min；
得到两个差向异构体，分别记为实施例16、实施例17：
实施例16：Rf1＝20.68min；实施例17：Rf2＝26.41min；
实施例16：白色固体
1H NMR(400MHz,MeOD)δ(ppm):7.33(dt,J1＝8.4Hz,J2＝0.8Hz,1H),7.12–7.05(m,2H),6.96(dd,J1＝8.4Hz,J2＝2.0Hz,1H),6.96–6.94(m,1H),6.78(d,J＝2.4Hz,1H),5.70(dd,J1＝6.0Hz,J2＝5.2Hz,1H),4.54(tt,J1＝4.4Hz,J2＝2.8Hz,1H),3.52(dd,J1＝10.8Hz,J2＝4.8Hz,1H),3.48(td,J1＝9.2Hz,J2＝7.2Hz,1H),3.39–3.34(m,2H),3.23(dt,J1＝10.4Hz,J2＝2.0Hz,1H),3.09(dd,J1＝14.4Hz,J2＝6.4Hz,1H),2.21–2.13(m,1H),2.08–2.01(m,1H)；HRMS(ESI):m/z,Calcd.for C19H18O3NF2[M+H]+:346.1249,Found 346.1265.
实施例17：白色固体
1H NMR(400MHz,MeOD)δ(ppm):7.33(d,J＝8.4Hz,1H),7.12–7.05(m,2H),6.97–6.94(m,2H),6.78(d,J＝2.4Hz,1H),5.70(t,J＝5.6Hz,1H),4.54(tt,J1＝4.8Hz,J2＝2.4Hz,1H),3.52(dd,J1＝10.4Hz,J2＝4.8Hz,1H),3.49–3.45(m,1H),3.40–3.34(m,2H),3.23(dt,J1＝10.4Hz,J2＝1.6Hz,1H),3.09(dd,J1＝14.4Hz,J2＝6.4Hz,1H),2.22–2.13(m,1H),2.08–2.02(m,1H)；HRMS(ESI):m/z,Calcd.for C19H18O3NF2[M+H]+:346.1249,Found346.1265.
实施例18：
3-(3,4-二氟苄基)-6-((S)-3-羟基吡咯烷-1-基)异苯并呋喃-1(3H)-酮的合成
将中间体47(400mg，1.18mmol)、(S)-3-吡咯烷醇(206mg，2.37mmol)、醋酸钯(27mg，0.12mmol)、Sphos(96mg，0.24mmol)和碳酸铯(769mg，2.36mmol)加入到50mL三颈瓶中，加入1,4-二氧六环15mL，氩气保护，90℃加热11h，原料消失。硅藻土助滤，滤掉不溶物，EA洗。Flash柱层析(20g柱，25-50％EA/PE，37％出峰)，得白色固体220mg，产率54％。
1H NMR(400MHz,DMSO-d6)δ(ppm):7.36(d,J＝8.4Hz,1H),7.36–7.27(m,2H),7.06–7.03(m,1H),6.92(dd,J1＝8.4Hz,J2＝2.4Hz,1H),6.67(d,J＝2.0Hz,1H),5.75(dd,J1＝7.2Hz,J2＝4.8Hz,1H),4.97(brs,1H),4.42–4.39(m,1H),3.44(dd,J1＝10.0Hz,J2＝4.8Hz,1H),3.39–3.28(m,3H),3.09(d,J＝10.8Hz,1H),3.02(dd,J1＝14.4Hz,J2＝7.2Hz,1H),2.08–1.99(m,1H),1.94–1.87(m,1H)；HRMS(ESI):m/z,Calcd.for346.1249,Found 346.1249.
实施例19：
3-(3,4-二氟苄基)-6-((R)-3-甲氧基吡咯烷-1-基)异苯并呋喃-1(3H)-酮的合成
将中间体47(160mg，0.47mmol)、(R)-3-甲氧基吡咯烷(98mg，0.71mmol)、醋酸钯(11mg，0.047mmol)、Xantphos(54mg，0.094mmol)和碳酸铯(460mg，1.41mmol)加入到25mL圆底烧瓶中，加入甲苯3mL，氩气保护，加热回流11h。过滤，硅藻土助滤，滤掉不溶物，DCM洗。滤液浓缩，Flash柱层析(30g柱，6-31％EA/PE)，过滤，正己烷洗，得类白色固体120mg，产率56.6％。
1H NMR(500MHz,DMSO-d6)δ(ppm):7.37(dd,J1＝8.5Hz,J2＝2.0Hz,1H),7.35–7.28(m,2H),7.06–7.03(m,1H),6.95(dd,J1＝8.5Hz,J2＝2.5Hz,1H),6.71(s,1H),5.75(dd,J1＝7.5Hz,J2＝4.5Hz,1H),4.10–4.08(m,1H),3.45(dd,J1＝11.0Hz,J2＝5.0Hz,1H),3.35–3.28(m,4H),3.27(s,3H),3.03(dd,J1＝14.5Hz,J2＝7.0Hz,1H),2.09–2.06(m,2H)；HRMS(ESI):m/z,Calcd.for C20H20O3NF2[M+H]+:360.1405,Found 360.1393.
药理实验：
1.化合物对MAO-B的抑制活性
1.1实验动物
健康SD(Sprague-Dawley)大鼠，♂，体重(250±10)g，购自斯贝福(北京)生物技术有限公司。
1.2试剂
二甲基亚砜(dimethyl sulfoxide，DMSO)，批号：WXBC7821V，购自Sigma；AmplexTMRed，批号：2140272，购自Ivitrogen；HRP(Peroxidase from horseradish)，批号：SLCG9756，购自Sigma；苄胺盐酸盐(Benzylamine hydrochloride)，批号：BCBV5878，购自Sigma；RIPA组织裂解缓冲液，BCA试剂盒，均购自北京普利莱基因技术有限公司。
1.3耗材与仪器
96孔全黑色荧光酶标板，Thermo；多功能酶标仪，PerkinElmer；电热恒温培养箱，上海一恒科学仪器有限公司；高速组织研磨仪，康涛科技公司；离心机，Eppendorf。
1.4实验方法：
1.4.1 MAO-B的提取
取SD大鼠肝组织适量，称重，按照1mg：10ml加入RIPA组织裂解缓冲液和研磨珠，在研磨仪(频率60Hz，时间60s)中充分裂解，冰浴静置30min。离心30min，4℃，rpm＝12000g。取上清液利用BCA法进行蛋白定量。-80℃冰箱冻存。
1.4.2实验分组
阴性对照组：96孔全黑色荧光酶标板中每孔加入100μL的浓度为200μg/mL的肝组织液以及2μL DMSO；
阳性对照组：在阳性药反应孔中，每孔加入100μL肝组织液以及2μL10-3Mol阳性药液；
空白对照组：每孔加入100μL 1X反应缓冲液以及2μL DMSO；
药物筛选组：每孔加入100μL肝组织液以及2μL不同浓度的待测化合物
1.4.3工作液配制
AmplexTM Red储备液：将1mg AmplexTM Red试剂溶解在200μLDMSO中，-20℃冰箱避光冻存。
HRP储备液：将5KU HRP试剂溶解在25mL 1X反应缓冲液中制备200U/mL的HRP储备液。-20℃冰箱冻存。
苄胺盐酸盐储备液：称取苄胺盐酸盐17.2mg溶解在1.2mL纯水中制备100mM储备溶液。-20℃冰箱冻存。
工作液：取200μL AmplexTM Red储备液，100μL HRP储备液，200μL苄胺盐酸盐储备液，加入9.5mL 1X反应缓冲液，混匀，制备10mL工作液。
1.4.4 Amplex Red荧光法检测MAO-B活性
具体的实验流程
加入各组的相应试剂，于37℃的恒温箱中避光预孵育30min。避光条件下每孔加入100μL工作液后于37℃的恒温箱中避光孵育30min。使用荧光酶标仪，并将有关参数设置为560±10nm的激发光和590±10nm的发射光条件，检测每孔荧光值。
1.4.5统计分析
化合物抑制率的计算：
阴性对照组：(阴性对照组平均值)-(阳性对照组平均值)/(阴性对照组平均值-空白对照组平均值)×100％
药物筛选组：(阴性对照组平均值)-(药物筛选组平均值)/(阴性对照组平均值-空白对照组平均值)×100％
为了计算化合物抑制MAO-B的IC50，每个化合物选取至少7-8个浓度，每个浓度至少n＝3，采用GraphPad Prism 8拟合出IC50。
实验结果见表1
表1.化合物抑制MAO-B的IC50
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Claims (10)
1.如通式I所示化合物及其药用盐，
在式I中，
R1、R2和R3独立地选自如下原子或基团或结构片断，包括：
H、F、Cl、Br、CN、甲基、乙基、三氟甲基、三氟乙基、CHF2、CONH2、OH、OCH3、OC2H5、亚甲二氧基、NH2、NHCH3、N(CH3)2、NHCOCH3；
R4选自如下结构片断：
选自取代或非取代的苯基、取代或非取代的含氮六元芳杂环、取代或非取代的五元芳杂环，其中取代基选自H、F、Cl、Br、CN、NO2、甲基、乙基、三氟甲基、三氟乙基、三氟甲氧基、CHF2、OH、OCH3、OC2H5、亚甲二氧基；所述的苯环、含氮六元芳杂环、五元芳杂环上可以是单取代，也可以是多取代；六元芳杂环可以含有1个氮原子，也可以含有多个氮原子；五元芳杂环可以含有一个杂原子，也可以含有多个杂原子，杂原子选自O,N,S。
2.一类化合物及其药用盐，其特征在于，所述的化合物选自：
3.根据权利要求1中的化合物及其药用盐，其特征在于，所述化合物的药用盐选自与无机酸、有机酸形成的盐。
4.根据权利要求3的化合物及其药用盐，其特征在于，所述的无机酸选自盐酸、氢溴酸、磷酸或硫酸；所述的有机酸选自甲磺酸、对甲苯磺酸、三氟乙酸、马来酸、酒石酸、富马酸、柠檬酸或乳酸。
5.制备权利要求1-4任一项化合物的方法，其特征在于，包括如下步骤：
异苯并呋喃-1(3H)-酮类化合物(通式I所示)的合成是以3-氧代-1,3-二氢异苯并呋喃-1-膦酸二甲酯I为起始原料，通过硝化反应，在异苯并呋喃-1(3H)-酮6-位引入硝基，得到中间体II；II与包含R4取代基的芳醛发生Wittig-Horner反应，得到中间体III；然后利用催化氢化将硝基和碳碳双键还原，制备化合物IV；通过Sandermayer反应引入卤素，制备关键中间体V；从关键中间体V出发，与(R)-3-吡咯烷醇进行偶联反应，得到目标化合物；
试剂及反应条件：(a)硝酸钾，浓硫酸，0℃；(b)取代的醛，三乙胺，四氢呋喃，0℃，氩气；(c)钯碳，氢气，甲醇或三氟乙醇，室温；(d)三甲基溴硅烷，亚硝酸钠，三乙基苄基氯化铵，乙腈，0℃；(e)醋酸钯，(R)-3-吡咯烷醇，Xphos或Sphos，碳酸铯，1,4-二氧六环，90-100℃，氩气
其中所述的R1、R2、R3和R4的定义如权利要求1-4任一项所述。
6.一种药物组合物，其特征在于，包括有效剂量的权利要求1-4中任一项的化合物及其药用盐和药效学上可接受的载体。
7.权利要求1-4中任一项的化合物及其药用盐在制备MAO-B抑制剂中的应用。
8.权利要求1-4中任一项的化合物及其药用盐在制备预防和\或治疗与MAO-B有关的疾病的药物中的应用。
9.根据权利要求8的应用，其特征在于，与MAO-B有关的疾病选自精神神经系统疾病。
10.根据根据权利要求9的应用，其特征在于，所述的精神神经系统疾病包括帕金森病、老年痴呆、抑郁、焦虑病。
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