CN108530241B - 一种具有苄位季碳中心的苯并环衍生物的制备方法 - Google Patents

一种具有苄位季碳中心的苯并环衍生物的制备方法 Download PDF

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CN108530241B
CN108530241B CN201810299022.0A CN201810299022A CN108530241B CN 108530241 B CN108530241 B CN 108530241B CN 201810299022 A CN201810299022 A CN 201810299022A CN 108530241 B CN108530241 B CN 108530241B
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alkyl halide
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CN108530241A (zh
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周强辉
刘泽水
钱光印
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Wuhan University WHU
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Abstract

本发明提供了一种具有苄位季碳中心的苯并环衍生物及氢溴酸依他佐辛的制备方法。以芳基碘化物和烷基化试剂为起始原料，在钯催化剂、膦配体、降冰片烯衍生物、碱的作用下，在30℃到120℃下于有机溶剂中搅拌反应，即可得具有苄位季碳中心的苯并环衍生物。该方法所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。同时，本发明还提供了一种合成氢溴酸依他佐辛化合物的方法，在本发明合成的具有苄位全碳季碳中心的1,2,3,4‑四氢化萘化合物的基础上只需要四步就可以合成具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛，该方法合成步骤短，操作简单，总产率高。

Description

一种具有苄位季碳中心的苯并环衍生物的制备方法
技术领域
本发明涉及一种具有苄位季碳中心的苯并环衍生物以及一种具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛的制备方法，属于有机合成和药物化学领域。
背景技术
具有苄位季碳中心的1,2,3,4-四氢化萘或1,2-二氢化茚结构骨架是一类重要的结构单元，广泛存在于具有生物活性的天然产物和医药试剂中([1]D.M.Roll,P.J.Scheuer,J.Am.Chem.Soc.1983,105,6177.[2]P.W.Brian,J.C.McGowan,Nature 1945,156,144；[3]J.MacMillan,A.E.Vanstone,S.K.Yeboah,Chem.Commun.1968,613；c)J.R.Hanson,Nat.Prod.Rep.1995,12,381.[4]C.A.L.Bercht,J.P.C.M.Van Dongen,W.Heerma,R.J.J.C.Lousberg,F.J.E.M.Küppers,Tetrahedron 1976,32,2939.[5]L.Garrido,E.ZubHa,M.J.Ortega,J.Salva,J.Org.Chem.2003,68,293.[6]S.Shiotani,T.Kometani,K.Mitsuhashi,T.Nozawa,A.Kurobe,O.Futsukaichi,J.Med.Chem.1976,19,803.[7]P.W.Smethurst,W.H.Forrest,J.Hayden,Br.J.Anaesth.1971,43,1129.)。例如，具有1,2,3,4-四氢化萘结构的镇痛药物氢溴酸依他佐辛。目前，合成1,2,3,4-四氢化萘和1,2-二氢化茚化合物的方法主要有：(1)芳香化合物分子内的付克烷基化反应([1]D.Basavaiah,M.Bakthadoss,G.J.Reddy,Synthesis 2001,919；[2]Kurteva,V.B.；Santos,A.G.；Afonso,C.A.M.Org.Biomol.Chem.2004,2,514.)；(2)过渡金属如铑催化的环加成反应(K.Tanaka,Y.Sawada,Y.Aida,M.Thammathevo,R.Tanaka,H.Sagae,Y.Otake,Tetrahedron 2010,66,1563)；(3)过渡金属如金催化的环异构化反应([1]C.M.Grisé,Louis Barriault,Org.Lett.2006,8,905；[2]C.M.Grisé,Eric M.Rodrigue,LouisBarriault,Tetrahedron2008,64,797)；(4)分子内的Heck反应([1]T.Takemoto,M.Sodeoka,H.Sasai,M.Shibasaki,J.Am.Chem.Soc.1993,115,8477；[2]G.Hirai,Y.Koizumi,S.M.Moharram,H.Oguri,M.Hirama,Org.Lett.2002,4,1627；[3]S.Kesavan,J.S.Panek,J.A.Porco,Org.Lett.2007,9,5203)；(5)自由基环化反应([1]C.-W.Kuo,J.-M.Fang,Synthetic Communications,2006,31,877；[2]W.Kong,N.Fuentes,A.Garca-Domnguez,E.Merino,C.Nevado,Angew.Chem.Int.Ed.2015,54,2487)。然而，这些方法大多需要预先合成特殊的官能团，极大地限制了这些方法的使用范围。因此发展高效、简洁的合成新方法显得尤为重要。本发明以芳基碘化物与烷基溴化物或烷基碘化物为起始原料，在催化剂、配体、降冰片烯衍生物、碱的作用下，在30℃到120℃下于有机溶剂中搅拌反应，即得到具有苄位全碳季碳中心的1,2,3,4-四氢化萘和1,2-二氢化茚化合物。该方法所用的原料廉价易得，反应条件温和，底物普适性好，产率高，制备过程简单。
临床药物氢溴酸依他佐辛，具有治疗癌痛及手术后疼痛的作用，现有的报道方法中需要7到20步才能完成合成([1]S.Shiotani,T.Kometani,K.Mitsuhashi,T.Nozawa,A.Kurobe,O.Futsukaichi,J.Med.Chem.1976,19,803；[2]T.Takemoto,M.Sodeoka,H.Sasai,M.Shibasaki,J.Am.Chem.Soc.1993,115,8477；[3]A.N.Hulme,S.S.Henry,A.I.Meyers,J.Org.Chem.1995,60,1265；[4]S.Shiotani,H.Okada,T.Yamamoto,K.Nakamata,J.Adachi,H.Nakamoto,Heterocycles 1996,43,113；[5]A.Fadel,P.Arzel,Tetrahedron:Asymmetry 1997,8,371；[6]S.K.Taylor,M.Ivanovic,L.J.Simons,M.M.Davis,Tetrahedron:Asymmetry 2003,14,743；[7]Y.Nakao,S.Ebata,A.Yada,T.Hiyama,M.Ikawa,S.Ogoshi,J.Am.Chem.Soc.2008,130,12874；[8]Q.Chen,X.Huo,Z.Yang,X.She,Chem.Asian J.2012,7,2543)，合成路线较长，效率低下。
发明内容
为了解决现有技术中存在的不足，本发明提供一种具有苄位季碳中心的苯并环衍生物的合成方法。在我们发明的合成具有苄位全碳季碳中心的1,2,3,4-四氢化萘化合物的方法的基础上，我们发明了一种高效合成氢溴酸依他佐辛的方法，该方法只需要四步，大大减少了合成步骤，提高了合成效率。
本发明提供的技术方案具体如下：
具有通式I所示结构的化合物：
Figure GDA0002784154240000021
其中:
R1为与环L并环的芳环、杂芳环或取代环L上氢的取代基，取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种；n表示R1的个数，0≤n≤4；
R2选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种；
R3为
Figure GDA0002784154240000031
m表示-CH2-的个数，0≤m≤10，
R3a选自氢、芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种；
R3b选自芳基、杂环芳基、烷基中的一种；
R4为取代或未取代的C0-10碳链，取代基为芳基、杂环芳基、烷基、酯基、醛基、羧基、羟基、硅基、氨基、氰基、硝基、酰胺基、磺酰基、烷氧基、卤素中的一种或几种；
Y1为N或CH；
Y2为-O-、-NH-或-CH2-；
式I中的L、T用于描述不同位置的环，不表示任何化学含义。
一种合成通式I所示化合物的方法，包括以下步骤：在惰性气体保护下，将式II所示芳香碘代物、(i)式III所示烷基卤化物或(ii)式IV所示烷基卤化物、钯催化剂、膦配体、碱、式V所示降冰片烯衍生物于30～120℃的有机溶剂中搅拌反应，反应结束后分离提纯，分别得到(i)式I-a或(ii)式I-b所示的化合物；
Figure GDA0002784154240000032
其中：k表示-CH2-的个数，1≤k≤10；R1、R2、R3a、R3b、R4、Y1、Y2、m、n具有上述所限定的相同的含义；
Figure GDA0002784154240000041
式V中：
R6为五元环上的取代基，e代表取代基个数，1≤e≤8；
R6独立地选自金属离子M的羧酸盐、酯基、氰基、硝基、酰胺基、磺酰基、C1-10烷氧基、芳基、杂环芳基、C1-10烷基、卤素中的一种，M为Li+、Na+、K+、Rb+、Cs+、Mg2+、Ca2+、Sr2+、Ba2+中的一种；e≥2时，各R6相同或不同。
本发明的方法优选使用钯催化剂来促进反应，可采用的钯催化剂包括零价或者二价的钯盐，例如：Pd(PPh3)4、Pd(dba)2、Pd2(dba)3、Pd(OAc)2、Pd(PhCN)2Cl2、Pd(MeCN)2Cl2、PdCl2、[Pd(allyl)Cl]2等。可用商品化试剂，无需特殊处理。
本发明的方法优选使用膦配体来促进反应，三芳基膦(如苯基、呋喃基等)、三烷基膦(如环己基等)、XPhos(二环己基(2',4',6'-三异丙基-[1,1'-二苯基]-2-基)膦)、BrettPhos(二环己基(2',4',6'-三异丙基-3,6-二甲氧基-[1,1'-二苯基]-2-基)膦)、SPhos(二环己基(2',6'-二甲氧基-[1,1'-二苯基]-2-基)膦)、DavePhos(2'-(二环己基膦基)-N,N-二甲基-[1,1'-二苯基]-2-胺)、RuPhos(二环己基(2',6'-二异丙氧基-[1,1'-二苯基]-2-基)膦)、三(呋喃-2-基)膦、(3S,5S,7S)-金刚烷-1-基((1R,5S)-金刚烷-2-基)(丁基)膦等。可用商品化试剂，无需特殊处理。
本发明的方法优选使用碱来促进反应，可采用碳酸钠、碳酸钾、碳酸铯、醋酸钠、醋酸钾、醋酸铯、磷酸三钾、甲酸钾、氢氧化钠、叔丁醇钠等。可用商品化试剂，无需特殊处理。
本发明方法两种反应物的投料摩尔比为芳基碘代物:烷基溴化物＝(1～10):1，优选为1.2:1。
本发明方法反应时间在48小时以内，反应温度为30～120℃。加热过程可采用油浴(例如硅油、石蜡油等)或者其它加热方式。
本发明优选在反应完成后对反应产物进行后处理，包括抽滤、浓缩和纯化。
所述抽滤过程可使用砂芯漏斗在减压的条件下过滤。
所述浓缩过程可采用常压蒸馏、减压蒸馏等方法，例如用旋转蒸发仪减压浓缩。
所述纯化过程是通过柱层析得到纯净的产物。
本发明还涉及一种氢溴酸依他佐辛的制备方法，其包含下列步骤：
(1)将化合物A中的醛基通过还原胺化的方法转化成二级胺，制得化合物B；
(2)将化合物B的苄位氧化成羰基，然后与甲醛发生Mannich反应，制得化合物C；
(3)化合物C在还原剂的作用下羰基被还原成亚甲基，同时脱掉氧上的保护基，制得依他佐辛；
(4)依他佐辛在氢溴酸的作用下制得依他佐辛的氢溴酸盐。
Figure GDA0002784154240000051
其中，R表示烷基、芳基、硅基、苄基等，这里优选苄基。
步骤(1)中，所述的还原胺化反应的方法和条件为本领域此类反应的常规方法和条件，本发明特别优选下述方法和条件：将化合物A、甲胺和还原剂溶于有机溶剂，搅拌反应，即可。其中，所述的溶剂较佳的为二氯甲烷、1,2-二氯乙烷、四氢呋喃、甲醇和乙醇中的一种或多种，优选甲醇。所述的甲胺可以是甲胺盐酸盐或者甲胺的溶液。所述的还原剂较佳的是硼氢化钠、氰基硼氢化钠、三乙酰氧基硼氢化钠，优选氰基硼氢化钠。所述的甲胺的用量较佳的为化合物A的摩尔量的1～10倍，优选5倍。所述的还原剂的用量较佳的为化合物A的摩尔量的1～5倍，优选2倍。所述的反应时间以监测反应完全为止，一般为5～12小时。所述的反应温度较佳的为0～50℃，优选30℃。
步骤(2)中，所述的苄位氧化和Mannich反应的方法和条件为本领域此类反应的常规方法和条件，本发明特别优选下述方法和条件：将化合物B和氧化剂于溶剂中搅拌反应一段时间后加入甲醛，继续搅拌反应，即可。其中，所述的氧化剂较佳的为二氧化锡、二氧化锰、三氧化铬、高锰酸钾等，优选三氧化铬。所述的氧化剂的用量较佳的为化合物B的摩尔量的1～5倍，优选2.5倍。所述的溶剂较佳的为二氯甲烷、1,2-二氯乙烷、四氢呋喃、1,4-二氧六环、丙酮、醋酸和水中的一种或多种，优选醋酸和水的混合物，其体积比为1:1～10:1，优选4:1。所述的反应时间以监测反应完全为止，一般为1～5小时。所述的反应温度较佳的为0～40℃，优选30℃。在后续的Mannich反应中，所述的甲醛可以是多聚甲醛或者甲醛的溶液。所述的甲醛的用量较佳的为化合物B的摩尔量的1～5倍，优选1.1倍。所述的反应时间以监测反应完全为止，一般为10～24小时。所述的反应温度较佳的为40～100℃，优选55℃。所述的苄位氧化和Mannich反应可以分步进行或者一锅法进行。
步骤(3)中，所述的还原羰基和脱保护的方法和条件为本领域此类反应的常规方法和条件，本发明特别优选下述方法和条件：将化合物C、还原剂和催化量的酸于有机溶剂中混合，氢气氛围下搅拌反应，即可。其中，所述的还原剂较佳的是钯/碳、氢氧化钯/碳。所述的还原剂的用量较佳的为化合物C的质量的5％～100％倍，优选30％倍。所述的溶剂较佳的甲醇和乙醇中的一种或多种。所述的酸较佳的为醋酸、硫酸、盐酸和高氯酸，优选高氯酸。所述的氢气压力为常压或者加压，优选40个大气压的压力。所述的反应时间以监测反应完全为止，一般为10～24小时。所述的反应温度较佳的为50～100℃，优选65℃。
步骤(4)中，所述的酸化成盐的方法和条件为本领域此类反应的常规方法和条件，本发明特别优选下述方法和条件：将化合物依他佐辛与氢溴酸搅拌反应，即可。其中，所述的氢溴酸百分比浓度为10％～48％，优选40％。所述的反应时间一般为10～60分钟。所述的反应温度较佳的为0～40℃，优选25℃。
本发明的方法可以高效地制备具有苄位季碳中心的1,2,3,4-四氢化萘或1,2-二氢化茚衍生物，和现有技术相比，本发明具有下列优势：
1、本发明所涉及的主要原料为芳基碘代物和烷基溴化物，此原料可用商品化试剂，无需特殊处理，且价格低廉，种类繁多；
2、本发明方法所涉及的反应使用的催化剂为廉价的金属钯盐，相比于之前的反应使用的催化剂或者络合物等是一个重要的补充；
3、本发明方法所涉及的反应使用的催化量的降冰片烯衍生物，相比于之前的反应使用的降冰片烯的用量大大减少；
4、本发明方法所涉及的反应对官能团具有很好的容忍性和普适性，取代基可以为烷基、烷氧基、氰基、酯基、硝基、卤原子(F、Cl、Br)等。
5、本发明方法可以大量(克级)制备1,2,3,4-四氢化萘和1,2-二氢化茚化合物，为工业化生产奠定了良好的基础。
6、本发明方法制备的1,2,3,4-四氢化萘衍生物可以高效、快捷(只需要四步)地转化成具有治疗癌痛及手术后疼痛的药物氢溴酸依他佐辛。
具体实施方式
下面通过实例对本发明给予进一步说明，值得注意的是，本发明不仅限于下述的实施例。
实施例1：化合物I-1的制备
Figure GDA0002784154240000071
在氩气体保护下，向干燥并装有磁力搅拌子的反应管中加入催化剂烯丙基氯化钯二聚体(3.7mg，0.01mmol)、配体XPhos(10.5mg,0.022mmol)、碳酸钾(69.1mg,0.5mmol)和干燥的乙腈(1.0mL)，该混合物在室温下搅拌反应15分钟。将溶有芳基碘化物[1-碘萘(61mg，0.24mmol)]、烷基溴化物[反式6-溴-3-甲基-2-己烯-1-醇(38.6mg，0.2mmol)]和5-降冰片烯-2-羧酸(5.5mg，0.04mmol)的干燥乙腈(1.0mL)溶液加入到上述反应管中，然后加热至70℃在氩气保护氛围下反应24小时。反应冷却至室温后，混合物用硅藻土过滤，乙酸乙酯洗涤，减压除去溶剂，柱层析提纯得化合物I-1(无色油状液体，产率81％)。1H NMR(400MHz,CDCl3):δ9.36(dd,J＝3.5,2.4Hz,1H),8.32(d,J＝8.7Hz,1H),7.81(dd,J＝8.1,1.5Hz,1H),7.63(d,J＝8.3Hz,1H),7.51–7.47(m,1H),7.43–7.39(m,1H),7.19(d,J＝8.3Hz,1H),3.44(dd,J＝16.0,2.4Hz,1H),3.03–2.91(m,2H),2.87(dd,J＝16.0,3.6Hz,1H),2.05–1.94(m,1H),1.93–1.85(m,3H),1.80(s,3H)；13C NMR(100MHz,CDCl3):δ203.4,136.4,136.3,133.9,131.6,129.9,128.8,127.7,125.8,125.5,124.4,54.8,42.2,37.1,32.8,28.7,18.8；HRMS(ESI-TOF):理论计算值：C17H18NaO[M+Na+]261.1250,实测值：261.1254。
实施例2：化合物I-2的制备
Figure GDA0002784154240000072
所用的烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-2(无色油状液体，产率68％)。1H NMR(400MHz,CDCl3):δ9.58(t,J＝1.6Hz,1H),8.34(d,J＝8.7Hz,1H),7.79(dd,J＝8.0,1.7Hz,1H),7.60(d,J＝8.3Hz,1H),7.46–7.36(m,2H),7.17(d,J＝8.4Hz,1H),2.98–2.87(m,2H),2.78–2.71(m,1H),2.31–2.22(m,1H),2.13–2.06(m,1H),1.95–1.81(m,4H),1.73–1.67(m,4H)；13C NMR(100MHz,CDCl3):δ202.7,137.2,136.6,133.7,132.4,129.6,128.8,127.2,125.5,125.3,124.3,40.7,40.3,38.0,34.0,33.1,28.6,19.1；HRMS(ESI-TOF):理论计算值：C18H20NaO[M+Na+]275.1406,实测值：275.1406。
实施例3：化合物I-3的制备
Figure GDA0002784154240000081
所用的芳基碘化物为2-甲基碘苯(52.3mg，0.24mmol)，其他条件同实施例1，得化合物I-3(无色油状液体，产率65％)。1H NMR(400MHz,CDCl3):δ9.50(t,J＝3.0Hz,1H),7.04–7.01(m,1H),6.96–6.94(m,2H),3.15(dd,J＝16.2,3.2Hz,1H),2.85–2.82(m,2H),2.53(dd,J＝16.2,2.8Hz,1H),2.49(s,3H),2.04–1.94(m,1H),1.86–1.76(m,3H),1.50(s,3H)；13CNMR(100MHz,CDCl3):δ203.4,140.0,138.0,136.3,131.2,128.4,126.3,54.1,41.7,37.0,32.3,27.9,23.8,19.3；HRMS(ESI-TOF):理论计算值：C14H18NaO[M+Na+]225.1250,实测值：225.1247。
实施例4：化合物I-4的制备
Figure GDA0002784154240000082
所用的芳基碘化物为2-甲基碘苯(52.3mg，0.24mmol)，烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-4(无色油状液体，产率75％)。1H NMR(400MHz,CDCl3):δ9.74(t,J＝1.6Hz,1H),7.02–6.98(m,1H),6.94–6.92(m,2H),2.80–2.77(m,2H),2.49–2.32(m,2H),2.45(s,3H),2.15–2.07(m,1H),1.82–1.72(m,4H),1.57–1.53(m,1H),1.41(s,3H)；13C NMR(100MHz,CDCl3):δ202.8,140.8,138.5,136.8,130.9,128.3,125.8,40.3,39.8,38.0,32.6(2C),27.8,23.5,19.4；HRMS(ESI-TOF):理论计算值：C15H20NaO[M+Na+]239.1406,实测值：239.1410。
实施例5：化合物I-5的制备
Figure GDA0002784154240000083
所用的芳基碘化物为2-乙基碘苯(55.7mg，0.24mmol)，其他条件同实施例1，得化合物I-5(无色油状液体，产率73％)。1H NMR(400MHz,CDCl3):δ9.52(t,J＝3.0Hz,1H),7.12–7.06(m,2H),6.96–6.93(m,1H),3.08(dd,J＝16.1,2.7Hz,1H),2.93–2.77(m,4H),2.62(dd,J＝16.1,3.2Hz,1H),1.96–1.88(m,1H),1.81–1.74(m,3H),1.55(s,3H),1.26(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3):δ203.7,143.1,139.5,137.9,129.4,128.0,126.4,55.0,42.0,37.0,32.7,29.0,27.4,19.2,16.7；HRMS(ESI-TOF):理论计算值：C15H20NaO[M+Na+]239.1406,实测值：239.1412。
实施例6：化合物I-6的制备
Figure GDA0002784154240000091
所用的芳基碘化物为2-异丙基碘苯(59.1mg，0.24mmol)，其他条件同实施例1，得化合物I-6(无色油状液体，产率60％)。1H NMR(400MHz,CDCl3):δ9.53(dd,J＝3.3,2.5Hz,1H),7.18(dd,J＝7.8,1.7Hz,1H),7.12(t,J＝7.5Hz,1H),6.95–6.92(m,1H),3.54–3.47(m,1H),3.08(dd,J＝16.2,2.5Hz,1H),2.83(t,J＝6.2Hz,2H),2.64(dd,J＝16.2,3.3Hz,1H),1.94–1.86(m,1H),1.80–1.75(m,3H),1.57(s,3H),1.26(t,J＝6.6Hz,6H)；13C NMR(100MHz,CDCl3):δ203.8,148.4,138.7,137.8,128.0,126.5,126.2,55.1,42.3,36.8,32.9,30.3,29.1,25.2,24.3,19.2；HRMS(ESI-TOF):理论计算值：C16H22NaO[M+Na+]253.1563,实测值：253.1564。
实施例7：化合物I-7的制备
Figure GDA0002784154240000092
所用的芳基碘化物为2-碘-1,1’-联苯(67.2mg，0.24mmol)，其他条件同实施例1，得化合物I-7(无色油状液体，产率63％)。1H NMR(400MHz,CDCl3):δ9.48(dd,J＝3.0,2.1Hz,1H),7.36–7.30(m,4H),7.17–7.09(m,3H),6.84(dd,J＝6.8,2.3Hz,1H),2.97–2.93(m,2H),2.51(dd,J＝16.8,2.1Hz,1H),2.17(dd,J＝16.8,3.0Hz,1H),1.95–1.77(m,3H),1.64–1.56(m,1H),1.33(s,3H)；13C NMR(100MHz,CDCl3):δ203.9,144.8,142.4,139.8,137.7,130.9,130.4,129.8,129.6,128.0,127.4,127.1,125.4,54.8,40.7,37.2,32.0,30.8,18.9；HRMS(ESI-TOF):理论计算值：C19H20NaO[M+Na+]287.1406,实测值：287.1409。
实施例8：化合物I-8的制备
Figure GDA0002784154240000101
所用的芳基碘化物为2-氟碘苯(53.3mg，0.24mmol)，其他条件同实施例1，得化合物I-8(无色油状液体，产率78％)。1H NMR(400MHz,CDCl3):δ9.57–9.56(m,1H),7.11–7.06(m,1H),6.90–6.1(m,2H),3.13(ddd,J＝15.6,2.3,1.2Hz,1H),2.82–2.71(m,2H),2.61(ddd,J＝15.6,3.4,1.4Hz,1H),1.91–1.85(m,1H),1.81–1.71(m,3H),1.47(d,J＝1.1Hz,3H)；13C NMR(100MHz,CDCl3):δ203.3,161.9(d,J＝246.1Hz),140.1(d,J＝4.9Hz),129.2(d,J＝11.7Hz),127.4(d,J＝9.9Hz),125.5(d,J＝2.7Hz),113.9(d,J＝24.5Hz),54.3(d,J＝6.2Hz),38.7,35.4(d,J＝1.9Hz),30.9(d,J＝2.7Hz),28.2(d,J＝3.7Hz),19.4；19F NMR(377MHz,CDCl3)δ–110.3；HRMS(ESI-TOF):理论计算值：C13H15FNaO[M+Na+]229.0999,实测值：229.1006。
实施例9：化合物I-9的制备
Figure GDA0002784154240000102
所用的芳基碘化物为2-氯碘苯(57.2mg，0.24mmol)，其他条件同实施例1，得化合物I-9(无色油状液体，产率64％)。1H NMR(400MHz,CDCl3):δ9.51(dd,J＝3.2,2.2Hz,1H),7.20–7.17(m,1H),7.06–6.99(m,2H),3.65(dd,J＝16.2,2.2Hz,1H),2.84–2.80(m,2H),2.65(dd,J＝16.2,3.2Hz,1H),1.97–1.88(m,1H),1.80–1.71(m,3H),1.58(s,3H)；13C NMR(100MHz,CDCl3):δ203.1,140.7,138.7,133.8,130.0,129.1,127.2,53.3,40.9,37.2,32.4,26.9,19.1；HRMS(ESI-TOF):理论计算值：C13H15ClNaO[M+Na+]245.0704,实测值：245.0710。
实施例10：化合物I-10的制备
Figure GDA0002784154240000111
所用的芳基碘化物为2-苄氧基碘苯(74.4mg，0.24mmol)，其他条件同实施例1，得化合物I-10(无色油状液体，产率71％)。1H NMR(400MHz,CDCl3):δ9.47(dd,J＝3.6,2.3Hz,1H),7.45–7.35(m,5H),7.09(t,J＝7.9Hz,1H),6.79–6.74(m,2H),5.07(s,2H),3.34(dd,J＝15.5,2.4Hz,1H),2.78(t,J＝6.1Hz,2H),2.46(dd,J＝15.5,3.6Hz,1H),1.85–1.68(m,4H),1.47(s,3H)；13C NMR(100MHz,CDCl3):δ204.7,157.4,139.6,137.0,130.0,128.8,128.2,127.8,127.0,122.8,109.9,70.4,54.1,40.4,35.9,31.7,27.4,19.4；HRMS(ESI-TOF):理论计算值：C20H22NaO2[M+Na+]317.1512,实测值：317.1514。
实施例11：化合物I-11的制备
Figure GDA0002784154240000112
所用的芳基碘化物为叔丁基(2-碘苄氧基)二甲基硅(83.6mg，0.24mmol)，其他条件同实施例1，得化合物I-11(无色油状液体，产率51％)。1H NMR(400MHz,CDCl3):δ9.45(dd,J＝3.6,2.1Hz,1H),7.30(dd,J＝7.6,1.6Hz,1H),7.14(t,J＝7.5Hz,1H),7.04(dd,J＝7.3,1.5Hz,1H),4.93(d,J＝12.2Hz,1H),4.77(d,J＝12.2Hz,1H),3.17(dd,J＝16.1,2.1Hz,1H),2.84(t,J＝6.4Hz,2H),2.51(dd,J＝16.2,3.5Hz,1H),1.93–1.86(m,1H),1.85–1.76(m,2H),1.75–1.69(m,1H),1.49(s,3H),0.91(s,9H),0.13(s,3H),0.11(s,3H)；13C NMR(100MHz,CDCl3):δ204.0,139.5,139.3,137.8,129.9,129.3,126.4,64.4,55.4,41.5,36.9,32.2,29.3,26.1,19.1,18.5,-4.9,-5.0；HRMS(ESI-TOF):理论计算值：C20H32NaO2Si[M+Na+]355.2064,实测值：355.2060。
实施例12：化合物I-12的制备
Figure GDA0002784154240000113
所用的芳基碘化物为N-Boc保护的3-氯-4-碘苯胺(84.9mg，0.24mmol)，其他条件同实施例1，得化合物I-12(无色油状液体，产率61％)。1H NMR(400MHz,CDCl3):δ9.50(dd,J＝3.3,2.2Hz,1H),7.05(s,1H),6.40(s,1H),3.60(dd,J＝16.1,2.2Hz,1H),2.77(t,J＝6.4Hz,2H),2.59(dd,J＝16.1,3.3Hz,1H),1.93–1.84(m,1H),1.78–1.68(m,3H),1.54(s,3H),1.50(s,9H)；13C NMR(100MHz,CDCl3):δ203.3,152.6,141.2,137.0,134.1,133.1,119.8,118.3,53.4,40.9,36.8,32.7,28.4,28.1,27.1,19.2；HRMS(ESI-TOF):理论计算值：C18H24ClNNaO3[M+Na+]360.1337,实测值：360.1335。
实施例13：化合物I-13的制备
Figure GDA0002784154240000121
所用的芳基碘化物为3-氟-2-甲基碘苯(56.6mg，0.24mmol)，其他条件同实施例1，得化合物I-13(无色油状液体，产率72％)。1H NMR(400MHz,CDCl3):δ9.49(t,J＝2.9Hz,1H),6.93–6.89(m,1H),6.85–6.80(m,1H),3.15(dd,J＝16.3,3.1Hz,1H),2.78(t,J＝6.0Hz,2H),2.56(dd,J＝16.3,2.8Hz,1H),2.36(d,J＝3.2Hz,3H),1.98–1.89(m,1H),1.82–1.72(m,3H),1.50(s,3H)；13C NMR(100MHz,CDCl3):δ202.8,160.6(d,J＝240.3Hz),141.8(d,J＝1.9Hz),133.2(d,J＝3.4Hz),128.7(d,J＝9.1Hz),123.1(d,J＝14.6Hz),113.2(d,J＝24.5Hz),54.1,41.5,37.3(d,J＝2.1Hz),31.8,27.9,19.3,13.8(d,J＝9.6Hz)；9F NMR(377MHz,CDCl3)δ–115.5；HRMS(ESI-TOF):理论计算值：C14H17FNaO[M+Na+]243.1156,实测值：243.1160。
实施例14：化合物I-14的制备
Figure GDA0002784154240000122
所用的芳基碘化物为4-氟-2-甲基碘苯(56.6mg，0.24mmol)，其他条件同实施例1，得化合物I-14(无色油状液体，产率70％)。1H NMR(400MHz,CDCl3):δ9.49(t,J＝3.0Hz,1H),6.68–6.64(m,2H),3.12(dd,J＝16.3,3.3Hz,1H),2.83–2.79(m,2H),2.51(dd,J＝16.3,2.7Hz,1H),2.47(s,3H),2.00–1.95(m,1H),1.83–1.73(m,3H),1.46(s,3H)；13C NMR(100MHz,CDCl3):δ203.0,160.4(d,J＝244.9Hz),140.4(d,J＝7.3Hz),138.8(d,J＝7.5Hz),135.7(d,J＝3.1Hz),117.6(d,J＝20.4Hz),114.1(d,J＝19.3Hz),54.1,41.6,36.6,32.6(d,J＝1.6Hz),28.0,23.8(d,J＝1.5Hz),19.0；19F NMR(377MHz,CDCl3)δ–118.8.HRMS(ESI-TOF):理论计算值：C14H17FNaO[M+Na+]243.1156,实测值：243.1161。
实施例15：化合物I-15的制备
Figure GDA0002784154240000131
所用的芳基碘化物为4-溴-2-甲基碘苯(71.3mg，0.24mmol)，其他条件同实施例1，得化合物I-15(无色油状液体，产率59％)。1H NMR(400MHz,CDCl3):δ9.50(t,J＝2.9Hz,1H),7.09(brs,2H),3.11(dd,J＝16.3,3.2Hz,1H),2.82–2.79(m,2H),2.52(dd,J＝16.3,2.6Hz,1H),2.45(s,3H),2.02–1.92(m,1H),1.82–1.72(m,3H),1.46(s,3H)；13C NMR(100MHz,CDCl3):δ202.7,140.3,139.1,138.6,133.6,130.9,119.9,53.9,41.3,36.8,32.2,27.8,23.5,19.0；HRMS(ESI-TOF):理论计算值：C14H17BrNaO[M+Na+]303.0355,实测值：303.0354。
实施例16：化合物I-16的制备
Figure GDA0002784154240000132
所用的芳基碘化物为4-硝基-2-甲基碘苯(63.1mg，0.24mmol)，其他条件同实施例1，得化合物I-16(无色油状液体，产率85％)。1H NMR(400MHz,CDCl3):δ9.53(t,J＝2.6Hz,1H),7.80–7.77(m,2H),3.22(dd,J＝16.8,2.9Hz,1H),2.93(t,J＝6.4Hz,2H),2.62(dd,J＝16.8,2.2Hz,1H),2.57(s,3H),2.07–2.02(m,1H),1.87–1.76(m,3H),1.49(s,3H)；13C NMR(100MHz,CDCl3):δ201.3,148.0,145.5,139.9,138.2,125.2,122.8,53.9,41.0,37.4,32.5,27.5,24.0,18.8；HRMS(ESI-TOF):理论计算值：C14H17NNaO3[M+Na+]270.1101,实测值：270.1105。
实施例17：化合物I-17的制备
Figure GDA0002784154240000141
所用的芳基碘化物为4-碘-3-甲基苯甲酸甲酯(66.3mg，0.24mmol)，其他条件同实施例1，得化合物I-17(无色油状液体，产率83％)。1H NMR(400MHz,CDCl3):δ9.48(t,J＝2.8Hz,1H),7.61–7.59(m,2H),3.88(s,3H),3.17(dd,J＝16.4,3.0Hz,1H),2.88(t,J＝6.3Hz,2H),2.58–2.53(m,4H),2.05–1.95(m,1H),1.85–1.74(m,3H),1.49(s,3H)；13C NMR(100MHz,CDCl3):δ202.4,167.2,145.4,138.4,136.6,131.9,129.4,127.7,53.9,52.1,41.4,37.3,32.3,27.7,23.8,19.1；HRMS(ESI-TOF):理论计算值：C16H20NaO3[M+Na+]283.1305,实测值：283.1306。
实施例18：化合物I-18的制备
Figure GDA0002784154240000142
所用的芳基碘化物为1-溴-4-碘萘(79.9mg，0.24mmol)，其他条件同实施例1，得化合物I-18(无色油状液体，产率60％)。1H NMR(400MHz,CDCl3):δ9.37(dd,J＝3.4,2.4Hz,1H),8.33–8.27(m,2H),7.56–7.49(m,3H),3.40(dd,J＝16.1,2.5Hz,1H),3.01–2.91(m,2H),2.87(dd,J＝16.1,3.4Hz,1H),2.05–1.98(m,1H),1.92–1.84(m,3H),1.78(s,3H)；13CNMR(100MHz,CDCl3):δ202.7,137.2,136.7,133.1,132.6,131.9,128.9,126.3,126.0,125.8,122.3,54.8,42.1,37.0,32.5,28.8,18.6；HRMS(ESI-TOF):理论计算值：C17H17BrNaO[M+Na+]339.0355,实测值：339.0359。
实施例19：化合物I-19的制备
Figure GDA0002784154240000143
所用的芳基碘化物为4-碘-2,3-二氢化茚(58.6mg，0.24mmol)，其他条件同实施例1，得化合物I-19(无色油状液体，产率58％)。1H NMR(400MHz,CDCl3):δ9.51(t,J＝3.0Hz,1H),7.04(d,J＝7.6Hz,1H),6.92(d,J＝7.6Hz,1H),3.13–3.03(m,2H),2.96–2.89(m,1H),2.83–2.79(m,4H),2.52(dd,J＝15.9,2.9Hz,1H),2.12–1.91(m,3H),1.85–1.74(m,3H),1.45(s,3H)；13C NMR(100MHz,CDCl3):δ203.7,143.7,141.5,138.3,135.1,128.5,122.8,53.9,40.0,36.8,35.2,32.4,31.5,27.9,26.2,19.6；HRMS(ESI-TOF):理论计算值：C16H20NaO[M+Na+]251.1406,实测值：251.1407。
实施例20：化合物I-20的制备
Figure GDA0002784154240000151
所用的芳基碘化物为5-碘-1,2,3,4,-四氢化萘(61.9mg，0.24mmol)，其他条件同实施例1，得化合物I-20(无色油状液体，产率53％)。1H NMR(400MHz,CDCl3):δ9.49(t,J＝3.0Hz,1H),6.90(s,2H),3.16(dd,J＝16.3,3.1Hz,1H),2.96(dt,J＝14.6,5.0Hz,1H),2.83–2.65(m,5H),2.55(dd,J＝16.4,2.8Hz,1H),1.98–1.93(m,1H),1.87–1.68(m,7H),1.53(s,3H)；13C NMR(100MHz,CDCl3):δ203.7,139.3,137.3,137.1,135.2,127.9,127.6,54.6,42.5,36.9,32.3,30.1,29.2,28.3,22.8,21.9,19.3；HRMS(ESI-TOF):理论计算值：C17H22NaO[M+Na+]265.1563,实测值：265.1566。
实施例21：化合物I-21的制备
Figure GDA0002784154240000152
所用的芳基碘化物为6-氯-5-碘-2,3-二氢螺(茚-1,2’-(1,3)二氧戊烷)(80.8mg，0.24mmol)，其他条件同实施例1，得化合物I-21(无色油状液体，产率75％)。1H NMR(400MHz,CDCl3):δ9.48(dd,J＝3.4,2.2Hz,1H),7.21(s,1H),4.20–4.14(m,2H),4.12–4.04(m,2H),3.63(dd,J＝16.1,2.3Hz,1H),2.82–2.54(m,5H),2.31–2.28(m,2H),1.94–1.87(m,1H),1.81–1.70(m,3H),1.57(s,3H)；13C NMR(100MHz,CDCl3):δ203.2,141.8,140.9,139.5,137.0,132.7,124.3,116.9,65.5,65.3,53.1,40.6,37.3,36.9,28.7,27.4,26.8,18.5；HRMS(ESI-TOF):理论计算值：C18H21ClNaO3[M+Na+]343.1071,实测值：343.1073。
实施例22：化合物I-22的制备
Figure GDA0002784154240000161
所用的芳基碘化物为3-苄氧基碘苯(74.4mg，0.24mmol)，烷基碘化物为反式6-碘-3-甲基-2-己烯-1-醇(48mg，0.2mmol)，催化剂烯丙基氯化钯二聚体(3.7mg，0.01mmol)、配体XPhos(10.5mg,0.022mmol)，其他条件同实施例1，得化合物I-22(无色油状液体，产率53％)。1H NMR(400MHz,CDCl3):δ9.54(dd,J＝3.6,2.4Hz,1H),7.45–7.37(m,4H),7.34–7.30(m,1H),7.01(d,J＝8.4Hz,1H),6.89(d,J＝2.6Hz,1H),6.77(dd,J＝8.4,2.6Hz,1H),5.03(s,2H),2.77(dd,J＝15.2,2.5Hz,1H),2.72(t,J＝6.1Hz,2H),2.53(dd,J＝15.2,3.5Hz,1H),1.88–1.71(m,3H),1.75–1.70(m,1H),1.38(s,3H)；13C NMR(100MHz,CDCl3):δ203.5,157.2,143.7,137.2,130.5,129.2,128.7,128.1,127.7,113.4,112.7,70.3,56.2,36.8,36.6,30.8,29.6,19.6；HRMS(ESI-TOF):理论计算值：C20H22NaO2[M+Na+]317.1512,实测值：317.1503。
实施例23：化合物I-23的制备
Figure GDA0002784154240000162
所用的芳基碘化物为叔丁基(3-碘苯氧基)二苯基硅烷(110mg，0.24mmol)，烷基碘化物为反式6-碘-3-甲基-2-己烯-1-醇(48mg，0.2mmol)，其他条件同实施例1，得化合物I-23(无色油状液体，产率48％)。1H NMR(400MHz,CDCl3):δ9.16(dd,J＝4.0,2.0Hz,1H),7.71(td,J＝8.1,1.5Hz,4H),7.45–7.33(m,6H),6.86(d,J＝8.1Hz,1H),6.67(dd,J＝8.3,2.5Hz,1H),6.52(d,J＝2.5Hz,1H),2.66–2.56(m,2H),2.32(dd,J＝15.0,2.1Hz,1H),2.15(dd,J＝15.1,4.0Hz,1H),1.74–1.63(m,3H),1.61–1.55(m,1H),1.12(s,9H),1.07(s,3H)；13C NMR(100MHz,CDCl3):δ203.7,153.9,142.9,135.6,133.2,133.1,130.3,130.1,130.0,129.1,127.9,118.1,117.6,56.1,36.6,36.2,30.6,29.6,26.7,19.6,19.6；HRMS(ESI-TOF):理论计算值：C29H34NaO2Si[M+Na+]465.2220,实测值：465.2215。
实施例24：化合物I-24的制备
Figure GDA0002784154240000171
所用的芳基碘化物为3-碘-2-甲氧基吡啶(56.4mg，0.24mmol)，其他条件同实施例1，得化合物I-24(无色油状液体，产率62％)。1H NMR(400MHz,CDCl3):δ9.52(dd,J＝3.6,2.1Hz,1H),7.87(d,J＝5.1Hz,1H),6.62(d,J＝5.2Hz,1H),3.93(s,3H),3.22(dd,J＝15.5,2.2Hz,1H),2.69(t,J＝6.2Hz,2H),2.56(dd,J＝15.6,3.6Hz,1H),1.88–1.82(m,1H),1.79–1.69(m,3H),1.42(s,3H)；13C NMR(100MHz,CDCl3):δ203.6,161.9,149.0,143.5,124.4,118.8,53.6,53.1,39.2,34.8,30.8,26.6,18.7；HRMS(ESI-TOF):理论计算值：C13H17NNaO2[M+Na+]242.1151,实测值：242.1151。
实施例25：化合物I-25的制备
Figure GDA0002784154240000172
所用的芳基碘化物为4-碘-喹啉(61.2mg，0.24mmol)，其他条件同实施例1，得化合物I-25(无色油状液体，产率65％)。1H NMR(400MHz,CDCl3):δ9.43(dd,J＝3.2,2.5Hz,1H),9.05(s,1H),8.24(dd,J＝8.9,1.1Hz,1H),7.94(dd,J＝8.1,1.5Hz,1H),7.70–7.66(m,1H),7.52(t,J＝7.5Hz,1H),3.32(dd,J＝16.0,2.5Hz,1H),3.16–3.13(m,2H),2.92(dd,J＝16.1,3.3Hz,1H),2.09–2.03(m,1H),1.98–1.88(m,3H),1.76(s,3H)；13C NMR(100MHz,CDCl3):δ202.4,151.7,151.6,134.5,130.0,129.6(2C),128.4,125.7,124.7,54.4,41.1,37.0,34.9,28.4,18.7；HRMS(ESI-TOF):理论计算值：C16H18NO[M+H+]240.1383,实测值：240.1386。
实施例26：化合物I-26的制备
Figure GDA0002784154240000173
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg，0.24mmol)，其他条件同实施例1，得化合物I-26(淡黄色固体，产率88％)。熔点：120–122℃，1H NMR(400MHz,CDCl3):δ9.49(dd,J＝3.5,2.3Hz,1H),7.43–7.29(m,10H),6.48(s,1H),5.10–5.13(m,4H),3.75(s,3H),3.18(dd,J＝15.5,2.3Hz,1H),2.74(t,J＝6.0Hz,2H),2.46(dd,J＝15.5,3.5Hz,1H),1.82–1.70(m,3H),1.68–1.61(m,1H),1.40(s,3H)；13C NMR(100MHz,CDCl3):δ204.4,167.6,156.3,154.7,141.8,136.8,128.7,128.6,128.2,127.9,127.6,127.4,127.0,115.8,108.6,75.7,70.5,54.4,52.6,40.1,35.8,32.4,28.7,19.1；HRMS(ESI-TOF):理论计算值：C29H30NaO5[M+Na+]481.1985,实测值：481.1990。
实施例27：化合物I-27的制备
Figure GDA0002784154240000181
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg，0.24mmol)，烷基溴化物为反式7-溴-4-甲基-3-庚烯-1-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-27(无色油状液体，产率61％)。1H NMR(400MHz,CDCl3):δ9.59(t,J＝2.0Hz,1H),7.42–7.31(m,10H),6.46(s,1H),5.07(s,2H),5.04(s,2H),3.73(s,3H),2.71(t,J＝5.7Hz,2H),2.41–2.33(m,1H),2.21–2.15(m,2H),1.78–1.61(m,4H),1.51–1.45(m,1H),1.33(s,3H)；13CNMR(100MHz,CDCl3):δ203.3,167.7,156.6,154.4,142.1,137.1,136.9,128.6,128.5,128.1,127.9,127.5,127.0,115.8,108.5,75.8,70.5,52.6,40.4,38.5,36.9,32.9,32.6,28.4,19.2；HRMS(ESI-TOF):理论计算值：C30H32NaO5[M+Na+]495.2142,实测值：495.2147。
实施例28：化合物I-28的制备
Figure GDA0002784154240000182
所用的芳基碘化物为5-苄氧基-6-碘-2，2-二甲基苯并[1,3]二氧-4-酮(98.4mg，0.24mmol)，其他条件同实施例1，得化合物I-28(无色油状液体，产率76％)。1H NMR(400MHz,CDCl3):δ9.47(dd,J＝3.1,2.1Hz,1H),7.56–7.54(m,2H),7.42–7.33(m,3H),6.49(t,J＝1.0Hz,1H),5.16(d,J＝10.2Hz,1H),5.02(d,J＝10.2Hz,1H),3.27(dd,J＝15.9,2.2Hz,1H),2.77(t,J＝6.2Hz,2H),2.50(dd,J＝15.9,3.1Hz,1H),1.82–1.70(m,8H),1.66–1.60(m,2H),1.41(s,3H)；13C NMR(100MHz,CDCl3):δ203.6,160.7,158.9,155.1,149.0,136.4,129.9,128.7(2C),128.5,112.4,105.3,105.1,54.3,39.7,35.9,32.7,28.3,26.1,25.2,18.8；HRMS(ESI-TOF):理论计算值：C24H26NaO5[M+Na+]417.1672,实测值：417.1670。
实施例29：化合物I-29的制备
Figure GDA0002784154240000191
所用的烷基溴化物为反式6-溴-1-甲氧基-3-甲基-2-己烯(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-29(无色油状液体，顺反异构体的总产率81％，比率为顺式：反式＝1:1.8)。化合物I-29反式构型的核磁和质谱数据为：1H NMR(400MHz,CDCl3):δ8.44–8.41(m,1H),7.76–7.72(m,1H),7.59(d,J＝9.0Hz,1H),7.39–7.32(m,2H),7.17(d,J＝8.4Hz,1H),6.14(d,J＝13.0Hz,1H),5.16(d,J＝13.0Hz,1H),3.47(s,3H),2.92(t,J＝6.2Hz,2H),1.91–1.73(m,4H),1.66(s,3H)；13C NMR(100MHz,CDCl3):δ147.5,138.0,135.5,133.7,132.1,128.8,128.5,128.1,127.0,124.4,124.2,115.4,56.2,44.2,38.2,32.5,28.8,18.7；HRMS(ESI-TOF):理论计算值：C18H20NaO[M+Na+]275.1406,实测值：275.1411.化合物I-29顺式构型的核磁和质谱数据为：1H NMR(400MHz,CDCl3):δ8.49–8.46(m,1H),7.77–7.74(m,1H),7.57(d,J＝8.3Hz,1H),7.41–7.33(m,2H),7.16(d,J＝8.3Hz,1H),5.76(d,J＝6.8Hz,1H),4.81(d,J＝6.8Hz,1H),3.43(s,3H),3.01–2.85(m,2H),2.12–1.99(m,2H),1.88–1.80(m,2H),1.79(s,3H)；13C NMR(100MHz,CDCl3):δ144.1,140.3,134.2,133.6,131.9,128.9,128.6,127.3,126.4,124.2,124.1,118.8,59.7,40.7,38.7,32.4,28.5,19.3；HRMS(ESI-TOF):理论计算值：C18H20NaO[M+Na+]275.1406,实测值：275.1411。
实施例30：化合物I-30的制备
Figure GDA0002784154240000192
所用的烷基溴化物为反式7-溴-4-甲基-3-庚烯-2-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-30(无色油状液体，产率71％)。1H NMR(400MHz,CDCl3):δ8.35(d,J＝8.8Hz,1H),7.80(dd,J＝8.1,1.6Hz,1H),7.60(d,J＝8.3Hz,1H),7.49–7.45(m,1H),7.41–7.37(m,1H),7.18(d,J＝8.4Hz,1H),3.45(d,J＝15.4Hz,1H),3.10(d,J＝15.4Hz,1H),3.01–2.89(m,2H),2.20–2.15(m,1H),1.88–1.80(m,3H),1.85(s,3H),1.78(s,3H)；13CNMR(100MHz,CDCl3):δ208.6,137.8,136.1,133.9,131.9,129.8,128.9,127.2,125.8,125.1,124.2,54.4,40.7,37.8,32.9,32.0,28.7,19.0；HRMS(ESI-TOF):理论计算值：C18H20NaO[M+Na+]275.1406,实测值：275.1409。
实施例31：化合物I-31的制备
Figure GDA0002784154240000201
所用的烷基溴化物为反式10-溴-7-甲基-6-癸烯-5-醇(49.8mg，0.2mmol)，其他条件同实施例1，得化合物I-31(无色油状液体，产率45％)。1H NMR(400MHz,CDCl3):δ8.35(d,J＝8.7Hz,1H),7.79(dd,J＝8.0,1.6Hz,1H),7.59(d,J＝8.3Hz,1H),7.48–7.43(m,1H),7.40–7.36(m,1H),7.18(d,J＝8.3Hz,1H),3.39(d,J＝15.7Hz,1H),3.10(d,J＝15.7Hz,1H),3.01–2.88(m,2H),2.22–2.08(m,3H),1.87–1.77(m,3H),1.77(s,3H),1.38–1.31(m,2H),1.14–1.04(m,2H),0.77(t,J＝7.3Hz,3H)；13C NMR(100MHz,CDCl3):δ210.7,138.0,136.0,133.9,131.8,129.8,128.9,127.1,125.9,125.0,124.1,53.3,44.4,40.7,37.8,32.9,28.6,25.7,22.3,19.0,13.9；HRMS(ESI-TOF):理论计算值：C21H26NaO[M+Na+]317.1876,实测值：317.1879。
实施例32：化合物I-32的制备
Figure GDA0002784154240000202
所用的烷基溴化物为反式9-溴-6-甲基壬烷-1,5-二烯-4-醇(46.6mg，0.2mmol)，其他条件同实施例1，得化合物I-31(无色油状液体，产率53％)。1H NMR(400MHz,CDCl3):δ8.41(d,J＝8.7Hz,1H),7.80(dd,J＝8.0,1.6Hz,1H),7.60(d,J＝8.3Hz,1H),7.49–7.44(m,1H),7.40–7.36(m,1H),7.18(d,J＝8.4Hz,1H),6.76–6.67(m,1H),5.98(dd,J＝15.5,1.7Hz,1H),3.32(s,2H),3.00–2.89(m,2H),2.19–2.14(m,1H),1.86–1.77(m,9H)；13C NMR(100MHz,CDCl3):δ199.8,142.1,138.5,135.8,133.9,133.1,131.8,129.7,128.8,127.2,126.1,125.0,124.1,50.4,40.6,38.0,32.9,28.5,18.9,18.3；HRMS(ESI-TOF):理论计算值：C20H22NaO[M+Na+]301.1563,实测值：301.1564。
实施例33：化合物I-33的制备
Figure GDA0002784154240000211
所用的烷基溴化物为反式6-溴-3-乙基-2-己烯-1-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-33(无色油状液体，产率72％)。1H NMR(400MHz,CDCl3)δ9.42(dd,J＝3.7,2.4Hz,1H),8.30(d,J＝8.2Hz,1H),7.80(dd,J＝8.0,1.6Hz,1H),7.62(d,J＝8.3Hz,1H),7.49–7.45(m,1H),7.42–7.38(m,1H),7.19(d,J＝8.3Hz,1H),3.42(dd,J＝15.7,2.5Hz,1H),2.96(t,J＝6.3Hz,2H),2.84(dd,J＝15.7,3.7Hz,1H),2.45–2.36(m,1H),2.21–2.09(m,2H),1.94–1.78(m,3H),0.78(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3)δ203.8,137.2,135.4,133.8,132.0,129.9,128.8,127.7,125.6,125.3,124.4,53.2,40.8,37.5,32.8,32.7,18.8,8.9；HRMS(ESI-TOF):理论计算值：C18H20NaO[M+Na+]275.1406,实测值：275.1414。
实施例34：化合物I-34的制备
Figure GDA0002784154240000212
所用的烷基溴化物为反式6-溴-3-苯基-2-己烯-1-醇(41.4mg，0.2mmol)，其他条件同实施例1，得化合物I-34(无色油状液体，产率67％)。1H NMR(400MHz,CDCl3)δ8.98(dd,J＝3.8,1.8Hz,1H),7.78(dd,J＝8.1,1.4Hz,1H),7.71(d,J＝8.4Hz,1H),7.39–7.14(m,9H),3.82(dd,J＝15.3,1.8Hz,1H),3.26(dd,J＝15.3,3.8Hz,1H),3.11–2.98(m,2H),2.25–2.18(m,1H),2.14–2.09(m,1H),1.80–1.71(m,2H)；13C NMR(100MHz,CDCl3)δ202.9,149.3,138.2,133.9,133.4,131.3,129.2,128.6,128.4,128.1,127.0,126.2,125.4,124.6,53.5,45.0,44.0,32.3,18.1；HRMS(ESI-TOF):理论计算值：C22H20NaO[M+Na+]323.1406,实测值：323.1406。
实施例35：化合物I-35的制备
Figure GDA0002784154240000221
所用的烷基溴化物为反式6-溴-2-己烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-35(无色油状液体，产率81％)。1H NMR(400MHz,CDCl3)δ9.92(dd,J＝2.0,0.9Hz,1H),7.88(d,J＝8.4Hz,1H),7.82(dd,J＝8.1,1.4Hz,1H),7.64(d,J＝8.3Hz,1H),7.53–7.49(m,1H),7.46–7.42(m,1H),7.20(d,J＝8.4Hz,1H),4.25–4.20(m,1H),2.96–2.93(m,2H),2.89–2.81(m,2H),1.99–1.86(m,4H)；13C NMR(100MHz,CDCl3)δ201.9,134.5,133.5,132.7,131.3,129.1,128.3,126.7,126.4,124.9,122.4,49.7,30.0,27.4,27.2,17.7；HRMS(ESI-TOF):理论计算值：C16H16NaO[M+Na+]247.1093,实测值：247.1094。
实施例36：化合物I-36的制备
Figure GDA0002784154240000222
所用的烷基溴化物为反式6-溴-3-甲基-2-己烯-1，5-二醇(41.8mg，0.2mmol)，其他条件同实施例1，得化合物I-36(无色油状液体，产率47％)。1H NMR(400MHz,CDCl3):δ9.76(t,J＝3.0Hz,1H),8.33(d,J＝8.7Hz,1H),7.83(d,J＝8.0,1H),7.68(d,J＝8.4Hz,1H),7.52–7.48(m,1H),7.45–7.41(m,1H),7.19(d,J＝8.4Hz,1H),4.28–4.21(m,1H),3.26–3.22(m,2H),3.14(dd,J＝15.6,2.7Hz,1H),2.99(dd,J＝16.2,9.5Hz,1H),2.34(dt,J＝13.2,2.8Hz,1H),1.94–1.90(m,1H),1.88(s,3H)；13C NMR(100MHz,CDCl3):δ202.8,136.3,134.3,132.8,131.2,129.9,128.7,128.5,125.9,125.7,124.8,63.8,53.7,50.0,41.6,39.4,30.2；HRMS(ESI-TOF):理论计算值：C17H18NaO2[M+Na+]277.1199,实测值：277.1206。
实施例37：化合物I-37的制备
Figure GDA0002784154240000231
所用的烷基溴化物为反式7-溴-2-庚烯-1-醇(38.6mg，0.2mmol)，其他条件同实施例1，得化合物I-37(无色油状液体，产率76％)。1H NMR(400MHz,CDCl3)δ9.80(dd,J＝2.7,1.3Hz,1H),8.18(d,J＝8.7Hz,1H),7.81(dd,J＝8.1,1.4Hz,1H),7.64(d,J＝8.3Hz,1H),7.52–7.48(m,1H),7.44–7.40(m,1H),7.25–7.22(m,1H),4.71–4.65(m,1H),3.20–3.07(m,2H),2.90–2.80(m,2H),2.06–1.96(m,2H),1.90–1.77(m,3H),1.56–1.53(m,1H)；13C NMR(100MHz,CDCl3)δ202.1,139.6,138.1,132.9,131.9,130.2,129.0,127.3,126.5,124.8,123.0,46.4,36.3,32.3,30.5,27.6,25.1；HRMS(ESI-TOF):理论计算值：C17H18NaO[M+Na+]261.1250,实测值：261.1255。
实施例38：化合物I-39的制备
Figure GDA0002784154240000232
所用的烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-39(无色油状液体，产率56％)。1H NMR(600MHz,CDCl3):δ9.60(t,J＝3.0Hz,1H),8.08(d,J＝8.5Hz,1H),7.88(d,J＝8.2Hz,1H),7.72(d,J＝8.2Hz,1H),7.50(t,J＝7.5Hz,1H),7.43(t,J＝7.6Hz,1H),7.35(d,J＝8.2Hz,1H),3.10–3.02(m,3H),2.95(dd,J＝15.1,3.5Hz,1H),2.39–2.35(m,1H),2.19–2.14(m,1H),1.70(s,3H)；13C NMR(100MHz,CDCl3):δ203.3,142.1,141.2,133.9,129.8,129.7,128.7,126.2,124.7,123.7,123.2,53.9,48.0,40.1,30.9,27.8；HRMS(ESI-TOF):理论计算值：C16H16NaO[M+Na+]247.1093,实测值：247.1096。
实施例39：化合物I-40的制备
Figure GDA0002784154240000241
所用的烷基溴化物为反式6-溴-4-甲基-3-己烯-1-醇(38.6mg，0.2mmol)，其他条件同实施例1，得化合物I-40(无色油状液体，产率60％)。1H NMR(400MHz,CDCl3):δ9.64(t,J＝1.4Hz,1H),8.07(d,J＝8.3Hz,1H),7.86(d,J＝7.9Hz,1H),7.70(d,J＝8.2Hz,1H),7.48–7.39(m,2H),7.34(d,J＝8.2Hz,1H),3.10–2.96(m,2H),2.48–2.41(m,2H),2.27–2.13(m,3H),2.05–1.98(m,1H),1.61(s,3H)；13C NMR(100MHz,CDCl3):δ202.7,142.4,141.6,133.7,130.3,129.5,128.3,126.0,124.6,123.7,123.2,49.4,40.6,39.3,33.2,31.1,28.1；HRMS(ESI-TOF):理论计算值：C17H18NaO[M+Na+]261.1250,实测值：261.1256。
实施例40：化合物I-41的制备
Figure GDA0002784154240000242
所用的芳基碘化物为2-甲基碘苯(52.3mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-41(无色油状液体，产率46％)。1H NMR(400MHz,CDCl3):δ9.67(t,J＝3.0Hz,1H),7.11–7.05(m,2H),6.95(d,J＝7.0Hz,1H),2.97–2.83(m,2H),2.82–2.71(m,2H),2.39(s,3H),2.24–2.17(m,1H),2.03–1.96(m,1H),1.46(s,3H)；13C NMR(100MHz,CDCl3):δ203.3,146.0,143.5,133.5,129.7,127.4,122.9,52.9,47.2,39.8,30.2,26.2,19.7；HRMS(ESI-TOF):理论计算值：C13H16NaO[M+Na+]211.1093,实测值：211.1098。
实施例41：化合物I-42的制备
Figure GDA0002784154240000243
所用的芳基碘化物为2-乙基碘苯(55.7mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-42(无色油状液体，产率50％)。1H NMR(400MHz,CDCl3):δ9.67(t,J＝3.0Hz,1H),7.18–7.04(m,1H),7.07–7.04(m,2H),2.97–2.84(m,2H),2.82–2.68(m,4H),2.23–2.17(m,1H),2.04–1.96(m,1H),1.50(s,3H),1.27(t,J＝7.5Hz,3H)；13C NMR(100MHz,CDCl3):δ203.3,145.5,143.6,140.1,127.6,127.5,122.6,53.7,47.3,40.0,30.2,27.2,25.0,15.6；HRMS(ESI-TOF):理论计算值：C14H18NaO[M+Na+]225.1250,实测值：225.1252。
实施例42：化合物I-43的制备
Figure GDA0002784154240000251
所用的芳基碘化物为2-氟碘苯(53.3mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-43(无色油状液体，产率50％)。1H NMR(400MHz,CDCl3):δ9.71(t,J＝3.0Hz,1H),7.18–7.13(m,1H),6.99(d,J＝7.4Hz,1H),6.84(t,J＝9.5Hz,1H),3.04–2.89(m,2H),2.86–2.78(m,2H),2.21–2.13(m,1H),2.08–2.00(m,1H),1.47(s,3H)；13C NMR(100MHz,CDCl3):δ202.8,159.7(d,J＝245.2Hz),146.4(d,J＝6.1Hz),134.6(d,J＝14.6Hz),129.3(d,J＝7.6Hz),120.8(d,J＝3.3Hz),113.9(d,J＝21.2Hz),53.3(d,J＝2.1Hz),46.1(d,J＝2.4Hz),39.3,31.0(d,J＝1.6Hz),26.5(d,J＝1.7Hz)；19F NMR(377MHz,CDCl3):δ–121.1；HRMS(ESI-TOF):理论计算值：C12H13FNaO[M+Na+]215.0843,实测值：215.0854。
实施例43：化合物I-44的制备
Figure GDA0002784154240000252
所用的芳基碘化物为2-氯碘苯(57.2mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-44(无色油状液体，产率42％)。1H NMR(400MHz,CDCl3):δ9.66(dd,J＝3.3,2.1Hz,1H),7.15–7.10(m,3H),3.09(dd,J＝15.6,2.1Hz,1H),3.00–2.89(m,2H),2.85(dd,J＝15.6,3.3Hz,1H),2.23–2.16(m,1H),2.05–1.98(m,1H),1.49(s,3H)；13C NMR(100MHz,CDCl3):δ202.8,146.0,144.5,130.5,128.8,128.5,123.7,52.4,47.7,39.2,30.4,25.8；HRMS(ESI-TOF):理论计算值：C12H13ClNaO[M+Na+]231.0547,实测值：231.0555。
实施例44：化合物I-45的制备
Figure GDA0002784154240000261
所用的芳基碘化物为2-甲氧基碘苯(56.2mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-45(无色油状液体，产率45％)。1H NMR(400MHz,CDCl3):δ9.65(dd,J＝3.8,2.2Hz,1H),7.18–7.13(m,1H),6.82(d,J＝8.0Hz,1H),6.69(d,J＝8.1Hz,1H),3.81(s,3H),2.99–2.83(m,3H),2.75(dd,J＝15.0,3.8Hz,1H),2.13–2.06(m,1H),2.01–1.94(m,1H),1.43(s,3H)；13C NMR(100MHz,CDCl3):δ204.4,156.4,145.1,135.3,128.8,117.5,108.8,55.1,53.1,46.4,39.6,30.6,26.0；HRMS(ESI-TOF):理论计算值：C13H16NaO[M+Na+]227.1043,实测值：227.1049。
实施例45：化合物I-46的制备
Figure GDA0002784154240000262
所用的芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯(113.8mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-46(无色油状液体，产率55％)。1H NMR(400MHz,CDCl3):δ9.61(dd,J＝3.4,2.2Hz,1H),7.44–7.33(m,10H),6.62(s,1H),5.10–5.04(m,4H),3.82(s,3H),2.96–2.81(m,2H),2.79–2.65(m,2H),2.13–2.05(m,1H),1.99–1.93(m,1H),1.39(s,3H)；13C NMR(100MHz,CDCl3):δ203.6,167.7,156.9,153.4,147.6,136.8(2C),132.7,128.7,128.6,128.3,127.9,127.8,126.9,116.0,104.8,76.1,70.8,53.3,52.7,46.3,39.4,31.2,27.1；HRMS(ESI-TOF):理论计算值：C28H28NaO5[M+Na+]467.1829,实测值：467.1834。
实施例46：化合物I-47的制备
Figure GDA0002784154240000271
所用的芳基碘化物为5-苄氧基-6-碘-2，2-二甲基苯并[1,3]二氧-4-酮(98.4mg，0.24mmol)，烷基溴化物为反式5-溴-3-甲基-2-戊烯-1-醇(35.8mg，0.2mmol)，其他条件同实施例1，得化合物I-47(无色油状液体，产率55％)。1H NMR(400MHz,CDCl3):δ9.57(dd,J＝3.0,2.1Hz,1H),7.53–7.50(m,2H),7.41–7.34(m,3H),6.58(s,1H),5.18(d,J＝10.3Hz,1H),5.02(d,J＝10.4Hz,1H),2.93–2.86(m,2H),2.81–2.67(m,2H),2.12–2.04(m,1H),1.98–1.91(m,1H),1.74(s,6H),1.36(s,3H)；13C NMR(100MHz,CDCl3):δ202.9,159.0,157.6,157.5,154.6,136.6,135.2,128.9,128.7,128.5,108.7,105.3,105.2,53.2,46.3,38.8,31.4,26.9,25.9,25.4；HRMS(ESI-TOF):理论计算值：C23H24NaO5[M+Na+]403.1516,实测值：403.1518。
实施例47：化合物D的制备
Figure GDA0002784154240000272
向干燥并装有磁力搅拌子的反应管中加入甲胺盐酸盐(40.1mg，0.59mmol)、氰基硼氢化钠(14.9mg,0.24mmol)和甲醇(0.5mL)，搅拌下缓慢加入化合物I-22(35mg，0.12mmol)的甲醇(2.0mL)溶液，然后于室温下搅拌12小时。加入饱和的碳酸氢钠溶液，二氯甲烷萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂，柱层析提纯得化合物D(白色固体，产率94％)，熔点188–190℃。1H NMR(400MHz,CDCl3):δ9.39(s,1H),7.46–7.44(m,2H),7.37–7.33(m,2H),7.30–7.27(m,1H),6.95(d,J＝8.4Hz,1H),6.86(d,J＝2.6Hz,1H),6.74(dd,J＝8.4,2.6Hz,1H),5.08(m,2H),2.83(td,J＝12.4,4.3Hz,1H),2.68–2.56(m,3H),2.51(s,3H),2.34(td,J＝12.9,4.5Hz,1H),2.04(td,J＝12.8,4.3Hz,1H),1.77–1.65(m,3H),1.61–1.55(m,1H),1.26(s,3H).13C NMR(100MHz,CDCl3):δ157.3,143.1,137.4,130.4,129.4,128.6,127.9,127.7,113.3,112.3,70.0,46.0,38.3,36.5,35.4,32.7,31.2,29.7,19.6.HRMS(ESI-TOF):理论计算值：C21H28NO[M+H+]310.2165,实测值：310.2167。
实施例48：化合物E的制备
Figure GDA0002784154240000281
向装有磁力搅拌子的反应管中加入化合物D(44mg,0.142mmol)和冰醋酸(3mL)，搅拌下缓慢加入三氧化铬(35.5mg,0.355mmol)的水/冰醋酸(1/4，1mL)溶液，然后于室温搅拌2小时。化合物D消失后，向反应体系中加入甲醇(0.5mL)，在室温下继续搅拌一小时。然后加入质量分数为37％的甲醛水溶液(0.155mmol)，反应体系升温至55℃，并在此温度下搅拌16小时。反应结束后恢复至室温，减压除去醋酸，粗产物加入水(3mL)，然后用10％的氢氧化钠水溶液中和至碱性，乙醚萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂，柱层析提纯得化合物E(白色固体，产率71％)，熔点175–177℃。1H NMR(400MHz,CDCl3):δ8.02(d,J＝8.5Hz,1H),7.43–7.32(m,5H),6.96–6.92(m,2H),5.11(s,2H),3.54(dd,J＝12.7,8.4Hz,1H),3.13(d,J＝12.7Hz,1H),2.87–2.82(m,1H),2.70–2.60(m,2H),2.56(s,3H),2.52–2.36(m,2H),2.27–2.21(m,1H),1.68–1.63(m,1H),1.48(s,3H)；13C NMR(100MHz,CDCl3):δ199.1,164.0,152.6,135.9,130.1,128.8,128.5,127.7,125.8,113.5,111.5,70.3,60.5,53.2,47.0,44.0,42.3,36.2,36.0,29.9；HRMS(ESI-TOF):理论计算值：C22H26NO2[M+H+]336.1958,实测值：336.1961。
实施例49：化合物(±)-eptazocine的制备
Figure GDA0002784154240000282
向装有磁力搅拌子的反应瓶中加入化合物E(30mg,0.09mmol)、钯/碳(9mg)、70％的高氯酸(2μL)和乙醇(2mL)，然后于40atm的氢气压力下65℃反应24小时。过滤除去钯/碳，减压蒸馏除去溶剂，粗产物加入水(3mL)，然后用10％的氢氧化钠水溶液中和至中性，乙醚萃取，合并有机相，饱和食盐水洗，无水硫酸钠干燥，减压除去溶剂，柱层析提纯得化合物(±)-eptazocine(无色油状液体，产率90％)。1H NMR(600MHz,Methanol-d4):δ6.88(d,J＝8.2Hz,1H),6.69(d,J＝2.5Hz,1H),6.56(dd,J＝8.3,2.5Hz,1H),3.08(t,J＝12.1Hz,1H),2.77(dd,J＝15.4,4.4Hz,1H),2.67(d,J＝13.1Hz,1H),2.45(td,J＝8.0,4.4Hz,1H),2.36(d,J＝15.4Hz,1H),2.24(s,3H),2.21(dd,J＝13.8,3.3Hz,1H),1.86(dd,J＝13.5,7.2Hz,1H),1.80–1.68(m,4H),1.23(s,3H)；13C NMR(100MHz,Methanol-d4):δ156.8,145.4,132.2,127.4,114.4,113.6,64.9,60.1,46.5,41.6,37.8,37.3,33.9,30.8；HRMS(ESI-TOF):理论计算值：C15H22NO[M+H+]232.1696,实测值：232.1697。
实施例50：化合物氢溴酸依他佐辛的制备
Figure GDA0002784154240000291
向装有磁力搅拌子的反应管中加入化合物(±)-eptazocine(18mg,0.08mmol)和40％的氢溴酸溶液(1mL)，室温下搅拌10分钟，减压蒸馏除去溶剂，即可得化合物氢溴酸依他佐辛(白色固体，产率91％)，熔点267–269℃。1H NMR(400MHz,Methanol-d4):δ6.97(d,J＝8.3Hz,1H),6.75(d,J＝2.6Hz,1H),6.64(dd,J＝8.3,2.5Hz,1H),3.71–3.63(m,1H),3.37–3.30(m,1H),2.92–2.87(m,1H),2.82(s,3H),2.73–2.62(m,3H),2.51(d,J＝16.2Hz,1H),2.17–2.11(m,1H),2.10–2.05(m,1H),1.99–1.92(m,2H),1.34(s,3H)；13C NMR(100MHz,Methanol-d4):δ157.7,143.4,132.7,125.8,115.5,113.6,63.6,59.8,47.6,43.4,40.8,37.2,36.4,33.1,28.7。

Claims (2)

1.一种合成具有苄位季碳中心的苯并环衍生物的方法，其特征在于，包括以下步骤：在惰性气体保护下，将芳香碘代物、烷基卤化物、烯丙基氯化钯二聚体、XPhos、碳酸钾、催化量的5-降冰片烯-2-甲酸于30～120℃的乙腈中搅拌反应，反应结束后分离提纯，得具有苄位季碳中心的苯并环衍生物；
当芳香碘代物为1-碘萘、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000011
当芳香碘代物为1-碘萘、烷基卤化物为反式7-溴-4-甲基-3-庚烯-1-醇时，得化合物
Figure FDA0002819690240000012
当芳基碘化物为2-甲基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000013
当芳基碘化物为2-甲基碘苯、烷基卤化物为反式7-溴-4-甲基-3-庚烯-1-醇时，得化合物
Figure FDA0002819690240000014
当芳基碘化物为2-乙基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000015
当芳基碘化物为2-异丙基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000021
当芳基碘化物为2-碘-1,1’-联苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000022
当芳基碘化物为2-氟碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000023
当芳基碘化物为2-氯碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000024
当芳基碘化物为2-苄氧基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000025
当芳基碘化物为N-Boc保护的3-氯-4-碘苯胺、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000026
当芳基碘化物为3-氟-2-甲基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000027
当芳基碘化物为4-氟-2-甲基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000031
当芳基碘化物为4-硝基-2-甲基碘苯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000032
当芳基碘化物为4-碘-3-甲基苯甲酸甲酯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000033
当芳基碘化物为1-溴-4-碘萘、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000034
当芳基碘化物为6-氯-5-碘-2,3-二氢螺(茚-1,2’-(1,3)二氧戊烷)、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000035
当芳基碘化物为3-碘-2-甲氧基吡啶、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000036
当芳基碘化物为4-碘-喹啉、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000037
当芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000041
当芳基碘化物为2,6-二苄氧基-3-碘苯甲酸甲酯，烷基卤化物为反式7-溴-4-甲基-3-庚烯-1-醇时，得化合物
Figure FDA0002819690240000042
当芳基碘化物为5-苄氧基-6-碘-2，2-二甲基苯并[1,3]二氧-4-酮、烷基卤化物为反式6-溴-3-甲基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000043
当芳香碘代物为1-碘萘、烷基卤化物为反式7-溴-4-甲基-3-庚烯-2-醇时，得化合物
Figure FDA0002819690240000044
当芳香碘代物为1-碘萘、烷基卤化物为反式6-溴-3-乙基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000045
当芳香碘代物为1-碘萘、烷基卤化物为反式6-溴-3-苯基-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000046
当芳香碘代物为1-碘萘、烷基卤化物为反式6-溴-2-己烯-1-醇时，得化合物
Figure FDA0002819690240000051
当芳香碘代物为1-碘萘、烷基卤化物为反式7-溴-2-庚烯-1-醇时，得化合物
Figure FDA0002819690240000052
当芳香碘代物为1-碘萘、烷基卤化物为反式6-溴-4-甲基-3-己烯-1-醇时，得化合物
Figure FDA0002819690240000053
2.根据权利要求1所述的方法，其特征在于：芳香碘代物与烷基卤化物的投料摩尔比为(1～10):1。
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