CN111533649A - 一种酸类化合物的合成方法 - Google Patents

一种酸类化合物的合成方法 Download PDF

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CN111533649A
CN111533649A CN202010484482.8A CN202010484482A CN111533649A CN 111533649 A CN111533649 A CN 111533649A CN 202010484482 A CN202010484482 A CN 202010484482A CN 111533649 A CN111533649 A CN 111533649A
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毛建友
林庭志
钱鹏程
谷元云
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Abstract

本发明属于有机合成领域，特别涉及一种酸类化合物的合成方法。采用酸酐类化合物和烷基溴代物或官能化烷基溴代物进行交叉亲电偶联反应合成酸类化合物，扩大了烷基溴化物在交叉亲电偶合反应中的应用，提供了一种新的、非传统的通过脱碳过程化学选择性地构建碳碳键的方法。且该合成方法简单、经济、绿色环保、适用性更加广泛或适于规模化生产。

Description

一种酸类化合物的合成方法
技术领域
本发明属于有机合成领域，特别涉及一种酸类化合物的合成方法。
背景技术
过渡金属催化的交叉偶联反应是构建碳碳键的重要手段，在药学和天然产物合成中有着广泛的应用。 过渡金属催化的两种不同的亲电体的交叉偶联反应具有良好的官能团耐受性，可以避免使用对水分敏感的 有机金属试剂，简化传统工艺。酸类化合物是重要的有机合成试剂，现有技术中，王进贤等人公开了在相 转移条件下，采用羰基钴催化羰化炔烃合成酸类化合物的方法，但该方法合成步骤较多，产率不高，合成 所用原料的稳定性差。
发明内容
本发明提供了一种过渡金属催化的环状酸酐与官能化烷基溴化物的交叉亲电偶联反应，可以得到多种 具有生物活性的酸类化合物，扩大了烷基溴化物在交叉亲电偶合反应中的应用，且该方法为一种新的、非 传统的通过脱碳过程化学选择性地构建碳碳键的方法。合成方法简单、经济、绿色环保、适用性更加广泛 或适于规模化生产。具体方案如下：
一种酸类化合物的合成方法，采用下述路线合成：
Figure BDA0002518614630000011
采用式1所示的酸酐类化合物和式2所示的溴代物进行交叉亲电偶联反应合成式3所示的酸类化合 物；或采用式4所示的酸酐类化合物和式2所示的溴代物进行交叉亲电偶联反应合成式5所示的酸类化合 物；
所述的式2所示的结构中的R为烷基或官能化烷基，式4所示的结构中的R1为烷基或官能化烷基 此处所述的“官能化烷基”是指的烷基上面具有官能团，例如卤素、酯基等官能团。
优选的，所述R为烷基，所述烷基是具有1-20个碳原子的支链或直链或环烷基，当R为支链或直 链烷基时，式2可能是一级溴代物，如1-溴辛烷，也可能是二级溴代物，如2-溴丁烷；或
所述R为官能化烷基，所述官能化烷基是官能化的具有1-20个碳原子的支链或直链或环烷基，所 述的官能化为含有至少一种下述官能团：苯并四氢呋喃基、卤素基、-COOR2、-OOCR3、苯基、取代苯基、 3～8个碳原子的环烷基、N-邻苯二甲酰亚胺基、呋喃基、1～5个碳原子的烷氧基、苄氧基，前述所述“取代 苯基”中的“取代”选自1～5个碳原子的烷氧基，前述R2、R3选自1～5个碳原子的烷基；和/或式4所示的 取代基R1为具有1-20个碳原子的支链或直链或环状烷基。
优选的，所述的R为烷基，所述烷基是具有1～8个碳原子的直链烷基或支链烷基或环烷基；或所述R为官能化烷基，所述官能化烷基是官能化的具有1-8个碳原子的支链或直链或环烷基，所述的官能化为 含有至少一种下述官能团：苯并四氢呋喃基、卤素基、-COOR2、-OOCR3、苯基、取代苯基、3～6个碳原 子的环烷基、N-邻苯二甲酰亚胺基、1～5个碳原子的烷氧基、苄氧基，前述所述“取代苯基”中的“取代”选 自甲氧基，前述R2、R3选自1～2个碳原子的烷基；和/或式4所示的取代基R1为具有1-4个碳原子的支 链或直链或环状的烷基。
优选的，所述的酸酐类化合物、溴代物以及产物酸类化合物为如下之一：
Figure BDA0002518614630000021
Figure BDA0002518614630000031
优选的，所述的合成是在过渡金属催化剂和过渡金属还原剂以及有机溶剂存在的条件下发生的。
优选的，所述的过渡金属催化剂为镍系催化剂或钯系催化剂；或所述的过渡金属还原剂为锌粉或者 锰粉；或所述的有机溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、2-甲基四氢呋喃、二甲基亚砜、乙 腈、四氢呋喃或甲苯。
优选的，所述的镍催化剂为双-(1,5-环辛二烯)镍、氯化镍及其水合物、溴化镍及其水合物、碘化 镍及其水合物、乙二醇二甲醚氯化镍、乙二醇二甲醚溴化镍或双(三苯基膦)氯化镍；或所述的钯催化剂为 四三苯基膦钯；
优选的，所述反应在惰性气体或氮气保护下进行。优选的，所述的惰性气体为氮气或氩气。
优选的，所述的过渡金属催化剂与吡啶类配体配位使用，所述的吡啶类配体选自如下：
Figure BDA0002518614630000041
优选的，反应中式1所示的酸酐、式2所示的溴代物、还原剂和催化剂的摩尔比为：2～1：1～2：2： 0.1，优选摩尔比为1.5：1：2：0.1。
优选的，所述反应温度为40℃～120℃，优选的温度为60℃～100℃，更加优选的温度为80℃。
本发明的有益效果为：采用酸酐类化合物和溴代物、在过渡金属催化剂、过渡金属还原剂和有机溶 剂存在的条件下，反应合成酸类化合物，扩大了烷基溴化物在交叉亲电偶合反应中的应用，提供了一种全 新的、非传统的通过脱碳过程化学选择性地构建碳碳键的方法。且该合成方法简单、经济、绿色环保、适 用性更加广泛或适于规模化生产的酸类化合物的合成方法。过渡金属催化剂与2,2'-联吡啶配位使用，可以 加强、活化催化剂的催化活性，使得催化效果更好。
附图说明
附图1A～附图5A分别为实施例1～5的产物的氢谱图，附图1B～附图5B分别为实施例1～5的产物的 碳谱图，附图6A～附图18A分别为实施例7、实施例11、实施例13、实施例14、实施例18、实施例20、 实施例21、实施例22、实施例24、实施例26、实施例27、实施例28、实施例30的产物的氢谱图；附图 6B～附图18B分别为实施例7、实施例11、实施例13、实施例14、实施例18、实施例20、实施例21、实 施例22、实施例24、实施例26、实施例27、实施例28、实施例30的产物的碳谱图。
具体实施例
为了便于本领域技术人员理解，下面结合实施例对本发明的构思做进一步的说明。以下实施例的具体 说明并非对本发明的限制，只是为了方便本领域技术人员理解本技术方案。说明书中所涉及的各种原料， 均购自市场，或经过简单的合成，其他药品等购自Sigma-Aldrich,Acros,Alfa Aesar,TCI China,Adamas-beta 或者J&K.，核磁共振谱仪型号为布鲁克400兆。
下述反应均在氩气保护下进行。下述实施例1～31中产物的收率或产率指的是产物的分离收率。实施 例中所涉及的分离收率是指柱层析分离计算得到的产率，GC收率是指通过气相色谱得到的收率。
实施例1
在手套箱中将双-(1,5-环辛二烯)镍(8.3mg，0.03mmol)与2,2'-联吡啶，即化学结构式结构式L1， (7.0mg，0.045mmol)加入微波管中，加入0.225mLN,N-二甲基乙酰胺配位一个小时，将锌粉(39.2mg， 0.6mmol，2.0当量)加入到微波管中，然后加入丁二酸酐(0.45mmol，1.5当量)和1-溴辛烷(0.3mmol， 1.0当量)，加盖从手套箱取出，在80℃下回流12小时，冷却至室温，启盖并加三滴水淬灭反应，减压 去除溶剂，粗产品柱层析分离(石油醚：乙酸乙酯＝5:1)，即可得11烷酸(47.0mg,84％yield)。产物的比 移值Rf＝0.81(石油醚：乙酸乙酯＝5:1)，产物的氢谱和碳谱核磁共振谱图分别为图1A和图1B，谱图数 据为:1HNMR(400MHz,Chloroform-d)δ2.35(t,J＝7.5Hz,2H),1.66–1.60(m,2H),1.28(d,J＝15.2Hz,14H), 0.90–0.86(m,3H).13C NMR(101MHz,Chloroform-d)δ180.1,34.1,31.8,29.5,29.4,29.3,29.2,29.0,24.6, 22.6.。
变换实施例1中的原料，其他条件和操作均保持不变，设计如下31组实验实施例，其中第1组实验 即为实施例1，对应的产物的核磁共振谱图为图1A和图1B。其余2-31各组产物的核磁共振谱图的序号如 下表所示：
实施例序号 附图序号 实施例序号 附图序号 实施例序号 附图序号
1 1A、1B 11 7A、7B 22 13A、13B
2 2A、2B 13 8A、8B 24 14A、14B
3 3A、3B 14 9A、9B 26 15A、15B
4 4A、4B 18 10A、10B 27 16A、16B
5 5A、5B 20 11A、11B 28 17A、17B
7 6A、6B 21 12A、12B 30 18A、18B
表中列出了1-31各实施例中产物的结构式，31个实施例中，仅采用的酸酐和溴代物的种类不同，其 他原料、用量、条件等均保持一致，并列出了各实施例的产物的产率。
Figure BDA0002518614630000051
Figure BDA0002518614630000061
Figure BDA0002518614630000071
实施例2：将实施例1中的酸酐和溴代物变为丁二酸酐(0.45mmol，1.5当量)和5-(2-溴乙基)-2,3- 二氢苯并呋喃(0.3mmol，1.0当量)，其他条件和操作均保持不变，最后可得产物(54.2mg,82％yield)。 产物的比移值Rf＝0.66(石油醚：乙酸乙酯＝2:1)，产物的氢谱和碳谱核磁共振谱图分别为图2A和图2B， 谱图数据为：1H NMR(400MHz,CDCl3)δ:7.00(s,1H),6.89(d,J＝8.1Hz,1H),6.69(d,J＝8.1Hz,1H),4.53 (t,J＝8.7Hz,2H),3.17(t,J＝8.7Hz,2H),2.55(t,J＝7.1Hz,2H),2.36(t,J＝7.0Hz,2H),1.69-1.61(m, 4H).ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.9,158.2,133.9,127.7,126.9,124.8,108.9,71.1,34.9, 33.9,31.2,29.8,24.2ppm.IR(neat):3438,3052,2948,2934,2856,1701,1653,1492,1409,1320,1247,1202, 981,816,737.HRMS:calcd for C13H17O3[M+H]+221.1178,found221.1177.
实施例3：最后可得白色固体产物(39.5mg,70％yield)。产物的比移值Rf＝0.63(石油醚：乙酸乙酯 ＝2:1)，产物的氢谱和碳谱核磁共振谱图分别为图3A和图3B，谱图数据为：1H NMR(400MHz,CDCl3)δ: 1H NMR(400MHz,Chloroform-d)δ4.06(t,J＝6.7Hz,2H),2.36(t,J＝7.4Hz,2H),2.05(s,3H),1.67–1.60 (m,4H),1.40-1.36(m,4H).13C{1H}NMR(101MHz,CDCl3)δ:179.6,171.3,64.4,33.9,28.6,28.3,25.6, 24.5,20.9.IR(neat):3459,2940,2863,1737,1721,1392,1248,1037,889,764,608,484,450.HRMS:calcd for C9H17O4[M+H]+189.1127,found 189.1129.
实施例4：最后可得白色固体产物(82.8mg,91％yield)，产物比移值Rf＝0.48(石油醚：乙酸乙酯＝2:1)， 产物的氢谱和碳谱核磁共振谱图分别为图4A和图4B，谱图数据为：1H NMR(400MHz,CDCl3)δ:1H NMR (400MHz,Chloroform-d)δ1H NMR(400MHz,Chloroform-d)δ7.85-7.83(m,2H),7.72-7.70(m,2H),3.67(t,J ＝7.3Hz,2H),2.34(t,J＝7.5Hz,2H),1.69-1.60(m,4H),1.36–1.33-1.32(m,8H).13C{1H}NMR(101MHz, CDCl3)δ:179.8,168.4,133.8,132.1,123.1,37.9,33.9,28.9,28.9,28.5,26.7,24.5.One resonance was notobserved due to overlapping resonances.IR(neat):3462,3099,2932,2856,1772,1716,1615,1465,1396,1233, 1055,930,720,711,531.HRMS:calcd for C17H22NO4[M+H]+304.1549,found 304.1545。
实施例5：最后可得无色油状产物(53.9mg,68％yield)，产物比移值Rf＝0.57(石油醚：乙酸乙酯＝2:1)， 产物的氢谱和碳谱核磁共振谱图分别为图5A和图5B，谱图数据为：1H NMR(400MHz,CDCl3)δ:7.34– 7.33(m,4H),7.30–7.26(m,1H),4.50(s,2H),3.46(t,J＝6.6Hz,2H),2.34(t,J＝7.5Hz,2H),1.64–1.57(m, 4H),1.35–1.31(m,8H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.9,138.6,128.3,127.6,127.5,72.8, 70.4,34.0,29.7,29.2,29.1,29.0,26.1,24.6ppm.IR(neat):3668,3114,2935,2857,1704,1683,1558,1453, 1362,1205,1098,849,738,698,523,461,419.HRMS:calcd for C16H25O3[M+H]+265.1804,found265.1804。
实施例6：最后可得无色油状产物(49.3mg,76％yield)，产物比移值Rf＝0.61(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图的谱图数据为：1H NMR(400MHz,CDCl3)δ:4.11(q,J＝7.1Hz, 2H),2.33(t,J＝7.5Hz,2H),2.27(t,J＝7.5Hz,2H),1.63–1.58(m,4H),1.31–1.30(m,6H),1.24(t,J＝7.1Hz, 3H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.9,173.9,60.2,34.3,34.0,28.9,28.82,28.80,24.8,24.5, 14.2ppm.IR(neat):3627,1658,1651,1373,1257,1185,1096,748,625,514,482,452,421.HRMS:calcdfor C11H21O4[M+H]+217.1440,found217.1440.
实施例7：最后可得无色油状产物(24.3mg,57％yield)，产物比移值Rf＝0.79(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图6A和图6B，谱图数据为：1H NMR(400MHz,CDCl3)δ: 1H NMR(400MHz,Chloroform-d)δ2.38(t,J＝7.0Hz,2H),1.83-1.78(m,3H),1.68–1.52(m,5H),1.30–1.26 (m,1H),1.10–1.09(m,2H).13C{1H}NMR(101MHz,CDCl3)δ:180.3,39.6,32.4,30.9,25.1.IR(neat):2431, 2950,2868,1709,1650,1453,1413,1283,1214,1090,936,816,632,505,430.HRMS:calcd for C8H15O2 [M+H]+143.1072,found 143.1072.
实施例8：最后可得无色油状产物(31.9mg,68％yield)，产物比移值Rf＝0.81(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1HNMR(400MHz,Chloroform-d)δ2.40–2.32(m,2H),1.75 –1.62(m,5H),1.57–1.50(m,2H),1.29–1.11(m,4H),0.95–0.84(m,2H).13C{1H}NMR(101MHz,CDCl3) δ:180.8,37.0,32.9,32.0,31.6,26.4,26.1.
实施例9：最后可得无色油状产物(50.0mg,87％yield)，产物比移值Rf＝0.78(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1HNMR(401MHz,Chloroform-d)δ2.35(t,J＝7.5Hz,2H), 1.63(p,J＝7.5Hz,2H),1.33–1.20(m,12H),0.91–0.86(m,3H).13C NMR(101MHz,Chloroform-d)δ180.21, 34.14,31.94,29.47,29.33,29.32,29.14,24.76,22.74,14.18.
实施例10：最后可得无色油状产物(55.3mg,92％yield)，产物比移值Rf＝0.78(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1HNMR(400MHz,Chloroform-d)δ2.35(t,J＝7.5Hz,2H), 1.63(p,J＝7.5Hz,2H),1.28(d,J＝16.3Hz,16H),0.92–0.85(m,3H).13C NMR(101MHz,Chloroform-d)δ179.97, 34.04,31.89,29.60,29.58,29.42,29.31,29.23,29.04,24.67,22.67,14.10.
实施例11：最后可得无色油状产物(29.9mg,63％yield)，产物比移值Rf＝0.88(石油醚：乙酸乙酯 ＝2:1)，经检测得产物的氢谱和碳谱核磁共振谱图分别为图7A和图7B，产物的谱图数据为：1H NMR(400 MHz,CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ1H NMR(400MHz,Chloroform-d)δ2.35(t,J＝7.5Hz, 2H),1.68-1.60(m,2H),1.55-1.48(m,1H),1.33-1.29(m,4H),1.19-1.15(m,2H),0.86(d,J＝6.6Hz,6H).13C{1H} NMR(101MHz,CDCl3)δ:38.7,33.9,29.3,27.9,26.9,24.7,22.6.IR(neat):3430,2955,2930,2869,1712, 1467,1412,1276,1232,939,764,749,596,437.HRMS:calcd for C9H19O2[M+H]+159.1385,found159.1385.
实施例12：最后可得无色油状产物(39.4mg,81％yield)，产物比移值Rf＝0.68(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz, Chloroform-d)δ1H NMR(400MHz,Chloroform-d)δ4.50(t,J＝6.1Hz,1H),4.38(t,J＝6.1Hz,1H),2.36(t,J＝ 7.5Hz,2H),1.74–1.70(m,1H),1.69–1.61(m,3H),1.45–1.34(m,6H).13C NMR(101MHz,Chloroform-d)δ 177.54,84.10(d,J1 C-F＝164.0Hz),33.97,30.28(d,J2 C-F＝19.4Hz),28.87,28.81,24.95(d,J3 C-F＝5.5Hz),24.51.IR(neat):3440,2936,1861,1705,1646,1469,1292,1099,1043,984,917,739,595,501,449.HRMS: calcd for C8H16FO2[M+H]+163.1134,found 163.1133.
实施例13最后可得无色油状产物(45.0mg,84％yield)，产物比移值Rf＝0.68(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图8A和图8B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ3.53(t,J＝6.8Hz,2H),2.36(t,J＝7.5Hz,2H),1.80–1.73(m, 2H),1.68-1.61(m,2H),1.48-1.41(m,2H),1.36-1.33(m,4H).13C NMR(101MHz,Chloroform-d)δ180.2,45.0, 33.9,32.5,28.8,28.5,26.6,24.5.IR(neat):3462,2936,2859,1713,1455,1412,1283,1247,1093,939,727,651,480.HRMS:calcd for C8H16ClO2[M+H]+239.0839,found239.0837.
实施例14最后可得无色油状产物(45.0mg,86％yield)，产物比移值Rf＝0.68(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图9A和图9B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ3.37(t,J＝6.6Hz,2H),3.33(s,3H),2.34(t,J＝7.4Hz,2H), 1.65-1.60(m,2H),1.58–1.53(m,2H),1.37–1.26(m,6H).13C NMR(101MHz,Chloroform-d)δ179.6,72.8, 58.5,33.9,29.5,29.0,28.9,25.9,24.6.IR(neat):3426,2934,2859,1737,1713,1462,1412,1199,1119,942,846,727,617,496.HRMS:calcd for C9H19O3[M+H]+175.1334,found 175.1330.
实施例15最后可得无色油状产物(45.0mg,90％yield)，产物比移值Rf＝0.73(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为1H NMR(400MHz,CDCl3)δ:7.29–7.24(m,2H),7.19– 7.16(m,3H),2.61(t,J＝7.6Hz,2H),2.35(t,J＝7.5Hz,2H),1.72–1.60(m,4H),1.43–1.35(m,2H).13C NMR (101MHz,Chloroform-d)δ180.1,142.4,128.4,128.3,125.7,35.7,33.9,31.1,28.6,24.5.IR(neat):3412, 3085,3027,2934,2858,1709,1496,1453,1288,1225,938,747,699,493.HRMS:calcd for C12H17O2 [M+H]+193.1229,found 193.1229.
实施例16最后可得白色固体产物(61.2mg,87％yield)，产物比移值Rf＝0.63(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz, Chloroform-d)δ7.00(s,1H),6.89(d,J＝8.1Hz,1H),6.69(d,J＝8.1Hz,1H),4.54(t,J＝8.6Hz,2H),3.17(t,J ＝8.6Hz,2H),2.54(t,J＝7.6Hz,2H),2.35(t,J＝7.5Hz,2H),1.70-1.63(m,2H),1.62–1.55(m,2H),1.42– 1.33(m,2H).13CNMR(101MHz,Chloroform-d)δ180.0,158.1,134.4,127.7,126.8,124.8,108.8,71.1,35.0,33.9,31.5,29.8,28.55,24.5.IR(neat):3440,2947,2926,2883,2854,1694,1639,1494,1408,1291,1187, 941,749,549,422.HRMS:calcd for C14H19O3[M+H]+235.1334,found235.1333.
实施例17：最后可得无色油状产物(44.9mg,74％yield)，产物比移值Rf＝0.57(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:4.05(t,J＝6.7Hz,2H),2.35 (t,J＝7.5Hz,2H),2.05(s,3H),1.66-1.59(m,4H),1.38-1.34(m,6H).13C NMR(101MHz,Chloroform-d)δ 179.8,171.3,64.5,33.9,28.9,28.8,28.5,25.7,24.5,20.9.IR(neat):3459,2936,2859,1738,1713,1651, 1463,1392,1367,1242,1040,898,727,608,490.HRMS:calcd for C10H19O4[M+H]+230.1283,found230.1284.
实施例18最后可得白色固体(85.7mg,90％yield)，产物比移值Rf＝0.40(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图10A和图10B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ7.85-7.83(m,2H),7.72-7.70(m,2H),3.68(t,J＝7.3Hz,2H), 2.34(t,J＝7.5Hz,2H),1.69-1.60(m,4H),1.33–1.29(m,10H).13C NMR(101MHz,Chloroform-d)δ179.8, 168.5,133.8,132.1,123.1,37.9,33.9,29.2,29.1,29.0,28.9,28.5,26.7,24.6.IR(neat):3467,2930,2849, 1772,1707,1701,1616,1465,1396,1252,1187,1054,720,711,530.HRMS:calcd for C18H24NO4 [M+H]+318.1705,found 318.1701.
实施例19最后可得白色固体(50.9mg,61％yield)，产物比移值Rf＝0.63(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:7.34–7.33(m,4H),7.30– 7.25(m,1H),4.50(s,2H),3.46(t,J＝6.6Hz,2H),2.34(t,J＝7.5Hz,2H),1.64–1.57(m,4H),1.34–1.26(m, 10H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:180.0,138.6,128.3,127.6,127.4,72.8,70.4,34.0,29.7, 29.34,29.31,29.1,29.0,26.1,24.6ppm.IR(neat):3651,3139,1681,1496,1455,1410,1361,1097,802,737, 698,472,441,421.HRMS:calcd for C17H27O3[M+H]+279.1960,found279.1961.
实施例20最后可得无色油状液体(44.2mg,64％yield)，产物比移值Rf＝0.62(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图11A和图11B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:4.11(q,J＝7.1Hz,2H),2.33(t,J＝7.5Hz,2H),2.27(t,J＝7.5Hz,2H),1.63–1.58(m,4H),1.40– 1.38(m,8H),1.24(t,J＝7.1Hz,3H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.9,173.9,60.2,34.3,34.0, 29.0,28.9,24.9,24.6,14.2ppm.Two resonances were not observed due to overlapping resonances.IR(neat): 3688,2856,1732,1714,1470,1302,1176,1024,932,861,753,677,523,425.HRMS:calcd for C12H23O4 [M+H]+231.1596,found231.1596.
实施例21最后可得无色油状液体(22.3mg,57％yield)，产物比移值Rf＝0.77(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图12A和图12B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:2.34(t,J＝7.6Hz,2H),1.65–1.56(m,2H),1.25–1.21(m,2H),1.10–1.05(m,1H),0.89(d,J＝6.6 Hz,6H).13C NMR(101MHz,Chloroform-d)δ179.9,38.2,34.4,27.7,22.6,22.4.IR(neat):3427,2956,2933, 2872,1710,1486,1412,1262,1109,946,752,655,632,465.HRMS:calcd for C7H15O2[M+H]+131.1072,found 131.1073.
实施例22最后可得无色油状液体(26.4mg,62％yield)，产物比移值Rf＝0.78(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图13A和图13B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ2.33(t,J＝7.4Hz,2H),2.29–2.21(m,1H),2.07–2.00(m,2H), 1.89–1.76(m,2H),1.61–1.51(m,4H),1.45–1.39(m,2H).13C NMR(101MHz,Chloroform-d)δ177.9,36.2, 35.7,33.9,28.2,22.4,18.4.IR(neat):3484,2934,2864,1709,1442,1412,1242,1120,933,914,748,596,488,465.HRMS:calcdfor C8H15O2[M+H]+143.1072,found 143.1072.
实施例23最后可得无色油状液体(38.9mg,83％yield)，产物比移值Rf＝0.76(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz, Chloroform-d)δ2.35(t,J＝7.5Hz,2H),1.76-1.72(m,3H),1.68–1.58(m,4H),1.52–1.50(m,2H),1.37-1.32 (m,2H),1.10–1.05(m,2H).13C NMR(101MHz,Chloroform-d)δ180.1,39.8,35.5,34.3,32.6,25.1, 23.9.IR(neat):3426,2949,2868,1709,1453,1413,1293,1211,1124,935,763,656,600,495.HRMS:calcd forC9H17O2[M+H]+157.1224,found 157.1229.
实施例24最后可得无色油状液体(38.8mg,76％yield)，产物比移值Rf＝0.70(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图为14A和14B，谱图数据为：1HNMR(400MHz,Chloroform-d)δ 2.33(t,J＝7.6Hz,2H),1.66(ddt,J＝15.7,7.8,3.6Hz,7H),1.27–1.14(m,6H),0.87(q,J＝10.5,9.2Hz,2H).13C NMR(101MHz,Chloroform-d)δ179.97,37.34,36.78,34.30,33.19,26.62,26.31,22.06.
实施例25最后可得无色油状液体(24.2mg,56％yield)，产物比移值Rf＝0.74(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,Chloroform-d)δ2.34(t,J＝7.8Hz, 2H),1.72–1.56(m,2H),1.38–1.29(m,3H),1.21–1.10(m,2H),0.88–0.84(m,6H).13C NMR(101MHz, Chloroform-d)δ180.2,35.9,34.4,34.1,29.3,22.3,19.0,11.3.IR(neat):3426,2959,2927,2856,1711,1463, 1412,1286,1115,938,750,597,496,477.HRMS:calcdfor C8H17O2[M+H]+145.1229,found 145.1231.
实施例26最后可得无色油状液体(46.9mg,71％yield)，产物比移值Rf＝0.71(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图15A和图15B，产物的谱图数据为：1H NMR(400MHz, Chloroform-d)δ7.28-7.24(m,2H),7.18-7.16(m,3H),2.68–2.60(m,1H),2.59-2.53(m,1H),2.33(t,J＝7.2Hz, 2H),1.68-1.60(m,3H),1.46–1.36(m,3H),1.25–1.18(m,1H),0.94(d,J＝5.6Hz,3H).13C NMR(101MHz,Chloroform-d)δ142.9,128.28,128.26,125.6,38.7,36.2,33.4,32.2,22.2,19.4.Oneresonance was not observed due to overlapping resonances.IR(neat):3427,3026,2953,2929,2870,1708,1496,1454,1275,1097, 939,746,699,514.HRMS:calcd forC14H21O2[M+H]+221.1542,found221.1539.
实施例27最后可得无色油状液体(50.3mg,67％yield)，产物比移值Rf＝0.67(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图16A和图16B，产物的谱图数据为：1H NMR(400MHz, Chloroform-d)δ7.09(d,J＝8.7Hz,2H),6.82(d,J＝8.7Hz,2H),3.78(s,3H),2.63–2.45(m,2H),2.35–2.32 (m,2H),1.72–1.55(m,3H),1.48–1.34(m,3H),1.25-1.16(m,1H),0.93(d,J＝6.3Hz,3H).13C NMR(101 MHz,Chloroform-d)δ157.6,134.9,129.2,113.7,55.2,38.9,36.2,32.4,32.1,22.2,19.4.One resonance wasnot observed due to overlapping resonances.IR(neat):3426,2952,2930,2869,1708,1612,1512,1463,1245, 1177,1037,822,655,561,523.HRMS:calcd for C15H23O3[M+H]+251.1647,found251.1648.
实施例28最后可得无色油状液体(80.3mg,80％yield)，产物比移值Rf＝0.57(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图17A和图17B，产物的谱图数据为：1H NMR(400MHz, CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ7.34-7.33(m,4H),7.29–7.24(m,1H),4.50(s,2H),3.46(t,J＝ 6.6Hz,2H),2.26-2.24(m,2H),1.93–1.90(m,1H),1.65-1.59(m,3H),1.37–1.25(m,10H),1.20–1.09(m, 2H),0.88(d,J＝6.6Hz,6H).13C NMR(101MHz,Chloroform-d)δ179.9,138.5,128.3,127.6,127.4,72.8, 70.4,43.6,39.2,33.9,32.5,29.8,29.7,29.4,26.2,26.1,25.2,22.72,22.70.IR(neat):3428,3088,3064, 3031,2929,2856,1705,1652,1454,1366,1275,1102,734,697,612.HRMS:calcd for C21H35O3 [M+H]+335.2586,found 335.2585.
实施例29最后可得无色油状液体(64.3mg,83％yield)，产物比移值Rf＝0.59(石油醚：乙酸乙酯＝2:1)， 产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:1H NMR(400MHz,Chloroform-d)δ 4.05(t,J＝6.7Hz,2H),2.28-2.25(m,2H),2.05(s,3H),1.94–1.91(m,1H),1.65–1.59(m,3H),1.35–1.29(m, 6H),1.21–1.10(m,2H),0.88(d,J＝6.6Hz,6H).13C NMR(101MHz,Chloroform-d)δ179.6,171.3,64.6, 43.5,39.1,33.9,32.5,28.5,26.1,25.9,25.2,22.8,22.7,20.9.IR(neat):3452,2955,2868,1739,1712,1467, 1367,1239,1042,674,599,481,460,430.HRMS:calcd for C14H27O4[M+H]+259.1909,found259.1905.
实施例30最后可得无色油状液体(63.2mg,72％yield)，产物比移值Rf＝0.53(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图分别为图18A和图18B，产物的谱图数据为1H NMR(400MHz, CDCl3)δ:7.34–7.33(m,4H),7.30–7.25(m,1H),4.51(s,2H),3.46(t,J＝6.6Hz,2H),2.37–2.32(m,1H), 2.16–2.10(m,1H),1.96–1.94(m,1H),1.64–1.57(m,2H),1.41–1.28(m,9H),1.21–1.18(m,1H),0.96(d,J ＝6.6Hz,3H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.5,138.6,128.3,127.6,127.5,72.8,70.4,41.6, 36.6,30.1,29.7,29.6,29.4,26.8,26.1,19.7ppm.IR(neat):3522,2929,2855,2793,1708,1603,1544,1496, 1408,1363,1298,1102,936,906,878,734,698,524,462.HRMS:calcd forC18H29O3[M+H]+293.2117, found293.2115.
实施例31最后可得无色油状液体(59.4mg,81％yield)，产物比移值Rf＝0.51(石油醚：乙酸乙酯＝2:1)， 经检测得产物的氢谱和碳谱核磁共振谱图数据为：1H NMR(400MHz,CDCl3)δ:4.11(q,J＝7.1Hz,2H), 2.36–2.26(m,3H),2.15–2.10(m,1H),1.94–1.93(m,1H),1.62–1.57(m,2H),1.30–1.22(m,11H),0.95(d, J＝6.6Hz,3H)ppm.13C{1H}NMR(101MHz,CDCl3)δ:179.5,173.9,60.2,41.5,36.5,34.3,30.1,29.3, 29.0,26.7,24.9,19.6,14.2ppm.IR(neat):3467,2933,2858,1736,1708,1465,1374,1249,1185,1034,975,901,860,725,612,524,496,419.HRMS:calcdfor C13H25O4[M+H]+245.1753,found245.1754.
实施例32～实施例36：将实施例1中的溶剂依次替换为下表中的其他溶剂，溶剂的浓度修改为 0.4mmol/ml，Ni(COD)2的用量为10mol％，配体用量为15mol％，其他条件、原料及操作均保持不变， 得到如下结果(下述表格中的收率为GC收率)：
实施例序号 溶剂 收率(％) 实施例序号 催溶剂 收率(％)
32 THF 34 35 DMSO 12
33 2-Me-THF 少量 36 CH<sub>3</sub>CN 23
34 DMF 63
实施例37～44将实施例1中的镍系催化剂依次替换为其他镍系催化剂，溶剂的浓度修改为0.4mmol/ml， 镍盐的用量为10mol％，配体用量为15mol％，其他条件、原料及操作均保持不变，得到如下结果(下述表 格中的收率为分离收率)：
实施例序号 催化剂 收率(％) 实施例序号 催化剂 收率(％)
37 NiF<sub>2</sub> 少量 41 NiCl<sub>2</sub>(PPh<sub>3</sub>)<sub>2</sub> 28
38 NiCl<sub>2</sub> 50 42 NiBr<sub>2</sub>.3H<sub>2</sub>O 27
39 NiBr<sub>2</sub> 23 43 NiBr<sub>2</sub>.DME 46
40 NiI<sub>2</sub> 52 44 NiCl<sub>2</sub>.DME 41
实施例45-51：将实施例1中的吡啶类配体依次替换为L2～L7，Ni(COD)2的用量为10mol％，配体 用量为15mol％，溶剂的浓度修改为0.4mmol/ml，其他条件、原料及操作均保持不变，L1～L7结构式如下：
Figure BDA0002518614630000121
得到如下结果(下述表格中的收率为分离收率)：
实施例序号 配体 收率(％) 实施例序号 配体 收率(％)
45 L1 63 49 L5 21
46 L2 32 50 L6 32
47 L3 26 51 L7 36
48 L4 25
实施例52-58：将实施例1中的溶剂的浓度修改为下表中的浓度，Ni(COD)2的用量为10mol％，配 体用量为15mol％，其他条件、原料及操作均保持不变，得到如下结果(下述表格中的收率为GC收率)：
实施例序号 浓度/M 收率(％) 实施例序号 浓度/M 收率(％)
52 0.4 62 56 1.0 70
53 0.5 61 57 1.3 87
54 0.7 62 58 2.0 86
55 0.8 63
实施例59
在与实施例1相同的反应条件下，当加入丁二酸酐(0.3mmol，1.0当量)和1-溴辛烷(0.6mmol，2.0 当量)也即改变原料比为1：2时，产率为72％；
实施例60
在与实施例1相同的反应条件下，当加入丁二酸酐(0.6mmol，2.0当量)和1-溴辛烷(0.3mmol，1.0 当量)，也即改变原料比为2：1时，产率为76％。
实施例61
在与实施例1相同的反应条件下，当仅改变反应温度为40℃时，产率为17％；当改变反应温度为 120℃时，产率为62％。

Claims (10)

1.一种酸类化合物的合成方法，其特征在于，
Figure FDA0002518614620000011
采用式1所示的酸酐类化合物和式2所示的溴代物进行交叉亲电偶联反应合成式3所示的酸类化合物；或
采用式4所示的酸酐类化合物和式2所示的溴代物进行交叉亲电偶联反应合成式5所示的酸类化合物；
所述的R为烷基或官能化烷基，式4所示的结构中的R1为烷基或官能化烷基。
2.根据权利要求1所述的合成方法，其特征在于，所述的R为烷基，所述烷基是具有1-20个碳原子的支链或直链或环烷基；或
所述的R为官能化烷基，所述官能化烷基是官能化的具有1-20个碳原子的支链或直链或环烷基，所述的官能化为含有下述至少一种官能团：苯并四氢呋喃基、卤素基、-COOR2、-OOCR3、苯基、取代苯基、3～8个碳原子的环烷基、N-邻苯二甲酰亚胺基、呋喃基、1～5个碳原子的烷氧基、苄氧基，前述所述“取代苯基”中的“取代”选自1～5个碳原子的烷氧基，前述R2、R3选自1～5个碳原子的烷基；
和/或
式4所示的取代基R1为具有1-20个碳原子的支链或直链或环状烷基。
3.根据权利要求1所述的合成方法，其特征在于，所述的R为烷基，所述烷基是具有1～8个碳原子的直链烷基或支链烷基或环烷基；或
所述的R为官能化烷基，所述官能化烷基是官能化的具有1-8个碳原子的支链或直链或环烷基，所述的官能化为含有至少一种下述官能团：苯并四氢呋喃基、卤素基、-COOR2、-OOCR3、苯基、取代苯基、3～6个碳原子的环烷基、N-邻苯二甲酰亚胺基、1～5个碳原子的烷氧基、苄氧基，前述所述“取代苯基”中的“取代”选自甲氧基，前述R2、R3选自1～2个碳原子的烷基；和/或
式4所示的取代基R1为具有1-4个碳原子的支链或直链或环状的烷基。
4.根据权利要求3所述的合成方法，其特征在于，所述的式1或式4所示的酸酐类化合物、式2所示的溴代物以及产物酸类化合物为如下之一：
Figure FDA0002518614620000012
Figure FDA0002518614620000021
Figure FDA0002518614620000031
5.根据权利要求1所述的合成方法，其特征在于，所述的合成是在过渡金属催化剂和过渡金属还原剂以及有机溶剂存在的条件下发生的。
6.根据权利要求5所述的合成方法，其特征在于，所述的过渡金属催化剂与吡啶类配体配位使用，所述的吡啶类配体选自如下：
Figure FDA0002518614620000032
Figure FDA0002518614620000041
7.根据权利要求5所述的合成方法，其特征在于，所述的过渡金属催化剂为镍系催化剂或钯系催化剂；和/或
所述的过渡金属还原剂为锌粉或者锰粉；和/或
所述的有机溶剂选自N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、2-甲基四氢呋喃、二甲基亚砜、乙腈、四氢呋喃或甲苯。
8.根据权利要求5所述的合成方法，其特征在于，所述的镍系催化剂选自双-(1,5-环辛二烯)镍、氯化镍及其水合物、溴化镍及其水合物、碘化镍及其水合物、乙二醇二甲醚氯化镍、乙二醇二甲醚溴化镍或双(三苯基膦)氯化镍；和/或所述的钯系催化剂为四三苯基膦钯；
和/或所述的式1或式4所示的酸酐类化合物与式2所示的溴代物中较少一种化合物的浓度为0.4mmol/ml～2.0mmol/ml。
9.根据权利要求5所述的合成方法，其特征在于，所述反应在惰性气体或氮气保护下进行。
10.根据权利要求5所述的合成方法，其特征在于，反应中式1或式4所示的酸酐、式2所示的溴代物、过渡金属还原剂和过渡金属催化剂的摩尔比为：2～1：1～2：2：0.1；和/或
所述反应温度为40℃～120℃。
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