CN115353464A - 一种含三氟甲基和氰基的联烯化合物及其合成方法 - Google Patents
一种含三氟甲基和氰基的联烯化合物及其合成方法 Download PDFInfo
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- CN115353464A CN115353464A CN202210815829.1A CN202210815829A CN115353464A CN 115353464 A CN115353464 A CN 115353464A CN 202210815829 A CN202210815829 A CN 202210815829A CN 115353464 A CN115353464 A CN 115353464A
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- 125000004093 cyano group Chemical group *C#N 0.000 title claims abstract description 29
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- 241001314535 Ophrys apifera Species 0.000 title description 2
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- 125000003118 aryl group Chemical group 0.000 claims abstract description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 37
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims description 36
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 claims description 36
- 229940125904 compound 1 Drugs 0.000 claims description 18
- 229910000160 potassium phosphate Inorganic materials 0.000 claims description 18
- 235000011009 potassium phosphates Nutrition 0.000 claims description 18
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- 229940126214 compound 3 Drugs 0.000 claims description 15
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- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 4
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- 125000004180 3-fluorophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C(F)=C1[H] 0.000 claims description 2
- 125000003349 3-pyridyl group Chemical group N1=C([H])C([*])=C([H])C([H])=C1[H] 0.000 claims description 2
- 125000004800 4-bromophenyl group Chemical group [H]C1=C([H])C(*)=C([H])C([H])=C1Br 0.000 claims description 2
- 125000004801 4-cyanophenyl group Chemical group [H]C1=C([H])C(C#N)=C([H])C([H])=C1* 0.000 claims description 2
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- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 2
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- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 1
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- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/35—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms, or by nitro or nitroso groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/37—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by etherified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/38—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
- C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
- C07C255/42—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms
- C07C255/44—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being further bound to other hetero atoms at least one of the singly-bound nitrogen atoms being acylated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
- C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
- C07C255/50—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
- C07C255/51—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings containing at least two cyano groups bound to the carbon skeleton
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/57—Nitriles
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域
本发明属于有机化合物合成工艺及应用技术领域,具体涉及一种含三氟甲基和氰基的联烯化合物及其合成方法。
背景技术
三氟甲基、氰基和联烯为有机化学中常见活性基团,同时它们是医药、农药、材料领域应用广泛的功能分子的重要组成结构单元。三氟甲基是一类重要的含氟基团,具有强吸电子诱导效应、亲脂性以及较强C-F键,因此,引入三氟甲基,可以增强功能分子的各项理化性质;氰基由于强吸电子性、较强极性、氢键相互作用,在医药、材料、化妆品、农用化学品领域广泛应用。联烯的两个π键呈垂直状,具有手性,其独特的结构,使之表现出不同于烯烃与炔烃的反应活性与选择性,同时,联烯化合物也在天然产物与药物中广泛存在,所以研究联烯化学具有很重要的意义。
三氟甲基、氰基以及联烯单元在多功能分子中应用广泛,但通过简捷高效的方法将三氟甲基、氰基和联烯三个高活性结构单元同时引入活性分子中的报道却很少,因此,有必要开发更高效的方法以合成多功能联烯化合物以拓展在医药、材料领域的应用。
发明内容
本发明旨在提供一种含三氟甲基和氰基的联烯化合物及其合成方法,在银盐的催化下,通过调整碱和反应溶剂,利用β-三氟甲基-1,3-烯炔化合物与丙二腈的选择性亲核加成反应构建含三氟甲基和氰基的联烯化合物。本发明合成方法简单易行,原料廉价易得,底物普适性广,产率较高,官能团耐受性好。同时该方法可实现药物活性分子布洛芬的后期修饰,利用含布洛芬的含三氟甲基的烯炔底物可合成得到含布洛芬、氰基与三氟甲基的联烯化合物,这将为布洛芬的改性研究提供合成基础。
其中,R1可为苯基、4-甲氧基苯基、3-甲基苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、4-溴苯基、4-氨基苯基、4-氰基苯基、3-吡啶基、4,4-二甲基硫代色满、苯基(S)-2-(4-异丁基苯基)丙酸酯、(R)-2-(4-异丁基苯基)-N-苯丙胺中的任意一种。
制备所述的含三氟甲基和氰基的联烯化合物的方法,以β-三氟甲基-1,3-烯炔化合物1和丙二腈2为反应原料,在催化剂和碱的共同作用下进行反应,合成含三氟甲基和氰基的联烯化合物3,所述反应过程如下方反应式所示:。
所述催化剂为硝酸银、氟化银、硫酸银、溴化银、醋酸银中的任意一种;所述碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯、磷酸钾、碳酸铯、碳酸钾、碳酸钠、碳酸氢钠、三乙胺、三乙烯二胺、4-二甲氨基吡啶、N-甲基吗啉中的任意一种;所述反应溶剂为N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、1,4-二氧六环、N,N-二甲基乙酰胺、甲苯、乙醚、乙腈中的任意一种。
所述反应原料β-三氟甲基-1,3-烯炔化合物1的用量与丙二腈2的用量摩尔比为1:(1-10);所述催化剂的摩尔用量为β-三氟甲基-1,3-烯炔化合物1的1-100 mol%;所述碱的摩尔用量为β-三氟甲基-1,3-烯炔化合物1的100-200 mol%;所述反应溶剂与β-三氟甲基-1,3-烯炔化合物1的比例为(1-15) mL: 1 mmol。
进一步的,所述β-三氟甲基-1,3-烯炔化合物1的用量与丙二腈2的用量摩尔比为1:1.5;所述最佳反应催化剂为硝酸银AgNO3;硝酸银摩尔用量为β-三氟甲基-1,3-烯炔化合物1的20 mol%;所述最佳碱为磷酸钾K3PO4;磷酸钾摩尔用量为原料β-三氟甲基-1,3-烯炔化合物1的150 mol%;所述最佳反应溶剂为N,N-二甲基甲酰胺;β-三氟甲基-1,3-烯炔化合物1与所使用的溶剂的比例为1 mmol:2 mL。
所述反应的温度为25-100 ℃;反应时间为2-6 h。
优选,反应温度为25 ℃;反应时间为4 h。
R1可以是但不仅仅局限于如上取代基。
下面以硝酸银催化剂、磷酸钾碱和N,N-二甲基甲酰胺溶剂为例来说明本发明的反应原理:首先丙二腈(2)在碱的活化作用下生成碳负离子(4),然后碳负离子亲核进攻β-三氟甲基-1,3-烯炔试剂(1)端位烯烃生成中间体(5),中间体(5)在该反应体系中极易互变异构成(6),最后在质子的作用下形成目标产物(3)。具体反应原理如下所示:。
本发明合成方法简单易行,原料价廉易得,反应条件温和,产率较高,官能团耐受性良好;本发明合成的联烯化合物兼具三氟甲基、联烯和氰基三个高活性结构单元,为该高活性联烯产物在医药和材料等领域的应用奠定了合成基础。本发明底物普适性广,产率较高,官能团耐受性好。同时该方法可实现药物活性分子布洛芬的后期修饰,利用含布洛芬的含三氟甲基的烯炔底物可合成得到含布洛芬、氰基与三氟甲基的联烯化合物,可为布洛芬的改性研究提供合成基础。
附图说明
图1为化合物3a的核磁谱图;
图2为化合物3b的核磁谱图;
图3为化合物3c的核磁谱图;
图4为化合物3d的核磁谱图;
图5为化合物3e的核磁谱图;
图6为化合物3f的核磁谱图;
图7为化合物3g的核磁谱图;
图8为化合物3h的核磁谱图;
图9为化合物3i的核磁谱图;
图10为化合物3g的核磁谱图;
图11为化合物3k的核磁谱图;
图12为化合物3l的核磁谱图;
图13为化合物3m的核磁谱图;
图14为实施例1-13所制备的化合物结构式。
具体实施方式
为使本发明实施例的目的、技术方案和优点更加清楚,下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例是本发明的一部分实施例,而不是全部的实施例;基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。
除非另有定义,所有在此使用的技术和科学术语,和本发明所属领域内的技术人员所通常理解的意思相同,在此公开引用及他们引用的材料都将以引用的方式被并入。
本领域技术人员意识到的通过常规实验就能了解到的描述的特定实施方案的等同技术,都将包含在本申请中。
下述实施例中的实验方法,如无特殊说明,均为常规方法。下述实施例中所用的仪器设备,如无特殊说明,均为实验室常规仪器设备;下述实施例中所用的实验材料,如无特殊说明,均为由常规生化试剂商店购买得到的。
实施本发明的过程、条件、试剂、实验方法等,除以下专门提及的内容之外,均为本领域的普遍知识和公知常识,本发明没有特别限制内容。以下实施例所给出的数据包括具体操作和反应条件及产物。产物纯度通过核磁鉴定。
在实施例1-13中,反应温度为25℃。
实施例1:化合物3a的合成:在15 mL反应试管中,加入(3-(三氟甲基)-3-烯-1-炔-1-基)苯(19.6 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),溴化银(3.6 mg, 0.02mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3a (21.2 mg, Yield: 81%)。
1H NMR (400 MHz, CDCl3):δ 7.66-7.64 (m, 2H), 7.49-7.47 (m, 3H), 6.38(d, J= 2.8 Hz, 1H), 3.92-3.82 (m, 1H), 3.20 (dd, J = 14.4, 8.4 Hz, 1H), 3.00(dd, J = 14.4, 6.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 142.0, 130.5,129.4, 129.3, 126.8 (q, 3 J CF3 = 2.9 Hz), 126.6, 125.2 (q, 1 J CF3 = 277.1 Hz),114.4, 114.0, 48.6 (q, 2 J CF3 = 30.8 Hz), 40.1, 37.9 (q, 3 J CF3 = 2.6 Hz) ppm; 19FNMR (376 MHz, CDCl3): δ -70.7 (s, 3F) ppm; FTMS (ESI): Calculated for C14H8F3N2(M-H)-: 261.06451; Found: 261.06327。
实施例2:化合物3b的合成:在15 mL反应试管中,加入1-甲氧基-4-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(22.6 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4mg, 0.02 mmol),1,8-二氮杂二环十一碳-7-烯(22.8 mg, 0.15 mmol),DMF (2 mL),25 ℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3b(24.5 mg, Yield: 84%)。
1H NMR (400 MHz, CDCl3): δ 7.60-7.57 (m, 2H), 7.00-6.96 (m, 2H), 6.24(d, J = 2.4 Hz, 1H), 3.86 (s, 3H), 3.85-3.81 (m, 1H), 3.18 (dd, J = 14.4, 8.4Hz, 1H), 2.98 (dd, J = 14.4, 6.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ161.2, 141.4, 128.1, 125.3 (q, 1 J CF3 = 277.1 Hz), 124.3 (q, 3 J CF3 = 2.7 Hz),121.8, 114.6, 114.6, 114.1, 55.4, 48.5 (q, 2 J CF3 = 30.5 Hz), 40.1, 37.9 (q,3 J CF3 = 2.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.9 (s, 3F) ppm。
实施例3:化合物3c的合成:在15 mL反应试管中,加入1-甲基-3-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(21.0 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF (2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3c (21.8 mg, Yield: 79%)。
1H NMR (400 MHz, CDCl3): δ 7.42 (d, J = 8.8 Hz, 2H), 7.33 (t, J = 7.6Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 6.32 (d, J = 2.8 Hz, 1H), 3.86-3.76 (m,1H), 3.14 (dd, J = 14.4, 8.8 Hz, 1H), 2.94 (dd, J = 14.0, 6.0 Hz, 1H), 2.39(s, 3H) ppm; 13C NMR (100 MHz, CDCl3): δ 141.9, 139.0, 131.2, 129.3, 129.0,127.1, 126.5 (q, 3 J CF3 = 2.8 Hz), 125.2 (q, 1 J CF3 = 276.9 Hz), 123.6, 114.5,114.0, 48.4 (q, 2 J CF3 = 30.7 Hz), 40.0, 37.8 (q, 3 J CF3 = 2.5 Hz), 21.3 ppm; 19FNMR (376 MHz, CDCl3): δ -70.7 (s, 3F) ppm。
实施例4:化合物3d的合成:在15 mL反应试管中,加入1-氟-4-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(21.4 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3d (21.6 mg, Yield: 77%)。
1H NMR (400 MHz, CDCl3): δ 7.66-7.61 (m, 2H), 7.21-7.14 (m, 2H), 6.32(d, J = 2.4 Hz, 1H), 3.92-3.81 (m, 1H), 3.19 (dd, J = 14.4, 8.4 Hz, 1H), 2.99(dd, J = 14.4, 6.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 163.8 (d, 1 J CF =250.8 Hz), 140.9, 128.7 (d, 3 J CF = 8.5 Hz), 126.9 (q, 3 J CF3 = 1.6 Hz), 125.6(d, 4 J CF = 3.5 Hz), 125.1 (q, 1 J CF3 = 277.0 Hz), 116.6, 116.4, 114.0 (d, 2 J CF =45.9 Hz), 48.5 (q, 2 J CF3 = 30.7 Hz), 40.2, 37.8 (q, 3 J CF3 = 2.5 Hz) ppm; 19F NMR(376 MHz, CDCl3): δ -70.7 (s, 3F), -108.9 (s, 1F) ppm。
实施例5:化合物3e的合成:在15 mL反应试管中,加入1-氟-3-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(21.4 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),碳酸钠(15.9 mg, 0.15 mmol),DMF (2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3e (21.0 mg, Yield: 75%)。
1H NMR (400 MHz, CDCl3): δ 7.49-7.43 (m, 2H), 7.33 (dt, J = 9.2, 1.6Hz, 1H), 7.20-7.14 (m, 1H), 6.41 (d, J = 2.8 Hz, 1H), 3.92-3.82 (m, 1H), 3.19(dd, J = 14.4, 8.4 Hz, 1H), 2.99 (dd, J = 14.4, 6.0 Hz, 1H) ppm; 13C NMR (100MHz, CDCl3): δ 162.8 (d, 1 J CF = 246.7 Hz), 140.6 (d, 4 J CF = 2.6 Hz), 131.3 (d,3 J CF = 7.8 Hz), 131.0 (d, 3 J CF = 8.3 Hz), 128.4 (q, 3 J CF3 = 2.7 Hz), 125.0 (q,1 J CF3 = 277.1 Hz), 122.3 (d, 4 J CF = 3.1 Hz), 117.5 (d, 2 J CF = 21 Hz), 114.1,113.7 (d, 2 J CF = 23.1 Hz), 113.7, 48.4 (q, 2 J CF3 = 30.8 Hz), 40.0, 37.7 (q, 3 J CF3= 2.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.6 (d, J = 8.3 Hz, 3F), -110.7to -110.8 (m, 1F) ppm。
实施例6:化合物3f的合成:在15 mL反应试管中,加入1-氟-2-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(21.4 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3f (21.3 mg, Yield: 76%)。
1H NMR (400 MHz, CDCl3): δ 7.64 (dt, J = 7.6, 1.6 Hz, 1H), 7.46-7.40(m, 1H), 7.28-7.17 (m, 2H), 6.58 (d, J = 2.4 Hz, 1H), 3.94-3.84 (m, 1H), 3.15(dd, J = 14.0, 8.4 Hz, 1H), 2.93 (dd, J = 14.4, 6.8 Hz, 1H) ppm; 13C NMR (100MHz, CDCl3): δ 160.4 (d, 1 J CF = 251.2 Hz), 135.8 (d, 3 J = 2.8 Hz), 131.7 (dq,4 J CF = 10.5 Hz, 3 J CF3 = 2.6 Hz), 128.5 (d, 4 J = 2.3 Hz), 125.1 (q, 1 J CF3 = 277.1Hz), 124.8 (d, 3 J = 3.6 Hz), 117.6 (d, 3 J CF = 12.4 Hz), 116.7 (d, 2 J CF = 22.4Hz), 114.0 (d, 2 J CF = 39.9 Hz), 48.9 (q, 2 J CF3 = 30.7 Hz), 41.0, 37.6 (q, 3 J CF3 =2.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.5 (s, 3F), -109.7 (s, 1F) ppm。
实施例7:化合物3g的合成:在15 mL反应试管中,加入1-氯-4-(3-(三氟甲基) -3-烯-1-炔-1-基)苯(23.0 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硫酸银(4.1 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMSO (2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3g (23.4 mg, Yield: 79%)。
1H NMR (400 MHz, CDCl3): δ 7.58 (dt, J = 8.4, 2.4 Hz, 2H), 7.45 (dt, J = 8.8, 2.4 Hz, 2H), 6.37 (d, J = 2.8 Hz, 1H), 3.91-3.80 (m, 1H), 3.18 (dd, J = 14.4, 8.4 Hz, 1H), 2.98 (dd, J = 14.4, 6.0 Hz, 1H) ppm; 13C NMR (100 MHz,CDCl3): δ 140.7, 136.5, 129.4, 127.8, 127.8, 127.5 (q, 3 J CF3 = 2.7 Hz), 125.0(q, 1 J CF3 = 277.1 Hz), 114.1, 113.7, 48.5 (q, 2 J CF3 = 30.7 Hz), 40.0, 37.6 (q,3 J CF3 = 2.3 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.6 (s, 3F) ppm。
实施例8:化合物3h的合成:在15 mL反应试管中,加入1-溴-4-(3-(三氟甲基)-3-烯-1-炔-1-基)苯(27.3 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF (2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3h (25.4 mg, Yield: 75%)。
1H NMR (400 MHz, CDCl3): δ 7.62 (dt, J = 8.4, 2.0 Hz, 2H), 7.51 (dt, J = 8.4, 2.0 Hz, 2H), 6.39 (d, J = 2.4 Hz, 1H), 3.91-3.81 (m, 1H), 3.20 (dd, J = 14.4, 8.4 Hz, 1H), 2.99 (dd, J = 14.4, 6.4 Hz, 1H) ppm; 13C NMR (100 MHz,CDCl3): δ 141.0, 132.5, 128.2, 128.1, 127.6 (q, 3 J CF3 = 2.7 Hz), 125.0 (q, 1 J CF3= 277.2 Hz), 125.0, 114.2, 113.7, 48.6 (q, 2 J CF3 = 30.8 Hz), 40.0, 37.8 (q,3 J CF3 = 2.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.6 (d, J = 8.3 Hz, 3F) ppm。
实施例9:化合物3i的合成:在15 mL反应试管中,加入4-(三氟甲基)-3-烯-1-炔-1-基)苯胺(21.1 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg, 0.02mmol),磷酸钾(31.8 mg, 0.15 mmol),乙腈(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3i (19.1 mg, Yield: 69%)。
1H NMR (400 MHz, CDCl3): δ7.44 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.8Hz, 2H), 6.14 (d, J = 2.8 Hz, 1H), 3.98 (s, 2H), 3.86-3.76 (m, 1H), 3.15 (dd,J = 14.0, 8.4 Hz, 1H), 2.95 (dd, J = 14.4, 6.0 Hz, 1H) ppm; 13C NMR (100 MHz,CDCl3): δ 148.4, 141.6, 128.0, 125.4 (q, 1 J CF3 = 276.9 Hz), 122.1 (q, 3 J CF3 =2.8 Hz), 119.1, 114.9, 114.8, 114.3, 48.4 (q, 2 J CF3 = 30.6 Hz), 39.9, 37.9 (q,3 J CF3 = 2.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -71.0 (s, 3F) ppm。
实施例10:化合物3j的合成:在15 mL反应试管中,加入4-(3-(三氟甲基)-3-烯-1-炔-1-基)苯甲腈(22.1 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg,0.02 mmol),磷酸钾(31.8 mg, 0.15 mmol),DMA (2 mL),25 ℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3j (18.6 mg, Yield: 65%)。
1H NMR (400 MHz, CDCl3): δ 7.79-7.74 (m, 4H), 6.54 (d, J = 2.8 Hz,1H), 3.98-3.87 (m, 1H), 3.24 (dd, J = 14.8, 8.8 Hz, 1H), 3.02 (dd, J = 14.4,6.4 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ 140.3, 133.5, 133.0, 130.5 (q,3 J CF3 = 2.7 Hz), 127.2, 124.9 (q, 1 J CF3 = 277.2 Hz), 117.1, 114.1, 113.8, 113.4,48.7 (q, 2 J CF3 = 31 Hz), 39.9, 37.7 (q, 3 J CF3 = 2.2 Hz) ppm; 19F NMR (376 MHz,CDCl3): δ -70.4 (s, 3F) ppm。
实施例11:化合物3k的合成:在15 mL反应试管中,加入3-(3-(三氟甲基)-3-烯-1-炔-1-基)吡啶(19.7 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg, 0.02mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3k (26.3 mg, Yield: 73%)。
1H NMR (400 MHz, CDCl3): δ 8.87 (d, J = 2.4 Hz, 1H), 8.68 (dd, J =4.8, 1.6 Hz, 1H), 7.95 (ddd, J = 8.4, 2.4, 2.0 Hz, 1H), 7.41 (ddd, J = 8.0,4.8, 0.4, Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 3.94-3.84 (m, 1H), 3.20 (dd, J =14.4, 8.4 Hz, 1H), 3.00 (dd, J = 14.4, 6.0 Hz, 1H) ppm; 13C NMR (100 MHz,CDCl3): δ 151.2, 147.7, 139.0, 133.5, 129.0 (q, 3 J CF3 = 2.7 Hz), 125.6, 124.9(q, 1 J CF3 = 277.2 Hz), 123.7, 113.8, 48.7 (q, 2 J CF3 = 30.9 Hz), 40.0, 37.5 (q,3 J CF3= 2.4 Hz) ppm; 19F NMR (376 MHz, CDCl3): δ -70.5 (s, 3F) ppm。
实施例12:化合物3l的合成:向装有磁石且烘干的圆底烧瓶(100 mL)中,依次加入3-羟基苯乙炔(1.1 mL, 10 mmol)、布洛芬(2.5 g, 12 mmol)、N,N'-二环己基碳二亚胺(3.1 g, 15 mmol)和4-二甲氨基吡啶(122.2 mg, 1 mmol),最后加无水CH2Cl2 (30 mL),室温搅拌24 h。反应结束后,用饱和NH4Cl溶液淬灭,乙酸乙酯提取有机相。用无水Na2SO4干燥萃取得到的有机相,经减压蒸馏除去有机溶剂,得到浓缩粗产品经快速柱层析色谱纯化可得到中间体1。将双三苯基磷二氯化钯(35.1 mg, 0.05 mmol)和碘化亚铜(19.0 mg, 0.1mmol)依次加入到装有磁石烘干的Schlenk管中。用油泵抽真空,氮气充气,交换气三次,使体系内充满氮气。紧接着通过注射器依次加入无水THF (2.5 mL),然后加入三乙胺(2.5mL)、中间体1(0.5 mL, 5 mmol)、2-溴-3,3,3-三氟丙烯(0.7 mL, 6.5 mmol)。将反应混合物在50℃下搅拌12 h。反应结束后,冷却至室温,用饱和NH4Cl溶液淬灭,乙酸乙酯萃取。用无水Na2SO4上干燥萃取得到的有机相,经减压蒸馏除去有机溶剂,得到的浓缩粗产品经快速柱层析色谱纯化可得中间体2。在15 mL反应试管中,加入中间体2 (40.0 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg, 0.02 mmol),磷酸钾(31.8 mg, 0.15mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3l (40.5 mg, Yield: 87%(以中间体2为原料)) 。
1H NMR (400 MHz, CDCl3): δ 7.44 (dt, J = 8.0, 1.6 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.24 (s, 1H), 7.13 (d, J = 8.0 Hz,2H), 7.08-7.05 (m, 1H), 6.28 (d, J = 2.4 Hz, 1H), 3.92 (q, J = 6.8 Hz, 1H),3.80-3.70 (m, 1H), 3.09 (dd, J = 14.4, 8.4 Hz, 1H), 2.89 (dd, J = 14.4, 6.0Hz, 1H), 2.44 (d, J = 7.2 Hz, 2H), 1.88-1.78 (m, 1H), 1.58 (d, J = 7.2 Hz,3H), 0.87 (d, J = 6.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 172.8, 151.3,140.9, 140.7, 136.8, 130.6, 130.2, 129.5, 128.0, 127.1, 125.0 (q, 1 J CF3 =277.2 Hz), 123.6 (q, 3 J CF3 = 4.0 Hz), 119.8 (q, 4 J CF3 = 1.8 Hz), 114.1, 113.7,48.4 (q, 2 J CF3 = 30.7 Hz), 45.1, 44.9, 39.9, 37.7 (q, 3 J CF3 = 2.2 Hz), 30.1,22.2, 18.3 ppm; 19F NMR (376 MHz, CDCl3): δ -70.6 (d, J = 1.1 Hz, 3F) ppm。
实施例13:化合物3m的合成:向装有磁石且烘干的圆底烧瓶(50 mL)中,依次加入4-氨基苯乙炔(0.3 g, 2.9 mmol)、布洛芬(0.6 g, 2.9 mmol)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(0.6 g, 2.9 mmol)和1-羟基苯并三唑(0.4 g, 2.9 mmol),最后加无水DMF,室温搅拌并用TLC板监测,直到原料耗尽。反应结束后,用饱和NH4Cl溶液淬灭,乙酸乙酯提取有机相。用无水Na2SO4干燥萃取得到的有机相,经减压蒸馏除去有机溶剂,得到浓缩粗产品经快速柱层析色谱纯化可得到中间体3。将双三苯基磷二氯化钯(35.1 mg, 0.05mmol)和碘化亚铜(19.0 mg, 0.1 mmol)依次加入到装有磁石烘干的Schlenk管中。用油泵抽真空,氮气充气,交换气三次,使体系内充满氮气。紧接着通过注射器依次加入无水THF(2.5 mL),然后加入三乙胺(2.5 mL)、中间体3(0.5 mL, 5 mmol)、2-溴-3,3,3-三氟丙烯(0.7 mL, 6.5 mmol)。将反应混合物在50℃下搅拌12 h。反应结束后,冷却至室温,用饱和NH4Cl溶液淬灭,乙酸乙酯萃取。用无水Na2SO4上干燥萃取得到的有机相,经减压蒸馏除去有机溶剂,得到的浓缩粗产品经快速柱层析色谱纯化可得中间体4。在15 mL反应试管中,加入中间体4 (39.9 mg, 0.1 mmol),丙二腈(9.9 mg, 0.15 mmol),硝酸银(3.4 mg, 0.02mmol),磷酸钾(31.8 mg, 0.15 mmol),DMF(2 mL),25℃条件下搅拌4小时,反应完毕后,干燥,过滤,浓缩,经柱层析分离得到黄色油状液体3m (30.7 mg, Yield: 66%(以中间体4为原料))。
1H NMR (400 MHz, CDCl3): δ 7.52 (s, 4H), 7.28 (s, 1H), 7.26-7.24 (m,2H), 7.17-7.15 (d, J = 8.0 Hz, 2H), 6.27 (d, J = 2.4 Hz, 1H), 3.87-3.77 (m,1H), 3.70 (q, J = 7.2 Hz, 1H), 3.15 (dd, J = 14.4, 8.8 Hz, 1H), 2.94 (dd, J =14.4, 6.4 Hz, 1H), 2.47 (d, J = 7.2 Hz, 2H), 1.91-1.80 (m, 1H), 1.58 (d, J =7.2 Hz, 3H), 0.90 (d, J = 6.8 Hz, 6H) ppm; 13C NMR (100 MHz, CDCl3): δ 172.9,141.3, 141.1, 139.9, 137.6, 129.9, 127.3, 127.3, 125.6 (q, 3 J CF3 = 2.5 Hz),125.2 (q, 1 J CF3 = 277.3 Hz), 124.8, 119.7, 114.4, 114.0, 48.5 (q, 2 J CF3 = 30.7Hz), 47.7, 44.9, 39.9, 37.8 (q, 3 J CF3 = 1.8 Hz), 30.1, 22.3, 18.4 ppm; 19F NMR(376 MHz, CDCl3): δ -70.7 (s, 3F) ppm。
实验例1:布洛芬(Ibuprofen)又称异丁苯丙酸,属于非甾体抗炎药,主要用于治疗头痛、类风湿关节炎和肌肉劳损等。与其他抗炎镇痛药物相比,效果好且对肾和造血机制几乎没有副作用,对阿司匹林、消炎痛等药物过敏的患者可服用此药品。但长期服用布洛芬会对胃肠道和皮肤等器官造成严重伤害。鉴于布洛芬的独特药效以及存在的不足,在上述研究的基础上,利用本发明构建的方法对布洛芬结构进行修饰,以期望研发出药代动力学性质更高的药物。
以3-羟基苯乙炔与布洛芬为起始原料,先合成中间体1,再与2-溴-3,3,3-三氟丙烯采用Sonogashira偶联法合成中间体2,具体反应如下所示。
然后采用本发明构建的合成方法以中间体2和丙二腈为原料反应可合成布洛芬结构衍生物3l。
实验例2:以4-氨基苯乙炔与布洛芬为起始原料,先合成中间体3,再与2-溴-3,3,3-三氟丙烯采用Sonogashira偶联法合成中间体4,具体反应如下所示。
然后采用本发明构建的合成方法以中间体4和丙二腈为原料反应可合成布洛芬结构衍生物3l。
最后应说明的是:以上各实施例仅用以说明本发明的技术方案,而非对其限制;尽管参照前述各实施例对本发明进行了详细的说明,本领域的普通技术人员应当理解:其依然可以对前述各实施例所记载的技术方案进行修改,或者对其中部分或者全部技术特征进行等同替换;而这些修改或者替换,并不使相应技术方案的本质脱离本发明各实施例技术方案的范围。
Claims (7)
2.根据权利要求1所述的含三氟甲基和氰基的联烯化合物,其特征在于:R1为苯基、4-甲氧基苯基、3-甲基苯基、4-氟苯基、3-氟苯基、2-氟苯基、4-氯苯基、4-溴苯基、4-氨基苯基、4-氰基苯基、3-吡啶基、4,4-二甲基硫代色满、苯基(S)-2-(4-异丁基苯基)丙酸酯、(R)-2-(4-异丁基苯基)-N-苯丙胺中的任意一种。
4.根据权利要求3所述的制备含三氟甲基和氰基的联烯化合物的方法,其特征在于:所述催化剂为硝酸银、氟化银、硫酸银、溴化银、醋酸银中的任意一种;
所述碱为1,8-二氮杂双环[5.4.0]十一碳-7-烯、磷酸钾、碳酸铯、碳酸钾、碳酸钠、碳酸氢钠、三乙胺、三乙烯二胺、4-二甲氨基吡啶、N-甲基吗啉中的任意一种;
所述反应溶剂为N,N-二甲基甲酰胺、四氢呋喃、二甲基亚砜、1,4-二氧六环、N,N-二甲基乙酰胺、甲苯、乙醚、乙腈中的任意一种;
所述反应原料β-三氟甲基-1,3-烯炔化合物1的用量与丙二腈2的用量摩尔比为1:(1-10);
所述催化剂的摩尔用量为β-三氟甲基-1,3-烯炔化合物1的1-100 mol%;
所述碱的摩尔用量为β-三氟甲基-1,3-烯炔化合物1的100-200 mol%;
所述反应溶剂与β-三氟甲基-1,3-烯炔化合物1的比例为(1-15) mL:1 mmol。
5.根据权利要求4所述的制备含三氟甲基和氰基的联烯化合物的方法,其特征在于:所述β-三氟甲基-1,3-烯炔化合物1的用量与丙二腈2的用量摩尔比为1:1.5;
所述反应催化剂为硝酸银AgNO3;硝酸银摩尔用量为原料β-三氟甲基-1,3-烯炔化合物1的20 mol%;
所述碱为磷酸钾K3PO4;磷酸钾摩尔用量为原料β-三氟甲基-1,3-烯炔化合物1的150mol%;
所述反应溶剂为N,N-二甲基甲酰胺;β-三氟甲基-1,3-烯炔化合物1与所使用的溶剂的比例为1mmol: 2mL。
6.根据权利要求3所述的制备含三氟甲基和氰基的联烯化合物的方法,其特征在于:所述反应的温度为25-100℃;反应时间为2-6h。
7.根据权利要求6所述的制备含三氟甲基和氰基的联烯化合物的方法,其特征在于:最优反应温度为25℃;最优反应时间为4h。
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