CN113024604B - 一种c3-烯基化的2-吡啶酮类衍生物的制备方法 - Google Patents
一种c3-烯基化的2-吡啶酮类衍生物的制备方法 Download PDFInfo
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- CN113024604B CN113024604B CN202110280385.1A CN202110280385A CN113024604B CN 113024604 B CN113024604 B CN 113024604B CN 202110280385 A CN202110280385 A CN 202110280385A CN 113024604 B CN113024604 B CN 113024604B
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- pyridone
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- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical class OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 238000000034 method Methods 0.000 claims abstract description 19
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 32
- 238000006243 chemical reaction Methods 0.000 claims description 30
- 239000003446 ligand Substances 0.000 claims description 27
- 150000001875 compounds Chemical class 0.000 claims description 18
- XYFCBTPGUUZFHI-UHFFFAOYSA-N Phosphine Chemical compound P XYFCBTPGUUZFHI-UHFFFAOYSA-N 0.000 claims description 16
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 16
- VOITXYVAKOUIBA-UHFFFAOYSA-N triethylaluminium Chemical compound CC[Al](CC)CC VOITXYVAKOUIBA-UHFFFAOYSA-N 0.000 claims description 16
- 229940125904 compound 1 Drugs 0.000 claims description 13
- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 12
- 125000003118 aryl group Chemical group 0.000 claims description 11
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 239000003054 catalyst Substances 0.000 claims description 8
- 229910000073 phosphorus hydride Inorganic materials 0.000 claims description 8
- 239000002841 Lewis acid Substances 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 6
- 125000005843 halogen group Chemical group 0.000 claims description 6
- 125000001072 heteroaryl group Chemical group 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- JLTRXTDYQLMHGR-UHFFFAOYSA-N trimethylaluminium Chemical compound C[Al](C)C JLTRXTDYQLMHGR-UHFFFAOYSA-N 0.000 claims description 4
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical group [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229940126214 compound 3 Drugs 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 2
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- 125000001153 fluoro group Chemical group F* 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 2
- 238000006467 substitution reaction Methods 0.000 claims description 2
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims 1
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 21
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- PXHVJJICTQNCMI-UHFFFAOYSA-N nickel Substances [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 17
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 16
- 238000005160 1H NMR spectroscopy Methods 0.000 description 16
- 239000003109 Disodium ethylene diamine tetraacetate Substances 0.000 description 16
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 16
- 238000001816 cooling Methods 0.000 description 16
- 235000019301 disodium ethylene diamine tetraacetate Nutrition 0.000 description 16
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 15
- 230000015572 biosynthetic process Effects 0.000 description 15
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 15
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- -1 C4-substituted 2-pyridones Chemical class 0.000 description 8
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- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 238000004519 manufacturing process Methods 0.000 description 7
- AUONHKJOIZSQGR-UHFFFAOYSA-N oxophosphane Chemical group P=O AUONHKJOIZSQGR-UHFFFAOYSA-N 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 239000011734 sodium Substances 0.000 description 5
- BOOYHBPHFVNWNH-OAHLLOKOSA-N 1-tert-butyl-6-[[(1R)-1-(4-chlorophenyl)ethyl]amino]-5-[(4-fluorophenyl)methyl]pyrazolo[3,4-d]pyrimidin-4-one Chemical compound C[C@H](C1=CC=C(C=C1)Cl)NC2=NC3=C(C=NN3C(C)(C)C)C(=O)N2CC4=CC=C(C=C4)F BOOYHBPHFVNWNH-OAHLLOKOSA-N 0.000 description 4
- KLWPJMFMVPTNCC-UHFFFAOYSA-N Camptothecin Natural products CCC1(O)C(=O)OCC2=C1C=C3C4Nc5ccccc5C=C4CN3C2=O KLWPJMFMVPTNCC-UHFFFAOYSA-N 0.000 description 4
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- 229940127093 camptothecin Drugs 0.000 description 4
- VSJKWCGYPAHWDS-UHFFFAOYSA-N dl-camptothecin Natural products C1=CC=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)C5(O)CC)C4=NC2=C1 VSJKWCGYPAHWDS-UHFFFAOYSA-N 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 238000005580 one pot reaction Methods 0.000 description 4
- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 125000005037 alkyl phenyl group Chemical group 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 150000002815 nickel Chemical class 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000004215 Carbon black (E152) Substances 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- PWHULOQIROXLJO-UHFFFAOYSA-N Manganese Chemical compound [Mn] PWHULOQIROXLJO-UHFFFAOYSA-N 0.000 description 2
- 125000005036 alkoxyphenyl group Chemical group 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 229910001873 dinitrogen Inorganic materials 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
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- 238000002474 experimental method Methods 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
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- 239000011572 manganese Substances 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
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- PRMWGUBFXWROHD-UHFFFAOYSA-N perampanel Chemical compound O=C1C(C=2C(=CC=CC=2)C#N)=CC(C=2N=CC=CC=2)=CN1C1=CC=CC=C1 PRMWGUBFXWROHD-UHFFFAOYSA-N 0.000 description 2
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Abstract
本发明公开了一种C3‑烯基化的2‑吡啶酮类衍生物的制备方法,该制备方法包括以下步骤:将原料在催化体系下反应制得C3‑烯基化的2‑吡啶酮类衍生物。本发明的制备方法是原子经济性的,符合绿色化学的要求,在大规模生产过程中也不会产生其它副产物,达到了简化工艺、降低成本和减少环境污染的目的。
Description
技术领域
本发明涉及化学合成技术领域,具体涉及一种C3-烯基化的2-吡啶酮类衍生物的制备方法。
背景技术
2-吡啶酮是2-羟基吡啶的互变异构体,是天然产物、生物活性分子和药物制剂中具有优势的杂芳香环之一。2-吡啶酮衍生物广泛应用于各类药物分子中以及具有生物活性的天然产物中,例如:有抗癌作用的喜树碱(camptothecin),抗菌作用的环匹罗司(ciclopirox)、强心剂米力农(milrinone)、急救药金雀花碱((-)-cytisine)、菲特霉素(fredericamycin)和吡仑帕奈(perampanel)等,因此具有很高的生物活性研究价值及反应催化研究等应用价值。
相关技术中C3-烯基化的2-吡啶酮通过以下方法进行合成:
1)C3-烯基化的2-吡啶酮由简单的2-吡啶酮和烯基酯在醋酸钯和醋酸银的催化条件下生成的。该反应使用贵金属钯作为催化剂,以及使用当量的醋酸银作为氧化剂;合成的成本比较高。
2)C3-烯基化的2-吡啶酮由C4-取代的2-吡啶酮与端位烯烃在醋酸钯和醋酸铜的催化条件系生成的。该反应使用贵金属钯作为催化剂,以及使用当量的醋酸铜作为氧化剂;同时也需要额外的加入当量的甲酸溶剂;该反应的选择性较差,不能够得到单一的产物,而且简单的吡啶酮不能发生反应。
3)C3-烯基化的2-吡啶酮是由C4-取代的2-吡啶酮与重氮在醋酸钯和醋酸铜的催化条件下生成的。在反应的条件中需要加入当量的碱,该反应的选择性不够好,不能够得到单一的产物,而且简单的吡啶酮也不能发生反应。
综上所述,尽管吡啶酮类衍生物在具有生物活性的天然产物中广泛的存在,但是现有的合成方法或者是步骤繁琐,要求操作严格,或者是体系昂贵,生产成本较高,条件苛刻,而且共有的弊端都是生成产物的选择性不高,使得规模化生产面临诸多难题。
因此,需要开发一种C3-烯基化的2-吡啶酮类衍生物的制备方法,该方法位点选择性好且成本低。
发明内容
本发明要解决的技术问题为:提供一种C3-烯基化的2-吡啶酮类衍生物的制备方法,该方法位点选择性好且成本低。
为解决上述第一个技术问题,本发明提供的技术方案为:一种C3-烯基化的2-吡啶酮类衍生物的制备方法,包括以下步骤:将如下式所示化合物1和下式所示化合物2,在催化剂、膦配体、路易斯酸和溶剂下反应,即得C3-烯基化的2-吡啶酮类衍生物,如下式所示化合物3;
其中,R1选自氢、烷基、芳基、杂芳基、卤素原子和硼取代基中的一种;
R1的取代位置选自所述化合物1中2-吡啶酮骨架中的C6-位、C5-位和C4-位中的一种;
R2、R3和R4均独立选自烷基或芳基;
R2、R3和R4相同或不同。
根据本发明的一些实施方式,所述烷基为C1~20烷基;优选地,所述烷基为C1~10烷基;优选地,所述烷基为甲基、乙基、丙基、丁基和叔丁基中的至少一种。
根据本发明的一些实施方式,所述卤素原子为氟原子、氯原子、溴原子和碘原子中的至少一种;优选地,所述卤素原子为溴原子。
根据本发明的一些实施方式,所述芳基为C20以下的芳基;优选地,所述芳基为C10以下的芳基;优选地,所述芳基为烷基苯基、烷氧基苯基、硝基苯基、卤代苯基或杂芳基。
根据本发明的一些实施方式,所述烷基苯基为一取代或二取代的烷基苯基;优选地,所述烷基苯基中烷基为C1~8烷基;优选地,所述C1~8烷基包括但不限于甲基和叔丁基。
根据本发明的一些实施方式,所述烷氧基苯基为C1~10烷氧基。
根据本发明的一些实施方式,所述卤代苯基为一取代或二取代苯基;优选地,所述卤代为F代、Cl代或Br代;优选地,所述二取代相同或不同。
根据本发明的一些实施方式,所述杂芳基是指C10以下且含N和O中至少一种的杂环;优选地,所述杂环为C5以下的含氮杂环;优选地,含氮杂环为吡啶基。
根据本发明的一些实施方式,所述化合物1和化合物2的摩尔比为1:1~2。
根据本发明的一些实施方式,所述催化剂包括镍盐和锰中的至少一种;优选地,所述镍盐包括Ni(cod)2(二(环辛1,5-二烯)镍)或Ni(acac)2(乙酰丙酮镍)中的至少一种。
根据本发明的一些实施方式,所述镍盐与化合物1的摩尔比为5~20:100。
根据本发明的一些实施方式,所述锰与化合物1的摩尔比为1~3:1。
根据本发明的一些实施方式,所述膦配体包括二苯基膦氧、三环己基膦和双氮取代的二级膦氧中的至少一种。
根据本发明的一些实施方式,所述双氮取代的二级膦氧包括双氮烷基取代二级膦氧或双氮芳基取代二级膦氧中的至少一种。
根据本发明的一些实施方式,所述双氮芳基取代二级膦氧包括双氮苯基取代二级膦氧和双氮取代苯基取代二级膦氧芳基中的至少一种。
根据本发明的一些实施方式,所述双氮取代苯基取代二级膦氧芳基包括双氮取代苯基取代二级膦氧包括双氮叔丁基取代苯基取代二级膦氧。
根据本发明的一些实施方式,所述膦配体与化合物2的摩尔比为15~40:100。
根据本发明的一些实施方式,所述膦配体包括手性二级膦氧。
根据本发明的一些实施方式,所述手性二级膦氧包括以TIDOL骨架的二级膦氧。
根据本发明的一些实施方式,所述TIDOL骨架如下式所示:
根据本发明的一些实施方式,所述TIDOL骨架包括L构型的酒石酸二酯或D构型的酒石酸二酯中的一种。
根据本发明的一些实施方式,所述膦配体的保护基包括丙酮叉保护基。
根据本发明的一些实施方式,所述路易斯酸包括铝试剂;优选地,所述铝试剂包括三甲基铝、三乙基铝、三异丁基铝和二乙基氯化铝中的至少一种。
根据本发明的一些实施方式,所述路易斯酸与化合物1的摩尔比为10~80:100。
根据本发明的一些实施方式,所述溶剂包括醚类溶剂和烃类溶剂中的至少一种;优选地,所述醚类溶剂包括四氢呋喃和1,4-二氧六环中的至少一种;优选地,所述烃类溶剂包括甲苯和正己烷中的至少一种。
根据本发明的一些实施方式,所述溶剂与化合物1的体积摩尔比为1mL~5mL:1mmol。
根据本发明的一些实施方式,所述反应的温度为50℃~150℃。
根据本发明的一些实施方式,所述反应的气氛为惰性气体;优选地,所述惰性气体为氮气。
根据本发明的一些实施方式,所述反应的时间为6h~10h。
根据本发明的一些实施方式,所述反应结束后还包括以下操作:
先冷却至室温,再减压除去溶剂,柱层析分离得到所述化合物3。
根据本发明实施方式的C3-烯基化的2-吡啶酮类衍生物的制备方法,至少具备如下有益效果:本发明所使用的大多试剂均商业所得,需合成的配体原料来源广泛,价格低廉,且在常温常压下能够稳定存在,操作处理方便,无须特殊处理;本发明进行了克量级实验,反应适合大量生产;本发明操作简便,一步反应即可得到化合物,避免了相关技术中所涉及到的空气和水极其敏感的格式试剂等危险试剂,规避了以往多步反应才能得到化合物的缺陷,对设备要求简单;大大降低了合成该类化合物的生产成本;本发明通过一步反应制得了单一位点的反应产物,且后处理简单方便,解决了多个位点选择性的问题,大大降低了产物分离成本;本发明所使用的催化剂廉价,且金属,配体等用量较低,在保持良好催化效果、降低成本的同时,方便后处理工序,减少环境污染等要求;本发明的制备方法完全是原子经济性的,符合绿色化学的要求,大量生产也不会有其它副产物,达到了简化工艺、降低成本、减少环境污染等要求。
具体实施方式
以下将结合实施例对本发明的构思及产生的技术效果进行清楚、完整地描述,以充分地理解本发明的目的、特征和效果。显然,所描述的实施例只是本发明的一部分实施例,而不是全部实施例,基于本发明的实施例,本领域的技术人员在不付出创造性劳动的前提下所获得的其他实施例,均属于本发明保护的范围。
本发明实施例中所制得的产物纯度通过核磁鉴定。
实施例1:(E)-3-(oct-4-en-4-yl)-1-phenylpyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(23.1mg,12mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1a(34.2mg,0.2mmol),化合物2a(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),50℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,再加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;再将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3a,无色油状物液体,收率(97%)。
1H NMR(400MHz,CDCl3)δ7.49-7.37(m,5H),7.28-7.26(m,2H),6.20(t,J=6.8Hz,1H),5.66(t,J=7.2Hz,1H),2.52(t,J=7.8Hz,2H),2.15(q,J=7.3Hz,2H),1.51-1.40(m,2H),1.38-1.29(m,2H),0.95(t,J=7.4Hz,3H),0.87(t,J=7.4Hz,3H).
13C NMR(100MHz,CDCl3)δ161.5,141.4,139.0,137.1,136.6,136.2,131.5,129.2,128.2,126.8,105.7,30.7,30.3,23.0,22.0,14.1,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C26H30NO 372.2322;Found 372.2326.
实施例2:(E)-1-methyl-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(23.1mg,12mol%),Ni(cod)2(5.6mg,10mol%),甲苯(1.0mL),化合物1b(21.8mg,0.2mmol),化合物2b(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3b,无色油状物液体,收率(99%)。
1H NMR(400MHz,CDCl3)δ7.25-7.12(m,2H),6.11(t,J=6.8Hz,1H),5.56(t,J=7.2Hz,1H),3.54(s,3H),2.51(t,J=7.6Hz,2H),2.15(q,J=7.2,2H),1.51-1.38(m,2H),1.33-1.24(m,2H),0.95(t,J=7.2Hz,3H),0.85(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ162.2,139.1,137.0,136.6,135.7,131.2,105.6,37.9,30.8,30.3,23.0,21.9,14.1,14.0.
HRMS(ESI)m/z:[M+H]+Calcd.for C14H22NO 220.1696;Found 220.1699.
实施例3:(E)-1-benzyl-6-methyl-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1c(52.4mg,0.2mmol),化合物2c(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3c,无色油状液体,收率(98%)。
1H NMR(400MHz,CDCl3)δ7.31–7.15(m,5H),7.13-7.12(m,2H),5.98(d,J=7.2Hz,1H),5.59(t,J=7.0Hz,1H),5.35(s,2H),2.54(t,J=7.6Hz,2H),2.25(s,3H),2.15(q,J=7.3Hz,2H),1.50-1.39(m,2H),1.36-1.26(m,2H),0.95(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ162.8,144.6,139.4,136.9,136.8,132.7,130.8,128.8,127.3,126.6,106.6,47.4,30.7,30.4,23.1,22.0,20.7,14.2,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C21H28NO310.2165;Found 310.2167.
实施例4:(E)-1-benzyl-5-methyl-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1d(52.4mg,0.2mmol),化合物2d(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3d,无色油状液体,收率(82%)。
1H NMR(400MHz,CDCl3)δ7.35-7.28(m,5H),7.03(d,J=2.4Hz,1H),6.97(s,1H),5.54(t,J=7.2Hz,1H),5.12(s,2H),2.54(t,J=7.6Hz,2H),2.14(q,J=7.3Hz,2H),2.02(s,3H),1.49-1.40m,2H),1.34-1.25(m,2H),0.95(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ161.0,139.7,139.3,137.1,135.7,133.0,131.2,128.9,128.2,127.9,114.8,52.0,30.8,30.3,23.0,22.0,17.3,14.2,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C21H28NO310.2165;Found 310.2162.
实施例5:(E)-1-benzyl-4-methyl-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1e(52.4mg,0.2mmol),化合物2e(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),150℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3e,无色油状液体,收率(49%)。
1H NMR(400MHz,Chloroform-d)δ7.35-7.28(m,5H),7.05(d,J=7.2Hz,1H),6.01(d,J=7.2Hz,1H),5.23(t,J=7.2Hz,1H),5.10(s,2H),2.40(t,J=8.0Hz,2H),2.24-2.18(m,2H),2.15(s,3H),1.48-1.41(m,2H),1.32-1.28(m,3H),0.96(t,J=7.2Hz,3H),0.90(t,J=7.2Hz,3H).
13C NMR(100MHz,Chloroform-d)δ161.8,146.5,137.0,136.4,134.2,133.6,131.3,128.9,128.4,127.9,109.4,52.0,32.6,30.2,23.1,22.0,20.4,14.7,14.2.
HRMS(ESI)m/z:Calcd.for C21H27NNaO[M+Na]+332.1990;Found 332.1989.
实施例6:(E)-1-benzyl-3-(oct-4-en-4-yl)-5-(trifluoromethyl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1f(50.6mg,0.2mmol),化合物2f(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3f,无色油状液体,收率(70%)。
1H NMR(400MHz,CDCl3)δ7.58(s,1H),7.37-7.33(m,5H),7.27(s,1H),5.63(t,J=6.8Hz,1H),5.15(s,2H),2.52(t,J=7.2Hz,2H),2.16(q,J=7.2Hz,2H),1.48-1.43(m,2H),1.32-1.27(m,2H),0.95(t,J=6.8Hz,3H),0.87(t,J=6.8Hz,3H).
13C NMR(100MHz,CDCl3)δ161.4,138.3,137.0,135.7,134.7(q,J=5.4Hz),132.8,131.9,129.2,128.5,128.5,123.6(q,J=268.5Hz),109.6(q,J=34.3Hz),53.0,30.7,30.4,22.9,22.0,14.1,14.1.
19F NMR(376MHz,CDCl3)δ-62.3.
HRMS(ESI)m/z:[M+H]+Calcd.for C21H25F3NO 364.1883;Found 364.1884.
实施例7:(E)-1-benzyl-3-(oct-4-en-4-yl)-5-(thiophen-3-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),化合物1g(53.5mg,0.2mmol),化合物2g(33.1mg,0.3mmol),四氢呋喃(1.0mL),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3g,无色固体,收率(88%)。
1H NMR(400MHz,Chloroform-d)δ7.45(d,J=2.8Hz,1H),7.43(d,J=2.4Hz,1H),7.37-7.28(m,6H),7.21(dd,J=2.8,1.6Hz,1H),7.13(dd,J=5.2,1.2Hz,1H),5.63(t,J=7.2Hz,1H),5.20(s,2H),2.57(t,J=8.0Hz,2H),2.17(q,J=7.2Hz,2H),1.51–1.42(m,2H),1.36–1.27(m 2H),0.96(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H).
13C NMR(100MHz,Chloroform-d)δ161.0,139.2,137.9,136.7,136.4,136.3,132.2,131.7,129.0,128.3,128.1,126.9,125.4,119.1,115.5,52.5,30.8,30.4,23.0,22.0,14.2,14.2.
HRMS(ESI)m/z:[M+Na]+Calcd.for C24H27NNaOS 400.1711;Found 400.1710.
实施例8:(E)-1-benzyl-5-(furan-3-yl)-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),1h(53.5mg,0.2mmol),2h(33.1mg,0.3mmol),之后再加入三甲基铝(1mol/L,60μL,3 0mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3h,无色固体,收率(80%)。
1H NMR(400MHz,Chloroform-d)δ7.55(s,1H),7.43(t,J=2.0Hz,1H),7.37-7.27(m,7H),6.46(s,1H),5.61(t,J=6.8Hz,1H),5.19(s,2H),2.56(t,J=7.6,2H),2.17(q,J=7.2Hz,2H),1.51-1.42(m,2H),1.35-1.28(m,2H),0.96(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H).
13C NMR(100MHz,Chloroform-d)δ161.0,144.0,139.2,137.7,136.7,136.5,136.0,131.7,131.5,129.0,128.2,128.1,122.5,111.8,108.2,52.4,30.8,30.4,23.0,22.0,14.2,14.2.
HRMS(ESI)m/z:[M+Na]+Calcd.for C24H27NNaO2 384.1939;Found 384.1938.
实施例9:(E)-1-benzyl-3-(oct-4-en-4-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1i(53.5mg,0.2mmol),化合物2i(33.1mg,0.3mmol),之后再加入三乙基铝(1M,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3i,白色固体,收率(88%)。
1H NMR(400MHz,Chloroform-d)δ7.66(s,1H),7.36(s,1H),7.27-7.17(m,5H),5.46(t,J=7.2Hz,1H),5.08(s,2H),2.44(t,J=8.0Hz,2H),2.06(q,J=7.2Hz,2H),1.41-1.34(m,2H),1.23(s,12H),1.20-1.18(m,2H),0.87(t,J=7.2Hz,3H),0.78(t,J=7.2Hz,3H).
13C NMR(100MHz,Chloroform-d)δ162.2,144.2,140.9,139.1,136.9,135.4,131.2,128.8,128.1,127.9,84.0,52.7,30.9,30.4,24.9,23.1,22.0,14.2,14.2,1.2.
HRMS(ESI)m/z:[M+Na]+Calcd.For C26H36BNNaO3,444.2680;Found 444.2683
实施例10:methyl
(E)-1-benzyl-5-(oct-4-en-4-yl)-6-oxo-1,6-dihydropyridine-3-carboxylate的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1j(48.6mg,0.2mmol),化合物2j(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3j,无色油状液体,收率(70%)。
1H NMR(400MHz,CDCl3)δ8.11(s,1H),7.68(s,1H),7.35-7.33(m,5H),5.61(t,J=7.2Hz,1H),5.17(s,2H),3.83(s,3H),2.51(t,J=7.6Hz,2H),2.15(q,J=7.2Hz,2H),1.52-1.38(m,2H),1.31-1.26(m,2H),0.95(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ165.2,161.8,140.8,138.3,135.9,135.6,135.1,132.3,129.1,128.4,109.6,53.0,52.1,30.6,30.4,22.9,21.9,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C22H28NO3 354.2064;Found 354.2069.
实施例11:(E)-1-benzyl-5-cyclopropyl-3-(oct-4-en-4-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1k(48.6mg,0.2mmol),化合物2k(33.1mg,0.3mmol),之后再加入三甲基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3k,无色油状液体,收率(53%)。
1H NMR(400MHz,CDCl3)δ7.33-7.29(m,5H),6.98(s,1H),6.95(s,1H),5.54(t,J=7.2Hz,1H),5.11(s,2H),2.53(t,J=7.6Hz,2H),2.14(q,J=7.2Hz,2H),1.62-1.57(m,1H),1.50-1.39(m,2H),1.33-1.25(m,2H),0.95(t,J=7.2Hz,3H),0.86(t,J=7.2Hz,3H),0.80-0.78(m,2H),0.48-0.46(m,2H).
13C NMR(100MHz,CDCl3)δ161.0,139.4,137.0,136.8,135.7,132.3,131.2,128.8,128.2,127.8,120.7,52.2,30.8,30.3,23.0,22.0,14.1,14.1,12.1,6.6.
HRMS(ESI)m/z:Calcd.for C23H29NO[M+H]+336.2322;Found 336.2327.
实施例12:(E)-1-benzyl-3-(oct-4-en-4-yl)-5-phenylpyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),1l(52.3mg,0.2mmol),2l(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3l,无色油状液体,收率(79%)。
1H NMR(400MHz,CDCl3)δ7.49-7.41(m,2H),7.38-7.27(m,10H),5.65(t,J=7.2Hz,1H),5.22(s,2H),2.58(t,J=7.6Hz,2H),2.18(q,J=7.2Hz,2H),1.52-1.41(m,2H),1.38-1.30(m,2H),0.96(t,J=7.2Hz,3H),0.88(t,J=7.2Hz,3H).
13C NMR(100MHz,CDCl3)δ161.0,139.3,137.0,136.8,136.7,136.1,132.8,131.7,129.1,129.0,128.3,128.1,127.2,126.0,120.0,52.6,30.8,30.4,23.0,22.0,14.2,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C26H30NO 372.2322;Found 372.2326.
实施例13:(E)-1-benzyl-3-(4,4-dimethylpent-2-en-2-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1m(52.3mg,0.2mmol),化合物2m(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3m,无色油状液体,收率(85%)。
1H NMR(400MHz,CDCl3)δ7.35-7.26(m,5H),7.20-7.13(m,2H),6.08(t,J=6.8Hz,1H),5.58(s,1H),5.13(s,2H),2.10(s,3H),1.19(s,9H).
13C NMR(100MHz,CDCl3)δ161.6,140.8,138.8,136.7,136.0,135.5,133.5,128.9,128.3,127.9,105.9,52.1,32.9,30.9,16.9.
HRMS(ESI)m/z:[M+H]+Calcd.For C19H24NO 282.1852;Found 282.1857.
实施例14:(E)-1-benzyl-3-(1-phenylprop-1-en-2-yl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1o(52.3mg,0.2mmol),化合物2o(33.1mg,0.3mmol),tBu3P(4.0mg,10mol%)之后再加入三乙基铝(1mol/L,60μL,30mol%),120℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3m,无色油状液体,收率(48%)。
1H NMR(400MHz,Chloroform-d)δ7.40-7.31(m,10H),7.29-7.27(m,1H),7.23-7.21(m,1H),6.96(s,1H),6.10(t,J=6.8Hz,1H),5.20(s,2H),2.26(s,3H).
13C NMR(100MHz,Chloroform-d)δ161.5,138.2,136.7,136.3,136.1,136.0,130.3,129.4,129.0,128.3,128.2,128.1,126.6,106.1,52.4,17.6.
HRMS(ESI)m/z:[M+Na]+Calcd.for C21H19NNaO 324.1364;Found 324.1360.
实施例15:(E)-1-benzyl-3-(1,2-diphenylvinyl)pyridin-2(1H)-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(9.6mg,5mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1p(52.3mg,0.2mmol),化合物2p(33.1mg,0.3mmol),tBu3P(4.0mg,10mol%),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3m,白色固体,收率(48%)。
1H NMR(400MHz,CDCl3)δ7.73(s,1H),7.34-7.29(m,8H),7.25-7.19(m,3H),7.13-7.10(m,1H),7.10-7.05(m,3H),6.98-6.95(m,2H),6.09(t,J=6.8Hz,1H),5.19(s,2H).
13C NMR(100MHz,CDCl3)δ161.5,140.2,138.5,138.5,137.6,136.6,136.0,133.5,131.5,130.1,129.9,129.0,128.7,128.3,128.1,127.8,127.4,126.7,105.8,52.5.
HRMS(ESI)m/z:[M+H]+Calcd.for C26H22NO 364.1696;Found 364.1698.
实施例16:(1R,5S)-3-benzyl-9-((E)-oct-4-en-4-yl)-1,2,3,4,5,6-hexahydro-8H-1,5-methanopyrido[1,2-a][1,5]diazocin-8-one的合成:
在氮气氛围中,向反应瓶中依次加入配体L1(23.1mg,12mol%),Ni(cod)2(5.6mg,10mol%),四氢呋喃(1.0mL),化合物1q(56.1mg,0.2mmol),化合物2q(33.1mg,0.3mmol),之后再加入三乙基铝(1mol/L,60μL,30mol%),100℃下搅拌6小时,冷却至室温,加入乙酸乙酯稀释,加入2mL 5%的乙二胺四乙酸二钠盐水溶液洗涤,分液,收集有机相;将有机相用无水硫酸钠干燥,浓缩后柱层析分离得化合物3m,无色油状物,收率(83%)。
1H NMR(400MHz,Chloroform-d)δ7.19-7.13(m,4H),7.01-6.93(m,2H),5.87(d,J=7.2Hz,1H),5.58(t,J=7.2Hz,1H),4.14(d,J=15.2Hz,1H),3.87(dd,J=15.2,6.4Hz,1H),3.49-3.35(m,2H),2.96-2.90(m,2H),2.84-2.81(m,1H),2.68-2.61(m,1H),2.58-2.50(m,1H),2.43-2.38(m,2H),2.28(d,J=10.4Hz,1H),2.18(q,J=7.6Hz,2H),1.93-1.90(m,1H),1.80-1.76(m,1H),1.49-1.44(m,2H),1.40-1.32(m,2H),0.97(t,J=7.6Hz,3H),0.90(t,J=7.2Hz,3H).
13C NMR(100MHz,Chloroform-d)δ162.2,149.5,139.6,138.4,136.4,131.4,130.4,128.2,128.2,126.9,104.2,62.0,60.3,60.2,50.2,35.6,30.8,30.3,28.5,26.2,23.1,22.0,14.1.
HRMS(ESI)m/z:[M+H]+Calcd.for C26H35N2O 391.2749;Found 391.2750.
综上所述,本发明的合成方法通过使用大多试剂均商业所得,需合成的配体原料来源广泛,价格低廉,且在常温常压下能够稳定存在,操作处理方便,无须特殊处理;本发明进行了克量级实验,反应适合大量生产;本发明操作简便,一步反应即可得到化合物,避免了相关技术中所涉及到的空气和水极其敏感的格式试剂等危险试剂,规避了以往多步反应才能得到化合物的缺陷,对设备要求简单;大大降低了合成该类化合物的生产成本;本发明一步反应便生成可单一位点的产物,后处理简单方便,解决了多个位点反应选择性的问题,大大降低了产物分离成本;本发明所使用的催化剂廉价,且金属配体用量较低,在保持良好催化效果、降低成本的同时,方便后处理工序,减少环境污染等要求;本发明的反应完全是原子经济性的,符合绿色化学的要求,大量生产也不会有其它副产物,达到了简化工艺、降低成本、减少环境污染等要求。
上面结合说明书内容对本发明实施例作了详细说明,但是本发明不限于上述实施例,在所属技术领域普通技术人员所具备的知识范围内,还可以在不脱离本发明宗旨的前提下作出各种变化。此外,在不冲突的情况下,本发明的实施例及实施例中的特征可以相互组合。
Claims (6)
1.一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:包括以下步骤:将如下式所示化合物1和下式所示化合物2,在催化剂、膦配体、路易斯酸和溶剂下反应,即得C3-烯基化的2-吡啶酮类衍生物,如下式所示化合物3;
其中,R1选自氢、烷基、芳基、杂芳基和卤素原子中的一种;
R1的取代位置选自所述化合物1中2-吡啶酮骨架中的C6-位、C5-位和C4-位中的一种;
R2、R3和R4均独立选自烷基或芳基;
R2、R3和R4相同或不同;
所述烷基选自甲基、乙基、丙基、正丁基和叔丁基中的一种;
所述芳基为苯基;
所述杂芳基是指C10以下且含N和O中至少一种的杂环;
所述卤素原子选自氟原子、氯原子、溴原子和碘原子中的一种;
所述催化剂为Ni(cod)2;
所述路易斯酸为三甲基铝和三乙基铝中的至少一种;
所述膦配体的结构式如L1所示:
所述溶剂为四氢呋喃和甲苯中的至少一种;
所述反应的温度为50℃~150℃。
2.根据权利要求1所述的一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:所述化合物1和化合物2的摩尔比为1:1~2。
3.根据权利要求1所述的一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:所述Ni(cod)2与化合物1的摩尔比为5~20:100。
4.根据权利要求1所述的一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:所述膦配体与化合物2的摩尔比为15~40:100。
5.根据权利要求1所述的一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:所述路易斯酸与化合物1的摩尔比为10~80:100。
6.根据权利要求1所述的一种C3-烯基化的2-吡啶酮类衍生物的制备方法,其特征在于:所述溶剂与化合物1的体积摩尔比为1mL~5mL:1mmol。
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