CN112521289A - 一种氧杂烯丙基胺类化合物及其制备方法和应用 - Google Patents
一种氧杂烯丙基胺类化合物及其制备方法和应用 Download PDFInfo
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- 229910052739 hydrogen Inorganic materials 0.000 claims description 30
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- JIAARYAFYJHUJI-UHFFFAOYSA-L zinc dichloride Chemical group [Cl-].[Cl-].[Zn+2] JIAARYAFYJHUJI-UHFFFAOYSA-L 0.000 claims description 28
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- 125000004201 2,4-dichlorophenyl group Chemical group [H]C1=C([H])C(*)=C(Cl)C([H])=C1Cl 0.000 claims description 4
- 125000004204 2-methoxyphenyl group Chemical group [H]C1=C([H])C(*)=C(OC([H])([H])[H])C([H])=C1[H] 0.000 claims description 4
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 4
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- AKEYUWUEAXIBTF-UHFFFAOYSA-N n-methylnaphthalen-1-amine Chemical compound C1=CC=C2C(NC)=CC=CC2=C1 AKEYUWUEAXIBTF-UHFFFAOYSA-N 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
- C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C217/46—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and unsaturated
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/56—Ring systems containing three or more rings
- C07D209/80—[b, c]- or [b, d]-condensed
- C07D209/82—Carbazoles; Hydrogenated carbazoles
- C07D209/86—Carbazoles; Hydrogenated carbazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the ring system
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
- C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
- C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
- C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
技术领域
本发明属于有机合成技术领域,具体涉及一种氧杂烯丙基胺类化合物及其制备方法和应用。
背景技术
官能化的胺类化合物普遍存在于天然产物、药物和其他具有生物活性的小分子中。其中,氧杂烯丙基胺类化合物是合成药物的关键中间体,近年来吸引了化学家们的广泛关注,例如:(a)Pramocaine盐酸盐可以降低神经细胞膜对钠离子的通透性,阻断神经冲动的产生和传导;(b)Propranolol是一种非选择性的β-adrenergic receptor(βAR)拮抗剂,对β1AR和β2AR具有高亲和力,Ki值分别为1.8nM和0.8nM。Propranolol抑制[3H]-DHA与大鼠脑膜制剂的结合,IC50为12nM。Propranolol用于高血压,嗜铬细胞瘤,心肌梗塞,心律不齐,心绞痛和肥大心肌病的相关研究;(c)Duloxetine((S)-Duloxetine)是5羟色胺-去甲肾上腺素重吸收(serotonin-norepinephrine reuptake)抑制剂,Ki为4.6nM,可作用于广泛性焦虑症;(d)Gefitinib(ZD1839)是一种有效,选择性和口服活性的EGFR酪氨酸激酶抑制剂,IC50为33nM。Gefitinib选择性抑制EGF刺激的肿瘤细胞生长(IC50为54nM),并阻断EGF刺激的肿瘤细胞中EGFR自磷酸化。Gefitinib还可诱导细胞自噬(autophagy)。Gefitinib具有抗肿瘤活性。
(E.Falk,S.Makai,T.Delcaillau,L.Grtler,and B.Morandi,Angew.Chem.Int.Ed.,2020,59,2–10.)
其结构式分别如下:
因此探究高效合成氧杂烯丙基胺类化合物的方法是十分有必要的。近年来,科学家们开发了各种合成方法来构建烯丙基胺类化合物:(1)过渡金属催化的烯丙醇直接烯丙基胺化;(2)过渡金属催化的氢胺化;(3)过渡金属催化的胺的乙烯基化;(4)过渡金属催化的烯丙基C-H胺化。(G.Hirata,H.Satomura,H.Kumagae,A.Shimizu,G.Onodera,andM.Kimura,Org.Lett.,2017,19,6148-6151;J.B.Sweeney,A.K.Ball,P.A.Lawrence,M.C.Sinclair,L.J.Smith,Angew.Chem.Int.Ed.,2018,57,10202–10206.N.Nishina,Y.Yamamoto,Angew.Chem.,Int.Ed.,2006,45,3314–3317;R.Blieck,J.Bahri,M.Taillefer,F.Monnier,Org.Lett.,2016,18,1482.Y.Xie,J.Hu,Y.Wang,C.Xia,andH.Huang,J.Am.Chem.Soc.,2012,134,20613-20616.T.Ramirez,A.;B.Zhao,Y.Shi,Chem.Soc.Rev.,2012,41,931-942.Q.Cheng,J.Chen,S.Lin,and T.Ritter,J.Am.Chem.Soc.,2020,142,17287-17293.)。
虽然烯丙基胺类化合物的合成策略已经非常成熟,但是对于氧杂烯丙基胺类化合物的合成方法却非常少,目前已知的方法中,可以通过苯基联烯醚和吗啉反应得到相应的氧杂烯丙基胺类化合物,但是反应的选择性非常差,产率不高,底物适用性受限,这就使得反应的转化效率低,不具有广阔的应用前景,同时也不符合绿色化学的发展理念。可见,氧杂烯丙基胺类化合物的合成仍然存在改善和提高的空间,探索发展新颖高效的合成方法具有非常重要的意义(L.Perego,A.R.Blieck,A.Groue,F.Monnier,M.Taillefer,I.Ciofini,L.Grimaud,ACS Catal.,2017,7,4253.)。
发明内容
为了克服现有技术存在的不足,需要发展铜催化联烯醚的氢胺化反应,为构建氧杂烯丙基胺类衍生物提供一种便捷高效的新合成策略;本发明的目的是提供一种氧杂烯丙基胺类化合物的合成及其制备方法和应用。
本发明的首要目的在于提供一种氧杂烯丙基胺类化合物的制备方法和应用。
本发明的另一目的在于提供通过上述方法制备得到氧杂烯丙基胺类化合物。
本发明目的通过以下技术方案实现。
本发明提供的氧杂烯丙基胺类化合物,其结构式如下所示:
其中,R1选自苯基、4-甲基苯基、4-氟苯基、4-溴苯基、4-正丁氧基苯基、3-甲基苯基、3,5-二氯苯基、萘环中的一种;
R2选自苯基、氢、甲基、乙基、烯丙基、苄基、4-羟基正丁基、1-萘甲基中的一种;
R3选自苯基、2-甲基苯基、2,4-二氯苯基、乙基、萘环、2-甲氧基苯基中的一种;
本发明提供的氧杂烯丙基胺类化合物的制备方法,包括如下步骤:
其中,R1选自苯基、4-甲基苯基、4-氟苯基、4-溴苯基、4-正丁氧基苯基、3-甲基苯基、3,5-二氯苯基、萘环中的一种;
R2选自苯基、氢、甲基、乙基、烯丙基、苄基、4-羟基正丁基、1-萘甲基中的一种;
R3选自苯基、2-甲基苯基、2,4-二氯苯基、乙基、萘环、2-甲氧基苯基中的一种;
上述的一种氧杂烯丙基胺类化合物的制备方法,其反应式如下所示:
进一步地,所述反应的温度为40~60℃。
进一步地,所述分离纯化包括:将反应液冷却至室温,用乙酸乙酯萃取,合并有机相,使用无水硫酸钠干燥,过滤,减压蒸馏除溶剂得粗产物,经薄层层析提纯得到所述的氧杂烯丙基胺类化合物。
进一步地,所述薄层层析提纯为以石油醚和乙酸乙酯的混合溶剂为展开剂的薄层层析,所述石油醚与乙酸乙酯的体积比为(5~500):1。
本发明的氧杂烯丙基胺类化合物在合成药物中的应用。
进一步地,所述的氧杂烯丙基胺类化合物在合成药物中的应用,其特征在于,所述药物为Pramocaine,其盐酸盐可以降低神经细胞膜对钠离子的通透性,阻断神经冲动的产生和传导。
本发明的反应原理是以联烯醚、胺为原料,在铜、添加剂的共同作用下,通过铜胺中间体对联烯醚的活化启动反应,得到烯基铜中间体,接着游离的胺亲核进攻,最后经质解一步合成氧杂烯丙基胺类化合物。
与现有技术相比,本发明具有如下优点和有益效果:
(1)本发明提供的合成方法以简单易得的联烯醚、脂肪胺或芳香胺作为反应原料合成一系列氧杂烯丙基胺类化合物,该方法具有原料简单易得,操作方便、条件温和,原子利用率高,步骤经济性高,底物适用性广,官能团的容忍性好等特点;
(2)本发明的合成方法新颖高效,并通过放大量实验初步证明了其在工业上的潜在应用价值,因而有望进一步应用于实际工业生产;
(3)本发明提供的合成方法在得到一系列氧杂烯丙基胺类化合物后,通过简单的还原就能得到相应的药物。
附图说明
图1和图2分别是实施例1所得目标产物的氢谱图和碳谱图;
图3和图4分别是实施例2所得目标产物的氢谱图和碳谱图;
图5和图6分别是实施例3所得目标产物的氢谱图和碳谱图;
图7和图8分别是实施例4所得目标产物的氢谱图和碳谱图;
图9和图10分别是实施例5所得目标产物的氢谱图和碳谱图;
图11和图12分别是实施例6所得目标产物的氢谱图和碳谱图;
图13和图14分别是实施例7所得目标产物的氢谱图和碳谱图;
图15和图16分别是实施例8所得目标产物的氢谱图和碳谱图;
图17和图18分别是实施例9所得目标产物的氢谱图和碳谱图;
图19和图20分别是实施例10所得目标产物的氢谱图和碳谱图;
图21和图22分别是实施例11所得目标产物的氢谱图和碳谱图;
图23和图24分别是实施例12所得目标产物的氢谱图和碳谱图;
图25和图26分别是应用例1所得目标产物的氢谱图和碳谱图。
具体实施方式
以下结合实例对本发明的具体实施作进一步说明,但本发明的实施和保护不限于此。需指出的是,以下若有未特别详细说明之过程,均是本领域技术人员可参照现有技术实现或理解的。所用试剂或仪器未注明生产厂商者,视为可以通过市售购买得到的常规产品。
以下实施例中所使用的联烯醚结构式为其通过如下方法制备得到:将酚(1.0当量)加到丙酮溶液中,室温搅拌下加入碳酸钾(2.1当量),搅拌15分钟后,将炔丙基溴(1.5当量)一滴滴缓慢加入,反应体系加热回流3小时。
反应结束加入饱和氯化铵溶液淬灭反应,萃取有机相,浓缩过柱分离得到炔丙基醚。将得到的炔丙基醚溶于四氢呋喃和叔丁醇1:3的混合溶剂中,再加入叔丁醇钾(1.5当量),将反应体系在室温下搅拌反应12小时后,加入饱和氯化铵溶液,用乙酸乙酯萃取有机相,干燥浓缩有机相,过柱分离即得到联烯醚类底物。
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔2-甲基-N-甲基苯胺和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为500:1的石油醚:乙酸乙酯混合溶剂,产率93%。
本实施例所得产物的氢谱图和碳谱图分别如图1和图2所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.30(t,J=7.6Hz,2H),7.15(dd,J=15.6,7.6Hz,2H),7.10-7.02(m,2H),7.01-6.90(m,J=9.1Hz,3H),6.46(d,J=6.0Hz,1H),4.92(q,J=6.4Hz,1H),3.75(d,J=6.8Hz,2H),2.72(s,3H),2.35(s,3H);
13C NMR(100MHz,CDCl3)δppm 157.4,151.6,142.2,132.8,131.0,129.6,126.3,122.7,119.8,116.4,109.3,50.0,41.1,18.3;
IR(KBr)3312,3053,2941,1705,1580,1488,1233,1082,914,749cm-1;
HRMS(ESI)Calcd for Chemical Formula:C17H20NO+[M+H]+:254.1539,found:254.1543。
经以上数据推断得到如下结构:
实施例2
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔N-甲基-1-萘胺和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为200:1的石油醚:乙酸乙酯混合溶剂,产率82%。
本实施例所得产物的氢谱图和碳谱图分别如图3和图4所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 8.37-8.22(m,1H),7.87-7.71(m,1H),7.50(d,J=8.0Hz,1H),7.48-7.38(m,2H),7.34(t,J=7.6Hz,1H),7.31-7.22(m,2H),7.10(t,J=5.4Hz,1H),7.02(t,J=7.2Hz,1H),6.95(d,J=7.6Hz,2H),6.48(dt,J=6.0,1.2Hz,1H),4.99(q,J=6.8Hz,1H),3.95(d,J=6.8Hz,2H),2.88(s,3H);
13C NMR(100MHz,CDCl3)δppm 157.2,149.5,142.5,134.8,129.6,129.3,128.2,125.6,125.1,124.0,123.1,122.7,116.3,115.5,109.0,51.0,41.7;
IR(KBr)νmax 3316,3057,2937,2778,1688,1583,1474,1366,1228,1028,900,764cm-1;
HRMS(ESI)Calcd for Chemical Formula:C20H20NO+[M+H]+:290.1539,found:290.1541。
经以上数据推断得到如下结构:
实施例3
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔N-烯丙基苯胺和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为200:1的石油醚:乙酸乙酯混合溶剂,产率81%。本实施例所得产物的氢谱图和碳谱图分别如图5和图6所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.32(t,J=8.0Hz,2H),7.19(t,J=8.0Hz,2H),7.11-6.97(m,3H),6.76(d,J=8.0Hz,2H),6.68(t,J=7.2Hz,1H),6.50(d,J=6.0Hz,1H),5.88(ddd,J=22.4,10.0,4.8Hz,1H),5.17(dd,J=28.8,17.2Hz,2H),4.92(q,J=6.4Hz,1H),4.14(d,J=6.8Hz,2H),3.94(d,J=4.8Hz,2H);
13C NMR(100MHz,CDCl3)δppm 157.2,148.4,142.3,134.3,129.7,129.1,122.9,116.5,116.1,112.7,108.7,53.3,44.5;
IR(KBr)νmax 2932,1681,1592,1491,1354,1231,1083,993,910,749cm-1;
HRMS(ESI)Calcd for Chemical Formula:C18H20NO+[M+H]+:266.1539,found:266.1545。
经以上数据推断得到如下结构:
实施例4
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔2,4-二氯苯胺和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为500:1的石油醚:乙酸乙酯混合溶剂,产率70%。
本实施例所得产物的氢谱图和碳谱图分别如图7和图8所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.33(t,J=8.0Hz,2H),7.24(d,J=2.4Hz,1H),7.16-6.91(m,4H),6.65(d,J=8.4Hz,1H),6.53(d,J=6.0Hz,1H),4.90(q,J=6.4Hz,1H),4.01(d,J=6.8Hz,3H);
13C NMR(100MHz,CDCl3)δppm 157.0,143.0,142.5,129.7,128.6,127.6,123.2,121.2,119.5,116.5,112.1,108.2,38.1;
IR(KBr)νmax 3448,1653,1017,762cm-1;
HRMS(ESI)Calcd for Chemical Formula:C15H14Cl2NO+[M+H]+:294.0447,found:294.0449.
经以上数据推断得到如下结构:
实施例5
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔2-甲基-N-甲基苯胺和0.3毫摩尔4-溴苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为500:1的石油醚:乙酸乙酯混合溶剂,产率92%。
本实施例所得产物的氢谱图和碳谱图分别如图9和图10所示;结构表征数据如下所示:
1H NMR(500MHz,CDCl3)δppm 7.43-7.34(m,2H),7.14(dt,J=19.0,7.0Hz,2H),7.05(d,J=7.5Hz,1H),6.95(t,J=7.5Hz,1H),6.87-6.79(m,2H),6.38(dt,J=6.0,1.5Hz,1H),4.96(dd,J=13.0,7.0Hz,1H),3.71(d,J=6.5Hz,2H),2.70(s,3H),2.33(s,3H);
13C NMR(125MHz,CDCl3)δppm 156.3,141.8,132.8,132.4,131.0,126.2,122.8,119.8,118.0,115.1,110.2,49.8,41.2,18.3;
IR(KBr)νmax 2939,1669,1582,1481,1345,1236,1077,833,748cm-1;
HRMS(ESI)Calcd for Chemical Formula:C17H19BrNO+[M+H]+:332.0645,found:332.0651.
经以上数据推断得到如下结构:
实施例6
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔2-甲基-N-甲基苯胺和0.3毫摩尔3-甲基苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为500:1的石油醚:乙酸乙酯混合溶剂,产率86%。
本实施例所得产物的氢谱图和碳谱图分别如图11和图12所示;结构表征数据如下所示:
1H NMR(500MHz,CDCl3)δppm 7.20-7.09(m,3H),7.06(d,J=8.0Hz,1H),6.94(t,J=7.5Hz,1H),6.86(d,J=7.5Hz,1H),6.77(d,J=8.5Hz,2H),6.45(d,J=7.0Hz,1H),4.89(q,J=6.5Hz,1H),3.72(d,J=7.0Hz,2H),2.71(s,3H),2.33(d,J=4.0Hz,6H);
13C NMR(125MHz,CDCl3)δppm 157.3,151.6,142.4,139.7,132.8,131.0,129.3,126.2,123.5,122.7,119.9,117.1 113.3,109.1,49.9,41.2,21.4,18.3;
IR(KBr)νmax 2936,1588,1469,1251,1146,755,572cm-1;
HRMS(ESI)Calcd for Chemical Formula:C18H22NO+[M+H]+:268.1696,found:268.1701.
经以上数据推断得到如下结构:
实施例7
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔2-甲基-N-甲基苯胺和0.3毫摩尔2-萘基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为200:1的石油醚:乙酸乙酯混合溶剂,产率91%。
本实施例所得产物的氢谱图和碳谱图分别如图13和图14所示;结构表征数据如下所示:
1H NMR(500MHz,CDCl3)δppm 7.78(dd,J=8.0,2.5Hz,2H),7.72(d,J=8.0Hz,1H),7.45(t,J=7.0Hz,1H),7.37(t,J=7.0Hz,1H),7.22-7.05(m,4H),6.95(t,J=7.0Hz,1H),6.59(d,J=6.0Hz,1H),5.00(q,J=7.0Hz,1H),3.78(d,J=7.0Hz,2H),2.74(s,3H),2.35(s,3H);
13C NMR(125MHz,CDCl3)δppm 155.1,142.2,134.2,132.8,131.1,129.9,129.7,127.7,127.0,126.6,126.2,124.4,122.8,119.9,118.5,110.5,109.9,50.0,41.3,18.4;
IR(KBr)νmax 3316,1586,1473,1344,1238,1078,851,748,447cm-1;
HRMS(ESI)Calcd for Chemical Formula:C21H22NO+[M+H]+:304.1696,found:304.1700.
经以上数据推断得到如下结构:
实施例8
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔咔唑和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为200:1的石油醚:乙酸乙酯混合溶剂,产率88%。
本实施例所得产物的氢谱图和碳谱图分别如图15和图16所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 8.09(d,J=7.7Hz,2H),7.52-7.36(m,4H),7.29-7.19(m,4H),7.00(t,J=7.4Hz,1H),6.84(d,J=7.9Hz,2H),6.54(d,J=12.2Hz,1H),5.50(dt,J=12.3,6.2Hz,1H),4.88(d,J=6.2Hz,2H);
13C NMR(100MHz,CDCl3)δppm 156.7,145.0,140.1,129.6,125.7,123.1,123.0,120.4,119.1,116.8,108.7,106.9,40.6;
IR(KBr)νmax 3048,1667,1591,1472,1326,1221,1115,1011,739,468cm-1;
HRMS(ESI)Calcd for Chemical Formula:C17H19ClNO+[M+H]+:288.1150,found:288.1153.
经以上数据推断得到如下结构:
实施例9
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔二乙胺和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为10:1的石油醚:乙酸乙酯混合溶剂加0.5%的三乙胺溶液,产率91%。
本实施例所得产物的氢谱图和碳谱图分别如图17和图18所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.31(t,J=7.6Hz,2H),7.06(d,J=7.4Hz,1H),6.99(d,J=8.1Hz,2H),6.50(d,J=6.2Hz,1H),4.93(q,J=7.0Hz,1H),3.35(d,J=7.2Hz,2H),2.56(q,J=7.2Hz,4H),1.07(t,J=7.2Hz,6H);
13C NMR(100MHz,CDCl3)δppm 157.3,142.3,129.5,122.6,116.3,108.7,46.7,45.9,11.8;
IR(KBr)νmax 2945,1756,1667,1591,1484,1237,755cm-1;
HRMS(ESI)Calcd for Chemical Formula:C13H20NO+[M+H]+:206.1539,Found:206.1537.
经以上数据推断得到如下结构:
实施例10
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔吗啉和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为10:1的石油醚:乙酸乙酯混合溶剂加0.5%的三乙胺溶液,产率98%。
本实施例所得产物的氢谱图和碳谱图分别如图19和图20所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.31(t,J=8.0Hz,2H),7.06(t,J=7.4Hz,1H),6.99(d,J=7.9Hz,2H),6.54(d,J=6.2Hz,1H),4.92(q,J=7.1Hz,1H),3.83–3.55(m,4H),3.22(d,J=8.4Hz,2H),2.52(s,4H);
13C NMR(100MHz,CDCl3)δppm 157.1,143.1,129.6,122.8,116.3,107.6,66.9,53.3,52.2;
IR(KBr)νmax 2934,2852,1667,1592,1488,1238,1116,1012,874,747cm-1;
HRMS(ESI)Calcd for Chemical Formula:C13H18NO2 +[M+H]+:220.1332,Found:220.1329。
经以上数据推断得到如下结构:
实施例11
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔4-苯基哌啶和0.3毫摩尔苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为10:1的石油醚:乙酸乙酯混合溶剂加0.5%的三乙胺溶液,产率93%。
本实施例所得产物的氢谱图和碳谱图分别如图21和图22所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 7.37–7.26(m,4H),7.26–7.18(m,3H),7.06(t,J=7.4Hz,1H),7.01(d,J=7.8Hz,2H),6.54(d,J=6.2Hz,1H),5.00(q,J=7.1Hz,1H),3.28(d,J=8.5Hz,2H),3.13(d,J=11.8Hz,2H),2.50(ddd,J=16.0,10.6,6.9Hz,1H),2.15(td,J=11.2,4.3Hz,2H),1.86(dd,J=8.4,3.1Hz,4H);
13C NMR(100MHz,CDCl3)δppm 157.2,146.3,142.8,129.6,128.4,126.9,126.1,122.8,116.4,108.5,54.1,52.2,42.6,33.4;
IR(KBr)νmax 3038,2928,2778,1743,1668,1592,1233,1111,1002,752,694cm-1;
HRMS(ESI)Calcd for Chemical Formula:C20H24NO+[M+H]+:294.1852,Found:294.1849.
经以上数据推断得到如下结构:
实施例12
在封管中,先依次加入0.01毫摩尔醋酸铜,0.01毫摩尔氯化锌溶于1.0毫升二氯甲烷溶剂中,最后加入0.2毫摩尔吗啉和0.3毫摩尔4-正丁氧基苯基联烯醚,在50摄氏度下转速700rpm下搅拌反应6小时,停止搅拌。加入5mL水,用乙酸乙酯萃取3次,合并有机相并使用0.5g无水硫酸钠干燥,过滤,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为10:1的石油醚:乙酸乙酯混合溶剂加0.5%的三乙胺溶液,产率90%。
本实施例所得产物的氢谱图和碳谱图分别如图23和图24所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 6.95–6.87(m,2H),6.86–6.79(m,2H),6.46(d,J=6.2Hz,1H),4.83(q,J=7.2Hz,1H),3.91(t,J=6.5Hz,2H),3.78–3.59(m,4H),3.21(d,J=7.3Hz,2H),2.52(s,4H),1.86–1.67(m,2H),1.57–1.39(m,2H),0.97(t,J=7.4Hz,3H).
13C NMR(100MHz,CDCl3)δppm 154.9,151.1,144.2,117.4,115.2,106.2,68.1,66.9,53.325,52.1,31.2,19.1,13.7.
IR(KBr)νmax 3045,2946,2864,1666,1581,1502,1386,1222,1115,1009,828,741,628,540,452cm-1.
HRMS(ESI)Calcd for Chemical Formula:[M+H]+:292.1907,found:292.1902.
经以上数据推断得到如下结构:
应用例1
在封管中,先依次加入0.015毫摩尔钯碳溶于2.0毫升甲醇和二氯甲烷1:1的混合溶剂中,最后加入0.3毫摩尔实施例12中得到的氧杂烯丙基胺化合物,置换氢气3-5次,在室温下转速700rpm下搅拌反应2小时,停止搅拌。用硅藻土滤去固体杂质,将得到的混合溶液,减压浓缩,再通过薄层层析分离纯化,得到目标产物,所用的薄层层析展开剂为体积比为100:1的石油醚:乙酸乙酯混合溶剂加0.5%的三乙胺溶液,产率94%。
本实施例所得产物的氢谱图和碳谱图分别如图25和图26所示;结构表征数据如下所示:
1H NMR(400MHz,CDCl3)δppm 6.82(s,4H),3.96(t,J=6.3Hz,2H),3.90(t,J=6.5Hz,2H),3.74–3.68(m,4H),2.58–2.37(m,6H),2.02–1.87(m,2H),1.73(dt,J=14.6,6.6Hz,2H),1.58–1.38(m,2H),0.96(t,J=7.4Hz,3H).
13C NMR(100MHz,CDCl3)δppm 153.3,152.9,115.3,68.3,66.9,66.7,55.6,53.7,31.4,26.5,19.2,13.8.
IR(KBr)νmax 3044,2946,2868,1582,1506,1384,1299,1225,1122,1042,826,740,520cm-1.
HRMS(ESI)Calcd for Chemical Formula:[M+H]+:294.2064,found:294.2061.
经以上数据推断得到如下结构:
以上实施例仅为本发明较优的实施方式,仅用于解释本发明,而非限制本发明,本领域技术人员在未脱离本发明精神实质下所作的改变、替换、修饰等均应属于本发明的保护范围。
Claims (10)
7.根据权利要求2-6任一项所述的氧杂烯丙基胺类化合物的制备方法,其特征在于,所述分离纯化包括:将反应液冷却至室温,用乙酸乙酯萃取,合并有机相,使用无水硫酸钠干燥,过滤,减压蒸馏除溶剂得粗产物,经薄层层析提纯得到所述氧杂烯丙基胺类化合物。
8.根据权利要求7所述的氧杂烯丙基胺类化合物的制备方法,其特征在于,所述薄层层析提纯为以石油醚和乙酸乙酯的混合溶剂为展开剂的薄层层析,所述石油醚与乙酸乙酯的体积比为(5-500):1。
9.权利要求1所述的氧杂烯丙基胺类化合物在合成药物中的应用。
10.根据权力要求9所述的氧杂烯丙基胺类化合物在合成药物中的应用,其特征在于,所述药物为Pramocaine。
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LUCA ALESSANDRO PEREGO等: "Copper-Catalyzed Hydroamination of Allenes:from Mechanistic Understanding to Methodology Development", 《ACS CATAL.》 * |
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