CN110386904B - 一种卤代异噁唑啉类化合物的合成方法 - Google Patents
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- -1 halogenated isoxazoline compound Chemical class 0.000 title claims description 15
- 150000002547 isoxazolines Chemical class 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 12
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 30
- SBTSVTLGWRLWOD-UHFFFAOYSA-L copper(ii) triflate Chemical group [Cu+2].[O-]S(=O)(=O)C(F)(F)F.[O-]S(=O)(=O)C(F)(F)F SBTSVTLGWRLWOD-UHFFFAOYSA-L 0.000 claims description 15
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- 150000001875 compounds Chemical class 0.000 claims description 11
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- 229910021595 Copper(I) iodide Inorganic materials 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Abstract
本发明公开了一种卤代异噁唑啉类化合物的合成方法,属于有机合成领域,该方法是在惰性气体保护条件下,将酮肟类化合物与有机卤代试剂混合溶于有机溶剂中,在配体、催化剂和碱的作用下,得到卤代异噁唑啉类化合物。本发明直接以酮肟为原料,进行分子内环化反应,整个过程不需要用到贵金属催化剂,降低了成本,原子经济性高,试剂廉价环保,反应操作简单,有利于在医药合成中的应用。
Description
技术领域
本发明涉及有机合成领域,尤其涉及一种卤代异噁唑啉类化合物的合成方法。
背景技术
异噁唑啉类化合物在天然产物中是一类很重要的结构单元,能够实现多种转化,为许多重要的有机化合物的合成提供了基础。如分子中含有的异噁唑啉部分的大分子化合物显示出令人惊异的抗炎症和抗菌活性。该类化合物还可应用于合成一种简单的异噁唑啉衍生物,该衍生物是一种非常有效的DNA甲基转移酶抑制剂。如式(a)所示,传统的合成异噁唑啉盐的方法是使用1,3-偶极环加成的腈氧化物与烯丙基卤化物(Diastereoselectivesynthesis of fused cyclopropyl-3-amino-2,4-oxazineβ-amyloid cleaving enzyme(BACE)inhibitors and their biological evaluation.Bioorg.Med.Chem.Lett.2018,28,1111–1115.),然而,该协议的产品产量不高。如式(b)所示,使用烯丙基氧基化合物的氧卤化可以实现异噁唑啉盐的合成(Iminoxyl Radical-Promoted Oxycyanation andAminocyanation of Unactivated Alkenes:Synthesis of Cyano-FeaturedIsoxazolines and Cyclic Nitrones Org.Lett.2017,19,3255-3258.)。
公开号为CN105001175A中公开了一种芳基酰胺化合物与1,2-二氯乙烷在碱性条件下制备2-芳基-2-噁唑啉的合成方法。该发明使用相对廉价的1,2-二氯乙烷取代了价格较高的氨基乙醇为原料,合成反应的经济性得到提高,在保证产品质量的情况下增加了产品的成本优势。
发明内容
本发明提供了一种卤代异噁唑啉类化合物的合成方法,具有较高的收率,高原子利用率、条件温和、原料廉价易得。
本发明的反应机理,如图1所示,该反应机理中不饱和酮肟(1)在碱的作用下脱氢形成亚氨氧基阴离子(A),Cu(II)被其还原为Cu(I),同时形成亚氨氧基自由基(B)。亚氨氧基自由基(B)与自身的不饱和双键进行环化形成自由基中间体(C),该自由基中间体(C)与卤代试剂进行反应形成卤代异噁唑啉类化合物。
一种卤代异噁唑啉类化合物的合成方法,包括:在惰性气体保护条件下,将酮肟与有机卤代试剂混合溶于有机溶剂中,在配体、催化剂和碱的作用下,得到的反应液经后处理得到卤代异噁唑啉类化合物。
所述的卤代异噁唑啉类化合物的结构式,如式(I)所示:
其中R1为烷基、芳基或呋喃基;R2、R3及R4为氢或甲基;X为Cl、Br所述的酮肟的结构式,如式(II)所示:
所述的有机卤代试剂的结构式,如式(III)和(IV)所示:
结构式(I)和(II)中R1、R2、R3、R4与X的定义相同;
所述的酮肟的结构式中R1选自C1~C8的烷基、苯基、呋喃基或含有卤素、硝基、三氟甲基、甲基、羟基、脂基及甲氧基取代的苯基;R2、R3及R4为氢或甲基。
所述的配体为1,10-菲啰啉、2,2’-联吡啶、四甲基乙二胺或三苯基磷,由于在该合成方法中含氮配体优于含磷配体,因此,进一步优选为1,10-菲啰啉。
所述的催化剂为含铜的盐,反应中,Cu(II)被其还原为Cu(I),起关键催化作用。所述的含铜的盐为三氟甲磺酸铜、氯化铜、碘化亚铜或醋酸铜。
由于催化剂中阴离子pKa的不同,对该合成方法的催化效果有影响,而三氟甲磺酸铜其阴离子的pKa适中,表现出最好的催化效果,因此,进一步优选为三氟甲磺酸铜。
所述的碱为碳酸钠、碳酸氢钠、碳酸钾、碳酸铯或磷酸钾中的一种,进一步优选为碳酸钠。
所述的溶剂的加入量以式(Ⅰ)所示的酮肟的物质的量计为1-10ml/mmol,进一步优选为1ml/mmol。
所述的有机溶剂为四氢呋喃、乙腈、乙醇、N,N-二甲基乙酰胺、二氯乙烷或甲苯中的一种,进一步优选为乙腈。
所述的合成方法的反应温度为10℃-100℃,进一步优选为80℃。
所述的合成方法的反应时间为0.15-15h,进一步优选为12h。
为了进一步的提高反应产率,提高原子的利用率,所述的反应式中酮肟、有机卤代试剂、配体、催化剂及碱的物质的量之比进一步优选为1:1-2:0.05:0.05:0.5-1.5。
所述的反应液的处理方法为:由于卤代异噁唑啉类化合物溶解于乙酸乙酯中,反应结束后用乙酸乙酯萃取3-5次,合并乙酸乙酯,用饱和食盐水洗涤1-2次,所得到的乙酸乙酯溶液用无水硫酸钠干燥,干燥后再进行减压浓缩得到粗产物,最后进行柱层析分离,以体积比为1-40:1的石油醚/乙酸乙酯混合液为洗脱剂,收集合并含目标化合物的洗脱液,蒸除溶剂后干燥。
与现有技术相比,本发明具有以下优点:
(1)本发明的原子经济性高,试剂廉价环保,操作简单,反应条件温和。
(2)本发明的底物适应性好,可以实现多种取代基的异噁唑啉类化合物的合成。
(3)本发明中直接以酮肟为原料,进行分子内环化反应,整个过程只需要催化量的铜催化剂,反应操作简单,更有利于其在医药合成中的应用。
附图说明
图1为一种卤代异噁唑啉类化合物合成方法的反应机理图;
图2为实施例1制备的产物化合物1的1H NMR谱;
图3为实施例2制备的产物化合物2的1H NMR谱;
图4为实施例3制备的产物化合物3的1H NMR谱;
图5为实施例4制备的产物化合物4的1H NMR谱;
图6为实施例5制备的产物化合物5的1H NMR谱;
图7为实施例6制备的产物化合物6的1H NMR谱;
图8为实施例7制备的产物化合物7的1H NMR谱;
图9为实施例8制备的产物化合物8的1H NMR谱;
图10为实施例9制备的产物化合物9的1H NMR谱。
具体实施方式
下面结合实施例对本发明作进一步说明。下述实施例中所使用的实验方法如无特殊说明,均为常规方法。实施例中所用的材料、试剂等,如无特殊说明,均可从商业途径得到。
实施例1
将1-苯基丁-3-烯-1-酮肟(32.2mg,0.2mmol)、N-氯代丁二酰亚胺(32.0mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为10:1)分离得到39.3mg,收率为81%。
产物表征:白色固体;m.p.51-52℃;1H NMR(500MHz,CDCl3)δ7.68–7.66(m,2H),7.43–7.40(m,3H),5.02–4.69(m,1H),3.71(dd,J=11.3,4.5Hz,1H),3.58(dd,J=11.2,7.4Hz,1H),3.42(dd,J=17.0,10.5Hz,1H),3.35(dd,J=17.0,6.3Hz,1H)(如图2所示)。
实施例2
将1-(对甲苯基)丁-3-烯-1-酮肟(35.0mg,0.2mmol)、N-氯代丁二酰亚胺(32.0mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为10:1)分离得到45.0mg,收率为97%。
产物表征:白色固体;m.p.76-77℃;1H NMR(500MHz,CDCl3)δ7.55(d,J=8.1Hz,2H),7.21(d,J=7.9Hz,2H),4.92–4.86(m,1H),3.49(dd,J=17.0,10.3Hz,1H),3.40(dd,J=10.5,4.1Hz,1H),3.18–3.24(m,2H),2.38(s,3H)(如图3所示)。
实施例3
将1-(4-甲氧基苯基)丁-3-烯-1-酮肟(38.2mg,0.2mmol)、N-氯代丁二酰亚胺(32.0mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为10:1)分离得到36.9mg,收率为83%。
产物表征:白色固体;m.p.72-74℃;1H NMR(500MHz,CDCl3)δ7.61–7.59(d,J=8.8Hz,2H),6.92–6.90(d,J=8.8Hz,2H),4,96–4.91(m,1H),3.83(s,1H),3.69(dd,J=11.2,4.4Hz,1H),3.55(dd,J=11.2,7.5Hz,1H),3.36(dd,J=16.9,10.5Hz,1H),3.30(dd,J=16.9,6.3Hz,1H)(图4所示)。
实施例4
将2、2-二甲基-1-(4-溴苯基)丁-3-烯-1-酮肟(53.63mg,0.2mmol)、N-氯代丁二酰亚胺(32.0mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为10:1)分离得到45.5mg,收率为76%。
产物表征:白色固体;m.p.61-62℃;1H NMR(500MHz,CDCl3)δ7.55–7.52(m,2H),7.51–7.47(m,2H),4.42(t,J=6.5Hz,1H),3.78(dd,J=11.6,6.2Hz,1H),3.71(dd,J=11.6,6.8Hz,1H),1.48(s,3H),1.33(s,3H)(图5所示)。
实施例5
将1-苯基丁-3-烯-1-酮肟(32.2mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到41.1mg,收率为85%。
产物表征:白色固体;m.p.59-61℃;1H NMR(500MHz,CDCl3)δ7.71–7.64(m,2H),7.45–7.37(m,3H),5.05–4.95(m,1H),3.58(dd,J=10.4,4.3Hz,1H),3.51(dd,J=17.0,10.5Hz,1H),3.41(dd,J=10.4,8.3Hz,1H),3.33(dd,J=17.0,6.4Hz,1H)(图6所示)。
实施例6
将1-(对甲苯基)丁-3-烯-1-酮肟(35.0mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到32.4mg,收率为64%。
产物表征:白色固体;m.p.85-86℃;1H NMR(500MHz,CDCl3)δ7.56(d,J=8.2Hz,2H),7.22(d,J=8.0Hz,2H),5.04–4.93(m,1H),3.57(dd,J=10.3,4.3Hz,1H),3.50(dd,J=17.0,10.4Hz,1H),3.40(dd,J=10.3,8.4Hz,1H),3.31(dd,J=17.0,6.3Hz,1H),2.38(s,3H)(图7所示)。
实施例7
将1-(4-甲氧基苯基)丁-3-烯-1-酮肟(38.2mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到40.6mg,收率为75%。
产物表征:白色固体;m.p.77-78℃;1H NMR(500MHz,CDCl3)δ7.60(d,J=8.9,2H),6.92(d,J=8.9,2H),5.01–4.91(m,1H),3.83(s,3H),3.57(dd,J=10.3,4.2Hz,1H),3.49(dd,J=16.9,10.4Hz,1H),3.39(dd,J=10.3,8.4Hz,1H),3.29(dd,J=16.9,6.3Hz,1H)(图8所示)。
实施例8
将1-(对甲苯基)丁-3-烯-1-酮肟(35.0mg,0.2mmol)、N-碘代丁二酰亚胺(42.3mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为10:1)分离得到58.0mg,收率为97%。
产物表征:白色固体;m.p.87-89℃;1H NMR(500MHz,CDCl3)δ7.56(d,J=8.2Hz,2H),7.22(d,J=8.0Hz,2H),4.94–4.88(m,1H),3.50(dd,J=17.0,10.3Hz,1H),3.42(dd,J=10.0,4.1Hz,1H),3.26–3.18(m,2H),2.38(s,3H)(图9所示)。
实施例9
将1-苯乙基丁-3-烯-1-酮肟(37.8mg,0.2mmol)、N-碘代丁二酰亚胺(32.0mg,0.24mmol)、1,10-菲啰啉(2.0mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到60.4mg,收率为96%。
产物表征:白色固体;m.p.54-55℃;1H NMR(500MHz,CDCl3)δ7.34–7.28(m,2H),7.23(dd,J=10.6,4.6Hz,3H),4.69(m,1H),3.27(dd,J=10.0,4.1Hz,1H),3.07–2.99(m,2H),2.93(td,J=8.0,2.3Hz,2H),2.74(dd,J=17.4,6.2Hz,1H),2.70–2.62(m,2H)(图10所示)。
实施例10
将1-苯基丁-3-烯-1-酮肟(32.2mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、2,2’-联吡啶(1.6mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到41.1mg,收率为55%。
产物表征:白色固体;m.p.59-61℃;1H NMR(500MHz,CDCl3)δ7.71–7.64(m,2H),7.45–7.37(m,3H),5.05–4.95(m,1H),3.58(dd,J=10.4,4.3Hz,1H),3.51(dd,J=17.0,10.5Hz,1H),3.41(dd,J=10.4,8.3Hz,1H),3.33(dd,J=17.0,6.4Hz,1H)(图6所示)。
实施例11
将1-苯基丁-3-烯-1-酮肟(32.2mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、四甲基乙二胺(1.2mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到41.1mg,收率为68%。
产物表征:白色固体;m.p.59-61℃;1H NMR(500MHz,CDCl3)δ7.71–7.64(m,2H),7.45–7.37(m,3H),5.05–4.95(m,1H),3.58(dd,J=10.4,4.3Hz,1H),3.51(dd,J=17.0,10.5Hz,1H),3.41(dd,J=10.4,8.3Hz,1H),3.33(dd,J=17.0,6.4Hz,1H)(图6所示)。
实施例12
将1-苯基丁-3-烯-1-酮肟(32.2mg,0.2mmol)、溴代丙二酸二乙酯(57.4mg,0.24mmol)、三苯基磷(2.6mg,0.01mmol),三氟甲磺酸铜(3.6mg,0.01mmol)以及碳酸钠(21.2mg,0.2mmol)加入到氩气保护反应瓶中,最后加入乙腈1ml,再在80℃下反应12h,反应结束后,用柱层析色谱法(洗脱液:石油醚/乙酸乙酯体积比为5:1)分离得到41.1mg,收率为26%。
产物表征:白色固体;m.p.59-61℃;1H NMR(500MHz,CDCl3)δ7.71–7.64(m,2H),7.45–7.37(m,3H),5.05–4.95(m,1H),3.58(dd,J=10.4,4.3Hz,1H),3.51(dd,J=17.0,10.5Hz,1H),3.41(dd,J=10.4,8.3Hz,1H),3.33(dd,J=17.0,6.4Hz,1H)(图6所示)。
Claims (4)
1.一种卤代异噁唑啉类化合物的合成方法,其特征在于,所述的合成方法是在惰性气体保护条件下,将酮肟类化合物与有机卤代试剂混合溶于有机溶剂中,在配体、催化剂和碱的作用下,得到卤代异噁唑啉类化合物;所述的配体为1,10-菲啰啉;所述的催化剂为三氟甲磺酸铜;所述的碱为碳酸钠;
所述的卤代异噁唑啉类化合物的结构式,如式(I)所示:
所述的酮肟类化合物的结构式,如式(II)所示:
所述的有机卤代试剂的结构式,如式(III)或(IV)所示:
其中,R1为C1~C8的烷基、苯基、呋喃基,含有卤素、硝基、三氟甲基、甲基、羟基或甲氧基取代的苯基;R2、R3及R4为氢或甲基;X为Cl、Br或I;当所述的有机卤代试剂的结构式为式(IV)所示时,式(I)中X为Br。
2.根据权利要求1所述的卤代异噁唑啉类化合物的合成方法,其特征在于,所述的有机溶剂为四氢呋喃、乙腈、乙醇、N,N-二甲基乙酰胺、二氯乙烷或甲苯。
3.根据权利要求1或2所述的卤代异噁唑啉类化合物的合成方法,其特征在于,所述的酮肟类化合物、有机卤代试剂、配体、催化剂及碱的投料物质的量之比为1:1-2:0.05:0.05:0.5-1.5。
4.根据权利要求1所述的卤代异噁唑啉类化合物的合成方法,其特征在于,所述的有机溶剂的加入量以式(II)所示的酮肟类化合物的物质的量计为1-10mL/mmol。
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