CN115197261B - 噁二氮杂硼衍生物的合成方法 - Google Patents
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- -1 oxadiazine boron derivative Chemical class 0.000 title claims abstract description 19
- 238000001308 synthesis method Methods 0.000 title abstract description 6
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- UBRFUPVMYXDNHD-UHFFFAOYSA-N oxadiazaborole Chemical class O1N=NB=C1 UBRFUPVMYXDNHD-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N1/00—Sampling; Preparing specimens for investigation
- G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
Abstract
本发明提供一种噁二氮杂硼衍生物的合成方法，在乙酸乙酯中使用硼酸、胺肟合成制得，反应在无催化剂和温和条件下进行，且所有产品均可通过过滤和洗涤快速纯化。本发明方法的优点包括无催化剂、反应时间短、易于后处理，以及它们能够适应广泛的底物，以及良好的产率。
Description
本申请要求2022年07月06日提交的中国专利申请2022107908290的优先权，所述申请的内容均援引加入本文。
技术领域
本发明属于药物开发技术领域，具体涉及噁二氮杂硼及其合成方法和用途。
背景技术
研究发现，噁二氮杂硼类化合物具有较强的杀菌作用(Pir,M.,Agirbas,H.,Budak,F.et al.Synthesis,characterization,antimicrobial activity,and QSARstudies on substituted oxadiazaboroles.Med Chem Res 25,1794–1812(2016).)
然而其制备方法需要高温反应，且反应时间长，不利于工业化生产。因此，有必要开发一种操作更安全且工艺时间短的方法来制备噁二氮杂硼类化合物。
发明内容
第一方面，本发明提供一类噁二氮杂硼化合物。
一类噁二氮杂硼化合物，结构式如下：
其中，R’为各自独立的氢，C1-C6的烷基或C1-C6的烷氧基，卤素、一个或多个卤素取代的甲基、苯基、硝基。
R为各自独立的氢，C1-C6的烷基或C1-C6的烷氧基，卤素、一个或多个卤素取代的甲基、苯基、硝基。
所述C1-C6烷基是指甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基或异己基；所述C1-C6的烷氧基是指甲氧基或乙氧基；所述卤素是氟、氯、溴或碘。
R’可以独立的为邻位、间位或对位，可以邻位、间位和对位同时取代，也可以单独取代。
R可以独立的为邻位、间位或对位，可以邻位、间位和对位同时取代，也可以单独取代。
所述式3化合物选自3a-3k化合物:
第二方面，本发明提供上述式3化合物的制备方法。
上述式3化合物合成路线如下：
反应溶剂选自四氢呋喃、甲醇、乙腈、N,N-二甲基甲酰胺、丙酮、乙酸乙酯中的一种或几种混合，优选乙酸乙酯。
本发明反应温度为室温，反应时间为5min。
进一步，本发明操作步骤为：在圆底烧瓶中将胺肟1、苯基硼酸2衍生物和乙酸乙酯混合在一起，并在室温下搅拌5分钟，当反应完成时将石油醚加入圆底烧瓶中，产物立即从反应体系中沉淀出来，过滤，用乙酸乙酯和石油醚混合溶剂洗涤，得纯品。
有益效果：
本发明提供一种噁二氮杂硼衍生物的合成方法，在乙酸乙酯中使用硼酸、胺肟合成制得，反应在无催化剂和温和条件下进行，且所有产品均可通过过滤和洗涤快速纯化。本发明方法的优点包括无催化剂、反应时间短、易于后处理，以及它们能够适应广泛的底物，以及良好的产率。此外，通过简单的过滤和洗涤，可以方便地纯化产品。
具体实施方式：
下面通过具体实施例对本发明进行具体描述，在此指出以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域的技术熟练人员可以根据上述发明内容对本发明作出一些非本质的改进和调整。
实施例
原料制备方法：
向圆底烧瓶中加入苄腈(19.4mmol，1.0equiv)、盐酸羟胺(29.1mmol，1.5equiv)、三乙胺(29.1mmol，1.5equiv)和乙醇(15mL)。将所得混合物在回流下加热至70℃并保持5小时。当反应完成时，将温度降低至25℃，然后减压除去溶剂并加入饱和NaCl溶液(25mL)。随后，水相用乙酸乙酯(4×20mL)萃取，用无水Na2SO4干燥，加入硅胶真空浓缩。残余物经柱层析(石油醚/乙酸乙酯4:1)纯化得到目标产物1。
在圆底烧瓶中将胺肟1(1.1mmol，1.0equiv)、苯基硼酸2(1.1mmol，1.0equiv)衍生物和乙酸乙酯(2mL)混合在一起并在室温下搅拌5分钟。用TLC监测反应进程。当反应完成时，将过量的石油醚(5mL)加入圆底烧瓶中，产物立即从反应体系中沉淀出来。过滤，用乙酸乙酯和石油醚(15：1)混合溶剂洗涤，得纯品。
结果与讨论
在初步试验中，胺肟1a和苯基硼酸2a溶解在四氢呋喃(THF)中，并在室温下将脱水剂TiCl4滴加到混合体系中。1小时后，通过薄层色谱(TLC)分析反应，但未检测到所需产物，可能是由于起始材料和TiCl4之间形成了盐(表1，条目1)。然后，发明人在不添加任何脱水剂的情况下在室温下再次测试。令人惊讶的是，当起始材料溶解在THF中时，反应迅速发生，产率约为85％(条目2)。随后，发明人将反应时间延长至1小时，但产物的收率没有显着差异(条目3)。此外，偕胺肟和苯基硼酸在各种溶剂中进行了研究，包括甲醇、乙醇、乙腈、乙酸乙酯等(条目4-9)。最后发现室温下乙酸乙酯中收率最高，且产物仅仅经过简单的过滤和洗涤即可得到高纯度目标产物。
表1.反应条件的优化
a反应条件：1a(1.1mmol，1.0equiv)、2a(1.1mmol，1.0equiv)和乙酸乙酯(2.0mL)。b添加脱水剂TiCl4(10mol％)。c分离产量。d没有反应。
在优化的条件下，发明人探索了取代偕胺肟和苯基硼酸之间底物反应的范围和一般性。如表2所示，多种硼酸和偕胺肟与该反应兼容。苯环上的给电子基团(如-Me、-Ph)、卤素基团(F和I)和吸电子基团都具有良好的耐受性，并且所需的产物以良好至优异的产率(表2,3a–3e,3g–3k,82–93％)。然而，当苯环带有羟基时，没有检测到产物3l。此外，2,6-二甲基苯基硼酸作为底物参与了反应。化合物3f(75％)的收率下降。
表2.噁二氮杂硼3合成的底物范围
综上所述，本发明提供一种噁二氮杂硼衍生物的合成方法，在乙酸乙酯中使用硼酸、胺肟合成制得，反应在无催化剂和温和条件下进行，且所有产品均可通过过滤和洗涤快速纯化。本发明方法的优点包括无催化剂、反应时间短、易于后处理，以及它们能够适应广泛的底物，以及良好的产率。此外，通过简单的过滤和洗涤，可以方便地纯化产品。
实验数据：
Amidoxime(1a)1.White solid(2.20g,85％yield),PE/EA＝4:1,mp 67-69℃.1HNMR(600MHz,DMSO-d6):δ9.63(1H,s),7.69–7.67(2H,m),7.38–7.36(3H,m),5.80(2H,s).13CNMR(151MHz,DMSO-d6):δ151.29,133.84,129.33,128.56,125.85.
Amidoxime(1b)2.White solid(2.20g,87％yield),PE/EA＝4:1,mp 124-127℃.1HNMR(600MHz,DMSO-d6)δ9.52(1H,s),7.56(2H,d,J8.2),7.17(2H,d,J8.0),5.73(1H,s),2.31(3H,s).13C NMR(151MHz,DMSO-d6)δ151.24,138.71,131.03,129.10,125.74,21.28.
Amidoxime(1c)2.White solid(2.20g,90％yield),PE/EA＝4:1,mp 107-110℃.1HNMR(600MHz,DMSO-d6)δ9.44(1H,s),7.61(2H,d,J8.9),6.92(2H,d,J8.9),5.71(2H,s),3.77(3H,s).13C NMR(151MHz,DMSO-d6)δ160.27,151.05,127.17,126.24,113.91,55.61.
Amidoxime(1d)3.White solid(2.00g,87％yield),PE/EA＝4:1,mp 157-160℃.1HNMR(600MHz,DMSO-d6)δ9.71(1H,s),7.74(2H,d,J8.3),7.47(2H,d,J8.1),5.83(2H,s).13CNMR(151MHz,DMSO-d6)δ150.61,137.36,133.38,127.90,95.70.
Amidoxime(1e)3.White solid(2.20g,85％yield),PE/EA＝4:1,mp 79-81℃.1HNMR(600MHz,DMSO-d6)δ9.63(1H,s),7.73–7.70(2H,m),7.20(2H,t,J8.9),5.83(2H,s).13CNMR(151MHz,DMSO-d6)δ163.79,162.16,150.52,130.31,130.29,128.02,127.96,115.49,115.34.
3,5-diphenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3a)4.White solid(0.22g,92％yield)；mp 158-160℃.1H NMR(600MHz,DMSO-d6)δ10.46(1H,s),8.00(2H,dd,J6.5,3.2),7.96(2H,d,J6.5),7.59(3H,dd,J 7.0,3.8),7.55(1H,d,J7.2),7.52(2H,t,J7.1).13C NMR(151MHz,DMSO-d6)δ159.75,134.38,131.59,131.24,129.45,128.73,127.20,126.78.11B NMR(193MHz,DMSO-d6)δ32.07.
3-phenyl-5-(p-tolyl)-4,5-dihydro-1,2,4,5-oxadiazaborole(3b)4.Whitesolid(0.22g,85％yield)；mp 143-146℃.1H NMR(600MHz,DMSO-d6)δ10.36(1H,s),7.98–7.95(2H,m),7.83(2H,d,J 7.9),7.58–7.53(4H,m),7.32(2H,d,J 7.5),2.37(4H,s).13CNMR(151MHz,DMSO-d6)δ159.66,141.31,134.42,131.22,129.45,129.41,127.22,126.74,21.77.11B NMR(193MHz,DMSO-d6)δ33.74.
5-(4-ethylphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3c).White solid(0.23g,82％yield)；mp 116-119℃.1H NMR(600MHz,DMSO-d6)δ10.37(1H,s),7.97(2H,dd,J 6.6,2.9),7.86(2H,d,J 7.8),7.58–7.57(3H,m),7.35(2H,d,J7.8),2.67(2H,q,J 7.6),1.22(4H,t,J 7.6).13C NMR(151MHz,DMSO-d6)δ159.67,147.51,134.51,131.22,129.44,128.22,127.23,126.75,28.83,15.80.11B NMR(193MHz,DMSO-d6)δ32.86.HRMS(ESI):m/z[M+H]+calculated for C15H16BN2O:251.1350,found:251.1344.
5-(4-fluorophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3d).White solid(0.24g,90％yield)；mp 192-194℃.1H NMR(600MHz,DMSO-d6)δ10.46(1H,s),8.03–8.00(2H,m),7.99–7.97(2H,m),7.60–7.58(3H,m),7.36(2H,t,J8.9).13C NMR(151MHz,DMSO-d6)δ165.49,163.84,159.75,136.91,136.85,131.27,129.46,127.12,126.74,115.99,115.86.11B NMR(193MHz,DMSO-d6)δ33.62.HRMS(ESI):m/z[M+H]+calculated for C13H11BN2OF:241.0943,found:241.0939.
5-(4-nitrophenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3e)4.White solid(0.27g,93％yield)；mp 254-256℃,1H NMR(600MHz,DMSO-d6)δ10.71(1H,s),8.35(2H,d,J8.5),8.18(2H,d,J8.5),7.97(2H,dd,J6.4,2.9),7.61–7.57(3H,m).13CNMR(151MHz,DMSO-d6)δ159.96,149.60,135.57,131.40,129.49,126.87,126.75,123.43.11B NMR(193MHz,DMSO-d6)δ34.03.
5-(2,6-dimethylphenyl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3f).White solid(0.21g,80％yield)；mp 148-151℃,1H NMR(600MHz,DMSO-d6)δ10.26(1H,s),7.95(3H,dd,J6.6,3.0),7.58–7.53(4H,m),7.25(2H,t,J7.6),7.07(3H,d,J 7.6),2.31(9H,s).13C NMR(151MHz,DMSO-d6)δ159.34,141.91,131.25,130.05,129.48,127.10,126.89,126.72,22.89.11B NMR(193MHz,DMSO-d6)δ33.97.HRMS(ESI):m/z[M+H]+calculated for C15H16BN2O:251.1350,found:251.1345.
5-(naphthalen-1-yl)-3-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3g).White solid(0.25g,84％yield)；mp 134-136℃,1H NMR(600MHz,DMSO-d6)δ10.58(1H,s),8.66(1H,d,J 8.4),8.23(1H,d,J 6.8),8.12(1H,d,J 8.1),8.06(3H,d,J 4.6),8.01(1H,d,J 8.1),7.67(3H,dd,J 13.0,6.3),7.60(5H,t,J 6.2).13C NMR(151MHz,DMSO-d6)δ159.70,136.00,135.73,133.44,131.80,131.32,129.47,129.08,128.37,127.34,127.13,126.97,126.46,125.81.11B NMR(193MHz,DMSO-d6)δ34.99.HRMS(ESI):m/z[M+H]+calculated for C17H14BN2O:273.1193,found:273.1196.
3-(4-methoxyphenyl)-5-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3h)5.White solid(0.21g,92％yield)；mp 176-179℃,1H NMR(600MHz,DMSO-d6)δ10.33(1H,s),7.94(5H,t,J 7.4),7.55(1H,t,J 7.2),7.51(2H,t,J 7.2),7.13(3H,d,J 8.7),3.85(4H,s).13C NMR(151MHz,DMSO-d6)δ161.60,159.41,134.35,131.52,128.71,128.34,119.46,114.85,55.82.11B NMR(193MHz,DMSO-d6)δ33.27.
5-phenyl-3-(p-tolyl)-4,5-dihydro-1,2,4,5-oxadiazaborole(3i)5.Whitesolid(0.21g,90％yield)；mp 151-154℃,1H NMR(600MHz,DMSO-d6)δ10.37(1H,s),7.94(2H,d,J6.7),7.87(2H,d,J 8.1),7.55(1H,t,J 7.3),7.51(2H,t,J 7.2),7.38(2H,d,J8.0),2.39(3H,s).13C NMR(151MHz,DMSO-d6)δ159.67,141.05,134.36,131.55,129.99,128.72,126.67,124.38,21.46.11B NMR(193MHz,DMSO-d6)δ33.27.
3-(4-iodophenyl)-5-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3j)5.White solid(0.16g,83％yield)；mp 219-221℃,1H NMR(600MHz,DMSO-d6)δ10.49(1H,s),7.97(2H,d,J 8.4),7.92(2H,d,J 6.7),7.76(2H,d,J 7.9),7.55(1H,t,J 7.3),7.50(2H,t,J 7.1).13C NMR(151MHz,DMSO-d6)δ159.22,138.35,134.36,131.67,128.76,128.56,126.63,98.39.11B NMR(193MHz,DMSO-d6)δ33.67.
3-(4-fluorophenyl)-5-phenyl-4,5-dihydro-1,2,4,5-oxadiazaborole(3k).White solid(0.19g,82％yield)；mp 192-195℃,1H NMR(600MHz,DMSO-d6)δ10.48(1H,s),8.04(2H,dd,J 8.7,5.4),7.94(2H,d,J 6.7),7.56(1H,t,J 7.3),7.52(2H,t,J 7.4),7.44(2H,t,J 8.8).13C NMR(151MHz,DMSO-d6)δ164.79,163.15,158.96,134.35,131.62,129.24,129.19,128.74,123.76,123.74,116.65,116.50.11B NMR(193MHz,DMSO-d6)δ33.47.HRMS(ESI):m/z[M+H]+calculated for C13H11BN2OF:241.0943,found:249.0941.
Claims (4)
1.一类式3所示噁二氮杂硼化合物的制备方法，其特征在于，所述式3化合物由化合物1和化合物2反应制得，合成路线如下：
所述式3化合物选自3a-3k化合物:
反应溶剂选自四氢呋喃、甲醇、乙腈、N,N-二甲基甲酰胺、丙酮、乙酸乙酯中的一种或几种混合；反应温度为室温，反应时间为5min。
2.如权利要求1所述的方法，其特征在于：反应溶剂为乙酸乙酯。
3.如权利要求1所述的方法，其特征在于：化合物1和化合物2的摩尔比为1：1。
4.如权利要求1所述的方法，其特征在于：操作步骤为：在圆底烧瓶中将胺肟1、苯基硼酸衍生物2和乙酸乙酯混合，在室温下搅拌反应5分钟，反应完成后将石油醚加入圆底烧瓶中，产物从反应体系中沉淀出来，过滤，用乙酸乙酯和石油醚混合溶剂洗涤，即得。
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