CN114133360A - 一种含氟苯并[d]-1,3-氧氮杂卓化合物及其合成方法 - Google Patents
一种含氟苯并[d]-1,3-氧氮杂卓化合物及其合成方法 Download PDFInfo
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- 229910052731 fluorine Inorganic materials 0.000 title claims abstract description 21
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D267/00—Heterocyclic compounds containing rings of more than six members having one nitrogen atom and one oxygen atom as the only ring hetero atoms
- C07D267/02—Seven-membered rings
- C07D267/06—Seven-membered rings having the hetero atoms in positions 1 and 3
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- Plural Heterocyclic Compounds (AREA)
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Abstract
本发明涉及一种含氟苯并[d]‑1,3‑氧氮杂卓化合物及其合成方法。所述合成方法由N‑叔丁氧羰基(Boc)保护的邻氨基苯丙烯类分子作为底物，在钯催化下和氟试剂发生反应制备而成。其制备方法为：将N‑Boc保护的邻氨基苯丙烯类分子溶解于溶剂中，在一定的温度下经过钯的催化和氟试剂发生反应，得到含氟苯并[d]‑1,3‑氧氮杂卓结构的化合物。该合成方法条件温和，收率较好，且具有多种官能团容忍性，能够用于构建多种氟化杂卓结构，在生物、医药、农药等领域有着潜在的应用。
Description
技术领域
本发明属于有机合成领域，具体涉及一种在生物、医疗、农药等领域有广泛应用前景的含氟苯并[d]-1,3-氧氮杂卓化合物及其合成方法。
背景技术
杂环类化合物广泛存在于天然产物中，它在生物、医药和材料等领域有着深入的研究与应用。其中氧氮杂卓结构在生物医药科学领域农药领域有着广泛的应用，例如：专利WO2006/116764A1“Polycyclic carbamoylpyridone derivative having HIV integraseinhibitory activity and their preparation”中发明了一类含有氧氮杂卓结构分子，具有良好的抗HIV功效；专利WO1997JP00754“5,11-dihydrodibenzo[b,e][1,4]oxazepinederivatives and pharmaceutical composi-tions containing the same”中发明了一种含氧氮杂卓结构的药物，具有二酰基甘油转移酶抑制活性，可用于治疗消化道功能异常。澳大利亚专利号AU2007309427B2“2,4-二氨基嘧啶的熔融双环衍生物作为ALK和c-Met抑制剂”中发明了一种含氧氮杂卓结构的衍生物用作ALK和c-Met激酶抑制剂来治疗增殖性疾病。该类似结构在医药领域的广泛存在，所以深入研究合成该类化合物具有重要意义。
氟代杂环化合物的研究一直以来都是研究热点。氟代基团与羟基基团具有相似的大小，极性和氢键作用，但是前者具有独特的亲脂性、立体电子效应及构象性质，因此常用来作为羟基的改性基团对生物活性杂环进行修饰。相关研究催生了许多氟代杂环类生物活性药物，例如替美洛坦、氟嘧菌酯、氟咯菌腈等。其中，糖基氟化物研究一直以来是糖化学领域的一个热点(Shimizu,M.,Togo,H.,Yo-koyama,M.,Chemistry of glycosylfluorides.Synthesis 1998,6:799-822)，其结构中的异头碳具有独特的同碳氧氟取代结构，赋予该类化合物独特的生物和化学活性，作为酶抑制剂或糖苷化试剂被广泛运用。
但是，到目前为止，同碳氧氟取代结构的构建方法仍然十分有限。常用的二乙氨基三氟化硫氟化方法学通常以羟基作为底物进行合成。近年来使用烯烃作为底物进行相关分子的合成逐渐被开发出来。2016年Ulmer等人使用苯甲酰基保护的邻氨基苯乙烯类分子与高价碘试剂反应，在发生高价碘活化以及氟化反应之后伴有苯基的[1,2]-迁移反应，合成出含氟苯并[d]-1,3-氧氮杂卓结构。(Ulmer,A.,Brunner,C.,Arnold,A.M.,
A.,Gulder,T.A fluorination/aryl migra-tion/cyclization cascade for the metal-free synthesis of fluoro-benzoxazepines.Chem.-Eur.J.2016,22,3660-3664.)同年Wu等人以N-Boc保护的α取代丙烯酰胺为底物，经过氧化-钯金属化，及重排氟化的串联过程，最终合成含O,N五元杂环的化合物。(Wu,H.；Yang,B.；Zhu,L.；Lu,R.；Li,G.；Lu,H.High-Valent Palla-dium-Promoted Formal Wagner-MeerweinRearrangement.Org.Lett.2016,18,5804-5807)其中一个底物以N-Boc保护的邻氨基苯丙烯为原料，在经过上述反应条件下实现苯并[d]-1,3-氧氮杂卓结构的构建。然而该反应受到副反应的影响收率较低。如何抑制副反应的发生，提高反应收率，是一个技术难题。
发明内容
本发明的目的在于提供一种含氟苯并[d]-1,3-氧氮杂卓化合物，本发明的另一目的是提供上述含氟苯并[d]-1,3-氧氮杂卓化合物的合成方法，该方法具有较好的底物普适性，在生物、医药、农药等领域有着潜在的应用。
本发明是通过如下技术方案实现的：
一种含氟苯并[d]-1,3-氧氮杂卓化合物，其结构式如下：
其中R1为甲基、苄基、环丙甲基、叔丁氧羰基(Boc)或
R2为甲基、乙基、
R3为氟、氯、溴、甲基、甲氧羰基、甲氧基、氟、硝基、乙酰基或三氟甲基。
优选含氟苯并[d]-1,3-氧氮杂卓化合物的结构式为：
本发明还提供了一种合成苯并[d]-1,3-氧氮杂卓骨架的方法，反应式如下：
具体操作步骤为，以N-叔丁氧羰基保护的邻氨基苯丙烯1为原料，与所需当量的氟试剂、钯催化剂、反应助剂和溶剂加入反应瓶中，在一定温度下反应；TLC跟踪反应结束后，将混合物过滤再使用柱层析分离，最终得到所述含氟苯并[d]-1,3-氧氮杂卓类化合物。
优选所述的氟试剂为1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(Selectfluor)或1-氟-4-甲基-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(SelectfluorII)；氟试剂与原料的当量比范围为1～2:1。
优选所述的钯催化剂为醋酸钯、新戊酸钯或三(二亚苄基)丙酮二钯；钯催化剂与原料的当量比范围为0.05～0.1:1。
优选所述的反应助剂无水硫酸钠；反应助剂与原料的当量比范围为1～2:1。
优选所述的溶剂为乙腈或乙腈与二氯甲烷的混合溶液；二氯甲烷和乙腈的体积比范围为0～1:1。优选所述的反应温度为5～40℃。
有益效果：
本发明的优点在于筛选出该反应条件的溶剂为二氯甲烷和乙腈混合溶剂，并且在反应中加入了无水硫酸钠，有效地抑制了副反应的发生，针对底物反应活性的不同筛选出最合适的钯催化剂促进反应的进行。该方法操作方便，官能团容忍性好，可以通过一步反应，成功高效地构含氟苯并[d]-1,3-氧氮杂卓骨架。
具体实施方式
以下结合具体实施例对本发明进行进一步描述，但所给的实施例不构成对权利要求饱和范围的限制。
实施例1：
化合物4-fluoro-1,4,7-trimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2a)的合成
向玻璃试管中加入原料tert-butyl me-thyl(4-methyl-2-(prop-1-en-2-yl)phenyl)carbamate(1a,26.1mg)，然后加入三(二亚苄基)丙酮二钯(4.6mg,0.05当量)和无水硫酸钠(14.1mg，1当量)，再加入乙腈(1ml)和二氯甲烷(1ml)，最后加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(71mg，2当量)，在25℃下进行搅拌反应。在反应的过程中用TLC板跟踪监测反应情况，大约4小时反应完全。然后使用短硅胶柱将反应液过滤，滤饼用乙酸乙酯洗涤。滤液收集后减压蒸除溶剂后剩余物用硅胶层析柱分离，得到17mg产物2a，收率为76％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.48–7.34(m,1H),7.33–7.13(m,3H),3.48(s,3H),3.35(t,J＝13.8Hz,1H),3.06(d,J＝14.1Hz,1H),1.52(dd,J＝17.8,1.1Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.00.13C NMR(101MHz,CDCl3)δ151.67,141.67,129.49,129.33,128.77,126.16,121.66,121.42,41.30,37.48,23.68。
实施例2：
化合物4-fluoro-8-methoxy-1,4-dimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2f)的合成
向玻璃试管中加入原料tert-butyl me-thyl(5-methoxy-2-(prop-1-en-2-yl)phenyl)carbamate(1f,27.7mg)，然后加入三(二亚苄基)丙酮二钯(4.6mg,0.05当量)和无水硫酸钠(28.2mg，2当量)，再加入乙腈(1ml)和二氯甲烷(1ml)，最后加入
(69mg，2当量)，在5℃下进行搅拌反应。在反应的过程中用TLC板跟踪监测反应情况，大约24小时反应完全。然后使用短硅胶柱将反应液过滤，滤饼用乙酸乙酯洗涤。滤液收集后减压蒸除溶剂后剩余物用硅胶层析柱分离，得到11mg产物2f，收率为44％。核磁数据:1H NMR(400MHz,Chloroform-d)δ7.16–7.04(m,1H),6.79–6.64(m,2H),3.82(s,3H),3.45(s,3H),3.23(d,J＝13.5Hz,1H),2.98(d,J＝14.3Hz,1H),1.50(dd,J＝17.8,1.1Hz,3H).19F NMR(470MHz,Chloroform-d)δ-83.53.13CNMR(101MHz,Chloroform-d)δ159.96,151.73,142.64,130.05,121.61,119.42,111.01,108.05,55.55,40.42(d,J＝32.8Hz),37.38,27.94,23.43(d,J＝27.2Hz)。
实施例3：
化合物4-fluoro-1-methyl-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2o)的合成
向玻璃试管中加入原料tert-butyl me-thyl(2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)carbamate(1o,33.0mg)，醋酸钯(2.3mg,0.1当量)，和无水硫酸钠(14.1mg，1当量)，再加入乙腈(2ml)，最后加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(40mg，1.1当量)，在40℃下进行搅拌反应。在反应的过程中用TLC板跟踪监测反应情况，大约3小时反应完全。然后使用短硅胶柱将反应液过滤，滤饼用乙酸乙酯洗涤。滤液收集后减压蒸除溶剂后剩余物用硅胶层析柱分离，得到23mg产物2o，收率为80％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.50(dd,J＝7.6,1.4Hz,1H),7.38–7.10(m,3H),3.93(d,J＝14.1Hz,1H),3.89–3.73(m,2H),3.56–3.30(m,5H),3.17(dd,J＝15.8,14.1Hz,1H),1.97–1.63(m,4H).19F NMR(376MHz,Chloroform-d)δ-93.49.13C NMR(101MHz,CDCl3)δ161.54,161.25,150.12,141.26,131.61,129.22,128.38,126.23,120.70,117.94,115.52,47.22,37.61,26.42,23.34。
实施例4：
化合物4-fluoro-N,N,1-trimethyl-2-oxo-1,2,4,5-tetrahydrobenzo[d][1,3]oxazepine-4-carboxamide(2p)的合成
向玻璃试管中加入原料tert-butyl me-thyl(2-(3-(dimethylamino)-3-oxoprop-1-en-2-yl)phenyl)carbamate(1p,30.4mg)，新戊酸钯(3.1mg,0.1当量)，和无水硫酸钠(14.1mg，1当量)，再加入乙腈(2ml)，最后加入1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐(40mg，1.1当量)，在40℃下进行搅拌反应。在反应的过程中用TLC板跟踪监测反应情况，大约3小时反应完全。然后使用短硅胶柱将反应液过滤，滤饼用乙酸乙酯洗涤。滤液收集后减压蒸除溶剂后剩余物用硅胶层析柱分离，得到24.7mg产物2p，收率为93％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.52(dd,J＝7.8,1.4Hz,1H),7.33(td,J＝7.8,1.6Hz,1H),7.26–7.12(m,1H),3.93(d,J＝14.1Hz,1H),3.49(s,3H),3.28(d,J＝1.9Hz,3H),3.16(dd,J＝16.1,14.1Hz,1H),2.91(d,J＝1.2Hz,3H),1.26(d,J＝3.2Hz,1H).19F NMR(376MHz,Chloroform-d)δ-90.76.13C NMR(101MHz,CDCl3)δ162.80,149.95,141.15,131.65,129.26,128.33,126.17,120.62,118.35,115.91,38.14,37.58,36.8。
实施例5
采用和实施例1相同的操作条件和操作步骤，合成出化合物2b-2e，2g-2n。反应收率和核磁数据如下：
化合物4-fluoro-1,4,8-trimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2b),以tert-butyl methyl(5-methyl-2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为48％。核磁数据:1H NMR(400MHz,Chloroform-d)δ7.05(d,J＝36.6Hz,3H),3.46(s,3H),3.29(s,1H),3.02(s,1H),2.38(s,3H),1.50(d,J＝17.8Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.19.13C NMR(101MHz,Chloroform-d)δ151.79,141.52,138.84,129.20,126.83,126.39,122.05,119.38,40.76(d,J＝32.8Hz),37.41,23.50(d,J＝27.2Hz),21.27。
化合物4-fluoro-1,4,9-trimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2c),以tert-butyl methyl(2-methyl-6-(prop-1-en-2-yl)phenyl)carbamate为原料收率为52％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.24–7.02(m,3H),3.31(s,3H),3.01(dd,J＝14.1,1.8Hz,2H),2.34(s,3H),1.42(dd,J＝17.9,1.1Hz,3H).19FNMR(376MHz,Chloroform-d)δ-84.18.13C NMR(101MHz,Chloroform-d)δ152.99,140.38,132.57,131.48,130.69(d,J＝8.8Hz),126.99,121.40,119.09,41.04(d,J＝32.7Hz),37.92,23.16(d,J＝26.8Hz),18.89。
化合物7-chloro-4-fluoro-1,4-dimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2d),以tert-butyl methyl(4-chloro-2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为48％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.41–7.32(m,1H),7.24(d,J＝2.4Hz,1H),7.14(d,J＝8.6Hz,1H),3.45(s,3H),3.41–3.22(m,1H),3.03(d,J＝14.1Hz,1H),1.54(dd,J＝17.8,1.1Hz,3H).19F NMR(376MHz,Chlo-roform-d)δ-83.24.13C NMR(101MHz,Chloroform-d)δ151.27,140.30,131.55–130.69(m),129.30,128.77,122.67,121.25,118.94,40.98(d,J＝33.7Hz),37.49,23.60(d,J＝26.9Hz)。
化合物methyl4-fluoro-1,4-dimethyl-2-oxo-1,2,4,5-tetrahydrobenzo[d][1,3]oxazepine-8-carboxylate(2e)，以methyl 3-((tert-butoxycarbonyl)(methyl)amino)-4-(prop-1-en-2-yl)benzoate为原料，收率为47％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.98–7.81(m,2H),7.34(d,J＝7.7Hz,1H),3.96(s,3H),3.53(s,3H),3.40(t,J＝13.8Hz,1H),3.15(d,J＝14.0Hz,1H),1.60–1.43(m,3H).19F NMR(376MHz,Chloroform-d)δ-82.98.13C NMR(101MHz,Chloroform-d)δ166.00,151.31,141.99,134.25,130.95,129.67,127.20,122.50,52.55,41.33(d,J＝33.5Hz),37.56,27.43,23.63(d,J＝27.0Hz)。
化合物4,9-difluoro-1,4-dimethyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2g)，以tert-butyl methyl(2-fluoro-6-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为40％。核磁数据：1H NMR(500MHz,Chloroform-d)δ7.30–7.00(m,3H),3.46(d,J＝2.9Hz,3H),3.39(s,1H),3.14(d,J＝14.1Hz,1H),1.53(d,J＝17.8Hz,3H).19FNMR(470MHz,Chloroform-d)δ-83.38,-119.03.13C NMR(126MHz,Chloro-form-d)δ155.28,153.28,150.63,140.61,126.75,123.62,118.38–114.06(m),40.02,36.42,28.69,22.26。
化合物1,4,4-trimethyl-7-nitro-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2h)，以tert-butyl methyl(4-nitro-2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为65％。核磁数据：1H NMR(400MHz,Chloroform-d)δ8.29(ddd,J＝8.9,2.7,0.6Hz,1H),8.17(d,J＝2.6Hz,1H),7.37(d,J＝8.8Hz,1H),3.54(s,3H),3.48–3.32(m,1H),3.23(d,J＝14.3Hz,1H),1.59(dd,J＝17.9,1.0Hz,3H).19F NMR(376MHz,Chlo-roform-d)δ-83.60.13C NMR(101MHz,CDCl3)δ150.64,147.38,144.83,130.56,124.36,121.84,121.15,118.82,77.03,41.48,37.64,23.65。
化合物7-acetyl-4-fluoro-1,4,4-trimethyl-4,5-dihydro-4l5-benzo[d][1,3]oxazepin-2(1H)-one(2i)，以tert-butyl methyl(4-acetyl-2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为58％。核磁数据：1H NMR(400MHz,Chloroform-d)δ8.04–7.70(m,2H),7.30–7.20(m,1H),3.51(s,3H),3.38(t,J＝13.9Hz,1H),3.16(d,J＝14.2Hz,1H),2.63(s,3H),1.55(dd,J＝18.0,1.0Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.32.13C NMR(101MHz,Chloroform-d)δ196.59,151.15,145.84,134.50,129.48(d,J＝44.1Hz),121.24,119.09,41.31(d,J＝33.3Hz),37.48,26.61,23.52(d,J＝26.9Hz)。
化合物4-fluoro-1,4-dimethyl-8-(trifluoromethyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2j)，以tert-butyl methyl(2-(prop-1-en-2-yl)-5-(trifluoromethyl)phenyl)carbamate为原料，收率为40％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.60–7.36(m,3H),3.52(s,3H),3.39(t,J＝13.9Hz,1H),3.15(d,J＝14.1Hz,1H),1.64–1.47(m,3H).19F NMR(376MHz,Chloroform-d)δ-62.61,-83.27.13C NMR(101MHz,Chloroform-d)δ151.09,142.32,133.23,131.35(d,J＝33.1Hz),130.12,122.87,121.22,118.90,118.41,41.19(d,J＝33.6Hz),37.51,23.56(d,J＝26.9Hz)。
化合物tert-butyl4-fluoro-4-methyl-2-oxo-4,5-dihydrobenzo[d][1,3]oxazepine-1(2H)-carboxylate(2k)以N,N-bis(tert-butyloxylcarbonyl)-2-(prop-1-en-2-yl)aniline为原料，收率为46％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.43–7.29(m,4H),3.47(t,J＝14.0Hz,1H),3.09(d,J＝14.2Hz,1H),2.30–2.03(m,3H),1.51(s,9H).19F NMR(376MHz,Chloroform-d)δ-85.72.13C NMR(101MHz,Chloroform-d)δ150.77,143.92,137.23,130.47,129.20,128.20,127.92,126.51,120.50,118.17,40.83,31.02,27.76,23.75。
化合物1-benzyl-4-fluoro-4-methyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2l)，以tert-butyl benzyl(2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为53％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.33–7.21(m,7H),7.21–7.10(m,2H),5.16(d,J＝15.2Hz,1H),4.99(d,J＝15.2Hz,1H),3.19–3.04(m,1H),2.92(d,J＝14.1Hz,1H),1.49(dd,J＝17.9,1.1Hz,3H).19F NMR(376MHz,Chloroform-d)δ-83.86.13CNMR(101MHz,CDCl3)δ152.06,140.49,136.55,130.18,130.10,129.60,129.59,127.84,127.78,126.43,122.17,121.85,119.54,77.39,53.88,41.29,23.61。
化合物1-(cyclopropylmethyl)-4-fluoro-4-methyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2m)，以tert-butyl(cyclopropylmethyl)(2-(prop-1-en-2-yl)phenyl)carbamate为原料，收率为47％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.41–7.06(m,4H),3.95(dd,J＝14.3,7.7Hz,1H),3.52(dd,J＝14.3,6.8Hz,1H),3.38(t,J＝13.7Hz,1H),2.98(d,J＝13.9Hz,1H),1.42(dd,J＝17.8,1.1Hz,3H),0.37(ddd,J＝7.9,2.7,1.6Hz,2H),0.33–0.23(m,1H),0.14–-0.04(m,2H).19F NMR(376MHz,Chloroform-d)δ-84.13.13C NMR(101MHz,Chloroform-d)δ151.81,140.69,130.76,129.48,129.17–128.17(m),126.29,122.59,121.58,119.27,54.86,41.09(d,J＝32.9Hz),23.46(d,J＝27.1Hz),9.95,3.67(d,J＝30.0Hz)。
化合物4-ethyl-4-fluoro-1-methyl-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2n)，以tert-butyl(2-(but-1-en-2-yl)phenyl)(methyl)carbamate为原料，收率为40％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.42–7.33(m,1H),7.24–7.15(m,3H),3.48(s,3H),3.28(t,J＝13.9Hz,1H),3.11(d,J＝14.2Hz,1H),1.90–1.64(m,2H),1.02(t,J＝7.5Hz,3H).19F NMR(376MHz,Chloroform-d)δ-94.55.13C NMR(101MHz,Chloroform-d)δ151.88,141.75,129.47,128.66,126.03,122.96,121.37,120.62,39.32(d,J＝33.2Hz),37.53,29.37(d,J＝25.6Hz),6.80。
实施例6
采用和实施例4相同的操作条件和操作步骤，合成出化合物2q-2v。反应收率和核磁数据如下：
化合物1-benzyl-4-fluoro-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2q)，以tert-butyl ben-zyl(2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)carbamate为原料，收率为84％。1H NMR(400MHz,Chloroform-d)δ7.54–7.40(m,1H),7.39–7.08(m,8H),5.21–4.95(m,2H),3.90–3.71(m,3H),3.54–3.26(m,2H),2.95(t,J＝14.8Hz,1H),1.97–1.72(m,4H).13C NMR(101MHz,Chloroform-d)δ161.34(d,J＝29.2Hz),150.55,140.17,136.32,131.75,129.85(d,J＝7.9Hz),128.77,128.35,127.92,127.72,126.45,121.42,118.04,115.61,54.13,47.18,46.92(d,J＝5.0Hz),37.46(d,J＝31.1Hz),28.76,26.38,23.31.19F NMR(376MHz,Chloroform-d)δ-94.16。
化合物4-fluoro-1-methyl-4-(morpholine-4-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2r)，以tert-butyl me-thyl(2-(3-morpholino-3-oxoprop-1-en-2-yl)phenyl)carbamate为原料，收率为73％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.61–7.46(m,1H),7.35(td,J＝7.8,1.7Hz,1H),7.25–7.14(m,2H),4.01–3.86(m,3H),3.73–3.56(m,5H),3.49(s,3H),3.18(dd,J＝16.2,14.2Hz,1H).19F NMR(376MHz,Chloroform-d)δ-90.17.13C NMR(101MHz,Chloroform-d)δ161.36(d,J＝29.0Hz),149.74,141.11,131.58,128.99(d,J＝8.1Hz),128.45,126.25,120.73,118.31,66.69(d,J＝23.4Hz),46.87,43.22,39.92–35.25(m),29.70。
化合物8-bromo-4-fluoro-1-methyl-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2s)，以tert-butyl(5-bromo-2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)(methyl)carbamate为原料，收率为81％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.39–7.29(m,3H),3.90(d,J＝14.1Hz,1H),3.82(t,J＝6.7Hz,2H),3.53–3.33(m,5H),3.09(t,J＝14.8Hz,1H),1.96–1.69(m,4H).19F NMR(376MHz,Chloroform-d)δ-93.84.13CNMR(101MHz,CDCl3)δ161.34,161.05,149.71,142.44,133.00,129.25,128.21,123.97,121.65,117.67,115.23,47.21,37.57,26.38,23.32。
化合物ethyl2-(4-fluoro-2-oxo-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-1(2H)-yl)acetate(2t)，以ethylN-(tert-butoxycarbonyl)-N-(2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)glycinate为原料，收率为77％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.53(dd,J＝7.5,1.5Hz,1H),7.37–7.19(m,2H),7.09(dd,J＝8.0,1.2Hz,1H),4.68(d,J＝17.5Hz,1H),4.49(d,J＝17.5Hz,1H),4.22(qd,J＝7.1,0.9Hz,2H),3.94(d,J＝14.1Hz,1H),3.88–3.72(m,2H),3.63(dd,J＝15.6,14.1Hz,1H),3.50–3.30(m,2H),1.95–1.76(m,3H),1.27(t,J＝7.1Hz,4H).19F NMR(470MHz,Chloroform-d)δ-93.99.13C NMR(101MHz,Chloroform-d)δ168.01,161.32(d,J＝29.1Hz),150.47,140.05,131.96,130.17(d,J＝8.3Hz),128.44,126.72,120.86,118.17,115.73,61.87,52.07,47.06(d,J＝31.0Hz),37.24(d,J＝31.4Hz),26.39,23.32,14.10。
化合物1-(cyclopropylmethyl)-4-fluoro-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2u)，以tert-butyl(cyclopropylme-thyl)(2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)carbamate为原料，收率为64％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.52(dd,J＝7.6,1.5Hz,1H),7.32(td,J＝7.7,1.6Hz,1H),7.24–7.15(m,2H),4.01–3.89(m,2H),3.88–3.73(m,2H),3.64(dd,J＝14.3,6.8Hz,1H),3.49–3.32(m,2H),3.27(dd,J＝15.5,14.1Hz,1H),1.98–1.67(m,4H),1.10(ddt,J＝7.9,6.8,4.9Hz,1H),0.55–0.41(m,2H),0.35(ddd,J＝10.6,4.7,1.9Hz,1H),0.25–0.11(m,1H).19F NMR(376MHz,Chlo-roform-d)δ-94.25.13C NMR(101MHz,Chloroform-d)δ161.48(d,J＝29.2Hz),150.31,140.27,131.65,130.44,128.31,126.35,121.80,117.93,115.50,55.08,47.05(d,J＝26.8Hz),37.43(d,J＝31.2Hz),27.11,26.39,23.32,9.91,3.68(d,J＝30.4Hz)。
化合物4-fluoro-7-methoxy-1-methyl-4-(pyrrolidine-1-carbonyl)-4,5-dihydrobenzo[d][1,3]oxazepin-2(1H)-one(2v)，以tert-butyl me-thyl(4-methoxy-2-(3-oxo-3-(pyrrolidin-1-yl)prop-1-en-2-yl)phenyl)carbamate为原料，收率为80％。核磁数据：1H NMR(400MHz,Chloroform-d)δ7.16–6.97(m,2H),6.85(dd,J＝8.8,2.9Hz,1H),3.99–3.76(m,6H),3.50–3.33(m,5H),3.14(dd,J＝16.0,14.1Hz,1H),1.95–1.75(m,4H).19FNMR(376MHz,Chloroform-d)δ-86.50–-101.74(m).13C NMR(101MHz,Chloroform-d)δ158.45,155.49,145.27,137.89,134.33,129.77,128.47,122.45,120.43,114.95,79.76,55.48,47.34(d,J＝279.4Hz),37.51(d,J＝115.8Hz),28.29,25.27(d,J＝197.9Hz)。
Claims (8)
1.一种含氟苯并[d]-1,3-氧氮杂卓化合物，其结构式如下：
其中R1为甲基、苄基、环丙甲基、叔丁氧羰基(Boc)或
R2为甲基、乙基、
R3为氟、氯、溴、甲基、甲氧羰基、甲氧基、氟、硝基、乙酰基或三氟甲基。
2.如权利要求1所述的含氟苯并[d]-1,3-氧氮杂卓化合物，其结构式为：
3.一种合成如权利要求1所述的含氟苯并[d]-1,3-氧氮杂卓化合物的方法，其具体操作步骤为，以N-叔丁氧羰基保护的邻氨基苯丙烯为原料，与所需当量的氟试剂、钯催化剂、反应助剂和溶剂加入反应瓶中，在一定温度下反应；TLC跟踪反应结束后，将混合物过滤再使用柱层析分离，最终得到所述含氟苯并[d]-1,3-氧氮杂卓类化合物。
4.如权利要求3所述的方法，其特征在于所述的氟试剂为1-氯甲基-4-氟-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐或1-氟-4-甲基-1,4-二氮杂双环[2.2.2]辛烷二(四氟硼酸)盐；氟试剂与原料的当量比范围为1～2:1。
5.如权利要求3所述的方法，其特征在于所述的钯催化剂为醋酸钯、新戊酸钯或三(二亚苄基)丙酮二钯；钯催化剂与原料的当量比范围为0.05～0.1:1。
6.如权利要求3所述的方法，其特征在于所述的反应助剂无水硫酸钠；反应助剂与原料的当量比范围为1～2:1。
7.如权利要求3所述的方法，其特征在于所述的溶剂为乙腈或乙腈与二氯甲烷的混合溶液；二氯甲烷和乙腈的体积比范围为0～1:1。
8.如权利要求3所述的方法，其特征在于所述的反应温度为5～40℃。
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