CN114773330B - 丁苯酞-噁/噻二唑类化合物及其制备方法和应用 - Google Patents
丁苯酞-噁/噻二唑类化合物及其制备方法和应用 Download PDFInfo
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- CN114773330B CN114773330B CN202210568842.1A CN202210568842A CN114773330B CN 114773330 B CN114773330 B CN 114773330B CN 202210568842 A CN202210568842 A CN 202210568842A CN 114773330 B CN114773330 B CN 114773330B
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- butyl
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- oxadiazol
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- 238000000034 method Methods 0.000 claims description 21
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
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Abstract
本发明属于药学技术领域，具体涉及丁苯酞‑噁/噻二唑类化合物及其制备方法和应用，本发明以丁苯酞为原料，依次通过硝化、还原、桑德迈尔反应、环化、取代、氧化的步骤制得一系列丁苯酞‑噁/噻二唑类衍生物。制得的丁苯酞‑噁/噻二唑类化合物具有优异抗血小板凝集作用的，其衍生物、异构体或光学异构体、消旋体、药用盐、水合物、溶剂化物、及药用载体或赋形剂均能够在制备预防或治疗由于血栓引起的心脑血管疾病及其并发症药物中进行应用。
Description
技术领域
本发明属于药学技术领域，具体来说丁苯酞-噁/噻二唑类化合物及其制备方法和应用。
背景技术
急性脑血管病即脑卒中，是以脑部缺血及出血性损伤症状为主要临床表现的重大心脑血管疾病，具有死亡率高、发病率高、复发率高、致残率高、并发症多“四高一多”的特点。据统计，在所有的脑卒中患者中，缺血脑卒中约占70～80％。缺血性脑卒中是一种复杂的全身性疾病，临床上虽可采取溶栓、抗凝、修复受损神经等措施控制患者病情，但整体效果并不理想，临床研究也表明目前没有某一类药物对所有的缺血性脑卒中病人都有效，即针对脑卒中没有真正意义上的特效药，因此研制用于治疗缺血性脑卒中的高效新药具有重大现实意义。
丁苯酞(3-n-butylphthalide，NBP)是从芹菜籽中提取出的一种苯并呋喃酮类化合物，于2002年在我国上市用于缺血性脑卒中的治疗。丁苯酞通过改善脑部血液循环、改善脑水肿和抗血栓三个方面对脑缺血的多个病理环节发挥治疗作用，但其总体疗效并不高，临床上需要与其他药物联合使用，限制了其使用，因此需要开发一种新的化合物结构。
发明内容
针对上述现有技术的不足，本发明的目的是提供丁苯酞-噁/噻二唑类化合物及其制备方法和应用，制得的丁苯酞-噁/噻二唑类化合物具有优异抗血小板凝集作用的，其衍生物、异构体或光学异构体、消旋体、药用盐、水合物、溶剂化物、及药用载体或赋形剂均能够在制备预防或治疗由于血栓引起的心脑血管疾病及其并发症中进行应用。
为解决上述技术问题，本发明采用如下技术方案：
丁苯酞-噁/噻二唑类化合物，所述丁苯酞-噁/噻二唑类化合物的结构如式(I)所示：
其中，Y为S或O，X为S、亚砜(SO)或砜(SO2)；
R为氢原子、烷基、环烷基、杂环基、杂环基烷基、烷氧基、芳基、杂芳基中的一种；
所述烷基、环烷基、杂环基、杂环基烷基、烷氧基、芳基、杂芳基还可分别被取代基取代。
本发明还保护了丁苯酞-噁/噻二唑类化合物的制备方法，包括如下步骤：
(1)将丁苯酞与硝酸钾和浓硫酸进行硝化反应，得到化合物1；
(2)将化合物1在铁粉催化作用下，于氯化铵的醇溶液中进行还原，得到化合物2；
(3)将化合物2先溶解于浓硫酸中，并向其中滴加去离子水，然后加入亚硝酸钠，进行桑德迈尔反应，得到化合物3；
(4)将化合物3、碱与溴乙酸乙酯进行醚化反应，得到化合物4；
(5)将化合物4于水合肼中进行肼解反应，得到化合物5；
(6)将化合物5与氢氧化钾和二硫化碳进行环化反应，得到化合物6；
(7)将化合物6与碳酸钾和卤代化合物进行醚化反应，得到化合物7；
(8)将化合物7与m-CPBA进行氧化反应，得到丁苯酞-噁/噻二唑类化合物。
本发明还保护了丁苯酞-噁/噻二唑类化合物在制备预防或治疗血栓引起的心脑血管疾病及其并发症药物中的应用，所述心脑血管疾病包括脑卒中和血管性老年痴呆症。
与现有技术相比，本发明具有的有益效果是：
为了提高丁苯酞的整体功效，尤其是其抗血栓作用，本发明以丁苯酞为先导化合物，对其芳环进行结构优化，设计、合成出了一系列丁苯酞-噁/噻二唑类化合物，并测试了该类化合物的体外抗血小板凝集活性及对大鼠脑缺血再灌注损伤的治疗作用；结果表明，较母体丁苯酞，具有优异的体外抗血小板凝集活性和对大鼠缺血再灌注损伤模型的治疗作用，具有新型、高效治疗与预防心脑血管疾病(包括脑卒中、血管性老年痴呆)及其并发症的潜力，获得了一类新型、高效的用于制备预防或治疗血栓引起的心脑血管疾病及其并发症药物。
3、本发明首次制备了丁苯酞-噁/噻二唑类化合物，并将其用于心脑血管疾病方面的研究，制备得到的丁苯酞-噁/噻二唑类化合物具有体外抗凝活性，且根据本发明对比验证后得出：3-丁基-6-((5-(环丙基甲基)亚砜基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(8b)；3-丁基-6-(5-苄基亚砜基)-1,3,4-噁二唑-2-甲氧基)-3-丁基苯并呋喃酮-1(3H)-酮(8c)；3-丁基-6-((5-(2-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8d)；3-丁基-6-((5-(噻吩-2-甲基)磺酰基)-1,3,4-噁二唑-2-甲氧基)异双呋喃-1(3H)-酮(8m)的丁苯酞-噁/噻二唑类化合物体外抗凝活性优于丁苯酞和阿司匹林。
附图说明
图1为本发明实施例2制得的化合物8b的氢谱图；
图2为本发明实施例2制得的化合物8b的碳谱图；
图3为本发明实施例3制得的化合物8c的氢谱图；
图4为本发明实施例3制得的化合物8c的碳谱图；
图5为本发明制得的化合物8b和8c分别对MACO模型损伤活性对照图。
具体实施方式
下面对本发明的具体实施方式进行详细描述，但应当理解本发明的保护范围并不受具体实施方式的限制。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。本发明各实施例中所述实验方法，如无特殊说明，均为常规方法。
化合物8a-8o均按照如下步骤制备：
实施例1
3-丁基-6-((5-(异丙基亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备方法，包括如下步骤：
(1)3-丁基-6-硝基异苯并呋喃-1(3H)-酮(化合物1)的合成：将丁苯酞(10g，52.6mmol)溶于40mL的98％H2SO4中，0-5℃下，分批次加入KNO3(6.9g，67.6mmol)，室温条件下搅拌3h；TLC检测待反应完全，加入冰水混合物(150mL)，并用乙酸乙酯(3×300mL)萃取三次，再经饱和食盐水洗涤(100mL)、无水Na2SO4干燥、浓缩、硅胶柱层析PE:EA＝10:1后，得淡黄色液体化合物1(9.3g，75.2％)；1HNMR(400MHz,CDCl3)δ8.72(d,1H,J＝2.0Hz),8.57(dd,1H,J＝8.4,2.0Hz),7.68(d,1H,J＝8.4Hz),5.62-5.59(m,1H),2.16-2.08(m,1H),1.87-1.78(m,1H),1.45-1.36(m,4H),0.94(t,3H,J＝6.8Hz,CH3)；13C NMR(100MHz,CDCl3)δ168.0,155.3,149.0,128.8,127.9,123.2,121.3,81.5,34.1,26.8,22.3,13.7；
(2)6-氨基-3-丁基异苯并呋喃-1(3H)-酮(化合物2)合成：将化合物1(8.8g，37.4mmol)、Fe粉(20.9g，374mmol)、NH4Cl(1.5g，28mmol)溶于EtOH(100mL)和H2O(20mL)中，氮气保护下100℃回流反应24h，TLC检测反应毕完毕后，经浓缩、硅藻土抽滤、乙酸乙酯洗涤滤饼、硅胶柱层析PE:EA＝4:1后，得白色固体化合物2(6.8g，88.7％)；m.p.118-124℃；1HNMR(400MHz,CDCl3)δ7.19(d,1H,J＝8.0Hz),7.10(d,1H,J＝2.0Hz),7.68(dd,1H,J＝8.4,2.4Hz),5.38-5.35(m,1H),3.95(s,2H,NH2),1.99-1.92(m,1H),1.74-1.66(m,1H),1.47-1.32(m,4H),0.91(t,3H,J＝6.8Hz,CH3)；13C NMR(100MHz,CDCl3)δ171.0,147.5,140.1,127.4,122.3,121.4,109.7,81.4,34.7,26.8,22.4,13.8；
(3)3-丁基-6-羟基异苯并呋喃-1(3H)-酮(化合物3)的合成：将化合物2(6.0g，29mmol)溶解在浓硫酸中(40mL)，0℃下缓慢滴加H2O(40mL)，氮气保护下，分批次加入亚硝酸钠(2.0g，29mmol)，并于0℃下反应30min；TLC检测全部生成重氮盐后，移至100℃油浴中反应12h，TLC检测反应完全后将反应液冷却至室温，向反应液中加入300g冰，乙酸乙酯萃取(3×200mL)，饱和碳酸氢钠调pH至7-8，有机相经无水硫酸钠干燥、浓缩、经200-300目硅胶柱层析VPE：VEA＝8:1纯化后得粗品，乙酸乙酯重结晶得白色固体化合物3(3.8g，64.3％)；m.p.120-121℃；1H NMR(400MHz,CDCl3)δ7.41(d,J＝2.0Hz,1H),7.29(d,J＝8.4Hz,1H),7.23(d,J＝8.4,1H),5.44(dd,J＝7.6,4.2Hz,1H),2.09-1.88(m,1H),1.83-1.65(m,1H),1.53-1.28(m,4H),0.90(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ171.6,157.3,142.2,127.3,122.8,111.0,82.0,34.5,26.8,22.4,13.9；HRMS(ESI)calcd for C12H15O3[M+H]+m/z:207.1021,found 207.1017；
(4)2-(1-丁基-3-氧代-1,3-二氢异苯并呋喃-5-基)乙酸乙酯(化合物4)的合成：将化合物3(1.7g，8mmol)与碳酸钾(1.4g，10mmol)溶解在DMF中(8mL)，缓慢滴加溴乙酸乙酯(1.4g，8mmol)，N2保护下56℃油浴反应8h，TLC检测反应完全；将反应液冷却至室温，加入40mL乙酸乙酯，用饱和氯化铵反萃(3×30mL)，然后继续用水反萃(3×20mL)、无水硫酸钠干燥、浓缩、经200-300目硅胶柱层析VPE：VEA＝15:1，得化合物4(1.9g，81.3％)；1H NMR(400MHz,CDCl3)δ7.36(d,J＝8.4Hz,1H),7.32(d,J＝8.4,1H),7.26(d,J＝2.0Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),4.70(s,2H),4.30(q,J＝7.2Hz,2H),2.04-1.97(m,1H),1.80-1.70(m,1H),1.68(s,1H),1.52-1.36(m,4H),1.33(t,J＝7.2Hz,3H),0.92(t,J＝7.2Hz,3H)；13CNMR(100MHz,CDCl3)δ170.4,168.2,158.8,143.5,127.5,123.5,122.9,108.3,81.4,65.5,61.6,34.5,26.9,22.4,14.1,13.9；HRMS(ESI)calcd for C16H21O5[M+H]+m/z:293.1389,found 293.1393；
(5)2-(1-丁基-3-氧代-1,3-二氢异苯并呋喃-5-酰基)乙酰肼(化合物5)的合成：将化合物4(1.9g，7mmol)溶于乙醇中(10mL)，于0℃下缓慢滴加85％水合肼(0.473g，15mmol)，N2保护下室温反应3h，TLC检测反应完全；将反应溶液浓缩，加入蒸馏水(15mL)，乙酸乙酯重结晶，得白色固体化合物5(1.9g,98.9％)，m.p.142-145℃；1H NMR(400MHz,DMSO-d6)δ9.44(s,1H),7.59(d,J＝8.4Hz,1H),7.40(dd,J＝8.4,2.4Hz,1H),7.29(d,J＝2.2Hz,1H),5.57(dd,J＝7.6,4.0Hz,1H),4.62(s,2H),4.36(s,2H),2.05-1.99(m,1H),1.71-1.62(m,1H),1.41-1.21(m,4H),0.86(t,J＝7.0Hz,3H)；13C NMR(100MHz,DMSO-d6)δ170.2,166.8,159.2,143.5,127.0,124.1,123.5,108.8,81.4,67.0,34.1,26.9,22.3,14.3；HRMS(ESI)calcd for C14H19N2O4[M+H]+m/z:279.1345,found 279.1338；
(6)3-丁基-6-(5-巯基-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(化合物6)的合成：将化合物5(1.8g，7mmol)分散在乙醇中(15mL)，0℃下分批次加入氢氧化钾(1.34g，14mmol)，搅拌0.5h后，继续于0℃下缓慢滴加二硫化碳(1.2g，16mmol)，室温搅拌0.5h，N2保护下，移至85℃下回流反应24h，TLC检测原料反应完全；经浓缩、加入50mL水、用1mol/L的HCl溶液调pH至3-4后，经二氯甲烷萃取(3×40mL)、合并有机相、无水硫酸钠干燥、浓缩、硅胶柱层析VPE：VEA＝3：1，得白色固体化合物6(324.8mg，14.5％)；m.p.114-116℃；1HNMR(400MHz,DMSO-d6)δ14.73(s,1H),7.63(d,J＝8.4Hz,1H),7.49(d,J＝2.4Hz,1H),7.46(dd,J＝8.4,2.4Hz,1H),5.59(dd,J＝7.6,3.8Hz,1H),5.41(s,2H),2.12-2.00(m,1H),1.71-1.63(m,1H),1.41-1.21(m,4H),0.87(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ178.8,170.8,158.6,158.1,144.4,127.6,123.8,123.3,108.7,81.8,60.2,34.4,26.9,22.4,13.9；HRMS(ESI)calcd for C15H17N2O4S[M+H]+m/z:321.0909,found 321.0901；
(7)化合物7a的合成：将化合物6(32mg，0.1mmol)溶于乙腈中(1mL)，加入碳酸钾(28mg，0.2mmol)，室温搅拌10min后，缓慢加入异丙基溴(0.12mmol)，氮气保护，于室温反应，TLC检测待反应完全后，反应液浓缩，经硅胶柱层析分离得化合物3-丁基-6-((5-(异丙基硫代)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(7a)；白色固体，产率：62.2％；m.p.37-38℃；1HNMR(600MHz,CDCl3)δ7.43(s,1H),7.37(d,J＝8.4Hz,1H),7.35-7.31(m,1H),5.47-5.40(m,1H),5.32-5.24(m,2H),3.95(m,1H),2.09-1.96(m,1H),1.78-1.68(m,1H),1.51(d,J＝2.0Hz,3H),1.50(d,J＝2.0Hz,3H),1.48-1.29(m,4H),0.91(t,J＝7.0Hz,3H)；13CNMR(150MHz,CDCl3)δ170.2,166.7,162.4,158.4,143.9,127.8,123.1,123.0,109.1,81.3,60.1,38.7,34.5,26.8,22.4,13.9,10.5,6.2；HRMS(ESI)calcd forC18H23N2O4S[M+H]+m/z:363.1379,found 363.1378；
(8)化合物8a的合成：将化合物7a(50mg，0.14mmol)溶于干燥二氯甲烷中(2mL)，0℃下缓慢加入m-CPBA(40mg，0.19mmol)，氮气保护，于室温反应，TLC检测反应进程，待反应完全后，将反应液浓缩，硅胶柱层析分离纯化得化合物3-丁基-6-((5-(异丙基亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(8a)；无色液体，产率70.5％；1H NMR(600MHz,CDCl3)δ7.43(s,1H),7.39(d,J＝8.4Hz,1H),7.34(d,J＝8.4,1H),5.44(dd,J＝7.8,4.2Hz,1H),5.39(s,2H),3.58(m,1H),2.02(m,1H),1.79-1.69(m,1H),1.52-1.33(m,10H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.0,166.9,164.4,158.1,144.3,127.9,123.3,123.2,109.0,81.4,60.2,54.7,34.5,26.8,22.4,15.7,14.7,13.9；HRMS(ESI)calcd for C18H23N2O5S[M+H]+m/z:379.1328,found 379.1335。
实施例2
3-丁基-6-((5-(环丙基甲基)亚砜基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的环丙基溴甲烷；
3-丁基-6-((5-(环丙基甲基硫代)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(7b):白色固体，产率74.2％；m.p.74-75℃；1H NMR(600MHz,CDCl3)δ7.43(d,J＝2.0Hz,1H),7.37(d,J＝8.4Hz,1H),7.34(dd,J＝8.4,2.4Hz,1H),5.44(dd,J＝7.8,4.0Hz,1H),5.27(s,2H),3.23(d,J＝7.4Hz,2H),2.03-1.98(m,1H),1.80-1.66(m,1H),1.52-1.32(m,4H),1.31-1.16(m,1H),0.91(t,J＝7.0Hz,3H),0.70-0.64(m,2H),0.40-0.34(m,2H)；13CNMR(150MHz,CDCl3)δ170.2,166.7,162.4,158.4,143.9,127.8,123.0,109.1,81.3,60.1,38.7,34.5,26.8,22.4,13.9,10.5,6.2；HRMS(ESI)calcd for C19H23N2O4S[M+H]+m/z:375.1379,found 375.1374；
3-丁基-6-((5-(环丙基甲基)亚砜基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(8b)：无色液体，产率36.9％；1H NMR(600MHz,CDCl3)δ7.43(d,J＝2.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.35(dd,J＝8.4,2.4Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.40(s,2H),3.40-3.31(m,2H),2.05-1.97(m,1H),1.80-1.70(m,1H),1.53-1.32(m,4H),1.20-1.18(m,1H),0.91(t,J＝7.2Hz,3H),0.78-0.71(m,2H),0.44-0.35(m,2H)；13C NMR(150MHz,CDCl3)δ170.0,167.7,164.3,158.1,144.3,127.9,123.3,123.1,109.0,81.4,60.1,60.0,34.5,26.8,22.4,13.9,5.5,5.0,4.2；HRMS(ESI)calcd for C19H23N2O5S[M+H]+m/z:391.1328,found 391.1330。
实施例3
3-丁基-6-(5-苄基亚砜基)-1,3,4-噁二唑-2-甲氧基)-3-丁基苯并呋喃酮-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的苄基溴；
6-(5-(苄硫基)-1,3,4-噁二唑-2-基)甲氧基-3-丁基苯并呋喃-1(3H)-酮(7c):无色液体，产率73.1％；1H NMR(400MHz,CDCl3)δ7.46-7.42(m,3H),7.41-7.31(m,5H),5.45(dd,J＝7.8,4.2Hz,1H),5.28(s,2H),4.51(s,2H),2.07-1.99(m,1H),1.82-1.68(m,1H),1.47-1.38(m,4H),0.95-0.91(m,3H)；13C NMR(100MHz,CDCl3)δ170.2,162.6,158.4,144.0,135.2,129.2,128.9,128.2,127.8,123.0,109.2,81.4,60.1,36.8,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C22H23N2O4S[M+H]+m/z:411.1379,found411.1372；
3-丁基-6-(5-苄基亚砜基)-1,3,4-噁二唑-2-甲氧基)-3-丁基苯并呋喃酮-1(3H)-酮(8c)：无色液体，产率53.8％；1H NMR(600MHz,CDCl3)δ7.41(d,J＝2.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.37-7.34(m,1H),7.34-7.32(m,2H),7.32-7.30(m,1H),7.24-7.21(m,2H),5.45(m,4.2Hz,1H),5.32(s,2H),4.65(d,J＝12.0Hz,1H),4.58(d,J＝12.0Hz,1H),2.04-1.99(m,1H),1.78-1.72(m 1H),1.51-1.34(m,4H),0.91(t,J＝7.0Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,167.1,164.3,158.1,144.3,130.2,129.4,129.2,127.9,127.5,123.3,123.1,108.9,81.4,60.6,60.0,34.5,26.9,22.4,13.9；HRMS(ESI)calcd forC22H23N2O5S[M+H]+m/z:427.1328,found427.1331。
实施例4
3-丁基-6-((5-(2-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的2-氟苄溴；
4-丁基-6-((5-(2-氟苄基)硫代)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(7d):白色固体，产率90.3％；m.p.66-71℃；1H NMR(600MHz,CDCl3)δ7.42(s,1H),7.37(d,J＝8.4Hz,1H),7.33(d,J＝8.4,1H),7.32-7.28(m,1H),7.21(d,J＝7.8Hz,1H),7.15(d,J＝9.4Hz,1H),7.00(t,J＝8.0Hz,1H),5.44(dd,J＝7.8,4.1Hz,1H),5.27(s,2H),4.47(s,2H),2.05-1.96(m,1H),1.79-1.70(m,1H),1.50-1.34(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.2,165.6,163.6,162.8,161.9,158.3,144.0,137.8,130.4,127.8,124.8,123.1,116.2,115.3,109.1,81.4,60.1,36.1,34.5,26.8,22.4,13.9；HRMS(ESI)calcd for C22H22N2O4SF[M+H]+m/z:429.1284,found429.1278；
3-丁基-6-((5-(2-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8d)：无色液体，产率70.9％；1H NMR(600MHz,CDCl3)δ7.43(s,1H),7.39(d,J＝8.4Hz,1H),7.37(m,1H),7.35(d,J＝8.4,2.4Hz,1H),7.30-7.27(m,1H),7.13(t,J＝7.6Hz,1H),7.08(t,J＝9.0Hz,1H),5.45(m,1H),5.37(s,2H),4.78(d,J＝13.2Hz,1H),4.62(d,J＝13.2Hz,1H),2.05-2.00(m,1H),1.77-1.73(m,1H),1.52-1.32(m,4H),0.91(m,3H)；13C NMR(150MHz,CDCl3)δ170.1,167.1,164.4,158.2,144.3,132.5,131.7,127.9,124.9,123.3,123.1,116.0,115.9,114.9,109.0,81.4,60.1,54.0,34.5,26.8,22.4,13.9；HRMS(ESI)calcd for C22H22N2O5SF[M+H]+m/z:445.1233,found445.1230。
实施例5
3-丁基-6-((5-(3-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的3-氟苄溴；
3-丁基-6-((5-(3-氟苄基)硫代)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(7e):无色液体，产率71.9％；1HNMR(600MHz,CDCl3)δ7.51(t,J＝7.6,1H),7.42(s,1H),7.37(d,J＝8.4Hz,1H),7.32(d,J＝8.4,1H),7.31-7.27(m,1H),7.12-7.05(m,2H),5.44(dd,J＝7.8,4.2Hz,1H),5.26(s,2H),4.52(s,2H),2.01(m,1H),1.79-1.69(m,1H),1.52-1.34(m,4H),0.91(t,J＝7.0Hz,3H)；13C NMR(150MHz,CDCl3)δ170.2,165.8,162.7,161.8,160.2,158.3,144.0,131.4,130.3,127.8,124.4,123.1,122.8,115.7,109.1,81.3,60.1,34.5,30.1,26.8,22.4,13.9；HRMS(ESI)calcd for C22H22N2O4SF[M+H]+m/z:429.1284found429.1278；
3-丁基-6-((5-(3-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8e)：无色液体，产率71.9％；1HNMR(600MHz,CDCl3)δ7.41(d,J＝2.4Hz,1H),7.39(d,J＝8.4Hz,1H),7.34-7.29(m,2H),7.07(t,J＝8.4,2.4Hz,1H),7.03(d,J＝7.8Hz,1H),6.99(d,J＝9.1Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.34(s,2H),4.64(d,J＝13.2Hz,1H),4.57(d,J＝13.2Hz,1H),2.07-1.96(m,1H),1.81-1.69(m,1H),1.52-1.33(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.0,166.9,164.4,158.1,144.3,130.8,127.9,126.0,123.3,123.0,117.4,117.3,116.6,116.4,108.9,81.4,60.0,59.9,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C22H22N2O5SF[M+H]+m/z:445.1233,found445.1225。
实施例6
3-丁基-6-((5-(4-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的4-氟苄溴；
4-丁基-6-((5-(4-氟苄基)硫代)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(7f)：无色液体，产率85.7％；1HNMR(600MHz,CDCl3)δ7.41(m,3H),7.36(d,J＝8.4Hz,1H),7.32(d,J＝8.4,1H),7.03-6.98(m,2H),5.43(dd,J＝7.8,4.2Hz,1H),5.26(s,2H),4.46(s,2H),2.04-1.95(m,1H),1.79-1.70(m,1H),1.50-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13CNMR(150MHz,CDCl3)δ170.1,165.7,163.3,162.7,161.7,158.4,144.0,131.1,130.9,127.8,123.1,115.9,109.1,81.4,60.1,36.0,34.5,26.9,22.4,13.9；HRMS(ESI)calcd forC22H22N2O4SF[M+H]+m/z:429.1284,found429.1280；
3-丁基-6-((5-(4-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8f)：无色液体；产率74.6％；1HNMR(600MHz,CDCl3)δ7.41(s,1H),7.39(d,J＝8.8Hz,1H),7.31(d,J＝8.4Hz,1H),7.23(d,J＝7.8,2H),7.01(d,J＝8.5Hz,2H),5.45(dd,J＝7.6,4.0Hz,1H),5.33(s,2H),4.62(d,J＝13.2Hz,1H),4.55(d,J＝13.2Hz,1H),2.04-1.99(m,1H),1.81-1.69(m,1H),1.48-1.33(m,4H),0.91(t,J＝6.8Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,166.9,164.4,158.1,144.3,132.2,132.1,127.9,123.3,123.1,116.4,116.2,108.8,81.4,60.0,59.6,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C22H22N2O5SF[M+H]+m/z:445.1233,found445.1236。
实施例7
3-丁基-6-((5-(3-氯苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的3-氯苄溴；
3-丁基-6-((5-(3-氯苄基)硫代)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(7g)：白色固体，产率67.4％；m.p.90-91℃；1HNMR(400MHz,CDCl3)δ7.44(s,2H),7.38(d,J＝8.4Hz,1H),7.34(dd,J＝5.7,2.6Hz,2H),7.28(d,J＝3.6Hz,3H),5.45(dd,J＝7.8,4.2Hz,1H),5.28(s,2H),4.46(s,2H),2.02(dd,J＝9.8,4.3Hz,1H),1.76(d,J＝7.8Hz,3H),1.42-1.37(m,4H),0.92(t,J＝7.0Hz,3H)；13C NMR(100MHz,CDCl3)δ170.2,162.8,158.3,144.0,137.4,134.6,130.1,129.2,128.4,127.8,127.4,123.1,109.1,81.4,60.1,36.0,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C22H22N2O4SCl[M+H]+m/z:445.0989,found445.0994；
3-丁基-6-((5-(3-氯苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8g)：无色液体，产率48.4％；1H NMR(600MHz,CDCl3)δ7.42(s,1H),7.40(d,J＝8.4Hz,1H),7.34(s,1H),7.33(s,1H),7.29(s,1H),7.27(m,2H),7.15(d,J＝7.6Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.35(s,2H),4.63(d,J＝13.2Hz,1H),4.56(d,J＝13.2Hz,1H),2.01(m,1H),1.81-1.69(m,1H),1.52-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,166.9,164.5,158.1,144.3,135.0,130.4,130.3,129.6,129.6,128.5,127.8,123.3,123.1,108.9,81.4,60.0,59.7,34.5,26.9,22.4,13.9；HRMS(ESI)calcd forC22H22N2O5SCl[M+H]+m/z:461.0938,found3461.0940。
实施例8
3-丁基-6-((5-(3-溴苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的3-溴苄溴；
5-(5-((3-溴苄基)硫代)-1,3,4-噁唑-2-甲氧基)-3-丁基苯并呋喃-1(3H)-酮(7h)：无色液体，产率56.3％；1H NMR(600MHz,CDCl3)δ7.59(s,1H),7.43(d,J＝6.8Hz,1H),7.42(s,1H),7.38(d,J＝5.3Hz,1H),7.36(d,J＝5.9Hz,1H),7.32(d,J＝8.4,1H),7.20(t,J＝8.0Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.26(s,2H),4.44(s,2H),2.04-1.96(m,1H),1.78-1.71(m,1H),1.52-1.31(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,165.5,162.8,158.3,144.0,137.6,132.1,131.4,130.4,127.8,127.8,123.1,123.0,122.7,109.1,81.4,60.1,35.9,34.0,26.9,22.4,13.9；HRMS(ESI)calcd forC22H22N2O4SBr[M+H]+m/z:489.0484,found489.0489；
3-丁基-6-((5-(3-溴苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8h)：无色液体，产率60.3％；1HNMR(600MHz,CDCl3)δ7.50(d,J＝7.0Hz,1H),7.42(d,J＝2.6Hz,1H),7.41(s,1H),7.39(d,J＝8.4Hz,1H),7.34(d,J＝8.4,1H),7.21(t,J＝10.4,1H),7.21(s,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.35(s,2H),4.62(d,J＝13.2Hz,1H),4.55(d,J＝13.2Hz,1H),2.03-1.99(m,1H),1.79–1.71(m,1H),1.51–1.33(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,166.8,164.5,158.1,144.3,133.2,132.5,130.6,129.8,129.0,127.8,123.3,123.2,123.1,108.9,81.4,60.1,59.7,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C22H22N2O5SBr[M+H]+m/z:505.0433,found 505.0434。
实施例9
3-丁基-6-((5-(3-甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的3-甲氧基苄溴；
4-丁基-6-((5-(3-甲氧基苄基)硫代)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(7i)：白色固体，产率93.2％；m.p.65-67℃；1H NMR(600MHz,CDCl3)δ7.43(s,1H),7.36(d,J＝8.4Hz,1H),7.32(d,J＝8.4,1H),7.24(t,J＝7.8Hz,1H),7.00(d,J＝7.6Hz,1H),6.98-6.96(m,1H),6.84(d,J＝8.2,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.26(s,2H),4.47(s,2H),3.80(s,3H),2.06-1.96(m,1H),1.78-1.70(m,1H),1.51-1.32(m,4H),0.91(t,J＝7.0Hz,3H).13C NMR(150MHz,CDCl3)δ170.2,166.0,162.6,159.9,158.4,144.0,136.6,129.9,127.8,123.1,123.0,121.4,114.7,113.8,109.2,81.4,60.1,55.3,36.8,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C23H25N2O5S[M+H]+m/z:441.1484,found441.1483；
3-丁基-6-((5-(3-甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8i)：无色液体，产率48.3％；1H NMR(600MHz,CDCl3)δ7.42(s,1H),7.39(d,J＝8.4Hz,1H),7.33(d,J＝8.4,1H),7.22(t,J＝8.0Hz,1H),6.89(d,J＝8.4,1H),6.80(d,J＝8.0,1H),6.78(s,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.33(s,2H),4.62(d,J＝13.2Hz,1H),4.56(d,J＝13.2Hz,1H),3.77(s,3H),2.03-1.99(m,1H),1.80-1.72(m,1H),1.51-1.33(m,5H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,167.2,164.3,160.1,158.2,144.3,130.3,128.8,127.9,123.3,123.1,122.4,115.6,115.1,108.9,81.4,60.7,60.0,55.3,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C23H25N2O6S[M+H]+m/z:457.1433,found457.1437。
实施例10
3-丁基-6-((5-(3-三氟甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的3-三氟甲氧基苄溴；
3-丁基-6-((5-(3-(三氟甲氧基)b-烯基)硫代)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(7j)：无色液体，产率37.5％；1H NMR(600MHz,CDCl3)δ7.61(d,J＝7.6Hz,1H),7.43(s,1H),7.38-7.34(m,2H),7.32(d,J＝8.4Hz,1H),7.28(d,J＝9.0Hz,1H),7.24(t,J＝11.6Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.26(s,2H),4.54(s,2H),2.05-1.97(m,1H),1.78-1.70(m,1H),1.52-1.31(m,4H),0.91(t,J＝7.0Hz,3H)；13C NMR(150MHz,CDCl3)δ170.2,165.8,162.8,158.4,147.6,144.0,131.7,129.9,128.0,127.8,126.9,123.1,123.0,120.1,109.1,81.4,60.1,34.5,31.0,26.9,22.4,13.9；HRMS(ESI)calcd forC23H22N2O5SF3[M+H]+m/z:495.1202,found495.1200；
3-丁基-6-((5-(3-三氟甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(8j)：无色液体，产率62.6％；1H NMR(600MHz,CDCl3)δ7.46-7.42(m,2H),7.40(m,2H),7.34(d,J＝8.4,1H),7.30(s,1H),7.28(d,J＝7.4Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.37(s,2H),4.82(d,J＝13.2Hz,1H),4.65(d,J＝13.2Hz,1H),2.07-1.97(m,1H),1.80-1.71(m,2H),1.52-1.34(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,167.0,164.5,158.2,148.0,144.3,133.1,131.3,127.9,127.2,123.3,123.1,123.1,120.3,120.0,108.9,81.4,60.1,54.9,34.5,26.9,22.4,13.9；HRMS(ESI)calcd forC23H22N2O6SF3[M+H]+m/z:511.1151,found511.1156。
实施例11
3-丁基-6-((5-(萘-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的2-溴甲基萘；
4-丁基-6-((5-(萘-2-甲基)硫代)-1,3,4-噁二唑-2-甲氧基)异苯并唑-1(3H)-酮(7k):无色液体，产率96.8％；1H NMR(600MHz,CDCl3)δ7.89(s,1H),7.84-7.79(m,3H),7.52(d,J＝8.4Hz,1H),7.50-7.46(m,2H),7.42(s,1H),7.34(d,J＝8.4Hz,1H),7.29(d,J＝8.4,1H),5.42(dd,J＝7.8,4.2Hz,1H),5.24(s,2H),4.66(s,2H),1.99(m,1H),1.73(m,1H),1.50-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,165.9,162.7,158.4,144.0,133.2,132.9,132.6,128.8,128.3,127.9,127.8,127.7,126.6,126.5,126.5,123.1,123.0,109.2,81.3,60.1,37.1,34.5,26.9,22.43,13.9；HRMS(ESI)calcdfor C26H25N2O4S[M+H]+m/z:461.1535,found 461.1539；
3-丁基-6-((5-(萘-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(8k)：无色液体，产率29.0％；1H NMR(600MHz,CDCl3)δ7.82(s,1H),7.79(t,J＝7.8Hz,2H),7.75(s,1H),7.53-7.47(m,2H),7.37-7.33(m,2H),7.29(d,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.24(s,2H),4.82(d,J＝13.2Hz,1H),4.74(d,J＝13.2Hz,1H),2.05-1.96(m,1H),1.77-1.69(m,1H),1.52-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,167.1,164.3,158.1,144.2,133.3,133.2,129.1,128.0,127.8,127.0,127.0,126.8,124.9,123.4,123.2,123.0,109.0,81.4,61.0,60.9,60.0,34.5,26.9,22.4,13.9；HRMS(ESI)calcd for C26H25N2O5S[M+H]+m/z:477.1484,found 477.1480。
实施例12
3-丁基-6-((5-(呋喃-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的2-溴甲基呋喃；
3-丁基-6-((5-(呋喃-2-甲基)硫代)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮(7l)：无色液体，产率93.3％；1H NMR(600MHz,CDCl3)δ7.43(s,1H),7.38-7.37(d,J＝8.4Hz,1H),7.36(d,J＝3.6Hz,1H),7.33(d,J＝8.4Hz,1H),6.38(d,J＝3.2Hz,1H),6.31(t,J＝3.2,1.9Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.27(s,2H),4.53(s,2H),2.08-1.93(m,1H),1.82-1.70(m,1H),1.51-1.31(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,165.5,162.8,158.4,148.3,144.0,143.0,127.8,123.1,123.0,110.8,109.7,109.2,81.4,60.1,34.5,29.3,26.9,22.4,13.9；HRMS(ESI)calcd for C20H21N2O5S[M+H]+m/z:401.1171,found 401.1165；
3-丁基-6-((5-(呋喃-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(8l)：无色液体，产率37.4％；1H NMR(600MHz,CDCl3)δ7.43(d,J＝2.4Hz,1H),7.40(d,J＝8.4Hz,1H),7.36(d,J＝2.4Hz,1H),7.34(s,1H),6.42(d,J＝3.0Hz,1H),6.35(dd,J＝3.0,1.8Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.39(s,2H),4.78(d,J＝13.2Hz,1H),4.66(d,J＝13.2Hz,1H),2.05-1.98(m,1H),1.79-1.70(m,1H),1.52-1.33(m,4H),0.91(t,J＝6.8Hz,3H)；HRMS(ESI)calcd for C20H21N2O6S[M+H]+m/z:417.1120,found417.1123。
实施例13
3-丁基-6-((5-(噻吩-2-甲基)磺酰基)-1,3,4-噁二唑-2-甲氧基)异双呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的2-溴甲基噻吩；
4-丁基-6-((5-(噻吩-2-甲基)硫代)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(7m)：无色液体，产率92.9％；1H NMR(600MHz,CDCl3)δ7.43(s,1H),7.37(d,J＝8.4Hz,1H),7.33(dd,J＝8.4,2.4Hz,1H),7.25(d,J＝4.8Hz,1H),7.12(d,J＝2.4Hz,1H),6.93(d,J＝4.8Hz,1H),5.43(q,J＝7.8,4.2Hz,1H),5.27(s,2H),4.73(s,2H),2.05-1.95(m,1H),1.79-1.70(m,1H),1.52-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,165.5,162.8,158.4,144.0,137.3,128.2,127.8,127.1,126.3,123.1,123.0109.2,81.3,60.1,34.5,31.5,26.9,22.4,13.9；HRMS(ESI)calcd for C20H21N2O4S2[M+H]+m/z:417.0943,found 417.0945；
3-丁基-6-((5-(噻吩-2-甲基)磺酰基)-1,3,4-噁二唑-2-甲氧基)异双呋喃-1(3H)-酮(8m)：无色液体，产率80.6％；1H NMR(600MHz,CDCl3)δ7.41(s,1H),7.39(d,J＝8.4Hz,1H),7.34(d,J＝8.4,1H),7.31(d,J＝5.1Hz,1H),7.03(d,J＝3.3Hz,1H),6.99(m,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.35(s,2H),4.89(d,J＝13.2Hz,1H),4.80(d,J＝13.2Hz,1H),2.02(m,1H),1.75(m,1H),1.52-1.33(m,4H),0.91(t,J＝7.0Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,166.9,164.4,158.1,144.3,130.4,128.2,127.9,127.9,127.5,123.3,123.1,109.0,81.4,60.1,55.1,34.5,26.9,22.4,13.9；HRMS(ESI)calcd forC20H21N2O5S2[M+H]+m/z:433.0892,found433.0896。
实施例14
3-丁基-6-((5-(((吡啶-2-甲基)磺基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的2-溴甲基吡啶；
3-丁基-6-((5-((吡啶-2-甲基)硫代)-1,3,4-噁二唑-2-基)甲氧基)-异苯并呋喃-1(3H)-酮(7n)：白色固体，产率92.8％；m.p.66-67℃；1HNMR(600MHz,CDCl3)δ8.58(d,J＝4.8Hz,1H),7.70(t,J＝7.8Hz,1H),7.53(d,J＝7.8Hz,1H),7.42(d,J＝2.2Hz,1H),7.36(d,J＝8.4Hz,1H),7.32(d,J＝8.4Hz,1H),7.25(t,J＝7.4Hz,1H),5.43(dd,J＝7.8,4.2Hz,1H),5.27(s,2H),4.65(s,2H),2.01(m,1H),1.79-1.70(m,1H),1.51-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.1,166.1,162.7,158.4,155.1,149.7,144.0,137.0,127.8,124.0,123.1,123.0,122.9,109.2,81.3,60.1,38.3,34.5,26.9,22.4,13.8；HRMS(ESI)calcd for C21H22N3O4S[M+H]+m/z:412.1331,found412.1332；
3-丁基-6-((5-(((吡啶-2-甲基)磺基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(8n)：无色液体，产率10.6％；1HNMR(600MHz,CDCl3)δ8.27(d,J＝6.4Hz,1H),7.53(d,J＝7.6Hz,1H),7.45(s,1H),7.39(d,J＝8.4Hz,1H),7.37(d J＝7.2Hz,1H),7.36-7.34(m,1H),7.33(m,1H),5.44(dd,J＝7.8,4.2Hz,1H),5.41(s,2H),5.14(d,J＝12.6Hz,1H),4.86(d,J＝12.6Hz,1H),2.02(m,1H),1.76(m,1H),1.53-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13C NMR(150MHz,CDCl3)δ170.2,167.1,162.8,158.3,146.4,144.0,139.4,127.8,127.1,125.9,125.5,123.2,123.1,108.9,81.4,77.2,77.0,76.8,60.1,34.5,31.6,26.9,22.4,13.9；HRMS(ESI)calcd for C26H22NO3S[M+H]+m/z:428.1320,found428.1284。
实施例15
3-丁基-6-(5-(甲磺酰基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮的制备：
与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的碘甲烷；
4-丁基-6-(5-(甲硫基)-1,3,4-噁二唑-2-基)-甲氧基)异苯并呋喃-1(3H)-酮(7o)：无色液体，产率95.5％；1H NMR(400MHz,CDCl3)δ7.45(s,1H),7.41-7.33(m,2H),5.45(dd,J＝7.8,4.2Hz,1H),5.29(s,2H),2.77(s,3H),2.03(m,1H),1.82-1.70(m,1H),1.44(m,4H),0.93(t,J＝7.2Hz,3H)；13C NMR(100MHz,CDCl3)δ170.2,167.1,162.6,158.4,144.0,127.8,123.1,123.0,109.2,81.4,60.1,34.5,26.9,22.4,14.6,13.9；HRMS(ESI)calcd forC16H19N2O4S[M+H]+m/z:335.1066,found335.1063；
3-丁基-6-(5-(甲磺酰基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮(8o)：无色液体，产率60.5％；1HNMR(600MHz,CDCl3)δ7.45(s,1H),7.40(d,J＝8.4Hz,1H),7.35(d,J＝8.4Hz,1H),5.45(dd,J＝7.8,4.2Hz,1H),5.42(s,2H),3.27(s,3H),2.01(m,1H),1.80-1.69(m,1H),1.51-1.32(m,4H),0.91(t,J＝7.2Hz,3H)；13CNMR(150MHz,CDCl3)δ170.1,168.1,164.6,158.2,144.3,127.8,123.3,108.9,108.8,81.4,60.2,39.7,34.4,26.8,22.4,13.9；HRMS(ESI)calcd for C16H19N2O6S[M+H]+m/z:367.0964,found 367.0962。
实施例16
3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(化合物8b-1)的合成方法：
将化合物8b(30mg，0.0768mmol)、47％Oxone(75mg，0.115mmol)溶于丙酮(2mL)和H2O(1mL)中，氮气保护回流反应1h，TLC监测反应完毕后，经饱和碳酸氢钠淬灭反应、乙酸乙酯萃取、重结晶，得无色油状液体化合物8b-1(13.5mg，43.2％)；1H NMR(400MHz,CDCl3)δ7.43(s,1H),7.40(d,J＝8.4Hz,1H),7.35(d,J＝8.4,1H),5.45(m,1H),5.42(s,2H),3.48(d,J＝7.4Hz,2H),2.08-1.96(m,1H),1.81-1.69(m,1H),1.50-1.33(m,4H),1.24-1.20(m1H),0.91(t,J＝7.2Hz,3H),0.75-0.68(m,2H),0.38-0.33(m,2H)；13C NMR(150MHz,CDCl3)δ170.0,163.9,163.3,158.0,144.4,127.9,123.3,123.1,108.9,81.4,77.2,77.0,76.8,60.9,60.1,34.5,29.3,26.8,22.4,13.9,4.5,3.7；HRMS(ESI)calcd for C19H23N2O6S[M+H]+m/z:407.1277,found 407.1273。
实施例17
3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(化合物8b-2)的合成方法：
3-丁基-6-(5-巯基-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(化合物6-1)的合成：将化合物5(900mg，3.23mmol)分散在无水乙醇中(25mL)，0℃下分批次加入KOH(670mg，7.14mmol)，搅拌30min后，缓慢滴加CS2(615mg，8.075mmol)，析出黄色固体；氮气保护，移至85℃回流反应2天，TLC监测反应完全；经冷却、浓缩、加入4mL 98％H2SO4室温下搅拌2h、加入冰水混合物20g、乙酸乙酯萃取(3×20mL)、合并有机相、无水硫酸钠干燥、硅胶柱层析VPE：VEA＝4:1分离纯化，得白色固体化合物6-1(199.7mg，18.4％)；m.p.175-177℃；1H NMR(600MHz,DMSO-d6)δ14.69(s,1H),7.63(d,J＝8.4Hz,1H),7.45(d,J＝2.0Hz,1H),7.44(d,J＝8.4Hz,1H),5.58(dd,J＝7.8,3.8Hz,1H),5.44(s,2H),2.04(m,1H),1.74-1.61(m,1H),1.41-1.20(m,4H),0.86(t,J＝7.2Hz,3H)；13C NMR(150MHz,DMSO-d6)δ189.2,170.0,159.5,158.4,144.2,127.2,124.4,123.7,109.3,81.5,64.8,34.0,26.9,22.3,14.3；HRMS(ESI)calcd for C15H17N2O3S2[M+H]+m/z:337.0681,found 337.0676；
化合物8b-2的合成：与实施例1的制备步骤相同，不同之处仅在于，将步骤(7)中的异丙基溴替换为等物质的量的环丙基溴甲烷，并与3-丁基-6-(5-巯基-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(化合物6-1)进行反应；
3-丁基-6-((5-((环丙基甲基)硫代)-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮(7b-1)无色液体，产率：45.3％；m.p.64-70℃；1HNMR(600MHz,CDCl3)δ7.43(s,1H),7.36(d,J＝8.4Hz,1H),7.31(d,J＝8.4,1H),5.48(s,2H),5.43(dd,J＝7.8,4.2Hz,1H),3.31(d,J＝7.4Hz,2H),2.05-1.96(m,1H),1.78-1.70(m,1H),1.51-1.32(m,4H),1.28-1.19(m,1H),0.91(t,J＝7.2Hz,3H),0.69-0.62(m,2H),0.39-0.33(m,2H)；13C NMR(150MHz,CDCl3)δ170.1,168.1,165.2,158.3,143.8,127.9,123.1,122.7,109.6,81.3,65.2,40.3,34.5,26.9,22.4,13.9,10.4,6.1；HRMS(ESI)calcd forC19H23N2O3S2[M+H]+m/z:391.1150,found 391.1153；
3-丁基-6-((5-((环丙基甲基)磺酰基)-1,3,4-噻二唑-2-基)甲氧基)-异苯并呋喃-1(3H)-酮(8b-2)：白色固体，产率58.1％；m.p.128-130℃；1H NMR(600MHz,CDCl3)δ7.43(d,J＝2.4Hz,1H),7.41(d,J＝8.4Hz,1H),7.34(d,J＝8.4Hz,1H),5.62(s,2H),5.45(dd,J＝7.8,4.2Hz,1H),3.52(s,1H),3.51(s,1H),2.07-1.97(m,1H),1.80-1.71(m,1H),1.51-1.33(m,4H),1.23-1.15(m,1H),0.91(t,J＝7.2Hz,3H),0.70-0.63(m,2H),0.33-0.31(m,2H)；13C NMR(150MHz,CDCl3)δ171.8,169.9,169.9,157.9,144.4,128.0,123.4,122.9,109.2,81.4,65.3,60.7,34.5,26.8,22.4,13.9,4.6,4.2；HRMS(ESI)calcd forC19H23N2O5S2[M+H]+m/z:423.1048,found423.1052。
具体的化合物如下表所示：
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下面对本发明实施例1-17分别制得的丁苯酞-噁二唑类化合物的生物活性进行测定，具体如下所示：
(1)抗血小板聚集活性评价
采用Born氏比浊法测试了本发明化合物对二磷酸腺苷(ADP)及花生四烯酸(AA)诱导的家兔血小板聚集的抑制活性。家兔心脏取血，用体积分数为3.8％枸橼酸钠1:9抗凝，以800r/min离心10min，得富血小板血浆(PRP)，剩余部分以3000r/min离心10min，得贫血小板血浆(PPP)；测试杯中加入PRP 238μL和不同浓度的受试化合物2μL，温孵5min，加入诱导剂ADP(终浓度10μmol/L)或AA(500μmol/L)10μL，观察记录5min内最大血小板聚集率，根据公式：
血小板聚集抑制率＝(空白组最大聚集率-给药组最大聚集率)/空白组最大聚集率)×100％；
计算各受试化合物对血小板聚集的抑制率(Aggregation inhibition rate,AIR)；再用Graphpad Prism 11软件计算出各化合物的IC50值。用不含化合物的2μl DMSO，以10μLADP或AA作为诱导剂测出DMSO对血小板聚集的抑制率用作空白对照，阳性对照为阿司匹林(ASP)和丁苯酞(NBP)。
化合物的抗血小板凝集活性结果如表1所示，从表1可以看出本发明的所有化合物对ADP诱导的血小板凝集的抑制活性(IC50＝13.28-349.6μM)均显著优于先导化合物丁苯酞(NBP，IC50>1000μM)和临床常用抗血小板凝集药物阿司匹林(ASP，IC50＝1140μM)，其中化合物8b(IC50＝19.99μM)、8d(IC50＝27.92μM)、8m(IC50＝27.65μM)和8n(IC50＝22.76μM)对AA诱导的血小板凝集的抑制活性显著优于丁苯酞(IC50＝318.8μM)和阿司匹林(IC50＝75.27μM)。综上所述，本发明所合成的化合物对ADP和AA所诱导的血小板聚集均有很好的抑制作用，其效果显著优于先导化合物丁苯酞，尤其是化合物8b、8c、8d和8m效果最为显著，具有一定的开发价值。
表1目标化合物在ADP和AA作为诱导剂下的抗血小板凝集活性结果对照表
(2)化合物8b和8c对大鼠脑缺血再灌注损伤模型(MCAO)的影响
分别选择对ADP和AA诱导的血小板凝集抑制活性表现最好的化合物8b和8c进行MACO活性评价，采用SD大鼠进行建模，用10％的水合氯醛(0.35mL/100g)腹腔注射麻醉后，颈部正中切开皮肤，分离各层组织，暴露右侧颈颈外动脉，分离至颈内动脉、颈外动脉分叉后一段，于颈内动脉、颈外动脉处用动脉夹夹闭，颈外动脉近心端及远心端手术线结扎，中间剪断，颈外动脉近结扎端斜向下剪一小口，将尼龙由颈外动脉插入至颈内动脉，继续插入颅内，插入至微感阻力，使线栓头端通过大脑中动脉起始处，此时即实现大脑中动脉的血流阻塞。在闭塞1小时后，将线取出，恢复大脑中动脉区血供，使之再灌注24h，用10％水合氯醛麻醉大鼠；取出大脑，将大脑分为5个2mm左右厚的冠状切片，在含2％TTC磷酸盐缓冲液中孵育10min，正常的脑组织呈现出红色，梗死的脑组织为白色，采用Pro+6.0图像系统计算脑梗死面积。
其结果如图5所示，化合物8b和8c在低(LD，5mg/kg)、中(MD，10mg/kg)、高(HD，20mg/kg)浓度下与模型组(Model)相比，均能显著减少MACO模型中大脑的梗死面积；同时，化合物8b和8c与丁苯酞在相同剂量下(20mg/kg)时，其治疗效果显著优于丁苯酞。
结果表明，本发明针对丁苯酞整体疗效不佳的缺陷，设计、合成了一系列丁苯酞-噁/噻二唑类衍生物，并成功发现了体外抗凝活性优于丁苯酞和阿司匹林的化合物，动物实验也证明本发明中的部分化合物具有较先导化合物丁苯酞优异的治疗效果。因此，该类化合物有望被用于制备治疗或预防由血栓引起的心脑血管疾病(包括脑卒中、血管性老年痴呆)及其并发症。
本领域的技术人员可以对本发明进行各种改动和变型而不脱离本发明的精神和范围。这样，倘若本发明的这些修改和变型属于本发明权利要求及其等同技术的范围之内，则本发明也意图包含这些改动和变型在内。
Claims (9)
1.丁苯酞-噁/噻二唑类化合物，其特征在于，所述丁苯酞-噁/噻二唑类化合物的结构如式(I)所示：
其中，Y为S或O，X为S、亚砜(SO)或砜(SO2)；
R为氢原子、烷基、环烷基、杂环基、杂环基烷基、烷氧基、芳基、杂芳基中的一种；
所述烷基、环烷基、杂环基、杂环基烷基、烷氧基、芳基、杂芳基还可分别被取代基取代；
所述取代基为一个或多个，其选自H、卤素原子、羟基、氨基、硝基、氰基、C1-4烷基、C1-4卤代烷基、C1-4烷氨基、C1-4二烷氨基、C1-4羟烷基、C1-4烷氧基、C1-4卤代烷氧基、C1-4卤代烷硫基或C1-4羟基烷氧基。
2.丁苯酞-噁/噻二唑类化合物，其特征在于，所述丁苯酞-噁/噻二唑类化合物的结构如式(I)所示：
所述丁苯酞-噁/噻二唑类化合物中的R选自：-CH3，
3.根据权利要求2所述的丁苯酞-噁/噻二唑类化合物，其特征在于，所述丁苯酞-噁/噻二唑类化合物为：3-丁基-6-((5-(异丙基亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-((5-(环丙基甲基)亚砜基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-(5-苄基亚砜基)-1,3,4-噁二唑-2-甲氧基)-3-丁基苯并呋喃酮-1(3H)-酮；3-丁基-6-((5-(2-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(3-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(4-氟苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(3-氯苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(3-溴苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(3-甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(3-三氟甲氧基苄基)亚砜基)-1,3,4-噁二唑-2-甲氧基)-苯并呋喃-1(3H)-酮；3-丁基-6-((5-(萘-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-((5-(呋喃-2-甲基)亚砜基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-((5-(噻吩-2-甲基)磺酰基)-1,3,4-噁二唑-2-甲氧基)异双呋喃-1(3H)-酮；3-丁基-6-((5-(((吡啶-2-甲基)磺基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的；3-丁基-6-(5-(甲磺酰基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮；3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮。
4.一种权利要求2-3任一项所述丁苯酞-噁/噻二唑类化合物的制备方法，其特征在于，包括如下步骤：
(1)将丁苯酞与硝酸钾和浓硫酸进行硝化反应，得到化合物1；
(2)将步骤(1)的化合物1在铁粉催化作用下，于氯化铵的醇溶液中进行还原，得到化合物2；
(3)将步骤(2)的化合物2先溶解于浓硫酸中，并向其中滴加去离子水，然后加入亚硝酸钠，进行桑德迈尔反应，得到化合物3；
(4)将步骤(3)的化合物3、碱与溴乙酸乙酯进行醚化反应，得到化合物4；
(5)将步骤(4)的化合物4于水合肼中进行肼解反应，得到化合物5；
(6)将步骤(5)的化合物5与氢氧化钾和二硫化碳进行环化反应，得到化合物6；
(7)将步骤(6)的化合物6与碳酸钾和卤代化合物进行醚化反应，得到化合物7；
(8)将步骤(7)的化合物7与m-CPBA进行氧化反应，得到丁苯酞-噁/噻二唑类化合物。
5.根据权利要求4所述的丁苯酞-噁/噻二唑类化合物的制备方法，其特征在于，所述步骤(7)的卤代化合物分别为：异丙基溴、环丙基溴甲烷、苄基溴、2-氟苄溴、3-氟苄溴、4-氟苄溴、3-氯苄溴、3-溴苄溴、3-甲氧基苄溴、3-三氟甲氧基苄溴、2-溴甲基萘、2-溴甲基呋喃、2-溴甲基噻吩、2-溴甲基吡啶、碘甲烷。
6.根据权利要求4所述的丁苯酞-噁/噻二唑类化合物的制备方法，其特征在于，当所述丁苯酞-噁/噻二唑类化合物为3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噁二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮时，其按照如下步骤制备：将3-丁基-6-((5-(环丙基甲基)亚砜基)-1,3,4-噁二唑-2-甲氧基)异苯并呋喃-1(3H)-酮与Oxone进行氧化反应。
7.根据权利要求4所述的丁苯酞-噁/噻二唑类化合物的制备方法，其特征在于，当所述丁苯酞-噁/噻二唑类化合物为3-丁基-6-((5-(环丙基甲磺酰基)-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮时，其按照如下步骤制备：
S1、3-丁基-6-(5-巯基-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备：将步骤(5)的化合物5采用CS2和氢氧化钾进行环化反应；
S2、3-丁基-6-((5-((环丙基甲基)硫代)-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮的制备：将步骤S1的3-丁基-6-(5-巯基-1,3,4-噻二唑-2-基)甲氧基)异苯并呋喃-1(3H)-酮与碳酸钾和环丙基溴甲烷进行醚化反应，然后与m-CPBA进行氧化反应。
8.一种权利要求1所述的丁苯酞-噁/噻二唑类化合物在制备预防或治疗血栓引起的心脑血管疾病及其并发症药物中的应用。
9.根据权利要求8所述的应用，其特征在于，所述心脑血管疾病包括脑卒中和血管性老年痴呆症。
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| GB1494877A (en) * | 1975-01-10 | 1977-12-14 | Commw Scient Ind Res Org | Heterocyclic compounds and plant growth regulating compositions |
| CN106916150A (zh) * | 2015-12-24 | 2017-07-04 | 中国科学院上海药物研究所 | 1,3,4-噁二唑-2-甲硫基-苯并噻唑衍生物、其制备方法和用途 |
| CN112010827A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类苄胺基苯酞类化合物、其制备方法和用途 |
| CN113292524A (zh) * | 2021-07-27 | 2021-08-24 | 中国医学科学院医学实验动物研究所 | 丁苯酞衍生物及其在制备保护神经细胞的药物中的应用 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2014197818A2 (en) * | 2013-06-07 | 2014-12-11 | The General Hospital Corporation | Small molecule activators of nrf2 pathway |
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| GB1494877A (en) * | 1975-01-10 | 1977-12-14 | Commw Scient Ind Res Org | Heterocyclic compounds and plant growth regulating compositions |
| CN106916150A (zh) * | 2015-12-24 | 2017-07-04 | 中国科学院上海药物研究所 | 1,3,4-噁二唑-2-甲硫基-苯并噻唑衍生物、其制备方法和用途 |
| CN112010827A (zh) * | 2019-05-28 | 2020-12-01 | 四川大学 | 一类苄胺基苯酞类化合物、其制备方法和用途 |
| CN113292524A (zh) * | 2021-07-27 | 2021-08-24 | 中国医学科学院医学实验动物研究所 | 丁苯酞衍生物及其在制备保护神经细胞的药物中的应用 |
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| CN114773330A (zh) | 2022-07-22 |
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