CN117586274A - 一种佛司可林扩环衍生物及其制备方法和应用 - Google Patents
一种佛司可林扩环衍生物及其制备方法和应用 Download PDFInfo
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- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
本发明属于药物化学和药理学技术领域,公开了一种佛司可林扩环衍生物及其制备方法和应用,该佛司可林扩环衍生物具有式(I)所示化学结构式,由佛司可林与氢氧化钾在甲醇中反应得到佛司可林重排产物1,然后佛司可林重排产物1与戴斯‑马丁氧化剂和吡啶在二氯甲烷中反应得到佛司可林重排产物2,然后佛司可林重排产物2与间氯过氧苯甲酸和碳酸氢钠在二氯甲烷中反应得到佛司可林重排扩环产物3,最后佛司可林重排扩环产物3在无水醋酸银、无水醋酸铜和醋酸钯催化下与芳基碘化物在无水二氯乙烷中反应得到佛司可林扩环衍生物4。本发明得到的佛司可林扩环衍生物具有较强的抗炎活性,可用于制备抗炎药物。
Description
技术领域
本发明属于药物化学和药理学技术领域,具体涉及一种佛司可林扩环衍生物及其制备方法和应用。
背景技术
近年来,Hergenrother,P.J.等发展了一种新的合成策略:复杂性到多样性策略(Complexity-to-Diversity Strategy,CtD)(Furiassi,L.;Tonogai,E.J.;Hergenrother,P.J.Limonin as a Starting Point for the Construction of Compounds with HighScaffold Diversity.Angew.Chem.Int.Ed.2021,60,16119-16128;Morrison.K.C.;Hergenrother,P.J.Natural Products as Starting Points for the Synthesis ofComplex and Diverse Compounds,Nat.Prod.Rep.2014,31,6-14)。该策略利用截短侧耳素、赤霉素、肾上腺甾酮等结构复杂而且含量丰富的天然产物作为起始原料,通过环断裂、环重排、环稠合、环缩小、环扩大等多种环变形反应(Ring-Distortion Reactions)来对天然产物的骨架结构进行重塑,获得具有复杂性和多样性天然产物类似物来进行药物筛选。
佛司可林是一种二萜类化合物,在抗癌、抗哮喘、抗高血压和正性肌力等方面都具有重要的药用价值。另外,佛司可林还可以与其他某些蛋白发生相互作用,如作用于葡萄糖转运蛋白和离子通道等。药效学研究结果表明,佛司可林可以有效促进中枢及周围神经系统中神经元的分化及神经突起生长,从而对心脑血管系统、呼吸系统及肿瘤等产生重要影响,具有强心、平喘、抗肿瘤、抗血栓及降低眼内压等药理作用。现临床上开始用于心脑血管病、肿瘤和老年常患疾病等的治疗,药理作用明显,临床应用前景广阔。佛司可林具有A、B、C三个并环环系、8个立体化学中心的化学结构,并且为丰产天然产物,非常适合作为环变形反应起始原料。
发明内容
本发明的目的在于提供一种佛司可林扩环衍生物及其制备方法和应用,通过采取复杂性到多样性策略(CtD strategy),对佛司可林进行化学转化并得到结构新颖性的佛司可林扩环衍生物,进一步开发其药学用途。
本发明提供了一种佛司可林扩环衍生物,该佛司可林扩环衍生物具有通式(I)所示结构:
其中,R1表示苯基、对氯苯基、对甲氧基苯基、对三氟甲氧基苯基、对叔丁基苯基、对硝基苯基和对氰基苯基中的一种。
进一步的,所述佛司可林扩环衍生物具有如式4a~4d中任意一项所示的结构:
其中,
R1为苯基时,该佛司可林扩环衍生物为式4a所示结构的化合物;
R1为对氯苯基时,该佛司可林扩环衍生物为式4b所示结构的化合物;
R1为对甲氧基苯基时,该佛司可林扩环衍生物为式4c所示结构的化合物;
R1为对三氟甲氧基苯基时,该佛司可林扩环衍生物为式4d所示结构的化合物;
本发明还提供了佛司可林扩环衍生物的制备方法,包括以下步骤:将佛司可林与氢氧化钾在甲醇中反应得到佛司可林重排产物1,然后佛司可林重排产物1与戴斯-马丁氧化剂和吡啶在二氯甲烷中反应得到佛司可林重排产物2,然后佛司可林重排产物2与间氯过氧苯甲酸和碳酸氢钠在二氯甲烷中反应得到佛司可林重排扩环产物3,最后佛司可林重排扩环产物3在无水醋酸银、无水醋酸铜和醋酸钯催化下与芳基碘化物在无水二氯乙烷中反应得到佛司可林扩环衍生物4。
其中,所述反应的反应式为:
其中,R1表示苯基、对氯苯基、对甲氧基苯基、对三氟甲氧基苯基、对叔丁基苯基、对硝基苯基和对氰基苯基中的一种。
具体的,该制备方法包括以下步骤:
(1)将氢氧化钾溶于甲醇中,加入佛司可林进行反应得第一反应液,将所述第一反应液冷却后,减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,无水MgSO4干燥,减压干燥,然后通过闪过柱层析得到白色固体佛司可林重排产物1,其中,佛司可林、氢氧化钾的摩尔比为1:13;
(2)将佛司可林骨架重排产物1溶于二氯甲烷中,加入戴斯-马丁氧化剂和吡啶进行反应,得到第二反应液,将所述第二反应液用有机溶剂稀释,加入饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液,过滤,有机相依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林重排产物2,其中佛司可林重排产物1、戴斯-马丁氧化剂、吡啶的摩尔比为1:2.5:2;
(3)将佛司可林重排产物2溶于二氯甲烷中,加入碳酸氢钠和间氯过氧苯甲酸进行反应,得到第三反应液,将所述第三反应液用有机溶剂稀释,加入10%的亚硫酸钠水溶液,过滤,有机相依次经过水洗,饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林扩环产物3,其中佛司可林重排产物2、碳酸氢钠、间氯过氧苯甲酸的摩尔比1:1:1.5;
(4)将佛司可林重排扩环产物3溶于无水二氯乙烷中,依次加入无水醋酸银、无水醋酸铜、醋酸钯和芳基碘化物进行反应,得到第四反应液,将所述第四反应液冷却后,用有机溶剂稀释,过滤,滤液减压浓缩,然后通过闪过柱层析得到白色固体佛司可林扩环衍生物4,其中佛司可林扩环产物3、无水醋酸银、无水醋酸铜、醋酸钯、芳基碘化物的摩尔比为1:1.2:2:0.05:2;
其中,所述芳基碘化物为碘苯、对氯碘苯、对甲氧基碘苯、对三氟甲氧基碘苯、对叔丁基碘苯、对硝基碘苯和对氰基碘苯中的一种。
进一步的,上述制备方法步骤(1)中,反应温度为65℃,反应时间为4h。
进一步的,上述制备方法步骤(2)中,反应温度为25℃,反应时间为12h。
进一步的,上述制备方法步骤(3)中,反应温度为25℃,反应时间为24h。
进一步的,上述制备方法步骤(4)中,反应温度为70℃,反应时间为12h。
进一步的,上述制备方法中,所述有机溶剂为甲醇、二氯甲烷、二氯乙烷和乙酸乙酯中的至少一种。
本发明还提供了上述的佛司可林扩环衍生物在制备抗炎药物中的应用。
与现有技术相比,本申请提供了一类佛司可林扩环衍生物及其制备方法和应用,此类化合物结构新颖并且具有优异的抗炎活性,可应用于抗炎药物的制备。
附图说明
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。
图1为本发明实施例2提供的佛司可林重排产物(2)的核磁共振1H谱图;
图2为本发明实施例2提供的佛司可林重排产物(2)的核磁共振13C谱图;
图3为本发明实施例3提供的佛司可林扩环产物(3)的核磁共振1H谱图;
图4为本发明实施例3提供的佛司可林扩环产物(3)的核磁共振13C谱图;
图5为本发明实施例4提供的佛司可林扩环衍生物(4a)的核磁共振1H谱图;
图6为本发明实施例4提供的佛司可林扩环衍生物(4a)的核磁共振13C谱图。
具体实施方式
下面将对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。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。
实施例1
将730mg(13.0mmol)的氢氧化钾溶于甲醇(10ml),然后加入410mg(1.0mmol)的佛司可林,65℃反应4小时。反应液减压浓缩,加入乙酸乙酯(10ml)稀释,然后依次水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(石油醚:乙酸乙酯=2:1)得到336mg白色固体,即佛司可林重排产物1(产率91%)。
1H NMR(400MHz,Methanol-d4)δ6.06(dd,J=17.5,10.9Hz,1H,H-14),5.16(dd,J=17.5,1.2Hz,1H,H-15),5.04(dd,J=10.9,1.2Hz,1H,H-15),4.16(dd,J=11.0,5.2Hz,1H,H-1),4.01(dd,J=4.1,1.7Hz,1H,H-6),3.64(d,J=1.6Hz,1H,H-7),3.19(d,J=14.4Hz,1H,H-12),1.90(d,J=14.3Hz,1H,H-12),1.79–1.68(m,1H),1.65(d,J=4.1Hz,1H,H-5),1.64–1.60(m,1H),1.52(s,3H,CH3),1.48(s,3H,CH3),1.47(s,3H,CH3),1.34–1.28(m,2H),1.26(s,3H,CH3),0.98(s,3H,CH3).13C NMR(100MHz,MeOD)δ143.89,111.35,106.48,91.76,90.54,88.51,88.44,71.18,64.92,47.66,45.98,44.38,40.55,33.31,30.00,28.38,26.45,24.95,23.14,13.44.
实施例2
将368mg(1.0mmol)佛司可林重排产物1溶于二氯甲烷(10ml)中,加入183μL(2.0mmol)吡啶、1.06g(2.5mmol)戴斯-马丁氧化剂,25℃反应12小时。反应液加入乙酸乙酯(10ml)、饱和碳酸氢钠水溶液、饱和硫代硫酸钠水溶液,过滤,有机相依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析(石油醚:乙酸乙酯=8:1)得到243mg白色固体,即佛司可林重排产物2(产率67%)。
1H NMR(400MHz,Chloroform-d)δ5.91(dd,J=17.4,10.7Hz,1H,H-15),5.18(d,J=17.4Hz,1H,H-16),5.12(d,J=10.7Hz,1H,H-16),4.64(s,1H,H-6),4.39(d,J=2.5Hz,1H,H-7),2.82(d,J=18.2Hz,1H,H-13),2.64–2.59(m,1H,6-OH),2.59–2.49(m,2H),2.47(d,J=2.7Hz,1H,H-5),2.46(d,J=18.1Hz,1H,H-13),1.82–1.71(m,2H),1.78(s,3H,CH3),1.42(s,3H,CH3),1.35(s,3H,CH3),1.26(s,3H,CH3),1.19(s,3H,CH3).13C NMR(100MHz,CDCl3)δ215.04,206.38,169.58,142.13,113.97,87.88,83.12,79.16,65.19,53.88,47.89,46.17,38.32,35.63,32.66,30.39,27.69,26.03,21.07,20.75.HRMS(ESI):m/zcalcd for C20H28O6Na:387.1778;found:387.1788[M+Na]+.
实施例3
将364mg(1.0mmol)佛司可林重排产物2溶于二氯甲烷(10ml)中,加入84mg(1.0mmol)碳酸氢钠、259mg(1.5mmol)间氯过氧苯甲酸,25℃下反应24小时。反应液加入二氯甲烷(10ml)稀释,加入10%的亚硫酸钠水溶液,过滤,有机相依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(乙酸乙酯:石油醚=5:1)得到171mg白色固体,即佛司可林重排扩环产物3(产率45%)。
1H NMR(400MHz,Chloroform-d)δ5.91(dd,J=17.4,10.7Hz,1H,H-15),5.21(d,J=17.0Hz,1H,H-16),5.20(d,J=11.0Hz,1H,H-16),4.54(dd,J=11.2,1.5Hz,1H,H-6),4.10(dd,J=10.7,1.5Hz,1H,H-7),3.93(d,J=10.8Hz,1H,OH),3.46(d,J=11.1Hz,1H,H-5),3.05(d,J=19.0Hz,1H,H-13),2.84(ddd,J=17.6,8.8,1.9Hz,1H,H-2),2.71(ddd,J=17.6,11.4,1.9Hz,1H,H-2),2.52(d,J=19.0Hz,1H,H-13),2.04(ddd,J=15.0,11.3,1.9Hz,1H,H-3),1.70(s,3H,CH3),1.56(s,3H,CH3),1.55–1.50(m,1H,H-3),1.47(s,3H,CH3),1.18(s,3H,CH3),1.17(s,3H,CH3).13C NMR(100MHz,CDCl3)δ218.9,171.9,170.1,140.8,115.6,82.2,80.8,80.7,80.1,76.7,52.4,46.0,36.3,33.1,31.7,31.5,29.3,25.6,24.1,20.7.HRMS(ESI):m/z calcd for C20H28O7Na:403.1733;found:403.1731[M+Na]+.
实施例4
将380mg(1.0mmol)佛司可林扩环产物3溶于无水二氯乙烷(10ml)中,依次加入200mg(1.2mmol)无水醋酸银、363mg(2.0mmol)无水醋酸铜、12mg(0.05mmol)醋酸钯、408mg(2.0mmol)碘苯,70℃反应12小时。反应液冷却后加入乙酸乙酯(10ml)稀释,过滤,滤液依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,通过闪过柱层析(石油醚:乙酸乙酯=8:1)得到305mg白色固体,即佛司可林扩环衍生物4a(产率67%)。
1H NMR(400MHz,)δ7.44–7.30(m,5H,ArH),6.58(d,J=16.1Hz,1H,H-16),6.33(d,J=16.1Hz,1H,
H-15),4.58(dd,J=11.2,2.0Hz,1H,H-6),4.13(dd,J=10.3,1.9Hz,1H,H-7),3.89(d,J=10.6Hz,1H,OH),3.30(d,J=11.1Hz,1H,H-5),3.11(d,J=18.9Hz,1H,H-13),2.72–2.56(m,2H,H-2),2.63(d,J=19.0Hz,1H,H-13),1.90(dd,J=10.0,4.7Hz,1H,H-3),1.72(s,3H,CH3),1.63(s,3H,CH3),1.61(s,3H,CH3),1.55–1.46(m,1H,H-3),1.25(s,3H,CH3),1.18(s,3H,CH3).13C NMR(100MHz,CDCl3)δ218.9,171.9,169.8,135.4,132.2,130.7,128.9,128.3,126.8,82.1,81.4,80.5,80.0,76.6,54.1,47.8,36.9,33.5,31.9,29.7,28.8,25.3,23.8,20.7.HRMS(ESI):m/z calcd for C26H32O7Na:479.2046;found:479.2041[M+Na]+.
实施例5~7
根据以上实施例4的方法,将碘苯换为对氯碘苯、对甲氧基碘苯、对三氟甲氧基碘苯,制备实施例化合物4b~4d。
下面列出是化合物4b~4d的理化数据:4b:产率76%。1H NMR(400MHz,Chloroform-d)δ7.34(q,J=8.6Hz,4H,ArH),6.51(d,J=16.2Hz,1H,H-16),6.28(d,J=16.2Hz,1H,H-15),4.59(dd,J=11.0,1.7Hz,1H,H-6),4.16(dd,J=10.6,1.7Hz,1H,H-7),3.99(d,J=10.5Hz,1H,OH),3.28(d,J=11.1Hz,1H,H-5),3.13(d,J=19.0Hz,1H,H-13),2.75(ddd,J=16.9,10.2,2.1Hz,1H,H-2),2.68–2.57(m,1H,H-2),2.62(d,J=18.8Hz,1H,H-13),1.91(ddd,J=15.1,10.1,1.8Hz,1H,H-3),1.73(s,3H,CH3),1.63(s,3H,CH3),1.61(s,3H,CH3),1.60–1.53(m,1H,H-3),1.20(s,3H,CH3),1.19(s,3H,CH3).13C NMR(100MHz,CDCl3)δ219.1,172.0,169.8,134.0,133.9,132.8,129.6,129.0,128.1,82.4,81.0,80.4,80.1,76.8,54.2,47.7,37.2,33.6,32.1,32.0,28.6,25.6,23.6,20.7.HRMS(ESI):m/zcalcd for C26H31O7NaCl:513.1656;found:513.1658[M+Na]+.
4c:产率54%。1H NMR(400MHz,)δ7.36(d,J=8.6Hz,2H,ArH),7.04–6.81(m,2H,ArH),6.53(d,J=16.1Hz,1H,H-16),6.17(d,J=16.1Hz,1H,H-15),4.58(dd,J=11.1,1.9Hz,1H,H-6),4.15–4.10(m,1H,H-7),3.92(d,J=10.5Hz,1H,OH),3.81(s,3H,OCH3),3.34(d,J=11.1Hz,1H,H-5),3.10(d,J=18.9Hz,1H,H-13),2.75–2.67(m,1H,H-2),2.65–2.55(m,1H,H-2),2.61(d,J=19.1Hz,1H,H-13),1.91(dd,J=14.6,10.5Hz,1H,H-3),1.73(s,3H,CH3),1.63(s,3H,CH3),1.61(s,3H,CH3),1.59–1.52(m,1H,H-3),1.25(s,3H,CH3),1.19(s,3H,CH3),1.18(s,3H,CH3).13C NMR(100MHz,CDCl3)δ219.3,171.9,169.8,159.7,130.3,130.0,128.1,128.1,114.3,82.2,81.2,80.5,80.1,76.7,55.3,54.0,48.0,37.0,33.5,31.9,31.9,28.6,25.4,23.8,20.7.HRMS(ESI):m/z calcd for C27H34O8Na:509.2151;found:509.2155[M+Na]+.
4d:产率73%。1H NMR(400MHz,Chloroform-d)δ7.48(d,J=8.7Hz,2H,ArH),7.25–7.14(m,2H,ArH),6.56(d,J=16.2Hz,1H,H-16),6.30(d,J=16.1Hz,1H,H-15),4.61(dd,J=11.1,1.6Hz,1H,H-6),4.18(dd,J=10.6,1.6Hz,1H,H-7),4.03(d,J=10.6Hz,1H,OH),3.31(d,J=11.1Hz,1H,H-5),3.17(d,J=19.0Hz,1H,H-13),2.77(ddd,J=16.9,10.3,1.9Hz,1H,H-2),2.69–2.60(m,1H,H-2),2.64(d,J=19.0Hz,1H,H-13),1.92(ddd,J=15.2,10.0,1.9Hz,1H,H-3),1.75(s,3H,CH3),1.65(s,3H,CH3),1.64(s,3H,CH3),1.62–1.56(m,1H,H-3),1.22(s,3H,CH3),1.21(s,3H,CH3).13C NMR(100MHz,CDCl3)δ219.1,172.0,169.8,149.0,134.2,133.3,129.3,128.2,121.3,82.4,81.0,80.4,80.1,76.9,54.2,47.7,37.2,33.6,32.1,32.0,28.7,25.6,23.5,20.7.HRMS(ESI):m/z calcd for C27H31O8 NaF3:563.1869;found:563.1874[M+Na]+.
为了更好地理解本发明的实质,下面分别用本发明提供的佛司可林扩环衍生物对LPS诱导的RAW264.7细胞NO释放的抑制作用的药理实验结果,说明其在抗炎药物研究领域中的新用途。药理实施例给出了代表性化合物的部分活性数据。必须说明,本发明的药理实施例是用于说明本发明而不是对本发明的限制。根据本发明的实质对本发明进行的简单改进都属于本发明要求保护的范围。
药物实施例1:化合物4a-4d、佛司可林和地塞米松对LPS诱导的RAW 264.7巨噬细胞NO释放的抑制活性
将RAW 264.7巨噬细胞以1×105个/m L的密度接种于96孔板上,在37℃、5% CO2培养箱中孵育24h。本实验设置对照组、LPS诱导组、阳性对照地塞米松(dexamethasone,DEX)组和实验组,阳性对照组和实验组以0.2、1.0、5.0、25.0μM待测化合物4a-4d或DEX加入到处理好的RAW 264.7巨噬细胞中。放置4h后在对照组加入10μL培养基,其余组加入LPS(1.0μg/mL)用以诱导细胞,培养孵育24h,离心,收集细胞上层清液,通过一氧化氮试剂盒测定NO的释放量,并用Graphpad5软件计算IC50。应用四甲基偶氮唑盐微量酶反应比色(MTT)法检测化合物在20μM对RAW 264.7巨噬细胞生长的影响。
表1化合物4a-4d、佛司可林和地塞米松对LPS诱导的RAW 264.7巨噬细胞NO释放的抑制活性
化合物 | IC50(μM) | 细胞存活率/% |
4a | 2.2 | 99.55±3.14 |
4b | 4.8 | 99.36±1.31 |
4c | 7.2 | 98.04±3.16 |
4d | 6.1 | 98.76±1.24 |
佛司可林 | 25.1 | 100.33±1.88 |
DEX | 8.6 | 99.27±2.43 |
根据表1可知,本发明提供的佛司可林扩环衍生物具有重要的生物活性,LPS诱导的RAW 264.7巨噬细胞NO释放的抑制活性试验表明:此类式(1)所示结构的佛司可林扩环衍生物对LPS诱导的RAW 264.7巨噬细胞NO释放具有较好的抑制活性,实施例中化合物4a-4d抑制效果明显优于阳性对照药地塞米松和佛司可林,并且没有明显的细胞毒性,有可能发展成为新的抗炎药物。
以上所述仅是本发明的优选实施方式,应当指出,对于本技术领域的普通技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (9)
1.一种佛司可林扩环衍生物,其特征在于,所述佛司可林扩环衍生物的结构如下式所示:
其中,R1表示苯基、对氯苯基、对甲氧基苯基、对三氟甲氧基苯基、对叔丁基苯基、对硝基苯基和对氰基苯基中的一种。
2.根据权利要求1所述的一种佛司可林扩环衍生物,其特征在于,所述佛司可林扩环衍生物具有如式4a~4d中任意一项所示的结构:
3.一种权利要求1所述的佛司可林扩环衍生物的制备方法,其特征在于,所述制备方法的反应式如下式所示:
所述制备方法包括以下步骤:
S1.将氢氧化钾溶于甲醇中,加入佛司可林进行反应得第一反应液,将所述第一反应液冷却后,减压浓缩,用有机溶剂稀释,依次经过水洗,饱和食盐水洗,无水MgSO4干燥,减压干燥,然后通过闪过柱层析得到白色固体佛司可林重排产物1,其中,佛司可林、氢氧化钾的摩尔比为1:13;
S2.将佛司可林重排产物1溶于二氯甲烷中,加入戴斯-马丁氧化剂和吡啶进行反应,得到第二反应液,将所述第二反应液用有机溶剂稀释,加入饱和碳酸氢钠水溶液和饱和硫代硫酸钠水溶液,过滤,有机相依次经过水洗、饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林重排产物2,其中佛司可林重排产物1、戴斯-马丁氧化剂、吡啶的摩尔比为1:2.5:2;
S3.将佛司可林重排产物2溶于二氯甲烷中,加入碳酸氢钠和间氯过氧苯甲酸进行反应,得到第三反应液,将所述第三反应液用有机溶剂稀释,加入10%的亚硫酸钠水溶液,过滤,有机相依次经过水洗,饱和食盐水洗,无水MgSO4干燥,减压浓缩,然后通过闪过柱层析得到白色固体佛司可林扩环产物3,其中佛司可林重排产物2、碳酸氢钠、间氯过氧苯甲酸的摩尔比1:1:1.5;
S4.将佛司可林扩环产物3溶于无水二氯乙烷中,依次加入无水醋酸银、无水醋酸铜、醋酸钯和芳基碘化物进行反应,得到第四反应液,将所述第四反应液冷却后,用有机溶剂稀释,过滤,滤液减压浓缩,然后通过闪过柱层析得到白色固体佛司可林扩环衍生物4,其中佛司可林重排扩环产物3、无水醋酸银、无水醋酸铜、醋酸钯、芳基碘化物的摩尔比为1:1.2:2:0.05:2;
其中,所述芳基碘化物为碘苯、对氯碘苯、对甲氧基碘苯、对三氟甲氧基碘苯、对叔丁基碘苯、对硝基碘苯和对氰基碘苯中的一种。
4.根据权利要求3所述的制备方法,其特征在于,所述步骤S1中,反应温度为65℃,反应时间为4h。
5.根据权利要求3所述的制备方法,其特征在于,所述步骤S2中,反应温度为25℃,反应时间为12h。
6.根据权利要求3所述的制备方法,其特征在于,所述步骤S3中,反应温度为25℃,反应时间为24h。
7.根据权利要求3所述的制备方法,其特征在于,所述步骤S4中,反应温度为70℃,反应时间为12h。
8.根据权利要求3所述的制备方法,其特征在于,所述有机溶剂为甲醇,二氯甲烷,二氯乙烷和乙酸乙酯中的至少一种。
9.权利要求1所述的佛司可林扩环衍生物在制备抗炎药物中的应用。
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