CN1326839C - 2-取代-4,4,5,5-四甲基-1-羟基咪唑啉,及其合成和应用 - Google Patents
2-取代-4,4,5,5-四甲基-1-羟基咪唑啉,及其合成和应用 Download PDFInfo
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- CN1326839C CN1326839C CNB2004100742099A CN200410074209A CN1326839C CN 1326839 C CN1326839 C CN 1326839C CN B2004100742099 A CNB2004100742099 A CN B2004100742099A CN 200410074209 A CN200410074209 A CN 200410074209A CN 1326839 C CN1326839 C CN 1326839C
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- Prior art keywords
- tetramethyl
- tetrahydroglyoxaline
- hydroxyl
- chcl
- phenyl
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Abstract
通式I的化合物,其中,R为取代苯基,或呋喃基,或吡啶基。通式I它们的制备方法,该方法包括Br2存在下2-硝基丙烷缩合生成2,3-二甲基-2,3-二硝基丁烷;在NH4Cl存在下2,3-二甲基-2,3-二硝基丁烷被锌粉还原为2,3-二甲基-2,3-二羟胺基丁烷;2,3-二甲基-2,3-二羟胺基丁烷与取代苯甲醛或糠醛或吡啶甲醛环合,生成1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷;1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷被氧化剂氧化为2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉;在酸性条件下,2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉被还原剂还原为2-取代-4,4,5,5-四甲基-1-氧基咪唑啉;2-取代-4,4,5,5-四甲基-1-氧基咪唑啉被还原为2-取代-4,4,5,5-四甲基-1-羟基咪唑啉。通式I的化合物可以用于舒张血管活性。
Description
技术领域
本发明涉及一类新型2-取代-4,4,5,5-四甲基-1-羟基咪唑啉,及其合成和应用。
背景技术
血管过度紧张可以导致一系列疾病,例如可以导致高血压症。寻找血管舒张药物是新药研究的重点之一。现有的血管舒张药物主要包括ACE抑制剂、α1受体阻滞剂、钙拮抗剂、酞嗪衍生物、钾通道开放剂和硝基血管扩张药。ACE抑制剂因为能够舒张动脉与静脉,所以能降低全身外周血管阻力,降低血压(陈修.肾素-血管紧张素及其抑制剂.见:陈修主编.心血管药理学.第一版北京:人民卫生出版社,1989,237)。ACE抑制剂通过减少AngII的生成缓解血管收缩作用、通过保存BK的作用诱导NO和PGI2生成,进而舒张血管、通过抑制交感神经递质的释放降低交感神经对心血管的张力。α1受体阻滞剂高度选择性阻滞血管平滑肌突触后膜α1受体,对α1受体有高度亲和力,能拮抗α1受体激动剂甲氧明和新福林的血管收缩及升压作用(van Zwieten PA.Development and trends in the drug treatment of essential hypertension.JHypertension 1992,1O(Suppl.7),S1)。钙拮抗剂通过对钙通道的阻滞作用,抑制胞外Ca2+的跨膜内流,降低血管平滑肌细胞内游离Ca2+,而使血管平滑肌松弛。钙拮抗剂主要通过扩张小动脉和降低外周血管阻力产生抗高血压作用。高钾去极化引起的收缩反应是依赖于胞外Ca2+的跨膜内流,在离体血管平滑肌标本实验中钙拮抗剂能抑制胞外Ca2+的跨膜内流(陈修.肾素-血管紧张素及其抑制剂.见:陈修主编.心血管药理学.(第二版)北京:人民卫生出版社,1996,325)。酞嗪衍生物主要作用于小动脉产生广大范围的血管扩张,选择性降低脑动脉、冠脉和肾动脉的血管阻力,而对骨骼肌与皮肤血管作用较小(.GerberJG,Nies AS.Antihypertensive agents and the drug therapy of hypertension,In:Goodman and Gilman’s.The Pharmacological basis of therapeutics.8th ed,Pergamon,New York:Macmillan 1990,784)。钾通道开放剂在体内的代谢产物能增加血管平滑肌细胞膜对K+的通透性、促进胞内K+外流、引起血管平滑肌细胞膜超极化使血管平滑肌松弛和血压下降(Murdoch D.Brogden RN.Sustainedrelease nifedipine formulations.Drugs 1991,41,737)。硝基血管扩张药包括硝酸酯类药和NO供体能释放NO、使cGMP升高而松弛血管平滑肌、还具有抗血小板聚集的作用。硝酸酯类药部分在肝脏代谢以后在血管壁产生NO。NO的受体是可溶性鸟苷酸环化酶上的活性中心铁离子,它们结合后使鸟苷酸环化酶的三维结构发生变化提高酶的活性。细胞内cGMP生成增多抑制PKC磷酸化作用可引起Ca2+内流、降低细胞内Ca2+释放、增加胞内Ca2+排出,最终降低胞内Ca2+浓度。收缩蛋白对Ca2+的敏感性也减弱,肌细胞膜上K+通道的活性也下降,从而导致血管舒张。NO供体如硝普钠、1,2,5-恶二唑、CHF2206均可释放NO扩张血管(Ferioli R et al.a new class of furoxan derivative as NO donors:mechanism of action and biological activety.Br J Pharmacol 1995,114,816;Civellim,et al.CHF2206,a new potent vasodilating and antiaggregating drug aspotential nitric oxide donor. Eur J Pharmacol 1994,255,17;Blatter CA,Wier WGNitric oxide decreases[Ca2+]:in vascular smooth muscle by inhibition of thecalcium current.Cell Calcium 1994,255,17)。
2-取代苯基-4,4,5,5-四甲基-1-氧基咪唑啉属于稳定的氮氧自由基,显著舒张血管,不影响心肌收缩力和循环系统的血液动力学性质(Ryusuke Tsunoda,Ken Okumura. Vasodilator effect of carboxy-2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxylin the coronary circulation:in vivo and invitro studies.European Journal of Pharmacology 1994,262,55-63)。发明人注意到,2-取代-4,4,5,5-四甲基-1-氧基咪唑啉增大血流量而不降低动脉血压、进入血液30分钟后仍有作用。2-取代-4,4,5,5-四甲基-1-氧基咪唑啉的这些优点使它明显区别于临床现有的舒血管药物。发展2-取代-4,4,5,5-四甲基-1-氧基咪唑啉具有明显的意义。
发明内容
本发明所要解决的技术问题是提供一种新型的2-取代-4,4,5,5-四甲基-1-羟基咪唑啉化合物。
本发明所要解决的技术问题还在于提供新型2-取代-4,4,5,5-四甲基-1-羟基咪唑啉化合物的制备方法及其应用。
本发明提供的化合物为如通式I的化合物,
通式I
其中,R为R1 n取代的苯基,或呋喃基,或吡啶基,取代苯基中的取代基为R1 n,n=0、1或2,当n=1时,R1 1为2-羟基、3-羟基、4-羟基、4-甲基、4-甲氧基、2,4-二甲氧基、3,4-二甲氧基、3,4-亚甲二氧、4-二甲氨基、2-氟、4-氯、4-溴、2-硝基、3-硝基、4-硝基;当n=2时,R1 2为3-羟基-4-甲氧基、3-甲氧基-4-羟基、2,4-二氯、3,4-二氯。
本发明还提供了通式I化合物的制备方法,该方法包括:在碱和Br2存在下2-硝基丙烷缩合生成2,3-二甲基-2,3-二硝基丁烷;在NH4Cl存在下2,3-二甲基-2,3-二硝基丁烷被锌粉还原为2,3-二甲基-2,3-二羟胺基丁烷;2,3-二甲基-2,3-二羟胺基丁烷与取代苯甲醛或糠醛或吡啶甲醛环合,生成1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷;1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷被氧化剂氧化为2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉;在酸性条件下,2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉被还原剂还原为2-取代-4,4,5,5-四甲基-1-氧基咪唑啉;2-取代-4,4,5,5-四甲基-1-氧基咪唑啉被还原为2-取代-4,4,5,5-四甲基-1-羟基咪唑啉,即通式I的化合物。
上述合成方法可以用以下过程表示:
其中R的定义如上所述。
本发明还提供了通式I化合物的血管舒张作用。
具体实施方式
为了解释本发明,下面给出一系列实施例。这些实例完全是例证性的,它们仅用来对本发明进行具体描述,不应当理解为对本发明的限制。
通则:中间体和产物的纯度以TLC确认,EI-MS用美国Thermo Finnigan公司的Trace MS System质谱仪测定。红外光谱(IR)采用美国Nicolet公司的Avatar 360傅立叶变换红外光谱仪测定。核磁共振谱(NMR)采用日本电子AL-300 FT NMR System测定。熔点采用北京科仪电光仪器厂生产的X75显微熔点仪测定,温度计未校正。层析用硅胶由青岛海洋化工厂生产。
中间体化合物2,3-二甲基-2,3-二硝基丁烷的制备
34.5g(0.39mol,35ml)2-硝基丙烷加到65ml NaOH(6mol/l)水溶液中。在冰盐浴搅拌条件下,滴加10ml(0.19mol)Br2,1h内滴加完。然后加入128ml乙醇。反应混合物于84℃回流搅拌3h,出现片状不溶物。将反应混合物乘热倒入400ml冰水中。滤出沉淀,得25g(73%)标题化合物,为白色片状结晶,mp110-112℃。
中间体化合物2,3-二甲基-2,3-二羟胺基丁烷的制备
将7.0g(40mmol)2,3-二甲基-2,3-二硝基丁烷和4.0g NH4Cl混悬于80ml乙醇(50%)溶液中。冰浴下搅拌。在3h内加入16.0g锌粉。锌粉加完后,撤去冰浴,继续室温搅拌反应3h,然后将反应液抽滤。滤饼用50%的乙醇水溶液反复洗涤。合并的滤液及洗涤液用浓盐酸调pH为2,减压浓缩至泥浆状。往泥浆状物中加入适量碳酸钾,拌匀后,使用索氏提取器,用氯仿为提取6h。提取液减压浓缩至少量,加入石油醚后析出2.60g(44%)标题化合物,为白色结晶,mp 157-159℃。
实施例1
2-苯基-4,4,5,5-四甲基-1-羟基咪唑啉的制备
212mg(2mmol)苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于3ml甲醇中,室温搅拌16h后,TLC显示原料点消失。滤出401mg(85%)1,3-二羟基-2-苯基-4,4,5,5-四甲基咪唑烷,为白色固体,直接用于下一步反应。样品经TLC纯化后,EI-MS:236.3[M]+;Rf0.64(CHCl3/CH3OH,10∶1),mp:168-169;IR(KBr)3340(OH);1600,1450;1H-NMR(CDCl3-d)δ(ppm)=1.14(s,12H,-CH3),4.78(s,1H,-CH),7.31-7.51(m,5H,Ar-H),7.71(s,2H,N-OH);元素分析:C13H20N2O2计算值为C 66.07,H8.53,N11.85;实测值为C 66.25,H 8.71 N 11.71。
95mg(0.4mmol)1,3-二羟基-2-苯基-4,4,5,5-四甲基二氢咪唑啉溶解于5ml甲醇中。往得到的溶液中加入0.5g PbO2,室温搅拌0.5h后,TLC显示原料点消失。滤去固体。滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得74mg(80%)2-苯基-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝黑色晶体。Rf0.54(CHCl3/CH3OH,20∶1);mp 84-85℃;EI-MS 233[M]+、201[M-32]+,145[M-88]+;IR(KBr)1610,1450(苯环)。元素分析:C13H17N2O2计算值为C66.93 H 7.34,N 12.01;实测值为C 66.69 H 7.55,N 11.98。
250mg(1.07mmol)2-苯基-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中,加入0.5ml水、500mgNaNO2、滴加2N HCl调pH 5,室温搅拌60min,反应液由蓝黑色变成橙红色。减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层,无水硫酸钠干燥。TLC检测为单一点。过滤,滤液室温下减压浓缩至干,得232mg(99%)2-苯基-4,4,5,5-四甲基-1-氧基咪唑啉,为红色油状物,Rf0.61(CHCl3/CH3OH,20∶1);EI-MS(m/z):217[M]+;元素分析:C13H17N2O计算值为C 71.86 H 7.89,N 12.89;实测值为C 71.69 H 7.75,N 12.99。
55mg(0.25mmol)2-苯基-4,4,5,5-四甲基-1-氧基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得38mg(69%)标题化合物,为浅黄色固体,Rf0.15(CHCl3/CH3OH,20∶1);mp 173-175℃;EI-MS(m/z):218[M]+;1H-NMR(CDCl3-d)δ(ppm)=1.15(s,12H,-CH3),7.29-7.62(m,5H,Ar-H);元素分析:C13H18N2O计算值为C 71.53 H 8.31,N 12.83;
实施例2
2-(2’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
244mg(2mmol)水杨醛(2-羟基苯甲醛)与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于1.5ml甲醇中,室温搅拌20h后,TLC显示原料点消失,滤出287mg(57%)1,3-二羟基-2-(2’-羟基苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.73(CHCl3/CH3OH,6∶1)。直接用于下一步反应。样品经TLC纯化,EI-MS:252[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.08(s,12H,-CH3),4.63(s,1H,-CH),6.70(m,2H,Ar-H),7.14(m,2H,Ar-H),8.12(s,1 H,-OH),8.35(s,2H,N-OH);IR(KBr):3325,1600,1500,765。元素分析:C13H20N2O3计算值为C61.88,H 7.99,N 11.10;实测值为C 61.65,H 7.77,N 11.41。
160mg(0.63mmol)1,3-二羟基-2-(2’-羟基苯基)-4,4,5,5-四甲基咪唑烷溶解于40ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌60min后,TLC显示原料点消失。滤去固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得100mg(64%)2-(2’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色固体;Rf0.75(CHCl3/CH3OH,20∶1);mp 83-85℃;EI-MS:249[M]+,217[M-32]+;IR(KBr):3345,1610,1500,1450;760。元素分析:C13H17N2O3计算值为C 62.64,H 6.87,N 11.24;实测值为C 62.80,H 6.65,N 11.41。
50mg(0.21mmol)2-(2’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于5 ml甲醇中、加入0.5ml水、100mg NaNO2、滴加2N HCl调pH5,室温搅拌60min,反应液由紫色变成红色,减压蒸除大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液室温下减压浓缩至干,得47mg(96%)2-(2’-羟基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙红色油状物,Rf0.83(CHCl3/CH3OH,20∶1);EI-MS(m/z):233[M]+;IR(KBr):1610,1450,760。元素分析:C13H17N2O2计算值为C 66.93,H 7.35,N 12.01;实测值为C 66.75,H 7.11,N 12.33。
59mg(0.25mmol)2-(2’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得29mg(49%)标题化合物,为浅黄色固体,Rf0.11(CHCl3/CH3OH,20∶1);mp 137-139℃;EI-MS(m/z):234[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.11(s,12H,-CH3),6.76(m,2H,Ar-H),7.34(m,2H,Ar-H),8.15(s,1H,Ar-OH);元素分析:C13H18N2O2计算值为C 66.64 H 7.74,N11.96;
实施例3
2-(3’-羟苯基)4,4,5,5-四甲基-1-羟基咪唑啉的制备
245mg(2mmol)3-羟基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中,室温搅拌24h,TLC显示原料点消失,滤出304mg(60.3%)1,3-二羟基-2-(3’-羟基苯基)-4,4,5,5-四甲基咪唑烷,为白色粉末,Rf0.56(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化后得到目的物,EI-MS:252[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),4.51(s,1H,-CH),6.89(m,4H,Ar-H),7.71(s,1H,-OH),7.95(s,2H,N-OH);IR(KBr):3320、1600、1500、880、795、695。元素分析:C13H20N2O3计算值为C 61.88,H 7.99,N,11.10;实测值为C 61.67,H 7.74,N,11.31。
252mg(1mmol)1,3-二羟基-2-(3’-羟基苯基)-4,4,5,5--四甲基咪唑烷溶解于40ml甲醇中。往该溶液中加入0.7g PbO2,室温搅拌10min后,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得192mg(76%)2-(3’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色菱形晶体。Rf0.33(CHCl3/CH3OH,20∶1);mp 137-139℃;EI-MS:249[M]+,218[M-31]+;IR(KBr):3340、1590、1500、1450、880、800、690。元素分析:C13H17N2O3计算值为:C 62.64,H 6.87,N 11.24;实测值为C 62.80,H 6.68,N 11.01。
55mg(0.22mmol)2-(3’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于5 ml甲醇中,加入0.5ml水,100mg NaNO2,滴加2N HCl使pH值约为5,室温搅拌60min,反应液由蓝色变成橙黄色,减压蒸去大部分溶剂,残留物用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点,过滤,滤液减压浓缩至干,得29mg(56%)2-(3’-羟基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色油状物,Rf0.52(CHCl3/CH3OH,20∶1);EI-MS(m/z):233[M]+;IR(KBr):3340、1590、880、790。元素分析:C13H17N2O2计算值为:C 66.93,H 7.35,N 12.01;实测值为C 66.70,H 7.52,N 12.24。
59mg(0.25mmol)2-(3’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得32mg(55%)标题化合物,为浅黄色固体,Rf0.10(CHCl3/CH3OH,20∶1);mp 173-174℃;EI-MS(m/z):234[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),7.12(m,4H,Ar-H),7.81(s,1H,Ar-OH);元素分析:C13H18N2O2计算值为C 66.64 H 7.74,N 11.96。
实施例4
2-(4’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
244mg(2mmol)对羟基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于3ml甲醇中,室温搅拌8h后,TLC显示原料点消失。滤得257mg(51%)1,3-二羟基-2-(4’-羟基苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.67(CHCl3/CH3OH,6∶1),直接用于下一步反应。EI-MS:252[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),4.39(s,1H,-CH),6.70(d,J=6.9Hz,2H,Ar-H),7.23(d,J=6.9Hz,2H,Ar-H),7.63(s,1H,Ar-OH),7.85(s,2H,N-OH);IR(KBr):3310、1610、1500、1450、830。元素分析:C13H20N2O3计算值为:C 61.88,H 7.99,N 11.10;实测值为C 61.66,H 7.78,N 11.23。
126mg(0.5mmol)1,3-二羟基-2-(4’-羟基苯基)-4,4,5,5--四甲基咪唑烷溶解于30ml甲醇中。往该溶液中加入300mg PbO2,室温搅拌40min后,TLC显示原料点消失。滤去固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得65mg(52%)2-(4’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为兰色固体。Rf0.13(CHCl3/CH3OH,20∶1);mp134-135℃,EI-MS:249[M]+,218[M-31]+;IR(KBr):3250、1500、1490、840。元素分析:C13H17N2O3计算值为:C 62.64,H 6.87,N 11.24;实测值为C 62.81,H 6.65,N 11.40。
25mg(0.1mmol)2-(4’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于3ml甲醇中,加入0.5ml水,加入50mg NaNO2,滴加2N HCl,直至反应液的颜色变成亮黄色,用饱和碳酸氢钠水溶液调pH=6~7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干,得15mg(65%)2-(4’-羟基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色固体,mp 98-100℃。Rf0.36(CHCl3/CH3OH,20∶1);EI-MS(m/z):235[M+2]+;元素分析:C13H17N2O2计算值为:C 66.93,H 7.35,N,12.01;实测值为C 66.70,H 7.54,N,12.25。
60mg(0.25mmol)2-(3’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得36mg(59%)标题化合物,为浅黄色固体,Rf0.10(CHCl3/CH3OH,20∶1);mp 197-198℃;EI-MS(m/z):234[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),6.76(d,J=6.9Hz,2H,Ar-H),7.45(d,J=6.9Hz,2H,Ar-H),7.73(s,1H,Ar-OH);元素分析:C13H18N2O2计算值为C 66.64 H 7.74,N 11.96。
实施例5
2-(4’-甲基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
240mg(2mmol,0.236 ml)4-甲基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中,室温搅拌12h后,TLC显示原料点消失。滤得350mg(60%)1,3-二羟基-2-(4’-甲基苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.61(CHCl3/CH3OH,10∶1),直接用于下一步反应。EI-MS:250[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.14(s,6H,-CH3),1.19(s,6H,-CH3),1.37(s,3H,-CH3),4.90(s,1H,-CH),7.68(d,J=9.0Hz,2H,Ar-H),8.22(d,J=5.7Hz,2H,Ar-H),8.35(s,2H,N-OH);IR(KBr):3335、2985、1600、1500、815。元素分析:C14H22N2O2计算值为:C 67.17,H 8.86,N 11.19;实测值为C 67.32,H 8.62,N 11.40。
250mg(1mmol)1,3-二羟基-2-(4’-甲基苯基)-4,4,5,5-四甲基咪唑烷溶解于60ml甲醇中。往该溶液中加入0.5g PbO2,室温搅拌30min后,TLC显示原料点消失。滤去固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得197mg(80%)2-(4’-甲基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色固体。Rf0.88(CHCl3/CH3OH,20∶1);mp 86-88℃;EI-MS:247[M]+,215[M-32]+;IR(KBr):2980、1610、1500、1450、810。元素分析:C14H19N2O2计算值为:C 67.99,H 7.74,N,11.33;实测值为C 67.77,H 7.91,N,11.55。
250mg(1mmol)2-(4’-甲基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中,加入0.5ml水、加入500mg NaNO2、滴加2N HCl,直至反应液的颜色变成亮黄色、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥后,TLC检测为单一点,过滤,滤液减压浓缩至干。过滤得200mg(86%)2-(4’-甲基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙黄色固体,mp156-157℃。Rf0.93(CHCl3/CH3OH,20∶1);EI-MS(m/z):231[M]+元素分析:C14H19N2O计算值为C 72.69,H 8.28,N 12.11;实测值为C 72.80,H 8.42,N12.32。
58mg(0.25mmol)2-(4’-甲基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得41mg(70%)标题化合物,为浅黄色固体,Rf0.15(CHCl3/CH3OH,20∶1);mp 79-81℃;EI-MS(m/z):232[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.15(s,12H,-CH3),1.38(s,3H,-CH3),7.50(d,J=9.0Hz,2H,Ar-H),8.12(d,J=5.7Hz,2H,Ar-H);元素分析:C14H20N2O计算值为C 72.38 H 8.68,N12.06。
实施例6
2-(4’-甲氧基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
273mg(2mmol)4-甲氧基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中,室温搅拌16h,TLC显示原料点消失。滤得372mg(70%)1,3-二羟基-2-(4’-甲氧基苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.52(CHCl3/CH3OH,10∶1),直接用于下一步反应。EI-MS:266[M]+;1H-NMR(DMSO-d6)δ(ppm)=0.99(s,6H,-CH3),1.03(s,6H,-CH3),3.73(s,3H,-OCH3),4.56(s,1H,-CH),6.88(d,J=4.2Hz,2H,Ar-H),7.38(d,J=5.7Hz,2H,Ar-H),7.77(s,2H,N-OH);IR(KBr):3340、2835、1600,1500、825。元素分析:C14H22N2O3计算值为C 63.14,H 8.33,N 10.52;实测值为C 63.31,H 8.55,N 10.71。
266mg(1mmol)1,3-二羟基-2-(4’-甲氧基苯基)-4,4,5,5-四甲基咪唑烷溶解于60ml甲醇中。往该溶液中加入0.6g PbO2,室温搅拌30min,TLC显示原料点消失。滤去固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得258mg(97%)2-(4’-甲氧基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色固体,Rf0.54(CHCl3/CH3OH,20∶1);mp 89-92℃;EI-MS:263[M]+,231[M-32]+;IR(KBr):2830、1600、835。元素分析:C14H19N2O3计算值为C63.86,H 7.27,N 10.64;实测值为C 63.64,H 7.41,N 10.42。
250mg(0.95mmol)2-(4’-甲氧基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中,加入0.5ml水,500mg NaNO2,滴加2N HCl调pH5,室温搅拌60min,反应液由蓝黑色变成朱红色,减压蒸除大部分溶剂,用饱和碳酸氢钠水溶液调pH=6~7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点,过滤,滤液减压浓缩至干,得212mg(86%)2-(4’-甲氧基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为红色固体;mp 42-43℃,Rf0.63(CHCl3/CH3OH,20∶1);EI-MS(m/z):247[M]+;IR(KBr):2830、1610、840。元素分析:C14H19N2O2计算值为C 67.99,H 7.74,N,11.33;实测值为C 67.77,H 7.55,N 11.55。
62mg(0.25mmol)2-(4’-甲氧基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg(含水45%)5%Pd/C粉末,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得51mg(83%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp 81-83℃;EI-MS(m/z):248[M)+;1H-NMR(DMSO-d6)δ(ppm)=1.01(s,12H,-CH3),3.73(s,3H,-OCH3),6.80(d,J=4.2Hz,2H,Ar-H),7.51(d,J=5.7Hz,2H,Ar-H);元素分析:C14H20N2O2计算值为C 67.71 H8.12,N11.28。
实施例7
2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
332mg(2mmol)2,4-二甲氧基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于5ml甲醇中,室温搅拌20h,TLC显示原料点消失。滤得349mg(59%)1,3-二羟基-2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.49(CHCl3/CH3OH,10∶1)。直接用于下一步反应。样品经TLC纯化后得到目的物,EI-MS:296[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,12H,-CH3),3.72(s,6H,-OCH3),4.99(s,1H,-CH),7.45(m,3H,Ar-H),7.79(s,2H,N-OH);IR(KBr):3295、2825、1600、1500、1450、810、865。元素分析:C15H24N2O4计算值为C 60.79,H 8.16,N 9.45;实测值为C 60.54,H 8.38,N 9.66。
296mg(1mmol)1,3-二羟基-2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌15min,TLC显示原料点消失。滤去固体,滤液减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得249mg(85%)2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为紫色固体,Rf0.37(CHCl3/CH3OH,20∶1);mp 75-77℃;EI-MS:293[M]+,261[M-32]+;IR(KBr):2830、1610、1590、1450、805、870。元素分析:C15H21N2O4计算值为C 61.42,H 7.22,N 9.55;实测值为C 61.61,H 7.43,N 9.72。
290mg(1mmol)2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH 5,室温搅拌60min,反应液由蓝色变成橙黄色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点,过滤,滤液减压浓缩至干。得178mg(64%)2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色固体,mp 77-79℃;Rf0.41(CHCl3/CH3OH,20∶1);EI-MS(m/z):277[M]+;IR(KBr):2850、1610、1590、1500、805、830。元素分析:C15H21N2O3计算值为C 64.96,H 7.63,N 10.10;实测值为C 64.72,H 7.41,N 10.22。
69mg(0.25mmol)2-(2’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得43mg(63%)标题化合物,为浅黄色固体,Rf0.12(CHCl3/CH3OH,20∶1);mp 97-99℃;EI-MS(m/z):278[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,12H,-CH3),3.73(s,6H,-OCH3),7.32(m,3H,Ar-H);元素分析:C15H22N2O3计算值为C 64.73 H7.97,N 10.06。
实施例8
2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-羟咪唑啉的制备
677mg(4mmol)3,4-二甲氧基苯甲醛与292mg(4mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于4ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得390mg(33%)1,3-二羟基-2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.52(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化后得到目的物,EI-MS:296[M]+;1H-NMR(DMSO-d6):δ(ppm)=1.05(s,12H,-CH3),3.74(s,6H,-OCH3),4.53(s,1H,-CH),6.85(m,3H,Ar-H),7.85(s,2H,N-OH);IR(KBr):3310、2825、1610、1500、815、865。元素分析:C15H24N2O4计算值为C 60.79,H 8.16,N,9.45;实测值为C 60.55,H8.01,N,9.67。
296mg(1mmol)1,3-二羟基-2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基咪唑烷溶解于100ml甲醇中。往该溶液中加入1.0g PbO2,室温搅拌20min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得246mg(83%)2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色方形晶体。Rf0.34(CHCl3/CH3OH,20∶1);mp 95-97℃;EI-MS:293[M]+;IR(KBr):2830、1600、1450、820、870。元素分析:C15H21N2O4计算值为:C 61.42,H 7.22,N 9.55;实测值为C 61.63,H 7.01,N 9.34。
290mg(1mmol)2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH 5,室温搅拌60min,反应液由蓝色变成橙黄色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩,得138mg(50%)2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色固体,mp74-75℃;Rf0.43(CHCl3/CH3OH,20∶1);EI-MS(m/z):277[M]+。元素分析:C15H21N2O3计算值为C 64.96,H 7.63,N 10.10;实测值为C 64.72,H 7.41,N 10.31。
69mg(0.25mmol)2-(3’,4’-二甲氧苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得27mg(40%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp 89-90℃;EI-MS(m/z):278[M]+;1H-NMR(DMSO-d6):δ(ppm)=1.05(s,12H,-CH3),3.75(s,6H,-OCH3),6.93(m,3H,Ar-H);元素分析:C15H22N2O3计算值为C 64.73,H 7.97,N 10.06。
实施例9
2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
300mg(2mmol)胡椒醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于4ml甲醇中,室温搅拌24h,TLC显示原料点消失,滤得240mg(43%)1,3-二羟基-2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.47(CHCl3/CH3OH,10∶1)。直接用于下一步反应。样品经TLC纯化后,EI-MS:280[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.11(s,12H,-CH3),4.66(s,1H,-CH),5.99(s,2H,-CH2),6.90(m,3H,Ar-H),7.83(s,2H,N-OH);IR(KBr):3315、1600、1235、1105、910。元素分析:C14H20N2O4计算值为C 59.99,H 7.19,N 9.99;实测值为C 59.78,H 7.01,N 9.75。
200mg(0.71mmol)1,3-二羟基-2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基咪唑烷溶解于60ml甲醇中,往该溶液中加入0.8g PbO2,室温搅拌15min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得162mg(64%)2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色固体。Rf0.75(CHCl3/CH3OH,20∶1);mp 97-99℃;EI-MS:277[M]+,246[M-32]+;IR(KBr):1600、1240、1100、910。元素分析:C14H17N2O4计算值为C 60.64,H 6.18,N 10.10;实测值为C 60.82,H 6.36,N 10.32。
300mg(1.1mmol)2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH为5,室温搅拌60min,反应液由蓝色变成橙红色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH为6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液室温下减压浓缩至干。得230mg(81%)2-(3’, 4’-亚甲二氧苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙红色固体,mp 46-47℃;Rf0.82(CHCl3/CH3OH,20∶1);EI-MS(m/z):261[M]+;IR(KBr):1450、935、1260、3420。元素分析:C14H17N2O3计算值为C 64.35,H 6.56,N,10.72;实测值为C 64.14,H 6.33,N,10.91。
65mg(0.25mmol)2-(3’,4’-亚甲二氧苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得47mg(72%)标题化合物,为浅黄色固体,Rf0.12(CHCl3/CH3OH,20∶1);mp109-110℃;EI-MS(m/z):262[M]+;1H-MR(DMSO-d6)δ(ppm)=1.15(s,12H,-CH3),5.99(s,2H,-CH2),7.02(m,3H,Ar-H);元素分析:C14H18N2O3计算值为C 64.73 H7.97,N 10.06;
实施例10
2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
304mg(2mmol)3-羟基,4-甲氧基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于4ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得276mg(49%)1,3-二羟基-2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.52(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS:282[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.04(s,6H,-CH3)3.72(s,3H,-OCH3),4.53(s,1H,-CH),6.82(s,2H,Ar-H),6.94(s,1H,Ar-H),7.65(s,1H,-OH),8.04(s,2H,N-OH);IR(KBr):3340、2825、1600、1500、1450、825。元素分析:C14H22N2O4计算值为C 59.56,H7.85,N 9.92;实测值为C 59.24,H 7.62,N 9.71。
141mg(0.5mmol)1,3-二羟基-2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌20min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得95mg(68%)2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色晶体。Rf0.34(CHCl3/CH3OH,20∶1);mp 117-119℃;EI-MS:279[M]+,247[M-32]+;IR(KBr):3320、2830、1590、1500、1460、820。元素分析:C14H19N2O4计算值为C 60.20,H 6.86,N 10.03;实测值为C 60.41,H 7.01,N 10.10。
250mg(0.9mmol)2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5,室温搅拌60min,反应液由蓝色变成橙黄色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干,得106mg(45%)2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色固体,mp70-71℃;Rf0.45(CHCl3/CH3OH,20∶1);EI-MS(m/z):263[M]+。元素分析:C14H19N2O3计算值为C 63.86,H 7.27,N 10.64;实测值为C 63.65,H 7.05,N 10.81。
65mg(0.25mmol)2-(3’-羟基-4’-甲氧基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25 mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得26mg(40%)标题化合物,为浅黄色固体,Rf0.19(CHCl3/CH3OH,20∶1);mp 156-157℃;EI-MS(m/z):264[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.05(s,12H,-CH3),3.73(s,3H,-OCH3),6.63(s,2H,Ar-H),6.98(s,1H,Ar-H),7.07(s,1H,Ar-H),7.59(s,1H,Ar-OH);元素分析:C14H20N2O3计算值为C 63.62,H 7.63,N 10.60。
实施例11
2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
304mg(2mmol)3-甲氧基,4-羟基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得186mg(33%)1,3-二羟基-2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.47(CHCl3/CH3OH,6∶1)。直接用于下一步反应。样品经TLC纯化后,EI-MS:282[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.00(s,6H,-CH3),1.03(s,6H,-CH3),3.74(s,3H,-OCH3),4.41(s,1H,-CH),6.70(d,J=7.8Hz,1H,Ar-H),6.85(d,J=8.1Hz,1H,Ar-H),7.02(s,1H,Ar-H),7.68(s,1H,-OH),8.05(s,2H,N-OH);IR(KBr):3310、2840、1600、1500、1450、 815、870。元素分析:C14H22N2O4计算值为C 59.56,H 7.85,N 9.92;实测值为C59.33,H 7.62,N 9.70。
141mg(0.5mmol)1,3-二羟基-2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌15min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得100mg(71%)2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色固体,Rf0.38(CHCl3/CH3OH,20∶1);mp 83-85℃;EI-MS:279[M]+,247[M-32]+;IR(KBr):3340、2830、1590、1490、1450、820、875。元素分析:C14H19N2O4计算值为C 60.20,H 6.86,N 10.03;实测值为C 60.41,H 7.02,N 9.88。
250mg(0.9mmol)2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5,室温搅拌60min,反应液由蓝色变成橙黄色,减压蒸除大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干。得95mg(40%)2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色油状物,Rf0.50(CHCl3/CH3OH,20∶1);EI-MS(m/z):263[M]+。元素分析:C14H19N2O3计算值为C 63.86,H 7.27,N 10.64;实测值为C 63.65,H 7.04,N 10.42。
65mg(0.25mmol)2-(3’-甲氧-4’-羟基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得21mg(32%)标题化合物,为浅黄色固体,Rf0.11(CHCl3/CH3OH,20∶1);mp113-115℃;EI-MS(m/z):264[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.02(s,12H,-CH3),3.74(s,3H,-OCH3),6.65(d,J=7.8Hz,1H,Ar-H),6.96(d,J=8.1Hz,1H,Ar-H),7.01(s,1H,Ar-H),7.62(s,1H,Ar-OH);元素分析:C14H20N2O3计算值为C 63.62,H 7.63,N 10.60。
实施例12
2-(4’-二甲氨基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
298mg(2mmol)4-N,N-二甲基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于4ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得173mg(31%)1,3-二羟基-2-(4’-二甲氨基苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.53(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化,EI-MS:279[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),2.85(s,6H,-CH3),4.01(s,1H,-CH),6.68(d,J=8.7Hz,2H,Ar-H),7.25(d,2H,J=8.7Hz,Ar-H),7.60(s,2H,N-OH);IR(KBr):3345、2840、1595、1450、840。元素分析:C15H25N3O2计算值为C 64.49,H 9.02,N 15.04;实测值为C 64.70,H 9.23,N 15.25。
140mg(0.5mmol)1,3-二羟基-2-(4’-二甲氨基苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌40min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得92mg(66%)2-(4’-二甲氨基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色晶体,Rf0.51(CHCl3/CH3OH,20∶1);mp 151-154℃;EI-MS:276[M]+,244[M-32]+;IR(KBr):2850、1595、1500、845。元素分析:C15H22N3O2计算值为C 65.19,H 8.02,N 15.21;实测值为C 65.41,H 8.25,N 15.00。
250mg(0.96mmol)2-(4’-二甲氨基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mgNaNO2、滴加2NHCl调pH5,室温搅拌60min,反应液由蓝色变成橙黄色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩,得117mg(47%)2-(4’-二甲氨基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为黄色固体,mp85-86℃;Rf0.67(CHCl3/CH3OH,20∶1);EI-MS(m/z):260[M]+。元素分析:C15H22N3O计算值为C 69.20,H 8.52,N 16.14;实测值为C 69.41,H 8.74,N 16.01。
65mg(0.25mmol)2-(4’-二甲氨基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得29mg(45%)标题化合物,为浅黄色固体,Rf0.11(CHCl3/CH3OH,20∶1);mp 65-67℃;EI-MS(m/z):261[M]+;1H-NMP(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.05(s,6H,-CH3),2.85(s,6H,-CH3),6.62(d,J=8.7Hz,2H,Ar-H),7.44(d,2H,J=8.7Hz,Ar-H);元素分析:C15H23N3O计算值为C 68.93 H8.87,N 16.08;
实施例13
2-(2’-氟苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
248mg(2mmol)2-氟苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于3ml甲醇中,室温搅拌24h,TLC显示原料点消失,滤得366mg(72%)1,3-二羟基-2-(2’-氟苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶。Rf0.69(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS:254[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.07(s,12H,-CH3),4.95(s,1H,-CH),7.18(m,2H,Ar-H),7.68(dd,J=8.7Hz,2H,Ar-H),8.14(s,2H,N-OH);IR(KBr):3310、1600、1500、1130、1235、775。元素分析:C13H19N2O2F计算值为C 61.40,H 7.53,N 11.02;实测值为C 61.21,H 7.32,N11.24。
254mg(1mmol)1,3-二羟基-2-(2’-氟苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌30min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得218mg(87%)2-(2’-氟苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色晶体。Rf0.52(CHCl3/CH3OH,20∶1);mp 112-114℃;EI-MS:251[M]+,219[M-32]+;IR(KBr):1610、1450、1135、1230、770。元素分析:C13H16N2O2F计算值为C 62.14,H 6.42,N 11.15;实测值为C 62.36,H 6.65,N 11.47。
250mg(1.06mmol)2-(2’-氟苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5,室温搅拌60min,反应液由蓝黑色变成橙红色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干。得一红色粘稠液体219mg(88%)2-(2’-氟苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为红色粘稠液体,Rf0.69(CHCl3/CH3OH,20∶1);EI-MS(m/z):235[M]+。元素分析:C13H16N2OF计算值为C 66.36,H 6.85,N 11.91;实测值为C 66.58,H 6.66,N 11.70。
59mg(0.25mmol)2-(2’-氟苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得44mg(76%)标题化合物,为浅黄色固体,Rf0.12(CHCl3/CH3OH,20∶1);mp 111-112℃;EI-MS(m/z):236[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.11(s,12H,-CH3),7.06-7.60(m,4H,Ar-H);元素分析:C13H17N2OF计算值为C 66.08,H7.25,N 11.86;
实施例14
2-(4’-氯苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
281mg(2mmol)对氯苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中,室温搅拌12h,TLC显示原料点消失。滤得330mg(61%)1,3-二羟基-2-(4’-氯苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.73(CHCl3/CH3OH,10∶1),直接用于下一步反应。EI-MS:270[M]+;1H-NMR(CDCl3-d)δ(ppm)=1.03(s,6H,-CH3),1.07(s,6H,-CH3),4.50(s,1H,-CH),7.38(d,J=8.7Hz,2H,Ar-H),7.48(d,J=8.4Hz,2H,Ar-H),7.80(s,2H,N-OH);IR(KBr):3325、1600、1500、1085、825。元素分析:C13H19N2O2Cl计算值为C57.67,H 7.07,N 10.35;实测值为C 57.44,H 7.25,N 10.13。
250mg(0.92mmol)1,3-二羟基-2-(4’-氯苯基)-4,4,5,5-四甲基咪唑烷溶解于30ml甲醇中。往该溶液中加入0.5g PbO2。室温搅拌10min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得240mg(97%)2-(4’-氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色细小针状晶体。Rf0.67(CHCl3/CH3OH,20∶1);mp 103-105℃;EI-MS:267[M]+,179[M-88]+;IR(KBr):1590、1500、1090(Cl)、820。元素分析:C13H16N2O2Cl计算值为C 58.32,H 6.02,N 10.46;实测值为C 58.55,H 6.25,N 10.23。
250mg(0.99mmol)2-(4’-氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5,室温搅拌60min,反应液由蓝黑色变成橙红色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干,得208mg(83%)2-(4’-氯苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为红色粘稠液体,Rf0.73(CHCl3/CH3OH,20∶1);EI-MS(m/z):251[M]+;IR(KBr):1600、1090、835。元素分析:C13H16N2OCl计算值为C 62.03,H 6.41,N 11.13;实测值为C 62.25,H 6.64,N 11.35。
63mg(0.25mmol)2-(4’-氯苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得46mg(73%)标题化合物,为浅黄色固体,Rf0.14(CHCl3/CH3OH,20∶1);mp 94-95℃;EI-MS(m/z):252[M]+;1H-NMR(CDCl3-d)δ(ppm)=1.05(s,6H,-CH3),1.07(s,6H,-CH3),7.30(d,J=8.7Hz,2H,Ar-H),7.56(d,J=8.4Hz,2H,Ar-H);元素分析:C13H17N2OCl计算值为C 61.78,H 6.78,N 11.08;
实施例15
2-(4’-溴苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
370mg(2mmol)对溴苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于2ml甲醇中。反应液室温搅拌16h,TLC显示原料点消失。滤得320mg(51%)1,3-二羟基-2-(4’-溴苯基)-4,4,5,5-四甲基咪唑烷,为无色固体,直接用于下一步反应。样品经TLC纯化后,EI-MS:314[M]+;Rf0.69(CHCl3/CH3OH,10∶1);IR(KBr):3310、1590、1450、1075、830。1H-NMR(CDCl3-d)δ(ppm)=1.14(s,12H,-CH3),4.77(s,1H,-CH),7.37(d,J=8.4Hz,2H,Ar-H),7.47(d,J=7.8Hz,2H,Ar-H),7.73(s,2H,N-OH)。元素分析:C13H19N2O2Br计算值为C 49.54,H 6.08,N 8.89;实测值为C 49.67,H 6.31,N 8.66。
250mg(0.8mmol)1,3-二羟基-2-(4’-溴苯基)-4,4,5,5-四甲基咪唑烷溶解于30ml甲醇中。往该溶液中加入0.5g PbO2。搅拌10min,滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得230mg(93%)2-(4’-溴苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色细小针状晶体。Rf0.85(CHCl3/CH3OH,20∶1);mp 89-91℃,EI-MS:311[M]+,279[M-32]+;IR(KBr):1600、1450、1070、825。元素分析:C13H16N2O2Br计算值为C 50.02,H 5.17,N,8.97;实测值为C 50.23,H 5.38,N,8.75。
250mg(0.8mmol)2-(4’-溴苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH 5、室温搅拌60min,反应液由蓝黑色变成橙红色,减压浓缩除去大部分溶剂,用饱和碳酸氢钠水溶液调pH 6-7,氯仿萃取,合并氯仿层,无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干,得232mg(98%)2-(4’-溴苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为红色固体,mp45-47℃;Rf0.95(CHCl3/H3OH,20∶1);EI-MS(m/z):296[M]+;IR(KBr):1590、1480、1070、840。元素分析:C13H16N2OBr计算值为C 52.72,H 5.44,N 9.46;实测值为C 52.92,H 5.67,N 9.67。
73mg(0.25mmol)2-(4’-溴苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得59mg(81%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp73-75℃;EI-MS(m/z):297[M]+;1H-NMR(CDCl3-d)δ(ppm)=1.15(s,12H,-CH3),7.46(d,J=8.4Hz,2H,Ar-H),7.5 1(d,J=7.8Hz,2H,Ar-H)。元素分析:C13H17N2OBr计算值为C52.54,H5.77,N 9.43。
实施例16
2-(2’,4’-二氯苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
350mg(2mmol)2,4-氯苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于3ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得427mg(70%)1,3-二羟基-2-(2’,4’-二氯苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.69(CHCl3/CH3OH,10∶1)。直接用于下一步反应。样品经TLC纯化后,EI-MS:305[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.11(s,12H,-CH3),5.01(s,1H,-CH),7.52(m,3H,Ar-H),7.79(s,2H,N-OH);IR(KBr):3315、1590、1450、995、820、865。元素分析:C13H18N2O2Cl2计算值为C 51.16,H 5.94,N 9.18;实测值为C 51.37,H 5.72,N 9.37。
305mg(1mmol)1,3-二羟基-2-(2’,4’-二氯苯基)-4,4,5,5-四甲基咪唑烷溶解于80ml甲醇中,往该溶液中加入1.0g PbO2,室温搅拌40min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得265mg(88%)2-(2’,4’-二氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为紫色固体,Rf0.54(CHCl3/CH3OH,20∶1);mp 123-125℃;EI-MS:302[M]+,270[M-32]+;IR(KBr):1590、1450、1000、825、870。元素分析:C13H15N2O2Cl2计算值为C 51.67,H 5.00,N 9.27;实测值为C 51.88,H 5.21,N 9.46。
300mg(1mmol)2-(2’,4’-二氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5、室温搅拌60min、反应液由蓝色变成橙黄色,减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥后,TLC检测为单一点。过滤,滤液减压浓缩至干。得255mg(90%)2-(2’,4’-二氯苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橘红色晶体,mp96-97℃Rf0.66(CHCl3/CH3OH,20∶1);EI-MS(m/z):286[M]+;IR(KBr):1600、1460、1000、825、870。元素分析:C13H15N2OCl2计算值为C 54.56,H 5.28,N 9.79;实测值为C 54.35,H 5.19,N 9.58。
71mg(0.25mmol)2-(2’,4’-二氯苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得57mg(79%)标题化合物,为浅黄色固体,Rf0.15(CHCl3/CH3OH,20∶1);mp 86-89℃;EI-MS(m/z):287[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.12(s,12H,-CH3),7.18-7.50(m,3H,Ar-H);元素分析:C13H16N2OCl2计算值为C 54.37,H 5.62,N 9.75。
实施例17
2-(3’,4’-二氯苯基)-4,4,5,5-四甲基1-羟咪唑啉的制备
1.75g(10mmol)3,4-氯苯甲醛与1.48g(10mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于10ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得2.13g(70%)1,3-二羟基-2-(3’,4’-二氯苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.69(CHCl3/CH3OH,10∶1)。直接用于下一步反应。样品经TLC纯化后,EI-MS(m/z):305[M]+。1H-NMR(DMSO-d6)δ(ppm)=1.06(s,12H,-CH3),4.99(s,1H,-CH),7.66(m,3H,Ar-H),7.92(s,2H,N-OH)。元素分析:C13H18N2O2Cl2计算值为C51.16,H 5.94,N 9.18;实测值为C 51.37,H 5.75,N 9.27。
610mg(2mmol)1,3-二羟基-2-(3’,4’-二氯苯基)-4,4,5,5-四甲基咪唑烷溶解于80ml甲醇中,加入3g PbO2,室温搅拌40min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干,残留物柱层析分离(氯仿为洗脱剂),得530mg(88%)2-(3’,4’-二氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为紫色固体,Rf0.54(CHCl3/CH3OH,20∶1);mp:123-125℃;EI-MS(m/z):302[M]+。元素分析:C13H15N2O2Cl2计算值为C 51.67,H 5.00,N 9.27;实测值为C51.45,H 5.22,N 9.46。
250mg(0.83mmol)2-(3’,4’-二氯苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5,室温搅拌60min、反应液由蓝色变成橙黄色、减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,滤液室温下减压浓缩至干,得178mg(75%)2-(3’,4’-二氯苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橘红色晶体,mp 66-67℃;Rf0.71(CHCl3/CH3OH,20∶1);EI-MS(m/z):286[M]+。元素分析:C13H15N2OCl2计算值为C 54.56,H 5.28,N 9.79;实测值为C 54.37,H 5.09,N 9.58。
71mg(0.25mmol)2-(3’,4’-二氯苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得49mg(69%)标题化合物,为浅黄色固体,Rf0.19(CHCl3/CH3OH,20∶1);mp 83-85℃;EI-MS(m/z):287[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.09(s,12H,-CH3),7.24-7.57(m,3H,Ar-H)。元素分析:C13H16N2OCl2计算值为C 54.37,H 5.62,N 9.75。
实施例18
2-(2,-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
302mg(2mmol)2-硝基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于5ml甲醇中,室温搅拌18h,TLC显示原料点消失,滤得410mg(73%)1,3-二羟基-2-(2’-硝基苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.54(CHCl3/CH3OH,10∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS:281[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.00(s,6H,-CH3),1.04(s,6H,-CH3),5.37(s,1H,-CH),7.52(d,J=6.6Hz,1H,Ar-H),7.72(m,2H,Ar-H),8.05(d,J=7.2Hz,1H,Ar-H),8.23(s,2H,N-OH);IR(KBr):3325、1535、1365、1600、1450、750。元素分析:C13H19N3O4计算值为C 55.51,H 6.81,N 14.94;实测值为C 55.73,H 6.99,N 14.72。
281mg(1mmol)1,3-二羟基-2-(2’-硝基苯基)-4,4,5,5-四甲基咪唑烷溶解于50 ml甲醇中,往该溶液中加入0.5g PbO2,室温搅拌40min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得208mg(75%)2-(2’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色晶体,Rf0.49(CHCl3/CH3OH,20∶1);mp 145-147℃;EI-MS:278[M]+,246[M-32]+;IR(KBr):1530、1360、1450、740。元素分析:C13H16N3O4计算值为C 56.11,H 5.79,N 15.10;实测值为C 56.33,H 5.57,N 15.31。
130mg(0.47mmol)2-(2’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于10ml甲醇中、加入0.5ml水、250mg NaNO2、滴加2N HCl调pH 5、室温搅拌60min、反应液由深蓝色变成橙黄色、减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,滤液减压浓缩至干,得89mg(72%)2-(2’-硝基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙色晶体,mp74-75℃;Rf0.52(CHCl3/CH3OH,20∶1);EI-MS(m/z):262[M]+。元素分析:C13H16N3O3计算值为C 59.53,H 6.15,N 16.02;实测值为C 59.74,H 6.36,N 16.21。
65mg(0.25mmol)2-(2’-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得46mg(71%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp 113-115℃;EI-MS(m/z):263[M]+;1H-NMR(DMSO-d6)δ(ppm)=0.99(s,6H,-CH3),1.04(s,6H,-CH3),7.55(d,J=6.6Hz,1H,Ar-H),7.68(m,1H,Ar-H),7.88(m,1H,Ar-H),8.22(d,J=7.2Hz,1H,Ar-H);元素分析:C13H17N3O3计算值为C 59.30,H 6.51,N 15.96。
实施例19
2-(3’-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
302mg(2mmol)3-硝基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于4ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得421mg(75%)1,3-二羟基-2-(3’-硝基苯基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.51(CHCl3/CH3OH,10∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS:281[M]+;1H-NMR(DMSO-d6)δ(ppm)=0.52(s,12H,-CH3),4.19(s,1H,-CH),7.04(dd,J=8.7Hz,J=8.1Hz,1H,Ar-H),7.34(d,J=6.0Hz,1H,Ar-H),7.57(d,J=7.5Hz,1H,Ar-H),7.77(s,1H,Ar-H),8.03(s,2H,N-OH);IR(KBr):3315、1530、1360、1600、1500、875、790、685。元素分析:C13H19N3O4计算值为C 55.51,H 6.81,N 14.94;实测值为C 55.74,H 6.60,N 14.72。
281mg(1mmol)1,3-二羟基-2-(3’-硝基苯基)-4,4,5,5-四甲基咪唑烷溶解于50ml甲醇中。往该溶液中加入0.7g PbO2,室温搅拌20min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得216mg(78%)2-(3’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为深蓝绿色固体。Rf0.69(CHCl3/CH3OH,20∶1);mp 162℃;EI-MS:278[M]+,247[M-31]+;IR(KBr):1530、1350、1600、1450、880、790、680。元素分析:C13H16N3O4计算值为C 56.11,H 5.79,N 15.10;实测值为C 56.32,H 5.97,N 15.31。
250mg(0.9mmol)2-(3’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于20ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5、室温搅拌60min、反应液由深蓝色变成橙黄色、减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,滤液减压浓缩至干,得172mg(73%)2-(3’-硝基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙色晶体,mp71-72℃;Rf0.78(CHCl3/CH3OH,20∶1);EI-MS(m/z):262[M]+;IR(KBr):1530、1350、1600、1450、800、680。元素分析:C13H16N3O3计算值为C 59.53,H 6.15,N 16.02;实测值为C 59.34,H 6.36,N 16.23。
65mg(0.25mmol)2-(3’-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得43mg(66%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp 97-99℃;EI-MS(m/z):263[M]+;1H-NMR(DMSO-d6)δ(ppm)=0.67(s,12H,-CH3),7.14-7.45(m,3H,Ar-H);元素分析:C13H17N3O3计算值为C 59.30,H 6.51,N 15.96。
实施例20
2-(4’-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
302mg(2mmol)对硝基苯甲醛与296mg(2mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于6ml甲醇中,室温搅拌12h,TLC显示原料点消失。滤得355mg(63%)1,3-二羟基-2-(4’-硝基苯基)-4,4,5,5-四甲基咪唑烷,为无色结晶,Rf0.59(CHCl3/CH3OH,10∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS:281[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.00(s,6H,-CH3),1.05(s,6H,-CH3),4.71(s,1H,-CH),7.70(d,J=9.0Hz,2H,Ar-H),8.21(d,J=7.2Hz,2H,Ar-H),8.40(s,2H,N-OH)。IR(KBr):3325、1365(NO2)、1590、1500、1450、835。元素分析:C13H19N3O4计算值为C 55.51,H 6.81,N 14.94;实测值为C 55.72,H 6.60,N 14.73。
281mg(1mmol)1,3-二羟基-2-(4’-硝基苯基)-4,4,5,5--四甲基咪唑烷溶解于50ml甲醇中。往该溶液中加入0.7g PbO2,室温搅拌40min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干。残留物柱层析分离(氯仿为洗脱剂),得203mg(73%)2-(4’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为黄绿色晶体。Rf0.65(CHCl3/CH3OH,20∶1);mp 175-176℃;EI-MS:278[M]+,246[M-32]+;IR(KBr):1360、1600、1500、1450、830。元素分析:C13H16N3O4计算值为C 56.11,H 5.79,N 15.10;实测值为C 56.34,H 5.58,N 15.32。
300mg(1.08mmol)2-(4’-硝基苯基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于15ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5、室温搅拌60min、反应液由蓝绿色变成红色、减压蒸除大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,,滤液减压浓缩至干,得200mg(71%)2-(4’-硝基苯基)-4,4,5,5-四甲基-1-氧基咪唑啉,为红色晶体,mp119-120℃;Rf0.74(CHCl3/CH3OH,20∶1);EI-MS(m/z):262[M]+;IR(KBr):1350、1520、1600、1450、1450、860。元素分析:C13H16N3O3计算值为C 59.53,H 6.15,N 16.02;实测值为C 59.32,H 6.36,N 16.24。
65mg(0.25mmol)2-(4’-硝基苯基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得41mg(63%)标题化合物,为浅黄色固体,Rf0.13(CHCl3/CH3OH,20∶1);mp 131-132℃;EI-MS(m/z):263[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,12H,-CH3),7.88(d,J=9.0Hz,2H,Ar-H),8.22(d,J=7.2Hz,2H,Ar-H)。元素分析:C13H17N3O3计算值为C 59.30,H 6.51,N 15.96。
实施例21
2-呋喃基-4,4,5,5-四甲基-1-羟基咪唑啉的制备
1.3g(13.6mmol,1.12ml)糠醛与2g(13.6mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于15ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得1.86g(61%)1,3-二羟基-2-呋喃基-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf0.34(CHCl3/CH3OH,10∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS(m/z):226[M]+;1H-NMR (DMSO-d6)δ(ppm)=1.04(s,12H,-CH3),4.59(s,1H,-CH),6.37(s,2H,=C-H),7.58(s,1 H,=C-H),7.92(s,2H,N-OH)。元素分析:C11H18N2O3计算值为C 58.39,H,8.02,N 12.38;实测值为C 58.60,H,8.24,N 12.16。
1.0g(4.4mmol)1,3-二羟基-2-呋喃基-4,4,5,5-四甲基咪唑烷溶解于100ml甲醇中、加入2.7g PbO2、室温搅拌60min、TLC显示原料点消失、滤除固体、滤液室温下减压浓缩至干、柱层析分离(氯仿为洗脱剂)、得658mg(67%)2-呋喃基-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝色晶体,Rf0.59(CHCl3/CH3OH,20∶1);EI-MS(m/z):223[M]+,191[M-32]+。元素分析:C11H15N2O3计算值为C59.18,H 6.77,N 12.55;实测值为C 59.01,H 6.58,N 12.76。
200mg(0.9mmol)2-呋喃基-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于10ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5、室温搅拌60min、反应液由蓝色变成红色、减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,滤液减压浓缩至干,得144mg(77%)2-呋喃基-4,4,5,5-四甲基-1-氧基咪唑啉,为橙红色油状物,Rf0.69(CHCl3/CH3OH,20∶1);EI-MS(m/z):207[M]+。元素分析:C11H16N2O2计算值为C 63.75,H 7.30,N 13.52;实测值为C 63.54,H 7.48,N 13.31。
51mg(0.25mmol)2-呋喃基-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得37mg(72%)标题化合物,为浅黄色固体,Rf0.12(CHCl3/CH3OH,20∶1);mp 95-96℃;EI-MS(m/z):208[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.05(s,12H,-CH3),6.30(s,2H,=C-H),7.40(s,1H,=C-H)。元素分析:C11H16N2O2计算值为C 63.44,H 7.74,N13.45。
实施例22
2-(3’-吡啶基)-4,4,5,5-四甲基-1-羟基咪唑啉的制备
1.07g(10mmol)3-吡啶甲醛与1.48g(10mmol)2,3-二甲基-2,3-二羟胺基丁烷溶于10ml甲醇中,室温搅拌20h,TLC显示原料点消失,滤得1.63g(69%)1,3-二羟基-2-(3’-吡啶基)-4,4,5,5-四甲基咪唑烷,为无色粉末,Rf051(CHCl3/CH3OH,6∶1),直接用于下一步反应。样品经TLC纯化后,EI-MS(m/z):238[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.04(s,6H,-CH3),1.07(s,6H,-CH3),4.55(s,1H,-CH),7.35(s,1H,Ar-H),7.81(s,1H,Ar-H),8.32(s,2H,N-OH),8.46(s,1H,Ar-H)8.62(s,1H,Ar-H)。元素分析:C12H19N3O2计算值为C 60.74,H8.07,N 17.71;实测值为C 60.52,H 8.28,N 17.50。
479mg(2mmol)1,3-二羟基-2-(3’-吡啶基)-4,4,5,5-四甲基咪唑烷溶解于60ml甲醇中,加入3g PbO2,室温搅拌20min,TLC显示原料点消失。滤除固体,滤液室温下减压浓缩至干,柱层析分离(氯仿为洗脱剂),得300mg(65%)2-(3’-吡啶基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉,为蓝紫色粉末,Rf0.41(CHCl3/CH3OH,20:1);EI-MS(m/z):234[M]+,218[M-16]+。元素分析:C12H16N3O2计算值为C 61.52,H 6.88,N 17.94;实测值为C 61.75,H 6.67,N 17.73。
200mg(0.85mmol)2-(3’-吡啶基)-4,4,5,5-四甲基-1,3-二氧基咪唑啉溶于10ml甲醇中、加入0.5ml水、500mg NaNO2、滴加2N HCl调pH5、室温搅拌60min、反应液由蓝色变成红色、,减压浓缩除去大部分溶剂、用饱和碳酸氢钠水溶液调pH 6-7、氯仿萃取、合并氯仿层、无水硫酸钠干燥、TLC检测为单一点。过滤,滤液减压浓缩至干,得134mg(72%)2-(3’-吡啶基)-4,4,5,5-四甲基-1-氧基咪唑啉,为橙红色油状物,Rf0.63(CHCl3/CH3OH,20∶1);EI-MS(m/z):218[M]+。元素分析:C12H17N3O计算值为C 66.03,H 7.39,N 19.26;实测值为C 66.25,H 7.17,N 19.50。
54mg(0.25mmol)2-(3’-吡啶基)-4,4,5,5-四甲基-1-羟基咪唑啉溶于10ml甲醇中,加入5mg 5%Pd/C粉末,该粉末含水2.25mg,密闭反应体系,抽真空后,向反应体系中通入H2,30分钟后,TLC检测为单一点。常压过滤,滤液室温下减压浓缩至干,得43mg(79%)标题化合物,为浅黄色固体,Rf0.11(CHCl3/CH3OH,20∶1);mp 87-89℃;EI-MS(m/z):208[M]+;1H-NMR(DMSO-d6)δ(ppm)=1.03(s,6H,-CH3),1.12(s,6H,-CH3),7.89-8.36(m,3H,Ar-H)。元素分析:C12H17N3O计算值为C 65.73,H 7.81,N 19.16。
实施例23
本发明化合物的舒张血管活性
体重250-300g雄性Wistar大鼠,术前禁食12小时,自由饮水,颈椎脱位致死,开胸迅速摘取胸主动脉,剥离附着的结缔组织,将血管剪成3-5mm长的动脉环,置于15ml灌流浴槽内。浴槽盛有15ml Krebs-Henseleit(KH)液,37℃恒温,通以体积比95%O2-5%CO2气体。固定动脉环的挂钩连接张力换能器,在二道记录仪上描记血管舒缩曲线,纸速为1mm/min。调整静止张力为1.0g,平衡30min后给予NE(去甲肾上腺素)(终浓度为10-7mol/L)使动脉收缩以起预激作用。洗去NE,平衡30min后给予NE(终浓度为10-7mol/L),待收缩张力持续稳定于平台水平后,加入无水乙醇15μl(空白)或加入本发明化合物溶于15μl无水乙醇的溶液(终浓度为1×10-4)。本发明化合物的血管舒张能力用降低NE(终浓度为10-7mol/L)最大收缩张力的百分比表示(n=6,已扣除溶剂因素,结果如表1)。
表1本发明化合物的血管舒张活性
Claims (8)
2、合成权利要求1所述的通式I化合物的方法,该方法包括:在碱和Br2存在下,2-硝基丙烷缩合生成2,3-二甲基-2,3-二硝基丁烷;在NH4Cl存在下,2,3-二甲基-2,3-二硝基丁烷被锌粉还原为2,3-二甲基-2,3-二羟胺基丁烷;2,3-二甲基-2,3-二羟胺基丁烷与取代苯甲醛或糠醛或吡啶甲醛环合,生成1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷;1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷被氧化剂氧化为2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉;在酸性条件下,2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉被还原剂NaNO2还原为2-取代-4,4,5,5-四甲基-1-氧基咪唑啉;2-取代-4,4,5,5-四甲基-1-氧基咪唑啉在氢化催化剂存在下被加氢还原为2-取代-4,4,5,5-四甲基-1-羟基咪唑啉,即通式I的化合物。
3、如权利要求2合成方法,其特征在于,所述将2-硝基丙烷缩合生成2,3-二甲基-2,3-二硝基丁烷用的碱为NaOH。
4、如权利要求2合成方法,其特征在于,所述将1,3-二羟基-2-取代-4,4,5,5-四甲基咪唑烷氧化为2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉的氧化剂为PbO2。
5、如权利要求2合成方法,其特征在于,所述将2-取代-4,4,5,5-四甲基-1,3-二氧基咪唑啉被还原为2-取代-4,4,5,5-四甲基-1-氧基咪唑啉的酸性条件是pH为5,用来调节pH的酸是常用无机酸。
6、如权利要求5的合成方法,其特征在于,所述酸为盐酸。
7、如权利要求2的合成方法,其特征在于,所述加氢催化剂为5%Pd/C。
8、通式I化合物在制备用于血管舒张的药物中的应用,其中通式I的定义如权利要求1所述。
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