新型C - 12 - 吡唑啉酮酮内酯的合成与抗菌活性 - 图文-

1、文章编号:1674 2974(200909 0063 04新型C 12吡唑啉酮酮内酯的合成与抗菌活性王永涛1,2,陈卫民2,胡艾希1 ,宋秋玲2(1.湖南大学化学化工学院,湖南长沙 410082; 2.暨南大学药学院,广东广州 510632摘 要:根据酮内酯的构效关系和生物电子等排原理,设计、合成了新型C 12吡唑啉酮酮内酯(1.1以吡唑啉酮结构单元替代泰利霉素11,12-氨基甲酸内酯环,以克拉霉素衍生物为原料合成1.1对红霉素敏感菌和耐药菌的体外活性测试表明:1对金黄色葡萄球菌(ATCC 6538p和表皮葡萄菌(AT CC 12228有良好的抑菌活性.关键词:酮内酯;大环内酯;酮内酯抗生素;

2、红霉素中图分类号:R915.11 文献标识码:ASynthesis and Antibacterial Activity of the NewC 12Pyrazolinonyl KetolideWANG Yong tao 1,2,CHEN Wei min 2,HU Ai x i 1 ,Song Qiu ling 2(1.Co llege of Chemistry and Chemical Engineering,Hunan U niv ,Changsha,Hunan 410082,China;2.College of Pharmay,Jinan Univ,Guangzhou,Guangdong

3、 510632,ChinaAbstract:According to the SAR study of ketolides and the bio isostere principle,a new type of ketolide(1,bearing a C 12py razolinonyl moeity instead of the C 11,12cyclic carbamate group in telithromycin,w as desig ned and synthesized starting from clarithromycin derivatives.T he antibac

4、terial activity of compound 1was tested inv itro ag ainst both erythromycin susceptible and erythrom ycin resistant organisms.Compound 1show s potent antibacterial activity ag ainst both S.aureus (ATCC 6538pand S.epidermidis (AT CC 12228.Key words:ketolides;m acrolides;ketolide;erythromy cin由于抗生素和抗菌

5、药在临床上的广泛应用和滥用,细菌的耐药性1-2迅速增加,近年来红霉素对肺炎球菌的耐药性由5%上升至40%,同时与青霉素交叉耐药的比例也不断上升,因此新的抗生素药物的开发迫在眉睫.过去几年里,在克服细菌耐药性方面已取得很大进展,以泰利霉素为代表的酮内酯化合物对大环内酯产生耐药性的肺炎链球菌、金黄色葡萄球菌、粪肠球菌和流感嗜血杆菌等均有良好的抗菌活性,同时对大环内酯敏感菌也有良好抗菌活性.这激发了化学家和药物学家对酮内酯研究的兴趣.依照酮内酯的构效关系3和生物电子等排原理,通过用吡唑啉酮结构单元替代泰利霉素的重要活性部位 11,12-氨基甲酸内酯环,设计新型3-酮基-6-O-甲基-12-(4,5-

6、二氢-1H-吡唑-5-基-12-脱羟基-21-脱甲基-红霉素A(1.以文献4中由克拉霉素经过7步反应得到的化合物2为关键中间体5-7,经过脱9,11位缩酮保护、氧化和醇解得到1,合成路线见图1.体外活性测试表明1对金黄色葡萄球菌(ATCC 6538p的抑菌活性与红霉素和克拉霉素相当,对表皮葡萄菌(AT CC 12228的抑菌活性优于红霉素和克拉霉素.收稿日期:2008 11 21基金项目:广东省自然科学基金资助项目(06025150作者简介:王永涛(1978-,男,河南周口人,石河子大学博士 通讯联系人,E mail:axhu0731第36卷 第9期2009年9月湖南大学学报(自然科学版Jou

7、rnal of Hunan U niversity (N atural SciencesVol.36,No.9Sep 2009图1 C12吡唑啉酮酮内酯(1的合成F ig.1 Synthesis o f C12pyrazolinonyl ketolide(11 实验部分1 1 仪器与试剂1H NM R,13CNMR用Bruker-AV400MHz型核磁共振仪测定,内标为T MS;ESI MS用API2000 LC/MS/M S测定;所用试剂均为分析纯和化学纯,并采用常规法对其进行干燥.GF254薄层层析板和柱层析硅胶由青岛海洋化工集团公司生产.化合物2按照文献4的方法合成.1 2 化合物3的合

8、成1.14g(1.5mmol化合物2,15mL的乙腈-水(二组分体积配比21混合液,加入1.9g(7.56 mmol对甲基苯磺酸的吡啶盐,搅拌下加热到68 !,反应20h,T LC板层检测完全反应,冷却至室温,加20mL乙酸乙酯和0.96g(1.15mmol碳酸钠,反应液用210mL饱和碳酸氢钠溶液和10 mL饱和食盐水洗涤,分出有机层,用210mL乙酸乙酯萃取水层,合并有机相,无水硫酸钠干燥,过滤,蒸出溶剂,柱层析(V石油醚V丙酮V三乙胺=31 0.01得0.97g化合物3,收率90%.1H NM R(CD Cl3 :0.68(d,J=7.2H z,3H,0.75(m,3H,0.89(m,2

9、H,0.90(d,J=6.8Hz,3H,0.99(d,J= 7.0Hz,3H,1.26(m,13H,1.42(m,1H,1.65 (m,1H,1.91(m,3H,2.31(s,6H,2.55(m, 1H,2.76(d,J=18.6H z,1H, 2.96(m,1H,3.19(s,3H, 3.36(d,J=10.2Hz,3H, 3.56(m, 2H, 3.89(m,1H,4.06(s,1H,4.78(d,J=7.5 Hz,1H,5.04(m,1H,5.49(d,J=8.7H z,1H,6.02(s,1H,6.52(s,1H,7.45(t,J=7.6Hz, 2H,7.57(t,J=7.4Hz,1H

10、,8.05(d,J=7.8Hz, 2H;13C NMR(CDCl3 :7.7,8.6,10.2,15.0, 19.3,21.4,21.1,23.1,31.9,32.5,34.4,34.9, 36.7,37.2,40.7,44.5,49.8,63.4,69.0,69.7, 70.8,71.9,80.3,83.1,100.2,128.3,129.7, 130.6,132.8,141.0,165.4,174.8.ESI MS(m/ z:720.9M+1+.1 3 化合物4的合成20mL二氯甲烷和0.72g(1mmol化合物3,搅拌溶解,冷却至-5!,加1.3mmol Dess M artin 氧化剂

11、,反应5min,冷却至-10!反应22h,补加1.3mmol Dess M artin氧化剂,反应22h,加入20 mL乙酸乙酯,用5mL11的饱和NaHCO3 NaS2O3 (10%混合溶液和20mL饱和NaCl溶液洗涤,无64 湖南大学学报(自然科学版2009年 水硫酸钠干燥,过滤,蒸出溶剂,柱层析(V石油醚V丙酮V三乙胺=310.01得到0.33g化合物4,收率45.3%.1H NMR(CDCl3 :0.75(t,J=7.4 Hz,3H,0.88(d,J=7.2Hz,3H, 1.12(d,J= 7.4Hz,4H, 1.21(d,J=6.9H z,3H, 1.27(d, J=6.1H z,

12、4H, 1.36(s,3H, 1.401.60(m, 3H, 1.64(s,3H,1.86(m,1H, 2.00(m,1H, 2.102.25(m,1H, 2.28(s,6H, 2.59(m,1H, 2.67(m,1H,2.79(s,3H, 2.90(m,2H,3.09 (m,1H, 3.42(q,J=7.0Hz,1H,3.57(m,1H, 4.04(d,J=10.1H z,1H, 4.48(d,J=7.5H z, 1H, 5.04(m,2H,6.89(s,1H,7.25(t,J=7.8 Hz,2H,7.46(t,J=7.8Hz,1H,8.02(d,J=7.3 Hz,2H;13C NMR(CD

13、Cl3 :7.5,10.8,14.4, 17.6,20.2,20.9,21.3,21.5,30.0,32.2,39.1, 41.2,42.2,49.6,50.7,51.8,53.9,63.8,69.6, 72.5,78.8,82.5,102.5,115.9,128.9,130.2, 130.6,133.5,149.0,165.7,169.2,187.1, 203.8,205.5.ESI M S(m/z:731.0M+1+.1 4 化合物1的合成0.73g(1mmol化合物4和5mL甲醇,回流15 h,TLC板层检测完全反应,旋蒸蒸除溶剂,柱层析(V石油醚V丙酮V三乙胺=310.01得到0.58

14、g目标化合物1,收率93%.1H NMR(CDCl3: :0.78(t,J= 7.4Hz,3H,1.13(d,J=7.6Hz,3H,1.19(m, 7H,1.28(d,J=6.9Hz,3H,1.35(s,3H,1.64(m, 3H,1.77(s,3H,2.04(m,1H,2.12(s,1H, 2.24 (s,6H,2.33(m,1H, 2.44(m,1H, 2.64(d,J= 18.8Hz,1H,2.81(s,3H,2.88(m,1H,2.96(d,J= 18.8Hz,1H, 3.16(t,J=8.5Hz,3H, 3.47(m, 2H,3.54(q,J=6.9Hz,1H,4.01(d,J=10

15、.2Hz, 1H,4.27(d,J=7.3Hz,1H, 5.04(dd,J=2.3Hz, J=11.2Hz,1H,6.87(s,1H;13C NMR(CDCl3 : 8.1,11.2,15.2,18.6,20.7,20.8,22.0,29.1, 30.4,31.7,39.4,41.1,43.0,50.6,50.9,52.6, 66.7,70.3,71.2,73.0,78.3,78.6,83.9,105.4, 116.7,149.1,169.7,187.3,204.6,206.1.ESI MS (m/z:627.0M+1+.2 结果与讨论2 1 缩酮水解与重排反应由化合物2制得化合物3涉及到缩酮

16、水解和4,5 -二氢-3H-吡唑-3-基的重排反应.Brown等8报道了对甲基苯磺酸使4,5-二氢-3H-吡唑-3-基重排为4,5 -二氢-1H-吡唑-5-基,文献9-10报道在三氟乙酸和盐酸等酸性条件下4,5-二氢-3H-吡唑-3-基也可发生重排反应,酸性环境可以促使4,5-二氢-3H-吡唑-3-基发生重排.实验发现使用对甲基苯磺酸吡啶盐在乙腈和水的混合溶剂也能发生重排反应:当化合物2在脱去9,11位缩酮保护基时,4,5-二氢-3H-吡唑-3-基重排为4,5-二氢-1H-吡唑-5-基得到化合物3,13C NMR在 141.6出现了吸收峰,经确证为4,5 -二氢-1H-吡唑-5-基氮碳双键的碳

17、原子吸收峰.可能是对甲基苯磺酸吡啶盐在乙腈和水的混合溶剂中游离出对甲基苯磺酸催化4,5-二氢-3H-吡唑-3-基重排为4,5-二氢-1H-吡唑-5-基.2 2 氧化反应由化合物3制得化合物4涉及到3,9-二羟基和4,5-二氢-1H-吡唑-5-基的氧化反应.大环内酯羟基氧化成酮的氧化方法很多:Pfitzner Moffatt氧化11,M offatt Sw ern氧化,Corey Kim氧化12-17, Dess Martin氧化18-20,Sw ern氧化21,PDD,PCC 和草酰氯等22,Corey Kim氧化和Dess Martin氧化是最常用的2种.其中Corey Kim氧化在反应过程

18、中释放出氯化氢气体,酸性较强,容易引起大环内酯分子内脱水,且反应结束后生成的二甲硫醚气味非常难闻,氧化反应过程还会伴生重排反应的发生.自1983年Dess和Martin首次报道Dess M artin氧化剂(苯并高碘酸酯以来23,Dess M artin氧化剂的实际应用已不仅局限于醇羟基的氧化,Dess Mar tin氧化已经出现了许多新的反应24-27,Dess Mar tin氧化条件最为温和,同时反应过程中释放的醋酸酸性弱,不易引发副反应.因此,选用Dess Martin氧化3,9-二羟基和4,5-二氢-1H-吡唑-5-基,研究结果表明,化合物3的氧化在室温下进行,11位羟基也可被氧化,不

19、能制得化合物4.当温度降低至-5 !时,可选择性氧化3位和9位羟基成酮而保留11位羟基.化合物3C12位4,5-二氢-1H-吡唑-5-基的碳氮双键 位的碳氢键被活化了,在该条件下C12位4,5-二氢-1H-吡唑-5-基也被氧化成吡唑酮结构.因此,采用Dess M artin氧化化合物3可一锅煮得到化合物4.2 3 生物活性采用二倍稀释法,测定了目标化合物1对金黄色葡萄球菌(ATCC6538p和表皮葡萄球菌(ATCC 12228以及耐药的金黄色葡萄球菌5676和金黄色葡萄球菌5677的抗菌活性,结果见表1.65第9期王永涛等:新型C12吡唑啉酮酮内酯的合成与抗菌活性表1 化合物1的体外抗菌活性T

20、ab.1 Antibacterial activities in vitro of compound1化合物M IC/(g#m L-1金黄色葡萄球菌A TCC6538p表皮葡萄球菌AT CC12228金黄色葡萄球菌5676金黄色葡萄球菌567710.250.25>128>128克拉霉素0.250.25>1024>1024红霉素0.250.25>1024>1024由表1可知,化合物1对金黄色葡萄球菌(ATCC6538p与红霉素和克拉霉素有相当的抑菌活性,对表皮葡萄球菌(AT CC12228的抑菌活性优于红霉素和克拉霉素,但对于临床上分离出来的耐甲氧苯青霉素金黄

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