CN1248974A - 侧链改性的环氧噻嗪酮 - Google Patents
侧链改性的环氧噻嗪酮 Download PDFInfo
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Abstract
本发明涉及在侧链中进行改性的环氧噻嗪酮。
Description
环氧噻嗪酮A和B业已公开;例如参见DE4 138 042和PCT/EP96/05 080。
本发明涉及在16,17-位进行改性的环氧噻嗪酮(epothilone)的制备方法,在该方法中,原料为3,7-保护或未保护的环氧噻嗪酮A或B并且
a)它们在16,17-双键处被氢化或
b)利用卤素在16,17-双键上进行加成反应或
c)在16,17-双键上进行环氧化,并且如果合适的话,将所得到的环氧化物还原成16-醇。
本发明方法的特征在于:在方法(a)中,利用二亚胺或氢以及多相或均相金属催化剂进行氢化作用,或者在方法(c)中,利用过酸或二环氧乙烷进行环氧化作用。
此外,本发明涉及2,3-不饱和环氧噻嗪酮N-氧化物的制备方法,在该方法中,或者(i)用本身已知的方法,将3,7-保护的环氧噻嗪酮A或B转化成N-氧化物,并通过碱除去3-取代基得到2,3-双键,或者(ii)用本身已知的方法,将在2,3-位有一双键的7-保护或7-未保护的环氧噻嗪酮A或B转化成N-氧化物,并且如果合适的话,使得到的N-氧化物进行O-烷基化作用,以便得到O-烷基化产物。
此外,本发明还涉及环氧噻嗪酮N-氧化物的制备方法,在该方法中,用本身已知的方法将3,7-保护或未保护的环氧噻嗪酮A或B转化成N-氧化物,并且如果合适的话,使得到的N-氧化物进行O-烷基化作用,以便得到O-烷基化产物。
根据本发明的该方法的特征在于:利用过酸或二环氧乙烷进行N-氧化作用,并且将亲电性烷基、芳基或杂芳基试剂,特别是甲基碘化物或四氟硼酸三甲基氧鎓盐用于非强制性的O-烷基化作用。
此外,根据本发明的该方法的特征在于:使所得到的N-氧化物进行Katada反应,特别是如Houben-Weyl(第E7b卷,第646页)中所述的。
此外,根据本发明的该方法的特征在于,利用活化羧酸衍生物,特别是羧酸酐或羧酸酰氯进行Katada反应。
此外,根据本发明的该方法的特征在于:利用乙酸酐进行Katada反应,并且如果合适的话,用本身已知的方法,使得到的21-乙酰氧基环氧噻嗪酮分解,以便得到21-羟基环氧噻嗪酮A或B(相应地为环氧噻嗪酮E和F)。
此外,根据本发明的该方法的特征在于:上述的非强制性的分解采用水解或酶解的方法进行。
此外,本发明还涉及在C19-位改性的环氧噻嗪酮的制备方法,在该方法中,在C19-位对3,7-保护或未保护的环氧噻嗪酮A或B进行金属取代,并且,用本身已知的方法,利用亲电性试剂如烷基-、芳基-、杂芳基-、卤素-、氧-、或硫-取代的、在C19-位被改性的环氧噻嗪酮进行捕获。
根据本发明的该方法的特征在于利用丁基锂进行金属取代。
此外,本发明还涉及在C27-位进行改性的环氧噻嗪酮的制备方法,在该方法中,用本身已知的方法,在C27-甲基基团上,用杂原子对烯丙基(C17,C16和C27)进行取代。
根据本发明的该方法的特征在于:C27-甲基基团被溴原子取代,特别是在N-溴代丁二酰亚胺的帮助下进行取代,并且如果合适的话,将得到的溴化物转化成C27-羟基化合物。
最后,本发明涉及由本发明的方法制得的化合物。
实施例1:二环氧基环氧噻嗪酮A,1a)
在0℃,用二甲基二环氧乙烷(0.4ml,28μmol,在丙酮中0.07M的溶液)对环氧噻嗪酮A的丙酮(1ml)溶液(5mg,10μmo1)进行处理。利用几个小时使溶液温度升至室温,并在该温度下搅拌20小时。由于TLC证实,仍然存在有原料,因此,再添加二甲基二环氧乙烷(0.25ml,17μmo1),在室温再次对反应混合物搅拌20小时。除去溶剂并通过PLC(0.25×200×200mm,10%MeOH∶CH2C12)对残留物进行提纯。分离得到下面的物质:
1)1.4mg(27%)二环氧基环氧噻嗪酮A(C16-C17的3∶2差向异构体混合物)。
Rf 0.63(10%MeOH∶CH2Cl2);Rf:6.79(异构体1)和7.39(异构体2)min(RP18,250×4mm,MeOH∶H2O 65∶35,1ml/min);MS∶(m/z)=510(M+);1H NMR(400M3Hz,CDCl3,所选信号,异构体1):δ=6.96(s,1H,H-19),5.48(dd,J=12.2和2.5Hz,1H,H-15),4.37(dbr,J=10.7Hz,1H,H-3),4.10(s,1H,H-17),3.67(dd,J=5.6和2.5Hz,1H,H-7),3.14(qd,J=6.6和2.5Hz,1H,H-6),3.00(ddd,J=9.7,3.6和2.5Hz,1H,H-13),2.88(dt,J=8.6和3.6Hz,1H,H-12),2.71(s,3H,H-21),2.53(dd,J=13.7和11.7Hz,1H,H-2a),1.41(s,3H,H-22),1.27(s,3H,H-26),1.17(d,J=6.6Hz,3H,H-24),1.08(s,3H,H-23),0.97(d,J=7.1Hz,3H,H-25);(异构体2)δ=6.98(s,1H,H-19),5.11(dd,J=11.7和2.5Hz,1H,H-15),4.27(dbr,J=10.7Hz,1H,H-3),4.14(s,1H,H-17),3.06(qd,J=6.6和2.9Hz,1H,H-6),2.96(ddd,J=9.7,3.6和2.5Hz,1H,H-13),2.31(dt,J=14.7和2.0Hz,1H,H-14a),1.36(s,3H,H-22),1.15(d,J=6.6Hz,3H,H-24),1.14(s,3H,H-26),1.07(s,3H,H-23).
2)0.8mg(16%)的环氧噻嗪酮A的N-氧化物
Rf 0.44(10%MeOH∶CH2Cl2);Rf:4.25min(RP18,250×4mm,MeOH∶H2O65∶35,1ml/min);MS:(m/z)=510(M+);1H NMR:参见方法1实施例2:二氢环氧噻嗪酮A,(1c)
将载于活性炭上的钯(5mg,10%)添加至环氧噻嗪酮A(11mg,22μmol)的乙醇(2ml)溶液中,并在室温使该黑色悬浮液暴露至H2气氛中为时24小时。由于TLC表明:反应尚未完成,因此,再添加一部分Pd/C,并在H2气氛中再搅拌20小时。通过PLC(1×200×200mm,10%MeOH∶CH2Cl2)对产物进行分离。分离得到下面物质:
1)0.5mg(5%)二氢环氧噻嗪酮A。
Rf0.60(10%MeOH∶CH2Cl2);Rf:10.80min(RP18,250×4mm,MeOH∶H2O65∶35,1ml/min); MS:(m/z)=496(M+),478,407,308;1H NMR(400MHz,CDCl3,所选信号):δ=7.05(d,J=6.6Hz,1H,OH),6.77(s,1H,H-19),5.23(dd,J=12.4和2.3Hz,1H,H-15),4.42(ddd,J=11.7,6.6和3.0Hz,1H,H-3),3.70(ddd,J=5.3和2Hz,1H,H-7),3.12(qd,J=6.6和3.0Hz,1H,H-6),3.07(d,J=12.7Hz,1H,H-17a),2.96(ddd,J=9.7,3.6和2.0Hz,1H,H-13),2.91(ddd,J=9.7,3.6 and 2.6Hz,1H,H-12),2.68(s,3H,H-21),2.51(dd,J=13.7和11.7Hz,1H,H-2a),2.24(d,J=12.7Hz,1H,H-17b),2.19(m,1H,H-16),2.13(dd,J=13.7和3.0Hz,1H,H-2b);1.35(s,3H,H-22),1.15(d,J=6.6Hz,3H,H-24),1.09(s,3H,H-23),0.99(d,J=7.1Hz,3H,H-25),0.93(d,J=6.6Hz,3H,H-26).
2)8mg(72%)15-脱氧二氢环氧噻嗪酸(epothilonic acid)。Rf0.10(10%MeOH∶CH2Cl2)。实施例3:16-羟基环氧噻嗪酮A,(1b)
将载于活性炭上的钯(10mg,10%)添加至二环氧基环氧噻嗪酮A(7mg,14μmol,C-16的1∶1的差向异构体混合物)的乙醇(2ml)溶液中,并在室温使该黑色悬浮液暴露至H2气氛中为时24小时。由于TLC表明:反应尚未完成,因此,再添加一部分Pd/C,并在H2气氛中再搅拌80小时。通过PLC(1×200×200mm,10%MeOH:CH2Cl2)对产物进行分离。分离得到下面物质:
1)3mg(43%)16-羟基环氧噻嗪酮A(异构体1)。Rf0.38(10%MeOH∶CH2Cl2);Rf:6.65min(RP18,250×4mm,MeOH∶H2O 65∶35,1ml/min);1H NMR(400MHz,CDCl3,所选信号):δ=6.85(s,1H,H-19),5.02(dd,J=11.7和2.0Hz,1H,H-15),4.38(dbr,J=11.2Hz,1H,H-3),3.67(dd,J=4和3Hz,1H,H-7),3.14(qd,J=6.8和3.0Hz,1H,H-6),2.95(d,J=15.3Hz,1H,H-17a),2.89(d,J=15.3Hz,1H,H-17b),2.89(ddd,J=10.2,3.6和2.0Hz,1H,H-13),2.81(ddd,J=9.7,3.6和2.5Hz,1H,H-12),2.70(s,3H,H-21),2.53(dd,J=15.8和11.7Hz,1H,H-2a),2.14(dd,J=15.8和2.0Hz,1H,H-2b),2.08(dt,J=14.3和2.0Hz,1H,H-14a),1.39(s,3H,H-22),1.25(s,3H,H-26),1.19(d,J=6.6Hz,3H,H-24),1.05(s,3H,H-23),0.99(d,J=7.1Hz,3H,H-25).
2)3mg(43%)16-羟基环氧噻嗪酮A(异构体2)。Rf0.31(10%MeOH∶CH2Cl2);Rf:6.10min(RP18,250×4mm,MeOH∶H2O 65∶35,1ml/min);1H NMR(300MHz,CDCl3,
所选信号):δ=6.85(s,1H,H-19),5.21(dd,J=11.3和1.9Hz,1H,H-15),4.42(dbr,J=10.5Hz,1H,H-3),3.71(sbr,1H,H-7),3.21(d,J=14.3Hz,1H,H-17a),3.13(qd,J=6.8和3.0Hz,1H,H-6),3.09(dt,J=9.8和3.4Hz,1H,H-13),2.87(dt,J=9.4和3.0Hz,1H,H-12),2.73(d,J=14.3Hz,1H,H-17b),2.68(s,3H,H-21),2.63(dd,J=16.6和11.7Hz,1H,H-2a),2.27(dt,J=14.7和2.3Hz,1H,H-14a),2.24(dd,J=16.6和2.6Hz,1H,H-2b),1.39(s,3H,H-22),1.22(s,3H,H-26),1.19(d,J=6.8Hz,3H,H-24),1.05(s,3H,H-23),0.99(d,J=7.2Hz,3H,H-25).
环氧噻嗪酮A N-氧化物(2a):将于0.5ml二氯甲烷中的100mg,70%的间-氯过苯甲酸添加至100mg于1ml二氯甲烷中的环氧噻嗪酮A中。在室温对混合物搅拌6小时之后,用二氯甲烷对其进行稀释,用亚硫酸钠溶液消耗过量的过酸并用碳酸氢钠溶液通过连续的振荡进行萃取。在真空中蒸发掉溶剂,并利用Nucleosil RP-18柱(250×20mm,洗脱剂甲醇/水60∶40),通过制备HPLC对残留物进行分离。得到60mg无色油。Rf=0.60(硅胶TLC铝箔,洗脱剂二氯甲烷/甲醇9∶1);UV(甲醇):λmax.240nm;13C NMR(CDCl3):C-1 170.5,C-2 39.9,C-3 70.8,C-4 55,1,C-5 221.4,C-6 40.9,C-7 72.9,C-8 37.6,C-9 31.8,C-1022.8,C-11 28.0,C-12 58.0,C-13 55.8,C-14 32.2,C-1575.5,C-16 144.5,C-17 111.4,C-18 143.4,C-19 110.3,C-20 145.6,C-21 13.5,C-22 15.4,C-23 23.3,C-24 12.0,C-25 16.5,C-27 18.2ppm;1H NMR(CDCl3):2a-H 2.12dd,2b-H 2.47dd,3-H 4.55dd,3-OH 6.48宽,6-H 3.25dq,7-H 3.72dd,8-H 1.81m,9a-H 1.34m,9b-H 1.56m,10-H2 1.48m,11a-H 1.27m,11b-H 1.87m,12-H 2.92ddd,13-H 2.98m,14a-H 1.67ddd,14b-H 2.23d,15-H 5.33d,17-H 6.82s,19-H 7.09s,21-H3 2.64s,22-H3 1.02s,23-H3 1.42s,24-H3 1.18d,25-H3 0.99d,27-H3 2.04s ppm.
21-乙酰氧基环氧噻嗪酮A(=21-乙酰基环氧噻嗪酮E)(3a):
将0.05ml 2,6-二叔丁基吡啶和0.1ml乙酸酐添加至于0.5ml二氯甲烷中的50mg环氧噻嗪酮A N-氧化物(2a)中。在75℃对混合物加热15分钟之后,在真空中蒸发掉溶剂和试剂,并利用NucleosilRP-18(250×20mm,洗脱剂甲醇/水60∶40),通过制备HPLC对残留物进行分离。得到30mg无色油。Rf=0.50(硅胶TLC铝箔,洗脱剂二氯甲烷/甲醇95∶5);ESI-MS(负离子)m/z 552;UV(甲醇):λmax.210,250nm;1H NMR(CDCl3,不同于2a的信号):15-H5.45dd,17-H 6.60s,19-H 7.15s,21-H2 5.35s,CH3CO2.15s ppm.
环氧噻嗪酮E(3b):将一滴浓氨水溶液添加至于0.5ml甲醇中的10mg 21-乙酰氧基环氧噻嗪酮A(3a)中,并于40℃对该混合物加热1小时,并在真空中蒸干。通过制备TLC分离残留物。得到6mg产物,该产物与环氧噻嗪酮E的真实试样相同。实施例4:19-甲基环氧噻嗪酮A,(4b)
在-90℃,用正丁基锂(100μl,160μmol,于己烷中1.6M的溶液)对环氧噻嗪酮A(15mg,30μmol)于THF(1ml)中的溶液进行处理。该溶液立即变成金黄色。在-90℃对该反应溶液搅拌15分钟之后,用甲基碘化物(100μl,1.6mmol)对其进行处理。将所得到的浅黄绿色溶液加热至-30℃并用pH=7.0的缓冲剂(2ml)进行骤冷。利用0.1N的盐酸使该乳液的pH值降至6。在用固体氯化钠饱和该混合物之后,用二氯甲烷(2×5ml)和乙酸乙酯(5ml)对水相进行萃取,在硫酸镁上对复合的有机相进行干燥,并进行过滤,然后利用旋转式蒸发器除去溶剂。通过PLC(1×200×200mm,10%MeOH∶CH2Cl2)和HPLC(RP-18,250×16mm,MeOH∶H2O 65∶35)进行提纯。分离得到下面物质:
1)2.5mg(17%)19-甲基环氧噻嗪酮A。
Rf 0.50(10%MeOH∶CH2Cl2);Rf:11.70min(RP18,250×4mm,MeOH∶H2O65∶35,1ml/min);MS:(m/z)=508(M+),420,320;1H NMR(300MHz,CDCl3,所选信号):δ=6.41(s,1H,H-17),5.46(dd,J=9.0和2.3Hz,1H,H-15),4.15(dd,J=10.5和3.0Hz,1H,H-3),3.77(dd,J=8和4Hz,1H,H-7),3.20(qd,J=6.8和4.5Hz,1H,H-6),3.04(dt,J=7.5和3.8Hz,1H,H-13),2.91(dt,J=7.5和3.8Hz,1H,H-12),2.61(s,3H,H-21),2.51(dd,J=14.4和10.5Hz,1H,H-2a),2.38(dd,J=14.4和3.0Hz,1H,H-2b),2.32(s,3H,H-27),2.15(ddd,J=15.1,3.8和3.0Hz,1H,H-14a),2.01(d,J=1.5Hz,3H.H-26),1.91(dt,J=15.1和8.8Hz,1H,H-14b);1.34(s,3H,H-22),1.16(d,J=6.8Hz,3H,H-24),1.10(s,3H,H-23),1.00(d,J=6.8Hz,3H,H-25).
2)约50%的环氧噻嗪酮A。实施例5:19-溴代环氧噻嗪酮A,(4a)
在-90℃,用正丁基锂(160μl,225μmol,于己烷中1.6M的溶液)对环氧噻嗪酮A(25mg,50μmol)于THF(2.5ml)中的溶液进行处理。该溶液立即变成金黄色。在-90℃对该反应溶液搅拌15分钟之后,添加溶解于THF(0.5ml)中的N-溴代丁二酰亚胺(27mg,150μmol)。该溶液将慢慢褪色。然后将浅棕色的反应混合物加热至-30℃并利用0.1N的盐酸(1ml)使该混合物的pH值降至6.5。在用固体氯化钠饱和该混合物之后,用二氯甲烷(2×5ml)和乙酸乙酯(5ml)对水相进行萃取,在硫酸镁上对复合的有机相进行干燥,并进行过滤,然后利用旋转式蒸发器除去溶剂。通过PLC(1×200×200mm,10%MeOH∶CH2Cl2)和HPLC(RP-18,250×16mm,MeOH∶H2O65∶35)进行提纯。分离得到下面物质:
1)2.6mg(9%)19-溴代环氧噻嗪酮A。
Rf 0.53(10%MeOH∶CH2Cl2);Rf:20.78min(RP18,250×4mm,MeOH∶H2O65∶35,1ml/min);MS:(m/z)=574和572(M+),556,554,468,466,386,384,341;1H NMR(300MHz,CDCl3,所选信号
):δ=6.43(s,1H,H-17),5.46(dd,J=8.7 and2.3Hz,1H,H-15),4.13(ddd,J=9.4,6.0和3.8Hz,1H,H-3),3.80(dd,J=8和4Hz,1H,H-7),3.38(d,J=6.OHz,1H,OH),3.22(qd,J=6.8和5.3Hz,1H,H-6),3.05(dt,J=8.3和4.1Hz,1H,H-13),2.91(dt,J=7.5和3.7Hz,1H,H-12),2.66(s,3H,H-21),2.55(dd,J=14.7和9.4Hz,1H,H-2a),2.47(dd,J=14.7和3.8Hz,1H,H-2b),2.16(d,J=1.1H2,3H,H-26),2.14(dt,J=14.7和3.8Hz,1H,H-14a),1.90(dt,J=158.3Hz,1H,H-14b);1.34(s,3H,H-22),1.17(d,J=6.8Hz,3H,H-24),1.11(s,3H,H-23),1.01(d,J=6.8Hz,3H,H-25).2)约60%的环氧噻嗪酮A。合成例1a-5a1a R1, R2=H,X,Y=-O-,R=Hb R1, R2H,X=OH Y=H,R=Hc R1, R2=H,X=H Y=H,R=H2a R1, R2=H,Z=O-,R=Hb R1, R2=H,Z=OCH3 BF4 -,R=H3a R1,R2=H,R3=acetyl,R=Hb R1,R2,R3=H,R=H4a R1,R2=H,V=Br,R=Hb V=CH3,R1,R2H,R=H5a R1,R2=H,W=OH,R=H
Claims (14)
1.在16,17-位被改性的环氧噻嗪酮的制备方法,在该方法中,原料为3,7-保护或未保护的环氧噻嗪酮A或B并且
a)它们在16,17-双键处被氢化或
b)利用卤素在16,17-双键上进行加成反应或
c)在16,17-双键上进行环氧化,并且如果合适的话,将所得到的环氧化物还原成16-醇。
2.根据权利要求1的方法,其特征在于:
在方法(a)中,利用二亚胺或氢以及多相或均相金属催化剂进行氢化作用,
或者在方法(c)中,利用过酸或二环氧乙烷进行环氧化作用。
3.2,3-不饱和环氧噻嗪酮N-氧化物的制备方法,在该方法中,
或者(i)用本身已知的方法,将3,7-保护的环氧噻嗪酮A或B转化成N-氧化物,并通过碱除去3-取代基得到2,3-双键,
或者(ii)用本身已知的方法,将在2,3-位有一双键的7-保护或7-未保护的环氧噻嗪酮A或B转化成N-氧化物,并且如果合适的话,使得到的N-氧化物进行O-烷基化作用,以便得到O-烷基化产物。
4.环氧噻嗪酮N-氧化物的制备方法,在该方法中,用本身已知的方法将3,7-保护或未保护的环氧噻嗪酮A或B转化成N-氧化物,并且如果合适的话,使得到的N-氧化物进行O-烷基化作用,以便得到O-烷基化产物。
5.根据权利要求3或4的方法,其特征在于:利用过酸或二环氧乙烷进行N-氧化作用,并且将亲电性烷基、芳基或杂芳基试剂,特别是甲基碘化物或四氟硼酸三甲基氧鎓盐用于非强制性的O-烷基化作用。
6.根据权利要求3或4的方法,其特征在于:使所得到的N-氧化物进行Katada反应,特别是进行如Houben-Weyl(第E7b卷,第646页)中所述的反应。
7.根据权利要求6的方法,其特征在于:利用活化羧酸衍生物,特别是羧酸酐或羧酸酰氯进行Katada反应。
8.根据权利要求7的方法,其特征在于:利用乙酸酐进行Katada反应,并且如果合适的话,用本身已知的方法,使得到的21-乙酰氧基环氧噻嗪酮分解,以便得到21-羟基环氧噻嗪酮A或B(相应地为环氧噻嗪酮E和F)。
9.根据权利要求8的方法,其特征在于:所述的分解是通过水解或酶解的方法进行的。
10.在C19-位改性的环氧噻嗪酮的制备方法,在该方法中,在C19-位对3,7-保护或未保护的环氧噻嗪酮A或B进行金属取代,并且,用本身已知的方法,利用亲电性试剂如烷基-、芳基-、杂芳基-、卤素-、氧-、或硫-取代的、在C19-位被改性的环氧噻嗪酮进行捕获。
11.根据权利要求10的方法,其特征在于:利用丁基锂进行金属取代。
12.在C27-位进行改性的环氧噻嗪酮的制备方法,在该方法中,用本身已知的方法,在C27-甲基基团上,用杂原子对烯丙基(C17,C16和C27)进行取代。
13.根据权利要求12的方法,其特征在于:C27-甲基基团被溴原子取代,特别是在N-溴代丁二酰亚胺的帮助下进行取代,并且如果合适的话,将得到的溴化物转化成C27-羟基化合物。
14.由前述任一项权利要求的方法得到的化合物。
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ES2178093T5 (es) * | 1995-11-17 | 2009-02-16 | Gesellschaft Fur Biotechnologische Forschung Mbh (Gbf) | Derivados de epotilon y su preparacion. |
US6441186B1 (en) * | 1996-12-13 | 2002-08-27 | The Scripps Research Institute | Epothilone analogs |
CN1128803C (zh) * | 1997-02-25 | 2003-11-26 | 生物技术研究有限公司(Gbf) | 环氧噻嗪酮b-n-氧化物及其制备方法 |
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1998
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