CN101899076B - 阿奇霉素衍生物、制备方法及中间体 - Google Patents
阿奇霉素衍生物、制备方法及中间体 Download PDFInfo
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Abstract
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技术领域
本发明涉及阿奇霉素衍生物及其制备方法,以及中间体。
背景技术
大环内酯类抗生素抗菌活性好,无过敏反应,副作用小,安全性高,经过近60年的发展,已成为仅次于β-内酰胺类抗生素的第二大类抗感染药物。第一代大环内酯抗生素代表药物-红霉素,曾被广泛用于治疗金黄色葡萄球菌、肺炎链球菌、溶血链球菌以及肺炎支原体等引起的感染,尤其适用于青霉素过敏者。但其存在酸介质不稳定、生物利用度低的缺点,使应用受到限制。以阿奇霉素为代表的第二代大环内酯抗生素解决了此问题,并在药效和药物动力学方面有了极大改善。阿奇霉素(化学名:9-脱氧-9a-氮杂-9a-甲基-9a-红霉素A)是第一个十五元大环内酯抗生素,也是第一个氮杂内酯类抗生素。它以红霉素为原料,经肟化、贝克曼重排、还原、N-甲基化等反应制得。其突出特点是:对酸性介质稳定、组织渗透性好、血浆半衰期长、临床适应症广、疗效显著和不良反应少。但是,随着抗生素的广泛应用,特别是持续、不当使用,细菌几乎对所有临床使用的抗生素产生了耐药性,给临床治疗带来了极大困难。因此,为应对耐药菌感染这一严峻问题,对大环内酯类抗生素深入研究,开发抗菌活性强、抗菌谱广的新颖大环内酯抗生素已经成为抗感染领域的研究热点。
4″-氨基甲酸酯大环内酯类化合物是1998年报道的一类新型大环内酯衍生物。该类化合物是在大环内酯克拉定糖的4″位连以芳香基取代的氨基甲酸酯侧链而形成的。其抗菌活性与酮内酯和酰内酯相似,而且不受耐药菌携带的基因种类的影响。C-4″位是大环内酯抗生素十分有潜力的修饰位点,在这个位点引入不同的氨基甲酸酯侧链是开发具有抗耐药菌活性的大环内酯抗生素的有效方法。目前,已报道的4″-氨基甲酸酯大环内酯衍生物有美国专利US6025350、US20080249033;世界专利WO2004101589、WO2005108413、WO2006050941、WO2006050942、WO2006050943、WO2008014221;中国专利:CN1980945等。其中世界专利W0206050941、W0206050942和W0206050943涉及用一系列2-5个碳原子长度的脂肪侧链通过甲酰胺键与阿奇霉素的C-4″位连接,并以醚、硫醚或胺键在末端连接具有不同取代基团的氮杂萘啶酮环或1-甲基-2,3-二氢-1H-苯并喹诺酮环。W20004101589涉及通过酯键在C-4″位引入2-5个碳原子的烷基侧链,并以醚、硫醚、酰胺键或胺键在末端连接取代氮杂萘啶酮环,或者末端连接哌嗪环、甲酰哌嗪环、八氢-1H-吡咯并[3,4-b]吡啶,并在哌嗪环、甲酰哌嗪环、八氢-1H-吡咯并[3,4-b]吡啶的氮原子上引入取代氮杂萘啶酮环。W2005108413和US20080249033涉及在C-4″位引入了烷基氨基甲酸酯侧链,其烷基侧链末端通过氨基、醚键、酰胺键、氨基甲酰键连接取代氮杂萘啶酮环,或者其侧链末端连接具有脂肪烃基取代的哌嗪环、咪唑环、八氢-1H-吡咯并[3,4-b]吡啶,并通过哌嗪环、咪唑环、八氢-1H-吡咯并[3,4-b]吡啶环中的氮原子连接取代氮杂萘啶酮环。
现有专利中的4″-氨基甲酸酯大环内酯类化合物,其C-4″位通过酯键、酰胺键、甲酰胺键、氨基甲酰基等引入含有哌嗪环、八氢-1H-吡咯并[3,4-b]吡啶的取代氮杂萘啶酮环侧链,其结构变化丰富。但是存在侧链长度过长和芳杂环太大的缺点。化合物在伸入多肽通道,与核糖体的作用位点结合过程中,4″位侧链长度过长容易使侧链片断堆积,这有可能会影响去氧氨基糖上的2′位羟基与A2058或A2059的结合,从而影响抗菌活性的发挥;芳杂环如果太大,会存在空间位阻效应,这也会影响大环内酯抗生素与核糖体的结合,影响抗菌活性。此外,现有一些专利中,在C-4″引入了含有酯键、醚键、硫醚键的侧链,酯键在体内容易被酯酶水解,而醚键和硫醚键则易发生氧化,使得体内非活性物质增多,这不但降低了化合物的抗菌活性,而且使副作用和毒性增大。
发明内容
针对上述现有技术,本发明提供了一类侧链长度适当、抗菌活性好、无毒副作用、构型稳定的大环内酯类衍生物:4″-取代苯甲酰哌嗪基氨基甲酸酯阿奇霉素衍生物,并提供了其制备方法,以及其制备中涉及的中间体。
本发明是通过以下技术方案实现的:
一种式(Ⅰ)表示的阿奇霉素衍生物或其药学上可接受的盐:
其中,R1代表氢、乙酰基或苯甲酰基;
R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、卤素、硝基、烷氧基或-AR7,优选氢、4-甲基、4-叔丁基、4-甲氧基、4-硝基、4-氟、4-氯、4-溴、3-甲基、3-硝基,3,5-二硝基;
R3代表OR5,R4代表羟基;或者:R3和R4形成具有如下结构的环:
X代表氧、氮,优选氧;
R5代表氢或CONHR6;
R6代表脂肪烃基、取代芳香烃基或取代芳杂环烃基,优选正丙基、异丙基、丙烯基、正丁基;
R7代表脂肪烃基、取代芳香烃基或取代芳杂环烃基;
n为1~6,优选3;
A为-O-,-CO-,-CONR8-,-NHCO-,-S-中的任一种。
本发明的4″-取代苯甲酰哌嗪基氨基甲酸酯阿奇霉素衍生物,可用于抗菌,用于治疗人体或动物的细菌感染。
一种药物组合物,该药物组合物包括作为活性成分的药学有效量的由式(Ⅰ)表示的阿奇霉素衍生物或其药学上可接受的盐,还包含药学上可接受的载体或稀释剂。
一种如式(Ⅱ)的中间体:
其中R1代表乙酰基或苯甲酰基。
一种如式(Ⅲ)的中间体:
其中R3和R4均代表羟基,或者R3和R4形成具有如下结构的环:
X代表氧、氮。
本发明的阿奇霉素衍生物的详细制备方法如下(包括侧链及中间体的制备):
所需侧链的制备方法,合成路线如下:
步骤如下:
1.将通式(Ⅶ)与氯化亚砜混合,50~100℃加热回流3~6小时,生成具有上述通式(Ⅷ)的化合物。
2.将哌嗪在丙酮与水的混合溶剂中,与通式(Ⅷ)在20-90℃的温度下反应,同时用有机碱中和生成的盐酸,维持PH=3~4,生成具有上述通式(Ⅸ)的化合物。
3.上述通式(Ⅸ)在有机和无机碱的存在下,在异丙醇溶剂中,与氯代脂肪胺盐酸盐反应,生成具有上述通式(Ⅵ)的化合物。
4″-取代苯甲酰哌嗪基氨基甲酸酯阿奇霉素衍生物的制备方法,合成路线如下:
制备方法如下:
4.将通式(Ⅳ)的2′-OH酰化保护,酰化试剂用醋酐、醋酸,乙酰氯,苯甲酸酐、苯甲酸或苯甲酰氯,在无机或有机碱类存在下,以丙酮、乙酸乙酯、四氢呋喃或二氯甲烷作为溶剂,在0~40℃的温度下进行反应,生成具有上述通式(Ⅱ)的化合物;
5.将具有通式(Ⅱ)的化合物在惰性溶剂中,在无机或有机碱存在下,与N,N′-二羰基咪唑(CDI)于0~110℃反应2~72h,生成具有通式(Ⅲ)的化合物;
6.上述通式(Ⅲ)的化合物与上述通式(Ⅵ),在N,N-二甲基甲酰胺、四氢呋喃、乙腈、乙腈-水之一或混合溶剂中反应,催化剂1.8-二氮杂二环(5.4.0)十一烯-7(DBU),于0~100℃反应2~4h,生成通式(Ⅰ)的化合物;
7.当上述通式(Ⅰ)的化合物R1为乙酰基或苯甲酰基时,进一步在低级醇类溶剂中醇解脱去2′-位上的酰基,产生通式(Ⅴ)的化合物。其中R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、氨基、羟基、卤素、硝基、烷氧基、-AR7,R3和R4均代表羟基或者R3和R4形成具有如下结构的环:
X代表氧、氮,R7代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R8代表氢、羟基、脂肪烃基、取代芳香烃基、取代芳杂环烃基,A为-O-,-CO-,-CONR8-,-NHCO-,-S-,n为1~6。
8.当上述通式(Ⅰ)的化合物,R2代表氢、烷基、卤素、硝基、烷氧基,R3和R4形成具有如下结构的环:
X代表氧、氮时,与脂肪胺、取代芳香胺和取代芳杂环脂肪胺反应,或溶于N-甲基咪唑、三乙胺或二乙胺等碱性溶剂,催化剂盐酸吡啶、咪唑等,于0~110℃反应12~120h,生成通式(Ⅹ)。其中R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、氨基、羟基、卤素、硝基、烷氧基、-AR7,R4代表羟基,R6代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R7代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R8代表氢、羟基、脂肪烃基、取代芳香烃基、取代芳杂环烃基,A为-O-,-CO-,-CONR8-,-NHCO-,-S-,n为1~6。
9.当上述通式(Ⅴ)的化合物,R2代表氢、烷基、卤素、硝基、烷氧基,R3和R4形成具有如下结构的环:
X代表氧、氮时,与脂肪胺、取代芳香胺和取代芳杂环脂肪胺反应,或溶于N-甲基咪唑、三乙胺或二乙胺等碱性溶剂,催化剂盐酸吡啶、咪唑等,于0~110℃反应12~120h,生成通式(Ⅺ)。其中R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、氨基、羟基、卤素、硝基、烷氧基、-AR7,R4代表羟基,R6代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R7代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R8代表氢、羟基、脂肪烃基、取代芳香烃基、取代芳杂环烃基,A为-O-,-CO-,-CONR8-,-NHCO-,-S-,n为1~6。
10.当上述通式(Ⅹ)的化合物R1为乙酰基或苯甲酰基时,进一步在低级醇类溶剂中醇解脱去2′-位上的酰基,产生通式(Ⅺ)的化合物。其中其中R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、氨基、羟基、卤素、硝基、烷氧基、-AR7,R4代表羟基,R6代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R7代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R8代表氢、羟基、脂肪烃基、取代芳香烃基、取代芳杂环烃基,A为-O-,-CO-,-CONR8-,-NHCO-,-S,n为1~6。
上述步骤1中:酰化试剂与克拉霉素的摩尔比1∶1~5,优选1∶2。
上述步骤1中:优选的乙酰化试剂是醋酐。
上述步骤1中:优选的有机碱是三乙胺。
上述步骤1中:优选的溶剂是二氯甲烷。
上述步骤1中:优选在25℃条件下进行反应3~24h。
优选的,上述步骤1中后处理方法如下:在碱介质中,优选在pH8.0~10.0下萃取,通过分离有机层并蒸干溶剂来分离产物。必要时,再通过重结晶(丙酮-水)或使用二氯甲烷-甲醇(15∶1)系统的硅胶柱层析进行纯化,可产生纯度达95%以上的具有Rf值为0.42的通式(Ⅱ)的化合物。
上述步骤2中:控制通式(Ⅱ)的化合物与CDI的摩尔比1∶1~6,优选摩尔比1∶2,可以产生纯度90%以上的Rf值为0.45(二氯甲烷/甲醇=15∶1)的通式(Ⅲ)的化合物。
上述步骤2中:惰性溶剂选自二氯甲烷、四氢呋喃或甲苯,优选甲苯。
上述步骤2中:所述的无机或有机碱选自碳酸氢钠、碳酸钠、碳酸钾、三乙胺、吡啶或4-二甲氨基吡啶,优选三乙胺。
上述步骤3中:反应溶剂优选N,N-二甲基甲酰胺。
上述步骤4中:低级醇优选甲醇,反应温度为55℃,反应时间为24h。
大环内酯抗生素与克林霉素和氯霉素的作用机制相似,都是通过作用于细菌核糖体50S亚单位来发挥抗菌活性。X-衍射研究表明,大环内酯、克林霉素和氯霉素与核糖体结合时分子结构相互重叠:大环内酯C-5位去氧氨基糖与克林霉素糖基处于同一位置,均与A2058和A2059结合;克林霉素脯氨酸基团接近A2451,与氯霉素对硝苯基团重叠,均与U2505和G2061结合。克林霉素作用于A和P位核苷酸,阻碍新生肽进入肽释放通道。本发明选择在阿奇霉素C-4″引入取代苯甲酰哌嗪基氨基甲酸酯侧链,其与氯霉素碳原子数目相近,键角和键长合适,与细菌核糖体作用时,能够指向肽酰转移酶中心,与A2451作用,从而增强抗菌活性。
本发明在阿奇霉素的C-4″羟基上首次引入结构特异且生理活性广泛的取代苯甲酰哌嗪侧链,提供一系列新颖的4″-取代苯甲酰哌嗪基氨基甲酸酯阿奇霉素衍生物。苯甲酰结构在许多药物中存在,苯环可以通过π电子堆积力与核糖体核苷酸结合,而甲酰基则可通过核糖体核苷酸作用,此外,苯环上变化丰富的取代基团,如羟基、酚羟基、氨基、芳杂环等可以通过氢键、静电力、π电子堆积力、范德华力等一系列化学键与生理条件下靶标核苷酸的腺苷或碱基密切结合,因此在阿奇霉素的C-4″位引入取代苯甲酰哌嗪氨基甲酸酯侧链能够增强整个分子与核糖体的亲和力,从而增强了目标化合物的抗菌活性,扩大抗菌谱。取代苯甲酰哌嗪是一类结构特异且生理学活性广泛的化合物,许多α,β受体阻断剂具有这类结构,其在抗高血压方面表现非常突出,并且具有优良的药代动力学。因此将取代苯甲酰哌嗪侧链引入阿奇霉素的4″羟基位置,能达到改善药代动力学性质的目的。
现有一些的专利缺乏对化合物抗菌活性的阐述。本发明测定了目标化合物对6种常见菌株的体外抗菌活性的,有利于考察C-4″位侧链的引入对抗菌活性的影响以及侧链末端取代基团的变化对抗菌活性的影响。通过测定抗菌活性发现,现有的化合物不仅对敏感的金黄色葡萄球菌,化脓链球菌和肺炎链球菌均保持了较好的体外抗菌活性,而且对erm基因介导的耐药肺炎链球菌、mef基因介导的耐药性肺炎链球菌以及erm和mef基因介导的混合耐药性肺炎链球菌的体外抗菌活性与对照药相比均显著改善。值得关注的是,大多数化合物对mef基因介导的外排泵耐药性肺炎链球菌表现出非常敏感的抗菌活性(MIC≤0.25),与对照药相比提高了32倍以上。发明人推测,原因肯呢个是由于:1.取代苯甲酰哌嗪侧链能够伸入肽通道,指向肽酰转移酶中心,通过氢键、静电力、π电子堆积力、范德华力等一系列化学键与A2451结合,增强了整个分子与核糖体的亲和力,从而使药物不易被耐药菌的外排泵泵出;2.取代苯甲酰哌嗪侧链的引入,改变了阿奇霉素的空间结构,使目标化合物不能被细菌外排泵识别,从而不易被泵出细胞膜。
综上,本发明的阿奇霉素衍生物,具有较好的抗菌活性,且对耐药的细菌也有较好的抗菌活性,可以作为抗细菌感染药物应用。
阿奇霉素衍生物的抗菌活性实验:
采用96孔板微量二倍稀释法测定了部分目标化合物对敏感金黄色葡萄球菌ATCC25923、敏感肺炎链球菌ATCC49619、敏感化脓性链球菌、MLSB型耐药肺炎链球菌B1(erm)、M型耐药肺炎链球菌A22072(mef)和MLSB+M型耐药肺炎链球菌(erm+mef)的体外抗菌活性。测定结果见表1。
表1阿奇霉素衍生物与现有主要大环内酯抗生素的抗菌活性MIC值(μg/mL)
其中,化合物1~46即为以下取代的一系列化合物:R2代表氢、脂肪烃基、取代芳香烃基、取代芳杂环烃基、氨基、羟基、卤素、硝基、烷氧基、-AR7,R3代表OR5,R4代表羟基,或者R3和R4形成具有如下结构的环:
X代表氧、氮,优选氧。R5代表氢、CONHR6,R6代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,优选正丙基、异丙基、丙烯基、正丁基,R7代表脂肪烃基、取代芳香烃基、取代芳杂环烃基,R8代表氢、羟基、脂肪烃基、取代芳香烃基、取代芳杂环烃基,A为-O-,-CO-,-CONR8-,-NHCO-,-S-,n为1~6。
化合物1~46依次代表的化合物如下:
1、4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
2、4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
3、4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
4、4″-O-(3-(4-(4-甲氧基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
5、4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
6、4″-O-(3-(4-(4-氟苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
7、4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
8、4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
9、4″-O-(3-(4-(3-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
10、4″-O-(3-(4-(3-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
11、4″-O-(3-(4-(3,5-二硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素、
12、4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
13、4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
14、4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
15、4″-O-(3-(4-(4-甲氧基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
16、4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
17、4″-O-(3-(4-(4-氟苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
18、4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
19、4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
20、4″-O-(3-(4-(3-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
21、4″-O-(3-(4-(3-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
22、4″-O-(3-(4-(3,5-二硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯、
23、11-O-正丙基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基酯阿奇霉素、
24、11-O-异丙基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基酯阿奇霉素、
25、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基酯阿奇霉素、
26、11-O-正丁基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基酯阿奇霉素、
27、甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
28、、11-O-正丙基氨基基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
29、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
30、11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
31、11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
32、11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
33、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
34、11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
35、11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
36、11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
37、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
38、11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
39、11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
40、11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
41、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
42、11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
43、11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
44、11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
45、11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素、
46、11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素。
由表1可知:所列的目标化合物1~46对敏感金黄色葡萄球菌及敏感肺炎链球菌表现出一定的抗菌活性;与对照药物红霉素、克拉霉素、阿奇霉素相比,所列的目标化合物1~46中的大部分化合物对不同耐药基因(erm或mef基因)介导的耐药肺炎链球菌表现出明显增强的抑制活性。
具体实施方式
下面通过实施例对本发明作进一步的说明。
实施例1.
苯甲酰氯的制备
将苯甲酸(1.00g,8.19mmol)置于50ml的圆底烧瓶中,加入氯化亚砜(15ml,0.20mol),80℃加热回流4小时,减压蒸去氯化亚砜,进入下一步反应。
实施例2
苯甲酰哌嗪的制备
将哌嗪(0.7g,8.19mmol)置于50ml三颈瓶中,加入16ml水使其溶解;滴加4滴甲基橙指示剂,用2mol/L的盐酸溶液调PH,使其恰好由黄变红;加入16ml丙酮,于50℃油浴搅拌下缓缓滴加苯甲酰氯,并不断用40%的醋酸钠溶液中和生成的HCl,使反应液PH保持在甲基橙的变色范围;反应30分钟,减压蒸除丙酮,用40%氢氧化钠溶液调PH=12,二氯甲烷提取,无水硫酸钠干燥,加压蒸干的无色油状物0.72g。收率45.2%,Rf为0.65(展开剂为二氯甲烷∶甲醇=5∶1)。
实施例3
4-(3-氨基丙基)哌嗪-1-基苯甲酮的制备
将苯甲酰哌嗪(0.72,3.78mmol)置于100ml圆底烧瓶中,加入10ml异丙醇溶解,加入氯丙胺盐酸盐(0.70g,5.67mmol)和三乙胺(1.06ml,6.56mmol),50℃油浴搅拌24h,90℃加热回流24h;加压蒸干,加水溶解,用40%NaOH调PH=12,二氯甲烷提取,饱和氯化钠洗涤,无水硫酸钠干燥,减压蒸馏的油状物0.7g,硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=20∶1),得无色油状物,即为目标化合物A1(0.3g,1.21mmol),收率45.2%,Rf为0.16(展开剂为二氯甲烷∶甲醇=5∶1)。
其它结构相近的化合物的制备采用与实施例3相同的方法。
实施例4.
2′-O-乙酰基-阿奇霉素的制备
将阿奇霉素(2.0g,2.67mmol)溶解于无水二氯甲烷(20mL),加入醋酐(0.50mL,5.34mmol)和三乙胺(1.48mL,10.68mmol),室温搅拌24h。反应完毕后,加入等体积5%碳酸氢钠溶液,分液,二氯甲烷提取(10mL×2),合并有机层,无水硫酸钠干燥。过滤,减压蒸干,得白色泡沫状固体,丙酮-水(2∶1)重结晶得白色目标产物(1.61g),收率95.2%。熔点147-150℃,Rf为0.59(展开剂为二氯甲烷∶甲醇=10∶1)。
实施例5.
a)4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素的制备
将2′-O-乙酰基-阿奇霉素(1.5g,1.90mmol)溶解于无水甲苯(20mL),加入三乙胺(0.60mL,4.33mmol)和N,N′-二羰基咪唑(CDI)(0.672g,3.80mmol),55℃下搅拌24h。反应完毕后,加入饱和碳酸氢钠溶液(20mL),分液,甲苯萃取(6mL×2),合并有机层,无水硫酸钠干燥。过滤,减压蒸干,得白色泡沫状固体1.6g,收率95.4%。熔点147-150℃,Rf为0.592(展开剂为二氯甲烷∶甲醇=10∶1)。
b)4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯的制备
将2′-O-乙酰基-阿奇霉素溶解(1.5g,1.90mmol)于无水甲苯(20mL),加入三乙胺(0.60mL,4.33mmol)和CDI(N,N′-二羰基咪唑)(1.23g,7.6mmol),75℃加热搅拌24h。反应完毕后,加入饱和碳酸氢钠溶液(40mL),分液,甲苯提取(6mL×2),合并有机层,无水硫酸钠干燥。过滤,减压蒸干,得白色泡沫状固体1.65g,收率95.5%。熔点117~120℃,Rf为0.61(展开剂为二氯甲烷∶甲醇=10∶1)。
实施例6.
a):4″-O-(3-(4-苯甲酰哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素的制备
将4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素(1.33g,1.50mmol)溶解于DMF(15mL)中,加入DBU(0.33mL,2.25mmol)和4-(3-氨基丙基)-哌嗪-1-基苯甲酮(0.84g,3.40mmol)(自行制备),室温搅拌24h。反应完毕后,加入水(30mL),乙酸乙酯(15mL×3)萃取,合并有机层,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色泡沫固体1.17g,收率72.1%。Rf为0.56(展开剂为二氯甲烷∶甲醇=10∶1)。
b):4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素的制备
将4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素(1.33g,1.50mmol)溶解于DMF(15mL)中,加入DBU(0.33mL,2.25mmol)和4-(3-氨基丙基)-哌嗪-1-基,4-甲基苯甲酮(0.98g,3.40mmol)(自行制备),室温搅拌24h。反应完毕后,加入水(30mL),乙酸乙酯(15mL×3)萃取,合并有机层,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色泡沫固体1.01g,收率65.0%。Rf为0.56(展开剂为二氯甲烷∶甲醇=10∶1)。
c):4″-O-(3-(4-苯甲酰哌嗪基)丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯的制备
将4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯(1.37g,1.50mmol)溶解于DMF(15mL)中,加入DBU(0.33mL,2.25mmol)和4-(3-氨基丙基)哌嗪-1-基苯甲酰基甲酮(0.84g,3.40mmol)(自行制备),室温搅拌24h。反应完毕后,加入水(30mL),乙酸乙酯(15mL×3)萃取,合并有机层,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色泡沫固体1.23g,收率74.3%。Rf为0.59(展开剂为二氯甲烷∶甲醇=10∶1)。
d):4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯的制备
将4″-O-(1-H-咪唑-1-羰基)-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯(1.33g,1.50mmol)溶解于DMF(15mL)中,加入DBU(0.33mL,2.25mmol)和4-(3-氨基丙基)-哌嗪-1-基,4-甲基苯甲酮(0.98g,3.40mmol)(自行制备),室温搅拌24h。反应完毕后,加入水(30mL),乙酸乙酯(15mL×3)萃取,合并有机层,饱和食盐水(15mL×3)洗涤,无水硫酸钠干燥,减压蒸干得白色泡沫固体1.01g,收率65.0%。Rf为0.56(展开剂为二氯甲烷∶甲醇=10∶1)。
其它结构相近的化合物的制备采用与实施例6相同的方法。
实施例7.
a):4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物1)的制备
将4″-O-(3-(4-苯甲酰哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素(1.17g)溶解于甲醇(30mL)中,45℃搅拌12h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=25∶1),得白色泡沫状固体。收率65.0%,mp:144-149℃,TLC Rf=0.16(甲醇/二氯甲烷,1∶10);IR(KBr):3335,2971,2936,2827,1725,1634,1577,1507,1459,1378,1257,1168,1108,1075,1043,1015cm-1;1HNMR(600MHz,CDCl3)δ7.43(m,5H,Ar-H),5.05(m,1H,1′-CH),4.70(m,1H,1″-CH),4.66-4.48(m,2H,4″-CH and 5″-CH),4.31-4.26(m,2H,1-CH and 13-CH),3.81-3.70(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.69(m,2H,2′-CH and 5′-CH),3.46(s,1H,3-CH),3.42-3.22(m,3H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr and 10-CH),2.84(d,J=9.6Hz,1H,5-CH),2.74-2.55(s,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.41-1.93(m,10H,3″-N(CH3)2,4-CH,2″-CH and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.67-1.51(m,6H,9-CH,2″-CH,8-CH,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.31-1.19(m,16H,6-CH3,3″-CH3,7-CH,2-CH3,5″-CH3 and 5′-CH3),1.12-1.06(m,9H,12-CH3,8-CH3 and 4-CH3),1.01(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C53H91N5O141022.2;found(M+H+)1023.2。
b):4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物2)
将4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素(1.17g)溶解于甲醇(30mL)中,45℃搅拌12h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=25∶1),得白色泡沫状固体。收率:66.2%,mp:112-118℃,TLC Rf=0.15(甲醇/二氯甲烷,1∶10):IR(KBr):3347,2971,2935,2828,1725,1635,1510,1458,1378,1334,1294,1257,1168,1109,1074,1045,1014cm-1;1HNMR(600MHz,CDCl3)δ7.28(d,J=8.0Hz,2H,Ar-H),7.19(d,J=7.5Hz,2H,Ar-H),5.12(m,1H,1′-CH),4.87(m,1H,1″-CH),4.67(d,J=9.3Hz,1H,4″-CH),4.52(d,J=9.0Hz,1H,5″-CH),4.32-4.25(m,2H,11-CH and 13-CH),3.67-3.52(m,2H,2′-CH and 5′-CH),3.44-3.38(m,2H,3-CH and10-CH),3.35-3.22(m,7H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 3″-OCH3),3.16-3.10(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.80(m,2H,2-CH and 5-CH),2.69-2.62(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.50(d,J=8.9Hz,2H,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.38(m,3H,Ar-CH3),2.33(s,6H,3″-N(CH3)2),2.31(s,3H,9a-NCH3),2.13-1.95(m,5H,4-CH,9-CH,2″-CH,8-CH and 4′-CH),1.97-1.75(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.67(m,1H,7-CH),1.34-1.24(m,9H,6-CH3,3″-CH3,7-CH and 13-CH 2CH3),1.19(s,9H,2-CH3,5″-CH3and 5′-CH3),1.13(s,3H,10-CH3),1.07(m,9H,12-CH3,8-CH3and 4-CH3),0.90(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C54H93N5O141036.2;found(M+H+)1037.2。
化合物3-11采用与实施例7a和7b相同的方法。
4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物3)白色晶体,收率:64.8%,mp:172-180℃,TLC Rf=0.16(甲醇/二氯甲烷,1∶10):IR(KBr):3323,2967,2826,1724,1632,1511,1462,1379,1294,1258,1168,1109,1076,1042,1012cm-1;1HNMR(600MHz,CDCl3)δ7.44-7.36(m,2H,Ar-H),7.32(d,J=8.1Hz,2H,Ar-H),5.03(m,1H,1′-CH and 1″-CH),4.63(s,1H,4″-CH),4.53(m,1H,5″-CH),4.25(s,1H,1-CH),4.19(s,1H,13-CH),3.75(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.65(m,1H,2′-CH),3.60(m,1H,5′-CH),3.45(s,1H,3-CH),3.34-3.23(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.20(d,J=14.4Hz,1H,10-CH),2.90(m,1H,5-CH),2.76-2.48(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.47-2.26(m,11H,3″-N(CH3)2,4-CH,9-CH,2″-CH,8-CH and 4′-CH),2.20-1.95(m,2H,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.74(s,1H,4-CH),1.70-1.54(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.49(m,1H,7-CH),1.42(m,9H,Ar-C(CH3)3),1.32-1.18(m,16H,6-CH3,3″-CH3,7a-CH,2-CH3,5″-CH3and 5′-CH3),1.17-0.95(m,9H,12-CH3,8-CH3and 4-CH3),0.90(t,J=7.2Hz,3H,13-CH2 CH 3 );MS:m/z calcd.forC57H99N5O141078.3;found(M+H+)1079.3。
4″-O-(3-(4-(4-甲氧基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物4)白色晶体,收率:67.3%,mp:134-140℃,TLC Rf=0.17(甲醇/二氯甲烷,1∶10):IR(KBr):3335,2971,2936,2829,1725,1631,1610,1575,1513,1459,1378,1333,1296,1251,1172,1108,1093,1074,1040,1015cm-1;1HNMR(600MHz,CDCl3)δ7.38(d,J=8.3Hz,2H,Ar-H),6.91(d,J=8.3Hz,2H,Ar-H),5.11-5.07(m,1H,1′-CH),4.91-4.86(s,1H,1″-CH),4.68(d,J=9.9Hz,1H,4″-CH),4.54(d,J=9.9Hz,1H,5″-CH),4.34(m,1H,1-CH),4.25(m,1H,13-CH),3.84-3.78(m,7H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and Ar-OCH 3 ),3.67(m,3H,2′-CH,5′-CH and 3-CH),3.26(m,3H,10-CH and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.80(m,1H,2-CH),2.71(d,J=6.3Hz,1H,5-CH),2.51(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.40-2.33(m,11H,3″-N(CH3)2,4-CH,9-CH,2″-CH,8-CH and 4′-CH),2.12-1.93(m,2H,4″-OCONHCH2CH 2 CH 2 N(CH2CH2)2NCOAr),1.75-1.69(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.54(m,1H,7-CH),1.28-1.15(m,16H,6-CH3,3″-CH3,7a-CH,2-CH3,5″-CH3 and 5′-CH3),1.13-0.97(m,9H,12-CH3,8-CH3 and 4-CH3),0.90(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C54H93N5O15 1052.1;found(M+H+)1053.1。
4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物5)白色晶体,收率:66.7%,mp:133-137℃,TLC Rf=0.18(甲醇/二氯甲烷,1∶10):IR(KBr):3345,2971,2934,1724,1636,1601,1525,1458,1378,1351,1313,1295,1258,1168,1125,1108,1076,1045,1013cm-1;1HNMR(600MHz,CDCl3)δ8.29(d,J=12.0Hz,2H,Ar-H),7.56(d,J=8.2Hz,2H,Ar-H),5.10-5.05(m,1H,1′-CH),4.88-4.78(m,1H,1″-CH),4.65(m,1H,4″-CH),4.59-4.49(m,1H,5″-CH),4.35(m,1H,11-CH),4.24-4.19(m,1H,13-CH),3.77(m,2H,2′-CH and 5′-CH),3.70-3.55(m,2H,3-CH and 10-CH),3.36-3.19(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),2.74(m,2H,2-CH and 5-CH),2.51(s,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.45-2.25(m,10H,3″-N(CH3)2 and4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.17(s,3H,9a-NCH3),2.97(m,5H,4-CH,9-CH,2″-CH,8-CH and 4′-CH),1.89(m,2H,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.78-1.53(m,3H,7-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.44(m,2H,13-CH 2CH3),1.27(m,7H,6-CH3,3″-CH3 and 7-CH),1.19(s,9H,2-CH3,5″-CH3and 5′-CH3),1.13(s,3H,10-CH3),1.06(m,12-CH3,8-CH3and 4-CH3),0.95-0.85(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C53H90N6O161067.0;found(M+H+)1068.0。
4″-O-(3-(4-(4-氟苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物6)白色晶体,收率:68.1%,mp:161-168℃,TLC Rf=0.16(甲醇/二氯甲烷,1∶10):IR(KBr):3305,2971,2936,2828,1724,1636,1605,1511,1459,1380,1333,1294,1257,1168,1125,1077,1044,1013cm-1;1HNMR(600MHz,CDCl3)δ7.46-7.37(m,2H,Ar-H),7.10(d,J=8.3Hz,2H,Ar-H),5.09(m,1H,1′-CH),4.71-4.65(m,1H,1″-CH),4.56(m,3H,4″-CH,5″-CHand 11-CH),4.30(m,1H,13-CH),3.75(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.70-3.57(m,2H,2′-CH and 5′-CH),3.44-3.34(m,2H,3-CH and 10-CH),3.37-3.19(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.89(m,1H,2-CH),2.75(m,1H,5-CH),2.58(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.46-2.24(m,6H,3″-N(CH3)2),2.16-1.97(m,7H,4-CH,9-CH,2″-CH,8-CH,4′-CH and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.95-1.84(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.45(m,H,7-CH),1.42-1.26(m,2H,13-CH 2 CH3),1.21-1.16(m,16H,6-CH3,3″-CH3,7-CH,2-CH3,5″-CH3and 5′-CH3),1.09(m,6H,12-CH3and 8-CH3),1.03(d,J=6.9Hz,3H,4-CH3),0.90(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C53H90FN5O141039.9;found(M+H+)1040.9。
4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物7)白色晶体,收率:64.8%,mp:136-144℃,TLC Rf=0.17(甲醇/二氯甲烷,1∶10):IR(KBr):3328,2971,2935,1725,1636,1597,1508,1459,1378,1333,1294,1257,1169,1108,1090,1043,1013cm-1;1HNMR(600MHz,CDCl3)δ7.40(d,J=3.0Hz,2H,Ar-H),7.38(m,J=3.0Hz,2H,Ar-H),4.65(m,2H,1′-CH and 1″-CH),4.54-4.45(m,3H,4″-CH,5″-CH and 11-CH),4.25(s,1H,13-CH),3.75(m,2H,2′-CH and 5′-CH),3.62(m,2H,3-CH and 10-CH),3.42-3.29(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),2.78(m,1H,2-CH),2.67(m,1H,5-CH),2.52(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.37-2.30(m,6H,3″-N(CH3)2),2.17-1.94(m,3H,9a-NCH3),2.01(m,5H,4-CH,9-CH,2″-CH,8-CH and4′-CH),1.84(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),1.74-1.62(m,3H,7-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.48-1.40(m,2H,13-CH 2 CH3),1.29-1.20(m,9H,6-CH3,3″-CH3,7-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.18(s,9H,2-CH3,5″-CH3 and 5′-CH3),1.06(m,9H,12-CH3,8-CH3 and 4-CH3),0.90-0.86(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C53H90ClN5O141056.0;found(M+H+)1057.0。
4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物8)白色晶体,收率:66.3%,mp:112-118℃,TLC Rf=0.15(甲醇/二氯甲烷,1∶10):IR(KBr):3331,2971,2932,1718,1632,1496,1458,1382,1333,1259,1169,1126,1078,1044,1011cm-1;1HNMR(600MHz,CDCl3)δ7.54(m,2H,Ar-H),7.43(m,2H,Ar-H),4.99(m,1H,1′-CH),4.53(m,1H,1″-CH),4.42(m,3H,4″-CH,5″-CH and 11-CH),4.21(m,1H,13-CH),3.89-3.80(m,2H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.43(m,2H,2′-CH and 5′-CH),3.37(m,2H,3-CH and 10-CH),3.26(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.92(m,2H,2-CH and 5-CH),2.52(s,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.37(m,6H,3″-N(CH3)2),1.91(m,7H,4-CH,9-CH,2″-CH,8-CH,4′-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.71(s,1H,7-CH),1.64(m,2H,4″-OCONHCH 2 CH 2 CH 2 N(CH2CH2)2NCOAr)),1.45(m,2H,13-CH 2CH3),1.27-1.17(m,16H,6-CH3,3″-CH3,7-CH,2-CH3,5″-CH3and 5′-CH3),1.08(d,J=16.9Hz,6H,12-CH3 and 8-CH3),1.01(s,3H,4-CH3),0.89(t,J=7.2Hz,3H,13-CH2 CH 3 );MS:m/z calcd.for C54H93N5O141102.1;found (M+H+)1103.1
4″-O-(3-(4-(3-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物9)白色晶体,收率:67.4%,mp:136-140℃,TLC Rf=0.18(甲醇/二氯甲烷,1∶10):IR(KBr):3315,2971,2936,2827,1724,1636,1584,1507,1460,1379,1333,1296,1256,1208,1169,1108,1075,1042,1013cm-1;1HNMR(600MHz,CDCl3)δ7.21(m,2H,Ar-H),7.16(d,J=7.4Hz,2H,Ar-H),5.04(m,1H,1′-CH),4.68(m,1H,1″-CH),4.52(m,3H,4″-CH,5″-CH and 11-CH),4.22(m,1H,13-CH),3.89-3.80(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 ) 2 NCOAr),3.71-3.55(m,2H,2′-CH and 5′-CH),3.46(m,2H,3-CH and 10-CH),3.28(m,2H,4″-OCONHCH 2 (CH2)2N(CH2CH2)2NCOAr and Ar-CH3),2.75-2.74(m,2H,2-CH and 5-CH),2.50(s,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.44-2.26(m,6H,3″-N(CH3)2),2.10-1.82(m,7H,4-CH,9-CH,2″-CH,8-CH,4′-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.79(s,1H,7-CH),1.76-1.58(m,2H,4″-OCONHCH 2 CH 2 CH 2 N(CH2CH2)2NCOAr)),1.52-1.43(m,2H,13-CH 2CH3),1.28-1.16(m,16H,6-CH3,3″-CH3,7-CH,2-CH3,5″-CH3 and 5′-CH3),1.09(m,6H,12-CH3 and 8-CH3),1.01(s,3H,4-CH3),0.90(t,J=7.2Hz,3H,13-CH2 CH 3 );MS:m/zcalcd.for C54H93N5O141036.2;found(M+H+)1037.2。
4″-O-(3-(4-(3-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物10)白色晶体,收率:68.1%,mp:182-186℃,TLC Rf=0.15(甲醇/二氯甲烷,1∶10):IR(KBr):3336,2973,2937,2828,2605,2498,1724,1640,1535,1458,1378,1351,1296,1257,1170,1108,1076,1039,1014cm-1;1HNMR(600MHz,CDCl3)δ8.36-8.25(m,2H,Ar-H),7.75(d,J=7.5Hz,2H,Ar-H),5.09-5.04(m,1H,1′-CH),4.69(m,1H,1″-CH),4.54-4.43(m,3H,4″-CH,5″-CH and 11-CH),4.29(m,1H,13-CH),3.75(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.66-3.55(m,2H,2′-CH and 5′-CH),3.40(m,2H,3-CH and 10-CH),3.27-3.05(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.86-2.80(m,1H,2-CH),2.78(m,1H,5-CH),2.71-2.54(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.47-2.27(m,6H,3″-N(CH3)2),2.27-1.95(m,7H,4-CH,9-CH,2″-CH,8-CH,4′-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),1.95-1.89(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.80-1.68(m,1H,7-CH),1.44-1.29(m,2H,13-CH 2CH3),1.28-1.18(m,16H,6-CH3,3″-CH3,7a-CH,2-CH3,5″-CH3 and 5′-CH3),1.09(d,J=10.6Hz,6H,12-CH3 and 8-CH3),1.04(s,3H,4-CH3),0.90(dd,J=15.1,6.9Hz,3H,13-CH2 CH 3 );MS:m/zcalcd.for C53H90N6O161067.0;found(M+H+)1068.0。
4″-O-(3-(4-(3,5-二硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素(目标化合物11)白色晶体,收率:63.7%,mp:140-146℃,TLC Rf=0.14(氯仿/甲醇,1∶10):IR(KBr):3458,3106,2972,2937,2828,1725,1644,1547,1507,1457,1377,1344,1276,1169,1109,1075,1044,1013cm-1;1HNMR(600MHz,CDCl3)δ8.56(m,3H,Ar-H),5.06-5.02(m,1H,1′-CH),4.84(m,1H,1″-CH),4.71(d,J=9.7Hz,1H,4″-CH),4.57(m,1H,5″-CH),4.37(s,1H,1-CH),4.27(m,1H,13-CH),3.85(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.77-3.60(m,2H,2′-CH and 5′-CH),3.45(m,1H,3-CH),3.43-3.17(m,3H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr and 10-CH),2.85(m,1H,5-CH),2.73-2.50(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.44-2.42(m,2H,4″-OCONHCH2CH 2 CH 2 N(CH2CH2)2NCOAr),2.30(m,6H,3″-N(CH3)2),2.13-1.94(m,2H,4-CH and 2″-CH),1.84-1.38(m,4H,9-CH,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.31-1.18(m,16H,6-CH3,3″-CH3,7a-CH,2-CH3,5″-CH3and 5′-CH3),1.05-1.02(m,9H,12-CH3,8-CH3and 4-CH3),0.98-0.87(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C53H89N7O181112.1;found(M+H+)1113.1。
c):4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物1)的制备
将4″-O-(3-(4-苯甲酰哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯(1.17g)溶解于甲醇(30mL)中,45℃搅拌12h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=25∶1),得白色泡沫状固体。收率:72.5%,mp:152-158℃,TLCRf=0.21(methanol/dichlormethane,1∶10);I
d):4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物2)的制备
将4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-2′-O-乙酰基-阿奇霉素-11,12-环碳酸酯(1.17g)溶解于甲醇(30mL)中,45℃搅拌12h,减压蒸干得白色泡沫状固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=25∶1),得白色泡沫状固体。收率:70.8%,mp:146-150℃,TLC Rf=0.22(methanol/dichlormethane,1∶10);
其它实施例(化合物12~22)采用与7c、7d相同的方法。
4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物12)白色固体,收率:72.5%,mp:152-158℃,TLC Rf=0.21(methanol/dichlormethane,1∶10);IR (KBr):3396,2975,2937,2826,1812,1723,1633,1577,1509,1459,1379,1352,1335,1294,1238,1166,1109,1074,1045,1015cm-1;1H NMR (600MHz,CDCl3):δ7.420(m,5H,HAr),5.05(d,1H,J=4.2Hz,1′-CH),4.90(d,1H,J=3.0Hz,1″-CH),4.88(m,1H,J=2.4Hz,13-CH),4.57(m,2H,4″-CH,5″-CH),4.54(m,1H,11-CH),4.33(m,2H,2′-CH,5′-CH),3.81(m,1H,5-CH),3.73(s,1H,3-CH),3.62(m,1H,10-CH),3.46(m,2H,4″-OCONHCH 2 (CH2)2N(CH 2 C-H2)2NCOAr),3.31(s,3H,3″-OCH3),3.28-3.25(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),2.87(m,3H,2-CH,3′-CH and 9b-CH),2.68(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.47(m,3H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.44(m,6H,3″-N(CH3)2),2.36-2.34(d,2H,9a-CH and 2″b-CH),2.21(s,3H,9a-NCH3),2.07-2.04(m,2H,8-CH and 4′b-CH),1.93(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.85(m,1H,2″a-CH),1.83(m,1H,4′a-CH),1.73(m,3H,12-CH3),1.63-1.59(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.46(s,3H,5′-CH3),1.29(s,3H,5″-CH3),1.28(m,3H,2-CH3),1.23(m,6H,3″-CH3,10-CH3),1.17(s,3H,6-CH3),1.08(d,3H,J=6.6Hz,8-CH3),1.04(d,3H,J=7.2Hz,4-CH3),0.95(d,3H,J=7.2Hz,13-CH2 CH 3);MS:m/z calcd.for C54H89N5O151048.2;found (M+H+)1049.2。
4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物13)白色泡固体,收率:70.8%,mp:146-150℃,TLC Rf=0.22(methanol/dichlormethane,1∶10);IR(KBr):3373,2971,2934,1813,1723,1632,1513,1459,1380,1353,1334,1295,1258,1238,1166,1123,1110,1075,1044,1014cm-1;1H NMR(600MHz,CDCl3):δ7.320(d,2H,J=7.8Hz,HAr),7.20(d,2H,J=7.8Hz,HAr),5.09(d,1H,J=4.2Hz,1′-CH),4.90(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.57(d,1H,J=10.2Hz,4″-CH),4.46(m,1H,5″-CH),4.40(m,4H,11-CH,13-CH,2′-CH and 5′-CH),3.78(m,1H,5-CH),3.66(s,1H,3-CH),3.62(d,1H,J=4.2Hz,10-CH),3.48(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.32(s,3H,3″-OCH3),3.29(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.88(m,3H,2-CH,3′-CH and 9b-CH),2.45(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.42(m,3H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.39(m,6H,3″-N(CH3)2),2.36(m,5H,9a-CH,2″b-CH and Ar-CH3),2.21(s,3H,9a-NCH3),2.06(m,2H,8-CH and 4′b-CH),1.93(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.84(m,1H,2″a-CH),1.82(m,1H,4′a-CH),1.72(m,3H,12-CH3),1.67-1.62(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.46(s,3H,5′-CH3),1.30(s,3H,5″-CH3),1.27(m,3H,2-CH3),1.23(m,6H,3″-CH3,10-CH3),1.17(s,3H,6-CH3),1.08(d,3H,J=6.6Hz,8-CH3),0.95-0.89(d,6H,J=7.2Hz,13-CH2 CH 3and4-CH3);MS:m/z calcd.for C55H92N5O151062.3;found(M+H+)1063.3。
4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物14)白色晶体,收率:71.8%,mp:132-138℃,TLC Rf=0.21(methanol/dichlormethane,1∶10);IR(KBr):3434,2970,2872,2827,1813,1724,1633,1510,1459,1379,1334,1295,1258,1238,1166,1110,1075,1045,1013cm-1;1HNMR(600MHz,CDCl3):δ7.41(d,2H,J=8.4Hz,HAr),7.33(d,2H,J=8.4Hz,HAr),5.08(d,1H,J=4.2Hz,1′-CH),4.90(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.55(d,1H,J=10.2Hz,4″-CH),4.40(m,4H,5″-CH,11-CH,13-CH and 2′-CH),3.78(m,1H,5-CH),3.62(s,1H,3-CH),3.60(d,1H,J=5.4Hz,10-CH),3.48(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.31(s,3H,3″-OCH3),3.27(m,2H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.88(m,3H,2-CH,3′-CH and 9b-CH),2.47(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.40(m,5H,4-CH and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.37(m,6H,3″-N(CH3)2),2.34(m,2H,9a-CH and 2″b-CH),2.18(s,3H,9a-NCH3),2.04(m,2H,8-CH and 4′b-CH),1.91(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.83(m,2H,2″a-CH and 4′a-CH),1.69(m,3H,12-CH3),1.65-1.62(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.48(s,3H,5′-CH3),1.32(s,12H,5″-CH3 and Ar-C(CH 3 )3),1.28(m,3H,2-CH3),1.20(m,6H,3″-CH3,10-CH3),1.14(s,3H,6-CH3),1.06(d,3H,J=6.6Hz,8-CH3),0.92-0.90(d,6H,J=7.2Hz,13-CH2 CH 3and4-CH3);MS:m/z calcd.for C57H98N5O151104.4;found(M+H+)1105.4。
4″-O-(3-(4-(4-甲氧基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物15)白色晶体,收率:69.6%,mp:136-142℃,TLC Rf=0.23(methanol/dichlormethane,1∶10):IR(KBr):3312,2970,2937,2829,1813,1723,1632,1610,1575,1513,1459,1379,1352,1334,1298,1251,1171,1109,1085,1044,1016cm-1;1H NMR(600MHz,CDCl3):δ7.38(d,1H,J=8.4Hz,HAr),6.91(d,1H,J=8.4Hz,HAr),5.08(m,1H,1′-CH),4.90(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.55(d,1H,J=9.60Hz,4″-CH),4.38-4.34(m,4H,5″-CH,11-CH,and 13-CH and 2′-CH),3.83(s,3H,Ar-OCH3),3.66(m,2H,5-CH and2H,3-CH),3.60(d,1H,J=5.4Hz,10-CH),3.48(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.30(s,3H,3″-OCH3),3.28(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.85(m,3H,2-CH,3′-CH and 9b-CH),2.44(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.40(m,6H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.37(m,6H,3″-N(CH3)2),2.34(m,2H,9a-CHand 2″b-CH),2.18(s,3H,9a-NCH3),2.04(m,2H,8-CH and 4′b-CH),1.91(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.83(m,2H,2″a-CH and 4′a-CH),1.70(m,3H,12-CH3),1.65-1.58(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.44(s,3H,5′-CH3),1.31(s,3H,5″-CH3),1.27(m,3H,2-CH3),1.20(m,6H,3″-CH3,10-CH3),1.15(s,3H,6-CH3),1.06(d,3H,J=6.6Hz,8-CH3),0.93-0.90(d,6H,J=7.2Hz,13-CH2 CH 3and4-CH3);MS:m/zcalcd.for C57H98N5O151078.2;found(M+H+)1178.2。
4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物16)白色晶体,收率:71.4%,mp:104-108℃,TLC Rf=0.22(methanol/dichlormethane,1∶10):IR(KBr):3305,2973,2937,2880,1811,1723,1640,1600,1525,1463,1379,1351,1313,1295,1237,1167,1123,1109,1075,1044,1013cm-1;1H NMR(600MHz,CDCl3):δ8.31(d,2H,J=4.2Hz,HAr),7.6(d,2H,J=10.5Hz,HAr),5.04(d,1H,J=4.2Hz,1′-CH),4.88(dd,1H,J=3Hz,J=3Hz,1″-CH),4.58(m,1H,13-CH),4.41(m,2H,11-CHand 4″-CH),4.27(m,2H,5″-CH and 2′-CH),3.85(m,2H,5′-CH and 3-CH),3.78(m,1H,5-CH),3.66(m,1H,3-CH),3.56(m,1H,10-CH),3.43(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.31(s,3H,3″-OCH3),3.28(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.88(m,3H,2-CH,3′-CH and 9b-CH),2.59(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.48(m,6H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.39(m,6H,3″-N(CH3)2),2.36(m,2H,9a-CHand 2″b-CH),2.22(s,3H,9a-NCH3),2.04(m,2H,8-CH and 4′b-CH),1.91(m,2H,4″-OCONHCH2 CH 2CH2N(CH2CH2)2NCOAr),1.83(m,2H,2″a-CH and 4′a-CH),1.70(m,3H,12-CH3),1.66-1.60(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.46(s,3H,5′-CH3),1.28(s,3H,5″-CH3),1.27(m,3H,2-CH3),1.24(m,6H,3″-CH3,10-CH3),1.18(s,3H,6-CH3),1.09(d,3H,J=6.6Hz,8-CH3),0.95-0.93(d,6H,J=7.2Hz,13-CH2 CH 3and 4-CH3);MS:m/zcalcd.for C54H88N6O171093.2;found(M+H+)1094.2。
4″-O-(3-(4-(4-氟苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物17)白色晶体,收率:72.4%,mp:134-140℃,TLC Rf=0.24(methanol/dichlormethane,1∶10);IR(KBr):3435,2972,2937,2827,1813,1724,1636,1605,1510,1458,1379,1353,1334,1295,1258,1235,1165,1109,1074,1045,1014cm-1;1HNMR(600MHz,CDCl3):δ7.41(m,2H,HAr),7.09(m,2H,HAr),5.09(d,1H,J=4.2Hz,1′-CH),4.90(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.54(d,1H,J=9.6Hz,4″-CH),4.41(m,1H,5″-CH),4.38(m,4H,11-CH,and 13-CH,2′-CH and 5′-CH),3.77(m,1H,5-CH),3.62(s,1H,3-CH),3.58(d,1H,J=4.2Hz,10-CH),3.49(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.31(s,3H,3″-OCH3),3.27(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.91(m,3H,2-CH,3′-CH and 9b-CH),2.85(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.48(m,3H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.42(m,6H,3″-N(CH3)2),2.34(m,2H,9a-CHand 2″b-CH),2.18(s,3H,9a-NCH3),2.07(m,2H,8-CH and 4′b-CH),2.00(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.91(m,1H,2″a-CH),1.70(m,1H,4′a-CH),1.68(m,3H,12-CH3),1.64-1.60(m,4H,7b-CH,7a-CH and 13-CH 2CH3),1.46(s,3H,5′-CH3),1.29(s,3H,5″-CH3),1.28(m,3H,2-CH3),1.23(m,6H,3″-CH3,10-CH3),1.17(s,3H,6-CH3),1.08(d,3H,J=6.6Hz,8-CH3),1.04(d,3H,J=7.2Hz,4-CH3),0.95(d,3H,J=7.2Hz,13-CH2 CH 3);MS:m/z calcd.for C54H88FN5O15 1066.1;found(M+H+)1067.1。
4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物18)白色晶体,收率:72.3%,mp:134-140℃,TLC Rf=0.21(methanol/dichlormethane,1∶10);IR(KBr):3446,2972,2938,2880,2827,1813,1723,1635,1597,1510,1459,1379,1353,1334,1296,1277,1258,1237,1166,1109,1088,1045,1013cm-1;1H NMR(600MHz,CDCl3):δ7.43(d,2H,J=3Hz,HAr),7.38(d,2H,J=6.6Hz,HAr),5.11(d,1H,J=4.2Hz,1′-CH),4.91(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.56(d,1H,J=4.20Hz,4″-CH),4.43-4.40(m,4H,5″-CH,11-CH,13-CH and 2′-CH),3.78(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.63(m,1H,10-CH),3.61(m,1H,5-CH),3.32(s,3H,3″-OCH3),3.28(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),2.88(m,2H,2-CH and 3′-CH),2.49(m,6H,3′-N(CH3)2),2.44(m,2H,4″OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.36(m,5H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr and 9b-CH),2.20(s,3H,9a-NCH3),2.07(m,1H,4-CH),2.01(m,2H,9a-CH,2″b-CH),1.93(m,2H,2″a-CH,8-CH),1.85(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.69(m,2H,4′b-CH and 7a-CH),1.65(m,2H,7b-CH and 4′a-CH),1.63(m,2H,13-CH 2 CH3),1.45(m,3H,12-CH3),1.28(m,3H,3″-CH3),1.23(m,9H,6-CH3 and 2-CH3 and 5′-CH3),1.10(m,3H,5″-CH3),1.08(m,6H,10-CH3 and8-CH3),0.94-0.93(m,6H,4-CH3 and 13-CH2 CH 3 );MS:m/z calcd.for C54H88ClN5O151082.2;found(M+H+)1083.2。
4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物19)白色晶体,收率:72.6%,mp:146-152℃,TLC Rf=0.22(methanol/dichlormethane,1∶10):IR(KBr):3423,2971,2930,1812,1723,1632,1512,1459,1383,1353,1296,1258,1167,1123,1109,1085,1046,1011cm-1;1HNMR(400MHz,CDCl3):δ7.55(d,2H,J=8.4Hz,HAr),7.38(s,2H,J=8.4Hz,HAr),5.07(d,1H,J=3Hz,1′-CH),4.89(dd,1H,J=3.0Hz,J=3.0Hz,1″-CH),4.56(d,1H,J=8.4Hz,4″-CH),4.46(d,1H,J=6.6Hz,11-CH),4.36(m,3H,5″-CH,13-CH and 2′-CH),3.76(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.66(m,1H,10-CH),3.60(d,1H,J=5.4Hz,5-CH),3.30(s,3H,3″-OCH3),3.27-3.25(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.86(m,2H,2-CH and 3′-CH),2.48(m,6H,3′-N(CH3)2),2.43(m,2H,4″-OCONH(CH2)2 CH 2 N(CH2CH2)2NCOAr),2.37(m,5H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr and 9b-CH),2.19(s,3H,9a-NCH3),2.04(m,1H,4-CH),2.01(m,2H,9a-CH,2″b-CH),1.91(m,2H,2″a-CH,8-CH),1.82(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.70(m,2H,4′b-CH and 7a-CH),1.68(m,2H,7b-CH and 4′a-CH),1.64(m,2H,13-CH 2 CH3),1.43(m,3H,12-CH3),1.27(s,3H,3″-CH3),1.24(m,9H,6-CH3 and 2-CH3 and 5′-CH3),1.15(m,3H,5″-CH3),1.06(m,6H,10-CH3and 8-CH3),0.93-0.90(m,6H,4-CH3 and 13-CH2 CH 3 );MS:m/z calcd.for C54H88BrN5O1511298.0;found(M+H+)1129.0。
4″-O-(3-(4-(3-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物20)白色晶体,收率:69.7%,mp:126-130℃,TLC Rf=0.24(methanol/dichlormethane,1∶10):IR(KBr):3435,2972,2937,2881,2826,1813,1724,1636,1584,1506,1459,1379,1353,1334,1296,1277,1236,1211,1166,1109,1086,1074,1045,1014cm-1;1H NMR(600MHz,CDCl3):δ7.21(d,2H,J=7.8Hz,HAr),7.38(s,2H,J=7.8Hz,HAr),5.09(d,1H,J=3.0Hz,1′-CH),4.89(d,1H,J=3.0Hz,1″-CH),4.88(m,1H,J=3.0Hz,13-CH),4.54(m,2H,4″-CH,5″-CH),4.40(m,1H,11-CH),4.38(m,1H,2′-CH,5′-CH),3.77(m,1H,5-CH),3.62(s,1H,3-CH),3.59(d,1H,10-CH),3.42(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.31(s,3H,3″-OCH3),3.27-3.25(m,4H,4″-OCONH(CH2)3N(CH2 CH 2)2NCOAr),2.92(m,1H,3′-CH),2.85(m,2H,2-CH,9b-CH),2.49(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.40(m,3H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.35(d,5H,9a-CH,2″b-CH and Ar-CH3),2.32(m,6H,3″-N(CH3)2),2.18(s,6H,9a-NCH3),2.04(m,2H,8-CH and 4′b-CH),2.03(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.91(m,1H,2″a-CH),1.82(m,1H,4′a-CH),1.70-1.58(m,7H,7b-CH,12-CH3,7a-CH and 13-CH 2CH3),1.43(s,3H,5′-CH3),1.28(s,3H,5″-CH3),1.25(m,3H,2-CH3),1.20(m,6H,3″-CH3,10-CH3),1.14(s,3H,6-CH3),1.07(d,3H,8-CH3),0.92-0.90(m,6H,4-CH3and 13-CH2 CH 3);MS:m/z calcd.for C55H92N5O151062.2;found(M+H+)1063.2。
4″-O-(3-(4-(3-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物21)白色晶体,收率:70.5%,mp:136-142℃,TLC Rf=0.21(methanol/dichlormethane,1∶10):IR(KBr):3362,3088,2972,2934,2875,1811,1721,1633,1533,1457,1380,1352,1297,1259,1237,1167,1123,1109,1084,1044,1014cm-1;1HNMR(600MHz,CDCl3):δ7.71(m,2H,HAr),7.38(m,2H,HAr),5.05(d,1H,J=3Hz,1′-CH),4.89(d,1H,J=3.6Hz,1″-CH),4.87(m,1H,J=3.0Hz,13-CH),4.55(m,2H,4″-CH and 5″-CH),4.48(m,1H,11-CH),4.38(m,1H,2′-CH and 5′-CH),3.80(m,1H,5-CH),3.70(s,1H,3-CH),3.60(d,1H,10-CH),3.41(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.30(s,3H,3″-OCH3),3.28-3.25(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.85(m,3H,2-CH,3′-CH and 9b-CH),2.53(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.44(m,3H,4-CH and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.41(m,6H,3″-N(CH3)2),2.37-2.34(d,2H,9a-CH and 2″b-CH),2.19(s,3H,9a-NCH3),2.06-2.03(m,2H,8-CH and4′b-CH),1.92(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.81(m,1H,2″a-CH),1.71(m,1H,4′a-CH),1.63-1.48(m,7H,7b-CH,12-CH3,7a-CH and 13-CH 2CH3),1.44(s,3H,5′-CH3),1.27(s,3H,5″-CH3),1.25(m,3H,2-CH3),1.20(m,6H,3″-CH3,10-CH3),1.15(s,3H,6-CH3),1.07(d,3H,8-CH3),0.93-0.90(m,6H,4-CH3and 13-CH2 CH 3);MS:m/z calcd.for C54H88N6O171092.9;found(M+H+)1093.9。
4″-O-(3-(4-(3,5-二硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(目标化合物22)白色晶体,收率:66.8%,mp:128-132℃,TLC Rf=0.20(methanol/dichlormethane,1∶10):IR(KBr):3435,3106,2973,2937,2880,2827,1811,1724,1645,1590,1546,1512,1463,1379,1345,1295,1238,1167,1110,1076,1045,1014cm-1;1H NMR(600MHz,CDCl3):δ9.90(m,1H,HAr),8.59(m,2H,HAr),5.05(d,1H,J=3.0Hz,1′-CH),4.88(d,1H,J=3.0Hz,1″-CH),4.87(m,1H,J=2.4Hz,13-CH),4.55(m,2H,4″-CH,5″-CH),4.48(m,1H,11-CH),4.38(m,2H,2′-CH,5′-CH),3.83(m,1H,5-CH),3.70(s,1H,3-CH),3.60(d,1H,10-CH),3.44(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.30(s,3H,3″-OCH3),3.27(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),2.85(m,3H,2-CH,3′-CH and 9b-CH),2.56(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.45(m,3H,4-CH and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.44(m,6H,3″-N(CH3)2),2.35(m,2H,9a-CHand 2″b-CH),2.19(s,3H,9a-NCH3),2.03(m,2H,8-CH and 4′b-CH),1.92(m,2H,4″-OCONHCH2 CH 2CH2N(CH2CH2)2NCOAr),1.83(m,1H,2″a-CH),1.71(m,1H,4′a-CH),1.63-1.58(m,7H,7b-CH,12-CH3,7a-CH and 13-CH 2CH3),1.44(s,3H,5′-CH3),1.29(s,3H,5″-CH3),1.28(m,3H,2-CH3),1.20(m,6H,3″-CH3,10-CH3),1.16(s,3H,6-CH3),1.06(d,3H,8-CH3),0.92-0.86(m,6H,4-CH3 and 13-CH2 CH 3);MS:m/zcalcd.for C54H87N7O191138.1;found(M+H+)1139.1。
实施例8.
11-O-正丙基氨基甲酰基-4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标产物23)的制备
4″-O-(3-(4-苯甲酰哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(0.84g,0.80mmol)溶解于正丙胺(5mL)中,室温搅拌2~5天,减压蒸干得白色泡沫固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=20∶1),得白色泡沫状固体(0.56g,0.51mmol),即为目标化合物23。收率62.7%。熔点108-113℃,Rf为0.55(展开剂为二氯甲烷∶甲醇=5∶1)。IR(KBr):3338,2971,2936,2875,2827,1812,1725,1631,1577,1518,1459,1378,1258,1165,1110,1075,1045,1015cm-1;1HNMR(600MHz,CDCl3)δ7.40(s,5H,Ar-H),5.14(m,1H,1′-CH),4.99-5.01(m,1H,1″-CH),4.53(d,J=9.3Hz,1H,4″-CH),4.46-4.36(m,1H,5″-CH),4.25(m,2H,11-CH and 13-CH),3.79-3.70(m,2H,2′-CH and 5′-CH),3.53(m,1H,3-CH),3.43-3.30(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.29-3.18(m,3H,3″-OCH3),3.16-3.10(m,4H,11-OCONHCH 2 CH2CH2CH3 and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.89-2.86(m,2H,2-CH and 5-CH),2.62-2.50(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.35(m,8H,3″-N(CH3)2 and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23-2.19(m,3H,9a-NCH3),2.17-1.99(m,4H,4-CH,9-CH,2″-CH and 8-CH),1.85(m,1H,4′-CH),1.69-1.61(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.53-1.45(m,3H,7-CH and11-OCONHCH2 CH 2 CH3),1.39-1.19(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3 and 2-CH3),1.18-1.14(m,6H,5″-CH3and 5′-CH3),1.06-0.96(m,9H,10-CH3,12-CH3and 8-CH3),0.93-0.89(m,9H,4-CH3,13-CH2 CH 3 and 11-OCONHCH2CH2 CH 3 );MS:m/z calcd.for C57H98N6O151107.0;found(M+H+)1108.0。
以下化合物24~46的制备采用与实施例8相同的方法。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标产物24)的制备
4″-O-(3-(4-苯甲酰哌嗪基)-丙基)-氨基甲酰基-阿奇霉素-11,12-环碳酸酯(0.84g,0.80mmol)溶解于正丙胺(5mL)中,室温搅拌2~5天,减压蒸干得白色泡沫固体。硅胶柱层析(洗脱剂为二氯甲烷∶甲醇=20∶1),得白色泡沫状固体(0.56g,0.51mmol),即为目标化合物24。收率:62.3%,mp:140-146℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3335,2972,2937,2827,1813,1724,1633,1577,1512,1458,1378,1294,1255,1165,1110,1074,1046,1015cm-1;1HNMR(600MHz,CDCl3)δ7.40(m,5H,Ar-H),5.01(m,1H,1′-CH),4.59(m,1H,1″-CH),4.53(d,J=9.6Hz,1H,4″-CH),4.47(m,1H,5″-CH),4.38(m,2H,11-CHand 13-CH),3.78(m,2H,2′-CH and 5′-CH),3.52(m,1H,3-CH),3.48-3.40(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.29(m,3H,3″-OCH3),3.26-3.23(m,4H,11-OCONHCH(CH3)2and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.75(m,2H,2-CHand 5-CH),2.62-2.53(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.41-2.38(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.28-2.19(m,3H,9a-NCH3),2.03-1.99(m,4H,4-CH,9-CH,2″-CH and 8-CH),1.89(m,1H,4′-CH),1.73(m,3H,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.63(m,7H,7-CH and11-OCONHCH(CH 3 ) 2 ,1.42(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.24(m,6H,5″-CH3and 5′-CH3),1.19-1.16(m,9H,10-CH3,12-CH3 and 8-CH3),0.93-0.89(m,9H,4-CH3,13-CH2 CH 3 and);MS:m/z calcd.for C57H98N6O151107.3;found(M+H+)1108.3。
11-O-丙烯基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物25)白色晶体,收率:63.1%,mp:154-158℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3320,2973,2934,1723,1628,1576,1524,1462,1379,1255,1166,1124,1076,1040,1016cm-1;1H NMR(600MHz,CDCl3):1HNMR(600MHz,CDCl3)δ7.40(s,5H,Ar-H),7.20(m,1H,11-OCONHCHCHCH3),5.15(d,J=9.5Hz,1H,1′-CH),5.00-4.94(m,2H,11-OCONHCHCHCH3and 1″-CH),4.54(d,J=9.2Hz,1H,4″-CH),4.46-4.40(m,1H,5″-CH),4.39-4.30(m,2H,11-CH and 13-CH),3.81-3.79(m,1H,2′-CH),3.73-3.69(m,1H,5′-CH),3.55-3.50(m,1H,3-CH),3.29-3.11(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.11-2.96(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.87-2.81(m,2H,2-CH and 5-CH),2.62-2.58(m,4H,4″-OCONH CH3)3N(CH 2 CH2)2NCOAr),2.39-2.32(m,8H,3″-N(CH3)2 and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23(s,3H,9a-NCH3),2.23-2.18(m,4H,4-CH,9-CH,2″-CH and 8-CH),2.17-1.99(m,3H,11-OCONHCHCHCH 3 ),1.88-1.86(m,1H,4′-CH),1.76-1.68(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.54-1.52(m,1H,7-CH),1.43-1.25(m,12H,6-CH3,3″-CH3,7-CH,13-CH 2CH3 and 2-CH3),1.17-1.10(m,6H,5″-CH3and 5′-CH3),1.05-0.88(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.forC58H100N6O151105.2;found(M+H+)1106.2。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-苯甲酰基哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物26)白色晶体,收率:61.9%,mp:124-130℃,TLC Rf=0.54(methanol/dichlormethane,1∶5):IR(KBr):3335,2971,2936,2874,2827,1813,1725,1633,1577,1511,1459,1377,1294,1255,1166,1109,1092,1074,1047,1015cm-1;1HNMR(600MHz,CDCl3)δ7.40-7.36(m,5H,Ar-H),4.98-4.94(m,2H,1′-CH and 1″-CH),4.54(d,J=9.4Hz,1H,4″-CH),4.40(m,1H,5″-CH),4.25(m,2H,11-CH and 13-CH),3.79-3.70(m,2H,2′-CHand 5′-CH),3.65-3.60(m,1H,3-CH),3.40-3.33(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.33-3.27(m,3H,3″-OCH3),3.12-3.08(m,4H,11-OCONHCH 2 CH2CH2CH3and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.89-2.82(m,3H,2-CH,5-CH and 3′-CH),2.50-2.44(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.41-2.36(m,3H,9-CH and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.37-2.30(m,6H,3′-N(CH3)2),2.23-2.16(m,3H,9a-NCH3),2.16-1.99(m,3H,4-CH,2″-CH and 8-CH),1.87-1.86(m,1H,4′-CH),1.70-1.62(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.52-1.40(m,3H,7-CH and11-OCONHCH2 CH 2 CH2CH3),1.32-1.23(m,13H,6-CH3,3″-O-CH3,13-CH 2CH3,2-CH3 and11-OCONHCH2CH2 CH 2 CH3),1.18-1.10(m,6H,5″-CH3 and 5′-CH3),1.09-1.02(m,9H,10-CH3,12-CH3 and 8-CH3),0.95-0.78(m,9H,4-CH3,13-CH2 CH 3 and11-OCONHCH2CH2CH2 CH 3 )。MS:m/z calcd.for C58H100N6O151120.8;found(M+H+)1121.8。
11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物27)白色晶体,收率:60.9%,mp:136-142℃,TLC Rf=0.57(methanol/dichlormethane,1∶5):IR(KBr):3318,2971,2937,2877,2827,1724,1624,1516,1460,1378,1294,1259,1165,1110,1077,1046,1015cm-1;1H NMR (600MHz,CDCl3):1HNMR(600MHz,CDCl3)δ7.30(d,J=6.9Hz,2H,Ar-H),7.21(d,J=6.0Hz,2H,Ar-H),4.99-4.97(m,2H,1′-CH and 1″-CH),4.67-4.65(m,1H,4″-CH),4.53(d,J=9.1Hz,1H,5″-CH),4.41(d,J=16.0Hz,1H,11-CH),4.28-4.27(m,1H,13-CH),3.77-3.76(m,1H,2′-CH),3.64-3.62(m,1H,5′-CH),3.55-3.53(m,1H,3-CH),3.45-3.43(m,1H,10-CH),3.37-3.36(m,2H,11-OCONHCH 2 CH2CH3),3.31(s,3H,3″-OCH3),3.23(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.13-3.12(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.92-2.74(m,2H,2-CH and 5-CH),2.62-2.39(m,10H,4″-OCONH(CH3)3N(CH 2 CH2)2NCOAr and 3″-N(CH3)2),2.23(m,4H,Ar-CH3 and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.15(m,2H,2″-CH and 4′-CH),1.99(s,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.86-1.84(m ,3H ,7-CH and11-OCONHCH2 CH 2 CH3),1.74-1.56(m,7H,6-CH3,3″-CH3and 7a-CH),1.53-1.19(m,16H,13-CH 2CH3,2-CH3,5″-CH3,5′-CH3and Ar-CH3),1.10-1.02(m,12H,10-CH3,12-CH3and8-CH3),0.99-0.96(m,6H,4-CH3and 13-CH2 CH 3 ),0.90-0.86(m,3H,11-OCONHCH2CH2 CH 3 );MS:m/z calcd.for C58H100N6O151122.1;found(M+H+)1123.1。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物28)白色晶体,收率:61.2%,mp:146-154℃,TLC Rf=0.56(methanol/dichlormethane,1∶5):IR(KBr):3319,2973,2937,2827,1724,1628,1515,1459,1378,1294,1255,1166,1100,1074,1015cm-1;1HNMR(600MHz,CDCl3)δ7.30(d,J=6.2Hz,2H,Ar-H),δ7.09(m,2H,Ar-H),5.15(d,J=9.0Hz,1H,1″-CH),5.00-4.99(m,1H,1′-CH),4.56-4.51(m,1H,4″-CH),4.48-4.47(m,1H,5″-CH),4.38-4.36(m,2H,11-CH and 13-CH),3.77(m,2H,2′-CH and 5′-CH),3.51(m,1H,3-CH),3.33-2.88(m,11H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr,10-CH,3″-OCH3,11-OCONHCH(CH3)2 and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.92-2.74(m,2H,2-CH and 5-CH),2.64-2.60(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.58-2.30(m,11H,3″-N(CH3)2and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr and Ar-CH 3 ),1.88-1.63(m,4H,2″-CH,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.47-1.44(m,7H,7-CH and11-OCONHCH2 (CH 3 ) 2 ,1.34-1.12(m,18H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3,2-CH3,,5″-CH3 and 5′-CH3),1.05-1.01(m,9H,10-CH3,12-CH3and 8-CH3),0.95-0.86(m,6H,4-CH3,13-CH2 CH 3 );MS:m/z calcd.for C58H100N6O15 1122.1;found(M+H+)1123.1。
11-O-丙烯基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物29)白色晶体,收率:62.3%,mp:178-180℃,TLC Rf=0.54(methanol/dichlormethane,1∶5):IR(KBr):3323,2974,2937,1722,1624,1519,1461,1379,1255,1167,1124,1077,1041,1014cm-1;1HNMR(600MHz,CDCl3)δ7.41(m,4H,Ar-H),7.33(d,J=7.5Hz,1H,11-OCONHCHCHCH3),4.99-4.87(s,3H,1′-CH,1″-CH and11-OCONHCHCHCH3),4.71-4.52(m,2H,4″-CH and 5″-CH),4.47-4.33(m,2H,11-CH and13-CH),3.76(m,2H,2′-CH and 5′-CH),3.65(m,1H,3-CH),3.50-3.29(m,7H,4″-OCONH(CH3)3N(CH2 CH 2 )2NCOAr,10-CH and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.19-3.09(m,4H,4″-OCONH(CH3)3N(CH 2 CH2)2NCOAr),2.90-2.88(m,2H,2-CH and 5-CH),2.66-2.23(m,14H,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr,3″-N(CH3)2,9a-NCH3and Ar-CH 3 ),1.97-1.87(m,9H,4-CH,9-CH,2″-CH,8-CH,11-OCONHCHCHCH 3 ,2″-CH and 4′-CH),1.66-1.45(m,4H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 7-CH),1.45-1.38(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.37-1.26(m,6H,5″-CH3and 5′-CH3),1.22-1.18(m,6H,5″-CH3 and 5′-CH3),1.09(d,J=12.9Hz,3H,4-CH3),0.97-0.83(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C58H98N6O151119.1;found(M+H+)1120.1。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-甲基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物30)白色晶体,收率:62.4%,mp:126-130℃,TLC Rf=0.58(methanol/dichlormethane,1∶5):IR(KBr):3318,2936,2874,2827,1725,1631,1514,1459,1377,1294,1255,1166,1110,1047,1015cm-1;1HNMR(600MHz,CDCl3)δ7.31(d,J=6.7Hz,2H,Ar-H),7.22(d,J=7.1Hz,2H,Ar-H),5.00-4.99(m,1H,1′-CH),4.68-4.66(m,1H,1″-CH),4.55(d,J=9.1Hz,1H,4″-CH),4.42(d,J=11.7Hz,5″-CH),4.28-4.25(m,2H,11-CH and 13-CH),3.78-3.76(m,1H,2′-CH),3.65(m,1H,5′-CH),3.54(m,1H,3-CH),3.33-3.27(m,5H,4″-OCONH(CH3)3N(CH2 CH 2 )2NCOAr and 10-CH),3.16-3.08(m,2H,4″-OCONHCH 2 (CH2)2CH2N(CH2CH2)2NCOAr and 11-OCONHCH 2 CH2CH2CH3),2.96(m,2H,2-CH and 5-CH),2.64-2.51(m,4H,4″-OCONH(CH3)3N(CH 2 CH2)2NCOAr),2.44-2.28(m,11H,Ar-CH3,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.21(s,3H,9a-NCH3),2.23-2.18(m,4H,4-CH,9-CH,2″-CH and 8-CH),2.16-2.00-1.98(m,6H,11-OCONHCH2 CH 2 CH2CH3),1.88-1.86(m,2H,2″-CH and 4′-CH),1.74-1.63(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.50(d,J=7.0Hz,1H,7-CH),1.45-1.18(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.16-1.14(m,6H,5″-CH3and 5′-CH3),1.13-0.92(m,11H,4-CH3,13-CH2 CH 3 and 11-OCONHCH2CH2 CH 2 CH 3 );MS:m/z calcd.forC59H102N6O151135.2;found(M+H+)1136.2。
11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-叔丁基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物31)白色晶体,收率:61.7%,mp:150-158℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3319,2969,2875,2827,1726,1631,1512,1461,1377,1294,1259,1165,1110,1075,1045,1012cm-1;1H NMR(600MHz,CDCl3):1HNMR(600MHz,CDCl3)δ7.41(d,J=7.3Hz,2H,Ar-H),δ7..33(d,J=6.0Hz,2H,Ar-H),5.02-5.00(m,1H,1′-CH),4.99-4.97(m,1H,1″-CH),4.54(d,J=9.5Hz,1H,4″-CH),4.41-4.40(s,1H,5″-CH),4.25-4.23(m,2H,11-CH and 13-CH),3.78-3.76(m,1H,2′-CH),3.74-3.72(m,1H,5′-CH),3.66-3.65(m,1H,3-CH),3.56-3.38(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.29(s,3H,3″-OCH3),3.12-2.97(m,4H,11-OCONHCH 2 CH2CH3and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.93-2.88(m,1H,2-CH),2.79-2.71(m,1H,5-CH),2.63-2.53(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.39(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23-1.99(m,7H,9a-NCH3,4-CH,9-CH,2″-CH and 8-CH),1.88-1.82(m,2H,2″-CH and 4′-CH),1.76-1.62(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.53-1.51(m,3H,7-CH and11-OCONHCH2 CH 2 CH3),1.32-1.27(m,19H,Ar-C(CH3)3,6-CH3,3″-CH3,7a-CH,13-CH 2CH3,2-CH3),1.25-1.17(m,6H,5″-CH3and 5′-CH3),1.15-1.02(m,9H,10-CH3,12-CH3and 8-CH3),0.95-0.86(m,9H,4-CH3,13-CH2 CH 3 and 11-OCONHCH2CH2 CH 3 );MS:m/z calcd.forC61H106N6O151163.1;found(M+H+)1164.1。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-叔丁苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物32)白色晶体,收率:60.7%,mp:120-124℃,TLC Rf=0.56(methanol/dichlormethane,1∶5):IR(KBr):3327,2971,2875,2827,1815,1727,1634,1510,1459,1376,1295,1254,1165,1110,1073,1048,1012cm-1;1HNMR (600MHz,CDCl3)δ7.40(d,J=7.6Hz,2H,Ar-H),7.33(d,J=7.7Hz,2H,Ar-H),5.00-4.99(m,1H,1′-CH),4.98-4.96(m,1H,1″-CH),4.71-4.69(m,1H,4″-CH),4.63-4.61(m,1H,5″-CH),4.52(d,J=9.6Hz,1H,11-CH),4.41(m,1H,13-CH),3.78-3.64(m,2H,2′-CH and 5′-CH),3.55-3.53(m,1H,3-CH),3.47-3.18(m,8H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr,10-CH,11-OCONHCH(CH3)2and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.60-2.28(m,15H,2-CH,5-CH,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr,3″-N(CH3)2 and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.22(s,3H,9a-NCH3),1.97-1.87(m,12H,4-CH,9-CH,2″-CH,8-CH,11-OCONHCH(CH 3 ) 2 ,2″-CH and 4′-CH),1.77-1.54(m,4H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 7-CH),1.48-1.32(m,18H,Ar-C(CH3)3,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.26-1.14(m,6H,5″-CH3and 5′-CH3),1.14-0.83(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.for C61H106N6O151164.1;found(M+H+)1165.1。
11-O-丙烯基氨基甲酰基-4″-O-(3-(4-(4-叔丁苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物33)白色晶体,收率:62.7%,mp:152-156℃,TLC Rf=0.56(methanol/dichlormethane,1∶5):IR(KBr):3327,2970,2627,1726,1630,1513,1461,1376,1254,1165,1110,1073,1046,1012cm-1;1HNMR(600MHz,CDCl3)δ7.41(d,J=6.9Hz,2H,Ar-H),7.33(d,J=6.0Hz,2H,Ar-H),7.20(m,1H,11-OCONHCHCHCH3),5.03-4.95(m,3H,11-OCONHCHCHCH3,1′-CH and 1″-CH),4.53(d,J=9.3Hz,1H,4″-CH),4.41(m,1H,5″-CH),4.25(m,2H,11-CH and 13-CH),3.80(m,2H,2′-CH and 5′-CH),3.66-3.51(m,1H,3-CH),3.43-3.30(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.29-3.18(m,3H,3″-OCH3),3.14(m,2H,4″-OCONHCH 2 (CH2)2N(CH2CH2)2NCOAr),2.89-2.86(m,2H,2-CH and 5-CH),2.61-2.50(m,4H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr),2.44-2.29(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23-2.20(m,3H,9a-NCH3),2.17-1.87(m,6H,4-CH,9-CH,2″-CH,8-CH,2″-CH and 4′-CH),1.70-1.61(m,3H,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.53-1.49(m,4H,7-CH and11-OCONHCHCHCH 3 ),1.48(m,9H,Ar-C(CH3)3)1.32-1.19(m,6H,5″-CH3 and 5′-CH3),1.17-1.14(m,9H,10-CH3,12-CH3and 8-CH3),1.15-0.88(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.for C61H104N6O151161.3;found(M+H+)1162.3。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-叔丁苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物34)白色晶体,收率:62.5%,mp:106-112℃,TLC Rf=0.57(methanol/dichlormethane,1∶5):IR(KBr):3311,2965,2873,1813,1725,1630,1515,1462,1378,1295,1255,1166,1110,1075,1046,1013cm-1;1HNMR (600MHz,CDCl3)δ7.43(d,J=9.6Hz,2H,Ar-H),7.32(d,J=6.0Hz,2H,Ar-H),4.99(m,2H,1′-CH and 1″-CH),4.54(d,J=9.6Hz,1H,4″-CH),4.41(m,1H,5″-CH),4.25(m,2H,11-CH and 13-CH),3.78(m,2H,2′-CH and 5′-CH),3.66(m,1H,3-CH),3.53-3.47,(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr and 10-CH),3.26-3.16(m,3H,3″-OCH3),3.16(m,4H,11-OCONHCH 2 CH2CH2CH3and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.93-2.84(m,2H,2-CH and 5-CH),2.63(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.40-2.35(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23-2.18(m,3H,9a-NCH3),1.99-1.87(m,6H,4-CH,9-CH,2″-CH,8-CH,2″-CH and 4′-CH),1.71-1.61(m,3H,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.58(m,4H,-OCONHCH2 CH 2 CH 2 CH3),1.49(m,9H,Ar-C(CH3)3),1.46-1.42(m,4H,7-CH and11-OCONH(CH2)3 CH 3 ),1.32-1.22(m,6H,5″-CH3and 5′-CH3),1.18-1.09(m,9H,10-CH3,12-CH3and 8-CH3),1.01-0.88(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.forC62H108N6O151177.2;found(M+H+)1178.2。
11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物35)白色晶体,收率:62.9%,mp:106-112℃,TLC Rf=0.57(methanol/dichlormethane,1∶5):IR(KBr):3338,2972,2935,2829,1804,1774,1723,1635,1524,1463,1383,1351,1314,1258,1166,1108,1074,1042,1013cm-1;1HNMR(600MHz,CDCl3)δ7.57(m,4H,Ar-H),5.01-4.99(m,1H,1′-CH),4.98-4.96(m,1H,1″-CH),4.53(d,J=9.2Hz,1H,4″-CH),4.41-4.39(m,1H,5″-CH),4.39-4.36(m,2H,11-CH and 13-CH),4.20-4.18(m,2H,11-OCONHCH 2 CH2CH3),3.79(m,1H,2′-CH),3.63(m,1H,5′-CH),3.53(m,1H,3-CH),3.29-3.19(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOArand 10-CH),3.17-3.08(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.85(m,2H,2-CH and 5-CH),2.62-2.52(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.47-2.31(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23(s,3H,9a-NCH3),2.23-2.18(m,4H,4-CH,9-CH,2″-CH and 8-CH),2.16-1.99(m,2H,11-OCONHCH2 CH 2 CH3),1.87-1.86(m,2H,2″-CH and 4′-CH),1.70-1.61(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.56-1.54(m,1H,7-CH),1.48-1.21(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.15-1.12(m,9H,5″-CH3and 5′-CH3),1.10-0.90(m,9H,4-CH3,13-CH2 CH 3 and 11-OCONHCH2CH2 CH 3 );MS:m/z calcd.forC97H97N7O171152.6;found(M+H+)1153.6。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物36)白色晶体,收率:63.1%,mp:138-142℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3324,2973,2937,2877,2827,1810,1724,1640,1601,1525,1459,1379,1351,1294,1255,1166,1109,1074,1046,1013cm-1;1HNMR(600MHz,CDCl3)δ7.58(d,J=7.5Hz,2H,Ar-H),7.10(m,2H,Ar-H),5.01-4.99(m,1H,1′-CH),4.98(m,1H,1″-CH),4.70(m,1H,4″-CH),4.62(m,1H,5″-CH),4.53(m,1H,11-CH),4.41(m,1H,13-CH),3.79(m,1H,2′-CH),3.65(m,1H,5′-CH),3.55(m,1H,3-CH),3.46-3.17(m,7H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr,10-CH and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.65-2.27(m,3H,2-CH,5-CH,11-OCONHCH(CH3)2,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr,3″-N(CH3)2and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23(s,3H,9a-NCH3),2.20-1.78(m,18H,4-CH,9-CH,2″-CH,8-CH,11-OCONHCH(CH 3 ) 2 ,2″-CH and 4′-CH),1.77-1.55(m,4H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 7-CH),1.36-1.31(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and2-CH3),1.28-1.12(m,6H,5″-CH3and 5′-CH3),1.10-0.84(m,6H,4-CH3,13-CH2 CH 3 );MS:m/z calcd.for C97H97N7O17 1152.0;found(M+H+)1153.0。
11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物37)白色晶体,收率:61.9%,mp:142-150℃,TLC Rf=0.58(methanol/dichlormethane,1∶5):IR(KBr):3335,2972,2937,2876,2828,1724,1639,1601,1526,1460,1377,1351,1313,1294,1260,1166,1109,1076,1044,1013cm-1;1HNMR(600MHz,CDCl3)δ8.29(d,J=7.8Hz,1H,Ar-H),7.94(m,2H,11-OCONHCHCHCH3),7.58(m,2H,Ar-H),5.07(m,1H,1′-CH),5.01(m,2H,11-OCONHCHCHCH3and 1″-CH),4.68(m,1H,4″-CH),4.39(m,1H,5″-CH),4.08(m,2H,11-CH and 13-CH),3.78(m,1H,2′-CH),3.74(m,1H,5′-CH),3.61(d,J=5.7Hz,1H,3-CH),3.31(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr and 10-CH),3.29(s,3H,3″-OCH3),2.93(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.59(m,1H,2-CH),2.78(m,1H,5-CH),2.76(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.40-2.37(m,8H,3″-N(CH3)2and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.22-2.15(m,7H,9a-NCH3,4-CH,9-CH,2″-CH and 8-CH),1.89(m,2H,2″-CH and 4′-CH),1.80-1.68(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.69(m,1H,7-CH),1.27(m,11H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3,2-CH3and 11-OCONHCHCHCH 3 ),1.18(m,6H,5″-CH3and5′-CH3),1.08(m,9H,10-CH3,12-CH3and 8-CH3),1.05-0.96(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.for C97H96N7O171150.1;found(M+H+)1151.1。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-硝基苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物38)白色晶体,收率:60.7%,mp:128-134℃,TLC Rf=0.56(methanol/dichlormethane,1∶5):IR(KBr):3324,2970,2936,2874,2828,1725,1641,1601,1526,1459,1378,1350,1313,1294,1257,1168,1108,1075,1045,1013cm-1;1HNMR(600MHz,CDCl3)δ8.29(m,2H,Ar-H),7.59(d,J=8.0Hz,2H,Ar-H),5.15-5.13(m,1H,1′-CH),5.02-5.00(m,1H,1″-CH),4.55(d,J=10.1Hz,1H,4″-CH),4.38(m,1H,5″-CH),4.27(m,2H,11-CH and 13-CH),3.81(m,1H,2′-CH),3.73(m,1H,5′-CH),3.65(d,J=5.7Hz,1H,3-CH),3.38-3.33(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOArand 10-CH),3.29(s,3H,3″-OCH3),3.21-2.97(m,4H,11-OCONHCH 2 CH2CH2CH3and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.90-2.88(m,1H,2-CH),2.78(m,1H,5-CH),2.71-2.53(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.39-2.36(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.24-2.01(m,7H,9a-NCH3,4-CH,9-CH,2″-CH and 8-CH),1.94-1.81(m,2H,2″-CH and 4′-CH),1.80-1.61(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.47-1.45(m,3H,7-CH and11-OCONHCH2 CH 2 CH2CH3),1.37-1.24(m,14H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3,2-CH3and 11-OCONHCH2CH2 CH 2 CH3),1.25-1.18(m,6H,5″-CH3and 5′-CH3),1.16-1.11(m,9H,10-CH3,12-CH3and 8-CH3),1.05-0.91(m,9H,4-CH3,13-CH2 CH 3 and11-OCONHCH2CH2 CH 3 );MS:m/z calcd.for C98H99N7O171166.2;found(M+H+)1167.2。
11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物39)白色晶体,收率:63.2%,mp:136-140℃,TLC Rf=0.54(methanol/dichlormethane,1∶5):IR(KBr):3326,2971,2937,2876,2827,1724,1631,1597,1525,1461,1378,1259,1165,1108,1089,1046,1013cm-1;1HNMR(600MHz,CDCl3)δ7.39(d,J=1.2Hz,2H,Ar-H),7.35(d,J=1.8Hz,2H,Ar-H),5.06(m,2H,1′-CHand 1″-CH),4.54(d,J=9.6Hz,1H,4″-CH),4.41(m,1H,5″-CH),4.22(m,2H,11-CH and13-CH),3.76(m,H,2′-CH),3.65(m,1H,5′-CH),3.53(m,1H,3-CH),3.38(m,5H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr and 10-CH),3.29(s,3H,3″-OCH3),3.12(m,4H,11-OCONHCH 2 CH2CH3and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.95(m,1H,2-CH),2.88(m,1H,5-CH),2.61-2.50(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.36(m,8H,3″-N(CH3)2and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.24-1.99(m,7H,9a-NCH3,4-CH,9-CH,2″-CH and 8-CH),1.85(m,2H,2″-CH and 4′-CH),1.70-1.62(m,3H,4′-CHand 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.51-1.45(m,3H,7-CH and11-OCONHCH2 CH 2 CH3),1.39-1.22(m,14H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.18-1.15(m,6H,5″-CH3and 5′-CH3),1.08-1.02(m,9H,10-CH3,12-CH3and 8-CH3),0.96-0.84(m,9H,4-CH3,13-CH2 CH 3 and 11-OCONHCH2CH2 CH 3 );MS:m/z calcd.forC57H97ClN6O151141.1;found (M+H+)1142.1。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物40)白色晶体,收率:62.9%,mp:152-156℃,TLC Rf=0.57(methanol/dichlormethane,1∶5):IR(KBr):3335,2972,2937,2827,1725,1633,1597,1510,1460,1377,1294,1256,1166,1090,1074,1046,1013cm-1;1HNMR(600MHz,CDCl3)δ7.43(m,2H,Ar-H),7.36(d,J=1.2Hz,2H,Ar-H),5.09(m,1H,1′-CH),5.10(m,1H,1″-CH),4.69(m,1H,4″-CH),4.62(m,1H,5″-CH),4.53(m,1H,11-CH),4.41(m,1H,13-CH),3.77-3.65(m,2H,2′-CH and 5′CH),3.55-3.50(m,1H,3-CH and11-OCONHCH 2 (CH3)2),3.42-3.27(m,7H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr,10-CHand 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.65-2.28(m,14H,2-CH,5-CH,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr,3″-N(CH3)2 and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23(s,3H,9a-NCH3),2.20(m,4H,4-CH,9-CH,2″-CH and 8-CH),2.00(m,4H,11-OCONHCH2(CH3)2),1.88-1.84(m,2H,2″-CHand 4′-CH),1.78-1.57(m,4H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 7-CH),1.37-1.10(m,18H,6-CH3,3″-CH3,7-CH,13-CH 2CH3,2-CH3,5″-CH3and 5′-CH3),1.09-0.84(m,9H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.for C57H97ClN6O151141.1;found(M+H+)1142.1。
11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物41)白色晶体,收率:62.5%,mp:154-158℃,TLC Rf=0.58(methanol/dichlormethane,1∶5):IR(KBr):3330,2973,2937,2827,1724,1632,1597,1520,1462,1378,1255,1165,1109,1089,1046,1013cm-1;1HNMR(600MHz,CDCl3)δ7.33(m,2H,Ar-H),δ7.31(m,3H,Ar-H and 11-OCOCHCHCH3),5.01-4.99(m,2H,1′-CHand 11-OCOCHCHCH3),4.97-4.96(m,1H,1″-CH),4.54(d,J=9.3Hz,1H,4″-CH),4.46-4.36(m,1H,5″-CH),4.25(m,2H,11-CH and 13-CH),3.79(m,2H,2′-CH and 5′-CH),3.55-3.51(m,1H,3-CH),3.43-3.30(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr and 10-CH),3.29-3.18(m,3H,3″-OCH3),3.16-3.10(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.89-2.86(m,2H,2-CH and 5-CH),2.60-2.50(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.45-2.30(m,8H,3″-N(CH3)2and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.23-2.20(m,3H,9a-NCH3),2.17-1.87(m,6H,4-CH,9-CH,2″-CH,8-CH,2″-CH and 4′-CH),1.72-1.63(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.53-1.47(m,4H,7-CH and 11-OCOCHCHCH 3),1.32-1.12(m,6H,5″-CH3and 5′-CH3),1.06-1.02(m,9H,10-CH3,12-CH3and 8-CH3),0.89-0.82(m,6H,4-CH3and 13-CH2 CH 3 );MS:m/z calcd.for C57H95ClN6O151139.0;found(M+H+)1140.0。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-氯苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物42)白色晶体,收率:61.8%,mp:130-136℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3322,2935,2874,2827,1724,1633,1597,1520,1462,1377,1254,1165,1109,1089,1048,1013cm-1;1HNMR(600MHz,CDCl3)δ7.39(m,2H,Ar-H),δ7.35(m,2H,Ar-H),5.0(m,1H,1′-CH),4.97(m,1H,1″-CH),4.54(d,J=9.6Hz,1H,4″-CH),4.46-4.40(m,1H,5″-CH),4.14-4.08(m,2H,11-CH and13-CH),3.77-3.70(m,2H,2′-CH and 5′-CH),3.55(m,1H,3-CH),3.42(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr and 10-CH),3.29(s,3H,3″-OCH3),3.27-3.19(m,2H,11-OCONHCH 2 (CH2)2CH3),3.17(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.78(m,2H,2-CH and 5-CH),2.60(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.49(s,6H,3″-N(CH3)2),2.37(m,2H,and 4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.20(s,3H,9a-NCH3),2.15-1.86(m,6H,4-CH,9-CH,2″-CH,8-CH,2″-CH and 4′-CH),1.65(m,3H,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.50-1.46(m,3H,7-CHand 11-OCOCH2 CH 2 CH2CH3),1.35-1.32(m,2H,11-OCOCH2CH2 CH 2 CH3),1.25-1.15(m,6H,5″-CH3and 5′-CH3),1.03-0.99(m,9H,10-CH3,12-CH3and 8-CH3),0.89-0.84(m,9H,4-CH3,11-OCOCH2CH2CH2 CH 3 and 13-CH2 CH 3 );MS:m/z calcd.for C58H99ClN6O15 1155.2;found(M+H+)1156.2。
11-O-正丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物43)白色晶体,收率:62.7%,mp:124-126℃,TLC Rf=0.58(methanol/dichlormethane,1∶5):IR(KBr):3318,2969,2935,2874,1725,1634,1592,1521,1461,1378,1295,1256,1165,1070,1047,1010cm-1;1H NMR(600MHz,CDCl3):1HNMR(600MHz,CDCl3)δ7.56(d,J=6.9Hz,2H,Ar-H),7.29(m,2H,Ar-H),4.97(m,1H,1′-CH),4.67(m,1H,1″-CH),4.54(d,J=9.7Hz,1H,4″-CH),4.40(m,1H,5″-CH),4.26(m,2H,11-CH and 13-CH),3.77(m,2H,2′-CH and 5′-CH),3.65(s,1H,3-CH),3.54-3.41(m,5H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr and 10-CH),3.35-3.22(m,3H,3″-OCH3),3.16(m,4H,11-OCONHCH 2 CH2CH3 and4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.94(m,2H,2-CH and 5-CH),2.63-2.42(m,6H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr and4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr),2.20(s,3H,9a-NCH3),1.99-1.72-1.70(m,4H,9-CH,8-CH,2″-CH and 4′-CH),1.62-1.50(m,2H,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.43-1.35(m,3H,7-CH and11-OCONHCH2 CH 2 CH3),1.23-1.18(m,6H,5″-CH3and 5′-CH3),1.15-1.10(m,9H,10-CH3,12-CH3 and 8-CH3),1.01(s,3H,4-CH3),0.98-0.88(m,6H,13-CH2 CH 3 and11-OCONHCH2CH2 CH 3 );MS:m/z calcd.for C57H97BrN6O151187.1;found(M+H+)1188.1。
11-O-异丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物44)白色晶体,收率:62.4%,mp:143-152℃,TLC Rf=0.56(methanol/dichlormethane,1∶5):IR(KBr):3326,2972,2937,2827,1724,1636,1509,1460,1378,1294,1257,1168,1109,1043,1010cm-1;1HNMR(600MHz,CDCl3)δ7.55(m,4H,Ar-H),5.07(m,2H,1′-CH and 1″-CH),4.55(d,J=9.9Hz,2H,4″-CH and 5″-CH),4.30-4.29(m,1H,13-CH),4.24-4.23(m,1H,11-CH),3.78-3.76(m,2H,2′-CH and 5′-CH),3.64(m,1H,3-CH),3.51-3.36(m,8H,10-CH,11-OCONHCH(CH3)2,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr,and 4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),3.31(s,3H,5″-O-CH3),3.26(m,4H,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr,2-CH and5-CH),2.77(m,2H,2-CH and 5-CH),2.49(m,10H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr and 3″-N(CH3)2),2.46-2.32(m,3H,9a-NCH3),2.00(m,11H,4-CH,9-CH,8-CH,11-OCONHCH(CH 3 ) 2 ,2″-CH and 4′-CH),1.74-1.66(m,4H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 7-CH),1.45-1.37(m,12H,6-CH3,3″-CH3,7a-CH,13-CH 2CH3and 2-CH3),1.37-1.26(m,6H,5″-CH3,5′-CH3),1.31-1.28(m,6H,5″-CH3and 5′-CH3),1.08(s,3H,4-CH3),1.02-0.91(m,3H,13-CH2 CH 3 );MS:m/z calcd.for C57H97BrN6O151188.1;found(M+H+)1188.1。
11-O-烯丙基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物45)白色晶体,收率:62.1%,mp:186-190℃,TLC Rf=0.57(methanol/dichlormethane,1∶5):IR(KBr):3328,2974,2937,2827,1724,1634,1591,1516,1461,1378,1255,1165,1110,1070,1046,1010cm-1;1HNMR(600MHz,CDCl3)δ7.24(m,3H,Ar-H and 11-OCONHCHCHCH3),δ7.27(d,J=7.5Hz,2H,Ar-H),5.02(m,1H,1′-CH and 11-OCONHCHCHCH3),4.97(d,J=10.9Hz,1H,1″-CH),4.56(m,1H,4″-CH),4.40(s,1H,5″-CH),4.27(m,2H,11-CH and 13-CH),3.74(m,2H,2′-CH and 5′-CH),3.63(m,1H,3-CH),3.53(m,1H,10-CH),3.43(m,4H,4″-OCONHCH2CH2CH2N(CH2 CH 2 )2NCOAr),3.26(m,3H,3″-OCH3),3.19-3.12(m,2H,4″-OCONHCH 2 CH2CH2N(CH2CH2)2NCOAr),2.94(m,2H,2-CH and 5-CH),2.41-2.28(m,4H,4″-OCONHCH2CH2CH2N(CH 2 CH2)2NCOAr),2.20(m,3H,9a-NCH3),1.97-1.85(m,6H,4-CH,9-CH,2″-CH,8-CH,2″-CH and 4′-CH),1.67-1.58(m,3H,4′-CH and4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.45-1.35(m,12H,7-CH,11-OCONHCHCHCH 3 and 4″-OCONH(CH2)3N(CH2CH2)2NCOAr),1.27-1.19(m,6H,5″-CH3and 5′-CH3),1.14-1.06(m,9H,10-CH3,12-CH3and 8-CH3),0.99(s,3H,4-CH3),0.92-0.81(m,3H,13-CH2 CH 3 ;MS:m/z calcd.for C57H95BrN6O151186.1;found(M+H+)1186.1。
11-O-正丁基氨基甲酰基-4″-O-(3-(4-(4-溴苯甲酰基)-哌嗪基)-丙基)-氨基甲酰基阿奇霉素(目标化合物46)白色晶体,收率:61.9%,mp:122-128℃,TLC Rf=0.55(methanol/dichlormethane,1∶5):IR(KBr):3342,2935,2874,2827,1725,1635,1592,1512,1460,1377,1295,1255,1166,1110,1047,1010cm-1;1HNMR(600MHz,CDCl3)δ7.55(m,4H,Ar-H),5.15(m,1H,1′-CH),5.01(m,1H,1″-CH),4.55(d,J=9.5Hz,1H,4″-CH),4.45(m,1H,5″-CH),4.39(m,2H,11-CH and 13-CH),3.77(m,2H,2′-CH and5′-CH),3.53(m,1H,3-CH),3.43(m,1H,10-CH),3.29(m,4H,4″-OCONH(CH2)3N(CH2 CH 2 )2NCOAr),3.16-3.08(m,4H,4″-OCONHCH 2 (CH2)2N(CH2CH2)2NCOAr and 11-OCONHCH 2 (CH2)2CH3),2.90(m,2H,2-CH,5-CH),2.65-2.26(m,19H,4″-OCONH(CH2)3N(CH 2 CH2)2NCOAr,3″-N(CH3)2,4″-OCONHCH2CH2 CH 2 N(CH2CH2)2NCOAr,9a-NCH3,4-CH,9-CH,2″-CH and 8-CH),1.82(m,4H,2″-CH,4′-CH and 4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr),1.64(m,7H,4′-CH,4″-OCONHCH2 CH 2 CH2N(CH2CH2)2NCOAr and 11-OCONHCH2 CH 2 CH 2 CH3),1.55-1.37(m,7H,7-CH and 6-CH3and 11-OCONH(CH2)3 CH 3 ),1.26-1.17(m,15H,3″-CH3,7a-CH,13-CH 2CH3,2-CH3,5″-CH3and 5′-CH3),1.05(m,3H,4-CH3),0.94-0.88(t,J=6.6Hz,3H,13-CH2 CH 3 )。;MS:m/z calcd.for C57H95BrN6O151201.0;found(M+H+)1202.0。
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