CN104610168B - 巴比妥酸手性环己烷螺环化合物及其制备方法与用途 - Google Patents
巴比妥酸手性环己烷螺环化合物及其制备方法与用途 Download PDFInfo
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- CN104610168B CN104610168B CN201510036802.2A CN201510036802A CN104610168B CN 104610168 B CN104610168 B CN 104610168B CN 201510036802 A CN201510036802 A CN 201510036802A CN 104610168 B CN104610168 B CN 104610168B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
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Abstract
本发明公开了Ⅰ所示的巴比妥酸手性环己烷螺环化合物或其晶型、药学上可接受的盐、水合物或溶剂合物:其中,R1、R2分别或同时选自芳香基或取代的芳香基;R3、R4、R5分别或同时选自氢、C1~C6烷基或C1~C6烷氧基。本发明公开的式Ⅰ所示的新化合物,对大肠杆菌、嗜麦芽单胞菌、诺菲不动杆菌、金黄色葡萄球菌、表皮葡萄球菌中的一种或多种具有抑制作用,为临床上筛选抗菌、抑菌、杀菌等药物提供了一种新的选择。
Description
技术领域
本发明涉及巴比妥酸手性环己烷螺环化合物及其制备方法与用途。
背景技术
螺环化合物是指两个单环共用一个碳原子的多环化合物,可以用于光致变色材料、电致发光材料、农药、医药等。
螺环化合物的结构不同,其理化性质也不相同,分别也都具有不同的用途,例如:具有除螨作用的螺环化合物(a)、抗焦虑药盐酸丁螺环酮(b)、延缓动脉硬化的螺环吲哚衍生物(c)、非甾体抗炎药螺环吲哚衍生物(d)、有生理活性的药物中间体氮杂螺环化合物(e)、具有抗环状杆菌的螺环化合物(f)、具有广谱抗菌活性螺杂环衍生物(g)、具有AP-1活性抑制功能的螺环化合物(h)、螺环抗菌药物(i)、具有乙酰胆碱激活作用的螺环化合物(j)等等(《螺环化合物化学》.魏荣宝编著,化学工业出版社,2007.7)。
巴比妥酸(又称丙二酰脲),化学名为2,4,6-嘧啶三酮,可用作分析试剂、有机合成原料、塑料和染料的中间体、聚合反应的催化剂等方面;丙二酰脲亚甲基上两个氢原子被烃基取代后的部分衍生物,具有镇静催眠的作用。
目前,未见有巴比妥酸手性环己烷螺环化合物的报道;也未见有巴比妥酸手性环己烷螺环化合物的制备方法以及其应用于抗菌药物的报道。
发明内容
本发明的目的在于提供一种巴比妥酸手性环己烷螺环化合物。
本发明提供的式Ⅰ所示的巴比妥酸手性环己烷螺环化合物或其晶型、药学上可接受的盐、水合物或溶剂合物:
其中,R1、R2分别或同时选自芳香基或取代的芳香基;R3、R4、R5分别或同时选自氢、C1~C6烷基或C1~C6烷氧基。
优选的,R1、R2分别或同时选自苯基、呋喃基、取代的苯基或取代的呋喃基;R3、R4、R5分别或同时选自氢、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基。
再优选的,R1、R2分别或同时选自苯基、呋喃基、卤素取代的苯基、C1~C6烷基取代的苯基、C1~C6烷氧基取代的苯基、卤素取代的呋喃基、C1~C6烷基取代的呋喃基或C1~C6烷氧基取代的呋喃基。
更优选的,式Ⅰ所示的巴比妥酸手性环己烷螺环化合物为:
本发明的另一目的在于提供上述式Ⅰ所示巴比妥酸手性环己烷螺环化合物的制备方法。
本发明提供的一种制备式Ⅰ所示巴比妥酸手性环己烷螺环化合物的方法,其合成路线为:
其中,R1、R2分别或同时选自芳香基或取代的芳香基;R3、R4、R5分别或同时选自氢、C1~C6烷基或C1~C6烷氧基;
它包括以下步骤:
a、化合物1、化合物2、有机催化剂和冰醋酸在腈类溶剂中,于25℃~30℃下搅拌反应3~4小时,得到化合物3的反应液;
所述有机催化剂选自 中的任意一种或多种,R6为三烷基硅基,R7、R8分别或同时选自芳香基或杂环,R9选自烷基或氢,R10选自烷基或杂环、R11选自苄基或氢;所述腈类溶剂选自乙腈、丙腈、丁腈、异丁腈、苯乙腈中的任意一种或多种;
b、向步骤a化合物3的反应液中加入化合物4、无机碱、季铵盐类催化剂,于60~65℃下搅拌反应,薄层色谱监测反应完全,得到反应液;将反应液除去溶剂,得到粗品;对粗品进行分离纯化,得到式Ⅰ所示的巴比妥酸手性环己烷螺环化合物;
所述无机碱选自碳酸钾、碳酸钠中的任意一种或多种;所述季铵盐类催化剂选自四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵中的任意一种或多种;
所述化合物1、化合物2、有机催化剂、冰醋酸、化合物4、无机碱、季铵盐类催化剂的摩尔比为1:(0.1~1):(0.02~0.1):(0.05~0.5):(0.1~1):(0.1~0.5):(0.01~0.05);所述化合物1与腈类溶剂的摩尔体积比为1:(1~10)mol/L。
优选的,
步骤a中,所述有机催化剂为(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷;所述腈类溶剂为乙腈;
步骤b中,所述无机碱为碳酸钾;所述季铵盐类催化剂为四丁基溴化铵;
所述化合物1、化合物2、有机催化剂、冰醋酸、化合物4、无机碱、季铵盐类催化剂的摩尔比为1:0.75:0.075:0.1:0.5:0.25:0.25;所述化合物1与腈类溶剂的摩尔体积比为1:(2~3)mol/L。
优选的,R1、R2分别或同时选自苯基、呋喃基、取代的苯基或取代的呋喃基;R3、R4、R5分别或同时选自氢、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基。
再优选的,R1、R2分别或同时选自苯基、呋喃基、卤素取代的苯基、C1~C6烷基取代的苯基、C1~C6烷氧基取代的苯基、卤素取代的呋喃基、C1~C6烷基取代的呋喃基或C1~C6烷氧基取代的呋喃基。
本发明还提供了上述式Ⅰ所示巴比妥酸手性环己烷螺环化合物在制备抗菌药物中的用途。
上述的巴比妥酸手性环己烷螺环化合物或其晶型、药学上可接受的盐、水合物或溶剂合物,在制备抗菌药物中的用途。
进一步,所述抗菌药物是指对大肠杆菌、嗜麦芽单胞菌、诺菲不动杆菌、金黄色葡萄球菌、表皮葡萄球菌中的任意一种或多种具有抗菌活性的抗菌药物。
更进一步,所述大肠杆菌为大肠杆菌ATCC2522;所述嗜麦芽单胞菌为嗜麦芽单胞菌S1;所述诺菲不动杆菌为诺菲不动杆菌N2或诺菲不动杆菌N3;所述金黄色葡萄球菌为金黄色葡萄球菌J4;所述表皮葡萄球菌为表皮葡萄球菌BP8或表皮葡萄球菌BP4。
本发明公开的式Ⅰ所示的新化合物,对大肠杆菌、嗜麦芽单胞菌、诺菲不动杆菌、金黄色葡萄球菌、表皮葡萄球菌中的一种或多种具有抑制作用,为临床上筛选抗菌、抑菌、杀菌等药物提供了一种新的选择。
本发明中提供的化合物和衍生物可以根据IUPAC(国际纯粹与应用化学联合会)或CAS(化学文摘服务社,Columbus,OH)命名系统命名。
关于本发明的使用术语的定义:除非另有说明,本文中基团或者术语提供的初始定义适用于整篇说明书的该基团或者术语;对于本文没有具体定义的术语,应该根据公开内容和上下文,给出本领域技术人员能够给予它们的含义。
“取代”是指分子中的氢原子被其它不同的原子或分子所替换。
碳氢基团中碳原子含量的最小值和最大值通过前缀表示,例如,前缀(C a~b)烷基表明任何含“a”至“b”个碳原子的烷基。因此,例如,C1~C4烷基是指包含1~4个碳原子的烷基。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料,和/或所形成的盐通常在化学上或物理上与构成某药物剂型的其它成分相兼容,并在生理上与受体相兼容。
术语“盐”和“可药用的盐”是指上述化合物或其立体异构体,与无机和/或有机酸和碱形成的酸式和/或碱式盐,也包括两性离子盐(内盐),还包括季铵盐,例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物,或其立体异构体,与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集,或在溶剂蒸发后回收而得到,或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明的某些实施方式中,本发明包括了同位素标记的化合物,所述同位素标记化合物是指与本文中所列化合物相同,但是其中的一个或多个原子被另一个原子取代,该原子的原子质量或质量数不同于自然界中常见的原子质量或质量数。可以引入式(I)化合物中的同位素包括氢、碳、氮、氧、硫,即2H,3H、13C、14C、15N、17O、18O、35S。含有上述同位素和/或其它原子同位素的式(I)的化合物及其立体异构体,以及该化合物、立体异构体的可药用的盐均应包含在本发明范围之内。
本发明中的关键中间体和化合物进行分离和纯化,所使用的方式是有机化学中常用的分离和纯化方法且所述方法的实例包括过滤、萃取、干燥、旋干和各种类型的色谱。可选择地,可以使中间体不经纯化即进行下一步反应。
在某些实施方式中,本发明的一种或多种化合物可以彼此联合使用。也可选择将本发明的化合物与任何其它的活性试剂结合使用,用于制备调控细胞功能或治疗疾病的药物或药物组合物。如果使用的是一组化合物,则可将这些化合物同时、分别或有序地对受试对象进行给药。
本发明化合物或药物组合物的施用方式没有特别限制,代表性的施用方式包括(但并不限于):口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中,活性化合物与至少一种常规惰性赋形剂(或载体)混合,如柠檬酸钠或磷酸二钙,或与下述成分混合:(a)填料或增容剂,例如,淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸;(b)粘合剂,例如,羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶;(c)保湿剂,例如,甘油;(d)崩解剂,例如,琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠;(e)缓溶剂,例如石蜡;(f)吸收加速剂,例如,季胺化合物;(g)润湿剂,例如鲸蜡醇和单硬脂酸甘油酯;(h)吸附剂,例如,高岭土;和(i)润滑剂,例如,滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠,或其混合物。胶囊剂、片剂和丸剂中,剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备,如肠衣和其它本领域公知的材料。它们可包含不透明剂,并且,这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时,活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外,液体剂型可包含本领域中常规采用的惰性稀释剂,如水或其它溶剂,增溶剂和乳化剂,例知,乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油,特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外,组合物也可包含助剂,如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外,悬浮液可包含悬浮剂,例如,乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液,和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂,或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料,是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分,它具有一定生理活性,但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位,而仅仅发挥辅助功效,这些辅助功效仅仅是对该成分已知活性的利用,是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用,仍然应属于本发明保护的范围。
显然,根据本发明的上述内容,按照本领域的普通技术知识和惯用手段,在不脱离本发明上述基本技术思想前提下,还可以做出其它多种形式的修改、替换或变更。
以下通过实施例形式的具体实施方式,对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。凡基于本发明上述内容所实现的技术均属于本发明的范围。
附图说明
图1式Ⅰ-a所示化合物的1H NMR谱图
图2式Ⅰ-a所示化合物的13C NMR谱图
图3式Ⅰ-a所示化合物的外消旋体高效液相谱图
图4式Ⅰ-a所示化合物的单一异构体高效液相谱图
图5式Ⅰ-b所示化合物的1H NMR谱图
图6式Ⅰ-b所示化合物的13C NMR谱图
图7式Ⅰ-b所示化合物的外消旋体高效液相谱图
图8式Ⅰ-b所示化合物的单一异构体高效液相谱图
图9式Ⅰ-c所示化合物的1H NMR谱图
图10式Ⅰ-c所示化合物的13C NMR谱图
图11式Ⅰ-c所示化合物的外消旋体高效液相谱图
图12式Ⅰ-c所示化合物的单一异构体高效液相谱图
定义与缩写:
“ee”代表“对映体过量”,是手性化合物的一种对映体相对于外消旋样品过量的量度,就给定的样品而言,以百分比表示。对映体过量被定义为100×(er-1)/(er+1),其中“er”是较多丰度对映体与较少丰度对映体之比。
“de”代表“非对映体过量”,是一种非对映体相对于具有等量非对映体的样品过量的量度,就给定的样品而言,以百分比表示。非对映体过量被定义为100×(dr-1)/(dr+1),其中“dr”是较多丰度非对映体与较少丰度非对映体之比。
下面有些流程和实施例可以省略常见反应(包括氧化、还原等)、分离技术和分析过程的细节,它们是有机化学领域普通技术人员已知的。这类反应和技术的细节可以在一些专著中找到,包括Richard larock,Comprehensive Organic Transformations(1999)和由Michael B.Smith and others编辑的多卷系列Compendium of Organic SyntheticMethods(1974~2005)。有些反应流程可以省略来自化学转化的次要产物(例如来自酯水解的醇、来自二元酸脱羧基化的CO2等)。另外,在有些情形下,反应中间产物可以无需分离或纯化即可用在随后的步骤中。
在下面有些反应流程和实施例中,某些化合物可以使用保护基团制备,它们防止在其他反应性部位发生不需要的化学反应。保护基团也可以用于提高溶解性或者以其他方式改变化合物的物理性质。关于保护基团策略的讨论,安装和除去保护基团的材料和方法的说明,和可用于常见官能团的保护基团的汇编等,参见T.W.Greene and P.G.Wuts,Protecting Groups in Organic Chemistry(1999)和P.Kocienski,Protective Groups(2000),它们完整引用在此作为参考。
一般而言,遍及说明书所述的化学转化可以使用基本上为化学计量量的反应试剂进行,不过某些反应可以受益于使用过量的一种或多种反应试剂。另外,很多遍及说明书所公开的反应可以在约RT(室温)和环境温度下进行,但是依赖于反应动力学、收率等,有些反应可以在高压下或者采用更高的(例如回流条件)或更低(例如-70℃~0℃)的温度进行。很多化学转化也可以采用一种或多种相容性溶剂,它们可以影响反应速率和收率。依赖于反应试剂的属性,一种或多种溶剂可以是极性质子溶剂(包括水)、极性质子惰性溶剂、非极性溶剂或者一些组合。本文中任何对于化学计量范围、温度范围、pH范围等的公开描述无论是否明确使用术语“范围”,也都包括所示端点。
除非另有规定,当特定的取代基标识符(R1、R2、R3等)关于结构式被第一次定义时,同一取代基标识符在用于随后的结构式中时将具有与在先结构式中相同的定义。
式Ⅰ所示化合物具有至少两个立体中心,由楔形键所示,包括R1、R2、R3等,它们是如上所定义的。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品,通过购买市售产品获得。
实施例1
以丙醛(0.4mmol)和化合物2-a(0.3mmol,市售,CAS号102-96-5)为原料,加入(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷作为催化剂(0.03mmol)和冰醋酸(0.04mmol),乙腈(1ml)作为溶剂,室温搅拌反应3~4小时,得到化合物3-a。
该反应完成后直接一锅法加入化合物4-a(0.2mmol)、碳酸钾(0.1mmol溶于1.0mL水中)和TBAB(0.01mmol;四丁基溴化铵),于60℃下搅拌反应,至TLC(薄层色谱)监测反应完全,得到反应液;将反应液旋干溶剂,经硅胶柱层析分离纯化,得到式Ⅰ-a所示化合物55.9mg,收率为62%,94%ee,94:6dr(1H NMR分析得到)。
式Ⅰ-a所示化合物的检测数据如下:
熔点为183℃~185℃;
[α]D 20+159(c=0.20,在CH2Cl2中);
ESI HRMS:C24H25N3O6Na+,检测值为474.1639;
1H NMR(400MHz,CDCl3):δ=7.46-7.32(m,5H),7.28-7.25(m,3H),7.10(brs,2H),5.98(t,J=10.8Hz,1H),4.35(d,J=6.8Hz,1H),4.12(d,J=12.0Hz,1H),3.26(s,3H),3.14(s,3H),3.09(t,J=11.2Hz,1H),2.96-2.93(m,1H),2.16(brs,1H),0.91(d,J=4.4Hz,3H)ppm;如图1所示;
13C NMR(100MHz,CDCl3):δ=170.27,168.76,150.10,137.59,132.51,129.36,129.02,128.14,127.95,90.99,62.71,52.99,51.77,38.58,31.60,28.94,28.48,22.67,16.13,14.14ppm;如图2所示;
ee值是由HPLC(高效液相色谱)测定得到,色谱柱:Chiralpak AD,10%2-丙醇/正己烷,1mL/min,UV 254nm,tmajor=14.6min,tminor=12.5min;
其中,外消旋体高效液相谱图中,两个峰面积相等或几乎相等的是两个异构体,其保留时间用作对照,单一异构体高效液相谱图中两个峰对照外消旋体高效液相谱图中的保留时间,通过峰面积计算出ee值;如图3和图4所示。
实施例2
以丙醛(0.4mmol)和化合物2-b(0.3mmol,市售,CAS号102-96-5)为原料,加入(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷作为催化剂(0.03mmol)和冰醋酸(0.04mmol),乙腈(1ml)作为溶剂,室温搅拌反应3~4小时,得到化合物3-b。
该反应完成后直接一锅法加入化合物4-b(0.2mmol)、碳酸钾(0.1mmol溶于1.0mL水中)和TBAB(0.01mmol;四丁基溴化铵),于60℃下搅拌反应,至TLC(薄层色谱)监测反应完全,得到反应液;将反应液旋干溶剂,经硅胶柱层析分离纯化,得到式Ⅰ-b所示化合物45.1mg,收率为51%,98%ee,85:15dr(1H NMR分析得到)。
式Ⅰ-b所示化合物的检测数据如下:
熔点为189℃~190℃;
[α]D 20+141(c=0.15,在CH2Cl2中);
ESI HRMS:C22H23N3O7Na+,检测值为464.1431;
1H NMR(400MHz,CDCl3):δ=7.41-7.34(m,5H),7.24-7.23(m,1H),6.20(dd,J1=2.0Hz,J2=3.2Hz,1H),6.11(d,J=3.2Hz,1H),5.85(t,J=7.2Hz,1H),4.31(d,J=11.6Hz,1H),4.22(d,J=10.4Hz,1H),3.31(s,3H),3.27(s,3H),3.12-3.09(m,1H),3.01(t,J=11.6Hz,1H),2.85-2.79(m,1H),0.85(d,J=6.4Hz,3H)ppm;如图5所示;
13C NMR(100MHz,CDCl3):δ=170.21,168.31,150.54,147.05,143.44,142.68,137.41,129.01,128.18,110.80,109.73,107.89,90.52,60.83,52.66,45.52,38.34,29.18,28.70,15.96ppm;如图6所示;
ee值是由HPLC(高效液相色谱)测定得到,色谱柱:Chiralpak AD,10%2-丙醇/正己烷,1mL/min,UV 254nm,tmajor=15.8min,tminor=17.3min;
其中,外消旋体高效液相谱图中,两个峰面积相等或几乎相等的是两个异构体,其保留时间用作对照,单一异构体高效液相谱图中两个峰对照外消旋体高效液相谱图中的保留时间,通过峰面积计算出ee值;如图7和图8所示。
实施例3
以丙醛(0.4mmol)和化合物2-c(0.3mmol,市售,CAS号102-96-5)为原料,加入(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷作为催化剂(0.03mmol)和冰醋酸(0.04mmol),乙腈(1ml)作为溶剂,室温搅拌反应3~4小时,得到化合物3-c。
该反应完成后直接一锅法加入化合物4-c(0.2mmol)、碳酸钾(0.1mmol溶于1.0mL水中)和TBAB(0.01mmol;四丁基溴化铵),于60℃下搅拌反应,至TLC(薄层色谱)监测反应完全,得到反应液;将反应液旋干溶剂,经硅胶柱层析分离纯化,得到式Ⅰ-c所示化合物52.9mg,收率为68%,98%ee,91:9dr(1H NMR分析得到)。
式Ⅰ-c所示化合物的检测数据如下:
熔点为201℃~203℃;
[α]D 20+133(c=0.24,在CH2Cl2中);
ESI HRMS:C25H27N3O7Na+,检测值为504.1742;
1H NMR(400MHz,CDCl3):δ=7.46-7.33(m,5H),6.99(d,J=8.4Hz,1H),6.72(d,J=8.8Hz,1H),6.20(dd,J1=6.0Hz,J2=12.8Hz,1H),4.85(dd,J1=6.0Hz,J2=11.6Hz,1H),4.58(d,J=12.8Hz,1H),3.97(t,J=6.0Hz,1H),3.72(s,3H),3.24(s,3H),3.20-3.13(m,1H),3.12(s,3H),1.91(d,J=6.0Hz,1H),0.87(d,J=6.8Hz,3H)ppm;如图9所示;
13C NMR(100MHz,CDCl3):δ=171.87,168.70,159.68,134.58,128.96,128.23,125.98,114.35,86.51,63.40,55.16,51.51,46.17,36.46,29.00,28.35,15.94ppm;如图10所示;
ee值是由HPLC(高效液相色谱)测定得到,色谱柱:Chiralpak AD,10%2-丙醇/正己烷,1mL/min,UV 254nm,tmajor=24.5min,tminor=13.8min;
其中,外消旋体高效液相谱图中,两个峰面积相等或几乎相等的是两个异构体,其保留时间用作对照,单一异构体高效液相谱图中两个峰对照外消旋体高效液相谱图中的保留时间,通过峰面积计算出ee值;如图11和图12所示。
为了说明本发明的有益效果,本发明提供以下试验例:
试验例1抗菌活性试验
本发明采用等倍稀释法测定式Ⅰ所示化合物的抗菌活性。
实验菌株的获得:
大肠杆菌ATCC2522,金黄色葡萄球菌ATCC25923为商购;其余均为由四川省人民医院、四川省妇幼保健院收集鉴定的临床分离致病菌。标本主要来源于血液、痰、尿液等,在收集单位经法国梅里埃(BioMeriruk)VITEK-32、VITEK-60自动微生物鉴定分析仪进行鉴定,并经四川抗菌素工业研究所用Biolog细菌鉴定仪(美国)API 20E、20NE、Staph系列和常规方法再次鉴定,分别命名为:大肠杆菌D7、嗜麦芽单胞菌S1、诺菲不动杆菌N2、诺菲不动杆菌N3、金黄色葡萄球菌J4、金黄色葡萄球菌J2、金黄色葡萄球菌J13、表皮葡萄球菌BP8、表皮葡萄球菌BP4,用于抗菌试验。
将精确称量的式Ⅰ所示化合物用2ml DMSO(二甲基亚砜)溶解,按等倍稀释法分别做10个浓度梯度,每一个梯度向MH培养皿中加入1ml含药溶液,并用14ml MH固体培养基(水解酪蛋白(Mueller-Hinton)培养基)混匀,做成含药不同的培养皿。然后用27孔的打孔器将含菌量为106的菌液接种于培养皿上,放入37℃的恒温培养箱,培养18h~24h,观察接种部位是否有细菌生长,以判断其抑菌效果,结果见表1;以左氧氟沙星作为参照。
抗菌活性是指抗菌药抑制或杀灭病原微生物的能力;可用体外抑菌试验和体内实验治疗法测定;体外抑菌实验对临床用药具有重要参考意义。能够抑制培养基内细菌生长的最低浓度为最小抑菌浓度(minimal inhibitory concentration,MIC)。抗菌药的抑菌作用和杀菌作用是相对的,有些抗菌药在低浓度时呈抑菌作用,而高浓度呈杀菌作用。
表1 本发明式Ⅰ所示化合物的抗菌活性MIC(mg/ml)
注:“-”表示在浓度为2mg/ml时,该化合物对该种菌株没有抗菌活性。
由上述试验可知,本发明式Ⅰ-a化合物、式Ⅰ-b化合物、式Ⅰ-c化合物均具有良好的抗菌活性,对大肠杆菌、嗜麦芽单胞菌、诺菲不动杆菌、金黄色葡萄球菌、表皮葡萄球菌中的一种或多种具有抑制作用。
综上所述,本发明公开的式Ⅰ所示的新化合物,对大肠杆菌、嗜麦芽单胞菌、诺菲不动杆菌、金黄色葡萄球菌、表皮葡萄球菌中的一种或多种具有抑制作用,为临床上筛选抗菌、抑菌、杀菌等药物提供了一种新的选择。
Claims (7)
1.式Ⅰ所示的巴比妥酸手性环己烷螺环化合物或其药学上可接受的盐:
式Ⅰ
其中,
R1、R2分别或同时选自苯基、呋喃基、卤素取代的苯基、C1~C6烷基取代的苯基、C1~C6烷氧基取代的苯基;
R3、R4、R5分别或同时选自氢、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基。
2.根据权利要求1所述的巴比妥酸手性环己烷螺环化合物或其药学上可接受的盐,其特征在于:式Ⅰ所示的巴比妥酸手性环己烷螺环化合物为:
、或。
3.一种制备式Ⅰ所示巴比妥酸手性环己烷螺环化合物的方法,其特征在于:其合成路线为:
其中,
R1、R2分别或同时选自苯基、呋喃基、卤素取代的苯基、C1~C6烷基取代的苯基、C1~C6烷氧基取代的苯基;
R3、R4、R5分别或同时选自氢、甲基、乙基、丙基、丁基、甲氧基、乙氧基、丙氧基或丁氧基;
它包括以下步骤:
a、化合物1、化合物2、有机催化剂和冰醋酸在腈类溶剂中,于25℃~30℃下搅拌反应3~4小时,得到化合物3的反应液;
所述有机催化剂为(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷;所述腈类溶剂选自乙腈、丙腈、丁腈、异丁腈、苯乙腈中的任意一种或多种;
b、向步骤a化合物3的反应液中加入化合物4、无机碱、季铵盐类催化剂,于60~65℃下搅拌反应,薄层色谱监测反应完全,得到反应液;将反应液除去溶剂,得到粗品;对粗品进行分离纯化,得到式Ⅰ所示的巴比妥酸手性环己烷螺环化合物;
所述无机碱选自碳酸钾、碳酸钠中的任意一种或多种;所述季铵盐类催化剂选自四丁基氟化铵、四丁基氯化铵、四丁基溴化铵、四丁基碘化铵中的任意一种或多种;
所述化合物1、化合物2、有机催化剂、冰醋酸、化合物4、无机碱、季铵盐类催化剂的摩尔比为1:(0.1~1):(0.02~0.1):(0.05~0.5):(0.1~1):(0.1~0.5):(0.01~0.05);所述化合物1与腈类溶剂的摩尔体积比为1:(1~10)mol/L。
4.根据权利要求3所述制备式Ⅰ所示巴比妥酸手性环己烷螺环化合物的方法,其特征在于:
步骤a中,所述有机催化剂为(2R)-2-[二苯基[三甲基硅氧基]甲基]-吡咯烷;所述腈类溶剂为乙腈;
步骤b中,所述无机碱为碳酸钾;所述季铵盐类催化剂为四丁基溴化铵;
所述化合物1、化合物2、有机催化剂、冰醋酸、化合物4、无机碱、季铵盐类催化剂的摩尔比为1:0.75:0.075:0.1:0.5:0.25:0.025;所述化合物1与腈类溶剂的摩尔体积比为1:(2~3)mol/L。
5.权利要求1~2任意一项所述的巴比妥酸手性环己烷螺环化合物或其药学上可接受的盐在制备抗菌药物中的用途,所述抗菌药物是指对诺菲不动杆菌具有抗菌活性的抗菌药物。
6.巴比妥酸手性环己烷螺环化合物或其药学上可接受的盐在制备抗菌药物中的用途,所述抗菌药物是指对嗜麦芽单胞菌具有抗菌活性的抗菌药物;所述的巴比妥酸手性环己烷螺环化合物为:
。
7.巴比妥酸手性环己烷螺环化合物或其药学上可接受的盐在制备抗菌药物中的用途,所述抗菌药物是指对表皮葡萄球菌具有抗菌活性的抗菌药物;所述的巴比妥酸手性环己烷螺环化合物为:
、。
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