CN1620462B - 具有(吡啶基)咪唑配体的过渡金属络合物 - Google Patents

具有(吡啶基)咪唑配体的过渡金属络合物 Download PDF

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CN1620462B
CN1620462B CN028133013A CN02813301A CN1620462B CN 1620462 B CN1620462 B CN 1620462B CN 028133013 A CN028133013 A CN 028133013A CN 02813301 A CN02813301 A CN 02813301A CN 1620462 B CN1620462 B CN 1620462B
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毛飞
A·赫勒
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Abbott Diabetes Care Inc
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Abstract

本发明描述了铁、钴、钌、锇和钒的新型过渡金属络合物。过渡金属络合物在基于酶的电化学传感器中作为氧化还原介体使用。过渡金属络合物包括取代或未取代的(吡啶基)咪唑配体。还描述了连接至聚合骨架上的过渡金属络合物。

Description

具有(吡啶基)咪唑配体的过渡金属络合物 
发明领域
本发明涉及具有(吡啶基)咪唑配体的过渡金属络合物。另外，本发明涉及过渡金属络合物的制备和过渡金属络合物作为氧化还原介体(mediator)的用途。 
发明背景
基于酶的电化学传感器被广泛应用于临床、环境、农业和生物技术应用中分析物的检测。可以在人体液的临床分析中测量的分析物包括，例如，葡萄糖、乳酸盐、胆固醇、胆红素和氨基酸类。这些分析物在生物液体，例如血液中的水平，对于疾病的诊断和监测是重要的。 
电化学分析通常在具有两个或三个电极的电池中进行，包括至少一个测量或工作电极和一个参比电极。在三个电极的系统中，第三个电极是对电极(counter-electrode)。在两个电极的系统中，参比电极也作为对电极。电极通过电路，例如恒电位仪相连。测量或工作电极是非腐蚀碳或金属导体。在电流通过工作电极的电路中，氧化还原酶被电氧化或电还原。酶对于待检测的分析物，或分析物的产物是特异的。酶的转换率通常与测试溶液中分析物本身，或其产物的浓度相关(优选，但不是必然的，线性)。 
酶的电氧化或电还原一般通过溶液中或电极上氧化还原介体的存在而促进。氧化还原介体有助于工作电极和酶之间的电连接。氧化还原介体可以溶于与电极电解接触的待分析液体中，或可以应用于与分析溶液电解接触的工作电极的涂层内。涂层优选不溶于水，但可以在水中膨胀。有用的装置可以通过，例如，用包括氧化还原介体和酶的薄膜涂覆电极而制备，其中酶对于所需分析物，或其产物是催化特异 性的。与涂覆的氧化还原介体相反，可以溶于或不溶于水的扩散性氧化还原介体通过，例如酶和电极之间的电子往复运动起作用。总之，当酶底物被电氧化时，氧化还原介体将电子从底物-还原的酶传递至电极；以及当底物被电还原时，氧化还原介体将电子从电极传递至底物-氧化的酶。 
最近，基于酶的电化学传感器已经使用了许多不同的氧化还原介体，例如单体二茂铁、醌型化合物，包括奎宁(即，苯醌)、环磺酸镍和钌胺类。这些氧化还原介体大多数具有一种或多种以下局限：氧化还原介体在测试溶液中的溶解度低，其化学、光、热和/或pH稳定性差，或其不能足够迅速地与酶或电极或两者交换电子。一些具有有利特性的介体难以合成。另外，在这些报道的氧化还原介体中，其中一些的氧化还原电势是如此具有氧化性，以至于在还原的介体在电极上被电氧化的电势下，除分析物之外，溶液中的其它组分也被电氧化。其它一些这些报道的氧化还原介体是如此具有还原性，以至于溶液组分，例如，诸如溶解的氧，也被迅速电还原。结果，使用这些介体的传感器特异性不高。 
发明概述
本发明涉及新型的过渡金属络合物。本发明也涉及络合物作为氧化还原介体的用途。优选的氧化还原介体通常与酶和电极迅速交换电子、其稳定、可以方便地合成，并且具有适合分析物，诸如，例如葡萄糖的电氧化反应的氧化还原电势。 
本发明的一个实施方案是具有以下通式的过渡金属络合物： 
Figure S02813301319950321D000021
在该通式中，M是钴、铁、钌、锇或钒；c是选自-1到-5、0或+1到+5的整数，代表正电荷、中性或负电荷；X表示至少一个抗衡离子；d是0到5的整数，表示抗衡离子X的数目；L和L′独立地选 自： 
Figure S02813301319950321D000031
以及L1和L2是其它配体。在L和L′的通式中，R′1是取代或未取代的烷基、链烯基或芳基。一般而言，R′3、R′4、Ra、R′b、Rc和Rd独立地是-H、-F、-Cl、-Br、-I、-NO2、-CN、-CO2H、-SO3H、-NHNH2、-SH、-OH、-NH2，或取代或未取代的烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、烷氧基、烷基氨基、二烷基氨基、烷酰基氨基、芳基酰胺基、肼基、烷基肼基、羟基氨基、烷氧基氨基、烷基硫代、链烯基、芳基或烷基。 
本发明的过渡金属络合物在电化学传感器中有效地用作氧化还原介体，其动力学非常快。本发明的传感器包括接近工作电极放置的酶和接近工作电极放置的氧化还原介体，其中氧化还原介体在工作电极上交联或者氧化还原介体和酶在工作电极上交联。更特别的是，当本发明的过渡金属络合物如此使用时，在传感器装置中，过渡金属络合物和酶和/或工作电极之间发生迅速的电子交换。这种电子交换足够迅速，促使电子转移到工作电极上，否则电子可能会转移到系统的另一个电子清除剂上。当上式介体的L2是带负电荷的配体时，介体的快速动力学通常被增强。 
本发明的过渡金属络合物也是非常稳定的。例如，当这种络合物作为电化学传感器中的介体使用时，化学稳定性一般是这样的，介体参与其中的主反应是介体和酶之间的电子转移反应和在工作电极上的电化学氧化还原反应。当上式的介体(其中L2是带负电荷的配体)具有“庞大的”化学配体L1，可以屏蔽氧化还原中心M，并因此减少了超过所需电化学活性的不希望的化学反应性时，化学稳定性得以增强。 
本发明过渡金属络合物的电化学稳定性也是非常可取的。例如，当这种络合物在电化学传感器中作为介体使用时，介体能够在这样的氧化还原电势范围内操作：普通干扰性物质的电化学活性最小，并且 介体的良好动力学活性得以保留。 
因此，本发明提供了新型过渡金属络合物，其在电化学传感应用中作为氧化还原介体是特别有用的。本发明过渡金属络合物的有利特性和特征使其成为理想的选择物，用于葡萄糖的电化学传感—一种在人类糖尿病的治疗中特别重要的应用。 
详细叙述
当在此处使用时，在以下引语中的定义限定了所用的术语。 
术语“烷基”包括直链或支链的饱和脂肪族烃。烷基的例子包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基等。除非另外注明，术语“烷基”包括烷基和环烷基。 
术语“烷氧基“描述了通过氧原子与结构的其他部分连接的烷基。烷氧基的例子包括甲氧基、乙氧基、正丙氧基、异丙氧基、丁氧基、叔丁氧基等。除非另外注明，术语“烷氧基”包括烷氧基和环烷氧基。 
术语“链烯基“描述了不饱和直链或支链的具有至少一个碳-碳双键的脂族烃。链烯基的例子包括乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、2-甲基-1-丙烯基等。 
“反应性基团”是分子的官能团，其能够与另一化合物反应，以将其它化合物的至少一部分结合至分子上。反应性基团包括羧基、活化的酯、磺酰卤、磺酸酯、异氰酸酯、异硫氰酸酯、环氧化物、氮丙啶、卤化物、醛、酮、胺、丙烯酰胺、硫醇、酰叠氮(acyl azide)、酰卤、肼、羟胺、烷基卤化物、咪唑、吡啶、苯酚、烷基磺酸酯、卤代三嗪、亚氨酸酯、马来酰亚胺、酰肼、羟基和光反应性叠氮基芳基。按照现有技术的理解，活化的酯，包括琥珀酰亚胺基(succinimidyl)、苯并三唑基或被诸如磺基、硝基、氰基或卤代基团的吸电子基团取代的芳基、或被碳二亚胺活化的羧酸的酯。 
“取代的”官能团(例如，取代的烷基、链烯基或烷氧基)包括至少一个选自以下的取代基：卤素、烷氧基、巯基、芳基、烷氧羰基、 烷基氨基羰基、二烷基氨基羰基、-OH、-NH2、烷基氨基、二烷基氨基、三烷基铵、烷酰基氨基、芳基酰胺基、肼基、烷基硫代、链烯基和反应性基团。 
“生物液体”是其中分析物可以被测量的任何体液或体液衍生物，例如血液、间隙液体、血浆、皮肤液体(dermal fluid)、汗液和泪液。 
“电化学传感器”是用于通过电化学氧化或还原反应，检测样品中分析物的存在或测量其浓度或含量的装置。这些反应通常可以转换成可以与分析物的量或浓度相关的电信号。 
“氧化还原介体”是直接，或经过一种或多种额外的电子转移试剂，在分析物或者分析物-还原的或分析物-氧化的酶和电极之间传送电子的电子转移试剂。包括聚合骨架的氧化还原介体也可以被称为“氧化还原聚合物”。 
“电解”是化合物直接在电极上或通过一种或多种电子转移试剂(例如，氧化还原介体或酶)的电氧化或电还原。 
除非另有说明，术语“参比电极”包括a)参比电极和b)也起对电极作用的参比电极(也就是，对/参比电极)。 
除非另有说明，术语“对电极”包括a)对电极和b)也起参比电极作用的对电极(也就是，对/参比电极)。 
一般而言，本发明涉及具有(吡啶基)咪唑配体的铁、钴、钌、锇和钒的过渡金属络合物。本发明还涉及过渡金属络合物的制备和过渡金属络合物作为氧化还原介体的用途。在至少一部分例子中，过渡金属络合物具有一个或多个以下特征：在特定范围内的氧化还原电势，与电极迅速交换电子的能力，在酶或其它分析物-特异性的氧化还原催化剂存在下，将电子迅速转移至酶或迅速从酶接收电子，以促进分析物的电氧化和电还原动力学的能力。例如，在葡萄糖氧化酶或PQQ-葡萄糖脱氢酶存在下，氧化还原介体可以促进葡萄糖的电氧化，这是一种在其它可电化学氧化的物质存在下可用于葡萄糖的选择性分析的方法。与其它过渡金属氧化还原介体相比，本发明的一些实 施方案对于合成性制备或在合成中使用更广泛可得或更成本有效的试剂更加容易或更加成本有效。 
具有下式1的化合物是本发明过渡金属络合物的例子。 
Figure S02813301319950321D000061
M是过渡金属，并通常是铁、钴、钌、锇或钒。钌和锇特别适合于氧化还原介体。 
L和L′独立地是具有以下结构2的二齿的取代或未取代的2-(2-吡啶基)咪唑配体。 
Figure S02813301319950321D000062
在结构2中，R′1是取代或未取代的芳基、链烯基或烷基。通常R′1是取代或未取代的C1-C12烷基或链烯基，或例如苯基的芳基，任选被选自-Cl、-F、-CN、氨基、羧基、C1-C6烷基、C1-C6烷基硫代、C1-C6烷基氨基、C1-C6二烷基氨基、C1-C6烷基氨基羰基、C1-C6烷氧基、C1-C6烷氧基羰基和C1-C6烷基酰胺基的取代基取代。R′1通常是甲基或任选被反应性基团取代的C1-C12烷基，或任选被C1-C2烷基、C1-C2烷氧基、-Cl或-F取代的芳基。 
一般而言，R′3、R′4、Ra、Rb、Rc和Rd独立地是-H、-F、-Cl、-Br、-I、-NO2、-CN、-CO2H、-SO3H、-NHNH2、-SH、-OH、-NH2、取代或未取代的烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、烷氧基、烷基氨基、二烷基氨基、烷酰基氨基、芳基酰胺基、肼基、烷基肼基、羟基氨基、烷氧基氨基、烷基硫代、链烯基、芳基或 烷基。或者，Rc和Rd结合和/或R′3和R′4结合可以形成饱和或不饱和的5-或6-元环，通常，烷基和烷氧基部分是C1到C12。任何取代基的烷基或芳基部分可以任选被-F、-Cl、-Br、-I、烷基氨基、二烷基氨基、三烷基铵(除了在芳基部分)、烷氧基、烷基硫代、芳基或反应性基团取代。一般而言，R′3、R′4、Ra、Rb、Rc和Rd独立地是-H或未取代的烷基。通常地，Ra和Rc是H，和R′3、R′4、Rb和Rd是-H或甲基。 
优选，L和L′配体相同。这里，有关L和L′的说明可以交换使用。 
在式1中，c是指示络合物电荷的整数。一般而言，c是代表正电荷或负电荷的选自-1到-5或+1到+5的整数，或是代表中性电荷的0。对许多锇络合物，c是+1、+2或+3。 
X表示抗衡离子。合适的抗衡离子的例子包括阴离子，诸如卤化物(例如，氟化物、氯化物、溴化物或碘化物)、硫酸根、磷酸根、六氟磷酸根和四氟硼酸根，以及阳离子(优选一价阳离子)，诸如锂、钠、钾、四烷基铵和铵。优选X是卤化物，诸如氯化物。X表示的抗衡离子不需要完全相同。 
d表示抗衡离子的数目和通常是0到5。 
L1和L2是通过配位键连接至过渡金属上的配体。L1和L2是单齿配体，其中至少一个是带负电荷的单齿配体。当L1和L2交换使用时，仅为方便起见，L2一般称为带负电荷的配体。此处，术语“带负电荷的配体”定义为这样的配体：其中配位原子本身带负电荷，所以与带正电荷的金属配位，正电荷被中和。例如，卤化物，例如氯化物或氟化物符合此定义，而带有带负电荷的磺酸盐基团的吡啶配体不符合此定义，因为磺酸盐基团没有参与配位。带负电荷的配体的例子包括，但不限于，-F、-Cl、-Br、-I、-CN、-SCN、-OH、烷氧基、烷基硫代和酚盐。通常带负电荷的单齿配体是卤化物。 
其它合适的单齿配体的例子包括，但不限于，H2O、NH3、烷基胺、二烷基胺、三烷基胺、或杂环化合物。任何配体的烷基或芳基部 分可以任选地被-F、-Cl、-Br、-I、烷基氨基、二烷基氨基、三烷基铵(除了芳基部分)、烷氧基、烷基硫代、芳基或反应性基团取代。单齿配体的任何烷基部分通常含1-12个碳原子。烷基部分更通常含1-6个碳原子。在其它实施方案中，单齿配体是含至少一个氮原子、氧原子或硫原子的杂环化合物。合适的杂环单齿配体的例子包括咪唑、吡唑、噁唑、噻唑、三唑、吡啶、吡嗪及其衍生物。合适的杂环单齿配体包括分别具有以下通式3和4的取代或未取代的咪唑和取代或未取代的吡啶。 
Figure S02813301319950321D000081
关于通式3，R7一般是取代或未取代的烷基、链烯基或芳基。一般而言，R7是取代或未取代的C1-C12烷基或链烯基，或诸如苯基的芳基，任选被选自-Cl、-F、-CN、氨基、羧基、C1-C6烷基、C1-C6烷基硫代、C1-C6烷基氨基、C1-C6二烷基氨基、C1-C6烷基氨基羰基、C1-C6烷氧基、C1-C6烷氧基羰基和C1-C6烷基酰胺基的取代基取代。R7通常是甲基或任选被反应性基团取代的C1-C12烷基，或任选被C1-C2烷基、C1-C2烷氧基、-Cl或-F取代的芳基。 
一般而言，R8、R9和R10独立地是-H、-F、-Cl、-Br、-I、-NO2、-CN、-CO2H、-SO3H、-NHNH2、-SH、-OH、-NH2、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、烷氧基、烷基氨基、二烷基 氨基、烷酰基氨基、芳基酰胺基、肼基、烷基肼基、羟基氨基、烷氧基氨基、烷基硫代、链烯基、芳基或烷基。或者，R9和R10结合形成饱和或不饱和的稠合的5-或6-元环。取代基的烷基部分一般含1-12个碳原子，并通常含1-6个碳原子。任何取代基的烷基或芳基部分可以任选被-F、-Cl、-Br、-I、烷基氨基、二烷基氨基、三烷基铵(除了在芳基部分)、烷氧基、烷基硫代、芳基，或反应性基团取代。在某些实施方案中，R8、R9和R10是-H或取代或未取代的烷基。优选R8、R9和R10是-H。 
至于通式4，R11、R12、R13、R14和R15独立地是-H、-F、-Cl、-Br、-I、-NO2、-CN、-CO2H、-OH、-NH2、烷氧基羰基、烷基氨基羰基、二烷基氨基羰基、烷氧基、烷基氨基、二烷基氨基、烷酰基氨基、芳基酰胺基、肼基、烷基肼基、羟基氨基、烷氧基氨基、烷基硫代、链烯基、芳基或烷基。任何取代基的烷基或芳基部分可以任选被-F、-Cl、-Br、-I、烷基氨基、二烷基氨基、三烷基铵(除了在芳基部分)、烷氧基、烷基硫代、芳基或反应性基团取代。一般而言，R11、R12、R13、R14和R15是-H、甲基、C1-C2烷氧基、C1-C2烷基氨基、C2-C4二烷基氨基、或被反应性基团取代的C1-C6低级烷基。 
一个实施例包括R11和R15是-H，而R12和R14相同，是-H或甲基，R13是-H、C1-C12烷氧基、-NH2、C1-C12烷基氨基、C2-C24二烷基氨基、肼基、C1-C12烷基肼基、羟基氨基、C1-C12烷氧基氨基、C1-C12烷基硫代或C1-C12烷基。任何取代基的烷基或芳基部分可以任选被-F、-Cl、-Br、-I、烷基氨基、二烷基氨基、三烷基铵(除了在芳基部分)、烷氧基、烷基硫代、芳基或反应性基团取代。 
合适的过渡金属络合物的例子包括[Os[1-甲基-2-(2-吡啶基)咪唑]2(1-甲基咪唑)Cl]2+2Cl-(也写作[Os(Py-MIM)2(MIM)Cl])2+2Cl-)，其中L1是：
L2是Cl；c是+2；d是2；X是Cl-；L和L′是： 
式1的过渡金属络合物也包括通过一个或多个L、L′、L1和L2与聚合骨架连接的过渡金属络合物。在一些实施方案中，聚合骨架具有至少一个作为过渡金属络合物的配体的官能团。这种聚合骨架包括，例如，聚(4-乙烯吡啶)和聚(N-乙烯基咪唑)，其中吡啶和咪唑基团分别作为过渡金属络合物的单齿配体。在其它实施方案中，过渡金属络合物可以是在前体聚合物上的反应性基团和前体过渡金属络合物(例如式1的络合物，其中如上所述L、L′、L1和L2中的一个包括反应性基团)配体上的反应性基团之间的反应产物。合适的前体聚合物包括，例如，聚(丙烯酸)(式7)、苯乙烯/马来酸酐共聚物(式8)、甲基乙烯基醚/马来酸酐共聚物(GANTREZ聚合物)(式9)、聚(乙烯基苄基氯)(式10)、聚(烯丙基胺)(式11)、聚赖氨酸(式12)、羧基-聚(乙烯基吡啶)(式13)和聚(4-苯乙烯磺酸钠)(式14)。在这些通式中表现不同的数字n、n′和n″可以变化很大。仅作为例子，在通式13中，[n′/(n′+n″)]x100％优选为约5％到约15％。 
Figure S02813301319950321D000111
Figure S02813301319950321D000121
或者，过渡金属络合物可以具有一个或多个反应性基团，用于将络合物固定或共轭至其它底物或载体，其例子包括，但不限于，大分子(例如酶)和表面(例如电极表面)。 
为了反应性连接至聚合物、底物或其它载体，过渡金属络合物前体包括至少一个与聚合物、底物或载体上的反应性基团反应的反应性基团。通常地，两个反应性基团之间形成共价键，以产生一个键。这种反应性基团的例子和产生的键在下表1中提供。一般而言，一个反应性基团是亲电体，而另一个基团是亲核体。 
表1.反应性基团和产生的键的例子 
Figure S02813301319950321D000131
本发明的过渡金属络合物能够溶于水或其它含水溶液，或有机溶 剂中。一般而言，过渡金属络合物可以通过具有适当的抗衡离子X而溶于含水或有机溶剂。例如，具有小抗衡阴离子，例如F-、Cl-和Br-的过渡金属络合物倾向于溶于水。另一方面，有大抗衡阴离子，例如I-、BF4 -和PF6 -的过渡金属络合物倾向于溶于有机溶剂。优选地，本发明过渡金属络合物对于所需溶剂的溶解度在25℃大于约0.1M(摩尔/升)。 
上述过渡金属络合物可以作为电化学传感器中的氧化还原介体，用于检测生物液体中的分析物。过渡金属络合物作为氧化还原介体的用途在，例如，U.S.专利No.5262035、No.5320725、No.5365786、No.5593852、No.5665222、No.5972199、No.6134161、No.6143164、No.6175752和No.6338790，以及U.S.专利申请序列号No.09/434026中描述，所有文献在此引作参考。此处描述的过渡金属络合物通常可以用于那些在上述参考文献中讨论，虽然这种使用的结果将会明显增强本发明给出的过渡金属络合物的特性，正如此处进一步的描述。 
一般而言，本发明的氧化还原介体布置在工作电极上或接近工作电极的地方(例如在环绕的溶液中)。氧化还原介体在工作电极和分析物之间转移电子。在一些优选的实施方案中，也包括酶，以促进转移。例如，在葡萄糖的酶催化反应中，氧化还原介体在工作电极和葡萄糖之间转移电子(通常通过酶)。氧化还原聚合物对于在工作电极上形成非浸出性涂层特别有用。这些可以通过，例如，在工作电极上交联氧化还原聚合物，或通过在工作电极上交联氧化还原聚合物和酶而形成。 
过渡金属络合物能够精确、可重复地以及迅速或连续地分析。过渡金属络合物氧化还原介体以较高速率从酶或分析物接受电子或将电子转移至酶或分析物，并与电极迅速交换电子。通常地，自交换—还原的氧化还原介体将电子转移至氧化的氧化还原介体的过程—的速率是迅速的。在限定的氧化还原介体浓度下，这在酶(或分析物)和电极之间提供了更迅速的电子转移，并因此缩短了传感器的响应时间。另外，在使用、储存和运输中遇到的周围光线和温度下，新型过渡金属 络合物氧化还原介体通常是稳定的。在使用之前或在存储条件下，优选过渡金属络合物不进行氧化和还原之外的化学变化，虽然氧化还原介体可以设计为，例如，通过与水或分析物的反应而被活化。 
过渡金属络合物可以与氧化还原酶联合作为氧化还原介体使用，以将分析物，或通过例如，分析物的水解而从分析物衍生的化合物电氧化或电还原。当分析物是被电氧化时，氧化还原介体的氧化还原电势通常比氧化还原酶的氧化还原电势更正性(即，更具有氧化性)，以及当分析物是被电还原时，更负性。例如，用葡萄糖氧化酶或PQQ-葡萄糖脱氢酶作为酶，用于电氧化葡萄糖的优选过渡金属络合物氧化还原介体对于Ag/AgCl参比电极的氧化还原电势在约-200mV到+200mV之间，对于Ag/AgCl参比电极，更优选介体的氧化还原电势在约-200mV到约+100mV之间。 
过渡金属络合物的合成实施例
以下提供的实施例显示了可以作为氧化还原介体使用的各种过渡金属络合物的合成，除非另有说明，所有化学试剂均购自AldrichChemical Co.(Milwaukee，WI)或其它来源。提供的数字是近似的。 
实施例1：[Os(Py-MIM)2(MIM)Cl]2+2Cl-的合成 
现在通过以下阐述，提供合成[Os(Py-MIM)2(MIM)Cl]2+2Cl-的实施例。
Figure S02813301319950321D000161
2-(2-吡啶基)咪唑的合成 
在装有温度计和加液漏斗的1L三颈圆底烧瓶中，于冰浴中搅拌吡啶-2-甲醛(151.4g，1.41摩尔)和乙二醛(40％在H2O中，205mL，1.79摩尔)于300mL乙醇(EtOH)中的溶液。当溶液冷却至低于5℃时，通过加液漏斗滴加浓NH4OH(28-30％，482mL，3.93摩尔)。控制滴加速度，使溶液的温度保持低于5℃。在滴加完毕后，继续在冰浴中搅拌溶液一小时然后在室温过夜。在搅拌过程中，溶液从淡黄色变成暗棕色。 
将溶液转移到2L圆底烧瓶中并通过旋转蒸发除去EtOH溶剂。得到的深色粘性物质转移到装有700mL EtOAc的4L烧杯中。加入 500mL饱和NaCl并将混合物搅拌2小时。溶液倾入2L分液漏斗并弃去黑色焦油状物质。从溶液中分离有机层，并用EtOAc萃取水层数次(每次500mL EtOAc)。有机层随后用无水Na2SO4干燥过夜，将得到的混合物重力过滤，用EtOAc(4x50mL)洗涤Na2SO4，溶液通过旋转蒸发浓缩至300-400mL。浓缩的溶液转移到1L锥形瓶中，并按照需要，用更多的EtOAc调节体积至400-500mL。溶液在4℃放置1-2天，以生成大量琥珀色晶体。通过抽滤收集晶体并用冷EtOAc(20-30mL)新的。滤液含有大量产物，所以进行进一步浓缩和结晶步骤。合并晶体并在高真空下于40-45℃干燥2天。得到约75g2-(2-吡啶基)咪唑。 
1-甲基-2-(2-吡啶基)咪唑的合成 
在装有温度计和加液漏斗的1L三颈圆底烧瓶中，于冰浴下搅拌吡啶-2-甲醛(50.5g，0.47摩尔)和乙二醛(40％在H2O中，68.3mL，0.60摩尔)在100-150mL乙醇(EtOH)中的溶液。当溶液冷至低于5℃时，通过加液漏斗滴加浓NH4OH(28-30％，161mL，1.31摩尔)。控制滴加速度，使溶液的温度保持低于5℃。加完后，继续在冰浴中搅拌溶液1小时并在室温下过夜。在搅拌过程中，溶液从淡黄色变成暗棕色。 
将溶液转移到1L圆底烧瓶中，并在50℃通过旋转蒸发除去EtOH和H2O溶剂。得到的物质进一步于50℃高真空干燥24小时，然后溶解在无水二甲基甲酰胺(DMF)中，然后溶液与更多DMF(总DMF450-500mL)一起转移至装有回流冷凝器的1L三颈圆底烧瓶中，然后搅拌。通过漏斗迅速加入叔丁醇钠(48.9g，0.51摩尔)，连续搅拌约1小时，得到暗棕色均相溶液。通过加液漏斗经约1.5-2小时滴加甲基碘(34.5mL，0.56)，得到白色NaI沉淀。混合物在室温下搅拌过夜，其颜色从暗棕色变成淡棕色。混合物倾入含1.5mL EtOAc的烧杯，并使用布氏漏斗抽滤除去NaI沉淀。用额外的EtOAc(3x100mL)新的沉淀。滤液转移至2L圆底烧瓶中，并旋转蒸发除去 EtOAc。 
得到的粘性物质转移至装有最少量EtOAc的1L烧杯中，然后通过旋转蒸发除去所述EtOAc。剩余的DMF通过使用低真空隔膜泵和油浴而真空蒸馏除去。在DMF的除去完成后，于100-110℃下高真空蒸馏产物。得到约36g1-甲基-2-(2-吡啶基)咪唑。 
Os(Py-MIM)2Cl2的合成 
在浸没于控温油浴中的，装有回流冷凝器的250mL三颈圆底烧瓶中，将1-甲基-2-(2-吡啶基)咪唑(3.4g，21.4毫摩尔)和六氯合锇(IV)酸铵(4.7g，10.7毫摩尔)与无水乙二醇(86mL)混合。反应混合物用N2脱气15分钟。混合物在N2下搅拌，同时开启加热器加热油浴，反应在130℃进行2小时，随后在140℃进行28小时，直至在反应中形成的中间物完全转化为终产物。将溶液冷却至室温，然后通过多孔玻璃漏斗抽滤至250mL三颈圆底烧瓶中，而弃去残留在漏斗中的少量橘黄色沉淀。溶液(溶液A)用N2脱气15分钟并保持在N2下。 
随后在冰/水浴冷却的并装有温度计的500mL三颈圆底烧瓶中，用N2将去离子H2O(320mL)脱气。脱气15分钟后，立即在N2下加入连二亚硫酸钠(85％，9.31g，53.5毫摩尔)并继续再脱气10-15分钟。溶液(溶液B)的温度低于5℃。然后在迅速搅拌下通过套管将溶液A经0.5小时加入溶液B中，形成暗紫色Os(Py-MIM)2Cl2沉淀。继续在N2下再搅拌0.5小时。得到的悬浮液通过0.4或0.3微米的尼龙膜抽滤。在N2下将悬浮液通过导管转移至抽气漏斗，以使在空气中暴露最小化。随后用最小量冰冷却水(2x5mL)洗涤暗紫色沉淀。沉淀立即通过冻干至少干燥24小时，得到约5.6gOs(Py-MIM)2Cl2。 
Os(Py-MIM)2(MIM)Cl]2+2Cl-的合成 
在装有回流冷凝器的2L三颈圆底烧瓶中，用N2将无水乙醇(1L)脱气15分钟。然后在N2下通过漏斗迅速加入Os(Py-MIM)2Cl2(3.1g，5.35毫摩尔)。搅拌并将悬浮液加热至回流。然后通过注射器立即加 入1-甲基咪唑(0.43mL，5.35毫摩尔)。继续回流直至反应结束。在反应过程中，溶液从暗棕色变成紫褐色。溶液冷却至室温，并通过多孔玻璃漏斗抽滤。通过旋转蒸发除去溶剂，得到还原形式的粗产物。 
使用30-50mL的H2O将产物转移至含约40mL AG1x4氯化物树脂(购自Bio-Rad)，或优选80mLDowex-1-氯化物(购自Aldrich)的400mL烧杯中。混合物露天搅拌24小时，以将Os(II)转化为Os(III)。混合物随后抽滤，并用H2O(5 x 30mL)洗涤树脂。于35℃下通过真空旋转蒸发，将合并的滤液浓缩至约50mL。 
将溶液加入LH-20柱(2″x22″)，用H2O洗脱。收集50mL洗脱液并通过CV分析，以寻找与产物有关的主紫褐色带。收集包含纯产物的部分，并通过旋转蒸发浓缩至约150mL。然后冷冻干燥溶液，得到产物。得到2.4gOs(Py-MIM)2(MIM)Cl]2+2Cl-。 
如此处所述，Os(Py-MIM)2(MIM)Cl]2+2Cl-是特别用作氧化还原介体的过渡金属络合物。 
实施例2：1-苯基-2-(2-吡啶基)咪唑的合成 
现在通过进一步的阐述，提供合成1-苯基-2-(2-吡啶基)咪唑的实施例。实施例证明了如何从1-(2-吡啶基)咪唑或其衍生物，和碘苯衍生物(如说明)或溴苯衍生物制备1-芳基-取代的2-(2-吡啶基)咪唑。 
Figure S02813301319950321D000191
在装有磁力搅拌器和回流冷凝器的250mL圆底烧瓶中，将2-(2-吡啶基)咪唑(6.91g)、碘苯(11.47g)、Cs2CO3(25g)和铜粉(15g)在60mL无水DMF中混合。混合物在室温下用N2脱气15分钟，然后在N2下于油浴中回流24小时。得到的混合物冷却至室温，并抽滤除去固体副产物。滤液用EtOAc(3x100mL)萃取。合并的有机层用H2O(2x100mL)洗涤，并随后用饱和NaCl(2x150mL)洗涤，随后用无水Na2SO4干燥。蒸发溶剂，得到粗1-苯基-2-(2-吡啶基)咪唑。粗产物的 纯度一般足以用于制备氧化还原介体，尽管粗产物可以使用硅胶柱并用MeOH/CHCl3洗脱而进一步纯化。 
上述1-苯基-2-(2-吡啶基)咪唑产物可按照与上述实施例1中使用的1-甲基-2-(吡啶基)咪唑的合成大体上相同的方式，用于过渡金属络合物，例如锇络合物的合成。 
更多过渡金属络合物的实施例 
在下表2中，提供了作为本发明氧化还原介体的更多过渡金属络合物：介体1-13。还提供了可得到的与这些氧化还原介体相关的氧化还原电势(相对于在pH为7的PBS缓冲液中的标准Ag/AgCl参比电极的E1/2(mV))。 
如下面的进一步描述，在表3和表4中，还提供了各种这些氧化还原介体及其相关的氧化还原电势和基本上收集电荷(μC)对给定体积(～315ηL)的生物液体，例如血液中葡萄糖浓度(mg/dL)的线形曲线的相关斜率k。还提供了已知氧化还原介体，即对比介体No.I、No.X、No.XII和No.XIII的对比信息。如下所述，表3和表4的斜率数据分别涉及在条件A和条件B下测试的氧化还原介体，反映不同的油墨批次(ink lot)。 
即，这些斜率数据是从各个实验中得到的，其中每种氧化还原介体和酶的混合物涂覆于工作电极上。工作电极由塑料底物上的传导性油墨层制成。使用本领域已知的标准工艺，将工作电极与对/参比电极一起层压。对/参比电极由塑料底物上的Ag/AgCl油墨层制成。通常可以观察到由不同油墨批次制成的测试条传感器中的变化。因此，在表3中，条件A是指使用由单批次制成的一系列测试条进行的测试，而在表4中，条件B同样是指使用不同于条件A的单批次制成的一系列测试条进行的测试。因此，不应将表3和表4显示的斜率数据进行对比，而表3或表4之中显示的斜率数据的比较对于介体性能是指导性的。
表2.本发明低电势介体的实施例 
Figure S02813301319950321D000211
Figure S02813301319950321D000221
Figure S02813301319950321D000241
表3.低电势锇介体和已知的对比介体的例子           及其在条件A下的性能 
Figure S02813301319950321D000261
表4.低电势锇介体和已知的对比介体的例子           及其在条件B下的性能 
Figure S02813301319950321D000291
Figure S02813301319950321D000301
本发明的过渡金属络合物由于其特定的电化学性质，非常适用于电化学传感应用。例如，如上所述，介体的氧化还原电势一般较低，例如相对于Ag/AgCl参比电极在约0mV到约-200mV范围内。这些氧化还原电势是电化学传感应用特别需要的，因为在这个范围内介体的动力学快，并且潜在的干扰物质的电化学活性最小。No.1-13的介体因此作为本发明所需的电化学介体的例子。 
刚才描述的潜在干扰物质的鉴定取决于特殊的电化学传感应用。仅用于举例，当电化学传感应用涉及生物液体、血液时，潜在的干扰物质包括抗坏血酸、对乙酰氨基酚和尿酸。作为电化学所需介体的例子的No.1-13介体在适于将所需潜在干扰物质的电化学活性最小化，同时不牺牲介体效率的电势下操作。 
另外，由于其在工作电极上收集电荷的能力增强，并因此增加传感器对被传感的分析物浓度的敏感性，本发明的过渡金属络合物是电化学传感应用中特别有效的氧化还原介体。例如，在电化学生物传感器，例如葡萄糖传感器的一般操作中，还原的酶、葡萄糖氧化酶或葡萄糖脱氢酶将其电子通过特殊的过程转移至工作电极。在该过程中，氧化还原介体的氧化形式与还原的酶相互作用，因此接收电子并变成还原态。还原的介体通常通过随机扩散移动到工作电极表面，于是其将收集的电子转移到电极上，由此变成氧化态。 
理想地，因为每一个葡萄糖分子在上述过程中失去两个电子，在工作电极上收集的电子或电荷总量应该等于被氧化的葡萄糖分子的数目的两倍。但实际上，收集的电荷的总量几乎总是少于理想或理论量，因为电子在从酶转移到电极的过程中会“丢失”。例如，还原的酶可能将电子转移到氧或其它化学物质上，而不是到氧化还原介体上。因此，一个有效的氧化还原介体应当顺利地完成电子从酶的转移。 
更进一步，理想的是，一旦氧化还原介体从酶接受电子，在工作电极上被氧化之前，它不应该将电子转移至另一种氧化性物质，例如氧或其它存在于传感器中的化学物质。因此如上所述，良好的介体应 该顺利完成电子从还原酶的转移，以及在其向工作电极的随机扩散过程中(其在所述工作电极上被氧化)基本上是化学惰性的。 
一个有效的介体在基于电量分析的电化学生物传感中是非常重要的，其中对于给定体积的生物液体，生物分析物的检测是基于在工作电极上收集的电荷总量。当在工作电极上收集更多电荷时，传感器有利地更敏感。对于基于电量分析的葡萄糖传感器，例如，传感器的敏感度可以通过等式y＝kx+b定义的电荷对葡萄糖浓度的线性图的斜率值表征，其中y是给定体积生物液体的收集电荷，单位是μC，k是斜率，单位是μC/(mg/dL)，x是葡萄糖浓度，单位是(mg/dL)，b是基于本底电荷的截距。如上证明，本发明的带有负电荷配体的介体，例如具有氯化物配体的No.1-13介体，具有明显高于那些具有含氮杂环配体环绕在金属氧化还原中心的介体(例如，对比介体No.I、X、XII和XII)的相关斜率值(例如，按照表3，高出约28％-约48％，按照表4，高出约11％-18％)。 
上述数据证明了过渡金属络合物的有利特性，所述特性使这些络合物成为特别希望的氧化还原介体。在电化学传感应用，例如葡萄糖的电化学传感中，过渡金属络合物从还原的酶有效收集电子，并在将这些电子释放至工作电极之前有效地保留收集的电子。 
正如此处所述，本发明的过渡金属络合物在电化学传感器中作为氧化还原介体使用。这些介体具有非常快的动力学，这样，在所述介体和酶和/或传感器装置的工作电极之间的电子交换迅速，更特别地是，迅速到足以促进电子转移到工作电极上，否则电子可能转移至其它电子清除剂，例如氧。上述No.1-13介体的所需斜率值k证明，当L2是带负电荷的配体，诸如氯化物配体时，式1介体的电子转移效力增加。通过比较，具有中性配体L2，诸如杂环含氮配体的介体，将电子从酶转移至工作电极的能力较低，正如上述对比介体No.I、X、XII和XIII的低斜率值所反映的。 
本发明的过渡金属络合物介体相对于酶和电极表面之外的化学物质的化学反应性方面也很稳定。例如，本发明介体的化学稳定性是这 样的：即优选主反应，或更优选仅所述介体参与其中的反应，涉及上述介体和酶之间的电子转移反应和工作电极上的电化学氧化还原反应。当式1介体(其中L2是带负电荷的单齿配体)具有可以空间或立体地屏蔽氧化还原中心的“大体积”化学配体L1，诸如Os2+/3+，并因此降低了超出本质上所需化学和电化学活性的不利化学反应性时，这种化学稳定性得以增加。上述介体No.1-13是本发明的这种“大体积”化学稳定介体的特例。 
进一步举例，本发明介体的热和光化学稳定性优选是这样的：在常规使用、储存和运输条件下独立地是温度和光稳定的。例如，本发明介体在正常光照条件下容易处理，并且所具有保存期限在室温下至少18个月，在57℃至少约两周。上述介体No.1-13是本发明的所述热和光化学稳定介体的特例。 
本发明的介体具有希望的氧化还原电势，在所述电势范围内，电子转移动力学最佳或最大化，并且存在于生物液体中的普通干扰物质的影响最小。以上介体No.1-13是具有合适氧化还原电势的介体的特例。 
本发明的过渡金属络合物还具有所需的溶解特性，一般在所需溶剂，通常是含水或与水混溶的溶剂中，于25℃下具有大于约0.1摩尔/升的溶解度。仅需要调节式1的抗衡离子X，就可以方便地获得所选溶剂中的所需溶解度，所述溶剂可以是含水或有机溶剂。 
总之，本发明提供了新型过渡金属络合物，其尤其在电化学传感应用中用作氧化还原介体。优选的氧化还原介体与酶和工作电极交换电子迅速、稳定，容易合成，并具有适于电氧化各种分析物，例如那些人体内各种生物液体中的分析物的氧化还原电势。尽管本发明介体大部分是根据葡萄糖传感进行描述的，但它们对于其它分析物，例如乳酸的传感也有用。一般而言，如果用于特定分析物-传感应用的酶的氧化还原电势相对于介体的氧化还原电势是负的，那么介体适合于该分析物传感应用。本发明过渡金属络合物的有利的特性和特征使其成为理想的选择物，用于葡萄糖的电化学传感—一种在人类糖尿病的 诊断和监测中非常重要的应用。 
本发明的各方面和特征已经根据理念或理论进行了解释或描述，但可以理解，本发明不受任何理念或理论的束缚。另外，各种改型、等同方法以及本发明适用的各种构成对本领域技术人员是显而易见的，对于他们而言，本发明建立在本说明书的观点上。虽然本发明的各个方面和特征已经根据此处的各种实施方案和特定实施例进行了描述，可以认为，本发明在附属的权利要求的全部范围内要求保护。

Claims (23)

1.一种具有下式的过渡金属络合物：
Figure FSB00000249176300011
其中c是负电荷、中性或正电荷，分别表示为-1到-5、0或+1到+5；
X表示抗衡离子；
d是不存在，或抗衡离子X的数目，分别表示为0，或1到5；
M是钴、铁、锇、钌或钒；
L1是具有下式的咪唑：
Figure FSB00000249176300012
其中R7是烷基或芳基；
R8是-H、烷基或芳基；以及
R9是-H或芳基且R10是-H，或R9和R10结合形成稠合的不饱和的5-或6-元环；
或具有下式的吡啶：
其中R11、R12、R14和R15是-H且R13是-H、烷氧基或烷基氨基；
L2是Cl；和
L和L′独立地是：
其中，R′1是烷基或芳基；
Ra是-H和Rb是-H或烷基；
R′3和R′4是-H；以及
Rc是-H和Rd是-H或烷基。
2.权利要求1的络合物，其中R′1是C1-C12烷基。
3.权利要求1的络合物，其中R′1是甲基。
4.权利要求1的络合物，其中R′1是芳基。
5.权利要求1的络合物，其中R′1是苯基。
6.权利要求1的络合物，其中c是0、+1、+2或+3。
7.权利要求1的络合物，具有下式：
其中d是抗衡离子X的数目，为1到5；
M是锇；和
L1是具有下式的咪唑：
Figure FSB00000249176300032
其中R7是烷基或芳基；
R8是-H、烷基或芳基；以及
R9是-H或芳基且R10是-H，或R9和R10结合形成稠合的不饱和的5-或6-元环。
8.权利要求7的络合物，其中d是2。
9.权利要求7的络合物，其中X是选自卤化物、硫酸盐、磷酸盐、六氟磷酸盐和四氟硼酸盐的阴离子。
10.权利要求7的络合物，其中X是氯化物的阴离子。
11.权利要求1的络合物，其中R7是C1-C12烷基或芳基。
12.权利要求1的络合物，其中R9和R10生成稠合的不饱和6元环。
13.权利要求1的络合物，其中R8是-H或烷基、R9是-H或芳基和R10是-H。
14.权利要求1的络合物，其中R13是烷基氨基。
15.权利要求1的络合物，其相对于Ag/AgCl参比电极具有的氧化还原电势为0mV到-200mV。
16.权利要求1的络合物，其中M是锇。
17.一种传感器，包括：
一个工作电极；
一个对电极；
接近工作电极放置的酶；
接近工作电极放置的氧化还原介体，所述氧化还原介体具有下式：
Figure FSB00000249176300041
其中c是负电荷、中性或正电荷，分别表示为-1到-5、0或+1到+5；
X表示抗衡离子；
d是不存在，或抗衡离子X的数目，分别表示为0，或1到5；
M是钴、铁、锇、钌或钒；
L1是具有下式的咪唑：
其中R7是烷基或芳基；
R8是-H、烷基或芳基；以及
R9是-H或芳基且R10是-H，或R9和R10结合形成稠合的不饱和的5-或6-元环；
或具有下式的吡啶：
其中R11、R12、R14和R15是-H且R13是烷氧基或烷基氨基；
L2是Cl；和
L和L′独立地是：
其中，R′1是烷基或芳基；
Ra和Rb是-H；
R′3和R′4是-H；以及
Rc是-H和Rd是-H或烷基。
18.权利要求17的传感器，其中氧化还原介体具有下式：
Figure FSB00000249176300061
其中d是抗衡离子X的数目，为1到5。
19.权利要求18的传感器，其中X是选自卤化物、硫酸盐、磷酸盐、六氟磷酸盐和四氟硼酸盐的阴离子。
20.权利要求17的传感器，其中
c是中性或正电荷，分别表示为0或+1到+3；
M是锇；
R′1是C1-C12烷基；和
R′3、R ′4、Ra、Rb和Rc是-H和Rd是-H，或者烷基。
21.权利要求17的传感器，其中相对于Ag/AgCl参比电极，氧化还原介体具有的氧化还原电势是0mV到-200mV。
22.权利要求17的传感器，其中氧化还原介体在工作电极上交联。
23.权利要求17的传感器，其中氧化还原介体和酶在工作电极上交联。
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US20060149067A1 (en) 2006-07-06
CN1620462A (zh) 2005-05-25
US20030096997A1 (en) 2003-05-22
US20100038242A1 (en) 2010-02-18
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US20090143584A1 (en) 2009-06-04
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WO2004009604A3 (en) 2004-11-25
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