CN101384576A - Benzonitrile derivative substituted by glucopyranosyl group, pharmaceutical composition containing the compound, its use and its preparation method - Google Patents
Benzonitrile derivative substituted by glucopyranosyl group, pharmaceutical composition containing the compound, its use and its preparation methodDownload PDFInfo
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Abstract
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Description
Translated fromChinese本发明涉及通式I的被吡喃型葡萄糖基取代的苯甲腈衍生物：The present invention relates to benzonitrile derivatives substituted by glucopyranosyl groups of general formula I:
其中基团R3定义见下文，包括其互变异构体、立体异构体、混合物及其盐。本发明还涉及含有本发明的式I化合物的药物组合物以及本发明的化合物在制备用于治疗代谢障碍的药物组合物中的用途。此外，本发明涉及用于制备本发明的药物组合物以及化合物的方法。Wherein the group R3 is defined as follows, including its tautomers, stereoisomers, mixtures and salts thereof. The present invention also relates to pharmaceutical compositions containing the compounds of formula I of the present invention and the use of the compounds of the present invention in the preparation of pharmaceutical compositions for the treatment of metabolic disorders. Furthermore, the invention relates to processes for the preparation of the pharmaceutical compositions and compounds of the invention.
在文献中，提出对钠依赖性葡萄糖协同转运蛋白SGLT2具抑制作用的化合物用于治疗疾病，尤其是糖尿病。In the literature, compounds with an inhibitory effect on the sodium-dependent glucose cotransporter SGLT2 are proposed for the treatment of diseases, especially diabetes.
从国际申请案WO 2005/092877及其中所引用的公开案已知被吡喃型葡萄糖基取代的芳香基团及其制备及其作为SGLT2抑制剂的可能活性。Aromatic groups substituted by glucopyranosyl groups, their preparation and their possible activity as SGLT2 inhibitors are known from International Application WO 2005/092877 and publications cited therein.
发明目标invention goal
本发明的目标为发现新颖的被吡喃型葡萄糖基取代的苯甲腈衍生物，尤其是那些对于钠依赖性葡萄糖协同转运蛋白SGLT(尤其是SGLT2)有活性的衍生物。本发明的另一目标为发现与已知结构类似的化合物相比，活体外及/或活体内对钠依赖性葡萄糖协同转运蛋白SGLT2具增强抑制作用及/或具有更好药理学或药物动力学特性的被吡喃型葡萄糖基取代的苯衍生物。The object of the present invention was to discover novel glucopyranosyl-substituted benzonitrile derivatives, especially those active against the sodium-dependent glucose cotransporter SGLT, especially SGLT2. Another object of the present invention is to find enhanced inhibitory effect and/or better pharmacology or pharmacokinetics on sodium-dependent glucose cotransporter SGLT2 in vitro and/or in vivo compared with known structurally similar compounds Characteristic glucopyranosyl-substituted benzene derivatives.
本发明的另一目标为提供适于预防及/或治疗代谢障碍、尤其是糖尿病的新颖药物组合物。Another object of the present invention is to provide novel pharmaceutical compositions suitable for the prevention and/or treatment of metabolic disorders, especially diabetes.
直接从上述及下述说明，本发明的其他目标对本领域技术人员而言将变得显而易见。Other objects of the invention will become apparent to those skilled in the art directly from the foregoing and following description.
发明目的purpose of invention
在第一方面中，本发明涉及式I的被吡喃型葡萄糖基取代的苯甲腈衍生物；包括其互变异构体、立体异构体或其混合物；及其生理学上可接受的盐：In a first aspect, the present invention relates to glucopyranosyl-substituted benzonitrile derivatives of formula I; including tautomers, stereoisomers or mixtures thereof; and physiologically acceptable salts thereof :
其中in
R3表示氢、氟、氯、溴、碘、甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、3-甲基-丁-1-基、环丙基、环丁基、环戊基、环己基、二氟甲基、三氟甲基、五氟乙基、2-羟基-乙基、羟基甲基、3-羟基-丙基、2-羟基-2-甲基-丙-1-基、3-羟基-3-甲基-丁-1-基、1-羟基-1-甲基-乙基、2，2，2-三氟-1-羟基-1-甲基-乙基、2，2，2-三氟-1-羟基-1-三氟甲基-乙基、2-甲氧基-乙基、2-乙氧基-乙基、羟基、甲氧基、乙氧基、异丙氧基、二氟甲氧基、三氟甲氧基、环丁基氧基、环戊基氧基、环己基氧基、(S)-四氢呋喃-3-基氧基、(R)-四氢呋喃-3-基氧基、四氢吡喃-4-基氧基、1-乙酰基-哌啶-4-基氧基、2-甲氧基-乙氧基、甲硫基、甲基亚磺酰基、甲磺酰基、乙基亚磺酰基、乙磺酰基、三甲基甲硅烷基及氰基，R3 represents hydrogen, fluorine, chlorine, bromine, iodine, methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, 3-methyl-but-1- radical, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, difluoromethyl, trifluoromethyl, pentafluoroethyl, 2-hydroxy-ethyl, hydroxymethyl, 3-hydroxy-propyl, 2-hydroxy-2-methyl-prop-1-yl, 3-hydroxy-3-methyl-but-1-yl, 1-hydroxy-1-methyl-ethyl, 2,2,2-trifluoro -1-Hydroxy-1-methyl-ethyl, 2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl, 2-methoxy-ethyl, 2-ethoxy -Ethyl, hydroxy, methoxy, ethoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, (S )-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, tetrahydropyran-4-yloxy, 1-acetyl-piperidin-4-yloxy, 2-methyl Oxy-ethoxy, methylthio, methylsulfinyl, methylsulfonyl, ethylsulfinyl, ethylsulfonyl, trimethylsilyl and cyano,
或其衍生物：其中β-D-吡喃型葡萄糖基的一或多个羟基被选自(C1-18烷基)羰基、(C1-18烷基)氧基羰基、苯基羰基及苯基-(C1-3烷基)-羰基的基团酰化。or its derivatives: wherein one or more hydroxyl groups of β-D-glucopyranosyl are selected from (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, phenylcarbonyl and Group acylation of phenyl-(C1-3 alkyl)-carbonyl.
本发明的化合物及其生理学上可接受的盐具有有价值的药理学特性，尤其是对钠依赖性葡萄糖协同转运蛋白SGLT(尤其是SGLT2)的抑制作用。此外本发明的化合物可具有对钠依赖性葡萄糖协同转运蛋白SGLT1的抑制作用。与对SGLT1的可能抑制作用相比，本发明的化合物优选地选择性抑制SGLT2。The compounds according to the invention and their physiologically acceptable salts have valuable pharmacological properties, especially the inhibitory effect on the sodium-dependent glucose cotransporter SGLT, especially SGLT2. In addition, the compounds of the invention may have an inhibitory effect on the sodium-dependent glucose cotransporter SGLT1. Compounds of the invention preferably selectively inhibit SGLT2 over possible inhibition of SGLT1.
本发明也涉及本发明的化合物与无机酸或有机酸形成的生理学上可接受的盐。The invention also relates to the physiologically acceptable salts of the compounds according to the invention with inorganic or organic acids.
本发明也涉及药物组合物，其含有至少一种本发明的化合物或本发明的生理学上可接受的盐，任选地连同一或多种惰性载体及/或稀释剂。The present invention also relates to pharmaceutical compositions comprising at least one compound according to the invention or a physiologically acceptable salt according to the invention, optionally together with one or more inert carriers and/or diluents.
本发明也涉及至少一种本发明的化合物或其生理学上可接受的盐在制备适于治疗或预防可由抑制钠依赖性葡萄糖协同转运蛋白SGLT(尤其是SGLT2)影响的疾病或病症的药物组合物中的用途。The invention also relates to the use of at least one compound according to the invention or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition suitable for the treatment or prevention of diseases or disorders which may be affected by the inhibition of the sodium-dependent glucose cotransporter SGLT, especially SGLT2 use in .
本发明也涉及至少一种本发明的化合物或其生理学上可接受的盐在制备适于治疗一或多种代谢障碍的药物组合物中的用途。The present invention also relates to the use of at least one compound according to the invention or a physiologically acceptable salt thereof for the manufacture of a pharmaceutical composition suitable for the treatment of one or more metabolic disorders.
在另一方面中，本发明涉及至少一种本发明的化合物或一种其生理学上可接受的盐在制备用于预防胰腺β细胞退化及/或用于改善及/或恢复胰腺β细胞功能的药物组合物中的用途。In another aspect, the present invention relates to the preparation of at least one compound of the present invention or a physiologically acceptable salt thereof for preventing degeneration of pancreatic beta cells and/or for improving and/or restoring the function of pancreatic beta cells Use in pharmaceutical compositions.
在另一方面中，本发明涉及至少一种本发明的化合物或一种其生理学上可接受的盐在制备用于预防、减缓、延迟或治疗由于有此需要的患者体内肝脏脂肪异常积累而导致的疾病或病症的药物组合物中的用途。In another aspect, the present invention relates to the preparation of at least one compound of the present invention or a physiologically acceptable salt thereof for preventing, slowing down, delaying or treating abnormal accumulation of fat in the liver in a patient in need thereof. Use in pharmaceutical compositions for diseases or disorders.
本发明也涉及至少一种本发明的化合物或其生理学上可接受的盐在制备用于抑制钠依赖性葡萄糖协同转运蛋白SGLT(尤其是SGLT2)的药物组合物中的用途。The present invention also relates to the use of at least one compound according to the invention or a physiologically acceptable salt thereof for the preparation of a pharmaceutical composition for inhibiting the sodium-dependent glucose cotransporter SGLT, especially SGLT2.
本发明还涉及用于制备本发明的药物组合物的方法，其特征在于通过非化学方法将本发明的化合物或一种其生理学上可接受的盐连同一或多种惰性载体及/或稀释剂中。The invention also relates to a process for the preparation of the pharmaceutical composition according to the invention, characterized in that the compound according to the invention or a physiologically acceptable salt thereof together with one or more inert carriers and/or diluents middle.
本发明也涉及用于制备本发明的通式I的化合物的方法，其特征在于The invention also relates to a process for the preparation of compounds of general formula I according to the invention, characterized in that
a)为制备如上文及下文所定义的通式I的化合物，a) for the preparation of compounds of general formula I as defined above and below,
在路易斯酸(Lewis)或布朗斯特酸(
其中in
R’表示H、C1-4烷基、(C1-18烷基)羰基、(C1-18烷基)氧基羰基、芳基羰基及芳基-(C1-3烷基)-羰基，其中烷基或芳基可被卤素单或多取代；R' represents H, C1-4 alkyl, (C1-18 alkyl) carbonyl, (C1-18 alkyl) oxycarbonyl, aryl carbonyl and aryl-(C1-3 alkyl)- Carbonyl, wherein the alkyl or aryl can be mono- or polysubstituted by halogen;
R8a、R8b、R8c、R8d彼此独立地表示氢或烯丙基、苄基、(C1-4烷基)羰基、(C1-4烷基)氧基羰基、芳基羰基、芳基-(C1-3烷基)-羰基及芳基-(C1-3烷基)-氧基羰基或RaRbRcSi基或缩酮或缩醛基，尤其是亚烷基或芳基亚烷基缩酮或缩醛基，同时在各情况下两个相邻基团R8a、R8b、R8c、R8d可形成环状缩酮或缩醛基或1，2-二(C1-3烷氧基)-1，2-二(C1-3烷基)-亚乙基桥，同时上述亚乙基桥连同吡喃糖环的两个氧原子及两个相关的碳原子形成被取代二噁烷环，尤其是2，3-二甲基-2，3-二(C1-3烷氧基)-1，4-二噁烷环，且同时烷基、烯丙基、芳基及/或苄基可被卤素或C1-3烷氧基单或多取代，且同时苄基也可经二-(C1-3烷基)氨基取代；且R8a , R8b , R8c , and R8d independently represent hydrogen or allyl, benzyl, (C1-4 alkyl) carbonyl, (C1-4 alkyl) oxycarbonyl, aryl carbonyl, Aryl-(C1-3 alkyl)-carbonyl and aryl-(C1-3 alkyl)-oxycarbonyl or Ra Rb Rc Si or ketal or acetal, especially alkylene or arylalkylene ketal or acetal group, while in each case two adjacent groups R8a , R8b , R8c , R8d can form a cyclic ketal or acetal group or 1,2 -bis(C1-3 alkoxy)-1,2-bis(C1-3 alkyl)-ethylene bridge, while the above-mentioned ethylene bridge together with two oxygen atoms of the pyranose ring and two The relevant carbon atoms form a substituted dioxane ring, especially a 2,3-dimethyl-2,3-di(C1-3 alkoxy)-1,4-dioxane ring, and at the same time an alkyl , allyl, aryl and/or benzyl may be mono- or polysubstituted by halogen or C1-3 alkoxy, and at the same time benzyl may also be substituted by di-(C1-3 alkyl)amino; and
Ra、Rb、Rc彼此独立地表示C1-4烷基、芳基或芳基-C1-3烷基，其中芳基或烷基可被卤素单或多取代；Ra , Rb , Rc independently represent C1-4 alkyl, aryl or aryl-C1-3 alkyl, wherein the aryl or alkyl can be mono- or multi-substituted by halogen;
同时上述基团的定义中所述的芳基指苯基或萘基，优选地为苯基；At the same time, the aryl group described in the definition of the above group refers to phenyl or naphthyl, preferably phenyl;
且其中R3基如上文及下文所定义；或and wherein the Rgroup is as defined above and below; or
b)为制备通式I的化合物，b) for the preparation of compounds of general formula I,
通式III的化合物Compounds of general formula III
其中R8a、R8b、R8c、R8d及R3如上文及下文所定义，其限制条件为至少一个选自R8a、R8b、R8c、R8d的取代基不为氢；wherein R8a , R8b , R8c , R8d and R3 are as defined above and below, with the proviso that at least one substituent selected from R8a , R8b , R8c , R8d is not hydrogen;
将不为氢的保护基R8a、R8b、R8c、R8d裂解；且Cleavage of protecting groups R8a , R8b , R8c , R8d that are not hydrogen; and
若需要，则通过酰化使由此获得的通式I化合物转化为相应的通式I的酰基化合物，及/或If desired, the thus obtained compound of general formula I is converted by acylation into the corresponding acyl compound of general formula I, and/or
若必需，则将上述反应中所用的任何保护基裂解及/或If necessary, any protecting groups used in the above reactions are cleaved and/or
若需要，则将由此获得的通式I化合物拆分为其立体异构体及/或If desired, the thus obtained compound of general formula I is resolved into its stereoisomers and/or
若需要，则将由此获得的通式I化合物转化为其盐，尤其对于医药用途转化为其生理学上可接受的盐。The compounds of the general formula I thus obtained are converted, if desired, into their salts, especially for pharmaceutical use, into their physiologically acceptable salts.
本发明的其他方面涉及如下文的反应流程中及实验部分中所述的新颖中间体。Other aspects of the invention relate to novel intermediates as described in the reaction schemes below and in the experimental section.
发明详述Detailed description of the invention
本发明的方面，具体地为化合物、药物组合物及其用途，涉及如上文及下文所定义的通式I的被吡喃型葡萄糖基取代的苯甲腈衍生物或其衍生物，包括其互变异构体、立体异构体或其混合物及其生理学上可接受的盐。Aspects of the present invention, specifically compounds, pharmaceutical compositions and uses thereof, relate to glucopyranosyl-substituted benzonitrile derivatives or derivatives thereof of general formula I as defined above and below, including their mutual Isomers, stereoisomers or mixtures thereof and physiologically acceptable salts thereof.
如所定义的β-D-吡喃型葡萄糖基的所有羟基优选地未被取代或仅β-D-吡喃型葡萄糖基的羟基O-6被取代。优选地取代基选自(C1-8烷基)羰基、(C1-8烷基)氧基羰基及苯基羰基。更优选取代基选自乙酰基、甲氧基羰基及乙氧基羰基，尤其是乙酰基及乙氧基羰基。All hydroxyl groups of the β-D-glucopyranosyl group as defined are preferably unsubstituted or only the hydroxyl group O-6 of the β-D-glucopyranosyl group is substituted. Preferred substituents are selected from (C1-8 alkyl)carbonyl, (C1-8 alkyl)oxycarbonyl and phenylcarbonyl. More preferred substituents are selected from acetyl, methoxycarbonyl and ethoxycarbonyl, especially acetyl and ethoxycarbonyl.
除非另外说明，否则上文及下文中所用的结构式的命名法中，如环状基团(基例如苯基环)的取代基的键显示朝向环状基团的中心表示此取代基可键合至具有H原子的环状基团的任何自由位置。Unless otherwise stated, in the nomenclature of the structural formulas used above and below, for example, a bond of a substituent of a cyclic group (eg, a phenyl ring) is shown towards the center of the cyclic group to indicate that this substituent can be bonded to to any free position of a cyclic group with an H atom.
可使用原理已知的合成方法获得本发明的化合物。优选地通过下文更详述的下述本发明的方法获得这些化合物。The compounds of the invention can be obtained using synthetic methods known in principle. These compounds are preferably obtained by the following methods of the invention as described in more detail below.
可通过添加所要有机金属化合物形式的苄基苯化合物从D-葡萄糖酸内酯或其衍生物来合成本发明的式II的葡萄糖衍生物(流程1)。The glucose derivatives of formula II of the present invention can be synthesized from D-gluconolactone or derivatives thereof by adding benzylbenzene compounds in the form of the desired organometallic compound (Scheme 1).
流程1：将有机金属化合物加成至葡萄糖酸内酯Scheme 1: Addition of organometallic compounds to gluconolactones
优选地从通式IV的卤化苄基苯化合物开始进行流程1的反应，其中Hal表示氯、溴或碘。流程1中R1表示氰基或随后可转化为氰基的基团，例如氯、溴、羧基、羧酸酯、羧酰胺或其衍生物、硼或甲硅烷基、例如缩醛或噻唑的被保护或被遮蔽的醛官能团，或例如硝基的被保护或被遮蔽的氨基官能团。可通过所谓卤素-金属交换反应或通过将金属插入碳-卤素键中从相应氯化、溴化或碘化苄基苯IV制备苄基苯的格氏试剂(Grignard)或锂试剂(V)。可(例如)以例如正、仲或叔丁基锂的有机锂化合物进行V的卤素-金属交换以合成相应的锂化合物。也可在无或有可加速金属化过程的例如氯化锂的其他盐存在下，通过与例如溴化异丙基镁或溴化仲丁基镁或氯化异丙基镁或氯化仲丁基镁或二异丙基镁或二仲丁基镁的合适格氏试剂的卤素-金属交换产生类似镁化合物；也可从合适前体原位产生特定转金属化有机镁化合物(例如参见Angew.Chem.2004，116，3396-3399及Angew.Chem.2006，118,165-169及其中所引用的文献)。此外，也可采用由于将例如氯化丁基镁或溴化丁基镁或氯化异丙基镁或溴化异丙基镁与丁基锂混合所产生的有机镁化合物的盐络合物(例如见Angew.Chem.2000，112，2594-2596及Tetrahedron Lett.2001，42，4841-4844及其中所引用的文献)。卤素-金属交换反应优选地在介于40℃至-100℃下，尤其优选地在介于10℃至-80℃下在惰性溶剂或其混合物(例如乙醚、二噁烷、四氢呋喃、甲苯、己烷、二甲亚砜、二氯甲烷或其混合物)中进行。可任选地以例如三氯化铈、氯化锌或溴化锌、氯化铟或溴化铟的金属盐使由此获得的镁或锂衍生的化合物转金属化以形成适于加成的其它有机金属化合物(V)。或者也可通过将金属插入卤代芳族化合物IV的碳-卤键中来制备有机金属化合物V。锂或镁为适于此转化的元素金属。插入可在-80至100℃，优选地在-70至40℃范围内的温度下在例如乙醚、二噁烷、四氢呋喃、甲苯、己烷、二甲亚砜及其混合物的溶剂中实现。在未发生自发反应的情况下，可能需要金属预活化例如以1，2-二溴乙烷、碘、三甲基甲硅烷基氯、乙酸、盐酸及/或超声处理。使有机金属化合物V加成至葡萄糖酸内酯或其衍生物(VI)的反应优选地在介于40℃至-100℃，尤其优选地在0至-80℃的温度下在惰性溶剂或其混合物中进行，以获得式II化合物。尽管所有上述反应优选地在例如氩气和氮气的惰性气氛中完成，但其也可在空气中进行。金属化及/或偶连反应亦可在能以高交换速率进行的微型反应器及/或微型混合器中进行；例如与WO 2004/076470中所述的方法类似。用于将金属化的苯基V加成至被适当保护的葡萄糖酸内酯VI中的适当溶剂为(例如)乙醚、二甲氧基乙烷、苯、甲苯、二氯甲烷、己烷、四氢呋喃、二噁烷、N-甲基吡咯烷酮及其混合物。加成反应可在无任何其他佐剂下或在例如BF3*OEt2或Me3SiCl的促进剂存在下缓慢反应的偶连搭配物的情况下进行(见M.Schlosser，Organometallics in Synthesis，John Wiley &Sons，Chichester/New York/Brisbane/Toronto/Singapore，1994)。流程1中取代基R8优选地定义为苄基、被取代苄基、烯丙基、三烷基甲硅烷基，尤其优选地为三甲基甲硅烷基、三异丙基甲硅烷基、烯丙基、4-甲氧基苄基及苄基。若两个相邻取代基R8连接在一起，则这两个取代基优选地为亚苄基缩醛、4-甲氧基亚苄基缩醛、异丙基缩酮的部分或与通过丁烷的2和3位与吡喃糖的相邻氧原子连接的2，3-二甲氧基-亚丁基构成二噁烷。R’基优选地表示氢、C1-4烷基、C1-4烷基羰基或C1-4烷基氧基羰基，尤其优选地为氢、甲基或乙基。在将有机金属化合物V或其衍生物加成至葡萄糖酸内酯VI之后引入R’基。若R’等于氢或C1-4烷基，则在例如乙酸、甲磺酸、甲苯磺酸、硫酸、三氟乙酸或盐酸的酸存在下以例如甲醇或乙醇的醇类或水处理反应溶液。也可在通过在例如三乙胺、乙基二异丙基胺、碳酸钠或碳酸钾或碳酸铯、氢氧化钠或氢氧化钾或氢氧化铯的碱存在下使异头(anomeric)羟基与例如甲基碘、硫酸二甲酯、乙基碘、硫酸二乙酯、乙酰氯或乙酸酐的合适亲电子试剂反应制备氢化合物II之后连接R’。也可在添加亲电子试剂之前用(例如)氢化钠使羟基去质子化。在连接R’期间，若保护基R8在所采用产生相应质子化的化合物(即R8等于H的化合物II)反应条件下不稳定，则R8可裂解。The reaction of Scheme 1 is preferably carried out starting from a halogenated benzylbenzene compound of formula IV, wherein Hal represents chlorine, bromine or iodine. R in Scheme1 represents a cyano group or a group which can subsequently be converted into a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or derivatives thereof, boron or silyl, for example acetal or thiazole A protected or masked aldehyde function, or a protected or masked amino function such as a nitro group. Grignard or lithium reagents (V) of benzylbenzenes can be prepared from the corresponding chlorinated, brominated or iodized benzylbenzenes IV by so-called halogen-metal exchange reactions or by insertion of metals into carbon-halogen bonds. Halogen-metal exchange of V can be performed, for example, with an organolithium compound such as n-, sec-, or tert-butyllithium to synthesize the corresponding lithium compound. It is also possible by reacting with, for example, isopropylmagnesium bromide or sec-butylmagnesium bromide or isopropylmagnesium chloride or sec-butyl chloride in the absence or presence of other salts such as lithium chloride which accelerate the metallization process. Halogen-metallization of suitable Grignard reagents of base magnesium or diisopropylmagnesium or di-sec-butylmagnesium yields analogous magnesium compounds; specific transmetallated organomagnesium compounds can also be generated in situ from suitable precursors (see, for example, Angew. Chem. 2004, 116, 3396-3399 and Angew. Chem. 2006, 118, 165-169 and literature cited therein). In addition, salt complexes of organomagnesium compounds resulting from mixing, for example, butylmagnesium chloride or butylmagnesium bromide or isopropylmagnesium chloride or isopropylmagnesium bromide with butyllithium ( See eg Angew. Chem. 2000, 112, 2594-2596 and Tetrahedron Lett. 2001, 42, 4841-4844 and references cited therein). The halogen-metal exchange reaction is preferably carried out at between 40°C to -100°C, especially preferably at between 10°C to -80°C, in an inert solvent or a mixture thereof (e.g. diethyl ether, dioxane, tetrahydrofuran, toluene, hexane alkane, dimethyl sulfoxide, dichloromethane or mixtures thereof). The magnesium or lithium derived compound thus obtained may optionally be transmetallated with a metal salt such as cerium trichloride, zinc chloride or bromide, indium chloride or indium bromide to form a compound suitable for addition. Other organometallic compounds (V). Alternatively, organometallic compound V can also be prepared by inserting a metal into the carbon-halogen bond of haloaromatic compound IV. Lithium or magnesium are suitable elemental metals for this transformation. Insertion can be achieved in solvents such as diethyl ether, dioxane, tetrahydrofuran, toluene, hexane, dimethylsulfoxide and mixtures thereof at temperatures in the range of -80 to 100°C, preferably -70 to 40°C. In cases where no spontaneous reaction occurs, metal preactivation such as with 1,2-dibromoethane, iodine, trimethylsilyl chloride, acetic acid, hydrochloric acid and/or sonication may be required. The reaction of adding the organometallic compound V to gluconolactone or its derivative (VI) is preferably at a temperature between 40°C and -100°C, especially preferably at a temperature of 0 to -80°C in an inert solvent or its mixture to obtain the compound of formula II. While all of the above reactions are preferably carried out in an inert atmosphere such as argon and nitrogen, they can also be performed in air. Metallation and/or coupling reactions can also be carried out in microreactors and/or micromixers capable of high exchange rates; eg analogously to the method described in WO 2004/076470. Suitable solvents for the addition of metallated phenyl V to appropriately protected gluconolactone VI are, for example, diethyl ether, dimethoxyethane, benzene, toluene, dichloromethane, hexane, tetrahydrofuran , Dioxane, N-Methylpyrrolidone and mixtures thereof. The addition reaction can be carried out without any other adjuvants or in the presence of slowly reacting coupling partners such as BF3* OEt2 or Me3 SiCl accelerators (see M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994). Substituent R in Scheme1 is preferably defined as benzyl, substituted benzyl, allyl, trialkylsilyl, especially preferably trimethylsilyl, triisopropylsilyl, alkene Propyl, 4-methoxybenzyl and benzyl. If two adjacent substituents R are linked together, the two substituents are preferably part of benzylidene acetal,4 -methoxybenzylidene acetal, isopropyl ketal or are combined with A 2,3-dimethoxy-butylene group in which the 2 and 3 positions of the alkane are linked to the adjacent oxygen atom of the pyranose constitutes a dioxane. The R' group preferably represents hydrogen, C1-4 alkyl, C1-4 alkylcarbonyl or C1-4 alkyloxycarbonyl, especially preferably hydrogen, methyl or ethyl. The R' group is introduced after the addition of the organometallic compound V or a derivative thereof to the gluconolactone VI. If R' is equal to hydrogen orC1-4 alkyl, the reaction solution is treated with an alcohol such as methanol or ethanol or water in the presence of an acid such as acetic acid, methanesulfonic acid, toluenesulfonic acid, sulfuric acid, trifluoroacetic acid or hydrochloric acid . It is also possible to react the anomeric hydroxyl group with Attachment of R' follows the reaction of a suitable electrophile such as methyl iodide, dimethyl sulfate, ethyl iodide, diethyl sulfate, acetyl chloride or acetic anhydride to prepare the hydrogen compound II. The hydroxyl group can also be deprotonated with, for example, sodium hydride prior to the addition of the electrophile. During attachment of R', the protecting group R can be cleaved if the protecting groupR is unstable under the reaction conditions employed which result in a correspondingly protonated compound (ie compound IIwithR equal to H).
可使用有机化学中的标准转化或至少从有机合成中的专业文献已知的方法进行式IV的卤代芳族化合物的合成(见J.March，Advanced OrganicReactions，Reactions，Mechanisms，and Structure，第4版，John Wiley & Sons，Chichester/New York/Brisbane/Toronto/Singapore，1992及其中所引用的文献等)。更尤其是，在不同专著中详述将过渡金属及有机金属化合物用于合成芳族化合物(例如见L Brandsma，S.F.Vasilevsky，H.D.Verkruijsse，Applicationof Transition Metal Catalystsin Organic Synthesis，Springer-Verlag，Berlin/Heidelberg，1998；M.Schlosser，Organometallics in Synthesis，JohnWiley & Sons，Chichester/New York/Brisbane/Toronto/Singapore，1994，PJ.Stang，F.Diederich，Metal-Catalyzed Cross-Coupling Reactions，Wiley-VCH，Weinheim，1997及其中所引用的文献)。下文中所述的合成方案通过实例提供证明。此外，也可使用相同合成方法使苷元部分与已存在吡喃糖部分混合。The synthesis of halogenated aromatic compounds of formula IV can be carried out using standard transformations in organic chemistry or at least methods known from the specialist literature in organic synthesis (see J. March, Advanced Organic Reactions, Reactions, Mechanisms, and Structure, 4 ed., John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1992 and references cited therein, etc.). More particularly, the use of transition metal and organometallic compounds for the synthesis of aromatic compounds is detailed in various monographs (see for example L Brandsma, S.F. Vasilevsky, H.D. Verkruijsse, Application of Transition Metal Catalysts in Organic Synthesis, Springer-Verlag, Berlin/Heidelberg, 1998; M. Schlosser, Organometallics in Synthesis, John Wiley & Sons, Chichester/New York/Brisbane/Toronto/Singapore, 1994, PJ. Stang, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Wiley-VCH, Weinheim, 1997 and references cited therein). The synthetic schemes described hereinafter are demonstrated by examples. In addition, aglycone moieties can also be mixed with existing pyranose moieties using the same synthetic method.
流程2：二芳基酮片段的合成Scheme 2: Synthesis of diaryl ketone fragments
流程2显示了应用弗瑞德-克来福特(Friedel-Crafts)酰化条件或其变体从苯甲酰氯和第二个芳香基团开始制备可用于合成式IV的卤代芳族化合物的前体化合物。流程2中的R1表示氰基或随后可转化为氰基的基团，例如氯、溴、羧基、羧酸酯、羧酰胺或其衍生物、例如硫缩醛或噻唑的被保护或被遮蔽的醛官能团，或例如硝基的被保护或被遮蔽的氨基官能团。此经典反应具有宽的底物范围，且通常在以催化或化学计量的量使用的例如AlCl3、FeCl3、碘、铁、ZnCl2、硫酸或三氟甲磺酸的催化剂存在下进行。也可使用相应羧酸、酸酐、酯或苯甲腈代替苯甲酰氯。反应优选在-30至120℃，优选地在30至100℃的温度下在例如二氯甲烷及1，2-二氯乙烷的氯化烃中进行。然而，也可以无溶剂反应或在微波炉中的反应。Scheme 2 shows the procedure for the preparation of haloaromatic compounds useful in the synthesis of formula IV starting from benzoyl chloride and a second aromatic group using Friedel-Crafts acylation conditions or variants thereof. body compound. R in Scheme2 represents a cyano group or a group that can subsequently be converted to a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or derivatives thereof, such as protected or masked thioacetals or thiazoles aldehyde functional groups, or protected or masked amino functional groups such as nitro groups. This classical reaction has a broad substrate scope and is usually carried out in the presence of catalysts such asAlCl3 ,FeCl3 , iodine, iron,ZnCl2 , sulfuric acid or trifluoromethanesulfonic acid used in catalytic or stoichiometric amounts. Instead of benzoyl chloride, the corresponding carboxylic acid, anhydride, ester or benzonitrile can also be used. The reaction is preferably carried out in a chlorinated hydrocarbon such as dichloromethane and 1,2-dichloroethane at a temperature of -30 to 120°C, preferably at a temperature of 30 to 100°C. However, solvent-free reactions or reactions in microwave ovens are also possible.
流程3：二芳基酮及二芳基甲醇还原为二芳基甲烷Scheme 3: Reduction of diaryl ketone and diaryl carbinol to diaryl methane
在流程3中取代基R表示C1-3烷基或芳基，且R1表示氰基或随后可转化为氰基的基团，例如氯、溴、羧基、羧酸酯、羧酰胺或其衍生物、硼或甲硅烷基、例如缩醛或噻唑的被保护或被遮蔽的醛官能团，或例如硝基的被保护或被遮蔽的氨基官能团。可自二芳基酮或二芳基甲醇开始以一或两个反应步骤获得二芳基甲烷。二芳基酮可以两个步骤通过相应二苯基甲醇或以一个步骤还原为二芳基甲烷。在两步骤变体中，以例如金属氢化物(例如NaBH4、LiAlH4或iBu2AlH)的还原剂还原酮以形成醇。在例如BF3*OEt2、InCl3或AlCl3的路易斯酸或例如盐酸、硫酸、三氟乙酸或乙酸的布朗斯特酸存在下以例如Et3SiH、NaBH4或Ph2SiClH的还原剂使所得醇转化为所要二苯基甲烷。可(例如)以例如Et3SiH的甲硅烷、例如NaBH4的硼氢化物或例如LiAlH4的氢化铝在例如BF3*OEt2、三(五氟苯基)硼烷、三氟乙酸、盐酸、氯化铝或InCl3的路易斯酸或布朗斯特酸存在下进行自酮开始获得二苯基甲烷的一步方法。反应优选地在-30至150℃，优选地在20至100℃的温度下在例如卤化烃(例如二氯甲烷、甲苯、乙腈或其混合物)的溶剂中进行。在例如Pd/C的过渡金属催化剂存在下的氢气还原为另一可能合成方法。也可为根据沃夫-奇希诺(Wolff-Kishner)或其变体的还原反应。首先以肼或其衍生物例如1，2-双(叔丁基二甲基甲硅烷基)肼使酮转化为腙，腙在强碱反应条件及加热下分解以形成二苯基甲烷及氮。反应可以一个反应步骤进行或以两个单独反应步骤分离腙或其衍生物之后进行。合适碱包括(例如)于例如乙二醇、甲苯、DMSO、2-(2-丁氧基乙氧基)乙醇或叔丁醇的溶剂中的KOH、NaOH或KOtBu；也可为无溶剂反应。反应可在介于20至250℃，优选地介于80至200℃之间的温度下进行。沃夫-奇希诺还原的碱性条件的替代条件为克莱门森(Clemmensen)还原，其在酸性条件下发生，本文也可使用。二芳基甲醇中醇官能团亦可首先转型为更好的离去基，例如氯、溴、碘、乙酸基、碳酸基、磷酸基或硫酸基；形成二芳基甲烷的随后还原步骤广泛描述于有机化学文献中。In Scheme 3, the substituent R represents a C1-3 alkyl or aryl group, andR represents a cyano group or a group that can be subsequently converted into a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or Derivatives, boron or silyl groups, protected or masked aldehyde functions such as acetals or thiazoles, or protected or masked amino functions such as nitro groups. Diarylmethanes can be obtained in one or two reaction steps starting from diaryl ketones or diaryl carbinols. Diaryl ketones can be reduced to diarylmethanes in two steps by the corresponding diphenylmethanols or in one step. In a two-step variant, the ketone is reduced with a reducing agent such as a metal hydride such asNaBH4 ,LiAlH4 oriBu2AlH to form the alcohol. In the presence of a Lewis acid such as BF3* OEt2 , InCl3 or AlCl3 or a Bronsted acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid or acetic acid with a reducing agent such as Et3 SiH, NaBH4 or Ph2 SiClH The resulting alcohol is converted to the desired diphenylmethane. For example, with monosilane such as Et3 SiH, borohydride such as NaBH4 or aluminum hydride such as LiAlH4 in e.g. BF3* OEt2 , tris(pentafluorophenyl)borane, trifluoroacetic acid, hydrochloric acid , aluminum chloride or InCl3 in the presence of Lewis or Bronsted acids for obtaining diphenylmethane in one step starting from ketones. The reaction is preferably carried out in a solvent such as a halogenated hydrocarbon such as dichloromethane, toluene, acetonitrile or a mixture thereof at a temperature of -30 to 150°C, preferably at a temperature of 20 to 100°C. Hydrogen reduction in the presence of transition metal catalysts such as Pd/C is another possible synthesis method. Reductions according to Wolff-Kishner or variants thereof are also possible. First, hydrazine or its derivatives such as 1,2-bis(tert-butyldimethylsilyl)hydrazine is used to convert the ketone into a hydrazone, and the hydrazone decomposes under strong base reaction conditions and heating to form diphenylmethane and nitrogen. The reaction can be carried out in one reaction step or after isolation of the hydrazone or its derivatives in two separate reaction steps. Suitable bases include, for example, KOH, NaOH or KOtBu in a solvent such as ethylene glycol, toluene, DMSO, 2-(2-butoxyethoxy)ethanol or tert-butanol; solvent-free reactions are also possible. The reaction can be carried out at a temperature between 20 and 250°C, preferably between 80 and 200°C. An alternative to basic conditions for the Wolf-Chishino reduction is the Clemmensen reduction, which occurs under acidic conditions, and can also be used herein. Alcohol functionality in diarylmethanols can also be converted first to a better leaving group such as chlorine, bromine, iodine, acetate, carbonic acid, phosphoric acid, or sulfate; the subsequent reduction step to form diarylmethanes is extensively described in in the literature of organic chemistry.
流程4：二芳基甲烷单元及其可能前体化合物的合成Scheme 4: Synthesis of diarylmethane units and their possible precursor compounds
流程4中R1表示氰基或随后可转化为氰基的基团，例如氯、溴、羧基、羧酸酯、羧酰胺或其衍生物、硼或甲硅烷基、例如缩醛或噻唑的被保护或被遮蔽的醛官能团，或例如硝基的被保护或被遮蔽的氨基官能团。术语“Alk”表示C1-4烷基且各取代基R彼此独立地选自H、C1-3烷基及C1-3烷氧基。流程4描述自金属化苯基开始合成二芳基甲烷及其可能前体化合物。可通过与(例如)丁基锂、异丙基镁卤化物或二异丙基镁的卤素-金属交换反应或通过将元素金属插入卤素-碳键中从氯化、溴化或碘化芳族化合物合成锂或镁取代的芳族化合物。可通过与例如硼酸酯或其衍生物的硼亲电子试剂反应从这些金属化苯基获得例如硼酸、硼酸酯或二烷基芳基硼烷的相应经硼取代的化合物。此外，也可从相应卤化或拟卤化前体及二硼或硼烷化合物经例如钯的过渡金属催化的反应来制备硼基化(borylated)芳族化合物(例如见Tetrahedron Lett.2003，第4895-4898页及其中所引用的文献)。将锂或镁取代的苯基化合物加至苯甲醛(步骤3)及苯甲酸或其衍生物(步骤4)(例如苯甲酸酯、例如温瑞伯(Weinreb)型的苯甲酰胺、苯甲腈或苯甲酰氯)中。这些反应从原理上讲可在无其他过渡金属催化剂下或未转金属化为例如铈、铟或锌的另一金属情况下进行；有时使用后述替代方法之一是有利的。可通过铑催化剂将芳基硼酸加至苯甲醛中以提供各个二芳基甲醇(例如见Adv.Synth.Catal.2001，第343-350页及其中所引用的文献)。此外，可由例如钯的过渡金属、其络合物或盐调节使芳基硼酸、其酯、二烷基芳基硼烷或芳基三氟硼酸酯与苯甲酰氯偶连以产生二芳基酮。可使金属化苯基与例如苄基氯、苄基溴或苄基碘的苄基亲电子试剂反应以得到二芳基甲烷。锂或镁衍生的苯基化合物有利地但并非总必需地在例如铜、铁或钯的过渡金属存在下反应(例如见Org.Lett.2001，3，2871-2874及其中所引用的文献)。从锂或镁转金属化为(例如)硼、锡、硅或锌分别提供(例如)相应芳族硼酸、锡烷、甲硅烷或锌化合物，其可进行与(例如)苄基卤化物、苄基碳酸酯、苄基磷酸酯、苄基磺酸酯或苄基羧酸酯的苄基亲电子试剂的偶连反应。反应在例如钯、镍、铑、铜或铁的过渡金属存在下进行(例如见Tetrahedron Lett.2004，第8225-8228页及Org.Lett.2005，第4875-4878页及其中所引用的文献)。R in Scheme4 represents a cyano group or a group which can subsequently be converted into a cyano group, such as chlorine, bromine, carboxyl, carboxylate, carboxamide or derivatives thereof, boron or silyl, for example acetal or thiazole A protected or masked aldehyde function, or a protected or masked amino function such as a nitro group. The term "Alk" represents C1-4 alkyl and each substituent R is independently selected from H, C1-3 alkyl and C1-3 alkoxy. Scheme 4 describes the synthesis of diarylmethanes and their possible precursor compounds starting from metallated phenyl groups. Chlorinated, brominated or iodinated aromatic Compound synthesis of lithium or magnesium substituted aromatic compounds. Corresponding boron-substituted compounds such as boronic acids, boronate esters or dialkylarylboranes can be obtained from these metallated phenyl groups by reaction with boron electrophiles such as boronate esters or derivatives thereof. In addition, borylated aromatic compounds can also be prepared from corresponding halogenated or pseudohalogenated precursors and diboron or borane compounds by transition metal-catalyzed reactions such as palladium (see for example Tetrahedron Lett. 2003, pp. 4895- 4898 pages and references cited therein). Lithium or magnesium substituted phenyl compounds are added to benzaldehyde (step 3) and benzoic acid or derivatives thereof (step 4) (e.g. benzoate esters, e.g. benzamides of the Weinreb type, benzonitrile or benzoyl chloride). These reactions can in principle be carried out without further transition metal catalysts or without transmetallation to another metal such as cerium, indium or zinc; sometimes it is advantageous to use one of the latter alternatives. Arylboronic acids can be added to benzaldehydes over a rhodium catalyst to provide the respective diarylcarbins (see eg Adv. Synth. Catal. 2001, pp. 343-350 and references cited therein). Additionally, the coupling of arylboronic acids, their esters, dialkylarylboranes, or aryltrifluoroborates with benzoyl chloride can be mediated by transition metals such as palladium, complexes or salts thereof to produce diaryl ketone. Metallated phenyl groups can be reacted with benzyl electrophiles such as benzyl chloride, benzyl bromide or benzyl iodide to give diarylmethanes. Lithium- or magnesium-derived phenyl compounds are advantageously, but not always necessarily, reacted in the presence of transition metals such as copper, iron or palladium (see for example Org. Lett. 2001, 3, 2871-2874 and literature cited therein). Transmetallation from lithium or magnesium to, for example, boron, tin, silicon, or zinc provides, for example, the corresponding aromatic boronic acid, stannane, silane, or zinc compound, respectively, which can be carried out with, for example, benzyl halides, benzyl halides, Coupling reactions of benzyl electrophiles with benzyl carbonate, benzyl phosphate, benzyl sulfonate, or benzyl carboxylate. The reaction is carried out in the presence of a transition metal such as palladium, nickel, rhodium, copper or iron (see for example Tetrahedron Lett. 2004, pp. 8225-8228 and Org. Lett. 2005, pp. 4875-4878 and literature cited therein) .
流程5：氰基部分的引入Scheme 5: Introduction of the cyano moiety
流程5显示了在合成目标分子的不同阶段使氰基残基连接于中心苯基的可能路径。可通过过渡金属介导的例如氰化钠、氯化钾、氰化锌或氰化铜的适当氰基来源与卤化或拟卤化苯基的偶连反应来引入氰基。合适催化剂可衍生于例如钯、铑、镍、铁或铜的过渡金属，这些过渡金属可以例如钯/碳的基本形式、以例如氯化钯、溴化钯或乙酸钯的盐或与例如三苯基膦、三叔丁基膦或1，1’-双(二苯基膦基)二茂铁(dppf)的膦的络合物或例如二亚苄基丙酮的烯烃使用。活性催化剂可原位产生或在添加至反应混合物之前产生。例如为元素或盐的锌的添加剂可为有利的(见Tetrahedron Lett.2005，46，1849-1853及Tetrahedron Lett.2005，46，1815-1818及其中所引用的文献)。使可通过卤素金属交换反应或通过将各个金属插入卤素键中从氯化、溴化或碘化化合物获得的相应锌、镁或锂化合物与例如对甲苯基磺酰基氰化物、溴化氰或氰酸2-吡啶的氰基亲电子试剂反应是加入氰基官能团的另一可行方法(例如见Synth.Commun.1996，3709-3714及其中所引用的文献)。Scheme 5 shows possible routes to attach the cyano residue to the central phenyl group at different stages in the synthesis of target molecules. The cyano group can be introduced by a transition metal mediated coupling reaction of an appropriate cyano source such as sodium cyanide, potassium chloride, zinc cyanide or copper cyanide with a halogenated or pseudohalogenated phenyl group. Suitable catalysts can be derived from transition metals such as palladium, rhodium, nickel, iron or copper, which can be used, for example, in the basic form of palladium on carbon, as salts of, for example, palladium chloride, palladium bromide or palladium acetate or with, for example, triphenyl Phosphine complexes of phosphine, tri-tert-butylphosphine or 1,1'-bis(diphenylphosphino)ferrocene (dppf) or olefins such as dibenzylideneacetone are used. The active catalyst can be generated in situ or prior to addition to the reaction mixture. Additives such as zinc as elements or salts may be advantageous (see Tetrahedron Lett. 2005, 46, 1849-1853 and Tetrahedron Lett. 2005, 46, 1815-1818 and literature cited therein). Corresponding zinc, magnesium or lithium compounds obtainable from chlorinated, brominated or iodized compounds by halogen metal exchange reactions or by insertion of the respective metal into a halogen bond, with e.g. p-tolylsulfonyl cyanide, cyanogen bromide or cyanogen The cyano electrophile reaction of the acid 2-pyridine is another possible method of adding the cyano function (see eg Synth. Commun. 1996, 3709-3714 and references cited therein).
流程6：自醛或羧酸衍生物引入氰基残基Scheme 6: Introduction of cyano residues from aldehyde or carboxylic acid derivatives
另一种氰基的引入为自醛或羧酰胺开始的合成(流程6)。醛官能团自身可以其本身、被保护或被遮蔽引入。醛官能团的通用保护基为缩醛类，但也可使用其他保护基(见T.W.Greene，P.G.M.Wuts，Protective Groups inOrganic Synthesis，John Wiley & Sons，Inc.，New York，1999)。醛官能团的合适遮蔽剂为(例如)烯烃及噻唑。可使用与(例如)甲酸、浓盐酸、多磷酸或吡啶-甲苯混合的(例如)羟胺使醛转化为氰基官能团。可将在这些反应条件下所形成的中间体肟分离，之后脱水以产生最终产物。也可使用例如双三氟乙酰基羟胺及NH2OSO3的其它羟胺试剂且在无其他试剂情况下得到腈。其他可用试剂为(例如)于乙酸中的NH4PO4H2及硝基丙烷、三甲基甲硅烷基叠氮化合物或S，S-二甲基硫二酰亚胺。Another introduction of cyano groups is the synthesis starting from aldehydes or carboxamides (Scheme 6). The aldehyde function itself can be introduced as such, protected or masked. Common protecting groups for aldehyde functional groups are acetals, but other protecting groups can also be used (see TW Greene, PGM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc., New York, 1999). Suitable masking agents for aldehyde functions are, for example, alkenes and thiazoles. Aldehydes can be converted to cyano functionality using eg hydroxylamine mixed with eg formic acid, concentrated hydrochloric acid, polyphosphoric acid or pyridine-toluene. The intermediate oxime formed under these reaction conditions can be isolated followed by dehydration to yield the final product. Other hydroxylamine reagents such as bistrifluoroacetylhydroxylamine andNH2OSO3 can also be used and give nitriles in the absence of other reagents. Other useful reagents are egNH4PO4H2 andnitropropane , trimethylsilylazide or S,S- dimethylsulfimide in acetic acid.
羧酰胺也可为合适腈前体。可以例如三氟乙酸酐、五氧化二磷、POCl3、CCl4-膦组合、Cl3COCl-胺组合、伯吉斯(Burgess)试剂、维斯梅耳(Vilsmeyer)试剂、SOCl2或氰尿酰氯的脱水剂进行转化。也可以从相应单烷基化羧酰胺、羧酸、酯或羧酰氯化物开始，在未分离任何中间体情况下一锅形成腈。Carboxamides are also suitable nitrile precursors. Can be for example trifluoroacetic anhydride, phosphorus pentoxide,POCl3 ,CCl4 -phosphine combination,Cl3COCl -amine combination, Burgess reagent, Vilsmeyer reagent,SOCl2 or cyanuria Acid chloride dehydrating agent for conversion. It is also possible to form nitriles in one pot starting from the corresponding monoalkylated carboxamides, carboxylic acids, esters or carboxylic acid chlorides without isolation of any intermediates.
流程7：自苯胺前体引入氰基残基Scheme 7: Introduction of cyano residues from aniline precursors
已建立的引入腈官能团的方法为与氰化铜及可通过各个苯胺衍生物的重氮化作用获得的相应重氮化合物的所谓山德迈耳(Sandmeyer)反应。重氮化合物的合成及其随后氰基去重氮化作用已广泛地证明于有机化学文献中。An established method for introducing nitrile functions is the so-called Sandmeyer reaction with copper cyanide and the corresponding diazo compounds obtainable by diazotization of the respective aniline derivatives. The synthesis of diazo compounds and their subsequent cyano-dediazotization has been extensively documented in the organic chemistry literature.
流程8：二芳基甲烷单元的另一种合成Scheme 8: Alternative synthesis of diarylmethane units
流程8中显示了用于构建二芳基甲烷单元的另一种方法。Another method for the construction of diarylmethane units is shown in Scheme 8.
使用市售或可通过上述方法获得的邻氟取代的苯甲腈。在碱性条件下使邻氟取代的苯甲腈与被R3取代的苯乙酸烷基酯反应(例如见J.Org.Chem.55，1990，4817-4821；J.Heterocycl.Chem，32，1995，1461-1466)随后酯裂解且脱羧(例如见J.Heterocycl.Chem，32，1995，1461-1466；Org.Prep.Proced.Int.37，2005，550-555)或直接脱烷氧基羰基(例如见J.Med.Chem.46，2003，5249-5257；Angew.Chem.Int.Ed.47，2004，6493-6496)。Ortho-fluoro-substituted benzonitriles are used which are commercially available or obtainable by the method described above. Under basic conditions, the benzonitrile substituted by o-fluorine is reacted with the alkyl phenylacetate substituted byR (for example, see J.Org.Chem.55, 1990, 4817-4821; J.Heterocycl.Chem, 32, 1995, 1461-1466) followed by ester cleavage and decarboxylation (see for example J.Heterocycl.Chem, 32, 1995, 1461-1466; Org.Prep.Proced.Int.37, 2005, 550-555) or direct dealkoxylation Carbonyl (see eg J. Med. Chem. 46, 2003, 5249-5257; Angew. Chem. Int. Ed. 47, 2004, 6493-6496).
为制备通式I的化合物，在本发明的方法a)中，在路易斯酸或布朗斯特酸存在下使通式II的化合物与还原剂反应，For the preparation of compounds of general formula I, in process a) according to the invention, compounds of general formula II are reacted with a reducing agent in the presence of a Lewis acid or a Bronsted acid,
其中R’及R3如上文所定义且wherein R' andR are as defined above and
R8a、R8b、R8c、R8d如上文所定义且彼此独立地代表(例如)乙酰基、新戊酰基、苯甲酰基、叔丁氧基羰基、苄基氧基羰基、烯丙基、三烷基甲硅烷基、苄基或被取代苄基或在各情况下两个相邻基团R8a、R8b、R8c、R8d形成亚苄基缩醛或亚异丙基缩酮或通过亚丁基的2和3位连接至吡喃糖环的氧原子的2，3-二甲氧基-亚丁基且与上述基团形成被取代的二噁烷，R8a , R8b , R8c , R8d are as defined above and independently of each other represent, for example, acetyl, pivaloyl, benzoyl, tert-butoxycarbonyl, benzyloxycarbonyl, allyl, Trialkylsilyl, benzyl or substituted benzyl or in each case two adjacent radicals R8a , R8b , R8c , R8d form benzylidene acetal or isopropylidene ketal or 2,3-dimethoxy-butylene linked to the oxygen atom of the pyranose ring via the 2 and 3 positions of the butylene group and forming a substituted dioxane with the above groups,
其可如上文所述获得。It can be obtained as described above.
反应的合适还原剂包括(例如)例如三乙基甲硅烷、三丙基甲硅烷、三异丙基甲硅烷或二苯基甲硅烷的甲硅烷、硼氢化钠、氰基硼氢化钠、硼氢化锌、硼烷、氢化铝锂、氢化二异丁基铝或碘化钐。还原在无或有例如盐酸、甲苯磺酸、三氟乙酸或乙酸的合适布朗斯特酸或例如醚合三氟化硼、三氟甲磺酸三甲基甲硅烷酯、四氯化钛、四氯化锡、三氟甲磺酸钪或碘化锌的路易斯酸存在下进行。视还原剂及酸而定，反应可在介于-60℃至120℃的温度下在例如二氯甲烷、氯仿、乙腈、甲苯、己烷、乙醚、四氢呋喃、二噁烷、乙醇、水或其混合物的溶剂中进行。试剂的一个尤其合适的混合由(例如)三乙基甲硅烷及醚合三氟化硼组成，该两种化合物方便地在-60℃与60℃温度下在乙腈或二氯甲烷中使用。此外可在例如Pd/C或阮内(Raney)镍的过渡金属催化剂存在下在例如四氢呋喃、乙酸乙酯、甲醇、乙醇、水或乙酸的溶剂中使用氢气用于转化。Suitable reducing agents for the reaction include, for example, silanes such as triethylsilane, tripropylsilane, triisopropylsilane or diphenylsilane, sodium borohydride, sodium cyanoborohydride, borohydride Zinc, borane, lithium aluminum hydride, diisobutylaluminum hydride, or samarium iodide. Reduction in the absence or presence of a suitable Bronsted acid such as hydrochloric acid, toluenesulfonic acid, trifluoroacetic acid or acetic acid or such as boron trifluoride etherate, trimethylsilyl trifluoromethanesulfonate, titanium tetrachloride, tetrachloride in the presence of Lewis acids of tin chloride, scandium triflate or zinc iodide. Depending on the reducing agent and acid, the reaction can be carried out at temperatures between -60°C and 120°C in, for example, dichloromethane, chloroform, acetonitrile, toluene, hexane, diethyl ether, tetrahydrofuran, dioxane, ethanol, water or in the solvent of the mixture. A particularly suitable mixture of reagents consists, for example, of triethylsilane and boron trifluoride etherate, both compounds conveniently used in acetonitrile or dichloromethane at temperatures of -60°C and 60°C. Furthermore hydrogen can be used for the conversion in the presence of transition metal catalysts such as Pd/C or Raney nickel in solvents such as tetrahydrofuran, ethyl acetate, methanol, ethanol, water or acetic acid.
或者，为制备本发明的方法b)的通式I的化合物，在通式III的化合物中，保护基裂解，Alternatively, for the preparation of compounds of general formula I in process b) of the present invention, in compounds of general formula III, the protecting group is cleaved,
其中R3如上文所定义且wherein Ris as defined above and
R8a至R8d表示上文所定义的保护基之一，例如酰基、芳基甲基、烯丙基、缩醛、缩酮或甲硅烷基，且其可(例如)通过自如上文所述的式II的化合物还原来获得。R8a to R8d represent one of the protecting groups defined above, such as acyl, arylmethyl, allyl, acetal, ketal or silyl, and it can be, for example, obtained by The compound of formula II is obtained by reduction.
应了解在上述合成方法中可改变基团R8a至R8d的一或若干基团。It will be appreciated that one or several of the groups R8a to R8d may be varied in the above synthetic methods.
所用任何酰基保护基(例如)在水性溶剂中(例如在水、异丙醇/水、乙酸/水、四氢呋喃/水或二噁烷/水中)在例如三氟乙酸、盐酸或硫酸的酸存在下或在例如氢氧化锂、氢氧化钠或氢氧化钾的碱金属碱存在下水解裂解或(例如)在碘化三甲基甲硅烷存在下在介于0至120℃之间的温度下，优选地在介于10至100℃之间的温度下非质子性裂解。优选地通过任选地在例如乙酸的溶剂存在下在介于50至120℃之间的温度下以例如盐酸的酸处理，或通过任选地在例如四氢呋喃或甲醇的溶剂存在下在介于0至50℃之间的温度下以氢氧化钠溶液处理使三氟乙酰基裂解。Any acyl protecting group used is, for example, in an aqueous solvent (for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water) in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulfuric acid or hydrolytic cleavage in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or, for example, in the presence of trimethylsilyl iodide at a temperature between 0 and 120° C., preferably Aprotic cleavage at temperatures between 10 and 100°C. Preferably by treatment with an acid such as hydrochloric acid, optionally in the presence of a solvent such as acetic acid at a temperature between 50 and 120 °C, or by treatment optionally in the presence of a solvent such as tetrahydrofuran or methanol at a temperature between 0 Treatment with sodium hydroxide solution at a temperature between 50°C cleaves the trifluoroacetyl group.
所用的任何缩醛或缩酮保护基(例如)在水性溶剂中(例如在水、异丙醇/水、乙酸/水、四氢呋喃/水或二噁烷/水中)在例如三氟乙酸、盐酸或硫酸的酸存在下水解裂解或(例如)在碘化三甲基甲硅烷存在下在介于0至120℃之间的温度下，优选地在介于10至100℃之间的温度下非质子性裂解。Any acetal or ketal protecting group used is, for example, in an aqueous solvent (for example in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water) in for example trifluoroacetic acid, hydrochloric acid or Acid hydrolytic cleavage in the presence of sulfuric acid or aprotic, for example in the presence of trimethylsilyl iodide at temperatures between 0 and 120°C, preferably between 10 and 100°C sexual lysis.
三甲基甲硅烷基(例如)在水、水性溶剂混合物或例如甲醇或乙醇的低级醇中在例如氢氧化锂、氢氧化钠、碳酸钾或甲醇钠的碱存在下裂解。Trimethylsilyl groups are cleaved, for example, in water, aqueous solvent mixtures or lower alcohols such as methanol or ethanol in the presence of bases such as lithium hydroxide, sodium hydroxide, potassium carbonate or sodium methoxide.
在水性或醇类溶剂中，例如盐酸、三氟乙酸或乙酸的酸也是适合的。为在例如乙醚、四氢呋喃或二氯甲烷的有机溶剂中裂解，使用例如氟化四丁基铵的氟化物试剂也是适合的。In aqueous or alcoholic solvents, acids such as hydrochloric acid, trifluoroacetic acid or acetic acid are also suitable. For cleavage in organic solvents such as diethyl ether, tetrahydrofuran or dichloromethane, the use of fluoride reagents such as tetrabutylammonium fluoride is also suitable.
(例如)在例如钯/炭的催化剂存在下在例如甲醇、乙醇、乙酸乙酯或冰醋酸的合适溶剂中，任选地在添加例如盐酸的酸下在介于0至100℃之间的温度下，但优选地在介于20至60℃之间的周围温度下且在1至7巴，但优选地在3至5巴的氢压力下以氢气使苄基、甲氧基苄基或苄氧基羰基有利地氢化裂解。然而，2，4-二甲氧基苄基优选地在苯甲醚存在下在三氟乙酸中裂解。(for example) in the presence of a catalyst such as palladium on carbon in a suitable solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at a temperature between 0 and 100°C benzyl, methoxybenzyl or benzyl with hydrogen, but preferably at an ambient temperature between 20 and 60°C and at a hydrogen pressure of 1 to 7 bar, but preferably at 3 to 5 bar Oxycarbonyl is advantageously hydrocleaved. However, 2,4-dimethoxybenzyl is preferably cleaved in trifluoroacetic acid in the presence of anisole.
优选地通过以例如三氟乙酸或盐酸的酸处理或通过任选地使用例如二氯甲烷、二噁烷、甲醇或乙醚的溶剂以碘化三甲基甲硅烷处理使叔丁基或叔丁氧基羰基裂解。The tert-butyl or tert-butoxy group is preferably rendered tert-butyl or tert-butoxy by treatment with an acid such as trifluoroacetic acid or hydrochloric acid or by treatment with trimethylsilyl iodide optionally using a solvent such as dichloromethane, dioxane, methanol or diethyl ether. cleavage of the carbonyl group.
在上述反应中，在反应期间所存在的例如乙炔基、羟基、氨基、烷基氨基或亚氨基的任何反应性基团可被在反应后再次裂解的常规保护基保护。In the above reactions, any reactive groups such as ethynyl, hydroxy, amino, alkylamino or imino groups present during the reaction can be protected by conventional protecting groups which are cleaved again after the reaction.
例如，乙炔基的保护基可为三甲基甲硅烷基或三异丙基。2-羟基异丙-2-基也可用作保护基。For example, the protecting group for ethynyl may be trimethylsilyl or triisopropyl. 2-Hydroxyisopropan-2-yl can also be used as a protecting group.
例如，羟基的保护基可为三甲基甲硅烷基、乙酰基、三苯甲基、苄基或四氢吡喃基。For example, a protecting group for a hydroxy group may be trimethylsilyl, acetyl, trityl, benzyl or tetrahydropyranyl.
氨基、烷基氨基或亚氨基的保护基可为(例如)甲酰基、乙酰基、三氟乙酰基、乙氧基羰基、叔丁氧基羰基、苄氧基羰基、苄基、甲氧基苄基或2，4-二甲氧基苄基。Protecting groups for amino, alkylamino or imino groups may be, for example, formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl base or 2,4-dimethoxybenzyl.
此外，如上文所述，所获得的通式I的化合物可拆分为其对映异构体及/或非对映异构体。因此，例如，顺/反混合物可拆分为其顺和反异构体，且具有至少一个光学活性碳原子的化合物可分离为其对映异构体。Furthermore, the obtained compounds of general formula I can be resolved into their enantiomers and/or diastereomers, as described above. Thus, for example, cis/trans mixtures can be resolved into their cis and trans isomers, and compounds having at least one optically active carbon atom can be separated into their enantiomers.
因此，例如，可通过色谱法使顺/反混合物拆分为其顺和反异构体，可通过本身已知的方法(比较Allinger N.L及Eliel E.L“Topics inStereochemistry”，第6卷，Wiley Interscience，1971中)使所获得的以外消旋物存在的通式I的化合物分离为其光学对映体且具有至少2个不对称碳原子的通式I的化合物可基于其物理-化学差异使用本身已知的方法(例如)通过色谱及/或分步结晶拆分为其非对映异构体，且若获得为外消旋形式的这些化合物，则随后可将其解析为如上所述的对映异构体。Thus, for example, a cis/trans mixture can be resolved into its cis and trans isomers by chromatography, by methods known per se (compare Allinger N.L and Eliel E.L "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 middle) separation of the obtained compounds of the general formula I in the form of racemates into their optical antipodes and which have at least 2 asymmetric carbon atoms can be used on the basis of their physico-chemical differences using known per se are resolved into their diastereomers, for example by chromatography and/or fractional crystallization, and if these compounds are obtained in racemic form, they can then be resolved into their enantiomers as described above Construct.
优选地通过在手性相上柱分离对映异构体或通过从光学活性溶剂中重结晶或通过与可与外消旋化合物形成盐或例如酯或酰胺的衍生物的光学活性物质(尤其是其酸及活性衍生物或醇类)反应，且(例如)基于其溶解度差异使由此获得的盐或衍生物的非对映异构体混合物分离来使对映异构体分离，同时可通过合适试剂的作用使游离对映体从纯的非对映异构盐或衍生物释放。常用光学活性酸为(例如)D-型及L-型酒石酸或二苯甲酰基酒石酸、二邻甲苯基酒石酸、苹果酸、扁桃酸、樟脑磺酸、谷氨酸、天冬氨酸或奎尼酸。光学活性醇可为(例如)(+)或(-)-薄荷醇且例如，酰胺中光学活性酰基可为(+)-或(-)-薄荷基氧基羰基。Preferably by separation of enantiomers on a column on a chiral phase or by recrystallization from an optically active solvent or by an optically active substance which can form a salt with a racemic compound or a derivative such as an ester or amide (in particular their acids and reactive derivatives or alcohols) and the separation of the enantiomers, e.g. The free enantiomer is liberated from the pure diastereomeric salt or derivative by action of a suitable reagent. Commonly used optically active acids are, for example, D- and L-forms of tartaric acid or dibenzoyl tartaric acid, di-o-cresyl tartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid or quinine acid. Optically active alcohols can be, for example, (+) or (-)-menthol and, for example, optically active acyl groups in amides can be (+)- or (-)-menthyloxycarbonyl.
此外，式I的化合物可转化为其盐，尤其是转化为与无机酸或有机酸形成的医药用途的生理学上可接受的盐。可用于此目的的酸包括(例如)盐酸、氢溴酸、硫酸、甲磺酸、磷酸、富马酸、琥珀酸、乳酸、柠檬酸、酒石酸或马来酸。Furthermore, the compounds of the formula I can be converted into their salts, especially into pharmaceutically acceptable physiologically acceptable salts with inorganic or organic acids. Acids that can be used for this purpose include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methanesulfonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
此外，所获得的化合物可转化为混合物，例如与氨基酸，尤其是与例如脯氨酸或苯丙氨酸的α-氨基酸形成的1:1或1:2混合物，这些氨基酸可具有尤其有利的特性，例如高结晶度。Furthermore, the compounds obtained can be converted into mixtures, for example 1:1 or 1:2 with amino acids, especially with alpha-amino acids such as proline or phenylalanine, which can have particularly favorable properties , such as high crystallinity.
也可使用下述实例中所述的方法有利地获得本发明的化合物，这些方法也可为此目的与本领域技术人员从文献中已知的方法(例如WO98/31697、WO 01/27128、WO 02/083066、WO 03/099836及WO 2004/063209中所述的方法)组合。The compounds of the invention can also be advantageously obtained using the methods described in the examples below, which can also be combined for this purpose with methods known to the person skilled in the art from the literature (e.g. WO98/31697, WO 01/27128, WO 98/31697, WO 01/27128, WO 02/083066, WO 03/099836 and WO 2004/063209) in combination.
本发明也涉及如上文的反应流程中所述及如下文的实验部分中所述的新颖中间化合物。The present invention also relates to novel intermediate compounds as described in the reaction schemes above and as described in the experimental section below.
具体地，下列中间化合物为本发明的其他方面：Specifically, the following intermediate compounds are other aspects of the present invention:
其中in
R8a至R8d如上文所定义且优选地表示H或乙酰基；R8a to R8d are as defined above and preferably represent H or acetyl;
R’如上文所定义且优选地表示H、甲基或乙基；R' is as defined above and preferably represents H, methyl or ethyl;
Alk表示C1-4烷基，优选地表示甲基或乙基；Alk represents C1-4 alkyl, preferably represents methyl or ethyl;
R1如上文所定义且优选地表示Br或CN，最优选表示CN；R1 is as defined above and preferably represents Br or CN, most preferably represents CN;
R3如上文所定义，例如环丙基或环丁基，且优选地是选自由氯、溴、甲基、乙基、正丙基、异丙基、环丙基、环丁基、环戊基、羟基、氰基、(S)-四氢呋喃-3-基氧基、(R)-四氢呋喃-3-基氧基、C3-7环烷基-氧基、C1-3烷氧基、羟基；R is as defined above, for example cyclopropyl or cyclobutyl, and is preferably selected from chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl Base, hydroxyl, cyano, (S)-tetrahydrofuran-3-yloxy, (R)-tetrahydrofuran-3-yloxy, C3-7 cycloalkyl-oxyl, C1-3 alkoxy, Hydroxy;
LG表示离去基例如Br、I、-O-(SO2)-CF3，优选地表示-O-(SO2)-CF3；LG represents a leaving group such as Br, I, -O-(SO2 )-CF3 , preferably represents -O-(SO2 )-CF3 ;
U表示Cl、Br、I、-O-CO-C1-4烷基、-O-C(＝O)-O-C1-4烷基或-OPO(O-C1-4烷基)2；优选地表示Br。U represents Cl, Br, I, -O-CO-C1-4 alkyl, -OC(=O)-OC1-4 alkyl or -OPO(OC1-4 alkyl)2 ; preferably represents Br .
如已提及的，本发明的通式I的化合物及其生理学上可接受的盐具有有价值的药理学特性，尤其是对钠依赖性葡萄糖协同转运蛋白SGLT(优选地为SGLT2)的抑制作用。As already mentioned, the compounds of the general formula I according to the invention and their physiologically acceptable salts have valuable pharmacological properties, especially the inhibitory effect on the sodium-dependent glucose cotransporter SGLT, preferably SGLT2 .
新颖化合物的生物学特性可如下研究：The biological properties of novel compounds can be studied as follows:
可在测试装置中证明这些物质抑制SGLT-2活性的能力，该测试装置中具有CHO-K1细胞株(ATCC号CCL-61)或HEK293细胞株(ATCC号CRL-1573)，所述细胞株被稳定转染表达载体pZeoSV(Invitrogen，EMBL寄存编号L36849)，所述细胞株含有编码人类钠葡萄糖协同转运蛋白2(Genbank Acc.号NM_003041)(CHO-hSGLT2或HEK-hSGLT2)的序列的cDNA。这些细胞株以钠依赖方式将14C-标记的α-甲基-吡喃型葡萄糖苷(14C-AMG，Amersham)转运至细胞内部。The ability of these substances to inhibit the activity of SGLT-2 can be demonstrated in a test device with CHO-K1 cell line (ATCC No. CCL-61) or HEK293 cell line (ATCC No. CRL-1573), which is tested by The expression vector pZeoSV (Invitrogen, EMBL accession number L36849) was stably transfected, and the cell line contained the cDNA encoding the sequence of human sodium glucose cotransporter 2 (Genbank Acc. No. NM_003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport14 C-labeled α-methyl-glucopyranoside (14 C-AMG, Amersham) into the cell interior in a sodium-dependent manner.
SGLT-2实验如下进行：The SGLT-2 experiment was performed as follows:
CHO-hSGLT2细胞在含有10％胎牛血清及250μg/mL Zeocin(Invitrogen)的Ham’s F12培养基(BioWhittaker)中培养，且将HEK293-hSGLT2细胞培养于含有10％胎牛血清及250μg/mL Zeocin(Invitrogen)的DMEM培养基中。通过以PBS洗涤2次且随后以胰蛋白酶/EDTA处理将细胞从培养烧瓶分离。添加细胞培养基后，将细胞离心，再悬于培养基中且在Casy细胞计数器中计数。将每孔40,000个细胞接种于经聚-D-赖氨酸涂布的白色96孔板中且在37℃、5％CO2下孵育过夜。将细胞以250μl实验缓冲液(Hanks平衡盐溶液(Hanks Balanced Salt Solution)，137mM的NaCl、5.4mM的KCl、2.8mM的CaCl2、1.2mM的MgSO4及10mM的HEPES(pH7.4)，50μg/mL庆大霉素(Gentamycin))洗涤2次。接着将250μl实验缓冲液及5μl测试化合物添加至各孔且将培养板在培养箱中再孵育15分钟。以5μl10％DMSO作为阴性对照。通过将5μl14C-AMG(0.05μCi)添加至各孔使反应开始。在37℃、5％CO2下培育2小时后，将细胞以250μl PBS(20℃)再次洗涤且接着通过添加25μl的0.1N的NaOH(在37℃下5分钟)使细胞溶解。将200μl的MicroScint20(Packard)添加至各孔且在37℃继续再孵育20分钟。此培育之后，在Topcount(Packard)中使用14C闪烁程式量测所吸收的14C-AMG的放射强度。CHO-hSGLT2 cells were cultured in Ham's F12 medium (BioWhittaker) containing 10% fetal bovine serum and 250 μg/mL Zeocin (Invitrogen), and HEK293-hSGLT2 cells were cultured in 10% fetal bovine serum and 250 μg/mL Zeocin ( Invitrogen) in DMEM medium. Cells were detached from the culture flasks by washing 2 times with PBS followed by trypsin/EDTA treatment. After addition of cell culture medium, cells were centrifuged, resuspended in medium and counted in a Casy cell counter. 40,000 cells per well were seeded in poly-D-lysine coated white 96-well plates and incubated overnight at 37°C, 5%CO2 . Cells were treated with 250 μl of assay buffer (Hanks Balanced Salt Solution (Hanks Balanced Salt Solution), 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2 , 1.2 mM MgSO4 and 10 mM HEPES (pH 7.4), 50 μg /mL gentamycin (Gentamycin)) and washed twice. Then 250 μl of assay buffer and 5 μl of test compound were added to each well and the plate was incubated for an additional 15 minutes in the incubator. 5 μl of 10% DMSO was used as a negative control. Reactions were initiated by adding 5 μl14 C-AMG (0.05 μCi) to each well. After incubation for 2 hours at 37°C, 5% CO2 , cells were washed again with 250 μl PBS (20° C.) and then lysed by adding 25 μl of 0.1 N NaOH (5 min at 37° C.). 200 μl of MicroScint20 (Packard) was added to each well and incubation was continued for a further 20 minutes at 37°C. After this incubation, the radioactivity of theabsorbed14C -AMG was measured in Topcount (Packard) usingthe14C scintillation program.
为测定对于人类SGLT1的选择性，建立类似测试，该测试中hSGLT1的cDNA(Genbank Acc.号NM_000343)代替hSGLT2cDNA在CHO-K1或HEK293细胞中表达。To determine selectivity for human SGLT1, a similar assay was set up in which the cDNA of hSGLT1 (Genbank Acc. No. NM_000343) was expressed in CHO-K1 or HEK293 cells instead of hSGLT2 cDNA.
本发明的化合物具有低于1000nM，尤其低于200nM，最优选低于50nM的EC50值。The compounds of the invention haveEC50 values below 1000 nM, especially below 200 nM, most preferably below 50 nM.
考虑到其抑制SGLT活性的能力，本发明的化合物及其相应可药用盐适于治疗及/或预防性治疗所有可通过抑制SGLT活性(尤其为SGLT-2活性)影响的病症或疾病。因此，本发明的化合物尤其适于预防或治疗疾病，尤其为代谢障碍或病症，例如1型及2型糖尿病、糖尿病并发症(例如视网膜病、肾病或神经病、糖尿病足、溃疡、大血管病变)、代谢性酸中毒或酮病、反应性低血糖症、高胰岛素血症(hyperinsulinaemia)、葡萄糖代谢障碍、胰岛素抵抗、代谢综合征、不同起因的血脂异常、动脉粥样硬化及相关疾病、肥胖、高血压、慢性心力衰竭、水肿及高尿酸血症。这些物质也适于预防β-细胞退化，例如胰腺β细胞的细胞凋亡或坏死。这些物质也适于改善或恢复胰腺细胞的功能性，且也增加胰腺β细胞的数量及大小。本发明的化合物也可用作利尿剂或抗高血压剂，且适于预防及治疗急性肾衰竭。In view of their ability to inhibit SGLT activity, the compounds of the invention and their corresponding pharmaceutically acceptable salts are suitable for the therapeutic and/or prophylactic treatment of all disorders or diseases which can be affected by inhibition of SGLT activity, especially SGLT-2 activity. The compounds according to the invention are therefore particularly suitable for the prophylaxis or treatment of diseases, especially metabolic disorders or conditions, such as type 1 and type 2 diabetes mellitus, diabetic complications (e.g. retinopathy, nephropathy or neuropathy, diabetic foot, ulcers, macrovascular disease) , metabolic acidosis or ketosis, reactive hypoglycemia, hyperinsulinaemia (hyperinsulinaemia), glucose metabolism disorders, insulin resistance, metabolic syndrome, dyslipidemia of different origins, atherosclerosis and related diseases, obesity, Hypertension, chronic heart failure, edema and hyperuricemia. These substances are also suitable for preventing β-cell degeneration, eg apoptosis or necrosis of pancreatic β-cells. These substances are also suitable for improving or restoring the functionality of pancreatic cells and also increasing the number and size of pancreatic beta cells. The compounds of the invention are also useful as diuretics or antihypertensive agents and are suitable for the prevention and treatment of acute renal failure.
通过给药本发明的化合物，可降低或抑制脂肪在肝脏中异常积累。因此，根据本发明的另一方面，提供一种用于预防、减缓、延迟或治疗由于有此需要的患者体内肝脏脂肪异常积累而导致的疾病或病症的方法，该方法的特征在于给药本发明的化合物或药物组合物。归因于肝脏脂肪的异常积累的疾病或病症尤其选自普通脂肪肝、非酒精性脂肪肝(NAFL)、非酒精性脂肪肝炎(NASH)、营养过度诱导的脂肪肝、糖尿病脂肪肝、酒精诱导的脂肪肝或中毒脂肪肝。Abnormal accumulation of fat in the liver can be reduced or inhibited by administering the compound of the present invention. Therefore, according to another aspect of the present invention, there is provided a method for preventing, slowing down, delaying or treating a disease or condition caused by abnormal accumulation of liver fat in a patient in need thereof, the method is characterized in that administering this Invented compound or pharmaceutical composition. The disease or condition attributable to abnormal accumulation of fat in the liver is especially selected from fatty liver common, non-alcoholic fatty liver (NAFL), non-alcoholic steatohepatitis (NASH), fatty liver induced by overnutrition, diabetic fatty liver, alcohol-induced fatty liver Fatty liver or toxic fatty liver.
具体地，本发明的化合物，包括其生理学上可接受的盐，适于预防或治疗糖尿病，尤其为1型及2型糖尿病及/或糖尿病并发症。In particular, the compounds according to the invention, including their physiologically acceptable salts, are suitable for the prophylaxis or treatment of diabetes, especially type 1 and type 2 diabetes and/or diabetic complications.
此外，本发明的化合物尤其适于预防或治疗超重、肥胖(包括I级、II级及/或III级肥胖)、内脏肥胖及/或腹部肥胖。Furthermore, the compounds according to the invention are especially suitable for the prevention or treatment of overweight, obesity (including class I, II and/or class III obesity), visceral obesity and/or abdominal obesity.
实现治疗或预防相应活性所需的剂量通常取决于给药的化合物、患者、疾病或病症的性质及严重程度及给药方法及频率，且由患者的医生决定。有利地，通过静脉内途径剂量可为1至100mg，优选地为1至30mg，且通过口服途径为1至1000mg，优选地为1至100mg，各情况中每日给药1至4次。为此目的，可任选地与其他活性物质，与一或多种惰性常规载体及/或稀释剂，例如与玉米淀粉、乳糖、葡萄糖、微晶纤维素、硬脂酸镁、聚乙烯吡咯烷酮、柠檬酸、酒石酸、水、水/乙醇、水/甘油、水/山梨糖醇、水/聚乙二醇、丙二醇、鲸蜡硬脂醇、羧甲基纤维素或例如硬脂的脂肪物质或其合适混合物一起来配制本发明的化合物，以产生常规盖伦(galenic)制剂，例如普通或包衣片剂、胶囊、粉末剂、混悬剂或栓剂。Dosages necessary to achieve therapeutic or prophylactic activity will generally depend on the compound being administered, the patient, the nature and severity of the disease or condition and the method and frequency of administration, and will be at the discretion of the patient's physician. Advantageously, the dosage may be from 1 to 100 mg, preferably from 1 to 30 mg, by the intravenous route, and from 1 to 1000 mg, preferably from 1 to 100 mg, by the oral route, administered in each case 1 to 4 times daily. For this purpose, it may optionally be mixed with other active substances, with one or more inert conventional carriers and/or diluents, for example with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, Citric acid, tartaric acid, water, water/ethanol, water/glycerin, water/sorbitol, water/polyethylene glycol, propylene glycol, cetearyl alcohol, carboxymethylcellulose or fatty substances such as stearin or Suitable mixtures are used together to formulate the compounds of the invention to give customary galenic formulations, eg plain or coated tablets, capsules, powders, suspensions or suppositories.
本发明的化合物也可与其他活性物质结合使用，尤其用于治疗及/或预防上述疾病或病症。适于这些组合的其他活性物质包括(例如)那些加强本发明的SGLT拮抗剂对于已提及适应症之一的治疗作用及/或使本发明的SGLT拮抗剂的剂量得以降低的活性物质。适于此组合的治疗剂包括(例如)抗糖尿病剂，例如二甲双胍、磺脲类(例如格列本脲(glibenclamide)、甲苯磺丁脲(tolbutamide)、格列美脲(glimepiride))、那格列奈(nateglinide)、瑞格列奈(repaglinide)、噻唑烷二酮(例如罗格列酮(rosiglitazone)、吡格列酮(pioglitazone))、PPAR-γ-激动剂(例如GI 262570)及拮抗剂、PPAR-γ/α调节剂(例如KRP 297)、α-葡糖苷酶抑制剂(例如阿卡波糖(acarbose)、伏格列波糖(voglibose))、DPPIV抑制剂(例如LAF237、MK-431)、α2-拮抗剂、胰岛素及胰岛素类似物、GLP-1及GLP-1类似物(例如艾生丁-4(exendin-4))或糊精(amylin)。目录也包括蛋白酪氨酸磷酸酶1抑制剂，其为影响去调节(deregulated)葡萄糖在肝脏中产生的物质，例如葡萄糖-6-磷酸酶或果糖-1，6-双磷酸酶、磷酸酯葡糖基转移酶抑制剂；胰高血糖素(glucagon)受体拮抗剂及磷酸烯醇丙酮酸羧基激酶抑制剂、糖原合成酶激酶抑制剂或丙酮酸脱氢激酶抑制剂；降脂剂，例如HMG-CoA还原酶抑制剂(例如辛伐他汀(simvastatin)、阿托伐他汀(atorvastatin))；贝特类(fibrates)(例如苯札贝特(bezafibrate)、非诺贝特(fenofibrate))；烟酸及其衍生物；PPAR-α激动剂；PPAR-δ激动剂；ACAT抑制剂(例如阿伐麦布(avasimibe))或例如依泽替米贝(ezetimibe)的胆固醇吸收抑制剂；例如消胆胺(cholestyramine)的胆汁酸结合物质；回肠胆汁酸转运抑制剂；HDL升高化合物，例如CETP抑制剂或ABC1调节剂；或治疗肥胖的活性物质，例如西布曲明(sibutramine)或四氢洛扑他汀(tetrahydrolipostatin)、右芬氟拉明(dexfenfluramine)、阿索开(axokine)；大麻碱1受体拮抗剂；MCH-1受体拮抗剂；MC4受体激动剂；NPY5或NPY2拮抗剂；或β3-激动剂，例如SB-418790或AD-9677及5HT2c受体激动剂。The compounds according to the invention can also be used in combination with other active substances, especially for the treatment and/or prophylaxis of the diseases or conditions mentioned above. Further active substances suitable for these combinations include, for example, those active substances which potentiate the therapeutic action of the SGLT antagonists according to the invention for one of the indications already mentioned and/or which allow the dosage of the SGLT antagonists according to the invention to be reduced. Therapeutic agents suitable for this combination include, for example, antidiabetic agents such as metformin, sulfonylureas (such as glibenclamide, tolbutamide, glimepiride), nagrate Nateglinide, repaglinide, thiazolidinediones (eg, rosiglitazone, pioglitazone), PPAR-gamma-agonists (eg, GI 262570) and antagonists, PPAR - Gamma/alpha modulators (eg KRP 297), alpha-glucosidase inhibitors (eg acarbose, voglibose), DPPIV inhibitors (eg LAF237, MK-431) , α2-antagonists, insulin and insulin analogs, GLP-1 and GLP-1 analogs (eg exendin-4) or amylin. The list also includes inhibitors of protein tyrosine phosphatase 1, which are substances that affect the production of deregulated glucose in the liver, such as glucose-6-phosphatase or fructose-1,6-bisphosphatase, phosphoglucose Glycosyltransferase inhibitors; glucagon receptor antagonists and inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrogenase; lipid-lowering agents such as HMG-CoA reductase inhibitors (eg, simvastatin, atorvastatin); fibrates (eg, bezafibrate, fenofibrate); Niacin and its derivatives; PPAR-alpha agonists; PPAR-delta agonists; ACAT inhibitors (such as avasimibe) or cholesterol absorption inhibitors such as ezetimibe; Bile acid-binding substances of cholestyramine; inhibitors of ileal bile acid transport; HDL-elevating compounds such as CETP inhibitors or ABC1 modulators; or active substances for the treatment of obesity such as sibutramine or tetrahydro Lopastatin (tetrahydrolipostatin), dexfenfluramine, axokine; cannabinoid 1 receptor antagonists; MCH-1 receptor antagonists; MC4 receptor agonists; NPY5 or NPY2 antagonists or beta3-agonists such as SB-418790 or AD-9677 and 5HT2c receptor agonists.
此外，与用于影响高血压、慢性心力衰竭或动脉粥样硬化的药物(例如A-II拮抗剂或ACE抑制剂、ECE抑制剂、利尿剂、β-阻断剂、Ca-拮抗剂、中枢作用抗高血压剂、α-2-肾上腺素受体拮抗剂、中性肽链内切酶抑制剂、血小板凝集抑制剂及其他药物或其组合)组合也是合适的。血管收缩素II受体拮抗剂的实例为坎地沙坦酯(candesartan cilexetil)、氯沙坦钾(potassiumlosartan)、甲磺酸依普罗沙坦(eprosartan mesylate)、缬沙坦(valsartan)、替米沙坦(telmisartan)、伊贝沙坦(irbesartan)、EXP-3174、L-158809、EXP-3312、奥美沙坦酯(olmesartan)、medoxomil、他索沙坦(tasosartan)、KT-3-671、GA-0113、RU-64276、EMD-90423、BR-9701等。血管收缩素II受体拮抗剂优选地用于治疗或预防高血压及糖尿病并发症，通常与例如氢氯噻嗪(hydrochlorothiazide)的利尿剂组合。In addition, with drugs used to affect hypertension, chronic heart failure, or atherosclerosis (eg, A-II antagonists or ACE inhibitors, ECE inhibitors, diuretics, beta-blockers, Ca-antagonists, CNS Antihypertensive agents, alpha-2-adrenoceptor antagonists, neutral endopeptidase inhibitors, platelet aggregation inhibitors and other drugs or combinations thereof) are also suitable. Examples of angiotensin II receptor antagonists are candesartan cilexetil, potassium losartan, eprosartan mesylate, valsartan, tilmet telmisartan, irbesartan, EXP-3174, L-158809, EXP-3312, olmesartan medoxomil, medoxomil, tasosartan, KT-3-671, GA-0113, RU-64276, EMD-90423, BR-9701, etc. Angiotensin II receptor antagonists are preferably used in the treatment or prevention of hypertension and diabetic complications, usually in combination with diuretics such as hydrochlorothiazide.
与尿酸合成抑制剂或排尿酸剂(uricosuric)的组合适于治疗或预防痛风。Combinations with uric acid synthesis inhibitors or uricosuric agents are suitable for the treatment or prophylaxis of gout.
与GABA-受体拮抗剂、Na-通道阻断剂、托吡酯(topiramat)、蛋白激酶C抑制剂、晚期糖基化终末化产物抑制剂或醛醣还原酶抑制剂的组合可用于治疗或预防糖尿病并发症。Combinations with GABA-receptor antagonists, Na-channel blockers, topiramate (topiramat), protein kinase C inhibitors, advanced glycation end product inhibitors or aldose reductase inhibitors can be used for treatment or prophylaxis Complications of diabetes.
有用的上述组合搭配物的剂量为通常所推荐的最低剂量的1/5直至通常所推荐剂量的1/1。Useful dosages of the above combination partners are 1/5 of the lowest usual recommended dosage up to 1/1 of the usual recommended dosage.
因此，在另一方面中，本发明涉及与至少一种作为组合搭配物的上述活性物质组合的本发明的化合物或此化合物的生理学上可接受的盐在制备适于治疗或预防可通过抑制钠依赖性葡萄糖协同转运蛋白SGLT影响的疾病或病症的药物组合物中的用途。这些疾病优选地为代谢疾病，尤其是上文所列疾病或病症之一，更尤其是糖尿病或糖尿病并发症。Thus, in a further aspect, the present invention relates to a compound according to the invention or a physiologically acceptable salt of this compound in combination with at least one of the above-mentioned active substances as a combination partner in the preparation of a compound suitable for the treatment or prophylaxis of sodium Use in a pharmaceutical composition for a disease or condition affected by the dependent glucose cotransporter SGLT. These diseases are preferably metabolic diseases, especially one of the diseases or conditions listed above, more especially diabetes or diabetic complications.
与另一活性物质组合使用本发明的化合物或其生理学上可接受的盐可同时或在交错时间发生，但尤其在短的时间间隔内发生。若同时给药，则将两种活性物质一起给予患者；而若在交错时间使用，则在小于或等于12小时，但尤其在小于或等于6小时的时间内将两种活性物质给予患者。The use of a compound according to the invention or a physiologically acceptable salt thereof in combination with another active substance can take place simultaneously or at staggered times, but especially within short time intervals. If administered simultaneously, the two active substances are administered to the patient together; and if administered at staggered times, the two active substances are administered to the patient within a period of less than or equal to 12 hours, but especially within a period of less than or equal to 6 hours.
因此，在另一方面中，本发明涉及药物组合物，其包含本发明的化合物或此化合物的生理学上可接受的盐及至少一种作为混合搭配物的上述活性物质，任选地连同一或多种惰性载体及/或稀释剂。Therefore, in a further aspect, the present invention relates to a pharmaceutical composition comprising a compound according to the invention or a physiologically acceptable salt of this compound and at least one of the above-mentioned active substances as a mixing partner, optionally together with one or Various inert carriers and/or diluents.
因此，例如，本发明的药物组合物包含本发明的化合物或此化合物的生理学上可接受的盐及至少一种血管收缩素II受体拮抗剂任选地与一或多种惰性载体及/或稀释剂的混合。Thus, for example, a pharmaceutical composition according to the invention comprises a compound according to the invention or a physiologically acceptable salt of this compound and at least one angiotensin II receptor antagonist, optionally together with one or more inert carriers and/or Mixing of diluents.
本发明的化合物或其生理学上可接受的盐及待与其组合的其他活性物质可一起存在于一种制剂中，例如片剂或胶囊，或分开地存在于两种相同或不同制剂中，例如作为所谓的部件试剂盒(kit-of-parts)。The compounds according to the invention or their physiologically acceptable salts and the other active substances to be combined therewith may be present together in one preparation, for example tablets or capsules, or separately in two identical or different preparations, for example as So-called kit-of-parts.
在上文及下文中，各情况下结构式中未明确表示羟基的H原子。下述实施例意欲说明本发明而不限制本发明。术语“室温”及“周围温度”可替换使用且表示约20℃的温度。Above and below, the H atom of the hydroxyl group is not explicitly represented in each case in the formula. The following examples are intended to illustrate the invention without limiting it. The terms "room temperature" and "ambient temperature" are used interchangeably and mean a temperature of about 20°C.
起始化合物的制备：Preparation of starting compounds:
实施例IExample I
4-溴-3-羟基甲基-1-碘-苯4-Bromo-3-hydroxymethyl-1-iodo-benzene
将草酰氯(13.0mL)添加至2-溴-5-碘-苯甲酸于CH2Cl2(200mL)中的冰冷溶液中。添加DMF(0.2mL)且将溶液在室温下搅拌6小时。接着将溶液在减压下浓缩且将残余物溶解于THF(100mL)中。将所得溶液在冰浴中冷却且分多份添加LiBH4(3.4g)。撤去冷却浴且将混合物在室温下搅拌1小时。将反应混合物以THF稀释且以0.1M盐酸处理。接着将有机层分离且将水层以乙酸乙酯萃取。将合并的有机层干燥(Na2SO4)且将溶剂在减压下蒸发以产生粗产物。Oxalyl chloride (13.0 mL) was added to an ice-cold solution of 2-bromo-5-iodo-benzoic acid inCH2Cl2 (200mL ). DMF (0.2 mL) was added and the solution was stirred at room temperature for 6 hours. The solution was then concentrated under reduced pressure and the residue was dissolved in THF (100 mL). The resulting solution was cooled in an ice bath and LiBH4 (3.4 g) was added in portions. The cooling bath was removed and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with THF and treated with 0.1M hydrochloric acid. Then the organic layer was separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried (Na2 SO4 ) and the solvent was evaporated under reduced pressure to yield the crude product.
产量：47.0g(理论值的99％)Yield: 47.0 g (99% of theory)
实施例IIExample II
4-溴-3-氯甲基-1-碘-苯4-Bromo-3-chloromethyl-1-iodo-benzene
将亚硫酰氯(13mL)添加至4-溴-3-羟基甲基-1-碘-苯(47.0g)于含有DMF(0.1mL)的二氯甲烷(100mL)中的悬浮液中。将混合物在周围温度下搅拌3小时。接着在减压下去除溶剂及过量试剂。将残余物以甲醇研磨且干燥。Thionyl chloride (13 mL) was added to a suspension of 4-bromo-3-hydroxymethyl-1-iodo-benzene (47.0 g) in dichloromethane (100 mL) containing DMF (0.1 mL). The mixture was stirred at ambient temperature for 3 hours. The solvent and excess reagents were then removed under reduced pressure. The residue was triturated with methanol and dried.
产量：41.0g(理论值的82％)Yield: 41.0 g (82% of theory)
实施例IIIExample III
4-溴-1-碘-3-苯氧基甲基-苯4-Bromo-1-iodo-3-phenoxymethyl-benzene
将溶解于4M的KOH溶液(60mL)中的苯酚(13g)添加至溶解于丙酮(50mL)中的4-溴-3-氯甲基-1-碘-苯(41.0g)中。添加NaI(0.5g)且将所得混合物在50℃下搅拌过夜。接着添加水且所得混合物以乙酸乙酯萃取。将合并的萃取液干燥且将溶剂在减压下蒸发。通过色谱法在硅胶(环己烷/乙酸乙酯19:1)上纯化残余物。Phenol (13 g) dissolved in 4M KOH solution (60 mL) was added to 4-bromo-3-chloromethyl-1-iodo-benzene (41.0 g) dissolved in acetone (50 mL). NaI (0.5 g) was added and the resulting mixture was stirred at 50 °C overnight. Water was then added and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried and the solvent was evaporated under reduced pressure. The residue was purified by chromatography on silica gel (cyclohexane/ethyl acetate 19:1).
产量：38.0g(理论值的79％)Yield: 38.0 g (79% of theory)
实施例IVExample IV
(5-溴-2-氯-苯基)-(4-甲氧基-苯基)-甲酮(5-Bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone
将38.3mL草酰氯及0.8mL二甲基甲酰胺添加至100g的5-溴-2-氯-苯甲酸于500mL二氯甲烷中的混合物中。将反应混合物搅拌14小时，接着过滤且在旋转蒸发器中分离所有挥发性组份。将残余物溶解于150mL二氯甲烷中，将所得溶液冷却至-5℃，且添加46.5g苯甲醚。接着逐批添加51.5g三氯化铝以使温度不超过5℃。将溶液在1至5℃下搅拌1小时且接着倾至碎冰上。将有机相分离，且将水相以二氯甲烷萃取。将合并的有机相以1M盐酸洗涤、以1M氢氧化钠洗涤2次且以盐水洗涤。接着将有机相经硫酸钠干燥，将溶剂移除且将残余物从乙醇中重结晶。38.3 mL of oxalyl chloride and 0.8 mL of dimethylformamide were added to a mixture of 100 g of 5-bromo-2-chloro-benzoic acid in 500 mL of dichloromethane. The reaction mixture was stirred for 14 hours, then filtered and all volatile components were separated on a rotary evaporator. The residue was dissolved in 150 mL of dichloromethane, the resulting solution was cooled to -5°C, and 46.5 g of anisole was added. Then 51.5 g of aluminum trichloride were added in batches so that the temperature did not exceed 5°C. The solution was stirred at 1 to 5°C for 1 hour and then poured onto crushed ice. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed with 1M hydrochloric acid, 2 times with 1M sodium hydroxide and with brine. The organic phase is then dried over sodium sulfate, the solvent is removed and the residue is recrystallized from ethanol.
产量：86.3g(理论值的64％)Yield: 86.3 g (64% of theory)
质谱(ESI+)：m/z＝325/327/329(Br+Cl)[M+H]+Mass spectrum (ESI+ ): m/z=325/327/329 (Br+Cl)[M+H]+
实施例VExample V
1-溴-4-氯-3-(4-甲氧基-苄基)-苯1-Bromo-4-chloro-3-(4-methoxy-benzyl)-benzene
将86.2g的(5-溴-2-氯-苯基)-(4-甲氧基-苯基)-甲酮及101.5mL三乙基甲硅烷于75mL二氯甲烷及150mL乙腈中的溶液冷却至10℃。接着在搅拌下添加50.8mL醚合三氟化硼以使温度不超过20℃。将溶液在周围温度下搅拌14小时，之后再添加9mL三乙基甲硅烷及4.4mL醚合三氟化硼。将溶液在45-50℃下再搅拌3小时的时间且接着冷却至周围温度。添加28g氢氧化钾于70mL水中的溶液且将所得混合物搅拌2小时。将有机相分离且将水相以二异丙基醚再萃取3次。将合并的有机相以2M氢氧化钾溶液洗涤2次且以盐水洗涤1次且接着经硫酸钠干燥。蒸发溶剂之后，将残余物以乙醇洗涤且在60℃下干燥。A solution of 86.2 g of (5-bromo-2-chloro-phenyl)-(4-methoxy-phenyl)-methanone and 101.5 mL of triethylsilane in 75 mL of dichloromethane and 150 mL of acetonitrile was cooled to 10°C. Then 50.8 mL of boron trifluoride etherate was added with stirring so that the temperature did not exceed 20 °C. The solution was stirred at ambient temperature for 14 hours after which an additional 9 mL of triethylsilane and 4.4 mL of boron trifluoride etherate were added. The solution was stirred at 45-50 °C for a further period of 3 hours and then cooled to ambient temperature. A solution of 28 g potassium hydroxide in 70 mL water was added and the resulting mixture was stirred for 2 hours. The organic phase was separated and the aqueous phase was extracted 3 more times with diisopropyl ether. The combined organic phases were washed twice with 2M potassium hydroxide solution and once with brine and then dried over sodium sulfate. After evaporation of the solvent, the residue was washed with ethanol and dried at 60°C.
产量：50.0g(理论值的61％)Yield: 50.0g (61% of theoretical value)
质谱(ESI+)：m/z＝310/312/314(Br+Cl)[M+H]+Mass spectrum (ESI+ ): m/z=310/312/314 (Br+Cl)[M+H]+
实施例VIExample VI
4-(5-溴-2-氯-苄基)-苯酚4-(5-Bromo-2-chloro-benzyl)-phenol
将14.8g的1-溴-4-氯-3-(4-甲氧基-苄基)-苯于150mL二氯甲烷中的溶液在冰浴中冷却。添加50mL三溴化硼于二氯甲烷中的1M溶液且将所得溶液在周围温度下搅拌2小时。接着将溶液再次在冰浴中冷却且逐滴添加饱和碳酸钾水溶液。在周围温度下将混合物以1M盐酸水溶液调节至pH1，将有机相分离且将水相以乙酸乙酯萃取3次。将合并的有机相经硫酸钠干燥且完全去除溶剂。A solution of 14.8 g of 1-bromo-4-chloro-3-(4-methoxy-benzyl)-benzene in 150 mL of dichloromethane was cooled in an ice bath. 50 mL of a 1M solution of boron tribromide in dichloromethane was added and the resulting solution was stirred at ambient temperature for 2 hours. The solution was then cooled again in an ice bath and saturated aqueous potassium carbonate was added dropwise. The mixture was adjusted to pH 1 with 1M aqueous hydrochloric acid at ambient temperature, the organic phase was separated and the aqueous phase was extracted 3 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was completely removed.
产量：13.9g(理论值的98％)Yield: 13.9 g (98% of theory)
质谱(ESI-)：m/z＝295/297/299(Br+Cl)[M-H]-Mass Spectrum (ESI− ): m/z=295/297/299 (Br+Cl)[MH]−
实施例VIIExample VII
[4-(5-溴-2-氯-苄基)-苯氧基]-叔丁基-二甲基-甲硅烷[4-(5-Bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane
将13.9g的4-(5-溴-2-氯-苄基)-苯酚于140mL二氯甲烷中的溶液在冰浴中冷却。接着添加于20mL二氯甲烷中的7.54g叔丁基二甲基甲硅烷基氯，随后添加9.8mL三乙胺及0.5g的4-二甲氨基吡啶。将所得溶液在周围温度下搅拌16小时且接着以100mL二氯甲烷稀释。将有机相以1M盐酸水溶液洗涤2次且以碳酸氢钠水溶液洗涤1次且接着经硫酸钠干燥。去除溶剂之后，将残余物经硅胶(环己烷/乙酸乙酯100:1)过滤。A solution of 13.9 g of 4-(5-bromo-2-chloro-benzyl)-phenol in 140 mL of dichloromethane was cooled in an ice bath. Then 7.54 g of tert-butyldimethylsilyl chloride in 20 mL of dichloromethane were added, followed by 9.8 mL of triethylamine and 0.5 g of 4-dimethylaminopyridine. The resulting solution was stirred at ambient temperature for 16 hours and then diluted with 100 mL of dichloromethane. The organic phase was washed twice with 1 M aqueous hydrochloric acid and once with aqueous sodium bicarbonate and then dried over sodium sulfate. After removal of the solvent, the residue was filtered over silica gel (cyclohexane/ethyl acetate 100:1).
产量：16.8g(理论值的87％)Yield: 16.8 g (87% of theory)
质谱(EI)：m/z＝410/412/414(Br+Cl)[M]+Mass spectrum (EI): m/z=410/412/414(Br+Cl)[M]+
实施例VIIIExample VIII
2，3，4，6-四-O-(三甲基甲硅烷基)-D-吡喃型葡萄糖酮(glucopyranone)2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone
将20g的D-葡萄糖酸-1，5-内酯及98.5mL的N-甲基吗啉于200mL四氢呋喃中的溶液冷却至-5℃。接着逐滴添加85mL三甲基甲硅烷基氯以使温度不超过5℃。接着将溶液在周围温度下搅拌1小时，在35℃下搅拌5小时且再次在周围温度下搅拌14小时。添加300mL甲苯之后，将溶液在冰浴中冷却且添加500mL水以使温度不超过10℃。将有机相分离且以磷酸二氢钠水溶液、水及盐水洗涤。将溶剂移除且将残余物以甲苯共沸干燥。A solution of 20 g of D-glucono-1,5-lactone and 98.5 mL of N-methylmorpholine in 200 mL of THF was cooled to -5°C. Then 85 mL of trimethylsilyl chloride was added dropwise so that the temperature did not exceed 5 °C. The solution was then stirred at ambient temperature for 1 hour, at 35°C for 5 hours and again at ambient temperature for 14 hours. After adding 300 mL of toluene, the solution was cooled in an ice bath and 500 mL of water was added so that the temperature did not exceed 10 °C. The organic phase was separated and washed with aqueous sodium dihydrogen phosphate, water and brine. The solvent was removed and the residue was azeotropically dried with toluene.
产量：52.5g(大约90％纯)Yield: 52.5 g (approximately 90% pure)
质谱(ESI+)：m/z＝467[M+H]+Mass spectrum (ESI+ ): m/z=467[M+H]+
实施例IXExample IX
1-溴-4-(1-甲氧基-D-吡喃型葡萄糖-1-基)-2-(苯氧基甲基)-苯1-Bromo-4-(1-methoxy-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
将iPrMgCl于THF(11mL)中的2M溶液添加至悬浮于THF(11mL)中的无水LiCl(0.47g)中。将混合物在室温下搅拌直至所有LiCl溶解。在氩气氛中将此溶液逐滴添加至冷却至-60℃的4-溴-1-碘-3-苯氧基甲基-苯(8.0g)于四氢呋喃(40mL)中的溶液中。将溶液温热至-40℃且接着添加于四氢呋喃(5mL)中的2，3，4，6-四-O-(三甲基甲硅烷基)-D-吡喃型葡萄糖酮(10.7g，90％纯)。将所得溶液在冷却浴中温热至-5℃且在此温度下再搅拌30分钟。添加NH4Cl水溶液且将所得混合物以乙酸乙酯萃取。将合并的有机萃取液经硫酸钠干燥且在减压下去除溶剂。将残余物溶解于甲醇(80mL)中且以甲磺酸(0.6mL)处理。在将反应溶液在35-40℃下搅拌过夜之后，将溶液以固体NaHCO3中和且在减压下移除甲醇。将剩余物以NaHCO3水溶液稀释且将所得混合物以乙酸乙酯萃取。将合并的萃取液经硫酸钠干燥且将溶剂蒸发以产生粗产物，该粗产物未经进一步纯化即进行还原。A 2M solution of iPrMgCl in THF (11 mL) was added to anhydrous LiCl (0.47 g) suspended in THF (11 mL). The mixture was stirred at room temperature until all LiCl was dissolved. This solution was added dropwise to a solution of 4-bromo-1-iodo-3-phenoxymethyl-benzene (8.0 g) in tetrahydrofuran (40 mL) cooled to -60°C under argon atmosphere. The solution was warmed to -40 °C and then 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone (10.7 g, 90% pure). The resulting solution was warmed to -5 °C in a cooling bath and stirred at this temperature for an additional 30 min. AqueousNH4Cl was added and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (80 mL) and treated with methanesulfonic acid (0.6 mL). After the reaction solution was stirred overnight at 35-40 °C, the solution was neutralized with solid NaHCO3 and methanol was removed under reduced pressure. The residue was diluted with aqueous NaHCO3 and the resulting mixture was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was evaporated to give the crude product which was reduced without further purification.
产量：7.8g(理论值的93％)Yield: 7.8 g (93% of theory)
可与实施例IX类似地获得下列化合物：The following compounds can be obtained analogously to Example IX:
(1)1-溴-4-(1-甲氧基-D-吡喃型葡萄糖-1-基)-2-氟-苯(1) 1-bromo-4-(1-methoxy-D-glucopyranose-1-yl)-2-fluoro-benzene
实施例XExample X
1-溴-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-2-(苯氧基甲基)-苯1-Bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene
以将温度维持在低于-10℃的速率将醚合三氟化硼(4.9mL)添加至冷却至-20℃的1-溴-4-(1-甲氧基-D-吡喃型葡萄糖-1-基)-2-(苯氧基甲基)-苯(8.7g)及三乙基甲硅烷(9.1mL)于二氯甲烷(35mL)及乙腈(50mL)中的溶液中。将所得溶液经1.5小时的时间温热至0℃且接着以碳酸氢钠水溶液处理。将所得混合物搅拌0.5小时，移除有机溶剂且将残余物以乙酸乙酯萃取。将合并的有机层经硫酸钠干燥且去除溶剂。将残余物溶解于二氯甲烷(50mL)中且将吡啶(9.4mL)、乙酸酐(9.3mL)及4-二甲氨基吡啶(0.5g)连续添加至溶液中。将溶液在周围温度下搅拌1.5小时且接着以二氯甲烷稀释。将此溶液以1M盐酸洗涤2次且经硫酸钠干燥。去除溶剂后，将残余物从乙醇中重结晶以提供呈无色固体的产物。Boron trifluoride etherate (4.9 mL) was added to 1-bromo-4-(1-methoxy-D-glucopyranose) cooled to -20°C at a rate to maintain the temperature below -10°C A solution of -1-yl)-2-(phenoxymethyl)-benzene (8.7 g) and triethylsilane (9.1 mL) in dichloromethane (35 mL) and acetonitrile (50 mL). The resulting solution was warmed to 0 °C over 1.5 h and then treated with aqueous sodium bicarbonate. The resulting mixture was stirred for 0.5 h, the organic solvent was removed and the residue was extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was removed. The residue was dissolved in dichloromethane (50 mL) and pyridine (9.4 mL), acetic anhydride (9.3 mL) and 4-dimethylaminopyridine (0.5 g) were successively added to the solution. The solution was stirred at ambient temperature for 1.5 hours and then diluted with dichloromethane. This solution was washed twice with 1M hydrochloric acid and dried over sodium sulfate. After removal of the solvent, the residue was recrystallized from ethanol to afford the product as a colorless solid.
产量：6.78g(理论值的60％)Yield: 6.78g (60% of theory)
质谱(ESI+)：m/z＝610/612(Br)[M+NH4]+Mass spectrum (ESI+ ): m/z=610/612(Br)[M+NH4 ]+
可与实施例X类似地获得下列化合物：The following compounds can be obtained analogously to Example X:
(1)1-溴-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-2-氟-苯(1) 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-fluoro-benzene
实施例XIExample XI
2-(苯氧基甲基)-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈2-(phenoxymethyl)-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzonitrile
将以1-溴-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-2-(苯氧基甲基)-苯(5.4g)、氰化锌(1.0g)、锌(30mg)、Pd2(二亚苄基丙酮)3*CHCl3(141mg)及四氟硼酸三叔丁基鏻(111mg)装料的烧瓶以氩气吹扫。接着添加NMP(12mL)且将所得混合物在室温下搅拌18小时。在以乙酸乙酯稀释之后，将混合物过滤且将滤液以碳酸氢钠水溶液洗涤。将有机相干燥(硫酸钠)且去除溶剂。将残余物从乙醇中重结晶。With 1-bromo-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-2-(phenoxymethyl)-benzene (5.4g ), zinc cyanide (1.0 g), zinc (30 mg), Pd2 (dibenzylidene acetone)3* CHCl3 (141 mg) and tri-tert-butylphosphonium tetrafluoroborate (111 mg) charged flask with argon purge. Then NMP (12 mL) was added and the resulting mixture was stirred at room temperature for 18 hours. After dilution with ethyl acetate, the mixture was filtered and the filtrate was washed with aqueous sodium bicarbonate. The organic phase was dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.
产量：4.10g(理论值的84％)Yield: 4.10 g (84% of theory)
质谱(ESI+)：m/z＝557[M+NH4]+Mass spectrum (ESI+ ): m/z=557[M+NH4 ]+
可与实施例XI类似地获得下列化合物：The following compounds can be obtained analogously to Example XI:
(1)2-氟-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈(1) 2-fluoro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzonitrile
实施例XIIExample XII
2-溴甲基-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈2-Bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzonitrile
将氢溴酸于乙酸(15mL)中的33％溶液添加至2-苯氧基甲基-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈(0.71g)及乙酸酐(0.12mL)于乙酸(10ml)中的溶液中。将所得溶液在55℃下搅拌6小时且接着在冰浴中冷却。将反应混合物以冷却碳酸钾水溶液中和，且将所得混合物以乙酸乙酯萃取。将合并的有机萃取液经硫酸钠干燥且在减压下去除溶剂。将残余物溶解于乙酸乙酯/环己烷(1：5)中，且将沉淀通过过滤分离且在50℃下干燥以产生纯产物。A 33% solution of hydrobromic acid in acetic acid (15 mL) was added to 2-phenoxymethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1 -yl)-benzonitrile (0.71 g) and acetic anhydride (0.12 mL) in a solution of acetic acid (10 ml). The resulting solution was stirred at 55 °C for 6 hours and then cooled in an ice bath. The reaction mixture was neutralized with cooled aqueous potassium carbonate, and the resulting mixture was extracted with ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate/cyclohexane (1:5), and the precipitate was isolated by filtration and dried at 50°C to yield pure product.
产量：0.52g(理论值的75％)Yield: 0.52g (75% of theory)
质谱(ESI+)：m/z＝543/545(Br)[M+NH4]+Mass spectrum (ESI+ ): m/z=543/545(Br)[M+NH4 ]+
实施例XIIIExample XIII
1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-(4-羟基苄基)-苯1-Chloro-4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzene
将4.0g的[4-(5-溴-2-氯-苄基)-苯氧基]-叔丁基-二甲基-甲硅烷于42mL无水乙醚中的溶液在氩气下冷却至-80℃。将11.6mL叔丁基锂于戊烷中的冷却(约-50℃)的1.7M溶液缓慢添加至冷却溶液中且接着将溶液在-80℃下搅拌30分钟。接着经以干冰冷却的转移针将此溶液逐滴添加至冷却至-80℃的4.78g2，3，4，6-四-O-(三甲基甲硅烷基)-D-吡喃型葡萄糖酮于38mL乙醚中的溶液中。将所得溶液在-78℃下搅拌3小时。接着添加1.1mL甲磺酸于35mL甲醇中的溶液且将所得反应溶液在周围温度下再搅拌16小时。接着将溶液以固体碳酸氢钠中和，添加乙酸乙酯且将所得溶液在减压下浓缩。将碳酸氢钠水溶液添加至以乙酸乙酯萃取4次的剩余溶液中。将合并的有机相经硫酸钠干燥且蒸发溶剂。将残余物溶解于30mL乙腈及30mL二氯甲烷中且将所得溶液冷却至-10℃。添加4.4mL三乙基甲硅烷后，逐滴添加2.6mL醚合三氟化硼以使温度不超过-5℃。添加完成后，将反应溶液在-5至-10℃下再搅拌5小时且接着通过添加碳酸氢钠水溶液中止。将有机相分离且将水相以乙酸乙酯萃取4次。将合并的有机相经硫酸钠干燥，去除溶剂且通过色谱法在硅胶(二氯甲烷/甲醇)上纯化残余物。由此获得的产物为β/α的约6:1混合物，其可通过以于二氯甲烷中的乙酸酐、吡啶及4-二甲氨基吡啶完全乙酰化羟基且从乙醇中重结晶所得乙酰化产物来分离。通过在甲醇中以4M氢氧化钾溶液移除乙酰基使由此获得的纯乙酰化β-产物转化为标题产物。A solution of 4.0 g of [4-(5-bromo-2-chloro-benzyl)-phenoxy]-tert-butyl-dimethyl-silane in 42 mL of anhydrous ether was cooled under argon to - 80°C. 11.6 mL of a cooled (approximately -50°C) 1.7M solution of tert-butyllithium in pentane was slowly added to the cooled solution and the solution was then stirred at -80°C for 30 minutes. This solution was then added dropwise via a transfer needle cooled with dry ice to 4.78 g of 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone cooled to -80°C In 38mL ether solution. The resulting solution was stirred at -78°C for 3 hours. Then a solution of 1.1 mL of methanesulfonic acid in 35 mL of methanol was added and the resulting reaction solution was stirred at ambient temperature for a further 16 hours. The solution was then neutralized with solid sodium bicarbonate, ethyl acetate was added and the resulting solution was concentrated under reduced pressure. Aqueous sodium bicarbonate solution was added to the remaining solution extracted 4 times with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was evaporated. The residue was dissolved in 30 mL of acetonitrile and 30 mL of dichloromethane and the resulting solution was cooled to -10 °C. After adding 4.4 mL of triethylsilane, 2.6 mL of boron trifluoride etherate was added dropwise so that the temperature did not exceed -5 °C. After the addition was complete, the reaction solution was stirred for an additional 5 hours at -5 to -10°C and then quenched by the addition of aqueous sodium bicarbonate. The organic phase was separated and the aqueous phase was extracted 4 times with ethyl acetate. The combined organic phases are dried over sodium sulfate, the solvent is removed and the residue is purified by chromatography on silica gel (dichloromethane/methanol). The product thus obtained is an approximately 6:1 mixture of β/α, which can be acetylated by complete acetylation of the hydroxyl group with acetic anhydride, pyridine and 4-dimethylaminopyridine in dichloromethane and recrystallization from ethanol. product to separate. The pure acetylated β-product thus obtained was converted to the title product by removal of the acetyl group with 4M potassium hydroxide solution in methanol.
产量：1.6g(理论值的46％)Yield: 1.6 g (46% of theory)
质谱(ESI+)：m/z＝398/400(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=398/400(Cl)[M+NH4 ]+
实施例XIVExample XIV
1-氯-2-(4-环戊氧基苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯1-Chloro-2-(4-cyclopentyloxybenzyl)-4-(β-D-glucopyranose-1-yl)-benzene
将0.16mL碘代环戊烷添加至0.25g的1-氯-4-(β-D-吡喃型葡萄糖-基)-2-(4-羟基苄基)-苯及0.4g碳酸铯于2.5mL二甲基甲酰胺中的混合物中将混合物在45℃下搅拌4小时，之后再添加0.1g碳酸铯及0.05ml碘代环烷。在45℃下再搅拌14小时后，添加氯化钠水溶液且将所得混合物以乙乙酯萃取。将有机相经硫酸钠干燥，去除溶剂且使用硅胶(二氯甲烷/甲1:0->5:1)纯化残余物。Add 0.16 mL of iodocyclopentane to 0.25 g of 1-chloro-4-(β-D-glucopyranose-yl)-2-(4-hydroxybenzyl)-benzene and 0.4 g of cesium carbonate at 2.5 mL of the mixture in dimethylformamide. The mixture was stirred at 45° C. for 4 hours, after which 0.1 g of cesium carbonate and 0.05 ml of iodocycloalkane were added. After stirring for a further 14 hours at 45°C, aqueous sodium chloride solution was added and the resulting mixture was extracted with ethyl ethyl ester. The organic phase was dried over sodium sulfate, the solvent was removed and the residue was purified using silica gel (dichloromethane/methanol 1:0 -> 5:1).
产量：0.23g(理论值的78％)Yield: 0.23g (78% of theory)
质谱(ESI+)：m/z＝466/468(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=466/468(Cl)[M+NH4 ]+
与实施例XIV类似地获得下列化合物：The following compounds were obtained analogously to Example XIV:
(1)1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-((R)-四氢呋喃-3-基氧基)-基]-苯(1) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-yl]-benzene
以(S)-甲苯-4-磺酸四氢呋喃-3-基酯作为偶连搭配物进行反应。The reaction was carried out with (S)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester as the coupling partner.
质谱(ESI+)：m/z＝451/453(Cl)[M+H]+Mass spectrum (ESI+ ): m/z=451/453(Cl)[M+H]+
(2)1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-((S)-四氢呋喃-3-基氧基)-苄基]-苯(2) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene
以(R)-甲苯-4-磺酸四氢呋喃-3-基酯作为偶连搭配物进行反应。The reaction was carried out with (R)-toluene-4-sulfonic acid tetrahydrofuran-3-yl ester as the coupling partner.
质谱(ESI+)：m/z＝451/453(Cl)[M+H]+Mass spectrum (ESI+ ): m/z=451/453(Cl)[M+H]+
(3)1-氯-2-(4-环丁氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯(3) 1-chloro-2-(4-cyclobutoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
质谱(ESI+)：m/z＝452/454(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=452/454(Cl)[M+NH4 ]+
(4)1-氯-2-(4-环己氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯(4) 1-chloro-2-(4-cyclohexyloxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
质谱(ESI+)：m/z＝480/482(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=480/482(Cl)[M+NH4 ]+
(5)1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(四氢呋喃-4-基氧基)-苄基]-苯(5) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4-(tetrahydrofuran-4-yloxy)-benzyl]-benzene
质谱(ESI+)：m/z＝487/489(Cl)[M+Na]+Mass spectrum (ESI+ ): m/z=487/489(Cl)[M+Na]+
(6)2-[4-(1-乙酰基-哌啶-4-基氧基)-苄基]-1-氯-4-(β-D-吡喃型葡萄糖-1-基)-苯(6) 2-[4-(1-acetyl-piperidin-4-yloxy)-benzyl]-1-chloro-4-(β-D-glucopyranose-1-yl)-benzene
以1-乙酰基-4-甲磺酰基氧基-哌啶作为亲电子试剂进行反应。The reaction was carried out with 1-acetyl-4-methanesulfonyloxy-piperidine as the electrophile.
质谱(ESI+)：m/z＝506/508(Cl)[M+H]+Mass spectrum (ESI+ ): m/z=506/508(Cl)[M+H]+
(7)1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲氧基-苄基)-苯(7) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-(4-methoxy-benzyl)-benzene
质谱(ESI+)：m/z＝412/414(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=412/414(Cl)[M+NH4 ]+
(8)1-氯-2-(4-乙氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯(8) 1-chloro-2-(4-ethoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
质谱(ESI+)：m/z＝426/428(Cl)[M+NH4]+Mass Spectrum (ESI+ ): m/z=426/428(Cl)[M+NH4 ]+
(9)1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-(4-异丙氧基-苄基)-苯(9) 1-chloro-4-(β-D-glucopyranose-1-yl)-2-(4-isopropoxy-benzyl)-benzene
实施例XVExample XV
1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯1-Chloro-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethanesulfonyloxy)-benzyl]-benzene
将10mg的4-二甲氨基吡啶添加至0.38g的1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-(4-羟基苄基)-苯、0.21ml三乙胺及0.39g N，N-双-(三氟甲磺酰基)-苯胺于10ml无水二氯甲烷中的溶液中。将溶液在周围温度下搅拌4小时且接着与盐水混合。将所得混合物以乙酸乙酯萃取、将有机萃取液经硫酸钠干燥且去除溶剂。通过色谱法在硅胶(二氯甲烷/甲醇1:0->4:1)纯化残余物。10 mg of 4-dimethylaminopyridine was added to 0.38 g of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-hydroxybenzyl)-benzene, 0.21 ml tris Ethylamine and 0.39g of N,N-bis-(trifluoromethanesulfonyl)-aniline in 10ml of anhydrous dichloromethane solution. The solution was stirred at ambient temperature for 4 hours and then mixed with brine. The resulting mixture was extracted with ethyl acetate, the organic extracts were dried over sodium sulfate and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 4:1).
产量：0.33g(理论值的64％)Yield: 0.33 g (64% of theory)
质谱(ESI+)：m/z＝530/532(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=530/532 (Cl) [M+NH4 ]+
与实施例XV类似地获得下列化合物：The following compounds were obtained analogously to Example XV:
(1)1-氰基-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯(1) 1-cyano-4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethanesulfonyloxy)-benzyl]-benzene
质谱(ESI+)：m/z＝504[M+H]+Mass spectrum (ESI+ ): m/z=504[M+H]+
实施例XVIExample XVI
1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯1-Chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethanesulfonyloxy) -Benzyl]-Benzene
将7mL吡啶、7.8mL乙酸酐及0.12g的4-二甲氨基吡啶相继添加至5.6g的1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基)-苯于75mL二氯甲烷中的溶液中。将溶液在周围温度下搅拌1小时。添加50mL水后，将所得混合物再搅拌5分钟。将有机相分离且以1M盐酸水溶液及碳酸氢钠水溶液洗涤。经硫酸镁干燥且蒸发有机溶剂后，产生呈白色固体的产物。7 mL of pyridine, 7.8 mL of acetic anhydride and 0.12 g of 4-dimethylaminopyridine were successively added to 5.6 g of 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4- (Trifluoromethanesulfonyloxy)-benzyl)-benzene in 75 mL of dichloromethane. The solution was stirred at ambient temperature for 1 hour. After adding 50 mL of water, the resulting mixture was stirred for a further 5 minutes. The organic phase was separated and washed with 1M aqueous hydrochloric acid and aqueous sodium bicarbonate. After drying over magnesium sulfate and evaporation of the organic solvent, the product was obtained as a white solid.
产量:7.0g(理论值的94％)Yield: 7.0g (94% of theory)
质谱(ESI+)：m/z＝698/700(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=698/700(Cl)[M+NH4 ]+
与实施例XVI类似地获得下列化合物：The following compounds were obtained analogously to Example XVI:
(1)1-氰基-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯(1) 1-cyano-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-2-[4-(trifluoromethanesulfonate Acyloxy)-benzyl]-benzene
质谱(ESI+)：m/z＝689[M+NH4]+Mass spectrum (ESI+ ): m/z=689[M+NH4 ]+
实施例XVIIExample XVII
1-氯-2-(4-乙炔基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯1-Chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
在氩气下将25mg碘化铜、44mg双-(三苯基膦)-二氯化钯、0.30ml三乙胺及最终0.14ml三甲基甲硅烷基乙炔添加至0.32g的1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基)-苯于3ml二甲基甲酰胺中的溶液中。将烧瓶紧密地密封且将混合物在90℃下搅拌8小时。接着再添加25mg双-(三苯基膦)-二氯化钯及0.1ml三甲基甲硅烷基乙炔且将溶液在90℃下再搅拌10小时。接着添加碳酸氢钠水溶液，将所得混合物以乙酸乙酯萃取3次，且将合并的有机相经硫酸钠干燥。蒸发溶剂之后，将残余物溶解于5ml甲醇中且与0.12g碳酸钾混合。将混合物在周围温度下搅拌1小时且接着以1M盐酸中和。接着蒸发掉甲醇，将残余物与盐水混合且以乙酸乙酯萃取。将所收集的有机萃取液经硫酸钠干燥，且去除溶剂。通过色谱法在硅胶(二氯甲烷/甲醇1:0->5:1)上纯化残余物。To 0.32 g of 1-chloro- A solution of 4-(β-D-glucopyranose-1-yl)-2-[4-(trifluoromethanesulfonyloxy)-benzyl)-benzene in 3 ml of dimethylformamide. The flask was tightly sealed and the mixture was stirred at 90°C for 8 hours. Then a further 25 mg of bis-(triphenylphosphine)-palladium dichloride and 0.1 ml of trimethylsilylacetylene are added and the solution is stirred at 90° C. for a further 10 hours. Aqueous sodium bicarbonate solution is then added, the resulting mixture is extracted 3 times with ethyl acetate, and the combined organic phases are dried over sodium sulfate. After evaporation of the solvent, the residue was dissolved in 5 ml methanol and mixed with 0.12 g potassium carbonate. The mixture was stirred at ambient temperature for 1 hour and then neutralized with 1M hydrochloric acid. Then methanol was evaporated off, the residue was mixed with brine and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 5:1).
产量：0.095g(理论值的40％)Yield: 0.095g (40% of theoretical value)
质谱(ESI+)：m/z＝406/408(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=406/408(Cl)[M+NH4 ]+
实施例XVIIIExample XVIII
1-氯-2-(4-乙基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯1-Chloro-2-(4-ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene
将2.87g的1-氯-2-(4-乙炔基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯溶解于10ml乙酸乙酯及5ml乙醇中。添加0.3g的10％钯/碳且将所得混合物在氢气氛(1大气压)下搅拌过夜。将反应混合物经硅藻土过滤且将滤液浓缩。通过色谱法在硅胶(二氯甲烷/甲醇1:0->5:1)上纯化残余物。2.87 g of 1-chloro-2-(4-ethynyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzene was dissolved in 10 ml ethyl acetate and 5 ml ethanol. 0.3 g of 10% palladium on carbon was added and the resulting mixture was stirred overnight under a hydrogen atmosphere (1 atm). The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 5:1).
产量：1.0g(理论值的34％)Yield: 1.0 g (34% of theory)
质谱(ESI+)：m/z＝410/412(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=410/412(Cl)[M+NH4 ]+
实施例XIXExample XIX
1-氯-2-[4-((S)-四氢呋喃-3-基氧基)-苄基]-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)苯1-Chloro-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(2,3,4,6-tetra-O-acetyl-β-D-pyridine glucopyranose-1-yl)benzene
将2.5mL吡啶、2.8mL乙酸酐及50mg的4-二甲氨基吡啶相继添加至2.02g的1-氯-4-(β-D-吡喃型葡萄糖-1-基)-2-[4-((S)-四氢呋喃-3-基氧基)-苄基]-苯于20mL二氯甲烷中的溶液中。将反应溶液在周围温度下搅拌4小时。将溶液以50mL二氯甲烷稀释，以50mL的1M盐酸洗涤2次且以碳酸氢钠溶液洗涤1次。经硫酸钠干燥之后，蒸发溶剂以产生产物。2.5 mL of pyridine, 2.8 mL of acetic anhydride and 50 mg of 4-dimethylaminopyridine were successively added to 2.02 g of 1-chloro-4-(β-D-glucopyranose-1-yl)-2-[4- A solution of ((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in 20 mL of dichloromethane. The reaction solution was stirred at ambient temperature for 4 hours. The solution was diluted with 50 mL of dichloromethane, washed twice with 50 mL of 1M hydrochloric acid and once with sodium bicarbonate solution. After drying over sodium sulfate, the solvent was evaporated to yield the product.
产量：2.53g(理论值的91％)Yield: 2.53 g (91% of theory)
质谱(ESI+)：m/z＝642/644(Cl)[M+Na]+Mass spectrum (ESI+ ): m/z=642/644(Cl)[M+Na]+
可与实施例XIX类似地获得下列化合物：The following compounds can be obtained analogously to Example XIX:
(1)1-氯-2-[4-((R)-四氢呋喃-3-基氧基)-苄基]-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(1) 1-Chloro-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(2,3,4,6-tetra-O-acetyl-β- D-glucopyranose-1-yl)-benzene
(2)1-氯-2-(4-环戊氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(2) 1-chloro-2-(4-cyclopentyloxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1- base)-benzene
质谱(ESI+)：m/z＝634/636(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=634/636(Cl)[M+NH4 ]+
(3)1-氯-2-(4-环丁氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(3) 1-chloro-2-(4-cyclobutoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1- base)-benzene
(4)1-氯-2-(4-环己氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(4) 1-chloro-2-(4-cyclohexyloxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1- base)-benzene
(5)1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(四氢呋喃-4-基氧基)-苄基]-苯(5) 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-2-[4-(tetrahydrofuran-4-yl Oxy)-benzyl]-benzene
(6)2-[4-(1-乙酰基-哌啶-4-基氧基)-苄基]-1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(6) 2-[4-(1-acetyl-piperidin-4-yloxy)-benzyl]-1-chloro-4-(2,3,4,6-tetra-O-acetyl- β-D-glucopyranose-1-yl)-benzene
(7)1-氯-2-(4-甲氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(7) 1-chloro-2-(4-methoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl )-benzene
质谱(ESI+)：m/z＝585/587(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=585/587(Cl)[M+NH4 ]+
(8)1-氯-2-(4-乙氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(8) 1-Chloro-2-(4-ethoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl )-benzene
(9)1-氯-2-(4-异丙氧基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(9) 1-chloro-2-(4-isopropoxy-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1- base)-benzene
(10)1-氯-2-(4-乙基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(10) 1-Chloro-2-(4-ethyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl) -benzene
(11)2-(4-乙酰氧基-苄基)-1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯(11) 2-(4-Acetoxy-benzyl)-1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl )-benzene
质谱(ESI+)：m/z＝608/610(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=608/610(Cl)[M+NH4 ]+
实施例XXExample XX
1-氯-2-(4-甲基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯1-Chloro-2-(4-methyl-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-benzene
将氢化二异丁基铝(54μL，于甲苯中的1mol/L)在Ar气氛下添加至1，1’-双(二苯基膦基)二茂铁-二氯化钯(II)(22mg)于THF(3mL)中的混合物中且在冰浴中冷却。将混合物在冰浴中搅拌0.5小时且接着相继添加1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯(0.60g)及Me2Zn(0.88mL，于甲苯中的1mol/L)。撤去冰浴且将混合物在回流下加热2.5小时。冷却至室温后，添加1M盐酸且将所得混合物以乙酸乙酯萃取。将所收集的萃取液经硫酸钠干燥，且去除溶剂。通过色谱法在硅胶(二氯甲烷/甲醇1:0->2:1)上纯化残余物。Diisobutylaluminum hydride (54 μL, 1 mol/L in toluene) was added to 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) chloride (22 mg ) in THF (3 mL) and cooled in an ice bath. The mixture was stirred in an ice bath for 0.5 hours and then 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-2 was added sequentially -[4-(Trifluoromethanesulfonyloxy)-benzyl]-benzene (0.60 g) andMe2Zn (0.88 mL, 1 mol/L in toluene). The ice bath was removed and the mixture was heated at reflux for 2.5 hours. After cooling to room temperature, 1M hydrochloric acid was added and the resulting mixture was extracted with ethyl acetate. The collected extracts were dried over sodium sulfate, and the solvent was removed. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 2:1).
产量：0.25g(理论值的52％)Yield: 0.25g (52% of theory)
实施例XXIExample XXI
1-氯-2-(4-氰基-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯1-Chloro-2-(4-cyano-benzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-benzene
在Ar气氛下将四(三苯基膦)钯(0???)(0.13g)添加至装有1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯(0.80g)及氰化锌(0.14g)的烧瓶中。混合物在100℃下搅拌3小时。冷却至室温后，添加乙酸乙酯且将所得混合物过滤，以NaHCO3水溶液洗涤，干燥(硫酸钠)且去除溶剂。将残余物从乙醇中重结晶。Tetrakis(triphenylphosphine)palladium(0???) (0.13 g) was added to a solution containing 1-chloro-4-(2,3,4,6-tetra-O-acetyl-β -D-Glucopyranos-1-yl)-2-[4-(trifluoromethanesulfonyloxy)-benzyl]-benzene (0.80 g) and zinc cyanide (0.14 g) in a flask. The mixture was stirred at 100°C for 3 hours. After cooling to room temperature, ethyl acetate was added and the resulting mixture was filtered, washed with aqueous NaHCO3 , dried (sodium sulfate) and the solvent was removed. The residue was recrystallized from ethanol.
产量：0.45g(理论值的69％)Yield: 0.45g (69% of theory)
质谱(ESI+)：m/z＝580/582(Cl)[M+Na]+Mass Spectrum (ESI+ ): m/z=580/582(Cl)[M+Na]+
实施例XXIIExample XXII
4-环丙基-苯基硼酸4-Cyclopropyl-phenylboronic acid
将于己烷(14.5mL)中的2.5M正丁基锂逐滴添加至冷却至-70℃的于THF(14mL)及甲苯(50mL)中的1-溴-4-环丙基-苯(5.92g)中。将所得溶液在-70℃下搅拌30分钟，之后添加硼酸三异丙酯(8.5mL)。将溶液温热至-20℃且接着以4M盐酸水溶液(15.5mL)处理。将反应混合物进一步温热至室温且接着将有机相分离。将水相以乙酸乙酯萃取且将合并的有机相干燥(硫酸钠)。将溶剂蒸发且残余物以乙醚与环己烷的混合物洗涤以产生呈无色固体的产物。2.5M n-butyllithium in hexanes (14.5 mL) was added dropwise to 1-bromo-4-cyclopropyl-benzene ( 5.92g). The resulting solution was stirred at -70°C for 30 min, after which triisopropyl borate (8.5 mL) was added. The solution was warmed to -20 °C and then treated with 4M aqueous hydrochloric acid (15.5 mL). The reaction mixture was further warmed to room temperature and then the organic phase was separated. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried (sodium sulfate). The solvent was evaporated and the residue was washed with a mixture of diethyl ether and cyclohexane to give the product as a colorless solid.
产量：2.92g(理论值的60％)Yield: 2.92g (60% of theory)
质谱(ESI-)：m/z＝207(Cl)[M+HCOO]-Mass Spectrum (ESI- ): m/z=207(Cl)[M+HCOO]-
可与实施例XXII类似地获得下列化合物：The following compounds can be obtained analogously to Example XXII:
(1)4-二氟甲氧基-苯基硼酸(1) 4-Difluoromethoxy-phenylboronic acid
质谱(ESI-)：m/z＝233(Cl)[M+HCOO]-Mass Spectrum (ESI- ): m/z=233(Cl)[M+HCOO]-
与上述过程不同，该化合物使用iPrMgCl从4-二氟甲氧基-1-碘-苯制备以产生芳基金属化合物且以硼酸三甲酯捕获此中间体。Unlike the procedure described above, this compound was prepared from 4-difluoromethoxy-1-iodo-benzene using iPrMgCl to yield the aryl metal compound and this intermediate was captured with trimethyl borate.
(2)4-二氟甲氧基-苯基硼酸(2) 4-Difluoromethoxy-phenylboronic acid
质谱(ESI+)：m/z＝172(Cl)[M+H]+Mass Spectrum (ESI+ ): m/z=172(Cl)[M+H]+
与上述过程不同，该化合物使用iPrMgCl从4-二氟甲基-1-碘-苯(使用于二氯甲烷中的二乙基氨基三氟化硫(DAST)从4-碘代苯甲醛制备)制备以产生芳基金属化合物且以硼酸三甲酯捕获此中间体。Unlike the above procedure, this compound was prepared from 4-difluoromethyl-1-iodo-benzene using iPrMgCl (prepared from 4-iodobenzaldehyde using diethylaminosulfur trifluoride (DAST) in dichloromethane) Prepared to give aryl metal compound and captured this intermediate with trimethyl borate.
实施例XXIIIExample XXIII
1-溴-4-氰基-3-(4-甲氧基-苄基)-苯1-Bromo-4-cyano-3-(4-methoxy-benzyl)-benzene
将25g的(4-甲氧基-苯基)-乙酸乙酯、27.4g1-溴-4-氰基-3-氟-苯及20mL的N-甲基-吡咯烷-2-酮的混合物缓慢添加至保持低于10℃的温度的于130mL的N-甲基-吡咯烷-2-酮中的31.4g叔丁醇钾中。在室温下搅拌1小时后，添加100mL甲醇及137mL的1M氢氧化钠水溶液且将混合物在室温下搅拌过夜。将甲醇部分蒸发，将残余物以1M氢氧化钠水溶液碱化且以叔丁基-甲基醚萃取。将水相以4M盐酸来酸化且以乙酸乙酯萃取数次。将合并的乙酸乙酯萃取液蒸发且将残余物与120mL的N，N-二甲基甲酰胺及24.9g碳酸钾在100℃下加热1小时。将反应混合物以碳酸氢钠水溶液稀释且以乙酸乙酯萃取数次。将合并的萃取液蒸发且将残余物从甲醇中结晶。A mixture of 25g of (4-methoxy-phenyl)-ethyl acetate, 27.4g of 1-bromo-4-cyano-3-fluoro-benzene and 20mL of N-methyl-pyrrolidin-2-one was slowly Add to 31.4 g of potassium tert-butoxide in 130 mL of N-methyl-pyrrolidin-2-one maintaining a temperature below 10°C. After stirring at room temperature for 1 hour, 100 mL of methanol and 137 mL of 1M aqueous sodium hydroxide solution were added and the mixture was stirred at room temperature overnight. The methanol was partially evaporated, the residue was basified with 1M aqueous sodium hydroxide solution and extracted with tert-butyl-methyl ether. The aqueous phase was acidified with 4M hydrochloric acid and extracted several times with ethyl acetate. The combined ethyl acetate extracts were evaporated and the residue was heated at 100° C. for 1 hour with 120 mL of N,N-dimethylformamide and 24.9 g of potassium carbonate. The reaction mixture was diluted with aqueous sodium bicarbonate and extracted several times with ethyl acetate. The combined extracts were evaporated and the residue crystallized from methanol.
产量：13g(理论值的33％)Yield: 13g (33% of theory)
质谱(ESI+)：m/z＝319/321(Br)[M+NH4]+Mass spectrum (ESI+ ): m/z=319/321(Br)[M+NH4 ]+
实施例XXIVExample XXIV
4-环丙基-苯乙酸乙酯4-Cyclopropyl-phenylacetic acid ethyl ester
根据Tetrahedron Lett.2002，43，6987-6990，在甲苯和水中通过过渡金属催化与环丙基硼酸偶连使用四氟硼酸三环己基鏻、乙酸钯、磷酸钾从4-溴-苯乙酸乙酯制备。According to Tetrahedron Lett. 2002, 43, 6987-6990, Transition metal-catalyzed coupling to cyclopropylboronic acid in toluene and water using tricyclohexylphosphonium tetrafluoroborate, palladium acetate, potassium phosphate from 4-bromo-ethyl phenylacetate preparation.
质谱(ESI+)：m/z＝205[M+H]+Mass spectrum (ESI+ ): m/z=205[M+H]+
最终化合物的制备：Preparation of final compound:
实施例1Example 1
4-(β-D-吡喃型葡萄糖-1-基)-2-[4-((S)-四氢呋喃基-3-氧基)-苄基]-苯甲腈4-(β-D-Glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuryl-3-oxyl)-benzyl]-benzonitrile
将1.00g的1-氯-2-[4-((S)-四氢呋喃基-3-氧基)-苄基]-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯、0.16g氰化钠及0.35g溴化镍于2.5mL的N-甲基-2-吡咯烷酮中的混合物在微波炉中在220℃下加热15分钟。冷却至室温后，添加水且将所得混合物以乙酸乙酯萃取。经硫酸钠干燥且蒸发溶剂之后，将残余物溶解于5mL甲醇中。添加4mL的4M氢氧化钾水溶液且将反应溶液在周围温度下搅拌3小时。将溶液以1M盐酸中和且蒸发甲醇。将残余物以乙酸乙酯萃取，将合并的萃取液经硫酸钠干燥且在减压下去除溶剂。通过色谱法在硅胶(二氯甲烷/甲醇4:1)上纯化残余物。1.00 g of 1-chloro-2-[4-((S)-tetrahydrofuryl-3-oxyl)-benzyl]-4-(2,3,4,6-tetra-O-acetyl-β -D-glucopyranose-1-yl)-benzene, a mixture of 0.16g sodium cyanide and 0.35g nickel bromide in 2.5mL of N-methyl-2-pyrrolidone was heated in a microwave oven at 220°C for 15 minute. After cooling to room temperature, water was added and the resulting mixture was extracted with ethyl acetate. After drying over sodium sulfate and evaporation of the solvent, the residue was dissolved in 5 mL of methanol. 4 mL of 4M aqueous potassium hydroxide solution was added and the reaction solution was stirred at ambient temperature for 3 hours. The solution was neutralized with 1M hydrochloric acid and methanol was evaporated. The residue was extracted with ethyl acetate, the combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane/methanol 4:1).
产量：0.35g(理论值的49％)Yield: 0.35g (49% of theory)
质谱(ESI+)：m/z＝442[M+H]+Mass spectrum (ESI+ ): m/z=442[M+H]+
可与实施例1类似地获得下列化合物：The following compounds can be obtained analogously to Example 1:
(2)4-(β-D-吡喃型葡萄糖-1-基)-2-[4-((R)-四氢呋喃-3-基氧基)-苄基]-苯甲腈(2) 4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzonitrile
(3)2-(4-环戊氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(3) 2-(4-cyclopentyloxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
(4)2-(4-环丁氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(4) 2-(4-Cyclobutoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
(5)2-(4-环己氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(5) 2-(4-cyclohexyloxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
(6)2-[4-(四氢呋喃-4-基氧基)-苄基]-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(6) 2-[4-(tetrahydrofuran-4-yloxy)-benzyl]-4-(β-D-glucopyranose-1-yl)-benzonitrile
(7)2-[4-(1-乙酰基-哌啶-4-基氧基)-苄基]-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(7) 2-[4-(1-Acetyl-piperidin-4-yloxy)-benzyl]-4-(β-D-glucopyranose-1-yl)-benzonitrile
(8)2-(4-甲氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(8) 2-(4-Methoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝403[M+NH4]+Mass spectrum (ESI+ ): m/z=403[M+NH4 ]+
除与叔丁基锂的反应在四氢呋喃中在-87℃下进行且与甲醇/甲磺酸的反应在55℃下进行之外，以与实施例XIII类似的方式从1-溴-4-氰基-3-(4-甲氧基苄基)-苯(实施例XXIII)及2，3，4，6-四-O-(三甲基甲硅烷基)-D-吡喃型葡萄糖酮也获得此化合物。From 1-bromo-4-cyano Base-3-(4-methoxybenzyl)-benzene (Example XXIII) and 2,3,4,6-tetra-O-(trimethylsilyl)-D-glucopyranone were also to obtain this compound.
(9)2-(4-乙氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(9) 2-(4-Ethoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝417[M+NH4]+Mass spectrum (ESI+ ): m/z=417[M+NH4 ]+
(10)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-异丙氧基-苄基)-苯甲腈(10) 4-(β-D-glucopyranose-1-yl)-2-(4-isopropoxy-benzyl)-benzonitrile
质谱(ESI+)：m/z＝431[M+NH4]+Mass spectrum (ESI+ ): m/z=431 [M+NH4 ]+
(11)2-(4-乙基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(11) 2-(4-Ethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝401[M+NH4]+Mass spectrum (ESI+ ): m/z=401 [M+NH4 ]+
(12)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-羟基-苄基)-苯甲腈(12) 4-(β-D-glucopyranose-1-yl)-2-(4-hydroxy-benzyl)-benzonitrile
从2-(4-乙酰氧基-苄基)-1-氯-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯制备该化合物。From 2-(4-acetoxy-benzyl)-1-chloro-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)- Benzene produces this compound.
质谱(ESI+)：m/z＝389[M+NH4]+Mass spectrum (ESI+ ): m/z=389[M+NH4 ]+
也可通过全乙酰化2-(4-甲氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(化合物1(8))随后以三溴化硼使醚裂解和脱乙酰化来获得该化合物。It can also be obtained by peracetylation of 2-(4-methoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile (compound 1(8)) followed by tribromo The compound is obtained by cleavage and deacetylation of the ether with boronide.
(13)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲基-苄基)-苯甲腈(13) 4-(β-D-glucopyranose-1-yl)-2-(4-methyl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝387[M+NH4]+Mass spectrum (ESI+ ): m/z=387[M+NH4 ]+
(14)2-(4-氰基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(14) 2-(4-cyano-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝398[M+NH4]+Mass spectrum (ESI+ ): m/z=398[M+NH4 ]+
实施例15Example 15
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲氧基乙氧基-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-methoxyethoxy-benzyl)-benzonitrile
将2-溴乙基甲醚(85μl)添加至4-(β-D-吡喃型葡萄糖-1-基)-2-(4-羟基苄基)-苯甲腈(0.30g)及碳酸铯(0.39g)于3mL二甲基甲酰胺中的混合物中。将混合物在80℃下搅拌16小时，之后添加水及盐水。将所得混合物以乙酸乙酯萃取，将合并的萃取液经硫酸钠干燥且在减压下去除溶剂。通过色谱法在硅胶(二氯甲烷/甲醇1:0->5:1)上纯化残余物。2-Bromoethylmethyl ether (85 μl) was added to 4-(β-D-glucopyranose-1-yl)-2-(4-hydroxybenzyl)-benzonitrile (0.30 g) and cesium carbonate (0.39g) in a mixture in 3mL of dimethylformamide. The mixture was stirred at 80 °C for 16 hours, after which time water and brine were added. The resulting mixture was extracted with ethyl acetate, the combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (dichloromethane/methanol 1:0 -> 5:1).
产量：0.19g(理论值的49％)Yield: 0.19 g (49% of theory)
质谱(ESI+)：m/z＝430[M+H]+Mass spectrum (ESI+ ): m/z=430[M+H]+
实施例16Example 16
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-三氟甲氧基-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethoxy-benzyl)-benzonitrile
将2-溴甲基-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈(0.25g)、4-三氟甲氧基-苯基硼酸(0.20g)、碳酸钾(0.26g)及脱气的丙酮与水的3:1混合物(4mL)装入经Ar填充的烧瓶。将混合物在室温下搅拌5分钟，之后在冰浴中冷却。接着添加二氯化钯(5mg)且将反应混合物在周围温度下搅拌16小时。接着将混合物以盐水稀释且以乙酸乙酯萃取。将合并的萃取液经硫酸钠干燥且在减压下去除溶剂。将残余物溶解于甲醇(9mL)中且以4M氢氧化钾水溶液(1mL)处理。将所得溶液在周围温度下搅拌1小时且接着以1M盐酸中和。将甲醇蒸发，且将残余物以盐水稀释且以乙酸乙酯萃取。将所收集的有机萃取液经硫酸钠干燥，且去除溶剂。将残余物在硅胶(二氯甲烷/甲醇1:0->8:1)上层析。2-Bromomethyl-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzonitrile (0.25g), 4-trifluoroform Oxy-phenylboronic acid (0.20 g), potassium carbonate (0.26 g), and a 3:1 mixture of degassed acetone and water (4 mL) were charged to an Ar-filled flask. The mixture was stirred at room temperature for 5 minutes before cooling in an ice bath. Palladium dichloride (5 mg) was then added and the reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then diluted with brine and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was dissolved in methanol (9 mL) and treated with 4M aqueous potassium hydroxide (1 mL). The resulting solution was stirred at ambient temperature for 1 hour and then neutralized with 1M hydrochloric acid. Methanol was evaporated, and the residue was diluted with brine and extracted with ethyl acetate. The collected organic extracts were dried over sodium sulfate, and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 8:1).
产量：0.145g(理论值的69％)Yield: 0.145 g (69% of theory)
质谱(ESI+)：m/z＝457[M+NH4]+Mass spectrum (ESI+ ): m/z=457[M+NH4 ]+
可与实施例16类似地获得下列化合物：The following compounds can be obtained analogously to Example 16:
(17)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-三氟甲基-苄基)-苯甲腈(17) 4-(β-D-glucopyranose-1-yl)-2-(4-trifluoromethyl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝441[M+NH4]+Mass spectrum (ESI+ ): m/z=441 [M+NH4 ]+
(18)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-异丙基-苄基)-苯甲腈(18) 4-(β-D-glucopyranose-1-yl)-2-(4-isopropyl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝415[M+NH4]+Mass spectrum (ESI+ ): m/z=415[M+NH4 ]+
(19)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-叔丁基-苄基)-苯甲腈(19) 4-(β-D-glucopyranose-1-yl)-2-(4-tert-butyl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝429[M+NH4]+Mass spectrum (ESI+ ): m/z=429[M+NH4 ]+
(20)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-三甲基甲硅烷基-苄基)-苯甲腈(20) 4-(β-D-glucopyranose-1-yl)-2-(4-trimethylsilyl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝445[M+NH4]+Mass spectrum (ESI+ ): m/z=445[M+NH4 ]+
(21)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲硫基-苄基)-苯甲腈(21) 4-(β-D-glucopyranose-1-yl)-2-(4-methylthio-benzyl)-benzonitrile
质谱(ESI+)：m/z＝419[M+NH4]+Mass spectrum (ESI+ ): m/z=419[M+NH4 ]+
(22)4-(β-D-吡喃型葡萄糖-1-基)-2-[4-(3-甲基-丁-1-基)-苄基]-苯甲腈(22) 4-(β-D-glucopyranose-1-yl)-2-[4-(3-methyl-but-1-yl)-benzyl]-benzonitrile
质谱(ESI+)：m/z＝443[M+NH4]+Mass spectrum (ESI+ ): m/z=443[M+NH4 ]+
(23)2-(4-氟-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(23) 2-(4-Fluoro-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝391[M+NH4]+Mass spectrum (ESI+ ): m/z=391 [M+NH4 ]+
(24)2-(4-氯-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(24) 2-(4-Chloro-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝407/409(Cl)[M+NH4]+Mass spectrum (ESI+ ): m/z=407/409(Cl)[M+NH4 ]+
(25)2-(4-二氟甲氧基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(25) 2-(4-Difluoromethoxy-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝439[M+NH4]+Mass spectrum (ESI+ ): m/z=439[M+NH4 ]+
(26)2-(4-二氟甲基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(26) 2-(4-Difluoromethyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝423[M+NH4]+Mass spectrum (ESI+ ): m/z=423[M+NH4 ]+
(27-1)2-(4-环丙基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(27-1) 2-(4-Cyclopropyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝413[M+NH4]+Mass spectrum (ESI+ ): m/z=413[M+NH4 ]+
根据实施例16获得该化合物，其中采用浸提物(XXII)4-环丙基-苯基硼酸代替4-三氟甲氧基-苯基硼酸。The compound was obtained according to Example 16, wherein the extract (XXII) 4-cyclopropyl-phenylboronic acid was used instead of 4-trifluoromethoxy-phenylboronic acid.
也可根据Tetrahedron Lett.2002，43，6987-6990，在甲苯及水中通过过渡金属催化使2-(4-溴-苄基)-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-苯甲腈或1-氰基-4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-[4-(三氟甲磺酰基氧基)-苄基]-苯(化合物XVI(1))与环丙基硼酸偶连使用于四氟硼酸三环己基鏻、乙酸钯、磷酸钾且随后以于甲醇中的KOH使偶连产物脱乙酰化来获得化合物(27)。Also according to Tetrahedron Lett.2002,43,6987-6990, 2-(4-bromo-benzyl)-4-(2,3,4,6-tetra-O-acetyl yl-β-D-glucopyranose-1-yl)-benzonitrile or 1-cyano-4-(2,3,4,6-tetra-O-acetyl-β-D-pyranyl Glucose-1-yl)-2-[4-(trifluoromethanesulfonyloxy)-benzyl]-benzene (compound XVI(1)) coupled with cyclopropylboronic acid for tricyclohexylphosphonium tetrafluoroborate , palladium acetate, potassium phosphate and subsequent deacetylation of the coupling product with KOH in methanol affords compound (27).
也可通过使2-氟-4-(2，3，4，6-四-O-乙酰基-D-吡喃型葡萄糖-1-基)-苯甲腈(化合物XI(1))与4-环丙基-苯乙酸乙酯(化合物XXIV)在碱性条件下反应随后酯水解和脱羧来获得化合物(27)。It can also be obtained by combining 2-fluoro-4-(2,3,4,6-tetra-O-acetyl-D-glucopyranose-1-yl)-benzonitrile (compound XI(1)) with 4 - Cyclopropyl-ethyl phenylacetate (compound XXIV) is reacted under basic conditions followed by ester hydrolysis and decarboxylation to obtain compound (27).
(27-2)2-(4-环丁基-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(27-2) 2-(4-Cyclobutyl-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
根据实施例(27-1)获得该化合物，其中(例如)采用4-环丁基硼酸(可与实施例XXII类似来获得)代替4-环丙基硼酸。The compound is obtained according to Example (27-1), wherein, for example, 4-cyclobutylboronic acid (obtainable analogously to Example XXII) is used instead of 4-cyclopropylboronic acid.
质谱(ESI-)：m/z＝427[M+NH4]+Mass spectrum (ESI- ): m/z=427[M+NH4 ]+
(28)4-(β-D-吡喃型葡萄糖-1-基)-2-(4-丙-1-基-苄基)-苯甲腈(28) 4-(β-D-glucopyranose-1-yl)-2-(4-propan-1-yl-benzyl)-benzonitrile
质谱(ESI+)：m/z＝415[M+NH4]+Mass spectrum (ESI+ ): m/z=415[M+NH4 ]+
实施例29Example 29
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-碘-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-iodo-benzyl)-benzonitrile
将一氯化碘于二氯甲烷(0.9mL)中的1M溶液添加至溶解于二氯甲烷(5mL)中的4-(β-D-吡喃型葡萄糖-1-基)-2-(4-三甲基甲硅烷基-苄基)-苯甲腈(0.26g)中。将溶液在室温下搅拌1小时且接着通过添加Na2S2O3水溶液及NaHCO3水溶液中止。将有机相分离且将水相以乙酸乙酯萃取。将合并的有机相经硫酸钠干燥且去除溶剂。将残余物在硅胶(二氯甲烷/甲醇1:0->8:1)上层析。A 1 M solution of iodine monochloride in dichloromethane (0.9 mL) was added to 4-(β-D-glucopyranose-1-yl)-2-(4 -trimethylsilyl-benzyl)-benzonitrile (0.26g). The solution was stirred at roomtemperature for 1 h and then quenched by the addition of aq.Na2S2O3 and aq.NaHCO3 . The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 8:1).
产量：0.15g(理论值的88％)Yield: 0.15g (88% of theory)
质谱(ESI+)：m/z＝499[M+NH4]+Mass spectrum (ESI+ ): m/z=499[M+NH4 ]+
可与实施例29类似地获得下列化合物：The following compounds can be obtained analogously to Example 29:
(30)2-(4-溴-苄基)-4-(β-D-吡喃型葡萄糖-1-基)-苯甲腈(30) 2-(4-Bromo-benzyl)-4-(β-D-glucopyranose-1-yl)-benzonitrile
质谱(ESI+)：m/z＝451/453[M+NH4]+Mass spectrum (ESI+ ): m/z=451/453 [M+NH4 ]+
根据实施例29的方法使用于二氯甲烷中的溴获得该化合物。This compound was obtained according to the method of Example 29 using bromine in dichloromethane.
实施例31Example 31
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-五氟乙基-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-pentafluoroethyl-benzyl)-benzonitrile
将以4-(2，3，4，6-四-O-乙酰基-β-D-吡喃型葡萄糖-1-基)-2-(4-碘-苄基)-苯甲腈(0.16g)、五氟乙基三甲基甲硅烷(0.14g)、KF(43mg)、Cul???(0.16g)、DMF(2mL)及Ar气氛装料的烧瓶在60℃下加热24小时。接着添加NaHCO3水溶液且将所得混合物以乙酸乙酯萃取。将合并的有机相经硫酸钠干燥且去除溶剂。将残余物溶解于甲醇(8mL)中且以4M的KOH溶液(0.8mL)处理。将溶液在室温下搅拌1小时，且接着以NaHCO3水溶液稀释。在减压下移除甲醇之后，将残余物以乙酸乙酯萃取，将合并的有机萃取液干燥且去除溶剂。将残余物在硅胶(二氯甲烷/甲醇1:0->8:1)上层析。4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranose-1-yl)-2-(4-iodo-benzyl)-benzonitrile (0.16 g), pentafluoroethyltrimethylsilane (0.14 g), KF (43 mg), Cul??? (0.16 g), DMF (2 mL) and a flask charged with an Ar atmosphere was heated at 60° C. for 24 hours. Then aqueous NaHCO3 was added and the resulting mixture was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was dissolved in methanol (8 mL) and treated with 4M KOH solution (0.8 mL). The solution was stirred at room temperature for 1 h, and then diluted with aqueous NaHCO3 . After removal of methanol under reduced pressure, the residue was extracted with ethyl acetate, the combined organic extracts were dried and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 8:1).
产量：0.08g(理论值的69％)Yield: 0.08g (69% of theory)
质谱(ESI+)：m/z＝491[M+NH4]+Mass spectrum (ESI+ ): m/z=491 [M+NH4 ]+
实施例32Example 32
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲基亚磺酰基-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-methylsulfinyl-benzyl)-benzonitrile
将于水(48μL)中的35％过氧化氢添加至于1，1，1，3，3，3-六氟异丙醇(2mL)中的4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲硫基-苄基)-苯甲腈(83mg)中。将所得溶液在周围温度下搅拌1小时且接着通过添加Na2S2O3水溶液及NaHCO3水溶液中止。将有机相分离且将水相以乙酸乙酯萃取。将合并的有机相经硫酸钠干燥且去除溶剂。将残余物在硅胶(二氯甲烷/甲醇1:0->5:1)上层析。35% hydrogen peroxide in water (48 μL) was added to 4-(β-D-glucopyranose-1 in 1,1,1,3,3,3-hexafluoroisopropanol (2 mL) -yl)-2-(4-methylthio-benzyl)-benzonitrile (83mg). The resulting solution was stirred at ambient temperature for 1 h and thenquenched by the addition of aq.Na2S2O3 and aq.NaHCO3 . The organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 5:1).
产量：24mg(理论值的28％)Yield: 24 mg (28% of theory)
质谱(ESI+)：m/z＝418[M+H]+Mass spectrum (ESI+ ): m/z=418[M+H]+
实施例33Example 33
4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲磺酰基-苄基)-苯甲腈4-(β-D-glucopyranose-1-yl)-2-(4-methylsulfonyl-benzyl)-benzonitrile
将3-氯过氧苯甲酸(70％，0.14g)添加至在冰浴中冷却的于二氯甲烷(2mL)中的4-(β-D-吡喃型葡萄糖-1-基)-2-(4-甲硫基-苄基)-苯甲腈(100mg)中。撤去冷却浴且将所得溶液在周围温度下搅拌1小时。添加Na2S2O3水溶液及NaHCO3水溶液之后，将有机相分离且将水相以乙酸乙酯萃取。将合并的有机相经硫酸钠干燥且去除溶剂。将残余物在硅胶(二氯甲烷/甲醇1:0->8:1)上层析。3-Chloroperoxybenzoic acid (70%, 0.14 g) was added to 4-(β-D-glucopyranose-1-yl)-2 in dichloromethane (2 mL) cooled in an ice bath -(4-Methylthio-benzyl)-benzonitrile (100 mg). The cooling bath was removed and the resulting solution was stirred at ambient temperature for 1 hour. After addition of aqueous Na2 S2 O3 and aqueous NaHCO3 , the organic phase was separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and the solvent was removed. The residue was chromatographed on silica gel (dichloromethane/methanol 1:0 -> 8:1).
产量：68mg(理论值的63％)Yield: 68 mg (63% of theory)
质谱(ESI+)：m/z＝451[M+NH4]+Mass spectrum (ESI+ ): m/z=451 [M+NH4 ]+
也可与上述实施例或从文献得知的其他方法类似制备下列化合物。The following compounds can also be prepared analogously to the above examples or other methods known from the literature.
现在将描述一些制剂的实施例，其中术语“活性物质”表示一或多种本发明的化合物，包括其前药或盐。在如前所述与一种其他活性物质组合的情况下，术语“活性物质”亦包括其他活性物质。Some examples of formulations will now be described, wherein the term "active substance" means one or more compounds of the invention, including prodrugs or salts thereof. In the case of combination with one other active substance as described above, the term "active substance" also includes the other active substance.
实施例AExample A
含有100mg活性物质的片剂Tablets containing 100 mg of active substance
组成：composition:
1片剂含有：1 tablet contains:
活性物质 100.0mgActive substance 100.0mg
乳糖 80.0mgLactose 80.0mg
玉米淀粉 34.0mgCorn starch 34.0mg
聚乙烯吡咯烷酮 4.0mgPolyvinylpyrrolidone 4.0mg
硬脂酸镁 2.0mgMagnesium Stearate 2.0mg
220.0mg...
制备方法：Preparation:
将活性物质、乳糖及淀粉混合在一起且以聚乙烯吡咯烷酮水溶液均一湿润。在将湿混合物过筛(2.0mm筛孔大小)且在架型(rack-type)干燥器中在50℃下干燥之后，将其再次过筛(1.5mm筛孔大小)且添加润滑剂。将最终混合物压片形成片剂。The active substance, lactose and starch are mixed together and moistened uniformly with an aqueous solution of polyvinylpyrrolidone. After the wet mixture was sieved (2.0 mm mesh size) and dried in a rack-type dryer at 50° C., it was sieved again (1.5 mm mesh size) and the lubricant was added. The final blend is compressed to form tablets.
片剂重量：220mgTablet Weight: 220mg
直径：10mm，双面，在两侧刻画且在一侧有V形刻痕。Diameter: 10mm, double-sided, engraved on both sides and V-shaped notch on one side.
实施例BExample B
含有150mg活性物质的片剂Tablets containing 150 mg of active substance
组成：composition:
1片剂含有：1 tablet contains:
活性物质 150.0mgActive substance 150.0mg
粉末状乳糖 89.0mgPowdered lactose 89.0mg
玉米淀粉 40.0mgCorn starch 40.0mg
胶状二氧化硅 10.0mgColloidal silica 10.0mg
聚乙烯吡咯烷酮 10.0mgPolyvinylpyrrolidone 10.0mg
硬脂酸镁 1.0mgMagnesium stearate 1.0mg
300.0mg
制备：preparation:
将与乳糖、玉米淀粉及二氧化硅混合的活性物质以20％聚乙烯吡咯烷酮水溶液润湿且通过1.5mm筛孔大小的筛。使在45℃下干燥的颗粒再次穿过相同筛且与特定量的硬脂酸镁混合。混合物压制成片剂。The active substance mixed with lactose, corn starch and silicon dioxide is moistened with 20% aqueous solution of polyvinylpyrrolidone and passed through a sieve with a mesh size of 1.5 mm. The granules dried at 45°C were again passed through the same sieve and mixed with the specified amount of magnesium stearate. The mixture is compressed into tablets.
片剂重量：300mgTablet weight: 300mg
直径：10mm，扁平Diameter: 10mm, flat
实施例CExample C
含有150mg活性物质的硬胶囊Hard capsules containing 150 mg of active substance
组成：composition:
1胶囊含有：1 capsule contains:
活性物质 150.0mgActive substance 150.0mg
玉米淀粉(干燥) 大约 180.0mgCorn starch (dried) approx. 180.0mg
乳糖(粉末状) 大约 87.0mgLactose (powder) Approx. 87.0mg
硬脂酸镁 3.0mgMagnesium stearate 3.0mg
大约 420.0mg Approx. 420.0 mg
制备：preparation:
将活性物质与赋形剂混合，通过0.75mm筛孔大小的筛且使用合适设备均匀混合。将最终混合物填充入规格1的硬胶囊中。The active substance is mixed with the excipients, passed through a sieve with a mesh size of 0.75 mm and mixed homogeneously using suitable equipment. The final mixture is filled into hard capsules of size 1.
胶囊填料：大约320mgCapsule Filler: about 320mg
胶囊外壳：规格1的硬胶囊。Capsule shell: hard capsule of size 1.
实施例DExample D
含有150mg活性物质的栓剂Suppository containing 150 mg of active substance
组成：composition:
1栓剂含有：1 suppository contains:
活性物质 150.0mgActive substance 150.0mg
聚乙二醇1500 550.0mgMacrogol 1500 550.0mg
聚乙二醇6000 460.0mgMacrogol 6000 460.0mg
聚氧化乙烯脱水山梨糖醇单硬脂酸酯 840.0mgPolyoxyethylene sorbitan monostearate 840.0mg
2，000.0mg...
制备：preparation:
在栓剂物质熔融之后，使活性物质均匀分布于其中，且将熔体倾入冷却模具中。After the suppository mass has melted, the active substance is distributed evenly therein, and the melt is poured into cooled moulds.
实施例EExample E
含有10mg活性物质的安瓿Ampoule containing 10 mg of active substance
组成：composition:
活性物质 10.0mgActive substance 10.0mg
0.01N盐酸适量Appropriate amount of 0.01N hydrochloric acid
双蒸水 加至 2.0mlAdd double distilled water to 2.0ml
制备：preparation:
将活性物质溶解于必需量的0.01N的HCl中，用食盐使其等张，无菌过滤且转移至2ml安瓿中。The active substance is dissolved in the necessary amount of 0.01 N HCl, made isotonic with common salt, sterile filtered and transferred into 2 ml ampoules.
实施例FExample F
含有50mg活性物质的安瓿Ampoule containing 50 mg of active substance
组成：composition:
活性物质 50.0mgActive substance 50.0mg
0.01N盐酸适量Appropriate amount of 0.01N hydrochloric acid
双蒸水 加至 10.0mlAdd double distilled water to 10.0ml
制备：preparation:
将活性物质溶解于必需量的0.01N的HCl中，用食盐使其等张，无菌过滤且转移至10ml安瓿中。The active substance is dissolved in the necessary amount of 0.01 N HCl, isotonic with common salt, sterile filtered and transferred into 10 ml ampoules.
Claims (12)
Translated fromChinese
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP06101711.7 | 2006-02-15 | ||
| EP06101711 | 2006-02-15 | ||
| EP06113412.8 | 2006-05-03 | ||
| EP06124833.2 | 2006-11-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101384576Atrue CN101384576A (en) | 2009-03-11 |
Family
ID=40463754
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007800056698APendingCN101384576A (en) | 2006-02-15 | 2007-02-14 | Benzonitrile derivative substituted by glucopyranosyl group, pharmaceutical composition containing the compound, its use and its preparation method |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN101384576A (en) |
| UA (1) | UA94087C2 (en) |
| ZA (1) | ZA200804802B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327027A (en)* | 2014-10-14 | 2015-02-04 | 中国药科大学 | New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor |
| WO2018127194A1 (en)* | 2017-01-09 | 2018-07-12 | 江苏天士力帝益药业有限公司 | C-glycoside sodium-glucose transporter 2 inhibitor |
| WO2019185026A1 (en)* | 2018-03-30 | 2019-10-03 | 南京明德新药研发有限公司 | Glucoside derivatives acting as inhibitors of sglts, and use thereof |
| CN112409344A (en)* | 2020-09-22 | 2021-02-26 | 江西师范大学 | A kind of synthetic method of natural product Scleropentaside A |
| CN113735921A (en)* | 2021-06-25 | 2021-12-03 | 北京惠之衡生物科技有限公司 | Method for synthesizing impurities of C-glucoside derivatives |
| CN114478454A (en)* | 2020-11-12 | 2022-05-13 | 南京桦冠生物技术有限公司 | SGLT2 inhibitor key intermediate and preparation method thereof |
- 2007
- 2007-02-14UAUAA200811053Apatent/UA94087C2/enunknown
- 2007-02-14CNCNA2007800056698Apatent/CN101384576A/enactivePending
- 2008
- 2008-06-03ZAZA200804802Apatent/ZA200804802B/enunknown
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104327027A (en)* | 2014-10-14 | 2015-02-04 | 中国药科大学 | New C-aryl glycosidase SGLT2 (sodium glucose transporter type-2) inhibitor |
| CN104327027B (en)* | 2014-10-14 | 2017-04-05 | 中国药科大学 | One class novel C aryl glucoside SGLT2 inhibitor |
| WO2018127194A1 (en)* | 2017-01-09 | 2018-07-12 | 江苏天士力帝益药业有限公司 | C-glycoside sodium-glucose transporter 2 inhibitor |
| CN108285439A (en)* | 2017-01-09 | 2018-07-17 | 江苏天士力帝益药业有限公司 | A kind of 2 inhibitor of carbon glycoside class sodium glucose transporter body |
| CN108285439B (en)* | 2017-01-09 | 2023-05-02 | 江苏天士力帝益药业有限公司 | Carbonoside sodium glucose transport protein body 2 inhibitor |
| WO2019185026A1 (en)* | 2018-03-30 | 2019-10-03 | 南京明德新药研发有限公司 | Glucoside derivatives acting as inhibitors of sglts, and use thereof |
| CN112409344A (en)* | 2020-09-22 | 2021-02-26 | 江西师范大学 | A kind of synthetic method of natural product Scleropentaside A |
| CN112409344B (en)* | 2020-09-22 | 2022-06-07 | 江西师范大学 | A kind of synthetic method of natural product Scleropentaside A |
| CN114478454A (en)* | 2020-11-12 | 2022-05-13 | 南京桦冠生物技术有限公司 | SGLT2 inhibitor key intermediate and preparation method thereof |
| CN113735921A (en)* | 2021-06-25 | 2021-12-03 | 北京惠之衡生物科技有限公司 | Method for synthesizing impurities of C-glucoside derivatives |
Also Published As
| Publication number | Publication date |
|---|---|
| ZA200804802B (en) | 2009-03-25 |
| UA94087C2 (en) | 2011-04-11 |
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