盐酸美金刚、NHC前体及其Pd配合物的合成
|
摘要
盐酸美金刚是出德国Merz公司开发的一种低中等程度亲和力的非竞争性N-甲基-D-天冬氨酸受体拮抗剂,2003年被美国食品和药品管理局(FDA)批准用于治疗中、重度阿尔茨海默病。
本文建立了一条以苊为起始原料,经过催化加氢、重排、乙酰胺基化、水解、成盐等反应合成盐酸美金刚的合成路线。该合成路线最大的优点是省去目前常用盐酸美金刚合成路线中1,3-二甲基金刚烷澳化这一步反应,简化了反应步骤。另外,该路线的起始原料苊廉价易得。
近年来,N-杂环卡宾被广泛应用于配位化学和均相催化领域。大位阻的N-杂环卡宾因有利于催化活性物质的生成并能促进催化循环中的还原消除步骤而受到格外关注。目前,将大位阻的N-杂环卡宾应用于Pd催化的偶联反应越来越来流行。
本文以盐酸美金刚为原料,合成了含大位阻3,5-二甲基金刚烷取代基的N-杂环卡宾前体：1,3-二(3,5-二甲基金刚烷基)咪唑啉盐酸盐、1,3-二(3,5-二甲基金刚烷基)咪唑盐酸盐和1-苄基-3-(N-3,5-二甲基金刚烷基乙酰胺基)咪唑盐酸盐。另外,将1-苄基-3-(N-3,5-二甲基金刚烷基乙酰胺基)咪唑盐酸盐用于Pd配合物的制备以期待获得高活性的Pd催化剂,其催化活性用卤代芳烃与苯硼酸之间的Suzuki-Miyaura反应进行了初步检测。
Memantine hydrochloride. developed by Merz Pharmaceuticals, is a moderate affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. It was approved by FDA in 2003 for the treatment of moderate to severe Alzheimer's disease.
A short and economical process route has been developed for the synthesis of memantine hydrochloride in this thesis. Starting from acenaphthene, the procedure involves sequential reactions such as catalytic hydrogenation, rearrangement, amidation, hydrolysis and acidation. Without bromination of 1,3-dimethyl-adamantane is regarded as a significant advantage of this synthetic route. Besides, acenaphthene is an inexpensive, commercially available raw material.
In recent years N-heterocyclic carbene (NHC) ligands have been widely used in the fields of coordination chemistry and homogeneous catalysis. Sterically very demanding NHCs are particularly attractive because they may facilitate the formation of catalytically active species, as well as enhance the reductive elimination step. Therefore, the use of sterically demanding NHCs in palladium-catalyzed cross-coupling reactions is rapidly gaining in popularity.
Starting from memantine hydrochloride, imidazol(in)ium chlorides bearing bulky 3,5-dimethyladamantyl substituent, 1,3-bis-(3,5-dimethyladamantyl)imidazolinium chloride, 1,3-bis-(3,5-dimethyladamantyl)imidazolium chloride and 1-benzyl-3-(N-3,5-dimethyladama-ntan-1-ylacetamido) imidazolium chloride were synthesized in this thesis. In order to find more efficient palladium catalysts, 1-benzyl-3-(N-3,5-dimethyladamantan-1-ylacetamido) imidazol-2-ylidene Pd complexe was prepared and its catalytic activity was simply examined in Suzuki-Miyaura reaction.
本文建立了一条以苊为起始原料,经过催化加氢、重排、乙酰胺基化、水解、成盐等反应合成盐酸美金刚的合成路线。该合成路线最大的优点是省去目前常用盐酸美金刚合成路线中1,3-二甲基金刚烷澳化这一步反应,简化了反应步骤。另外,该路线的起始原料苊廉价易得。
近年来,N-杂环卡宾被广泛应用于配位化学和均相催化领域。大位阻的N-杂环卡宾因有利于催化活性物质的生成并能促进催化循环中的还原消除步骤而受到格外关注。目前,将大位阻的N-杂环卡宾应用于Pd催化的偶联反应越来越来流行。
本文以盐酸美金刚为原料,合成了含大位阻3,5-二甲基金刚烷取代基的N-杂环卡宾前体：1,3-二(3,5-二甲基金刚烷基)咪唑啉盐酸盐、1,3-二(3,5-二甲基金刚烷基)咪唑盐酸盐和1-苄基-3-(N-3,5-二甲基金刚烷基乙酰胺基)咪唑盐酸盐。另外,将1-苄基-3-(N-3,5-二甲基金刚烷基乙酰胺基)咪唑盐酸盐用于Pd配合物的制备以期待获得高活性的Pd催化剂,其催化活性用卤代芳烃与苯硼酸之间的Suzuki-Miyaura反应进行了初步检测。
Memantine hydrochloride. developed by Merz Pharmaceuticals, is a moderate affinity, uncompetitive N-methyl-D-aspartate receptor antagonist. It was approved by FDA in 2003 for the treatment of moderate to severe Alzheimer's disease.
A short and economical process route has been developed for the synthesis of memantine hydrochloride in this thesis. Starting from acenaphthene, the procedure involves sequential reactions such as catalytic hydrogenation, rearrangement, amidation, hydrolysis and acidation. Without bromination of 1,3-dimethyl-adamantane is regarded as a significant advantage of this synthetic route. Besides, acenaphthene is an inexpensive, commercially available raw material.
In recent years N-heterocyclic carbene (NHC) ligands have been widely used in the fields of coordination chemistry and homogeneous catalysis. Sterically very demanding NHCs are particularly attractive because they may facilitate the formation of catalytically active species, as well as enhance the reductive elimination step. Therefore, the use of sterically demanding NHCs in palladium-catalyzed cross-coupling reactions is rapidly gaining in popularity.
Starting from memantine hydrochloride, imidazol(in)ium chlorides bearing bulky 3,5-dimethyladamantyl substituent, 1,3-bis-(3,5-dimethyladamantyl)imidazolinium chloride, 1,3-bis-(3,5-dimethyladamantyl)imidazolium chloride and 1-benzyl-3-(N-3,5-dimethyladama-ntan-1-ylacetamido) imidazolium chloride were synthesized in this thesis. In order to find more efficient palladium catalysts, 1-benzyl-3-(N-3,5-dimethyladamantan-1-ylacetamido) imidazol-2-ylidene Pd complexe was prepared and its catalytic activity was simply examined in Suzuki-Miyaura reaction.
引文
[1]程焱,张楠,杜红坚,等.盐酸美金刚治疗阿尔茨海默病的多中心随机对照研究[J].中华神经科杂志,2009,42(2)：268-272.
[2]谌青纯.阿尔茨海默病患者的常见问题及护理对策[J].中国当代药,2010,17(6)：107-108.
[3]Albasanz J L, Perez S, Barrachina M, et al. Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease[J]. Brain Pathology,2008,18(2): 211-219.
[4]陈泽峰.阿尔茨海默病的药物治疗研究进展[J].医学综述,2009,15(16)：2449-2452.
[5]吴思缈,周黎明.阿尔茨海默病的发病机制及红物治疗的进展[J].四川生理科学杂志,2009,31(1)：36-39.
[6]姚莹.老年性痴呆治疗药物的研究进展[J].实用医药杂志,2005,22(2)：159-161.
[7]汪春运.美国官方批准的阿尔茨海默病药物治疗[J].国外医学·老年医学分册,2009,30(2)：52-56.
[8]许慧.新型乙酰胆碱酯酶抑制剂的设计、合成与生物活性测定[D].长沙：中南大学,2009,
[9]罗京京,何玲,刘国卿.治疗阿尔茨海默病新药盐酸美金刚[J].中国新药杂志,2006,15(9)：742-744.
[10]Jain K K. Evaluation of memantine for neuroprotection in dementia[J]. Expert Opin. Invest. Drugs,2000,9(6):1397-1406.
[11]Marvanova M, Lakso M, Pirhonen J, et al. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain[J]. Mol. Cell. Neurosci.,2001,18(3):247-258.
[12]Badio B, Padgett W L, Daly J W. Ibogaine:a potent noncompetitive blocker of ganglionic/neuronal nicotinic receptors[J]. Mol. Pharm.,1997,51:1-5.
[13]Mills J, Krumkalns E. Adamantyl secondary amines:US,3391142[P].1968-07-02.
[14]邹永,朱杰,熊晓云,等.美金刚胺盐酸盐的制备方法：CN,1400205A[P].2003-03-05.
[15]周杏琴,曹国宪,项景德,等.盐酸美金刚胺的合成[J].化工时刊,2005,19(3)：11-15.
[16]Reddy J M, Prasad G, Raju V, et al. An improved synthesis of memantine hydrochloride: anti-Alzheimer's drug[J]. Org. Process Res. Dev.,2007,11(2):268-269.
[17]Madhra M K, Sharma M, Khanduri C H. New synthetic approach to memantine hydro-chloride starting from 1,3-dimethyl-adamantane[J]. Org. Process Res. Dev. 2007,11(5):922-923.
[18]Arduengo A J, Harlow R L, Kline M. A stable crystalline carbene[J]. J. Am. Chem. Soc,1991,113(1):361-363.
[19]Arduengo A J, Dias H V R, Kline M, et al. Electronic stabilization of nucleophilic carbenes[J]. J. Am. Chem. Soc.,1992,114(14):5530-5534.
[20]Arduengo A J, Goerlich J R, Marshall W J. A stable diaminocarbene[J]. J. Am. Chem. Soc.,1995,117(44):11027-11028.
[21]Herrmann W A, Elison M, Fischer J, et al. N-Heterocyclic carbenes'(?):generation under mild conditions and formation of group 8-10 transition metal complexes relevant to catalysis[J]. Chem. Eur. J.,1996,2(7):772-780.
[22]Kuhn N, Kratz T. Synthesis of imidazol-2-ylidenes by reduction of imidazole-2(3H)-thiones[J]. Synthesis,1993,1993(6):561-562.
[23]Hahn F E, Paas M, Van D L, et al. Simple access to unsymmetrically substituted, saturated N-heterocyclic carbenes[J]. Angew. Chem. Int. Ed.,2003,42 (42):5243-5246.
[24]Denk M K, Thadani A, Hatano K, et al. Steric stabilization of nucleophilic carbenes[J]. Angew. Chem. Int. Ed. Engl.,1997,36(23):2607-2609.
[25]Nyce G W, Waymouth R M, Hedrick J L, et al. A general and versatile approach to thermally generated N-heterocyclic carbenes[J]. Chem. Eur. J.,2004,10(16):4073-4079.
[26]Blum A P, Ritter T, Grubbs R H. Synthesis of N-heterocylic carbene-containing metal complexes from 2-(pentafluorophenyl)imidazolidines[J]. Organometallics,2007,26 (8):2122-2124.
[27]Korotkikh N I, Raenko G F, Pekhtereva T M, et al. Stable carbenes. synthesis and properties of benzimidazol-2-ylidenes[J]. Russ. J. Org. Chem.,2006,42(12):1822-1833.
[28]Herrmann W A, GooBen L G, Spiegler M. Functionalized imidazoline-2-ylidene complexes of rhodium and palladium [J]. J. Organomet. Chem.,1997,547(2):357-366.
[29]Bohm V P W, Weskamp T, Gstottmayr C W K, et al. Nickel-catalyzed cross-coupling of aryl chlorides with aryl Grignard reagents[J]. Angew. Chem. Int. Ed.,2000, 39(9):1602-1604.
[30]Herrmann W A, Kocher C, GooBen L G, et al. Heterocyclic carbenes:a high-yielding synthesis of novel, functionalized N-heterocyclic carbenes in liquid ammonia[J]. Chem. Eur. J.,1996,2(12):1627-1636.
[31]Bildstein B, Malaun M, Kopacka H, et al. N, N'-Diferrocenyl-N-heterocyclic carbenes and their derivatives[J]. Organometallics,1999,18(21):4325-4336.
[32]Huang J, Nolan S P. Efficient cross-coupling of aryl chlorides with aryl Grignard reagents (Kumada Reaction) mediated by a palladium/imidazolium chloride system [J]. J. Am. Chem. Soc.,1999,121 (42):9889-9890.
[33]Gridnev A A, Mihaltseva I M. Synthesis of 1-alkylimidazoles[J]. Synth. Commun. 1994,24(11):1547-1555.
[34]Furstner A, Alcarazo M, Cesar V, et al. Convenient, scalable and flexible method for the preparation of imidazolium salts with previously inaccessible substitution patterns[J]. Chem. Commun.,2006, (20):2176-2178.
[35]Glorius F, Hirano K, Urban S, et al. A modular synthesis of highly substituted imidazolium salts[J]. Org. Lett.,2009,11 (4):1019-1022.
[36]Glorius F, Altenhoff G, Goddard R, et al. Ein N-heterocyclischer carbenligand mit flexiblem sterischem anspruch ermoglicht die Suzuki-Kreuzkupplung sterisch gehinderter arylchloride bei raumtemperatur[J]. Angew. Chem.,2003,115(31): 3818-3821.
[37]Glorius F, Altenhoff G, Goddard R, et al. An N-heterocyclic carbene Ligand with flexible steric bulk allows Suzuki cross-coupling of sterically hindered aryl chlorides at room temperature[J]. Angew. Chem. Int. Ed.,2003,42(31):3690-3693.
[38]Glorius F, Altenhoff G, Goddard R, et al. Sterically demanding, bioxazoline-derived N-heterocyclic carbene ligands with restricted flexibility for catalysis[J]. J. Am. Chem. Soc.,2004,126(46):15195-15201.
[39]Arduengo A J, Krafczyk R, Schmutzler R. Imidazolylidenes, imidazolinylidenes and imidazolidines[J]. Tetrahedron,1999,55(51):14523-14534.
[40]Stylianides N, Danopoulos A A, Pugh D, et al. Cyclometalated and alkoxyphenyl-substituted palladium imidazolin-2-ylidene complexes. synthetic, structural, and catalytic studies [J]. Organometallics,2007,26(23):5627-5635.
[41]Garber S B, Kingsbury J S, Hoveyda A H, et al. Efficient and recyclable monomeric and dendritic Ru-based metathesis catalysts[J]. J. Am. Chem. Soc.,2000,122 (34): 8168-8179.
[42]Alcarazo M, Roseblade S J, Lassaletta J M, et al.1,3-Bis(N, N-dialkylamino) imidazolin-2-ylidenes:synthesis and reactivity of a new family of stable N-heterocyclic carbenes[J]. J. Am. Chem. Soc.,2004,126(41):13242-13243.
[43]Scholl M, Ding S, Grubbs R H, et al. Synthesis and activity of a new generation of Ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands[J]. Org. Lett.,1999,1 (6):953-956.
[44]Mayr M, Buchmeiser M R, Wurst K. Synthesis of a silica-based heterogeneous second generation grubbs catalyst[J]. Adv. Synth. Catal.,2002,344(6-7):712-719.
[45]Kuhn K M, Grubbs R H. A facile preparation of imidazolinium chlorides[J]. Org. Lett.,2008,10(10):2075-2077.
[46]Waltman A W, Grubbs R H. A new class of chelating N-heterocyclic carbine ligands and their complexes with palladium[J]. Organometallics,2004,23(13):3105-3107.
[47]Hadei N, Kantchev E A B, Organ M G, et al. Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst[J]. J. Org. Chem.,2005,70(21):8503-8507.
[48]Paczal A, Benyei A C, Kotschy A. Modular synthesis of heterocyclic carbene precursors[J]. J. Org. Chem.,2006,71(16):5969-5979.
[49]Orru R V A, Bon R S, Lutz M, et al. Multicomponent synthesis of N-heterocyclic carbene complexes[J]. J. Org. Chem.,2007,26(15):3639-3650.
[50]Orru R V A, Bon R S, Sprenkels N E, et al. Multicomponent.synthesis of 2-imidazolines [J]. J. Org. Chem.,2005,70(9):3542-3553.
[51]Orru R V A, Bon R S, Hong C, et al. Novel multicomponent reaction for the combinatorial synthesis of 2-imidazolines[J]. Org. Lett.,2003,5(20):3759-3762.
[52]Bertrand G, Jazzar R, Liang H, et al. A new synthetic method for the preparation of protonated-NHCs and related compounds[J]. J. Organomet. Chem.,2006,691 (14): 3201-3205.
[53]Bertrand G, Jazzar R, Bourg J B, et al. Intramolecular "hydroiminiumation and-amidiniumation" of alkenes:a convenient, flexible, and scalable route to cyclic iminium and imidazolinium salts[J]. J. Org. Chem.,2007,72(9):3492-3499.
[54]McGuinness D S, Cavell K J. Donor-functionalized heterocyclic carbene complexes of palladium(Ⅱ):efficient catalysts for C-C coupling reactions[J]. Organometallics,2000,19(5):741-748.
[55]Yen S K, Koh L L, Hahn F E, et al. Convenient entry to mono-and dinuclear palladium(Ⅱ) benzothiazolin-2-ylidene complexes and their activities toward Heck coupling[J]. Organometallics,2006,25(21):5105-5122.
[56]Altenhoff G, Wurtz S, Glorius F. The first palladium-catalyzed Sonogashira coupling of unactivated secondary alkyl bromides[J]. Tetrahedron Lett.,2006,47 (17):2925-2928.
[57]Viciu M S, Kissling R M, Nolan S P, et al. An air-stable palladium/N-heterocyclic carbene complex and its reactivity in aryl amination[J]. Org. Lett.,2002,4(13): 2229-2231.
[58]Iyer S, Jayanthi A. Saturated N-heterocyclic carbene oxime and amine palladacycle catalysis of the Mizoroki-Heck and the Suzuki reactions[J]. Synlett.,2003,2003 (8):1125-1128.
[59]Frey G D, Schutz J, Herrmann W A, et al. Synthesis and characterization of N-heterocyclic carbene phospha-palladacycles and their properties in Heck catalysis[J]. Organometallics,2005,24(18):4416-4426.
[60]Bedford R B, Betham M, Coles S J, et al. An evaluation of phosphine and carbene adducts of phosphiteand phosphinite-based palladacycles in the coupling of alkyl bromides with aryl boronic acids[J]. Tetrahedron,2005,61(41):9663-9669.
[61]Bedford R B, Betham M, Blake M E, et al. N-Heterocyclic carbene adducts of orthopalladated triarylphosphite complexes[J]. Dalton Trans.,2005, (16):2774-2779.
[62]Viciu M S, Stevens E D, Nolan S P, et al. Synthesis, characterization, and catalytic activity of N-heterocyclic carbene (NHC) palladacycle complexes [J]. Org. Lett.,2003,5 (9):1479-1282.
[63]Navarro 0, Marion N, Nolan S P, et al. Suzuki-Miyaura, a-ketone arylation and dehalogenation reactions catalyzed by a versatile N-heterocyclic carbene-palladacycle complex[J]. J. Org. Chem.,2006,71 (2):685-692.
[64]Navarro 0, Kelly R A, Nolan S P. A general method for the Suzuki-Miyaura cross-coupling of sterically hindered aryl chlorides:synthesis of di-and tri-ortho-substituted biaryls in 2-propanol at room temperature [J]. J. Am. Chem. Soc.,2003,125(52):16194-16195.
[65]O'Brien C J, Valente C, Organ M G, et al. Easily prepared air-and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes:a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction[J]. Chem. Eur. J.,2006,12(18):4743-4748.
[66]Organ M G, Avola S, Dubovyk I, et al. A user-friendly, all-purpose Pd-NHC (NHC=N-heterocyclic carbene) precatalyst for the Negishi reaction:a step towards a universal cross-coupling catalyst[J]. Chem. Eur. J.,2006,12(18):4749-4755.
[67]Organ M G, Avola S, Hadei N, et al. Biaryls made easy:PEPPSI and the Kumada-Tamao-Corriu Reaction[J]. Chem. Eur. J.,2007,13(1):150-157.
[68]Liao C Y, Chan K T, Lee H M, et al. Nonchelate and chelate complexes of palladium (II) with N-heterocyclic carbene ligands of amido functionality[J]. Organometallics,2007,26(7):1692-1702.
[69]Ray L, Shaikh M M, Ghosh P P. Air-stable, convenient to handle Pd based PEPPSI (pyridine enhanced precatalyst preparation, stabilization and initiation) themed precatalysts of N/O-functionalized N-heterocyclic carbenes and its utility in Suzuki-Miyaura cross-coupling reaction[J]. Dalton Trans.,2007, (40):4546-4555.
[70]Gstottmayr C W K, Bohm V P W, Herrmann W A, et al. A defined N-heterocyclic carbene complex for the palladium-catalyzed Suzuki cross-couplingof aryl chlorides at ambient temperatures[J]. Angew. Chem. Int. Ed.,2002,41(8):1363-1365.
[71]Lavallo V, Canac Y, Bertrand G, et al. Stable cyclic (alkyl)(amino)carbenes as rigid or flexible, bulky, electron-rich ligands for transition-metal catalysts: a quaternary carbon atom makes the difference[J]. Angew. Chem. Int. Ed.,2005, 44(35):5705-5709.
[72]Marion N, Navarro 0, Nolan S P, et al. Modified (NHC)Pd(allyl)Cl (NHC N-heterocyclic carbene) complexes for room-temperature Suzuki-Miyaura and Buchwald-Hartwig reactions[J]. J. Am. Chem. Soc.,2006,128(12):4101-4111.
[73]Navarro 0, Marion N, Nolan S P, et al. Rapid room temperature Buchwald-Hartwig and Suzuki-Miyaura couplings of heteroaromatic compounds employing low catalyst loadings[J]. Chem. Eur. J.,2006,12(19):5142-5148.
[74]Navarro 0, Marion N, Nolan S P, et al. Synthesis of novel (NHC)Pd(acac)Cl complexes (acac= acetylacetonate) and their activity in cross-coupling reactions[J]. Tetrahedron,2005,61(41):9716-9722.
[75]Marion N, Navarro 0, Nolan S P, et al. (IPr)Pd(acac)Cl:an easily synthesized, efficient, and versatile precatalyst for C-N and C-C bond formation[J]. J. Org. Chem.,2006,71(10):3816-3821.
[76]Christmann U, Vilar R. Monoligated palladium species as catalysts in cross-coupling reactions[J]. Angew. Chem. Int. Ed.,2005,44(3):366-374.
[77]Grasa G A, Viciu M S, Nolan S P, et al. Suzuki-Miyaura cross-coupling reactions mediated by palladium/imidazolium salt systems [J]. Organometallics,2002,21 (14): 2866-2873.
[78]胡晓春,孔黎春.1,3-二甲基金刚炕的合成[J].合成化学,2006,14(2)：206-207.
[79]Wanka L, Cabrele C, Vanejews M, et al. γ-Aminoadamantanecarboxylic acids through direct C-H bond amidations[J]. Eur. J. Org. Chem.,2007,2007(9):1474-1490.
[80]任会学,林吉茂,薛云,等.1-乙酰氨基-3，5-二甲基金刚烷的水解反应研究[J].精细化工中间体,2005,35(3)：29-31.
[81]Zang Y, Wu X M, Liu Q X, et al.1-Benzylimidazolium hexafluorophosphate-1-benzyl-imidazole(1/1)[J]. Acta Cryst.,2008, E64:o478.
[82]Berding J, Kooijman H, Bouwman E, et al. Another silver complex of 1,3-dibenzylimidazol-2-ylidene:solution and solid-state structures[J]. J. Organomet. Chem.,2009,694(14):2217-2221.
[83]Guzen K P, Cella R, Stefani H A. Ultrasound enhanced synthesis of 1,5-benzodiazepinic heterocyclic rings[J]. Tetrahedron Lett.,2006,47(46):8133-8136.
[84]Chianese A R, Mo A, Datta D. Flexible, bowl-shaped N-heterocyclic carbene ligands: substrate specificity in iridium-catalyzed ketone hydrosilylation[J]. Organometallics,2009,28(2):465-472.
[85]Vincentiis L D. Demande de brevet d'invention:FR,2522327[P].1982-10-27.
[86]Naruse Y, Suzuki T. Selective preparation of cis-perhydroacenaphthene:US, 4783565[P].1988-11-08.
[87]Rohac V, Censky M, Zala D, et al. Vapor pressure and liquid heat capacity of perhydroacenaphthylene and perhydrophenanthrene[J]. J. Chem. Eng. Data.,2000, 45(6):1205-1210.
[88]McKervey M A, Johnston D E, Rooney J J. Preparation of diamondoid hydrocarbons by rearrangement employing a chlorinated platinum-alumina catalyst[J]. J. Am. Chem. Soc.,1971,93(11):2798-2799.
[89]Varushchenko R M, Pashchenko L L, Druzhinina A I, et al. Thermodynamics of vaporization of some alkyladamantanes[J]. J. Chem. Thermodyn.,2001,33(7):733-744.
[90]Schleyer P V R, Engler E M, Farcasiu M, et al. Mechanism of adamantane rearrangements[J]. J. Am. Chem. Soc.,1973,95(17):5769-5771.
[91]Klimochkin Y N, Bagrii E I, Dolgopolova T N, et al. Synthesis of alkoxycarbonyl-amino-adamantanes and acetylamino-adamantanes in nitric acid[J]. Russ. Chem. Bull.,1988,37(4):757-759.
[92]Sakaguchi S, Hirabayashi H, Ishii Y. First Ritter-type reaction of alkylbenzenes using N-hydroxyphthalimide as akey catalyst [J]. Chem. Commun.,2002, (5):516-517.
[93]Kumar R, Chaudhary P, Chandra R, et al. An efficient synthesis of 1,5-benzadiaze-pine derivatives catalyzed by silver nitrate [J]. Green Chem.,2006,8(6):519-521.
[94]Chen W Y, Lu J. Molecular-iodine-catalyzed one-pot synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions [J]. Synlett.,2005,2005 (8):1337-1339.
[95]O'Brien C J, Chass G A, Organ M G, et al. Towards the rational design of palladium-N-heterocyclic carbine catalysts by a combined experimental and computational approach[J]. Tetrahedron,2005,61(41):9723-9735.
[2]谌青纯.阿尔茨海默病患者的常见问题及护理对策[J].中国当代药,2010,17(6)：107-108.
[3]Albasanz J L, Perez S, Barrachina M, et al. Up-regulation of adenosine receptors in the frontal cortex in Alzheimer's disease[J]. Brain Pathology,2008,18(2): 211-219.
[4]陈泽峰.阿尔茨海默病的药物治疗研究进展[J].医学综述,2009,15(16)：2449-2452.
[5]吴思缈,周黎明.阿尔茨海默病的发病机制及红物治疗的进展[J].四川生理科学杂志,2009,31(1)：36-39.
[6]姚莹.老年性痴呆治疗药物的研究进展[J].实用医药杂志,2005,22(2)：159-161.
[7]汪春运.美国官方批准的阿尔茨海默病药物治疗[J].国外医学·老年医学分册,2009,30(2)：52-56.
[8]许慧.新型乙酰胆碱酯酶抑制剂的设计、合成与生物活性测定[D].长沙：中南大学,2009,
[9]罗京京,何玲,刘国卿.治疗阿尔茨海默病新药盐酸美金刚[J].中国新药杂志,2006,15(9)：742-744.
[10]Jain K K. Evaluation of memantine for neuroprotection in dementia[J]. Expert Opin. Invest. Drugs,2000,9(6):1397-1406.
[11]Marvanova M, Lakso M, Pirhonen J, et al. The neuroprotective agent memantine induces brain-derived neurotrophic factor and trkB receptor expression in rat brain[J]. Mol. Cell. Neurosci.,2001,18(3):247-258.
[12]Badio B, Padgett W L, Daly J W. Ibogaine:a potent noncompetitive blocker of ganglionic/neuronal nicotinic receptors[J]. Mol. Pharm.,1997,51:1-5.
[13]Mills J, Krumkalns E. Adamantyl secondary amines:US,3391142[P].1968-07-02.
[14]邹永,朱杰,熊晓云,等.美金刚胺盐酸盐的制备方法：CN,1400205A[P].2003-03-05.
[15]周杏琴,曹国宪,项景德,等.盐酸美金刚胺的合成[J].化工时刊,2005,19(3)：11-15.
[16]Reddy J M, Prasad G, Raju V, et al. An improved synthesis of memantine hydrochloride: anti-Alzheimer's drug[J]. Org. Process Res. Dev.,2007,11(2):268-269.
[17]Madhra M K, Sharma M, Khanduri C H. New synthetic approach to memantine hydro-chloride starting from 1,3-dimethyl-adamantane[J]. Org. Process Res. Dev. 2007,11(5):922-923.
[18]Arduengo A J, Harlow R L, Kline M. A stable crystalline carbene[J]. J. Am. Chem. Soc,1991,113(1):361-363.
[19]Arduengo A J, Dias H V R, Kline M, et al. Electronic stabilization of nucleophilic carbenes[J]. J. Am. Chem. Soc.,1992,114(14):5530-5534.
[20]Arduengo A J, Goerlich J R, Marshall W J. A stable diaminocarbene[J]. J. Am. Chem. Soc.,1995,117(44):11027-11028.
[21]Herrmann W A, Elison M, Fischer J, et al. N-Heterocyclic carbenes'(?):generation under mild conditions and formation of group 8-10 transition metal complexes relevant to catalysis[J]. Chem. Eur. J.,1996,2(7):772-780.
[22]Kuhn N, Kratz T. Synthesis of imidazol-2-ylidenes by reduction of imidazole-2(3H)-thiones[J]. Synthesis,1993,1993(6):561-562.
[23]Hahn F E, Paas M, Van D L, et al. Simple access to unsymmetrically substituted, saturated N-heterocyclic carbenes[J]. Angew. Chem. Int. Ed.,2003,42 (42):5243-5246.
[24]Denk M K, Thadani A, Hatano K, et al. Steric stabilization of nucleophilic carbenes[J]. Angew. Chem. Int. Ed. Engl.,1997,36(23):2607-2609.
[25]Nyce G W, Waymouth R M, Hedrick J L, et al. A general and versatile approach to thermally generated N-heterocyclic carbenes[J]. Chem. Eur. J.,2004,10(16):4073-4079.
[26]Blum A P, Ritter T, Grubbs R H. Synthesis of N-heterocylic carbene-containing metal complexes from 2-(pentafluorophenyl)imidazolidines[J]. Organometallics,2007,26 (8):2122-2124.
[27]Korotkikh N I, Raenko G F, Pekhtereva T M, et al. Stable carbenes. synthesis and properties of benzimidazol-2-ylidenes[J]. Russ. J. Org. Chem.,2006,42(12):1822-1833.
[28]Herrmann W A, GooBen L G, Spiegler M. Functionalized imidazoline-2-ylidene complexes of rhodium and palladium [J]. J. Organomet. Chem.,1997,547(2):357-366.
[29]Bohm V P W, Weskamp T, Gstottmayr C W K, et al. Nickel-catalyzed cross-coupling of aryl chlorides with aryl Grignard reagents[J]. Angew. Chem. Int. Ed.,2000, 39(9):1602-1604.
[30]Herrmann W A, Kocher C, GooBen L G, et al. Heterocyclic carbenes:a high-yielding synthesis of novel, functionalized N-heterocyclic carbenes in liquid ammonia[J]. Chem. Eur. J.,1996,2(12):1627-1636.
[31]Bildstein B, Malaun M, Kopacka H, et al. N, N'-Diferrocenyl-N-heterocyclic carbenes and their derivatives[J]. Organometallics,1999,18(21):4325-4336.
[32]Huang J, Nolan S P. Efficient cross-coupling of aryl chlorides with aryl Grignard reagents (Kumada Reaction) mediated by a palladium/imidazolium chloride system [J]. J. Am. Chem. Soc.,1999,121 (42):9889-9890.
[33]Gridnev A A, Mihaltseva I M. Synthesis of 1-alkylimidazoles[J]. Synth. Commun. 1994,24(11):1547-1555.
[34]Furstner A, Alcarazo M, Cesar V, et al. Convenient, scalable and flexible method for the preparation of imidazolium salts with previously inaccessible substitution patterns[J]. Chem. Commun.,2006, (20):2176-2178.
[35]Glorius F, Hirano K, Urban S, et al. A modular synthesis of highly substituted imidazolium salts[J]. Org. Lett.,2009,11 (4):1019-1022.
[36]Glorius F, Altenhoff G, Goddard R, et al. Ein N-heterocyclischer carbenligand mit flexiblem sterischem anspruch ermoglicht die Suzuki-Kreuzkupplung sterisch gehinderter arylchloride bei raumtemperatur[J]. Angew. Chem.,2003,115(31): 3818-3821.
[37]Glorius F, Altenhoff G, Goddard R, et al. An N-heterocyclic carbene Ligand with flexible steric bulk allows Suzuki cross-coupling of sterically hindered aryl chlorides at room temperature[J]. Angew. Chem. Int. Ed.,2003,42(31):3690-3693.
[38]Glorius F, Altenhoff G, Goddard R, et al. Sterically demanding, bioxazoline-derived N-heterocyclic carbene ligands with restricted flexibility for catalysis[J]. J. Am. Chem. Soc.,2004,126(46):15195-15201.
[39]Arduengo A J, Krafczyk R, Schmutzler R. Imidazolylidenes, imidazolinylidenes and imidazolidines[J]. Tetrahedron,1999,55(51):14523-14534.
[40]Stylianides N, Danopoulos A A, Pugh D, et al. Cyclometalated and alkoxyphenyl-substituted palladium imidazolin-2-ylidene complexes. synthetic, structural, and catalytic studies [J]. Organometallics,2007,26(23):5627-5635.
[41]Garber S B, Kingsbury J S, Hoveyda A H, et al. Efficient and recyclable monomeric and dendritic Ru-based metathesis catalysts[J]. J. Am. Chem. Soc.,2000,122 (34): 8168-8179.
[42]Alcarazo M, Roseblade S J, Lassaletta J M, et al.1,3-Bis(N, N-dialkylamino) imidazolin-2-ylidenes:synthesis and reactivity of a new family of stable N-heterocyclic carbenes[J]. J. Am. Chem. Soc.,2004,126(41):13242-13243.
[43]Scholl M, Ding S, Grubbs R H, et al. Synthesis and activity of a new generation of Ruthenium-based olefin metathesis catalysts coordinated with 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ligands[J]. Org. Lett.,1999,1 (6):953-956.
[44]Mayr M, Buchmeiser M R, Wurst K. Synthesis of a silica-based heterogeneous second generation grubbs catalyst[J]. Adv. Synth. Catal.,2002,344(6-7):712-719.
[45]Kuhn K M, Grubbs R H. A facile preparation of imidazolinium chlorides[J]. Org. Lett.,2008,10(10):2075-2077.
[46]Waltman A W, Grubbs R H. A new class of chelating N-heterocyclic carbine ligands and their complexes with palladium[J]. Organometallics,2004,23(13):3105-3107.
[47]Hadei N, Kantchev E A B, Organ M G, et al. Room-temperature Negishi cross-coupling of unactivated alkyl bromides with alkyl organozinc reagents utilizing a Pd/N-heterocyclic carbene catalyst[J]. J. Org. Chem.,2005,70(21):8503-8507.
[48]Paczal A, Benyei A C, Kotschy A. Modular synthesis of heterocyclic carbene precursors[J]. J. Org. Chem.,2006,71(16):5969-5979.
[49]Orru R V A, Bon R S, Lutz M, et al. Multicomponent synthesis of N-heterocyclic carbene complexes[J]. J. Org. Chem.,2007,26(15):3639-3650.
[50]Orru R V A, Bon R S, Sprenkels N E, et al. Multicomponent.synthesis of 2-imidazolines [J]. J. Org. Chem.,2005,70(9):3542-3553.
[51]Orru R V A, Bon R S, Hong C, et al. Novel multicomponent reaction for the combinatorial synthesis of 2-imidazolines[J]. Org. Lett.,2003,5(20):3759-3762.
[52]Bertrand G, Jazzar R, Liang H, et al. A new synthetic method for the preparation of protonated-NHCs and related compounds[J]. J. Organomet. Chem.,2006,691 (14): 3201-3205.
[53]Bertrand G, Jazzar R, Bourg J B, et al. Intramolecular "hydroiminiumation and-amidiniumation" of alkenes:a convenient, flexible, and scalable route to cyclic iminium and imidazolinium salts[J]. J. Org. Chem.,2007,72(9):3492-3499.
[54]McGuinness D S, Cavell K J. Donor-functionalized heterocyclic carbene complexes of palladium(Ⅱ):efficient catalysts for C-C coupling reactions[J]. Organometallics,2000,19(5):741-748.
[55]Yen S K, Koh L L, Hahn F E, et al. Convenient entry to mono-and dinuclear palladium(Ⅱ) benzothiazolin-2-ylidene complexes and their activities toward Heck coupling[J]. Organometallics,2006,25(21):5105-5122.
[56]Altenhoff G, Wurtz S, Glorius F. The first palladium-catalyzed Sonogashira coupling of unactivated secondary alkyl bromides[J]. Tetrahedron Lett.,2006,47 (17):2925-2928.
[57]Viciu M S, Kissling R M, Nolan S P, et al. An air-stable palladium/N-heterocyclic carbene complex and its reactivity in aryl amination[J]. Org. Lett.,2002,4(13): 2229-2231.
[58]Iyer S, Jayanthi A. Saturated N-heterocyclic carbene oxime and amine palladacycle catalysis of the Mizoroki-Heck and the Suzuki reactions[J]. Synlett.,2003,2003 (8):1125-1128.
[59]Frey G D, Schutz J, Herrmann W A, et al. Synthesis and characterization of N-heterocyclic carbene phospha-palladacycles and their properties in Heck catalysis[J]. Organometallics,2005,24(18):4416-4426.
[60]Bedford R B, Betham M, Coles S J, et al. An evaluation of phosphine and carbene adducts of phosphiteand phosphinite-based palladacycles in the coupling of alkyl bromides with aryl boronic acids[J]. Tetrahedron,2005,61(41):9663-9669.
[61]Bedford R B, Betham M, Blake M E, et al. N-Heterocyclic carbene adducts of orthopalladated triarylphosphite complexes[J]. Dalton Trans.,2005, (16):2774-2779.
[62]Viciu M S, Stevens E D, Nolan S P, et al. Synthesis, characterization, and catalytic activity of N-heterocyclic carbene (NHC) palladacycle complexes [J]. Org. Lett.,2003,5 (9):1479-1282.
[63]Navarro 0, Marion N, Nolan S P, et al. Suzuki-Miyaura, a-ketone arylation and dehalogenation reactions catalyzed by a versatile N-heterocyclic carbene-palladacycle complex[J]. J. Org. Chem.,2006,71 (2):685-692.
[64]Navarro 0, Kelly R A, Nolan S P. A general method for the Suzuki-Miyaura cross-coupling of sterically hindered aryl chlorides:synthesis of di-and tri-ortho-substituted biaryls in 2-propanol at room temperature [J]. J. Am. Chem. Soc.,2003,125(52):16194-16195.
[65]O'Brien C J, Valente C, Organ M G, et al. Easily prepared air-and moisture-stable Pd-NHC (NHC=N-heterocyclic carbene) complexes:a reliable, user-friendly, highly active palladium precatalyst for the Suzuki-Miyaura reaction[J]. Chem. Eur. J.,2006,12(18):4743-4748.
[66]Organ M G, Avola S, Dubovyk I, et al. A user-friendly, all-purpose Pd-NHC (NHC=N-heterocyclic carbene) precatalyst for the Negishi reaction:a step towards a universal cross-coupling catalyst[J]. Chem. Eur. J.,2006,12(18):4749-4755.
[67]Organ M G, Avola S, Hadei N, et al. Biaryls made easy:PEPPSI and the Kumada-Tamao-Corriu Reaction[J]. Chem. Eur. J.,2007,13(1):150-157.
[68]Liao C Y, Chan K T, Lee H M, et al. Nonchelate and chelate complexes of palladium (II) with N-heterocyclic carbene ligands of amido functionality[J]. Organometallics,2007,26(7):1692-1702.
[69]Ray L, Shaikh M M, Ghosh P P. Air-stable, convenient to handle Pd based PEPPSI (pyridine enhanced precatalyst preparation, stabilization and initiation) themed precatalysts of N/O-functionalized N-heterocyclic carbenes and its utility in Suzuki-Miyaura cross-coupling reaction[J]. Dalton Trans.,2007, (40):4546-4555.
[70]Gstottmayr C W K, Bohm V P W, Herrmann W A, et al. A defined N-heterocyclic carbene complex for the palladium-catalyzed Suzuki cross-couplingof aryl chlorides at ambient temperatures[J]. Angew. Chem. Int. Ed.,2002,41(8):1363-1365.
[71]Lavallo V, Canac Y, Bertrand G, et al. Stable cyclic (alkyl)(amino)carbenes as rigid or flexible, bulky, electron-rich ligands for transition-metal catalysts: a quaternary carbon atom makes the difference[J]. Angew. Chem. Int. Ed.,2005, 44(35):5705-5709.
[72]Marion N, Navarro 0, Nolan S P, et al. Modified (NHC)Pd(allyl)Cl (NHC N-heterocyclic carbene) complexes for room-temperature Suzuki-Miyaura and Buchwald-Hartwig reactions[J]. J. Am. Chem. Soc.,2006,128(12):4101-4111.
[73]Navarro 0, Marion N, Nolan S P, et al. Rapid room temperature Buchwald-Hartwig and Suzuki-Miyaura couplings of heteroaromatic compounds employing low catalyst loadings[J]. Chem. Eur. J.,2006,12(19):5142-5148.
[74]Navarro 0, Marion N, Nolan S P, et al. Synthesis of novel (NHC)Pd(acac)Cl complexes (acac= acetylacetonate) and their activity in cross-coupling reactions[J]. Tetrahedron,2005,61(41):9716-9722.
[75]Marion N, Navarro 0, Nolan S P, et al. (IPr)Pd(acac)Cl:an easily synthesized, efficient, and versatile precatalyst for C-N and C-C bond formation[J]. J. Org. Chem.,2006,71(10):3816-3821.
[76]Christmann U, Vilar R. Monoligated palladium species as catalysts in cross-coupling reactions[J]. Angew. Chem. Int. Ed.,2005,44(3):366-374.
[77]Grasa G A, Viciu M S, Nolan S P, et al. Suzuki-Miyaura cross-coupling reactions mediated by palladium/imidazolium salt systems [J]. Organometallics,2002,21 (14): 2866-2873.
[78]胡晓春,孔黎春.1,3-二甲基金刚炕的合成[J].合成化学,2006,14(2)：206-207.
[79]Wanka L, Cabrele C, Vanejews M, et al. γ-Aminoadamantanecarboxylic acids through direct C-H bond amidations[J]. Eur. J. Org. Chem.,2007,2007(9):1474-1490.
[80]任会学,林吉茂,薛云,等.1-乙酰氨基-3，5-二甲基金刚烷的水解反应研究[J].精细化工中间体,2005,35(3)：29-31.
[81]Zang Y, Wu X M, Liu Q X, et al.1-Benzylimidazolium hexafluorophosphate-1-benzyl-imidazole(1/1)[J]. Acta Cryst.,2008, E64:o478.
[82]Berding J, Kooijman H, Bouwman E, et al. Another silver complex of 1,3-dibenzylimidazol-2-ylidene:solution and solid-state structures[J]. J. Organomet. Chem.,2009,694(14):2217-2221.
[83]Guzen K P, Cella R, Stefani H A. Ultrasound enhanced synthesis of 1,5-benzodiazepinic heterocyclic rings[J]. Tetrahedron Lett.,2006,47(46):8133-8136.
[84]Chianese A R, Mo A, Datta D. Flexible, bowl-shaped N-heterocyclic carbene ligands: substrate specificity in iridium-catalyzed ketone hydrosilylation[J]. Organometallics,2009,28(2):465-472.
[85]Vincentiis L D. Demande de brevet d'invention:FR,2522327[P].1982-10-27.
[86]Naruse Y, Suzuki T. Selective preparation of cis-perhydroacenaphthene:US, 4783565[P].1988-11-08.
[87]Rohac V, Censky M, Zala D, et al. Vapor pressure and liquid heat capacity of perhydroacenaphthylene and perhydrophenanthrene[J]. J. Chem. Eng. Data.,2000, 45(6):1205-1210.
[88]McKervey M A, Johnston D E, Rooney J J. Preparation of diamondoid hydrocarbons by rearrangement employing a chlorinated platinum-alumina catalyst[J]. J. Am. Chem. Soc.,1971,93(11):2798-2799.
[89]Varushchenko R M, Pashchenko L L, Druzhinina A I, et al. Thermodynamics of vaporization of some alkyladamantanes[J]. J. Chem. Thermodyn.,2001,33(7):733-744.
[90]Schleyer P V R, Engler E M, Farcasiu M, et al. Mechanism of adamantane rearrangements[J]. J. Am. Chem. Soc.,1973,95(17):5769-5771.
[91]Klimochkin Y N, Bagrii E I, Dolgopolova T N, et al. Synthesis of alkoxycarbonyl-amino-adamantanes and acetylamino-adamantanes in nitric acid[J]. Russ. Chem. Bull.,1988,37(4):757-759.
[92]Sakaguchi S, Hirabayashi H, Ishii Y. First Ritter-type reaction of alkylbenzenes using N-hydroxyphthalimide as akey catalyst [J]. Chem. Commun.,2002, (5):516-517.
[93]Kumar R, Chaudhary P, Chandra R, et al. An efficient synthesis of 1,5-benzadiaze-pine derivatives catalyzed by silver nitrate [J]. Green Chem.,2006,8(6):519-521.
[94]Chen W Y, Lu J. Molecular-iodine-catalyzed one-pot synthesis of 1,5-benzodiazepine derivatives under solvent-free conditions [J]. Synlett.,2005,2005 (8):1337-1339.
[95]O'Brien C J, Chass G A, Organ M G, et al. Towards the rational design of palladium-N-heterocyclic carbine catalysts by a combined experimental and computational approach[J]. Tetrahedron,2005,61(41):9723-9735.