药物中4-（溴代苯基）-二氢嘧啶-2-酮检测方案(微波合成仪)

Parallel Scale-up of the Biginelli Cyclocondensation Relevant for： Academic Research， Pharmaceutical Research， Medicinal Chemistry The Biginelli dihydropyrimidine synthesis is a simple but powerful one-pot three-componentcyclocondensation involving ureas， aldehydes and CH-acidic carbonyl compounds. Thesynthesis of structures with the dihydropyrimidine (DHPM) scaffold has become of certaininterest during the last years as DHPMs show widespread biological and pharmaceuticalactivities. Figure 1： Multiwave 5000 Introduction An effective and rapid protocol to produce numerousDHPM derivatives has attracted considerable interest.Microwave-mediated parallel synthesis allowsgenerating various DHPMs within only one run inmultigram scale. Herein the parallel synthesis of different bromophenyl-DHPMs suitable for further scaffold decorations tointroduce broader diversity into the basic structure ispresented. 2 Experimental The reactions were carried out in Rotor 16MF100employing the p/T Sensor in Synthos 3000， apredecessor of Multiwave 5000. Using the same rotor， vessels and accessories themethod is reliably adaptable for Multiwave 5000. Urea and 10 mol% of the Lewis-acid catalyst weresuspended in acetonitrile and stirred for approximately10 min to accomplish dissolution. Then 1 equiv. corresponding aldehyde and 1.5 equiv.B-ketoester were added and the sealed vessels weresubjected to the rotor. After irradiation and cooling， the mixtures are kept in arefrigerator (4°℃) overnight to enable maximumprecipitation of the desired compounds. To accomplish quantitative recovery the mixtureswere treated with crushed ice， filtered and theprecipitates were dried to furnish the correspondingDHPMs in good yield and excellent purity. Figure 2： Biginelli Synthesis of 4-(bromophenyl)-dihydropyrimidin-2-ones Reaction Mixtures 40 mmol urea (2.40 g) · 4 mmol Yb(OTf)3(2.48g) 20 mL acetonitrile (MeCN) 40 mmol bromobenzaldehyde (7.40 g) 60 mmol ethyl acetoacetate (7.80 g， 7.65 mL) Temp.[C] Ramp[mm：ss] Hold[mm：ss] Fan 1 120 03：00 15：00 1 2 50 --- 11：40 3 5FReferences Table 1： Temperature settings C. O. Kappe， A. Stadler， "The BiginelliDihydropyrimidine Synthesis“ in Organic Reactions2004， Vol.63，1-116， L. E. Overman (Ed.)， OrganicReactions Inc. Results J. Wannberg et al. J. Comb. Chem. 2005，574-583 No. X Amount Yield* 1 2-Br 8.80 g 65% 2 3-Br 10.30 g 76% 3 4-Br 9.25 g 68% D. Dallinger et al. a) Org. Lett. 2003， 1205-1208； b) Molecules 2003， 229-245 Table 2： Results， *isolated product， average per vessel “C. O. Kappe， Eur. J. Med. Chem. 2000， 1043-1052 4Discussion The importance of DHPMs with various biological andpharmaceutical activities as potential lead compoundsin medicinal chemistry has resulted in increasingresearch activities during the last decade. The classical acid-catalyzed Biginelli protocol inethanolic solution has been widely modified undermicrowave conditions， using different solvents andemploying several catalysts. Whereas the usually utilized catalyst HCl may causesubstrate decomposition at elevated temperatures，several Lewis acids can be used to accomplish thedesired cyclization even with rather sensitive buildingblocks. Moreover， most of these Lewis acids， such asthe used ytterbium triflate in the presented method，provide products of higher purity compared to theclassical protocols involving mineral acids as acatalyst. Thus， work-up is simplified as no additionalpurification step is needed. The resulting brominated DHPMs have beensuccessfully used in Suzuki- and Heck-type carbon-carbon-coupling reactions to achieve more distincttarget molecules.2 Further diversity can be introduced by e.g. acylation ofthe Biginelli compounds at N3， which has proven to2-4yield exceptionally active compounds. Contact Anton Paar GmbHTel： +43 316257-0asc@anton-paar.com|www.anton-paar.com AN-Awww.anton-paar.com 反应在Multiwave 3000（Multiwave 5000的前身）中的p / T传感器中，在Rotor 16MF100转子中进行，使用相同的转子，容器和附件该方法可靠地适用于Multiwave 5000。