Srivastava S K, Haq W, Chauhan P M
Division of Medicinal Chemistry, Central Drug Research Institute, Lucknow, India.
Comb Chem High Throughput Screen. 1999 Feb;2(1):33-7.
A novel general synthesis of substituted pyrimidine 3 has been carried out on solid support. The C-atoms carring the cyano, amino, carboxamido, as well as anchoring site have exploited to generate libraries of compounds 6-8, 10, 13, 15, 17, 19, 21, 23, 25 and 27. A novel strategy to cleave the resin to resin-site unsubstituted system has been developed and it provides 5,6-disubstituted pyrimidines 6-8. In addition, synthesis of 2,5,6-trisubstituted pyrimidines of prototype 10 were carried out by nucleophilic displacement of the anchor by various amines. Further investigations were directed toward the solid phase synthesis of pyrimido[4,5-d]pyrimidines 12, 16, 20 and 24 in which C-atoms carring the oxo, thio, amino, anchoring site as well as NH could be introduced as center of diversity to generate libraries of compounds for potential use. 4-Aminopyrimido[4,5-d]pyrimidines 13 and 17 were obtained from fusion of 3a with urea or thiourea followed by cleavage of support while 3-phenylpyrimido[4,5-d]pyrimidines 21 and 27 were synthesized from cyclisation of 4 with phenyl isocyanate or isothiocyanate followed by release of resin. 7-substituted pyrimido[4,5-d]pyrimidines 15, 19, 23 and 27 were obtained by oxidation of 12, 16, 20 and 24 followed by aminolytic cleavage of support.
一种新型的取代嘧啶3的通用合成方法已在固相载体上实现。带有氰基、氨基、羧酰胺基以及连接位点的碳原子已被用于生成化合物6 - 8、10、13、15、17、19、21、23、25和27的文库。已开发出一种将树脂裂解为树脂位点未取代体系的新策略，该策略可提供5,6 - 二取代嘧啶6 - 8。此外，通过用各种胺对连接基团进行亲核取代反应，合成了原型为10的2,5,6 - 三取代嘧啶。进一步的研究针对嘧啶并[4,5 - d]嘧啶12、16、20和24的固相合成，其中带有氧代、硫代、氨基、连接位点以及NH的碳原子可作为多样性中心引入，以生成潜在可用化合物的文库。4 -氨基嘧啶并[4,5 - d]嘧啶13和17是通过3a与尿素或硫脲熔融，随后裂解载体得到的，而3 -苯基嘧啶并[4,5 - d]嘧啶21和27是由4与苯基异氰酸酯或异硫氰酸酯环化，随后释放树脂合成的。7 - 取代嘧啶并[4,5 - d]嘧啶15、19、23和27是通过对12、16、20和24进行氧化，随后进行氨解裂解载体得到 的。
