Parallel solution-phase synthesis of a 2,6,8,9-tetrasubstituted purine library via a sulfur intermediate.
Purine analogues exhibiting a wide range of pharmacological activities have been considered a privileged structure in medicinal chemistry. In addition, the purine core consisting of four points of structural diversity is a well-sought scaffold in combinatorial chemistry. Although most of the efforts have been focused on 2,6,9-, 6,8,9-, or 2,8,9-trisubstituted purines, syntheses of 2,6,8,9-tetrasubstituted purines are rare. This paper presents a parallel solution phase approach for the synthesis of fully substituted purines via a 6-sulfur-substituted pyrimidine as the key intermediate. This strategy combining construction and modification of the purine ring thus increases the structural diversity of the final products. Sequential substitution of chlorines in 4,6-dichloro-2-methyl-5-nitropyrimidine with primary amine and benzylmercaptan afforded the 4-(substituted)amino-6-benzylthio-5-nitropyrimidine, which was readily converted to its diaminopyrimidine analogue by reduction of the nitro group. The diaminopyrimidine intermediate was cyclized to construct the purine ring with a C-8 substituent. Eventual oxidation of sulfur to sulfone and subsequent displacement by a primary or secondary amine provided the desired 2,6,8,9-tetrasubstituted purine analogues. This synthetic methodology was validated with the synthesis of a 216-member purine library.
Liu
Jinglin
J
Center for Combinatorial Chemistry and Drug Discovery, Jilin University, 75 Jinlai Street, Changchun, Jilin 130012, China.
Dang
Qun
Q
Wei
Zhonglin
Z
Zhang
Hengbin
H
Bai
Xu
X
D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D011687:Purines / Q000138:chemical synthesis* / Q000737:chemistry*; D013455:Sulfur / Q000737:chemistry*
D011687:Purines; D013455:Sulfur