Saxena N K, Hagenow B M, Genzlinger G, Turk S R, Drach J C, Townsend L B
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor 48109.
J Med Chem. 1988 Aug;31(8):1501-6. doi: 10.1021/jm00403a005.
Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (5). However, ammonolysis of 5 at 130 degrees C furnished 4-amino-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]-pyrrolo[2,3- d]pyrimidine (6), which on desulfurization with Raney Ni yielded 4-amino-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (7) (acyclic analogue of tubercidin). The oxidation of 6 with m-chloroperbenzoic acid provided the sulfone derivative 8. A nucleophilic displacement of the 2-methylsulfonyl group from 8 with methoxide anion provided 4-amino-2-methoxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (9). Demethylation of 9 with iodotrimethylsilane gave 4-amino-2-hydroxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (10). Treatment of 2,4-dichloropyrrolo[2,3-d]pyrimidine (11) with 3 gave the protected acyclic compound 12, which on deacetylation and ammonolysis under controlled reaction conditions gave 2,4-dichloro-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (13) and 4-amino-2-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (14), respectively. The condensation of 2-acetamido-4-chloropyrrolo[2,3-d]pyrimidine (15) with 3 gave the protected acyclic compound 16, which on concomitant deacetylation and ammonolysis with methanolic ammonia at an elevated temperature yielded 2,4-diamino-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (17) in moderate yield. In tests involving human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), only slight activity and cytotoxicity were observed. The most active compounds (12 and 13) were slightly more active against HCMV than acyclovir, but both compounds were inactive against HSV-1. The activity against HCMV, however, was not well separated from cytotoxicity leading to the conclusion that these compounds did not merit further study.
用（2 - 乙酰氧基乙氧基）甲基溴（3）处理4 - 氯 - 2 - （甲硫基）吡咯并[2,3 - d]嘧啶（2）的钠盐，得到4 - 氯 - 2 - （甲硫基）- 7 - [（2 - 乙酰氧基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（4）。4在室温下进行氨解反应，得到4 - 氯 - 2 - （甲硫基）- 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（5）。然而，5在130℃下进行氨解反应，得到4 - 氨基 - 2 - （甲硫基）- 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（6），6用雷尼镍脱硫得到4 - 氨基 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（7）（杀结核菌素的无环类似物）。用间氯过苯甲酸氧化6得到砜衍生物8。用甲醇阴离子从8中亲核取代2 - 甲基磺酰基，得到4 - 氨基 - 2 - 甲氧基 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（9）。用碘代三甲基硅烷对9进行脱甲基反应，得到4 - 氨基 - 2 - 羟基 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（10）。用3处理2,4 - 二氯吡咯并[2,3 - d]嘧啶（11），得到受保护的无环化合物12，12在受控反应条件下进行脱乙酰化和氨解反应，分别得到2,4 - 二氯 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（13）和4 - 氨基 - 2 - 氯 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（14）。2 - 乙酰氨基 - 4 - 氯吡咯并[2,3 - d]嘧啶（15）与3缩合得到受保护的无环化合物16，16在高温下与甲醇氨同时进行脱乙酰化和氨解反应，以中等产率得到2,4 - 二氨基 - 7 - [（2 - 羟基乙氧基）甲基]吡咯并[2,3 - d]嘧啶（17）。在涉及人巨细胞病毒（HCMV）和单纯疱疹病毒1型（HSV - 1）的试验中，仅观察到轻微的活性和细胞毒性。活性最高的化合物（12和13）对HCMV的活性略高于阿昔洛韦，但这两种化合物对HSV - 1均无活性。然而，其对HCMV的活性与细胞毒性没有很好地区分开来，因此得出这些化合物不值得进一步研究的结论。
