2,4-bis(pivaloylamino)-6-bromopyrido<2,3-d>pyrimidine | 138609-27-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2,4-bis(pivaloylamino)-6-bromopyrido<2,3-d>pyrimidine
• 英文别名: 2,4-dipivaloylamino-5-bromopyrido[2,3-d]pyrimidine；2,4-dipivaloylamino-6-bromopyrido<2,3-d>pyrimidine；2,4-dipivaloylamino-6-bromopyrido[2,3-d]pyrimidine；F7Buq3H9GQ；N-[6-bromo-2-(2,2-dimethylpropanoylamino)pyrido[2,3-d]pyrimidin-4-yl]-2,2-dimethylpropanamide
• CAS: 138609-27-5
• 化学式: C₁₇H₂₂BrN₅O₂
• 分子量: 408.298
• InChiKey: CQSPARJMYYRUMZ-UHFFFAOYSA-N

物化性质

• 密度：
  1.434±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  96.9
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,4-bis(pivaloylamino)-6-bromopyrido<2,3-d>pyrimidine 在 palladium diacetate 、 copper(l) iodide 、 三乙胺-硼烷 、 sodium methylate 、 臭氧 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 二氯甲烷 、 溶剂黄146 、 乙腈 为溶剂， 反应 106.0h， 生成 6-[(3,4,5-Trimethoxyanilino)methyl]pyrido[2,3-d]pyrimidine-2,4-diamine
  参考文献：
  名称：

  Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates

  摘要：

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.

  DOI：

  10.1021/jm9606913
• 作为产物：
  描述：

  三甲基乙酸酐 、 6-溴吡啶并[2,3-D]-2,4-二氨基嘧啶 在 吡啶 作用下， 反应 8.0h， 生成 2,4-bis(pivaloylamino)-6-bromopyrido<2,3-d>pyrimidine
  参考文献：
  名称：

  2,4-二氨基-5,10-二氮杂非经典抗叶酸剂的合成

  摘要：

  吡咯烷酮化后，将2,4,6-三氨基嘧啶（8）与溴代丙二醛（9）缩合，得到2,4-二哌戊酰基-6-溴代吡啶并[2,3- d ]嘧啶（11）。这个6-溴衍生物充当关键中间体2,4-二氨基-6-的合成[2-（3'，4'-二甲氧基苯基）乙烯基〕吡啶并[2,3- d ]嘧啶（5）通过一个钯催化的碳-碳与3,4-二甲氧基苯乙烯的偶联（12）。作为二氢叶酸还原酶的潜在抑制剂，化合物5，其9,10-二氢类似物6和5,6,7,8,9,10-六氢类似物7是令人感兴趣的。化合物通过5％Pd-C的催化加氢从5合成6和7。

  DOI：

  10.1002/jhet.5570280717

文献信息

• Synthesis of 2,4-diamino-5,10-dideaza nonclassical antifolates
  作者：Aleem Gangjee、Rajesh Devraj、Fu-Tyan Lin

  DOI：10.1002/jhet.5570280717

  日期：1991.11

  6-triaminopyrimidine (8) with bromomalonaldehyde (9) afforded, after pivaloylation, 2,4-dipivaloyl-6-bromopyrido[2,3-d]pyrimidine (11). This 6-bromo derivative served as a key intermediate for the synthesis of 2,4-diamino-6-[2-(3′,4′-dimethoxyphenyl)ethenyl]pyrido[2,3-d]pyrimidine (5) via a palladium catalyzed carbon-carbon coupling with 3,4-dimethoxystyrene (12). Compound 5, its 9,10-dihydro analogue

  吡咯烷酮化后，将2,4,6-三氨基嘧啶（8）与溴代丙二醛（9）缩合，得到2,4-二哌戊酰基-6-溴代吡啶并[2,3- d ]嘧啶（11）。这个6-溴衍生物充当关键中间体2,4-二氨基-6-的合成[2-（3'，4'-二甲氧基苯基）乙烯基〕吡啶并[2,3- d ]嘧啶（5）通过一个钯催化的碳-碳与3,4-二甲氧基苯乙烯的偶联（12）。作为二氢叶酸还原酶的潜在抑制剂，化合物5，其9,10-二氢类似物6和5,6,7,8,9,10-六氢类似物7是令人感兴趣的。化合物通过5％Pd-C的催化加氢从5合成6和7。
• Synthesis of new 2,4-Diaminopyrido[2,3-d]pyrimidine and 2,4-Diaminopyrrolo[2,3-d]pyrimidine inhibitors of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductase
  作者：Andre Rosowsky、Han Chen、Hongning Fu、Sherry F. Queener

  DOI：10.1016/s0968-0896(02)00325-5

  日期：2003.1

  groups with base. Also prepared via a scheme based on the Taylor ring expansion/ring annulation synthesis were three heretofore undescribed 2,4-diamino-5-(substituted benzyl)-7H-pyrrolo[2,3-d]pyrimidines (3b-c). Standard spectrophotometric assays were used to compare the ability of 2a-e and 3b-c to inhibit dihydrofolate reductase (DHFR) from Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium

  开发了一条简洁的新路线，可轻松获得五个以前未报告的2,4-二氨基-6-（取代的苄基）吡啶并[2,3-d]嘧啶（2a-e），涉及2,4-二戊酰氨基-5的缩合。催化量的[1,1'-双（二苯基膦基）二茂铁]二氯钯（II）.CH（2）Cl（2）存在下，将溴化吡啶并[2,3-d]嘧啶（6）与有机锌卤化物，然后用碱除去新戊酰基。还通过基于泰勒环膨胀/环环合成的方案制备了三个迄今为止未描述的2,4-二氨基-5-（取代的苄基）-7H-吡咯并[2,3-d]嘧啶（3b-c）。使用标准分光光度法比较了2a-e和3b-c抑制卡氏肺孢子虫，弓形虫和鸟分枝杆菌的二氢叶酸还原酶（DHFR）的能力，艾滋病患者由于免疫功能低下而极易受到机会病原体侵害的三个例子。为了进行比较，还评估了13种先前未经测试的2,4-二氨基-6-（取代的苄基）喹唑啉（17a-m）作为这些酶以及大鼠肝脏酶的抑制剂。测试的喹唑啉或吡啶嘧啶类化合物对卡
• US5508281A
  申请人：——

  公开号：US5508281A

  公开（公告）日：1996-04-16
• US6114339A
  申请人：——

  公开号：US6114339A

  公开（公告）日：2000-09-05
• Synthesis and Dihydrofolate Reductase Inhibitory Activities of 2,4-Diamino-5-deaza and 2,4-Diamino-5,10-dideaza Lipophilic Antifolates
  作者：Aleem Gangjee、Rajesh Devraj、Sherry F. Queener

  DOI：10.1021/jm9606913

  日期：1997.2.1

  Two series of nonclassical antifolates (2,4-diamino-5-deaza compounds 2-5 and 5,10-dideaza compounds 6-13) were synthesized as inhibitors of dihydrofolate reductase (DHFR) from Pneumocystis carinii (pc) and Toxoplasma gondii (tg) organisms that are responsible for fatal opportunistic infections in AIDS patients. Rat liver (rl) DHFR served as the mammalian reference enzyme to determine selectivity. Syntheses of the target 5-deaza compounds were achieved by initial construction of the pivaloyl-protected 2,4-diamino-6-bromopyrido[2,3-d]-pyrimidine 17 via a cyclocondensation of 2,4,6-triaminopyrimidine with bromomalonaldehyde. Sequential Heck coupling of 17 with styrene followed by ozonolysis afforded the g-formyl derivative 19. Reductive amination of 19 with 3,4,5-trimethoxyaniline afforded the N10-H analog. The NIO-Me and NIO-Et analogs were synthesized by nucleophilic displacement of the 6-bromomethyl derivative 22 (obtained from the g-formyl derivative 19 by reduction and bromination) with the appropriate N-alkylaniline. The trans-5,10-dideaza analogs 6-8 were synthesized via a Heck coupling of the appropriate methoxystyrene with 17, and selective reduction of the resulting 9,10-double bond afforded target compounds 9-11. Further reduction to the tetrahydro derivatives afforded analogs 12 and 13. The 5-deaza NIO-Me 3,4,5-trimethoxy analog 3 maintained the best balance of potency and selectivity against both tgDHFR and pcDHFR. Compared to trimethoprim, compound 3 was only slightly less selective but was 300-fold more potent against tgDHFR. The 5,10-dideaza analogs were generally less potent and selective than the 5-deaza compounds.