2,6-dimethyl-1,2,3,4-tetrahydroquinazolin-4-one | 133933-29-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2,6-dimethyl-1,2,3,4-tetrahydroquinazolin-4-one
• 英文别名: 2,6-dimethyl-1,2-dihydro-3H-quinazolin-4-one；2,6-dimethyl-2,3-dihydro-1H-quinazolin-4-one
• CAS: 133933-29-6
• 化学式: C₁₀H₁₂N₂O
• 分子量: 176.218
• InChiKey: CHMYJIVVAVLYFY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  13
• 可旋转键数：
  0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  41.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2,6-dimethyl-1,2,3,4-tetrahydroquinazolin-4-one 在 sodium hydroxide 、 N-溴代丁二酰亚胺(NBS) 、 过氧化氢苯甲酰 、 magnesium oxide 作用下， 以 四氯化碳 、 乙醇 、 二氯甲烷 、 N,N-二甲基乙酰胺 为溶剂， 反应 23.0h， 生成 2-desamino-2-methyl-N¹⁰-propargyl-5,8-dideaza-1,2-dihydrofolic acid
  参考文献：
  名称：

  Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid

  摘要：

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.

  DOI：

  10.1021/jm00113a011
• 作为产物：
  描述：

  2,6-二甲基-3H-喹唑啉-4-酮 在 sodium tetrahydroborate 、 溶剂黄146 作用下， 以70%的产率得到2,6-dimethyl-1,2,3,4-tetrahydroquinazolin-4-one
  参考文献：
  名称：

  Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid

  摘要：

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.

  DOI：

  10.1021/jm00113a011

文献信息

• Application of Organolithium in Organic Synthesis: A Simple and Convenient Procedure for the Synthesis of More Complex 6-Substituted 3 H -Quinazolin-4-ones
  作者：Gamal A. El-Hiti

  DOI：10.1007/s00706-003-0110-5

  日期：2004.3.1

  6-Methyl-3 H -quinazolin-4-one reacted with alkyllithium reagents at −78°C in THF to give 2-alkyl-1,2-dihydro-6-methyl-3 H -quinazolin-4-ones in high yields. However, no reaction took place when LDA was used as the lithium reagent. 6-Bromo-3 H -quinazolin-4-one reacted with excessive butyllithium to give 2-butyl-1,2-dihydro-3 H -quinazolin-4-ones in very good yields. However, the lithiation of 6-bromo-3

  在-78°C下，6-甲基-3 H- 喹唑啉-4-酮与烷基锂试剂在 THF中 反应， 以高收率得到2-烷基-1,2-二氢-6-甲基-3 H- 喹唑啉-4-酮。然而，当 LDA 用作锂试剂时，没有反应发生 。6-溴-3 H- 喹唑啉-4-酮与过量的丁基锂反应，以非常好的收率得到2-丁基-1,2-二氢-3 H- 喹唑啉-4-酮。然而，通过在-78°C下在 THF中 使用甲基锂（1.1当量）和 叔丁基 锂（2.2当量） 的组合，实现了6-溴-3 H- 喹唑啉-4-酮 的锂化 。如此获得的二硫代试剂与各种亲电试剂（H 2 O，碘乙烷，苯甲醛，茴香醛，环己酮，2-己酮，二苯甲酮，苯基异硫氰酸酯， TITD ）反应，得到相应的6-取代的3 H- 喹唑啉-4-酮高产。二硫代试剂与1，3-二溴丙烷的反应得到6，6′-（丙二基）双（3 H- 喹唑啉-4-酮）。
• Folate analogs. 35. Synthesis and biological evaluation of 1-deaza, 3-deaza, and bridge-elongated analogs of N10-propargyl-5,8-dideazafolic acid
  作者：Shu Wen Li、M. G. Nair、Donna M. Edwards、R. L. Kisliuk、Y. Gaumont、I. K. Dev、D. S. Duch、J. Humphreys、G. K. Smith、Robert Ferone

  DOI：10.1021/jm00113a011

  日期：1991.9

  Structural modifications at the pyrimidine ring and at the C-9,N-10-bridge region of the thymidylate synthase (TS) inhibitors N-10-propargyl-5,8-dideazafolate (1; PDDF; CB 3717), 2-desamino-N10-propargyl-5,8-dideazafolate (2, DPDDF), and 2-desamino-2-methyl-N-10-propargyl-5,8-dideazafolate (3, DMPDDF) have been carried out. Methods for the synthesis of 2-desamino-N-10-propargyl-1,5,8-trideazafolate (4), 2-desamino-2-methyl-N-10-propargyl-3,5,8-trideazafolate (5a), and 2-desamino-2-methyl-N10-propargyl-5,8-dideaza-1,2-dihydrofolate (6) have been developed. The bridge-extended analogues isohomo-PDDF (7) and isohomo-DMPDDF (8) contain an additional methylene group interposed between N-10 and the phenyl ring of 1 and 3, respectively. All new compounds were evaluated as inhibitors of TS and the growth of tumor cells in culture. Selected analogues were tested as substrates of folylpolyglutamate synthetase (FPGS) and striking differences in substrate activity were observed among these compounds, indicating that structural modifications at the pyrimidine ring of classical antifolates profoundly influence their polyglutamylation. Enzyme inhibition data established that both N1 and N3-H of the pyrimidine ring are essential for efficient binding of quinazoline-type antifolates to human TS.