(S)-2-Amino-4-(1-tert-butoxycarbonyl-1-methyl-ethylcarbamoyl)-butyric acid tert-butyl ester | 158805-02-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-2-Amino-4-(1-tert-butoxycarbonyl-1-methyl-ethylcarbamoyl)-butyric acid tert-butyl ester
• 英文别名: H-gGlu(OtBu)-Aib-OtBu；tert-butyl (2S)-2-amino-5-[[2-methyl-1-[(2-methylpropan-2-yl)oxy]-1-oxopropan-2-yl]amino]-5-oxopentanoate
• CAS: 158805-02-8
• 化学式: C₁₇H₃₂N₂O₅
• 分子量: 344.451
• InChiKey: OOKISPMLPVPJOS-NSHDSACASA-N

物化性质

• 沸点：
  457.4±40.0 °C(predicted)
• 密度：
  1.055±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  24
• 可旋转键数：
  10
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4--N-prop-2-ynylamino>benzoic acid, trifluoroacetate salt 、 (S)-2-Amino-4-(1-tert-butoxycarbonyl-1-methyl-ethylcarbamoyl)-butyric acid tert-butyl ester 在 三乙胺 、 焦碳酸二乙酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以72%的产率得到(S)-4-(1-tert-Butoxycarbonyl-1-methyl-ethylcarbamoyl)-2-{4-[(2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl)-prop-2-ynyl-amino]-benzoylamino}-butyric acid tert-butyl ester
  参考文献：
  名称：

  Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)

  摘要：

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.

  DOI：

  10.1021/jm960878u
• 作为产物：
  描述：

  Z-谷安酸叔丁基酯 在 palladium on activated charcoal N-甲基吗啉 、 氢气 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 6.84h， 生成 (S)-2-Amino-4-(1-tert-butoxycarbonyl-1-methyl-ethylcarbamoyl)-butyric acid tert-butyl ester
  参考文献：
  名称：

  Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-N¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)

  摘要：

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.

  DOI：

  10.1021/jm960878u

文献信息

• Folate-Based Inhibitors of Thymidylate Synthase:  Synthesis and Antitumor Activity of γ-Linked Sterically Hindered Dipeptide Analogues of 2-Desamino-2-methyl-<i>N</i>¹⁰-propargyl-5,8-dideazafolic Acid (ICI 198583)
  作者：Vassilios Bavetsias、Ann L. Jackman、Jonathan H. Marriott、Rosemary Kimbell、William Gibson、F. Thomas Boyle、Graham M. F. Bisset

  DOI：10.1021/jm960878u

  日期：1997.5.1

  In an effort to synthesize inhibitors of thymidylate synthase (TS) that do not undergo polyglutamation, a series of gamma-linked sterically hindered dipeptide analogues of 2-desamino-2-methyl-N-10-propargyl-5 ,8-dideazafolic acid (ICI 198583) was prepared. A methyl, ethyl, or propargyl group was incorporated into the gamma-glutamyl amide bond of gamma-linked L,L dipeptide derivatives of ICI 198583, such as ICI 198583-gamma-L-Glu. In addition, steric bulk was introduced on either side of the gamma-glutamyl bond of ICI 198583-gamma-L-Glu or ICI 198583-gamma-L-Ala. The resulting dipeptide analogues, e.g., ICI 198583-gamma-MeGlu and ICI 198583-gamma-Aib, were apparently stable to in vivo hydrolysis but poorer inhibitors of TS and L1210 cell growth. However, introduction of 7-Me, 2'-F substitution into the quinazoline nucleus gave significant improvement in the inhibitory activity against thymidylate synthase. Compounds 28-30, the 7-Me, 2'-F derivatives of ICI 198583-gamma-MeGlu, ICI 198583-gamma-EtGlu, and ICI 198583-gamma-PgGlu, respectively, were potent inhibitors of TS (Ki(iapp) = 0.21-1.1 nM) and L1210 cell growth (IC50 = 0.05-0.34 mu M) and were similar to that seen with the most potent gamma-linked L,D dipeptide derivatives of ICI 198583 previously synthesized. Furthermore, the low cross-resistance ratios for the L1210:R-D1694/L1210 cell line indicated that 28-30 do not undergo polyglutamation.