Methyl 4-[3-(2,4-diaminopteridin-6-yl)-1-methoxy-1-oxopropan-2-yl]naphthalene-1-carboxylate | 173677-83-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: Methyl 4-[3-(2,4-diaminopteridin-6-yl)-1-methoxy-1-oxopropan-2-yl]naphthalene-1-carboxylate
• CAS: 173677-83-3
• 化学式: C₂₂H₂₀N₆O₄
• 分子量: 432.439
• InChiKey: WLBHZFPQCQIZJP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  156
• 氢给体数：
  2
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  Methyl 4-[3-(2,4-diaminopteridin-6-yl)-1-methoxy-1-oxopropan-2-yl]naphthalene-1-carboxylate 在 sodium hydroxide 、 三乙胺 、 氯甲酸异丁酯 作用下， 以 乙二醇甲醚 、 水 、 二甲基亚砜 为溶剂， 反应 82.5h， 生成 N-{4-[2-(2,4-diamino-6-pteridinyl)ethyl]-1-naphthoyl}-L-glutamic acid diethyl ester
  参考文献：
  名称：

  Analogues of 10-Deazaaminopterin and 5-Alkyl-5,10-dideazaaminopterin with the 4-Substituted 1-Naphthoyl Group in the Place of 4-Substituted Benzoyl

  摘要：

  10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5,10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxy-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (la) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-ethyl-5-deazapteridines (Ib and Ic, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5-methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with la failed as did attempted further alkylation (by EtBr) of the product derived from la and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the E0771 mammary adenocarcinoma in mice, 9a was less active than MTX.

  DOI：

  10.1021/jm9506940
• 作为产物：
  描述：

  4-carboxy-1-naphthaleneacetic acid 在 硫酸 、 sodium hydride 作用下， 反应 23.75h， 生成 Methyl 4-[3-(2,4-diaminopteridin-6-yl)-1-methoxy-1-oxopropan-2-yl]naphthalene-1-carboxylate
  参考文献：
  名称：

  Analogues of 10-Deazaaminopterin and 5-Alkyl-5,10-dideazaaminopterin with the 4-Substituted 1-Naphthoyl Group in the Place of 4-Substituted Benzoyl

  摘要：

  10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5,10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxy-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (la) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-ethyl-5-deazapteridines (Ib and Ic, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5-methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with la failed as did attempted further alkylation (by EtBr) of the product derived from la and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the E0771 mammary adenocarcinoma in mice, 9a was less active than MTX.

  DOI：

  10.1021/jm9506940

文献信息

• Analogues of 10-Deazaaminopterin and 5-Alkyl-5,10-dideazaaminopterin with the 4-Substituted 1-Naphthoyl Group in the Place of 4-Substituted Benzoyl
  作者：James R. Piper、Balakrishnan Ramamurthy、Cheryl A. Johnson、Glenys M. Otter、Francis M. Sirotnak

  DOI：10.1021/jm9506940

  日期：1996.1.1

  10-Deaza modifications of classical antifolate analogues bearing the 1,4-disubstituted naphthalene ring in place of the 1,4-disubstituted benzene ring were prepared and tested for antitumor activity. Naphthalene analogues (9a-c, respectively) of 10-deazaaminopterin, 5-methyl-5,10-dideazaaminopterin, and 5-ethyl-5,10-dideazaaminopterin were prepared by a route consisting of C-alkylations of the anion derived from 4-carboxy-1-naphthaleneacetic acid dimethyl ester (2) by 6-(bromomethyl)-2,4-diaminopteridine (la) and 6-(bromomethyl)-2,4-diamino-5-methyl- and -5-ethyl-5-deazapteridines (Ib and Ic, respectively) followed by ester hydrolysis and subsequent decarboxylation to give naphthalene analogues (7a-c, respectively) of 4-amino-4-deoxy-10-deazapteroic acid and 4-amino-4-deoxy-5-methyl- and -5-ethyl-5,10-dideazapteroic acids. Peptide coupling of 7a-c with L-glutamic acid dialkyl ester followed by mild ester hydrolysis gave target compounds 9a-c. The key advantage of this route is circumvention of a hydrogenation step requiring selectivity as in earlier approaches involving 9,10-olefinic precursors. Steric limitations thwarted plans to prepare the naphthalene analogue of 10-ethyl-10-deazaaminopterin; attempted alkylations of 2-(4-carboxy-1-naphthyl)butyric acid dimethyl ester with la failed as did attempted further alkylation (by EtBr) of the product derived from la and 2. Growth inhibition tests against three tumor cell lines (L1210, S180, and HL60) showed 9a to be 4-6-fold more inhibitory than methotrexate but not as inhibitory as 10-ethyl-10-deazaaminopterin; 9b and 9c were no more inhibitory than MTX. In tests against the E0771 mammary adenocarcinoma in mice, 9a was less active than MTX.