3-(3-Ethoxy-5-methyl-isoxazol-4-yl)-propionic acid ethyl ester | 197508-73-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-(3-Ethoxy-5-methyl-isoxazol-4-yl)-propionic acid ethyl ester
• 英文别名: Ethyl 3-(3-ethoxy-5-methyl-1,2-oxazol-4-yl)propanoate
• CAS: 197508-73-9
• 化学式: C₁₁H₁₇NO₄
• 分子量: 227.26
• InChiKey: VQMGGJRWMSTGBU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  16
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  61.6
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-(3-Ethoxy-5-methyl-isoxazol-4-yl)-propionic acid ethyl ester 在 二异丁基氢化铝 作用下， 以 正己烷 、 甲苯 为溶剂， 反应 24.6h， 生成 N-[(R)-1-tert-Butylcarbamoyl-3-(3-ethoxy-5-methyl-isoxazol-4-yl)-propyl]-N-((S)-1-phenyl-ethyl)-benzamide
  参考文献：
  名称：

  (S)-Homo-AMPA, a Specific Agonist at the mGlu₆ Subtype of Metabotropic Glutamic Acid Receptors

  摘要：

  Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu(6) subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu(6) (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the ''Ugi four-component condensation'', 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on H-1 NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu(1-7) were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu(6) (EC50 = 58 +/- 11 mu M) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 mu M). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu(1-7), turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 mu M).

  DOI：

  10.1021/jm9703597
• 作为产物：
  描述：

  溴乙烷 、 Aethyl-3-(3-hydroxy-5-methylisoxazol-4-yl)propionat 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 反应 24.0h， 以48%的产率得到3-(3-Ethoxy-5-methyl-isoxazol-4-yl)-propionic acid ethyl ester
  参考文献：
  名称：

  (S)-Homo-AMPA, a Specific Agonist at the mGlu₆ Subtype of Metabotropic Glutamic Acid Receptors

  摘要：

  Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu(6) subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu(6) (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the ''Ugi four-component condensation'', 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on H-1 NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu(1-7) were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu(6) (EC50 = 58 +/- 11 mu M) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 mu M). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu(1-7), turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 mu M).

  DOI：

  10.1021/jm9703597

文献信息

• (<i>S</i>)-Homo-AMPA, a Specific Agonist at the mGlu₆ Subtype of Metabotropic Glutamic Acid Receptors
  作者：Haleh Ahmadian、Birgitte Nielsen、Hans Bräuner-Osborne、Tommy N. Johansen、Tine B. Stensbøl、Frank A. Sløk、Naohiro Sekiyama、Shigetada Nakanishi、Povl Krogsgaard-Larsen、Ulf Madsen

  DOI：10.1021/jm9703597

  日期：1997.10.1

  Our previous publication (J. Med. Chem. 1996, 39, 3188-3194) described (RS)-2-amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid (Homo-AMPA) as a highly selective agonist at the mGlu(6) subtype of metabotropic excitatory amino acid (EAA) receptors. Homo-AMPA has already become a standard agonist for the pharmacological characterization of mGlu(6) (Trends Pharmacol. Sci. Suppl. 1997, 37-39), and we here report the resolution, configurational assignment, and pharmacology of (S)- (6) and (R)- (7) Homo-AMPA. Using the ''Ugi four-component condensation'', 3-(3-ethoxy-5-methylisoxazol-4-yl)propanal (10) was converted into the separable diastereomeric derivatives of 6 and 7, compounds 12 and 11, respectively. Deprotection of 12, in one or two steps, gave extensively racemized 6, which was converted in low yield into 6 (99.0% ee) through several crystallizations. 6 (99.7% ee) and 7 (99.9% ee) were finally obtained by preparative chiral HPLC. The configurational assignments of 6 and 7 were based on H-1 NMR spectroscopic studies on 12 and 11, respectively, and circular dichroism studies on 6 and 7. Values of optical rotations using different solvents and the chiral HPLC elution order of 6 and 7 supported the results of the spectroscopic configurational assignments. The activities of 6 and 7 at ionotropic EAA (iGlu) receptors and at mGlu(1-7) were studied. (S)-Homo-AMPA (6) was shown to be a specific agonist at mGlu(6) (EC50 = 58 +/- 11 mu M) comparable in potency with the endogenous mGlu agonist (S)-glutamic acid (EC50 = 20 +/- 3 mu M). Although Homo-AMPA did not show significant effects at iGlu receptors, (R)-Homo-AMPA (7), which was inactive at mGlu(1-7), turned out to be a weak N-methyl-D-aspartic acid (NMDA) receptor antagonist (IC50 = 131 +/- 18 mu M).