ethyl 4-(3-((tert-butyldimethylsilyl)oxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate | 482655-63-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: ethyl 4-(3-((tert-butyldimethylsilyl)oxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
• 英文别名: ethyl 4-[3-[tert-butyl(dimethyl)silyl]oxyphenyl]-6-methyl-2-sulfanylidene-3,4-dihydro-1H-pyrimidine-5-carboxylate
• CAS: 482655-63-0
• 化学式: C₂₀H₃₀N₂O₃SSi
• 分子量: 406.621
• InChiKey: ISYMCZRLUYSSNO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.43
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  91.7
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  ethyl 4-(3-((tert-butyldimethylsilyl)oxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate 在 sodium ethanolate 作用下， 以 乙醇 、 甲苯 为溶剂， 反应 16.0h， 生成 (-)-4-(3-hydroxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid ethyl ester
  参考文献：
  名称：

  外消旋菊酯的合成和制备规模拆分的改进

  摘要：

  Yb（OTf）3催化3-羟基苯甲醛，乙酰乙酸乙酯和硫脲的Biginelli环缩合反应，得到相应的二氢嘧啶-2-硫酮，称为monastrol，分离产率为95％。通过非对映异构体N -3呋喃核糖基酰胺的制备规模（约100 mg），通过驱动蛋白Eg5的抑制作用，将手性拆分消旋莫纳斯特罗尔（一种有丝分裂阻滞剂）进行了手性拆分。

  DOI：

  10.1016/s0040-4039(02)01269-8
• 作为产物：
  描述：

  乙酰乙酸乙酯 在 咪唑 、 ytterbium(III) triflate 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 1.0h， 生成 ethyl 4-(3-((tert-butyldimethylsilyl)oxy)phenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate
  参考文献：
  名称：

  Monastrol, a 3,4-dihydropyrimidin-2(1 H )-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α 1 β 2 δ GABA A receptors

  摘要：

  The (alpha(4)beta delta subtype of the gamma-aminobutyric acid (GABA) type A receptors (GABA(A)Rs) has been shown to be implicated in high-affinity binding of the neuromodulator gamma-hydroxybutyric acid (GHB), but may not be the only GHB high-affinity binding sites. Monastrol has been identified as a modulator of GHB high affinity binding and is furthermore reported as an allosteric modulator selective for the alpha(1)beta(2)delta GABAARs. Therefore, structural determinants for selectivity at the two targets were investigated. 39 structural diverse monastrol analogues were synthesized by employing the Biginelli cyclocondensation and examined for modulation of GHB high-affinity binding using the GHB-specific ligand [H-3]NCS-382 [(E,RS)=6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid] in rat brain homogenate. Only limited modifications were allowed on the monastrol scaffold in order to maintain modulation of GHB high-affinity binding. However, three analogues of monastrol (11,12 and 24) enhanced the maximal binding of [H-3]NCS-382 to a higher maximal level than seen for monastrol itself. Selected compounds were further characterized as modulators at alpha(1)beta(2)delta, alpha(1)beta(2)gamma(2s) and alpha(1)beta(2) GABA(A)Rs. Most of these modulators were shown to have delta-specific GABA-potentiating effects. The dual effect shown for monastrol to modulate the GHB high-affinity binding and alpha(1)beta(2)delta GABA(A)R activity was also shown for the compounds 11, 18 and 24. Compound 29 displayed minimal modulatory effect on GABA(A)Rs and therefore appears to be a GHB high-affinity binding preferring modulator. However, compounds 34 and 37 were shown to be alpha(1)beta(2)delta GABA(A)R selective modulators, without modulatory effects on GHB high-affinity binding. Thus, our study shows that minor modifications in the structure of monastrol affects the selectivity profile for the two targets under study enabling separation of the dual activity. (C) 2017 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2017.06.024

文献信息

• Monastrol, a 3,4-dihydropyrimidin-2(1 H )-thione, as structural scaffold for the development of modulators for GHB high-affinity binding sites and α 1 β 2 δ GABA A receptors
  作者：Maria Damgaard、Anas Al-Khawaja、Mia Nittegaard-Nielsen、Rebekka F. Petersen、Petrine Wellendorph、Bente Frølund

  DOI：10.1016/j.ejmech.2017.06.024

  日期：2017.9

  The (alpha(4)beta delta subtype of the gamma-aminobutyric acid (GABA) type A receptors (GABA(A)Rs) has been shown to be implicated in high-affinity binding of the neuromodulator gamma-hydroxybutyric acid (GHB), but may not be the only GHB high-affinity binding sites. Monastrol has been identified as a modulator of GHB high affinity binding and is furthermore reported as an allosteric modulator selective for the alpha(1)beta(2)delta GABAARs. Therefore, structural determinants for selectivity at the two targets were investigated. 39 structural diverse monastrol analogues were synthesized by employing the Biginelli cyclocondensation and examined for modulation of GHB high-affinity binding using the GHB-specific ligand [H-3]NCS-382 [(E,RS)=6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)acetic acid] in rat brain homogenate. Only limited modifications were allowed on the monastrol scaffold in order to maintain modulation of GHB high-affinity binding. However, three analogues of monastrol (11,12 and 24) enhanced the maximal binding of [H-3]NCS-382 to a higher maximal level than seen for monastrol itself. Selected compounds were further characterized as modulators at alpha(1)beta(2)delta, alpha(1)beta(2)gamma(2s) and alpha(1)beta(2) GABA(A)Rs. Most of these modulators were shown to have delta-specific GABA-potentiating effects. The dual effect shown for monastrol to modulate the GHB high-affinity binding and alpha(1)beta(2)delta GABA(A)R activity was also shown for the compounds 11, 18 and 24. Compound 29 displayed minimal modulatory effect on GABA(A)Rs and therefore appears to be a GHB high-affinity binding preferring modulator. However, compounds 34 and 37 were shown to be alpha(1)beta(2)delta GABA(A)R selective modulators, without modulatory effects on GHB high-affinity binding. Thus, our study shows that minor modifications in the structure of monastrol affects the selectivity profile for the two targets under study enabling separation of the dual activity. (C) 2017 Elsevier Masson SAS. All rights reserved.
• Improved synthesis and preparative scale resolution of racemic monastrol
  作者：Alessandro Dondoni、Alessandro Massi、Simona Sabbatini

  DOI：10.1016/s0040-4039(02)01269-8

  日期：2002.8

  Biginelli cyclocondensation reaction of 3-hydroxybenzaldehyde, ethyl acetoacetate and thiourea afforded the corresponding dihydropyrimidine-2-thione, called monastrol, in 95% isolated yield. The chiral resolution of racemic monastrol, a mitosis blocker by kinesin Eg5 inhibition, was carried out on a preparative scale (ca. 100 mg) through diastereomeric N-3 ribofuranosyl amides.

  Yb（OTf）3催化3-羟基苯甲醛，乙酰乙酸乙酯和硫脲的Biginelli环缩合反应，得到相应的二氢嘧啶-2-硫酮，称为monastrol，分离产率为95％。通过非对映异构体N -3呋喃核糖基酰胺的制备规模（约100 mg），通过驱动蛋白Eg5的抑制作用，将手性拆分消旋莫纳斯特罗尔（一种有丝分裂阻滞剂）进行了手性拆分。