(4R,5R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-5--2-piperidone | 229182-28-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (4R,5R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-5--2-piperidone
• 英文别名: tert-butyl (4R,5R)-4-(4-chlorophenyl)-2-oxo-5-phenoxycarbothioyloxypiperidine-1-carboxylate
• CAS: 229182-28-9
• 化学式: C₂₃H₂₄ClNO₅S
• 分子量: 461.966
• InChiKey: OXCUJTYYMJWAHS-MOPGFXCFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  97.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (4R,5R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-5--2-piperidone 在 二-叔-丁基过氧草酸酯 、 三正丁基氢锡 作用下， 以 丙酮 为溶剂， 反应 18.0h， 以94%的产率得到(R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidinone
  参考文献：
  名称：

  Synthesis and Pharmacology of the Baclofen Homologues 5-Amino-4-(4-chlorophenyl)pentanoic Acid and the R- and S-Enantiomers of 5-Amino-3-(4-chlorophenyl)pentanoic Acid

  摘要：

  (RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acid(B) (GABA(B)) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R,5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12.HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABA(A) or GABA(B) receptor sites and was inactive as an agonist or an antagonist at GABA(B) receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABA(A) receptor sites, and in agreement with the findings far (S)-baclofen, 12 did not interact significantly with GABA(B) receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 mu M), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 mu M) as an inhibitor of GABA(B) binding. Accordingly, 11 (EC50 = 150 +/- 23 mu M) was shown to be weaker than 2 (EC50 = 11 +/- 1 mu M) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABA(B) antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 mu M) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.

  DOI：

  10.1021/jm990076+
• 作为产物：
  描述：

  硫代氯甲酸苯酯 、 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 18.0h， 以85%的产率得到(4R,5R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-5--2-piperidone
  参考文献：
  名称：

  Synthesis and Pharmacology of the Baclofen Homologues 5-Amino-4-(4-chlorophenyl)pentanoic Acid and the R- and S-Enantiomers of 5-Amino-3-(4-chlorophenyl)pentanoic Acid

  摘要：

  (RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acid(B) (GABA(B)) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R,5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12.HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABA(A) or GABA(B) receptor sites and was inactive as an agonist or an antagonist at GABA(B) receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABA(A) receptor sites, and in agreement with the findings far (S)-baclofen, 12 did not interact significantly with GABA(B) receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 mu M), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 mu M) as an inhibitor of GABA(B) binding. Accordingly, 11 (EC50 = 150 +/- 23 mu M) was shown to be weaker than 2 (EC50 = 11 +/- 1 mu M) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABA(B) antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 mu M) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.

  DOI：

  10.1021/jm990076+

文献信息

• Synthesis and Pharmacology of the Baclofen Homologues 5-Amino-4-(4-chlorophenyl)pentanoic Acid and the <i>R</i>- and <i>S</i>-Enantiomers of 5-Amino-3-(4-chlorophenyl)pentanoic Acid
  作者：Rolf Karla、Bjarke Ebert、Christian Thorkildsen、Claus Herdeis、Tommy N. Johansen、Birgitte Nielsen、Povl Krogsgaard-Larsen

  DOI：10.1021/jm990076+

  日期：1999.6.1

  (RS)-5-Amino-4-(4-chlorophenyl)pentanoic acid (10) and the R-form (11) and S-form (12) of (RS)-5-amino-3-(4-chlorophenyl)pentanoic acid, which are homologues of the 4-aminobutanoic acid(B) (GABA(B)) receptor agonist (RS)-4-amino-3-(4-chlorophenyl)butanoic acid (baclofen), were synthesized. Compound 10 was synthesized by homologation at the carboxyl end of baclofen using a seven-step reaction sequence. N-Boc-protected (4R,5R)-4-(4-chlorophenyl)-5-hydroxy-2-piperidone (18) was deoxygenated via a modified Barton-McCombie reaction to give N-Boc-protected (R)-4-(4-chlorophenyl)-2-piperidone (20), which was ring opened and deprotected to give 11.HCl. The corresponding S-enantiomer, 12.HCl, was synthesized analogously from the 4S,5S-enantiomer of 18, compound 21. The enantiomeric purities of 11.HCl (ee = 99.8%) and 12.HCl (ee = 99.3%) were determined by chiral HPLC. Compound 10 did not show detectable affinity for GABA(A) or GABA(B) receptor sites and was inactive as an agonist or an antagonist at GABA(B) receptors in the guinea pig ileum. Like the enantiomers of baclofen, neither 11 nor 12 showed detectable affinity for GABA(A) receptor sites, and in agreement with the findings far (S)-baclofen, 12 did not interact significantly with GABA(B) receptor sites. Compound 11 (IC50 = 7.4 +/- 0.6 mu M), a homologue of (R)-baclofen (2), was shown to be some 50 times weaker than 2 (IC50 = 0.14 +/- 0.01 mu M) as an inhibitor of GABA(B) binding. Accordingly, 11 (EC50 = 150 +/- 23 mu M) was shown to be weaker than 2 (EC50 = 11 +/- 1 mu M) as an inhibitor of electrically induced contractions of the guinea pig ileum. However, whereas this effect of 2 was sensitive to the GABA(B) antagonist, CGP35348 (4), the inhibition by 11 was not significantly affected. Furthermore, 12 (EC50 = 310 +/- 16 mu M) was shown to be one-half as potent as 11 in this test system, and this effect of 12 also was insensitive to 4. The dissimilarities of the pharmacological effects of 2 and compounds 11 and 12 were emphasized by the observation that whereas 2 only inhibits the ileum contraction by 59 +/- 5%, 11 as well as 12 were shown to inhibit this response by approximately 94%. Neither 11 nor 12 appeared to affect significantly cholinergic mechanisms in the ileum, and their mechanism(s) of action remain enigmatic.