(R)-5--3-(4-chlorophenyl)pentanoic acid | 229182-32-5

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 苯丙酸
• 英文名称: (R)-5--3-(4-chlorophenyl)pentanoic acid
• 英文别名: (R)-5-((tert-butoxycarbonyl)amino)-3-(4-chlorophenyl)pentanoic acid；(3R)-3-(4-chlorophenyl)-5-[(2-methylpropan-2-yl)oxycarbonylamino]pentanoic acid
• CAS: 229182-32-5
• 化学式: C₁₆H₂₂ClNO₄
• 分子量: 327.808
• InChiKey: JYQKUMGPBHVMSF-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  75.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-5--3-(4-chlorophenyl)pentanoic acid 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 反应 24.0h， 以96%的产率得到(R)-5-amino-3-(4-chlorophenyl)pentanoic acid hydrochloride
  参考文献：
  名称：

  铑/二烯催化的N -Boc保护的α，β-不饱和δ-内酰胺与芳基硼酸的不对称芳基化：4-芳基-2-哌啶酮的对映选择性合成

  摘要：

  利用甲苯/异丙醇（20：1至40：1）作为溶剂，并使用KHF 2作为添加剂，芳基硼酸的铑/二烯催化的不对称芳基化（RCAA）反应生成N -Boc保护的α，β-不饱和δ -内酰胺顺利进行，得到高至优异的收率（高达94％）和对映选择性（高达> 99％ee）的手性4-芳基-2-哌啶子酮。还提出了将加合物（R）-1-（叔丁氧基羰基）-4-（4-氯苯基）-2-哌啶酮进一步转化为（R）-高巴氯芬盐酸盐。

  DOI：

  10.1016/j.tet.2012.09.001
• 作为产物：
  描述：

  (4R,5R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-5--2-piperidone 在 lithium hydroxide 、 二-叔-丁基过氧草酸酯 、 三正丁基氢锡 作用下， 以 四氢呋喃 、 丙酮 为溶剂， 反应 23.0h， 生成 (R)-5--3-(4-chlorophenyl)pentanoic acid
  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

• Rhodium/diene-catalyzed asymmetric arylation of N-Boc-protected α,β-unsaturated δ-lactam with arylboronic acids: enantioselective synthesis of 4-aryl-2-piperidinones
  作者：Zhi-Tao He、Ya-Bing Wei、Hong-Jie Yu、Cai-Yun Sun、Chen-Guo Feng、Ping Tian、Guo-Qiang Lin

  DOI：10.1016/j.tet.2012.09.001

  日期：2012.11

  toluene/isopropanol (20:1 to 40:1) as a solvent and KHF2 as an additive, the rhodium/diene-catalyzed asymmetric arylation (RCAA) reaction of arylboronic acids to N-Boc-protected α,β-unsaturated δ-lactam proceeded smoothly to afford chiral 4-aryl-2-piperidinones with high to excellent yields (up to 94%) and enantioselectivities (up to >99% ee). Further conversion of adduct (R)-1-(tert-butyloxycarbonyl

  利用甲苯/异丙醇（20：1至40：1）作为溶剂，并使用KHF 2作为添加剂，芳基硼酸的铑/二烯催化的不对称芳基化（RCAA）反应生成N -Boc保护的α，β-不饱和δ -内酰胺顺利进行，得到高至优异的收率（高达94％）和对映选择性（高达> 99％ee）的手性4-芳基-2-哌啶子酮。还提出了将加合物（R）-1-（叔丁氧基羰基）-4-（4-氯苯基）-2-哌啶酮进一步转化为（R）-高巴氯芬盐酸盐。
• 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.