(R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidinone | 229182-29-0

• 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: (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidinone
• 英文别名: (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidone；tert-butyl (4R)-4-(4-chlorophenyl)-2-oxopiperidine-1-carboxylate
• CAS: 229182-29-0
• 化学式: C₁₆H₂₀ClNO₃
• 分子量: 309.793
• InChiKey: QKOMGPLQRSIKIF-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidinone 在 盐酸 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 水 为溶剂， 反应 24.5h， 生成 (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：

  三(P-氯苯基)环硼氧炔 在 bis(ethylene)rhodium acetylacetonate 4-二甲氨基吡啶 、 (R)-2,2'-bis(diarylphosphino)-1,1'-binaphthyl 、 水 作用下， 以 1,4-二氧六环 、 乙腈 为溶剂， 反应 32.0h， 生成 (R)-1-(tert-butyloxycarbonyl)-4-(4-chlorophenyl)-2-piperidinone
  参考文献：
  名称：

  铑催化的有机硼试剂向5,6-二氢-2（1H）-吡啶酮的不对称1,4-加成反应。4-芳基-2-哌啶酮的不对称合成。

  摘要：

  在手性双膦-铑催化剂存在下，芳基硼试剂向5,6-二氢-2（1H）-吡啶酮的不对称1,4-加成反应，首次实现了4-芳基-2-哌啶酮的催化不对称合成。 。在引入4-氟苯基的反应中，在40℃下使用4-氟苯基环硼氧烷和1当量（对硼）的水以最高的对映选择性（98％ee）得到最高的芳基化产物产率。此处获得的（R）-4-（4-氟苯基）-2-哌啶酮是合成（-）-帕罗西汀的关键中间体。

  DOI：

  10.1021/jo0103930

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.
• 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。
• Rhodium-Catalyzed Asymmetric 1,4-Addition of Organoboron Reagents to 5,6-Dihydro-2(1<i>H</i>)-pyridinones. Asymmetric Synthesis of 4-Aryl-2-piperidinones
  作者：Taichi Senda、Masamichi Ogasawara、Tamio Hayashi

  DOI：10.1021/jo0103930

  日期：2001.10.1

  Catalytic asymmetric synthesis of 4-aryl-2-piperidinones was realized for the first time by asymmetric 1,4-addition of arylboron reagents to 5,6-dihydro-2(1H)-pyridinones in the presence of a chiral bisphosphine-rhodium catalyst. In the reaction introducing 4-fluorophenyl group, the use of 4-fluorophenylboroxine and 1 equiv (to boron) of water at 40 degrees C gave the highest yield of the arylation

  在手性双膦-铑催化剂存在下，芳基硼试剂向5,6-二氢-2（1H）-吡啶酮的不对称1,4-加成反应，首次实现了4-芳基-2-哌啶酮的催化不对称合成。 。在引入4-氟苯基的反应中，在40℃下使用4-氟苯基环硼氧烷和1当量（对硼）的水以最高的对映选择性（98％ee）得到最高的芳基化产物产率。此处获得的（R）-4-（4-氟苯基）-2-哌啶酮是合成（-）-帕罗西汀的关键中间体。