(-)-BMY 14802

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (-)-BMY 14802
• 英文别名: (S)-1-(4-Fluoro-phenyl)-4-[4-(5-fluoro-pyrimidin-2-yl)-piperazin-1-yl]-butan-1-ol；(1S)-1-(4-fluorophenyl)-4-[4-(5-fluoropyrimidin-2-yl)piperazin-1-yl]butan-1-ol
• 化学式: C₁₈H₂₂F₂N₄O
• 分子量: 348.396
• InChiKey: ZXUYYZPJUGQHLQ-KRWDZBQOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  52.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  alpha-(4-氟苯基)-4-(5-氟-2-嘧啶基)-1-哌嗪丁醇 在 三氯硅烷 、 三乙胺 作用下， 以 甲苯 、 苯 为溶剂， 反应 216.0h， 生成 (-)-BMY 14802
  参考文献：
  名称：

  Synthesis and biological characterization of .alpha.-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogs as potential atypical antipsychotic agents

  摘要：

  A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[H-3]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.

  DOI：

  10.1021/jm00102a002

文献信息

• Biocatalytic synthesis of some chiral drug intermediates by oxidoreductases
  作者：Ramesh N. Patel、Ronald L. Hanson、Amit Banerjee、Laszlo J. Szarka

  DOI：10.1007/s11746-997-0237-3

  日期：1997.11

  AbstractChiral intermediates were prepared by biocatalytic processes with oxidoreductases for the chemical synthesis of some pharmaceutical drug candidates. These include: (i) the microbial reduction of 1‐(4‐fluorophenyl)‐4‐[4‐(5‐fluoro‐2‐pyrimidinyl)‐1‐piperazinyl]‐1‐butanone (1) to R‐(+)‐1‐(4‐fluorophenyl)‐4‐[4‐(5‐fluoro‐2‐pyrimidinyl)‐1‐piperazinyl]‐1‐butanol (2) [R‐(+)‐BMY 14802], an antipsychotic agent; (ii) the reduction of N‐4‐(1‐oxo‐2‐chloroacetyl ethyl) phenyl methane sulfonamide (3) to the corresponding chiral alcohol (4), an intermediate for d‐(+)‐N‐4‐1‐hydroxy‐2‐[(‐methylethyl)amino]ethyl}phenyl methanesulfonamide [d‐(+) sotalol], a β‐blocker with class III antiarrhythmic properties; (iii) biotransformation of Nɛ‐carbobenzoxy (CBZ)‐l‐lysine (7) to Nɛ‐CBZ‐l‐oxylysine (5), an intermediate needed for synthesis of (S)‐1‐[6‐amino‐2‐[hydroxy(4‐phenylbutyl)phosphinyl]oxy}1‐oxohexyl]‐l‐proline (ceronapril), a new angiotensin converting enzyme inhibitor (6) and (iv) enzymatic synthesis of l‐β‐hydroxyvaline (9) from α‐keto‐β‐hydroxyisovalerate (16). l‐β‐Hydroxyvaline (9) is a key chiral intermediate needed for the synthesis of S‐(Z)‐[1‐(2‐amino‐4‐thiazolyl)‐2‐[2,2‐dimethyl‐4‐oxo‐1‐(sulfooxy)‐3‐azetidinyl] amino}‐2‐oxoethylidene]amino}oxyacetic acid (tigemonam) (10), an orally active monobactam.
• Resolution of α-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol (BMS 181100) and α-(3-chloropropyl)-4-fluorobenzenemethanol using lipase-catalyzed acetylation or hydrolysis
  作者：Ronald L. Hanson、Amit Banerjee、F.Taha Comezoglu、K.David Mirfakhrae、Ramesh N. Patel、Laszlo J. Szarka

  DOI：10.1016/s0957-4166(00)86268-0

  日期：1994.10

  alpha-(3-Chloropropyl)-4-fluorobenzenemethanol, a possible intermediate for synthesis of a potential anti-psychotic agent alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol (BMS 181100), was resolved by acetylation using isopropenyl acetate and lipase PS-30 in heptane. S-alcohol was obtained in 42% yield with >99% optical purity. R-acetate was obtained with 92.6% optical purity by stopping the reaction after 46% conversion. The enzymatically produced acetate was hydrolyzed by lipase PS-30 to give R-alcohol with >99% optical purity after 62-72% conversion. BMS 181100 acetate ester was treated with lipase GC-20 in buffer containing 10% toluene to give the R-alcohol with 97.9% optical purity after 47.6% conversion. The rate and enantioselectivity of hydrolysis by lipase GC-20 were very dependent on the organic solvent. E values ranged from 1 in the absence of organic solvent to >100 with dichloromethane and toluene.
• Synthesis and biological characterization of .alpha.-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazinebutanol and analogs as potential atypical antipsychotic agents
  作者：Joseph P. Yevich、James S. New、Walter G. Lobeck、Pierre Dextraze、Edith Bernstein、Duncan P. Taylor、Frank D. Yocca、Michael S. Eison、Davis L. Temple

  DOI：10.1021/jm00102a002

  日期：1992.11

  A series of 1-(pyrimidin-2-yl)piperazine derivatives were prepared and evaluated in receptor binding assays and in in vivo behavioral paradigms as potential atypical antipsychotic agents. Compound 16 (BMS 181100 (formerly BMY 14802)) emerged as the lead compound from within the series on the basis of its good activity and duration of action in the inhibition of both conditioned avoidance responding and apomorphine-induced stereotopy in the rat. Compound 16 not only failed to induce catalepsy in the rat but was quite effective in reversing the cataleptic effect of neuroleptic agents, thus indicating a low propensity for causing extrapyramidal side effects. In comparison to reference antipsychotic agents, 16 appeared to be less sedating and was relatively weaker in causing muscle incoordination. The compound was essentially inactive in binding to dopamine D2 receptors and its chronic administration to rats did not result in dopamine receptor supersensitivity. It exhibited modest to weak affinity for 5-HT1A and alpha1 receptors but was found to be a fairly potent ligand for sigma binding sites (IC50 vs (+)-[H-3]-3-PPP = 112 nM). Although the resolved enantiomers of racemic 16 did not show dramatic differences from racemate or from each other in most tests, the R(+) enantiomer was up to 11-fold more potent than its antipode in binding to sigma sites. Several studies have indicated that 16 may be a limbic-selective agent which may modulate dopaminergic activity by an indirect mechanism. The compound has been selected for clinical evaluation in the treatment of psychosis.