3-[3-(甲基磺酰基)苯基]-1-丙基哌啶 | 146798-66-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 3-[3-(甲基磺酰基)苯基]-1-丙基哌啶
• 中文别名: 异噻唑,3-乙基-5-(2-吡咯烷基)-,(S)-(9CI)；1,4'-二哌啶-1'-甲酸叔丁酯
• 英文名称: (S)-(-)-3-(3-methanesulfonyl)phenyl-1-propylpiperidine
• 英文别名: (-)-OSU 6162；S-(-)-3-[3-(methylsulfonyl)phenyl]-1-propyl-piperidine；Piperidine, 3-(3-(methylsulfonyl)phenyl)-1-propyl-, (S)-；(3S)-3-(3-methylsulfonylphenyl)-1-propylpiperidine
• CAS: 146798-66-5
• 化学式: C₁₅H₂₃NO₂S
• 分子量: 281.419
• InChiKey: GZVBVBMMNFIXGE-CQSZACIVSA-N

物化性质

• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  45.8
• 氢给体数：
  0
• 氢受体数：
  3

ADMET

代谢

PNU-96391已知的人类代谢物包括3-(3-(甲磺酰基)苯基)哌啶。

PNU-96391 has known human metabolites that include 3-(3-(Methylsulfonyl)phenyl)piperidine.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  3-[3-(甲基磺酰基)苯基]-1-丙基哌啶 在 盐酸 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 1.5h， 以10.45 kg的产率得到(3S)-3-(3-甲基磺酰基苯基)-1-丙基哌啶盐酸盐
  参考文献：
  名称：

  The Synthesis of OSU 6162:  Efficient, Large-Scale Implementation of a Suzuki Coupling

  摘要：

  The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 ((1) under bar), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone ((4) under bar) and pyridyl borane ((14) under bar). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqueous hydroxide, delivered free base ((6) under bar) or hydrochloride salt ((15a) under bar) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt ((15b) under bar) of the coupled product could be obtained in reproducible 92-94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium-halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmethoxy borane. This highly exothermic series of transformations yielded crystalline diethyl-3-pyridyl borane in reproducible 75-80% yield on scales ranging up to 200-kg input. Selective reduction of the biaryl, classical resolution and introduction of the propyl group via the Gribble reductive amination procedure completed the synthesis of OSU 6162 free base. This route was employed to deliver over 35 kg of clinical-quality bulk drug in short order.

  DOI：

  10.1021/op025620u
• 作为产物：
  描述：

  二乙基(3-吡啶基)-硼烷 在 sodium tetrahydroborate 、 四(三苯基膦)钯 、 platinum on carbon 、 四丁基溴化铵 、 氢气 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 磷酸 、 水 为溶剂， -5.0~98.0 ℃ 、413.7 kPa 条件下， 反应 18.5h， 生成 3-[3-(甲基磺酰基)苯基]-1-丙基哌啶
  参考文献：
  名称：

  The Synthesis of OSU 6162:  Efficient, Large-Scale Implementation of a Suzuki Coupling

  摘要：

  The synthesis of the chiral, nonracemic 3-aryl piperidine, OSU 6162 ((1) under bar), a potential CNS agent from Pharmacia Corporation, is presented. The key construction in the described synthesis is a palladium-catalyzed aryl cross-coupling reaction between bromosulfone ((4) under bar) and pyridyl borane ((14) under bar). Initially developed conditions for this Suzuki reaction, conducted in tetrahydrofuran/aqueous hydroxide, delivered free base ((6) under bar) or hydrochloride salt ((15a) under bar) in reproducible 80% yield. However, by changing the solvent to toluene and the base to carbonate, significant decreases in catalyst requirement were realized, and the methane sulfonate salt ((15b) under bar) of the coupled product could be obtained in reproducible 92-94% yield on 200-kg input. The success of the Suzuki reaction was critically dependent on a bulk source of the pyridyl borane coupling partner. Cryogenic conditions were developed for its generation via lithium-halogen exchange to generate thermally labile 3-lithiopyridine followed by transmetalation with diethylmethoxy borane. This highly exothermic series of transformations yielded crystalline diethyl-3-pyridyl borane in reproducible 75-80% yield on scales ranging up to 200-kg input. Selective reduction of the biaryl, classical resolution and introduction of the propyl group via the Gribble reductive amination procedure completed the synthesis of OSU 6162 free base. This route was employed to deliver over 35 kg of clinical-quality bulk drug in short order.

  DOI：

  10.1021/op025620u

文献信息

• Centrally acting substituted phenylazacycloalkanes
  申请人：The Upjohn Company

  公开号：US05462947A1

  公开（公告）日：1995-10-31

  A compound of Formula I ##STR1## or a pharmaceutically acceptable salt thereof wherein n is 1 or 2; R.sup.1 and R.sup.2 are independently H (provided only one is H at the same time), --OH, CN, CH.sub.2 CN, 2-- or 4--CF.sub.3, CH.sub.2 CF.sub.3, CH.sub.2 CHF.sub.2, CH.dbd.CF.sub.2, (CH.sub.2).sub.2 CF.sub.3, ethenyl, 2-propenyl, OSO.sub.2 CH.sub.3, OSO.sub.2 CF.sub.3, SSO.sub.2 CF.sub.3, COR, COOR, CON(R).sub.2, SO.sub.x CH.sub.3 (where, x is 0-2), SO.sub.x CF.sub.3, O(CH.sub.2).sub.x CF.sub.3, SO.sub.2 N(R).sub.2, CH.dbd.NOR, COCOOR, COCOON(R).sub.2, C.sub.1-8 alkyls, C.sub.3-8 cycloalkyls, CH.sub.2 OR, CH.sub.2 (R).sub.2, NRSO.sub.2 CF.sub.3, NO.sub.2, halogen, a phenyl at positions 2, 3 or 4, thienyl, furyl, pyrrole, oxazole, thiazole, N-pyrroline, triazole, tetrazole or pyridine; R.sup.3 is hydrogen, CF.sub.3, CH.sub.2 CF.sub.3, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.9 cycloalkyl-methyl, C.sub. 2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, --(CH.sub.2).sub.m --R.sup.5 (where m is 1-8), CH.sub.2 SCH.sub.3 or a C.sub.4 -C.sub.8 alkylene bonded to said nitrogen and one of its adjacent carbon atoms inclusive whereby a heterocyclic structure is formed; R.sup.4 and R are independently selected from hydrogen, CF.sub.3, CH.sub.2 CF.sub.3, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.9 cycloalkyl-methyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl, 3,3,3-trifluoropropyl, 4,4,4-trifluorobutyl, --(CH.sub.2).sub.m --R.sup.5 where m is 1-8; R.sup.5 is phenyl, phenyl (substituted with a CN, CF.sub.3, CH.sub.2 CF.sub.3, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.9 cycloalkyl-methyl, C.sub.2 -C.sub.8 alkenyl, C.sub.2 -C.sub.8 alkynyl), 2-thiophenyl, 3-thiophenyl, --NR.sup.6 CONR.sup.6 R.sup.7, or --CONR.sup.6 R.sup.7 ; R.sup.6 and R.sup.7 are independently hydrogen, C.sub.1 -C.sub.8 alkyl, C.sub.3 -C.sub.8 cycloalkyl, C.sub.4 -C.sub.9 cycloalkylmethyl, C.sub.2 -C.sub.8 alkenyl or C.sub.2 -C.sub.8 alkynyl; and with the proviso that when R.sup.1 is CN, R.sup.2 and R.sup.4 are H, R.sup.3 is n-Pr and n is 1, then such compound is a pure enantiomer, and when R.sup.1 or R.sup.2 is OH, halogen, CONH.sub.2 or alkyl, then R.sup.4 is not hydrogen. The Formula I compounds possess selective pharmacological properties and are useful in treating central nervous system disorders related to dopamine receptor activity including depression symptoms, geriatric disorders in the improvement of mental and motor functions, schizophrenia, narcolepsy, MBD, obesitas, and disturbances of sexual functions and impotence.

  公式I的化合物##STR1##或其药用盐，其中n为1或2；R.sup.1和R.sup.2独立地为H（同时仅有一个为H），-OH，CN，CH.sub.2 CN，2-或4-CF.sub.3，CH.sub.2 CF.sub.3，CH.sub.2 CHF.sub.2，CH.dbd.CF.sub.2，（CH.sub.2）.sub.2 CF.sub.3，乙烯基，2-丙烯基，OSO.sub.2 CH.sub.3，OSO.sub.2 CF.sub.3，SSO.sub.2 CF.sub.3，COR，COOR，CON（R）.sub.2，SO.sub.x CH.sub.3（其中，x为0-2），SO.sub.x CF.sub.3，O（CH.sub.2）.sub.x CF.sub.3，SO.sub.2 N（R）.sub.2，CH.dbd.NOR，COCOOR，COCOON（R）.sub.2，C1-8烷基，C3-8环烷基，CH.sub.2 OR，CH.sub.2（R）.sub.2，NRSO.sub.2 CF.sub.3，NO.sub.2，卤素，在2、3或4位的苯基，噻吩基，呋喃基，吡咯基，噁唑基，噻唑基，N-吡咯烯基，三唑基，四唑基或吡啶基；R.sup.3为氢，CF.sub.3，CH.sub.2 CF.sub.3，C1-C8烷基，C3-C8环烷基，C4-C9环烷基甲基，C2-C8烯基，C2-C8炔基，3,3,3-三氟丙基，4,4,4-三氟丁基，-(CH.sub.2).sub.m-R.sup.5（其中m为1-8），CH.sub.2 SCH.sub.3或与所述氮结合并形成异环结构的相邻碳原子之一的C4-C8烷基；R.sup.4和R独立地选自氢，CF.sub.3，CH.sub.2 CF.sub.3，C1-C8烷基，C3-C8环烷基，C4-C9环烷基甲基，C2-C8烯基，C2-C8炔基，3,3,3-三氟丙基，4,4,4-三氟丁基，-(CH.sub.2).sub.m-R.sup.5，其中m为1-8；R.sup.5为苯基，苯基（取代有CN，CF.sub.3，CH.sub.2 CF.sub.3，C1-C8烷基，C3-C8环烷基，C4-C9环烷基甲基，C2-C8烯基，C2-C8炔基），2-噻吩基，3-噻吩基，-NR.sup.6 CONR.sup.6 R.sup.7或-CONR.sup.6 R.sup.7；R.sup.6和R.sup.7独立地为氢，C1-C8烷基，C3-C8环烷基，C4-C9环烷基甲基，C2-C8烯基或C2-C8炔基；但是当R.sup.1为CN时，R.sup.2和R.sup.4为H，R.sup.3为n-Pr且n为1时，该化合物为纯对映体，当R.sup.1或R.sup.2为OH，卤素，CONH.sub.2或烷基时，R.sup.4不为氢。公式I的化合物具有选择性药理特性，并可用于治疗与多巴胺受体活性相关的中枢神经系统疾病，包括抑郁症状，老年病患者的精神和运动功能改善，精神分裂症，嗜睡症，MBD，肥胖症以及性功能障碍和阳痿。
• Treatments for restless legs syndrome
  申请人：——

  公开号：US20020107257A1

  公开（公告）日：2002-08-08

  The invention provides methods and use of heterocyclic amines, and phenylazacycloalkane compounds, and their pharmacologically acceptable salts for the treatment of Restless Legs Syndrome (RLS).

  这项发明提供了异环胺类化合物和苯基氮杂环烷烃类化合物的方法和用途，以及它们的药理学可接受的盐，用于治疗不宁腿综合征（RLS）。
• An efficient synthesis of the novel dopamine autoreceptor antagonist S-(−)-OSU6162, via palladium catalyzed cross-coupling reaction
  作者：Clas Sonesson、Jonas Lindborg

  DOI：10.1016/0040-4039(94)88428-5

  日期：1994.11

  Optically active S-(−)-OSU6162 ((−)-1) has been synthesized in 4 steps with an overall yield of 48 %. The four steps consists of palladium catalyzed cross-coupling, catalytic hydrogenation, classical resolution with tartaric acid and reductive amination.

  光学活性的S -（-）- OSU6162（（-）- 1）已分4步合成，总产率为48％。这四个步骤包括钯催化的交叉偶联，催化加氢，酒石酸的经典拆分和还原胺化。
• DISUBSTITUTED PHENYLPYRROLIDINES AS MODULATORS OF CORTICAL CATECHOLAMINERGIC NEUROTRANSMISSION
  申请人：Sonesson Clas

  公开号：US20100179211A1

  公开（公告）日：2010-07-15

  The present invention relates to the use of compounds which increase extracellular levels of catecholamines, dopamine and norepinephrine, in cerebral cortical areas of the mammalian brain, and more specifically to the use of 3-disubstituted phenyl-1-pyrrolidinols for the treatment of central nervous system disorders.

  本发明涉及利用增加哺乳动物大脑脑皮层区域儿茶酚胺、多巴胺和去甲肾上腺素的细胞外水平的化合物，更具体地涉及利用3-二取代苯基-1-吡咯烷醇治疗中枢神经系统疾病。
• TREATMENTS FOR RESTLESS LEGS SYNDROME
  申请人：——

  公开号：US20030212065A1

  公开（公告）日：2003-11-13

  The invention provides methods and use of heterocyclic amines, and phenylazacycloalkane compounds, and their pharmacologically acceptable salts for the treatment of Restless Legs Syndrome (RLS).

  本发明提供了使用杂环胺和苯基氮杂环烷化合物及其药学上可接受的盐治疗不宁腿综合症（RLS）的方法和用途。