trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl piperidine | 318279-38-8

• 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: trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl piperidine
• 英文别名: (4-(4-fluorophenyl)-1-methylpiperidin-3-yl)methanol；trans 4-(4'-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine；4-(4'-fluorophenyl)-3-hydroxymethyl-1-methyl-piperidine；cis-4-p-Fluorophenyl-3-hydroxymethyl-1-methylpiperidine；trans-(4R,3S)-[4-(4-fluoro-phenyl)-1-methyl-piperidin-3-yl]-methanol；(+/-)-trans-4-(4'-fluorophenyl)-3-hydroxymethyl-N-methylpiperidine；[4-(4-fluorophenyl)-1-methylpiperidin-3-yl]methanol
• CAS: 318279-38-8
• 化学式: C₁₃H₁₈FNO
• 分子量: 223.29
• InChiKey: CXRHUYYZISIIMT-UHFFFAOYSA-N

物化性质

• 沸点：
  300.3±42.0 °C(Predicted)
• 密度：
  1.092±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  23.5
• 氢给体数：
  1
• 氢受体数：
  3

安全信息

• 危险类别码：
  R22,R41,R51/53
• 危险品运输编号：
  UN3077
• 海关编码：
  2933399090
• 包装等级：
  III

反应信息

• 作为反应物：
  描述：

  二甲基十二/十四烷基叔胺 、 对甲苯磺酰氯 、 反式-4-(4-氟苯基)-3-羟甲基-1-甲基哌啶 、 trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl piperidine 在 sodium hydroxide 作用下， 以 二氯甲烷 为溶剂， 生成 4-(4-氟苯)-1-甲基-3-[(4-甲苯磺酰氧基)甲基]哌啶
  参考文献：
  名称：

  Novel process

  摘要：

  一种制备式（1）化合物的方法：其中R1是烷基，芳基烷基，烯丙基，烷氧羰基，芳基烷氧羰基，酰基或炔基；R2是取代苯基，特别是3,4-亚甲二氧基苯基；X是氢或易于去除的基团，例如氯，溴或碘。

  公开号：

  US20030187269A1
• 作为产物：
  描述：

  4-(4-氟苯基)-1-甲基-2,6-二氧代哌啶-3-羧酸乙酯 在 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以65%的产率得到trans-4-(4'-Fluorophenyl)-3-hydroxymethyl-N-methyl piperidine
  参考文献：
  名称：

  Process for preparing aryl-piperidine carbinols and novel intermediates

  摘要：

  公开了一种制备化合物的过程，其化学式为(I)：其中Ar是芳基或取代芳基，R.sup.3是氢、烷基或芳基烷基，该过程包括还原化合物的过程的化学式(II)：其中Ar和R.sup.3如与式(I)相关定义，R.sup.4是烷基。化合物的化学式(I)可用作化学中间体。

  公开号：

  US04902801A1

文献信息

• [EN] ENANTIOSPECIFIC PROCESS FOR THE PREPARATION OF PAROXETINE INTERMEDIATE<br/>[FR] PROCEDE ENANTIOSPECIFIQUE PERMETTANT DE PREPARER UN INTERMEDIAIRE DE PAROXETINE
  申请人：NATCO PHARMA LTD

  公开号：WO2005063707A1

  公开（公告）日：2005-07-14

  A novel, improved, and enantiospecific process for the preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine of formula-(I), an advanced intermediate in the manufacture of antidepressant drug paroxetine is disclosed in the present invention. Compound of formula-(XXII) is prepared by resolution of compound of formula-(XX) using a chiral acid followed by hydrogenation of the resolved amine. Michael addition of the compound of formula-(XXII) onto acrylate esters gave the compounds of formula-(XXIII). Conversion of the hydroxy group present in compound of formula-(XXIII) into a leaving group followed by treatment with a strong base gave the enantiospecific intramolecularly cyclized piperidine derivative of formula-(XXV). Reduction of the ester group present in compound of formula-(XXV) with a metal hydride reducing agent gave the compound of formula-I with more than 97% chiral purity. Further purification of compound of formula-I to >99.5% is achieved by one recrystallization from a number of solvents. Present process is easily adaptable for commercial preparation of (-)-trans-4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine of formula-(I).

  本发明揭示了一种用于制备抗抑郁药帕罗西汀的先进中间体(-)-反式-4-(4-氟苯基)-3-羟甲基-1-甲基哌啶的改进和对映具体过程。通过使用手性酸对化合物XX进行拆分，然后对已拆分的胺进行氢化，制备了化合物XXII的方法。将化合物XXII与丙烯酸酯发生迈克尔加成反应，得到了化合物XXIII。将化合物XXIII中的羟基转化为一个脱离基，然后经过强碱处理，得到了对映具体的分子内环化哌啶衍生物XXV。将化合物XXV中的酯基还原为金属氢化物还原剂，得到了具有超过97%对映纯度的化合物I。通过在多种溶剂中进行一次结晶，将化合物I进一步纯化至>99.5%。本过程易于用于商业制备(-)-反式-4-(4-氟苯基)-3-羟甲基-1-甲基哌啶的方法。
• Substituted phenylpiperidines with serotoninergic activity and enhanced therapeutic properties
  申请人：Gant G. Thomas

  公开号：US20070112031A1

  公开（公告）日：2007-05-17

  Chemical syntheses and medical uses of novel inhibitors of the uptake of monoamine neurotransmitters and pharmaceutically acceptable salts and prodrugs thereof, for the treatment and/or management of psychotropic disorders, anxiety disorder, generalized anxiety disorder, depression, post-traumatic stress disorder, obsessive-compulsive disorder, panic disorder, hot flashes, senile dementia, migraine, hepatopulmonary syndrome, chronic pain, nociceptive pain, neuropathic pain, painful diabetic retinopathy, bipolar depression, obstructive sleep apnea, psychiatric disorders, premenstrual dysphoric disorder, social phobia, social anxiety disorder, urinary incontinence, anorexia, bulimia nervosa, obesity, ischemia, head injury, calcium overload in brain cells, drug dependence, and/or premature ejaculation are described.

  化学合成和新型单胺神经递质摄取抑制剂的医药用途，以及其药用盐和前药，用于治疗和/或管理精神疾病、焦虑症、广泛性焦虑症、抑郁症、创伤后应激障碍、强迫症、恐慌症、潮热、老年痴呆症、偏头痛、肝肺综合征、慢性疼痛、伤害性疼痛、神经病性疼痛、疼痛性糖尿病视网膜病变、双相抑郁症、阻塞性睡眠呼吸暂停、精神疾病、经前期失调性障碍、社交恐惧症、社交焦虑症、尿失禁、厌食症、暴食症、肥胖症、缺血、头部损伤、脑细胞钙超载、药物依赖和/或早泄。
• [EN] NOVEL PROCESS FOR THE PREPARATION OF 4-ARYL-3-HYDROXYMETHYL-1-METHYLPIPERIDINES.<br/>[FR] NOUVEAU PROCEDE DE PREPARATION DE 4-ARYL-3-HYDROXYMETHYL-1-METHYLPIPERIDINES
  申请人：NATCO PHARMA LTD

  公开号：WO2004043921A1

  公开（公告）日：2004-05-27

  A novel, improved, and general process for the preparation of 4-aryl-3-hydroxymethyl-1-methylpiperidines is disclosed in the present invention. 4-(4-Fluorophenyl)-3-hydroxymethyl-1-methylpiperidine is a well-known intermediate in making the anti-depressant drug, paroxetine ((-)-trans-4-p-fluorophenyl-3-(3',4'-methylenedioxy-phenoxymethyl)piperidine). Novel N-methyl-N-[3-(4-substitutedphenyl (F, Me, OMe))-3-hydroxy]propylamines are prepared from the Mannich salts such as 3-dimethylamino- or 3-(N-methyl-N-benzylamino)-4'-substituted (F, Me, OMe) propiophenone hydrochlorides by conventional methods. The N-methyl-N-[3-(4-substitutedphenyl (H, F, Me, OMe))-3-hydroxy]propylamines thus obtained are reacted with ethyl or methyl acrylate to get the corresponding Michael addition products. The hydroxy group present in the Michael addition products is converted into a facile leaving group and treated with a strong base to get 4-aryl-N-methylpiperidine-3-carboxylates via the intramolecular cyclization in good yields. Reduction of the ester group present in these piperidine-3-carboxylates gave the title compounds as crystalline solids. Present process is easily adaptable for commercial preparation of the paroxetine intermediate (4-(4-fluorophenyl)-3-hydroxymethyl-1-methylpiperidine).

  本发明揭示了一种新颖的、改进的、通用的制备4-芳基-3-羟甲基-1-甲基哌啶的方法。4-(4-氟苯基)-3-羟甲基-1-甲基哌啶是制造抗抑郁药物帕罗西汀((-)-trans-4-p-氟苯基-3-(3',4'-亚甲二氧基苯氧甲基)哌啶)的已知中间体。新型的N-甲基-N-[3-(4-取代苯基(F，Me，OMe))-3-羟基]丙胺可通过常规方法从Mannich盐制备而来，例如3-二甲氨基或3-(N-甲基-N-苄基氨基)-4'-取代(F，Me，OMe)丙酮盐酸盐。因此获得的N-甲基-N-[3-(4-取代苯基(H，F，Me，OMe))-3-羟基]丙胺与乙基或甲基丙烯酸酯反应，得到相应的Michael加成产物。Michael加成产物中存在的羟基转化为容易离去的基团，并用强碱处理，通过分子内环化以良好的产率得到4-芳基-N-甲基哌啶-3-羧酸酯。这些哌啶-3-羧酸酯中存在的酯基还原后，得到了晶体固体的目标化合物。目前的方法易于用于商业制备帕罗西汀中间体(4-(4-氟苯基)-3-羟甲基-1-甲基哌啶)。
• PREPARATION OF PAROXETINE HYDROCHLORIDE HEMIHYDRATE
  申请人：Thippannachar Mathad Vijayavitthal

  公开号：US20060264637A1

  公开（公告）日：2006-11-23

  A process for preparing paroxetine hydrochloride hemihydrate.

  制备帕罗西汀盐酸盐半水合物的工艺。
• [EN] AN IMPROVED PROCESS FOR MINIMISING THE FORMATION OF DEHALOGENATED BYPRODUCTS<br/>[FR] PROCÉDÉ AMÉLIORÉ PERMETTANT DE RÉDUIRE AU MINIMUM LA FORMATION DE SOUS-PRODUITS DÉSHALOGÉNÉS
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2015071831A1

  公开（公告）日：2015-05-21

  The present invention provides an improved process for preparation of organic compounds represented by Formula-Z; wherein effectively minimising the formation of dehalogenated by-products is achieved. In the process, the reduction is carried out using suitable reducing agent; more preferably Lithium Aluminium Hydride (LAH) in a solvent system, wherein at least one of the solvent is selected from halogenated solvents, which acts as co-solvent. The process of the present invention is useful for minimising of the formation of dehalogenated by-products during synthesis of various active pharmaceutical ingredients such as Paroxetine Hydrochloride, Cinacalcet, Eletriptan and Asenapine.

  本发明提供了一种改进的有机化合物制备方法，该化合物由Formula-Z表示；在该过程中，有效地最小化了去卤代副产物的形成。在该过程中，使用适当的还原剂进行还原；更好地使用锂铝氢化物（LAH）在溶剂系统中进行还原，其中至少一种溶剂是选自卤代溶剂的协溶剂。本发明的方法对于在合成各种活性药物成分（如盐酸帕罗西汀、西那卡塞特、厄利替普坦和阿塞那平）期间最小化去卤代副产物的形成非常有用。

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