3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one | 158697-66-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
• 英文别名: 3-[2-[4-[(2,4-Difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-on；3-(2-{4-[(2,4-difluorophenyl)-hydroxyimino-methyl]-piperidin-1-yl}ethyl)-2-methyl-6,7,8,9-tetrahydro-pyrido[1,2-a]pyrimidin-4-one；3-(2-(4-((E)-(2,4-Difluorophenyl)(hydroxyimino)methyl)piperidin-1-yl)ethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido(1,2-a)pyrimidin-4-one；3-[2-[4-[C-(2,4-difluorophenyl)-N-hydroxycarbonimidoyl]piperidin-1-yl]ethyl]-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one
• CAS: 158697-66-6
• 化学式: C₂₃H₂₈F₂N₄O₂
• 分子量: 430.498
• InChiKey: BRCINVRBDDVLDW-UHFFFAOYSA-N

物化性质

• 沸点：
  569.0±60.0 °C(Predicted)
• 密度：
  1.34±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  68.5
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one 以86.03的产率得到利培酮
  参考文献：
  名称：

  苯并异恶唑类抗精神病药利培酮的制备方法

  摘要：

  本发明涉及一种苯并异恶唑类抗精神病药利培酮的制备方法，属于利培酮的制备技术领域。本发明所述的苯并异恶唑类抗精神病药利培酮的制备方法，是以(z)-[3-[4-[(2,4-二氟苯基)甲基肟基]哌啶基]-1-乙基]-2-甲基-6,7,8,9-4H-吡啶并[1,2-a]嘧啶-4-酮为初始物料，在二氯甲烷与浓碱水的混合溶剂体系中进行环合反应，制得目标产物利培酮。本发明操作简单，对设备要求低，制备的产品纯度高，适合工业化生产。

  公开号：

  CN104557918A
• 作为产物：
  描述：

  2,4-二氟苯甲酰 以64的产率得到3-[2-[4-[(2,4-difluorophenyl)-(hydroxyimino)-methyl]-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  Arch. Pharmacal. Res. 2005, 28, 1019-1022

  摘要：

  DOI：

文献信息

• [EN] A PROCESS FOR THE PREPARATION OF ANTIPSYCHOTIC RISPERIDONE<br/>[FR] PROCEDE DE PREPARATION DE RISPERIDONE ANTIPSYCHOTIQUE
  申请人：AUROBINDO PHARMA LTD

  公开号：WO2004009591A1

  公开（公告）日：2004-01-29

  This invention relates to a process for the preparation of antipsychotic risperidone (Formula I); which comprises reacting 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one (Formula II); with 4-(2,4-difluorobenzoyl)piperidine oxime (Formula III); to form oxime (Formula IV); and in situ cyclization of oxime (Formula IV) to form risperidone (Formula I) in a solvent selected from the group consisting of acetonitrile, N,N-dimetylformamide and methyl isobutyl ketone.

  这项发明涉及一种制备抗精神病药利培酮（化学式I）的方法；包括将3-(2-氯乙基)-6,7,8,9-四氢-2-甲基-4H-吡啶并[1,2-a]嘧啶-4-酮（化学式II）与4-(2,4-二氟苯甲酰)哌啶肟（化学式III）反应，形成肟（化学式IV）；并原位将肟（化学式IV）环化形成利培酮（化学式I），所用溶剂选自丙腈、N,N-二甲基甲酰胺和异丁基甲酮。
• Process for making risperidone and intermediates therefor
  申请人：——

  公开号：US20040097523A1

  公开（公告）日：2004-05-20

  The formation of risperidone is enhanced by the use of enriched Z-isomer oxime intermediate(s) of formula (3) or (7). 1 The oxime(s) can be isomerically enriched by a variety of techniques including the use of the novel acetic acid salt thereof, which affords, inter alia, resolution of the isomers and/or by heat conversion.

  利用富集的Z异构体肟中间体（3）或（7）的使用增强了利培酮的形成。 1 这些肟可以通过各种技术进行异构体富集，包括使用其新颖的乙酸盐，该盐提供了异构体的分离，或通过热转化。
• [EN] PROCESS FOR PREPARING RISPERIDONE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE LA RISPÉRIDONE
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2009077551A1

  公开（公告）日：2009-06-25

  The present invention concerns an improved process of preparing risperidone (I).

  这项发明涉及一种改进的制备利培酮（I）的方法。
• Process for the preparation of 3-{2-'4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl!ethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido'1,2-methyl-4h-pyrido',2-a!pyrimidin-4-one
  申请人：Pongo Laszlo

  公开号：US20050004141A1

  公开（公告）日：2005-01-06

  The invention relates to a process for the preparation of 3-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the Formula (I), and pharmaceutically acceptable acid addition salts thereof by subjecting the oxime of the Formula (II), to ring-closure in the presence of an alkali hydroxide, alkali carbonate or alkali-C 1-4 alkoxide in an inert organic solvent, converting the base of the Formula I thus obtained into an acid addition salt or setting free the base of the Formula I from an acid addition salt thereof which comprises reacting a halogen derivative of the general Formula (XIV), (wherein Hal is halogen) with piperidine oxime derivative of the Formula (V), or an acid addition salt thereof in the presence of a base, and using by the ring-closure of the oxime of the Formula II formed a C 1-4 -alkanol as inert solvent. The process of the present invention enables the economical preparation of a product having a purity suitable for pharmaceutical purposes.

  本发明涉及一种制备公式（I）中的3-2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基}-6,7,8,9-四氢-2-甲基-4H-吡啶[1,2-a]嘧啶-4-酮及其药学上可接受的酸加成盐的过程，包括在惰性有机溶剂中在碱性氢氧化物、碱性碳酸盐或碱性C1-4烷氧化物的存在下，使公式（II）的肟在环闭合的情况下，将公式I的碱转化为酸加成盐或从其酸加成盐中释放出公式I的碱。其中，该过程包括在碱的存在下，使用公式（XIV）的卤代衍生物（其中Hal是卤素）与公式（V）的哌啶肟衍生物或其酸加成盐在惰性溶剂C1-4-烷醇中进行肟的环闭合。本发明的过程能够经济地制备出适用于药物用途的纯度合适的产物。
• Process for the preparation of 3-{2-′4- (6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyllethyl}-6,7,8,9-tetrahydro-2-methyl-4h-pyrido′1,2-methyl-4h-pyrido′,2-a!pyrimidin-4-one
  申请人：EGIS Gyógyszergyár Rt.

  公开号：US07307168B2

  公开（公告）日：2007-12-11

  The invention relates to a process for the preparation of 3-2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl}-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one of the Formula (I), and pharmaceutically acceptable acid addition salts thereof by subjecting the oxime of the Formula (II), to ring-closure in the presence of an alkali hydroxide, alkali carbonate or alkali-C1-4 alkoxide in an inert organic solvent, converting the base of the Formula I thus obtained into an acid addition salt or setting free the base of the Formula I from an acid addition salt thereof which comprises reacting a halogen derivative of the general Formula (XIV), (wherein Hal is halogen) with piperidine oxime derivative of the Formula (V), or an acid addition salt thereof in the presence of a base, and using by the ring-closure of the oxime of the Formula II formed a C1-4-alkanol as inert solvent. The process of the present invention enables the economical preparation of a product having a purity suitable for pharmaceutical purposes.

  本发明涉及一种制备式（I）的3-2-[4-(6-氟-1,2-苯并异噁唑-3-基)-1-哌啶基]乙基}-6,7,8,9-四氢-2-甲基-4H-吡啶[1,2-a]嘧啶-4-酮及其药学上可接受的酸加盐物的方法。该方法通过在惰性有机溶剂中，在碱性氢氧化物、碱性碳酸盐或碱性C1-4醇酸酸盐的存在下，使式（II）的肟转化为环闭合，将所得的式（I）的碱转化为酸加盐物或从其中释放出式（I）的碱加盐物，包括在碱的存在下，用式（V）的哌啶肟衍生物或其酸加盐物与通式（XIV）的卤代衍生物（其中Hal是卤素）反应，并使用C1-4醇作为惰性溶剂来进行肟的环闭合。本发明的方法使得经济地制备出适用于制药目的的纯度合适的产品。