N-benzyloxycarbonyl-(4S)-fluoro-L-proline | 72204-21-8

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: N-benzyloxycarbonyl-(4S)-fluoro-L-proline
• 英文别名: N-Cbz-cis-4-fluoro-L-proline；cis-N-Carbobenzyloxy-4-fluor-L-prolin；(2S,4S)-1-((benzyloxy)carbonyl)-4-fluoropyrrolidine-2-carboxylic acid；(2S,4S)-4-fluoro-1-phenylmethoxycarbonylpyrrolidine-2-carboxylic acid
• CAS: 72204-21-8
• 化学式: C₁₃H₁₄FNO₄
• 分子量: 267.257
• InChiKey: CORSVESTDJTBDT-QWRGUYRKSA-N

物化性质

• 熔点：
  123-124 °C
• 沸点：
  440.9±45.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  66.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-benzyloxycarbonyl-(4S)-fluoro-L-proline 在 palladium on activated charcoal N-乙基吗啉 、 氢气 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 20.0~25.0 ℃ 、206.84 kPa 条件下， 反应 3.5h， 生成 (4S)-fluoro-L-proline n-butylamide
  参考文献：
  名称：

  Inhibitors of Tripeptidyl Peptidase II. 3. Derivation of Butabindide by Successive Structure Optimizations Leading to a Potential General Approach to Designing Exopeptidase Inhibitors

  摘要：

  The cholecystokinin-8 (CCK-8)-inactivating peptidase is a serine peptidase that has been shown to be a membrane-bound isoform of tripeptidyl peptidase II (EC 3.4.14.10). It cleaves the neurotransmitter CCK-8 sulfate at the Met-Gly bond to give Asp-Tyr(SO(3)H)-Met-OH + GlyTrp-Met-Asp-Phe-NH(2). Starting from Val-Pro-NHBu, a dipeptide of submicromolar affinity that had previously been generated to serve as a lead, successive optimization at P3, P1, and then P2 gave Abu-Pro-NHBu (18, K(i) = 80 nM). Further transformation (by making a benzologue) gave the indoline analogue, butabindide (33) as a reversible inhibitor having nanomolar affinity (Ki = 7 nM). Retrospective analysis suggested the possibility of a general approach to designing exopeptidase inhibitors starting from the structure of the first hydrolysis product. Application of this approach to CCK-8 led to Abu-Phe-NHBu (37), but this only had K(i) = 9.4 mu M. Molecular modeling, to determine the minimum energy conformations and explain the 1000-fold better affinity of butabindide, indicated that 37 cannot access the likely active conformation of butabindide.

  DOI：

  10.1021/jm0500830
• 作为产物：
  描述：

  (2S,4S)-4-氟-1,2-吡咯烷二羧酸 2-甲基 1-(苯基甲基)酯 在 sodium hydroxide 作用下， 以 甲醇 为溶剂， 生成 N-benzyloxycarbonyl-(4S)-fluoro-L-proline
  参考文献：
  名称：

  HIV整合酶抑制剂的发现和合成：开发有效的和口服可生物利用的N-甲基嘧啶酮。

  摘要：

  人类1型免疫缺陷病毒（HIV-1）编码三种对于病毒复制必不可少的酶：逆转录酶，蛋白酶和整合酶。后者负责将病毒基因组整合到人类基因组中，因此代表了对AIDS进行化学疗法干预的诱人靶标。基于这种机制的药物尚未获得批准。在我们的实验室中发现苄基-二羟基嘧啶-羧酰胺是一类新型的，代谢稳定的药物，对HIV整合酶链转移步骤具有有效的抑制作用。进一步的努力导致了基于结构相关的N-Me嘧啶酮骨架的非常有效的化合物。该系列中最有趣的化合物之一是2-N-Me-吗啉代衍生物27a，其显示在血清存在下细胞中的CIC95为65 nM。该化合物在三种临床前物种中均具有良好的药代动力学特性，并且在几种抗筛选试验中未显示任何责任。

  DOI：

  10.1021/jm0704705

文献信息

• PROCESS FOR PRODUCTION OF CIS-4-FLUORO-L-PROLINE DERIVATIVES
  申请人：Taisho Pharmaceutical Co. Ltd.

  公开号：EP1657237A1

  公开（公告）日：2006-05-17

  The present invention provides a safer method for production of a cis-4-fluoro-L-proline derivative under milder conditions and in good yield to give a product of high purity on an industrial scale at low cost. Namely, the present invention provides a method for producing a cis-4-fluoro-L-proline derivative, which comprises reacting a trans-4-hydroxy-L-proline derivative of the following Formula [I]: (wherein R1 represents a protecting group for an α-amino group, and R2 represents a protecting group for a carboxyl group) with N,N-diethyl-N-(1,1,2,3,3,3-hexafluoropropyl)amine in the presence of a hydrogen fluoride-scavenger.

  本发明提供了一种更安全的方法，用于在较温和的条件下且高产率地生产cis-4-氟-L-脯氨酸衍生物，以在工业规模下以低成本提供高纯度的产品。换句话说，本发明提供了一种生产cis-4-氟-L-脯氨酸衍生物的方法，包括将以下式[I]的trans-4-羟基-L-脯氨酸衍生物（其中R1代表α-氨基的保护基，R2代表羧基的保护基）与N,N-二乙基-N-(1,1,2,3,3,3-六氟丙基)胺在氢氟酸清除剂的存在下反应。
• [EN] NOVEL DIPEPTIDYL PEPTIDASE IV INHIBITORS; PROCESS FOR THEIR PREPARATION AND COMPOSITIONS CONTAINING THEM<br/>[FR] NOUVEAUX INHIBITEURS DE LA DIPEPTIDYL PEPTIDASE IV, PROCEDE DE PREPARATION DE CES INHIBITEURS ET COMPOSITIONS CONTENANT CES INHIBITEURS
  申请人：GLENMARK PHARMACEUTICALS LTD

  公开号：WO2006011035A1

  公开（公告）日：2006-02-02

  The present invention relates to novel organic compounds, more particularly, novel Dipeptidyl peptidase IV (DPP-IV) inhibitors of general formula (I) wherein: Y is -S(O)m-, -CH2-, -CHF-, or -CF2; X and Z are independently -C(=O)-, -NR3-, - O- or -S(O)m-; each occurrence of m is independently 0, 1 or 2; a is 0, 1 or 2; b is 0, 1 or 2; the dotted line [----] in the carbocyclic ring represents an optional double bond; R1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkylalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted arylalkyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic ring, substituted or unsubstituted heterocyclylalkyl, or substituted or unsubstituted heteroarylalkyl; R2 is hydrogene, nitrile (-CN), COOH, or an isostere of carboxylic; or analogs, tautomers, enantiomers, diastereomers, regioisomers, stereoisomers, polymorphs, pharmaceutically acceptable salts, N-oxides, pharmaceutically acceptable solvates and pharmaceutical compositions containing them.

  该发明涉及新型有机化合物，更特别地，一般式（I）的新型二肽基肽酶IV（DPP-IV）抑制剂，其中：Y为-S(O)m-，-CH2-，-CHF-或-CF2；X和Z独立地为-C(=O)-，-NR3-，-O-或-S(O)m-；m的每次出现独立地为0，1或2；a为0，1或2；b为0，1或2；在碳环中的虚线[----]表示一个可选的双键；R1为取代或未取代的烷基，取代或未取代的烯基，取代或未取代的炔基，取代或未取代的环烷基，取代或未取代的环烷基烷基，取代或未取代的环烯基，取代或未取代的芳基，取代或未取代的芳基烷基，取代或未取代的杂芳基，取代或未取代的杂环烷基，或取代或未取代的杂芳基烷基；R2为氢，腈（-CN），COOH，或羧基的同分异构体；或其类似物，互变异构体，对映异构体，非对映异构体，位置异构体，立体异构体，多晶型，药学上可接受的盐，N-氧化物，药学上可接受的溶剂化合物和含有它们的药物组合物。
• 一种BTK抑制剂及其应用
  申请人：成都施贝康生物医药科技有限公司

  公开号：CN108129483B

  公开（公告）日：2019-06-04

  本发明公开了一种式I所示的吡咯烷类BTK抑制剂、其立体异构体或药学上可接受的盐，其中R为氢、烷基羰基、烷氧基羰基、环烷基羰基、环烷氧基羰基或芳基氧基羰基；R1、R2、R3独立地为氢、羟基、氰基、C1‑4烷基、卤素或卤素取代的C1‑4烷基，本发明还提供了式I化合物、其立体异构体或药学上可接受的盐在制备预防或治疗BTK介导的疾病中的药物中的应用。
• [EN] NOVEL 4-FLUOROPYRROLIDINE-2-CARBONYL FLUORIDE COMPOUNDS AND THEIR PREPARATIVE METHODS<br/>[FR] NOUVEAUX FLUORURES DE 4-FLUOROPYRROLIDINE-2-CARBONYLE ET LEURS MÉTHODES DE SYNTHÈSE
  申请人：IM & T RES INC

  公开号：WO2010081014A1

  公开（公告）日：2010-07-15

  Novel 4-fluoropyrrolidine-2-carbonyl fluoride compounds as useful fluorinated intermediates are disclosed. Their preparative methods are also disclosed. Useful applications of the 4-fluoropyrrolidine-2-carbonyl fluorides are shown.

  本发明公开了4-氟吡咯烷-2-羰基氟化物化合物作为有用的氟代中间体。其制备方法也被公开。展示了4-氟吡咯烷-2-羰基氟化物的有用应用。
• N-Substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase
  申请人：Crescenzi Benedetta

  公开号：US20080275004A1

  公开（公告）日：2008-11-06

  N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula: are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R 1 , R 2 , R 3 and R 4 are defined herein. These compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described.

  本文描述了式子中定义的具有N取代的5-羟基嘧啶-6-酮-4-羧酰胺的化合物，这些化合物是HIV整合酶的抑制剂和HIV复制的抑制剂，其中R1、R2、R3和R4在此处定义。这些化合物在预防和治疗HIV感染以及预防、延迟发病和治疗艾滋病方面非常有用。这些化合物可以作为化合物本身或药物可接受的盐的形式用于对抗HIV感染和艾滋病。这些化合物及其盐可以作为药物组成部分，与其他抗病毒药物、免疫调节剂、抗生素或疫苗可选地结合使用。还描述了预防、治疗或延迟艾滋病发病的方法以及预防或治疗HIV感染的方法。