5-(4-氟-苯基)-2-异丙基-1-(3-氧代-丙基)-4-苯基-1H-吡咯-3-羧酸苯胺 | 110862-46-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 中文名称: 5-(4-氟-苯基)-2-异丙基-1-(3-氧代-丙基)-4-苯基-1H-吡咯-3-羧酸苯胺
• 英文名称: 5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N,4-diphenyl-1H-pyrrole-3-carboxamide
• 英文别名: 5-(4-fluorophenyl)-1-(2-formylethyl)-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide；5-(4-fluorophenyl)-2-(1-methylethyl)-1-(3-oxopropyl)-N ,4-diphenyl-1 H - pyrrole-3-carboxamide；5-(4-fluorophenyl)-1-(3-oxopropyl)-N,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide
• CAS: 110862-46-9
• 化学式: C₂₉H₂₇FN₂O₂
• 分子量: 454.544
• InChiKey: VHFAMHWIQKTZMV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  34
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  51.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-(4-氟-苯基)-2-异丙基-1-(3-氧代-丙基)-4-苯基-1H-吡咯-3-羧酸苯胺 在 sodium tetrahydroborate 、 (S)-2-(N-3-叔丁基亚水杨基)氨基-3-甲基-1-丁醇 、 二乙基甲氧基硼烷 、 sodium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 54.0h， 生成 lipitor
  参考文献：
  名称：

  Synthetic studies on statins. Part 1: a short and cyanide-free synthesis of atorvastatin calcium via an enantioselective aldol strategy

  摘要：

  A short and cyanide-free enantioselective synthesis of atorvastatin calcium has been achieved starting from a commercially available highly substituted 1,4-diketone in an overall yield of 40%. The key step in this approach is the asymmetric aldol reaction of an aldehyde with diketene in the presence of Ti(O-i-Pr)(4)-Schiff base complex to create the (5R)-stereochemistry of atorvastatin calcium. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2012.12.009
• 作为产物：
  描述：

  4-甲基-3-酮基-N-苯基戊酰胺 在 草酰氯 、 对氨基苯酚 、 3-乙基-5-(2-羟乙基)-4-甲基噻唑溴化物 、 溶剂黄146 、 二甲基亚砜 、 三乙胺 、 三甲基乙酸 作用下， 以 四氢呋喃 、 正己烷 、 正庚烷 、 二氯甲烷 、 甲苯 为溶剂， 反应 70.0h， 生成 5-(4-氟-苯基)-2-异丙基-1-(3-氧代-丙基)-4-苯基-1H-吡咯-3-羧酸苯胺
  参考文献：
  名称：

  阿托伐他汀钙的总合成†

  摘要：

  实用且收敛的不对称途径合成了阿托伐他汀钙（1）。阿托伐他汀钙（1）的合成是通过远程1,5-抗不对称诱导作用在硼介导的β-烷氧基甲基酮（4）与吡咯醛（3）的羟醛反应中进行的，这是关键步骤。6步后从醛（3）中获得阿托伐他汀钙，总收率为41％。

  DOI：

  10.1039/c5ob02546j

文献信息

• PROCESS FOR THE PREPARATION OF ATORVASTATIN AND INTERMEDIATES
  申请人：Wang Fan

  公开号：US20060194867A1

  公开（公告）日：2006-08-31

  A process is provided for preparing (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, R-substituted ester 9 comprising: (a) reacting the aldehyde 1 with the enolate form of (S)-2-hydroxy-1,2,2-triphenylethyl acetate substituent in a chelating co-solvent; (b) hydrolysis of (R,S)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-3-hydroxy-1-pentanoic acid, (S)-2-hydroxy-1,2,2-triphenylethyl ester (2a and 2b) using a base, preferably an alkali metal base, preferably in a solvent to form the carboxylic acid 7; (c) treating the acid 7 with a chiral base to form a salt and purifying the salt to obtain enantiomerically enriched (R)-7 chiral base salt; (d) alkylation of the (R)-7 chiral base salt or the free base derived from (R)-7, forming (R)-5-[2-(4-fluorophenyl)-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrol-1-yl]-5-hydroxy-3-oxo-1-heptanoic acid, R-substituted ester 9 and atorvastatin calcium 6, wherein R is a C1 to C6 alkyl, C6 to C9 aryl or C7 to C10 aralkyl.

  提供了一种制备(R)-5-[2-(4-氟苯基)-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-基]-5-羟基-3-氧代-1-庚酸，R-取代酯9的过程，包括：(a)将醛1与(S)-2-羟基-1,2,2-三苯乙基醋酸酯取代物的烯醇形式在螯合共溶剂中反应；(b)水解(R,S)-5-[2-(4-氟苯基)-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-基]-3-羟基-1-戊酸，(S)-2-羟基-1,2,2-三苯乙基酯(2a和2b)使用碱，优选为碱金属碱，优选在溶剂中形成羧酸7；(c)用手性碱处理酸7以形成盐并纯化盐以获得对映富集的(R)-7手性碱盐；(d)烷基化(R)-7手性碱盐或由(R)-7衍生的游离碱，形成(R)-5-[2-(4-氟苯基)-5-(1-甲基乙基)-3-苯基-4-[(苯基氨基)羰基]-1H-吡咯-1-基]-5-羟基-3-氧代-1-庚酸，R-取代酯9和阿托伐他汀钙6，其中R是C1到C6烷基，C6到C9芳基或C7到C10芳基甲基。
• PREPARATION PROCESS USEFUL IN SYNTHESIS OF ATORVASTATIN
  申请人：Cho Dong-Ock

  公开号：US20110112309A1

  公开（公告）日：2011-05-12

  The present invention relates to a preparation process useful in synthesis of atorvastatin, more particularly a process for preparing atorvastatin is effective in treating hyperlipemia, comprising protecting the dihydroxy group at C3 and C5 positions of the starting material cis-t-butyl-6-substituted-3,5-dihydroxy-hexanoate with trialkyl orthoformate, reducing the terminal nitro or cyano group to amine group, performing JV-alkylation by sequentially reacting with ethyl 4-fluorobenzene-2-haloacetate and isobutyryl chloride, cyclizing with JV,3-diphenylpropynamide, and performing deprotection and hydrolysis.

  本发明涉及一种在阿托伐他汀合成中有用的制备过程，更具体地，涉及一种制备阿托伐他汀的处理方法，用于治疗高脂血症，包括通过使用三烷基正甲酸酯保护起始物质顺丁基-6-取代-3,5-二羟基己酸酯的C3和C5位置的二羟基基团，将末端硝基或氰基还原为胺基团，通过依次与乙基4-氟苯基-2-卤代乙酸酯和异丁酰氯反应进行JV-烷基化，与JV，3-二苯基丙炔酰胺环化，并进行去保护和水解。
• [EN] FLUOROMALONYL HALFTHIOESTERS<br/>[FR] SEMI-THIOESTERS DE FLUOROMALONYLE
  申请人：ETH ZUERICH

  公开号：WO2016075085A1

  公开（公告）日：2016-05-19

  The present invention relates to Fluoromalonyl Halfthioesters (F-MAHTs) of formula (I), wherein R1 represents hydrogen, halogen, an optionally substituted alkyl group, an optionally substituted cycloalkyl group, an optionally substituted aryl group; and R2 represents an optionally substituted aryl group, an optionally substituted cycloalkyl group, an optionally substituted heteroaryl group, an optionally substituted heterocyclyl group; an optionally substituted alkyl group. The invention further relates to their synthesis and to their use, particularly as masked fluoroacetates in the preparation of pharmaceutical active ingredients.

  本发明涉及公式（I）的氟马隆酰半硫酯（F-MAHTs），其中R1代表氢、卤素、可选择取代的烷基、可选择取代的环烷基、可选择取代的芳基；R2代表可选择取代的芳基、可选择取代的环烷基、可选择取代的杂芳基、可选择取代的杂环烷基；可选择取代的烷基。该发明还涉及它们的合成和用途，特别是作为制备药用活性成分中的假氟乙酸酯。
• [EN] PROCESS FOR PREPARING 5-(4-FLUOROPHENYL)-1-[2R,4R)-4-HYDROXY-6-OXO-TETRAHYDRO-PYRAN-2-YL)ETHYL]-2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3-CARBOXYLIC ACID PHENYLAMIDE<br/>[FR] PROCEDE DE PREPARATION DE PHENYLAMIDE D'ACIDE CARBOXYLIQUE 5-(4-FLUOROPHENYL)-1-[2-((2R,4R)-4-HYDROXY-6-OXO-TETRAHYDRO-PYRAN-2-YL)ETHYL]-2-ISOPROPYL-4-PHENYL-1H-PYRROLE-3
  申请人：WARNER LAMBERT CO

  公开号：WO2004089894A1

  公开（公告）日：2004-10-21

  A method for preparing 5-(4-fluorophenyl)-1-[2-((2R,4R)-4-hydroxy-6-oxo-tetrahydro-pyran-2-yl)ethyl]-2-isopropyl-4-phenyl-1H-pyrrole-3-carboxylic acid phenylamide (I), a key intermediate in the synthesis of atorvastatin calcium, is described.

  本文描述了一种制备阿托伐他汀钙合成中的关键中间体5-(4-氟苯基)-1-[2-((2R,4R)-4-羟基-6-氧代四氢吡喃-2-基)乙基]-2-异丙基-4-苯基-1H-吡咯烷-3-羧酸苯酰胺(I)的方法。
• Atorvastatin, an HMG-COA reductase inhibitor and effective lipid-regulating agent. Part II. Synthesis of side-chain-labeled [14C]atorvastatin
  作者：Helen T. Lee、Peter W. K. Woo

  DOI：10.1002/(sici)1099-1344(199902)42:2<129::aid-jlcr174>3.0.co;2-o

  日期：1999.2

  5.7%. The label was introduced as sodium [1-14C]acetate, which was converted via the acid chloride to the (S)-2-hydroxy-1,2,2-triphenylethyl ester 4. Chiral condensation of 4 with aldehyde 5 gave the chiral ester intermediate 6 with a yield of about 70%. Following transesterification of 6 to a methyl ester and condensation with tert-butyl lithioacetate to give (R)-β-ketoester 8, a second chiral center

  [14C]阿托伐他汀以10步顺序合成，总产率为5.7%。标记物以 [1-14C] 乙酸钠形式引入，通过酰氯转化为 (S)-2-羟基-1,2,2-三苯乙酯 4。4 与醛 5 的手性缩合得到手性酯中间体6，产率约70%。在 6 酯交换为甲酯并与硫代乙酸锂叔丁酯缩合得到 (R)-β-酮酯 8 后，通过还原羟基酮 3 生成第二个手性中心，得到 (R,R)-二羟基酯 9然后通过酸将其转化为内酯11。在结晶过程中从母液中获得的所需纯非对映异构体11然后转化为相应的钙盐(2:1)13(阿托伐他汀)。版权所有 © 1999 John Wiley & Sons, Ltd.