ethyl 4-(2-phthalimidoethoxy)-2-(2'-chlorobenzylidene)-acetoacetate

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: ethyl 4-(2-phthalimidoethoxy)-2-(2'-chlorobenzylidene)-acetoacetate
• 英文别名: ethyl 2-(o-chlorobenzylidene)-4-(2-phthalimidoethoxy)acetoacetate；Ethyl 2-(2-chlorobenzylidene)-4-(2-(1,3-dioxoisoindolin-2-yl)ethoxy)-3-oxobutanoate；ethyl (2Z)-2-[(2-chlorophenyl)methylidene]-4-[2-(1,3-dioxoisoindol-2-yl)ethoxy]-3-oxobutanoate
• 化学式: C₂₃H₂₀ClNO₆
• 分子量: 441.868
• InChiKey: HIMWFGTVILLKOV-AQTBWJFISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  90
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl 4-(2-phthalimidoethoxy)-2-(2'-chlorobenzylidene)-acetoacetate 、 3-氨基巴豆酸乙酯 以 乙醇 、 溶剂黄146 、 异丙醇 为溶剂， 以43.6 g (30%)的产率得到Diethyl 4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl) ethoxy] methyl}-6-methyl-1.4-dihydro-3.5-pyridine dicarboxylate
  参考文献：
  名称：

  Process for making amlodipine

  摘要：

  氨氯地平及其相关类似物是通过以下一般反应方案制备的：R1和R2各自独立代表C1-C4烷基基团。该过程可高产率和纯度地形成化合物的结构式（1）。此外，结构式（1）的化合物可用作钙通道阻滞剂，或用作氨氯地平纯度检查的参考标准或参考标记。

  公开号：

  US06653481B2
• 作为产物：
  描述：

  哌啶 、 2-氯苯甲醛 、 乙基-4-(2-邻苯二甲酰亚胺基乙氧基)乙酰乙酸乙酯 在 溶剂黄146 作用下， 以 异丙醇 为溶剂， 生成 ethyl 4-(2-phthalimidoethoxy)-2-(2'-chlorobenzylidene)-acetoacetate
  参考文献：
  名称：

  Process for making amlodipine

  摘要：

  氨氯地平及其相关类似物是通过以下一般反应方案制备的：R1和R2各自独立代表C1-C4烷基基团。该过程可高产率和纯度地形成化合物的结构式（1）。此外，结构式（1）的化合物可用作钙通道阻滞剂，或用作氨氯地平纯度检查的参考标准或参考标记。

  公开号：

  US06653481B2

文献信息

• Process for making amlodipine, derivatives therof, and precursors therefor
  申请人：——

  公开号：US20020143046A1

  公开（公告）日：2002-10-03

  Amlodipine and related analogues thereof are prepared by the following general reaction scheme: 1 R 1 and R 2 each independently represent a C 1 -C 4 alkyl group. The process provides for the formation of compounds of formula (1) in good yield and purity. Further, the compounds of formula (1) can be used as calcium channel blockers or as reference standards or reference markers for checking the purity of amlodipine.

  氨氯地平及其相关类似物是通过以下一般反应方案制备的：1R1和R2各自独立表示C1-C4烷基基团。该过程提供了以良好产率和纯度形成化合物的方法。此外，化合物的公式（1）可用作钙通道阻滞剂，或用作氨氯地平纯度检查的参考标准或参考标记。
• Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate
  申请人：——

  公开号：US20040044218A1

  公开（公告）日：2004-03-04

  Process for the preparation of anti-ischemic and anti-hypertensive drug amlodipine besylate [2-{(2-aminoethoxy)-methyl-4-(2-chlorophenyl) 3-ethoxy carbonyl-5-methoxycarbonyl-6-methyl-1,4-dihydropyridine} benzene sulphonate]. Phthalic anhydride is condensed with monoethanol amine at 150-190° C. The resulting N-(2-hydroxyethyl) phthalimide is coupled with 4-chloroethyl acetoacetate in the presence of sodium hydride in an organic solvent in an inert atmosphere at −11 to −15° C. Ethyl-4-[-2(phthalimido) ethoxy] acetoacetate formed is coupled with orthochloro benzaldehyde in the presence of pyridine salt at 70-90° C. Ethyl-2-(2-chloro benzylidine)4-[-2(phthalimido) ethoxy] acetoacetate fanned is condensed with methyl amino crotonate at 20-40° C. in the presence of acetic acid to form phthaloyl amlodipine [2-(2-Phthalimidoethoxy) methyl-3-carboethoxy 1(chlorophenyl)-S-carbomethoxy-6-methyl-1,4-dihydropyridin] which is purified by dissolving in an organic solvent in the ratio 1:2-1:5 w/v and precipitated by the addition of water at 35-60° C. Purified phthaloyl amlodipine is hydrolysed with methylamine in the presence of a protic solvent at 20-50° C. Amlodipine base [2-(aminoethoxy) methyl-3-carboethoxy-4-(2-chlorophenyl)-5-carbomethoxy-6-methyl-1,4-dihydropyridin] formed is reacted with benzene sulfonic acid. The resulting amlodipine besylate is purified in an organic solvent at 30-70° C. and precipitated by the addition of an insoluble solvent.

  制备抗缺血和抗高血压药物氨氯地平苯酸盐的过程。邻苯二甲酸酐与单乙醇胺在150-190°C下缩合。得到的N-（2-羟乙基）邻苯二甲酰亚胺在有机溶剂中与氯乙酰乙酮在惰性气氛中在-11至-15°C下偶联。形成的乙酸乙酯-4-〔-2-（邻苯二甲酰亚胺）乙氧〕乙酸乙酯与邻氯苯甲醛在70-90°C下在吡啶盐存在下偶联。形成的乙酸乙酯-2-（2-氯苯基亚甲基）4-〔-2-（邻苯二甲酰亚胺）乙氧〕乙酸乙酯在存在乙酸的情况下与甲氨基丙烯酸甲酯在20-40°C下缩合，形成邻苯二甲酰氨氯地平。通过在有机溶剂中溶解比例为1:2-1:5 w/v，然后通过在35-60°C下加水来沉淀，纯化邻苯二甲酰氨氯地平。纯化的邻苯二甲酰氨氯地平在20-50°C下在具有质子溶剂的情况下与甲胺水解。形成的氨氯地平碱与苯磺酸反应。得到的氨氯地平苯酸盐在30-70°C下在有机溶剂中纯化，并通过添加不溶溶剂来沉淀。
• PROCESS FOR PREPARING AMLODIPINE
  申请人：Bolugoddu Vijayabhaskar

  公开号：US20070260065A1

  公开（公告）日：2007-11-08

  A process for preparing phthalimidoamlodipine, which is useful as an intermediate for the preparation of amlodipine and its salts.

  制备邻苯二甲酰亚氨基氨基氨基庚烷，该化合物可用作氨氯地平及其盐的中间体的方法。
• [EN] PROCESS FOR THE PREPARATION OF PURE AMLODIPINE<br/>[FR] PROCEDE DE PREPARATION D'AMLODIPINE PURE
  申请人：MATRIX LAB LTD

  公开号：WO2006003672A1

  公开（公告）日：2006-01-12

  The present invention relates to an improved process for the preparation of pure Amlodipine via the effective purification of phthalimido Amlodipine (3-ethyl-5-methyl -2-[(2-phthalimido ethoxy) methyl]-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5-dicarboxylate).

  本发明涉及一种改进的制备纯氨氯地平的方法，通过对邻苯二甲酰亚氨基氨氯地平（3-乙基-5-甲基-2-[(2-邻苯二甲酰亚氨基)乙氧基]甲基-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-二羧酸酯）进行有效的纯化。
• Process for determining the purity of amlodipine
  申请人：Bioorganics B.V.

  公开号：EP1577298A1

  公开（公告）日：2005-09-21

  The invention relates to a process, which comprises assaying amlodipine, a pharmaceutically acceptable salt thereof, or a composition containing the same for the presence of at least one of specific compounds 1(b)-1(f), to a process of testing the purity of phthalimidoamlodipine, which comprises assaying phthalimidoamlodipine, a pharmaceutically acceptable salt thereof, or a composition containing the same for the presence of at least one of the specific compounds 2b-2e, and to a process of producing amlodipine, which comprises the steps of: (a) assaying a sample from a batch of phthalimidoamlodipine for at least one phthalimidoamlodipine impurity selected from the group consisting of the compounds 2b-2e: (b) determining whether said at least one phthalimidoamlodipine impurity is contained in said sample below a predetermined limit, and, if below said predetermined limit; (c) subjecting said phthalimidoamlodipine batch to deprotection to form a batch of amlodipine.

  本发明涉及一种方法，其包括检测氨氯地平、其药学上可接受的盐或含有其的组合物中是否存在特定化合物1(b)-1(f)中的至少一种，以及一种测试邻苯二甲酰亚氨基氨氯地平纯度的方法，其包括检测邻苯二甲酰亚氨基氨氯地平、其药学上可接受的盐或含有其的组合物中是否存在特定化合物2b-2e中的至少一种，并且涉及一种生产氨氯地平的方法，其包括以下步骤：(a)检测邻苯二甲酰亚氨基氨氯地平批次中的样品，至少包括化合物2b-2e中的一种邻苯二甲酰亚氨基氨氯地平杂质；(b)确定该至少一种邻苯二甲酰亚氨基氨氯地平杂质是否在预定限制以下，如果在预定限制以下；(c)对邻苯二甲酰亚氨基氨氯地平批次进行去保护作用，形成氨氯地平批次。