(R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate
• 英文别名: tert-butyl 4-[6-chloro-5-[(2R)-4-methoxy-4-oxobutan-2-yl]pyrimidin-4-yl]piperazine-1-carboxylate
• 化学式: C₁₈H₂₇ClN₄O₄
• 分子量: 398.89
• InChiKey: QGPSWIOAIJKRMU-GFCCVEGCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  84.9
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate 在 甲酸 、 4-异丙基甲苯 、 palladium on activated charcoal 、 1,3-双(二苯基膦)丙烷 、 potassium tert-butylate 、 水 、 palladium diacetate 、 sodium carbonate 、 caesium carbonate 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 5.0~75.0 ℃ 、800.01 kPa 条件下， 反应 111.0h， 生成 tert-butyl 4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate
  参考文献：
  名称：

  [EN] HETEROCYCLIC COMPOUND WITH AKT KINASE INHIBITORY ACTIVITY, PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF
  [FR] COMPOSÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ INHIBITRICE DE KINASE AKT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION MÉDICALE
  [ZH] 具有AKT激酶抑制活性的杂环化合物及其制备方法和医药用途

  摘要：

  提供具有 AKT 激酶抑制活性的杂环化合物及其制备方法和医药用途。具体地，提供涉及通式(I)所示的化合物，其制备方法，含有其的药物组合物，以及其作为 AKT 激酶抑制剂在预防和/或治疗异常细胞生长如癌症的药物中的用途。通式(I)中的各基团的定义与说明书中的定义相同。

  公开号：

  WO2023109540A1
• 作为产物：
  描述：

  trimethyl 2-methylpropane-1,1,3-tricarboxylate 在 2,6-二甲基吡啶 、 sodium methylate 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 甲醇 、 aq. phosphate buffer 、 甲苯 为溶剂， 反应 60.5h， 生成 (R)-tert-butyl 4-(6-chloro-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate
  参考文献：
  名称：

  Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up

  摘要：

  Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a beta(2)-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt.

  DOI：

  10.1021/op500270z

文献信息

• [EN] PROCESS FOR MAKING HYDROXYLATED CYCLOPENTYLPYRIMIDINE COMPOUNDS<br/>[FR] PROCÉDÉ DE FABRICATION DE COMPOSÉS CYCLOPENTYLPYRIMIDINES HYDROXYLÉES
  申请人：ARRAY BIOPHARMA INC

  公开号：WO2013173736A1

  公开（公告）日：2013-11-21

  The invention provides new processes for making and purifying hydroxylated cyclopenta[d]pyrimidine compounds, which are useful for the treatment of diseases such as cancer as AKT protein kinase inhibitors, including the compound (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

  这项发明提供了制备和纯化羟基化环戊[ｄ]嘧啶化合物的新工艺，这些化合物可用于治疗癌症等疾病作为AKT蛋白激酶抑制剂，包括化合物(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊[ｄ]嘧啶-4-基)哌嗪-1-基)-3-(异丙氨基)丙酮。
• PROCESS FOR MAKING HYDROXYLATED CYCLOPENTYLPYRIMIDINE COMPOUNDS
  申请人：Array BioPharma Inc.

  公开号：US20150099881A1

  公开（公告）日：2015-04-09

  The invention provides new processes for making and purifying hydroxylated cyclopenta[d]pyrimidine compounds, which are useful for the treatment of diseases such as cancer as AKT protein kinase inhibitors, including the compound (S)-2-(4-chlorophenyl)-1-(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)-3-(isopropylamino)propan-1-one.

  本发明提供了制备和纯化羟基化环戊二氮杂嘧啶化合物的新工艺，该化合物可作为AKT蛋白激酶抑制剂用于治疗癌症等疾病，包括(S)-2-(4-氯苯基)-1-(4-((5R,7R)-7-羟基-5-甲基-6,7-二氢-5H-环戊二氮杂嘧啶-4-基)哌嗪-1-基)-3-(异丙基氨基)丙酮。
• [EN] HETEROCYCLIC COMPOUND WITH AKT KINASE INHIBITORY ACTIVITY, PREPARATION METHOD THEREFOR AND MEDICAL USE THEREOF<br/>[FR] COMPOSÉ HÉTÉROCYCLIQUE AYANT UNE ACTIVITÉ INHIBITRICE DE KINASE AKT, SON PROCÉDÉ DE PRÉPARATION ET SON UTILISATION MÉDICALE<br/>[ZH] 具有AKT激酶抑制活性的杂环化合物及其制备方法和医药用途
  申请人：[en]THE NATIONAL INSTITUTES OF PHARMACEUTICAL R&D CO., LTD;[zh]中国医药研究开发中心有限公司

  公开号：WO2023109540A1

  公开（公告）日：2023-06-22

  提供具有 AKT 激酶抑制活性的杂环化合物及其制备方法和医药用途。具体地，提供涉及通式(I)所示的化合物，其制备方法，含有其的药物组合物，以及其作为 AKT 激酶抑制剂在预防和/或治疗异常细胞生长如癌症的药物中的用途。通式(I)中的各基团的定义与说明书中的定义相同。
• US9309204B2
  申请人：——

  公开号：US9309204B2

  公开（公告）日：2016-04-12
• Synthesis of Akt Inhibitor Ipatasertib. Part 2. Total Synthesis and First Kilogram Scale-up
  作者：Travis Remarchuk、Frederic St-Jean、Diane Carrera、Scott Savage、Herbert Yajima、Brian Wong、Srinivasan Babu、Alan Deese、Jeffrey Stults、Michael W. Dong、David Askin、Jonathan W. Lane、Keith L. Spencer

  DOI：10.1021/op500270z

  日期：2014.12.19

  Herein, the first-generation process to manufacture Akt inhibitor Ipatasertib through a late-stage convergent coupling of two challenging chiral components on multikilogram scale is described. The first of the two key components is a trans-substituted cyclopentylpyrimidine compound that contains both a methyl stereocenter, which is ultimately derived from the enzymatic resolution of a simple triester starting material, and an adjacent hydroxyl group, which is installed through an asymmetric reduction of the corresponding cyclopentylpyrimidine ketone substrate. A carbonylative esterification and subsequent Dieckmann cyclization sequence was developed to forge the cyclopentane ring in the target. The second key chiral component, a beta(2)-amino acid, is produced using an asymmetric aminomethylation (Mannich) reaction. The two chiral intermediates are then coupled in a three-stage endgame process to complete the assembly of Ipatasertib, which is isolated as a stable mono-HCl salt.