2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid | 244761-03-3

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid
• 英文别名: 2-Carboxymethyl-2-hydroxy-6-methylhept-5-enoic Acid；2-hydroxy-2-(4-methylpent-3-enyl)butanedioic acid
• CAS: 244761-03-3
• 化学式: C₁₀H₁₆O₅
• 分子量: 216.234
• InChiKey: DRFNZQPZTGLTJC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  15
• 可旋转键数：
  6
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  94.8
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid 在 甲酸 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以100%的产率得到2-carboxymethyl-6,6-dimethyl-2-tetrahydro-pyranecarboxylic acid
  参考文献：
  名称：

  The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety

  摘要：

  (2'R,3S,4S,5R)-(-)-齐墩果酸甲酯 2 由 cephalotaxine 直接酯化制得，采用适当取代的四氢吡喃甲酸的活化形式作为立体紧凑的手性侧链前体，随后通过选择性开环得到相应的 (2'R,3S,4S,5R)-(-)-anhydrohomoharringtonine 6。干酰基部分的两个对映体通过以下两种方法制备：一种方法是对适当取代的烯基 α-酮酯 7 进行不对称 α-羟基烷基化，然后进行酸性环化；另一种方法是通过对 (-)-金鸡纳碱形成非对映异构体来分离对应的外消旋混合物。外消旋 cephalotaxine 以及其两个对映体均由天然的部分外消旋的 (-)-cephalotaxine 1 制得。版权 © 1999 Elsevier Science Ltd，保留所有权利。

  DOI：

  10.1016/s0040-4039(99)00327-5
• 作为产物：
  描述：

  ethyl 6-methyl-2-oxohept-5-enoate 在 氢氧化钾 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 4.0h， 生成 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid
  参考文献：
  名称：

  The first semi-synthesis of enantiopure homoharringtonine via anhydrohomoharringtonine from a preformed chiral acyl moiety

  摘要：

  (2'R,3S,4S,5R)-(-)-齐墩果酸甲酯 2 由 cephalotaxine 直接酯化制得，采用适当取代的四氢吡喃甲酸的活化形式作为立体紧凑的手性侧链前体，随后通过选择性开环得到相应的 (2'R,3S,4S,5R)-(-)-anhydrohomoharringtonine 6。干酰基部分的两个对映体通过以下两种方法制备：一种方法是对适当取代的烯基 α-酮酯 7 进行不对称 α-羟基烷基化，然后进行酸性环化；另一种方法是通过对 (-)-金鸡纳碱形成非对映异构体来分离对应的外消旋混合物。外消旋 cephalotaxine 以及其两个对映体均由天然的部分外消旋的 (-)-cephalotaxine 1 制得。版权 © 1999 Elsevier Science Ltd，保留所有权利。

  DOI：

  10.1016/s0040-4039(99)00327-5

文献信息

• [EN] DIOXOLANONE INTERMEDIATE USEFUL IN THE SYNTHESIS OF HOMOHARRINGTONINE<br/>[FR] INTERMÉDIAIRE DE DIOXOLANONE UTILE DANS LA SYNTHÈSE DE L'HOMOHARRINGTONINE
  申请人：INDENA SPA

  公开号：WO2018019549A1

  公开（公告）日：2018-02-01

  The invention discloses 2-((2R,4R)-4-(4-(benzyloxy)-4-methylpent-2-yn-1-yl)-2-(tert-butyl)-5-oxo-1,3-dioxolan-4-yl)acetic acid of formula (XIX), a process for its preparation and processes for its conversion into enantiomerically pure (R)-2-(2-methoxy-2-oxoethyl)-6,6-dimethyltetrahydro-2H-pyran-2-carboxylic acid of formula (I), a molecule useful for the synthesis of Homoharringtonine.

  该发明公开了式（XIX）的2-((2R,4R)-4-(4-(苄氧基)-4-甲基戊-2-炔-1-基)-2-(叔丁基)-5-氧代-1,3-二氧杂环戊-4-基)乙酸，其制备方法以及将其转化为式（I）的对映纯(R)-2-(2-甲氧基-2-氧代乙基)-6,6-二甲基四氢-2H-吡喃-2-羧酸的方法，该分子可用于合成吉非替林。
• Process for Preparing 2-Methoxycarbonylmethyl-6,6-Dimethyl-2-Tetrahydropyran Carboxylic Acid
  申请人：Ferrari Massimo

  公开号：US20090043093A1

  公开（公告）日：2009-02-12

  Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) comprising: a) Reaction of 5-bromo-2-methyl-2-pentene (III) with magnesium and then diethyloxalate to obtain ethyl-2-oxo-6-methyl-5-heptenoate (IV); b) Reaction of ethyl-2-oxo-6-methyl-5-heptenoate (IV) with an alkali amide and methyl acetate to obtain ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V); c) Reaction of ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V) with an alkali metal hydroxide to obtain the corresponding 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI); d) Cyclisation of 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI) with formic acid to give 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII); e) Monoesterification of 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII) to 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I), characterised in that in stage (e) the 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) is purified by means of the formation of the corresponding salt with cyclohexylamine (IA).

  制备2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸（I）的过程包括： a）将5-溴-2-甲基-2-戊烯（III）与镁反应，然后与草酸二乙酯反应，得到乙酸乙酯-2-氧代-6-甲基-5-庚烯酸酯（IV）； b）将乙酸乙酯-2-氧代-6-甲基-5-庚烯酸酯（IV）与碱金属酰胺和乙酸甲酯反应，得到乙酸乙酯-2-甲氧羰基甲基-2-羟基-6-甲基-5-庚烯酸酯（V）； c）将乙酸乙酯-2-甲氧羰基甲基-2-羟基-6-甲基-5-庚烯酸酯（V）与碱金属氢氧化物反应，得到相应的2-羧甲基-2-羟基-6-甲基-5-庚烯酸（VI）； d）将2-羧甲基-2-羟基-6-甲基-5-庚烯酸（VI）与甲酸环化，得到2-羧甲基-6,6-二甲基-2-四氢吡喃羧酸（VII）； e）将2-羧甲基-6,6-二甲基-2-四氢吡喃羧酸（VII）进行单酯化反应，得到2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸（I），其特征在于在阶段（e）中，通过与环己胺（IA）形成相应的盐来纯化2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸（I）。
• Novel cephalotaxane derivatives and process for their preparation
  申请人：——

  公开号：US20020045750A1

  公开（公告）日：2002-04-18

  The present invention concerns a new general process for asymetric hemisynthesis of harringtonines and their analogs, that are alcaloïds used in chimiotherapy. This process comprises direct esterification of a natural cephalotaxine with an acylating compound constituted of a side chain precursor which backbone and fonctionalization are entirely preformed.

  本发明涉及一种新的用于制备哈林顿碱及其类似物的不对称半合成的通用过程，这些化合物是用于化疗的生物碱。该过程包括将天然的头孢松碱与由侧链前体组成的酰化化合物直接酯化，该侧链前体的骨架和功能化已经完全形成。
• Cephalotaxane derivatives and their processes of preparation and purification
  申请人：Robin Jean-Pierre

  公开号：US20050090484A1

  公开（公告）日：2005-04-28

  The present invention concerns a new general process for asymmetric hemisynthesis of harringtonines and their analogs, that are alkaloids used in chemotherapy. This process comprises direct esterification of a natural cephalotaxine with an acylating compound constituted of a side chain precursor which backbone and functionalization are entirely preformed. The invention also concerns a natural, synthetic or semi-synthetic harringtonines including their tautomeric forms and their salts of the following formula: wherein n=2 (i.e. harringtonine) or n=3 (i.e. homoharringtonine), in which the total content of impurities, possibly including enantiomeric forms, is lower than 1%, and/or the content of the major impurity is lower than 0.9%, and/or the chromatographic assay exhibits a harringtonines content higher than 97.5%.

  本发明涉及一种新的不对称半合成哈林顿碱及其类似物的通用工艺，这些碱是用于化疗的生物碱。该工艺包括将天然的头孢松与一个酰化化合物直接酯化，该化合物由一个侧链前体构成，其主干和功能化已经完全形成。该发明还涉及以下式子的天然、合成或半合成哈林顿碱及其互变异构体和盐：其中n=2（即哈林顿碱）或n=3（即同型哈林顿碱），其中可能包括对映异构体在内的总杂质含量低于1％，和/或主要杂质含量低于0.9％，和/或色谱测定显示哈林顿碱含量高于97.5％。
• Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid
  申请人：Erregierre S.p.A.

  公开号：US08008514B2

  公开（公告）日：2011-08-30

  Process for preparing 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) comprising: a) Reaction of 5-bromo-2-methyl-2-pentene (III) with magnesium and then diethyloxalate to obtain ethyl-2-oxo-6-methyl-5-heptenoate (IV); b) Reaction of ethyl-2-oxo-6-methyl-5-heptenoate (IV) with an alkali amide and methyl acetate to obtain ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V); c) Reaction of ethyl-2-methoxycarbonylmethyl-2-hydroxy-6-methyl-5-heptenoate (V) with an alkali metal hydroxide to obtain the corresponding 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI); d) Cyclisation of 2-carboxymethyl-2-hydroxy-6-methyl-5-heptenoic acid (VI) with formic acid to give 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII); e) Monoesterification of 2-carboxymethyl-6,6-dimethyl-2-tetrahydropyrancarboxylic acid (VII) to 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I), characterised in that in stage (e) the 2-methoxycarbonylmethyl-6,6-dimethyl-2-tetrahydropyran carboxylic acid (I) is purified by means of the formation of the corresponding salt with cyclohexylamine (IA).

  制备2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸(I)的过程包括： a）5-溴-2-甲基-2-戊烯(III)与镁反应，然后与乙酰乙酸二乙酯反应，得到乙酸乙酯-2-氧代-6-甲基-5-庚烯酸乙酯(IV)； b）乙酸乙酯-2-氧代-6-甲基-5-庚烯酸乙酯(IV)与碱金属酰胺和乙酸甲酯反应，得到乙酸乙酯-2-甲氧羰基甲基-2-羟基-6-甲基-5-庚烯酸乙酯(V)； c）乙酸乙酯-2-甲氧羰基甲基-2-羟基-6-甲基-5-庚烯酸乙酯(V)与碱金属氢氧化物反应，得到相应的2-羧甲基-2-羟基-6-甲基-5-庚烯酸(VI)； d）2-羧甲基-2-羟基-6-甲基-5-庚烯酸(VI)与甲酸环化，得到2-羧甲基-6,6-二甲基-2-四氢吡喃羧酸(VII)； e）2-羧甲基-6,6-二甲基-2-四氢吡喃羧酸(VII)单酯化为2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸(I)，其特征在于在步骤(e)中，通过与环己胺形成相应的盐来纯化2-甲氧羰基甲基-6,6-二甲基-2-四氢吡喃羧酸(I)。