isobutyric acid 4-oxo-[1,3]-dioxolan-2(R)-yl-methyl ester | 444730-15-8

• 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: isobutyric acid 4-oxo-[1,3]-dioxolan-2(R)-yl-methyl ester
• 英文别名: (R)-isobutyric acid 4-oxo-[1,3]dioxolan-2-ylmethyl ester；(R)-(4-oxo-1,3-dioxolan-2-yl)methyl isobutyrate；(R)-lactone B；isobutyric acid-4-oxo-[1,3]-dioxolan-2-(R)-yl methyl ester；isobutyric acid 4-oxo-[1,3]-dioxolan-2(R)-yl methyl ester；isobutyric acid-4-oxo[1,3]dioxolan-2(R)-yl methyl ester；[(2R)-4-oxo-1,3-dioxolan-2-yl]methyl 2-methylpropanoate
• CAS: 444730-15-8
• 化学式: C₈H₁₂O₅
• 分子量: 188.18
• InChiKey: STKSTTXGUPJHDV-SSDOTTSWSA-N

物化性质

• 沸点：
  283.1±20.0 °C(Predicted)
• 密度：
  1.189±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  isobutyric acid 4-oxo-[1,3]-dioxolan-2(R)-yl-methyl ester 在 sodium azide 、 三氟甲磺酸三甲基硅酯 、 lithium tri-t-butoxyaluminum hydride 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 isobutyric acid 4(R)-(2,6-diazido-purin-9-yl)-[1,3]-dioxolan-2(R)-yl-methyl ester
  参考文献：
  名称：

  Synthesis of (−)‐DAPD

  摘要：

  A new synthesis of (-)-DAPD, suitable for large scale development, is described.

  DOI：

  10.1081/ncn-200040643
• 作为产物：
  描述：

  isobutyric acid 2,2-dimethoxy-ethyl ester 在 三氟化硼乙醚 作用下， 以 乙腈 为溶剂， 生成 isobutyric acid 4-oxo-[1,3]-dioxolan-2(R)-yl-methyl ester
  参考文献：
  名称：

  Synthesis of (−)‐DAPD

  摘要：

  A new synthesis of (-)-DAPD, suitable for large scale development, is described.

  DOI：

  10.1081/ncn-200040643

文献信息

• Enzymatic Kinetic Resolution of 1,3-Dioxolan-4-one and 1,3-Oxathiolan-5-one Derivatives: Synthesis of the Key Intermediate in the Industrial Synthesis of the Nucleoside Reverse Transcriptase Inhibitor AMDOXOVIR
  作者：Alfred Popp、Andrea Gilch、Anne-Laure Mersier、Hermann Petersen、Jodoca Rockinger-Mechlem、Jürgen Stohrer

  DOI：10.1002/adsc.200303184

  日期：2004.5

  The resolution of racemic 1,3-dioxolan-4-one and 1,3-oxathiolan-5-one derivatives such as (4-oxo-1,3-dioxolan-2-yl)methyl 2-methylpropanoate (2) by enzymatic solvolysis was investigated. The resolution of 2, a precursor for the synthesis of the nucleoside reverse transcriptase inhibitor Amdoxovir, was optimized in terms of solvent/nucleophile, reaction conditions, and enzyme. The use of lipase from

  通过酶促拆分外消旋的1,3-二氧戊环-4-酮和1,3-氧杂噻喃-5-酮衍生物，例如（4-氧代-1,3-二氧杂环戊烷-2-基）2-甲基丙酸甲酯（2）研究了溶剂分解。在溶剂/亲核试剂，反应条件和酶方面优化了2的分辨率（一种用于合成核苷逆转录酶抑制剂Amdoxovir的前体）。使用来自南极假丝酵母B（CALB）的脂肪酶和甲醇作为亲核试剂和溶剂可产生有效的拆分效果，并且可以轻松分离出产物（R）-2。可以分离底物分解的产物，并将其重新用于合成外消旋体2。通过具有不同取代模式的其他底物的拆分，证明了该酶拆分的广泛应用。该方法为对映体纯的1,3-二氧杂戊环4-酮和1,3-氧杂噻吩基5-酮提供了前所未有的新途径。
• Methods to manufacture 1,3-dioxolane nucleosides
  申请人：Sznaidman Marcos

  公开号：US20060036092A1

  公开（公告）日：2006-02-16

  This application provides a process for preparing enantiomerically pure β-D-dioxolane nucleosides. In particular, a new synthesis of (−)-DAPD, suitable for large scale development, is described. In one embodiment the invention provides a process for preparing a substantially pure β-D- or β-L-1,3-dioxolane nucleosides comprising a) preparing or obtaining an esterified 2,2-dialkoxy ethanol; b) cyclizing the esterified 2,2-dialkoxy ethanol with glycolic acid to obtain a 1,3-dioxolane lactone; c) resolving the 1,3-dioxolane lactone to obtain a substantially pure D- or L-lactone; d) selectively reducing and activating the D- or L-chiral lactone to obtain a substantially pure D- or L-1,3-dioxolane; e) coupling the D- or L-1,3-dioxolane to an activated and/or protected purine or pyrimidine base; and f) optionally purifying the nucleoside to obtain a substantially pure protected β-D- or P-L-1,3-dioxolane nucleoside.

  该应用程序提供了一种制备对映纯β-D-二氧杂环核苷的方法。具体来说，描述了一种适用于大规模开发的新合成方法，用于制备(−)-DAPD。在一种实施方式中，该发明提供了一种制备基本纯β-D-或β-L-1,3-二氧杂环核苷的方法，包括a) 制备或获取酯化的2,2-二烷氧基乙醇；b) 将酯化的2,2-二烷氧基乙醇与甘醇酸环化以获得1,3-二氧杂环内酯；c) 分解1,3-二氧杂环内酯以获得基本纯的D-或L-内酯；d) 选择性还原和激活D-或L-手性内酯以获得基本纯的D-或L-1,3-二氧杂环；e) 将D-或L-1,3-二氧杂环与激活和/或保护的嘌呤或嘧啶碱基偶联；f) 可选地纯化核苷以获得基本纯的保护的β-D-或P-L-1,3-二氧杂环核苷。
• MONOPHOSPHATE PRODRUGS OF DAPD AND ANALOGS THEREOF
  申请人：Schinazi Raymond F.

  公开号：US20120142627A1

  公开（公告）日：2012-06-07

  The present invention is directed to compounds, compositions and methods for treating or preventing cancer and viral infections, in particular, HIV and HBV, in human patients or other animal hosts. The compounds are certain 6-substituted-2-amino-purine dioxolane monophosphates or phosphonates, and pharmaceutically acceptable, salts, prodrugs, and other derivatives thereof.

  本发明涉及用于治疗或预防癌症和病毒感染，特别是HIV和HBV，在人类患者或其他动物宿主中的化合物、组合物和方法。这些化合物是某些6-取代-2-氨基嘧啶二氧杂环己糖单磷酸盐或膦酸盐，以及其药用可接受的盐、前药和其他衍生物。
• Scaleable processes for the synthesis of (−)-β-d-2,6-diaminopurine dioxolane (Amdoxovir, DAPD) and (−)-β-d-2-aminopurine dioxolane (APD)
  作者：Longhu Zhou、Steven J. Coats、Hongwang Zhang、Junxing Shi、Drew R. Bobeck、Raymond F. Schinazi

  DOI：10.1016/j.tet.2012.05.039

  日期：2012.7

  efficient and scalable synthesis of (−)-DAPD and (−)-APD has been developed. We discovered that t-butyl cyanoacetate can be used as a new additive for the sugar nucleoside base coupling step en route to DAPD with improved β-selectivity and an isolated yield four-fold greater than the original process scale method. Using this new process, (−)-DAPD has been prepared on greater than 20 g scale. In the synthesis

  已经开发了 (-)-DAPD 和 (-)-APD 的有效且可扩展的合成。我们发现氰基乙酸叔丁酯可用作糖核苷碱基偶联步骤的新添加剂，用于 DAPD 的过程中，具有改进的β-选择性和比原始工艺规模方法高四倍的分离产率。使用这种新工艺，(-)-DAPD 的制备量超过 20 克。在 (-)-APD 的合成中，关键的酶催化水解反应提供了水溶性脱保护的 α-端基异构体，而 β-端基异构体完全不受影响。
• STEREOSELECTIVE PROCESS FOR PREPARING PURINE DIOXOLANE NUCLEOSIDE DERIVATIVES
  申请人：Coats Steven J.

  公开号：US20100210840A1

  公开（公告）日：2010-08-19

  A cost-effective process scale method for preparing purine dioxolane nucleoside derivatives in racemic or optically pure form is disclosed, as are nucleoside derivatives prepared by the method. The method involves reacting a purine or a mono- or polysilylated purine derivative with an activated dioxolane analog to produce the dioxolane nucleoside analog in commercially useful yields. Direct reaction of purine or a mono- or polysilylated purine with dioxolanes takes place with highest reported chemical yields and excellent stereoselectivity when an additive in the form of an alpha cyano carbonyl compound or silylated alpha cyano carbonyl compounds is present in the reaction mixture during the glycosylation reaction.

  本发明公开了一种制备嘌呤二氧兰核苷衍生物的成本效益的工艺规模方法，可以制备出外消旋或光学纯的核苷衍生物。该方法涉及将嘌呤或单个或多个硅烷基化嘌呤衍生物与活性二氧兰类似物反应，以产生商业上有用的二氧兰核苷类似物收率。当在糖基化反应期间反应混合物中存在α-氰基羰基化合物或硅烷化α-氰基羰基化合物形式的添加剂时，嘌呤或单个或多个硅烷基化嘌呤与二氧兰的直接反应具有最高的化学收率和优异的立体选择性。同时，本发明还公开了通过该方法制备的核苷衍生物。