(1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tri(acetoxy)-6′-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydrospiro-[isobenzofuran-1(3H),2′-[2H]pyran] | 1005142-67-5

• 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: (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tri(acetoxy)-6′-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydrospiro-[isobenzofuran-1(3H),2′-[2H]pyran]
• 英文别名: (1S,3'R,4'S,5'R,6'R)-3',4',5'-tri(acetoxy)-6'-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3',4',5',6'-tetrahydrospiro[isobenzofuran-1(3H),2'-[2H]pyran]；[(2'R,3S,3'R,4'S,5'R)-3',4',5'-triacetyloxy-6-chloro-5-[(4-ethylphenyl)methyl]spiro[1H-2-benzofuran-3,6'-oxane]-2'-yl]methyl acetate
• CAS: 1005142-67-5
• 化学式: C₃₀H₃₃ClO₁₀
• 分子量: 589.039
• InChiKey: KFRRZVRXBYHYAO-RLXMVLCYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  41
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  124
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tri(acetoxy)-6′-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydrospiro-[isobenzofuran-1(3H),2′-[2H]pyran] 在 甲醇 、 potassium fluoride 、 1,2,3,4,5-五苯基-1′-(二叔丁基膦)二茂铁 、 potassium carbonate 、 bis(dibenzylideneacetone)-palladium⁽⁰⁾ 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 (3S,3'R,4'S,5'S,6'R)-5-[(4-ethylphenyl)methyl]-6'-(hydroxymethyl)-6-phenylspiro[1H-2-benzofuran-3,2'-oxane]-3',4',5'-triol
  参考文献：
  名称：

  Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

  摘要：

  Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

  DOI：

  10.1021/jm300884k
• 作为产物：
  描述：

  在 二氯二茂钛 、 三甲基氯硅烷 、 四丁基溴化铵 、 sodium carbonate 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 水 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.0h， 生成 (1S,3′R,4′S,5′S,6′R)-3′,4′,5′-tri(acetoxy)-6′-acetoxymethyl-5-chloro-6-[(4-ethylphenyl)methyl]-3′,4′,5′,6′-tetrahydrospiro-[isobenzofuran-1(3H),2′-[2H]pyran]
  参考文献：
  名称：

  Discovery of Tofogliflozin, a Novel C-Arylglucoside with an O-Spiroketal Ring System, as a Highly Selective Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor for the Treatment of Type 2 Diabetes

  摘要：

  Inhibition of sodium glucose cotransporter 2 (SGLT2) has been proposed as a novel therapeutic approach to treat type 2 diabetes. In our efforts to discover novel inhibitors of SGLT2, we first generated a 3D pharmacophore model based on the superposition of known inhibitors. A search of the Cambridge Structural Database using a series of pharmacophore queries led to the discovery of an O-spiroketal C-arylglucoside scaffold. Subsequent chemical examination combined with computational modeling resulted in the identification of the clinical candidate 16d (CSG452, tofogliflozin), which is currently under phase III clinical trials.

  DOI：

  10.1021/jm300884k

文献信息

• EP2048153
  申请人：——

  公开号：——

  公开（公告）日：——
• A new and improved process for C-aryl glucoside SGLT2 inhibitors
  作者：Yonghai Liu、Tingming Fu、Zhidong Chen、Chunyan Ou

  DOI：10.1007/s00706-015-1458-z

  日期：2015.10

  A practical and scalable synthesis of C-glycosides identified as highly potent sodium-dependent glucose transporter 2 (SGLT2) inhibitors is described. Highlights of the synthetic process are a concise, ten-step synthesis of a structurally complex active pharmaceutical ingredient from a known intermediate via a selective and quantitative addition of an aryl species to the Weinreb amide, and the isomers of undesired ortho-products were avoided during the preparation. The chemistry developed has been applied to prepare SGLT2 inhibitors without recourse to chromatography.