tert-butyl ((2R,3S,5S)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]-pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate | 1107484-78-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡唑类
• 英文名称: tert-butyl ((2R,3S,5S)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]-pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
• 英文别名: tert-butyl N-[(2R,3S,5S)-2-(2,5-difluorophenyl)-5-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl)oxan-3-yl]carbamate
• CAS: 1107484-78-5
• 化学式: C₂₁H₂₆F₂N₄O₃
• 分子量: 420.459
• InChiKey: DOAYKRFFPQZMBX-UCLAIMLFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  79.5
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  tert-butyl ((2R,3S,5S)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]-pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 生成 (2R,3S,5S)-2-(2,5-difluorophenyl)-5-(4,6-dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl)oxan-3-amine
  参考文献：
  名称：

  Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (23)

  摘要：

  A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.07.061
• 作为产物：
  描述：

  2,5-二氟苯甲酰氯 在 盐酸 、 sodium tetrahydroborate 、 sodium periodate 、 rhodium(III) chloride 、 癸硼烷 、 sodium hydride 、 N,N-二异丙基乙胺 、 锌 作用下， 以 甲醇 、 乙醇 、 正己烷 、 水 为溶剂， 生成 tert-butyl ((2R,3S,5S)-2-(2,5-difluorophenyl)-5-(pyrrolo[3,4-c]-pyrazol-5(1H,4H,6H)-yl)tetrahydro-2H-pyran-3-yl)carbamate
  参考文献：
  名称：

  Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3-amine (23)

  摘要：

  A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.07.061

文献信息

• Asymmetric Synthesis of Highly Functionalized Tetrahydropyran DPP-4 Inhibitor
  作者：Feng Xu、Michael J. Zacuto、Yoshinori Kohmura、Jon Rosen、Andrew Gibb、Mahbub Alam、Jeremy Scott、David Tschaen

  DOI：10.1021/ol502661g

  日期：2014.10.17

  A practical synthesis of a highly functionalized tetrahydropyran DPP-4 inhibitor is described. The asymmetric synthesis relies on three back-to-back Ru-catalyzed reactions. A Ru-catalyzed dynamic kinetic resolution (DKR) reduction establishes two contiguous stereogenic centers in one operation. A unique dihydropyran ring is efficiently constructed through a preferred Ru-catalyzed cycloisomerization

  描述了高度官能化的四氢吡喃DPP-4抑制剂的实用合成。不对称合成依赖于三个背对背Ru催化的反应。Ru催化的动态动力学拆分（DKR）还原可在一次操作中建立两个连续的立体生成中心。通过优选的Ru催化的环异构化可有效地构建独特的二氢吡喃环。硼氢化然后Ru催化氧化可提供所需的官能化吡喃酮核心支架。最后，立体选择性还原胺化反应和随后的酸性脱保护反应以25％的总收率提供了所需的有效DPP-4抑制剂。
• Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes
  作者：John Y. L. Chung、Jeremy P. Scott、Camille Anderson、Brian Bishop、Nadine Bremeyer、Yang Cao、Qinghao Chen、Robert Dunn、Amude Kassim、David Lieberman、Aaron J. Moment、Faye Sheen、Michael Zacuto

  DOI：10.1021/acs.oprd.5b00267

  日期：2015.11.20

  Development of a convergent synthesis of omarigliptin (MK-3102) suitable for commercial manufacture is described. The target molecule is assembled through a diastereoselective reductive amination of a highly functionalized pyranone, with a mesylated pyrazole followed by deprotection of a Boc group. The synthesis of the pyranone relies on three Ru-catalyzed, reactions : (1) a PKR reduction of a rac-alpha-aminoketone to set the two contiguous stereogenic Centers, (2) a cycloisomerization of bis-homopropargylic alcohol to a dihydropyran, and, finally, (3) a Ru-catalyzed oxidation of a Pyranol to the desired pyranone. The regioselective synthesis of 4 N-Boc-1-mesyl pyrazole fragment was achieved via base promoted mesyl group isomerization to afford 30:1 selectivity. A highlight, of the endgame process development is telescoping a Boc deprotection and reductive amination followed by direct crystallization of the penultimate from the reaction mixture. This avoids handling of an unstable, mutagenic 1-mesylpyrazole BSA salt used in the earlier multikilogram deliveries and improves the overall diastereoselectivity and efficiency of the route.