tert-butyl 1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate | 1226781-81-2

• 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 1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
• 英文别名: tert-butyl 1-methylsulfonyl-4,6-dihydropyrrolo[3,4-c]pyrazole-5-carboxylate
• CAS: 1226781-81-2
• 化学式: C₁₁H₁₇N₃O₄S
• 分子量: 287.34
• InChiKey: YQHMKJTVIUNLNL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  89.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-(甲基磺酰基)-2,6-二氢吡咯并[3,4-c]吡唑-5(4H)-羧酸叔丁酯 、 tert-butyl 1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate 以99的产率得到2,4,5,6-四氢-2-(甲基磺酰基)吡咯并[3,4-C]吡唑苯磺酸盐
  参考文献：
  名称：

  Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes

  摘要：

  本发明涉及结构式I的新型取代氨基四氢吡喃化合物，它们是二肽基肽酶IV酶的抑制剂，可用于治疗或预防二肽基肽酶IV酶参与的疾病，如糖尿病，特别是2型糖尿病。本发明还涉及包含这些化合物的药物组合物以及在预防或治疗二肽基肽酶IV酶参与的这些疾病中使用这些化合物和组合物。

  公开号：

  US08143289B2
• 作为产物：
  描述：

  1,4,5,6-四氢吡咯并[3,4-C]吡唑 在 sodium hydride 、 三乙胺 作用下， 以 二氯甲烷 、 乙腈 为溶剂， 生成 tert-butyl 1-(methylsulfonyl)-4,6-dihydropyrrolo[3,4-c]pyrazole-5(1H)-carboxylate
  参考文献：
  名称：

  Evolution of a Manufacturing Route to Omarigliptin, A Long-Acting DPP-4 Inhibitor for the Treatment of Type 2 Diabetes

  摘要：

  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.

  DOI：

  10.1021/acs.oprd.5b00267

文献信息

• AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES
  申请人：Biftu Tesfaye

  公开号：US20100120863A1

  公开（公告）日：2010-05-13

  The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

  本发明涉及结构式I的新型取代氨基四氢吡喃衍生物，它们是二肽基肽酶-IV酶的抑制剂，可用于治疗或预防二肽基肽酶-IV酶参与的疾病，如糖尿病，特别是2型糖尿病。该发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗二肽基肽酶-IV酶参与的疾病中的用途。
• [EN] AMINOTETRAHYDROPYRANS AS DIPEPTIDYL PEPTIDASE-IV INHIBITORS FOR THE TREATMENT OR PREVENTION OF DIABETES<br/>[FR] AMINOTÉTRAHYDROPYRANES EN TANT QU'INHIBITEURS DE DIPEPTIDYLE PEPTIDASE-IV POUR LE TRAITEMENT OU LA PRÉVENTION DU DIABÈTE
  申请人：MERCK SHARP & DOHME

  公开号：WO2010056708A1

  公开（公告）日：2010-05-20

  The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

  本发明涉及结构式I的新型取代氨基四氢吡喃衍生物，其是二肽基肽酶IV酶的抑制剂，并且在治疗或预防二肽基肽酶IV酶参与的疾病，如糖尿病和特别是2型糖尿病方面非常有用。本发明还涉及包含这些化合物的制药组合物，以及在预防或治疗二肽基肽酶IV酶参与的这些疾病方面使用这些化合物和组合物。
• Aminotetrahydropyrans as dipeptidyl peptidase-IV inhibitors for the treatment or prevention of diabetes
  申请人：Merck Sharp & Dohme Corp.

  公开号：US08143289B2

  公开（公告）日：2012-03-27

  The present invention is directed to novel substituted aminotetrahydropyrans of structural formula I which are inhibitors of the dipeptidyl peptidase-IV enzyme and which are useful in the treatment or prevention of diseases in which the dipeptidyl peptidase-IV enzyme is involved, such as diabetes and particularly Type 2 diabetes. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which the dipeptidyl peptidase-IV enzyme is involved.

  本发明涉及结构式I的新型取代氨基四氢吡喃化合物，它们是二肽基肽酶IV酶的抑制剂，可用于治疗或预防二肽基肽酶IV酶参与的疾病，如糖尿病，特别是2型糖尿病。本发明还涉及包含这些化合物的药物组合物以及在预防或治疗二肽基肽酶IV酶参与的这些疾病中使用这些化合物和组合物。
• PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS
  申请人：Zacuto Michael J.

  公开号：US20140107346A1

  公开（公告）日：2014-04-17

  A process for the preparation of pyrazolopyrolidines of structural formula I: and W is or P, wherein in P is an amine protecting group. These compounds are useful in the synthesis of dipeptidyl peptidase-IV inhibitors for the treatment of Type 2 diabetes. Also provided are useful intermediates obtained from the process.

  一种制备结构式I的吡唑吡啶烷衍生物的过程：其中W为O或P，其中P为氨基保护基。这些化合物在合成二肽基肽酶-IV抑制剂用于治疗2型糖尿病方面是有用的。同时还提供了从该过程中获得的有用中间体。
• Omarigliptin (MK-3102): A Novel Long-Acting DPP-4 Inhibitor for Once-Weekly Treatment of Type 2 Diabetes
  作者：Tesfaye Biftu、Ranabir Sinha-Roy、Ping Chen、Xiaoxia Qian、Dennis Feng、Jeffrey T. Kuethe、Giovanna Scapin、Ying Duo Gao、Youwei Yan、Davida Krueger、Annette Bak、George Eiermann、Jiafang He、Jason Cox、Jacqueline Hicks、Kathy Lyons、Huaibing He、Gino Salituro、Sharon Tong、Sangita Patel、George Doss、Aleksandr Petrov、Joseph Wu、Shiyao Sherrie Xu、Charles Sewall、Xiaoping Zhang、Bei Zhang、Nancy A. Thornberry、Ann E. Weber

  DOI：10.1021/jm401992e

  日期：2014.4.24

  In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.