2,3-Dihydro-2-oxo-5-(trifluoromethyl)-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester | 161468-46-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 2,3-Dihydro-2-oxo-5-(trifluoromethyl)-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester
• 英文别名: 1-Boc-5-trifluoromethylbenzimidazole-2-one；tert-butyl 2-oxo-5-(trifluoromethyl)-3H-benzimidazole-1-carboxylate
• CAS: 161468-46-8
• 化学式: C₁₃H₁₃F₃N₂O₃
• 分子量: 302.253
• InChiKey: IXLGXZLUUGEPGS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2,3-Dihydro-2-oxo-5-(trifluoromethyl)-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester 在 盐酸 、 potassium carbonate 作用下， 以 乙醚 、 乙腈 为溶剂， 反应 3.0h， 生成 1,3-Dihydro-1-(phenylmethyl)-6-(trifluoromethyl)-2H-benzimidazol-2-one
  参考文献：
  名称：

  Regiospecific Functionalization of 1,3-Dihydro-2H-benzimidazol-2-one and Structurally Related Cyclic Urea Derivatives

  摘要：

  Methods for selectively protecting one of the degenerate nitrogen atoms of the cyclic urea derivatives 1,3-dihydro-2H-benzimidazol-2-one (6a), 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11), 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones (20), 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (22), and 1,3-dihydro-4-phenyl-2H-imidazol-2-one (27) were developed. Heating these cyclic ureas with ethyl 2-pyridyl carbonate in the presence of a base in CH3CN at reflux or DMF at 100 degrees C cleanly provided the monoethoxycarbonyl derivatives 7a, 12, 21, 23, and 28, respectively. Alternatively, treatment of 6a with an excess of diethyl pyrocarbonate or di-tert-butyl dicarbonate afforded the bis-alkoxycarbonyl derivatives 8a and 8b, respectively, which underwent disproportionation to 7a and 7b upon heating with 1 mol equiv of 6a and K2CO3 in CH3CN at reflux. The regiochemistry of the introduction of alkoxycarbonyl groups to benzimidazol-2-one derivatives was not significantly influenced by an electron-withdrawing (CF3, 6b) or an electron-donating (OCH3, 6c) substituent at C-5 of the heterocyclic ring. However, the reaction was found to be sensitive to steric factors since a chlorine substituent ortho to one of the urea N atoms (6e) completely directed the alkoxycarbonyl moiety to the less sterically encumbered N atom, affording a single product (7f, 7g). Alkylation of 7a-g proceeded efficiently to provide products 10a-10ag after removal of the protecting group. Halogenation of monoprotected benzimidazol-2-one 7a occurred regiospecifically to give the monohalo derivatives 7h, 7i, and 7k, the identity of which were readily established from the characteristic chemical shift and spin coupling pattern in their 1H NMR spectra. A protecting group interchange strategy that took advantage of the distinctive chemical reactivities of the EtO(2)C and t-BuO(2)C protecting groups toward isopropylamine was developed that provided access to the isomerically substituted series of monohalo, mono-N-alkylated benzimidazol-2-ones 71 and 7m. The efficient derivatization of the unprotected N atom of these monoprotected cyclic urea derivatives was accomplished by treating with activated and unactivated halides in the. presence of K2CO3 or exposure to alcohols under Mitsunobu conditions. In several cases, mixtures of O- and N-alkylated products were produced which were readily separated by chromatography. Alkylation of 7h with activated halides, using K2CO3 in CH3CN at reflux, occurred without protecting group equilibration; however, a mixture of isomeric alkylated products was obtained when 7h was heated at 110 degrees C in DMF with cyclohexylmethyl bromide in the presence of K2CO3 as the base. Derivatization of 7h under Mitsunobu reaction conditions proceeded with retention of the topological substituent relationships. Subsequent removal of the alkoxycarbonyl moiety afforded monoalkylated cyclic urea derivatives.

  DOI：

  10.1021/jo00111a014
• 作为产物：
  描述：

  3,4-二胺基苄氧基三氟化物 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 25.25h， 生成 2,3-Dihydro-2-oxo-5-(trifluoromethyl)-1H-benzimidazole-1-carboxylic acid 1,1-dimethylethyl ester
  参考文献：
  名称：

  Regiospecific Functionalization of 1,3-Dihydro-2H-benzimidazol-2-one and Structurally Related Cyclic Urea Derivatives

  摘要：

  Methods for selectively protecting one of the degenerate nitrogen atoms of the cyclic urea derivatives 1,3-dihydro-2H-benzimidazol-2-one (6a), 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11), 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones (20), 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (22), and 1,3-dihydro-4-phenyl-2H-imidazol-2-one (27) were developed. Heating these cyclic ureas with ethyl 2-pyridyl carbonate in the presence of a base in CH3CN at reflux or DMF at 100 degrees C cleanly provided the monoethoxycarbonyl derivatives 7a, 12, 21, 23, and 28, respectively. Alternatively, treatment of 6a with an excess of diethyl pyrocarbonate or di-tert-butyl dicarbonate afforded the bis-alkoxycarbonyl derivatives 8a and 8b, respectively, which underwent disproportionation to 7a and 7b upon heating with 1 mol equiv of 6a and K2CO3 in CH3CN at reflux. The regiochemistry of the introduction of alkoxycarbonyl groups to benzimidazol-2-one derivatives was not significantly influenced by an electron-withdrawing (CF3, 6b) or an electron-donating (OCH3, 6c) substituent at C-5 of the heterocyclic ring. However, the reaction was found to be sensitive to steric factors since a chlorine substituent ortho to one of the urea N atoms (6e) completely directed the alkoxycarbonyl moiety to the less sterically encumbered N atom, affording a single product (7f, 7g). Alkylation of 7a-g proceeded efficiently to provide products 10a-10ag after removal of the protecting group. Halogenation of monoprotected benzimidazol-2-one 7a occurred regiospecifically to give the monohalo derivatives 7h, 7i, and 7k, the identity of which were readily established from the characteristic chemical shift and spin coupling pattern in their 1H NMR spectra. A protecting group interchange strategy that took advantage of the distinctive chemical reactivities of the EtO(2)C and t-BuO(2)C protecting groups toward isopropylamine was developed that provided access to the isomerically substituted series of monohalo, mono-N-alkylated benzimidazol-2-ones 71 and 7m. The efficient derivatization of the unprotected N atom of these monoprotected cyclic urea derivatives was accomplished by treating with activated and unactivated halides in the. presence of K2CO3 or exposure to alcohols under Mitsunobu conditions. In several cases, mixtures of O- and N-alkylated products were produced which were readily separated by chromatography. Alkylation of 7h with activated halides, using K2CO3 in CH3CN at reflux, occurred without protecting group equilibration; however, a mixture of isomeric alkylated products was obtained when 7h was heated at 110 degrees C in DMF with cyclohexylmethyl bromide in the presence of K2CO3 as the base. Derivatization of 7h under Mitsunobu reaction conditions proceeded with retention of the topological substituent relationships. Subsequent removal of the alkoxycarbonyl moiety afforded monoalkylated cyclic urea derivatives.

  DOI：

  10.1021/jo00111a014

文献信息

• Benzoureas Having Anti-Diabetic Activity
  申请人：Lui Weiguo

  公开号：US20080076810A1

  公开（公告）日：2008-03-27

  Benzourea compounds of Formula I having aryl-(CH 2 ) x -oxazolidinedione or aryl-(CH 2 ) x -thiazolidinedione substituents on one of the N atoms of the benzourea ring, wherein x is 0 or 1, are PPAR gamma agonists or partial agonists and are useful in the treatment and control of type II diabetes, including hyperglycemia and other symptoms such as dyslipidemia, hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, and obesity, that are often associated with type 2 diabetes.

  具有在苯甲酰脲环的一个N原子上具有芳基-(CH2)x-噁唑啉二酮或芳基-(CH2)x-噻唑啉二酮取代基的公式I的苯甲酰脲化合物，其中x为0或1，是PPAR gamma激动剂或部分激动剂，并且在治疗和控制II型糖尿病，包括高血糖和其他症状，如血脂异常、高脂血症、高胆固醇血症、高三酰甘油血症和肥胖症方面非常有用，这些症状通常与2型糖尿病相关。
• Benzimidazolones: A New Class of Selective Peroxisome Proliferator-Activated Receptor γ (PPARγ) Modulators
  作者：Weiguo Liu、Fiona Lau、Kun Liu、Harold B. Wood、Gaochao Zhou、Yuli Chen、Ying Li、Taro E. Akiyama、Gino Castriota、Monica Einstein、Chualin Wang、Margaret E. McCann、Thomas W. Doebber、Margaret Wu、Ching H. Chang、Lesley McNamara、Brian McKeever、Ralph T. Mosley、Joel P. Berger、Peter T. Meinke

  DOI：10.1021/jm201061j

  日期：2011.12.22

  A series of benzimidazolone carboxylic acids and oxazolidinediones were designed and synthesized in search of selective PPAR gamma modulators (SPPAR gamma Ms) as potential therapeutic agents for the treatment of type II diabetes mellitus (T2DM) with improved safety profiles relative to rosiglitazone and pioglitazone, the currently marketed PPAR gamma full agonist drugs. Structure activity relationships of these potent and highly selective SPPAR gamma Ms were studied with a focus on their unique profiles as partial agonists or modulators. A variety of methods, such as X-ray aystallographic analysis, PPAR gamma transactivation coactivator profiling, gene expression profiling, and mutagenesis studies, were employed to reveal the differential interactions of these new analogues with PPAR gamma receptor in comparison to full agonists. In rodent models of T2DM, benzimidazolone analogues such as (5R)-5-(3-[3-(5-methoxybenzisoxazol-3-yl)benzimidazol-1-yl]methyl}phenyl)-5-methyloxazolidinedione (Si) demonstrated efficacy equivalent to that of rosiglitazone. Side effects, such as fluid retention and heart weight gain associated with PPAR gamma full agonists, were diminished with 51 in comparison to rosiglitazone based on studies in two independent animal models.
• Regiospecific Functionalization of 1,3-Dihydro-2H-benzimidazol-2-one and Structurally Related Cyclic Urea Derivatives
  作者：Nicholas A. Meanwell、Sing Yuen Sit、Jinnian Gao、Henry S. Wong、Qi Gao、Denis R. St. Laurent、Neelakantan Balasubramanian

  DOI：10.1021/jo00111a014

  日期：1995.3

  Methods for selectively protecting one of the degenerate nitrogen atoms of the cyclic urea derivatives 1,3-dihydro-2H-benzimidazol-2-one (6a), 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (11), 1,3-dihydro-2H-imidazo[4,5-b]quinolin-2-ones (20), 1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one (22), and 1,3-dihydro-4-phenyl-2H-imidazol-2-one (27) were developed. Heating these cyclic ureas with ethyl 2-pyridyl carbonate in the presence of a base in CH3CN at reflux or DMF at 100 degrees C cleanly provided the monoethoxycarbonyl derivatives 7a, 12, 21, 23, and 28, respectively. Alternatively, treatment of 6a with an excess of diethyl pyrocarbonate or di-tert-butyl dicarbonate afforded the bis-alkoxycarbonyl derivatives 8a and 8b, respectively, which underwent disproportionation to 7a and 7b upon heating with 1 mol equiv of 6a and K2CO3 in CH3CN at reflux. The regiochemistry of the introduction of alkoxycarbonyl groups to benzimidazol-2-one derivatives was not significantly influenced by an electron-withdrawing (CF3, 6b) or an electron-donating (OCH3, 6c) substituent at C-5 of the heterocyclic ring. However, the reaction was found to be sensitive to steric factors since a chlorine substituent ortho to one of the urea N atoms (6e) completely directed the alkoxycarbonyl moiety to the less sterically encumbered N atom, affording a single product (7f, 7g). Alkylation of 7a-g proceeded efficiently to provide products 10a-10ag after removal of the protecting group. Halogenation of monoprotected benzimidazol-2-one 7a occurred regiospecifically to give the monohalo derivatives 7h, 7i, and 7k, the identity of which were readily established from the characteristic chemical shift and spin coupling pattern in their 1H NMR spectra. A protecting group interchange strategy that took advantage of the distinctive chemical reactivities of the EtO(2)C and t-BuO(2)C protecting groups toward isopropylamine was developed that provided access to the isomerically substituted series of monohalo, mono-N-alkylated benzimidazol-2-ones 71 and 7m. The efficient derivatization of the unprotected N atom of these monoprotected cyclic urea derivatives was accomplished by treating with activated and unactivated halides in the. presence of K2CO3 or exposure to alcohols under Mitsunobu conditions. In several cases, mixtures of O- and N-alkylated products were produced which were readily separated by chromatography. Alkylation of 7h with activated halides, using K2CO3 in CH3CN at reflux, occurred without protecting group equilibration; however, a mixture of isomeric alkylated products was obtained when 7h was heated at 110 degrees C in DMF with cyclohexylmethyl bromide in the presence of K2CO3 as the base. Derivatization of 7h under Mitsunobu reaction conditions proceeded with retention of the topological substituent relationships. Subsequent removal of the alkoxycarbonyl moiety afforded monoalkylated cyclic urea derivatives.