2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide | 131828-30-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide
• 英文别名: 3-benzyloxy-2-isobutyl-6-methoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide；2-(benzyloxy)-3-isobutyl-5-methoxy-6-[(tetrahydropyran-2-yloxy)methyl]pyrazine 4-oxide；2-methoxy-6-(2-methylpropyl)-3-(oxan-2-yloxymethyl)-1-oxido-5-phenylmethoxypyrazin-1-ium
• CAS: 131828-30-3
• 化学式: C₂₂H₃₀N₂O₅
• 分子量: 402.491
• InChiKey: NUVKHABZNCIMBQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  75.3
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide 在 盐酸 四丁基碘化铵 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 、 苯 为溶剂， 反应 2.5h， 生成 2-(benzyloxy)-6-(iodomethyl)-3-isobutyl-5-methoxypyrazine 4-oxide
  参考文献：
  名称：

  The first total synthesis of OPC-15161

  摘要：

  The first total synthesis of OPC-15161, a novel inhibitor of superoxide generation by guinea pig macrophages, has been accomplished via a convergent and efficient route exploiting the coupling of the fully functionalized pyrazine part with the indolyl group. 2-(Hydroxyimino)-4-methylpentanoic acid and ethyl aminocyanoacetate were condensed with DCC to afford the amide 3, which was converted to pyrazinone N-oxide 4 via intramolecular cyclization between the oxime and cyano groups. O-Benzylation of 4 followed by reduction of the ethoxycarbonyl group by DIBALH gave the aminopyrazine alcohol 7. The aryl chloride 8 was obtained by the direct substitutive deamination using isoamyl nitrite and copper salts. After protection of the hydroxyl group, the methoxy group was introduced at the 5-position via treatment of 2,5-bis(benzyloxy)pyrazine 4-oxide 10 with methoxide to afford 11. The methoxy compound 11 was converted to benzylic iodide 14 via deprotection, mesylation, and iodination. The functionalized pyrazine skeleton 14 was coupled with the zinc salt of indole to produce 17, which upon catalytic hydrogenolysis afforded OPC-15161.

  DOI：

  10.1021/jo00016a012
• 作为产物：
  描述：

  2-(hydroxyimino)-4-methylpentanoic acid 在 4-二甲氨基吡啶 、 对甲苯磺酸 N-羟基丁二酰亚胺 、 四丁基溴化铵 、 sodium hydride 、 二异丁基氢化铝 、 potassium hydrogencarbonate 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 、 copper(l) chloride 、 copper dichloride 、 亚硝酸异戊酯 作用下， 以 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 34.84h， 生成 2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide
  参考文献：
  名称：

  The first total synthesis of OPC-15161

  摘要：

  The first total synthesis of OPC-15161, a novel inhibitor of superoxide generation by guinea pig macrophages, has been accomplished via a convergent and efficient route exploiting the coupling of the fully functionalized pyrazine part with the indolyl group. 2-(Hydroxyimino)-4-methylpentanoic acid and ethyl aminocyanoacetate were condensed with DCC to afford the amide 3, which was converted to pyrazinone N-oxide 4 via intramolecular cyclization between the oxime and cyano groups. O-Benzylation of 4 followed by reduction of the ethoxycarbonyl group by DIBALH gave the aminopyrazine alcohol 7. The aryl chloride 8 was obtained by the direct substitutive deamination using isoamyl nitrite and copper salts. After protection of the hydroxyl group, the methoxy group was introduced at the 5-position via treatment of 2,5-bis(benzyloxy)pyrazine 4-oxide 10 with methoxide to afford 11. The methoxy compound 11 was converted to benzylic iodide 14 via deprotection, mesylation, and iodination. The functionalized pyrazine skeleton 14 was coupled with the zinc salt of indole to produce 17, which upon catalytic hydrogenolysis afforded OPC-15161.

  DOI：

  10.1021/jo00016a012
• 作为试剂：
  描述：

  甲醇 、 sodium;hydride 、 N,N-二甲基甲酰胺 、 2,5-bis-(benzyloxy)-3-isobutyl-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide 在 四丁基溴化铵 水 、 magnesium sulfate 、 silica gel 、 ethyl acetate n-hexane 、 2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide 作用下， 以 乙醚 为溶剂， 反应 1.0h， 以to obtain 50 mg of 3-benzyloxy-2-isobutyl-6-methoxy-5-(2-tetrahydropyranyloxymethyl)pyrazine 1-oxide (Compound B-15) as a colorless oily substance的产率得到2-(benzyloxy)-3-isobutyl-5-methoxy-6-<(tetrahydropyran-2-yloxy)methyl>pyrazine 4-oxide
  参考文献：
  名称：

  Indole derivatives

  摘要：

  通式（1）所表示的新型吲哚衍生物及其盐，例如对豚鼠巨噬细胞通过刺激释放的超氧化物（O.sub.2.sup.-）具有抑制作用，并对Masugi肾炎具有抗蛋白尿活性，在各种临床领域中作为预防和治疗与上述超氧自由基相关的疾病和病例的药物，例如自身免疫性疾病（如风湿病），动脉硬化，缺血性疾病，缺血性脑病，肝功能不全和肾功能不全，以及预防和治疗肾炎方面具有用途。

  公开号：

  US05238938A1

文献信息

• INDOLE DERIVATIVES, PREPARATION THEREOF, AND DRUG FOR PREVENTING AND TREATING NEPHRITIS CONTAINING SAME
  申请人：OTSUKA PHARMACEUTICAL CO., LTD.

  公开号：EP0411150A1

  公开（公告）日：1991-02-06

  This invention relates to indole derivatives of general formula (1) and salts thereof, a method for preparing same, and applications thereof in the prevention and treatment of nephritis, wherein R represents hydrogen, cyano or one of various other substituents, 1 is an integer of 1 or 2, R' represents hydrogen, one of various substituents or a group of formula (2) (wherein A represents a single bond, -CH(OH)-, -CH=, -C(=0)- or alkyl, and R2, R3, R4, R5 and R6 each represents one of various substituents),and Z represents hydrogen or a group of formula (2) provided that R1 represents a group of formula (2) when Z represents hydrogen.

  本发明涉及通式(1)的吲哚衍生物及其盐、制备方法以及在预防和治疗肾炎中的应用，其中R代表氢、氰基或其它各种取代基之一，1为1或2的整数，R'代表氢、其中 A 代表单键、-CH(OH)-、-CH=、-C(=0)- 或烷基，R2、R3、R4、R5 和 R6 各代表各种取代基之一），Z 代表氢或式（2）基团，但当 Z 代表氢时，R1 代表式（2）基团。
• US5238938A
  申请人：——

  公开号：US5238938A

  公开（公告）日：1993-08-24
• The first total synthesis of OPC-15161
  作者：Yoshihiko Ito、Hideaki Sato、Masahiro Murakami

  DOI：10.1021/jo00016a012

  日期：1991.8

  The first total synthesis of OPC-15161, a novel inhibitor of superoxide generation by guinea pig macrophages, has been accomplished via a convergent and efficient route exploiting the coupling of the fully functionalized pyrazine part with the indolyl group. 2-(Hydroxyimino)-4-methylpentanoic acid and ethyl aminocyanoacetate were condensed with DCC to afford the amide 3, which was converted to pyrazinone N-oxide 4 via intramolecular cyclization between the oxime and cyano groups. O-Benzylation of 4 followed by reduction of the ethoxycarbonyl group by DIBALH gave the aminopyrazine alcohol 7. The aryl chloride 8 was obtained by the direct substitutive deamination using isoamyl nitrite and copper salts. After protection of the hydroxyl group, the methoxy group was introduced at the 5-position via treatment of 2,5-bis(benzyloxy)pyrazine 4-oxide 10 with methoxide to afford 11. The methoxy compound 11 was converted to benzylic iodide 14 via deprotection, mesylation, and iodination. The functionalized pyrazine skeleton 14 was coupled with the zinc salt of indole to produce 17, which upon catalytic hydrogenolysis afforded OPC-15161.
• Indole derivatives
  申请人：Otsuka Pharmaceutical Co., Ltd.

  公开号：US05238938A1

  公开（公告）日：1993-08-24

  The novel indole derivatives and salts thereof represented by the general formula (1) ##STR1## possess, for example, an inhibitory effect against superoxide (O.sub.2.sup.-) released from the macrophage cells of guinea pig by stimulation and an anti-albuminuria activity against Masugi nephritis, and are useful in various clinical fields as an agent for preventing and treating diseases and cases associated with the above superoxide radical, for example, autoimmune diseases (e.g. rheumatism), arteriosclerosis, ischemic disease, ischemic encephalopathia, hepatic insufficiency and renal insufficiency, and also as an agent for preventing and treating nephritis.

  通用公式（1）表示的新的吲哚衍生物及其盐具有抑制豚鼠巨噬细胞释放的超氧化物（O.sub.2.sup.-）的作用，例如，对马杉肾炎引起的抗白蛋白尿活性，并且在各种临床领域中作为预防和治疗与上述超氧自由基相关的疾病和情况的药物，例如自身免疫疾病（例如风湿病），动脉硬化，缺血性疾病，缺血性脑病，肝功能不全和肾功能不全，以及作为预防和治疗肾炎的药物。