ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate | 99198-61-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate
• 英文别名: benzyl 4-(6-ethoxy-5,6-dioxohexyl)piperidine-1-carboxylate
• CAS: 99198-61-5
• 化学式: C₂₁H₂₉NO₅
• 分子量: 375.465
• InChiKey: FLSUQKXDDBANHE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  ethyl 6-(1-benzyloxycarbonyl-4-piperidyl)-2-oxohexanoate 以34%的产率得到
  参考文献：
  名称：

  KORI, MASAKUNI;ITOH, KATSUMI;SUGIHARA, HIROSADA, CHEM. AND PHARM. BULL., 35,(1987) N 6, 2319-2326

  摘要：

  DOI：
• 作为产物：
  描述：

  ethyl (2S)-6-(1-benzyloxycarbonyl-4-piperidyl)-2-hydroxyhexanoate 以52%的产率得到
  参考文献：
  名称：

  KORI, MASAKUNI;ITOH, KATSUMI;SUGIHARA, HIROSADA, CHEM. AND PHARM. BULL., 35,(1987) N 6, 2319-2326

  摘要：

  DOI：

文献信息

• Synthesis and angiotensin converting enzyme-inhibitory activity of 1,5-benzothiazepine and 1,5-benzoxazepine derivatives. III.
  作者：KATSUMI ITOH、MASAKUNI KORI、YOSHIYUKI INADA、KOHEI NISHIKAWA、YUTAKA KAWAMATSU、HIROSADA SUGIHARA

  DOI：10.1248/cpb.34.3747

  日期：——

  A seires of (R)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acids (8) and (S)-3-amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzoxazepine-5-acetic acids (9) having an (S)-1-carboxy-ω-(4-piperidyl)alkyl group on the amino group at the 3-position was prepared as part of a search for long-acting inhibitors of the angiotensin converting enzyme (ACE). The length (n) of the carbon chain in the piperidylalkyl moiety was varied from two six in order to determine the optimal structure. The most prolonged activity in vivo was observed with (R)-3-[(S)-1-carboxy-5-(4-piperidyl)pentyl]amino-4-oxo-2, 3, 4, 5-tetrahydro-1, 5-benzothiazepine-5-acetic acid (8c : CV-5975) on i.v. and p.o. administrations.

  一系列具有(S)-1-羧基-ω-(4-哌啶基)烷基基团的(R)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯噻氮卓-5-乙酸（8）和(S)-3-氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯并噻氮卓-5-乙酸（9）被制备，作为寻找具有长效作用的血管紧张素转化酶（ACE）抑制剂的一部分。在哌啶基烷基部分中，碳链的长度(n)从二到六进行了变化，以确定最佳结构。在静脉注射和口服给药中，观察到(R)-3-[(S)-1-羧基-5-(4-哌啶基)戊基]氨基-4-氧代-2, 3, 4, 5-四氢-1, 5-苯噻氮卓-5-乙酸（8c：CV-5975）具有最持久的体内活性。
• 3-Amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04548932A1

  公开（公告）日：1985-10-22

  Novel 3-amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzoxazepine derivatives of the formula ##STR1## [wherein R.sup.1 and R.sup.2 are independently hydrogen, halogen, trifluoromethyl, lower alkyl or lower alkoxy, or both jointly form tri- or tetramethylene; R.sup.3 is hydrogen, optionally substituted lower alkyl or optionally substituted aralkyl; R.sup.4 is hydrogen, optionally substituted alkyl, optionally substituted aralkyl or optionally substituted cycloalkylalkyl; Y is a carboxyl group which may be esterified or amidated; m is 1 or 2] and salts thereof. These compounds and salts thereof exhibits inhibitory activity on angiotensin converting enzyme and so forth, and are of value as an agent for diagnosis, prevention and treatment of circulatory diseases (e.g. hypertension, cardiopathy, cerebral apoploxy).

  新颖的3-氨基-4-酮基-2,3,4,5-四氢-1,5-苯并噁唑啉衍生物的化学式为##STR1##[其中R.sup.1和R.sup.2独立地为氢、卤素、三氟甲基、低碳烷基或低碳氧基，或者共同形成三元或四元亚甲基；R.sup.3为氢、可选择取代的低碳烷基或可选择取代的芳基烷基；R.sup.4为氢、可选择取代的烷基、可选择取代的芳基烷基或可选择取代的环烷基烷基；Y为可酯化或酰胺化的羧基；m为1或2]及其盐。这些化合物及其盐对肾素转换酶等具有抑制活性，可作为循环系统疾病（如高血压、心脏病、脑卒中）的诊断、预防和治疗药物。
• An improved synthesis of the new angiotensin converting enzyme inhibitor CV-5975 via a chemoenzymatic process.
  作者：MASAKUNI KORI、KATSUMI ITOH、HIROSADA SUGIHARA

  DOI：10.1248/cpb.35.2319

  日期：——

  A chemoenzymatic synthesis of the new angiotensin converting enzyme inhibitor CV-5975 (1) is described. The optically active key intermediate for the synthesis of 1, ethyl (R) -6- (1-benzyloxycarbonyl-4-piperidyl) -2-hydroxyhexanoate ((R) -4), was prepared by kinetic resolution of the racemic α-hydroxyester ((RS) -4) with a lipase and also by asymmetric reduction of the α-oxoester (3) with baker's yeast. The enantiomeric excess (ee) of the α-hydroxyester ((R) -4) produced by these enzymatic procedures exceeded 60%. This optically active alcohol ((R) -4) was converted to its mesylate ((R) -5), which was then subjected to SN2 reaction with the aminobenzothiazepine derivative (2) followed by deprotection to yield 1.

  本文描述了一种新型血管紧张素转换酶抑制剂 CV-5975 (1) 的化学合成方法。合成 1 的光学活性关键中间体(R) -6-(1-苄氧羰基-4-哌啶基) -2-羟基己酸乙酯（(R) -4）是通过外消旋α-羟酯（(RS) -4）与脂肪酶的动力学解析以及α-氧酯（3）与面包酵母的不对称还原制备的。通过这些酶解方法制得的α-羟酯（(R) -4）的对映体过量（ee）超过了 60%。这种具有光学活性的醇（(R) -4）被转化为其甲磺酸酯（(R) -5），然后与氨基苯并硫氮杂卓衍生物（2）发生 SN2 反应，再进行脱保护，得到 1。
• Piperidine derivatives
  申请人：Takeda Chemical Industries, Ltd.

  公开号：US04816466A1

  公开（公告）日：1989-03-28

  Novel Compounds of the formula: ##STR1## [wherein A is an .alpha.-amino acid residue; B is a group represented by the formula: ##STR2## (wherein R.sup.4 is hydrogen, lower alkyl, aralkyl or amino-lower alkyl), whereby the linkage between the symbols A and B designates a peptide bond and the group R.sup.4 is B may be linked with A; R.sup.1 is hydrogen, lower alkyl or aralkyl; R.sup.2 is hydrogen, lower alkyl, aralkyl or acyl; X is alkylene] and salts thereof posses, for example, inhibitory activity on angiotension converting enzyme, and are useful as an agent for diagnosis, prevention or treatment of hypertension as well as circulatory diseases such as cardiopathy and cerebral apoplexy.

  具有以下结构的新化合物：##STR1## [其中A是一个α-氨基酸残基；B是一个由以下结构表示的基团：##STR2##（其中R.sup.4是氢、低碳基、芳基碳基或氨基低碳基），其中符号A和B之间的连接表示肽键，基团R.sup.4是B可能与A连接；R.sup.1是氢、低碳基或芳基碳基；R.sup.2是氢、低碳基、芳基碳基或酰基；X是烷基]及其盐具有例如对抑制血管紧张素转化酶的活性，并可用作高血压以及心脏病和脑卒中等循环疾病的诊断、预防或治疗剂。
• Synthesis and Angiotensin Converting Enzyme-Inhibitory Activity of N-((1S)-1-Carboxy-5-(4-piperidyl)pentyl)-L-alanine Derivatives.
  作者：Masakuni KORI、Katsumi ITOH、Yoshiyuki INADA、Takeshi KATOH、Yasuhiro SUMINO、Kohei NISHIKAWA、Hirosada SUGIHARA

  DOI：10.1248/cpb.42.580

  日期：——

  As part of a search for potent and long-lasting angiotensin converting enzyme (ACE) inhibitors, various types of N-[(1S)-1-carboxy-5-(4-piperidyl)pentyl]-L-alanine derivatives (7a, 8-11) were prepared. The key synthetic intermediate, N-[(1S)-5-(1-benzyloxycarbonyl-4-piperidyl)-1-ethoxycarbonylpentyl]-L-alanine (17a), was synthesized by asymmetric reduction of the α-oxoester (13) with Lactobacillus paracasei subsp. paracasei followed by a substitution reaction with tert-butyl L-alaninate (15) and subsequent treatment with hydrogen chloride. Compounds 7a and 8-11 showed potent and long-lasting ACE-inhibitory activity in rats.

  为了寻找强效、长效的血管紧张素转换酶（ACE）抑制剂，我们制备了各种类型的 N-[(1S)-1-羧基-5-(4-哌啶基)戊基]-L-丙氨酸衍生物（7a、8-11）。关键合成中间体 N-[(1S)-5-(1-苄氧羰基-4-哌啶基)-1-乙氧羰基戊基]-L-丙氨酸（17a）是通过副卡氏乳杆菌亚种不对称还原α-氧代酯（13），然后与 L-丙氨酸叔丁酯（15）发生取代反应，再用氯化氢处理而合成的。化合物 7a 和 8-11 对大鼠的 ACE 具有强效和持久的抑制活性。