[羟基(4-苯丁基)氧膦基]乙酸 | 83623-61-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: [羟基(4-苯丁基)氧膦基]乙酸
• 中文别名: 4-苯丁基2-羧基乙次膦酸；福辛普利杂质A
• 英文名称: acetic acid
• 英文别名: (hydroxy(4-phenylbutyl)-phosphinyl)acetic acid；((4-Phenylbutyl)hydroxyphosphoryl)acetic acid；2-[hydroxy(4-phenylbutyl)phosphoryl]acetic acid
• CAS: 83623-61-4
• 化学式: C₁₂H₁₇O₄P
• 分子量: 256.238
• InChiKey: WRXLMKMDSUIHDK-UHFFFAOYSA-N

物化性质

• 密度：
  1.252

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  17
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险品标志：
  Xn
• 危险类别码：
  R48/22,R41,R43
• 海关编码：
  2931900090
• 安全说明：
  S22,S26,S36/37/39
• WGK Germany：
  3

制备方法与用途

用途：福辛普利钠中间体

反应信息

• 作为反应物：
  描述：

  1,4-dithia-7-azaspiro<4.4>nonane-8-(S)-carboxylic acid methyl ester hydrochloride 、 [羟基(4-苯丁基)氧膦基]乙酸 在 三乙胺 、 N,N'-羰基二咪唑 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以92%的产率得到(S)-7-{2-[Hydroxy-(4-phenyl-butyl)-phosphinoyl]-acetyl}-1,4-dithia-7-aza-spiro[4.4]nonane-8-carboxylic acid methyl ester
  参考文献：
  名称：

  Angiotensin-converting enzyme inhibitors. Mercaptan, carboxyalkyl dipeptide, and phosphinic acid inhibitors incorporating 4-substituted prolines

  摘要：

  Analogues of captopril, enalaprilat, and the phosphinic acid [hydroxy(4-phenylbutyl)phosphinyl]acetyl]-L-proline incorporating 4-substituted proline derivatives have been synthesized and evaluated as inhibitors of angiotensin-converting enzyme (ACE) in vitro and in vivo. The 4-substituted prolines, incorporating alkyl, aryl, alkoxy, aryloxy, alkylthio, and arylthio substituents were prepared from derivatives of 4-hydroxy- and 4-ketoproline. In general, analogues of all three classes of inhibitors with hydrophobic substituents on proline were more potent in vitro than the corresponding unsubstituted proline compounds. 4-Substituted analogues of captopril showed greater potency and duration of action than the parent compound as inhibitors of the angiotensin I induced pressor response in normotensive rats. The S-benzoyl derivative of cis-4-(phenylthio)captopril, zofenopril, was found to be one of the most potent compounds of this class and is now being evaluated clinically as an antihypertensive agent. In the phosphinic acid series, the 4-ethylenethioketal and trans-4-cyclohexyl derivatives were found to be the most potent compounds in vitro and in vivo. A prodrug of the latter compound, fosinopril, is also being evaluated in clinical trials.

  DOI：

  10.1021/jm00401a014
• 作为产物：
  描述：

  2-[乙氧基(4-苯基丁基)磷酰基]乙酸 以 四氢呋喃 、 正己烷 为溶剂， 生成 [羟基(4-苯丁基)氧膦基]乙酸
  参考文献：
  名称：

  Phosphinylalkanoyl substituted 4,5-dihydropyrazole-5-carboxylic acid

  摘要：

  公式为##STR1##的化合物被披露。这些化合物由于其抑制血管紧张素转化酶的活性而被用作降压药物。

  公开号：

  US04371526A1

文献信息

• Phosphinylalkanoyl substituted prolines
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04337201A1

  公开（公告）日：1982-06-29

  Esters of phosphinylalkanoyl prolines and phosphinylalkanoyl substituted prolines are inhibitors of angiotensin converting enzyme and are useful in the treatment of hypertension.

  磷酰基丙氨酰脯氨酸酯和磷酰基丙氨酰取代脯氨酸酯是抑制血管紧张素转化酶的抑制剂，并且在治疗高血压方面具有用处。
• Phosphinylalkanoyl amino acids
  申请人：F. R. Squibb & Sons, Inc.

  公开号：US04396772A1

  公开（公告）日：1983-08-02

  Angiotensin converting enzyme activity is inhibited by compounds having the formula ##STR1## and salts thereof wherein R.sub.1 is alkyl, aryl, arylalkyl, cycloalkyl, or cycloalkyl(alkyl); R.sub.2 and R.sub.4 each is independently hydrogen, alkyl, arylalkyl or ##STR2## wherein X is hydrogen, alkyl, or phenyl and Y is hydrogen, alkyl, phenyl or alkoxy, or together X and Y are --(CH.sub.2).sub.2 --, --(CH.sub.2).sub.3 --, --CH.dbd.CH--or ##STR3## R.sub.3 is hydrogen or alkyl; ##STR4## is a residue of an amino acid selected from the group consisting of glycine, alanine, valine, norvaline, leucine, N-methylleucine, norleucine, isoleucine, phenylalanine, tyrosine, serine, threonine, cysteine, methionine, aspartic acid, glutamic acid, arginine, lysine, asparagine, glutamine, histidine, or tryptophane; and n is 0 or 1.

  血管紧张素转换酶活性受到具有以下结构式##STR1##及其盐的化合物的抑制，其中R.sub.1为烷基、芳基、芳基烷基、环烷基或环烷基(烷基)；R.sub.2和R.sub.4各自独立地为氢、烷基、芳基烷基或##STR2##其中X为氢、烷基或苯基，Y为氢、烷基、苯基或烷氧基，或者X和Y一起为--(CH.sub.2).sub.2 --、--(CH.sub.2).sub.3 --、--CH.dbd.CH--或##STR3##R.sub.3为氢或烷基；##STR4##为从甘氨酸、丙氨酸、缬氨酸、正缬氨酸、亮氨酸、N-甲基亮氨酸、正亮氨酸、异亮氨酸、苯丙氨酸、酪氨酸、丝氨酸、苏氨酸、半胱氨酸、蛋氨酸、天冬氨酸、谷氨酸、精氨酸、赖氨酸、天冬酰胺、谷氨酰胺、组氨酸或色氨酸的氨基酸残基中选择的残基；n为0或1。
• Mild Arbuzov reactions of phosphonous acids
  作者：John K. Thottathil、Claire A. Przybyla、Jerome L. Moniot

  DOI：10.1016/s0040-4039(01)81506-9

  日期：——

  A very mild and simple method for the preparation of phosphinic acids from phosphonous acids through the intermediacy of silylalkyl phosphonites is described.

  描述了一种非常温和而简单的方法，该方法通过甲硅烷基烷基亚膦酸酯从亚膦酸制备次膦酸。
• Method for making phosphinic acid intermediates
  申请人：E. R. Squibb & Sons, Inc.

  公开号：US04602092A1

  公开（公告）日：1986-07-22

  A method is provided for preparing phosphinic acid prodrug intermediates which are useful in preparing phosphinic acid angiotensin-converting enzyme inhibitors which method includes the step of coupling a phosphonous acid or its ester of the structure ##STR1## wherein R is H or lower alkyl and R.sup.1 is lower alkyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl, with an alkylating agent of the structure ##STR2## wherein Hal is Cl, Br or I, n is 0 or 1, R.sup.2 is H or lower alkyl, and Z is H, lower alkyl, --CO.sub.2 R.sup.3 (wherein R.sup.3 is H or lower alkyl), ##STR3## (wherein R.sup.4 is H, lower alkyl, aryl or arylalkyl), --CN, or ##STR4## (wherein R.sup.5 and R.sup.6 may be the same or different and are selected from the group consisting of H, lower alkyl, aryl, aryl-lower alkyl, cycloalkyl or cycloalkylalkyl and at least one of R.sup.5 and R.sup.6 is other than H, or R.sup.5 and R.sup.6 can be taken with the N-atom to form a 5-, 6- or 7-membered heterocyclic ring which 5-, 6- or 7-membered N-containing ring may or may not contain a CO.sub.2 R.sup.3 group and which 5- or 6-membered N-containing ring may or may not be fused to an aryl ring), in the presence of a silylating agent, to form the phosphinic acid intermediate of the structure ##STR5## wherein R, R.sup.1, R.sup.2, n and Z are as defined above.

  提供了一种制备磷酸酰胺前药中间体的方法，该方法有助于制备磷酸酰胺型血管紧张素转化酶抑制剂，其中包括将具有以下结构的膦酸或其酯的磷酸酰胺偶联物与以下结构的烷基化剂偶联的步骤：##STR1## 其中R为H或较低的烷基，R.sup.1为较低的烷基、芳香族、芳香族烷基、环烷基或环烷基烷基，Hal为Cl、Br或I，n为0或1，R.sup.2为H或较低的烷基，Z为H、较低的烷基、--CO.sub.2 R.sup.3（其中R.sup.3为H或较低的烷基）、##STR3##（其中R.sup.4为H、较低的烷基、芳香族或芳香族烷基）、--CN或##STR4##（其中R.sup.5和R.sup.6可以相同也可以不同，且选自H、较低的烷基、芳香族、芳香族-较低的烷基、环烷基或环烷基烷基，且R.sup.5和R.sup.6中至少有一个不为H，或R.sup.5和R.sup.6可以与N原子结合形成5、6或7元杂环环，该5、6或7元杂环含有N原子，可以或不可以含有CO.sub.2 R.sup.3基团，该5或6元杂环可以或不可以与芳香族环融合）。在硅基化剂的存在下进行上述步骤，形成具有以下结构的磷酸酰胺中间体：##STR5## 其中R、R.sup.1、R.sup.2、n和Z如上所定义。
• Process for the preparation of fosinopril and intermediates thereof
  申请人：Dipharma Francis S.r.l.

  公开号：EP2264039A1

  公开（公告）日：2010-12-22

  Process for the preparation of intermediates useful in the synthesis of [1[S(R)],2α,4β]-4-cyclohexyl-1-[[[(2-methyl-1-oxypropoxy) propoxy](4-phenylbutyl) phosphinyl]acetyl]-L-proline, and the synthesis thereof, in particular as sodium salt.

  制备中间体的过程，该中间体在合成[1[S(R)],2α,4β]-4-环己基-1-[[[(2-甲基-1-氧丙氧基)丙氧基](4-苯基丁基)膦酰基]乙酰基]-L-脯氨酸时有用，特别是其钠盐的合成过程。