3-乙酰硫基-2-甲基丙酰氯 | 74345-73-6

• 物质功能分类: 化学试剂 - 有机试剂 - 酰卤
• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 硫代羧酸及其衍生物
• 中文名称: 3-乙酰硫基-2-甲基丙酰氯
• 中文别名: (R)-3-(乙酰硫基)异丁酰氯；L-3-(乙酰基硫基)-2-甲基丙酰氯；3-乙酰硫基异丁酰氯；(R)-3-(乙酰基硫代)-2-甲基丙酰氯
• 英文名称: (2R,S)-3-Acetylthio-2-methylpropanoyl chloride
• 英文别名: L-3-acetylthio-2-methylpropionyl chloride；(R)-3-(acetylthio)-2-methylpropanoyl chloride；(R)-3-acetylthio-2-methyl propanoyl chloride；(R)-3-acetylthio-2-methylpropanoyl chloride；(R)-3-(Acetylthio)isobutyryl Chloride；S-[(2R)-3-chloro-2-methyl-3-oxopropyl] ethanethioate
• CAS: 74345-73-6
• 化学式: C₆H₉ClO₂S
• 分子量: 180.655
• InChiKey: LUDPWTHDXSOXDX-SCSAIBSYSA-N

物化性质

• 沸点：
  229℃
• 密度：
  1.224
• 闪点：
  92℃
• 稳定性/保质期：
  远离氧化物、碱和水。

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  10
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  59.4
• 氢给体数：
  0
• 氢受体数：
  3

安全信息

• 安全说明：
  S36,S37,S39
• 危险类别码：
  R34
• 海关编码：
  2930909090
• 储存条件：
  应将存放于充满惰性气体的密封容器中，并存放在阴凉、干燥处。避免与空气、湿气及氧化剂接触，需避光保存。

制备方法与用途

用途：用于制备医药中间体，主要应用于卡托普利原料药的生产。

反应信息

• 作为反应物：
  描述：

  3-乙酰硫基-2-甲基丙酰氯 在 sodium periodate 、 sodium carbonate 作用下， 以 甲醇 、 水 为溶剂， 反应 1.0h， 生成 (1S,4S)-1-<3-(acetylthio)-2-methyl-1-oxopropyl>-4-(phenylsulfinyl)-L-proline
  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：

  3-乙酰基硫基-2-甲基丙酸 在 吡啶 、 氯化亚砜 作用下， 以 甲苯 为溶剂， 反应 1.5h， 生成 3-乙酰硫基-2-甲基丙酰氯
  参考文献：
  名称：

  Angiotensin-converting enzyme inhibitors. New orally active antihypertensive (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives

  摘要：

  A variety of N-substituted (mercaptoalkanoyl)- and [(acylthio)alkanoyl]glycine derivatives was synthesized and their ability in inhibiting the activity of angiotensin-converting enzyme (ACE) was examined in vitro and in vivo. The acylthio derivatives prepared are assumed to act as prodrugs since they are much less active than the corresponding free SH compounds in vitro and can be expected to act in vivo only after conversion to the free sulfhydryl compounds. A number of these compounds are potent ACE inhibitors that lowered blood pressure in Na-deficient, conscious spontaneously hypertensive rats (SHR), a high renin model. One of the most active members of the series was (S)-N-cyclopentyl-N-[3-[(2,2-dimethyl-1-oxopropyl)thio]-2-methyl-1 -oxopropyl]glycine (REV 3659-(S), pivopril). Structure-activity relationships are discussed.

  DOI：

  10.1021/jm00379a013

文献信息

• Synthesis of 1-((S)-3-acetylthio-2-methylpropanoyl)-L-propyl-L-phenylalanine (alacepril) and one of its active metabolites, the desacetyl derivative (DU-1227).
  作者：Tadahiro SAWAYAMA、Akira ITOKAWA、Kanji SHIMADA、Yasumasa DOI、Yoshitaka KIMURA、Haruki NISHIMURA

  DOI：10.1248/cpb.38.529

  日期：——

  The synthesis of 1-((S)-3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine 1 (alacepril, code name : DU-1219), a clinically used antihypertensive agent, and one of its active metabolites, 1-((S)-3-mercapto-2-methylpropanoyl)-L-prolyl-L-phenylalanine 2 (code name : DU-1227), is described. The application of chloral to the N-formylation of L-proline is also described. The presence of an intramolecular hydrogen bond in the trans conformer of 1 in solution is suggested on the basis of spectroscopic examinations of 1 and its ethyl ester 4.

  报道了临床使用的抗高血压药物1-((S)-3-乙酰巯基-2-甲基丙酰基)-L-脯氨酰-L-苯丙氨酸1（阿拉普利，代码名：DU-1219）及其活性代谢物之一1-((S)-3-巯基-2-甲基丙酰基)-L-脯氨酰-L-苯丙氨酸2（代码名：DU-1227）的合成。还描述了氯醛在L-脯氨酸N-甲酰化中的应用。根据1及其乙酯4的光谱检查结果，推测溶液中1的反式构象分子内存在氢键。
• Structural Basis of Metallo-β-Lactamase Inhibition by Captopril Stereoisomers
  作者：Jürgen Brem、Sander S. van Berkel、David Zollman、Sook Y. Lee、Opher Gileadi、Peter J. McHugh、Timothy R. Walsh、Michael A. McDonough、Christopher J. Schofield

  DOI：10.1128/aac.01335-15

  日期：2016.1

  enzyme inhibition, has been reported to inhibit MBLs by chelating the active site zinc ions via its thiol(ate). We report systematic studies on B1 MBL inhibition by all four captopril stereoisomers. High-resolution crystal structures of three MBLs (IMP-1, BcII, and VIM-2) in complex with either the l- or d-captopril stereoisomer reveal correlations between the binding mode and inhibition potency.

  β-内酰胺是最成功的抗菌剂，但它们的有效性受到耐药性的威胁，最重要的是产生丝氨酸和金属β-内酰胺酶 (MBL)。MBLs 越来越受到关注，因为它们催化几乎所有 β-内酰胺类抗生素的水解，包括最近一代的碳青霉烯类。已开发出临床有用的丝氨酸-β-内酰胺酶抑制剂，但此类抑制剂不适用于 MBL。l-Captopril 用于通过抑制血管紧张素转换酶来治疗高血压，据报道它通过其硫醇（酸盐）螯合活性位点锌离子来抑制 MBL。我们报告了所有四种卡托普利立体异构体对 B1 MBL 抑制的系统研究。三种 MBL 的高分辨率晶体结构（IMP-1、BcII、和 VIM-2) 与 l- 或 d- 卡托普利立体异构体复合揭示了结合模式和抑制效力之间的相关性。该结果将有助于设计具有广泛选择性的 MBL 抑制剂，用于临床应用对抗耐碳青霉烯类肠杆菌科细菌和其他引起 MBL 介导的耐药性感染的生物体。
• Pharmaceutically active compounds
  申请人：FISONS plc

  公开号：EP0384636A1

  公开（公告）日：1990-08-29

  There are described compounds of formula I, processes for their preparation and pharmaceutical formulations containing them, ZCHR₁COR₂      I in which R₂ is a group of formula II, -NRxCHRyCOOH      II in which Rx and Ry are each alkyl optionally substituted by phenyl; phenylalkyl C7 to 12, phenyl, phenyloxyalkyl, N-alkyl, O-alkyl, or together Rx and Ry may form a heterocyclic group optionally substituted by alkyl, phenyl; phenylalkyl C7 to 12, phenyl, phenyloxyalkyl, N-alkyl, O-alkyl, or one of Rx and Ry may be hydrogen, provided that one of Rx and Ry, the heterocyclic group formed by Rx and Ry or the optional substituents is substituted by one or two groups -COOR₉ R₉ is phenyl, -(CH₂)xCONR₁₄R₁₅, -(CH₂)yCOOR₁₆ or alkyl optionally substituted by phenyl; R₁₄, R₁₅, R₁₆, x and y, are as described in the specification, and pharmaceutically acceptable salts thereof.

  描述了化合物的公式I，其制备过程和含有它们的制药配方，其中R₂是公式II的一个基团，-NRxCHRyCOOH，在其中Rx和Ry各自是可选择由苯基取代的烷基；苯基烷基C7至12，苯基，苯氧基烷基，N-烷基，O-烷基，或者Rx和Ry可以共同形成一个杂环基团，该基团可选择由烷基、苯基取代；苯基烷基C7至12，苯基，苯氧基烷基，N-烷基，O-烷基，或者Rx和Ry中的一个可以是氢，前提是Rx和Ry中的一个，由Rx和Ry形成的杂环基团或可选择的取代基团之一被一个或两个基团取代，-COOR₉R₉是苯基，-(CH₂)xCONR₁₄R₁₅，-(CH₂)yCOOR₁₆或者可选择由苯基取代的烷基；R₁₄，R₁₅，R₁₆，x和y如规范中所述，并且其药学上可接受的盐。
• 一种卡托普利异构体的制备方法
  申请人：山东新华制药股份有限公司

  公开号：CN109608378A

  公开（公告）日：2019-04-12

  本发明提供了一种卡托普利异构体的制备方法，先将混旋的3‑乙酰硫基‑2‑甲基丙酸拆分成L‑3‑乙酰硫基‑2‑甲基丙酸，再与氯化亚砜反应制备L‑3‑乙酰硫基‑2‑甲基丙酰氯(简称L‑酰氯)；L‑酰氯与L‑脯氨酸或D‑脯氨酸反应生成1‑(3‑乙酰硫基‑2‑甲基丙酰基)‑脯氨酸(简称游离酸)，游离酸水解脱保护而制得异构体；本发明提供一种的卡托普利异构体制备方法，拆分效果好，得到的异构体光学纯度高；拆分反应时间、温度范围较大，易于控制。
• Thiazaspirane derivatives, process for their preparation, and medicaments
  申请人：Luitpold-Werk Chemischpharmazeutische Fabrik GmbH & Co.

  公开号：US04587250A1

  公开（公告）日：1986-05-06

  Novel thiazaspirane derivatives of the general formula ##STR1## including salts thereof with physiologically acceptable acids and bases, processes for their preparation and medicaments containing them.

  新型噻唑螺环衍生物的一般式为##STR1##，包括其与生理可接受的酸和碱盐，其制备过程以及含有它们的药物。