(S)-α-fluoromethylhistidine dihydrochloride

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (S)-α-fluoromethylhistidine dihydrochloride
• 英文别名: (S)-alpha-Fluoromethylhistidine 2 HCl；(2S)-2-amino-2-(fluoromethyl)-3-(1H-imidazol-5-yl)propanoic acid;hydrochloride
• 化学式: C₇H₁₀FN₃O₂*2ClH
• 分子量: 260.096
• InChiKey: AJTAPCUFVRUIEO-OGFXRTJISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.13
• 重原子数：
  14
• 可旋转键数：
  4
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  92
• 氢给体数：
  4
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-α-fluoromethylhistidine dihydrochloride 在 ammonium hydroxide 作用下， 以57%的产率得到(S)-α-fluoromethylhistidine
  参考文献：
  名称：

  高效合成α-氟甲基组氨酸二盐酸盐并证明其作为谷胱甘肽S-转移酶抑制剂的功效。

  摘要：

  组氨酸脱羧酶（HDC）是一种将组氨酸转化为组胺的酶。抑制HDC具有多种医学应用，并且HDC抑制剂对于组氨酸代谢的研究具有相当大的意义。（S）-α-氟甲基组氨酸二盐酸盐（α-FMH）是一种有效的HDC抑制剂，仅少量即可高价出售。在这里我们报告了一种新颖，廉价，有效的方法，使用2-氮丙啶基-3-甲基（N-三苯基甲基-4-咪唑基）丙酸酯和HF /吡啶合成α-FMH，实验产率为57％。为了确定α-FMH的新靶标，我们开发了一个三步骤计算机模拟工作流程，用于鉴定物理上可行的蛋白质靶标。该工作流程导致21个蛋白质目标命中，包括涉及谷胱甘肽代谢的几种酶，特别是，谷胱甘肽S-转移酶（GST）超家族的两个同工酶，在药物代谢中起着核心作用。鉴于该预测数据，在体外研究了α-FMH作为GST抑制剂的功效。已证明α-FMH在微摩尔浓度下是GST的有效抑制剂，这表明α-FMH的脱靶作用可能会限制GST依赖性机制的生理

  DOI：

  10.1016/j.bmcl.2017.02.024
• 作为产物：
  描述：

  (2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-4-(fluoromethyl)-4-<(N_im-tritylimidazol-4'-yl)methyl>-1-methyl-1,3-imidazolidin-5-one 在 盐酸 作用下， 以 甲苯 为溶剂， 反应 30.0h， 生成 (S)-α-fluoromethylhistidine dihydrochloride
  参考文献：
  名称：

  A novel stereoselective route to (S)-(+)-.alpha.-(fluoromethyl)histidine: .alpha.-halomethylation of (2R,4S)-3-benzoyl-2-(1,1-dimethylethyl)-1-methyl-4-[(N-tritylimidazol-4-yl)methyl]-1,3-imidazolidin-5-one. Synthesis and proton NMR spectroscopy

  摘要：

  A method is described for the alpha-enantioretentive methylation of L-histidine (S) to give (S)-(+)-alpha-(fluoromethyl)histidine (8). The synthesis involves the conversion of N(im)-trityl-L-histidine methyl ester (1) to both the ''trans''-(2S,4S)- and ''cis''-(2R,4S)-2-(1,1-dimethylethyl)-l-methyl-1,3-imidazolidin-5-one analogs 4 and 5. The cis isomer was regioselectively alkylated with chlorofluoromethane to give a single diastereomer 6 with retention of the original absolute configuration of the histidine alpha-position (S). .Deprotection and hydrolysis of the 1,3-imidazolidin-5-one intermediate 6 yielded the desired (S)-(+)-alpha-(fluoromethyl)histidine (8). Additionally, this reaction sequence was repeated using bromochloromethane as the alkylating agent to yield (S)-(+)-alpha-(chloromethyl)histidine (8a). Yields of this product, however, were very low due to an intramolecular alkylation reaction to give 3-benzoyl-2-(1,1-dimethylethyl)-l-methylspiro[imidazolidine-4,6'(7'H)-[5H]pyrrolo[1,2-c]imidazol]5-one (9). The structure and stereochemistry of the trans and cis 1,3-imidazolidin-5-one intermediates, as well as other members of the series, were confirmed using H-1 NMR spectroscopy, including two-dimensional NOE correlation spectroscopy (2D NOESY). The existence of slow chemical exchange in solution was detected for several members of the series based on the appearance of both positive and negative cross-peaks in the 2D NOESY spectra.

  DOI：

  10.1021/jo00055a027

文献信息

• Acid addition salts of N-trityl-.alpha.-fluoromethylhistidine enantiomer
  申请人：Merck & Co., Inc.

  公开号：US04347374A1

  公开（公告）日：1982-08-31

  A process for resolving a mixture of .alpha.-fluoromethylhistidine enantiomers is described. The process features use of an ester derivative of .alpha.-fluoromethylhistidine. Novel diastereoisomer salts of said derivative are also disclosed.

  本发明涉及一种处理混合物α-氟甲基组氨酸对映体的方法。该方法采用α-氟甲基组氨酸的酯衍生物。此外，本发明还揭示了该衍生物的新的对映异构体盐。
• Synergistic combination of (R,S)alpha-fluoromethylhistidine and cimetidine as an anti-ulcer agent
  申请人：Merck & Co., Inc.

  公开号：EP0046290A1

  公开（公告）日：1982-02-24

  There is disclosed a novel combination of two known compounds, (R,S)α-fluoromethylhistidine and cimetidine, which has surprisingly been found to synergistically reduce gastric ulcer incidence and histamine levels when administered to animals. Compositions containing the synergistic combinations are also disclosed.

  本研究公开了两种已知化合物--(R,S)α-氟甲基组氨酸和西咪替丁--的新型组合，令人惊讶地发现这种组合在给动物用药时能协同降低胃溃疡发病率和组胺水平。此外，还公开了含有协同组合物的组合物。
• Oral absorption enhancement of carboxylic acid pharmaceuticals using (5-alkyl-2-oxo-1,3-dioxolen-4-yl)methyl ester group
  申请人：Merck & Co., Inc.

  公开号：EP0070013A1

  公开（公告）日：1983-01-19

  The (5-R-2-oxo-1,3-dioxolen-4-yl)methyl moiety: wherein R is loweralkyl of 1-6 carbon atoms, especially methyl or t-butyl; when utilized as an ester on a pharmaceutical having a carboxylic acid functionality, enhances oral absorption of the pharmaceutical. This effect is applicable to a broad range of pharmaceutically active substances, including antibiotics, and antihypertensives as well as other classes of therapeutic agents.

  (5-R-2-氧代-1,3-二氧戊环-4-基)甲基： 其中 R 是 1-6 个碳原子的低级烷基，特别是甲基或叔丁基；当作为酯用于具有羧酸官能团的药物时，可促进药物的口服吸收。这种效果适用于多种药物活性物质，包括抗生素、抗高血压药以及其他类别的治疗剂。
• US4347374A
  申请人：——

  公开号：US4347374A

  公开（公告）日：1982-08-31
• US4479947A
  申请人：——

  公开号：US4479947A

  公开（公告）日：1984-10-30