(R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione | 213208-73-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: (R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione
• 英文别名: (5R)-5-[(4-bromophenyl)methyl]-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione
• CAS: 213208-73-2
• 化学式: C₁₇H₁₃BrCl₂N₂O₂
• 分子量: 428.112
• InChiKey: FXUMGHSXHJBQLB-QGZVFWFLSA-N

物化性质

• 密度：
  1.586±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  49.4
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione 在 双(三甲基硅烷基)氨基钾 、 甲胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 3.58h， 生成 butylamino-nor-BIRT
  参考文献：
  名称：

  Binding Site Elucidation of Hydantoin-Based Antagonists of LFA-1 Using Multidisciplinary Technologies:  Evidence for the Allosteric Inhibition of a Protein−Protein Interaction

  摘要：

  The binding site on the lymphocyte function-associated antigen-1 (LFA-1) of a class of hydantoin-based antagonists of leukocyte cell adhesion has been identified. This site resides in the inserted-domain (I-domain) of the CD11a chain at a location that is distal to residues known to be required for interactions with the intercellular adhesion molecules. This finding supports the hypothesis that the molecules are antagonizing cell adhesion via an allosteric modification of LFA-1. The binding site was identified using an integrated immunochemical, chemical, and molecular modeling approach. Antibodies that map to epitopes on the I-domain were blocked from binding to the purified protein by the hydantoins, indicating that the hydantoin-binding site resides on the I-domain. Photoaffinity labeling of the I-domain followed by LC/MS and LC/MS/MS analysis of the enzymatic digest identified proline 281 as the primary amino acid residue covalently attached to the photoprobe. Distance constraints derived from this study coupled with known SAR considerations allowed for the construction of a molecular model of the I-domain/inhibitor complex. The atomic details of the protein/antagonist interaction were accurately predicted by this model, as subsequently confirmed by the X-ray crystal structure of the complex.

  DOI：

  10.1021/ja0104249
• 作为产物：
  描述：

  3,5-二氯苯胺 在 N-甲基吗啉 、 sodium hydroxide 、 苄基三甲基氢氧化铵 、 三乙胺 、 三氟乙酸 、 lithium hexamethyldisilazane 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 正戊烷 为溶剂， 生成 (R)-5-(4-bromobenzyl)-3-(3,5-dichlorophenyl)-5-methylimidazolidine-2,4-dione
  参考文献：
  名称：

  立体中心的自我再生：LFA-1拮抗剂BIRT-377的实用对映体合成。

  摘要：

  [反应：见正文]通过8个步骤，LFA-1拮抗剂BIRT-377的有效对映体合成达到了43％的总收率。关键的转化包括反式咪唑烷酮7的立体定向形成，随后的烷基化以及二取代的咪唑烷酮9的有效水解。该方法实用，可靠且具有成本效益。它已在中试工厂成功实施，可生产多千克量的BIRT-377药物。

  DOI：

  10.1021/ol000147v

文献信息

• Application of asymmetric alkylation of malonic diester with phase-transfer catalysis: synthesis of LFA-1 antagonist BIRT-377
  作者：Takuya Kanemitsu、Saeka Furukoshi、Michiko Miyazaki、Kazuhiro Nagata、Takashi Itoh

  DOI：10.1016/j.tetasy.2015.01.006

  日期：2015.2

  efficient asymmetric synthesis of LFA-1 antagonist BIRT-377 using enantioselective phase-transfer catalytic alkylation has been developed. The alkylation of α-monosubstituted tert-butyl methyl malonate was catalyzed by a quaternary ammonium salt derived from a cinchona alkaloid to obtain the product with a quaternary stereogenic carbon in high yield and with high enantioselectivity. The chiral α,α-disubstituted

  使用对映选择性相转移催化的烷基化LFA-1拮抗剂BIRT-377的有效不对称合成已经研制成功。的烷基化α单取代叔丁基甲基丙二酸二乙酯通过从金鸡纳衍生的季铵盐催化生物碱，得到产物与以高产率和高对映选择性的季立体碳。由此获得的手性α，α二取代的产物通过交替两个酯基随后Curtius重排的脱保护化学选择性转化为BIRT-377。
• Self-Regeneration of Stereocenters:  A Practical Enantiospecific Synthesis of LFA-1 Antagonist BIRT-377
  作者：Nathan K. Yee

  DOI：10.1021/ol000147v

  日期：2000.9.1

  [reaction: see text] An efficient enantiospecific synthesis of the LFA-1 antagonist BIRT-377 has been achieved in 43% overall yield in eight steps. The key transformations involve the stereospecific formation of the trans imidazolidinone 7, subsequent alkylation, and the efficient hydrolysis of disubstituted imidazolidinone 9. The process is practical, robust, and cost-effective; it has been successfully

  [反应：见正文]通过8个步骤，LFA-1拮抗剂BIRT-377的有效对映体合成达到了43％的总收率。关键的转化包括反式咪唑烷酮7的立体定向形成，随后的烷基化以及二取代的咪唑烷酮9的有效水解。该方法实用，可靠且具有成本效益。它已在中试工厂成功实施，可生产多千克量的BIRT-377药物。
• Convenient preparation of chiral phase-transfer catalysts with conformationally fixed biphenyl core for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377
  作者：Yong-Gang Wang、Mitsuhiro Ueda、Xisheng Wang、Zhenfu Han、Keiji Maruoka

  DOI：10.1016/j.tet.2007.02.079

  日期：2007.6

  Chiral phase-transfer catalysts (S)-1a, (S)-1b, and (S)-2 with conformationally fixed biphenyl cores were conveniently prepared from the known, easily available (S)-6,6′-dimethylbiphenyl-2,2′-diol 3 and (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyl-2,2′-dicarboxylic acid 14, respectively, in five steps. The catalysts, (S)-1a and (S)-1b are readily applicable to asymmetric alkylation of N-(diphenylmethylene)glycine

  具有构象固定的联苯核的手性相转移催化剂（S）-1a，（S）-1b和（S）-2由已知的，易于获得的（S）-6,6'-二甲基联苯-2， 2'-二醇3和（S）-4,5,6,4'，5'，6'-六甲氧基联苯-2,2'-二羧酸14分别在五个步骤中。催化剂（S）-1a和（S）-1b易于用于N-（二苯基亚甲基）甘氨酸叔丁基的不对称烷基化丁酯具有出色的对映选择性。特别地，发现催化剂（S）-1b对对映选择性表现出独特的温度影响，并且甘氨酸衍生物在室温下的不对称烷基化比在0℃下具有更高的对映体过量。此外，催化剂（S）-2在N-（二苯基亚甲基）甘氨酸叔丁酯和N-（对氯苯基亚甲基）丙氨酸叔丁酯的不对称烷基化反应中表现出较高的催化性能（0.01-1 mol％）。丁酯与现有的手性相转移催化剂相比，从而可以实现通用且有用的程序，用于高度实用的对映选择性合成结构多样的天然和非天然α-烷基-α-氨基酸以及α，α-二烷基- α
• Convenient preparation of highly active phase-transfer catalyst for catalytic asymmetric synthesis of α-alkyl- and α,α-dialkyl-α-amino acids: application to the short asymmetric synthesis of BIRT-377
  作者：Zhenfu Han、Yukako Yamaguchi、Masanori Kitamura、Keiji Maruoka

  DOI：10.1016/j.tetlet.2005.09.185

  日期：2005.12

  A highly active phase-transfer catalyst was conveniently prepared from the known, easily available (S)-4,5,6,4′,5′,6′-hexamethoxybiphenyldicarboxylic acid. This catalyst exhibited the high catalytic performance (0.01–1 mol %) in the asymmetric alkylation of N-(diphenylmethylene)glycine tert-butyl ester and N-(p-chlorophenylmethylene)alanine tert-butyl ester compared to the existing chiral phase-transfer

  由已知的，容易获得的（S）-4,5,6,4'，5'，6'-六甲氧基联苯二羧酸方便地制备高活性相转移催化剂。与现有的手性相转移相比，该催化剂在N-（二苯基亚甲基）甘氨酸叔丁酯和N-（对氯苯基亚甲基）丙氨酸叔丁酯的不对称烷基化反应中表现出较高的催化性能（0.01-1 mol％）。催化剂，因此可以实现通用且有用的程序，用于高度实用的对映选择性合成结构多样的天然和非天然α-烷基-α-氨基酸以及α，α-二烷基-α-氨基酸。
• Improved Schöllkopf construction of quaternary α-amino acids: efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377
  作者：Stamatia Vassiliou、Plato A. Magriotis

  DOI：10.1016/j.tetasy.2006.06.019

  日期：2006.7

  The Schöllkopf methodology for the asymmetric synthesis of α-amino acids which was previously not applicable to the construction of α,α-dialkylated (quaternary) α-amino acids, has been rendered practical for this purpose and applied in a highly efficient enantioselective synthesis of integrin LFA-1 antagonist BIRT-377.

  Schöllkopf方法用于α-氨基酸的不对称合成，以前不适用于α，α-二烷基化（季）α-氨基酸的构建，为此已被实用化并用于高效的对映体选择性合成。整联蛋白LFA-1拮抗剂BIRT-377。