3-(3,5-二氯苯基)-1-甲基海因 | 27387-90-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 中文名称: 3-(3,5-二氯苯基)-1-甲基海因
• 英文名称: 3-(3,5-dichlorophenyl)-1-methylimidazolidine-2,4-dione
• 英文别名: 3-(3,5-dichlorophenyl)-1-methyl-2,4-imidazolidinedione；3-(3,5-dichlorophenyl)-1-methyl-imidazole-2,4-dione
• CAS: 27387-90-2
• 化学式: C₁₀H₈Cl₂N₂O₂
• 分子量: 259.092
• InChiKey: JFMOAIVHTYQOKA-UHFFFAOYSA-N

物化性质

• 熔点：
  202-203.5 °C(Solv: ethanol (64-17-5))
• 沸点：
  377.3±52.0 °C(Predicted)
• 密度：
  1.507±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  16
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  2

安全信息

• 海关编码：
  2933990090

反应信息

• 作为反应物：
  描述：

  3-(3,5-二氯苯基)-1-甲基海因 在 四氢吡咯 、 1-氯乙基氯甲酸酯 、 magnesium sulfate 、 sodium sulfate 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 反应 68.5h， 生成
  参考文献：
  名称：

  Discovery and Development of 5-[(5S,9R)-9- (4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1- methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non- 7-yl-methyl]-3-thiophenecarboxylic Acid (BMS-587101)A Small Molecule Antagonist of Leukocyte Function Associated Antigen-1

  摘要：

  LFA-1 (leukocyte function-associated antigen-1), is a member of the beta2-integrin family and is expressed on all leukocytes. This letter describes the discovery and preliminary SAR of spirocyclic hydantoin based LFA-1 antagonists that culminated in the identification of analog 8 as a clinical candidate. We also report the first example of the efficacy of a small molecule LFA-1 antagonist in combination with CTLA-4Ig in an animal model of transplant rejection.

  DOI：

  10.1021/jm0610806
• 作为产物：
  描述：

  2-(甲基氨基)乙酸乙酯 、 3,5-二氯苯异氰酸酯 在 sodium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以96%的产率得到3-(3,5-二氯苯基)-1-甲基海因
  参考文献：
  名称：

  LFA-1 / ICAM抑制剂的千克合成

  摘要：

  描述了BMS-587101（1）的工艺开发和千克规模的合成。合成的特征是[3 + 2]甲亚胺叶立德环加成反应，以非对映选择性方式有效构建螺环核，然后通过经典拆分得到所需对映体，其对映体过量> 98％。分四步制备靶标，总产率为22％。

  DOI：

  10.1021/op9003168

文献信息

• Spiro-hydantoin compounds useful as anti-inflammatory agents
  申请人：——

  公开号：US20040009998A1

  公开（公告）日：2004-01-15

  Compounds having the formula (I), and pharmaceutically-acceptable salts, hydrates, enantiomers, and diastereomers, and prodrugs thereof, 1 are useful as inhibitors of LFA-1/ICAM and as anti-inflammatory agents, wherein L and K are O or S; Z is N or CR 4b ; Ar is an optionally-substituted aryl or heteroaryl; G is a linker attached to T or M or is absent; J, M and T are selected to define a three to six membered saturated or partially unsaturated non-aromatic ring; and R 2 R 4a , R 4b , and R 4c are as defined in the specification.

  具有公式(I)的化合物，以及药用可接受的盐、水合物、对映异构体、非对映异构体和前药，可用作LFA-1/ICAM的抑制剂和作为抗炎剂，其中L和K是O或S；Z是N或CR4b；Ar是可选地取代的芳基或杂芳基；G是连接到T或M的连接剂或不存在；J、M和T被选用来定义一个三到六成员的饱和或部分不饱和的非芳香环；R2R4a, R4b, 和R4c如说明书所定义。
• Synthesis of lead LFA-1 antagonist [¹⁴C]spyrocyclic hydantoin
  作者：Scott B. Tran、Brad D. Maxwell、Shiang-Yuan Chen、Samuel J. Bonacorsi、Leslie Leith、Marc Ogan、J. Kent Rinehart、Balu Balasubramanian

  DOI：10.1002/jlcr.1596

  日期：2009.5.30

  Radiolabelled drug lead candidate leukocyte function-associated antigen 1 antagonist [14C]spyrocyclic hydantoin: 5-(((5S,9R)-9-(4-[14C]-cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonan-7-yl)methyl)thiophene-3-carboxylic acid, 12, was conveniently prepared in three radiochemical steps from (5S,9R)-tert-butyl 9-(4-bromophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]nonane-7-carboxylate 9. The radiochemical yield of 12 was 28.5% from the resolved bromide 9. The preparation of the racemic spyrocyclic hydantoin 3 was obtained via a [3+2]dipolar cycloaddition reaction between 2 and N-benzyl-N-(methoxymethyl)trimethylsilylmethylamine. The introduction of [14C] cyanide was completed via a palladium (0) catalyzed reaction by the addition of Zn(14CN)2 to aryl bromide 9. The radiochemical and chiral purities of 12 determined by high-performance liquid chromatography were 98.7 and 99.7%, respectively. The specific activity of 12 was 87.5 µCi/mg (48.6 mCi/mmol). Copyright © 2009 John Wiley & Sons, Ltd.

  放射标记药物先导候选物白细胞功能相关抗原1拮抗剂[14C]螺环氢噻唑：5-(((5S,9R)-9-(4-[14C]-氰基苯)-3-(3,5-二氯苯)-1-甲基-2,4-二氧-1,3,7-三氮杂螺[4.4]呋喃-7-基)甲基)噻吩-3-羧酸，12，通过三步放射化学反应从(5S,9R)-叔丁基9-(4-溴苯)-3-(3,5-二氯苯)-1-甲基-2,4-二氧-1,3,7-三氮杂螺[4.4]呋喃-7-羧酸酯9成功合成。通过分离的溴化物9得到的12的放射化学产率为28.5%。手性对映体螺环氢噻唑3的制备是通过在2和N-苄基-N-(甲氧基甲基)三甲基硅基甲胺之间进行[3+2]偶极环加成反应获得的。通过引入[14C]氰化物完成了对芳基溴化物9的钯(0)催化反应，添加Zn(14CN)₂。通过高效液相色谱法测得，12的放射化学和手性纯度分别为98.7%和99.7%。12的比活性为87.5 µCi/mg (48.6 mCi/mmol)。版权所有 © 2009 John Wiley & Sons, Ltd.
• Crystalline forms and process for preparing spiro-hydantoin compounds
  申请人：DelMonte J. Albert

  公开号：US20060074099A1

  公开（公告）日：2006-04-06

  A process is provided for preparing spiro-hydantoin compounds of the formula II wherein Z is N or CR 4b ; K and L are independently O or S; Ar is an optionally substituted aryl or heteroaryl; A 2 is a linker, G′ is a linker; Q is a linker; and R 2 , R 4a , R 4c , and R h are defined in the specification. The process optionally includes the enantiomeric separation of intermediates to allow preparation of enantiomers of the spiro-hydantoin compounds of formula II. Substituted spiro-hydantoin compounds may be prepared from the spiro-hydantoin compounds of formula II. The spiro-hydantoin compound of formula II and the substituted spiro-hydantoin compounds are useful in the treatment of immune or inflammatory diseases. Also, provided are products made by the instant inventive process and crystalline forms (prepared by any process) of the substituted spiro-hydantoin compound, 5-[(5S, 9R)-9-(4-Cyanophenyl)-3-(3,5-dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-7-ylmethyl]-thiophene-3-carboxylic acid, including solvates and salts thereof, as well as methods of use thereof. Crystalline forms of certain intermediates are provided.

  提供了一种用于制备公式II中的螺环咪唑烷酮化合物的过程，其中Z为N或CR4b；K和L分别为O或S；Ar为可选择取代的芳基或杂芳基；A2为连接物，G'为连接物；Q为连接物；R2、R4a、R4c和Rh在规范中有定义。该过程可选择包括对中间体进行对映体分离，以便制备公式II中的螺环咪唑烷酮化合物的对映体。可从公式II中的螺环咪唑烷酮化合物制备取代的螺环咪唑烷酮化合物。公式II的螺环咪唑烷酮化合物和取代的螺环咪唑烷酮化合物在治疗免疫或炎症性疾病方面具有用途。还提供了通过即时创新过程制备的产品以及取代的螺环咪唑烷酮化合物5-[(5S, 9R)-9-(4-氰基苯基)-3-(3,5-二氯苯基)-1-甲基-2,4-二氧代-1,3,7-三氮杂螺[4.4]壬-7-基甲基]-噻吩-3-羧酸的结晶形式（通过任何过程制备），包括其溶剂合物和盐，以及其使用方法。提供了某些中间体的结晶形式。
• Kilogram Synthesis of a LFA-1/ICAM Inhibitor
  作者：Albert J. DelMonte、Robert E. Waltermire、Yu Fan、Douglas D. McLeod、Zhinong Gao、Kirsten D. Gesenberg、Kevin P. Girard、Miguel Rosingana、Xuebao Wang、Jennifer Kuehne-Willmore、Alan D. Braem、John A. Castoro

  DOI：10.1021/op9003168

  日期：2010.5.21

  The process development and the kilogram-scale synthesis of BMS-587101 (1) are described. The synthesis features a [3 + 2] azomethine ylide cycloaddition to efficiently build the spirocyclic core in a diastereoselective fashion followed by a classical resolution which affords the desired enantiomer in >98% enantiomeric excess. The target was prepared in four steps in an overall yield of 22%.

  描述了BMS-587101（1）的工艺开发和千克规模的合成。合成的特征是[3 + 2]甲亚胺叶立德环加成反应，以非对映选择性方式有效构建螺环核，然后通过经典拆分得到所需对映体，其对映体过量> 98％。分四步制备靶标，总产率为22％。
• Nephrotoxic and hepatotoxic potential of imidazolidinedione-, oxazolidinedione- and thiazolidinedione-containing analogues of N-(3,5-dichlorophenyl)succinimide (NDPS) in Fischer 344 rats
  作者：Erica L Kennedy、Ruy Tchao、Peter J Harvison

  DOI：10.1016/s0300-483x(02)00692-3

  日期：2003.4

  Nephrotoxicity of the agricultural fungicide N-(3,5-dichlorophenyl)succinimide (NDPS) in rats is believed to involve metabolism on the succinimide ring. To further investigate this hypothesis, we synthesized and tested the following NDPS analogues, which contain other cyclic imide rings and may therefore be metabolized differently than NDPS: 3-(3,5-dichlorophenyl)-2,4-oxazolidinedione (DCPO), 3-(3

  人们认为，农用杀菌剂N-（3,5-二氯苯基）琥珀酰亚胺（NDPS）对大鼠的肾毒性涉及琥珀酰亚胺环上的代谢。为了进一步研究该假设，我们合成并测试了以下NDPS类似物，其包含其他环状酰亚胺环，因此可能与NDPS代谢不同：3-（3,5-二氯苯基）-2,4-恶唑烷二酮（DCPO），3 -（3,5-二氯苯基）-2,4-咪唑烷二酮（DCPI），3-（3,5-二氯苯基）-1-甲基-2,4-咪唑烷二酮（DCPM）和3-（3,5-二氯苯基） -2,4-噻唑烷二酮（DCPT）。雄性Fischer 344大鼠接受DCPO，DCPI，DCPM，DCPT（0.6或1.0 mmol / kg，ip在玉米油中），NDPS（0.6 mmol / kg，ip在玉米油中）或玉米油（4 ml / kg）。如利尿，蛋白尿，血尿素氮水平升高，肾脏重量增加和近端肾小管损伤，NDPS对大鼠产生严重的肾毒性。相反，DCPO，DCPI，D