N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide | 120452-49-5

• 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: N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide
• 英文别名: Cbz-D-Phe-N(CH3)OCH3；benzyl N-[(2R)-1-[methoxy(methyl)amino]-1-oxo-3-phenylpropan-2-yl]carbamate
• CAS: 120452-49-5
• 化学式: C₁₉H₂₂N₂O₄
• 分子量: 342.395
• InChiKey: VAZMRCRWGLSXOE-QGZVFWFLSA-N

物化性质

• 密度：
  1.185±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide 在 palladium dihydroxide lithium aluminium tetrahydride 、 [VCl3(thf)3] 、 铜 、 N,N-二异丙基乙胺 、 锌 、 环己烯 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 58.0h， 生成 (4R,5S,6S,7R)-hexahydro-5,6-bis[2-(trimethylsilyl)ethoxymethoxy]-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one
  参考文献：
  名称：

  Preparation and Structure−Activity Relationship of Novel P1/P1‘-Substituted Cyclic Urea-Based Human Immunodeficiency Virus Type-1 Protease Inhibitors

  摘要：

  A series of novel P1/P1'-substituted cyclic urea-based HIV-1 protease inhibitors was prepared. Three different synthetic schemes were used to assemble these compounds. The first approach uses amino acid-based starting materials and was originally used to prepare DMP 323. The other two approaches use L-tartaric acid or L-mannitol as the starting material. The required four contiguous R,S,S,R centers of the cyclic urea scaffold are introduced using substrate control methodology. Each approach has specific advantages based on the desired P1/P1' substituent. Designing analogs based on the enzyme's natural substrates provided compounds with reduced activity. Attempts at exploiting hydrogen bond sites in the S1/S1' pocket, suggested by molecular modeling studies, were not fruitful. Several analogs had better binding affinity compared to our initial leads. Modulating the compound's physical properties led to a 10-fold improvement in translation resulting in better overall antiviral activity.

  DOI：

  10.1021/jm960083n
• 作为产物：
  描述：

  N-苄氧羰基-D-苯丙氨酸 在 N-甲基吗啉 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.83h， 生成 N-methoxy-N-methyl-(R)-N²-Cbz-phenylalaninamide
  参考文献：
  名称：

  四氢嘧啶酮的设计，合成和评估，作为非肽类HIV蛋白酶抑制剂一般方法的一个例子。

  摘要：

  对HIV蛋白酶（HIVPR）抑制剂的环状脲类设计的重新审查提出了设计新型非肽环状HIVPR抑制剂的一般方法。该过程涉及线性HIVPR抑制剂的核心过渡态等位体的立体化学中心的反转，以及使用合适的环化试剂环化所得核心。例如，该方法应用于HIVPR抑制剂的二氨基醇类，得到四氢嘧啶酮。四氢嘧啶酮的构象分析及其与HIVPR活性位点相互作用的模型表明，修饰导致了非常有效的HIVPR抑制剂（24种，Ki = 0.018 nM）。具有HIVPR的24配合物的X射线晶体学结构证实了分析和模型预测。

  DOI：

  10.1021/jm970081i

文献信息

• Solid-phase synthesis of C-terminal peptide aldehydes from amino acetals anchored to a backbone amide linker (BAL) handle
  作者：Fanny Guillaumie、Joseph C Kappel、Nicholas M Kelly、George Barany、Knud J Jensen

  DOI：10.1016/s0040-4039(00)00950-3

  日期：2000.8

  Peptide aldehydes were synthesized, starting from amino acetals, by a solid-phase backbone amide linker (BAL) strategy.

  通过固相主链酰胺接头（BAL）策略从氨基缩醛开始合成肽醛。
• An efficient and enantioselective synthesis of a chiral primary amine
  作者：Youngchan Son、Chihyo Park、Jong Sung Koh、Nakyen Choy、Chang S. Lee、Ho-il Choi、Sung Chun Kim、Heungsik Yoon

  DOI：10.1016/s0040-4039(00)73087-5

  日期：1994.5

  An efficient and enantioselective method for the preparation of a chiral primary amine has been developed. Starting from N-protected L or D-amino acid the sequence involves coupling with N-methoxy-N-methylamine, acylation, olefination with potassium bis(trimethylsilyl)amide, and hydrogenation.

  已经开发了制备手性伯胺的有效和对映选择性的方法。从N-保护的L或D-氨基酸开始，该序列包括与N-甲氧基-N-甲胺偶联，酰化，与双（三甲基甲硅烷基）酰胺钾的烯化以及氢化。
• Highly diastereoselective synthesis of (3R,4R)- and (3R,4S)-.BETA.,.GAMMA.-diamino acids from D-phenylalanine.
  作者：SHINZO KANO、TSUTOMU YOKOMATSU、HARUO IWASAWA、SHIROSHI SHIBUYA

  DOI：10.1248/cpb.36.3341

  日期：——

  (2R, 3S)-N-Boc-2-Amino-3-hydroxy-1-phenylbutane (9a) and (2R, 3S)-N-Boc-2-amino-3-hydroxy-1-phenylpentane (9b) were converted to (3R, 4R)-N3-Boc-3, 4-diaminopentanoic acid (12a) and (3R, 4R)-N3-Boc-3, 4-diaminohexanoic acid (12b) through SN2 type substitution of the hydroxy group to an amino group and oxidation of the phenyl group to a carboxyl group. In a similar way, the (3R, 4S)-isomers (18a, b) were also synthesized from (2R, 3R)-N-Boc-2-amino-3-hydroxy-1-phenylbutane (15a) and (2R, 3R)-N-Boc-2-amino-3-hydroxy-1-phenylpentane (15b), respectively, derived from (2R, 3S)-N-Cbz-2-amino-3-hydroxy-1-phenylbutane (6a) and (2R, 3S)-N-Cbz-2-amino-3-hydroxy-1-phenylpentane (6b) by means of the diastereoconversion reaction.

  (2R, 3S)-N-Boc-2-氨基-3-羟基-1-苯基丁烷 (9a) 和 (2R, 3S)-N-Boc-2-氨基-3-羟基-1-苯基戊烷 (9b) 通过对羟基进行SN2型取代转化为氨基，及将苯基氧化为羧基，生成(3R, 4R)-N3-Boc-3, 4-二氨基戊酸 (12a) 和(3R, 4R)-N3-Boc-3, 4-二氨基己酸 (12b)。以类似的方式，(3R, 4S)-异构体 (18a, b) 也分别由(2R, 3R)-N-Boc-2-氨基-3-羟基-1-苯基丁烷 (15a) 和(2R, 3R)-N-Boc-2-氨基-3-羟基-1-苯基戊烷 (15b) 合成，这两者是通过二手态转化反应由(2R, 3S)-N-Cbz-2-氨基-3-羟基-1-苯基丁烷 (6a) 和(2R, 3S)-N-Cbz-2-氨基-3-羟基-1-苯基戊烷 (6b) 得到的。
• Cyclic ureas and analogues useful as retroviral protease inhibitors
  申请人：THE DU PONT MERCK PHARMACEUTICAL COMPANY

  公开号：EP0765873A1

  公开（公告）日：1997-04-02

  This invention relates to substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating viral infection.

  本发明涉及可用作逆转录病毒蛋白酶抑制剂的取代环羰基及其衍生物、含有此类化合物的药物组合物以及使用这些化合物治疗病毒感染的方法。
• Substituted cyclic carbonyls and derivatives thereof useful as retroviral protease inhibitors
  申请人：THE DU PONT MERCK PHARMACEUTICAL COMPANY

  公开号：EP0858999A1

  公开（公告）日：1998-08-19

  This invention relates to substituted cyclic carbonyls and derivatives thereof useful as Human Immunodeficiency Virus (HIV) protease inhibitors, to pharmaceutical compositions comprising such compounds, and to methods of using these compounds for treating HIV infection.

  本发明涉及可用作人类免疫缺陷病毒（HIV）蛋白酶抑制剂的取代环羰基及其衍生物，涉及包含此类化合物的药物组合物，还涉及使用这些化合物治疗 HIV 感染的方法。