(2S)-2-tert-butoxycarbonylamino-3-methyl-1-phenyl-1-butanone hydrochloride

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (2S)-2-tert-butoxycarbonylamino-3-methyl-1-phenyl-1-butanone hydrochloride
• 英文别名: (S)-2-amino-3-methyl-1-phenylbutan-1-one hydrochloride；(2S)-2-amino-3-methyl-1-phenylbutan-1-one;hydrochloride
• 化学式: C₁₁H₁₅NO*ClH
• 分子量: 213.707
• InChiKey: AKTPDJALGJGCJC-PPHPATTJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.27
• 重原子数：
  14
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  43.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (2S)-2-tert-butoxycarbonylamino-3-methyl-1-phenyl-1-butanone hydrochloride 在 盐酸 、 4-二甲氨基吡啶 、 三乙胺 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 5.5h， 生成 (6S)-N-1-(tert-butoxycarbonyl)-5-phenyl-6-isopropyl-1,2,3,6-tetrahydro-2-pyrazinone
  参考文献：
  名称：

  由具有1,2,3,6-四氢吡嗪-2-一结构的α，β-（Z）-二氢氢化物衍生物不对称合成α-氨基酸

  摘要：

  手性（Ž）-α，β-didehydroamino酸（DDAA）衍生物14，15和16是从所获得的新的手性iminic环状甘氨酸模板与1,2,3,6- tetrahydropyrazin -2-酮结构10通过与羰基缩合化合物，Eschenmoser盐和Bredereck试剂。使用Heck烯化和乙烯基亲核取代，二氢丙氨酸衍生物15和烯胺酮16可以得到DDAA衍生物14。这些DDAA衍生物14和15 进行非对映选择性环丙烷化，1，3-偶极和Diels-Alder环加成反应，水解后得到相应的环状和双环α-氨基酸。

  DOI：

  10.1016/s0040-4020(01)00553-1
• 作为产物：
  描述：

  (S)-tert-butyl (3-methyl-1-oxo-1-phenylbutan-2-yl)carbamate 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 生成 (2S)-2-tert-butoxycarbonylamino-3-methyl-1-phenyl-1-butanone hydrochloride
  参考文献：
  名称：

  Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P₄-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles

  摘要：

  Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P-4 pocket and optimization of the P-1' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P-4-capped inhibitors were also found to have improved PK profile.

  DOI：

  10.1021/jm801632a

文献信息

• Friedel–Crafts Acylation of Aminocarboxylic Acids in Strong Brønsted Acid Promoted by Lewis Base P₄O₁₀
  作者：Hao Wu、Akinari Sumita、Yuko Otani、Tomohiko Ohwada

  DOI：10.1021/acs.joc.2c01761

  日期：2022.11.18

  (triflic acid, TfOH) if the Lewis base P4O10 is added. Here we describe the Friedel–Crafts acylation reactions of anthranilic acid and α- to δ-aminocarboxylic acids with benzene derivatives in the presence of P4O10. Non-amino-containing carboxylic acids as well as N-containing heteroaromatic carboxylic acids are available, and α-amino acids can be directly utilized without any protective group. Most substrates

  氨基羧酸中的氨基具有足够的碱性，可以在强酸中质子化，因此，由于电荷-电荷排斥，羧酸向酰基离子的电离被阻止。因此，芳香族化合物的酰化在 Friedel-Craft 型反应中显着延迟。我们发现，如果添加路易斯碱 P 4 O 10 ，即使在强布朗斯台德酸（三氟甲磺酸，TfOH）中，氨基羧酸的 Friedel-Crafts 酰化也可以顺利进行。在这里，我们描述了邻氨基苯甲酸和 α- 到 δ-氨基羧酸与苯衍生物在 P 4 O 10存在下的 Friedel-Crafts 酰化反应. 既有不含氨基的羧酸，也有含N的杂芳族羧酸，α-氨基酸可直接使用，无需任何保护基团。尽管可能会发生一些差向异构化/外消旋化，但大多数底物都能提供高产率的酰化产物。密度泛函理论 (DFT) 计算表明 P 4 O 10中和质子化胺，将 N-H 共价键转化为 N-氢键，并使羧酸 OH 官能团充当良好的离去基团。
• Chiral (Z)-α,β-didehydroamino acid derivatives from a new chiral glycine equivalent with a 1,2,3,6-tetrahydropyrazin-2-one structure: applications to the synthesis of 1-aminocyclopropanecarboxylic acids and bicyclic α-amino acids
  作者：Tomás Abellán、Carmen Nájera、José M Sansano

  DOI：10.1016/s0957-4166(00)00023-9

  日期：2000.3

  The new chiral glycine equivalent 9, easily obtained from(+)-alpha-aminoisovalerophenone and glycine, afforded chiral (Z)-alpha,beta-didehydroamino acid (DDAA) derivatives 13 and 14 with a 1,2,3,6-tetrahydropyrazin-2-one structure. Compounds 13 and 14 were synthesised by reaction of 9 with Eschenmoser's salt and by condensation reactions with aldehydes or acetone under PTC conditions, respectively. The diastereoselective cyclopropanation of 14, followed by hydrolysis, furnished (-)-allo-norcoronamic acid with high ee, whilst diastereoselective Diels-Alder reaction of dienophile 13 and cyclopentadiene afforded, after double bond hydrogenation and hydrolysis, (-)-2-aminonorbornane-2-carboxylic acid. (C) 2000 Elsevier Science Ltd. All rights reserved.
• JPS62209058A
  申请人：——

  公开号：JPS62209058A

  公开（公告）日：1987-09-14
• Asymmetric synthesis of α-amino acids from α,β-(Z)-didehydroamino acid derivatives with 1,2,3,6-tetrahydropyrazin-2-one structure
  作者：Tomás Abellán、Balbino Mancheño、Carmen Nájera、José M Sansano

  DOI：10.1016/s0040-4020(01)00553-1

  日期：2001.7

  structure 10 by condensation with carbonyl compounds, Eschenmoser's salt and Bredereck's reagent, respectively. The didehydroalanine derivative 15 and the enaminone 16 can give DDAA derivatives 14 using Heck olefination and vinylic nucleophilic substitution. These DDAA derivatives 14 and 15 undergo diastereoselective cyclopropanation, 1,3-dipolar and Diels–Alder cycloaddition reactions giving, after

  手性（Ž）-α，β-didehydroamino酸（DDAA）衍生物14，15和16是从所获得的新的手性iminic环状甘氨酸模板与1,2,3,6- tetrahydropyrazin -2-酮结构10通过与羰基缩合化合物，Eschenmoser盐和Bredereck试剂。使用Heck烯化和乙烯基亲核取代，二氢丙氨酸衍生物15和烯胺酮16可以得到DDAA衍生物14。这些DDAA衍生物14和15 进行非对映选择性环丙烷化，1，3-偶极和Diels-Alder环加成反应，水解后得到相应的环状和双环α-氨基酸。
• Toward the Back-Up of Boceprevir (SCH 503034): Discovery of New Extended P₄-Capped Ketoamide Inhibitors of Hepatitis C Virus NS3 Serine Protease with Improved Potency and Pharmacokinetic Profiles
  作者：Stéphane L. Bogen、Weidong Pan、Sumei Ruan、Latha G. Nair、Ashok Arasappan、Frank Bennett、Kevin X. Chen、Edwin Jao、Srikanth Venkatraman、Bancha Vibulbhan、Rong Liu、Kuo-Chi Cheng、Zhuyan Guo、Xiao Tong、Anil K. Saksena、Viyyoor Girijavallabhan、F. George Njoroge

  DOI：10.1021/jm801632a

  日期：2009.6.25

  Hepatitis C is the most prevalent liver disease. Viral hepatitis C (HCV), a small (+)-RNA virus, infects chronically an estimated 300 million people worldwide. Results of Phase I clinical studies with our first generation HCV inhibitor Boceprevir, SCH 503034 (1), presented at the 56th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD) were encouraging, and thus, additional human clinical studies are underway. In view of the positive data from our first generation compound, further work aimed at optimizing its overall profile was undertaken. Herein, we report that extension of our earlier inhibitor to the P-4 pocket and optimization of the P-1' capping led to the discovery of new ketoamide inhibitors of the HCV NS3 serine protease with improved in vitro potency. In addition to being potent inhibitors of HCV subgenomic RNA replication, some of the new P-4-capped inhibitors were also found to have improved PK profile.