(3aS,8aR)-2,2-dimethyl-3-(3-phenylpropanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazole | 141018-37-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: (3aS,8aR)-2,2-dimethyl-3-(3-phenylpropanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazole
• 英文别名: 1-[(3aR,8bS)-2,2-dimethyl-4,8b-dihydro-3aH-indeno[1,2-d][1,3]oxazol-1-yl]-3-phenylpropan-1-one
• CAS: 141018-37-3
• 化学式: C₂₁H₂₃NO₂
• 分子量: 321.419
• InChiKey: XKDHFAMBZCXKMC-QUCCMNQESA-N

物化性质

• 沸点：
  498.3±45.0 °C(Predicted)
• 密度：
  1.140±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3aS,8aR)-2,2-dimethyl-3-(3-phenylpropanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazole 在 盐酸 、 正丁基锂 、 potassium 2-methylbutan-2-olate 、 异丙醇 作用下， 生成 茚地那韦
  参考文献：
  名称：

  手性非外消旋酰胺烯酸酯与（S）-缩水甘油基甲苯磺酸酯的高度非对映选择性反应。口服活性HIV-1蛋白酶抑制剂L-735,524的合成

  摘要：

  手性酰胺烯酸酯Li-1与（S）-缩水甘油基甲苯磺酸酯11的反应以高非对映体选择性得到环氧化物3，产率为72％。环氧化物3以71％的分离产率转化为口服活性的HIV-1蛋白酶抑制剂L-735,524。

  DOI：

  10.1016/s0040-4039(00)75787-x
• 作为产物：
  描述：

  (1S,2R)-(-)-1-氨基-2-茚醇 在 4-甲基苯磺酸吡啶 、 三乙胺 作用下， 生成 (3aS,8aR)-2,2-dimethyl-3-(3-phenylpropanoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazole
  参考文献：
  名称：

  Asymmetric synthesis of α-amino acid derivatives via an electrophilic amination of chiral amide cuprates with Li t-butyl-N-tosyloxycarbamate

  摘要：

  The utility of lithium t-butyl-N-tosyloxycarbamate (LiBTOC) as a (+)NHBOC synthon in highly diastereoselective reactions with chiral cis-aminoindanol derived amide cuprates is described. The diastereoselectivities of these reactions ranged from 96% to greater than 99%. The subsequent transformation of these adducts to alpha-amino acids ir also described (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4039(97)00477-2

文献信息

• Cyclic imidate salts in acyclic stereochemistry: Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides
  作者：P.E. Maligres、S.A. Weissman、V. Upadhyay、S.J. Cianciosi、R.A. Reamer、R.M. Purick、J. Sager、K. Rossen、K.K. Eng、D. Askin、R.P. Volante、P.J. Reider

  DOI：10.1016/0040-4020(95)01114-5

  日期：1996.2

  Reaction of 2-alkyl-4-enamides with 1+ and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins with essentially no iodolactone by-product. The reaction appears to proceed through a cyclic imidate type intermediate. This methodology has been successfully employed for the synthesis of the epoxide intermediate of the orally active HIV-1 protease inhibitor

  2-烷基-4-烯酰胺与1 +和碳酸氢钠水溶液的反应导致相应的碘代醇的非对映选择性形成，而基本上没有碘代内酯副产物。反应似乎通过环状亚氨酸酯型中间体进行。该方法已成功地用于合成口服活性HIV-1蛋白酶抑制剂MK-639（硫酸茚地那韦）的环氧中间体。
• Asymmetric Synthesis of Chiral Organofluorine Compounds:  Use of Nonracemic Fluoroiodoacetic Acid as a Practical Electrophile and Its Application to the Synthesis of Monofluoro Hydroxyethylene Dipeptide Isosteres within a Novel Series of HIV Protease Inhibitors
  作者：Andrew G. Myers、Joseph K. Barbay、Boyu Zhong

  DOI：10.1021/ja010113y

  日期：2001.8.1

  (diastereomeric ratios 12:1-84:1), efficient and stereoselective routes to each of the four targeted inhibitors were achieved. The optimized synthetic route to the most potent inhibitor (syn,syn-4, K(i) = 2.0 nM) proceeded in seven steps (87% average yield per step) from aminoindanol hydrocinnamide 40 and (S)-fluoroiodoacetic acid, and allowed for the preparation of more than 1 g of this compound. The inhibition

  描述了一系列 HIV 蛋白酶非对映异构体抑制剂（默克 HIV 蛋白酶抑制剂茚地那韦的单氟化类似物）的两种立体选择性途径。这两条路线的特点是通过不对称烷基化反应立体选择性地构建氟化核心亚基。第一代合成基于来自伪麻黄碱 α-氟乙酰胺的烯醇锂与硝基烯烃 12 的共轭加成，这是一种适度的非对映选择性转化。开发了一种更实用的第二代合成路线，该路线基于一种不对称合成有机氟化合物的新方法，通过使用光学活性氟碘乙酸作为亲电子试剂与手性酰胺烯醇化物相结合进行烯醇化物烷基化。用麻黄碱拆分氟碘乙酸可提供 > 或 = 96% ee 的亲电子试剂的对映体形式。与这种稳定且可储存的手性氟化前体的烷基化反应显示出以高度立体定向的方式进行。随着底物控制的 α-氟酮 44 和 45（非对映体比率 12:1-84:1）的顺式或反选择性还原的发展，实现了四种靶向抑制剂中每一种的有效和立体选择性途径。最有效抑制剂 (syn,syn-4
• Process for preparing acetonides
  申请人：——

  公开号：US20020132837A1

  公开（公告）日：2002-09-19

  Acetonides are obtained in a one-step reaction of a carboxylic acid halide, a 1,2-aminoalcohol, and 2-alkoxypropene or 2,2-dialkoxypropane in an ether solvent and in the presence of an inorganic base. Acetonides are also obtained in a two-step reaction scheme in which an acid halide and 1,2-aminoalcohol are reacted in an ether solvent in the presence of LiOH to form a hydroxyamide, which is then reacted with 2-alkoxypropene or 2,2-dialkoxypropane in the presence of acid to form the acetonide. The acetonides resulting from the one-step and two-step protocols can be further reacted with an allylating agent such as an allyl halide in the presence of a strong base to provide the corresponding allyl acetonide. The acetonides and allyl acetonides can serve as intermediates in the production of certain HIV protease inhibitors which are useful for treating HIV infection and AIDS.

  Acetonides是通过在醚溶剂中，在无机碱的存在下，将羧酸卤、1,2-氨基醇和2-烷氧基丙烯或2,2-二烷氧基丙烷进行一步反应而获得的。Acetonides也可以通过两步反应方案获得，其中酸卤和1,2-氨基醇在醚溶剂中在LiOH的存在下反应以形成羟基酰胺，然后在酸的存在下与2-烷氧基丙烯或2,2-二烷氧基丙烷反应以形成缩醛。通过一步和两步方案得到的缩醛可以进一步与烯丙基卤等烯丙基化试剂在强碱的存在下反应，从而得到相应的烯丙基缩醛。这些缩醛和烯丙基缩醛可以作为某些用于治疗HIV感染和艾滋病的HIV蛋白酶抑制剂的生产中间体。
• Antiviral protease inhibitors
  申请人：Medivir AB

  公开号：US20010044547A1

  公开（公告）日：2001-11-22

  Compounds of formula (I), wherein A and A are independently the same or different group of formula (II) wherein: R′ is H, CH 3 , C(CH 3 ) 2 ,—OR a , —N(R a ) 2 , —N(R a )OR a or -DP; R is H or CH 3 ; R a is H, C 1 -C 3 alkyl; D is a bond, alkylene, —C(═O)—, —S(O)— or S(O) 2 —; P is an optionally substituted, mono or bicyclic carbo- or hetereocycle; R″ is H, any of the sidechains found in the natural amino acids, carboxacetamide, or a group (CH 2 ) n DP; M is a bond or —C(═O)N(R′″)-; Q is absent, a bond, —CH(OH)— or CH 2 —; or R″ together with Q, M and R define an optionally substituted 5 or 6 membered carbo- or heterocyclic ring which is optionally fused with a further 5 or 6 membered carbo- or heterocyclic ring; with the proviso that R is —OR a , -, N(R a ) 2 , —N(R a )OR a or -DP, if M is a bond and Q is absent; X is H, OH, OCH 3 , Y is H, OH, OCH 3 , but X and Y are not both H; Z′ and Z″ are independently —(CH 2 ) m P where P is as defined above; n and m are independently 0, 1 or 2; and pharmaceutically acceptable salts and prodrugs thereof have utility as aspartyl protease inhibitors of HIV. They can be prepared in a facile two step synthesis from novel 2,5-di-O-benzyl-L-mannaro-1,4:6,3-dilactone intermediates.

  化合物的式子（I），其中A和A独立地是式子（II）的相同或不同的基团，其中：R'是H，CH3，C（CH3）2，—ORa，—N（Ra）2，—N（Ra）ORa或-DP; R是H或CH3; Ra是H，C1-C3烷基; D是键，烷基，—C(═O)—，—S（O）—或S（O）2—; P是一个可选的取代的，单环或双环的碳或杂环；R″是H，天然氨基酸中发现的任何侧链，羧乙酰胺或一个组（CH2）nDP; M是键或—C(═O)N（R'″）-; Q不存在，是键，—CH（OH）—或CH2—; 或R″与Q、M和R一起定义一个可选的取代的5或6元环或杂环，该环可以与另一个可选的取代的5或6元环或杂环融合；条件是，如果M是键且Q不存在，则R是—ORa，-，N（Ra）2，—N（Ra）ORa或-DP；X是H，OH，OCH3，Y是H，OH，OCH3，但X和Y不都是H；Z′和Z″独立地是—（CH2）mP，其中P如上定义；n和m独立地是0、1或2；以及其药学上可接受的盐和前药具有作为HIV天冬氨酸蛋白酶抑制剂的用途。它们可以从新的2,5-二-O-苄基-L-曼纳罗-1,4:6,3-二内酯中间体中方便地进行两步合成。
• Diastereoselective syn-epoxidation of 2-alkyl-4-enamides to epoxyamides: Synthesis of the Merck HIV-1 protease inhibitor epoxide intermediate
  作者：P.E. Maligres、V. Upadhyay、K. Rossen、S.J. Cianciosi、R.M. Purick、K.K. Eng、R.A. Reamer、D. Askin、R.P. Volante、P.J. Reider

  DOI：10.1016/0040-4039(95)00273-f

  日期：1995.3

  Reaction of 2-alkyl-4-enamides 2, 9-15 with NIS and aqueous sodium bicarbonate results in the diastereoselective formation of the corresponding iodohydrins 3, 16-22 with essentially no iodolactone by-product. This methodology has been successfully employed for the synthesis of the epoxide intermediate 4 of the orally active Merck HIV-I protease inhibitor L-735,524.