CI-1029, PD-178390
6(S)-[2-(4-氨基苯基)乙基]-3-[2-叔丁基-4-(羟甲基甲基)-5-甲基苯基磺酰]-4-羟基-6-异丙基-5,6-二氢-2H-吡喃-2-1Chemical Name: 6(S)-[2-(4-Aminophenyl)ethyl]-3-[2-tert-butyl-4-(hydroxymethyl)-5-methylphenylsulfanyl]-4-hydroxy-6-isopropyl-5,6-dihydro-2H-pyran-2-one
CAS No. 207736-05-8
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:The condensation of 5-[4-(tert-butoxycarbonylamino)phenyl]-2-methyl-3-pentanone (I) with tert-butylacetate (II) by means of LDA in THF,followed by hydrolysis of the ether with LiOH gives the racemic 3-hydroxypentanoic acid (III),which is submitted to optical resolution with (S)-alpha-methylbenzylamine affording the (S)-enantiomer (IV).The condensation of (IV) with the magnesium salt of monoethyl malonate (V) affords the beta-keto ester (VI),which is cyclized by means of NaOH to provide the dihydropyrone (VII).The condensation of (VII) with thiosulfonate (VIII) by means of K2CO3 in DMF yields the expected thioether (IX),which is finally treated with NaOH in DMSO/water to eliminate the tert-butoxycarbonyl protecting group.
📌 参考资料/链接：
参考文献标题:Nonpeptidic HIV protease inhibitors possessing excellent antiviral activities and therapeutic indices.PD 178390: A lead HIV protease inhibitor
文献作者:Vara Prasad,J.V.N.; Boyer,F.E.; Domagala,J.M.; Ellsworth,E.L.; Gajda,C.; Hamilton,H.W.; Hagen,S.E.; Markoski,L.J.; Steinbaugh,B.A.; Tait,B.D.; Humblet,C.; Lunney,E.A.; Pavlovsky,A.; Rubin,J.R.; Ferguson,D.; Graham,N.; Holler,T.; et al.
参考来源:Bioorg Med Chem 1999,7(12),2775
📄 详细内容
合成路线:The hydrolysis of the ketoester (I) with NaOH gives the corresponding ketoacid (II),which is condensed with 4-nitrobenzaldehyde (III) by means of pyridine to yield the hydroxyketone (IV).The reaction of (IV) with acetic anhydride and pyridine affords the acetoxy compound (V),which is dehydrated by means of hot pyridine to provide the enone (VI).The condensation of (VI) with benzyl acetate (VII) by means of LDA gives 3-hydroxy-3-isopropyl-5-(4-nitrophenyl)-4-pentenoic acid benzyl ester (VIII),which is fully hydrogenated with H2 over Pd(OH)2 to yield the amino acid (IX).Finally,(IX) is treated with acetic anhydride to afford the target 5-(4-acetamidophenyl)-3-hydroxy-3-isopropylpentanoic acid intermediate (X).
参考文献标题:Application of the Sch鰌f method to optimization of the synthesis of 3-[2-(p-N-acetylaminophenyl)ethyl]-3-hydroxy-4-methylpentanoic acid: Simultaneous reduction of three functional groups to maximine yield and throughput
文献作者:Deering,C.F.; et al.
参考来源:Org Process Res Dev 2000,4(6),596
产品链接: CAS No. 207736-05-8››