CL-191983, OCA-983

Chemical Name: (1R,5S,6S)-6-[1(R)-Hydroxyethyl]-1-methyl-2-[2(R)-(L-valylaminomethyl)tetrahydrofuran-3(R)-ylsulfanyl]-1-carba-2-penem-3-carboxylic acid
CAS No. 161856-02-6
项目整合开发状态: Preclinical
项目研究机构: Wyeth Pharmaceuticals (Originator)
合成路线:Azetidineacetic acid derivative (I) was activated with 1,1'-carbonyldiimidazole and then condensed with p-nitrobenzyl malonate magnesium salt (II) to afford ketoester (III).Desilylation of (III) with methanolic HCl then gave alcohol (IV).Dodecylbenzenesulfonyl azide (VI) was prepared by treatment of sulfonyl chloride (V) with NaN3.Reaction of (IV) with sulfonyl azide (VI) provided diazo ester (VII).Ring closure of (VII) in the presence of rhodium diacetate in hot cyclohexane,followed by condensation with diphenylphosphoric chloride furnished carbapenem phosphate (VIII).

合成路线:1,2-Dideoxy-D-ribose (IX) was converted to bismesylate (X) upon treatment with methanesulfonyl chloride and pyridine.Displacement of the primary mesylate group of (X) with LiN3 in DMF gave azide (XI).The secondary mesylate group was further displaced with potassium thioacetate to provide (XII).Thiol (XIII) was then prepared by hydrolysis of the thioester function with NaOMe in THF.

合成路线:In an alternative procedure,deoxyribose (XIV) was reduced to 2-deoxy-D-erythropentitol (XV) with NaBH4.Acid-catalyzed cyclization of (XV) produced (IX),which was converted to triflate (XVI) using trifluoromethanesulfonic anhydride and pyridine.Displacement with tetrabutylammonium azide provided azido derivative (XVII).Further treatment with trifluoromethanesulfonic anhydride gave triflate (XVIII),which was then displaced with potassium thioacetate to yield thioester (XII).This was hydrolyzed with NaOMe as above to furnish thiol (XIII).

合成路线:Coupling of carbapenem phosphate (VIII) with thiol (XIII) using diisopropylethylamine gave rise to sulfide (XIX).Hydrogenolysis of the p-nitrobenzyl group of (XIX) with simultaneous azide reduction in the presence of Pd/C provided (XX).Treatment of p-nitrobenzyl chloroformate (XXI) with p-nitrophenol (XXII) afforded the nitrophenyl carbonate (XXIII),which was coupled with L-valine (XXIV),yielding carbamate (XXV).Activation of (XXV) with N-hydroxy succinimide and DCC then produced the succinimidyl ester (XXVI).Amine (XX) was coupled with succinimidyl ester (XXVI) to furnish amide (XXVII).The p-nitrobenzyl ester was finally removed by hydrogenation over Pd/C to provide the title compound.