PNU-180164
Chemical Name: N-[3-[1-(2-Hydroxyacetyl)-2(R)-methyl-2,3-dihydro-1H-indol-5-yl]-2-oxooxazolidin-5(S)-ylmethyl]acetamide
CAS No. 312305-71-8
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:2-Methylindole (I) was nitrated employing NaNO3 in H2SO4 and the resultant 5-nitroindole (II) was further reduced to the corresponding indoline (III) by means of NaBH3CN in the presence of HOAc.Catalytic hydrogenation of the nitro group of (III) over Pd/C furnished diamine (IV),which was converted to the bis-carbamate (V) by treatment with benzyl chloroformate.Oxazolidinone (VII) was then obtained by condensation of carbamate (V) with (R)-glycidyl butyrate (VI) in the presence of BuLi at -78 C.After conversion of alcohol (VII) to the corresponding nosylate (VIII),displacement of its sulfonate group with ammonium hydroxide gave rise to the primary amine (IX).Acetylation of amine (IX),followed by hydrogenolysis of the remaining N-benzyloxycarbonyl group,yielded acetamide (X).The indoline N of (X) was then acylated by acetoxyacetyl chloride (XI) to produce amide (XII).The title compound was then obtained by smooth hydrolysis of the acetoxy group of (XII) with K2CO3,followed by separation of the resultant mixture of diastereoisomers by chiral HPLC.
📌 参考资料/链接：
参考文献标题:Bicyclic oxazolidinones as antibacterial agent
文献作者:Hester,J.B.Jr.; Barbachyn,M.R.; Johnson,P.D.; Genin,M.J.(Pharmacia Corp.)
参考来源:EP 1181288; US 6387896; WO 0073301
📄 详细内容
合成路线:2-Methylindole (I) was nitrated employing NaNO3 in H2SO4 and the resultant 5-nitroindole (II) was further reduced to the corresponding indoline (III) by means of NaBH3CN in the presence of HOAc.Catalytic hydrogenation of the nitro group of (III) over Pd/C furnished diamine (IV),which was converted to the bis-carbamate (V) by treatment with benzyl chloroformate.Oxazolidinone (VII) was then obtained by condensation of carbamate (V) with (R)-glycidyl butyrate (VI) in the presence of BuLi at -78 C.After conversion of alcohol (VII) to the corresponding nosylate (VIII),displacement of its sulfonate group with ammonium hydroxide gave rise to the primary amine (IX).Acetylation of amine (IX),followed by hydrogenolysis of the remaining N-benzyloxycarbonyl group,yielded acetamide (X).The indoline N of (X) was then acylated by acetoxyacetyl chloride (XI) to produce amide (XII).The title compound was then obtained by smooth hydrolysis of the acetoxy group of (XII) with K2CO3,followed by separation of the resultant mixture of diastereoisomers by chiral HPLC.
参考文献标题:The potentiating effect of remote chirality on the antibacterial activity of a series of 2-substituted indolinyl phenyloxazolidinones
文献作者:Genin,M.J.; Barbachyn,M.R.; Grega,K.C.; et al.
参考来源:41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001,Chicago) 2001,Abst F-1042