(S)-螺[1-氮杂双环[2.2.2]辛烷-3,5'-恶唑啉]-2'-酮 4-氨基甲酰吡啶-3-羧酸酯 (9CI)-螺[1-氮杂双环[2.2.2]辛烷-3,5-噁唑啉]-2-酮Chemical Name: (S)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-one
CAS No. 178419-47-1 ((-)-enantiomer), 178419-46-0 ((+)-enantiomer), 178419-45-9 (undefined isomer)
项目整合开发状态: Preclinical
项目研究机构: AstraZeneca (Originator)
合成路线:Condensation of 3-quinuclidinone (I) with tert-butyl acetate using LDA in THF at low temperature gave hydroxy ester (II).Acid cleavage of the tert-butyl ester of (II),followed by esterification with MeOH and H2SO4 produced the methyl ester (III),which was transformed to hydrazide (IV) upon treatment with hydrazine in refluxing MeOH.Nitrosation of (IV) with NaNO2 and HCl,followed by Curtius rearrangement of the intermediate acyl azide furnished the target spiro oxazolidinone (V).The required (S)-enantiomer was then isolated by resolution with dibenzoyl-D-tartaric acid.
📄 详细内容
合成路线:Condensation of 3-quinuclidinone (I) with tert-butyl acetate using LDA in THF at low temperature gave hydroxy ester (II).Acid cleavage of the tert-butyl ester of (II),followed by esterification with MeOH and H2SO4 produced the methyl ester (III),which was transformed to hydrazide (IV) upon treatment with hydrazine in refluxing MeOH.Nitrosation of (IV) with NaNO2 and HCl,followed by Curtius rearrangement of the intermediate acyl azide furnished the target spiro oxazolidinone (V).The required (S)-enantiomer was then isolated by resolution with dibenzoyl-D-tartaric acid.
合成路线:In an alternative procedure,reaction of quinuclidinone (I) with (R)-2-hydroxy-1,2,2-triphenylethyl acetate (VI) gave adduct (VII) as a single enantiomer.Subsequent ester hydrolysis of (VII) provided the chiral carboxylic acid (VIII).Finally,rearrangement of (VIII) in the presence of diphenyl phosphorylazide yielded the title compound.
参考文献标题:The synthesis and nicotinic receptor subtype profile of AR-R17779,a conformationally restricted analog of acetylcholine
文献作者:Napier,J.; Mack,R.; Loch,J.III; et al.
参考来源:15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998,Edinburgh) 1998,Abst P.149
合成路线:Condensation of 3-quinuclidinone (I) with tert-butyl acetate using LDA in THF at low temperature gave hydroxy ester (II).Acid cleavage of the tert-butyl ester of (II),followed by esterification with MeOH and H2SO4 produced the methyl ester (III),which was transformed to hydrazide (IV) upon treatment with hydrazine in refluxing MeOH.Nitrosation of (IV) with NaNO2 and HCl,followed by Curtius rearrangement of the intermediate acyl azide furnished the target spiro oxazolidinone (V).The required (S)-enantiomer was then isolated by resolution with dibenzoyl-D-tartaric acid.
参考文献标题:(-)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin-2'-one],a conformationally restricted analogue of acetylcholine,is a highly selective full agonist at the alpha7 nicotinic acetylcholine receptor
文献作者:Mullen,G.; Napier,J.; Balestra,M.; DeCory,T.; Hale,G.; Macor,J.E.; Mack,R.; Loch,J.III; Wu,E.S.C.; Kover,A.; Verhoest,P.R.; Sampognaro,A.; Phillips,E.; Zhu,Y.; Murray,R.J.; Griffith,R.; Blosser,J.; Gurley,D.; Machulskis,A.; et al.
参考来源:J Med Chem 2000,43(22),4045