【药物名称】AR-R17779, AR-R13489(racemate)
化学结构式(Chemical Structure):
参考文献No.38129
标题:Spiro-azabicyclic cpds. useful in therapy
作者:Murray, R.J.; Gordon, J.C.; Griffith, R.C.; Balestra, M. (AstraZeneca plc)
来源:WO 9606098
合成路线图解说明:

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No.561274
标题:The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine
作者:Napier, J.; Mack, R.; Loch, J. III; et al.
来源:15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998,Abst P.149
合成路线图解说明:

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.

合成路线图解说明:

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No.597581
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
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.
来源:J Med Chem 2000,43(22),4045
合成路线图解说明:

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.

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