AR-R17779, AR-R13489(racemate), -Drug Synthesis Database

【结构式】

【药物名称】AR-R17779, AR-R13489(racemate)

【化学名称】(S)-Spiro[1-azabicyclo[2.2.2]octane-3,5'-oxazolidin]-2'-one

【CA登记号】178419-47-1 ((-)-enantiomer), 178419-46-0 ((+)-enantiomer), 178419-45-9 (undefined isomer)

【分子式】C₉H₁₄N₂O₂

【分子量】182.22413

【开发单位】AstraZeneca (Originator)

【药理作用】Anxiolytics, Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, PSYCHOPHARMACOLOGIC DRUGS, Nicotinic alpha7 Agonists

合成路线1 合成路线2

合成路线1

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.

参考文献中间体

【1】 Mullen, G.; Balestra, M.; Napier, J.; et al.; (-)-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. J Med Chem 2000, 43, 22, 4045.
【2】 Napier, J.; Mack, R.; Loch, J. III; et al.; The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.149.
【3】 Murray, R.J.; Gordon, J.C.; Griffith, R.C.; Balestra, M. (AstraZeneca plc); Spiro-azabicyclic cpds. useful in therapy. WO 9606098 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	16925	3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one	1193-65-3	C₇H₁₁NO	详情	详情
(II)	30111	tert-butyl 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetate		C₁₃H₂₃NO₃	详情	详情
(III)	30112	methyl 2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetate		C₁₀H₁₇NO₃	详情	详情
(IV)	30113	2-(3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl)acetohydrazide		C₉H₁₇N₃O₂	详情	详情
(V)	30114	Spiro[oxazolidine-5,3'-quinuclidin]-2-one		C₉H₁₄N₂O₂	详情	详情

合成路线2

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.

参考文献中间体

【1】 Napier, J.; Mack, R.; Loch, J. III; et al.; The synthesis and nicotinic receptor subtype profile of AR-R17779, a conformationally restricted analog of acetylcholine. 15th European Federation for Medicinal Chemistry International Symposium on Medicinal Chemistry (Sept 6 1998, Edinburgh) 1998, Abst P.149.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	16925	3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one	1193-65-3	C₇H₁₁NO	详情	详情
(VI)	11540	(1S)-2-hydroxy-1,2,2-triphenylethyl acetate; (R)-(+)-1,1,2-Triphenyl-1,2-ethanediol 2-acetate	95061-47-5	C₂₂H₂₀O₃	详情	详情
(VII)	30115	(1S)-2-hydroxy-1,2,2-triphenylethyl 2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetate		C₂₉H₃₁NO₄	详情	详情
(VIII)	30116	2-[(3R)-3-hydroxy-1-azabicyclo[2.2.2]oct-3-yl]acetic acid		C₉H₁₅NO₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)