新产品编号:1666355
Chemical Name: 2-Azaspiro[4.5]decane-4(R)-carboxylic acid hydrochloride
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II),which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V).The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI),which is esterified with methanol/HCl giving the methyl ester (VII).The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII),which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX).The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b).The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer.Finally,this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.
📌 参考资料/链接：
参考文献标题:Conformationally constrained amino acid cpds.having affinity for the alpha2delta subunit of a calcium channel
文献作者:Horwell,D.C.; Bryans,J.S.; Receveur,J.-M.(Pfizer Inc.)
参考来源:WO 9961424
📄 详细内容
合成路线:The condensation of cyclohexanone (I) with ethyl cyanacetate (II) gives the cyclohexylidene derivative (II),which is cyclized with N-benzylglycine (IV) and formal-dehyde by means of TEA in refluxing benzene yielding the spiro derivative (V).The decarboxylative hydrolysis of (V) with refluxing 6N HCl affords 2-benzyl-2-azaspiro [4,5]decane-4-carboxylic acid (VI),which is esterified with methanol/HCl giving the methyl ester (VII).The debenzylation of (VII) with H2 over Pd(OH)2 in methanol yields 2-azaspiro[4.5]decane-4-carboxylic acid methyl ester (VIII),which is reprotected with benzyl chloroformate and pyridine to provide the carbamate (IX).The hydrolysis of the methyl ester group of (IX) with NaOH in dioxane/water afford the protected carboxylic acid (Xa-b) as a racemic mixture that is treated with oxalyl chloride in dichloromethane to give the acyl chloride (XIa-b).The condensation of (XIa-b) with the chiral (R)(+)-1-(2-naphthyl)ethylamine (XII) yields the amide (XIIIa-b) as a diastereomeric mixture that is resolved by flash chromatography providing chiral (XIV) as a single diastereomer.Finally,this compound is hydrolyzed and deprotected with 6N HCl in refluxing THF.
参考文献标题:Synthesis and biological evaluation of conformationally restricted gabapentin analogues
文献作者:Receveur,J.M.; Bryans,J.S.; Field,M.J.; Singh,L.; Horwell,D.C.
参考来源:Bioorg Med Chem Lett 1999,9(16),2329