-药物合成数据库

【药物名称】

化学结构式(Chemical Structure):

参考文献No.	41329
标题:	Conformationally constrained amino acid cpds. having affinity for the alpha2delta subunit of a calcium channel
作者:	Horwell, D.C.; Bryans, J.S.; Receveur, J.-M. (Pfizer Inc.)
来源:	WO 9961424

合成路线图解说明: 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No.	547892
标题:	Synthesis and biological evaluation of conformationally restricted gabapentin analogues
作者:	Receveur, J.M.; Bryans, J.S.; Field, M.J.; Singh, L.; Horwell, D.C.
来源:	Bioorg Med Chem Lett 1999,9(16),2329

合成路线图解说明: 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.