L-780945, SNAP-6991-(+), (+)-SNAP-6991
Chemical Name: (+)-3-[N-[2-[N-(cis-4-Cyano-4-phenylcyclohexyl)amino]ethyl]carbamoyl]-4-(3,4-difluorophenyl)-6-(methoxymethyl)-2-oxo-1,2,3,4-tetrahydro-5-pyrimidinecarboxylic acid methyl ester
CAS No. 191353-53-4 ((+)-trans-isomer, monoHCl)
项目整合开发状态: Preclinical
项目研究机构: Synaptic (Originator)
合成路线:The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III),which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V).The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII),which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography.The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX),already reported.The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
合成路线:The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III),which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V).The optical resolution of (V) by chiral chromatography affords the (+)(IX) isomer,which is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane giving the active 4-nitrophenyl ester (+)(X).The hydrolysis of the enol methyl ether of (X) with HCl in ether/dichloromethane yields the pyrimidinone (+)(XI),which is finally condensed with 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) in dichloromethane.The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
📌 参考资料/链接：
参考文献标题:Dihydropyrimidines and uses thereof
文献作者:Nagarathnam,D.; Wong,W.C.; Miao,S.W.; Patane,M.A.; Gluchowski,C.(Merck & Co.,Inc.; Synaptic Pharmaceutical Corp.)
参考来源:EP 0866708; JP 2000500470; WO 9717969
📄 详细内容
合成路线:The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III),which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V).The optical resolution of dihydropyrimidine (V) can also be performed as follows: Dihydropyrimidine (V) is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP giving the 4-nitrophenyl ester (VII),which is treated with (R)-(+)-alpha-methylbenzylamine [(R)-MBA] yielding amide (VIII) as mixture of diastereomers that is separated by column chromatography.The (+) isomer was then treated with DBU in hot toluene to provide the dihydropyrimidine (+)(IX),already reported.The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
合成路线:The reaction of 3,4-difluorobenzaldehyde (I) with methyl 4-methoxyacetoacetate (II) by means of piperidinium acetate in benzene gives the 3-benzylidene derivative (III),which is cyclized with O-methylisourea (IV) yielding dihydropyrimidine (V).The optical resolution of (V) by chiral chromatography affords the (+)(IX) isomer,which is condensed with 4-nitrophenyl chloroformate (VI) by means of DMAP in dichloromethane giving the active 4-nitrophenyl ester (+)(X).The hydrolysis of the enol methyl ether of (X) with HCl in ether/dichloromethane yields the pyrimidinone (+)(XI),which is finally condensed with 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) in dichloromethane.The intermediate 2-(trans-4-cyano-4-phenylcyclohexyl)ethylamine (XII) has been obtained by reductocondensation of 4-cyano-4-phenylcyclohexanone (XIII) with ethylenediamine (XIV) by means of p-toluenesulfonic acid and NaBH4 and separation of the isomers by careful chromatography.
参考文献标题:Design,synthesis and evaluation of dihydropyrimidinones as alpha-1A selective antagonists: 7.Modification of the piperidine moiety into 4-aminocyclohexane; identification and structure-activity relationship of SNAP 6991 analogs
文献作者:Nagarathnam,D.; et al.
参考来源:217th ACS Natl Meet (March 21 1999,Anaheim) 1999,Abst MEDI 110