新产品编号:1179099

Chemical Name: 7-[3-[4-[N-(4-Cyclohexylbutyl)carbamoyl]oxazol-2-yl]phenyl]-7-(3-pyridyl)-6(E)-heptenoic acid
项目整合开发状态: Biological Testing
项目研究机构: Lilly (Originator)
合成路线:1,4-Benzenedimethanol (I) was monoprotected with tert-butyldimethylsilyl chloride in the presence of imidazole,and the resulting silyl ether (II) was oxidized with MnO2 in refluxing THF to aldehyde (III).This was treated with 3-lithiopyridine (IV),(generated from 3-bromopyridine and butyllithium at -78 C in Et2O),to give carbinol (V),which was oxidized with MnO2 to ketone (VI).Wittig reaction with 5-carboxypentylphosphonium bromide (VII) and t-BuOK in THF at low temperature yielded a 4:1 mixture of Z and E heptenoic acids (VIII).Subsequent reaction with diazomethane provided a mixture of esters,from which the E isomer (IX) was separated by column chromatography.Oxidation of TBDMS ether with Jones reagent provided acid (X),and this was coupled with N-(4-cyclohexylbutyl)-L-serinamide (XI) using N-(dimethylaminopropyl)-N'-ethylcarbodiimide.HCl (EDC) in the presence of HOBT and N-methylmorpholine to give amide (XII).Cyclization to oxazolidine (XIII) was effected by treatment with triphenyl phosphine and diisopropylethylamine.

合成路线:Oxazolidine (XIII) was oxidized to oxazole (XIV) with nickel peroxide in the presence of 4 ?molecular sieves,and finally hydrolyzed with 1 M NaOH in THF-MeOH to the title acid.

合成路线:1,3-Benzenedimethanol (I) was monoprotected with tert-butyldimethylsilyl chloride in the presence of imidazole,and the resulting silyl ether (II) was oxidized with MnO2 in refluxing THF to aldehyde (III).This was treated with 3-lithiopyridine (IV),generated from 3-bromopyridine and butyllithium at -78 C in Et2O,to give carbinol (V),which was oxidized with MnO2 to ketone (VI).Wittig reaction with 5-carboxypentylphosphonium bromide (VII) and t-BuOK in THF at low temperature yielded a 3:1 mixture of Z and E heptenoic acids (VIII).Subsequent reaction with diazomethane provided a mixture of esters,from which the E isomer (IX) was separated by column chromatography.Oxidation of TBDMS ether with Jones reagent provided acid (X),and this was coupled with N-(4-cyclohexylbutyl)-L-serinamide (XI) using N-dimethylaminopropyl-N'-ethylcarbodiimide.HCl (EDC) in the presence of HOBT and N-methylmorpholine to give amide (XII).Cyclization to oxazolidine (XIII) was effected by treatment with triphenyl phosphine and diisopropylethylamine.

合成路线:Oxazolidine (XIII) was oxidized to oxazole (XIV) with nickel peroxide in the presence of 4 ?molecular sieves,and finally hydrolyzed with 1 M NaOH in THF-MeOH to the title acid.