-药物合成数据库

【药物名称】

化学结构式(Chemical Structure):

参考文献No.	469669
标题:	Development of dual-acting agents for thromboxane receptor antagonism and thromboxane synthase inhibition. 2. Design, synthesis, and evaluation of a novel series of phenyl oxazole derivatives
作者:	Takeuchi, K.; Kohn, T.J.; Mais, D.E.; True, T.A.; Wyss, V.L.; Jakubowski, J.A.
来源:	Bioorg Med Chem Lett 1998,8(15),1943-1948

合成路线图解说明: 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.

合成路线图解说明: 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.

合成路线图解说明: 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.

合成路线图解说明: 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.