新产品编号:384935
Chemical Name: 4-[4-[6,6-Dimethyl-2-(4-methylphenyl)-1-cyclohexen-1-yl]-3(E)-buten-1-ynyl]benzoic acid
CAS No. 208253-18-3
项目整合开发状态: Preclinical
项目研究机构: Allergan (Originator)
合成路线:Iodination of 3-methylcyclohexenone (I) using iodine and azidotrimethylsilane produced the iodo ketone (II) (1).Palladium-catalyzed coupling of iodide (II) with 2-(tributylstannyl)ethenyltrimethylsilane (III),prepared from (trimethylsilyl)acetylene and tributyltin hydride,furnished the silylethenyl cyclohexenone (IV),which was further treated with iodine to yield vinyl iodide (V) (1,2).Ethyl 4-ethynylbenzoate (VIII) was prepared by reaction of ethyl 4-iodobenzoate (VI) with (trimethylsilyl)acetylene (VII) in the presence of palladium catalyst (1).Heck reaction between acetylene (VIII) and vinyl iodide (V) provided adduct (IX).Conjugate addition of the in situ generated lithium dimethylcuprate to the unsaturated ketone (IX) gave the 3,3-dimethyl cyclohexanone (X).Treatment of (X) with triflic anhydride and a hindered base produced the desired vinyl triflate (XI) along with its vinyl regioisomer,which were separated by preparative chromatography.Reaction of triflate (XI) with 4-tolylzinc bromide (XIII),prepared from 4-iodotoluene (XII),yielded the phenylcyclohexene derivative (XIV).The ethyl ester group of (XIV) was finally hydrolyzed to the corresponding carboxylic acid using NaOH.
📌 参考资料/链接：
参考文献标题:Aryl- and heteroarylcyclohexenyl substd.alkenes having retinoid agonist,antagonist or inverse agonist type biological activity
文献作者:Beard,R.L.; Johnson,A.T.; Teng,M.; Vuligonda,V.; Chandraratna,R.A.(Allergan,Inc.)
参考来源:EP 0970036; JP 2001513113; US 5760276; WO 9839284
📄 详细内容
合成路线:Iodination of 3-methylcyclohexenone (I) using iodine and azidotrimethylsilane produced the iodo ketone (II) (1).Palladium-catalyzed coupling of iodide (II) with 2-(tributylstannyl)ethenyltrimethylsilane (III),prepared from (trimethylsilyl)acetylene and tributyltin hydride,furnished the silylethenyl cyclohexenone (IV),which was further treated with iodine to yield vinyl iodide (V) (1,2).Ethyl 4-ethynylbenzoate (VIII) was prepared by reaction of ethyl 4-iodobenzoate (VI) with (trimethylsilyl)acetylene (VII) in the presence of palladium catalyst (1).Heck reaction between acetylene (VIII) and vinyl iodide (V) provided adduct (IX).Conjugate addition of the in situ generated lithium dimethylcuprate to the unsaturated ketone (IX) gave the 3,3-dimethyl cyclohexanone (X).Treatment of (X) with triflic anhydride and a hindered base produced the desired vinyl triflate (XI) along with its vinyl regioisomer,which were separated by preparative chromatography.Reaction of triflate (XI) with 4-tolylzinc bromide (XIII),prepared from 4-iodotoluene (XII),yielded the phenylcyclohexene derivative (XIV).The ethyl ester group of (XIV) was finally hydrolyzed to the corresponding carboxylic acid using NaOH.
参考文献标题:Phenylcyclohexene and phenylcyclohexadiene substituted compounds having retinoid antagonist activity
文献作者:Beard,R.L.; Klein,E.S.; Standeven,A.M.; Escobar,M.; Chandraratna,R.A.S.
参考来源:Bioorg Med Chem Lett 2001,11(6),765