【药物名称】
化学结构式(Chemical Structure):
参考文献No.55934
标题:Inhibitors of histone deacetylase
作者:Holms, J.H.; Davidsen, S.K.; Michaelides, M.R.; Guo, Y.; Heyman, H.R.; Curtin, M.L.; Wada, C.K.; Dai, Y.; Vasudevan, A.; Frey, R.R.; Ji, Z. (Abbott Laboratories Inc.)
来源:WO 0246129
合成路线图解说明:

The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.

合成路线图解说明:

The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.

参考文献No.686193
标题:Electrophilic ketone-based histone deacetylase inhibitors as cancer chemotherapeutic agents
作者:Garland, R.B.; Curtin, M.L.; Frey, R.R.; et al.
来源:224th ACS Natl Meet (Aug 18 2002, Boston) 2002,Abst MEDI 121
合成路线图解说明:

The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.

合成路线图解说明:

The known methyl 7-hydroxyheptanoate (I) is hydrolyzed with LiOH and subsequently converted to the benzyl ester (II) by treatment with benzyl bromide and NaHCO3. Swern oxidation of the primary alcohol function of (II) yields aldehyde (III), which is subjected to Wadsworth-Emmons condensation with the tetrahydropyranyl-protected phosphonate (IV) to afford the O-tetrahydropyranyl enol ether (V). Further acidic hydrolysis of (V) provides keto diester (VI). Alternatively, aldehyde (III) is condensed with the silyl-protected phosphonate (VII) to give (VIII), which is then deprotected to (VI) by desilylation with CsF. Displacement of the methyl ester function of (VI) with methylamine yields amide (IX). The benzyl ester group of (IX) is then removed by hydrogenolysis over Pd/C to produce acid (X). Finally, coupling of acid (X) with the thiazolyl amine (XI) leads to the title compound.

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