PX-117794, -Drug Synthesis Database

【结构式】

【药物名称】PX-117794

【化学名称】3-[4-(3,4-Dimethoxyphenylsulfonamido)phenyl]-2-propenohydroxamic acid

【CA登记号】342372-36-5, 414872-01-8 ((E)-isomer)

【分子式】C₁₇H₁₈N₂O₆S

【分子量】378.40681

【开发单位】MethylGene (Originator), TopoTarget (Originator)

【药理作用】ONCOLYTIC DRUGS, Histone Deacetylase (HDAC) Inhibitors

合成路线1 合成路线2

合成路线1

Acylation of 4-iodoaniline (I) with 3,4-dimethoxybenzenesulfonyl chloride (II), followed by basic methanolysis leads to sulfonamide (III). Heck coupling of aryl iodide (III) with acrylic acid (IV) in the presence of tris(dibenzylideneacetone)dipalladium and tri(o-tolyl)phosphine gives the cinnamic acid derivative (V). This is then coupled to the tetrahydropyranyl-protected hydroxylamine (VI) by means of EDC/HOBt to furnish (VII). The tetrahydropyranyl hydroxamate (VII) is finally deprotected under acidic conditions to produce the title compound.

参考文献中间体

【1】 Bouchain, G.; Leit, S.; Frechette, S.; et al.; Development of potential antitumor agents. Synthesis and biological evaluation of a new set of sulfonamide derivatives as histone deacetylase inhibitors. J Med Chem 2003, 46, 5, 820.
【2】 Lavoie, R.; Bouchain, G.; Frechette, S.; et al.; Design and synthesis of a novel class of histone deacetylase inhibitors. Bioorg Med Chem Lett 2001, 11, 21, 2847.
【3】 Delorme, D.; Ruel, R.; Lavoie, R.; Thibault, C.; Abou-Khalil, E. (MethylGene Inc.); Inhibitors of histone deacetylase. EP 1233958; JP 2003514904; WO 0138322 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	26393	4-iodoaniline; 4-iodophenylamine	540-37-4	C₆H₆IN	详情	详情
(II)	47469	3,4-dimethoxybenzenesulfonyl chloride	23095-31-0	C₈H₉ClO₄S	详情	详情
(III)	63287	N-(4-iodophenyl)-3,4-dimethoxybenzenesulfonamide		C₁₄H₁₄INO₄S	详情	详情
(IV)	19139	acrylic acid	79-10-7	C₃H₄O₂	详情	详情
(V)	63288	(E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoic acid		C₁₇H₁₇NO₆S	详情	详情
(VI)	52106	2-(aminooxy)tetrahydro-2H-pyran; O-tetrahydro-2H-pyran-2-ylhydroxylamine		C₅H₁₁NO₂	详情	详情
(VII)	63289	(E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-N-(tetrahydro-2H-pyran-2-yloxy)-2-propenamide		C₂₂H₂₆N₂O₇S	详情	详情

合成路线2

In a different method, p-aminocinnamic acid (I) is acylated by 3,4-dimethoxybenzenesulfonyl chloride (II) to yield sulfonamide (III). After activation of the carboxylic acid (III) with oxalyl chloride, the resultant acid chloride (IV) is condensed with hydroxylamine to furnish the target hydroxamic acid.

参考文献中间体

【1】 Harris, C.J.; Finn, P.W.; Kalvinsh, I.; Piskunova, I.; Starchenkov, I.; Watkins, C.J.; Romero-Martin, M.-R.; Moore, K.G.; Ritchie, J.; Loza, E.; Dikovska, K.; Gailite, V.; Vorona, M.; Adrianov, V.; Duffy, J.E.S. (TopoTarget A/S); Carbamic acid cpds. comprising a sulfonamide linkage as HDAC inhibitors. EP 1328510; WO 0230879 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	63290	(E)-3-(4-aminophenyl)-2-propenoic acid		C₉H₉NO₂	详情	详情
(II)	47469	3,4-dimethoxybenzenesulfonyl chloride	23095-31-0	C₈H₉ClO₄S	详情	详情
(III)	63288	(E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoic acid		C₁₇H₁₇NO₆S	详情	详情
(IV)	63291	(E)-3-(4-{[(3,4-dimethoxyphenyl)sulfonyl]amino}phenyl)-2-propenoyl chloride		C₁₇H₁₆ClNO₅S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)