-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】5-Bromo-2-[N-[4-(2-butynyloxy)phenylsulfonyl]-N-methylamino]-3-(4-methylpiperazin-1-ylmethyl)benzohydroxamic acid

【CA登记号】

【分子式】C₂₄H₂₉BrN₄O₅S

【分子量】565.49053

【开发单位】Amgen (Originator), Wyeth Pharmaceuticals (Originator)

【药理作用】Antiarthritic Drugs, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, TNF-alpha-Converting Enzyme (TACE) Inhibitors

合成路线1 合成路线2

合成路线1

Sulfonylation of methyl 5-bromo-3-methylanthranilate (I) with acid chloride (II) affords sulfonamide (III). Subsequent alkylation of the sulfonamide N of (III) with iodomethane and K2CO3 yields (IV). After protection of the phenolic hydroxyl group of (IV) as the silyl ether (V), benzylic halogenation with N-bromosuccinimide furnishes bromide (VI). Displacement of its benzylic bromide with 1-methylpiperazine (VII) occurs with concomitant desilylation to give (VIII). Mitsunobu coupling of phenol (VIII) with 2-butyn-1-ol (IX) leads to the propargyl ether (X). The methyl ester group of (X) is then hydrolyzed under alkaline conditions to furnish the carboxylic acid (XI).

参考文献中间体

【1】 Levin, J.I.; Chen, J.M.; Du, M.T.; Nelson, F.C.; Killar, L.M.; Skala, S.; Sung, A.; Jin, G.; Cowling, R.; Barone, D.; March, C.J.; Mohler, K.M.; Black, R.A.; Skotnicki, J.S.; Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group. Bioorg Med Chem Lett 2002, 12, 8, 1199.

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)	60447	methyl 2-amino-5-bromo-3-methylbenzoate		C₉H₁₀BrNO₂	详情	详情
(II)	54660	4-hydroxybenzenesulfonyl chloride		C₆H₅ClO₃S	详情	详情
(III)	60448	methyl 5-bromo-2-{[(4-hydroxyphenyl)sulfonyl]amino}-3-methylbenzoate		C₁₅H₁₄BrNO₅S	详情	详情
(IV)	60449	methyl 5-bromo-2-[[(4-hydroxyphenyl)sulfonyl](methyl)amino]-3-methylbenzoate		C₁₆H₁₆BrNO₅S	详情	详情
(V)	60450	methyl 5-bromo-2-[[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)sulfonyl](methyl)amino]-3-methylbenzoate		C₂₂H₃₀BrNO₅SSi	详情	详情
(VI)	60451	methyl 5-bromo-3-(bromomethyl)-2-[[(4-{[tert-butyl(dimethyl)silyl]oxy}phenyl)sulfonyl](methyl)amino]benzoate		C₂₂H₂₉Br₂NO₅SSi	详情	详情
(VII)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(VIII)	60452	methyl 5-bromo-2-[[(4-hydroxyphenyl)sulfonyl](methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoate		C₂₁H₂₆BrN₃O₅S	详情	详情
(IX)	42514	2-butyn-1-ol	764-01-2	C₄H₆O	详情	详情
(X)	60453	methyl 5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoate		C₂₅H₃₀BrN₃O₅S	详情	详情
(XI)	60454	5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoic acid		C₂₄H₂₈BrN₃O₅S	详情	详情

合成路线2

Acid (XI) is then activated as the corresponding acid chloride (XII) upon treatment with oxalyl chloride in the presence of DMF. Finally, reaction of acid chloride (XII) with hydroxylamine leads to the title hydroxamic acid.

参考文献中间体

【1】 Levin, J.I.; Chen, J.M.; Du, M.T.; Nelson, F.C.; Killar, L.M.; Skala, S.; Sung, A.; Jin, G.; Cowling, R.; Barone, D.; March, C.J.; Mohler, K.M.; Black, R.A.; Skotnicki, J.S.; Anthranilate sulfonamide hydroxamate TACE inhibitors. Part 2: SAR of the acetylenic P1' group. Bioorg Med Chem Lett 2002, 12, 8, 1199.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	60454	5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoic acid		C₂₄H₂₈BrN₃O₅S	详情	详情
(XII)	60455	5-bromo-2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)amino]-3-[(4-methyl-1-piperazinyl)methyl]benzoyl chloride		C₂₄H₂₇BrClN₃O₄S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)