Marimastat, TA-2516, BB-2516, -Drug Synthesis Database

【结构式】

【药物名称】Marimastat, TA-2516, BB-2516

【化学名称】N1-[2,2-Dimethyl-1(S)-(N-methylcarbamoyl)propyl]-N4,3(S)-dihydroxy-2(R)-isobutylsuccinamide
　　　　　　3(R)-[N-[2,2-Dimethyl-1(S)-(N-methylcarbamoyl)propyl]carbamoyl]-2(S)-hydroxy-5-methylhexanohydroxamic acid
　　　　　　N2-[3(S)-Hydroxy-4-(N-hydroxyamino)-2(R)-isobutylsuccinyl]-N1-methyl-L-tert-leucinamide

【CA登记号】154039-60-8

【分子式】C₁₅H₂₉N₃O₅

【分子量】331.41548

【开发单位】British Biotech (Originator), Schering-Plough (Licensee), Tanabe Seiyaku (Licensee)

【药理作用】Breast Cancer Therapy, Gastric Cancer Therapy, Lung Cancer Therapy, Oncolytic Drugs, Pancreatic Cancer Therapy, Angiogenesis Inhibitors, Matrix Metalloproteinase Inhibitors

合成路线1 合成路线2

合成路线1

Treatment of butanedioate derivative (I) with methallyl iodide (II) and LDA in THF affords alkene (III), which is then reduced by hydrogenation over Pd/C and subjected to saponification by means of KOH in dioxane to yield succinic acid (IV). Protection of (IV) with 2,2-dimethoxypropane (V) and p-TsOH in DMF provides derivative (VI), which is then coupled with pentafluorophenol (VII) by using EDC in CH2Cl2 to furnish activated ester (VIII). Displacement of the pentafluorophenol moiety of (VIII) by treatment with L-tert-leucine methylamide (IX) in DMF gives methylamide derivative (X), which is deprotected with THF and HCl and condensed with O-benzylhydroxylamine (XI) by means of EDC to afford derivative (XII). Finally, (XII) is debenzylated by hydrogenation over Pd/C in EtOH to give the target compound.

参考文献中间体

【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983.
【2】 Dickens, J.P.; Crimmin, M.J.; Beckett, R.P. (British Biotech plc); Natural amino acid derivs. as metalloproteinase inhibitors. EP 0651738; EP 0651739; GB 2268933; GB 2268934; JP 1995509460; JP 1998204081; WO 9402446; WO 9402447 .

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)	43782	diisopropyl (2S)-2-hydroxybutanedioate		C₁₀H₁₈O₅	详情	详情
(II)	43783	3-iodo-2-methyl-1-propene		C₄H₇I	详情	详情
(III)	43784	diisopropyl (2S,3R)-2-hydroxy-3-(2-methyl-2-propenyl)butanedioate		C₁₄H₂₄O₅	详情	详情
(IV)	43785	(2S,3R)-2-hydroxy-3-isobutylbutanedioic acid		C₈H₁₄O₅	详情	详情
(V)	10722	1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane	77-76-9	C₅H₁₂O₂	详情	详情
(VI)	43786	(2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoic acid		C₁₁H₁₈O₅	详情	详情
(VII)	22662	2,3,4,5,6-pentafluorophenol	771-61-9	C₆HF₅O	详情	详情
(VIII)	43787	2,3,4,5,6-pentafluorophenyl (2R)-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanoate		C₁₇H₁₇F₅O₅	详情	详情
(IX)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(X)	43788	(2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide		C₁₈H₃₂N₂O₅	详情	详情
(XI)	14640	O-benzylhydroxylamine; 1-[(aminooxy)methyl]benzene	622-33-3	C₇H₉NO	详情	详情
(XII)	43789	(2S,3R)-N(1)-(benzyloxy)-N(4)-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-hydroxy-3-isobutylbutanediamide		C₂₂H₃₅N₃O₅	详情	详情

合成路线2

An improved method for the obtaining of the desired product is the direct coupling of carboxylic acid derivative (VI) with L-tert-leucine methylamide (IX) by using EDC in CH2Cl2 to furnish methylamide derivative (X), followed by final treatment of (X) with hydroxylamine (NH2OH) in THF.

参考文献中间体

【1】 Davenport, R.J.; Watson, R.J.; An improved synthesis of the broad spectrum matrix metalloprotease inhibitor marimastat. Tetrahedron Lett 2000, 41, 41, 7983.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	43876	(1S,2S,3R,4S,7R,9S,10S,12R,15S)-4,12-bis(acetoxy)-15-([(2R,3S)-3-(benzoylamino)-3-phenyl-2-[(triethylsilyl)oxy]propanoyl]oxy)-1-hydroxy-10,14,17,17-tetramethyl-11-oxo-9-[[(2,2,2-trichloroethoxy)carbonyl]oxy]-6-oxatetracyclo[11.3.1.0(3,10).0(4,7)]h		C₅₆H₆₆Cl₃NO₁₆Si	详情	详情
(IX)	18843	(2S)-2-amino-N,3,3-trimethylbutanamide	89226-12-0	C₇H₁₆N₂O	详情	详情
(X)	43788	(2R)-N-[(1S)-2,2-dimethyl-1-[(methylamino)carbonyl]propyl]-2-[(4S)-2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl]-4-methylpentanamide		C₁₈H₃₂N₂O₅	详情	详情

Extended Information