-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-Methyl-N-(2-methyl-1H-indol-3-ylmethyl)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)-2(E)-propenamide

【CA登记号】335029-51-1

【分子式】C₂₂H₂₂N₄O₂

【分子量】374.44624

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antibacterial Drugs, ANTIINFECTIVE THERAPY, Enoyl-(acyl-carrier protein) Reductase Fabl Inhibitors

合成路线1 合成路线2 合成路线3

合成路线1

2-Methyl-3-(methylaminomethyl)indole (II) was obtained by the reductive amination of indole aldehyde (I) with methylamine. Acylation of amine (II) with acryloyl chloride (III) furnished the corresponding acrylamide (IV).

参考文献中间体

【1】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 .

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)	56109	2-Meethylindole-3-carboxaldehyde		C₁₀H₉NO	详情	详情
(II)	56110	N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N-methyl(2-methyl-1H-indol-3-yl)methanamine		C₁₁H₁₄N₂	详情	详情
(III)	11577	Acryloyl chloride; Acrylyl chloride;2-Propenoyl chloride	814-68-6	C₃H₃ClO	详情	详情
(IV)	56111	N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]acrylamide		C₁₄H₁₆N₂O	详情	详情

合成路线2

Reduction of 2-aminonicotinic acid (V) by means of LiAlH4 afforded amino alcohol (VI). Subsequent bromination of (VI) with N-bromosuccinimide gave 2-amino-5-bromo-3-(hydroxymethyl)pyridine (VII). Alcohol (VII) was then converted to the bromomethyl pyridine derivative (VIII) by treatment with concentrated hydrobromic acid. Condensation of bromo amine (VIII) with dimethyl malonate led to the naphthyridine carboxylate (IX). Basic hydrolysis of the methyl ester of (IX), followed by decarboxylation under acidic conditions, gave rise to naphthyridinone (X).

参考文献中间体

【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690.
【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(V)	55933	2-Aminonicotinic acid; 2-Aminopyridine-3-carboxylic acid	5345-47-1	C₆H₆N₂O₂	详情	详情
(VI)	56112	(2-amino-3-pyridinyl)methanol	23612-57-9	C₆H₈N₂O	详情	详情
(VII)	56113	(2-amino-5-bromo-3-pyridinyl)methanol		C₆H₇BrN₂O	详情	详情
(VIII)	56114	5-bromo-3-(bromomethyl)-2-pyridinamine; 5-bromo-3-(bromomethyl)-2-pyridinylamine	335033-38-0	C₆H₆Br₂N₂.HBr	详情	详情
(IX)	56115	methyl 6-bromo-2-oxo-1,2,3,4-tetrahydro[1,8]naphthyridine-3-carboxylate	335031-10-2	C₁₀H₉BrN₂O₃	详情	详情
(X)	56116	6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one		C₈H₇BrN₂O	详情	详情

合成路线3

The title compound was obtained from the bromo naphthyridinone (X) by two related methods. Palladium-catalyzed Heck coupling of bromide (X) with acrylamide (IV) yielded directly the desired naphthyridinyl acrylamide. Alternatively, bromo naphthyridinone (X) was subjected to Heck coupling with tert-butyl acrylate (XI) to give adduct (XII). After acidic cleavage of the tert-butyl ester group of (XII), the resultant naphthyridinyl acrylic acid (XIII) was coupled to the indolylmethyl amine (II) to furnish the desired amide.

参考文献中间体

【1】 Seefeled, M.A.; et al.; Discovery and characterization of highly potent naphthyridine-based FabI inhibitors with in vivo activity. 41st Intersci Conf Antimicrob Agents Chemother (Dec 16 2001, Chicago) 2001, Abst F-1690.
【2】 Uzinskas, I.N.; Miller, W.H.; Newlander, K.A.; Jakas, D.R.; Seefeld, M.A.; DeWolf, W.E. Jr. (GlaxoSmithKline Inc.); Fab I inhibitors. EP 1226138; WO 0127103 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	56110	N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]amine; N-methyl(2-methyl-1H-indol-3-yl)methanamine		C₁₁H₁₄N₂	详情	详情
(IV)	56111	N-methyl-N-[(2-methyl-1H-indol-3-yl)methyl]acrylamide		C₁₄H₁₆N₂O	详情	详情
(X)	56116	6-bromo-3,4-dihydro[1,8]naphthyridin-2(1H)-one		C₈H₇BrN₂O	详情	详情
(XI)	12760	tert-butyl acrylate	1663-39-4	C₇H₁₂O₂	详情	详情
(XII)	56117	tert-butyl (E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoate		C₁₅H₁₈N₂O₃	详情	详情
(XIII)	56118	(E)-3-(7-oxo-5,6,7,8-tetrahydro[1,8]naphthyridin-3-yl)-2-propenoic acid		C₁₁H₁₀N₂O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)