AG-14699, AG-014447 (as free base), -Drug Synthesis Database

【结构式】

【药物名称】AG-14699, AG-014447 (as free base)

【化学名称】8-Fluoro-2-[4-(methylaminomethyl)phenyl]-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one phosphate

【CA登记号】459868-92-9, 283173-50-2 (free base), 773059-19-1 (hydrochloride), 773059-22-6 (L-tartrate), 773059-23-7 (acetate)

【分子式】C₁₉H₂₁FN₃O₅P

【分子量】421.3593

【开发单位】Cancer Research UK (GB); Pfizer (US).

【药理作用】PARP Inhibitor, Oncolytic

合成路线1 合成路线2

合成路线1

Reductive cyclization of 6-fluoro-3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester (I) by means of Zn and HCl in methanol/water gives 8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (II), which is brominated by means of Pyr/HBr/Br2 in THF/dichloromethane to afford the 2-bromo derivative (III). Condensation of the brominated compound (III) with 4-formylphenylboronic acid (IV) by means of Pd(PPh3)4 and Na2CO3 in refluxing H2O/ethanol/toluene provides 8-fluoro-2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one (V), which is finally reductocondensed with methylamine (VI) by means of NaBH4 (1). Scheme 1.

参考文献中间体

【1】 Webber, S.E., Thoresen, L.H., Tikhe, H., Canan-Koch, S.S. (Agouron Pharmaceuticals, Inc.; Cancer Research UK). Tricyclic inhibitors of poly(ADP-ribose) polymerases. CA 2360003, EP 1140936, JP 2002534523, US 6495541, WO 2000042040.

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)	65864	6-fluoro-3-(2-nitroethyl)-1H-indole-4-carboxylic acid methyl ester		C₁₂H₁₁FN₂O₄	详情	详情
(II)	65865	8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₁H₉FN₂O	详情	详情
(III)	65866	2-bromo-8-fluoro-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₁H₈BrFN₂O	详情	详情
(IV)	61564	4-Formylphenylboronic acid; 4-Formylbenzeneboronic acid; 4-Boronobenzaldehyde; Benzaldehyde-4-boronic acid; 4-Formylphenylboronic acid	87199-17-5	C₇H₇BO₃	详情	详情
(V)	65867	8-fluoro-2-(4-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one		C₁₈H₁₃FN₂O₂	详情	详情
(VI)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情

合成路线2

Reaction of 5-fluoro-2-hydroxybenzoic acid (VII) with MeOH and H2SO4 gives the corresponding methyl ester (VIII), which is treated with tetramethylammonium nitrate and TFAA to yield 5-fluoro-2-hydroxy-3-nitrobenzoic acid methyl ester (IX). Condensation of the hydroxybenzoate (IX) with the phenylacetylene derivative (X) by means of TF2O, PdCl2(PPh3)2 and TEA affords the diphenylacetylene derivative (XI). Reduction of the NO2 group of (XI) by means of Fe, HCl and NH4Cl provides the aniline derivative (XII), which is cyclized by means of CuI at 100 °C to give the indole derivative (XIII). Condensation of indole (XIII) with N-(2-nitrovinyl)-N,N-dimethylamine (XIV) by means of TFA yields the 3-(2-nitrovinyl)indole derivative (XV), which is reduced with NaBH4 to afford the 3-(2-nitroethyl)indole derivative (XVI). Reductive cyclization of indole (XVI) by means of H2 over RaNi in AcOH provides the tricyclic compound (XVII), which is finally decarboxylated by means of HBr/AcOH (2). Scheme 2.

参考文献中间体

【2】 Ma, C., Nayyar, N., Stankovic, N.S. (Pfizer Inc.; Cancer Research Technology Ltd.). Method of preparing poly(ADP-ribose) polymerases inhibitors. CA 2580833, EP 1794163, JP 2008513538, US 2006063926, US 7323562, WO 2006033003.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	65868	5-Fluorosalicylic acid; 5-Fluoro-2-hydroxybenzoic acid	345-16-4	C₇H₅FO₃	详情	详情
(VIII)	65869	Methyl 5-Fluoro-2-Hydroxybenzoate; Methyl 5-Fluorosalicylate	391-92-4	C₈H₇FO₃	详情	详情
(IX)	65870	5-fluoro-2-hydroxy-3-nitrobenzoic acid methyl ester; Methyl 5-fluoro-2-hydroxy-3-nitrobenzoate	880160-63-4	C₈H₆FNO₅	详情	详情
(X)	65871			C₁₂H₁₃NO₂	详情	详情
(XI)	65872			C₂₀H₁₇FN₂O₆	详情	详情
(XII)	65873			C₂₀H₁₉FN₂O₄	详情	详情
(XIII)	65874			C₂₀H₁₉FN₂O₄	详情	详情
(XIV)	65875	(E)-N,N-dimethyl-2-nitroethenamine;	1190-92-7	C₄H₈N₂O₂	详情	详情
(XV)	65876			C₂₂H₂₀FN₃O₆	详情	详情
(XVI)	65877			C₂₂H₂₂FN₃O₆	详情	详情
(XVII)	65878			C₂₁H₂₀FN₃O₃	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)