Indanone, Indacrinic acid, Indacrinone, MK-196

茚达立酮Chemical Name: 6,7-Dichloro-2-methyl-2-phenyl-1-oxo-5-(indanyloxy)acetic acid
CAS No. 57296-63-6
项目整合开发状态: Biological Testing
项目研究机构: Merck Sharp & Dohme (Originator)
合成路线:The condensation of 2,3-dichloroanisole (I) with phenylacetyl chloride (A) by means of AlCl3 in CS2 gives 2,3-dichloro-4-phenylacetylanisole (II),which by reaction with bis(dimethylamino)methane (B) in acetic anhydride is converted into 2,3-dichloro-4-(2-phenylacryloyl)anisole (III).The cyclization of (III) by means of H2SO4 yields 6,7-dichloro-2-phenyl-5-methoxy-1-indanone (IV),which by demethylation with pyridine hydrochloride at 190 C yields 6,7-dichloro-2-phenyl-5-hydroxy-1-indadone (V).The treatment of the phenol (V) with iodoacetic acid (C) and K2CO3 in acetone affords 6,7-dichloro-2-phenyl-1-oxo-5-indanyloxyacetic acid (VI),which is finally methylated with methyl iodide and NaH in DMF.

合成路线:The condensation of 2,3-dichloroanisole (I) with isobutyryl chloride (D) by means of AlCl3 in CH2Cl2 gives 2',3'-dichloro-4'-methoxyisobutyrophenone (VII),which is brominated with Br2 in acetic acid yielding 2-bromo-2',3'-dichloro-4'-methoxyisobutyrophenone (VIII).The dehydrobromination of (VIII) with LiBr in DMF affords (IX),which is cyclized with H2SO4 giving 6,7-dichloro-2-methyl-5-methoxy-1-indanone (X).The phenylation of (X) with diphenyliodonium chloride (E) and potassium tert-butoxide in tert-butanol gives 6,7-dichloro-2-methyl-2-phenyl-5-methoxy-1-indanone (XI),which is demethylated with pyridine hydrochloride at 190 C yielding 6,7-dichloro-2-methyl-2-phenyl-5-hydroxy-1-indanone (XII).Finally,(XII) is treated first with ethyl bromoacetate (G) and K2CO3 in DMF,and then with KOH in hot water-methanol.The phenol (XII) can also be treated with chloroacetonitrile (H) and K2CO3 in acetone to give 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxyacetonitrile (XIII),which is finally hydrolyzed with H2SO4 in acetic acid.The phenol (XII) can also be condensed with diethyl bromomalonate (F) by means of NaH in dimethoxyethane giving diethyl 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonate (XIV),which is hydrolyzed with Na2CO3 in refluxing ethanol yielding 6,7-dichloro-2-methyl-2-phenyl-1-oxo-5-indanyloxymalonic acid (XV).Finally,this acid is decarboxylated by heating at 150 C.