Indanone, Indacrinic acid, Indacrinone, MK-196-药物合成数据库

【药物名称】Indanone, Indacrinic acid, Indacrinone, MK-196

化学结构式(Chemical Structure):

参考文献No.	47604
标题:	Substituted indanones
作者:	Cragoe, E.J. Jr.; Woltersdorf, O.W. Jr. (Merck & Co., Inc.)
来源:	DE 2448454; ES 430900; FR 2247218; GB 1474459

合成路线图解说明: 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.

合成路线图解说明: 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.

参考文献No.	63637
标题:	MK 196
作者:	Casta馿r, J.; Chatterjee, S.S.
来源:	Drugs Fut 1977,2(3),179

合成路线图解说明: 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.

合成路线图解说明: 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.