Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O瑿HCl3) under Schotten-Baumann conditions.

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O瑿HCl3) under Schotten-Baumann conditions.

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O瑿HCl3) under Schotten-Baumann conditions.

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O瑿HCl3) under Schotten-Baumann conditions.

Reformatskii reaction between 7-methoxy-1-tetralone (I) and the organozinc reagent generated from ethyl bromoacetate, followed by dehydration of the intermediate carbinol in the presence of P2O5 gives 2-(7-methoxy-1,2,3,4-tetrahydro-1-naphthylidene)acetic acid ethyl ester (II). Aromatization of compound (II) by heating with sulfur at 215 C results in the corresponding naphthalene derivative (III), which is submited to basic hydrolysis of the ethyl ester group (III) to provide 2-(7-methoxy-1-naphthyl)acetic acid (IV). After activation of (IV) with SOCl2, the crude acid chloride is treated with ammonium hydroxide to produce amide (V), which by direct reduction with LiAlH4 furnishes amine (VI) in low yields. An alternative procedure consists of the dehydration of amide (V) with trifluoroacetic anhydride to afford nitrile (VII), which is then reduced to the desired amine (VI) by catalytic hydrogenation. Finally, agomelatine is obtained by reaction of amine (VI) with acetyl chloride in pyridine or in a biphasic medium (H2O瑿HCl3) under Schotten-Baumann conditions.