Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.

Reaction of 3-bromoanisole (I) with Mg turnings in refluxing THF provides Grignard reagent (II), which is converted into tramadol base (VI) by treatment with Mannich base (III) (obtained in turn via Mannich reaction of cyclohexanone (IV) with dimethylamine hydrochloride and formaldehyde). Alternatively, the transformation of (II) into (VI) can be performed by first treatment of (II) with additive TDA-1 (tris(2-(2-methoxyethoxy)ethylamine) to form complex (V), followed by addition of Mannich base (III). Alternatively, the additive used can be replaced by the following reagents: 1-methylimidazole, diglyme, 4-methylmorpholine, diazabicyclo(5.4.0)undec-7-ene, triethylamine, N,N,N',N',N''-pentamethyldiethylenetriamine, pyridine, 1,2-dimethylimidazole, 1-methylpyrrolidine, 1,4-dimethylpiperazine, pyrazine, S-(-)-nicotine, 1-methylpyrrole, 4-methoxypyridine, quinoline, 1,5-diazabicyclo(4.3.0)non-5-ene, 1-benzylimidazole or 1-butylimidazole. Once tramadol base (VI) is obtained, treatment with HCl in acetonitrile or isopropanol allows formation of the corresponding hydrochloride salt as an isomeric mixture of the trans/cis forms (VII). The desired isomer cis-(XII) can be obtained by many different routes: (a) recrystallization of (VII) from acetonitrile. (b) recrystallization of (VII) from dioxane/H2O. (c) recrystallization of (VII) from isopropanol. (d) heating of the mixture (VI) with p-toluenesulfonic acid or phosphoric acid or formic acid, followed by a recrystallization process. (e) treatment of (VII) with acetic anhydride in DMF, followed by crystallization from isopropanol. (f) treatment of (VII) with thionyl chloride in chlorobenzene, followed by crystallization from isopropanol. (g) treatment of (VII) with trifluoroacetic acid and sodium azide, followed by basification with K2CO3 and final recrystallization from isopropanol. (h) formation of tramadol hydrate (VIII) by treatment with water in diisopropyl ether, followed by hydrochloride formation with HCl. (i) formation of tramadol hydrobromide (IX) by treatment with hydrobromic acid, filtration of the solid obtained, obtaining of the free base by treatment with NaOH (5) and final conversion into the hydrochloride form by means of HCl. (j) formation of tramadol hydroiodide (X) by treatment with hydroiodic acid, filtration of the solid obtained and final conversion into the hydrochloride form by means of HCl.