合成路线1

The reaction of 3-bromoanisole (I) with magnesium in THF gives 3-methoxyphenylmagnesium bromide (II), which is condensed with 3-bromopyridine (III) in THF by means of dichlorobis(triphenylphosphine)nickel yielding 3-(3-pyridinyl)anisole (IV). The alkylation of (IV) with propylbromide (A) in acetone at 110 C (under pressure) affords N-propyl-3-(3-methoxyphenyl)pyridinium bromide (V), which is reduced with H2 over Pt in methanol to give 1-propyl-3-(3-methoxyphenyl)piperidine (VI). Finally, this compound is demethylated by treatment with refluxing aqueous 48% HBr. The reduction of (IV) with H2 over Pt in methanol gives 3-(3-methoxyphenyl)piperidine (VII), which is acylated and reduced simultaneously with propionic acid (B) and NaBH4 in refluxing benzene to yield (VI), already obtained.

合成路线2

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.

合成路线3

In a different synthetic strategy, 4-formylbenzoic acid (XI) was first coupled to diethylamine by means of EDC to yield N,N-diethyl 4-formylbenzamide (XII). The intermediate iminium salt produced by condensation between aldehyde (XII) and the chiral piperazine (IX) was then isolated as the benzotriazole adduct (XIII). Displacement of the benzotriazolyl group by the Grignard reagent (XIV) produced the title diastereoisomer as the major product, which was further enriched by recrystallization from acetonitrile/water.

合成路线4