Formaldehyde → 3-(Dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one--hydrogen chloride (1/1)

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WO2008012047 describes yet another method for the preparation of tapentadol, wherein 1-(3-methoxyphenyl)propan-1-one is reacted with dimethyl amine hydrochloride and paraformaldehyde under Mannich reaction condition to get 3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one hydrochloride, which after reacting with sodium hydroxide is reacted with (2R,3R)—O,O′-dibenzoyl tartaric acid monohydrate to get (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one L-(−)-dibenzoyltartarate. The dibenzoyl tartrate salt is further reacted with diethyl amine to isolate keto compound (S)-3-(dimethylamino)-1-(3-methoxyphenyl)-2-methylpropan-1-one. The keto compound is reacted with ethyl magnesium halide under Grignard condition to isolate the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol. The hydrochloride salt of the compound (2S,3R)-1-(dimethylamino)-3-(3-methoxyphenyl)-2-methylpentan-3-ol on reaction with aqueous hydrochloric acid undergoes dehydration yielding the compound (R)-3-(3-methoxyphenyl)-N,N,2-trimethylpent-3-en-1-amine, which after hydrogenation using homogeneous or heterogeneous catalyst results in the mixture of compound (2R,3R))-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine and (2R,3S)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine having Z:E ratio of 5.5:1. The required compound (2R,3R)-3-(3-methoxyphenyl)-N,N,2-trimethylpentan-1-amine is separated from the mixture by making hydrochloride salt. The isolated salt is dissolved in methane sulphonic acid and treated with methionine to get the compound 3-[(2R,3R)-1-(dimethylamino)-2-methylpentan-3-yl]phenol of Formula-I, which is isolated as hydrochloride salt of tapentadol hydrochloride.

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