Thionyl Chloride → (-)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride

HRID 875298Notes

Reaction equation

CC[C@H]([C@H](CN(C)C)C)C1C=CC=C(O)C=1.[ClH:17].[CH3:18][N:19]([CH3:35])[CH2:20][C@H:21]([CH3:34])[C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)(O)[CH2:23][CH3:24].S(Cl)([Cl:38])=O>>[ClH:38].[Cl:17][C@@:22]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=1)([CH2:23][CH3:24])[C@@H:21]([CH3:34])[CH2:20][N:19]([CH3:35])[CH3:18]

Participants

Reactant 3

HCID 24386Thionyl Chloride

HCID 9838022Tapentadol

HCID 67043376(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride

Product 1

HCID 67043315(-)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride

Procedure

According to the '737 patent, tapentadol is prepared by the reaction of (−)-(2S,3S)-1-dimethylamino-3-(3-methoxyphenyl)-2-methylpentan-3-ol hydrochloride with thionyl chloride to produce (−)-(2S,3S)-[3-chloro-3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride, followed by subsequent removal of the ‘Cl’ substituent by treatment with zinc borohydride, zinc cyanoborohydride or tin cyanoborohydride, to produce (−)-(2R,3R)-[3-(3-methoxyphenyl)-2-methylpentyl]-dimethylamine hydrochloride. The (−)-(2R,3R)-[3-(3-methoxy phenyl)-2-methylpentyl]-dimethylamine hydrochloride is then converted to (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methylpropyl)-phenol (tapentadol) by reacting with concentrated hydrobromic acid at reflux.

Sources & evidence

ORD record: ord-2814d38eab46421ca8ae269629dc3825
Source dataset: uspto-grants-2015_03
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08981154B2

Reaction notes

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