Intermediates of bupropion metabolites synthesis
a technology of intermediates and metabolites, which is applied in the preparation of amino-hyroxy compounds, carbonyl compounds, organic racemisation, etc., can solve the problems of complex array of chiral compounds, dose limitation, and racemic bupropion not being free of adverse effects
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example 1
5.1. Example 1
Synthesis of (S,S)-Hydroxybupropion
[0112] This synthesis, which follows that depicted in Scheme 5 of the Detailed Description, comprises three steps.
[0113] Z-1-(3-Chlorophenyl)-1-tert-butyldimethylsilyloxy-1-propene: A solution of LDA (33.0 mmol) in THF (100 mL) was cooled to −78° C. and HMPA (5 mL) was added. The ketone [1-(3-chlorophenyl)-propanone] (8.6 g) in THF (20 mL) was slowly added over 45 minutes to this rapidly stirring mixture. After an additional 3 minutes at −78° C., TBSCl (33.0 mL, 1.0 M in hexane) was added. This mixture was stirred at −78° C. for 5 minutes and allowed to warm to room temperature over 40 minutes. NaHCO3 (60 mL, saturated aqueous solution) was added and the mixture was extracted with CH2Cl2 (2×80 mL). The organic extracts were combined, washed with brine, dried over Mg2SO4 and concentrated to give a crude mixture. The product was purified by flash chromatography eluted with hexane / TEA (99.5 / 0.5), yielding 13.4 g product (Z / E ratio>99)....
example 2
5.2. Example 2
Synthesis of Optically Pure Hydroxybupropion
[0117] 3′-Chloro-2-bromo-propiophenone: To a solution of 3′-chloropropiophenone (50.0 g, 297 mmol) in acetonitrile (595 mL) was added bromine (16.67 mL, 327 mmol) at room temperature. The reddish-yellow solution was allowed to stir for 18 h at room temperature. The solution was concentrated in vacuo to provide a reddish solid. The crude material was dissolved in 400 mL of ethyl acetate and washed with 400 mL of water. The organic layer was dried (Na2SO4), filtered and concentrated in vacuo to give 72.6 g (98%) of crude product. 1H NMR (CDCl3) δ 1.90 (d, J=6 Hz, 3H), 5.21 (q, J=6 Hz, 1H), 7.37-7.88 (m, 3H), 7.98 (s, 1H).
[0118] 2-Hydroxy-2-(3′-chlorophenyl)-3,5,5-trimethylmorpholine: To a solution of 3′-chloro-2-bromo-propiophenone (61.2 g, 247 mmol) in acetonitrile (752 mL) was added 2-amino-2-methyl-1-propanol (56.5 g, 630 mmol). The reaction mixture was allowed to reflux for 8 hours, then slowly cooled to room temperature....
example 3
5.3. Example 3
Synthesis of Optically Pure Dihydrobupropion
[0124] (Racemic Erythro)-Dihydrobupropion: A three-neck 1 L RBF was charged with 3.0 g (10.8 mmol) of racemic bupropion. To the flask was added 30 mL of dry toluene. The suspension was cooled to −78° C. and to it was slowly added 7.2 mL (23.7 mmol) of a 3.3 M solution of Red-Al. After stirring at −78° C. for 2 h, the reaction was allowed to slowly warm to 23° C. overnight. 5N NaOH was added to the reaction, and this stirred for 30 min. The layers were separated, and the organic layer was washed with water (100 mL). The organic layer was dried (MgSO4) and concentrated in vacua to provide 2.6 g (86%) of crude product (Erythro:Threo ratio: 15:1).
[0125] (Racemic Erythro)-Dihydrobupropion Hydrochloride: Crude erythro dihydrobupropion (2.5 g, 10.3 mmol) was dissolved in 25 mL of methyl tert-butyl ether. The solution was stirred at 0° C. as anhydrous 2N HCl in ether (7.76 mL, 15.5 mmol) was slowly added. After stirring for 1 h at ...
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