(2S)-1-(3-chlorophenyl)-2-hydroxypropan-1-one

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Compound (S)-10a was synthesized by a procedure similar to that described for (R)-10a using (Z)-tert-butyl(1-(3-chlorophenyl)prop-1-enyloxy)dimethylsilane (9a, 8.8 g, 0.031 mol), AD-mix-α (43.5 g), and CH3SO2NH2 (3a, 3 g, 0.032 mol) in tert-butyl alcohol-water (120 mL:120 mL). The reaction mixture was quenched with sodium sulfite (31.1 g). After purification, 4.51 g (78%) of the (S)-10a was isolated. Characterization data is similar with data reported in Fang, Q. K.; Han, Z.; Grover, P.; Kessler, D.; Senanayake, C. H.; Wald, S. A., Tetrahedron: Asymmetry 2000, 11, 3659-3663. Compound (S)-10a was synthesized by a procedure similar to The reaction mixture was quenched with sodium sulfite (31.1 g) After purification, 4.51 g (78%) of the (S)-10a was isolated

Conditions: temp:-50.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Following the procedure described for (2S,3S)-4a, a sample of (S)-1-(3-Chlorophenyl)-2-hydroxypropan-1-one ((S)-10a, 4.5 g, 0.024 mol), was dissolved in CH2Cl2 (75 mL) and treated with Proton sponge (6.3 g) and cooled to −50° C. Next, triflic anhydride (4.5 mL, 32 mmol) was added slowly, and the reaction mixture was stirred at 0° C. for an additional hour. The resulting orange slurry was transferred by syringe to another flask containing a solution of 2-amino-2-methyl-1-propanol, (4.7 g, 0.052 mol) in CH3CN. After purification, 3.3 g (78%) of the (2R,3R)-4a was isolated and converted to 2.7 g of the Hemi-L-tartrate salt (>99% ee): mp 128-131° C.; [α]23D −13.0° (c 0.79, CH3OH). Characterization data is similar to data reported in Fang, Q. K. et al., Tetrahedron: Asymmetry 2000, 11, 3659-3663. The resulting orange slurry was transferred by syringe to another flask After purification, 3.3 g (78%) of the (2R,3R)-4a was isolated

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of (R)-3′-chloro-2-hydroxyl-propiophenone (300 mg) in CH2Cl2 (6 mL) at −78° C. was added trifluoromethanesulfonic anhydride (0.5 g), followed by addition of 2,6-lutidine (0.26 g). The reaction mixture was allowed to warm to −40° C. and stirred at this temperature for 40 minutes. 2-Amine-2-methyl-1-propanol (0.4 g, 2.5 eq) was added, and stirred for 2 hours at −40° C. The reaction mixture was warmed to room temperature and stirred overnight. It was extracted with CH2Cl2 (10 mL). The extract was washed with NaHCO3, water, and brine, concentrated to give a residue. The final product was purified by chromatography eluted with CH3CN (180 mg, e.e.>99%). 1H NMR (CDCl3) δ 0.78 (d, 3H), 1.1 (s, 3H), 1.4 (s, 3H), 3.2 (q, 1H), 3:4 (d, 1H), 3.8 (d, 2H), 7.2-7.65 (m, 4H). [a]=+66°(c=1, EtOH). (5,5)-hydroxybupropion free base was treated with HCl in diethyl ether to give its HCl salt. [a]=±30.6°(c=1, EtOH). 1H NMR (DMSO-d6) δ 1.0 (d, 3H), 1.32 (s, 3H), 1.56 (s, 3H), 3.4 (s, 1H), 3.4 (d, 1H), 4.0 (d, 1H), 7.5 (m, 5H), 8.8 (s, 1H), 10.1 (s, 1H). e.e. 99.4% as determined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm, hexane/ethanol/diethylamine (98:2:0.1). (R,R)-hydroxybupropion was prepared from (S)-3′-chloro-2-hydroxyl-propiophenone with 97% e.e. as determined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm, hexane/ethanol/diethylamine (98:2:0.1).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: (S,S)-Iiydroxybupropion: To a solution of (R)-3′-chloro-2-hydroxyl-propiophenone (300 mg) in CH2Cl2 (6 mL) at −78° C. was added trifluoromethanesulfonic anhydride (0.5 g), followed by addition of 2,6-lutidine (0.26 g). The reaction mixture was allowed to warm to −40° C. and stirred at this temperature for 40 minutes. 2-Amine-2-methyl-1-propanol (0.4 g, 2.5 eq) was added, and stilTed for 2 hours at −40° C. The reaction mixture was warmed to room temperature and stirred overnight. It was extracted with CH2Cl2 (10 mL). The extract was washed with NaHCO3, water, and brine, concentrated to give a residue. The final product was purified by chromatography eluted with CH3CN (180 mg, e.e.>99%). 1H NMR (CDCl3) δ0.78 (d, 3H), 1.1 (s, 3H), 1.4 (s, 3H), 3.2 (q, 1H), 3:4 (d, 1H), 3.8 (d, 2H), 7.2-7.65 (m, 4H). [α]=+66°(c=1, EtOH). (S,S)-hydroxybupropion free base was treated with HCl in diethyl ether to give its HCl salt. [α]=+30.6°(c=1, EtOH). 1H NMR (DMSO-d6) δ1.0 (d, 3H), 1.32 (s, 3H), 1.56 (s, 3H), 3.4 (s, 1H), 3.4 (d, 1H), 4.0 (d, 1H), 7.5 (m, 5H), 8.8 (s, 1H), 10.1 (s, 1H). ee 99.4% as determined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm, hexane/ethanol/diethylamine (98:2:0.1). (R,R)-hydroxybupropion was prepared from (S)-3′-chloro-2-hydroxyl-propiophenone with 97% e.e. as determined by HPLC with chiral column, ChiralCEl GD. 4.6×250 mm, 10 nm, hexane/ethanol/diethylamine (98:2:0.1).