(S)-1-(3-Chlorophenyl)-2-hydroxy-1-propanone → (2R,3R)-2-(3-chlorophenyl)-3,5,5-trimethyl-2-morpholinol
Reaction equation
CCC[CH2:4][CH2:5][CH3:6].[CH2:7]([OH:9])C.C([NH:12]CC)C.[Cl:15][C:16]1[CH:17]=[C:18]([C:22](=[O:26])[C@@H:23](O)[CH3:24])[CH:19]=[CH:20][CH:21]=1>CCO>[CH3:24][C@H:23]1[NH:12][C:5]([CH3:4])([CH3:6])[CH2:7][O:9][C@:22]1([OH:26])[C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([Cl:15])[CH:17]=1Participants
Reactant 2
Product 1
Reagents, catalysts & solvents 1
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).
Sources & evidence
- ORD record
- ord-cd118750c7384083b0f2170276698afb
- Source dataset
- uspto-grants-2002_01
- Patent number
- US06342496B1
Reaction notes
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