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CAPLUS COPYRIGHT 2013 ACS
|Patent Number: ||US 8299305 |
|Title: ||Process for preparation of atomoxetine |
|Inventor(s): ||Chen, Bo-Fong; Li, Yan-Wei; Yeh, Jinun-Ban; Wong, Wei-Chyun |
|Patent Assignee(s): ||SCI Pharmtech, Inc., Taiwan |
|Source: ||U.S. Pat. Appl. Publ., 6pp. CODEN: USXXCO |
|Language: ||English |
This invention provides a process for the preparation of atomoxetine, which comprises Mannich reaction of acetophenone, formaldehyde, and methylhydroxylamines HNMe(OR) [wherein R is H, alkyl, or aryl] to give the corresponding amino ketones Ph(C=O)(CH2)2NMe(OR) [wherein R is the same as defined above], followed by enantioselective reduction to afford the intermediate (R)-PhCH(OH)(CH2)2NMe(OR) [wherein an absolute configuration of a chiral center is R], which undergoes reductive N,O-cleavage reaction and ether formation with 2-fluorotoluene. For example, Mannich reaction of N,O-dimethylhydroxylamine hydrochloride, paraformaldehyde, and acetophenone gave 3-(N-methoxy-N-methylamino)-1-phenyl-1-propanone hydrochloride salt in 87.6% yield, followed by RuCl2-((S)-DMSEGPHOS)((S)-DAIPEN)-catalyzed asym. hydrogenation to afford (R)-3-(N-methoxy-N-methylamino)-1-phenyl-1-propanol in 98.8% yield and 99% ee, which underwent Raney-nickel-catalyzed reductive N,O-cleavage reaction and etherification with 2-fluorotoluene. The present invention provides an improved and industrially advantageous method for preparing atomoxetine.
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