116539-55-0Relevant articles and documents
An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers
Wheeler,Kuo
, p. 213 - 223 (1995)
Two 14C-isotopomers of duloxetine HCl (S-(+)-N-methyl-3(1-naphthalenyloxy)-3(2-thiophene)propanamine hydrochloride), a potent mixed serotonin/norepinephrine Uptake inhibitor have been prepared by an asymmetric synthesis. The palladium catalyzed cross-coupling of 2-thienoyl chloride (3c) (or its [carbonyl-14C] isotopomer 3d) with vinyl tri-n-butylstannane, followed by addition of HCl afforded the key pro-chiral intermediate chloroketone (5a,b). Chiral reduction with borane in the presence of the appropriate oxazaborolidine catalyst (14a or b) provided the S-chloroalcohol (7a) and its 14C-labeled counterpart 7b or the analogous R-chloroalcohol (6). Activation of 7a,b by reaction with NaI/acetone, followed by reaction of the corresponding iodoalcohol with methylamine yielded the penultimate aminoalcohols (8a,b). Formation of the alkoxide with NaH, followed by reaction with 1-fluoronaphthalene yielded duloxetine or its 14C-labeled isotopomer 9. Alternatively, reaction of 6 with 1-naphthol-[1-14C] under Mitsunobu conditions afforded aryl-ether 10a,b, which was in turn activated by reaction with NaI/acetone Subsequent reaction of 10c,d with methylamine followed by salt formation yielded duloxetine or its naphthalene-labeled isotopomer (13) as their HCl salts.
Resolution of 3-(methylamino)-1-(2-thienyl)propan-1-ol, a new key intermediate for duloxetine, with (S)-mandelic acid
Sakai, Kenichi,Sakurai, Rumiko,Yuzawa, Atsushi,Kobayashi, Yuka,Saigo, Kazuhiko
, p. 1631 - 1636 (2003)
The resolution of racemic 3-(methylamino)-1-(2-thienyl)propan-1-ol 3, a new key intermediate for duloxetine 1, was studied. The conditions were optimized for an industrial-scale resolution of 3 by using (S)-mandelic acid 4 as a resolving agent and 2-butanol containing 2 equimolar amounts of water as a solvent. The (S)-3·(S)-4·H2O diastereomeric salt was crystallized to give pure (S)-3 with >99.9% e.e. after liberation of the amine. The absolute configuration of liberated (-)-3 was determined as (S) by X-ray crystallography.
Novel synthetic method for duloxetine intermediate
-
Paragraph 0008; 0021, (2018/09/08)
The invention provides a novel synthetic method for a duloxetine intermediate (S)-N-methyl-3-hydroxy-3-(2-thienyl)-1-propylamine (a compound 1 as described in the specification). According to the method, thiophene and succinic anhydride are used as raw materials and undergo Friedel-Crafts acylation, esterification, aminolysis, asymmetric hydrogenation, and oxidative degradation so as to obtain theduloxetine intermediate (the compound 1).
west Luo river sandbank chiral method for the preparation of intermediates
-
Paragraph 0038, (2017/03/08)
The invention relates to a preparation method of a chiral duloxetine intermediate, namely (S)-N-methyl-3-hydroxy-(2-thienyl)-1-propylamine, belonging to the technical field of drug synthesis. The preparation method comprises the following steps: reacting trans-N-methyl-3-(2-thienyl)-crotonamide with a boron compound in a solvent in the presence of a chiral catalyst, copper salt and alkali under the nitrogen protection to obtain a reaction product, and performing oxidation reduction on the reaction product to obtain (S)-N-methyl-3-hydroxy-(2-thienyl)-1-propylamine. The preparation method is easy and feasible; the prepared target product is high in yield and optical purity, low in purification difficulty and suitable for a research on scale production.