116539-55-0Relevant academic research and scientific papers
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.
Chemoenzymatic synthesis of duloxetine and its enantiomer: Lipase-catalyzed resolution of 3-hydroxy-3-(2-thienyl) propanenitrile
Kamal, Ahmed,Khanna, G. B. Ramesh,Ramu,Krishnaji
, p. 4783 - 4787 (2003)
An efficient and facile chemoenzymatic synthesis of duloxetine by lipase mediated resolution of 3-hydroxy-3-(2-thienyl)propanenitrile has been achieved. This process also describes an enantioconvergent synthesis of duloxetine via a Mitsunobu reaction.
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.
Method for synthesizing (S)-3-methylamino-1-(thiophene-2-yl) propyl alcohol
-
Paragraph 0040-0042; 0045-0047, (2018/04/21)
The invention discloses a method for synthesizing (S)-3-methylamino-1-(thiophene-2-yl) propyl alcohol. The method is characterized by comprising the following steps: taking 3-methylamino-1-(thiophene-2-yl) acetone as a raw material in an environment of alkali and solvents, carrying out a catalytic hydrogenation reaction in the presence of a transition metal complex catalyst, thereby obtaining the(S)-3-methylamino-1-(thiophene-2-yl) propyl alcohol. According to the method disclosed by the invention, the high-purity product can be obtained by the one-step catalytic hydrogenation reaction only,the process cycle is greatly shortened, the catalyst amount is small, the production cost is low, the reaction conditions are mild, the process is stable, the conversion rate is high, the environmental pollution produced in the reaction is less, and industrialized production is facilitated.
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).
(S)- (-) - 3 - methylamino - 1 - (2 - thienyl) - 1 - propanol synthetic method
-
Paragraph 0069; 0070; 0071; 0072; 0073; 0074, (2017/08/25)
The present invention relates to a method for preparing (S)-(-)-3-methylamino-1-(2-thienyl)-1-propanol with high purity. The method comprises: taking the (S)-(-)-3-dimethylamino-1-(2-thienyl)-1-propanol as an starting material; in the presence of an organic solvent, protecting hydroxyl by a hydroxy protecting agent, then carrying out a demethylation reaction; and finally, carrying out a hydroxyl de-protection reaction in a strong alkaline environment in the presence of a hydroxyl de-protection agent, thereby obtaining a target product. According to the synthetic method, the (S)-(-)-3-methylamino-1-(2-thienyl)-1-propanol is over 99% in purity and ee value, and is over 80% in the yield, and the method is suitable for industrial production.
Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides
Chen, Xiang,Liu, Zhi-Qiang,Lin, Chao-Ping,Zheng, Yu-Guo
supporting information, p. 82 - 89 (2016/02/23)
A chemoenzymatic strategy was developed for (S)-duloxetine production employing carbonyl reductases from newly isolated Rhodosporidium toruloides into the enantiodetermining step. Amongst the ten most permissive enzymes identified, cloned, and overexpressed in Escherichia coli, RtSCR9 exhibited excellent activity and enantioselectivity. Using co-expressed E. coli harboring both RtSCR9 and glucose dehydrogenase, (S)-3-(dimethylamino)-1-(2-thienyl)-1-propanol 3a was fabricated with so far the highest substrate loading (1000 mM) in a space-time yield per gram of biomass (DCW) of 22.9 mmol L-1 h-1 g DCW-1 at a 200-g scale. The subsequent synthetic steps from RtSCR9-catalyzed (S)-3a were further performed, affording (S)-duloxetine with 60.2% overall yield from 2-acethylthiophene in >98.5% ee.
Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
-
, (2016/12/01)
The present invention relates to a method for preparing an optically active 3-amino-1-arylpropan-1-ol derivative, including the step of making an optically active 3-chloro-1-arylpropan-1-ol compound react with an amine derivative. The method according to the present invention allows direct amination of an optically active 3-chloro-1-arylpropan-1-ol derivative through a single-step reaction. Thus, it is possible to provide a compound functioning as a key intermediate of various optically active molecules through a simple process with high yield, while maintaining the optical purity of the reactant. Therefore, the method may be used for preparing medicines, such as (S)-Duloxetin, (R)-Fluoxetine, (R)- Tomoxetine or (R)- Nisoxetine, with high optical purity by combining the method for preparing an optically active 3-chloro-1-arylpropan-1-ol derivative as a reactant of the method with an additional substitution reaction.(AA) Tomoxetine(BB) Fluoxetine(CC) 3-amino-1-propanol(DD) Nisoxetine(EE) DuloxetineCOPYRIGHT KIPO 2016
Preparation method for chiral gamma-sec-amino-alcohol
-
Paragraph 0265-0267; 0271; 0279, (2016/10/08)
The invention provides a preparation method for chiral gamma-sec-amino-alcohol. The preparation method is characterized in that an acid addition salt of beta-sec-amino-ketone as shown in a general formula (I) which is described in the specification, alkali, a metal salt additive and a bisphosphine-rhodium complex are added into a solvent and a reaction is carried out in a hydrogen atmosphere so as to produce a chiral gamma-sec-amino-alcohol compound as shown in a general formula (II) which is described in the specification; and in the general formula (I) and the general formula (II), Ar represents an aryl group with or without substituent, R represents an alkyl group or aralkyl group, and HY represents acid. The preparation method is simple in synthesis route and process; the metal salt additive substantially improves the technical effect of rhodium in catalysis of asymmetric hydrogenation and enhances reaction yield and optical purity of the product; and production process is simplified, production cost is lowered, and the preparation method is suitable for industrial large-scale production.
west Luo river sandbank chiral method for the preparation of intermediates
-
, (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.
