cas 116539-55-0, 3-Methylamino-1-(2-thienyl)-1-propanol

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An asymmetric synthesis of duloxetine hydrochloride, a mixed uptake inhibitor of serotonin and norepinephrine, and its C-14 labeled isotopomers
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.
Wheeler,Kuo
p. 213 - 223
(1995)
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Chemoenzymatic synthesis of duloxetine and its enantiomer: Lipase-catalyzed resolution of 3-hydroxy-3-(2-thienyl) propanenitrile
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.
Kamal, Ahmed,Khanna, G. B. Ramesh,Ramu,Krishnaji
p. 4783 - 4787
(2003)
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Resolution of 3-(methylamino)-1-(2-thienyl)propan-1-ol, a new key intermediate for duloxetine, with (S)-mandelic acid
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.
Sakai, Kenichi,Sakurai, Rumiko,Yuzawa, Atsushi,Kobayashi, Yuka,Saigo, Kazuhiko
p. 1631 - 1636
(2003)
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Novel synthetic method for duloxetine intermediate
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).
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Paragraph 0008; 0021

(2018/09/08)

Method for synthesizing (S)-3-methylamino-1-(thiophene-2-yl) propyl alcohol
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.
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Paragraph 0040-0042; 0045-0047

(2018/04/21)

(S)- (-) - 3 - methylamino - 1 - (2 - thienyl) - 1 - propanol synthetic method
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.
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Paragraph 0069; 0070; 0071; 0072; 0073; 0074

(2017/08/25)

Method for preparation of optically active 3-amino-arylpropan-1-ol derivatives from 3-chloro-1-arylpropan-1-ol derivatives
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
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Paragraph 0074; 0075; 0077

(2016/12/01)

west Luo river sandbank chiral method for the preparation of intermediates
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.
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(2017/03/08)

Preparation method for chiral gamma-sec-amino-alcohol
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.
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Paragraph 0265-0267; 0271; 0279

(2016/10/08)

Chemoenzymatic synthesis of (S)-duloxetine using carbonyl reductase from Rhodosporidium toruloides
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.
Chen, Xiang,Liu, Zhi-Qiang,Lin, Chao-Ping,Zheng, Yu-Guo
p. 82 - 89
(2016/02/23)

A method for preparing optically active 3-amino-1-propanol derivatives as an intermediate and a method for preparing (S)-duloxetine using the same
The present invention relates to a method for preparing optically active 3-AMNO1-propanol derivatives as an intermediate and a method for preparing (s)-duloxetine using the same. This method can obtain optically active 3-AMNO1-propanol with higher yield and optical purity (ee) than any other conventional methods. Using this as an intermediate compound, it is possible to manufacture duloxetine which is enantiomerically pure and has high optical purity (ee).(DD) Nisoxetine(EE) Duloxetine(CC) 3-amino-1-propanol(BB) Fluoxetine(AA) TomoxetineCOPYRIGHT KIPO 2015
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Paragraph 0210; 0213

(2016/12/01)

ZnCl2-promoted asymmetric hydrogenation of β-secondary-amino ketones catalyzed by a P-chiral rh-bisphosphine complex
A new catalytic system has been developed for the asymmetric hydrogenation of β-secondary-amino ketones using a highly efficient P-chiral bisphosphine-rhodium complex in combination with ZnCl2 as the activator of the catalyst. The chiral γ-secondary-amino alcohols were obtained in 90-94% yields, 90-99% enantioselectivities, and with high turnover numbers (up to 2000 S/C; S/C = substrate/catalyst ratio). A mechanism for the promoting effect of ZnCl2 on the catalytic system has been proposed on the basis of NMR spectroscopy and HRMS studies. This method was successfully applied to the asymmetric syntheses of three important drugs, (S)-duloxetine, (R)-fluoxetine, and (R)-atomoxetine, in high yields and with excellent enantioselectivities.
Hu, Qiupeng,Zhang, Zhenfeng,Liu, Yangang,Imamoto, Tsuneo,Zhang, Wanbin
supporting information
p. 2260 - 2264
(2015/02/19)

Total synthesis of fluoxetine and duloxetine through an in situ imine formation/borylation/transimination and reduction approach
We report efficient, catalytic, asymmetric total syntheses of both (R)-fluoxetine and (S)-duloxetine from α,β-unsaturated aldehydes conducting five sequential one-pot steps (imine formation/copper mediated β-borylation/transimination/reduction/oxidation) followed by the specific ether group formation which deliver the desired products (R)-fluoxetine in 45% yield (96% ee) and (S)-duloxetine in 47% yield (94% ee). This journal is the Partner Organisations 2014.
Calow, Adam D. J.,Fernandez, Elena,Whiting, Andrew
p. 6121 - 6127
(2014/08/05)

PROCESS FOR PREPARING (S)-3-N-METHYLAMINO-1-(2-THIENYL)-1-PROPANOL
The present invention relates to a method for preparing (S)-3-N-methylamino-1-(2-thienyl)-1-propanol and salts thereof.
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Paragraph 0073

(2014/02/16)

Copper(ii)-catalyzed enantioselective hydrosilylation of halo-substituted alkyl aryl and heteroaryl ketones: Asymmetric synthesis of (R)-fluoxetine and (S)-duloxetine
A set of reaction conditions has been established to facilitate the non-precious copper-catalyzed enantioselective hydrosilylation of a number of structurally diverse β-, γ- or ε-halo-substituted alkyl aryl ketones and α-, β- or γ-halo-substituted alkyl heteroaryl ketones under air to afford a broad spectrum of halo alcohols in high yields and good to excellent enantioselectivities (up to 99% ee). The developed procedure has been successfully applied to the asymmetric synthesis of antidepressant drugs (R)-fluoxetine and (S)-duloxetine, which highlighted its synthetic utility.
Zhou, Ji-Ning,Fang, Qiang,Hu, Yi-Hu,Yang, Li-Yao,Wu, Fei-Fei,Xie, Lin-Jie,Wu, Jing,Li, Shijun
p. 1009 - 1017
(2014/02/14)

A practical synthesis of the antidepressant (S)-duloxetine
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Lee, Sun-Ah,Sadu, Venkata Subbaiah,Park, No-Joong,Hwang, In-Taek,Lee, Kee-In
p. 1894 - 1896
(2014/07/07)

METHOD FOR PRODUCING OPTICALLY ACTIVE N-MONOALKYL-3-HYDROXY-3-ARYLPROPYLAMINE COMPOUND
The present invention provides a method for producing an N-monoalkyl-3-hydroxy-3-arylpropylamine compound represented by Formula (2): wherein Ar represents an optionally substituted aryl or an optionally substituted heteroaryl, R represents an optionally substituted C1-5 alkyl, and * represents an asymmetric carbon atom; the method comprising:reacting, in the presence of an asymmetric reduction catalyst, hydrogen gas with an N-benzyl-N-monoalkyl-3-oxo-3-arylpropenylamine compound represented by Formula (1): wherein Ar and R are as defined above. The present invention allows an optically active N-monoalkyl-3-hydroxy-3-arylpropylamine compound to be produced easily and inexpensively under industrially advantageous conditions.
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Page/Page column 3

(2013/02/28)

Chemoenzymatic asymmetric synthesis of fluoxetine, atomoxetine, nisoxetine, and duloxetine
The asymmetric synthesis of two well-known anti-depressant drugs, fluoxetine and duloxetine has been accomplished in a chemoenzymatic manner. The main highlight of the synthesis is the enantioselective cyanohydrin formation by a plant (R)-HNL (hydroxynitrile lyase). The enantiopure cyanohydrins are then synthetically manipulated into the above two drug molecules and two of their structural analogues, atomoxetine and nisoxetine.
Rej, Rohan Kalyan,Das, Tapas,Hazra, Suman,Nanda, Samik
p. 913 - 918
(2013/09/23)

Concise enantioselective synthesis of duloxetine via direct catalytic asymmetric aldol reaction of thioamide
Direct catalytic asymmetric aldol reaction of thioamide offers a new entry to the concise enantioselective synthesis of duloxetine. The direct aldol protocol was scalable (>20 g) to afford the aldol product in 92% ee after LiAlH4 reduction, and 84% of the chiral ligand was recovered after recrystallization. The following four steps of transformation delivered duloxetine.
Suzuki, Yuta,Iwata, Mitsutaka,Yazaki, Ryo,Kumagai, Naoya,Shibasaki, Masakatsu
p. 4496 - 4500
(2012/06/30)

Process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine by using an optically active methylhydroxylaminopropanol compound as intermediate
The present invention provides (S)-methylhydroxylaminopropanol compound as an intermediate in preparation of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. The present invention also provides a process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine with higher yield and lower cost by using the (S)-methylhydroxylaminopropanol compound as an intermediate.
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(2011/12/01)

PROCESS FOR PREPARING (S)-(+)-N-METHYL-3-(1-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE BY USING OPTICALLY ACTIVE METHYLHYDROXYLAMINOPROPANOL COMPOUND AS INTERMEDIATE
The present invention provides (S)-methylhydroxylaminopropanol compound as an intermediate in preparation of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine. The present invention also provides a process for preparing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine with higher yield and lower cost by using the (S)-methylhydroxylaminopropanol compound as an intermediate.
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(2011/11/13)

RUTHENIUM COMPLEX AND METHOD FOR PREPARING OPTICALLY ACTIVE ALCOHOL COMPOUND
The present invention provides a novel ruthenium complex which has an excellent catalytic activity in terms of reactivity for asymmetric reduction of a carbonyl compound and enantioselectivity, a catalyst using the ruthenium complex, and a method for preparing optically active alcohol compounds using the ruthenium complex. The present invention relates to a ruthenium complex having ruthenacycle structure, a catalyst for asymmetric reduction consisting of the ruthenium complex, and a method for preparing optically active alcohol using the ruthenium complex.
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Page/Page column 33

(2011/11/13)

A facile asymmetric synthesis of (S)-duloxetine
The asymmetric-transfer hydrogenation of 2-tosyloxy-1-(2-thiophenyl) ethanone and further elaboration of the cyclic carbamate derived from ?-aminoalcohol to provide a facile synthesis of (S)-duloxetine, a potent dual inhibitor of serotonin and norepinephrine reuptake, is described. ARKAT USA, Inc.
Kwak, Se Hun,Seo, Jung Min,Leea, Kee-In
experimental part
p. 55 - 61
(2011/01/12)

PREPARATION OF DULOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS BY THE USE OF ASYMMETRIC TRANSFER HYDROGENATION PROCESS
The invention deals with the preparation of duloxetine or its pharmaceutically acceptable salts with high enantiomeric and chemical purity via beta-keto amines wherein the amino group is optionally protected and the subsequent asymmetric transfer hydrogenation using chiral Ru- or Rh-catalyst to the corresponding alcohol.
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Page/Page column 23

(2010/04/03)

KETOREDUCTASE POLYPEPTIDES FOR THE PRODUCTION OF 3-ARYL-3-HYDROXYPROPANAMINE FROM A 3-ARYL-3-KETOPROPANAMINE
The present disclosure provides engineered ketoreductase enzymes having improved properties as compared to a naturally occurring wild-type ketoreductase enzyme. Also provided are polynucleotides encoding the engineered ketoreductase enzymes, host cells capable of expressing the engineered ketoreductase enzymes, and methods of using the engineered ketoreductase enzymes to synthesize a variety of chiral compounds. The engineered ketoreductase polypeptides are optimized for catalyzing the conversion of N-methyl-3-keto-3-(2-thienyl)-1-propanamine to (S)—N-methyl-3-hydroxy-3-(2-thienyl)-1-propanamine.
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(2010/07/10)

Process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines and their optical stereoisomers
The invention provides a process for the preparation of enantiomerically pure 3-hydroxy-3-arylpropylamines via novel semiester derivatives containing o-carboxy benzoyl group as intermediates. The 3-hydroxy-3-arylpropylamines serve as precursor for the preparation of serotonin or noradrenalin reuptake inhibitors such as duloxetine, atomoxetine, fluoxetine, nisoxetine and norfluoxetine.
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Page/Page column 8

(2009/06/27)

Process for making duloxetine and related compounds
A compound of formula 10 is useful in making duloxetine.
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Page/Page column 7

(2008/12/06)

Synthesis of (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol: Revisiting Eli Lilly's resolution-racemization-recycle synthesis of duloxetine for its robust processes
(±)-3-(N,N-Dimethylamino)-1-(2-thienyl)propan-1-ol (6), prepared from 2-acetylthiophene (4) in a two-step overall yield of 79%, is resolved into (S)-6 of 93% ee as its diastereomeric salt (8) with (S)-mandetic acid (7) according to Eli Lilly's procedures developed for the resolution-racemization- recycle (RRR) synthesis of duloxetine (2) with some modifications in terms of practicality. On its liberation from 8, (S)-6 undergoes N-demethylative ethyl carbamate formation in two discrete but successive steps in an overall yield of 87% from 8: (1) O-ethyl carbonate formation and (2) ethyl carbamate formation with concomitant loss of the N-methyl group. Alkaline hydrolysis then affords (S)-3-(N-methylamino)-1-(2-thienyl)propan-1-ol (1) of 100% ee, an alleged penultimate precursor to duloxetine (2), in 75% yield after a single recrystallization from ethylcyclohexane. In the overall process thus developed, PhMe is substituted successfully for t-BuOMe, a solvent that has been used favorably in Eli Lilly's original RRR synthesis of 2.
Fujima, Yoshito,Ikunaka, Masaya,Inoue, Toru,Matsumoto, Jun
p. 905 - 913
(2012/12/23)

METHOD FOR PURIFYING (1S)-3-METHYLAMINO-1-(2-THIENYL)-1-PROPANOL
The invention relates to a method for purifying (1S)-3-methylamino-1-(2-thienyl)-1-propanol by the distillation of a reaction mixture containing between 25 and 99 wt. % (1S)-3-methylamino-1-(2-thienyl)-1-propanol.
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Page/Page column 3

(2008/06/13)

PROCESS FOR THE PREPARATION OF ENANTIOMERICALLY PURE 1-SUBSTITUTED-3-AMINOALCOHOLS
Provided is a process for the preparation of N-monosubstituted β-aminoalcohol sulfonates of formula (Ia), (Ib) wherein R1 is C6-20 aryl or C4-12 heteroaryl, each optionally being substituted with one or more halogen atoms and/or one or more C1-4 alkyl or C1-4 alkoxy groups, R2 is C1-4-alkyl or C6-20 aryl, each aryl optionally being substituted with one or more halogen atoms and/or one or more C1-4-alkyl or C1-4-alkoxy groups, and wherein R3 is selected from the group consisting of C1-18 alkyl, C6-20 cycloalkyl, C6-20 aryl and C7-20 aralkyl residues, comprising the steps of a) reacting a methyl ketone, a primary amine, formaldehyde and a sulfonic acid, at a pressure above 1.5 bar, optionally in a organic solvent, said organic solvent optionally containing water, to afford N-monosubstituted β-aminoketone sulfonates of formula (II), wherein R1, R2 and R3 are as defined above, and b) asymmetrically hydrogenating said sulfonates in the presence of a base and a catalyst, comprising a transition metal and a diphosphine ligand, in a polar solvent, optionally in the presence of water.
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Page/Page column 25-27

(2008/06/13)

Process for preparing optically active 3-(methylamino)-1-(2-thienyl) propan-1-ol and intermediates for preparation
Disclosed is a process for commercial preparation of 3-(methylamino)-1-(2-thienyl)propan-1-ol (hereinafter abbreviated as “MMAA”) of the formula below: The process is carried out by the diastereomeric salt formation method using optically active mandelic acid or its derivatives, or an optically active tartaric acid derivative as the resolving agent. The product compound, diastereomeric satls, is useful as the intermediate for producing pharmaceuticals, such as duloxetine.
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Page/Page column 4

(2008/06/13)

5-Phenylthio-1,3-oxazinan-4-ones via hetero Diels-Alder reactions: synthesis of (R)- and (S)-Duloxetines and Fluoxetines
The synthesis of 5-phenylthio-1,3-oxazinan-4-ones, through a hetero Diels-Alder strategy, is described. The cycloadducts thus prepared have been shown to be useful intermediates for the synthesis of 1,3-aminoalcohols, valuable intermediates in the preparation of biologically significant molecules, e.g., optically active Duloxetines and Fluoxetines. In the course of this elaboration a novel microwave assisted desulfurization reaction is reported.
Panunzio, Mauro,Tamanini, Emiliano,Bandini, Elisa,Campana, Eileen,D'Aurizio, Antonio,Vicennati, Paola
p. 12270 - 12280
(2007/10/03)

Amino alcohol enatioselectively hydrogenation method
A process for the enantioselective preparation of amino alcohols of formula I by enantioselective hydrogenation of amino ketones of the formula II in the presence of a non-racemic catalyst. The catalyst is a transition-metal complex in which the transition metal is complexed to a chiral diphosphine ligand.
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Page/Page column 18-19

(2008/06/13)

Process for the preparation of enantiomerically pure 1-substituted-3-aminoalcohols
Provided is a process for the preparation of enantiomerically pure 1-substituted-3-amino-alcohols, particularly of (S)-(-)- and (R)-(+)-3-N-methylamino-1-(2-thienyl)-1-propanol, by asymmetrically hydrogenating salts of a carboxylic acids with an aminoketone of the formula wherein R1 is selected from the group consisting of 2-thienyl, 2-furanyl and phenyl, each optionally substituted with one or more halogen atoms and/or one or more C1-4-alkyl or C1-4-alkoxy groups, and wherein R2 is C1-4-alkyl or phenyl, each optionally substituted with one or more halogen atoms and/or one or more C1-4-alkyl or C1-4-alkoxy groups, and wherein the corresponding aminoalcohols are obtained by subsequent hydrolysis of their salts. Furthermore provided are salts of a carboxylic acid with said aminoketones and the aminoalcohols obtained by asymmetriacally hydrogenating said aminoketones, respectively.
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Page/Page column 6

(2010/02/13)

METHOD FOR PRODUCING ENANTIOMER-PURE AMINOALCOHOLS
The invention relates to a method for producing the enantiomer-pure aminoalcohol of formula (I), by (i) reducing the ketone of formula (3) to the racemic alcohol of formula (4), (ii) enantioselectively acylating the racemic alcohol of formula (4) with succinic anhydride in the presence of a lipase to the succinic acid semi-ester of formula (7), (iii) removing the succinic acid semi-ester of formula (7) from the unreacted enantiomer of formula (4), and (iv) reacting the enantiomer-pure alcohol of formula (4) with methylamine to give the enantiomer-pure alcohol of formula (1).
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Page/Page column 4

(2008/06/13)

METHODS FOR THE PRODUCTION OF 3-METHYLAMINO-1-(THIENE-2-YL)-PROPANE-1-OL
The invention relates to enzymatic and non-enzymatic methods for the production of 3-methylamino-1-(thiene-2-yl)-propane-1-ol; in addition to enzymes for carrying out said method; nucleic acid sequences coding for said enzymes, expression cassettes containing them, vectors and recombinant hosts.
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Page/Page column 43-44

(2008/06/13)

PROPANOLAMINE DERIVATIVES, PROCESS FOR PREPARATION OF 3-N-METHYLAMINO-1-(2-THIENYL)-1-PROPANOLS AND PROCESS FOR PREPARATION OF PROPANOLAMINE DERIVATIVES
The present invention provides means for preparing a racemate or an optically active substance (S- or R-isomer) of 3-N-methylamino-1-(2-thienyl)-1-propanol represented by the following general formula (I): wherein R1 represents any of a hydrogen atom, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group and R2 represents any of a hydrogen atom, a C1-8 alkyl group, a substituted or substituted benzyl group, a C1-8 acyl group, a substituted or substituted C1-8 alkyloxycarbonyl group and a substituted or substituted phenyloxycarbonyl group, with the exception that R1 is a hydrogen atom and R2 is a methyl group or a hydrogen atom, in a simple manner at low cost and in high yield.
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Page/Page column 27

(2010/02/10)

Process for the asymmetric hydrogenation of beta-amino ketones
The invention relates to a process for the preparation of enantiomerically enriched or enantiomerically pure (S)- or (R)-N-monosubstituted β-amino alcohols of formula ???and enantiomers and their addition salts of proton acids, X represents S or O, and R represent C1-6-alkyl, C3-8-cycloalkyl, aryl or aralkyl.
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Page/Page column 8

(2008/06/13)

Practical synthesis of enantiopure γ-amino alcohols by rhodium-catalyzed asymmetric hydrogenation of β-secondary-amino ketones
(Chemical Equation Presented) Another way to antidepressants: A series of β-secondary-amino ketone hydrochlorides (e.g. 1) were hydrogenated with remarkably high enantioselectivities by using a Rh complex containing P-chiral bisphospholane 2. These results establish a short and practical means for the synthesis of enantiopure N-monosubstituted γ-amino alcohols (e.g. 3), which are key intermediates in the synthesis of important antidepressants. (nbd = norbornadiene; TON = turnover number).
Liu, Duan,Gao, Wenzhong,Wang, Chunjiang,Zhang, Xumu
p. 1687 - 1689
(2007/10/03)

METHOD FOR THE PRODUCTION OF (S)-3-METHYLAMINO-1-(THIEN-2-YL)PROPAN-1-OL
The invention relates to a method for the production of enantiomer-pure (S)-3-methylamino-1-(thien-2-yl)propan-1-ol of formula (II-S) by obtaining (S)-3-hydroxy-3-thien-2-ylproipionitril from its enantiomer mixture with the R-isomer and by subsequently reacting (S)-3-hydroxy-3-thien-2-ylpropionitril with hydrogen and methylamine in the presence of a catalyst in order to obtain (II-S).
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Page/Page column 20

(2010/02/06)

PROCESSES AND INTERMEDIATES FOR THE PREPARATION OF OPTICALLY ACTIVE 3-AMINO-1-(2-THIENYL)-1-PROPANOL DERIVATIVES
Enantiomerically enriched 3-amino-1-(2-thienyl)-1-propanols of the fomulae (S)-I or (R)-I wherein R1 and R2 independently denote H, C1-6-alkyl, C5-7-cycloalkyl, aralkyl or aryl, were prepared by reducing a 3-amino-1-(2-thienyl)-1-propanone of the formula (II) wherein R1 and R2 are defined as above, using a hydrogen donor in the presence of a metal catalyst, an optically active nitrogen-containing ligand and optionally a base.
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Page 15

(2008/06/13)

3-METHYLAMINO-1-(2-THIENYL)-1-PROPANONE, PRODUCTION AND USE THEREOF
The invention relates to the production of 3-methylamino-1-(2-thienyl)-1-propanone and the use thereof for producing the pharmaceutical (+)-(S)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine oxalate (trade name Duloxetine?).
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Page/Page column 6

(2008/06/13)

PROCESS FOR THE PREPARATION OF OPTICALLY ACTIVE 3-N-METHYLAMINO-1-(2-THIENYL)-1-PROPANOL
Enantiomerically enriched (S)-(-)-3-N-methylamino-l-(2-thienyl)-1-propanol or (R)-(+)-3-N-methylamino-l-(2-thienyl)-l-propanol of the formulae, or mirror image are prepared by i) treating an enantiomeric mixture of the amines Ia and Ib with (-)-2,3:4,6-di-O-isopropylidene-2-keto-L-gulonic acid or (+)-2,3:4,6-di-O-isopropylidene-2-keto-D-gulonic acid of the formulae (IIa) or mirror image ii) crystallizing the obtained diastereomerically enriched salts from the reaction mixture obtained in step i), iii) optionally recrystallizing said diastereomerically enriched salts IIIa or IVb, and iv) treating the diastereomerically enriched salts IIIa or IVb obtained in step ii) or step iii) with a base to liberate the enantiomerically enriched amines Ia or Ib.
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Page 20

(2008/06/13)

Process for production of optically active amino alcohols
The present invention is to provide a process for producing an optically active amino alcohol which is useful for the synthesis of natural substances and as an intermediate for drugs and agricultural chemicals in a high yield, a high selectivity and an economical manner with a good working efficiency and the present invention relates to a process for producing an optically active amino alcohol represented by the following formula (2) (in the formula, R1 is a hydrocarbon group, a substituted hydrocarbon group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an aliphatic heterocyclic group or a substituted aliphatic heterocyclic group; R2 and R3 each independently is hydrogen atom, a hydrocarbon group, a substituted hydrocarbon group, an acyl group, an acyloxy group, an alkyloxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an aliphatic heterocyclic group or a substituted aliphatic heterocyclic group; R4 is hydrogen atom or a protective group; two or more of R1, R2, R3 and R4 may be bonded to each other to form a ring; and * is asymmetric carbon atom, provided that when R2 or R3 is hydrogen atom, the carbon atom to which R2 or R3 is bonded is not an asymmetric carbon atom) or a salt thereof which comprises subjecting a compound represented by the following formula (1) or a salt thereof to an asymmetric hydrogenation: (in the formula, R1 is a hydrocarbon group, a substituted hydrocarbon group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an aliphatic heterocyclic group or a substituted aliphatic heterocyclic group; R2 and R3 each independently is hydrogen atom, a hydrocarbon group, a substituted hydrocarbon group, an acyl group, an acyloxy group, an alkyloxycarbonyl group, an aralkyloxycarbonyl group, an aryloxycarbonyl group, an aromatic heterocyclic group, a substituted aromatic heterocyclic group, an aliphatic heterocyclic group or a substituted aliphatic heterocyclic group; R4 is hydrogen atom or a protective group; two or more of R1, R2, R3 and R4 may be bonded to each other to form a ring; and the double bond between the carbon atoms to which R2 and R3 are attached is either cis or trans or a mixture thereof).
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Page 19

(2008/06/13)

3-HYDROXY-3-(2-THIENYL)PROPIONAMIDE COMPOUND, PROCESS FOR PRODUCING THE SAME, AND PROCESS FOR PRODUCING 3-AMINO-1-(2-THIENYL)-1-PROPANOL COMPOUND THEREFROM
The object of the present invention is to provide 3-hydroxy-3-(2-thienyl)propionamides useful as synthesis intermediates of pharmaceutical preparations and the like and a method for obtaining optically active 3-amino-1-(2-thienyl)-1-propanols using the same with high reaction yield, high optical yield and industrially low cost.According to the present invention, 3-amino-1-(2-thienyl)-1-propanols are obtained by carrying out asymmetric reduction of a β-ketocarbonyl compound having thiophene ring in the presence of a catalyst constituted from a compound of a group VIII or IX metal in the periodic table (e.g., a ruthenium compound) and an asymmetric ligand represented by a specified optically active diamine derivative (e.g., a diphenylethylenediamine derivative), or using a cell, a treated product of said cell or the like of a microorganism, and as occasion demands, carrying out amidation of the ester group and then carrying out reduction of the amido group.
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Page 33

(2010/02/09)

Enantioselective Hydrogenation of β-Keto Esters using Chiral Diphosphine-Ruthenium Complexes: Optimization for Academic and Industrial Purposes and Synthetic Applications
Enantioselective hydrogenation using chiral complexes between atropisomeric diphosphines and ruthenium is a powerful tool for producing chiral compounds. Using a simple and straightforward in situ catalyst preparation, the conditions were optimized using molecular hydrogen for both academic and industrial purposes. This led to the best conditions and the lowest catalytic ratio required for the pressure used. Hydrogenation of various β-keto esters was efficiently performed at atmospheric and higher pressures, leading to the use of very low catalyst-substrate ratios up to 1/20,000. Asymmetric hydrogenations were used in key-steps towards the total synthesis of corynomycolic acid, Duloxetine and Fluoxetine.
Ratovelomanana-Vidal,Girard,Touati,Tranchier,Ben Hassine,Genet
p. 261 - 274
(2007/10/03)

Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
A series of naphthalenyloxy-arylpropylamines have been prepared and are demonstrated to be inhibitors of both serotonin and norepinephrine reuptake. One member of this series, duloxetine (Cymbalta) has proven to be effective in clinical trials for the treatment of depression.
Bymaster,Beedle,Findlay,Gallagher,Krushinski,Mitchell,Robertson,Thompson,Wallace,Wong
p. 4477 - 4480
(2007/10/03)

Process for preparing arylaminopropanols
The invention relates to a process for preparing enantiomerically enriched aryl-aminopropanols and to their use and also to intermediates.
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Page 11-12

(2008/06/13)