- METHOD FOR PRODUCING DULOXETINE HYDROCHLORIDE
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PROBLEM TO BE SOLVED: To provide a new method for producing (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (general name: duloxetine hydrochloride) useful as an antidepressant. SOLUTION: In a method for producing duloxetine hydrochloride, a solution obtained by dissolving a crude product containing duloxetine hydrochloride in a dissolving solvent (a first dissolution step) and acetone are mixed (a mixing step), the duloxetine hydrochloride precipitated in the obtained mixed solution is temporarily dissolved (a second dissolution step), and then the duloxetine hydrochloride is precipitated. SELECTED DRAWING: None COPYRIGHT: (C)2017,JPOandINPIT
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Paragraph 0064
(2017/05/05)
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- PROCESS FOR THE PREPARATION OF N-METHYL-O-ARYLOXY PROPANAMINE DERIVATIVES AND PHARMACEUTICALLY ACCEPTABLE SALT THEREOF
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A process for the preparation on N-methyl-aryloxy-propanamine derivatives of the formula I and salts thereof. The invention also relates to the preparation and use novel intermediate of the formula XII. The invention also relates to the process of further conversion of novel intermediate into N-methyl-aryloxy propanamine derivatives and salts thereof. Wherein Q and P independently represents substituted or unsubstituted aryl group such as phenyl, naphthyl, pyridine, furanyl, pyranyl thienyl, and the like optionally substituted aryl by a halogen, a straight chain or branched alkyl group containing 1 to 6 carbon atoms, —O-alkyl group containing straight chain or branched C1-C6 alkyl group, an alkoxy group containing a straight chain or branched alkyl group having 1 to 6 carbon atoms, which comprises demethylation of N,N-dimethyl analogues of compound of formula IA.
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Paragraph 0070
(2013/03/26)
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- Synthesis and dual 5-ht1a/ssri activities of some novel arylpiperazine derivatives of duloxetine
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A series of novel arylpiperazine derivatives of duloxetine were designed and synthesized from the key intermediate 5 by acylation, alkylation and reduction based on 5-HT1A/SSRI drugs design strategies. Compound 5 was obtained through the reaction sequence including condensation, reduction, O-etherification, Von Braun reaction, hydrolysis reaction. Structures of the synthesized compounds were confirmed by MS, 1H NMR and HRMS. Furthermore, these compounds were evaluated for their dual 5-HT1A/5-HTT activities. The results indicated that all the compounds exhibited certain affinity to 5-HTT and 5-HT1A receptor.
- Chen, Shao-Rui,Li, Ai-Jun,Chen, Ming-Ming
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experimental part
p. 1680 - 1684
(2012/08/28)
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- NOVEL PROCESS FOR PREPARATION OF DULOXETINE HYDROCHLORIDE
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An improved, safer and easy to operate on plant scale process for synthesis of duloxetine hydrochloride (1) having chiral purity greater than 99.9% that is characterized by the following: (i) preparation of racemic condensed compound (RS)-N,N-di methyl-3- (1-naphthyloxy)-3-(2-thienyl)propanamine (4) by reaction of racemic hydroxy compound (2) with 1-fluronaphthalene (3) in presence of a base such as sodamide, potassium amide or potassium bis(trimethylsilyl)amide (KHDMS) in polar aprotic solvent, (ii) optical resolution of racemic condensed compound (5a + 5b) with di-benzoyl-L-tartaric acid (7, DBTA, R = H) or di-para-anisoyl-L-tartaric acid (7, DATA, R = OCH3) to obtain crude (S)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine dibenzoyl tartarate salt (8a) or (S)-N.N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine di-p-anisoyl tartarate salt (9a) respectively, (iii) optionally purification of crude tartarate salts (8a or 9a) by crystallization, (iv) optionally purification of duloxetine hydrochloride (1) by crystallization and (v) racemization of undesired (R)-N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by treatment with base potassium bis(trimethylsilyl)amide (KHDMS) to obtain racemic mixture of condensed compounds (5a and 5b). A novel salt S(+)-N.N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine dibenzoyl -(L)- tartarate (8a) and S(+)-N.N-dimethyl-3-(1-naphthylenyloxy)-3-(2-thienyl)propanamine di-p-anisoyl-(L)- tartarate (9a). Novel process for racemization of undesired (R)-N,N-di methyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine (5b) by treatment with KHDMS to obtain racemic mixture condensed compounds (5a and 5b).
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Page/Page column 27-28
(2008/12/07)
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- Process for the Preparation of 1-Naphthol Mixed Ethers and Intermediates of Crystalline Forms of (+) and (-)-Duloxetine
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The invention relates to a process for the preparation of duloxetine (1a), comprising the reaction between 1-fluoronaphthalene and 3-N,N-dimethylamino-1-(2-thienyl)-propan-1-ol in the presence of 1,3-dimethyl-2-oxo-hexahydropyrimidine (DMPU) as the solvent; a method for the identification of duloxetine enantiomers and for the determination of its optical purity is also disclosed.
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Page/Page column 3
(2008/12/09)
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- A process for the preparation of aryloxypropylamines
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A process for the preparation of a compound of formula (I), or a salt thereof, both as the as individual isomer and as mixtures thereof, wherein each of A and B is independently aryl or heteroaryl optionally substituted with 1 to 4 substituents; and R and R1, which can be the same or different, are hydrogen, C1-C6 alkyl or an amino-protecting group; comprising the reaction of a compound (II) wherein A and B are as defined above, with a compound (III) wherein each of R and R1 is independently C1-C6 alkyl or an amino-protecting group; and X is a leaving group; in the presence of a basic agent; and, if desired the conversion of a compound (I) to another compound (I); and/or, if desired, the separation of an isomeric mixture of a compound (I) into the individual isomers; and/or, if desired, the conversion of a compound (I) to a salt thereof.
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Page/Page column 5
(2010/11/28)
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- PROCESS FOR THE PREPARATION OF ARYLOXYPROPYLAMINES
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A process for preparation of a compound of formula (I), or a salt thereof, both as individual isomer and as mixtures thereof, wherein each of A and B is independently aryl or heteroaryl optionally substituted with 1 to 4 substituents; and R and R1, which can be the same or different, are hydrogen, C1-C6 alkyl or an amino-protecting group; comprising the reaction of a compound (II) wherein A and B are as defined above, with a compound (III) wherein each of R and R1 is independently C1-C6 alkyl or an amino-protecting group; and X is a leaving group; in the presence of a basic agent; and, if desired the conversion of a compound (I) to another compound (I); and/or, if desired, the separation of an isomeric mixture of a compound (I) into the individual isomers; and/or, if desired, the conversion of a compound (I) to a salt thereof.
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Page/Page column 3
(2010/11/29)
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- A METHOD FOR THE PREPARATION OF (S)-N-METΗYL-3-(l-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE)
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A method of preparation of (S)-N-methyl-3-(l-naphthyloxy)-3-(2-mienyl)propylamine of Formula(I) and its pharmaceutically acceptable salts, comprising a) reaction of (RS)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (III) with optically active D-tartaric acid or an acid salt derived from D-tartaric acid forming a mixture of diastereoisomeric salts of N,N-dimethyl-3-(l-naphthyloxy)- 3-(2-thienyl)propylamine and D-tartaric acid (2:1), b) isolation of the salt (S)-N,N-dimethyl-3-(naphthyloxy)-3-(2- thienyl)propylamine/D-tartrate (2:1) from the mixture of diastereoisomeric salts in an organic solvent, water or a mixture thereof and release of (S)-N,N-dimethyl-3-(l- naphthyloxy)-3-(2-thienyl)ρropylamine of formula (S)-(III) by action of an inorganic or organic base, c) demethylation of (S)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine by action of an alkylchloroformate of formula ClCOOR (R = C1 - C5 alkyl, or C6 - C12 aryl or alkylaryl), especially phenyl, ethyl or methyl chloroformate, and d) hydrolytic release of the duloxetine base of formula (I) and optionally conversion of the base to a salt with the respective acid, or salt of a weak base, wherein one uses, as the optically active substance in step (a), D-tartaric acid in the molar ratio 1:2 relative to the substance of formula (III), or an alkali metal acid D-tartrate or ammonium tartrate, or alternatively alkylammonium tartrate of formula (IV) in the molar ratio 1:1 relative to the substance of formula (III).
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Page/Page column 8; 9
(2008/06/13)
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- A process for the preparation of an intermediate useful for the asymmetric synthesis of (+)duloxetine
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A process for the preparation of (+)duloxetine, or an acid addition salt thereof, comprising: (i) Resolving racemic (±)N-methyl duloxetine with a less than stoichiometric amount of a chiral acid in combination with suitable amounts of a hydrohalogen acid to give a salt of the chiral acid and (+)N-methyl duloxetine, substantially free from (-)N-methyl duloxetine; (ii) Demethylating the (+)N-methyl duloxetine prepared in step (i) to give (+)duloxetine or another acid addition salt in enantiomerically pure form.
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Page/Page column 5
(2010/11/28)
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- METHOD OF MANUFACTURING (S)-N-METHYL-3-(1-NAPHTHYLOXY)-3-(2-THIENYL)PROPYLAMINE HYDROCHLORIDE (DULOXETINE)
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A method of preparation of (S)-N-methyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (I) or its pharmaceutically acceptable salt, in which (RS)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (III) is reacted with an optically active acid, after which a crystallization is made of that diastereoisomer which yields, by reaction with an inorganic or organic base, (S)-N,N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl)propylamine of formula (S)-III, which is then demethylated using alkylchloroformates, followed by a hydrolysis and optional conversion of the compound of formula (I) to its salt.
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Page/Page column 6
(2008/06/13)
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- A PROCESS FOR PREPARATION OF AN ANTIDEPRESSANT COMPOUND
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The present invention provides optically pure (S)-(+)-N-methyl-3-(1-naphthaleneoxy)-3-(2-thienyl)propanamine, a compound of formula (I), and optically pure (S)-isomer of compound of formula 4, wherein R1 and R2 both are methyl or R1 is methyl and R2 is benzyl or substituted benzyl group and process for preparation thereof. Formula (I) and (IV). In another aspect the present invention provides a process for preparation of an acid addition salt of compound of formula (I).
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Page/Page column 21; 22
(2008/06/13)
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- A PROCESS FOR PREPARING DULOXETINE AND INTERMEDIATES FOR USE THEREIN
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A process for preparing (+)duloxetine, or an acid addition salt thereof, which process comprises resolving racemic (±)duloxetine with a chiral acid so as to obtain a salt of the chiral acid and (+)duloxetine, substantially free of (-)duloxetine; and (ii) if desired, converting the salt prepared in step (i) to the free base or another acid addition salt as appropriate. The process for preparing (+)duloxetine, or an acid addition salt thereof, can further comprise an O-alkylation intermediate process step which is carried out in the presence of a base and a phase transfer catalyst.
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- Duloxetine (Cymbalta), a dual inhibitor of serotonin and norepinephrine reuptake.
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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
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p. 4477 - 4480
(2007/10/03)
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