132335-47-8

Usage

Chemical Properties

White Solid

InChI:InChI=1/C19H21NOS/c1-20(2)13-12-18(19-11-6-14-22-19)21-17-10-5-8-15-7-3-4-9-16(15)17/h3-11,14,18H,12-13H2,1-2H3/t18-/m0/s1

Synthetic route

oxalic acid (144-62-7) + N-methyl-(S)-duloxetine (132335-46-7) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
In Isopropyl acetate; water at 20℃; for 21h; Product distribution / selectivity;	84.2%
In Isopropyl acetate; isopropyl alcohol at 20℃; for 2h; Product distribution / selectivity;	78.6%
In methanol; Isopropyl acetate at 20℃; for 16h; Product distribution / selectivity;	78.9%

1-Fluoronaphthalene (321-38-0) + oxalic acid (144-62-7) + α-[2-(dimethylamino)ethyl](thiophene-2-yl)methanol (132335-49-0) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Stage #1: oxalic acid; α-[2-(dimethylamino)ethyl](thiophene-2-yl)methanol With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333h; Stage #2: 1-Fluoronaphthalene In N,N-dimethyl acetamide at 110℃; for 1h;	75.6%

1-Fluoronaphthalene (321-38-0) + oxalic acid (144-62-7) + (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol (132335-44-5) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Stage #1: 1-Fluoronaphthalene; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With tetrabutylammomium bromide; sodium hydroxide In dimethyl sulfoxide at 50 - 65℃; Stage #2: oxalic acid In toluene at 55 - 60℃; for 1h; optical yield given as %ee; enantioselective reaction;	59.9%
Stage #1: 1-Fluoronaphthalene; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With potassium tert-butylate at 90 - 100℃; Stage #2: oxalic acid In methanol at 0 - 30℃;

1-Fluoronaphthalene (321-38-0) + (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol (132335-44-5) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
With sodium hydride 1) DMSO, 25 deg C, 25 min 2) 48-72 h, 45-50 deg C; Yield given. Multistep reaction;

2-Acetylthiophene (88-15-3) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Multi-step reaction with 3 steps 1: 91 percent / 12N HCl / ethanol / 24 h / Heating 2: LiAlH4, (2R,3S)-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol / tetrahydrofuran; toluene / 16 h / -70 °C 3: 1) NaH / 1) DMSO, 25 deg C, 25 min 2) 48-72 h, 45-50 deg C View Scheme

3-(dimethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride (5424-47-5) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Multi-step reaction with 2 steps 1: LiAlH4, (2R,3S)-(+)-4-dimethylamino-1,2-diphenyl-3-methyl-2-butanol / tetrahydrofuran; toluene / 16 h / -70 °C 2: 1) NaH / 1) DMSO, 25 deg C, 25 min 2) 48-72 h, 45-50 deg C View Scheme
Multi-step reaction with 2 steps 1.1: sodium hydroxide; sodium tetrahydroborate / water; methanol / 2 h / 35 - 40 °C 2.1: sodium hydride / dimethyl sulfoxide / 20 °C 2.2: 48 - 50 °C 2.3: 5 h / 20 °C View Scheme

oxalic acid (144-62-7) + N,N-dimethylamino-3-(1-naphthanyloxy)-3-(2-thienyl)-1-propanamine (116817-11-9) → (R)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (932013-45-1) + (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
In ethyl acetate at 20℃; for 1h;

oxalic acid (144-62-7) + (R)-(-)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine (878757-08-5) + N-methyl-(S)-duloxetine (132335-46-7) → (R)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate (932013-45-1) + (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
In ethyl acetate at 20℃; for 1h;

1-Fluoronaphthalene (321-38-0) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
With oxalic acid In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil	3.5 g (80 %)

3-(N,N-dimethylamino)-1-(thien-2-yl)propan-1-ol (13636-02-7, 132335-44-5, 132335-49-0) + 1-Fluoronaphthalene (321-38-0) + oxalic acid (144-62-7) → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Stage #1: 3-(N,N-dimethylamino)-1-(thien-2-yl)propan-1-ol With sodium hydride In dimethyl sulfoxide at 20℃; Stage #2: 1-Fluoronaphthalene In dimethyl sulfoxide at 48 - 50℃; Stage #3: oxalic acid In ethyl acetate at 20℃; for 5h;

N,N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine mandelate → (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / dichloromethane; water / 0.5 h / 20 - 25 °C / pH 11 - 12 2.1: sodium hydride / dimethyl sulfoxide / 20 °C 2.2: 48 - 50 °C 2.3: 5 h / 20 °C View Scheme

(S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) → Duloxetine (116539-58-3, 116539-59-4, 116539-60-7, 116817-13-1)

Conditions	Yield
With hydrogenchloride; formic acid; triethylamine; zinc; 2,2,2-Trichloroethyl chloroformate 1) toluene, 30 min, 25 deg C 2) DMF; Yield given. Multistep reaction;
Multi-step reaction with 2 steps 1.1: potassium carbonate / toluene; water / 0.5 h 1.2: 3 h / 35 - 45 °C 2.1: potassium hydroxide / water; tetrahydrofuran / 4 h / 55 °C View Scheme

(S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) → N-methyl-(S)-duloxetine (132335-46-7)

Conditions	Yield
With ammonium hydroxide In water; toluene at 25℃; for 0.333333 - 0.5h;
With sodium hydroxide In water; toluene at 40℃; for 0.5h; Product distribution / selectivity;
With sodium hydroxide In water at 20 - 25℃; Product distribution / selectivity;

(S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) → duloxetine hydrochloride (136434-34-9)

Conditions	Yield
Stage #1: (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate With ammonia In water; toluene at 40℃; for 0.166667h; Stage #2: With N-ethyl-N,N-diisopropylamine; phenyl chloroformate In toluene at 55℃; for 1.25h; Stage #3: With hydrogenchloride; sodium hydrogencarbonate Product distribution / selectivity; more than 3 stages;
Multi-step reaction with 3 steps 1.1: sodium hydroxide / toluene; water / 20 - 45 °C / pH 11 - 12 2.1: N-ethyl-N,N-diisopropylamine / toluene / 2 h / 15 - 20 °C 2.2: 1 h / 40 - 45 °C 3.1: potassium hydroxide / toluene / 7 h / 80 - 85 °C 3.2: 0 - 5 °C View Scheme
Multi-step reaction with 3 steps 1.1: potassium carbonate / toluene; water / 0.5 h 1.2: 3 h / 35 - 45 °C 2.1: potassium hydroxide / water; tetrahydrofuran / 4 h / 55 °C 3.1: hydrogenchloride / water; ethyl acetate View Scheme

(S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) + phenyl chloroformate (1885-14-9) → C26H25NO3S

Conditions	Yield
Stage #1: (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate With water; sodium hydroxide In dichloromethane Stage #2: phenyl chloroformate With N-ethyl-N,N-diisopropylamine In dichloromethane at 25 - 30℃;

(S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) → (S)-N-methyl-N-phenoxycarbonyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propylamine (947686-09-1)

Conditions	Yield
Multi-step reaction with 2 steps 1.1: sodium hydroxide / toluene; water / 20 - 45 °C / pH 11 - 12 2.1: N-ethyl-N,N-diisopropylamine / toluene / 2 h / 15 - 20 °C 2.2: 1 h / 40 - 45 °C View Scheme

carbonochloridic acid 1-chloro-ethyl ester (50893-53-3) + (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate (132335-47-8) → 1-chloroethyl-N-methyl-((S)-3-(naphthalene-1-yloxy)-3-(thiophen-2-yl)propyl)carbamate (953028-77-8)

Conditions	Yield
Stage #1: (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-(2-thienyl)propanamine oxalate With potassium carbonate In water; toluene for 0.5h; Stage #2: carbonochloridic acid 1-chloro-ethyl ester With N-ethyl-N,N-diisopropylamine In toluene at 35 - 45℃; for 3h;	184.7 g

Upstream product

• 321-38-0 1-Fluoronaphthalene 
• 132335-44-5 (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol 
• 144-62-7 oxalic acid 
• 878757-08-5 (R)-(-)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine 
• 132335-46-7 N-methyl-(S)-duloxetine 
• 132335-49-0 α-[2-(dimethylamino)ethyl](thiophene-2-yl)methanol 
• 13636-02-7 3-(N,N-dimethylamino)-1-(thien-2-yl)propan-1-ol 
• 116817-11-9 N,N-dimethylamino-3-(1-naphthanyloxy)-3-(2-thienyl)-1-propanamine 
• 5424-47-5 3-(dimethylamino)-1-(thiophen-2-yl)propan-1-one hydrochloride 
• 88-15-3 2-Acetylthiophene 

Downstream Products

• 116539-58-3 Duloxetine 
• 136434-34-9 duloxetine hydrochloride 
• 947686-09-1 (S)-N-methyl-N-phenoxycarbonyl-3-(1-naphthyloxy)-3-(2-thienyl)-1-propylamine 
• 132335-46-7 N-methyl-(S)-duloxetine 

Relevant academic research and scientific papers

MANUFACTURING METHOD OF DULOXETINE HYDROCHLORIDE AND DULOXETINE HYDROCHLORIDE WITH NOVEL CRYSTAL STRUCTURE

PROBLEM TO BE SOLVED: To provide a method of providing crystal of (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine hydrochloride (general name:duloxetine hydrochloride) useful as an antidepressant with high purity and high bulk density. SOLUTION: There is provided a manufacturing method of duloxetine hydrochloride for depositing the duloxetine hydrochloride in a resulting mixture by mixing a solution by dissolving duloxetine hydrochloride into a solvent for dissolution containing at least one kind of polar solvent selected from water and alcohol having 1 to 3 carbon atoms with acetone, and setting a temperature when dissolving the duloxetine hydrochloride into the solvent for dissolution at 60°C or less. SELECTED DRAWING: Figure 1 COPYRIGHT: (C)2016,JPOandINPIT

IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND ITS PHARMACEUTICALLY ACCEPTABLE SALT

The present invention relates to an improved process for racemizing one of the enantiomers, or an enantiomerically enriched mixture, of an optically active compound (S)-N, N-dimethyl-3-(2-thienyl)-3-hydroxypropanamine, a key intermediate used for the preparation of (S)-N-methyl-3-(1-naphthalenyloxy)-3-(2- thienyl) propanamine (duloxetine) or its hydrochloride salt. Moreover, the present invention also relates to an improved process for the preparation of (S)-N-methyl-3- (1-naphthalenyloxy)-3-(2-thienyl) propanamine (duloxetine) or its hydrochloride salt having low content of undesired R-isomer and chiral purity not less than 99%.

AN IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND SALTS THEREOF

The present invention relates to improved process for the preparation of Duloxetine of formula (I) and salts thereof wherein said improvement takes place in step of condensation.

Gastro-resistant pharmaceutical oral compositions comprising duloxetine or its pharmaceutically acceptable derivatives

The present invention relates to a pharmaceutical composition comprising an active core comprising duloxetine or its pharmaceutically acceptable derivatives, a separating layer comprising a water soluble alkaline substance and a gastro-resistant coating comprising a gastro-resistant polymer selected from methacrylic acid copolymers and optionally an over-coating layer.

An investigation on key parameters that influence the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine: A key intermediate for duloxetine

This document highlights the systematic study of influencing factors such as temperature, base, catalyst, and solvent volume in the synthesis of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine oxalate 11a, without affecting the chiral

A METHOD FOR THE PREPARATION OF DULOXETINE HYDROCHLORIDE

The present invention relates to an improved process for the preparation of Duloxetine and its intermediates (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl)propanamine by reacting (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3-. hydroxypropanamine with 1-fluoronaphthalene in the presence of a base; wherein the improvement lies in conducting the reaction in the absence of solvent.

SYNTHESIS AND PREPARATIONS OF DULOXETINE SALTS

The invention relates to an improved process for the preparation of duloxetine hydrochloride.

DNT-FUMARATE AND METHODS OF PREPARATION THEREOF

(S)-N,N-Dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine fumarate (DNT-fumarate) and polymorphs of DNT-fumarate, compositions of DNT-fumarate and its polymorphs, processes for the preparation of DNT-fumarate and its polymorphs, and processes for the preparation of duloxetine hydrochloride from DNT-fumarate are provided.

DNT-succinate and methods of preparation thereof

(S)-N,N-Dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine succinate (DNT-succinate) and polymorphs of DNT-succinate, compositions of DNT-succinate and its polymorphs, processes for the preparation of DNT-succinate and its polymorphs, and processes for the preparation of duloxetine hydrochloride from DNT-succinate are provided.

DNT-MALEATE AND METHODS OF PREPARATION THEREOF

(S)-N,N-Dimethyl-3-(l-naphtlialenyloxy)-3-(2-thienyl)propanamine nialeate (DNT-maleate) and polymorphs of DNT-maleate, compositions of DNT-maleate and its polymorphs, processes for the preparation of DNT-maleate and its polymorphs, and processes for the preparation of duloxetine hydrochloride from DNT-maleate are provided.