132335-47-8

Basic information

• Product Name: S-(+)-N,N-Dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-1-propylamine oxalate
• Synonyms: Duloxetine N-Methyl Oxalate;(S)-(+)-N,N-diMethyl-3-(naphthloxy)-3-(2-thienyl);2-Thiophenepropanamine, N,N-dimethyl-γ-(1-naphthalenyloxy)-, eth;S-(+)-N,N-Dimethyl-3-(1-phthoxy)-3-(2-thienyl)-1-propylamine oxalate;s-(+)-n,n-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)-1-propanamine oxalate;(S)-N,N-Dimethyl-g-(1-naphthalenyloxy)-2-thiophenepropanamine ethanedioate (1:1);S-(+)-N,N-Dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-1-propylamine oxalate;(S)-(+)-N,N-Dimethyl-3-(1-Naphthalenyloxy)-3-(2-Thinyl)Propanamine Oxalate
• CAS NO: 132335-47-8
• Molecular Formula: C₂H₂O₄*C₁₉H₂₁NOS
• Molecular Weight: 401.48
• EINECS: 1806241-263-5
• Product Categories: Chiral Reagents;Intermediates & Fine Chemicals;Pharmaceuticals;Sulfur & Selenium Compounds
• Mol File: 132335-47-8.mol
• Article Data: 11

Chemical Properties

• Boiling Point: 459.7 °C at 760 mmHg
• Flash Point: 231.8 °C
• Appearance: /
• Density: 1.146 g/cm3
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: 1.624
• Storage Temp.: under inert gas (nitrogen or Argon) at 2–8 °C
• Solubility: DMSO (Slightly), Methanol (Slightly)
• CAS DataBase Reference: S-(+)-N,N-Dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-1-propylamine oxalate(CAS DataBase Reference)
• NIST Chemistry Reference: S-(+)-N,N-Dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-1-propylamine oxalate(132335-47-8)
• EPA Substance Registry System: S-(+)-N,N-Dimethyl-3-(1-naphthoxy)-3-(2-thienyl)-1-propylamine oxalate(132335-47-8)

Safety Data

• Hazardous Substances Data: 132335-47-8(Hazardous Substances Data)

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 
• 88-15-3 2-Acetylthiophene 
• 144-62-7 oxalic acid 
• 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 
• 878757-08-5 (R)-(-)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propylamine 
• 132335-46-7 N-methyl-(S)-duloxetine 
• 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 

Downstream Products

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

Relevant articles and documents

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

AN IMPROVED PROCESS FOR THE PREPARATION OF DULOXETINE AND SALTS THEREOF

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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.