116539-57-2

Basic information

• Product Name: (R)-(+)-3-(N-METHYLAMINO)-1-(2-THIENYL)-1-PROPANOL
• Synonyms: (1R)-3-(Methylamino)-1-(2-thienyl)-1-propanol;(R)-3-Methylamino-1-(2-thienyl)-1-propanol;N-Methyl[(R)-3-hydroxy-3-(2-thienyl)propyl]amine;(R)-3-(Methylamino)-1-(thiophen-2-yl)propan-1-ol;(R)-(+)-3-(N-METHYLAMINO)-1-(2-THIENYL)-1-PROPANOL
• CAS NO: 116539-57-2
• Molecular Formula: C₈H₁₃NOS
• Molecular Weight: 171.26
• EINECS: 171.26
• Mol File: 116539-57-2.mol
• Article Data: 18

Chemical Properties

• Boiling Point: 294.3±35.0 °C(Predicted)
• Appearance: /
• Density: 1.128
• Storage Temp.: 2-8°C(protect from light)
• PKA: 13.77±0.20(Predicted)
• CAS DataBase Reference: (R)-(+)-3-(N-METHYLAMINO)-1-(2-THIENYL)-1-PROPANOL(CAS DataBase Reference)
• NIST Chemistry Reference: (R)-(+)-3-(N-METHYLAMINO)-1-(2-THIENYL)-1-PROPANOL(116539-57-2)
• EPA Substance Registry System: (R)-(+)-3-(N-METHYLAMINO)-1-(2-THIENYL)-1-PROPANOL(116539-57-2)

Safety Data

• Hazardous Substances Data: 116539-57-2(Hazardous Substances Data)

Usage

Uses

(R)-3-Methylamino-1-(2-thienyl)-1-propanol is a reactant used in the synthesis of enantiomerically pure Duloxetine (D721000), an antidepressant. A dual serotonin and norepinephrine reuptake inhibitor (SNRI). Used in treatment of stress urinary incontinence.

Synthetic route

N-methyl-3-(thien-2-yl)-3-morpholino-propylamine hydrochloride → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With hydrogen; potassium carbonate; [Rh{(RC,SP)-duanphos}(norbornadiene)]SbF6 In methanol at 20℃; under 7500.6 Torr; for 12h;	93%

(R)-(3-hydroxy-3-thiophen-2-yl-propyl)carbamic acid ethyl ester (597581-30-1) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With lithium aluminium tetrahydride In tetrahydrofuran for 1.5h; Heating;	88%
With lithium aluminium tetrahydride In tetrahydrofuran for 14h; Reflux;	87%
With lithium aluminium tetrahydride In tetrahydrofuran for 2h; Heating;

N-methyl-3-(thien-2-yl)-3-morpholino-propylamine hydrochloride → (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With lithium aluminium tetrahydride Product distribution / selectivity;	A 74% B n/a
With hydrogen; sodium methylate; bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate; (S)-(-)-(6,6’-dimethoxybiphenyl-2,2’-diyl)bis(diphenylphosphine) In methanol at 30 - 50℃; under 22502.3 Torr; for 24h; Product distribution / selectivity;	A 12.7 - 20.4 %Chromat. B n/a
With hydrogen; sodium methylate; ethyl acetoacetate; [(12aS)-6,7-dihudrodibenzo[e,g][1,4]dioxocin-1,12-diyl]bis[diphenylphosphine]; bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate In methanol at 50℃; under 22502.3 Torr; for 24h; Product distribution / selectivity;	A 6.2 %Chromat. B n/a
With hydrogen; [(12aS)-6,7-dihudrodibenzo[e,g][1,4]dioxocin-1,12-diyl]bis[diphenylphosphine]; [ruthenium(II)(η6-1-methyl-4-isopropyl-benzene)(chloride)(μ-chloride)]2 In methanol at 50℃; under 22502.3 Torr; for 24h; Product distribution / selectivity;	A 11.6 %Chromat. B n/a
With hydrogen; [(12aS)-6,7-dihudrodibenzo[e,g][1,4]dioxocin-1,12-diyl]bis[diphenylphosphine]; bis(1,5-cyclooctadiene)rhodium(I) tetrafluoroborate In methanol at 50℃; under 22502.3 Torr; for 24h; Product distribution / selectivity;	A 4 %Chromat. B n/a

(R)-3-chloro-1-thiophenyl-2-yl-propan-1-ol (164071-55-0) + methylamine (74-89-5) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
In ethanol at 90℃; Sealed tube;	62%
In ethanol; water at 130℃; for 1h; Sealed tube;	55%
In ethanol at 90℃; Sealed tube;	41%
In ethanol at 90℃; Sealed tube;	41%

N-methyl-3-(thien-2-yl)-3-morpholino-propylamine hydrochloride + (1S,2R)-1-amino-2-indanol (7480-35-5, 13286-59-4, 74165-73-4, 126456-43-7, 136030-00-7, 140632-19-5, 140632-20-8) → (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With sodium hydroxide; (p-cymene)-ruthenium(II) chloride dimer In isopropyl alcohol at 20 - 85℃; for 5h;	A 39% B n/a

3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-56-1) → (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With (S)-Mandelic acid In water at 29 - 50℃;	A 27% B n/a
With diethylamine In ethanol; n-heptane Resolution of racemate;

(2R,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-3-methyl-6-(thiophen-2-yl)-1,3-oxazinane (919530-16-8) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With hydrogenchloride In tetrahydrofuran; water at 20℃; for 4h;

(2R,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-6-(thiophen-2-yl)-[1,3]oxazinan-4-one (919530-11-3) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: LiHMDS / tetrahydrofuran / 0 - 20 °C 2: Ph2SiH2 / RhH(CO)(PPh3)3 / tetrahydrofuran / 15 h / 20 °C 3: HCl / H2O; tetrahydrofuran / 4 h / 20 °C View Scheme

(2R,6R)-N-methyl-2-[(S)-1-triisopropylsilyloxyethyl]-6-(thiophen-2-yl)-[1,3]oxazinan-4-one (919530-13-5) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: Ph2SiH2 / RhH(CO)(PPh3)3 / tetrahydrofuran / 15 h / 20 °C 2: HCl / H2O; tetrahydrofuran / 4 h / 20 °C View Scheme

thiophene-2-carbaldehyde (98-03-3) + polymer-bound-N-(3-(4-bromophenyl)-3-oxopropanamide) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 54 percent / BF3*Et2O / CH2Cl2 / -78 - 20 °C 2: aluminum amalgam / propan-2-ol 3: LiHMDS / tetrahydrofuran / 0 - 20 °C 4: Ph2SiH2 / RhH(CO)(PPh3)3 / tetrahydrofuran / 15 h / 20 °C 5: HCl / H2O; tetrahydrofuran / 4 h / 20 °C View Scheme

(2R,5R,6R)-2-[(S)-1-triisopropylsilyloxyethyl]-6-(thiophen-2-yl)-5-phenylthio-[1,3]oxazinan-4-one (919530-02-2) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: aluminum amalgam / propan-2-ol 2: LiHMDS / tetrahydrofuran / 0 - 20 °C 3: Ph2SiH2 / RhH(CO)(PPh3)3 / tetrahydrofuran / 15 h / 20 °C 4: HCl / H2O; tetrahydrofuran / 4 h / 20 °C View Scheme

2-Acetylthiophene (88-15-3) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: HCl / ethanol / 110 °C 2: 93 percent / hydrogen; K2CO3 / [Rh{(RC,SP)-duanphos}(norbornadiene)]SbF6 / methanol / 12 h / 20 °C / 7500.6 Torr View Scheme

2-Thenoylacetonitrile (33898-90-7) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: borane-dimethylsulfide complex; polymer-supported chiral sulfonamide / tetrahydrofuran / Heating 2: sodium hydrogen carbonate / CH2Cl2; H2O / 2 h / 20 °C 3: lithium aluminum hydride / tetrahydrofuran / 2 h / Heating View Scheme

(R)-3-amino-1-(thiophen-2-yl)propan-1-ol (858130-53-7) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: sodium hydrogen carbonate / CH2Cl2; H2O / 2 h / 20 °C 2: lithium aluminum hydride / tetrahydrofuran / 2 h / Heating View Scheme
Multi-step reaction with 2 steps 1: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 2: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme
Multi-step reaction with 2 steps 1: sodium hydrogencarbonate / dichloromethane; water / 1 h 2: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme

2-chloro-1-(thiophen-2-yl)ethanone (29683-77-0) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions

Yield

Multi-step reaction with 6 steps 1: 90 percent / NaBH4 / methanol / 0.5 h / 20 °C 2: 77 percent / methanol; H2O / 4 h / 20 °C 3: 43 percent / immobilised lipase from Pseudomonas cepacia; phosphate buffer / diisopropyl ether / 14 h / pH 7.2 4: BH3*Me2S / tetrahydrofuran / 2 h / Heating 5: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 6: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme

2-(1-hydroxy-2-chloroethyl)-thiophene (49703-01-7) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: 77 percent / methanol; H2O / 4 h / 20 °C 2: 43 percent / immobilised lipase from Pseudomonas cepacia; phosphate buffer / diisopropyl ether / 14 h / pH 7.2 3: BH3*Me2S / tetrahydrofuran / 2 h / Heating 4: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 5: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme

(±)-3-hydroxy-3-(thiophen-2-yl)propanenitrile (235085-83-3) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 43 percent / immobilised lipase from Pseudomonas cepacia; phosphate buffer / diisopropyl ether / 14 h / pH 7.2 2: BH3*Me2S / tetrahydrofuran / 2 h / Heating 3: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 4: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme
Multi-step reaction with 4 steps 1: Candida antarctica lipase B-W104A; sodium carbonate / toluene / 24 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 2: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 3: sodium hydrogencarbonate / dichloromethane; water / 1 h 4: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: Candida antarctica lipase B; dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 25 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 2: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 3: sodium hydrogencarbonate / dichloromethane; water / 1 h 4: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 4 steps 1: Candida antarctica lipase B; sodium carbonate / toluene / 4 h / 80 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 2: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 3: sodium hydrogencarbonate / dichloromethane; water / 1 h 4: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme

(R)-1-hydroxy-3-(thiophen-2-yl)propanenitrile (524047-48-1) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: BH3*Me2S / tetrahydrofuran / 2 h / Heating 2: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 3: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme

acetic acid 2-cyano-1-thiophen-2-yl-ethyl ester → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 4 steps 1: 41 percent / immobilised lipase from Pseudomonas cepacia; phosphate buffer / acetone / 14 h / pH 7.2 2: BH3*Me2S / tetrahydrofuran / 2 h / Heating 3: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 4: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme

(R)-2-cyano-1-(thiophen-2-yl)ethyl acetate (597581-26-5) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 3 steps 1: BH3*Me2S / tetrahydrofuran / 2 h / Heating 2: K2CO3 / CH2Cl2; tetrahydrofuran / 0.5 h / 20 °C 3: 88 percent / LAH / tetrahydrofuran / 1.5 h / Heating View Scheme
Multi-step reaction with 3 steps 1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 2: sodium hydrogencarbonate / dichloromethane; water / 1 h 3: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme

methylamine (74-89-5) → (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Stage #1: 3-chloro-1-(2-thienyl)propan-1-one With sodium hydroxide; D-glucose; 2,3,4,5,6-pentahydroxy-hexanal In water at 30℃; for 2 - 8h; pH=6.0; Stage #2: methylamine In water at 60℃; for 6h; pH=6.0;	A n/a B n/a

C8H13NO2S (1035456-56-4) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Stage #1: C8H13NO2S With acetic acid; zinc In water at 50℃; for 1.5h; Stage #2: With sodium hydroxide In water

thiophene-2-carbaldehyde (98-03-3) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 18 h / -78 °C / Inert atmosphere 2.1: Candida antarctica lipase B-W104A; sodium carbonate / toluene / 24 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3.1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4.1: sodium hydrogencarbonate / dichloromethane; water / 1 h 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 18 h / -78 °C / Inert atmosphere 2.1: Candida antarctica lipase B; sodium carbonate / toluene / 4 h / 80 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3.1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4.1: sodium hydrogencarbonate / dichloromethane; water / 1 h 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 5 steps 1.1: lithium diisopropyl amide / tetrahydrofuran; hexane / 0.5 h / -78 °C / Inert atmosphere 1.2: 18 h / -78 °C / Inert atmosphere 2.1: Candida antarctica lipase B; dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 25 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3.1: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4.1: sodium hydrogencarbonate / dichloromethane; water / 1 h 5.1: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme

(S)-1-hydroxy-3-(thiophen-2-yl)propanenitrile (591727-36-5) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 5 steps 1: dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 0.08 h / 80 °C / Inert atmosphere 2: Candida antarctica lipase B-W104A; sodium carbonate / toluene / 24 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4: sodium hydrogencarbonate / dichloromethane; water / 1 h 5: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 0.08 h / 80 °C / Inert atmosphere 2: Candida antarctica lipase B; sodium carbonate / toluene / 4 h / 80 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4: sodium hydrogencarbonate / dichloromethane; water / 1 h 5: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme
Multi-step reaction with 5 steps 1: dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 0.08 h / 80 °C / Inert atmosphere 2: Candida antarctica lipase B; dicarbonyl(chloro)(η5-pentaphenylcyclopentadienyl)ruthenium(II); potassium tert-butylate; sodium carbonate / tetrahydrofuran; toluene / 25 h / 50 °C / Inert atmosphere; Resolution of racemate; Enzymatic reaction 3: dimethylsulfide borane complex / tetrahydrofuran / 2 h / 80 °C 4: sodium hydrogencarbonate / dichloromethane; water / 1 h 5: lithium aluminium tetrahydride / tetrahydrofuran / 14 h / Reflux View Scheme

(Z)-3-(methylamino)-1-(thiophen-2-yl)prop-2-en-1-one (663603-70-1) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With ruthenium(II) dichloro{(S)-(-)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl}[(2S)-(+)-1,1-bis(4-methoxyphenyl)-3-methyl-1,2-butanediamine]; potassium tert-butylate; hydrogen In isopropyl alcohol at 20℃; under 750.075 Torr; for 24h; Autoclave; optical yield given as %ee; enantioselective reaction;	> 99 %Spectr.

N-methyl-(3S)-3-hydroxy-3-(thien-2-yl)propanamide → (S)-3-methylamino-1-(2-thienyl)-1-propanol (116539-55-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
With dimethylsulfide borane complex In tetrahydrofuran at 20℃; for 4h; Overall yield = 98 %; Optical yield = 89 %ee;

3-chloro-1-(2-thienyl)propan-1-one (40570-64-7) → (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2)

Conditions	Yield
Multi-step reaction with 2 steps 1: (S)-1-methyl-3,3-diphenyl-hexahydropyrrolo[1,2-c][1,3,2]oxazaborole; dimethylsulfide borane complex / toluene / 1 h / 0 °C 2: water; ethanol / 1 h / 130 °C / Sealed tube View Scheme

di-tert-butyl dicarbonate (24424-99-5) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (3-hydroxy-3-thiophen-2-yl-propyl)-methyl-carbamic acid tert-butyl ester (597581-31-2)

Conditions	Yield
With triethylamine In dichloromethane at 20℃; for 2h;	88%

3-fluorobromobenzene (1073-06-9) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (R)-3-(3-bromophenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine

Conditions	Yield
Stage #1: (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 20℃; for 0.5h; Stage #2: 3-fluorobromobenzene In N,N-dimethyl acetamide; mineral oil at 90℃; for 3h;	83%
With sodium hydride In N,N-dimethyl acetamide at 90℃; for 3h;

1-Fluoronaphthalene (321-38-0) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (R)-Duloxetine (116539-60-7)

Conditions	Yield
With sodium hydride In dimethyl sulfoxide for 8h;	81%
Stage #1: (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol With sodium hydride In dimethyl sulfoxide; mineral oil at 20℃; for 0.5h; Stage #2: 1-Fluoronaphthalene In dimethyl sulfoxide; mineral oil at 50℃; for 1h;	80%
With sodium hydride In dimethyl sulfoxide at 45 - 50℃; for 1h;

o-fluorobromobenzene (1072-85-1) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (R)-3-(2-bromophenoxy)-N-methyl-3-(thiophen-2-yl)propan-1-amine

Conditions	Yield
With potassium tert-butylate In dimethyl sulfoxide at 60℃; for 8h; Inert atmosphere;	78%
With potassium tert-butylate In dimethyl sulfoxide at 60℃; for 8h; Inert atmosphere;	78%

6-fluoroquinoline (396-30-5) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (R)-N-methyl-3-(quinolin-6-yloxy)-3-(thiophen-2-yl)propan-1-amine

Conditions	Yield
Stage #1: (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol With sodium hydride In N,N-dimethyl acetamide; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 6-fluoroquinoline In N,N-dimethyl acetamide; mineral oil at 50℃; for 1.5h; Inert atmosphere;	59%

5-fluoro phthalazine (103119-77-3) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (R)-N-methyl-3-(phthalazin-5-yloxy)-3-(thiophen-2-yl)propan-1-amine

Conditions	Yield
Stage #1: (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol With sodium hydride In dimethyl amine; mineral oil at 0℃; for 0.5h; Inert atmosphere; Stage #2: 5-fluoro phthalazine In dimethyl amine; mineral oil at 50℃; for 1.5h;	49%

(R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → Duloxetine (116539-58-3, 116539-59-4, 116539-60-7, 116817-13-1)

Conditions	Yield
Multi-step reaction with 3 steps 1: 88 percent / triethyl amine / CH2Cl2 / 2 h / 20 °C 2: 51 percent / PPh3; DIAD / tetrahydrofuran / 24 h 3: 70 percent / TFA / CHCl3 View Scheme

(R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (S)-N-BOC-duloxetine (597581-32-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: 88 percent / triethyl amine / CH2Cl2 / 2 h / 20 °C 2: 51 percent / PPh3; DIAD / tetrahydrofuran / 24 h View Scheme

1-Fluoronaphthalene (321-38-0) + oxalic acid (144-62-7) + (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol (116539-57-2) → (-)-duloxetine oxalate (116817-78-8)

Conditions	Yield
Stage #1: (R)-3-(methylamino)-1-(thiophen-2-yl)propan-1-ol With sodium hydride; potassium hexanoate In tetrahydrofuran; dimethyl sulfoxide at 20℃; for 1h; Stage #2: 1-Fluoronaphthalene In tetrahydrofuran; dimethyl sulfoxide at 60℃; for 6h; Stage #3: oxalic acid In isopropyl alcohol Product distribution / selectivity;	n/a

Upstream product

• 74-89-5 methylamine 
• 40570-64-7 3-chloro-1-(2-thienyl)propan-1-one 
• 663603-70-1 (Z)-3-(methylamino)-1-(thiophen-2-yl)prop-2-en-1-one 
• 591727-36-5 (S)-3-hydroxy-3-(thiophen-2-yl)propanenitrile 
• 98-03-3 thiophene-2-carbaldehyde 
• 1035456-56-4 C₈H₁₃NO₂S 
• 645411-16-1 N-methyl-3-(thien-2-yl)-3-morpholino-propylamine hydrochloride 
• 7480-35-5 (1S,2R)-1-amino-2-indanol 
• 597581-26-5 (R)-2-cyano-1-(thiophen-2-yl)ethyl acetate 
• 49703-01-7 2-(1-hydroxy-2-chloroethyl)-thiophene 
• 29683-77-0 2-chloro-1-(thiophen-2-yl)ethanone 
• 858130-53-7 (R)-3-amino-1-(thiophen-2-yl)propan-1-ol 
• 33898-90-7 2-Thenoylacetonitrile 
• 88-15-3 2-Acetylthiophene 

Downstream Products

• 116539-60-7 (R)-Duloxetine 
• 116539-58-3 Duloxetine 

Relevant articles and documents

A chemoenzymatic dynamic kinetic resolution approach to enantiomerically pure (R)- and (S)-duloxetine

The synthesis of (R)-duloxetine is described. Dynamic kinetic resolution of β-hydroxynitrile rac-1 using Candida antarctica lipase B (CALB, N435) and ruthenium catalyst 6 afforded β-cyano acetate (R)-2 in high yield and in excellent enantioselectivity (98% ee). The subsequent synthetic steps were straightforward and (R)-duloxetine was isolated in 37% overall yield over 6 steps. The synthetic route also constitute a formal total synthesis of (S)-duloxetine.

COMPOUNDS HAVING MULTIMODAL ACTIVITY AGAINST PAIN

The present invention relates to a compound of formula (I): wherein the meanings for the various substituents are as disclosed in the description, having dual pharmacological activity towards both the α2δ subunit, in particular the α2δ- 1 subunit, of the voltage-gated calcium channel and the NET receptor, to processes of preparation of such compounds, to pharmaceutical compositions comprising them, and to their use in therapy, in particular for the treatment of pain.

NITROGEN CONTAINING BICYCLIC DERIVATIVES FOR TREATING PAIN AND PAIN RELATED CONDITIONS

The present invention relates to new compounds of formula (I): showing great affinity and activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels or dual activity towards the subunit α2δ of voltage-gated calcium channels (VGCC), especially the α2δ-1 subunit of voltage-gated calcium channels, and the noradrenaline transporter (NET).