65% |
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Example 7; (S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :lambda solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (750 ml) was added lot wise to a mixture of 60percent sodium hydride (47.3 g, 1.18 mole) in dimethyl sulphoxide (475 ml) at 30-350C. This mixture was stirred for 30 min and the temperature was raised to 60-65° C followed by dropwise addition of 1 -fluoronaphthalene (152 g, 1.04 mole). Reaction mixture was stirred for 6-8 hrs. After cooling, methanol was added to quench the excess sodium hydride followed by addition of water (4.9 L) to the reaction mass and extraction with ethyl acetate. The combined organic extracts were washed with water and dried over sodium sulphate. The organic layer was concentrated under reduced pressure to get oil (298 g). 8 percent aqueous solution of acetic acid (1.49 L) was added to this oil and stirred for 30 min. Aqueous mixture was washed with methyl tert butyl ether (3x1.49 L). Aqueous layer was then basified with 5 percent aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 192 g (65percent).Example 8(S)-(+)-N, N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (6) :To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60percent sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. The temperature was raised to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 h. After cooling methanol was added to quench the excess <n="16"/>sodium hydride followed by addition of ethyl acetate (250 ml) and water (4.9 L) . Layers were separated and lower aqueous layer was extracted with ethyl acetate (2x250 ml). The combined organic extracts were washed with water. 8 percent aqueous solution of acetic acid (1.49 L) was added to this layer and stirred for 30 min. Aqueous layer was basified with 5 percent aqueous sodium hydroxide solution and extracted with ethyl acetate. The organic layer was washed with water, dried over sodium sulphate and concentrated under reduced pressure to get (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl)propanamine as oil. Yield: 19O g (65percent). Example 9(S)-(+)-N, N-dimethyI-3-(l-naphthalenyloxy)-3-(2-thienyl) propanaminc (7): To the solution of (S)-(-)-3-(dimethylamino)-l-(2-thienyl)-l-propanol (175 g, 0.945 mole) in dimethyl sulphoxide (1225 ml), 60percent sodium hydride (47.3 g, 1.18 mole) was added lot wise at 30-350C. This mixture was stirred for 30 minutes. Then raised temperature to 60-65° C and 1 -fluoronaphthalene (152 g, 1.04 mole) was added drop wise. Reaction mixture was stirred for 6-8 hrs. After cooling methanol is added to quench the excess sodium hydride then ethyl acetate (250 ml) followed by water (4.9 L) was added to the reaction mass. Layers were separated and lower aq. layer was extracted with ethyl acetate (2X250 ml). The combined organic extracts were washed with water. 8 percent aqueous solution of acetic acid (1.49 L) was added to this organic layer and stirred the mixture for 30 minutes. Separated aqueous layer was basified with 5 percent aqueous sodium hydroxide solution and extracted with toluene (3X175 ml). The organic layer was washed with water, dried over sodium sulphate. |
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To a 1 lt/4 neck round bottom flask fitted with a mechanical stirrer, reflux condenser and calcium chloride drying tube under an atmosphere of nitrogen gas were charged dimethyl sulphoxide (DMSO) (225 ml) and (S)-(-)-3-methylamino-l-(thio[phene-2-yl) propan-1-ol and the colorless solution cooled to 10-15omicronC. The solution when cooled sodium hydride (12.5 gm, 60percent dispersion) was added lot wise over a period of 60 minutes keeping the temperature at 10-20°C and the contents were stirred for 30 minutes at the same temperature. Slowly heat the reaction mixture to 60-65°C and charge drop wise 1-Fluoronaphthalene (50 gm). The solution was stirred at 60omicronC to 65omicronC and the progress of the reaction was monitored by TLC. After complete conversion, cooled the reaction mass followed by the reaction mixture was poured into mixture of 10 ml acetic acid in 1000 ml water. Allow the temperature raise to ambient temperature. 10omicronC to 20omicronC and stirred for 15 to 20 minutes. Adjust the pH of the reaction mixture to 12 using 30percent caustic solution. Extract the reaction mixture with toluene (3 X 150 ml). Combined organic layer washed with water (1 X 50 ml). Dry over anhydrous sodium sulphate. Use the organic layer as such for the next step. |
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25 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (125 ml) at room temperature. Sodium hydride (5.75 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 2.5 gm of potassium 4-methyl benzoate was added and stirred for 15 minutes. The reaction mixture was heated to about 55 0C and then 1-fiuoronapthalene (25 gm) was added slowly for 45 minutes. The reaction mixture was maintained for 4 hours at about 65 0C. After completion of the reaction, the reaction mass is quenched into ice cold water (150 ml) and pH was adjusted to about 4 with 25 ml of acetic acid. Reaction mixture was washed with pet ether (3 X -25 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 50 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3X50 ml) and further dried with sodium chloride. The organic layer was distilled completely under vacuum to give 29 gm of title compound as residue. |
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Example 1Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl) Propylamine Oxalic Acid Salt(S-3-Dimethylamino-1-(2-thienyl)-1-propanol (50 g, 0.270 moles) and sodium hydroxide (21.6 g, 0.540 moles, 2 eq.) were heated in DMSO (500 mL) at 60-80° C. for 1 hour. The temperature was controlled at 60° C.+/-4° C. before 1-fluoronaphthalene (43.6 g, 38.5 mL, 0.299 moles) was added. The mixture heated at this temperature for 64 hours. Water (500 mL) was added, and the mixture extracted with toluene (2.x.500 mL). The organic layers were then combined and washed with water (500 mL). HPLC analysis of an evaporated aliquot showed the molar ratio of Compound IV to Compound S-II to be 90:10 and Compound IV to be 88percent ee. Pyridine sulfur trioxide (6.4 g, 0.040 moles) was added to the mixture, the mixture was stirred for 30 minutes, and was then washed with water (500 mL). The organic layers were then concentrated by distillation until 600 mL of solvent was removed, and ethyl acetate (500 mL) was added. Oxalic acid dihydrate (27.2 g, 0.216 moles) was then added. The resulting suspension was stirred for 16 hours and filtered to yield the product as a white solid. The resulting product was slurried in additional ethyl acetate (200 mL), filtered and dried under vacuum to yield 63.3 g of the product as a white solid (0.158 moles, Yield: 59percent). The resulting product had a molar ratio of Product:(S)-3-dimethylamino-1-(2-thienyl)-1-propanol: 1-fluoronaphthalene of 99.53:0.46:0.02 and 88percent ee. |
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Example 14Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3dimethylamino-1-(2-thienyl)-1-propanol (50 g, 269.8 mmoles), sodium hydroxide (21.58 g, 539.7 mmoles), potassium carbonate (83.91 g, 607.2 mmoles) and 1-methyl-2-pyrrolidinone (500 mL) were charged in a reactor. The suspension was heated to 80° C. and 10 mL of solvent distilled under vacuum in 4 hours. The mixture then was allowed to cool to 40° C. under argon and 1-fluoronaphthalene (38 mL, 296.8 mmoles) was added. The mixture was stirred at 40° C. for 40 hours, and then at 60° C. for 24 hours. The mixture was allowed to cool to ambient temperature. Water (350 mL) and isopropyl acetate (150 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (130 mL). The organic layers were combined and washed with water (250 mL). To this solution pyridine sulfur trioxide complex (4.3 g, 27.0 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 mL). The aqueous pH was 6. To the organic layer was added oxalic acid dihydrate (27.2 g, 215.8 moles). The mixture was stirred for 20 hours at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (2.x.40 mL) and dried under vacuum at 50° C. to yield 57.39 g of the product as a-white solid (Yield: 53percent; HPLC (peak area at 220 nm) oxalic acid 2.69percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.21percent, 1-naphthol 0.43percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.42percent; XRD analysis as shown in FIG. 6, Form B; IR as shown in FIG. 7, Form B; Titration 93.14percent). |
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Example 6; Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium hydroxide (0.324 kg, 8.1 moles, 2 eq), potassium carbonate (126 kg, 9.1 moles, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (750 g, 4.05 moles), were heated in DMSO (7.5 L) at 80° C. for 3 hours and cooled to 40° C. 1-fluoronaphthalene (770'gi.5.3 mol, 1.3 eq) was then added over 5 minutes. Next, the mixture was heated at 40° C. for 17 hour and then at 50-60° C. for 40 hours. The molar ratio of product (Compound IV) to staring alcohol (Compound S-II) was 85.3:14.7, and Compound IV was 92percent ee as determined by HPLC of an aliquot. The mixture was then cooled to 20° C. and quenched with water (5 L). The mixture was divided in two and each portion was extracted twice with isopropyl acetate (2.x.2 L). The four organic phases were combined, washed with water (5 L), and pyridine sulphur trioxide complex (110 g, 0.69 moles, 0.17 eq.) was added. The mixture was then stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.38 kg, 3.0 moles, 0.75 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and slurried in acetone (2.5 L) and isopropyl acetate (5 L) for one hour, and then filtered to yield 2.1 kg (wet product) of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (Yield: 75percent; equivalent to 1.21 kg, (dry product)). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 98.7:1.3 as determined by HPLC. Compound IV oxalate salt was 92percent ee as determined by chiral HPLC.; Example 7Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (8.635 g, 216 mmol, 2 eq), potassium carbonate (33.565 g, 243 mmol, 2.25 eq.) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmol), were heated in DMSO (200 mL) at 80° C. (temperature inside flask) under vacuum such that approximately 100 mL of DMSO were distilled in 1 hour. An additional 100 mL of DMSO were then added, and the mixture heated at 80° C. for a further 2 hours. Thereafter, the mixture was cooled to 40° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (17.35 g, 119 mmol, 1.1 eq) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analysed by NMR. Once an approximately 92percent conversion had been achieved (24 hours), as determined by the ratio of Compounds IV and S-II in the 1H-NMR spectrum, the mixture was cooled to 25° C., quenched with water (150 mL) and extracted twice with isopropyl acetate (2.x.100 mL). The two organic phases were combined, washed with water (75 mL), and pyridine sulphur trioxide complex (1.72 g, 10.8 mmol, 0.1 eq.) was added. The mixture was then stirred at 20° C. for 60 minutes and washed with water (150 mL). The aqueous layer was analysed to be pH 6.8. Oxalic acid dihydrate (10.9 g, 86 mmol, 0.8 eq.) was then added, and the mixture stirred at 15-20° C. for 16 hours. The mixture was then filtered and homogenized to yield 41.83 g of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt as an off-white solid (Loss on drying: 6.94percent, Titration: 98.1percent, Karl Fischer: 0.06percent).Example 8Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine Oxalic Acid SaltSodium hydroxide (34.2 kg), potassium carbonate (133 kg) and (S)-3-dimethylamino-1-(2-thienyl)-1-propanol (80 kg), were heated in DMSO (1328 kg) at 70-80° C. for one hour and then distilled under vacuum at this temperature such that approximately 445 kg of DMSO were distilled within 4 hours. After this time the mixture was cooled to 40-45° C. and stirred under an atmosphere of nitrogen. 1-Fluoronaphthalene (69 kg) was then added, and the mixture maintained with stirring at 40° C. Samples were taken periodically and analyzed by HPLC. Once approximately 92percent conversion had been achieved (24 hours), the mixture was cooled to 25° C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2.x.460 kg). The two organic phases were combined, washed with water (400 kg), and added to pyridine sulphur trioxide complex (6.8 kg.). The mixture was then stirred at 20-25° C. for 30 minutes and then a solution made from ammonium chloride (32 kg) in water (533 kg) was added and the mixture stirred for 30 minutes. The aqueous layer was adjusted to pH 6.5-pH 7.0, the mixture stirred for an additional 30 minutes before the aqueous phases were separated. Oxalic acid dihydrate (44 kg) was dissolved in methanol (173 kg), and this solution was added over a period of 2 hours to the organic mixture above maintained at 40-45° C. The mixture was placed under vacuum at this temperature and 500 kg of solvent removed by distillation. Iso-propyl acetate (1000 kg) was added and a further 500 kg removed by distil... |
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Example 5Preparation of (S)-N-methyl-(3-(1-naphthyloxy)-3-thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride)Sodium tert-pentoxide (1.06 kg of a 40percent solution in toluene, 3.85 moles, 0.95 eq.) was added over 10 minutes to a suspension of (S)-3-dimethylamino-12-thienyl)-1-propanol (750 g, 4.05 moles) dissolved in DMSO (3 L) at a temperature of 13-15° C. The (S)-3-dimethylamino-1-(2-thienyl)-1-propanol was dissolved completely to form a brown solution. The mixture was then heated to 70° C. for one hour before 1-fluoronaphthalene (710 g, 4.86 moles) was added over 5 minutes. The mixture was then heated at 70° C. for 7 hours. The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was observed to be 91.6:8.4 as determined by HPLC of an aliquot. The mixture was next cooled to 20° C., quenched with water (5 L), and extracted twice with isopropyl acetate (4+3 L). The organic layers were then combined, washed with water (4 L), and pyridine sulphur trioxide complex (64 g, 0.4 moles, 0.1 eq.) was added. The mixture was stirred at 20° C. for 30 minutes, and washed with water (5 L). Oxalic acid dihydrate (0.41 kg, 3.2 moles, 0.8 eq.) was then added, and the mixture was stirred at 25° C. for 2.5 hours and then at 20° C. for 2 days. The mixture was next filtered and washed with isopropyl acetate (2.5 L) to yield (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt as an off-white solid (2.3 kg (wet product), equivalent to 1.3 kg (dry product) in 80percent yield). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 99.6:0.4 as determined by HPLC. |
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Example 13Preparation of (S)-N,N-dimethyl-3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-3-dimethylamino-1-(2-thienyl)-1-propanol (20 g, 108 mmoles), potassium hydroxide (12.11 g, 216 mmoles) and DMSO (300 mL) were charged in a reactor. The suspension was heated to 75-80° C. and 100 mL of solvent distilled under vacuum in 1 hour. The mixture then was allowed to cool to 40° C. under nitrogen and 1-fluoronaphthalene (15.3 mL, 119 mmoles) was added. The mixture was stirred at 40° C. for 46 hours. The mixture was allowed to cool to ambient temperature. Water (300 mL) and isopropyl acetate (200 mL) were added; the mixture was stirred and the layers were separated. The aqueous layer was extracted with isopropyl acetate (100 mL). The organic layers were combined and washed with water (100 mL). To this solution pyridine sulfur trioxide complex (1.7 g, 11 mmoles) was added and the mixture stirred at room temperature for 1 hour. The mixture was washed with water (50 mL). The aqueous pH was 6.5. To the organic layer was added oxalic acid dihydrate (10.9 g, 86 mmoles). The mixture was stirred for 1 hour at ambient temperature and then filtered. The filter cake was washed with isopropyl acetate (25 mL) and dried under vacuum at 50° C. to yield 28.96 g of the product as a white solid (Yield: 67percent; Titration 89.68percent; HPLC (peak area at 220 nm) oxalic acid 2.09percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.045percent, 1-naphthol 0.20percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.19percent; XRD analysis as shown in FIG. 4, Form C; IR as shown in FIG. 5, Form C). |
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Stage-IV: Preparation of (3S)-N, N-dimethyl-3-(l-naphthyloxy)-3-(2-thienyl) propan-1-ammonium oxalateCharge DMSO (500 ml) to the flask. Charge S-(-)-3-(dimethylamino)-l-(2-thienyl) propan-1-ol (100 g) to the flask. Stir the reaction mass for 10 mins to get clear solution. Cool to 10-150C. Charge Sodium hydride (23.84 g) to the reaction mass at 10-150C. Stir the reaction mixture for 30 min at ambient temperature. Add Potassium Iodide (9.0 g) at 20-250C. Heat the reaction mixture to 65-75°C. Add a solution of 1-Fluoronaphthalene in DMSO (71.6 ml in 100 ml) to the reaction mixture. Stir the reaction mixture for 5 hrs. After the completion of the reaction, cool the reaction mixture to 20-250C. Add methanol (5 ml) at 20-250C under nitrogen. Add D M Water (6000 ml) to the reaction mixture. Add Ethyl acetate (500 ml) to the reaction mixture. Stir the reaction mixture for 15 mins. Separate the org. layer. Re-extract the org. layer with Ethyl acetate (500 ml). Combine both org. layer and wash with D M Water (300 ml). Remove Ethyl acetate (-500 ml) under vacuum at below 500C. Add Ethyl acetate (500 ml) to the residual mass. Add Oxalic acid dihydrate (71.5 g) to the reaction mass. Add Methanol (50 ml) to the reaction mass. Stir the reaction mixture for 1 hr. Cool the reaction mixture to 0-50C. Stir the reaction mixture for 2 hrs. at 0-50C. Filter the content. Wash the wet cake with Ethyl acetate (100 ml). Suck dry the wet cake. Dry the wet material in hot air oven at 50-600C. |
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Example 2: <n="8"/>A 150 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at 200C. The mixture was stirred until complete dissolution, and 4.20 g of NaOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 600C, and stirred for 5 days or till full consumption of AT-OL.To the reaction mixture was added water, followed by 5 ml AcOH and 60 ml ethyl acetate. After phase separation, the water phase was extracted with ethyl acetate and the organic extracts were combined, and concentrated to dryness to give 17.34 g of brownish oil containing 8.80 percent enantiomer R. |
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Example 7:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7 g OfNa+MeO" were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 26 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 19 g of brownish oil containing 5.87 percent enantiomer R.Example 8:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7 g OfNa+MeO" were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 1100C, and stirred for 26 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, dried on <n="10"/>MgSO4, and concentrated to dryness to give 13.37 g of brownish oil containing 9.53 percent enantiomer R. |
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Example 5:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMF at room temperature under N2- The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an <n="9"/>additional time. After 15 minutes, S ml of 1 -fluoronaphthalene were added, the solution was heated to 600C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 16.16 g of brownish oil containing 1.49 percent enantiomer R. |
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Example 4:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml ACN at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 22.2 g of brownish oil containing 0.53 percent enantiomer R. |
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Example 3:A 100 ml reactor three necked flask equipped with mechanical stirrer, thermometer, and condenser was charged with 1O g of AT-OL and 60 ml DMSO at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 400C, and stirred for 120 hours (or until completion).' To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give brownish oil containing 5.80percent enantiomer R. |
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Example 6:A 250 ml two necked flask equipped with magnetic stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 15 minutes, 8 ml of 1 -fluoronaphthalene were added, the solution was heated to 6O0C, and stirred for 27 hours.To the reaction mixture was added water, followed by 10 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 20.37 g of brownish oil containing 1.35 percent enantiomer R.Example 9:A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 30 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to SO0C, and stirred for 18 hours.To the reaction mixture was added 90 ml of water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 20 g of brownish oil containing 0.52percent enantiomer R.Example 10:A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature. The mixture was stirred until complete dissolution, and 7.11 g of KOH were added and stirred for an additional time. After 30 minutes, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 1100C, and stirred for 26 hours.To the reaction mixture was added 90 ml of water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 21 g of brownish oil containing 0.47 percent enantiomer R. Example 11 :A 250 ml reactor equipped with a mechanical stirrer, and condenser was charged with 1O g of AT-OL and 60 ml DMA at room temperature under N2. The mixture was stirred until complete dissolution, and 6 g of KOH were added and stirred for an additional time. After one hour, 8 ml of 1-fluoronaphthalene were added, the solution was heated to 800C, and stirred at the same temperature. During the following 4 hours, two portions of KOH were added (6 g), and the reaction mixture kept at the same temperature for an additional hour.To the reaction mixture was added water, followed by 12 ml HCl (5percent) and 60 ml ethyl acetate. After phase separation, the organic phase was concentrated to dryness to give 25 g of brownish oil containing 4.85 percent enantiomer R. |
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Example 5 Preparation of DNT To a solution of 7 g. of AT-OL in 42 ml of DMSO at room temperature were added 5 g of KOH, and stirred for an additional time. After 1 hour, 5 ml of 1-fluoronaphthalene were added, the solution was heated to 60° C., and stirred overnight. To the reaction mixture was added water, followed by 80 ml HCl [5percent], and extracted with 40 ml ethyl acetate (twice). After phase separation, the organic phase was washed with brine, and concentrated to dryness to give 10.5 g of brownish oil containing 0.12percent of DNT-ISO3: 0.12percent. |
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e) Preparation of (1S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamineSodium hydride (7.27 g) was added to the residue obtained from step (d) in dimethyl sulfoxide (122 mL) at 10-20° C. in portions over a period of 30 minutes. The mixture was stirred at about 25° C. for 30 minutes. Potassium benzoate (237 g, 0.0173 mole) was added to the reaction mixture and stirred at about 25° C. for 30 additional minutes. A solution of 1-fluoronaphthalene (30.3 g) in dimethyl sulfoxide (61 mL) was added to the reaction mixture at about 25° C. The reaction mixture was stirred at 50-55° C. for 3-4 h. After the completion of the reaction, the reaction mixture was cooled to 10° C. and acidified to the pH of 4-4.5 with acetic acid. The reaction mixture was diluted with water (732 mL) and further acidified to the pH of 1.5-2.0 with 6 N hydrochloric acid. The reaction mixture was washed with hexane (2.x.290 mL) at about 25° C. The pH of the aqueous layer was adjusted to about 11 using 30percent aqueous sodium hydroxide solution and subsequently extracted with ethyl acetate (2.x.584 mL). The ethyl acetate layer was washed with water (2.x.584 mL) and concentrated under reduced pressure to obtain the title compound as an oily mass. |
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Example1Preparation of (S)-(+)-N,N-dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine_10 g of (S)-(-)-3-(dimethylamino)-1-(thiophen-2-yl)propan-1-ol was dissolved in 60 mL of dimethyl sulfoxide at 25° C. To the soln. 2.3g of NaH (1.1 eq neat) was added slowly as 60percent dispersion in mineral oil with vigorous stirring. Reaction mass was stirred for 15 minutes. 0.86g of Potassium benzoate was added and stirred at the 25 to 30° C for 15 minutes. 9.46g of 1-Flouoro Naphthalene was added slowly to the reaction mixture. After complete addition, mixture was stirred at 25 to 30° C for 48h. Reaction mixture was quenched by pouring it into crushed ice. 60mL of Ethyl acetate was added and stirred for 10 minutes. The biphasic mixture was filtered through celite. Separated the layers aqueous phase was stirred again with 30mL Ethyl acetate. Separated the layers aqueous phase was extracted with 30mL Ethyl acetate. Combined extract was washed with water. Organic layer was dried over sodium sulfate concentrated under vacuum at 40-45° C to obtain syrup. |
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With sodium hydride; In dimethyl sulfoxide; mineral oil; at 20 - 50℃; for 18h; |
Into a suspension of DMSO (75 mL) and NaH (60 percent suspension in mineral oil; 2.9 g) (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was added carefully at 20-25 °C. The reaction mixture was then heated to 40 °C and a solution of F- naphthalene (9 mL) in DMSO (10 mL) was slowly added dropwise. After complete addition the suspension was heated to 50 °C and kept at 50 °C over night. After 18 hours the mixture was cooled to 20 °C and carefully poured into the ice-cold mixture of water (200 mL) and acetic acid ( 12 mL). After quenching the mixture was heated to 20 °C, pl l was measured (5-5.5) and hexane (80 mL) was added. After 10 minutes of stirring the phases were separated. The aqueous phase was alkalized with 10 percent NaOI I and extracted into toluene (100 mL). The toluene phase was rinsed with water ( 1 x 60 mL). The toluene phase of (S)-N.N-dimethyl-3-(naphthalen-l-yloxy)-3-(thiophen-2- yl)propan-l -amine was heated to 55 °C, diisopropylethylamine (0.69 ml.) was added and phenyl chloro formate (10.35 mL) was added slowly dropwise. It was heated for 1.25 hours, 1 percent NaHCOj (215 mL) was added and after 10 minutes at 40-50 °C the phases were separated. The organic phase was rinsed with 0.5 M HC1 (2 X 50 mL) and 1 percent NaHC03 (50 mL). The rinsed toluene phase was concentrated on a rotary evaporator to a constant mass, dissolved in DMSO (150 mL), heated to 45 °C, the aqueous solution (50 mL) of NaOH (8.7 g) was added and heated for 18 hours at 50 °C. After the hydrolysis was completed the cooled mixture was poured into an ice- cold mixture of water (250 mL) and acetic acid (12 mL, pH about 5-5.5). The aqueous phase was rinsed with hexane (40 mL), alkalized with a 10 percent base and a duloxetine base was extracted into isopropyl acetate (2 X 60 mL). The organic phase was rinsed with water (2 x 40 mL), treated in hot with activated carbon and the hot filtrate was cooled. To the cooled filtrate acetic acid (5 mL) was added and the product was precipitated with 2.5 M HCi in isopropyl acetate (23 mL). The suspension was stirred at 10 °C - 15 °C for 5-6 hours. The precipitate was filtered off and rinsed with cold isopropyl acetate. The product was dried in a vacuum drier at 50 °C for 5 hours. 13.5 g (75percent) with 99.71 percent HPLC purity and 99 percent ee were obtained, which was recrystallized from iPrOH. 12.46 g (92percent) of pure product (HPLC purity 99.92 percent and 99.9 percent ee) were obtained. |
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Example 1 Preparation of (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine III; In a 5 liters four necked round bottom flask equipped with mechanical stirrer, reflux condenser and thermometer sulfolane (300 mL) and sodium hydride 60percent in mineral oil (25 g) are loaded. To the resulting suspension a solution of II [(S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine] (100 g, in 450 ml of sulfolane) is quickly added. The suspension is heated to 70°C for 1 hour, 1-fluoronaphthalene (77 mL) is added and the mixture is further heated at 110°C for 3 hours. The mixture is then cooled at 10°C and quenched adding 3500 mL of water. Cyclohexane is then added (1L) and the phases are separated. The aqueous phase is further extracted with cyclohexane, the combined organic layer is washed with water and evaporated to dryness. The distilled cyclohexane can be reused in the same step, wile the resulting oil is dissolved in a 20percent aqueous solution of acetic acid at pH 4.5 and extracted with hexane twice. The hexane phase can be evaporated to residue to obtain distilled hexane which can be reused and a residue of 1-fluoronaphthalene which is recovered. The aqueous phase is made neutral with ammonium hydroxide and extracted with toluene (1L). About 100 mL of toluene are distilled in order to eliminate water as a water/toluene azeotrope and the resulting toluene solution containing III is used in the following step. |
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With sodium hydride; |
The duloxetine alkyl carbamate represented by the formula (Ib) was synthesized by a known method (steps 1 to 4 of the above scheme).Specifically, 2-acetylthiophene (63.1 g; 0.5 mol), dimethylamine hydrochloride (53.0 g; 0.65 mol), paraformaldehyde (19.8 g; 0.22 mol) and ethanol (80 ml) (1 ml) to give 3-dimethylamino-1- (2-thienyl) -1-propanone hydrochloride,Reduction with sodium borohydride, resolution with optically active mandelic acid yielded optically active (S) N, N-dimethyl-3- (2-thienyl) -3-hydroxypropylamine.Next, by reaction of 1-fluoronaphthalene with sodium hydride, N, N-dimethyl-duloxetine was obtained.Subsequently, the reaction with the corresponding alkyl chloroformate (4.6 ml; 48.5 mmol) gave the duloxetine alkyl carbamate represented by the above formula (Ib). The ethanol solution (10 mL) of the potassium hydrate (87percent of purity, 2.16g;33.5mmol) was added to the toluene solution (10 mL) of the obtained duloxetine ethyl carbamate (Ib) and (2.5g;6.7mmol) at the room temperature. It heated until it flowed back at 85 to 90 degree C about mixed liquor, and the solvent was distilled off until the internal temperature became 100 degrees C from there. Repeating distilling off of a solvent furthermore, in the range of 95 to 100 degree C, temperature was maintained and it stirred for 2 hours. It cooled to the room temperature and washed the organic layer obtained by adding water (10 mL) and ethyl acetate (10 mL) with water (20 mL). With sodium sulfate, it dried, concentration drying was filtered and carried out, and the compound of the title was obtained at 1.96 g (yield: 98.4percent, optical isomer:0.16percent).[0054]1H-NMR(400-MHz, DMSO-d6):8.23-8.20 (m, 1H), 7.86-7.82 (m, 1H), 7.53-7.49 (m, 2H), 7.44-7.41 (m, 2H), 7.33 (t, 1H), 7.21 (dd, 1H), 7.05(d,1H),6.97(dd,1H),5.99(t,1H),2.62(2H,t)2.26(3H,s),2.36-2.29(m,1H),2.12-2.03(m,1H) |