Structure of 132335-46-7
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CAS No. : | 132335-46-7 |
Formula : | C19H21NOS |
M.W : | 311.44 |
SMILES Code : | CN(C)CC[C@H](OC1=C2C=CC=CC2=CC=C1)C3=CC=CS3 |
MDL No. : | MFCD08458281 |
GHS Pictogram: |
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Signal Word: | Warning |
Hazard Statements: | H361 |
Precautionary Statements: | P501-P202-P201-P280-P308+P313-P405 |
* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | at 20℃; for 21 h; | Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40° C. to yield 10.87 g of the product as a white solid (Yield: 84.2percent; HPLC (peak area at 220 nm) oxalic acid 1.78percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10percent, 1-naphthol 0.35percent, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65percent; Titration: 99.5percent; Karl Fischer: 0.06percent; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6° C.). |
78.6% | at 20℃; for 2 h; | Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50° C. to yield 10.14 g of the product as a white solid (Yield: 78.6percent; HPLC (peak area at 220 nm) oxalic acid 1.56percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36percent; Titration: 99.4percent; Karl Fischer: 0.06percent; IR essentially as shown in FIG. 3, Form A). |
78.9% | at 20℃; for 16 h; | Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55° C. to yield 10.21 g of the product as a white solid (Yield: 78.9percent; HPLC (peak area at 220 nm) oxalic acid 1.66percent, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24percent; Titration: 100.1percent; Karl Fischer: 0.22percent; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A). |
77% | at 20℃; for 1 h; | Preparation of DNT Oxalate Example 6 To a solution of 2.1 g of DNT-base (12percent enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g (77percent yield) of DNT-oxalate were obtained containing 12percent of enantiomer R. |
88 % ee | Stage #1: With pyridine-SO3 complex In dimethyl sulfoxide; toluene for 0.5 h; Stage #2: for 16 h; |
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. |
92 % ee | Stage #1: With pyridine-SO3 complex In Isopropyl acetate; dimethyl sulfoxide at 20℃; for 1 h; Stage #2: at 15 - 20℃; for 16 h; |
Example 6Preparation 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). |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
With ammonium hydroxide; In water; toluene; at 25℃; for 0.333333 - 0.5h; | Example 18: A 2 liter reactor, equipped with a mechanical stirrer, was charged with a mixture of 100 g of (S)-(+)-DNT-Oxal, 600 ml of water, 96 ml of a 22 percent ammonium hydroxide solution, and 1 liter of toluene. The mixture was stirred at 25C for 20 to 30 minutes, and the organic phase was separated and washed three times with 300 ml of water, providing a toluene solution of (S)-DNT-base, which was used in Example 19 without evaporation. | |
With sodium hydroxide; In water; toluene; at 40℃; for 0.5h;Product distribution / selectivity; | The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt (2.0 kg, 1.15 kg dry mass equivalent, 2.9 moles) was then suspended in water (5 L) and toluene (4 L) and sodium hydroxide (50% aqueous solution, 600 g, 7.5 moles, 2.6 eq) was then added. The mixture was then stirred vigorously and the layers were separated. The aqueous layer was extracted with toluene (3 L), and the organic layers were combined, washed with water (2×2.5 L), dried with sodium sulphate (300 g) and filtered. The mixture was then evaporated to a final volume of about 4.5 L, and diisopropylethylamine (37 g, 0.29 moles, 0.1 eq.) was added followed by the addition of 1-chloroethyl chloroformate (456 g, 3.2 moles,1.1 eq.) over 20 minutes at a temperature of between 20 and 30 C. The mixture was heated to 50 C. for 5 hours, cooled to 30 C., and washed with 10% aqueous sodium hydroxide (1 L) followed by water (1 L). Methanol (5 L) was added, and the mixture stirred at 30 C. for 44 hours. The methanol was then distilled under vacuum at a temperature of 30 C., and acetone (5 L) was added to the residue causing precipitation. The mixture was next stirred at 20 C. for 17 hours, cooled to 0 C. for 90 minutes, and filtered (and the filter cake with acetone (2×1 L)). The resulting solid was dried under vacuum at 40 C. to yield 535 g of duloxetine hydrochloride as an off-white solid, (1.602 moles, 99.0% ee; Yield: 56% from the oxalate intermediate, 45% from (S)-3-dimethylamino-1-(2-thienyl)-1-propanol).; Example 9Preparation of (S)-N-methyl-(3-(1-naphthyloxy-3thien-2-yl) Propylamine Hydrochloride (Duloxetine Hydrochloride) Acetone Solvate(S)-N,N-Dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine oxalic acid salt, (161.93 kg humid from the procedure above containing 4% of (R)enantiomer, 132.78 kg dry mass equivalent), was suspended in 608 kg of deionised water and 882 kg of toluene. The mixture was stirred for 30 minutes before 61.4 kg of 50% sodium hydroxide aqueous solution was added at a rate such that the temperature did not exceed 40 C. The temperature was adjusted to 20-25 C. and the layers separated. The aqueous layer was extracted with toluene (547 kg), and the organic phases were combined and washed with deionised water (301 kg). The mixture was heated and distilled to remove 547 kg of solvent and then cooled to 20-25 C. Diisopropylethylamine (4.25 kg) was added over 30 minutes and without allowing the temperature to increase above 30 C., then 56.7 kg of 1-chloroethyl chloroformate was added. The mixture was heated to 50+/-3 C. and stirred for 2 hours at this temperature. It was then cooled to 20-25 C. and washed first with a mixture made from 85 kg of water and 47.3 kg of 30% aqueous ammonium hydroxide and then water 67 kg. To the organic layer, 519 kg of methanol was added, and the mixture stirred at 30-40 C. for not less than 24 hours. The mixture was filtered and distilled under vacuum to remove 823 kg of solvent without the internal temperature going above 40 C. Filtered acetone (518 kg) was added, and the mixture stirred at 20-25 C. for 2 hours. The mixture was cooled to 0-5 C., stirred for 2 hours and then filtered in a centrifuge filter, washing the product with 2×15 kg of acetone to yield 108.32 kg of duloxetine hydrochloride acetone solvate (Loss on drying 26.89%; Assay (titration) 99.62%; Karl Fischer analysis 0.00% water; analysis: 99.75% by HPLC peak area at 220 nm, impurities 1-naphthol 0.01%, 4-(3-Methylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol 0.01%, N,N-dimethyl-3-(1-naphthaleneyloxy)-3-(2-thienyl)-1-propylamine. 0.01%; Chiral assay: 99.2% (S)-duloxetine hydrochloride, 0.8% (R)-duloxetine hydrochloride). | |
With sodium hydroxide; In water; at 20 - 25℃;Product distribution / selectivity; | The (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine oxalic acid salt (2.0 kg, 1.16 kg dry mass equivalent, 2.9 moles) was then suspended in water (7.5 L), and sodium hydroxide (50% aqueous solution, 600 g, 7.5 moles, 2.6 eq.) was added with stirring at 20-25 C. The mixture was extracted twice with toluene (5+3 L) and the organic layers were combined, washed with water (2×2.5 L) filtered and concentrated to dryness to yield 859 g of the amine as an oil. 850 g of the oil was then dissolved in toluene (5 L) and diisopropylethylamine (79 g, 0.6 moles, 0.22 eq.) was added, followed by 1-chloroethyl chloroformate (247 g, 1.7 moles, 0.6 eq.) over 30 minutes at a temperature of 20 C. The mixture was next heated to 50 C. for 90 minutes, cooled to 36 C. and an additional 165 g of 1-chloroethyl chloroformate (1.2 moles, 0.4 eq.) was added over 15 minutes. The mixture was then heated to 50 C. for 30 minutes, cooled to 25 C., and washed with 10% aqueous sodium hydroxide (2 L). Methanol (5 L) was then added, and the mixture stirred at 25 C. for 16 hours and then at 30 C. for 24 hours. The methanol was distilled under vacuum at a temperature of 30 C., and acetone (5 L) added to the residue causing precipitation. The mixture was then stirred at 20 C. for 2 days, filtered, and the filter cake was washed-with acetone (3×0.5 L). The solid was then dried under vacuum at 40 C. to yield 371 g of (S)-duloxetine hydrochloride as an off-white solid (1.111 moles, 99.3% ee; Yield: 39% from the oxalate intermediate, 29% from (S)-3-dimethylamino-1-(2-thienyl)-1-propanol). |
With sodium hydroxide; In water; toluene; for 0.5h;pH 9 - 10; | Stage-IV: Preparation of Duloxetine HydrochlorideCharge D M Water (300 ml) to the flask. Charge (3S)-N, N- dimethyl-3-(l-naphthyloxy)-3-(2-thienyl) propan-1 -ammonium oxalate (100 g) to the flask. Stir the reaction mixture for 10-15 mins. Add Toluene (500 ml) to the flask. Add IN NaOH solution to the reaction mixture and adjust pH 9-10.Stir the reaction mixture for 30 mins. Separate the org. layer. Re-extract aq. layer with Toluene (500 ml). Combine both org. layer and wash with D M Water. Remove Toluene upto half volume under vacuum at below 500C. Make up the volume upto 1000 ml with Toluene (-500 ml) at 25-35C. Add Triethylamine (6.95 ml) to the reaction mixture 25-35C. Add Phenyl chloro formate (46.8 ml) to the reaction mixture25-35C. Heat the reaction mixture. Stir the reaction mixture for 1 hr at 60-650C. Add Triethylamine (6.95 ml) to the reaction mixture. Stir the reaction mixture at 60-650C. After the completion of the reaction; cool the reaction mixture to 20-250C. Add 10 % Sod. Carbonate soln to the reaction mixture. Stir the reaction mixture for 15-30 mins. Separate the org. layer. Wash the org. layer with D M Water. Remove Toluene completely under vacuum at below 500C. Cool the residual mass to 25-35C. Charge DMSO (500 ml) to the residual mass. Add 30% Sod. Hydroxide soln (150 ml) to reaction mixture. Heat the reaction mixture to 85-900C. Stir the reaction mixture at 85-900C for 3 hrs. After the completion of the reaction; cool the reaction mass to 20-250C. Add D M Water to the reaction mixture. Add Ethyl acetate to the reaction mixture. Stir the reaction mixture. Separate the org. layer. Re-extract the aq. layer with Ethyl acetate. Combine both org. layer and wash with D M Water. Remove Ethyl acetate completely under vacuum at below 500C. Add Acetone (300 ml) to the residual mass at 20-250C. Stir the reaction mixture for 10-15 mins. Add Ethyl acetate Hydrochloride (-40 ml) to the reaction mixture to adjust pH 1-2. Stir the reaction mixture for 1 hrs at 20-250C. Filter the content. Wash the wet cake with Acetone. Wash the wet cake with Ethyl acetate. Suck dry the wet cake. Dry the material under vacuum at 40-500C. | |
With ammonia; In water; toluene; at 25℃; for 0.333333 - 0.5h;Product distribution / selectivity; | Example 12:Preparation of (S)-DNT-baseA 2 liter reactor, equipped with a mechanical stirrer, was charged with a mixture of 100 g of(S)-(+)-DNT-Oxal. 600 ml of water, 96 ml of a 22 percent ammonium hydroxide solution, and 1 liter of toluene. The mixture was stirred at 25C for 20 to 30 minutes, and the organic phase was separated and washed three times with 300 ml of water, providing a toluene solution of (S)-DNT-base, which was used in Example 13 without evaporation. | |
With sodium hydroxide; In water; toluene; at 20 - 45℃;pH 11 - 12; | 50 g of (5 -jV,N-Dimethyl-3-( l -naphthalenyloxy)-3-(2-thienyl) propanamine oxalate was taken in 200 ml toluene and 100 ml water at room temperature. The pH of the resulting mixture was adjusted between 1 1 - 12 using 30% sodium hydroxide solution. The resulting mass was heated at 40-45C for 1 hour. The reaction mass was cooled to room temperature, filtered and washed with toluene. The layers were separated and the aqueous layer was extracted with toluene. The organic layer is combined, wash with water and distilled under vacuum at 50-55C. To the resulting oily residue, 200 ml toluene and 8.g diisopropyl ethylamine was added at room temperature. The resulting mixture was cooled at 1 5-20C and 23.2 g of phenyl chloroformate was added. The reaction mass was stirred for 2 hr, sodium bicarbonate solution ( 1 %) was added and the resulting mixture was heated at 40-45C for 1 hr. The resulting mixture was cooled to room temperature and the layers were separated. The organic layer was first washed with 0.5 N HC1 solutions and then with 1 % NaHC0 solution. Finally the organic layers was combined and washed with water. To the resulting organic layer, 32.9 g potassium hydroxide was added and heated at 80-85C for 7 hr. The resulting mixture was cooled to room temperature and water was added under stirring. The organic layers were separated, and wash the aqueous layer with toluene. The organic layers were combined and filter through hyflo. The resulting filtrate was washed with water till pH 8-9 and the layers were separated. The organic layer was washed with water and distilled under vacuum to obtain oily residue. The resulting oily mass was taken in 500 ml ethyl acetate, cool to 0-5C and concentrated hydrochloric acid was added, stirred for 1 -2 hr as a result solid precipitate off. The resulting solid was filtered, washed with ethyl acetate and dried under vacuum 40-45C for 12- 13 hr to obtain title compound.Yield : 62-66%; Chiral purity: 99.5%. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
84.2% | In Isopropyl acetate; water; at 20℃; for 21h;Product distribution / selectivity; | Example 10; Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 moles, 0.8 eq) in water (30 mL) was then added. The resulting mixture was stirred for 21 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 40 C. to yield 10.87 g of the product as a white solid (Yield: 84.2%; HPLC (peak area at 220 nm) oxalic acid 1.78%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.10%, 1-naphthol 0.35%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 97.65%; Titration: 99.5%; Karl Fischer: 0.06%; XRD as shown in FIG. 1 (Form A); IR essentially as shown in FIG. 3 (Form A); TGA DSC as shown in FIG. 2, mp onset 152.6 C.). |
78.6% | In Isopropyl acetate; isopropyl alcohol; at 20℃; for 2h;Product distribution / selectivity; | Example 12Preparation of (S)-N,N-dimethyl(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in isopropanol (30 mL) was then added dropwise. The resulting mixture was stirred for 2 hours and filtered. The filter cake was dried under vacuum at 50 C. to yield 10.14 g of the product as a white solid (Yield: 78.6%; HPLC (peak area at 220 nm) oxalic acid 1.56%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.36%; Titration: 99.4%; Karl Fischer: 0.06%; IR essentially as shown in FIG. 3, Form A). |
78.9% | In methanol; Isopropyl acetate; at 20℃; for 16h;Product distribution / selectivity; | Example 11Preparation of (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine Oxalic Acid Salt(S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine (10 g, 32.1 mmoles) was dissolved in isopropyl acetate (50 mL) at ambient temperature. A solution of oxalic acid dihydrate (3.64 g, 25.7 mmoles, 0.8 eq) in methanol (4 mL) was then added. An additional volume of isopropyl acetate (50 mL) was added for improved stirring. The resulting mixture was stirred for 16 hours and filtered. The filter cake was washed with isopropyl acetate (10 mL) and dried under vacuum at 55 C. to yield 10.21 g of the product as a white solid (Yield: 78.9%; HPLC (peak area at 220 nm) oxalic acid 1.66%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol not detected, 1-naphthol not detected, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 98.24%; Titration: 100.1%; Karl Fischer: 0.22%; XRD as shown in FIG. 1 (Form A); IR as shown in FIG. 3 (Form A). |
77% | In ethyl acetate; at 20℃; for 1h; | Preparation of DNT Oxalate Example 6 To a solution of 2.1 g of DNT-base (12% enantiomer R) dissolved in 12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g (77% yield) of DNT-oxalate were obtained containing 12% of enantiomer R. |
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 (2×500 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 88% 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: 59%). 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 88% ee. | ||
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 (2×40 mL) and dried under vacuum at 50 C. to yield 57.39 g of the product as a-white solid (Yield: 53%; HPLC (peak area at 220 nm) oxalic acid 2.69%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.21%, 1-naphthol 0.43%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.42%; XRD analysis as shown in FIG. 6, Form B; IR as shown in FIG. 7, Form B; Titration 93.14%). | ||
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: 67%; Titration 89.68%; HPLC (peak area at 220 nm) oxalic acid 2.09%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.045%, 1-naphthol 0.20%, (S)-N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2-yl)propylamine 95.19%; XRD analysis as shown in FIG. 4, Form C; IR as shown in FIG. 5, Form C). | ||
Example 15Preparation 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 analysed by HPLC. Once approximately 92% conversion had been achieved (24 hours), the mixture was cooled to 25 C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2×460 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. Isopropyl Acetate (1000 kg) was added and a further 500 kg removed by distillation under vacuum. At this point precipitation occurred and the mixture was cooled to 0-5 C. and stirred for 2 hours. The product was filtered in a centrifuge filter, washed with isopropyl acetate (40 kg) and homogenised to yield 161.93 kg of the moist product as an off-white solid (Loss on Drying: 16.35%; Titration: 97.45%; Chiral Assay: 96% (S), 4% (R)-enantiomer; HPLC: oxalic acid 1.65%, 4-[3-dimethylamino-1-(2-thienyl)-1-propyl]naphthol 0.005%, 1-naphthol 0.02%, N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine 98.09%; XRD as shown in FIG. 8, Form E; IR as shown FIG. 9, Form E). | ||
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 40% 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 80% yield). The molar ratio of product (Compound IV) to starting alcohol (Compound S-II) was 99.6:0.4 as determined by HPLC. | ||
Example 6Preparation 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 92% 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 (2×2 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: 75%; 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 92% 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 92% 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 (2×100 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: 6.94%, Titration: 98.1%, Karl Fischer: 0.06%). | ||
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 92% conversion had been achieved (24 hours), the mixture was cooled to 25 C., quenched with water (533 kg) and extracted twice with isopropyl acetate (2×460 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 distillation under vacuum. At this point precipitation occurred, and the mixture was cooled to 0-5 C. and stirred for 2 hours. The product was filtered in a centrifuge filter, washed with isopropyl acetate (40 kg) and homogenized to give 161.93 kg of the moist product as an off-white solid (Loss on drying: 16.35%, Titration: 97.45%, Chiral assay (HPLC): 96% (S), 4% (R)-enantiomer, HPLC: oxalic acid 1.65%, 4-(3-Dimethylamino-1-thiophen-2-yl-propyl)-naphthalen-1-ol 0.005%, 1-naphthol 0.02%, N,N-dimethyl-(3-(1-naphthyloxy)-3-thien-2 yl)propylamine 98.09%). | ||
In methanol; ethyl acetate; for 1h; | 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 65-75C. 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. |
Yield | Reaction Conditions | Operation in experiment |
---|---|---|
In ethyl acetate; at 20℃; for 1h; | To a solution of 2.1 g of DNT-base (12% enantiomer R) dissolved in12 ml of ethyl acetate was added a solution of 0.6 g of oxalic acid in 12 ml of ethyl acetate. The resulting mixture was stirred at room temperature for an hour, filtrated and washed with ethyl acetate. After drying, in a vacuum oven for overnight, 2 g(77% yield) of DNT-oxalate were obtained containing 12% of enantiomer R. |
Tags: 132335-46-7 synthesis path| 132335-46-7 SDS| 132335-46-7 COA| 132335-46-7 purity| 132335-46-7 application| 132335-46-7 NMR| 132335-46-7 COA| 132335-46-7 structure
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H300 | Fatal if swallowed |
H301 | Toxic if swallowed |
H302 | Harmful if swallowed |
H303 | May be harmful if swallowed |
H304 | May be fatal if swallowed and enters airways |
H305 | May be harmful if swallowed and enters airways |
H310 | Fatal in contact with skin |
H311 | Toxic in contact with skin |
H312 | Harmful in contact with skin |
H313 | May be harmful in contact with skin |
H314 | Causes severe skin burns and eye damage |
H315 | Causes skin irritation |
H316 | Causes mild skin irritation |
H317 | May cause an allergic skin reaction |
H318 | Causes serious eye damage |
H319 | Causes serious eye irritation |
H320 | Causes eye irritation |
H330 | Fatal if inhaled |
H331 | Toxic if inhaled |
H332 | Harmful if inhaled |
H333 | May be harmful if inhaled |
H334 | May cause allergy or asthma symptoms or breathing difficulties if inhaled |
H335 | May cause respiratory irritation |
H336 | May cause drowsiness or dizziness |
H340 | May cause genetic defects |
H341 | Suspected of causing genetic defects |
H350 | May cause cancer |
H351 | Suspected of causing cancer |
H360 | May damage fertility or the unborn child |
H361 | Suspected of damaging fertility or the unborn child |
H361d | Suspected of damaging the unborn child |
H362 | May cause harm to breast-fed children |
H370 | Causes damage to organs |
H371 | May cause damage to organs |
H372 | Causes damage to organs through prolonged or repeated exposure |
H373 | May cause damage to organs through prolonged or repeated exposure |
Environmental hazards | |
Code | Phrase |
H400 | Very toxic to aquatic life |
H401 | Toxic to aquatic life |
H402 | Harmful to aquatic life |
H410 | Very toxic to aquatic life with long-lasting effects |
H411 | Toxic to aquatic life with long-lasting effects |
H412 | Harmful to aquatic life with long-lasting effects |
H413 | May cause long-lasting harmful effects to aquatic life |
H420 | Harms public health and the environment by destroying ozone in the upper atmosphere |
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