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Chemical Structure| 161005-84-1 Chemical Structure| 161005-84-1

Structure of 161005-84-1

Chemical Structure| 161005-84-1

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Product Details of [ 161005-84-1 ]

CAS No. :161005-84-1
Formula : C19H24NO5PS
M.W : 409.44
SMILES Code : CN(C)CC[C@H](OC1=C2C=CC=CC2=CC=C1)C3=CC=CS3.O=P(O)(O)O
English Name :(S)-N,N-Dimethyl-3-(naphthalen-1-yloxy)-3-(thiophen-2-yl)propan-1-amine phosphate
MDL No. :MFCD08458281

Safety of [ 161005-84-1 ]

Application In Synthesis of [ 161005-84-1 ]

* 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.

  • Downstream synthetic route of [ 161005-84-1 ]

[ 161005-84-1 ] Synthesis Path-Downstream   1~6

  • 1
  • [ 161005-84-1 ]
  • [ 1885-14-9 ]
  • [ 136434-34-9 ]
YieldReaction ConditionsOperation in experiment
With hydrogenchloride; ammonium hydroxide; sodium hydroxide; sodium hydrogencarbonate; acetic acid; N-ethyl-N,N-diisopropylamine In hexane; water; dimethyl sulfoxide; ethyl acetate; toluene 2 (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride Preparation 2 (S)-(+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride Five g of the product of Example 1 was stirred in a mixture of 40 ml of toluene and 40 ml of water at 40° C., and 2.5 ml of 30% ammonium hydroxide solution was added. The mixture was stirred for 10 minutes at constant temperature and the layers were separated. The organic phase was washed with water, dried with magnesium sulfate and filtered. The filtrate was concentrated to half volume under vacuum and was heated to 55° C. Then 0.16 g of diisopropylethylamine was added, followed by the dropwise addition of 2.39 g of phenyl chloroformate. The mixture was stirred at 55° C. for 1.25 hours, and 50 ml of 1% sodium bicarbonate solution was added. The mixture was stirred for ten minutes at 40°-50° C., and the phases were separated. The organic phase was washed twice with 0.5 N hydrochloric acid, and then washed with 1% sodium bicarbonate solution. The washed organic phase was divided in half, and one aliquot was evaporated under vacuum and 26 ml of dimethylsulfoxide was added to the residue. The mixture was heated to 45° C., and 1 g of sodium hydroxide and 6 ml of water was added dropwise. The basic mixture was stirred for 18 hours at 50° C., diluted with 17 ml of water, and acidified to pH 5.0-5.5 by addition of acetic acid. Then 20 ml of hexane was added, the mixture was stirred for ten minutes, and the phases separated. The aqueous phase was made basic to pH 10.5 by addition of 50% aqueous sodium hydroxide, and 17 ml of ethyl acetate was added. After stirring for 10 minutes, the phases were separated, and the aqueous layer was extracted with another 17 ml of ethyl acetate. The combined organic extracts were washed with water and concentrated to 10 ml under vacuum. 0.46 g of concentrated hydrochloric acid was added to the residue, and then a seed crystal and an additional 10 ml of ethyl acetate was added. The mixture was stirred for 30 minutes more, and the solution was concentrated to 10 ml under vacuum. The residue was stirred for 1 hour at ambient temperature and 1 hour at 0° C. to produce a slurry, which was filtered. The solid was washed with chilled ethyl acetate to obtain 1.32 g of the desired product, which was duloxetine as a white solid of potency 99.8%.
  • 2
  • [ 321-38-0 ]
  • [ CAS Unavailable ]
  • [ 132335-44-5 ]
  • [ 161005-84-1 ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In hexane; water; dimethyl sulfoxide; mineral oil 1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt EXAMPLE 1 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt A 13.5 g portion of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine was dissolved in 80 ml of dimethylsulfoxide at 25° C. To the solution was slowly added 3 g of sodium hydride as a 60% dispersion in mineral oil, with vigorous stirring. After 15 minutes of stirring, 1.17 g of potassium benzoate was added and stirring was continued at approximately constant temperature for another 15 minutes. Then, 12.8 g of 1-fluoronaphthalene was slowly added to the reaction mixture, and after the addition was complete, the mixture was heated and was stirred for 2.5 hours at 60°-65° C. The mixture was then poured slowly into 190 ml of cold water and the DH was adjusted to 4.8 by addition of acetic acid. The temperature of the mixture was brought to 25° C., and 75 ml of hexane was added and stirring was continued for 10 minutes. The layers were then separated and the aqueous phase was stirred again with 75 ml of hexane and the phases separated. The pH of the aqueous phase was adjusted to 10.2 by addition of aqueous sodium hydroxide, and 75 ml of ethyl acetate was added. That mixture was stirred for 15 minutes at 25° C., and the 2-phase mixture was vacuum filtered through a pad of filter aid. The phases of the filtrate were allowed to separate, and the aqueous phase was extracted with 75 ml of ethyl acetate. The extract was combined with the previous ethyl acetate layer, and that mixture was washed with 100 ml of water. The organic layer was stirred at 25° C., and to it was added, dropwise, 7 g of 85% phosphoric acid. After the addition was complete, the mixture was stirred for 20 minutes more and was then cooled to 0° C. and stirred for 1 hour at that temperature. The slurry was then filtered and the solids washed three times with 20 ml portions of cold ethyl acetate. The solid was dried at 60° C. to afford 24.19 g of the title compound as a white solid, 98.1% potency, adjusted yield 79.6%, 91% EE.
YieldReaction ConditionsOperation in experiment
3 (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride PREPARATION 3 (+)-N-methyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine hydrochloride Five g of the product of Preparation 2 was stirred in a mixture of 40 ml oftoluene and 40 ml of water at 40°, and 2.5 ml of 30% ammonium hydroxide solution was added. The mixture was stirred for 10 minutes at constant temperature and the layers were separated. The organic phase was washed with water, dried with magnesium sulfate and filtered. The filtratewas concentrated to half volume under vacuum and was heated to 55°.
  • 4
  • [ 321-38-0 ]
  • [ CAS Unavailable ]
  • [ 161005-84-1 ]
YieldReaction ConditionsOperation in experiment
With phosphoric acid In mineral oil,with; hexane; water; dimethyl sulfoxide; ethyl acetate 2 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt PREPARATION 2 (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt A 13.5 g portion of (S)-(-)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanaminewas dissolved in 80 ml of dimethylsulfoxide at 25°. To the solution was slowly added 3 g of sodium hydride as a 60% dispersion in mineral oil,with vigorous stirring. After 15 minutes of stirring, 1.17 g of potassium benzoate was added and stirring was continued at approximately constant temperature for another 15 minutes. Then, 12.8 g of 1-fluoronaphthalene was slowly added to the reaction mixture, and after the addition was complete, the mixture was heated and was stirred for 2.5 hours at 60°-65°. The mixture was then poured slowly into 190 ml of cold water and the pH was adjusted to 4.8 by addition of acetic acid. The temperature of the mixture was brought to 25°, and 75 ml of hexane was added and stirring was continued for 10 minutes. The layers were then separated and the aqueous phase was stirred again with 75 ml of hexane andthe phases separated. The pH of the aqueous phase was adjusted to 10.2 by addition of aqueous sodium hydroxide, and 75 ml of ethyl acetate was added. That mixture was stirred for 15 minutes at 25°, and the 2-phase mixture was vacuum filtered through a pad of filter aid. The phases of the filtrate were allowed to separate, and the aqueous phase wasextracted with 75 ml of ethyl acetate. The extract was combined with the previous ethyl acetate layer, and that mixture was washed with 100 ml of water. The organic layer was stirred at 25°, and to it was added, dropwise, 7 g of 85% phosphoric acid. After the addition was complete, themixture was stirred for 20 minutes more and was then cooled to 0° and stirred for 1 hour at that temperature. The slurry was then filtered and the solids washed three times with 20 ml portions of cold ethyl acetate. The solid was dried at 60° to afford 24.19 g of the title compound as a white solid, 98.1% potency, adjusted yield 79.6%, 91% EE.
  • 5
  • [ 321-38-0 ]
  • [ 132335-44-5 ]
  • [ 161005-84-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: 1-Fluoronaphthalene; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With potassium hydroxide In diethylene glycol dimethyl ether at 120℃; for 3 - 6h; Stage #2: With phosphoric acid In water; ethyl acetate for 1.08333 - 1.25h; 1 EXAMPLE 1; Arylation of (S)-(-)-N,N-dimethyl-3(2-thienyl)-3-hydroxypropanamine To a 25 mL 3-neck round bottom flask equipped with a condenser, N2 inlet, thermocouple, and overhead stirrer charge Compound Ib (0.55 g, 3 mMol), powdered KOH (0.9 g, 14.2 mMol), diglyme (6 mL) and 1-fluoronaphthalene (0.5 mL). Heat the mixture with good agitation to 120° C. for 3 to 6 hrs. Cool to ambient temp. and dilute with water (6 mL) and EtOAc (6 mL). Separate layers, back extract aqueous with EtOAc (6 mL). Separate layers and combine organic layers. Place organic layers in a 25 mL 3-neck round bottom flask with overhead agitation. Slowly add 85% H3PO4 (0.25 mL). Seed after 10 drops have been added. Stir 5-15 minutes, complete acid addition and stir 1 hr. Filter and wash cake with EtOAc (10 mLs). Dry under reduced pressure to yield 1.0 g of the title compound. % ΔR:0.2. Monitor the % R enantiomer by chiral HPLC under the following conditions: Column; Diacel Chiralcel OD-H, 5micron silica, 4.6×250 mm internal diameter, 40° C.; Solvent: 95% hexane, 5% isopropanol+0.2% DEA, 1 mL/min; detection UV 280 nm.
Stage #1: (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol With sodium hydride In dimethyl sulfoxide at 20℃; for 2h; Stage #2: 1-Fluoronaphthalene With potassium 4-methylbenzoate In dimethyl sulfoxide at 20 - 65℃; for 5h; Stage #3: With phosphoric acid In ethyl acetate for 0.5h; 1 100 gm of (S) - (+)-N, N-Dimethyl-3-(2-thienyl)-3-hydroxypropanamine is dissolved in DMSO (500 ml) at room temperature. Sodium hydride (23 gm) is added over a period of 1 hour in three equal lots at room temperature and stirred for 1 hour. 10 gm of potassium 4-methyl benzoate as added and stirred for 15 minutes. The reaction mixture was heated to about 55 °C and then 4-fluoronapthalene (100 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 (600 ml) and pH was adjusted to about 4 with 140 ml of acetic acid. Reaction mixture was washed with pet ether (3 X 100 ml). Aqueous layer was separated and pH adjusted about 8.5 with caustic soda and extracted with ethyl acetate (2 X 200 ml; 1 X 150 ml). The organic layer was washed with saturated aqueous sodium chloride solution (3x200) and further dried with sodium chloride. The organic layer pH was adjusted to about 2 with phosphoric acid and maintain for 30 minutes. The precipitated phosphate salt was filtered and washed with ethyl acetate to obtain 230 gm of the title compound as wet solid.
  • 6
  • [ 161005-84-1 ]
  • [ 1885-14-9 ]
  • [ 947686-09-1 ]
YieldReaction ConditionsOperation in experiment
Stage #1: (S)-(+)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine, phosphoric acid salt With ammonia In water; toluene for 0.166667h; Stage #2: phenyl chloroformate With triethylamine In toluene at 50℃; for 1.75h; 2 100 gm of dry (S)-(+) N, N-Dimethyl-3-(l-naphthalenyloxy)-3-(2- thienyl) propanamine phosphate was charged in a flask containing 1000 ml of water and 425 ml of toluene and stirred for 5 minutes. 87.5 ml of aqueous ammonia solution was added and stirred for 10 minutes. Separate the aqueous layer and extract with toluene (2 X 250 ml). Total organic layer was washed with 10 % aqueous sodium chloride solution (2 X 200 ml) and further dried with sodium chloride. The " organic layer was distilled completely under vacuum to obtain 75 gm of freebase. 75 gm of the above obtained freebase was dissolved in toluene (125 ml) and added triethylamine (6.2 gm) and stirred for 15 minutes. A mixture of phenylchloroformate (60 gm) and toluene (65 ml) was added slowly for about 30 minutes at below 50 0C and stirred for about 1 hour. The reaction mixture was cooled to room temperature and washed with 5% aqueous sodium bicarbonate solution (2 X 100 ml). The organic layer was washed with 5% aqueous HCl solution(2 X 100 ml) followed by with 5% aqueous sodium bicarbonate solution (2 X 100 ml) .The organic layer was washed with 10 % aqueous sodium chloride solution (3 X 100ml) and further dried with sodium chloride. The final organic layer was distilled completely under vacuum to obtain 100 gm of the title compound as residue.
 

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