* 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.
Reference：
[1] Justus Liebigs Annalen der Chemie, 1931, vol. 487, p. 270,282
[2] Bulletin des Societes Chimiques Belges, 1966, vol. 75, p. 577 - 581
[3] Journal of Organic Chemistry, 2011, vol. 76, # 19, p. 7975 - 7984
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Yield
Reaction Conditions
Operation in experiment
75.6%
Stage #1: With sodium hydride In N,N-dimethyl acetamide at 70℃; for 0.333333 h; Stage #2: at 110℃; for 1 h;
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60percent sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 ° C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 ° C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6percent).
Reference：
[1] Patent: JP2016/172704, 2016, A, . Location in patent: Paragraph 0027; 0053
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Reference：
[1] Organic Process Research and Development, 2009, vol. 13, # 5, p. 854 - 856
[2] Patent: WO2009/87463, 2009, A2, . Location in patent: Page/Page column 7-8
With oxalic acid In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil
Example 4 Synthesis of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate In 50 ml of dimethylacetamide 0.5 g of sodium hydride (suspension in mineral oil) is suspended. Suspension is stirred and in few portions 2 g of (s)-3-(dimethylamino)-1-(thienyl)-propan-1-ol is added. After the addition is completed the suspension is warmed up to 70°C. 1.27 ml of 1-fluoronaphthalene is added and the reaction mixture is heated to 110°C. At this temperature the solution is stirred for another three hours. Then the reaction solution is dissolved with 300 ml of water and extracted twice with 100 ml ether. Combined ether phases are rinsed with water, dried with sodium sulphate end evaporated to dryness. Obtained oil is dissolved in 50 ml ethyl acetate and 0.9 g of oxalic acid is added. The suspension is further stirred for one hour, filtered off the product and washed with ethyl acetate. The product is dried to obtain 3.5 g (80 percent) of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate.
Example (T):Preparation of (S)-(+)-N,N-dimethyl-3-(l-naphthalenyloxy)-3-(2-thienyl) propanamine oxalate:1 -Fluoronaphthalene (118.3g) and (S)-(-)-N,N-dimethyl-3-(2-thienyl)-3- hydroxypropanamine (10Og) was taken in a 500 mL round bottom flask and stirred for 10 minutes. Powdered potassium tertiary butoxide was added to the reaction mass, heated to 90-1000C and maintained for 20-22 hrs for the completion of the reaction. After completion of the reaction; the reaction mass was cooled and to it was added toluene and stirred. The layers were separated and the aqueous layer was extracted with toluene. The combined toluene layer was washed with water followed by 5% HCl solution. The acidic aqueous layer was extracted with dichloromethane and combined organic layer was washed with 5% sodium hydroxide then with water. The organic layer <n="9"/>was distilled atmospherically and finally under vacuum to get the thick mass. Ethyl acetate was added to the thick mass and distilled out dichloromethane completely under vacuum and stirred the reaction mass followed by the addition of ethyl acetate under stirring at 25-300C. A solution of methanol and oxalic acid were added to the reaction mass at 25-300C and stirred for 60-90 minutes at 0-50C. The solid was filtered washed with cold ethyl acetate twice and dried to yield the titled compound. Yield 154.g
With oxalic acid; In ISOPROPYLAMIDE; water; (S)-3-dimethylamino-1-(2-thienyl)propan-1-ol; ethyl acetate; mineral oil;
Example 4 Synthesis of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate In 50 ml of dimethylacetamide 0.5 g of sodium hydride (suspension in mineral oil) is suspended. Suspension is stirred and in few portions 2 g of (s)-3-(dimethylamino)-1-(thienyl)-propan-1-ol is added. After the addition is completed the suspension is warmed up to 70C. 1.27 ml of 1-fluoronaphthalene is added and the reaction mixture is heated to 110C. At this temperature the solution is stirred for another three hours. Then the reaction solution is dissolved with 300 ml of water and extracted twice with 100 ml ether. Combined ether phases are rinsed with water, dried with sodium sulphate end evaporated to dryness. Obtained oil is dissolved in 50 ml ethyl acetate and 0.9 g of oxalic acid is added. The suspension is further stirred for one hour, filtered off the product and washed with ethyl acetate. The product is dried to obtain 3.5 g (80 %) of (S)-N,N-dimethyl-3-(1-naphthalenyloxy)-3-(2-thienyl)propanamine oxalate.
200 g of N,N-Dimethyl-3-hydroxy-3-(2-thienyl) propanamine mandelate was mixed with 250 ml water and 500ml dichloromethane. The pH of the reaction mixture was adjusted between 1 1 - 12 using 30% sodium hydroxide solutions. The reaction mixture was stirred at 20-25C for 30 minutes. The layers were separated and the aqueous layer was extracted with dichloromethane ( 100 ml). The organic layers were combined and washed with water, The organic layer was concentrated under vacuum. The resulting mass was taken in 450ml dimethylsulphoxide and was stirred at room temperature. To this, 28.4 g sodium hydride was added and the mixture was stirred. To the resulting mass, 103.6 g of 1 - fluoronaphthalene was added and the reaction mass was stirred at 48-50C for 14-16 hours. After completion of the reaction, the reaction mass was cooled to room temperature. The resulting mass was transfer to another flask containing water at temperature 5- 10C. The pH of the resulting mixture was adjusted to 5-6 using acetic acid and cyclohexane was added under stirring at 10- 1 5C. The layers were separated and to the aqueous layer, toluene was added, pH was adjusted between 10- 1 1 .0 using 30% sodium hydroxide solution. The resulting mass was stirred at room temperature for few minutes. The organic layer was separated and aqueous layer was extracted with toluene. The organic layers were combined and distilled out. The resulting reaction mass was taken in 1400ml ethyl acetate at room temperature and 71 .0 g oxalic acid was added. The reaction mass was stirred for 5hr at room temperature. The resulting solid was filtered and washed with ethyl acetate and dried under vacuum at 50-55C for 4hr to obtain title compound.Yield : 90-92%
DX-A 03 (2.0 g, 0.011 mol)Was dissolved in dimethylacetamide (100 mL)A solution of 60% sodium hydride (463 mg, 0.012 mol)Dropwise.The resulting mixture was heated at 70 C. for 20 minutes.1-Fluoronaphthalene (1.27 mL, 0.012 mol)Was added dropwise to this mixed solution,And heated at 110 C. for 60 minutes.The reaction mixture was diluted with water,And extracted twice with diethyl ether.The extracts are combined,Wash with water,Then washed with saturated sodium chloride solution,It was dried over anhydrous sodium sulfate,After concentration under reduced pressure,To obtain an oily compound (DX-A 04, 3.28 g, 75.6%).
With potassium tert-butylate; In toluene; at 120℃; for 20h;Inert atmosphere; Sealed tube;
This embodiment provides a preparation method of bis(4-methoxyphenyl)(1-naphthyl)phosphine oxide, which is specifically as follows:In a nitrogen atmosphere, add 0.20mmol bis(4-methoxyphenyl) phosphine oxide, 0.20mmol 1-fluoronaphthalene, 0.30mmol potassium tert-butoxide, 1.5mL toluene solvent, and heat to 120deg C after sealing the tube, keep stirring for 20h, stop the reaction, cool to room temperature, wash with water to remove excess alkali and salt generated in the reaction, extract the aqueous phase with dichloromethane to obtain the organic phase, dry with anhydrous sodium sulfate, distill under reduced pressure to remove the solvent, crude product The target product can be obtained after separation by column chromatography with a separation yield of 64%.
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