* 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.
Stage #1: With thionyl chloride In dichloromethane for 6 h; Heating / reflux Stage #2: With triethylamine In dichloromethane at 5 - 10℃; for 1 h;
4-Benzyloxyphenyl acetic acid (10Og, 0.41mol) was reacted with thionyl chloride (45ml, 0.62mol) in refluxing dichloromethane in the presence of a catalytic amount of NJSl- dimethyl formamide (one drop) for 6 hours. The acid chloride solution was added to a well stirred mixture of dimethylamine hydrochloride (101g, 1.24mol) and triethylamine (174ml, 1.24mol) in dichloromethane whilst maintaining the temperature below 5°C. After completion of the addition, stirring was continued for a further 1 hour at 5-100C. The reaction was quenched by adding water (1000ml) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 x 500ml) and the combined extracts were washed with water (2 x 500ml). The organic layer was dried over anhydrous sodium sulphate and concentration of the organic layer afforded a residue. To the residue obtained, hexane (700ml) was added and stirred for 1 hour at 25-300C. It was then filtered to obtain acetamide (III) as an off-white solid. The structure of the product was confirmed by 1H-NMR. Weight of the product = 10Og; molar yield = 90percent.
Reference：
[1] Patent: WO2008/93142, 2008, A1, . Location in patent: Page/Page column title page; 11; Sheet 3/3
2
[ 100-39-0 ]
[ 919475-15-3 ]
Yield
Reaction Conditions
Operation in experiment
92%
With potassium carbonate In N,N-dimethyl-formamide at 20 - 60℃; for 97 h;
4-(Dimethylcarbamoylmethyl)phenol (35.6 g, 198.5 mmol) in dimethylformamide (DMF) (400 mL) was treated with K2CO3 (35.6 g, 258.0 mmol) followed by benzyl bromide (28 mL, 238 mmol). The mixture was stirred at room temperature for 4 days followed by heating at 60° C. for 1 h. The mixture was concentrated to remove DMF, diluted with EtOAc and washed with water 3*. Dry MgSO4 was added, the mixture filtered and concentrated to low volume. Hexane was added to precipitate product. Solids were collected via filtration and dryed to give 49 g, 92percent yield of a solid.
A solution of 2N lithium diisopropylamide (LDA) (48.25 mL, 96.5 mmol) was cooled to -78° C. and diluted with 25 mL of tetrahydrofuran (THF). To this was added dropwise, a solution of 2-(4-Benzyloxy-phenyl)-N,N-dimethyl-acetamide (20 g, 74.3 mmol) in 250 mL of THF. The mixture was warmed to 0° C., then cooled back to -78° C. A solution of 1,4-cyclohexanedione mono-ethylene ketal (14.1 g) in 350 mL of THF was added. The solution was allowed to warm to -20° C. Highthroughput liquid chromatography (HPLC) assay still showed starting material. Another 1 g of ketal was added and the solution was warmed to 0° C. for 2 hour. The reaction was quenched with a mixture of 25 g NH4Cl in 200 mL of water. EtOAc was added and the layers separated. The organic layer was dried with MgSO4, filtered and concentrated. Column chromatography (50percent EtOAc/hexanes) gave 30.3 g, 96percent yield of a solid
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 97h;
4-(Dimethylcarbamoylmethyl)phenol (35.6 g, 198.5 mmol) in dimethylformamide (DMF) (400 mL) was treated with K2CO3 (35.6 g, 258.0 mmol) followed by benzyl bromide (28 mL, 238 mmol). The mixture was stirred at room temperature for 4 days followed by heating at 60° C. for 1 h. The mixture was concentrated to remove DMF, diluted with EtOAc and washed with water 3*. Dry MgSO4 was added, the mixture filtered and concentrated to low volume. Hexane was added to precipitate product. Solids were collected via filtration and dryed to give 49 g, 92percent yield of a solid.
With potassium carbonate; In N,N-dimethyl-formamide; at 20 - 60℃; for 1h;
4-(Dimethylcarbamoylmethyl)phenol in dimethylformamide (DMF) is treated with K2CO3 followed by benzyl bromide.The mixture is stirred at room temperature followed by heating at 60° C. for 1 hour. The mixture is concentrated to remove DMF, diluted with EtOAc and washed with water. Dry MgSO4 is added, the mixture filtered and concentrated to low volume. Hexane is added to precipitate the ketal intermediate product. Solids are collected via filtration and dried.
4-Benzyloxyphenyl acetic acid (10Og, 0.41mol) was reacted with thionyl chloride (45ml, 0.62mol) in refluxing dichloromethane in the presence of a catalytic amount of NJSl- dimethyl formamide (one drop) for 6 hours. The acid chloride solution was added to a well stirred mixture of dimethylamine hydrochloride (101g, 1.24mol) and triethylamine (174ml, 1.24mol) in dichloromethane whilst maintaining the temperature below 5°C. After completion of the addition, stirring was continued for a further 1 hour at 5-100C. The reaction was quenched by adding water (1000ml) and the organic layer was separated. The aqueous layer was extracted with dichloromethane (3 x 500ml) and the combined extracts were washed with water (2 x 500ml). The organic layer was dried over anhydrous sodium sulphate and concentration of the organic layer afforded a residue. To the residue obtained, hexane (700ml) was added and stirred for 1 hour at 25-300C. It was then filtered to obtain acetamide (III) as an off-white solid. The structure of the product was confirmed by 1H-NMR. Weight of the product = 10Og; molar yield = 90percent.
A solution of lithium hexamethyl disilazide (LHMDS) in tetrahydrofuran (388.5ml, 0.46mol) was added to a well stirred solution of acetamide (III) (50g, 0.185mol) in dry tetrahydrofuran (1000ml) maintaining the temperature at -600C to -700C. The mixture was stirred for 15 minutes. Cyclohexanone (23ml, 0.223mol) was added maintaining the temperature at -600C to -700C. After completion of the reaction, a saturated aqueous solution of ammonium chloride was added. Dilute hydrochloric acid was added to adjust <n="14"/>the pH to 4.0 and the mixture was extracted with ethyl acetate (3 x 150ml). The combined organic extracts were washed with water and dried over anhydrous sodium sulphate. Concentration of the extracts afforded the desired amide (IV) as an off-white solid. The structure of the product was confirmed by 1H-NMR. Weight of the product = 56g; molar yield = 82%.
In certain embodiments, the following procedure was employed. 150 g of 2-(4- benzyloxy)phenyl-N,N-dimethylacetamide, 945 g (1062 mL) of THF was charged to a 5 L jacketed reactor. 550 mL of isopropylmagnesium chloride (2.0 M in tetrahydrofuran) was added and the mixture was stirred for 1 h. 115 g of cyclohexanone was added to the reactor and mixed for 1 h. 360 g of RedAI (sodium bis(2-methoxyethoxy)aluminum hydride-65percent w/w in toluene) was added to the reactor and stirred for 16 h. When the reaction was complete the mixture was- 66 -LAI-2932341vl <n="69"/>added to 2005 g of 22percent w/w aqueous citric acid. 420 g (600 mL) of heptane was charged to the reactor and stirred for 15 min. The stirring was stopped and the top layer was removed. 250 g of 50percent NaOH was added to adjust the pH to 9-10, followed by stirring. 1114 g (1500 mL) of MTBE was added to the reactor. The mixture was warmed to 45 +/- 5°C to dissolve the solids. The stirring was stopped and the bottom layer was removed. The organic layer was washed twice with 750 g of water at 450C. 750 mL of MTBE was removed by distillation and 750 mL of methanol was added. About 750 mL of MTBE/methanol was removed by distillation and 300 g of methanol and 300 g of water were added. The slurry was cooled to 0 0C and stirred for 30 min. The slurry was filtered and the solid washed with 375 g of (4:1 methanohwater). The solid was dried to yield 161 g of 1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl) cyclohexanol.[00261] In certain embodiments, the following procedure was employed. To a 200 gallon reactor was charged 22.98 kg of 2-(4-benzyloxy)phenyl-N,N-acetamide and 145.1 kg of THF. With agitation, the temperature was adjusted to 5 0C to 10 0C. To the reactor was charged 82.9 kg of isopropylmagnesium chloride, 2.0M in THF, while maintaining the temperature between 5 0C to 35 0C. The lines were rinsed with 2.78 kg of THF. The contents were agitated for 61 minutes at 10 0C to 20 0C. To the reactor was added 9.31 kg of cyclohexanone while maintaining the temperature between 5 0C to 35 0C. The lines were rinsed with 2.77 kg of THF. The temperature was adjusted to 15 0C to 25 0C and the contents were agitated for 17 minutes at this temperature range after which the reaction was complete. To the reactor was charged 55.8 kg of sodium bis(2-methoxyethoxy)aluminum hydride (65 wtpercent in toluene) while maintaining the temperature at 15 0C to 35 0C. The contents were agitated for 10 h (<3percent starting material remained). The reaction mixture was added to 334.1 kg of 22percent citric acid solution cooled to 0 0C to 2 °C. THF (22.9 kg) and n-heptane (63.3 kg) were added to the reaction. The mixture was agitated for 15 minutes then the stirring was stopped and the phases were allowed to separate. The top layer was removed and the reactor was charged with 45.4 kg of 50percent sodium hydroxide. The reactor was charged 169.9 kg of MTBE and the temperature was adjusted to 40-50 0C. The contents were agitated for 14 minutes and the agitation was stopped to allow the phases to separate for 15 minutes. The aqueous layer was removed and 115 L of USP purified water was added. The temperature was adjusted to 40 0C to 50 0C. The contents were agitated for 15 minutes and the agitation was stopped to allow the phases to separate for 13 minutes. The aqueous bottom layer was removed. The reactor was charged with 115 L of USP purified water and the temperature was adjusted to 40 0C to 50 0C. The contents were agitated for 15 minutes and the agitation was stopped to allow the phases to separate. The aqueous bottom layer was removed. The solution was distilled under vacuum to a final volume of 188 L. To the reactor- 67 -LAI-2932341vl <n="70"/>was charged 115.2 kg of methanol and the solution was distilled under vacuum to a final volume of 131 L. To the reactor was charged 46.0 kg of methanol and 57 L of USP purified water. The temperature was adjusted to 0 0C. The slurry was stirred for 41 minutes at -5 0C to 5 CC and the mixture was filtered. The cake was washed with 46.2 kg of methanol and 11.6 kg of USP purified water (cooled to -5 0C to 5 0C). The wet cake (30.66 kg) was dried at 40-50 0C to yield 24.47 kg of 1-(2-(dimethylamino)-1-(4-benzyloxyphenyl)ethyl)cyclohexanol.
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