1-[2-(4-chlorophenyl)ethylamino]propan-2-ol

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In Stage 2, 2-(4′-chlorophenyl)ethyl bromide was reacted with 1-amino-2-propanol to form the secondary amine, 1-[2-(4-chloro-phenyl)-ethylamino]-propan-2-ol. 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol was separated from excess 1-amino-2-propanol and water soluble byproducts by extraction into toluene and removing water from the toluene containing 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol by azetropic distillation and can be used directly into the next step without further purification and without isolation.

Conditions: temp:42.51; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N,N-Dimethylacetamide (DMA), 0.614 mL, 6.60 mmol, 0.301 eq) was added to the substantially water-free mixture of intermediate 1-(4-chlorophenethylamino)propan-2-ol in toluene as it was stirred under nitrogen at 40-45° C. Thionyl chloride (2.04 mL, 28.0 mmol, 1.274 eq) was then added while the stirred mixture was maintained at 50-60° C. The stirred reaction mixture was then heated at 62° C. for three hours. LC/MS analysis of the crude reaction mixture indicated that conversion of the intermediate 1-(4-chlorophenethyl-amino)propan-2-ol was substantially complete after two hours. After the reaction mixture had been cooled to 0-5° C., isopropanol (5 mL) was added while the stirred product mixture was maintained at 0-5° C. Stirring at that temperature was continued for 2-3 hours, and then toluene (5 mL) was added to the suspension. After the resulting mixture had been heated to 60° C. for 30 minutes, the solid product was recovered by filtration, washing with isopropanol (2×5 mL), and vacuum drying at 72° C. overnight to provide off-white solid 2-chloro-N-(4-chlorophenethyl)propan-1-amine hydrochloride (4.38 g, 74.3% yield, 99.60% purity by HPLC peak area). was maintained at 50-60° C The stirred reaction mixture was then heated at 62° C. for three hours LC/MS analysis of the crude reaction mixture After the reaction mixture had been cooled to 0-5° C. was maintained at 0-5° C Stirring at that temperature was continued for 2-3 hours After the resulting mixture had been heated to 60° C. for 30 minutes the solid product was recovered by filtration washing with isopropanol (2×5 mL), and vacuum drying at 72° C. overnight

Conditions: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 2-(4-Chlorophenyl)-N-(2-hydroxypropyl)acetamide (5.0 g, 21.96 mmol, 1.00 eq), tetrahydrofuran (THF, 7.5 mL), and sodium borohydride (1.662 g, 43.9 mmol, 2.00 eq) were charged to a 100 mL round bottomed flask. The resulting stirred white suspension was cooled to −10° C., and a solution of iodine (5.574 g, 21.96 mmol, 1.00 eq) in THF (10 mL) was added dropwise over 30 minutes while cooling of the reaction suspension was continued. Hydrogen gas evolved during the addition. After the addition, the dark brown reaction suspension was heated and stirred at 70° C. until 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide conversion was substantially complete. Such conversion was achieved in 3.5 hours at 70° C. The reaction mixture was cooled to 0° C., and methanol (15 mL) was added sufficiently slowly to maintain the stirred reaction mixture at about 0° C. with external cooling. The methanol addition was initially accompanied by fairly vigorous evolution of gas. After the resulting mixture had been heated at 65° C. for 0.5 hr, solvents were evaporated under vacuum. To the residual white slurry was added 50 wt % aqueous NaOH (15 mL, 286 mmol, 13 eq) while the stirred product mixture was maintained at 0° C. The resulting mixture was heated with stirring at 80° C. for 1.5 hr. After 0.5 hr of such heating, mild foaming stopped, and a mixture of two clear, homogenous layers was obtained. Toluene (20 mL) was added, and the resulting mixture was heated and stirred at 50° C. to extract the product into toluene. The lower aqueous layer was drained, and the upper organic layer was washed with water (two 15 mL portions). The washed organic layer was evaporated to dryness under vacuum at 60° C. Vacuum drying of the evaporation residue at 60° C. was continued for 2 hr to yield intermediate 1-(4-chlorophenethylamino)-propan-2-ol as an off-white solid (4.23 g, 90.1% yield, 96.17% purity by HPLC peak area). To the intermediate 1-(4-chlorophenethylamino)propan-2-ol in a round bottomed flask was added toluene (20 mL). (One skilled in the art can achieve substantially the same water-free mixture of intermediate 1-(4-chlorophenethylamino)propan-2-ol in toluene by azeotropic removal of water without evaporation of the majority of the toluene.) while cooling of the reaction suspension After the addition the dark brown reaction suspension was heated The reaction mixture was cooled to 0° C. to maintain the stirred reaction mixture at about 0° C. with external cooling After the resulting mixture had been heated at 65° C. for 0.5 hr solvents were evaporated under vacuum was maintained at 0° C The resulting mixture was heated with stirring at 80° C. for 1.5 hr After 0.5 hr of such heating, mild foaming stopped a mixture of two clear homogenous layers was obtained the resulting mixture was heated stirred at 50° C. to extract the product into toluene the upper organic layer was washed with water (two 15 mL portions) The washed organic layer was evaporated to dryness under vacuum at 60° C Vacuum drying of the evaporation residue at 60° C. was continued for 2 hr

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In Stage 2, 2-(4′-chlorophenyl)ethyl bromide was reacted with 1-amino-2-propanol to form the secondary amine, 1-[2-(4-chloro-phenyl)-ethylamino]-propan-2-ol. 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol was separated from excess 1-amino-2-propanol and water soluble byproducts by extraction into toluene and removing water from the toluene containing 1-[2-(4-Chloro-phenyl)-ethylamino]-propan-2-ol by azetropic distillation and can be used directly into the next step without further purification and without isolation.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A 1-L jacketed reactor was equipped with a retreat curve stir blade, overhead stirring, a thermocouple, a condenser, and a nitrogen bubbler. 1-Aminopropan-2-ol (110 mL, 1429 mmol) was added and heated to 85 and 90° C. 1-Chloro-4-(2-chloroethyl)benzene (50.032 g, 286 mmol) was added over 1 h at <97° C. and upon completion of the addition stirring was continued at 90 to 95° C. for 2.5 h. The internal temperature was reduced to 75° C. and chlorobenzene (100 mL) and water (50 mL) were added. The mixture was stirred for 15 min at 70 to 75° C. before the phases were separated. The upper aqueous phase was extracted with chlorobenzene at 70 to 75° C. (2×50 mL). The combined organic phases were washed with water at 70-75° C. (2×50 mL) and then held over the weekend at room temperature. The solution was then concentrated at 60 to 65° C. (bath) at 40 to 45 mbar to remove 143 g of distillate. A 1-L jacketed reactor was equipped with a retreat curve overhead stirring stirring was reduced to 75° C. The mixture was stirred for 15 min at 70 to 75° C. before the phases were separated The upper aqueous phase was extracted with chlorobenzene at 70 to 75° C. (2×50 mL) The combined organic phases were washed with water at 70-75° C. (2×50 mL) held over the weekend at room temperature The solution was then concentrated at 60 to 65° C. (bath) at 40 to 45 mbar to remove 143 g of distillate

Conditions: temp:80.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 5-L jacketed reactor equipped with a chiller, overhead stirring, an anchor impeller, a thermocouple, a glycol condenser, and a nitrogen inlet vented to a caustic scrubber, was charged 1-aminopropan-2-ol (1102 mL, 14.3 mol). The reactor contents were heated to 80° C. and 1-chloro-4-(2-chloroethyl)benzene (Method 4, Step A, 500 g, 2856 mmol) was slowly charged over 40 min. The temperature of the gold-colored reaction mixture reached 97° C. during the addition and 101° C. approximately 1 min after addition was complete. The mixture was then allowed to cool to 90 to 95° C. and stirring was continued at that temperature for 2 h. Water (500 mL) and toluene (1000 mL) were added and the mixture was stirred at 75 to 80° C. for 15 min. The layers were allowed to separate at 70 to 75° C. The organic phase was removed and the aqueous phase was extracted with toluene at 70 to 75° C. for 15 min (2×500 mL). The combined organic phases were washed with water at 70 to 75° C. for 15 min (2×500 mL) and stirred overnight under nitrogen at 50° C. The solution was concentrated by distillation at 60° C. (jacket) under reduced pressure, and the residue was diluted with toluene to a total volume of about 800 mL. This solution was distilled a second time at 65° C. (jacket) under reduced pressure and the residue was diluted with toluene to a total volume of about 400 mL. The water content of the solution was 0.03% by Karl Fisher titration. Into a 5-L jacketed reactor equipped with a chiller after addition to cool to 90 to 95° C. stirring the mixture was stirred at 75 to 80° C. for 15 min to separate at 70 to 75° C The organic phase was removed the aqueous phase was extracted with toluene at 70 to 75° C. for 15 min (2×500 mL) The combined organic phases were washed with water at 70 to 75° C. for 15 min (2×500 mL) stirred overnight under nitrogen at 50° C The solution was concentrated by distillation at 60° C. (jacket) under reduced pressure the residue was diluted with toluene to a total volume of about 800 mL This solution was distilled a second time at 65° C. (jacket) under reduced pressure the residue was diluted with toluene to a total volume of about 400 mL

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Into a 1-L jacketed reactor equipped with a retreat curve stir blade, overhead stirring, a thermocouple, a condenser, and a nitrogen bubbler was charged 1-aminopropan-2-ol (110 mL, 1430 mmol), which was then heated to 85 and 90° C. 1-Chloro-4-(2-chloroethyl)benzene (50.054 g, 286 mmol) was charged via addition funnel over 1 h with a maximum reaction temperature of 93° C. Stirring was then continued at 90 to 95° C. for 2.5 h. Chlorobenzene (100 mL) and water (50 mL) were added and the mixture was stirred at 70 to 75° C. for 15 min. The phases were allowed to separate and the aqueous phase was extracted with chlorobenzene (2×50 mL) at 70 to 75° C. The combined organic phases were then washed with water (2×50 mL) at 70 to 75° C. and concentrated by distillation under reduced pressure. The residue was dissolved in chlorobenzene to a total weight of 503 g and allowed to stand at room temperature overnight. A solid precipitate formed which was redissolved by adding chlorobenzene (50 mL) and heating the mixture at 30 to 35° C. Into a 1-L jacketed reactor equipped with a retreat curve overhead stirring Stirring the mixture was stirred at 70 to 75° C. for 15 min to separate the aqueous phase was extracted with chlorobenzene (2×50 mL) at 70 to 75° C The combined organic phases were then washed with water (2×50 mL) at 70 to 75° C. concentrated by distillation under reduced pressure The residue was dissolved in chlorobenzene to a total weight of 503 g to stand at room temperature overnight A solid precipitate formed which was redissolved heating the mixture at 30 to 35° C.

Conditions: temp:90.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a 500-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (96 g, 1277 mmol). This was heated in oil bath at 90° C. and the solution of chloro-4-(2-chloroethyl)benzene from Step A was slowly added over 1.25 h at a maximum temperature of 95° C. The reaction was stirred at 90 to 95° C. for 2 h and then toluene (80 mL) and water (40 mL) were added. The mixture was stirred for 15 min at 70 to 80° C. and then the phases were allowed to separate at room temperature. The aqueous phase was extracted with toluene (2×40 mL). The combined toluene phases were washed with water (2×40 mL) at 70 to 80° C. and then concentrated under reduced pressure at 60° C. Toluene was added to the residue to give a total volume of 170 mL and the solution was stirred overnight at 55° C. (bath). This solution was found to contain 0.052% water by Karl Fischer titration. In a 500-mL round-bottom flask equipped with a magnetic stir bar The mixture was stirred for 15 min at 70 to 80° C. to separate at room temperature The aqueous phase was extracted with toluene (2×40 mL) The combined toluene phases were washed with water (2×40 mL) at 70 to 80° C. concentrated under reduced pressure at 60° C Toluene was added to the residue to give a total volume of 170 mL the solution was stirred overnight at 55° C. (bath)

Conditions: temp:85.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: In a separate 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, was charged 1-aminopropan-2-ol (60.1 g, 800 mmol), which was then heated to 85° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at <99° C. On completion of the addition, stirring was continued at 90 to 95° C. for 2 h. Toluene (50 mL) and water (25 mL) were added and the mixture was stirred at 70 to 75° C. for 15 minutes before the phases were separated at room temperature. The upper aqueous phase was extracted with toluene (2×25 mL) at 70 to 75° C. Then, the combined organic phases were washed with water (2×25 mL) at 70 to 75° C., and concentrated by distillation under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 112.5 mL and the yellow solution was stirred under nitrogen overnight at 50° C. (bath). Karl Fischer titration showed 0.091% water. In a separate 250-mL round-bottom flask equipped with a magnetic stir bar while maintaining the reaction temperature at <99° C On completion of the addition the mixture was stirred at 70 to 75° C. for 15 minutes before the phases were separated at room temperature The upper aqueous phase was extracted with toluene (2×25 mL) at 70 to 75° C Then, the combined organic phases were washed with water (2×25 mL) at 70 to 75° C. concentrated by distillation under reduced pressure at 60° C. (bath) The residue was diluted with toluene to a total volume of 112.5 mL the yellow solution was stirred under nitrogen overnight at 50° C. (bath)

Conditions: temp:120.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 1-Aminopropan-2-ol (60.0 g, 799 mmol) was charged to a 250-mL round-bottom flask equipped with a magnetic stir bar, a thermocouple, a condenser, and a nitrogen bubbler vented to a caustic scrubber, and heated to 120° C. To this was slowly added the toluene solution of 1-chloro-4-(2-chloroethyl)benzene from Step A while maintaining the reaction temperature at 120-125° C. On completion of the addition, stirring was continued at 115-120° C. for 2.5 h. NaOH (50%, 12.78 g, 160 mmol) was added followed by water (25 mL) and the mixture was stirred at 70 to 75° C. for 15 min. The organic phase was separated and washed with water (4×25 mL) at 70 to 75° C. The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C. Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath). The residue was diluted with toluene to a total volume of 104 mL and the golden solution was stirred overnight at 50° C. (bath) under nitrogen. Karl Fischer titration showed 0.052% water. equipped with a magnetic stir bar while maintaining the reaction temperature at 120-125° C On completion of the addition the mixture was stirred at 70 to 75° C. for 15 min The organic phase was separated washed with water (4×25 mL) at 70 to 75° C The combined aqueous phases were extracted with toluene (38 mL) for 15 min at 70 to 75° C Then, the combined organic phases were concentrated under reduced pressure at 60° C. (bath) The residue was diluted with toluene to a total volume of 104 mL the golden solution was stirred overnight at 50° C. (bath) under nitrogen