氯卡色林杂质D

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:0.00; pressure:0.00; stir:

反应条件: temp:-10.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 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

反应条件: temp:40.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

实验步骤: 2-(4-Chlorophenyl)acetic acid (1.9 kg, 11.1 mol, 1.00 eq), toluene (1 L), phenylboronic acid (67 g, 549 mmo, 0.049 eq.), and boric acid (68 g, 1.10 mol. 0.099 eq) where charged to a 20 L jacketed reactor in the specified order. After the resulting mixture had been heated with stirring to 40° C., 1-amino-2-propanol (908 g, 12.09 mol, 1.085 eq) and toluene (1 L) were added. The reaction mixture was then heated to reflux while the water coproduct was removed in a Dean-Stark trap. Refluxing and water removal were continued until conversion of 2-(4-chlorophenyl)acetic acid exceeded 98%. Such conversion is usually achieved with 8-12 hours of refluxing. Water coproduct removed in the Dean-Stark trap totaled 265 mL (14.72 mol). After the reaction mixture had been cooled to 60-70° C., 5 wt % aqueous sodium bicarbonate (2 L) was added slowly while the reaction mixture was maintained at 60-70° C. Water (10 mL) was then added slowly while the stirred reaction mixture was maintained at ≧50° C. The diluted reaction mixture was cooled to 30° C. and stirred at that temperature for 30 minutes. The resulting solid precipitate was filtered and vacuum dried for 48 hours at 50° C. to provide 2-(4-chlorophenyl)-N-(2-hydroxypropyl)acetamide (2.356 kg, 92.9% yield not corrected for purity, 90.12% purity by HPLC peak area). After the resulting mixture had been heated The reaction mixture was then heated was removed in a Dean-Stark trap Refluxing water removal of refluxing Water coproduct removed in the Dean-Stark trap After the reaction mixture had been cooled to 60-70° C. 5 wt % aqueous sodium bicarbonate (2 L) was added slowly while the reaction mixture was maintained at 60-70° C Water (10 mL) was then added slowly while the stirred reaction mixture was maintained at ≧50° C The diluted reaction mixture was cooled to 30° C. stirred at that temperature for 30 minutes The resulting solid precipitate was filtered vacuum dried for 48 hours at 50° C.