反应详情

温度

-10 °C

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.)

1. temperaturewhile cooling of the reaction suspension
2. additionAfter the addition
3. temperaturethe dark brown reaction suspension was heated
4. temperatureThe reaction mixture was cooled to 0° C.
5. temperatureto maintain
6. customthe stirred reaction mixture at about 0° C. with external cooling
7. temperatureAfter the resulting mixture had been heated at 65° C. for 0.5 hr
8. customsolvents were evaporated under vacuum
9. temperaturewas maintained at 0° C
10. temperatureThe resulting mixture was heated
11. stirringwith stirring at 80° C. for 1.5 hr
12. waitAfter 0.5 hr of such heating, mild foaming stopped
13. additiona mixture of two clear
14. customhomogenous layers was obtained
15. temperaturethe resulting mixture was heated
16. stirringstirred at 50° C.
17. extractionto extract the product into toluene
18. washthe upper organic layer was washed with water (two 15 mL portions)
19. customThe washed organic layer was evaporated to dryness under vacuum at 60° C
20. customVacuum drying of the evaporation residue at 60° C.
21. waitwas continued for 2 hr