反应详情

温度

-60 °C

The product of Example 66F (9.5 g, 33.4 mmol) and phenylboronic acid (4.1 g, 33.6 mmol) were combined in toluene (150 mL) and refluxed for 2.5 hours with azeotropic water removal (Dean-Stark trap). Toluene (100 mL) was distilled out at atmospheric pressure, then the remaining toluene was removed under vacuum, to provide a yellow syrup which was dissolved in DMF (50 mL) and cooled to -60° C. A solution of 5-(p-nitrophenyloxycarbonyloxy-methyl)thiazole (9.5 g, 33.5 mmol) in DMF (50 mL) was added over 45 minutes. The resulting mixture was stirred for 8 hours at -55°±5° C., then 14 hours at -25° C., then was allowed to warm to room temperature. The reaction mixture was diluted with 1N HCl (250 mL) and washed with CH2Cl2 (2×80 mL). The combined organic layers were back-extracted with 1N HCl (60 mL). The combined aqueous HCl layers were cooled in an ice-bath to 2° C., and conc. (37%) HCL (30 mL) was added over 5 minutes. The desired product (bis HCl salt) began to precipitate within 30 minutes. The slurry was stirred 3 hours at 2°-5° C., then the product (bis HCl salt) was collected by filtration and dried in a vacuum oven at 55°-60° C. Yield 11.4 g (68%).

1. distillationToluene (100 mL) was distilled out at atmospheric pressure
2. customthe remaining toluene was removed under vacuum
3. customto provide a yellow syrup which
4. custom14 hours
5. customat -25° C.
6. temperatureto warm to room temperature
7. washwashed with CH2Cl2 (2×80 mL)
8. extractionThe combined organic layers were back-extracted with 1N HCl (60 mL)
9. temperatureThe combined aqueous HCl layers were cooled in an ice-bath to 2° C.
10. additionconc. (37%) HCL (30 mL) was added over 5 minutes
11. customto precipitate within 30 minutes
12. stirringThe slurry was stirred 3 hours at 2°-5° C.
13. filtrationthe product (bis HCl salt) was collected by filtration
14. customdried in a vacuum oven at 55°-60° C