Benzyl Alcohol → Benzyl (5-methylpyrazin-2-yl)carbamate

Temperature

15 °C

To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-methylpyrazine-2-carboxylic acid (1.0 eq), toluene (2.5 vols) and di-isopropylethylamine (1.50 eq) under a nitrogen atmosphere. The mixture was vacuum distilled at a batch temperature of 50° C., distilling to a final volume of 2 vols. The batch was sampled to ensure the water content was <0.1% w/w, then cooled to 15±2° C., and diphenylphosphorylazide (1.00 eq) was added over a time period of 5-6 hours, maintaining the temperature of the reaction mixture at 15±2° C. The mixture was stirred for a further 1.5 hours. Meanwhile to a second flask was added benzyl alcohol (3.00 eq) and toluene (11 vols). The mixture was azeotropically dried to a volume of 10 vols. The contents of the second flask were sampled to ensure the water content was <0.1% w/w, then heated to 85-90° C. The contents of the first flask were added slowly to the contents of the second flask over approximately 2 hours, maintaining the reaction temperature at approximately 85° C. The reaction mixture was stirred for 1 hour at 85° C., then cooled to 20° C. 5% w/w Sodium hydroxide solution (1.75 eq) was added slowly over 1 hour, the mixture cooled to 5° C., agitated at 5° C. for 1 hour, then filtered. The isolated solid was washed sequentially with water (2 vols), then methanol (2 vols). After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 78-85%). 1H NMR (400 MHz, CDCl3): 9.41 bs (1H), 9.24 s (1H), 7.87 s (1H), 7.39-7.41 m (5H), 5.22 s (2H), 2.31 s (3H)

1. customTo a flask fitted with overhead stirrer, condenser
2. distillationdistilled at a batch temperature of 50° C.
3. distillationdistilling to a final volume of 2 vols
4. aliquotThe batch was sampled
5. temperaturemaintaining the temperature of the reaction mixture at 15±2° C
6. dry with materialThe mixture was azeotropically dried to a volume of 10 vols
7. aliquotThe contents of the second flask were sampled
8. temperatureheated to 85-90° C
9. additionThe contents of the first flask were added slowly to the contents of the second flask over approximately 2 hours
10. temperaturemaintaining the reaction temperature at approximately 85° C
11. stirringThe reaction mixture was stirred for 1 hour at 85° C.
12. temperaturecooled to 20° C
13. temperaturethe mixture cooled to 5° C.
14. stirringagitated at 5° C. for 1 hour
15. filtrationfiltered
16. washThe isolated solid was washed sequentially with water (2 vols)
17. customAfter drying in the vacuum oven at 40° C. overnight

ORD record

ord-d669b63f1dda42928eb186084343181d

Source dataset

uspto-grants-2011_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08076481B2