Iodine → 2,4-Dichloro-6-ethyl-5-fluoropyrimidine

Temperature

15 °C

To a stirred mixture of magnesium turnings (12.1 kg) in tetrahydrofuran (161 L) was added a solution of bromoethane (54.3 kg) in tetrahydrofuran (53 L) maintaining the reaction temperature below 50° C. during the addition. The solution of the Grignard reagent was cooled to 0° C. and a solution of the compound of part (i) (56 kg) in dimethoxyethane (170 L) added, maintaining the reaction temperature below 15° C. during the addition. The reaction was stirred for 1 hour at 15° C. and cooled to 0° C. A solution of triethylamine (34 kg) in tetrahydrofuran (70 L) was added, maintaining the reaction temperature at about 5° C., followed by a solution of iodine (85 kg) in tetrahydrofuran (256 L), maintaining the reaction temperature below 15° C. The reaction was then quenched with water (840 L), maintaining the reaction temperature below 25° C. The pH was adjusted to 1 using 5N aqueous hydrochloric acid solution (50 L) and the mixture extracted with toluene (1×490 L followed by 1×210 L). The combined organic layers were washed with 2% w/w aqueous sodium metabisulphite solution (700 L) then water (700 L) added and the remaining tetrahydrofuran removed by distillation under reduced pressure. The mixture was cooled, the organic layer separated, washed with water (425 L) and then concentrated under reduced pressure to provide the product as an oil (50 kg).

1. temperaturemaintaining the reaction temperature below 50° C.
2. additionduring the addition
3. temperaturemaintaining the reaction temperature below 15° C.
4. additionduring the addition
5. temperaturecooled to 0° C
6. temperaturemaintaining the reaction temperature at about 5° C.
7. temperaturemaintaining the reaction temperature below 15° C
8. customThe reaction was then quenched with water (840 L)
9. temperaturemaintaining the reaction temperature below 25° C
10. extractionthe mixture extracted with toluene (1×490 L followed by 1×210 L)
11. washThe combined organic layers were washed with 2% w/w aqueous sodium metabisulphite solution (700 L)
12. additionwater (700 L) added
13. customthe remaining tetrahydrofuran removed by distillation under reduced pressure
14. temperatureThe mixture was cooled
15. customthe organic layer separated
16. washwashed with water (425 L)
17. concentrationconcentrated under reduced pressure

ORD record

ord-630790db7d0446ae8dcdf1ea562cd8a0

Source dataset

uspto-grants-2003_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06586594B1