Potassium Fluoride → N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide

Temperature

117.5 °C

A mixture of 100 g (0.52 mol, 1 eq.) of 2,4-dichloro-3-nitropyridine, 105 g (1.81 mol, 3.48 eq.) of potassium fluoride and 11.73 g (0.036 mol, 0.07 eq.) of tetrabutylammonium bromide (TBAB) in 500 ml of toluene and 330 ml of 1-methyl-2-pyrrolidinone is heated with stirring in a first reaction vessel at 115-120 ° C. for 4.5 hours. The reaction mixture is cooled to 20° C. and filtered into a second reaction vessel using 170 ml of 1-methylpyrrolidinone to transfer the batch. 160 g (0.456 mol. 0.88 eq.) of (R)-N-[1-[(3-chlorothien-2-yl)methyl]propyl]-4-methylbenzenesulfonamide lithium salt is then added to the mixture at 35° C. The reaction mixture is stirred at 85° C. for 3.5 hours and then cooled to 20° C. The cooled mixture is partitioned between 500 ml of brine, 1.6 L tert-butylmethyl ether and 200 ml of toluene. The organic layer is washed with 1 L of water, dried over magnesium sulfate and concentrated under reduced pressure. The resulting solid is dissolved in 200 ml of ethyl acetate and triturated with 65 ml of heptane. The mixture is cooled at −6° C. for 48 hours and the resulting solid is isolated by filtration and washed with a cold (−8° C.) mixture of ethyl acetate/heptane (4:1 v/v). The solid is dried under vacuum with a nitrogen bleed at 40-45° C. to give (R)-N-[1-[3-chlorothien-2-yl )methyl]propyl]-N-(2-fluoro-3-nitropyrid-4-yl)-4-methylbenzenesulfonamide (138.7 g. 63% yield. 95.4 A% pure (HPLC)).

1. temperatureis heated
2. temperatureThe reaction mixture is cooled to 20° C.
3. filtrationfiltered into a second reaction vessel
4. stirringThe reaction mixture is stirred at 85° C. for 3.5 hours
5. temperaturecooled to 20° C
6. customThe cooled mixture is partitioned between 500 ml of brine, 1.6 L tert-butylmethyl ether and 200 ml of toluene
7. washThe organic layer is washed with 1 L of water
8. dry with materialdried over magnesium sulfate
9. concentrationconcentrated under reduced pressure
10. dissolutionThe resulting solid is dissolved in 200 ml of ethyl acetate
11. customtriturated with 65 ml of heptane
12. temperatureThe mixture is cooled at −6° C. for 48 hours
13. customthe resulting solid is isolated by filtration
14. washwashed with a cold (−8° C.) mixture of ethyl acetate/heptane (4:1 v/v)
15. customThe solid is dried under vacuum with a nitrogen
16. custombleed at 40-45° C.

ORD record

ord-d1646a9de185463384becc6c48da9f3d

Source dataset

uspto-grants-2002_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06429315B1