General procedure for the synthesis of the potassium salt of di-tert-butyl phosphate from di-tert-butyl phosphite:
1. di-tert-butyl phosphite (40.36 mmol) was mixed with potassium bicarbonate (24.22 mmol) in 35 mL of water.
2. the mixed solution was placed in an ice bath with stirring and potassium permanganate (28.25 mmol) was added in three equal portions over a period of 1 hour.
3. The reaction continues to be stirred at room temperature for 30 minutes.
4. Decolorized carbon (600 mg) was added and the reaction mixture was heated to 60 °C and maintained for 15 min.
5. The reaction mixture was vacuum filtered to remove the solid manganese dioxide. 6.
6. The solid was washed several times with water.
7. The filtrate was combined with 1 g of decolorized carbon and heated at 60 °C for 20 min.
8. The filtrate was filtered again to give a colorless solution followed by vacuum evaporation to give the crude di-tert-butyl potassium phosphate salt.
9. The crude potassium salt of di-tert-butyl phosphate (5 g, 20.14 mmol) was dissolved in methanol (15 g).
10. A slight excess of concentrated hydrochloric acid was slowly added to the solution at 0 °C while maintaining effective stirring.
11. After addition of hydrochloric acid, potassium chloride precipitated, filtered and washed with methanol.
12. An equimolar amount of tetramethylammonium hydroxide (3.65 g, 20.14 mmol) was added to the mother liquor while the reaction was kept cool and effectively stirred in a salt/ice bath.
13. The resulting clarified solution was placed under reduced pressure to give the crude product.
14. Tetramethylammonium di-tert-butyl phosphate was dissolved in refluxed dimethoxyethane, chloroiodomethane (4.3 g, 24.16 mmol) was added and stirred for 1-2 hours.
15. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give a solution of dimethoxyethane.
16. The chloromethyl di-tert-butyl phosphate (12-16%) from this solution was used directly in the next step in the synthesis of 4-(5-(2-(2-(3,5-bis(trifluoromethyl)phenyl)-N,2-dimethylpropanamido)-4-(o-tolyl)pyridin-2-yl)-1-methyl-1-((phosphonoyloxy)methyl)piperazin-1-ium without further purification (60% yield).
Characterization data:
1H NMR (CD3OD, 300 MHz) δ 1.51 (s, 12H), 5.63 (d, 2H, J = 14.8 Hz).
31P NMR (CD3OD, 300 MHz) δ -11.3 (s, 1P).
