Phosphoric Acid → Tamiflu

Participants

Reaction Conditions

Reaction Steps

To a solution of 3.96 g (3R,4R,5S)-4-azido-5-tert.-butoxycarbonylamino-3-(1-ethylpropoxy)cyclohex-1-enecarboxylic acid ethylester (10 mmol) in 50 ml ethyl acetate were added 2.0 g wet Raney-Cobalt catalyst and the suspension was stirred and hydrogenated at room temperature for 20 h (˜1.1 bar H2; 500 rpm). After removing the catalyst by filtration, 1.53 ml triethylamine (11 mmol =1.11 g) and 0.99 ml acetic anhydride (10.5 mmol =1.07 g) were added all at once and the colorless solution was stirred at room temperature for 1 h. Then 5.26 ml 5.7 M HBr/acetic acid (30 mmol HBr) were added to the colorless solution and the reaction mixture was stirred at room temperature for 20 h. Then ca. 55 ml 2 N NaOH (pH ca. 9.5) were added under stirring and the organic layer was separated and washed twice with 30 ml, a total of 60 ml 20% brine. All three aqueous layers were extracted sequentially and twice with 30 ml, a total of 60 ml ethyl acetate and the combined organic layers were dried (Na2SO4). After filtration and removal of the solvent by rotary evaporation (50°/≧1 mbar) the yellowish, viscous residue (3.47 g) was dissolved in 20 ml ethanol and added under stirring to a 50° C. warm solution of 0.98 g ortho-phosphoric acid (10 mmol) in 40 ml ethanol over 30 min (after the addition of two third, the 50° C. warm solution was seeded with pure title product). The white suspension was cooled down (2 h) and stirred at 0° C. for 3 h. The crystals were filtered, washed with ca. 20 ml acetone and dried (50°/10 mbar/16 h) affording 3.41 g (83.2%) white, crystalline phosphoric acid salt, m.p. 198-199° C. (dec.).

Provenance & Evidence