Chlorotrimethylsilane → Oseltamivir

Temperature

90 °C

Trifluoroacetic acid (0.5 mL) was added to a solution of the compound 7 (215 mg, 0.422 mmol) in dichloromethane (1 mL) at 23° C. under argon atmosphere. The reaction mixture was stirred for 2 hrs at 23° C. before removing the solvent and trifluoroacetic acid under reduced pressure. To a solution of the resulting compound 12 in dichloromethane (1.5 mL) were added a catalytic amount of dimethyl formamide (one drop) and oxalyl chloride (357 μL, 4.22 mmol) at 0° C. The resulting reaction mixture was stirred for 1 hour at 23° C. before removing the solvent and excess oxalyl chloride under reduced pressure. Saturated aqueous sodium azide (0.5 mL) was added to a solution of the crude material of the resulting compound 13 in acetone (1 mL) at 0° C. The resulting reaction mixture was stirred for 20 min at 0° C. before being quenched by addition of water. The aqueous layer was extracted three times with trichloromethane. The combined organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to give the crude material of the compound 14. The crude material of the compound 14 was dissolved in acetic anhydride (2 mL), and the reaction mixture was stirred for 36 hrs at 90° C. before removing the solvent under reduced pressure. To a solution of the crude material of the compound 16 in ethanol (3 mL) was added hydrazine monohydrate (40.9 μL, 0.844 mmol) at 23° C. under argon atmosphere. The resulting reaction mixture was stirred for 2 hrs at 23° C. before removing the solvent under reduced pressure. Activated Zn powder (1.38 g, 21.1 mmol, washed with 1 N hydrochloric acid, water, ethanol, and diethyl ether before use) was added to a solution of the crude material of the resulting compound 17 in ethanol (4 mL) and trimethyl chlorosilane (1.62 mL, 12.7 mmol) at 23° C. under argon atmosphere. The reaction mixture was stirred for 1 hour at 70° C. before bubbling ammonia gas for 10 min at 0° C. To the resulting reaction mixture was added potassium carbonate (1.17 g, 8.44 mmol) at 23° C. and stirred for 6 hrs at 23° C. before filtration. After removing excess ethanol under reduced pressure, 2 N hydrochloric acid was added to the residue at 0° C. The aqueous layer was washed with ethyl acetate followed by adjustment to pH of 11 with 28% ammonium hydroxide in water. The aqueous layer was extracted three times with 10% methanol-trichloromethane. The combined organic layer was washed with saturated aqueous sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure to afford (−)-oseltamivir (compound 1, 109.5 mg, yield 83% calculated from the compound 8 as a standard).

1. custombefore removing the solvent under reduced pressure
2. customThe resulting reaction mixture
3. stirringwas stirred for 2 hrs at 23° C.
4. custombefore removing the solvent under reduced pressure
5. stirringThe reaction mixture was stirred for 1 hour at 70° C.
6. custombefore bubbling ammonia gas for 10 min at 0° C
7. customTo the resulting reaction mixture
8. stirringstirred for 6 hrs at 23° C. before filtration
9. customAfter removing excess ethanol under reduced pressure, 2 N hydrochloric acid
10. additionwas added to the residue at 0° C
11. washThe aqueous layer was washed with ethyl acetate
12. extractionThe aqueous layer was extracted three times with 10% methanol-trichloromethane
13. washThe combined organic layer was washed with saturated aqueous sodium chloride
14. dry with materialdried over magnesium sulfate
15. concentrationconcentrated under reduced pressure

ORD record

ord-e481f53b42a44e7cb506e1247df8ca92

Source dataset

uspto-grants-2013_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08501980B2