Trimethyl-(2-tributylstannanylmethoxymethoxy-ethyl)-silane → N-{1-[(5-Hydroxy-1-isopropyl-3-methyl-4-oxo-pent-2-enyl)-methyl-carbamoyl]-2,2-dimethyl-propyl}-3-methyl-2-methylamino-3-phenyl-butyramide

Temperature

-78 °C

To a solution of trimethyl-(2-tributylstannanylmethoxymethoxy-ethyl)-silane (933 mg, 2.07 mmole, E. Fernandez-Megia and S. V. Ley; Synlett 2000, 4, 455-8) in 6 mL tetrahydrofuran at −78° C. is added dropwise 1.6 M n-butyllithium solution in hexanes (1.25 mL, 2.0 mmole). The resulting yellow solution is stirred for 10 mins at −78° C. Then a solution of N,β,β-trimethyl-L-phenylalanyl-N1 {(1S,2E)-1-isopropyl-4-[methoxy(methyl)amino]-3-methyl-4-oxobut-2-enyl}-N1,3-dimethyl-L-valinamide (258 mg, 0.5 mmole, Example 52) in tetrahydrofuan (5 mL) at −78° C. is added dropwise and the reaction mixture stirred at −78° C. for 15 mins and then at −60° C. for 45 mins. The reaction is quenched with a saturated aqueous solution of ammonium chloride (2 mL), warmed to room temperature and partioned between ethyl acetate (50 mL) and saturated aqueous solution of ammonium chloride (50 mL). The aqueous layer is extracted with ethyl acetate (30 mL) and the combined organic layer is washed with water, brine, dried over sodium sulfate, filtered and the residue treated with a mixture of trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at 0° C. and stirred for 1 hour, evaporated and then purified by HPLC to give 52 mg of an off-white solid, MS (ES): m/z 488.4 (M+H).

1. stirringthe reaction mixture stirred at −78° C. for 15 mins
2. waitat −60° C. for 45 mins
3. customThe reaction is quenched with a saturated aqueous solution of ammonium chloride (2 mL)
4. temperaturewarmed to room temperature
5. extractionThe aqueous layer is extracted with ethyl acetate (30 mL)
6. washthe combined organic layer is washed with water, brine
7. dry with materialdried over sodium sulfate
8. filtrationfiltered
9. additionthe residue treated with a mixture of trifluoroacetic acid (10 mL) and dichloromethane (5 mL) at 0° C.
10. stirringstirred for 1 hour
11. customevaporated
12. custompurified by HPLC

ORD record

ord-a3ba2a7c02b04f9c9c5f47be1b3559a1

Source dataset

uspto-grants-2008_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07390910B2