Toluene → (4aS,5R,7aS)-7a-(2-Fluoro-5-(2-(pyrazin-2-yl)-1H-imidazol-5-yl)phenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine

di-tert-Butyl {(4aS,5R,7aS)-7a-[2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-yl}imidodicarbonate (0.1 g, 0.17 mmol) was dissolved in dry methanol (1 mL) and dry toluene (1 mL). To the solution was added 2-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrazine (mixture of isomers) (0.054 g, 0.15 mmol), palladium-triphenylphosphine (1:4) (0.020 g, 0.02 mmol) and Na2CO3 (0.33 mL, 1M solution in water) and the reaction was stirred at reflux in a sealed tube overnight. The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM and the layers separated. The aqueous layer was extracted with DCM (×2) and the combined organics were dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (0-15% MeOH in DCM). The product, (4aS,5R,7aS)-7a-{2-fluoro-5-[2-(pyrazin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl]phenyl}-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine was dissolved in EtOH (5 mL) and CHCl (2 mL) and the reaction was stirred at reflux overnight to remove the SEM protecting group. The reaction mixture was concentrated in vacuo and loaded onto a SCX ion exchange cartridge washing with MeOH followed by 2N NH3 in MeOH. The basic fraction was concentrated in vacuo. The residue was purified by column chromatography (gradient 0-15% MeOH in EtOAc) to afford the title compound (15 mg, yellow film). 1H NMR (400 MHz, MeOH-d4) δ ppm: 9.32 (s, 1 H), 8.65 (t, J=1.0 Hz, 1 H), 8.54 (d, J=2.5 Hz, 1 H), 7.73-8.01 (m, 2 H), 7.58 (br. s., 1 H), 7.17 (dd, J=12.1, 8.6 Hz, 1 H), 4.63 (d, J=9.1 Hz, 1 H), 4.30-4.40 (m, 1 H), 3.82 (dd, J=8.6, 2.3 Hz, 1 H), 3.16 (dd, J=13.5, 3.9 Hz, 1 H), 2.88 (dd, J=13.4, 4.0 Hz, 1 H), 2.61 (dt, J=8.3, 4.1 Hz, 1 H), 1.34 (d, J=6.1 Hz, 3 H).

1. temperatureat reflux in a sealed tube overnight
2. customThe reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM
3. customthe layers separated
4. extractionThe aqueous layer was extracted with DCM (×2)
5. dry with materialthe combined organics were dried (MgSO4)
6. filtrationfiltered
7. concentrationconcentrated in vacuo
8. customThe residue was purified by column chromatography (0-15% MeOH in DCM)
9. dissolutionThe product, (4aS,5R,7aS)-7a-{2-fluoro-5-[2-(pyrazin-2-yl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-5-yl]phenyl}-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine was dissolved in EtOH (5 mL)
10. stirringCHCl (2 mL) and the reaction was stirred
11. temperatureat reflux overnight
12. customto remove the SEM
13. concentrationThe reaction mixture was concentrated in vacuo
14. washwashing with MeOH
15. concentrationThe basic fraction was concentrated in vacuo
16. customThe residue was purified by column chromatography (gradient 0-15% MeOH in EtOAc)

ORD record

ord-53b6a302a84742cb9f1d3a331f72e61c

Source dataset

uspto-grants-2014_09

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08822455B2