반응 #155548

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2-(5-bromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl)pyrazine

Na2CO3

toluene

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

→

title compound

수율 24.4%

(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

수율 24.4%

용매

methanol

반응 조건

후처리

1. 1
   온도at reflux in a sealed tube overnight
2. 2
   기타The reaction mixture was partitioned between saturated aqueous NaHCO3 and DCM
3. 3
   기타the layers separated
4. 4
   추출The aqueous layer was extracted with DCM (×2)
5. 5
   건조the combined organics were dried (MgSO4)
6. 6
   여과filtered
7. 7
   농축concentrated in vacuo
8. 8
   기타The residue was purified by column chromatography (0-15% MeOH in DCM)
9. 9
   workup.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. 10
    workup.STIRRINGCHCl (2 mL) and the reaction was stirred
11. 11
    온도at reflux overnight
12. 12
    기타to remove the SEM
13. 13
    농축The reaction mixture was concentrated in vacuo
14. 14
    세척washing with MeOH
15. 15
    농축The basic fraction was concentrated in vacuo
16. 16
    기타The residue was purified by column chromatography (gradient 0-15% MeOH in EtOAc)

실험 절차

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).

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