Reacción #159074

Ecuación de reacción

DIEA

EtOAc

HBr

HATU

DIEA

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester

→

(1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

Disolventes

AcOH

DMF

—

hexanes

DCM

Condiciones de reacción

Tratamiento posterior

1. 1
   Filtraciónthe solid was collected via filtration
2. 2
   Lavadowas washed with hexanes
3. 3
   OtroThe crude material was used in the next step without further purification
4. 4
   workup.DISSOLUTIONThe crude material was dissolved in DMF (4.0 mL)
5. 5
   workup.STIRRINGThe reaction was stirred at room temperature
6. 6
   workup.WAITAfter 50 minutes
7. 7
   Lavadowas washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine
8. 8
   Secadowas dried over sodium sulfate
9. 9
   FiltraciónFiltration and removal of solvents in vacuo
10. 10
    Otrogave the crude material, which
11. 11
    Otrowas purified by silica gel chromatography (eluent: EtOAc/hexanes)

Procedimiento

6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (800 mg, 1.38 mmol) was dissolved in DCM (15 mL) and HBr in AcOH (37%, 2 mL) was added and stirring at room temperature was continued. After 180 minutes, the suspension was diluted with hexanes and the solid was collected via filtration and was washed with hexanes and subjected to vacuum. The crude material was used in the next step without further purification. The crude material was dissolved in DMF (4.0 mL) and DIEA (356 mg, 2.76 mmol) was added. A solution of 2-(L)-Methoxycarbonylamino-3-methyl-butyric acid (242 mg, 1.38 mmol), HATU (524 mg, 1.38 mmol) and DIEA (178 mg, 1.38 mmol) in DMF (1 mL) was added. The reaction was stirred at room temperature. After 50 minutes, the reaction was diluted with EtOAc and was washed with aqueous bicarbonate solution, aqueous LiCl solution (5%), brine, and was dried over sodium sulfate. Filtration and removal of solvents in vacuo gave the crude material, which was purified by silica gel chromatography (eluent: EtOAc/hexanes) to yield the slightly impure product (1-{6-[5-(7-Bromo-9,9-difluoro-9H-fluoren-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (878 mg). LCMS-ESI+: calc'd for C29H29BrF2N4O3: 599.5 (M+). Found: 598.5/600.5 (M+H+).

Fuente