Reaktion #606297

Reaktionsgleichung

3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester

bromine

MeOH

di-tert-butyl dicarbonate

→

3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester

Ausbeute 38.0%

Lösungsmittel

AcOH

AcOH

Reaktionsbedingungen

Aufarbeitung

1. 1
   SonstigeThe reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8
2. 2
   workup.STIRRINGthe reaction mixture was stirred at ambient temperature for 1.5 h
3. 3
   ExtraktionThe aqueous solution was extracted with EtOAc (3×10 mL)
4. 4
   Waschenthe combined organic phase was washed with saturated brine (10 mL)
5. 5
   Trocknendried over Na2SO4
6. 6
   Filtrationfiltered
7. 7
   SonstigeThe filtrate was evaporated to dryness
8. 8
   Sonstigethe residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether)

Vorschrift

To a solution of 3-methyl-3-[(R)-1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-azetidine-1-carboxylic acid tert-butyl ester (diastereomer 1, 0.283 g, 0.683 mmol) in AcOH (1 mL) was added a solution of bromine (0.070 mL, 1.366 mmol) in AcOH (1 mL) drop-wise and the reaction mixture was stirred for 1 h at ambient temperature. The reaction mixture was quenched by the addition of saturated aqueous NaS2O3 solution and aqueous NaHCO3 solution to pH 7-8. MeOH (5 mL), TEA (0.146 g, 1.439 mmol) and di-tert-butyl dicarbonate (0.188 g, 0.864 mmol) were added in sequence to the above mixture and the reaction mixture was stirred at ambient temperature for 1.5 h. The aqueous solution was extracted with EtOAc (3×10 mL) and the combined organic phase was washed with saturated brine (10 mL), dried over Na2SO4 and filtered. The filtrate was evaporated to dryness and the residue was purified by prep-TLC (eluting with 50% EtOAc in petroleum ether) to give 3-[(R)-1-((R)-7-bromo-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-ethyl]-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.128 g, 36%) as a solid. LC/MS (Table 1, Method 25) Rt=0.913 min.; MS m/z: 437 [M+H−56]+ and 439 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.26 (brs, 1H), 7.25 (s, 1H), 6.70 (s, 1H), 4.75-4.70 (m, 1H), 4.60 (d, J=12.8 Hz, 2H), 3.98-3.91 (m, 2H), 3.55 (m, 2H), 3.44 (d, J=8.4 Hz, 1H), 1.52 (d, J=6.8 Hz, 3H), 1.46 (s, 9H), 1.32-1.27 (m, 6H).

Quelle