Reaktion #162445

Reaktionsgleichung

sodium hydride

7-Bromo-3-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one

Sodium hydride

Ethyl isocyanoacetate

NaH THF

diethyl chlorophosphate

→

8-Bromo-4-methyl-6-phenyl-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester

Lösungsmittel

THF

THF

Reaktionsbedingungen

Aufarbeitung

1. 1
   Temperaturwarm to rt over a 3 h period
2. 2
   TemperaturThe reaction mixture was again cooled to −10° C.
3. 3
   SonstigeThe cooling bath was then removed
4. 4
   workup.STIRRINGstirring
5. 5
   Sonstigeafter which the solution which resulted
6. 6
   workup.STIRRINGto stir for 3 h
7. 7
   TemperaturAfter 3 h the first flask was cooled to −30° C.
8. 8
   Sonstigethe solution in the 2nd reaction flask
9. 9
   workup.ADDITIONwas added to the first flask via a cannula
10. 10
    workup.STIRRINGto stir for 24 h
11. 11
    Temperaturcooled with an ice-water bath
12. 12
    Sonstigeslowly quenched with acetic acid (10 mL)
13. 13
    workup.ADDITIONWater was added to the reaction mixture after which it
14. 14
    Extraktionwas extracted with EtOAc
15. 15
    Waschenwashed with aq NaHCO3, brine
16. 16
    Trocknendried (Na2SO4)
17. 17
    SonstigeAfter removal of the solvent under reduced pressure
18. 18
    Sonstigethe solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:2, 1:1, 2:1)

Vorschrift

7-Bromo-3-methyl-5-phenyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 132 (16.6 g, 0.052 mol) was suspended in dry THF (250 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 4.36 g, 0.109 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (12.7 mL, 0.09 mol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 4.2 g, 0.1 mol) was suspended in dry THF (250 mL) at −10° C. in another flask. Ethyl isocyanoacetate (6.78 mL, 0.06 mol) was added to the NaH/THF suspension, after which the solution which resulted was allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. and the solution in the 2nd reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, and then cooled with an ice-water bath and slowly quenched with acetic acid (10 mL). Water was added to the reaction mixture after which it was extracted with EtOAc. The EtOAc layers were combined, washed with aq NaHCO3, brine and dried (Na2SO4). After removal of the solvent under reduced pressure, the solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:2, 1:1, 2:1). The ester 133 was a white solid (8.76 g, 40%). mp 164-165° C.; IR (KBr, cm−1) 2925, 1706, 1622, 1557, 1495, 1266, 1185; 1H NMR (CDCl3) δ 7.89 (s, 1 H), 7.73 (dd, J=1.73 Hz, 1 H), 7.51-7.36 (m, 7 H), 6.66 (q, J=7.30, 1 H), 4.45-4.30 (m, 2 H), 1.40 (t, J=7.11, 3 H), 1.25 (d, J=7.38 Hz, 3 H). MS (EI) m/e (relative intensity) 426 (M++2, 15), 425 (M++1, 58), 424 (M+, 15), 423 (58), 380 (24), 379 (71), 378 (35), 377 (69), 352 (50), 351(100), 350 (67), 349 (92), 270 (38), 229 (16); [α]26D=38.2 (c 0.45, EtOAc).

Quelle