Reaktion #162443

Reaktionsgleichung

sodium hydride

7-bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one

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

Sodium hydride

Ethyl isocyanoacetate

NaH THF

diethyl chlorophosphate

→

8-Bromo-4-methyl-6-pyridin-2-yl-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
   Sonstigethe solution which resulted
6. 6
   workup.STIRRINGto stir for 3 h
7. 7
   workup.WAITAfter 3 h
8. 8
   Temperaturthe first flask was cooled to −30° C.
9. 9
   Sonstigethe solution in the 2nd reaction flask
10. 10
    workup.ADDITIONwas added to the first flask via a cannula
11. 11
    workup.STIRRINGto stir for 24 h
12. 12
    Temperaturcooled with an ice-water bath
13. 13
    Sonstigeslowly quenched with acetic acid (10 mL)
14. 14
    workup.ADDITIONWater was added to the reaction mixture after which it
15. 15
    Extraktionwas extracted with EtOAc
16. 16
    Waschenwashed with aq NaHCO3, brine
17. 17
    Trocknendried (Na2SO4)
18. 18
    SonstigeAfter removal of the solvent under reduced pressure
19. 19
    Sonstigethe solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:1, 2:1, 3:1)

Vorschrift

The 7-bromo-3-methyl-5-pyridin-2-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 125 (3.3 g, 10 mmol) was suspended in dry THF (200 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.48 g, 12 mmol) 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 (2.31 mL, 16 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. At this time, sodium hydride (60% dispersion in mineral oil, 0.56 g, 14 mmol) was suspended in dry THF (150 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.31 mL, 12 mmol) was added to the NaH/THF suspension, 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 1:1, 2:1, 3:1). The ester 126 was a white solid (1.40 g, 33%). mp 193-195° C.; IR (KBr, cm−1) 2962, 1719, 1260, 1021; 1H NMR (CDCl3) δ 7.92 (s, 1 H), 7.72 (dd, J=8.5, 1.5 Hz, 1 H), 7.6 (t, J=6.9 Hz, 1 H), 7.48 (d, J=8.5 Hz, 1 H), 7.42-7.49 (m, 2 H), 7.23-7.29 (m, 1 H), 7.05 (t, J=9.3 Hz, 1 H), 6.71 (q, J=7.3 Hz, 1 H), 4.41 (m, 2 H), 1.42 (t, J=7.1 Hz, 3 H), 1.29 (d, J=7.2, 3 H).

Quelle