Reaktion #162439

Reaktionsgleichung

sodium hydride

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

Sodium hydride

Ethyl isocyanoacetate

NaH THF

diethyl chlorophosphate

→

8-Bromo-6-(2-fluorophenyl)-4-methyl-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
   workup.STIRRINGto stir for 3 h
6. 6
   TemperaturAfter 3 h the first flask was cooled to −30° C. with a cooling bath
7. 7
   workup.ADDITIONthe mixture in the second reaction flask was added to the first flask via a cannula
8. 8
   workup.STIRRINGto stir for 24 h
9. 9
   Temperaturafter which it was cooled to 0° C. with an ice-water bath
10. 10
    Sonstigeslowly quenched with acetic acid (5 mL)
11. 11
    workup.ADDITIONWater was then added to the reaction mixture
12. 12
    Extraktionthis was extracted with EtOAc
13. 13
    Waschenwashed with aq NaHCO3, brine
14. 14
    Trocknendried (Na2SO4)
15. 15
    SonstigeAfter removal of the solvent under reduced pressure
16. 16
    Sonstigethe solid was purified by flash chromatography (silica gel, EtOAc:hexane: gradient elution 1:2, 1:1, 2:1)

Vorschrift

7-Bromo-5-(2-fluorophenyl)-3-methyl-1,3-dihydro-benzo[e][1,4]diazepin-2-one 117 (3.78 g, 10.88 mmol) was suspended in dry THF (150 mL) and cooled to −10° C. Sodium hydride (60% dispersion in mineral oil, 0.52 g, 13.07 mol) was added into the suspension in one portion. The reaction mixture was allowed to stir and then warm to rt over a 3 h period. The reaction mixture was again cooled to −10° C. and diethyl chlorophosphate (2.65 mL, 17.42 mmol) was added. The cooling bath was then removed and stirring continued for 3 h. During this time, sodium hydride (60% dispersion in mineral oil, 0.61 g, 15.24 mmol) was suspended in dry THF (60 mL) at −10° C. in another flask. Ethyl isocyanoacetate (1.43 ml, 13.07 mnol) was added to the NaH/THF suspension and this mixture allowed to stir for 3 h. After 3 h the first flask was cooled to −30° C. with a cooling bath and the mixture in the second reaction flask was added to the first flask via a cannula. The reaction mixture was allowed to stir for 24 h, after which it was cooled to 0° C. with an ice-water bath and slowly quenched with acetic acid (5 mL). Water was then added to the reaction mixture and this 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 ethyl ester 118 was a white solid (1.82 g, 38%). mp 190-192° C.; IR (KBr, cm−1) 3316, 2925, 1693, 1621, 1485, 1448, 1371; 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). MS (EI) m/e (relative intensity) 442 (M+, 5), 428 (7), 381 (58), 355 (100), 303 (37); [α]26D=10.6 (c 0.53, EtOAc).

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