تفاعل #162443

معادلة التفاعل

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

المذيبات

THF

THF

ظروف التفاعل

المعالجة

1. 1
   درجة الحرارةwarm to rt over a 3 h period
2. 2
   درجة الحرارةThe reaction mixture was again cooled to −10° C.
3. 3
   أخرىThe cooling bath was then removed
4. 4
   workup.STIRRINGstirring
5. 5
   أخرىthe solution which resulted
6. 6
   workup.STIRRINGto stir for 3 h
7. 7
   workup.WAITAfter 3 h
8. 8
   درجة الحرارةthe first flask was cooled to −30° C.
9. 9
   أخرىthe 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
    درجة الحرارةcooled with an ice-water bath
13. 13
    أخرىslowly quenched with acetic acid (10 mL)
14. 14
    workup.ADDITIONWater was added to the reaction mixture after which it
15. 15
    استخلاصwas extracted with EtOAc
16. 16
    غسيلwashed with aq NaHCO3, brine
17. 17
    تجفيفdried (Na2SO4)
18. 18
    أخرىAfter removal of the solvent under reduced pressure
19. 19
    أخرىthe solid was purified by flash chromatography (silica gel, EtOAc:hexane, gradient elution 1:1, 2:1, 3:1)

الإجراء التجريبي

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).

المصدر