반응 #76141

반응 방정식

diisopropylethylamine

tert-butyl 4-[N-[2-diethylaminomethyl-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate

3-(aminomethyl)pyridine

PyBOP

→

4-[N-[2-Diethylaminomethyl-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide

용매

dichloromethane

trifluoroacetic acid

DMF

반응 조건

후처리

1. 1
   기타The solvents were then removed in vacuo
2. 2
   workup.ADDITIONthe oily residue was treated with dicloromethane/toluene
3. 3
   농축concentrated in vacuo
4. 4
   건조the solid was dried in vacuo over P2O5
5. 5
   workup.DISSOLUTIONThis solid was dissolved in anhydrous DMF (1.3 ml)
6. 6
   기타the solution was placed in an ice-bath under argon
7. 7
   workup.WAITwas continued at 0° C. for 3 min
8. 8
   기타then the ice-bath was removed
9. 9
   workup.STIRRINGstirring
10. 10
    workup.WAITwas continued for an additional 3 h
11. 11
    기타The reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate (100 ml)
12. 12
    세척The organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml) and brine (100 ml)
13. 13
    건조dried (Na2SO4)
14. 14
    농축concentrated in vacuo
15. 15
    기타Purification by column chromatography
16. 16
    세척on elution with a gradient of methanolin dichloromethane (2 to 3%)
17. 17
    기타afforded a glass which
18. 18
    기타was reprecipitated from dichloromethane/hexanes
19. 19
    여과The white solid was collected by filtration
20. 20
    세척washed with hexanes
21. 21
    건조dried in vacuo over P2O5 (0.049 g, 52%), mp 180-182° C.

실험 절차

A solution of tert-butyl 4-[N-[2-diethylaminomethyl-7-chloro-3-methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (Preparation Example 15) (0.090 g, 0.17 mmol) in dichloromethane (1.2 ml) and trifluoroacetic acid (1.6 ml) was stirred at. room temperature for 55 min with protection from the light. The solvents were then removed in vacuo and the oily residue was treated with dicloromethane/toluene, then concentrated in vacuo and the solid was dried in vacuo over P2O5. This solid was dissolved in anhydrous DMF (1.3 ml) and the solution was placed in an ice-bath under argon. A solution of 3-(aminomethyl)pyridine (0.028 g, 0.255 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.093 g, 0.178 mmol) and finally diisopropylethylamine (0.131 g, 1.02 mmol). Stirring was continued at 0° C. for 3 min; then the ice-bath was removed and stirring was continued for an additional 3 h. The reaction mixture was partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate (100 ml). The organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml) and brine (100 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on elution with a gradient of methanolin dichloromethane (2 to 3%), afforded a glass which was reprecipitated from dichloromethane/hexanes. The white solid was collected by filtration, washed with hexanes and dried in vacuo over P2O5 (0.049 g, 52%), mp 180-182° C.; 1H-NMR (DMSO-d6) 0.95 (t, J=7.11 Hz, 6H, 2×CH2CH3), 2.58 (obscured, J=7.0 Hz, 4H, 2×CH2CH3), 3.19 (s, 1H, C≡CH), 3.62 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.37 (s, 2H, CH2C≡C), 4.44 (d, J=5.7 Hz, 2H, CONHCH2), 4.77 (s, 2H, 6-CH2), 6.78 (d, J=8.9 Hz, 2H, 3,5′-ArH), 7.32 (dd, J=4.8, 7.8 Hz, 1H, pyr 5-H), 7.67 (d, J=7.7 Hz, 1H, pyr 4-H), 7.75 (d, J=8.7 Hz, 2H, 2′,6′-ArH), 7.80, 7.91 (2×s, 2H, 5-H, 8-H), 8.42 (d, J=5.3 Hz, pyr 6-H), 8.51 (s, 1H, pyr 2-H), 8.74 (t, J=6.03 Hz, 1H, CONH).; MS (ESI, m/z) 557,559 [(M+H)+, 100%, 38% respectively; Cl isotopic pattern]. FAB-HRMS; measured 557.2414; calculated for C31H34ClN6O2 (M+H)+: 557.2432.

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