반응 #76148

반응 방정식

HCl

NaOH

3-(aminomethyl)pyridine

tert-butyl 4-[N-[7-chloro-3-diethylcarbamoylmethyl-4-oxo-2-(piperidin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate

tert-Butyl 4-[N-[7-Chloro-3-diethylcarbamoylmethyl-4-oxo-2-(piperidin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate

PyBOP

→

4-[N-[7-Chloro-3-diethylcarbamoylmethyl-4-oxo-2-(piperidin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]-N-(3-pyridylmethyl)benzamide

용매

water

DMF

dichloromethane

trifluoroacetic acid

반응 조건

후처리

1. 1
   기타The solvent was then removed in vacuo
2. 2
   workup.ADDITIONthe remainder was treated with toluene/dichloromethane
3. 3
   농축concentrated in vacuo
4. 4
   건조the residue was dried in vacuo over P2O5
5. 5
   workup.DISSOLUTIONThis material was dissolved in anhydrous DMF (1.3 ml) under argon
6. 6
   기타then the ice-bath was removed
7. 7
   workup.STIRRINGthe reaction mixture was stirred for an additional 3 hours
8. 8
   기타before being partitioned between ethyl acetate (100 ml) and saturated aqueous bicarbonate (80 ml)
9. 9
   추출The aqueous layer was extracted with more ethyl acetate (2×50 ml)
10. 10
    세척The combined organic extracts were washed With brine (80 ml)
11. 11
    건조dried (Na2SO4)
12. 12
    농축concentrated in vacuo
13. 13
    기타The residue was purified by column chromatography
14. 14
    기타The product was reprecipitated from dichloromethane/hexanes
15. 15
    기타to give a white solid
16. 16
    기타a white precipitate was obtained
17. 17
    여과This was collected by filtration
18. 18
    세척washed with water
19. 19
    건조dried in vacuo over P2O5 (0.040 g, 60%), mp>105° C.

실험 절차

A solution of tert-butyl 4-[N-[7-chloro-3-diethylcarbamoylmethyl-4-oxo-2-(piperidin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.065 g, 0.10 mmol) (Preparation Example 29) in dichloromethane (1 ml) and trifluoroacetic acid (1.3 ml) was stirred at room temperature for 1 hour with protection from the light. The solvent was then removed in vacuo and the remainder was treated with toluene/dichloromethane, concentrated in vacuo and the residue was dried in vacuo over P2O5. This material was dissolved in anhydrous DMF (1.3 ml) under argon and the solution was placed in.an ice-bath. A solution of 3-(aminomethyl)pyridine (0.016 g, 0.15 mmol) in DMF (0.3 ml) was then added followed by PyBOP® (0.055 g, 0.10 mmol) and diusopropylethylamine (0.077 g, 0.60 mmol). Stirring was continued at 0° C. for 3 min; then the ice-bath was removed and the reaction mixture was stirred for an additional 3 hours before being partitioned between ethyl acetate (100 ml) and saturated aqueous bicarbonate (80 ml). The aqueous layer was extracted with more ethyl acetate (2×50 ml). The combined organic extracts were washed With brine (80 ml), dried (Na2SO4) and concentrated in vacuo. The residue was purified by column chromatography using a gradient of methanol in dichloromethane (2 to 5%). The product was reprecipitated from dichloromethane/hexanes to give a white solid. This was suspended in water (5 ml) and the pH was first adjusted to ˜1 with 1N HCl, then to ˜11 with 1N NaOH; a white precipitate was obtained. This was collected by filtration , washed with water and dried in vacuo over P2O5 (0.040 g, 60%), mp>105° C.; 1H-NMR (DMSO-d6), 1.00, 1.18 (2×t, 6H, 2×CH2CH3), 1.40 (br s, 6H, piperidine CH2CH2CH2), 2.32 (br s, 4H, piperidine CH2NCH2), 3.24, 3.40 (2×q obscured by water peak, 4H, 2×CH2CH3), 4.37 (s, 2H, CH2C≡C), 4.43 (d, J=5.6 Hz, 2H, CONHCH2), 4.77 (s, 2H, 6-CH2), 5.10 (s, 2H, N3—CH2), 6.77 (d, J=8.8 Hz, 2H, 3,5′-ArH), 7.31 (dd, J=4.8, 7.8 Hz, 1H, pyr 5-H), 7.67 (d, J=7.8 Hz, 1H, pyr 4-H), 7.73 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.83, 7.86 (2×s, 2H, 5-H, 8-H), 8.42 (d, J=3.2 Hz, 1H pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.73 (t, J=5.6 Hz, 1H, CONH).; MS (ESI, m/z) 668, 670 [(M+H)+, 100%, 37% respectively; Cl isotopic pattern].

출처