反应 #76144

反应方程式

3-(aminomethyl)pyridine

HCl

PyBOP

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

NaOH

diisopropylethylamine

→

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

溶剂

DMF

water

dichloromethane

trifluoroacetic acid

反应条件

后处理

1. 1
   其他The trifluoroacetic acid was then removed in vacuo
2. 2
   workup.ADDITIONthe residue was treated with dichloromethane/toluene
3. 3
   浓缩concentrated in vacuo
4. 4
   其他to leave an orange glass which
5. 5
   干燥was dried in vacuo over P2O5 (0.114 g)
6. 6
   workup.DISSOLUTIONThis was dissolved in anhydrous DMF (2.5 ml) under argon
7. 7
   其他The solution was placed in an ice-bath
8. 8
   其他the ice-bath was removed
9. 9
   workup.STIRRINGstirring
10. 10
    workup.WAITwas continued under argon for 3 h
11. 11
    其他The clear solution was then partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate (100 ml)
12. 12
    洗涤The organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml)
13. 13
    干燥dried (Na2SO4)
14. 14
    浓缩concentrated in vacuo
15. 15
    其他Purification by column chromatography
16. 16
    洗涤on gradient elution with methanol in dichloromethane (5 to 15%)
17. 17
    其他afforded a glass
18. 18
    其他to give a clear solution
19. 19
    其他a pale yellow precipitate was obtained
20. 20
    过滤The solid was collected by filtration
21. 21
    洗涤washed with water
22. 22
    干燥dried in vacuo over P2O5 (6.065 g, 40%), mp 115-117° C.

实验过程

A solution of tert-butyl 4-[N-[7-chloro-3-methyl-2-(4-(2-hydroxyethyl)ethyl-piperazin-1-yl)methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.157 g, 0.27 mmol) (Preparation Example 21) in dichloromethane (1.6 ml) and trifluoroacetic acid (2.6 ml) was stirred at room temperature for 55 min with protection from the light. The trifluoroacetic acid was then removed in vacuo, and the residue was treated with dichloromethane/toluene, concentrated in vacuo to leave an orange glass which was dried in vacuo over P2O5 (0.114 g). This was dissolved in anhydrous DMF (2.5 ml) under argon. The solution was placed in an ice-bath and then a solution of 3-(aminomethyl)pyridine (0.043 g, 0.40 mmol) in anhydrous DMF (1.5 ml) was added followed by PyBOP® (0.147 g, 0.28 mmol), and.finally diisopropylethylamine (0.209 g, 1.62 mmol). The solution was stirred at 0° C. for 5 min, then the ice-bath was removed and stirring was continued under argon for 3 h. The clear solution was then 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), brine (100 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in dichloromethane (5 to 15%), afforded a glass. This was suspended in water (6 ml) and the pH was first adjusted to 1 with 1N aqueous HCl to give a clear solution, then to ˜9 with 1N NaOH; a pale yellow precipitate was obtained. The solid was collected by filtration, washed with water, and dried in vacuo over P2O5 (6.065 g, 40%), mp 115-117° C.; 1H-NMR (DMSO-d6) 2.35 (t obscured, J=6.3 Hz, 2H, NCH2CH2OH), 2.38, 2.46 (2×br s, 8H, N(CH2CH2)2), 3.18 (s, 1H, C≡CH), 3.46 (q, J=6.1 Hz, 2H, NCH2CH2OH), 3.60 (s, 5H, N3-Me, 2-CH2), 4.26 (t, J=5.3 Hz, 1H, NCH2CH2 OH), 4.36 (d, J=1.8 Hz, 2H, CH2C≡C), 4.45 (d, J=5.8 Hz, 2H, CONHCH2), 4.77 (s, 2H, 6-CH2), 6.79 (d, J=8.9 Hz, 2H, 3,5′-ArH), 7.33 (dd, J=4.8, 7.8 Hz, 1H, pyr 5-H), 7.69 (dt, J=1.8, 7.8 Hz, pyr 4-H), 7.76 (d, J=8.8 Hz, 2H, 2′,6′-ArH), 7.80, 7.91 (2×s, 2H, 5-H, 8-H), 8.43 (dd, J=1.6, 4.8 Hz, 1H, pyr 6-H), 8.52 (s, 1H, 2-H pyr), 8.72 (t, J=5.8 Hz, 1H, CONH).

来源