Реакция #76144

Уравнение реакции

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

Растворители

DMF

water

dichloromethane

trifluoroacetic acid

Условия реакции

Обработка

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

Методика

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).

Источник