Реакция #76147

Уравнение реакции

HCl

NaOH

3-(aminopropyl)imidazole

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

PyBOP

→

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

Растворители

water

DMF

dichloromethane

trifluoroacetic acid

Условия реакции

Обработка

1. 1
   ДругоеThe solvents were then removed in vacuo
2. 2
   workup.ADDITIONthe residue was treated with dichloromethane/toluene
3. 3
   Концентрированиеconcentrated in vacuo
4. 4
   Другоеto leave a pale yellow solid which
5. 5
   Сушкаwas dried in vacuo over P2O5
6. 6
   workup.DISSOLUTIONThis solid was dissolved in anhydrous DMF (1.8 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 2.5 h
11. 11
    ДругоеThe clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (80 ml)
12. 12
    ПромывкаThe organic layer was washed with more saturated aqueous sodium bicarbonate (80 ml), brine (80 ml)
13. 13
    Сушкаdried (Na2SO4)
14. 14
    Концентрированиеconcentrated in vacuo
15. 15
    ДругоеPurification by column chromatography
16. 16
    Промывкаon gradient elution with methanol in chloroform (15 to 20%)
17. 17
    Другоеafforded a white solid
18. 18
    ФильтрацияThe white solid was collected by filtration
19. 19
    Промывкаwashed with water
20. 20
    Сушкаdried in vacuo over P2O5 (0.036 g, 40%), mp>115° C. (softens)

Методика

A solution of tert-butyl 4-[N-[7-chloro-3-methyl-2-(4-methyl-piperazin-1-yl)methyl-4-oxo-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.082 g, 0.15 mmol) (Preparation Example 14) in dichloromethane (1.2 ml) and trifluoroacetic acid (1.6 ml) was stirred at room temperature for 55 min. The solvents were then removed in vacuo, and the residue was treated with dichloromethane/toluene, concentrated in vacuo to leave a pale yellow solid which was dried in vacuo over P2O5. This solid was dissolved in anhydrous DMF (1.8 ml) under argon. The solution was placed in an ice-bath and then a solution of 1-(3-(aminopropyl)imidazole (0.029 g, 0.23 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.083 g, 0.16 mmol), and finally diusopropylethylamine (0.135 g, 1.05 mmol). The solution was stirred at 0° C. for 5 min, then the ice-bath was removed and stirring was continued under argon for 2.5 h. The clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (80 ml). The organic layer was washed with more saturated aqueous sodium bicarbonate (80 ml), brine (80 ml), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography, on gradient elution with methanol in chloroform (15 to 20%), afforded a white solid. This was suspended in water (6 ml) and the pH was first adjusted to ˜1 with 0.5N HCl and then to ˜12 with 1N NaOH. The white solid was collected by filtration, washed with water, and dried in vacuo over P2O5 (0.036 g, 40%), mp>115° C. (softens); 1H-NMR (DMSO-d6) 1.91 (m, 2H, CONHCH2CH2CH2), 2.14 (s, 3H, N-Me piperazine), 2.30 (br s) and 2.49 br s (obscured)) (8H, N(CH2CH2)2N—), 3.18 (m, 2H, CONHCH2CH2CH2), 3.20 (s, 1H, C≡CH), 3.59, 3.61 (2×s, 5H, N3-Me and 2-CH2), 3.98 (t, J=6.84 Hz, 2H, CONHCH2CH2CH2) 4.37 (s, 2H, CH2C≡C), 4.76 (s, 2H, 6-CH2), 6.78 (d, J=8.5 Hz, 2H, 3,5′-ArH), 6.88, 7.19 (2×s, 2H, imidazole 4-H and 5-H), 7.64 (s, 1H, imidazole 2-H), 7.71 (d, J=8.2 Hz, 2H, 2′,6′-ArH), 7.81, 7.91 (2×s, 2H, 5-H, 8-H), 8.17 (t, J=5.0 Hz, 1H, CONH).

Источник