Hydrochloric Acid → 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

Temperature

0 °C

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).

1. customThe solvents were then removed in vacuo
2. additionthe residue was treated with dichloromethane/toluene
3. concentrationconcentrated in vacuo
4. customto leave a pale yellow solid which
5. dry with materialwas dried in vacuo over P2O5
6. dissolutionThis solid was dissolved in anhydrous DMF (1.8 ml) under argon
7. customThe solution was placed in an ice-bath
8. customthe ice-bath was removed
9. stirringstirring
10. waitwas continued under argon for 2.5 h
11. customThe clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (80 ml)
12. washThe organic layer was washed with more saturated aqueous sodium bicarbonate (80 ml), brine (80 ml)
13. dry with materialdried (Na2SO4)
14. concentrationconcentrated in vacuo
15. customPurification by column chromatography
16. washon gradient elution with methanol in chloroform (15 to 20%)
17. customafforded a white solid
18. filtrationThe white solid was collected by filtration
19. washwashed with water
20. dry with materialdried in vacuo over P2O5 (0.036 g, 40%), mp>115° C. (softens)

ORD record

ord-501f2426052d4c84bb3700aed7d2d63a

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06699861B1