Hydrochloric Acid → 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

Temperature

0 °C

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).

1. customThe trifluoroacetic acid was then removed in vacuo
2. additionthe residue was treated with dichloromethane/toluene
3. concentrationconcentrated in vacuo
4. customto leave an orange glass which
5. dry with materialwas dried in vacuo over P2O5 (0.114 g)
6. dissolutionThis was dissolved in anhydrous DMF (2.5 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 3 h
11. customThe clear solution was then partitioned between ethyl acetate (200 ml) and saturated aqueous sodium bicarbonate (100 ml)
12. washThe organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml)
13. dry with materialdried (Na2SO4)
14. concentrationconcentrated in vacuo
15. customPurification by column chromatography
16. washon gradient elution with methanol in dichloromethane (5 to 15%)
17. customafforded a glass
18. customto give a clear solution
19. customa pale yellow precipitate was obtained
20. filtrationThe solid was collected by filtration
21. washwashed with water
22. dry with materialdried in vacuo over P2O5 (6.065 g, 40%), mp 115-117° C.

ORD record

ord-b350273c97b84ecb92c62e5b14b0cf82

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06699861B1