3-Pyridinemethanamine → 4-[n-[7-Chloro-3-methyl-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-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-4-oxo-2-(4-phenylpiperazin-1-yl)methyl-3,4-dihydroquinazolin-6-ylmethyl]-N-(prop-2-ynyl)amino]benzoate (0.140 g, 0.23 mmol) (Preparation Example 22) in dichloromethane (1.7 ml) and trifluoroacetic acid (2.3 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, and dried in vacuo over P2O5 (0.182 g). This was dissolved in anhydrous DMF (2 ml) under argon. The solution was placed in an ice-bath and then a solution of 3-(aminomethyl)pyridine (0.037 g, 0.34 mmol) in anhydrous DMF (0.2 ml) was added followed by PyBOP® (0.125 g, 0.24 mmol), and finally diisopropylethylamine (0.178 g, 1.38 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 (150 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 (2 to 5%), afforded a white solid which was reprecipitated from dichloromethane/hexanes (0.104 g, 71%), mp 214-216° C. 1H-NMR (DMSO-d6) 2.76 (br s) and 3.11 (br s) (8H, N(CH2CH2)2), 3.20 (s, 1H, C≡CH), 3.63 (s, 3H, N3-Me), 3.70 (s, 2H, 2-CH2), 4.37 (s, 2H, CH2C≡C), 4.45 (d, J 5.7 Hz, 2H, CONHCH2), 4.78 (s, 2H, 6-CH2), 6.74 (t obscured, 1H), 6.90 (d, J=8.6 Hz, 2H), and 7.20 (t, J=8.20 Hz, 2H) (C6H5—N(CH2CH2)2N—), 6.76 (d, J=8.7 Hz, 2H, 3,5′-ArH), 7.32 (dd, J=4.6, 7.8 Hz, 1H, pyr 5-H), 7.68 (d, J=7.7 Hz, pyr 4-H), 7.75 (d, J=8.6 Hz, 2H, 2′,6′-ArH), 7.83, 7.93 (2×s, 2H, 5-H, 8-H), 8.43 (d, J=4.7 Hz, pyr 6-H), 8.52 (s, 1H, pyr 2-H), 8.76 (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. dry with materialdried in vacuo over P2O5 (0.182 g)
5. dissolutionThis was dissolved in anhydrous DMF (2 ml) under argon
6. customThe solution was placed in an ice-bath
7. customthe ice-bath was removed
8. stirringstirring
9. waitwas continued under argon for 3 h
10. customThe clear solution was then partitioned between ethyl acetate (150 ml) and saturated aqueous sodium bicarbonate (100 ml)
11. washThe organic layer was washed with more saturated aqueous sodium bicarbonate (100 ml), brine (100 ml)
12. dry with materialdried (Na2SO4)
13. concentrationconcentrated in vacuo
14. customPurification by column chromatography
15. washon gradient elution with methanol in dichloromethane (2 to 5%)
16. customafforded a white solid which
17. customwas reprecipitated from dichloromethane/hexanes (0.104 g, 71%), mp 214-216° C

ORD record

ord-52323126c4234be08b6d0e73d22f59b6

Source dataset

uspto-grants-2004_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06699861B1