Hydrochloric Acid → (2E)-4-(dimethylamino)-N-(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}pyrido[3,4-d]pyrimidin-6-yl)-2-butenamide

Temperatur

45 °C

To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.32 g, 8.20 mmol) and water (1.4 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.38 mL, 16.4 mmol). After addition the mixture was stirred at 45° C. (bath) for 25 h. It was cooled to 0° C. (bath). This is called solution A. KOH (2.36 g, 42.0 mmol) was dissolved in water (7 mL) at room temperature under a nitrogen atmosphere. It was cooled to 0° C. (bath). This is called solution B. To a stirred heterogeneous mixture of compound 229 (1.85 g, 3.28 mmol) and THF (7 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4 mL) to give a homogeneous solution. LiCl (139 mg, 3.28 mmol) was added and stirred at 0° C. (bath) for 15 min. The cold solution B was added and stirred at 0° C. for 2 min. Then the cold solution A was added and the final reaction mixture was continued to stir at 0° C. under a nitrogen atmosphere. The reaction was monitored by TLC (DCM-MeOH-10:1). After stirred further for 30 min. it was poured into water (200 mL). Petroleum ether (200 mL) was added and stirred at room temperature for 15 min. Petroleum ether layer was decanted. More petroleum ether (200 mL) was added and stirred for 15 min. The solid was collected by suction filtration; washed with water (4×30 mL); dried under reduced pressure over silica gel/KOH to give (2E)-4-(dimethylamino)-N-(4-{[1-(3-fluorobenzyl)-1H-indazol-5-yl]amino}pyrido[3,4-d]pyrimidin-6-yl)-2-butenamide (2) (1.55 g, 95%) as a pale yellow solid, mp 240-243; HPLC: 96.7% pure; 1H NMR δ [(CD3)2SO] 10.87 (s, 1H), 10.29 (s, 1H), 9.01 (s, 1H), 8.98 (s, 1H), 8.53 (s, 1 H), 8.18 (d, J=0.7 Hz, 1H), 8.16 (d, J=0.4 Hz, 1H), 7.73 (br d, J=9.0 Hz, 1H), 7.70 (dd, J=9.0, 1.7 Hz, 1H), 7.41-7.33 (m, 1H), 7.14-7.02 (m, 3H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 5.70 (s, 2 H), 3.09 (dd, J=6.0, 1.1 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C27H25FN8O.1.2H2O: C, 62.59; H, 5.33; N, 21.63%. Found C, 62.59; H, 5.25; N, 21.59%.

1. additionAfter addition the mixture
2. temperatureIt was cooled to 0° C. (bath)
3. temperatureIt was cooled to 0° C. (bath)
4. customto give a homogeneous solution
5. stirringstirred at 0° C. (bath) for 15 min
6. stirringstirred at 0° C. for 2 min
7. customthe final reaction mixture
8. stirringto stir at 0° C. under a nitrogen atmosphere
9. stirringAfter stirred further for 30 min. it
10. stirringstirred at room temperature for 15 min
11. customPetroleum ether layer was decanted
12. additionMore petroleum ether (200 mL) was added
13. stirringstirred for 15 min
14. filtrationThe solid was collected by suction filtration
15. washwashed with water (4×30 mL)
16. customdried under reduced pressure over silica gel/KOH

ORD-Eintrag

ord-e7bf0eb6fb794cbda89df79b7fc26135

Quelldatensatz

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US09101632B2