Hydrochloric Acid → HCID 51037661, compound

Temperature

45 °C

To a stirred mixture of 2,2-diethoxy-N,N-dimethylethanamine (1.56 g, 9.70 mmol) and water (1.6 mL) at room temperature and under a nitrogen atmosphere was added an aq. 37% HCl (1.62 mL, 19.3 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 (2.76 g, 49.3 mmol) was dissolved in water (8 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 235 (1.76 g, 3.85 mmol) and THF (8 mL) at room temperature and under a nitrogen atmosphere was added minimum amount of DMA (4 mL) to give a homogeneous solution. LiCl (163 mg, 3.85 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 for 30 min. it was poured into water (300 mL). Petroleum ether (300 mL) was added and stirred at room temperature for 10 min. Petroleum ether layer was decanted. More petroleum ether (300 mL) was added and stirred for 10 min. The solid was collected by suction filtration; washed with water (4×20 mL); dried under reduced pressure over silica gel/KOH to give compound 8 (1.38 g, 92%) which was found only 89.7% pure by HPLC. Thus, the sample was stirred with MeOH (ca. 40 mL) for 30 min. The insoluble material was filtered off and to the filtrates was added one volume of water to precipitate out the required product. The solid was collected, washed with water/MeOH=3:1 (3×15 mL) and dried to give (2E)-4-(dimethylamino)-N-[4-(3-ethynyl-4-fluoroanilino)pyrido[3,4-d]pyrimidin-6-yl]-2-butenamide (8) (1.28 g, 85%) as a yellow/brown solid, mp 152-155° C.; 1H NMR δ [(CD3)2SO] 10.93 (s, 1H), 10.29 (s, 1H), 9.02 (s, 1H), 8.99 (s, 1H), 8.61 (s, 1H), 8.04 (dd, J=6.4, 2.7 Hz, 1H), 7.94-7.85 (m, 1H), 7.35 (t, J=9.1 Hz, 1H), 6.87 (dt, J=15.4, 6.0 Hz, 1H), 6.52 (br d, J=15.4 Hz, 1H), 4.53 (s, 1H), 3.09 (br d, J=6.0 Hz, 2H), 2.19 (s, 6H). Anal. Calcd for C21H19FN6O.0.8H2O.0.7MeOH: C, 61.00; H, 5.52; N, 19.67%. Found C, 61.26; H, 5.25; N, 19.47%.

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 for 30 min. it
10. stirringstirred at room temperature for 10 min
11. customPetroleum ether layer was decanted
12. additionMore petroleum ether (300 mL) was added
13. stirringstirred for 10 min
14. filtrationThe solid was collected by suction filtration
15. washwashed with water (4×20 mL)
16. customdried under reduced pressure over silica gel/KOH

ORD record

ord-9e4886682c334479aedb898964c11bf5

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09101632B2