Acryloyl chloride → N-(5-{[5-Chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}-4-methoxy-2-{4-methylpiperazin-1-yl}phenyl)prop-2-enamide

온도

0 °C

Acryloyl chloride (0.621 mL, 1M in THF, 0.62 mmol) was added dropwise to N′-[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]-4-methoxy-6-(4-methylpiperazin-1-yl)benzene-1,3-diamine (Intermediate 74, 288 mg, 0.62 mmol) and DIPEA (0.119 mL, 0.68 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, and then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting residue was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL) and the resulting solution was washed with water and sat. brine. The organic solution was dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 1-8% 7M methanolic ammonia in CH2Cl2 gave crude product as a pale brown dry film. This material was dissolved in CH2Cl2 and a beige solid precipitated from the solution. The solution was diluted with diethyl ether and then mixture filtered. The collected solid was washed with further diethyl ether and dried to give the title compound (134 mg, 42%) as a beige solid; 1H NMR: 2.27 (3H, s), 2.53-2.59 (4H, m), 2.87-2.94 (4H, m), 3.79 (3H, s), 5.70 (1H, d), 6.17 (1H, dd), 6.60 (1H, dd), 6.89 (1H, s), 7.01 (1H, t), 7.16 (1H, t), 7.45 (1H, d), 8.20 (1H, s), 8.27 (1H, d), 8.35 (1H, s), 8.43 (1H, s), 8.49 (1H, d), 8.96 (1H, s), 11.81 (1H, s); m/z: ES+ MH+ 518.51.

1. temperatureto warm to r.t
2. concentrationconcentrated in vacuo
3. dissolutionThe resulting residue was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL)
4. washthe resulting solution was washed with water and sat. brine
5. dry with materialThe organic solution was dried (MgSO4)
6. concentrationconcentrated in vacuo
7. customPurification by FCC
8. washeluting with 1-8% 7M methanolic ammonia in CH2Cl2
9. customgave crude product as a pale brown dry film
10. customa beige solid precipitated from the solution
11. additionThe solution was diluted with diethyl ether
12. filtrationmixture filtered
13. washThe collected solid was washed with further diethyl ether
14. customdried

ORD 기록

ord-835f259ebdba4dbda67f90ed0bee8cd1

출처 데이터셋

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08946235B2