Acryloyl chloride → N-(5-{[5-Chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]amino}-2-{(3R)-3-dimethylaminopyrrolidin-1-yl}-4-methoxyphenyl)prop-2-enamide

Temperatur

0 °C

Acryloyl chloride (0.459 mL, 1M in THF, 0.46 mmol) was added dropwise to a mixture of N-[5-chloro-4-(1-methylindol-3-yl)pyrimidin-2-yl]-4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-6-methoxybenzene-1,3-diamine (Intermediate 85, 226 mg, 0.46 mmol) and DIPEA (0.088 mL, 0.51 mmol) in THF (15 mL) at 0° C. under N2. The resulting suspension was stirred at 0° C. for 1 h, then allowed to warm to r.t. The mixture was then diluted with water (15 mL) and concentrated in vacuo. The resulting material was dissolved in a mixture of CH2Cl2 (20 mL) and CH3OH (5 mL). 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 a yellow dry film after concentration of appropriate fractions in vacuo. This material was dissolved in CH2Cl2 and the resulting solution was diluted with diethyl ether. This resulted in a yellow gelatinous solid precipitating from the solution. The mixture was concentrated in vacuo and dried to give the title compound (142 mg, 57%) as a yellow solid; 1H NMR: 1.68-1.81 (1H, m), 2.04-2.14 (1H, m), 2.18 (6H, s), 2.64-2.75 (1H, m), 3.22 (3H, dd), 3.32-3.44 (1H, m), 3.78 (3H, s), 3.90 (3H, s), 5.66 (1H, dd), 6.16 (1H, dd), 6.49 (1H, dd), 6.54 (1H, s), 7.08 (1H, t), 7.23 (1H, t), 7.49 (1H, d), 7.54 (1H, s), 8.29-8.39 (3H, m), 8.53 (1H, s), 9.35 (1H, s); m/z: ES+ MH+ 546.57.

1. temperatureto warm to r.t
2. concentrationconcentrated in vacuo
3. dissolutionThe resulting material 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 a yellow dry film after concentration of appropriate fractions in vacuo
10. customThis resulted in a yellow gelatinous solid
11. customprecipitating from the solution
12. concentrationThe mixture was concentrated in vacuo
13. customdried

ORD-Eintrag

ord-5c12dc6fb0394563bc25947f862230f1

Quelldatensatz

uspto-grants-2015_02

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08946235B2