反应详情

温度

90 °C

1-(4-Chlorophenyl)-N2-isopropyl-N1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine (0.075 g, 0.181 mmol), Pd(PPh3)4 (0.017 g, 0.015 mmol), and 2N Na2CO3 (0.226 mL, 0.452 mmol) were added to a solution of (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate (0.050 g, 0.151 mmol) in n-propanol (0.464 mL, 0.151 mmol). The suspension was degassed by bubbling nitrogen through the solution. The dark suspension was heated at 90° C. for 14 hours. The mixture was cooled to room temperature and then concentrated. The resulting residue was diluted with ethyl acetate and filtered. The filtrate was washed with saturated NaHCO3 and brine. The organic layer was dried and concentrated. The resulting residue was purified by Biotage SP4 (C18, 25+0-100% ACN). The product-containing fractions were collected and repurified by Gilson C18 (5-95 ACN/H2O+1% TFA). Tubes containing product were identified by LCMS, collected and evaporated. The material was partially dissolved in CH2Cl2, and HCl (g) was bubbled through the mixture to precipitate solid (5R,7R)-4-(4-(1-(4-chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol hydrochloride (8.10 mg, 12%). LCMS APCI+ (M+H+): 437 (100%), 439 (30%), rt 2.55 minutes. HPLC purity at 254 nm>99%, rt=2.17 minutes. 1H NMR (400 MHz, d6-acetone) δ 8.88 (s, 1H), 7.81 (d, J=8.2 Hz, 1H), 7.78 (d, J=8.6 Hz, 1H), 7.59 (d, J=3.5 Hz, 1H), 7.58 (d, J=3.1 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H), 6.65 (t, J=9.0 Hz, 2H), 5.26 (m, 1H), 5.15 (td, J=7.4, 4.3 Hz, 1H), 3.88 (m, 2H), 3.62 (br s, 2H), 3.50 (br s, 1H), 2.17 (m, 2H), 1.45 (m, 2H), 1.41 (d, J=6.6 Hz, 6H), 1.10 (t, J=7.0 Hz, 3H), 0.88 (m, 1H).

1. customThe suspension was degassed
2. customby bubbling nitrogen through the solution
3. temperatureThe mixture was cooled to room temperature
4. concentrationconcentrated
5. additionThe resulting residue was diluted with ethyl acetate
6. filtrationfiltered
7. washThe filtrate was washed with saturated NaHCO3 and brine
8. customThe organic layer was dried
9. concentrationconcentrated
10. customThe resulting residue was purified by Biotage SP4 (C18, 25+0-100% ACN)
11. customThe product-containing fractions were collected
12. customrepurified by Gilson
13. additionTubes containing product
14. customcollected
15. customevaporated
16. dissolutionThe material was partially dissolved in CH2Cl2
17. customHCl (g) was bubbled through the mixture
18. customto precipitate solid (5R,7R)-4-(4-(1-(4-chlorophenyl)-2-(isopropylamino)ethylamino)phenyl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol hydrochloride (8.10 mg, 12%)
19. custom437 (100%), 439 (30%), rt 2.55 minutes
20. customat 254 nm>99%, rt=2.17 minutes