Trifluoroacetic acid → HCID 71014653, compound

Temperature

50 °C

Under argon, phosphoric acid di-tert-butyl ester chloromethyl ester (1.24 g, 4.81 mmol) and Cs2CO3 (3.14 g, 9.63 mmol) were added to a solution of 3-(1H-indol-3-yl)-4-[2-(4-methyl-piperazin-1-yl)-quinazolin-4-yl]-pyrrole-2,5-dione (2.0 g, 4.01 mmol) in acetone (40 mL). The reaction mixture was stirred under argon for 16 h at 50° C. followed by concentration at reduced pressure. The residue was partitioned between EtOAc and a saturated aqueous NH4Cl solution, the layers were separated and the organic layer was dried over anhydrous Na2SO4. Concentration at reduced pressure afforded the crude product as a red foam. The crude product was purified by reverse phase Gilson HPLC as described above. After concentration of the desired fractions in vacuo, a red solid was obtained. UPLC-MS indicated that partial cleavage of the t-butyl ester groups had occurred. The thus obtained mixture (280 mg) was dissolved in a mixture of 1,2-dichloroethane (4 mL) and acetonitrile (2.0 mL). TFA (145 mg, 98 μL, 1.27 mmol) was added and the resulting solution was stirred for 3 h under argon at 0° C. when UPLC-MS indicated that full conversion of the starting material had occurred. The reaction mixture was diluted with 1,2-dichloroethane (4.0 mL) and concentrated at reduced pressure to afford the crude product as a red solid. The crude reaction product was dissolved in MeOH (3 mL) and slowly concentrated at reduced pressure until crystallization started to occur. The crystals were filtered off and washed with Et2O and pentane to afford the title compound as an orange solid. 1H-NMR (400 MHz, DMSO-d6): 12.27 (s, 1H), 8.21 (s, 1H), 7.72-7.66 (m, 2H), 7.58 (d, 1H), 7.40 (d, 1H), 7.14 (t, 1H), 7.02 (t, 1H), 6.65 (t, 1H), 6.24 (d, 1H), 5.34 (d, 2H), 4.14-3.72 (bs, 4H), 3.00-2.73 (bs, 4H), 2.60 (s, 3H). 31P-NMR (162 MHz, DMSO-d6): −2.7. LCMS: [M]+=548.6, Rt(1)=1.72 min., Rt(2)=0.73 min.

1. concentrationfollowed by concentration at reduced pressure
2. customThe residue was partitioned between EtOAc
3. customa saturated aqueous NH4Cl solution, the layers were separated
4. dry with materialthe organic layer was dried over anhydrous Na2SO4
5. concentrationConcentration at reduced pressure
6. customafforded the crude product as a red foam
7. customThe crude product was purified by reverse phase Gilson HPLC
8. customAfter concentration of the desired fractions in vacuo, a red solid was obtained
9. stirringthe resulting solution was stirred for 3 h under argon at 0° C. when UPLC-MS
10. concentrationconcentrated at reduced pressure
11. customto afford the crude product as a red solid
12. customThe crude reaction product
13. concentrationslowly concentrated at reduced pressure until crystallization
14. filtrationThe crystals were filtered off
15. washwashed with Et2O and pentane

ORD record

ord-29b4629149354c66b50ad711c52ec42e

Source dataset

uspto-grants-2014_04

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08703782B2