Trifluoroacetic acid → HCID 178434345, compound

To a flask was added tert-butyl 6-(4-(cyclopropylamino)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (12.5 g, 29.7 mmol), DCM (270 mL) and TFA (45.8 mL, 595 mmol). The mixture was stirred for about 4 h. The mixture was concentrated and the residue was dissolved in MeOH (100 mL). The resulting solution was added into stirred aqueous NaHCO3 (10 wt %, 1000 mL) and the mixture was allowed to stir for about 1 h. The resultant suspension was filtered. To the solid was added hot water (60° C., 1000 mL) and the mixture was stirred for about 45 min and then filtered. The solid was then added to a mixture of DCM (270 mL) and MeOH (30 mL) in a flask, the mixture was heated to reflux then additional MeOH (25 mL) was added portion wise over a period of about 45 min, until a clear solution formed. The solution was filtered while hot. The filtrate was cooled in an ice bath for about 1 h. The mixture was then filtered to provide the desired product (6 g). The filtrate was combined with silica gel (15 g, 200-400 mesh size) and concentrated to a free flowing powder. The material was purified via column chromatography (0-3% MeOH in DCM over 35 min; 120 g silica gel) to give additional product (2.2 g). The two batches of product were combined to give N4-cyclopropyl-N2-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidine-2,4-diamine (8.2 g, 86%); LC/MS (Table 2, Method c) Rt=1.61 min.; MS m/z: 321 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1H), 9.04 (s, 1H), 8.44 (s, 1H), 8.06 (d, J=2.1 Hz, 1H), 7.83 (s, 1H), 7.46 (d, J=8.7 Hz, 1H), 7.26 (dd, J=8.8, 1.7 Hz, 1H), 6.75 (d, J=2.1 Hz, 1H), 3.00 (td, J=7.1, 3.6 Hz, 1H), 2.41 (s, 3H), 0.90-0.83 (m, 2H), 0.68-0.61 (m, 2H). Syk IC50=A

1. concentrationThe mixture was concentrated
2. dissolutionthe residue was dissolved in MeOH (100 mL)
3. additionThe resulting solution was added
4. stirringinto stirred aqueous NaHCO3 (10 wt %, 1000 mL)
5. stirringto stir for about 1 h
6. filtrationThe resultant suspension was filtered
7. additionTo the solid was added hot water (60° C., 1000 mL)
8. stirringthe mixture was stirred for about 45 min
9. filtrationfiltered
10. additionThe solid was then added to a mixture of DCM (270 mL) and MeOH (30 mL) in a flask
11. temperaturethe mixture was heated
12. temperatureto reflux
13. additionadditional MeOH (25 mL) was added portion wise over a period of about 45 min
14. customuntil a clear solution formed
15. filtrationThe solution was filtered while hot
16. temperatureThe filtrate was cooled in an ice bath for about 1 h
17. filtrationThe mixture was then filtered

ORD record

ord-cc261285dabf46559abdbcbdfdcbbe04

Source dataset

uspto-grants-2013_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08551981B2