Trifluoroacetic acid → 2-(2-Methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-5-(2,6-diazaspiro[3.5]nonan-2-yl)-1,3,4-thiadiazole

Temperature

120 °C

DIPEA (116 μL, 0.666 mmol) was added to a stirred suspension of 2-bromo-5-(2-methoxy-4-(1-methyl-1H-pyrazol-4-yl)phenyl)-1,3,4-thiadiazole (78 mg, 0.222 mmol) and tert-butyl 2,6-diazaspiro[3.5]nonane-6-carboxylate (acetic acid salt, 127 mg, 0.444 mmol) in NMP (444 μL) and the mixture was heated at 120° C. for 3 hours. The reaction mixture was diluted with DCM (10 mL), washed with saturated NaHCO3(aq) (10 mL), and the organic phase was separated. TFA (342 μL, 4.44 mmol) was added and the resulting solution was stirred at room temperature for 18 hours. A further 1 mL TFA was added and the reaction mixture was warmed to 35° C. and stirred for 48 hours. The reaction mixture was loaded onto a 1 g SCX cartridge (pre-wet with MeOH) and the cartridge was washed with MeOH (10 mL) then flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the crude product as a brown oil. The crude material was purified by UV directed preparative HPLC under acidic conditions (TFA modified) and the product containing fractions were loaded onto a 1 g SCX cartridge (pre-wet with MeOH). The cartridge was washed with MeOH (10 mL) and flushed with 7M NH3 in MeOH (10 mL). The MeOH/NH3 was removed in vacuo to afford the title compound a white foam-like solid (40.5 mg, 46% yield). LC-MS: Rt 0.83 min; MS m/z 397.1 [M+H]+ [Method D], 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (s, 1H), 8.06 (d, J=8.08 Hz, 1H), 7.99 (s, 1H), 7.37 (d, J=1.52 Hz, 1H), 7.29 (dd, J=8.08, 1.52 Hz, 1H), 4.00 (s, 3H), 3.88 (s, 3H), 3.81 (d, J=7.58 Hz, 2H), 3.74 (d, J=7.58 Hz, 2H), 2.82 (s, 2H), 2.60 (t, J=5.05 Hz, 2H), 1.73 (t, J=5.56 Hz, 2H), 1.41 (quin, J=5.56 Hz, 2H).

1. washwashed with saturated NaHCO3(aq) (10 mL)
2. customthe organic phase was separated
3. temperaturethe reaction mixture was warmed to 35° C.
4. stirringstirred for 48 hours
5. washthe cartridge was washed with MeOH (10 mL)
6. customthen flushed with 7M NH3 in MeOH (10 mL)
7. customThe MeOH/NH3 was removed in vacuo
8. customto afford the crude product as a brown oil
9. customThe crude material was purified by UV
10. additionthe product containing fractions
11. washThe cartridge was washed with MeOH (10 mL)
12. customflushed with 7M NH3 in MeOH (10 mL)
13. customThe MeOH/NH3 was removed in vacuo

ORD record

ord-d8a41dd90f24401f85af582390e8000f

Source dataset

uspto-grants-2015_05

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09040712B2