Acetic Acid → HCID 178422949, compound

To a solution of 2-(5,7-dichloro-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}pyrazolo[1,5-a]pyrimidin-2-yl)-1H-isoindole-1,3(2H)-dione (1.0 g, 1.979 mmol) in Tetrahydrofuran (THF) (30 mL) was added sodium hydroxide (1.187 mL, 5.94 mmol). The reaction mixture was stirred at rt for 18 h. Sodium hydroxide (1.187 mL, 5.94 mmol) was added to the reaction. The reaction mixture was stirred at rt for 3 h. Water (20 mL) and EtOAc (20 mL) was added in. The reaction mixture was acidified with acetic acid (0.680 mL, 11.87 mmol). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with brine (30 mL), dried (MgSO4) and concentrated. To the crude in Ethanol (5 mL) was added morpholine (1.035 mL, 11.87 mmol). The reaction was subjected to MW irradiation at 150° C. for 7 h. The reaction was concentrated. To the crude was added Ethanol (20 mL) and hydrazine (0.097 mL, 1.979 mmol). The reaction mixture was refluxed for 3 h. The reaction was concentrated and purified by reversed phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA)). NMR is not clean. To the solution of 2-amino-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(4-morpholinyl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (0.13 g, 0.319 mmol) in Acetonitrile (4 mL) was added phthalic anhydride (0.142 g, 0.957 mmol). The reaction mixture was stirred at 100° C. for 6 h. The reaction was concentrated. The residue was purified on a silica column (20˜60% EtOAc/Hexane) and then (0˜10% MeOH/DCM). To the purified material was added Ethanol (10 mL) and hydrazine (0.020 mL, 0.638 mmol). The reaction mixture was refluxed for 1 h. The reaction mixture was concentrated and purified by reverse phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA)). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.45 (s, 3H) 3.25 (m, 4H) 3.64 (m, 4H) 3.81 (s, 2H) 4.99 (s, 1H) 7.11-7.24 (m, 1H) 7.25-7.33 (m, 1H) 7.53 (m, 1H); LC/MS: MS (ES+) m/e 408.1 [M+H]+.

1. stirringThe reaction mixture was stirred at rt for 3 h
2. extractionThe aqueous phase was extracted with EtOAc (30 mL)
3. washThe combined organic phases were washed with brine (30 mL)
4. dry with materialdried (MgSO4)
5. concentrationconcentrated
6. customThe reaction was subjected to MW irradiation at 150° C. for 7 h
7. concentrationThe reaction was concentrated
8. temperatureThe reaction mixture was refluxed for 3 h
9. concentrationThe reaction was concentrated
10. custompurified by reversed phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA))
11. stirringThe reaction mixture was stirred at 100° C. for 6 h
12. concentrationThe reaction was concentrated
13. customThe residue was purified on a silica column (20˜60% EtOAc/Hexane)
14. temperatureThe reaction mixture was refluxed for 1 h
15. concentrationThe reaction mixture was concentrated
16. custompurified by reverse phase HPLC (20˜50% CH3CN (0.1% TFA)/Water (0.1% TFA))

ORD record

ord-6b6ac804bf4941c5a37c96f538d19a63

Source dataset

uspto-grants-2015_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09096605B2