Hydrochloric Acid → HCID 58292983, compound

A solution of diethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate (105 mg, 0.23 mmol) and methyl 4-(7-amino-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)-1-{[tert-butyl(dimethyl)silyl]oxy}cyclohexanecarboxylate (Compound 278A, 110 mg, 0.26 mmol) in TFE (3 mL) was charged with TFA (75 mg, 0.66 mmol) and irradiated on the microwave at 100° C. for 30 min. The reaction mixture was diluted with EtOAc (30 mL), washed with sat. aq. NaHCO3 (2×10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the crude material was used in next step without further purification. The above material was dissolved in THF (6 mL), then TBAF (2.0 mL, 2.0 mmol, 1M solution in THF) was added. The resulting mixture was stirred at rt overnight. The reaction mixture was diluted with EtOAc (30 mL), washed with water (10 mL), brine (10 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure, and the crude material was used in the hydrolysis without further purification. The above crude ester was dissolved in THF (2 mL), MeOH (2 mL) and H2O (2 mL), then lithium hydroxide monohydrate (48.5 mg, 1.16 mmol) was added. The resulting mixture was stirred at rt for 1 h. The mixture was acidified with aq. 1M HCl to pH=3, then extracted with EtOAc (3×10 mL), the combined organic phases were washed with brine (10 mL), and dried over anhydrous sodium sulfate. The solvents were evaporated under reduced pressure and the residue was purified by silica gel chromatography (ISCO system: MeOH/DCM=0-10%) to give the title compound as a white solid, 62 mg, 36% yield over three steps. LC-MS and 1H NMR showed that it was a single isomer. 1H NMR (DMSO-d6): 1.20 (t, J=7.0 Hz, 6H), 1.55-1.65 (m, 2H), 1.74-1.99 (m, 6H), 2.58 (m, 1H), 3.07 (s, 3H), 3.24 (d, J=21.2 Hz, 2H), 3.76 (s, 3H), 3.95-4.04 (m, 4H), 4.51 (s, 2H), 4.99 (s, 1H), 6.90 (d, J=7.8 Hz, 1H), 7.05 (s, 1H), 7.26 (m, 1H), 7.51 (m, 1H), 8.38 (s, 1H), 8.98 (s, 1H), 10.57 (s, 1H), 12.38 (s, 1H). MS (ES+): m/z=722.17 [MH+]. HPLC: tR=3.43 min (ZQ3, polar—5 min).

1. customirradiated on the microwave at 100° C. for 30 min
2. washwashed with sat. aq. NaHCO3 (2×10 mL), brine (10 mL)
3. dry with materialdried over anhydrous sodium sulfate
4. customThe solvents were evaporated under reduced pressure
5. customthe crude material was used in next step without further purification
6. dissolutionThe above material was dissolved in THF (6 mL)
7. washwashed with water (10 mL), brine (10 mL)
8. dry with materialdried over anhydrous sodium sulfate
9. customThe solvents were evaporated under reduced pressure
10. customthe crude material was used in the hydrolysis without further purification
11. stirringThe resulting mixture was stirred at rt for 1 h
12. extractionextracted with EtOAc (3×10 mL)
13. washthe combined organic phases were washed with brine (10 mL)
14. dry with materialdried over anhydrous sodium sulfate
15. customThe solvents were evaporated under reduced pressure
16. customthe residue was purified by silica gel chromatography (ISCO system: MeOH/DCM=0-10%)

ORD record

ord-223a9cceaa1d4138a0bf58ffd093b7b2

Source dataset

uspto-grants-2013_03

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08399433B2