Sodium Sulfite → 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol

3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone (compound of Formula II-F where Z3=3-cyclobutyl and Q1=Ph-(3-OBn)): 3-Oxo-cyclobutanecarboxylic Acid [(3-benzyloxy-phenyl)-(3-chloro-pyrazin-2-yl)-methyl]-amide (compound of Formula III where R1=3-cyclobutanone and Q1=Ph-(3-OBn)) (614.0 mg, 1.5 mmol) was dissolved in POCl3 (8.0 mL) and CH2Cl2 (2.0 mL) and allowed to stir at 55° C. for 24 h. The reaction mixture was concentrated in vacuo to a yellow solid, dissolved in cold EtOAc and neutralized with cold sat. NaHCO3. The aqueous layer was extracted with EtOAc (3×) and the combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Purification via HPFC using a 20 g Jones silica gel column (50% EtOAc:Hex to 1% MeOH:CH2Cl2) followed by a recrystalization from hot EtOH yielded the desired product as a light yellow solid; 1H NMR (CDCl3, 400 MHz) δ 3.61-3.68 (m, 2H), 3.86-3.95 (m, 3H), 5.15 (s, 2H), 7.00-7.09 (m, 1H), 7.30-7.47 (m, 9H), 7.61 (d, 1H, J=5.0 Hz); MS (ES) 404.2 (M+1), 406.2 (M+3). Alternatively, 3-[1-(3-Benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-cyclobutanone can be prepared from 1-(3-benzyloxyphenyl)-8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazine (Example 44b) as follows: To a solution of 1-(3-benzyloxyphenyl)-8-chloro-3-(3-methylenecyclobutyl)-imidazo[1,5-a]pyrazine (100 mg, 0.25 mmol) in THF (3 mL) and water (1 mL) were added NMO (0.1 mL, 0.5 mmol, 50% aq. solution) and K2OsO4.H2O (5 mg, 0.013 mmol). The resulting mixture was stirred at rt overnight. TLC showed the reaction was complete. The reaction was quenched with Na2SO3 (160 mg, 1.25 mmol), then diluted with EtOAc (40 mL) and water (5 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure to give 3-[1-(3-benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol as a yellow solid (100 mg). LC-MS (ES, Pos.): m/z 436/438 (3/1) [MH+]. The solution of 3-[1-(3-benzyloxy-phenyl)-8-chloro-imidazo[1,5-a]pyrazin-3-yl]-1-hydroxymethyl-cyclobutanol in THF (3 mL) and water (1 mL) was cooled to 0° C. and charged with sodium periodate (64 mg, 0.3 mmol). The resulting mixture was slowly warmed to rt in 2 h. TLC showed the reaction was complete. The mixture was diluted with EtOAc (40 mL) and water (5 mL), washed with brine (20 mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure and the crude product was purified by silica gel column chromatography (Hexanes:EtOAc=50:50→30:70) to give the title compound as a yellow solid (70 mg, 70% yield over two steps); LC-MS (ES, Pos.): m/z 404/406 (3/1) [MH+]; 1H NMR (CDCl3, 400 MHz) δ 3.60-3.67 (m, 2H), 3.81-3.94 (m, 3H), 5.14 (s, 2H), 3.81-3.94 (m, 3H), 7.06 (m, 1H), 7.27-7.47 (m, 9H), 7.59 (d, J=4.9 Hz, 1H).

1. washwashed with brine (20 mL)
2. dry with materialdried over anhydrous sodium sulfate
3. concentrationThe filtrate was concentrated under reduced pressure

ORD record

ord-104a869108d043fc8b0fcdaf87130798

Source dataset

uspto-grants-2008_12

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07459554B2