Reaction #48295

Reaction equation

cesium carbonate

di-tert-butyl(2-(2-isopropylnaphthalen-1-yl)-3,4,5,6-tetramethylphenyl)phosphine

N-((1S,2R)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

methanol

→

title compound

N-((1S,2R)-3-(((4′S)-6′-(2,2-dimethylpropyl)-8′-(methyloxy)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide

Solvents

toluene

Conditions

Workup

1. 1
   workup.ADDITIONwere added
2. 2
   Otherthe vial was flushed with N2 5×
3. 3
   FiltrationThe reaction mixture was filtered through a small plug of silica gel
4. 4
   Otherthe residue purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 Å, 150×30 mm)
5. 5
   Washeluting at 45 mL/min with an linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes

Procedure

To a 2 mL microwave vial is added cesium carbonate (283 mg, 869 μmol), di-tert-butyl(2-(2-isopropylnaphthalen-1-yl)-3,4,5,6-tetramethylphenyl)phosphine (71 mg, 159 μmol), palladium(II) acetate (33 mg, 145 μmol), and N-((1S,2R)-3-(((4′S)-8′-chloro-6′-(2,2-dimethylpropyl)-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano[2,3-c]pyridin]-4′-yl)amino)-1-((3-fluorophenyl)methyl)-2-hydroxypropyl)acetamide (75 mg, 145 μmol) were added and the vial was flushed with N2 5×, then methanol (160 μl, 3619 μmol) and toluene (1 mL) were added simultaneously. The reaction was heated in the microwave at 110° C. for 30 min. LCMS shows 100% conversion. The reaction mixture was filtered through a small plug of silica gel, and the residue purified by reverse phase HPLC on a Phenomenex Synergi column (5 micron, MAX-RP, 80 Å, 150×30 mm) eluting at 45 mL/min with an linear gradient of 10% (v/v) to 100% MeCN (0.1% v/v TFA) in water (0.1% TFA) over 30 minutes to give the title compound as a tan amorphous solid. MS m/z: 514.2(M+1).

Source