Sodium Methoxide → HCID 178521001, compound

HRID 931249Notes

Reaction equation

HRID 931249 reaction equation
[NH2:1][C:2]1[C:7]([NH:8][C:9]([C:11]2([C:14]3[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=3)[CH2:13][CH2:12]2)=O)=[CH:6][CH:5]=[C:4]([N:21]2[CH2:26][CH2:25][CH2:24][C@@H:23]([C:27]([N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[O:28])[CH2:22]2)[N:3]=1.C[O-].[Na+]>C(O)C(C)C.CO.C(OCC)(=O)C>[N:29]1([C:27]([C@@H:23]2[CH2:24][CH2:25][CH2:26][N:21]([C:4]3[N:3]=[C:2]4[NH:1][C:9]([C:11]5([C:14]6[CH:15]=[N+:16]([O-:20])[CH:17]=[CH:18][CH:19]=6)[CH2:13][CH2:12]5)=[N:8][C:7]4=[CH:6][CH:5]=3)[CH2:22]2)=[O:28])[CH2:33][CH2:32][CH2:31][CH2:30]1

Participants

6

Reactant 2

HCID 10942334Sodium MethoxideHCID 117966496HCID 117966496, compound

Product 1

HCID 178521001HCID 178521001, compoundYield 29.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6560IsobutanolSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
110 °C

Procedure

To a solution of (R)-3-(1-(2-amino-6-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)pyridin-3-ylcarbamoyl)cyclopropyl)pyridine 1-oxide (0.25 g, 0.55 mmol) in isobutanol (5 mL) was added a solution of sodium methoxide (0.15 g, 2.77 mmol) in methanol (2 mL) at room temperature. The reaction mixture was heated to 110° C. for 16 h. The mixture was then cooled to room temperature, diluted with ethyl acetate, and washed with water. The organic layer was dried, filtered, and concentrated under reduced pressure. The resulting residue was purified first via flash chromatography (100-200 mesh silica gel, 0-10% methanol in dichloromethane) then via preparative HPLC to obtain the product which was further purified by chiral separation to afford (R)-3-(1-(5-(3-(pyrrolidine-1-carbonyl)piperidin-1-yl)-3H-imidazo[4,5-b]pyridin-2-yl)cyclopropyl)pyridine 1-oxide (70 mg). Chiral HPLC retention time: 13.808 min (Method: CHIRAL PAK IA, 4.6×250 mm 5 μm column, Mobile Phase: A: 0.1% DEA in n-hexane, Mobile Phase B: ethanol; isocratic; 70:30, 1 mL/min, Temperature 25 C) min MS (ES+APCI) (M+H) 433.1; LCMS retention time 4.698 min (Method B1). 1H NMR (400 MHz, CD3OD) δ 1.52-1.57 (m, 2H), 1.59-1.69 (m, 1H), 1.71-1.84 (m, 4H), 1.86-2.08 (m, 5H), 2.75 (t, 2H), 2.88-3.00 (m, 2H), 3.43 (t, 2H), 3.47-3.57 (m, 1H), 3.68 (br s, 1H), 4.27 (d, 1H), 4.52 (d, 1H), 6.78 (d, 1H), 7.50-7.56 (m, 1H), 7.58-7.72 (m, 2H), 8.26 (d, 1H), 8.31 (br s, 1H).

Workup

  1. temperatureThe mixture was then cooled to room temperature
  2. washwashed with water
  3. customThe organic layer was dried
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe resulting residue was purified first via flash chromatography (100-200 mesh silica gel, 0-10% methanol in dichloromethane)
  7. customvia preparative HPLC to obtain the product which
  8. customwas further purified by chiral separation

Sources & evidence

ORD record
ord-fc2c2e737aaa4ab78e5e9cb0cf36731e
Source dataset
uspto-grants-2016_03
Patent number
US09296745B2

Reaction notes

Loading…