Methanol → HCID 90409019, compound

HRID 589110Notes

Reaction equation

HRID 589110 reaction equation
[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([OH:25])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH3:30]O>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23]([O:25][CH3:30])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1

Participants

4

Reactant 2

HCID 887MethanolHCID 90408827HCID 90408827, compound

Product 1

HCID 90409019HCID 90409019, compoundYield 99%

Reagents, catalysts & solvents 1

HCID 1118Sulfuric AcidCatalyst

Conditions

Temperature
80 °C

Procedure

A solution of 3-[7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (294 mg, 0.7493 mmol) in methanol (60.0 mL) was treated with one drop of concentrated sulfuric acid and heated in a sealed tube overnight at 80° C. The reaction mixture was then concentrated to a crude residue. This residue was diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution and stirred at room temperature for 1 hour. After dissolution, the aqueous layer was separated and extracted with ethyl acetate (2×). The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (300 mg, 99%) as a racemic mixture. 1H NMR (400 MHz, DMSO-d6) δ 8.63 (dd, J=4.6, 1.5 Hz, 1H), 7.56 (dd, J=8.1, 4.6 Hz, 1H), 7.29 (dd, J=8.1, 1.4 Hz, 1H), 6.89 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.00 (dd, J=2.9, 2.9 Hz, 1H), 4.53 (d, J=2.9 Hz, 2H), 3.91 (s, 3H), 2.26 (s, 3H), 2.09 (s, 3H); LCMS calculated for C21H19N4O5 (M+H)+: m/z=407.1. found: 407.0.

Workup

  1. concentrationThe reaction mixture was then concentrated to a crude residue
  2. additionThis residue was diluted with ethyl acetate (100 mL) and saturated aqueous sodium bicarbonate solution
  3. dissolutionAfter dissolution
  4. customthe aqueous layer was separated
  5. extractionextracted with ethyl acetate (2×)
  6. washThe combined organic layers were washed with water and brine
  7. dry with materialdried over magnesium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated
  10. customto give the crude product
  11. customPurification by preparative LCMS (XBridge C18 column
  12. washeluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min)

Sources & evidence

ORD record
ord-b947cd9a7b234913b972eed674b0aebd
Source dataset
uspto-grants-2016_01
Patent number
US09227985B2

Reaction notes

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