Phosphorus oxychloride → HCID 71478182, compound

HRID 1396223Notes

Reaction equation

HRID 1396223 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:33])([CH2:27][N:28]1[CH:32]=[N:31][N:30]=[N:29]1)[C:10]([F:26])([F:25])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[N:19][C:20](OC)=[N:21][CH:22]=2)=[CH:13][N:12]=1.P(Cl)(Cl)([Cl:36])=O>CN(C=O)C>[Cl:36][C:20]1[N:19]=[CH:18][C:17]([C:14]2[CH:15]=[CH:16][C:11]([C:10]([F:26])([F:25])[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])([OH:33])[CH2:27][N:28]3[CH:32]=[N:31][N:30]=[N:29]3)=[N:12][CH:13]=2)=[CH:22][N:21]=1

Participants

4

Reactant 2

HCID 24813Phosphorus oxychlorideHCID 71143727HCID 71143727, compound

Product 1

HCID 71478182HCID 71478182, compoundYield 31%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
80 °C

Procedure

To 2-(2,4-difluorophenyl)-1,1-difluoro-1-(5-(2-methoxypyrimidin-5-yl)pyridin-2-yl)-3-(1H-tetrazol-1-yl)propan-2-ol (37; 80 mg, 0.17 mmol) was added phosphorus oxychloride (POCl3; 1.0 mL) followed by DMF (cat) at RT under inert atmosphere. The reaction mixture was gradually heated to 80° C. and stirred for 2 h. After complete consumption of the starting material (by TLC), the reaction mixture was cooled to RT, diluted with ice-cold water (30 mL), made basic (pH ˜8) using satd NaHCO3 solution and extracted with EtOAc (2×50 mL). The combined organic extracts were washed with water (50 mL) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude material. Purification by silica gel column chromatography (eluting with 38% EtOAc/hexane) afford 57 (25 mg, 0.05 mmol, 31%) as a semi-solid. 1H NMR (500 MHz, CDCl3): δ 8.84 (s, 2H), 8.74 (s, 1H), 8.71 (s, 1H), 8.01 (dd, J=8.0, 2.5 Hz, 1H), 7.77 (d, J=8.0 Hz, 1H), 7.42-7.39 (m, 1H), 7.05 (br s, OH), 6.82-6.77 (m, 1H), 6.73-6.69 (m, 1H), 5.52 (d, J=14.5 Hz, 1H), 5.23 (d, J=14.5 Hz, 1H). MS (ESI): m/z 466 (M+H)+. HPLC: 93%.

Workup

  1. customAfter complete consumption of the starting material (by TLC)
  2. temperaturethe reaction mixture was cooled to RT
  3. additiondiluted with ice-cold water (30 mL)
  4. extractionextracted with EtOAc (2×50 mL)
  5. washThe combined organic extracts were washed with water (50 mL) and brine (50 mL)
  6. dry with materialdried over anhydrous Na2SO4
  7. concentrationconcentrated under reduced pressure
  8. customto obtain the crude material
  9. customPurification
  10. washby silica gel column chromatography (eluting with 38% EtOAc/hexane)

Sources & evidence

ORD record
ord-4e4fc9af58594c9ca9543046d9afd931
Source dataset
uspto-grants-2014_12
Patent number
US08901121B2

Reaction notes

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