m-Chloroperbenzoic acid → HCID 57072329, compound

HRID 489474Notes

Reaction equation

HRID 489474 reaction equation
[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:25])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(C(C)C)[P:30]([O:39][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)(C)C.ClC1C=C(C=CC=1)C(OO)=[O:55]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[P:30]([O:25][C@@:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([C@H:16]([C:18]1[C:23]([F:24])=[CH:22][N:21]=[CH:20][N:19]=1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([O:31][CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)([O:39][CH2:40][C:41]1[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1)=[O:55]

Participants

6

Reactant 3

HCID 70297m-Chloroperbenzoic acidHCID 71616(+/-)-Voriconazole2×HCID 196621Bis(benzyloxy)(diisopropylamino)phosphine

Product 1

HCID 57072329HCID 57072329, compoundYield 60%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6344DichloromethaneSolvent3×

Procedure

A solution of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol (the compound of Example 7, EP 0440372, also known as voriconazole, 17.0 g, 48.7 mmol), 4-dimethylaminopyridine (10.2 g, 83.5 mmol) 10.2 g, 146 mmol) and dibenzyl diisopropylphosphoramidite (33.6 g, 97.4 mmol) in methylene chloride (100 ml) was stirred at reflux for 2 hours and a further 16 hours at room temperature under a nitrogen atmosphere. The reaction mixture was then washed with hydrochloric acid and then sodium bicarbonate, dried (MgSO4) and concentrated. The crude product phosphite was purified by column chromatography (silica gel, 300 g, eluting with 3:1 to 1:1 hexane:ethyl acetate gradient) to give a pale yellow oil. This was dissolved in methylene chloride (100 ml) and cooled to −10° C., whereupon a solution of 3-chloroperoxybenzoic acid (14.8 g, 57% w/w, 48.9 mmol) in methylene chloride (100 ml) was added maintaining the temperature below 0° C. The resulting mixture was allowed to warm to room temperature for 10 minutes before washing with aqueous sodium metabisulphite and sodium bicarbonate. After drying (MgSO4) and concentrating the crude product was purified by column chromatography (silica gel, 300 g, eluting with ethyl acetate) to give the subtitle compound as a viscous syrup (17.86 g, 60%).

Workup

  1. washThe reaction mixture was then washed with hydrochloric acid
  2. dry with materialsodium bicarbonate, dried (MgSO4)
  3. concentrationconcentrated
  4. customThe crude product phosphite was purified by column chromatography (silica gel, 300 g, eluting with 3:1 to 1:1 hexane:ethyl acetate gradient)
  5. customto give a pale yellow oil
  6. additionwas added
  7. temperaturemaintaining the temperature below 0° C
  8. temperatureto warm to room temperature for 10 minutes
  9. washbefore washing with aqueous sodium metabisulphite and sodium bicarbonate
  10. dry with materialAfter drying (MgSO4)
  11. concentrationconcentrating the crude product
  12. customwas purified by column chromatography (silica gel, 300 g, eluting with ethyl acetate)

Sources & evidence

ORD record
ord-ba796dad4d7441eb98d62b3e1c21b788
Source dataset
uspto-grants-2005_12
Patent number
US06977302B2

Reaction notes

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