Iodine → 6-Chloro-alpha-(2,4-difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol

HRID 496813Notes

Reaction equation

HRID 496813 reaction equation
II.[F:3][C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:5]=1[C:11](=[O:18])[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1.Br[CH:20]([C:22]1[N:27]=[CH:26][N:25]=[C:24]([Cl:28])[C:23]=1[F:29])[CH3:21]>O1CCCC1.[Zn]>[Cl:28][C:24]1[C:23]([F:29])=[C:22]([CH:20]([CH3:21])[C:11]([C:5]2[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:4]=2[F:3])([OH:18])[CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[N:27]=[CH:26][N:25]=1

Participants

6

Reactant 3

HCID 807Iodine2×HCID 5880801-(2,4-Difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanoneHCID 109116334-(1-Bromoethyl)-6-chloro-5-fluoropyrimidine

Product 1

HCID 110363926-Chloro-alpha-(2,4-difluorophenyl)-5-fluoro-beta-methyl-alpha-(1H-1,2,4-triazol-1-ylmethyl)-4-pyrimidineethanol

Reagents, catalysts & solvents 2

HCID 23994ZincCatalystHCID 8028TetrahydrofuranSolvent3×

Conditions

Temperature
2 °C

Procedure

A solution of iodine (2.25 g) in tetrahydrofuran (6 ml) was added dropwise to a stirred slurry of zinc (Britannia Alloys) (3.00 g) and lead (0.15 g) in tetrahydrofuran (19 ml) under a nitrogen atmosphere at 25° C. The reaction temperature was allowed to rise during the addition. The mixture was then cooled to 2° C. A solution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g), 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.84 g) and iodine (0.02 g) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction temperature was limited to a maximum of 16° C. during the addition by cooling. Further cooling was then applied to obtain a temperature below +5° C. The reaction was stirred below +5° C. for 30 minutes. A sample of the reaction mixture was taken and subjected to HPLC analysis according to the conditions set out in Example 1. The analysis showed a 10.3:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of the title compound. The yield of the 2R,3S/2S,3R enantiomeric pair was calculated to be 90% using an internal standard.

Workup

  1. additionto rise during the addition
  2. additionThe reaction temperature was limited to a maximum of 16° C. during the addition
  3. temperatureby cooling
  4. temperatureFurther cooling
  5. customto obtain a temperature below +5° C

Sources & evidence

ORD record
ord-7c8fb72e88cd416db68bd18754fefe64
Source dataset
uspto-grants-2005_09
Patent number
US06946555B2

Reaction notes

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