Phenylsilane → (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)butan-2-ol

HRID 1051190Notes

Reaction equation

HRID 1051190 reaction equation
C1([SiH3])C=CC=CC=1.[F:8][C:9]1[C:10]([CH:15]=[CH2:16])=[N:11][CH:12]=[N:13][CH:14]=1.[Cl:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])=[O:20]>O1CCCC1.CN([C@@H]([C]1[C](P(C2C=CC=CC=2)C2C=CC=CC=2)[CH][CH][CH]1)C1C=CC=C(P(C2C=CC=CC=2)C2C=CC=CC=2)C=1)C.[CH]1[CH][CH][CH][CH]1.[Fe]>[Cl:17][CH2:18][C@@:19]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[C@H:15]([C:10]1[C:9]([F:8])=[CH:14][N:13]=[CH:12][N:11]=1)[CH3:16]

Participants

6

Reactant 3

HCID 12752PhenylsilaneHCID 5880832-Chloro-1-(2,4-difluorophenyl)ethanoneHCID 736728815-Fluoro-4-vinylpyrimidine2×

Product 1

HCID 90103134(2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)butan-2-olYield 74%

Reagents, catalysts & solvents 2

HCID 16218483CID 16218483CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
2.5 °C

Procedure

To CuF(PPh3)3 methanol solvate (0.137 g) and (RP)-1-[(R)-α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene (0.100 g) was added tetrahydrofuran (14 mL). The mixture was stirred at 0-5° C. (under argon) for 30 minutes until all solids were dissolved. To this solution was then added phenyl silane (0.789 g). After 10 minutes, a solution of 5-fluoro-4-vinylpyrimidine (0.903 g) and 2-chloro-1-(2,4-difluorophenyl)ethanone (1.68 g) in tetrahydrofuran (22 mL) was added over 30 minutes. The reaction mixture was stirred for 1 hour at 0-5° C. after which no further 5-fluoro-4-vinylpyrimidine was observable by HPLC. The reaction was quenched by addition of aqueous ammonium chloride (1 M, 15 mL), followed by methyl tert-butyl ether (30 mL). The organic layer was dried to a residue which was then subjected to purification by column chromatography (eluting with 5-40% ethyl acetate in cyclohexane) to give (2R,3S)-1-chloro-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)butan-2-ol as a white solid (1.70 g, 74% yield).

Workup

  1. dissolutionwere dissolved
  2. waitAfter 10 minutes
  3. customThe reaction was quenched by addition of aqueous ammonium chloride (1 M, 15 mL)
  4. customThe organic layer was dried to a residue which
  5. customwas then subjected to purification by column chromatography (eluting with 5-40% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-057583f42b57412489d315c6e34eedb5
Source dataset
uspto-grants-2016_07
Patent number
US09388167B2

Reaction notes

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