Phenylsilane → (2R,3S)-1-chloro-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)butan-2-ol

HRID 1051189Notes

Reaction equation

HRID 1051189 reaction equation
C1([SiH3])C=CC=CC=1.[Cl:8][C:9]1[C:14]([F:15])=[C:13]([CH:16]=[CH2:17])[N:12]=[CH:11][N:10]=1.[Cl:18][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])=[O:21].C(C1N=CC=CN=1)=C>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:18][CH2:19][C@@:20]([C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29])([OH:21])[C@H:16]([C:13]1[C:14]([F:15])=[C:9]([Cl:8])[N:10]=[CH:11][N:12]=1)[CH3:17]

Participants

7

Reactant 4

HCID 12752PhenylsilaneHCID 5880832-Chloro-1-(2,4-difluorophenyl)ethanoneHCID 101250522-EthenylpyrimidineHCID 736728834-Chloro-6-ethenyl-5-fluoropyrimidine

Product 1

HCID 90102121(2R,3S)-1-chloro-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)butan-2-olYield 148%

Reagents, catalysts & solvents 2

HCID 16218483CID 16218483CatalystHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
20 °C

Procedure

To CuF(PPh3)3 methanol solvate (0.0094 g) and (RP)-1-[(R)-α-(dimethylamino)-2-(diphenylphosphino)benzyl]-2-diphenylphosphinoferrocene (0.0068 g) under argon was added tetrahydrofuran (1 mL). The mixture was stirred at 20° C. (under argon) for 30 minutes until all solids were dissolved. The solution was then cooled to −20° C. and phenyl silane (0.027 g) was added. After 10 minutes, a solution of 4-chloro-5-fluoro-6-vinylpyrimidine (0.180 g) and 2-chloro-1-(2,4-difluorophenyl)ethanone (0.095 g) in tetrahydrofuran (1.5 mL) was added over approximately 5 minutes. The reaction mixture was stirred for 1 hour at −20° C. until complete consumption of the vinyl pyrimidine was observed by HPLC analysis. The reaction was quenched by addition of aqueous ammonium chloride (1 M, 3 mL), followed by methyl tert-butyl ether (5 mL). The organic layer was dried to a residue which was then subjected to purification by column chromatography (eluting with 0-20% ethyl acetate in cyclohexane) to give (2R,3S)-1-chloro-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)butan-2-ol (0.259 g, 65% yield) as a white solid.

Workup

  1. dissolutionwere dissolved
  2. temperatureThe solution was then cooled to −20° C.
  3. waitAfter 10 minutes
  4. customThe reaction was quenched by addition of aqueous ammonium chloride (1 M, 3 mL)
  5. customThe organic layer was dried to a residue which
  6. customwas then subjected to purification by column chromatography (eluting with 0-20% ethyl acetate in cyclohexane)

Sources & evidence

ORD record
ord-0779d6254eb94f558d203cc0f702f098
Source dataset
uspto-grants-2016_07
Patent number
US09388167B2

Reaction notes

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