Sodium bis(trimethylsilyl)amide → 3-(6-Chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one

HRID 1749380Notes

Reaction equation

HRID 1749380 reaction equation
C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C@H:19]([N:21]2[CH:29]([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22]2=[O:42])[CH3:20])=[CH:15][CH:14]=1.Cl[C:44]1[C:49]([F:50])=[C:48]([Cl:51])[N:47]=[CH:46][N:45]=1>O1CCCC1.C(OCC)(=O)C.O>[Cl:51][C:48]1[N:47]=[CH:46][N:45]=[C:44]([C:29]2([CH3:30])[C:28]3[C:23](=[CH:24][C:25]([C:31]4[CH:32]=[N:33][N:34]([CH:36]5[CH2:41][CH2:40][CH2:39][CH2:38][O:37]5)[CH:35]=4)=[CH:26][CH:27]=3)[C:22](=[O:42])[N:21]2[C@@H:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH3:20])[C:49]=1[F:50]

Participants

7

Reactant 3

HCID 2724254Sodium bis(trimethylsilyl)amideHCID 112866754,6-Dichloro-5-fluoropyrimidineHCID 904082912-[(1R)-1-(4-Methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one

Product 1

HCID 904080383-(6-Chloro-5-fluoro-pyrimidin-4-yl)-2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-oneYield 103%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 8028TetrahydrofuranSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

Add sodium bis(trimethylsilyl)amide (210 mL, 210 mmol, 1 M THF) drop wise over 60 minutes to an ice cold suspension of 2-[(1R)-1-(4-methoxyphenyl)ethyl]-3-methyl-6-(1-tetrahydropyran-2-ylpyrazol-4-yl)isoindolin-1-one (62 g, 144 mmol) and 4,6-dichloro-5-fluoropyrimidine (31 g, 186 mmol) in tetrahydrofuran (620 mL). Stir the solution 60 minutes at 0° C. and then dilute the mixture with ethyl acetate (1 L) and water (1 L). Wash the organic phase with saturated aqueous sodium chloride and evaporate under reduced pressure. Dissolve the residue in 1:1 petroleum ether/ethyl acetate, filter through a pad of silica gel, and evaporate to give the title compound as a yellow foam (83 g, 103%). ES/MS m/z: 562 (M+H).

Workup

  1. washWash the organic phase with saturated aqueous sodium chloride
  2. customevaporate under reduced pressure
  3. dissolutionDissolve the residue in 1:1 petroleum ether/ethyl acetate
  4. filtrationfilter through a pad of silica gel
  5. customevaporate

Sources & evidence

ORD record
ord-247e438b108e466dae7d5cb2d45e977b
Source dataset
uspto-grants-2015_10
Patent number
US09156824B2

Reaction notes

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