4-Aminopyrimidine → 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide

HRID 528563Notes

Reaction equation

HRID 528563 reaction equation
[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23](OC3C(F)=C(F)C(F)=C(F)C=3F)(=[O:25])=[O:24])[CH:21]=[CH:22][C:14]1=2)#[N:2].[N:38]1[CH:43]=[CH:42][C:41]([NH2:44])=[N:40][CH:39]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C(O)(=O)C.C1COCC1>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([F:11])([F:12])[F:10])[CH:6]=[CH:5][C:4]=1[N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[C:20]([S:23]([NH:44][C:41]3[CH:42]=[CH:43][N:38]=[CH:39][N:40]=3)(=[O:24])=[O:25])[CH:21]=[CH:22][C:14]1=2)#[N:2]

Participants

6

Reactant 3

HCID 689584-AminopyrimidineHCID 2733832Lithium HexamethyldisilazideHCID 89762001perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate

Product 1

HCID 717116964-(2-cyano-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamideYield 65.5%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 8028TetrahydrofuranSolvent

Procedure

A round bottom flask was charged with perfluorophenyl 4-(2-cyano-4-(trifluoromethyl)phenyl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonate (INTERMEDIATE AB, 46.12 mg, 0.084 mmol), pyrimidin-4-amine (11.95 mg, 0.126 mmol), and THF (1 mL) to give a clear, colorless solution. The flask was cooled in a dry ice-acetone bath for 5 min, then lithium bis(trimethylsilyl)amide (1M in THF) (176 μL, 0.176 mmol) was added dropwise over 30 s to give a light-yellow solution. After 5 min, the flask was lowered into an ice bath for 1 h. Glacial acetic acid (2 drops) was added, and the mixture was concentrated under a vacuum. The product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM) to give 4-(2-cyano-4-(trifluoromethyl)phenyl)-N-(pyrimidin-4-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (25.2 mg, 0.055 mmol) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.10 (br. s., 1 H), 8.65 (s, 1 H), 8.42-8.35 (m, 2 H), 8.09 (dd, J=2.0, 8.8 Hz, 1 H), 7.74 (d, J=8.6 Hz, 1 H), 7.38 (d, J=2.1 Hz, 1 H), 7.31 (dd, J=2.2, 8.6 Hz, 1 H), 7.04 (d, J=6.0 Hz, 1 H), 6.80 (d, J=8.6 Hz, 1 H), 4.38-4.32 (m, 2 H), 3.89-3.84 (m, 2 H). m/z (ESI) 462.4 (M+H)+.

Workup

  1. customto give a clear, colorless solution
  2. temperatureThe flask was cooled in a dry ice-acetone bath for 5 min
  3. customto give a light-yellow solution
  4. waitthe flask was lowered into an ice bath for 1 h
  5. concentrationthe mixture was concentrated under a vacuum
  6. customThe product was purified by chromatography on silica gel (12 g column with 0 to 10% MeOH/DCM)

Sources & evidence

ORD record
ord-24fd949efc674304a3df4ac07754b9bb
Source dataset
uspto-grants-2016_05
Patent number
US09346798B2

Reaction notes

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