Lithium Hexamethyldisilazide → 2-Propen-1-yl {5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

HRID 590052Notes

Reaction equation

HRID 590052 reaction equation
[F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[CH:4][C:3]=1[NH:12][C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:29][C:30]1[N:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1>C1COCC1>[Cl:29][C:30]1[N:35]=[C:34]([CH2:36][C:6]([C:5]2[CH:10]=[CH:11][C:2]([F:1])=[C:3]([NH:12][C:13](=[O:14])[O:15][CH2:16][CH:17]=[CH2:18])[CH:4]=2)=[O:8])[CH:33]=[CH:32][N:31]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 116296072-Chloro-4-methylpyrimidineHCID 57989714Methyl 4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

Product 1

HCID 579897362-Propen-1-yl {5-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamateYield 84.2%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of methyl 4-fluoro-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (60 g, 237 mmol) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 735 mmol, 735 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (30.5 g, 237 mmol) in THF (50 mL) was then added dropwise to the solution of ester and base at 0° C. over 20 min. The solution was allowed to stir 1 h at rt. TLC showed the reaction was complete. The reaction was quenched by addition of the saturated aqueous NH4Cl (200 mL) at 0° C. The reaction mixture was extracted with EtOAc (500 mL×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the crude product, which was purified by flash column on silica gel, eluting with DCM. This solution was evaporated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the title compound (69.8 g, 81.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.66 (br, 0.55H), 8.79-8.83 (m, 0.36H), 8.53-8.61 (m, 0.91H), 8.33-8.37 (m, 0.59H), 7.65-7.72 (m, 0.40H), 7.50-7.57 (m, 0.59H), 7.26-7.30 (m, 0.35H), 7.08-7.19 (m, 1H), 6.92-7.12 (br, 1H), 6.87-6.92 (m, 0.64H), 5.90-6.21 (m, 1.5H), 5.39 (d, J=18.1 Hz, 1H), 5.29 (d, J=10.4 Hz, 1H), 4.70 (d, J=5.5 Hz, 2H), 4.44 (s, 1H).

Workup

  1. stirringto stir 1 h at rt
  2. customThe reaction was quenched by addition of the saturated aqueous NH4Cl (200 mL) at 0° C
  3. extractionThe reaction mixture was extracted with EtOAc (500 mL×3)
  4. washThe combined organic layers were washed with water and brine successively
  5. dry with materialdried over Na2SO4
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customto give the crude product, which
  9. customwas purified by flash column on silica gel
  10. washeluting with DCM
  11. customThis solution was evaporated
  12. customto obtain a solid
  13. customThe orange solid was triturated with a small amount of EtOAc
  14. filtrationfiltered
  15. washrinsing with diethyl ether

Sources & evidence

ORD record
ord-63d701ab4e304f7db7d2a8f275c4f613
Source dataset
uspto-grants-2016_01
Patent number
US09233956B2

Reaction notes

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