Lithium Hexamethyldisilazide → 2-Propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamate

HRID 1961838Notes

Reaction equation

HRID 1961838 reaction equation
[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([O:16][CH2:17][CH:18]=[CH2:19])=[O:15])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:30][C:31]1[N:36]=[C:35]([CH3:37])[CH:34]=[CH:33][N:32]=1>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5](=[O:7])[CH2:37][C:35]2[CH:34]=[CH:33][N:32]=[C:31]([Cl:30])[N:36]=2)[C:3]=1[O:2][CH3:1])[CH:18]=[CH2:19]

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 116296072-Chloro-4-methylpyrimidineHCID 57989622Methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate

Product 1

HCID 579896212-Propen-1-yl [3-[(2-chloro-4-pyrimidinyl)acetyl]-2-(methyloxy)phenyl]carbamateYield 67.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of methyl 2-(methyloxy)-3-{[(2-propen-1-yloxy)carbonyl]amino}benzoate (123 g, 464 mmol,) in dry THF (800 mL) at −10° C., LiHMDS (1M in THF, 1440 mmol, 1440 mL) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of 2-chloro-4-methylpyrimidine (72 g, 560 mmol) in THF (150 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 (800 mL) at 0° C. The reaction mixture was extracted with EtOAc (1 L×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 of Step E (109.9 g, 67.8% yield). 1H NMR (400 MHz, CDCl3) δ ppm 13.64-13.68 (br, 1H), 8.38 (d, J=5.3 Hz, 1H), 8.15-8.21 (m, 1H), 7.31-7.39 (m, 2H), 7.15-7.18 (m, 1H), 6.87 (d, J=5.3 Hz, 1H), 6.19 (s, 1H), 5.92-6.15 (m, 1H), 5.23-5.40 (m, 2H), 4.66-4.70 (m, 2H), 3.76 (s, 3H).

Workup

  1. stirringto stir 1 h at rt
  2. customThe reaction was quenched by addition of the saturated aqueous NH4Cl (800 mL) at 0° C
  3. extractionThe reaction mixture was extracted with EtOAc (1 L×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-baa3bbf0b4df47c38fb6c03fbd877ab5
Source dataset
uspto-grants-2013_04
Patent number
US08415345B2

Reaction notes

Loading…