Lithium Hexamethyldisilazide → 2-Propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

HRID 239259Notes

Reaction equation

HRID 239259 reaction equation
[CH2:1]([O:4][C:5]([NH:7][C:8]1[C:9]([F:18])=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=O)=[O:6])[CH:2]=[CH2:3].[Li+].[CH3:20][Si]([N-][Si](C)(C)C)(C)C.[Cl-:29].[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>C1COCC1>[Cl:29][C:31]1[N:32]=[C:33]([CH2:20][C:11]([C:10]2[C:9]([F:18])=[C:8]([NH:7][C:5](=[O:6])[O:4][CH2:1][CH:2]=[CH2:3])[CH:17]=[CH:16][CH:15]=2)=[O:13])[CH:34]=[CH:35][N:30]=1

Participants

5

Reactant 3

HCID 2733832Lithium HexamethyldisilazideHCID 22046915HCID 22046915, compoundHCID 57989974HCID 57989974, compound

Product 1

HCID 579899922-Propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

To a solution of methyl 3-(allyloxycarbonylamino)-2-fluorobenzoate (86.7 g, 342 mmol, 1 eq) in dry THF (500 mL) at −10° C., LiHMDS (1M in THF, 1198 mmol, 1198 mL, 3.5 eq) was added dropwise and the solution was allowed to stir for 1 h at 0° C. A solution of pyrimidine chloride (48.0 g, 376 mmol, 1.2 eq) in THF (200 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, rinsing with DCM. This solution was concentrated to obtain a solid. The orange solid was triturated with a small amount of EtOAc and filtered, rinsing with diethyl ether to give the product (240.1 g, 67.0%, three batches combined). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.70 (s, 1H), 8.52 (dd, J=0.8, 4.8 Hz, 0.3H), 8.34 (dd, J=0.8, 5.2 Hz, 1H), 8.27 (s, 0.4H), 8.10 (s, 1H), 7.47 (t, J=8.0 Hz, 1.4H), 7.22-7.12 (m, 1.8H), 6.96 (s, 1.4H), 6.85 (d, J=4.2 Hz, 1H), 6.07 (s, 1H), 5.97-5.86 (m, 1.4H), 5.32 (d, J=15.6 Hz, 1.4H), 5.24 (d, J=6.4 Hz, 1.4H), 4.64 (d, J=6.0 Hz, 2.8H), 4.38 (d, J=2.8 Hz, 0.8H).

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

Sources & evidence

ORD record
ord-9b381931b39841c294e48e4b48d62799
Source dataset
uspto-grants-2014_02
Patent number
US08642759B2

Reaction notes

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