Methylamine → HCID 21088995, compound

HRID 1713242Notes

Reaction equation

HRID 1713242 reaction equation
[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].ClC(OCC(C)C)=O.[CH3:40][N:41]1CCOCC1.CN>CN(C)C(=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:41][CH3:40])=[O:14])[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]

Participants

7

Reactant 4

HCID 6329MethylamineHCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 21089022HCID 21089022, compound

Product 1

HCID 21088995HCID 21088995, compoundYield 27%

Reagents, catalysts & solvents 2

HCID 6344DichloromethaneSolventHCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
0 °C

Procedure

To a cooled (0° C.) solution of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.18 g, 0.38 mmol) in N,N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.60 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.46 mmol) and 4-methylmorpholine (0.55 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.50 mmol). Stirred at 0° C. for 35 min. Added methylamine (0.29 mL of 2M solution in THF, 0.57 mmol). After 1 h, distilled DMA and purified the crude product by preparatory HPLC using a 10-90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) δ7.86 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H, J=8.0 Hz), 6.98 (m, 2H), 5.52 (q, 2H, J=12.8 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 2.09 (s, 3H). ESHRMS m/z 493.0659 (M+H calculated for C21H20BrF2N4O3 requires 493.0681).

Workup

  1. additionwas added
  2. waitAfter 1 h
  3. distillationdistilled DMA
  4. custompurified the crude product by preparatory HPLC
  5. customa 10-90% CH3CN/H2O (30 min) gradient
  6. additioncontaining 0.5% TFA at a flow rate of 80 mL/min
  7. concentrationconcentrated to approximately 20 mL under reduced pressure
  8. additionAdded 5% NaHCO3 (20 mL)
  9. extractionextracted with DCM (3×15 mL)
  10. dry with materialThe organic extracts were dried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated under reduced pressure
  13. customdried in vacuo

Sources & evidence

ORD record
ord-e4613dd23be846d3a3b1d3ebce9717e5
Source dataset
uspto-grants-2010_09
Patent number
US07795271B2

Reaction notes

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