Methylamine → HCID 22050977, compound

HRID 1832122Notes

Reaction equation

HRID 1832122 reaction equation
[CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23](O)=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:3][CH2:2]1.ClC(OCC(C)C)=O.[CH3:44][N:45]1CCOCC1.CN>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH:1]1([NH:4][C:5]([NH:7][CH2:8][C:9]2[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:10]=2[CH2:11][O:12][C:13]2[CH:18]=[C:17]([CH3:19])[N:16]([C:20]3[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=3[CH3:29])[C:23]([NH:45][CH3:44])=[O:24])[C:15](=[O:30])[CH:14]=2)=[O:6])[CH2:2][CH2:3]1

Participants

7

Reactant 4

HCID 6329Methylamine2×HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 22050315HCID 22050315, compound

Product 1

HCID 22050977HCID 22050977, compound

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 6228DimethylformamideSolvent

Procedure

To a cooled (−15° C.) solution of 3-[4-{[2-({[(cyclopropylamino)carbonyl]amino}methyl)-4-fluorobenzyl]oxy}-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoic acid (see Example 651) (0.30 g, 0.63 mmol) and isobutyl chloroformate (0.10 mL, 0.75 mmol) in DMF (3.00 mL) was added 4-methylmorpholine (0.08 mL, 0.75 mmol). The solution instantly turned yellow and was dark brown within minutes. After 20 min, methylamine (0.47 mL of 2.0M solution in THF, 0.94 mmol) was added. The reaction was carried out at RT. After 2.5 h, a catalytic amount of DMAP and additional methylamine (0.47 mL, 0.94 mmol) were added. After an additional 2.5 h, the reaction was concentrated to a dark red oil. The crude product was purified by preparatory HPLC. Acetonitrile was evaporated and the solution washed with 5% NaHCO3 (20 mL) and extracted in DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated to an off-white solid, dried in vacuo (0.06 g, 19%). 1H NMR (CD3OD/400 MHz) δ 7.85 (m, 1H), 7.58 (s, 1H), 7.48 (m, 2H), 7.14 (m, 1H), 7.02 (m, 1H), 6.23 (s, 1H), 6.09 (s, 1H), 5.20 (s, 2H), 4.45 (s, 2H), 2.90 (s, 3H), 2.49 (m, 1H), 2.11 (s, 3H), 1.91 (s, 3H), 0.71 (m, 2H), 0.48 (m, 2H). ES HRMS m/z 493.2260 (M+H calculated for C27H30N4O4F requires 493.2246).

Workup

  1. waitThe solution instantly turned yellow and was dark brown within minutes
  2. customwas carried out at RT
  3. waitAfter 2.5 h
  4. waitAfter an additional 2.5 h
  5. concentrationthe reaction was concentrated to a dark red oil
  6. customThe crude product was purified by preparatory HPLC
  7. customAcetonitrile was evaporated
  8. washthe solution washed with 5% NaHCO3 (20 mL)
  9. extractionextracted in DCM (3×15 mL)
  10. dry with materialThe organic extracts were dried over Na2SO4
  11. filtrationfiltered
  12. concentrationconcentrated to an off-white solid
  13. customdried in vacuo (0.06 g, 19%)

Sources & evidence

ORD record
ord-5597c3acc3c54a9d92bc2642c12169f1
Source dataset
uspto-grants-2006_06
Patent number
US07067540B2

Reaction notes

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