4-Methylmorpholine → HCID 22050063, compound

HRID 1867144Notes

Reaction equation

HRID 1867144 reaction equation
[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][C:47]([CH3:51])([OH:50])[CH2:48][NH2:49]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:29])[N:4]([CH2:19][C:20]2[N:21]=[CH:22][C:23]([C:26]([NH:49][CH2:48][C:47]([OH:50])([CH3:51])[CH3:46])=[O:27])=[N:24][CH:25]=2)[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]

Participants

6

Reactant 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 123861811-Amino-2-methyl-propan-2-ol hydrochlorideHCID 22050084HCID 22050084, compound

Product 1

HCID 22050063HCID 22050063, compoundYield 75%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
-10 °C

Procedure

To a solution of 5-{[3-bromo-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]methyl}pyrazine-2-carboxylic acid (0.42 g, 0.9 mmol) in DMF (3.0 mL) was added isobutylchloroformate (0.126 g, 0.13 mmol) followed by the addition of N-methylmorpholine (0.11 g, 1.1 mmol) and stirred at −10° C., under argon atmosphere. After 20 min, added a solution of 1,1 dimethyl-2-aminoethanol hydrochloride (0.135 g, 1.1 mmol) in DMF (2.0 mL) containing N-methylmorpholine (0.11 g, 1.1 mmol). The mixture was stirred at room temperature for 1 h, and concentrated to dryness in vacuo. The resulting residue was purified by reverse-phase HPLC using 10-90% CH3CN/Water gradient (60 min) at a flow rate of 70 mL/min. The appropriate fractions (m/z=537 M+H were combined and freeze dried to give a white powder. This was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL). The organic layer was washed with water, dried (Na2SO4), and concentrated to dryness to afford the title compound (0.35 g, 75%) as a white powder: 1H NMR (CD3OD/400 MHz) δ 9.1 (d, 1H, J=1.6 Hz), 8.71 (d, 1H, J=1.6 Hz), 7.61 (m 1H), 7.02 (m, 2H), 6.54 (s, 1H), 5.54 (s, 2H), 5.30 (s, 2 h). 3.30 (s, 2 h), 2.55 (s, 3H), and 1.21 (s, 6H); 19F NMR (CD3OD/400 MHz) −111.67 (m) and −116.05 (m); ES-HRMS m/z 537.0948 (M+H calcd for C23H24BrF2N4O4 requires 537.0943).

Workup

  1. stirringThe mixture was stirred at room temperature for 1 h
  2. concentrationconcentrated to dryness in vacuo
  3. customThe resulting residue was purified by reverse-phase
  4. custom10-90% CH3CN/Water gradient (60 min)
  5. customfreeze dried
  6. customto give a white powder
  7. customThis was partitioned between 5% NaHCO3 (10 mL) and EtOAc (15 mL)
  8. washThe organic layer was washed with water
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated to dryness

Sources & evidence

ORD record
ord-3e7f15bcfecc442fb4bc59eb4907ea05
Source dataset
uspto-grants-2009_12
Patent number
US07629363B2

Reaction notes

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