4-Methylmorpholine → 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamide

HRID 350924Notes

Reaction equation

HRID 350924 reaction equation
[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([OH:14])=O)[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28].ClC(OCC(C)C)=O.CN1CCOCC1.[NH2:44][C@@H:45]([CH3:48])[CH2:46][OH:47]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[CH3:18])[C:12]([NH:44][C@@H:45]([CH3:48])[CH2:46][OH:47])=[O:14])[CH:5]=[N:4][C:3]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 80307L-AlaninolHCID 210892753-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid

Product 1

HCID 588061633-[5-bromo-4-[(2,4-difluorobenzyl)oxy)-6-oxopyrimidin-1(6H)-yl]-N-[(1S)-2-hydroxy-1-methylethyl]-4-methylbenzamideYield 67.8%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
0 °C

Procedure

To a cooled (0° C.) solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 1) (0.80 g, 1.77 mmol) in DMA (3.2 mL) was added isobutyl chloroformate (0.28 mL, 2.13 mmol) and 4-methylmorpholine (0.25 mL, 2.30 mmol). Stirred at 0° C. for 5 min, ambient temperature for 30 min. Added (S)-(+)-2-amino-1-propanol (0.21 mL, 2.66 mmol) and DMAP (0.02 g, 0.18 mmol). Stirred at ambient temperature overnight. Purified 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=509) 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 pale yellow foam (0.61 g, 67%).

Workup

  1. stirringStirred at ambient temperature overnight
  2. customPurified crude product by preparatory HPLC
  3. customa 10–90% CH3CN/H2O (30 min) gradient
  4. additioncontaining 0.5% TFA at a flow rate of 80 mL/min
  5. concentrationconcentrated to approximately 20 mL under reduced pressure
  6. additionAdded 5% NaHCO3 (20 mL)
  7. extractionextracted with DCM (3×15 mL)
  8. dry with materialThe organic extracts were dried over Na2SO4
  9. filtrationfiltered
  10. concentrationconcentrated under reduced pressure
  11. customdried in vacuo

Sources & evidence

ORD record
ord-f1c51db90bf44702b9eace4c064ec1ff
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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