4-Methylmorpholine → HCID 58806160, compound

HRID 350938Notes

Reaction equation

HRID 350938 reaction equation
[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([OH:20])=O)[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:45][C@H:46]([CH3:49])[CH2:47][OH:48]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C>[F:1][C:2]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:3]=1[CH2:4][O:5][C:6]1[N:7]=[CH:8][N:9]([C:15]2[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=2[CH3:24])[C:18]([NH:45][C@H:46]([CH3:49])[CH2:47][OH:48])=[O:20])[C:10](=[O:14])[C:11]=1[CH2:12][CH3:13]

Participants

7

Reactant 4

HCID 79724-MethylmorpholineHCID 62365Isobutyl chloroformateHCID 80308(R)-(-)-2-Amino-1-propanolHCID 21089196HCID 21089196, compound

Product 1

HCID 58806160HCID 58806160, compoundYield 70.5%

Reagents, catalysts & solvents 2

HCID 142844-(Dimethylamino)pyridineCatalystHCID 31374DimethylacetamideSolvent

Conditions

Temperature
0 °C

Procedure

To a cooled solution (0° C.) of 3-[4-[(2,4-difluorobenzyl)oxy]-5-ethyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (from Step 4) (0.25 g, 0.62 mmol) and 4-methylmorpholine (0.10 mL, 0.94 mmol) in DMA (2 mL) was added isobutyl chloroformate (0.12 mL, 0.94 mmol). Stirred 5 min at 0° C., 30 min at ambient temperature. Added (R)-(−)-2-amino-1-propanol (0.07 mL, 0.94 mmol) and DMAP (0.02 g, 0.12 mmol) to the cooled (0° C.) reaction mixture. Stirred at ambient temperature for 3 h. 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=458) 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 an off-white foam (0.20 g, 70%). 1H NMR (CD3OD/400 MHz) δ8.18 (s, 1H), 7.90 (m, 1H), 7.73 (m, 1H), 7.57 (q, 1H, J=8.4 Hz), 7.50 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.52 (q, 2H, J=12.4 Hz), 4.16 (m, 1H), 3.57 (m, 2H), 2.21 (q, 2H, J=7.6 Hz), 2.17 (s, 3H), 1.22 (m, 3H), 1.05 (t, 3H, J=7.2 Hz). ESHRMS m/z 458.1855 (M+H calculated for C24H26F2N3O4 requires 458.1886).

Workup

  1. custom(0° C.) reaction mixture
  2. stirringStirred at ambient temperature for 3 h
  3. customPurified crude product by preparatory HPLC
  4. customa 10–90% CH3CN/H2O (30 min) gradient
  5. additioncontaining 0.5% TFA at a flow rate of 80 mL/min
  6. concentrationconcentrated to approximately 20 mL under reduced pressure
  7. additionAdded 5% NaHCO3 (20 mL)
  8. extractionextracted with DCM (3×15 mL)
  9. dry with materialThe organic extracts were dried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customdried in vacuo

Sources & evidence

ORD record
ord-53c9dce7958d4893866ea855b318915a
Source dataset
uspto-grants-2007_02
Patent number
US07183287B2

Reaction notes

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