4-Methylmorpholine → (+/-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide

HRID 350905Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 350905
[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)[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29].C(OC(Cl)=O)C(C)C.CN1CCOCC1.Cl.[CH3:46][NH:47][C:48](=[O:51])[CH2:49][NH2:50]>CC(N(C)C)=O.CN(C1C=CN=CC=1)C.ClCCl>[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:50][CH2:49][C:48]([NH:47][CH3:46])=[O:51])=[O:14])[C:5]([CH3:19])=[N:4][C:3]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=1[F:29]

Komponenten

8

Edukt 4

HCID 79724-Methylmorpholine2×HCID 62365Isobutyl chloroformateHCID 138422022-amino-N-methylacetamide hydrochlorideHCID 210892453-[5-Bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid

Produkt 1

HCID 21088988(+/-) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamideAusbeute 65 %

Reagenzien, Katalysatoren, Lösungsmittel 3

HCID 142844-(Dimethylamino)pyridineKatalysatorHCID 6344DichloromethaneLösungsmittelHCID 31374DimethylacetamideLösungsmittel

Reaktionsbedingungen

Temperatur
0 °C

Versuchsvorschrift

To a solution of 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoic acid (1.0 g, 0.022 mol) in dimethylacetamide (10.0 mL) at −20° C. was added isobutylchloroformate (0.36 g, 0.0028 mol), followed by dropwise addition of N-methylmorpholine (0.30 g, 0.003 mol) and stirred for 10 min under nitrogen atmosphere. The reaction mixture was then stirred at room temperature for 20 min, cooled to 0° C., and added N-methylmorpholine (0.30 g, 0.003 mol) followed by the addition of N-methylglycine amide hydrochloride (0.35 g, 0.0028 mol) and DMAP (0.025 g). The reaction mixture was stirred at room temperature for 4 h, and concentrated in vacuo. The resulting the residue was purified by reverse-phase HPLC using 10–90% CH3CN/Water gradient (40 min) at a flow rate of 80 mL/min. The appropriate fractions (MH+, m/z=535) were combined, and freeze-dried to give a white solid. This was dissolved in dichloromethane (25 mL), washed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL), dried (Na2SO4), and concentrated to dryness to afford the racemic title compound (0.75 g, 65%) as a white amorphous substance: 1H NMR (CD3OD/400 MHz) δ 7.96 (dd 1H, J=1.6 Hz, 8.0 Hz), 7.72 (d, 1H, J=1.6 Hz), 7.62 (m, 1H), 7.56 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.55 (abq, 2H), 3.99 (s, 2H), 2.74 (s, 3H), 2.18 (s, 3H), and 2.14 (s, 3H); ES-HRMS m/z 535.0792 (M+H calcd for C23H22N4O4F2Br requires 535.0787). 19F NMR(CD3OD/400 MHz) −111.85 (m) and −115.91 (m).

Aufarbeitung

  1. stirringThe reaction mixture was then stirred at room temperature for 20 min
  2. stirringThe reaction mixture was stirred at room temperature for 4 h
  3. concentrationconcentrated in vacuo
  4. customThe resulting the residue was purified by reverse-phase
  5. custom10–90% CH3CN/Water gradient (40 min)
  6. customfreeze-dried
  7. customto give a white solid
  8. washwashed successively with 5% sodium bicarbonate (2×20 mL), water (2×20 mL)
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated to dryness

Quellen und Nachweise

ORD-Eintrag
ord-f9e0380a12e14503ac2785ce81d4fc98
Quelldatensatz
uspto-grants-2007_02
Patentnummer
US07183287B2

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