Diisopropylethylamine → (S)-tert-Butyl 4-(2-Fluoro-5-nitrophenyl)-1,4-dimethyl-6-oxotetrahydropyrimidin

HRID 1042081Notes

Reaction equation

HRID 1042081 reaction equation
F[C:2]1C=CC=[CH:4][C:3]=1[C:8](=O)C.Cl.[CH3:12][N:13](C)CCCN=C=NCC.[NH2:23][C@@:24]([C:31]1[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=1[F:40])([CH3:30])[CH2:25][C:26]([O:28]C)=O.[CH:41](N(CC)C(C)C)(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:3]([C@H:4]1[NH:23][C:24]([C:31]2[CH:36]=[C:35]([N+:37]([O-:39])=[O:38])[CH:34]=[CH:33][C:32]=2[F:40])([CH3:30])[CH2:25][C:26](=[O:28])[N:13]1[CH3:12])([CH3:41])([CH3:2])[CH3:8]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 96744o-FluoroacetophenoneHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 57505083(S)-Methyl 3-Amino-3-(2-fluoro-5-nitrophenyl)butanoate

Product 1

HCID 86666430(S)-tert-Butyl 4-(2-Fluoro-5-nitrophenyl)-1,4-dimethyl-6-oxotetrahydropyrimidinYield 58%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
45 °C

Procedure

Preparation 1 (55.6 g, 292.5 mmol) and 1-(3-(dimethylamino)propyl)-3-ethylcarbodiimide hydrochloride (67.3 g, 351 mmol) were added to a solution of crude amine 6 (68.0 g, ca. 234 mmol) and N,N-diisopropylethylamine (184 mL, 1053 mmol) in DMF (1050 mL) and the reaction mixture stirred at 45° C. for 18 h. After this time, the reaction mixture was then diluted with water (2500 mL) and ethyl acetate (2500 mL) and stirred vigorously until the phases cleared. The phases were separated and the aqueous layer extracted with ethyl acetate (2×1 L). The combined organics were sequentially washed with 1 N hydrochloric acid (2500 mL), saturated aqueous sodium carbonate (2500 mL), and then brine (2500 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica, eluent: ethyl acetate/heptane) to afford carbamate 8 (43.9 g, 49%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ10.49 (s, 1H), 8.27-8.13 (m, 2H), 7.31-7.24 (m, 1H), 3.45 (dd, J=16.4, 1.8 Hz, 1H), 3.22 (s, 3H), 2.95 (d, J=16.4 Hz, 1H), 1.80 (s, 3H), 1.57 (s, 9H); ESI MS m/z 381 [M+H]+. Also afforded 7 (23.9 g, 26%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.16 (s, 1H), 8.21 (dd, J=9.1, 2.5 Hz, 1H), 8.09 (d, J=2.5 Hz, 1H), 7.08 (d, J=9.1 Hz, 1H), 3.66 (s, 3H), 3.55 (s, 3H), 2.85 (d, J=15.0 Hz, 1H), 2.74 (d, J=15.0 Hz, 1H), 1.82 (s, 3H), 1.54 (s, 9H); ESI MS m/z 393 [M+H]+.

Workup

  1. stirringstirred vigorously until the phases
  2. customThe phases were separated
  3. extractionthe aqueous layer extracted with ethyl acetate (2×1 L)
  4. washThe combined organics were sequentially washed with 1 N hydrochloric acid (2500 mL), saturated aqueous sodium carbonate (2500 mL)
  5. dry with materialbrine (2500 mL), dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated under reduced pressure
  8. customThe residue was purified by column chromatography (silica, eluent: ethyl acetate/heptane)

Sources & evidence

ORD record
ord-1ec805a40beb4c1f976fd3915c59fd52
Source dataset
uspto-grants-2013_10
Patent number
US08557826B2

Reaction notes

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