2,2,2-Trifluoro-1-methoxyethanol → N2-{[5-hydroxy-1-methyl-4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-1,4-dihydropyridin-2-yl]methyl}-N-methyl-L-alaninamide

HRID 1519057Notes

Reaction equation

HRID 1519057 reaction equation
[OH:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH2:9][NH:10][C@@H:11]([CH3:16])[C:12]([NH:14][CH3:15])=[O:13])[N:6]([CH3:8])[CH:7]=1.C[O:19][CH:20](O)[C:21]([F:24])([F:23])[F:22].C(=O)([O-])[O-].[K+].[K+].[NH4+].[OH-]>CC#N.CC(O)C>[OH:1][C:2]1[C:3](=[O:17])[CH:4]=[C:5]([CH2:9][NH:10][C@H:11]([C:12]([NH:14][CH3:15])=[O:13])[CH3:16])[N:6]([CH3:8])[C:7]=1[CH:20]([OH:19])[C:21]([F:24])([F:23])[F:22]

Participants

7

Reactant 4

HCID 98922,2,2-Trifluoro-1-methoxyethanolHCID 11430Potassium CarbonateHCID 14923Ammonium HydroxideHCID 70805245(S)-2-((5-hydroxy-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide

Product 1

HCID 49870020N2-{[5-hydroxy-1-methyl-4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-1,4-dihydropyridin-2-yl]methyl}-N-methyl-L-alaninamide

Reagents, catalysts & solvents 2

HCID 3776IsopropanolSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
77.5 °C

Procedure

A mixture of (S)-2-((5-hydroxy-1-methyl-4-oxo-1,4-dihydropyridin-2-yl)methylamino)-N-methylpropanamide (3.13 g, 13.1 mmol), trifluoroacetaldehyde methyl hemiacetal (3.6 mL, 38.0 mmol) and potassium carbonate (2.62 g, 19.0 mmol) in CH3CN (35 mL) was heated at 75-80° C. for overnight. Analysis of the reaction mixture by TLC using a solvent mixture of 28-30% conc. NH4OH in IPA as eluant indicated incomplete consumption of the starting material. A further portion of trifluoroacetaldehyde methyl hemiacetal (4 mL) was added, and the mixture was heated at 95-100° C. for another 24 h. On cooling to room temperature, the mixture was purified by column chromatography on silica gel using a mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate). Thus, the title compound N2-{[5-hydroxy-1-methyl-4-oxo-6-(2,2,2-trifluoro-1-hydroxyethyl)-1,4-dihydropyridin-2-yl]methyl}-N-methyl-L-alaninamide, Apo7033, was obtained as a yellowish solid (1.53 g) in 35% yield. 1H NMR (DMSO-D6) δ (ppm): 7.79 (t, J=4.4 Hz, 1H, NH), 6.30 (s, 1H), 5.87 (q, J=8.7 Hz, 1H, CHCF3), 3.82 (s, 3H, NCH3), 3.61-3.65 (dd, 2J=14.5 and 4J=1.9 Hz, 1H, 0.5 NHCH2), 3.47-3.52 (apparent t, J=15.2 Hz, 1H, 0.5 NHCH2), 3.08 (q, J=6.8 Hz, 1H, CHCH3), 2.59 (d, J=4.2 Hz, 3H, NHCH3), 1.12 (dd, 2J=6.8 and 4J=2.3 Hz, 3H, CHCH3); 13C NMR (DMSO-D6) δ (ppm): 175.0 (C═O), 169.6 (C═O), 149.2, 147.3, 125.6, 125.0 (q, J=283 Hz, CHCF3), 113.1 (CH), 65.2 (q, J=33 Hz, CHCF3), 56.9 (CH), 48.9 (CH2), 36.6 (NCH3), 25.8 (NHCH3), 19.6 (CH3); MS m/z 360 [M+Na]+, 338 (100%) [M+1]+, 236.

Workup

  1. customconsumption of the starting material
  2. additionA further portion of trifluoroacetaldehyde methyl hemiacetal (4 mL) was added
  3. temperaturethe mixture was heated at 95-100° C. for another 24 h
  4. temperatureOn cooling to room temperature
  5. customthe mixture was purified by column chromatography on silica gel using
  6. additiona mixture of MeOH and ethyl acetate as eluant (solvent gradient of 10, 15 and 20% MeOH in ethyl acetate)

Sources & evidence

ORD record
ord-dd9f6f7cf76d47b9a31a0b55943f2cff
Source dataset
uspto-grants-2015_07
Patent number
US09073865B2

Reaction notes

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