4-Methylmorpholine → 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate

HRID 1396974Notes

Reaction equation

HRID 1396974 reaction equation
[CH:1]1([CH2:6][C@H:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.CN1CCOCC1.[F:50][C:51]1[CH:52]=[CH:53][C:54]([NH2:57])=[N:55][CH:56]=1>C(#N)C>[CH:1]1([CH2:6][C@@H:7]([C:8]([N:10]2[CH:14]([C:15]([NH:57][C:54]3[CH:53]=[CH:52][C:51]([F:50])=[CH:56][N:55]=3)=[O:17])[CH2:13][CH:12]=[N:11]2)=[O:9])[CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])[CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 27340604-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-iumHCID 27377012-Amino-5-fluoropyridineHCID 682877191-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid

Product 1

HCID 682881271,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoateYield 78%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
0 °C

Procedure

To a solution of 1-{(2R)-2-(cyclopentylmethyl)-4-[(1,1-dimethylethyl)oxy]-4-oxobutanoyl}-4,5-dihydro-1H-pyrazole-5-carboxylic acid (352 mg, 1.0 mmol) in acetonitrile (10 mL) at 0° C. was added 4-[4,6-bis(methyloxy)-1,3,5-triazin-2-yl]-4-methylmorpholin-4-ium (656 mg, 2.0 mmol) and N-methylmorpholine (0.28 mL, 2.5 mmol). The reaction mixture was stirred for 2 hours at 0° C. After this time, 5-fluoro-2-pyridinamine (146 mg, 1.3 mmol) was added to the mixture, which was then allowed to warm to room temperature and stirred for 3 hours. The solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL) were added to the remaining residue. The phases were separated. The aqueous phase was extracted twice with DCM (15 mL), and the combined organic phases were dried over sodium sulfate and concentrated. The remaining residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex) to give 1,1-dimethylethyl (3R)-3-(cyclopentylmethyl)-4-(5-{[(5-fluoro-2-pyridinyl)amino]carbonyl}-4,5-dihydro-1H-pyrazol-1-yl)-4-oxobutanoate (350 mg, 0.78 mmol, 78% yield) as a yellow oil. MS: 447 ([M+H]+).

Workup

  1. temperatureto warm to room temperature
  2. stirringstirred for 3 hours
  3. customThe solvent was removed under reduced pressure, and water (5 mL) and DCM (15 mL)
  4. additionwere added to the remaining residue
  5. customThe phases were separated
  6. extractionThe aqueous phase was extracted twice with DCM (15 mL)
  7. dry with materialthe combined organic phases were dried over sodium sulfate
  8. concentrationconcentrated
  9. customThe remaining residue was purified by Combiflash silica gel chromatography (0-100% EtOAc in hex)

Sources & evidence

ORD record
ord-5c93db9d1b1642b3a4adb3de31e67dc6
Source dataset
uspto-grants-2014_12
Patent number
US08901119B2

Reaction notes

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