Sodium hydride → morpholine-4-carboxylic acid 6-(4-fluorophenyl)-5-oxo-7-(2-phenoxypyrimidin-4-yl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl ester

HRID 7666Notes

Reaction equation

HRID 7666 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([N:11]2[CH2:15][CH:14]([O:16][C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])[CH2:13][N:12]2[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:28]=2)=O)=[O:10])=[CH:4][CH:3]=1.[H-].[Na+]>CN(C)C=O.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:10])[N:11]3[CH2:15][CH:14]([O:16][C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH2:13][N:12]3[C:25]=2[C:27]2[CH:32]=[CH:31][N:30]=[C:29]([O:33][C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:28]=2)=[CH:4][CH:3]=1

Participants

5

Reactant 2

HCID 24758Sodium hydrideHCID 20724735Morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-2-(2-phenoxypyrimidine-4-carbonyl)-pyrazolidin-4-yl ester

Product 1

HCID 10118690morpholine-4-carboxylic acid 6-(4-fluorophenyl)-5-oxo-7-(2-phenoxypyrimidin-4-yl)-2,3-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-2-yl esterYield 32%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
0 °C

Procedure

A solution of morpholine-4-carboxylic acid 1-[2-(4-fluorophenyl)acetyl]-2-(2-phenoxypyrimidine-4-carbonyl)-pyrazolidin-4-yl ester, 42, (154 mg, 0.287 mmol) in dimethylformamide (3 mL) is added dropwise to a −10° C. suspension of sodium hydride (16.4 mg of a 60% dispersion in mineral oil, 0.410 mmol) in tetrahydrofuran (3 mL). After 1 hour at −10° C., the reaction was warmed to 0° C. for 2 hours. The orange-colored solution is then quenched by slowly adding saturated NH4Cl (400 μL). The cooling bath is removed, and the solution allowed to warm to room temperature. The reaction mixture is concentrated in vacuo and the resulting residue is dissolved in THF (25 mL) and filtered through a pad of Celite. The filtrate is concentrated in vacuo and the residue purified by Prep HPLC to afford 47 mg (32% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J=4.9 Hz, 1H), 7.47–7.18 (m, 9H), 7.08 (t, J=8.7 Hz, 2H), 6.89 (d, J=4.9 Hz, 1H), 5.66 (m, 1H), 4.16 (m, 2H), 4.02 (d, J=12.9Hz, 1H), 3.87 (dd, J=12.9, 5.1 Hz, 1H), 3.79–3.30 (m, 8H); HRMS m/z calcd for C27H25FN5O5 (MH+) 518.1840, found 518.1815.

Workup

  1. customThe orange-colored solution is then quenched by slowly adding saturated NH4Cl (400 μL)
  2. customThe cooling bath is removed
  3. temperatureto warm to room temperature
  4. concentrationThe reaction mixture is concentrated in vacuo
  5. dissolutionthe resulting residue is dissolved in THF (25 mL)
  6. filtrationfiltered through a pad of Celite
  7. concentrationThe filtrate is concentrated in vacuo
  8. customthe residue purified by Prep HPLC

Sources & evidence

ORD record
ord-c544afb083bd431097b42993f61f5952
Source dataset
uspto-grants-2006_08
Patent number
US07087615B2

Reaction notes

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