4-Fluorobenzyl chloride → 3-Cyano-1-(4-fluoro-benzyl)-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid 4-fluoro-benzylamide

HRID 536119Notes

Reaction equation

HRID 536119 reaction equation
[H-].[Na+].[F:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8]N)=[CH:6][CH:5]=1.[F:12][C:13]1[CH:35]=[CH:34][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][NH:29][N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:15][CH:14]=1.FC1C=CC(CCl)=CC=1>CN(C=O)C>[F:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:17][NH:18][C:19]([C:21]2[N:22]=[C:23]3[C:31]([C:32]#[N:33])=[CH:30][N:29]([CH2:8][C:7]4[CH:10]=[CH:11][C:4]([F:3])=[CH:5][CH:6]=4)[N:24]3[C:25](=[O:28])[C:26]=2[OH:27])=[O:20])=[CH:34][CH:35]=1

Participants

5

Reactant 3

HCID 96024-Fluorobenzyl chlorideHCID 24758Sodium hydrideHCID 866430543-cyano-N-[(4-fluorophenyl)methyl]-6-hydroxy-7-oxo-1H-pyrazolo[1,5-a]pyrimidine-5-carboxamide;(4-fluorophenyl)methanamine

Product 1

HCID 668103533-Cyano-1-(4-fluoro-benzyl)-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid 4-fluoro-benzylamideYield 37.5%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Conditions

Temperature
90 °C

Procedure

Sodium hydride (11.0 mg, 0.367 mmol) was added in one portion to a stirred suspension of 3-Cyano-6-hydroxy-7-oxo-1,7-dihydro-pyrazolo[1,5-a]pyrimidine-5-carboxylic acid 4-fluoro-benzylamide compound with 4-fluorobenzylamine (Example 3.1) (100 mg, 0.306 mmol) in DMF (2 mL) under nitrogen at room temperature. The mixture was stirred for 30 min before p-fluorobenzyl chloride (40 μL, 0.366 mmol) was added and the mixture heated at 90° C. for 2 days. After this time, the reaction was cooled to room temperature and partitioned between ethyl acetate (10 mL) and aqueous hydrochloric acid (1M, 10 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (3×10 mL). The combined organics were washed with water (3×10 mL), brine (10 mL) and then concentrated. The residue was purified by column chromatography (95:5:1 dichloromethane:methanol: aqueous ammonia) to afford the desired product (50 mg, 36%).

Workup

  1. additionwas added
  2. temperatureAfter this time, the reaction was cooled to room temperature
  3. custompartitioned between ethyl acetate (10 mL) and aqueous hydrochloric acid (1M, 10 mL)
  4. customThe organic layer was separated
  5. extractionthe aqueous layer was extracted with ethyl acetate (3×10 mL)
  6. washThe combined organics were washed with water (3×10 mL), brine (10 mL)
  7. concentrationconcentrated
  8. customThe residue was purified by column chromatography (95:5:1 dichloromethane:methanol: aqueous ammonia)

Sources & evidence

ORD record
ord-3003eca09637431080807f027926dd36
Source dataset
uspto-grants-2014_10
Patent number
US08859563B2

Reaction notes

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