Water → tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2-furanylmethylcarbamate

HRID 1865030Notes

Reaction equation

HRID 1865030 reaction equation
[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[C:16]2[CH:15]=[CH:14][CH:13]=1.[H-].[Na+].[O:33]1[CH2:37][CH2:36][CH2:35][CH:34]1[CH2:38]Cl.O>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[C:5]([CH3:11])[C:4]=1[C:12]1[N:17]2[N:18]=[C:19]([O:29][CH3:30])[C:20]([N:21]([CH2:38][CH:34]3[CH2:35][CH2:36][CH2:37][O:33]3)[C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[C:16]2[CH:15]=[CH:14][CH:13]=1

Participants

7

Reactant 4

HCID 962WaterHCID 181502-Chloromethyl tetrahydrofuranHCID 24758Sodium hydrideHCID 21984512tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate

Product 1

HCID 21984687tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl)-N-tetrahydro-2-furanylmethylcarbamate

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

After dissolving tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]carbamate (50 mg) in N,N-dimethylformamide (2 mL), sodium hydride (60%, 15 mg) was added while cooling on ice, and then 2-tetrahydrofuranylmethyl chloride (16 μL) was added and the mixture was stirred for 3 hours at 60° C. under a nitrogen stream. Water was added to the reaction mixture, extraction was performed with ethyl acetate and the extract washed with brine. After drying over anhydrous magnesium sulfate and filtration, the solvent was concentrated under reduced pressure to obtain tert-butyl N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylcarbamate. The crude product was dissolved in ethyl acetate (2 mL) without purification, a 4 N hydrochloric acid/ethyl acetate solution (4 mL) was added, and the mixture was stirred at 40° C. for 1 hour. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide while cooling on ice, and then extraction was performed with ethyl acetate and the organic layer washed with water and brine. The obtained organic layer was dried over anhydrous magnesium sulfate and filtered, and the solvent was concentrated under reduced pressure to obtain N-[7-(2,4-dimethoxy-6-methylphenyl)-2-methoxypyrazolo[1,5-a]pyridin-3-yl]-N-tetrahydro-2-furanylmethylamine as a crude product. This was dissolved in tetrahydrofuran (2 mL) without purification, and after adding cyclopropanecarboxyaldehyde (27 μL) and 3 M aqueous sulfuric acid (0.121 mL), sodium borohydride (9 mg) was added in five portions while vigorously stirring on ice, and stirring was continued for 30 minutes. Saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, extraction was performed with ethyl acetate, the solvent was concentrated, the residue was purified by silica gel column chromatography, and the title compound (31 mg) was obtained from the n-hexane:ethyl acetate (5:1) fraction as a yellow oil.

Workup

  1. additionwas added
  2. temperaturewhile cooling on ice
  3. washthe extract washed with brine
  4. dry with materialAfter drying over anhydrous magnesium sulfate and filtration
  5. concentrationthe solvent was concentrated under reduced pressure

Sources & evidence

ORD record
ord-f9131f8499fe478f9ed996a4e544e9af
Source dataset
uspto-grants-2009_12
Patent number
US07625925B2

Reaction notes

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