Sodium borohydride → 5-{4-[(4,4-Dimethylpentylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamide

HRID 131011Notes

Reaction equation

HRID 131011 reaction equation
[CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26].[BH4-].[Na+]>CO>[CH3:21][C:22]([CH3:28])([CH3:27])[CH2:23][CH2:24][CH2:25][NH:26][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([O:19][CH3:20])[CH:4]=1

Participants

5

Reactant 3

HCID 4311764Sodium borohydrideHCID 144547574,4-Dimethylpentan-1-amineHCID 597299775-(4-Formyl-2-methoxyphenoxy)pyrazine-2-carboxamide

Product 1

HCID 100448095-{4-[(4,4-Dimethylpentylamino)methyl]-2-methoxyphenoxy}pyrazine-2-carboxamideYield 37.3%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Procedure

Place 5-(4-formyl-2-methoxyphenoxy)pyrazine-2-carboxamide (Example 719, Part A) (0.700 g, 2.56 mmol), 4,4-dimethylpentylamine (0.310 g, 2.69 mmol) and 3 {acute over (Å)} molecular sieves in a vial. Add methanol (12.8 mL), cap and stir overnight. Add NaBH4 (0.0969 g, 2.56 mmol) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 25 g ISCO® pre-load column. Dry the column in a vacuum oven at room temperature. Purify by eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes. Concentrate the fraction containing the product, then add EtOAc (100 mL). Wash the organic solution with 1.0 N NaOH (2×25 mL), dry it over Na2SO4, filter and concentrate. Dissolve the product in ether:dichloromethane (5:1) (25 mL), add hexanes (20 mL), and then concentrate to about a quarter of the volume. Filter the precipitate to give the title compound (0.356 g, 37.3%): TOF MS ES+ 373.2 (M+H)+, HRMS calcd for C20H29N4O3 373.2240 (M+H)+, found 373.2245, time 0.39 min; HPLC [YMC-Pro pack C-18 (150×4.6 mm, S-5 microm), 0.05% TFA/acetonitrile in 0.05% TFA/water at 1.0 mL/min, 10-20% over 5 min, 20-95% over 18], tR=12.0 min, 98.7% purity.

Workup

  1. customDry the column in a vacuum oven at room temperature
  2. customPurify
  3. washby eluting through a 40 g ISCO® column with 5% to 20% (2.0 M NH3 in methanol) in ethyl acetate over 45 minutes
  4. concentrationConcentrate the fraction
  5. additioncontaining the product
  6. washWash the organic solution with 1.0 N NaOH (2×25 mL)
  7. dry with materialdry it over Na2SO4
  8. filtrationfilter
  9. concentrationconcentrate
  10. dissolutionDissolve the product in ether:dichloromethane (5:1) (25 mL)
  11. additionadd hexanes (20 mL)
  12. concentrationconcentrate to about a quarter of the volume
  13. filtrationFilter the precipitate

Sources & evidence

ORD record
ord-dc89326c3f4f4e1b880ae3594453062f
Source dataset
uspto-grants-2008_06
Patent number
US07381719B2

Reaction notes

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