1,2-Dimethoxyethane → 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide

HRID 1191211Notes

Reaction equation

HRID 1191211 reaction equation
Br[C:2]1[C:3]([NH2:9])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.COCCOC.[C:16]([C:20]1[C:21]([Cl:29])=[C:22]([C:26](Cl)=[O:27])[N:23]([CH3:25])[N:24]=1)([CH3:19])([CH3:18])[CH3:17].[NH4+].[Cl-].[CH3:32][O:33][C:34]1[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=1>CCOC(C)=O.O>[Br:8][C:6]1[N:7]=[C:2]([NH:39][CH2:38][C:37]2[CH:40]=[CH:41][C:34]([O:33][CH3:32])=[CH:35][CH:36]=2)[C:3]([NH:9][C:26]([C:22]2[N:23]([CH3:25])[N:24]=[C:20]([C:16]([CH3:19])([CH3:18])[CH3:17])[C:21]=2[Cl:29])=[O:27])=[N:4][CH:5]=1

Participants

8

Reactant 5

HCID 80711,2-DimethoxyethaneHCID 25517Ammonium ChlorideHCID 754524-MethoxybenzylamineHCID 6200042-Amino-3,5-dibromopyrazineHCID 866574055-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride

Product 1

HCID 866574125-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

To a solution of 3,5-dibromo-pyrazin-2-ylamine (252 mg, 1.00 mmol) in DME (10 mL) 60% NaH (120 mg, 3.00 mmol) was added portion wise. The resulting mixture was stirred at room temperature for 30 min and then treated with 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carbonyl chloride (234 mg, 1.00 mmol, prepared as described in Example 1, STEP C). The resulting mixture was stirred at room temperature for 2 h and treated with saturated NH4Cl (20 mL) followed by EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated. The resulting residue was dissolved in 1,4-dioxane (10 mL) and treated with 4-methoxybenzylamine (0.650 mL, 5.00 mmol). The resulting mixture was stirred at 65° C. for 2 h. The resulting mixture was allowed to cool to room temperature and then treated with water (10 mL) and EtOAc (20 mL). The organic layer was separated, dried (Na2SO4) and concentrated. The resulting residue was purified on silica (0:100-50:50 EtOAc:hexane) to yield 5-tert-butyl-4-chloro-2-methyl-2H-pyrazole-3-carboxylic acid [5-bromo-3-(4-methoxy-benzylamino)-pyrazin-2-yl]-amide. 1H-NMR (400 MHz, CDCl3) δ: 8.77 (br. s., 1H), 7.70 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.88 (d, J=8.6 Hz, 2H), 6.28-6.36 (m, 1H), 4.59 (d, J=5.1 Hz, 2H), 4.08 (s, 3H), 3.80 (s, 3H), 1.40 (s, 9H).

Workup

  1. stirringThe resulting mixture was stirred at room temperature for 2 h
  2. customThe organic layer was separated
  3. dry with materialdried (Na2SO4)
  4. concentrationconcentrated
  5. dissolutionThe resulting residue was dissolved in 1,4-dioxane (10 mL)
  6. stirringThe resulting mixture was stirred at 65° C. for 2 h
  7. temperatureto cool to room temperature
  8. customThe organic layer was separated
  9. dry with materialdried (Na2SO4)
  10. concentrationconcentrated
  11. customThe resulting residue was purified on silica (0:100-50:50 EtOAc:hexane)

Sources & evidence

ORD record
ord-db5452fa3afc464e81a58718a80db788
Source dataset
uspto-grants-2014_03
Patent number
US08680098B2

Reaction notes

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