Triethylamine → Methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate

HRID 1259324Notes

Reaction equation

HRID 1259324 reaction equation
I[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[C:3]=1[CH3:23].[NH2:24][C:25]([CH3:37])([CH3:36])[CH2:26][NH:27][C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>C(#N)C>[C:32]([C:31]1[CH:30]=[CH:29][C:28]([NH:27][CH2:26][C:25]([NH:24][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[C:5](=[O:12])[N:4]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=3)[C:3]=2[CH3:23])([CH3:36])[CH3:37])=[CH:35][CH:34]=1)#[N:33]

Participants

5

Reactant 3

HCID 8471TriethylamineHCID 66738777Methyl 6-iodo-5-methyl-3-oxo-4-[3-(trifluoromethyl)phenyl]-3,4-dihydropyrazine-2-carboxylateHCID 68731979Benzonitrile, 4-[(2-amino-2-methylpropyl)amino]-

Product 1

HCID 68764650Methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylateYield 23.1%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Conditions

Temperature
50 °C

Procedure

In a bomb tube of stainless steel (Parr) fitted with an internal cylindrical glass vessel and magnetic stirrer, methyl 6-iodo-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (SM1, 1447 mg, 3.3 mmol), 4-(2-amino-2-methylpropylamino)benzonitrile (750 mg, 4.0 mmol), triethylamine (3.2 mL, 23 mmol) and acetonitrile (35 mL) were mixed. The mixture was purged with argon for 10 minutes. After adding bis(tributylphosphine)palladium (120 mg, 0.23 mmol), the bomb tube was sealed, evacuated and back-filled with carbon monoxide five consecutive times. The contents of the bomb tube were stirred under carbon monoxide (6.5 bar) at 50° C. for 9 h. LC-MS indicated about 50% conversion to desired product and unreacted SM. The dark red-brown solution was concentrated to dryness, dissolved in ethyl acetate (200 mL), washed with water (2×50 mL), dried over anhydrous sodium sulfate, filtered and concentrated with silica to dryness. Flash chromatography on silica with ethyl acetate/n-heptane (1:3 and 1:1) as eluents gave methyl 6-(1-(4-cyanophenylamino)-2-methylpropan-2-ylamino)-5-methyl-3-oxo-4-(3-(trifluoromethyl)phenyl)-3,4-dihydropyrazine-2-carboxylate (0.38 g, 22%) as a yellow solid.

Workup

  1. customThe mixture was purged with argon for 10 minutes
  2. customthe bomb tube was sealed
  3. customevacuated
  4. additionback-filled with carbon monoxide five consecutive times
  5. concentrationThe dark red-brown solution was concentrated to dryness
  6. dissolutiondissolved in ethyl acetate (200 mL)
  7. washwashed with water (2×50 mL)
  8. dry with materialdried over anhydrous sodium sulfate
  9. filtrationfiltered
  10. concentrationconcentrated with silica to dryness

Sources & evidence

ORD record
ord-a40c60a1e1f74e28a90d5dcacfa4ae3c
Source dataset
uspto-grants-2013_06
Patent number
US08466284B2

Reaction notes

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