Diisopropylethylamine → (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrimidin-5-ylmethyl)acrylamide

HRID 1486977Notes

Reaction equation

HRID 1486977 reaction equation
[F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([OH:22])=O)[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[N:25]1[CH:30]=[C:29]([CH2:31][NH2:32])[CH:28]=[N:27][CH:26]=1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>ClCCl.CO>[F:24][C:2]([F:23])([F:1])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][CH2:31][C:29]3[CH:30]=[N:25][CH:26]=[N:27][CH:28]=3)=[O:22])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1

Participants

7

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 18953632Pyrimidin-5-ylmethanamineHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71493804(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(pyrimidin-5-ylmethyl)acrylamideYield 80%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6344DichloromethaneSolvent2×

Conditions

Temperature
-20 °C

Procedure

In a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.2 g, 1.0 eq.) was charged along with dichloromethane (5 mL, 10V). The reaction mixture was cooled to −20° C. and then added pyrimidine-5-ylmethanamine (0.075 g, 1.2 eq), T3P (50% in EtOAc) (0.4 mL, 1.2 eq) followed by DIPEA (0.2 ml, 2 eq) dropwise into the reaction mixture. The reaction mixture was stirred at −20° C. for another 30 min. The progress of the reaction was followed by TLC analysis on silica gel with 5% Methanol in dichloromethane as mobile phase and visualization with UV. Reaction mixture was concentrated by rotary evaporation (25° C., 20 mm Hg) to afford crude compound. The crude reaction mixture was purified by column chromatography using 60/120 mesh silica and methanol: dichloromethane as mobile phase. The column was packed in dichloromethane and started eluting in MeOH in gradient manner starting with fraction collections (500 mL fractions). The compound started eluting from 4% methanol in dichloromethane. Fractions containing such TLC profile were collected together to obtain pure compound 0.2 g. Yield: 80%.

Workup

  1. customIn a 50 mL, 3N round-bottomed flask equipped with nitrogen inlet
  2. customReaction mixture
  3. concentrationwas concentrated by rotary evaporation (25° C., 20 mm Hg)
  4. customto afford crude compound
  5. customThe crude reaction mixture
  6. customwas purified by column chromatography
  7. washstarted eluting in MeOH in gradient manner
  8. washThe compound started eluting from 4% methanol in dichloromethane
  9. additionFractions containing such TLC profile
  10. customwere collected together

Sources & evidence

ORD record
ord-d8854004c5a64b359e52644be9f81b4c
Source dataset
uspto-grants-2016_08
Patent number
US09428490B2

Reaction notes

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