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

HRID 1523346Notes

Reaction equation

HRID 1523346 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.[CH2:25]([N:27]1[CH2:32][CH2:31][N:30]([NH2:33])[CH2:29][CH2:28]1)[CH3:26].C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:33][N:30]3[CH2:31][CH2:32][N:27]([CH2:25][CH3:26])[CH2:28][CH2:29]3)=[O:22])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:23])[F:1])[CH:8]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 111923Propylphosphonic anhydrideHCID 30157254-Ethylpiperazin-1-amineHCID 86703006(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid

Product 1

HCID 71493323(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(4-ethylpiperazin-1-yl)acrylamideYield 18.2%

Reagents, catalysts & solvents 1

HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
-40 °C

Procedure

A cold (−40° C.) solution of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.25 g) in EtOAc (20 mL) was treated with 4-ethylpiperazin-1-amine (0.12 g). T3P (50% in EtOAc, 0.84 mL) and DIPEA (0.24 mL) were added simultaneously and the reaction mixture was stirred for 30 min at −40° C. before being quenched with ice-cold water and extracted with EtOAc (3×20 mL). The combined organic extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure (35° C., 20 mmHg) to afford 0.280 g of crude compound. Purification by combi-flash chromatography (eluting with 2% MeOH in CH2Cl2) followed by purification on a preparative TLC plate (eluting with 10% MeOH in CH2Cl2) afforded 60 mg (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-N-(4-ethylpiperazin-1-yl)acrylamide. 1H NMR (400 MHz, CF3COOD) δ: 10.75 (s, 1H), 8.31-8.29 (d, J=10.2 H), 7.98 (s, 1H), 7.21-7.23 (d, 1H), 6.08-6.10 (d, 1H), 3.52-3.54 (m, 3H), 3.36 (s, 1H), 3.11 (m, 8H), 1.19-1.22 (m, 3H); LCMS for C19H21F6N6O [M+H]+ 463.40. found 463.23 (RT 2.43 min, purity: 98.63%).

Workup

  1. custombefore being quenched with ice-cold water
  2. extractionextracted with EtOAc (3×20 mL)
  3. washThe combined organic extracts were washed with brine
  4. dry with materialdried over anhydrous Na2SO4
  5. concentrationconcentrated under reduced pressure (35° C., 20 mmHg)
  6. customto afford 0.280 g of crude compound
  7. customPurification
  8. washby combi-flash chromatography (eluting with 2% MeOH in CH2Cl2)
  9. customfollowed by purification on a preparative TLC plate (eluting with 10% MeOH in CH2Cl2)

Sources & evidence

ORD record
ord-34e45d7ab34f4194b51c62ca32022654
Source dataset
uspto-grants-2015_07
Patent number
US09079865B2

Reaction notes

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