Diisopropylethylamine → trans-3-(3-Bromophenyl)-1-(4-cyclobutylpiperazin-1-yl)prop-2-en-1-one

HRID 572021Notes

Reaction equation

HRID 572021 reaction equation
[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([OH:12])=O)[CH:5]=[CH:6][CH:7]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[CH:47]1([N:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:50][CH2:49][CH2:48]1>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4](/[CH:8]=[CH:9]/[C:10]([N:54]2[CH2:55][CH2:56][N:51]([CH:47]3[CH2:50][CH2:49][CH2:48]3)[CH2:52][CH2:53]2)=[O:12])[CH:5]=[CH:6][CH:7]=1

Participants

6

Reactant 4

HCID 81531Diisopropylethylamine2×HCID 776461m-Bromocinnamic acidHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 230903791-Cyclobutylpiperazine hydrochloride

Product 1

HCID 57619002trans-3-(3-Bromophenyl)-1-(4-cyclobutylpiperazin-1-yl)prop-2-en-1-oneYield 123.6%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent2×

Procedure

In a 500 mL round bottom flask were added trans-3-(3-bromophenyl)acrylic acid (10.0 g, 44.0 mmol), HATU (20.1 g, 52.9 mmol), anhydrous DMF (130 mL) and DIPEA (18.4 mL, 0.11 mol). This mixture was left stirring for 30 min. 1-cyclobutylpiperazine hydrochloride (10.3 g, 48.5 mmol), DMF (20 mL) and DIPEA (20 mL, 0.11 mol) were added to another flask and the resulting mixture stirred until the solution was homogeneous. The solution containing the amine was added to the first solution dropwise and stirred overnight at RT. The DMF was concentrated in vacuo at 60° C. and the resulting semi-solid was dissolved with EtOAc (800 mL) and NaHCO3 sat. (300 mL). The aq. phase was separated and extracted with EtOAc (3×150 mL). The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting brown oil was purified by flash-chromatography (DCVC) eluting with Hexane/EtOAc/NH4OH 100:0:0 to 0:99:1 to afford 19 g 33A (>100% yield) as a beige solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.62-2.14 (m, 6H) 2.32-2.47 (m, 4H) 2.73-2.86 (m, 1H) 3.58-3.83 (m, 4H) 6.86 (d, J=15.5 Hz, 1H), 7.20-7.28 (m, 1H), 7.44 (dd, J=15.0, 7.9 Hz, 2H), 7.56 (d, J=15.4 Hz, 1H), 7.65 (t, J=1.7 Hz, 1H).

Workup

  1. waitThis mixture was left
  2. stirringthe resulting mixture stirred until the solution
  3. additionwas added to the first solution dropwise
  4. stirringstirred overnight at RT
  5. concentrationThe DMF was concentrated in vacuo at 60° C.
  6. dissolutionthe resulting semi-solid was dissolved with EtOAc (800 mL) and NaHCO3 sat. (300 mL)
  7. customThe aq. phase was separated
  8. extractionextracted with EtOAc (3×150 mL)
  9. dry with materialThe organic phase was dried over anhydrous Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customThe resulting brown oil was purified by flash-chromatography (DCVC)
  13. washeluting with Hexane/EtOAc/NH4OH 100:0:0 to 0:99:1

Sources & evidence

ORD record
ord-788dea5a0a2a4dadbc60524d2f121254
Source dataset
uspto-grants-2015_05
Patent number
US09029381B2

Reaction notes

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