Diisopropylethylamine → (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide

HRID 632698Notes

Reaction equation

HRID 632698 reaction equation
[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1.Cl.CN.[CH3:36][N:37](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:16]=[CH:15][C:14](/[CH:17]=[CH:18]/[C:19]([NH:37][CH3:36])=[O:20])=[CH:13][CH:12]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:32]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 6364545Methylamine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 78322700(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid

Product 1

HCID 78324257(E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamideYield 84%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a vial containing (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)-benzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (15.9 mg, 0.035 mmol) was added DMF (1.0 mL), followed by methylamine hydrochloride (7.1 mg, 0.105 mmol), HATU (19.9 mg, 0.052 mmol), and DIEA (0.030 mL, 0.174 mmol). The mixture was stirred at room temperature for 12 h after which the reaction was quenched with water and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give the crude product which was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((6-hydroxy-2-(4-(trifluoromethyl)phenyl)benzo[b]thiophen-3-yl)oxy)phenyl)-N-methylacrylamide (13.8 mg, 0.029 mmol, 84% yield). 1H NMR (400 MHz, CD3OD) δ ppm=2.82 (s, 3 H), 6.43 (d, J=15.66 Hz, 1 H), 6.82 (dd, J=8.59, 2.02 Hz, 1 H), 6.89-7.02 (m, 2 H), 7.13-7.30 (m, 2 H), 7.37-7.52 (m, 3 H), 7.61 (d, J=8.08 Hz, 2 H), 7.85 (d, J=8.08 Hz, 2 H). HRMS (m/z, MH+): 470.1018.

Workup

  1. customwas quenched with water
  2. extractionextracted with EtOAc
  3. dry with materialThe combined organic layers were dried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customto give the crude product which
  7. customwas purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O)

Sources & evidence

ORD record
ord-ac5031d9b29b416b970d8305352610ec
Source dataset
uspto-grants-2016_04
Patent number
US09321746B2

Reaction notes

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