4-Methylmorpholine → (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide

HRID 632699Notes

Reaction equation

HRID 632699 reaction equation
[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19](O)=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1.[CH3:30][N:31](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.CN.CN1CCOCC1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([O:10][C:11]3[CH:12]=[CH:13][C:14](/[CH:17]=[CH:18]/[C:19]([NH:31][CH3:30])=[O:20])=[N:15][CH:16]=3)=[C:8]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[S:7][C:6]=2[CH:29]=1

Participants

6

Reactant 4

HCID 79724-MethylmorpholineHCID 6364545Methylamine hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 136213601(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid

Product 1

HCID 136213605(E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamideYield 37%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a solution of (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)acrylic acid (0.057 g, 0.14 mmol) in DMF (1.406 mL) was added HATU (0.064 g, 0.17 mmol), methylamine hydrochloride (10.45 mg, 0.16 mmol) and NMM (0.077 mL, 0.70 mmol). The resulting mixture was stirred at room temperature for 48 h after which time the reaction was quenched with sat. aq. NH4Cl and extracted with EtOAc (3×). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the crude product which was purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O) to afford (E)-3-(5-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)pyridin-2-yl)-N-methylacrylamide (30 mg, 0.05 mmol 37% yield). 1H NMR (400 MHz, (CD3)2SO) δ ppm=2.67-2.72 (m, 3 H), 6.77-6.90 (m, 4 H), 7.14-7.23 (m, 2 H), 7.30 (d, J=2.02 Hz, 1 H), 7.36 (d, J=15.16 Hz, 1 H), 7.44-7.51 (m, 3 H), 8.42 (d, J=3.03 Hz, 1 H), LC/MS (m/z, MH+): 419.3.

Workup

  1. customwas quenched with sat. aq. NH4Cl
  2. extractionextracted with EtOAc (3×)
  3. concentrationconcentrated in vacuo
  4. customto afford the crude product which
  5. customwas purified by reverse phase HPLC (acidic condition, 3% TFA in 10-100% CH3CN/H2O)

Sources & evidence

ORD record
ord-b6aaf771f935433a9e403b9815d8a6a7
Source dataset
uspto-grants-2016_04
Patent number
US09321746B2

Reaction notes

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