Diisopropylethylamine → (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide

HRID 632635Notes

Reaction equation

HRID 632635 reaction equation
[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28](O)=[O:29])=[CH:22][CH:21]=2)=[C:4]([CH3:31])[CH:3]=1.[O:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH:33]1[O:38][NH2:39].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>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:21]=[CH:22][C:23](/[CH:26]=[CH:27]/[C:28]([NH:39][O:38][CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37][O:32]3)=[O:29])=[CH:24][CH:25]=2)=[C:4]([CH3:31])[CH:3]=1

Participants

6

Reactant 4

HCID 81531DiisopropylethylamineHCID 5142091O-(Tetrahydropyran-2-yl)hydroxylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 86730646(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid

Product 1

HCID 86730650(E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamideYield 86.1%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

To a 30 mL screw cap vial, (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (50 mg, 0.115 mmol) was dissolved in DMF (2 mL). The vial was charged with O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (27.0 mg, 0.230 mmol), HATU (65.6 mg, 0.173 mmol), and DIEA (0.060 mL, 0.345 mmol). The reaction mixture was stirred for 30 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by column chromatography (SiO2, 1-80% Heptanes/EtOAc) to afford (E)-3-(4-((2-(4-fluoro-2-methylphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)-N-((tetrahydro-2H-pyran-2-yl)oxy)acrylamide (53 mg, 0.099 mmol, 86% yield). 1H NMR (400 MHz, CD3OD) δ ppm=1.48-1.73 (m, 3 H), 1.73-1.96 (m, 3 H), 2.36 (s, 3 H), 3.56-3.70 (m, 1 H), 3.89 (s, 3 H), 3.98-4.14 (m, 1 H), 4.96 (br. s., 1H), 6.35 (d, J=15.66 Hz, 1 H), 6.79-6.95 (m, 3 H), 6.95-7.07 (m, 2 H), 7.26-7.39 (m, 2 H), 7.39-7.48 (m, 3 H), 7.52 (d, J=16.17 Hz, 1 H), LC/MS (m/z, MH+): 534.1.

Workup

  1. customTo a 30 mL screw cap vial
  2. customThe reaction was quenched with sat. NH4Cl
  3. additiondiluted with DCM
  4. customThe organic phase was collected (phase separator)
  5. concentrationconcentrated by vacuum
  6. customto afford to crude product
  7. customThe crude material was purified by column chromatography (SiO2, 1-80% Heptanes/EtOAc)

Sources & evidence

ORD record
ord-6169a5240be84c5381c839ea8ded048f
Source dataset
uspto-grants-2016_04
Patent number
US09321746B2

Reaction notes

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