Lithium hydroxide, monohydrate → 2-cyano-N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide

HRID 1774669Notes

Reaction equation

HRID 1774669 reaction equation
[C:1]([C:3](=[CH2:51])[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:18](=[O:50])[N:19]([CH3:49])[CH:20]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([N:30]4[C:35](=[O:36])[C:34]5[S:37][C:38]6[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=6[C:33]=5[CH:32]=[N:31]4)[C:24]=3[CH2:44][O:45]C(=O)C)[CH:22]=2)[N:11]=1)=[O:5])#[N:2].O[Li].O>C1COCC1.O>[C:1]([C:3](=[CH2:51])[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:18](=[O:50])[N:19]([CH3:49])[CH:20]=[C:21]([C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([N:30]4[C:35](=[O:36])[C:34]5[S:37][C:38]6[CH2:43][CH2:42][CH2:41][CH2:40][C:39]=6[C:33]=5[CH:32]=[N:31]4)[C:24]=3[CH2:44][OH:45])[CH:22]=2)[N:11]=1)=[O:5])#[N:2]

Participants

5

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 1181169742-cyano-N-[2-[[6-[[5-[5-fluoro-2-(acetoxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamide

Product 1

HCID 1181166142-cyano-N-[2-[[6-[[5-[5-fluoro-2-(hydroxymethyl)-3-(4-oxo-6,7,8,9-tetrahydrobenzothiopheno[2,3-d]pyridazin-3-yl)phenyl]-1-methyl-2-oxo-3-pyridyl]amino]-2-pyridyl]oxy]ethyl]prop-2-enamideYield 16%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of 117b (80 mg, 0.112 mmol) in THF (5 mL) was added LiOH.H2O (10 mg, 0.224 mmol) in H2O (5 mL) to pH 10-11. The reaction mixture was stirred at rt for 4 h and concentrated. The residue was purified by prep-HPLC to give 117 (12 mg, 16%) as white solid. The amide bond was partially cleaved under basic conditions. 1H NMR (500 MHz, CDCl3): δ8.57 (s, 1H), 8.29 (s, 1H), 7.99 (bs, 1H), 7.49 (t, J=8 Hz, 2H), 7.26-7.24 (m, 1H), 7.12 (d, J=10 Hz, 1H), 6.48 (d, J=8 Hz, 1H), 6.26 (d, J=8 Hz, 1H), 4.41 (t, J=5 Hz, 2H), 4.31 (bs, 2H), 4.00-3.98 (m, 1H), 3.72 (s, 3H), 3.63 (t, J=5.5 Hz, 1H), 3.58-2.56 (m, 1H), 2.99 (t, J=5 Hz, 2H), 2.87 (t, J=5 Hz, 2H), 2.00-1.96 (m, 4H). ESI-LCMS: m/z=668.0 [C34H30FN7O5S+H]+

Workup

  1. concentrationconcentrated
  2. customThe residue was purified by prep-HPLC

Sources & evidence

ORD record
ord-c41833c3dd7e4837a92af211a64f13c6
Source dataset
uspto-grants-2016_02
Patent number
US09260415B2

Reaction notes

Loading…