Lithium hydroxide, monohydrate → N-[(1S)-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]-1-methyl-ethyl]prop-2-enamide

HRID 1774649Notes

Reaction equation

HRID 1774649 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][O:33]C(=O)C)=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1.O[Li].O>C1COCC1.CC(O)C.O>[F:1][C:2]1[CH:3]=[C:4]([N:37]2[C:42](=[O:43])[C:41]3[S:44][C:45]4[CH2:50][CH2:49][CH2:48][CH2:47][C:46]=4[C:40]=3[CH:39]=[N:38]2)[C:5]([CH2:32][OH:33])=[C:6]([C:8]2[CH:9]=[C:10]([NH:16][C:17]3[N:22]=[C:21]([O:23][CH2:24][C@@H:25]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])[CH3:26])[CH:20]=[CH:19][CH:18]=3)[C:11](=[O:15])[N:12]([CH3:14])[CH:13]=2)[CH:7]=1

Participants

6

Reactant 2

HCID 168937Lithium hydroxide, monohydrateHCID 118117062N-[(1S)-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]-1-methyl-ethyl]prop-2-enamide

Product 1

HCID 118116785N-[(1S)-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]-1-methyl-ethyl]prop-2-enamideYield 30.5%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 3776IsopropanolSolventHCID 8028TetrahydrofuranSolvent

Procedure

To a mixture of 108d (70 mg, 0.1 mmol) in THF (6 mL), i-PrOH (2 mL) and H2O (2 mL) was added LiOH.H2O (42 mg, 1 mmol). The reaction mixture was stirred at rt for 16 h and concentrated. The residue was purified by prep-HPLC to give 108 (20 mg, 8% for two steps) as yellow solid. 1H NMR (500 MHz, DMSO-d6): δ 8.61 (d, J=10 Hz, 2H), 8.49 (s, 1H), 8.04-8.03 (m, 1H), 7.52-7.50 (m, 2H), 7.40-7.35 (m, 2H), 6.87 (d, J=8 Hz, 1H), 6.21-6.15 (m, 2H), 6.05-6.02 (m, 1H), 5.54 (d, J=10 Hz, 1H), 4.73 (bs, 1H), 4.30 (bs, 2H), 4.15 (bs, 2H), 4.02 (bs, 1H), 3.61 (s, 3H), 2.93 (bs, 2H), 2.84 (bs, 2H), 1.86 (bs, 4H), 0.97 (bs, 3H). ESI-LCMS: m/z=657.3 [C34H33FN6O5S+H]+

Workup

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

Sources & evidence

ORD record
ord-1180d5aac62c498891cbd99ef0933430
Source dataset
uspto-grants-2016_02
Patent number
US09260415B2

Reaction notes

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