Sodium Hydroxide → Ivacaftor carboxylate

HRID 1617303Notes

Reaction equation

[C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]2[O:12][C:11](=[O:13])[C:10]([CH3:15])([CH3:14])[C:9]=2[CH:16]=1)([CH3:4])([CH3:3])[CH3:2].[OH-:31].[Na+]>CO>[C:1]([C:5]1[C:6]([NH:17][C:18]([C:20]2[C:29](=[O:30])[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[NH:22][CH:21]=2)=[O:19])=[CH:7][C:8]([OH:31])=[C:9]([C:10]([CH3:15])([CH3:14])[C:11]([OH:12])=[O:13])[CH:16]=1)([CH3:4])([CH3:2])[CH3:3]

Participants

Conditions

Temperature: 40 °C

Procedure

To a stirred solution of compound 21 (0.9 g, 2.45 mmol) in MeOH (50 mL) was added NaOH (1.5 g, 37.5 mmol) at 0° C. After stirring for 16 hours at 40° C., the solvent was evaporated in vacuo, then the residue was dissolved in H2O (50 ml). The precipitate was filtered and the filtrate was washed with DCM (100 mL×1) and ethyl acetate (100 mL×1). The aqueous layer was acidified with 2N HCl to pH 1-2. The precipitate was filtered and washed with H2O (80 mL) and heptane (50 mL). It was dried in vacuo to give compound 28 as a white solid. 1H NMR (DMSO-d6; 400 MHz) δ 12.85 (s), δ 11.84 (s), δ 11.77 (s), δ 9.39 (s), δ 8.86 (s), δ 8.33 (s), δ 7.79 (m), δ 7.52 (m), δ 7.18 (s), δ 7.09 (s), δ 1.44 (s), δ 1.40 (s). MS found (M+H) 423.08.

Workup

customthe solvent was evaporated in vacuo
dissolutionthe residue was dissolved in H2O (50 ml)
filtrationThe precipitate was filtered
washthe filtrate was washed with DCM (100 mL×1) and ethyl acetate (100 mL×1)
filtrationThe precipitate was filtered
washwashed with H2O (80 mL) and heptane (50 mL)
customIt was dried in vacuo

Sources & evidence

ORD record: ord-4420f905982e4d9ea95957906d64e199
Source dataset: uspto-grants-2014_07
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08765957B2

Reaction notes

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