Sodium Hydroxide → 2,6-Difluorobenzenesulfonic acid 7-methyl-3-(1-methylpiperidin-4-yl)-1H-indol-5-yl ester

HRID 1766270Notes

Reaction equation

HRID 1766270 reaction equation
[CH3:1][C:2]1[CH:3]=[C:4]([OH:18])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[OH-:19].[Na+].[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29](Cl)(=[O:31])=[O:30]>O1CCCC1>[CH3:1][C:2]1[CH:3]=[C:4]([O:18][S:29]([C:23]2[C:24]([F:28])=[CH:25][CH:26]=[CH:27][C:22]=2[F:21])(=[O:31])=[O:30])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:23]=1[S:29]([OH:31])(=[O:30])=[O:19]

Participants

6

Reactant 3

HCID 14798Sodium HydroxideHCID 27342712,6-Difluorobenzenesulfonyl chlorideHCID 179800997-Methyl-3-(1-methylpiperidin-4-yl)-1H-indole-5-ol

Product 2

HCID 102956402,6-Difluorobenzenesulfonic acid 7-methyl-3-(1-methylpiperidin-4-yl)-1H-indol-5-yl esterHCID 14766952Dabrafenib Impurity 8

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

By a method similar to Example 31, using 7-methyl-3-(1-methylpiperidin-4-yl)-1H-indole-5-ol (3.1 mmol, 0.756 g), tetrahydrofuran (10 mL),0.2N sodium hydroxide (3.1 mmol, 15.5 mL) and 2,6-difluorobenzenesulfonyl chloride (3.7 mmol,0.7895 g) in tetrahydrofuran (10 mL) afforded the title compound as a fractional salt of 2,6-difluorobenzene sulfonic acid. The material was dissolved in methanol and 5N sodium hydroxide (1 eq) was added. The mixture was then applied to a Mega Bond Elute SCX column. The column was treated with one column volume of the following: methylene chloride, methanol, 3:1 methylene chloride:methanol. The product was eluted with 3:1 methylene chloride: 2M ammonium in methanol. Fractions containing the title compound were concentrated in vacuo to an oil. The oil was dissolved in diethyl ether, then placed in freezer (approximately −4° C.). The resulting crystals were collected by filtration to afford 0.296 g of the title compound. The filtrate was concentrated in vacuo and resubjected to SCX chromatography as described above. An additional 0.313 g of material was collected. A total of 0.609 g (47%) of the title compound was isolated: MS (ion spray): m/z=421(M+1); 1H NMR (DMSOd6): 11.04 (s, 1H), 7.90 (m, 1H), 7.40 (m, 2H), 7.16 (1H), 6.88 (1H), 6.69 (1H), 2.78 (m, 2H), 2.54 (m, 1H), 2.39 (s, 3H), 2.19 (s, 3H), 1.94 (m, 2H), 1.65 (m, 2H), 1.51 (m, 2H); Calculated for C21H22F2N2O3S: C, 59.99; H, 5.27; N, 6.66. Found: C, 59.96; H, 5.21; N, 6.65.

Sources & evidence

ORD record
ord-3cfebb38c7204fdda4f819e141dd2f8e
Source dataset
uspto-grants-2007_06
Patent number
US07230011B2

Reaction notes

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