p-Toluenesulfonic acid monohydrate → (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

HRID 1847930Notes

Reaction equation

HRID 1847930 reaction equation
[F:1][C:2]1([F:41])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]4[CH2:32][O:31]C(C)(C)[O:29]4)[C:21]([C:35]([CH3:40])([CH2:37][CH2:38][OH:39])[CH3:36])=[CH:20]5)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.FC1(F)OC2C=CC(C3(C(NC4C=C5C(=CC=4F)NC(C(C)(CCO)C)=C5)=O)CC3)=CC=2O1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CO.O>[F:41][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][C:25]=4[F:26])[N:22]([CH2:27][C@@H:28]([OH:29])[CH2:32][OH:31])[C:21]([C:35]([CH3:36])([CH2:37][CH2:38][OH:39])[CH3:40])=[CH:20]5)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1

Participants

6

Reactant 3

HCID 521998p-Toluenesulfonic acid monohydrateHCID 591295491-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamideHCID 67044201(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide

Product 1

HCID 46199644(R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamideYield 31%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
80 °C

Procedure

To a solution of (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide containing some 1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (315 mg, 0.55 mmol) in methanol (3 mL) and water (0.3 mL) was added p-TsOH.H2O (21 mg, 0.11 mmol). The mixture was heated at 80° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water and the aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with saturated. NaHCO3 solution and brine and dried over MgSO4. After the removal of solvent, the residue was purified by column chromatography (20-80% ethyl acetate-hexanes) to provide (R)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)-N-(1-(2,3-dihydroxypropyl)-6-fluoro-2-(4-hydroxy-2-methylbutan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (92 mg, 31%). ESI-MS m/z calc. 534.2. found 535.5 (M+1)+. Retention time 1.72 minutes. 1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 7.53 (d, J=1.0 Hz, 1H), 7.43-7.31 (m, 4H), 6.17 (s, 1H), 4.97-4.92 (m, 2H), 4.41 (dd, J=2.4, 15.0 Hz, 1H), 4.23 (t, J=5.0 Hz, 1H), 4.08 (dd, J=8.6, 15.1 Hz, 1H), 3.87 (s, 1H), 3.48-3.44 (m, 1H), 3.41-3.33 (m, 1H), 3.20 (dd, J=7.4, 12.7 Hz, 2H), 1.94-1.90 (m, 2H), 1.48-1.45 (m, 2H), 1.42 (s, 3H), 1.41 (s, 3H) and 1.15-1.12 (m, 2H) ppm.

Workup

  1. customThe reaction was partitioned between ethyl acetate and water
  2. extractionthe aqueous layer was extracted with ethyl acetate twice
  3. washThe combined organic layers were washed with saturated
  4. dry with materialNaHCO3 solution and brine and dried over MgSO4
  5. customAfter the removal of solvent
  6. customthe residue was purified by column chromatography (20-80% ethyl acetate-hexanes)

Sources & evidence

ORD record
ord-1aaac237b45d4b05ac80c54bcff9f939
Source dataset
uspto-grants-2015_02
Patent number
US08952049B2

Reaction notes

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