2-Methyl-2-butene → 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carboxylic acid

HRID 338429Notes

Reaction equation

HRID 338429 reaction equation
[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:15][CH:14]=1.CC(=CC)C.Cl([O-])=[O:34].[Na+].P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].S([O-])([O-])=O.[Na+].[Na+]>C(#N)C.C(O)(C)(C)C.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:34])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:23][CH2:22][CH2:21][N:20]2[S:24]([CH3:27])(=[O:26])=[O:25])=[CH:15][CH:14]=1

Participants

8

Reactant 5

HCID 105532-Methyl-2-butene2×HCID 24243Trisodium Phosphate2×HCID 24437Sodium SulfiteHCID 23668197Sodium Chlorite2×HCID 866987616-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carbaldehyde

Product 1

HCID 866987626-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carboxylic acidYield 51.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent3×HCID 22050040Acetonitrile tert-butanolSolvent

Conditions

Temperature
0 °C

Procedure

To a mixture of 6-chloro-5-{4-[1-(methylsulfonyl)pyrrolidin-2-yl]phenyl}-1H-indole-3-carbaldehyde (75 mg, 0.19 mmol) in acetonitrile/t-butanol (4.5 mL/4.5 mL) was added 2-methyl-2-butene (3.00 mL, 28.2 mmol). The reaction mixture was cooled to 0° C. followed by the addition of an aqueous solution of sodium chlorite (377 mg, 5.58 mmol) and sodium phosphate (monobasic and monohydrate, 770 mg, 5.58 mmol) in water (9 mL) dropwise via additional funnel. The ice bath was removed and the reaction was stirred at room temperature overnight. The following morning, 2-methyl-2-butene (1.50 mL, 14.1 mmol) and an aqueous solution of sodium chlorite (125 mg, 1.86 mmol) and sodium phosphate (monobasic and monohydrate, 257 mg, 1.86 mmol) in water (3 mL) was added in a dropwise manner. The reaction was allowed to stir overnight at room temperature. The reaction was quenched with sodium sulfite (940 mg, 7.44 mmol) in water (3 mL). The reaction mixture was concentrated under reduced pressure to remove the volatile organics. The aqueous layer was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by reverse phase HPLC to give the desired product (40.1 mg, 51.2% yield). MS (ES+) 441.0 (M+Na)+. 1H NMR (400 MHz, DMSO-d6) δ 11.95 (s, 1H), 8.07 (s, 1H), 7.95 (s, 1H), 7.64 (s, 1H), 7.40 (m, 4H), 4.94-4.91 (m, 1H), 3.51-3.49 (s, 2H), 2.95 (s, 3H), 2.40-2.30 (m, 1H), 1.91-1.86 (m, 3H).

Workup

  1. customThe ice bath was removed
  2. stirringto stir overnight at room temperature
  3. concentrationThe reaction mixture was concentrated under reduced pressure
  4. customto remove the volatile organics
  5. extractionThe aqueous layer was extracted three times with ethyl acetate
  6. dry with materialThe combined organic layers were dried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe resulting residue was purified by reverse phase HPLC

Sources & evidence

ORD record
ord-654a16c226fb4c57aeda1510fa003f48
Source dataset
uspto-grants-2014_11
Patent number
US08889730B2

Reaction notes

Loading…