Hydrochloric Acid → 6-methoxy-1H-indole-2-carboxylic acid

HRID 392766

Reaction equation

HRID 392766 reaction equation
C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([O:15][CH3:16])[CH:9]=2)=[O:5])C.[OH-].[Li+].Cl>C1COCC1.O>[CH3:16][O:15][C:10]1[CH:9]=[C:8]2[C:13]([CH:14]=[C:6]([C:4]([OH:5])=[O:3])[NH:7]2)=[CH:12][CH:11]=1

Participants

6

Reactant 3

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 612959Ethyl 6-methoxy-1H-indole-2-carboxylate

Product 1

HCID 4103276-methoxy-1H-indole-2-carboxylic acidYield 105.5%

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 8028TetrahydrofuranSolvent

Procedure

6-Methoxy-1H-indole-2-carboxylic acid ethyl ester (5.0 g) was treated with lithium hydroxide (2.33 g) in THF (90 mL) followed by water (30 mL) and stirred at ambient temperature for 16 h. The solution was acidified with 10% hydrochloric acid, diluted with water and extracted with ethyl acetate. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford 6-Methoxy-1H-indole-2-carboxylic acid (4.60 g). This material (4.64 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL) were treated with N-methylpiperazine (3.23 mL) and stirred at ambient temperature for 16 h. The reaction mixture was poured into dichloromethane (200 mL), washed with water, saturated sodium hydrogencarbonate solution and then brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give (6-Methoxy-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (6.60 g). This material (0.16 g) was dissolved in dichloromethane (10 mL). At room temperature, 1 M boron tribromide (1.5 mL) was added dropwise. The reaction mixture was heated to reflux overnight, and then cooled, quenched with saturated sodium hydrogencarbonate solution, and extracted with dichloromethane. The organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified via silica gel chromatography (0-10% 2 M ammonia in methanol/dichloromethane) to give the title compound (0.12 g). 1H NMR (400 MHz, CDCl3/CD3OD): δ 7.22 (d, J=8.41 Hz, 1H), 6.62 (d, J=2.15 Hz, 1H), 6.5′-6.47 (m, 2H), 3.69 (br s, 4H), 2.30 (t, J=5.09 Hz, 4H), 2.13 (s, 3H). MS (electrospray): exact mass calculated for C14H17N3O2, 259.13; m/z found, 260.1 [M+H]+.

Workup

  1. extractionextracted with ethyl acetate
  2. washThe organic extracts were washed with brine
  3. dry with materialdried over sodium sulfate
  4. filtrationfiltered
  5. concentrationconcentrated

Sources & evidence

ORD record
ord-0a2ddf514e334860a0fcd3b939324804
Source dataset
uspto-grants-2004_10
Patent number
US06803362B2

Linked notes

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