6-METHOXY-1H-INDOLE-2-CARBOXYLIC ACID Chemical Properties

Melting point:

198-203℃

Boiling point:

447.6±25.0 °C(Predicted)

Density 

1.381±0.06 g/cm3(Predicted)

storage temp. 

Sealed in dry,Room Temperature

solubility 

DMSO (Slightly)

pka

4.54±0.30(Predicted)

form 

Solid

color 

Light Pink

InChIKey

XNBGANWAZJWOHS-UHFFFAOYSA-N

CAS DataBase Reference

16732-73-3(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

36/37/38

Safety Statements 

26

WGK Germany 

3

HazardClass 

IRRITANT

HS Code 

2933998090

6-METHOXY-1H-INDOLE-2-CARBOXYLIC ACID Usage And Synthesis

Uses

• ;Reactant for demethylation reactions using ionic liquids under microwave irradiation1• ;Reactant for preparation of pyrazinoindoledione via Ugi reaction and microwave-assisted cyclization2• ;Reactant for preparation of isoquinolinecarboxamides and their derivatives as opioid receptor antagonists3• ;Synthetic intermediate for preparation of indole fatty alcohol derivatives4• ;Reactant for preparation of acylaminoalkylindoles as MT2-selective melatonin antagonists5

Uses

• Reactant for demethylation reactions using ionic liquids under microwave irradiation
• Reactant for preparation of pyrazinoindoledione via Ugi reaction and microwave-assisted cyclization
• Reactant for preparation of isoquinolinecarboxamides and their derivatives as opioid receptor antagonists
• Synthetic intermediate for preparation of indole fatty alcohol derivatives
• Reactant for preparation of acylaminoalkylindoles as MT2-selective melatonin antagonists

Synthesis

Ethyl 6-methoxy-1H-indole-2-carboxylate (5.0 g) was dissolved in tetrahydrofuran (90 mL), lithium hydroxide (2.33 g) and water (30 mL) were added and the reaction was stirred for 16 hours at room temperature. After completion of the reaction, the reaction mixture was acidified with 10% hydrochloric acid solution, diluted with water and subsequently extracted with ethyl acetate. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give 6-methoxy-1H-indole-2-carboxylic acid (4.60 g). The resulting carboxylic acid (4.64 g) was dissolved with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.60 g) in dichloromethane (200 mL), N-methylpiperazine (3.23 mL) was added, and the reaction was stirred for 16 hours at room temperature. The reaction mixture was diluted with dichloromethane (200 mL), washed sequentially with water, saturated sodium bicarbonate solution and brine, the organic phase was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% 2M ammonia in methanol solution/dichloromethane) to give (6-methoxy-1H-indol-2-yl)-(4-methylpiperazin-1-yl)-methanone (6.60 g). The product (0.16 g) was dissolved in dichloromethane (10 mL) and 1M boron tribromide solution (1.5 mL) was added slowly and dropwise at room temperature, followed by heating the reaction mixture to reflux overnight. After cooling, the reaction was quenched with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 0-10% 2M ammonia in methanol solution/dichloromethane) to give 6-methoxyindole-2-carboxylic acid as final product.

References

[1] Patent: US2003/207893, 2003, A1
[2] Patent: WO2004/22061, 2004, A1. Location in patent: Page/Page column 71
[3] Patent: EP1373204, 2016, B1. Location in patent: Paragraph 0216
[4] Bioorganic and Medicinal Chemistry Letters, 2017, vol. 27, # 9, p. 1943 - 1948
[5] Patent: CN106478606, 2017, A. Location in patent: Paragraph 0122; 0123; 0128; 0129

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