Potassium Hydroxide → (S)-7-Cyano-4-((3-hydroxypyridin-4-yl)methyl)-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester

Participants

Reaction Conditions

Reaction Steps

A mixture of (S)-4-((3-bromopyridin-4-yl)methyl)-7-cyano-1,2,3,4-tetrahydrocyclopenta[b]indol-2-ylcarbamic acid isopropyl ester (3.81 g, 7.05 mmol), potassium hydroxide (1.34 g, 23.9 mmol), 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol), tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) in water (50 mL) and 1,4-dioxane (50 mL) is heated at 100° C. for one hour. Tris(dibenzylideneacetone)dipalladium (110 mg, 120 μmol) and 2-di-tert-butylphosphino-3,4,5,6-tetramethyl-2′,4′,6′-triisopropyl-1,1′-biphenyl (230 mg, 479 μmol) are added and the mixture is heated for 3 h. The reaction is diluted with water and dichloromethane. The layers are then separated and the aqueous layer is washed with dichloromethane twice. The aqueous portion is acidified to pH 1-2 with a few drops of 5 M HCl and then neutralized to pH 7 with potassium carbonate. Ethyl acetate is added and the bi-layer is filtered. The organic phase is separated, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to obtain a brown residue. The residue is triturated with ether twice and dried under vacuum. It is then purified by flash chromatography eluting with 1% to 6% methanol in chloroform to obtain impure product (˜2.8 g). It is purified by preparative super critical fluid chromatography (column: ethylpyridine 20×150 mm (Princeton Chromatography, Inc.); flow rate: 70 mL/min @ 35° C. and 100 psi; eluent: 5-50% MeOH with 0.1% isopropylamine:carbon dioxide) to obtain the title compound as a white solid (548 mg, 20%). LC-ES/MS m/z 391.2 [M+H]+, TR=2.63 min.

Provenance & Evidence