2-Bromobutanoic acid → 2-[2-[5-(4-Chlorobenzyl)-2-methyl-8-(5-phenylpyridin-2-ylmethoxy)-3,5-dihydro-2H-thiopyrano[4,3,2-cd]indol-4-yl]ethoxy]butyric acid

Participants

Reaction Steps

To a solution of product from Step 6 (130 mg, 0.23 mmol) in THF (2 mL) there was added 97% NaH (23 mg, 1 mmol) and the mixture was stirred at r.t. for 15 min. There was added a solution of 2-bromobutyric acid (84 mg, 0.5 mmol) in THF (1.5 mL) and the mixture was refluxed for 20 hours. After cooling, there was added more NaH (46 mg) and 2-bromobutyric acid (170 mg) and the mixture was refluxed for a further 24 hours. The cooled mixture was diluted with H2O, made strongly basic with 1N aq NaOH, and extracted twice with Et2O. The aqueous fraction was then acidified with 1N HCl and extracted 3× with EtOAc. The crude product thus obtained was purified by esterification with ethereal diazomethane and the resulting ester chromatographed on preparative TLC silica gel plates, eluting with a 1:4 mixture of EtOAc and toluene. After extraction of the silica with EtOAc, the purified ester (54 mg) was hydrolyzed. It was dissolved in THF (1.5 mL) and MeOH (1.5 mL) and there was added 1M aq LiOH (0.8 mL). The mixture was heated to 50° C. for 30 min., then the organic solvents were evaporated. The residue was diluted with H2O (4 mL) and centrifuged. The supernatant was decanted and the insoluble lithium salt was suspended in H2O (4 mL). The mixture was acidified with 1N aq HCl, stirred vigorously and filtered to afford the title compound as a light yellow solid; m.p. 159°-162° C.

Provenance & Evidence