5-CARBOXYOXINDOLE

A suspension of 93 g of 5-chloroacetyl-2-oxindole was stirred in 90 mL pyridine at 80 to 90° C. for 3 hours then cooled to room temperature. The precipitate was collected by vacuum filtration and washed with 20 mL ethanol. The solid was dissolved in 90 mL 2.5N sodium hydroxide and stirred at 70 to 80° C. for 3 hours. The mixture was cooled to room temperature and acidified to pH 2 with 0.5 N hydrochloric acid. The precipitate was collected by vacuum filtration and washed thoroughly with water to give crude 5-carboxy-2-oxindole as a dark brown solid. After standing overnight the filtrate yielded 2 g of 5-carboxy-2-oxindole as a yellow solid. The crude dark brown product was dissolved in hot methanol, the insoluble material removed by filtration and the filtrate concentrated to give 5.6 g of 5-carboxy-2-oxindole as a brown solid. The combined yield was 97percent.A suspension of 9.3 g of 5-chloroacetyl-2-oxindole was stirred in 90 ML pyridine at 80 to 90° C. for 3 hours then cooled to room temperature.. Step 1: A mixture of compound 1 (200 mg, 1.0 mmol) and HC1 (2.0 M in H20, 5 mL) was heated to 100°C for overnight. The mixture was concentrated to get compound 2 (180 mg, 97percent) as light yellow solid.Into a 50-mL round-bottom flask was placed methyl 2-oxo-2, 3-dihydro-1H- indole-5-carboxylate (800 mg, 4.18 mmol, 1.00 equiv) and methanol (10 mL). This was followed by the addition of a solution of NaOH (670 mg, 16.75 mmol, 4.00 equiv) in water (10 mL) dropwise with stirring at 0Step 2: Oxindole-5-carboxylic acidIndole-5-carboxylic acid 5.00g (31.0 mmol) solution in ethanol 99percent 120mL and tert-butanol 180mL in a 1L RB flask was cooled on ice bath to +5 °C. Meanwhile, a solution of lithium bromide 9.0g (103.6 mmol) in neat acetic acid 60mL was placed into an addition funnel. Neat bromine 5.0 mL (16.0g; 100.1 mmol) was then charged to this LiBr solution and the resulting bromine + LiBr solution was dropwise added into the vigorously stirred indolecarboxylic acid solution at +5 °C over a 90 min period. (After a complete addition the addition funnel was then washed with EtOH (2 x 5 mL) and the washings were added to the reaction mix). At the end of the bromine addition the cooling bath was let to expire and the reaction mix was stirred at +5 to +15 °C bath for 1 hour and at 15 °C for additional 15 min. The reaction mixture was then diluted with additional acetic acid lOOmL. Zn dust 20g [Aldrich; <10 μΜ] (306 mmol) was added in one portion (gas evolution) and the mixture was stirred in an open flask on ambient water bath overnight (16 hours). The next day, the precipitated solids were collected by filtration, washed with ethanol and dried by suction. The solid (containing a mix of the product, unreacted Zn metal and Zn salts) was transferred into a large beaker on a hotplate, suspended in boiling methanol (300mL) and filtered. The extraction with boiling methanol was repeated twice more, to separate the unreacted Zn metal from the product. The combined methanolic filtrates were evaporated to dryness. Separately, the acetic acid + LiBr - containing filtrates from the reaction mix were concentrated to a small volume on rotovap and the produced salt-rich residue was diluted with water 0.6L and acidified with 6M HC1 to about pH= 1.5. This mixture was then combined with the evaporation residue obtained from the methanolic filtrates. The solids in the flask were re-suspended by a brief sonication (5 min) and the slurry was cooled down on ice bath, then placed into a freezer (-20 °C) for 4 hours. The precipitated product was collected by filtration, washed with ice-cold water, dried by suction and on highvac. Y=5.23g (95percent) of a light tan solid. 1H-NMR (d6-DMSO, 400MHz): 12.58 (br s, 1H), 10.72(s, 1H), 7.82 (dd, 8.3Hz, 1.6Hz, 1H), 7.75 (s, 1H), 6.88 (d, 8.3Hz, 1H), 3.54 (s, 2H)

Molecular Weight:177.16
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:3
Rotatable Bond Count:1
Exact Mass:177.042593085
Monoisotopic Mass:177.042593085
Topological Polar Surface Area:66.4
Heavy Atom Count:13
Complexity:251
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes