2-aMino-5-cyanobenzoic acid

Pale yellow solid

To a slurry of methyl 2-amino-5-cyanobenzoate (9.55 g, 54.2 mmol) in methanol (200 [ML)] was added aqueous sodium hydroxide (30 mL, 6.0 molar, [180] mmol). This mixture was stirred at room temperature and became a solution after 1 hour. After a total of 27.5 hours, the solvent was evaporated, and the residue was dissolved in water (300 mL). This solution was washed with methylene chloride (2 X 200 [ML)] and then acidified with concentrated [HC1.] The product was extracted into ethyl acetate (500 mL). The organics were dried over MgS04 and evaporated leaving the product as 8.57 g (97.5percent) of yellow solid that was used without further purification.2-amino-5-cyanobenzoic acid. To a solution of methyl 2-amino-5- cyanobenzoate (0.120 g, 0.68 mmol) in THF (3.5 ml), was added a solution of lithium hydroxide (0.033 g, 1.36 mol, 2.0 eq) in HMethyl [2-AMINO-5-CYANOBENZOATE] (5.0 g, 28.41 mmol) was dissolved in MeOH (105 mL). Then 6M [NAOH] (14 mL) was added. The resulting mixture was stirred at RT O/N. The reaction mixture was diluted with H20 (143 mL), washed with DCM to remove any unreacted S. M. The product was precipitated from aqueous layer by addition of conc. [HC1] to pH 1 and extracted with EtOAc (3 x 100 mL). The combined organic layers were dried over MgS04 Solid was removed by filtration, and filtrate was concentrated to dryness under reduced pressure. The light yellow product was obtained in the yield of 94percent. [APOS;H NMR] (300 MHz, DMSO-d6) 8 8.08 (d, 1H), 7.56 (dd, [1H), ] 7.50 (br), 6.85 (d, 1H).To a 3-L, three-necked, round bottom flask equipped with a reflux condenser was added methyl-2-amino-5-bromobenzoate (7, 125 g, 543 mmol), copper cyanide (56.2 g, 624 mmol), and NMP (1 L). The reaction was heated to [200 °C] and stirred for 4 h under nitrogen. The dark brown reaction mixture was allowed to cool and a brown precipitate was formed. The mixture was poured into a 16-L beaker containing sodium cyanide solution (1 kg [NACN] in 6 L H20) followed by the addition [OF ETOAC] (4 L). The precipitate was dissolved by agitation and the layers were separated. The aqueous layer was extracted with EtOAc (2 x 1.5 L) and the combined organic layers were washed with 10percent [NACN] solution (2 L), H20 (2 L) and then dried [OVER MGS04.] The light brown solution was concentrated and then dried in a vacuum oven overnight. The ester was then dissolved in [ETOH] (2 L) and added to a 3-L round bottom flask followed by KOH solution (96.7 g of KOH in 500 mL [H20).] The reaction mixture was heated to 50 [°C] and stirred for 2 h. The resultant dark-brown solution was poured into a chilled 2 N HC1 solution (1.5 L), creating a yellowish precipitate. The solid was collected on a sintered glass filter frit, washed with cold water, and dried at [35 °C] in a vacuum oven overnight to give 64.0 g (73percent) of [5-CYANOANTHRANILIC] acid [: LH] NMR (DMSO-d6) 8 7.16 (d, J= 8.7, 1H), 7.79 (dd, J= 2.5, 8.7, 1H), 7.87 (d, J= 2.4, 1H)2-araino-5-broraobenzoic acid (2, 31 mmol) and CuCN (2.78 mmol) were heated to reflux in NMP (5 ml, ) for 3 h. The reaction mixture was poured into a solution of FeC-3 3H2-amino-5-cyanobenzoic [00144] 2-amino-5-bromobenzoic acid (2.31 mmol) and CuCN (2.78 mmol) were heated to reflux in NMP (5 mL) for 3 h. The reaction mixture was poured into a solution of FeClCompound 363 (6) (100 mg, 0.62 mmol) was mixedwith aniline (7) (68 mg, 0.75 mmol), DMSO (0.5 mL), and a catalyticamount of DMAP (3 mg) in a microwave glass vial that was irradiated ina microwave apparatus (LABMAT) at 130 C, 250W for 30 min. Afterthe reaction mixture was cooled to ambient temperature, the purplebrown reaction mixture was diluted with ethyl acetate and sonicated todissolve the entire residue. The organic fraction was washed with water(3×10 mL), dried over MgSO4, filtered, and evaporated to give thecrude product. Flash chromatography [eluted with hexane: Ethylacetate (8:2)] afforded 8 (130 mg, 89%) as pale yellow powder. 1HNMR (D4-MeOH) delta (ppm) 8.04 (d, 1H, J=1.8 Hz), 7.66 (d, 2H, J=8.4 Hz), 7.50 and 7.48 (dd, 1H, J=1.8 Hz and J=9.0 Hz), 7.37 (t, 2H, J=7.2 Hz and J=7.8 Hz), 7.17 (t, 1H, J=8.4 Hz, J=7.2 Hz), 6.86 (d, 1H, J=9.0 Hz). (6, Scheme II ) (100 mg, 0.62mmol) was mixed with aniline (69mg, 0.74mmol), DMSO (0.5mL), and catalytic amount of DMAP (3mg) in a microwave glass vial that was irradiated in a microwave (LABMAT) at 130 C, 250 W for 30 min. After the reaction mixture was cooled to ambient temperature, the reaction mixture diluted with ethyl acetate and sonicated to dissolve the entire residue. The organic fraction was washed with water (3 x 10 mL), dried over MgS04, filtered, and evaporated to give the crude product. Flash chromatography [eluted with hexane : Ethyl acetate (80/20)] afforded 5-cyano-N- phenylbenzamide (8, Scheme II) (123mg, 84%) as pale yellow powder. 1H-NMR (500MHz, D4-MeOH) delta (ppm) = 8.04 (d, IH, J=1.8Hz), 7.66 (d, 2H, J=8.4Hz), 7.50 and 7.48 (dd, IH, J=1.8Hz, J=9.0Hz), 7.37 (t, 2H, J=7.2Hz and J=7.8Hz), 7.17 (t, IH, J=8.4Hz, J=7.2Hz), 6.86 (d, IH, J=9.0Hz).

Molecular Weight:162.15
XLogP3:0.7
Hydrogen Bond Donor Count:2
Hydrogen Bond Acceptor Count:4
Rotatable Bond Count:1
Exact Mass:162.042927438
Monoisotopic Mass:162.042927438
Topological Polar Surface Area:87.1
Heavy Atom Count:12
Complexity:231
Covalently-Bonded Unit Count:1
Compound Is Canonicalized:Yes