N-(2-aminophenyl)acetamide

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-aminophenyl)acetamide (59 mg, 57%) as a yellow solid was synthesized from 1,2-diaminobenzene (216 mg, 2.00 mmol), EDCI (764 mg, 4.00 mmol), HOBt (540 mg, 4.00 mmol), DMAP (488 mg, 4.00 mmol), acetic acid (120 mg, 2.00 mmol) and DMF (1 mL) using the procedure similar to that described for compound 1 (Example 1): LCMS: 531 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.03 (s, 3H), 4.85 (s, 2H), 6.52 (m, 1H), 6.70 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 9.11 (s, 1H).

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: N-(2-aminophenyl)acetamide (59 mg, 57%) as a yellow solid was synthesized from 1,2-diaminobenzene (216 mg, 2.00 mmol), EDCI (764 mg, 4.00 mmol), HOBt (540 mg, 4.00 mmol), DMAP (488 mg, 4.00 mmol), acetic acid (120 mg, 2.00 mmol) and DMF (1 mL) using the procedure similar to that described for compound 1 (Example 1): LCMS: 531 [M+1]+. 1H-NMR (400 MHz. DMSO-d6) δ 2.03 (s, 3H), 4.85 (s, 2H), 6.52 (m, 1H), 6.70 (m, 1H), 6.89 (m, 1H), 7.15 (m, 1H), 9.11 (s, 1H).

Conditions: temp:170.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: A mixture of N-(2-aminophenyl)acetamide (315 mg, 2.1 mmol), bromo-compound 4 (680 mg, 2 mmol), triethylamine (200 mg, 280 μL, 2 mmol), and ethanol (2 mL) was microwave-heated at 170° C. for 1 h (2-5 mL vial, pressure 13 bar). The shiny white crystalline mass was filtered, washed, and recrystallized from ethanol to give 5 (392 mg, 51% yield): mp>250° C.; 1H NMR (DMSO-d6): δ 9.17 (s, 1H), 7.69 (d, 1H, pyrrole CH, J=8.06 Hz), 7.33-7.14 (m, 6H), 7.10-6.94 (m, 3H), 3.31 (s, 3H), 3.17 (s, 3H), 1.87 (s, 3H). MS (ES+) (m/z): [M+1]+ calculated for C22H21N4O3, 389.43. found 389.19. The shiny white crystalline mass was filtered washed recrystallized from ethanol

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: Synthesis of PPQ-102—Synthesis of PPQ-102 was achieved in six steps as illustrated in FIG. 2B. Commercially available 6-methyluracil 1 was methylated using dimethylsulfate to produce 1,3,6-trimethyluracil 2, which upon Friedel-Crafts acylation using zinc chloride as a catalyst yielded 5-benzoyl-1,3,6-trimethylpyrimidine-2,4(1H,3H)-dione 3 as a white powder. Bromination of 3 followed by reaction with N-(2-aminophenyl)acetamide generated amino-protected intermediate 5. The acetamido function of 5 was hydrolyzed and resultant intermediate 6 was cyclocondensed with 5-methylfurfural to yield yellowish-white racemic PPQ-102 7. Aromatic compound 8, which lacks a stereocenter, was prepared from 7 by oxidation with potassium permanganate.

Conditions: temp:0.01; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: To a solution of benzene-1,2-diamine (100 g, 0.93 mol) in dichloromethane (1 L) at 0° C. was added acetic anhydride (87 mL, 0.92 mol). After stirring at 0° C. for 2 hours, the mixture was stand at 0° C. for 12 hours and the precipitate was collected by filtration, washed by dichloromethane and ether, dried in air to afford the product N-(2-aminophenyl)acetamide (25 g, yield 18%). 1H NMR (400 MHz, CDCl3) δ ppm 7.14-7.26 (m, 2H), 7.04-7.08 (m, 1H), 6.78-6.81 (m, 2H), 3.86 (br s, 2H), 2.20 (s, 3H). at 0° C. for 12 hours the precipitate was collected by filtration washed by dichloromethane and ether dried in air

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(2-aminophenyl)acetamide (36 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(2-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as an off-white solid. Yield: 26 mg (24%). 1H-NMR: 10.01 (s, 1H), 9.60 (s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.24-7.16 (m, 3H), 7.11-7.08 (m, 2H), 3.85-3.80 (m, 2H), 2.47 (d, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.69-1.60 (m, 2H). The residue was purified eluting with 0-40% EtOAc in hexanes The resulting solid was triturated with dichloromethane/hexanes

Conditions: temp:0.00; pressure:0.00; stir:; See reaction.notes.procedure_details.

Procedure: 4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzoic acid (1) (100 mg, 0.32 mmol) was treated with N-(2-aminophenyl)acetamide (36 mg, 0.24 mmol) using method B. The residue was purified using flash chromatography eluting with 0-40% EtOAc in hexanes. The resulting solid was triturated with dichloromethane/hexanes to give N-(2-acetamidophenyl)-4-(3,4-dihydroquinolin-1(2H)-ylsulfonyl)benzamide as an off-white solid. Yield: 26 mg (24%). 1H-NMR: 10.01 (s, 1H), 9.60 (s, 1H), 8.07 (d, J=8.5 Hz, 2H), 7.77 (d, J=8.5 Hz, 2H), 7.63 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.5 Hz, 2H), 7.24-7.16 (m, 3H), 7.11-7.08 (m, 2H), 3.85-3.80 (m, 2H), 2.47 (d, J=7.0 Hz, 2H), 2.06 (s, 3H), 1.69-1.60 (m, 2H). The residue was purified eluting with 0-40% EtOAc in hexanes The resulting solid was triturated with dichloromethane/hexanes