4, 6-DIHYDROXYNICOTINIC ACID ETHYL ESTER

White solid

Diethyl 3-oxopentanedioate (1, 10.00 g, 49.45 mmol), triethyl orthoformate (7.33 g, 49.45 mmol) and acetic anhydride (10.10 g, 98.93 mmol) were combined and stirred at 120 °C for 2 h then allowed to cool to ambient temperature. The volatiles were removed under vacuum. The residue was then cooled in an ice bathand aqueous ammonia (25 mL) was added in portions with stirring. The reaction mixture was stirred at 0 C for 1 h and was then acidified with 2N hydrochloric acid to pH < 5. The precipitate was collected by filtration and allowed to dry to provide 2 as yellowsolid. Yield: 81.6percent. Mp: 207-210 °C. 1H NMR (400 MHz, DMSO-d6, ppm) d: 11.78 (s, br, 1H), 10.74 (s, br, 1H), 8.02 (s, 1H), 5.61 (s, 1H), 4.27 (q, 2H, J 7.1), 1.29 (t, 3H, J 7.1). 13C NMR (100 MHz, DMSOd6, ppm) d: 166.57, 166.40, 164.00, 142.97, 100.44, 98.96, 61.35, 14.46.Step 1: A mixture of 5.0 g (24.73 mmol) diethyl 1, 3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12OG] Preparation of compound 5 -G A mixture of 5.0 g (24.73 mmol) diethyl 1, 3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate is heated to 120A mixture of 5.0 g (24.73 mmol) diethyl 1, 3-acetonedicarboxylate, 5.05 g (49.45 mmol) acetic anhydride and 3.7 g (24.73 mmol) ethyl orthoformate was heated to 12OA mixture of scheme 1 compound 1 (50.0 g, 247.5 mmol), triethyl orthofomate (40.3 g, 272.3 mmol) and acetic anhydride (50.5 g, 495.0 mmol) was heated at 120 °C for 1.5h with vigorous stirring. The dark yellow solution was cooled in an ice bath, and mixed with ammonia (20 mL, 30percent water solution). The resulting mixture was stirred at 0 °C for lh. A yellow solid formed in the mixture. After the mixture was acidified with 2N HC1 to pH = 5, a white solid formed. The mixture was filtered, washed with water and air dried to give scheme 1 compound 2 (10.0 g, yield: 22.0percent) as a white solid. 1H NMR (400 MHz, MeOD): δ 8.16 (s, 1H, ArH), 5.79 (s, 1H, ArH), 4.38 (q, J= 7.2 Hz, 2H, CH(E. Wallace, B. Hurley, H. W. Yang, J. Lyssikatos and J. Blake, Int. Pat. App. WO200523759, 2005): Trimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1, 3-acetonedicarboxylate (i) (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under NTrimethylorthoformate (5.95 mL, 54.4 mmol) was added to a solution of diethyl 1, 3-acetonedicarboxylate 34 (8.98 mL, 49.5 mmol) in acetic anhydride (9.34 mL, 99.0 mmol). The reaction mixture was heated under N3-Oxo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethyl orthoformate (81.4 g, 0.55 mol) and acetic anhydride (102 g, 1 mol) were combined and heated to 120° C. for 2 h. Diethyl 1, 3-acetonedicarboxylate (2 x 50 g, 1.0 eq, Aldrich) was added in portions to acetic anhydride (2 x 58.6 g, 2.0 eq) in a round bottomed flask. To this solution, triethyl orthoformate (2 x 51 g, 1.2 eq) was added slowly and the contents heated under a reflux condenser at 120°C for 3 h. The contents were cooled to 0°C and 25percent aqueous ammonia was added slowly while stirring. The mixture continued stirring for 1 h at 0°C and the mixture acidified with 3N HC1 solution. The solid that separated out was filtered and dried under vacuum to obtain product as white solid ethyl 4, 6-dihydroxynicotinate (75.1 g, 82.8percent). LCMS: Purity: 99.84percent, MS: 184.18 (M+H).Example C3: 3-0xo-pentanedioic acid diethyl ester (101 g, 0.5 mmol), triethylorthoformate (81.4 g, 0.55mol) and acetic anhydride (102 g, 1 mol) were combined andheated to 120°C for 2 h. The resulting mixture was cooled toRT and dissolved in DCM (1L). After further cooling to 0°C, ammonia (30percent, 80 mL) was added and the reaction mixturewas allowed to warm to RT overnight. The product was extracted with water (2x) and theaqueous layer was acidified to pH 5 with cone. HCl. The precipitate was collected byfiltration to afford ethyl 4, 6-dihydroxynicotinate (60.0 g, 60percent yield). 1H NMR (400 MHz, DMSO-d6): 8 7.99 (s, 1 H), 5.58 (s, 1 H), 4.23 (q, J = 6.8, 14.0 Hz, 2 H), 1.25 (t, J = 7.2 Hz, 3H); MS (ESI) mlz: 184.1 [M+Ht.