Preparation of cycloheptano[B]pyridine-5,9-dione_Industrial additives

Preparation background and overview of cyclohepta[B]pyridine-5,9-dione

Cycloheptano[B]pyridine-5,9-dione is an organic intermediate. It can be prepared from 2,3-pyridinedicarboxylic acid dimethyl ester and glutarate dimethyl ester as starting materials. Prepared by one step reaction.

Preparation of cyclohepta[B]pyridine-5,9-dione

Preparation step 1 of cyclohepta[B]pyridine-5,9-dione,

To a solution of dimethyl 2,3-pyridinedicarboxylate (750 g, 3.84 mol) and dimethyl glutarate (935 g, 5.84 mol) in toluene (5.25 L) was added potassium tert-butoxide (1.0 M of THF, 9.6 L, 9.6 mol), maintaining the internal temperature <30 °C. The reaction mixture was heated to 55-60°C over 1 hour and held for 1 hour. The reaction mixture was concentrated in vacuo to <7 L and then cooled to 0-5°C. To the concentrated reaction mixture, n-heptane (11.3 L) was added, followed by ice-water (10.9 L), maintaining the internal temperature <5 °C. The pH of the reaction mixture was then adjusted to 6.0-6.5 with glacial acetic acid (435 ml) at 0-5°C. Filter the obtained slurry, mica and wash the filter cake with water (2.3 L) and n-heptane (3.7 L) successively, and then dry it under vacuum at 50-55°C to obtain 5,9-dihydroxy-pinacol diborate. 7H-Cyclohept[b]pyridine-6,8-dicarboxylic acid dimethyl ester. White solid, yield 822 g, 73%.

Preparation step 2 of cyclohepta[B]pyridine-5,9-dione,

Dimethyl 5,9-dihydroxy-7H-cyclohept[b]pyridine-6,8-dicarboxylate (610 g, 2.09 mol) in HCl (6.0 N, 3.3 L, 19.8 mol) Heat at 75-80°C for 5 hours, then cool to 0-5°C. The pH of the mixture was adjusted to 5.0-5.5 with saturated sodium bicarbonate solution at 0-5°C, and then extracted with dichloromethane (3.0L × 2). The organic phases were combined and filtered through charcoal (300 g) and concentrated in vacuo. The product was crystallized from ethyl acetate (0.75 L) and n-heptane (1.5 L) at 0-5 °C, filtered and dried under vacuum at 40 °C to give 6. Cycloheptano[B]pyridine-5,9-dione(6), white crystals, 330 g, 82%. Mp = 61.8- 62.6 °C; ¹H NMR ( MHz, CDCl ₃) δ 8.89 (dd, J = 4.6, 1.7 Hz, 1H), 8.18 (dd, J = 7.9, 1.6 Hz, 1H), 7.56 (dd, J = 7.9, 4.6 Hz, 1H ), 2.98 (t, J = 7.0 Hz, 2H), 2.92 (dd, J = 7.7, 5.5 Hz, 2H), 2.16 (pentet, J = 6.8 Hz, 2H); ¹³C NMR (100 MHz, CDCl₃) δ 200.7, 200.4, 154.1, 153.0, 136.8, 133.1, 125.9, 41.8, 41.7, 17.6.

References

[1] From Organic Letters, 14(18), 4938-4941; 2012