3-CHLORO-1,1,1-TRIFLUORO-PENTANE-2,4-DIONE synthesis

Yield:-

Reaction Conditions:

with sulfuryl dichloride in benzene at 20;

Steps:

15; 16

To a stirred solution of Int-1 (7 g, 45.4 mmol) in benzene (7 ml) was added sulfuryl chloride (3.6 ml, 45.4 mmol) slowly over a period of 2 hours. After addition of SO₂Cl₂, the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched with 7 ml of water followed by ethyl acetate (10 ml). The organic phase was separated, dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure at 25° C. to a volume of about 10 mL which was used for the next step without any purification. ¹H NMR (200 MHz, CDCl₃): δ 2.44 (s, 3H), 4.49 (s, 1H). To a solution of 2-amino-pyridine (3.65 g, 38.8 mmol) in DME (40 ml) was added Int-2 at room temperature. The reaction mixture was refluxed for 3 hours. After disappearance of starting material the volatiles were removed under reduced pressure and the crude mass was purified by silica gel column chromatography using EtOAc:Hexane as eluent to provide Int-3 (2 g, 22%) as white solid. ¹H NMR (200 MHz, CDCl₃): δ 2.75 (s, 3H), 7.16-7.26 (m, 1H), 7.55-7.63 (t, 1H), 7.85 (d, J=9.2 Hz, 1H), 9.77 (d, J=7 Hz, 1H); Mass (M⁺): 228. Int-3 (2.9 g, 12.7 mmol) in DMFDMA (30 ml) and one drop of DMF were refluxed for 16 hours. The volatiles were removed under reduced pressure and the crude was triturated with hexane (40 ml) to afford Int-4 (3 g, 83%) as a solid. ¹H NMR (200 MHz, CDCl₃): δ 2.95 (s, 3H), 3.20 (s, 2H), 5.68 (d, J=12.4 Hz, 1H), 6.96-7.03 (t, 1H), 7.35-7.39 (t, 1H), 7.72 (d, J=8.8 Hz, 1H), 7.82 (d, J=12.4 Hz, 1H), 9.30 (d, J=7.2 Hz, 1H); Mass (M⁺): 283. To a stirred solution of Int-4 (2 g, 7.06 mol) in DMF (30 ml) was added Int-5 (4.09 g, 21.2 mmol), potassium carbonate (2.9 g, 21.2 mmol) and the mixture was stirred at 110° C. for 18 hours. After disappearance of starting material, the reaction mixture was cooled to room temperature and diluted with water (300 ml), and stirred for 30 minutes. The resulting precipitate was filtered, washed with water (50 ml) and dried under vacuum to furnish critical cyclized Int-6 (1.8 g, 62%) as a brown solid. ¹H NMR (200 MHz, CDCl₃): δ 3.91 (s, 3H), 6.99-7.0 (t, 1H), 7.21-7.26 (m, 1H), 7.46-7.50 (m, 2H), 7.71-7.84 (m, 3H), 8.02 (d, J=8.8 Hz, 2H), 8.63 (d, J=5 Hz, 1H), 9.17 (d, J=7.4 Hz, 1H); Mass (M⁺): 413. Int-6 (1.2 g, 2.9 mmol) in 4 N HCl (50 ml) was refluxed for 3 hours. The progress of reaction was monitored by TLC. After complete disappearance of starting material, heating was removed and the reaction mixture was cooled to room temperature. The resulting precipitate was filtered, washed with water (50 ml) and dried under vacuum to provide Int-7 (0.9 g, 78%) as yellow solid. ¹H NMR (200 MHz, dmso-d₆): δ 7.17-7.23 (m, 2H), 7.57-7.64 (t, 1H), 7.84-7.92 (m, 5H), 8.76 (d, J=5.2 Hz, 1H), 9.12 (d, J=7.4 Hz, 1H), 10.29 (s, 1H); Mass (M⁺): 399. To a solution of Int-7 (1 g, 2.5 mmol) in DMF (15 ml) was added EDCI (1.05 g, 5.5 mmol), HOBt (0.33 g, 2.5 mmol) and DIPEA (1.1 ml, 6.2 mmol) at 0° C. followed by NH₂-OTHP (0.43 g, 3.7 mmol) at 0° C. The reaction mixture was stirred at room temperature for 16 hours, diluted with water (40 ml), and stirred for another 30 minutes. The precipitated solid was filtered, washed with water (20 ml), dried under vacuum and purified by silica gel column chromatography using (EtOAc:Hexane, 7:3) to give Int-8 (0.7 g, 56%) as a brown solid. ¹H NMR (200 MHz, dmso-d₆): δ 1.53-1.70 (m, 6H), 4.33-4.35 (m, 1H), 4.85-4.89 (m, 1H), 4.96 (s, 1H) 7.14-7.20 (m, 2H), 7.61-7.64 (t, 1H), 7.69 (d, J=8.8 Hz, 2H), 7.85 (d, J=8.8 Hz, 3H), 10.19 (s, 1H), 11.45 (s, 1H); Mass (M⁺): 498.

References:

US2010/29638,2010,A1 Location in patent:Page/Page column 73