反应详情

温度

78 °C

To a solution of 3,5-difluorobenzoic acid (9.36 g, 59.2 mmol), chloroform (200 mL) and triethylamine (16.34 g, 161.5 mmol) at 25° C. was added HBTU (22.5 g, 59.2 mmol). The mixture was heated to 40-42° C. for 45 min resulting in the formation of a white suspension. The suspension was cooled to 10° C. and a solution of (2S,3R)-3-amino-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]octane (11.7 g, 53.8 mmoles) in chloroform (50 mL) was added over a 15-20 min period and stirred for 1.5 h. The reaction mixture was heated to 40-42° C. and additional 3,5-difluorobenzoic acid (2.0 g, 13 mmol) and HBTU (4 g, 11 mmol) were added, followed by stirring at 40-42° C. for 2 h and then at ambient temperature for 16 h. The reaction mixture was quickly quenched with water (200 mL), and under stirring, the pH of the aqueous layer was adjusted to pH=10-11 with 10 wt % aqueous sodium hydroxide. The layers were separated and the organic layer was washed twice with water (100 mL). The solvent was removed in vacuo to afford 22.9 g of a viscous orange solid. The strength of the product in the crude oil was determined at 66.0 wt % by quantitative HPLC against a reference standard; this corresponds to a yield of 15.1 g (78%). The oil was dissolved in methyl ethyl ketone (50 mL) which was subsequently distilled off in vacuo; this process was repeated a total of three times. A 500 mL three-necked, round-bottomed flask, equipped with an overhead stirrer, temperature probe, dropping funnel and condenser, was charged with fumaric acid (4.9 g, 42 mmol) and methyl ethyl ketone (150 mL). The suspension was heated to 78° C. which led to complete dissolution of the acid. A solution of the (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide in methyl ethyl ketone (50 mL) was added slowly, keeping the internal temperature above 75° C. After completion of the addition, the suspension was stirred for 30-45 min at 78° C. and the heat source was turned off. The suspension was stirred overnight, filtered and the cake was dried at 50° C. in vacuo for 16 h to afford (2S,3R)-N-2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide fumarate as a light yellow, crystalline solid (99.6% pure by HPLC), mp 208-210° C. Yield: 65% for two steps. 1H NMR (D2O, 400 MHz): δ 8.30 (d, J=5.6 Hz, 1H); 8.06 (d, J=7.5 Hz, 1H); 7.48 (dd, J=8.7 Hz, J=5.6 Hz, 1 H); 6.97-7.06 (m, 1H); 6.75-6.85 (m, 2 H); 6.49 (s, 2H); 4.15 (d, J=7.5 Hz, 1H); 3.69-3.81 (m, 1H); 3.40-3.59 (m, 2H); 3.17-3.40 (m, 4 H); 2.03-2.18 (m, 2H); 1.91-2.03 (m, 2 H), 1.78-1.91 (m, 1H).

1. distillationwas subsequently distilled off in vacuo
2. customA 500 mL three-necked, round-bottomed flask, equipped with an overhead stirrer
3. dissolutionled to complete dissolution of the acid
4. customthe internal temperature above 75° C
5. additionAfter completion of the addition
6. stirringThe suspension was stirred overnight
7. filtrationfiltered
8. customthe cake was dried at 50° C. in vacuo for 16 h