反应详情

温度

5 °C

MVK adduct 10 (15.04 kg, 39.38 mol) was charged to a vessel and THF (150.4 L) was added. The resulting slurry was cooled to 5° C. and methane sulfonic acid (7.57 kg, 78.8 mol) was added via a diaphragm pump maintaining an internal temperature below 25° C. The batch was heated to 60° C. and allowed to age overnight. After aging overnight HPLC showed the reaction to be 83% complete, thus a further charge of methane sulfonic acid (3.78 kg, 39.3 mol) was added via a diaphragm pump and heating was continued for a further 2 h. It is important to note that charging 3 equiv. of MSA directly to the reaction mixture led to the product oiling out during the course of the reaction. Initially charging 2 equiv. of MSA allowed a seed bed to form which controlled the crystallization during the remainder of the reaction after the final equivalent of MSA had been added. After 2 h HPLC confirmed complete consumption of the starting material. The batch was cooled to 20° C. then filtered and the cake was washed with THF (20 L). The resultant solid was dried in a vacuum oven (T=60° C.) for 36 h, to give 12 (17.4 kg, 36.7 mol) as a pale tan solid. 2% lost to the liquors. m.p. 126.4° C. 1H NMR (400 MHz, d6-DMSO): δ 7.86 (bs, 3H), 7.44 (d, 1H, J=8.5 Hz), 7.35 (d, 1H, J=1.1 Hz), 7.06 (dd, 1H, J=8.5 Hz, 1.1 Hz), 3.75 (t, 2H, J=5.6 Hz), 3.69 (t, 2H, J=6.9 Hz), 3.15 (m, 2H), 2.93 (t, 2H, J=5.6 Hz), 2.36 (s, 6H), 2.14 (s, 3H). 13C NMR (100.6 MHz, d6-DMSO): δ 207.8, 163.1, 147.7, 144.7, 128.6, 120.6, 115.7, 110.6, 46.7, 44.2, 41.3, 40.1 (identified by dept), 37.4, 30.5. HRMS (ESI): m/z [M++H] calcd for C13H16ClN3O2: 282, 1009. found: 282, 1012.

1. temperaturemaintaining an internal temperature below 25° C
2. temperatureThe batch was heated to 60° C.
3. customallowed to age overnight
4. customthe reaction
5. additionwas added via a diaphragm pump
6. temperatureheating
7. waitwas continued for a further 2 h
8. customled to the product oiling out during the course of the reaction
9. customto form which
10. customthe crystallization
11. customduring the remainder of the reaction after the final equivalent of MSA
12. additionhad been added
13. customAfter 2 h HPLC confirmed complete consumption of the starting material
14. temperatureThe batch was cooled to 20° C.
15. filtrationthen filtered
16. washthe cake was washed with THF (20 L)
17. customThe resultant solid was dried in a vacuum oven (T=60° C.) for 36 h