C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]([C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=2[N:20]=1)[CH2:11][CH2:12][C:13](=[O:15])[CH3:14])(C)(C)C.CS(O)(=O)=O>C1COCC1>[NH2:7][CH2:8][CH2:9][N:10]([C:16]1[O:17][C:18]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:19]=2[N:20]=1)[CH2:11][CH2:12][C:13](=[O:15])[CH3:14]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.
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