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In tetrahydrofuran at -5 - 5℃; for 2 - 2.25h; |
6
Example 6; Alternative Means to Prepare the Compound of Formula 16; Compound 16 can be prepared in accordance with the procedure described above in Example 1, or alternatively, may be prepared from the salt of the precursor acid as shown below. Into a 100 gallon glass lined reactor equipped with a thermocouple, N2 inlet and feed tank was charged 26.4 kg of the compound Formula E1a. Tetrahydrofuran (THF) dried to a Karl Fischer titration of less than 0.05% water (202 liters,) was charged at ambient temperature (20° C. to 25° C.) into the reaction vessel to dissolve the charge of compound E1a. When dissolution was complete, the batch was concentrated at 1 atmosphere to a volume of about 140 liters and the temperature was maintained between 20° C. and 30° C. The batch was cooled and maintained at a temperature of between -5° C. and +5° C. Over a period of 30 minutes, 7.3 kg of the compound Formula E2 was charged while maintaining the batch temperature between -5° C. and +5° C. After addition, while maintaining the same temperature, the batch was agitated for 90 minutes. At the end of the agitation period the reactor was charged with 7.8 kg supercel, followed by 54 liters of heptane. The batch was filtered under N2, and the filter cake was washed with 30% v/v THF in heptane. The filtrate and washes were combined and concentrated under vacuum to a batch volume of about 71 liters. The concentrate was warmed to ambient temperature and can be used to prepare the compound of Formula 19 or other amines in accordance with Examples 1 to 5. The concentrate thus obtained was analyzed by proton NMR (1HNMR in CDCl3) with the following results (chemical shift relative to TMS, multiplicity). 5.33 (1H, d); 4.41 (1H, d); 3.51 (1H, dd); 1.36 (9H, s), 1.22 (9H, s); 1.02 (9H, s); Alternative Preparation Example 6; To a stirred suspension of 60.0 g (0.136 mol) of E1a in 420 ml of THF was charged under nitrogen 16.6 g (0.138 mol, 1.0 eq.) of compound E2 dropwise at 0° C. over 15 minutes. The resulting mixture was stirred for 2 hours at 0° C. After addition of 18 g of supercel and 120 ml of heptane at 0° C., the mixture was filtered under N2, and the filter cake was washed with 120 ml of 30% v/v THF in heptane. The filtrate and washes were combined and concentrated under vacuum to about 150 ml. The NMR analysis showed it contained 43.3 g (92.5%) of active compound 16. The solution was stored in a refrigerator and could be used to prepare the compound of Formula 19 or other amines in accordance with Examples 1 to 5. 1HNMR in CDCl3: 5.33 (1H, d); 4.41 (1H, d); 3.51 (1H, dd); 1.36 (9H, s), 1.22 (9H, s); 1.02 (9H, s) |
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