| 95% |
With acetic acid; In toluene; |
Synthesis of Form C Toluamisole by Traditional Technology:In a 500 ml four-necked flask, 50 g of 3,4-diaminobenzophenone was added.O-methylisourea formic acid methyl acetate toluene solution 32.8g (13%, pure)32.5g of acetic acid, warmed to 40C (35-45C), heat-retained for 16 hours (16-17 hours). 70g of formic acid was added, heated to reflux, temperature was 80C (78-85C), refluxed for 6 hours (6-7 hours) ? Reduce the temperature to 65C (60-70C), add 85ml of methanol, and heat and stir at 65C (60-70C) for 1 hour (1-2 hours). Cool down to 35C (30-40C). It was filtered, washed with 50 ml of methanol, and the filter cake was dried at 100 C (90-110 C) for 24 hours to obtain 62.6 g of a crude product with a yield of 90%.In a 500 ml four-necked flask, add 30 g of crude tomidazole, 125 g of formic acid, and 0.6 g of activated carbon. Stir, heat to 65 C (60-70 C), keep at least 1 hour, and heat filter. The filtrate was transferred to a 500-ml four-necked flask, and the temperature was lowered to 50 C (40-60 C). 100 ml of water for crystallization was added once, and 0.5 g of tomidazole C crystal seed was added. Turn down the stirring speed, lower the temperature to 40C (35-45C), and keep it for 1 to 2 hours. Add 260ml of secondary crystallization water, continue to lower the temperature to 20 C (15-25C), and keep it for 1 to 2 hours. Filtered, washed with 360ml purified water, and the filter cake was dried at 90 C (80-100C) to obtain 29g of C-type tomidimazole with a yield of 95%. Comparative Example 2In a 500ml four-necked flask, add 50g of crude tomidazole and 250ml of methanol, stir, heat to 55C (50-60C), dropwise add 16g of sulfuric acid, dissolve the material, add 1.0g of activated carbon, keep at least 1 hour, and heat filter.The filtrate was transferred to a 500 ml four-necked flask, and the temperature was lowered to 50 C (40-60C), and 1 g of crystal C-formimidazole seed crystals were added and kept for 1 hour. The temperature was lowered to 40 C (35-45C), 200 ml of water was added, 100 g of 15% sodium hydroxide was added dropwise, the pH was adjusted to 6, and the temperature was maintained for 1 to 2 hours. Filter, 300mlIt was washed with purified water, and the filter cake was dried at 90 C (80-100C) to obtain 48.5 g of toluzazole in the C crystal form with a yield of 95%. In this comparative example, the crystal form conversion in methanolic sulfuric acid was adopted, and the yield of the toluzazole in the crystal form C was significantly lower than that in methanol nitrate.Comparative Example 3In a 500ml four-necked flask, add 50g of crude tomidazole and 250ml of methanol, stir, heat to 55C (50-60C), dropwise add 16g of sulfuric acid, dissolve the material, add 1.0g of activated carbon, keep at least 1 hour, and heat filter.The filtrate was transferred to a 500 ml four-necked flask, and the temperature was lowered to 50 C (40-60C), and 1 g of crystal C-formimidazole seed crystals were added and kept for 1 hour. The temperature was lowered to 40 C (35-45C), 200 ml of methanol was added, 100 g of 15% sodium hydroxide was added dropwise, the pH was adjusted to 6, and the temperature was maintained for 1 to 2 hours.Filtration, washing with 300 ml of purified water, drying of the filter cake at 90 C (80-100C), 49 g of A-type tomidazole were obtained with a yield of 96% and 100% of A-type. In the crystallization process of this comparative example, the addition of methanol instead of water could not achieve the correct conversion of the crystal form, and only Form A tolumidazole was obtained, and Form C Toluidazole was not obtained. |
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With hydrogenchloride; In chloroform;Cooling with ice; Reflux; |
General procedure: The methoxy(1-iminoethyl)carbamate (1equiv) and compound 4 (1equiv) in chloroform were cooled in an ice bath and stirred mechanically. To the solution, concentrated hydrochloric acid (1equiv) was added dropwise at such rate to keep the temperature below 10C throughout the addition. Stirring was continued for additional 30min, and then the mixture was heated under reflux for overnight. After cooling, the precipitate was filtered and the solvent was rotary-evaporated to give crude product. Then, the crude product was purified by silica gel column chromatography using PE-EA as an eluent (yield 41.2-66.7%). 5.3.1 Compound 5a: methyl(5-benzoyl-1H-benzo(d)imidazol-2-yl)carbamate 1H NMR (400MHz, CDCl3) delta 7.91 (d, J=15.0Hz, 1H), 7.86 (d, J=3.1Hz, 1H), 7.82 (s, 1H), 7.80 (d, J=3.3Hz, 1H), 7.61 (ddd, J=12.8, 7.9, 3.3Hz, 1H), 7.54 (d, J=1.0Hz, 1H), 7.51 (s, 1H), 7.48 (d, J=3.0Hz, 1H), 3.73 (s, 3H). 13C NMR (100MHz, CDCl3) delta 197.53, 158.22, 148.36, 138.05, 136.76, 133.39, 133.01, 132.42, 129.91, 128.63, 122.62, 117.16, 107.49, 53.52. MS: m/z=318.0861 (M+Na)+. |
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