* All experimental methods are cited from the reference, please refer to the original source for details. We do not guarantee the accuracy of the content in the reference.
With hydrogenchloride; dihydrogen peroxide In water at 63℃; for 11 h;
A four-neck 200 mL flask provided with a thermometer, Dimroth condenser and stirrer was charged with 35 g of the wet crystals of the MBA-HCl-containing composition having a purity of 99.7percent obtained in Example 1 (mass in terms of dried product: 30.8 g (0.177 mol)), 153.3 g of water was added thereto, and they were stirred. Then, 46.1 g of 33.7percent hydrochloric acid (theoretical molar ratio to MBA-HCl: 2.4) was dropped into the four-neck flask under the ordinary temperature for 30 minutes. After the dropping, the inner temperature was increased to 63° C. and 25.6 g of 33.6percent hydrogen peroxide water (theoretical molar ratio to MBA-HCl: 1.43) was dropped into the four-neck flask for 30 minutes while maintaining the temperature. The reaction was carried out at 63° C. for 10 hours and the heating was finished when the remaining amount of MBA-based substances was confirmed to be 0.5percent or less by the HPLC analysis. The reaction liquid was gradually cooled (about 5-15° C./hour) to carry out crystallization. Precipitation of crystals was confirmed at 48° C. and the state of a liquid temperature of 48° C. was therefore held for 1 hour. The cooling was continued at a cooling rate of 5-15° C./hour to 5° C. and the state of a liquid temperature of 5° C. was held for 1 hour. The reaction liquid after being held was filtrated to obtain a wet cake, which was washed with 48.7 g of isopropyl alcohol cooled to 5° C., and 31.4 g of wet crystals of a first CMBA-HCl-containing composition were obtained. The obtained wet crystals were dried using a vacuum drier and a dried product of 26.5 g of white crystals was obtained as the first CMBA-HCl-containing composition. The yield was 71.1 mol percent and the HPLC purity was 99.1percent. In the CMBA-HCl-containing composition, 0.08percent of MBA-based substances remained and 0.84percent of dichloro products were generated as by-products.
Reference:
[1] Journal of Medicinal Chemistry, 2001, vol. 44, # 7, p. 1025 - 1027
[2] Patent: US2017/44091, 2017, A1, . Location in patent: Paragraph 0054
With hydrogenchloride; dihydrogen peroxide; In water; at 63℃; for 11h;
A four-neck 200 mL flask provided with a thermometer, Dimroth condenser and stirrer was charged with 35 g of the wet crystals of the MBA-HCl-containing composition having a purity of 99.7% obtained in Example 1 (mass in terms of dried product: 30.8 g (0.177 mol)), 153.3 g of water was added thereto, and they were stirred. Then, 46.1 g of 33.7% hydrochloric acid (theoretical molar ratio to MBA-HCl: 2.4) was dropped into the four-neck flask under the ordinary temperature for 30 minutes. After the dropping, the inner temperature was increased to 63 C. and 25.6 g of 33.6% hydrogen peroxide water (theoretical molar ratio to MBA-HCl: 1.43) was dropped into the four-neck flask for 30 minutes while maintaining the temperature. The reaction was carried out at 63 C. for 10 hours and the heating was finished when the remaining amount of MBA-based substances was confirmed to be 0.5% or less by the HPLC analysis. The reaction liquid was gradually cooled (about 5-15 C./hour) to carry out crystallization. Precipitation of crystals was confirmed at 48 C. and the state of a liquid temperature of 48 C. was therefore held for 1 hour. The cooling was continued at a cooling rate of 5-15 C./hour to 5 C. and the state of a liquid temperature of 5 C. was held for 1 hour. The reaction liquid after being held was filtrated to obtain a wet cake, which was washed with 48.7 g of isopropyl alcohol cooled to 5 C., and 31.4 g of wet crystals of a first CMBA-HCl-containing composition were obtained. The obtained wet crystals were dried using a vacuum drier and a dried product of 26.5 g of white crystals was obtained as the first CMBA-HCl-containing composition. The yield was 71.1 mol % and the HPLC purity was 99.1%. In the CMBA-HCl-containing composition, 0.08% of MBA-based substances remained and 0.84% of dichloro products were generated as by-products.
43-1) 5-Hydroxymethyl-1-(4-methoxybenzyl)imidazole The title compound was obtained in a yield of 30percent according to the same procedure as Preparation 31-1) using dihydroxyacetone and 4-methoxybenzylamine hydrochloride as starting materials. 1H NMR(CDCl3+CD3OD) delta3.75(s, 3H), 4.50(s, 2H), 5.15(s, 2H), 6.86(m, 3H), 7.08(d, 2H), 7.42(s, 1H)