Preparation of methylaminoacetal dimethyl acetate_industrial additives

Overview^[1]

Methylaminoacetal dimethyl acetal can be used as an intermediate in pharmaceutical synthesis, such as the preparation of methimazole. Its chemical name is 1-methylimidazole-2-thiol. It is an antithyroid drug. Its mechanism of action is to inhibit thyroid hormone secretion. Peroxidase, thus hindering the oxidation of iodide absorbed into the thyroid and the coupling of tyrosine, and hindering the synthesis of thyroxine (T4) and triiodothyronine (T3). Animal experiments have observed that B lymphocytes synthesize antibodies, reduce the level of thyroid-stimulating antibodies in the blood circulation, and restore suppressive T cells to normal.

Preparation^[1]

Methylaminoacetal dimethyl acetal is prepared as follows:

Add 3.00kg of chloroacetal dimethyl acetal and 30kg of 33% methylamine methanol solution into the autoclave, close the autoclave valve, heat to 130-135°C, the maximum pressure is 1.2MPa, and then continue to decrease, and the insulation reaction After 6 hours, cool down to 25°C and press to neutralization tank. Stir and lower the temperature to below 10°C, dropwise add 3.26kg of 40% sodium methoxide methanol solution, and keep the mixture at 0-5°C for 2-3 hours. Filter, wash the filter cake with methanol, and transfer the filtrate to the distillation tank. Distill methanol under normal pressure until it no longer evaporates. Change to distillation under reduced pressure. Turn on brine condensation to collect the intermediates. Collect the 52-60°C/24mmHg fraction to obtain 2.51kg of methylaminoacetaldehyde dimethylacetal. The purity detected by GC is 94.6 %, yield 83.1%.

Apply^[1]

Put 1.44kg sodium thiocyanate and 8.9kg purified water into the cyclization reaction kettle, dissolve it under stirring at room temperature, add 1.60kg methylaminoacetaldehyde dimethyl acetal, add hydrochloric acid (concentration 36% – 40%) 1.44kg, control the temperature below 30°C, complete the dropwise addition in about one hour, the ph value is 1-2, react at 50-60°C for 13 hours, then drop to room temperature and let stand for 8 hours. Remove water by distillation under reduced pressure, add 5L of ethyl acetate and 500g of anhydrous sodium sulfate, reflux for 30 minutes, and hot filter. The filtrate is heated and distilled, and about one-third of the ethyl acetate remains. Cool to 0°C, incubate at 0-5°C for 2-3 hours, filter, wash with cold ethyl acetate, and dry in a vacuum to obtain 0.86kg of methimazole. The rate is 59.3%. According to GC measurement, the product purity is 99.5%.

Main reference materials

[1] CN201710376949.5 A kind of preparation method of methimazole