Clonitazepam impurity and preparation method thereof
A technology for clonazepam and impurities, applied in the field of drug synthesis, can solve the problems of complicated separation, less amount of impurities, no impurities and reports in synthesis, and achieves the effect of high yield and guaranteed product quality
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Embodiment 1
[0054]The preparation method of clonazepam impurity 4-(2-chlorophenyl)-6-nitroquinazoline is carried out according to the following steps:
[0055] (1) Add chloride (10.00g, 36.23mmol) to the reaction flask, add 100ml of methanol, stir to dissolve and clarify, add 7M ammonia methanol solution (10ml, 70.80mmol) dropwise at 25°C, and the system becomes light yellow after the dropwise addition The turbid system, continue to stir at room temperature for 1h, then heat up to 65°C for 2h;
[0056] (2) add trioxymethylene (6.50g, 72.46mmol), acetic acid (4.35g, 72.46mmol) to the reaction system, continue to react for 5h, cool down to 25 ℃;
[0057] (3) Filtration to obtain light yellow powder, which was then recrystallized with absolute ethanol to obtain an off-white solid, which was dried and weighed 6.5 g, yield 67.1%, and HPLC purity 98.55%. The chloride is specifically 2-amino-5-nitro-2'-chlorobenzophenone, the same in the following embodiments.
Embodiment 2
[0059] The preparation method of clonazepam impurity 4-(2-chlorophenyl)-6-nitroquinazoline is carried out according to the following steps:
[0060] (1) Add chloride (10.00g, 36.23mmol) to the reaction flask, add 100ml of methanol, stir to dissolve and clarify, add 7M ammonia methanol solution (10ml, 70.80mmol) dropwise at 25°C, and the system becomes light yellow after the dropwise addition The turbid system, continue to stir at room temperature for 1h, then heat up to 65°C for 2h;
[0061] (2) 10ml of 38% aqueous formaldehyde solution, acetic acid (4.35g, 72.46mmol) were added to the reaction system, the reaction was continued for 5h, and the temperature was lowered to 25°C;
[0062] (3) Filtration to obtain a pale yellow powder, and then recrystallized with absolute ethanol to obtain an off-white solid, which was dried and weighed 4.5 g, yield 46.5%, and HPLC purity 95.55%.
Embodiment 3
[0064] The preparation method of clonazepam impurity 4-(2-chlorophenyl)-6-nitroquinazoline is carried out according to the following steps:
[0065] (1) Chloride (10.00g, 36.23mmol) was added to the reaction flask, 100ml of methanol was added to stir to dissolve and clarify, and 10ml of ammonia water was added dropwise at 25°C. After the dropwise addition, the system became a pale yellow turbid system, and the reaction was continued to stir at room temperature for 1h. The temperature was raised to 65°C for 2h;
[0066] (2) 10ml of 38% aqueous formaldehyde solution, acetic acid (4.35g, 72.46mmol) were added to the reaction system, the reaction was continued for 5h, and the temperature was lowered to 25°C;
[0067] (3) Filtration to obtain a pale yellow powder, and then recrystallized with absolute ethanol to obtain an off-white solid, which was dried and weighed 2.5 g, the yield was 18.8%, and the HPLC purity was 90.55%.
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