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A kind of green synthesis method of lonidazole and its deuterated derivatives
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A technology for lonidazole and green synthesis, which is applied in the field of chemical synthesis, can solve the problems of low cost, difficult operation and low price of highly toxic chemicals, and achieves the effects of low price, easy operation and ideal yield
Active Publication Date: 2021-02-23
东莞暨南大学研究院 +1
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Among them, the traditional methylation reagents used in the first step of nitrogen methylation reaction, such as dimethyl sulfate, methyl trifluoromethanesulfonate, methyl iodide, etc., are highly toxic or have highly toxic chemicals and are not cheap. The third step The trichloroacetyl isocyanate or dibutyltin oxide used are very toxic and not cheap, which not only increases the cost, but also is not environmentally friendly; in addition, the anhydrous and oxygen-free conditions are not easy to operate
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Embodiment 1
[0044] Embodiment 1: the synthesis of lonidazole
[0045] Step 1: Preparation of 1-methyl-5-nitroimidazole
[0046] Add 200mg (1.77mmol) of 4-nitroimidazole, 33.6mg (0.18mmol) of p-toluenesulfonic acid monohydrate, and 3ml of methanol into a 10ml sealed tube, heat it to 150°C in an airtight environment, react for 8h, cool, spin Most of the solvent was removed, extracted with saturated aqueous sodium bicarbonate (20ml) and ethyl acetate (30ml*3), the organic phase was dried with anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography[ Ethyl acetate / n-hexane (volume ratio) is 3:1] to obtain 167 mg of 1-methyl-5-nitroimidazole with a yield of 74%.
[0047] The proton nuclear magnetic spectrum data of gained 1-methyl-5-nitroimidazole is as follows: 1 H NMR (300MHz, CDCl 3)δ7.98 (d, J=0.8Hz, 1H), 7.55 (s, 1H), 4.00 (s, 3H); ESI-MS: 128.0 (M+1)
[0048] Step 2: Preparation of 1-...
Embodiment 2
[0054] Example 2: D 3 -Synthesis of ronidazole
[0055] Step 1: Preparation of 1-trideuteromethyl-5-nitroimidazole
[0056] Add 200mg (1.77mmol) of 4-nitroimidazole, 33.6mg (0.18mmol) of p-toluenesulfonic acid monohydrate and 2ml of CD into a 10ml sealed tube 3 OH, sealed and heated to 150°C under air environment, reacted for 8 hours, cooled, spin off most of the solvent, extracted with saturated aqueous sodium bicarbonate solution (20ml) and (30ml*3) ethyl acetate, and used anhydrous sodium sulfate for the organic phase After drying and filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography [ethyl acetate / n-hexane (volume ratio) was 3:1] to obtain the title compound 1-(trideuteromethyl)-5-nitroimidazole 163mg, yield 69%. 1 H NMR (300MHz, CDCl 3 )δ7.98(s,1H),7.54(s,1H).
[0057] The preparation of 1-trideuteromethyl-5-nitroimidazole can also be obtained by the two-step reaction of step a and step b...
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Abstract
The invention belongs to the technical field of chemical synthesis and discloses a green synthesis method of ronidazole and deuterated derivatives thereof. The method comprises the following steps: 4-nitroimidazole and methanol or deuterated methanol undergo a nitrogen methylation reaction or a nitrogen deuterated methylation reaction under the action of a catalyst to generate 1-methyl-5-nitroimidazole or 1 ‑trideuteromethyl‑5‑nitroimidazole; nucleophilic addition reaction of the resulting product with paraformaldehyde yields 1methyl‑2‑hydroxymethyl‑5‑nitroimidazole or 1‑trideuteromethyl‑ 2‑Hydroxymethyl‑5‑nitroimidazole; the product of nucleophilic addition and urea are heated and reacted in the presence of an accelerator to generate lonidazole or its deuterated derivatives. The raw materials used in the present invention are almost all green reagents, the raw materials are easy to obtain, and the price is low; the conditions are simple, easy to operate, and the pollution is small; the only by-products of the three-step reaction are water and ammonia; the post-treatment method is simple, and the product is easy to purify , the yield is ideal.
Description
technical field [0001] The invention belongs to the technical field of chemical synthesis, and in particular relates to a green synthesis method of ronidazole and deuterated derivatives thereof. Background technique [0002] Ronidazole, the chemical name is 1-methyl-2-carbamoyloxy-5-nitroimidazole. Nitroimidazoles are antibiotic drugs widely used in the prevention and treatment of poultry and human diseases. Lonidazole has anti-parasitic (turkey flagellate, trichomoniasis), anti-fumigation and anti-bacterial effects , especially against Treponema hyodysenteriae is very effective; in addition, it is also a good growth promoter. [0003] In addition, studies have found that these nitroimidazole compounds are potentially carcinogenic and mutagenic, so the European Union, the United States and my country have successively made clear regulations on the use of such drugs, so the detection of nitroimidazole drugs in farmed animals Residues are particularly important to human healt...
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