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A kind of preparation method of Arbidol key intermediate
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A technology of arbidol and intermediates, applied in the field of drug synthesis, can solve the problems of cumulative explosion, toxicity, easy to upgrade, etc., and achieve the effects of improving quality, reducing environmental pollution and convenient operation.
Active Publication Date: 2022-03-11
浦拉司科技(上海)有限责任公司
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Although it can be synthesized in one step, the raw material benzoquinone has strong toxicity and is easy to catalyze. During the Nenitzescu reaction, due to the heat release, there will be a cumulative explosion.
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Embodiment 1
[0021] The first step: the synthesis of intermediate formula 2
[0022]
[0023] In a reaction flask, dissolve 100 g (0.403 mol) of 4-aminophenylboronic acid methyliminodiacetate in 500 mL of 1,2-dichloroethane, cool to -5°C to 0°C, and add NBS 82.5 in batches g (0.463mol), after the addition was completed, it was raised to room temperature and stirred for 2 hours. TLC showed that the reaction was complete. Add sodium bisulfite to quench, separate layers, wash the organic phase with water, and dry the organic phase with anhydrous sodium sulfate to obtain 3-bromo-4-aminophenylboronic acid methyliminodiacetate / 1,2-dichloroethane Solution 790g, liquid phase external standard yield 90.8%, HPLC: 94.5%; HNMR (400MHz, CDCl 3 ):7.20-7.14 (m, 1H), 6.91-6.72 (m, 2H), 6.27 (s, 2H), 3.30-3.25 (m, 4H), 2.24 (s, 3H); directly used in the next reaction.
[0024] The second step: the synthesis of intermediate formula 3
[0025] In the reaction bottle, add the above-mentioned 3-bromo-4-a...
Embodiment 2
[0031]
[0032] The first step: the synthesis of intermediate 2
[0033] In the reaction flask, dissolve 80 g (0.402 mol) of potassium 4-aminophenyltrifluoroborate in 800 mL of ethyl acetate, cool to -5°C to 0°C, add 82.5 g (0.463 mol) of NBS in batches, and add After completion, it was raised to room temperature and stirred for 5 hours. TLC showed that the reaction was complete, quenched by adding sodium bisulfite, separated layers, washed the organic phase with water, concentrated the organic phase, added methyl tert-butyl ether / n-heptane (3 / 1) mixed solvent to make a slurry to obtain 3-bromo-4- Aminophenyl potassium trifluoroborate 99.8g, yield 89.3%, HPLC 97.1%. 1 HNMR (400MHz, DMSO-d 6 ):7.53-7.42(m,1H),7.10-6.97(m,2H),6.27(s,2H).
[0034] Step 2: Synthesis of Intermediate 3
[0035] In the reaction flask, add 99.8g (0.359mol) of potassium 3-bromo-4-aminophenyltrifluoroborate, 280mL of dioxane and 2.1g of indium trichloride, stir well, raise the temperature to 50°C, ...
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Abstract
The invention discloses a method for preparing a key intermediate of Arbidol, which belongs to the technical field of drug synthesis. 4‑Aminophenylboronic acid derivative 1 reacts with NBS bromination to obtain intermediate 2, then condenses with ethyl acetoacetate under the action of indium catalyst to obtain intermediate 3, then copper salt catalyzed ring closure reaction to obtain intermediate 4, and finally passes hydrogen peroxide Oxidation affords ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate 5. The process of the present invention is simple and stable in operation, high in yield, and environmentally friendly. Compared with the existing process, benzoquinone that is highly toxic and easy to decompose is avoided, and the production safety risk of the existing Arbidol intermediate is greatly reduced. Up to 99.5%, single impurity less than 0.1%.
Description
technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of a key intermediate of Arbidol. Background technique [0002] Arbidol: Arbidol, the chemical name is 6-bromo-4-dimethylaminomethyl-5-hydroxy-1-methyl-2-(phenylthiomethyl)-1H-indole-3-carboxylic acid Ethyl ester, an antiviral drug developed by the Soviet Medicinal Chemistry Research Center, is suitable for the prevention and treatment of influenza A or B in adults and children, acute viral respiratory tract infection, severe acute respiratory disease syndrome, and concurrent bronchitis and pneumonia . Clinical application proves that Arbidol has few side effects and is not easy to produce drug resistance, so it is an antiviral drug with good clinical application prospects. [0003] 5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester, English name: ethyl 5-hydroxy-2-methyl-1H-indole-3-carboxylate, molecular formula C 12 h 13 NO ...
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