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Synthesis method of imiquimod intermediate

A synthesis method and intermediate technology, applied in the field of synthesis of imiquimod intermediate quinoline, capable of solving problems such as potential safety hazards in nitration reactions, and achieving the effects of high production efficiency, simple reaction operation, and low price

Active Publication Date: 2021-10-01
江苏法安德医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The nitrification reaction will produce a large amount of strong acid wastewater, and highly toxic brown-yellow gas will be produced during the reaction process. The nitrification reaction itself has certain safety hazards.

Method used

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  • Synthesis method of imiquimod intermediate
  • Synthesis method of imiquimod intermediate
  • Synthesis method of imiquimod intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Step 1, the preparation of compound 2

[0026] In a 500ml four-neck flask, add 200ml of ethanol, 25.83g of quinoline (0.20mol), 42.72g of NBS (0.24mol) and 3.75g of copper nitrate (0.020mol) in sequence, stir at room temperature for 0.5h, then raise the temperature to 50°C for 3h . HPLC detection showed 1-2% starting material remaining. Cool down to 20°C, pour the reaction solution into 200ml of water, and stir for 2h. After suction filtration, the filter cake was stirred with 200 ml of water at room temperature for 1 h, suction filtration, and dried at 50° C. to obtain an off-white solid with a yield of 86.9%.

[0027] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 8.75 (d, 1H), 8.30 (dd, 1H), 8.15 (d, 1H), 7.82 (dd, 1H), 7.76 (d, 1H), 7.62 (dd, 1H).

[0028] Step 2, the preparation of compound 3

[0029] In a 250ml four-necked flask, add 150ml N-methylpyrrolidone, 20.81g compound 2 (0.10mol), 8.04g isobutylamine (0.11mol), 27.64g potassium carbonate (0.20mol), 2.49g potassiu...

Embodiment 2

[0039] Step 1, the preparation of compound 2

[0040] In a 500ml four-neck flask, add 200ml ethanol, 25.83g quinoline (0.20mol), 42.72g NBS (0.24mol) and 1.59g copper oxide (0.020mol) in sequence, stir at room temperature for 0.5h, then raise the temperature to 50°C for 3h . HPLC detection showed 1-2% starting material remaining. Cool down to 20°C, pour the reaction solution into 200ml of water, and stir for 2h. After suction filtration, the filter cake was stirred with 200 ml of water at room temperature for 1 h, suction filtration, and drying at 50°C to obtain an off-white solid with a yield of 77.3%.

[0041] 1 H NMR (400MHz, CDCl 3 )δ (ppm): 8.75 (d, 1H), 8.30 (dd, 1H), 8.15 (d, 1H), 7.82 (dd, 1H), 7.76 (d, 1H), 7.62 (dd, 1H).

[0042] Step 2, the preparation of compound 3

[0043] In a 250ml four-necked flask, add 150ml N-methylpyrrolidone, 20.81g compound 2 (0.10mol), 8.04g isobutylamine (0.11mol), 8.02g sodium hydroxide (0.20mol), 2.49g potassium iodide (0.015 mo...

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Abstract

The invention discloses a synthesis method of an imiquimod intermediate, the synthesis method comprises the following steps: step 1, under the condition of a catalyst, heating quinoline and NBS in a solvent for reaction to obtain a compound 2; step 2, in the solvent, mixing the compound 2 with isobutylamine, adding a catalyst, and carrying out a heating reaction to obtain a compound 3; step 3, heating the compound 3 and NBS in the solvent for reaction to obtain a compound 4; step 4, in the first stage, the compound 4 and formamide are subjected to a heating reaction under the action of the catalyst; and in the second stage, hydrochloric acid is used for treatment to obtain a compound 1. Compared with the prior art, the method has the advantages of low price of initial raw materials, simple reaction operation in each step, high yield, less three wastes and high production efficiency.

Description

technical field [0001] The invention belongs to the technical field of synthesis of imiquimod intermediates, and in particular relates to a synthesis method of an imiquimod intermediate (3-amino-4-(2-methylpropylamino)quinoline. Background technique [0002] Imiquimod (Imiquimodcas, CAS No.99011-02-6), an imidazoquinoline amine interleukin agonist developed and produced by 3M Pharmaceuticals in the United States, belongs to the drug for treating genital warts. It is an immunomodulator that can be clinically used to treat adult genital and perianal genital warts. It is easy to use, well tolerated and has a unique mechanism of action, making it the drug of choice for the treatment of genital warts. In addition, it has been reported that imiquimod can also be used for viral skin diseases such as common warts, flat warts, molluscum contagiosum, and herpes simplex, basal cell carcinoma, Bowen's disease, Bowen-like papulosis, and actinic keratosis , skin T-cell tumor, Kaposi's sa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/42
CPCC07D215/42
Inventor 计雄荣马彦婷周禾
Owner 江苏法安德医药科技有限公司
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