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Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline

A technology of methoxyquinoline and synthetic method, which is applied in the field of drug synthesis, can solve the problems of unfavorable large-scale production operation, low yield, and low purity of the reaction system, and achieve the effect of clear reaction process and increased yield

Pending Publication Date: 2022-08-02
NANJING JIEYUN PHARMA TECH CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Although this method has relatively short steps, the Weiersmeier-Hacker reaction exothermic is violent, which is not conducive to large-scale production operations.
At the same time, the one-step reaction involves three reaction steps of aldehyde group, cyclization and chlorination, and there are many reaction possibilities, resulting in low purity of the reaction system and low yield.

Method used

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  • Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline
  • Synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0030] 3-benzyl-6-bromo-2-methoxyquinoline, including the following four steps:

[0031] Synthesis of Compound (I)

[0032] Phosphorus oxychloride (169 g, 1.1 mol) was added dropwise to a solution of N,N-dimethylformamide (80 g, 1.1 mol) in acetonitrile (1000 ml) at 10 °C, and the reaction was stirred at 10 to 20 °C for 0.5 h, add p-bromoaniline (172 g, 1 mol) at 10-20°C, heat up to 80°C for 4-6h after the addition, control the reaction in HPLC, complete the reaction, cool down to 0-5°C, slowly add aqueous sodium hydroxide solution , control the internal temperature below 20 degrees Celsius, add and stir for 0.5h, filter out the solid with a Buchner funnel, rinse with water twice, and dry to obtain 17.4g of off-white solid with a purity of 97.3% and a yield of 86.2%.

[0033] Synthesis of Compound (II)

[0034] Triethylamine (105 g, 1.1 mol) and compound I (200 g, 1.0 mol) were successively added to dichloromethane (1000 ml) at 25 °C, cooled to 0-5 °C in an ice bath, and phe...

Embodiment 2

[0040] 3-benzyl-6-bromo-2-methoxyquinoline, including the following four steps:

[0041] Synthesis of Compound (I)

[0042] Phosphorus oxychloride (30.7 g, 0.2 mol) was added dropwise to a solution of N,N-dimethylformamide (14.6 g, 0.2 mol) in acetonitrile (100 ml) at 10 °C, and stirred at 10 to 20 °C after the addition was complete. After reaction for 0.5h, p-bromoaniline (17.2g, 0.1mol) was added at 10-20°C, the temperature was raised to 80°C for 4-6h, the reaction was controlled by HPLC, the reaction was completed, the temperature was lowered to 0-5°C, and added slowly Aqueous sodium hydroxide solution, control the internal temperature to be lower than 20 degrees Celsius, add and stir for 0.5h, filter out the solid with a Buchner funnel, rinse twice with water, and dry to obtain 15.9g of off-white solid with a purity of 98.2% and a yield of 79.6 %.

[0043] Synthesis of Compound (II)

[0044] Pyridine (8.7 g, 0.11 mol) and compound I (20.0 g, 0.1 mol) were successively a...

Embodiment 3

[0050] 3-benzyl-6-bromo-2-methoxyquinoline, including the following four steps:

[0051] Synthesis of Compound (I)

[0052] Phosphorus oxychloride (23.0 g, 0.15 mol) was added dropwise to a solution of N,N-dimethylformamide (11.0 g, 0.15 mol) in acetonitrile (100 ml) at 10 °C, and stirred at 10 to 20 °C after the addition was complete. After the reaction for 0.5h, p-bromoaniline (17.2g, 0.1mol) was added at 10-20°C, the temperature was raised to 80°C for 4-6h after the addition, and the reaction was controlled by HPLC. After the reaction was completed, the temperature was lowered to 0-5°C and slowly added Sodium hydroxide aqueous solution, control the internal temperature to be lower than 20 degrees Celsius, add and stir for 0.5h, filter out the solid with a Buchner funnel, rinse twice with water, and dry to obtain 17.1g of off-white solid with a purity of 98.5% and a yield of 85.4 %.

[0053] Synthesis of Compound (II)

[0054] Triethylamine (10.5g, 0.11mol) and compound I...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of 3-benzyl-6-bromo-2-methoxyquinoline. The synthesis method comprises the following steps: step 1, reacting p-bromoaniline with phosphorus oxychloride and N, N-dimethylformamide to generate a compound I; step 2, enabling the compound I to react with benzene propionyl chloride to generate N-(4-bromine-2-formyl phenyl)-3-benzene propionamide; 3, reacting the compound II with phosphorus oxychloride to generate a compound III; 4, reacting the compound III with sodium methoxide to generate a compound IV; the reaction process is clearer, and the yield is obviously improved compared with that of the original process; according to the Vilsmeier-Haack provided by the invention, only one aldehyde group is needed, and meanwhile, a solvent is added to participate in the reaction process, so that the problems of insufficient reaction, violent heat release and the like which are not beneficial to large-scale production operation caused by a curing phenomenon in the early-stage reaction of phosphorus oxychloride and N, N-dimethylformamide are avoided.

Description

technical field [0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing 3-benzyl-6-bromo-2-methoxyquinoline. Background technique [0002] Bedaquiline was developed by Johnson & Johnson Pharmaceuticals, Inc., and was approved by the U.S. Food and Drug Administration on December 28, 2012 for the treatment of drug-resistant tuberculosis. Its chemical name is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1-phenyl- 2-Butanol, bedaquiline inhibits the proton transfer chain of mycobacterial ATP synthase and prevents Mycobacterium tuberculosis from using ATP to generate energy, thereby exerting an anti-tuberculosis effect, which is a brand-new anti-tuberculosis. way of action. Bedaquiline is the first anti-TB drug with a new mechanism of action approved for clinical use in more than 40 years, and it is currently the only drug for the treatment of MDR-TB. 3-benzyl-6-bromo-2-methoxyquinoline is a...

Claims

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Application Information

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IPC IPC(8): C07D215/227
CPCC07D215/227
Inventor 宋兴昌陈毅华阳刘郝敏吴晓东
Owner NANJING JIEYUN PHARMA TECH CO LTD
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