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Preparation method of roflumilast

A technology of roflumilast and difluoromethoxybenzoic acid, which is applied in the field of drug synthesis, can solve problems such as unfavorable industrial production, strong corrosion of equipment, and reduced production efficiency, so as to avoid high temperature and reduced pressure distillation and simple production conditions , The effect of increasing the reaction yield

Inactive Publication Date: 2014-11-26
INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

In the route of the above-mentioned literature, due to the presence of thionyl chloride during the reaction, a large amount of hydrogen chloride gas will be produced during the preparation of the acid chloride, which is highly corrosive to the equipment and will pollute the environment, and high temperature and decompression are required in the post-treatment process Distillation and other operations can obtain relatively pure products, which is very unfavorable for industrial production, reduces production efficiency, and has the disadvantages of serious environmental pollution, long production cycle, low yield and high cost.

Method used

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  • Preparation method of roflumilast

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 2

[0036] Dissolve 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (250g) in 2L of dichloromethane, then add 3,5-dichloro-4-aminopyridine (202g) and then Cool down to 0~20°C. Add 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (330g) in batches, stir and lower the temperature by 10-20°C, and stir until the raw materials disappear.

[0037] Dissolve triethylamine (121.2g) in 0.2L of dichloromethane and add it dropwise to the above system. After the addition, continue to stir for 3 hours and then analyze the raw material 3-cyclopropylmethoxy-4-difluoromethoxy by TLC Benzoic acid basically disappeared. Suction filtration, wash the filter cake with a small amount of dichloromethane, then place the filtrate at 0~5°C for 12 hours, a small amount of white precipitate precipitates, filter, evaporate the filtrate to dryness to obtain 206g of the final product Roflumilast, and collect The yield is 85.6%, and the purity is 98.9%.

Embodiment 3

[0039]Dissolve 2,4-dimethoxy-6-chloro-1,3,5-s-triazine (5.25kg) in 3L of dichloromethane, and 3-cyclopropylmethoxy-4-difluoromethane Add oxybenzoic acid (6.6kg) to the above dichloromethane solution, stir and cool down to 0~10°C, add pyridine (2.4kg) dropwise to the above system, continue stirring for 3 hours after the addition, and analyze 3-cyclopropane by TLC The methoxy-4-difluoromethoxybenzoic acid basically disappeared.

[0040] Dissolve 3,5-dichloro-4-aminopyridine (4.07kg) in 2L of dichloromethane and add it dropwise to the reaction solution. Stirring is continued for 2 hours after the addition, and the intermediate active ester disappears according to TLC analysis. Suction filtration, the filtrate once with saturated NaHCO 3 solution, saturated NaCl solution, anhydrous Na 2 SO 4 Drying, suction filtration, and reduced pressure below 45°C yielded 6.432 kg of the final product, roflumilast, with a yield of 92.5% and a purity of 99.3%.

Embodiment 4

[0042] 1-Hydroxybenzotriazole (160.6 g) was dissolved in 2 L of dichloromethane, and 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (258 g) was added to the above dichloromethane In the solution, stir and cool down to -10~0°C, add N-methylmorpholine (121.2g) dropwise to the above system, continue stirring for 3 hours after the addition, TLC analysis of the raw material 3-cyclopropylmethoxy-4 - Difluoromethoxybenzoic acid essentially disappeared.

[0043] 3,5-dichloro-4-aminopyridine (164 g) was added dropwise to the reaction solution, and stirring was continued for 2 h after addition, and the reaction was complete by TLC analysis. Suction filtration, the filtrate was successively washed with saturated NaHCO 3 solution, saturated NaCl solution, anhydrous Na 2 SO 4 Dry, filter with suction, and reduce pressure below 45°C to obtain the final product Roflumilast 260.5. Yield 92.0%, purity 99.1%.

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Abstract

The invention belongs to the technical field of drug synthesis, and specifically relates to a preparation method of roflumilast. The preparation method comprises the following steps: (1) dissolving an activating reagent into a solvent, adding 3-cyclopropylmethoxyl-4-difluoromethoxylbenzoic acid into the solvent to carry out reactions in the presence of an alkali; (2) adding 3,5-dichloro-4-aminopyridine into the solution obtained in the step (1) to carry out reactions so as to obtain the roflumilast. The 2,4-dimethoxyl-6-chloro-1,3-5-s-triazine and other reagents used in the preparation method are conventional reagents in production, and are easily available. Moreover, the production conditions are simple. Sulfoxide chloride, which has high requirements on production conditions and severely pollutes the environment, is replaced; and conditions that are not suitable for industrialization such as high temperature reduced pressure distillation, and the like are avoided at the same time, so the preparation method is a novel synthesis method suitable for industrial operation. Because the synthesis route is reasonably designed, and the reaction activity is high, the reaction yield is prominently improved, and can reach 86-95%.

Description

technical field [0001] The invention belongs to the technical field of drug synthesis, and in particular relates to a preparation method of roflumilast. Background technique [0002] Roflumilast [0003] Molecular formula: C 17 h 14 Cl 2 f 2 N 2 o 3 [0004] Molecular weight: 403.21 [0005] Structural formula: [0006] In July 2010, the European Union approved the listing of Nycomed's roflumilast (Daxas) for the treatment of chronic obstructive pulmonary disease (COPD). This product is a selective phosphodiesterase 4 (PDE4) inhibitor, which is a new class of COPD treatment drug approved by the European Union for the first time in more than ten years. Mechanism of action: Roflumilast selectively inhibits PDE4, blocks inflammatory response signal transmission, and then inhibits lung tissue damage caused by respiratory diseases such as COPD and asthma. [0007] The synthesis of roflumilast is currently mainly to react 3-cyclopropylmethoxy-4-difluoromethoxybenzoic ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D213/75
CPCC07D213/75
Inventor 孙敬勇赵爱慧汪海洋孙捷石秀娟窦春水王延风
Owner INST OF PHARMACY SHANDONG PROV ACAD OF MEDICAL SCI
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