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Preparation method of avanafil intermediate

A technology of avanafil and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve the problems of low purity of m-CPBA chemicals, unsuitability for large-scale industrialization, and increased difficulty of post-processing, etc. Industrialized production, reduced manpower, and simple operation

Active Publication Date: 2018-10-16
无锡富泽药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] (1) The reaction control is difficult, and the methylthio group is easily over-oxidized to obtain a sulfone structure;
[0006] (2) Nitrogen oxides with genotoxicity will be produced during the oxidation process, and residues in the raw materials are a serious challenge to product quality;
[0007] (3) The purity of m-CPBA chemicals is generally not high, and the by-products produced during the reaction will increase the difficulty of post-processing;
[0008] (4) As an oxidizing agent, the reaction residue of m-CPBA will cause production danger if not handled in time, so it is not suitable for large-scale industrialization

Method used

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  • Preparation method of avanafil intermediate

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Experimental program
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Effect test

Embodiment 1

[0038] 4-(3-Chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol), ascorbic acid (52.8g, 300mmol) were dissolved in 500mL toluene, added Iron tetraphenylporphyrin (0.67g, 1mmol) was fully stirred to disperse evenly, and transferred to a pressurized reactor. Air was introduced at 25°C, the reaction pressure was adjusted and controlled at 1.0 atm, and the reaction was stirred for 8 hours. After the reaction, the metalloporphyrin catalyst in the reaction solution was removed by filtration, and the organic phase was washed with purified water and saturated NaCl once, and concentrated under reduced pressure to obtain a white thick liquid, which was the avanafil intermediate, 4-(3 -Chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylsulfinylpyrimidine 36.47g (95.0% yield, 99.3% purity) was directly used in the next reaction.

[0039] IR(neat)cm -1 :3350,1695,1590,1570,1500,1460,1440

[0040] MS(m / z):384(M+H) +

Embodiment 2

[0042] Dissolve 4-(3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol), isobutyraldehyde (7.2g, 100mmol) in 1000mL acetic acid Ethyl ester was added manganese tetraphenylporphyrin (0.33g, 0.5mmol) and stirred well to disperse evenly, and then transferred to a pressurized reactor. Oxygen was introduced at 25° C., the reaction pressure was adjusted and controlled at 5.0 atm, and the reaction was stirred for 16 hours. After the reaction, the metalloporphyrin catalyst in the reaction solution was removed by filtration, the organic phase was washed with purified water and saturated NaCl once, and concentrated under reduced pressure to obtain a white thick liquid, which was the avanafil intermediate, 4-( 35.05 g of 3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylsulfinylpyrimidine (91.3% yield, 98.0% purity) was directly used in the next reaction.

Embodiment 3

[0044]Dissolve 4-(3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylthiopyrimidine (36.8g, 100mmol), propionaldehyde (29.0g, 500mmol) in 100mL tetrahydrofuran, Add cobalt tetraphenylporphyrin (0.07 g, 0.1 mmol) and stir well to make the dispersion uniform, and transfer to a pressurized reactor. Air was introduced at 25°C, the reaction pressure was adjusted and controlled at 2.5 atm, and the reaction was stirred for 20 hours. After the reaction was completed, the metalloporphyrin catalyst in the reaction solution was removed by filtration, and the reaction solution was concentrated under reduced pressure to dryness. Add 500mL ethyl acetate and stir to dissolve, the organic phase is washed with purified water and saturated NaCl once, and concentrated under reduced pressure to obtain a white thick liquid, which is the intermediate of avanafil, 4-(3-chloro-4-methyl Oxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine 34.05g (yield 88.7%, purity 98.6%) was directly use...

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Abstract

The invention provides a preparation method of an avanafil intermediate. The preparation method comprises the following steps: dissolving a starting raw material 4-(3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylthiopyrimidine in a reaction solvent; adding metal porphyrin as a catalyst, thoroughly stirring for dispersing uniformly, and transferring to a reaction kettle; inflating an oxidizing gas at room temperature, and reacting while stirring to produce 4-(3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl-2-methylsulfinylpyrimidine. According to the preparation method, with substituentmetal porphyrin as the catalyst and air or oxygen as an oxidant, a sulfoxide intermediate of avanafil is prepared through catalytic oxidation of a thioether compound under a normal temperature condition; after a reaction, a target product is easily separated from the catalyst and has the characteristics of high yield, good purity and the like; the difficulty of separation and purification of theproduct in the later stage is greatly reduced; the recycled catalyst can be reused; the preparation cost can be significantly reduced.

Description

technical field [0001] The present invention relates to the technical field of pharmaceutical chemical synthesis, in particular to a preparation method of an avanafil intermediate, and further relates to 4-(3-chloro-4-methoxybenzylamino) 5-ethoxycarbonyl- The preparation method of 2-methylsulfinylpyrimidine. Background technique [0002] Avanafil CAS registration number: 330784-47-9, see the compound structure figure 1 shown. It is a drug developed by the American Vivus (Vivus) pharmaceutical company authorized by Japan Tanabe Mitsubishi Pharmaceutical Co., Ltd. for the treatment of male erectile dysfunction. On April 27, 2012, it was approved by the US FDA and launched in the United States under the trade name of Stendra. [0003] At present, the preparation route of avanafil intermediate refers to figure 2 shown. The intermediate 1,4-(3-chloro-4-methoxybenzylamino)5-ethoxycarbonyl-2-methylsulfinylpyrimidine plays a prominent role in the synthesis of avanafil and is i...

Claims

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Application Information

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IPC IPC(8): C07D239/47
CPCC07D239/47Y02P20/584
Inventor 李浩源吴鹏程蔡亮亮何智健
Owner 无锡富泽药业有限公司
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