A new preparation process of azilsartan

Abstract

The invention relates to a preparation method for azilsartan. The method is characterized by comprising the following steps: enabling 2-fluorine-3-bromine nitrobenzene to react with a midbody 3 prepared from suzuki reaction, replacing 2 fluorines and then reducing by nitro group; reacting with tetraethyl orthocarbonate, closing the ring and forming a benzimidazole ring; reacting with hydroxylamine hydrochloride and compounding a phenyl substituted oxadiazole ring under the effect of CDI; forming formic acid with carbon dioxide under the catalysis of n-butyllithium, thereby acquiring the product. The preparation method has the advantages of easily acquired raw materials, simple process, high overall yield, few side products, simplicity in post-processing and suitability for industrial production.

Description

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular to a method for synthesizing Azilsartan. Background technique

[0002] Azilsartan is a new type of antihypertensive drug developed by Japan's Takeda Pharmaceutical Company. Its trade name is Edabi. The patent protection period is until 2025. It belongs to the 3.1 new drug category of chemical drugs. It was approved for marketing by the US FDA in February 2011, and was approved for marketing in Japan on January 28, 2012. It is suitable for antihypertensive clinically, and can competitively and reversibly block the combination of angiotensin and AT1 receptors to lower blood pressure. It is superior to valsartan and olmesartan in antihypertensive aspects, and is used in the clinic. As the prodrug of azilsartan medoxomil, after oral administration, it will be hydrolyzed into azilsartan by aromatic esterase in the gastrointestinal tract or plasma, and has a strong and long...

Examples

Embodiment 1

[0020] The synthesis of embodiment 1. compound 3:

[0021] Compound 1 (7.4g, 40mmol), compound 2 (5.9g, 40mmol), Na 2 CO 3 (2M, 80 mmol, ), Pd(dppf)Cl 2 (2mmol) and 150mL of ethylene glycol dimethyl ether were added successively in a 500mL flask under a nitrogen atmosphere, refluxed for 2 hours, then extracted with ethyl acetate, NaHCO3 solution, brine were washed successively, dried over anhydrous magnesium sulfate, filtered, The crude product obtained by concentration was directly used in the next step without purification.

Embodiment 2

[0022] The synthesis of embodiment 2. compound 5:

[0023] Compound 4 (9.0g, 41mmol), Na 2 CO 3 (8.7g, 82mmol), compound 3 (8.1g, crude product) and 150mL of DMF were added to a 250mL flask, reacted at 130°C for 2h, cooled, concentrated, diluted with water, extracted with ethyl acetate, dried, and purified by column chromatography 5 (13g, yield, 80%)

Embodiment 3

[0024] The synthesis of embodiment 3. compound 6:

[0025] SnCl 2 (10g, 54mmol) was added in the ethyl acetate (300mL) solution of compound 5 (13g, 32mmol), then refluxed for 17h, after monitoring that the reaction was complete, direct concentration column chromatography purified to obtain compound 6 (10.5g, yield 87%)

technical field

[0001] The invention belongs to the field of medicine and chemical industry, in particular to a method for synthesizing Azilsartan. Background technique

[0002] Azilsartan is a new type of antihypertensive drug developed by Japan's Takeda Pharmaceutical Company. Its trade name is Edabi. The patent protection period is until 2025. It belongs to the 3.1 new drug category of chemical drugs. It was approved for marketing by the US FDA in February 2011, and was approved for marketing in Japan on January 28, 2012. It is suitable for antihypertensive clinically, and can competitively and reversibly block the combination of angiotensin and AT1 receptors to lower blood pressure. It is superior to valsartan and olmesartan in antihypertensive aspects, and is used in the clinic. As the prodrug of azilsartan medoxomil, after oral administration, it will be hydrolyzed into azilsartan by aromatic esterase in the gastrointestinal tract or plasma, and has a strong and long...

Examples

Embodiment 1

[0020] The synthesis of embodiment 1. compound 3:

[0021] Compound 1 (7.4g, 40mmol), compound 2 (5.9g, 40mmol), Na 2 CO 3 (2M, 80 mmol, ), Pd(dppf)Cl 2 (2mmol) and 150mL of ethylene glycol dimethyl ether were added successively in a 500mL flask under a nitrogen atmosphere, refluxed for 2 hours, then extracted with ethyl acetate, NaHCO3 solution, brine were washed successively, dried over anhydrous magnesium sulfate, filtered, The crude product obtained by concentration was directly used in the next step without purification.

Embodiment 2

[0022] The synthesis of embodiment 2. compound 5:

[0023] Compound 4 (9.0g, 41mmol), Na 2 CO 3 (8.7g, 82mmol), compound 3 (8.1g, crude product) and 150mL of DMF were added to a 250mL flask, reacted at 130°C for 2h, cooled, concentrated, diluted with water, extracted with ethyl acetate, dried, and purified by column chromatography 5 (13g, yield, 80%)

Embodiment 3

[0024] The synthesis of embodiment 3. compound 6:

[0025] SnCl 2 (10g, 54mmol) was added in the ethyl acetate (300mL) solution of compound 5 (13g, 32mmol), then refluxed for 17h, after monitoring that the reaction was complete, direct concentration column chromatography purified to obtain compound 6 (10.5g, yield 87%)

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