The synthetic method of 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid

Abstract

The invention discloses a synthesizing method for 3'-amino-2'-hydroxy biphenyl-3-carboxylic acid.2-bromine-6-nitrophenol serves as a staring material, 2-bromine-6-aminophenol is obtained through a reduction reaction, ring formation and Suzuki coupling are carried out, a hydrolysis reaction is carried out, and 3'-amino-2'-hydroxy biphenyl-3-carboxylic acid is obtained. According to the method, raw materials are easy to obtain, the path is short, and the method is novel, low in cost, high in yield and environmentally friendly. Tests show that the obtained product is reliable in quality, stable in performance and capable of being further used for preparing a thrombopoietin receptor stimulant, namely, eltrombopag olamine.

Description

technical field

[0001] The invention relates to the field of medicine and chemical industry, in particular to a method for synthesizing 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, which is a key intermediate for synthesizing Eltrombopag. Background technique

[0002] 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid, structural formula (IV)

[0003]

[0004] The chemical name is 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, which is the key intermediate for the preparation of the thrombopoietin receptor agonist-Eltrombopag. There are many reports on its synthesis method, and the specific Synthetic methods are:

[0005] Pyrazolone derivatives as TPO regulators and their preparation, pharmaceutical compositions and use in the treatment of thrombocytopenia such as Deng, Bingchu: CN, 101481352 [P]. Methane protects the hydroxyl group, and then performs Suzuki coupling reaction with 3-carboxyphenylboronic acid, then reduces the nitro group to an amino group through palladium...

Examples

Embodiment 1

[0056] Embodiment 1: the preparation of 2-bromo-6-aminophenol (compound I)

[0057]15g (68.8mmol) of 2-bromo-6-nitrophenol, 300mL of methanol, stirred and dissolved, added 1.84g (34.4mmol) of ammonium chloride, 19.27g (344mmol) of iron powder were added in batches, after the addition was completed, the temperature was raised to reflux Reacted for 2 hours, TLC detected that the reaction was complete, added saturated sodium bicarbonate to adjust pH = 7-8, filtered, the filtrate was spin-dried, added ethyl acetate and water for extraction, and the organic phase was spin-dried to give 2-bromo-6-aminophenol (compound I ) 11.2g, yield 86.5%.

Embodiment 2

[0058] Embodiment 2: the preparation of 2-bromo-6-aminophenol (compound I)

[0059] 15g (68.8mmol) of 2-bromo-6-nitrophenol, 400mL of methanol, stirred and dissolved, 22.36g (344mmol) of zinc powder was added in batches, after the addition was completed, the temperature was raised to reflux for 3 hours, TLC detected that the reaction was complete, and saturated carbonic acid was added Sodium hydrogen was used to adjust the pH to 7-8, filtered, the filtrate was spin-dried, ethyl acetate and water were added for extraction, and the organic phase was spin-dried to obtain 11.38 g of 2-bromo-6-aminophenol (compound I), with a yield of 88%.

Embodiment 3

[0060] Embodiment 3: the preparation of 2-bromo-6-aminophenol (compound I)

[0061] 15g (68.8mmol) of 2-bromo-6-nitrophenol, 300mL of methanol, and 150mL of glacial acetic acid were stirred and dissolved, and 19.27g (344mmol) of iron powder was added in batches. After the addition was completed, the reaction was carried out at room temperature for 3 hours. The reaction was detected by TLC and filtered. , washed with water, the filtrate was spin-dried, washed with saturated sodium bicarbonate, then washed with saturated brine, and the organic phase was spin-dried to obtain 11.38 g of 2-bromo-6-aminophenol (compound I), with a yield of 88%.

technical field

[0001] The invention relates to the field of medicine and chemical industry, in particular to a method for synthesizing 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, which is a key intermediate for synthesizing Eltrombopag. Background technique

[0002] 3'-Amino-2'-hydroxybiphenyl-3-carboxylic acid, structural formula (IV)

[0003]

[0004] The chemical name is 3'-amino-2'-hydroxybiphenyl-3-carboxylic acid, which is the key intermediate for the preparation of the thrombopoietin receptor agonist-Eltrombopag. There are many reports on its synthesis method, and the specific Synthetic methods are:

[0005] Pyrazolone derivatives as TPO regulators and their preparation, pharmaceutical compositions and use in the treatment of thrombocytopenia such as Deng, Bingchu: CN, 101481352 [P]. Methane protects the hydroxyl group, and then performs Suzuki coupling reaction with 3-carboxyphenylboronic acid, then reduces the nitro group to an amino group through palladium...

Examples

Embodiment 1

[0056] Embodiment 1: the preparation of 2-bromo-6-aminophenol (compound I)

[0057]15g (68.8mmol) of 2-bromo-6-nitrophenol, 300mL of methanol, stirred and dissolved, added 1.84g (34.4mmol) of ammonium chloride, 19.27g (344mmol) of iron powder were added in batches, after the addition was completed, the temperature was raised to reflux Reacted for 2 hours, TLC detected that the reaction was complete, added saturated sodium bicarbonate to adjust pH = 7-8, filtered, the filtrate was spin-dried, added ethyl acetate and water for extraction, and the organic phase was spin-dried to give 2-bromo-6-aminophenol (compound I ) 11.2g, yield 86.5%.

Embodiment 2

[0058] Embodiment 2: the preparation of 2-bromo-6-aminophenol (compound I)

[0059] 15g (68.8mmol) of 2-bromo-6-nitrophenol, 400mL of methanol, stirred and dissolved, 22.36g (344mmol) of zinc powder was added in batches, after the addition was completed, the temperature was raised to reflux for 3 hours, TLC detected that the reaction was complete, and saturated carbonic acid was added Sodium hydrogen was used to adjust the pH to 7-8, filtered, the filtrate was spin-dried, ethyl acetate and water were added for extraction, and the organic phase was spin-dried to obtain 11.38 g of 2-bromo-6-aminophenol (compound I), with a yield of 88%.

Embodiment 3

[0060] Embodiment 3: the preparation of 2-bromo-6-aminophenol (compound I)

[0061] 15g (68.8mmol) of 2-bromo-6-nitrophenol, 300mL of methanol, and 150mL of glacial acetic acid were stirred and dissolved, and 19.27g (344mmol) of iron powder was added in batches. After the addition was completed, the reaction was carried out at room temperature for 3 hours. The reaction was detected by TLC and filtered. , washed with water, the filtrate was spin-dried, washed with saturated sodium bicarbonate, then washed with saturated brine, and the organic phase was spin-dried to obtain 11.38 g of 2-bromo-6-aminophenol (compound I), with a yield of 88%.

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