Preparation method of 3'-nitro-2'-hydroxybiphenyl-3-formic acid

Abstract

The invention provides a preparation method of 3'-nitro-2'-hydroxybiphenyl-3-formic acid. The method uses 2-halogenated acrolein and nitromethane as starting raw materials, obtains 2-halo-4-nitro-n-butyraldehyde through an addition reaction, obtains 2-(3-alkoxycarbonyl)phenyl-4-halo-6-nitro-n-hexa-2-enoate through dehydration and condensation with 3-alkoxycarbonyl phenylacetate, obtains 3'-nitro-2'-hydroxybiphenyl-3-formate through a cyclisation reaction and a hydrolysis reaction, and obtains the 3'-nitro-2'-hydroxybiphenyl-3-formic acid through acidification. The method of the invention has the advantages of cheap and easily available raw materials, simple and short process flow, low cost, less waste acid and wastewater production amount, environment protection, good reaction selectivity,less side reactions and high product yield and purity, and is suitable for large-scale production.

Description

technical field

[0001] The invention relates to a preparation method of 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid, which belongs to the technical field of medicinal chemistry. Background technique

[0002] Eltrombopag, chemical name: 3'-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro -4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-bis-aminoethanol salt (1:2), is a small Molecular Thrombopoietin Receptor Agonist. Eltrombopag was approved by the FDA in November 2008 and launched in the United States (trade name: Promacta), for the first time as a short-term treatment of chronic idiopathic thrombocytopenic purpura (ITP) drug, and is the first oral drug approved for the treatment of adults with chronic ITP. Non-peptide thrombopoietin receptor agonist. In November 2012, Eltrombopag was approved for the treatment of thrombocytopenia in patients with chronic hepatitis C. Subsequently, clinical studies confirmed that Eltrombopag can not only promote ...

Examples

Embodiment 1

[0052] Embodiment 1: the preparation of 2-chloro-4-nitro n-butyraldehyde (Ⅱ1)

[0053] Add 30.0 g of THF, 9.0 g (0.1 mole) of 2-chloroacrolein, 6.2 g (0.1 mole) of nitromethane, and 0.1 g of DBU into a 500 ml four-necked flask connected with a stirring and thermometer, and stir at 45 to 50 °C React for 5 hours. After the solvent was recovered by distillation, the (80-100°C / 1-2mmHg) fraction was collected by vacuum distillation to obtain 13.9 g of 2-chloro-4-nitro-n-butyraldehyde (II1), with a yield of 91.8% and a gas phase purity of 99.7%.

Embodiment 2

[0054] Embodiment 2: the preparation of 2-chloro-4-nitro n-butyraldehyde (Ⅱ1)

[0055] Add 90.0 g (1.0 mol) of 2-chloroacrolein, 64.0 g (1.0 mol) of nitromethane, and 1.0 g of DBU into a 500 ml four-neck flask connected with a stirring and thermometer, and stir at 60 to 65° C. for 5 hours. Fractions (80-100°C / 1-2mmHg) were collected by distillation under reduced pressure to obtain 149.3 g of 2-chloro-4-nitro-n-butyraldehyde (II1), with a yield of 98.6% and a gas phase purity of 99.6%.

Embodiment 3

[0056] Embodiment 3: the preparation of 2-bromo-4-nitro n-butyraldehyde (Ⅱ2)

[0057] Add 30.0 g of acetonitrile, 13.5 g (0.1 mole) of 2-bromoacrolein, 6.2 g (0.1 mole) of nitromethane, and 0.1 g of DBU into a 500 ml four-neck flask connected with a stirring and thermometer, and stir at 55 to 60 ° C React for 3 hours. After recovering the solvent by distillation, the (95-115°C / 1-2mmHg) fraction was collected by vacuum distillation to obtain 17.6 g of 2-bromo-4-nitro-n-butyraldehyde (II2), with a yield of 89.8% and a gas phase purity of 99.5%.

technical field

[0001] The invention relates to a preparation method of 3'-nitro-2'-hydroxybiphenyl-3-carboxylic acid, which belongs to the technical field of medicinal chemistry. Background technique

[0002] Eltrombopag, chemical name: 3'-{(2Z)-2-[1-(3,4-xylyl)-3-methyl-5-oxo-1,5-dihydro -4H-pyrazole-4-ylidene]hydrazino}-2'-hydroxy-3-biphenylcarboxylic acid-bis-aminoethanol salt (1:2), is a small Molecular Thrombopoietin Receptor Agonist. Eltrombopag was approved by the FDA in November 2008 and launched in the United States (trade name: Promacta), for the first time as a short-term treatment of chronic idiopathic thrombocytopenic purpura (ITP) drug, and is the first oral drug approved for the treatment of adults with chronic ITP. Non-peptide thrombopoietin receptor agonist. In November 2012, Eltrombopag was approved for the treatment of thrombocytopenia in patients with chronic hepatitis C. Subsequently, clinical studies confirmed that Eltrombopag can not only promote ...

Examples

Embodiment 1

[0052] Embodiment 1: the preparation of 2-chloro-4-nitro n-butyraldehyde (Ⅱ1)

[0053] Add 30.0 g of THF, 9.0 g (0.1 mole) of 2-chloroacrolein, 6.2 g (0.1 mole) of nitromethane, and 0.1 g of DBU into a 500 ml four-necked flask connected with a stirring and thermometer, and stir at 45 to 50 °C React for 5 hours. After the solvent was recovered by distillation, the (80-100°C / 1-2mmHg) fraction was collected by vacuum distillation to obtain 13.9 g of 2-chloro-4-nitro-n-butyraldehyde (II1), with a yield of 91.8% and a gas phase purity of 99.7%.

Embodiment 2

[0054] Embodiment 2: the preparation of 2-chloro-4-nitro n-butyraldehyde (Ⅱ1)

[0055] Add 90.0 g (1.0 mol) of 2-chloroacrolein, 64.0 g (1.0 mol) of nitromethane, and 1.0 g of DBU into a 500 ml four-neck flask connected with a stirring and thermometer, and stir at 60 to 65° C. for 5 hours. Fractions (80-100°C / 1-2mmHg) were collected by distillation under reduced pressure to obtain 149.3 g of 2-chloro-4-nitro-n-butyraldehyde (II1), with a yield of 98.6% and a gas phase purity of 99.6%.

Embodiment 3

[0056] Embodiment 3: the preparation of 2-bromo-4-nitro n-butyraldehyde (Ⅱ2)

[0057] Add 30.0 g of acetonitrile, 13.5 g (0.1 mole) of 2-bromoacrolein, 6.2 g (0.1 mole) of nitromethane, and 0.1 g of DBU into a 500 ml four-neck flask connected with a stirring and thermometer, and stir at 55 to 60 ° C React for 3 hours. After recovering the solvent by distillation, the (95-115°C / 1-2mmHg) fraction was collected by vacuum distillation to obtain 17.6 g of 2-bromo-4-nitro-n-butyraldehyde (II2), with a yield of 89.8% and a gas phase purity of 99.5%.

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