Preparation method of nintedanib

Abstract

The invention relates to a preparation method of nintedanib (I). The preparation method comprises the steps that 2-oxoindole-6-methyl formate (III) and benzaldehyde (II) are used as raw materials to generate a condensation reaction, so as to obtain a compound IV; then halogen or halogenating reagents are added to generate a substitution reaction, so as to obtain a compound V; the compound V and the compound IV are condensed under the action of alkali, so as to obtain the nintedanib (a compound I). The method has the advantages of short reaction time, low cost, high yield and environmental friendliness of used reagents and is suitable for industrial production. The structural formulas are shown in the description.

Description

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of nintedanib. Background technique

[0002] Nintedanib ethanesulfonate is an oral triple tyrosine kinase inhibitor developed by Boehringer Ingelheim, Germany. It is currently mainly used in the treatment of tumors, such as colorectal cancer, ovarian cancer, and multiple myeloma. Research on respiratory diseases mainly revolves around the clinical treatment of advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF).

[0003] In June 2014, Boehringer Ingelheim announced that the marketing authorization application for nintedanib ethanesulfonate for the treatment of idiopathic pulmonary fibrosis (IPF) was confirmed by the European Medicines Agency (EMA) and included in the accelerated approval list by EMA . On October 15, 2014, the US Food and Drug Administration (FDA) approved nintedanib ethanesulfonate (trade name: Ofev), ...

Examples

Embodiment 1

[0030] Preparation of Compound IV

[0031]

[0032] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction flask, start stirring, then add 16.8ml (17.6g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 ℃, reacted for 2 hours, cooled naturally to 20℃-30℃, filtered the precipitate, washed the filter cake with absolute ethanol, and dried in vacuum at 50℃ for 5 hours to obtain 40.2g of yellow solid (IV), yield: 96.0%.

[0033] Preparation of Compound V

[0034]

[0035] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 9.6ml (29.9g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours. After the reaction was completed, the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and ...

Embodiment 2

[0042] Preparation of Compound IV

[0043] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction bottle, start stirring, then add 30.3ml (31.8g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 After reacting at ℃ for 2 hours, cool naturally to 20℃-30℃, filter the precipitate, wash the filter cake with absolute ethanol, and dry in vacuum at 50℃ for 5 hours to obtain 38.7g of yellow solid (IV), yield: 92.4%.

[0044] Preparation of Compound V

[0045] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 3.1ml (9.7g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours , the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and vacuum-dried at 60°C to obtain 36.1g of off-white solid ...

technical field

[0001] The invention relates to the technical field of drug synthesis, in particular to a preparation method of nintedanib. Background technique

[0002] Nintedanib ethanesulfonate is an oral triple tyrosine kinase inhibitor developed by Boehringer Ingelheim, Germany. It is currently mainly used in the treatment of tumors, such as colorectal cancer, ovarian cancer, and multiple myeloma. Research on respiratory diseases mainly revolves around the clinical treatment of advanced non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF).

[0003] In June 2014, Boehringer Ingelheim announced that the marketing authorization application for nintedanib ethanesulfonate for the treatment of idiopathic pulmonary fibrosis (IPF) was confirmed by the European Medicines Agency (EMA) and included in the accelerated approval list by EMA . On October 15, 2014, the US Food and Drug Administration (FDA) approved nintedanib ethanesulfonate (trade name: Ofev), ...

Examples

Embodiment 1

[0030] Preparation of Compound IV

[0031]

[0032] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction flask, start stirring, then add 16.8ml (17.6g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 ℃, reacted for 2 hours, cooled naturally to 20℃-30℃, filtered the precipitate, washed the filter cake with absolute ethanol, and dried in vacuum at 50℃ for 5 hours to obtain 40.2g of yellow solid (IV), yield: 96.0%.

[0033] Preparation of Compound V

[0034]

[0035] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 9.6ml (29.9g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours. After the reaction was completed, the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and ...

Embodiment 2

[0042] Preparation of Compound IV

[0043] Add 28.7g of methyl 2-oxindole-6-carboxylate and 130ml of ethanol to a 250ml reaction bottle, start stirring, then add 30.3ml (31.8g) of benzaldehyde, 2.97ml of piperidine, heat to 70°C—80 After reacting at ℃ for 2 hours, cool naturally to 20℃-30℃, filter the precipitate, wash the filter cake with absolute ethanol, and dry in vacuum at 50℃ for 5 hours to obtain 38.7g of yellow solid (IV), yield: 92.4%.

[0044] Preparation of Compound V

[0045] Add 30g of compound IV and 360ml of dichloromethane into a 500ml reaction flask, cool to 0-5°C with ice water, add 3.1ml (9.7g) of bromine dropwise, raise the temperature to 20-30°C after dropping, and react for 3 hours , the reaction solution was washed once with 150ml of water, and the dichloromethane layer was concentrated and dried to obtain an oily substance, which was crystallized by adding 200ml of absolute ethanol, filtered, and vacuum-dried at 60°C to obtain 36.1g of off-white solid ...

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