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Preparation method of nintedanib key intermediate

A nintedanib and intermediate technology, which is applied in the field of pharmaceutical intermediate synthesis, can solve the problems of high reaction environment, equipment and operator requirements, limited feasibility of industrial production, harsh reaction conditions, etc., to avoid flammable Explosive, ensure the reaction yield, the effect of mild reaction conditions

Active Publication Date: 2021-10-26
长沙康鹏医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0007] The synthesis of the key intermediate compound I, in which the last step needs to be obtained through nitro reduction reaction, the main preparation method requires the use of a hydrogenation reactor, which requires hydrogenation, pressurization and other operations, because of its relatively high requirements for the reaction environment, equipment and operators. High, there are limitations in the method of industrial mass production, which limits the feasibility of its industrial production
In addition, Chinese patent CN 111777576 A reports a preparation method of a key intermediate of nintedanib, which provides three schemes, the first scheme using trichlorosilane and organic base for nitro reduction reaction; the second scheme Utilize ammonium formate and dry palladium carbon with a palladium content of 10% for nitro reduction reaction; the third scheme uses hydrazine hydrate, ferric chloride and activated carbon for nitro reduction reaction, and the first scheme trichlorosilane reacts with water Vigorous, poisonous gas will be released, and the reaction conditions are relatively harsh; the catalyst used in the second scheme is dry palladium carbon with a palladium content of 10%, and the palladium carbon consumption is relatively large, and the water content is low. Its potential safety hazard is higher, and cost is also higher; In the third scheme, the consumption of hydrazine hydrate is relatively large, and the yields of the three schemes are all relatively low, all about 80%, and they are all synthesized in a small amount in the laboratory without process verify

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  • Preparation method of nintedanib key intermediate
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  • Preparation method of nintedanib key intermediate

Examples

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Effect test

Embodiment 1

[0052] A preparation method of nintedanib key intermediate, comprising the following steps: raw material N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl) ethyl Amide (1.1 kg, 3.77 mol) was put into a 10 L reaction kettle, ethanol (5.5 L) was added, and stirring was started. After the solution was clear, hydrazine hydrate (471.8 g, 9.43 mol) was added, stirred well, and replaced with nitrogen to remove air. Add 5% wet palladium carbon (44.0 g) at a temperature of 0-10 °C, the reaction releases heat and a large amount of bubbles are generated, after the addition is completed, stir until no obvious bubbles are generated, then raise the temperature to 40 °C and stir under reflux for 1 h, then take a sample for TLC (expanded The reagent is dichloromethane:methanol=10:1) to detect that the reaction is complete, stop the reaction.

[0053] The reaction liquid was naturally cooled down to room temperature, and the bottom valve of the reactor was opened to put the reaction liquid ...

Embodiment 2

[0063] A preparation method of nintedanib key intermediate, comprising the following steps: raw material N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl) ethyl Amide (1.1 kg, 3.77 mol) was put into a 10 L reaction kettle, tetrahydrofuran (5.5 L) was added, and stirring was started. After the solution was clear, hydrazine hydrate (660.5 g, 13.2 mol) was added, stirred well, and replaced with nitrogen five times. Add 5% wet palladium carbon (88.0 g) at a temperature control of 0-10 °C, the reaction releases heat and a large number of bubbles are generated, after the addition is completed, stir until no obvious bubbles are generated, heat up to 80 °C, stir and reflux for 0.5 h, and take a sample for TLC (expanded The reagent is dichloromethane:methanol=10:1) to detect that the reaction is complete, stop the reaction.

[0064] The reaction liquid was naturally cooled down to room temperature, and the bottom valve of the reactor was opened to put the reaction liquid into the r...

Embodiment 3

[0066] A preparation method of nintedanib key intermediate, comprising the following steps: raw material N-methyl-2-(4-methylpiperazin-1-yl)-N-(4-nitrophenyl) ethyl Amide (1 kg, 3.42 mol) was put into a 10 L reaction kettle, ethanol (5 L) was added, and stirring was started. After the solution was clear, hydrazine hydrate (1.318 kg, 26.3 mol) was added first, and then activated carbon (50.0 g) was added in turn. and anhydrous ferric chloride (10.0 g), heated to 80 °C, stirred and refluxed for 3.5 h, sampled by TLC (developing solvent: dichloromethane: methanol = 10: 1) to check that the reaction was complete, and stopped the reaction.

[0067] The reaction solution was naturally cooled down to room temperature, opened the bottom valve of the reaction kettle, put the reaction solution into the receiving bucket, filtered through a 10 L filter device, washed the filter cake with methanol for 3 times, put the filtrate back into the 10 L reaction kettle, and desolvated under reduced...

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Abstract

The invention provides a method for preparing a key intermediate of nintedanib, belonging to the technical field of synthesis of pharmaceutical intermediates. There are two preparation methods, wherein the first method includes the following steps: using alcohol reagents or tetrahydrofuran as a solvent, compound IV uses hydrazine hydrate as a reducing agent, and palladium carbon (Pd / C) as a catalyst to carry out the nitro reduction reaction to complete, The catalyst is removed by filtration under the protection of nitrogen, the solvent is removed by precipitating, dissolving with dichloromethane, filtering to remove impurities, and precipitating to obtain compound I; method two includes the following steps: compound IV uses hydrazine hydrate as a reducing agent, anhydrous ferric chloride Carry out the nitro reduction reaction with activated carbon as a catalyst until complete, remove the catalyst by filtration, remove the solvent by precipitating, dissolve in dichloromethane, dry with anhydrous sodium sulfate, filter, and precipitate to obtain compound Ⅰ. The preparation method provided by the invention has high yield, strong operability and high safety, belongs to an environment-friendly process, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide, a key intermediate of nintedanib (Compound I) Preparation method. Background technique [0002] Nintedanib (BIBF1120), chemical name (3Z)-[1-[4-[N-methyl-N-[2-(4-methyl-1-piperazinyl)acetyl]amino]aniline Base]-1-phenylene]-2-oxo-2,3-dihydro-1H-indole-6-carboxylate, a multi-target protein tyrosine developed by Boehringer Ingelheim, Germany Kinase inhibitors, which can simultaneously inhibit vascular endothelial growth factor receptors (VEGFR 1-3), platelet-derived growth factor receptors (PDGFR α, β) and fibroblast growth factor receptors (FGFR 1-3), for the treatment of Idiopathic pulmonary fibrosis (IPF). In addition, clinical studies have shown that nintedanib has anti-tumor effects on non-small cell non-cancer (NSCLC), colorectal cancer (CRC), ovarian cancer (OC), liver cancer ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D295/15B01J27/128B01J21/18
CPCC07D295/15B01J27/128B01J21/18
Inventor 薛海鹏闵雄唐承顺宋嘉栖蔡芬
Owner 长沙康鹏医药有限公司