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Preparation method of osimertinib intermediate

A technology for intermediates and compounds, applied in the direction of organic chemistry, etc., can solve the problems of low total yield and high cost of raw materials, and achieve the effects of low cost, high reaction selectivity and environmental protection.

Active Publication Date: 2019-03-19
XINFA PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] Aiming at the deficiencies of the prior art, especially the defects of high raw material cost and low total yield, the present invention provides an osimertinib intermediate 2-(2-methoxy-4-fluoro-5-nitro)aniline A low-cost synthetic method for base-4-(N-methylindol-3-yl)pyrimidine, the raw materials used are cheap and easy to obtain, the process route is short, and the waste water discharge is greatly reduced, which is beneficial to environmental protection, and the whole reaction process is The total yield is as high as more than 85%, and it is easy for industrial production

Method used

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  • Preparation method of osimertinib intermediate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] Example 1: Preparation of 1-(2-nitro)phenyl-4,4-dimethoxy-2-butanone (IV)

[0064] Into a 500 ml four-neck flask, add 68.5 g (0.5 mole) o-nitrotoluene, 69.0 g (0.6 mole) 3,3-dimethoxypropionitrile, 0.8 g piperidine, react at 110 ° C for 4 hours, gas phase detection The reaction is complete. Reduce to 25°C, add 50g of 10% ammonium chloride aqueous solution, 250g of dichloromethane, stir at 25-30°C for 2 hours. The reaction solution was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with 50 g of dichloromethane each time, and the organic phases were combined. The organic phase was washed 3 times with water, each time with 20 ml of water, dried with 10 g of anhydrous sodium sulfate for 4 hours, filtered, and after the filtrate recovered dichloromethane, it was distilled under reduced pressure (80-95°C / 5mmHg) to obtain a light yellow viscous liquid 1 -(2-nitro)phenyl-4,4-dimethoxy-2-butanone (IV) 121.3 g, gas phase...

Embodiment 2

[0068] Example 2: Preparation of 1-(2-nitro)phenyl-4,4-dimethoxy-2-butanone (IV)

[0069] In a 500 ml four-neck flask, add 68.5 grams (0.5 moles) of o-nitrotoluene, 69.0 grams (0.6 moles) of 3,3-dimethoxypropionitrile, 1.0 grams of DBU, react at 100 ° C for 4 hours, and detect the reaction by gas phase complete. Reduce to 25°C, add 50g of 10% ammonium chloride aqueous solution, 250g of dichloromethane, stir at 25-30°C for 2 hours. The reaction solution was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with 50 g of dichloromethane each time, and the organic phases were combined. The organic phase was washed 3 times with water, each time with 20 ml of water, dried with 10 g of anhydrous sodium sulfate for 4 hours, filtered, and after the filtrate recovered dichloromethane, it was distilled under reduced pressure (80-95°C / 5mmHg) to obtain a light yellow viscous liquid 1 -(2-nitro)phenyl-4,4-dimethoxy-2-butanone (IV) 120...

Embodiment 3

[0070] Example 3: Preparation of 1-(2-nitro)phenyl-4,4-diethoxy-2-butanone (IV)

[0071] In a 500 ml four-neck flask, add 68.5 g (0.5 mole) o-nitrotoluene, 85.8 g (0.6 mole) 3,3-diethoxypropionitrile, 1.0 g morpholine, react at 110°C for 3 hours, and gas phase detection The reaction is complete. Reduce to 25°C, add 50g of 10% ammonium chloride aqueous solution, 250g of dichloromethane, stir at 25-30°C for 2 hours. The reaction solution was transferred to a separatory funnel, and the layers were separated. The aqueous layer was extracted twice with 50 g of dichloromethane each time, and the organic phases were combined. The organic phase was washed 3 times with water, each time with 20 ml of water, dried with 10 g of anhydrous sodium sulfate for 4 hours, filtered, and after the filtrate recovered dichloromethane, it was distilled under reduced pressure (90-105°C / 5mmHg) to obtain a light yellow viscous liquid 1 -(2-nitro)phenyl-4,4-diethoxy-2-butanone (IV) 131.5 g, gas phase p...

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Abstract

The invention relates to a preparation method of an osimertinib intermediate, comprising: subjecting ortho-nitrotoluene and 3,3-dialkoxypropanenitrile as raw materials to alkali-catalyzed nucleophilicaddition to obtain 1-(2-nitro)phenyl-4,4-dialkoxy-2-butanone, subjecting 1-(2-nitro)phenyl-4,4-dialkoxy-2-butanone and N,N-dimethylformamide dimethyl acetal to thermal condensation to obtain 1-dimethylamino-2-(2-nitro)phenyl-5,5-dialkoxy-3-n-pentanone, subjecting the attained reaction liquid to direct catalytic hydrogenation to obtain 3-(3,3-dialkoxy)propionylindole, subjecting 3-(3,3-dialkoxy)propionylindole to reaction with a methylation reagent under alkaline conditions to generate 3-(3,3-dialkoxy)propionyl-N-methylindole, and subjecting 3-(3,3-dialkoxy)propionyl-N-methylindole and 2-methoxy-4-fluoro-5-nitrophenylguanidine to exocondensation to obtain the osimertinib intermediate. The materials herein are low in price and easy to attain, the route is short, and the preparation method is environmentally friendly and high in yield.

Description

technical field [0001] The invention relates to a method for synthesizing indole derivatives, which can be used to prepare osimertinib, and belongs to the field of pharmaceutical biochemical industry. Background technique [0002] Osimertinib, the trade name is Tagrisso, and the English name is Osimertinib. This oral drug was developed by AstraZeneca. It was approved by the U.S. Food and Drug Administration (FDA) on November 13, 2015, for specific epidermal growth factor Treatment of advanced non-small cell lung cancer patients with receptor (EGFR) T790M mutation and other tyrosine kinase inhibitor (TKI) resistance. Osimertinib is an irreversible inhibitor of EGFR, which can form covalent bonds with molecular targets, so the chance of drug resistance is correspondingly reduced. Osimertinib is the first drug approved for this group of people, and it is also the third-generation TKI. Patients with EGFR-positive disease respond to first-line EGFR inhibitors, including erlotin...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/04
CPCC07D403/04
Inventor 孟鲁波戚聿新张明峰鞠立柱
Owner XINFA PHARMA
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