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Preparation method of afatinib compound

An afatinib and compound technology, which can be applied in chemical instruments and methods, compounds of Group 5/15 elements of the periodic table, organic chemistry, etc., and can solve the problems of high cost oxidative degradation, unfavorable industrial production, difficult long-term storage, etc. problem, to achieve the effect of convenient long-term storage, low cost and easy operation

Active Publication Date: 2015-03-25
JIANGSU AOSAIKANG PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The raw materials dimethylaminoacetaldehyde and dimethylaminoacetaldehyde diethyl acetal used in this process are relatively expensive and easy to be oxidized and degraded. They are difficult to store for a long time, which is not conducive to industrial production, and the process needs to provide an argon environment during the production process.
At the same time, the process constructs trans double bonds through the Wittig-Horner-Emmons reaction. Due to the difference in stereoselectivity, there are still a small amount of cis-isomer impurities in the product.

Method used

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  • Preparation method of afatinib compound
  • Preparation method of afatinib compound
  • Preparation method of afatinib compound

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1 Formula V compound preparation

[0038]

[0039] Phosphorus trichloride (0.5g) was slowly dropped into diphenylphosphineacetic acid (2.37g) dissolved in 25mL of dichloromethane solution, and the reaction temperature was controlled at 0°C. After the dropwise reaction was stirred at 15°C for 2 hours, it was cooled to 0°C. Triethylamine (1.02g) and 4-[(3-chloro-4-fluorophenyl)-amino]-6-amino-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline (3.41g) was dissolved in 25mL of 1,2-dichloroethane solution and slowly added dropwise to the above solution, after the drop was completed, the reaction was carried out at 25°C for 2 hours. After the reaction was monitored by TLC, 20 mL of purified water was added to the extraction layer, and the organic phase was washed with 20 mL of purified water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to an oil, and tetrahydrofuran / isopropyl ether (1:1) was added. 40 mL was...

Embodiment 2

[0042]Example 2 Preparation of Formula III Compound

[0043]

[0044] n-Butyllithium (1.5M, 6ml) was slowly dropped into the compound of formula V (5g) in 28mL of dry tetrahydrofuran solution at a controlled internal temperature of 0°C. After dropping, cool to -10°C; drop ethyl dimethylaminoacetate (1.05g) into the above solution, after dropping, rise to room temperature and stir for 0.5 hours. After the reaction is monitored by TLC, add saturated chloride Ammonium solution 12mL, saturated sodium chloride solution 8mL, dichloromethane 12mL for extraction and layering, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain an oil, which was recrystallized by adding tetrahydrofuran / isopropyl ether (1:2) 40mL An off-white solid (compound of formula III) was obtained.

[0045] n-Butyllithium (1.5M, 6ml) was slowly dropped into the compound of formula V (5g) dissolved in 28mL of dry 2-methyltetrahydrofuran solut...

Embodiment 3

[0047] Embodiment 3 Formula II compound preparation

[0048]

[0049] Add sodium borohydride (0.15g) into a solution of compound of formula III (5g) dissolved in 50mL of methanol, heat at 75°C for 0.5 hours and cool to room temperature, add 50mL of saturated ammonium chloride solution, distill off part of the solvent under reduced pressure, add 50mL Saturated sodium chloride solution, 80mL of dichloromethane for extraction and layering, the organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, the residue was added with 50mL of dichloromethane / n-heptane (1:3) and stirred for crystallization to obtain light yellow Solid (compound of formula II).

[0050] Add sodium borohydride (0.27g) into a solution of compound of formula III (5g) dissolved in 50mL of isopropanol, heat and reflux at 65°C for 4 hours, then cool to room temperature, add 50mL of saturated ammonium chloride solution, and distill off part of the solvent unde...

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Abstract

The invention provides a novel preparation method of an afatinib compound. Raw materials and reagents used in the preparation method have the advantages of low cost, stable chemical property and convenience in long-term storage and the content of an impurity cis-isomer in the prepared afatinib compound is very low.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a new preparation method of afatinib compound and afatinib maleate. Background technique [0002] Afatinib dimaleate is a tyrosine kinase inhibitor. Approved by the FDA in July 2013, the product name is GILOTRIF, which is used as a first-line drug for the treatment of epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 (L858R) substitution mutation of metastatic non-small cell lung cancer (NSCLC) patients. [0003] Afatinib compound (Example 1 compound (10)) is disclosed in CN1481370A. [0004] Disclose a kind of method for preparing Afatinib maleate among CN1867564A, by N 4 -(3-Chloro-4-fluoro-phenyl)-7-((S)-tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine reacts with diethylphosphonoacetic acid to obtain aryl Amide, then react with 2-aminoacetaldehyde (or its acetal) to produce afatinib by Wittig-Horner-Emmons reaction, and then form a salt with...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D405/12C07F9/6558
CPCC07D405/12C07F9/65586
Inventor 陈庆财赵俊赵小伟潘迅
Owner JIANGSU AOSAIKANG PHARMA CO LTD
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