Preparation method of canertinib (I)

A canetinib and morpholine-based technology, applied in the field of preparation of canetinib, can solve the problems of many steps, unsuitable requirements for industrialization, and difficulty in obtaining raw materials, and achieves easy availability of raw materials, promotion of development, and promotion of economy. effect of technology

Inactive Publication Date: 2015-02-18
安徽金太阳生化药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because the intermediate (VII) is a fluorine-containing compound, the raw material is not easy to obtain, there are many steps, and many steps need to be separated and purified by column chromatography, so it is not suitable for industrialization requirements

Method used

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  • Preparation method of canertinib (I)
  • Preparation method of canertinib (I)
  • Preparation method of canertinib (I)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] At room temperature, add diisopropyl azodicarboxylate (3mL, 15mmol) and 5mL of tetrahydrofuran into a 100mL three-necked flask, add dropwise a solution of triphenylphosphine (4.0g, 15mmol) in 25mL of tetrahydrofuran at room temperature, and keep at room temperature for reaction 2 Hour. Under nitrogen protection, 3-(4-morpholinyl)-1-propanol (0.5g, 3.4mmol) in tetrahydrofuran 5mL solution was added dropwise to the above reaction system, after the addition was complete, 4-chloro- 6-Amino-7-hydroxyquinazoline (II) (0.59 g, 3.0 mmol), stirred at room temperature for 4 hours. A 5 mL solution of 3-(4-morpholino)-1-propanol (0.38 g, 2.6 mmol) in tetrahydrofuran was added dropwise, and the reaction was continued at room temperature for 2 hours, and the reaction was completed by TLC monitoring. The solvent was recovered by distillation under reduced pressure, the residue was adjusted to pH=5-6 with dilute hydrochloric acid, extracted with ethyl acetate, and the organic phase wa...

Embodiment 2

[0029] Add 4-chloro-6-amino-7-[3-(4-morpholinyl)propoxy]quinazoline (III) (0.81g, 2.5mmol), triethylamine (0.25g , 2.5mmol) and 20mL of dichloromethane, heated to 40-45°C, stirred until the system was dissolved uniformly. When the temperature was lowered to below 10°C, a solution of acryloyl chloride (0.20 g, 2.8 mmol) in 10 mL of dichloromethane was slowly added dropwise. After the drop was completed, the reaction was continued at room temperature for 6 hours, and the reaction was detected by TLC. The reaction solution was washed with 10% sodium bicarbonate solution and water, and dried over anhydrous sodium sulfate. The solvent was recovered under reduced pressure, and the residue was recrystallized from ethyl acetate to obtain 4-chloro-7-[3-(4-morpholino)propoxy]-6-acrylamidoquinazoline (IV) as a pale yellow solid 0.80g, yield 85.1%.

Embodiment 3

[0031] Add 4-chloro-7-[3-(4-morpholinyl) propoxy]-6-acrylamidoquinazoline (IV) (1.13g, 3.0mmol), triethylamine ( 0.45g, 4.5mmol) and isopropanol 30mL, stirred until the system was dissolved uniformly. A solution of 4-fluoro-3-chloroaniline (0.48 g, 3.3 mmol) in 20 mL of isopropanol was slowly added dropwise. After the drop was completed, the reaction was continued at room temperature for 12 hours, and the reaction was detected by TLC. The reaction solution was poured into 100 mL of ice water and filtered. After the filter cake was dried, it was recrystallized with dimethyl sulfoxide to obtain 1.25 g of canertinib (I) as a pale yellow solid with a yield of 85.9%.

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Abstract

The invention discloses a preparation method of canertinib (I). The preparation method comprises the following steps that 4-chloro-6-amino-7-hydroxy quinazoline (II) and 3-(4-morpholino)-1-propyl alcohol carry out etherification reaction to generate 4-chloro-6-amino-7-[3-(4-morpholino)propoxy]quinazoline (III), the compound (III) and acrylic acid or acryloyl chloride carry out acylation reaction to generate 4-chloro-7-[3-(4-morpholino)propoxy]-6-acrylamide quinazoline (IV), and the compound (IV) and 4-chloro-3-chloroaniline carry out condensation reaction to prepare the canertinib (I). The preparation method is concise, economical and environment-friendly in process and is suitable for the requirement of industrial amplification.

Description

[0001] The patent of the present invention can refer to the other two invention patent applications submitted by the applicant on the same day, the names of which are respectively "Preparation method of 4-chloro-6-amino-7-hydroxyquinazoline" and "A kind of 4-chloro-6 - Preparation method of amino-7-hydroxyquinazoline". technical field [0002] The invention belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and in particular relates to a preparation method of canertinib. Background technique [0003] Canertinib (Canertinib, I), the chemical name is 4-(3-chloro-4-fluoroanilino)-7-[3-(4-morpholinyl)propoxy]-6-acrylamidoquinoline Oxazoline is an irreversible epidermal growth factor receptor (pan-ErbB) selective inhibitor jointly developed by Pfizer and Warner Lambert, which can bind to the adenosine triphosphate binding site on the surface of all members of the ErbB family point, thereby inhibiting the activatio...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/94
Inventor 许学农
Owner 安徽金太阳生化药业有限公司
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