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Preparation method for copanlisib

A technology of morpholine and oxypropoxy, which is applied in the field of preparation of the drug Copanicil, can solve problems such as side reactions, product quality and adverse effects of the purification process, and achieve the effects of easy availability of raw materials, promotion of development, and simple process

Active Publication Date: 2015-12-09
SUZHOU LIXIN PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

As can be seen from the design process of this reaction route, there are two chlorine atoms on the quinazoline ring after chlorination, which will cause the substitution reaction to produce competitive side reactions in different positions, which will bring about a negative impact on the quality of the product and the purification process. Negative Effects

Method used

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  • Preparation method for copanlisib
  • Preparation method for copanlisib
  • Preparation method for copanlisib

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044]In a nitrogen atmosphere, add 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (II) (5.82g, 20mmol) and dioxane in a dry reaction flask 50 mL was collected, and benzoyl isocyanate (3.23 g, 22 mmol) was added at room temperature and stirred at room temperature for 20 hours. TLC detected that the reaction was complete. Stand still, filter, the filter cake is washed with a mixed solvent of n-hexane and ethyl acetate (4:1), and dried in vacuo to obtain off-white solid 4-amino-7-(3-morpholin-4-ylpropoxy)-8 -Methoxyquinazolin-2(1H)-one (III) 4.55 g, yield 68.1%; mass spectrum (EI): m / z 335 (M+H). Embodiment two:

Embodiment 2

[0045] In a nitrogen atmosphere, add 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy)benzonitrile (II) (5.82 g, 20 mmol) and 50 mL of tetrahydrofuran into a dry reaction flask, A solution of chlorosulfonic acid isocyanate (3.25 g, 23 mmol) in tetrahydrofuran (15 mL) was added dropwise at 0-5°C. After dropping, warm up to room temperature, stir and react for 6-8 hours, and TLC detects that the reaction is complete. The pH was adjusted to neutral with 5% sodium hydroxide, and extracted three times with dichloromethane. The organic phases were combined and washed with water and saturated brine. Concentrate under reduced pressure, the residue is washed with a mixed solvent of n-hexane and ethyl acetate (4:1), and dried in vacuo to give an off-white solid 4-amino-7-(3-morpholin-4-ylpropoxy)-8- Methoxyquinazolin-2(1H)-one (III) 5.10 g, yield 76.3%; mass spectrum (EI): m / z 335 (M+H).

Embodiment 3

[0047] In a nitrogen atmosphere, add 4-amino-7-(3-morpholin-4-ylpropoxy)-8-methoxyquinazolin-2(1H)-one (III) (3.3g , 10mmol), 2-chloroethanol (0.97g, 12mmol), potassium tert-butoxide (1.68g, 15mmol) and N,N-dimethylformamide 25mL, heated to 80-90°C, stirred for 4-6 hours . Cool down to room temperature, pour the reaction solution into a 5% sodium hydroxide solution by weight, heat to 60°C, keep warm for 2 hours, cool to room temperature, solids precipitate out, filter, wash with water, wash with n-hexane, and dry in vacuum Yellow solid 7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydroimidazo[1,2-c]quinazolin-5(6H)-one ( IV) 2.12 g, yield 58.9%; mass spectrum (EI): m / z 361 (M+H).

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Abstract

The invention discloses a preparation method for copanlisib (BAY80-6946). An unknown compound 2-amino-3-methoxy-4-(3-morpholin-4-ylpropoxy) cyanophenyl is taken as a starting material, and elementary reactions such as heterocyclization, condensation and cyclization, halogenated amination and amidation are carried out to obtain a target compound namely the copanlisib. The preparation method is environmentally-friendly and suitable for industrial production, the raw material is easily obtained, and the process is simple.

Description

technical field [0001] 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 Copanicil, a drug that can be used to treat leukemia. Background technique [0002] Copanlisib is a novel oral phosphoinositide 3-kinase (PI3K) inhibitor developed by Bayer, Germany. Existing clinical studies have shown that the drug inhibits the growth of cancer cells in leukemia and lymphoma patients by blocking the PI3K signaling pathway. In order to further prove the prospect of this drug, Bayer launched two clinical phase III studies in 2015: by using alone or in combination with Rituxan to treat a rare non-Hodgkin's lymphoma (NHL), and using it alone or in combination with Rituxan The effect of Rituxan was compared. In addition, Bayer plans to conduct a phase II study of Copanlisib in diffuse large B-cell lymphoma, a malignant subtype of NHL. Because the medicine...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D487/04
CPCC07D487/04A61K31/35A61K31/381A61K31/427A61K31/4436C07D493/10A61K31/5377A61P35/02
Inventor 许学农王喆包志坚张文件苏健顾新禹薛佳袁玉环
Owner SUZHOU LIXIN PHARMA
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