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Synthesis method of copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate

A technology of aminopyrimidine and methyl carboxylate, which is applied in the field of medicine, can solve the problems of excessive waste liquid and waste water, cumbersome reactions, etc., and achieve the effects of less three wastes, simple preparation method and high yield

Active Publication Date: 2021-05-11
苏州莱克施德药业有限公司
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  • Description
  • Claims
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Problems solved by technology

[0005] In order to solve the problems that the reaction of the existing Copanisil intermediate 2-aminopyrimidine-5-carboxylate methyl ester is cumbersome, high-risk raw materials need to be used, and waste liquid and waste water are generated during the production process, the present invention provides A new method for the synthesis of 2-aminopyrimidine-5-carboxylate methyl ester, a new Cooperanisil intermediate, has the advantages of simple preparation method, safe and controllable reaction process, cheap and easy-to-obtain raw materials, high yield, and produced The advantages of less waste

Method used

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  • Synthesis method of copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate
  • Synthesis method of copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate

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preparation example Construction

[0017] Below in conjunction with accompanying drawing, the present invention is described in detail, and the synthetic method chemical equation of this Shen Kupanicil intermediate 2-aminopyrimidine-5-carboxylate is as follows figure 2 Shown, concrete reaction step comprises:

[0018] Step 1: Dissolve sodium methoxide in methanol, cool to room temperature, add ethyl formate, control the temperature in an ice-water bath to less than 30°C, then dropwise add methyl 3,3-dimethoxypropionate, and react at room temperature for 5 hours;

[0019] Step 2: After the reaction, add guanidine hydrochloride and heat up to 50-55°C for 2 hours;

[0020] Step 3: After the reaction is completed, cool down to room temperature, filter with suction, rinse the filter cake with methanol, and dry to obtain the product methyl 2-aminopyrimidine-5-carboxylate.

[0021] The mass ratio of methanol to methyl 3,3-dimethoxypropionate is 10:1~15:1; the molar ratio of sodium methoxide to methyl 3,3-dimethoxypr...

Embodiment 1

[0023] Add 1.0Kg of methanol and sodium methoxide (36.7g, 0.68mol) into a 3L four-necked flask with mechanical stirring and a thermometer, stir to dissolve, cool to room temperature, add ethyl formate (50.4g, 0.68mol), and control the temperature in an ice-water bath The temperature is not higher than 30°C, add 3,3-dimethoxypropionate methyl ester (100.0g, 0.68mol) dropwise, and stir at room temperature for 5 hours after the dropwise addition, after the reaction, add guanidine hydrochloride (64.1g, 0.68mol) , heated to 50-55° C. for 2 hours, cooled to room temperature, suction filtered, washed with methanol, and dried to obtain 86.9 g of methyl 2-aminopyrimidine-5-carboxylate, with a yield of 84%. 1H-NMR (DMSO-d6): δ8.69 (s, 2H), δ7.57 (brs, 2H), δ3.79 (s, 3H).

Embodiment 2

[0025] Add 1.5Kg of methanol and sodium methoxide (36.7g, 0.68mol) into a 3L four-necked flask with mechanical stirring and a thermometer, stir to dissolve, cool to room temperature, add ethyl formate (50.4g, 0.68mol), and control the temperature in an ice-water bath The temperature is not higher than 30°C, add 3,3-dimethoxypropionate methyl ester (100.0g, 0.68mol) dropwise, and stir at room temperature for 5 hours after the dropwise addition, after the reaction, add guanidine hydrochloride (64.1g, 0.68mol) , heated to 50-55° C. for 2 hours, cooled to room temperature, suction filtered, washed with methanol, and dried to obtain 84.1 g of methyl 2-aminopyrimidine-5-carboxylate, with a yield of 81%. 1H-NMR (DMSO-d6): δ8.69 (s, 2H), δ7.57 (brs, 2H), δ3.79 (s, 3H).

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Abstract

The invention provides a synthetic method of a copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate, which comprises the following specific reaction steps: reacting sodium methoxide, ethyl formate and methyl 3,3-dimethoxypropionate in a methanol solvent at room temperature for 5 hours, then adding guanidine hydrochloride, conducting reacting at 50-55 DEG C for 2 hours, conducting cooling to room temperature after the reaction is completed, and conducting filtering and drying to obtain methyl 2-aminopyrimidine-5-carboxylate. The invention solves the problems of tedious reaction, high-risk raw material need, much waste liquid and waste water generated in the production process and the like in the existing reaction of the copanlisib intermediate methyl 2-aminopyrimidine-5-carboxylate, and provides a novel synthetic method of the copanlisib intermeidate methyl 2-aminopyrimidine-5-carboxylate, and the preparation method is simple, safe and controllable in reaction process, cheap and easily available in raw materials, high in yield, less in generated three wastes and the like.

Description

technical field [0001] The invention belongs to the technical field of medicine, and in particular relates to a synthesis method of 2-aminopyrimidine-5-carboxylate methyl ester, a cooperanicil intermediate. . 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. [0003] However, the existing method for synthesizing the 2-aminopyrim...

Claims

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Application Information

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IPC IPC(8): C07D239/42
CPCC07D239/42
Inventor 刘同昶俞菊荣
Owner 苏州莱克施德药业有限公司
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