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A kind of preparation method of neratinib intermediate

A neratinib and intermediate technology, applied in the field of chemical synthesis, can solve the problems of difficulty in industrialized production, low utilization rate of raw materials, and high production cost, and achieve the effects of improving product utilization rate, reducing reaction difficulty, and reducing production cost

Active Publication Date: 2020-03-31
江苏阿尔法集团盛基药业(宿迁)有限公司
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  • Abstract
  • Description
  • Claims
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Problems solved by technology

[0003] It is not difficult to find out from the prior art that the formation of the quinoline ring in the structure needs to be carried out at a high temperature of 250 ° C, so it is necessary to use the high boiling point solvent Dowtherm A, which is expensive, and the yield of this step is only 42%, resulting in a total Yield is only 23%, raw material utilization rate is low, and production cost is higher
At the same time, the introduction of the cyano group in the structure of compound IX needs to be provided by the intermediate 2-cyano-3-ethoxyethyl acrylate or trans-3-(dimethylamino)acrylonitrile. The sources of these two raw materials are relatively Limited and expensive, which brings certain difficulties to industrial production

Method used

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  • A kind of preparation method of neratinib intermediate
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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] The specific process of compound II synthesis is as follows: add compound I (1mol) to the reaction flask, dissolve in acetic acid (1L), stir to dissolve, heat up to 60°C, add acetic anhydride (1.5mol) dropwise to the solution, and the dropwise addition is completed , Control the temperature at 60°C for 2h. HPLC detection showed that the raw materials were completely reacted. The reaction solution was lowered to room temperature, poured into water, stirred for 1 h, a solid precipitated out, filtered with suction, and dried in vacuum at 40°C to obtain Compound II (0.96mol) with a yield of 96%.

[0037] The specific process of compound III synthesis is as follows: add compound II (1mol) to the reaction flask, dissolve it in DMF (1L), add potassium carbonate (1.8mol), stir and mix, and heat up to 60-62°C. Bromoethane (1.3 mol) was added dropwise to the system. After the dropwise addition was completed, the temperature was controlled at 60° C. for 2 h. TLC spots the plate,...

Embodiment 2

[0046] Add compound I (1mol) to the reaction flask, dissolve in DMF (1L), stir to dissolve, raise the temperature to 60°C, add acetic anhydride (1mol) dropwise to the solution, and control the temperature at 60°C for 2h. HPLC detection showed that the raw materials were completely reacted. The reaction solution was lowered to room temperature, poured into water, stirred for 1 h, a solid was precipitated, filtered with suction, and dried in vacuum at 40°C to obtain compound II (0.89 mol) with a yield of 89%.

[0047] The synthesis process of compounds III~IX is the same as that in Example 1.

Embodiment 3

[0049] Add compound I (1mol) to the reaction flask, dissolve in acetic acid (500ml) and dichloromethane (500ml), stir to dissolve, heat up to reflux, add acetic anhydride (2mol) dropwise to the solution, after the addition is complete, reflux reaction 2h. HPLC detection showed that the raw materials were completely reacted. The reaction solution was lowered to room temperature, poured into water, stirred for 1 h, a solid precipitated, filtered with suction, and dried in vacuum at 40°C to obtain compound II (0.95 mol) with a yield of 95%.

[0050] The synthesis process of compounds III~IX is the same as that in Example 1.

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Abstract

The invention relates to the field of chemical synthesis, and specifically relates to a preparation method of a Neratinib intermediate. A compound (I) is taken as the raw material, and through a series of reactions, the intermediate compound (VIII) of a novel antitumor drug Neratinib is obtained. A high efficient synthesis route is provided and has the characteristics of low cost, few byproducts, high yield, and little environmental pollution.

Description

technical field [0001] The invention relates to the field of chemical synthesis, in particular to a preparation method of a neratinib intermediate. Background technique [0002] Neratinib is a new type of anticancer drug with strong market potential, and compound IX is its important intermediate. [0003] It is not difficult to find out from the prior art that the formation of the quinoline ring in the structure needs to be carried out at a high temperature of 250 ° C, so it is necessary to use the high boiling point solvent Dowtherm A, which is expensive, and the yield of this step is only 42%, resulting in a total The yield is only 23%, the raw material utilization rate is low, and the production cost is relatively high. At the same time, the introduction of the cyano group in the compound IX structure needs to be provided by the intermediate 2-cyano-3-ethoxy ethyl acrylate or trans-3-(dimethylamino)acrylonitrile, and the sources of these two raw materials are relatively ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/54
CPCC07D215/54
Inventor 陈本顺
Owner 江苏阿尔法集团盛基药业(宿迁)有限公司
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