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Synthesis method of quinoline compound intermediate

A synthesis method and compound technology, applied in organic chemistry, chemical recovery, etc., can solve the problems of low yield, complicated operation, unsuitable for industrial production, etc., achieve high yield, improve the purity of crude products, and be suitable for industrial scale production Effect

Active Publication Date: 2022-05-24
CHINA RESOURCES SANJIU MEDICAL & PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0006]Therefore, the technical problem to be solved in the present invention is to overcome the low yield that exists in the synthetic method of the quinoline compound intermediate in the prior art, complex operation, unsuitable defects in industrial production

Method used

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  • Synthesis method of quinoline compound intermediate
  • Synthesis method of quinoline compound intermediate
  • Synthesis method of quinoline compound intermediate

Examples

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Embodiment 1

[0079] Example 1 Synthesis of the quinoline compound intermediate shown in formula II

[0080] The present embodiment provides a synthetic method of a quinoline compound intermediate shown in formula II, comprising the following steps:

[0081] 15.8kg (36mol, 1.0eq) of the compound of formula IV and 79L (5V) of NMP were added to the reactor, the temperature in the control reactor was 20~30°C, stirred for 0.75h until the reaction solution was dissolved, and 5.7kg (72mol, pyridine) was added. 2.0eq) into the reactor. Control the temperature in the reaction kettle to be 20~30°C, slowly add phenyl chloroformate 6.2kg (39.6mol, 1.1eq) dropwise to the reaction kettle, stir at 20~30°C for 2.5h, use HPLC to check that the compound of formula IV reacts completely ( 95%), add 15.7kg (252mol, 7.0eq) of 80% (w / w) hydrazine hydrate aqueous solution to the reaction kettle, and stir for 3h at 20-30°C. Slowly add 237L (15V) of purified water dropwise to the reaction kettle (dropping time 4....

Embodiment 2

[0097] Example 2 Synthesis of the quinoline compound intermediate shown in formula II

[0098] The present embodiment provides a synthetic method of a quinoline compound intermediate shown in formula II, comprising the following steps:

[0099] 15.8kg (36mol, 1.0eq) of the compound of formula IV and 79L (5V) of NMP were added to the reaction kettle, the temperature in the reaction kettle was controlled to be 20~30°C, stirred for 1h until the reaction solution was clear, and 5.7kg (72mol, 2.0%) of pyridine was added. eq) into the reactor. Control the temperature in the reaction kettle to be 20~30°C, slowly add 6.2kg (39.6mol, 1.1eq) of phenyl chloroformate dropwise to the reaction kettle, stir at 20~30°C for 2h, use HPLC to check that the compound of formula IV reacts completely (95%), add 15.7kg (252mol, 7.0eq) of 80% (w / w) hydrazine hydrate aqueous solution into the reaction kettle, and stir at 20-30°C for 2h. Slowly add 237L (15V) of purified water dropwise into the reactio...

Embodiment 3

[0100] Example 3 Synthesis of the quinoline compound intermediate shown in formula II

[0101] The present embodiment provides a synthetic method of a quinoline compound intermediate shown in formula II, comprising the following steps:

[0102] 15.8kg (36mol, 1.0eq) of the compound of formula IV and 79L (5V) of NMP were added to the reaction kettle, the temperature in the reaction kettle was controlled to be 20~30°C, stirred for 1h until the reaction solution was clear, and 5.7kg (72mol, 2.0%) of pyridine was added. eq) into the reactor. Control the temperature in the reaction kettle to be 20~30 ℃, slowly add phenyl chloroformate 6.2kg (39.6mol, 1.1eq) dropwise into the reaction kettle, stir at 20~30 ℃ for 6h, use HPLC to check that the compound of formula IV reacts completely (95%), add 15.7kg (252mol, 7.0eq) of 80% (w / w) hydrazine hydrate aqueous solution to the reaction kettle, and stir at 20-30°C for 6h. Slowly add 237L (15V) of purified water dropwise into the reaction k...

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Abstract

The invention relates to the technical field of organic synthesis, and particularly provides a synthesis method of a quinoline compound intermediate as shown in a formula II, which comprises the following steps: (1) taking a compound as shown in a formula IV, a basic catalyst and phenyl chloroformate, and contacting and reacting in an NMP environment to obtain a reaction solution; (2) mixing and reacting the reaction liquid prepared in the step (1) with hydrazine hydrate to obtain the quinoline compound intermediate shown in the formula II, the method not only can realize two-step homogeneous reaction and greatly improve the yield of the quinoline compound intermediate shown in the formula II, but also only needs the last-step purification process, does not need to evaporate the original reaction solvent to remove the original reaction solvent and then replace the original reaction solvent with a new solvent in the process, is convenient to operate, and is beneficial to industrial large-scale production; nMP is adopted as a solvent to achieve homogeneous reaction, the dosage of hydrazine hydrate is greatly reduced (the molar equivalent is reduced to 6.0-8.0 eq from 60.0 eq in the prior art), and environmental protection and production safety are facilitated.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for synthesizing a quinoline compound intermediate. Background technique [0002] Quinoline compounds are often used for the treatment of malignant tumors, for example, Chinese patent document CN102977014A describes the compound with formula I and its salt in the specification, and it is described in the specification that it can be used to inhibit lung cancer cells, colon cancer cells, gastric cancer cells, and liver cancer cells. cells, breast cancer cells, glioblastoma cells and other tumor cells. [0003] [0004] [0005] The compound shown in formula II is used as an important intermediate of the above-mentioned quinoline compound. At present, the synthetic method of this intermediate mainly adopts the compound shown in the formula IV through two-step synthesis. Reaction in the environment of acetone, purification, the compound shown in formula III...

Claims

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Application Information

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IPC IPC(8): C07D401/12
CPCC07D401/12Y02P20/584Y02P20/55
Inventor 罗枭陈东谢鸷生程婷婷秦超马鹏岗
Owner CHINA RESOURCES SANJIU MEDICAL & PHARMA
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