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Preparation method of FAP-alpha inhibitor and tumor diagnosis developer intermediate 6-methoxy-4-carboxylic acid quinoline

A methoxyquinoline, alpha inhibitor technology, applied in organic chemistry and other directions, can solve the problems of strict control requirements for production equipment and reaction conditions, reduced safety factor, increased cost, etc., and achieves low requirements for reaction equipment and high purity. , the effect of short synthesis steps

Active Publication Date: 2022-01-28
南京恒远科技开发有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Microwave reaction bottles are used in the synthesis process, and the reaction process requires high temperature and high pressure, which greatly reduces the safety factor in the production process. The requirements for the control of production equipment and reaction conditions are extremely strict, which greatly increases the cost of industrial production.

Method used

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  • Preparation method of FAP-alpha inhibitor and tumor diagnosis developer intermediate 6-methoxy-4-carboxylic acid quinoline
  • Preparation method of FAP-alpha inhibitor and tumor diagnosis developer intermediate 6-methoxy-4-carboxylic acid quinoline
  • Preparation method of FAP-alpha inhibitor and tumor diagnosis developer intermediate 6-methoxy-4-carboxylic acid quinoline

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0027] Preparation of 6-methoxyl-4-carboxylic acid quinoline, according to the following steps:

[0028] (1) Preparation of 6-methoxy-4-carboxylic acid quinoline crude product:

[0029] Add 50g of 6-methoxyquinoline and 150g of ethyl acetate into the reaction flask, stir and cool, add 88.9g of chlorosulfonyl isocyanate dropwise at T=0℃, the mixture of 6-methoxyquinoline and chlorosulfonyl isocyanate The molar ratio is 1.0:2.0, the temperature is maintained at 0~5°C, and the dropwise addition is completed. Continue to stir and react for 12-14 hours, keep the reaction temperature at about 25°C, and TLC detects that the reaction is basically complete.

[0030] The reaction solution was slowly added to 250 g of ice water, and the dropwise temperature did not exceed 5°C. After the dropwise addition, start to add 1N hydrochloric acid aqueous solution dropwise to adjust the pH=1~2, extract twice with ethyl acetate 250ml×2, combine the organic layer, wash the organic layer with 250m...

Embodiment 2

[0036] Preparation of 6-methoxyl-4-carboxylic acid quinoline, according to the following steps:

[0037] (1) Preparation of 6-methoxy-4-carboxylic acid quinoline crude product:

[0038] Add 50g of 6-methoxyquinoline and 150g of ethyl acetate into the reaction flask, stir and cool, add 111.1g of chlorosulfonyl isocyanate dropwise at T=0°C, the mixture of 6-methoxyquinoline and chlorosulfonyl isocyanate The molar ratio is 1.0:2.5, the temperature is maintained at 0~5°C, and the dropwise addition is completed. Continue to stir and react for 12-14 hours, keep the reaction temperature at about 25°C, and TLC detects that the reaction is basically complete.

[0039] The reaction solution was slowly added to 250 g of ice water, and the dropwise temperature did not exceed 5°C. After the dropwise addition, start to add 1N hydrochloric acid aqueous solution dropwise to adjust the pH=1~2, extract twice with ethyl acetate 250ml×2, combine the organic layer, wash the organic layer with 25...

Embodiment 3

[0043] Preparation of 6-methoxyl-4-carboxylic acid quinoline, according to the following steps:

[0044] (1) Preparation of 6-methoxy-4-carboxylic acid quinoline crude product:

[0045] Add 50g of 6-methoxyquinoline and 150g of ethyl acetate into the reaction flask, stir and cool, add 133.3g of chlorosulfonyl isocyanate dropwise at T=0℃, the mixture of 6-methoxyquinoline and chlorosulfonyl isocyanate The molar ratio is 1.0:3.0, the temperature is maintained at 0~5°C, and the dropwise addition is completed. Continue to stir and react for 12-14 hours, keep the reaction temperature at about 25°C, and TLC detects that the reaction is basically complete.

[0046] The reaction solution was slowly added to 250 g of ice water, and the dropwise temperature did not exceed 5°C. After the dropwise addition, start to add 1N hydrochloric acid aqueous solution dropwise to adjust the pH=1~2, extract twice with ethyl acetate 250ml×2, combine the organic layer, wash the organic layer with 250...

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Abstract

The invention relates to a preparation method of an FAP-alpha inhibitor and a tumor diagnosis developer intermediate 6-methoxy-4-carboxylic acid quinoline. The preparation method comprises the following steps of: adding 6-methoxyquinoline into ethyl acetate, dropwise adding chlorosulfonyl isocyanate at 0-5 DEG C, performing a complete reaction at room temperature, and adding an obtained reaction product into ice water so as to quench the product; dropwise adding a 1N hydrochloric acid aqueous solution until the pH value is 1-2, performing extraction with an organic solvent, washing an organic layer with a saturated sodium chloride aqueous solution, and carrying out reduced pressure distillation on the organic layer until the organic layer is dry, so as to obtain a crude product; and adding the crude product into water, carrying out reflux recrystallization, and carrying out filtering to obtain the 6-methoxy-4-carboxylic acid quinoline. The synthesis process route is simple to operate and suitable for industrial production.

Description

technical field [0001] The invention relates to the technical field of organic synthesis, in particular to a method for preparing a FAP-α inhibitor and a tumor diagnostic imaging agent intermediate 6-methoxy-4-quinoline carboxylate. Background technique [0002] 6-Methoxy-4-quinoline carboxylate is an important pharmaceutical intermediate and a key raw material for the synthesis of FAP-α inhibitors and tumor diagnostic imaging agents. It has broad application prospects and high market value. [0003] Cancer associated fibroblasts (CAFs) are an important part of stromal cells in the tumor microenvironment. Studies have shown that CAFs are transformed from normal fibroblasts or fibroblast progenitor cells. [0004] A prominent feature of CAFs is the high expression of fibroblast activation protein (FAP-α). FAP-α is generally not expressed in normal human tissues. FAP-α is selectively expressed on the surface of stromal fibroblasts in more than 90% of epithelial malignant tum...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/50
CPCC07D215/50
Inventor 徐佩胡峻计炜
Owner 南京恒远科技开发有限公司