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Preparation method of medical intermediate 8-chloro-1, 7-naphthyridin-3-formaldehyde

A synthesis method and intermediate technology are applied in the field of synthesis of pharmaceutical intermediate 8-chloro-1,7-naphthyridine-3-formaldehyde, which can solve the problems of unfavorable large-scale industrial production, high price, environmental pollution and the like, and achieve raw material Inexpensive, good quality, high yield

Active Publication Date: 2020-04-03
CHENGDA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] There are deficiencies in the current existing synthetic routes, such as long steps, expensive reagents and catalysts, dangerous reagents such as flammable, explosive and highly poisonous reagents or production processes, and serious environmental pollution. Conducive to large-scale industrial production

Method used

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  • Preparation method of medical intermediate 8-chloro-1, 7-naphthyridin-3-formaldehyde
  • Preparation method of medical intermediate 8-chloro-1, 7-naphthyridin-3-formaldehyde
  • Preparation method of medical intermediate 8-chloro-1, 7-naphthyridin-3-formaldehyde

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Experimental program
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Embodiment 1

[0031] Step 1) Compound (I) 8-chloro-1,7-naphthyridine-3-carboxylate is dissolved in a solvent as a starting material, and reduced to obtain 2-chloro-1,7-naphthalene under the catalysis of a Lewis acid Pyridine-3-methanol, compound (III);

[0032] Under a nitrogen atmosphere, 50.0g of 8-chloro-1,7-naphthyridine-3-carboxylic acid ethyl ester (0.21mol, 1.0eq) was added to the reaction flask, dissolved in 750g of tetrahydrofuran, and 35.2g of calcium chloride (0.32mol, 1.5eq), lower the temperature to 0-10°C, slowly add 11.9g of sodium borohydride (0.32mol, 1.5eq) in batches, slowly raise the temperature to 40-50°C and keep the reaction. After the reaction is complete, control the reaction temperature below 20°C, slowly add 500g of 1N hydrochloric acid solution, separate layers, take the organic phase, distill to a certain volume, add n-heptane to crystallize, filter, and dry to obtain 32.7g of a light yellow solid (yield 80 %), that is, compound (III) 2-chloro-1,7-naphthyridine...

Embodiment 2

[0036] Step 1) Compound (I) 8-chloro-1,7-naphthyridine-3-carboxylate is dissolved in a solvent as a starting material, and reduced to obtain 2-chloro-1,7-naphthalene under the catalysis of a Lewis acid Pyridine-3-methanol, compound (III);

[0037]Under a nitrogen atmosphere, add 46.8g 8-chloro-1,7-naphthyridine-3-methyl carboxylate (0.21mol, 1.0eq) into the reaction flask, dissolve in 750g methyl tert-butyl ether, add 43.6g chloride Zinc (0.32mol, 1.5eq), cool down to 0-10°C, slowly raise the temperature to 40-50°C and keep warm for reaction with boron trifluoride ether solution (containing 21.7g, 0.32mol, 1.5eq) of boron trifluoride. After the reaction is complete, control the reaction temperature below 20°C, slowly add 500g of 1N hydrochloric acid solution, separate layers, take the organic phase, distill to a certain volume, add n-heptane to crystallize, filter, and dry to obtain 33.5g of a light yellow solid (yield 82 %), that is, compound (III) 2-chloro-1,7-naphthyridine...

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Abstract

The invention discloses a preparation method of a medical intermediate 8-chloro-1, 7-naphthyridin-3-formaldehyde and belongs to the field of synthesis and preparation of medical intermediates. The preparation method comprises the following steps: step 1) dissolving a compound I 8-chloro-1, 7-naphthyridin-3-formate as an initial raw material in a solvent, and under the catalysis of Lewis acid, performing reduction to obtain 2-chloro-1, 7-naphthyridin-3-methanol, namely a compound III, and 2) carrying out TEMPO oxidation on the compound III 2-chloro-1, 7-naphthyridin-3-methanol to obtain 8-chloro-1, 7-naphthyridin-3-formaldehyde, namely a compound II. The preparation method disclosed by the invention is suitable for industrial production, relatively low in cost and simple to operate, and canbe used for producing active compounds of various novel immunomodulators.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates and organic chemical intermediates, and relates to a method for synthesizing a pharmaceutical intermediate 8-chloro-1,7-naphthyridine-3-carbaldehyde. Background technique [0002] 1,7-Naphthyridine is a class of important pharmaceutical intermediates, widely used, for example, in Novartis Pharmaceuticals, Switzerland in the type 4 phosphodiesterase (PDE4) inhibitor (CN101018791A), Spain Omiro laboratory in p38 Cleavage-activated protein kinase inhibitors (CN101501034A), dihydroorotate dehydrogenase (DHODH) inhibitors (J. Med. Chem. 2018, 61, 5162), etc. all use 1,7-naphthyridine derivatives thing. [0003] 8-Chloro-1,7-naphthyridine-3-carbaldehyde, as an important derivation type of 1,7-naphthyridine, provides convenience and possibility for the derivation of 8-position and 3-position of 1,7-naphthyridine skeleton sex. Recently, Incyte Company of the United Sta...

Claims

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Application Information

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IPC IPC(8): C07D471/04
CPCC07D471/04Y02P20/55
Inventor 钱伟施裕华冯宇黄兴党军奎董昌明王植鹏许宏黄宗玺陈叶沈华飞张俊
Owner CHENGDA PHARM CO LTD
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