Preparation and application of hydrochlorides of 5-cyano-4-methoxy-2-picolinic acid

A technology for pyridinecarboxylic acid hydrochloride and picolinic acid, which is applied in the field of heterocyclic compound pharmaceutical intermediates and its preparation, can solve the problems of unreported synthesis process routes of compounds, and achieve reduced risks, simple synthesis routes and excellent reaction conditions. mild effect

Active Publication Date: 2017-02-22
河北正朗制药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] The synthesis process route of the compound of this structure has not been reported at present

Method used

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  • Preparation and application of hydrochlorides of 5-cyano-4-methoxy-2-picolinic acid
  • Preparation and application of hydrochlorides of 5-cyano-4-methoxy-2-picolinic acid
  • Preparation and application of hydrochlorides of 5-cyano-4-methoxy-2-picolinic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0036] In the embodiments, unless otherwise specified, the means used are conventional technical means in the art. Example 1. Synthesis of 5-bromo-4-methoxy-2-pyridinecarboxylic acid (H1) by 5-bromo-4-methoxy-2-picoline (H0)

[0037] Its synthesis method is as follows:

[0038]

[0039] In the there-necked flask, install a mechanical stirrer and a thermometer, dissolve 10 grams (0.05mol) of 5-bromo-4-methoxy-2-methylpyridine in 100ml of acetone solution, cool down to 0°C, and slowly add 5% KMnO 4 100ml of aqueous solution, kept at 0°C for 2 hours, continued to react for 16 hours when the temperature was raised to room temperature, and detected the end point of the reaction with TLC until 5-bromo-4-methoxy-2-methylpyridine disappeared, and added 20ml of ethyl alcohol Diol terminated the reaction, continued to stir for 30min, and filtered to remove MnO 2 solid, the reaction solution was concentrated to dryness, and 100ml of 5% NaHCO was added 3 Make it dissolve completely...

Embodiment 2

[0042] Example 2. Synthesis of 5-bromo-4-methoxy-2-pyridinecarboxylic acid methyl ester (H2) from 5-bromo-4-methoxy-2-pyridinecarboxylic acid (H1)

[0043] Its synthesis method is as follows:

[0044]

[0045] In the there-necked flask, install a mechanical stirrer and a thermometer, dissolve 20 grams (0.05mol) of 5-bromo-4-methoxy-2-pyridinecarboxylic acid (H1) in 200mL of methanol, add 10ml of sulfuric acid (mass fraction 98%) Concentrated sulfuric acid), heat up to 60-70°C, keep warm and continue to react for 16 hours, detect with TLC until the raw material disappears, stop the reaction, concentrate to dryness, add 100ml of ethyl acetate, add 50ml of 5% NaHCO 3 Neutralize, wash with water until neutral, dry with anhydrous sodium sulfate, filter, concentrate, and crystallize with a mixture of toluene and ethyl acetate to obtain an off-white solid with a yield of 95%. The structure of the compound is characterized by NMR.

[0046] 1 HNMR (CDCl 3 ): σ9.23ppm (1H), σ8.48p...

Embodiment 3

[0048] Example 3. Synthesis of 5-cyano-4-methoxy-2-pyridinecarboxylic acid methyl ester (H3) from 5-bromo-4-methoxyl-2-pyridinecarboxylic acid methyl ester (H2)

[0049] Its synthetic reaction is as follows:

[0050]

[0051] In the there-necked flask, install a mechanical stirrer and a thermometer, and dissolve 12.5 grams (0.05mol) of 5-bromo-4-methoxy-2-pyridinecarboxylic acid methyl ester (H2) in 200ml volume ratio (1:2) DMF / In the MeCN solvent, pass through the argon replacement protection, add 44 grams (0.5mol) CuCN, 1 gram of Pd (PPh 3 ) 4 and 20 grams PPh 3 , keep warm at 90°C, detect with TLC until the raw material disappears, stop the reaction, concentrate to dryness, add 50ml 5% NaHCO 3 and 50ml 5% NaCl solution, extracted with 100ml ethyl acetate each time, extracted 3 times altogether, combined organic phase, washed with water to neutrality, dried with anhydrous magnesium sulfate, concentrated by filtration, washed with ethyl acetate and sherwood oil (volume...

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Abstract

The invention provides a preparation method of hydrochlorides of 5-cyano-4-methoxyl-2-picolinic acid. According to the preparation method, 5-bromo-4-methoxy-2-methylpyridin is used as raw materials to form 5-bromo-4-methoxyl-2-methyl picolinate sequentially through oxidation and esterification; under the catalysis effect of tetrakis(triphenylphosphine)palladium, the reaction is taken with nucleophilic reagents to obtain the 5-cyano-4-methoxyl-2-methyl picolinate; hydrolysis is performed to obtain 5-cyano-4-methoxy-2-picolinic acid; obtained 5-cyano-4-methoxy-2-picolinic acid reacts with acid to form salts. A novel synthesis path is provided by the invention; a prepared intermediate product of 5-cyano-4-methoxy-2-picolinic acid (H4) can take a reaction with hydrochloric acid under a conventional condition to obtain the hydrochlorides of the 5-cyano-4-methoxy-2-picolinic acid. The intermediate product of active compounds for preparing uretica, natruresis promoting medicine and valuable medicine for treating cardiovascular diseases and diseases due to retention of excessive salts and hydropexis.

Description

technical field [0001] The invention belongs to the field of organic synthesis, and in particular relates to a heterocyclic compound pharmaceutical intermediate and a preparation method thereof. Background technique [0002] 5-cyano-4-methoxy-2-pyridine carboxylate hydrochloride compound is a synthetic chemical drug: an important optional intermediate for extrarenal extramedullary potassium channel inhibitors, containing this pyridine structure Inhibitors of extrarenal extramedullary potassium channels, useful as diuretics and natriuretics, and also for the treatment and prevention of disorders caused by excess salt and water retention, including cardiovascular diseases such as hypertension and chronic and acute heart failure. [0003] The chemical structure of this intermediate that can be used for screening and synthesizing a kind of extrarenal extramedullary potassium channel inhibitor is as follows: [0004] [0005] There is no report on the synthesis process route...

Claims

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Application Information

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IPC IPC(8): C07D213/84A61K31/4412A61P7/10A61P9/00
CPCA61K31/4412C07D213/84
Inventor 谢素琼侯利民刘金城
Owner 河北正朗制药有限公司
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