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Preparation method of high-purity fudosteine

A high-purity, water-soluble technology, applied in the field of preparation of high-purity fudosteine, can solve the problems of unreachable unknown impurities, difficult source of starting materials, high unknown impurities, etc., achieve low cost, mild reaction conditions, The effect of high yield

Inactive Publication Date: 2018-09-28
HENAN NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] In the reported synthetic routes, the sources of starting materials are not easy to obtain, and the reaction conditions generally require high process equipment, and the obtained products contain high levels of unknown impurities, which cannot meet the requirement of less than 0.1% of unknown impurities.

Method used

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  • Preparation method of high-purity fudosteine
  • Preparation method of high-purity fudosteine
  • Preparation method of high-purity fudosteine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0023] In the there-necked flask, add 30mL (0.22mol) of triethylamine, take 100g of distilled water, after dissolving, the temperature drops to -20°C, then add 13.3g (0.11mol) of L-cysteine, stir to dissolve, slowly drop Solubilize the ethanol (10g) solution that has 20g (0.11mol) of 3-bromopropyl acetate, after the HPLC monitoring reaction finishes, extract three times with 67g n-heptane, adjust pH to 5-6 with nitric acid in aqueous phase, concentrate, Obtain crude fodosteine.

[0024] In a one-mouth bottle, add the crude product of fudosteine ​​mentioned above, heat in an oil bath until dissolved, add 135g of acetone to reflux for 1h, heat-preserve and suction filter, reflux the filtrate for 1h, cool down to crystallize, and suction filter, and the obtained filter cake is refluxed with 90g of ethanol for beating for 1h. After suction filtration and drying of the filter cake, 19.2 g of refined fudosteine ​​was obtained, with a molar yield of 97.5%, an HPLC purity of 99.9%, an...

Embodiment 2

[0026] In the there-necked flask, add 64g (0.6mol) of sodium carbonate, take 290g of distilled water, after dissolving, the temperature drops to 30°C, then add 14.5g (0.12mol) of L-cysteine, stir to dissolve, and the temperature rises to 100 ℃, slowly dropwise add the methanol (150g) solution that is dissolved in 50g (0.37mol) of 3-chloropropyl acetate, HPLC monitors that the reaction finishes, after the reaction finishes, extract three times with 290g n-hexane, and adjust the pH of the aqueous phase with hydrochloric acid to 5-6, concentrated to obtain the crude product of fudosteine.

[0027] In a one-mouth bottle, add the above-mentioned fudosteine ​​crude product, heat in an oil bath until dissolved, add 460 g of ethanol to reflux for 1 h, heat-preserve and suction filter, reflux the filtrate for 1 h, cool down to crystallize, and suction filter, and obtain a filter cake with 230 g of ethanol to reflux for beating for 1 h. After filtration, the filter cake was dried to obt...

Embodiment 3

[0029] In the there-necked flask, add 25g (0.44mol) of potassium hydroxide, take 500g of distilled water, after dissolving, the temperature drops to 0°C, then add 26.6g (0.22mol) of L-cysteine, stir to dissolve, slowly add Dissolve the acetone (25g) solution of 50g (0.22mol) of 3-iodopropyl acetate, HPLC monitors the end of the reaction, after the end of the reaction, extract three times with 266g cyclohexane, adjust the pH of the aqueous phase to 5-6 with formic acid, Concentrate to obtain the crude product of fudosteine.

[0030] In a single-necked bottle, add the crude product of fudosteine ​​mentioned above, heat in an oil bath until dissolved, add 720 g of methanol to reflux for 1 hour, heat-preserve and suction filter, reflux the filtrate for 1 hour, cool down to crystallize, and suction filter, and the obtained filter cake is refluxed with 270 g of ethanol for beating for 1 hour. After suction filtration and drying of the filter cake, 38.9 g of refined fudosteine ​​was ...

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Abstract

The invention discloses a preparation method of high-purity fudosteine, and belongs to the technical field of synthesis of pharmaceutical compounds. The preparation method is characterized in that with 3-halogenated propyl acetate or 3-halogenated propyl propionate and L-cysteine as starting materials, a fudosteine crude product is prepared through a reaction in an aqueous alkali solution, and high-purity fudosteine is obtained by refining the fudosteine crude product. The preparation method has the advantages that the reaction conditions are mild, the reaction process is simple, the yield ishigh, the cost is low, the requirement that the content of unknown impurities is lower than 0.1% can be met, and the preparation method is suitable for industrial application.

Description

technical field [0001] The invention belongs to the technical field of synthesis of medical compounds, and in particular relates to a preparation method of high-purity fudosteine. Background technique [0002] The chemical name of Fudosteine ​​is: 3-hydroxypropylthioalanine, and its structural formula is as follows: [0003] [0004] Fudosteine ​​can effectively reduce the secretion of mucus in patients with chronic respiratory diseases, so it has good antitussive and phlegm-reducing effects. Fudosteine ​​is widely used in the treatment of bronchial asthma, bronchiectasis, chronic bronchitis, tuberculosis, pulmonary Emphysema and other chronic respiratory diseases. [0005] At present, the synthesis of fudosteine ​​is reported to use L-cysteine ​​as the starting material, which is prepared by docking with different side chains. The disclosed synthetic method of fudosteine ​​includes: 1. It is prepared by reacting L-cysteine ​​with allyl alcohol. The patent with the pub...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C319/14C07C323/58
CPCC07B2200/07C07C319/14C07C323/58
Inventor 姜玉钦杨雨晴范丽明张玮玮徐桂清李伟
Owner HENAN NORMAL UNIV
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