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Fudosteine oxide impurity and preparation method thereof

A technology for oxidizing impurities and fodosteine, applied in chemical instruments and methods, preparation of organic compounds, organic chemistry, etc., can solve the problems affecting the quality and safety of fodosteine ​​drugs, difficult to obtain high purity, etc. The effect of high product purity and improved drug quality

Active Publication Date: 2014-04-23
迪嘉药业集团股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore the existence of impurity (formula I) has a strong impact on the drug quality and medication safety of fudosteine, need to carry out key control
Simultaneously, the structure of impurity (formula I) is similar to fudosteine, soluble in water, almost insoluble in organic solvents, common preparation method is difficult to obtain high-purity impurity (formula I) as reference substance

Method used

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  • Fudosteine oxide impurity and preparation method thereof
  • Fudosteine oxide impurity and preparation method thereof
  • Fudosteine oxide impurity and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Example 1: Synthesis of (R)-2-(tert-butoxycarbonylamino)-3-(3 hydroxypropylthio)propionic acid

[0038] Dissolve 10.84g fudosteine ​​and 2.66g sodium hydroxide in 100ml water and 40ml tert-butanol, add 13.85g di-tert-butyl dicarbonate (Boc 2 O), stirred reaction, overnight at room temperature. The reaction solution was adjusted to pH 1-2 with potassium bisulfate, then extracted with 2*40mL ethyl acetate, dried over anhydrous magnesium sulfate, and concentrated to obtain (R)-2-(tert-butoxycarbonylamino)-3-(3-hydroxy Propylthio)propionic acid.

Embodiment 2

[0039] Embodiment 2: Synthesis of (R)-2-(tert-butoxycarbonylamino)-3-(3 hydroxypropylthio)propionic acid benzyl ester

[0040] Dissolve (R)-2-(tert-butoxycarbonylamino)-3-(3-hydroxypropylthio)propionic acid obtained in the previous step in 50ml of methanol, adjust the pH to 7 with potassium bicarbonate, spin off the solvent and dry in vacuo . After drying, dissolve in 55ml of DMF, add 11.79g of benzyl bromide, react at room temperature for 5h, dilute with 150mL of water, and extract with 2*40mL of ethyl acetate. The organic layer was washed with 50 mL of water, dried over anhydrous magnesium sulfate, and concentrated to obtain 18.63 g of benzyl (R)-2-(tert-butoxycarbonylamino)-3-(3-hydroxypropylthio)propionate. The two-step yield is 83.2%.

Embodiment 3

[0041] Example 3: Synthesis of (R)-benzyl 2-(tert-butoxycarbonylamino)-3-(3 hydroxypropylsulfonyl)propionate.

[0042] Dissolve 17.15g of benzyl (R)-2-(tert-butoxycarbonylamino)-3-(3-hydroxypropylthio)propionate in 20ml of methanol, and slowly add 42.36g of potassium hydrogen persulfate under ice cooling Composite salt solution (content 42%, dissolved in 20ml of water), removed from the ice room temperature and reacted overnight. The methanol was removed under reduced pressure, the residue was dissolved in 60 mL of water, extracted with 3*30 mL of ethyl acetate, the organic layers were combined, washed with 30 mL of water, dried over anhydrous magnesium sulfate to obtain (R)-2-(tert-butoxycarbonylamino 13.8 g of benzyl )-3-(3 hydroxypropylsulfonyl)propionate, yield 75%, purity 98.9%.

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Abstract

The invention relates to a Fudosteine oxide impurity (R)-2-amino-3-(3-hydroxypropyl sulfonyl) propionic acid (formula I shown in the specification) and a preparation method thereof. The pharmacological activity of Fudosteine (formula II shown in the specification) comes from closed sulfydryl in structure, which is metabolized into a free mercapto derivative in vivo to play a role. If sulphur atom is oxidized, normal metabolism can not be carried out in vivo to obtain the pharmacological activity. Therefore, existence of the impurity (formula I shown in the specification) has a strong impact on medicine quality and medication safety of Fudosteine and needs key control. The specific structure of the oxide impurity is as follows.

Description

Technical field: [0001] The invention relates to a fudosteine ​​oxidation impurity (R)-2-amino-3-(3-hydroxypropylsulfonyl)propionic acid (formula I) and a preparation method thereof. Its specific structure is as follows: [0002] Background technique: [0003] Fudosteine ​​(Fudosteine) (formula II) is a class of cysteine ​​derivatives, developed by Japan's Mitsubishi Welfide Company and SSP Company, for cough, chronic bronchitis, bronchiectasis, pneumoconiosis, emphysema, non- It has a strong expectorant effect for certain diseases such as acid-fast bacteria disease; it has the advantages of strong drug efficacy, small side effects, and wide indications, and has gradually become the first choice for expectorant drugs for chronic respiratory diseases. Its chemical name is (R)-2-amino-3-(3-hydroxypropylthio)propionic acid, and its specific structure is as follows: [0004] [0005] The existence of related substances is directly related to the quality and safety of dru...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C315/04C07C317/48
Inventor 苗华明王海波蔡亚辉
Owner 迪嘉药业集团股份有限公司
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