A preparation method of fudosteine ​​oxide impurities

Abstract

The present application provides a method for preparing fudosteine ​​oxidized impurities, which belongs to the technical field related to the preparation of sulfone or sulfoxide. Fudosteine ​​is added to water for dissolution, and after dissolution, an oxidant is added, and the temperature is raised to 60-70°C for reaction, and the reaction time is 2-3 hours. After the reaction, an organic solvent is added for crystallization, cooling, suction filtration and drying to obtain the target product (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl) propionic acid. The present application uses fudosteine ​​and water for reaction, with fewer side reactions, simple post-processing, high yield and good purity, and is used for methodological detection and methodological development of fudosteine ​​API and tablets.

Description

Technical Field

[0001] The present application relates to a method for preparing fudosteine ​​oxidized impurities, and belongs to the technical field related to the preparation of sulfone or sulfoxide. Background Art

[0002] Fudosteine ​​is a type of cysteine ​​derivative with a basic skeleton of steine ​​developed by Mitsubishi Pharma Corporation and SS Pharmaceutical Co., Ltd. of Japan. It has multiple pharmacological effects on chronic respiratory diseases: inhibiting the proliferation of respiratory epithelial cells, normalizing the ratio of trehalose / sialic acid in sputum, restoring the state of ciliary transport of airway secretions, and having anti-inflammatory effects; it has the advantages of strong efficacy, small side effects, wide indications, and great market potential. It is suitable for expectoration of chronic respiratory diseases such as bronchial asthma, chronic bronchitis, bronchiectasis, tuberculosis, pneumoconiosis, emphysema, atypical mycobacterial infection, and diffuse bronchiolitis.

[0003] Fudosteine ​​Chemical Name: (-)-( R )-2-amino-3-(3-hydroxypropylthio)propionic acid; molecular formula: C6H 13 NO3S; Molecular weight: 179.24; Properties: This product is white or off-white powder, soluble in water, slightly soluble in acetic acid, and almost insoluble in ethanol; Its structural formula is as follows:

[0004] .

[0005] Currently, there is no disclosure on the method for preparing fudosteine ​​oxide impurity. Summary of the invention

[0006] In view of this, the present application provides a method for preparing a fudosteine ​​oxide impurity with a simple process and high purity. Fudosteine ​​is oxidized and crystallized to obtain the impurity (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl)propionic acid.

[0007] Specifically, the present application is implemented through the following scheme:

[0008] A method for preparing fudosteine ​​oxidized impurities comprises the following steps: adding fudosteine ​​into water for dissolution, adding an oxidant after dissolution, heating to 60-70°C for reaction for 2-3 hours, adding an organic solvent for crystallization after reaction, cooling, filtering and drying to obtain the target product (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl)propionic acid.

[0009] The structural formula of the above-mentioned (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl)propionic acid is as follows:

[0010] .

[0011] Further, as a preference:

[0012] The mass ratio of fudosteine ​​to water is 1:2 to 5. More preferably, the mass ratio of fudosteine ​​to water is 1:2.5 to 4.

[0013] The oxidant is hydrogen peroxide or potassium persulfate. More preferably, the mass ratio of fudosteine ​​to the oxidant is 1:1.

[0014] The reaction temperature was 65°C and the reaction time was 3 h. The yield and purity were improved with the extension of the insulation time, and the best level could be obtained at 3 h.

[0015] The organic solvent is a mixture of any one or more of ethanol, methanol and isopropanol. Compared with ethanol, the addition ratio of methanol is larger.

[0016] The mass ratio of fudosteine ​​to the organic solvent is between 1:10 and 60.

[0017] The above scheme provides a method for preparing (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl)propionic acid, which is simple, has fewer side reactions, simple post-treatment, high yield and high purity, and provides corresponding reference substances for the impurity calibration of fudosteine, and is used for methodological detection and methodological development of fudosteine ​​raw materials and tablets. DETAILED DESCRIPTION

[0018] In this embodiment, fudosteine ​​oxide impurity is prepared by the following reaction formula:

[0019] .

[0020] Fudosteine ​​can be directly crystallized to obtain the impurity (-)-(R)-2-amino-3-(3-hydroxypropylsulfinyl)propionic acid through oxidation reaction. See the following Examples 1-6 for details.

[0021] Example 1

[0022] Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 8 g of the target product with a yield of 80% and a purity of 99.21%.

[0023] Example 2

[0024] Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7 g of the target product with a yield of 70% and a purity of 99.31%.

[0025] Compared with Example 1, the amount of organic solvent added in this example is increased, and the solvent is replaced by methanol. Under the same conditions, the purity is improved to a certain extent, but the yield is not improved. It can be seen that compared with methanol, ethanol has a better crystallization effect.

[0026] Example 3

[0027] Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of potassium persulfate, raise the temperature to 65 °C, and keep the temperature for 3 hours. After the temperature is kept, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 8.2 g of the target product with a yield of 82% and a purity of 99.24%.

[0028] Compared with Example 1, the holding time was prolonged, and the yield and purity were improved. It can be seen that increasing the reaction time is beneficial to the preparation of oxidized impurities.

[0029] Example 4

[0030] Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of potassium persulfate, raise the temperature to 65 °C, and keep the reaction for 3 hours. After the reaction is completed, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7.9 g of the target product with a yield of 79% and a purity of 99.44%.

[0031] Compared with Example 2, the yield is significantly improved and the purity is slightly improved by extending the holding time; combined with Example 3, it can be seen that the increase in reaction time has a more significant effect on the yield of oxidized impurities.

[0032] Example 5

[0033] Dissolve 10 g of fudosteine ​​in 40 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7.1 g of the target product with a yield of 71% and a purity of 99.32%.

[0034] Compared with Example 1, the yield was reduced by increasing the addition ratio of water, but the purity was improved. It can be seen that the addition ratio of water can improve the quality of impurities to a certain extent.

[0035] Example 6

[0036] Dissolve 10 g of fudosteine ​​in 40 g of water, add 10 g of hydrogen peroxide, raise the temperature to 65 °C, and keep the temperature for 2 hours. After the temperature is kept, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 6.5 g of the target product with a yield of 65% and a purity of 99.41%.

[0037] Compared with Example 2, the yield decreased significantly and the purity was improved by increasing the amount of water added. It can be seen that when methanol is the organic solvent, the addition ratio of water has a more significant effect on the yield; combined with Example 5, it can be seen that the increase in the addition ratio of water has an impact on the yield of the oxidized impurities and the purity has a certain improvement.

[0038] The above embodiment adopts a one-step reaction to obtain the oxidized impurity, has a short preparation route, is simple to operate, has a yield that meets production requirements, and has a purity of more than 99%. The purity is relatively high, and a corresponding relationship is formed between it and fudosteine, which can be directly used to evaluate the performance of fudosteine.

Claims

1. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 8 g of the target product.

2. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7 g of the target product.

3. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of potassium persulfate, heat to 65 °C, and keep warm for 3 hours. After the heat preservation, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 8.2 g of the target product.

4. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 25 g of water, add 10 g of potassium persulfate, heat to 65 °C, keep warm for 3 hours, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7.9 g of the target product.

5. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 40 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, and keep warm for 2 hours. After the heat preservation, add 160 g of ethanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 7.1 g of the target product.

6. A method for preparing fudosteine ​​oxidized impurities, characterized in that: Dissolve 10 g of fudosteine ​​in 40 g of water, add 10 g of hydrogen peroxide, heat to 65 °C, keep warm for 2 hours, add 530 g of methanol, cool to 0 °C, filter, and dry in a vacuum oven to obtain 6.5 g of the target product.