阅读说明：本技术 磷酸特地唑胺的精制方法 (Method for refining tedizolid phosphate ) 是由 马国旺 王俊臣 鲁锐 耿电光 陈金春 张宏周 赵臻 马奇 张立 周新建 梁雪莲 于 2019-09-11 设计创作，主要内容包括：本发明公开了一种磷酸特地唑胺的精制方法。该方法包括：将纯化水与磷酸特地唑胺粗品混合后加入抗降解剂,加入碱溶液,调至pH＝7～9；再加入活性炭脱色,过滤得磷酸特地唑胺钠盐水溶液；将磷酸特地唑胺钠盐水溶液中加入到四氢呋喃中,控温搅拌,过滤,得到固体；将固体加入到纯化水中,搅拌使固体溶解,用冰乙酸调至pH＝6.0～7.0；活性炭脱色,过滤；将滤液中加入到四氢呋喃中,再加入无水柠檬酸调节pH＝2～3,析晶；过滤,洗涤,干燥滤饼,得到终产物磷酸特地唑胺。本发明在成盐步骤中加入抗降解剂,能够有效降低降解杂质；精制条件较为温和,精制周期短,无有毒有害物质,制备所得磷酸特地唑胺纯度高,且收率高。(The invention discloses a refining method of tedizolid phosphate. The method comprises the following steps: mixing purified water and a tedizolid phosphate crude product, adding an antidegradant, adding an alkali solution, and adjusting the pH value to 7-9; adding active carbon for decoloring, and filtering to obtain a tedizolid phosphate sodium salt aqueous solution; adding the aqueous solution of tedizolid phosphate sodium salt into tetrahydrofuran, stirring at controlled temperature, and filtering to obtain a solid; adding the solid into purified water, stirring to dissolve the solid, and adjusting the pH value to 6.0-7.0 by using glacial acetic acid; decolorizing with activated carbon, and filtering; adding the filtrate into tetrahydrofuran, adding anhydrous citric acid to adjust the pH value to be 2-3, and crystallizing; filtering, washing and drying a filter cake to obtain the final product of tedizolid phosphate. According to the invention, the antidegradant is added in the salifying step, so that the degradation impurities can be effectively reduced; the refining condition is mild, the refining period is short, toxic and harmful substances are not generated, and the prepared tedizolid phosphate has high purity and high yield.)

1. A method for refining tedizolid phosphate is characterized by comprising the following steps:

(1) mixing purified water and a tedizolid phosphate crude product, adding an antidegradant, adding an alkali solution, and adjusting the pH value to 7-9; adding active carbon, stirring, decoloring and filtering to obtain a tedizolid phosphate sodium salt aqueous solution;

(2) slowly adding the tedizolid phosphate sodium salt aqueous solution obtained in the step (1) into tetrahydrofuran, stirring at controlled temperature, and filtering to obtain a solid;

(3) adding the solid obtained in the step (2) into purified water, stirring to dissolve the solid, and adjusting the pH value to 6.0-7.0 by using glacial acetic acid; adding active carbon, stirring for decoloring, and filtering; and

(4) adding the filtrate obtained in the step (3) into tetrahydrofuran, adding anhydrous citric acid in batches to adjust the pH to be 2-3, and stirring for crystallization; filtering, washing with purified water, and drying the filter cake to obtain the final product tedizolid phosphate.

2. The purification process according to claim 1, wherein in the step (1), the antidegradant is tributylphosphine.

3. The refining method according to claim 1, wherein, in the step (1), the alkali solution is a sodium hydroxide solution; preferably, the concentration of the sodium hydroxide solution is 1 mol/L.

4. The refining method according to claim 1, wherein in the step (1), the stirring time is 1 to 3 hours; preferably, the stirring time is 2 h.

5. The refining method according to claim 1, wherein in the step (1), the mass ratio of the tedizolid phosphate crude product to the purified water to the tributylphosphine to the activated carbon is 1: 4-6: 0.05-0.1; preferably, the mass ratio of the crude tedizolid phosphate, the purified water, the tributylphosphine and the activated carbon is 1:5:0.8: 0.8.

6. The refining method according to claim 1, wherein in the step (2), the stirring time is 10 to 15 hours; and/or the mass ratio of the filtrate to tetrahydrofuran is 1: 10-30, and preferably 1: 20.

7. The refining method according to claim 1, wherein in the step (3), the stirring time is 6 to 24 hours; and/or the stirring temperature is 15-25 ℃; and/or the mass ratio of the solid to the purified water to the activated carbon is 1: 4-6: 0.1-0.3, preferably the mass ratio of the solid to the purified water to the activated carbon is 1:5: 0.2.

8. The refining method according to claim 1, wherein in the step (4), the stirring crystallization time is 36 to 72 hours, and preferably, the stirring crystallization time is 48 hours.

9. The refining method according to claim 1, wherein in the step (4), the mass ratio of the filtrate, tetrahydrofuran and anhydrous citric acid is 1: 4-6: 2.4-2.8, and preferably the mass ratio of the filtrate, tetrahydrofuran and anhydrous citric acid is 1:5: 2.6.

10. The refining process of claim 1, wherein the refining process is carried out at a temperature of 15-25 ℃.

Technical Field

The invention relates to the technical field of medicinal chemistry, in particular to a refining method of tedizolid phosphate.

Background

Tedizolid phosphate (Tedizolid phosphate), chemical name is: (R) -3- (4- (2- (2-methyltetrazol-5-yl) pyridin-5-yl) -3-fluorophenyl) -5-hydroxymethyloxazolidin-2-one dihydrogen phosphate having the formula: .

Tedizolid phosphate is a second generation oxazolidinone antibiotic developed by Dong-a Pharmaceutical, and commercially developed by Cubist Pharmaceuticals and Bayer, and has been approved by FDA for marketing at 2014, 06, 20. Tedizolid phosphate is used for treating acute bacterial skin and skin structure infection caused by Staphylococcus aureus (including methicillin-resistant strains and methicillin-sensitive strains) and various gram-positive bacteria such as Streptococcus and enterococcus faecalis.

Disclosure of Invention

The invention aims to provide a method for refining tedizolid phosphate, which has mild conditions, does not generate toxic and harmful substances, can effectively reduce impurities in a tedizolid phosphate product, and can ensure that the prepared tedizolid phosphate has higher purity and high product yield.

In order to achieve the above object, the present invention provides a method for refining tedizolid phosphate, comprising the following steps: (1) mixing purified water and a tedizolid phosphate crude product, adding an antidegradant, adding an alkali solution, and adjusting the pH value to 7-9; adding active carbon, stirring, decoloring and filtering to obtain a tedizolid phosphate sodium salt aqueous solution; (2) slowly adding the tedizolid phosphate sodium salt aqueous solution obtained in the step (1) into tetrahydrofuran, stirring at controlled temperature, and filtering to obtain a solid; (3) adding the solid obtained in the step (2) into purified water, stirring to dissolve the solid, and adjusting the pH value to 6.0-7.0 by using glacial acetic acid; adding active carbon, stirring for decoloring, and filtering; adding the filtrate obtained in the step (3) into tetrahydrofuran, adding anhydrous citric acid in batches to adjust the pH value to be 2-3, and stirring for crystallization; filtering, washing with purified water, and drying the filter cake to obtain the final product tedizolid phosphate.

In a preferred embodiment, in step (1), the above-mentioned antidegradant is tributylphosphine.

In a preferred embodiment, in step (1), the alkali solution is a sodium hydroxide solution; preferably, the concentration of the sodium hydroxide solution is 1 mol/L.

In a preferred embodiment, in the step (1), the stirring time is 1-3 h; preferably, the stirring time is 2 hours.

In a preferred embodiment, in the step (1), the mass ratio of the crude tedizolid phosphate, the purified water, the tributylphosphine and the activated carbon is 1: 4-6: 0.05-0.1; preferably, the mass ratio of the crude tedizolid phosphate, the purified water, the tributylphosphine and the activated carbon is 1:5:0.8: 0.8.

In a preferred embodiment, in the step (2), the stirring time is 10 to 15 hours; and/or the mass ratio of the filtrate to tetrahydrofuran is 1: 10-30, preferably 1: 20.

In a preferred embodiment, in the step (3), the stirring time is 6 to 24 hours; and/or the stirring temperature is 15-25 ℃; and/or the mass ratio of the solid to the purified water to the activated carbon is 1: 4-6: 0.1-0.3, preferably 1:5: 0.2.

In a preferred embodiment, in the step (4), the stirring crystallization time is 36 to 72 hours, and preferably, the stirring crystallization time is 48 hours.

In a preferred embodiment, in the step (4), the mass ratio of the filtrate, tetrahydrofuran and anhydrous citric acid is 1: 4-6: 2.4-2.8, and preferably, the mass ratio of the filtrate, tetrahydrofuran and anhydrous citric acid is 1:5: 2.6.

In a preferred embodiment, the purification process is carried out at a temperature of 15 to 25 ℃.

Compared with the prior art, the invention has the following beneficial effects:

(1) according to the invention, the antidegradant is added in the salifying step, so that the degradation impurities can be effectively reduced.

(2) The refining method provided by the invention has the advantages of mild conditions, short refining period, no toxic or harmful substances, high purity of the prepared tedizolid phosphate and high yield.

Detailed Description

The following detailed description of specific embodiments of the invention is provided, but it should be understood that the scope of the invention is not limited to the specific embodiments.