阅读说明：本技术 一种高纯度洛索洛芬钠的新成盐方法 (Novel salt forming method of high-purity loxoprofen sodium ) 是由 董红光 綦秀杰 连捷 于 2019-11-11 设计创作，主要内容包括：本发明提供一种高纯度洛索洛芬钠的新成盐方法,所述洛索洛芬钠的成盐过程如下：洛索洛芬酸溶于乙酸乙酯,加热,脱色,过滤；滤液降温后加入纯化水、碳酸氢钠、甲醇保温反应；反应完成后升温过滤,滤液补加乙酸乙酯稀释后,降温析晶；析晶完成后过滤,固体经干燥得到洛索洛芬钠。本发明使用新的钠离子源-碳酸氢钠,能够解决成盐过程中碱性过强带来的一系列问题,制备的产品纯度高。<Image he="124" wi="700" file="DDA0002267149160000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The invention provides a novel salt forming method of high-purity loxoprofen sodium, which comprises the following steps: dissolving loxoprofen acid in ethyl acetate, heating, decolorizing, and filtering; cooling the filtrate, adding purified water, sodium bicarbonate and methanol, and reacting under heat preservation; after the reaction is finished, heating and filtering, adding ethyl acetate into the filtrate for dilution, and cooling and crystallizing; and filtering after crystallization is finished, and drying the solid to obtain the loxoprofen sodium. The invention uses a new sodium ion source-sodium bicarbonate, can solve a series of problems caused by over-strong alkalinity in the salt forming process, and the prepared product has high purity.)

1. A novel salifying method of high-purity loxoprofen sodium is characterized by comprising the following specific steps:

loxoprofen acid (formula (I)) and sodium bicarbonate are converted into salt in methanol and ethyl acetate to prepare loxoprofen sodium (formula (II)).

2. The novel salt formation method of high-purity loxoprofen sodium as claimed in claim 1, wherein the salt formation process of loxoprofen sodium is as follows:

step 1), dissolving loxoprofen acid in ethyl acetate, heating, decoloring and filtering;

step 2), cooling the filtrate, adding purified water, sodium bicarbonate and methanol, and reacting under heat preservation;

step 3), heating and filtering after the reaction is finished, adding ethyl acetate into the filtrate for dilution, and cooling and crystallizing;

and 4) filtering after crystallization is finished, and drying the solid to obtain the loxoprofen sodium.

3. The novel salifying method of high-purity loxoprofen sodium as claimed in claim 2, wherein the decolorizing by heating in step 1) is carried out by heating to 45-50 ℃ for 15-45 min.

4. The novel salification method of high-purity loxoprofen sodium as claimed in claim 2, wherein the decolorant used for decoloring is activated carbon.

5. The novel salt formation method of high purity loxoprofen sodium as claimed in claim 2, wherein the ratio of loxoprofen acid in step 1): the molar ratio of ethyl acetate is 1: 20-100.

6. The novel salifying method of high-purity loxoprofen sodium as claimed in claim 2, wherein the temperature of the filtrate in step 2) is reduced to-5 to 5 ℃, and the reaction is carried out for 1 to 10 hours under the condition of heat preservation.

7. The novel salt formation method of high-purity loxoprofen sodium according to claim 2, wherein the ratio of loxoprofen acid: purifying water: sodium bicarbonate: the molar ratio of methanol is 1: 2.5-10.0: 1.0-1.2: 10 to 100.

8. The new salt forming method of high-purity loxoprofen sodium according to claim 2, characterized in that the temperature in the step 3) is raised to 20 to 45 ℃, the temperature is lowered to-5 to 5 ℃, and the additional ethyl acetate is 1/2 volume of the ethyl acetate used in the step 1).

9. The novel salification method of high-purity loxoprofen sodium according to claim 2, wherein the drying temperature in step 4) is 30 to 60 ℃ and the drying time is 1 to 10 hours.

10. The novel salification method of high-purity loxoprofen sodium according to claim 2, wherein the crystallization time in the step 4) is 4 to 10 hours.

Technical Field

The invention relates to a preparation method of a compound, in particular to a novel salifying method of high-purity loxoprofen sodium.

Background

Loxoprofen sodium belongs to phenylpropionic acid non-steroidal anti-inflammatory drugs, is firstly developed by three co-located companies in Japan, is the first variety of non-steroidal anti-inflammatory drugs to be sold in Japan, is already collected by the Japanese pharmacopoeia and is imported in China. The product is listed in one of the new product development recommended trial varieties in nine five countries and 2010. Compared with the similar clinical medicines, the loxoprofen sodium has the characteristics that: stronger (good clinical effect), quicker (the peak value can be reached after the oral administration for 30 minutes), safer (little side effect). The other characteristic is wide adaptation diseases, and can be widely used for anti-inflammatory and analgesic treatment of rheumatoid arthritis, lumbago, scapulohumeral periarthritis, neck, shoulder and wrist syndrome, etc., analgesic and anti-inflammatory treatment after operation, trauma and tooth extraction, antipyretic and analgesic treatment of acute upper respiratory inflammation, etc.

In the relevant data such as commercial products or published documents and patents (such as CN200710156147, CN201510386438, CN201511020131, CN201711166565 and CN201810182842) on the market at present, sodium hydroxide is generally adopted as a base in the process of preparing the loxoprofen sodium from the loxoprofen acid, and a source of sodium ions is provided. Sodium hydroxide is commonly called caustic soda, caustic soda and caustic soda, is strong caustic soda with strong corrosivity, easily destroys a substrate loxoprofen acid in the manufacturing process of the loxoprofen sodium, introduces new impurities to cause great difficulty in subsequent purification of products, and a small amount of sodium hydroxide residue can also cause adverse factors such as discoloration and impurity increase of finished products in the stable placing process, so that the effective period of the raw material medicines is shortened. Sodium hydroxide, as a strong corrosive strong base, corrodes equipment seriously, and other metal ions (such as iron ions and the like) are easily introduced in the preparation process of the raw material medicine, so that the quality of the product is reduced while the equipment is damaged, the subsequent production process is damaged, and the quality of the preparation product is reduced.

Therefore, there is an urgent need for a new salt-forming method that avoids the use of sodium hydroxide as a source of sodium ions to solve the above problems.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a novel salt forming method of high-purity loxoprofen sodium, a novel sodium ion source-sodium bicarbonate is used, a series of problems caused by over-strong alkalinity in the salt forming process can be solved, and the prepared product has high purity.

In order to solve the technical problems, the invention provides the following technical scheme:

on one hand, the invention provides a novel salifying method of high-purity loxoprofen sodium, which comprises the following specific steps:

loxoprofen acid (formula (I)) and sodium bicarbonate are converted into salt in methanol and ethyl acetate to prepare loxoprofen sodium (formula (II)).

Further, the salt formation process of the loxoprofen sodium is as follows:

step 1), dissolving loxoprofen acid in ethyl acetate, heating, decoloring and filtering;

step 2), cooling the filtrate, adding purified water, sodium bicarbonate and methanol, and reacting under heat preservation;

step 3), heating and filtering after the reaction is finished, adding ethyl acetate into the filtrate for dilution, and cooling and crystallizing;

and 4) filtering after crystallization is finished, and drying the solid to obtain the loxoprofen sodium.

Further, the heating for decoloring in the step 1) is heating to 45-50 ℃ for decoloring for 15-45 min; preferably 30 min.

Further, the decoloring agent used for decoloring is activated carbon or the like. The usage amount of the decolorizing agent is 0.5-5% of the weight of the loxoprofen acid.

Further, the loxoprofen acid in the step 1): the molar ratio of ethyl acetate is 1: 20 to 100.

Further, the temperature of the filtrate in the step 2) is reduced to-5 ℃, preferably 0-5 ℃, and the heat preservation reaction is carried out for 1-10 hours, preferably 3-4 hours.

Further, the loxoprofen acid in the step 2): purifying water: sodium bicarbonate: the molar ratio of methanol is 1: 2.5-10.0: 1.0-1.2: 10 to 100 parts; preferably 1: 3.5-5.5: 1.0-1.2: 10 to 50

Further, in the step 3), the temperature is raised to 20-45 ℃, preferably 20-25 ℃, and the temperature is lowered to-5 ℃, preferably 0-5 ℃; the additional ethyl acetate was 1/2 volumes of the ethyl acetate used in step 1).

Further, the drying temperature in the step 4) is 30-60 ℃, preferably 40 ℃, and the drying time is 1-10 hours, preferably 8 hours.

Further, the crystallization time in the step 4) is 4-10 hours, preferably 5 hours.

Advantageous effects

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

the invention provides a novel salifying method of high-purity loxoprofen sodium, which has the following advantages:

Detailed Description

The present invention will be described in further detail with reference to specific embodiments, but it should not be construed that the scope of the subject matter of the present invention is limited to the examples.

The process equipment or devices not specifically noted in the following examples are conventional in the art; all reagents are commercially available.