CN117720481A - Preparation method of eperisone hydrochloride and application of eperisone hydrochloride in preparation - Google Patents

Abstract

The invention provides a method for preparing eperisone hydrochloride with high yield and high purity, which takes p-ethyl propiophenone as a starting material and prepares the eperisone hydrochloride through mannich reaction under the catalysis of proline. The preparation method has the advantages of few reaction impurities, simple steps and convenient operation, and the prepared eperisone hydrochloride has high yield and good quality, and is favorable for preparing the eperisone hydrochloride preparation for clinical use.

Description

Preparation method of eperisone hydrochloride and application of eperisone hydrochloride in preparation

Technical Field

The invention belongs to the field of pharmaceutical chemical synthesis, and particularly provides a preparation method of eperisone hydrochloride.

Background

The chemical name of the eperisone hydrochloride (shown as a structural formula I) is 1- (4-ethylphenyl) -2-methyl-3- (piperidin-1-yl) -1-propanone hydrochloride, which is a beta aminoketone central muscle relaxant developed by Japanese kava, and the product acts on central nervous system and vascular smooth muscle, can inhibit animal experimental rigidity, dilate blood vessels, improve blood circulation, resist dizziness and relieve pain. Compared with tolperisone, the eperisone hydrochloride has improved dosage, action time and action intensity, and is suitable for treating cerebral palsy, neck-shoulder-wrist syndrome, spinal cord injury, cerebrovascular disease, lumbago, scapulohumeral periarthritis, muscle tension, head injury, amyotrophic lateral sclerosis, spasticity paralysis, spinocerebellar degeneration, cervical spondylosis, muscle tension and spasticity paralysis caused by spinal cord tumor and the like.

Eperisone hydrochloride has the structural formula:。

the molecular structure of the eperisone hydrochloride contains a chiral center and a pair of corresponding isomers, and the racemic form of the eperisone hydrochloride is pharmaceutically used. The preparation method of the eperisone hydrochloride comprises the following steps:

。

the preparation method takes ethylbenzene as a raw material, and prepares the p-ethyl propiophenone through acylation reaction with propionyl chloride, and then prepares the eperisone hydrochloride through mannich condensation reaction with paraformaldehyde and piperidine hydrochloride. Wherein, the second mannich condensation reaction is a key step of the eperisone hydrochloride, the yield difference reported in each literature of the step is larger, and the yield is 97% reported in the literature of' patent JPH06256330The yield reported by "patent US3995047" is 65.7%, the yield reported by "patent CN106588817" is 87-89%, and the yield reported by "patent CN103232415" is 75-85%.

In the process of preparing the eperisone hydrochloride by mannich condensation reaction, the reaction temperature is higher, the reaction time is longer, and the reaction system is easy to generate specific impurity 4' -ethyl-2-methacryloyl benzene (shown in formula III) after piperidine is eliminated. The impurity contains a genotoxic warning structural fragment, and the excessive impurity can affect the yield and the quality of the product, and even increase the risk of use for patients.

。

The mannich condensation reaction preparation process reported in the JPH06256330 differs from the processes reported in the patents US3995047, CN106588817 and CN103232415 in that: a small amount of hydrochloric acid was added. The inventors repeated this preparation process and found that the addition of hydrochloric acid did significantly reduce the production of 4' -ethyl-2-methacryloyl benzene impurity, thereby increasing the yield to 97%. However, the addition of hydrochloric acid is not friendly to shop workers or laboratory personnel, as well as to equipment and the environment.

In view of the foregoing, there remains a need to develop a process for preparing eperisone hydrochloride in high yield and purity.

Disclosure of Invention

The invention provides a preparation method of eperisone hydrochloride, which is characterized in that p-ethyl propiophenone shown in a formula II is used as a starting material, and the starting material is subjected to mannich condensation reaction with paraformaldehyde and piperidine hydrochloride under the catalysis of proline to prepare the eperisone hydrochloride.

。

Wherein the mannich condensation reaction temperature is 80-85 ℃, the feeding amount of proline is 5% of the weight of the compound in the formula II, and the reaction solvent is ethanol.

The HPLC chromatographic conditions used for this preparation method are as follows: octadecylsilane chemically bonded silica is used as a filler; the flow rate is 1mL per minute; a UV detector detecting 254nm; mobile phase: methanol-water-diethylamine= (700-300-5, pH adjusted to 7.5 with glacial acetic acid).

From literature or prior knowledge, it is known that products prepared by mannich reactions, such as those containing chiral centers, can incorporate small molecule chiral catalysts (e.g., proline) to enhance or induce the formation of the dominant single optical isomer therein. The eperisone hydrochloride is prepared by taking racemate consisting of a pair of enantiomers 1:1 as medicines. The inventor searches for a better method for controlling the impurity 4' -ethyl-2-methacryloyl benzene shown in the formula III, and unexpectedly discovers that proline can reduce the activation energy required by the reaction, reduce the reaction temperature and shorten the reaction time, thereby greatly reducing the content of the impurity and further improving the yield and the quality.

In addition, the small molecular catalyst proline has low cost and obvious advantages compared with hydrochloric acid catalysis, and is environment-friendly.

In conclusion, compared with the prior art, the preparation method provided by the invention can overcome the defects of the prior art, can obtain the eperisone hydrochloride with high yield, high purity and simple preparation process, and further can prepare the eperisone hydrochloride tablet, and the method can play an important role in drug production and quality control.

Drawings

FIG. 1 is a HPLC detection chart of the eperisone hydrochloride reaction solution obtained in example 1 of the present invention;

FIG. 2 is a HPLC detection chart of comparative example 1 (JPH 06256330 method) for preparing eperisone hydrochloride reaction;

FIG. 3 is a HPLC detection chart of comparative example 2 (US 3995047 method) for preparing eperisone hydrochloride reaction;

FIG. 4 is a HPLC detection chart of impurity 4' -ethyl-2-methacryloyl benzene;

FIG. 5 is an HPLC detection chart of p-ethyl propiophenone.

Detailed Description

The following description of the invention is intended to be illustrative, and is to be taken as being within the scope of the invention, as various alternatives or combinations may be devised by those of ordinary skill in the art as well as conventional approaches.

EXAMPLE 1 preparation of the Compound of formula I, repidil hydrochloride

120g of p-ethyl propiophenone, 28.8g of paraformaldehyde and 107g of piperidine hydrochloride are sequentially added into 60mL of ethanol, 6g of proline is added, stirring is carried out, the temperature is raised to 80-85 ℃ and stirring is carried out for 2h, and the HPLC monitoring reaction is finished (figure 1). 500mL of acetone is added, the mixture is stirred and filtered, a filter cake is washed by a proper amount of acetone, 214g of eperisone hydrochloride is obtained after drying, and the yield is 98%.

Comparative example 1 preparation of the Compound of formula I, eperisone hydrochloride (JPH 06256330 method)

To 15mL of isopropyl alcohol, 30g of ethyl acetone, 13.5g of trioxymethylene and 27.1g of piperidine hydrochloride were added 0.9mL of concentrated hydrochloric acid, and the mixture was stirred and reacted at 95℃for 4 hours, followed by HPLC monitoring (FIG. 2). The solvent was distilled off, dissolved by adding water, washed once with ethyl acetate, the pH of the aqueous layer was adjusted to 8 with sodium hydroxide, and extracted with methyl tert-butyl ether. The organic layer is filled with dry hydrogen chloride gas to salify the eperisone, filtered and dried to obtain 53.1g of eperisone hydrochloride with 97% yield.

Comparative example 2 preparation of the Compound of formula I, eperisone hydrochloride (US 3995047 method)

120g of p-ethyl propiophenone, 28.8g of paraformaldehyde and 107g of piperidine hydrochloride are added into 60mL of isopropanol in sequence, stirred, heated to 110 ℃ for reflux reaction for 2h, and the reaction is monitored by HPLC (figure 3). 500mL of acetone is added, the mixture is stirred and filtered, a filter cake is washed by a proper amount of acetone, 144g of eperisone hydrochloride is obtained by drying, and the yield is 65.7%.

EXAMPLE 2 preparation of eperisone hydrochloride tablets

200g of eperisone hydrochloride, 100g of microcrystalline cellulose PH-101, 100g of polyethylene glycol, 51g of croscarmellose sodium and 400g of purified water prepared according to the method of example 1 are taken, granulated, dried, sieved and granulated, 6g of magnesium stearate is added, and the mixture is uniformly mixed, and tabletting and coating are carried out according to the specification of 50mg, thus obtaining the eperisone hydrochloride tablet.

Claims (4)

1. A method for preparing the eperisone hydrochloride shown in the formula I is characterized in that the eperisone hydrochloride is prepared by taking p-ethyl propiophenone shown in the formula II as a starting material and carrying out mannich condensation reaction with paraformaldehyde and piperidine hydrochloride under the catalysis of proline,

。

2. the method of claim 1, wherein: the mannich condensation reaction temperature is 80-85 ℃.

3. The method of claim 1, wherein: the amount of proline added was 5% by weight of the compound of formula II.

4. The method of claim 1, wherein: the reaction solvent is ethanol.