CN114685278A - Trimethylbenzotriphenol impurity compound, preparation method and application thereof - Google Patents

Abstract

The invention belongs to the technical field of medicines, and discloses a trimethylphloroglucinol impurity compound, a preparation method and application thereof. The impurity compound meets the requirement of an impurity reference substance in quality control, can be used for quality control in a trimethyl phloroglucinol synthesis process, can be used as the impurity reference substance for accurately and quantitatively detecting trimethyl phloroglucinol, and is beneficial to improvement of quality control of corresponding raw material medicines.

Description

Trimethylbenzotriphenol impurity compound, preparation method and application thereof

Technical Field

The invention relates to the technical field of medicines, and particularly relates to a trimethylphloroglucinol impurity compound, a preparation method and application thereof.

Background

Phloroglucinol (Phloroglucinol, structural formula shown in formula II) is a myotropic non-atropine non-papaverine pure smooth muscle antispasmodic drug, and can directly act on the smooth muscle of gastrointestinal tract and genitourinary tract. Compared with other smooth muscle spasmolytic medicines, phloroglucinol has the greatest characteristic of no choline resistance, can not generate a series of choline-like adverse reactions while relieving the spasm of the smooth muscle, can not cause symptoms such as hypotension, heart rate acceleration or arrhythmia, has little influence on cardiovascular functions, only acts on the spastic smooth muscle, and has little influence on normal smooth muscle. The traditional Chinese medicine composition is clinically used for treating acute spasmodic pain caused by dysfunction of digestive system and biliary tract, acute spasmodic pain of urethra, scrofula and kidney and gynecological spasmodic pain, and has the advantages of quick spasmodic and analgesic effects, obvious effect and good tolerance.

Trimethyl phloroglucinol (1, 3, 5-Trimethoxybenzene, structural formula shown in formula III) is an effective antispasmodic drug, can directly act on smooth muscle, and is used as an important pharmaceutical composition in phloroglucinol injection or solid preparation. A small amount of trimethyl phloroglucinol exists in the prescription of the phloroglucinol injection, so that sphincter muscles and urethral smooth muscles are more sensitive to drugs through synergistic effect, and the spasmolytic and analgesic effects of the phloroglucinol injection are enhanced.

In the process of researching the preparation process of trimethyl phloroglucinol, an unknown impurity with high content is found, and is determined to be 2, 4, 6-trimethoxy methyl benzoate (a compound shown in a formula I) through separation and identification. The compound of formula I has not been reported in the literature as an impurity in trimethylphloroglucinol. If the impurities are generated in the process, the impurities may remain in the trimethyl phloroglucinol raw material medicine, so that the medicine quality and the medicine safety are influenced. In the process of drug research, the drug impurity spectrum must be comprehensively analyzed, and the possible impurities must be systematically researched and strictly controlled, so that the quality and safety of the drug can be ensured. If no corresponding impurity reference substance exists, the analysis method cannot be developed and verified in a targeted manner so as to ensure that the corresponding impurities can be effectively detected and controlled.

Based on the defects of the prior art, a new preparation method for the compound of formula I and an impurity reference substance are needed to be provided, so that the quality control of trimethyl phloroglucinol is improved.

Disclosure of Invention

1. Problems to be solved

Impurities of the compound of formula I may be generated in the trimethylphloroglucinol synthesis process, and may remain in the bulk drug. At present, no relevant report and targeted detection method exist. Aiming at the problem that trimethyl phloroglucinol in the prior art possibly has a potential impurity and cannot be effectively controlled, the invention aims to provide a method for preparing the impurity compound with simple process and high product purity, and provide a qualified impurity reference substance for the quality control of trimethyl phloroglucinol.

2. Technical scheme

In order to solve the problems, the technical scheme adopted by the invention is as follows:

the invention provides a trimethylphloroglucinol impurity compound (formula I), which has a structural formula as follows:

in the preferred scheme, the purity of the trimethylphloroglucinol impurity compound is 95-100%.

In a preferred embodiment, the preparation method of the trimethylphloroglucinol impurity compound comprises the following steps:

1) dissolving phloroglucinol in an organic solvent, dropwise adding dimethyl sulfate under an alkaline condition, and heating for reaction;

2) and after the reaction is finished, filtering, decompressing, concentrating and drying the filtrate, and purifying by column chromatography to obtain the trimethylphloroglucinol impurity compound.

Preferably, the organic solvent includes any one or a combination of ketone solvents.

Preferably, the ketone solvent comprises any one or combination of acetone or butanone.

Preferably, the alkali species in step 1) includes sodium carbonate, potassium carbonate or cesium carbonate.

In a preferable scheme, the trimethylphloroglucinol impurity compound is used as an impurity reference substance and is applied to the quality control of trimethylphloroglucinol.

3. Advantageous effects

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

(1) the trimethylphloroglucinol impurity compound has higher purity, meets the requirement of an impurity reference substance in quality control, can be used for developing and verifying a trimethylphloroglucinol analysis method, and is beneficial to improving the quality standard of the trimethylphloroglucinol, so that the product quality of the trimethylphloroglucinol is better controlled.

(2) The preparation method of the trimethylphloroglucinol impurity compound has simple process, the purity of the prepared impurity compound is 95-100%, and a qualified impurity reference substance can be provided for the quality control of the trimethylphloroglucinol.

Drawings

FIG. 1 is a mass spectrum of a trimethylphloroglucinol impurity compound obtained in example 1 of the present invention.

FIG. 2 is the nuclear magnetic hydrogen spectrum of the trimethylphloroglucinol impurity compound obtained in example 1 of the present invention.

FIG. 3 is a high performance liquid chromatogram of trimethylphloroglucinol impurity compound obtained in example 1 of the present invention.

FIG. 4 is a high performance liquid chromatogram of trimethylphloroglucinol obtained in example 4 of the present invention.

Detailed Description

The invention is further described with reference to specific examples.

It should be noted that the terms "upper", "lower", "left", "right" and "middle" used in the present specification are for the sake of clarity, and are not intended to limit the scope of the present invention, and changes or adjustments of the relative relationship thereof may be made without substantial technical changes.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs; as used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.

As used herein, the term "about" is used to provide the flexibility and inaccuracy associated with a given term, measure or value. The degree of flexibility for a particular variable can be readily determined by one skilled in the art.

As used herein, at least one of the terms "is intended to be synonymous with one or more of. For example, "at least one of A, B and C" explicitly includes a only, B only, C only, and combinations thereof, respectively.

Concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such a range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a numerical range of about 1 to about 4.5 should be interpreted to include not only the explicitly recited limit values of 1 to about 4.5, but also include individual numbers (such as 2, 3, 4) and sub-ranges (such as 1 to 3, 2 to 4, etc.). The same principle applies to ranges reciting only one numerical value, such as "less than about 4.5," which should be construed to include all of the aforementioned values and ranges. Moreover, such an interpretation should apply regardless of the breadth of the range or feature being described.

Any steps recited in any method or process claims may be executed in any order and are not limited to the order presented in the claims.

The invention is further described with reference to specific examples.

Example 1

This example prepares a trimethylphloroglucinol impurity compound (formula I) by the following reaction scheme:

the preparation method of the trimethylphloroglucinol impurity compound comprises the following steps:

9g of phloroglucinol, 90mL of acetone and 49.3g of potassium carbonate are added into a reaction bottle, 27g of dimethyl sulfate is dropwise added under the stirring condition of 60 ℃, and after the dropwise addition is finished, the reaction is carried out for 2 hours under the heat preservation condition. After the reaction, the reaction mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. And (4) purifying by column chromatography to obtain 2.4g of the trimethylphloroglucinol impurity compound (yield is 14.9 percent, purity is 98.3 percent).

Characterization of trimethylphloroglucinol impurity compounds:

(1) mass spectrometry (ESI-MS) was performed on the trimethylphloroglucinol impurity compound prepared in example 1: m/z 227.1[ M + H ]]⁺。

(2) Nuclear magnetic analysis was performed on the trimethylphloroglucinol impurity compound prepared in example 1:¹H-NMR(400MHz，CDCl₃)δ6.10(2H，s)，3.88(3H，s)，3.81(3H，s)，3.80(6H，s)。

example 2

The preparation method of the trimethylphloroglucinol impurity compound comprises the following steps:

9g of phloroglucinol, 90mL of butanone and 49.3g of potassium carbonate are added into a reaction bottle, 27g of dimethyl sulfate is dripped under the condition of stirring at 60 ℃, and the reaction is carried out for 2 hours after the dripping is finished. After the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. And (4) purifying by column chromatography to obtain 2.1g of the trimethylphloroglucinol impurity compound (the yield is 13.0 percent, and the purity is 97.6 percent).

Example 3

The preparation method of the trimethylphloroglucinol impurity compound comprises the following steps:

9g of phloroglucinol, 90mL of acetone and 37.8g of sodium carbonate are added into a reaction bottle, 27g of dimethyl sulfate is dripped into the reaction bottle under the condition of stirring at the temperature of 60 ℃, and the reaction is carried out for 2 hours after the dripping is finished. After the reaction, the mixture was filtered, and the filtrate was concentrated to dryness under reduced pressure. And (4) purifying by column chromatography to obtain 2.5g of the trimethylphloroglucinol impurity compound (yield is 15.5 percent, and purity is 98.0 percent).

Example 4

This example provides the use of trimethylphloroglucinol impurity compounds as a control in the quality control of the trimethylphloroglucinol preparation process.

The preparation process route of the trimethyl phloroglucinol is as follows:

the trimethyl phloroglucinol prepared and refined by the process route is subjected to HPLC detection, and the detection conditions are as follows: a column packed with octadecylsilane-bonded silica gel (Inertsil ODS-4, 4.6X 250mm, 5 μm); using 0.01mol/L potassium dihydrogen phosphate solution (pH3.0) (1.36 g of potassium dihydrogen phosphate is weighed, 1000ml of water is added to adjust the pH value to 3.0 by using phosphoric acid for dissolution) as a mobile phase A, using 0.01mol/L potassium dihydrogen phosphate solution (pH3.0) -acetonitrile (20: 80) as a mobile phase B, and detecting the wavelength is 265 nm; the flow rate is 1.0 ml/min; column temperature: 30 ℃; the injection volume was 20. mu.l.

The spectrum obtained by the HPLC method is shown in FIG. 4.

Claims (7)

1. A trimethyl phloroglucinol impurity compound is characterized in that: the structural formula is as follows:

2. the trimethylphloroglucinol impurity compound according to claim 1, characterized in that: the purity of the impurity compound is 95-100%.

3. The method for preparing trimethylphloroglucinol impurity compounds according to claim 1 or 2, characterized in that: the method comprises the following steps:

1) dissolving phloroglucinol in an organic solvent, dripping dimethyl sulfate under the alkaline condition, and heating for reaction;

2) and after the reaction is finished, filtering, concentrating the filtrate under reduced pressure to be dry, and performing column chromatography separation and purification to obtain the trimethylphloroglucinol impurity compound.

4. The method of claim 3, wherein the method comprises the steps of: the organic solvent comprises any one or combination of ketone solvents.

5. The method of claim 4, wherein the method comprises the steps of: the ketone solvent comprises any one or combination of acetone or butanone.

6. The method of claim 3, wherein the method comprises the steps of: the alkali species in step 1) include sodium carbonate, potassium carbonate or cesium carbonate.

7. Use of the trimethylphloroglucinol impurity compound of claim 1 or 2 as an impurity control in the quality control of trimethylphloroglucinol.

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