Synthesis method of amorolfen medicine EP impurity B

Abstract

The invention discloses a synthesis method of an amorolfen drug EP impurity B. The technical scheme has the advantages of short steps, simple operation, short preparation period, low cost and environmental protection, and the prepared amorolfen drug impurity is high in purity, has no obvious impurity points, meets the requirements of impurity reference substances, and is suitable for industrial production. The standard substance can be applied to qualitative and quantitative research and detection of the amorolfen medicine impurities as a standard substance of the amorolfen medicine impurities, and has certain significance on quality control of amorolfen medicine raw material medicines and related preparations thereof; in the synthesis process, purification is simple, the yield is high, hazardous materials such as highly toxic and explosive materials are not used, and the modern environment-friendly and sustainable development concepts are met.

Description

Technical Field

[0001] The invention relates to the technical field of drug synthesis, in particular to a method for synthesizing an amorolfine drug EP impurity B. Background Art

[0002] The chemical name of amorolfine compound is cis-4[3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropane]-2,6-dimethyl-morpholine, white crystalline powder, boiling point is 407.1℃, molecular weight is 317.50900, chemical formula structure is Amorolfine hydrochloride ointment with it as the main ingredient shows high activity against vaginal candidiasis, onychomycosis (onychomycosis) and various skin fungal diseases, but has no effect on organ fungi.

[0003] The quality of drugs is an important criterion for measuring the quality of drugs, among which impurities are the main factors affecting the purity of drugs. If the drugs contain impurities exceeding the limit, it is possible to change the physical and chemical constants, change the appearance characteristics, and affect the stability of the drugs. The increase of impurities will inevitably lead to a low content or reduced activity of the drug, and a significant increase in toxic and side effects. Therefore, the impurity inspection of drugs is a very important link in controlling the purity of drugs and improving the quality of drugs. The European Pharmacopoeia (EP for short) includes the EP impurity B of amorolfine drugs, which is an impurity that must be studied in drug production. The standard sample of EP impurity B of amorolfine drugs can meet the needs of studying EP Pharmacopoeia impurity B in the quality research of amorolfine drugs.

[0004] The synthesis of the impurity sample does not have an efficient and convenient synthesis method. The present invention prepares an amorolfine drug EP impurity B, the presence of which may affect the effectiveness and safety of amorolfine raw materials and preparations thereof. Therefore, the preparation and research of the impurity are of great significance to the research and quality control of amorolfine raw materials and preparations. Summary of the invention

[0005] 1. Technical issues to be resolved

[0006] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing impurity B of amorolfine drug EP, which solves the problems mentioned in the above background technology.

[0007] (II) Technical solution

[0008] To achieve the above object, the present invention is implemented by the following technical scheme: a method for synthesizing impurity B of amorolfine drug EP, specifically comprising the following synthesis steps:

[0009] Step 1, dissolving styrene in an organic solvent;

[0010] Step 2: After the solution is completely dissolved, 2,6-dimethylpyridine, cobalt chloride, methyl blue and hydrogen peroxide are added in sequence;

[0011] Step 3, stirring the reaction under constant temperature under 310 nm wavelength light;

[0012] Step 4: After the reaction is completed, cool to room temperature, extract with ethyl acetate, and separate the liquids;

[0013] Step 5, the organic phase is dried with anhydrous sodium sulfate, concentrated, filtered, and ethyl acetate is removed under reduced pressure to obtain a crude product;

[0014] Step 6: then add the crude product into ethyl acetate, heat to reflux to dissolve, and stir at room temperature overnight;

[0015] Step 7: Filter and dry to obtain the final product, which is the amorolfine drug EP impurity B.

[0016] Preferably, the organic solvent in step 1 is acetonitrile.

[0017] Preferably, in step three, stirring reaction is carried out, and the reaction time is 20 to 24 hours.

[0018] Preferably, in step three, the stirring reaction is carried out in a low-temperature constant-temperature reaction bath.

[0019] Preferably, the water bath temperature in step three is 0°C.

[0020] Preferably, in step 3, after the reaction is completed, the mixture is moved to a constant temperature heated magnetic stirrer, stirred continuously, and heated to 80° C. for reflux.

[0021] Preferably, in step six, the reflux dissolution temperature is 70°C to 80°C.

[0022] Preferably, the extraction times in step 4 is 3 to 4 times.

[0023] (III) Beneficial effects

[0024] The invention provides a method for synthesizing an amorolfine drug EP impurity B. Compared with the prior art, the method has the following beneficial effects: the method for synthesizing an amorolfine drug EP impurity B, the technical scheme has the advantages of short synthesis route, simple operation, short preparation cycle, low cost and environmental protection, the prepared amorolfine drug impurity has high purity, no obvious impurity point, meets the requirements of impurity reference substances, can be used as an amorolfine drug impurity standard substance for qualitative and quantitative research and detection of amorolfine drug impurities, and has certain significance for the quality control of amorolfine drug raw materials and related preparations; the purification is simple in the synthesis process, the yield is high, and no highly toxic and explosive dangerous goods are used, and no expensive photosensitizer is required, which meets the modern environmental protection and sustainable development concepts, and can provide convenience for the impurity analysis and research of amorolfine drug raw materials and preparations thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] Figure 1 A nuclear magnetic hydrogen spectrum provided for a method for synthesizing impurity B of amorolfine drug EP of the present invention;

[0026] Figure 2 A chromatogram provided for a method for synthesizing impurity B of amorolfine drug EP of the present invention;

[0027] Figure 3 An infrared spectrum diagram provided for a synthesis method of amorolfine drug EP impurity B of the present invention. DETAILED DESCRIPTION

[0028] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0029] The embodiment of the present invention provides the following technical solutions:

[0030] Example 1

[0031] A method for synthesizing impurity B of amorolfine drug EP, specifically comprising the following synthesis steps:

[0032] Step 1: Dissolve 5.0 g (14.12 mmol) of cis-4[3-[4-(1,1-dimethylpropyl)phenyl]-2-methylpropane]-2,6-dimethyl-morpholine in 50 mL of acetonitrile solution;

[0033] Step 2: After the solution is completely dissolved, add 3.0 g of 2,6-dimethylpyridine, 110 mg of methyl blue, 100 mg of cobalt chloride, and 10 ml of hydrogen peroxide in sequence;

[0034] Step 3: Stir the reaction in a 0°C reaction bath under 310 nm wavelength light for 20 h, then move to a constant temperature heated magnetic stirrer, continue stirring, and heat to 80°C for reflux;

[0035] Step 4: After the reaction is completed, cool to room temperature and extract with 50 mL of ethyl acetate three times, and separate the liquids;

[0036] Step 5, the organic phase is dried with anhydrous sodium sulfate, concentrated, filtered, and ethyl acetate is removed under reduced pressure to obtain a crude product;

[0037] Step 6: Then add the crude product into 50 mL of ethyl acetate, heat to 70°C to reflux and dissolve, and stir at room temperature overnight;

[0038] Step 7: Filter and dry to obtain the final product, which is the amorolfine drug EP impurity B.

[0039] The technical solution has the advantages of simple operation, short preparation cycle, low cost and environmental protection. The prepared amorolfine drug impurities have high purity and no obvious impurity points, which meets the requirements of impurity reference substances. It can be used as an amorolfine drug impurity standard substance for qualitative and quantitative research and detection of amorolfine drug impurities, which has certain significance for the quality control of amorolfine drug raw materials and related preparations. The purification is simple and the yield is high in the synthesis process, and no highly toxic and explosive dangerous goods are used, which conforms to the modern environmental protection and sustainable development concepts, and can provide convenience for the impurity analysis and research of amorolfine drug raw materials and preparations.

[0040] Meanwhile, the contents not described in detail in this specification belong to the prior art known to those skilled in the art.

[0041] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device.

[0042] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing impurity B of amorolfine drug EP, characterized in that: The specific synthesis steps include: Step 1, dissolving styrene in an organic solvent; Step 2: After the solution is completely dissolved, 2,6-dimethylpyridine, cobalt chloride, methyl blue and hydrogen peroxide are added in sequence; Step 3, stirring the reaction under constant temperature conditions with 310 nm wavelength light; Step 4: After the reaction is completed, cool to room temperature, extract with ethyl acetate, and separate the liquids; Step 5, the organic phase is dried with anhydrous sodium sulfate, concentrated, filtered, and ethyl acetate is removed under reduced pressure to obtain a crude product; Step 6: then add the crude product into ethyl acetate, heat to reflux to dissolve, and stir at room temperature overnight; Step 7: Filter and dry to obtain the final product, which is the amorolfine drug EP impurity B.

2. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: The organic solvent in the step 1 is acetonitrile.

3. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: In the step 3, the reaction is stirred and the reaction time is 20 to 24 hours.

4. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: In the step 3, the stirring reaction is carried out in a low-temperature constant-temperature reaction bath.

5. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: The water bath temperature in step 3 is 0°C.

6. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: In the step 3, after the reaction is completed, the mixture is transferred to a constant temperature heating magnetic stirrer, stirred continuously, and heated to 80° C. for reflux.

7. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: In the step six, the reflux dissolution temperature is 70°C to 80°C.

8. The method for synthesizing the impurity B of amorolfine drug EP according to claim 1, characterized in that: The number of extractions in step 4 is 3 to 4 times.

Images