Vesloxazine hydrochloride product impurity as well as synthesis method and application thereof

Abstract

The invention provides a viloxazine hydrochloride product impurity as well as a synthesis method and application thereof, and belongs to the technical field of medicine synthesis. The viloxazine hydrochloride product impurity is shown as a formula (I), the synthesis method comprises the following steps: adding epichlorohydrin and organic alkali into 2-ethoxyphenol for preliminary reaction, adding an alkaline solution for further reaction, and purifying to obtain a compound 1; and dissolving the compound 1, adding piperazine for reaction, stirring to obtain a reaction mixture, and purifying to obtain the viloxazine hydrochloride product impurity. The invention also provides an application of the viloxazine hydrochloride product impurity. Compared with the prior art, the synthesis method provided by the invention is simple and feasible, the raw materials are easily available, and the operation is convenient; the prepared viloxazine hydrochloride product impurity can be applied to quality control of a viloxazine hydrochloride product. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of drug synthesis, and in particular relates to an impurity of a viloxazine hydrochloride product and a synthesis method and application thereof. Background Art

[0002] The chemical name of viloxazine hydrochloride is: (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride, and the chemical structure is as follows:

[0003]

[0004] Viloxazine hydrochloride is a selective norepinephrine reuptake inhibitor that is active on serotonin receptors and norepinephrine transporters. It is a new type of non-stimulant drug independently developed by Supernus Pharmaceuticals with the trade name QelbreeTM, which is used to treat attention deficit hyperactivity disorder (ADHD) in children aged 6 to 17 years old.

[0005] According to ICH Q3 and the Technical Guidelines for the Study of Impurities in Chemical Drugs, conducting research on impurities in a standardized manner and controlling them within a safe and reasonable limit will be directly related to the quality and safety of marketed drugs. The study of impurities and the validation of analytical methods require the use of impurity reference substances to investigate the separation of analytical methods and to conduct quantitative studies on impurities. The quality standards of viloxazine hydrochloride are not yet included in the pharmacopoeias and national standards of various countries. It is necessary to analyze the possible impurities based on the process impurities that may be produced in the synthesis process of viloxazine hydrochloride and the degradation impurities that may be produced in the product, and to conduct targeted synthesis on them. There is no information related to this impurity disclosed in existing patents or literature, and there is no commercially available reference substance for this impurity.

[0006] The invention of CN112592342B relates to the technical field of organic synthesis, and provides a method for preparing a butorphanol decyclobutyl impurity compound. The preparation of the impurity has always been a difficulty in the relevant technical field, either the reaction route is too long or the yield is too low. The invention can realize the simple and efficient synthesis of the impurity. Compound 1 is catalyzed by a strong Lewis acid and reacted with a reducing agent to obtain a butorphanol decyclobutyl impurity intermediate (compound 2), and then a cyclization reaction and a demethoxylation reaction are performed without column chromatography purification to obtain a high-purity butorphanol decyclobutyl impurity (compound 4); the invention can fully illustrate that when controlling the impurity content of a drug, the impurity content needs to be limited to a certain range, and a suitable impurity standard must be selected during the drug quality analysis process. When the impurity is not sold on the market and there is no public technology, it is necessary to study a synthesis method to synthesize such compounds.

[0007] Therefore, how to provide a method for synthesizing impurities in viloxazine hydrochloride products is of great significance for promoting the establishment of analytical methods for related substances in viloxazine hydrochloride drugs and the progress of impurity quality control. Summary of the invention

[0008] The present invention aims at the problem that the impurities of viloxazine hydrochloride products and preparation methods thereof are missing in the prior art. The present invention provides a viloxazine hydrochloride product impurity and a synthesis method thereof. The synthesis method has mild reaction conditions, simple operation, high purity of the obtained product, and is suitable for amplification. It can provide a research standard for viloxazine hydrochloride, thereby promoting the impurity research of related drugs. It has positive significance for improving the quality standard of viloxazine hydrochloride drugs and ensuring drug safety.

[0009] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0010] The present invention provides an impurity in a viloxazine hydrochloride product, whose chemical name is 3,3'-(piperazine-1,4-diyl)bis(1-(2-ethoxyphenoxy)propan-2-ol), hereinafter referred to as impurity C, and the chemical structural formula of impurity C is as follows:

[0011]

[0012] The present invention also provides a method for synthesizing a viloxazine hydrochloride product impurity (impurity C), comprising the following steps:

[0013] (1) adding epichlorohydrin and an organic base to 2-ethoxyphenol for preliminary reaction, adding an alkaline solution for further reaction, and purifying to obtain compound 1;

[0014] (2) dissolving the compound 1 obtained in step (1), adding piperazine to react, and stirring to obtain a reaction mixture;

[0015] (3) purifying the reaction mixture obtained in step (2) to obtain the viloxazine hydrochloride product impurities.

[0016] Preferably, the reaction process of step (1) is as follows:

[0017]

[0018] Preferably, the main reaction performed in step (2) is as follows:

[0019]

[0020] Preferably, the organic base in step (1) is selected from at least one of diethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 1,8-diazobispiro[5.4.0]undec-7-ene, 2,6-lutidine, imidazole and N-methylimidazole.

[0021] More preferably, the organic base is triethylamine.

[0022] Preferably, the conditions of the preliminary reaction in step (1) are: reaction temperature 75-85° C., reaction time 2-5 h.

[0023] More preferably, the temperature is lowered to 0-10°C after the preliminary reaction.

[0024] Preferably, the alkaline solution in step (1) is added dropwise.

[0025] Preferably, the alkaline solution in step (1) is selected from at least one of a lithium hydroxide aqueous solution, a sodium hydroxide aqueous solution, a potassium hydroxide aqueous solution, a rubidium hydroxide aqueous solution, a cesium hydroxide aqueous solution, an ammonium carbonate aqueous solution and a potassium carbonate aqueous solution.

[0026] Further preferably, the alkaline solution is an aqueous sodium hydroxide solution.

[0027] Preferably, the further reaction time in step (1) is 0.5-3 h.

[0028] Preferably, the purification in step (1) comprises the following steps:

[0029] ① Add ethyl acetate, raise the temperature to 20-30°C, and let stand to obtain ethyl acetate phase and water phase;

[0030] ② extracting the aqueous phase obtained in step ① with ethyl acetate to obtain an extracted ethyl acetate phase;

[0031] ③ combining the ethyl acetate phase obtained in step ① and the extracted ethyl acetate phase obtained in step ② to obtain a combined ethyl acetate phase;

[0032] ④ Wash the combined ethyl acetate phase obtained in step ③ with water, and collect the ethyl acetate phase after washing;

[0033] ⑤ The washed ethyl acetate phase collected in step ④ is concentrated and dried under reduced pressure at 50-60° C., ethanol is added, the temperature is lowered to 0-10° C. with stirring, filtered under reduced pressure, the filter cake is collected, and the filter cake is dried under reduced pressure at 50-60° C. to complete the purification.

[0034] Preferably, the reaction conditions in step (2) are: reaction time 1-6h, reaction temperature 50-60°C.

[0035] Preferably, the solvent used for dissolving in step (2) is an alcohol solvent.

[0036] Further preferably, the alcohol solvent is selected from at least one of methanol, ethanol and isopropanol.

[0037] Most preferably, the alcohol solvent is ethanol.

[0038] Preferably, the purification in step (3) is as follows: lowering the temperature of the reaction mixture to 20-30° C., stirring, filtering, collecting the filter cake, and drying.

[0039] More preferably, the stirring time is 1.5-3 h, and the filtration is reduced pressure filtration.

[0040] The present invention also provides application of the impurities of the viloxazine hydrochloride product in quality control of the viloxazine hydrochloride product.

[0041] Compared with the prior art, the present invention has the following beneficial effects:

[0042] The invention provides a new impurity (impurity C) of a viloxazine hydrochloride product and provides a method for synthesizing the impurity C. The synthesis method provided by the invention is simple and easy to implement, has readily available raw materials, mild conditions, low cost and convenient operation; the prepared impurity C can be applied to the quality control of the viloxazine hydrochloride product. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 This is the HPLC spectrum of impurity C in Example 2.

[0044] Figure 2 This is the mass spectrum of impurity C in Example 2.

[0045] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of impurity C in Example 2.

[0046] Figure 4 This is the carbon NMR spectrum of impurity C in Example 2. DETAILED DESCRIPTION

[0047] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0048] It is worth noting that the raw materials used in the present invention are all common commercially available products, and their sources are not specifically limited.

[0049] The following sources of raw materials are provided for illustrative purposes:

[0050] 2-Ethoxyphenol and triethylamine are commercially available chemical reagents, and the supplier is Shanghai MacLean Biochemical Technology Co., Ltd.;

[0051] Sodium hydroxide, ethyl acetate, and piperazine (anhydrous piperazine) are conventional commercially available chemical reagents, and the supplier is Sinopharm Reagent;

[0052] Methanol, ethanol, and isopropanol are conventional commercially available chemical reagents, and the supplier is Tianjin Komiou Chemical Reagent Co., Ltd.;

[0053] Epichlorohydrin is a commercially available chemical reagent supplied by Dongying Hebang Chemical Co., Ltd. It can be used directly without further treatment.

[0054] First, the present invention detects the content of the impurity C in the product and its content in the purified product. The detection finds that the crude product needs to be refined multiple times to obtain a qualified finished product, indicating that the impurities provided by the present invention are difficult to remove and it is necessary to use standard products to control the quality of the viloxazine hydrochloride product.

[0055] Test Example: The content of an impurity (impurity C) in a viloxazine hydrochloride product and its content after product purification

[0056] The formulation of the impurity content standard of this application is based on the "Technical Guiding Principles for the Study of Impurities in Chemical Drugs". In this principle, it is pointed out in the explanation of terms in VIII (based on IX, Appendix) that when the maximum daily dose is ≤2g, the impurity limit allowed by the quality standard of the raw material drug is higher than the reported concentration (0.05%), and specific test data should be reported. Impurities above the identification limit (0.10%) should be qualitatively analyzed to determine their chemical structure. Therefore, when the impurity limit of impurity C in the product is greater than 0.10%, it is necessary to conduct qualitative and quantitative analysis of impurity C. Specifically, a synthetic method of impurity C is first required to prepare impurity C for qualitative and quantitative analysis.

[0057] This application first collects crude viloxazine hydrochloride products from different production batches and performs HPLC testing. The test results are as follows:

[0058]

[0059]

[0060] It can be seen from the above results that the content of impurity C in the two batches of crude viloxazine hydrochloride products is greater than 0.10%. Therefore, it is very necessary to provide a synthesis method of impurity C for the qualitative and quantitative analysis and quality control of impurity C.

[0061] Example 1 Synthesis of Compound 1 (2-((2-ethoxyphenoxy)methyl)ethylene oxide)

[0062] Take a three-necked flask, add 2-ethoxyphenol (201.00 g, 1.45 mol, 1.0 eq), epichlorohydrin (535.43 g, 5.79 mol, 4.0 eq) and triethylamine (14.68 g, 0.15 mol, 0.1 eq), stir, heat to 80°C, and stir for 3 h; lower the reaction temperature to 5°C, add NaOH (aq) (NaOH: 229.56 g, 5.74 mol, 4.0 eq; water: 1 L) dropwise to the reaction solution, and after the addition is completed, stir for 1 h. After the reaction, 1L of ethyl acetate was added, and then the temperature was raised to 25°C, and the mixture was stirred for 10 minutes at this temperature. The stirring was stopped, the mixture was allowed to stand for stratification, the organic phase was collected, and the aqueous phase was retained; 1L of ethyl acetate was added to the aqueous phase, the mixture was stirred for 10 minutes, the stirring was stopped, the mixture was allowed to stand for stratification, the organic phase was collected, and the aqueous phase was treated as waste liquid; the organic phases were combined, 1L of water was added, the mixture was stirred for 10 minutes, the mixture was allowed to stand for stratification, and the organic phase was collected; the organic phase was concentrated to dryness under reduced pressure at 55°C; 1L of ethanol was added to the concentrated solution, the temperature was lowered to 0-10°C, the mixture was stirred for 2 hours, the filter was filtered under reduced pressure, the filter cake was collected, the filter cake was transferred to a single-necked flask, and the mixture was concentrated to dryness under reduced pressure at 55°C to obtain a light yellow liquid compound 1 (184.66 g, 65% yield, 99.1% HPLC).

[0063] 1H NMR(DMSO-d6,400MHz)δ6.95-6.98(m,2H),6.84-6.92(m,2H),4.28(dd,J=11.50Hz,J′=2.69Hz,1H ), 4.01 (q, J = 6.96Hz, 2H), 3.81 (dd, J = 11.47Hz, J′ = 6.45Hz, 1H), 3.30-3.35 (m, 1H), 2.83 (dd, J = 5. 15Hz,J′=4.21Hz,1H),2.69(dd,J=5.13Hz,J′=2.66Hz,1H),1.33(t,J=6.97Hz,3H).13CNMR(DMSO- d6,100MHz) δ148.34,148.01,121.48,120.76,114.11,113.61,69.86,63.74,49.87,43.78,14.78

[0064] Example 2 A method for synthesizing the impurity C (3,3'-(piperazine-1,4-diyl)bis(1-(2-ethoxyphenoxy)propan-2-ol)) of the viloxazine hydrochloride product

[0065] Take a 250mL three-necked flask, add piperazine (3.0g, 34.8mmol, 1.0eq), compound 1 (16.9g, 87.0mmol, 2.5eq), and methanol (85mL), stir evenly; heat to 55°C, react for about 4h. Cool to 25°C, stir for 2h, filter, collect the filter cake, and dry at 50°C to obtain a white solid as compound impurity C (13.47g, 81% yield).

[0066] The characterization results of impurity C obtained in Example 2 are as follows Figure 1-4 shown.

[0067] 1 H NMR(DMSO-d6,400MHz)δ6.96(s,4H),6.87(s,4H),4.76(s,2H),3.85-4.01(m,10H),2.35-2.51(m,12H),1.32(s,6H). 13 C NMR(DMSO-d6,100MHz)δ148.68,148.49,121.13,120.96,114.37,114.09,72.13,66.60,63.91,61.25,53.64,14.86.

[0068] Example 3 A method for synthesizing the impurity C (3,3'-(piperazine-1,4-diyl)bis(1-(2-ethoxyphenoxy)propan-2-ol)) of the viloxazine hydrochloride product

[0069] Take a 250mL three-necked flask, add piperazine (1.9g, 22.1mmol, 1.0eq), compound 1 (8.6g, 44.3mmol, 2.0eq), and methanol (85mL), stir evenly; heat to 60℃, react for about 6h. Cool to 20℃, stir for 1.5h, filter, collect the filter cake, and dry at 50℃ to obtain a white solid as compound impurity C (7.5g, 72% yield).

[0070] Example 4 A method for synthesizing the impurity C (3,3'-(piperazine-1,4-diyl)bis(1-(2-ethoxyphenoxy)propan-2-ol)) of the viloxazine hydrochloride product

[0071] Take a 250mL three-necked flask, add piperazine (5.0g, 58.0mmol, 1.0eq), compound 1 (28.2g, 145.2mmol, 2.5eq), and isopropanol (140mL), stir evenly; heat to 50°C, react for about 1h. Cool to 30°C, stir for 3h, filter under reduced pressure, collect the filter cake, and dry at 50°C to obtain a white solid as compound impurity C (21.6g, 78% yield).

[0072] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, rather than to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions of the technical solution of the present invention by ordinary technicians in this field do not deviate from the essence and scope of the technical solution of the present invention.

Claims

1. A viloxazine hydrochloride product impurity, characterized in that: The chemical name is 3,3'-(piperazine-1,4-diyl)bis(1-(2-ethoxyphenoxy)propan-2-ol), and the structural formula is shown in formula (Ⅰ):

2. The method for synthesizing impurities of the viloxazine hydrochloride product according to claim 1, characterized in that: The following steps are involved: (1) adding epichlorohydrin and an organic base to 2-ethoxyphenol for preliminary reaction, adding an alkaline solution for further reaction, and purifying to obtain compound 1; (2) dissolving the compound 1 obtained in step (1), adding piperazine to react, and stirring to obtain a reaction mixture; (3) purifying the reaction mixture obtained in step (2) to obtain the viloxazine hydrochloride product impurity; The reaction route is as follows:

3. The synthesis method according to claim 2, characterized in that: The organic base in step (1) is selected from at least one of diethylamine, triethylamine, N-methylmorpholine, N,N-diisopropylethylamine, pyridine, 1,8-diazobispiro[5.4.0]undec-7-ene, 2,6-lutidine, imidazole and N-methylimidazole; the alkaline solution in step (2) is selected from at least one of lithium hydroxide aqueous solution, sodium hydroxide aqueous solution, potassium hydroxide aqueous solution, rubidium hydroxide aqueous solution, cesium hydroxide aqueous solution, ammonium carbonate aqueous solution and potassium carbonate aqueous solution.

4. The synthesis method according to claim 2, characterized in that: The conditions of the preliminary reaction in step (1) are: reaction temperature 75-85°C, reaction time 2-5h; after the preliminary reaction, the temperature is lowered to 0-10°C.

5. The synthesis method according to claim 2, characterized in that: The solvent used for dissolving in step (2) is an alcohol solvent.

6. The synthesis method according to claim 5, characterized in that: The alcohol solvent is selected from at least one of methanol, ethanol and isopropanol.

7. The synthesis method according to claim 2, characterized in that: The reaction conditions in step (2) are: reaction temperature is 50-60° C., and reaction time is 1-6 h.

8. The synthesis method according to claim 2, characterized in that: The purification in step (3) is as follows: lowering the temperature of the reaction mixture to 20-30° C., stirring, filtering, collecting the filter cake, and drying.

9. The synthesis method according to claim 8, characterized in that: The stirring time is 1.5-3h, and the filtration is reduced pressure filtration.

10. Application of impurities of viloxazine hydrochloride product in quality control of viloxazine hydrochloride product, characterized in that: The viloxazine hydrochloride product impurity is the viloxazine hydrochloride product impurity described in claim 1 or is synthesized by any one of the synthesis methods described in claims 2-9.

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