Synthesis method of viloxazine hydrochloride product impurity

Abstract

The invention belongs to the field of compound synthesis, and provides a synthesis method of a viloxazine hydrochloride product impurity. 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; 2-ethoxyphenol and organic alkali are added into the obtained compound 1 for a reaction, and purification is performed to obtain the viloxazine hydrochloride product impurity. Compared with the prior art, the synthesis method of the viloxazine hydrochloride product impurity provided by the invention has the advantages that the synthesis method is novel, the raw materials are easy to obtain, the cost is low, the reaction conditions are mild, and the operation is convenient; and an impurity reference substance can be provided for quality detection of a viloxazine hydrochloride product.

Description

Technical Field

[0001] The invention belongs to the field of compound synthesis, and in particular relates to a method for synthesizing impurities in a viloxazine hydrochloride product. 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, the study of impurities is carried out in a standardized manner and controlled within a safe and reasonable limit range, which will be directly related to the quality and safety of marketed drugs. The study of impurities and the verification 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 have not yet been 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 by the product, and to synthesize them in a targeted manner. Page 12 of patent IN202121046927A discloses the impurities of the viloxazine hydrochloride product described in the present invention, but does not disclose the synthesis method of the impurities of the viloxazine hydrochloride product.

[0006] Therefore, how to provide a method for synthesizing impurities in viloxazine hydrochloride products is of great significance for promoting the establishment of methods for related substances in viloxazine hydrochloride drugs and the progress of quality control of impurities. Summary of the invention

[0007] The present invention aims at the problem that it is difficult to provide an impurity reference substance for the impurity detection method of the viloxazine hydrochloride product in the prior art, and provides a method for synthesizing the impurities of the viloxazine hydrochloride product. In the present invention, the structural formula of the impurities of the viloxazine hydrochloride product is as follows:

[0008]

[0009] In the present invention, the impurity in the above-mentioned viloxazine hydrochloride product has a chemical name of 1,3-bis(2-ethoxyphenoxy)propan-2-ol, hereinafter referred to as impurity A.

[0010] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0011] A method for synthesizing impurities of a viloxazine hydrochloride product comprises the following steps:

[0012] (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;

[0013] (2) adding 2-ethoxyphenol and an organic base to the compound 1 obtained in step (1) to react, and purifying to obtain the impurities of the viloxazine hydrochloride product.

[0014] Preferably, the reaction process of step (1) is as follows:

[0015]

[0016] Preferably, the reaction process of step (2) is as follows:

[0017]

[0018] 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.

[0019] More preferably, the organic base is triethylamine.

[0020] Preferably, the preliminary reaction conditions in step (1) are 75-85° C. for 2-5 h.

[0021] More preferably, the temperature is lowered to 0-10°C after the preliminary reaction.

[0022] Preferably, the alkaline solution in step (1) is added dropwise.

[0023] 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.

[0024] Further preferably, the alkaline solution is an aqueous sodium hydroxide solution.

[0025] Preferably, the further reaction time in step (1) is 0.5-3 h.

[0026] Preferably, the purification in step (1) comprises the following steps:

[0027] ① Add ethyl acetate, raise the temperature to 20-30°C, and let stand to obtain ethyl acetate phase and water phase;

[0028] ② extracting the aqueous phase obtained in step ① with ethyl acetate to obtain an extracted ethyl acetate phase;

[0029] 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;

[0030] ④ Wash the combined ethyl acetate phase obtained in step ③ with water, and collect the ethyl acetate phase after washing;

[0031] 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.

[0032] Preferably, the organic base in step (2) 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.

[0033] More preferably, the organic base is triethylamine.

[0034] Preferably, the reaction conditions in step (2) are heating to 50-80° C. and reaction time is 1-5 h.

[0035] Preferably, the purification in step (2) comprises the following steps:

[0036] ① Add 8-12% by mass of sodium hydroxide aqueous solution and methyl tert-butyl ether, stir for 5-10 minutes, stand for stratification, and obtain an organic layer;

[0037] ② Add 8-12% by mass of sodium hydroxide aqueous solution to the organic layer obtained in step ①, stir for 5-10 minutes, and stand for stratification to obtain a treated organic layer;

[0038] ③ Wash the treated organic layer obtained in step ② with water, stir for 5-10 minutes, and stand for stratification to obtain a washed organic layer;

[0039] ④ The washed organic layer obtained in step ③ was concentrated and dried at 50-60° C. to complete the purification.

[0040] The present invention also provides the use of impurity A synthesized by the above-mentioned synthesis method in the quality control of viloxazine hydrochloride products.

[0041] The present invention also provides the reason for the generation of the impurity A of viloxazine hydrochloride of the present invention:

[0042] 1. The original research route of the viloxazine hydrochloride product is as follows:

[0043]

[0044] 2. Causes of Impurity A

[0045] The generation of impurity A mainly depends on the following two pathways, namely pathway a and pathway b:

[0046] ①Path a

[0047] 2-Ethoxyphenol removes protons under alkaline conditions, and the oxygen anion attacks the primary carbon connected to chlorine in epichlorohydrin. The chloride ion leaves to generate Epoxide1. The generated Epoxide1 will continue to react with the excess deprotonated 2-ethoxyphenol to generate impurity A.

[0048] ②Path b

[0049] 2-Ethoxyphenol removes protons under alkaline conditions, and oxygen anions attack the secondary carbon connected to oxygen in epichlorohydrin, breaking the carbon-oxygen bond in epichlorohydrin to generate new compounds, which then react with partially deprotonated 2-ethoxyphenol to generate impurity A.

[0050] The processes of path a and path b are as follows:

[0051]

[0052] Compared with the prior art, the present invention has the following beneficial effects:

[0053] The invention provides a method for synthesizing impurities of a viloxazine hydrochloride product. The synthesis method provided by the invention is novel, and the raw materials are readily available and low in cost, the reaction conditions are mild, and the operation is convenient; and an impurity reference substance can be provided for quality detection of the viloxazine hydrochloride product. BRIEF DESCRIPTION OF THE DRAWINGS

[0054] Figure 1 The HPLC spectrum of impurity A synthesized in Example 2.

[0055] Figure 2 This is the mass spectrum of impurity A synthesized in Example 2.

[0056] Figure 3 This is the hydrogen nuclear magnetic resonance spectrum of impurity A synthesized in Example 2.

[0057] Figure 4 This is the carbon NMR spectrum of impurity A synthesized in Example 2. DETAILED DESCRIPTION

[0058] 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.

[0059] 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.

[0060] The following sources of raw materials are provided for illustrative purposes:

[0061] 2-Ethoxyphenol and triethylamine are commercially available chemical reagents, and the supplier is Shanghai MacLean Biochemical Technology Co., Ltd.;

[0062] Sodium hydroxide, ethyl acetate, and diisopropylethylamine are conventional commercially available chemical reagents, and the supplier is Sinopharm Chemical Reagent Co., Ltd.;

[0063] Methyl tert-butyl ether is a conventional commercially available chemical reagent, and its supplier is Chengdu Kelong Chemical Co., Ltd.;

[0064] Ethanol is a conventional commercially available chemical reagent, and its supplier is Tianjin Komiou Chemical Reagent Co., Ltd.;

[0065] Epichlorohydrin is a commercially available chemical reagent, and its supplier is Dongying Hebang Chemical Co., Ltd.;

[0066] The above conventional commercially available chemical reagents do not need to be further processed and can be used directly.

[0067] Example 1 Synthesis of Compound 1 (2-(2-ethoxyphenoxymethyl)ethylene oxide)

[0068] Preliminary synthesis of compound 1:

[0069] 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 hours; lower the reaction temperature to 5 ° C, add NaOH (aq) (NaOH: 229.56 g, 5.74 mol, 4.0 eq; water: 1 L), and after the addition is completed, stir for 1 hour.

[0070] Purification of compound 1:

[0071] After the reaction, add 1L of ethyl acetate, then heat to 25°C, and stir for 10 minutes at this temperature. Stop stirring, let stand to separate, collect the organic phase, and retain the aqueous phase; add 1L of ethyl acetate to the aqueous phase, stir for 10 minutes, stop stirring, let stand to separate, collect the organic phase, and treat the aqueous phase as waste liquid; combine the organic phases, add 1L of water, stir for 10 minutes, let stand to separate, and collect the organic phase; concentrate the organic phase under reduced pressure at 55°C to dryness; add 1L of ethanol to the concentrate, cool to 0-10°C, stir for 2 hours, filter under reduced pressure, collect the filter cake, transfer the filter cake to a single-necked flask, and concentrate under reduced pressure at 55°C to dryness to obtain compound 1 (2-(2-ethoxyphenoxy)methyl)oxirane (184.66 g, 65% yield, 99.1% HPLC).

[0072] 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=11.4 7Hz,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).13C NMR (DMSO-d6, 100 MHz) δ 148.34, 148.01, 121.48, 120.76, 114.11, 113.61, 69.86, 63.74, 49.87, 43.78, 14.78. Example 2 Synthesis of Impurity A

[0073] Preliminary synthesis of impurity A

[0074] Compound 1 (10 g, 51.5 mmol, 1.0 eq), 2-ethoxyphenol (10.7 g, 77.4 mmol, 1.5 eq) and triethylamine (0.52 g, 5.1 mmol, 0.1 eq) were added into the reaction bottle, stirred, heated to 65° C., and stirred for 3 h.

[0075] Purification of impurity A

[0076] After the reaction was completed, the temperature was lowered to 25°C, 50 mL of 10% mass fraction sodium hydroxide (aq) and 50 mL of methyl tert-butyl ether were added, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 30 mL of 10% mass fraction sodium hydroxide (aq) was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 50 mL of water was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water, and the organic phase was concentrated at 55°C to obtain a white solid as impurity A (15.9 g, 93% yield)

[0077] The characterization data of impurity A synthesized in this example are as follows Figure 1-4 shown.

[0078] 1H NMR(DMSO-d6,400MHz)δ7.00-7.01(m,2H),6.92-6.95(m,2H),6.84-6.90(m,4H),5.31(d,J=5.18 Hz,1H),4.12-4.19(m,1H),4.00-4.10(m,4H),3.98(q,J=6.98Hz,4H),1.28(t,J=6.97Hz,6H).13C NMR(DMSO-d6,100MHz)δ148.50,121,30,120.92,114.27,114.00,70.37,67.52,63.89,14.79.

[0079] Example 3 Synthesis of Impurity A

[0080] Preliminary synthesis of impurity A

[0081] Compound 1 (1.3 g, 6.7 mmol, 1.0 eq), 2-ethoxyphenol (1.8 g, 13.0 mmol, 2.0 eq) and triethylamine (68 mg, 0.7 mmol, 0.1 eq) were added into the reaction bottle, stirred, heated to 50° C., and stirred for 5 h.

[0082] Purification of impurity A

[0083] After the reaction, the temperature was lowered to 20°C, 10 mL of 8% mass fraction sodium hydroxide (aq) and 10 mL of methyl tert-butyl ether were added, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 6 mL of 8% mass fraction sodium hydroxide (aq) was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 10 mL of water was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water, and the organic phase was concentrated at 50°C to obtain a white solid as compound impurity A (1.9 g, 86% yield).

[0084] Example 4 Synthesis of Impurity A

[0085] Preliminary synthesis of impurity A

[0086] Compound 1 (2.0 g, 10.3 mmol, 1.0 eq), 2-ethoxyphenol (2.1 g, 15.2 mmol, 1.5 eq) and diisopropylethylamine (0.14 g, 0.1 mmol, 0.1 eq) were added into the reaction bottle, stirred, heated to 80°C, and stirred for 1 h.

[0087] Purification of impurity A

[0088] After the reaction was completed, the temperature was lowered to 30°C, 10 mL of 12% mass fraction sodium hydroxide (aq) and 10 mL of methyl tert-butyl ether were added, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 6 mL of 12% mass fraction sodium hydroxide (aq) was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water; 10 mL of water was added to the organic layer, stirred for 10 min, allowed to stand for stratification, the organic layer was collected, and the aqueous layer was treated as waste water. The organic phase was concentrated at 60°C to obtain a white solid as compound impurity A (3.1 g, 91% yield)

[0089] Comparative Example

[0090] The literature (Journal of Medicinal Chemistry, 1976, 19, 223-224) describes a synthetic route for 1,3-bis(3-ethoxyphenyl)propan-2-ol, using 3-ethoxyphenol and epichlorohydrin as starting materials, 1,4-dioxane as solvent, and intermolecular substitution reaction under the action of sodium hydroxide, and the crude product of the target compound is obtained through water washing, extraction, drying, concentration and other operations. The specific reaction route is as follows:

[0091]

[0092] This route can obtain the target compound through a one-step reaction, but the operation is complicated, the yield is low (21% yield), many types of solvents are used, and the product obtained is a crude product, which cannot meet the needs of being used as an impurity reference or standard.

[0093] 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 method for synthesizing impurities of a viloxazine hydrochloride product, 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) adding 2-ethoxyphenol and an organic base to the compound 1 obtained in step (1) to react, and purifying to obtain the impurities of the viloxazine hydrochloride product; The structural formula of the impurity of the viloxazine hydrochloride product is shown as impurity A in the following reaction formula; The reaction route is as follows:

2. The synthesis method according to claim 1, 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.

3. The synthesis method according to claim 1, characterized in that: The initial reaction conditions in step (1) are 75-85° C. for 2-5 hours.

4. The synthesis method according to claim 1, characterized in that: The alkaline solution in step (1) is added dropwise.

5. The synthesis method according to claim 1, characterized in that: 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.

6. The synthesis method according to claim 1, characterized in that: After the initial reaction in step (1), the temperature is lowered to 0-10° C., and the further reaction time is 0.5-3 h.

7. The synthesis method according to claim 1, characterized in that: The purification in step (1) comprises the following steps: ① Add ethyl acetate, raise the temperature to 20-30°C, and let stand to obtain ethyl acetate phase and water phase; ② extracting the aqueous phase obtained in step ① with ethyl acetate to obtain an extracted ethyl acetate phase; 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; ④ Wash the combined ethyl acetate phase obtained in step ③ with water, and collect the ethyl acetate phase after washing; 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.

8. The synthesis method according to claim 1, characterized in that: The organic base in step (2) 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.

9. The synthesis method according to claim 1, characterized in that: The reaction conditions of step (2) are heating to 50-80° C. and reaction time is 1-5 h.

10. The synthesis method according to claim 1, characterized in that: The purification in step (2) comprises the following steps: ① Add 8-12% by mass of sodium hydroxide aqueous solution and methyl tert-butyl ether, stir for 5-10 minutes, stand for stratification, and obtain an organic layer; ② Add 8-12% by mass of sodium hydroxide aqueous solution to the organic layer obtained in step ①, stir for 5-10 minutes, and stand for stratification to obtain a treated organic layer; ③ Wash the treated organic layer obtained in step ② with water, stir for 5-10 minutes, and stand for stratification to obtain a washed organic layer; ④ The washed organic layer obtained in step ③ was concentrated and dried at 50-60° C. to complete the purification.

11. Use of impurities in a viloxazine hydrochloride product synthesized by the synthesis method according to any one of claims 1 to 10 in quality control of a viloxazine hydrochloride product.

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