A medicinal soothing preparation and a method for its production

Abstract

The application belongs to the field of pharmaceutical preparations and discloses a soothing pharmaceutical preparation and a preparation method thereof. The preparation method comprises the following steps: firstly, preparing synthetic naphazoline hydrochloride by using compound 1 containing a cyano group, wherein a composite solvent composed of toluene and ethyl acetate is used for condensation reaction in the synthesis process, and dilute hydrochloric acid is used for salt formation; secondly, preparing synthetic pheniramine maleate by using compound 2 containing a halogen group and compound 3 containing a cyano group, wherein a weak base catalyst is used for condensation reaction in the synthesis process; finally, adding functional additives, naphazoline hydrochloride and pheniramine maleate into water, stirring and dissolving, and filling to obtain the soothing pharmaceutical preparation, wherein the pH of the soothing pharmaceutical preparation is 5.7-6.3. The soothing pharmaceutical preparation prepared by the above method can effectively avoid the adverse influence of impurities in naphazoline hydrochloride and pheniramine maleate on the soothing effect.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical preparations, specifically to a medicinal soothing preparation and its preparation method. Background Technology

[0002] With changes in modern lifestyles, people have significantly increased their exposure to various chemicals, dust mites, pollen, and other allergens. When the human body comes into contact with these allergens or physical stimuli (such as ultraviolet rays, high temperatures, dry air, etc.), it often leads to discomfort such as itching, redness, and burning of the skin and mucous membranes. Society has an increasingly urgent need for soothing products that can quickly relieve these symptoms.

[0003] Naphazoline hydrochloride, an imidazoline sympathomimetic agonist, acts directly on α-adrenergic receptors on the walls of mucosal arterioles, causing vasoconstriction and thus rapidly reducing mucosal congestion and edema. Feniramine maleate, an alkylamine antihistamine, competitively blocks histamine H1 receptors, inhibiting histamine-mediated capillary dilation and increased permeability. The combination of the two drugs can synergistically enhance their effects through two different pathways: vasoconstriction and anti-allergy. It is widely used in soothing preparations to relieve symptoms such as itching and redness caused by allergies.

[0004] However, during the synthesis of naphthazol hydrochloride, the naphthalene ring is easily oxidized under locally over-acidic and aerobic conditions, generating naphthoquinone impurities with strong electrophilic properties. Simultaneously, fenamistatin maleate contains residual cyanide-containing reactive nitrogen-containing intermediates from its synthesis, as well as reactive nitrogen-containing intermediates with free secondary or primary amine structures resulting from N-demethylation degradation during storage due to factors such as light, heat, and oxygen. These two types of impurities undergo addition reactions in the formulation: naphthoquinone impurities, acting as electrophiles, covalently bind to the nitrogen nucleophilic center in the nitrogen-containing structure of fenamistatin, forming quinone-amine adducts. This side reaction consumes the pharmacologically active active ingredient and, on the other hand, the resulting adducts interfere with receptor binding sites, leading to a weakened synergistic effect of vasoconstriction and antihistamine in the soothing formulation, ultimately resulting in decreased soothing efficacy and poor product stability. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a pharmaceutical soothing preparation and its preparation method, aiming to solve the problem that the reaction between naphthoquinone impurities in naphthozoline hydrochloride and active nitrogen-containing intermediate impurities in feniramine maleate leads to a decrease in soothing effect.

[0006] To address the aforementioned technical problems, a method for preparing a medicinal soothing agent is proposed, comprising the following steps:

[0007] S1. Naphthiazoline hydrochloride was synthesized using compound 1. The synthesis process involved a condensation reaction using a composite solvent composed of toluene and ethyl acetate, and a salt-forming reaction using dilute hydrochloric acid. The structural formula of compound 1 is shown below:

[0008] ;

[0009] S2. Fenilamin maleate was synthesized using compounds 2 and 3. A weak base catalyst was used in the condensation reaction during the synthesis. The structural formulas of compounds 2 and 3 are shown below:

[0010] , ,

[0011] In compound 2, the R group is a halogen group;

[0012] S3. Add the functional additives, naphazoline hydrochloride, and feniramine maleate to water, stir to dissolve, and fill into a container to obtain a pharmaceutical soothing preparation. The pH of the pharmaceutical soothing preparation is 5.7-6.3.

[0013] In some embodiments, step S1 includes:

[0014] S1.1. Compound 1 and methanol are added to a composite solvent and stirred. Hydrogen chloride gas is introduced at 30-40°C to carry out a condensation reaction for 60-90 minutes to obtain a reaction solution. Then, the reaction solution is cooled to 0-2°C for crystallization, filtration, and drying to obtain intermediate 1. The mass ratio of compound 1 to hydrogen chloride gas is 1:(0.3-0.6).

[0015] S1.2 Add intermediate 1 and ethylenediamine to ethanol, heat to 80~100℃ for cyclization for 1~2h to obtain an intermediate solution containing intermediate 2, wherein the ethanol also contains 5~10wt% acid-binding agent, and the mass ratio of intermediate 1 to ethanol is 1:(2~4).

[0016] S1.3 Add dilute hydrochloric acid to the intermediate solution at 20~25℃ in 2~4 batches. After the addition is complete, raise the temperature to 35~40℃ and stir for 1~2 hours. Then concentrate under reduced pressure at 35℃ and 0.07~0.08MPa and filter to obtain naphthiazoline hydrochloride filter cake.

[0017] S1.4 Add the naphazoline hydrochloride filter cake to the dissolving solution and stir to dissolve at 55~65℃. Then, first cool to 40℃ at a rate of 2℃ / h and keep warm for 1~2h. Then, cool to 0~5℃ at a rate of 5℃ / h and keep warm to crystallize for 2~4h. After filtration, wash the filter cake with pure isopropanol and dry to obtain naphazoline hydrochloride.

[0018] In some embodiments, in step S1, the molar ratio of compound 1:methanol:ethylenediamine is 1:(2~4):(1.2~1.5), the concentration of dilute hydrochloric acid is 10~15wt%, the mass ratio of toluene to ethyl acetate in the composite solvent is (2~4):1, and the mass ratio of compound 1 to the composite solvent is 1:(3~6).

[0019] In some embodiments, the acid-binding agent in step S1.2 includes at least one of triethylamine, N,N-diisopropylethylamine, and pyridine, and the solution in step S1.4 is composed of isopropanol and water mixed in a mass ratio of (90~95):(5~10).

[0020] In some embodiments, the weak base catalyst in step S2 includes at least one of potassium carbonate, potassium acetate, and sodium acetate, and step S2 includes:

[0021] S2.1. Compound 3 is added to a solvent containing a weak base catalyst and stirred at 20-40°C for 0.5-1 h to obtain a pretreated solution. Then, compound 2 is added to the pretreated solution, and the mixture is heated to 60-80°C and reacted for 4-8 h to obtain a condensation solution. The molar ratio of compound 2:compound 3:weak base catalyst is 1:(0.8-1.0):(1.0-1.5), and the concentration of the weak base catalyst in the solvent is 5-15 wt%.

[0022] S2.2 After the condensation solution is cooled to 40~50℃, add the alkylation aid and 2-chloro-N,N-dimethylethylamine to the condensation solution, heat to 60~80℃ and react for 7~9h. After the reaction is completed, quench with water, extract with ethyl acetate, take the organic phase, wash, dry and concentrate under reduced pressure to obtain the intermediate product, wherein the mass ratio of 2-chloropyridine:alkylation aid:2-chloro-N,N-dimethylethylamine is 1:(1.5~2.2):(1.2~1.5);

[0023] S2.3 After the intermediate product is completely dissolved in an alcohol solvent, a 40-50 wt% potassium hydroxide aqueous solution is added. The mixture is heated to 80-100℃ and stirred for 2-4 hours to obtain a hydrolysate. When the hydrolysate is cooled to 40-50℃, a 25-35 wt% hydrogen peroxide aqueous solution is added dropwise. The mixture is kept warm and oxidized for 1-2 hours to obtain an oxidized solution. Finally, the pH of the oxidized solution is adjusted to 4-5 with a 10-20 wt% dilute formic acid. The mixture is refluxed at 100-120℃ for 2-3 hours to obtain a decarboxylate solution. When the decarboxylate solution is cooled to room temperature, the pH is adjusted to 10-12. The solution is extracted, washed, dried, and concentrated with ethyl acetate to obtain fenilamin base. The mass ratio of intermediate product: alcohol solvent: potassium hydroxide aqueous solution: hydrogen peroxide aqueous solution is 1:(5-10):(3-6):(2-4).

[0024] S2.4 Add pheniramine base to an organic solvent and stir at 50-60℃ to dissolve, obtaining a pheniramine base solution. Then dissolve maleic acid in the same organic solvent and add it dropwise to the pheniramine base solution. Keep warm and stir for 0.5-1h, then cool down to 10-15℃ at 3-5℃ / min and keep warm for 1-2h. Filter, take the filter cake, wash it with the same organic solvent at 0-5℃, and dry it to obtain maleic acid pheniramine. The molar ratio of pheniramine base to maleic acid is 1:(1-1.05).

[0025] In some embodiments, the solvent in step S2.1 includes at least one of acetonitrile, N,N-dimethylformamide, ethanol, and tetrahydrofuran; the alkylation aid in step S2.2 is composed of potassium iodide and potassium carbonate in a mass ratio of 1:(4~6); the alcohol solvent in step S2.3 includes at least one of ethylene glycol, propylene glycol, and glycerol; and the organic solvent in step S2.4 includes at least one of isopropanol, ethanol, acetone, and ethyl acetate.

[0026] In some embodiments, the functional adjuvant in step S3 includes at least one of antibacterial agents, buffers, stabilizers, and isotonic regulators.

[0027] In some embodiments, the antibacterial agent includes at least one of benzalkonium chloride, chlorobutanol, and phenethyl alcohol;

[0028] The buffer consists of an acidic buffer and a basic buffer, wherein the acidic buffer includes at least one of boric acid, citric acid, and sodium dihydrogen phosphate, and the basic buffer includes at least one of sodium borate, borax, sodium citrate, and disodium hydrogen phosphate.

[0029] Stabilizers include at least one of disodium edetate, sodium bisulfite, and sodium thiosulfate;

[0030] The isotonicity regulator is sodium chloride.

[0031] In addition, a medicinal soothing preparation is provided, which is prepared by the method described above for preparing a medicinal soothing preparation.

[0032] In some embodiments, the pharmaceutical soothing preparation comprises, by mass fraction, the following components: active ingredient, 0.01-0.1 wt% antibacterial agent, 0.5-3.0 wt% buffer, 0.01-0.1 wt% stabilizer, 0.5-0.6 wt% isotonic regulator, and the balance being water;

[0033] The active ingredient consists of naphazoline hydrochloride at a concentration of 0.2-0.3 mg / ml and feniramine maleate at a concentration of 2-4 mg / ml.

[0034] It should be noted that during the preparation of pharmaceutical soothing agents, the pH of the preparation is adjusted by using hydrochloric acid (for excessively high pH) or sodium hydroxide (for excessively low pH) to keep the pH of the preparation between 5.7 and 6.3.

[0035] The beneficial effects of this invention are as follows:

[0036] In the synthesis of naphthazolium hydrochloride, a condensation reaction is carried out using a composite solvent composed of toluene and ethyl acetate. The hydrophobic properties of toluene can effectively reduce the activity of free water in the system, thereby reducing the hydrolysis of the imine ester intermediate to generate 1-naphthaleneacetic acid. Meanwhile, the carbonyl oxygen atom of ethyl acetate can form weak hydrogen bonds and dipole interactions with the imine group of the intermediate, stabilizing the configuration of the target molecule and reducing polymerization side reactions caused by disordered intermolecular collisions. This inhibits the accumulation of oxidized precursors of the naphthalene ring structure from the source. On this basis, dilute hydrochloric acid is used for the salt formation reaction, avoiding the local over-acidic oxidation environment caused by the one-time addition of concentrated hydrochloric acid, and reducing the risk of the naphthalene ring being oxidized to generate colored impurities such as naphthoquinone. In the synthesis of feniramine maleate, a weak base catalyst is used for the condensation reaction. The acidic byproducts generated by the neutralization reaction drive the reaction equilibrium to the right, improving the reaction conversion rate of compound 1 and compound 2 and reducing the residue of cyanide-containing intermediates. When the final pH of the formulation is adjusted to a weakly acidic range of 5.7-6.3, both the pyridine nitrogen and dimethylamino group in the feniramine maleate molecule are in a protonated state, their lone pair electrons are occupied, and their nucleophilicity is basically lost, making it difficult for naphthoquinone impurities to covalently bind with them. In addition, this pH range also inhibits the N-demethylation degradation of feniramine during storage, reducing the formation of active nitrogen-containing intermediates with free secondary or primary amine structures. The above-mentioned synthesis process not only avoids the generation of naphthoquinone electrophilic reagents and active nitrogen-containing nucleophilic reagents at the source, but also passivates the reactivity of residual impurities at the formulation level, effectively blocking the Michael addition reaction between the two and avoiding the formation of quinone-nitrogen adducts. This ensures that the vasoconstrictive efficacy of naphthoquinone hydrochloride and the antihistamine efficacy of feniramine maleate can be fully exerted, thereby improving the stability and clinical soothing effect of the soothing formulation. Attached Figure Description

[0037] Figure 1 This is a schematic flowchart of a method for preparing a medicinal soothing agent in one embodiment;

[0038] Figure 2 Slit-lamp examination of the left eye of a New Zealand rabbit 1 hour after the last administration of the pharmaceutical soothing preparation prepared in Example 1.

[0039] Figure 3 Slit-lamp examination of the right eye of a New Zealand rabbit 1 hour after the last administration of the pharmaceutical soothing preparation prepared in Example 1.

[0040] Figure 4This is a diagram of the drug application site on the surface of guinea pigs after 24 hours of stimulation and de-drug removal of the pharmaceutical soothing preparation prepared in Example 1.

[0041] Figure 5 This is a process route diagram for the preparation of naphthiazoline hydrochloride;

[0042] Figure 6 This is a process route diagram for the preparation of feniramine maleate. Detailed Implementation

[0043] In the description of this application, it should be noted that, unless specific conditions are specified in the examples, conventional conditions or conditions recommended by the manufacturer are followed. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0044] Please refer to Figure 1 This invention proposes a method for preparing a medicinal soothing agent, the method comprising the following steps:

[0045] S1. Naphthiazoline hydrochloride was synthesized using compound 1. The synthesis process involved a condensation reaction using a composite solvent composed of toluene and ethyl acetate, and a salt-forming reaction using dilute hydrochloric acid. The structural formula of compound 1 is shown below:

[0046] .

[0047] In the synthesis of naphthazolium hydrochloride, a condensation reaction is carried out using a composite solvent composed of toluene and ethyl acetate. The hydrophobic properties of toluene can effectively reduce the activity of free water in the system, thereby reducing the hydrolysis of the imine ester intermediate to generate 1-naphthaleneacetic acid. Meanwhile, the carbonyl oxygen atom of ethyl acetate can form weak hydrogen bonds and dipole interactions with the imine group of the intermediate, stabilizing the configuration of the target molecule and reducing polymerization side reactions caused by disordered intermolecular collisions. This inhibits the accumulation of oxidized precursors of the naphthalene ring structure from the source. On this basis, dilute hydrochloric acid is used for the salt formation reaction, avoiding the local over-acidic oxidation environment caused by the one-time addition of concentrated hydrochloric acid. This significantly reduces the risk of the naphthalene ring being oxidized to generate colored impurities such as naphthoquinones, thus cutting off the source of electrophilic reagents that can undergo Michael addition reactions with nitrogen-containing substances.

[0048] Step S1 includes:

[0049] S1.1. Compound 1 and methanol are added to a composite solvent and stirred. Hydrogen chloride gas is introduced at 30-40°C to carry out a condensation reaction for 60-90 minutes to obtain a reaction solution. Then, the reaction solution is cooled to 0-2°C for crystallization, filtration, and drying to obtain intermediate 1. The mass ratio of compound 1 to hydrogen chloride gas is 1:(0.3-0.6).

[0050] The hydrophobic properties of toluene in the composite solvent used in S1.1 can effectively reduce the activity of free water in the system, thereby reducing the risk of intermediate hydrolysis generating impurities such as 1-naphthaleneacetic acid. At the same time, the carbonyl oxygen atom of ethyl acetate can form weak hydrogen bonds and dipole interactions with imine groups, stabilizing the target molecule configuration and inhibiting polymerization side reactions caused by disordered intermolecular collisions, thus improving reaction selectivity. After the condensation reaction, the temperature is lowered to 0~2℃ for crystallization. The intermediate's solubility is significantly reduced at low temperatures to achieve selective precipitation, while unreacted raw materials and byproducts are retained in the mother liquor. After filtration and drying, high-purity intermediate 1 can be obtained.

[0051] S1.2 Add intermediate 1 and ethylenediamine to ethanol, heat to 80~100℃ for cyclization for 1~2h to obtain an intermediate solution containing intermediate 2. The ethanol also contains 5~10wt% acid-binding agent, and the mass ratio of intermediate 1 to ethanol is 1:(2~4).

[0052] The acid-binding agent includes at least one of triethylamine, N,N-diisopropylethylamine, and pyridine. Using the acid-binding agent can neutralize the hydrogen chloride generated during the reaction in a timely manner, avoiding the adverse effects of the acidic environment on the stability of intermediate 1 or product intermediate 2. At the same time, by consuming by-products, it can drive the cyclization reaction equilibrium to the positive direction, significantly improving the reaction conversion rate. Ethanol, as the reaction solvent, can fully dissolve intermediate 1 and ethylenediamine to form a homogeneous reaction system, and also has a moderate boiling point, which is convenient for recovery and reuse by distillation after the reaction. Controlling the mass ratio of intermediate 1 to ethanol to 1:(2~4) can maintain a suitable reaction concentration while ensuring that the reactants are fully dissolved, and promote effective intermolecular collisions. The reaction temperature of 80~100℃ provides sufficient activation energy to drive the cyclization reaction to proceed rapidly, while avoiding polymerization or degradation side reactions caused by high temperature.

[0053] S1.3 Add dilute hydrochloric acid to the intermediate solution at 20~25℃ in 2~4 batches. After the addition is complete, raise the temperature to 35~40℃ and stir for 1~2 hours. Then concentrate under reduced pressure at 35℃ and 0.07~0.08MPa and filter to obtain naphazoline hydrochloride filter cake.

[0054] Adding dilute hydrochloric acid in batches (10-15 wt%) avoids the localized over-acidity caused by adding concentrated hydrochloric acid all at once, effectively suppressing the side reaction of naphthalene ring oxidation to form colored naphthoquinone impurities under strongly acidic conditions. Simultaneously, the protonation effect of dilute hydrochloric acid ensures the stable and complete conversion of the free base of naphthozoline into hydrochloride, improving salt formation efficiency. Secondly, controlling the acid addition temperature at 20-25℃ further reduces the oxidation reaction rate, and raising the temperature to 35-40℃ after acid addition and stirring ensures the complete completion of the salt formation reaction. Finally, vacuum concentration at 35℃ and 0.07-0.08 MPa allows for rapid evaporation of solvents and low-boiling-point impurities at lower temperatures, avoiding the impact of prolonged high-temperature concentration on the product's thermal stability. This also promotes the precipitation of naphthozoline hydrochloride in crystal form, resulting in a filter cake with higher purity after solid-liquid separation.

[0055] S1.4 Add the naphazoline hydrochloride filter cake to the dissolving solution and stir to dissolve at 55~65℃. Then, first cool to 40℃ at a rate of 2℃ / h and keep warm for 1~2h. Then, cool to 0~5℃ at a rate of 5℃ / h and keep warm to crystallize for 2~4h. After filtration, wash the filter cake with pure isopropanol and dry to obtain naphazoline hydrochloride.

[0056] The solution is composed of isopropanol and water in a mass ratio of (90~95):(5~10). The high proportion of isopropanol in the solution forms a mixed solvent system with moderate polarity, exhibiting good solubility for naphthiazoline hydrochloride at 55-65℃. The introduction of water adjusts the solvent polarity, ensuring that pigments and polar impurities maintain high solubility in the solution and do not precipitate with the target product. A staged cooling strategy, first slowly lowering the temperature to 40℃ at 2℃ / h and holding it for 1-2h, promotes slow crystal growth under low supersaturation, forming a regular and dense crystal structure, effectively reducing the physical encapsulation of impurities by lattice defects. Subsequently, cooling to 0-5℃ at 5℃ / h and holding for 2-4h rapidly increases the crystal yield, while the low-temperature environment further reduces the residue of the target product in the mother liquor. Finally, the filter cake is washed with pure isopropanol, utilizing its good volatility and solubility for surface impurities to effectively remove adsorbed pigments and residual mother liquor from the filter cake surface without dissolving the active pharmaceutical ingredient.

[0057] S2. Fenilamin maleate was synthesized using compounds 2 and 3. A weak base catalyst was used in the condensation reaction during the synthesis. The structural formulas of compounds 2 and 3 are shown below:

[0058] , ,

[0059] In compound 2, the R group is a halogen group.

[0060] Depending on the halogen group, compound 2 can be called 2-fluoropyridine, 2-chloropyridine, 2-bromopyridine, and 2-iodopyridine.

[0061] In the synthesis of feniramine maleate, a weak base catalyst is used for the condensation reaction. The acidic byproducts generated by the neutralization reaction drive the reaction equilibrium to the right, improve the reaction conversion rate of compound 1 and compound 2, and reduce the residue of cyanide-containing intermediates.

[0062] In step S2, the weak base catalyst includes at least one of potassium carbonate, potassium acetate, and sodium acetate. Step S2 includes:

[0063] S2.1. Add compound 3 to a solvent containing a weak base catalyst and stir at 20-40°C for 0.5-1 h to obtain a pretreated solution. Then add compound 2 to the pretreated solution and heat to 60-80°C to react for 4-8 h to obtain a condensation solution. The molar ratio of compound 2: compound 3: weak base catalyst is 1:(0.8-1.0):(1.0-1.5).

[0064] The solvents mentioned above include at least one of acetonitrile, N,N-dimethylformamide, ethanol, and tetrahydrofuran. The main purpose of using a weak base catalyst instead of a strong base catalyst in this step is to precisely control the concentration of benzyl cyanide α-carbanion through the synergistic effect of appropriate alkalinity and steric hindrance. The pKa of a weak base can only partially deprotonate benzyl cyanide, keeping the active intermediate at a low concentration. This effectively suppresses side reactions such as self-condensation, polyalkylation, and 2-halopyridine decomposition that are prone to occur under strong base conditions. At the same time, in the condensation reaction, the acidic byproducts generated by the neutralization reaction drive the reaction equilibrium to the right, improve the reaction conversion rate of compound 1 and compound 2, and reduce the residue of cyanide-containing intermediates.

[0065] S2.2 After the condensation solution is cooled to 40~50℃, add alkylation aid and 2-chloro-N,N-dimethylethylamine to the condensation solution, heat to 60~80℃ and react for 7~9h. After the reaction is completed, quench with water, extract with ethyl acetate, take the organic phase, wash, dry and concentrate under reduced pressure to obtain the intermediate product, wherein the mass ratio of 2-chloropyridine: alkylation aid: 2-chloro-N,N-dimethylethylamine is 1:(1.5~2.2):(1.2~1.5).

[0066] In step S2.2, the alkylation auxiliaries consist of potassium iodide and potassium carbonate in a mass ratio of 1:(4~6). Potassium carbonate, as a weak base, neutralizes the hydrogen chloride generated in the reaction, shifting the alkylation equilibrium to the forward direction while maintaining a slightly alkaline environment in the reaction system to prevent the decomposition of 2-chloro-N,N-dimethylethylamine or product degradation under acidic conditions. Potassium iodide converts 2-chloro-N,N-dimethylethylamine into the more reactive iodinated derivative (2-iodo-N,N-dimethylethylamine) through halogen exchange, significantly enhancing the nucleophilic substitution reaction. The reaction rate is optimized to ensure efficient completion of the alkylation reaction under relatively mild conditions. Controlling the mass ratio of 2-chloropyridine, alkylating agent, and 2-chloro-N,N-dimethylethylamine ensures that an excess of alkylating agent is used to promote complete reaction while avoiding the burden of impurities during post-processing. Quenching with water after the reaction effectively terminates the reaction and dissolves inorganic salts. Ethyl acetate extraction selectively extracts the target product. Combined with washing, drying, and vacuum concentration, potassium iodide, potassium carbonate, and water-soluble byproducts are efficiently removed, yielding a high-purity intermediate product.

[0067] S2.3. After the intermediate product is completely dissolved in an alcohol solvent, a 40-50 wt% potassium hydroxide aqueous solution is added. The mixture is heated to 80-100℃ and stirred for 2-4 hours to obtain a hydrolysate. After the hydrolysate is cooled to 40-50℃, a 25-35 wt% hydrogen peroxide aqueous solution is added dropwise. The mixture is kept warm and oxidized for 1-2 hours to obtain an oxidized solution. Finally, the pH of the oxidized solution is adjusted to 4-5 with a 10-20 wt% dilute formic acid. The mixture is refluxed at 100-120℃ for 2-3 hours to obtain a decarboxylate solution. After the decarboxylate solution is cooled to room temperature, the pH is adjusted to 10-12. The solution is extracted, washed, dried, and concentrated with ethyl acetate to obtain fenilamin base. The mass ratio of intermediate product: alcohol solvent: potassium hydroxide aqueous solution: hydrogen peroxide aqueous solution is 1:(5-10):(3-6):(2-4).

[0068] In step S2.3, the alcohol solvent includes at least one of ethylene glycol, propylene glycol, and glycerol. High-boiling-point alcohol solvents such as ethylene glycol, propylene glycol, or glycerol are selected to stably dissolve the reactants under heating conditions of 80-100℃, avoiding the inhomogeneity of the system caused by the volatilization of low-boiling-point solvents. The potassium hydroxide aqueous solution provides a strongly alkaline environment to promote the hydrolysis of cyano groups to carboxylate groups, while hydrogen peroxide converts heteroatoms or unsaturated bonds in the intermediates into removable groups through oxidation. Dilute formic acid is used to precisely adjust the pH to 4-5, achieving selective decarboxylation under reflux conditions of 100-120℃, which completely removes the cyano-derived structure while avoiding excessive reaction that damages the pyridine ring. After subsequent alkalization to pH 10-12, extraction with ethyl acetate can efficiently separate the non-nilamin base from the water-soluble byproduct.

[0069] S2.4 Add pheniramine base to an organic solvent and stir at 50-60℃ to dissolve, obtaining a pheniramine base solution. Then dissolve maleic acid in the same organic solvent and add it dropwise to the pheniramine base solution. Keep warm and stir for 0.5-1h, then cool down to 10-15℃ at 3-5℃ / min and keep warm for 1-2h. Filter, take the filter cake, wash it with the same organic solvent at 0-5℃, and dry it to obtain maleic acid pheniramine. The molar ratio of pheniramine base to maleic acid is 1:(1-1.05).

[0070] In step S2.4, the organic solvent includes at least one of isopropanol, ethanol, acetone, and ethyl acetate. Isopropanol, ethanol, acetone, or ethyl acetate are selected to fully dissolve the reactants at 50-60°C, promoting complete salt formation. The molar ratio of fenilamin base to maleic acid is controlled at 1:(1-1.05) to ensure complete conversion of the free base while avoiding excessive maleic acid residue. The temperature is rapidly reduced to 10-15°C at 3-5°C / min and maintained at this temperature for crystallization. Selective crystallization is achieved by utilizing the difference in solubility between the target product and impurities during the cooling process. Combined with low-temperature washing, surface-adsorbed impurities are effectively removed, thereby obtaining a high-purity, high-yield fenilamin maleic acid final product.

[0071] S3. Add the functional additives, naphazoline hydrochloride, and feniramine maleate to water, stir to dissolve, and fill into a container to obtain a pharmaceutical soothing preparation. The pH of the pharmaceutical soothing preparation is 5.7-6.3.

[0072] When the final pH of the formulation is adjusted to a weakly acidic range of 5.7 to 6.3, both the pyridine nitrogen and dimethylamino groups in the feniramine maleate molecule are in a protonated state, their lone pair electrons are occupied, and their nucleophilicity is essentially lost, making it difficult for naphthoquinone impurities to covalently bind to them. In addition, this pH range also inhibits the N-demethylation degradation of feniramine during storage, reducing the formation of active nitrogen-containing intermediates with free secondary or primary amine structures.

[0073] Among them, functional additives include at least one of antibacterial agents, buffers, stabilizers, and isotonic regulators.

[0074] In some embodiments, the antibacterial agent includes at least one of benzalkonium chloride, chlorobutanol, and phenethyl alcohol;

[0075] The buffer consists of an acidic buffer and a basic buffer, wherein the acidic buffer includes at least one of boric acid, citric acid, and sodium dihydrogen phosphate, and the basic buffer includes at least one of sodium borate, borax, sodium citrate, and disodium hydrogen phosphate.

[0076] Stabilizers include at least one of disodium edetate, sodium bisulfite, and sodium thiosulfate;

[0077] The isotonicity regulator is sodium chloride.

[0078] In addition, a medicinal soothing preparation is provided, which is prepared by the method described above for preparing a medicinal soothing preparation.

[0079] Active ingredient, 0.01~0.1wt% antibacterial agent, 0.5~3.0wt% buffer, 0.01~0.1wt% stabilizer, 0.5~0.6wt% isotonic conditioner, and the balance being water;

[0080] The active ingredient consists of naphazoline hydrochloride at a concentration of 0.2-0.3 mg / ml and feniramine maleate at a concentration of 2-4 mg / ml.

[0081] For example, the present invention provides the following specific embodiments to illustrate the specific preparation method:

[0082] Example 1

[0083] A method for preparing a medicinal soothing agent includes the following steps:

[0084] S1.1. Compound 1 and methanol were added to a composite solvent composed of toluene and ethyl acetate in a mass ratio of 3:1 and stirred. Hydrogen chloride gas was introduced at 35°C to carry out a condensation reaction for 75 min to obtain a reaction solution. The reaction solution was then cooled to 1°C for crystallization, filtration, and drying to obtain intermediate 1. The mass ratio of compound 1 to hydrogen chloride gas was 1:0.45.

[0085] S1.2. Add intermediate 1 and ethylenediamine to ethanol, heat to 90℃ and cyclize for 1.5h to obtain an intermediate solution containing intermediate 2. The ethanol also contains 8wt% triethylamine, and the mass ratio of intermediate 1 to ethanol is 1:3.

[0086] S1.3 Add 12wt% dilute hydrochloric acid to the intermediate solution at 22℃. After the addition is complete, raise the temperature to 38℃ and stir for 1.5h. Then concentrate under reduced pressure at 35℃ and 0.075MPa and filter to obtain naphthiazoline hydrochloride filter cake.

[0087] S1.4 Add the naphazoline hydrochloride filter cake to a solution composed of isopropanol and water in a mass ratio of 92:8, stir to dissolve at 60°C, then cool to 40°C at a rate of 2°C / h and keep at that temperature for 1.5h, then cool to 3°C at a rate of 5°C / h and keep at that temperature for 3h to crystallize. After filtration, wash the filter cake with pure isopropanol and dry it to obtain naphazoline hydrochloride.

[0088] S2.1. Compound 3 was added to N,N-dimethylformamide containing 10wt% potassium carbonate and stirred at 30°C for 0.8h to obtain a pretreated solution. Then, 2-chloropyridine (compound 2) was added to the pretreated solution and the mixture was heated to 70°C and reacted for 6h to obtain a condensation solution. The molar ratio of 2-chloropyridine:compound 3:weak base catalyst was 1:0.9:1.2.

[0089] S2.2 After the condensation solution is cooled to 45°C, add the alkylation auxiliary composed of potassium iodide and potassium carbonate in a mass ratio of 1:5 and 2-chloro-N,N-dimethylethylamine to the condensation solution. Heat to 70°C and react for 8 hours. After the reaction is completed, quench with water and extract with ethyl acetate. Take the organic phase, wash, dry and concentrate under reduced pressure to obtain the intermediate product. The mass ratio of 2-chloropyridine:alkylation auxiliary:2-chloro-N,N-dimethylethylamine is 1:1.8:1.35.

[0090] S2.3. After the intermediate product is completely dissolved in ethylene glycol, a 45wt% potassium hydroxide aqueous solution is added. The mixture is heated to 90℃ and stirred for 3 hours to obtain a hydrolysate. After the hydrolysate is cooled to 45℃, a 30wt% hydrogen peroxide aqueous solution is added dropwise. The mixture is kept at this temperature for 1.5 hours to obtain an oxidized solution. Finally, the pH of the oxidized solution is adjusted to 4.5 with a 15wt% dilute formic acid, and the mixture is refluxed at 110℃ for 2.5 hours to obtain a decarboxylate solution. After the decarboxylate solution is cooled to room temperature, the pH is adjusted to 11. The solution is then extracted, washed, dried, and concentrated with ethyl acetate to obtain fenilamin base. The mass ratio of intermediate product: ethylene glycol: potassium hydroxide aqueous solution: hydrogen peroxide aqueous solution is 1:8:4.5:3.

[0091] S2.4 Add feniprine to isopropanol and stir at 55°C to dissolve it, obtaining a feniprine solution. Then dissolve maleic acid in isopropanol and add it dropwise to the feniprine solution. Keep warm and stir for 0.8 h, then cool down to 12°C at 4°C / min and keep warm for 1.5 h. Filter, take the filter cake, wash it with isopropanol at 3°C, and dry it to obtain maleic acid feniprine. The molar ratio of feniprine to maleic acid is 1:1.03.

[0092] S3.1 Add 0.05wt% benzalkonium chloride, 1.47wt% boric acid, 1.1wt% sodium borate, 0.05wt% disodium edetate, and 0.55wt% sodium chloride to water, stir to dissolve, and obtain a mixed solution;

[0093] S3.2 Add naphazoline hydrochloride and feniramine maleate to the mixed solution, continue stirring to dissolve, and adjust the pH to 5.7~6.3. Fill the solution to obtain a pharmaceutical soothing preparation, wherein the concentrations of naphazoline hydrochloride and feniramine maleate in the pharmaceutical soothing preparation are 0.25mg / ml and 3mg / ml, respectively.

[0094] Example 2

[0095] The method is basically the same as in Example 1, except that the concentrations of naphazoline hydrochloride and feniramine maleate in the pharmaceutical soothing preparation are 0.2 mg / ml and 2 mg / ml, respectively.

[0096] Example 3

[0097] The method is basically the same as in Example 1, except that the concentrations of naphazoline hydrochloride and feniramine maleate in the pharmaceutical soothing preparation are 0.3 mg / ml and 4 mg / ml, respectively.

[0098] Comparative Example 1

[0099] The process is basically the same as in Example 1, except that the same mass of methyl tert-butyl ether is used to replace the composite solvent in step S1.1, and the concentration of hydrochloric acid in the dilute hydrochloric acid used is adjusted to 36 wt%.

[0100] Comparative Example 2

[0101] The process is essentially the same as in Example 1, except that the weak base catalyst in step S2.1 is replaced with the same mass of sodium amide, a strong base catalyst.

[0102] Comparative Example 3

[0103] It is basically the same as Example 1, except that the pH of the medicinal soothing preparation obtained in step S3 is 7.0.

[0104] Comparative Example 4

[0105] The process is essentially the same as in Example 1, except that the same mass of methyl tert-butyl ether is used to replace the composite solvent in step S1.1, and the concentration of hydrochloric acid in the dilute hydrochloric acid used is adjusted to 36 wt%.

[0106] Replace the weak base catalyst in step S2.1 with the same mass of strong base catalyst sodium amide.

[0107] The pH of the medicinal soothing preparation obtained in step S3 is 7.0.

[0108] Performance testing:

[0109] New Zealand rabbit eye irritation test experiment:

[0110] Using ordinary New Zealand rabbits, and based on the pharmaceutical soothing preparations obtained in Examples 1-3 and Comparative Examples 1-4, a total of 7 test groups were set up, with 3 rabbits per group, both male and female. A left-right control was used. The test drug (2 drops / eye, clinical concentration) was instilled into the conjunctival sac of the left eye, and 0.9% sodium chloride injection (2 drops / eye) was instilled into the conjunctival sac of the right eye as a control. The drugs were administered 4 times daily, with approximately 2 hours between each administration, for 4 consecutive weeks. One hour after the fourth administration on days 1, 8, 15, and 22, both eyes were stained with 2% sodium fluorescein solution and examined using a handheld ultraviolet lamp and / or a slit-lamp microscope to observe the conjunctiva, cornea, iris, and other damage. The degree of irritation from the test drug was determined according to the ocular irritation response score and evaluation criteria. The ocular irritation response scores and ocular irritation evaluation criteria are shown in Tables 1 and 2, respectively.

[0111] Table 1. Eye Irritation Response Scores

[0112]

[0113] Table 2. Criteria for Evaluating Eye Irritation

[0114]

[0115] The test results are shown in Table 3:

[0116] Table 3. Data from the New Zealand rabbit eye irritation test.

[0117]

[0118] From Table 3, Figure 2-3 It can be seen that when the medicinal soothing preparation prepared in Example 1 was instilled into the eyes of New Zealand rabbits, no obvious abnormal symptoms were observed in the conjunctiva, cornea, and iris of the eyes. Therefore, it can be concluded that the medicinal soothing preparation prepared in Example 1 of this application is non-irritating. Similarly, according to Table 3, the medicinal soothing preparations prepared in Examples 2-3 are all non-irritating.

[0119] In Comparative Examples 1-3, when the concentration of the composite solvent used in the condensation reaction of naphazoline hydrochloride and the hydrochloric acid used in the salt formation reaction changed, or the basicity of the catalyst used in the condensation reaction of feniramine maleate changed, or the pH of the final preparation changed, the prepared pharmaceutical soothing preparations showed some irritation after continuous use for 22 days, but the final result was still non-irritating.

[0120] Finally, observation of Comparative Example 4 shows that when the concentration of the composite solvent used in the condensation reaction of naphazoline hydrochloride, the concentration of hydrochloric acid used in the salt formation reaction, the basicity of the catalyst used in the condensation reaction of feniramine maleate, and the pH of the final formulation are all changed simultaneously, the final result is mild irritation.

[0121] Guinea pig patch test:

[0122] SPF-grade Hartley guinea pigs were randomly divided into a negative control group (0.9% sodium chloride injection, 0.2 mL / animal for both sensitization and challenge), a positive control group (1-chloro-2,4-dinitrophenyl petrolatum ointment, sensitization concentration 1%, challenge concentration 0.2%, sensitization and challenge dose 0.2 g / animal), and a test substance group (the pharmaceutical soothing preparation prepared in Example 1, 0.2 mL / animal for both sensitization and challenge dose). Each of the negative control, positive control, and test substance groups consisted of 10 animals, half male and half female. The sensitization and challenge application area was approximately 2 cm × 2 cm. Sensitization was achieved by applying the drug to the shaved area on the left back (near the left forelimb) for 6 hours, followed by removal of the drug. Sensitization was repeated on days 7 and 14, for a total of 3 times. Challenge was achieved 14 days after the last sensitization by applying the drug to the shaved area on the right back (near the right hindlimb), followed by removal of the drug after 6 hours. Skin allergic reactions at the drug application site were observed and scored at 1 and 24 hours after each sensitization and challenge drug administration. The skin scoring criteria are shown in Table 4.

[0123] Table 4 Skin Scoring Criteria

[0124]

[0125] Results Interpretation: Calculation of sensitization rate and evaluation of sensitization intensity: According to Table 4, a total score greater than 0 indicates a positive skin allergic reaction. The average score and sensitization rate of allergic reactions in each group of animals were calculated. The intensity of allergic reaction to the test drug was judged according to the sensitization rate and grading standards in Table 5.

[0126] Average score = (Total score for erythema formation + Total score for edema formation) / Total number of animals;

[0127] Sensitization rate = (Number of animals exhibiting erythema, edema, or systemic allergic reactions / Total number of test animals) × 100%.

[0128] Table 5. Evaluation Criteria for Skin Sensitization Intensity

[0129]

[0130] The test results are shown in Table 6:

[0131] Table 6. Guinea Pig Closed Sensitization Test

[0132]

[0133] Based on the Buehler experiment in guinea pigs and Figure 4As a result, the medicinal soothing preparation prepared in Example 1 did not show erythema or edema after stimulation, the positive reaction rate was 0%, and the sensitization intensity was weak, indicating that the medicinal soothing preparation prepared in Example 1 did not show obvious skin sensitization.

[0134] The above embodiments are preferred embodiments of this application, but the implementation of this application is not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of this application shall be considered equivalent substitutions and shall be included within the protection scope of this application.

Claims

1. A method for preparing a medicinal soothing agent, characterized in that, The method for preparing the soothing agent includes the following steps: Step S1 includes: S1.

1. Compound 1 and methanol are added to a composite solvent and stirred. Hydrogen chloride gas is introduced at 30-40°C to carry out a condensation reaction for 60-90 minutes to obtain a reaction solution. The reaction solution is then cooled to 0-2°C for crystallization, filtration, and drying to obtain intermediate 1. The mass ratio of compound 1 to hydrogen chloride gas is 1:(0.3-0.6). The structural formula of compound 1 is shown below: ； S1.2 Add intermediate 1 and ethylenediamine to ethanol containing 5-10 wt% acid-binding agent, heat to 80-100℃ for cyclization for 1-2 h to obtain an intermediate solution containing intermediate 2, wherein the mass ratio of intermediate 1 to ethanol is 1:(2-4). S1.3 Add dilute hydrochloric acid to the intermediate solution at 20~25℃ in 2~4 batches. After the addition is complete, raise the temperature to 35~40℃ and stir for 1~2 hours. Then concentrate under reduced pressure at 35℃ and 0.07~0.08MPa and filter to obtain naphthiazoline hydrochloride filter cake. S1.4 Add the naphazoline hydrochloride filter cake to the dissolving solution, stir and dissolve at 55~65℃, then first cool to 40℃ at a rate of 2℃ / h, keep at this temperature for 1~2h, then cool to 0~5℃ at a rate of 5℃ / h, keep at this temperature for 2~4h to crystallize, filter the filter cake, wash and dry it with pure isopropanol to obtain naphazoline hydrochloride; Step S2 includes: S2.

1. Compound 3 is added to a solvent containing potassium carbonate and stirred at 20-40°C for 0.5-1 h to obtain a pretreated solution. Then, compound 2 is added to the pretreated solution, and the mixture is heated to 60-80°C and reacted for 4-8 h to obtain a condensation solution. The molar ratio of compound 2:compound 3:potassium carbonate is 1:(0.8-1.0):(1.0-1.5), and the concentration of potassium carbonate in the solvent is 5-15 wt%. The structural formula of compound 3 is shown below: ， Compound 2 is 2-chloropyridine; S2.2 After the condensation solution is cooled to 40~50℃, add the alkylation aid and 2-chloro-N,N-dimethylethylamine to the condensation solution, heat to 60~80℃ and react for 7~9h. After the reaction is completed, quench with water, extract with ethyl acetate, take the organic phase, wash, dry and concentrate under reduced pressure to obtain the intermediate product, wherein the mass ratio of 2-chloropyridine:alkylation aid:2-chloro-N,N-dimethylethylamine is 1:(1.5~2.2):(1.2~1.5); S2.3 After the intermediate product is completely dissolved in an alcohol solvent, a 40-50 wt% potassium hydroxide aqueous solution is added. The mixture is heated to 80-100℃ and stirred for 2-4 hours to obtain a hydrolysate. When the hydrolysate is cooled to 40-50℃, a 25-35 wt% hydrogen peroxide aqueous solution is added dropwise. The mixture is kept warm and oxidized for 1-2 hours to obtain an oxidized solution. Finally, the pH of the oxidized solution is adjusted to 4-5 with a 10-20 wt% dilute formic acid. The mixture is refluxed at 100-120℃ for 2-3 hours to obtain a decarboxylate solution. When the decarboxylate solution is cooled to room temperature, the pH is adjusted to 10-12. The solution is extracted, washed, dried, and concentrated with ethyl acetate to obtain fenilamin base. The mass ratio of intermediate product: alcohol solvent: potassium hydroxide aqueous solution: hydrogen peroxide aqueous solution is 1:(5-10):(3-6):(2-4). S2.4 Add pheniramine base to an organic solvent and stir at 50-60℃ to dissolve it, obtaining a pheniramine base solution. Then dissolve maleic acid in the same organic solvent and add it dropwise to the pheniramine base solution. Keep warm and stir for 0.5-1h, then cool down to 10-15℃ at 3-5℃ / min and keep warm for 1-2h. Filter, take the filter cake, wash it with the same organic solvent at 0-5℃, and dry it to obtain maleic acid pheniramine. The molar ratio of pheniramine base to maleic acid is 1:(1-1.05). Step S3 includes: S3. Add the functional additives, naphazoline hydrochloride, and feniramine maleate to water, stir to dissolve, and fill into a container to obtain a pharmaceutical soothing preparation. The pH of the pharmaceutical soothing preparation is 5.7-6.

3.

2. The method for preparing a medicinal soothing agent according to claim 1, characterized in that, In step S1, the molar ratio of compound 1:methanol:ethylenediamine is 1:(2~4):(1.2~1.5), the mass ratio of compound 1 to the composite solvent is 1:(3~6), the acid-binding agent includes at least one of triethylamine, N,N-diisopropylethylamine, and pyridine, the concentration of dilute hydrochloric acid is 10~15wt%, and the solution is composed of isopropanol and water mixed in a mass ratio of (90~95):(5~10).

3. The method for preparing a medicinal soothing agent according to claim 1, characterized in that, The solvent in step S2.1 includes at least one of acetonitrile, N,N-dimethylformamide, ethanol, and tetrahydrofuran; the alkylation aid in step S2.2 is composed of potassium iodide and potassium carbonate in a mass ratio of 1:(4~6); the alcohol solvent in step S2.3 includes at least one of ethylene glycol, propylene glycol, and glycerol; and the organic solvent in step S2.4 includes at least one of isopropanol, ethanol, acetone, and ethyl acetate.

4. The method for preparing a medicinal soothing agent according to claim 1, characterized in that, The functional additives in step S3 include at least one of antibacterial agents, buffers, stabilizers, and isotonic regulators.

5. The method for preparing a medicinal soothing agent according to claim 4, characterized in that, The antibacterial agent includes at least one of benzalkonium chloride, chlorobutanol, and phenylethanol. The buffer consists of an acidic buffer and a basic buffer, wherein the acidic buffer includes at least one of boric acid, citric acid, and sodium dihydrogen phosphate, and the basic buffer includes at least one of sodium borate, borax, sodium citrate, and disodium hydrogen phosphate. Stabilizers include at least one of disodium edetate, sodium bisulfite, and sodium thiosulfate; The isotonicity regulator is sodium chloride.

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