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CN-122010841-A - Medicinal soothing preparation and preparation method thereof

CN122010841ACN 122010841 ACN122010841 ACN 122010841ACN-122010841-A

Abstract

The application belongs to the field of pharmaceutical preparations and discloses a medicinal preparation and a preparation method thereof, wherein the preparation method comprises the following steps of firstly preparing and synthesizing naphazoline hydrochloride through a compound 1 containing cyano, wherein a complex solvent formed by mixing toluene and ethyl acetate is adopted to carry out condensation reaction in the synthesis process, dilute hydrochloric acid is adopted to carry out salt formation reaction, then compound 2 containing halogen groups and compound 3 containing cyano are adopted to prepare and synthesize feniramine maleate, wherein a weak base catalyst is used to carry out condensation reaction in the synthesis process, and finally, functional auxiliary agents, naphazoline hydrochloride and feniramine maleate are added into water, stirred, dissolved and filled to obtain the medicinal preparation, wherein the pH value of the medicinal preparation is 5.7-6.3. The medicinal soothing preparation prepared by the method can effectively avoid adverse effects of impurities in naphazoline hydrochloride and pheniramine maleate on the soothing effect.

Inventors

  • CHEN WEIHAN
  • LIN ZHIZHONG
  • ZHANG PENG
  • HE CAIPING
  • HUANG WEIJING

Assignees

  • 广州大光制药有限公司

Dates

Publication Date
20260512
Application Date
20260414

Claims (10)

  1. 1. A method for preparing a pharmaceutical soothing formulation, comprising the steps of: S1, preparing synthetic naphazoline hydrochloride through a compound 1, wherein in the synthetic process, a composite solvent formed by mixing toluene and ethyl acetate is adopted for condensation reaction, dilute hydrochloric acid is adopted for salifying reaction, and the structural formula of the compound 1 is shown as follows: ; S2, preparing synthetic maleic acid feniramin through a compound 2 and a compound 3, wherein a weak base catalyst is used for condensation reaction in the synthesis process, and the structural formulas of the compound 2 and the compound 3 are shown as follows: 、 , Wherein, R groups in the compound 2 are halogen groups; And S3, adding the functional auxiliary agent, naphazoline hydrochloride and the fenuramine maleate into water, stirring, dissolving and filling to obtain the medicinal soothing preparation, wherein the pH value of the medicinal soothing preparation is 5.7-6.3.
  2. 2. The method for preparing a pharmaceutical soothing formulation according to claim 1, wherein step S1 comprises: S1.1, adding a compound 1 and methanol into a composite solvent, stirring and mixing, introducing hydrogen chloride gas at 30-40 ℃ for condensation reaction for 60-90 min to obtain a reaction liquid, and then reducing the reaction liquid to 0-2 ℃ for crystallization, filtering and drying to obtain an intermediate 1, wherein the mass ratio of the compound 1 to the hydrogen chloride gas is (0.3-0.6); S1.2, adding the intermediate 1 and ethylenediamine into ethanol, heating to 80-100 ℃ for cyclization for 1-2 hours to obtain an intermediate solution containing the intermediate 2, wherein the ethanol also contains 5-10wt% of acid binding agent, and the mass ratio of the intermediate 1 to the ethanol is 1 (2-4); S1.3, adding dilute hydrochloric acid into an intermediate solution at 20-25 ℃ for 2-4 batches, heating to 35-40 ℃ after the addition, stirring for reacting for 1-2 hours, and then concentrating under reduced pressure and filtering at 35 ℃ and 0.07-0.08 MPa to obtain a naphazoline hydrochloride filter cake; S1.4, adding a naphazoline hydrochloride filter cake into a dissolving solution, stirring and dissolving at 55-65 ℃, then cooling to 40 ℃ at a rate of 2 ℃ per hour, preserving heat for 1-2 hours, cooling to 0-5 ℃ at a rate of 5 ℃ per hour, preserving heat and crystallizing for 2-4 hours, washing the filter cake with pure isopropanol after filtering, and drying to obtain naphazoline hydrochloride.
  3. 3. The preparation method of the medicinal soothing preparation according to claim 2, wherein in the step S1, the molar ratio of the compound 1 to the methanol to the ethylenediamine is 1 (2-4) (1.2-1.5), the concentration of the dilute hydrochloric acid is 10-15 wt%, the mass ratio of the toluene to the ethyl acetate in the composite solvent is (2-4): 1, and the mass ratio of the compound 1 to the composite solvent is 1 (3-6).
  4. 4. The method for preparing a pharmaceutical soothing preparation according to claim 2, wherein the acid binding agent in the step S1.2 comprises at least one of triethylamine, N-diisopropylethylamine and pyridine, and the dissolution liquid in the step S1.4 is formed by mixing isopropanol and water according to a mass ratio of (90-95) to (5-10).
  5. 5. The method for preparing a pharmaceutical soothing formulation according to claim 1, wherein the weak base catalyst in step S2 comprises at least one of potassium carbonate, potassium acetate, sodium acetate, and step S2 comprises: S2.1, adding the compound 3 into a solvent containing a weak base catalyst, stirring for 0.5-1 h at 20-40 ℃ to obtain a pretreatment liquid, then adding the compound 2 into the pretreatment liquid, and heating to 60-80 ℃ to react for 4-8 h to obtain a condensation liquid, wherein the molar ratio of the compound 2 to the 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%; S2.2, cooling the condensation liquid to 40-50 ℃, adding an alkylation auxiliary agent and 2-chloro-N, N-dimethylethylamine into the condensation liquid, heating to 60-80 ℃ for reacting for 7-9 hours, adding water for quenching after the reaction is finished, extracting by using ethyl acetate, taking organic phase, washing, drying and concentrating under reduced pressure to obtain an intermediate product, wherein the mass ratio of the 2-chloropyridine to the alkylation auxiliary agent to the 2-chloro-N, N-dimethylethylamine is 1 (1.5-2.2): (1.2-1.5); S2.3, adding an intermediate product into an alcohol solvent to be completely dissolved, then adding a potassium hydroxide aqueous solution with the concentration of 40-50wt%, heating to 80-100 ℃, stirring and reacting for 2-4 hours to obtain a hydrolysate, cooling the hydrolysate to 40-50 ℃, dropwise adding a hydrogen peroxide aqueous solution with the concentration of 25-35 wt%, carrying out heat preservation and oxidation for 1-2 hours to obtain an oxidized solution, finally adjusting the pH of the oxidized solution to 4-5 by using a dilute formic acid with the concentration of 10-20wt%, carrying out reflux reaction for 2-3 hours to obtain a decarboxylated solution, adjusting the pH to 10-12 when the decarboxylated solution is cooled to room temperature, and extracting, washing, drying and concentrating by using ethyl acetate to obtain the non-Nilamine, wherein the intermediate product is the alcohol solvent, namely the potassium hydroxide aqueous solution, and the hydrogen peroxide aqueous solution with the mass ratio of 1 (5-10): (3-6): (2-4); S2.4, adding the financin base into an organic solvent, stirring and dissolving at 50-60 ℃ to obtain a financin base solution, then dissolving maleic acid into the same organic solvent, dripping the solution into the financin base solution, carrying out heat preservation and stirring for 0.5-1 h, cooling to 10-15 ℃ at 3-5 ℃ per min, carrying out heat preservation for 1-2 h, filtering, taking a filter cake, washing with the same organic solvent at 0-5 ℃ and drying to obtain the maleic acid, wherein the molar ratio of the financin base to the maleic acid is 1 (1-1.05).
  6. 6. The method for preparing a pharmaceutical preparation according to claim 5, wherein the solvent in step S2.1 comprises at least one of acetonitrile, N-dimethylformamide, ethanol and tetrahydrofuran, the alkylating aid in step S2.2 comprises potassium iodide and potassium carbonate according to a mass ratio of 1 (4-6), the alcohol solvent in step S2.3 comprises at least one of ethylene glycol, propylene glycol and glycerin, and the organic solvent in step S2.4 comprises at least one of isopropanol, ethanol, acetone and ethyl acetate.
  7. 7. The method for preparing a pharmaceutical soothing formulation according to claim 1, wherein the functional auxiliary agent in step S3 comprises at least one of a bacteriostatic agent, a buffering agent, a stabilizing agent, and an isotonicity adjusting agent.
  8. 8. The method of preparing a pharmaceutical soothing formulation of claim 7 wherein the bacteriostatic agent comprises at least one of benzalkonium chloride, chlorobutanol, phenethyl alcohol; The buffer consists of an acidic buffer and an alkaline buffer, wherein the acidic buffer comprises at least one of boric acid, citric acid and sodium dihydrogen phosphate, and the alkaline buffer comprises at least one of sodium borate, borax, sodium citrate and disodium hydrogen phosphate; The stabilizer comprises at least one of disodium edentate, sodium bisulphite and sodium thiosulfate; the isotonic regulator is sodium chloride.
  9. 9. A pharmaceutical soothing formulation, characterized in that it is prepared by a process for the preparation of a pharmaceutical soothing formulation according to any one of claims 1 to 8, and the pharmaceutical soothing formulation is in the form of a liquid formulation or a spray formulation.
  10. 10. The pharmaceutical soothing preparation according to claim 9, which comprises the following components, by mass, active ingredients, 0.01-0.1wt% of a bacteriostatic agent, 0.5-3.0wt% of a buffering agent, 0.01-0.1wt% of a stabilizing agent, 0.5-0.6wt% of an isotonic regulator and the balance of water; the active ingredients comprise naphazoline hydrochloride with the concentration of 0.2-0.3 mg/ml and pheniramine maleate with the concentration of 2-4 mg/ml.

Description

Medicinal soothing preparation and preparation method thereof Technical Field The application relates to the field of pharmaceutical preparations, in particular to a medicinal soothing preparation and a preparation method thereof. Background With the change of modern life style, the opportunities for people to contact various chemical products, dust mites, pollen and other allergens are obviously increased, when human bodies contact the allergens or physical stimuli (such as ultraviolet rays, high temperature, dry air and the like), the discomfort phenomena of itching, redness, burning and the like of skin and mucous membrane are often caused, and the demands of society on relief products capable of rapidly relieving the symptoms are increasingly urgent. Naphazoline hydrochloride is taken as an imidazoline sympathomimetic agonist, can directly act on alpha-adrenergic receptors on the wall of arteriolar blood vessels of mucous membranes to cause vascular smooth muscle contraction, thereby rapidly relieving congestion and edema of mucous membranes, and the pheniramine maleate is an alkylamine antihistamine which can competitively block histamine H 1 receptors, inhibit histamine-mediated telangiectasis and permeability increase, and can be synergistically enhanced from two different ways of vasoconstriction and antiallergic by combining the two ways, so that the naphazoline hydrochloride can be widely used in a relieving preparation to relieve symptoms such as pruritus and red swelling caused by allergy. However, in the synthesis process of naphazoline hydrochloride, naphthalene rings are easy to oxidize under the conditions of local peracid and oxygen to generate naphthoquinone impurities with strong electrophilicity, and at the same time, active nitrogen-containing intermediate impurities containing cyano groups remain in the synthesis process of the beniramin maleate and are influenced by factors such as light, heat, oxygen and the like in the storage process to generate active nitrogen-containing intermediate impurities with free secondary amine or primary amine structures through N-demethylation degradation. The two impurities undergo addition reaction in the preparation, namely naphthoquinone impurities are used as electrophiles and are covalently combined with nitrogen nucleophilic centers in a non-Nilapamin nitrogen-containing structure to generate quinone-amine adducts. The side reaction consumes the active ingredients with pharmacological activity on one hand, and the generated adduct interferes with the receptor binding site, so that the vasoconstriction and antihistamine synergistic effect of the soothing preparation are weakened, and finally the soothing effect is reduced and the product stability is poor. Disclosure of Invention The invention aims to solve the technical problem of providing a medicinal soothing preparation and a preparation method thereof, and aims to solve the problem that the soothing effect is reduced due to the reaction of naphthoquinone impurities in naphazoline hydrochloride in the soothing preparation and active nitrogenous intermediate impurities in pheniramine maleate. In order to solve the technical problems, a preparation method of a medicinal soothing preparation is provided, and the preparation method of the soothing preparation comprises the following steps: S1, preparing synthetic naphazoline hydrochloride through a compound 1, wherein in the synthetic process, a composite solvent formed by mixing toluene and ethyl acetate is adopted for condensation reaction, dilute hydrochloric acid is adopted for salifying reaction, and the structural formula of the compound 1 is shown as follows: ; S2, preparing synthetic maleic acid feniramin through a compound 2 and a compound 3, wherein a weak base catalyst is used for condensation reaction in the synthesis process, and the structural formulas of the compound 2 and the compound 3 are shown as follows: 、, Wherein, R groups in the compound 2 are halogen groups; And S3, adding the functional auxiliary agent, naphazoline hydrochloride and the fenuramine maleate into water, stirring, dissolving and filling to obtain the medicinal soothing preparation, wherein the pH value of the medicinal soothing preparation is 5.7-6.3. In some embodiments, step S1 comprises: S1.1, adding a compound 1 and methanol into a composite solvent, stirring and mixing, introducing hydrogen chloride gas at 30-40 ℃ for condensation reaction for 60-90 min to obtain a reaction liquid, and then reducing the reaction liquid to 0-2 ℃ for crystallization, filtering and drying to obtain an intermediate 1, wherein the mass ratio of the compound 1 to the hydrogen chloride gas is (0.3-0.6); S1.2, adding the intermediate 1 and ethylenediamine into ethanol, heating to 80-100 ℃ for cyclization for 1-2 hours to obtain an intermediate solution containing the intermediate 2, wherein the ethanol also contains 5-10wt% of acid binding agent, and the mass ratio of the interme