Preparation method of epinastine hydrobromide

Abstract

The invention relates to the technical field of medicines, in particular to a preparation method of epinastine hydrobromide, which comprises the following steps: taking a substance A as a raw material to generate a substance B through reduction reaction; carrying out hydrolysis reaction on the substance B to generate a substance C; judging whether the hydrolysis reaction meets a preset standard or not according to the yield of the substance C, and increasing the hydrolysis reaction temperature under the condition that the hydrolysis reaction does not meet the preset standard; under the condition that the hydrolysis reaction meets the preset standard, the substance C is subjected to a condensation cyclization reaction to generate epinastine hydrobromide; the qualification of preparation is judged according to the yield of epinastine hydrobromide, the reason of unqualified preparation is determined based on the unqualified condition, and the stirring speed or duration of the condensation cyclization reaction is increased; and the preparation is finished under the condition of qualified preparation. According to the invention, the preparation yield is improved, and the quality and stability of the product are ensured.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical technology, and particularly to a preparation method of epinastine hydrobromide. Background Art

[0002] Epinastine hydrobromide, with the chemical name of 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine hydrobromide, has the molecular formula of C 16 H 15 N3·HBr, and its chemical structural formula is as follows: Epinastine hydrobromide, as an important pharmaceutical ingredient, has attracted much attention due to its unique pharmacological effects and wide application fields. It is a highly effective selective histamine H1 receptor antagonist, which can effectively relieve histamine-mediated allergic reactions by competitively blocking the binding of histamine to the H1 receptor. Structurally, epinastine hydrobromide has stable chemical properties, which makes it easy to handle and store during the pharmaceutical process. At the same time, its good water solubility also facilitates its absorption and distribution in the body.

[0003] Chinese Patent Application Publication No.: CN108341821A discloses a synthesis method of epinastine hydrochloride, which relates to the field of pharmaceutical technology and includes the following steps: using 6-cyano-6,11-dihydro-1H-dibenzo[b,e]azepine as a raw material, in the presence of Raney-Ni, using ammonia methanol solution as a solvent, introducing hydrogen to carry out a reduction reaction to obtain 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azepine; cyclizing 6-(aminomethyl)-6,11-dihydro-1H-dibenzo[b,e]azepine with cyanogen bromide and then neutralizing with an alkali to obtain 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine; and salifying 3-amino-9,13b-dihydro-1H-dibenzo[c,f]imidazo[1,5-a]azepine with hydrochloric acid to obtain the product. However, there are the following problems in the prior art: the raw materials in the prior art are difficult to obtain and have high costs. Summary of the Invention

[0004] Therefore, the present invention provides a preparation method of epinastine hydrobromide to overcome the problems of difficult raw material acquisition and high costs in the prior art.

[0005] To achieve the above object, the present invention provides a preparation method of epinastine hydrobromide, including: using substance A as a raw material to generate substance B through a reduction reaction; subjecting substance B to a hydrolysis reaction to generate substance C; Determine whether the hydrolysis reaction meets the preset standard according to the yield of Substance C, and increase the hydrolysis reaction temperature under the condition of not meeting the preset standard; Under the condition that the hydrolysis reaction meets the preset standard, generate epinastine hydrobromide from Substance C through a condensation cyclization reaction; Determine the qualification of the preparation according to the yield of epinastine hydrobromide, determine the reason for the unqualified preparation based on the unqualified conditions, and increase the stirring rate or duration of the condensation cyclization reaction; Complete the preparation under the condition of qualified preparation; Among them, Substance A is 6-phthalimidomethyl-5H-dibenz[b,e]azepine, Substance B is 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine, and Substance C is 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine.

[0006] Further, the reduction reaction process includes: dissolving Substance A in a mixed solvent of dichloromethane and ethanol, adding sodium borohydride under the condition of an ice bath, reacting at room temperature for a first preset duration, then dropping acetic acid to quench the unreacted sodium borohydride, and obtaining Substance B after extraction, where the sodium borohydride is a reducing agent.

[0007] Further, the hydrolysis reaction process includes: heating and refluxing Substance B and hydrazine hydrate in an ethanol solvent for a second preset duration, cooling to room temperature and filtering after the reaction is completed, concentrating the filtrate, extracting with dichloromethane, and then drying the organic phase to obtain Substance C.

[0008] Further, the process of determining whether the hydrolysis reaction meets the preset standard according to the yield of Substance C includes: Take a sample for pretreatment after the hydrolysis reaction is completed; Obtain the yield of Substance C through chromatographic detection and analysis; Compare the yield of Substance C with the preset yield; Based on the comparison result that the yield is less than the preset yield, determine that the hydrolysis reaction does not meet the preset standard, and increase the hydrolysis reaction temperature according to the difference between the preset yield and the yield; Based on the comparison result that the yield is greater than or equal to the preset yield, determine that the hydrolysis reaction meets the preset standard, and carry out a condensation cyclization reaction on Substance C.

[0009] Further, there are several adjustment methods for the hydrolysis reaction temperature, and each adjustment method has a different adjustment range for the hydrolysis reaction temperature.

[0010] Further, the condensation cyclization reaction process includes: dissolving substance C in dichloromethane solution, slowly dropping bromine gas under ice bath conditions, adding sodium cyanide after reacting for a third preset duration, heating to a preset temperature and then reacting for a fourth preset duration, and hydrolyzing the cyano group under strong acid conditions to obtain epinastine hydrobromate.

[0011] Further, the qualification of the preparation is determined according to the yield of epinastine hydrobromate. Among them, if the yield is less than the preset yield, it is determined that the preparation is unqualified, and the reason for the unqualified preparation is determined according to the difference between the preset yield and the yield; based on the condition that the yield is greater than or equal to the preset yield, it is determined that the preparation is qualified, and the preparation of epinastine hydrobromate is completed.

[0012] Further, the reason for the unqualified preparation is determined according to the yield difference. Among them, if the yield difference is less than the preset yield difference, it is determined that the reason for the unqualified preparation is insufficient stirring in the condensation cyclization reaction, and the stirring rate is increased according to the first yield deviation threshold; the yield difference is the difference between the second preset yield and the yield; the first yield deviation threshold is the ratio of the preset yield difference to the yield difference.

[0013] Further, if the yield difference is greater than or equal to the preset yield difference, it is determined that the reason for the unqualified preparation is insufficient time in the condensation cyclization reaction, and the duration of the condensation cyclization reaction is increased according to the second yield deviation threshold. Further, the duration of the condensation cyclization reaction is positively correlated with the second yield deviation threshold, where the second yield deviation threshold is the ratio of the yield difference to the preset yield difference.

[0014] Compared with the prior art, the beneficial effect of the present invention is that the present invention selects 6-phthalimidomethyl-5H-dibenz[b,e]azepine as the raw material. Compared with the raw materials in the traditional preparation method, the acquisition difficulty of this raw material is lower and the cost is more economical, thus significantly reducing the production cost of epinastine hydrobromate and improving its market competitiveness.

[0015] Further, through the setting and monitoring of reaction conditions, the present invention realizes the efficient control of key steps. The hydrolysis reaction temperature is flexibly adjusted according to the yield of substance C, ensuring the full progress of the hydrolysis reaction and improving the yield and quality of substance C.

[0016] Further, the preparation process in the present invention, including yield detection, condition determination, parameter adjustment, etc., is all carried out based on preset standards and actual detection results, which provides the possibility for future intelligent and automated production. By integrating advanced detection technologies and control systems, real-time monitoring and automatic adjustment of the preparation process can be achieved, further improving production efficiency and product quality.

[0017] Furthermore, the present invention effectively solves the unqualified problems that may be encountered in the preparation process through strict yield determination criteria and flexible parameter adjustment strategies. For this problem, specific solutions are provided, significantly improving the preparation qualification rate of epinastine hydrobromide. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1 It is a flowchart of the preparation method of epinastine hydrobromide according to an embodiment of the present invention; Figure 2 It is a synthetic route diagram of epinastine hydrobromide according to an embodiment of the present invention; Figure 3 It is a flowchart for determining whether the hydrolysis reaction meets the preset criteria according to an embodiment of the present invention; Figure 4 It is a flowchart for determining the preparation qualification according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0019] In order to make the objectives and advantages of the present invention clearer, the present invention will be further described below in conjunction with embodiments; it should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0020] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. Those skilled in the art should understand that these embodiments are only used to explain the technical principles of the present invention and do not limit the protection scope of the present invention.

[0021] It should be noted that the data in this embodiment are all obtained through comprehensive analysis and evaluation of the historical test data and corresponding historical test results of the present invention in the three months before this test. Those skilled in the art can understand that the determination method of the above single parameter of the present invention can be to select the value with the highest proportion according to the data distribution as the preset standard parameter, use weighted summation to obtain the value as the preset standard parameter, substitute each historical data into a specific formula and use the value obtained by the formula as the preset standard parameter or other selection methods, as long as it satisfies that the present invention can clearly define different specific situations in the single determination process through the obtained values.

[0022] Please refer to Figures 1 to 4 as shown, which are respectively a flowchart of the preparation method of epinastine hydrobromide according to an embodiment of the present invention; a synthetic route diagram of epinastine hydrobromide according to an embodiment of the present invention; a flowchart for determining whether the hydrolysis reaction meets the preset criteria according to an embodiment of the present invention; a flowchart for determining the preparation qualification according to an embodiment of the present invention.

[0023] The preparation method of epinastine hydrobromide according to an embodiment of the present invention includes: Using substance A as a raw material to generate substance B through a reduction reaction; Substance B is hydrolyzed to form Substance C; Determine whether the hydrolysis reaction meets the preset standard according to the yield of Substance C, and increase the hydrolysis reaction temperature under the condition that the preset standard is not met; Under the condition that the hydrolysis reaction meets the preset standard, Substance C is subjected to a condensation cyclization reaction to form epinastine hydrobromide; Determine the qualification of the preparation according to the yield of epinastine hydrobromide, determine the reason for the unqualified preparation based on the unqualified conditions, and increase the stirring rate or duration of the condensation cyclization reaction; Complete the preparation under the condition that the preparation is qualified; Among them, Substance A is 6-phthalimidomethyl-5H-dibenz[b,e]azepine, Substance B is 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine, and Substance C is 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine.

[0024] Specifically, the reduction reaction process includes: dissolving Substance A in a mixed solvent of dichloromethane and ethanol, adding sodium borohydride under ice bath conditions, reacting at room temperature for a first preset duration, then adding acetic acid dropwise to quench the unreacted sodium borohydride, and obtaining Substance B after extraction, where the sodium borohydride is a reducing agent.

[0025] In the embodiment of the present invention, the first preset duration is set to 2 hours, and the reduction reaction process includes: dissolving 50 g of Substance A in a mixed solvent of 500 mL of dichloromethane and 200 mL of ethanol, slowly adding 20 g of sodium borohydride under ice bath conditions, reacting at room temperature for 2 hours, adding acetic acid dropwise to quench the unreacted sodium borohydride, and obtaining Substance B after extraction.

[0026] Specifically, the hydrolysis reaction process includes: heating Substance B and hydrazine hydrate in an ethanol solvent under reflux for a second preset duration, cooling to room temperature and filtering after the reaction is completed, concentrating the filtrate, extracting with dichloromethane, and then drying the organic phase to obtain Substance C.

[0027] In the embodiment of the present invention, an excessive amount of hydrazine hydrate is added to the ethanol solvent, specifically not limited, the reflux temperature is between 78 and 82 °C, the second preset duration is set to 6 hours, and the aqueous phase is extracted with dichloromethane 3 times, and then the organic phases are combined and dried.

[0028] Specifically, the process of determining whether the hydrolysis reaction meets the preset standard according to the yield of Substance C includes: Sampling for pretreatment after the hydrolysis reaction is completed; Obtaining the yield of Substance C through chromatographic detection and analysis; Comparing the yield of Substance C with the preset yield of 80%; Based on the comparison result that the yield is less than the preset yield, it is determined that the hydrolysis reaction does not meet the preset standard, and the hydrolysis reaction temperature is increased according to the difference between the preset yield and the yield. Based on the comparison result that the yield is greater than or equal to the preset yield, it is determined that the hydrolysis reaction meets the preset standard, and substance C is subjected to a condensation cyclization reaction.

[0029] Specifically, after the hydrolysis reaction is completed, 10 mL of the sample is taken. The pretreatment process includes: filtration to remove possible solid impurities or suspended matters; adjusting the pH value of the sample according to the properties of substance C and the requirements of chromatographic detection; if the concentration of substance C in the sample is too high or too low, appropriate dilution or concentration is required; centrifuging the sample to further remove possible fine particles or precipitates.

[0030] Specifically, in the embodiment of the present invention, a chromatograph is used for chromatographic detection.

[0031] Specifically, the preset yield is taken as 80%, but the above value is not limited thereto, and those skilled in the art can adjust this value according to actual needs.

[0032] Specifically, there are several adjustment methods for the hydrolysis reaction temperature, and each adjustment method has a different adjustment range for the hydrolysis reaction temperature. Among them, if the yield difference is less than the first preset yield difference of 5%, the hydrolysis reaction temperature is increased to the corresponding value using the first temperature adjustment coefficient of 1.08; If the yield difference is greater than or equal to the first preset yield difference and less than the second preset yield difference of 10%, the hydrolysis reaction temperature is increased to the corresponding value using the second temperature adjustment coefficient of 1.12; If the yield difference is greater than or equal to the second preset yield difference, the hydrolysis reaction temperature is increased to the corresponding value using the third temperature adjustment coefficient of 1.15; The yield difference is the difference between the preset yield and the yield.

[0033] Specifically, the initial temperature of the hydrolysis reaction is set at 78 °C, the first preset yield difference is taken as 5%, and the second preset yield difference is taken as 10%, but the above values are not limited thereto, and those skilled in the art can adjust these values according to actual needs.

[0034] Specifically, the condensation cyclization reaction process includes: dissolving substance C in dichloromethane solution, slowly dropping bromine gas under ice bath conditions, adding sodium cyanide after reacting for the third preset duration, heating to the preset temperature and then reacting for the fourth preset duration, and hydrolyzing the cyano group under strong acid conditions to obtain epinastine bromate.

[0035] In the embodiment of the present invention, the third preset duration is set to 1 hour, the fourth preset duration is set to 4 hours, and the strong acid is concentrated hydrochloric acid. The cyano hydrolysis is completed after dropping concentrated hydrochloric acid until the pH = 1 and stirring at room temperature for 2 hours.

[0036] Specifically, the qualification of the preparation is determined according to the yield of epinastine hydrobromide. Among them, if the yield is less than the preset yield of 85%, it is determined that the preparation is unqualified, and the reason for the unqualified preparation is determined according to the difference between the preset yield and the yield; based on the condition that the yield is greater than or equal to the preset yield, it is determined that the preparation is qualified, and the preparation of epinastine hydrobromide is completed.

[0037] Specifically, the reason for the unqualified preparation is determined according to the yield difference. Among them, if the yield difference is less than the preset yield difference of 5%, it is determined that the reason for the unqualified preparation is insufficient stirring in the condensation cyclization reaction, and the stirring rate is increased according to the first yield deviation threshold; the yield difference is the difference between the second preset yield and the yield; the first yield deviation threshold is the ratio of the preset yield difference to the yield difference.

[0038] Specifically, if the yield difference is greater than or equal to the preset yield difference, it is determined that the reason for the unqualified preparation is insufficient time in the condensation cyclization reaction, and the duration of the condensation cyclization reaction is increased according to the second yield deviation threshold. In the embodiment of the present invention, the preset yield is taken as 85%, and the preset yield difference is taken as 5%. However, the above values are not limited to this, and those skilled in the art can adjust the values according to actual needs.

[0039] Specifically, the duration of the condensation cyclization reaction is positively correlated with the second yield deviation threshold. Among them, if the second yield deviation threshold is less than the first preset deviation value of 1.02, the first duration adjustment coefficient is used to increase the duration of the condensation cyclization reaction to the corresponding value; If the second yield deviation threshold is greater than or equal to the first preset deviation value and less than the second preset deviation value of 1.05, the second duration adjustment coefficient is used to increase the duration of the condensation cyclization reaction to the corresponding value; If the second yield deviation threshold is greater than or equal to the second preset deviation value, the third duration adjustment coefficient is used to increase the duration of the condensation cyclization reaction to the corresponding value; The second yield deviation threshold is the ratio of the yield difference to the preset yield difference.

[0040] In the embodiment of the present invention, the first preset deviation value is taken as 1.02, and the second preset deviation value is taken as 1.05. However, the above values are not limited to this, and those skilled in the art can adjust the values according to actual needs.

[0041] So far, the technical solution of the present invention has been described in conjunction with the preferred embodiments shown in the accompanying drawings. However, it is easy for those skilled in the art to understand that the protection scope of the present invention is obviously not limited to these specific embodiments. Without departing from the principle of the present invention, those skilled in the art can make equivalent changes or substitutions to the relevant technical features, and the technical solutions after these changes or substitutions will all fall within the protection scope of the present invention.

[0042] The above are only the preferred embodiments of the present invention and are not used to limit the present invention; for those skilled in the art, the present invention can have various changes and modifications. Any modification, equivalent substitution, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A preparation method of epinastine hydrobromide, characterized in that, Including: Using substance A as a raw material to generate substance B through a reduction reaction; Subjecting substance B to a hydrolysis reaction to generate substance C; Judging whether the hydrolysis reaction meets the preset standard according to the yield of substance C, and increasing the hydrolysis reaction temperature under the condition of not meeting the preset standard; Under the condition that the hydrolysis reaction meets the preset standard, subjecting substance C to a condensation cyclization reaction to generate epinastine hydrobromide; Judging the qualification of the preparation according to the yield of epinastine hydrobromide, determining the reason for the unqualified preparation based on the unqualified conditions, and increasing the stirring rate or duration of the condensation cyclization reaction; Completing the preparation under the condition of qualified preparation; Wherein, substance A is 6-phthalimidomethyl-5H-dibenz[b,e]azepine, substance B is 6-(phthalimidomethyl)-6,11-dihydro-5H-dibenz[b,e]azepine, and substance C is 6-aminomethyl-6,11-dihydro-5H-dibenz[b,e]azepine.

2. The preparation method of epinastine hydrobromide according to claim 1, characterized in that, The reduction reaction process includes: dissolving substance A in a mixed solvent of dichloromethane and ethanol, adding sodium borohydride under the condition of an ice bath, reacting at room temperature for a first preset time, then dripping acetic acid to quench the unreacted sodium borohydride, and obtaining substance B after extraction, wherein the sodium borohydride is a reducing agent.

3. The preparation method of epinastine hydrobromide according to claim 1, characterized in that, The hydrolysis reaction process includes: heating and refluxing substance B and hydrazine hydrate in an ethanol solvent for a second preset time, cooling to room temperature and filtering after the reaction is completed, concentrating the filtrate, extracting with dichloromethane, and then drying the organic phase to obtain substance C.

4. The preparation method of epinastine hydrobromide according to claim 1, characterized in that, The process of judging whether the hydrolysis reaction meets the preset standard according to the yield of substance C includes: Sampling for pretreatment after the hydrolysis reaction is completed; Obtaining the yield of substance C through chromatographic detection and analysis; Comparing the yield of substance C with the preset yield; Judging that the hydrolysis reaction does not meet the preset standard based on the comparison result that the yield is less than the preset yield, and increasing the hydrolysis reaction temperature according to the difference between the preset yield and the yield; Judging that the hydrolysis reaction meets the preset standard based on the comparison result that the yield is greater than or equal to the preset yield, and subjecting substance C to a condensation cyclization reaction.

5. The preparation method of epinastine hydrobromide according to claim 4, characterized in that, There are several adjustment methods for the hydrolysis reaction temperature, and each adjustment method has a different adjustment range for the hydrolysis reaction temperature.

6. The preparation method of epinastine hydrobromide according to claim 1, wherein, The condensation cyclization reaction process includes: dissolving substance C in a dichloromethane solution, slowly dripping bromine gas under the condition of an ice bath, reacting for a third preset time, adding sodium cyanide, heating to a preset temperature and reacting for a fourth preset time, and hydrolyzing the cyano group under strong acid conditions to obtain epinastine bromate.

7. The preparation method of epinastine hydrobromide according to claim 1, characterized in that, Judging the qualification of the preparation according to the yield of epinastine hydrobromide. Wherein, if the yield is less than the preset yield, it is judged that the preparation is unqualified, and the reason for the unqualified preparation is determined according to the difference between the preset yield and the yield; based on the condition that the yield is greater than or equal to the preset yield, it is judged that the preparation is qualified, and the preparation of epinastine hydrobromide is completed.

8. The preparation method of epinastine hydrobromide according to claim 7, characterized in that, Determine the reason for unqualified preparation according to the yield difference. Among them, if the yield difference is less than the preset yield difference, it is determined that the reason for unqualified preparation is insufficient stirring in the condensation and cyclization reaction, and the stirring rate is increased according to the first yield deviation threshold; the yield difference is the difference between the second preset yield and the yield; the first yield deviation threshold is the ratio of the preset yield difference to the yield difference.

9. The preparation method of epinastine hydrobromide according to claim 8, wherein, If the yield difference is greater than or equal to the preset yield difference, it is determined that the reason for unqualified preparation is insufficient time for the condensation and cyclization reaction, and the duration of the condensation and cyclization reaction is increased according to the second yield deviation threshold.

10. The preparation method of epinastine hydrobromide according to claim 9, characterized in that, The duration of the condensation and cyclization reaction is positively correlated with the second yield deviation threshold, where the second yield deviation threshold is the ratio of the yield difference to the preset yield difference.

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