Preparation method of phenazopyridine hydrochloride and phenazopyridine hydrochloride capsule preparation

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of phenazopyridine hydrochloride and a phenazopyridine hydrochloride capsule preparation. The preparation method of phenazopyridine hydrochloride comprises the following steps: dissolving 2, 6-diamino-3-phenylazopyridine dihydrochloride in water, dropwise adding ammonia water until the pH value is 8-9, dissolving the obtained 2, 6-diamino-3-phenylazopyridine in ethanol, and dropwise adding hydrochloric acid until the pH value is 3-4 to obtain a phenazopyridine hydrochloride crude product; and dissolving the crude product in water, dropwise adding ammonia water until the pH value is 8-9, dissolving the obtained solid in ethanol, dropwise adding hydrochloric acid until the pH value is 3-4 to obtain the phenazopyridine hydrochloride, and the purity of the phenazopyridine hydrochloride is greater than or equal to 99.9%. The preparation method is stable in process and high in yield, the obtained phenazopyridine hydrochloride is high in purity and suitable for industrial production, and powerful support is provided for preparation of phenazopyridine hydrochloride bulk drugs and preparations thereof.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of phenazopyridine hydrochloride and a phenazopyridine hydrochloride capsule preparation. Background Art

[0002] Phenazopyridine hydrochloride, molecular formula is C 11 H 11 N5·HCl, molecular weight 249.70. Preparations prepared from the active pharmaceutical ingredient phenazopyridine hydrochloride, including capsules and tablets, are primarily used to relieve urethral and bladder pain, burning sensation, and discomfort such as frequent and urgent urination caused by cystitis, prostatitis, urethritis, gonococcal urethritis, as well as endoscopic examinations and urethral catheterization. Since phenazopyridine hydrochloride does not participate in the systemic blood circulation system after administration and is excreted unchanged in the urine, it is highly safe and widely used clinically. Its chemical structure is as follows:

[0003]

[0004] Currently, phenazopyridine hydrochloride is mainly synthesized by the following two routes:

[0005] 1) Using aniline as the starting material, diazotization and coupling are performed to obtain phenazopyridine dihydrochloride (2,6-diamino-3-phenylazopyridine dihydrochloride), which is then hydrolyzed to obtain phenazopyridine hydrochloride. The reaction scheme is as follows:

[0006]

[0007] 2) Using N,N-dimethylaniline as a solvent, pyridine reacts with an excess of sodium amide to produce 2,6-diaminopyridine in a single step. 2,6-diaminopyridine is then coupled with diazonium chloride under acidic conditions to produce phenazopyridine hydrochloride, which is then recrystallized from water to obtain the finished product. The reaction scheme is as follows:

[0008]

[0009] In Route 1, after phenazopyridine dihydrochloride is hydrolyzed to phenazopyridine hydrochloride, the reaction solution is viscous and difficult to filter, making solid-liquid separation difficult. The resulting product has a high impurity content and low purity, making it difficult to industrialize. In Route 2, the resulting product is mostly a mixture of phenazopyridine dihydrochloride and monohydrochloride, which also suffers from low product purity. The purity of phenazopyridine hydrochloride is generally between 97% and 98.5%. Summary of the Invention

[0010] In view of this, the object of the present invention is to provide a preparation method of phenazopyridine hydrochloride and a phenazopyridine hydrochloride capsule preparation. The preparation method of the present invention can obtain phenazopyridine hydrochloride with high purity.

[0011] The present invention provides a method for preparing phenazopyridine hydrochloride, comprising the following steps:

[0012] 1) dissolving 2,6-diamino-3-phenylazopyridine dihydrochloride in water, adding aqueous ammonia dropwise until the pH value is 8-9, and performing a first solid-liquid separation to obtain 2,6-diamino-3-phenylazopyridine;

[0013] 2) dissolving the 2,6-diamino-3-phenylazopyridine in ethanol, adding hydrochloric acid dropwise until the pH value is 3-4, and performing a second solid-liquid separation to obtain a crude product of phenazopyridine hydrochloride;

[0014] 3) dissolving the crude phenazopyridine hydrochloride in water and adding aqueous ammonia dropwise until the pH value is 8-9, performing a third solid-liquid separation, dissolving the obtained solid in ethanol and adding hydrochloric acid dropwise until the pH value is 3-4, and performing a fourth solid-liquid separation to obtain phenazopyridine hydrochloride; the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0015] Preferably, the mass ratio of 2,6-diamino-3-phenylazopyridine dihydrochloride to water in step 1) is 1:15-20.

[0016] Preferably, the rate of adding the ammonia water is 45-55 mL / min, the mass fraction of the ammonia water is 26%, and the temperature of the reaction system is controlled to be lower than 25° C. during the process of adding the ammonia water.

[0017] Preferably, the rate of adding hydrochloric acid is 14-16 mL / min, the concentration of hydrochloric acid is 12 mol / L, and the temperature of the reaction system is controlled to be lower than 30° C. during the process of adding hydrochloric acid.

[0018] Preferably, after dissolving in ethanol in step 2), the process further comprises: decolorizing with activated carbon, wherein the mass ratio of activated carbon to 2,6-diamino-3-phenylazopyridine in the decolorizing with activated carbon is 0.04 to 0.06:1.

[0019] Preferably, the preparation method of 2,6-diamino-3-phenylazopyridine dihydrochloride comprises the following steps:

[0020] After mixing aniline and hydrochloric acid solution, an aqueous solution of sodium nitrite is added dropwise to carry out diazotization reaction, and then a hydrochloric acid solution of 2,6-diaminopyridine is added dropwise to the obtained diazotization reaction solution to carry out coupling reaction to obtain the 2,6-diamino-3-phenylazopyridine dihydrochloride.

[0021] Preferably, after the coupling reaction, the method further comprises: crystallizing the obtained coupling reaction solution, performing solid-liquid separation on the crystallization system, and washing and drying the obtained solid;

[0022] The crystallization comprises: heating the coupling reaction liquid to a first temperature for a first stirring, and then cooling it to a second temperature for a second stirring; the first temperature is 35-45° C., the first stirring time is 0.5-1 hour, the second temperature is 10-20° C., and the second stirring time is 1.5-2.5 hours.

[0023] Preferably, the mass ratio of aniline to sodium nitrite is 1:0.7-0.9.

[0024] Preferably, the mass ratio of aniline to 2,6-diaminopyridine is 1:1 to 1.3.

[0025] The present invention also provides a phenazopyridine hydrochloride capsule preparation, comprising a capsule shell, talc powder filled in the capsule shell, and phenazopyridine hydrochloride obtained by the preparation method described in the above technical solution, wherein the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0026] Compared with the prior art, the present invention has the following beneficial effects:

[0027] The invention provides a preparation method of phenazopyridine hydrochloride, comprising the following steps: 1) dissolving 2,6-diamino-3-phenylazopyridine dihydrochloride in water, dripping ammonia water until the pH value is 8-9, performing a first solid-liquid separation to obtain 2,6-diamino-3-phenylazopyridine; 2) dissolving the 2,6-diamino-3-phenylazopyridine in ethanol, dripping hydrochloric acid until the pH value is 3-4, performing a second solid-liquid separation to obtain a crude phenazopyridine hydrochloride; 3) dissolving the crude phenazopyridine hydrochloride in water, dripping ammonia water until the pH value is 8-9, performing a third solid-liquid separation, dissolving the obtained solid in ethanol, dripping hydrochloric acid until the pH value is 3-4, and performing a fourth solid-liquid separation to obtain phenazopyridine hydrochloride; the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0028] The present invention provides a method for preparing phenazopyridine hydrochloride. 2,6-diamino-3-phenylazopyridine dihydrochloride is first dissolved in water and then neutralized with ammonia. Hydrochloric acid is then added dropwise to the resulting 2,6-diamino-3-phenylazopyridine in ethanol to form a salt, thereby obtaining a crude phenazopyridine hydrochloride product. Finally, the crude phenazopyridine hydrochloride product is neutralized with ammonia and then further salted with hydrochloric acid to obtain the target product, phenazopyridine hydrochloride. Both the system after neutralization with ammonia and the reaction solution after salt formation are easy to separate into solids and liquids. Impurities dissolve in the liquid, and the liquid removes the impurities during the solid-liquid separation process. The resulting phenazopyridine hydrochloride product is highly pure. The present invention uses ethanol to dissolve 2,6-diamino-3-phenylazopyridine in a solid state, resulting in uniform, large crystals that facilitate separation from impurities. The phenazopyridine hydrochloride API prepared in this embodiment has a high purity of over 99.9%.

[0029] Furthermore, the present invention prepares 2,6-diamino-3-phenylazopyridine dihydrochloride through diazotization and coupling reactions: using aniline as a raw material, sodium nitrite is added dropwise to a hydrochloric acid solution for diazotization reaction, and then 2,6-diaminopyridine is added dropwise for coupling reaction. After the addition of 2,6-diaminopyridine, the resulting reaction solution is a viscous liquid that is difficult to filter directly. The crystallization operation of the present invention, which first heats up and then cools down, converts 2,6-diamino-3-phenylazopyridine dihydrochloride into regular crystals, which facilitates solid-liquid separation.

[0030] The data from the examples show that the phenazopyridine hydrochloride obtained by the present invention has high purity and high yields in each step. The yields of the diazotization and coupling reactions are 85-95%, the yield of the salt-forming reaction is 80-90%, and the yield after purification reaches 85-95%. This helps to reduce production costs and improve economic benefits. The specific conditions of the diazotization coupling reaction, neutralization reaction, and salt-forming reaction of the present invention improve the stability of the preparation method and are suitable for large-scale industrial production. The route of the present invention produces less waste liquid and waste residue during the reaction process, which are easy to handle and meet environmental protection requirements. At the same time, the high yield also reduces the waste of raw materials and further reduces pollution to the environment. The product obtained by the preparation method of the present invention has high purity and meets pharmaceutical requirements. In addition, the raw materials are readily available and the reaction conditions are mild, making it a feasible synthetic route. BRIEF DESCRIPTION OF THE DRAWINGS

[0031] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0032] Figure 1 This is a flow chart of the diazo coupling reaction in the embodiment;

[0033] Figure 2 This is a flow chart for preparing the crude phenazopyridine hydrochloride in the examples;

[0034] Figure 3 This is a flow chart of the purification of phenazopyridine hydrochloride in the embodiment;

[0035] Figure 4 This is the HPLC chart of the phenazopyridine hydrochloride product obtained in Example 1;

[0036] Figure 5 This is the NMR spectrum (1H) of the product obtained in Example 1;

[0037] Figure 6 This is the NMR image (13C) of the product obtained in Example 1;

[0038] Figure 7 This is the NMR image (DEPT135) of the product obtained in Example 1;

[0039] Figure 8 This is the COSY NMR spectrum of the product obtained in Example 1;

[0040] Figure 9 This is a flow chart for the preparation of phenazopyridine hydrochloride capsules according to Example 4. DETAILED DESCRIPTION

[0041] The present invention provides a method for preparing phenazopyridine hydrochloride, comprising the following steps:

[0042] 1) dissolving 2,6-diamino-3-phenylazopyridine dihydrochloride in water, adding aqueous ammonia dropwise until the pH value is 8-9, and performing a first solid-liquid separation to obtain 2,6-diamino-3-phenylazopyridine;

[0043] 2) dissolving the 2,6-diamino-3-phenylazopyridine in ethanol, adding hydrochloric acid dropwise until the pH value is 3-4, and performing a second solid-liquid separation to obtain a crude product of phenazopyridine hydrochloride;

[0044] 3) dissolving the crude phenazopyridine hydrochloride in water and adding aqueous ammonia dropwise until the pH value is 8-9, performing a third solid-liquid separation, dissolving the obtained solid in ethanol and adding hydrochloric acid dropwise until the pH value is 3-4, and performing a fourth solid-liquid separation to obtain phenazopyridine hydrochloride, wherein the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0045] In the present invention, unless otherwise specified, the materials and equipment used are commercially available products in the art.

[0046] 1) The present invention dissolves 2,6-diamino-3-phenylazopyridine dihydrochloride in water, adds ammonia water dropwise until the pH value is 8-9, and performs a first solid-liquid separation to obtain 2,6-diamino-3-phenylazopyridine.

[0047] In the present invention, the preparation method of 2,6-diamino-3-phenylazopyridine dihydrochloride preferably comprises the following steps:

[0048] After mixing aniline and hydrochloric acid solution, an aqueous solution of sodium nitrite is added dropwise to carry out diazotization reaction, and then a hydrochloric acid solution of 2,6-diaminopyridine is added dropwise to the obtained diazotization reaction solution to carry out coupling reaction to obtain the 2,6-diamino-3-phenylazopyridine dihydrochloride.

[0049] In the present invention, the hydrochloric acid solution used in the mixture of aniline and hydrochloric acid solution preferably comprises water and concentrated hydrochloric acid, the concentration of the concentrated hydrochloric acid is preferably 12 mol / L, the mass ratio of the water to the concentrated hydrochloric acid is preferably 0.7:3; the mass ratio of the aniline to the concentrated hydrochloric acid is preferably 1:3.

[0050] In the present invention, the temperature of mixing the aniline and the hydrochloric acid solution is preferably 0-10° C., the time is preferably 20 minutes, and the mixing of the aniline and the hydrochloric acid solution is preferably carried out under stirring.

[0051] In the present invention, the mass concentration of the aqueous solution of sodium nitrite is preferably 15 to 25%. The mass ratio of aniline to sodium nitrite is preferably 1:0.7 to 0.9, more preferably 1:0.78.

[0052] In the present invention, the rate of adding the aqueous solution of sodium nitrite is preferably 0.05 to 0.11 L / min; the rate described in the present invention can ensure the safety and stability of the reaction and improve the yield. During the process of adding the aqueous solution of sodium nitrite, the temperature of the reaction system is preferably controlled to be 0 to 20°C. The end point of the addition is preferably until the reaction solution turns the potassium iodide test paper blue. The reaction formula of the diazotization reaction is preferably as shown below:

[0053]

[0054] In the present invention, the concentration of 2,6-diaminopyridine in the hydrochloric acid solution of 2,6-diaminopyridine is preferably 0.2 kg / L, the concentration of HCl is preferably 6 mol / L. The mass ratio of aniline to 2,6-diaminopyridine is 1:1-1.3, more preferably 1:1.17.

[0055] In the present invention, the rate of dripping the hydrochloric acid solution of 2,6-diaminopyridine is preferably 0.08 to 0.11 L / min. The dripping rate described in the present invention is conducive to controlling the stability of the reaction rate and is conducive to the complete reaction. During the dripping process, the temperature of the reaction system is preferably controlled to be 0 to 20°C, and the dripping time is preferably 60min±10min. After the dripping, stirring is preferably continued for 3 to 4h. The endpoint of the coupling reaction is preferably: the content of the starting raw material aniline is less than 5%, and the content of 2,6-diaminopyridine is less than 10%. The reaction formula of the coupling reaction is preferably as shown below:

[0056]

[0057] In the present invention, after the coupling reaction, the further steps include: crystallizing the obtained coupling reaction solution, performing solid-liquid separation on the crystallization system, and washing and drying the obtained solid;

[0058] The crystallization is preferably performed by heating the coupled reaction solution to a first temperature for a first stirring step, and then cooling it to a second temperature for a second stirring step; the first temperature is preferably 35-45°C, the first stirring time is preferably 0.5-1 hour, the second temperature is preferably 10-20°C, and the second stirring time is preferably 1.5-2.5 hours, specifically 2 hours. The present invention heats the solution first and then cools it, which promotes crystal formation, reduces impurity content, and facilitates solid-liquid separation in the next step. This solves the problem of direct crystallization causing the reaction solution to be very viscous and difficult to filter.

[0059] The solid-liquid separation is preferably performed by centrifugation or filtration; the washing agent is preferably anhydrous ethanol; the drying temperature is preferably 50-60° C., and the moisture content of the dried solid is less than 10%.

[0060] The 2,6-diamino-3-phenylazopyridine dihydrochloride obtained by the invention has a high yield of 85% to 95%.

[0061] In the present invention, the water is preferably purified water, and the mass ratio of the 6-diamino-3-phenylazopyridine dihydrochloride to water is preferably 1:15 to 20, more preferably 1:17. The dissolving of 2,6-diamino-3-phenylazopyridine dihydrochloride in water is preferably carried out under stirring.

[0062] In the present invention, the rate of adding ammonia water is preferably 45 to 55 mL / min, and the mass fraction of ammonia water is 26%. During the process of adding ammonia water, the temperature of the reaction system is preferably controlled to be lower than 25°C, and the addition process is preferably accompanied by stirring. The purpose of adding ammonia water in the present invention is to cause the 2,6-diamino-3-phenylazopyridine dihydrochloride in the system to undergo a neutralization reaction with ammonia water, and the precipitated yellow solid is 2,6-diamino-3-phenylazopyridine. The reaction formula is shown below:

[0063]

[0064] In the present invention, after the dropwise addition of ammonia water, the method preferably further comprises continuing stirring, and the time for continuing stirring is preferably 2 hours. The first solid-liquid separation method is preferably centrifugation and filtration, and after the first solid-liquid separation, the method preferably further comprises: washing the obtained solid; the washing reagent is preferably purified water, and after the washing, a 2,6-diamino-3-phenylazopyridine wet product is obtained, and the water content of the wet product is preferably 65-75%. The present invention preferably uses the 2,6-diamino-3-phenylazopyridine wet product to directly proceed to the next step. The 2,6-diamino-3-phenylazopyridine wet product is viscous and requires a long drying time. The present invention directly uses the wet product, which can reduce production costs and is conducive to large-scale production.

[0065] 2) After obtaining 2,6-diamino-3-phenylazopyridine, the present invention dissolves the 2,6-diamino-3-phenylazopyridine in ethanol, adds hydrochloric acid dropwise until the pH value reaches 3-4, and performs a second solid-liquid separation to obtain a crude product of phenazopyridine hydrochloride.

[0066] In the present invention, dissolving the 2,6-diamino-3-phenylazopyridine in ethanol is preferably carried out under stirring, and the stirring temperature is preferably 35-45°C.

[0067] In the present invention, after dissolving in ethanol, the process preferably further comprises: adding activated carbon for decolorization, stirring, filtering to remove carbon, and collecting the filtrate. The mass ratio of the activated carbon to 2,6-diamino-3-phenylazopyridine is preferably 0.04-0.06:1, more preferably 0.05:1; the stirring time is preferably 0.5-1 hour; and after filtering to remove carbon, the filter cake is preferably washed with anhydrous ethanol. The collected filtrate is combined with the filtrate obtained from the filtering to remove residual 2,6-diamino-3-phenylazopyridine on the activated carbon, thereby reducing the loss of the active ingredient. The hydrochloric acid is added dropwise to the filtrate.

[0068] In the present invention, the rate of adding hydrochloric acid is preferably 14 to 16 mL / min, and the concentration of hydrochloric acid is 12 mol / L. During the process of adding hydrochloric acid, the temperature of the reaction system is preferably controlled to be lower than 30°C, and the addition process is preferably accompanied by stirring. The purpose of adding hydrochloric acid is to salt the 2,6-diamino-3-phenylazopyridine in the system with hydrochloric acid, and the precipitated purple-red solid is the crude product of phenazopyridine hydrochloride. The reaction formula is shown below:

[0069]

[0070] In the present invention, the step of adding hydrochloric acid preferably includes continued stirring, and the stirring time is preferably 3 to 4 hours. The second solid-liquid separation method is preferably centrifugation or filtration. After the second solid-liquid separation, the step of washing and drying the obtained solid is preferably performed. The washing agent is preferably anhydrous ethanol. The drying preferably includes maintaining the temperature at 55 to 60°C for 6 hours, then heating to 70 to 75°C and drying until the moisture content is less than 5%.

[0071] The crude phenazopyridine hydrochloride obtained by the invention has a high yield of 80-90%.

[0072] 3) After obtaining the crude phenazopyridine hydrochloride, the present invention dissolves the crude phenazopyridine hydrochloride in water and drips ammonia water until the pH value is 8-9, performs a third solid-liquid separation, dissolves the obtained solid in ethanol, drips hydrochloric acid until the pH value is 3-4, and performs a fourth solid-liquid separation to obtain phenazopyridine hydrochloride, wherein the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0073] In the present invention, in step 3), the crude phenazopyridine hydrochloride is dissolved in water and ammonia water is added dropwise to a pH value of 8 to 9. The third solid-liquid separation is preferably the same as the method of dissolving 2,6-diamino-3-phenylazopyridine dihydrochloride in water and adding ammonia water dropwise to a pH value of 8 to 9 in step 1), and the first solid-liquid separation is carried out, except that 2,6-diamino-3-phenylazopyridine dihydrochloride is replaced by the crude phenazopyridine hydrochloride, which will not be described in detail here.

[0074] In the present invention, the solid obtained in step 3) is dissolved in ethanol and hydrochloric acid is added dropwise to a pH value of 3 to 4. The fourth solid-liquid separation is preferably the same as the method of dissolving 2,6-diamino-3-phenylazopyridine in ethanol, adding hydrochloric acid dropwise to a pH value of 3 to 4, and the second solid-liquid separation in step 2). 2,6-diamino-3-phenylazopyridine is replaced by the solid obtained in the third solid-liquid separation, which will not be repeated here.

[0075] According to the present invention, the crude phenazopyridine hydrochloride product is dissolved in water for subsequent treatment, thereby reducing residual impurities and improving the purity of the target product.

[0076] In the present invention, the obtained solid is dissolved in ethanol and hydrochloric acid is added dropwise to a pH value of 3 to 4, preferably in a reactor in a Class D clean area.

[0077] In the present invention, after the fourth solid-liquid separation, the process preferably further comprises washing and drying the obtained solid; the washing agent is preferably anhydrous ethanol; and the drying preferably comprises heating the solid to 55-60°C within 60 minutes, maintaining the temperature for 8-16 hours, and then heating the temperature to 70-75°C and drying the solid until the moisture content is less than 5% and the ethanol content is less than 0.5%. The phenazopyridine hydrochloride obtained by the present invention has a high yield of 85-95% and a high purity of 99.9% or above.

[0078] The present invention also provides a phenazopyridine hydrochloride capsule preparation, comprising a capsule shell, talc powder filled in the capsule shell, and phenazopyridine hydrochloride obtained by the preparation method described in the above technical solution.

[0079] In the present invention, the preparation method of the phenazopyridine hydrochloride capsule preparation comprises the following steps:

[0080] The talc powder and the phenazopyridine hydrochloride obtained by the preparation method described in the above technical solution are mixed and filled into capsule shells to obtain the phenazopyridine hydrochloride capsule preparation, and the purity of the phenazopyridine hydrochloride is ≥99.9%.

[0081] The mass ratio of the phenazopyridine hydrochloride to talc is preferably 1:1.2. The mixing of the phenazopyridine hydrochloride and talc is preferably carried out in a multi-directional motion mixer, the rotation speed is preferably 10-100 r / min, and the mixing time is preferably 10-20 min, specifically 15 min.

[0082] The method of filling the capsule shell preferably further includes polishing.

[0083] The present invention first prepares 2,6-diamino-3-phenylazopyridine dihydrochloride through a diazo coupling reaction: aniline is used as the raw material. A sodium nitrite solution is added dropwise to a hydrochloric acid solution at low temperature for a diazotization reaction, and then 2,6-diaminopyridine is added dropwise for a coupling reaction. Secondly, 2,6-diamino-3-phenylazopyridine is prepared through a neutralization reaction: 2,6-diamino-3-phenylazopyridine dihydrochloride is dissolved in water and neutralized with ammonia. Finally, a crude phenazopyridine hydrochloride (2,6-diamino-3-phenylazopyridine hydrochloride) is prepared through a salt formation reaction: hydrochloric acid is added dropwise to 2,6-diamino-3-phenylazopyridine in ethanol. Finally, the target product is purified: the crude phenazopyridine hydrochloride is neutralized by adding ammonia dropwise, and then hydrochloric acid is added dropwise to form a salt to obtain the target product, phenazopyridine hydrochloride. The present invention controls the reaction conditions and post-processing steps to obtain a high-quality phenazopyridine hydrochloride API.

[0084] To further illustrate the present invention, the preparation method of phenazopyridine hydrochloride and the phenazopyridine hydrochloride capsule preparation provided by the present invention are described in detail below with reference to the accompanying drawings and examples, but they should not be construed as limiting the scope of protection of the present invention.

[0085] Example 1 Preparation of Phenazopyridine Hydrochloride API

[0086] 1. Diazo coupling reaction (preparation process as follows Figure 1 shown)

[0087] In a 30L reactor, add 1.0kg of aniline, 0.7kg of water, and 3.0kg of concentrated hydrochloric acid (12mol / L). Start stirring, cool to 0-10°C, and continue stirring for 20 minutes. Add sodium nitrite solution dropwise (0.78kg of sodium nitrite, 2.34kg of purified water, and stir until the solution is clear). Control the temperature at 0-20°C during the addition process. Complete the addition over 60 minutes. The diazotization reaction is considered to have terminated when the potassium iodide test paper turns blue with the reaction solution.

[0088] Add a solution of 2,6-diaminopyridine in hydrochloric acid dropwise (1.17 kg of 2,6-diaminopyridine to 5.4 L of 6 mol / L hydrochloric acid, stirring until the solution is clear). Control the temperature at 0-20°C during the addition process over 60 minutes. Stir at 0-20°C for 4 hours. High-performance liquid chromatography (HPLC) is used to monitor the reaction endpoint. The coupling reaction is considered complete when the HPLC indicates that the content of the starting material, aniline, is less than 5% and the content of 2,6-diaminopyridine is less than 10%.

[0089] Heat to 35-45°C and stir for 0.5h; cool to 10-20°C and stir for 2h (crystallization).

[0090] The mixture was centrifuged and filtered, and the filter cake was washed with anhydrous ethanol. The filter cake was collected and the filtrate was disposed of as waste liquid. The filter cake was placed in a forced air drying oven at 50-60°C until the moisture content was less than 10%. The mixture was weighed to obtain 3.06 kg of 2,6-diamino-3-phenylazopyridine dihydrochloride (hereinafter referred to as IM1), with a yield of 94.5%.

[0091] 2. Production of crude phenazopyridine hydrochloride (preparation process as follows Figure 2 shown)

[0092] Add 17 times the weight of intermediate IM1 to a 100L reactor. Start stirring and slowly add IM1, stirring until uniform. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of ammonia. A yellow solid will precipitate and stirring will continue for 2 hours. Centrifuge, filter, and wash the filter cake with purified water. Determine the dryness of the wet product from the filter cake and weigh it. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM2) in the filter cake to be 2.0 kg.

[0093] Add 10 times the weight of dry IM2 (anhydrous ethanol) to a 50L reactor. Start stirring, then add wet IM2. Control the temperature at 35-45°C and stir until the solution is clear. Add activated carbon and continue stirring for 0.5 h. Remove the carbon, filter, and wash the filter cake with anhydrous ethanol. Collect the filtrate.

[0094] Transfer the filtrate to a 100 L reactor and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 h.

[0095] The mixture was centrifuged and filtered, and the filter cake was washed with anhydrous ethanol. The filter cake was placed in a forced air drying oven and dried at 55-60°C for 6 h, and then dried at 70-75°C until the moisture content was less than 5%. The mixture was weighed to obtain 2.15 kg of crude phenazopyridine hydrochloride (hereinafter referred to as IM3) with a yield of 85.3%.

[0096] 3. Purification of phenazopyridine hydrochloride (preparation process as follows Figure 3 shown)

[0097] Add 17 times the weight of intermediate IM3 to a 100L reactor. Start stirring and slowly add IM3, stirring until the solution is homogeneous. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of aqueous ammonia. A yellow solid will precipitate. Continue stirring for 2 hours. Centrifuge and filter, then wash the filter cake with purified water. Determine the dryness of the wet product from the filter cake and weigh it. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM4) in the filter cake, which is 1.8 kg.

[0098] Add anhydrous ethanol to a 50L reactor, start stirring, add the wet IM4 product, control the temperature at 35-45°C and stir until the solution is clear, add activated carbon, and continue stirring for 0.5h. Remove the carbon, filter, wash the filter cake with anhydrous ethanol, and collect the filtrate.

[0099] Transfer the filtrate to a 100L reactor (Class D clean area) and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 hours. Centrifuge, filter, and wash the filter cake with anhydrous ethanol.

[0100] The wet material was transferred to a drying oven and heated to 55-60°C within 60 minutes. After 12 hours, the temperature was raised to 70-75°C and dried until the moisture content was less than 1% and the ethanol content was less than 0.5%. The weight was weighed to obtain 1.85 kg of phenazopyridine hydrochloride with a yield of 92.1% and a HPLC purity of 100.0% (such as Figure 4 shown).

[0101] The yield calculation formula in steps 1 to 3 is shown in Table 1 below:

[0102] Table 1 Yield calculation formula

[0103]

[0104] The structure of the phenazopyridine hydrochloride raw material prepared in Example 1 was identified, and the NMR spectrum was shown in FIG. Figures 5 to 8 By comparing with the standard, it was identified as phenazopyridine hydrochloride.

[0105] Example 2 Preparation of Phenazopyridine Hydrochloride API

[0106] 1. Diazo coupling reaction (preparation process as follows Figure 1 shown)

[0107] The only difference from Example 1 is the crystallization process, and the other steps are the same. The crystallization process is as follows:

[0108] Heat to 25-30°C and stir for 0.5h; cool to 10-20°C and stir for 2h (crystallization).

[0109] The mixture was weighed to obtain 2.91 kg of 2,6-diamino-3-phenylazopyridine dihydrochloride (hereinafter referred to as IM1) with a yield of 89.7%.

[0110] 2. Production of crude phenazopyridine hydrochloride (preparation process as follows Figure 2 shown)

[0111] Add 17 times the weight of intermediate IM1 to a 100L reactor. Start stirring and slowly add IM1, stirring until uniform. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of ammonia. A yellow solid will precipitate and stirring will continue for 2 hours. Centrifuge, filter, and wash the filter cake with purified water. Determine the dryness of the wet product from the filter cake and weigh it. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM2) in the filter cake to be 1.87 kg.

[0112] Add 10 times the weight of dry IM2 (anhydrous ethanol) to a 50L reactor. Start stirring, then add wet IM2. Control the temperature at 35-45°C and stir until the solution is clear. Add activated carbon and continue stirring for 0.5 h. Remove the carbon, filter, and wash the filter cake with anhydrous ethanol. Collect the filtrate.

[0113] Transfer the filtrate to a 100 L reactor and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 h.

[0114] The mixture was centrifuged and filtered, and the filter cake was washed with anhydrous ethanol. The filter cake was placed in a forced air drying oven and dried at 55-60°C for 6 h, and then dried at 70-75°C until the moisture content was less than 5%. The mixture was weighed to obtain 2.0 kg of crude phenazopyridine hydrochloride (hereinafter referred to as IM3) with a yield of 83.4%.

[0115] 3. Purification of phenazopyridine hydrochloride (preparation process as follows Figure 3 shown)

[0116] Add 17 times the weight of intermediate IM3 to a 100L reactor. Start stirring and slowly add IM3, stirring until the solution is homogeneous. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of aqueous ammonia. A yellow solid will precipitate. Continue stirring for 2 hours. Centrifuge and filter, then wash the filter cake with purified water. Determine the dryness of the wet product and weigh the filter cake. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM4) in the filter cake to 1.71 kg.

[0117] Add anhydrous ethanol to a 50L reactor, start stirring, add the wet IM4 product, control the temperature at 35-45°C and stir until the solution is clear, add activated carbon, and continue stirring for 0.5h. Remove the carbon, filter, wash the filter cake with anhydrous ethanol, and collect the filtrate.

[0118] Transfer the filtrate to a 100L reactor (Class D clean area) and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 hours. Centrifuge, filter, and wash the filter cake with anhydrous ethanol.

[0119] The wet material was transferred to a drying oven and heated to 55-60°C within 60 minutes. After 12 hours, the temperature was raised to 70-75°C and dried until the moisture content was less than 1% and the ethanol content was less than 0.5%. The product was weighed to obtain 1.74 kg of phenazopyridine hydrochloride with an HPLC purity of 99.8% and a yield of 91%.

[0120] Example 3 Preparation of Phenazopyridine Hydrochloride API

[0121] 1. Diazo coupling reaction (preparation process as follows Figure 1 shown)

[0122] The only difference from Example 1 is the crystallization process, and the other steps are the same. The crystallization process is as follows:

[0123] Heat to 50-55°C and stir for 0.5h; cool to 10-20°C and stir for 2h (crystallization).

[0124] The mixture was weighed to obtain 2.98 kg of 2,6-diamino-3-phenylazopyridine dihydrochloride (hereinafter referred to as IM1) with a yield of 92%.

[0125] 2. Production of crude phenazopyridine hydrochloride (preparation process as follows Figure 2 shown)

[0126] Add 17 times the weight of intermediate IM1 to a 100L reactor. Start stirring and slowly add IM1, stirring until uniform. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of aqueous ammonia. A yellow solid will precipitate and stirring will continue for 2 hours. Centrifuge, filter, and wash the filter cake with purified water. Determine the dryness of the wet product from the filter cake and weigh the filter cake. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM2) in the filter cake to be 1.94 kg.

[0127] Add 10 times the weight of dry IM2 (anhydrous ethanol) to a 50L reactor. Start stirring, then add wet IM2. Control the temperature at 35-45°C and stir until the solution is clear. Add activated carbon and continue stirring for 0.5 h. Remove the carbon, filter, and wash the filter cake with anhydrous ethanol. Collect the filtrate.

[0128] Transfer the filtrate to a 100 L reactor and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 h.

[0129] The mixture was centrifuged and filtered, and the filter cake was washed with anhydrous ethanol. The filter cake was placed in a forced air drying oven and dried at 55-60°C for 6 h. It was then dried at 70-75°C until the moisture content was less than 5%. The mixture was weighed to obtain 2.07 kg of crude phenazopyridine hydrochloride (hereinafter referred to as IM3) with a yield of 84.3%.

[0130] 3. Purification of phenazopyridine hydrochloride (preparation process as follows Figure 3 shown)

[0131] Add 17 times the weight of intermediate IM3 to a 100L reactor. Start stirring and slowly add IM3, stirring until the solution is homogeneous. Keep the temperature below 25°C and adjust the pH of the solution to 8.0-9.0 by dropwise addition of aqueous ammonia. A yellow solid will precipitate. Continue stirring for 2 hours. Centrifuge and filter, then wash the filter cake with purified water. Determine the dryness of the wet product from the filter cake and weigh it. Based on the dryness, calculate the mass of 2,6-diamino-3-phenylazopyridine (hereinafter referred to as IM4) in the filter cake to be 1.76.

[0132] Add anhydrous ethanol to a 50L reactor, start stirring, add the wet IM4 product, control the temperature at 35-45°C and stir until the solution is clear, add activated carbon, and continue stirring for 0.5h. Remove the carbon, filter, wash the filter cake with anhydrous ethanol, and collect the filtrate.

[0133] Transfer the filtrate to a 100L reactor (Class D clean area) and start stirring. Keep the temperature below 30°C and add concentrated hydrochloric acid dropwise to slowly precipitate a purple-red precipitate. Adjust the pH of the solution to 3.0-4.0, stop adding dropwise, and continue stirring for 4 hours. Centrifuge, filter, and wash the filter cake with anhydrous ethanol.

[0134] The wet material was transferred to a drying oven and heated to 55-60°C within 60 minutes. After 12 hours, the temperature was raised to 70-75°C and dried until the moisture content was less than 1% and the ethanol content was less than 0.5%. The product was weighed to obtain 1.81 kg of phenazopyridine hydrochloride with an HPLC purity of 99.9% and a yield of 91.1%.

[0135] Example 4 Preparation of Phenazopyridine Hydrochloride Capsules (preparation process as shown in Figure 9 shown)

[0136] Using the phenazopyridine hydrochloride prepared in Example 1 as the raw material, the capsule formula is shown in Table 2:

[0137] Table 2 Capsule formula

[0138] Material Name 1000 tablets unit effect Phenazopyridine hydrochloride 100 g raw material talcum powder 122 g Auxiliary materials (lubricants) 3# gelatin hollow capsules 1000 grain Excipients

[0139] Weigh the prescribed amount of phenazopyridine hydrochloride and talc. Add these raw materials and excipients to a multi-directional mixer at 50 rpm and mix for 15 minutes. Add the mixed materials to a capsule filling machine for filling. Polish the filled capsules and, after passing inspection, package them for inner and outer packaging.

[0140] As can be seen from the above examples, the present invention significantly simplifies the synthesis steps and improves process stability by optimizing the conditions of the diazo coupling reaction, neutralization reaction, and salt formation reaction. At the same time, by precisely controlling the reaction parameters and post-processing process, the purity and yield of the product are effectively improved, production costs are reduced, and environmental pollution is reduced. The present invention improves the quality of the phenazopyridine hydrochloride API and ensures product stability and consistency.

[0141] Although the above embodiments provide a detailed description of the present invention, they are only part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on the embodiments of the present invention without creative work, and these embodiments all fall within the scope of protection of the present invention.

Claims

1. A method for preparing phenazopyridine hydrochloride, characterized in that: The following steps are involved: 1) dissolving 2,6-diamino-3-phenylazopyridine dihydrochloride in water, adding aqueous ammonia dropwise until the pH value is 8-9, and performing a first solid-liquid separation to obtain 2,6-diamino-3-phenylazopyridine; 2) dissolving the 2,6-diamino-3-phenylazopyridine in ethanol, adding hydrochloric acid dropwise until the pH value is 3-4, and performing a second solid-liquid separation to obtain a crude product of phenazopyridine hydrochloride; 3) dissolving the crude phenazopyridine hydrochloride in water and adding aqueous ammonia dropwise until the pH value is 8-9, performing a third solid-liquid separation, dissolving the obtained solid in ethanol and adding hydrochloric acid dropwise until the pH value is 3-4, and performing a fourth solid-liquid separation to obtain phenazopyridine hydrochloride; the purity of the phenazopyridine hydrochloride is ≥99.9%.

2. The preparation method according to claim 1, characterized in that The mass ratio of 2,6-diamino-3-phenylazopyridine dihydrochloride to water in step 1) is 1:15-20.

3. The preparation method according to claim 1 or 2, characterized in that The rate of adding the ammonia water dropwise is 45-55 mL / min, the mass fraction of the ammonia water is 26%, and the temperature of the reaction system is controlled to be lower than 25° C. during the process of adding the ammonia water dropwise.

4. The preparation method according to claim 1, characterized in that The rate of adding hydrochloric acid is 14-16 mL / min, the concentration of hydrochloric acid is 12 mol / L, and the temperature of the reaction system is controlled to be lower than 30° C. during the process of adding hydrochloric acid.

5. The preparation method according to claim 1 or 4, characterized in that After dissolving in ethanol in step 2), the method further comprises: decolorizing with activated carbon, wherein the mass ratio of activated carbon to 2,6-diamino-3-phenylazopyridine in the decolorizing with activated carbon is 0.04 to 0.06:

1.

6. The preparation method according to claim 1, characterized in that The preparation method of the 2,6-diamino-3-phenylazopyridine dihydrochloride comprises the following steps: After mixing aniline and hydrochloric acid solution, an aqueous solution of sodium nitrite is added dropwise to carry out diazotization reaction, and then a hydrochloric acid solution of 2,6-diaminopyridine is added dropwise to the obtained diazotization reaction solution to carry out coupling reaction to obtain the 2,6-diamino-3-phenylazopyridine dihydrochloride.

7. The preparation method according to claim 6, characterized in that After the coupling reaction, the method further comprises: crystallizing the obtained coupling reaction liquid, performing solid-liquid separation on the crystallization system, and washing and drying the obtained solid; The crystallization comprises: heating the coupling reaction liquid to a first temperature for a first stirring, and then cooling it to a second temperature for a second stirring; the first temperature is 35-45° C., the first stirring time is 0.5-1 hour, the second temperature is 10-20° C., and the second stirring time is 1.5-2.5 hours.

8. The preparation method according to claim 6, characterized in that The mass ratio of the aniline to the sodium nitrite is 1:0.7-0.

9.

9. The preparation method according to claim 6, characterized in that The mass ratio of the aniline to the 2,6-diaminopyridine is 1:1 to 1.

3.

10. A phenazopyridine hydrochloride capsule preparation, characterized in that: The invention comprises a capsule shell, talc powder filled in the capsule shell and phenazopyridine hydrochloride obtained by the preparation method according to any one of claims 1 to 9, wherein the purity of the phenazopyridine hydrochloride is ≥99.9%.

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