Preparation method of high-purity minoxidil

Abstract

The invention discloses a preparation method of high-purity minoxidil, and relates to the field of medicine synthesis. According to the method, guanidine carbonate and ethyl cyanoacetate are taken as initial raw materials, and high-purity minoxidil is obtained through alkaline condensation reaction, sulfonylation activation reaction, mild oxidation reaction, substitution reaction and refining. The method is low in raw material price, simple in process, safe and environmentally friendly, the prepared minoxidil product is high in purity, the content of total impurities and single impurities in the product reaches the standard, especially the content of several key impurities in minoxidil can be well controlled, and the method can be used as an industrial preparation method for large-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, and in particular to a method for preparing high-purity minoxidil. Background Art

[0002] There are many ways and drugs used to treat hair loss. Among them, topical medications are simple and easy to use, have definite effects, do not have the side effects of oral anti-androgen drugs, are cheaper than oral and surgical treatments, and are easy for patients to accept. Minoxidil is a pyrimidine derivative and is the first topical drug approved by the U.S. Food and Drug Administration for the treatment of hair loss. As a non-hormonal drug, long-term topical use of this drug is highly safe and will not produce serious side effects. The Chinese chemical name of minoxidil is 6-(1-piperidinyl)-2,4-pyrimidinediamine-3-oxide, and the English chemical name is: 6-(1-Piperidinyl)-2,4-pyrimidinediamine 3-oxide. Its chemical structure is as follows:

[0003]

[0004] In the industrial production of minoxidil, due to differences in production processes, several key known impurities are present in the product and are difficult to completely remove, seriously affecting the product quality. They are: Impurity A, Impurity B, and Impurity E, whose structural formulas are as follows:

[0005]

[0006] In addition, there are potential impurities C, D and F, whose structural formulas are as follows:

[0007]

[0008] According to the existing technical literature on minoxidil synthesis, the synthesis of minoxidil can be mainly divided into the following methods:

[0009] Method 1: CN107235919 discloses using 2,4-diamino-6-chloro-pyrimidine as a raw material, oxidizing it with m-chloroperbenzoic acid to produce 2,4-diamino-6-chloro-pyrimidine-1-oxide, which is then directly condensed with piperidine to produce crude minoxidil, which is then purified in isopropyl alcohol to produce minoxidil. The process route is as follows:

[0010]

[0011] Method 2: CN 107129470 discloses using 2,4-diamino-6-chloro-pyrimidine as a raw material, oxidizing it with peroxybenzoic acid at low temperature to produce 2,4-diamino-6-chloro-pyrimidine-1-oxide, then directly condensing it with piperidine in hexahydropyridine to produce crude minoxidil. Minoxidil is then refined with ethanol-water for the first time and methanol for the second time, or refined with acetonitrile-methanol-water for the first time and acetonitrile for the second time. The process route is as follows:

[0012]

[0013] Method 3: The content disclosed in PL 165362 is similar to Methods 1 and 2. Both methods use 2,4-diamino-6-chloro-pyrimidine as the raw material, except that 2,4-diamino-6-chloro-pyrimidine-1-oxide is oxidized with magnesium monoperoxyphthalate hexahydrate and then directly condensed with piperidine to produce crude minoxidil. The process route is as follows:

[0014]

[0015] Method 4: FR2604707 and US4866174 disclose using 2,6-diaminopyrimidine-4-p-toluenesulfonate as a raw material, oxidizing it with magnesium monoperoxyphthalate hexahydrate to obtain 2,6-diaminopyrimidine-4-p-toluenesulfonate-1-oxide, and then directly condensing it with piperidine to obtain crude minoxidil. The process route is as follows:

[0016]

[0017] Method 5: Patent documents, DE1620649, US3382247, US3461461, US3644364, DAS214877, collectively disclose the following technical routes:

[0018]

[0019] None of the aforementioned synthesis methods address the control of minoxidil impurities A–F. Today, generic drug consistency evaluations place extremely stringent demands on raw materials, posing significant challenges to the environmental impact assessment of industrialized raw material production. Therefore, developing high-purity synthesis methods to reduce or eliminate impurities A–F in minoxidil products is of great value. Summary of the Invention

[0020] Based on the technical problems existing in the background technology, the present invention proposes a method for preparing high-purity minoxidil with high yield. The obtained minoxidil has high purity, wherein impurities A, B, C, D and F are not detected, and only a very small amount of impurity E is present. The method can be used as an industrial preparation method for large-scale production.

[0021] The present invention provides a method for preparing high-purity minoxidil, comprising the following steps:

[0022] a. Under nitrogen protection, in the presence of sodium ethoxide, guanidine carbonate and ethyl cyanoacetate are heated under reflux in a solvent for condensation reaction to obtain intermediate IV;

[0023] b. In the presence of an acid-binding agent, reacting the intermediate IV with p-toluenesulfonic acid chloride in a solvent for sulfonylation activation to obtain the intermediate III;

[0024] c. Under the action of an oxidizing agent, magnesium monoperoxyphthalate hexahydrate, intermediate III undergoes an oxidation reaction in a solvent to obtain intermediate II;

[0025] d. Heating intermediate II with piperidine in an alcohol solvent to carry out a substitution reaction to obtain crude minoxidil;

[0026] e. Purifying the crude minoxidil with activated carbon and a mixed solvent of alcohol and water to obtain high-purity minoxidil, the structural formula of which is shown in Formula I.

[0027] The synthetic route of the present invention is as follows:

[0028]

[0029] In step a of the present invention, guanidine carbonate is used as a synthetic raw material, and the yield reaches 95% to 98%. Compared with guanidine hydrochloride and guanidine nitrate, the yield is unexpectedly improved. In addition, the solvent ethanol used and the ethanol generated during the reaction can be directly reused after being recovered under reduced pressure at 40 to 45° C., and the recovery rate of ethanol is above 90%. The reaction by-product carbonic acid does not interfere with the recovery.

[0030] In the prior art, minoxidil is produced by condensing 2,4-diamino-6-chloro-pyrimidine prepared by the chlorination method with piperidine. However, during the condensation with piperidine, the high reaction temperature due to poor activity produces a series of impurities that are difficult to remove. The impurities produced include impurity A (incomplete reaction), impurity B (high-temperature deoxidation impurity), impurity E (high-temperature deoxidation impurity), and impurity F (high-temperature dechlorination impurity). The method of the present invention, steps b and c, first synthesizes intermediate III, then synthesizes intermediate II, and then reacts intermediate II with piperidine for a substitution reaction. This method has high reaction activity and low reaction temperature, avoiding the generation of these impurities.

[0031] In the N-oxidation process of pyrimidine, the currently recorded methods include: the m-chloroperbenzoic acid method, the perbenzoic acid method, the magnesium monoperoxyphthalate hexahydrate method, and the hydrogen peroxide-urea-phthalic anhydride method. In step c, the present invention creatively selects the magnesium monoperoxyphthalate hexahydrate method to carry out oxidation under mild conditions in an alcohol-water system, thereby avoiding the generation of a series of side reactions on the amino group and the formation of related impurities.

[0032] In the prior art, the method of directly condensing intermediate II with piperidine will lead to the production of a large amount of impurity E. In the present invention, in step d, an alcohol solvent with excellent solubility for intermediate II is used as a reaction medium, and a substitution reaction is carried out in the reaction medium, which significantly reduces the content of impurity E. In addition, this method does not require the use of excessive piperidine, greatly reducing the difficulty of post-processing.

[0033] In summary, the present invention uses guanidine carbonate and ethyl cyanoacetate as starting materials, and obtains high-purity minoxidil through condensation reaction, sulfonylation activation reaction, mild oxidation reaction, substitution reaction, and purification. Through the above reaction route and optimization of key process parameters, minoxidil is obtained with high yield and high purity, wherein impurities A, B, C, D, and F are not detected, and only a very small amount of impurity E is found. The method can be used as an industrial method for large-scale production.

[0034] Preferably, in step a, the solvent is ethanol; in step a, the heating reflux time is 2 to 3 hours; in step a, the molar ratio of guanidine carbonate to ethyl cyanoacetate is 1:0.9 to 1.1; in step a, the molar ratio of guanidine carbonate to sodium ethoxide is 1:1 to 1.5.

[0035] Preferably, in step a, after the reaction is completed, the method further comprises: concentrating the obtained reaction solution to remove the solvent, then adding water, adjusting the pH to 6.5-7.0, cooling to 0-5°C, standing for 2-3 hours, then filtering, washing the obtained solid with water, and drying; wherein the reagent for adjusting the pH is an aqueous solution of acetic acid or an aqueous solution of phosphoric acid with a concentration of 20%-30%.

[0036] Preferably, in step b, the solvent is any one of acetonitrile, N-methylpyrrolidone, and DMF, and the acid binding agent is sodium hydroxide; in step b, the reaction process is: first react at 0-5°C for 0.5-1h, then warm to room temperature and react for 4-6h; in step b, the molar ratio of intermediate IV to p-toluenesulfonic acid chloride is 1:0.9-1.1; in step b, the molar ratio of intermediate IV to acid binding agent is 1:0.9-1.1. In step b, when using an acid binding agent, an acid binding agent solution with a concentration of 15-25% can be first prepared using ethanol or water.

[0037] Preferably, in step b, after the reaction is completed, the method further comprises: adding water to the reaction solution, adjusting the pH to 6.5-7.0, standing for crystallization, filtering, washing the obtained solid with water, and drying; wherein the reagent for adjusting the pH is an aqueous solution of acetic acid with a concentration of 20%-30%.

[0038] Preferably, in step c, the solvent is a mixed solvent of methanol and water or a mixed solvent of ethanol and water; in step c, the reaction temperature is 5-10° C. and the reaction time is 4-6 hours; in step c, the molar ratio of intermediate III to magnesium monoperoxyphthalate hexahydrate is 1:1.5-3.

[0039] Preferably, in step c, the solvent is a mixed solvent consisting of methanol and water in a volume ratio of 1:1 to 4, or a mixed solvent consisting of ethanol and water in a volume ratio of 1:1 to 4.

[0040] Preferably, in step c, after the reaction is completed, the process further comprises: adding water to the reaction solution, stirring at 15-20° C. for 1-2 hours, filtering, washing the obtained solid with water, then with ethanol aqueous solution, and drying.

[0041] Preferably, in step d, the alcohol solvent is any one of propylene glycol, ethylene glycol, and glycerol; in step d, the heating reaction temperature is 60-65° C. and the time is 2-4 hours; in step d, the molar ratio of intermediate II to piperidine is 1:1-1.2.

[0042] Preferably, in step d, after the reaction is completed, the process further comprises: adding water to the reaction solution under insulation conditions, adjusting the pH to 7.0-7.5, stirring for 1-2 hours, then cooling to 15-25° C., stirring for 2-3 hours, filtering, washing the obtained solid with water, and drying; wherein the reagent for adjusting the pH is an aqueous sodium hydroxide solution.

[0043] Preferably, in step e, the specific step of refining the crude minoxidil with activated carbon and an alcohol-water mixed solvent includes: mixing the crude minoxidil with the alcohol-water mixed solvent, adding activated carbon, heating and refluxing for 20 to 30 minutes, filtering while hot, cooling the obtained filtrate to 0 to 5° C., keeping warm for 2 to 4 hours, and then filtering, washing the obtained solid with an alcohol-water mixed solvent, and drying; the alcohol-water mixed solvent is obtained by mixing alcohol and water in a volume ratio of 1:1 to 5, wherein the alcohol is ethylene glycol or propylene glycol.

[0044] The beneficial effects of the present invention are as follows:

[0045] a) Using guanidine carbonate and ethyl cyanoacetate as starting materials, the raw materials are cheap and easily available;

[0046] b) The process is simple and efficient, involves little solvent with extremely low toxicity, is easy to recycle, produces very little three wastes, and is safe and environmentally friendly;

[0047] c) The minoxidil product prepared by the present invention has a high yield and high purity, and only one refining step is required to achieve a purity of ≥99.8%. As for total impurities, the total impurity content is less than 0.1%, which is much lower than the standards of ≤1% in the United States Pharmacopoeia, ≤1% in the Chinese Pharmacopoeia, and ≤0.3% in the European Pharmacopoeia. For individual known impurities, the European Pharmacopoeia standard stipulates that impurity E is ≤0.2%, impurity B is ≤0.15%, and the maximum unknown single impurity is ≤0.1%. The product of the present invention contains only a very small amount of impurity E, and the content of impurity E is ≤0.1%. Impurities A, impurity B, impurity C, impurity D, and impurity F are not detected. BRIEF DESCRIPTION OF THE DRAWINGS

[0048] Figure 1 The figure is a HPLC chart showing the specificity of the related substances of minoxidil detected by the present invention.

[0049] Figure 2 HPLC chart of high-purity minoxidil prepared in Example 1 of the present invention.

[0050] Figure 3 This is the HPLC chart of commercially available minoxidil. DETAILED DESCRIPTION

[0051] The technical solution of the present invention is described in detail below through specific embodiments.

[0052] Example 1

[0053] a. Preparation of Intermediate IV:

[0054] Under N2 atmosphere, 540g guanidine carbonate (4.5mol), 3.5L ethanol, 340g sodium ethoxide (5.0mol) were mixed and heated to 45-50°C, kept warm and stirred for 30min, and then 508g ethyl cyanoacetate (4.5mol) was added dropwise. After the addition was complete, the temperature was raised to reflux and the reaction was allowed to react for 2h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol: chloroform: ethyl acetate = 4:5:1). After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure at 40°C, the ethanol was recovered and reused, the residue was cooled to room temperature, 5L water was added, the pH was adjusted to 6.5-7.0 with 25% aqueous acetic acid solution, cooled to 4°C, allowed to stand for 2h, filtered, and the obtained solid was washed twice with water and dried at 90°C for 3h to a moisture content of <1% to obtain 551g of off-white powdery solid intermediate IV with a yield of 97.1% and mp: 285-287°C.

[0055] b. Preparation of Intermediate III:

[0056] 819g of p-toluenesulfonic acid chloride (4.29mol), 300mL of acetonitrile, and 858mL of a 20% aqueous sodium hydroxide solution were mixed to obtain a p-toluenesulfonic acid chloride solution; 540g of intermediate IV (4.28mol) was added to 5.4L of acetonitrile, cooled to 4°C, and then the p-toluenesulfonic acid chloride solution was added dropwise. After the addition was complete, the mixture was stirred at 4°C for 0.5h, then warmed to room temperature and stirred for 4h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of ethyl acetate: petroleum ether = 1:4). After completion of the reaction, 10L of water was added to the reaction solution, and the pH was adjusted to 6.5-7.0 with a 25% aqueous acetic acid solution. The mixture was allowed to stand for crystallization for 2h and filtered. The resulting solid was washed three times with water and dried with air at 60°C for 5h until the moisture content was <2% to obtain 1091g of intermediate III as a light yellow powder with a yield of 90.8%;

[0057] c. Preparation of Intermediate II

[0058] 1065g of intermediate III (3.8mol), 15L of ethanol and 15L of water were mixed and stirred at 8°C for 30min, then 3760g of magnesium monoperoxyphthalate hexahydrate (7.6mol) was added and reacted at 8°C for 5h. The reaction endpoint was identified by HPLC and the reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol:chloroform:ethyl acetate = 4:5:1). When the content of intermediate III in the reaction solution was ≤0.5wt%, 15L of water was added and stirred at 18°C for 1h. The mixture was filtered and the obtained solid was washed three times with water and then washed once with a 20% ethanol aqueous solution. The mixture was dried under forced air at 60°C for 4h until the moisture content was <1% to obtain 1047g of off-white powdery solid intermediate II with a yield of 93.0% and mp: 127-129°C.

[0059] d. Preparation of Minoxidil

[0060] 1037g of intermediate II (3.5mol), 5L of propylene glycol, and 328g of piperidine (3.85mol) were mixed and heated to 60°C. The mixture was stirred and reacted for 3h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol:chloroform:ethyl acetate = 4:5:1). After the reaction was completed, 10L of water was added to the reaction solution while keeping warm. The pH was adjusted to 7.0-7.5 with a 20% aqueous sodium hydroxide solution. The mixture was stirred and kept warm for 1h. The temperature was then lowered to 20°C, stirred and kept warm for 2h, and filtered. The resulting solid was washed twice with water and dried at 95°C with air for 3h to obtain 643.7g of crude minoxidil as a white powder with a yield of 88.0%, mp: 259-261°C, and HPLC purity of 99.1%.

[0061] e. Refining of Minoxidil:

[0062] 640 g of crude minoxidil, 1920 mL of propylene glycol, and 1920 mL of water were mixed, 6 g of activated carbon was added, and the mixture was heated under reflux for 20 min. The mixture was filtered while hot, and the filtrate was cooled to 4°C, kept at 4°C for purification for 3 h, and filtered. The obtained solid was washed with an aqueous solution of propylene glycol (obtained by mixing propylene glycol and water in a volume ratio of 1:1), and dried with air at 95°C for 3 h to obtain 601 g of white crystalline minoxidil with a yield of 93.8%, mp: 257-259°C, and HPLC purity of 99.8%.

[0063] Example 2

[0064] a. Preparation of Intermediate IV:

[0065] Under N2 atmosphere, 540g guanidine carbonate (4.5mol), 4L ethanol, 408g sodium ethoxide (6.0mol) were mixed, heated to 45°C, kept warm and stirred for 30min, and then 542g ethyl cyanoacetate (4.8mol) was added dropwise. After the addition was complete, the temperature was raised to reflux and the reaction was allowed to react for 3h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol: chloroform: ethyl acetate = 4:5:1). After the reaction was complete, the reaction solution was concentrated to dryness under reduced pressure at 45°C, the ethanol was recovered and reused, the residue was cooled to room temperature, 6L water was added, the pH was adjusted to 6.5-7.0 with 30% aqueous acetic acid solution, cooled to 5°C, allowed to stand for 3h, filtered, and the obtained solid was washed twice with water and dried at 90°C for 3h to a moisture content of <1% to obtain 542g of off-white powdery solid intermediate IV with a yield of 95.5%, mp: 285-287°C;

[0066] b. Preparation of Intermediate III:

[0067] 858g of p-toluenesulfonic acid chloride (4.5mol), 400mL of acetonitrile, and 900mL of a 20% aqueous sodium hydroxide solution were mixed to obtain a p-toluenesulfonic acid chloride solution; 540g of intermediate IV (4.28mol) was added to 5.5L of acetonitrile, cooled to 5°C, and then the p-toluenesulfonic acid chloride solution was added dropwise. After the addition was complete, the mixture was stirred at 5°C for 1h, then warmed to room temperature and stirred for 6h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of ethyl acetate: petroleum ether = 1:4). After completion of the reaction, 12L of water was added to the reaction solution, and the pH was adjusted to 6.5-7.0 with a 20% aqueous acetic acid solution. The mixture was allowed to stand for crystallization for 2h and filtered. The resulting solid was washed three times with water and dried with air at 60°C for 5h until the moisture content was <2% to obtain 1088g of intermediate III as a light yellow powder with a yield of 90.6%;

[0068] c. Preparation of Intermediate II

[0069] 1065g of intermediate III (3.8mol), 15L of ethanol and 25L of water were mixed and stirred at 5°C for 30min, followed by the addition of 4700g of magnesium monoperoxyphthalate hexahydrate (9.5mol). The mixture was reacted at 5°C for 6h. The reaction endpoint was identified by HPLC and the reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol:chloroform:ethyl acetate = 4:5:1). When the content of intermediate III in the reaction solution was ≤0.5wt%, 20L of water was added and the mixture was stirred at 20°C for 2h. The mixture was filtered and the obtained solid was washed three times with water and then once with a 20% ethanol aqueous solution. The mixture was dried under forced air at 60°C for 4h until the moisture content was <1%, to give 1066g of off-white powdery solid intermediate II with a yield of 94.7% and mp: 127-129°C.

[0070] d. Preparation of Minoxidil

[0071] 1037g of intermediate II (3.5mol), 6L of ethylene glycol, and 336g of piperidine (3.85mol) were mixed and heated to 65°C. The mixture was stirred and kept warm for 4h. The reaction progress was monitored by TLC (TLC conditions were a volume ratio of methanol:chloroform:ethyl acetate = 4:5:1). After the reaction was completed, 10L of water was added to the reaction solution while keeping warm. The pH was adjusted to 7.0-7.5 with a 20% aqueous sodium hydroxide solution. The mixture was stirred and kept warm for 2h, then cooled to 25°C, stirred and kept warm for 3h, filtered, and the obtained solid was washed twice with water and dried at 95°C with air for 3h to obtain 640.5g of crude minoxidil as a white powder with a yield of 87.6%, mp: 259-261°C, and HPLC purity of 99.2%.

[0072] e. Refining of Minoxidil:

[0073] Mix 640 g of crude minoxidil, 2300 mL of ethylene glycol, and 1540 mL of water, add 8 g of activated carbon, heat under reflux for 30 min, filter while hot, cool the filtrate to 5°C, keep it at 5°C for 4 h, filter, and wash the resulting solid with an ethylene glycol aqueous solution (obtained by mixing ethylene glycol and water in a volume ratio of 1:3) and air-dry at 95°C for 3 h to obtain 604 g of white crystalline minoxidil with a yield of 94.4%, mp: 257-259°C, and HPLC purity of 99.8%.

[0074] Test example

[0075] Impurity analysis was performed on the minoxidil prepared in Example 1 of the present invention and commercially available minoxidil, wherein:

[0076] Impurity A to F reference substances were all commercially available standards, and each was prepared into a 0.1 mg / ml solution in methanol for use as the reference solution for each impurity;

[0077] System suitability solution: Take 23 mg of commercially available minoxidil hydrochloride standard and place it in a 100 ml volumetric flask. Add 20 ml of methanol and dissolve it. Then add 1 ml of each of the above 6 impurity reference solutions, mix well, and dilute to 100 ml with methanol.

[0078] Detection method: HPLC (CP2015 General Chapter 0512); Chromatographic conditions: Column: C18 (25 cm × 4.6 mm, 5 μm); Detector: UV detector (254 nm for 3 minutes, then changed to 318 nm); Column temperature: 25°C; Mobile phase A: water-formic acid (200:1), adjusted to pH 8.5 with 28% ammonia; Mobile phase B: acetonitrile-mobile phase A (4:1); Injection volume: 20 μl; Flow rate: 1.0 ml / min; Gradient conditions are shown in Table 1:

[0079] Table 1

[0080]

[0081] The system suitability solution prepared above was subjected to HPLC detection using the above method to obtain a specific HPLC map of the related substances of minoxidil, as shown in FIG. Figure 1 As shown. Figure 1 It can be seen that impurity C, impurity E, impurity A, impurity B, impurity D, minoxidil and impurity F appear in sequence with high separation, indicating that this chromatographic condition is suitable for the detection of impurities A to F in minoxidil.

[0082] The above method was used to perform HPLC detection on the high-purity minoxidil prepared in Example 1 of the present invention and commercially available minoxidil (methanol was used to prepare a 1 mg / mL test solution during the detection), and the HPLC graphs of the high-purity minoxidil prepared in Example 1 of the present invention and commercially available minoxidil were obtained, as shown in FIG. Figure 2 、 Figure 3 As shown. Figure 2 、 3 By comparison, it can be seen that the minoxidil product prepared by the method of the present invention contains only a very small amount of impurity E, and impurities A, B, C, D and F are not detected; while the amount of impurity E in the commercially available minoxidil is significantly higher than that in the embodiment, and the detected amount is about 3 times that of the embodiment.

[0083] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. A method for preparing high-purity minoxidil, characterized in that: The following steps are involved: a. Under nitrogen protection, in the presence of sodium ethoxide, guanidine carbonate and ethyl cyanoacetate are heated under reflux in a solvent for condensation reaction to obtain intermediate IV; b. In the presence of an acid-binding agent, reacting the intermediate IV with p-toluenesulfonic acid chloride in a solvent for sulfonylation activation to obtain the intermediate III; c. Under the action of an oxidizing agent, magnesium monoperoxyphthalate hexahydrate, intermediate III undergoes an oxidation reaction in a solvent to obtain intermediate II; d. Heating intermediate II with piperidine in an alcohol solvent to carry out a substitution reaction to obtain crude minoxidil; e. Refining the crude minoxidil with activated carbon and a mixed solvent of alcohol and water to obtain high-purity minoxidil.

2. The method for preparing high-purity minoxidil according to claim 1, wherein In step a, the solvent is ethanol; in step a, the heating reflux time is 2 to 3 hours; in step a, the molar ratio of guanidine carbonate to ethyl cyanoacetate is 1:0.9 to 1.1; in step a, the molar ratio of guanidine carbonate to sodium ethoxide is 1:1 to 1.

5.

3. The method for preparing high-purity minoxidil according to claim 1, wherein In step a, after the reaction is completed, the method further comprises: concentrating the obtained reaction solution to remove the solvent, then adding water, adjusting the pH to 6.5-7.0, cooling to 0-5° C., standing for 2-3 hours, then filtering, washing the obtained solid with water, and drying; wherein the reagent for adjusting the pH is an aqueous solution of acetic acid or an aqueous solution of phosphoric acid with a concentration of 20%-30%.

4. The method for preparing high-purity minoxidil according to claim 1, wherein In step b, the solvent is any one of acetonitrile, N-methylpyrrolidone, and DMF, and the acid-binding agent is sodium hydroxide; in step b, the reaction process is: first reacting at 0-5° C. for 0.5-1 h, then heating to room temperature and reacting for 4-6 h; in step b, the molar ratio of intermediate IV to p-toluenesulfonic acid chloride is 1:0.9-1.1; in step b, the molar ratio of intermediate IV to the acid-binding agent is 1:0.9-1.

1.

5. The method for preparing high-purity minoxidil according to claim 1, wherein In step b, after the reaction is completed, the method further comprises: adding water to the reaction solution, adjusting the pH to 6.5-7.0, standing the reaction solution for crystallization, filtering the reaction solution, washing the obtained solid with water, and drying the solid; wherein the pH adjusting agent is an aqueous solution of acetic acid with a concentration of 20%-30%.

6. The method for preparing high-purity minoxidil according to claim 1, wherein In step c, the solvent is a mixed solvent of methanol and water or a mixed solvent of ethanol and water; in step c, the reaction temperature is 5-10° C., and the reaction time is 4-6 hours; in step c, the molar ratio of intermediate III to magnesium monoperoxyphthalate hexahydrate is 1:1.5-3.

7. The method for preparing high-purity minoxidil according to claim 1, wherein In step c, after the reaction is completed, the method further comprises: adding water to the reaction solution, stirring at 15-20° C. for 1-2 hours, filtering, washing the obtained solid with water, then with ethanol aqueous solution, and drying.

8. The method for preparing high-purity minoxidil according to claim 1, wherein In step d, the alcohol solvent is any one of propylene glycol, ethylene glycol, and glycerol; in step d, the heating reaction temperature is 60-65° C. and the time is 2-4 hours; in step d, the molar ratio of intermediate II to piperidine is 1:1-1.

2.

9. The method for preparing high-purity minoxidil according to claim 1, wherein In step d, after the reaction is completed, the method further comprises: adding water to the reaction solution under insulation conditions, adjusting the pH to 7.0-7.5, stirring for 1-2 hours, then cooling to 15-25° C., stirring for 2-3 hours, filtering, washing the obtained solid with water, and drying; wherein the reagent for adjusting the pH is an aqueous sodium hydroxide solution.

10. The method for preparing high-purity minoxidil according to claim 1, wherein In step e, the specific steps of refining the crude minoxidil product with activated carbon and an alcohol-water mixed solvent include: mixing the crude minoxidil product with the alcohol-water mixed solvent, adding activated carbon, heating and refluxing for 20 to 30 minutes, filtering while hot, cooling the obtained filtrate to 0 to 5° C., keeping the temperature for 2 to 4 hours, and then filtering, washing the obtained solid with an alcohol-water mixed solvent, and drying; the alcohol-water mixed solvent is obtained by mixing alcohol and water in a volume ratio of 1:1 to 5, wherein the alcohol is ethylene glycol or propylene glycol.

Images