Preparation method of minoxidil

Abstract

The invention belongs to the technical field of medicine synthesis processes, and particularly relates to a preparation method of high-yield and high-purity minoxidil. According to the invention, 2, 4-diamino-6-chloropyrimidine is used as a raw material, and a brand new oxidation system, namely an ammonium persulfate / hydrogen peroxide mixed system, is used for preparing the minoxidil intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide. A water / alcohol mixed solvent is further used as a reaction solvent, the 2, 6-diamino-4-chloropyrimidine-1-oxide and piperidine react to prepare a minoxidil crude product, the minoxidil crude product and acid generate minoxidil salt in the solvent, and a minoxidil finished product is prepared under the action of alkali. The oxidation system adopted by the method is mild in reaction condition, the yield of three wastes in the process is small, the process production period is short, the process operability is good, the safety is good, and minoxidil prepared by using a specific reaction solvent and a purification method is high in yield and purity.

Description

Technical Field

[0001] The invention relates to the field of pharmaceutical chemistry, and in particular to a method for preparing high-purity and high-yield minoxidil. Background Art

[0002] Minoxidil is a potassium channel opener developed in the 1960s. It has a strong vasodilating effect and was mainly used to treat severe and refractory hypertension in the early days. However, during clinical use, it was found that patients who took the drug for more than one month would have varying degrees of hair growth and thickening, so it was used in the clinical treatment of hair loss. In 1996, the U.S. Food and Drug Administration (FDA) first approved the minoxidil lotion produced by Upjohn for the treatment of alopecia areata and androgenic alopecia, and it was subsequently marketed in Europe and the United States.

[0003] For the preparation of minoxidil, 2,4-diamino-6-chloropyrimidine is generally used as the raw material, which is then oxidized and reacted with piperidine to produce minoxidil. Although the mainstream reaction routes and intermediates are the same, the oxidation conditions, piperidine substitution reaction conditions and finished product refining conditions are very different. Different synthetic routes and process safety, operability and cost competitiveness are also very different.

[0004] Under the existing technology, although there are many methods for preparing minoxidil, the mainstream preparation route of the oxidation step uses oxidants such as m-chloroperoxybenzoic acid and peroxybenzoic acid. Although m-chloroperoxybenzoic acid is a common chemical on the market, it is relatively expensive, and the minoxidil produced is not cost-competitive. Benzoic acid peroxide is a controlled explosive chemical with a low melting point and potential explosiveness. When evaporating the solvent, it must be inspected for peroxides, which is a great challenge to safe production.

[0005] Chinese patent documents CN107235919 and CN113979952 report a method for preparing minoxidil using meta-chloroperbenzoic acid as an oxidant, wherein 2,4-diamino-6-chloropyrimidine is used as a raw material, and 2,6-diamino-4-chloropyrimidine-1-oxide is obtained after oxidation with meta-chloroperbenzoic acid. 2,6-diamino-4-chloropyrimidine-1-oxide is reacted with piperidine under alkali catalysis to produce a crude minoxidil product, and the crude minoxidil product is recrystallized to obtain minoxidil.

[0006]

[0007] This synthetic route uses meta-chloroperbenzoic acid as an oxidant. Meta-chloroperbenzoic acid is a commercially available explosive chemical, but it is expensive, so the minoxidil prepared has no price advantage and is difficult to produce on an industrial scale.

[0008] CN107129470A reports a method for preparing minoxidil using benzoic acid peroxide as an oxidant. The method uses 2,4-diamino-6-chloropyrimidine as a raw material, and obtains 2,6-diamino-4-chloropyrimidine-1-oxide after oxidation with benzoic acid peroxide. The 2,6-diamino-4-chloropyrimidine-1-oxide reacts with piperidine in potassium carbonate / dioxane or in potassium hydroxide / acetonitrile to produce a crude minoxidil product. The crude minoxidil product has a low purity and needs to be recrystallized twice to obtain minoxidil.

[0009]

[0010] This synthetic route uses benzoic acid peroxide as an oxidant, and the reaction conditions are harsh. In addition, benzoic acid peroxide is a dangerous and explosive chemical that is difficult to obtain commercially. Self-made benzoic acid peroxide has a greater safety risk, and scaled-up production poses a greater safety hazard.

[0011] CN115572265A reports a green synthesis process for high-purity minoxidil. The specific preparation method is: using 2,4-diamino-6-chloropyrimidine as the starting material, an oxidation reaction is performed to obtain a crude 2,6-diamino-4-chloropyrimidine-1-oxide product, which is then purified by water and triethylamine to obtain a fine 2,6-diamino-4-chloropyrimidine-1-oxide product, the intermediate is condensed with piperidine in an aqueous solution in the presence of an inorganic base to obtain a crude minoxidil product, and finally a water-ethanol decolorization and crystallization is performed to obtain a finished minoxidil product.

[0012]

[0013] The oxidant perbenzoic acid reported in the patent document is obtained by oxidative hydrolysis of benzoyl peroxide. The reaction process is to use hydrogen peroxide to oxidize benzoyl peroxide under alkaline conditions to obtain sodium perbenzoate, and then extract it with sulfuric acid to obtain an ethyl acetate solution of benzoic acid peroxide. Benzoic acid peroxide requires multiple steps to be prepared. The output of three wastes in the process is large, the process production cycle is long, and the process operability is poor; benzoic acid peroxide is a controlled high-risk reagent that is easy to make explosives. The preparation conditions such as heating and vigorous stirring in the preparation process of benzoic acid peroxide have great safety hazards, and the process safety is poor.

[0014] The above-mentioned prior art and literature all adopt the recrystallization method to purify the minoxidil finished product, but during the preparation process of the recrystallization scheme, the precipitation temperature of minoxidil is too high, and a very high temperature needs to be maintained in the decolorization stage after dissolution for hot filtration, which has poor operability and there are great safety risks in scaled-up production.

[0015] In summary, most of the existing minoxidil preparation technologies have problems such as poor reaction safety, high material cost, long reaction time, low yield, large output of three wastes, poor product properties, and high impurity content in finished products. These problems have always been the key technical issues restricting the scale-up of minoxidil production. Summary of the invention

[0016] In order to solve the problems of the prior art, the present invention adopts a new oxidation system, i.e., a mixed system of ammonium persulfate / hydrogen peroxide, in the process of preparing the minoxidil intermediate 2,6-diamino-4-chloropyrimidine-1-oxide. The oxidation system has mild reaction conditions, low output of three wastes in the process, short process production cycle, good process operability and good safety. Both ammonium persulfate and hydrogen peroxide are conventional commercially available chemical reagents, low in price and easy to purchase. Further, a crude minoxidil product is obtained by reacting 2,6-diamino-4-chloropyrimidine-1-oxide with piperidine using a water / n-butanol mixed solvent as a solvent, and a specific three-phase solvent is used to purify minoxidil by acid-base adjustment, thereby improving the yield and purity of minoxidil.

[0017] The synthetic route of the present invention is:

[0018]

[0019] In order to achieve the above object, the present invention adopts the following technical scheme:

[0020] A method for preparing and refining high-purity minoxidil comprises the following steps:

[0021] (1) 2,4-diamino-6-chloropyrimidine is used as a raw material and an oxidant is reacted in anhydrous ethanol under base catalysis to prepare 2,6-diamino-4-chloropyrimidine-1-oxide, wherein the oxidant is ammonium persulfate and hydrogen peroxide, the molar ratio of 2,4-diamino-6-chloropyrimidine to ammonium persulfate and hydrogen peroxide is 1:1.2-1.4:1.5-3, the molar ratio of 2,4-diamino-6-chloropyrimidine to the base is 1:0.3-1.0, the base is sodium carbonate, and the reaction temperature is 30-60°C.

[0022] Preferably, the molar ratio of 2,4-diamino-6-chloropyrimidine to ammonium persulfate to hydrogen peroxide is 1:1.3 to 1.4:2.

[0023] Preferably, the equivalent ratio of 2,4-diamino-6-chloropyrimidine to the base is 1:0.5

[0024] Preferably, the reaction temperature is 50-60°C.

[0025] (2) The 2,6-diamino-4-chloropyrimidine-1-oxide obtained in step (1) is reacted with piperidine in a mixed solvent of water and C1-C4 alcohol to obtain a crude minoxidil product, wherein the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine is 1:1.5-3.5, the reaction temperature is 60-100° C., and the weight ratio of water to C1-C4 alcohol is 10-30:1.

[0026] Preferably, the solvent is a mixed solvent of water and n-butanol, and the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine is 1:1.8-2.2.

[0027] Preferably, the reaction temperature is 70-80°C.

[0028] Preferably, the weight ratio of water to n-butanol is 19:1.

[0029] (3) The crude minoxidil obtained in step (2) is reacted with an acid in a three-phase solvent to generate a minoxidil salt solution, and then a base is added to the minoxidil salt solution to obtain a minoxidil finished product under the action of the base. The acid is one or more of formic acid, acetic acid, sulfuric acid, and hydrobromic acid, the three-phase solvent is solvent A, solvent B, and water, solvent A is one or more of methanol, anhydrous ethanol, and isopropanol, solvent B is one or more of acetonitrile, acetone, 1,4-dioxane, and tetrahydrofuran, and the weight ratio of the crude minoxidil, solvent A, solvent B, and water is 1:2 to 5:1 to 3:1; the base is one or more of sodium carbonate, sodium hydroxide, and potassium hydroxide.

[0030] Preferably, the acid is formic acid.

[0031] Preferably, solvent A is isopropanol, solvent B is acetone, and the weight ratio of crude minoxidil, solvent A, solvent B and water is 1:3-4:2-2.5:3, more preferably 1:3:2:1;.

[0032] Preferably, the base is sodium hydroxide.

[0033] Through the application of the above technical solution, the present invention has the following advantages compared with the prior art:

[0034] 1. In order to avoid the use of highly dangerous and expensive oxidants, reduce the safety risks of the oxidation process, and improve the market cost competitiveness of minoxidil, the present invention adopts an oxidation system composed of a mixture of ammonium persulfate / hydrogen peroxide as the oxidation system of the present invention. The oxidation system has a mild reaction, low safety risk, and a low market price. The prepared minoxidil has a good cost competitive advantage. At the same time, if no catalyst is added, the reaction time is long when the ammonium persulfate / hydrogen peroxide mixed system is used for oxidation. In order to improve atom economy and reduce production cycle, the present invention selects a specific type of base catalysis to increase the reaction speed and reduce the surplus of raw materials, thereby significantly improving the purity and yield of the intermediate 2,6-diamino-4-chloropyrimidine-1-oxide.

[0035] 2. In order to reduce the use of piperidine, a precursor chemical, and reduce the production cost of minoxidil, the present invention adopts a mixed solvent containing water as a solvent, does not use other alkaline reagents for acid binding, can complete the reaction at a lower piperidine equivalent, and after the reaction is completed, a high-yield crude minoxidil product can be obtained by simple centrifugation.

[0036] 3. In order to improve the operability of the refining process and effectively reduce the content of impurities in minoxidil, the present invention selects a three-phase solvent to adjust the acid and base to purify minoxidil. The acid-base adjustment method can avoid the precipitation of minoxidil during the filtration process. At the same time, the selection of the three-phase solvent can effectively remove impurities in minoxidil, and obtain high-yield, high-purity minoxidil. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 The present invention discloses a hydrogen spectrum (H-NMR) of 2,6-diamino-4-chloropyrimidine-1-oxide prepared by the method of the present invention.

[0038] Figure 2 The material spectrum of 2,6-diamino-4-chloropyrimidine-1-oxide prepared by the method of the present invention.

[0039] Figure 3 The present invention discloses the hydrogen spectrum (H-NMR) of minoxidil prepared by the method of the present invention.

[0040] Figure 4 The minoxidil mass spectrum is obtained by the method of the present invention.

[0041] Figure 5 The liquid phase spectrum of minoxidil prepared by the method of the present invention. DETAILED DESCRIPTION

[0042] The following is a further detailed description of the above content of the present invention through specific implementation methods in the form of examples, but the examples cannot be understood as any limitation of the present invention. The scope of protection of the present invention is subject to the claims. Unless otherwise specified, the following examples are all completed using conventional existing technologies. Specific examples are described as follows:

[0043] Example 1: Effect of different oxidation systems on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide

[0044] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add different oxidant systems, keep warm at 50-60°C for reaction after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and the reaction is monitored by starch potassium iodide paper until the quenching is complete, and then cooled to 10-20°C, filtered after crystallization for 2 hours, and dried to obtain 2,6-diamino-4-chloropyrimidine-1-oxide.

[0045] Product testing method: high performance liquid chromatography.

[0046] Method source: EP11.0 (Minoxidil).

[0047] The effects of different oxidation systems on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide are shown in the following table.

[0048]

[0049] *: 24h monitoring without reaction, direct post-processing

[0050] The experimental results show that it is difficult to react with hydrogen peroxide or ammonium persulfate alone, the product quality and yield obtained by oxidants such as peracetic acid or m-chloroperbenzoic acid are poor, and the product quality obtained by using a benzoyl peroxide / hydrogen peroxide oxidation system is poor. The use of an ammonium persulfate / hydrogen peroxide oxidation system has obvious advantages, such as short reaction time, high product yield and good quality.

[0051] Example 2: Effect of ammonium persulfate and hydrogen peroxide equivalent on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add ammonium persulfate, slowly drop 30% hydrogen peroxide after addition, slowly drop 48.8 g of 15% sodium carbonate aqueous solution after addition, keep warm at 50-60°C for reaction after addition, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and monitored by starch potassium iodide test paper until quenching is completed, cooled to 10-20°C, filtered after crystallization for 2 hours, and dried to obtain 2,6-diamino-4-chloropyrimidine-1-oxide.

[0052] Product testing method: high performance liquid chromatography.

[0053] Method source: EP11.0 (Minoxidil).

[0054] The effects of ammonium persulfate and hydrogen peroxide equivalents on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide are shown in the following table.

[0055]

[0056] *: If no reaction is completed after 12 hours of monitoring, direct post-processing is performed.

[0057] The experimental results show that when the equivalent of ammonium persulfate to hydrogen peroxide is low, the reaction conversion rate is low, and when the equivalent of ammonium persulfate to hydrogen peroxide is too high, the product purity is poor. The best effect is achieved when the equivalent of 2,4-diamino-6-chloropyrimidine to ammonium persulfate to hydrogen peroxide is 1:1.3 to 1.4:2.

[0058] Example 3: Effect of different base catalysts on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide

[0059] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add 41.0 g of ammonium persulfate, add 31.4 g of 30% hydrogen peroxide after the addition is complete, add 0.5 eq of base catalyst, keep warm at 50-60°C for reaction after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and monitored by starch potassium iodide test paper until quenching is complete, cooled to 10-20°C, filtered after crystallization for 2 hours, and dried to obtain 2,6-diamino-4-chloropyrimidine-1-oxide.

[0060] Product testing method: high performance liquid chromatography.

[0061] Method source: EP11.0 (Minoxidil).

[0062] The effects of different bases on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide are shown in the following table.

[0063] Serial number Alkali Reaction time purity(%) Raw material remaining (%) Yield (%) 1 5% Sodium carbonate 7h 90.23 5.67 64.2 2 10% Sodium carbonate 6h 94.31 4.11 70.5 3 15% Sodium carbonate 6h 98.89 0.08 85.6 4 15% Sodium Hydroxide 6h 82.33 1.26 69.7 7 15% Potassium Hydroxide 12h 79.88 1.03 62.4 8 10% Sodium Bicarbonate 13h 86.76 4.34 74.3 9 N,N-Diisopropylethylamine 13h 85.28 1.06 70.3 10 Triethylamine 12h 86.73 2.77 69.6 11 — 12h 88.77 5.26 74.3

[0064] The experimental results show that the product purity is poor when using inorganic strong bases such as sodium hydroxide and potassium hydroxide, and the catalytic reaction effect of other inorganic weak bases such as sodium bicarbonate or organic bases such as N, N-diisopropylethylamine or triethylamine is not obvious. The use of sodium carbonate in the reaction process can significantly increase the reaction rate, improve the purity and yield of the product, and 15% sodium carbonate has the best effect.

[0065] Example 4: Effect of the amount of sodium carbonate on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide

[0066] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add 41.0 g of ammonium persulfate, add 31.4 g of 30% hydrogen peroxide after the addition is complete, add 15% sodium carbonate aqueous solution, keep warm at 50-60°C for reaction after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and the reaction is monitored by starch potassium iodide test paper until the quenching is complete, and the temperature is cooled to 10-20°C, and the crystallization is filtered after 2 hours, and the 2,6-diamino-4-chloropyrimidine-1-oxide is obtained by drying.

[0067] Product testing method: high performance liquid chromatography.

[0068] Method source: EP11.0 (Minoxidil).

[0069] The effect of sodium carbonate equivalent on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide is shown in the following table.

[0070]

[0071] The experimental results show that when 0.3 equivalents of sodium carbonate are used, the reaction is incomplete, and as the sodium carbonate equivalent is increased, the purity of the product tends to decrease. Therefore, the optimal equivalent of sodium carbonate is 0.5 equivalents.

[0072] Example 5: Effect of different solvents on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide

[0073] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of solvent to a 2000 mL reaction bottle, add 41.0 g of ammonium persulfate, add 31.4 g of 30% hydrogen peroxide after the addition is complete, add 48.8 g of 15% sodium carbonate aqueous solution, keep warm at 50-60°C for reaction after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and the reaction is monitored by starch potassium iodide test paper until the quenching is complete, and the temperature is cooled to 10-20°C, and the crystallization is filtered after 2 hours, and the 2,6-diamino-4-chloropyrimidine-1-oxide is obtained by drying.

[0074] Product testing method: high performance liquid chromatography.

[0075] Method source: EP11.0 (Minoxidil).

[0076] The effects of different solvents on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide are shown in the following table.

[0077] Serial number Solvents Reaction time purity(%) Raw material remaining (%) Yield (%) 1 Methanol 6h 98.73 0.10 69.7 2 Anhydrous ethanol 6h 98.89 0.08 85.6 3 Isopropyl alcohol 9h 94.49 0.16 82.7 4 Acetonitrile 24h* 80.53 10.34 56.87 5 acetone 24h* 76.44 14.28 50.22 6 Dichloromethane 24h*(Reflux) 76.32 23.33 40.7 7 Chloroform 24h* 52.63 42.80 37.6

[0078] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0079] The experimental results show that when acetonitrile, acetone, dichloromethane and chloroform are used as solvents, the reaction conversion rate is low, the yield of the obtained product is low and the quality is poor; when methanol is used as solvent, the yield is low, and when isopropanol is used as solvent, the product quality is poor, so the best solvent is anhydrous ethanol.

[0080] Example 6: Effect of different reaction temperatures on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide

[0081] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add 41.0 g of ammonium persulfate, add 31.4 g of 30% hydrogen peroxide after the addition is complete, add 48.8 g of 15% sodium carbonate aqueous solution, keep warm after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and the reaction is monitored by starch potassium iodide test paper until the quenching is complete, and the temperature is lowered to 10-20°C, and the crystallization is filtered after 2 hours, and the 2,6-diamino-4-chloropyrimidine-1-oxide is obtained by drying.

[0082] Product testing method: high performance liquid chromatography.

[0083] Method source: EP11.0 (Minoxidil).

[0084] The effects of different reaction temperatures on the preparation of 2,6-diamino-4-chloropyrimidine-1-oxide are shown in the following table.

[0085] Serial number Reaction temperature (℃) Reaction time purity(%) Raw material remaining (%) Yield (%) 1 10～20 24h* 72.34 15.82 54.4 2 20～30 17h 94.33 2.94 68.7 3 30～40 12h 96.39 0.83 80.6 4 40～50 9h 97.67 0.56 81.2 5 50～60 6h 98.89 0.08 85.6 6 60～70 4h 78.96 0 37.7 7 Reflow 3h 59.72 0 25.6

[0086] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0087] The experimental results show that when the reaction temperature is lower than 20°C, a large amount of raw materials will still remain after 24 hours of reaction; when the reaction temperature is higher than 60°C, obvious by-products will appear during the reaction, affecting the yield and quality of the product; reacting at 30-60°C can obtain products with high yield and good quality, and the optimal reaction temperature is 50-60°C.

[0088] Example 7: Effects of different solvents and acid-binding agents on the preparation of crude minoxidil

[0089] Add 30.0 g of 2,6-diamino-4-chloropyrimidine-1-oxide, 28.6 g of piperidine and 300 g of solvent to a 1000 mL reaction bottle, add 1.1 eq of acid binding agent and heat to reflux, monitor by TLC until the reaction is complete. The reaction solution is cooled to -10 to 0°C, crystallized for 2 hours, filtered, and dried to obtain crude minoxidil.

[0090] Product testing method: high performance liquid chromatography.

[0091] Method source: EP11.0 (Minoxidil).

[0092] The effects of different solvents and acid binders on the preparation of crude minoxidil are shown in the following table.

[0093]

[0094]

[0095] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0096] The experimental results show that compared with not using an additional base as an acid-binding agent, the product yield and quality are reduced to varying degrees when using bases such as potassium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, N,N-diisopropylethylamine as acid-binding agents; the product yield and quality obtained by using organic solvents such as 1,4-dioxane, acetonitrile, acetone, and N-methylpyrrolidone as solvents are poor; the quality of the product obtained by using water as the reaction solvent is slightly lower than that of the product obtained by using a water / n-butanol mixed solvent. The reaction effect is best when using a water / n-butanol mixed solvent as the solvent and no additional base is added.

[0097] Example 8: Effect of different solvent alcohol-water ratios on the preparation of crude minoxidil

[0098] Add 30.0 g of 2,6-diamino-4-chloropyrimidine-1-oxide, 28.6 g of piperidine and 300 g of solvent to a 1000 mL reaction bottle, raise the temperature, and monitor by TLC until the reaction is complete. The reaction solution is cooled to -10 to 0°C, crystallized for 2 hours, filtered, and dried to obtain a crude minoxidil product.

[0099] Product testing method: high performance liquid chromatography.

[0100] Method source: EP11.0 (Minoxidil).

[0101] The effects of different reaction temperatures on the preparation of crude minoxidil are shown in the following table.

[0102] Serial number Solvent (mass ratio) Reaction time purity(%) Yield (%) 1 Water: methanol = 19:1 4h 99.66 44.3 2 Water: ethanol = 19:1 4h 99.59 62.6 3 Water: Isopropyl alcohol = 19:1 4h 99.60 76.6 4 Water: n-butanol = 10:1 4h 99.54 86.9 5 Water: n-butanol = 19:1 4h 99.69 92.7 6 Water: n-butanol = 30:1 4h 99.20 91.0

[0103] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0104] The experimental results show that although good quality products can be obtained by using alcohols and water as mixed solvents, the solubility of the products in different alcohols is different and the reaction yields vary greatly. Therefore, n-butanol / water is selected as the solvent, and the best effect is achieved when the ratio of water:n-butanol=19:1.

[0105] Example 9: Effect of different reaction temperatures on the preparation of crude minoxidil

[0106] Add 30.0 g of 2,6-diamino-4-chloropyrimidine-1-oxide, 28.6 g of piperidine and 300 g of water / n-butanol (19:1) to a 1000 mL reaction bottle, raise the temperature, and monitor by TLC until the reaction is complete. The reaction solution is cooled to -10 to 0°C, crystallized for 2 hours, filtered, and dried to obtain the crude minoxidil.

[0107] Product testing method: high performance liquid chromatography.

[0108] Method source: EP11.0 (Minoxidil).

[0109] The effects of different reaction temperatures on the preparation of crude minoxidil are shown in the following table.

[0110] Serial number Reaction temperature (℃) Reaction time purity(%) Yield (%) 1 20～30 24h* 67.82 30.5 2 40～60 24h* 79.61 50.7 3 60～70 18h 98.14 89.8 4 70～80 4h 99.69 92.7 5 80～90 8h 97.93 87.1 6 90～100 7h 95.24 83.2

[0111] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0112] The experimental results show that when the reaction temperature is low, the yield is low; when the reaction temperature is higher than 70-80°C, larger by-products will be generated and the product purity will decrease. Therefore, the optimal reaction temperature is 70-80°C.

[0113] Example 10: Effect of the feed ratio of piperidine to 2,6-diamino-4-chloropyrimidine-1-oxide on the preparation of crude minoxidil

[0114] Add 30.0 g of 2,6-diamino-4-chloropyrimidine-1-oxide, piperidine and 300 g of water / n-butanol to a 1000 mL reaction bottle, raise the temperature, and monitor by TLC until the reaction is complete. The reaction solution is cooled to -10 to 0°C, crystallized for 2 hours, filtered, and dried to obtain a crude minoxidil product.

[0115] Product testing method: high performance liquid chromatography.

[0116] Method source: EP11.0 (Minoxidil).

[0117] The effects of different feed ratios of piperidine to 2,6-diamino-4-chloropyrimidine-1-oxide on the preparation of crude minoxidil are shown in the following table.

[0118] Serial number Molar ratio of piperidine to 2,6-diamino-4-chloropyrimidine-1-oxide Reaction time purity(%) Yield (%) 1 1:1.2～1.4 24h* 88.75 79.6 2 1:1.5～1.7 12h 98.97 89.3 3 1:1.8～2.2 4h 99.69 92.7 4 1:2.3～2.7 4h 99.52 91.4 5 1:2.8～3.4 4h 99.62 90.7 6 1:3.5～3.9 4h 99.62 86.5 7 1:4.0～4.5 4h 99.59 79.3

[0119] *: If no reaction is completed after 24 hours of monitoring, direct post-processing is performed.

[0120] The experimental results show that when the feed ratio of piperidine to 2,6-diamino-4-chloropyrimidine-1-oxide is lower than 1:1.4, the reaction cannot be completed after 24 hours. When the feed ratio is higher than 1:3.5, the yield tends to decrease because piperidine also has a certain solubility in the product. Therefore, the molar range is selected to be 1.5~3.5, among which the optimal feed molar ratio is 1:1.8~2.2.

[0121] Example 11: Effect of different acids on the preparation of minoxidil

[0122] Add 30.0 g of crude minoxidil, 150.0 g of water, 300.0 g of isopropanol and 150.0 g of acetone to a 2000 mL reaction bottle, add acid dropwise under stirring until the crude product is completely dissolved, filter, add 20% sodium hydroxide solution dropwise to the filtrate to adjust the pH value of the reaction solution to 7-8, cool to -10-0°C, filter after crystallization for 2 hours, and dry to obtain minoxidil.

[0123] Product testing method: high performance liquid chromatography.

[0124] Method source: EP11.0 (Minoxidil).

[0125] The effects of different acids on the preparation of minoxidil are shown in the table below.

[0126] Serial number acid purity(%) Yield (%) 1 Formic acid 99.95 94.5 2 acetic acid 99.87 91.2 3 hydrochloric acid 83.26 73.3 4 sulfuric acid 99.83 89.3 5 Phosphoric acid 88.34 79.6 6 Hydrobromic acid 99.83 89.8 7 Trifluoroacetic acid 76.51 65.4

[0127] The experimental results show that the quality of minoxidil products obtained by using different acids varies greatly. Formic acid, acetic acid, sulfuric acid and hydrobromic acid can all produce products with high yield and good quality. Among them, formic acid is the best acid.

[0128] Example 12: Effect of different bases on the preparation of minoxidil

[0129] Add 30.0 g of crude minoxidil, 150.0 g of water, 300.0 g of isopropanol and 150.0 g of acetone to a 2000 mL reaction bottle, add formic acid dropwise under stirring until the crude product is completely dissolved, filter, add alkali to the filtrate to adjust the pH value of the reaction solution to 7-8, cool to -10-0°C, filter after crystallization for 2 hours, and dry to obtain minoxidil.

[0130] Product testing method: high performance liquid chromatography.

[0131] Method source: EP11.0 (Minoxidil).

[0132] The effects of different bases on the preparation of minoxidil are shown in the table below.

[0133]

[0134]

[0135] The experimental results show that the quality of minoxidil products obtained by using different types and concentrations of alkalis varies greatly. Sodium carbonate, sodium hydroxide and potassium hydroxide can all produce products with high yield and good quality. The best alkali is 20% sodium hydroxide aqueous solution.

[0136] Example 13: Effect of different solvents on the preparation of minoxidil

[0137] Add 30.0 g of crude minoxidil and solvent to a 2000 mL reaction bottle, add formic acid dropwise under stirring until the crude product is completely dissolved, filter, add 20% sodium hydroxide solution dropwise to the filtrate to adjust the pH value of the reaction solution to 7-8, cool to -10-0°C, filter after crystallization for 2 hours, and dry to obtain minoxidil.

[0138] Product testing method: high performance liquid chromatography.

[0139] Method source: EP11.0 (Minoxidil).

[0140] The effects of different solvents on the preparation of minoxidil are shown in the following table.

[0141]

[0142]

[0143] The experimental results show that there is a large difference in the quality and yield of minoxidil produced by using different types and proportions of solvents. Solvent A is methanol, anhydrous ethanol, isopropanol, and solvent B is acetonitrile, acetone, 1,4-dioxane, and tetrahydrofuran, which can produce products with high yield and good purity. The best solvent is crude product: water: isopropanol: acetone = 1:3~4:2~2.5:3.

[0144] Embodiment 14: Best Embodiment

[0145] Add 20.0 g of 2,4-diamino-6-chloropyrimidine and 200 g of anhydrous ethanol to a 2000 mL reaction bottle, add 41.0 g of ammonium persulfate, add 31.4 g of 30% hydrogen peroxide after the addition is complete, add 48.8 g of 15% sodium carbonate aqueous solution, keep warm at 50-60°C for reaction after the addition is complete, and monitor by TLC until the reaction is complete. The reaction solution is cooled to 0-5°C, 30% sodium thiosulfate aqueous solution is added dropwise, and monitored by starch potassium iodide test paper until quenching is complete, cooled to 10-20°C, filtered after crystallization for 2 hours, and dried to obtain 18.53 g of 2,6-diamino-4-chloropyrimidine-1-oxide, with a yield of 83.42% and a purity of 98.89%.

[0146] Add 30.0 g of 2,6-diamino-4-chloropyrimidine-1-oxide, 28.6 g of piperidine and 300 g of water / n-butanol (19:1) to a 1000 mL reaction bottle, heat to 90-100 ° C, and monitor by TLC until the reaction is complete. The reaction solution is cooled to -10-0 ° C, filtered after crystallization for 2 hours, and dried to obtain 36.24 g, with a yield of 92.69% and a purity of 99.69%.

[0147] To a 2000mL reaction bottle, add 30.0g of crude minoxidil, 90.0g of water, 90.0g of isopropanol and 60.0g of acetone, add formic acid dropwise under stirring until the crude product is completely dissolved, filter, add 20% sodium hydroxide aqueous solution to the filtrate to adjust the pH value of the reaction solution to 7-8, cool to -10-0°C, filter after crystallization for 2h, and dry to obtain 28.29g of minoxidil, with a yield of 94.30% and a purity of 99.95%.

[0148] Example 15: Comparative Example (refer to Example 1 of Chinese Patent CN107129470)

[0149] Take a 500mL three-necked flask, add 19.3g of the intermediate 2,6-diamino-4-chloropyrimidine-1-oxide, 50mL of 1,4-dioxane, add 13.3g of piperidine and 21.6g of potassium carbonate under stirring, heat to 100°C and react for 4h, monitor a small amount of reaction by TLC, continue the reaction for 24h, the reaction is not completed, and this scheme cannot be completed (the yield in the literature is 80.2%, and the purity is 94.8%).

[0150] Example 16: Comparative Example (refer to Example 0075 of Chinese Patent CN107235919)

[0151] Take a 500mL three-necked flask, add 12g of the intermediate 2,6-diamino-4-chloropyrimidine-1-oxide, 37.5g of acetone, 20.7g of potassium carbonate, and 7.0g of piperidine, heat to reflux reaction for 12h, the reaction is completed, the reaction solution is cooled to -10~0°C, crystallized for 2h, filtered, and dried to obtain 12.73g of crude minoxidil, with a yield of 81.40% and a purity of 91.39%.

[0152] Example 17: Comparative Example (refer to Example 1 of Chinese Patent CN113979952)

[0153] Take a 250mL three-necked flask, add 21.0g of the intermediate 2,6-diamino-4-chloropyrimidine-1-oxide and 180.6g of piperidine, raise the temperature to 100-110°C, reflux for 6h until the reaction is complete, cool to 5°C, crystallize for 12h, filter, and dry to obtain 22.0g of minoxidil with a purity of 95.7%, a maximum single impurity of 3.35%, and a yield of 80.4%.

[0154] Example 18: Comparative Example (refer to Example 1 of Chinese Patent CN107987027)

[0155] Take a 250mL three-necked flask, add 10.0g of crude minoxidil and 80.0g of anhydrous ethanol, heat to reflux, add anhydrous ethanol dropwise until completely dissolved, continue to reflux for 2h and then filter hot. The product precipitates directly in the Buchner funnel, the operability is poor, and the yield is low.

Claims

1. A method for preparing minoxidil, characterized in that The steps include: (1) Using 2,4-diamino-6-chloropyrimidine as a raw material and an oxidant in anhydrous ethanol under base catalysis to prepare 2,6-diamino-4-chloropyrimidine-1-oxide, the oxidant is ammonium persulfate and hydrogen peroxide, the molar ratio of 2,4-diamino-6-chloropyrimidine to ammonium persulfate and hydrogen peroxide is 1:1.2-1.4:1.5-3, the molar ratio of 2,4-diamino-6-chloropyrimidine to the base is 1:0.3-1.0, the base is sodium carbonate, and the reaction temperature is 30-60°C; (2) reacting the 2,6-diamino-4-chloropyrimidine-1-oxide obtained in step (1) with piperidine in a reaction solvent to obtain a crude minoxidil product, wherein the reaction solvent is a mixed solvent of water and a C1-C4 alcohol, the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine is 1:1.5-3.5, the reaction temperature is 60-100° C., and the weight ratio of water to the C1-C4 alcohol is 10-30:1; (3) The crude minoxidil obtained in step (2) is reacted with an acid in a three-phase solvent to generate a minoxidil salt solution, and then a base is added to the minoxidil salt solution to obtain a minoxidil finished product under the action of the base, wherein the acid is one or more of formic acid, acetic acid, sulfuric acid, and hydrobromic acid, the three-phase solvent is a mixed solvent of solvent A, solvent B, and water, the solvent A is one or more of methanol, anhydrous ethanol, and isopropanol, the solvent B is one or more of acetonitrile, acetone, 1,4-dioxane, and tetrahydrofuran, and the weight ratio of the crude minoxidil, solvent A, solvent B, and water is 1:2 to 5:1 to 3:3; and the base is one or more of sodium carbonate, sodium hydroxide, and potassium hydroxide.

2. The method according to claim 1, characterized in that In the step (1), the equivalent ratio of 2,4-diamino-6-chloropyrimidine to ammonium persulfate to hydrogen peroxide is 1:1.3 to 1.4:

2.

3. The method according to claim 1, characterized in that In the step (1), the equivalent ratio of 2,4-diamino-6-chloropyrimidine to the base is 1:0.

5.

4. The method according to claim 1, characterized in that The reaction temperature in step (1) is 50-60°C.

5. The method according to claim 1, characterized in that In the step (2), the molar ratio of 2,6-diamino-4-chloropyrimidine-1-oxide to piperidine is 1:1.8-2.2; the reaction solvent is a water / n-butanol mixed solvent, the weight ratio of water to n-butanol is 19:1, and the reaction temperature is 70-80°C.

6. The method according to claim 1, characterized in that In the step (3), the acid is formic acid.

7. The method according to claim 1, characterized in that In the step (3), solvent A is isopropanol, solvent B is acetone, and the weight ratio of crude minoxidil, solvent A, solvent B and water is 1:3 to 4:2 to 2.5:

3.

8. The method according to claim 7, characterized in that In the step (3), the weight ratio of the crude minoxidil, solvent A, solvent B and water is 1:3:2:

1.

9. The method according to claim 1, characterized in that In the step (3), the alkali is sodium hydroxide.

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