Synthetic method of minoxidil

Abstract

The invention belongs to the field of organic synthesis, and particularly relates to a minoxidil synthesis method, which comprises the following steps: by taking 2, 4-diamino-6-chloropyrimidine as a starting material, oxidizing the starting material by sodium perborate tetrahydrate, and carrying out synergistic catalysis by adopting piperidine and ionic liquid. According to the invention, sodium perborate tetrahydrate and EDTA are adopted to inhibit the occurrence of peroxidation by-products; the ionic liquid is adopted, decomposition of oxides caused by high temperature is avoided, and the ionic liquid effectively inhibits side reactions; the dosage ratio of piperidine to 2, 4-diamino-6-chloropyrimidine-3-oxide is reduced, so that complete reaction is ensured, and side reaction caused by excessive piperidine is avoided; according to the method, the safety of the oxidation process is high, side reactions are effectively avoided, post-treatment is simple, and the method is green and environmentally friendly.

Description

Technical Field

[0001] The invention belongs to the field of organic synthesis, and particularly relates to a minoxidil synthesis method. Background Art

[0002] Minoxidil, a potassium channel opener pioneered by Upjohn in the 1960s, has a potent vasodilating effect and is primarily used to treat severe, refractory hypertension. It has been clinically used for many years, but one of its side effects is hirsutism after oral administration. As early as the early 1980s, some hospitals exploited this side effect by crushing minoxidil tablets and dissolving them in appropriate solvents to create topical solutions or ointments for use in patients with hair loss. However, these preparations lacked systematic research and conclusions on their efficacy and safety.

[0003] In 1987, the U.S. FDA approved the marketing of 2% minoxidil solution in the United States under the trade name Rogaine for the treatment of male pattern baldness. In 1996, the U.S. Food and Drug Administration (FDA) approved Upjohn to produce minoxidil ointment for the treatment of alopecia areata and androgenic alopecia. Subsequently, European countries such as France and the United Kingdom also began to market it. Since the 2% minoxidil solution was launched in Canada in 1986, it has enjoyed a good reputation for safety. The incidence of side effects was less than 2% among approximately 24,500 users, and no serious side effects occurred.

[0004] According to relevant literature reports at home and abroad, there have been many reports on minoxidil in recent years. All of them use 2,4-diamino-6-chloropyrimidine as the raw material, oxidize it with an oxidant to obtain 2,4-diamino-6-chloropyrimidine-3-oxide, and then react with piperidine to undergo nucleophilic substitution reaction to further synthesize minoxidil. The reaction equation is as follows:

[0005]

[0006] The main difference in different synthesis literature is the oxidants used, which mainly include: hydrogen peroxide and ferrate (catalyst), meta-chloroperbenzoic acid, peracetic acid, hydrogen peroxide combined with urea, sodium perborate, potassium persulfate, potassium permonosulfate, potassium permonosulfate-acetone, dimethyl ketone peroxide, tert-butyl peroxide, isopropyl benzene peroxide, performic acid, peroxypropionic acid, peroxybutyric acid, peroxysuccinic acid, trifluoroperacetic acid, peroxybenzoic acid, meta-chloroperbenzoic acid, and one of the magnesium salts of monoperoxyphthalic acid.

[0007] The main disadvantages are: (1) low oxidation safety: the traditional process uses meta-chloroperbenzoic acid or hydrogen peroxide as an oxidant, which has the risk of flammability or explosion (for example, CN107235919A uses meta-chloroperbenzoic acid, which requires strict temperature control); (2) high solvent toxicity: most methods rely on toxic solvents such as acetonitrile and acetone (for example, CN107129470A uses a mixture of one or more of chloroform, dichloromethane, dichloroethane, ethanol, and ether), which increases environmental and health risks; (3) low yield and high impurity content: the yield of existing processes is generally lower than 85% (for example, CN113979952A has a yield of only 75%), and impurity control is poor; (4) complex post-processing: traditional refining relies on recrystallization with organic solvents (such as isopropanol and methanol), which requires a large amount of solvent and causes serious pollution; (5) requires inorganic base catalysis: traditional condensation reactions require the addition of inorganic bases such as potassium carbonate, which leads to complex post-processing and residual risks. Summary of the Invention

[0008] In view of the problems existing in the prior art, the present invention provides a minoxidil synthesis method. By adopting the present invention, the oxidation process is highly safe, the occurrence of side reactions is effectively avoided, the post-processing is simple, and the product is green and environmentally friendly.

[0009] The invention discloses a method for synthesizing minoxidil, which uses 2,4-diamino-6-chloropyrimidine as a starting material, oxidizes the product with sodium perborate tetrahydrate, and then condenses the product with piperidine under the action of an ionic liquid.

[0010] The specific steps are:

[0011] (1) dissolving 2,4-diamino-6-chloropyrimidine, sodium perborate tetrahydrate, and EDTA in solvent I, reacting at 25-30° C., and post-treating to obtain 2,4-diamino-6-chloropyrimidine-3-oxide;

[0012] The post-treatment comprises: cooling to 0-10° C., adding a saturated sodium sulfite solution dropwise at a temperature controlled at 0-10° C. (the amount added is 1.5 to 2 times the molar ratio of sodium perborate tetrahydrate), filtering to remove insoluble solids (boric acid, sodium metaborate, and other inorganic salts produced by the decomposition of sodium perborate), concentrating the filtrate under reduced pressure, cooling, and filtering to obtain 2,4-diamino-6-chloropyrimidine-3-oxide;

[0013] (2) Adding 2,4-diamino-6-chloropyrimidine-3-oxide, piperidine and ionic liquid to propylene glycol methyl ether, condensing at 95-100°C to obtain crude minoxidil; replacing acetone with propylene glycol methyl ether to reduce volatile organic compound (VOC) emissions;

[0014] (3) The crude minoxidil is dissolved in acetic acid, crystallized with NaOH, and dried to obtain the finished product.

[0015] In the present invention, the molar ratio of 2,4-diamino-6-chloropyrimidine to sodium perborate tetrahydrate is 1:(1.2-1.5).

[0016] The added mass of EDTA is 0.1-0.3% of the mass of sodium perborate tetrahydrate. The introduction of EDTA can complex metal ions, prolong the oxidizing property of sodium perborate tetrahydrate, promote the forward reaction, and reduce the residual starting material 2,4-diamino-6-chloropyrimidine (i.e., EP impurity B).

[0017]

[0018] In step (1), the solvent I is a mixed solvent of acetic acid and water; in terms of volume ratio, acetic acid: water = 3:1.

[0019] The solvent I is a mixed solvent of acetic acid and water, with a volume ratio of acetic acid to water of 3:1. The use of the mixed solvent in the present invention can reduce the polarity of the solvent and the solubility of the oxide, making it easier for 2,4-diamino-6-chloropyrimidine-3-oxide to crystallize after cooling. The use of the mixed solvent also lowers the boiling point and concentration temperature, improving safety. The use of the mixed solvent also helps suppress the precipitation of inorganic salt impurities (borates and sulfates), making it easier to separate the oxide from the 2,4-diamino-6-chloropyrimidine-3-oxide during intermediate filtration.

[0020] The ionic liquid is [BMIM]BF4; the molar ratio of piperidine to ionic liquid is 1:(1.05-1.25). The addition of the ionic liquid improves solubility, increases the activity of reactants, stabilizes reaction intermediates, reduces the energy of the reaction transition state, and increases the reaction rate. The molar ratio of 2,4-diamino-6-chloropyrimidine-3-oxide to piperidine is (1.05-1.1):1.

[0021] The crude minoxidil obtained by the present invention is dissolved in 0.5M acetic acid, and then 0.1M NaOH is added dropwise to adjust the pH to 6.5-7.0, the crystallization temperature is 0-5°C, and the product is stirred for 2.4 hours to crystallize.

[0022] The present invention has the following beneficial effects:

[0023] (1) Sodium perborate tetrahydrate + EDTA is used to inhibit the appearance of peroxidation byproducts;

[0024] (2) The use of ionic liquids avoids the decomposition of oxides caused by high temperatures, and ionic liquids effectively inhibit side reactions;

[0025] (3) The ratio of piperidine to 2,4-diamino-6-chloropyrimidine-3-oxide is reduced, which ensures the complete reaction and avoids side reactions caused by excessive piperidine;

[0026] (4) Sodium perborate tetrahydrate is quenched with sodium sulfite to completely reduce the residual peroxide and prevent the generation of free radical impurities by high-temperature decomposition. DETAILED DESCRIPTION

[0027] Example 1

[0028] A method for synthesizing minoxidil comprises the following steps: using 2,4-diamino-6-chloropyrimidine as a starting material, oxidizing the product with sodium perborate tetrahydrate, and then using piperidine and ionic liquid as the synergistic catalyzer.

[0029] The specific steps are:

[0030] (1) Dissolve 50.6 g of 2,4-diamino-6-chloropyrimidine, 65.0 g of sodium perborate tetrahydrate, and 6.5 g of EDTA in solvent 1 (V) 乙酸 :V 水 =3:1), react at 25 ° C for 6 hours, cool to 0 ° C, add 85.14 g of saturated sodium sulfite solution dropwise at 0 ° C, filter to remove insoluble solids, concentrate the filtrate under reduced pressure, cool, and filter to obtain 54.2 g of 2,4-diamino-6-chloropyrimidine-3-oxide, with a yield of 96.5%;

[0031] (2) Add 42.2 g of 2,4-diamino-6-chloropyrimidine-3-oxide, 21.3 g of piperidine, and 59.5 g of ionic liquid to propylene glycol methyl ether, and condense at 100° C. for 3 h to obtain crude minoxidil;

[0032] (3) The crude minoxidil was dissolved in 0.5 M acetic acid, and 0.1 M NaOH was added dropwise to adjust the pH to 6.5. The crystallization temperature was 0° C. and the mixture was stirred for 2.4 hours to crystallize. The product was dried to obtain 50.4 g of the finished product with a yield of 96.3%, a purity of 99.8%, and an impurity B content of 350 ppm.

[0033] Example 2

[0034] A method for synthesizing minoxidil comprises the following steps: using 2,4-diamino-6-chloropyrimidine as a starting material, oxidizing the product with sodium perborate tetrahydrate, and then using piperidine and ionic liquid as the synergistic catalyzer.

[0035] The specific steps are:

[0036] (1) Dissolve 50.6 g of 2,4-diamino-6-chloropyrimidine, 80.5 g of sodium perborate tetrahydrate, and 24.15 g of EDTA in solvent 1 (V) 乙酸 :V 水 =3:1), react at 30 ° C for 4 hours, cool to 5 ° C, add 98.82 g of saturated sodium sulfite solution dropwise at 5 ° C, filter to remove insoluble solids, concentrate the filtrate under reduced pressure, cool, and filter to obtain 54.7 g of 2,4-diamino-6-chloropyrimidine-3-oxide, with a yield of 97.3%;

[0037] (2) Add 44.1 g of 2,4-diamino-6-chloropyrimidine-3-oxide, 21.3 g of piperidine, and 64.9 g of ionic liquid to propylene glycol methyl ether, and condense at 95° C. for 3.5 h to obtain crude minoxidil;

[0038] (3) The crude minoxidil was dissolved in 0.5 M acetic acid, and 0.1 M NaOH was added dropwise to adjust the pH to 7.0. The crystallization temperature was 5° C. and the mixture was stirred for 2.4 hours to crystallize. The product was dried to obtain 51.1 g of the finished product with a yield of 97.7%, a purity of 99.8%, and an impurity B content of 360 ppm.

[0039] Example 3

[0040] A method for synthesizing minoxidil comprises the following steps: using 2,4-diamino-6-chloropyrimidine as a starting material, oxidizing the product with sodium perborate tetrahydrate, and then using piperidine and ionic liquid as the synergistic catalyzer.

[0041] The specific steps are:

[0042] (1) Dissolve 50.6 g of 2,4-diamino-6-chloropyrimidine, 67.5 g of sodium perborate tetrahydrate, and 13.5 g of EDTA in solvent 1 (V) 乙酸 : V water = 3:1), react at 30 ° C for 6 hours, cool to 10 ° C, add 82.91 g of saturated sodium sulfite solution dropwise at 10 ° C, filter to remove insoluble solids, concentrate the filtrate under reduced pressure, cool and filter to obtain 55.2 g of 2,4-diamino-6-chloropyrimidine-3-oxide, with a yield of 98.2%;

[0043] (2) Add 43.4 g of 2,4-diamino-6-chloropyrimidine-3-oxide, 21.3 g of piperidine, and 70.5 g of ionic liquid to propylene glycol methyl ether, and condense at 100° C. for 4 h to obtain crude minoxidil;

[0044] (3) The crude minoxidil was dissolved in 0.5 M acetic acid, and 0.1 M NaOH was added dropwise to adjust the pH to 7.0. The crystallization temperature was 0° C. and the mixture was stirred for 2.4 hours to crystallize. The product was dried to obtain 50.1 g of the finished product with a yield of 95.8%, a purity of 99.9%, and an impurity B content of 345 ppm.

[0045] Comparative Example 1

[0046] The sodium perborate tetrahydrate in step (1) was replaced by m-chloroperbenzoic acid, and the solvent was replaced by acetone. The rest of the process was the same as in Example 1. The final yield was 78.5%, the purity was 74.8%, and the impurity B content was 4000 ppm.

[0047] Comparative Example 2

[0048] The ionic liquid in step (2) was omitted, and the rest was the same as in Example 2. The final yield was 78.5%, the purity was 84.2%, and the impurity B content was 3500 ppm.

[0049] Comparative Example 3

[0050] EDTA in step (1) was omitted, and the rest was the same as in Example 3. The final yield was 77.2%, the purity was 80.3%, and the impurity B content was 4300 ppm.

Claims

1. A method for synthesizing minoxidil, characterized in that: The starting material is 2,4-diamino-6-chloropyrimidine, which is oxidized by sodium perborate tetrahydrate and then condensed with piperidine under the action of ionic liquid.

2. A minoxidil synthesis method according to claim 1, characterized in that, The specific steps are: (1) dissolving 2,4-diamino-6-chloropyrimidine, sodium perborate tetrahydrate, and EDTA in solvent I, reacting at 25-30° C., and post-treating to obtain 2,4-diamino-6-chloropyrimidine-3-oxide; (2) adding 2,4-diamino-6-chloropyrimidine-3-oxide, piperidine and ionic liquid to propylene glycol methyl ether, and condensing at 95-100° C. to obtain crude minoxidil; (3) The crude minoxidil is dissolved in acetic acid, crystallized with NaOH, and dried to obtain the finished product.

3. A minoxidil synthesis method according to claim 1, characterized in that, In terms of molar ratio, 2,4-diamino-6-chloropyrimidine: sodium perborate tetrahydrate = 1: (1.2-1.5).

4. A minoxidil synthesis method according to claim 2, characterized in that, The added mass of EDTA is 0.1-0.3% of the mass of sodium perborate tetrahydrate.

5. A minoxidil synthesis method according to claim 2, characterized in that, In step (1), the solvent I is a mixed solvent of acetic acid and water; in terms of volume ratio, acetic acid: water = 3:

1.

6. A minoxidil synthesis method according to claim 1, characterized in that, The ionic liquid is [BMIM]BF4; in terms of molar ratio, piperidine:ionic liquid=1:(1.05-1.25).

7. A minoxidil synthesis method according to claim 1, characterized in that, In terms of molar ratio, 2,4-diamino-6-chloropyrimidine-3-oxide:piperidine=(1.05-1.1):1.

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