CN107235919B - Process for synthesizing minoxidil - Google Patents
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- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
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Abstract
The invention discloses a process for synthesizing minoxidil, which comprises the steps of oxidizing 2, 4-diamino-6-chloropyrimidine by m-chloroperoxybenzoic acid to obtain an intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide, condensing the intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide and piperidine into a minoxidil crude product under an alkaline condition, and finally crystallizing and purifying the minoxidil crude product in isopropanol to obtain a refined minoxidil finished product. The invention has simple process principle, convenient operation, high product yield and good purity.
Description
Technical Field
The invention relates to the field of medicine synthesis, in particular to a process for synthesizing minoxidil.
Background
Minoxidil, also known as minoxidil, has a molecular formula and relative molecular mass of C9H15N5O ═ 209.25, and is white or off-white crystalline powder, slightly soluble in water or chloroform, slightly soluble in ethanol, slightly soluble in acetone, and soluble in glacial acetic acid. Can directly act on the vascular wall, dilate arteriole, reduce peripheral resistance, reduce blood pressure, increase heart rate and cardiac output, but has obvious and lasting antihypertensive effect compared with hydralazine.
Dilute solutions of minoxidil are of great interest as a drug effective in the treatment of hair loss. In the current society, as the living pace is accelerated, the pressure of people is increased, so that more and more alopecia patients are caused, the demand of the anti-alopecia cosmetic medicine is increased year by year, and the minoxidil dilute solution serving as a medicine for safely and effectively treating alopecia has good application value and market prospect.
In China, the research on the synthesis of the minoxidil is only rarely reported, and the synthesis process of the minoxidil at abroad is relatively complex and has low yield. Therefore, the method has certain significance for the research on the synthesis of the minoxidil.
Disclosure of Invention
The invention provides a synthesis process of minoxidil, which has high yield and high product purity.
The technical scheme adopted by the invention is as follows:
a process for synthesizing minoxidil is characterized by comprising the following steps:
A. oxidation reaction
(1) Adding an organic solvent into a reaction kettle, and controlling the temperature in the kettle to be 15-18 ℃;
(2) slowly adding the 2, 4-diamino-6-chloropyrimidine solid into a reaction kettle, heating and raising the reaction kettle until the solvent flows back, wherein the mass ratio of the 2, 4-diamino-6-chloropyrimidine to the organic solvent is 150: 300-350;
(3) adding an organic solvent into another clean reaction kettle, adding m-chloroperoxybenzoic acid into the reaction kettle, and uniformly stirring, wherein the mass ratio of the m-chloroperoxybenzoic acid to the organic solvent is (180-) -220): (620-650);
(4) pumping the organic solution of the m-chloroperoxybenzoic acid dissolved in the step (3) into a head tank, dropwise adding the organic solution of the 2, 4-diamino-6-chloropyrimidine obtained in the step (2) in batches under reflux for 10-12 hours, dropwise adding the organic solution of the 2, 4-diamino-6-chloropyrimidine in batches, and continuously stirring for at least 3 hours under reflux, wherein the mass ratio of the m-chloroperoxybenzoic acid to the 2, 4-diamino-6-chloropyrimidine is (185-220): 150;
(5) naturally cooling to room temperature after the reaction is finished, enabling the solution to be turbid and white, tracking and monitoring the reaction by using TLC (thin layer chromatography), enabling ethyl acetate to be a developing agent, and enabling water and ninhydrin to be a color developing agent, and entering a post-treatment stage when TLC shows that the reaction is finished;
(6) intermediate product post-treatment:
a. cooling the reaction kettle, dropwise adding an aqueous solution of reducing salt into the kettle, controlling the temperature to be 25-30 ℃, quenching the reaction, dropwise adding the aqueous solution for 3-5 hours, standing for layering, separating an inorganic phase from an organic phase, adding saturated salt solution into the organic phase, stirring, standing for layering, and separating the inorganic phase from the organic phase again;
b. adding petroleum ether into the organic phase, stirring, controlling the temperature to 25-30 deg.C in water bath, and standing overnight;
c. slowly putting the reaction liquid after the overnight stay into a filter frame for suction filtration and vacuum filtration, washing the obtained filter cake with petroleum ether for multiple times, then pumping out, and finally performing vacuum drying to obtain a reaction intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide;
B. condensation reaction
(1) Adding acetone into a reaction kettle, adding potassium carbonate into the acetone, uniformly stirring, sequentially adding the intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide and piperidine prepared in the step A according to a proportion, fully stirring, setting the water bath temperature to be 55-60 ℃, carrying out condensation reaction, refluxing for 10-11 hours, cooling to room temperature, tracking and monitoring the reaction by using TLC (thin layer chromatography), taking ethyl acetate as a developing agent, taking water and ninhydrin as a color developing agent, and preparing a post-treatment stage when the TLC shows that the reaction is finished, wherein the intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide is prepared: piperidine: acetone: the mass ratio of the potassium carbonate is 120:70-80:370-380: 205-220;
(2) product post-treatment:
a. slowly dripping an acidity regulator into the reaction kettle in the step (1) to regulate the pH value of the system;
b. when the pH value of the system is adjusted to 4.5-4, stopping dropwise adding the acidity regulator, distilling to remove the solvent acetone, adding ethyl acetate into the reaction kettle, stirring, standing, layering, and separating an organic phase from an inorganic phase;
c. adding ethyl acetate into the inorganic phase, stirring, standing, layering, separating organic phase and inorganic phase, and separating inorganic phase with ethyl acetate;
d. finally, combining the obtained organic phase, namely an ethyl acetate layer, adding a proper amount of saturated saline solution, stirring, standing for 30-40 minutes, layering, separating an inorganic layer from the ethyl acetate layer, drying the ethyl acetate layer by using anhydrous sodium sulfate, filtering to remove a drying agent, distilling the filtrate under reduced pressure, removing and recovering ethyl acetate, and concentrating a product to obtain a crude product;
C. refining of crude product
(1) Adding a solvent isopropanol into a reaction kettle, adding the obtained crude product into the reaction kettle, stirring and dissolving, and cooling a system by using an ice water bath, wherein the addition amount of the isopropanol is 3-4 times of the mass of the crude product;
(2) when the temperature of the system is reduced to 4 ℃, crystallization begins to occur, the temperature of the system is reduced to 0-4 ℃ by ice-water bath, pulping is carried out, after 10 hours, a large amount of white solid appears, centrifugal filtration is carried out, and a filter cake is leached by petroleum ether for multiple times to obtain a white solid 1;
(3) mixing the filtrate and the eluent, standing, generating a large amount of solid, performing suction filtration, and leaching the filter cake with petroleum ether for multiple times to obtain a white solid 2;
(4) and (3) drying the white solid 1 and the white solid 2 at 50 ℃ for 5-6 hours in vacuum to obtain a final product.
The synthesis process of the minoxidil is characterized by comprising the following steps: the organic solvent in the oxidation reaction stage is one or more of chloroform, dichloromethane, dichloroethane, ethanol and diethyl ether.
The reducing salt is a soluble sulfite or thiosulfate, preferably sodium sulfite.
The synthesis process of the minoxidil is characterized by comprising the following steps: the acid regulator used in the condensation reaction stage post-treatment is selected from one of saturated citric acid aqueous solution, saturated tartaric acid aqueous solution, saturated malic acid aqueous solution and saturated lactic acid aqueous solution.
The synthetic route of minoxidil is as follows:
(1) process flow
① Oxidation Process scheme FIG. 1
② condensation reaction scheme is shown in FIG. 2
③ refining reaction process scheme is shown in FIG. 3.
Advantageous effects
The synthesis process of the minoxidil has the advantages of simple process, easy operation, little pollution, high yield, high purity (up to 75 percent) and high purity (up to 92 percent). The production process is mature, the requirements of enterprises on batch production can be completely met no matter from raw material supply, production operation, process control and technical and economic indexes of all aspects, and good guarantee can be completely provided.
Drawings
FIG. 1 is a flow diagram of an oxidation reaction process;
FIG. 2 is a flow diagram of a condensation reaction process;
FIG. 3 is a flow chart of a purification reaction process.
Detailed Description
A process for synthesizing minoxidil comprises the following steps:
the first step is as follows: oxidation reaction to produce intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide,
firstly, the method comprises the following steps: equation of reaction
II, secondly: material proportioning meter
Thirdly, the method comprises the following steps: detailed description of the invention
1. Adding 310kg of chloroform into a clean 2T reaction kettle, wherein the temperature in the kettle is 17 ℃;
2. slowly adding 150.0 kg of 2, 4-diamino-6-chloropyrimidine solid, slightly releasing heat when adding, and not needing to use an ice water bath for cooling;
3. heating to reflux;
4. adding 620kg of chloroform and 189kg of m-chloroperoxybenzoic acid into another clean 2T reaction kettle, releasing heat, and not needing to use an ice water bath for cooling;
5. pumping a chloroform solution of m-chloroperoxybenzoic acid into an overhead tank, dropwise adding the chloroform solution of m-chloroperoxybenzoic acid into a chloroform solution of 2, 4-diamino-6-chloropyrimidine in batches under reflux, releasing heat when adding raw materials, obviously increasing the temperature, completing dropwise adding in batches within 10-12 hours, wherein the temperature in a kettle is 62 ℃, the liquid is slightly turbid, stirring in a refluxing manner for at least 3 hours, naturally cooling to room temperature, the reaction liquid contains solids, the turbid solution is white, performing TLC tracking and monitoring reaction, using ethyl acetate as a developing agent, using water and ninhydrin as a color developing agent, completing the TLC display reaction, and preparing for post-treatment;
fourthly, the method comprises the following steps: post-treatment
1. Setting a water bath at 25 ℃, cooling, and controlling the temperature to be 25-30 ℃;
2. dropwise adding an aqueous solution of sodium sulfite (sodium carbonate), controlling the temperature to be 25-30 ℃, and quenching the reaction for about 3-5 hours;
3. standing and layering; adding saturated salt solution into the organic phase, stirring, standing and layering;
4. adding 800kg of petroleum ether into the organic phase, reacting for about 70 minutes to generate a large amount of white solid, and continuously controlling the temperature to be between 25 and 30 ℃ in a water bath for overnight;
5. performing suction filtration, namely performing suction filtration by using a filter frame with the specification of 300 kilograms, slowly adding reaction liquid in batches, and performing vacuum suction filtration; 6. adding 100L of petroleum ether into the filter cake for leaching, draining the filter cake, adding 100L of petroleum ether into the filter cake for leaching, and draining the filter cake again;
7. drying to obtain 153.2kg of intermediate white solid; yield: 92.0 percent.
The second step is that: condensation reaction to obtain a crude product
Firstly, the method comprises the following steps: equation of reaction
II, secondly: material proportioning meter
Thirdly, the method comprises the following steps: detailed description of the invention
1. 375kg of acetone is firstly added into a clean 2T reaction kettle, 207 kg of potassium carbonate solid is added, and then 120kg of 2, 6-diamino-4-chloropyrimidine-1-oxide and 70kg of piperidine are sequentially added;
2. refluxing for 10 hours in a water bath at 55-60 ℃;
3. cooling to room temperature, monitoring by TLC (thin layer chromatography), taking ethyl acetate as a developing agent, taking water and ninhydrin as a color developing agent, and performing after-treatment after TLC (thin layer chromatography) to show that the reaction is finished;
fourthly, the method comprises the following steps: post-treatment
1. Dropwise adding a saturated citric acid solution into the reaction liquid to adjust the pH value, wherein a large amount of bubbles are generated during the addition, the citric acid is slowly dropwise added to prevent the filling, the temperature is 20 ℃ when the citric acid solution is added, the solution is clear and transparent when the pH is adjusted to be neutral, the temperature is 17 ℃, the solution becomes turbid when the saturated citric acid solution is continuously dropwise added to adjust the pH value to 6, no bubbles are generated, the pH value is continuously dropwise added to adjust the pH value to 4, and the acetone is removed through distillation;
2. adding 400L of ethyl acetate into the reaction kettle, stirring, standing and layering; adding 400L of ethyl acetate into the water layer to the reaction kettle, stirring, standing and layering; adding 100L of ethyl acetate into the water layer for the third time, stirring, standing, layering, combining ethyl acetate layers, adding 100L of saturated salt solution into the reaction kettle, stirring, standing for 30 minutes, layering, drying the ethyl acetate layer with anhydrous sodium sulfate, filtering, concentrating the filtrate, recovering ethyl acetate, and drying to obtain 130kg of crude minoxidil product;
the third step: refining of crude product
Firstly, the method comprises the following steps: material proportioning meter
II, secondly: detailed description of the invention
1. 400kg of isopropanol and 130kg of minoxidil crude product are added into a clean 1T reaction kettle, the heat release is very obvious when the minoxidil crude product is added, the temperature is reduced by using ice water bath to prevent the temperature in the kettle from being too high,
2. and (3) reducing the temperature to 4 ℃, enabling the liquid in the kettle to start to be turbid, continuing to reduce the temperature by using an ice water bath, controlling the temperature to be between 0 and 4, and pulping.
3. After 10 hours, a large amount of white solid was formed;
4. filtering, adding 20L petroleum ether into the filter cake for leaching,
5. vacuum drying the filter cake for 5 hours at 50 ℃ to obtain a product,
6. adding the petroleum ether leached twice and the mother liquor together, placing the mixture into a 1T reaction kettle, standing the mixture, generating a large amount of solid, performing suction filtration again, adding 20L petroleum ether into the filter cake to leach twice to obtain a white solid product, wherein the solid is bulkier than the solid at the last time;
7. the twice white solid was dried under vacuum at 50 ℃ for 5 hours to obtain 117kg of the final product, yield: 75 percent.
Note: the mother liquor recovered product is generally not placed together with the primary finished product, the batch number can be reset, and in addition, the output time is different.
Claims (4)
1. A process for synthesizing minoxidil is characterized by comprising the following steps:
A. oxidation reaction
(1) Adding an organic solvent into a reaction kettle, and controlling the temperature in the kettle to be 15-18 ℃;
(2) slowly adding the 2, 4-diamino-6-chloropyrimidine solid into the reaction kettle in the step (1), heating the reaction kettle until the solid is dissolved and reflows, wherein the mass ratio of the 2, 4-diamino-6-chloropyrimidine to the organic solvent is 150: 300-350;
(3) adding an organic solvent into another clean reaction kettle, adding m-chloroperoxybenzoic acid into the reaction kettle, and uniformly stirring, wherein the mass ratio of the m-chloroperoxybenzoic acid to the organic solvent is 180-220: 620-650;
(4) pumping the organic solution of the m-chloroperoxybenzoic acid dissolved in the step (3) into a head tank, dropwise adding the organic solution of the 2, 4-diamino-6-chloropyrimidine obtained in the step (2) in batches under reflux, dropwise adding the organic solution of the 2, 4-diamino-6-chloropyrimidine in batches within 10 to 12 hours, and continuously stirring for at least 3 hours under reflux, wherein the mass ratio of the m-chloroperoxybenzoic acid to the 2, 4-diamino-6-chloropyrimidine is 185-220: 150;
(5) naturally cooling to room temperature after the reaction is finished, enabling the solution to be turbid and white, tracking and monitoring the reaction by using TLC (thin layer chromatography), enabling ethyl acetate to be a developing agent, and enabling water and ninhydrin to be a color developing agent, and entering a post-treatment stage when TLC shows that the reaction is finished;
(6) intermediate product post-treatment:
a. cooling the reaction kettle, dropwise adding an aqueous solution of reducing salt into the kettle, controlling the temperature to be 25-30 ℃, quenching the reaction, dropwise adding the aqueous solution for 3-5 hours, standing for layering, separating an inorganic phase from an organic phase, adding saturated salt solution into the organic phase, stirring, standing for layering, and separating the inorganic phase from the organic phase again;
b. adding petroleum ether into the organic phase, stirring, controlling the temperature to 25-30 deg.C in water bath, and standing overnight;
c. slowly putting the reaction liquid after the overnight stay into a filter frame for suction filtration and vacuum filtration, washing the obtained filter cake with petroleum ether for multiple times, then pumping out, and finally performing vacuum drying to obtain a reaction intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide;
B. condensation reaction
(1) Adding acetone into a reaction kettle, adding potassium carbonate into the acetone, uniformly stirring, sequentially adding the intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide and piperidine prepared in the step A according to a proportion, fully stirring, setting the water bath temperature to be 55-60 ℃, carrying out condensation reaction, refluxing for 10-11 hours, cooling to room temperature, tracking and monitoring the reaction by using TLC (thin layer chromatography), taking ethyl acetate as a developing agent, taking water and ninhydrin as a color developing agent, and preparing a post-treatment stage when the TLC shows that the reaction is finished, wherein the intermediate 2, 6-diamino-4-chloropyrimidine-1-oxide is prepared: piperidine: acetone: the mass ratio of the potassium carbonate is =120:70-80:370-380: 205-220;
(2) product post-treatment:
a. slowly dripping an acidity regulator into the reaction kettle in the step (1) to regulate the pH value of the system;
b. when the pH value of the system is adjusted to 4.5-4, stopping dropwise adding the acidity regulator, distilling to remove the solvent acetone, adding ethyl acetate into the reaction kettle, stirring, standing, layering, and separating an organic phase from an inorganic phase;
c. adding ethyl acetate into the inorganic phase, stirring, standing, layering, separating organic phase and inorganic phase, and separating inorganic phase with ethyl acetate again;
d. finally, combining the obtained organic phase, namely an ethyl acetate layer, adding a proper amount of saturated saline solution, stirring, standing for 30-40 minutes, layering, separating an inorganic layer from the ethyl acetate layer, drying the ethyl acetate layer by using anhydrous sodium sulfate, filtering to remove a drying agent, distilling the filtrate under reduced pressure, removing and recovering ethyl acetate, and concentrating a product to obtain a crude product;
c. Refining of crude product
(1) Adding a solvent isopropanol into a reaction kettle, adding the obtained crude product into the reaction kettle, stirring and dissolving, and cooling a system by using an ice water bath, wherein the addition amount of the isopropanol is 3-4 times of the mass of the crude product;
(2) when the temperature of the system is reduced to 4 ℃, crystallization begins to occur, the temperature of the system is reduced to 0-4 ℃ by ice-water bath, pulping is carried out, after 10 hours, a large amount of white solid appears, centrifugal filtration is carried out, and a filter cake is leached by petroleum ether for multiple times to obtain a white solid 1;
(3) mixing the filtrate and the eluent, standing, generating a large amount of solid, performing suction filtration, and leaching the filter cake with petroleum ether for multiple times to obtain a white solid 2;
(4) drying the white solid 1 and the white solid 2 at 50 ℃ for 5-6 hours in vacuum to obtain a final product;
the organic solvent in the oxidation reaction stage is selected from chloroform.
2. The process for the synthesis of minoxidil according to claim 1, wherein: the reducing salt in the oxidation reaction stage is soluble sulfite or thiosulfate.
3. The process for the synthesis of minoxidil according to claim 1, wherein: the acid regulator used in the condensation reaction stage post-treatment is selected from one of saturated citric acid aqueous solution, saturated tartaric acid aqueous solution, saturated malic acid aqueous solution and saturated lactic acid aqueous solution.
4. The process for the synthesis of minoxidil according to claim 2, characterized in that: the reducing salt in the oxidation reaction stage is sodium sulfite.
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| CN107987027A (en) * | 2018-01-18 | 2018-05-04 | 天津药物研究院药业有限责任公司 | A kind of minoxidil crystal, preparation method and the pharmaceutical composition containing this crystal |
| CN110272391B (en) * | 2019-07-03 | 2022-10-28 | 天津药物研究院药业有限责任公司 | Refining method of minoxidil |
| CN113979952A (en) * | 2021-10-28 | 2022-01-28 | 昆明源瑞制药有限公司 | Preparation method of minoxidil |
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