CN110272391B - Refining method of minoxidil - Google Patents
Refining method of minoxidil Download PDFInfo
- Publication number
- CN110272391B CN110272391B CN201910596438.3A CN201910596438A CN110272391B CN 110272391 B CN110272391 B CN 110272391B CN 201910596438 A CN201910596438 A CN 201910596438A CN 110272391 B CN110272391 B CN 110272391B
- Authority
- CN
- China
- Prior art keywords
- minoxidil
- isopropanol
- water
- refining
- crude product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/74—Separation; Purification; Use of additives, e.g. for stabilisation
- C07C29/76—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment
- C07C29/80—Separation; Purification; Use of additives, e.g. for stabilisation by physical treatment by distillation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
- C07D239/28—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 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/50—Three nitrogen atoms
Abstract
The invention relates to a method for refining minoxidil, which adopts isopropanol and water as refining solvents to refine a minoxidil crude product, and comprises the following specific refining steps: taking a minoxidil crude product, and dissolving the minoxidil crude product with isopropanol and water; step two, heating and dissolving, and filtering while the solution is hot to obtain a minoxidil refined solution; step three, cooling and crystallizing the minoxidil refined solution, filtering the crystal liquid, washing and drying to obtain refined minoxidil; the weight ratio of the crude minoxidil, isopropanol and water is 1:3-6:3-6, and the weight ratio of the crude minoxidil, isopropanol and water is preferably 1:3-5:4-6. The scheme is simple and convenient to operate, the refining process is low in toxicity and corrosion, the refining process can be recycled and reused, the product content is improved to over 99.7% from 98.5%, the product yield is 90-95%, isopropanol can be recycled, low cost and high yield are really realized, and the method is very suitable for industrial production.
Description
Technical Field
The invention relates to a method for refining minoxidil.
Background
Minoxidil is available under the trade name of minoxidil and minoxidil. The chemical name is 6- (1-piperidyl) -2,4-pyrimidinediamine-3-oxide, which is white or white-like crystalline powder and has a molecular formula: c 9 H 15 N 5 O, molecular weight: 209.2, it mainly acts on the vascular wall, dilates arterioles, and reduces blood pressure, and is used to treat intractable hypertension, essential hypertension or renal hypertension. Minoxidil solution can also be usedFor preventing seborrheic alopecia. The structural formula is as follows:
the documents of the domestic minoxidil refining methods are few, and in the prior patents, a pure organic solvent is generally used as a refining solvent, for example, isopropanol is used as the refining solvent (patent number 201710478721.7, publication number CN107235919A, patent name is a minoxidil synthesis process), and methanol, acetone and the like are used as the refining solvent (patent number 201710439588.4, publication number CN107129470A, patent name is a minoxidil synthesis and refining method); in the technical content, the isopropanol is used as a refined solvent, so that the cost is high, the crystallization time is 10 hours, the working time is long, and the purity of the obtained refined minoxidil is only 92 percent, which is very unfavorable for industrial production; methanol and acetone are used as refined solvents, the methanol is a second solvent with high toxicity, the acetone is an easily toxic solvent, and the mixed solvent has certain influence on the environment. In addition, the foreign synthesis method and the purification method are very complex, and the content and the yield are low, so that the requirements of industrial production are difficult to meet.
Disclosure of Invention
In order to solve the technical problems, the invention provides a method for refining minoxidil.
The technical scheme adopted by the invention is as follows: a method for refining minoxidil comprises refining a minoxidil crude product by using isopropanol and water as refining solvents.
Preferably, the specific refining steps are as follows:
taking a minoxidil crude product, and dissolving the minoxidil crude product with isopropanol and water;
step two, heating and dissolving, and filtering while the solution is hot to obtain a minoxidil refined solution;
and step three, cooling and crystallizing the minoxidil refined solution, filtering the crystal liquid, washing and drying to obtain the refined minoxidil.
Preferably, the weight ratio of the crude minoxidil, the isopropanol and the water is 1:3-6:3-6, and the weight ratio of the crude minoxidil, the isopropanol and the water is 1:3-5:4-6.
Preferably, the temperature for heating for dissolution in step two is 75-90 deg.C, preferably 80-85 deg.C.
Preferably, the third step is to cool the minoxidil refined solution at 10-30 ℃, keep the temperature and stir for 1-2h to form a crystal liquid, the stirring speed is 30-80r/min, the crystal liquid is filtered, the obtained crystal is washed once by water and dried under the vacuum environment of 70-80 ℃, the vacuum degree is-0.07-0.09 MPa, and the drying time is 1-12h.
Preferably, the cooling and stirring time is 1-1.5h, and the stirring speed is 30-50r/min.
The invention has the advantages and positive effects that:
the scheme 1 is simple and convenient to operate, the refining process is low in toxicity and corrosion and can be recycled, the product content is improved from 98.5% to more than 99.7%, the product yield is 90-95%, the low cost and high yield are really realized, and the method is very suitable for industrial production;
2, due to the difference of boiling points between isopropanol (boiling point 82.4 ℃) and water (boiling point 100 ℃), by utilizing a rectification technology, the recovery rate of the isopropanol is 80-90%, the content of the recovered isopropanol is 95-98%, and the isopropanol can be recycled; the main component of the recovered waste liquid is water, and the waste liquid is sent into a sewage treatment system, so that the zero discharge of sewage in the production process is realized, and the environmental protection is facilitated.
Detailed Description
An embodiment of the present invention is explained below.
The invention relates to a method for refining minoxidil, which adopts isopropanol and water as refining solvents to refine a minoxidil crude product.
The refining steps are as follows:
taking a minoxidil crude product, and dissolving the minoxidil crude product with isopropanol and water;
step two, heating and dissolving, and filtering while the solution is hot to obtain a minoxidil refined solution;
and step three, cooling and crystallizing the minoxidil refined solution, filtering the crystal liquid, washing and drying to obtain the refined minoxidil.
The specific implementation steps can be carried out according to the following method:
adding isopropanol and water into a reaction kettle, adding a minoxidil crude product while stirring, and dissolving the minoxidil crude product by using the isopropanol and the water, wherein the isopropanol and the water are added according to the weight ratio of 1:3-6:3-6;
step 2, heating the reaction kettle to 75-90 ℃, refluxing for 30min, filtering while the solid materials of the minoxidil crude product are completely dissolved, and feeding the filtrate into a crystallization kettle to obtain a minoxidil refined solution;
step 3, cooling the minoxidil refined solution in the crystallization kettle to 10-30 ℃, keeping the temperature and stirring for 1-2 hours to form a crystal liquid, wherein the stirring speed is 30-80r/min, filtering the crystal liquid, washing the obtained crystal with water once, drying the crystal in a vacuum environment at 70-80 ℃, and obtaining refined minoxidil, wherein the vacuum degree is-0.07-0.09 MPa, and the drying time is 1-12 hours;
refining to obtain refined minoxidil with melting point of 272 ℃, HPLC content of 99.87% (normalization method), white crystalline powder product appearance, weighing the weight and calculating the yield, the scheme is used for industrial production, and the filtrate can be further treated and recycled;
and step 4, pumping the filtrate into a rectifying still, controlling the temperature to be 82-86 ℃, and distilling at normal pressure to recover the isopropanol.
In order to further improve the purity of the minoxidil, the crude minoxidil in the step 1 can be controlled, and isopropyl alcohol and water are added according to the weight ratio of 1:3-5:4-6. The refining effect of the present solution is further verified by several examples below.
Example 1
1.1 Material proportioning Table
1.2 detailed procedures
In a 2000L reactor, the vacuum stop was opened, 300kg of isopropanol and 600kg of water were pumped into the kettle, and the vacuum was turned off. Stirring, and adding the minoxidil crude product from a kettle mouth. Opening a steam stop valve, slowly heating to 80-85 ℃, refluxing for 30 minutes, filtering when the solid materials are completely dissolved, feeding the filtrate into a crystallization kettle while the solid materials are hot, stirring (40 r/min), opening a cooling medium stop valve of the crystallization kettle after the filtration is finished, cooling the filtrate to 10-20 ℃, and stirring for 1 hour. And opening a lower port cut-off valve of the crystallization kettle, opening a centrifugal machine for spin-drying, washing a filter cake once with water, and continuously spin-drying. And (3) placing the filter cake into a tray, putting the tray into a vacuum drying oven, controlling the drying temperature to be 70-80 ℃, controlling the vacuum degree to be-0.07-0.09 MPa, and drying for 12 hours. Weighing 94kg of the product, and obtaining 94% of yield. The melting point was determined to be 272 ℃ and the HPLC content was 99.87% (normalization), and the product was a white crystalline powder in appearance.
Then the filtrate is pumped into a rectifying still, the temperature is controlled at 82-86 ℃, and the normal pressure distillation is carried out, thus obtaining 246kg of isopropanol with 96.9 percent of content and 82 percent of recovery rate.
Example 2
2.1 Material proportioning Table
2.2 detailed procedures
In a 2000L reactor, the vacuum stop was opened, 500kg of isopropanol and 400kg of water were pumped into the kettle, and the vacuum was turned off. Stirring, and adding the minoxidil crude product from a kettle mouth. Opening a steam stop valve, slowly heating to 80-85 ℃, refluxing for 30 minutes, filtering when solid materials are completely dissolved, putting the filtrate into a crystallization kettle while the solid materials are hot, stirring (30 revolutions per minute), opening a cooling medium stop valve of the crystallization kettle after the filtration is finished, cooling the filtrate to 10-20 ℃, and stirring for 1 hour. And opening a lower port cut-off valve of the crystallization kettle, opening a centrifugal machine for spin-drying, washing a filter cake once with water, and continuously spin-drying. And (3) placing the filter cake into a tray, putting the tray into a vacuum drying oven, controlling the drying temperature to be 70-80 ℃, controlling the vacuum degree to be-0.07-0.09 MPa, and drying for 12 hours. Weighing the mixture to obtain 91kg of product with the yield of 91 percent. The melting point was determined to be 272 ℃ and the HPLC content was 99.81% (normalization), and the product was a white crystalline powder in appearance.
Then pumping the filtrate into a rectifying still, controlling the temperature at 82-86 ℃, and distilling at normal pressure. 430kg of isopropanol with the content of 96.4 percent and the recovery rate of 86 percent is obtained.
Example 3
3.1 Material proportioning Table
3.2 detailed procedures
In a 2000L reactor, the vacuum stop was opened, 350kg of isopropanol and 550kg of water were pumped into the kettle, and the vacuum was turned off. Stirring, and adding the minoxidil crude product from a kettle mouth. Opening a steam stop valve, slowly heating to 80-85 ℃, refluxing for 30 minutes, filtering when the solid materials are completely dissolved, feeding the filtrate into a crystallization kettle while the solid materials are hot, stirring (40 revolutions per minute), opening a cooling medium stop valve of the crystallization kettle after the filtration is finished, cooling the filtrate to 10-20 ℃, and stirring for 1 hour. And opening a lower port cut-off valve of the crystallization kettle, opening a centrifugal machine for spin-drying, washing a filter cake once with water, and continuously spin-drying. And (3) placing the filter cake into a tray, putting the tray into a vacuum drying oven, controlling the drying temperature to be 70-80 ℃, controlling the vacuum degree to be-0.07-0.09 MPa, and drying for 12 hours. Weighing to obtain 90kg of product, and the yield is 90%. The melting point was found to be 271 ℃ and the HPLC content was found to be 100% (normalization), and the product was white crystalline powder in appearance.
And pumping the filtrate into a rectifying still, controlling the temperature at 82-86 ℃, and distilling at normal pressure. 294kg of isopropanol is obtained, the content is 97 percent, and the recovery rate is 84 percent.
The effect of the present invention is further illustrated by comparing experimental data of the present scheme and the prior art, the results are shown in the following table:
TABLE 1
As can be seen from the contents in table 1, the yield of this solution is significantly higher than that of the two comparative solutions, and the total content of impurities is also lower, wherein the example of CN107129470a uses methanol and acetone as the delicate solvent, and the effect is slightly inferior to that of this solution, while the example of CN107235919a using pure isopropanol as the delicate solvent, both the delicate effect and the yield are much lower than those of the present solution. Therefore, the scheme really achieves the production purposes of low toxicity, low corrosion, low cost and high yield in the refining process.
While one embodiment of the present invention has been described in detail, the description is only a preferred embodiment of the present invention and should not be taken as limiting the scope of the invention. All equivalent changes and modifications made within the scope of the present invention shall fall within the scope of the present invention.
Claims (1)
1. A method for refining minoxidil is characterized by comprising the following steps: isopropanol and water are used as refining solvents to refine the minoxidil crude product;
the refining steps are as follows:
taking a minoxidil crude product, dissolving the minoxidil crude product with isopropanol and water, wherein the weight ratio of the isopropanol to the water is 1:3-5:4-6;
step two, heating and dissolving at the temperature of 80-85 ℃, and filtering while the solution is hot to obtain a minoxidil refined solution;
step three, cooling and crystallizing the minoxidil refined solution, filtering the crystal liquid, washing and drying to obtain refined minoxidil; rectifying to recover isopropanol; cooling the minoxidil refined solution at 10-30 ℃, stirring for 1-2h at the constant temperature to form a crystal liquid, wherein the stirring speed is 30-50r/min, the duration is 1-1.5h, filtering the crystal liquid, washing the obtained crystal with water once, and drying at 70-80 ℃ in a vacuum environment, wherein the vacuum degree is-0.07-0.09 MPa, and the drying time is 1-12h.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910596438.3A CN110272391B (en) | 2019-07-03 | 2019-07-03 | Refining method of minoxidil |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910596438.3A CN110272391B (en) | 2019-07-03 | 2019-07-03 | Refining method of minoxidil |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110272391A CN110272391A (en) | 2019-09-24 |
| CN110272391B true CN110272391B (en) | 2022-10-28 |
Family
ID=67962843
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910596438.3A Active CN110272391B (en) | 2019-07-03 | 2019-07-03 | Refining method of minoxidil |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110272391B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113979952A (en) * | 2021-10-28 | 2022-01-28 | 昆明源瑞制药有限公司 | Preparation method of minoxidil |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0295218A1 (en) * | 1987-05-08 | 1988-12-14 | ISTITUTO FARMACOLOGICO SERONO SpA | A process for the preparation of 2,4-diamino-6-(1-piperidinyl)-pyrimidine N-oxide |
| US4959475A (en) * | 1989-01-04 | 1990-09-25 | Lonza Ltd. | Process for the production of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide |
| US4986563A (en) * | 1989-07-21 | 1991-01-22 | Grant Fred W | Emergency hand truck |
| CN107129470A (en) * | 2017-06-12 | 2017-09-05 | 常州市天华制药有限公司 | A kind of synthesis of minoxidil and process for purification |
| CN107235919A (en) * | 2017-06-22 | 2017-10-10 | 安徽拜善晟制药有限公司 | A kind of synthesis technique of minoxidil |
-
2019
- 2019-07-03 CN CN201910596438.3A patent/CN110272391B/en active Active
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0295218A1 (en) * | 1987-05-08 | 1988-12-14 | ISTITUTO FARMACOLOGICO SERONO SpA | A process for the preparation of 2,4-diamino-6-(1-piperidinyl)-pyrimidine N-oxide |
| US4959475A (en) * | 1989-01-04 | 1990-09-25 | Lonza Ltd. | Process for the production of 2,4-diamino-6-piperidinyl-pyrimidine-3-N-oxide |
| US4986563A (en) * | 1989-07-21 | 1991-01-22 | Grant Fred W | Emergency hand truck |
| CN107129470A (en) * | 2017-06-12 | 2017-09-05 | 常州市天华制药有限公司 | A kind of synthesis of minoxidil and process for purification |
| CN107235919A (en) * | 2017-06-22 | 2017-10-10 | 安徽拜善晟制药有限公司 | A kind of synthesis technique of minoxidil |
Non-Patent Citations (1)
| Title |
|---|
| 以偏简单溶液理论指导长压定精制工艺;金小吾，等;《中国医药工业杂志》;19911231;第22卷(第1期);第440-442页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110272391A (en) | 2019-09-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108658858A (en) | A kind of preparation method of the preparation and process for purification and its sulfate of hydroxychloroquine | |
| CN107337618B (en) | Production method for simultaneously improving purity and yield of metformin hydrochloride | |
| CN110590746A (en) | Preparation method of low-impurity vonoprazan fumarate | |
| CN111548323B (en) | Recovery method of aminothiazoly loximate | |
| CN110272391B (en) | Refining method of minoxidil | |
| CN112062802A (en) | Chenodeoxycholic acid butyl acetate extracting solution and preparation method thereof, and chenodeoxycholic acid ammonium salt and chenodeoxycholic acid preparation method | |
| CN113372227A (en) | Synthesis process of high-purity benzethonium chloride | |
| CN104592004A (en) | Long chain organic acid refining method | |
| CN104355990B (en) | Method for recycling and mechanically using L- (+) -tartaric acid in D-ethyl ester production | |
| CN113979877A (en) | Refining method for improving purity of 4-chloro-2-trifluoroacetylaniline mother liquor | |
| CN109456172B (en) | Method for purifying dodecanedioic acid in water phase | |
| CN110407737B (en) | Preparation method of cyproheptadine hydrochloride | |
| CN106188023A (en) | A kind of process for purification of epirizole group | |
| CN112979592A (en) | Improved process for refining and crystallizing furan ammonium salt | |
| CN106279108B (en) | A kind of method of industrialized production Rabeprazole and dextral-rabeprazole intermediate | |
| CN115850199B (en) | Preparation method of high-purity sodium sulfaisoxazole | |
| CN115385787B (en) | Preparation method of 2-carboxyl benzaldehyde | |
| CN110857279B (en) | Preparation method of 2-acrylamide-2-methylpropanesulfonic acid | |
| JP2019525946A (en) | Method for producing hydronidone | |
| CN108101836A (en) | A kind of method for preparing Cilnidipine impurity or its oxide impurity | |
| CN111825614B (en) | Preparation method of gliquidone intermediate | |
| CN108864090B (en) | A kind of preparation method of Eliquis N-1 crystal | |
| CN116969922A (en) | Refining method of mizolastine | |
| JP2019524811A (en) | Method for producing hydronidone | |
| CN115385849A (en) | Method for purifying N-Boc-3-fluoro-4-piperidone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |