CN107129470A - A kind of synthesis of minoxidil and process for purification - Google Patents
A kind of synthesis of minoxidil and process for purification Download PDFInfo
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- CN107129470A CN107129470A CN201710439588.4A CN201710439588A CN107129470A CN 107129470 A CN107129470 A CN 107129470A CN 201710439588 A CN201710439588 A CN 201710439588A CN 107129470 A CN107129470 A CN 107129470A
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- minoxidil
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- 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
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The invention discloses a kind of synthesis of minoxidil and process for purification, belong to the field of chemical synthesis.This method is with 2, the chlorine pyrimidine of 4 diaminourea 6 is that raw material obtains minoxidil crude product through low-temperature oxidation, base catalysis condition condensation two-step reaction, then recrystallized through polar solvent, the purification of the techniques such as activated carbon decolorizing obtains sterling minoxidil, sterling high purity 99.7% after refined, is a kind of preparation method easy to operate, being adapted to industrialized production.
Description
Technical field
The invention belongs to the field of chemical synthesis, it is related to synthesis and the process for purification of a kind of minoxidil, specifically this method
Be with 2,4- diaminourea -6- chlorine pyrimidine be raw material it is oxidized, condensation two-step reaction obtain minoxidil crude product, then through being refining to obtain
It is a kind of preparation method of suitable industrialized production to sterling minoxidil.
Background technology
Minoxidil also known as minoxidilum, minoxidil, chemical entitled 6- (1- piperidyls) -2,4- pyrimidinediamine -3- oxides,
It is a kind of antihypertensive of potassium channels opening medicine, there is selectivity for angiectatic effect, with stronger drop
Pressure is acted on, and is clinically generally used with other synthesis depressor compatibilities, for treating anxious Asia property and essential hypertension.Also simultaneously
With the effect for promoting hair regeneration, local topical alopeciaing therapeutic is alternatively arranged as.
The synthetic method of current minoxidil only has a small amount of document report, is specifically following methods：
Using methyl cyanoacetate and guanidine nitrate as raw material, by cyclization, chlorination, oxidation, condensation four-step reaction with obtaining minot
You, total recovery is 25.9%.But the guanidine nitrate that the method is used is raw material, and it easily explodes as explosive wastewater raw material, exist tight
Weight potential safety hazard, it is impossible to realize industrialized production.
The content of the invention
The present invention be directed to synthesis and the process for purification that above-mentioned problem provides a kind of minoxidil.
The purpose of the present invention can be achieved through the following technical solutions：
A kind of synthesis of minoxidil and process for purification, it is characterised in that：This method is 2,4- diaminourea -6- chlorine pyrimidine warp
Benzoyl hydroperoxide low-temperature oxidation obtains 6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidines, and described 6- amino -
1,2- dihydro -1- hydroxyls -2- imino groups -4- chlorine pyrimidine carries out condensation reaction with hexahydropyridine in the condition that base catalyst is present,
Obtain minoxidil crude product, after obtained crude product is dissolved by heating in a solvent add activated carbon decolorizing, filter, be dried to obtain it is pure
Product minoxidil.
In technical solution of the present invention：The temperature of oxidation reaction is -15-25 DEG C.As preferred：The time of oxidation reaction is 2-
8h。
In technical solution of the present invention：Base catalyst used in condensation reaction is potassium carbonate, potassium hydroxide, sodium hydroxide and acetic acid
At least one of sodium.As preferred：The temperature of condensation reaction is 40-120 DEG C.As preferred：The time of condensation reaction is 4-
12h。
In technical solution of the present invention：Solvent used in dissolving crude product is one kind or several in methanol, ethanol, acetone, acetonitrile
Plant the mixing of solvent.
Beneficial effect：
This law has reaction condition gentle, and safe operation, reactions steps are few, convenient post-treatment, and product yield is high, by essence
Purity is up to more than 99.5% after system.It is a kind of safety simple to operate, cost is low, be easy to the effective ways of industrialized production.
Embodiment
With reference to embodiment, the present invention will be further described, but protection scope of the present invention not limited to this.
Embodiment 1
6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidine is synthesized
Weigh 2,4- diaminourea -6- chlorine pyrimidines (323g, 2.0mol, 1.0eq), dichloromethane (970mL) and be added to 2L's
In four-hole boiling flask, stirring and dissolving clarification is cooled to -10 DEG C, adds benzoyl hydroperoxide (533g, 2.2mol, 1.1eq), stirring
15min, be then slowly added at -10 DEG C of temperature control 30% sodium hydrate aqueous solution (347g), then heat to 5 DEG C, insulation is anti-
Answer 6h, TLC monitoring raw material disappearances (VDCM/MeOH=15：1) reaction, filtering, dry 6- amino -1,2- dihydro -1- hydroxyls, are stopped
Base -2- imino group -4- chlorine pyrimidine 255g, yield is 79.4%, and it is 189 DEG C to determine fusing point, HPLC purity 97.3%,1H-NMR
(d6-DMSO)δ：3.07 (s, 1H, OH) δ：6.08 (s, 1H, C-H), δ：7.54 (s, H, NH), δ：8.56 (s, 2H, NH2)。
Minoxidil is synthesized
Weigh 6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidines (192.6g, 1.2mol, 1.0eq), 1,
4- dioxane (500mL) is added in 2L four-hole boiling flask, and dissolving clarification is stirred at room temperature, hexahydropyridine is then added
(132.8g, 1.56mol, 1.3eq), potassium carbonate (216g, 1.56mol, 1.3eq), is warming up to 100 DEG C of reaction 4h, TLC monitoring former
Material disappearance (VCHCl3/MeOH=10：1), stop reaction, be cooled to 5 DEG C, separate out solid, filtering produces minoxidil crude product 201g,
Yield is 80.2%, and purity is 94.8%.
Minoxidil is refined
201g minoxidils crude product is added to 3000mL ethanol, heating is completely dissolved, cooled down, be added dropwise 3200 milliliters
Water, is stirred at room temperature 1h, obtains faint yellow product；Filtering, drying.The minoxidils of 190g after purification are dissolved in 2500mL methanol
In, after heating is completely dissolved, plus activated carbon decolorizing, filtering, 0 DEG C is cooled to, filtering, 50 DEG C of vacuum drying produce white solid
Minoxidil highly finished product 172g, yield is 85.6%.Determine m.p：271 DEG C, purity 99.6%.
Embodiment 2
6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidine is synthesized
Weigh 2,4- diaminourea -6- chlorine pyrimidines (582g, 3.6mol, 1.0eq), dichloromethane (1800mL) and be added to 5L's
In four-hole boiling flask, stirring and dissolving clarification is cooled to -10 DEG C, adds benzoyl hydroperoxide (1046g, 4.32mol, 1.2eq), stirring
15min, be then slowly added at -10 DEG C of temperature control 30% sodium hydrate aqueous solution (720g), then heat to 15 DEG C, insulation is anti-
Answer 4h, TLC monitoring raw material disappearances (VDCM/MeOH=15：1) reaction, filtering, dry 6- amino -1,2- dihydro -1- hydroxyls, are stopped
Base -2- imino group -4- chlorine pyrimidine 492g, yield is 85.1%, and it is 190 DEG C to determine fusing point.
Minoxidil is synthesized
Weigh 6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidines (192.6g, 1.2mol, 1.0eq), second
Nitrile (400mL) is added in 1L four-hole boiling flask, be stirred at room temperature dissolving clarification, then add hexahydropyridine (153.3g,
1.80mol, 1.5eq), potassium hydroxide (100.8g, 1.80mol, 1.5eq), be warming up to 80 DEG C reaction 7h, TLC monitoring raw materials disappear
Lose (VCHCl3/MeOH=10：1), stop reaction, be cooled to 5 DEG C, separate out solid, filtering produces minoxidil crude product 218.5g, received
Rate is 87%, and purity is 96.1%.
Minoxidil is refined
218g minoxidils crude product is added to 1600mL acetonitrile and 400mL methanol, heating is completely dissolved, cooled down, drop
Plus 2400 milliliters of water, 1h is stirred at room temperature, faint yellow product is obtained；Filtering, drying.The minoxidils of 209g after purification are dissolved in
In 1500mL acetonitriles, after heating is completely dissolved, plus activated carbon decolorizing, filtering, 0 DEG C is cooled to, is filtered, 50 DEG C of vacuum drying, i.e.,
White solid minoxidil highly finished product 201g is obtained, yield is 92.2%.Determine m.p：272 DEG C, purity 99.7%.
Claims (7)
1. synthesis and the process for purification of a kind of minoxidil, it is characterised in that：This method is that 2,4- diaminourea -6- chlorine pyrimidine passes through
Oxybenzoic acid low-temperature oxidation obtains 6- amino -1,2- dihydro -1- hydroxyl -2- imino group -4- chlorine pyrimidines, described 6- amino -1,
2- dihydros -1- hydroxyls -2- imino groups -4- chlorine pyrimidine carries out condensation reaction with hexahydropyridine in the condition that base catalyst is present, and obtains
Activated carbon decolorizing is added to minoxidil crude product, after obtained crude product is dissolved by heating in a solvent, filters, be dried to obtain sterling
Minoxidil.
2. synthesis and the process for purification of minoxidil according to claim 1, it is characterised in that：The temperature of oxidation reaction
For -15-25 DEG C.
3. the synthesis of minoxidil according to claim 1 and refined method, it is characterised in that：The time of oxidation reaction
For 2-8h.
4. synthesis and the process for purification of minoxidil according to claim 1, it is characterised in that：Alkali is urged used in condensation reaction
Agent is at least one of potassium carbonate, potassium hydroxide, sodium hydroxide and sodium acetate.
5. synthesis and the process for purification of minoxidil according to claim 1, it is characterised in that：The temperature of condensation reaction is
40-120℃。
6. synthesis and the process for purification of minoxidil according to claim 1, it is characterised in that：The time of condensation reaction is
4-12h。
7. synthesis and the process for purification of minoxidil according to claim 1, it is characterised in that：It is molten used in dissolving crude product
Agent be methanol, ethanol, acetone, acetonitrile in one or more of solvents mixing.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201710439588.4A CN107129470A (en) | 2017-06-12 | 2017-06-12 | A kind of synthesis of minoxidil and process for purification |
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| CN201710439588.4A CN107129470A (en) | 2017-06-12 | 2017-06-12 | A kind of synthesis of minoxidil and process for purification |
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110272391A (en) * | 2019-07-03 | 2019-09-24 | 天津药物研究院药业有限责任公司 | A kind of refining methd of minoxidil |
| CN113979952A (en) * | 2021-10-28 | 2022-01-28 | 昆明源瑞制药有限公司 | Preparation method of minoxidil |
| CN114315738A (en) * | 2022-01-15 | 2022-04-12 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
| CN115572265A (en) * | 2022-10-10 | 2023-01-06 | 江苏海悦康医药科技有限公司 | Green synthesis process of high-purity minoxidil |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3644364A (en) * | 1970-03-31 | 1972-02-22 | Upjohn Co | Compounds and process |
-
2017
- 2017-06-12 CN CN201710439588.4A patent/CN107129470A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3644364A (en) * | 1970-03-31 | 1972-02-22 | Upjohn Co | Compounds and process |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN110272391A (en) * | 2019-07-03 | 2019-09-24 | 天津药物研究院药业有限责任公司 | A kind of refining methd of minoxidil |
| 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 |
| CN114315738A (en) * | 2022-01-15 | 2022-04-12 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
| CN114315738B (en) * | 2022-01-15 | 2023-08-18 | 重庆东寰科技开发有限公司 | Preparation method of 2,4-diaminopyrimidine-3-oxide |
| CN115572265A (en) * | 2022-10-10 | 2023-01-06 | 江苏海悦康医药科技有限公司 | Green synthesis process of high-purity minoxidil |
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