CN106967069A - A kind of preparation method of triamterene - Google Patents
A kind of preparation method of triamterene Download PDFInfo
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- CN106967069A CN106967069A CN201710172907.XA CN201710172907A CN106967069A CN 106967069 A CN106967069 A CN 106967069A CN 201710172907 A CN201710172907 A CN 201710172907A CN 106967069 A CN106967069 A CN 106967069A
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- Prior art keywords
- triamterene
- preparation
- sodium
- solvent
- refining
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D475/00—Heterocyclic compounds containing pteridine ring systems
- C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
- C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
Abstract
The present invention relates to a kind of preparation method of triamterene, comprise the following steps：5 nitrosos 2 are added into condensation reaction kettle, 4,6 Triaminopyrimidines and benzene acetonitrile, add aprotic polar solvent and add base catalyst under agitation, 0 50 DEG C are cooled to after being warming up to 50 120 DEG C of 3 10h of insulation, triamterene crude product is filtered to obtain, crude product is refined using aprotic polar solvent, washing produces end product ammonia phenyl pteridine.The present invention uses suitable solvent for reaction and refining solvent, can make reaction yield up to 85.7%, effectively reduce production cost, reduce the pollutant emissions such as waste water；Using suitable solvent refining, refining solvent usage amount is effectively reduced, purification efficiency is improved, refining solvent can be recovered by distillation and apply mechanically again, and no waste water is produced, and environmental pollution is small, material can be recycled, the features such as product purity is high, suitable further genralrlization application.
Description
Technical field
The present invention relates to chemosynthesis technical field, and in particular to a kind of preparation method of triamterene.
Background technology
Triamterene, chemical name is 2,4,7- triamido -6- phenyl pteridine, and medicine alias is Ademine, English name
Title is Dyrenium, Urocaudol, Pterofen, Triamterene, and molecular formula is C12H11N7, molecular weight is 253.27, is melted
316 DEG C of point, yellow crystalline powder is atomic to be dissolved in glacial acetic acid, is practically insoluble in water, ethanol, chloroform, odorless, tasteless；Structural formula
For：
It is mainly used in isokalaemic diuretic, clinically for controlling
Refractory edema or ascites caused by heart failure, hepatic sclerosis and chronic nephritis etc. are treated, also for Hydrochioro or spirolactone
Invalid case.
In the prior art, triamterene preparation (referring to medical technique collect the 428-430 pages) be by 5- nitroso -2,
4,6- Triaminopyrimidines and absolute ethyl alcohol flow back together, add part benzene acetonitrile and caustic alcohol, its surplus benzene is added after backflow
Acetonitrile and caustic alcohol, continue to flow back, and are cooled to 10 DEG C or so, filtering is washed with boiling water, obtains triamterene crude product.By crude product, dense
Sulfuric acid and activated carbon are added in the water of 80 times of crude product weight, and backflow is filtered while hot, and filtrate is heated to boiling, adds EDETATE DISODIUM,
Adjusted to pH=9, filtered with concentrated ammonia liquor, washed, dried, obtain finished product, the advantage of the technique is sodium alkoxide catalysis, and yield is
70.88%, 3000L kettle refine it is a collection of about finished product 18kg, production one ton of triamterene nearly hundred tons of acid waste water of generation, shortcoming
It is：Crude product is washed and refined wastewater amount is especially big, produces the very intractable waste water of very large amount, and pollution is big.People in the art
It is to make catalyst using solid sodium hydroxide and sodium carbonate mixed base that what member was carried out to this technique, which is partially improved, may be such that yield reaches
73%, but subtractive process still uses 80 times of crystal's system, still produces substantial amounts of difficult waste water.In view of the above-mentioned problems, exploitation one
The preparation method for planting the triamterene that yield is higher, post processing waste water is less is that those skilled in the art's technology urgently to be resolved hurrily is asked
Topic.
The content of the invention
The technical problems to be solved by the invention are：To overcome the technical problem mentioned in above-mentioned background technology, there is provided one
Plant the preparation method for the triamterene that yield is higher, post processing waste water is less.
The technical solution adopted for the present invention to solve the technical problems is：
A kind of preparation method of triamterene, the preparation method comprises the following steps：
Step 1) crude product preparation
5- nitrosos -2,4,6- Triaminopyrimidines and benzene acetonitrile are added into condensation reaction kettle, aprotonic polar is added molten
Agent, is added dropwise or adds base catalyst by several times, system is warming up to 50-120 DEG C by base catalyst addition after terminating under agitation
It is incubated 3-10h；Insulation is cooled to 0-50 DEG C and filters to obtain triamterene crude product and filtrate, crude product refining, after filtrate distillation after terminating
Reuse；
Step 2) it is refined
Above-mentioned triamterene crude product is put into refining kettle, refining solvent is added, is warming up to 100-150 DEG C and filters while hot,
Filtrate is cooled to 0-30 DEG C, filters, and triamterene finished product is dried to obtain in washing.
The step 1) in aprotic polar solvent be N, N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide
(DMAC), sulfolane, 1-METHYLPYRROLIDONE (NMP), hexamethyl phosphoramide (HMPA), acetonitrile, tetrahydrofuran, dimethyl sulfoxide (DMSO)
(DMSO), one or more of mixtures in 1,3- methylimidazoles alkanone (DMI)；Base catalyst is inorganic base solid, alcohol
One or more of mixtures in sodium solid, inorganic base alcoholic solution or sodium alkoxide alcoholic solution；The step 2) in refining solvent
It is：N, N-dimethylformamide, DMAC N,N' dimethyl acetamide, sulfolane, 1-METHYLPYRROLIDONE (NMP), hexamethyl phosphoramide
(HMPA), one or more of mixed solvents in dimethyl sulfoxide (DMSO), 1,3- methylimidazole alkanones.
Further limit, above-mentioned technical proposal step 1) in, benzene acetonitrile and 5- nitrosos -2,4,6- Triaminopyrimidines mole
Amount ratio is (1.2~3.0):1；The mol ratio of 5- nitrosos -2,4,6- Triaminopyrimidines and base catalyst is：1:(0.01~
0.65)；Aprotic polar solvent is (2-15) with 5- nitroso -2,4,6- Triaminopyrimidines mass ratio：1, aprotonic polar is molten
Agent is DMAC N,N' dimethyl acetamide；The step 2) in, refining solvent is (8-18) with triamterene crude product quality ratio:1, refine
Solvent is DMAC N,N' dimethyl acetamide.
Further preferably, the step 1 of above-mentioned technical proposal) in, benzene acetonitrile and 5- nitrosos -2,4,6- Triaminopyrimidines rub
Your amount ratio is (1.5~1.85):1；5- nitrosos -2,4,6- Triaminopyrimidines：Base catalyst mol ratio is 1:(0.15~
0.40)；Aprotic polar solvent is (3-8) with 5- nitroso -2,4,6- Triaminopyrimidines mass ratio：1；The step 2) in,
Refining solvent is (10-18) with triamterene crude product quality ratio:1, refining solvent is DMA.
Further limit, the step 1 of above-mentioned technical proposal) in, inorganic base solid is bicarbonate in described base catalyst
One kind in sodium, sodium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide；Sodium alkoxide solid is sodium methoxide, caustic alcohol or the tert-butyl alcohol
One kind in sodium；
Further preferably, described base catalyst is one kind in sodium hydroxide, potassium hydroxide or alcohol sodium alcohol solution
Or two kinds of combination.
Further limit, the step 1 of above-mentioned technical proposal) in, alkali content >=96.0% in the inorganic base solid；Sodium alkoxide
Total alkali is 18.5-20% in alcoholic solution, it is preferable that the sodium alkoxide alcoholic solution is alcohol sodium alcohol solution.
Further limit, in above-mentioned technical proposal, benzene acetonitrile content >=99.0% in the benzene acetonitrile, moisture≤
0.5%；5- nitrosos -2,4,6- Triaminopyrimidines are red powder, content >=98.5%, moisture≤1.0%；Caustic alcohol ethanol
Solution is brownish red or weak yellow liquid；Solid caustic soda is white plates or granular solids；DMAC N,N' dimethyl acetamide (DMAC) is nothing
Color transparency liquid, purity >=99.5% meets HG/T4470-2012 standards.What is used in technical scheme is feed stock
Matter is：1. natrium carbonicum calcinatum：White, off-white color crystallization or crystalline powder, content >=99.0%；2. sodium acid carbonate：White knot
Crystalline substance powder, total alkali content >=99.0% meets GB/T1606-2008；3. solid potassium hydroxide：This product is greyish white, bluish-green or light
Purple sheet or bulk, content >=90.0% meet GB/T1919-2000；4. anhydrous lithium hydroxide：White particle, purity >=
98.0%；5. DMAC N,N' dimethyl acetamide：Colourless transparent liquid, purity >=99.5% meets HG/T4470-2012 standards；⑥
Sulfolane：It is colourless to light yellow transparent liquid, content >=99.0%；7. acetonitrile：Colourless transparent liquid, content >=99.0%, symbol
Close SH/T1627-2014；8. hexamethyl phosphoramide (HMPA)：Colourless or light yellow transparent liquid, content >=99.0%；9. tetrahydrochysene
Furans (THF)：Colourless transparent liquid, content >=99.8%；10. DMSO is colourless transparent liquid or crystal, meets GB/T21395-
2008。
Beneficial effect：Compared with prior art, using technical scheme, 3000L kettles refine a collection of 150kg, receive
Rate can effectively reduce production cost up to 85.7%, reduce the pollutant emissions such as waste water；Using solvent refining, essence is effectively reduced
Solvent usage amount processed, improves purification efficiency, and refining solvent can be recovered by distillation and apply mechanically again, and no waste water is produced, energy-conserving and environment-protective, fits
Suitable further genralrlization application.
Embodiment
Embodiments illustrated below does not play any restriction effect to the content of the invention described in claim, also, below
The full content of composition represented by embodiment is not limited to necessary to the solution as the invention described in claim.
Embodiment 1
A kind of preparation method of triamterene, it is characterized in that：The preparation method comprises the following steps：
(1) prepared by crude product
400kg reactions are put into reactor and use DMAC, 100kg5- nitrosos -2,4,6- Triaminopyrimidines, 120kg benzene
Acetonitrile, 5kg solid sodium hydroxides open stirring, in 20-30 DEG C, start that 37kg alcohol sodium alcohol solutions are added dropwise, 1-2h is dripped off, drip
Plus 30 DEG C are cooled to after 90-100 DEG C, insulation 5h are to slowly warm up to after terminating, blowing filters to obtain the wet crude product of triamterene.
(2) refine
By in the wet crude product input refining kettle of above-mentioned triamterene, input 1200kg is refined to use DMAC, and stirring is warming up to 110-
120 DEG C, filter while hot, filtrate enters crystallization kettle, filtrate is cooled to 20-25 DEG C, dried after filtering, obtain phenalgin dish pyridine 140.8kg,
Yield is 85.7%, and content is 99.64%.
Embodiment 2
A kind of preparation method of triamterene, it is characterized in that：The preparation method comprises the following steps：
(1) prepared by crude product
400kg reactions are put into reactor and use DMAC, 100kg5- nitrosos -2,4,6- Triaminopyrimidines, 120kg benzene
Acetonitrile, opens stirring, in 20-30 DEG C, starts point 3-4 addition 6kg solid sodium hydroxide and a 8kg sodium carbonate, and 1-2h is added, hydrogen-oxygen
After change sodium is all added, 90-100 DEG C is to slowly warm up to, 5h is incubated, is cooled to 30 DEG C, suction filtration obtains the wet crude product of triamterene.
(2) refine
By in the wet crude product input refining kettle of above-mentioned triamterene, input 1200kg is refined to use DMAC, and stirring is warming up to 110-
120 DEG C, filter while hot, filtrate enters crystallization kettle, filtrate is cooled to 20-25 DEG C, dried after filtering, obtain phenalgin dish pyridine 132kg, receive
Rate is 80.3%, and content is 98.59%.
Embodiment 3
A kind of preparation method of triamterene, it is characterized in that：The preparation method comprises the following steps：
(1) prepared by crude product
400kg reactions are put into reactor and use DMAC, 100kg5- nitrosos -2,4,6- Triaminopyrimidines, 120kg benzene
Acetonitrile, opens stirring, in 20-30 DEG C, point 2 addition 5kg solid potassium hydroxides, and 50kg alcohol sodium alcohol solutions are then added dropwise again,
1-2h is dripped off, and is to slowly warm up to 90-100 DEG C after completion of dropwise addition, is cooled to 30 DEG C after insulation 5h, blowing filter triamterene is wet
Crude product.
(2) refine
By in the wet crude product input refining kettle of above-mentioned triamterene, input 1200kg is refined to use DMAC, and stirring is warming up to 110-
120 DEG C, filter while hot, filtrate enters crystallization kettle, filtrate is cooled to 20-25 DEG C, dried after filtering, obtain phenalgin dish pyridine 137.2kg,
Yield is 83.5%, and content is 99.65%.
Using the above-mentioned desirable embodiment according to the present invention as enlightenment, by above-mentioned description, relevant staff is complete
Various changes and amendments can be carried out without departing from the scope of the technological thought of the present invention' entirely.The technology of this invention
Property scope is not limited to the content on specification, it is necessary to its technical scope is determined according to right.
Claims (7)
1. a kind of preparation method of triamterene, it is characterized in that：The preparation method comprises the following steps：
Step 1) crude product preparation
5- nitrosos -2,4,6- Triaminopyrimidines and benzene acetonitrile are added into condensation reaction kettle, aprotic polar solvent is added,
It is added dropwise under stirring condition or adds base catalyst by several times, system is warming up to 50-120 DEG C of insulation 3- by base catalyst addition after terminating
10h；Insulation is cooled to 0-50 DEG C and filters to obtain triamterene crude product and filtrate after terminating, crude product refining is reused after filtrate distillation；
Step 2) it is refined
Above-mentioned triamterene crude product is put into refining kettle, refining solvent is added, is warming up to 100-150 DEG C and filters while hot, filtrate
0-30 DEG C is cooled to, triamterene finished product is dried to obtain in filtering.
The step 1) in, aprotic polar solvent be DMF (DMF), DMA (DMAC),
Sulfolane, 1-METHYLPYRROLIDONE (NMP), hexamethyl phosphoramide (HMPA), acetonitrile, tetrahydrofuran, dimethyl sulfoxide (DMSO) (DMSO),
One or more of mixtures in 1,3- methylimidazoles alkanone (DMI) etc.；
The step 1) in base catalyst be inorganic base solid, sodium alkoxide solid, inorganic base alcoholic solution or sodium alkoxide alcoholic solution in one
Plant or several mixtures；
The step 2) in refining solvent be：N, N-dimethylformamide, DMAC N,N' dimethyl acetamide, sulfolane, N- methyl pyrroles
It is one or more of in pyrrolidone (NMP), hexamethyl phosphoramide (HMPA), dimethyl sulfoxide (DMSO), 1,3- methylimidazole alkanones
Mixed solvent.
2. a kind of preparation method of triamterene according to claim 1, it is characterized in that：Step 1) in, benzene acetonitrile and 5-
Nitroso -2,4,6- Triaminopyrimidines mole dosage ratio is (1.2~3.0):1；5- nitrosos -2,4,6- Triaminopyrimidines and alkali
The mol ratio of catalyst is：1:(0.1~0.65)；Aprotic polar solvent and 5- nitroso -2,4,6- Triaminopyrimidine quality
Than for (2-15)：1, aprotic polar solvent is DMA；The step 2) in, refining solvent and triamterene
Crude product quality ratio is (8-18):1, refining solvent is DMA.
3. a kind of preparation method of triamterene according to claim 1, it is characterized in that：Step 1) in, described alkali is urged
Inorganic base solid is one kind in sodium acid carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide or lithium hydroxide in agent；Sodium alkoxide is consolidated
Body is one kind in sodium methoxide, caustic alcohol or sodium tert-butoxide.
4. a kind of preparation method of triamterene according to claim 2, it is characterized in that：The step 1) in, benzene acetonitrile
With 5- nitrosos -2,4,6- Triaminopyrimidines mole dosage ratio is (1.5~1.85):1；5- nitrosos -2,4,6- triamidos are phonetic
Pyridine：Base catalyst mol ratio is 1:(0.15~0.40)；Aprotic polar solvent and 5- nitroso -2,4,6- Triaminopyrimidine matter
Amount is than being (3-8)：1.
5. a kind of preparation method of triamterene according to claim 3, it is characterized in that：Step 1) described in base catalyst
For the combination of one or both of sodium hydroxide, potassium hydroxide or alcohol sodium alcohol solution.
6. a kind of preparation method of triamterene according to claim 1, it is characterized in that：Step 1) in, the inorganic base
Alkali content >=96.0% in solid；Total alkali is 18.5-20% in sodium alkoxide alcoholic solution.
7. a kind of preparation method of triamterene according to claim 6, it is characterized in that：The sodium alkoxide alcoholic solution is ethanol
Sodium ethoxide solution.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107629055A (en) * | 2017-09-19 | 2018-01-26 | 湖北美林药业有限公司 | A kind of triamterene compound and preparation method thereof |
| CN113173887A (en) * | 2021-04-01 | 2021-07-27 | 河北利德检测技术有限公司 | Synthetic method of triamterene intermediate |
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| US4252809A (en) * | 1977-01-03 | 1981-02-24 | Rohm Pharma Gmbh | Substituted pteridine compounds and pharmaceutical compositions containing the same |
| HU195817B (en) * | 1985-08-16 | 1988-07-28 | Gyogyszerkutato Intezet | Process for producing 2,4,7-thiamino-6-phenyl-pteridine |
| US4874763A (en) * | 1987-11-28 | 1989-10-17 | Roehm Gmbh Chemische Fabrik | Pharmaceutically efficacious pteridine derivatives |
| US4910203A (en) * | 1984-03-02 | 1990-03-20 | Christian Rietzel | Pteridine compounds |
| US5124326A (en) * | 1989-04-21 | 1992-06-23 | Roehm Gmbh Chemische Fabrik | Pharmaceutically efficacious pteridine derivatives |
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| RU2047616C1 (en) * | 1993-03-17 | 1995-11-10 | Государственный научно-исследовательский институт "Кристалл" | Method of synthesis of 2,4,6-triamino-6-phenylpteridine |
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2017
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| US3081230A (en) * | 1960-09-08 | 1963-03-12 | Smith Kline French Lab | Diuretic and antihypertensive triaminoarylpteridines |
| US4252809A (en) * | 1977-01-03 | 1981-02-24 | Rohm Pharma Gmbh | Substituted pteridine compounds and pharmaceutical compositions containing the same |
| US4910203A (en) * | 1984-03-02 | 1990-03-20 | Christian Rietzel | Pteridine compounds |
| HU195817B (en) * | 1985-08-16 | 1988-07-28 | Gyogyszerkutato Intezet | Process for producing 2,4,7-thiamino-6-phenyl-pteridine |
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| US5124326A (en) * | 1989-04-21 | 1992-06-23 | Roehm Gmbh Chemische Fabrik | Pharmaceutically efficacious pteridine derivatives |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107629055A (en) * | 2017-09-19 | 2018-01-26 | 湖北美林药业有限公司 | A kind of triamterene compound and preparation method thereof |
| CN113173887A (en) * | 2021-04-01 | 2021-07-27 | 河北利德检测技术有限公司 | Synthetic method of triamterene intermediate |
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