CN105585506A - Method for removing impurities in amantadine hydrochloride waste material - Google Patents
Method for removing impurities in amantadine hydrochloride waste material Download PDFInfo
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- CN105585506A CN105585506A CN201510958791.3A CN201510958791A CN105585506A CN 105585506 A CN105585506 A CN 105585506A CN 201510958791 A CN201510958791 A CN 201510958791A CN 105585506 A CN105585506 A CN 105585506A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/82—Purification; Separation; Stabilisation; Use of additives
- C07C209/84—Purification
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/06—Preparation of carboxylic acid amides from nitriles by transformation of cyano groups into carboxamide groups
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a method for removing impurities in an amantadine hydrochloride waste material. The method comprises the following steps of adding 510 L of water, 186 Kg of the waste material and 23.6 L of saturated sodium hydroxide into a reaction kettle, introducing steam into a jacket for boiling the mixture for 2-3 hours, and maintaining pH to be 9-10 in the boiling process; then slowly adding hydrochloric acid for regulating pH value to be 3-4, conducting direct filtration, removing residues, regulating PH value of obtained mother liquor with alkali liquor (sodium hydroxide) to be 10, separating out solids, and conducting filtration, washing and drying, so that an amantadine pure product is obtained.
Description
Technical field
The present invention relates to pharmaceutical technology field, particularly relate to a kind of impurity-removing method of amantadine hydrochloride waste material.
Background technology
Flu is one of modal disease of puzzlement people, is also one of foremost incurable disease in the world. To orderBefore till, the mankind also cannot stop morbidity and the infection of flu completely. In various diseases, flu is modal frequently-occurring disease.Correspondingly, the user of cold drug is also maximum, and they have formed huge cold drug market. Cold drug market isThe fiercest field of China OTC medicine competition. According to statistics, approximately 30,000,000,000 yuan of Chinese OTC drugs consumption total values in 2003, and feelEmit medicine to account for nearly 15% share, approximately 4,000,000,000 yuan of year amount of consumptions, and also annual growth rate is more than 20%. The tempting market space is inhaledDraw numerous pharmaceutical manufacturers and set foot in one after another, fight for market cake. In more than 6000 pharmacy corporation of China, there is family more than 1000 giving birth at presentProduce different types of cold drug, input is not stinted with much money aspect advertisement by fierce market competition Shi Ge cold drug manufacturing enterprise, shortPin means are also varied, had at least twenty or thirty kind by the known cold drug kind of consumer. But investigation shows, in occupation of senseEmit just feeling health, Tylenol, day and night hundred taking several brands such as muddy, New contac capsule, morning-night of medicine market overwhelming majority shares, andThe sales volume of these brands is led over other brand with larger advantage.
Domestic amantadine bulk drug is mainly used in compounded anti-cold preparation, accounts for 77% of total amount, due to delivery outletAmount statistics is incomplete, approximately 30 tons of actual export volumes. Amantadine single preparations of ephedrine output is more stable, 10 tons of year consumption amantadine raw materialsLeft and right. Amantadine veterinary medicine market is increase year after year trend.
Tradition is prepared amantadine and is taked the ammonification again of first bromo, or the first nitrated route restoring, and reaction equation is as follows:
Bromination route is raw materials used normally to be prepared by excessive bromine, and not only price is more expensive, corrosivity also compared with strong andAnd be difficult to reclaim, cause seriously polluted.
Summary of the invention
The object of the invention is for the technological deficiency existing in prior art, and a kind of amantadine hydrochloride waste material is providedImpurity-removing method.
For realizing the technical scheme that object of the present invention adopts be: a kind of high yield is prepared the work of amantadine hydrochlorideSkill, is characterized in that comprising the following steps:
(1) prepare 1-acetylamino adamantane;
1. using the mass fraction of adamantane as 1 as primary standard substance, prepare each component according to following ratio of quality and the number of copies: 1-20 partOleum, the acetonitrile of 0.1-10 part, the carrene of 1-20 part, the water of 1-20 part, the buck of 1-10 part; Described buckMass fraction is 2%;
2. first reactor is shifted to an earlier date to precooling, progressively add oleum, stir 10 minutes, at-5 DEG C, add in batches3/4ths adamantane, in reinforced process, temperature can not exceed 0 DEG C, adds rear lasting stirring half an hour;
3. at-5 DEG C, drip acetonitrile, in dropping process, temperature can not exceed 0 DEG C; Drip off and continue to stir half an hour, slowly riseWarm to 35 DEG C, insulation reaction 3 hours;
4. after becoming clarification, reactant liquor slowly adds the adamantane of residue 1/4th; In reinforced process, keep temperature not go upRise, after adding, stir again 3 hours;
5. in second reactor, add water, and be cooled to below 0 DEG C; Drip the reactant liquor obtaining in step (4), controlTemperature processed can not exceed 10 DEG C, drips and continues to stir half an hour again;
6. in second reactor, add the carrene of 2/3rds quality, and be warming up to 20 DEG C, continue to stir halfHour, there is layering standing half an hour, the carrene that is positioned at lower floor is extracted out and introduced the 3rd reactor;
7. in second reactor, add the carrene of remaining 1/3rd quality, continue to stir half an hour, quietPut and occur layering half an hour, the carrene that is positioned at lower floor is extracted out and introduced the 3rd reactor; In the 3rd reactor, addEnter buck, making its pH value is 10, separates dichloromethane layer, and decompression distillation carrene obtains product 1-acetylamino adamantane.
(2) prepare amantadine hydrochloride;
1. the 1-acetylamino adamantane mass fraction of preparing using step (1) is as 1 as primary standard substance; By the hydrogen of 0.5-5 partSodium oxide molybdena adds in the water of 1-10 part, and stirring and dissolving, then the TBAB that adds 0.001-0.01 part, be poured into high pressureIn still; Pour the ethylene glycol of 5-50 part into autoclave again; Continue the 1-acetyl adamantane that stirring is descended and added 1 part; Continue to stirMix and make most of dissolving; Autoclave is warming up to 190 DEG C gradually;
2. timing during since 190 DEG C, reacts after 12 hours and stops heating, continues to stir, and temperature is down to 40 DEG C and is made, venting,Take out reactant liquor;
3. in reactant liquor, add the hydrochloric acid that 0.5-5 part mass fraction is 36%, regulating the pH value of reactant liquor is 4; DecompressionDistillation ethylene glycol, reduces pressure by vacuum oil pump after heat-conducting oil heating; The hydroxide that in autoclave, suction mass fraction is 0.25%Soda water, stirs rotation; The butyl acetate of suction 1-10 part again, 60 DEG C of heating rotations;
4. cooling after reactant liquor clarification, pours spherical reactor into, and separatory obtains butyl acetate layer and water layer; Wherein, water layerWith the n-butyl acetate extraction of 1-10 part, after stirring separatory, obtain butyl acetate layer, merge the butyl acetate of twice, under stirring, add againEnter pH value and be 4 hydrochloric acid, after fully stirring, point water-yielding stratum; Water layer is carried out obtaining amantadine hydrochloride after decompression distillation.
Preferably, a kind of high yield is prepared the technique of amantadine hydrochloride, it is characterized in that comprising the following steps:
(1) prepare 1-acetylamino adamantane;
1. using the mass fraction of adamantane as 1 as primary standard substance, prepare each component according to following ratio of quality and the number of copies: 5 partsOleum, the acetonitrile of 0.5 part, the carrene of 7 parts, the water of 12 parts, the buck of 3 parts; The mass fraction of described buck is2％；
2. first reactor is shifted to an earlier date to precooling, progressively add oleum, stir 10 minutes, at-5 DEG C, add in batches3/4ths adamantane, in reinforced process, temperature can not exceed 0 DEG C, adds rear lasting stirring half an hour;
3. at-5 DEG C, drip acetonitrile, in dropping process, temperature can not exceed 0 DEG C; Drip off and continue to stir half an hour, slowly riseWarm to 35 DEG C, insulation reaction 3 hours;
4. after becoming clarification, reactant liquor slowly adds the adamantane of residue 1/4th; In reinforced process, keep temperature not go upRise, after adding, stir again 3 hours;
5. in second reactor, add water, and be cooled to below 0 DEG C; Drip the reactant liquor obtaining in step (4), controlTemperature processed can not exceed 10 DEG C, drips and continues to stir half an hour again;
6. in second reactor, add the carrene of 2/3rds quality, and be warming up to 20 DEG C, continue to stir halfHour, there is layering standing half an hour, the carrene that is positioned at lower floor is extracted out and introduced the 3rd reactor;
7. in second reactor, add the carrene of remaining 1/3rd quality, continue to stir half an hour, quietPut and occur layering half an hour, the carrene that is positioned at lower floor is extracted out and introduced the 3rd reactor; In the 3rd reactor, addEnter buck, making its pH value is 10, separates dichloromethane layer, and decompression distillation carrene obtains product 1-acetylamino adamantane.
(2) prepare amantadine hydrochloride;
1. the 1-acetylamino adamantane mass fraction of preparing using step (1) is as 1 as primary standard substance; By the hydroxide of 1 partSodium adds in the water of 2 parts, stirring and dissolving, then add the TBAB of 0.01 part, be poured in autoclave; Again by 10 partsEthylene glycol pour autoclave into; Continue the 1-acetyl adamantane that stirring is descended and added 1 part; Lasting stirring makes most of dissolving;Autoclave is warming up to 190 DEG C gradually;
2. timing during since 190 DEG C, reacts after 12 hours and stops heating, continues to stir, and temperature is down to 40 DEG C and is made, venting,Take out reactant liquor;
3. in reactant liquor, adding 0.8 mass fraction is 36% hydrochloric acid, and regulating the pH value of reactant liquor is 4; Decompression distillationEthylene glycol, reduces pressure by vacuum oil pump after heat-conducting oil heating; The sodium hydroxide alkali that in autoclave, suction mass fraction is 0.25%Water, stirs rotation; The butyl acetate of 2 parts of suction again, 60 DEG C of heating rotations;
4. cooling after reactant liquor clarification, pours spherical reactor into, and separatory obtains butyl acetate layer and water layer; Wherein, water layerWith the n-butyl acetate extraction of 1 part, after stirring separatory, obtain butyl acetate layer, merge the butyl acetate of twice, under stirring, add againPH value is 4 hydrochloric acid, after fully stirring, and point water-yielding stratum; Water layer is carried out obtaining amantadine hydrochloride after decompression distillation.
The present invention also provides a kind of technique of preparing amantadine unhindered amina by amantadine hydrochloride, it is characterized in thatAccording to following operation: successively adding mass ratio in reactor is water and the amantadine hydrochloride of 1:4, after stirring, uses hydrogenIt is 10 that sodium oxide molybdena or sodium carbonate regulate its pH value; Separate out after solid, continue to stir 0.5h, filter washing, dry, obtain adamantaneAmine unhindered amina sterling.
In the preparation method of above-mentioned amantadine hydrochloride, in each crystalline mother solution and extraction residue, can produce a large amount ofAmination waste material, wherein remains amantadine hydrochloride. Again utilize in order to realize refuse, reduce chemical substance discharge, the present inventionAlso provide one repeatedly to regulate impurity in pH, removal amantadine hydrochloride tailing and waste material to obtain amantadine unhindered amina sterlingMethod, it is characterized in that according to following operation: add water 510L at reactor, waste material 186Kg, adds the saturated hydrogen-oxygen of 23.6LChange sodium, the logical steam of chuck boils 2～3 hours, and maintaining during this time pH is 9～10; Slowly adding salt acid for adjusting pH value is 3～4 again, straightTake over filter, remove residue, it is 10 that the mother liquor obtaining uses alkali lye (NaOH) to regulate pH value again, separates out after solid, filters washing,Dry, obtain amantadine sterling.
It is a kind of by amantadine unhindered amina salify, decolouring, crystallization that the present invention also provides, and directly obtains the Buddha's warrior attendant of various acidThe method of alkanamine sterling, is characterized in that according to following operation: amantadine is added in 5 times of water gagings, use target acid to adjustJoint pH to 4, filters; The filtrate obtaining adds activated carbon decolorizing, again filters; The filtered fluid obtaining after filtering is concentrated into atherosclerotic,Be cooled to 0～10 DEG C, filtration drying, obtains the amantadine salt of target acid.
Described target acid is organic acid and inorganic acid.
Compared with prior art, the invention has the beneficial effects as follows:
(1) in the time of preparation 1-acetylamino adamantane, environment for use close friend, little to human injury, control simple and controlThe concentrated acid class that standard processed is relatively loose, substitutes the halogen (bromine) that traditional handicraft is used;
(2) through test of many times, obtain feeding intake and post processing ratio of science, prepare 1-acetylamino gold compared with traditional handicraftJust alkane, can improve yield; Especially adamantane is added in batches, the adamantane that approaches 1/4 is added after temperature approaches room temperature,Can better control reaction process, utilize to greatest extent acid and acetonitrile, improve the ingredient proportion of adamantane, increase unit productAmount;
(3), while preparing amantadine hydrochloride, use phase transfer catalyst to promote the effect of reacting, by what select after screeningDicyandiamide solution can improve the conversion ratio of reaction and yield;
(4) the invention provides in the technique of preparing amantadine hydrochloride, can in a reactor, make hydrochloric acid Buddha's warrior attendantAlkanamine, has simplified operating procedure, reduces costs, energy consumption and environmental pollution.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail. Should be appreciated that described herein concreteEmbodiment only, in order to explain the present invention, is not intended to limit the present invention.
Embodiment:
High yield is prepared a technique for amantadine hydrochloride, comprises the following steps:
(1) prepare 1-acetylamino adamantane;
1. prepare each raw material;
2. first reactor that is 50L by specification, precooling in advance, progressively adds oleum 25L (47.5kg),, stirMix 10 minutes, add the adamantane of 7.5kg at-5 DEG C in batches, in reinforced process, temperature can not exceed 0 DEG C, after adding, continues to stirMix half an hour;
3. at-5 DEG C, drip acetonitrile 6.5L (5.2kg), in dropping process, temperature can not exceed 0 DEG C; Drip off and continue to stir halfHour, be slowly warming up to 35 DEG C (room temperatures), insulation reaction 3 hours;
4. after becoming clarification, reactant liquor slowly adds 2.5kg adamantane; In reinforced process, keep temperature not rise, after addingStir again 3 hours;
Add again, and be warming up to 20 DEG C. Stirring half an hour. About stratification half an hour. Separate dichloromethane layer (Lower floor), then add carrene 17kg, stir half an hour, about stratification half an hour. Separate dichloromethane layer. Merge twoChloromethanes layer suction reactor, prepares in advance adding, and makes its pH value in 10 left and right. Separate dichloromethane layer, subtract steaming dichloroMethane. Obtain product acid amides.
5. in second reactor of 300L, add 120kg water, by water-cooling circulating system, reactor is cooled to 0Below DEG C; Drip the reactant liquor obtaining in step (4), control temperature and can not exceed 10 DEG C, drip and continue again to stir half an hour;
6. in second reactor, add carrene 34kg, and be warming up to 20 DEG C, continue to stir half an hour, leave standstill halfHour occur layering, the carrene that will be positioned at lower floor is extracted out and is introduced the 3rd reactor;
7. in second reactor, add carrene 17kg, continue to stir half an hour, occur layering standing half an hour,Extract the carrene that is positioned at lower floor out introduce 100L the 3rd reactor; In the 3rd reactor, add 30kg buck(containing NaOH 2%), making its pH value is 10, separates dichloromethane layer, decompression distillation carrene obtains product 1-acetylaminoAdamantane.
(2) prepare amantadine hydrochloride;
1. 225g NaOH is added in 500g water, stirring and dissolving, then add TBAB 1.5g, be poured intoIn the autoclave of 5L, then pour ethylene glycol 2250ml into autoclave. Under stirring, add 1-acetyl adamantane 250g. Stirring makes greatlyBe partly dissolved. Autoclave is warming up to 190 DEG C gradually.
2. timing during since 190 DEG C, reacts after 12 hours and stops heating, continues to stir, and temperature is down to 40 DEG C and is made, venting,Take out reactant liquor;
3. in reactant liquor, adding 650ml mass fraction is 36% hydrochloric acid, and regulating the pH value of reactant liquor is 4; Decompression is steamedHeat up in a steamer ethylene glycol, after heat-conducting oil heating, reduce pressure by vacuum oil pump; The NaOH that in autoclave, suction mass fraction is 0.25%Buck (comprising the water of 1000g and the NaOH of 25g), stirs rotation; The butyl acetate of suction 500ml again, 60 DEG C of heating rotations;
4. cooling after reactant liquor clarification, pours spherical reactor into, and separatory obtains butyl acetate layer and water layer; Wherein, water layerWith the n-butyl acetate extraction of 250ml, after stirring separatory, obtain butyl acetate layer; Merge the butyl acetate of twice, then use 300g waterStir and wash, water layer is separated. In butyl acetate, add water 500g, under stirring, adding pH value is 4 hydrochloric acid again again, stir 40 minutes,Divide water-yielding stratum, water layer is carried out obtaining amantadine hydrochloride after decompression distillation.
Above-mentioned amantadine hydrochloride is prepared the technique of amantadine unhindered amina, according to following operation: in reactor successivelyAdd water 200L and amantadine hydrochloride 50Kg, after stirring, regulating its pH value with NaOH or sodium carbonate is 10; Separate outAfter solid, continue to stir 0.5h, filter washing, dry, obtain amantadine unhindered amina sterling.
In the preparation method of above-mentioned amantadine hydrochloride, in each crystalline mother solution and extraction residue, can produce a large amount ofAmination waste material, wherein remains amantadine hydrochloride. Again utilize in order to realize refuse, reduce chemical substance discharge, the present inventionAlso provide one repeatedly to regulate impurity in pH, removal amantadine hydrochloride tailing and waste material to obtain amantadine unhindered amina sterlingMethod, according to following operation: add water 510L at reactor, waste material 186Kg, adds the saturated NaOH of 23.6L, chuck is logicalSteam boils 2～3 hours, and maintaining during this time pH is 9～10; Slowly adding salt acid for adjusting pH value is 3～4 again, directly filters, and removesResidue, it is 10 that the mother liquor obtaining uses alkali lye (NaOH) to regulate pH value again, separates out after solid, filters washing, dry, obtains goldJust alkanamine sterling.
It is a kind of by amantadine unhindered amina salify, decolouring, crystallization that the present invention also provides, and directly obtains the Buddha's warrior attendant of various acidThe method of alkanamine sterling, according to following operation: amantadine is added in 5 times of water gagings, use target acid for adjusting pH to 4, mistakeFilter; The filtrate obtaining adds activated carbon decolorizing, again filters; The filtered fluid obtaining after filtering is concentrated into atherosclerotic, is cooled to 0～10DEG C, filtration drying, obtains the amantadine salt of target acid.
Described target acid is organic acid and inorganic acid.
The above is only the preferred embodiment of the present invention, it should be pointed out that the common skill for the artArt personnel, under the premise without departing from the principles of the invention, can also make some improvements and modifications, these improvements and modificationsAlso should be considered as protection scope of the present invention.
Claims (1)
1. an impurity-removing method for amantadine hydrochloride waste material, is characterized in that according to following operation: add water at reactor510L, waste material 186Kg, adds the saturated NaOH of 23.6L, and the logical steam of chuck boils 2～3 hours, maintain during this time pH and be 9～10; Slowly adding salt acid for adjusting pH value is 3～4 again, directly filters, and removes residue, and the mother liquor obtaining is used alkali lye (hydroxide againSodium) to regulate pH value be 10, separates out after solid, filters washing, dry, obtains amantadine sterling.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325005A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | Separating and extracting process and device prepared by a kind of amantadine and its hydrochloride |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
| CN113372225A (en) * | 2021-06-08 | 2021-09-10 | 四川众邦制药有限公司 | Treatment method of bromine and amantadine combined wastewater in amantadine hydrochloride production |
-
2015
- 2015-12-18 CN CN201510958791.3A patent/CN105585506A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107325005A (en) * | 2017-08-14 | 2017-11-07 | 四川众邦制药有限公司 | Separating and extracting process and device prepared by a kind of amantadine and its hydrochloride |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
| CN113372225A (en) * | 2021-06-08 | 2021-09-10 | 四川众邦制药有限公司 | Treatment method of bromine and amantadine combined wastewater in amantadine hydrochloride production |
| CN113372225B (en) * | 2021-06-08 | 2023-09-01 | 四川众邦新材料股份有限公司 | Method for treating wastewater combining bromine and amantadine in production of amantadine hydrochloride |
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