CN109232270A - The preparation method of rimantadine hydrochloride preparation - Google Patents
The preparation method of rimantadine hydrochloride preparation Download PDFInfo
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- C07—ORGANIC CHEMISTRY
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- C07C17/00—Preparation of halogenated hydrocarbons
- C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
- C07C17/10—Preparation of halogenated hydrocarbons by replacement by halogens of hydrogen atoms
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- C07C249/04—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of oximes
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- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
The invention discloses the preparation methods of rimantadine hydrochloride preparation, it is prepared including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, the preparation of adamantane formyl chloride, the preparation of adamantane methyl ketone, 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, the preparation of rimantadine hydrochloride preparation, wherein adamantane methyl ketone preparation step are as follows: (CH is added in flask3)3Then Sb, nickel formate are added dropwise the acetonitrile solution of adamantane formyl chloride, make adamantane formyl chloride and (CH3)3Sb reaction generates adamantane methyl ketone, after the reaction was completed pours into reaction solution in ice water, then filters, is dry, and the lurid precipitating of gained is adamantane methyl ketone.Have the beneficial effect that the preparation method feature of environmental protection of rimantadine hydrochloride preparation of the present invention is good, synthetic method mild condition, simple process is feasible, and product yield is high.
Description
Technical field
The present invention relates to pharmaceutical technology fields, more particularly, to the preparation method of rimantadine hydrochloride preparation.
Background technique
Rimantadine hydrochloride is the aminoderivative of saturated tricyclic decane, chemistry entitled Alpha-Methyl tricyclic [3,3,1, the 1] last of the ten Heavenly stems
Alkane -1- methylamine hydrochloride, the research and development of Bristol Myers Squibb company of the U.S. are listed in France, 1993 for 1987 for the first time
U.S. FDA approval is better than amantadine for preventing and treating influenza A infection, clinical efficacy.Such compound has
Antivirus action.Rimantadine mechanism of action is the surface charge for changing host cell, and virus is inhibited to penetrate sensitive cells and release
The process for putting nucleic acid is suppressed the proliferation of virus.Rimantadine can also be used for treating unexpected severe pain and morbilli, absorb fast
And completely, adverse reaction is few.People had further research to the synthetic method of Rimantadine in recent years.
1- bromo adamantane is first made using adamantane as raw material in Sakski T, Kell DR etc., then existing for the concentrated sulfuric acid
Under the conditions of reacted with acetylene gas, then hydrolyze be made 1- adamantane methyl ketone, then reacted with formamide at 168 DEG C -180 DEG C
Catalytic hydrogenation obtains product Rimantadine afterwards.This method has used low-boiling acetylene, and commercial recovery is difficult to recycle and have
Dangerous property, the total recovery of product are low.
Adamantane is made using adamantane as starting material in Cai little Hua etc. under conditions of the concentrated sulfuric acid and formic acid again after bromination
Then formic acid reacts with thionyl chloride and adamantane formyl chloride is made, then obtain adamantane with hydrolysis after diethyl malonate reaction
Methyl ketone then produces oxime in hydroxylamine hydrochloride, and finally catalytic hydrogenation obtains Rimantadine at Pd/C.This method has used low boiling
Point solvent ether, is difficult to recycle in the industrial production and has risk.
Du Pont, Stetter H, Aldrich PE etc. is using adamantane as raw material, through bromination, carboxylic acid, acyl chlorides, ketone and ketone
Rimantadine is made in the intermediate products such as oxime, and catalyst used is LiAH4It is expensive.
Huang Shengjian, Chen Xia etc. obtain the rigid alkane formyl chloride of 1- through chloride with adamantanecarboxylic acid, then with diethyl malonate second
Oxygroup magnesium reaction generate adamantane formylmaloic acid diethylester, then through sour one step of hydrolysis decarboxylation generate ketone, then with hydroxylamine hydrochloride
Oxime is generated, Raney-Ni catalytic hydrogenation finally obtains Rimantadine at salt in ethyl acetate.
In summary method is it is found that the synthesis key of rimantadine is the synthesis of intermediate adamantane methyl ketone.It is above-mentioned
Method only has different improvement on by the route of adamantane synthesizing adamantane methyl ketone, and in the choosing of solvent and catalyst
Selecting also has different views.
The prior art such as Authorization Notice No. is the Chinese invention patent of CN 104610067B, and it is cheap to disclose a kind of raw material,
The synthetic method of the low Rimantadine of synthesis cost is reacted with adamantane and bromine, obtains 1- bromine adamantane；Then with 1- bromine gold
Rigid alkane is acidified acquisition adamantanecarboxylic acid after reacting with magnesium and anhydrous ether again；Again with adamantanecarboxylic acid and thionyl chloride back flow reaction
Obtain adamantane formyl chloride；Again with adamantane formyl chloride and (CH3)2CdCu reaction obtains adamantane methyl ketone；Finally by adamantane
Methyl ketone is hydrogenated under the conditions of sodium borohydride, is reacted with hydrochloric acid, reacting with ammonia water up to Rimantadine.But the Rimantadine
Synthesis step is more, and the time is long, and not environmentally.
Summary of the invention
It is good that the purpose of the present invention is to provide a kind of feature of environmental protection, synthesis technology simple possible, and product yield is high, disease-resistant toxic effect
The preparation method of the good rimantadine hydrochloride preparation of fruit.
The present invention in view of the above technology in the problem of mentioning, the technical solution taken are as follows:
The preparation method of rimantadine hydrochloride preparation, including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, adamantane first
Acyl chlorides preparation, the preparation of adamantane methyl ketone, the preparation of 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, rimantadine hydrochloride
Preparation preparation, specific steps include:
The preparation of adamantane methyl ketone: (CH is added in three-necked flask3)3Sb, nickel formate, then with 0.1-0.5mL/min drop
The acetonitrile solution for adding adamantane formyl chloride makes adamantane formyl chloride and (CH3)3Sb reaction generates adamantane methyl ketone, and reaction is completed
Reaction solution is poured into afterwards and obtains lurid compound in ice water, then filtering, 100 DEG C of dry 5h, obtain lurid precipitating, as
Adamantane methyl ketone；(CH3)3Sb can generate methyl ketone groups with the rapid chemical combination of chlorine in formyl chloride, it may be possible to because of formyl chloride
In chlorine atom and C=O base have strong sucking action to the electronics in C-C key, cause C atom in electropositive, and (CH3)3Free radical of the Sb due to having neither part nor lot in reaction in the presence of a pair in Sb, there is electron donating property, generates so as to rapidly with formyl chloride compound
Object, weaken C-Cl key between bond energy, further leave chlorine radical, and the carbon radicals of non-bonding due to electron rich and with
Positively charged methyl free radicals combine, and generate methyl ketone groups, and synergy can be generated with trimethylantimony by adding nickel formate
Effect, while cooperating polar solvent acetonitrile, the activity of trimethylantimony is substantially increased, reaction is promoted to carry out, improves product yield；
The preparation of 1- bromine adamantane: in reaction flask, sequentially adding adamantane, excess liquid bromine, in 80-90 DEG C of reaction 6-7h,
Be warming up to 110-115 DEG C of reaction 3-4h again, stand overnight, be distilled to recover bromine, then with saturation solution of sodium bisulfite restore more than
Under bromine, filtering, filter cake is washed to neutrality, and dry, recrystallizing methanol obtains Light yellow crystals, as 1- bromine adamantane；
Adamantanecarboxylic acid preparation: 98% concentrated sulfuric acid being added into flask, and stirring, keeping temperature is 5-10 DEG C, and 1- is added
Bromine adamantane, tetrahydrofuran quickly under stirring, are added dropwise formic acid with the speed of 0.5-1mL/min, at 5-10 DEG C, react 3-4h, will
Reaction solution pours into ice water, stands, and filters, dry, and gained white solid object is dissolved in ether, is extracted with sodium hydroxide, then use
Dilute hydrochloric acid acidification, it is dry, obtain the 1- adamantanecarboxylic acid precipitating of white；
The preparation of adamantane formyl chloride: adamantanecarboxylic acid and excessive thionyl chloride are added in three-necked flask, is heated to 70-90
DEG C, then back flow reaction 1-3h, vacuum distillation recycling thionyl chloride is added acetonitrile and is extracted, gained extract liquor is Buddha's warrior attendant
The acetonitrile solution of alkane formyl chloride；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 90-
110 DEG C, solution distills to obtain solids, is washed with water, filtered and dried in homogeneous, addition adamantane methyl ketone, reflux 1-3h, obtains 1- gold
Rigid alkane methyl ketoxime；
Rimantadine hydrochloride preparation: in autoclave pressure, be added 1- adamantane methyl ketoxime, glacial acetic acid, palladium carbon catalyst and
Nano diatomite, under room temperature and 0.35-0.45MPa Hydrogen Vapor Pressure, successive reaction 12-24h, Filtration of catalyst and diatom
Soil, filtrate are concentrated into a quarter of original volume, add deionized water, then plus 1-2.5mol/L sodium hydroxide tune pH9-10,
It is extracted, is dried, filtered with methylene chloride, led to dry hydrogen chloride gas, obtain rimantadine hydrochloride；Experiment discovery addition is received on a small quantity
The activity of palladium carbon catalyst can be improved in rice diatomite, accelerates reaction to carry out, and can improve yield, this may be because of nano-silicon
Diatomaceous earth particle can be completed when palladium metal is catalyzed, be parsed in reaction, immediately by the nano diatomite of surrounding with load palladium metal
Particle capture, circulation participates in catalysis reaction again, not only increases the reaction compartment of palladium catalyst while improving catalyst
Utilization rate；
The preparation of rimantadine hydrochloride preparation: by rimantadine hydrochloride, to second phthalein amino phenols, pseudoephedrine hydrochloride and Malaysia
Sour chlorphenamine is uniformly mixed by prescription ratio, makees adhesive with sodium carboxymethylcellulose, second alcohol and water is solvent, and centrifugation is made
Preparation is made to get rimantadine hydrochloride preparation in grain, dry, sieving, coating powder coating.
Preferably, nickel formate dosage is the 5-20% of trimethylantimony dosage in adamantane methyl ketone preparation step.
Further preferably, in adamantane methyl ketone preparation step, nickel formate dosage is the 10% of trimethylantimony dosage, to three
The auxiliary catalysis effect of methyl antimony is most strong.
Preferably, the dosage of nano diatomite is the 10- of trimethylantimony dosage in rimantadine hydrochloride preparation step
30%.
Compared with the prior art, the advantages of the present invention are as follows: the synthetic route of rimantadine hydrochloride of the present invention such as Fig. 1 institute
Show.The route of synthesizing adamantane methyl ketone before reaction route of the invention changes, uses trimethylantimony ((CH3)3Sb it) tries
Agent, and the Enhanced agents of catalysis reaction have been screened, discovery methyl nickel has synergistic function, first to the catalysis reaction of trimethylantimony
Base nickel uses simultaneously with trimethylantimony, and catalysis reaction efficiency is high, and reaction is fast, and yield is high；Reaction route of the invention uses palladium charcoal
Reducing agent, and it is synergistic using nano diatomite, and reductone to alcohol, dosage is few, and environmental protection；Hydrochloric acid Buddha's warrior attendant produced by the present invention
Ethamine preparation can be effectively prevented and treated influenza a virus infection, moreover it is possible to cold symptoms be effectively relieved.
Detailed description of the invention
The reaction route schematic diagram of Fig. 1 rimantadine hydrochloride synthetic method
The route schematic diagram of Fig. 2 adamantane methyl ketone synthetic reaction.
Specific embodiment
The present invention program is described further below by embodiment:
Embodiment 1:
The preparation method of rimantadine hydrochloride preparation, including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, adamantane first
Acyl chlorides preparation, the preparation of adamantane methyl ketone, the preparation of 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, rimantadine hydrochloride
Preparation preparation, specific steps include:
The preparation of 1- bromine adamantane: in reaction flask, sequentially adding adamantane, the 24mL bromine addition excess liquid bromine of 30g,
85 DEG C of reaction 6h, then 110 DEG C are warming up to, 3h is reacted in oil bath, stands overnight, and is distilled to recover bromine, then be saturated sulfurous acid with 20mL
Hydrogen sodium solution restores remaining bromine, filtering, and filter cake is washed to neutrality, and dry, recrystallizing methanol obtains Light yellow crystals 44g, yield
93%, as 1- bromine adamantane；
Adamantanecarboxylic acid preparation: 98% concentrated sulfuric acid 50mL being added into flask, and stirring, keeping temperature is 5-10 DEG C, is added
Enter 1- bromine adamantane 2.2g, tetrahydrofuran 50mL, quickly under stirring, formic acid 4.5mL is added dropwise with the speed of 0.7mL/min, is added dropwise
After, 5-10 DEG C is maintained the temperature at, 3h is reacted, reaction solution is poured into ice water, is stood, white solid object is filtered, it is dry, it will
Gained white solid object is dissolved in ether, is extracted with sodium hydroxide, then be acidified with dilute hydrochloric acid, dry, obtains the 1- adamantane of white
Formic acid precipitates 1.7g, yield 95%；
The preparation of adamantane formyl chloride: adamantanecarboxylic acid 1.8g and 3.6mL thionyl chloride is added in three-necked flask, is heated to
80 DEG C, back flow reaction 2h, then vacuum distillation recycling thionyl chloride is added acetonitrile 5mL × 2 and is extracted, gained extract liquor is straight
It connects for reacting in next step；
The preparation of adamantane methyl ketone: 0.23g (CH is added in three-necked flask3)3Sb, 0.02g nickel formate, then with
The acetonitrile solution of adamantane formyl chloride is added dropwise in 0.25mL/min, makes adamantane formyl chloride and (CH3)3Sb reaction generates adamantane first
Reaction solution is poured into obtain lurid compound in ice water after the reaction was completed by base ketone, and then filtering, 100 DEG C of dry 5h, obtain pale yellow
Color precipitates adamantane methyl ketone 1.95g, yield 90%；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride 1.9g, pyridine 10mL and dehydrated alcohol is added
10mL is heated to 100 DEG C, and solution distills to obtain solids, 10mL is gone in homogeneous, addition 1.42g adamantane methyl ketone, reflux 2h
Ion is washed with water, filtered and dried drying, obtains 1- adamantane methyl ketoxime 1.57g, yield 97%；
Rimantadine hydrochloride preparation: in autoclave pressure, 1- adamantane methyl ketoxime 1.89g, glacial acetic acid 40mL, palladium charcoal is added
Catalyst 0.9g and nano diatomite 0.1g, under room temperature and 0.40MPa Hydrogen Vapor Pressure, successive reaction 18h is filtered to remove catalysis
Agent and diatomite, filtrate are concentrated into a quarter of original volume, add deionized water 30mL, then plus 2mol/L sodium hydroxide tune
PH9-10 is extracted three times with 45mL methylene chloride, and anhydrous magnesium sulfate dries, filters, and leads to dry hydrogen chloride gas, obtains hydrochloric acid gold
Rigid ethamine 2.05g, yield 95%；
The preparation of rimantadine hydrochloride preparation: by rimantadine hydrochloride, to second phthalein amino phenols, pseudoephedrine hydrochloride and Malaysia
Sour chlorphenamine is uniformly mixed by prescription ratio, makees adhesive with sodium carboxymethylcellulose, second alcohol and water is solvent, and centrifugation is made
Preparation is made to get rimantadine hydrochloride preparation in grain, dry, sieving, coating powder coating.
Embodiment 2:
The preparation method of rimantadine hydrochloride preparation, including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, adamantane first
Acyl chlorides preparation, the preparation of adamantane methyl ketone, the preparation of 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, rimantadine hydrochloride
Preparation preparation, specific steps include:
The preparation of 1- bromine adamantane: in reaction flask, adamantane, excess liquid bromine are sequentially added, in 80 DEG C of reaction 6h, then is heated up
To 120 DEG C, 3h is reacted in oil bath, stands overnight, and is distilled to recover bromine, then restore remaining bromine with saturation solution of sodium bisulfite,
Filtering, filter cake are washed to neutrality, dry, and recrystallizing methanol obtains Light yellow crystals, as 1- bromine adamantane；
Adamantanecarboxylic acid preparation: 98% concentrated sulfuric acid being added into flask, and stirring, keeping temperature is 5-10 DEG C, and 1- is added
Bromine adamantane, tetrahydrofuran quickly under stirring, are added dropwise formic acid with the speed of 0.5mL/min, after being added dropwise, maintain the temperature at
5-10 DEG C, 3h is reacted, reaction solution is poured into ice water, stood, filters white solid object, it is dry, gained white solid object is molten
It in ether, is extracted with sodium hydroxide, then is acidified with dilute hydrochloric acid, it is dry, obtain the 1- adamantanecarboxylic acid precipitating of white；
The preparation of adamantane formyl chloride: being added adamantanecarboxylic acid and thionyl chloride in three-necked flask, is heated to 80 DEG C, reflux
2h is reacted, then vacuum distillation recycling thionyl chloride is added acetonitrile and is extracted, gained extract liquor is directly used in anti-in next step
It answers；
The preparation of adamantane methyl ketone: (CH is added in three-necked flask3)3Then gold is added dropwise with 0.1mL/min in Sb, nickel formate
The acetonitrile solution of rigid alkane formyl chloride, makes adamantane formyl chloride and (CH3)3Sb reaction generates adamantane methyl ketone, after the reaction was completed will
Reaction solution, which pours into, obtains lurid compound in ice water, then filtering, 100 DEG C of dry 5h, obtain light-yellow precipitate adamantane methyl
Ketone；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 100
DEG C, solution distills to obtain solids, deionization is washed with water, filtered and dried drying, obtains 1- in homogeneous, addition adamantane methyl ketone, reflux 2h
Adamantane methyl ketoxime；
Rimantadine hydrochloride preparation: in autoclave pressure, be added 1- adamantane methyl ketoxime, glacial acetic acid, palladium carbon catalyst and
Nano diatomite, under room temperature and 0.35MPa Hydrogen Vapor Pressure, successive reaction 12h, Filtration of catalyst and diatomite, filtrate
Be concentrated into a quarter of original volume, add deionized water, then plus 1mol/L sodium hydroxide tune pH9-10, mentioned with methylene chloride
It takes three times, anhydrous magnesium sulfate dries, filters, and leads to dry hydrogen chloride gas, obtains rimantadine hydrochloride；
The preparation of rimantadine hydrochloride preparation: by rimantadine hydrochloride, to second phthalein amino phenols, pseudoephedrine hydrochloride and Malaysia
Sour chlorphenamine is uniformly mixed by prescription ratio, makees adhesive with sodium carboxymethylcellulose, second alcohol and water is solvent, and centrifugation is made
Preparation is made to get rimantadine hydrochloride preparation in grain, dry, sieving, coating powder coating.
Embodiment 3:
The preparation method of rimantadine hydrochloride preparation, including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, adamantane first
Acyl chlorides preparation, the preparation of adamantane methyl ketone, the preparation of 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, rimantadine hydrochloride
Preparation preparation, specific steps include:
The preparation of 1- bromine adamantane: in reaction flask, adamantane, excess liquid bromine are sequentially added, in 90 DEG C of reaction 7h, then is heated up
To 120 DEG C, 4h is reacted in oil bath, stands overnight, and is distilled to recover bromine, then restore remaining bromine with saturation solution of sodium bisulfite,
Filtering, filter cake are washed to neutrality, dry, and recrystallizing methanol obtains Light yellow crystals, as 1- bromine adamantane；
Adamantanecarboxylic acid preparation: 98% concentrated sulfuric acid being added into flask, and stirring, keeping temperature is 5-10 DEG C, and 1- is added
Bromine adamantane, tetrahydrofuran quickly under stirring, are added dropwise formic acid with the speed of 1mL/min, after being added dropwise, maintain the temperature at 5-
10 DEG C, 3h is reacted, reaction solution is poured into ice water, stood, filters white solid object, it is dry, gained white solid object is dissolved in
Ether is extracted with sodium hydroxide, then is acidified with dilute hydrochloric acid, dry, obtains the 1- adamantanecarboxylic acid precipitating of white；
The preparation of adamantane formyl chloride: being added adamantanecarboxylic acid and thionyl chloride in three-necked flask, is heated to 80 DEG C, reflux
2h is reacted, then vacuum distillation recycling thionyl chloride is added acetonitrile and is extracted, gained extract liquor is directly used in anti-in next step
It answers；
The preparation of adamantane methyl ketone: (CH is added in three-necked flask3)3Then gold is added dropwise with 0.5mL/min in Sb, nickel formate
The acetonitrile solution of rigid alkane formyl chloride, makes adamantane formyl chloride and (CH3)3Sb reaction generates adamantane methyl ketone, after the reaction was completed will
Reaction solution, which pours into, obtains lurid compound in ice water, then filtering, 100 DEG C of dry 5h, obtain light-yellow precipitate adamantane methyl
Ketone；
The preparation of 1- adamantane methyl ketoxime: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 100
DEG C, solution distills to obtain solids, deionization is washed with water, filtered and dried drying, obtains 1- in homogeneous, addition adamantane methyl ketone, reflux 2h
Adamantane methyl ketoxime；
Rimantadine hydrochloride preparation: in autoclave pressure, be added 1- adamantane methyl ketoxime, glacial acetic acid, palladium carbon catalyst and
Nano diatomite, under room temperature and 0.45MPa Hydrogen Vapor Pressure, successive reaction for 24 hours, Filtration of catalyst and diatomite, filtrate
Be concentrated into a quarter of original volume, add deionized water, then plus 2.5mol/L sodium hydroxide tune pH9-10, use methylene chloride
It extracts three times, anhydrous magnesium sulfate dries, filters, and leads to dry hydrogen chloride gas, obtains rimantadine hydrochloride；
The preparation of rimantadine hydrochloride preparation: by rimantadine hydrochloride, to second phthalein amino phenols, pseudoephedrine hydrochloride and Malaysia
Sour chlorphenamine is uniformly mixed by prescription ratio, makees adhesive with sodium carboxymethylcellulose, second alcohol and water is solvent, and centrifugation is made
Preparation is made to get rimantadine hydrochloride preparation in grain, dry, sieving, coating powder coating.
Comparative example 1:
(CH is not added in adamantane methyl ketone preparation step3)3Sb, nickel formate, rest part and embodiment 1 are completely the same.
Comparative example 2:
(CH is not added in adamantane methyl ketone preparation step3)3Sb, rest part and embodiment 1 are completely the same.
Comparative example 3:
Nano diatomite is not added in rimantadine hydrochloride preparation step, rest part and embodiment 1 are completely the same.
Embodiment 4:
It regard embodiment 1 as test group, comparative example 1, comparative example 2, comparative example 31, control group 2, control group as a control group
3, the yield of adamantane methyl ketone and rimantadine hydrochloride is shown in Table 1.
The yield of table 1 adamantane methyl ketone and rimantadine hydrochloride
| Project | Adamantane methyl ketone yield (%) | Rimantadine hydrochloride yield (%) |
| Test group | 90 | 95 |
| Control group 1 | 0 | 0 |
| Control group 2 | 83 | 95 |
| Control group 3 | 90 | 90 |
As shown in Table 1, the adamantane methyl ketone yield of test group and the yield of rimantadine hydrochloride will be much higher than control
Group 1, control group 2, control group 3；Wherein, in control group 1, the yield of adamantane methyl ketone yield and rimantadine hydrochloride is 0,
Illustrate not add catalyst, reaction does not generate adamantane methyl ketone and rimantadine hydrochloride；Adamantane methyl ketone is received in test group
Rate is higher than control group 2, illustrates nickel formate to (CH3)3The catalytic efficiency of Sb plays the role of synergy；Hydrochloric acid Buddha's warrior attendant in test group
Ethamine yield is higher than control group 3, illustrates that nano diatomite has synergistic function to the catalytic efficiency of palladium carbon catalyst.
Embodiment 5:
Rimantadine hydrochloride preparation is used to treat inhibitory activity when H1N1 virus
Test procedure:
1) inoculation mdck cell is to 96 hole cell culture mediums, and culture is to growing up to single layer；
2) culture solution is abandoned, 100TCID is added in every hole50H1N1 100 μ L of virus, be incubated for 1 hour in 37 DEG C；
3) remove virus, the test medicine for having diluted concentration 200 μ L into cell is added in every hole；
4) it cultivates 48 hours for 37 DEG C, inhibitory activity of the test medicine to H1N1 virus of various concentration is detected with mtt assay.Number
According to the results are shown in Table 3.
Inhibitory activity when 3 rimantadine hydrochloride preparation for treating H1N1 virus of table
| Rimantadine hydrochloride anti-virus formulation concentration (μ g/mL) | To the inhibiting rate (%) of H1N1 virus |
| 500.00 | 8 |
| 250.00 | 42 |
| 125.00 | 83 |
| 62.50 | 59 |
| 31.25 | 32 |
| 15.63 | 18 |
As shown in Table 3, the inhibition when rimantadine hydrochloride anti-virus formulation of 125 μ g/mL is used to treat H1N1 virus is lived
Property be greater than 80%, illustrate rimantadine hydrochloride anti-virus formulation of the present invention to treatment H1N1 virus inhibitory activity effect it is bright
It is aobvious, prompt this extract infected by influenza to have preferable therapeutic effect.
Routine operation in operating procedure of the invention is well known to those skilled in the art, herein without repeating.
Technical solution of the present invention is described in detail in embodiment described above, it should be understood that the above is only
For specific embodiments of the present invention, it is not intended to restrict the invention, all any modifications made in spirit of the invention,
Supplement or similar fashion substitution etc., should all be included in the protection scope of the present invention.
Claims (9)
1. the preparation method of rimantadine hydrochloride preparation, including the preparation of 1- bromine adamantane, adamantanecarboxylic acid preparation, adamantane formyl
Chlorine preparation, the preparation of adamantane methyl ketone, the preparation of 1- adamantane methyl ketoxime, rimantadine hydrochloride preparation, rimantadine hydrochloride system
Agent preparation, it is characterised in that: the adamantane methyl ketone preparation step are as follows: (CH is added in flask3)3Sb, nickel formate, then
The acetonitrile solution of adamantane formyl chloride is added dropwise, makes adamantane formyl chloride and (CH3)3Sb reaction generates adamantane methyl ketone, has reacted
Reaction solution is poured into ice water after, then filters, is dry, the lurid precipitating of gained is adamantane methyl ketone.
2. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the adamantane methyl
In ketone preparation step, nickel formate dosage is the 5-20% of trimethylantimony dosage.
3. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the 1- bromine adamantane
Preparation step are as follows: in reaction flask, sequentially add adamantane, excess liquid bromine in 80-90 DEG C of reaction 6-7h, then is warming up to 110-
115 DEG C of reaction 3-4h, stand overnight, and are distilled to recover bromine, then restore remaining bromine with saturation solution of sodium bisulfite, filter,
Filter cake is washed to neutrality, dry, and recrystallizing methanol obtains Light yellow crystals, as 1- bromine adamantane.
4. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the adamantanecarboxylic acid
Preparation step are as follows: 98% concentrated sulfuric acid is added into flask, stirring, keeping temperature is 5-10 DEG C, and 1- bromine adamantane, tetrahydro is added
Furans quickly under stirring, is added dropwise formic acid with the speed of 0.5-1mL/min, at 5-10 DEG C, reacts 3-4h, reaction solution is poured into ice
It in water, stands, filters, it is dry, gained white solid object is dissolved in ether, is extracted with sodium hydroxide, then be acidified with dilute hydrochloric acid, is done
It is dry, obtain the 1- adamantanecarboxylic acid precipitating of white.
5. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the adamantane formyl
Chlorine preparation step are as follows: adamantanecarboxylic acid and excessive thionyl chloride are added in three-necked flask, is heated to 70-90 DEG C, back flow reaction
Then 1-3h, vacuum distillation recycling thionyl chloride are added acetonitrile and are extracted, gained extract liquor is the second of adamantane formyl chloride
Nitrile solution.
6. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the 1- adamantane first
Base ketoxime preparation step are as follows: in reaction flask, hydroxylamine hydrochloride, pyridine and dehydrated alcohol is added, is heated to 90-110 DEG C, solution is in
Homogeneously, adamantane methyl ketone is added, flow back 1-3h, distills to obtain solids, is washed with water, filtered and dried, obtains 1- adamantane methyl ketone
Oxime.
7. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the hydrochloric acid Buddha's warrior attendant second
Amine preparation step are as follows: in autoclave pressure, 1- adamantane methyl ketoxime, glacial acetic acid, palladium carbon catalyst and nano diatomite is added,
Under room temperature and 0.35-0.45MPa Hydrogen Vapor Pressure, successive reaction 12-24h, Filtration of catalyst and diatomite, filtrate are concentrated into
The a quarter of original volume, adds deionized water, then plus 1-2.5mol/L sodium hydroxide tune pH9-10, mentioned with methylene chloride
It takes, dries, filters, lead to dry hydrogen chloride gas, obtain rimantadine hydrochloride.
8. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the hydrochloric acid Buddha's warrior attendant second
In amine preparation step, the dosage of nano diatomite is the 10-30% of trimethylantimony dosage.
9. the preparation method of rimantadine hydrochloride preparation according to claim 1, it is characterised in that: the hydrochloric acid Buddha's warrior attendant second
The preparation step of amine preparation are as follows: pressed by rimantadine hydrochloride, to second phthalein amino phenols, pseudoephedrine hydrochloride and chlorphenamine maleate
Prescription ratio is uniformly mixed, and makees adhesive with sodium carboxymethylcellulose, and second alcohol and water is solvent, and centrifugal granulating is dry, sieving,
Coating powder coating, is made preparation to get rimantadine hydrochloride preparation.
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| CN112239410A (en) * | 2019-07-19 | 2021-01-19 | 上海安谱实验科技股份有限公司 | Stable isotope deuterium-labeled rimantadine hydrochloride and synthesis method thereof |
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| CN112239410A (en) * | 2019-07-19 | 2021-01-19 | 上海安谱实验科技股份有限公司 | Stable isotope deuterium-labeled rimantadine hydrochloride and synthesis method thereof |
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