CN109516920A - A kind of synthetic method of amantadine - Google Patents
A kind of synthetic method of amantadine Download PDFInfo
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- CN109516920A CN109516920A CN201811385510.XA CN201811385510A CN109516920A CN 109516920 A CN109516920 A CN 109516920A CN 201811385510 A CN201811385510 A CN 201811385510A CN 109516920 A CN109516920 A CN 109516920A
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- amantadine
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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
- C07C209/04—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups
- C07C209/06—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms
- C07C209/08—Preparation of compounds containing amino groups bound to a carbon skeleton by substitution of functional groups by amino groups by substitution of halogen atoms with formation of amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2603/00—Systems containing at least three condensed rings
- C07C2603/56—Ring systems containing bridged rings
- C07C2603/58—Ring systems containing bridged rings containing three rings
- C07C2603/70—Ring systems containing bridged rings containing three rings containing only six-membered rings
- C07C2603/74—Adamantanes
Abstract
The invention discloses a kind of synthetic methods of amantadine, this method are as follows: 1- bromo adamantane and ammonium hydrogen carbonate are added in autoclave, it is uniformly mixed, is warming up to reaction temperature and carries out aminating reaction, be cooled to room temperature after reaction, then it adds water and stirs, solid, filtering is precipitated, filter cake is washed to obtain yellow amantadine crude product, crude product is dissolved in recrystallization solvent and be recrystallized to give white solid, as amantadine product；Reaction equation is as follows:
Description
Technical field
The present invention relates to a kind of synthetic methods of amantadine.
Background technique
Adamantane is a kind of caged hydrocarbon of high degree of symmetry, and entire ring system has straight symmetrical, highly stable structure feature,
And under certain condition, the reaction of the types such as cytoskeleton rearrangement, oxidation, alkylation can also occur for adamantane molecule, as a result, Buddha's warrior attendant
The designability of alkane molecule is very strong, thus in medicine, functional polymer, lubricant, surfactant, catalyst, photographic material
Etc. tool have been widely used, (Yang Hui is poor, and Li Bin caged hydrocarbon adamantane shows for fine chemical material referred to as of new generation
Shape and Progress in synthesis Hunan Institute Of Engineering journal, 2005,15 (4): 92.).Amantadine is the amino of adamantane
Derivative, amantadine and its derivative generally have good fat-soluble and hypotoxicity, and show unique pharmacological action,
(such as amantadine, Rimantadine, tromantadine, somantadine, more hitherto it is found that a variety of amantadine analog derivatives and its salt
Bar amantadine and its hydrochloride, carboxylate etc.) clinically there is special efficacy pharmacological property, can be used for antiviral and antitumor, reducing blood lipid or
As cerebral vasodilator, artificial blood, treatment parkinsonism etc., (Wang Lingfeng, Zhao Shengxian, Hu Hongyu adamantane spread out
Biology and its biologically active drugBiochemical industry, 2017, 3(1): 70)；In addition, in synthesizing new functional polymer material
The fields such as material, molecular sieve also have potential use.In consideration of it, the Study of synthesis method of amantadine is constantly subjected to extensive concern.
About the synthetic method of amantadine, synthetic route reported in the literature mainly has following three kinds of approach:
1, it using adamantane as starting material, first carries out reacting with halogen generating halogenated adamantane, then be carried out again with amination reagent
Aminating reaction obtains amantadine (the synthesis of department of chemistry, Lanzhou University adamantanamine hydrochlorideMedical industry, 1973, 4
(6): 14.), as shown in formula (I-1)；
2, it using adamantane as starting material, first carries out nitration reaction and generates 1- nitro adamantane, restore to obtain amantadine
(Park, KK; OH, CH; Sim, WJ. Chemoselective reduction of nitroarenes and
nitroalkanes by sodium dithionite using octylviologen as an electron transfer
catalyst. J.Org. Chem,1995, 60, 6202.), as shown in formula (I-2)；
3, using adamantane as starting material, pass through the oxidation reaction synthesizing adamantane alcohol nitrate of nitric acid-sulfuric acid system, reamination
Obtaining amantadine, (Niu Yahui, Shi Lei, orchid make the progress of equality amantadine analog derivativeMedical science and technology,
2016,40,59.), as shown in formula (I-3).
It is industrial at present main using formula (I-1) route, i.e., the technique that amantadine is combined to by bromo amantadine, often
Use urea as amination reagent (Shao Guizhen, red bayberry, Wu ChunliChemical intermediate, 2009, (7): 55.), technique tool
There are the advantages such as short reaction time, high income, at low cost.In the method, urea is although cheap, but used in amounts is significantly excessive, high
In temperature reaction, urea is difficult to recycle because resolving into the debirs such as isocyanic acid, cyanuric acid and ammelide, waste water
Solid state fermentation higher cost.Patent US5599998 (Kraus, GA. Method for the synthesis of
Adamantane amines. US5599998,1997-02-04) it reports bromine (halogen) and is first reacted with lithium metal for adamantane,
Then the method for obtaining amantadine is reacted with amination reagents such as hydroxylamine-o-sulfonic acid salt, monochloro amines under ultrasound condition.The reaction
It needs using lithium metal, at high price, and react and need ultrasound condition, complex process, ultimate yield is not also high.There are also correlations
Patent uses liquefied ammonia as aminating agent, finally obtains amantadine (Mills, J in 170 DEG C or so reaction 15h under confined conditions;
Krumkalns, E. Adamantyl secondary amines. US3391142,1966-07-02.).But this method is anti-
It answers overlong time and reaction yield is lower than 15%.
Summary of the invention
For the above-mentioned problems in the prior art, it is an object of the present invention to provide a kind of process stabilizing, it is cheap, three
The higher amantadine synthetic method of the less and yield that gives up.
A kind of synthetic method of amantadine, it is characterised in that 1- bromo adamantane and ammonium hydrogen carbonate are added to autoclave
In, it is uniformly mixed, is warming up to reaction temperature and carries out aminating reaction, reaction terminates to be cooled to room temperature, then add water and stir, and is precipitated solid
Body, filtering, filter cake are washed to obtain amantadine crude product, crude product are dissolved in and carries out being recrystallized to give white solid in solvent, as
Amantadine product；Its reaction equation is as follows:
。
The synthetic method of a kind of amantadine, it is characterised in that 1- bromo adamantane and feeding intake for ammonium hydrogen carbonate are rubbed
You are than being 1: 2.0~30, preferably 1: 5.0~10.
A kind of synthetic method of the amantadine, it is characterised in that the temperature for carrying out aminating reaction is 110 ~ 160 DEG C,
Preferably 120 ~ 140 DEG C；The time for carrying out aminating reaction is 2 ~ 10h, preferably 3 ~ 6h.
The synthetic method of a kind of amantadine, it is characterised in that recrystallization solvent for use is water and water-miscible organic solvent
Mixed liquor, water and water-miscible organic solvent volume ratio are 1:1.0 ~ 9.0, preferably 1:1.0 ~ 4.0.
A kind of synthetic method of the amantadine, it is characterised in that the water-miscible organic solvent be methanol, ethyl alcohol,
One or more mixtures of propyl alcohol, isopropanol, acetone, tetrahydrofuran, acetonitrile.
A kind of synthetic method of the amantadine, it is characterised in that the water-miscible organic solvent be ethyl alcohol, acetone,
One or more mixtures of tetrahydrofuran, acetonitrile.
The present invention uses ammonium hydrogen carbonate to prepare amantadine for amination reagent using 1- bromo adamantane as raw material, reaction
It is carried out under heating melting state, ammonium hydrogen carbonate heat resolve generates ammonia, carbon dioxide and water, wherein ammonia and 1- bromo gold
Rigid alkane carries out aminating reaction, and the by-products such as carbon dioxide, excessive ammonia that ammonium bicarbonate breaks down generates can directly be lined up, not divide
The ammonium hydrogen carbonate of solution can also recycle out through that can be washed easily removal, the ammonium hydrogen carbonate for washing.Therefore, with current industry
Change common urea to compare as amination reagent, amination reagent of the invention has that reaction cost is low, quantity of three wastes is few, post-processing
Conveniently, the advantages that yield is higher.
Specific embodiment
The present invention is further explained in the light of specific embodiments, but the scope of protection of the present invention is not limited thereto.
Embodiment 1
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 39.5g(0.5 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 125 DEG C, sustained response 4 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake is washed to obtain yellow amantadine crude product, then crude product 20mL water and 20mL ethyl alcohol are mixed
It is amantadine product that liquid, which is recrystallized to give white solid 12.6g(white solid), yield 83.6%.
Fusing point: 205 ~ 207 DEG C；1H NMR (500 MHz, CDCl3) δ 8.19 (s, 2H), 2.08 (m, 4H),
1.82(m, 3H), 1.70 (m, 4H), 1.57 (m, 4H)。
Embodiment 2
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 55.3g(0.7 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 130 DEG C, sustained response 5 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake wash to obtain yellow amantadine crude product, then by crude product 10mL water and 30mL mixed liquor third
It is amantadine product that ketone, which is recrystallized to give white solid 13.1g(white solid), yield 86.8%.
Embodiment 3
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 79.0g(1 mol) ammonium hydrogen carbonate mixing
Uniformly, it directly heats to reacting at 135 DEG C, sustained response 6 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake wash to obtain yellow amantadine crude product, then by crude product 8mL water and 32mL tetrahydrofuran weight
It is amantadine product that crystallization, which obtains white solid 14.3g(white solid), yield 94.7%.
Embodiment 4
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 47.4g(0.6 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 120 DEG C, sustained response 5 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake is washed to obtain yellow amantadine crude product, then crude product is tied again with 10mL water and 30mL acetonitrile
It is amantadine product that crystalline substance, which obtains white solid 12.7g(white solid), yield 84.1%.
Embodiment 5
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 63.2g(0.8 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 140 DEG C, sustained response 4 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake is washed to obtain yellow amantadine crude product, then crude product is tied again with 15mL water and 25mL ethyl alcohol
It is amantadine product that crystalline substance, which obtains white solid 13.4g(white solid), yield 88.7%.
Embodiment 6
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 39.5g(0.5 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 125 DEG C, sustained response 4 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake is washed to obtain yellow amantadine crude product, then crude product is tied again with 20mL water and 20mL acetonitrile
It is amantadine product that crystalline substance, which obtains white solid 12.7g(white solid), yield 84.2%.
Embodiment 7
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 71.1g(0.9 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 130 DEG C, sustained response 6 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake wash to obtain yellow amantadine crude product, then by crude product 10mL water and 30mL tetrahydrofuran
Being recrystallized to give white solid 14.0g(white solid is amantadine product), yield 92.7%.
Embodiment 8
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 47.4g(0.6 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 125 DEG C, sustained response 4 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake is washed to obtain yellow amantadine crude product, then crude product is tied again with 15mL water and 25mL acetone
It is amantadine product that crystalline substance, which obtains white solid 12.5g(white solid), yield 82.8%.
Embodiment 9
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 63.2g(0.8 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 120 DEG C, sustained response 3 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake wash to obtain yellow amantadine crude product, then by crude product 10mL water, 10mL ethyl alcohol and 20mL
It is amantadine product that the mixed liquor of acetone, which is recrystallized to give white solid 12.7g(white solid), yield 84.1%.
Embodiment 10
In 250 mL autoclaves, 21.5g(0.1 mol is added) 1- bromo adamantane and 55.3g(0.7 mol) ammonium hydrogen carbonate is mixed
It closes uniformly, directly heats to reacting at 135 DEG C, sustained response 5 hours；Reaction terminates, and reaction solution is cooled to room temperature, and water is added and stirs
It mixes, solid is precipitated；Filtering, filter cake wash to obtain yellow amantadine crude product, then by crude product 10mL water, 10mL ethyl alcohol, 10mL
It is amantadine product that the mixed liquor of acetone and 10mL acetonitrile, which is recrystallized to give white solid 14.1g(white solid), yield
93.0%。
Content described in this specification is only to enumerate to inventive concept way of realization, and protection scope of the present invention is not answered
When the concrete form for being seen as limited by embodiment and being stated.
Claims (6)
1. a kind of synthetic method of amantadine, it is characterised in that 1- bromo adamantane and ammonium hydrogen carbonate are added in autoclave,
It being uniformly mixed, is warming up to reaction temperature and carries out aminating reaction, reaction terminates to be cooled to room temperature, then add water and stir, solid is precipitated,
Filtering, filter cake are washed to obtain amantadine crude product, crude product are dissolved in and carries out being recrystallized to give white solid, as Buddha's warrior attendant in solvent
Alkanamine product；Its reaction equation is as follows:
。
2. a kind of synthetic method of amantadine according to claim 1, it is characterised in that 1- bromo adamantane and carbonic acid
The molar ratio of hydrogen ammonium is 1: 2.0~30, preferably 1: 5.0~10.
3. a kind of synthetic method of amantadine according to claim 1, it is characterised in that carry out the temperature of aminating reaction
It is 110 ~ 160 DEG C, preferably 120 ~ 140 DEG C；The time for carrying out aminating reaction is 2 ~ 10h, preferably 3 ~ 6h.
4. a kind of synthetic method of amantadine according to claim 1, it is characterised in that recrystallization solvent for use is water
With the mixed liquor of water-miscible organic solvent, water and water-miscible organic solvent volume ratio are 1:1.0 ~ 9.0, preferably 1:1.0 ~ 4.0.
5. a kind of synthetic method of amantadine according to claim 4, it is characterised in that the water-miscible organic solvent
For one or more mixtures of methanol, ethyl alcohol, propyl alcohol, isopropanol, acetone, tetrahydrofuran, acetonitrile.
6. a kind of synthetic method of amantadine according to claim 5, it is characterised in that the water-miscible organic solvent
For one or more mixtures of ethyl alcohol, acetone, tetrahydrofuran, acetonitrile.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205190A (en) * | 2020-01-11 | 2020-05-29 | 天津民祥药业有限公司 | Synthesis method of amantadine |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
| CN114409547A (en) * | 2022-01-27 | 2022-04-29 | 浙江普洛康裕制药有限公司 | Continuous production method and device of amantadine |
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| US5599998A (en) * | 1994-10-24 | 1997-02-04 | Iowa State University Research Foundation, Inc. | Method for the synthesis of adamantane amines |
| CN1424304A (en) * | 2002-12-12 | 2003-06-18 | 厦门市先端科技有限公司 | Preparation for aniline, phenol and derivative thereof |
| CN108084033A (en) * | 2017-12-29 | 2018-05-29 | 山东诚汇双达药业有限公司 | A kind of preparation method of N, N- diethyl ethylenediamine |
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2018
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| US5599998A (en) * | 1994-10-24 | 1997-02-04 | Iowa State University Research Foundation, Inc. | Method for the synthesis of adamantane amines |
| CN1424304A (en) * | 2002-12-12 | 2003-06-18 | 厦门市先端科技有限公司 | Preparation for aniline, phenol and derivative thereof |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111205190A (en) * | 2020-01-11 | 2020-05-29 | 天津民祥药业有限公司 | Synthesis method of amantadine |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
| CN114409547A (en) * | 2022-01-27 | 2022-04-29 | 浙江普洛康裕制药有限公司 | Continuous production method and device of amantadine |
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