CN102241594A - Adamantanamine synthesis method through adamantanol aminolysis - Google Patents
Adamantanamine synthesis method through adamantanol aminolysis Download PDFInfo
- Publication number
- CN102241594A CN102241594A CN2010101719945A CN201010171994A CN102241594A CN 102241594 A CN102241594 A CN 102241594A CN 2010101719945 A CN2010101719945 A CN 2010101719945A CN 201010171994 A CN201010171994 A CN 201010171994A CN 102241594 A CN102241594 A CN 102241594A
- Authority
- CN
- China
- Prior art keywords
- adamantanol
- aminolysis
- amantadine
- reaction
- synthesizing
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a low-cost and environment-friendly adamantanamine synthesis method through an adamantanol aminolysis. According to the invention, first adamantine is oxidized with oxygen under catalysis of NHPI and Co(OAc)2 to obtain adamantanol; then the adamantanol is aminated with urea under a high temperature to obtain an object product adamantanamine. The method is easy for operation and with low costs, can substantially reduce environmental pollution, and has good application prospects.
Description
Technical field
The present invention relates to a kind of green synthesis method of amantadine, specifically a kind of method through adamantanol amination reaction synthesizing amantadine.
Background technology
Amantadine is the aminoderivative of the saturated tricyclic decane of synthetic, is antiviral, can stop influenza A virus to penetrate host cell and the effect of prophylaxis of viral infections is arranged, and also can suppress uncoating and suppresses virus multiplication.Find that by clinical practice amantadine treatment parkinsonism has better effects, and various Parkinsonism symptom is also had mitigation, discovered in recent years also has better effects to the treatment of chronic hepatitis C.
According to the literature, amantadine has multiple synthetic method at present, as (JAm Chem Soc, 1969,91 (23): 6457-6460) with the methylene dichloride be solvent, use NCl such as Kovacic
3-AlCl
3Make amantadine with the diamantane reaction, productive rate 87%, but this reaction process is comparatively complicated, and the temperature control that different steps requires is different, operates more loaded down with trivial details; Jirgensons etc. (Synthesis, 2000, be substrate 12:1709-1712), with ClCH with the 1-adamantanol
2Make the 1-adamantanamine hydrochloride with the thiocarbamide reaction again after the CN reaction, but used ClCH in this reaction
2CN strong toxicity, price height do not possess using value yet.
Existing industrial process is to replace by excessive bromine and diamantane generation bromine to generate 1-bromine diamantane, at high temperature reacts with urea to prepare amantadine again.The bromine price is more expensive, and corrodibility is strong and be difficult to reclaim, and environmental pollution is serious, therefore finds more to save cost more operation readiness and the eco-friendly mode of production are very necessary.
Summary of the invention
The object of the present invention is to provide a kind of reducing cost, reduce the method for the green synthesizing amantadine that pollutes.
The technical solution that realizes the object of the invention is: a kind of method of adamantanol aminolysis synthesizing amantadine, and step is as follows:
Step 1, diamantane oxidation: raw material diamantane and oxygen are at NHPI, Co (OAc)
2Carrying out oxidizing reaction under the catalytic condition, is mixed solvent with acetate, ethyl acetate, and reaction is revolved steaming after finishing, and revolves to steam to remove ethyl acetate, adds water again white solid product is separated out, and filtration, washing obtain the product adamantanol;
Step 2, amination reaction: pyroreaction in high boiling solvent with adamantanol and urea, reaction finishes the back and drips concentrated hydrochloric acid, filter the amantadine hydrochloric acid soln, drip the alkaline solution neutralization and obtain the flocks of amantadine white, filter, dry the pure product of amantadine.
The present invention compared with prior art, its remarkable advantage: this preparation method's environmental protection, simple to operate, raw material is cheap and easy to get.As: the production method of traditional amantadine is diamantane and liquid bromine generation bromo-reaction, carry out amination reaction with urea again, wherein liquid bromine price is more expensive, and equipment is had very strong corrodibility, also very serious to atmospheric pollution, also can cause very big injury to experiment operator; The synthetic method of other of amantadine has much all been used severe toxicity or expensive reagent, is not suitable for industrial production; And the present invention uses dioxygen oxidation earlier, carries out amination reaction with urea again, and raw material is cheap and easy to get, and total synthetic cost is very low, wherein with oxygen as oxygenant, environmental protection, pollution-free, equipment is not had corrosion, easy and simple to handle, have a good application prospect.
Embodiment
The method of a kind of adamantanol aminolysis of the present invention synthesizing amantadine, step is as follows:
Step 1, diamantane oxidation: raw material diamantane and oxygen are at NHPI, Co (OAc)
2Carrying out oxidizing reaction under the catalytic condition, is mixed solvent with acetate, ethyl acetate, and reaction is revolved steaming after finishing, and revolves to steam to remove ethyl acetate, adds water again white solid product is separated out, and filtration, washing obtain the product adamantanol;
Step 2, amination reaction: pyroreaction in high boiling solvent with adamantanol and urea, reaction finishes the back and drips concentrated hydrochloric acid, filter the amantadine hydrochloric acid soln, drip the alkaline solution neutralization and obtain the flocks of amantadine white, filter, dry the pure product of amantadine.
In the step 1 of the present invention, oxidizing reaction temperature is 60～110 ℃, and more excellent temperature of reaction is 70～80 ℃, and the reaction times is 1～6h, and the more excellent reaction times is 5h, and acetate and ethyl acetate volume ratio are 5: 1～1: 1; More excellent volume ratio is 5: 3.
Adamantanol and urea mol ratio are greater than 1: 10 in the step 2, and the high boiling solvent that uses is DMF, DMA or DMSO equal solvent; Temperature of reaction is controlled at 145～195 ℃, and more excellent temperature of reaction is 170～180 ℃; Reaction times is 10～60min, and the more excellent reaction times is 20～30min; The concentration of hydrochloric acid solution that drips is 5～38%; The alkali that drips is strong caustic, also available hydrogen potassium oxide, and volumetric molar concentration is 1～20mol/L, with saturated sodium hydroxide solution optimum.
The invention will be further described below in conjunction with embodiment.
Embodiment 1:
Oxidizing reaction: in the 150mL flask, add the 6.8g diamantane, 1.63g NHPI, 0.2g cobaltous acetate (II), solvent acetic acid: 50mL, ethyl acetate: 30mL 80 ℃ of reactions down, uses the conduit aerating oxygen, reaction 5h.Reaction spins off partial solvent after finishing, and adds water, and then the adularescent solid is separated out, and suction filtration, solid washing then obtain the product adamantanol;
Interpretation of result calculates:
Diamantane transformation efficiency: 98%
Adamantanol productive rate: 90%
Amination reaction: get in two mouthfuls of flasks of 10g adamantanol, 50g urea adding 250mL, add 20mL DMF, be heated to 175 ℃, reaction 30min.After reaction finishes, drip concentrated hydrochloric acid, filtration, the neutralization of dropping sodium saturated solution obtain product amantadine 7.9g.
Interpretation of result calculates:
Adamantanol transformation efficiency: 82%
Amantadine productive rate: 79%
Embodiment 2-5:
Change oxidizing reaction temperature, other operational condition and step are with embodiment 1, and the adamantanol productive rate is as shown in table 1.
Table 1 temperature is to the influence of reaction
Implement 6-8:
Change the oxidation solvent volume ratio, other operational condition and step are with embodiment 1, and the productive rate of adamantanol is as shown in table 2.
The influence of table 2 solvent volume comparison reaction
Embodiment 9-12:
Change oxidation time, other operational condition and step are with embodiment 1, and the adamantanol productive rate is as shown in table 3.
Table 3 reaction times is to the influence of productive rate
Embodiment 13-15:
Change the amination reaction temperature, other operational condition and step are with embodiment 1, and productive rate is as shown in table 4.
Table 4 temperature is to the influence of productive rate
Embodiment 16-18:
Change the amination reaction time, other operational condition and step are with embodiment 1, and productive rate is as shown in the table.
Table 5 time is to the influence of productive rate
Embodiment 19:
The solvent that does not add amination reaction, other operational condition and step are with embodiment 1.
Interpretation of result calculates:
Adamantanol transformation efficiency: 60%
Amantadine productive rate: 55%
Embodiment 20:
Dripping hydrochloric acid concentration is 5% when changing the amination reaction aftertreatment, and other operational condition and step be with embodiment 1, amantadine productive rate 50%.
Embodiment 21:
Dropping sodium concentration is 1mol/L when changing aftertreatment, and other operational condition and step be with embodiment 1, amantadine productive rate 48%.
Claims (10)
1. the method for an adamantanol aminolysis synthesizing amantadine is characterized in that comprising the steps:
Step 1, diamantane oxidation: raw material diamantane and oxygen are at NHPI, Co (OAc)
2Carrying out oxidizing reaction under the catalytic condition, is mixed solvent with acetate, ethyl acetate, and reaction is revolved steaming after finishing, and revolves to steam to remove ethyl acetate, adds water again white solid product is separated out, and filtration, washing obtain the product adamantanol;
Step 2, amination reaction: pyroreaction in high boiling solvent with adamantanol and urea, reaction finishes the back and drips concentrated hydrochloric acid, filter the amantadine hydrochloric acid soln, drip the alkaline solution neutralization and obtain the flocks of amantadine white, filter, dry the pure product of amantadine.
2. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: oxidizing reaction temperature is 60～110 ℃ in the step 1.
3. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: the volume ratio of mixed solvent acetate and ethyl acetate is 5: 5～5: 1 in the step 1.
4. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: oxidation time is 1～6h in the step 1.
5. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: the mol ratio of adamantanol and urea is greater than 1: 10 in the step 2.
6. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: temperature of reaction is 145～195 ℃ in the step 2.
7. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: the reaction times is 10～60min in the step 2.
8. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: high boiling solvent can be selected DMF, DMA or DMSO solvent for use in the step 2.
9. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: dripping hydrochloric acid concentration is 5～38% in the step 2.
10. the method for adamantanol aminolysis synthesizing amantadine according to claim 1 is characterized in that: the alkaline solution that drips in the step 2 is sodium hydroxide or potassium hydroxide solution, and volumetric molar concentration is 1～20mol/L.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101719945A CN102241594A (en) | 2010-05-14 | 2010-05-14 | Adamantanamine synthesis method through adamantanol aminolysis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010101719945A CN102241594A (en) | 2010-05-14 | 2010-05-14 | Adamantanamine synthesis method through adamantanol aminolysis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102241594A true CN102241594A (en) | 2011-11-16 |
Family
ID=44959875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010101719945A Pending CN102241594A (en) | 2010-05-14 | 2010-05-14 | Adamantanamine synthesis method through adamantanol aminolysis |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102241594A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864621A (en) * | 2014-02-21 | 2014-06-18 | 南京理工大学 | Energetic material 4, 4, 8, 8-tetranitroadamantane-2, 6-dinitrate and preparation method thereof |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185757A (en) * | 1996-02-07 | 1998-06-24 | 大赛璐化学工业株式会社 | Oxidation catalyst system and process for oxidation with the same |
| CN1259514A (en) * | 1999-01-07 | 2000-07-12 | 济南新中智科技开发有限责任公司 | Improved technology of synthesizing tert-butyl amine using tert-butyl alcohol urea method |
-
2010
- 2010-05-14 CN CN2010101719945A patent/CN102241594A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1185757A (en) * | 1996-02-07 | 1998-06-24 | 大赛璐化学工业株式会社 | Oxidation catalyst system and process for oxidation with the same |
| CN1259514A (en) * | 1999-01-07 | 2000-07-12 | 济南新中智科技开发有限责任公司 | Improved technology of synthesizing tert-butyl amine using tert-butyl alcohol urea method |
Non-Patent Citations (3)
| Title |
|---|
| E.A.SHOKOVA等: "Adamantylation and Adamantylalkylation of Amides, Nitriles, and Ureas in Trifluoroacetic Acid", 《RASIAN JOURNAL OF ORGANIC CHEMISTRY》 * |
| PETER KOVACIC等: "Amination of Adamantanes Their Precursors With Trichloroamine-Aluminum Chloride", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| YASUTAKA ISHII等: "Innovation of Hydrocarbon Oxidation with Molecular Oxygen and Related Reactions", 《ADV.SYNTH.CATAL.》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103864621A (en) * | 2014-02-21 | 2014-06-18 | 南京理工大学 | Energetic material 4, 4, 8, 8-tetranitroadamantane-2, 6-dinitrate and preparation method thereof |
| CN103864621B (en) * | 2014-02-21 | 2016-03-02 | 南京理工大学 | Energetic material 4,4,8,8-tetranitro adamantane-2,6-dinitrate and preparation method thereof |
| CN111960949A (en) * | 2020-08-26 | 2020-11-20 | 中涛新材料有限公司 | High-yield amantadine preparation method |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104418736B (en) | A kind of synthetic method of acrylate | |
| CN104130216B (en) | The technique of hydrogen peroxide direct oxidation propylene propane mixture continuous preparation of epoxypropane | |
| CN104086464B (en) | A kind of method that H acid denitration exhaust-gas resource utilizes | |
| CN105148990B (en) | A kind of preparation method and applications of sulfonic acid carbon nano tube/graphene oxide composite catalyst | |
| CN103055938B (en) | Preparation method of acid-base bifunctional graphene-based nano heterogeneous catalyst | |
| CN102391158A (en) | Preparation method of isooctanol polyoxypropylene ether sodium sulfosuccinate diester | |
| CN109081767A (en) | A kind of the synthesis rectification technique and its equipment of monochloro methane | |
| CN101362692A (en) | Technology method for producing isopropyl trifluoroacetate and apparatus | |
| CN103191780A (en) | Functionalized carbon nitride photocatalyst capable of performing catalytic oxidization on benzene to synthesize phenol | |
| CN105622400A (en) | Acrylate synthesis method | |
| CN104624239A (en) | Catalyst for synthesizing phenol by virtue of hydroxylation of benzene and preparation method of catalyst | |
| CN108689838A (en) | A kind of method that swellable acid poly ion liquid catalysis formic acid prepares formic acid esters with alkene esterification | |
| CN103664656A (en) | Synthesis and application of quaternary ammonium salt ionic liquid based on heteropolyacid | |
| CN106732768A (en) | A kind of solid-carrying type ionic-liquid catalyst for carbon dioxide cycloaddition reaction and preparation method thereof | |
| JP2014532734A (en) | Method and apparatus for recovering ethylene in vinyl acetate production process | |
| CN102241594A (en) | Adamantanamine synthesis method through adamantanol aminolysis | |
| CN110981721A (en) | Method for continuously producing n-propyl acetate | |
| CN103316696B (en) | Preparation method of acetyl tri-n-butyl citrate and catalyst used in preparation method | |
| CN111675598B (en) | Production system for preparing electronic-grade isopropanol by acetone hydrogenation | |
| CN106378189B (en) | Catalyst and its preparation method and application for synthesizing polymethoxy dimethyl ether | |
| CN103254101B (en) | Prepare the method and apparatus of Urethylane | |
| CN104610087A (en) | Device and method for purifying yellow phosphorus tail gas and continuously synthesizing oxamide | |
| CN102442992A (en) | Method for synthesizing glycerol carbonate with biodiesel based crude glycerine and dimethyl carbonate | |
| CN104844455A (en) | Method used for catalyzed synthesis of tert-butyl acrylate | |
| CN104028286A (en) | Method for preparing copper-based catalyst |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20111116 |