CN103965068A - 1-amide adamantane preparation method - Google Patents
1-amide adamantane preparation method Download PDFInfo
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Abstract
The present invention discloses a 1-amide adamantane preparation method, which comprises: (1) in fuming sulfuric acid, carrying out a reaction of a compound represented by a formula I and an organic nitrile compound RCN, wherein the reaction temperature is 15-50 DEG C, and R is methyl, ethyl, phenyl, C1-C3 alkyl benzene or C3-C5 cycloalkyl; and (2) adopting any one of the following methods, wherein the methods comprise: the method 1: adding the reaction solution in the step (1) to a protonic organic solvent and/or ester solvent to obtain a mixed solution a, and adding the mixed solution a to water to obtain a mixed solution b, wherein the temperature of the mixed solution a is controlled to 0-10 DEG C, and the temperature of the mixed solution b is controlled to 0-5 DEG C; and the method 2: adding the reaction solution in the step (1) to an inorganic salt aqueous solution to obtain a mixed solution c, wherein the temperature of the mixed solution c is controlled to -20 to -5 DEG C. According to the present invention, the 1-amide adamantane is directly obtained through the one-step reaction so as to simplify the operation process and reduce the cost.
Description
Technical field
The present invention relates to the synthetic field of medicine, relate in particular to a kind of preparation method of 1-amide group diamantane.
Background technology
1-amide group diamantane is important intermediate synthetic antiviral, treatment parkinsonism medicine amantadine, and their molecular structure is respectively as shown in the formula shown in II compound and formula III compound.Amantadine is the first antiviral drug of U.S.'s approval, and within 1964, first Davis finds its antivirus action, and is in succession written into British Pharmacopoeia, American Pharmacopeia, Japanese Pharmacopoeia and Chinese Pharmacopoeia.Domestic beginning in 1971 produces.In addition, folk prescription amantadine sheet is mainly used in treating Parkinson's disease.
1-amide group diamantane amantadine
Document medicine industry 1973,4 (6), 14-15 has reported the synthetic method of amantadine, under the condition that the first step of reaction need to reflux at bromine, react with diamantane (compound shown in formula I), prepare intermediate 1-bromo diamantane (compound shown in formula IV), this reaction environment is seriously polluted, and bromine simple substance price is higher, also needs can obtain 1-kharophen diamantane through two-step reaction.
Document Journal ofMedicinal Chemistry1963,6 (6), the synthetic method of 760-763 report 1-kharophen amantadine, the first step of reaction need to be used aluminum chloride and tertiary butyl chloride, prepare intermediate 1-chloro diamantane (formula V) by diamantane (formula I), this reaction environment is seriously polluted, and aluminum chloride aftertreatment is loaded down with trivial details, and the method need to just can make 1-acetamido diamantane through two-step reaction.
Patent CN101891570A has reported the synthetic method of 1-adamantanol (compound shown in formula VI), and the method only can be prepared the intermediate 1-adamantanol for the synthesis of 1-amido diamantane, and can not a step make 1-amide group diamantane.
Document Chemische Berichte1959,92 (7), the synthetic method of 1629-1635 report 1-kharophen diamantane: 1-adamantanol (formula VI) is as the synthetic 1-kharophen diamantane of raw material, need to use strongly-acid system, and use nitration mixture also to increase cost as solvent, in addition this synthetic method productive rate only 61%.Its reaction is as follows:
Document Synthesis2000; (12); the synthetic method of 1709-1712 report N-chloracetyl diamantane-1-amine (formula VII): 1-adamantanol (formula VI) reacts with chloromethyl cyanide as raw material and obtains formula VII compound, and the latter reacts with thiocarbamide and directly makes adamantanamine hydrochloride (formula VIII).This synthetic route has been used the chloromethyl cyanide that price is higher, causes the increase of cost.
Summary of the invention
Technical problem solved by the invention is that the preparation method's step in order to overcome existing 1-amide group diamantane is many, productive rate is not high, aftertreatment is complicated; be unfavorable for the defect of suitability for industrialized production and environment protection, a kind of preparation method of 1-amide group diamantane is provided.Preparation method's reaction conditions gentleness of the present invention, easy and simple to handle, by product is few, and aftertreatment is simple, is suitable for suitability for industrialized production, and can make high yield, highly purified 1-amide group diamantane.
The present invention solves the problems of the technologies described above by the following technical programs:
The preparation method who the invention provides a kind of 1-amide group diamantane, it comprises the steps:
Step (1), in oleum, is reacted formula I compound with organic nitrile compound R CN, the temperature of described reaction is 15 ~ 50 DEG C; Wherein, R is methyl, ethyl, phenyl, C
1～C
3alkylbenzene or C
3~ C
5cycloalkyl;
Step (2) adopts any in following method:
Method one: the reaction solution of step (1) is added and in protic organic solvent and/or esters solvent, obtains mixed solution a, then this mixed solution a is added to the water and obtains mixed solution b; The temperature control of described mixed solution a is 0 ~ 10 DEG C, and the temperature control of described mixed solution b is 0 ~ 5 DEG C;
Method two: the reaction solution of step (1) is added and in inorganic salt solution, obtains mixed solution c; The temperature control of described mixed solution c is-20～-5 DEG C;
In step (1), described R is preferably methyl or ethyl, is more preferably methyl.
In step (1), described oleum refers to the sulphuric acid soln of sulphur trioxide; Described oleum is preferably 5% ~ 50% oleum for sulphur trioxide accounts for mass ratio, is more preferably 15% ~ 25% oleum for sulphur trioxide accounts for mass ratio, is 20% oleum best for sulphur trioxide accounts for mass ratio.The consumption of described oleum be do not affect reaction normally; This oleum is 5 ~ 7ml/g with the volume mass of formula I compound than preferably, is more preferably 5.5 ~ 6.5ml/g, is 5.9ml/g best; In this oleum with H
2sO
4calculating mole number is preferably 15 ~ 20 times of formula I compound mole number.
In step (1), the mol ratio of described organic nitrile compound R CN and formula I compound is preferably 1:1 ~ 2:1, is more preferably 1:1 ~ 1.3:1.
In step (1), described organic nitrile compound R CN adds mode preferably for organic nitrile compound R CN is added dropwise in the mixture of formula I compound and oleum; The temperature of described formula I compound and the mixture of oleum is preferably 5 ~ 15 DEG C, is more preferably 10 ~ 15 DEG C.
In step (1), the temperature of described reaction is preferably 15 ~ 40 DEG C, is more preferably 28 ~ 30 DEG C.
In step (1), the process of described reaction can be monitored by this area conventional means (as vapor-phase chromatography (GC)), while generally disappearance using formula I compound, as the terminal of reaction, the time of described reaction is preferably 2 ~ 4 hours, is more preferably 3 ~ 4 hours.
In the present invention, the reaction solution that described step (1) obtains can directly carry out step (2) without aftertreatment.
In the method one of step (2), it is 0 ~ 5 DEG C that the temperature of described mixed solution a is preferably controlled.
In the method one of step (2), the described reaction solution by step (1) adds in protic organic solvent and/or esters solvent and preferably the reaction solution of step (1) is added dropwise in protic organic solvent and/or esters solvent, and drop rate is preferably controlled at 4 ~ 6 seconds/drips.Described is added to the water this mixed solution a preferably this mixed solution a is added dropwise in water, and drop rate is preferably controlled at 4 ~ 6 seconds/drips.
In the method one of step (2), described protic organic solvent and/or esters solvent are can be miscible with sulfuric acid and be can very exothermic between-10 DEG C ~ 30 DEG C or conventional protic organic solvent and/or the esters solvent in this area that react in temperature; Described protic organic solvent is preferably ethanol and/or Glacial acetic acid, and described esters solvent is preferably ethyl acetate and/or butylacetate.
In the method one of step (2), the mol ratio of described protic organic solvent and/or esters solvent and described formula I compound is preferably 15:1 ~ 20:1.The mol ratio of described water and described formula I compound is preferably 150:1 ~ 200:1.
In the method two of step (2), the temperature of described mixed solution c is preferably controlled as-20～-15 DEG C.
In the method two of step (2), the described reaction solution by step (1) adds in inorganic salt solution and preferably the reaction solution of step (1) is added dropwise in inorganic salt solution, and drop rate is preferably controlled at 4 ~ 6 seconds/drips.
In the method two of step (2), as long as this inorganic salt solution is to ensure any inorganic salt solution of existing with liquid form at the temperature of-20～-5 DEG C.Described inorganic salt solution is preferably one or more in sodium chloride aqueous solution, calcium chloride water and magnesium chloride brine.The massfraction of described inorganic salt solution is preferably 15% ~ 30%.The volume ratio of the reaction solution of described inorganic salt solution and step (1) is preferably 3.7:1 ~ 4.3:1.
In the present invention, after described step (2) finishes, can also carry out aftertreatment, be further purified formula II compound.The mode of described aftertreatment can be the post processing mode of this area routine, preferably includes following steps: with dichloromethane extraction, extraction liquid is used saturated sodium bicarbonate aqueous solution and saturated common salt water washing successively, dry filter, and filtrate evaporate to dryness.The number of times of described extraction is preferably 3 times.The described dry anhydrous magnesium sulfate drying that preferably adopts.
Meeting on the basis of this area general knowledge, above-mentioned each optimum condition, can arbitrary combination, obtains the preferred embodiments of the invention.
Agents useful for same of the present invention and raw material be commercially available obtaining all.
Positive progressive effect of the present invention is:
(1) in the present invention, utilize diamantane as starting raw material, single step reaction directly obtains 1-amido diamantane, has simplified operating process, reduce costs, and reaction conditions gentleness, aftertreatment is easy, is conducive to industrial production and environment protection.
(2) reaction described in the present invention can obtain high yield, highly purified formula II compound.
(3) the formula II compound being made by the present invention, can further be used for preparing amantadine, and productive rate and purity all can reach industrial requirement.
Embodiment
Mode below by embodiment further illustrates the present invention, but does not therefore limit the present invention among described scope of embodiments.The experimental technique of unreceipted actual conditions in the following example, according to ordinary method and condition, or selects according to catalogue.
Embodiment 1
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the 45ml dehydrated alcohol of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 1 hour, dropwise, obtain incarnadine clarification mixed solution.Again this mixed solution is dropped in the 135ml water of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 2 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtains white solid (7.83g, productive rate 92%, GC(vapor-phase chromatography) detect purity be 95.2%), [GC normalization method: chromatographic column is (5%) phenyl-(95%) methyl polysiloxane capillary chromatographic column; Method: column temperature, in 220 DEG C of insulation 1min, rises to 250 DEG C with the heat-up rate of 10 DEG C of per minute intensifications, at 250 DEG C of insulation 10min, injector temperature is 220 DEG C, detector temperature is 300 DEG C].mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 2
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the 45ml acetic acid of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 1 hour, dropwise, obtain achromaticity and clarification mixed solution.Again this mixed solution is dropped in the 135ml water of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 2 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.0% that GC detects purity for 8.06g, productive rate 94.7%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 3
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the 45ml ethyl acetate of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 1 hour, dropwise, obtain achromaticity and clarification mixed solution.Again this mixed solution is dropped in the 135ml water of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 2 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.1% that GC detects purity for 8.00g, productive rate 94%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 4
Preparation 1-kharophen diamantane
By diamantane (6.0g, 44.1mmol) add the 20% oleum (35ml of 10 DEG C, 678mmol) (calculate mole number with H2SO4), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, is reacted 3 hours, and reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the 45ml butylacetate of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 1 hour, dropwise, obtain achromaticity and clarification mixed solution.Again this mixed solution is dropped in the 135ml water of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 2 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.1% that GC detects purity for 8.03g, productive rate 94.3%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 5
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the sodium chloride solution that the 135ml massfraction of-15 DEG C is 28%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.1% that GC detects purity for 8.06g, productive rate 94.3%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 6
Preparation 1-kharophen diamantane
By diamantane (6.0g, 44.1mmol) add the 20% oleum (35ml of 10 DEG C, 678mmol) (calculate mole number with H2SO4), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, is reacted 3 hours, and reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the magnesium chloride solution that the 135ml massfraction of-15 DEG C is 15%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.3% that GC detects purity for 7.98g, productive rate 93.7%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 7
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the calcium chloride solution that the 135ml massfraction of-15 DEG C is 15%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 98.5% that GC detects purity for 7.93g, productive rate 93.1%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 8
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 45 ~ 50 DEG C, to be reacted 3 hours, reaction finishes to obtain brown color clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the sodium chloride solution that the 135ml massfraction of-15 DEG C is 28%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 91.1% that GC detects purity for 7.57g, productive rate 88.3%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 9
Preparation 1-kharophen diamantane
Add 50% oleum (35ml, 783mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 45 ~ 50 DEG C, to be reacted 3 hours, reaction finishes to obtain black suspension.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the sodium chloride solution that the 135ml massfraction of-15 DEG C is 28%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of tawny.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 82.3% that GC detects purity for 1.75g, productive rate 20.6%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Embodiment 10
Preparation 1-kharophen diamantane
By diamantane (6.0g, 44.1mmol) add the 20% oleum (35ml of 10 DEG C, 678mmol) (calculate mole number with H2SO4), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, is reacted 3 hours, and reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the sodium chloride solution that the 135ml massfraction of-15 DEG C is 28%, control temperature while dropping and, between-18 DEG C～-15 DEG C, within approximately 1.5 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 82.5% that GC detects purity for 7.88g, productive rate 94.3%).mp144.3-145.5℃。ESI-MS（m/z）：[M+H]
+194.15，[M+2H]
+195.17，[2M+H]
+387.10；
1H-NMR(400MHz,CDCl
3)δ:5.28（brs,1H），2.05-1.98（m,3H），1.98-1.90（m,6H），1.88（s,3H），1.67-1.59（m,6H）。
Comparative example 1
Preparation 1-kharophen diamantane
Add 20% oleum (35ml, 678mmol) of 10 DEG C (with H diamantane (6.0g, 44.1mmol)
2sO
4calculate mole number), be added dropwise to afterwards acetonitrile (2.4g, 58.5mmol), in dropping process, control temperature and be no more than 15 DEG C, reinforced complete, reaction solution heated for controlling temperature, between 28 ~ 30 DEG C, to be reacted 3 hours, reaction finishes to obtain faint yellow clear liquid.This reaction solution is cooled to 0 DEG C of left and right, then is added dropwise in the water of 0 ~ 5 DEG C, control temperature while dropping and, between 0 ~ 5 DEG C, within approximately 3 hours, dropwise, obtain the thick suspension liquid of oyster white.By this methylene dichloride (100ml × 3) extraction for suspension liquid, merge organic phase, use successively afterwards 100ml saturated sodium bicarbonate and the water washing of 100ml saturated common salt, after anhydrous magnesium sulfate drying, filter, filtrate decompression evaporate to dryness, obtain white solid (it is 87.5% that GC detects purity for 7.79g, productive rate 91.4%).
Claims (12)
1. a preparation method for 1-amide group diamantane, it comprises the steps:
Step (1), in oleum, is reacted formula I compound with organic nitrile compound R CN, the temperature of described reaction is 15 ~ 50 DEG C; Wherein, R is methyl, ethyl, phenyl, C
1～C
3alkylbenzene or C
3~ C
5cycloalkyl;
Step (2) adopts any in following method:
Method one: the reaction solution of step (1) is added and in protic organic solvent and/or esters solvent, obtains mixed solution a, then this mixed solution a is added to the water and obtains mixed solution b; The temperature control of described mixed solution a is 0 ~ 10 DEG C, and the temperature control of described mixed solution b is 0 ~ 5 DEG C;
Method two: the reaction solution of step (1) is added and in inorganic salt solution, obtains mixed solution c; The temperature control of described mixed solution c is-20～-5 DEG C;
2. preparation method as claimed in claim 1, is characterized in that, described oleum is that to account for mass ratio be 5% ~ 50% oleum to sulphur trioxide.
3. preparation method as claimed in claim 2, is characterized in that, described oleum is that to account for mass ratio be 15% ~ 25% oleum to sulphur trioxide.
4. preparation method as claimed in claim 3, is characterized in that, described oleum is that to account for mass ratio be 20% oleum to sulphur trioxide.
5. preparation method as claimed in claim 1, is characterized in that, in described oleum with H
2sO
4calculating mole number is 15 ~ 20 times of formula I compound mole number.
6. preparation method as claimed in claim 1, is characterized in that, the mol ratio of described organic nitrile compound R CN and formula I compound is 1:1 ~ 2:1.
7. preparation method as claimed in claim 1, it is characterized in that, the mode that adds of described organic nitrile compound R CN is that organic nitrile compound R CN is added dropwise in the mixture of formula I compound and oleum, and the temperature of described formula I compound and the mixture of oleum is 5 ~ 15 DEG C; The temperature of described reaction is 15 ~ 40 DEG C.
8. preparation method as claimed in claim 7, is characterized in that, the temperature of described formula I compound and the mixture of oleum is 10 ~ 15 DEG C; The temperature of described reaction is 28 ~ 30 DEG C.
9. preparation method as claimed in claim 1, is characterized in that, the temperature control of described mixed solution a is 0 ~ 5 DEG C.
10. preparation method as claimed in claim 1, is characterized in that, the temperature control of described mixed solution c is-20～-15 DEG C.
11. preparation methods as claimed in claim 1, is characterized in that, described protic organic solvent is ethanol and/or Glacial acetic acid, and described esters solvent is ethyl acetate and/or butylacetate.
12. preparation methods as claimed in claim 1, is characterized in that, described inorganic salt solution is one or more in sodium chloride aqueous solution, calcium chloride water and magnesium chloride brine, and the massfraction of described inorganic salt solution is 15% ~ 30%.
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| CN201310030052.9A CN103965068A (en) | 2013-01-25 | 2013-01-25 | 1-amide adamantane preparation method |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112250594A (en) * | 2020-10-19 | 2021-01-22 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112939798A (en) * | 2021-02-09 | 2021-06-11 | 浙江理工大学 | Preparation method of amantadine |
-
2013
- 2013-01-25 CN CN201310030052.9A patent/CN103965068A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112250594A (en) * | 2020-10-19 | 2021-01-22 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112250594B (en) * | 2020-10-19 | 2023-09-12 | 浙江荣耀生物科技股份有限公司 | Method for preparing 3-acetamido-1-adamantanol |
| CN112939798A (en) * | 2021-02-09 | 2021-06-11 | 浙江理工大学 | Preparation method of amantadine |
| CN112939798B (en) * | 2021-02-09 | 2022-07-19 | 肯特催化材料股份有限公司 | Preparation method of amantadine |
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Application publication date: 20140806 |