The present invention relates to a new process of preparin N-(l-adamantyl)aσylamides from adamantane and nitriles.

N-(l-adamantyl)acylamides are valuable intermediates of synthetizing 1-aminoadamantane (amantadin) .

1-aminoadamantane, preferably in the form of mineral acid salts such as hydrochlorides or sulphates, is a valuable thera¬ peutic active compound, e.g. in combatting virus.

Several syntheses of preparing 1-aminoadamantane are previously known.

From the German Offenlegungsschrift 1,294,371 it is known to react l-bromoadamantane or l-chloroadamantane at elevated temperatures with urea or derivatives thereof. Among others e.g. l-bromoadamantane and urea were heated to 180°C till an exoterm reaction started, whereupon the temperature rose to 240°C. The reaction product was worked up and yielded 1-amino¬ adamantane in 95% yield in this step, l-bromoadamantane is prepared by the bromination of adamantane with Br2• The yield of the last step is attractive, but the exotermic reaction and elevated temperature may provide difficulties in monitoring the reaction - particularly on commercial scale as it is carried out without solvent.

Further it is known from the Belgian Patent 646.581 to prepare N-(l-adamantyl)acetamide as an intermediate of preparing 1-aminoadamantane by reacting l-bromoadamantane with acetoni- trile. The reaction is accomplished in the presence of concen¬ trated sulphuric acid. 1-aminoadamantane was prepared from the intermediate obtained by the hydrolysis with NaOH in (HOC2H4)2θ by heating at 180°C in 5 hours.

The reaction of l-bromoadamantane with acetonitrile to N-(l-adamantyl)acetamide yielded 90% in this step. The work up of the product is performed by dilution in great amounts of water. The synthesis from adamantane through the 1-bromo- derivative to N-(l-adamantyl)acetamide thus takes place in two steps. The bromination is said to yield 99%.

Further Bewic, A.; Edwards, C.J. ; Showns S.R. ; Miller, J.M. in Tetrahedron Letters 1976 (8) 631-4 describe the

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preparation of N-(l-adamantyl)acetamide by preparative electro¬ lysis of adamantane in acetonitrile and quenching the reaction with H ₂ 0. The yield achieved is said to be 74%. This process includes 1 step less than the previous, however, equipment for preparative electrolysis is not standard equipment which is commonly available for industrial processes.

The German Offenlegungsschrift 1,197,091, (inventor Wolfgang Haaf) , discloses the preparation of 1-aminoadamantane through N-(l-adamantyl)formamide as intermediate product, which is then hydrolysed by sodium hydroxyde in diethyleneglycol. The preparation of N-(l-adamantyl)formamide is accomplished by reacting adamantane with sulphuric acid, hydrogen cyanide and tertiary butanol. The total yield is said to be 70% 1-amino¬ adamantane. Similar investigations performed by Wolfgang Haaf has among other in the same reaction substituted acetonitrile for hydrogen cyanide, and a yield of N-(l-adamantyl)acetamide of 35% of theoretical was then achieved, (Haaf,W. Ber 97. (1964) 3234) .

Although the synthesis with hydrogen cyanide provides satisfying yields, the handling of great amounts of hyrogen cyanide is undesirable in a commercial processs of preparation.

It was thus an aim of the present invention to provide a new and improved process of preparing N-(l-adamantyl)acyl amides from adamantane.

It was a particular aim of such a process that particularly toxic reactants such as hydrogen cyanide (HCN) should be eliminated, and also strongly exotermic reactions and elevated temperatures which are difficult to monitor in commercial processes.

According to the present invention a new and enhanced process of preparing N-(l-adamantyl)acyl amides is provided characterized by the reaction of adamantane with a nitrile in the presence of a strong mineral acid.

By this process N-(l-adamantyl)acyl amides are prepared in one single operation step.

Preferably a mineral acid is used as acid or a mixture of mineral acids.

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Preferably this mineral acid is nitric acid, and particu¬ larly fuming nitric acid (HN0 ₃ ) . Preferably the reaction is carried out in an inert organic solvent, particularly cyclo¬ hexane, hexane and tetrachloromethane. The use of cyclohexane provides for good separation of a nitric acid phase comprising product and acetonitrile and a cyclohexane phase containing unreacted adamantane. By separating the phases prior to work up cyclohexane and possible unreacted adamantane may be recircula¬ ted.

By continuous extraction of the nitric acid phase with e.g. tetrachloromethane the nitric acid may be recovered.

As the nitrile perferably acetonitrile is used.

The following experimental specification is illustrating but shall not be construed as limiting to the invention the scope of which is defined by the following claims.

Example 1-4

The reactions were performed under magnetic stirring. Prelimi¬ nary experiments with fuming nitric acid indicated that the reactions with adamantane were complete after 4-5 hours. The reactions were quenched by the addition of water, the products were extracted by dichloromethane, the organic phase separated and washed with aqueous NaHC0 ₃ and dried on Na ₂ S0 ₄ before the solvent was evaporated. The yields of the examples are achieved by gasσhro atographic analysis (25M fused silica/SE30, p-nitrotoluene as internal standard) .

Reactants and yields of examples 1-4:

Example 1:

Adamantane (8 mg) , acetonitril (1 ml) , tetrachloromethane (3 ml), nitric acid (90%, 3 ml), - 74% of theoretical.

Example 2:

As example 1, but with Ru0 ₂ xH ₂ 0 (5 mg) - 69% of theoretical.

Example 3:

As example 1, but with 65% nitric acid, - 9% of theoretical, 80% adamantane recovered.

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Example 4:

As example 1, but without tetrachloromethane - 19% of theoretical.

Example 5-6:

In the reactions 5 and 6 the yields represent worked up and purified product. The products were identified by comparing the melting points and spectral characteristics ¹ H MR, ¹³ CNMR and MS with the corresponding of authentic samples.

Example 5:

To a solution of adamantane (1.0 g, 7 mmole) and aceto¬ nitrile (6.5 ml, 124 mmole) in cyclohexane fuming nitric acid (17 ml, 405 mmole) was added and stirred on a water bath. The phases were worked up separately by adding NaOH to pH>7 followed by extraction with dichloromethane. The organic phases were washed with aqueous NaHCθ ₃ , dried on MgS0 ₄ and evaporated to dryness. The yield was 97 % of theoretical. Totally 99 % of the adamantane was reacted, whereas 1 % was recovered.

Example 6:

The reaction was performed as described in example 5. Subsequent to the separation of the phases the nitric acid phase was added H 0 (30 ml) and continuously extracted with CCI4. Washing of the CCI4 phase with NaOH (1 M) , drying on MgS0 ₄ and evaporation to dryness yielded 0,77 g product of 100 % purity representing a 54 % yield.

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