991

LX1X.-Coiztributions to our Knowledge of the Aconite dlkaloi'ds. Part VI. Conversion of Aconitine in to Isaconitine.

By WYNDHAM R. DUNSTAN, M.A., F.R.S., and FRANCrS R. CARR, Assistant in the Research Laboratory of the Pharmaceutical Society.

I N Part IV of these Contributions (this vol., 4431, an account was given of a new alkaloid, isaconitine, which occurs along with aconitine in Aconitum Napellus. These two alkaloids were shown to be isomerides, and to furnish, when hydrolysed, the same products, na,mely, nconine and benzoic acid.

We have since attempted to gain some information with reference t0 the nature of this isomerism, and are now able to show that under certain conditions aconitine changes into isaconitine. In experi- ments made with aconitine hydrobromide, i t was observed tliat after the salt had been several times recrystallised from hot aqueous s o h - fions, it underwent modification in respect of certain properties, and in particular exhibited a higher and higher melting point as the recrystallisation was repeated. The form of the crystals became like that of isaconitine hydrobromide, and they separated in the same eharacteristic manner from a hot solution duying evaporation.

In order to prove that aconitine hydrobromide undergoes, when heated in aqueous solution, a gradual conversion into isaconitine hydrobromide, the following experiments were made.

PuIe crystalline aconitine (m. p. 188-189" corr.), prepared by fractiooal precipitation of the hFdrobromide with dilute ammonia, the first fraction being crystallised from ether, was converted into the hydrobromide by dissolving it in cold dilute hydrobromic acid, and evaporating the aqueous solution in a vacuous desiccator over sulphuric acid. The crystals thus obtaiaed melted at 163" (corr.), the melting point of the pure salt (Part 11). They were diwolved in water, and the concentrated aqueous solution heated in an open dish on the water-bath for one week, the water lost by evaporation being replaced from time to time. In order to separate aconitine from any isaconitine that might have been formed, t h e aqueous solution was partially precipitated with dilute ammonia, and the aikalo'id extracted by shaking with ether. The ethereal solution when spontaneously evaporated left a crystalline residue, ahowitg that it confiisted chiefly of aconitine. The o r i g i d aqueous solution was further precipitated, but not entirely, with dilute ammonia, and the liberated alkalo'id again extracted by ether. The ethereal residue was again crystalline. The reniainder of the original solution was now mixed with excess of dilute ammonia, aud

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992 DUNSTAN AND CARR:

the alkaloiId completely removed by repeated extraction with ether. This last ethereal solution did not leave a crystalline residue when spontaneously evaporated, although its physiological action proved that it contained aconitine. This residue was dissolved in dilute hydrobromic acid, and the neutral solution evaporated on the water- bath with constant stirring. The crystalline crust which separated was recrystallised from water. The crystals, which resembled isacon- jtine hydrobromide in appearance, melted at 281.2" (corr.). The melting point of isaconitine hydrobromide is 282" (Part IV). The base regenerated from this salt was amorphous, and resembled isaconitine. I ts salts were very bitter, but produced no tingling sensation. In order to completely establish the identity of this alkalojid with isaconitine, it was converted into hydrochloride, and precipitated with auric chloride. A copious, yellow, amorphous precipitate was produced. I t has previously been shown (Part IV) that both nconitine and isaconitine furnish the amorphous pre- cipitate, but whilst the aconitine compound crystallises irom its alcoholic solution as the jellow aurichloride, the isaconitine com- pound furnishes on crystallisation, not an aurichloride, but a aoloui-- less aurichlor-derivative. The precipitate was dissolved in alcohol, and the alccholic solution mixed with ether, and then with light, petroleum. On standing in a stoppered bottle, the small, colourless, characteristic crystals of aurichlorisaconitine made their appear- ance. These melted at the proper temperature, namely, 204.3" (corr.). A determination of the gold gave 21.24 per cent.; that calculated for C,H,,(AuCI,)NO3 is 21.44 per cent.

Further experimeri ts proved that the conversion occurs more readily when about 2 per cent. of free bydrohromic acid is present in the hot saturated f olution of aconitine hydrobromide, and that the change may be somewhat hastened by heating the liquid for 24 hours in a closed tube a t 110-115". By working in this way and regenerating the alkalo'id in the manner above described, rather more than 35 per cent. of the aconitine may be obtained as is- aconitine. I n an experiment in which 2 grams of aconitine were employed, and the saturated acidified solution of the hydrobromide was continuously heated for one month in an open dish on the water-bath, nearly 75 per cent. oE the alkaloid was obtained as isaconitine.

The conversion could not be effected by stirring strong aqueous hydrobromic acid into a strong solution of aconitine hydrobromide. After several repetitions of this process of precipitation, the aconitine still remained unchanged. Neither did heating the solu- tion of aconitine hydrnbromide with strong aqueous hydrobromic acid answer well ; most of the aconitine underwent hydrolysis into

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CONVERSION OF ACONITINE INTO ISACONITME. 993

aconine, and very little isaconitine could be isolated. The passage of dry hydrogen chloride into a solution of aconitine hydrochloride in chloroform did not lead to the production of isaconitine, neither did the aqueous hydrochloride nor h j driodide of aconitiiie exhibit the same readiness to change into isaconitine as the hydrobromide.

Aconitine nitrate showed no tendency t o change into isaconitine, even when its aqueous solution was warmed with dilute nitric acid. Experiments were also made with sulphuric acid. Aconitine was dissolved, in small quantities at a time, in well cooled, concen- trated sulphuric acid, and the solution allowed to stand for some time at 15". On pouring the solution into ice-cold water, and regenerating the alkaloid in the usual way, no isaconitine was obtained, but apparently the aconitine had been almost entirely hydro- Jysed. Trials were also made with aconitine sulphate, which was heated in aqueous solution for some hours on the water-bath in presence of about 1 per cent.'of sulphuric acid, but no isaconitine was formed.

Glacial acetic acid produces little or no effect on aconitine, even when the alkaloid is heated with the acid for some hours at 100". When, however, the experiment is made in a closed tube at 12U", and the heating is continued for about 24 hours, the aconitine is almost entirely converted into anhydroaconitine, but not a trace of isaconitine could be detected. Strong aqueous tartaric acid under similar conditions leads t o the same result.

Since i t seemed probable that in the hydrolysis of aconitine, not only by acid but also by alkali, this alkaloid first changes into isaconitine, careful search was made for isaconitine in t,he initial stages of the liydrolysis of aconitine by soda. Solutions of aconitine hydrochloride were precipitated by an excess of strong soda solu- tion, and the mixtures well shaken for some hours and then allowed to stand for several days at the ordiuary temperature. The precipitate slowly dissolved with formation of aconine, but no isaconitine has 80 far been obtained under these conditions. As isaconitine is itself readily hydrolysed by alkali, it is not to be expected that its actual isolation would be easy to accomplish. The conversion of aconitine iuto isaconitine under the conditions we have described, and the circumstance that no conversion occurs when aconitine is brought in contact with d r y hydrogen chloride, strong aqueous hydrobromic acid, sulphuric acid, or acetic acid, has also suggested the possibility of the isaconitine taking its origin in a reac- tion between aconine and beneoic acid, previously formed hy the hydrolysis of some of the aconitine; the reaction between the aconine and benzoic acid being facilitated by the presellce of dilute hydrobmmic acid, So far, however, we have not been able to obtain

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994 DCJNST-4N AND JOWETT :

confirmation of this suggestion as t o the mechanism of the change. Although numerous experiments have been made with benzoic acid and aconine, we have not yet succeeded in forming isaconitine from them ; these experiments are being continued.

The fact that an aqueous solution of aconitine hydrobromide, when heated slowly, undergoes conversion into the isaconitine salt must be borne in mind in conuection with the purification of aconitine by conversion into this salt, and ci*ystallisation of it from water. Under ordinary circumstances, when a neutral aqueous solution is employed, and this is riot heated for long a t one time, the risk of conversion is not great. Prolonged heating of an acid solution of aconitine hydro- bromide should be carefuliy avoided in any process which is being conducted for the purpose of obtaining aconitine.

Research Laboratory, Pharmaceutical Society, London.

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