A determination of its specific rotation gave the following result: = a, +1.93°; l=1 dcm. ; c=4.974; [a] = +38.8°. The anhydrous salt melts at 159° (corr.). Isopilocarpine Hydrobromide is obtained in a similar manner to the hydrochloride by adding ether to an alcoholic solution. The crystals are anhydrous and melt at 147° (corr.). A determination of its specific rotation gave the following result: == а1 = +1·5°; l=2 dcm. ; c = 2.288; [a] = +32·8°. Isopilocarpine Picrate, prepared by adding picric acid to the aqueous solution of the hydrochloride and recrystallising from water or alcohol, forms long, brilliant yellow needles which melt at 161° (corr.). Isopilocarpine Aurichloride is formed by adding a solution of auric chloride to a solution of pure isopilocarpine hydrochloride, and allowing the amorphous precipitate to become crystalline. The crystals are anhydrous and melt at 158-159° (corr.). On analysis : 0.1888 gave 0.0678 Au. Au= 35.91. C1H16ON,HAuCl, requires Au=35.96 per cent. Isopilocarpine Gold Chloride is prepared by boiling the aurichloride in water, when crystals separate exactly as in the case of the corresponding pilocarpine salt; these melt at 185-186° (corr.). On analysis: 0.1564 gave 0·0604 Au. Au = 38.61. C11H16ON,AuCl, requires Au= 38.5 per cent. Isopilocarpine Platinichloride, obtained by the usual method, crystallises in orange scales, which melt at 226-227° (corr.) with blackening and effervescence. On analysis: 0.2508 gave 0.0592 Pt. Pt= 23.60. (C11H16O2N2)2, H,PtCl requires Pt = 23.58 per cent. Isopilocarpine Methiodide is obtained by dissolving pure dry isopilocarpine in excess of methyl iodide, allowing it to stand, then removing the excess of methyl iodide, and recrystallising the residue from absolute alcohol until pure. It melts at 114° (corr.). A determination of the specific rotation gave the following result: ad= +0.83°; 7=1 dem.; c=2·734; [a] = +30·4°. On analysis, the following result was obtained: 0.2597 required 7.6 c.c. N/10 silver nitrate for precipitation. I=37·1. C11H16ON,CH,I requires I = 36.23 per cent. Properties of Isopilocarpine. Isopilocarpine can be obtained by a similar method to that used for pilocarpine, and the two bases possess very similar properties. Petit and Polonowsky have described it as forming large crystals, which are very hygroscopic, and soluble in all proportions in water and in alcohol I have not obtained it in a crystalline form, but have found that it can be distilled in a vacuum without decomposition, and forms a colourless, viscid oil, becoming quite fluid on warming. It boils at 261° under 10 mm. pressure, and the distillate yields a nitrate melting at 159°, thus proving that the base distils unchanged. The specific rotation was observed with the same precautions as detailed under pilocarpine, with the following results: = +5°; 1= 1 dcm. ; c=11652; [a] +42.91°. Three determinations of the specific rotation of the base, to which a molecular proportion of sodium hydroxide had been added, showed the solution to be inactive, and on adding excess of alkali no activity was observed. Copper Isopilocarpate could not be obtained pure, though evidence of its existence was obtained. An aqueous solution of pure isopilocarpine was boiled with an excess of freshly precipitated copper hydroxide, filtered, and the blue filtrate evaporated to dryness; this was extracted with chloroform, the chloroform solution precipitated with ether, and the mother liquor evaporated to dryness. All three products were then analysed, with the following results: (1). Portion insoluble in chloroform : 0.0744 gave 0.0068 CuO. Cu 7.3 per cent. (2). Portion soluble in chloroform, but precipitated by ether: 0.0888 gave 0·01 CuO. Cu8.99 per cent. (3). Portion soluble in the mixture of chloroform and ether: 0.7238 gave 0.0192 CuO. Cu=2·12 per cent. (C11H15O3N2)2Cu requires Cu 12:47 per cent. The last product was chiefly isopilocarpine, but the others contained copper isopilocarpate. Isopilocarpine Argento-nitrate.—On adding excess of silver nitrate in aqueous solution to an aqueous solution of isopilocarpine, an oily precipitate was obtained which contained silver, but could not be obtained crystalline. Existence of Isopilocarpine in the Alkaloids obtained from Jaborandi Leaves and in the Pilocarpine Nitrate of Commerce. The settlement of this question was one of the most important points in this inquiry, and unexpectedly proved to be a most difficult and tedious task. Harnack, and more recently Merck, have stated that the alkaloid yielding the crystalline nitrate accompanying pilocarpine is pilocarpidine, C10H1,N2O2, and it has been generally assumed that any impurity in pilocarpine nitrate would be pilocarpidine nitrate, or less likely jaborine nitrate. Petit and Polonowsky, on the other hand, state that the impurity existing in the pilocarpine nitrate of commerce, sometimes to the extent of 50-60 per cent., is isopilocarpine nitrate, and that this alkaloid is found in the leaves. There are thus apparently two opposite statements, both supported by experimental proof. The only proof adduced by Petit and Polonowsky as to the identity of isopilocarpine prepared from pilocarpine with that obtained from the leaves, or from the pilocarpine nitrate of commerce, is that auric chloride behaves in precisely the same manner with isopilocarpine obtained from the first two sources. My experiments prove conclusively that the impurity existing in the pilocarpine nitrate at present on the market, and in the alkaloid prepared from jaborandi leaves at present obtainable is isopilocarpine, identical with that formed from pilocarpine, and further that isopilocarpine exists ready formed in the leaves. Two samples of pilocarpine nitrate from different manufacturers were used, and a quantity of impure pilocarpine nitrate was prepared from the jaborandi leaves at present in the market, called Maranham jaborandi. The process of purification employed was one of repeated fractional crystallisation until a product of constant melting point was obtained. All three products behaving similarly, they were at a certain stage mixed, and the results obtained therefore relate to all three specimens. By repeated fractional recrystallisation, a nitrate was obtained of melting point 146°, which was not changed by two recrystallisations, and when obtained in two fractions both melted at 146°; this was regarded as a pure product, and therefore was converted into the hydrochloride, from which, by recrystallisation from absolute alcohol, and finally by fractional recrystallisation from alcohol and ether, a quantity of pure pilocarpine salt was separated. A hydrochloride, however, was obtained melting at 150°, which was unchanged by two recrystallisations from alcohol and ether, and by collection in two fractions. From this product, the aurichloride, platinichloride, picrate, and base were prepared, and the hydrochloride, auri chloride, and platinichloride analysed. In all cases, melting points and specific rotations were obtained, differing but slightly from those of the corresponding isopilocarpine salts, and the analytical results agreed exactly with those required for the latter base. On recrystallisation of the hydrobromide and nitrate, however, the product was found to still contain pilocarpine; and from the nitrate-which was expected to melt at 146°, but which actually melted at 150°-by recrystallising it seven times, pure isopilocarpine was finally obtained. It had thus been necessary to recrystallise the nitrate and hydrochloride about 20 times and in about 40 fractions before obtaining a pure product and a satisfactory result. The proof of the identity of the base with isopilocarpine was furnished by the physical constants and analyses of the base, nitrate, hydrochloride, hydrobromide, picrate, aurichloride, gold chloride, and platinichloride. In view of the importance of this point, the analytical data are here given; the melting points in all cases agreed exactly with those recorded for the salts of isopilocarpine. The agreement of these figures likewise affords proof of the correctness of the constants previously given. Base obtained from impure pilocarpine nitrate. +1.5°; 7 = 1 dcm. ; c=3·549; [a]»= +42·2°. With excess of alkali, ap= Nitrate.-Specific rotation: 0°. α= +6·1°; 7=2 dem. ; c=8·784; [a]= +34 72°. The solubility in water and in alcohol was determined, with the following results: Solubility in water: 6.401 of solution at 19° gave 0.7262 salt; hence 1 part is soluble in 7·8 parts of water at 19°. Solubility in absolute alcohol: 15.48 of solution at 19° gave 0.045 salt; hence 1 part is soluble in 343 parts of absolute alcohol at 19°. Hydrochloride.-Specific rotation : ap = +2·7°; 7=1 dcm. ; c=7·036; [a] = +38.3°. 07278 lost 0.0242 H2O when the air-dried salt was dried until of constant weight. H2O-3-32 per cent. Hydrobromide.-Specific rotation: = a1 = +0·75°; l = 1 dcm. ; c = 2.182 ; [a] = +34·3°. Aurichloride.-Analysis: 0·1956 gave 0·0704 Au. Au=35.99. Gold Chloride.-Analysis: 0·0516 gave 0·0198 Au. Au=38.37. Platinichloride.-Analysis: 0.12 salt gave 0.0282 Pt. Pt=23.5. (C11H16O2N2)2,H¿PtCl ̧ requires Pt=23.58 per cent. These figures, together with the melting points, afford conclusive proof of the identity of the base obtained from impure pilocarpine nitrate with isopilocarpine prepared from pilocarpine by the action of heat or alkali. The mother liquors from the nitrate last obtained were then examined, and a base isolated which at first was thought to be a new alkaloid with a nitrate melting at 144°, as this constant was not altered by four recrystallisations. By preparing the picrate, however, and recrystallising several times, the base was found to be a mixture of pilocarpine and isopilocarpine. In order to obtain further evidence that these mixtures, which in some respects behaved as a pure substance, consisted of pilocarpine and isopilocarpine, four mixtures of the nitrates were made in certain proportions and recrystallised from alcohol. The results fully confirmed those previously obtained. (1) A mixture of 90 per cent. of pure pilocarpine nitrate and 10 per cent. of pure isopilocarpine nitrate, after one crystallisation, melted at 170°, and after five recrystallisations yielded pure pilocarpine nitrate. (2) A mixture of equal parts of the two nitrates melted indefinitely at 144-147°, and after five recrystallisations yielded an impure product melting at 160-165°, which seemed to be unaltered by further recrystallisation. (3) A mixture of 33 parts of pilocarpine nitrate and 66 parts of isopilocarpine nitrate melted at 144°, and this melting point was not altered by three recrystallisations. (4) A mixture of 90 per cent. isopilocarpine nitrate and 10 per cent. pilocarpine nitrate melted first at 157°, and after two recrystallisations yielded pure isopilocarpine nitrate. These experiments fully explain the difficulties above-mentioned, and also a statement that pure pilocarpine nitrate melting at 141.7° was not changed by recrystallisation (Paul and Cownley, loc. cit.). The alkaloid prepared by me from the leaves was not subjected to any conditions that would convert any appreciable amount of the pilocarpine into isopilocarpine; the latter, however, was found to be present, although only in small quantity, and it certainly exists in the leaves. |