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United States Patent Patented Aug. 17, 1948 2,447,214 UNITED STATES PATENT OFF ICE 2,447,214 OPTICALLY ACTIVE SALTS OF THE LY SERGIC AND SOLYSERGIC ACD DE RVATIVES AND A PROCESS FOR, THER PREPARATION AND SOLATION Arthur Stoll and Albert Hofmann, Basel, Switzer land, assignors to Sandoz Ltd., Fribourg, Swit zerland, a Swiss firm No Drawing. Application August 23, 1943, Serial No. 499,714. In Switzerland September 16, 1942 16 Claims. (CI. 260-236) 2 The preparation and the isolation of the thera The synthetically prepared derivatives of the peutically valuable and active derivatives con lysergic acid which also correspond to the above tained in ergot is a problem that has occupied cited formula possess also the same lability as chemistry and pharmacy for more than 120 years. the natural lysergic acid derivatives. Their is0 Actually it is known that the action of ergot is 5 lation and preparation encounters the same dif due to the alkaloids contained therein, which have ficulties as in the case of the lysergic acid hydra been isolated in recent years and which are zides C15H15N2CONHNH2 (made according to U. S. always present as pairs of isomers. Chrono Letters Patent 2,090,429) and in the case of the logically the following alkaloids have become alkaloids of the type of ergobasine, which can be 0 prepared by partial synthesis and in which the known up to noW: lysergic acid is combined with an amine in form Ergotinine (1875). Ergotoxine (1906) of an acid amide (see U. S. Letters Patent No. Ergotamine (1918) Ergotaminine (1918) 2,090,430). ." Ergobasine (1935) Ergobasinine (1935) The separation of the natural as well as of the Ergosinine (1936) Ergosine (1936) synthetical lysergic acid derivatives has been Ergocristine (1937) Ergocristinine (1937) generally carried out by conversion into inorganic The long period which has been necessary in or organic acid salts. For instance, ergotoxine order to isolate the active compounds of ergot was purified, many years before the base was ob shows the great difficulties which are encountered tained in a crystallized form, by converting the with regard to their isolation and preparation in 20 same into its phosphate which crystallizes in a a pure form. These difficulties are especially due conglomeration of needles. The technical litera to the complication and especially to the easy ture further described salts of ergot alkaloids decomposition of the ergot alkaloids which be With sulfuric acid, hydrochloric acid, oxalic acid, come transformed into dark amorphous products tartaric acid, picric acid and the like. Although already under the action of light and of the air these salts possess sometimes good crystallisa oxygen. Also acids as well as alkalis and in Some tion properties, they are generally so rapidly cases even solvents are capable of transforming. decomposed that they cannot be used for repeated the ergot alkaloids, this being proved by the fact . recrystallisations. Therefore, they are generally that they become dark colored and lose their crys not useful for the preparation of lysergic acid tallisation power. Further difficulties lay in the 30 derivatives in pure forms. The dextro-rotary fact of the easy transposition of the levo-rotary isomers of he ergot alkaloids, the derivatives of form into the dextro-rotary form of the alkaloids the iso-lysergic acid, give with the generally used this leading again to mixtures which may be acids no crystallized salts at all. crystallised only with difficulties. It has now been found that new suitable comin' The ergot alkaloids having the properties of pounds are obtained by converting compounds producing mixed crystals between the levo- and containing the lysergic acid radical into acid salts dextro-rotary form, often false conclusions have of acylated tartaric acids of the formula been made, so that mixtures of different products HOOC.CHOX-CHOX COOH have often been considered as pure individuals. It will be seen in the following that the property 40 wherein X stands for an aroyl radical, like for of alkaloids consisting in giving isomorph crys instance benzoyl or p-toluyl, the new compounds tallisations has also led to the fact that prepara being very suitable for the separation and prepa tions from ergot have been considered as uniform ration in pure form of basic compounds contain compounds, whereas in truth they were mixtures ing the lysergic acid radical and corresponding to of different alkaloids. the general formula C15H15N2COR. The ob The great decomposition power of the ergot, tained new salts possess an excellent crystallizing alkaloids is based on the lability of the basic . property, stability, good solubilisation properties radical which is characteristic for all the alka and an astonishing separation property. They loids. This radical is the lysergic acid of the can, without noticeable loss of substance, be re formula C15H15N2COOH. The said compound Crystallized several times. It appears that the consists of an unsaturated nitrogen-containing above cited substituted tartaric acids give besides ring system, the constitution of which is hitherto the pure salt formation a stable combination with not completely cleared up and which is present the lysergic acid radical thus decreasing the labil in two isomer forms turning easily into each ity of the lysergic acid. Moreover, it is astonish other. The ergot alkaloids known up to now 5 5 ing that the derivatives of the strongly dextro correspond to the general formula C15H15N2COR; rotary isolysergic acid give also stable salt com therefore, the individual ergot... alkaloid pairs pounds with the above cited substituted tartaric differ from each other only in the constitution of acids. the substituent R, which is linked to the car In order to carry out the new process we use boxylic group of the lysergic acid. 60 generally dibenzoyl- and di-(p-toluy) tartaric 2,447,214 3 acids, but also differently substituted tartaric and fraction III from methanol under addition of acids may be used for the preparation of stable Water. Salts with natural and synthetical lysergic acid The following table shows the property of the derivatives. Such substituted tartaric acids are Salts of the three alkaloids thus obtained: for example the dianisoyl-, di-(2-methoxyben 5 ZOyl)-, di-veratroyl-, di-(a-naphthoyl)-tartaric melting acid and the like. point a The formation of the salts is preferably carried fraction (corr.) (in solubility out by dissolving the components in a solvent like positiondecom- ethanol)thanol methanol, ethanol, acetone, or in another organic oC. Degrees Solvent miscible in Water and by mixing the solu I---------- 187 --68 difficultly soluble in ethanol and tion of the components in equimolecular quanti methanol. 86 --103 soluble in the thirty fold quantity ties. The desired salts crystallize out immediately of hot methanol. or can be brought to crystallization in fractions 80 --103 easily soluble in ethanol and by adding water in small quantities. The salt methanol. formation can also be carried out by mixing for instance the barium salt of a substituted tartaric The alkaloids freed from the above salt frac acid with the sulfate of the alkaloid. tions are three different and uniform chemical The usefulness of the new compounds for the individuals. The base obtainable from fraction I preparation in pure state of the active compounds O is identical with ergocristine described by A. Stoll of ergot and especially for the separation of the and E. Burckhardt (Hoppe-Seyler's Ztschr. f. mixtures of ergot alkaloids into their components physiol. Chem. 250, 1 (1937)), while the alkaloids is proved by the fact, that, according to the pres obtainable from fractions II and III are hereto ent process, it is possible to separate ergotoxine, fore unknown ergot alkaloids, to which we have which has been isolated in 1906 and which has al given the names of ergocryptine and ergocornine ways been considered as a homogeneous chemical respectively. The expression "ergotoxine' shall, Compound, into 3 different alkaloids, two of which therefore, be used as a denomination for the iso have not been known hitherto. in orphic crystallisation of the three parent alka For instance, different ergotoxine-preparations loids ergocristine, ergocornine and ergocryptine. which have been recrystallized from benzene and .." In the ergotoxine preparations actually analysed which crystallize from this solvent in beautiful, ... i the ergo cornine represents the main quantity. brilliant and uniform plates containing benzene The composition and the most important prop of crystallization, and which preparations possess erties of the three alkaloids obtained from ergo all of the properties mentioned in the literature, toxine according to the new process are illustrated such as for instance the optical rotation and the in the following table: ergocristine ergocryptine ergocornine empirical formula--------------------- Cash.390sNs--- C32H1ON5 - C3H3OsNs. decompositiond? (corr.) --- - 1609-170° C. 208-210° C. 1829-1849 C. oD20 (c=l in CHCl3).--------- -- -183--------- -187------- -188. (a (c=1 in CECl3).----------------. -221--------- -226------- -226. crystallization from Inethanol--------- easily Soluble-- prisms------ polyhedrons. decomposition point, have been converted into the 45 On treatment with acids or alkalis or on heat ing in ethanol, the new alkaloids may be trans acid salt by means of 1-di-(p-toluyl) startaric acid. formed, like ergocristine and all the other ergot The white crystal mass thus obtained has been alkaloids known up to now,
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