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, into their strongly decomposed by means of ethanol into a difficultly dextro-rotary isomers. We have given to these soluble fraction (I) and into an easily soluble 50 new, isomers the names of ergocryptinine and fraction. This easily soluble fraction was then ergoCorninine, as this nomenclature is usual in this class of compounds. dissolved in methanol, whereby a rather difficult The following table gives the principal proper ly soluble fraction (II) crystallized out. The eas ties of the isoly Sergic acid forms of the three ily Soluble fraction (III) has been crystallized by 55 alkaloids of the ergotoxine group,
ergocristinine ergocryptinine ergocorninine
empirical formula.---- C35H3905Ns------C32F41OsNs------C31E390sNs. depoposition point 220-222 C------240-242 C------220-222 C. C.O.) aro20 (in CEICl3).----- 371------408------409. (a) (in CHCl).------463------508------510°. solubility in ethanol... difficultly soluble... moderately soluble... easily soluble. crystallisition from needles------needles------large prisms. eano. adding water until the methanolic mother-lye be On cleavage of the three alkaloids of the ergo came turbid. Fraction I Was then recrystallized toxine group the following constituents of the from absolute ethanol, fraction II from methanol alkaloids have been found: ergocristine. lysergic acid--- dimethyl-pyro- d-proline-1-phenyl-alanine. racenic acid anide.
ergocryptine.------do--- --do--- -- l-leucine. ergoCornine------do--- -- l-valine. 2,447,214 5 6 in the ergocornine l-valine has been found for the constituents the radical of the optically ac the first time as constituent of an ergot alkaloid. tive or inactive lysergic and isolysergic acids. The present process based on the use of the The present invention will now be illustrated salts of substituted tartaric acids has been also by the following examples, wherein the parts are applied with great success for the separation of by Weight. : ...... alkaloid mixtures which are obtained for instance - ...... Eacample 1 during the partial Synthesis of ergobasine or com pounds similar to ergobasine. In these con 32.5 parts (0.1 molecule) of the crystallized pounds the carboxyl group of lysergic acid is condensation product, prepared according to the linked inform of an amidolinkage to an amino 10 process of the U. S. Letters Patent 2,090,430 by alcohol...... : . . interaction of d,l-isolysergic acid azide with (--) - By working according to the process of the 2-aminopropanol-1, which therefore consistS in a U. S. Letters Patent 2,090,430, thus using as start mixture of d-isolysergic acid- (--)-isopropanol ing compounds dl-isolyse'gic acid azide and Con amide (ergobasinine) and of l-isolysergic acid densing the same with (--)-2-aminopropanol-1, (-)-isopropanolamide, and which possesses in an isomorphic crystallized mixture consisting of chloroform the specific rotation of Colo= +30, disolysergic acid- (--)-isopropanolamide (ergo are dissolved in 400 parts of methanol and treated basinine) and l-isolysergic acid- (--)-isopropanol at the boiling temperature with a solution of 35.8 amide is obtained, which mixture cannot be de parts (0.1 mol.) of di-dibenzoyl tartaric acid (pre composed into its components by a usual crystal 20 pared according to F. Zetsche and M. Hubacher, lisation. If, however, this mixture of alkaloids Helvetica Chimica Acta, 9, 291 (1926)) in 100 is first converted into a salt of a suitably Substi parts of methanol. The crystallization takes tuted tartaric acid for instance into the acid Salt place immediately. After cooling down and of d-dibenzoyltartaric acid, then by recrystalliza allowing the reaction mass to stand for several tion from methanol it will be possible to obtain hours in a refrigerator, the crystal mass consist pure ergobasinine-di-dibenzoyltairtrate in form of ing of white pointed prims is filtered by suction difficultly soluble crystals, whereas the stereo and washed with some methanol. Thus, 30.5 isonerical - isolysergic: acid - (--) - isopropanol parts of practically pure ergobasinine-dibenzoyl amide-d-dibenzoyltartrate remains in Solution. tartrate are obtained, this corresponding to a Also with still simpler derivatives of lysergic 3) yield of 89% of the theory. - ...... acid of the formula C15H5N2COR, Wherein R rep In order to prepare the free base, the salt resents for example the hydrazine radical, Suitable thus obtained is suspended in water, then an salts will be obtained with substituted tartaric excess of a sodium bicarbonate solution is added acids which are perfectly stable and Suitable for thereto and the base extracted with ether. After the separation of the isomers. . evaporation of the ether and treating the residue In this manner it is possible to effect the sepa with a small quantity of acetone the residue crys ration of the d.l-isolysergic acid hydrazide into tallizes in beautiful prisms. Melting point 196 its optically active isomers in a nearly. quantita C. (corr.) under decomposition. Specific rota tive yield, the dl-isolysergic acid hydrazide which tion (c.120=-|-415 in chloroform. This substance is obtainable by the interaction of hydrazine with 40 is identical with the natural ergobasinine. lysergic acid derivatives (see U.S. Letters Patent By treating the mother-lye of ergobasinine-d- 2,090,429) by preparing the acid salt in methanol dibenzoyltairtrate with alkali and recrystallizing solutions by means of d- or 1-di-(p-toluyl)-tar the free base from acetone, pure l-isolysergic taric acid. By using the d-acid the l-isolysergic acid-(+)-isopropanolamide having the melting acid hydrazide salt crystallizes out, while the Salt 4. point 192°. C. (corr.) under decomposition and a of the dextro-rotary antipode remains in solution. specific rotation Etzl?0=-351 in chloroform will On the other hand, by using the l-di- (p-toluyl)- be obtained. - ...... tartaric acid for the salt formation, the d-iso ... : : - Eacample 2 lysergic acid hydrazide salt precipitates in form of a rather difficultly soluble crystallizate. 50 28.2 parts of dl-isolysergic acid hydrazide (o The above cited examples show the advantages molecule), prepared according to the U.S. Letters. resulting from the new process for the separation Patent 2,090,429, are finely pulverized and sus of the mixtures of ergot alkaloids. By using pended in 450 parts of boiling methanol. While d- or 1-tartaric acid and by suitably selecting the thoroughly stirring a solution of 38.6 parts of aroyl substituent of the tartaric acid it is now 55 d-di-(p-toluyl)-tartaric acid (, molecule) in 100 possible to separate mixtures of lysergic acid parts of methanol is added to the said suspension. compounds by simple fractional crystallization After some seconds the hydrazide goes completely into pure, uniform compounds...... in solution, whereupon the l-isoly Sergic acid hy One object of the present invention is there drazide-d-di-(p-toluyl)-bitartrate begins imme fore the use of acylated tartaric acids, for the diately to crystallize out in form of white needles. separation of mixtures of basic compounds con 80 After cooling down to the room temperature and taining the lysergic acid radical, into their pure allowing the whole to stand for about 1 hour, components. the crystals are filtered off and washed with Another object of the present invention consists methanol. 30 parts of practically pure l-iso in the new salts produced by interaction of basic 65 lysergic acid hydrazide-d-di-(p-toluyl)-bitar compounds containing the lysergic acid radical trate are thus obtained. Specific rotation with acylated tartaric acids, which possess ex Coil0=-215 (c-0.4 in 50% ethanol). After a cellent crystallisation properties and allow the single recrystallization from methanol the op preparation of the pure bases of the alkaloids tically pure salt will be obtained showing then containing the lysergic acid radical. The ex the specific rotation of Iol.0=-238°. pression “basic compounds containing the lyser O In order to recover the free l-isolysergic acid gic acid radical' used in the present Specifica hydrazide the salt is treated in an aqueous sus tion is employed to designate the Synthetical and pension with sodium bicarbonate and the hy the natural alkaloids and the other basic com drazide extracted with ethyl-acetate. After pounds containing in their molecule as one of 75 evaporations of the ethyl acetate the residue is 2,447,24 7 8 dissolved in methanol, from which the purel-iso 960 parts of boiling absolute ethanol, whereby it lysergic acid hydrazide of the formula. became rapidly dissolved. After a rapid cooling down to room temperature and rubbing the Walls with a glass stick, a fraction which is difficultly crystallizes in form of beautiful prisms. Melting Soluble in ethanol began to crystallise out. In point 202-204° C. (corr.) under decomposition. order to complete the crystallisation the maSS WaS Specific rotation (c.120=-452° (c=0.8 in pyri allowed to stand for about 5 hours. After filtra dine). tion, washing with ethanol and drying il parts From the methanolic mother-ye of the l-iso of a product (fraction I) were obtained. The lysergic acid hydrazide-d-di-Cp-toluyl)-bitar alcoholic mother-lye was then evaporated to dry trate the d-isoly Sergic acid hydrazide Salt can be ness in vacuo and the residue dissolved in 370 parts obtained as a raw product by evaporation in of boiling methanol. After cooling down the vacuo. For the preparation of the pure diso Solution, the crystallization of a difficultly soluble ySergic acid hydrazide it is advantageous to use salt took place. The crystals then separated and the -di-p-toluyltartaric acid for Splitting of the 5 dried, weighed 10 parts (fraction II). d-l-isoly Sergic acid hydrazide. In this case the The methylalcoholic mother-lye (400 parts) d-isolysergic acid hydrazide--d- (p-toluiyl)-bitar were diluted with 400 parts of water. In order to trate precipitates as a more difficultly soluble complete the crystallization taking place the mix crystal mass. By treating the same with sodium ture was allowed to Stand for 5 hours, Whereupon bicarbonate and extracting with ethyl acetate the 20 the crystals have been filtered off and washed with d-isoly Sergic acid hydrazide of the formula 50% aqueous methanol. After drying the crystals C15H5N2CONHNH2 crystallizes out from meth Weighed 24 parts (fraction II). ano in beautiful prisins melting at 202-204 C. The fraction I was purified in the following (corr.) under decomposition and possessing the way: It was dissolved in chloroform, the chlo specific rotation of Ial?0---452° C. (c=0.8 in 25 roform solution evaporated to dryness in vacuo pyridine). and the amorphous residue dissolved in 220 parts The di- (p-toluyl)-tartaric acid is not described of absolute ethanol. From this Solution 8 parts in the literature and can be prepared by esterifi of pure ergocrystine-l-di-(p-toluyl)-bitart rate cation of d- and I-tartaric acid respectively with crystallized out in form of a conglomerate of p-toluyl chloride according to the process de 30 pointed sheets which are difficulty soluble in scribed in Helvetica. Chimica, Acta, 9, 291 (1926). nethanoi and ethanol. The decomposition point The di- (p-toluyl)-tartaric acid possesses the of the product is 187° C. (corr.). Eal?0=-|-68° formula C20H18O8 and melts, when recrystallized (c=0.2 in ethanol). from water, at 170°-172°C. (corr.) under decom The free ergocristine was isolated by Suspending position. The d-din (p-toluyl)-tartaric acid pre the salt in water, treating it with sodium bicar pared from d-tartaric acid has the Specific rota bonate and extracting the same with chloroform. tion of Lal?0=-140° (c=1.0 in ethanol), where After evaporation of the chloroform solution the as its optical antipode has the Specific rotation amorphous residue was crystallized from acetone, of Ial,0=-|-140°. whereby beautiful prisms with a decomposition Ecomple 3 40 point of 160°-170° C. were obtained. The ergocristine is very easily soluble in methanol and ... The ergotoxine-preparation used for the sepa ethanol and cannot be crystallized from these ration into its constituents was crystallized twice solvents, this being a specific difference from the from benzene and possessed the following prop alkaloids ergocryptine and ergoCornine. From erties which correspond to those found in the the hot saturated solution in benzene it crystal technical literature for ergotoxine: it crystallized lizes out in beautiful plates containing crystal from benzene in uniform brilliant, strongly light solvent and possessing the same habitus as the breaking plates which on drying in high vacuo at benzene crystallisate of ergotoxine. Lal?0= 80° C. lose 21% of their weight which represents -83; the quantity of the crystallisation solvent and 50 oal- -22 was easily soluble in ethanol, methanol, acetone, chloroform, ethylacetate, but sparingly soluble (ca.1 in chloroform). in ether and not crystallizable from these Solvents. Also the other properties are identical with The product dried in high vacuo melted between those given for ergocristine in the work of A, 70°, and 200° C. under decomposition and pos 55 schrift f. physiolog. Chemie, 250, 1 (1937)). sessed a specific rotation of La J0=-185° (in For the purification the fraction II (10 parts) chloroform). The phosphate of this ergotoxine was dissolved by a short boiling in 10 times its preparation crystallized from 90% ethanol in Weight of methanol. On cooling down 7 parts of round aggregates consisting of fine needles. the salt Crystallized out. This salt was then sub 30 parts of the ergotoxine possessing the above 30 jected to a repeated recrystallization, first in 20 characteristics (40 molecule) are dissolved with times, then in 30 times its Weight of boiling out Warning in 150 parts of absolute ethanol and methanol. In this nanner 3.5 parts of pure mixed. With a solution of 19.3 parts of 1-di-(p- ergocryptine-1-di-(p-toluyl)-bitartrate were ob toluyl)-tartaric acid (A30 molecule) in 100 parts of tained in flat needles melting under decomposi absolute ethanol. On careful addition of totally 65 tion at 186° C. (corr.) and possessing the specific 250 parts of Water which are added thereto with rotation of (al?0=-|-103° (c-0.2 in ethanol). in half an hour under good stirring, the salt be The free ergocryptine was recovered by treating gan to precipitate after a short time from the its Suspension in Water With sodium bicarbonate bright brown solution in form of white crystal and extraction with chloroform. After evapora needles; finally the Whole Solution became con 70 tion to dryness the amorphous residue was crys verted into a thick Crystal paste. After filtration. tallized from ethanol, whereby pointed prisms by suction and subsequent Washing with 50% With the decomposition point of 210° C. (corr.) aqueous ethanol 48 parts of dry, practically color Were obtained. Ergocryptine crystallizes from less crystals were obtained. methanol in straight cut prisms. It is easily solu The salt thus obtained was then introduced into 75. ble in chloroform. From the hot saturated ben
2,447,214 10 Zene solution it crystallizes out in beautiful bril corninine is easily soluble in methanol and liant plates containing crystal Solvent and poS ethanol. When crystallized from ethanol it gives sessing the same habitus as the benzene Crystal beautiful prisms, decomposition point 220-222°C. lizate of ergotoxine. Lal=-187; (corr.) ) Ial?---409; asa- -226° 5 Lola = - 50° (c=1 in chloroform). According to the analysis (c-1 in chloroform). According to the elemen the product has the following composition tary analysis ergocorninine has the formula C32H4O5N5. C3H39ONs. On acid and alkaline hydrolysis and on thermi 0 On acid and alkaline hydrolysis and on thermic cleavage in high vacuo the following constituents cleavage in high vacuo the following components of the ergocryptine have been isolated: lysergic of ergocornine have been isolated: lysergic acid, acid, dimethyl-pyro-tartaric acid amide, d-pro dimethyl-pyro-tartaric acid-amide, d-proline and line and 1-leucine. The condensation of the four 1-valine. The condensation of these four cleavage cleavage products under elimination of 3 mole components under separation of 3 molecules of cules of water yields a product of the formula water leads to the ergocornine and ergocorninine C32H4105N5 which corresponds to the result ob of the formula C31HagO5N5, which formula has tained by analysis. 8 been found on analysis. By boiling with methanol it is possible to trans By taking advantage of the different solubility form ergocryptine into its dextro-rotary isomer. 20 of the three components it has been possible to Ergocryptinine crystallizes from methanol and obtain further quantities of pure salt fractions ethanol in long needles melting under decompo from the mother-lyes of the fractions I to III. sition at 240-242 C. (corr.). Its optical rota What we claim is: tionis (al?0=-|-408; 1. A process for the separation of a mixture of --508° basic compounds containing the lysergic acid als radical, comprising the steps of treating a solu (c=1 in chloroform). tion of the said mixture with a solution of a According to the elementary analysis the ergo mononuclear, aroylated tartaric acid of the gen cryptinine possesses the formula C32H4105N5. eral formula In order to purify the fraction III the crystals Were first dissolved in 10 times their Weight of 30 HOOC-CHOX-CHOX-COOH methanol, whereby, after standing 1.4 parts of the wherein X stands for a mononuclear aroyl radi salt of the ergocryptine fraction crystallized out. cal, and separating the pure salts thus obtained After Separation of these crystals the methanolic by fractional crystallization. mother-ye Was diluted with Water in Order to 2. A process for the separation of a mixture of give a 80% aqueous methanol solution, Whereby 35 basic compounds containing the lysergic acid the ergocornine-l-di-(p-toluyl)-bitartrate crys radical, comprising the steps of treating a solu tallized out. These crystals were then recrystal tion of the said mixture with a solution of a di lized three times from methanol (in 10 times their benzoyl tartaric acid and separating the pure weight), wherein it is easily soluble; then 20% of salts thus obtained by fractional crystallisation. water Were added thereto thus separating 15 40 3. A process for the separation of a mixture of parts of pure ergocornine-l-di-(p-toluyl)-bitar basic compounds containing the lysergic acid trate. y radical, comprising the steps of treating a solu From 80% aqueous methanol the ergocornine tion of the said mixture with a solution of a di 1-di- (p-toluyl)-bitaritrate crystallizes out in form toluy tartaric acid and separating the pure Salts of beautiful thin hexagonal plates. Its decompo thus obtained by fractional Crystallisation. sition point is 180° C. (corr.) and its specific 4. A process for the separation of a mixture of rotation al?0=-|-103°. (c=0.2 in ethanol). basic compounds containing the lysergic acid The free base was obtained by treating the radical, comprising the steps of treating a Solu suspension of the salt in Water With sodium bi tion of a mixture of alkaloids known under the carbonate and extraction with chloroform. By name of Ergotoxine with a solution of a ditoluyl dissolving in methanoi the amorphous residue tartaric acid and separating the pure salts thus obtained after evaporation of chloroform, the obtained by fractional crystallization. ergoCornine crystallized out in beautiful polyhe 5. As new products of manufacture the salts drons. Decomposition point 182°-184° C. (corr.). 55 of mixtures of basic compounds containing the ErgoCornine is difficulty soluble in methanol, ySergic acid radica. With a mononuclear thus differing from ergocristine which is easily aroylated tartaric acid of the general formula Soluble in this solvent, and cannot be crystallized from methanol. With regard to the solubility HOOC-(CHOX-CHOX-COOH ergoCryptine has a middle position; it is easily Soluble in methanol, but can be crystallized from 60 wherein X stands for a mononuclear aroyl radi this solvent. Ergocornine is also relatively dif cal, these salts being well crystallized compounds ficultly soluble in ethanol and acetone. On cool yielding on treatment with alkalis the free bases ing the hot Saturated solution in benzene, it crys of the lysergic acid derivatives. tallizes Out, like ergocristine and ergocryptine, in 6. As new products of manufacture the Saits beautiful plates containing crystal solvent and 65 of mixtures of basic compounds containing the pOSsessing the same habitus as the benzene crys lysergic acid radical with benzoylated tartaric tallizate of ergotoxine. Ial= -188; acids of the general formula, HOOC-(CHOX-CHOX-COOH (c=1 in chloroform). The elementary analysis Wherein X Stands for benzoyl, these salts being has given results corresponding to the formula Well crystallized compounds yielding on treat C3H39C)5N5. ment With alkalis the free bases of the lysergic By careful treatment of ergocornine with an acid derivatives. alcoholic potassium hydroxide Solution it can be 7. As new products of manufacture the salts of transformed into its dextro-rotary isomer. Ergo 75 mixtures of basic compounds containing the 2,447,214 11 12 lysergic acid radical with toluylated tartaric acids 12. As new products of manufacture the Opti of the formula...... cally active salts of basic compounds containing the lysergic acid radical with optically active di HOOC-CHOX-CHOX-COOH benzoyl tartaric acids, these salts being well wherein X stands for toluyl, these salts being Well crystallized compounds yielding on treatment crystallized compounds yielding on treatment with alkalis the free bases of the lysergic acid with alkalis the free bases of the lysergic acid derivatives. derivatives. 13. As new products of manufacture the opti 8. As new products of manufacture, the Opti cally active salts of basic compounds containing cally active salts of basic compounds containing 1) the lysergic acid radical with optically active di the lysergic acid radical with mononuclear toluy tartaric acids, these salts being Well aroylated tartaric acids of the general formula. crystallized compounds yielding on treatment HOOC-CHOX-CHOX-COOH with alkalis the free bases of the lysergic acid derivatives. wherein X stands for a mononuclear aroyl radi 14. The optically active salts of propanolamides cal, these salts being well crystallized compounds, 5 containing the lysergic acid radical With di yielding on treatment with alkalis the free bases benzoyl tartaric acids, which salts are well of the lysergic acid derivatives. crystallized compounds yielding on treatment 9. As new products of manufacture the opti with alkalis the free bases of the lysergic acid cally active salts of basic compounds containing derivatives. the lysergic acid radical with optically active 20 15. The optically active salts of hydrazides con mononuclear-aroylated tartaric acids of the gen taining the lysergic acid radical with ditoluyl eral formula tartaric acids, Which salts are Well crystallized HOOC-(CHOX -CHOX-COOH compounds yielding on treatment with alkalis the 25 free bases of the lysergic acid derivatives. wherein X stands for a mononuclear aroyl radi 16. The optically active Salts of the lysergic cal, these salts being well crystallized compounds, acid derivative called ergocristine With di- (p- yielding on treatment with alkalis the free bases toluyl)-tartaric acids. of the lysergic acid derivatives. 10. As new products of manufacture the ARTHUR SOLL. dextro-rotary salts of basic compounds contain 30 ALBERT HOF MANN. ing the lysergic acid radical With non-Onlclear REFERENCES CTED aroylated tartaric acids of the general formula The following references are of record in the HOOC-(CHOX-CHOX COOH file of this patent: wherein X stands for a mononuclear aroyl radi 35 cal, these salts being Well crystallized compounds UNITED STATES PATENTs yielding on treatment with alkalis the free bases Number Name Date of the lysergic acid derivatives. 2,090,429 Stoll et al. ------Aug. 17, 1937 11. As new products of manufacture the levo OTHER REFERENCES rotary salts of basic compounds containing the 40 lysergic acid radical with mononuclear-aroylated Gilman: “Organic Chemistry’ (John Wiley & tartaric acids of the general formula, Sons, Inc., 1938; New York, N. Y.). Pages. 191 and 192. HOOC-CHOX-CHOX-COOH Hoppe-Seyler's Zeitschrift für Physiologische wherein X stands for a mononuclear aroyl radi Chemie, vol. 250, pages 1-10 (1937); ibid., vol. cal, these salts being Well crystallized compounds 251, pages 155-163 (1938). yielding on treatment with alkalis the free bases of the lysergic acid derivatives, Certificate of Correction Patent No. 2,447,214 August 17, 1948 ARTHUR STOLL ET AL. It is hereby certified that errors appear in the printed specification of the above numbered patent requiring correction as follows: Column 2, line 31, for the words “he ergot' read the ergot; column 6, line 26, for “prims' read prisms; column 8, line 54, after “of A.' insert Stoll and E. Burckhardt (Hoppe-Seyler's Zeit-; column 10, line 5, for that portion of the formula reading
-- and“-510°' that theread said --510; Letters Patent should be read with these corrections therein that --- the same may conform to the record of the case in the Patent Office. Signed and sealed this 14th day of February, A. D. 1950.
sEAL
THOMAS F. MURPHY, Assistant Commissioner of Patents.