Patented Oct. 3, 1944 2,359,688 UNITED STATES PATENT OFFICE 2,359,688 HYDRAZIDES OF DIHYDRO LYSERGIC ACID AND DEHYDRO SOLYSERGIC ACID AND A PROCESS FOR THER MANUEFACTURE Arthur Stoll and Albert Hofmann, Basel, Switzer land, assignors to Sandoz. Ltd., . Fribourg, Switzerland, a corporation of Switzerland No Drawing. Application May 4, 1942, Serial No. 44,754. In Switzerland May 13, 1941 9 Claims. (C. 260-236) The present invention relates to hydrazides of active dihydro isolysergic acid hydrazide is ob dihydro lysergic and dihydro isolysergic acids tained; by using as starting material dihydroly which are valuable products for the manufacture sergic- or isolysergic acid esters respectively, the of alkaloids of the ergot type and to a process same result will be reached. for their manufacture. Besides the aforesaid advantage consisting in It is known that the natural ergot alkaloids on that during the hydrazine treatment no racemisa treatment with hydrazine or hydrazine hydrate tion and isomerization takes place, a further ad become split, whereby as a component of all ergot vantage will be obtained insofar as the yield of alkaloids the lysergic acid can be isolated in form hydrazide increases to 90 to 100% when hydro Of racemic isoly Sergic hydrazide (see U. S. Patent 0. genated alkaloids are used, instead of a yield of No. 2,090,429). This racemic isolysergic acid hy only 70-80% when natural alkaloids are subject drazide is a suitable starting product, for example, ed to the treatment. The treatment of dihydro for the Synthesis of ergobasine, the highly utero derivatives of the lysergic acid with hydrazine active natural ergot alkaloid, and of its homo or hydrazine hydrate is carried out by dissolving logues and derivatives as well as for the syn 15 the starting material in hydrazine or hydrazine thesis of other acid amides of lysergic acid (see hydrate and boiling the solution during e. g. 1 U. S. Patent No. 2,090,430). hour at a reflux condenser. It is also possible to The high-active natural ergot alkaloids like work at a lower temperature, for instance at 50° ergotamine, ergotoxine, ergobasine are deriva C. or under pressure but preferably at a higher tives of d-lysergic acid. By their transformation 20 temperature, for instance, at 150° C. Accord into the isolysergic acid form, i.e. into ergot ing to the method used the time of the reaction aminine, ergotinine, ergobasinine, there results a can be longer. or shorter. Sometimes it is ad strong decrease of their physiological activity. vantageous to work in presence of a suitable sol Practically inactive are also the derivatives of the Went such as butanol, pyridine and the like and l-lysergic acid which is not found in the nature in an inert atmosphere, such as in nitrogen. and which represents the optical antipode of, for The dihydrolysergic. acid hydrazide prepared instance, the natural ergobasine (see A. Stoll & according to the present invention for example A. Hofmann, Hoppe-Seyler's Zeitschrift für from dihydro ergotamine or another dihydro physiolog. Chemie 251, 163 (1938l). As the ly alkaloid of the physiologically active series, or sergic acid hydrazides are prepared to be used 30 from a-dihydro lysergic acid ester (see W. A. for the synthesis of the highly active ergot alka Jacobs and L. C. Craig, Journ. Biol. Chem. 115, loids, the isomerization and racemisation of the 227 (1936]) possesses the following properties. lysergic acid molecule taking place during the It is very difficultly soluble in chloroform, ether treatment with hydrazine, present an important and benzene, rather difficultly soluble in hot Wa draw-back. Thus, for instance, by starting from 35 ter, easily soluble in Warm methanol and ethanol. racemic isolysergic acid hydrazide, it will be nec The new compound is also very easily soluble in essary, before making the synthesis of the al dilute aqueous Organic.' and inorganic acids. kaloid, to subject it to optical splitting into the From a hot-Saturated Solution in methanol the active d-lysergic acid and into the inactive dihydro lysergic acid hydrazide crystallises out l-lysergic acid, or into the isolysergic acid deriva 40 in centimeter-long Smooth white needles melting tive, and thereupon to subject it to a transfor under decomposition at 247 C. (corr.). mation from the isolysergic acid series into the The elementary analysis of the compound dried lysergic acid series. All these operations decrease in high vacuo at 100° C. has given the following the yield of the desired product, owing to the Values: fact that all of these compounds are very sensi tive to the various chemical operations. "C 67.54; 67.25%; H 7.54; 7.27%; N 19,66; 19.67% It has now been found that the isomerization and the racemisation of the lysergic acid group For C16H2OON, the calculated values are: during the treatment with hydrazine can be C 67.56%; H 7.09%; N 19.72% avoided, when, instead of using the natural al 50 kaloids of the ergot, their dihydro derivatives The optical rotation has been found to be (see U. S. A. application Ser. No. 395,198) are (c.10--124° (c=0.4 in pyridine). subjected to the hydrazine treatment. During the The typical color reactions of the ergot sub treatment of the dihydro alkaloids of the lysergic stances are also given by the dihydro lysergie acid series, like dihydroergotamine or dihydro 55 acid hydrazide in the same strength. ergosine, with hydrazine a homogeneous op An alcoholic solution of the hydrazide contain tically active dihydro lysergic acid will be ob ing 1% of p-dimethylaminobenzaldehyde yields, tained, while from the dihydro alkaloids of the by underlaying with concentrated sulfuricaeid, a isolysergic acid series, like dihydroergotaminine beautiful violet Zone (reaction of Van Urk). or dihydroergosinine, a homogeneous optically 60 A Small quantity of the substance dissolved in 2 2,359,688 glacial acetic acid containing some iron chloride - Eacample 3. produces with concentrated sulfuric acid a beau 1 part of dihydro lysergic acid methylester tiful blue coloration (reaction of Keller). The (identical With a-dihydro lysergic acid methyl blue coloration given by the dihydro lysergic ester of Jacobs & Craig 1. C.) is dissolved in 4 acid hydrazide is somewhat redder as compared 5 parts of anhydrous hydrazine and heated during to that given by the non-hydrogenated lysergic 12 hours at 50° C. By diluting the solution with acids or lysergic acid derivatives. 2.3 parts of water, the dihydrolysergic acid hy The dihydro isolysergic acid hydrazide ob drazide crystallizes out in pure form. tained from the dihydro alkaloids of the iso Yield: 0.94 part=94% of the theory. lysergic acid series like dihydro ergotaminine or O from dihydro isolysergic acid ester (y-dihydro Eacample 4 isolysergic acid methylester of Jacobs & Craig, 1. part of dihydro ergotaminine is dissolved in . c.) possesses similar solubility as the dihydro - - 2 parts of anhydrous hydrazine and heated during lysergic acid hydrazide. From concentrated So 1 hour to boiling at a reflux condenser. The clear lution in methanol the new compound crystallizes yellow solution is diluted still warm with 1.l parts out in long smooth white needles melting under of water, whereby the dihydroisolysergic acid hy decomposition at 260° C. - (corr.). The elemen drazide begins immediately to: crystallize out in tary analysis of the compound dried in high form of colorless needles. The crystals are filtered vacuo at 100° C. has given the following values: off and washed with water... Yield: 0.45 part= 20 93% of the theory. This compound possesses the c. 67.41; 67.60%; H 7.38; 7.60%; N 19.71; 19.59% properties described above. For C16H200N4 the calculated values are: Eacample 5 C 67.56%; H 7.09%; N 19.72% 1 part of dihydro ergotinine is introduced, to The specific optical rotation has been found 25 gether with 4 parts of hydrazine hydrate, into a to be glass tube, which is then hermetically sealed, and heated in an oil bath during A2 hour at 150° C. Iol20=+56° (c=0.6 in pyridine). On cooling down the reaction solution becomes: The characteristic color reactions of the ergot converted into a crystal paste Which, after diluting compounds remain the same for the dihydro iso 30 with water, is filtered. Yield: 0.44 part of pure lysergic acid hydrazide, as for the dihydro lysergic dihydro isolysergic acid hydrazide or 95% of the acidThe hydrazide. new compounds prepared by the present. . . theory. ... - process are valuable starting products for the Eacample 6 manufacture of amides and esters of the type 35 1 part of dihydro isolysergic acid methylester of ergot alkaloids. (identical with y-dihydrolysergic acid methyl The following examples, without being limita ester of Jacobs & Craig, l. c.) is dissolved in 3 tive, describe the present invention; the parts be parts of butanol and, after addition of 1 part of ing by Weight: hydrazine hydrate, the whole is boiled under re Eacample 1 40 flux and in a nitrogen atmosphere during 3 1 part of dihydro ergotamine (containing CryS hours. The solution is then evaporated in vacuo talacetone-water) is dissolved in 3-parts of an to about half its volume, whereby a thick crystal hydrous hydrazine and heated at a reflux COI)- paste is obtained. The crystals are filtered and denser to boiling. A clear yellowish solution washed with water. Yield: 0.92 part of pure di 45 hydro isolysergic acid hydrazide=92% of the will be obtained very rapidly when heating at theOry. . ; about 113° C. After boiling for 1 hour the Solu What We claim is: tion is diluted with 1.7 parts of Water in order to 1. A process for the manufacture of a hydrazide convert the hydrazine into hydrazine hydrate, in of a dihydrolySergic acid, comprising the step of which dihydro lysergic acid hydrazide is very heating a dihydro compound selected from the difficultly soluble. Therefore the new compound 50 class consisting of amides and esters of lysergic begins to crystallise out in form of colorless nee. and isolysergic acids with hydrazine. m dies and, after a very short time, the whole reac 2. A process for the manufacture of a hydrazide tion mass becomes transformed into a paste of of a dihydro lysergic acid, comprising the step crystals. After a short standing the crystals are of heating at a temperature of 50°-150° C. a di filtered, washed with water and dried in vacuo 55 hydro compound selected from the class consist over calcium chloride. . . ing of amides and esters of lysergic and isolysergic Yield: 0.38 part of pure dihydrolysergic acid acids with hydrazine...... hydrazide or 98% of the theory. 3. A process for the manufacture of a hydrazide The compound thus obtained possesses the of a dihydro lysergic acid, comprising the step properties cited above. . . 60 of heating at a temperature of 50-150° C. and in Eacample 2 the presence of an organic solvent and in an inert atmosphere a dihydro compound selected from 1 part of dihydro ergosine is heated during 1 the class consisting of amides and esters of hour at reflux with 10 parts of hydrazine hydrate. lysergic and isolysergic acids with hydrazine. Already after a few minutes all of the Substance 65 4. A process for the manufacture of dihydro goes into solution. By cooling down the reaction lysergic acid hydrazide, comprising the step of mixture, the dihydro lysergic acid hydrazide heating dihydroergotamine with hydrazine to crystallises out inform of colorless needles. After about 113 C...... standing for several hours in a cool place the 5. A process for the manufacture of dihydro crystals are filtered and Washed With Water. By 70 lysergic acid hydrazide, comprising the step of concentrating the mother-liquor to about 3 parts, heating dihydrolysergic acid methylester with further small amounts of hydrazide can be ob hydrazine to about 113 C...... tained.Total yield: 0.48 part=93% of the theory of 6. A process for the manufacture of dihydro pure dihydrolysergic acid hydrazide. 75 isolysergic acid hydrazide, comprising the step of 2,359,688 3 heating dihydro ergotamine with hydrazine to ether and benzene, but easily soluble in warm about 13 C. methanol and ethanol, prepared for use as an 7. A hydrazide of a dihydrolysergic acid which intermediate for the preparation of a therapeuti is contained in the ergot alkaloids, which hydra cally active compound of the type of the ergot Zide possesses the general formula C16H2OON4, alkaloids. which is a white Crystallised compound giving the 9. The dihydro isolysergic acid hydrazide corre typical color reactions of the ergot alkaloids and sponding to the general formula C16H2OON4, which which is difficultly soluble in chloroform, ether is a white Crystallised compound melting under and benzene, but easily soluble in warm methanol decomposition at 260' C., whose optical rotation and ethanol, prepared for use as an intermediate O is Iolor=-|-56° (c=0.6 in pyridine), which gives for the preparation of a therapeutically active the typical color reactions of the ergot alkaloids compound of the type of the ergot alkaloids. and which is difficultly soluble in chloroform, 8. The dihydro lysergic acid hydrazide corre ether and benzene, but easily soluble in Warm sponding to the general formula C16H2OON4, which methanol and ethanol, prepared for use as an is a white crystallised compound melting under 15 intermediate for the preparation of a therapeuti decomposition at 247 C., whose optical rotation cally active compound of the type of the ergot is cyl20D=-124 (c=0.4 in pyridine), which gives alkaloids. the typical color reactions of the ergot alkaloids ARTHUR, STOIL, and which is difficultly soluble in chloroform, ALBERT HOF MANN.