Patented July 18, 1950 2,516,002 UNITED STATES PATENT OFFICE 2,516,002 HALOGENATED DERIVATIVES OFLYSERGIC ACID, ISOLYSERGIC ACID, AND THEIR, DE RIVATIVES, AND A PROCESS OF MAKING SAME Albert Hofmann and Franz Troxler, Basel, Swit zerland, assignors to Sandoz A. G., Basel, Swit zerland No Drawing. Application July 16, 1948, Serial No. 39,174. In Switzerland July 22, 1947 12 Claims. (C. 260-236) 2 The preparation of halogen compounds of lysergic acid, isolysergic acid and their deriva TABLE I C15H4N2Hall.COR tives, such as esters or amides (e.g. ergot alka R = OH, bromo-lysergic acid loids), and of the dihydro compounds of these R =OCH, bromo-lysergic acid methyl ester R =N(CH3)2, bromo-lysergic acid diethylamide acids and their derivatives, has hitherto en R =CH20ON, brom-ergotamine countered great difficulties on account of the R. = C19H24ONs, brom-ergocristine great sensitiveness of these materials, particu R = C5H24O4N, brom-ergocorninebrom-egocorninine larly their sensitiveness to acids and oxidising R =C3HON, brom ergobasine agents. Reagents, which for example evolve free R = C17H2004 Na, iod-ergotamine halogen or hydrogen halide, react with the same 0. TABLE II with extensive decomposition and with resinifi. cation of the starting materials. For this rea C15H16N2Hal.R= OCH3, COR bromo-dihydrolysergic acid methyl ester = GHoON, brom-dihydroergotamine son, although some halogenated compounds have = C5H24O4Ns, brom-dihydroergocristine been obtained in very poor yields, the products =CH200N, chloro-dihydroergotamine 5 =CHON, chloro-dihydroergocristine have been ill-defined. =OCH, iodo-dihydro-lysergic acid methyl ester According to the present invention it has now =CEgoON3, iodo-dihydroergotamine been found that well defined monohalogenated =CHON3, iodo-dihydroergocristine compounds of the above named acids and their derivatives, in which the halogen is attached to The new halogeno-derivatives are very stable, the indol nitrogen atom, can be obtained by dis 20 well crystallised compounds which give colour Solving the compound to be halogenated in an reactions With Keller's reagent which is charac inert Solvent and causing it to react with an teristic for the ergotalkaloids. The compounds amide Or imide of a carboxylic or sulphonic acid may serve for therapeutic purposes and as inter which has been halogenated on the nitrogen mediate compounds for the preparation of thera atom. 25 peutic substances. As halogenating agents for this purpose there The following examples illustrate how the in are suitable for example. N-bromacetamide, N vention may be carried out in practice, but these bronophthalimide, N - bromo-p-toluenesulphon examples are in no way limitative. amide, N-bromo-di-p-toluenesulphonimide, N EXAMPLE 1. bromo- or N-chloro-benzoic acid sulphimide and 30 Preparation of brom-ergotamine N-bromo- or -iodo-Succinimide. The halogenation of the lysergic acids or their 500 mg. ergotamine which has been dried in a derivatives can advantageously take place ac high vacuum are dissolved in 45 cc. dioxane at Cording to this invention in an inert solvent such 65° C. and a solution of 185 mg. brom-succini as dioxane, ether, carbon tetrachloride and the 35 mide in 10 cc. dioxane at 65° C. added thereto. like, and can be carried out at room temperature The mixture which is kept for 5 minutes at 70° or at a somewhat higher temperature. The new C. becomes immediately coloured in a brownish halogeno-compounds can most advantageously yellow shade and within minute becomes black be separated from accompanying materials by red with a slight turbidity. After the addition means of the chromatographic adsorption meth 40 * of 200 cc. chloroform and Washing with Sodium od of their solutions. In this way the new com bicarbonate Solution in a Separating funnel and pounds are obtained as oily substances which drying with sodium sulphate and evaporation to can, however, be converted into the crystalline dryness of the organic layer a residue is obtained state by dissolution in a suitable solvent such as containing a crude reaction product which is acetone, benzene, chloroform, ether or methanol, 45 then Subjected to chromatographic Separation. from which Solutions they can be obtained in For this purpose it is dissolved in 5 cc. of abso well developed crystalline forms, in Some cases lute chloroform and the Solution poured onto a containing crystallisation solvent. column of 40 g. aluminium oxide, and the chro When carrying out the method of our present matogram developed with absolute chloroform. invention, the halogen atom enters onto the 50 From a uniform zone slightly luminous in ultra indol nitrogen atom. The new compounds cor violet light, there is obtained 331 mg. of colour respond to the general formula C15H14N2Hall.COR, less oil in the filtrate. After evaporation to dry and C15H16N2Hall.COR. In these formulae R, ness, the residue is crystallised from 90% ace stands for groups such as OH, OCH3, etc, as seen tone and 260 mg. of rectangular plates of melt from the following tables: 55 ing point 197-198° C. are obtained. By re-crys 2,516,002 3. 4 tallisation from methanol. 5 or 6 cornered leaf tained 145 mg. colourless oil, which when crys lets are obtained, melting point 207-208 C. tallised from benzene gives 6-cornered leaflets ap20 = -163 (chloroform). Which contain 2 molecule of benzene of crystal Keller reaction: the same as for ergotamine. lisation. The new bron-ergotamine does not fluoresce Melting point: 229° C. in ultraViolet light in methanol solution. From methanol, in which brom-egocorninine is The analytical figures agree very well indeed ;Sparingly soluble, there were obtained long white with those required for the , empirical formula needles With molecule of methanol of crystal C33H34O5N5Br. lisation, which melted already at 190-1989 C. O all of the dry brom-ergocorninine: --425 EXAMPLE 2 (chloroform). Preparation of bron-ergocristine Keller reaction: the Same as With ergo 200 mg. ergocristine are treated at 65° C. in 25 COrninine. cC. dioxane with 70 mg. bron-succinimide in 10 The brom-ergocorninine does not fluoresce in cc. of the same solvent at the same temperature ultra-violet light in methanol solution. for 5 minutes. By working up in the manner de The analytical figures show a good agreement Scribed in Example 1 and using a column of 20 g. With the empirical formula C31H3805N5Br. aluminium oxide, 132 mg. of colourless oil are ob EXAMPLE 5 tained. Preparation of brom-ergobasine After recrystallisation from benzene, platelets are obtained containing 2 molecules of benzene A Solution of 200 mg. ergobasine, in 20 cc. di of crystallisation. Oxane, at 60°C. is treated with 130 mg. brom-suc Melting point 178-183° C. cinimide in 10 cc. dioxane, whereby a black-red Eal?0 for the preparation dried in a high precipitate immediately ensues. The mixture is Waco -189 (chloroform). maintained for 5 minutes at 60° C., then shaken Keller's reaction: pure blue, and within 30 sec out with chloroform and saturated brine con Onds changes to dirty brown. taining Sodium bicarbonate and the chloroform The product does not fluoresce in ultra-violet dioxane layer separated, dried with sodium sul light in methanol solution. phate and evaporated to dryness. The dry res The analytical figures show a very good agree O idue is chromatographically adsorbed on 20 g. ment with the empirical formula C35H38O5N5Br. aluminium oxide. For this purpose it is dissolved in the Smallest possible quantity of chloroform EXAMPLE 3 to which 5% of alcohol has been added, the solu Preparation of brom-ergocornine tion poured onto the aluminium oxide column and the chromatogram developed first with chlo A Solution of 200 mg. ergocornine in 15 cc. roform and then with chloroform to which 1% of dioxane at 65° C. is treated with 65 mg. brom-suc alcohol has been added. With the latter solvent cinimide in 10 cc. of warm dioxane and the red the uniform Zone having a violet fluorescence in Coloured mixture heated for a further 5 minutes ultra-violet light soon reaches the filtrate. By at 70° C. and worked up as described in Ex 4. evaporation of the latter there remains 136 mg. ample . of slightly reddish oil, which by recrystalisation The chromatographic separation of the crude from chloroform furnishes 72 mg. of slightly product With 20 g. aluminium oxide furnishes truncated rods containing molecule of chloro a uniform quickly moving zone only slightly form of crystalisation which Sinters at about 18° luminous in ultra-violet light. By evaporation of C. and nets at 22-28 C. the filtrate there is obtained 13 mg. of colourless (alpo of the brom-ergobasine free from sol oil Which on recrystallisation from chloroform vent of Crystallisation gave -16 (pyridine). yields 92 mg. of prisms pointed at both ends, or Keller's reaction: as ergobasine. Very long Six-Cornered plates containing 2 mole The methanol Solution of the bron-ergobasine Cules of crystallisation of the solvent. fluoresces in a violet colour in ultra-violet light Melting point 187-1890 C. With the same intensity as a solution of ergo all of the preparation after drying in a high basine in the same solvent. The analytical fig vacuo -215 (chloroform). Ures correspond closely to the empirical formula Keller's reaction: first pure blue; after 10 sec C19H22O2NBr. Onds violet-blue; after 15 seconds violet; after 45 s Seconds brown-violet. Final colour after 24, EXAMPLE 6 minutes, brown. Preparation of bromo-lysergic acid methylester The bron-ergOCornine does not fluoresce in 115 mg. of lysergic acid methylester are dis ultra-violet light in methanol solution. Solved in 12 cc. of dioxane at 65° C. and treated The analytical data show very good agreement, O With a Solution of 85 Ing, bron-succinimide in 5 cc. with the empirical formula C31H36O5N5Br. dioxane at the same temperature, whereby a red EXAMPLE 4. dish-black precipitate separates out. The mix ture is heated a further 3 minutes at 60-65° C. Preparation of bromo-ergocorminine and thereupon the crude reaction products are 200 mg. ergocorninine are dissolved in 20 cc." : 65 isolated as in Example 1. These are subjected dioxane at 65° C. and treated with a solution of 74 to chromatographic Separation with 20 g. alumin mg. bron-Succinimide in 10 cc. warm dioxane. ium oxide. On development of the chromato After treatment for 5 minutes at 70° C. the crude gram. With absolute chloroform 2 Zones are product is isolated as described in Example 1 and formed, namely, one having only a slight lumi subjected to chromatographic adsorption with 20 20 nosity in ultra-violet light quickly passing into g. aluminium oxide. By developing the chroma the filtrate and the second a somewhat more togram with absolute chloroform a uniform Zone slowly moving Zone fluorescent in ultra-violet quickly going into the filtrate is obtained, this light which consists of some of the starting ma Zone being only slightly luminous in ultra-violet terial. light. By evaporation of the filtrate there is ob : The filtrate containing the first zone is evap 2,516,002 5 6 orated to dryness and the residue thus obtained 57 mg. N-bromo-acetamide in 10 cc. of cold diox recrystallised from benzene. Crystals were ob ane. At first there is no visible reaction, but on tained containing two molecules of benzene of Standing at room temperature the mixture be crystallisation. comes gradually yellow within 2 minutes, orange Melting point 177-178° C. after 5 minutes and Orange-brown after 15 min (alD20 of the preparation free from solvent of utes. Thereupon the reaction product is isolated re-crystallisation --41 (chloroform). as described in Example 1 and chromatographed Keller's reaction: as ySergic acid methyester. with 20 g. aluminium oxide. By development of In methanol Solution in ultra-violet light brom the chromatogram With absolute chloroform lysergic acid methylester has a very weak fluo O there is obtained a uniform Zone in the filtrate rescence. which is only slightly luminous in ultra-violet The analytical figures show a close agreement light and which amounts to 78 mg. of colourless with the empirical formula C17H17O2N2Br. oil. This is evaporated to dryness and the resi due crystallised from 90% acetOne. 47 mg. rec EXAMPLE 7 tangular leaflets of melting point 191-196° C. are Preparation of bromo-lysergic acid-diethylamide obtained. The crystals lose 10% of their weight ... A solution of 200 mg. lysergic acid diethylamide On drying in a high vacuo at 100° C. in 15 cc. dioxane at 40° C. is treated with 130 mg. a D20 of the bromo-dihydroergotamine dried brom-succinimide in 10 cc. of cold dioxane. The in a high vacuum -87 (pyridine). mixture immediately becomes red coloured with Keller's colour reaction: pure blue. separation of a precipitate. It is kept at 40° C. The analytical figures agree well. With the emi for another 10 minutes and thereupon the crude pirical formula C33H36O5N5Br. product is isolated as described in Example 1. EXAMPLE 10 With the chromatographic method with 20 g. Preparation of bron-dihydroergocristine of aluminium oxide, dissolved in absolute benzene, 25 there is obtained a uniform slightly luminous Zone 200 mg. dihydro-ergocristine are dissolved in which rapidly passes into the filtrate. On evap 15 cc. of dioxane at 70° C. and treated with 148 oration this yields 100 mg. of oil which can be Ing. brono-phthalinide in 10 cc. of Warm diox crystallised from ether, from which then colour ane. The red Solution is maintained for another less spears are obtained. The crystals begin to 30 5 minutes at 70° C. and the crude reaction prod sinter at about 105° C. and melt very indefinitely uct worked up as in Example 1 and chromato at about 123° C.; they do not contain solvent of graphed with 20 g. aluminium oxide, crystallisation. The development of the chromatogram with alD20---53° (chloroform). absolute chloroform yields 18 mg. of a red non Keer's colour reaction: as for lySergic acid crystallising oil, and thereupon 99 mg. of bromo diethylamide. dihydro-ergocristine. The latter crystallizes Brom-lysergic acid-diethylamide does not fluo from benzene in boat-shaped plates and in trun resce in methanol solution in ultra-violet light. cated polyhedral prisms which contain 2 mole The analytical figures agree well with the em cules of benzene of crystallisation. Melting point pirical formula C20H24ON3Br. it) 187-190° C. Lol?0 of the bromo-dihydroergocristine free EXAMPLE 8 from solvent -78 (pyridine). Preparation of bromo-dihydrolysergic acid Keller's colour reaction: pure blue. methylester The analytical figures agree well with the em 284 mg. dihydrolysergic acid-methylester are pirical formula C35H40O5N5Br. dissolved in 50 cc. of hot carbon tetrachloride and EXAMPLE 1. to the Warm solution at 55C, 385 mg. brom succinimide are added. It is shaken vigorously Preparation of iodo-dihydro-ergocristine for 5 minutes and thereupon the brown Solution 50 500 mg. dihydroergocristine are dissolved in 25 and the precipitate are washed with Sodium bi cc. of dioxane and mixed at 60° C. With a warm carbonate Solution. Solution of 216 ng iodosuccinimide (1.5 mo), After filtering the carbon tetrachloride solu dissolved in 10 cc. of dioxane. The clear broWn tion and drying it with Sodium Sulphate and Orange Solution is heated for further 5 minutes evaporation to dryness, there are obtained 250 55 at 60-65 C., thereupon 50 cc. of chloroform are mg. brown oil which is subjected to chromato added thereto and the solution thus obtained graphic separation with 25 g. aluminium oxide. washed with sodium carbonate. After drying On development of the chomatogram with abSO the chloroform dioxane Solution of the raw prod lute chloroform there are first obtained in the uct With sodium Sulphate, the solution is evapor filtrate 42 mg. of red non-crystallisable oil and 60 ated in vacuo to dryness and the remaining thereupon 145 mg. of the bromo-dihydrolySergic residue chromatographed with 50 g. of aluminium acid-methylester, which after evaporation of the oxide. By developing the chronatogram. With filtrate is obtained from methanol in many-sur absolute chloroform there are first obtained 100 faced straight cut prisms. Melting point 214-215 mg. of a red non-crystallisable oil and then there C. The compound can be sublimed in a high 65 are eluated 366 mg. of an oily compound, that vacuo at 180-190° C. after crystallisation fron benzene gives 370 mg. a JD20s-92 (chloroform). (air-dried) of Spherical aggregates of Orange-red Keller's colour reaction: pure blue. uncharacteristical crystals, or by slow crystal The analytical figures agree well with the em Iisation plates with 6 edges to irregular prisms pirical formula C17H1902NBr. 70 showing a plurality of Surfaces. EXAMPLE 9 Melting point, 187-192° C.; 185-190° C. IoD20--70 (in pyridine). Preparation of bron-dihydroergotamine The crystallisate contains 1 nol of crystal 200 mg. dihydroergotamine are dissolved in 30 benzene and loses by drying in high vacuo at 100° . cc. of cold dioxane and treated with a solution of 75 C. 14% of its weight. 2,516,002 7 8 Lop?0 of high vacuo dried substance -82 roform it is possible to separate pure chlorodi (pyridine). hydro-ergocristine which crystallizes from ben Analysis.-C35H40OsN5I, calculated: C 56.97, zene in on both sides pointed prisms containing H5.47, N 9.50%. Found: C 57.67, H. 5.39, N 9.13; i mol of crystal benzene and melting at 172 C 57.62, H 5.45, N 9.05. 175° C. Keller's colour reaction: reddish blue. Ial20=-70 (in pyridine). Formula: C35H40O5N5C1, calculated: N 10.85%; EXAMPLE 12 found: 0.19%. Preparation of iodo-dihydro-lysergic acid Keller's colour reaction: pure blue. methyl ester O EXAMPLE 14 460 mg. of dihydrolysergic acid methylester Preparation of chlorodihydro-ergotamine dried in high vacuo are dissolved in 15 cc. of cold dioxane and treated with a solution of 400 mg. 500 mg. of dihydro-ergotamine dried in high iodo-succinimide (1.1 mol), dissolved in 15 cc. of vacuo are dissolved in 40 cc. of warm dioxane. dioxane, whereby the mixture becomes yellow. 5 At room temperature a solution of 317 mg. (1.3 The solution is left standing at room tenniper mol) of 2.6-dichloro-4-nitro-N-chloracetanilide ature, first for 20 minutes and then heated for in 10 cc. of dioxane are added. The light brown 15 minutes at 65-70° C. colored solution is allowed to stand for 1 hour To the solution are then added 50 cc. Of chloro at room temperature, diluted with 100 cc. of form, the solution is washed with sodium bir 20 chloroform and washed with 2n sodium carbon carbonate solution in a shaking funnel and the ate solution. The separated chloroform-diox chloroform-dioxane solution of the raw product ane solution is dried and evaporated to dryness is dried with sodium sulphate and evaporated in vacuo. The residue is then Subjected to the to dryness in vacuo. For purification the raw chromatographic adsorption method with a Col product is subjected to chromatographic adsorp 25 umn of 40 g. of aluminium oxide. Where develop tion analysis with 50 g. of aluminium oxide. By ing the chromatogram with chloroform con developing the chromatogram with absolute taining 42% of ethanol, first 270 mg. of 2.6- chloroform are first obtained 80 mg. of red oil dichloro-4-nitroacetanilide are washed out. By and thereon 450 mg. of a product that by slow developing With chloroform containing 0.75% of crystallisation from a mixture of chloroform and 30 ethanol, 320 mg. of chlorodihydro-ergotamine ether crystallises in form of needles, partly in can be eluated. The new compound crystallizes smail bundles, whereas by rapid crystallisation from chloroform or from 90% acetone in straight an uncharacteristical colourless crystallisate of cut plates melting from 176-178° C. and con melting point 242-243; 246-247° is obtained. taining solvent of Crystallization. Dried during The iodo-dihydro-lysergic acid methylester 35 2 hours in high vacuo at 100° C., the chloro can easily be Sublimated Without decomposition dihydro-ergotamine shows an optical rotation in high vacuo at 210° C. M. P. of the Sublimate, Ial20=-81 (in pyridine). 247-249 C. Keller's colour reaction: pure blue. Ial?0=-130° (in pyridine). The analytical figures correspond to the em Analysis.-C17H1902N2, calculated: C 49.75, H. 40 pirical formula C33H36O5N5C1. 4.67, N 6.83. Found: C 49.89, H 4.30, N 6.22; C EXAMPLE 1.5 50.11, H 4.13, N 6.66. One part of iodo-dihydrolysergic acid methyl Preparation of iodo-dihydro-ergotamine ester dissolves at boiling-heat in about 600 parts To a solution of 500 mg. of dihydro-ergotamine of methanol, 150-200 parts of chloroform or 300 in 25 cc. of dioxane is added a Solution of 260 mg. of iodo-Succinimide (1.3 mol) in 10 cc. of parts of benzene. Colour reaction according to dioxane. The solution is left for 10 minutes at Exeller: reddish blue. room temperature and hereupon for 10 minutes EXAMPLE 3 at 65° C. After dilution with 100 cc. of chloro Preparation of chlorodihydro-ergocristine form, Washing with a sodium carbonate Solution, separating and drying the chloroform-dioxane 250 mg. of dihydro-ergocristine are dissolved solution with sodium sulphate, the former is in 40 cc. of dioxane and treated at room tempera evaporated in vacuo to dryness. The residue is ture with 14 mg. (1.3 mol) of N-chlorobenzoic subjected to the chromatographic adsorption acid sulfimide dissolved in 10 cc. of dioxane. The 5 method on 40 g. Of aluminium oxide. On de yellow solution thus obtained is allowed to stand velopment with chloroform containing 4% eth hour at room temperature. Then 100 cc. Of anol first 40 ring. Of a red non-Crystallisable oil chloroform are added thereto and the Solution are obtained and hereupon 406 Ing. of an un washed with 2n-Sodium carbonate Solution in the colored oil. From the lattel iodo-dihydro-ergot separating funnel. After drying with sodium Sul () amine is isolated by crystallisation from 90% phate the chloroform-dioxane Solution is evap acetone. The crystals are straight cut plates orated to dryness in vacuo and the raw product melting from 179-181 C. and contain crystal subjected to chromatographic adsorption anal. lising solvent. The optical rotation La20) of ysis with 25 g. of aluminium oxide. By develop this substance, when dried at 100° C. in high ing the chromatogram with chloroform contain- ( Vacuo, is -90° (in pyridine). ing 1% of ethanol, still 76 mg. of oil will be ob Iodo-dihydro-ergotamine gives the same Kel tained. The parts more closely adhering to the ler's colour reaction as dihydro-ergotamine and column are by-products giving no Keller's colour its empirical formula C33H36O5N5I has been reaction. These 76 mg. first washed out are a, proved by analysis: Calculated: C 55.83; H 5.12; mixture of chloro dihydro-ergocristine with some 70 N 9.88%. Found: C 56.01; H 5.52; N 9.43%. starting material which it is very difficult to Sep arate. For the preparation of pure chloro dihy EXAMPLE 16 dro-ergocristine this mixture is chromatographed Preparation of iodo-ergotamine a second time with 10 g. of aluminium oxide. By 500 mg. of ergotamine dried in high vacuo are developing the chromatogram with absolute chlo dissolved in 30 cc. of dioxane and mixed with a 2,516,002 10 Solution of 260 mg. (1.3 mol) of iodo-succinimide genated amides and imides of carboxylic and in 10 cc. of dioxane. The Orange colored solution Sulfonic acids in an inert solvent reaction me is allowed to stand at Ordinary temperature dur dium. ing 15 minutes, whereby the solution becomes 2. A process according to claim i, wherein the turbid. After addition of 100 cc. of chloroform, Solvent is dioxane. the mixture is shaken with a sodium carbonate 3. A process according to claim 1, wherein the Solution, the chloroform dioxane solution sepa compound of the lysergic acid series is a dihydro rated, dried with sodium sulphate and evaporated ergot alkaloid and the product is a halogenated to dryneSS in vacuo. The chromatographic treat derivative of such dihydro-ergot alkaloid where ment of the residue is carried out with 40 g, of O in the halogen is bound to the indol nitrogen. aluminium oxide and the chromatogram devel 4. A proceSS for the manufacture of brom oped first With absolute chloroform, whereby ergotamine, wherein bromine is bound to the traces of yellow by-products are separated. On indol nitrogen, which comprises treating ergot Subsequent eluation with chloroform containing annine With bromo-Succinimide in dioxane. A% ethanol iodo-ergotamine is washed out. 5 5. A process for the manufacture of brom This eluation is continued until a Zone, which ergocristine, wherein bromine is bound to the in ultraViolet light shows an intense violet lumi indol nitrogen, which comprises treating ergo nation, begins to be washed out. From the Cristine With brono-Succinimide in dioxane. chloroform-ethanol mixture containing the iodo 6. A process for the manufacture of bron ergotamine which is not luminous in ultraviolet 20 ergocornine, wherein bromine is bound to the light 260 mg. of pure iodo-ergotamine are ob indol nitrogen, which comprises treating ergo tained by crystallisation from 90% acetone. The cornine with brom-Succinimide in dioxane. Crystals are straightly cut plates, melting at 7. A halogenated compound of the lysergic acid 174: C. With decomposition and containing crys series wherein the halogen atom is bound to the ta. Solvent. 25 nitrogen atom of the indol ring and the lysergic Iodo-ergotamine gives the Keller's colour re acid skeleton is otherwise unattered. action like ergotamine, possesses an optical ro 8. A halogenated ergot alkaloid wherein the tation, When dried in high vacuo at 100° C., of halogen atom is bound to the indol nitrogen. (a)=-156 (in chloroform). 9. A halogenated dihydro ergot alkaloid where The empirical formula C33H34O5N5I is con 30 in the halogen atom is bound to the indol ni firmed by analysis: Calculated: C 55.59; H 4.85; trogen, N 9.90%. Found: C 56.29; H 5.41; N 9.92%. 10. Brom-ergotamine, the bronine being bound What We claim is: to the indo nitrogen. 1. A process for the manufacture of a halo 11. Brom - ergocristine, the bromine being genated derivative of a compound of the lysergic 35 bound to the indol nitrogen. acid Series Wherein the halogen atom is bound 12. Brom - ergocornine, the bromine being to the nitrogen atom of the indol ring and the bound to the indol nitrogen. ySergic acid skeleton is otherwise unaltered, ABERT HOEMANN. which comprises treating a compound of the FRANZ, TROXER. lysergic acid series wherein the lysergic acid 40 skeleton is unaltered, with a halogen compound No references cited. Selected from the group consisting of N-halo