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United States Patent Office 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.
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