DE921149C - Process for the preparation of d, l-dihydro-nor-lysergylglycine amide - Google Patents

Process for the preparation of d, l-dihydro-nor-lysergylglycine amide

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Publication number
DE921149C
DE921149C DES31248A DES0031248A DE921149C DE 921149 C DE921149 C DE 921149C DE S31248 A DES31248 A DE S31248A DE S0031248 A DES0031248 A DE S0031248A DE 921149 C DE921149 C DE 921149C
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Germany
Prior art keywords
dihydro
carbobenzyloxy
amide
lysergylglycine
preparation
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Expired
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DES31248A
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German (de)
Inventor
Juerg Dr Rutschmann
Arthur Dr Stoll
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Sandoz AG
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Sandoz AG
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Publication date
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Publication of DE921149C publication Critical patent/DE921149C/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Description

Verfahren zur Herstellung von d,1-Dihydro-nor-lysergylglycinamid Es wurde gefunden, daß man zu d, 1-Dihydro-norlysergylglycinamid (VI) gelangen kann, indem man einen racemischen Dihydro-nor-lysergsäureester (I) über das Carbobenzyloxyderivat (II) und dessen Hydrazid (III) in das Carbobenzyloxy-dihydro-norlysergsäureazid (IV) überführt, dieses mit Glykokollamid umsetzt zu Carbobenzyloxy-dihydro-nor-lysergylglycinamid (V) und den Carbobenzyloxyrest durch katalytische Reduktion entfernt Zu diesem Zweck wird z. B. d,1-Dihydro-norlysergsäuremethylester (I) mit Carbobenzyloxychlorid, der d,1-Carbobenzyloxy-dihydro-nor-lysergsäuremethylester (II) mit wasserfreiem Hydrazin umgesetzt und das hergestellte Hydrazid (III) durch Behandlung mit salpetriger Säure in das entsprechende Azid (IV) übergeführt. Das d, 1-Carbobenzyloxy-dihydro-norlysergsäureazid wird mit Glykokollamid kondensiert und das Carbobenzyloxy-dihydro-nor-lysergylglycinamid mit katalytisch angeregtem Wasserstoff reduziert, wobei das d,1-Dihydro-nor-lysergylklycinamid (VI) erhalten wird.Process for the preparation of d, 1-dihydro-nor-lysergylglycine amide It has been found that d, 1-dihydro-nor-lysergylglycine amide (VI) can be obtained by converting a racemic dihydro-nor-lysergic acid ester (I) via the carbobenzyloxy derivative (II ) and its hydrazide (III) converted into the carbobenzyloxy-dihydro-norlysergic acid azide (IV), this reacts with glycocollamide to form carbobenzyloxy-dihydro-nor-lysergylglycine amide (V) and the carbobenzyloxy radical is removed by catalytic reduction For this purpose z. B. d, 1-dihydro-norlysergic acid methyl ester (I) with carbobenzyloxy chloride, the d, 1-carbobenzyloxy-dihydro-nor-lysergic acid methyl ester (II) reacted with anhydrous hydrazine and the hydrazide (III) produced by treatment with nitrous acid into the corresponding azide (IV) transferred. The d, 1-carbobenzyloxy-dihydro-norlysergic acid azide is condensed with glycocollamide and the carbobenzyloxy-dihydro-nor-lysergylglycine amide is reduced with catalytically excited hydrogen, the d, 1-dihydro-nor-lysergylklycine amide (VI) being obtained.

Das auf diese Weise hergestellte, bisher unbekannte d,1-Dihydro-nor-lysergylglycinamid ist ein farbloser, aus Wasser in Nadelbüscheln vom F. = 173 bis 176' kristallisierender Körper. Es zeichnet sich durch eine unerwartete pharmakologische Wirkung aus und soll als Therapeutikum verwendet werden.The previously unknown d, 1-dihydro-nor-lysergylglycine amide produced in this way is a colorless one that crystallizes from water in tufts of needles from F. = 173 to 176 ' Body. It is characterized by an unexpected pharmacological effect and intended to be used as a therapeutic agent.

Beispiel 370 mg Dihydro-nor-lysergsäuremethylester werden in 7 cm3 absolutem Pyridin gelöst und bei - i5° mit 2 cm3 Carbobenzyloxychlorid versetzt. Nach dem Stehen über Nacht zersetzt man das überschüssige Chlorid durch Zugabe von 3 cm3 Wasser, läßt 5 Minuten stehen und gießt dann in 75 cm3 2 n-Salzsäure. Das Produkt fällt schön kristallisiert aus; Ausbeute 350 mg. ioo mg unveränderter Ester werden aus der Mutterlauge durch Alkalischmachen und Ausschütteln mit Chloroform zurückgewonnen. Zur Analyse wird der Carbobenzyloxydihydro-norlysergsäuremethylester aus Äthanol umkristallisiert. F. (korr.) = 237 bis 239° (im Vakuum). G24 H24 ()4'N2 Berechnet C 71,27 H 5,98 N 6,93>/o Gefunden 71,39 6,10 6,880/, Eine Mischung aus 350 mg dieser Verbindung, 5 cm3 wasserfreiem Hydrazin und io cm3 Butanol wird 2 Stunden auf dem Wasserbad erwärmt und dann über Nacht stehengelassen. Beim Eindampfen kristallisiert das Carbobenzyloxy-dihydro-nor-lysergsäurehydrazid aus. Es wird aus Äthanol umkristallisiert. Ausbeute quantitativ. F. (korr.) = 213 bis 2i5° (im Vakuum).Example 370 mg of methyl dihydro-nor-lysergic acid are dissolved in 7 cm3 of absolute pyridine and 2 cm3 of carbobenzyloxychloride are added at -15 °. After standing overnight, the excess chloride is decomposed by adding 3 cm3 of water, left to stand for 5 minutes and then poured into 75 cm3 of 2N hydrochloric acid. The product is nicely crystallized; Yield 350 mg. 100 mg of unchanged ester are recovered from the mother liquor by making it alkaline and shaking it out with chloroform. For analysis, the methyl carbobenzyloxydihydro-norlysergate is recrystallized from ethanol. F. (corr.) = 237 to 239 ° (in a vacuum). G24 H24 () 4'N2 Calculated C 71.27 H 5.98 N 6.93> / o Found 71.39 6.10 6.880 /, A mixture of 350 mg of this compound, 5 cm3 of anhydrous hydrazine and 10 cm3 of butanol is heated on the water bath for 2 hours and then left to stand overnight. The carbobenzyloxy-dihydro-nor-lysergic acid hydrazide crystallizes out on evaporation. It is recrystallized from ethanol. Quantitative yield. F. (corr.) = 213 to 25 ° (in a vacuum).

Man löst 350 mg Hydrazid in einer Mischung aus 5 cra3 Salzsäure, 25 cm3 Eisessig und 25 cm3 Wasser und kühlt in Eiswasser.- -Dann fügt man unter intensivem Rühren so viel i n=Natriumnitritlösung zu, bis eine gelbliche Färbung aufzutreten beginnt (etwa o,9 cm3). Man rührt noch. 5 Minuten und schüttelt dann mit eiskaltem Essigester dreimal aus. Die Auszüge werden mit Eiswasser und gekühlter Natriumbicarbonatlösung gewaschen und schnell über Natriumsulfat getrocknet. Die erhaltene Lösung des Azids wird einige Minuten an der Wasserstrahlpumpe eingedampft, um die Kohlensäure zu entfernen, und dann zur Weiterverarbeitung verwendet. 350 mg of hydrazide are dissolved in a mixture of 5 cra3 hydrochloric acid, 25 cm3 glacial acetic acid and 25 cm3 water and cooled in ice water. 9 cm3). One is still stirring. 5 minutes and then shake out three times with ice-cold ethyl acetate. The extracts are washed with ice water and chilled sodium bicarbonate solution and quickly dried over sodium sulfate. The resulting solution of the azide is evaporated for a few minutes on the water jet pump to remove the carbonic acid and then used for further processing.

Die Lösung des Carbobenzyloxy-dihydro-nor-lysergsäureazids (etwa 150 cm3) wird bei o° mit einer Lösung von 7,50 mg Glycinamid in 50 cm3 Isopropanol vereinigt und 24 Stunden im Eisschrank stehengelassen. Dann wäscht man sie mit Wasser und Natriumbicarbonatlösung, dampft im Vakuum ein und löst den Rückstand in io cm3 Aceton. Man chromatographiert über 2o g Aluminiumoxyd und erhält zwei scharf getrennte Fraktionen, wobei die zweite Fraktion die gesuchte Verbindung enthält. Carbobenzyloxy-dihydro-nor-lysergylglycinamid kristallisiert sofort aus Methanol in Form. rhomboedrischer Plättchen vom F. (korr.) = 245 bis 248° (im Vakuum). Ausbeute 28o mg. G25 H2 6 04 1\T4 Berechnet C 67,24 H 5,87 N 12,550/, Gefunden 66,7o 5,95 22,o8 0/0 28o mg dieser Verbindung werden in 40 cm3 Äthanol und 0,5 cm3 2 n-Salzsäure aufgeschlämmt und mit ioo mg Palladiummohr unter Wasserstoff 4 Stunden geschüttelt. Der Katalysator wird darauf abfiltriert und das Lösungsmittel im Vakuum abdestilliert. Den Rückstand löst man in einigen Kubikzentimeter Wasser und filtriert die Lösung, die das Hydrochlorid des d,1-Dihydro-nor-lysergylglycinamids enthält. Bei Zusatz von Ammoniak kristallisiert die freie Base aus: Sie wird aus verdünntem Methanol umkristallisiert. Ausbeute i8o mg (fast quantitativ). Nadelbüschel, F. = 173 bis i76°. C17 H20 02 N4 Berechnet C 65,36 H 6,45 N 17,94 0/0 Gefunden 65,53 6,65 17,880/, The solution of the carbobenzyloxy-dihydro-nor-lysergic acid azide (about 150 cm3) is combined at 0 ° with a solution of 7.50 mg of glycinamide in 50 cm3 of isopropanol and left to stand for 24 hours in the refrigerator. They are then washed with water and sodium bicarbonate solution, evaporated in vacuo and the residue is dissolved in 10 cm3 of acetone. It is chromatographed over 20 g of aluminum oxide and two sharply separated fractions are obtained, the second fraction containing the compound sought. Carbobenzyloxy-dihydro-nor-lysergylglycine amide immediately crystallizes from methanol in the form. rhombohedral platelets from F. (corr.) = 245 to 248 ° (in a vacuum). Yield 28o mg. G25 H2 6 04 1 \ T4 Calculated C 67.24 H 5.87 N 12.550 /, Found 66.7o 5.95 22.08 0/0 280 mg of this compound are suspended in 40 cm3 of ethanol and 0.5 cm3 of 2N hydrochloric acid and shaken with 100 mg of palladium black under hydrogen for 4 hours. The catalyst is then filtered off and the solvent is distilled off in vacuo. The residue is dissolved in a few cubic centimeters of water and the solution, which contains the hydrochloride of d, 1-dihydro-nor-lysergylglycinamide, is filtered. When ammonia is added, the free base crystallizes out: It is recrystallized from dilute methanol. Yield 180 mg (almost quantitative). Tuft of needles, F. = 173 to i76 °. C17 H20 02 N4 Calculated C 65.36 H 6.45 N 17.94 0/0 Found 65.53 6.65 17.880 /,

Claims (1)

PATENTANSPRUCH: Verfahren zur Herstellung von d, 1-Dihydro-norlysergylglycinamid, dadurch gekennzeichnet, daß man einen d, 1-Dihydro-nor-lysergsäureester carbobenzoxyliert, das Carbobenzyloxyderivat durch Umsetzen mit Hydrazin in d, 1-Carbobenzyloxydihydro-nor-lysergsäurehydrazid überführt, dieses mit salpetriger Säure behandelt, das erhaltene d,1-Carbobenzyloxy-dihydro-nor-lysergsäureazid mit Glykokollamid umsetzt und aus der erhaltenen Verbindung den Carbobenzyloxyrest durch katalytische Hydrierung entfernt. Claim: Process for the preparation of d, 1-dihydro-norlysergylglycine amide, characterized in that a d, 1-dihydro-nor-lysergic acid ester is carbobenzoxylated and the carbobenzyloxy derivative is converted into d, 1-carbobenzyloxydihydro-nor-lysergic acid hydrazine by reaction with hydrazine treated with nitrous acid, the d, 1-carbobenzyloxy-dihydro-nor-lysergic acid azide obtained is reacted with glycocollamide and the carbobenzyloxy radical is removed from the compound obtained by catalytic hydrogenation.
DES31248A 1951-11-30 1952-11-28 Process for the preparation of d, l-dihydro-nor-lysergylglycine amide Expired DE921149C (en)

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CH921149X 1951-11-30

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DE921149C true DE921149C (en) 1954-12-09

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1040560B (en) * 1955-11-21 1958-10-09 Lilly Co Eli Process for the production of lysergic acid amides

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1040560B (en) * 1955-11-21 1958-10-09 Lilly Co Eli Process for the production of lysergic acid amides

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