Method of preparing lysergol derivatives
专利摘要:
A novel process is disclosed for the preparation of derivatives of lysergol having the general formula: According to this process lysergol is directly used as the starting compound and, after the methylation at the 1 position of the corresponding 10 alpha-methoxy-lumilysergol, the methylated compound is directly esterified with a carboxylic acid R-COOH, the acid being selected in the group comprisig aliphatic, cycloatiphatic, aromatic, and heterocyclic carboxylic acids, containing up to 10 carbon atoms. 公开号:SU884572A3 申请号:SU792748500 申请日:1979-04-04 公开日:1981-11-23 发明作者:Корви Мора Энрико 申请人:За витель; IPC主号:
专利说明:
in the presence of dicyclohexylcarbodiimide. Preferably, ultraviolet light is irradiated with a mercury lamp in methanol containing 6–20 vol.% Sulfuric acid in an inert gas atmosphere at a temperature of lO – SO C. Methylation is preferably carried out at a temperature of 10–4 oC in the presence of dry finely ground hereafter. The acylation is preferably carried out in tetrahydrofuran and use a 2-4 fold excess of carboxylic acid with respect to alcohol. Example. 1-Methyl-10;., - methox-lumilizhergol-8 (5-bromo) -nicotinate a) 10c1. -Methoxyluylmillergol. 50.35 g of lysergol is dissolved in. 1500 ml of a mixture of CHjOH / H, (40/7 by volume), and the mixture is, if possible, heated to 35-40 ° C. The solution is placed in a photochemical p actor, and irradiation begins at 20–40 ° C and in an inert gas atmosphere. The light source is a HP LR-N 260W Phillips lamp. The course of the reaction is monitored by thin layer chromatography (TLC) using silica gel as an adsorbent, CHijOH / CHClI / NH OH 20/80 / 0.2 as eluent and UV radiation I 254 nm. At the end of the reaction, the contents of the reactor are poured. in 6 l of ice water, the mixture is alkalinized with (650 ml) and extracted to complete extraction with floroform. The combined organic extracts are washed with water, dried, filtered and concentrated under reduced pressure and a temperature of 30-35 ° C. The residue is recrystallized from acetonitrile, to obtain 45 g (yield 80%) of 10 O1-methoxy-ethylmilgol, so pl. 183-ia5 ° C. b) 1-Methyl-10s1-methoxy-luminizer goal (Xl) 30.5 g of dry, finely ground KOH and 250 ml of dimethyl sulfoxide are loaded into the reactor with a mechanical stirrer and a thermometer. The mixture is stirred for 10 minutes and then 39 g of IL-methoxylu-milyer-ergol are added and stirring is continued at 1520 ° C for 45 minutes and then 9.9 MP is added in drops, the temperature is maintained at 25-35 ° C. At the end, the reaction mixture is stirred for about 45 minutes, and the progress of the reaction is monitored by TLC under the same conditions as in stage (and the contents of the reactor are poured into ice water, the precipitate is filtered and the filtrate is extracted with CHCl j ,. The combined organic solutions are washed with water and then dried Small 50, filtered and concentrated to obtain a residue under reduced pressure at. The crude residue is combined with the precipitate from water and recrystallized from acetone to obtain 28-30 g (yield about 70%). -methyl-10-o1 .-methoxylu-imylolgol, mp 213-21b "C. c) 1-Methyl-10c-methoxy-ilumilgol-8 (5-bromicotinate. To a solution containing 79.4 g of 5bromnicotinic acid, 27.05 g of 1-methyl-Uo-methoxyl-amiloergo a and 900 ml of tetrahydrofuran in a reactor equipped with a thermometer and a stirrer, add 20.62 g of dicyclohexylcarbodiimide, while the temperature is maintained at about 30 ° C. The reaction is monitored by TLC under the same conditions as above. The mixture is cooled to, the dicyclohexyl urea precipitate is filtered off and the filtrate is concentrated under reduced pressure at 35 ° C. The residue is treated with 800 ml and the mixture is stirred with a saturated aqueous solution of NaHCO 3 to isolate unreacted 5-bromonicotinic acid. After separation of the phases, the organic phase is washed with water, dried), filtered and concentrated to dryness under reduced pressure at 30 ° C. The residue is recrystallized from ether. Obtain 40 g (about 90% yield) of 1-methyl-10 ot bromicotinic ester. -methoxyluyl megalgola, mp. 135-13bs. The alkaline phase is acidified to pH 3 with HC.1 and the reacted bromicotinic acid is isolated by filtration (yield about 75%). Example 2. 1-Methyl-10o-methoxyluyl-memegl-8-nicotinate. The starting 1-methyl-10o-methoxy-il-ml-ergol is obtained, KaiK is described in example 1, through stages (aj and (b), and esterification is carried out under experimental conditions similar to stage (BJ, using 48.3 g of nicotinic acid, 27.04 g 10A-methoxyluylmilgol, 750 ml of tetrahydrofuran and 20.62 g of dicyclohexylcarbodiimide. At the end of the process, 32 g (yield 88%) of pure ester is obtained, mp PL; 124-126 ° C. The yield of unreacted nicotinic acid is about 73% .. . 1-Methyl-10o1. Methoxylumyl-mese-8- (2-furan carboxylate., Complex effcr is prepared according to the conditions of Measure 1. Esterification is carried out using 13.5 g of lOet-methoxylu-mylizer, 10.3 g of dicyclohexylcarbodiimide, 250 tJui of tetrahydrofuran and 20.34 g of 2-furancarboxylic acid, 16 g are obtained (yield 90% ester, t. 142-144 C. The yield is unreacted where R is nicotinyl, 5-bromonicotinyl, oL-furanyl, by irradiating the lysergin derivative with ultraviolet, light in methanol containing sulfuric acid, including methylation with ylioux methyl in a solvent at 2-furancarboxylic acid about 40%.
权利要求:
Claims (4) [1] Claims 1. A method of producing lysergol derivatives of the general formula HJOCOR in the absence of a base and acylation in a solvent, characterized in that, in order to simplify the process, lysergol derivative of the formula 20 is used as a lysergin derivative and the 10-methoxylylisol obtained in this case is methylated in dimethyl sulfoxide in the presence of alkali, followed by adylation with a carboxylic acid of the general formula R RCOOH, where R has the above values, taken in excess with respect to alcohol, in the presence of dicyclohexylcarbodiimide [2] 2. Method POP.1, characterized in that the irradiation with ultraviolet light is carried out using a mercury lamp in methanol containing 5-20% by volume of sulfuric acid in an atmosphere of inert gas at a temperature of 10-50 C. [3] 3. The method according to claim 1, wherein the methylation is carried out at a temperature of 10-40 ° C in the presence of dry finely ground alkali. [4] 4. Method POP.1, different from the fact that the acylation is carried out in tetrahydrofuran and use a 2-4-fold excess of carboxylic acid relative to alcohol. Sources of information taken into account in the examination 1. The patent of France K 2084678, cl. C 07 d 57/00, 1972.
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同族专利:
公开号 | 公开日 YU41151B|1986-12-31| EP0004664A1|1979-10-17| FI66376C|1984-10-10| DD142713A1|1980-07-09| FR2421901B1|1983-07-22| IT1094965B|1985-08-10| GB2018245B|1982-09-02| US4232157A|1980-11-04| NO791139L|1979-10-08| GB2018245A|1979-10-17| PL214713A1|1980-01-02| YU80179A|1983-02-28| EP0004664B1|1982-04-14| FI791110A|1979-10-06| DK148259C|1985-10-14| AT369366B|1982-12-27| ZA791609B|1980-04-30| AU4571379A|1979-11-01| NO150799B|1984-09-10| FI66376B|1984-06-29| GR66982B|1981-05-15| DE2962494D1|1982-05-27| IT7822011D0|1978-04-05| CA1124713A|1982-06-01| ES476725A1|1979-12-16| NO150799C|1984-12-27| HU177591B|1981-11-28| AU530864B2|1983-08-04| PL115244B1|1981-03-31| PT69426A|1979-05-01| ATA246679A|1982-05-15| DK138879A|1979-10-06| DK148259B|1985-05-20| FR2421901A1|1979-11-02|
引用文献:
公开号 | 申请日 | 公开日 | 申请人 | 专利标题 US3228943A|1962-06-11|1966-01-11|Lumilysergol derivatives | ES290275A2|1962-07-26|1964-03-01|Farm Italia|Procedure for preparing new compounds for 6-methyl and 1,6-dimethyl-er-golina ii | US3879554A|1970-03-20|1975-04-22|Farmaceutici Italia|Use of 1,6-dimethyl-8-{62 --10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders| NL7102982A|1970-03-20|1971-09-22|Farmaceutici Italia| NL159384B|1971-03-13|1979-02-15|Farmaceutici Italia|PROCEDURE FOR PREPARING A MEDICINAL PRODUCT WITH AN ADRENOLYTIC ACTIVITY, AS WELL AS A PROCEDURE FOR PREPARING AN ESTER OF 1-METHYL-10-METHOXYLUMILYSERGOL.| YU39278B|1976-12-22|1984-10-31|Lek Tovarna Farmacevtskih|Process for preparing 5-bromo nicotinic acid esters|US4382940A|1979-12-06|1983-05-10|Farmitalia Carlo Erba S.P.A.|Ercoline derivatives and therapeutic compositions having CNS affecting activity| IT1173489B|1984-03-27|1987-06-24|Inverni Della Beffa Spa|PREPARATION PROCEDURE FOR 1-METHYL-10ALPHA-METHOXYLUMIL SYNERGY AND FOREIGN SUCKS, AND INTERMEDIATES FOR THEIR PREPARATION| IT1213206B|1984-08-07|1989-12-14|Inverni Della Beffa Spa|PROCEDURE FOR THE PREPARATION OF LYSERGOL DERIVATIVES.| HU193781B|1985-06-21|1987-11-30|Richter Gedeon Vegyeszet|Process for producing 10alpha-methoxy-6-methylergoline derivatives and acid additional salts thereof| HU193782B|1985-06-21|1987-11-30|Richter Gedeon Vegyeszet|Process for producing 2-halogeno-nicergoline derivatives and acid additional salts thereof| FR2584720B1|1985-07-11|1987-10-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF ERGOLINE| FR2584719B1|1985-07-11|1987-10-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF LYSERGOL AND METHOXY-10A LUMILYSERGOL| FR2584721B1|1985-07-11|1987-10-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF METHYL DIHYDROLYSERGATE OR METHYL METHOXYLUMILYSERGATE| CH674367A5|1987-06-16|1990-05-31|Arysearch Arylan Ag| US5120784A|1988-09-01|1992-06-09|Basf Aktiengesellschaft|Heat-resistant thermoplastic molding compositions| US6060483A|1996-06-27|2000-05-09|Pharmacia & Upjohn S.P.A.|Antineurodegenerative ergoline derivatives| FR2786099B1|1998-11-24|2000-12-29|Aventis Laboratoire|NEW THERAPEUTIC APPLICATION OF 1,6-DIMETHYL-8BETA- HYDROXYMETHYL-10ALPHA-METHOXYERGOLINE| CN111116580A|2019-12-27|2020-05-08|上海应用技术大学|Improved preparation method of nicergoline|
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申请号 | 申请日 | 专利标题 IT22011/78A|IT1094965B|1978-04-05|1978-04-05|LISERGOL DERIVATION PREPARATION PROCEDURE| 相关专利
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