• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Method for producing trans-eB-octahydro-2H-pyrrolo
    公开号:SU1113006A3
    申请号:SU802790756
    申请日:1980-07-31
    公开日:1984-09-07
    发明作者:Джеймс Бах Николас；Карл Корнфельд Эдмунд
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    1 The invention relates to methods for the preparation of novel pyrrolo (3, A-d) xynolin, which are intermediates for the synthesis of compounds used as dopamine antagonists, especially as inhibitors of prolactin secretion and in the treatment of parkinsonism. A known method for producing pyrrole derivatives, based on the reaction of El1 ina-West and consisting of a reaction. the mode of action of N-substituted C-amino acids with acetic anhydride at the boiling point of mixture I. The aim of the invention is to develop, on the basis of a known method, a method of producing new compounds, which are intermediate products for the synthesis of compounds possessing valuable pharmacological properties. This goal is achieved by obtaining TpaHC-d-octahydro-2H-pyrup (3,4-d) quinolines of general formula 1: -oci where R, is hydrogen or acetyl; R2 is hydrogen, C -C-alkyl or bH, ethoxycarbonyl, hydroxymethyl or mesyloxymethyl, provided that if R2 is C -C, -alkyl, then R and Ro n may be hydrogen, or their salts, which means that the compound is Formulas P:. xgt (where R, 2. C ;, is Ca-alkyl or benzyl; R is hydrogen or ethoxycarbonyl, is reacted with potassium glycine, followed by treatment of the resulting compound with acetic anhydride, and the target product is either free salt, or subjected to hydrolysis 6 to obtain a compound of general formula I, where R is hydrogen, or reduced to a compound of general formula I, where R is hydroxymethyl, or the latter is reacted with methanesulfonyl chloride, or a compound of general formula I, where R2 is benzyl, and Ro is hydrogen, debenzyl Example 1. The glycine potassium salt is prepared by reacting 975 mg of glycine with 730 mg of potassium hydroxide hydrate in 100 ml of anhydrous ethanol. 2.8 gtpls of dE-1-methyl-6-oco-7-dimethylaminomethylene decahydroquinoline is added and the mixture is heated at a temperature reflux in the presence of nitrogen for 3 hours. The reaction mixture is cooled, the easily evaporated components are removed in vacuo and the residue is diluted with ether. The mixture is filtered. The addition product weighs 3.5 g. The glycine adduct is then cyclized, decarboxylated and acetylated by heating with 100 ml of acetic anhydride at reflux temperature in the presence of nitrogen for 45 minutes. The acetylation mixture is cooled and the easily evaporated components are stripped off by evaporation to dryness. The residue containing tpaHC -d.-2-acetyl-5-methyl-4,4 °, 5,6,7, 8,8a, 9-octagidro-2H-pyroprol (3,4-d) xi-noline, is suspended in methylene chloride and the suspension is filtered to obtain 1.7 g of solid particles. Methylene dichloride filtrate — Chromatograph over 150 g of phlorisyl using methylene chloride as the eluent with increasing content (0-5%) of methanol. The fractions which, according to TLC, contain the same substances, are mixed and washed with sodium bicarbonate and saturated aqueous sodium chloride, and then dried. Evaporation of the solvent in vacuo gives a residue, which is rechromatographed on 30 g of phlorisil, using chloroform containing 5% methanol as eluent. The fractions which, according to TLC, contain the same substances, are mixed to obtain a viscous orange oil in the amount of 1.72 g (57%) containing purified trans -dB-2-acetyl5-metsh-1-4, 4a, 5, 6,7,8 , 8С |, 9-octahydro-2H-propolo (3,4-d) xinoline. The orange oil was dissolved in ether, and a solution of 870 mg of maleic acid in ether was added to the resulting solution. The maleic acid salt thus obtained melts at 201-203 ° C after recrystallization from methanol-ether (1: 2). Calculated,%: C 62.05; H 6.94; N 8.04. Found,%: C 61.81; H 6.82; N 7.97. Following this method, trans dB-2-acetyl-5-H-propyl-4, 4a, 5,6,7,8, 8th, 9-octahydro-2H-pyrrolo (3,4-ё) hino LIN is prepared from troc C-6-1-n-propyl-6-oxo-7-dimethylaminomethylene decahydroquinoline by reaction with the potassium salt of glycine followed by reaction with acetic anhydride. The compound is purified by chromatography. Follow the specified method. Trans-d -1-benzyl-6-oxo-7-dimethylaminomethylene decahydroquinoline is reacted with the potassium salt of glycine and ususic anhydride to obtain trans-dE-2-acetyl-5-benzoyl-4,4fl | 5,6,7,8, 8С1,9-octahydro-2H-pyrrolo (3,4-d) quinoline. This derivative is purified by chromatography on florisil and then converted into the maleic acid salt. Trans -d6-2-acetyl-5-benzyl4, 40,5,6,7,8,8q, 9-octahydro-2H-pyrrole- (3.4 -d) The cinolone malate melts at 162-1 ° C to 4 ° C after recrystallization from methanol-ether mixture. Calculated,%: C 67.91; H 6.65; N 6.60. Found,%: C 67.76; H 6.40; N 6.58. PRI mme R 2. Preparation of trais-dE-2-acet-5-H-propyl-4,4C (, 5, 6,7,8,8q, 9-octahydro-2H-pyrrolo (3,4- d). The solution is prepared from 2.5 g Trans-d 2-acetyl-5-benzyl-4,4a, 5,6,7,8,8q, 9 octahydro-2H-pyroprol (3,4-d) xinolin and 200 ml of methylene chloride. 4 g of cyanium bromide is added and the resulting mixture is stirred at ambient temperature under nitrogen for 16 hours. The easily evaporated components are evaporated in vacuo. The chloroform solution of the residue containing C to C -dE-2-acetyl -5-cyano-4, 4a, 5,6,7,8,8a, 9-octahydro-2H-pyrrole (3,4-d) quinoline, obtained in this reaction, chromatographic 200 g using the chloroform as eluent. The recovered fractions containing the desired components are collected and the solvent is removed from there. Recrystallization of the residue from the ester results in a crystalline trans-yE-2-acetyl 5 cyano-4,4a, 5,6,7 , 8,8a, 9-octahydro-2H-pyrrolo (3,4-d) xinoline, boiling at 135-137 ° С (total yield 630 mg). A mixture of 0.6 g Tra HC-d6-2-acetyl-5 cyano- 4, 4a, 5,6,7,8,8 I, 9-octahydro-2H-pyropolo (3,4-d) quinoline, 50 ml of glacial acetic acid, 10 ml of water and 3 g of zinc petit are heated at the reflux temperature in the atmosphere nitrogen for 7 hours. Reaction mixture The filter is then filtered and the filtrate is poured onto ice. The aqueous filtrate is alkalinized with 14 and. ammonium hydroxide water. The aqueous alkaline layer is extracted several times with a mixture of chloroform and isopropanol. The organic extracts are mixed, the mixed extracts are washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent in vacuo gives a precipitate, which is visible as one spot of the substance in the process. The residue is dissolved in 50 ml of dimethylformamide, to which is then added 0.8 g of potassium carbonate and 0.4 ml of iodide propyl. The reaction mixture was stirred at ambient temperature under nitrogen for 16 hours. The reaction mixture was then diluted with rho, and the dissolved mixture was extracted with ethyl acetate. The ethyl acetate extract is washed with water and saturated aqueous sodium chloride, h. then dried. Evaporation of the solvent in vacuo gives a residue which, according to TLC, contains in one main spot of the product Three to c-d B-2-acetyl-5-M-propyl-4, 4a, 5,6,7,8, 8ct, 9- octahydro-2H-pyrrolo (3,4-d) xinoline. PRI me R 3. Preparation of Trans-de-2-acetyl-4,4a, 5,6,7,8,8a, 9 octahydro-2H-pyropolo (3,4-d) quinoline. 3.5 g trans-d6-2-acetyl-5-benzyl-4.4q, 5,6,7,8,8oi, 9-octa hydro-2H-pyrrole (3,4-d) quinoline is dissolved in 196 ml of ethanol. To this solution is added 0.5 g of a 5% palladium carbon catalyst. The mixture is hydrogenated in a Leds device at room temperature and an initial hydrogen pressure of 4 .1 3x10 AHFI / CM. After two hours, a 100% theoretical amount of hydrogen was absorbed. The hydrogenated mixture is removed from the device and the catalyst is separated by filtration. Thin-layer chromatography shows two large spots, one of which is the starting material. The filtrate is concentrated in vacuo to obtain a crystalline material. The concentration of the filtrate leads to the further formation of a crystalline material. These two portions are mixed, dissolved in water, and the aqueous solution is made alkaline with 1A n. ammonium hydroxide water. The alkaline layer is extracted several times with a mixture of chloroform and isopropanol, the organic extracts are mixed, and the mixed extracts are washed with saturated aqueous sodium chloride and then dried. Evaporation of the solvent gives a precipitate containing traisoe-2-acetyl-4, Ac (, 5,6,7,8,8а, 9-octahydro-2H-pyropolo (3,4-d) xinoline, obtained by the above hydrogenation. The residue is washed hexane. The mixture is melted at 89-91 ° C. The maleic acid salt is prepared by dissolving the residue in ether and adding excess maleic acid to the ether in Lenin. Sola.1 ((einic acids are recrystallized from methanol and ether). It melts at 150-15GS. EXAMPLE 4. Preparation of tra HC-d C-4, 4c |, 5, 6.7, 8, 8a, 9-octahydr 2H-propylene (3,4-d) xif olina. 0.3 gpOlHC-d6-2-acetyl-4,4a, 5,6, 8,8s (, 9-ok agidro-2P-pyrrolo (3, 4-d) quinoline is dissolved in 15 ml of methanol to which 2 ml of 2N aqueous sodium hydroxide is added. The hydrolysis mixture is stirred at ambient temperature in the presence of nitrogen for 3/4 h The reaction mixture is then diluted with water and the alkaline layer is extracted with a mixture of chloroform and isopropanol. The organic extracts are separated, washed with saturated aqueous sodium chloride and dried, evaporating the solvent to give a residue, which is shown on one spot. The residue is dissolved in ether, and an excess amount of the ether solution of low-benzoic acid is added to the solution. The resulting precipitates are separated, dissolved in methanol, and the methanol solution is diluted with ether to form a crystalline material. Tra HC -d8-4,4a, 5,6,7,8, 8C |, 9-octahydro-2H-pyro (3,4-d) quinolinemate, thus prepared, melts at 190 ° C with decomposition. i EXAMPLE 5. Preparation of Trays-y6-2-acetyl-5-H-propyl-7-ethoxycarbonyl-4, 4d, 5,6,7,8,8q, 9-octahydro-2H-pyroprol (3 , 4-d) xinolina. The potassium salt of glycine is prepared by reacting 280 mg of potassium hydroxide with 370 ml of glycine in 50 ml of anhydrous ethanol. 1.3 GlraHC-d2-1-H-napropyl-3-ethoxycarbonyl-6-oxo-7-dimethylaminomethylene decahydroquinoline is added, and the mixture is heated under nitrogen at reflux temperature for about 3 hours. The reaction mixture is cooled and readily evaporated components are removed by evaporation in vacuo. 50 ml of acetic anhydride is added to this residue and the resulting mixture is heated at reflux temperature under nitrogen atmosphere for 45 minutes, thus cyclizing, decarboxylating and acetylating in one step. The reaction mixture is then cooled again and the easily evaporated components are recovered by evaporation. The residue is then diluted with an aqueous solution of sodium bicarbonate and the resulting alkaline aqueous layer is extracted with chloroform. The chloroform extract is separated, washed with a saturated aqueous solution of sodium bicarbonate and then dried. Evaporation of chloroform leads to the formation of a residue, which is chromatographed on 35 g of phlorisil using chloroform, containing increasing amounts (0-1%) of methanol, as eluent. Fractions that, according to thin layer chromatography, contain a target country -2-iethyl 5-H-propyl-7-ethoxycarbonyl-4, 4a, 5, 6.7, 8.8Q, 9-octahydropyrrole (3, 4;) quinoline, formed in reactions are mixed. The solvent was distilled off from the combined fractions by evaporation, and the resulting residue was dissolved in ether. This solution of the ester is treated with excess maleic acid-KIK-A-C in the ester. The resulting sediment, co, cher:; pschie maleic acid salt throne with -df
    权利要求:
    Claims (1)
    [1]
    The method of obtaining trans-Pb-octahydro-2H-pyrrolo (3,4-d) quinolines of the general formula £:
    where R { is hydrogen or acetyl;
    Ry hydrogen, Cysoalkyl or benzyl;
    Ry hydrogen, ethoxycarbonyl, hydroxymethyl or mesyloxymethyl, provided that if Ry Su is C1-6alkyl, then R 4 and Rye may be hydrogen, or their salts, characterized in that the compound of general formula II:
    where Rj is C 4 is C ^ alkyl or benzyl; R ^ - hydrogen or ethoxycarbonyl, is reacted with potassium glycinate followed by treatment of the obtained compound with acetic anhydride, and the target product is either isolated in free form or converted to salt, or hydrolyzed to obtain a compound of general formula 1, where Ry is hydrogen, or reduced to compounds of the general formula 'I, where Ry is oxymethyl, either the latter is reacted with methanesulfonyl chloride, or a compound of the general formula I, where Ry is benzyl and Ry is hydrogen, is debenzylated.
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    法律状态:
    优先权:
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