• 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:
    A compound of the formula wherein R1 is an alkyl group with 1 - 3 carbon atoms, R2 and R3 are the same or different and each is hydrogen, chlorine or bromine; and pharmaceutically acceptable salts and optical isomers thereof; methods and intermediates for the preparation of the compounds; pharmaceutical preparations containing them and their medical use.
    公开号:SU818481A3
    申请号:SU792739699
    申请日:1979-03-22
    公开日:1981-03-30
    发明作者:Леннарт Флорвалл Геста；Ове Егрен Свен
    申请人:Астра Лекемедель Актиеболаг Аб (Фирма)；
    IPC主号:
    专利说明:

    by filtration. Such a salt can be dissolved in water and converted to the free base by known techniques, for example, by adding sodium hydroxide solution. The resulting benzamide derivatives can be used as an antipsychotic. Example 1. 30 ml of thionyl chloride and added to 18.2 g (0.1 mol) of 2,6-dimethoxybenzoic acid and the mixture is heated on the steam bath for 30 min. 50 ml of toluene are added to the solution, the solvent and the excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in 50 ml of dry methyl ethyl ketone. After stirring, the solution is added dropwise to 12.8 g (0.1 mol) of 2- (aminomethyl) -1-atylpyrrolidine in 50 ml of methyl ethyl ketone. The mixture is then stirred at room temperature for 30 minutes. The precipitate is filtered, washed with ether, recrystallized from a mixture of ethanol and isopropyl ether, and 26.7 g of M-ethyl-2- (2, b-dimethoxy-benzyl-1mido methyl) pyrrolidine hydrochloride are obtained. , mp, 182-184 Example 2, 30 ml of thionyl chloride was added to 17.6 g (0.067 mol of 3-bromo-2,6-dimethoxybenzoic acid and the mixture was heated on the steam bath for 30 minutes. 50 ml of toluene was added to the solution. The solvent and the excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in 50 ml of methyl ethyl acetate. While stirring, the solution is added dropwise to 9.23 g (0.072 mol) of 2- (aminomethyl -1-ethylpyrrolidine in 50 ml of methyl ethyl ketone. After stirring at room temperature, 150 MP of ether are added for 30 minutes. The precipitate is filtered and washed simple ether and recrystallized twice from smzsi ethanol with simple isopropyl ether. After the first recrystallization, 21.0 g of N-ethyl-2- (3-bromo-2/6-dimethoxybenzamidomethyl) -pyrrolidine hydrochloride are obtained with m, 182-184c, after the second recrystallization, the melting point of the desired product is 184185 ° C, ep 3, 30 ml of thionyl chloride was added to 17.0 g (0.078 mol) of 3-chloro-2,6-dimethoxybenzoic acid and the mixture was heated on a steam bath for 30 min., 50 ml of toluene was added to the solution. The solvent and excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in 50 ml of dry methyl ethyl ketone. While stirring, growing riop drops is added to 10.0 g (0.078 mol) of 2- (aminomethyl) -1-ethylpyrrolidine in 50 ml of methyl ethyl ketone. After stirring; 150 ml of ether are added at room temperature for 30 minutes. The precipitate is filtered, washed with ether and recrystallized twice from ethanol / isopropyl ether. After the first recrystallization, 21.3 g of N-ethyl-2/3-chloro-2, 6-dimethoxybenzamidomethyl) -pyrrolidine hydrochloride are obtained, mp, 175-177 ° C, and after the second recrystallization, the melting point of the desired product is 179-180s. , Example 4, Example 3 is repeated with the difference that 20.4 g (0.06 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid, 50 ml of thionyl chloride and 7.7-g (0, 06 mol) 2- (aminomethyl) -1-ethylpyrrolidine. After recrystallization from a mixture of ethanol and ethyl ether, 20.2 g of N-ethyl-2- (3,5-dibrom-2,6-dimethoxybenzamidomethyl) pyrrolide hydrochloride are obtained. and with m, pl, 164-165s, the free base is precipitated from the aqueous solution of the hydrochloride by the addition of sodium hydroxide. The melting point of the free base is 133-134 ° C, Example 5, 20 ml of thionyl chloride is added to 11.9 g (0.047 mol) of 3,5-dichloro-2,6-dimethoxybenzoic acid and the mixture is heated on a steam bath for 30 minutes. To solution 50 ml of toluene are added. The solvent and excess thionyl chloride are evaporated under reduced pressure, and the residue is dissolved in 50 ml of dry ethyl ether. While stirring, the solution, 50 ml of ethyl ether are added dropwise to 6.0 g (0.047 mol) of 2- (aminomethyl) -1-ethylpyrrolidine. After stirring at room temperature for 30 minutes, 300 ml of water are added. The aqueous phase is separated and made alkaline with sodium hydroxide solution, which is added dropwise with stirring and ice-cooling. The precipitate is collected, washed with water and 9.0 g of N-ethyl-2- (3,5-dichloro-2,6-dimethoxybenzamidomethyl) -pyrrolidine are obtained with m, mp, 120-121 ° C. Example 6, 20 ml of thionyl chloride is added to 11.82 g (0.04 mol) -bromo-5-chloro-2,6-dimethoxybenzoic acid and the mixture is heated on a steam bath for 1 h. To the solution, 50 Ml of an oluol is added. The solvent and excess ionyl chloride are evaporated under reduced pressure, and the residue is dissolved in 50 ml of dry methyl ethyl ketone. While stirring the solution, 5.13 g (0.04 mol) of 2- (aminomethyl) 1-ethylpyrrolidine in 50 ml of methyl ethyl ketone is added dropwise. After stirring at room temperature for 30 minutes, 300 ml of ether are added. The semisolid product being recovered is separated and dissolved in 300 ml of water. Then add the hydroxide solution while stirring and cooling with ice. The precipitate is collected, washed with water and receive 12.0 g of N-ethyl-2- (3-bromo-5-chloro-2,6-dimethoxybenzamidomethyl) -pyrrolide, with t, pl. 124-125 0.
    Example 7. 20 ml of thionyl chloride was added to 12.2 (0.036 mol) of 3,5-dibromo-2,6-dimethoxybenzoic acid and the mixture was heated on a steam bath for 30 minutes. Toluene is added to the solution. The solvent and excess thionyl chloride are evaporated under reduced pressure. While stirring, the extract is added dropwise to the residue, obtained as follows. 75 ml of 30% sodium hydroxide are added to 10.0 g (0.036 mol) of (+) -2- (aminomethyl) -1-ethylpyrrolidine d-tartrate, the mixture is extracted with 100 ml of chloroform, and the extract is dried with magnesium sulfate. After adding the extract, the solution is heated on the steam bath for 10 minutes. The solvent was evaporated, and the residue was dissolved in 150 ml of water, acidified with hydrochloric acid, and extracted with ether. The aqueous phase is made alkaline with sodium hydroxide solution, the precipitate is collected, washed with water and 7.0 g of N-ethyl-2- (3,5-dibrom-2, b-dimethoxybenzamidomethyl) -pyrrolidine are obtained with m.p. 161-162 C +53, (1% in acetone).
    Example 8. Example 7 is repeated, with the difference that 19.8 g (0.056 mol) of 3,5-dibrom-2, b-dimethoxybenzoic acid, 30 ml of thionyl chloride and 15.58 g (0.056 mol) of Y-tartrate are used. (-j) -2- (aminomethyl) -1-ethylpyrrolidine. Obtain 14.3 g of N-ethyl-2- (3, 5-dibromo-2,6-dimethoxyben-amidomethyl) -pyrrolidine with so pl. 161-162s, -56.4 (a, 4% in acetone). The free base is converted to the hydrochloride by treating 13.0 g of the base in 50 ml of acetone with hydrogen chloride in ether. Obtain 13.5 g of the hydrochloride of the desired product with so pl. 159-160 ° C.
    Example 9. 23.8 g (0.09. Mol Z-bromo-2,6-dimethoxybenzoic acid.
    lots and 35 ml of thionyl chloride are heated on the steam bath for 30 minutes. After the addition of toluene, the excess thionyl chloride is evaporated under reduced pressure. While stirring, a mixture of 12.6 g (0.09 mol) of triethylamine was added dropwise to the residue; with the extract, get this as follows. 100 ml of a 30% sodium hydroxide solution are added to 25.0 g (0.09 mol) -tartrate of (-) - 2- (aminomethyl) -1o-ethyl pyrrolidine, the mixture is extracted with 150 ml of chloroform and the extract is dried over magnesium sulfate. After addition of the extract, the solution is heated on a steam bath for 10 minutes. The solvent is evaporated and the residue is dissolved in water, acidified with hydrochloric acid and extracted with ether. The aqueous phase is alkalinized with sodium hydroxide and extracted with chloroform. The extract is dried
    0 over magnesium sulfate and the solvent evaporated. An oil is obtained which is dissolved in ether and acidified with hydrogen chloride. The resulting precipitate is collected by filtration.
    5 As a result, 23.3 g of M-ethyl-2- (3-bromo-2,6-dimethoxybenzamidomethyl) -pyrrolidine hydrochloride are obtained, m.p. 16 "-168 C, II, f (0.5% in water).
    0
    Example 10. Example 9 is repeated with the difference that 8.4 g (0.032 mol) of 3-bromo-2,6-dimethoxybenzoic acid, 20 ml is used.
    5 thionyl chloride and 9.0 g (0.032 mol) o-tartrate (f) -2- (aminomethyl-1-ethylpyrrolidine. This reaction is carried out in the absence of triethylamine S, resulting in 7., 5 g of hydrochloride M-ethyl-2- (3-bromo-2,6-dime-0 hydroxybenzamidomethyl) -pyrrolidium with a melting point of 1–6–168 ° C, +10.70. (0.05% in water).
    权利要求:
    Claims (1)
    [1]
    The table summarizes the physical data of N-ethyl-2- (2,6-dialkoxybenzamidomethyl) -pyrrolidine derivatives. The invention The method of obtaining benzamide derivatives of the general formula. -Pa), coiracH where R is alkyl with 1-3 C; R2 and 3 are the same or equal and denote water chlorine or bromine, or their salts, or racemic cm, or stereoisomers, characterized in that the compound of the general formula "" "is where R, Rg and R have RVR. the values are reacted with an amine of the general formula iN-CRj-k J (S), -:. CrH5 in an organic solvent medium and the target product is isolated in free form or in the form of a salt, or a racemic mixture, or a stereoisomer. Sources of information taken into account during the examination 1. K. Buhler, D. Pearson. Organic syntheses. M., 1973, Part 2, p. 388.
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    同族专利:
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    引用文献:
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    FR2294698B1|1974-12-18|1979-03-16|Synthelabo|SE8101536L|1981-03-11|1982-09-12|Astra Laekemedel Ab|Benzamide derivative|
    US4470977A|1981-06-04|1984-09-11|Adria Laboratories, Inc.|Antiemetic and antipsychotic agents|
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    法律状态:
    优先权:
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    SE7803411A|SE411118B|1978-03-23|1978-03-23|A PROCEDURE FOR THE PREPARATION OF 2,6-DIALCOXIBENSAMIDES WITH THERAPENTIC PROPERTIES|LV930821A| LV5469A3|1978-03-23|1993-06-30|Saturation to obtain benzamide derivatives or their islands or racemic mixtures or stereoisomers|
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