• 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:
    The invention relates to heterocyclic compounds, in particular to the preparation of 4-benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, which can be used as an intermediate in the synthesis of 4-hydroxypyrrolidin-2-one-1-yl -acetamide (oxyracetam), acting on the function of the brain. The goal is to develop a method for obtaining new compounds possessing the indicated action. The preparation is carried out by transesterification of 4- (C 1 -C 4 ) -alkoxy-3-pyrrolin-2-one with benzyl alcohol in the presence of sulfonic acid at 60 - 100 ° C. The resulting 4-benzyloxy-3-pyrrolin-2-one is alkylated with C 1 -C 4 -alkyl ester of 2-bromoacetic acid in the presence of an alkali metal hydride in an aprotic solvent at 0-40 ° C, followed by treatment of the resulting C 1 -C 4 - 4-benzyloxy-3-pyrrolin-2-one-1-yl-acetic acid alkyl ester in an autoclave at 60 - 80 ° C. 2 tab.
    公开号:SU1556537A3
    申请号:SU874203180
    申请日:1987-08-26
    公开日:1990-04-07
    发明作者:Меул Томас
    申请人:Лонца Аг (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to the field of obtaining a new chemical compound, 4-benzyloxy-3 pyrrolin-2-one--1-yl-acetamide, which can be used as an intermediate product in the synthesis of 4-hydroxy-pyrro-LIDIN-2-OH-1 -yl-acetamide (oxiracetam), acting on the function of the brain.
    The aim of the invention is to develop, on the basis of the known methods, a method of obtaining a new intermediate product, which makes it possible to simplify the synthesis of oxyracetam, which has a valuable pharmacological property.
    Approximate. Preparation of 4-benzyloxy-3-pyrrolin-2-one.
    5.7 g of 4-methoxy-3 pyrrolin-2-one and 10.8 g of benzyl alcohol are subjected to an exchange reaction with 0.4 g of methanesulfonic acid with stirring for 24 hours at 80 ° C and 20 mbar. Then the reaction solution is reacted with 50 ml of ice water and 100 ml of methylene chloride and neutralized with 4 ml of a saturated solution of NaHCO ,. The aqueous phase is extracted twice more with methylene chloride 50 ml. After drying the organic phase with Na «S04 and distilling off the solvent, the residue is subjected to reaction SP
    O5 SP
    WITH
    3

    cm
    With 150 ml of ice water, heated to 100 ° C and 100 ml of a mixture of water and benzyl alcohol are distilled off azeotropically. The crystals precipitated during cooling are recrystallized from 50 ml of hot toluene. 6.7 g of a white crystalline product are obtained with a mp. 1Ц7-1 8 ° С.
    b. Obtaining ethyl ester -ben zyloxy-3-pyrrolin-2-one-acetic acid.
    Dissolve 8, D g -benzyloxy-3- -pyrrolin-2-one and g of bromoacetic acid ethyl ester (95%) in 50 ml of anhydrous acetonitrile and cool to 0 ° C. To this reaction solution was added 1.67 g of sodium hydride (80% in bleached oil) over 20 minutes. Stir for another 2 hours, acidify with concentrated hydrochloric acid to pH 6-7 and distill off the solvent. Balance added
    权利要求:
    Claims (1)
    [1]
    The claims of the method for producing -benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, are described in that 4- (C / s) to a mixture of water and methylene chloride,
    After isolation of the organic phase, the 2s C «) -alkoxy-3-pyrrolin-2-one is subjected to k, k g of the crude product, which transesterifications with benzyl alcohol are dried. 8.7 g (7U) tom are obtained in the presence of sulfonic acid of the product (by thin layer chromatography at 60–100 ° C, obtained by this fium) without by-products. M.p. 4-benzyloxy-3-pyrrolin-2-one alkyl- 62-65 C.3Q rut C (-C-alkyl ester of 2-bromo. Preparation of 4-Benzyloxy 3-pyrcic acid in the presence of rolin-2-one hydride 1-yl-acetamide.
    8.7 g of the product obtained in the previous step are dissolved in 20 ml of methanol, a previously saturated gaseous alkali metal, in an aprotic solvent medium at 0-AO ° C, followed by treatment with the resulting C-Cq-alkyl ester of -Benzyloxy-C with ammonia
      1 C d JI gchk | JIWDV I k h cllpra -f IS: H LILI | AND
    ammonia at -10 - 0 ° C. Reaction - JD -pyrrolin-2-one-1-yl-acetic acid
    this solution is stirred for
    in the autoclave at 60-80 ° C.
    65374
    12 h at 60 - 8P ° C in an autoclave. After distillation of methanol and washing the crude product with carbon tetrachloride, it is recrystallized from water. Get 473 g (60,8%) of pure (by thin layer chromatography) product.
    Analogously to example 1, the target product can be obtained by using the corresponding starting compounds in examples 2-k listed in table. 1 and 2.
    The conditions for the re-esterification reaction (step a) are given in table. one.
    15
    The conditions for the alkylation and amidation reactions (stage biv) are given in Table. 2
    The invention of the method for producing -benzyloxy-3-pyrrolin-2-one-1-yl-acetamide, is characterized in that 4- (C / C ") -alkoxy-3-pyrrolin-2-one is subjected to of transesterification with benzyl alcohol in the presence of sulfonic acid at 60-100 ° С, the 4-benzyloxy-3-pyrrolin-2-one obtained is alkylated with C (-C-alkyl ester of 2-bromoacetic acid in the presence of hydride
    alkali metal in an aprotic solvent at 0-AO ° C, followed by treatment with ammonia of the benzoxy-3-C-alkyl ester formed
      1 C d JI gchk | JIWDV I k h cllpra -f IS: H LILI | AND
    -pyrrolin-2-he-1-yl-acetic acid
    in the autoclave at 60-80 ° C.
    Table 1
    2 Methyl KN Dimethylformamide 20 60-80
    3 Butyl NaH Acetonitrile 0 60-80 4 Ztil NaH Dimethylacetamide 10 60-80
    table 2
    46.9 1 + 9.5 48.3
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    同族专利:
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    US4843166A|1989-06-27|
    ES2017677B3|1991-03-01|
    EP0252353A1|1988-01-13|
    IL82937D0|1987-12-20|
    JPS638368A|1988-01-14|
    US4879393A|1989-11-07|
    AT55985T|1990-09-15|
    CS271472B2|1990-10-12|
    HUT44492A|1988-03-28|
    CA1280426C|1991-02-19|
    IL82937A|1991-03-10|
    SU1581220A3|1990-07-23|
    US4877884A|1989-10-31|
    DK325387D0|1987-06-25|
    DK325387A|1987-12-27|
    NO872671D0|1987-06-25|
    NO872671L|1987-12-28|
    EP0252353B1|1990-08-29|
    US4868314A|1989-09-19|
    CS470587A2|1990-02-12|
    CH668424A5|1988-12-30|
    US4849528A|1989-07-18|
    DE3764559D1|1990-10-04|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US2784191A|1957-03-05|Process for the production of lactams |
    US2535010A|1948-10-02|1950-12-19|Rohm & Haas|Transetherification of beta-ethersubstituted esters|
    DE850007C|1950-12-22|1952-09-22|Basf Ag|Process for the preparation of N-aryl-ª ‡ -pyrrolidones|
    US3299095A|1964-04-16|1967-01-17|Merck & Co Inc|1-benzyl tetramic acid derivatives|
    JPS4941521A|1972-06-02|1974-04-18|
    IT1045043B|1975-08-13|1980-04-21|Isf Spa|PYROLIDINE DERIVATIVES|
    IT1075564B|1977-02-11|1985-04-22|Isf Spa|PROCEDURE FOR THE PREPARATION OF PYROLIDINE DERIVATIVES|
    IT1075280B|1977-02-11|1985-04-22|Isf Spa|PROCEDURE FOR THE PREPARATION OF PYROLIDINE DERIVATIVES|
    JPS5812272B2|1981-04-28|1983-03-07|Denki Kagaku Kogyo Kk|
    FI83510C|1985-02-22|1991-07-25|Ciba Geigy Ag|Process for the preparation of novel therapeutically useful bi-2H-pyrroli ndions|US5274097A|1988-04-19|1993-12-28|Bayer Aktiengesellschaft|1,3-disubstituted pyrrolidines|
    DE3835291A1|1988-04-19|1989-11-02|Bayer Ag|1,3-DISUBSTITUTED PYRROLIDINES|
    EP0358128B1|1988-09-06|1995-06-28|Lonza Ag|Process for the preparation of 5-alkyltetramic acids|
    CH680293A5|1990-06-26|1992-07-31|Lonza Ag|
    JP2001072592A|1999-07-01|2001-03-21|Kyowa Hakko Kogyo Co Ltd|Telomerase inhibitor|
    WO2007128458A1|2006-04-28|2007-11-15|Laboratorios Del Dr. Esteve, S.A.|Bicyclic tetrahydropyrrole compounds|
    CN102432516B|2011-12-14|2013-10-09|山东阿如拉药物研究开发有限公司|Method for refining oxiracetam|
    CN104276992B|2014-09-17|2017-02-15|浙江工业大学|Synthesis process for oxiracetam key intermediate 2--acetamide|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    CH2567/86A|CH668424A5|1986-06-26|1986-06-26|4-BENZYLOXY-3-PYRROLIN-2-ON-L-YL-ACETAMIDE, THE PRODUCTION AND USE THEREOF.|
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