• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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  • 优先权
    • 专利摘要:
    2-Oxo-pyrrolidine-N-alkylamides of the formula I in which n is 1 to 4 are prepared by electrolytic reduction of a corresponding 2,5-dioxopyrrolidine-N-alkylamide. The latter is obtained simply from the corresponding omega-haloalkylamide by condensation with sodium succinimide. The final products have therapeutic significance.
    公开号:SU893131A3
    申请号:SU772439826
    申请日:1977-01-12
    公开日:1981-12-23
    发明作者:Црнич Здравко；Дйокич Слободан；Гашперт Бранимир；Вайтнер Златко；Маасбел Альфред
    申请人:Плива.Фармацойтише Унд Хемише Фабрик (Инофирма)；Карл О.Хельм (Инофирма)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING 2-OXOPIRROLID1Sh-MI
    This invention relates to an improved process for the preparation of 2-oxopyrrolidine-M-alkylamides, which are used in medicine.
    A known method for producing 2-oxopyrrolidine-M-alkylamides of the general formula
    {CHtj ,, CONHi
    where p Oh, 1,2,
    the interaction of 2-oxopyrrolidine-sodium and-halo-substituted alkylamides 1.
    There is also known a method for producing 2-oxopyrrolidine-M-butyramide by the action of liquid ammonia on T-butyrolactone at high temperatures and pressures of C21.
    The disadvantage of the methods is in the nepBON case, the difficulty of obtaining one of the initial vetetos, namely the oxo derivative of pyrrolidium-sodium, -ALKYLAMIDES
    in addition, the latter polymerizes spontaneously during the processing, and in the second, the process is conducted at high temperatures and pressures and the formation of the indicated compound as a by-product.
    The purpose of the invention is to simplify the process and expand the range of target products.
    This goal is achieved by
    10 that according to the process for the preparation of 2-oxo-pyrrolidine-M-alkylamides, the total
    shape
    d.
    ((Sig Sosch
    where n is an integer of 1–4; succinimide of the general formula is used as pyrrolidine sodium;
    I
    No and its condensation product with and -halogen is kil kilamide of the general formula Ha8tCW, j) nCONHQ (where Hal is chlorine or bromine, n is an integer of 1-4, which is 2,5-dioxopyrrolidine-M-alkylamide of the general formula { NHf) CONHf where p has the indicated value, is electrolytically reduced in an acidic medium. Sodium succinimide is reacted with UJ -halogen-substituted alkylamides in ethanol, dimethylformamide, toluene, or another suitable solvent at 80-150 ° C, and converted into 2,5-oxopyrrolidine N-alkylamides. These compounds are then subjected to electrolytic reduction, preferably at O-ZO C in a cell for electrolysis with a metal cathode (for example, lead) using a diaphragm in an acidic medium at a constant current density, preferably from 5 to 8 A. Such metals can serve as an anode. like platinum or lead. Over the course of the reaction can be traced by thin layer chromatography. Processing the electrolyte after carrying out the reaction by neutralizing with alkali at 0-5 ° C, filtering and extracting the filtrate to dryness in vacuum gives a crystalline crude product from which the desired product can be extracted with a suitable solvent, for example ethanol. A pure product can be obtained from the solution obtained after crystallization by crystallization using known methods. The advantages of the proposed method in comparison with the known ones, which are based on the use of sodium salt of pyrrolidone as a starting material, consist in the fact that to obtain sodium succinimide it is possible to refuse the use of metallic sodium or sodium hydroxide, so that an intermediate for electrolysis is obtained. the product is very spilled with good yield and sufficient purity, and that the use of electrolytic reduction for 14 compounds leads to a very good quantitative and qualitative cut. ltatam. The whole process is generally characterized by ease of implementation, minor pollution of the environment, as well as low cost of the feedstock. In addition, a single method has been created for the preparation of known compounds obtained by various methods. Preparation of 2,5-dioxopyrrolidine-N-alkylamides, Example 1. 2,5-dioxopyrrolidium-A-acetamide. 18.78 g (0.155 mol) of sodium succinimide and 14.50 g (0.155 mol) of chloroacetamide in 500 ml of ethanol are heated to boiling for 5 hours with cooling under reflux. The precipitated sodium chloride crystals are filtered. 9.4 g of the product was recovered from the solution over 48 hours. Melting point 140-143 0. After filtration of the product, evaporation of ethanol in vacuo to dryness and crystallization from ethanol gives another 10.4 g of product, melting point 140-143 ° C. Total yield 19.8 g (81.8% -). Calculated,%: C, 46.15; H, 5.16; N, 17.94. (156.14). Found: C, 46.30, H 5.02, N 17.77. G-spectrum (KVg): -CO-N-CO 1780 (Sh), 1710 (s), -CONHa 1630-1690 (VS) -NH13455 (s), 3410 (m), 3310 (s), 3170 (s ). NMR spectrum (flMSO-d) -CG-CHf CHQ -Cav shift 2.63, multiplicity - singlet, integ. 4, C-NCHQ.-: shift 3.90, multiplicity - singlet, integra. 2, C-CONHQi: shift 7.27, multiplicity - doublet, integ. 2. Example 2. 2,5-Dioxopyrrolidine-N-propionamide. Analogously to example 1, from 4.84 g (o, 04 mol) of sodium succinimide and 6.07 g (0.04 mol) of fb-bromopropionamide in 120 ml of dimethylformamide, at And 8-120 ° C, together with 1.14 g of unreacted sodium succinimide, 2.96 g (61.3%) of the desired product. Melting point 110-111 ° C. A pure analytical product with a melting point of 112-113 ° C is obtained by crystallization from a mixture of benzene and ethanol. 5 Calculated D: C 49.40, H 5.92, N 16.46. 4H, oNfjp (170,17). Found,%: C 49.67, H 5.64, N 16.19. IR spectrum (KBG): -CO-N-CO1770 (S), 1685 (VS), -CONHa-1660 1630 (Sh), -NHa3395 (S), 3320 (Sh 3260 (Sh), 3210 (S). NMR spectrum (flMSO-d) shift 2.28, multiplicity - three plet, integral 2, -CO-CHi CHQ-CH-: shift 2.26, multiplicity - singly years, integral 4, -NCH2: shift 3 , 56 multiplicity - triplet, integral -CONHo. Shift 7.01, multiplicity - doublet, integral. 2. Example 3. 2,5-Dioxopyrrolidine-N- (b-propionamide. Analogously to Example 2, but at 150 ° С and a reaction time of 3 hours, 1.18 g of unreacted succinamide and 2.6 g (54.5%) of the desired product are obtained with a melting point of 109-111 ° C. Example 4. 2.5-Dioxopyrrolidine-Nf-butyramide. Similar Example 1 is obtained from 2.42 g (0.02 mol) of sodium succinimide and 2.43 g (0.02 mol) of 7-chloro-butyramide in 30 ml of dimethylformamide in which 0.2 g of sodium iodide is added, at the reaction temperature P .8-120 ° C after 5 hours, 0.6 g of unreacted succinimide and 0.92 g O5.8%) of the desired product. Melting point 79-81® C. Pure for an analytical product, crystallization from a mixture of benzene, ethanol and simple ether. Melting point 82-84 ° C. Calculated,%: C 52.16, H 6.57, N 15.21. CeHfiM O (184.19) Found: C, 52.30; H, 6.51; N, 15.30; . . IR spectrum (KVG): -CO-N-CO1770 (Sh), 1680 (VS), -CONHj 1660 (Sh), 1630 (VS), -NH 3415 (3350 (VS), 3290 (m), 3170 ( VS). NMR spectrum (flMSO-d) shift 1.5-2.2, multiplicity - M integral 4, -CO-CHQ GHij -CGP: shift 2.60, multiplicity - singlet, integral 4; -NCH (shift 3,36, mule type –– triplet, integral 2, -CONHn: shift 6.88, multiplicity – doublet, integral 2. 2. 1 Example .5. 2,6-Dioxopyridine-K-T-Butyramide. Analogously to an example 4 is carried out in 100 ml of absolute toluene, 0.8 g of unreacted succinimide and 0.667 g (32.6%) of the desired product are obtained. Melting point 80-82 ° C. Preparation of 2-oxodirolidine-M-alkylamides elec. by rolitic reduction of the corresponding 2,5-dioxopyrrolidine-N-alkylamides Example 6. 2-Oxo-pyrrolidine-N-acetamide 1 g (0.0064 mol) of 2,5-dioxopyrrolidine-N-acetamide is dissolved in 80 ml of 50% sulfuric acid at 0–5 ° C and electrically reduced in an electrolysis cell with a volume of about 100 ml at a constant current of 8 A using a lead cathode with a surface of 50 cm and a lead anode at 0–5 ° C. Anodic and:. the cathode space is separated from each other by a synthetic diffragm. Mixing the electrolyte of the cathode space is achieved using a magnetic stirrer. The reaction was controlled by thin layer chromatography (the ratio of chloroform to methanol was 9: 1). The product was isolated by neutralization with sodium hydroxide solution at 0-5 ° C to a pH value of 7 and then filtering the sodium sulfate formed from the reaction solution. By evaporation of the filtrate in vacuo to dryness, a product is obtained which is purified by extraction and crystallization. 0.66 g (72.6%) of the desired product is obtained with a melting point of 149-151 ° C. Example 7. 2-Oxopyrrolidine-N-acetamide. Analogously to Example 6, when carrying out the reaction at a constant current of 5 A and a reaction temperature of 30 ° C, 0.44 g (48.4%) of the desired product is obtained with a melting point of 148-150 0. Example 8. 2-Oxopyrrolidine-N- - propionamide. Analogously to Example 6, from 0.5 g (0.00294 mol) of 2.5-dioxopyrrolidine-N-L-propionamide, 0.31 g (67.5%) of the desired product is obtained, with a melting point of 135-137 ° C. Example 9. 2-Oxopyrrolidine-. -N- -JT -butyramide.
    (dream,) „som /
    where p is an integer of 1-4 by condensation of an oxo-derivative of pyrrolidine-sodium with and / -haloalkylamide. This is distinguished by the fact that, in order to simplify the process and increase the range of target products, succinimide of the general formula is used as oxo-pyrrolidine-sodium.

    Na
    ((SNN "SONN ,,
    where n has the indicated values, is electrolytically reduced in an acidic medium.
    Sources of information taken into account during the examination 1. Patent of Great Britain К10391 13, cl. C 2 C, 1966 (prototype; 2. US Patent No. 3250784, Cl. 260-326.3, 1966.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining 2-oxopyrrolidine-N-alkylamides of the General formula
    SDO (CHjJnCONH / where η is an integer of 1-4 by condensation of the oxo derivative of pyrrolidine sodium with uJ-haloalkylamide. Characterized in that, in order to simplify the process and expand the range of target products, succinimide of the general form is used as the oxo derivative of pyrrolidine sodium
    I Να and the product of its condensation with a u-haloalkylamide of the general formula where On 1 is chlorine or bromine, η - has the above values, which is 2,5-dioxopyrrolidin-N ~ alkylamide of the general formula where n - has the indicated meanings, is electrolytically reduced in an acidic medium .
    FROM
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