• 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 the preparation of novel N-substituted alkyl-N-nitrosocarbamoyl azides and to the compounds obtained thereby. The novel N-substituted alkyl-N-nitrosocarbamoyl azides can be reacted with amines, diamines, aminoalcohols, aminoacids or aminoacid derivatives to prepare unsymmetrically 1,3-disubstituted nitrosoureas which show therapeutical activity.
    公开号:SU973019A3
    申请号:SU792806959
    申请日:1979-08-27
    公开日:1982-11-07
    发明作者:Айзенбранд Герхард
    申请人:Дейчес Кребсфоршунгсцентрум (Фирма)；
    IPC主号:
    专利说明:

    (5) METHOD FOR OBTAINING N-HALOGENALKYL-NITROSOCARBAMOILAZIDE
    one
    This invention relates to a process for the preparation of N-haloalkyl-N-nitroso-carbamoyl azide of the general formula
    ABOUT
    II
    Na1-CH2-1H2-I-1-} 5
    t
    where HaP-CPi F ,, 0
    which is used as a starting material for the preparation of disubstituted nitrosoureas, which are used for the treatment of experimental and clinical tumors. j5
    Asymmetric 1.3-disubstituted N-nitrosoureas are obtained by selective nitrosation of a specific nitrogen atom of urea, for example a nitrogen atom containing a 2-chloroethyl group 20 in the case of asymmetrically substituted homologues of trozourea. Nitrosation in undiluted formic acid Cl leads to the fact that the formation of 1- (2-chloroethyl) - 25
    -1-nitroso compounds occur only in those cases where the geometry of the substituent in position 3 creates steric control and directs the nitroso group to a specific position. However, selective nitrosation is not effective in the absence of steric control.
    Selective nitrosation is achieved using as a starting material for the preparation of disubstituted nitrosoureas N-alkyl substituted N -nitrozokarbamoilazida M-haloalkyl-T4 nitrozokarbamoilazida, in particular, N- (2-haloethyl) -N-nitrozokarbamoilazid, preferably N- (2-chloroethyl) -compound, and N- (2-fluoroethyl) -compound, which are obtained in a single-step process and without the use of pyridine from the corresponding carbamoylazide, obtained by reacting the corresponding isocyanate with activated sodium azide. The purpose of the invention is to obtain new M-haloalkyl-M-nitrosocarbamoyl azide of the general formula (1). This goal is achieved by the fact that a haloalkylcarbamoyl azide of the general formula II (P) At 1- (H 2-iH2-m-i - N 3 is treated with nitrogen tetroxide in an inert solvent at a temperature of from -20 to 0 ° C. Example 1. Preparation 2- Chloroethylcarbamoylazide A solution of 2-chloroethyl isocyanate (0.2 mol) in 100 ml of benzene is slowly added to a stirred solution of jpy activated sodium azide (about 2 mol) in 100 ml of hydrochloric acid (13%) whose temperature is 0 ° C. The biphasic reaction mixture was stirred for 4 hours at which time the water phase was removed, 2-chloroethylcarbamoylyazide crystallized from the mixture of benzene - petroleum ether. Crystals fall out in the form of needles of white color. The yield of the product is 88, TPL 49.6-50.2 ° C. The structure of the substance is confirmed by the NMR-spectrum data. Preparation of N- (2-chloroethyl) -M-nitrosocarbamoyl azide. Nitrogen tetroxide (0.3 mol) is slowly added to a suspension of anhydrous sodium acetate (0.6 mol) in 300 carbon tetrachloride at. After heating to 0 ° C, slowly, continuously stirring with a spatula, add 2-chloroethylcarbamoyl azide (0.2 mol). A white precipitate is formed (AcOH). After 15 min, the reaction mixture was poured into ice water. The separated organic phase is extracted twice with 50 ml of a cold solution of NaHCOj (one nominal) and then washed twice with 50 ml of ice-water, saturated with NaCI, then dried with anhydrous nitrile sulfate. N- (2-chloroethyl) -N-nitrosocarbamoglaside does not isolate, as it is dangerous. An NMR spectrographic study of the CCP solution (in accordance with the TMS standard) shows the complete absence of the NH signal, and also shows that the sample is typical of A Ba-sys tem of the nitrated 2-chloro-ethylamine group 9: cL 3.5 hours per million (t, 2H-CH2-N-NO); 4.1ii ppm (t, 2H, Cf-CH, 2) The solution should be as cold as possible, for example deeply cooled, since at constant room temperature the pseudotriplet line directed towards the strong field gradually disappears and at the same time appears a new pseudo triplet line, the middle of which passes inc 3.8 f.h. per million. This spectral change, which ends after 8 hours, is due to the thermally induced rearrangement of the compound, probably due to the migration of 1.3 azide to the diazo ether from: azidocarboxylic acid. If the temperature of the solution is -30 ° C, then such a phenomenon is not observed. PRI me R 3. 2-fluoroethylcarbamo-elazide is prepared analogously to 2-chloroethylcarbamoyl azide. Output 63%, so pl. below room temperature, RFO, 82, uniform. PRI me R 4. N- (2-fluorophenyl) -N-nitrosocarbamoyl azide was prepared as in Example 1, using pentane / ether / CioSep () as the solvent. RFO, 95 homogeneous. Example 5: Preparation of N- (2-chloroethyl-N-nitrosocarbamoylazide. Nitrogen tetroxide (0.3 mol) was added slowly to a suspension of anhydrous sodium acetate (0.6 mol) with 300 ml of carbon tetrachloride. 10 ° C. After cooling, 2-chloroethylcarbamoyl azide is added slowly to the solution while a white precipitate forms (AcOH). After 90 min, the reaction mixture is poured into ice-water. The separated organic phase is extracted twice with 50 ml of cold NaHCO Cl solution, mol) and then washed until neutral with twice 50 ml of ice-cold saturated NaCl water . It is then dried with anhydrous sodium sulfate. N- (2-chloroethyl) -N-nitrosocarbamoyl azide is not isolated because it is potentially explosive. An NMR spectroscopic examination of the CC64 solution (internal standard TMS) shows the absence of an NH signal and shows a sample that is typical of the ArjBn system of the nitrosated 2-chloroethylamino group: 3.50 ppm.
    (t, 2H, -CHj-N-NO); t.lS parts per million (t, 2H, CJ-CH -).
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    I. The method of obtaining the N-halo -. kil-N-nitrosocarbamoyl azide of the general formula (O
    ABOUT
    Hal- (JH2-C42 "-C-H3
    "Oh where HaE-Ctj G,
    730196
    characterized in that the haloalkylcarbamoyl azide of the general form is:
    ABOUT
    II
    Hal- (JH2 - ((- NS
    where HaE has the indicated meanings, is treated with nitrogen tetroxide in
    10 inert solvent at a temperature of from -20 to 0 ° C,
    Sources of information taken into account in the examination I.Jdinstov .--. Bed. With hem, 1966, .9, p. 892-911.
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    法律状态:
    优先权:
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