• 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 compound known as Cimethidin, N-cyano-N'-methyl-N''-[2- {[(5-methylimidazol-4-yl)-methyl]- thio}-ethyl]-guanidine, is made by reacting chlorodiacetyl with ethylene glycol, reacting the resultant ketal hemiketal with N-cyano-N'-methyl- N''-(2-mercaptoethyl)-guanidine to form N-cyano-N'-methyl-N''-[2- (butane-2,3-dionyl)thioethyl]- guanidine ethyleneketal hemiketal, hydrolyzing this to give the corresponding alpha -diketone and condensing the latter with formaldehyde and ammonia to produce Cimethidin, which can be incorporated in pharmaceutical compositions for gastric secretion reduction or inhibition.
    公开号:SU886744A3
    申请号:SU792790358
    申请日:1979-07-19
    公开日:1981-11-30
    发明作者:Црнич Здравко；Карлович Гордана；Радоболья Горьяна；Дьекич Слободан
    申请人:Плива Фармацевтическо-Химическии Завод (Инопредприятие)；
    IPC主号:
    专利说明:

    Union of Soviet Socialist Republics
    USSR State Committee for Inventions and Discoveries
    DESCRIPTION OF THE INVENTION
    TO THE PATENT (61) Supplementary to the patent. (22) Declared 19.07.79 (23) Priority <.. ”8867.44 (31) P 1725/78 (21) 2790358 / 23-04 (32) 19.07.78 (33) SFRY
    Published on November 30th, 2001. Bulletin No. 44
    Date of publication of the description 3Q11J81 (51) M. Cl 3
    C 07 D 233/64 //
    Ar 61 K 31/415 (53) UDC547.781.
    .785 (088.8) (72) The inventors
    Foreigners
    Zdravko Tsrnich, Gordana Karlovich, Goryana RadObOlya ”and Slobodan Dyekich g. : 1 (SFRY) J _ί (71) Applicant
    Foreign enterprise |
    Pliva Pharmaceutical Chemical Plant ((SFRY) · 1
    I
    I
    (54) METHOD FOR PRODUCING N-LWAHO-N 1 -METHYL-M 1 '- [2 - [(5-METHYLMIDAZOL-4-YL) -METHYLTHIO] -ETHYL] -GUANIDINE
    This invention relates to a new method for producing N-cyan-N'- ,. methyl N- {2- [(5-methylimidazol-4-yl) methylthio] ethyl] guanidine (cimetidine), which inhibits the secretion of gastric acid and pepsin and exhibits a therapeutic effect in ulcers and in repeated duodenal ulcers, and in throwing food into the esophagus, and under other conditions when a decreased secretion of gastric acid is desired.
    A known method of producing cimetidine by the interaction of 5-methyl-4- [(2-, aminoethyl) thiomethyl] imidazole with N-nnaHO-N! S-dimethylisourea [1].
    . -e- with dH 3-ene cN g $ g £ n-r mn NNSC-b, 0 ^ 0 I I ___ T est r cN g • it is subjected kislotnomu.gidrolizu and eL-diketone formed was condensed with formaldehyde and ammonia. 25
    In this case, cimetidine is obtained in a rather high yield.
    The method is described by the following examples, which, however, do not limit this invention.
    The disadvantage of this method is the inaccessibility of the starting 5-methyl-4 [(2-aminoethyl) thiomethyl] imidazole. Its synthesis consists of 3-4 stages.
    The purpose of the invention is to simplify the process.
    This goal is achieved by the interaction of chlordiacetyl with ethylene glycol, the corresponding ketal is formed, the half-ketal is reacted with N-cyano-N 1 -methyl-N '' - (2mer.aptoethyl) -guanidine obtained by N-UH.aHO-N '-methyl-N ' 1 - [2- (butane-2, 3 days) -thioethyl] -guanidine ethylene ketal semi-ketal of the formula • II
    Example 1. A solution of 4.82 g (0.04 mol) of chlordiacetyl, 5.5 g (0.088 mol) of ethylene glycol and a catalytic amount of para-toluenesulfonic acid in 250 ml of dry benzene are heated for 10 hours under reflux. By evaporating the solution to dryness in vacuo, a crude product is obtained, from which, after purification (crystallization or chromatography), pure chlordiacetyl ethylene ketal is a semi-ketal having a melting point of 99-101 ° C.
    Example 2. 9.484 g (0.021 mol) of sodium are dissolved in 60 ml of isopropanol and 1.11 g (0.007 mol) of K-cyan-I'-methyl- (2-mercaptoethyl) guanidine is added. After 30 minutes stirring at room temperature, 1.59 g (0.007 mol) of chlodiacetyl ethylene ketal of half-ketal are added and stirred for 5 hours at the boiling point of the solution. The resulting precipitate was removed by suction, the mother liquor was evaporated to dryness in vacuo, and after purification (crystallization or chromatography), N-uHaHo-N'Ϊμθτηπ-Ν - {2- (butane-2,3-dionyl) thio, ethyl] was obtained from the residue -guanidine ethylene ketal semi-ketal in the form of white hygroscopic crystals with a melting point of <120 ° C.
    Example 3. Similar to the method described in example 2, from
    0.92 g (0.021 mol) of 55% hydride. sodium, 1.11 g (0.007 mol) of N-cyanoN'-methyl-N '' - (2-mercaptoethyl) -guanidine and 1.59 g (0.007 mol) of chloroacetyl-ethylene ketal of half-ketal in 20 ml of Ν ( N 1 -dimethyl formamide at 20-25 ° C for 30 hours receive N-cyano ~ Ν 1- methyl-N 1 1 - [2- (bu- ^ en-2,3-dionyl) • thioethyl] -guanidine ethylene ketal semi-ketal.
    Example 4. Similar to the method described in example 2, from
    0.31 g (0.007 mol) of 55% sodium hydride, 1.11 g (0.007 mol) of N-cyanoN'-methyl-N 11 - (2-mercaptoethyl) guanidine, and 1.59 g (0.007 mol) of chloroacetyl half-ethylene ketal in 50 ml of acetonitrile at the boiling point of the mixture, I-cyano-I'-methyl-N 1 [2- (butane-2,3-dionyl) thioethyl] guanidine ethylene ketal is obtained.
    EXAMPLE 5 Analogously to the process described in Example 2,] n <* H and C--e- 27N0N 3 / g of OEI ene-8 he is subjected to acid hydrolysis and ei-diketone formed was condensed with formaldehyde and Diakom · s.
    0.161 g (0.007 mol) of sodium,
    1.11 g (0.007 mol) of N-cyano-Ν'-MethylΝ ' 1 - (2-mercaptoethyl) guanidine and 1.59 g (0.007 mol) of chloroacetyl-ethylene ketal of half-ketal in 20 ml of ethanol at room temperature give N-unaHo -N * -methyl-N ' 1 - £ 2- (butane-2,3dionyl) -thioethyl] -guanidine ethylene ketal of the semi-ketal.
    Example 6. A mixture of
    0.35 g (0.001 mol) Ν-ΠΗβΗο-Ν'methyl-N '' - [2- (butane-2,3-dionyl) thioethyl. 1-guanidine ethylene ketal half-ketal, 50 ml of acetone and 15 ml of 1% sulfuric acid is heated at 55-57 ° C for 2-4 hours and then evaporated to dryness in vacuo. The residue is dissolved in 2 ml of water or ethanol, and at 0-5 ° C, 0.5-0.7 ml (0.0070.009 mol) of 25% aqueous or this, zero ammonia solution is added dropwise and then 0.08 -0.12 ml (0.001-0.0015 mol) of 40% formaldehyde and stirred for another 10-20 hours. Then, the reaction solution was evaporated to dryness in vacuo, and after purification (crystallization or chromatography), N-cyanoN 1 -methyl-N ' 1 - [2 [(5-methylimidaeol-4yl) -methylthio] ethyl] -guanidine was obtained with mp. 140-142 ° C.
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of producing I-cyano-I'-methyl-N '' - {2- [(5-methylimidazole-4-Yl) methylthio] ethyl] guanidine, characterized in that, in order to simplify the process chlordiacetyl is reacted with ethylene glycol. the corresponding ketal formed, the half-ketal is reacted with N-unaHo-N 1 -methyl-N 1 '- (2-mercaptoethyl) -guanidine, obtained N-cyano-N'-methyl-N 1 ' - [2- (butane-2 , 3-Dionyl) thioethyl] -guanidine ethylene ketal semi-metal, formulas
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    同族专利:
    公开号 | 公开日
    IT1121013B|1986-03-26|
    DE2928857A1|1980-02-07|
    ATA498379A|1981-07-15|
    IT7968506D0|1979-07-19|
    CH643246A5|1984-05-30|
    GB2025969B|1982-09-02|
    YU172578A|1982-10-31|
    GB2025969A|1980-01-30|
    YU40716B|1986-04-30|
    DE2928857B2|1981-07-23|
    AT366033B|1982-03-10|
    DE2928857C3|1988-02-11|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1397436A|1972-09-05|1975-06-11|Smith Kline French Lab|Heterocyclic n-cyanoguinidines|
    GB1531221A|1974-09-02|1978-11-08|Smith Kline French Lab|Process for preparing guanidine derivatives|
    GB1533380A|1974-09-02|1978-11-22|Smith Kline French Lab|Process for the preparation of heterocyclic substituted thioureas and h-cyanoguanidines|HU185636B|1981-06-26|1985-03-28|Richter Gedeon Vegyeszet|Process for preparing new cimetidine-hydrate /cimetidine-h/|
    HU185298B|1981-06-26|1984-12-28|Richter Gedeon Vegyeszet|Process for producing cimetidine|
    MY100734A|1986-09-01|1991-01-31|Mitsui Petrochemical Ind|Process for preparation of guanidine derivative.|
    JPH0629234B2|1986-12-26|1994-04-20|三井石油化学工業株式会社|α-acyloxyketone derivative|
    US5808090A|1996-02-22|1998-09-15|Endo Pharmaceuticals Inc.|Process for preventing precipitation in cimetidine injection solutions|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    YU1725/78A|YU40716B|1978-07-19|1978-07-19|Process for obtaining n-cyano-n'-methyl-n'-û2-|5-metylimidazole4-yl)-methyl¨-thioethylù guanidine|
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