• 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:
    10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imines, derivatives and pharmaceutically acceptable salts thereof are useful as antianxiety agents, as muscle relaxants and in the treatment of extrapyramidal disorders such as in Parkinson's disease. They are prepared by treatment of a 5H-diben- zo[a,d]cyclohepten-5-one with ammonia to give the 5-imine, acylation of the imine, treatment of the protected imine with an organolithium to provide the 5-substituted-5-acylamino compound, treatment with acid or base to cause ring closure to a 5-substituted-5,10-acylimino compound followed by removal ' of the protecting group, either hydrolytically or hydrogenolytically.
    公开号:SU1025328A3
    申请号:SU802925102
    申请日:1980-05-23
    公开日:1983-06-23
    发明作者:Л.Шепард Кеннет；Дж.Бреннер Даниэл
    申请人:Мерк Энд Ко.,Инк.(Фирма)；
    IPC主号:
    专利说明:

    This invention relates to an improved process for the preparation of 5-methyl-1O, 11-dihydro-5H-dibenzo (a, d) -cyclohepten-5,10-imine, which has pharmacological properties and can be used in medicine. A method of producing 5-methi 10,11-dihydrr-5H-dibenzo (a, d) -hepten-5,10-imine cycle is known, which consists in that 12-hydroxy-5-methyl-10,11-dihydro- 5H-dibenzr- (a, 3) -cyclohepten5, 10-imine is reduced (fl). However, according to this method, the original compound is obtained by seven-step synthesis, starting with 10-bromo5n-dibe from the o- (a / d) -cycloheptene n-5-one, which, in turn, in two stages, is obtained from 5H-dibenzo- (a , d) -. cyclohepten-5-she 2. The aim of the invention is to simplify the process by reducing the number of stages in obtaining the desired product. ; The goal is achieved by the fact that according to the method of obtaining 5-me | Tyl-10,11-dihydro-5H-dibenzo- (a, d) cyclohepten-5, 10-imine of the formula on 5H-dibenzo- (a, d) -cylohepten- 5-o act with gaseous ammonia in the presence of titanium tetrachloride, the resulting 5H-dibenzo- (a, d) -cyclolepten-5-imine is acylated in the presence of an acid acceptor to the corresponding acylimine, which reacts with methyl lithium on the acylamide formed in this process or the base with the subsequent treatment of the resulting acylimine FOEadule sy flax acid or strong base. The first step is carried out in an environment of an inert organic solvent in which the raw materials are soluble, especially in such an aromatic solvent, to toluene, benzene, and the like. The temperature is not critical and can be in the range of about -10-50 ° C, preferably in the range between the temperature of the ice bath and the room temperature, the reaction time is 2-10 hours, usually 3-5 hours. The second stage includes standard acylation conditions , such as contacting the two reactants in an inert organic solvent medium, in the presence of an acid acceptor, for example, an organic base, in particular pyridine, which can be used as a solvent, triethylamine or an inorganic base, in particular, an alkali metal carbonate or resin in an alkaline form or the like. Duration and reaction temperature 1-6 hours at 0-50 ° C, 2-4 i at a temperature of 6 tons of ice bath temperature to room temperature, although the duration of the reaction is not Okay: em harmful effects. The third stage involves the interaction of the resulting acylimine stage with the organolithium compound in an inert organic solvent, ether, such as diethyl ether, tetrahydrofuranH, 1/2-dimethoxyethane, and stirring at, preferably at room temperature, for 0.5- 4 hours, preferably about 1-3 hours. Longer mixing times have no adverse effect. The fourth stage leads to the formation of an imino bridge by adding the acylamino group in the conjugated double bond. Cycling may be confused with treatment with a base, such as an alkali metal oxide hydrate, in particular sodium or potassium hydroxide in the front of a high-boiling ether-type solvent, such as diglyme. The reaction temperature is 150170 ° C, the reaction time is 24-48 hours. The fifth and last stage, the formation of the compound of formula 1, includes disamination of the imine group. These acyl groups can be removed by carrying out acidic or basic hydrolysis at 25-150 ° C for 2-48 hours, preferably 6-24 hours. Strong inorganic acids, such as hydrochloric, sulfuric, etc., are used. be mixed with organic acids such as acetic acid and tilt. In the case of the presence of protective arylsulfonyl groups, they are also removed by conducting hydrogenolysis with an excess of sodium hydrate bis (2-methoxyethoxy) al 4ini in an inert organic solvent such as toluene at 15-50 ° C, preferably 20-30 ° C, for 6 -48 hours, preferably 12-24 hours. The advantage of the proposed method is to carry out the process.
    in five stages instead of nine, starting with the same starting material, 5H-dibenzo- (a, 1) -cycloheten-5-one.
    An example. . 5-Methyl-10,11-dihydro-3H2 dibyo-jenzo- (a, d) -cycloheptene 5g10-im
    The first stage is the preparation of 5H-di6eH3o (a, d) -cyclohepten-5-imine.
    Gaseous ammonia was bubbled for 30 minutes in a cooled ice-moving mixture of 25 g of 5H-dibenzo (a, d) cyclone ten-5-ona and GO titanium tetrachloride in 750 ml of toluo. The cooling bath is removed and the stirring is maintained at room temperature. Thereafter, the mixture is heated at the boiling point under reflux for 5/5 hours. The mixture is added to 1 l of saturated sodium carbonate aqueous solution with stirring.
    The toluene layer is washed with 500 ml of an octagonal sodium carbonate solution and 300 ml of a saturated solution of sodium chloride. The initial aqueous layer was extracted with two portions of ethyl acetate and 500 ml each, and the combined extracts were washed with saturated aqueous sodium carbonate and sodium chloride solutions. The toluene phase and ethyl acetate extracts are combined dried over anhydrous sodium sulphate and concentrated and evaporated to dryness. The residue after trituration with petrol ether gives 20.6 g of 5H-dubeazo- (a, c) -cyclohepten 5-imnag melting at 60-62 ° С,
    In the second stage, 5-p-toluenesulfonimino-5H-dibenzo- (a, d) | cyclo-1) ten is obtained.
    ; PgTblueunsulfonyl chloride (22.3 g) is added in portions to ox: laden with ice / stirring solution of 24 g of 5H-dibenzo- (a, C1) -cyclohepten-5-imine in 200 ml, pyridine Ice bath is removed and stirring is continued with room temperature (approximately), during non-working end of the week. Methylene chloride (600 ml) is added and the mixture is extracted with three portions of 5b) ml of 1N. hydrochloric acid1. The methylene chloride phase is dried over sodium sulfate and concentrated and evaporated to dryness. The residue (39/2 g) P1e is recrystallized by dissolving hot ethanol in 300 m by filtration / concentration to a volume of 500 ml and cooling to obtain 16/7 g of 5-P-toluenesulfonimoyo-5H-dibenzo- (a / d} cycloheptene / which after recrystallization from ethanol, it melts at 15 / 5-158 / 5 C.
    In the third stage, 5-meth TIl-5-Y-1-luolsulfonamido-5H-dibenzo- (a / c1) -ikl6gepten is obtained.
    A solution of 5.0 g of 5-11 -toluenesulfonimino-5H-dibenzo (a, d) -cycloheptene in 75 ml of anhydrous tetrahydrofuran is stirred under a nitrogen atmosphere and treated by adding dropwise to a 1.4 M solution of methyl lithium in ethyl ether. After stirring overnight at room temperature under a nitrogen atmosphere, the reaction mixture is added to 100 ml of a 10% aqueous solution of ammonium chloride. Oles extracted with ethyl acetate. The extract is washed with water and a saturated solution of sodium chloride, filtered, dried over anhydrous sodium sulphate and evaporated to dryness to obtain 6.4 g of product / which after recrystallization From ethanol gives 2.8 g of 5-methyl-5 - " toluenesulfonamido-5H-dibenzo - (a, d) -cycloheptene, melting at 175-178 C.
    In the fourth stage, 5-methyl-12-p-toluenesulfonyl-5H-dibenzo-{a, d) -cyclopentene-5/10-imine is obtained.
    A mixture of 1 g of 5-methyl-5-n.-toluenesulfonamido-5H-dibenzo- (a, d) -cycloheptev and 5 g of hydrate tablets, potassium oxide (86.1%) in 50 ml of diglyme is heated in an oil bath at 160170 ° C for 42 hours, is added to 200 ml of water and neutralized (ply 7) by means of concentrated hydrochloric acid. The solution is extracted with two portions of 200 ml of diethyl ether and each of the Ether extracts is washed with three portions of 100 ml of water. The ether extracts are separately dried on anhydrous sodium sulfate / filtered and evaporated to dryness to obtain, respectively, 330 and 100 mg of product. After recrystallization from ethanol and drying, it receives 5-methyl-1 - -toluene-fonyl-5H-Dibe H3o- (a, d) -cyclohepten-5/1 .6-imine / melting at V186 / 5-188.5 ° С .
    In the fifth stage, 5-methyl 10, 11-digd-5H-dibenzo (a, d) -cyclohepten-5, 10-im is obtained.
    A mixture of 290 mg of 5-methyl-12-p-toluenesulfonyl-5n-dibenzo- (a, d) -cyclo: heptene-5, 10-imine, 5 ml of glacial acetic acid and 5 ml of concentrated hydrochloric acid is heated at a temperature. reflux overnight. The clear solution is added to 100 ml of water and a 20% aqueous solution of sodium hydroxide is added until the pH is at a level of 9. The mixture is extracted with three portions mm 100 ml of methylene chloride. The extract is washed with sodium hydroxide solution and dried anhydrous sodium sulfate and evaporated to obtain 210 mg of an oil. The oil is dissolved in acetone and treated with 142 mg of oxalic acid in acetone. (iecb is cooled and the precipitate is collected to obtain 100 mg of 5-methyl-10, 11-digdp-5H-devereno- (cyclohepten-5.1 b-imine, melting at 211-212 C.
    权利要求:
    Claims (1)
    [1]
    METHOD FOR PRODUCING 5-METHYL-10, 11-dahydro-5I-DIBENZO- [a, d] -CYCLOGEPTEN- 5, 10-IMINE formulas with the fact that, in order to simplify the process, on 5Idibenzo- [a, d] -cyclohepten-5-one is affected by gaseous ammonia in the presence of tetrachloride-titanium, the obtained 5H-dibenzo- [a-cyclohepten-5-imine is acylated in the presence of an acid acceptor to the corresponding acylimine, which is reacted with methyl lithium, on the resulting acylamide act with an acid or base, followed by treatment of the resulting acylamine uly
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    引用文献:
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    NL7007464A|1969-05-30|1970-12-02|
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    BE794904A|1972-02-04|1973-08-02|Roussel Uclaf|NEW DIBENZOCYCLOHEPTENE DERIVATIVES AND THEIR PREPARATION|
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    US4123546A|1977-07-01|1978-10-31|E. I. Du Pont De Nemours And Company|Antidepressant compounds|
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    法律状态:
    优先权:
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