• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    1,2-Dithiole derivatives of the formula: <IMAGE> wherein Het represents a pyridazin-3-yl radical, or a pyrimidin-2-yl, -4-yl or -5-yl radical, each such radical being optionally substituted by a halogen atom or by an alkyl radical of 1 through 4 carbon atoms, an alkoxy radical of 1 through 4 carbon atoms, the mercapto radical, an alkylthio radical of 1 through 4 carbon atoms or a dialkylamino group having 1 through 4 carbon atoms in each alkyl radical, are new compounds useful in the treatment of bilharziasis and amoebiases.
    公开号:SU837324A3
    申请号:SU772450452
    申请日:1977-02-10
    公开日:1981-06-07
    发明作者:Барро Мишель；Котрель Клод；Жанмар Клод
    申请人:Рон-Пуленк Эндюстри (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING 1,2-DITIOLANE DERIVATIVES of aqueous saturated sodium bicarbonate solution. The solution is stirred for 12 hours at 20 ° C and the residue is filtered off. The aqueous phase is decanted and washed with 360 gll of methylene chloride. The organic phases are combined, dried over magnesium sulfate, filtered, and evaporated to dryness under reduced pressure. . The resulting residue is dissolved in 50 ml of methylene chloride and the resulting solution is filtered through 420 g of silica gel contained in a column of 5 cm in diameter. Then, 1400m of methylene chloride is eluted, this eluate is discarded. Then, 2700 ml of methylene chloride are eluted, and the corresponding eluate is concentrated to dryness under reduced pressure. The solid residue is 4 times 25 ml of carbon disulfide, then 2 times 50 ml of diisopropyl ether. After recrystallization, and from 800 ml of 1,2-dichloroethane, 2.7 g of 5- (3-pyridazinyl) -1,2,2-dithiolthione are obtained. 3, a plate at 250s. Ethyl-3- {3-pyridazinyl) -3-oxopropionate can be obtained by adding a solution of 93.5 g of ethyl acetate and 95.4 g of ethyl- (3-pyridazinyl) -, -carboxylate n 200 ml of anhydrous toluene to suspension 67 g of dry sodium ethoxide in 350 ml of dry toluene, pr 25c. The reaction mixture was then heated for 18 hours at. After cooling to 20 ° C, 3500 ml of water was added to the suspension. The aqueous phase is decanted, washed with 1000 ml of ether and acidified with 50 ml of concentrated hydrochloric acid. The oil, which does not dissolve, is extracted with 1000 ml of methylene chloride, then the vadny phase is decanted and washed with 4 ml of 250 ml of methylene chloride. The combined organic phases are dried with magnesium sulfate, filtered and evaporated with BcUOT under reduced pressure, to obtain 86-, 8 g of ethyl-3- (3-pyridazinyl) -3-oxopropionite as brown. oil. Example2. To a suspension of 2.34 g of phosphorus pentasulfide in 20 ml of toluene heated to boiling point, 1.456 g of ethyl-3- (6-methyl-3-pyridazinyl) -3-oxopropionate in 9 MP of toluene is added in 8 minutes, the boiling is continued within 38 min. After cooling, the insoluble product is filtered off, then it is stirred for 30 minutes with a mixture of 50 ml of methylene chloride, 10 ml of distilled water and 10 ml of ammigis (, 92). The aqueous phase is separated by decantation and rolled with 20 ml of methylene chloride. The combined organic phases are washed by decantation with 10 ml of distilled water, dried over sodium sulfate. Filter and evaporate to dryness under reduced pressure. The resulting residue is dissolved in 16 ml of methylene chloride and the solution is filtered through 16 g of silica gel contained in a 1.6 cm column. 144 ml of methylene chloride are eluted and this eluate is discarded. Then 48 ml of methylene chloride are eluted, the eluate is evaporated under reduced pressure to give 0.11 g of 5- (6-methyl-3-pyridazinyl) -1,2-dithiolthion-3, melted at. Ethyl-3- (b-methyl-3-pyridazinyl) -3-oxopropionate can be obtained by adding a solution of 5.5 g of ethyl (6 methyl-3-pyridazinyl) -carboxylate in 29 ml of ethyl acetate to the suspension 3.55 g of sodium tert-butylate in 60 ml of dry toluene is stirred for an additional hour at 20 ° C and the reaction mixture is poured into 260 ml of distilled water. The organic phase is separated by decantation and washed with 40 ml of distilled water. The combined aqueous phases are washed with 100 ml of ether, acidified with 6 ml of 4N. hydrochloric acid, then extracted with 100 ml, then 4 times in 50 ml of methylene chloride. The combined organic phases are dried with sodium sulfate, filtered and evaporated to dryness under reduced pressure. The residue is stirred with 20 ml of ether. The insoluble part is filtered off and washed with 2 times 5 ml of ether. The combined filtrates are evaporated to dryness under reduced pressure, to obtain 0.9 g of ethyl 3- (6-methyl-3-pyridazinyl) -3-oxopropionate, melted at. . . An ethyl (b-methyl-3-pyridazinyl) carboxylate can be obtained by heating at a boiling point for 17 hours a suspension of 13.8 g of (6-methyl-3-pyridazinyl) -carboxylic acid in 50 ml of ethanol, 50 ml of 1 , 2-dichloroethane and 10.6 g of methanesulfonic acid. After cooling to 20 ° C, 100 ml of an aqueous 10% sodium carbonate solution are added to the reaction mixture. The aqueous phase is separated by decantation and washed 3 times with 70 ml of methylene chloride. The combined organic fractions are obtained by decanting 30 ml of distilled water, and dried over sodium sulfate. After filtration and concentration to dryness under reduced pressure, 14 g of ethyl- (6-methyl-3-pyridazinyl) -carboxylate are obtained as a yellow oil. (B-Methyl-3-pyridazinyl) -carboxylic acid can be obtained by heating at boiling point within 1 h of a solution of 68.9 g of 3-cyano-6-methylpyridazine in a mixture of 865 mp of distilled water, 290 ml of 10 n, sodium hydroxide solution and 380 ml of ethanol. After cooling to 200 ° C, 250 ml of 12 N are added to the reaction mixture. hydrochloric acid. After concentration to dryness under reduced pressure, 1400 ml of ethanol are added to the obtained residue and the suspension is stirred for 70 minutes at. The insoluble product is filtered off and washed 3 times with 100 ml of ethanol. The combined filtrates are evaporated to dryness under reduced pressure to obtain 70 g of (b-methyl-3-pyridazinyl) -carboxylic acid, melting upon decomposition. . P p and me r 3. For 1 h, a suspension of 28 g of ethyl 3- (6-dimethylamino-3-pyridazinyl) -3-oxopropionate and 44.4 g of phosphorus pentasulfide in 590 ml of toluene is heated. After cooling to an insoluble part, it is filtered, then stirred for 1 hour with 350 ml of chlorofor / la, 200 1 ml of ammonia (, 92) and 280 ml of distilled water. After separation of the insoluble part by filtration, the aqueous phase is decanted, and it is passed through 3 times 100 ml of chloroform. The combined organic fractions are dried with magnesium sulfate, filtered and evaporated to dryness at low pressure, the resulting residue is dissolved in 250 ml of methylene chloride and filtered through 210 g of silica gel contained in a column of 3.5 cm in diameter. 2000 ml of methylene chloride are eluted. this eluate is discarded. Then, 1750 ml of chloroform is eluted, the eluate is evaporated under reduced pressure to dryness, obtained after recrystallization of the residue from 120 ml of 1,2-dichloroet into 0.82 g of 5- (6-dimethylamino-3-pyrid zinnl) -1,2-dithiolthione - W, melted at 272 ° С. Ethyl 3- (6-dimethylamino-3-pyridasyl) -3-oxopropionate can be obtained by adding in 10 minutes at. a solution of 39 g of ethyl- (6-dimethylamino-3-pyridazinyl) carboxylate and 35.2 g of ethyl acetate in 480 ml of anhydrous toluene to a suspension of 38.4 g of sodium tert-butylate in 350 ml of anhydrous toluene. The reaction mixture is stirred for 60 hours at, then 35 ml of 12 N are added. hydrochloric acid and 600 ml of distilled soda. The aqueous phase is separated by decantation and washed 2 times with 200 ml of hydrochloric chloride. The combined organic fractions are dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure, to obtain 39.7 g of ethyl 3- (6-dimethylamino-3-pyridazinyl) -3-oxopropionate as a yellow oil Ethyl (b-dimethylamino-3 -pyridaine-carboxylate can be obtained by heating LINE; 70s for 4.5 hours of a suspension of 52.7 g of 3-cyano-b-dimethylaminopyridazine in bio ml of distilled water, 200 ml of 10 n sodium hydroxide solution and 400 ml of ethanol After cooling to a mixture, 200 ml of methylene chloride are added to the reaction mixture and left for 12 hours at. The azure is separated by decantation, acidified by addition of 150 ml: 12N hydrochloric acid and evaporation to dryness under reduced pressure. To the residue obtained is added .360 ml of ethanol, 360 ml of 1,2-dichloroethane and 7bg of pure metasulfonic acid; .. the mixture is refluxed for 20 hours. After cooling, the insoluble material is separated by filtration and washed 3 times with 20 ml of methylene chloride. To the resulting filtrate is added 720 ml of an aqueous saturated sodium carbonate solution. The insoluble product that is formed is separated by filtration and washed 2 times with 200 ml of methylene chloride. The aqueous phase is separated by decantation and washed 2 times with 100 ml of methylene chloride. United OR-. Ganic fractions are dried with sodium sulfate, filtered and evaporated under reduced pressure; 50.81 g of ethyl (6-dimethylamino-3-pyridazinyl) carboxylate, melting at 112 s, is obtained. Z-Cyano-6-dimetidaminopyridazine can be obtained by heating at 150 ° C for 10 minutes a suspension of 63.7 g of 3-iodine-6-dimethylaminopyridazine and 34.34 g of copper cyanide (1) in 380 ml of dimethylformamide. After cooling to 20 ° C, the reaction mixture was poured into a mixture of 3,000 liters of distilled water, 700 ml of methylene chloride, 101 g of ammonium bicarbonate and 115 ml of ammonia (, 92). After stirring for 10 minutes at 20c, the aqueous fad was decanted and washed 3 300 ml of methylene chloride. The combined organic phases are dried with magnesium sulfate, filtered and evaporated to dryness under reduced pressure, to obtain 30.5 g of 3-cyanodimethylaminopyrididine, melting at 150 ° C. . , 3-Iodine-6-dimethylaminopyridazine can be obtained by stirring at 20 ° C for 48 hours a solution of 203.7 g of 3,6-diiodopyridaen and 276 g of dimethylamine in 1500 ml of methanol. After evaporation to dryness under reduced pressure, the residue obtained is stirred for 15 minutes with 1500 ml of distilled water. The insoluble product is filtered off and washed with 2 times 200 ml of distilled water, to obtain 113.7 g of 3-iodine-6-dimethylaminopyridazine, melting at 135 C. Example 4. To a solution of 73 g of phosphorus pentasulfide in 760 ml of pyridine, heated before within 2 minutes, a solution of 55.4 g of ethnp-3- (4-pyrimidinyl) -3-oxopropionate in 100 ml of pyridine. Heat the mixture while continuing for 1 hour. After cooling to 40 ° C, the reaction mixture is poured into 800 ml of distilled water. Chestnut brown suspension is 18 h at 20 s. The insolubles were filtered and washed with 1500 ml of distilled water. After drying, neither the resulting residue is stirred for 2 hours with 2500 ml of 1,2-dysloretna at boiling point. The boiling suspension is filtered and the filtrate is evaporated to dryness under reduced pressure. The resulting residue is dissolved in 100 ml of methylene chloride and the resulting solution is filtered through 70 g of silica gel, contained in a column with a diameter of 2.4. Then elute 700 MP methylene chloride. This loat is discarded. Then elyuir5pot; 1000 ml of methylene chloride, the resulting eluate is evaporated to dryness under continuous pressure. After recrystallization from 140 ml of 1,2-dichloroethane, 2.3 g of 5- (4-pyrimidinyl) -1, 2 - dithiolthion-3, melting at 214 ° C, are obtained. .
    Ethyl 3- (4-pyrimidinyl) -3-oxopropionate can be t5biTb added for 1 hour with a solution of 52 g of methyl (4-pyrimidinyl) carboxylate and 56.5 g of ethyl acetate in 200 ml of anhydrous toluene to a suspension of 40 g of ethylate sodium and 200 ml of anhydrous toluene. The reaction mixture is then heated at 7 hours. By cooling down to 20 ° C, 1700 gll of water is added. The aqueous phase is separated by decantation and acidified to pH 5 by the addition of 28 ml of 12 ml of hydrochloric acid. 800 g of crystalline sodium chloride are then added, then the aqueous is washed by decantation 4 times with 300 ml of methylene chloride. The organic phases are combined, dried with sodium sulfate, filtered and evaporated to dryness with a clear. 55.9 g of (4-pyrimidinyl) -3-oxopropionate is obtained as a yellow oil.
    EXAMPLE 5. To a suspension of 2 g of phosphorus pentasulfide suspended in 20 MP of toluene at a boiling point, a suspension of 2.2 g of C-ethylenedithio-1- (b-dimethylamino-3-pyridazinyl) is added over 5 minutes -1-oxopropene-2 in 22 ml of toluene. Heating is continued for 1 hour. After cooling to insoluble, the product is filtered, then stirred for 2 hours with 1 ml of acetic acid, 20 MP of distilled water and 40 ml of chlorofluoride a. Then, 30 g of potassium carbonate is added, the aqueous phase is separated by decantation and washed with 2 reaUO MP chloroform. The combined organic phases are dried over sodium sulfate, filtered, and dried to dryness under reduced pressure. The resulting residue is dissolved in 20 ml of methylene chloride, and the resulting solution is filtered through 30 g of the slice gel contained in a 1.5 cm column. 25 ml of methylene chloride are eluted and this eluate is discarded. Then, 100 ml of methylene chloride is eluted, the corresponding eluate is evaporated to dryness under reduced pressure, to give 0.05 g of 5- (b-Dimethylamino-3-pyridazinyl) -1,2-dithiolthion-3, melting at.
    3,3-Ethyldithio-1- (6-dimethylamino-3-pyridazinyl) -1-oxopropen-2 can be obtained by adding over a period of 20 min with a mixture of 2.6 g of 3-acetyl-6-dimethylaminopyridazine and 1.2 g of carbon disulfide 90 hp anhydrous toluene to a suspension of 3.02 g of sodium tert-butylate in 21 ml of anhydrous toluene. Stir for another 10 minutes at 25 ° C, then over the course of 5 minutes, 2.95 g of 1,2-dibromoethane in 15 ml of anhydrous toluene is added to the reaction mixture. The reaction mixture is then heated at 102 ° C for 5 hours. After cooling, the reaction mixture is poured into 250 ml of distilled water. The aqueous phase is separated by decantation and washed 3 times with 100 ml of methylene chloride. The combined organic phases are dried with sodium sulphate, filtered and dried to dryness under reduced pressure to give 2, 5 g of 3,3-ethylenedithio-1- (6-dimethylamino-3 -pyridazinyl) -1-oxopropene-2, melted at 180
    3-Ethyl-b-dimethyls1Minopyridazine can be obtained by adding over a period of 15 minutes with a suspension of 4.4 g of 3-cyano-B.-dimethylaminopyridazine in 80 ml of anhydrous diethyl ether to a solution of 16.6 g of methylmagnesium iodide and 90 ml of anhydrous ether by stirring for 30 min at Then the reaction mixture is poured into a mixture of 200 ml of distilled water, 150 g of ice and 100 g of ammonium chloride. The aqueous phase is separated by decantation and washed 3 times with 50 ml of ether. The combined organic phases are dried with sodium sulfate, filtered and evaporated to dryness under reduced pressure. After recrystallization of the obtained solid from 20 ml of distilled water, 2 g of 3-acetyl-6-dimethylaminopyrididine, melting at 130 ° C, are obtained.
    权利要求:
    Claims (1)
    [1]
    1. A method for preparing 1,2-dithiolan derivatives of the general formula
    HB1
    W
    where Het is 3-pyridazinyl. or 2-, 4nly 5 pyrimindins 1, which can be substituted with C-C alkyl or dialkylamine with an alkyl part, characterized in that the phosphorus pentasulfide is reacted with a heterocyclic compound of the general formula Het-CO -CH, j, -COOR where Het has the indicated meaning, and R is alkyl Q-C, or with a heterocyclic compound of the general formula Het-CO-CH "C (SR) 2 ,. where Het has the indicated value, and R alkyl C, - C, H, an alkali metal atom or two R, together represent alkylene in an organic solvent at 50-200s. 2, Method-according to claim 1, characterized in that benzene, toluene, xylene or chlorobenzene is used as a solvent. Priority signs: 10.02.76 with Het - Z-pyridaenyl, unsubstituted or substituted by alkyl C - disshylamine with the alkyl part of C | - ABOUT ; 11/30/76 with Het - 2-, 4- or 5-pyri: t-dinyl, unsubstituted or substituted with C – C or dialkylamine with alkyl part C. Sources of information taken into account during examination 1. USSR author's certificate 172835, cl . C 07 O 339/04, 2106.64.
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    同族专利:
    公开号 | 公开日
    ATA71978A|1978-08-15|
    DE2705582A1|1977-08-11|
    JPS52105181A|1977-09-03|
    AU505778B2|1979-11-29|
    CA1075239A|1980-04-08|
    OA05566A|1981-04-30|
    IE44462B1|1981-12-02|
    AU2213977A|1978-08-17|
    CH616161A5|1980-03-14|
    PT66174B|1978-07-10|
    ATA90177A|1978-08-15|
    HU172527B|1978-09-28|
    PH12622A|1979-07-05|
    AR220892A1|1980-12-15|
    JPS625912B2|1987-02-07|
    ES458019A1|1978-08-16|
    DE2705582C3|1981-09-24|
    NL7701103A|1977-08-12|
    GB1520231A|1978-08-02|
    SE427273B|1983-03-21|
    DK55677A|1977-08-11|
    PT66174A|1977-03-01|
    NL175823B|1984-08-01|
    DE2705582B2|1980-08-21|
    IE44462L|1977-08-10|
    US4104386A|1978-08-01|
    SE7701459L|1977-08-11|
    IL51402A|1980-07-31|
    AT349029B|1979-03-12|
    IL51402D0|1977-04-29|
    NL175823C|1985-01-02|
    AT349028B|1979-03-12|
    EG13192A|1982-12-31|
    LU76727A1|1977-08-18|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7603603A|FR2340736B1|1976-02-10|1976-02-10|
    FR7636038A|FR2371925B1|1976-11-30|1976-11-30|
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