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    1351031 Derivatives of 2-iminothiazolidine IMPERIAL CHEMICAL INDUSTRIES Ltd 4 July 1972 [27 July 1971] 35206/71 Heading C2C The invention comprises the compounds of Formula II and their acid addition salts, wherein R<SP>1</SP> is phenyl nitrophenyl, aminophenyl or tolyl, and R<SP>2</SP> is H, alkyl, alkenyl, aralkyl or aryl, and a process in which they are ring closed to give tetramisole or its 6-nitrophenyl, aminophenyl or tolyl analogues. The compounds II may be prepared by (i) acidic hydrolysis of the corresponding N-alkanoyl, -aroyl or -aralkanoyl compounds, or (ii) reaction of the diamine wherein Y is Cl, Br or SO 2 H, with thiourea or R<SP>2</SP>NCS. Intermediates otherwise prepared are 1-(2- acetylamino- and -benzoylamino - 2 - phenylethyl)aziridine; #N-acyl derivatives of XII; analogues of XII where Y is OH; 3-(2-hydroxy- 2-phenylethyl) - 2 - iminothiazolidine; and 3-styryl-2-iminothiazolidine.
    公开号:SU847915A3
    申请号:SU721815874
    申请日:1972-07-26
    公开日:1981-07-15
    发明作者:Эдвард Макменим Майкл
    申请人:Империал Кемикал Индастриз Лимитед (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a process for the preparation of imidazo derivatives (2, 1-b thiazole, namely tetramisole, its analogues, as well as their salts, which have high anthelmintic activity. A known method for the preparation of tetramisole, the starting acid 2-phenyl-1- (n -toluenesulfonyl) aziridine. By this method, the indicated compound under the reaction of verggiot with ethanolamia, the hydrochloride formed with N- (1-phenyl-2-L-oxyethylaminoethyl) -l-toluenesulfonamide is further treated with thionyl chloride and the reaction product M- {1-phenyl-2 (2-iminothiazolidin-3-yl) ethyl} -p-tol wolsulfonamide cyclized under the action of sulfuric or polyphosphoric acid in 6-phenyl-2, 3,5,6-tetrahydroimidazo 2,1-6 thiazole (tetramisole). The proposed method is more economical and eliminates the use of hazardous derivatives of ethyleneimia, which have mutagenic properties. With the present isoset, a method has been developed for the preparation of compounds of the general formula - .N..1 7 () where R is a phenyl, nitrophenyl, aminophenyl or tolily radical, as well as their acid addition salts, meaning that the compound total rmuly. . kng i-I where R has the indicated values; K is hydrogen, alkyl, alkenyl, aralkyl or aryl, or its acid addition salt is cyclized. In those cases of x, when R is predstav.-. It may be a nitrophenyl, aminophenyl or tolyl radical, it may be, for example, meta-nitrophenyl, meta-aminophenyl or meta-capsyl. In cases where the symbol is an alkyl or alkenyl radical, it may be a wallpaper, for example, a scraper containing not more than five carbon atoms, such as a methyl, ethyl, isopropyl, isobutyl, isoamyl, 3-pentyl or allyl radical . In cases where the symbol R is an aryl or aralkyl radical, it may be, for example, a radical containing not more than ten carbon atoms, for example a phenyl or benzyl radical.
    This ring closure reaction may be implemented by various method variations. In one embodiment, the starting material thiazolidine is reacted in water at elevated temperature, for example, at 80-150 ° C. For example, at reflux, at pH 8, preferably 2-4. In another embodiment (used only when the symbol R is a hydrogen atom), the thiazolidine starting material is reacted in water with nitrous acid and this reaction is preferably carried out at about room temperature. Nitrous acid can be formed in situ in the reaction mixture by using nitrite, e.g. alkali metal nitrite, and acid, e.g. inorganic acid such as hydrochloric acid. In another embodiment, the starting material, thiazolidine, in the form of a salt from the addition of an acid, is heated at 30 ° C. In this embodiment, the starting material may be heated as such, or it may be heated in the presence of an inert diluent that is stable at 200-300 ° C, for example a mixture of diphenyl and diphenyl ether. In another embodiment, the thiazolidine starting material as a salt from an acid addition is heated at 100-150 ° C in a dipolar aprotic solvent, such as dimethylformamide.
    It can be assumed that the ring closure process described proceeds in accordance with the following mechanism (with the exception of the variant in which nitric acid is used):
    "Uhh
    R.-clHdHN1
    P
    Prince
    g f
     KNH 0.
    1 T I
    K-IN 1NgK
    NHj
    HNHj
    rth
    TO
    , ub®.
    R
    KIN, en, "5nIVT1
    -NCjHjCHj H
    Nvi
     The compounds of the formula (V) are intermediates that cannot be isolated. The compounds of the formula V are relatively unstable since they are easily oxidized, but they can be isolated.
    The starting material of the formula II, in which R and have the indicated meanings, and its acid addition salts can be obtained as a result of this sequence of operations.
    5847915
    RdHOHCHjNHCiHzCHjX
     u .1NaOHNHdOft
    R (, Y 7 ...... ,,,, - T, 4cH / r f
    f "// TivR tjjj SNg
    0 H tiHjO
    Nhz
    Nhz
    IcJHCiHjN eHzClHjY.
    Both R and R have the above values, R is hydrogen or an alkyl radical with not more than 5 carbon atoms, or an aryl, or aralkyl radical with no more than 10 carbon atoms, X is a chlorine or bromine atom, or hydroxy - radical, Y is a chlorine atom or a bromine atom, or a hydrogen-sulphate radical (-05С „Н). Example 1. 3- (2-Amino-2-phenylethyl) -2-iminothiolidine dihydrochloride (1 g) is dissolved in water (10 ml) and the solution maintained at reflux temperature for 16 h. Then the solution is alkalinized 2 n sodium hydroxide solution to pH 11 and extracted with methylene dichloride (2 L, 20 ml); the combined extracts are dried over anhydrous sodium sulphate and evaporated to dryness under vacuum. The residue is dissolved, as far as possible, in benzene (20 ml), the mixture is filtered and a saturated solution of hydrogen chloride is added to the filtrate in isopropanol until the pH is set at 2-3. The white precipitate formed is filtered off, successively washed with benzene (5 ml) and diethyl ether (5 m and dried in air at 1 Lamina temperature. Tetramisole hydrochloride is obtained, melting at 255260 C. After crystallization from ethanol, the sample melts at 258-260 ° C .mig1g, o
    Thiong (6,
    K (iN0
    NHCiOR R jj g
    To CH SNG-N
    JCtt
    0
    H uHiO The thiazolidine derivative, used as a starting material, is prepared as follows. Sulfuric acid (98 wt.%, 80 g) is added to acetonitrile (12.3 g) with stirring at a temperature below 50 ° C, the solution is cooled to -H-s and N- (2-OXY) is added in portions over 15 minutes -2-phenylethyl) -ethanolamine (18.1 g) while maintaining the temperature below. The reaction mixture is stirred for 1 hour and then stirred at 25 ° C for 2 hours. The mixture is then poured onto ice (200 g) and the pH of the resulting mixture is adjusted to level 5 with 18N. caustic ngGtra solution, with ice added to maintain the temperature below. The solution is evaporated to dryness at a pressure of 15 mm. Hg The residue is extracted with ethanol T500 ml) and the extract is filtered, and the filtrate is evaporated at 50 ° C to dryness in vacuo. The residue was dissolved in boiling ethanol (100 ml) and the solution was allowed to cool to room temperature. The resulting crystals are filtered, washed with one portion of ethanol (20 ml) and dried at 70 ° C. Get N- (2-acetylamino-2-phenylethyl) -ethanolamine-0-sulfate with so pl. 210-212C. A solution of N- (2-acetyl-Al-2-phenyl ethyl) -ethanolamine-0-sulfate (3.0 g) in water (10 ml) was added to a solution of caustic soda 1.2 g in water (10 ml) at 70 ° C. The solution is heated at reflux for 20 minutes and then cooled and extracted with methylene dichloride (ml). The combined extracts are dried over anhydrous sodium sulphate and evaporated under vacuum to give a white solid. This product is crystallized from ethyl acetate. N- (2-acetylamino-2-phenylethyl) aziardine is obtained with m.p. 114-116s.
    This aziridine derivative (0.51 g) is added to a stirred solution of thiourea (0.228 g) and sulfuric acid (98 wt.%, 0.14 ml) in water (3 ml) at 20 ° C. The solution is kept at room temperature in for 10 minutes and then heated on a steam bath for 4 hours. The solution is cooled and alkalinized (pH 11 with 18N sodium hydroxide solution, extracted with methylene dichloride (2 x 20 ml) and the combined extracts are evaporated to dryness under vacuum. The residue is dissolved in benzene (5 ml) and the product is precipitated by adding diethyl ether (5 ml). Filter cake washed, washed with diethyl ether (5 ml) and allowed to air dry at room temperature, 3- (2-acetylamino-phenyl-2-ethyl) -2-iminothiazolidine is obtained with mp., 136-138CC.
    3- (2-Acetylamino-2-phenylethyl) -2-iminothiazolidine (2 g) is dissolved in 5N. hydrochloric acid (15 ml) and the solution is heated at reflux temperature for 6 h. The solution is evaporated to dryness at a pressure of 15 mm Hg. to obtain a solid crystalline substance which is dissolved in ethanol (20 ml). The solution is heated at reflux for 5 minutes. The solution is cooled to room temperature, the resulting mixture is filtered and the crystalline precipitate is washed with ethanol (20 ml) and dried at. Get dihydrochloride 3- (2-aminophenylamino) -2-iminothiazolidine with so pl. 202-2050С.
    Example 2. 3- (2-Amino-2-phenylethyl) -2-methyliminothiazolidine dihydrochloride (1.54 g) is dissolved in water (10 ml) and the solution is heated at reflux for 22 h, maintaining the pH value solution level 4-1 by periodically adding 2N. caustic solution. Then magnitude. The pH of the solution is set to 11 with 2 n. sodium hydroxide solution, extracted with methylene dichloride (2ii20 ml) and the combined extracts are dried over anhydrous sodium sulphate and evaporated
    dry at a pressure of 15 mmHg The residue is dissolved, as far as ETO is possible, in benzene (20 ml), the mixture is filtered and the pH of the filtrate is adjusted to a level of 2-3 by adding a saturated solution of hydrogen chloride in isopropanol. The white precipitate formed is filtered off, washed with chloroform (10 ml) and dried in air at room temperature. Tetramisole hydrochloride is obtained with m. Pl. 2552580s.
    The thiazolidine derivative used as starting material was prepared as follows.
    Sulfuric acid (98 wt.%, 80 g) is added to the stirred benzyl cyanide (39 g) at a temperature below 5 ° C. The solution is cooled to temperature, and in portions within 15 minutes, M- (2-hydroxy-2-phenylethyl) -ethanolamine (18.1 g) is added while keeping the temperature on the level below O-C. The reaction mixture was stirred at 0 ° C for 1 h and then at 2 h. The mixture was poured into a stirred mixture of ice (200 g) and ethyl acetate (200 ml). The white precipitate formed is filtered off and successively washed with ethyl acetate (200 ml) and water (200 m and then crystallized from water. The N- (2-phenylacetylamino-2-phenylstil) -ethanolamine-0-sulfate is obtained with m.p. 228-229CC.
    M- (2-Phenylacetylamino-2-phenylethyl) -ethanolamine-0-sulfate (7.56 g) was suspended in water (20 ml) and 2N was added to it. sodium hydroxide solution to pH 9. Then a solution of methyl isothiocyanate (2 ml) in ethanol (10 ml) is added dropwise to the stirred solution and stirring is continued for 2 hours at room temperature. The pH of the solution is adjusted to 12 with sodium hydroxide solution, methylenedichloride (2) 1.25 ml is extracted, the combined extracts are dried over anhydrous sodium sulphate and evaporated to dryness at a pressure of 15 mm Hg. The solid residue is dried in air at room temperature to obtain 2-methyl amino-3- (2-phenylacetylamino-2-phenylethyl) -thiazlidine. A sample recrystallized from a mixture of benzene and petroleum ether (b.p., 60 ° C) melts at 144-145 ° C.
    2-Methylimino-3- (2-phenylacetylmino-2-phenylethyl) -thiazolidine (3.53 g) is dissolved in 5N. hydrochloric acid (15 ml) and the solution is heated at the boiling point under reflux for 9 hours. The plant thief is evaporated to dryness under vacuum and the crystalline residue is crystallized from ethanol, washed with ethanol (5 ml) and acetone (10 ml) and 3- (2-Amino-2-phenylethyl) -2-methyliminothiazolide dihydrochloride with m.p. 195-198 C. A similar sequence of reactions is possible with the use of the intermediate product 3- (2-acetyl amnno-2-phenylethyl) -2-methyliminothiaz lidine (crystallized from a mixture of benzene and petroleum ether with so-called kip, 80-100 ° C) t. pl. 130-133 ° C. Example 3. 3- (2-amino-2-phenylethyl) -2-imino-thiazolidine (0.75 g) dihydrochloride (0.75 g) is dissolved in water (4.0 ml) and sodium nitrite (0, 40 g) The solution is stirred until the sodium nitrite is dissolved, and then 5N hydrochloric acid (0.20 ml) is added. Then samples (about 5 µl) of the resulting solution are applied to chromatography plates | On a thin layer made of Merck GF 254 silica gel. The plates are eluted with a solvent consisting of toluene (50 parts by volume), acetone (50 hours by volume). volume) and ammonium hydroxide (sp. weight 0,880, 1.5 h. n volume). The reaction products are identified by comparison with notorious samples using Rf values and characteristic colors, which are developed when the plates are sprayed with a mixture consisting of equal parts of a 0.3% (w / v) aqueous solution of hydrochloric acid and 6% (w / volume) of an aqueous solution of potassium iodide. The reaction products were found to be tet ramizole, 2-imino-3-styrylthiazolidine and 2-imino-3- (2-hydroxy-2-phenylethyl) - -thiazolidine, present in an approximately 1: 1: 2 ratio. Example 4. 3- (2-Amino-2-phenylethyl) -2-methylimine thiazolidine dihydrobromide (0.50 g) is dissolved in water (5 ml) and the solution is heated at reflux temperature for 18 hours. The solution is evaporated dry under a pressure of 15 mm Hg. Isopropanol (20 ml) was added to the residue and the mixture was heated at boiling point with reflux for 5 minutes, after which the mixture was allowed to cool to room temperature. The resulting mixture was filtered and the solid residue was washed with acetone (5 ml) and dried to obtain tetramisole hydrobromide, melting at 238-24 (with decomposition). The thiazolidine derivative used as a starting material can be prepared as follows. 2-Methylimino-3- (2-phenylacetylamino-2-phenylethyl) -thiazolidine (3.0 g) is suspended in a mixture of water (7.5 ml) and aqueous hydrobromic acid (48%, 7.5 ml) and the mixture is heated at the boiling point under reflux for 10 hours. The resulting solution is evaporated to dryness under a pressure of 15 mm Hg. and the crude product is crystallized from isopropanol. 3- (2-Amino-2-phenylethyl) -2-methylimino-thiazolidine dihydrobromide is obtained with m.p. 236-238c. Example 5. 3- (2-Amino-2-phenylethyl) -2-ethyliminothiazolidine dihydrochloride (0.50 g) is dissolved in a mixture of ethanol (5 ml) and water (5 ml) and the solution is heated at the boiling point within 44 hours. After that, the solution is evaporated to dryness under a pressure of 15 mm Hg. and the residue is crystallized from isopropanol (5 ml). The tetramisole hydrochloride obtained is filtered off, successively washed with isopropanol (2 ml) and diethyl sfir (10 ml) and dried, the resulting product is melted at 256-258 ° C. The thiazolidine derivative used as starting material can be obtained as follows. N - (2-Phenylacetylamino-2-phenylethyl) -ethanolamine-0-sulfate (18.9 g) is dissolved in 2N. sodium hydroxide solution (25 ml) and water (25 ml). Zthanol (25 ml) and ethyl isothiocyanate (4.35 g) are added. After that, the pH of the solution is maintained at 9 + 0.5 by adding 2 n. sodium hydroxide solution, which is added until the total amount added is 25 ml. Water (25 ml) is then added and the mixture is filtered. The solid residue is successively washed with water (50 ml) and petroleum ether (b.p. 60-80 s, 60 ml) and dried at 500 s. 2-ethyl imino-3- (2-phenylacetylamino-2-phenylethyl) -thiazolidine is obtained. A sample crystallized from petroleum ether (b.p., 100-120 ° C) melts at 142-144s. 2-ethylamino-3- (2-phenylac-tilamyl-. But-2-phenylethyl) -thiazolidine (10.2 g) and 5 n. hydrochloric acid (40 ml) is heated at the boiling point under reflux for 10 hours and the resulting solution is evaporated to dryness under a pressure of 15 mm Hg. The residue is crystallized from isopropanol (50 ml). 2-ethylimino-3- (2-amino-2-phenyl ethyl) -thiazolvine dihydrochloride is obtained, m.p. 188-191 ° C. An example. 3- (2-Amino-2-phenylethyl) -2-isopropylimine thiazolyline (0.5 g) is placed in a small test tube and the tube is placed in an oil bath at 245 ° C and maintained at this temperature for 5 minutes. After that, a sample is taken, cooled to room temperature.
    The temperature is triturated with a kilogram of zopropanol (3 ml) and allowed to drain. The mixture is filtered, the solid residue is sequentially washed with eopropanol (1 ml) and acetone (2 ml). Get tetraizol hydrochloride with so pl. 25.5-258 ° C.
    The thiazolidine derivative used as a starting material is prepared in the usual manner from the corresponding dihydrochloride as follows.
    3 (2-Phenylacetylamino-2-phenylethyl) -2-isopropyliminothiazolidine (7.0 g) with m.p. 112-114 ° C, after the crystallization from petroleum ether (m.p. 100-12000), similar to that described in example 5, is dissolved in 5 n. hydrochloric acid (30 ml) and the solution is heated at reflux for 10 hours. The solution is evaporated to dryness under a pressure of 15 mm Hg, and the residue is crystallized from ethanol (20 ml), washed with ethanol (5 ml) and dried at. 3- (2-amino-2-phenylethyl) -2-isopropyl-amino-thiazolidine with m.p. 206-211s (with decomposition).
    Example 7 The 2-isobutylimino-3- (2-amino-2-phenylethyl) -thiazolidine dihydrochloride (0.5 g) is dissolved in dimethylformamide (2 ml) and the solution is heated at 40 hours. After the reaction mixture is allowed to cool, the resulting mixture filtered and the crystalline solid residue is successively washed with isopropanol (2 ml) and diethyl ether (5 ml) and dried at 50CC. Get tetramisole hydrochloride with so pl. 257-259 0.
    The thiazolidine derivative used as starting material is obtained as follows.
    2-Isobutylimino-3- (2-phenylacetylamino-2) -phenylethylthiazolidine (7.6 g) with m. Pl. 153-154 ° C (similar to the use of vhemus when preparing the ethyl homolog, example 5) after crystallization from petroleum ether (m.p. 100-120 0) is dissolved in 5 n. hydrochloric acid (30 ml) and the solution is heated at reflux for 9 hours. After that, the solution is cooled to and washed with chloroform (30 ml). The aqueous solution is evaporated to dryness under a pressure of 15 mm Hg. The residue is crystallized from isopropanol (15 ml), and then about MH BcuoT with isopropanol (5 ml) and dried, to give 2-isobutyl-amino-3- (2-amino-2-phenylethyl) -thiazolidine dihydrochloride, m.p. 188-190 C.
    Example 8. 2-yzsamilimino-3- (2-amino-2-phenylethyl) -thiazoliline dihydrochloride (0.20 g) was dissolved in water (5 ml) and the solution was heated at reflux temperature for 24 hours. After evaporation dry under a pressure of 15 mm Hg. the residue is crystallized from isopropanol (1 ml) and liethyl ether (5 ml) and dried with BO-O. Get tetramisole hydrochloride with so pl. 256-259 s.
    The thiazolidine derivative, used as a starting material, is obtained by a method similar to that used when preparing an ethyl homologue (see example. The melting point of this derivative after crystallization from petroleum ether (bp. 100-1200) is 135-137 °.
    2-Isoamylimino-3- (2-phenylacetylamino-2-phenylethyl) -thiazolidine (2.2 g) is dissolved in 5N. hydrochloric acid (10 ml) and the solution is heated at reflux temperature for 10 hours. The solution is evaporated to dryness under a pressure of 15 mm Hg. and the residue is crystallized from isopropanol (10 ml), washed with isopropanol (2 ml) and cyiaaT at. In this case, 2-isoamylimino-3- (2-amine O-2-phenylethyl) -thiazolidine dihydrochloride is obtained with m. Pl. 192-198 0 (with decomposition).
    Example 9. 2- (3-Pentylamino-) -3- (2-amino-2-phenylethyl) -thiazolidine (0.4 g) is dissolved in water (5 ml) by adding 7.0% w / w perchloric acid until the pH value is set to level 4. After that, the solution is heated at reflux temperature for 100 h, cooled to room temperature, alkalinized to pH 12 with 18N. sodium hydroxide solution, extracted with methylene chloride (20 ml) and the extract evaporated to dryness under a pressure of 15 mm Hg. The residue was dissolved in isopropanol (5 ml) and the solution was acidified to pH 2 with gaseous hydrogen chloride. The mixture is filtered, the solid residue is washed successively with isopropanol (2 ml) and diethyl ether (5 ml) and dried at 50 ° C to obtain tetramisole hydrochloride, mp 257-25900.
    The thiazolidine derivative used as a starting material is prepared as follows.
    N- (2-Phenylacetylamino-2-phenylethyl) -thanolamine-0-sulfate (6.43 g) is dissolved in 1N. a solution of sodium hydroxide (17 ml) and a solution of 3-pentyl isothiocyanate (2.2 g) in ethanol (15 ml) is added. After that, 1 n is added. a solution of sodium hydroxide (17 ml) and the solution is stirred for 18 hours at 25 °, then heated at reflux for 2 hours. After cooling to room temperature, the reaction mixture is extracted with methylene chloride (50 ml) and the organic extract is evaporated dry under a pressure of 15 mm Hg. Art. The residue was dissolved in acetonitrile (15 ml) and gaseous hydrogen chloride was passed through the solution until the pH was reduced to 2-3. After that, the product is precipitated from the solution by adding dimethyl ether (15 ml), filtered off, washed with diethyl ether (20 ml) and dried at. A sample, crystallized from ethyl acetate, melts at 145148 ° C. This hydrochloride (2.5 g) was dissolved in 5N. hydrochloric acid (10 ml) and the solution is heated at reflux for 10 hours and evaporated to dryness under a pressure of 15 mm Hg. The residue is crystallized from isopropanol (10 ml), successively washed with isopropanol (2 ml) and diethyl ether (5 ml) and dried at 500 s. At. This gives 2- (3-petylimino) -3- (2-amino-2-phenylethyl) -thiazolidide dihydrochloride with m.p. 197-201 C (with decomposition). This hydrochloride (0.5 g) is dissolved in water. (5 ml) and an aqueous solution of ammonia (specific weight 0.880) is added until the pH is at a level of 9. The precipitated oil is extracted with methylene chloride (20 ml and the extract is dried over anhydrous magnesium sulphate and evaporated to dryness under a pressure of 15 mm Hg. 2- (3-pentylimino) -3- (2-amino-2-phenylethyl) -thiazolidine is obtained as a colorless oil. The absorption spectrum of this oil in the infrared region shows strong absorption bands at a wavelength of 3390, 3000, 2960, 2900, 1640, 1453, 1295, 1245, and 710 cm. Example lOv Dihydrochloride. 2- llimo-3- (2-amino-2-phenylethyl) -thiazolidine (0.5 g) is dissolved in water (5 ml) and the solution is heated at reflux temperature for 30 h. The solution is evaporated to dryness under a pressure of 15 mm Hg and the residue is crystallized from isopropanol (5 ml) and washed successively with isopropanol (1 ml) and diethyl ether (5 ml). Tetramisole hydrochloride is obtained with a melting point of 256-2590 G. Derived thiazolidine, used as a starting material material is prepared according to a method similar to that used in the preparation of the ethyl homolog (see ep 5). A sample crystallized from a mixture (1: 1 by volume) of toluene and petroleum ether (m.p. 100-120 s), melted at 138-140 ° C. 2-ALLYLIMINO-2- (iJ-phenylacetylamino-2-phenylethyl) - thiazolidine (10 g) is dissolved in 5 n. hydrochloric acid (40 ml) and the solution is heated at reflux for 9 hours. The solution is cooled to and washed with chloroform (50 ml). The aqueous phase is evaporated to dryness under a pressure of 15 mm Hg. The 2-allyl-amino-3-dihydrochloride is obtained. - (2-amino-2-phenylethyl) -thiazolidine. A sample crystallized from a mixture (1: 1, v / v) of isopropanol and tetrahydrofuran, melts at 168175 ° C (with decomposition). Example 11. 2-Ethylamino-3- (2-amino-2-phenylethyl) -thiazolidine (0.65 g) is dissolved in water (10 ml) by adding p-toluenesulfonic acid monohydrate to adjust the pH to 4. The resulting solution is heated at reflux temperature for 24 hours and then evaporated to dryness under a pressure of 15 mm Hg. The residue is crystallized from isopropanol (5 ml) and the crystals are successively washed with isopropanol (2 ml) and diethyl ether (5 ml) and dried at 50 ° C. Get tetramisole p-toluensulfonate with m.p. 159-160 ° C. Example 12. Sulfuric acid (68 ml) is added dropwise with vigorous stirring and cooling to acetonitrile (29 ml) while maintaining the temperature below 15 s. After all the acid has been added to the mixture in small portions, while maintaining the temperature below 20 ° C, N- (2-hydroxy-2-phenylethyl) ethanolamine (45.25 g) is added with continuous stirring. The reaction mixture was stirred at 20-25 ° C for 4 hours and then poured into a mixture of water (450 ml) and toluene (50 ml). After the azeotropic mixture of toluene, acetonitrile and water is distilled from the solution until the vapor temperature reaches 100 ° C. The distillation is stopped and the solution is heated at the boiling point under reflux for 5 hours. Then above the solution, cooled to a temperature below BOOC, with the addition of 18N. sodium hydroxide solution to pH 12, nitrogen is passed. The temperature is then set at 350 ° C and methylene chloride (150 ml) is added. The organic phase is separated, and the aqueous solution is extracted with three portions of chlorine and methylene while maintaining the solution temperature at 35 ° C under nitrogen. The combined extracts in methylene chloride are then azeotroped to a dry residue to distill off the total volume of methylene chloride in 150 ml.
    The solution obtained in this way is (2-a114 inino-2-phenylethyl) -ethanol-pa is half neutralized by gaseous hydrogen chloride and added to a stirring mixture of thionyl chloride (20 ml) and methylene chloride (50 ml) for 30 minutes 30 0. The reaction mixture is stirred at 20-25 0 for 16 hours. M- (2-amino-2 phenylethyl) -2-chloroethylamine is present in it. A solution of thiourea (15.2 g) in water (300 ml) is added. . Methylene chloride is separated and discarded, and the solution is heated at reflux temperature under nitrogen atmosphere for 17 hours. In order to complete the cyclization of the 2-IMINO-3- (2-amino-2-phenylethyl) -taaolidine semiproduct to tetramisole, the pH of the solution is set to a level of 3.5-4.0 by adding 18 n. sodium hydroxide solution and the solution is heated at reflux for a further 5 hours under nitrogen. After that, the pH of the solution is adjusted to 11-12 by adding 18N. sodium hydroxide solution and the solution is extracted with toluene (100 ml, then 50 ml). The combined extracts were dried over anhydrous sodium sulphate, activated carbon (2.5g) was added and the mixture was filtered, and the solid residue was washed with toluene. (25 Mji). Isopropanol (35 ml) is added to the washed filtrate to the washings and hydrogen chloride is passed through the solution until the pH is set to 2-3. The mixture is allowed to cool to room temperature and the resulting mixture is filtered. The solid residue is washed with isopropanol (25 ml) and dried to obtain tetramisole hydrochloride. The sample, crystallized from ethanol, melts at 2582 ° C.
    Example 13. N- (2-amino-2-phenylethyl) -2-chloroethylamine dihydrochloride (2.715 g) is dissolved in water (15 ml) and potassium thiocyanate (0.97 g) is added. After that, the solution is heated at for 16 h, then cooled to room temperature, alkalinized using 18 n. 1N sodium hydroxide solution to pH 11 and extracted with methylene chloride (2 x 2 o ml).
    The combined extracts are dried with anhydrous sodium sulfate and filtered to the filtrate until the pH is at. level 2, added, 3 n, a solution of hydrogen chloride in isopropanol,
    After that, the solution is kept until the crystallization is complete, the crystals are filtered off, successively washed with isopropanol (5) and acetone (10), and dried to obtain technical tetramisole hydrochloride. A sample crystallized from ethanol is melted at 2582600 ° C.
    The amino derivative used as starting material is obtained by the following method.
    The technical N- (2-amino-2-phenylethyl) ethanolamine, prepared according to the method described in Example 12 and isolated by evaporation of the extract in methylene chloride to dryness at a pressure of 15 Hg, and containing 88.7 g of the compound is dissolved in dichloroethane (450 ml).
    The solution is saturated with gaseous hydrogen chloride with vigorous stirring and, dropwise, at 50 ° C, for half an hour, thionyl chloride (58.6 ml) is added. The temperature is then raised to 2 hours and isopropanol (60 ml) is added dropwise. The reaction mixture is allowed to cool before and the mixture is filtered. The crystalline residue is successively washed with dichloroethane (50 ml) and acetone (50 ml) and dried at 70 ° C to obtain N- (2-amino-2-feiylethyl) -2-chloro-ethylamine dihydrochloride. A sample crystallized from a mixture (1: 1, v / v) of methanol with ethanol melted at 194–19 ° C (a volatile capillary).
    Example 14. 2-Phenylimino-3- (2-amino-2-phenylethyl-thiazolidine dihydrochloride (0.5 g) is dissolved in water (5 ml) and the solution is heated at reflux temperature for 48 h. The reaction mixture cooled to 25 ° C, basified with 2N sodium hydroxide solution to pH 11 and extracted with methylene chloride (5 ml). The organic extract was evaporated to dryness under a pressure of 15 mm Hg, the residue was dissolved in isopropanol (5 ml) and added 3 n. a solution of hydrogen chloride in isopropanol until the pH is at a level of 2. A precipitated product of filtered, washed with acetone (5 ml) and dried at 50 ° C. Tetramysole hydrochloride is obtained, melting at 257-259 ° C.
    The thiao-olydine derivative used as an original product is prepared as follows.
    N- (2-amino-2-phenylethyl) -2-chloroethylamine dihydrochloride (5.43 g) was dissolved in water (10 ml) and ethanol (20 ml) and a solution of phenyl eothiocyanate (2.7 g) in ethanol ( 10 ml). The pH of the solution is adjusted to 5.5 by adding 2 n. sodium hydroxide solution and maintained at the azan level for 2 hours. The solution
    acidified to pH 1 with concentrated hydrochloric acid and evaporated to dryness under a pressure of 15 mm Hg. The residue is extracted with ethanol (100 ml) under heating at the boiling point under reflux, the mixture is filtered and. the filtrate is evaporated to dryness under a pressure of 15 mm Hg. Art. The residue was dissolved in isopropanol (5 ml) and the solution was diluted with tetrahydrofuran (500 ml) and held for 5 days. The crystals that separated were filtered out, washed with diethyl ether (10 ml) and dried at room temperature. 2-Phenyl-imino-3-2- (2-amino-2-phenylethyl) -thiazolidine dihydrochloride is obtained, m.p. 183-18 bs
    Example 15. N- (2-amino-2-phenylethyl) -2-bromomethylamine di-p-toluenesulfonate (5.87 g), thiourea (1.4 g), p-toluenesulfonic acid (0.57 g) and water (15 ml) is heated at reflux for 18 hours. A solution of sodium hydroxide solution (1.85 ml) is then added and the solution is heated at reflux for a further 6 hours. Then 2N is added. the sodium hydroxide solution until the pH is at a level of 12; and the mixture is held until the crystallization is complete. The crystals are filtered, washed with water (20 ml) and dried at room temperature to obtain tetramisole. A sample crystallized from cyclohexane melts at 92-93c.
    The original product is obtained as follows.
    Technical N- (2-amino-2-phenyl ethyl) -ethanolamine obtained by the method described in Example 12 and isolated by evaporation of the dried extracts in methylene chloride to dryness under a pressure of 15 mm Hg, containing 37.0 g the compounds were dissolved in dichloroethane (200 ml) and 48% w / w hydrobromic acid (25.5 ml) was added. The solution was subjected to azeotropic distillation until water was completely removed, and the residue was added dropwise over 1 hour to a mixture of dichloroethane (50 ml) and phosphorus tribromide (28.6 ml) at. Thereafter, the reaction mixture was stirred for 16 hours, isopropanol (400 ml) was added and the solution was decanted to separate from the insoluble resin, p-toluenesulfonic acid (76.0 g) was added to the solution, and then, after stirring for 2 hours, filter the product di-p-toluensulfonate (N- (2-amino-2-phenylethyl) -2-bromoethylamine), which is consistently nicknamed with isopropanol (50 ml) and diethyl
    ether (100 ml) and dried at room temperature. The resulting product has so pl. 190-192 0.
    Example 16. 2-imino-3- (2-benzoylamino-2-phenylethyl) -thiazolidine hydrochloride (1.0 g), suspended in 2N. sulfuric acid (50 ml) and the mixture 1 § is heated at the boiling point under reflux for 6 days .. After that, the mixture is cooled to room temperature,
    o Supplement to pH 12 with 18 n. sodium hydroxide solution, extracted with toluene (25 ml) and 3N hydrochloric acid is added to the toluene extract. hydrogen chloride solution in
    5 with isopropanol until the pH is set to level 2. The precipitated product is filtered off, washed with toluene (10 ml), dried at, dissolved in water (5 ml) and basified to pH 12 with 18N. sodium hydroxide solution. The dried tetramisole is filtered off, washed with water (10 ml) and dried at, after which its melting point is 92-93 ° C.
    5 The original product is obtained as follows.
    N- (2-Benzoylamino-2-phenylethyl) -ethanolamine-0-sulfate (35.0 g) was added to a mixture of a solution of sodium hydroxide hydrate (11.2 g) in water (200 ml) and toluene (200 ml) and the mixture is stirred at reflux temperature for 2 hours. After cooling to room temperature, the mixture is divided into phases, the aqueous phase is extracted with toluene (200 ml) and the combined organic phase, and the organic extract is dissolved over anhydrous magnesium sulphate and evaporated dry under a pressure of 15 mmHg A crude N- (2-benzoylamino-2-phenylethyl) -azyridine is obtained.
    This aziridine derivative (11.4 g) was dissolved in toluene (200 ml) and a solution of potassium thiocyanate (4.75 g) and concentrated hydrochloric acid (15 ml) in water (185 ml) was added. The mixture is stirred and heated at reflux for 4 hours and then cooled to room temperature. The mixture is filtered and the solid residue is successively washed with water (10 ml) and toluene (10 ml) and then
    5 dried at.
    The solid product is suspended in a mixture of 2 n. sodium hydroxide solution (120 ml) and toluene (120 ml) and the resulting mixture is stirred
    When heated at the boiling point under reflux for 30 minutes, cooled to room temperature and the phases are separated. The aqueous phase is extracted with toluene (100 ml)
    5 and the combined organic.
    and the extract is dried over anhydrous magnesium sulphate and evaporated to dryness under a pressure of 15 mm Hg. The residue was dissolved in toluene (25 ml) and 3N was added to the solution. solution of hydrogen chloride in isopropanol to pH 2. The precipitate is filtered off, -. washed with toluene (ml) and dried at. 2-imino-3- (2-benzoylamino-2-phenylethyl) -thiazolidine hydrochloride is obtained, melting at 2572600 s.
    Example 17 2-benzylimino-3- (2-amino-2-phenylethyl-thiazolidine dihydrochloride (1.0 g) was dissolved in water (10 ml) and the solution was heated at reflux temperature for 24 hours.) cooled to SJC, alkalinized using 18 n. The sodium hydroxide solution to pH 12 and the precipitated tetramieol are filtered, washed with water (20 ml) and dried at room temperature. The product melts at 92-93 ° C after recrystallization from cyclohexane,
    ; The thiazolidine derivative, used as the starting product, is prepared according to a method similar to that described for the methyl derivative in Example 2.
    2-Benzylamino-3- (2-acetylamino-2-feiylethyl) -thiazolidine (5.7 g) solution of 1N in 5N hydrochloric acid (25 g) and the solution is heated at reflux temperature for 16 The solution is cooled to 20 ° C, filtered to remove insoluble material, and the filtrate is evaporated to dryness under a pressure of 15 mm Hg. The resulting resin was dissolved in isopropanol (30 ml), toluene (20 ml) was added and the solution was evaporated with a pressure of 15 mm Hg. The residue was dissolved in isopropanol (15 ml) while heating under a teglperar. The mixture was heated under reflux and the solution was allowed to cool. . The resulting mixture is filtered and the solid residue, 2-benzylimino-3- (2-amino-2-phenylethyl) -thiazolidine DIHYDROCHLORID, is successively washed with isopropanol (5 ml) and diethyl ether (10 ml) and dried at room temperature, after which the product is melted pr-and 190-194 ° C (with decomposition).
    Example 18. 2-Amino-3- (2-amino-2- (3-aminophenyl) ethylthiazolidine trihydrochloride (0.13 g) was dissolved in water (5 ml) and the solution was heated at reflux temperature for 17 The solution is cooled to room temperature, alkalized with 18N sodium hydroxide solution to pH 12 and extracted with methylene dichloride (2 "10 ml). The combined extracts are dried over anhydrous magnesium sulphate and evaporated
    under pressure of 15 mm Hg The residue was dissolved in methanol (2 ml) and the solution was acidified to pH 1 with 3N. solution of hydrogen chloride in isopropanol. The resulting mixture is evaporated to dryness under a pressure of 15 mm Hg. and the residue is taken up in a solid state by trituration with acetonitrile (3 ml), the product is filtered, sieved with acetonitrile (1 ml) and dried at room temperature.
    The product, a 6-3-aminophenyl (-2,3,5,6-tetrahydroimidazo (2,1-b) -thiaole) dihydrochloride, is characterized by its mass spectrum, which indicates the presence of a molecular ion with a mass number of 219.0833 (which is corresponds to a molecular formula of -11, fragment ions with an approximate mass number of 219
    0 (which corresponds to C ,, H,), 191 (C n-NjS) or (H ,, NjS),
    163
    (,) 127 (102 () and 45 (CHS).
    A thiazolidine derivative used as a starting material is prepared as follows.
    .2-Imino-3- (2-acetoamido-2- (3-acetamidophenyl) ethylthiazolidine) is dissolved in 5N hydrochloric acid (20 ml) and the solution is heated at reflux temperature for 10 hours and then evaporated to dryness under a pressure of 15 mm Hg. The residue is dissolved in warm ethanol (10 ml) and the solution is allowed to cool to room temperature. The resulting mixture is filtered, the crystalline residue is washed with ethanol (2 ml) and dried at room temperature. -imino-3- (2-amino-2- (3-aminophenyl) ethylthiazolidine, melted at 211-215 s (c back to top).
    The α-acetamido derivative used as starting material is obtained as follows.
    权利要求:
    Claims (4)
    [1]
    2-Imino-3- (2-OXY-2- (3-acetamidophenyl) ethylthiazolidine (2.37 g) is dissolved in acetonitrile (2.8 g) and dropwise with stirring and maintaining the temperature at : e 20 ° C, sulfuric acid (10.2 g) was added at 98% (w / w). The resulting solution was stirred at room temperature for 4 hours, then poured onto ice and basified to pH 12 with an 18 n solution. sodium oxide hydrate maintaining the temperature below by adding ice. The solution is extracted with methylene chloride (2 x 25 ml) and the combined extracts are dried over anhydrous sulfate m of magnesium and evaporated to dryness under a pressure of 15 mm Hg to obtain technical 2-imino-3- (2-acetamido-2- (3-acetam-dophenyl) ethylthiaeolidine, Claim 1. The method of obtaining imidae derivatives (2, 1-c) thiazole of the general formula IHHR I-i- where R is phenyl, nitrophenyl, aminophenyl or tolyl, as well as their acid addition salts, differing from the fact that the compound of the general formula B- <RTI ID = 0.0> </ RTI> where M is as defined, R2 is hydrogen, alkyl, alkenyl, arylalkyl, or aryl, or its acid addition salt is cyclized.
    [2]
    2. A method according to claim 1, characterized in that the reaction is carried out in a medium of water, elevated temperature and pH K (less than 8.
    [3]
    3. The method according to claim 1, wherein it is so that, if in the starting product R is hydrogen, the reaction is carried out in a medium of water in the presence of nitrous acid, preferably at room temperature,
    [4]
    4. The method according to claim 1, wherein the starting product is used as an acid addition salt and the reaction is carried out at a temperature of 200-300 ° C, preferably in the presence of an inert diluent, or at a temperature of 100-150 ° C in a dipolar aprotic solvent .
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    同族专利:
    公开号 | 公开日
    DD103645A5|1974-02-05|
    BE786416A|1973-01-18|
    GB1351031A|1974-04-24|
    AU4462272A|1974-01-24|
    ZA724731B|1973-04-25|
    FR2147214A1|1973-03-09|
    YU194572A|1980-04-30|
    HU164067B|1973-12-28|
    AU462760B2|1975-07-03|
    US3845070A|1974-10-29|
    YU35261B|1980-10-31|
    JPS5229317B1|1977-08-01|
    DE2236970A1|1973-02-08|
    FR2147214B1|1979-01-12|
    AR198178A1|1974-06-07|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4179460A|1977-07-06|1979-12-18|Dso "Pharmachim"|Derivatives of R,S-[X2--1-phenyl]-ethylamine, and process|
    CA1135270A|1978-11-06|1982-11-09|American Cyanamid Company|Processes for the preparation oftetramisole and novel intermediates|
    US4370500A|1978-11-06|1983-01-25|American Cyanamid Company|Compound: d-N--2-methoxyethylamine and process for preparing the same by selective crystallization|
    EP0010851B1|1978-11-06|1982-08-04|American Cyanamid Company|Process for the preparation of tetramisole|
    US4339603A|1979-01-08|1982-07-13|American Cyanamid Company|Process for converting optically active l-N--2-methoxyethylamine to the corresponding dl-derivative|
    JPS5775113U|1980-10-28|1982-05-10|
    JPS57120713U|1981-01-20|1982-07-27|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    GB3520671|1971-07-27|
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