• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    An R,S-[2-(2-hydroxyethylamino)-1-phenyl]-ethylamine of the formula III <IMAGE> (III) wherein R represents hydrogen, allyl, propargyl or benzyl. These compounds provide valuable intermediates for the synthesis of Tetramisole.
    公开号:SU922109A1
    申请号:SU787770241
    申请日:1978-07-05
    公开日:1982-04-23
    发明作者:Георгиев Георгиев Атанас；Петров Даскалов Христо；Георгиев Михайлов Венцел；Веселинова Константинова Кина
    申请人:Дсо Фармахим София (Инопредприятие)；
    IPC主号:
    专利说明:

    Union of Soviet Socialist Republics
    | Mudaretkmy COMMITTEE OF THE USSR
    DESCRIPTION OF THE INVENTIONS TO COPYRIGHT CERTIFICATE (tn 922109 (89) 24864 (NRB) (72) Authors of the invention (71) Applicant (61) Additional to the author certificate - (22) Declared 0507.78 (21) 7770241 / 23-04 (23) Priority - (32) Rev. 07.77 (31) 37908 (33) URB
    Published on April 23 ,.82 £ Bulletin No. 15
    Date of publication of the description 23.0432 (51) M. Cl
    S 07 0 513/0 * (53) UDC 5 47, 7 89, .1 (088.8)
    Foreigners
    Atanas Georgiev Georgiev. Hristo PetrovDaskalov, Wenzel Georgiev Mikhailov and Kina Yarsrpinoda Konstantinova (NRB) I aa’’I
    Foreign enterprise f ' M DSO Farmahim Sofia j 4¾. 4 ^ .1. - (NRB) jjg (54) METHOD FOR PRODUCING, 5-2,3,5,6-TETRAHYDRO-6-PENYLIMIDAZO12,1-B1TIIA30LA. 2
    A number of methods for the synthesis of tetramisole are known. where the formation of the tetrahydroimidazothiazole system is most often done by creating a bond between the carbon atom in position 6 and the nitrogen atom in position 7 (formula I), i.e. educated bond C (6). This is done pos: redstvom elimination XY in SRI connected with the general formula. ' v
    The invention relates to a method for producing R, S-2,3., 5,6-tetrahydro-6-phenylimidazole ~ 2.1-b) thiazole (tetramisole) having the formula
    as well as its pharmacologically tolerated salts with inorganic and organic acids.
    Tetramisole is known to have pharmacological properties, which is why it is used as a powerful broad-spectrum anthelmintic. , 15 Recently, it has increased significantly. interest in him in connection with the discovery of the immunoregulatory properties of the drug, and its use in the treatment of neoplasmic diseases.
    The antidepressant and antinergic effects of R.S-2,3,5.6-tetrahydro-6-phenylimidazo [2,1-bl thiazole and its pharmacologically active salts are described.
    adk X ΎΝ CH
    where X is OH,
    - C1, Vg,
    - NHS0 2 SASCH g -P,
    - NH Z. -NHC0R;
    Y is hydrogen, but it can be either an RCO or an alkyl radical. The synthesis method of the starting compounds with the general formula (II) is five-step syntheses for which reagents such as styrene and styrene oxide are used. phenacyl bromide. ethanolamine. Asian 20>. 922109 ridin. sodium borohydride, inorganic acid chlorides, thiocarbamide, derivatives of thiocyanic acid and dr. These methods do not have the advantage of being considered, since their more multi-stage scheme for obtaining the final product includes some compounds. which are hard to reach. Bearing in mind the above complications and the fact that the opening of the aziridine ring in a compound of the formula
    occurs not only by breaking the N (7) - C (5) bond (formula III), but also by the Y (7) - C (6) bond (formula 111).
    A synthesis method is known in which the tetrahydro-6-phenylimidazothiazole system is created by the simultaneous formation of N (4) -C (5) and C (6) -N (7) bonds (formula I) in the reaction of 1-phenyl-1.2-dibromoethane and 2-aminothiazoline-2.
    The disadvantage of this method is the impossibility of the formation of the 5 ~ Phenyl derivative of the considered double ring heterocyclic system and the low yield of the target product.
    There is also a known method of constructing a • tetrahydroimidazothiazole ring · system by means of an add-on of the · originally created imidazole ring system. The second heterocycle-thiazolidine part of the molecule is obtained by simultaneously creating the bonds S (-1) -0 (2) and C (3) N (4) (formula 1).
    The disadvantages of this synthetic scheme are as follows: the difficult accessibility of the initial key product 4-phenylimide - ^ 5 zolidin-2-thione - expensive and dangerous when working, lithium amide is a condensing agent, low yield of the final product * especially when using sodium carbonate under the guise of a condensing ^ agent.
    The creation of a tetrahydroimidazo * thiazole system via cyclization of C (3) -N (4) (formula I) is described.
    To the synthetic method of construction), the tetrahydroimidazothiazole system is method f where the heterocycle is obtained by creating a bond
    I 4 (1) - C (2) (formula I). The sole purpose of this method is to use R, S - (+) - 2,3,5,6-tetrahydro-6-phenylimidazo (2.1-b] thiazole-foreign product with separation of the racemic mixture of tetramisole.
    This is accomplished by converting the physiologically inactive RS - (+) - 2,3,5,6-tetrahydro-6-phenylimidazo [2.1-b] thiazole into racemic RS-1- (2-hydroxyethyl-4-phenylimidazolidin-2-thion ( CN) by means of a multistage complex and technologically sophisticated scheme under the influence of thionyl chloride R t S-1- (2-hydroxy, roxyethyl) -4-phenylimidazolidin-2-thoh (VII) cyclize again to the racemic mixture of tetramisole. The yield in this process is 40% theoretical
    The key intermediate in the preparation of RS-2,3,5,6-tetpahydro-b-phenylimidazoE. 1-th thiazole (I) is the compound RS-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thion (UP ) The method is almost not applicable in a production environment due to these reasons.
    However, it is impossible to obtain compound K, 5-1- (2-hydroxyethyl) -3-phenylimidazolidin-2-thione (UP) without preliminary preparation of tetramisole according to any of the known schemes, a method for producing physiologically inactive stereoisomer R.S - (+) -
    2.3.5.6-tetrahydro-6-phenylimidazo £ 2,1-L1thiazole does not give any rational solution to the problem of creating a tetrahydroimidazothiazole structure.
    The aim of the invention is to create. the new method of obtaining R.S-2,3,
    5.6- tetrahydro-6-phenylimidazo [2.1-L1thiazole (tetramisole), which would be technologically easily feasible convenient for use in an industrial environment and at the same time be based on the use of more accessible starting materials (raw materials), primarily R, S- oL- (2 - hydroxyethylamine * tyl) benzylamine (IV) the name from compound IV is given according to nomenclature rules, the same compound can also be called RS-2- (2-hydroxyethylamino | | - 1-phenyl -ethylamine), which is obtained from the main products of organic synthesis.
    "·. 922109
    The method for producing R, S-2,3,5,6-TeTrahydro-6-phenylimidazo [2,1-b] thiazole is carried out by reacting R, S-aL- (hydroxyethylaminomethyl) benzylamines ^. 'having the formula (IV),' with carbon 4 carbon in an aqueous or aqueous-organic medium) In this reaction, the compound RS-N- (2) 2-hydroxyethylamino (-1-phenylethyl amide dithiofar acid, 'having 10 formula
    which, for its part, turns into R3 - 1 (2-hydroxyethyl) -4-phenyl-imidazolidin-2-thion having the formula
    I - CH 2 CH 2 _ ~ 9H (one of the following ways:
    a) by thermal cyclization of compound (Va) by melting or in an inert solvent medium,.
    b) by chemically induced cyclization of compound (Va) with reagents having the general formula
    R, where R is the lower alkyl) residue, and X is the acid residue. Such reagents may be methyl iodide, dimethyl sulfate, diethyl sulfate, butilbroyid, alkyl esters, R. trluolsulfonovoy, methyl tansulfonovoy 35 and fluorosulfonic acid *
    c) by conversion of the compound. (Va) eR, SN-r2- (rMflpoxyethylamino) -1-phenyl) amide-S-alkyl- 40 di-angioic acid esters having the formula 6 n 5 - Cu - ch 2 -ch 2 -nh-CR 2 CH 2 -one
    S-R in which R 'represents an allyl, benzyl or dynamyl residue and then melts compound 50 (V6) to compound (VII).
    In this way, according to option (C), the compound (VII) is synthesized from compound (IV) according to the following scheme
    R’Bf / vi /.
    --- C6a 5 ^ -CH2-NH-ai2-CT2 ~ OH ϊΠη I
    Under the guise of alkylating agents R X having the formula (VI), it is best to use alyl bromide, benzyl bromide ^ propargyl bromide and cyamyl bromide. Preferably, the above reactions are carried out in an aqueous, aqueous alcoholic or alcoholic medium.
    By cyclodehydration of the compound (VII) thus obtained with various acidic agents, such as polyphosphoric acid or its esters, phosphorus pentoxide, concentrated sulfuric acid, hydrochloric acid or a mixture of the already mentioned substances, RS-2,3 is obtained at elevated temperatures ,! , 6-tetrahydro-6-phenylimidazo [2,1-b] thiazole having the formula (I)
    According to a preferred embodiment, tetramisole is obtained by reacting compound (IV) with sulfur carbon, melting the obtained compound (Va), converting it to RS-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thion (VII), and cyclizing it, hydrochloric acid medium. Thus, the proposed method enables a new, unfamiliar and very simple way to directly obtain the physiologically applicable salt of R, S-2,3,5,6-tetrahydro-6-phenylimidazole [2,1-Ythiazole hydrochloride (tetramisole hydrochloride) .
    The proposed method provides a cost-effective and easily feasible method for the synthesis of the key intermediate product R, S-1- (2-hydroxyethyl) -4-phenylimidazolidi-2-thione (VII), which is obtained with significantly better quality in
    C 6 H 5 -CH-CH 2 -NH-CH 2 -CH 2 -OH-f-CS 2 - nh 2 indicators, for example, the melting point according to the invention is 10 ° higher than that indicated in the indicated
    922109 θ above the method. This significant advantage explains the quantitative yield of tetramisole, as well as its very, high quality indicators. In this way, there is no need to use special methods of purification of the target product.
    The method according to the invention provides a new, cost-effective method for converting R ^ -1- (2-hydr- H oxyethyl) -4-phenylimidazolidin-2-thione; (Vii) in tetramisole. Through it, a holistic and cost-effective synthesis scheme for RS-2,3,5,6-tetrahydro-6-phenylimidazo 15 Ώ, 1-b] thiazole (I) is carried out.
    Example 1. R, S-N- [2 (2-Hydr-; hydroxyethylamino) -1-phenyl-ethyl] amide * of di-carbonic acid (Va).
    With mechanical stirring, 20 mixed 18 g (0.10 mol) of R, S- <i- (2hydroxyethylaminomethyl) benzylamino (IV) and 60 ml of 96% Ethanol. After obtaining a homogeneous solution, at a temperature of 4θ 6 C, 11.4 g (0.15 mol of carbon disulfide) are added dropwise over 2 $. After four hours of refluxing with a laboratory * refrigerator, the separated precipitate is filtered and washed with 10 ml of ethyl alcohol / water. RS- yield N- 2- (2-
    - hydroxyethylamino) -1-phenylethyl] amide of dithiocolic acid (Va) -1o, 1 g (70% of theory), mp. 136-138 ^ C (with decomposition). 35
    Elemental analysis (M-256j38).
    Calculated,%: С 51.52 ^ Н 6.29, N 10.93 *, S 25.01, С о H ( b N20S 2
    Found,%: C 51.95; H, 6.35.
    N ’10, 70; S 24.80.
    Example 2. R, S-1- (2-Hydroxyethyl) -4-phenylimidazolidin-2-thion (VII). Cyclization by molten compound (Va).
    97 g (0.38 mol) R, S- {2- (2-) are heated in an oil bath at 45 150 ° C.
    - hydroxyethylamino) -1-phenylethyl]. amide of dithiol acid in continuation
    h. After this, cooled to 20 ° C melt was added 120 ml of 50 Me- tilenhlorida. The resulting solution was filtered. The filtrate is extracted with 120 ml of 10% potassium hydroxide, washed with 120 ml of hydrochloric acid (1: 3) and then the methylene chloride extract is washed with 55 water to pH = 5 and dried over sodium sulfate. After distilling off the solvent, 42 g of RS-1- are distilled off. (2-rHflpoKCH3Tnn '
    -4-phenylimidazolidin-2-thione (VII) mp = 91-93 * C. The yield is 50% of theoretical.
    Example 3. R.S-1- (2-Hydroxyethyl) -4-phenylimidazolidin-2-thion (VII) Cyclization with dimethyl sulfate.
    25.6 g (O, 10 mol) of R, S-N- 2- (2-hydroxy-ethylamino) -1-phenylethyl amide of di-carbonic Acid (Va) are added to 100 ml of a 5% aqueous solution of sodium hydroxide. After that, the solution is filtered through an asbestos-cellulose surface.
    The filtrate was cooled to - 5 and in which the S. dropwise at bavlyayut · 13 g (0.10 mol] dimetilsulfafata, the reaction mixture was stirred mechanically These constructed J obtained sheet-like mass and the upper aqueous layer otdekandiruyut aqueous layer and smolistoobraznuyu mass.. After drying of the methylene chloride solution with sodium sulfate and complete distillation of the methylene chloride, 10J4 g, 5-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione (VIII) is obtained. After recrystallization of the crude product from butylacetate, RS-1 is obtained. - (2-hydroxyethyl) -4-pheni imidazolidine-2-thione (VII) with mp 91-93 ° C Yield -. 4 /% of theory.
    Example 4. R.S-1- (2-rnflpoKCH ethyl) -4-phenylimidazolidi n-2-thion (VII) Cyclization with n-butyl bromide.
    100 ml of water are suspended in 25.6 g (0.10 mol) of RS-N - [2- (2-hydroxyethylamino) -1-phenylethyl] amide of dithiocolic acid (Va). The suspension was added to 159 ml of 5% _ aqueous solution of sodium hydroxide. The resulting solution is filtered through an asbestos-cellulose surface. 16.5 g (0.12 mol) of butyl bromide are added to the filtrate.
    : at 50 ° C. After four hours of stirring, 100 ml of methylene chloride layer is added, separated, dried, after which the solvent is completely distilled off. The resulting crude R £ -1- (2-hydr.oxyethyl-4-phenylimidazolidin-2-thion (Vl 1) -10-, 7 g was recrystallized from butyl acetate. Mp 91-93 ° C. Yield -48.2% of theory.
    Example 5. R, S-N -12- (2-Hydroxyethylamino) -1-phenylethyl] amide-S-allyther of dithiocarbonic acid (V6) ’The suspension is added to 150 ml of a 5% aqueous solution of sodium hydroxide. The resulting solution is filtered through
    922109 10 asbestos-cellulose surface. To the filtrate was added 14.5 g (0.1.2 mol) of allyl bromide. The mixture is stirred for an hour at room temperature. After this, s 100 ml of methylene chloride is added to it, and crystals are isolated which are filtered off. The obtained k, SN [2- (2-hydroxyethylamino) -1-phenylethyl} amide-B-alylether of dithiocolic acid - 8.7 g has Yu.pl. 124-12b ° C. Yield -32% theoretical
    IR spectrum: suspension in nujole & CH = CHg) "1b25 cm ' 1 .
    Elemental analysis (M = 282.42) is Calculated. %: C 55.31 ', H 6.38;
    N, 9.92; S 22 j69. With 4% H ^ NgOSe.
    Found,%: C 55.01) And 6.70j N 10.20; S 22.93.
    PRI me R 6. R.S- 1- (2 ~ Hydroxy-j® ethyl) -4-phenylimidazolidin-2-thion (VII). Cyclization by melting ··· melting of compound (V6).
    In continuation heated 2h 8.7 g (0.032 mol) RS-N- £ 2- (2-gidroksietil25 amino) -1-phenylethyl] amide-S-alilefira ditiougolnoy acid (V6) at 150 C. After cooling the mixture to room 50 ml of methylene chloride are added to the temperature and the solution is filtered through ed asbestos-cellulose surface. The filtrate is washed initially with 25 ml of a 10% aqueous solution of sodium hydroxide; RA, then 25 ml of an aqueous solution of hydrochloric acid (1: 3) and at the end of 50 ml of water to pH = 6. · The methylene chloride extract is dried with sodium sulfate. After distilling off the methylene chloride gives 2.47 g of crude R £ -1- (2-hydroxyethyl-fenilimidazrlidin -4-2-thione (VII), mp 91- 40 ° C 93 Yield -.. 3k% of theoretical.
    Example 7. R.S-2.3.5.6-Tetrahydro-6-phenylimidaeo G2,1-Ythiazole hydrochloride, Cyclodehydration with hydrochloric acid. ^ 5
    With mechanical stirring. Dissolve 11.2 g (0.05 mol) of RS -. -1 -. (2-hydroxyethyl) -4-phenylimidazolidin-2-thione (VII) in 100 ml of hydrochloric acid. The reaction mixture is heated and refluxed for 3 hours, after which; the solvent is distilled off under reduced pressure. The resulting crude product was suspended in 40 ml of isopropanol and filtered. Yield of R, S-2,3,5,6-tetrahydro-6-phenylimidazo [2.1-b] ~ thiazole hydrochloride-11.6 g, m.p. 256-258 ° C quantitative.
    Example 8. R.S-2.3.5,6-Tetrahydro-6-phenylimidazo £ 2,1-b] thiazole (I).
    Cyclodehydration with polyphosphoric acid.
    To 8.9 g (0.04 mol) of finely ground RS-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione (VII) 200 ml of polyphosphoric acid are added. The reaction mixture was heated at 150 C. Continuing e 6 hrs. And then poured into a mixture of 600 g of broken ice and 200 ml of water .. The acidic mixture alkalizing 45% aqueous sodium hydroxide to pH = 11'1.
    The chain solution is extracted 3 times each time with 200 ml of methylene chloride. After distillation of the solvent, 2 g of R, S-2,3.5.6-TeTparMfl-6-phenylimidazo £ 2.1-b] tyazole are obtained.; * (I). Mp recrystallized product - 90-92 ° C. The yield is 24% of theoretical.
    Example 9. R. S.-2,3,5,6-Tetrahydrob-phenylimidazo £ 2,1-b] thiazole (I). Cyclodehydration with Phosphorus Bicarbonate.
    With mechanical stirring, 22.2 g (0.10 mol) of R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione (VII) are dissolved in 250 ml of mesitylene. After adding 28.4 g. '(0.20 mole) of phosphorus dvupyatiokisi suspension was stirred at 110 C continued for 1 hour. The reaction mixture was cooled to room temperature, 100 ml of 30% aqueous sodium hydroxide solution and the organic layer was separated from the alkaline solution. The organic layer was washed twice with water until neutral. Sodium sulfate is added to the washed organic layer for drying. After evaporation of mesitylene under reduced pressure, 12 g of RS- are obtained
    2,3,5,6-tetrahydro-6-fenylimidazo £ 2,1-l thiazole (I). Mp recrystallized from cyclohexane, · product - 90-92 e C. Yield - 58.5% of theoretical,
    Example Y. R, S-2.3,5,6-TeTrahydro-6-phenylimidazo [2,1-b] thiazole hydrochloride (I). Cyclodehydration with sulfuric acid.
    To 196 g (2 mol) of sulfuric acid cooled to -5 ° C, 22.2 g (0.10 mol) of R.S-1- (2-hydroxyethyl-4-phenylimidazolidin-2-thione (VIII) was added.
    After this, the reaction mixture was stirred at room temperature for 10 h. The acidic mixture was alkalized with a 30% aqueous solution of sodium hydroxide to pH = 11.5. The silk mixture 5 is extracted 3 times, each time with 100 ml of methylene chloride. The methylene chloride extract is washed with water until neutral, and then dried with sodium sulfate. After complete- * 0 race of methylene chloride R.S-2,3.5.6-tetrahydro-6-phenylimidazo [2,1-bl thiazole (I) is obtained. The crude R, S-2,3,5,6tetrahydro-6-phenylimidazo 12,1-b) thiazole is dissolved in acetone and precipitated with * 5 'is a 20% solution of hydrogen chloride in isopropanol. The resulting R, S2,3,5,6-tetrahydro-b-phenylimidazo 12,1-b] thiazole has a melting point of 254-256. C.
    权利要求:
    Claims (2)
    [1]
    readin.  sodium borohydride, inorganic acid chloride, thiocarbamide, thiocyanic acid derivatives and cr,.  These methods do not have the advantage of being considered, since their more multi-step scheme for obtaining the final product includes some compounds that are difficult to access.  In view of the above-mentioned complications and the fact that the opening of the aziridine cycle in a compound having the formula occurs not only by breaking the N (7) –C (5) bond (formula III), but also by the H (7) –C bond (6 ) (formula I and).  A known synthesis method is used in which the tetrahydr1O-6-phenylimidazothiazole system is created by the simultaneous formation of N (a) -C (5) and C (6) -M (7) bonds (formula I) in the interaction of 1-phenyl-1. 2-dibromoethane and 2-aminothiazolin-2.  The disadvantage of this method is the impossibility of the formation of the 5 Phenyl derivative of the considered heterocyclic heterocyclic system and low yield of the target product.  There is also known a method for constructing a tetrahydroimidazothiazole ring system by means of a superstructure of the initially created imidazral ring system.  The second heterocycle-thiazolidine part of the molecule is obtained by simultaneously creating S (1) -C (2) and C (3) N (k) bonds (formula 1). The disadvantages of this synthetic scheme are the difficult availability of the outcome: the key product 1-phenylimidazole dyn-2-on-, expensive and dangerous when working amide lithium - a condensing agent, low yield of the final product.  especially when using sodium carbonate under the guise of a condensing agent.  The creation of the tetrahydroimidazo-thiazole system has been described by means of the cyclization of C (3) -. N (i) (formula I).  The synthetic method of building the tetrahydroimidazothiazole system is the method where the heterocycle is obtained by creating a bond (1) - C (2) (formula I).  The sole purpose of this method is to use R, S - (+) - 2,3,5,6-tetrahydro-6phenylimidazo G2. 1-thiazole-foreign product in the separation of the racemic mixture of tetramisole.  This is accomplished by converting the physiologically inactive R, S - (+) - 2,3,5,6-tetrahydro-6-phenylimidazoG2. 1-Tyrazole in the racemic R, S- 1 - (2-hydroxyethyl-t-phenylimidazolidine-2-TION (mind) by means of a multistage complex and technologically:; TMOH (VII) is cyclized again to the racemic mixture of tetramisole.  The output from this process is kQ% theoretical; who  A key intermediate product upon receipt of R. S-2,3,5 j6-teRZHyd rots-6-phenylimidazo C2,1-Y thiazole (I) is the compound RS-1- (2-hydroxy ethyl) -phenylimidazolidin-2-thione (Yn).  The method is almost not applicable in the production of military conditions due to the specified reasons.  However, it is impossible to obtain the compound R, S-1- (2-hydroxy-TilV3-phenyl-imidazolidin-2-thione (UE) without first obtaining tetramisole according to any known method; obtaining physiologically inactive N1x stereoisomer R. $ - () 2, 3.5, b-tetrahydro-6-phenylimidazo C2,1-b1 thiazole does not provide any rational solution to the problem of creating a tetrahydroimidazothiazole structure. ; The aim of the invention is to create a new method for obtaining R, S-2,3.  5,6-tetrahydro-6-phenylimidazo-2. 1-bltiazol (tetramisole), which would have been technologically easy to implement.  convenient for use in industrial conditions and at the same time based on the use of more available starting materials (raw materials) before this R, S-oL- (2. -hydroxyethylaminomethyl) -benzylamine (IV) the name from compound IV is given according to nomen. . According to the rules, the same compound can also be called R, S-2- (2-hydroxyethylaminoi-l-phenyl-ethylamine), which is obtained from the main products of organic synthesis.  five.  9 The method for the preparation of K, 5-2,3,5,6-tetrahydro-6-phenylimidazo 2, 1-L1 thiazole is carried out by reacting R, S -oL- (hydroxyethylaminomethyl) benzene amine.  having the formula (IV), with carbon disulfide in an aqueous or aqueous-organic medium. This interaction produces compound R. SN- (2) 2-hydroxyethylamino (-1-phenylet; And dithiogolic acid amide having the formula CgHj-SI-CHg-NHg-CH2-CHg-OH n-s- s which, for its part, turns c into R, 3 1- ( 2-hydroxyethyl) -4-phenyl-imidazolidin-2-one having the formula C6H5-f s -N-CH2-CH2-OH) by one of the following methods; a) by thermal cyclization of compound (Va) during melting or in inert solvents,.  b) by chemically inducing cyclization of compound (Va) with reagents having the general formula R, where R denotes a lower alkyl residue and X is an acid residue.  Such reagents can be methyl iodide, dimethyl sulfate, diethyl sulfate, butylbrodide, alkyl esters p. -trluoolsulfonic, methanesulfonic and fluorosulfonic acids; c) by converting the compound. (U / o. ) in R, S-l-H2- (hydroxyethylamino) -1-phenylZamide-Zalkyl esters of dithioic acid, having the formula CgHs-cn-sng-cNg-cn-cNcCnz-one I g cn-0, SR In which R represents an alyl, benzyl or dynamyl residue and then melting the compound (V6) to the compound (VII).  In this way, according to option (c), compound (Vll) is synthesized from compound (IV) according to the following scheme CsH5-CH-CH2-NH-CH2-CHg-OHtCS2-NHa CftHs-cn-Shg-SNg-Cr-onRBf / Vl / - Sba-sn-sng-sh-sng-sng-on r. s NH-c: IN-C H2- 2-OH Under the guise of alkylating agents R X having the formula (VI), it is best to use alil bromide, benzyl bromide, propargyl bromide and cyamyl bromide.  Preferably, the above reactions are carried out in an aqueous, water-alcoholic or alcoholic medium.  By cyclodehydration of the thus obtained compound (VII) with various acidic a. genes, such as polyphosphoric acid or its esters, phosphorus diphoxide. , concentrated sulfuric acid, hydrochloric acid, or a mixture of the already mentioned substances; at elevated temperatures, R, S-2,3, 6-tetrahydro-6-phenylimidazo 2, 1-b thiazole having the formula (|) CeHs-f YI jvi1 In a preferred variant, tetramisole is obtained by reacting compound (IV) with carbon disulfide, melting the resulting compound (Va), converting it to R.  S -1 - (2-hydroxyethyl) - "- phenylimidazolidine-2-TION (VII) and its cyclization, in hydrochloric acid.  Thus, the proposed method makes it possible to directly obtain the physiologically applicable salt R, S-2, 3,5,6-tetrahydro-6-phenylimidazole C2,1-L7thiazole HYDROCHLORIDE (tetramisole hydrochloride) directly, in a new, unfamiliar and very simple way.  The proposed method provides a cost-effective and easily feasible method for the synthesis of the key intermediate R, S-1- (2-hydroxyethyl) -4-phenylimidazolidi-2-thione (VII), which is obtained with significantly better quality indicators, for example, the melting point according to the invention 10 ° higher than that noted in the above 79 method.  This significant advantage explains the quantitative yield of tetramisole, as well as its very high quality indicators.  In this way, there is no need to apply special methods of purification of the target product.  The method according to the invention represents a new cost-effective method for converting R-l- (2-hydroxyethyl) - -phenylimidazolidine-2-thio (Vll) to tetramisole.  Through it is carried out a coherent and cost-effective synthesis scheme R. S-2, 3,5,6-tetrahydro-6-phenylimidazo U2,1-b thiazole (1).  .  Example 1  B, $ - M-C2 (2-hydroxyethylamino) -1-phenyl-ethyl amide of dithiogradic acid (Va).  With mechanical stirring, 18 g (0.10 mol) of R, S-cL- (2-hydroxyethylaminomethyl) -benzylamino (IV) and 60 ml of 96% ethyl alcohol are mixed.  After obtaining a homogeneous solution, 11, g (0.15 mol) is added dropwise at a temperature of lOC. carbon disulfide.  After four hours of refluxing with a laboratory reflux, the separated precipitate is filtered and washed with 10 ml of ethyl alcohol.  Yield of R, (2-hydroxyethylamino) -1-phenylethylamine: yes and di-di-capric acid (Va) -1o, 1 g (70 theoretical), t. square  13b-138 (with decomposition).  Elemental analysis (M-25b 38).  Calculated: C 51. 52; H 6.29.  N 10.93; S 25. 01, C ,, H bN20S2 Found: C, 51.95; H 6.35.  N -10. 70; S 2.80, Example 2.  R, S-1- (2-Hydroxyethyl) -phenylimidazolidin-2-thione (VI)).  Cyclization with molten compound (Va).  97 g (0.38 mol) of R, S- &amp; (2-hydroxyethylamino) -1-phenylethyl, amide of dithiogolic acid, are heated in an oil bath at 150 ° C in an hour.  After that, 120 ml of methylene chloride is added to the cooled to the melt.  The resulting solution is filtered.  The filtrate was extracted with 120 10% potassium hydroxide, washed with 120 ml of hydrochloric acid (1: 3) and then the methylene chloride extract was washed with water and dried over sodium sulfate.  After distilling off the solvent. rolls k2 g R. S-l- (2-hydroxyethyl 8-phenylimidazolidin-2-thione (VM) with t. square  91-93 C, Yield - 50 theoretical.  Example 3  R. S-1- (2-Hydroxyethyl) -phenylimidazolidin-2-thione (VII) Cyclization with dimethyl sulfate.  To 100 ml of a 5% aqueous solution of sodium hydroxide, 25.6 g (o, 10 mol) of 2- (2-hydroxylthylamino) -1-phenylethyl amide of dithiol acid (Va) are added.  After that, the solution is filtered through an asbestos-cellulose surface.  The filtrate is cooled to a temperature -.  in which 13 g (0.10 mol of dimethyl sulphate) is added dropwise, the reaction mixture is mechanically stirred.  Get smog sheet-like mass and the upper aqueous layer.  The aqueous layer is decandoned, and the resinous mass is dissolved in methylene chloride.  After drying the sodium chloride sulphate solution and distilling off the methylene chloride completely, 10 g of R, 5-l- (2-hydroxyethyl) -ylJ-phenylimidazolidin-2-thione (VIII) are obtained.  After recrystallization of the crude product from butyl acetate, R. is obtained. S-1- (2-hydroxyethyl) - -phenylimidazolide-2-TION (VII) with t. square  91-93 S.  Output - 47 theoretical.  Example j.  R. S-1- (2-hydroxyl ethyl) -phenylimidazolidin-2-thione (VI I) Cyclization; with n-butyl bromide.  25.6 g (0.10 mol) of R. are suspended in 100 ml of water. S-M-G2- (2-hydroxyethylamino) -1-phenylethylX amide of dithiogradic acid (Va).  The suspension is added to 159 ml of a 5% aqueous solution of sodium hydroxide.  The resulting solution is filtered through an asbestos-cellulose surface.  16 are added to the filtrate. 5 g (0.12 mol) of butyl bromide.  at 50 ° C.  After four hours of stirring, 100 ml of the methylene chloride layer are added, dried, and the solvent is completely distilled off.  The resulting crude (2-hydroxyethyl-4-phenylimidazolidin-2-thione (VII) -10-, 7 g of recrystallized from butyl acetate.  T. square  91-93C Exit -48.2% of theoretical.  Example 5  R, S-N-C2- (2-Hydr xyethylamino-1-phenylethyl-amide-5-aliether of dithiogracial acid (V6). The suspension is added to 150 ml of 5% aqueous sodium hydroxide solution. The solution obtained is filtered through an asbestos-cellulose surface.  To the filtrate add r (0. 12 mol alilbromida.  The mixture is stirred for an hour at room temperature.  Thereafter, 100 ml is added to it. methylene chloride, and crystals are filtered out.  The resulting h, t2- (2-hydroxyethyl-amino) -1-phenylethyl amide-5. dithiocarbonic acid ester - 8.7 g has t. square  12 "-12b S.  Exit -32% ieopetM.  IR Spectrum: Suspension in Nujol-1B25 cm-.  The element "| th analysis (. 2} Calculated.  % g C 55.31, H 6, SE; N 9.92; S.  0, %%% OS,. v Found: C 55. 01 H 6. 70j N 10. 20; S 22. 93. H P r i m e.  p 6.  TO. 5-1- {2-Hydroxyethyl) -A-phenylimidazolidin-2-Thion (VII).  Cyclization by melting of the compound (V6).  In the continuation of 2 m heated 8.7 g (0.032 mol) R. SiN-2- (2-hydroxyethyl-amino) -1-phenylamine amide-S-aliphene of dithiogleic acid (V6) at.  After the mixture was cooled to room temperature, 50 ml of methylene chloride was added and filtered through an asbestos-cellulose surface.  The filtrate is washed initially with 25 m of a 10% aqueous solution of caustic soda, followed by 25 ml of an aqueous solution.  hydrochloric acid (1: 3) and at the end of 50 wi. .  water to pHab.   The methylene chloride extract is dried with sodium sulfate.  After the race, 2 j 47 crude R -1- (2-hydroxyethyl - -phenyl imidaer lidin-2-thione {VII) t is obtained from the methyl methyl chloride reaction. PL  91, Exit - theoretical; P ROME er 7.  R. S-2. 3 five. 6-TectaHydro-6-phenylimidazbt2, 1-l1-thiazole hydrochloride. Cyclodehydration with hydrochloric acid, V With mechanical stirring, dissolve 11. 2 g (0.05 mol) of R. S -1-.  (2-hydroxyethyl) -L-phenylimidazrlidine-2-thione (vn) in 100 ml of hydrochloric acid.  The reaction mixture is heated at reflux for 3 hours, after which.  the solvent is distilled off under reduced pressure.  The resulting crude product is suspended in kO ml of isopropanol and filtered.  The yield of R, S-2,3i5, S-tetrahydro-6-phenylimidazo, 1-T is thiazole hydrochloride-11.6 g with t. square  256-258 ° C quantitative.  Example 8  R, S-2. 3,5,6-Tetrahydro-6-phenylimidazoG2, 1-bj thiazole (I), Cyprdehydration with polyphosphoric acid.  200 ml of polyphosphoric acid are added to 8.9 g (O, O mol) of finely ground R, S-l- (2-hydroxyethyl) -phenylimidazolidine-2-thione (VM).  The reaction mixture is heated for a further 6 hours, after which it is poured onto a mixture of 600 g of broken ice and 200 ml of water.  The acidic mixture is alkalized with a 5% aqueous solution of sodium hydroxide to.   The squirrel solution is extracted 3 times each time with 200 ml of methylene chloride.  After distilling off the solvent, 2 g of R, S-2,3,5 are obtained. 6-tetrahydro-6gphenylimidazo 2. 1-b} tyazole (I).  T. PL, recrystallized product - 90-92 C.  Output - 2 theoretical.  PRI me R 9. R. S -2,3,516-Tetrahydro-6-phenylimidazo 2, 1-L1-thiazole (1), Cyclodehydration with phosphorus two-toxicity. .  With mechanical stirring, 22.2 g (0.10 mol) of R, S-1- (2-hydroxyethyl) -4-phenylimide-: zolididin-2-thione (VII) are dissolved in 250 ml of mesitylene.  After adding 28, A g.  : (0.20 mol) phosphorus two-thioxide, the suspension is stirred for 1 hour.  The reaction mixture is cooled to room temperature, 100 ml of a 30% aqueous solution of sodium hydroxide are added and the organic layer is separated from the alkaline solution.  The organic layer is washed twice with water until neutral. Sodium sulfate is added to the washed organic layer to dry.  After evaporation of mesitylene under reduced pressure: 12 g of R, S2, 3 are obtained.  5,6-tetrahydrP-6-phenylimidazo 2, 1-L1 thiazole (I).  T. square  recrystallized from cyclohexane, - product - 90-92 C, Yield - 58.5% of theoretical.  Example 10  R, S-2,3,5,6-TeTragidro-6-phenylimidazo 2, 1-Snthiazole hydrochloride (I).  Cyclodehydration with sulfuric acid.   To 196 g (2 mol) cooled to sulfuric acid, 22.2 g (0.10 mol) K, 5-1- (2-hydroxyethyl-phenylimidazolidin-2-thione (VIII)) are added.  .  eleven.  After that, the reaction mixture is stirred at room temperature for 10 h.  The acidic mixture is alkalized with a 30% aqueous solution of sodium hydroxide, 5.  The silk mixture is extracted 3 times, each time with 100 ml of methylene chloride.  The methylene chloride extract is washed with water until neutral, then dried with sodium sulfate.  After complete distillation of the methylene chloride, R, S-2 are obtained. 315. 6-tetrahydro-6-phenylimidazo 2,1-Ythiazole (I).  The crude R, S-2,3,5, tetrahydro-6-phenylimidazo 2,1-O, azole is dissolved in acetone and precipitated with a 20% solution of water chloride of the genus in isopropanol.  The resulting R, S 2,3,5,6-tetrahydro-6-phenylimidazo C2,1-β-Thiazole has t. square   Claim 1.  The method of obtaining R, S-2,3,5,6 tetrahydro-6-phenylimidazo 2,1-β1-thiazole of formula -O2 OR its pharmacologically tolerable salts with inorganic and organic acids, and that R, 5-el- (2-hydr hydroxyethylaminomethyl) benzylamine of formulas - CH - CHf NH-CHz-CHg-OH NHg is reacted with carbon disulfide to form R, SN-L2- (2-hydroxyethylamino-1-phenylethylZ-amide of dithiohydric acid) Formula CeHs-CH-CHg-NHg-CH3-CH3-OH which is cyclized to R. S- 1- (2-hydroxyethyl) - -phenylimidazolidin-2-thione of formula B CeH5-t S IN-CH2-CH2-OH which has 14 dehydration to R, S2. 3.5. 6-tetrahydro-6-phenylimidazo G2. 1-b thiazole, 2.  Way pop 1, which is also distinguished by the fact that the interaction of R, S-oL- (2-hydroxyethylaminomethyl) benzylamine with carbon disulfide was carried out in aqueous or aqueous-organic media 12 3. The method according to claim. 2, characterized in that the process is carried out at boiling in an ethyl alcohol medium.  four. The method according to claim. 1, which does so.  that R, S — N — 2- (hydroxyethylamino-1-phenylethyl amide of dithioacidic acid is cyclized to R, S-1- {2-hydroxyethyl phenyl-imidazolidin-2-thion when heated, 5. The method according to claim.  1 I’m casting off with the fact that R, SN - (- (2-hydroxyethyl but) - 1-phenylethyl amide of dithioacidic acid is cyclized to R, S- 1- (2-hydroxyethyl) -t-phenylimidazolidin-2-thion at heated in an organic solvent environment.  6 Way pop 1, and with the fact that R, S-N6- 2- (2-hydroxy-ethylamino) -1-phenylethyl amide of dithiogloic acid is cyclized to intermediate S-alkylation in an alkaline medium with alkylating agents of the formula RX, where R denotes the lower alkyl radical with the number of carbon atoms, X is the acid residue, 7. Way pop 1, differing from the fact that R, S-N-L2- (2-hydroxyethylamino) -1-phenyl ethyl amide of dithiogloic acid is alkylated with alkylating agents of the formula R X, where R is an alyl hydrocarbon radical, propargyl. or benzyl type, X is halogen to form R, SN-2- (2-hydroxyethylamino) -1-phenylethyl-amide-5-alkyl ether of dithioic acid, which, when heated, cyclized to R, S-1- (2-hydroxyethyl - -phenylimidazolidin-2-thione, 8. The method according to claim 1, 1 and 2 with the fact that the cyclodehydration of R, S is 1–2-hydroxyethyl) -phenylymine dazolidin-2-thione to tetramisole occurs at boiling in hydrochloric acid, and tetramisole hydrochloride is released directly.  9. Sposbb on p. 1, that is, with the fact that cyclodehydration of R, S-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione to tetramisole is carried out by heating in an environment of polyphosphoric acid or its esters .  ten. . The method according to claim. 1, characterized in that cyclodehydration 13922, B, 5-1- (2-hydroxyethyl) -4-phenylimidazolidin-2-thione to tatramizole is carried out by heating in inert organic solvents in the presence of two-thioxy (11.  The method according to claim.  1, that is, with the fact that cyclodehydration I, 5-1- (2-hydroxyethyl).  phenylimidazolidin-2-thione to tetra1091 mizol is carried out in a medium of concentrated sulfuric acid,
    [2]
    2. The method according to p; 1, that is, with the fact that the cyclodehydration of s R, S-1- (2-hydroxyethyl) - "- phenylimidazolidin-2-thione to tetramizrel is carried out by heating in mixtures of cyclodehydrating agents, for example, polyphosphoric acid and hydrochloric acid, concentrated sulfuric acid, and phosphorus two-thioxy.
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    同族专利:
    公开号 | 公开日
    GB2000777A|1979-01-17|
    FR2396747B1|1984-05-18|
    DE2829821A1|1979-02-01|
    US4179460A|1979-12-18|
    NL7807265A|1979-01-09|
    IT7850171D0|1978-07-05|
    CA1100146A|1981-04-28|
    DE2829821C2|1982-07-01|
    IT1174325B|1987-07-01|
    FR2396747A1|1979-02-02|
    JPS5436234A|1979-03-16|
    ES471354A1|1979-09-16|
    BE868745A|1978-11-03|
    CS208942B1|1981-10-30|
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    BE786416A|1971-07-27|1973-01-18|Ici Ltd|PRODUCTION OF TETRAMISOLS|
    OA04567A|1972-11-30|1980-05-31|Rhone Poulenc Sa|New derivatives of imidazo thiazole and their preparation.|US5019274B1|1984-08-30|1992-12-29|Petrolite Corp|
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    US5516647A|1993-11-05|1996-05-14|Abbott Laboratories|Compounds useful as alkaline phosphatase inhibitors and therapeutic agents|
    JP5867730B2|2010-06-29|2016-02-24|国立研究開発法人産業技術総合研究所|Halide detection agent, method for detecting the same and detection sensor|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    BG3790877|1977-07-06|
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