• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Novel compounds I and their acid addition salts <IMAGE> in which R is phenyl or phenylthio show activity against some fungi, yeasts and gram positive aerobic and anaerobic bacteria. The new compounds can be prepared by condensing 1-(2',4'- dichlorophenyl)-2-(N-imidazolyl- methyl)-ethanol with 4-chloromethyl- biphenyl, 4-bromomethyl-biphenyl, 1- phenylthio-4-chloromethyl-benzene or 1-phenylthio-4-bromomethyl-benzene in a solvent, most preferably dimethylsulphoxide.
    公开号:SU816399A3
    申请号:SU792771698
    申请日:1979-05-17
    公开日:1981-03-23
    发明作者:Нарди Данте；Массарани Елена；Тайана Альберто；Веронезе Марио
    申请人:Рекордати С.А.Кемикал Энд Фармасьютикалкомпани (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING SUBSTITUTED DIBENZYL ETHERS OR THEIR ACID ADDITIVE SALTS
    The invention relates to a process for the preparation of new substituted dibenzyl esters or their acid addition salts, which can be used as physiologically active compounds with antibacterial activity in the pharmaceutical industry. The proposed method for the preparation of substituted dibenzylEa: 1x ethers is based on the well-known condensation reaction of aromatic hydroxy compounds with halobenzyl and their conversion into salt in a known manner. The purpose of the invention is to develop a process for the preparation of esters or their salts. The goal is achieved by the fact that, in the method of producing substituted dibenzyl ethers of the general formula </ BR> where R is CgHy or CjiHyS. or their acid additive salts, 1- (2,4-dichlorophenyl) -2- (M-imidazolylmethyl-ethanol is subjected to condensation with halobenzyl formula where K C NuH-C1, Bv carboxamide in the presence of an alkali metal hydride, or in an aliphatic Cz-C alcohol in the presence of an alkali metal alcoholate with the release of the target product as bases or their salts. Dimethylformamide and hexamethylphosphoramide are used as carboxamides, but condensation proceeds more completely if dimethyl sulfoxide is used. This leads to a higher yield and a cleaner product. The base obtained by condensation is not purified by chromatography, because purification is necessary only when dimethylformamide or hexamethylphosphoramide is used as solvents. Filtration of the base solution through a column of sylcagel leads to retention of small amounts of impurities. wherein the symbol R represents a phenyl group, filtering is not necessary and crystallization of the nitrate results in a product sufficient internally clean headlamps for devel- purposes. When using the described aprotic solvents, an alkali metal hydride is used which is capable of forming a salt with a hydroxyl group of an ethanol derivative. The condensation solvent used is ali-phatic alcohol containing from 3 to b carbon atoms, such as tert-butanol, in which case the alkali metal hydride is replaced by an alkali metal alcohol, for example, potassium t-butylate. Acid addition salts of substituted dibenzyl esters are prepared in a known manner, for example, by adding an equimolar amount of acid to the base followed by crystallization of the salt thus obtained with a suitable solvent. , The starting 1- (2, 4-dichlorophenyl) -2- (N-imidazolyl) -ethanol is obtained from 1-chloroacetyl-2,4-dichlorobenzene by reduction of the latter with sodium borohydride and subsequent condensation with imidazolyl. 2, 4-Dichloro Example 1.1phenyl) -2-chloroethanol. 49.5 g of sodium borohydride are slowly added in small portions to a suspension of 233 g of 1- (1-hydroxy-2-chloro-3-ethyl) -2,4-dichlorobenzene in 1 l of methanol, stirred at room temperature. The resulting solution was stirred at room temperature for another 2 hours and then poured into 1L 5N. hydrochloric acid cooled with ice. After extraction with ethyl acetate or chloroform, the extract is washed with water, 1N. with a solution of sodium hydroxide and again with water until neutral, and finally, with an essential solution of sodium chloride, the extract is dried, the solvent is evaporated and I get. 220 g of oil1. The oil solidifies on aging and the resulting solid melts at 48-51 ° C. H 3.19, Found,%: C 42.75, C) - 47.43. n, ciiO. C Calculated,%: C 42.61, H 3.13, 47.17. Example 2, 1- (2,4-Dichlorophenyl) -2- {N-imidazolyl) -ethanol. 30 g of sodium are added to a solution of 88.5 p of imidaeol. And 60-0 ml of methanol, then the solvent is evaporated. The residue is dissolved in 300 ml of dimethylformamnd and heated to 115120 ° C. To the resulting solution added; With drops and under stirring, a solution of 225 g of 1- (2.4-dichlorophenyl) -2-chloroethanol in 400 ml of dimethylformamide. The mixture is heated to 115-120 ° C and maintained at this temperature for 20 minutes, and after further cooling, 2500 ml of ice water are added with vigorous stirring. The product precipitated with stirring for a period of time of about 2 hours is freed from the upper layer of liquid, which is decanted, another 2500 ml of water is added and, after aging, the mixture is filtered. The resulting precipitate is dried and crystallized from toluene. 170 g of the expected product are obtained, melting at 134-135 ° C. Found,%; C 51.62, H 3.80, N 10.73, C1 27.76. C. Calculated: C 51.38, H 3.92, N 10.89, C) 27.58., Example 3. 2,4-Dichloro-4 tphenylthio- (N-imidazolylmethyl) -dibenzyl ether ( 1: R - C / Hr-S). A solution of 2.57 g of 1- (2,4-dichlorophenyl) -2- (M-imidazole) -ethanol, in 10 ml of hexamethylphosphoramide is added dropwise, and, to a suspension, 0.52 g of sodium hydride (50% solution in oil) in 5 ml of hexamethylphosphoramide. After the evolution of hydrogen ceases, the salt formation is completed by heating for 1 h at. After cooling to 25 ° C, 2.58 g of 1-chloromethyl-4-phenylthiobenzene is added. The temperature is raised to and the mixture is kept at this temperature for 12 hours. Upon completion of the reaction, the mixture is poured into 200 ml of water, the product is extracted with diethyl ether, the solvent is evaporated and the residue is purified twice on a silica gel column using various ethyl acetate as a eluent. fractions by thin layer chromatography. The solvent is evaporated from the middle fractions to obtain 2.4 g of the desired base in the form of a yellowish oil, giving one spot on a thin layer chromatogram. Found: C, 63.86; H, 4.24; N, 6.41; C1, 15.29; -S, 6.97. 44420 2CoOS. Calculated: C 63.30, H 4.44, N 6.13, C1 15.57, S 7.04. Example 4. 2,4-Dichloro-4-phenyl-o1- (N-imidazolyl-methyl) -dibenzyl ether (, 1: R CgHy). A mixture consisting of 2.02 g of tert-potassium silicate in 30 ml of tert-butanol is prepared at, in an az. Atmosphere. 3.86 g of 1- (2.4-. -Dichlorophenyl) -2- (N-imide-zolyl) -ethanol is added. The solution is heated at reflux for 1 hour and then cooled to 20-25 seconds. 3.03 g of 4-chloromethylbiphenyl is added and the solution is heated again at reflux for 5 hours. After cooling to 20-25 seconds, the mixture is poured into water and the base is extracted with ethyl acetate. The extract is washed with diethyl ether and the solvent is evaporated. The residue was dissolved in diethyl ether (80 ml) and left overnight. The solvent is filtered off and the filtrate is treated with nitric acid dissolved in diethyl ether. An oil is obtained, which is an extract when aged. The residue consisting of nitrate 2., 4-dichloro-4-phenyl-ot- (M-imidazolyl-methyl) -dibenzyl ether, is crystallized from ethanol or ethyl acetate. The product (4.3 g) is pure, as evidenced by thin layer chromatography and melted at 140-141 C.
    Found,%: C 59.17, H 4.14, N 8.61, C1 14.46.
    14 "104 1.0. HNOj. Calculated,%; C 59.25, H 4.35, N 8.64, C1 14.57.
    Example 5. To a solution of 3.86 g of 1- (2, 4-dichlorophenyl) -2- (i-imidazolyl) -ethanol in 15 ml of dimethyl sulfoxide (dried over calcium hydride) was added 0.66 g of sodium hydride in a nitrogen atmosphere, with 2 ° -25 ° C. The mixture is heated at 50-60 ° C until the gas is pre-hygienic. Thereafter
    the mixture is cooled to 20–25 ° C, 0.5 g of potassium iodide is added, and a solution of 3.03 g of 4-chloromethylbiphenyl in 7 ml of dimethyl sulfoxide (dried over calcium hydride) is added dropwise. The mixture is stirred for approximately 20 h at 20-25 C and then poured into water. The product is extracted with ethyl acetate and then treated as described.
    Q Output is 4.6 g.
    Salts of 2, 4-dichloro-4-phenylthio-c - (N-imidazalyl-methyl) -dibenzyl ether are obtained by reacting the free base, dissolved in ethanol, with an alcohol
     with a solution of the desired acid, followed by crystallization of the resulting salt in a suitable solvent. The free base is prepared in accordance with Example 3.
    0 In the table. 1 shows the solvents used for crystallization, the data of elemental analysis and the melting point of some salts of the compounds of the formula 1 where R.
    5 In table. 2 shows some data for a number of salts of 2,4-dichloro-4-phenyl-ot- (N-imidazolyl-methyl) -dibenzyl ether, obtained in accordance with the examples given.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
     The process for the preparation of substituted diO-elenyl ethers of the general formula
    g, L1)
    ten
    where R or CjHpS
    HJdM of their acid addition salts,
    characterized in that
    1- (2 j 4 -dichlorophenyl) 2- (M-imidazolyl- (methyl) -ethanol is subjected to condensation with halondbenzyl formula
    , (and)
    ,
    "JS X - C1, Br,
    where R in the environment of the carboxamide 8 in the presence of an alkaline metal hydride or in the environment of an aliphatic alcohol in the presence of. trap metal from the distribution of the target product in the form of bases or salts.
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    同族专利:
    公开号 | 公开日
    SE444812B|1986-05-12|
    AU4714979A|1979-11-22|
    AT372950B|1983-11-25|
    EG14345A|1983-09-30|
    GB2025395A|1980-01-23|
    FR2426047A1|1979-12-14|
    DD143608A5|1980-09-03|
    AR219596A1|1980-08-29|
    FI71309C|1986-12-19|
    NL930014I1|1993-05-03|
    ATA345079A|1983-04-15|
    YU112279A|1983-01-21|
    DK153838C|1989-01-30|
    GR68396B|1981-12-29|
    IT1096361B|1985-08-26|
    HU182565B|1984-02-28|
    NO152840B|1985-08-19|
    IT7823546D0|1978-05-18|
    IL57245A|1983-02-23|
    PT69537A|1979-05-01|
    NO152840C|1985-11-27|
    FI71309B|1986-09-09|
    SE7904319L|1979-11-19|
    NO791599L|1979-11-20|
    CH639075A5|1983-10-31|
    GB2025395B|1982-07-28|
    DK196579A|1979-11-19|
    IE48372B1|1984-12-26|
    JPS54151974A|1979-11-29|
    JPS605592B2|1985-02-12|
    IL57245D0|1979-09-30|
    DE2917244C2|1985-09-05|
    ES480552A1|1980-04-01|
    FR2426047B1|1982-11-05|
    AU523053B2|1982-07-08|
    MX5927E|1984-08-29|
    FI791543A|1979-11-19|
    DK153838B|1988-09-12|
    NZ190412A|1981-03-16|
    IE790958L|1979-11-18|
    NL7903872A|1979-11-20|
    NL930014I2|1993-09-16|
    NL189255C|1993-02-16|
    CA1115718A|1982-01-05|
    DE2917244A1|1979-11-22|
    ZA792015B|1980-04-30|
    PH14782A|1981-12-09|
    引用文献:
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    SU557755A3|1968-08-19|1977-05-05|Янссен Фармасьютика Н.В. |Method for preparing imidazole derivatives|
    GB1475271A|1975-04-30|1977-06-01|Pfizer Ltd|1-aryl-2-1-imidazolyl-alkyl ethers and thioethers and their use as antifungal agents|CA1155853A|1980-06-06|1983-10-25|Joseph A. Martin|Imidazole derivatives and preparation thereof|
    EP0117811A3|1983-02-23|1987-06-03|Sanofi S.A.|Fungicidal pharmaceutical compositions for oral administration|
    FR2541114B1|1983-02-23|1986-04-11|Sanofi Sa|ANTIFUNGAL PHARMACEUTICAL COMPOSITIONS FOR ORAL USE CONTAINING OMOCONAZOLE|
    CA1250586A|1984-02-02|1989-02-28|Manuel Raga|1h-imidazole derivatives and process for theirproduction|
    DE3413365A1|1984-04-09|1985-12-19|Merz + Co GmbH & Co, 6000 Frankfurt|SUBSTITUTED PHENYLETHYL DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS|
    IT1200422B|1985-03-19|1989-01-18|Ripari Gero Ist Farm Biolog|COMPOUND WITH ANTIMICROBIA ACTIVITY, ITS PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN IT|
    ES2249992B1|2004-09-13|2007-03-01|Ferrer Internacional, S.A.|A PROCEDURE FOR MANUFACTURING ENANTIOMERIC COMPOUNDS OF IMIDAZOL.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    IT23546/78A|IT1096361B|1978-05-18|1978-05-18|THERAPEUTICALLY ACTIVE REPLACED BONDS|
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