• 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:
    The preparation of 6-bromo-7,8-dimethoxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepines is described by direct bromination of the nucleus.
    公开号:SU976847A3
    申请号:SU772544154
    申请日:1977-11-16
    公开日:1982-11-23
    发明作者:Вейнсток Джозеф
    申请人:Смитклайн Корпорейшн (Фирма)；
    IPC主号:
    专利说明:

    the house and the desired product are isolated in free form or in salt form. Pharmaceutically acceptable additive salts of acids of formula (I), obtained by well-extracted methods, are formed with both acid and potassium acid, succinic acid, succinic acid, succinic acid, succinic acid, succinic acid, and succinic acid. , tartaric, salicylic, citric, gluconic, paraaminobenzoic, glutamic, aspartic, stearmic, palmitic, itaconic, glycolic, benzenesulfonic, hydrochloric, hydrobromic, ernoy, cyclohexylsulfamic phosphoric and nitric acids. Similarly, quaternary salts include those derived from organic halide compounds such as methyl iodide, ethyl iodide, and benzyl chloride. Example. 7,8-dimethoxy-1-phenyl-2, 3, 5-tetrahydro-1H-3 benzazepine (280 g, 0.75 M) was dissolved in 1700 ml of acetic acid. Bromine was added in a thin stream in an amount of 280 g (M). The reaction mixture was stirred for 2 hours. The precipitate, which formed high, one hour after stirring, was collected and washed with ether. It was dissolved in boiling methyl alcohol and acetone was added to destroy excess bromine. 6-bromo-7,8-dimethoxy-1-phenyl-2,3, 5 tetrahydro -1H-3-benzazepine hydrobromic was crystallized from methanol and the second yield was obtained by adding ether to the mother liquor. The total yield was 298 g (77), melting point 23b-233 s. This bromination can be applied to any 7 8 dialkoxy or alkanoyloxy benzazepine having a free position. The resulting benzazepine hydrobromide salt was agitated in a mixture of excess 10% caustic soda and methylene chloride. The organic layer was separated, dried and evaporated to obtain a solid base, which was crystallized from a mixture of toluene and hexane. You move was 238 g (97) j melting point izs-ize c. The base (12 g, 0.033 mol) was dissolved in 200 ml of methylene chloride and cooled to -15 ° C. Boron tribromide (15 ml, 16 M) was carefully added. The solvent was distilled off and the flask was cooled to -1.5 ° C. Dry methanol was added to destroy the boron tribromide complexes. Then he was driven off. The residue was crystallized from water, then boiled in acetonitrile in order to dry the compound. The yield of hydrobromic 6-bromo-7,8-dioxy-1-phenyl-2,3, 5-tetrahydro-1H-3 benzazepine was 10.26 g (75), melting point 2kQ-2h2 C after drying under vacuum. Example 2: Soloxidic 6, -chloro-7, 8-dimethoxy-1-phenyl-2,3,, 5-tetrahydro-1H-3-benzazepine (3.27 g. O, 0103 M) it was freed from its hydrochloride by giving it basicity to an aqueous solution and extracting the mixture with methylene chloride. The solvent was thoroughly dried and cooled to -15 ° C in a methanol and ice bath. A ml of boron tribromide was added and the reaction mixture was stirred at room temperature for 2 hours. The solvent and excess tribromide were distilled off and the flask was cooled to -78 ° C. Methyl alcohol was carefully added until the product was completely dissolved. The methanol was distilled off, and the residue was crystallized from hot water. The crystals were boiled in dry acetonitrile for one hour, then the resulting hydrobromic 6-chloro-7,8-dioxy-1-phenyl-2,3, 5 tetrahydro-1H-3-benzazepine, which had a yield of 56, was collected. The temperature melting 256 260 ° C. Example 3: The product obtained in Example 5 (0.87 g, 2.50 M) in 25 ml of dry methylene chloride was cooled in a bath of ice and methyl alcohol and added dropwise. , 5 ml (25.0 m) of boron tribromide in methylene chloride. After stirring for h, the mixture was cooled in an ice bath, while methyl methyl alcohol was carefully added, which after crystallization from a mixture of methyl alcohol and ethyl acetate gave 0.37 g of 6-chloro-7,8-dioxy-1-paraoxyphenyl -2, 3,., 5-tetrahydro-1H 3-benzazepine hydrobromide with a melting point of 215 ° C. The base was reconstituted from the hydrobromic salt using a solution of sodium carbonate. The reaction of the base in a mixture of methanol and tetrahydrofuran with various acids gave the following salts: dl-tartrate, acetate, fumara hydrochloride, sulfate, acetate, and the most water-soluble salt, methyl sulfonate. An example. A mixture, 5 g of 6-chloro-7, 8-dimethoxy-1-phenyl-2,3. F. 3-tetrahydro-W-Zbenzazepine, 0.02 ml of n-butyl bromide and 0.02 M potassium hydroxide were dissolved in 120 ml of dry methyl alcohol and heated at reflux for 8 hours. The reaction mixture was evaporated to dryness, taken up in ethyl acetate and filtered to remove inorganic salts. The filtrate was washed with water, dried, evaporated and 3-n-butyl-6-chloro-7, 8-dimethoxy-1-phenyl-2,3, 5-tetrahydro-1H-3-benzazepine was obtained. Hbb-benzazepine (0.01 M) was diluted with 120 ml of dry methylene chloride -10 ° C. 0.032 M boron tribromide was added dropwise. The solution was heated to room temperature and stirred for two hours. Excessive boron tribromide was broken down with methyl alcohol added dropwise with ice cooling. The cold solution was heated to reflux on a steam bath to remove hydrogen bromide, and then after evaporation, 3-n-butyl-6-chloro-7.8-dioxy-1-phenyl-2, 3, 5 tetrahydro-1H-3-benzazepine Hydrobromic. T. pl. 183-185 ° C. PRI and MER 5. A solution of g of 6-chloro-7, 8-dimethoxy-1-phenyl-2, tetrahydro-1H-3-benzazepine in 15 ml of formic acid and 10 ml of formaldehyde was heated in a vessel with a reflux condenser. for 18 h, the reaction mixture was evaporated to dryness, 20 ml of six-normal hydrochloric acid was added, and the solution was again evaporated to dryness to obtain a liquid. The latter was treated with 20 ml of a 10% sodium hydroxide solution and the mixture was extracted with ether. The dried extract was evaporated to give b-chloro-7,8-dimethoxy-Serpentyl-1-phenyl-2, k, 5-tetrahydro-1H-3-benzazepine. The 3 methylbenzazepine obtained (2.6 g) was dissolved in 120 ml of dry methylene chloride and 6.8 g (0.027.M) of boron tribromide were added dropwise. The resulting pactBop was warmed to room temperature and stirred for 2 hours. Excessive boron tribromide was destroyed with methanol, added dropwise with ice cooling. The solution was heated at reflux on a steam bath to remove hydrogen bromide and then evaporated to dryness. Hydrobromic 6-chloro-7,8-dioxy-3-methyl-1-phenyl-2,3, t, 5 tetrahydro- was obtained. -1H-3-benzazepine, melting point 249 ° C. PRI and MER 6 .. Replacing the stoichiometric amount of 2-ftpr-3, -dimethoxy-ethoxyphenylamine in the synthesis process, shown in example 2, resulted in 6 - fluoro-7,8-dimetsksi-1-phenyl- 2, 3,., 5-tetrahydro-1H-3-BS zazepina. Hydrolysis with boron tribromide, as in Example 2, gave 6-fluoro-7, 8, -diox and-1-phen-yl-2,3, 5 tetra-hydro-1H-3-benzazepine (hydrogen hydrochloride. Mp. . 277 ° C). Replacement of 2-trifluoromethyl-3, 4-dimethoxytoluene in Example 2 gave 6-trifluoromethyl-7,8-dimethoxy-1-phenyl-2, 3), 5-tetrahydro-1H-3-benzazepine ( mp 230-232 ° C) and then hydrolysis with boron tribromide gave b-trifluoromethyl-7, 8-dioxy-1-phenyl-3, 5-tetrahydro-1H-3-benzazepine (hydrochloride. T mp 255 ° C). PRI and MER 7-Mixture, 8 g of sodium in mineral oil and 70 ml of dry dimethyl sulfoxide were stirred for 80 minutes at 6-5 ° C. After diluting 70 ml of dry tetrahydrofuran, the mixture was cooled to 0 ° C, a solution of 19.0 j), 093M) of trimethylsulfonium iodide was added at this time to 100 ml of dimethylsulfoxide. A solution of 12.6 g (0.0928 M) -C-anisic aldehyde in 40 ml of tetrahydrofuran was quickly added. After stirring a for 15 minutes at and for 1-0.5 hours at 25 ° C, the mixture was poured with water. The combined organic layers were washed with brine, dried and concentrated to give 13 g of crude epoxide. It was mixed with 13.0 g of 2- (2-chlorop-3, dimethoxyphenyl) ethylamine and heated at 110 ° C for 4 hours. The product was chromatographed on silica gel with a mixture of 31 methanol and chloroform. The light fractions were distilled off to obtain 19 g of (2-chloro-3, 5-dimethoxyphenyl) ethyl -2-hydroxy-2-m-methoxyphenylethylamine, melting point 95.5-96.5 ° C. The related para-chlorophenyl compound melts at 99-100 ° C. Rod
    权利要求:
    Claims (1)
    [1]
    Claim
    The method of obtaining derivatives of 1-phenyl-2, 3,4,5 ~ tetrahydro-1H-3 “benzazepine of the General formula where R is hydrogen, lower alkyl or allyl;
    R ^ is halogen or trifluoromethyl;
    R 2 is hydrogen, trifluoromethyl, halogen, methyl or oxy group, or their salts, characterized in that, the compound of the General formula where
    R and R ^ have the indicated meanings; .
    R 2 is hydrogen, trifluoromethyl, halogen, methyl or lower alkoxy;
    Rj and R ^ are lower alkyl; they are treated with boron trichloride or tribromide or hydrogen bromide, and the target product is isolated in its free form or in the form of a salt.
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    同族专利:
    公开号 | 公开日
    ES464044A1|1978-08-01|
    NO147029C|1983-01-19|
    SE7712944L|1978-05-18|
    FR2371430B1|1980-06-27|
    NL7712567A|1978-05-19|
    MY8500382A|1985-12-31|
    IL53377D0|1978-01-31|
    IT1126216B|1986-05-14|
    JPS6366808B2|1988-12-22|
    HU176709B|1981-04-28|
    CS219333B2|1983-03-25|
    AU509754B2|1980-05-22|
    RO72905A|1981-11-04|
    JPS6125697B2|1986-06-17|
    NL930026I1|1993-06-01|
    DK156057B|1989-06-19|
    PL109672B1|1980-06-30|
    FI773448A|1978-05-18|
    YU270777A|1983-02-28|
    FI67374C|1985-03-11|
    NO147029B|1982-10-11|
    MX4682E|1982-07-28|
    IE46087L|1978-05-17|
    CA1092107A|1980-12-23|
    BG30019A3|1981-03-16|
    NL930026I2|1993-11-01|
    AR224495A1|1981-12-15|
    NL185563C|1990-05-16|
    PL202177A1|1978-09-25|
    NO773901L|1978-05-19|
    DE2751258C2|1990-01-04|
    JPS62155218A|1987-07-10|
    JPS5363335A|1978-06-06|
    JPS58113153A|1983-07-05|
    CH635079A5|1983-03-15|
    GB1595502A|1981-08-12|
    DK156057C|1989-11-13|
    YU40490B|1986-02-28|
    SE436646B|1985-01-14|
    US4160765A|1979-07-10|
    AT362379B|1981-05-11|
    PT67260B|1979-04-18|
    ATA816377A|1980-10-15|
    PH14740A|1981-11-20|
    ZA775910B|1978-05-30|
    IN150172B|1982-04-07|
    DD133563A5|1979-01-10|
    FR2371430A1|1978-06-16|
    DE2751258A1|1978-06-01|
    JPS6225658B2|1987-06-04|
    DK500477A|1978-05-18|
    IL53377A|1982-09-30|
    IE46087B1|1983-02-23|
    AU3062677A|1979-05-24|
    BE860774A|1978-05-16|
    PT67260A|1977-12-01|
    PH13611A|1980-08-05|
    SG31784G|1985-03-08|
    FI67374B|1984-11-30|
    NL185563B|1989-12-18|
    LU78513A1|1978-03-20|
    CY1246A|1984-08-31|
    引用文献:
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/742,965|US4160765A|1976-11-17|1976-11-17|Method for 6-bromination of 1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine compounds|
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