• 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:
    Compounds of formula …<CHEM>… wherein… R<1> is hydrogen, hydroxy or methoxy,… R<2>, R<3> and R<4> independently are C1-C5 alkyl;… R0 is C1-C10 alkyl, benzyl or CH2R<6>, in which R<6> is C2-7 alkenyl or C3-C6 cycloalkyl, the pharmaceutically acceptable acid addition and quaternary piperidinium salts thereof, are potent analgesics. Pharmaceutical formulations containing such compounds, a method for effecting analgesia, intermediates and a process for preparing such compounds, are provided.
    公开号:SU967275A3
    申请号:SU792847573
    申请日:1979-11-28
    公开日:1982-10-15
    发明作者:Майкл Зиммерман Деннис
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    (St) METHOD OF OBTAINING 4-PHENYLPIPERIDI 1SH .1 The invention relates to methods for making new 4-phenylpiperidines that can be used in. as anesthetics. The known alkylation reaction of the monium salts with lithium-i-compounds is known. The aim of the invention is to develop a method for the preparation of new compounds with valuable pharmacological properties based on a known method. This goal is achieved by the method of obtaining 4-phenyl-piperidines of the general formula. f R where Kl is hydroxy or methoxy group “7. ";; b4 ob, alkyl with 1-4 C, OR THEIR SALTS, which consists in the interaction of the immonium salt of the formula in which R, R, R and R have the indicated meanings, and X is BF with C alkylating agent RLI, where R has the indicated value. The group of compounds of the formula I also includes pharmaceutically acceptable acid addition salts. Such salts are salts that are prepared using commonly used inorganic acids such as hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric, and similar acids. Organic acids can also be used to form salts of Formula T. Commonly used organic acids include acetic, maleic, picric, benzoic, succinic, Jmino, ascorbic, and similar acids. The piperidines of formula I additionally form four ammonium salts with a number of alkylating agents such as methyl chloride, ethyl bromide, allyl iodide, dimethyl sulfate, and the like. The 1-alkylation reaction to obtain the tetra-substituted piperidines of the formula I is carried out by mixing the appropriately Alkyl-rich-each reagent with 1, 4, 3-trizametro-4-aryl-3, 4,5, b-tetrahydropyryl diium salt. The alkylating reagent is typically used in more than one molar excess, for example, from about 1 to about 100 molar excess. to the immonium salt. Alkylation can be carried out in / on any of organic solvents such as diethyl ether, tefr &amp; hydrofuran, dichloromethane, benzene, dioxane and the like. Reactions at a temperature of from about 20 to about usually essentially complete in about 1-10 hours. The obtained tetrasubstituted 4-arylpiperidine of formula 1 can be easily isolated by decomposing any unreacted alkylating agent, for example, washing the reaction mixture with an aqueous solution of chloride ammonium or similar. The organic layer is then separated off, and the solvent is evaporated from it to produce a 1,2,4,5-tetra-substituted 4-arylpiperidine of the formula 1. The compound obtained can. be further purified if necessary by conventional methods, for example by chromatography, distillation, crystallization, and similarly. PRI me R 1. l, 2,4,5-tetramethyl-4- (3-methoxyphenyl) -piperidine. A solution of 34.3 g of 1,4,5-trimethyl-4- (3-methoxyphenyl) -3,4,5,6-tetrahydropyridinium tetrafluoroborate in 60 ml of a 1.6 M solution of methyl lithium in cystic ether is stirred for two hours at . The reaction mixture is then diluted with 50 ml of a saturated aqueous solution of amlonium chloride. The organic layer is separated, washed several times with water, dried, and the solvent is removed by evaporation at a reduced pressure to obtain 3.2 g of 1,2,4,5 tetramethyl-4- (3-label syphenyl) -piperidine. The product obtained in this way is dissolved in 35 ml of diisopropyl ether containing 1.5 g of maleic acid in 75 ml of ethyl acetate. The resulting solid precipitate is collected, dried and identified as 1,2,4, 5-tetramethyl-4- (3-methoxyphenyl) PI-peridinium male-T, T, mp. 119-121, Analysis for Calculated: C 66.09, H 8.04, N 3.85. Found: C, 65.88; H, 7.82; N. Example 2. 1, 2.4, 5-tetra.methyl-4- (3-6xifeNelo / -piperidine. A solution of 900 mg 1,2,4,5-tetramethyl-4- (3-methoxy. 10 ml of glacial acetic acid, containing 10 ml of a 48% aqueous solution of hydrobromic acid, is stirred at 24 ° C for 24 hours. The reaction mixture is then diluted with water and alkalized to pH 10 with sodium hydroxide solution and aqueous alkaline solution | extracted with diethyl ether, the ether extracts combined, washed with fresh water and dried. Removal of the solvent by evaporation under reduced pressure and em oil, the oil thus obtained crystallizes with ethyl acetate. Recrystallization of the product from 95 ml of ethyl acetate gives 640 mg of I, 2,4,5-tetramethyl-4- (3-hydroxyphenyl) -piperidine. mp. 2X) 77 C (with decomposition). Analysis for QJC- HaiNO. Calculated: C, 77.21; H, 9.94; N, 6.00. Found: C, 76.94; H, 9.76; N, 5.89. EXAMPLE 3. 1,2,3-trimethyl-4-n-propyl-4- (3-methoxyphenyl) -piperidine. l . A solution of 10 g of 1,5-dimethyl-4-n-propyl-4g of (3-methoxyphenyl) -3,4,5,6-tetrahydropyridine tetrafluoroborate in 200 ml of diethyl ether containing 100 MP 1.6 M methyl lithium in diethyl ether the mixture is stirred at ambient temperature for 4 hours. The reaction mixture is then washed with 100 ml of a saturated aqueous solution of ammonium chloride, several times with water and dried. Removal of the solvent by evaporation at a lower pressure gives 9,, 4 g of l, 2,5-trimethyl-4-n-propyl-4- (3-methoxyphenyl) -piperidine. A solution of 790 g of the product thus obtained is dissolved in 20 ml of ethyl acetate and stirred at 340 mg maleic acid. The resulting precipitate is collected, dried and identified as 5-trimethyl-4-n-propyl-4- (3-labels | :: ifenyl) -piperidinium maleate. T.-pl. 114g-116s. .Analysis dl. Calculated; C, 67.49; H, 8.50; N, 3.58. Found: with J, 29 H 8.24, N 3.88. Following the described procedure (Example 2) 1.1 g l, 2., 5-trimethyl-4-n-propyl-4- (3-methoxyphenyl | piperidine.
    权利要求:
    Claims (1)
    [1]
    Claim
    1. The method of obtaining 4-phenylpiperidines of General formula I
    R 4
    Branch of the PPP Patent, Uzhgorod, Project 4,
    II
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    同族专利:
    公开号 | 公开日
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    引用文献:
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    US3080372A|1960-03-25|1963-03-05|Res Lab Dr C Janssen|1-aroylalkyl-4-arylpiperidine derivatives|
    FR4208M|1963-09-18|
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    US4115400A|1976-05-27|1978-09-19|Eli Lilly And Company|1-Azoniabicyclo[3.1.0]hexanes|
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    US4581456A|1983-09-21|1986-04-08|Eli Lilly And Company|Processes for preparing picenadol precursors and novel intermediates thereof|
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    法律状态:
    优先权:
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