• 专利附录
  • 专利说明
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    • 专利摘要:
    Trans-4a-phenyl and substituted phenyl 2,3,4,4a,5,6 7,7a-octahydro-1H-2-pyrindines of the formula <CHEM> wherein: R1 is hydrogen, C1-C8 alkyl, CH2R3, <CHEM> in which: R3 is C2-C7 alkenyl, C3-C6 cycloalkyl, furyl, or tetrahydrofuryl; R4 and R5 independently are hydrogen, C1-C3 alkyl, or halogen; n is 0, 1, 2, or 3; m is 0 or 1, except that when m is o, n is other than O; X is CO, CHOH, CH=CH, S, or O, except that when n is O, X is other than S or O; R2 is hydrogen, hydroxy, C1-C3 alkoxy, or C1-C3 alkanoyloxy; and the non-toxic pharmaceutically acceptable acid addition salts thereof, are useful as analgesic agents having mixed agonist and antagonist properties. The compounds can be prepared by reacting a 4a-aryl-2-substituted-3,4,4a, 5,6,7-hexahydro-2-pyrindine with hydrogen and platinum oxide.
    公开号:SU841586A3
    申请号:SU782701053
    申请日:1978-12-26
    公开日:1981-06-23
    发明作者:Майкл Зиммерман Деннис
    申请人:Эли Лилли Энд Компани (Фирма)；
    IPC主号:
    专利说明:

    Target products vnschel dissolved in the form of salts with inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, phosphoric, nitric, perchloric, nitric, or such organic acids as the uksusns, propionic, paratoluolsulfoksilota, chloroacetic, maleic, cinnamic, tartaric, oxalic, citric, lactic, palmitic, stearic, benzoic and other acids. Salts of the compounds of formula (I) are prepared by dissolving 4a-aryl-2-oiled octahydro-1H-2-pyridine in an appropriate solvent, for example diethyl ether, ethyl acetate, non-acetic acid or ethanol, and an equivalent amount or excess of the corresponding acid is added. . The resulting precipitated salt is separated by filtration. Compounds of the general formula SG have two asymmetric centers, namely, in the 4a and 7a positions and can be isolated as optical isomers or racemic mixtures of these of the cells. However, only trans isomers of formula (1). The hydrogenation of compounds of general formula (D) is carried out in an organic solvent, for example, methanol or ethanol, usually for 1-8 hours under a hydrogen pressure of 2.74 to 5.48 atm. After hydrogenation, a mixture of 1.7a-trans and 1.7a-cis isomers is usually obtained, in which the trans isomer constitutes the majority. The isomers are separated by recrystallization of their salts. For example, rac. The octahydropyrindines mixture is converted to picrate or maleate, with cis-racemate usually crystallizing with the first solvent such as diethyl ether or diisopropyl ether, and therefore can be separated from the trans-racemate by filtration. The starting 1,7a-hexahydropyrin dynes are obtained by condensation of phenylthi or 3-substituted phenyllyl with 1-alkyl-4-piperidine, followed by dehydration of the corresponding 1-alkyl-4-phenyl - or substituted phenyl-4-hydroxypiperidine to 1-alkyl4-aryl- 1-, 2,3, b-tetrahydropyridine ,. which is treated with dihalopropylene, for example 3-chloropropyl bromide, and the resulting 1-alkyl-4-aryl4 3-halopropyl J-1,2,3,4-tetrahydropyridine is then cyclized by reaction with sodium iodide in acetonitrile and get the corresponding 4-aryl-2 -alkyl-3,4,4a, 5, b, 7-hexahydro-2-pyrindine. Starting Materials Primer, A solution of 159 ml of butyl lithium in 100 ml of hexane, containing 47.7 g of 3-methoxybromobenzene, is stirred at -25 ° C for 20 minutes, then heated to room temperature and stirred for another 1 hour to obtain 3- methoxyphenyllithium. The reaction mixture is cooled before and with stirring, a solution of 50 g of 1-methyl-4-piperidone in 100 ml of diethyl is added dropwise. ether for 30 minutes After the addition is complete, the reaction mixture is stirred for another 2 hours, then 50 ml of a saturated sodium chloride solution is added. The solution is extracted several times with diethyl ether, the ether extracts are combined and the solvent is evaporated. Yield 38 g of 1-methyl-4-hydroxy-4-3 methoxyphenyl-piperidine. ExampleB To a stirred solution (200 ml) of 50 g of phosphorus pentaoxide in methanesulfonic acid are added in portions over 4 minutes 59 g of 1-methyl-4-oxime-4- | 3-hydroxyphenyl-piperidine. As a result of the exothermic reaction, the temperature rises to. After the addition of the piperidine derivative is completed, the reaction mixture is poured onto 200 g of ice, the aqueous mixture is alkalinized with ammonium hydroxide, extracted several times with diethyl ether, the ether extracts are combined, washed with water, dried, the solvent is distilled off in vacuo and 44.7 g of product are obtained in the form of oils. This oil is distilled and 1-methyl-4-13 methoxyphenyl 1-1, 2,3,6-tetrahydropyridine is obtained with a bp 123-138 ° C 0.1 mm. Hg Calculated% C, 76.81; H 8.43; N 6.89% N0 Found: C 76.52, H 8.15, N 6.67%. Example To a stirred cold (-5 to -l.) Solution of 25 g of 1-methyl-4-phenyl-1,2,3, b-tetrahydropyridine in 450 ml of tetrahydrofuran, 90 ml of 1.6 are added dropwise over 30 minutes. molar, butyl lithium in hexane. After the addition is complete, the solution is stirred for 10 min at -IcPc, then cooled to. The cold solution is added dropwise over the course of 20 minutes to a stirred solution of 73.3 g of 3-chloropropyl bromide in 300 ml of diethyl ether, cooled to -50 ° C. After the addition is complete, the reaction mixture is heated to and diluted with 500 ml of saturated aqueous sodium chloride solution cooled to. The organic layer is separated, washed with water and extracted with 1200 ml of 1N hydrochloric acid. The aqueous acidic layer was washed with diethyl ether and made alkaline by adding dropwise a concentrated aqueous solution of sodium hydroxide. The alkaline solution was extracted several times with diethyl ether, the ether extracts were combined, washed with water and dried. After removal of the solvent, an oil is obtained which is dissolved by IB with 2500 ml of acetonitrile containing 52.5 g of sodium iodide. The reaction mixture is boiled under stirring for 24 hours, after which the solvent is distilled off under reduced pressure. The crude product is dissolved in a mixture of 800 with a 1N solution of sodium hydroxide and 1000 ml of diethyl ether, and the mixture is intensively stirred for 45 minutes. Then, the ether layer was separated by washing with a saturated aqueous solution of sodium chloride and dried. After distilling off the solvent under reduced pressure, the product is obtained in the form of an oil, which after distillation gives 21.5 g of 4 phenyl-2-methyl-3, 4, 6,7, -hexag of 2-pyridine. Bp 110-112C at a pressure of 0.075 mm Hg Calculated,%: C 84.46; H 8.98; 6.57,% N Found; C 84.74, H 8.72, N 6.28%. Example 1-methyl-4-Z-mephenyl -1,2,3,6-tetrahydropyridine is reacted with 3-chloropropyl bromide and sodium iodide according to the procedure described in Example C to obtain 4a-3-methoxyphenyl -2-methyl-3, 4.4a, 5,6,7-hexahyd, ro-2-pyridine with bp. 132-134 C / / 0.1 mm. Hg C 78.97; H 8.70; Calculated,% 5.76%% Ch: C 76.58, H 8.28, Found, N 5.36%. (M / e theoretically 243, found 243). Target Products Example A solution of 5.0 g of 4-phenyl-2-methyl-3, 4.4a, 5,6,7-hexahydro-2-pyridine in 50 ml. ethanol containing 500 mg of platinum oxide is stirred at room temperature for 4 hours in a hydrogen atmosphere under a pressure of 4.13 atm. The mixture is then filtered and the solvent is distilled off and. an oil is obtained which, according to NMR spectrum and liquid chromatography, is 40% from cis-4a-phenyl-2-methyl-2, 3,4,4a, 5, 6, 7,7a-octahydro-1H-2- pyridine - 60% of the corresponding trans isomer. The mixture is dissolved in 50 ml of diethyl ether and acidified by the addition of a saturated solution of hydrogen bromide dissolved in diethyl ether. After distilling off the ether, the precipitated crystals are filtered and the precipitate is cross-crystallized from 30 ml of isopropanol and 70 ml of diisopropyl ether to obtain 2.6 g of cis-4a-phenyl-2-methyl 2,3,4,4a, 5,6,7,7- octahydro-1H-2 pyrindine hydrobromide. The filtrate is evaporated to dryness and the 6d is dissolved in water. The aqueous solution is heated by adding 1N sodium hydroxide solution and aqueous (The alkaline solution is extracted with diethyl ether. The ether extracts are combined, washed with water and dried. Distillation of the solvent under reduced pressure gives 2 57 g of trans-4a-phenyl2-methyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine. The trans-pyrindine derivative is dissolved in 120 ml of ethanol and reacted with 2.76 g of picric acid, 2.7 g of trans-4aphenyl-2-methyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyrindine picrate with mp 167- 168 0. Calculated,%: C 56.75, H 5.44, N 12.61 C2- (Hi4N4 ° 7 Found,%: C 56.99, 5.65, rf 12.46. P m and m p 2. Repeat the procedure of example 1, but translate the reaction of the transpiridine derivative with maleic acid and trans-4-phenyl-2-methyl-2, 3,4,4a, 5,6,7a-octahydro-1H-2-pyrindinium maleate with mp 113-114 C. Calculated,%: C 68.86, H 7.60; N4.23 c Has-N 4 Found,%: C 68.66} H 7.82; N 3.98 Pr-p and m er 3. According to the procedure of Example 1, 4a; 3-methoxyphenyl -2-methyl3,4,4a, 5,6,7-hexahydro-2-pyrindine is hydrogenated onto platinum oxide and the mixture is 60:40 trance -4a-Cz-metroxyphenyl -2-methyl-2,3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine and corresponding guide cis-isomer. The trans isomer is crystallized as picrate. The transisomer was isolated as a free base, i.e., trans-4a-Cz-methoxyoxyphenyl -2-methyl2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine with m.p. 40-430C. Calculated,%: C 78.32; H 9.45; 5.71 S-Gb1CH N0 C 78.26; H 9.31; Found,%: 5.61%. 4. Solution of 3.5 g Example of -4a-Gz-methoxyphenyl i-2-methyl, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridine in 35 ml of glacial acetic acid containing 35 ml of 50% hydrobromic acid is stirred at the boiling point for 15 h. Then the reaction mixture is cooled to room temperature and diluted with 100 g of water. The acidic aqueous solution is alkalified by adding a concentrated solution of caustic tent: to H 9.8 and the aqueous alkaline solution is cracked several times with diethyl ether. The ether extracts are combined, washed with water and dried. Distillation of the solvent under reduced pressure yields 1.8 g of the product as the first substance. This substance is recrystallized with 8 ml of ethyl acetate and 1.65 g of trans-4a-3-hydroxyphenyl} 2-methyl-2, 3,4,4a, 5,6,7,7a-octahydro-1H-2-pyridindine with t. square 192-194c.
    Calculated,%: C77,88; H 9.15; N 6.05
    .
    Found,%: C 77.48; H 8.71; N 5.67.
    权利要求:
    Claims (2)
    [1]
    1. The method of obtaining trans-4a-phenyl (substituted phenyl) -2,3,4,4a, 5,6, 7,7a-octahydro-1H-2-pyrindines is of the general formula
    but
    ./V-/
    f
    where Rjj-C -C is alkyl; R. - an atom of hydrogen, hydroxy or alkoxy, or their salts, of which is compound o6rr (eii of the formula
    (u)
    / V-fl
    i)
    where R (is a hydrogen atom or a skil), R has the above values is subjected to hydrogenation with hydrogen in the presence of platinum oxide, then alkylated if RJ is a hydrogen atom, and the obtained target product is either isolated in free form or as a salt, or necessary when the Rg-C-Cj alkoxy group is dealkylated and the resulting compound, where the hydrogen atom is separated, is isolated.
    [2]
    2. The method according to claim 1, wherein the dealkylation is carried out in the presence of glacial acetic and aqueous hydrobromic acids,
    Sources of information taken into account in the examination
    1. K. Buhler and D. Pearson. Organic syntheses. M., Pir, 1973, v.1 p.27-28.
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    同族专利:
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    引用文献:
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    DE2336559A1|1972-07-20|1974-01-31|Du Pont|4A-ARYL-TRANS-DECAHYDROCHINOLINES AND THE METHOD FOR THEIR PRODUCTION|
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    PT67194B|1976-11-02|1979-03-23|Lilly Co Eli|Process for preparing 4a-aryl-octahydro-1h-2-pyrindines|US4537963A|1981-12-28|1985-08-27|E. I. Du Pont De Nemours And Company|Intermediates for octahydrobenzofuro[3,2-E]isoquinolines|
    US4579952A|1981-12-28|1986-04-01|E. I. Du Pont De Nemours And Company|Intermediates for octahydrobenzofuro[3,2-e]isoquinolines|
    US4415736A|1981-12-28|1983-11-15|E. I. Du Pont De Nemours & Co.|Certain tetrahydropyridine intermediates|
    FR2617481B1|1987-07-03|1989-11-10|Roussel Uclaf|NOVEL TETRAHYDROPYRIDINE DERIVATIVES, PROCESS FOR THEIR PREPARATION AND PREPARATION INTERMEDIATES, THEIR APPLICATION AS MEDICAMENTS AND THE PHARMACEUTICAL COMPOSITIONS CONTAINING THEM|
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    法律状态:
    优先权:
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