• 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:
    A process for the O-methylation of hydroxyaporphines is disclosed. This process utilizes a trimethylphenylammonium base as the alkylating agent.
    公开号:SU925249A3
    申请号:SU782700555
    申请日:1978-12-21
    公开日:1982-04-30
    发明作者:Хартенштайн Йоганнес；Затцингер Герхард
    申请人:Варнер Ламберт Компани (Инофирма)；
    IPC主号:
    专利说明:

    RjjRjtR - 5b has the above values, provided that at least one of RI Rj-jRg and R is a hydroxyl group, is methylated with phenyltrimethylammonium hydroxide in a solvent at 100-150 ° C, followed by isolation of the target product in free form or as salt . As a pactvopitel, a mixture of carbon monoxide and a polar solvent is used, preferably a mixture of toluene and / or li xylene with dimethylformamide, dimethyl sulfoxide and / or hexa methylphosphoric triamide. The polar solvent is used in an amount of 10-20 by volume of the solvent mixture. Between 1.25 and 2 mol of phenyltrimethylammonium hydroxide are preferably used to methylate each hydroxyl group. The advantage of this method is the replacement of explosive diazomethane with a less explosive methylating agent, which simplifies the process. Example 1. 1,2,9,10-Tetramethoxyaporfin. Option A. 0-Methyl (+) - 2, 9-dirxy-1,10-dimethoxyaporphine. 327 mg of (+ -) - 2,9-Dioxy-1,10-dimethoxy-porphine in a mixture of 2 ml of dimethylformamide and 20 ml of toluene are heated to SO-SS C and 3.5 ml of 1N are added dropwise. a solution of phenyltrimethylammonium hydroxide in methanol, continuously stirring and at the same time azeotrope methanol: toluene. The entire procedure takes about 10-15. After the introduction of the reagent is complete, the reaction mixture is heated until the temperature of the stripping fraction reaches approximately. After that, heating is continued for another 15-30 minutes. According to thin-layer chromatography, by the end of the reaction, the starting material is practically absent. The reaction mixture is cooled, the precipitated phenyltrimethyl ammonium hydroxide is filtered off and the filtrate is evaporated in a vacuum created by a water-jet pump. The dimethylaniline formed as a result of the reaction is as fully as possible distilled off at a temperature of 70 ° C and a pressure of 0.1 mm Hg. on the rotor, the residue is dissolved in toluene and potassium hydroxide, and then with water. After drying the organic phase and distilling off the solvent, a yellowish oily consistency response is obtained, which is dissolved in a small volume of ethanol and mixed with a small amount of hydrogen bromide, in the form of a 48% aqueous solution, relative to the calculated one. at ambient temperature, hydrobromide (1) -1, 2.9, 10-tetramethoxy-porphine crystals precipitate; m.p. 221-224 ° C; yield 366 mg (8 of the theoretical), + 86.9 (0.2% in ethanol). The aqueous extracts are combined and slightly acidified with hydrochloric acid, then mixed with ammonia. After extraction with chloroform, drying and separation of the organic phase, 3 mg of a mixture of two isomeric monomethylated products, i.e. 2-hydroxy-1, 9-10-trimethoxy-porphine and 9-hydroxy-1, 2,10-trimethoxy-porphine, which can be reused in the methylation step. If dimethyl sulfoxide or methylphosphoric triamide hexemol is used instead of dimethylformamide, the yield of these products is 70 and 85 of the theoretical, respectively. Option B. 0-Meti1 1p6in (+) - 2-Oxy-1, 9,10-trimethoxyaporphine. 6.5 g of (+) -2-hydroxy-1,9, U-tri-label of syaporphine is dissolved by heating in 300 ml of a mixture of toluene: ethanol (8: 2 by volume). At a bath temperature of 9095 ° C, the resulting solution is added dropwise over about 10 minutes with vigorous stirring and simultaneous distillation of the azeotrope of toluene: ethanol ijO ml of 1N is added. phenyltrimethylammonium hydroxide solution. After the introduction of the reagent is completed, the temperature in the bath is increased until it reaches the boiling point; waste; 4th fraction. Boiling continued for 1 hour, after which the analysis by thin layer chromatography shows the complete absence of the starting compound. Further processing of the reaction mixture is carried out in accordance with the procedure described in embodiment A, you) (one of (+) - 1,2,9,10-tetramethoxy-porphine hydrobromide is 6.1 g (70 of the theoretical), so pl. 221223C Option C. O-Methylation of (+) - 1,9-Dioxy-2,10-dimethoxy-porphine. Similarly to Option A, 327 mg of (+) -, 9-dioxy-2,10 dimethoxy pyrophene is reacted in toluene: dimethylformamide with i ml of 1N methanol solution of phenyltrimethyl ammonium hydroxide. After appropriate treatment and recrystallization of the residue from diethyl ether, half a pure (±) 1,2,9,10-m tetramethoxyagurfin with an output of more than 75 from the theoretical, mp 138-139 C. Example 2. Nn-Propyl-1,2, 9,1O-tetramethoxy-H-noraporphin-tartrate 0-Methylation (+) - 1-hydroxy -K-n-propyl-2,9,1O-trimethoxy-N-HOpanopfina. Similarly to variant A of example 1, 2 g of (1) -1-hydroxy-M -n-propyl-2,9,10- trimethoxy-H-norapene in a mixture of 15 ml of dimethylformamide and 200 ml of toluene with 16.5 ml of 1 and a non-nanol solution of phenyltrimethyl ammonium hydroxide. After appropriate treatment of the mixture, 2.1 g of a yellow syrup-like substance is obtained, which, as shown by analysis using the thin layer chromatography method, consists of practically one 0-methylated product. After mixing with an ethanolic solution of vinic acid, P-n-propyl-1,2,9,10-tetramethoxy-K-noraporphintartrate, racemate is obtained, m.p. 188189 ° C. Not only the starting compound (±) -1-hydroxy-Nn-propyl-2, 9,10-trimethoxy-N-noproporphine, but also the derivative of permethylated aporphine derived from it is a novel and pharmacologically valuable compound. (±) -1-hydroxy-M-n-propyl-2,9,10-trimethoxy-M-noraphosphine, used as the starting compound, was prepared as follows. 1- (3, -Dimethoxybenzyl) -6-methoxy-7-benzyloxy-31 -Dyhydroisohmolonia, obtained from 27 g of the corresponding hydrochloride, is mixed with 100 ml of 1-iodo-propane. The reaction mixture is slowly heated to 80-85 ° C with stirring and no light. First get rastVor, from which falls propiodid. After conducting the reaction for 3 hours, the duct is filtered on a Buchner funnel and washed with acetone. 27 g of obtained iodide 1 (3, -dimethoxy-benzyl) -2-n-propyl-6-methoxy-7-benzyloxy-3-dihydroisoquinoline cyc pendyryyuf in 500 ml of methanol and mixed in portions at a temperature of about 6 g of sodium borohydride, translated compound into solution. Thereafter, most of the solvent is removed by vacuum and the product is crystallized from methanol at. The crystals are filtered on a vacuum funnel, and then washed with isopropanol, get 17, g (t) -1 - (3, C -dimethoxybenzyl -2-n-propyl-6-methoxy-7-benzyloxy-1, 2,3, - tetrahydroisoquinoline, mp: 71-73 ° C. 15 g of the obtained tetrahydroisoquinoline is dissolved in 75 ml of glacial acetic acid. After the solution is frozen in an ice bath, 30 ml of concentrated nitric acid are added to the solution at a temperature of approx. C for 5 minutes. After that, the reaction mixture is mixed with ice, alkalinized with a concentrated solution of ammonia and extra g41 is chloroform.After drying and distilling off the chloroform, the residue is recrystallized from methanol to give 10.5 g of (1) -1- (3, dimethoxy-6-nitrobenzyl) -2-n-propyl-6-methoxy-7- benzyloxy-1, 2,3-tetrahydroisoquinoline, mp 119-120 C. 10 g of the obtained nitro compound is dissolved in 300 ml of 80% aqueous ethanol and acidified with dilute hydrochloric acid. The resulting pale brown solution is hydrogenated at room temperature in the presence of 5 g of carbon-palladium catalyst, the supply of hydrogen is stopped after 30 minutes. The reaction mixture is filtered, the filtrate is evaporated under vacuum. The residue is subjected to aiming with ammonia and then extracted with chloroform. After the usual treatment, (±) -1- (3, -dimethoxy-6-aminobenzyl) -2-n-propyl-6-methoxy-7-oxy-1, 2.3-tetrahydroisoquinoline is obtained in the form of a syrup, with which they re-share without further purification. The crude product is dissolved in 150 ml of 20% sulfuric acid and
    权利要求:
    Claims (1)
    [1]
    Claim
    A process for preparing 0-methylated derivatives oksiaporfinov g of the general formula I
    VNIIIPI branch of PPP Patent, Uzhhorod, st. Project, 4
    类似技术:
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    同族专利:
    公开号 | 公开日
    FR2430942A1|1980-02-08|
    AT362535B|1981-05-25|
    JPS54119474A|1979-09-17|
    BE872843A|1979-04-17|
    CH645629A5|1984-10-15|
    ATA913578A|1980-10-15|
    CS238601B2|1985-12-16|
    DE2757335B2|1981-05-27|
    DE2757335A1|1979-06-28|
    DD141830A5|1980-05-21|
    NL7812394A|1979-06-26|
    FR2430942B1|1985-02-22|
    GB2010841B|1982-08-18|
    HU177060B|1981-06-28|
    FI68222B|1985-04-30|
    GB2010841A|1979-07-04|
    US4309542A|1982-01-05|
    FI68222C|1985-08-12|
    FI783951A|1979-06-23|
    DE2757335C3|1982-03-25|
    引用文献:
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    US1100998A|1912-05-06|1914-06-23|Firm Of Mckesson & Robbins|Process of manufacuring alkyl-ethers of morphin.|
    GB1364318A|1971-03-15|1974-08-21|Bellon Labor Sa Roger|Laurotetanine derivatives|
    DE2337507A1|1973-07-24|1975-02-13|Research Corp|Aporphines synthesis by cyclisation of an amine inter - specif. the corresp. 1--1,2,3,4-tetra-hydroisoquinolines|
    DE2625116C2|1976-06-04|1984-01-26|Gödecke AG, 1000 Berlin|Process for the preparation of 4-hydroxy-aporphine derivatives|
    JP4428113B2|2004-04-07|2010-03-10|凸版印刷株式会社|Mouth plug with pull ring for opening liquid containers|DE3118521A1|1981-05-09|1982-12-02|Gödecke AG, 1000 Berlin|DIBENZOCHINOLIN DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE IN THE FIGHT AGAINST COLD DISEASES AND ALLERGIES|
    US4795759A|1985-07-27|1989-01-03|Sandoz Ltd.|Use of dibenzindoles|
    US6210680B1|1999-06-11|2001-04-03|Univera Pharmaceuticals, Inc.|Method for the prevention and treatment of chronic venous insufficiency|
    WO2002016325A1|2000-08-23|2002-02-28|Mingjai Su|Uses of thaliporphine or its derivatives in treatment of cardiac diseases and preparation of same|
    TWI225397B|2000-05-04|2004-12-21|Nat Science Council|Uses of thaliporphine or its derivatives in treatment of cardiac diseases and preparation of the same|
    AU2003242227A1|2003-06-19|2005-01-04|Lotus Pharmaceutical Co., Ltd.|Aporphine and oxoaporphine and the medical use thereof|
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    TWI531369B|2014-05-30|2016-05-01|資元堂生物科技股份有限公司|Use of an aporphine alkaloid derivative in manufacturing a medication effective in ampk activation|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE2757335A|DE2757335C3|1977-12-22|1977-12-22|Process for the O-methylation of hydroxyaporphines|
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