• 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 invention relates to substituted pyridines, in the preparation of the 5-methyl 3 / i- (N-benzyl-methyl-2-methyl) ethyl ester 2,6-dimethyl-4-g (3-nitrophenyl) -1,4-dihydropyrncin- -3,5-dicarboxylic acid or its hydrochloric acid salt, which is a cerebral and coronary carrier used in medicine. The goal is to increase the yield of the target product and simplify the process. The latter is carried out by partial hydrolysis of 2,6-dimethyl-4- (3-nitrophenip) -1,4-dihydropyridine-3 dimethyl ester, 5-dicarboxylic acid in the presence of NaOH in methanol medium at boiling, followed by treatment with M- (2- chloroethyl-K-benzonylmethipamine in an inert organic solvent medium in the presence of a proton acceptor, triethylamine at 120 C. The target product is added as a base or as a hydrochloric acid salt. These conditions eliminate the need for cleaning, since the target product is obtained with a mp. 202-206 ° C and a yield of 66% (base) or with m.p. 129-132 ° C and 70% yield (salt). i a; o ate
    公开号:SU1419516A3
    申请号:SU864027513
    申请日:1986-05-20
    公开日:1988-08-23
    发明作者:Антончич Любо；Язбец Изток；Коцан Дарко；Кривец Ивана
    申请人:Лек Товарна Фармацевтских Ин@ Кемичних Изделков Н.Сол.О.(Фирма)；
    IPC主号:
    专利说明:

     about
    AND: oTHocntcH is indicated for the production of heterocyclic compounds, in particular the improved method for the preparation of the derivative 1, A-dihydropyridine of the formula
    Hjcoo
    coosNgSNgM
    This is its hydrochloric acid salt, which is a cerebral and coronary aerator.
    The purpose of the invention is to increase the yield of the target product, as well as simplify the process by eliminating additional purification steps.
    Example. N- (2-Chloroethyl) -H-benzylmethylamine.
    I. To a solution of 16.5 g (0.1 mol) of H- (2-hydroxyethyl) -K-benzylmethylamine in 100 ml of chloroform with stirring
    and at room temperature, under conditions which exclude the presence of moisture, 13 g (0.11 mol) of thionyl chloride are gradually added. The reaction mixture is heated to its boiling point, then further stirred for 30 minutes at the same temperature. Then, the reaction mixture was washed three times with a 10% aqueous solution of sodium hydrogencarbonate, 200 ml of this solution were applied each time, and then two times washed with water, each time using 200 ml of the latter. - The organic layer is dried over anhydrous sodium sulphate, filtered, and then the filtrate is evaporated to dryness.
    As a result, 1A is obtained in the form of an oily residue, 3 g (78%) of the title compound. Gross C formula. Molecular Weight 183.
    II. A solution of 12.1 g (mol) of N- -benzylmethylamine, 14.3 g (0.1 mol) of 1-bromo-2-chloroethane and 14 g (0.1A mol) of triethylamine in 100 ml of toluene is stirred into for 4 h at the boiling point of the reaction mixture. The organic solution is evaporated, the oily residue is dissolved in a small amount of a mixture containing ethyl acetate, methyl alcohol and ammonia in a ratio of 80: 30: 3, after which the resulting products are separated using chromatography on a column filled with cpc gel. In pe0
    five
    0
    5 0 c Q

    g
    As a result, 2 g (10.9%) of N- (2-chloroethyl) -N-benzipmetkpamine and 4 g (14.9%) of dimeric 1,2-bis-M-benzylmethylaminoethane are obtained in a half oily substance. Gross formula C, oH, NCl. Molecular Weight 183.
    III.3-Methyl 2,6-dimethyl- -4- (3-nitrophenyl) -, 4-dihydropyridinedicarboxylic acid-3,5.
    17.3 g (0.05 mol) of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridinedicarboxylic-3,5-dimethyl ester are suspended in 280 ml of methyl alcohol, after which the prepared suspension while stirring at room temperature, mix with a solution of 15.9 g (0.4 mol) of sodium hydroxide in 52 ml of water. The reaction mixture is stirred for 5 hours at reflux temperature. Then the reaction mixture is cooled, with stirring, mixed with 1050 MP of water and filtered. The precipitate is the starting compound which did not react, namely the 2,6-dimethyl-4- (3-nitrophenyl) -1,4-digipropyridyridicarboxylic acid dimethyl ester-3, 5 acid. The clear filtrate is mixed with 1 g of activated carbon and the mixture is stirred for 30 minutes at 50-60 C. Then the mixture is cooled, the activated carbon is filtered by adding 1N. the hydrochloric acid filtrate is acidified to a pH of 2.5, after which the precipitate formed is separated by filtration. The precipitate is additionally washed twice with water, each time applying 15 ml of the latter. The result is 11 g (66%) of pure compound. Melting point of the product is 202-206 ° C. Gross formula C gHigN O. Molecular weight 332. L
    NM (LMSO-ab): 2.4 (6H, S C.g-CH,); 3.6 (3H, S -COOCHj); 5.1 (1H, S,); 9 (1H, -N-H).
    IV.Hydrochloride 5-methyl 36- - (N-benzyl-N-methylamino) -ethyl 2,6-dimethyl-4- (3-nitrophenyl) -, 4--dipropyridine-3, 5-dicarboxylic acid (nicardipine hydrochloride) .
    I
    A solution of 3.32 g (0.01 mol) of 2,6-dimethyl-4- (3-nitrophenyl) -, 4-digewropyridine dicarbono 3-methyl ester. howl-3,5 acids, 1.83 g (0.01 mol) of N- (2-chloroethyl) -N-benzylmethylamine and 1.4 g (0.014 mol) of triethylamine in 60 ml of N butyl alcohol are heated
    for 2 h at 120 ° C. The reaction mixture is then evaporated, resulting in an oily residue, which contains crude 5-methyl 3ft- (K-benzyl-M methyl; -to) ethyl ester 2,6-dimethyl-4- (3-nitrophenyl ) -1,4-dig1-shpyridine-3,5-dicarboxylic acid (nicardipine as base).
    The oily residue is dissolved in 22.2 ml of chloroform, the solution is washed with 16.0 MP of a 10% hydrochloric acid solution, after which the solution is washed three more times with water, using each time 10 ml of the latter. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off in vacuo under reduced pressure. The oily residue is dissolved in 17 ml of ethyl acetate and the resulting solution is stirred for 2 hours at. The precipitate formed is filtered off, dried under vacuum and recrystallized from acetone. 3.6 g (70.0%) of the product (nicardipine hydrochloride) are obtained, the melting point of which is 129-132 ° C (with decomposition).
    Gross formula Cjg H-joN. Molecular Weight 515.
    NMR (DMSO-dt): 5 2.21 (G, S,
    h
    -NV); 2.36 (bn, s, s ,, b-skz); 2.7
    (2H, t, N-CHi); 3.5 (2H, S,)
    3.7 (3H, S, -COO-CHE); 4.2 (2H, t,
    -COOCHj-); 5.15 (1I, S, C4.-H); 9,13
    (Jh,),
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    . Method of producing 5-methyl 3ft- (L-benzyl-K-meth-lamino) -ethyl
    the ester of 2,6-dimethyl-4- (3 -nitrofemil;) - -1,4-digi; 1, ropyridin-3, 3-dicarG penI) acid of the formula
    irr TOSN
    HjCOOCN COOCH CH N /, - ..
    NCLWN 2 w
     n
    or its hydrochloric acid salt, characterized in that, in order to increase the yield of the target product and simplify the process, 2,6-dimethyl-4- (3-nitrophensh) dimethyl ester 4-: dihydropyridine-3, 5-dicarboxylic acid partially hydro; using an aqueous solution of an alkali metal hydroxide, such as sodium hydroxide, in the presence of an inert organic
    a solvent, such as methanol, at the boiling point of the reaction mixture and the resulting 3,6-methyl ester of 2,6-dimethyl-4- (3-nitrophenyl) -1,4-dihydropyridine-3,5-dicarboxylic acid
    formulas
    N0
    NSSOOSu COO
    H
    subjected to interaction with N- (2- -chloroethyl) -N-benzyl-methylamine of formula
    C1CH2CH2N
    NZS
    in the presence of an inert organic solvent and a proton acceptor, such as triethylamine, at 120 ° C and inject the desired product as a base or its hydrochloric acid salt.
    Editor V.Danko
    Compiled by N. Bannikova
    Tehred M.Hodanich Proofreader V.Girn to
    Order 4159/58
    Circulation 370
    VNIIPI USSR State Committee
    for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
    Subscription
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    引用文献:
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    DE2218644C3|1972-04-18|1982-08-19|Bayer Ag, 5090 Leverkusen|Basic esters of 1,4-dihydropyridines, processes for their preparation and their use as pharmaceuticals|
    US3974275A|1972-04-18|1976-08-10|Bayer Aktiengesellschaft|1,4-Dihydropyridine carboxylic acid esters useful as coronary vessel dilators and anti-hypertensives|
    US3996234A|1972-04-18|1976-12-07|Bayer Aktiengesellschaft|1,4-Dihydropyridine carboxylic acid esters|
    JPS5930704B2|1973-02-20|1984-07-28|Yamanouchi Pharma Co Ltd|
    DE2847236A1|1978-10-31|1980-05-14|Bayer Ag|NEW DIHYDROPYRIDINE WITH SUBSTITUTED ESTER GROUPS, MORE PROCEDURES FOR THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS|
    US4483985A|1978-10-31|1984-11-20|Bayer Aktiengesellschaft|Production of 1,4-dihydropyridinecarboxylic acids|
    DE2847237A1|1978-10-31|1980-05-14|Bayer Ag|Cardiovascular 1,4-di:hydro-pyridine-3-carboxylic acids prodn. - by alkaline hydrolysis of ester with electron withdrawing substit.|
    US4285955A|1978-10-31|1981-08-25|Bayer Aktiengesellschaft|1,4-Dihydropyridinecarboxylic acids|
    JPS59137461A|1983-01-27|1984-08-07|Kyowa Hakko Kogyo Co Ltd|1,4-dihydropyridine derivative|
    ZA848907B|1983-11-16|1985-06-26|Ciba Geigy Ag|Novel amide compounds|
    US4672068A|1984-05-04|1987-06-09|Fujirebio Kabushiki Kaisha|Antihypertensive 1,4-dihydropyridines having a conjugated ester|
    JPH0517905B2|1984-07-13|1993-03-10|Taisho Pharma Co Ltd|
    JPH0528224B2|1984-07-13|1993-04-23|Taisho Pharma Co Ltd|DE3833893A1|1988-10-05|1990-04-12|Bayer Ag|USE OF BASIC NITRO-PHENYL-DIHYDROPYRIDINE AMIDES AS A MEDICINAL PRODUCT, NEW COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF NEW INTERMEDIATE PRODUCTS|
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    US7585978B2|2006-11-28|2009-09-08|Navinta Llc|Processes of manufacturing substituted-1,4-dihydropyridines, improved aqueous solutions thereof, and processes of manufacturing the solutions|
    ES2332168B1|2008-04-30|2010-10-27|Consejo Superior De Investigaciones Cientificas|PSEUDOPOLIMORFICA FORM OF NICARDIPINE HYDROCLORIDE, PROCEDURE FOR PREPARATION AND FORMULATION CONTAINING IT.|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    YU847/85A|YU43409B|1985-05-21|1985-05-21|Process for preparation 2--ethyl methyl 2,6-dimethyl-4--1,4-dihydropiridine-3,5-dicarbooxilate|
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