• 专利附录
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  • 类似技术
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    • 专利摘要:

    公开号:SU784775A3
    申请号:SU782637592
    申请日:1978-07-20
    公开日:1980-11-30
    发明作者:Ручман Рудольф
    申请人:Лек Товарна Фармацевтских Ин Кемичних Изделков Н. Сол. О. (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD OF OBTAINING N-SUBSTITUTE OF PRISONER COMPLEX
    The invention relates to a process for the preparation of new lysergic acid derivatives, specifically L-substituted esters of 9,10-dihydrolizer. Traic acid of the general formula I, L eooR. where R is alkyl, alkenyl-Cj-Cj or cycloalkyl-C -Cij-; R - is a hydrogen atom or alkoxyl residue
    X is a hydrogen atom or a bromine atom with valuable pharmacological properties20 l.
    Using the well-known N-alkylation method of heterocyclic compounds using an alkylating agent such as dimethyl sulfate, 25 makes it possible to obtain new derivatives of 9,10-dihydrol-arginic acid of formula G.
    The purpose of the present invention to obtain new derivatives of 9,10-di- 30
    where X and Rj are as defined above,
    is reacted with a compound of general formula III., where R is as defined above, Y is a halogen atom or sulphate
    residue,
    and the process is carried out in the presence of a catalyst for the phase transfer of tetrabutylammonium salt such as tetrabutylammonium hydrogensulfate or tetrabutylammonium bromide in a two-phase system consisting of inert hydrolyzeric acid, possessing valuable pharmacological properties. The goal is achieved by the described method, which consists in the following: 9-10-dng zdroliesergic acid of general formula 1I is organic acid solids that cannot be mixed with water and an alkaline aqueous phase, after which the target products are equipped with HSBecTHEiuviH Mbtods. The advantage of this method is to simultaneously obtain several known compounds of the formula T, where R is methyl or ethyl, and R. and X are a hydrogen atom or R are methyl, and Rg is a methoxy group, X is a hydrogen atom, which are important intermediate products with selectivity. Example 1. 2.7 g (10 mmol) of 9,10-lysergic acid and 7 g (20 mmol) of tetrabutylammonium hydrogensulfate are suspended in 200 ml of 45% sodium hydroxide solution. A solution of 4.2 g (.300 mmol) of methyl iodide in 300 ml of benzene was added to the prepared suspension and the reaction mixture was vigorously stirred for 1 hour. Then the organic phase was separated and the aqueous phase was extracted twice more with 150 ml of benzene. containing .2D g (15 mmol) of methyl iodide. The benzene extracts are combined, washed with water until the neutral reaction, and then the solvent is evaporated to obtain 2.62 g or 88% of the theoretically calculated value of the pure crystalline methyl ester of 1-methyl-9,10-dihydro-lysergic acid, m.p. , 116-119 Th-61.1 (with O, 5, chloroform). Example 2. A two-phase system consisting of 200 ml of a 50% sodium hydroxide solution, 7 g (20 mmol) of tetrabutylammonium hydrogensulfate, 2.8 g (20 mmol) of methyl iodide and 300 ml of benzene was added with vigorous stirring 2 , 84 g (10 mmol) of methyl ester 9-10 - Dihydrolysergic acid. The reaction mixture is stirred for 30 minutes and immediately after that the phases are separated. 200 ml of benzene with 2.2 g (15 mmol) of methyl iodide were added to the aqueous phase and mixed for 30 min. Then both phases are separated from each other and the vial phase is extracted twice more with benzene, each time using 150 ml of the latter. All four beisole extracts are washed with water until neutrality of the reaction and evaporated to give 2.7 or 91%, of the theoretically calculated value, of the pure 1-methyl 10-dihydrolisergic acid crystal methyl ester. 3. 2.7 g (10 mmol) of 9,10-dihydrolisergic acid and 6.44 g (20 mmol) of tetrabutylammonium bromide are suspended in 200 g of a 45% sodium hydroxide solution. A solution of 3.78 g is added to the prepared suspension ( 30 mmol) of dimethyl sulfate in 300 ml of benzene and the reaction mass is vigorously stirred for 1 hour. Then the organic phase is separated and the aqueous phase is extracted twice more with 150 ml of benzene and 2.1 g (15 mmol) of methyl iodide. The benzene extracts are combined, washed with water until neutral, and then evaporated in vacuo to give 2.36 g, or 82.6%, of the theoretically calculated value of the pure crystalline methyl ester of 1-methyl-9,10-dihydrolyserginic acid. Example 4. 2.7 g (10 mg-yl) of 9,10-dihydrolysergic acid and 6.44 g (20 mmol) of tetrabutylammonium hydrogensulfate are suspended in 200 ml of 45% sodium hydroxide solution and solution 4 is added to the prepared suspension. 62 g (30 mmol) of diethyl sulfate in 300 t.ui of toluene. Then the reaction mass was vigorously stirred for 8 hours, then the organic phase was separated, and the aqueous phase was extracted for 4 hours, 300 ml of toluene and 1.54 g (10 mmol) of diethyl sulfate. The toluene extracts are combined, washed with water until neutral, and then evaporated in vacuo to give 2.15 g or 68.7% of the theoretically calculated value of pure 1-ethyl-9,10-dihydrolysergic acid crystalline ethyl ester, m.p. 80-82 ° C; And -70.6 ° (with 0.5, chloroform). Example 5. 2.7 g (10 mmol) of 9,10-dihydrolisergic acid and 7 g (20 mmol) of tetrabutylammonium hydrogensulfate are suspended in 200 ml of 45%. sodium hydroxide solution. A solution of 4.85 g (40 mmol) of allyl bromide in 300 ml of benzene was added to the prepared suspension and the reaction mixture was vigorously stirred for 2 hours. Then the phases were separated and the aqueous phase was extracted twice more with 200 ml of benzene each time. 2.42 g (20 mmol) of allyl bromide. The benzene extracts are combined, washed with water until neutral, and then evaporated in vacuo, yielding 2.3 g or 66% of the theoretically calculated value of 1-allyl-9,10-dihydrolyzerginic acid allyl ester in the form of a tarless, resinous product, ° C -69, (with 0.5, chloroform). Ex. 6. 0.3 g (1 mmol) of 10 - ((1-methoxylumyl-lizergic acid and 0.7 g (2 mm9l) of tetrabutylammonium hydrogensulfate are suspended in 20 ml of 45% sodium hydroxide solution and the prepared suspension is extracted three times when using each time, 30 ml of benzene and 0.42 g (3 mmol) of methyl iodide, each time the mass is vigorously stirred for 1 hour. The combined benzene extracts are washed with water and evaporated in vacuo to give 0.25 g or 77%, from the theoretically calculated value of 1-methyl-10-oC-medoxylumyl-erginic acid methyl ester in the form of a colorless resinous product, +9 (with 0.5, chloroform).
    EXAMPLE 7 A mixture consisting of 4.5 g (13.22 mmol) of lO-d-methoxylymyl-mesynergic acid methyl ester, 8.67 g (26.44 mmol) of tetrabutylammonium hydrogensulfate, 200 ml of a 45% sodium hydroxide solution, 300 ml of toluene and 3.33 g (26.44 mmol of dimethyl sulfate, are vigorously stirred for 20 minutes at a temperature. Then the toluene phase is separated from the aqueous phase and the aqueous phase is extracted three more times with 200 ml of toluene each time. ; (13.22 mmol) of dimethyl sulfate, and each time the mixture is vigorously stirred for 20 minutes at. The combined toluene ex the tracts are washed with water and evaporated in vacuo; 3.8 g of methyl 1-methyl ester of 10-4-methoxylumyl-erginic acid are obtained in the form of a colorless resinous product, +8.7 (with 0.5, chloroform).
    Example 8.K suspension containing 140 ml of 45% sodium hydroxide solution, 4.87 g (14.3 mmol of tetrabutylammonium hydrogensulfate, 250 ml of benzene and 3 g (21.5 mmol) of methyl iodide, at a temperature of 35 ° C With vigorous stirring, 2.6 g (7.16 mmol) of 2-bromo-9,10-dihydrol-zeginic acid methyl ester in 65 ml of benzene are added. The solution is stirred for 30 minutes and immediately after that the organic phase is separated from the aqueous phase. The aqueous phase is extracted twice more using 150 ml of benzene and 1.5 g (10.7 mmol) of methyl iodide each time. The benzene extracts are extracted with water and evaporated in vacuo.The dry residue is recrystallized from methyl alcohol to give 2.42 g or 90% of the theoretically calculated value of the crystalline 1-methyl-2-bromo-9,10-dihydrolyrosine acid, methyl ester, m. 1G7-168 C, A -94.2 ° (with 0.5, methyl alcohol).
    Example 9. To a suspension consisting of a BO of a 45% sodium hydroxide solution, 3.5 g (10 mmol) of tetrabutylammonium hydrogensulfate, 200 ml of cyclohexane and 3.51 g (22.5 mmol) of ethyl iodide are added to vigorously stirring 1.45 g (5 mmol) of 9,10-dihydrolisergic acid ethyl ester. The reaction mass is stirred vigorously for 18 h at. After separation of the two phases, the aqueous phase is extracted once more with 150 ml of cyclohexane and 1.56 g (10 mmol) of ethyl iodide, the cyclohexanose fractions are combined, washed with water and evaporated to obtain 1.22 g or 80%, from the theoretically calculated value, ethyl ethyl 1-ethyl-9,10-dihydrolisable acid, so pl. 80-83 s, -70 ° (with 0.5, chloroform).
    TIpHMep 10. A two-phase system consisting of 200 ml of 45% sodium hydroxide solution, 7 g (200 mmol) of tetrabutylammonium hydrogensulfate, 200 ml of toluene and 2.52 g (20 mmol) of dimethyl sulfate are added with vigorous stirring 3.16 g (10 mmol) of 9,10-dihydrol-erginic acid 2-fluoroethyl ester in 100 ml of toluene and the reaction mixture is stirred for 2 hours. The toluene extract is separated from the aqueous solution and then the aqueous solution is extracted twice more with each 200 ml of toluene and 0.63 g (5 mmol) of dimethyl sulfate. The combined toluene extracts are washed with water and evaporated in vacuo to dryness, to obtain 2.14 g or 71.8% of the theoretically calculated value of the crystalline 1-methyl-9 methyl ester, 10-hydroxy-acid acid
    Example 11. According to the method described in Example 1, 2.7 g (10 mmol) of 9,10-dihydrol-azine acid are alkylated with 4.53 g (30 mmol) of 2-pentyl bromide. After separation and crystallization from 80% ethanol, 2.81 g (82.6% of theory) of 2- pentyl ester of 1- (2-pentyl) -9,10-dihydrol-acetic acid, m.p. 98-200 ° C, tilT -52 ° (with 0.5, chloroform).
    Example 12. In accordance with the method described in Example 1, 2.7 g (10 mmol) of 9,10-dihydrolysergic acid are alkylated with 5.36 g (36 mmol) of cyclopentyl bromide.
    After spinning and crystallization from methanol, 2.65 g (78.4% of theory) of 1-cyclopentyl-9 cyclopentyl ester, 10-U-dihydrulysergic acid, mp, 112-116 s and specific rotation of Qitf 81 (with 0.5 chloroform).
    Example 13. According to the method described in Example 1, 3.12 g (10 mmol of 10-propyloxy-9,10-dihydrol-acetic acid) was alkylated to 6.675 g (50 mmol) of 4-bromo-1-butene, to obtain 4-butene-1 -sulfur 1 - (4-butene-1-yl) -10- (n-propyloxy) -9,10-dihydrolisergic acid in the form of a non-crystallizing pure resin with a specific rotation of -11, (with 0.5, chloroform).
    权利要求:
    Claims (1)
    [1]
    Claims of Invention The method of producing N-substituted esters of 9,10-dihydrolisergic acid of the general formula t, m - for where is alkyl, alkenyl C, C. or cycloalkyl R / hydrogen atom or alkoxyl residue, X is a hydrogen atom or a bro atom, characterized in that the 9,10-dihydrol-glycetic acid of the general formula;, where X and R have the above-mentioned characteristics, is reacted with a compound of the general formula R is as above, Y is a halogen atom or sulphate residue, and the process is carried out in the presence of a catalyst for the phase transfer of tetrabutylammonium salt, an inert organic solvent not capable of being mixed with water, and an alkaline aqueous phase, after which the target odukty isolated. Information sources. taken into account during the examination 1. Fizer L., Fizer. M. Reagents for organic synthesis. M., Mir, t. 1, p. 315-317.
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    引用文献:
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    CA631701A|1961-11-28|Sandoz A.G.|Compounds of the lysergic acid series alkylated at the indol nitrogen atom|
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    US3232942A|1964-06-02|1966-02-01|Sandoz Ltd|1-substituted -lysergol|
    GB1298277A|1969-04-18|1972-11-29|Sandoz Ltd|Preparation of ergot peptide alkaloids|
    US3879554A|1970-03-20|1975-04-22|Farmaceutici Italia|Use of 1,6-dimethyl-8-{62 --10 {60 -methoxyergoline in treating cerebral and peripheral metabolic vascular disorders|
    NL159384B|1971-03-13|1979-02-15|Farmaceutici Italia|PROCEDURE FOR PREPARING A MEDICINAL PRODUCT WITH AN ADRENOLYTIC ACTIVITY, AS WELL AS A PROCEDURE FOR PREPARING AN ESTER OF 1-METHYL-10-METHOXYLUMILYSERGOL.|
    DE2330912C3|1972-06-22|1979-01-11|Societa Farmaceutici Italia S.P.A., Mailand |Process for the preparation of bromergoline compounds|US4563461A|1983-03-10|1986-01-07|Eli Lilly And Company|Selective method for blocking 5HT2 receptors|
    FR2584721B1|1985-07-11|1987-10-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF METHYL DIHYDROLYSERGATE OR METHYL METHOXYLUMILYSERGATE|
    FR2584720B1|1985-07-11|1987-10-02|Rhone Poulenc Sante|PROCESS FOR THE PREPARATION OF N-METHYL DERIVATIVES OF ERGOLINE|
    US4939258A|1985-10-01|1990-07-03|Eli Lilly And Company|Cycloalkanol esters of dihydrolysergic acid|
    US4714704A|1985-10-01|1987-12-22|Eli Lilly And Company|Alkoxy cycloalkanol esters of dihydrolysergic acid useful as 5HT receptor antagonists|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
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