• 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:
    Pharmacologically valuable furocoumarins of the general formula (I) wherein R is selected from the group consisting of hydrogen, a hydroxyl group and a lower alkoxy group, are prepared by reacting a substituted coumarin of the general formula (II) wherein R has the aforesaid meaning, or an alkali metal salt thereof, with a haloacetale of the general formula (III) wherein R1 is a lower alkyl group and Hal is selected from the group consisting of chlorine and bromine, in an inert, nonaqueous organic solvent or solvent mixture, to obtain an intermediate product of the general formula (IV) wherein R and R1 have the aforesaid meanings, which is treated with a dilute acid at an elevated temperature, to obtain a compound of the general formula V wherein R has the aforesaid meaning, which is converted into the end product of the general formula I by treating with a dilute alkaline solution.
    公开号:SU715026A3
    申请号:SU772552299
    申请日:1977-12-12
    公开日:1980-02-05
    发明作者:Илпо Тапио Мяки Юхани；Йосеппи Мялкенен Пентти；Эдвард Нуппонен Хейкки
    申请人:Ой Стар Аб (Фирма)；
    IPC主号:
    专利说明:

    I
    This invention relates to a new process for the preparation of furocoumarins of general formula (1).

    The aim of the invention is to simplify the process, increase the yield and expand the range of target products.
    The goal is achieved by the fact that 7-hydroxymarin common (U)
    E
    de R is a hydrogen atom, hydroxy group; OR lower alkoxy group, which possess valuable biologically active HfaMM properties.
    The known method of producing methoxalene (R-OCHj) (consisting in trmg) is that 7-hydroxy-8-methoxycoumarin is reacted with bromine allyl in the presence of potash while boiling in acetone, the obtained 7-allyloxy-8-methoxycoumarin is boiled in diethylaniline, the resulting b-allyl-7-hydroxy 8-methoxycoumarin is oxidized with oxy "c 1" and the resulting 6-formylmethyl-7-hydroxy-8-methoxycoumarin is cyclized in the presence of orthophosphoric acid at 100 ° C.
    The shortcomings of this method are the low yield of the target product (13%), the four-stage process. In addition, according to this method, only one compound is obtained - methoxen.
    ten
    where R is as defined above, or its alkali metal salt is reacted with a haloacetal of the general formula (yj)
    CH-dH -Hal
    /
    where IR is lower alkyl; NaB is a chlorine or brsma atom,
    in an inert, anhydrous organic solvent or mixture of solvents, forms the most advanced compound of the general formula (IV) CH, where -R m R have vnegnaekaneanknye .. process 0.05 - 2 N, water with a solution of a strong acid at 50 LOOC And the resulting compound of the general formula ) CHO. k f, K has the values indicated above, is subjected to cyclization in medium 0, n aqueous alkali solution at 40-100 ° C with subsequent neutralization of the reaction mixture. As a strong acid, sulfuric, hydrochloric nitrogen, or chosfork acid is used, Е-:; As a solution of an alkali, a solution of hydroxide and TakHx metals, such as lithium, sodium carbonate or potassium, as well as a solution of hydroxide almmonium or their mixture, Stage A (see, 1), is coagulated with a compound of formula (I) or, preferably, its sodium salt. , in an inert, anhydrous organic solvent or mixture of solvents for 2-8 hours at TO-ITO Ex: A mixture of tetrohydrofuran and dimethylformamide is used sparingly and the fc-process is carried out at boiling point for 24 hours or dimethylformacide for a duration of 8 hours. x b k c kag Revolving mock; solubate from 15 minutes to 4 hours. This method can be easily applied: - Industrialized (Scale, as a result of which Stages B and C can be Combined (see, ps-iep 2), P; The process is carried out in 3 stages instead of 4 using the well-known fljf method and also a high yield of target: products (50-95%) "Except for GO; according to this method, only methoxen is obtained, but also the compounds of the formula (}, where R has other values The intermediates of the formulas (-) and (Y,) obtained in steps A and -B are new compounds. All industrial and final products are identified by NMR, IR and mass spectra, as well as by using melting points and elemental analysis data, and their purity was determined using TLC and chromatography. Pr m and me 1, Stage A, 19.2 g (Op1 mol) of 7-hydroxy-8 methoxycoumarin was dissolved in 70 ml of anhydrous tetra Gldrofuran , then 5.0 g of a 50% sodium hydroxide dispersion in oil is added and the mixture is boiled with a reflux condenser. stirring for 30 min. Then, with stirring, 23.6 g {0.12 mol of bromoacetaldehyde diethylacetal (bromoacetal) dissolved in 140 ml of anhydrous dimethylformamide are added to the mixture while boiling under reflux with stirring for 24 hours. The mixture is then cooled and ether and Eodo are added. The ether phase is separated and the aqueous phase is washed with ether. The ether extracts are combined and rinsed with water, diluted with potassium carbonate and water, dried, evaporated to a small volume and cooled, as a result of which the acetal precipitates. It is separated by filtration, washed with cold ether and dried, resulting in about 18.5 g (yield 60%) of 8-methoxycoumaryl-7-hydroxy acetaldehyde diethyl acetal, which can optionally be recrystallized from ether, mp. 91-93 ° C. Step B. The resulting acetal is converted to the corresponding aldehyde in the following way. 30.8 g (0.1 mol) of the crude product are refluxed under stirring for 1.5 hours at 0.1 N. sulfuric acid solution and cooled, resulting in a rolling out aldehyde. The product is separated by filtration, washed with water and dried. The yield of colorless 8-methoxycoumaril-7-hydroxy acetaldehyde is about 22 g, (87%), so pl. . 110-112 ° C (from acetone, contains 1 mol of crystallized water), Stage B, Furocoumarin (methoxalen, R-OCHj) of formula (I) is obtained from the aldehyde synthesized above in the following way. 23.4 g (0.1 mol) of the aldehyde is boiled under reflux with stirring for 30 minutes in 0.1 N sodium hydroxide solution, cooled and acidified with dilute phosphoric acid, resulting in a light yellow, milky-like solution. The solution is extracted and the extract is evaporated to dryness in vacuo. The solid residue is recrystallized from methanol. The yield of colorless methoxalene 18.5 g (80%), so pl. 147-148 ° C. Example 2. The reactions were carried out as in Example 1, but stages B and C are combined, the reaction mixture in acid after boiling for 1.5 hours is neutralized and treated with 0.1N. caustic soda, and then continue to boil for 30 min. The desired product is isolated according to Example 1 (Step B). Example 3. When carrying out the reaction as indicated in example 1, but using 7-hydroxycoumarin (a compound of formula II, where R-H) is used as starting material, psoralen is obtained, mp. 160-162 ° C, yield 85%.
    Example 4 When carrying out the reaction as indicated in Example I {Step A), but using 7-hydroxycoumarin (Formula II, where RH) and dimethylformamide as a solvent and a reaction time of 8 hours at 150 ° C as the starting material, acetal is obtained (Type 1, where is RH). The output of about .75%, so pl. 62-64 ° C (from ether).
    According to Example 1 (Stage B), this acetal can be converted into an aldehyde of the formula V, melting point, 118-120 ° C (contains 1 mole of crystallized water), yield 95%.
    Example 5. The reaction was carried out as described in Example 1 (Step A), but using 7,8-dioxycoumarin (Formula II, where R is OH) as the starting compound. 8-Oxycoumarin-7-oxyacetaldehyde diethyl acetal is obtained in a yield of about 50%, which is then converted into the desired product (formula 1, where R-OH), as in Example 1 (stages B, C), resulting in 8-oxyfurocoumarin, m.p. 248-249 ° C (from ethanol).
    权利要求:
    Claims (1)
    [1]
    1. The method of producing furocoumarins of the general FORMULA (I)
    where R is a hydrogen atom, hydroxy group or lower alkoxy group using 7-hydroxycoumarin, characterized in that, in order to simplify the process, increase the yield and expand the range of target products, 7-hydroxy coumarin of general formula / m)
    where R is as defined above, or its alkali metal salt is reacted with haloacetal of the general formula
    Rlo
    (; n, -na1
    1.0
    where R- (- lower
    NaE. - chlorine or bromine atom,
    in an inert, anhydrous organic solvent or solvent mixture at a temperature of TO-ITO C; formed, the compound of General formula (IV)
    15
    R, 0.
    20
    where R and R are as defined above,
    treated with 0.05-2 and. an aqueous solution of a strong acid at a temperature of 50-100 ° C and the resulting compound of the general formula (V)
    thirty
    where R has the above character.
    2n
    subjected to cyclization in an environment of 0.05 vodnbb solution of bleach at a temperature. 40 ° C, followed by neutralization of the reaction mixture.
    Information sources,. taken into consideration during the examination
    1. N, J, de Zoig, R. V. Nayak, E. Secio, Synthetic Furocoumarins J. Heterocycl. Chem., 1966, 3, c. 42 (prototype).
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    同族专利:
    公开号 | 公开日
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    DE2749825C2|1986-01-02|
    SE436424B|1984-12-10|
    HU174622B|1980-02-28|
    US4169840A|1979-10-02|
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    FI772899A|1979-04-04|
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    LU80224A1|1979-06-01|
    GR63112B|1979-09-05|
    NO146540C|1982-10-20|
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    SE7712060L|1979-04-04|
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    BE870296A|1979-03-07|
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    引用文献:
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    US2889337A|1956-07-19|1959-06-02|William L Stanley|Isolation of furocoumarins|
    US3201421A|1962-05-09|1965-08-17|Dept Of Chemistry|Preparation of alkyl psoralens|
    BE791345A|1971-11-16|1973-05-14|Riker Laboratories Inc|NEW BENZOFURANS SUBSTITUTES AND MEDICINAL PRODUCTS CONTAINING THEM|DE3234184C2|1982-09-15|1986-09-25|Salzgitter Maschinen Und Anlagen Ag, 3320 Salzgitter|Continuously working centrifuge|
    IT1165797B|1982-10-18|1987-04-29|Consiglio Nazionale Ricerche|PREPARATION PROCESS FOR ALCHYLANGELICINS FREE OF PSORALENES AND ALCHYLANGOLICINS OBTAINED BY THE PROCEDURE|
    US6117342A|1996-11-26|2000-09-12|Medisystems Technology Corporation|Bubble trap with directed horizontal flow and method of using|
    US5983947A|1997-03-03|1999-11-16|Medisystems Technology Corporation|Docking ports for medical fluid sets|
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FI772899A|FI59598C|1977-10-03|1977-10-03|NYTT FOERFARANDE FOER FRAMSTAELLNING AV I 9-STAELLNINGEN EVENTUELLT METOXISUBSTITUERADE 7H-FURO BENSOPYRAN-7-ONER|
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