• 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:
    Process for the preparation of d,l-5-methyltetrahydrofolic acid and its salts of the formula 1 in which X is hydrogen, an alkali metal or the equivalent of an alkaline earth metal, by reduction of folic acid with NaBH4 and methylation of the tetrahydrofolic acid obtained with aqueous solutions of formaldehyde and sodium borohydride in an inert gas atmosphere. The process is simple and can be carried out without separation of intermediates while carrying out the process steps successively in the same reaction vessel. The final products are obtained in a yield of more than 80%, relative to folic acid employed, in a purity of more than 99%. The compounds of the formula I obtained are non-toxic, stable at physiological pH and suitable for the preparation of liquid or solid pharmaceutical compositions for any type of application in human therapy. Such compositions exhibit haematopoietic action, hepatoprotective and antineoplastic action. <IMAGE>
    公开号:SU747427A3
    申请号:SU782588551
    申请日:1978-02-21
    公开日:1980-07-23
    发明作者:Дженнари Федерико
    申请人:Биорисерч С.А.С. (Фирма)；
    IPC主号:
    专利说明:

    various ion exchange resins 21. The yield of the target product 31%.
    The disadvantages of the method are the low yield of the target product and the difficulty of isolating the desired nj product due to the use of multiple ion exchange purification.
    The purpose of the invention is to increase the yield of the target product and simplify the process of its production.
    This goal is achieved by a method for producing dD-5-methyltetrahydrofolic acid or its salts by reducing folic acid with sodium borohydride at a weight ratio of sodium borohydride; folic acid 0.5-1: 3-1 in water at pH 7-8 and temperature 60-80 ° C, methylation of the resulting product with an aqueous solution of formaldehyde and sodium borohydride at a weight ratio of formaldehyde: tetrahydrofolic acid 0.8-2.5: 1 and the weight ratio of sodium borohydride: tetrahydrofolic acid 0.251, 5: 1, at pH 6-8 at a temperature of 25-30 ° C, an aqueous solution of form: maldepeda added portionwise and the last portion is added at a weight ratio of formaldehyde: terahydrofolic acid 0 , 15: 1 in the presence of a restorer, followed by the allocation of the left product in the form of a salt or acid.
    Distinctive features1 of the method according to the invention are the reduction of folic acid at a weight ratio of sodium borohydride: folic acid 0.5-1: 3-1, temperature BO-C0 and pH 7-8, methylation at a weight ratio of formaldehyde: tetrahydrofolic acid 0, 25-1.5: 1, at pHb-8 and a temperature of 25-30 ° C, batch adding water-about solution of the hydrochloride and the introduction of the last portion of it at a weight ratio of formaldehyde: tetrahydrofolic acid 0.15: 1 in the presence of a reducing agent.
    The reduction is preferably carried out at a weight ratio of sodium borohydride: folic acid 0.7-1: 2-1 and a temperature of 70 ° C, and methylation at a weight ratio of formaldehyde: tetrahydrofolic acid 1.4: 1 and sodium borohydride; tetrahydrofolic acid 0.5-1: 1, temperature, pH 6.5 using cysteine as a reducing agent.
    Cysteamsin, reduced glutathione, pantethein can also be used as a reducing agent.
    The method according to the invention allows to increase the yield of the target product up to 80% and eliminate complex
    multiple ion exchange purification.
    Example 1. BO g of deionized water is fed to the reactor and 2.4 kg of d, 1 -folic acid are suspended in it. Solid sodium carbonate is then added with stirring until folic acid is completely dissolved (pH of the final solution is 7.8), then
    4.8 kg of sodium borohydride dissolved in 40 liters of water and the reaction mixture is heated to 70 ° C. The mixture was stirred and heated for 1 hour under nitrogen. At the end of the reaction, the reactor is cooled to 30 ° C.
    and under stirring, 3.5 kg of aqueous formaldehyde and 2.4 kg of sodium borohydride dissolved in 20 liters of water are added. The reaction is continued for 1 h with stirring in a stream of nitrogen. After that, an additional 0.15 kg of 37% formaldehyde and 1 kg of cysteine are added.
    17 kg of activated carbon are suspended in 100 l of deaerated water and the suspension of carbon is added with stirring to the reaction mixture, the pH of which is adjusted to 6.5. After a few minutes, the mixture is filtered under nitrogen atmosphere and sedimented coal. filter with {-F11 water, containing 1% cysteine, before removing the inorganic salts. Coal from sediment is suspended in 100 l of elute following
    (volume) composition: 2-methoxyethanol 80, water {containing 5% cysteine) 20, ammonia (34%) The suspension is stirred for several minutes, then filtered and the filtrate is concentrated to a volume of
    20 l. The concentrated filtrate is poured into a solution containing 700 g of calcium chloride in 100 liters of ethanol. The calcium salt of 5-methyltetrahydrofolic acid precipitates,
    se is filtered off under nitrogen, washed with ethanol, and then dried in vacuo. 2.3 kg of product are obtained, which is a yield of 86% based on the starting folic acid.
    UV analysis of the product shows the following characteristics (pH 7, E 32-10): maximum absorption at 290 nm, minimum absorption at 245 nm, the ratio
    with u gto
    290 245 - °
    The analysis on a Sephadex DEAE A-25 chromatographic column using the method of Nixon and Bertino shows only the peak of 5-methyltetrahydrofolic acid. Preparative thin layer chromatography (HPLC / Partisil-lOSAX, 4.6 x 250 mm column, eluent 5% amgloni citrate, pH b) detect only 5-methyltetrahydrofolic acid. YF spectrum:
    cmnglet, typical for, -groups, with t: 7, 5.
    1 kg of calcium 5-methyltetrahydrofolate prepared by this method is dissolved in 40 liters of water containing 1 kg of cysteine when heated under a nitrogen atmosphere. The pH is adjusted to 6 with dilute hydrochloric acid and the mixture is left in the cold.
    5-Methyltetrahydrofolic acid is precipitated in a GRIP, it is filtered, washed with cool water and dried. The product shows the value of Ejiqo /
    The same process is repeated, but is replaced by 2-methoxyethanol in the eluting mixture with ethanol, methanol, 1- or 2-propanol, n-butanol, tert-butanol, sec-butanol and isobutanol, respectively. In each case, a product is obtained with the same characteristics and with the same yield.
    I Example 2. A 5-methyltetrahydrofolic acid salt is prepared as described in Example 1. The coal is eluted with a mixture of the following (volumetric) composition: methanol 80, water (containing 5% reduced glutathione) 20, ammonia (34%) 2.
    After filtering the activated carbon, 700 calcium chloride, dissolved in a small amount of water, is added to the eluate. Calcium 5-methyltetrahydrofolate precipitates, it is filtered off under a stream of nitrogen, washed with ethanol and dried in vacuo. 2.1 kg of product are obtained, which is a yield of 80% based on folic acid. The product has the same characteristics as the product obtained in Example 1.
    Example 3. The method is carried out as in example 1, the filter cake is treated with an eluting mixture consisting of 2-propanol and water, containing a small percentage of ammonium hydroxide and cysteine, and the filter eluate is then concentrated to a volume of 20 liters.
    This solution is lyophilized, giving 2.1 kg of 5-methyltetrahydrofolic acid sodium salt in a yield of 80%. The product detects Eg9o / F-245 3.8.
    Example 4: REPEAT the process of Example 1, including concentration of the eluate. In this experiment, the eluate is treated with 1.3 kg of barium chloride, dissolved in 100 liters of ethanol. The barium salt of 5-methyltetrahydrofolic acid precipitates, giving a yield of 83%. Value / 245 3.79.
    Example b. The process of Example 1 is repeated. In this experiment, the eluate is treated with 0.6 kg of magnesium chloride dissolved in 100 liters of ethanol. The magnesium salt of 5-methyltetrahydrofolic acid precipitates. Its yield is 82%. The value of o / g4 3.8. Example 6 100 g of the calcium salt of 5-methyltetrahydrofolic acid, prepared as described in Example 1, are dissolved in 4 liters of water. To the resulting solution is added a stoichiometric amount of sodium sulfate. Calcium sulfate is precipitated, and it is separated by filtration. The clear solution is lyophilized to obtain the sodium salt of 5-methyltetrahydrofolic acid.
     Example 7. Cooking
    calcium salt of 5-methyltetrahydrofolic acid.
    2.50 kg of folic acid are suspended in 10 l of water and 1 l is added to the suspension with stirring
     40% sodium carbonate solution. The pH of the medium is then adjusted to 7.8 with sodium carbonate, and after cooling in a nitrogen atmosphere, 1.7 kg of sodium bergid is added.
    5 The mixture was stirred for 2 hours to complete the reaction, then 4.0 kg of a 37% aqueous formaldehyde solution was added and that 0.80 kg of sodium borohydride was added. The sodium borate precipitated is filtered off, and the excess borohydride is destroyed by adjusting the pH of the solution to 6 with hydrochloric acid. Then added with stirring
    5 1 kg of calcium chloride dissolved in 2 l of water, and the resulting reaction mixture is left overnight at. The calcium salt of methyltetrahydrofolate acid precipitates as
    0 amorphous white powder, which is filtered and washed with water.
    This salt is dissolved in 10 liters of boiling water and the cooled solution is left to stand overnight. After precipitating, the crystalline salt is filtered off, washed and dried in vacuo. 2.40 kg of calcium 5-methyltetrahydrofolate pentahydrate are obtained in a total yield of 80% based on the starting material.
    folic acid.
    Under identical conditions, a magnesium salt is obtained, which, however, is difficult to filter.
    权利要求:
    Claims (1)
    [1]
    1. The method of obtaining d, 8-5-methyltetrahydrofolic acid or its salts of the general formula
    COQX
    30} GN-CH
    CH2
    CH, J
    n n
    Sooh
    where X is hydrogen, alkali metal or equivalent alkaline earth metal /
    by reducing folic acid with sodium borohydride in water under an inert gas atmosphere, methylation of the resulting product with an aqueous solution of formaldehyde and sodium borohydride, and isolating it as calcium or barium salt, and so on, in order to increase the yield of the target product and to avoid the process, The reduction is carried out at a weight ratio of sodium borohydride: folic acid 0.5-1: 3-1 at pH 7, at a temperature of 7 ° C and a temperature of 0–10 ° C, methylated at a weight ratio of degenerate; tetrahydrofolic acid 0.8-2.5: 1 and a weight ratio of sodium borohydride: tetrahydrofolic acid 0, 5: 1, at pH. 6–8 and a temperature of 25–30 ° C, an aqueous solution of formaldehyde is added in portions and the last batch of added K) at a weight ratio of Foam aldehyde: tetrahydrofolic acid 0.15: 1 in the presence of reducing agents, followed by depreciation of the target product as a salt acids,
    2, The method according to and. 1, and the fact that the reduction is carried out at a weight ratio of sodium borohydride: folic acid, 0.7-1: 2-1, at 70 ° C, is methylated at a weight ratio of formaldehyde: tetrahydrofolic acid 1 , 4: 1 and sodium borohydride:: tetrahydrofolic acid 0.51: 1, SO-C temperature, pH 6.5 in the presence of cysteine.
    Sources of information taken into account in the examination
    1. WHA i g J. A., Saunders K, J. Convenient method for preparation of (i) -5-methygtetrahydrofo acid. Biochem, 1970, 34 (2), p. 376.
    2, Buediger H., Sieck R ,, Eine neue Methode zur HersteEPunq und Reinigung von SMethyEtetrahydrofogic acid-. Z. Na turforsch. , TeiEc, 1973, 28 (11-12), p, 650 (prototype).
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    NL80276C|
    GB1293541A|1969-03-18|1972-10-18|John Alexander Blair|Folic acid derivatives|
    US3856959A|1972-07-24|1974-12-24|Department Of Health Education|Inhibition of leukemia utilizing 5-methyltetrahydrohomofolate|
    US4148999A|1977-08-22|1979-04-10|The Government Of The United States Of America|Preparation and purification of citrovorum factor|
    CH649550A5|1984-02-09|1985-05-31|Eprova Ag|Process for the preparation of alkaline earth metal salts of 5-methyltetrahydrofolic acid|JPS5838285A|1981-08-25|1983-03-05|Kanegafuchi Chem Ind Co Ltd|Preparation of 5-methyl--5,6,7,8-tetrahydro-l-folic acid magnesium salt or its free acid|
    GB8621268D0|1986-09-03|1986-10-08|Univ Strathclyde|Separation of substances|
    IT1229517B|1989-01-31|1991-09-03|Bioresearch Spa|USE OF 5-METHYLTETRAHYDROPHOLIC ACID, OF 5 FORMYLTHETRAHYDROPHOLIC ACID, AND OF THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE SUITABLE FOR BEING EMPLOYED IN THE TREATMENT OF DISORDERS IN THE TREATMENT OF DISORDERS.|
    IT1229203B|1989-03-22|1991-07-25|Bioresearch Spa|USE OF 5 METHYLTHETRAHYDROPHOLIC ACID, 5 FORMYLTHETRAHYDROPHOLIC ACID AND THEIR PHARMACEUTICALLY ACCEPTABLE SALTS FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS IN THE FORM OF CONTROLLED RELEASE ACTIVE IN THE THERAPY OF MENTAL AND ORGANIC DISORDERS.|
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    CH680731A5|1990-04-12|1992-10-30|Sapec Fine Chemicals|
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    CH683261A5|1991-10-10|1994-02-15|Applied Pharma Res|A process for the preparation of Methyltetrahydrofolic in the form) N-5 and separation of the active diastereoisomer) N-5) in the form of salts.|
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    法律状态:
    优先权:
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