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    • 专利摘要:

    公开号:SU862828A3
    申请号:SU782585300
    申请日:1978-02-24
    公开日:1981-09-07
    发明作者:Джон Шаффер Ховард
    申请人:Дзе Велкам Фаундейшн Лимитед (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING 9-C2-OXYETHOXIMETHYL) -GUANINPHOSPHATES
    权利要求:
    Claims (2)
    [1]
    The invention relates to the field of the chemistry of organophosphorus compounds, namely, to a process for the preparation of new 9- (2-hydroxyethoxymethyl) -guanine phosphates of the general formula (I) 4X (5H op-oz (H20 (HjV where W, Z are the same or different and represent). are a hydrogen or a pharmaceutically acceptable cation, which have antiviral activity and can be used to treat viral diseases in a mammal G The method for preparing 9- (2-hydroxyethoxymethyl) -guanine phosphates of formula (T) is not described in the literature. for example 2-cyanethylphosphate This reaction is carried out in ether in the presence of pyridine with cooling. The intermediate product is decomposed by adding its ethereal solution to a mixture of pyridine aqueous solution with ice. Target product | 2-cyanoethyl phosphate is isolated are in the form of a crystalline barium salt (yield 60%). i A known method for producing guanosine-3-phosphate is by phosphorylation of guanosine with phosphorus oxychloride in pyridine at a temperature of (-40) to (-10) ° С 2. However, 9- (2 - oxyethox methyl) -guaninfosfaty of formula (I) obtained by the above methods were not. The aim of the invention is to develop a method for producing new 9- (2-hydroxyethoxymethyl) -guanine phosphates. The goal is achieved by the described method of obtaining 9- (2-6 kyethoxymethyl) -guanine phosphates of formula (I), concluding that 2-oxyethoxymethylguanine is subjected to interaction with phosphorus oxychloride in trialkyl phosphate at a temperature of from -) 30 to C + 25 ° C the subsequent hydrolysis of the phosphoric acid ester obtained and the isolation of the target product in the form of an acid or its salt. Pharmaceutically acceptable salts of 9- (2-hydroxyethoxymethyl) -guanine phosphate are obtained by neutralizing 9- (2-hydroxy-toxymethyl) -guanine phosphate with an equimolar amount of a base, for example, hydroxide, bicarbonate or carbonate containing ka; thione, sodium, potassium, ammonium, calcium, lithium, magnesium or aluminum. The above salts can also be prepared by exchange reactions in which the salt of 9- (2-hydroxyethoxy methyl) -guanine phosphate is treated with an aqueous solution of a salt containing the required cation. The proposed method allows to obtain 9- (2-hydroxyethoxymethyl) -guanine phosphate in a yield of up to 65%. Example, Obtaining 9- (2-ox ethoxymethyl) -guanine phosphate. 0.76 MP of phosphorus oxychloride is added to a stirred mixture of 6.225 f 9- (2-hydroxyethoxymethyl) -guanine and 5 ml of triethyl phosphate cooled to (-) icf. The temperature of the reaction mixture is raised to 30 minutes and maintained for 2 h. The resulting mixture is then drunk into a mixture of water and ice, and the PI of the medium is adjusted to 7 2N. water ratios: potassium hydroxide assembly. The resulting solvent was extracted two times with chloroform and once with ether, the pH of the remaining aqueous solution was adjusted to 7.1 2N. an aqueous solution of potassium hydroxide, then filtered. The resulting white solid is dissolved in 7 ml of water and 7 ml of methanol is added to precipitate the inorganic salts, which are then separated by filtration. 70 ml of an acetone is added to the filtrate, and a white gum is precipitated. It is dissolved in 7 ml of water, 7 ml of ethanop is added and the mixture is filtered, a large excess of acetone is added to the filtrate to 70 mp, and again the resin precipitates. This resin was dissolved in 20 ml of ethanol, the solvent was distilled off, and 2.6 g of a white powder was obtained, which is a mixture of inorganic salts and the desired product. The solid precipitate is dissolved in 10 ml of water, treated on a C-column with bio-gel P-2 (200-40 0 mesh 2.7x90 cm) and eluted with water. Thin-layer chromatography data, Eastmen Chrogram cellulose in a mixture of propanol and water (70:30 by volume, 26 for 9- {2-hydroxyethoxymethyl) -guanine phosphate and Rf 0.11 for 9- (2-hydroxyethoxymethyl) -guanium potassium Eluate is filtered and the result O, 28 g of solid water, S which, according to UV spectroscopy, contains 0.2 g of the desired product. Yield 65%, the product begins to decompose at 210c. Elementary analysis: Found,% t С 31,23; H 3.85j N 23.00; R 10.09, Calculated,%: C 31.49; H 3.96; N 22.95} P 10.15, Example 2, Preparation of 9- (2-hydroxyethoxymethyl) -guanamine phosphate. 0.28 g of 9- {2-hydroxyethoxymethyl) -guanine phosphate is dissolved in 30 ml of water and the pH of the solution is adjusted to 6 with 6 g of an aqueous solution of hydrochloric acid. The product is absorbed by 14 ml of compacted carbon (Fisher 5-69OB, 5000 mesh, acid and deactivated with toluene). The coal is washed with water and eluted with 70 ml of 50% aqueous ethanol containing 2% concentrated ammonium hydroxide solution. The solvent is distilled off under reduced pressure to obtain 0.048 g of 9- {2-hydroxyethoxymethyl) -guanamine phosphate; , 30 on Eastmen pulp in a mixture of propanol and water (70:30 by volume), yield 15%; the product begins to decompose at 210 ° C. Example 3. Tablets of the following composition are prepared, mg: 9- (2-Oxymethoxymethyl) -guanine sodium phosphate100 Lac Toza200 Starch50 Polyvinylpyrrolidone, 5 Magnesium stearate .4 P P i e R 4. An ophthalmic solution of the following composition is prepared: 9 - (2-hydroxyethoxymethyl) guanine sodium phosphate 1, 0 g Sodium chloride (analytical) .0.9 g Thimerosal 0.001 g Distilled water Up to 100 ml pH5.5-7.5 Example. A solution of dp injections of the following composition is prepared, 9- (2-hydroxyethoxymethyl) -guanine sodium phosphate, 775 g Sterile, pyrogen-free, phosphate buffer with pH 7T to 25 ml Example 6. Preparation of 9- {2-hydroxyethoxymethyl) -gu anidine sodium phosphate. 54 ml of phosphorus oxychloride are added over 3 hours to the stirred cooled from {-30) ° C to (-20) C mixture of 25 g of 9- (2-hydroxyethoxymethyl) -guanine and 250 mt of ethyl phosphate. The temperature of the reaction mixture is raised to 0 ° C over 45 minutes and the mixture is maintained at this temperature for another 45 minutes, then the pH of the mixture is adjusted to 1 2N. aqueous solution of sodium hydroxide. The resulting solution is extracted once with chloroform and once with ether. The pH of the remaining aqueous solution is up to 6.8 2N. a good solution of t of sodium hydroxide, then - to 7.3. aqueous solution of sodium hydroxide. The final volume of the mixture is 2.5 liters. The neutralized solution is introduced into the column from 2000 g. Dowex Ix 8 / balanced 50 KHCO-J, Elution is carried out at a linear gradient of 30 l 50-500 mmol KHCOj with subsequent washing with 30 l 500 mmol KHCOj. The fractions containing the desired product are combined, most of the KHCO are removed by adding Dowex 50-H and removing CO, j in vacuo. The volume is reduced to 2 liters under vacuum and the product is precipitated by adding 10 liters of acetone. A dried precipitate in the amount of 55 g was added to the column with bio-gel P-2 10x110 cm and eluted with water. 22 g of solid are obtained. The substance is recrystallized at acidic garden from a solution with pH 3. Most of the substance is obtained from the mother liquor by crystallization from 20% ethanol at pH 3. The acid salt is dissolved in a minimum volume of water at pH 8.5 (due to sodium hydroxide) and precipitate with 2 volumes of ethanol at 4 ° C. The resulting precipitate is dissolved in 100 ml of water, precipitated with 9 volumes of ethanol at 4 ° C and 15.1 g of 9- (2-hydroxyethoxymethyl) -guanine sodium phosphate dihydrate are obtained. The purity of the product is confirmed by elemental analysis, pressure chromatography and ultraviolet spectrum. Found%: with 25.20-, H 3.63; N 18.10; R 7.89. CaH, UNa-lHaO. calculated,%: C 24.949 j H 3.66 ;. 18.19) P 8.04. UV spectrum: Medium 12970 225 272 0.1 M HC1 254 14060 219 266 209 11760 228 255-264 0.1 M NaOH According to liquid chromatography under pressure, purity 99%. Base to phosphate ratio 1.00: 1.01. A yield of 35%, the softening of the product is observed in the vicinity with gradual decomposition and darkening 4 at a temperature of 250 ° C. DETAILED DESCRIPTION Method for producing .9- (2-hydroxyethoxymethyl} -guanine phosphates of the general formula "H20CDg (H, 0-p-02 where W and Z are the same or different AND are hydrogen or a pharmaceutically acceptable cation, consisting in that 2 -Oxyethoxymethylguanine is reacted with phosphorus oxychloride in an environment of trialkylphosphate at a temperature of (-) 30 to (+) 25 ° C, followed by hydrolysis of the phosphoric acid anhydride obtained and the release of the target product in the form of an acid or its syrup. ih at eq Spertise 1.Purdela D., Valchanu R. Chemistry of organic compounds of phosphorus. Chemistry, M., 1972, pp. 407.
    [2]
    2. Michelson A.M., Todd. Mondnucleotides derived from Adenesin, Guanoslne, Cyt {cline and Urldine. L. Chem Soc. 1949, 2476-2486.
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    同族专利:
    公开号 | 公开日
    BG41818A3|1987-08-14|
    BE864316A|1978-08-24|
    ZM2478A1|1979-12-21|
    BG41819A3|1987-08-14|
    EG14176A|1983-09-30|
    SU991951A3|1983-01-23|
    ZA781087B|1979-09-26|
    GB1590500A|1981-06-03|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    US4880820A|1983-06-24|1989-11-14|Merck & Co., Inc.|Guanine derivatives|
    US5879700A|1991-10-15|1999-03-09|Hostetler; Karl Y.|Nucleoside analogue phosphates for topical use|
    US5580571A|1991-10-15|1996-12-03|Hostetler; Karl Y.|Nucleoside analogues|
    US5654286A|1993-05-12|1997-08-05|Hostetler; Karl Y.|Nucleotides for topical treatment of psoriasis, and methods for using same|
    US6015573A|1993-05-12|2000-01-18|Hostetler; Karl Y.|Nucleoside phosphate therapy for viral infection|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US77177877A| true| 1977-02-24|1977-02-24|
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