• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:
    Several novel dextrotatory spiro-hydantoin compounds have been obtained by resolving the corresponding dl-compounds which are initially synthesized by first condensing the appropriate carbonyl ring compound, such as the corresponding 4-chromanone or thiochroman-4-one, as the case may be, with potassium cyanide and ammonium carbonate. The resulting optically-active hydantoin derivatives, such as d-6-fluoro-spiro-[chroman-4,4'-imidazolidine]-2',5'-dione and d-6'-fluoro-spiro-[imidazolidine-4,4'-thiochroman]-2,5-dione, are particularly useful in preventing or alleviating chronic diabetic complications.
    公开号:SU873885A3
    申请号:SU782616255
    申请日:1978-05-17
    公开日:1981-10-15
    发明作者:Заргес Райнхард
    申请人:Пфайзер Инк.(Фирма)；
    IPC主号:
    专利说明:

    a lower alkanol containing 1-3 carbon atoms, using t-brucine as a resolving agent. In practice, it is usually preferable to use equimolecular amounts of the racemic compound and separating agent to reduce costs and increase the purity of the product, but a small excess of alkaloid can be used without any influence on the output of the salt formation stage or on the nature of the final product. The time is not critical and depends on the nature of the starting products, their concentration in the solution and the actual temperature used. After completion of the salt formation stage, the lower diastereoismer is normally separated from the mixture by fractional crystallization and this usually requires from 2 to 24 hours within a crystallization temperature of -20 to +60 C. Then the diasteroisomer is purified by recrystallization. using a solvent, as in the salt formation stage to achieve optical purity, i.e. confirmed by melting point and constant optical rotation of the diastereoisomer.
    By converting the 2-brucine or Z-cinchonidine salts thus obtained into optically active hydantoins, it is most easy to decompose by decomposing with acid and preferably using standard methods of acid hydrolysis. For example, the salt may be treated in an aqueous medium of a mineral acid, for example, sulfuric, hydrochloric, hydrobromic or hydroiodic, or an organic acid, for example, acetic, chloropropionic, or trichloroacetic acid. In practice, it is most convenient to use dilute aqueous acid, and it is generally preferred that -; sulfuric acid or hydrochloric acid to further facilitate the hydrolysis step, a suitable water-miscible organic solvent, such as ethyl acetate, is used with the diluted acid, and then the target optically active spirohydantoic compound is extracted into the organic layer and extracted from it in the usual way 1, - spirohydantoin compounds used for separation, which are easily synthesized first by condensing the corresponding
    4-chromanone or thiachroman-4-one with an alkali metal cyanide (sodium cyanide or potassium cyanide) and ammonium carbonate to form the final spirohydantoin product (i.e., racemic compound) of the indicated structural formula. This reaction is usually carried out in the presence of an inert organic solvent in which both reactants and reagents are mutually miscible. It is preferred to use dioxane, tetrahydrofuran, ethylene glycol, trimethylene 5 glycol, methanol, ethanol and isopropanol as well as H, M- as organic solvent. dimethylformamide, N, M-diethylformamide and N, M-dimethylacetamide. Typically, the reaction is carried out at a temperature of from 20 to 120 ° C for D from two hours to four days. Although the amount of reactant and reagents used in the reaction can vary somewhat, it is preferable to have at least a small molar excess of alkali metal cyanide relative to the starting chromanone or tiachromanone to ensure maximum yield. At the end of the reaction, the final product is easily isolated in the usual manner, i.e. first by diluting the reaction mixture with water (if boiling, if necessary) and then cooling the resulting solution to room temperature, followed by acidification to isolate the final d, 2-spirohydantoic compound in the form of an easily recoverable precipitate.
    The starting materials required for the preparation of d, & amphibotripohydantoin compounds j are for the most part known compounds that can be synthesized using the conventional method of organic synthesis. For example, 6-fluoro-thiochroman-4-one is 5 known compound, and 6-fluoro-4-chromanone is easily obtained by the condensation of | b- (para-fluorophenoxy) propionic acid in the presence of polyphosphoric acid.
    0 The desired product can also be isolated as a salt, using sodium, potassium, calcium or magnesium hydroxides for this.
    权利要求:
    Claims (2)
    [1]
    Example 1. A mixture consisting of 5 of 3.5 g (0.019 mi) of J- (para-fluorophenoxy) propionic acid and 40 g of polyphosphoric acid is heated for 40 minutes on a steam bath and then sewn in 300 ml of ice water. The resulting aqueous mixture is extracted with three separate portions of ethyl acetate and the combined organic layers are successively washed with diluted aqueous sodium bicarbonate solution and water and then dried over anhydrous magnesium sulfate. After filtering off the drying agent and evaporating the solvent under reduced pressure, a residue is obtained, which is recrystallized from ethanol, to obtain 2.93 g (93%) of pure 6-fluoro-4-chromanone, m.p. 114-116 ° C. Found: C, 63.24; H 4.15 Calculated for CaH-ROL-0.25 NlO: C 63.34; H 4.43. TI p and m. 2. A mixture of 397 g (2.39 mol) of 6-fluoro-4-chromanone (prepared as described in Example O of 233 g (3.58 mol) of potassium cyanide and 917 g (9.56 mol) of powder ammonium carbonate in 3000 ml of 50% aqueous ethanol, heated for about 63 hours. Then, the reaction mixture was cooled to room temperature (25 ° C), diluted with 2000 ml of water, after which it was acidified with 6N salt. The resulting pale yellow crystals are separated by filtration with suction, washed with water and then dissolved in 2N aqueous sodium hydroxide solution T after extraction of this solution with 1000 ml in portions of ethyl acetate and the following acidification of an alkaline aqueous phase with 6N hydrochloric acid yielded pale yellow crystals, which were again washed with water and dried in air to constant weight. After recrystallization from boiling methanol (initial volume 9 l reduced to 5 l) get 276 g (14%) of pure d, C-6-fluoro-spiro- (chroman-4.4 g -imidazolidine) -2,5-dione, mp 239-24lc. the filtrate obtained another 82 g of crystals, which increases the yield of the pure product to 64%. Example 3. The preparation procedure is carried out as in example 2, except for taking 191 g (1.05 tiojib) 6-fluorothiochromium-4-one, 102 g (1.57 mol) of potassium cyanide and 391 g (4.08 g). mol) carbon dioxide ammonium powder, which is reacted in 1000 ml of 50% aqueous ethanol with an oil bath for about 66 hours. The reaction qMecb is poured into 1500 ml of water, 1556 minutes for the destruction of excess ammonium carbonate. . After cooling to room temperature, it is acidified with concentrated hydrochloric acid and processed as described in Example 2. 224 g (85%) of pure d, 6-6 -fluoro-spiro- (imidazolidin-4, 4-thiochroman-2, 5-dione with a melting point of 200-202 ° C without any need for recrystallization. EXAMPLE 4 A solution consisting of 120 g (0.508 mol) d, 2-6-fluoro-spiro- (chroman) 4, 4-imidazolidine) -2, 5-dione (mp 239-24lc) and 237 g (0.508 mol) of 2-brucine tetrahydrate in 1.8 l of boiling ethanol are slowly cooled and the precipitated crystals A are collected by filtration, with suction and the resulting filter At B is stored. Crystals A consists of the E-brucine salt of d-6-fluoro-spiro- (chrome-4, 4-imidazolidine) -2, 5-dione, isolated in the form of ethanolate, mp. (dec.), after recrystallization from ethanol. Found: C 63.60; H 6.07; N 8.22 Calculated for C ligf QO-Cy-iHiiQ i XC, HgOH: C 63.88, H 6, 12, N 8.28. Following the following recrystallization from ethanol (1.5 l) of crystals A, the diastererizomer is treated with 1.0 l of ethyl acetate and 1.0 l of 1N. hydrochloric acid. The separated organic layer was collected, dried over anhydrous magnesium sulphate, filtered and then concentrated in vacuo to give a solid residue. This residue is recrystallized from 1 liter of ethanol and 45 g of crude product are obtained, i.e. 6-fluoro-spiro- (chroman-1,5-imidazolidine) -2, 5 -diol. By recrystallizing it from 300 ml of ethanol, 37 g (62%) of pure d-6-fluoro-spiro- (chroman-4,4-imidazolidine) -2, 5-dione are obtained, i.e. 241-243C / L | five . + 54.0 ° C (in methanol), Found: C 55.59i H 3.88, N 11.52 Calculated for Nd F C 55.93i H 3.84, N 11.86 Initial filtrate B is then processed 75 ml of 10% o-hydrochloric acid, the precipitated crystals are collected in the usual way and get 6-6-fluoro-pyro (chroman-4,4-imidazolidine) rucine salt -2, 5 dione, in the form of onochloride dihydrate, so pl. 172-174 C. Found: C 58.05; H 5.79; N 7.98 Calculated for QvHeFNnOa QefJo-Pi X UNSg 2H2.0: SG 2fe C 58.07, - H 5.73i N 7.97. The diastereoisomer (m.p. 172-174 s) is treated with 1.0 liter of ethyl acetate and 600 ml of 10% aqueous sulfuric acid, the resulting organic layer is separated, dried over anhydrous magnesium sulfate, filtered, then concentrated in vacuo and 41- g crude 0-isomer. Recrystallization from 400 ml of ethanol gives 34 g (52%) of pure 6-6-fluoro-spiro- (chroman-4,4-imidazolidi-3,5-dione, mp. 241-243 C / A-54 (in methanol) Found: C 55.59 {H 3.89, N 11.80 Calculated for C, HgFNijp: C 55.93; H 3.84 N 11.86. Example 5. A solution consisting of 2.52 g (0.01 mol) d, E-6-fluoro-spiro- (imidazolidin-4,4-thiochroman) -2,5-dione (mp 200–202 C) and 4.3 g (o, 01 mol) 0-brucine dihydrate, dissolved in 125 ml of boiling ethanol, is slowly cooled and the precipitated crystals A are collected by suction filtration and the resulting filtrate B is saved. Then the crystals A are recrystallized twice from 1 00 ml of ethanol to obtain 2.1 g of brucine salt of db-fluoro-spiro- (imidazolidin-4, 4-thio-chroman) of 2,5-dione, isolated as ethanolate, mp 1.47-149 0. Found: G 62.22; H 6.23; N 8.06 Calculated for Gj H FNnOASX C N 204 -% C jHjOH: C 62.40; H 5.97, N 8.09. Crystals A are shaken with 100 ml ethyl acetate and 200 ml of 3N hydrochloric acid to convert the diastereoisomer to the corresponding optically active hydantoin. The separated organic layer thus obtained is dried over anhydrous magnesium sulphate, filtered and the filtrate is concentrated in vacuo to a residue. After recrystallization of the latter, 230 mg (18%) of pure d-b-fluoro-spiro- (imidazolidin-4,4-thiochroman) -2,5-dione are obtained from 20 ml of ethanol, m.p. 224-226 ° C, | eLl. - 71, (eel in methanol). Found: C 52.19-, H 3.44 $ N 10.94 Calculated for Hg C 52.37, H 3.60, N 11.11. 5-8 The filtrate B is concentrated in vacuo and the resulting crystalline residue is recrystallized from 50 ml of ethanol to give 1.6 g of crystals. consisting of pure Z-6-fluoro-spiro- (imidazolidin-1,4-thiochroman), 5-dione, isolated in the form of ethanolate, so pl. 120-124 0. Found: C, 62.21; H 5.94, N 8.09 Calculated for C.) HgFN / j O S X CjHsOH C 62.40, H 5.97, N 8.09. The diastereisomer (mp. 120-124 ° C) is shaken with 100 ml of ethyl acetate and 200 ml of 1N. the aqueous hydrochloric acid, the resulting organic layer is separated, dried over anhydrous magnesium sulphate, filtered and then evaporated to dryness under reduced pressure. The residue (190 mg) is recrystallized from 10 ml of ethanol and, finally, from a mixture of ethyl acetate / / n-hexane and obtain 64 mg (5.8%) of pure B-6 -fluoro-spiro- (imidazolidin-4, 4-thiochroman) -2,5-dione, so pl. 223-2250С, IdLlJ -73.8С. (in methanol). . Found: C, 52.37; H 3.66; N 1.1.00. Calculated for Cx | y (HgFNnO S :. C 52.37; H 3.60, N 11.1 1. Example 6. Sodium salt of d-6-fluoro-spiro- (chroman-4,4-imidazolidine) -2 , 5-dione is obtained by dissolving this compound in water containing an equimolar amount of sodium hydroxide and then drying it at a lower temperature.This way, the alkali metal hydantoin salt is obtained in the form of an amorphous powder readily soluble in water. Similarly, the potassium and lithium salts are obtained, as well as all alkali metal salts of db-fluoro-spiro- (imidazolid-4,4-thiochroman) -1,5-dione. Example 7. The calcium salt of d-6-fluoro pyro (imidazolidin-4,4-thiochroman) -2,5-dione is obtained by dissolving this compound in water containing an equimolar amount of calcium hydroxide and then dried at a lower temperature. The corresponding magnesium salt is also obtained in a similar way as all other alkaline and alkaline-earth not only of this compound, but also d-6-fluoro-spiro- (chroman-4,4-imidazolidine) -2, 5-dione. Claim 1. Method for preparing d-isomers of spirohydantoin derivatives of general formula I kAv where y is oxygen or sulfur, or their salts, different By treating the corresponding racemate of d, E-spirohydantoin with B-brucine or P-cinchonidine in an innocent organic solvent; isomer of the corresponding spirohydantoin derivative and allocation of the target product in free form or as a salt.
    [2]
    2. A method according to claim 1, characterized in that a lower alkanol with 1 to 3 carbon atoms is used as an inert organic solvent. Sources of information taken into account during the examination 1. J. Greenstein, M. Vinits. Chemistry of amino acids and peptides. World, 1965, p. 63-98.
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    US05/799,586|US4130714A|1977-05-23|1977-05-23|Hydantoin therapeutic agents|
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