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    • 专利摘要:
    The compounds correspond to the formula: <IMAGE> in which R'c represents hydrogen or a C1-C4 alkyl, alkenyl or alkynyl. They are prepared by reacting the 7-aminocephalosporanic acid first with the syn isomer of a 2-(2-Rd-amino-4-thiazolyl)-2-(R'd-oxyimino)acetic acid or of a functional derivative of this acid; Rd and R'd represent groups which can be removed by acid hydrolysis or by hydrogenolysis, or chloroacetyl groups, it being possible for R'd to additionally represent a C1-C4 alkyl, alkenyl or alkynyl. An acid hydrolysis or a hydrogenolysis is then carried out or, in the case of chloracetyl groups, a treatment with thiourea. The compounds and their salts of the carboxylic group have a good antibiotic activity and can be used for the treatment of various infectious diseases.
    公开号:SU822754A3
    申请号:SU772439818
    申请日:1977-01-18
    公开日:1981-04-15
    发明作者:Эйме Рене；Лютц Андре
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    FROM -30 C to ambient temperature and the resulting acid of the formula
    I ..- i- (
    , Q -Ny "dH2-o-e- (iH
    ° .i dooH about
    in the form of syn-isomer, in which R ;, and RI have the indicated values, if necessary, the network is treated with thiourea and / or subjected to acid hydrolysis and the desired product is isolated as a free acid or as an alkali metal salt or organic amine 7-Aminocephalosporanic acid treating functional acid derivatives such as acid anhydride or acid chloride, whereby the anhydride can be formed in place by the action of isobutyl chlorotic acid ester or dicyclohexylcarbodiimide on the acid. It is also possible to use other acid halides or other anhydrides formed in situ by the action of other alkyl esters of chloroic acid, dialkylcarbodIimide or another dicycloalkylcarbodiimide. Other acid derivatives, such as acid azide, activated. Amide acid. Or activated acid ester formed, for example, with oxysuccinimide, para-nitrophenol or 2,4-dinitrophenol can also be consumed. When 7-aminocephalosporanic acid is reacted with an acid halide of the general formula U or with an anhydride formed with isobutyl chlorotic acid ester, a base is taken, for example, an alkali metal carbonate or a tertiary organic base such as N-methylmorpholine, pyridine or trialkylamines such as triethylamine.
    As a reagent for acid hydrolysis, to which the product is subjected to formation of a diy, it is possible to cite formic acid, trifluoroxy acid or acetic acid. These acids can be consumed anhydrous or in aqueous solution. As a hydrolysis reagent it is possible to propose, in particular, the system zinc - acetic acid.
    Anhydrous trifluoroacetic acid or formic or acetic acid dissolved in water is preferably used as the acidic hydrolysis reagent to remove a protective group such as trityl.
    The reaction of the thiourea with the product, when RI is chloroacetyl, is preferably carried out in a neutral or acidic medium.
    The free acid may be salified by, for example, acting on the acid with a mineral base such as, for example, sodium or potassium hydroxide or sodium bicarbonate, or by the action of a salt with a substituted or unsubstituted aliphatic carboxylic acid, such as diethyl acetic acid, ethylhexanoic acid or acetic acid.
    Preferred salts of the abovementioned acids are sodium salts.
    The conversion to the salt can also be carried out by the action of an organic base, for example triethylmino.
    For the preparation of salts, free acid solvates can be used as starting materials instead of free acids, for example solvates prepared with water, formic acid or alcohol.
    Solvates with an alcohol, in particular with ethanol, can also be obtained, for example, by treating with a mixture of an alcohol and water of a solvate formed with formic acid, this treatment being followed by concentration of the solution.
    The conversion to salt is preferably carried out in a mixture of the solvent T. Such as water, ethyl ether, methanol, ethanol or acetone.
    Salts are obtained in amorphous form or in the form of crystals, depending on the reaction conditions used.
    The crystallized salts are preferably prepared by reacting the free acids or their solvates, formed, for example, with formic acid or with ethanol, with one of the salts of the above-mentioned aliphatic carboxylic acids, preferably sodium acetate.
    Upon receipt of the sodium salt, the reaction is carried out in an appropriate organic solvent, for example methanol, and the solvent may contain small amounts of water.
    In addition, it is possible to transform amorphous salts into crystallized salts. For this, an amorphous sodium salt which can be in the form of a solvate, for example, with 0.5 to 1 or 1.5 moles of water can be dissolved in an appropriate organic solvent, preferably in a low molecular weight alcohol such as methanol, crystallization can be carried out directly by adding other solvents such as ethanol, isopropanol, n-butanol, acetone, esters, and organic solvents compatible with methanol.
    If the starting material, solvent or both components contain water, then the crystallized salt can be obtained in the form of a hydrate. For example, the crystallized sodium salt of 3-acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-cef-3-em-4-carboxylic acid, syn-eomer, could be distinguished, for example, with 0, 5, 1 or 1.5 mol of water. Pr and m. E 1. 3-Acetoxymethyl-7- 2- (2-tritylamino-4-thiaoolyl) -2-trityl-oxyiminoacetamido cef-3-em -4-carboxylic acid. A suspension of 8.5 g of 2- (2-tritylamino-4-thiazolyl) -2-trityloxyiminoacetic acid in 50 m of methanol is stirred and 5 ml of N-methylmorpholine are added. Stir for 10 minutes at, add 30 ml of methane chloride, concentrate, add 100 ml of ether, destroy, suction, wash with ether, dry and get the first yield of 7.2 g of salt. Concentrate to dryness, take away ether and receive the second exit of the same product. 4.24 g of the obtained morpholine salt was injected into the suspension with stirring in gravitational gas in 60 ml of methylene chloride. Stir for 5 minutes, cool to -5 ° C and add 6 ml of molar. Chloroic Acid Isobutyl Ester in Methylene Chloride. Allow 15 minutes with stirring at -5 ° C, cool before, and add a solution of 1,7-aminocephalic spororanic acid in 25 ml of methylene chloride and 1.4 ml of triethylamine. It is left for 1 hour at room temperature, washed with 50 ml of water containing 10 ml of 1N hydrochloric solution, sucked off, decanted, washed with water and concentrated to dryness, triturated in ether, filtered off with suction, washed with ether and 4 are obtained. 5 g of raw product. Stir the crude product for 1 h at + 10 ° C in 10 ml of methylene chloride. The insoluble substance is sucked off and rinsed with methylene chloride. 50 ml of ether are added to the filtrate, stirred, the precipitate is sucked off, washed with ether and 2.29 g of the expected product are obtained. A second yield of 0.856 g is obtained, i .e. In the amount of 3.146 g of the target product. Example 2. 3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-oxyiminoacetamido cef-3-em-4-carboxylic acid. 2.29 g of the product obtained in Example 1 was introduced into suspension in 18.4 ml of a 50% aqueous solution of formic acid. Stir vigorously with 15 mi at 55 ° C. Cool, add 10 ml of water, suction, wash with water, concentrate in vacuo, add acetone, suction, add 30 ml of ether, stir, suck, wash with ether and obtain 0.665 g of product. Another 0.123 g of product is obtained which crystallizes, i.e. In the amount of 0.788 g. Dissolve 0.735 g of the product in 7.5 mji of ethanol and 7.5 mp of acetone. 70 mg of carbon black are added, suction is removed, the solvents are distilled off, destroyed in ethanol, pushed with ethanol and the first yield is 0.450 g, the second yield is 0.105 g. IR spectrum:; With O 1774 cm (p-lactam) 1740 cm 1676 cm C-NH, 1630 cm-T NH 152t) cm-Example 3. 3-Acetoxymethyl-7- 2- (2-tritylamino-4-thiazolyl) -2-. methoxyiminoacetamido cef-3-em-4-carboxylic acid. Dry 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid is dissolved in 30 ml of dry methylene chloride, 0.78 g of dicyclohexylcarbodiimide is added and stirred for 1 hour at room temperature. The dicyclohexyl urea formed is filtered off with suction, cooled to -10 ° C, a solution of 7 g of aminoacephalosporanic acid in 13 ml of methylene chloride and 0.9 ml of triethyl amine is added. The temperature was allowed to rise to room temperature, 1 ml of acetic acid was added, sucked off, washed with water containing hydrochloric acid, dried, concentrated to dryness, taken up in 10 ml of dioxane, 1 ml of water and 3 ml of saturated sodium bicarbonate was added. Stir, suck, wash and concentrate to dryness. Collected with methylene chloride, washed with 10 ml of water and 5 ml of 1N. hydrochloric acid solution, decanted, washed with water, dried, destroyed in ether and get 1,747 g of crude product, which is purified by dissolving in ethyl acetate in ether, followed by precipitation in ether. This gives 1.255 g of pure product which has a syn conformation. Example 4. 3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid. Oh, .975 g of the product obtained in Example 3 is stirred for 10 minutes at 55 ° C in 4 ml of a 50% aqueous solution of formic acid. 4 ml of water are added, sucked off, concentrated to dryness in vacuo. It is destroyed in 2 ml of ethanol, filtered off with suction, washed with ethanol, ai is then etherim, and 0.428 g of pure product is obtained. . Found,%: C 42.3, H 4.1; N 15.2; S 13.8 C 42.19; H 3.76, Calculated,% N, 15.37; S 14.08 :, C-i "K, 0,
    The resulting product has a conformation of syn,
    NMR (dimethyl sulfoxide 60 MHz) ppm: 2.03 (-C CH-, doublet) .5
    9.58 (j 8 Hz, CONH); 6.76 (proton of the thiazole ring).
    EXAMPLE 5 Diethylamine salt 3f-acetoxymethyl-7- 2- (2-tritylamino-4-thiaoolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid.
    Crude Z-acetoxymethyl-7- 2- (2-tritylamino-4-thiazolyl) -2- {methoxyimino) acetamido cef-3-em-4-carboxylic acid, prepared analogously to example 3 and 40.8 g / -aminocephalosporanic acid, dissolved in 350 ml of dioxane. With stirring, 350 ml of sulfuric ether are slowly added, followed by 33 ml of diethylamine. After stirring for 20 ppm, the diethylamine salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid is sucked off, which crystallizes out. This salt is washed twice with 30 ml of the previous dioxane ether mixture and 62.6 g are obtained. The filtrate is concentrated to a syrupy density and about two and a half liters of sulfuric ether are added. Stir and suck. - 110.3 g of the desired diethylamine salt are obtained. The resulting product has a syn conformation.
    Example 6. 3-Acetoxymethyl-7- 2- (2-amins-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid.
    36 g of the product obtained in Example 5 was added to 180 ml of a 50% strength solution of formic acid at. The mixture is stirred at 50 ° C for 20 minutes, the formed triphenyl carbinol is sucked off. 180 ml of ethanol are added and the mixture is concentrated to dryness under reduced pressure. The residue is taken up with a mixture of 100 ml of water and 20 ml of ethanol and concentrated again. They are taken in 100 ml of water, stirred for 15 minutes at, sucked off, washed with water and then with ether and 15.6 g of the expected product are obtained.
    The product is identical to that obtained in example 4.
    Example 7. Sodium salt of 3-acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamide cef-3-em-4-carboxylic acid.
    To 45.55 g of pure 3-acetoxymethyl-7- 2- (2-aMino-4-thiazolyl) -2-methoxyiminoacetamido cef-3m-4-carboxylic acid, prepared according to examples 4 or 6, is added 100 ml distilled water. 8 g of sodium bicarbonate and about 20 ml of ethanol are gradually added.
    80 ml of ethanol and 4.5 g of activated carbon are added again, stirred for 5 minutes, filtered, rinsed with ethanol and concentrated to dryness in vacuo. The mixture is taken up in 100 ml of ethanol, concentrated to dryness and the residue is dissolved in 100 ml of methanol. 2 liters of acetone are added, vigorously stirred, sucked off, rinsed with acetone, and then ether. After drying in vacuum, 43.7 g of a white product is obtained, which is hydrated again and its final weight reaches 45.2 r.fol 55 ± 2 ° (0.8% of water).
    0
    Found,%: C 40.3; H 3.8; N 14.4, S 13.3, Na 4.84. Calculated,%: C 40.24; "3.38N 14.67; S 13.43;
    5 Na 4.81. Cl6H, The resulting product has a syn configuration.
    NMR (60 MHz, 02.0) parts per mill0 he: 2.01 (COCH) pair of electrons at 9.53,
    j 8 Hz. (NHCO (6,75) thiazole proton).
    5 Example 8. 3-Acetoxymethyl-7- 2- (2-tritz1amino-4-thiazolyl) -2- (2-propenyloxyimino) acetamido cef-3-em-4-carboxylic acid.
    470 mg of 2- (2-tritylamine Q no-4-thiazolyl) -2- (2-propenyloxyimino) acetic acid, 5 ml of methylene chloride and 130 mg of dicyclohexylcarbodiimide are mixed, rinsed with a small amount of methylene chloride and left under stirring for 1 h. At room temperature, the dicyclohexyl urea formed is filtered off with suction, the filtrate is cooled, and 136 mg of 7-aminocephalosporanic acid in a solution of 2.4 ml of methylene chloride and 0.14 ml of triethylamine are added in an inert gas atmosphere. Leave for 1 hour at room temperature, add 2 ml of 1N. hydrochloric acid solution and water, stirred, decanted, 5 washed with water, dried, concentrated and receive 610 mg of crude product.
    The resulting product has a syn conformation.
    Example 9. 3-acetoxymethyl (2-amino-4-thiazolyl) 2- (2-propenyloxyimino) acetamido cef-3-em-4-carboxylic acid.
    610 mg of the product obtained in Example 8 and 3 Pcs of a 50% aqueous solution of formic acid are heated at 15 min to 4 minutes, 4 ml of water are added, stirred, and separated. triphenylcarbinol is rinsed, rinsed with water, concentrated to dryness under vacuum, taken up with water, disintegrated, 0 is sucked off, rinsed and 120 mg of the target acid are obtained. M.p. s: i60 ° C.
    UV spectrum ;,
    On the ground 236 MMK
     e 18000 bend 252 mmk E.316 bend 295 mmk In a mixture of ethanol — 0.1 N, hydrochloric acid:, ffOt, c 263 mmk 18300 bend 280 mmk E 317 NMR (Dimethyl sulfoxide, 90 MHz) ppm: 2, 02 (OAc), 6.68 (thiazole protonX Therefore, the product has a syn conformation. Example 10. 3-Acetoxymethyl-7-2- (.2-tritylamino-4-thiazolyl) -2-ethoxyiminoacetamido cef-3-em-4 Caboic acid. 3.43 g of 2- (2-tritylamino-4-thiazolyl) -2-ethoxymino-cyclic acid is added to 34 ml of methylene chloride, the suspension is cooled and 970 mg of dicyclohexylcarbodiimide are added, rinsed with methyl chloride. Stir for 1 h at room temperature. Dicyclohexyl urea is sucked in. The filtrate is cooled before and a solution of 1.02 g of 7-aminocephalosporanic acid in 18 ml of methylene chloride and 1.06 ml of triethylamine is applied at a time. , add 1.8 ml of acetic acid, add 9 ml of 1N hydrochloric acid solution, stir, decant, Wash with WATER, extract with chlorine methylene, dry, concentrate to obtain 4.56 g of the desired product. The resulting product has the configuration syn. Example 11. 3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-ethoxyaminoacetamido cef-3-em-4-carboxylic acid. 4.56 g of the product obtained in Example 10 are introduced into 23 ml of a 50% aqueous solution of formic acid hydrochloride, heated for 15 minutes at, diluted with water (30 ml), and triphenyl carbinol is sucked off. The filtrate is concentrated to dryness, taken up with water, stirred, sucked off, rinsed, dried, and 116 mg of contaminated product is obtained. A second yield of 674 mg of crystallized product is obtained by concentration of the filtrate, i.e. get a total of 790 mg. Cleaning is carried out as follows. 1.063 g of the crude product is converted into a dough in 5 ml of water, heated for 5 minutes with chilling, stirred for half an hour, sucked off, rinsed, dried, and 815 mg of purified product are isolated. These 815 mg are taken in 2 ml of water and 3 ml of acetone, slightly heated, the insoluble matter is sucked off, 3 ml of water is added, the dO is distilled off and the acetbone is distilled off, the nitrogen is bubbled off, the seeds are rinsed with water and then ether and 438 mg of the target product; Found,%: C 44.5; H 4.4; N 14.8; S 13.3. Calculated,%: C 43.49; H 4.08; N 14.92; S 13.66. C ,, The product has a syn configuration. NMR (60 MHz, dimethyl sulfoxide) ppm: 2.05 (OAc), 6.75 (proton of the thiazole ring). And p D m e D 12. 3-Acetoxymethyl-7- 2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido cf-. 3. W-em-4-carboxylic acid. Under an argon atmosphere, 4.89 g of 2- (2-tritylamino-4-thiazolyl) -2- (1-methylethoxyimino) acetic acid are added to 13.5 ml of dimethylformamide. After dissolution, cool in an ice bath and add 1.62 g of dicyclohexnylcarbodiimide in 16 ml of methylene chloride. Dicyclohexyl urea crystallizes. The mixture is stirred in an ice bath, sucked off, rinsed with methylene chloride, dried and 1.424 g of dicyclohexyl urea are separated. The mixture is cooled with methanol-ice and a solution of 1.41 g of 7-dminocephalosporanic acid in 30 ml of methylene chloride and 1.45 ml of triethylamine is added. The mixture is stirred at room temperature for 3 hours, 20 ml of 1N hydrochloric acid solution are added, stirred, decanted, extracted with methylene chloride, dried, sucked off and 9.05 g of mixture of the desired product with the original product are obtained. They are taken with methylene chloride, seeded, allowed to crystallize with stirring, the crystals are sucked off, rinsed, dried, 1.6 g of the pure, initial product is obtained, concentrated to dryness, the residue is taken up in isopropyl ether with vigorous stirring and 4 g of insoluble viscous product are collected, those. target product. The resulting product has a syn configuration. Example 13. 3-Acetoxymethyl-7-12- (2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido} cef-3-it-4-carboxylic acid. 4. 91 g of the crude product obtained in Example 12 is introduced into 30 ml of a 50% aqueous solution of formic acid. The mixture is stirred in a water bath at 60 ° C, diluted with water, the formed triphenylcarbinol is sucked off, rinsed with water, dried and 1.39 g of triphenylcarbinol are separated. It is concentrated to dryness, taken away with water, destroyed, sucked off, rinsed with water, dried, and 800 mg of the desired product are obtained. A sample is obtained for analysis, a solution of 972 mg of crude product in 4 ml of methanol, then 20 ml of ether is diluted, the insoluble matter is filtered off with suction, rinsed, dried and 404 mg of pure target acid are obtained. Mp-200c. Found,%: C 44.5; H 4.5; N 14.1; S 13.2. Calculated,%: C, 44.71; H 4.38; N 14.48; S 13.26. Eve Hg 07N5-S i Product has configuration of syn. NMR (60 MHz, dimethyl sulfoxide) ppm: 2.01 (CHjCO); a pair of electrons at 9.46 j 8 Hz (CONH); 6.7 (proton of the thiazole ring). Example 14. 3-Acetoxymethyl-7- 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid, syn-isomer. 15.3 g of 2 - (, 2-chloroacetic acid; 4-thiazolyl) -2-methoxyiminoacetic acid in 80 ml of methylene chloride. -When 8 ml of triethylamine was added, at 0 ° C under nitrogen atmosphere, 3.8 ml of thionyl chloride and 26 ml of methylene chloride was added, and the mixture was added 15% at. And then 7 ml of triethylamine were added. At 0 ° C in an atmosphere of nitrogen, 13.6 g of 7-aminocephalosporanic acid are introduced into 100 ml of methylene chloride and 14 ml of triethylamine. Raise the temperature to, and then stirred for 1 hour. The solution is distilled to dryness in vacuum at 30-35 ° C. The residue is dissolved in 250 ml of water, treated with animal charcoal, 50 ml of 2N hydrochloric acid solution are added. Remove the precipitate, washed with water. The resulting crude product is introduced into a suspension of 80 ml of ethanol. At 5 ° C, 7 ml of triethylamine are added. By stirring, sodium hydroxide solution (15 m 4 N.) of sulfuric acid solution is added at one time, and 15 months later, the product crystallizes. The mixture is filtered off with suction, washed with ethanol and then dried with ether in vacuo to give 18.6 g of the desired product (.) 26 ° + 1 ° with 1% in dimethylformamide. Ya.M.R. (Dimethyl sulfoxide 60 MHz A .ii. 0 M (a) singlet 2.03 ppm; (b) singlet 3.90 ppm; (c) singlet 4.38 ppm; (d) singlet 7.45 ppm. Example 15. 3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxy-imino-acetamido-cef-3-em-4-carboxylic acid, syn-isome. P. 5.32 g of the acid obtained in Example 14 were added to a suspension of 10.6 ml of water and 912 mg of thiourea. 1 g of potassium bicarbonate was added at 20 ° C. After dissolution, the mixture was stirred for 6 hours at 20 ° C. under nitrogen atmosphere. Adhesive precipitation begins after 1.5 hours (approximately). Add 30 ml of water and 3 ml of formic acid, cool to, suction washed with water containing 10% formic acid. The residue is dissolved at a temperature of about 5 ° C in 30 ml of water containing triethylamine. 3 ml of formic acid is added, the precipitate is sucked off, washed with a mixture of formic acid The sticky dark brown resin is removed. The aqueous layers are combined and treated with animal charcoal. A light yellow solution is obtained which is saturated with ammonium sulfate. The precipitate is sucked off, transformed into dough with water, sucked off, washed with water and precipitate A is obtained. The ammonium sulphate is added to the solutions, which gives a precipitate, which is sucked off, washed 3 times and precipitate B is obtained. Precipitates A and B are combined. The ethanol is taken up, stirred for 1 hour at 20 ° C and left for 16 hours at. It is filtered off with suction, washed with ethanol, ether, dried under vacuum, and 3.47 g of the desired product is obtained, the syn-isomer. Y 15) (d), o - Y Ht-od-CHj ° CHi (-OjK I Ya.M.R. (Dimethyl sulfoxide 60 MHz). (A) singlet 2.03 ppm / glln; (b) singlet 3 , 55 ppm; (c) doublet of 5.19 ppm at j 5 Hz; (d) Singlet of 6.8 ppm: Example 16. Salt of diethylamine 3 is acetoxymethyl-7-G2- (2-tritylamino -4-thiazolyl) -2-methoxyiminoacetamidoCzef-3-em-4-carboxylic acid, syn-isomer. 200 g of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, and then 120- 0 ml of methylene chloride. The suspension is heated under reflux with stirring and under argon atmosphere, and then distilled under normal pressure with 600 ml of methyl chloride a.Add to 18-20 ° C, and then injected, discharging a temperature of 54 g of dicyclohexylcarbodiimide in 54 ml of methylene chloride, stirred for 1 hour at 18-20 ° C under argon atmosphere, and then the solution was added in 15 minutes at this temperature prepared from 61.4 g of 7-aminocephalosporanic acid in 900 ml of methylene chloride and 63 ml of triethylamine. The mixture is stirred for 1.5 hours at pH 6.5-7. Then 50 ml of acetic acid are added and left for 15 minutes stirring at, and then suction to remove the original 7-aminoacephalosporanic acid. Rinse four times with 200 ml of methylene chloride. The organic solution is washed three times with 400 ml of demineralized water and then dried over magnesium sulphate. Suction is carried out, rinsed twice with 200 ml of methylene chloride, and distilled in a vacuum and in an argon atmosphere until dry. The oily dry extract is dissolved at 2025 with stirring under argon in 700 ml of dioxane. 300 ml of a mixture of dioxane and methylene chloride is distilled in vacuum and under argon at a temperature below 30 ° C. Bring to, and then add 500 ml of sulfuric ether. 52 ml of diethylamine are added. After about 10 minutes (approximately) 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, diethylamine salt crystallizes. Leave for 1 hour under argon at 20 ° C. Suction is carried out, rinsed 3 times with 100 ml of dioxane ether solution. The recovered diethylamine salt is dried and obtained 113.6 g. The organic solution is precipitated for 30 minutes with stirring in 3.25 g of isopropyl ether. The mixture is left under stirring for 15 minutes and then sucked off in vacuo. Rinsed twice with 400 ml of isopropyl ether, dried in vacuum and 182 g of product, identical to the product obtained in example 5.
    Example 17. 3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamidoCzef-3-em-carboxylic acid, syn-isomer.
    182 g of the product obtained in Example 16 are introduced with stirring under an argon atmosphere at 20 in 347 ml of formic acid and 87 ml of demineralized water. Triphenyl carbinol is completely dissolved and crystallized. The mixture is left under stirring under argon for 2 hours 30 minutes at 28-30 seconds, and then precipitated for 15 minutes with stirring in 1740 ml of demineralized water and 847 g of ammonium sulfate. Leave for 30 minutes with stirring. The mixture is filtered off with suction, washed twice with 174 ml of demineralized water, dried in vacuo at 3A-3A and 147 g of the mixture of the desired product and triphenyl carbinol are obtained. The crude product is converted into a dough for 1 hour at 18–20 ° C in 735 ml of sulfuric ether. Sucked off, rinsed two times 147 ml of sulfuric ether, dried at 25-30 C and receive 89 g of the target product.
    This product is turned into a dough with stirring under a nitrogen atmosphere in 445 g of ethanol. The suspension is brought to 45-50 ° C with stirring and kept for 1 hour under these conditions. Then stirred for 1 h at 18-20s. It is filtered off with suction, dried twice, dried in vacuo at 20 ° C and 76.85 g of the expected product are obtained.
    This product is left in the presence of 230 ml of acetic acid. The mixture is stirred for 15 minutes in nitrogen, and then 77 ml of demineralized water are added. About 700 ml of water are then added to this solution. Leave 1 hour with stirring at 18 - and then add
    5-10 minutes, about 269 g of ammonium sulfate is left for 15 minutes, and then 3.85 g of animal charcoal is added. Leave 15 minutes with stirring, suction,
    0 washed with 77 ml of demineralized water containing 25% acetic acid. At 18-20 s, 154 ml of formic acid are added with stirring, seed of the final product is added, and then crystallization is carried out by scraping. Leave for 2 hours with stirring at 18-20 ° C, and then 2 hours at 0 ° -. Suction is carried out, washing four times with 77 MP of demineralized water containing 5% formic acid. Dry at 20-25 ° C in vacuo. 49.45 g of product are obtained in the form of formic ester.
    The resulting formic acid ester is concentrated under stirring for 1 hour at 45-50 seconds in 250 ml of ethanol, and then left for 1 hour at 18-20 ° C. It is sucked off and rinsed twice with 50 ml of ethanol. Dried under vacuum, and
    0 then 10-15 hours at 35-40 ° C. 45.45 g of the expected product are obtained. (e (), 5 C at 0.5% in water, 0.5% in Manso.
    The product is identical with the product of examples 4.6 and 15.
    Example 18. Crystallized
    5 Sodium salt of 3-acetoxymethyl-7-2- (2-amino-4-thiazolyl -2-methoxyiminoacetamido3, Cef-3-em-4-carboxylic acid, syn-isomeo.
    19.8 g of 3-g1 acetoxymethyl-7- 2- (20-amino-4-thiazolyl) -2-methoxy-amino acetamido-cef-3-em-4-carboxylic acid, syn-isomer, prepared according to examples 1.6 and 15 or 17, dissolved in 65 ml of a solution of acetic sodium hydroxide in methanol. The mixture is allowed to crystallize for 35 minutes at room temperature, 40 ml of ethanol is added over 1 hour, stirring is continued for 2 hours and 30 minutes in an ice bath, it is sucked off, washed with two
    0 times — Using 10 ml of a mixture of methanol / ethanol (1-1); twice using 10 MP of ethanol, and then twice using 20 ml of ether. After drying for 2 hours in vacuum and 48 hours in a desiccator in a sulphate vacuum, 16.191 g of crystallized product are obtained.
    Avoid contact with moisture in the air of the surrounding atmosphere, get a product with a physically constant:
     (Karl Fischer) 0.2%.
    Methanol 0.1% Determination of homotographic ethanol 0.45% in the vapor phase
    Mol.ves 477,5. C 33.9; H 3.5;
    Found,% N, 14.5; S 13, l; Na 4.8.
    Calculated,%: C 40.24; H 3.38 N 14.67; Na 4.81. , N, S2.Na
    The product left in the air is rehydrated.
    The X-ray spectrum (Debu Scherrer) allowed us to confirm the crystalline nature of the obtained product. Isopropanol can also be used instead of ethanol to crystallize the desired product.
    EXAMPLE 19 Crystallized sodium salt 3-acetoxymethyl-7-2-(2-amino-4-thiazolyl) -2-methoxyiminoacetasimido cef-3-em-4-carboxylic acid, c and H- and 3-omer .
    Phase A. Solvate between 3-acetoxymethyl-7-1.2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido-cef-3-em-4-carboxylic ACID, syn-isomer and formic acid.
    87.2 g of the diethylamine salt of 3-acetoxymethyl-7-2 (2-trithylamino-4-thiazolyl) -2-methoxyiminoacet1Mido-cef-3-em-4-carboxylic acid, prepared as in Example 5, are added in small quantities and with stirring, to a mixture of 220 ml of pure formic acid and .220 ml of water. Stir for 30 minutes at, cool, remove 30.1 g of triphenylcarbinol by filtration. 450 ml of water are poured into the filtrate, the light precipitate is removed by charcoal and concentrated at 40 ° C in vacuo to form a precipitate. 200 ml of anhydrous ethanol is added, cooled with ice, filtered, washed with ethanol and ether and dried in vacuo.
    Get 31.1 - the target product
    Found%: C N
    39.2; H 4.1; 13.2; S 12.8; HjjO 4.15. C 39.3; H 4.08;
    Calculated,%; N 13.48; S 12.34,
     3.46
     Nj-O-jS - Mol. weight. 541.5 Phase B. Crystallized sodium salt.
    15 g of a freshly prepared solvate obtained by the method of phase A is dissolved in 75 ml of methanol, the solution is treated with 4.5 g of potassium acetate and 3 g of activated carbon. After filtration, add 5 ml of isopropanol with stirring. After
    aging for 16 hours at 0 ° C, the crystals were separated, washed with ethanol and ether, and dried for 2 hours under high vacuum at 5 ° C.
    7.95 g of the expected product are obtained.
    The product is then left for a short time in fresh air.
    The pier weight is 495.5.
    Found,%: C 38.6; H 3.7;
    N 13.8; Na 4.6;
    S 13.2.
    C, 38.78; H 3.66;
    Calculated%
    14.14; Na 4.64;
    N S 12.94.
    C-ta NjNaO-fSa.- lHa.0
    Example 20 Amorphous sodium salt of 3-acetoxymethyl-7-t2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-3-em-4-carboxylic acid syn-isomer.
    F a .3 a A. Solvat to M-c-acetoxymethyl-7-2- (2-amino-4-thiazolyl) -2-labels with them butylacetate amido-cef-3-em-4-carboxylic acid, syn-isomero and ethanol.
    52 g of the solvate of formic acid obtained in phase A of Example 19 is dissolved in a mixture of 3 l of 96% ethanol and 350 ml of water. Concentrate in vacuo to a volume of about 300 ml. The solvate begins to crystallize during concentration. Cool for 1 h in an ice bath, filter, wash with a small amount of ethanol, and dry in vacuo at room temperature in the presence of concentrated sulfuric acid.
    Obtain 44 g of the target product.
    0.8 mol C2.H5-OH. Mol., 3.
    Found,%: C 43.0; H 4.4; N 14.1; S 12.9.
    Calculated,%: C, 42.94; H 4.46;
    N 14.23; S 13.02. Ci (, NyO-jS
    Phase B. Amorphous sodium salt.
    3 g of the ethanol solvate obtained in the A. phase is introduced into 60 ml of water at and 0.504 g of sodium bicarbonate dissolved in 6 ml of water is added with stirring. The product is then left for a short time in fresh air.
    Weight 504.47.
      NffNaO-Sa.- 1, 5
    Found,%: C 38.2; H 3.9; N 13,
    Calculated,%: C 38.09; H 3.8; N 13.88.
    PRI me R, 21. Crystallized sodium salt of 3-acetoxymethyl- - 2- (2-amino-4-thiazolyl) -2-methoxyimino-adhetamido} Cyf-3-em-4-carboxylic acid, syn-isomer.
    To 4.95 g of 3-acetoxymethyl-7-2- {2-amino-4-thiazolyl) -2-methoxyiminoacetamido-1TZ-em-4-carboxylic acid, the syn-isomer obtained in Example 4, 6.15, or 17, added are
    5 ml of ethanol, and then with stirring in an ice bath 10 ml. A 1 molar aqueous solution of sodium bacarbonate. After dissolution, add 15 ml of ethanol, concentrate in vacuo, collect with ethanol, and dry to a constant veda. A powder is obtained which is taken up in 15 ml of methanol. Crystallization is seeded and left overnight in a refrigerator. 3.407 g of crystallized product is recovered.
    Example 22. Crystallized sodium salt of 3-acetoxine-71 2- (2-amino-4-thiazolyl) -2-methoxyimino acetamido) cef-3-em-4-carboxylic acid, syn-isomer.
    0.5 g of the amorphous sodium salt obtained in Example 2O is dissolved in 2 ml of methanol, 0.25 ml of n-butanral is added slowly with stirring and cooled 48 hours in a refrigerator at a temperature of about 6 ° C. The crystals are washed with a small amount of cold methanol and dried for 3 hours under vacuum with concentrated sulfuric acid.
    0.2 g of crystallized product is obtained and left for a short time. fresh air.
    Weight 504.47.
    Found,%: C 38.4; H 3.8; . N 13.8; About 27.1.
    Calculated,%: C 38.09; H 3.8;
    N 13.88; About 26.96.
     Hi6 N ;; .2. 1.5
    Under similar conditions, similar crystalline species are obtained, containing, for example, 0.5 mol of water or 1 mol of water and 1 mol of methanol.
    The X-ray spectra (Debu Scherrer) of the products obtained above confirm the crystalline nature of the products obtained.
    Example 23. A preparation for injection is prepared.
    3-Acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-oxyiminoacetamido 1 cef-3-em-4-carboxylic acid, mg 500 Sterile water, ml to 5.
    P ip and mep 24. Prepare the drug for injection.
    3-Acetoxime1 yl-7-2- {2-amino-4-thiazolyl) -2
    - methoxyiminoacetamido
    cef-3-e - 4-carboxylic acid, mg 500
    Sterile water ml 5.
    Example 25. The preparation is prepared for injection.
    Sodium salt of 3-acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxy-iminoacetamido cef-3-em-4-carboxylic acid, 500 mg mg
    Sterile water, ml Up to 5
    Example 26. A preparation for injection is prepared.
    H-Acetoxymethyl-7- 2 {2-amino-4-thiazolyl) -2- (1-methylethoxyimino) acetamido cef-3-em-4-carboxylic acid, mg 500 Sterile water, mg 5 Example 27. Gelatinous capsules are prepared .
    3-Acetoxymethyl-.7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetate amido) cef-3-em-4-carboxylic acid, mg 250 Gelatin to make one capsule, mg400
    Example 28. Prepare
    5 gelatin capsules.
    Sodium salt of 3-acetoxymethyl-7- 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido cef-30-ith-4-carboxylic acid, mg 250 Gelatin to make one capsule, mg 400 Example 29
    5 gelatin capsules.
    3-Acetoxymethyl-7- 2- (2 amino-4-thiazolyl) -2- (1-methylethyl-xyimino) acetamido cef-3-it-4-carboxylic acid ./-irronf A.
    slots, mg
    Gelatin to obtain
    400
    one capsule mg
    35
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of obtaining (2-aminothiazolyl-4) -2-hydroxyiminoacetamido-3-acetoxymethyl-3-methyl 40 -4-carboxylic acid derivatives of general formula
    CNG
    Tlfh.
    , i-Ku Chsng- | o-) e- | s1n
    Yooa
    in the form of syn-isomers, in which R is a hydrogen atom,. alkyl or C2-e 4 alkenyl; A represents a hydrogen atom or an alkali metal or an equivalent of an organic amine, characterized in that the 7-aminocephalosporanic acid of the formula
    NGN:.,.
    to SNG-o - - UH 3
    60 yo on
    is reacted with an acid of the general formula kn-Br I-C-boon in the form of a syn-isomer, in which R is an alkylL, alkoyl or protective group such as trityl or tetrahydropyranyl; Rg is chloroacetyl or a protective group such as trityl or with its functional derivative, in an environment it is dissolved in the presence of a base at a temperature from ambient to ambient temperature and the resulting acid is of the formula "g NHf hF d (JONHl OBi with -N. dHo-o-ci in the form of syn-isomer R and R are as defined above, if necessary, treated with tirmourea and / or subjected to acid hydrolysis and isolate the desired product as the free acid or as an alkali metal salt or an organic amine. The priority is based on features 01/23/76 with R-methyl and A is a hydrogen or sodium atom. 11.06.76 with R-ethyl or allyl and A - a hydrogen or sodium atom. 18.08.76 when R is isopropyl and A is a hydrogen atom. 18.01.77 when R is an alkyl or C2.-C4 alkenyl or allyl and A is an alkali metal atom or an equivalent of an organic amine. Sources of information taken into account in the examination 1. US Patent No. 3891635, cl. 260-243 C, published 1975.
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    GB1399086A|1971-05-14|1975-06-25|Glaxo Lab Ltd|Cephalosporin compounds|
    DK154939C|1974-12-19|1989-06-12|Takeda Chemical Industries Ltd|METHOD OF ANALOGUE FOR THE PREPARATION OF THIAZOLYLACETAMIDO-CEPHEM COMPOUNDS OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF|
    GB1536281A|1975-06-09|1978-12-20|Takeda Chemical Industries Ltd|Cephem compounds|
    DE2760123C2|1976-01-23|1986-04-30|Roussel-Uclaf, Paris|7-Aminothiazolyl-syn-oxyiminoacetamidocephalosporanic acids, their preparation and pharmaceutical compositions containing them|
    JPS6011713B2|1976-09-08|1985-03-27|Takeda Chemical Industries Ltd|DK162391C|1976-04-12|1992-03-09|Fujisawa Pharmaceutical Co|ANALOGY PROCEDURE FOR PREPARING SYN-ISOMERS OF 3,7-DISUBSTITUTED 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS|
    GB1576625A|1976-04-12|1980-10-08|Fujisawa Pharmaceutical Co|Syn isomer 3,7 disubstituted 3 cephem 4 carboxylic acid compounds and processes for the preparation thereof|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    AU520269B2|1977-03-14|1982-01-21|Fujisawa Pharmaceutical Co., Ltd.|Cephem and cepham compounds|
    PH17188A|1977-03-14|1984-06-14|Fujisawa Pharmaceutical Co|New cephem and cepham compounds and their pharmaceutical compositions and method of use|
    DE2714880A1|1977-04-02|1978-10-26|Hoechst Ag|CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    FR2408613B2|1977-07-19|1980-04-18|Roussel Uclaf|
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    JPS6341914B2|1977-09-13|1988-08-19|Fujisawa Pharmaceutical Co|
    FR2410655B1|1977-12-05|1982-06-11|Roussel Uclaf|
    JPH0142955B2|1978-01-13|1989-09-18|Takeda Chemical Industries Ltd|
    FR2387235B1|1978-01-23|1981-11-06|Fujisawa Pharmaceutical Co|
    FR2432521B1|1978-03-31|1981-12-04|Roussel Uclaf|
    SE445350B|1978-04-14|1986-06-16|Roussel Uclaf|OXIMO DERIVATIVES OF 3-AZIDOMETHYL-7-AMINO-THIAZOLYL-ACETAMIDO-CEPHALOSPORANIC ACID AND ITS USE AS ANTIBIOTICS|
    US4284631A|1978-07-31|1981-08-18|Fujisawa Pharmaceutical Co., Ltd.|7-Substituted cephem compounds and pharmaceutical antibacterial compositions containing them|
    FR2448543B1|1979-02-09|1982-02-12|Roussel Uclaf|
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    FR2461712B1|1979-07-23|1984-03-02|Hoechst Ag|
    JPH0254348B2|1981-03-16|1990-11-21|Mitsui Toatsu Chemicals|
    FR2506307B1|1981-05-22|1984-03-23|Roussel Uclaf|
    JPS64399B2|1981-08-13|1989-01-06|Takeda Chemical Industries Ltd|
    DE3775798D1|1986-03-19|1992-02-20|Banyu Pharma Co Ltd|CEPHALOSPORINE COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL AGENTS.|
    HUT53892A|1989-04-07|1990-12-28|Technologishen Kom Za Promy Mi|Process for producing synaminothiazolyl and synaminooxazolyl derivatives|
    CN112457271A|2020-11-18|2021-03-09|河北合佳医药科技集团股份有限公司|Continuous flow synthesis method of aminothiazoly loximate intermediate|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7601834A|FR2346014B1|1976-01-23|1976-01-23|
    FR7617743A|FR2361893B2|1976-01-23|1976-06-11|
    FR7625051A|FR2361894B2|1976-01-23|1976-08-18|MD94-0269A| MD228C2|1977-01-18|1994-09-08|Method of preparation of 7--2-oxyiminoacetamido)-3-acetoxymethyl-3-cefem-4-carbonic acid or salts thereof with alcaline matals|
    MD94-0268A| MD227C2|1976-01-23|1994-09-08|Method of 7--2-oxyiminoacetamido)-3-acetoxymethyl-3-cefem-4-carbonic acid preparation in the form of sin-isomers|
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