• 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:
    The compounds correspond to the formula: <IMAGE> in which R1 represents hydrogen or certain protective groups, R2 represents certain alkyl radicals, R3 represents C1-C4 alkyl or alkoxy radicals and A represents hydrogen, an alkali metal, alkaline-earth metal, magnesium or amine cation or an ester group; the preferred compounds have the syn configuration. The preparation is carried out by creating the amide bond from the carboxyl component and the substituted 7-aminocephem component, followed by an acid hydrolysis, a hydrogenolysis or a treatment with thiourea when it is desired to remove the protective groups R1 and A. The compounds are active with respect to gram (+) and (-) bacteri; they can be used in the treatment of relevant infections.
    公开号:SU841590A3
    申请号:SU782578251
    申请日:1978-02-14
    公开日:1981-06-23
    发明作者:Эйме Рене；Люц Андре
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    The invention relates to a method for producing new cephalosporin antibiotics, namely derivatives of 7- [2- (2-amino-4-thiazolyl) -2-al- _ hydroxyiminoacetamido] -3- (1,2,4-ty- 5 adiazole- 5-ylthiomethyl) cef-3-em-4-carboxylic acid or their salts with alkali metals in the form of syn-isomers, which may find application in me. _ dicine as 11 medicines.
    A known method for producing .syn isomers of 7- [2- (2-amino-4-thiazolyl) -2-alkoxyiminoacetamido-3-acetoxy-15 methylcef-3-em-4-carboxylic acids or their salts, in particular with alkali metals by reacting 7-aminocephalosporanic acid with N-protected 2- (2-amino-4-thiazolyl) -2-alkoxy-20 iminoacetic acid or with its reactive derivative. These compounds are antibiotics [1J.
    Soba preparation of derivatives of 7- ^ 2- (2-amino-4-thiazolyl) -2-alkoxyiminoacetamido] -3- (1,2,4-thiadiazol-5-ylmethyl) cef-3-em-4-carboxylic acid of the formula I
    in the form of syn-isomers where R. is C ^ -Cd alkyl;
    R 2 is methyl or methoxy;
    A hydrogen atom or an alkali metal, such as sodium, which consists in the fact that the compound of formula P
    The purpose of the invention is the expansion of the arsenal of means of influence on a living organism.
    This goal is achieved by the well-known acylation reaction of 7-aminoceph of losporanic acid using epo-
    where Rj has the indicated meanings, is reacted with an acid of formula III
    syn-eeomer, values, · in the form where R has the specified
    R; - trityl, or a more reactive derivative, in a medium of a chlorine-containing organic solvent or mixture of solvents at a temperature of from 0 to minus 10 ° С, followed by treatment of the resulting product with an acid hydrolysis agent and isolation of the target product in the form of free acid-.2Q you or its salts with an alkali metal, such as sodium.
    The compounds of formula T may also exist as a configuration described by the formula
    And they have the indicated
    where R, R ^ h
    The compound of formula II is treated with a functional derivative of an acid of formula IU, for example an acid anhydride or chlorine anhydride. The anhydride can be formed directly during this process by chemically acting on the acid with the .40 chloroformate of isobutyl or dicyclohexylcarbodiimide. Other halides or other anhydrides can also be used that are formed directly during this process by chemically attacking the acid of another alkyl chloroformate, dialkyl carbodiimide or other dicycloalkyl carbodiimide.
    The reaction of the compound of formula II with 5-acid acid halide hydride of formula "il" with the anhydride which is formed with isobutyl chloroformate is carried out in the presence of a basic agent. As such an agent, it is possible to use, for example, an alkali metal carbonate or a tertiary organic base, such as N-methylmorpholine, pyridine or trialkylamine, for example triethylamine.
    This reaction proceeds in such a 60 solvent or mixture of solvents as methylene chloride or chloroform.
    As an acid hydrolysis agent, formic, trifluoroacetic or acetic acid is used. These 65 acids can be used in an anhydrous state. Or in the form of aqueous solutions.
    Salts of compounds of formula I are obtained, for example, by exposing these acids to inorganic bases, such as sodium hydroxide or potassium hydroxide, sodium bicarbonate or sodium acetate.
    The preparation of salts is preferably carried out in a solvent medium or in a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone. Salts can be obtained in an amorphous or crystalline state.
    Products of the general formula T have a high antibiotic effect, on the one hand on gram-positive bacteria such as staphylococci, streptococci and especially on penicillin-resistant staphylococci, and on the other hand on gram-negative bacteria, especially colipod-like bacteria, bacteria of the Klebsiella, Salmonella ch Proteus genus.
    The compounds of formula T can be used to prepare pharmaceutical compositions containing at least one of these oxides as an active ingredient. The compositions can be introduced into the body through the mouth, through the rectum, parenterally, by intramuscular injection, or used locally by applying them to a specific area of the skin or mucous membrane.
    The administered dose of the drug varies depending on the nature of the disease, the cause of the disease, the method of administration of the drug into the body and the type of compound. The dose of the drug introduced into the human body through the mouth can be from 0.250 to 4 g per day, or when this pregarata is administered by intramuscular injection of 0.500-1 g per day. >
    Example Ϊ. 7- £ 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (3-methoxy-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid, syn isomer.
    Stage A. 7- [2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetamido} -3- (3-methoxy-1,2,4-thiadiaeolyl-5-ylthiomethyl) -cef-3-em-4 -carboxylic acid, syn isomer.
    To 3 ^ .3 6 g of the syn-isomer of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid sodium salt is added 60 ml of methylene chloride and 10 ml of 2-normal hydrochloric acid. The mixture is decanted, washed with water, dried and brought to a complete dry state. In this way, free acid is obtained.
    The residual product obtained is dissolved in 30 ml of methylene chloride and 950 g of dicyclohexylcarbodiimide are introduced into the solution. Stirred for one hour, the precipitate formed / squeezed on the filter (750 ml of dicyclohexylurea). The filtrate was cooled to -10 C and added in one portion a solution of 1.36 g of 7-amino-Z- (W-methoxy-1,2,4-thiadiazol-5-yl thiomethyl) tsef- 3-em-4 -carboxylic acid in 13 ml of chloroform and 1.3 ml of triethylamine. This mixture is brought to room temperature until it is washed with 2-normal hydrochloric acid, then with water, dried, filtered, brought to a dry state, resulting in 4.8 g of a crude product. This product is purified by chromatography using 500 g of silica and eluting with an acetone-water mixture (90-10%). Thus, 1.6 g of purified product is isolated with an index of Rp = 0.45.2Q. This product is again purified by chromatographic method using 160 g of silica. 1.1 g of pure product are finally obtained.
    Stage B. 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (3-methoxy-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4- carboxylic acid, syn-isomer.
    The aqueous formic acid solution of 50% in an amount of 5 ml ^ is heated at a temperature of 55 C. To the solution was added 1.1 g of the product obtained in step A and .nagrevayut mixture for 25 minutes at a temperature of 55-60 ° C. The precipitate of triphenylcarbinol (390 g) is squeezed out on a filter. The filtrate is dried, thickened in ethanol, squeezed on a filter, washed in ethanol, dried to obtain 470 mg of product. This product is again diluted in water, then squeezed on the filter and dried. Obtain 330 mg of the desired product.
    Elemental analysis.
    Calculated,%: C 37.56) H 3.115 s 47 n 47 fJ 7 ° 6 s 4
    Found,%: C 37.4; N. 3.2 UV spectrum (in a mixture of ethanol-hydrochloric acid [0.1 normal])
    Inflection Maximum = 270 nm E. Inflection The syn-isomer of the 2- (2-triethylamino-4-thiazolyl) -2-methoxyiminoacetic acid sodium salt used as the starting material in Example 1 was prepared as follows.
    Stage A. 2 * -chloro-p / -methoxyiminoacetyl ethyl.
    'U'-Chloro-o (ethyl hydroxyiminoacetylacetate in an amount of 22.5 g is mixed with 100 ml of methylene chloride. The mixture is cooled in an ice bath and slowly added to it while stirring a fresh solution of diazomet 10 = 240 nm E] = 310 £ = 17000; = 423 E = 23000 = 280 nm = 403
    60.
    Demand for (21.6 g / l) 275 ml. The mixture is contacted with the specified solution for five minutes and the excess diazomethane is decomposed with alumina hydrate, the product is concentrated, then purified using silica and eluting with methylene chloride. 11.93 g of the desired product are obtained.
    Stage B. Ethyl 2- (2-amino-4-thiazolyl) -2-methoxyimioacetate.
    Mix 1 g of ^ -chloro-c ^ -methoxyiminoacetyl ethyl acetate in 3 ml of absolute ethanol with 0.42 g of crushed thiourea. The mixture was stirred at room temperature for 2 hours. Then it was diluted with 60 ml of diethyl ether, the hydrochloride formed was crystallized, stirred, squeezed on a filter, washed with diethyl ether and dried. This yields 685 mg of hydrochloride. This product was dissolved in 4 ml of water at 50 ° σ ΰ, potassium acetate added until the pH = 6, wherein the free amine crystallized .. The product is drained on a filter, washed with water and dried. The result is 270 mg syn-isomer (with T PA 161 ° C).
    Stage C. 2- (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetate ethyl, syn-isomer.
    The product obtained in the previous step, in an amount of 4.6 g, is dissolved at a temperature of 30 ° C in 92 ml of methylene chloride. The solution is cooled to minus 10 ° C, 2.9 ml of triethylamine is added, cooled again to minus 35 ° C, 6.1 g of trityl chloride are added over 15 minutes, the temperature is brought to room temperature for 2.5 hours. The product is washed with water, then 0.5 normal. hydrochloric acid and an aqueous solution of sodium acetate, dried, concentrated, dissolved in diethyl ether, concentrated again, dissolved in methanol, added water and diethyl ether, crystallized, squeezed on a filter, washed with diethyl ether, resulting in 6 15 g of the desired product with T pd. 120 ° C.
    Stage D. Sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, syn-isomer.
    The ester obtained in step C in an amount of 7.01 g is dissolved in 35 ml of dioxane. This solution was heated to 110 C in an oil bath and circulated for 5 minutes 9 ml of 2-normal'nogo sodium hydroxide for 30 minutes was heated to reflux while stirring. The sodium salt crystallizes. It is cooled, squeezed on a filter, washed with dioxane, then with diethyl ether and a batch is obtained
    Ί salt in the amount of 5.767 g. The mother liquor is concentrated and a second batch of salt in the amount of 1.017 g is obtained, the total yield of sodium salt is 6.784 g.
    7-amino-3- (3-methoxy-1,2,4-thiadi-azol-5-ylthiomethyl) cef-3-em-4-carbo- 3 new acid is prepared as follows.
    Stage A. 3-Methoxy-5-mercapto-1,2,4-thiadiazole.
    A suspension of 6.16 g of ground sodium hydrosulfide in 300 ml of ethanol is cooled to 0 ° C and 15 g of 3-methoxy-5-chloro-1,2, 4-thiadiazole are added dropwise to it. The mixture is stirred for 3 hours at OC temperature, 15 then kept overnight under ice cooling, filtered, washed with methylene chloride, whereby 13.6 g of a crystallized mixture are obtained. This mixture was subjected to chromatographic separation using silica and eluting with a mixture of chloroformmethanol (95-5%). 3 g of the desired product are obtained (R £ = 0.35). These 3 g of 25 product are dissolved in 150 ml of methylene chloride with heating. The mixture is filtered and concentrated until crystalline.
    lysis and again incubated overnight while cooling with ice. Then this mixture is squeezed on the filter, washed with methylene chloride, dried and a total of 2.6 g of the desired product is obtained with .T 146 s ' C.
    Stage B. 7-amino-3- (3-methoxy-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid.
    2.72 g of 7-aminocephalosporanoic acid are mixed with 27 ml of distilled water, 840 mg of sodium bicarbonate and 1.48 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole in a nitrogen atmosphere. This mixture was stirred at 60 ° C for 5 hours, 0.74 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole was added, stirred for 2 hours at 60 ° C, acidified to pH = 4 using acetic acid, washed with water, then acetone, dried and 2.2 g of crude product are obtained.
    This product is purified · by dissolving it in a solution of sodium bicarbonate, treated with soot and filtered. The filtrate was acidified with acetic acid, squeezed on the filter, washed in water and in acetone, dried and 1.3 g of the desired product were obtained.
    Example 2. 7- £ 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3- (3-methyl-1,2,4- * iadiazol-5 ~ ylthio-60 methyl) cef-3- e-4-carboxylic acid, syn-isomer.
    Stage A. 7- £ 2- (2-Tritylamino-4-thiazolyl) - g-methoxyiminoacetamido - ] * 3- (З-methyl-1,2,4-thiadiazol-5-ylthio-65 methyl) cef-З- I-4-carboxylic acid, syn-isomer.
    To 2.7 g of the syn-isomer of the 2- (2-tritylamino-1,2,4-triazolyl) -2-methoxyiminoacetic acid sodium salt is added 60 ml of methylene chloride and 6 ml of 2-normal hydrochloric acid. The mixture is decanted, washed with water, dried and brought to a complete dry state.
    The oily residual product was dissolved in 30 ml of methylene chloride and 690 mg of dicyclohexylcarbodiimide was added. The mixture was stirred for one hour at room temperature, then the precipitated dicyclohexylurea was pressed on a filter to obtain 570 mg of product.
    The product is cooled to minus 10 ° C and 1 g of 7-amino-3- (3-methyl-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid in 10 ml is added in one portion methylene chloride and 1 ml of triethylamine. Lower the temperature to room temperature within one and a half hours. The product is washed with Normal hydrochloric acid, then with water, dried, filtered, brought to a complete dry state. The residual product is dissolved in 10 ml of dioxane and 1 ml of water, and 3 ml of sodium bicarbonate are added to this solution in the form of a saturated solution. The mixture is stirred for 30 minutes, a portion of the starting sodium salt of the acid precipitates. After squeezing on the filter and drying, 580 mg of product is obtained. The filtrate is brought to a dry state, dissolved in 20 ml of methylene chloride, washed with water, normal hydrochloric acid, dried, filtered and brought to a complete dry state. 1.95 g of the desired product are obtained. This product is thickened in diethyl ether, squeezed on a filter, dried, resulting in 1.7 g of purified product. This product is then chromatographed using 450 g of silica and eluting with an acetone-water mixture (9010%). 1.2 g of the desired product are obtained, which are dissolved in 4 ml of ethyl acetate. The product precipitates when several milliliters of diethyl ether are added. Ultimately, 940 mg of pure product is obtained. .
    Stage B. 7- £ 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido J-3- (3-methyl-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4- carboxylic acid, synisomer.
    An aqueous solution of formic acid with a concentration of-50% in an amount of 4 ml is heated to 55 ° C. To this solution was added 940 mg of the product obtained in Example 3. It was stirred for 20 minutes at 55 ° C, squeezed triphenylcarbinol, washed with water and · as a result, 340 mg of the product with T PA 158 ° C was obtained.
    The filtrate was brought to dryness, the precipitated product was diluted with 3 ml of ethanol. Then the product is squeezed on the filter, washed with ethanol, and then with diethyl ether, dried · and get 415 mg of the desired product.
    UV spectrum in the ethanol-hydrochloric acid system (0.1 normal)
    Inflection = 234 nm e / = 325 £ = 17000. '. Maximum = 269-270 nm e / = 525 £ = · 27500
    Inflection. = 280 nm E ^ = 488 Used as starting material in Example 2, 7-amino-3- (3-methyl-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid is prepared as follows way.
    2.72 g of 7.-aminocephalosporanic acid is mixed with 27 ml of distilled water and 0.84 g of sodium bicarbonate in a nitrogen atmosphere. In this case, partial dissolution is achieved. 1.45 g of 3-methyl-5-mercapto-1,2,4-thiadiazole are added to the mixture. The mixture is stirred for 4 hours and 30 minutes at 60-70 ° C. This mixture was acidified with acetic acid until a pH = 4 was reached. Squeezed, washed with water, acetone, then diethyl ether, dried, resulting in 2.4 g of product.
    Example 3. Sodium salt of 7- [2 (2-amino-4-thiaz0lyl) -2-methoxyimino ~ acetamido] -3- £ (3-methoxy-1,2,4-thiadiazolyl-5-yl) thiomethyl] cef -3-em-4-carboxylic acid, syn isomer.
    To 200 g of the product obtained in Example 1 was added 0.1 N sodium hydroxide solution and the resulting mixture was kept at room temperature for 10 min, evaporated in vacuo at a temperature not exceeding 30 C, and the sodium salt was isolated. The decomposition temperature of salt is 250-260 ° C.
    Example 4. Sodium salt of 7-L2- (aminothiaeolyl) -2-methoxyiminoacetamido] -3- [(3-methyl-1,2,4-thiadiazol-5-yl) thiomethyl] cef-3-em-4-carbon acids, syn isomer.
    To 50 mg of the product obtained in example 2, add 0.1 N sodium hydroxide solution, the resulting mixture is left to stand at room temperature for 10 minutes, evaporated in vacuo at a temperature not exceeding. 30 ° C, and the target sodium salt is isolated. Decomposition temperature ,, is 250 C.
    fifteen.
    Example 5. A preparation is prepared for injection of the composition 7- {2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido ^ -Z-C (3-methoxy-1,2,4-thiadiazol-5-yl) thiomethyl ] cef-3-em-4-carboxylic acid, syn-isomer (500 mg), sterile water (up to 5 cm ^).
    Example 6. A preparation is prepared for injection of the composition 7- [2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] -3— £ (3-methyl-1,2,4-thiadiazol-5-yl) - thiomethyl] cef-3-em-4-carboxylic acid, syn-isomer (500 mg), sterile water (up to 5 cm ^).
    Example 7. Gelatin capsules of the composition 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetamido] - $ - [(3-methoxy-1,2,4-thiadiazol-5-yl) thiomethyl are prepared ] cef-3-em-4-carboxylic acid, syn-isomer (250 mg), excipient for preparing the finished ampoule (400 mg).
    权利要求:
    Claims (1)
    [1]
    where is rj. has the indicated values, it reacts with an acid of the formula III -V as a syn-eomer, where R. has the indicated values, R is trityl, or its reaction-derivative, in a chlorine-containing organic solvent or solvent mixture at temperatures from 0 to minus 10 C, followed by treating the resulting product with an acid hydrolysis agent and isolating the target product as a free acid or its salt with an alkali metal, for example sodium. The compounds of the formula I can also exist in the form of the configuration described by the formula v A have the indicated meanings The compound of the formula II is treated with a functional acid derivative of the formula III, for example anhydride or chloro acid hydride. Anhydride can be formed directly in this process by chemically acting with isobutyl chloroformate or dicyclohexylcarbodiimide on acids. You can also use other halide anhydrides or other anhydrides formed directly during the course of the process by chemically affecting the acid of another alkylhl formate, dialkylcarbodiimide or ddyl d dy didroxylcarbodiimide. dicycloalkylcarbodiimide. The reaction of a compound of formula II with an acid hydride of formula III and with an anhydride, which is formed with isobutyl chloroformate, is carried out in the presence of an agent that carries the main agent. As such an agent, it is possible to use, for example, an alkali metal carbonate or a tertiary organic base, such as N-methylmorpholine, pyridine or trialkylamine, for example, triethylamine. This reaction takes place in a solvent or mixture of a solvent such as methylene chloride or chloroform. As an acidic hydrolic agent, formic, trifluoroacetic or acetic acid is used. These acids can be used in the anhydrous state or as aqueous solutions. Salts of the compounds of the formula T will, for example, be prepared by subjecting these acids to inorganic bases, such as hydrate, sodium oxide or potassium hydroxide, sodium bicarbonate or sodium acetate. The preparation of the salts is carried out advantageously in a solvent or mixture of solvents, such as water, ethyl ether, methanol, ethanol or acetone. Salts can be prepared in amorphous or crystalline state. The products of the general formula T have a high antibiotic effect, on the one hand, on gram-positive bacteria, such as staphylococci, streptococci, and especially on penicillin-resistant staphylococci, and on the other hand, on gram-negative bacteria, especially on colby-like bacteria, bacteria of the genus Klebsiella, Salmonella I Protheus. The compounds of formula 1 can be used to prepare pharmaceutical compositions containing at least one of these oxides as an active ingredient. The compositions can be administered to the body through the mouth, through the rectum, parenterally, by intramuscular injection, or used locally, by applying them to a specific area of skin or to the mucosa. I The administered dose of the drug varies depending on the nature of the disease, the cause of the disease, the route of administration of the drug and the type of compound. The dosage of the drug administered to the human body through the mouth can be from 0.250 to 4 g per day, or upon administration of this drug by intramuscular injection, 0.500-1 g per day, Example 1. (2-Amino-4-thiazolyl) - 2-methoxyiminoacetamido-3- (3-methoxy-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid, syn-isomer. Stage A. (2-Tritylamino-4-thiazolyl) -2-methoxyiminoacetamido7-3- (3-methoxy-1,2,4-thiadiazolyl-5-ylthiomethyl) -ceph-3-em-4-carboxylic acid, syn- isomer. 60 g of methylene chloride and 10 ml of 2-normal hydrochloric acid are added to a g of syn-isomer of sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid. The mixture is decanted, washed with water, dried, and brought to full state. In this way, the free acid is obtained. The resulting residue was dissolved in 30 ml of methylene chloride and 950 g of dicyclohec silcarbodiimide was added to the solution. Stir for one hour to form a precipitate — press on the filter (750 ml of dicyclohexylurea). The filtrate is cooled to a temperature of minus 10 ° C and a solution of 1.36 7-amino-3- (3-methoxy-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carbono is added in one portion. acid in 13 ml of chloroform and 1.3 ml of triethylamine. This mixture is brought to room temperature, washed with 2-normal hydrochloric acid then with water, dried, filtered, brought to dryness, in the result of which 4.8 g of crude product is obtained. This α-product is purified by chromatography using 500 g of silica and eluted with acetone-water (90 -10%). Thus, 1.6 g of purified product is isolated with an index of R 0.4. This product is again purified by chromatography using 160 g silicon dioxide. Finally, 1.1 g of pure product is obtained. Step B. (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido3-3- (3-methoxy-1, 2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid, syn-isomer. An aqueous solution of formic acid with a concentration of 50% in the amount of 5.5 ml is heated at a temperature of 55 ° C. To the solution is added 1.1 g of the product obtained in stage A, and the mixture is heated for 25 minutes at a temperature of 55-60 ° C. The precipitate of triphenylcarbinol (390 g) is squeezed onto a filter. The filtrate is dried, thickened in ethanol, pressed on a filter, washed with ethanol, dried to obtain 470 mg of product. This product is diluted in water, then pressed on a filter and dried to give 330 mg of the desired product. Elemental analysis. Calculated,%: C 37.56; H 3.115 P7; Found,%: C 37.4; H.3.2 UV spectrum (in ethanol-hydrochloric acid tO mixture, l is normal) Bend 240 nm E 310 17000 Maximum 270 nm E; 423 E 23000 Bend 280 nm E 403 The Sin isomer of the sodium salt of 2- (2 triethylamino-4-thiazolyl) -2-methoxyiminoacetic acid, used as a starting material in Example 1, is prepared as follows. Stage A. - Chloro-o-methoxyimino ethyl acetate ethyl. 22.5 g of Y-Chloro-a (α-hydroxyiminoacetyl ethyl acetate is mixed with 100 ml of methylene chloride. The mixture is cooled in an ice bath and a fresh solution of diazomethane (21.6 g / l) 275 ml is slowly added to it with simultaneous stirring. The mixture is contacted with this solution for five minutes and the excess diazomethane is decomposed by alumina hydrate. The product is concentrated, then purified using silica and eluted with methylene chloride. 11.93 g of the desired product is obtained. Step B. 2- (2 -Amino-4-thiazolyl-2-methoxyim; ethyl yuacetate. Mix 1 g of α-chloro-o-methoxyiminoacetylacetate in 3 ml of absolute ethanol with 0.42 g of crushed thiourea. The mixture is stirred at room temperature for 2 hours. diluted with 60 ml of diethyl ether, the hydrochloride formed is crystallized, stirred, drained on the filter, washed with diethyl ether and dried to give 685 mg of hydrochloride. This product is dissolved in 4 ml of water at a temperature, and potassium acetate is added until pH 6 is reached. free amine at fl It crystallizes. The product is drained on a filter, washed with water and dried. The result is 270 mg of the syn-isomer 161 ° C). Stage C. 2- (2-Tritylamino-4-thiazolyl) -2-methoxyimino ethyl acetate, syn-isomer. The product obtained in the previous stage, in an amount of 4.6 g, is dissolved at a temperature of 30 ° C in 92 ml of methylene chloride. The solution is cooled to minus, 2.9 ml of triethylamine is added, cooled again to minus 35 ° C, 6.1 g of trityl chloride are added within 15 minutes, the temperature is brought to room temperature for 2.5 hours. The product is washed with water, then 0 , 5-normal-. hydrochloric acid and an aqueous solution of sodium acetate, dried, concentrated, dissolved in diethyl ether, concentrated again, dissolved in methanol, water and diethyl ether were added, crystallized, pressed on a filter, mixed with ethyl ether, and a result was obtained 6.15 g of the desired product with a T pl. Stage D. Sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid, syn-isomer. The ester obtained in stage, in the amount of 7.01 g, is dissolved in 5 ivur dioxane. This solution is heated to an oil bath and added to it over 5 minutes to 9 ppm of normal sodium hydroxide, heated for 30 minutes under reflux with simultaneous stirring. The sodium salt crystallizes. It is cooled, squeezed on an eltre, washed with dioxane, then ethyl ether and a batch of salt is obtained in an amount of 5.767 g. The mother liquor is concentrated and a second batch of salt is obtained in an amount of 1.017 g, the total yield of sodium salt is 6.784 g. 7-amino-3- (3-methoxy-1,2,4-thiadiaeol-5-ilthiomethyl) cef-3-em-4-carboxylic acid is prepared as follows. Stage A. 3 Methoxy-5-mercapto-1, 2.4 thiadiazole. A suspension of 6.16 g of powdered sodium hydrosulfide in 300 ml of ethanol is cooled before and 15 g of 3-methoxy-5-chloro-1,2, 4-thiadiazole is added dropwise to it. The mixture is stirred for 3 hours at a temperature of 0 ° C, then incubated overnight with ice cooling, filtered, washed with methylene chloride, resulting in a yield of 13.6 g of crystallized mixture. This mixture was subjected to chromatographic separation using silica and elution was carried out with chloroform-methanol (95-5%). 3 g of the desired product are obtained. (R 0.35). These 3 g of product are dissolved in 150 ml of methylene chloride with heating. The mixture is filtered and concentrated until crystallisation begins and is again incubated overnight with ice cooling. Then this mixture is squeezed out on a filter, washed with methylene chloride, dried and a total of 2.6 g of the desired product is obtained with C. 146-C. Step B. 7-Amino-3- (3-methoxy-1, 2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid. 2.72 g of 7 - aminocephalosporic acid with 27 ml of distilled water, 840 mg of sodium bicarbonate, and 1.48 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole are mixed under nitrogen atmosphere. This mixture was stirred for 5 hours, 0.74 g of 3-methoxy-5-mercapto-1,2,4-thiadiazole was added, stirred for 2 hours at 60 ° C, acidified to pH 4 using acetic acid. acid, washed with water, then with acetone, dried, and the resulting 2.2 g of crude product. This product is purified., Its solution in sodium bicarbonate solution is treated with carbon black and filtered. Filtrate with acidic acid with acetic acid, press on filter, wash with water and acetone, dry, and obtain 1.3 g of the desired product. Example 2. 7-C2- (2-Amino-4-thiazolyl) -2-methoxyimine-acetamido3-3 (3-methyl-1, 2, 4--1iadiazol-5 ylthiomethyl) cef-3-em-4-carboxylic acid, syn isomer. Stage A. (2-Tritylamino-4-thiazolyl) -2-methoxyiminoaceta1 Lido7: 3- (3-methyl-1,2,4-thiadiazol-5-ylthioethyl) cef-3-em-4-carboxylic acid, syn-isomer . 60 ml of methylene chloride and 6 ml of 2-normal hydrochloric acid are added to 2.7 g of the syn-isomer of sodium soybean 2- (2-tritylamino-1,2,4-triazolyl) -2-methoxyiminoacetic acid. The mixture is decanted, washed with water, dried and brought to a complete dry state. The oily residual is dissolved in 30 ml of methylene chloride and 690 mg of dicyclohexylcarbodiimide are added. The mixture is stirred for one hour at room temperature, then the resulting dicyclohexylurea precipitate is pressed on a filter, resulting in 570 mg of product. The product is cooled to minus 10 ° C and 1g 7-amino-3- (3-methyl-1,2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid is added in one portion in 10 ml of methylene chloride and 1 ml of triethylamine. The temperature is lowered to room temperature within one and a half hours. The product is washed with normal hydrochloric acid, then with water, dried, filtered, and brought to dryness. The residual product was dissolved in 10 ml of dioxane and 1 ml of water, and 3 ml of sodium bicarbonate was added to this solution as a saturated solution. The mixture is stirred for 30 minutes, and a portion of the starting sodium salt of the acid precipitates. After pressing on the filter and drying, 580 mg of product is obtained. The filtrate is taken to dryness, dissolved in 20 ml of methylene chloride, washed with water, normal hydrochloric acid, dried, filtered and brought to a complete dry state. 1.95 g of the desired product are obtained. This product is thickened in diethyl ether, wrung out on the filter, dried, resulting in a gain of 1.7 g of purified product. This product is further chromatographed using 450 g of silica and eluted with acetone-water (9010%). 1.2 g of the desired product are obtained, which is dissolved in 4 ml of ethyl acetate. The product precipitates upon addition of a few milliliters of diethyl ether. Finally 940 mg of pure product is obtained. . Stage B. (2-Amino-4-thiazolyl) -2-methoxyiminoacetamido J-3- (3-methyl-1, 2,4-thiadiazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid, synisomer. An aqueous solution of formic acid concentration of 50% in the amount of 4 ml is heated to. 940 mg of the product obtained in Example 3 is added to this solution. Stir for 20 minutes at 55 ° C, and triphenylcarbinol is squeezed. washed with water. 340 mg of product are obtained as a result. c. The filtrate is taken to dryness, the precipitated product is diluted with 3 ml of ethanol. The product is then pressed on a filter, washed with ethanol and then with diethyl ether, dried and 415 mg of the desired product are obtained. UV spectrum in ethanol-hydrochloric acid (0.1 normal) Bend 234 nm E / 325 E 17000. Maximum 269- 270 nm E / 525 f 2750 Fold. 280 nm E 488 7-Amino-3- (3-m thyl-1,2,4-thiadiaool-5-ylthiomethyl) Ce-3-em-4-carboxylic acid used as the starting material in Example 2 was prepared as follows . 2.72 g of 7.-aminocephalosporanic acid is mixed with 27 ml of distilled water and 0.84 g of sodium bicarbonate in a nitrogen atmosphere. In this case, partial dissolution is achieved. 1.45 g of 3-methyl-5-mer capto-1,2,4-thiadiazole is added to the mixture. The mixture is stirred for 4 h 30 min at BS-70 s. This mixture is acidified with acetic acid to a pH of 4. Squeeze, rinse with water, acetone, then diethyl ether, and dry to give 2.4 g of product. Example 3. Sodium salt of (2-amino-4-thiaz6lyl) -2-methoxyiminoacetamido-3-I (3-methoxy-1, 2,4-thiazoisolyl-5-yl) -thiomethyl-cef-3-em-4-carbon acids, syn-isomer. To 200 g of the product obtained in Example 1, a 0.1 N sodium hydroxide solution is added and the mixture is kept at room temperature for 10 minutes, evaporated under vacuum at a temperature not exceeding 30 ° C, and the sodium salt is isolated. The decomposition temperature of the salt is 250-260 ° C. Example 4. Sodium salt (aminothiazolyl) -2-methoxyiminoacetamido-3- (3-methyl-1,2,4-thiadiazol-5-yl) -thiomethyl) cef-3-pm-4 -carboxylic acid, syn-isomer. To 50 mg of the product obtained in Example 2, 0.1 N sodium hydroxide solution is added, the resulting mixture is withdrawn: at room temperature for 10 minutes, evaporated under vacuum at a temperature not exceeding. 30 ° C, and the desired sodium salt is separated. The decomposition temperature is. Example 5. A preparation for injecting the formulation of (2-amino-4-thiazpryl) -2-methoxyiminoacetamido: -3-C (3-methoxy-1, 2, 4-thiadiazole. -5-yl) -thiomethyl cef- 3-itm-4-carboxylic acid, syn-isomer (500 mg), sterile water (up to 5 cm). Example 6. A preparation is prepared for the injection of the composition of (2-amino-4-thiazolyl) -2-methoxy-amino-tetamido J-3- (3-methyl-1,2,4-thiadiazol-5-yl) -thiomethyl} cef-3 -4-carboxylic acid, syn-isomer (500 mg), sterile water (up to 5 cm). Example 7. Prepared gelatin capsules of 7-C2- (2-amino-4-thiazolyl) -2-methoxy-thymino-acetamide-3 CZ-methoxy-1,2,4-thiadiaeol-5-yl) thiomethyl 1 cef-3-em -4-carboxylic acid, syn-isomer (250 mg), filler for preparing the finished ampoule (400 mg). Claims for the preparation of 7-f2- (2-amino-4-thiazolyl) -2-alkoxy-amino-acetamido-3- (1,2,4-cy1-Diazol-5-ylthiomethyl) cef-3-em-4-carboxylic acid derivatives of the formula I sAj O IL / c-ww-p., - D- :( CO.A S as syn isomers, de R is alkyl; 2, methyl or methoxy, A is a hydrogen or alkali metal atom, such as sodium, characterized in that the formula formula GG p-rS J- / 1 / / l l i (,. so.n 5 de K2 has the indicated values, interacts with the acid of formula III in the form of the syn-isomer, e RX - has the indicated values; R g - trityl , and with its reactive proizdnym, in the medium of chlorine holding ornicheskogo solvent or mixture at a temperature stvriteley IIA, followed by treatment of the product razuyuschegos agent kis118415901
    logo of hydrolysis and input of target sources of information,
    product in the form of free acid taken into account during the examination
    or its salts with an alkali metal, on 1. USSR patent on application
    example is sodium. No. 2439118 / 23-04, cl. C07 0501/34, 19V6
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    同族专利:
    公开号 | 公开日
    FI69468C|1986-02-10|
    IE46651B1|1983-08-10|
    IL54043D0|1978-04-30|
    AU516076B2|1981-05-14|
    ES467090A1|1979-06-01|
    FI780444A|1978-08-19|
    HU181961B|1983-11-28|
    GR71703B|1983-06-21|
    BE864074A|1978-08-17|
    NL7801834A|1978-08-22|
    IE780364L|1978-08-18|
    ATA120978A|1979-08-15|
    IL54043A|1983-02-23|
    PT67673A|1978-03-01|
    AT355722B|1980-03-25|
    YU33678A|1983-01-21|
    ES475956A1|1979-12-16|
    SE434268B|1984-07-16|
    GB1575180A|1980-09-17|
    ZA78847B|1979-03-28|
    PT67673B|1980-03-03|
    YU41583B|1987-10-31|
    FR2381053B1|1979-06-01|
    FI69468B|1985-10-31|
    CH633016A5|1982-11-15|
    AU3337578A|1979-08-23|
    CA1132537A|1982-09-28|
    DE2806226A1|1978-08-24|
    LU79080A1|1978-09-28|
    DK68978A|1978-08-19|
    FR2381053A1|1978-09-15|
    JPS53108996A|1978-09-22|
    SE7800790L|1978-08-18|
    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|
    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|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|DE2714880A1|1977-04-02|1978-10-26|Hoechst Ag|CEPHEMDER DERIVATIVES AND PROCESS FOR THEIR PRODUCTION|
    BE878433A|1978-08-31|1980-02-25|Fujisawa Pharmaceutical Co|PROCESS FOR THE PREPARATION OF 3-CEPHEM-4-CARBOXYLIC ACID DERIVATIVES 3,7-DISUBSTITUTED, NOVEL PRODUCTS THUS OBTAINED AND THEIR USE FOR THEIR ANTIBACTERIAL ACTIVITY|
    BE878514A|1978-09-04|1980-02-29|Fujisawa Pharmaceutical Co|PROCESS FOR THE PREPARATION OF 3-CEPHEM-4-CARBOXYLIC ACID COMPOUNDS WITH DISUBSTITUTION IN POSITIONS 3 AND 7, NOVEL PRODUCTS THUS OBTAINED AND THEIR USE FOR THEIR ANTIBACTERIAL ACTIVITY|
    US4341775A|1978-09-11|1982-07-27|Fujisawa Pharmaceutical Co., Ltd.|Cephem compounds|
    DE2945248A1|1978-11-13|1980-05-22|Fujisawa Pharmaceutical Co|CEPHEM COMPOUNDS, METHOD FOR THEIR PRODUCTION AND ANTIBACTERIAL PHARMACEUTICAL AGENTS CONTAINING THE SAME|
    US4399132A|1980-08-11|1983-08-16|American Cyanamid Company|7-Beta-[alpha-syn-methoxyimino-alpha--acetamido]-3-[methyl]-3-cephem-4-carboxylic acid and C1 -C6 alkyl derivatives thereof|
    US4761409A|1984-08-16|1988-08-02|Sumitomo Pharmaceuticals Company, Limited|Cephem derivatives|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7704745A|FR2381053B1|1977-02-18|1977-02-18|
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