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  • 专利说明
  • 权利要求
  • 类似技术
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  • 引用文献
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    • 专利摘要:
    New cyanomethylthioacetylcephalosporins of the following general formula, and their salts WHEREIN R is hydrogen, lower alkyl, aralkyl, tri(lower alkyl)silyl, a salt forming ion or the group ; R1 and R2 each is hydrogen, lower alkyl, lower alkenyl, aryl or aralkyl, each of which may be substituted, or R1 and R2 may together complete a carbocyclic ring; R3 is hydrogen, lower alkyl, lower alkenyl, cyclo-lower alkyl, unsaturated cyclo-lower alkyl, aryl, aralkyl or a heterocyclic group; R4 is lower alkyl, aryl or aralkyl and X is hydrogen, hydroxy, lower alkanoyloxy, lower alkoxy, lower alkylthio, aroyloxy, aralkanoyloxy, the radical of a nitrogen base, a quaternary ammonium radical or together X and R represent a bond linking carbon and oxygen in a lactone ring; are useful as antibacterial agents.
    公开号:SU886747A3
    申请号:SU731957329
    申请日:1973-08-03
    公开日:1981-11-30
    发明作者:Бройер Герман；Тройнер Уве
    申请人:И.Р. Сквибб Энд Санз, Инк (Фирма)；
    IPC主号:
    专利说明:

    (54) METHOD FOR OBTAINING CEFALOSPORINE 12 The invention relates to a method for producing new cephalosporin compounds possessing antibacterial activity against both gram-positive and gram-negative glycopro-organisms. The literature describes a method of producing cephalosporin compounds of formula -iij-CHI CHI in CHI-CHI CHI. С-КГБЭ about sgde R - carboxyl group; the acetoxy group or the residue of a weakly basic tertiary amine or R and R.1 together form a lactone bridge; hydrogen, alkyl, alko group, consisting in the fact that the dinene formula NgK-, YNg jf ciH2-: Ri I
    COMPOUNDS are introduced into interaction with the acid chloride of the formulas of the Cn-Sose. The purpose of the invention is the expansion of the range of products acting on a living organism. This goal is achieved by a method based on the known acylation of 7-aminocephalosporic acid 2 and resulting in the preparation of new cephalosporin compounds. The method of obtaining cephalosporin compounds form where R is a hydrogen or an alkali metal atom; R., and R 2. each is hydrogen; R, i is hydrogen or phenyl; X is hydrogen or hydroxy. is that the compound of the formula HzN-r-Y.eng where X and R have the above values, is acylated with an acid of formula I. -CH-dooH ili-d-dif where Rjj. have the above-mentioned terms, or its reactive derivative. To the reactive derivatives of the acids of formula III, with ts, acid halides, acid anhydrides, mixed acid anhydrides. The target products can exist in various isomeric forms or optically active forms ;. Compounds obtained according to the invention according to the invention have a broad spectrum of antibacterial activity against microorganisms, for example, Staphy1ococcus aureus, Salmonella schottmuei I regimen, Pseudomonas aeruqinosa, Proteus Vulgaris, Esherichia coli and Streptus coccus pyogenes. These compounds can be used as antibacterial agents for prophylactic purposes or to fight infections caused by the above microorganisms. The compounds of formula I can be administered to different species of animals in an amount of from 1 d 100 mg / kg of body weight per day orally or parenterally. They can also be used in compositions for cleaning or disinfecting, for example, for cleaning barns or equipment for milk processing at concentrations of 0.2-1% by weight, mixed, suspended or dissolved in an inert carrier for washing or spraying. They can also be used as additives in animal feed. Example 1. Methyl ester of 2- (cyanomethyl) -thio-acetic acid. 31, .8 g (0.3 mol) of thioacetic acid methyl ester are added to 130 ml (0.3 mol) of 2N. sodium methoxide solution. 22.6 g (0.3 mol) of chloroacetonitrile dissolved in 30 ml of methanol are added dropwise with stirring and cooling. The mixture was stirred overnight, then heated by reverse distillation for 30 minutes. The reaction mixture is cooled and the solvent is distilled off. To the residue is added; “100 ml of water and water solution is extracted twice with ether. The combined ether extracts are decolorized with activated carbon and dried with magnesium sulfate. The ester is stripped off and the residue is distilled under vacuum. 30.5 g of methyl 2- (cyanomethyl) -THoJ-acetic acid methyl ester are obtained with a bp. 132-134 (10 mm) .. Example 2. Kaliev salt 2- Shianomethyl) -thi-acetic acid. 14.5 g (0.1 mol) of 2 (cyanomethyl) thio-acetic acid methyl ester are dissolved in ethanol and a solution of 6.7 g (0.12 mol) of potassium hydroxide in 40 ml of ethanol is added dropwise with cooling. . The mixture is stirred for 4 hours at room temperature and 1 hour at 0 ° C. The precipitate formed is filtered with suction, washed with ethanol and ether and dried. Obtain 15.4 g of the potassium salt of 2- (cyanomethyl) thio-acetic acid with so pl. 203-205С (decomposition). The free acid is obtained by dissolving the potassium salt in water and treating it with an equivalent amount of aqueous sulfuric acid. The ether solution is dried, concentrated and the free acid is obtained. Example 3. 2- (cyanomethyl) thioJ-acetyl chloride. 30 g of the potassium salt of 2- (cyanomethyl) -thio-acetic acid are suspended in benzene, 5 drops of pyridine are added and the mixture is cooled to. At this temperature, 76.7 g of oxalyl chloride in 150 ml of benzene is added dropwise with stirring. After cessation of vigorous evolution of gas, the reaction mixture is stirred for 1 h at room temperature. Then it is filtered and the filtrate is concentrated at room temperature. The residue was distilled in vacuo and 19.8 g of 2- (cyanomethyl) thio acetyl chloride were obtained with a bp. 110-115 ° C (0.1 mm). Example 4. (Cyanomethyl) thio) -acetamide-3-deacetoxycephalosporanic acid. 2.14 g (0.01 mol) of 7-amino-3-deacetoxycephalosporanic acid are suspended in 50 ml of water at room temperature. 1.4 ml of the triethylamine salt is added and the mixture is stirred until a clear solution is obtained. 50 ml of acetone are added and the solution is cooled to. At the same time, a solution of 1.65 g (0.01 mol) of 2- (cyanomethyl) -thio acetyl chloride in 15 ml of acetone and a solution of 1.4 ml of triethylamine in 15 ml of acetone are added dropwise while mixing and pH 7.5-8. The mixture is stirred for another 30 min at 5 ° C. Then 50 ml of ethyl acetate are added, cooled to and acidified with 2N. solution of hydrochloric acid to pH 1.5. The mixture is filtered, the layers are separated, the organic phase is washed three times; water, dried with magnesium sulfate. and the solvent is evaporated on a rotary evaporator. 1.9 g of 7- 2- {cyanomethyl) -thio-acetamide-3-de-acetoxycephalosporanic acid are obtained. The crude product is dissolved in methanol, filtered, and 5 ml of 2N is added. solution of potassium ethylhexanoate in n-butanol. This solution is poured into 300 ml of ether. The precipitate is filtered off with suction and washed with ether.
    The yield is 1.8 g of the potassium salt of (cyanomethyl) thio) -acetamide-3-deacetoxycephalosporanic acid with mp. 175 (decomposition). The amorphous product is crystallized from a small amount of methanol, so pl. 197-200 ° (decomposition). .
    Example 5. Cyanomethylthio) -acetamide-cephalosporanic acid.
    Replacing the 7-amino-3-deacetoxycene-lospranoic acid in Example 4 with 7-aminocephalosporanic acid gives (cyanomethyl) -thio) -acetamide -cephalosporanic acid and crystalline potassium salt with mp 1668-170 ° С (decomposition).
    Example 6. DL-2- (Cyanomethyl) -thio -2-phenylacetic acid 16.8 g (0.1 mol) of DL-2-phenylthioacetic acid and 22.7 g (0.225 mol) of triethylamine are dissolved in 200 ml of anhydrous tetrahydrofuran . The solution is cooled before a solution of 7.54 g (OD mol) of chloroacetonitrile is added dropwise at this temperature. The mixture is stirred at 3 hours and then kept at room temperature overnight. Then the solution is evaporated, the residue is washed with water, acidified with 2N. solution of hydrochloric acid and extracted several times with ether. The ether extracts are washed with water, dried with magnesium sulfate and evaporated. The residue is crystallized and 20.6 g of DL-2- (cyanomethyl) -thio--2-phenyl-acetic acid are obtained with a mp. 110-112 ° C. After recrystallization from benzene, this acid has so pl. 114 C.
    Example 7. 7-DL-2- (Cyanomethyl) -TIO-) 2-phenylacetamide-cephalosporanic acid.
    1.1 g (0.0054 mol) 01- "1g-2- (cyanomethyl mercapto) -phenylacetic acid is dissolved in 12.5 ml of dioxane. A solution of 0.98 g of 2,4-dinitro phenol in 12.5 ml of dioxane is added / the mixture is cooled with ice water and added. 1.08 g of dicyclohexylcarbodiimide. The mixture is stirred for 30 minutes with cooling and 30 minutes at room temperature, the precipitated precipitate (dicyclohexylurea 1.1 g) is filtered off with suction. The filtrate is evaporated in vacuo at room temperature. While cooling a solution of 1.36 g is added to the oily residue
    (0.05 mol) of 7-aminocephalosporanic acid and 1.06 g of triethylamine in 12.5 ml of methylene chloride. The mixture is outweighed for 16 hours at room temperature. The light turbidity of the solution was removed by filtration and the solution was slowly added to 200 ml of cold, strongly stirred ether. After filtration with suction, the residue is dissolved in a small amount of methylene chloride and precipitated as described above. The yield is 1.7 g of the triethylamine salt of 7-01-2- (cyanomethyl) -TIO -) - 2-phenylacetamide-cephalosporic acid. In the sample of this product were only traces of dinitrophenol, detected by thin layer chromatography.
    To obtain the free acid, 1.6 g of the triethylamine salt is dissolved in 40 ml of water, a layer of ethyl acetate is placed on top and acidified with 2N. with hydrochloric acid solution with cooling and stirring. The layers are separated, the aqueous layer is extracted several times with ethyl acetate, the combined extracts are washed three times with water, decolorized with activated charcoal, dried with magnesium sulfate and evaporated to dryness. The viscous residue is dissolved in 25 ml of methylene chloride and the solution is poured into 200 ml of strongly stirred petroleum ether. 0.9 g of 7-DL-2- (cyanomethyl) thio) -2-phenylacetamide-cephalosporanic acid is obtained.
    The potassium salt is obtained by dissolving 0.8 g of the acid in 10 ml of methanol, then 1.25 ML1 of a 2N solution of ethyl hexanoate in n-butanol is added to the solution. . Light turbidity is filtered off and the solution is slowly poured into 200 ml of strongly stirred ether.
    Obtain 0.75 g of potassium salt with so pl. below (decomposition).
    权利要求:
    Claims (2)
    [1]
    Invention Formula
    The method of obtaining cephalosporin compounds of the general formula
    Ra- dH-u - WH- CH - (. Ji
    .L-tHfX.
    Si-d-uK
    doom-vg
    where R is a hydrogen or an alkali metal atom; R, j is each hydrogen;
    R is hydrogen or phenyl; X is hydrogen or hydroxy, which also differs in that the compound of the formula
    J z -r-fS
    -11.1ng
    JOOB 7886747 where-X and R have the above meanings are acylated with an acid of the formula "1 - / w-c plgt -.CH-COOH5. , g 8 where R.Rj. have the above values, or its reactive derivative, followed by isolation of the target product. Sources of information taken into account in the examination of the 1 st application of Germany 1166199, cl. 12 q 4, publ. 1964.
    [2]
    2. US Patent No. 3338896, cl. 260-243, pub. 1967.
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