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    • 专利摘要:
    Novel alkyloximes of 7-amino-thiazolyl-acetamido-cephalosporanic acids of the formula <IMAGE> I wherein R is selected from the group consisting of alkyl of 1 to 5 carbon atoms, cycloalkyl of 3 to 5 carbon atoms and -CH2-SR', R' is selected from the group consisting of acyl of an alkanoic acid of 2 to 4 carbon atoms, 1-methyl-tetrazolyl and 2-methyl-1,3,4-thiadiazolyl, R1 is selected from the group consisting of hydrogen and a group easily removeable by acid hydrolysis or hydrogenolysis, R2 is selected from the group consisting of alkyl of 1 to 4 carbon atoms and alkenyl and alkynyl of 2 to 4 carbon atoms, A is selected from the group consisting of hydrogen, an alkali metal cation, an equivalent of an alkaline earth metal or magnesium, or organic amine base cation and an ester group easily removeable by acid hydrolysis or hydrogenolysis with the proviso that when R1 is hydrogen, A is not an ester group easily removeable by hydrogenolysis or acid hydrolysis and the wavy line means that OR2 is in one or the other of the two possible syn or anti isomeric positions having a very good antibiotic activity and novel processes and intermediates for their preparation.
    公开号:SU791246A3
    申请号:SU772462904
    申请日:1977-03-23
    公开日:1980-12-23
    发明作者:Эймес Рене；Лютц Андре
    申请人:Руссель-Юклаф (Фирма)；
    IPC主号:
    专利说明:

    or with a functional derivative of this acid, where Rj is chloroacetyl or a protecting group such as trityl, and R is as defined above, in a solvent medium in the presence of a base at a temperature of (-35) ° C to room temperature and the resulting compound is treated with thiourea and or is subjected to acidic hydrolysis and the desired product is isolated as a free acid or as an alkali metal salt or an organic amine. In a preferred process method, the forglula product (|) is reacted with a functional acid derivative of formula (III), such as an anhydride or an acid chloride, and the anhydride can be formed in place by the action of isobutyl chloroacid ester or dicyclohexyl ester with acid. It is also possible to use other hydroxy genes or other anhydrides formed in situ by the action of other alkyl esters of chlorotic acid, dialkylcarbodiimes, or other cycloalkylcarbodimimi. Other acid derivatives such as azide, amide, or acid ester formed, for example, with oxysuccinimines, P-nitrophenol or 2,4-dinitrophenol, can also be consumed. In the case where the reaction of the product of formula (II) is carried out with an acid halide of the general formula (III) or with an anhydride formed with isobutyl ester of a chloro acid salt, it is preferable to act in the presence of an alkaline agent. As the alkaline agent, for example, alkali carbonate carbonate or a tertiary organic base, such as N-me ± ylmorpholine, pyridine or trialkyls such as triethylamine, can be chosen. Acid hydrolysis is preferably carried out in solvent media at room temperature to boiling point of the reaction mixture. As an acidic hydrolysis agent, formic, trifluoroacetic acid or acetic acid can be given. These acids can be consumed either anhydrous or in an aqueous solution. It is also possible to use a zinc-acid system. Preferably, an acidic hydrolysis agent such as anhydrous trifluoroacetic acid or aqueous formic or acetic acid is used. The conversion of the desired product to a salt can be accomplished by acting on these acids with an inorganic base, such as sodium or potassium hydroxide or sodium bicarbonate, or with a substituted or unsubstituted aliphatic salt. a carboxylic acid, such as distil acetic acid, ethylhexanoic acid or, in particular, acetic acid. Preferred salts are sodium salts. Conversion to salt can also be obtained by the action of an organic base such as triethylamine or diethylamine. For the preparation of salts, it is also possible to use solvates of free acids as a starting material instead of free acids. Conversion to the salt is preferred, but is carried out in a solvent or in a mixture of solvents such as water, ethyl ether, methanol, ethanol or acetone. Salts are formed in amorphous or crystalline form, depending on the reaction conditions used. Crystal salts are preferably prepared by reacting the free acids with one of the salts of the aforementioned aliphatic carboxylic acids, preferably sodium acetate. Upon receipt of the sodium salt, the reaction is carried out in a suitable organic solvent, such as methanol, i.e. solvent, which may contain small amounts of water. I The above examples illustrate the role learning of both target and initial products. Example 1. 7-t2- (27Tpitylamino-4-thiazolyl-2-methoxy-amino-acetyl) amino-3-G (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-Cel) -3-em-4 -carboxylic acid. 2.5 g of sodium salt of 2- (2-tritylmino-4-thiazolyl) -2-methoxyiminoacetic acid are mixed with 40 ml of methylene chloride and 5 ml of 2N. hydrochloric acid solution. Decanted, washed with water, dried and concentrated. The crude acid is dissolved in 30 ml of dry tetrahydrofuran. 0.7 g of dicyclohexylcarbodiimide is added, the mixture is stirred for 45 minutes at room temperature, the formed dicyclobhexylurea is sucked off, cooled to (-sfc, and a solution of 0.895 g of 7-amino-3- (2-methyl-1,3,4-thiadiazole-5 is added) -yl) -thiomethyl cef-3-em-4 -carboxylic acid and -20 MP oxides and 0.9 ml of triethylamine, previously cooled to 0 ° C. Allow to rise to room temperature for 30–30 minutes; -Hydrofuran, 40 ml of methylene chloride are added, the mixture is poured with hydrochloric acid and then with water, dried and concentrated to dryness. 3 ml of dioxa Na and added dropwise 3 ml of saturated sodium bicarbonate solution, stirred for 30 minutes, filtered, taken into ether, recovered 0.554 g of the starting product as sodium salt, dioxane is distilled off, taken up in methylene chloride, washed 1 hydrochloric acid solution and then with water, dried and concentrated to dryness, triturated in ether, sucked off, washed and 1.9 g of crude product are obtained.
    This product is stirred in 5 ml of ethyl acetate, 5 ml of ether are added, stirred, sucked, washed. 1.47 g of a partially purified product is obtained, which is dissolved in 2 ml of methylene chloride and precipitated by the addition of 25 ml of ether. After suctioning and washing, 1.4 g of the expected product are obtained.
    7- {2-2-tritylamino-4-thiazolyl-2-methoxyiminoacetyl) amino-3-G (2-methyl-1, 3, 4-thiadiazol-5-yl) thiomethyl cef-3-em-4 is thus obtained. -carboxylic acid, which has a configuration-syn.
    The initial sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyimine cycloic acid, syn-isomer, is prepared by the following method.
    Phase A: T-chloro d-methoxyiminoacetoacetic acid ethyl ester.
    22.5 g of T-chloro-L-oxamino acetoacetic acid ethyl ester are introduced into 100 MP of methylene chloride. The mixture is placed in an ice bath and a fresh solution of diazomethane (21.6 g / l) is added slowly with stirring, i.e. 275 MP. Leave in contact for 5 minutes and decompose the excess diazomethane with a small amount of aluminum hydroxide. It is concentrated and then purified by elution on silica with methylene chloride. 11.93 g of the expected product are obtained.
    Phase B: 2- (2-Amino-4-thiazolyl) -2-methoxyiminoacetic acid ethyl ester.
    1 g of f-chloro-c ethyl ester is mixed. - methoxyimino acetoacetic acid, 3 ml of absolute ethanol and 0.42 g of ground thiourea. Stir at room temperature for 2 hours. Dilute with 60 ml of ether. The resulting hydrochloride crystallizes. Stirred, sucked off, washed, dried and receive 635 mg of hydrochloride. Dissolve them in 4 MP of water at 50 ° C, add potassium acetate to pH 6. The liberated amine crystallizes. It is cooled, sucked off, washed with water, dried, and 270 mg of the expected product is obtained. M.p. 161 ° C.
    The resulting product has a configuration-syn.
    NMR (COCEj 60 MHz) parts per million: 4.0 (N-OCHj), 6.7 (proton of the thiazole cycle),
    Phase B: 2- (2-Trithylamino-4-thiazolyl) -2-methoxyimino oxuic acid ethyl ester.
    4.6 g of the product obtained in phase B is dissolved in 92 ml of methylene chloride. Cooled to
    (-lO) t :, 2.9 ml of triethylamine are added, cooled further to (-35) C, 6.1 g of trityl chloride are added in 15 minutes, the temperature is allowed to rise to room temperature, for 2 hours 30 minutes. Washed with water, then 0.5 n. hydrochloric acid solution and sodium acetate in water. It is dried, concentrated, taken up in ether, reconcentrated, dissolved in methanol, water and ether are added, allowed to crystallize, sucked off, washed with ether and 6.15 g of the expected product are obtained. M.p.
    The resulting product has a configuration-syn.
     Sodium salt of 2- (2-tritylamino-4-TIfSolyl) 2-methoxyiminoacetic acid.
    7.01 g of the ester prepared in phase B are dissolved in 35 ml of dioxane. Heat to 110 in an oil bath and add 9 ml of 2N over 5 minutes. sodium hydroxide solution, leave for 30 minutes with stirring with reflux. The sodium salt crystallizes. It is cooled, sucked off, washed with dioxane and then with ether, and the first yield is obtained in 5.767 g of salt. The mother liquor is concentrated and a second yield is obtained in 1.017 g, i.e. 6.734 g of sodium salt.
    The resulting product has a configuration-syn.
    PRI mme R 2. 7- (2- (2-amino-4-thiazolyl) 2-methoxyiminoacetyl) amino-D- 3- (2-methyl-1, 3, 4-thiadiazol-5-yl) thiomethyl cef- 3m-4-carboxylic acid.
    1.4 g of the product obtained in Example 1 is heated for 15 minutes at 57 ° C while stirring in 5 ml of a 50% aqueous solution of formic acid. 5 ml of water are added, cooled to room temperature, sucked off, 5 ml of ethanol are added, the mixture is concentrated to dryness, the residue is triturated in 5 ml of ethanol, sucked off, washed with ethanol and ether and 0.637 mg of crude product is obtained.
    The product is dissolved in 7 ml of water and 0.2 ml of triethylamine, filtered off with suction, rinsed and acidified with O, 2 ml of a 50% formic acid solution. Mix, suction, washed with alcohol and ether.
    Get the first exit in 0,275 g.
    Found,%: C 39.3, H 3.5, N 17.9, S 23.1.
     . C, Hr, gN7S4 (0.5 C2.H50H)
    Calculated,%: C 39.25, H 3.66, K 17.80, S 23.28.
    The resulting product has a configuration-syn.
    NMR (Dimethyl sulfoxide, 60 MHz) parts per million: 3.85 (N-AXIS) 6, 76 (proton of the thiazole cycle).
    Example 3: 7- (2- (2-tritylamino 4-thiaoolyl-2-methoxyiminoacetyl) amino 3-3-P1-methyltetrazol-5-yl) thiomethyl cef-3-em-4-carboxylic acid.
    2.33 g of sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetic acid are consumed. In Example 1, a crude acid is obtained, which is dissolved in 30 ml of methylene chloride. 0.7 g of dicyclohexylcarbodiimide is added and the mixture is left at room temperature for 50 minutes with stirring and under an inert gas atmosphere, the dicyclohexyl urea formed is filtered off with suction, cooled to (-5) C and a solution of 0.854 g of 7-amino-3-f is added at a time ( 1-methyltetrazol-5-yl) -thiomethyl cef-3-em-4-carboxylic acid in 10 ml of methylene chloride and 0.75 ml of triethylamine. The temperature is allowed to rise to room temperature, 1 ml of acetic acid is added, sucked off after 10 minutes, washed with water containing hydrochloric acid, dried, concentrated, taken up in 8 ml of dioxane, and 2.5 ml of saturated sodium bicarbonate are added. The sodium salt of the initial trityl acid is sucked off, rinsed with ether-dioxane (1-1), and then with ether. Dioxane is distilled off, taken up in methylene chloride, punctured with water, hydrochloric acid is contained, dried and concentrated. Triturated in ether, sucked off, sieved with ether and obtain 2.29 g of crude product. The product is then stirred for 1 hour while in ethanol, sucked off, and then mixed with ether and 1.42 g of purified product is obtained.
    The resulting product has the configuration of these.
    EXAMPLE 4 7- 2- {2-Amino-4- -thiazolyl-2-methoxyiminoacetyl) -amino 3-3- {(1-methyltetrazol-5-yl) -thiomethyl. Zef-3-e -4-carboxylic acid.
    1.4 g of the product obtained in Example 3 is heated in 5 mp of a 50% aqueous solution of formic acid in a water bath at 55 s. After 15 minutes, 5 ml of water was added, cooled, sucked off, the filtrate was concentrated after the addition of 5 ml of ethanol. Take in 5 ml of alcohol, triturated, sucked off, washed with ethanol, and then with ether, sucked off, dried, concentrated in a mixture of methylene ether (1 - 1), sucked off, progenyut and get 0,557 g of pure product.
    Found,%: C 38.1, H 3.9, N 22.5, S 17.7
    CibHtjOjNgSj (0.5 CiHjOH)
    Calculated,%: C 38.19, H 3.77,
    N 23.58, S 18.00.
    the resulting product has a configuration
    rschiyu-sin.
    NMR (dimethyl sulfoxide, 60 MHz) ppm: 3.83 (N-OCH) b773 (proton of the thia-ethanol cycle).
    PRI mme R.5. 3-acetylthiomethyl 7- (2- (2-tritylamino-4-thiazolyl) -2-methoxy-imino-acetyl) amino cef-3-em-4-carboxylic acid.
    Starting with 3.1 g of sodium salt of 2- (2-tritylamino-4-thiazolyl) -2-methoxyimino-acetic acid in 40 ml of methylene chloride and 6.5 ml of 2N hydrochloric acid, the corresponding acid is prepared in Example 1. This acid is dissolved in 30 ml of methylene chloride. Add 0.8 g of dicyclohexylcarbodiimide and mix for 1 hour 30 minutes in a bath of water and ice. The resulting dicyclohexyl urea is sucked off, cooled to (-5) ° C and a solution of 1.1 g of 7-amino-3-acetylthiomethyl ceph-3-em-4-carboxylic acid in 13 ml of methylene chloride and 0.9 ml of triethylamine is added at one time at 0 ° C. The temperature was allowed to rise to room temperature, 1 ml of acetic acid was added, the insoluble matter was sucked off, washed with water containing hydrochloric acid and then water, the residue was concentrated by dioxane, 3.5 ml of saturated sodium bicarbonate was added, and it was sucked off after 30 min, washed with dioxane-ether and recovered 0.64 g of sodium trithiol acid. Dioxane is distilled off, taken in 30 ml of methylene chloride, washed with water containing hydrochloric acid (10 ml of water and 10 ml of 2N hydrochloric acid), with water and concentrated. Triturated in 25 ml, sucked off, washed and get 1.89 g of crude product.
    Re-precipitate two times by dissolving in 3 ml of ethyl acetate and addition of 25 ml of ether. 0.89 g of the expected product is obtained.
    The resulting product has a configuration. Ration-syn.
    The starting 7-amino-3-acetylthiomethyl-cef-3-em-4-carboxylic acid is obtained in the following manner.
    5.44 g of 7-aminocephalosporanic acid and 50 ml of a 1% aqueous solution of hydroquinone are placed in an atmosphere of an inert gas. 1.7 g of sodium bicarbonate is stirred and added, and then, after dissolving, 3 g of kgshi thioacetate are added. Stir for 3 hours with bo, cool and acidify with acetic acid. Stir at room temperature, suction, wash, dry and obtain 4.9 g of the intended product.
    Example 6. 3-Acetylthiomethyl-7- (2- (2-amino-4-thiazolyl) -2-methoxyimine acyl) amino cef-3-em-4-carboxylic acid.
    Obtained in example 5, the product is stirred for 15 min in a bath at 55 ° C with 5 ml of an aqueous solution of formic acid. 5 ml of water are added, the mixture is cooled to a room volume / peter, sucked off, 5 ml of alcohol are added to the filtrate and concentrated to dryness. 5 ml of alcohol are added and 440 mg of product is obtained in two yields, which is dissolved in 6 ml of 50% aqueous acetone solution. 20 mg of animal charcoal is added, the acetone is sucked off and partly distilled off. After suction, 0.265 g of pure product is obtained. Found,%: C 41.2, H 3.8, N 14, S 19.8. Q, bH ,,, {0.25 С {ЦСОСН) Calculated,%: s 41.39, H 3.33., N 14.41, S 19.73. The resulting product has a configuration syn-syn. NMR (Dimethyl sulfoxide 60 MHz) ppm: 3.83 (N-OCHa), 6.73 (proton of the thiazole cycle. Example 7. 7-1, toethical butyl ether (2 - (2-tritylamino-4-thiazolyl) -2) β-methoxyiminoacetyl) aminos 3-VI zopropylif-3-em-4-carboxylic acid The free acid is obtained from 1.65 g of sodium salt (2-tritylamino-4-thiazolyl) -2-methoxy-imino acetic acid according to Example 1. The resulting the acid is dissolved in 25 ml of dry methylene chloride. 0.71 g of dicyclohexylcarbodiimide is added, the mixture is stirred for 10 min in an ice-water bath and 0.965 g of tertiary butyl ester is added. 3-isopropyl ceph-3-em-4-carboxylic acid. Leave for 2 under stirring at room temperature, dicyclohexyl urea is aspirated, washed with water (10 ml) containing 2 ml of 2N hydrochloric acid and then water , then 10 ml of water containing 5 ml of saturated sodium bicarbonate solution, dried and concentrated to dryness. The residue is dissolved in ether, filtered off with suction, washed with isopropyl ether and 1.66 g of the expected product is obtained. The resulting product has a configuration-syn. Example 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl) amino-3-isopropylceph-3-em-4-carboxy, and acid. 1.66 g of the product obtained in Example 7 was stirred for 15 minutes at a roping temperature with 6 ml of trifluoroacetic acid. 60 ml of isopropyl ether are added, the mixture is suction filtered, a mixture of isopropyl ether is obtained, and 0.825 g of the product is obtained in Eide trifluoroacetic acid. Dissolve the product in 6 ml of water and 4 ml of acetone. 0.2 ml of pyridine is added, acetone is distilled off. The first yield is obtained at 0.232 g. The filtrate is concentrated, taken into 3 MP of water, and another 0.194 g of go-Ki is obtained, i.e. in general, 0.426 Found: C 46.1, H 4.7, N 15.5, 14.1. Sa (0,25 CHjCOCH,) Calculated,%: C 46.23, H 4.88, 15.41, S 14.10. The product has a configuration-syn. NMR (Dimethyl sulfoxide 60 MHz) parts per million: 3.83 (N-OCHj), 6.78 (proton of the thiazole ring). PRI me R 9. Tertiary butyl ester of 7- (2- (2-tritylamino-4-thiazolyl) -2-methoxyiminoacetyl) amino -. -3-methylceph-3-em-4-carboxylic acid. A free acid is obtained from a 2.3 g sodium salt of 2- (2-tritylamino-4-thiazoyl) -2-methoxyiminoacetic acid according to example 1. The resulting crude acid is dissolved in 30 ml of methylene chloride, 1.1 g of dicyclohexylcarbodiimide are added, and then, after 5 minutes, 1.35 g of 7-aminodeoacetoxycetophalosporanic acid tertiary butyl ester. Stir for 2 hours, suction, wash with water, water, acidified with hydrochloric acid, water, and finally with a saturated solution of sodium bicarbonate, dry, concentrate, take up ether, suction, concentrate to dryness and obtain 2.8 g of pure product. The resulting product has a configuration-syn. PRI me R 10. 7- (2- (2-amino-4-thiazolyl) -2-methoxyaminoacetyl) amino-3-methylceph-3-em-4-carboxylic acid. To 2.3 g of the product obtained in Example 9 was added 8 ml of trifluoroacetic acid. Stir for 15 minutes at room temperature and add 80 ml of isopropyl ether. Stir, suction and wash with isopropyl ether. 1.12 g of product is obtained in the form of a trifluoroacetic acid salt. Take them in 10 ml of ethanol at. The crystallization is completed with the addition of 0.2 MP of pyridine, cooled to 10 ° C, sucked off, spilled with ethanol and ether, and 0.531 g of pure product is obtained. Found,%: C 42.2, H 3.9, N 16.6, S 15.5. 2 (0.25 C,) q H OjNjS Calculated,%: C 42.6, H 4.06, 17.13, S, 15.68. The resulting product has a configuration-syn. NMR {Dimethyl sulfoxide, 60 MHz) ppm: 3.85 (N-OCHj), 6.78 (proton of the thiazole ring). EXAMPLE 11 Sodium salt of 7- U 2- (2-amino-4-thiazolyl) -2-methoxyimino-acetyl) amino-3- (2-methyl-1, 3,4-thiadiazole-5- or) thiomethyl cef-3-em-4-carboxylic acid. To a solution in 5 ml of acetone, 2.3 g of 7- (2- (2-amino-4-thiazolyl) 2-methoxyiminoacetyl) gi shno5-3- (2-methyl-1, 3,4-thiadiaeol-5gyl) thiomethyl cef-3-em-4-carboxylic acid, syn-isomer obtained in example 2, is added with an aqueous solution of sodium bicarbonate to pH 7. Add 0.4 g of animal charcoal, mix for 5 minutes, suck the coal and wash it with water acetone solution 1-1.
    50 MP of ethanol is added to the bleached filtrate and concentrated to dryness in vacuo at 30 ° C. The residue is taken in 5 ml of ethanol, triturated crystals, sucked off, washed with ethanol; and then ether. 1.3 g of the expected product are obtained.
    Found,%: Na 4.70.
    Calculated,%: Na 4,18.
    UV in ethanol:
    Max. 235 MMK E
    €
    19800
    360 265 mmk E g 322 17700
    Kink
    280 MMK E 295
    B 0.1 n. solution of hydrochloric acid in ethanol.
    Kink
    218 MMK E; J 244
    Max. 266-267 - 406 f 22300
    Kink
    280 MMK E 363.
    L p and m er 12. Salt of sodium 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl) amino} -3- (1-methyltetraZOL-5-IL) thiomethyl cef-3-em- 4-carboxylic acid, syn-isomer.
    3.35 g prepared according to Example 4 / 7- (2- (2-amino-4-thiaoolyl) -2-methoxyiminoacetyl) amino-3- (1-methyl tetrazol-5-yl) thiomethyl3 cef-3-em-4 -carboxylic acid, syn-isomer, is introduced into 7 ml of methanol and 7 ml of a molar aqueous solution of nari bicarbonate. Stir for 5 minutes at room temperature, insoluble precipitate is sucked off and rinsed twice with methanol-water 1-1.
    While stirring, 85 MP of ethanol was added, the sodium salt crystallized, then 170 MP of ether was added, pereidashivigot 10 microns, sucked off, washed with ethanol-ether 1-1, and then with ether and dried. Get 3.26 g of the target product.
    The product is purified by sludge.
    The resulting salt is dissolved in 40 m of water, 0.6 ml of acetic acid is added to give 6.3-7, diluted with ethanol, and the solvents are distilled off under reduced pressure at a temperature below 35 ° C. Take ethanol to remove water and bring to dryness. The residue is taken up in 16 ml of methanol and then diluted with 160 ml of acetone. The salt crystallizes. Stirred for 5 minutes, sucked off, washed with acetone and then with ether.
    2.3 g of the expected product are obtained.
      -13, (at 1%, in water).
    Found,%: Na 4.8.
    Calculated,%: N and 4.31.
    Example 13. Sodium salt of 3-azegylthiomethyl-7- (2- (2-amino-4-thiazog1) IL-2-methoxyiminoacetyl) amino-ceph-3-em-4-carboxylic acid, syn-isomer.
    At room temperature, 4.5 g, prepared as described in Example 6, 3-acetide thiomethyl 7-f (2- (2-amino-4-thiazolyl) -2-methoxy-imino-acetyl) amino cef-3-em-4-carboxylic acid, syn- isomer, is introduced into 9 MP of methanol and 9 ml of a sodium bicarbonate molar solution in water. Stir for 5 minutes at room temperature, insoluble parts are sucked off, rinsed with methanol-water (1-1). With stirring, 110 mp of ethanol is added, and the sodium salt crystallizes. Dilute with 220 ml of diethyl ether, mix, suction, wash with ethanol-ether 1-1, and then with ether. Dry and get the target product.
    The resulting sodium salt is purified as follows.
    The product is dissolved in 40 Mp of water, adjusted to pH 6.8-7 by the addition of a few drops of acetic acid. 100 ml of ethanol is reduced and then the solvents are distilled off under reduced pressure at a temperature below 35 ° C. The concentrate is taken, two vases are destroyed with 50 ml of ethanol, and the second rae is brought to dryness. The residue is dissolved in 15 MP of methanol, the insoluble matter is filtered off, and then the methanol solution is diluted with 150 MP of acetone.
    The sodium salt is crystallized, the mixture is stirred for 5 minutes, the crystals are sucked off, washed with acetone and then with ether. Dry under reduced pressure. 1.8 g of the expected product are obtained.
     dli -31 ° C ± 2 (at o, 6%, in water).
    Found,%: Na 4.9. Credited,%: Na 4,65. UV in ethanol:
    EI 419 Max. 235 MMK E :; 343 Kink 260 MMK
    Ё :; 122 Bend 300 micron In ethanol - 0.1.n. salt on sour.
    Bend 230 mmk E 280 Max. 263 MMK E: J 391 19700 Example 14. A microcrystalline sodium salt of 3-acetylthiomethyl 7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl) amino cef-3-em-4-carboxylic acid, syn- isomer.
    47.5 mg prepared according to Example 6 J3-acetylthiomethyl-7- (2- (2-amino-4-thiazolyl) -2-methoxyiminoacetyl) amino, cef-3-em-4-carboxylic acid, syc-isomer are mixed, with 1,5mp molar solution of anhydrous acetate
    sodium in anhydrous methanol. 0.5 ml of ethanol is added, insoluble matter is sucked off, 2 ml of ethanol is added, and the sodium salt crystallizes. Sucked off, washed with methanol, and then dried in a drying cabinet at 45 ° C under vacuum.
    0.25 g of a non-hygroscopic salt is obtained.
    Found,%: Na 4,6.
    Calculated,%: Na 4,66.
    Example 15. 3-acetylthiomethyl-7- (2- (2-amino-4-thiazolyl) -2-labels :: imino acetyl) amino cef-3-em-4-carronic acid, syn-isomer.
    Phase A: 3-acetylthiomethyl-7- (2- {2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetyl) amino} cef-3-em-4-carboxylic acid, syn-isomer.
    15.3 g of 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetic acid, syn-isomer, in 80 ml of methylene chloride are added. At 5c, 8 ml of triethylamine is added. At 0 ° C, under nitrogen atmosphere, 3.8 ml of tinil chloride and 26 ml of methylene chloride are introduced. It is kept at 0 ° C for 15 minutes and then 7 ml of triethylamine are added. At 0 ° C, 14.4 g of 7-amino-3-acetylthiomethyl-cef-3-em-4-carboxylic acid are introduced into 100 ml of methylene chloride and 14 g of triethylamine in atmospheric nitrogen. The temperature is allowed to rise to 20 ° C and then stirred for 1 hour. The solution is distilled to dryness in vacuo at about 30-35 s. The residue is dissolved in 250 ml of water, treated with charcoal, 50 ml of 2N are added. hydrochloric acid solution. The precipitate is filtered off with suction and washed with water. The resulting crude product is suspended in 80 ml of ethanol. At 5 ° C, .7 MP of triethylamine is added. With cross-radiation and at 5 ° C, 15 ml of 4N are added at a time. sulfuric acid solution. The product crystallizes after 15 minutes. The mixture is filtered off with suction, washed with ethanol with the aid of condensation, and then with ether, dried under vacuum, and the expected product is obtained.
    Phase B: 3-acetylthiomethyl-7- (2- (2-amino-4-thiazolyl) -2-methoxy-aminoacetyl) amine cef-3-em-4-carboxylic acid, syn-isomer.
    5.48 g of the phase A acid is suspended in 10.6 ml of water with 912 mg of thiourea. At 2 ° C, 1 g of potassium bicarbonate is added. After dissolution, the mixture is stirred for 6 hours at about 20 ° C in a nitrogen atmosphere. Resinous precipitation begins after about an hour and a half. Then 30 ml of water and 3 ml of formic acid are added. Cooled to 5 ° C. Sucked off, swallowed with water containing 10% formic acid. The residue is dissolved at about 30 ml of water containing triethylsmin. 3 ml of formic acid is added and the precipitate is filtered off with suction, washed with condensation water containing formic acid. The dark brown gum is removed. The aqueous layers are combined and treated with charcoal. A light yellow solution is obtained which is saturated with ammonium sulfate. The precipitate is sucked off, concentrated with water, sucked off, washed with water and precipitate A is obtained.
    The stock solutions are saturated with ammonium sulfate, the precipitate formed is filtered off with suction, washed 3 times with water and a half precipitate is obtained.
    Precipitates A and B are combined. The ethanol was taken in for 1 hour at 20 ° C and left for 16 hours at 0 ° C. It is stripped off, washed with ethanol, ether, dried under vacuum and the desired product is obtained, the syn-isomer. The product is identical with the product obtained in examples 6 and 18.
    Used in example 2- (2-chloro acetamido-4-thiazolyl) -2-methoxyiminoacetic acid, the syn-isomer was prepared as follows:
    a) Ethyl ester of 2- (2-chloroacetamido-4-thiazolyl) g2-methoxyiminoacetic
    5 acid, syn-isomer:
    45.8 g of 2- (2-amino-4-thiazolyl) -2-methoxyiminoacetic acid ethyl ester, the syn-isomer is introduced into 200 ml of methylene chloride. 20 ml are distilled off
    fi for drying, cooled to 10 ° C and 50 ml of pyridine was added. 41 g of monochloroacetic anhydride are added and slightly heated to dissolve. Leave for 6 hours at 20 ° C in an atmosphere of nitrogen, add 5 ml of water, stir, and pour into 300 ml of a 2N hydrochloric acid solution. Decanted, extracted with methylene chloride, washed with water, bicarbonate.
    With sodium, water, dried, treated with activated carbon, concentrated and 300 ml of isopropyl ether are added. The product crystallizes; concentrated to a thick dough, ice-nt, sucked off, washed with isopropyl ether, dried, and 45.4 g of product were obtained. M.p. 113 C.
    A pure sample is obtained by recrystallization in a mixture of methylene chloride isopropyl ether. So pl. 118C.
    0
    b) 2- (2-chloroacetamido-4-thiazolyl) -2-methoxyiminoacetic acid syn-isomer.
    46 g of the product obtained in the previous phase a) are introduced into 230 ml of absolute ethanol. At 20 ° C and under nitrogen, 30 ml of pure sodium hydroxide solution are added. The product dissolves. The sodium salt begins to crystallize, and then the medium solidifies. After 16 h
    0 sucked off and washed. The resulting salt was dissolved in water, ice nt, 100 ml of 2N was added. hydrochloric acid solution, saturated with sodium chloride, extracted with ethyl ether, containing 10% ethanol. Dried, treated with charcoal, distilled under vacuum, distilled water with benzene, taken with methylene chloride, distilled to dryness, taken with methylene chloride, ice nt, sucked off, washed, dried, and 34.5 g of the desired product were obtained, mp. about 200 ° C. The product is purified by recrystallization in aetonisopropyl ether.
    Found,%: C 34.8, H 2.8, N 14.8, C1 12.6, S 11.5.
    CgHgO NjCES 277.68
    Credited,%: C 34.60, H 2.90, N 15.13, C1 12.77, S 11.55.
    distinguishing
    with the fact that the compound of the formula
    (Ijj
    where R has
    meaning and you are,
    sheh; and A is an atom
    hydrogen or group
    forming a complex compound, is reacted with an acid
    Formulas
    NO-Kg
    权利要求:
    Claims (2)
    [1]
    Claim
    1. The method of obtaining derivatives
    7 - [2- (2-aminothiazolyl-4) -2-alkoxyiminoacetamido] '- 3-Cephem-4-carboxylic acid 20 of the general formula wherein
    Forming a complex efreviruyut interaction with Formulas
    R and A * matter, - the hydrogen atom indicated is a group, the ι group, acid * HHi (| And) of this and the above,
    30 as syn isomers,.
    where R is the radical -CH X ~ SR, in which Rl> -C x -C 4 -acyl, 2-methyl-1,3,4-thiadiazolyl or 1-methyltetrazolyl, or R -C, -C ^ -alkyl ,
    R is C L —C A is alkyl;
    Ά - a hydrogen atom or an alkali metal or the equivalent of an organic amine,
    UH-Rz about ι - 1 it
    С-С-ОН II N or с with a functional derivative of an acid, where R 2 is Chloracetyl or a shield group, such as trityl, R v has the meanings in a solvent medium at a temperature from (-35) ° С to room temperature and the resulting the compound is treated with thiourea and / or subjected to acid hydrolysis and the chain product is isolated as a free acid or as an alkali metal salt or an organic amine.
    [2]
    2. The method according to claim 1, characterized in that the acid hydrolysis is carried out in a solvent medium at a temperature from room temperature to the boiling point of the reaction mixture.
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    同族专利:
    公开号 | 公开日
    PT66353B|1979-01-18|
    GB1581184A|1980-12-10|
    JPS58192890A|1983-11-10|
    HRP931392B1|1996-04-30|
    YU43087B|1989-02-28|
    BE852860A|1977-09-26|
    CH623590A5|1981-06-15|
    SU795482A3|1981-01-07|
    DE2760156C2|1987-08-27|
    DK161253B|1991-06-17|
    US4396618A|1983-08-02|
    YU41573B|1987-10-31|
    NL8004943A|1980-11-28|
    JPS638116B2|1988-02-19|
    NL7703219A|1977-09-27|
    CS209878B2|1981-12-31|
    CH622800A5|1981-04-30|
    JPH0257072B2|1990-12-03|
    JPS568392A|1981-01-28|
    ZA771664B|1978-04-26|
    DE2713272C2|1983-01-20|
    ATA211177A|1978-10-15|
    IL51670A|1981-07-31|
    IL51670D0|1977-05-31|
    ES469116A1|1978-11-16|
    LU77014A1|1977-10-03|
    PL124945B1|1983-03-31|
    AT350182B|1979-05-10|
    AU2360877A|1978-09-28|
    SE7702909L|1977-09-26|
    HK21582A|1982-05-28|
    NZ183692A|1979-10-25|
    PL118475B1|1981-10-31|
    JPS52116492A|1977-09-29|
    JPS62174084A|1987-07-30|
    YU72577A|1983-10-31|
    PT66353A|1977-04-01|
    AR220333A1|1980-10-31|
    FR2345153A1|1977-10-21|
    PL196886A1|1979-07-16|
    JPH0322849B2|1991-03-27|
    AR219916A1|1980-09-30|
    CA1334407C|1995-02-14|
    JPS6229436B2|1987-06-25|
    ES457115A1|1978-08-16|
    FR2345153B1|1979-10-05|
    DD130788A5|1978-05-03|
    OA05606A|1981-04-30|
    IE45130L|1977-09-25|
    DK129477A|1977-09-26|
    SE439485B|1985-06-17|
    US4476122A|1984-10-09|
    DE2713272A1|1977-10-06|
    IT1077500B|1985-05-04|
    DE2759885C2|1985-06-27|
    HU173005B|1979-01-28|
    DD134526A5|1979-03-07|
    MX5129E|1983-03-25|
    AU509857B2|1980-05-29|
    JPS62174018A|1987-07-30|
    YU189382A|1983-01-21|
    IE45130B1|1982-06-30|
    DK161253C|1991-12-09|
    GR63125B|1979-09-17|
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    FR2367756B1|1976-04-12|1985-07-05|Fujisawa Pharmaceutical Co|2-ALCOXYAMINO-2-ACETICS DERIVATIVES AND THEIR USE|
    GR63088B|1976-04-14|1979-08-09|Takeda Chemical Industries Ltd|Preparation process of novel cephalosporins|
    JPH0158193B2|1979-04-03|1989-12-11|Fujisawa Pharmaceutical Co|
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    DE3177090D1|1980-12-31|1989-09-28|Fujisawa Pharmaceutical Co|7-acylaminocephalosporanic acid derivatives and processes for the preparation thereof|
    JPS64399B2|1981-08-13|1989-01-06|Takeda Chemical Industries Ltd|
    EP0081971A3|1981-12-08|1984-09-26|Tanabe Seiyaku Co., Ltd.|Novel cephalosporin compound and process for preparing the same|
    JPS60178891A|1984-02-24|1985-09-12|Kureha Chem Ind Co Ltd|Cephalosporin derivative, preparation thereof and medicine containing said derivative|
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    US5261314A|1988-12-05|1993-11-16|Hirotaka Manufacturing Co., Ltd.|Directional control valve for pneumatic cylinder|
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    CN108586491B|2017-12-26|2021-03-02|山东裕欣药业有限公司|Preparation method of cefetamet pivoxil hydrochloride|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    FR7608690A|FR2345153B1|1976-03-25|1976-03-25|MD94-0270A| MD226C2|1976-03-25|1994-09-08|Method of 7--2-alkoxyiminoacetamido)-3-cefem-4 carbonic acid derivatives preparation|
    MD94-0278A| MD248C2|1976-03-25|1994-09-08|Method of preparation of derivatives of 7--2-alkoxyiminoacetamido)-3-thiomethyl-3 cefem-4-carbonic acid in the form of sin-isomers.|
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