• 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:
    1501476 Preparation of penicillanic and cephalosporanic acid compounds CHINOIN GYOGYSZER ES VEGYESZETI TERMEKEK GYARA RT 30 July 1975 [30 July 1974] 31937/75 Heading C2C Acid amides of Formula I or salts thereof, wherein R<SP>1</SP> is H or an easily removable ester-forming or a salt-forming group, R<SP>2</SP> is H, an alkyl group optionally having an aryl heterocyclic substituent, an alkenyl group, an alkaryl group or an aryl, aralkyl or heterocyclic group optionally having one or more substituents, R<SP>3</SP> is H or a salt-forming group, or an optionally substituted aryl, alkyl cycloalkyl or aralkyl group, and X is a group of the formulµ are obtained by acylating a compound of the general Formula II wherein R<SP>4</SP> is an easily-removable ester group or a salt-forming group, using as acylating agent an ester of the general Formula III wherein R<SP>5</SP> is optionally substituted aryl, alky cycloalkyl, or aralkyl, and if desired, substituents R<SP>4</SP> and/or R<SP>5</SP> is/are split off, and/or if desired the obtained product is converted into its salt or a salt is converted into the free acid. When the compound of Formula III is a dipentachlorophenyl ester of a substituted ma- Ionic acid the resulting novel product of Formula I in which R<SP>3</SP> is pentachlorophenyl, may be further reacted with an alcohol or phenol of the general formula R<SP>3</SP>OH to form a product of Formula I in which R<SP>3</SP> is as defined above.
    公开号:SU797579A3
    申请号:SU752163056
    申请日:1975-07-30
    公开日:1981-01-15
    发明作者:Хун Магда；Сабо Габор；Решофски Габор；Шомфай Ева
    申请人:Хиноин Дьедьсер Еш Ведьесети Термекекдьяра Pt (Инопредприятие)；
    IPC主号:
    专利说明:

    (54) A METHOD FOR OBTAINING AMIDES OF ACIDS OR THEIR SALTS WITH ALKALI METALS OR TRIALKYLAMINES The goal is achieved by a method for producing amides of the formula I, which consist in the acylation of compounds of the general formula IG and II COORt. where X is as defined above; R4 is trialkylammonium, trichloroethyl or is carried out by a malonic acid derivative of the formula in Rj -CHCOOCfiCtg COOB.5 wherein Rj is as defined above; phenyl, phenyl, substituted by halogen or halogen or alkyl groups, benzyl, indanyl; and the acylation is carried out at a temperature of from -10 to + 30 ° C in the presence of a tertiary amine, for example triethylamine or pyridine, in an inert organic solvent, usually methylene chloride or dichloroethane, and the compounds of the formula D are isolated in free form or their salts with alkali metals or trial by kylamine. The direction of the reaction and the nature of the compounds obtained can be controlled by changing the amount of the introduced tertiary base. For example, if dipentachlorophenylarylmalonate is used as an acylating agent and only 1 mole of a tertiary base is added to the reaction mixture, based on the mole of the acylating agent, then the corresponding a-carboxy hydroxy derivative is obtained. However, if 2 moles of a tertiary base are introduced, a ketene derivative of the corresponding arylmalonic amide is formed in the reaction medium, which, after being treated with a dilute sodium carbonate solution, gives the corresponding sodium carboxylate compound. So, if the corresponding α-carboxy-b-APA or 7-ACC derivatives are obtained, then esters of malonic acid of general formula PI are added to the reaction, preferably the corresponding pentachlorofesh esters derived from different hemi-esters of malonic acid with the corresponding amines in the presence of one mole equivalent tertiary base. The reaction is carried out at a temperature of from -10 to + 30 ° C and is obtained with excellent yields and with a high degree of purity, derivatives of sarboxypenicillanic acid or cephalo-spororanic acid, respectively, or their esters. 4 If dipenachlorophenylmalonate is used as the acylating agent and the reaction is carried out in the presence of one molar equivalent of a tertiary base, a-carboxyphenylpenicillanic acid or cephalosporanic acid pentachlorophenyl ester or cephalosporanic acid is obtained, respectively. The adiluating agents of the formula III can be obtained in good yields and high purity from the corresponding aryl halonic acid dichlorohydrides. These compounds do not need to be distilled off; they do not decompose during storage and can be used at any time for. the formation of a-carboxyaryl ketenes. The reaction is carried out under mild conditions under which the destruction of the skeleton of the sensitive 6-APC or 7-ACC does not occur. The reaction is very fast, usually c. a period of time from several minutes to 1-2 hours. As the preferred reaction medium, an organic solvent, preferably halogenated hydrocarbons, such as methylene chloride, chloroform, dichloroethane, etc., can be used, but other organic solvents can be used, for example, benzene, dioxane, ether, tetrahydrofuran and .t. p. As a tertiary base, for example, a lower tertiary alkylamine, such as triethylamine, can be used, in addition, an aromatic amine can be used, for example pyridine, J, N-dialkylaniline, etc. The reaction conditions are not critical and not need to withstand any special conditions. The reaction proceeds very quickly, since ketene formed during the synthesis Germans reacts with the amine compound. The proposed method can be used for the industrial synthesis of 7- (a-carboxyphenylacetamino) -3-methylcephalosporanic acid or a-carboxybenzylpenicillin, respectively. In addition, the acylation is carried out in the presence of at least 2 molar equivalents, preferably about 3 molar equivalents of the tertiary base, based on the amount of acylating agent. When you get a (halogeno) to help you methylcephalosporane compounds, such as 7- {a - (pentachlorophenoxycarbonyl) -phene-1-acetamido-3-methylcephalosporanic acid, use a maximum of 1.5 mol, preferably I mol of a tertiary base per 1 mol of acylating agent.
    As an acylating agent, for example, phenyl substituted malonic acid dipentachlorophenyl ester can be used,
    as well as Z-thienyl, o-chlorophenyl, or p-chlorophenyl compound. However, mixed malonic acid esters can also be used when only one of the esterified groups is pentachlorophenyl.
    Thus, it is possible to carry out the operation of the acid, pentachlorophenyl-p-nitrobenzyl phenylmalonic acid, pentachlorophenylphenacyl ester lmalonovoy acid, p-pentachlorophenyl ester nitrofenatsilovym phenylmalonic acid i.n.
    The protective group R4 can be cleaved by known methods. The choice of method is determined by the nature of the protective group and the ring
    system.
    If it is necessary to obtain a penicillanic acid derivative, a triapkylamino group is preferably used as a protecting group. This group can be preferably removed by hydrolysis or, if it is preferable to obtain a salt, by adjusting the pH to an appropriate value.
    For example, a protective trialkylamino group is used in the preparation of carbenicillin. This group can be split in
    moderately alkaline medium, preferably in the presence of phosphate buffer,
    If desired, compounds of the general formula D can be converted into their alkali metal salts, for example, potassium or sodium salts.
    By acylation of an ester derivative of 7-ACC, such as trichloroxyethyl ester, a displaced ester is obtained, the ester group attached to the dihydrothiazine ring can be selectively cleaved, for example, by puriololya.
    For example, a mixture of zinc and hydrochloric acid can be used to selectively remove the trichloroethyl group.
    The proposed method can be interrupted at any stage of the synthesis or can be carried out on the basis of any intermediate that is obtained in the precursors. operations. In addition, the starting materials can also be formed directly in the reaction medium.
    Depending on the reaction conditions used, the final products are obtained either as free acids or as their sop. Salts can be converted to free acids. In turn, the free acids can be converted into their salts by reacting with bases, in particular with a base containing a pharmaceutically acceptable cation. These compounds can be used in therapy in the form of pharmaceutical compositions.
    A thin layer chromatography study was performed on kieselgur using o-toluidine / potassium iodide as the developing agent. The following solvent systems were used: a mixture of benzene with ethyl acetate 20:10 and a mixture of ethyl acetate, pyridine, glacial acetic acid, and water 120: 120: 2: 1.
    The structure of the compounds was confirmed by IR and NMR spectroscopy, as well as by elemental analysis. The degree of purity is verified by a conventional iodometric and acidometric procedure.
    Example 1. 6- (a-Carboxyphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid.
    56 ml (0.4 mol) of triethylamine are added to a suspension of 42 g (10.3 mol) of 6-APA in 600 ml of methylene chloride. The resulting solution is cooled to 0 ° C and 136 g (0.2 mol) of phenylmalonic acid dipentachlorophenyl ester is added to this solution at such a rate that the temperature does not rise more than + 5 ° C. Then, 28 ml (0, 2 mol) of triethylamine, and the phenyl-malic acid dipentachlorophenyl ester is immediately dissolved. The mixture was stirred for 30 minutes, then 200 ml of 8% aqueous sodium bicarbonate solution was added. The pH of the mixture is adjusted to 7 and the methylene chloride phase is separated. The aqueous phase is poured over with 300 ml of ethyl acetate and acidified to 10% phosphoric acid.
    The ethyl acetate phase is separated, washed 3x100 ml with water, dissolved in magnesium sulfate and diluted with 200 ml of acetone. The sodium diethyl acetate is then added to the mixture to precipitate the product as its sodium salt. The precipitate formed is filtered off and washed with 200 ml of acetone, the substance is obtained, and 67 g (80%) of sodium salt of 6- (a-carboxyphenylacetamido)-2,2-dimethylpenam-3-carboxylic acid are obtained with a purity of 100% (determined by iodometry).
    Example 2. 6- (a-Pentachlorophenoxycarbonylphenylacetamido) - 2,2-dimethylpenam-3-carboxylic acid. 5.6 ml (0.04 mol) of triethylamine was added to a suspension of 4.2 g (0.02 mol) of 6-APA in 60 ml of methylene chloride. The resulting mixture is stirred until a clear solution is obtained, and then 13 g (0.02 mol) of phenylmalonic acid dipentachlorophenyl ester is added. The mixture is stirred at room temperature for 2 hours, after which the resulting clear solution is evaporated in vacuo. The residue is treated with 60 ml of ethyl acetate. The solution is cooled to 0 ° C, neutralized to 100 ml of 5% aqueous sodium bicarbonate solution. . The organic phase is separated. The aqueous phase is poured over with 100 ml of ethyl acetate and acidified to aqueous hydrochloric acid. The phases are separated from each other. The ethyl acetate solution was washed with 3x300 ml of ice water, dried, and the solvent was evaporated. 8.5 g (64%) of 6- (a-pentachlorophenyloxycarbonyl) - benzylpenicillin are obtained in the form of a yellowish-white solid foam. Degree of purity 90% (determined by titrimetry). Example 3. 6- (a-Carboxyphenylacetate amido) -2,2-d11metx1penam-3-carboxylic acid. 12.5 g (0.02 mol) of 6- (a-pentachlorophenoxycarbonylphenalacetamido) 2,2-dimethylpenam-3-carboxylic acid, prepared as described in example 2, are suspended in 120 ml of methylene chloride. The suspension is cooled to 0 ° C, 2.8 ml (0.02 mol) of triethylamine are added and the mixture is stirred at room temperature for 30 minutes. The reaction mixture is then decomposed with 8% aqueous sodium bicarbonate solution. Then, according to the method of Example 1, 5.7 g (70%) of 6- (a-carboxyphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid disodium salt are obtained. Example 4. 6- (a-benzyloxycarbonylphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid. 2.8 ml (0.02 mol) of triztilamine was added to a suspension of 2.2 (0.01 mol) of 6-APC in 30 m methylene chloride, then 5.16 g (0.02 mol) of pentachlorophenyl was added to the resulting solution felshmalonovoy benzyl ester. The reaction mixture was stirred at room temperature for 2 hours, after which it was decomposed with 8% aqueous sodium bicarbonate solution. The mixture is worked up as described above and 3.5 g (75%) of 6- (a-benzyloxycarbonylphensh1 acetamido) -2,2-dimethylpenam-3-carboxylic acid are obtained in the form of amy amor powder, 7 (on the 1/2 system 9). Example 5, 6- (a-4; arboxyphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid. The aqueous alkaline mixture obtained in Example 4 after the decomposition stage is hydrogenated with palladium on carbon in the presence of a catalyst. The catalyst is filtered off, the filtrate is poured over 50 ml of ethyl acetate and the aqueous phase is acidified to pH-2 2 n. hydrochloric acid. The ethyl acetate phase is washed with water, dried, diluted with 50 ml of acetone and sodium diethyl acetate, and the disodium salt is precipitated with 6- (a-carboxyphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid. The precipitate is filtered off and washed with acetone. 2.2 g (50%) of the desired product are obtained. Example 6. (5-Indanoxycarbonyl) -suphetamine-2,2-dimethylpenes-3-carboxylic acid, sodium salt. 56 ml (0.4 mol) of triethylamine are added to a suspension of 42 g (0.2 mol) of 6-APA in 600 ml of methylene chloride. The resulting solution is cooled to 10 ° C and 43.0 g (50 ml 0.4 mol) of trimethylchlorosilane is added. The mixture was kept for 60 minutes at 35 ° C, then cooled to 0 ° C, and 108.3 g (0.2 mol) of phenylmalonic acid pentachlorophenyl-5-indanyl ester was added. Then 28 ml | (0.02 mol) are added dropwise. triethylamine to the reaction mixture, then the mixture is stirred at 0 ° C for 3 hours. The pH of the mixture is set to 7 with 200 ml of 8% aqueous sodium bicarbonate solution. The aqueous phase is separated, washed with ethyl acetate, then poured with 200 ml of ethyl acetate, acidified to pH 2 with 2N hydrochloric acid. The ethyl acetate phase is separated, washed with water, dried over magnesium sulphate and neutralized with sodium 2-ethylene hexanoate. The solvent is evaporated, the residue is triturated with diisopropyl ether. Obtain 80 g (85%) of the sodium salt of (5-indanyloxycarbonyl) -phenylacetamido -2,2-dimethylpenam-3-carbono-) acid; t, pl. 220-222 ° C. IR spectrum (extinction bands): 1790 (lactam), 1750 (ester), Rf 0.75 (in the system 1/2 9). Example 7. 6- (a- (5-Indanioxy-ap-., Bonyl) -phenylacetamido-2,2-dimethylpenam-3-carboxylic acid, triethylammonium salt. 12.88 ml (0.092 mol) of triethylamine are added to suspension 9, 66 g (046 mol) of 6-APA in 150 ml of methylene chloride, the mixture is stirred at room temperature until solution is obtained. The solution is cooled to 0 ° C and 25 g (0.046 mol) of pentachlorophenyl-5-indium phenyl ester are added to it. such that the temperature of the mixture remains below 5 ° C. The mixture is stirred at 0 ° C. for 1 h, then evaporated, the solvent is kept in a vacuum, and the residue is mixed with 10 0 ml of ethyl acetate, followed by separation of 26 g (98%) of the triethylammonium salt of - (5-indaphyloxycarbonyl) -feature of acetates up to 1 -2,2-dimeshpenenam-3-carbonoxy (acid in the form of crystals. Mp 153-155 ° C, Calculated,%: C 64.4; H 7.04; N 7.04. Found,%: C 64.16; H 7.24; N 7.08.
    Degree of purity: 99% (determined by iodometry). IR spectrum (absorption bands): 1780 cm (lactam, ester). , 7 (in the system 1/2 9).
    Example 8. The triethylammonium salt of 6- a- (2,4-dimethylphenoxycarbonyl) -phenylacetamido-2,2-dimethylpenam-3-carboxylic acid.
    4.2 ml (0.03 mol) of triethylamine was added to a suspension of 3.24 g (0.015 mol) of 6-APA in 60 ml of methylene chloride and the mixture was stirred at room temperature until a clear solution was formed. The solution is cooled to and 8 g (0.015 mol) of phenylmalonic acid 2,4-dimethylphenylpentachlorophenyl ester is added. The mixture is stirred for 1 hour at 0 ° C, then the solvent is distilled off and the residue is mixed with 30 ml of ethyl acetate. 8.4 g (95%) of the triethylammonium salt of 6 a- (2,4-dimethylphenoxycarbonyl) -phenylacetamido-2, 2-dimethylpenam-3-carboxylic acid are isolated in the form of a white crystalline substance. T, pl, 160165C.
    Calculated,%: C, 63.8; H, 7.19; N 7.19
    Found,%: C 62.47; H 7.20; N 7.19.
    The degree of purity is 98% (determined by iodometry). Rf 0.7 (on the system 1/2 9).
    IR absorption bands; 1790 cm (lactam) .1760 (ester).
    Example 9. The triethylammonium salt of 6- a- (3,4-dimethylphenoxycarbonyl) -phenylacetamido) -2,2-dimethylpenam-3-carboxylic acid.
    3.6 ml (0.026 mol) of triethylamine was added to a suspension of 2.8 g (0.013 mol) of 6-APA in 50 ml of methylene chloride, and the mixture was stirred at room temperature until a clear solution was obtained. The solution is cooled to 0 ° C, 7 g (0.013 mol) of 3,4-dimethylphenyl-pentachlorophenyl phenylmalonic acid ester is added, and the mixture is stirred for another 1 hour at the same temperature. Then the solvent is evaporated in vacuo, the residue is mixed with 30 ml of ethyl acetate. 7.5 g of the triethylammonium salt (95%) (3,4-dimethylphenoxycarbonyl) -phenylacetamido -2,2-dimethylpenam-3-carboxylic acid were isolated as white crystals. T. pl. 155-160 ° C.
    Calculated: C 63,8; H 7.19; N 7.19.
    Found,%: C 63.54; H 7.2; N 7.24.
    The degree of purity is 98% (determined by iodometry). Absorption band of IR spectrum: 1780 cm (lactam, ester), RF 0.7 (in the system 1/2 9).
    Example 10. The triethylammonium salt of 6-a-phenoxycarbonylphenylamine and amido) -2,2-dimethylpenam-3-carboxylic acid.
    11.2 ml (0.08 mol) of triethylamine added to a suspension of 8.68 g (0.04 mol) of 6-APC
    in 120 ml of methylene chloride. The resulting solution is cooled to 0 ° C and phenylpentachlorophenyl phenylmalonic acid is added in small portions so that the temperature of the mixture does not exceed 5 ° C. The mixture is stirred at 5 ° C for 1 h, then the solvent is triturated with 150 ml of ethyl acetate. The precipitated crystalline O substance is filtered off and washed with ethyl acetate. Get 20 g (90%) of triethylammonium salt of 6- (a-phenoxycarbonylphenylacetamido) - 2,2-dimethylpenam-3-carboxylic acid. T. pl. 125 ° C s Calculated, l-: C 63.0; H 6.1; N 7,6
    Found,%: C 62.86; H 6.20; N 7.44
    Absorption band: IR spectrum: 1790 (lactam, ester). Degree of purity: 99% (determined by iodometry). Rf 0.7 Q (in the 1/29 system).
    Example 11. The triethylammonium salt of 6- (a- (5-indanyloxycarbonyl) -phenylacetamido -2, 2-dimethylpenam-3-carboxylic acid.
    2.8 ml (0.02 mol) of triethyl 5 amine is added to a suspension of 2.17 g (0.01 mol) of 6-APC in 50 ml of methylene chloride, the resulting solution is cooled to -10 ° C and 6.6 g (6 0.01 mole) of phenylmalonic acid dipentachlorophenyl ester. The mixture is stirred at the same temperature for 30 minutes, then 1.4 ml (0.01 mol) of triethylamine and 1.34 g (0.01 mol) of 5-1 Shdanol are added successively. Raise the temperature of the mixture to -5 ° C. The mixture is stirred at this temperature for another 1 h, then the solvent is evaporated and the residue is thoroughly triturated with α-diisopropyl ether. The triethylammonium salt of 6- (a- (5-indanyloxycarbonyl) -phenylacetamido-2,2-dimethylpenam-3-carboxylic acid in the amount of 4.2 g (70%) was isolated as a white powder.
    0 T. pl. 153-155 ° C.
    Example 12. Triethylammonium salt of (2,4-dimethylphenoxycarbonyl) -phenylacetamido -2, 2-dimethylpenam-3-carboxylic
    acid. five
    Add 2.8 ml (0.02 mol) of triethylamine to a suspension of 2.17 g (0.01 mol) of b-APA in 50 ml of methylene chloride. The resulting solution is cooled to -10 ° C and 6.6 g added.
    O (OiOl mole) of diphentachlorophenyl ester of phenylmalonic acid. The mixture is stirred at this temperature for 30 minutes, after which 1.4 ml (0.1 mol) of triethylamine and 1 22 g (0.01 mol) of 2,4-xylene are added,
    the temperature of the mixture rises to 0-5 C.   The mixture is stirred at this temperature for 1 hour, after which the solvent is evaporated, and the residue is triturated with diisopropyl ether.  4 g (69%) of triethylammonium salt (2,4-lmethylphenoxycarbonyl) -phenylacetamide -2, 2-dimethylpenes-3-carboxylic acid are obtained.  T.  P .  160-165 ° C.  For example 13.  6- (a-Phenoxycarbonylphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid, triethylammonium salt.  2.8 ml (0, Q2 mol) of triethylamine was added to a suspension of 2.17 g (0.01 mol) of 6-APC in 50 ml of methylene chloride.  The resulting solution was cooled to and added 6.6 g (0.01 mol) of phenylmalonic acid dilentchlorophenyl ester.  The mixture was stirred at this temperature for 30 minutes, after which 1.4 ml (0.01 mol) of triethylamine and 1 g (0.011 mol) of phenol were added.  Raise the temperature to. 0-5 ° C and mix the mixture for 1 hour.  The solvent is evaporated and the residue is triturated with diisopropyl ether.  3.9 g (70%) of 6- (a-phenoxycarbonylphenylacetamido) -2,2-dimethylpenam-3-carboxylic acid are obtained in the form of its triethylammonium salt.  Example 14  (5-Indanoxycarbonyl) -phenylethamido -2,2-dimethylpenam-3-carboxylic acid, sodium salt.  A suspension of 25 g (0.043 mol) of triethylammonium salt of (6-indanyloxycarbonyl) -phenylacetamido 1 - 2,2-dimethylpenam-3 -carboxylic acid in 150 ml of ethyl acetate is cooled to 0 ° C and the suspension is acidified with 18 ml of 2 and aqueous hydrochloric acids to pH = -2. The organic phase is separated, and the acidic aqueous phase is extracted with 2 x 20 ml of ethyl acetate.  Combine the organic solutions, wash with 3x20 ml of a saturated aqueous solution of sodium chloride, dry over magnesium sulfate, filter, and neutralize with sodium diethyl acetate solution containing 6.7 g (0.048 mol) in 30 ml acetone. About half of the solvent is evaporated in vacuo.  To the concentrate was added 100 ml of din propyl ether, the mixture was cooled and a white powder was obtained which was filtered to obtain 18 g (80%) of the sodium salt (5 indanyloxycarbonyl) phenylacetamido -2,2-dimethylpenam-3-carboxylic acid.  T.  mp 220-222 ° C.  IR absorption spectrum: 1790 cm (lactam), 1750 (ester).  Calculated,%: j: 60.3; H 5.03; N 5.40.  Found,%:, 87; H 5.2; N 5.34, Purity: 99% (determined by irdometry).  Rf 0.75 (in the system 1/2 9).  Example 15  6- (o-phenoxycarbonylphenylacetamido) -2,2-dimethylpenamt3-carboxylic acid, sodium salt.  A suspension of 48 g (0.09 mol) of the triethylammonium salt of 6- (a-phenoxycarbosphenne acetamido) 2,2-dimethylpenam-3-carboxylic acid in 250 ml of ethyl acetate is cooled to 0 ° C and acidified with 2 N aqueous hydrochloric acid to pH 2, five.  The organic phase is separated, washed with 2x30 ml of a saturated aqueous solution of sodium chloride, filtered and a solution of 12 g (0.09 mol) of sodium diethyl acetate in 50 ml of acetone is added to the filtrate.  Fallen white powder is filtered off.  Obtain 35 g (85%) of the sodium salt of 6- (a-phenoxycarbonylphenylacetamido) 2, 2-dimethylenes-3-carboxylic acid.  T.  square  233-235 ° C   IR irradiance bands: 1790 (lactam), 1760 (ester).  75 (in the system 1/2 9).  Example 16  Sodium salt of 6- (a-phenoxycarbonylphenylacetamido) - 2,2-dimethylpenam-3-carboxylic acid.  56 ml (0.4 mol) of triethylamine are added to a suspension of 42 g (0.2 mol) of 6-APA in 600 ml of methylene chloride.  To the resulting solution, 430 g (0.4 mol, 50 ml) of trimethylchlorosilane were then added at 10 ° C. The mixture was stirred for 60 minutes.  The mixture is then heated to 35 ° C, 104 g (0.2 mol) of phenylmalonic acid phenylpentachlorophenyl ester is added, after which 28 ml (0.2 mol) of triethylamine are added dropwise to the mixture.  The reaction mixture is stirred at room temperature for 3 hours, then neutralized to a ml of 8% aqueous sodium bicarbonate solution.  The aqueous phase is separated and washed with ethyl acetate.  Then 200 ml of ethyl acetate are poured into the aqueous phase, and the aqueous layer is acidified to p 2 with 2N aqueous hydrochloric acid.  The ethyl acetate phase is separated, washed with water, dried over magnesium sulfate, filtered, and a solution of sodium 2-ethylhexanoate is added to the filtrate.  Filter the precipitated product.  Obtain 80 g (73%) of sodium salt of 6- (a-phenoxycarbonylphenylacetamido) -2, 2-dimethylpenam-3-carboxylic acid with a purity of 99% (determined by iodometry).  Example 17  Disodium salt of 6-a-carboxy-2- (3-thienyl) -acetamido -2,2-dimershenam-3-carboxylic acid.  5.6 ml (0.04 mol) of triethylamine are added to a suspension of 4.2 g (0.02 mol) of 6-APA in 60 ml of methylene chloride.  The resulting solution is cooled to 0 ° C and 13.64 g (0.02 mol) of 3-thienylmalonic acid dipentachlorophenyl ester is added at such a rate that the temperature does not increase.  Then, 2.8 ml (0.02 mol) of triethylamine was added to the mixture; The resulting clear solution is stirred for 30 minutes, then neutralized to pH 7 with 3D ml of a sodium bicarbonate aqueous solution in%.  The organic phase is separated.  The aqueous phase is poured with ethyl acetate and acidified to pHXZ I09fc-Hofl with aqueous phosphoric acid.  The ethyl acetate phase is separated, washed three times with water, and dried with ND; magnesium sulfate, filter and dilute the filtrate with acetone.  Sodium distiylacetate is then added to the solution to precipitate out.  The precipitate is filtered off, washed with acetone and dried.  6.7 g (80%) of the disodium salt of 6- (a-carboxy-3-thienylacetamido) -2,2-dimethylpenam-3-ka carboxylic acid are obtained with a purity of 100% (determined by iodometry).  Example 18  7- (a-Phenoxycarbonylphenyl acetamido) -3-methyl cephem-3-4-carboxylic acid.  42 ml (0.03 mol) of triethylamine were added to a suspension of 2.2 g (0.01 mol) of 7-ACC in 80 ml of acetonitrile and 2 ml of water.  The resulting clear solution is cooled to 0 ° C and 5.02 g (0.01 mol) of phenylmalonic acid phenylpentachlorophenyl ester is added.  The mixture was stirred at room temperature for 2 hours, then the acetonitrile was removed by evaporation.  The residue is mixed with ethyl acetate and acidified with 2 and aqueous hydrochloric acid.  Separate the ethyl acetate phase, dry and evaporate.  The residue is triturated with diisopropyl ether to obtain 3.4 g (75%) of 7- (a-phenoxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxylic acid.  T.  square  PB-PVA.  Calculated%: C 61.0; H 4.64; N 6.18.  Found,%: C 60.9; H 4.50; N 6.00.  , 8 (in the 1/29 system).  Example 19  (5-Indanyloxycarbonyl) -phenylacetamido-3-methylceph-3-em-4-carboxylic acid.  42 g (0.03 mol) of triethylamine are added to a suspension of 2.2 g (0.01 mol) of 7-ACC in 50 ml of acetonitrile in 2 ml of water.  The resulting clear solution is cooled to 0 ° C and 5.4 g (0.01 mol) of phenylmalonic acid ester is added.  The mixture is stirred at room temperature for 2 hours.  The acetonitrile is then evaporated off, the residue is extracted with ethyl acetate and acidified with a solution of 2 and aqueous hydrochloric acid.  The ethyl acetate phase is separated, dried and evaporated.  The residue is triturated with diisopropyl ether to give 3.8 g (76%) of 7-o (5-indanyloxycarbonyl) -phenylacetamido-3-methylceph-3-em4-carboxylic acid.  T.  square  168-170 ° C.  Calculated. %: C 63.0; N.  5.4; N, 5.4 Found: C, 62.25; H 5.25; N.  Example 20  Triethylammonium salt of 7- (cc-phenoxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxylic acid.  4.2 ml (0.03 mol) of triethylamine was added to a suspension of 2.2 g (0.01 mol) 7. ACC 914 in 50 ml of acetonitrile and 2 ml of water.  The resulting clear solution is cooled to -10 ° C and 6.67 g (0.01 mol) of feinylmalonic acid dipentachlorophenle ester is added at such a rate that the temperature of the mixture does not rise above -10 ° C.  Phenylmalonic acid dipentachlorophenyl ester is dissolved in the mixture.  A mixture of nepeMeujUBaraT at this temperature for 30 minutes then a solution of 1 g of phenol and 1.4 ml of triethylamine in 10 ml of acetonitrile is added dropwise.  The mixture is heated to 0 ° C and stirred at this temperature for 60 minutes.  Then evaporated acetonitrnl.  the residue is triturated with diisopropyl ether.  Obtain 4.2 g (72%) of triethylammonium salt of 7- (a-phenoxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxylic acid in the form of a yellowish-white amorphous powder.  Example 21  7- (a-Carboxy-3-thieshyl acetamido) -3-methylceph-3-em-4-carboxylic acid.  4.2 ml of triethylamine are added to a suspension of 2.2 g (0.01 mol) of 7-ACC in 50 ml of acetonitrile and 2 ml of water.  The resulting clear solution is cooled to 0 ° C and 6.80 g (0.01 mol) of 3-thienylmalonic acid dipentachlorophenyl ester is added at such a rate that the temperature of the mixture does not exceed 5 ° C.  Then 1.4 ml (0.01 mol) of triethylamine was added, the resulting solution was stirred for 30 minutes.  The mixture is mixed with 10 ml of 8% aqueous sodium bicarbonate solution, and the acetonitrile is evaporated in vacuo.  The resulting aqueous residue is poured over with 30 ml of ethyl acetate and the pH of the aqueous phase is adjusted to 2 with 2N aqueous hydrochloric acid.  The ethyl acetate phase is separated, washed with water, dried over magnesium sulphate and evaporated in vacuo.  The residue is triturated with ether.  Get 3 g (80%) of 7- (o (-carboxy-3-thienylacetamido) -3-methylceph-3-em-carboxylic acid with a purity of 99% (determined by acidometry).  Calculated,%: C 46. 9; H 4.28; N 7.5; S 16.6.  Found,%: C 45.9; H 4.15; N 7.4; S 15.9.  Example 22  7- (5-Indanyloxycarbonyl) -phenylacetamido-3-methylceph-3-em-4-carboxylic acid trichloroethyl ester.  2.8 ml (0.02 mol) of triethylamine was added to a suspension of 3.8 g (0.02 mol) of 7-amIno-3-methylceph-3-em-4-carboxylic acid trichloroethyl ester in 30 ml of methylene chloride.  The triethylamine hydrochloride precipitated is filtered off, the filtrate is cooled to 0 ° C, and 5.05 g (0.01 mol) -pentachlorophenyl-5-indanyl phenylmalonic acid ester is added.  The resulting clear solution is stirred at this temperature for 30 minutes, then washed with 2 and iodic hydrochloric acid.  The solvent is evaporated, and the residue is mixed with absolute ethanol.  4.8 g (80%) of 7- (a- (5-indanylcarbonyl) -phenylacetamido) -3-methylceph-3-ism-4-carboxylic acid trichloroethyl ester is obtained.  It is a white crystalline substance, melting at 135-138 ° C.  Calculated,%: C 54.1; H 3.86; N 4.50; S 16.9.  Found,%: C 53.9; H 3.50; N 4.24; S 15.5.  Rf 0.7 (in system 13).  Example 24  7- (a-Benzyloxycarbonyl-phenylacetamido) -3-methylceph-3-em-4-carboxylic acid.  1.8 ml of pyridine was added to a suspension of 2.17 g (0.01 mol) of 7-ACC in 40 ml of acetonitrile and 2 ml of water.  Cool the resulting solution to 0 ° C, add 5.6 g (0.01 mol) of phenylmalonic acid pentachlorophenylbenzyl ester, transfer the mixture for 4 h.  Evaporated.  acetonitrile, the residue is treated with 50 ml of ethyl acetate, and the ethyl acetate solution is mixed with a saturated sodium bicarbonate solution.  The aqueous phase is washed with ethyl acetate, then it is poured 50. ml of ethyl acetate and acidified to with 2N aqueous hydrochloric acid.  The ethyl acetate phase is separated, dried and evaporated.  3.5 g (75%) of 7- (o-benzyloxycarbonylphenylacetamido) -3-methylceph-3-4-carboxylic acid are obtained with a purity of 95% (determined by titrimetry).  IR absorption spectrum: 1790 (lactone), 1760 (complex ether).  .  Example 25  Trichlorostil zirr 7- (o-phenoxycarbonylphenyl-tetraamido) -3-methyl cef-3-em-4-carboxylic acid.  2.8 ml (0.02 mol) of triztilamine are added to the suspension, 3.8 g (0.01 mol) of trichloroethyl hydrochloride acid 7. amino-3-methyl-ceph-3-em-4-carboxylic acid in 30 ml of methylene chloride.  The triethylamine hydrochloride precipitated is filtered off, the filtrate is cooled to 0 ° C and 5.02 g (0.01 mol) of phenylmalonic acid phenylmalonic acid is added.  The resulting clear solution was stirred at this temperature for 30 minutes, then washed with 2N aqueous hydrochloric acid and the solvent was distilled off.  The residue is treated with absolute ethanol.  4.7 i (80%) of 7- (o-phenoxycarboiylpheylacetamido) -8-methylcepha-3-e-4-carbric acid is obtained.  It is a white crystalline substance with m.  square  120135 ° C.  , 7 (in system 13).  Calculated,%: C 51.6; H 3.44; N 4.81; S 18.1 Naideio,%: C 51.7; H 3.30; N 4.60; S 18.5.  Example 26  7- (a-Carboxyphenylacetamido) -3-methylceph-3-em-4-carH) onic acid.  4.2 ml (0.03 mol) of triztilamine are added to a suspension of 2.17 g (0.01 mol) of 7-ACC in 30 ml of acetonitrile in 2 ml of water.  Cool the resulting clear solution to 0 ° C and add 6.8 g (0.01 mol) of phenylmalonic acid phenyl chlorophenyl ether.  The solution is moved at 0 ° C for 4 hours, then acetonitrile is distilled off in vacuo.  The residue is treated with ethyl acetate, the solution is shifted from 50 ml of an aqueous solution of sodium bicarbonate.  The aqueous phase is separated, washed with 30 ml of ethyl acetate, then it is poured with 50 ml of ethyl acetate and acidified to with 4N aqueous; hydrochloric acid.  The ethyl acetate phase is separated, dried over magnesium sulphate and evaporated in vacuo.  The residue was triturated with a small amount of ether to give 3 g (79%) of 7- (a-carboxyphenylacetamido) -3-methylceph-3-em-4-carboxylic acid.  It is a white amorphous powder, melting at 180-181 ° C.  Degree of purity: 98% (determined by acidometry).  Example 27  7- (No. pentachlorophenoxycarbonylphenylacetamido) trichloroethyl ester) 3-methylceph-3-em-4-carboxylic acid.  18 ml (0.2 mol) of pyridine was added to a suspension of 38 g (0.1 mol) of 7-ACC hydrochloric acid and trichloroethyl ether.  The resulting clear solution is cooled to 0 ° C and 68 g (0.1 mol) of phenylmalonic acid dipentachlorophenyl ether are added in small portions.  The mixture is stirred at this temperature for 4 hours, after which the precipitate formed is filtered off.  68 g (90%) of 7- (No. pentachlorophenoxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxy acids are obtained.   T.  square  202 ° C.  Absorption bands of the IR spectrum: 1790 cm (lactam), 1745 cm (ester), 1360 and 1390 (pentachlorophenyl).  Calculated,%: C 39.8: H 2.1; N 3.70; S 37.6.  Found,%: C 39.74; H 2.05; N 3.52; S 37.49.  Example 28  7- (obenzyloxycarbonylphenylacetamido) -3-methylceph-3-carboxylic acid trichloroethyl ester.  1.8 ml (0.02 mol) of pyridine was added to a suspension of 3.8 g (0, UI mol of 7-ACC hydrochloric acid ether in 30 ml of methylene chloride.  The mixture was cooled to 0 ° C and 5.16 g (0.01 mol) of phenylmalonic acid benzyl ethyl chloro phenyl ether was added.  The reaction mixture is stirred for 5 hours, then the solvent is distilled off, and the residue is recrystallized from absolute ethanol.  4.8 g of trichloroethyl Jpipa 7- (o-benzyloxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxylic acid are obtained.  T.  square  148-150 ° C.  Calculated: C 52.45; H 2.87; N 4.70; S 17.60 Found: C 51.90; H 2.75; N 4.90; S 17.85.  Example 29  p-nitrophenacyl.  7- ((X-Pentachlorophenoxycarbonylphenylacetamido) ester) -3-methylceph-C-em-4-carboxylic ester Add 1.6 ml (0.016 mol) of pyridine to a solution of 3.5 g (0.008 mol) of p-nitrophenacyl ester 7 ACC in 50 ml of methylene chloride.  The solution is cooled to 0 ° C. 5.4 g (0.003 mol) of phenylmalonic acid dipentachlorophenyl ester is added, the mixture is stirred for 5 hours; The precipitated product is filtered off.  5 g (80%) of 7- (a: -pentachlorophenoxycarbonylphenylacetamido) p-nitrophenacyl ester are obtained; 3-methylceph-3-em-carboxylic acid, T.  mp 188-190 ° C.  Calculated,%: C 47.60; H 2.7; N 5.4; S 22.3.  Found,%: C 47.94; H 2.64; N 5.30; S 23.6.  Example 30  7- (a-phenoxycarbonylphenylacetamido) -3-methyldef-3-em-4-carboxylic acid trichloroethyl ester.  2.8 ml (0.02 mol) of triethylamine and 1 g (0.01 mol) of phenol at 0 ° C are added to a suspension of 7.56 g (0.01 mol) of 7- (0-pentachlorophenoxycarbonyl acetylacetamido) -3- trichloroethyl ether methylceph-3-em-4-carboxylic acid in 50 ml of methylene chloride.  The reaction mixture was stirred at 0 ° C for 1 h at room temperature, then washed with 2 and aqueous hydrochloric acid. The solution is dried and evaporated.  The residue is treated with absolute ethanol.  4.4 g (75%) of 7- (0-phenoxycarbonylphenylacetamido) -3-methyldef-3-em-4-carboxylic acid are obtained.  T.  square  120-125 ° C,, 7 (in system 13).  Example 31  7- (a-Phenoxycarbonylphenylacetamido) -3-methylceph-3-em-4-carboxylic acid.  1.4 ml (0.01 mol) of triethyla were added to a suspension of 1.9 g (0.005 mol) of 7-ACC trichloroethyl ether in the form of its hydrochloric acid salt in 50 ml of methylene chloride.  The mixture is cooled to 0 ° C, 2.5 g (0.005 mol) of phenylmalonic acid phenylpentachlorophenyl ester is added, and the mixture is stirred at this temperature for 1 hour.  Stirring is then continued for 3 hours at room temperature. The reaction mixture is washed with 20 ml of 2 and aqueous hydrochloric acid, after which 20 ml of 2 N aqueous hydrochloric acid and 2 g of activated dink are added.  The mixture is stirred at room temperature for 2 hours.  The methylene chloride is separated. The 18th phase is washed, washed with water and extracted with a saturated aqueous solution of sodium bicarbonate.  The aqueous alkaline solution is washed with ethyl acetate, then poured with ethyl acetate and acidified to pH 2 with 2N aqueous hydrochloric acid.  The ethyl acetate phase is separated and evaporated.  The residue is triturated with diisopropyl ether to obtain 1.5 g (66%) of 7- (a-phenoxycarbonylfsnlaeni-amido) -3-methylceph-3-em-4-carboxylic acid as white crystals with m.  square  PB-PV S.  Example 32  7- (a-Carboxypropylacetamido) -3-methylceph-3-em-4-carboxylic acid.  5.6 ml (0.04 mol) of triethylamine are added to a suspension of 2.2 g (0.01 mol) of diptyllaphenyl ester and methyl piophenol acid.  The reaction mixture is stirred for 3 hours.  The resulting clear solution was evaporated, and the residue was dissolved in ethyl acetate.  The solution is washed with 2N aqueous hydrochloric acid and water, dried, and evaporated.  The residue is triturated with diisopropyl ether to obtain 2.2 g (65%) of 7- (01: -car6oxypropylacetamido) -3-meth11lcef-3-em-4-k; 1-carboxylic acid.  T.  mp 178-180 ° C.  Calculated: C 47.5; P, 5.1; N 8.2 Found: C 46. 9; H 5. 3: N 8.5.  Prim with p 33.  Trichloroethyl 7- (a-carboxypropyl ester) -3-mntncef-3-em-4-carboxylic acid.  4.2 ml (0.03 mol) of triethylamine are added to a suspension of 3.8 g (0. 01 mol) of 7-ACC hydrochloric acid ethyl ether in 50 ml of methylene chloride.  The mixture is cooled to 0 ° C and 6 is added. 24 g (o, 01 mol) of ethyl maloic acid dimethyl phenyl ester.  Raise the temperature of the mixture to 5 ° C and obtain a transparent solution after 30 min of stirring.  The mixture was stirred for 3 hours, then it was washed with 2N aqueous hydrochloric acid and water, dried and evaporated.  The residue is treated with ether.  3.5 g (77%) of 7- (a-carboxypropyl-amide amido) -3-methylceph-3-em-4-carboxylic acid trichloroethyl ester are obtained.  .  T.  square  155-160C.  Calculated,%: C 39.3; H 3.7; N 6.1; S 22.9.  Found 7g: C 38.5; H 3.5; N 6. 0; S 22.0.  Example 34  7- (ft-Carboxy-p-chlorphenyleladamido) -3-methylceph-3-em-4-carboxylic acid.  Add 5.6 ml (0. 04 mol) of triethylamine to a suspension of 2.17 g (0.01 mol) of 7-ACC in 50 ml of adetonitrile and 2 ml of water.  Cool the resulting clear solution to 0 ° C and add 7.1 g (0.01 mol) of dipentachlorf. p-chlorophenylmalonic acid nyl ester at a rate such that the temperature of the mixture does not rise above 5 ° C.  Stir the resulting clear solution for 30 minutes, then acetonitrile is evaporated.  The residue is dissolved in 50 ml of ethyl acetate, the solution is washed with 2x10 ml of 2 and aqueous hydrochloric acid, then with water, dried and the solvent is evaporated.  The rest of the residue is triturated with ether, and 3.3 g (80%) of 7- (d1-carboxy-p-chlorophenylacetamido) -3-methylceph-3-em-4-carboxylic acid as white amorphous powder is obtained.  Degree of purity: 99% (determined by acidimetrically).  Calculated,%; C, 49.8; H 3.66; N 6.84; CE 8.55 Found,%: C 47.9; H 3.48; N 6.70; CE 8.30.  Example 35  7- (o (Carboxy-o-bromo phenylendetamido) -3-methyl ethyl 3-em-4-carboxylic acid.  5.6 ml (0.04 mol) of triethylamine are added to a suspension of 2.17 g (0.01 mol) of 7-ACC in 50 ml of adetonitrile and 2 ml of water.  The resulting solution is cooled to 0 ° C and 7.5 g of d-pentachlorophenyl o-bromophenylmalonic acid ester is added at such a rate that the temperature of the mixture does not rise above 5 ° C.  The resulting clear solution is stirred for 30 minutes, then the adonitrile is evaporated.  The residue is dissolved in 50 ml of ethyl adatate.  The ethyl acetate solution was washed with 2N aqueous hydrochloric acid, dried, and the solvent was evaporated.  The residue is triturated with ethyl ether to give 3.6 g (80%) of 7- (acarboxy-o-bromophenylacetamido) -3-methyldef-3-em-4-carboxylic acid with a purity of 98% (determined by acidimetry).  Calculated,%: C 44.8; H 3.29; N 6.16; Вг 17,6.  Found,%: C 43.9; H 3.10; N 6.00; Вг 17.05.  Example 36  The disodium salt of 6- (Qf-carboxy-p-chlorophenylacetamido) -2,2-dimethylpenam-3-carboxylic acid.  Add 2.8 ml (0.02 mol) of the triethi pes to the suspension. .  2.17 g (0.01 mol) of 6-APK in 50 ml of methylene chloride.  The resulting solution is cooled to 0 ° C and 7.1 g (0.01 mol) of p-chlorophenylmalonic acid dipentachlorophenyl ester is added.  The mixture is stirred for 1 hour at this temperature.  The resulting clear solution is neutralized to saturated aqueous sodium bicarbonate.  The aqueous alkaline phase is separated, washed with ethyl acetate and dried by freezing.  3.85 g (80%) of the disodium salt of 6- (o-carboxy-p-chlorophenylacetamido) -2,2-dimethylpenam-3-carboxylic acid are obtained.  Purity: 98.5% (determined by iodometry) or 97% (determined acidimetrically), respectively.  Calculated,%: C 44.8; H 3.29; N 6.15, CE 7.70 Found,%: C 43.5; H 3.33; N 6.25; From 7.20.  Example 37  The disodium salt of 6- (0-carboxy-o-bromophenylacetamido) 2,2-dimethylpenam-3-carboxylic acid.  Add 2.8 ml (0.02 mol) of triethylamine to a suspension of 2.17 g (0.01 mol) of 6-APA.  The resulting solution is cooled to 0 ° C and 7.5 g (0.01 mol) of o-bromophenylmalonic acid dipentachlorophenyl ester is added.  The mixture is stirred at this temperature for 1 h.  The resulting clear solution is extracted with a saturated sodium bicarbonate solution.  The aqueous alkaline solution is washed with ethyl acetag and freeze dried.  3.7 g (75%) of the disodium salt of 6- (af-carboxy-o-bromophenylethamido) -2,2-dimethylpenam-3-carboxylic acid are obtained.  Purity: 99.5% (determined by iodometry) or 98.5% (determined acidimetrically), respectively.  Calculated,%: C 40.8; H 3.00; N 5.60; Br 16.0.  Found,%: C 39.2; H 2.98; N 5.15; Вг 16,55.  Example 38  7- (o: -carboxybutyramido) -3-methyldef-3-em-4-carboxylic acid.  8.4 ml (0.06 mol) of triethylamine was added to a suspension of 8.4 ml (0.02 mol) of 7-ACC in 50 ml of acetonitrile and 2 ml of water.  The resulting clear solution is cooled to 0 ° C and 13.0 g (0.02 mol) of ethylmalonic acid dipentachlorophenyl ester is added.  The solution is stirred for 2 hours. then acetonitrile is distilled off.  50 ml of ethyl acetate is added to the residue and shaken with sodium bicarbonate.  The aqueous phase is again treated with ethyl acetate and acidified with 10% hydrochloric acid.  Dry the ethyl acetate phase.  The solvent is distilled off.  The residue is triturated with ether and dried under vacuum.  4.7 g (72%) of 7- (a-carboxybutyramido) -3-methylceph-3-em-4-carboxylic acid are obtained.  T.  square  186-187 ° C.  Elemental analysis for  Calculated,%: C 48.15; H 4.91; N 7.4 Paydeno,%: C 48.9; H 4.10; N 7.5.  Example 39  7- (a -carboxycetamido) -3-metsh1cef-3-em-4-carboxylic acid trichloroethyl ester.  3.8 g (0.01 mol) of trichloroethyl ether 7-ACC hydrochloride ester is suspended in 50 ml of methylene chloride and mixed with 50 ml of saturated sodium bicarbonate solution.  Separate the formed layers.  The methylene chloride phase is dried and filtered.  The solution is cooled to 0 ° C, 0.8 ml is added to it.
    权利要求:
    Claims (3)
    [1]
    Claim
    1. The method of producing amides of acids of General formula I
    Soybean order 9822/81 where 4 has the above meanings;
    R <t -trialkylammonium, trichlorethyl or sodium; derivatives of malonic acid, characterized in that, in order to increase the yield of quality improvement and simplify the process, an ester of the formula IG is taken as a derivative of malonic acid
    And a -ON-SOOC b CC 5 COORj where R 2 has the above meanings;
    R 5 is phenyl, phenyl substituted with halogen or halogens or alkyl groups, benzyl or indanyl; and acylation is carried out at a temperature of from -10 ° C to +30 ° C in the presence of tertiary amine, in an inert organic solvent, followed by isolation of the target product in free form or salts with alkali metals or trialkylamines.
    [2]
    2. The method of pop. 1, distinguishing - with the fact that triethylamine or pyridine is used as a tertiary amine.
    [3]
    3. The method according to claims 1 and 2, characterized in that methylene chloride or dichloroethane is used as an inert organic solvent.
    类似技术:
    公开号 | 公开日 | 专利标题
    CA1092110A|1980-12-23|Antibacterial agents
    EP1767538B1|2014-05-07|Process for producing 1-oxacephalosporin-7alpha-methoxy-3-chloromethyl derivative
    US4788282A|1988-11-29|Deprotection of allylic esters and ethers
    US3943123A|1976-03-09|Novel beta-lactams and novel process
    CS228520B2|1984-05-14|Method for the production of 4-hydroxy-2-methyl-n-2-pyridyl-2h-1,2-benzothiazin-3-carboxamid-1,1-dioxide
    SU662013A3|1979-05-05|Method of obtaining hetacephalexin or salts thereof
    SU797579A3|1981-01-15|Method of preparing acid amides or their salts with alkaline metals or trialkylamines
    DK163584B|1992-03-16|7-AMINO-3-PROPENYLECEPHALOSPORIC ACID DERIVATIVES AND PROCEDURES FOR PREPARING THEREOF
    SU546282A3|1977-02-05|The method of obtaining 7-α-amino-7 methoxy-cephalosporin esters
    KR20010034671A|2001-04-25|Process for purification of a cephalosporin derivative
    US3976641A|1976-08-24|Cephalosporin intermediates and process therefor
    SU886747A3|1981-11-30|Method of preparing cephalosporin compounds
    US4171303A|1979-10-16|Process for the preparation of reactive penicillanic acid and cephalosporanic acid derivatives
    JPH064641B2|1994-01-19|Method for producing cefalosporin derivative
    SU563918A3|1977-06-30|Method of producing cephalosporane derivatives,or their salts,or esters
    KR950001026B1|1995-02-07|Process for preparing penicillanic acid derivatives
    DK141502B|1980-03-31|Process for preparing a 7-acylamido-3-methyl-3-cephem-4-carboxylic acid ester.
    US4659812A|1987-04-21|Cephalosporin intermediates
    HU188008B|1986-03-28|Process for epymerizing penicillin
    SU419038A3|1974-03-05|Method for producing 6-aminopenicillanic acid derivatives
    SU527138A3|1976-08-30|Method for preparing carboxy derivatives of 6-aminopenicillanic acid or their salts
    US5731433A|1998-03-24|Process for the preparation of rufloxacin and salts thereof
    KR100292568B1|2001-09-17|Manufacturing method of condensed carbapenem derivative
    US4148995A|1979-04-10|Process for preparing cephem lactones for cephalosporin-type antibiotics
    JP2604794B2|1997-04-30|Method for producing 4-acetoxy-3-hydroxyethylazetidin-2-one
    同族专利:
    公开号 | 公开日
    DE2559913C2|1984-02-09|
    CA1072951A|1980-03-04|
    IN142322B|1977-06-25|
    AU8347675A|1977-02-03|
    AU499851B2|1979-05-03|
    DE2533273C2|1984-06-07|
    PL100796B1|1978-11-30|
    FI66186C|1984-09-10|
    DK156221B|1989-07-10|
    ES439835A1|1977-06-16|
    NO153532B|1985-12-30|
    SE431546B|1984-02-13|
    FR2280372B1|1978-10-20|
    GB1501476A|1978-02-15|
    IL47797A|1979-01-31|
    US4304717A|1981-12-08|
    HU168914B|1976-08-28|
    FI66186B|1984-05-31|
    ATA580775A|1977-03-15|
    FR2280372A1|1976-02-27|
    DE2533273A1|1976-02-19|
    ES455786A1|1978-03-01|
    JPS5141381A|1976-04-07|
    CS185355B1|1978-09-15|
    YU37170B|1984-08-31|
    DK156221C|1989-12-04|
    FI752156A|1976-01-31|
    NO752673L|1976-02-02|
    SE7508515L|1976-01-31|
    NL7509026A|1976-02-03|
    AR216287A1|1979-12-14|
    AT340048B|1977-11-25|
    BG25519A3|1978-10-10|
    YU187975A|1983-04-27|
    BE831917A|1975-11-17|
    DD120023A1|1976-05-20|
    DK343975A|1976-01-31|
    JPS5545080B2|1980-11-15|
    NO153532C|1986-04-09|
    IL47797D0|1975-10-15|
    EG12375A|1980-03-31|
    CH625805A5|1981-10-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    FR3684M|1963-04-23|Beecham Group Ltd|New penicillin.|
    GB1193302A|1967-03-07|1970-05-28|Beecham Group Ltd|7-Aminocephalosporanic Acid Derivatives|
    GB1321815A|1969-07-03|1973-07-04|Beecham Group Ltd|Penicillins|
    BE759498A|1969-11-26|1971-05-26|Pfizer|NEW ESTERS OF ALPHA-CARBOXYBENZYLPENICILLIN|
    IL41409A|1972-02-04|1977-04-29|Richter Gedeon Vegyeszet|Lysergic acid amides and process for their preparation|
    AT329744B|1972-09-05|1976-05-25|Biochemie Gmbh|PROCEDURE FOR TEMPORARY PROTECTION OF CARBOXYL GROUPS IN PENICILLINES, PENICILLIN SULFOXIDES OR CEPHALOSPORINES|
    US4171303A|1974-07-30|1979-10-16|Chinoin Gyogyszer Es Vegyeszeti Termekek Gyara Rt.|Process for the preparation of reactive penicillanic acid and cephalosporanic acid derivatives|JPS5848141Y2|1976-07-02|1983-11-02|
    IL67672D0|1982-01-22|1983-05-15|Beecham Group Plc|Penicillin derivatives,their preparation and pharmaceutical compositions containing them|
    JPS60167398U|1984-04-17|1985-11-06|
    JPH037594U|1989-06-12|1991-01-24|
    US6906250B2|2002-09-09|2005-06-14|Monsanto Technology, L.L.C.|Inbred corn line LH331|
    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    HUCI1499A|HU168914B|1974-07-30|1974-07-30|
    [返回顶部]