CH629210A5 - Process for the preparation of cephem compounds - Google Patents

Abstract

Compounds of the formula: <IMAGE> in which R<1> is hydrogen or acyl and R<3> is the radical of a nitrogen-containing heterocyclic thiol compound are prepared from corresponding compounds of the formula: <IMAGE> in which W is acetonyl, -X-COOH or -X-OH, and X is an organic radical, by reaction with a nitrogen-containing heterocyclic thiol compound. The products of the process are antibiotics.

Description

       

  
 

** WARNING ** beginning of DESC field could overlap end of CLMS **.

 



   PATENT CLAIMS
1. Process for the preparation of cephem compounds of the formula:
EMI1.1
 in which R1 is hydrogen or an acyl group and R3 is the residue of a nitrogen-containing, heterocyclic thiol compound and its salts, characterized in that a compound of the formula:
EMI1.2
 in which Rl has the meaning given above and W denotes an acetonyl group or one of the groups -X-COOH and -X OH, in which X represents an organic radical, or a salt thereof with a nitrogen-containing heterocyclic thiol compound or a salt thereof.



   2. The method according to claim 1, characterized in that the acyl group Rl of the formula:
EMI1.3
 in which R4 corresponds to acetyl, haloacetyl, phenyl, p-hydroxyphenyl, thienyl, 2-imino-4-thiazclin-4-yl, 2-oxo-4-thiazolin-4-yl, tetrazolyl, phenoxy or 3-amino-3 -carboxypropyl and R5 are hydrogen, sulfo, amino or hydroxy and the amino and carboxyl groups in R4 and R5 can be protected.



   3. The method according to claim 2, characterized in that the protective group of the amino group is one of the following: phthaloyl, benzoyl, p-nitrobenzoyl, toluoyl, naphthoyl, p-tert. -Butylbenzoyl, p-tert-butylbenzenesulfonyl, phenylacetyl, benzenesulfonyl, phenoxyacetyl, toluenesulfonyl, chlorobenzoyl, acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaloyl, Camphorsulfonyl, methanesulfonyl, chloroacetyl, t-butoxycarbonyl, ethoxycarbonyl, iso-bornyloxycarbonyl , Phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, t3-methylsulfonylethoxycarbonyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and 2-methoxycarbonyl-1-methylvinyl.



   4. The method according to claim 1, characterized in that Rl 2- (2-imino-4-thiazolin-4-yl) acetyl, W acetonyl and R3 (1 - [2- (N, N-dimethylamino) ethyl] - 1 Represent H-tetrazolj-yl) thio and 5-mercapto-1 - [2- (N, N-dimethylamino) ethyl] - 1H-tetrazole is used as nitrogen-containing, heterocyclic thiol compound.



   5. The method according to claim 1, characterized in that Rl D-5-phthalimido-5-carboxyvaleryl, W acetonyl and R3 (1 j2- (N, N-dimethylamino) ethyl] - 1 H-tetrazol-5-yl) thio represent and 5-mercapto-1 - [2- (N, N-dimethylamino) ethyl] - 1H-tetrazole is used as nitrogen-containing, heterocyclic thiol compound.



   6. The method according to claim 1, characterized in that R1 represents D-5-phthalimido-5-carboxyvaleryl, W acetonyl and R3 (1-methyl-1H-tetrazol-5-yl) thio and 5-mercapto-1 methyl-1H -tetrazole is used as nitrogen-containing, heterocyclic thiol compound.



   The invention relates to a new process for the preparation of gephem compounds which correspond to the following formula:
EMI1.4
 in which R1 is hydrogen or an acyl group and R3 is the residue of a nitrogen-containing, heterocyclic thiol compound.



   The process according to the invention consists in that a compound of the formula:
EMI1.5
 in which R1 has the meaning given above and W is an acetonyl group or one of the groups -X-COOH and -X
OH means wherein X represents an organic radical, or a salt thereof with a nitrogen-containing, heterocyclic thiol compound or a salt thereof.



     As is known, the reaction by which the 3-acetoxymethyl group of a cephalosporin compound is substituted with a nucleophilic reactant causes a simultaneous decomposition of the starting material, intermediate and end product and leads to an extended reaction time. Therefore, lower yields are achieved [A.B. Taylor, J. Chem. Soc., 7020 (1965)].



   Therefore, research has been conducted into a denvate that has a group that is easier to substitute than the acetoxy group.



   In order to solve the above-mentioned problems, extensive studies have been made and it has been found that the use of diketene or of compounds of formula m or IV, which are mentioned below as acylating agents, the O-acylation of the (3-hydroxymethyl group of the 3- Hydroxymethyl compound (or) cephalosporadesinic acid) enables high yield and that the O-acylated cephalosporin thus produced can be very easily substituted by a nucleophilic compound. The present invention is based on this finding.



   The above-mentioned compounds of formula (I) include, for example, those compounds in which R1 is hydrogen, phenylacetyl, phenoxyacetyl, 5-anüno-5-carboxyvaleryl, the amino and / or carboxyl group of which is or may be protected, or one of the groups that can be in the 6- or 7-position of penicillin or gephalosporin derivatives



   nen. So e.g. the acyl group R1 can be an aliphatic acyl group, such as formyl, acetyl, propionyl, butyryl, isobutyryl,
Valeryl, iso-valeryl, cyclopentylcarbonyl, cyclohexylcarbonyl, cycloheptylcarbonyl, cyclopentylacetyl, cyclohexadienylacetyl or the like, an aromatic acyl group such as e.g.

  Benzoyl, @ p-nitrobenzoyl, toluoyl, naphthoyl, or the like, a monosubstituted, aliphatic acyl group, such as e.g. 2-thienylacetyl,
Cyanoacetyl, acetoacetyl, 4-chloro-3-oxobutyryl, 4-bromo-3 oxobutyryl, chloroacetyl, bromoacetyl, 4-methylthio-3-oxobutyryl, 4-carbamoylmethylthio-3-oxobutyryl, a-phenoxypropionyl, a-phenoxybutyryl Tetrazolylthioacetyl, tetrazolylacetyl, p-nitrophenylacetyl, trifluoromethylthioacetyl, trifluoromethylsulfinylacetyl, trifluoromethylsulfonylacetyl, cyanomethylthio acetyl, thiadiazolylthioacetyl, p-nitrophenyyrylacyl (4-nitro) , (2-Imino-4-thiazolin-4-yl) acetyl, (2-thioxo-4-thiazolin-4-yl) acetyl, 4-pyridylthioacetyl,

   (3-Sydnon) acetyl, 1-pyrazolylacetyl, 2-furylacetyl, (2-oxo-3-methylpyridazinyl) thioacetyl, (2-aminomethylphenyl) acetyl, (2-aminomethylcyclohexenyl) acetyl or the like, a di substituted, aliphatic acyl group, such as a-carboxyphenylacetyl, Mandelyl, a-sulfophenylacetyl, a-sulfo- (p-aminophenyl) acetyl, phenylglycyl, (4-hydroxyphenyl) glycyl, (4 methyl-thiophenyl) glycyl, (4-methoxyphenyl) glycyl, ( 4-methanesulfinylphenyl) glycyl, (3-methanesulfonamidophenyl) glycyl, 1-cyclohexenylglycyl, thienylglycyl, furylglycyl, cyclohexadiene nylglycyl, (3,4-dihydroxyphenyl) glycyl or the like, 5-methyl-3-phenyl-4-isoxazolyl

   3- (2,6-dichlorophenyl) -5-methyl 4-isoxazolyl-carbonyl or the like. be. The groups mentioned above are only intended as examples of the acyl groups which can be used according to the invention, preferably those acyl groups which have the formula are used
EMI2.1
 in which R4 are acetyl, haloacetyl, phenyl, p-hydroxyphenyl, thienyl, 2-imino-4-thiazolin-4-yl, 2-oxo-4-thiazolin-4-yl, tetrazolyl, phenoxy, 3-amino-3 -carboxypropyl or the like. and R5 hydrogen, sulfo, amino, hydroxy or the like. mean.



   Any functional group in these acyl groups, e.g. the amino and / or carboxyl group are protected accordingly. Aromatic acyl groups such as e.g.



  Phthaloyl, benzoyl, p-nitrobenzoyl, toluoyl, naphthoyl, p-tert-butylbenzoyl, p-tert-butylbenzenesulfonyl, phenylacetyl, benzenesulfonyl, phenoxyacetyl, toluenesulfonyl, chlorobenzoyl or the like, aliphatic acyl groups such as e.g. Acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaroyl, camphorsulfonyl, methanesulfonyl, chloroacetyl or the like, esterified carboxyl groups such as e.g. tert-butoxycarbonyl, ethoxycarbonyl, iso-bornyloxycarbonyl, phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, ss-methylsulfonylethoxycarbonyl, or the like, carbamoyl groups such as e.g. Methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl, the corresponding thiocarbamoyl groups, 2-methoxycarbonyl-1-methylvinyl or the like. to call.

  Protective groups for the carboxyl groups of the acyls mentioned under R and the 4-carboxyl group of the cephem ring are methyl, ethyl, tert-butyl, tert-amyl, benzyl, p-mtrobenzyl, p-methoxybenzyl, benzhydryl , 1-indanyl, phenacyl, phenyl, p-nitrophenyl, methoxymethyl, ethoxymethyl, benzyloxymethyl, acetoxymethyl, pivaroyloxymethyl, ss-methylsulfonyl-ethyl, methylthiomethyl, trityl, ss, ss, ss-trichloroethyl, silyl groups, such as trimethyl. to call.



  These carboxyl groups can also be in the form of inorganic or organic salts with alkali metals such as lithium, sodium, potassium, magnesium or the like, alkaline earth metals such as calcium or various amines, e.g. Dicyclohexylamine, triethylamine, tributylamine, di-n-butylamine, di-n-propylamine or the like. be used.



   The organic radical designated X in the compound of the formula I is generally a carbon chain which has a 5- or 6-membered ring with the grouping
EMI2.2
 can form and can have a double bond or oxygen, hydrogen or sulfur, preferably oxygen.



  The carbon atoms of the carbon chain are optionally substituted. Examples of suitable substituents are: carboxyl, halogen, nitro, alkyl, e.g. Methyl, ethyl, propyl, methylene, ethylene, aralkyl, e.g. Benzyl, phenethyl or the like, aryl e.g. Phenyl, tolyl, or the like. and mercapto groups or hydroxy groups substituted by these groups, e.g.



  Methoxy, p-chlorophenylthio or the like. If two or more substituents are present, they can form a ring with the carbon chain.



   In the process according to the invention, the reaction proceeds at a rate which is 4 to 16 times greater than that when 3-acetoxy compounds are used, and moreover runs almost quantitatively.



   Examples of the nitrogen-containing, heterocyclic thiols are those with one or more nitrogen atoms, which may be in the form of an oxide and / or may contain oxygen and / or sulfur in addition to the oxygen and may optionally be nucleus-substituted.



  Examples of nitrogen-containing heterocyclic groups of such thiol compounds are pyridyl, N-oxide pyridyl, pyrimidyl, pyridazinyl, N-oxide pyridazinyl, pyrazolyl, diazolyl, thiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4 oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-triazolyl , 1,2,4-tri-oyl, 1H-tetrazolyl, 2H-tetrazolyl or the like. Substituents for these nitrogen-containing heterocyclic groups of such thiol compounds are, for example, monovalent groups such as hydroxy, mercapto, amino, carboxyl, carbamoyl, lower alkyl, e.g.

  Methyl, ethyl, trifluoromethyl, propyl, isopropyl, butyl, isobutyl or the like, lower alkoxy groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy or the like, halogens such as chlorine, bromine or the like. and various substituent groups bonded to each other by lower alkylene groups, -S-, -N- or other polyvalent groups. If the polyvalent groups are lower alkylene groups, the substituents can e.g. Hydroxy, mercapto, amino, morpholino, carboxyl, sulfo, carbamoyl, alkoxycarbonyl, lower alkylcarbamoyl, alkoxy, alkylthio, alkylsulfonyl, acyloxy, morpholinocarbonyl or the like. be.

  If the polyvalent group is -S or -N-, the substituents can be lower alkyls or lower alkylene groups which have the above-mentioned substituents. If the polyvalent group is -N-, substituents e.g. Carboxyl, alkoxycarbonyl, acyl, carbamoyl, mederalkylcarbamoyl or the like. be directly bound.

 

  Examples are in particular substituted alkyl groups such as e.g.



  Carboxymethyl, carbamoylmethyl, N-lower alkylcarbamoylmethyl e.g. N, N-dimethylcarbamoylmethyl, hydroxy lower alkyl, e.g. Hydroxymethyl, 2-hydroxyethyl, acyloxy lower alkyl e.g. Acetoxymethyl, 2-acetoxyethyl, alkoxycarbonylmethyl, e.g. Methoxycarbonylmethyl, hexyloxycarbonylmethyl, octyloxycarbonylmethyl, methylthiomethyl, methylsulfonylmethyl, N-lower alkylamino-lower alkyl, e.g. N, N-dimethylaminomethyl, N, N-dimethylaminoethyl, N, N, N-trimethylammonium ethyl, morpholinomethyl or the like, substituted amino groups such as e.g. Lower alkylamino, e.g. Methylamino, sulfo-lower alkylamino, e.g. 2-sulfoethylamino, hydroxy lower alkylamino, e.g. Hydroxyethylamino, lower alkylamino lower alkylamino, e.g. 2-dimethylaminoethylamino, 2-trimethylammonium ethylamino, acylamino, e.g.

  Acetylamino, 2-dimethylaminoacetylamino, 2-trimethylammonium acetylamino, lower alkoxycarbonylamino, e.g. Methoxycarbonylamino or the like and substituted thio (mercapto) groups such as e.g. Methylthio, 2-hydroxyethylthio, 2-acyloxyethylthio, e.g. 2-acetoxyethylthio, 2-phenylacetoxyethylthio, 2-caproyloxyethylthio, carboxymethylthio, alkoxycarbonylmethylthio, e.g. Methoxycarbonylthio, hexyloxycarbonylmethylthio, carbamoylmethylthio, N-lower alkylcarbamoylmethythio, e.g. N, N-dimethylcarbamoylmethylthio, acetylmethylthio, N-lower alkylamino lower alkylthio, e.g. 2-N, N-dimethylaminoethylthio, 2-N, N, N-trimethylammoniumethylthio, morpholinocarbonylmethylthio, 2-sulfoethylthio or the like. be. In particular, various heterocyclic thiols, e.g.

  Tetrazolthiol, Methyltetrazolthiol, Phenyltetrazolthiol, (2-N, N-dimethylaminoethyl) tetrazolthiol, Methylthiadiazolthiol, Hydroxyäthylthiothiadiazolthiol, Methylthiothiadiazolthiol, Thiadiazolthiol, Carbamoylaminothiadiazolthiol, Carbamoylmethylthiothiadiazolthiol, thiazolethiol, Methylthiazolthiol, Carboxymethylthiazolthiol, Triazoltbiol, Dimethyltriazolthiol, Pyrozolthiol, Äthoxycarbonylmethyltriazolthiol, imidazolethiol, Methyloxadiazolthiol, pyridinethiol, pyrimidinethiol , Methylpyridazinthiol, triazinthiol or the like. called. In addition, aliphatic or aromatic thiols containing nitrogen, heterocyclic compounds, e.g. Methanethiol, ethanethiol, thiophenol called.



   The substitution reaction between such a thiol compound and a compound of formula I is usually carried out in a solvent. Water is most often used, but there are also hydrophilic organic solvents such as acetone, tetrahydrofuran, dimethylformamide, methanol, ethanol, dimethyl sulfoxide or the like. and aqueous solvents such as mixtures of water and inert polar solvents, as mentioned above, are preferably used.



   Although the compound of formula I can be free, it is advantageous to subject it to the reaction in the form of an alkali metal salt such as e.g. a sodium, potassium or other salt or an organic amine salt, e.g. of a triethyl.



  to subject amine salt, trimethylamine salt or another amine salt. The thiol compound is also used either freely or in the form of its alkali metal salt, organic amine salt or other salt.



   The quantitative ratio of the thiol compound used in the reaction is preferably one equivalent or more based on one equivalent of the compound of the formula I.



  Although the optimum pH depends on the nuclophilic thiol compound used and the compound of the formula I, the reaction is generally preferably carried out in a slightly acidic to slightly alkaline medium. The reaction temperature is preferably between 40 and 70 ° C., but these are not critical limits. The duration of the reaction depends on the reaction temperature, the pH, the type of thiol compound and other factors. At 60 ° C. the reaction proceeds approximately The reaction can be carried out in the presence of an inorganic salt added to the reaction system, such as chloride, bromide, iodide, thiocyanide or nitrate of lithium, sodium, potassium, ammonium or the like.



   The starting products of the formula I, in which W is acetonyl, can be obtained by reacting a compound of the general formula:
EMI3.1
 wherein R2 represents hydrogen or an acyl group can be prepared with diketene. The diketene can also be used in the form of an adduct with acetone, acetophenone or the like.



  This is an equimolar reaction product, i.e. the compound of formula II and diketene can each be used in equimolar amounts. In order to take into account possible decomposition of the diketene, as occurs in the presence of water or alcohol, the diketene can be used in excess. In general, the reaction can be carried out successfully by reacting a 3-hydroxymethylcephalosporin of the formula II with diketene in an inert solvent at temperatures from -30 to 40 ° C. The inert solvents are, for example, dichloromethane, chloroform, dichloroethane, dimethylformamide, dimethylacetamide, Tetrahydrofuran, acetonitrile, ethyl acetate, acetone, dioxane, ether, or the like. And mixtures of these substances are suitable.

  The reaction of the diketene with the 3-hydroxymethylcephalosporin of the formula II takes place at a high rate, but since the reaction rate depends on the temperature and to ensure that the reaction proceeds to the end, the reaction is carried out within a period of 0.5 carried out up to 15 hours. An amine, e.g. Triethylamine can be added. When the starting material of formula II is an alkali metal salt, the corresponding equivalent of e.g. Tri äthylaminhydrochlorid be used to effect a salt exchange before the start of the reaction.



   If W in formula I -X <OOH means, the compound by reacting a 3-hydroxymethylcephalosporin II with a compound of the general formula
EMI3.2
 where X has the meaning given above.



   As specific examples of compounds of the formula m are maleic anhydride, succinic anhydride, phthalic anhydride, glutaric anhydride, diglycolic anhydride, thio diglycolic anhydride, p-chlorophenyl anhydride, methylene succinic anhydride, 3-nitrophthalic anhydride, trimellitic anhydride.

 

   In general, the reaction of the compound of formula II with the compound of formula III can be carried out with good success in the presence of a suitable inert solvent as set out above. The stoichiometric quantitative ratios of the reactants, the reaction temperature and the other reaction conditions can be selected similarly to that given above.



   The compounds I in which W is -X-OH can be reacted with a compound of the general formula by reacting a 3-hydroxymethylcephalosporin II
EMI3.3
  in which X has the meaning given above.



   Examples of compounds of the formula IV are O-carboxymandelic anhydride, O-carboxy-a-hydroxypropionic anhydride, O-carboxy-a-hydroxypropionic anhydride, O-carboxy-3-methylsalicylic anhydride, O-carboxy-3methylsalicylic anhydride, O-carboxy- (a- hydroxy-a-phenyl) propionic anhydride, O-carboxy (a-hydroxy-a-phenyl) propionic anhydride or the like. called.



   The conditions in the reaction of the compound of formula II with that of formula IV are similar to those set out above. If the starting material of formula II has an unprotected amino group, the reaction thereof with diketene or a compound of formula III or IV can be carried out so that both the 3-hydroxy group and the amino group are acylated by the same acyl group.



   The resulting compound of formula I also has antibiotic effects.



   The compound of formula I, in which Rl represents an acyl group, can be eliminated by cleavage of the 7-acyl group according to one of from US Pat. No. 3,632,578, known processes can be converted into the corresponding compound in which R1 is hydrogen (Japan. Patent Publication No. 13862/1966, No. 40899/1970, JA-OS 34387/1972, 95292 / 1975 and 96591/1975, Japan. Patent Publication No. 35079/1975, U.S. Patent 3,632,578 or the like).



   In this compound, an acyl group, as mentioned above under the examples for R1 as a substituent of position 6 or 7 in penicillin or cephalosporin compounds, can be introduced by prior activation thereof in a manner known per se. So e.g. a compound in which R1 is 4-halo-3-oxobutyryl can be obtained by reacting the 7-amino compound with a 4-halo-3-oxybutyric acid halide which in turn is used with thiourea to form 7- [2- (2-imino -4-thiazolin-4 yl) acetamido] compound is implemented. Although the antibiotic activity of these compounds depends to a certain extent on the 3-position substituent, it is excellent.

  So e.g. the compound in which the 3-position is 1-methyltetrazol-5-ylthiomethyl is particularly useful, and it can achieve the same effect as about five times the amount of cephazoline.



   The invention is illustrated by the examples below. In the description are g, mg, ml, cm, Hz, DMSO and Zers. Abbreviations for grams, milligrams, milliliters, centimeters, Hertz, dimethyl sulfoxide and decomposition.



  The resins labeled Amberlite are from Rohm & BR <Haas Co. products made in the USA. Celite and Sephadex are owned by John-Manville Sales Corporation and



  distributed by Pharmacia AB. The temperatures are uncorrected and all percentages are percentages by weight, unless stated otherwise. The magnetic core resonance spectra were carried out on a Varian Model HA 100 (100 MHz) or T60 (60 MHz) spectrometer with tetramethylsilane as an internal standard, all o values are given in ppM. The symbol s means singlet, d doublet, t triplet, q quartet, m multiplet, and J coupling constant.



  Production of the starting products
example 1
7.05 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3-hydroxymethyl-3-cephem4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane, then 0.92 g of diketene were added. The reaction was carried out at room temperature within 3 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure, the residue was diluted with water and the pH was adjusted to 6 with sodium bicarbonate. The aqueous solution was washed twice with ethyl acetate, adjusted to pH 2.0 with 4N-HCl and extracted three times with ethyl acetate. The ethyl acetate solution was washed with a saturated aqueous sodium chloride solution, treated with magnesium sulfate and filtered.

  The solvent was then distilled off under reduced pressure. The residue was mixed with ether and the resulting powder was filtered off, washed with ether and dried. 5.48 g of 7 (3- [D-5-phthalimido-5-carboxyvalerainidoj-3 - (3-oxobutyryloxy) methyl-3-cephem-3-carboxylic acid were obtained in 93.2% yield by the above procedure.



      IR (KBr): 3350.1775.1740.1715.1640.1530 cml
NMR (6 in d, -DMSO): 1.30-2.40 (6H, m), 2.17 (3H, s), 3.46 (2H, ABq, J = 18Hz), 3.60 (2H, s), 4.72 (1H, t), 4.90 (2H, ABq, J = 12Hz), 5.01 (1H, d, J = 5Hz), 5.62 (1H, dd, J = 5 & 8Hz), 7.88 (4H, s), 8.80 (1H, d , J = 8Hz)
Example 2
6.69 g of 7ss- [D-5-benzamido-5-carboxyvaleramido] -3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane. Then 1.01 g of triethylamine and 1.68 g of diketene were added at room temperature and the reaction was continued for 3 hours.



  After the reaction had ended, the reaction mixture was treated as described in Example 1. 5.12 g of 7.8- [D-5-benzamido-5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained in 91.3% yield.



   IR (KBr): 3350, 1780, 1735, 1720, 1640, 1530 cm- 'NMR (o in d6-DMSO): 1.45-2.40 (6H, m), 2.18 (3H, s), 3.50 (2H, ABq, J = 19Hz), 4.34 (1H, m), 4.88 (2H, ABq, J = 13Hz), 5.05 (lH, d, J = 5Hz), 5.65 (lH, dd, J = 5 & 9Hz), 7.27 8.0 ( 5H, m), 8.46 (1H.dJ = 8Hz), 8.75 (1H.dJ = 9Hz)
Example 3
7.29 g of 7- [D-5- (p-toluenesulfonamido) -5-carboxyvaleramido] -3-hydroxymethyl-3-ce phem-3-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane and then at room temperature 0.1 51 g of triethylamine and 1.26 g of diketene were added. The reaction was continued for 4 hours and the reaction mixture was treated as described in Example 1.

  5.64 g of 7- [D-5- (p-toluenesulfonamido) -5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained in 92.3% yield.



   IR (KBr): 3275.1780, 1740, 1730.1715, 1640, 1535 cm-NMR (in d6-DMSO): 1.30-1.80 (4H, m), 2.0-2.4 (2H, m), 2.16 (3H, s), 2.33 (3H, s), 3.45 (2H, ABq, J = 19Hz), 4.91 (2H, Abq, J = 12Hz), 5.0 (1H, d, J = 5Hz), 5.57 (1H, dd, J = 5 & 8Hz), 7.40 (4H, m), 7.81 (1H, d, J = 9Hz), 8.64 (1H, d, J = 8Hz)
Example 4
In 50 ml of dichloromethane, 7.35 g of 7- [D-5- (p-tert-butylbenzamido) -5-carbozyvaleramido] -3-hydroxymethyl-3-ce phem-4-carboxylic acid-ditriethylamine salt were dissolved and then 1.01 g of triethylamine and 1.68 g of diketene were added at room temperature. The reaction was carried out within 2 hours and the reaction mixture was then treated as described in Example 1.

  According to this process, 5.78 g of 7- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-ce were obtained in a yield of 93.8%. Obtained phem-4-carboxylic acid.



   IR (KBr): 3280, 1780, 1740, 1725, 1710, 1640, 1530 cm-NMR (6 in d6-DMSO): 1.32 (9H, s), 1.50-2.40 (6H, m), 2.18 (3H, s ), 3.48 (2H, br), 3.57 (2H, s), 4.35 (1H, m), 4.94 (2H, ABq, J = 13Hz), 5.06 (1H, dJ - 5Hz), 5.62 (1H, dd , J = 5 & 8Hz), 7.46 (2H, d, J = 8Hz), 7.85 (2H, d, J- 8Hz), 8.35 (1H, d, J = 8Hz), 8.78 (1H, d, J = 8Hz )
Example 5
In 50 ml of dichloromethane, 6.01 g of 7- (D-5-caprylamido-5-carboxyvaleramido] -3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved and then with 1.01 g of triethylamine and 1.68 g The reaction was carried out at room temperature within 3 hours, after which time the reaction mixture was treated as described in Example 1.

  4.36 g of 7- [D-5-caprylamido-5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained in a yield of 90.3%.



   IR (KBr): 3320.1780.1745.1725.1715.1645.1535 cm-1 NMR (6 in d6-DMSO): 0.70-2.40 (2 1H, m), 2.22 (3H, s), 3.53 (2H , broad), 3.60 (2H, s), 4.18 (1H, m), 4.91 (2H, ABq, J = 12Hz), 5.04 (1H, d, J = 5Hz), 5.65 (1H, dd, J = 5 & 8Hz), 7.87 (1H, d, J = 8Hz), 8.70 (1H, d, J = 8Hz)
Example 6
4.49 g of 7-phenyl-acedamido-3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 50 ml of dichloromethane, and 0.51 g of triethylamine and 1.26 g of diketene were then added at room temperature. The reaction was carried out within 2 hours, after which time the solvent was distilled off under reduced pressure. The residue was diluted with water and adjusted to a pH of 6.0.

  This aqueous solution was extracted twice with ethyl acetate, brought to pH 2.0 with 4N-HCl and extracted three times with ethyl acetate.



  The ethyl acetate solution was washed with a saturated aqueous sodium chloride solution, treated with magnesium sulfate and filtered off. The solvent was distilled off under reduced pressure and the residue was recrystallized from ethyl acetate / ether. 4.16 g of 7-phenylacetamido-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained in a yield of 96.3%.



   IR (KBr): 3270, 1785, 1745, 1715, 1655, 1540 1 NMR (o in d6-DMSO): 2.14 (3H, s), 3.52 (6H, broad), 4.86 (2H, Abq, J = 13Hz) , 5.00 (1H, dj = 5Hz), 5.63 (1H, dd, J = 5 & 9Hz), 7.22 (5H, s), 8.93 (1H, d, J = 9Hz)
Example 7
4.55 g of 7ss- (2-thienylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 30 ml of dichloromethane, and 1.50 g of succinic anhydride were then added. The mixture was stirred at room temperature for 2 hours. The dichloromethane was distilled off, followed by the addition of 100 ml of 3% aqueous phosphoric acid and extraction of the residue with 150 ml of ethyl acetate.

  The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (100 mlX 2), dried over magnesium sulfate, and concentrated under reduced pressure. The residue was treated with ether and the resulting powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 4.00 g of 7- (2-thienylacetamido) -3- (3-carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



      IR (KBr): 1782 ((3-lactam), 1 733 (O2H) cm-1 NMR (o in d6-DMSO): 2.50 (4H, -CO (CH2) 2 -), 3.40 & BR <3.63 (2H, ABq, J = 18Hz, 2-CH2), 3.75 (2H, s, -CH2CONH-), 4.71 & 5.07 (2H, ABq, J = 13Hz, 3-CH2), 5.07 (1H, d, J = 5Hz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 6.90 & 7.30 (3H,
EMI5.1
 9.10 (1H, d, J = 8Hz, -CONH-)
Example 8
3.60 g of 7ss- (2-thienylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 25 ml of dichloromethane, and 1.80 g of phthalic anhydride were then added. The mixture was stirred at room temperature for 2 hours and, after this period, treated similarly as described in Example 7. 3.44 g of 7ss- (2-thienylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid was obtained by this process.



     NMR (# in d6-DMSO): 3.50 & 3.70 (2H, ABq, J = 18Hz, 2-CH2), 3.77 (2H, s, -CH2CO-), 4.91 & 5.29 (2H, ABq, J = 13Hz, 3 -CH2), 5.10 (1H, d, J = 5Hz, 6-H), 5.70 (1H, dd, J = 5 & 8Hz, 7-H), 6.92 & 7.32 (3H,
EMI5.2
 7.64 (4H,
EMI5.3
 9.12 (1H, d, J = 8Hz, -CONH-)
Example 9
7-Mandelamido-3-hydroxyrnethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 40 ml dichloromethane and then 1.50 g succinic anhydride was added. The mixture was stirred at room temperature for 1 hour and 30 minutes.



  After the reaction was complete, the mixture was treated as described in Example 7, and 4.45 g of 7ss-mandelamido-3 - (3-carboxypropionyloxy) methyl-3-cephem-3-carboxylic acid were obtained.



   IR (KBr): 1776, 1737, 1684 (shoulder) cm-1 NMR (in d6-DMSO): 2.48 (4H, -CO (CH2) 2-), 3.3.- 3.7 (2H, 2-CH2), 4.69 & 5.03 (2H, ABq, J = 13Hz, 3-CH2), 4.99 (1H,
EMI5.4
 5.06 (1H, d, J = 5Hz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 7.35 (5H,
EMI5.5
   9.31 (1H, d, J = 8Hz, ONH-)
Example 10
0.68 g of 7ss- (2-thienylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 7 ml of dichloromethane and 0.34 g of glutaric anhydride was added. The mixture was stirred at room temperature for 2½ hours. The dichloromethane was distilled off, then 15 ml of 3% aqueous phosphoric acid were added and the residue was extracted with 25 ml of ethyl acetate.

  The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (15 ml x 2) and dried over magnesium sulfate.



  A powder was obtained after adding a 2N solution of sodium 2-ethylhexanoate in isopropyl alcohol (1.50 ml). This powder was filtered off, washed with ethyl acetate-ether and dried over phosphorus pentoxide. 0.42 g of 7ss- (2-thienylacetamido) -3 - (4.carboxybutyryloxy) methyl-3-cephem-4-carboxylic acid disodium salt was obtained.

 

   IR (KBr): 1760, 1736 (shoulder), 1661, 1609 cm NMR (o in D2C): 1.90 (2H, -CH2ClI2CH2-), 2.28 (4H, ff2HCH2CII2-), 3.21 & 3.61 (2H, ABq, J = 18Hz, 2-CH2), 3.78 (2H, s,
EMI5.6
 4.4-4.9 (2H, 3-CH2), 4.98 (1H, d, J = 5Hz, 6-H), 5.60 (1H, d, J = 5Hz, 7-H), 6.95 & 7.28 (3H,
EMI5.7

Example 11
In 50 ml of dimethylformamide, 7.35 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3 cephem-4-carboxylic acid-ditriethylamine salt were dissolved and then with 1.5 g of succinic anhydride transferred. The mixture was stirred at room temperature for 30 minutes. After the reaction was complete, 250 ml of 3% aqueous phosphoric acid were added and extraction with 500 ml of ethyl acetate.

  The ethyl acetate layer was washed with water (250 ml x 2), dried over magnesium sulfate and concentrated under reduced pressure. A powder was obtained by adding ether. This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 6.20 g of 7ss- [D-5- (p-t-butylbenzamido) carboxyvaleramido] -3- (3-carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



  IR (KBr): 1779.1732.1640 cm-1 NMR (# in d6-DMSO): 1.28 (9H, s, 2.24 (6H, - (CH2) 3-),
EMI6.1
 1.73 & BR <2.50 (4H, -COCH2CH2CO-), 3.38 & 3.63 (2H, ABq, J = 18Hz, 2-CH2), 4.37 (1H, -CH-NH-), 4.71 & 5.06 (2H, ABq, J = 13Hz, 3-CH2), 5.04 (1H, d, J = 5Hz, 6-H), 5.66 (1H, dd, J = 5 & 8Hz, 7-H), 7.44 & 7.81 (4H,
EMI6.2
 8.43 (1H, d, J = 8Hz,
EMI6.3
 8.80 (1H, d, J = 8Hz, -CONH-)
Example 12
In 50 ml of dimethylformamide, 7.35 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramidoj-3-hydroxymethyl-3 cephem-4-carboxylic acid-diethylamine salt were dissolved and then mixed with 1.63 g of phthalic anhydride . The mixture was stirred at room temperature for 30 minutes and then treated as described in Example 11.

  6.70 g of 7ss- [D-5- (p-t-butylbenzamido) -5-carboxyvaleramido] -3- (2-carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1784, 1726, 1642 cm
NMR (o in d6-DMSO): 1.27 (9H, s, 2.22 (6H,
EMI6.4
 ), 1.72 & BR <- (CH2) 3-), 3.46 & 3.71 (2H, ABq, J = 18Hz, 2-CH2), 4.37 (1H, -CH-), 4.89 & 5.27 (2H, ABq, J = 13Hz, 3-CH2 ), 5.08
NH (1H, d, J = 5Hz, 6-H), 5.67 (1H, dd, J = 5 & 8Hz, 7-H), 7.43 & 7.81 (4H,
EMI6.5
   7.62 (411,
EMI6.6
 8.42 (1H, d, J = 8Hz, -CHNHCO-), 8.80 (1H, d, J = 8Hz, -CONH-)
Example 13
In 50 ml of dimethylformamide, 7.35 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved and 1.49 g of maleic anhydride were added . The mixture was stirred at room temperature for 30 minutes and then treated as described in Example 11.

  6.05 g of 7ss- [D-5- (p-t-butylbenzamido) -5-carboxyvaleramido-3- (3-carbexyacryloyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



      IR (KBr): 1780.1727.1640 cm-1 NMR (o in d6-DMSO): 1.32 (9H, s ,.



  2.26 (6H, - (CH2) 3-),
EMI6.7
 1.77 & BR <3.41 & 3.65 (2H, ABq, J = 18Hz, 2-CH2), 4.37 (1H,
EMI6.8
 4.80 & 5.16 (2H, ABq, J = 13Hz, 3-CH2), 5.02 (1H, d, J = 5Hz, 6-H), 5.66 (1H, dd, J = 5 & 8Hz, 7-H), 6.34 (2H, -CH = CH-), 7.44 & 7.82 (4H,
EMI6.9
   8.40 (1H, d, J = 8Hz, -CHNHCO-), 8.80 (1H, d, J = 8Hz, -CONH-)
Example 14
In 20 ml of dichloromethane, 14.7 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3-ce phem-4-carboxylic acid-ditriethylamine salt were dissolved and then treated with 0.51 g of p-chlorophenylthiosuccinic anhydride. The mixture was stirred at room temperature for 1 hour and after this period was treated as described in Example 7.

  1.50 g of 7ss- [D-5- (pt-butylbenzamido) - 5-carboxyvaleramido] -3- [3-carboxy3 (or 2) - (p-chlorophenylthio) propionyloxy] methyl-3-cephem Receive -4-carboxylic acid.



   IR (KBr): 1778, 1728, 1636 cm-1 NMR (o in d6-DMSO): 1.28 (9H, s, (6H,
EMI6.10
 1.74 & 2.24 - (CH2) 3-), 2.73 (2H,
EMI6.11
   3.3-3.8 (2H, 2-CH2), 4.03 (1H, -CH-S), 4.40 (1H, -CH-NH-), 4.73 & 5.07 (2H, ABq, J = 13Hz, 3-C112), 5.02 (111, d, J = 5Hz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 7.42 (4H, C
EMI6.12
 7.44 & BR <7.82 (4H,
EMI6.13
   p.44 (1H, d, J = 8Hz, -CHNHCO-), 8.82 (1H, d, J = 8Hz, -CONH-) Example 15
7.05 g of 7p- (D-5-phthalimido-5-carboxyvaleramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane, and 1.50 g of succinic anhydride were added to the salt.

  The mixture was stirred at room temperature for 1/2 hour, after which time it was treated as described in Example 7.



  5.43 g of 7 (3- (D-5-phthalimido-5-carboxyvaleramido) -3 - (3-carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1777.1710.1644 cm-1 NMR (o in d6-DMSO): 1.52 & 2.17 (6H, - (CH2) 3-), 2.50 (4H, - (CH2) 2-), 3.3- 3.8 (2H, 2-CH2), 4.70 & 5.03 (2H, ABq, J = 13Hz, 3-CH2), 4.72 (1H, t, J = 7Hz, -CH-), 5.01 (1H, d, J = 5Hz, 6-H), 5.62 (1H, dd, J = 5 & 8Hz, 7-H), 7.86 (4H, s,
EMI6.14
 8.78 (1H, d, J = 8Hz, -CONH-)
Example 16
7.05 g of 7P- (D-5-phthalimido-5-carboxyvaleramido) -3-hydroxymethyl-ss-cephem-4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane, and 2.22 g of phthalic anhydride were then added. The mixture was stirred at room temperature for 11/2 hours and, after this period, treated as described in Example 7. 6.39 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (2carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1772, 1714, 1643 cm NMR (o in d6-DMSO): 1.52 & 2.18 (6H, - (CH2) 3-), 3.42 & BR <3.69 (2H, ABq, J = 18Hz, 2-CH2), 4.74 (1H, t, J = 8Hz, -CH-), 4.89 & BR <5.28 (2H, ABq, l 3Hz, 3-CH2), 5th floor (1H, d, J = 5Hz, 6-H), 5.66
EMI6.15


 <tb> (1H, dd, J = 5 <SEP> & 8Hz, 7-11), <SEP> 7.64 (4H,
 <tb> <SEP> o
 <tb> <SEP> II
 <tb> <SEP> 8.81 <SEP> (1H, d, J = 8Hz, -CON11-)
 <tb> <SEP> II
 <tb> <SEP> 0
 <tb> 7.86 (4H, s,
Example 17 7ss- (2-thienylacetamido) -3 - (3-carboxyacryloyloxy) methyl 3-cephem-4-carboxylic acid was prepared as described in Example 7.



   IR (KBr): 1780, 1725, 1638 cm-
NMR (d6-DMSC): # 3.43 & 3.76 (2H, ABq, J = 18Hz, 2 CH2), 3.75 (2H, s, -CH2CO -), 4.79 & 5.14 2H, ABq, J = 13Hz, 3-CH2) , 5.07 (1H, d, J = 5Hz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 6.35 (2H, s, -CH = CH-), 6.90 & 7.29 ( 3H,
EMI7.1
 9.10 (1H, d, J = 8Hz, -CONH-)
Example 18
A mixture of 2.20 g of 7ss- [D-5 (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3-cephern-4-carboxylic acid-ditriethylamine salt and 1.16 g of 3-nitrophthalic anhydride were added 15 ml of dichloromethane were added together with 0.42 ml of triethylamine. The resulting solution was stirred at room temperature for 1¸ hours.

  After the reaction had ended, the dichloromethane was distilled off under reduced pressure and 120 ml of 3% aqueous phosphoric acid and 160 ml of ethyl acetate were added to the residue. The ethyl acetate layer was washed with water (80 ml x 2), dried over magnesium sulfate and concentrated under reduced pressure. A powder was obtained after the addition of ether.



  This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. There were 2.10 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3-cephem-4-carboxylic acid receive.



   IR (KBr): 1783, 1735, 1640 cm-1 NMR (o in d6-DMSO): 1.28 (9H, s, -C (CH3) 3), 1.53 & BR <2.23 (6H, - (CH2) 3-), 3.43 & 3.70 (2HABq, J = 18Hz, 2-CH2), 4.37 (1H, -C11-), 4.96 & 5.41 (2H, ABq, J = 13Hz, 3 -CH2), 5.07 (1H, d, J = 5Hz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 7.42 & 7.80 (4H,
EMI7.2
 7.8-8.4 (3H,
EMI7.3
 8.44 (1H, d, J = 8Hz, -C11-Nw), 8.84 (1H, d, J = 8Hz, -CONH-)
Example 19
A mixture of 2.12 g of 7ss- (D-5-phthalimido-5-carboxy-valeramido) -3-hydroxymethyl-3-cephem-4-carboxylic acid diethylamine salt and 1.16 g of 3-nitrophthalic anhydride were mixed with 15 ml of dichloromethane are mixed with 0.42 ml of diethylamine.

  The solution obtained was stirred at room temperature for 1½ hours and, after this period, treated as described in Example 18. 2.08 g of 713- (D-5-phthalimido-5-carboxyvaleramido) -3- (2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1775 (shoulder), 1718, 1642 cm-t NMR (5 in d6-DMSO): 1.54 & 2.19 (6H, - (CH2) 3-), 3.40 & BR <3.68 (2H, ABq, J = 18Hz, 2-CH,), 4.73 (1H, t, J = 7Hz, -CH-), 4.98 & 5.42 (2H, ABq, J = 13Hz, 3-C112), 5.06 (111, d, J = 5Hz, 6-H), 5.66 (1H, dd, J = 5 & 8Hz, 7-H), 7.7-8.4 (3H,
EMI7.4
 7.86 (4H, s,
EMI7.5
 8.81 (1H, d, J = 8Hz, -CONH-)
Example 20
2.20 g of 7ss- (D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3-cephem-4-carboxylic acid di-diethylamine salt and 1.15 g of trimellitic anhydride were mixed with 15 ml of dichloromethane and 0 , 84 ml of triethylamine were added and the resulting solution was stirred at room temperature for 1 hour.

  After the reaction had ended, the mixture was treated as described in Example 18. 2.14 g of 7, B- [D-5- (p-t-butylbenzamido) -5-carboxyvaleramido] -3- (2,4 (or 5) -dicarboxybenzoyloxy) methyl-3-cephem-4- receive carboxylic acid.



   IR (KBr): 1777, 1724, 1636 cm-1 NMR (δ in d6-DMSO): 1.29 (9H, s, -C (CH3) 3), 1.54 & BR <2.25 (6H, - (CH2) 3-), 3.99 & 3.72 (2H, ABq, J = 18Hz, 2-CH2), 4.38 (1H, -CH-), 4.95 & 5.30 (2H, ABq, J = 13Hz , 3-CH2), 5.11 (1H, d, J = 5Hz, 6-H), 5.70 (1H, dd, J = 5 & 8Hz, 7-H), 7.43 & 7.82 (4H,
EMI7.6
 7.7-8.3 (3H,
EMI7.7
 8.43 (1H, d, J = 8Hz, -CH-NH-), 8.84 (1H, d, J = 8Hz, -CONH-) Example 21
2.16 g of deacetylcephalosporin C were suspended in 10 ml of dimethylformamide, then 0.83 ml of concentrated hydrochloric acid were added with ice cooling. The resulting solution was mixed with 10 ml of dimethylformamide together with 4.20 ml of triethylamine and 3.86 g of 3-nitrophthalic anhydride, and the mixture was stirred at room temperature for 2 hours.

  After the reaction had ended, the mixture was diluted with 150 ml of 3% phosphoric acid and extracted with 2 × 250 ml of ethyl acetate. The ethyl acetate layer was washed with 200 ml of water and 200 ml of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated under reduced pressure. A powder was obtained by adding ether. This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 3.77 g of (7ss- [D-5- (2-carboxy-6 (or 3) nitrobenzamido) -5-carboxyvaleramido] -3 - (2-carboxy-6 (or 3) nitrobenzoyloxy) methyl-3 were obtained -cephem-4 carboxylic acid obtained.

 

     1R (KBr): 1780 (shoulder), 1729, 1638, 1534, 1348 cm-1 NMR (o in d6-DMSO): 1.67 & 2.23 (6H, - (CH2) 3-), 3.6O (2H, 2-CH2), 4.39 (1H, - @ -CH-), 4.97 & 5.40 (2H, ABq, J = 13Hz, 3-CH2), 5.08 (1H, d, J = SHz, 6-H), 5.68 (1H, dd, J = 5 & 8Hz, 7-H), 7.5-8.5 (7H,
EMI7.8
 X2 & -CH-NH-), 8.78 (1H, d, J = 8Hz, -CONH-)
Example 22
4.55 g of 7ss- (2-thienylacetamido) -3-hydroxymethyl-3-cephem-4-carboxylic acid triethylamine salt were dissolved in 30 ml of dichloromethane, and 2.38 g of O-carboxymandelic anhydride were added. The mixture was stirred at room temperature for one hour and after this period the dichloromethane was distilled off. The residue was mixed with 100 ml of 3% aqueous phosphoric acid and extracted with 150 ml of ethyl acetate.

  The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (100 ml X 2), dried over magnesium sulfate and concentrated under reduced pressure. Then a powder was obtained by adding ether. This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 4.00 g of (7B- (2-thienylacetamido) -3-mandelyloxymethyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1778, 1742, 1666 cm-1 NMR (o in d6-DMSO): 3.24 & 3.45 (2H, ABq, J = 18Hz, 2- CH2), 3.74 (2H, s, -CH2CONH-), 4.76 & 5.06 (2H, ABq, J = 13Hz, 3-CH,), 5.03 (1H, d, J = 5Hz, 6-H), 5.16 (1H, s,
EMI8.1
   5.68 (1H, dd, J = 5 & 8Hz, 7-H), 6.90 & 7.34 (811,
EMI8.2
 9.09 (1H, d, J = 8Hz, -CONH-)
EMI8.3

Example 23
3.86 g of sodium 7ss-mandelamido-3-hydroxymethyl-3-cephem-4-carboxylate were dissolved in 40 ml of dimethylformamide, and 2.67 g of O-carboxymandelic anhydride were added. The mixture was stirred at room temperature for 30 minutes and then 150 ml of 2% H3PO4 was added.

  The mixture was then extracted with 250 ml of ethyl acetate and the ethyl acetate layer was washed with water (150 ml of X 2), dried over magnesium sulfate and concentrated under reduced pressure. Then a powder was obtained by adding ether. This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 3.68 g of 7ss-mandelamido-3-mandelyloxymethyl-3-cephem-4carboxylic acid were obtained.



      IR (KBr): 1777.1745, 1669 cm-1 NMR (6 in d6-DMSO): 3.2-3.7 (2H, 2-CH2), 4.7-5.2 (5H, 3 CH2, 6-H & -CH-x2 ), 5.69) 1H, 7-H), 7.2-7.6 (10H, 8.67 (1H, -CONH-)
EMI8.4

Example 24
7.35 g of 7ss- (D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-hydroxymethyl-3 cephem-4-carboxylic acid-diethylamine salt were dissolved in 50 ml of dimethylformamide and salted with 2.67 g of O- The mixture was stirred at room temperature for 30 minutes, after which time 250 ml of 3% aqueous phosphoric acid was added and extracted with 500 ml of ethyl acetate, and the ethyl acetate layer was washed with water (250 ml X 2) Magnesium sulfate dried and concentrated under reduced pressure.

  Then a powder was obtained by adding ether. This powder was filtered off, washed with ether and dried over phosphorus pentoxide under reduced pressure. 6.30 g of 7ss- [D-5- (p-t-butylbenzamido) -5-carboxyvaleramido] -3-mandelyloxymethyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1778, 1736, 1642 cm 1 NMR (o in d6-DMSO): 1.29 (9H, s, -C (CH3) 3), 1.73 & BR <2.23 (6H, - (CH,), -), 3.2-3.6 (2H, 2-CH,), 4.38 (1H, -CH-NH-), 4.75 & 5.04 (2H, ABq, J = 13Hz, 3 -CH,), 5.02 (1H, d, J = 5Hz, 6-H), 5.16 (1H, s,
EMI8.5
 5.66 (1H, dd, J = 5 & 8Hz, 7-! 1), 7.2-7.5 (5H,
EMI8.6
 7.43 & 7.81 (4H,
EMI8.7
 8.43 (1H, d, J = 8Hz, -CH-NH-), 8.80 (1H, d, J = 8Hz, -CONH-)
Example 25
7.05 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] 3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane, and 2.38 g of O-carboxymandelic anhydride were added. The mixture was stirred at room temperature for one hour and after this period was treated as described in Example 22.

  6.25 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3-mandelyloxymethyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1773, 1715, 1647 (shoulder) cm-1 NMR (#ind d6-DMSO): 1.54 & 2.22 (611, - (CH2) 3 -), 3.27 & 3.49 (2H, ABq, J = 18Hz , 2-CH2), 4.73 (1H, t, J = 7Hz, -CH-N #), 4.74 & 5.03 (2H, ABq, J = 13Hz, 3-CH2), 4.98 (1H, d, J = 5Hz, 6-H), 5.16 (1H, s,
EMI8.8
   5.61 (1H, dd, J = 5 & 8Hz, 7-H), 7.2-7.5 (5H,
EMI8.9
 7.86 (4H, s, 8.77 (1H, d, J = 8Hz, WONH-)
EMI8.10

Example 26
6.51 g of 7ss- [D-5-phthalimido-5-carboxyvaleramidol-3 - (2-carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid were suspended in 25 ml of dichloromethane. Then 4.20 ml of triethylamine was added at a temperature of not more than 10 ° C.

  The solution thus obtained was mixed with 10.4 ml of N, N-dimethylaniline together with 4.40 ml of dimethyldichlorosilane. The mixture was stirred at 20-25 C for 30 min.



  Then, after cooling to -30 C, 4.20 g of phosphorus pentachloride were added to the mixture. The mixture was then kept at -25 # +2 C for 30 minutes for reaction, after which time 25 ml of methanol was added dropwise at a temperature of not more than -20 C. The mixture was then reacted at -15 to -10 ° C. for 20 minutes and, after adding 50 ml of water, stirred vigorously for 5 minutes. The reaction mixture was separated and the aqueous layer was stripped off, washed with ethyl acetate and adjusted to a pH of 3.2 with a 40% strength aqueous potassium carbonate solution. The resulting crystals were filtered off, washed with water, 50% aqueous methanol and acetone and dried.

  3.43 g of 7ss-amino-3- (2-carboxybenzoyloxy) methyl-3-cephem4-carboxylic acid were obtained.



   IR (KBr): 3170, 1798, 1730, 1700, 1615 cm- 'NMR (o in D2O + NaOD): 3.55 (2H, ABq, J = 18Hz), 4.6-5.6 (4H, m), 7.30-7, 90 (4H, m)
Example 27
5.8 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3 - (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were suspended in 70 ml of dichloromethane. Then, at a temperature of not more than 10 C, 2.80 ml of triethylamine, then 10.0 ml of N, N-dimethylaniline and 3.13 ml of dimethyldichlorosilane were added. The mixture was stirred at 20-25 C for 30 min and 4.20 g of phosphorus pentachloride were added at a temperature of -30 C. Then the mixture was stirred at -25 C +2 C for 30 minutes, after which time 25 ml of methanol was added dropwise at a temperature of not more than -20 C.

  The reaction was then continued for a further 20 minutes at -15 to -10 ° C., then 50 ml of water were added at this temperature and the mixture was stirred vigorously for 5 minutes. The water layer was removed, washed with dichloromethane and adjusted to a pH of 3.5 with a 40% aqueous potassium carbonate solution. The resulting crystals were filtered off, washed with water, 50% aqueous methanol and acetone and dried. 2.84 g of 7ss-amino-3- (3oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained:
IR (KBr): 3200, 1800, 1745, 1720, 1622 cm-1 NMR (# in D2O-NAOD): 2.27 (3H, s), 3.48 (2H, Abq, J = 18Hz), 4.6-5.6 (4H, m)
Example 28
15.7 g of 7ss-amino-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were dissolved in 80 ml of dichloromethane. At -10 C, 10.1 g of triethylamine were added.

  A solution of 1.41 mmol / g (44.9 g) of 4-chloro-3-oxobutyryl chloride was added dropwise to the resulting solution within 20 min at a temperature of from -20 to 15 ° C. After the dropwise addition was complete, the reaction was carried out within one hour at a temperature of not more than -5.degree. When the reaction was complete, the dichloromethane was distilled off and the residue was dissolved by adding 50 ml of tetrahydrofuran, 100 ml of ethyl acetate and 10% aqueous phosphoric acid. The resulting solution was separated and the organic layer was removed. The water layer was extracted with a mixed solvent of ethyl acetate-tetrahydrofuran (5: 1). The extracts were combined, washed with saturated aqueous sodium chloride solution, dried over magnesium sulfate and filtered.

  The solvent was distilled off and the residue was treated with ethyl acetate-ether. The resulting powder was filtered off, washed with ether and dried. 20.4 g of 7ss- (4-chloro-3-oxobutyrylamido) -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained.



      IR (KBrj: 3325, 1782, 1740, 1732, 1715, 1685, 1650 cm 1 NMR (6 in d6-DMSO): 2.14 (3H, s), 3.55 (4H, s), 3.54 (2H, br), 4.44 (2H, s3, 4.90 (2H, Abq, J = 13Hz), 5.05 (1H, d, J = 5Hz), 5.54 (1H, q'.J = 5 & 8Hz), 8.96 (1H, d, J = 8Hz)
The 4-chloro-3-oxobutyryl chloride solution used in this reaction was prepared by dissolving 84.0 g of diketene in 420 ml of dichloromethane and introducing 78.1 g of chlorine gas at -30 to -35 C within one hour.



   Example 29
4.33 g of 7ss- (4-chloro-3-oxobutylamido) -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were dissolved in 10 ml of acetone and then with ice-cooling with 10 ml of water and 0.84 g of thiourea transferred. Then 0.84 g of sodium bicarbonate and 10 ml of water were added. The mixture was reacted for 5 hours at room temperature and, after this period, cooled with ice. The resulting crystals were filtered off, washed with water, acetone and ether and dried. 4.22 g of 7ss- [2- (2-imino-4-thiazolin-4-yl) acetamido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1775.1740.1710.1661 cm-1 NMR (o in d6-DMSO): 2.17 (3H, s, -CH2CONH-),
EMI9.1
 3.38 (2H, s, 3.51 (2H, 2-CH,), 3.59 (2H, s, ABq, J = 13Hz, 3-CH2), 5.05
EMI9.2
 4.77 & 5.06 (2H, (1H, d, J = 5Hz, 6-H), 5.69 (1H, dd, J = 5 & 9Hz, 7-H), 6.23 (1H, s, thiazoline-H), 8.82 ( 1H, d, J = 9Hz, ZONH-)
Example 30
600 mg of 7ss-amino-3- (3-carboxypropionylo :: y) methyl-3-cephem-4-carboxylic acid were suspended in 7 ml of dichloromethane and 0.7 ml of N, N-dimethylacetamide was added. A solution of 294 mg (1H-tetrazol-l-yl) acetyl chloride in 2 ml of dichloromethane was then added with ice cooling and stirring. The mixture was stirred at room temperature for 1 hour, after which time it was placed in an aqueous sodium bicarbonate solution and separated.

  The water layer was removed, washed with dichloromethane, acidified with phosphoric acid and extracted with ethyl acetate. The extract was extracted again with an aqueous sodium bicarbonate solution to convert the desired compound into the aqueous phase. This aqueous solution was purified by column chromatography on SephadexLH-20. The fractions containing the main product were combined and lyophilized. The 7ss- [2- (1H-tetrazol1-yl) acetamido] -3- (3-carboxypropionyloxy) methyl-3-cephem 4-carboxylic acid dinate salt was obtained.



   IR (KBr): 1765.1620 cm-1 NMR (8 in D2O): 2.60 (4H, m, - (CH2) 2-), 3.44 & BR <3.74 (2H, ABq, J = 17Hz, 2-CH2), 5.20 (1H, d, J = 5Hz, 6-H), 5.59 (2H, s, NCH2CO-), 5.76 (111, d, J = 5Hz , 7-H), 9.33 (1H, s, tetrazole-H)
Example 31
942 mg of 7ss-amino-3- (3oxybutyryloxy) methyl-3-cephem-4-carboxylic acid were suspended in 10 ml of dichloromethane and 1 ml of N, N-dimethylacetamide was added. A solution of 441 mg (111-tetrazol-1-yl) acetyl chloride in 3 ml dichloromethane was then added with ice cooling and stirring. The mixture was stirred at room temperature for a further 30 min and, after this period had elapsed, introduced into an aqueous sodium bicarbonate solution.

  The water layer, i.e. the aqueous extract was purified by column chromatography on Se phadex LH-20. The fractions with the highest content of the desired product were combined, concentrated, acidified with phosphoric acid and extracted with ethyl acetate.



  The extract was dried, concentrated and treated with ether. 7ss- [2- (1H-tetrazol-1-y) acetamido] -3- (3-oxy-butyryloxy) methyl-3-cephem-4-carboxylic acid was obtained.



   (IR (KBr): 1782, 1707 cm 'NMR (o in d6-DMSO): 2.17 (3H, s, -CH3), 3.55 (2H, broad, 2-CH2), 3.59 (2H, s,
EMI9.3
 4.78 & 5.08 (2H, ABq, J = 13Hz, 3-CH2), 5.09 (1H, d, J = 5Hz, 6-H), 5.34 (2H, s, NCH2CO-), 5.71 (1H, dd, J = 5 & 8Hz, 7-H), 9.28 (1H, s, etrazol-H), 9.46 (1H, d, J = 8Hz, -CONH-)
Example 32
2.68 g of D-a-t butoxycarbonylamine-a- (p-hydroxyphenyl) acetic acid were dissolved in 30 ml of dry tetrahydrofuran and 1.08 g of 2,6-lutidine were added. While cooling to -10 ° C. and stirring, 1.08 g of ethyl chloroformate was then carefully added and the mixture was stirred at this temperature for 20 minutes.

  Then an ice-cooled, mixed solution of 3.14 g of 7ss-Alrsino-3- (3-oxobutyryloxy) - methyl-3-cephem-4-carboxylic acid and 1.0 g of sodium bicarbonate in 30 ml of water was added all at once. The entire mixture was stirred at -3 C for 10 min and then with ice cooling for 2 hours. After adding 60 ml of water, the mixture was washed with 50 ml of ethyl acetate, and then 50% phosphoric acid was carefully added in the presence of 100 ml of ethyl acetate to adjust the pH to 3.0. The ethyl acetate layer was removed, rinsed with 100 ml of water, dried over anhydrous sodium sulfate and treated with a 2N solution of sodium 2-ethylhexanoate in 6 ml of isopropyl alcohol.

  The resulting precipitate was decanted, loosened with ethyl acetate, filtered off and dried over phosphorus pentoxide under reduced pressure. The brown powder thus obtained was purified by means of column chromatography on Amberlite XAD-2. The 7ss- [D-? -T-butoxycarbonylamino.a- (p-hydroxyphenyl) acetamido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid sodium salt was obtained.



   IR (KBr): 3400, 1770, 1680, 1610 cm 'NMR (6 in D2O): 1.45 (9H, s), 2.30 (3H, s), 3.43 (2H, broad), 5.65 (1H, d, J = 5Hz, 7-H), 6.76-7.40 (4H, m) Example of the invention
example 1
In 50 ml of water, 5.88 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-cephem-4 carboxylic acid were added together with 1.5 g of 5-mercapto-1- methyl-1H-tetrazole and 2.10 g of sodium bicarbonate dissolved. After adding 15.0 g of sodium chloride, the solution was adjusted to a pH of 5.0 and then reacted at 60 ° C. for 50 minutes.



  After cooling, a saturated aqueous sodium chloride solution (50 ml) was added and the pH of the mixture was adjusted to 1.5 with 4N-HCl. The resulting solid precipitate was filtered off, washed with a saturated aqueous sodium chloride solution (20 ml) and dissolved in ethyl acetate / water (100 ml: 20 ml). After the separation, the ethyl acetate solution was dried and, after adding 50 ml of toluene, concentrated to dryness. The solid precipitate was filtered off, washed with toluene ether and dried. This procedure gave 5.75 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3- (1-methyl-111-tetrazol-5-yl) thiomethyl-3-cephem-4 in 95.5% yield -carboxylic acid.



   IR (KBr): 3325, 1780, 1730, 1715, 1650, 1545 cm¯l NMR (# in d6-DMSO): 1.40-1.76 (2H, m), 2.0-2.4 (4H, m), 3.64 (2H, ABq, J = 19Hz), 3.93 (3H, s), 4.30 (2H, Abq, J = 15Hz), 4.73 (1H, t, J = 8HZ), 5.01 (1H, d, J = 5Hz), 5.62 (1H , dd, J = 5 & BR <9Hz), 7.85 (4H, s), 8.80 (d, J = 9Hz)
Example II
5.8 g of 7ss- [D-5-phthali mido-5-carboxyvaleramidol-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid together with 2.90 g of 2- (2-hydroxyethylthio) -5mercapto were added to 60 ml of water -1,3,4-thiadiazole and 2.20 g of sodium bicarbonate dissolved.



  After adding 30 g of sodium bromide, the pH of the solution was adjusted to 5.5 and the reaction was continued at 60 C for 50 min. After the reaction had ended, the reaction mixture was diluted with 40 ml of water and the pH was adjusted to 5.0. The aqueous solution was washed twice with ethyl acetate, adjusted to pH 2.0 with 4N HCl and extracted three times with a mixture of ethyl acetate and tetrahydrofuran (4: 1). The organic layer was washed with a saturated sodium chloride aqueous solution, dried over magnesium sulfate, filtered, and distilled under reduced pressure to remove the solvent. Ethyl acetate / ether was added to the residue, and the resulting powder was filtered off, washed with ether and dried.

  This procedure gave, in 96.6% yield, 6.56 g of 7t3- [D-5-phthalimido-5-carboxyvaleramidoj-3- [2- (2-hydroxyethylthio) -1,3,4-thiadiazol-5-yl] thiomethyl-3-cephem4-carboxylic acid.



      IR (KBr): 3325, 1780, 1715, 1645, 1530 cm '
NMR (d6-DMSO): 81.30-2.40 (6H, m), 3.20-3.80 (6H, m), 4.27 (2H, ABq, J = 12Hz), 4.65 (1H, t, J = 9Hz), 4.96 (1H, d, J = 5Hz), 5.55 (1H, dd, J = 5 & 8Hz), 7.87 (4H, s), 8.70 (1H, d, J = 8Hz)
Example III
In a mixture of 50 ml of water and 30 ml of tetrahydrofuran, 5.88 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] -3- (3-oxybutyryloxy) methyl-3-cephem-4-carboxylic acid were added together with 2.28 g of 2-carbamoylmethylthio-5-mercapto-1,3,4thiadiazole and 2.20 g of sodium bicarbonate dissolved. The solution was adjusted to a pH of 5.8 and then reacted at 60 ° C. for 70 minutes.

  After cooling, 30 ml of water was added and the pH of the aqueous solution was adjusted to 5.0, then the solution was washed twice with ethyl acetate and adjusted to pH 2.0 with 4N-HCl. This was followed by extraction three times with a mixed solvent of ethyl acetate-tetrahydrofuran (2: 1) and washing the organic layer with a saturated, aqueous sodium chloride solution and drying over magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was treated with ethyl acetate. The resulting powder was filtered off, washed with ethyl acetate and dried.

  According to this process, 5.83 g of 7ss- [D-5-phthalimido-5-carboxyvaleramido] 3 - (2-carbamoylmethylthiol-1,3,4-thiadiazol-5-yl) thiomethyl were obtained in 84.2% yield -3-cephem-4-carboxylic acid obtained.



   IR (KBr): 3430, 3340, 1776, 1717, 1680, 1535 cm-1
NMR (d6-DMSO): 61.30-2.40 (6H, m), 3.57 (2H, br), 4.40 (2H, s), 4.32 (2H, ABq, J = 12Hz), 4.70 (1H, t, J = 8Hz ), 5.0 (1H, d, J = 5Hz), 5.55 (111, dd, J = 5 & 8Hz), 7.20 (1H, broad), 7.60 (1H, broad), 7.86 (4H, s), 8.74 (1H , d, J = 8Hz)
Example IV
908 mg of 7- [2- (2-imino-4-thiazolin-4-yl) acetamido] -3- (3-oxobutyryloxy) methyl-3-cephem were added to 40 ml of a phosphate buffer solution with a pH of 6.4 -4-carboxylic acid dissolved together with a nitrogen-containing, heterocyclic thiol (2.2 mmol) and 336 mg sodium bicarbonate. The solution was stirred at 60 ° C for 1 hour and then concentrated to a volume of about 20 ml under reduced pressure.

  The concentrate was subjected to column chromatography on Amberlite XAD-2 and eluted with water, 5% ethanol and 10% ethanol. The fractions containing the desired product were combined and lyophilized to obtain one of the following compounds. The yield was determined on the basis of the value determined by liquid chromatography immediately after the reaction.



   (1) 7- [2-Imido-4-thiazolin-4-yl) acetamido] -3- (2-carboxy-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4carboxylic acid- Disodium salt, (yield 85%)
IR (KBr): 1761 cm 1 NMR (# in D2O): 3.56 & 3.92 (2H, ABq, J = 18Hz, 2-CH2), 3.76 (2H, s, -CO, CO), 4.16 (2H, s, -CH, CO), 4.20 & BR <4.62 (2H, ABq, J = 13Hz, 3-CH2), 5.24 (1H, d, J = SHz, 6-H), 5.79 (1H, d, J = 5Hz, 7-H), 6.65 (1H, 2, thiazolin-5-H).

 

   (2) 7- [2- (2-imino-4-thiazolin-4-yl) acetamido] 3- (3-hydroxymethyl-4-methyl-1,2,4-triazol-5-yl) thiomethyl 3-cephem4-carboxylic acid sodium salt, (yield 82%) IR (KBr): 1760 cm 1 NMR (# in D2O): 3.40 & 3.82 (2H, ABq, J = 18Hz, 2-CH2), 3.62 (2H , s, -CH2CO), 3.74 (2H, s, -CH3), 3.72 & BR <4.34 (211, Abq, J = 1 3Hz, 3-CH2), 4. 82 (2H, s, CH, OH), 5.08 (1H, d, J = 5Hz, 6-H), 5.64 (1H, d , J = 5Hz, 7-H), 6.52 (1H, s, thiazolin-5-H).



   Example V
In 50 ml of water, 5.61 g of 7- [D-5- (benzamido) adi pinamido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were added together with 1.50 g of 5-mercapto -1-methyl-1H-tetrazole and 2.20 g of sodium bicarbonate dissolved. The pH was adjusted to 5.2 and the reaction was then carried out at 60 C within 50 min. After cooling, 100 ml of saturated aqueous sodium chloride solution were added and the pH was adjusted to 1.5 with 4N-HCl. The solid precipitate was filtered off, rinsed with 20 ml of saturated aqueous sodium chloride solution and then dissolved in 100 ml of ethyl acetate-tetrahydrofuran (2: 1) and 20 ml of water. The organic layer was dried and the solvent was distilled off under reduced pressure.

  The residue was mixed with ether-ethyl acetate and the resulting powder was filtered off, rinsed with ether and dried. 5.45 g of 7- (D-5-benzamido-5-carboxyva leramido] -3 - (1-methyl-IH-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained, ( Yield 94.8
IR (KBr):

   3340, 1783, 1730, 1645, 1535 cm NMR (o in d6-DMSO): 1.50-2.0 (4H, m), 2.05-2.45 (2H, m), 3.70 (2H, broad), 3.93 (3H, s, N CH3), 4.15-4.55 (3H, m), 5.10 (1H, d, J = 5Hz, 6-H), 5.66 (1H, dd, J = 5 & 9Hz, 7-H), 7.327.97 (5H m
EMI11.1
 8.43 (1H, d, J = 8Hz, -CONH-), 8.73 (1H, d J = 9Hz, -CONH-)
Example VI
6.11 g of 7- [D-5- (p-toluenesulfonamido) adipinamido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid together with 1.50 g of 5-mercapto-1 were added to 50 ml of water -methyl-1H- tetrazole and 2.20 g of sodium bicarbonate dissolved. After adjusting the pH to 5.0, the reaction was carried out at 60 C within 50 min. After the reaction had ended, the reaction mixture was treated as described in Example V.

  5.96 g of 7- (D-5- (p-toluenesulfonamido) -5-carboxyvaleramido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained (Yield 95.1%).



   IR (KBr): 3275, 1780, 1727, 1635, 1535 cm- 'NMR (o in d6-DMSO): 1.45-1.78 (4H, m), 2.0-2.3 (2H, m), 2.41 (3H, s, -CH3), 3.71 (2H, broad, 2-CH2), 3.95 (3H, s, -NC113), 4.28 (2H, broad), 5.06 (1H, d, J = 5Hz, 6-H), 5.62 (1H , dd, J = 5.0 & 9.0Hz, 7-H), 7.47 (4H, m ,.
EMI11.2




  7.91 (1H, d, J = 9.0Hz), 8.68 (1H, d, J = 9.OHz)
Example VII
In 50 ml of water were 6.17 g of 7- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3 cephem-4-carboxylic acid together with 1.74 g 5-Mercapto-1methyl-1H-tetrazole and 2.50 g of sodium bicarbonate dissolved. The pH of the solution was adjusted to 5.0 and the reaction at 60 C within 50 min. accomplished. When the reaction was complete, the mixture was treated as described in Example V, and 6.02 g of 7- [D-5- (p-tert-butylbenzamido) -5-carboxyvaleramidoj-3 - (1-methyl-111-tetrazole) were obtained -5 -yl) thio-methyl-3-cephem-4-carboxylic acid obtained (yield 95.3%).



   IR (KBr): 3350.1780.1725.1643.1532.1504 cm-1 NMR (o in d6-DMSO): 1.30 (9H, s, (CH3) 3), 1.50- 2.45 (6H, m, - ( CH2) 3-), 3.64 (2H, broad, 2-CH2), 3.93 (3H, s, -NCH3), 4.27 (2H, broad, 3-CH2), 4.36 (1H, m, -CH-), 5.05 (1H, d, J = 5Hz, 6-H), 5.62 (1H, dd, J = 5.0 & 8.0Hz, 7-H), 7.35 (2H, d, J = 8.0Hz), 7.70 (2H, d, J = 8Hz), 8.36 (1H, d, J = 8.0Hz, -CONH-), 8.76 (1H, d, J = 8.0Hz, -CONH-)
Example VIII
In 50 ml of water there were 4.83 g of 7- [D-5- (caprylamido) -5carboxyvaleramido] -3- (3-oxobutyryloxy) methyl-3-cephemcarboxylic acid together with 1.74 g of 5-mercapto-1-methyl-1H - dissolved tetrazole and 250 g sodium bicarbonate. After adjusting the pH to 5.0 and adding 35.0 g of sodium bromide, the reaction was carried out at 60 C within 45 min. accomplished.



  After this period, the reaction mixture was treated as described in Example V. 4.78 g of 7- [D-5 - (caprylamido) -5-carboxyvaleramido] 3- (1-methyl-1Htetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained (yield 96.3 %).



   IR (KBr): 3380.1775.1725.1655, 1640.1545.1533 cm-1 NMR (o in d6-DMSO): 0.60-2.40 (21H, m), 3.70 (2H, broad, 2-CH2) 3.95 (3H, s, NCH3), 4.15 (1H, m), 4.27 (2H, broad, 3-CH2), 5.03 (1H, d, J = 5Hz, 6-H), 5.65 (1H, dd, J = 5.0 & 8.0Hz, 7-H), 7.97 (1H, d, J = 8.0Hz, -CONH-), 8.76 (1H, d, J = 8.0Hz, -CONH-)
Example IX
In 50 ml of water were 4.32 g of 7-phenylacetamido-3- (3oxobutyryloxy) methyl-3-cephem-4-carboxylic acid together with 1.50 g of 5-mercapto-1-methyl-1H-tetrazole and 1.68 g of sodium bicarbonate dissolved and the reaction was at 60 C within 50 min. accomplished. After cooling, the pH of the reaction mixture was adjusted to 5.0, the mixture was washed with ethyl acetate. Then the mixture was adjusted to pH 2.0 and extracted three times with ethyl acetate.

  The ethyl acetate solution was distilled with a saturated sodium chloride aqueous solution and under reduced pressure to remove the solvent. The residue was recrystallized from ethyl acetate: ether. 4.29 g of 7-phenylacetamido-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained (yield 96.2%).



     1R (KBr): 3270, 1785, 1733, 1662, 1628, 1542 cm-1 NMR (o in d6-DMSO): 3.55 (2H, s, 112CO-), 3.60 (2H, broad, 2-CH2), 3.92 (2H, s, NCH3), 4.26 (2H, broad, 2-CH2), 5.00 (1H, d, J = 5.0Hz, 6-H), 5.60 (1H, dd, J = 5.0 & 8.0Hz, 7-H), 7.23 (5H, s,
EMI11.3
 8.98 (1H, d, J = 8Hz, -CONH-)
Example X
561 mg of 7- [D-5-benzamido-5-carboxyvaleramidol-3 - (3-oxobutyryloxy) -methyl-3-cephem-4-carboxylic acid were added to 10 ml of water together with 252 mg of sodium bicarbonate and 212 mg of 2-methylthio-5-mercapto -1,3,4-thiadiazole dissolved. The reaction was carried out at 60 C within 50 min. completed, after cooling the reaction mixture was washed with ethyl acetate and freeze-dried.

  The resulting solid was dissolved in a small amount of methanol and treated with acetone. The resulting crystals were filtered off and rinsed with ether. 614 mg of 7- [D-5-benzamido-5-carboxyvaleramido] -3- (2-methylthio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid disodium salt were obtained.

 

   IR (KBr): 3400.1766.1640.1600.1530 cm-1 NMR (in D20): 1.40-2.55 (6H, m, - (CH2) 3-), 2.68 (3H, s, SCH3), 3.33 ( 21H, ABq, J = 18Hz, 2-C112), 4.14 (2H, ABq, J = 14Hz, 3-CH2), 4.30 (1H, m, -CH-), 5.01 (1H, d, J = 4.5Hz, 6-H), 5.58 (1H, d, J = 4.5Hz, 7-H), 7.25-7.95 (5H, m,
EMI11.4

Example XI
In 10 ml of water were 561 mg of 7- [D-5-benzamido-5-carboxyvaleramido] -5 - (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid together with 252 mg of sodium carbonate and 224 mg of 5-mercapto-2-ethoxycarbonylmethyl-1H -1,3,4-triazole dissolved. The reaction was carried out at 60 C within 50 min.



  completed, after cooling, the reaction mixture was treated as described in Example X. 642 mg of 7- [D-5 benzamido-5-carboxyvaleramidol-3 - (2-ethoxycarbonylmethyl1H-1,3,4-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid disodium salt were obtained.



   IR (KBr): 3400.3280, 1765, 1745, 1640, 1603, 1535 cm-1
NMR (in D2O): 1.20 (3H, t, J = 8.0Hz, -CH2CH3), 1.50-2.50 (6H, m, aCH2) 3 -), 3.32 (2H, ABq, J = 19Hz, 2-CH2), 3.80-4.50 (7H, m), 4.95 (lH, d, J = 4.5Hz, 6-H), 5.52 (1H, d, J = 4.5Hz, 7-H), 7.20-7.90 (5H, m ,
EMI12.1

Example XII
1.27 g of 7ss- [D-5- (pt-butylbenzamido) 5-carboxyvaleramido] -3 - (3-carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid were added to 0.25 in 12 ml of water 5-mercapto-1-methyl-1H-tetrazole and 0.68 g of sodium bicarbonate were dissolved, then the mixture was stirred at 60 ° C. for 1 hour and 30 minutes. The reaction solution was cooled to room temperature and mixed with 30 ml of 4% aqueous phosphoric acid solution, then extracted with 60 ml of ethyl acetate.

  The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (40 ml X 2), dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was mixed with ether and the resulting powder was filtered off, washed with ether and dried under reduced pressure over phosphorus pentoxide, 1.02 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- ( 1-methyl-1H-tetrazol-5-yl) thiomethyl3-cephem-4-carboxylic acid obtained.



   The IR and NMR spectra showed good agreement of this product with that obtained in Example VII.



   Example XIII
1.26 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramidoj-3- (3-carboxyacryloxy) methyl-3-cephem-4-carboxylic acid, 0.25 g of 5 -Mercapto-1-methyl-1H-tetrazole and 0.68 g of sodium bicarbonate dissolved, the solution was stirred for 2 hours at 60 C and then treated as described in Example XII. 0.88 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4- Obtained carboxylic acid, this product was in good agreement with the product prepared according to Example VII, as the IR and NMR spectra showed.



      Example XIV
The procedure was as described in Example XIII, using 1.36 g of 7ss- [D-5- (p-t-butylbenzamido) -
5-carboxyvaleramido] -3- (2-carboxybenzoyloxy) methyl-3-ce phem-4-carboxylic acid. 0.97 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4- receive carboxylic acid, the IR and
NMR spectra of this product showed good agreement with the product prepared according to Example VII.



   Example XV
In 12 ml of water, 1.55 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- [3-carboxy-3 (or 2) - (p chlorophenylthio) propionyloxyjmethyl-3- cephem-4-carboxylic acid, 0.25 g of 5-mercapto-1-methyl-1H-tetrazole and
0.68 g of sodium bicarbonate dissolved, the solution was 1 hour 30 min. stirred at 60 C and then treated as described in Example XII. There were 0.99 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3 - (1-methyl-111-tetrazol-5-yi) thiomethyl-3-cephem-4-carboxylic acid receive. The IR and NMR spectra of this product showed good agreement with the product obtained according to Example VII.



   Example XVI
The reaction according to Example XV was repeated using 1.21 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (3 carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid. 1.00 g of 7ss- (D-5-phthalimido-5-carboxy-valeramido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained, the IR - And NMR spectra of this product showed good agreement with the product obtained according to Example I.



   Example XVII
The reaction according to Example XV was repeated using 1.30 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (2-carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid. 0.94 g of 7ss- (D-5-phthalimido-5-carboxy-valeramido) -3 - (1-methyl-1H-tetrazol-5-yl) thlomethyl-3-cephem-4-carboxylic acid was obtained. The IR and NMR spectra of this product showed good agreement with the product prepared according to Example I.



   Example XVIII
In 6 ml of water, 0.78 g of 7ss- [D-5- (2-carboxy-6- (or 3) -nitrobenzamido) -5-carboxyvaleramido] -3- (2-carboxy6 (or 3) -nitrobenzoyloxy) methyl became methyl -3-cephem-4-carboxylic acid dissolved together with 0.12 g of 5-mercapto-1-methyl-1H-tetrazole and 0.42 g of sodium bicarbonate. The solution was at 60 C 30 min. stirred and then treated as described in Example XII. 0.50 g of 7ss- [D-5- (2-carboxy-6 (or 3) nitrobenzamido) -5-carboxyvaleramido] -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl- Obtained 3-cephem-4-carboxylic acid.



   IR (KBr): 1782, 1731, 1645, 1537, 1351 cm- '
NMR (d6-DMSO): ö 1.73 & 2.26 (6H, - (CH2) 3-), 3.69 (2H, 2-CH2), I 3.94 (3H, s, # N-CH3), 4.32 (2H, 3- CH2), 4.52 (1H, -CH-), 5.06 (1H, d, J = 5Hz, 6-H), 5.67 (1H, dd, J = 5 & 8Hz, 7-H), 7.6-8.4 (4H, -CONH-)
EMI12.2
  & -CH-NH-), 8.79 (1H, d, J = 8Hz, example XIX
In 6 ml of water, 0.73 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3-cephem- 4-carboxylic acid together with 0.12 g of 5-mercapto-l-methyl-1H-tetrazole and 0.34 g of sodium bicarbonate. The mixture was at 60 C 30 min. stirred and then treated as described in Example XII.

  0.53 g of 7 $ - [D-5- (p-t-butylbenzamido) -5-carboxyvaleramidoj- 3 - (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained.

 

   The IR (Kr) and NMR (d, -DMSO) spectra show good agreement of this product with those prepared according to Example VII.



   Example XX
The reaction according to Example XVIII was carried out using 0.73 g of 7 t3- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (2,4 (or 5) -dicarboxybenzoyloxy) methyl-3 -cephem4- carboxylic acid repeated to 0.52 g (7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (1-methyl-1H-tetrazol-5-yl) - thiomethyl- 3-cephem-4-carboxylic acid The IR (KBr) and NMR (d, -DMSO) spectra showed good agreement of this product with that prepared according to Example VII.



   Example XXI
In 6 ml of water, 0.70 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3-cephem-4-carboxylic acid was added together with 0 , 13 g of 5-mercapto-2-methyl-1,3,4-thiadliazole and 0.34 g of sodium bicarbonate dissolved. The solution was 30 min. stirred at 60 C and treated after this period as described in Example VII. 0.51 g of 7ss- (D-5-phthalimido-5-carboxyvaler-amido) -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was obtained receive.



   IR (KBr): 1773 (sh), 1715, 1648 (2H) cm1
NMR (d6-DMSO): # 1.53 & 2.15 (6H, - (CH2) 3-), 2.67 (3H, s, -CH3), 3.45 & 3.72 (2H, ABq, J = 18Hz, 2-CH2), 4.19 & 4.50 (2H, ABq, J = 13Hz, 3-CH2), 4.72 (1H, t, J = 7Hz, -. CH-), 5.02 (1H, d, J = SHz, 6-H), 5 5.61 ( 1H, dd, J = 5 & 8Hz, 7-H), 7.87 (4H, s,
EMI13.1
 8.74 (1H, d, J = 8Hz, -CONH-)
Example XXII
The reaction according to Example XXI was carried out using 0.73 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido-3 - (2-carboxy-6 (or 3) -nitrobenzoyloxy) methyl-3 -ce- phem-4-carboxylic acid repeated,

   and 0.55 g of 7t3- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem Receive -4-carboxylic acid.



   IR (KBr): 1780, 1728, 1644 cm-
NMR (d6-DMSO): ö 1.28 (9H, s, -C (CH3) 3), 1.74 & 2.23 (6H, - (CH2) 3-), 2.66 (3H, s, -CH3), 3.50 & 3.75 ( 2H, ABq, J = 18Hz, 2-CH2), 4.20 & 4.50 (2H, ABq, J = 13Hz, 3-CH2), 4.39 (1H, -CH-), 5.05 (1H, d, J = 5Hz, 6 -H), 5.65 (1H, dd,
EMI13.2


 <tb> J = 5 <SEP> & 8Hz, 7-H), <SEP> 7.44 <SEP> & 7.80 (4H, <SEP> -nS <SEP>), <SEP> 8.42 (1H, d,
 <tb> J <SEP> = <SEP> 8Hz, <SEP> -CH-NW), <SEP> 8.80 (1H, d, J <SEP> = <SEP> 8Hz, <SEP> ONH-)
 Example XXIII
0.46 g of 7ss- (D-mandelamido) -3- (3-carboxypropionyloxy) methyl-3-cephem-4-carboxylic acid together with 0.12 g of 5-mercapto-1-methyl- 1H-tetrazole and 0.25 g sodium bicarbonate dissolved.

  The solution was 1 hour 30 min.



  stirred at 60 C. After cooling in air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2, eluted with water and then with a mixed solvent of water and methanol. The fractions containing the desired compound were combined, concentrated and lyophilized. 0.31 g of 7, B- (D-mandelamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.



   IR (KBr): 1761, 1675, 1604 cm- '
NMR (D2O): # 3.25 & 3.68 (2H, ABq, J = 18Hz, 2-CH2), 3.95 (3H, s,
N-CH3), 4.02 & 4.29 (2H, ABq, J = 13Hz, 3-CH2), 4.97 (1H, d, J = 5Hz, 6-H), 5.18 (1H, s, -CH-), 5.51 (1H, d, J = 5Hz, 7-H), 7.37 (5H, s,
EMI13.3

Example XXIV
The following compounds were prepared by the similar procedures described in Example XXI: (1) 7P- (D-5-phthalimido-5-carboxyvaleramido) -3- [2- (2hydroxyethylthio) -1,3,4-thiadiazole-5- yl] thiomethyl-3-cephem4-carboxylic acid.



   IR (KBr): 3325.1780.1715.1645.1530 cm-1
NMR (d6-DMSO): # 1.30-2.40 (m, 6H), 3.20-3.80 (m, 6H), 4.27 (AB-q, 2H, J = 12Hz); 4.65 (t, 1H, J = 9Hz), 4.96 (d, 1H, J = 5Hz), 5.55 (q, 1H, J = 5H & 8Hz), 7.87 (s, 4H), 8.70 (d, 1H, J = 8Hz) (2) 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (2 carbamoylmethylthio-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid.



   IR (KBr): 3430.3340, 1776, 1717, 1680, 1535 cm-1 NMR (d6-DMSO): Ï .30-2.40 (m, 6H), 3.57 (broad; 2H), 4.40 (s, 2H) , 4.32 (AB-q, 2H, J = 12Hz), 4.70 (t, 1H, J = 8.0Hz), 5.0 (d, 1H, J = 5Hz), 5.55 (q.1H, J = 5 & 8Hz), 7.20 (br.lH), 7.60 (br.1H), 7.86 (s, 4H), 8.74 (d, 1H, J = 5Hz)
Example XXV 7ss- (2-thienylacetamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid was prepared by a procedure similar to that described in Example XXIII.



  With 0.50 g of 7ss- (2-thienylacetamido) -3- (2-carboxybenzoyloxy) methyl-3-cephem-4-carboxylic acid as the starting material), 37 g were obtained.



   IR (KBr): 1776.1734.1672 cm-1
NMR (d6-DMSO): 6 3.56 & 3.78 (2H, ABq, J = 18Hz, 2 CH2), 3.73 (2H, s, -CH2CO-), 3.92 (3H, s, #N CH3), 4.21 & 4.37 ( 2H, Abq, J = 13Hz, 3-CH2), 5.05 (1H, d, J = 5Hz, 6-H), 5.66 (1H, dd, J = 5 & 8Hz, 7-H), 6.90 & 7.29 (3H ,
EMI13.4
   9.10 (1H, d, J = 8Hz, -CONH-)
Example XXVI
1.33 g of 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] -3-mandelyloxymethyl-3-cephem-4-carboxylic acid together with 0.25 g of 5-mercapto- 1-methyl-1H-tetrazole and 0.51 g of sodium bicarbonate dissolved. The mixture was at 60 0C 30 min. stirred and then cooled to room temperature.

  After adding 31 ml of 4% aqueous phosphoric acid, the reaction mixture was extracted with 60 ml of ethyl acetate. The ethyl acetate layer was washed with a saturated aqueous sodium chloride solution (40 mlX2), dried over magnesium sulfate, and concentrated under reduced pressure. Then a powder was obtained by adding ether. This powder was filtered off, washed with ether and dried under reduced pressure over phosphorus pentoxide. 1.14 g of 7ss- [D-5- (p-t-butylbenzamido) -5-carboxyvaleramido] 3- (1-methyl-1H-tetrazol-5yl) thiomethyl3-cephem-4-carboxylic acid were obtained.

 

   The IR (KBr) and NMR (d6-DMSO) spectra showed good agreement of this compound with that prepared according to Example VII.



      Example XX VII
1.27 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -5-mandelyloxymethyl-3-cephem-4-carboxylic acid were added to 12 ml of water together with 0.25 g of 5-mercapto-1-methyl-1Htetrazole and 0, Dissolved 51 g sodium bicarbonate. The solution was 30 min. stirred at 60 C. After the reaction had ended, the reaction mixture was treated as described in Example XXVI. 1.12 g of 7P- (D-5-phthalimido-5-carboxyvaler-amido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem4-carboxylic acid were obtained.



   The IR (KBr) and NMR (d6-DMSO) spectra showed good agreement of this product with the compound prepared according to Example I.



   Example XX VIII
0.5 ml of 7ss- (D-mandelamido) -3-mandelyloxymethyl-3-cephem-4-carboxylic acid was added to 5 ml of water together with 0.12 g of 5-mercapto-1-methyl-1H-tetrazole and 0.17 g Sodium bicarbonate dissolved. The solution was stirred at 60 ° C. for 30 minutes.



  After cooling in air, the reaction mixture was subjected to column chromatography on Amberlite XAD-2 and eluted with water and a mixed solvent of water and methanol. The fractions containing the desired product were combined, concentrated and lyophilized. 0.34 g of 7ss- (D-mandelamido) -3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid sodium salt was obtained.



   The IR and NMR spectra showed good agreement of this compound with the product obtained according to Example XXIII.



   Example XXIX
0.49 g of 7ss- (2-thienylacetamido) -3-mandelyloxymethyl3-cephem-4-carboxylic acid was dissolved in 4 ml of water together with 0.12 g of 5-mercapto-1-methyl-1H-tetrazole and 0.17 g of sodium bicarbonate . The solution was 30 min. stirred at 60 "C.



  After the reaction had ended, the reaction mixture was treated in a manner similar to that described in Example XXVI. 0.40 g of 7ss- (2-thienylacetamido) -3- (1-methyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid was obtained.



   The IR and NMR spectra showed good agreement of this compound with the product prepared according to Example XXV.



   Example XXX
The following compounds were prepared by the similar procedures described in Examples XXVI and XXVII: (1) 7ss- [D-5- (pt-butylbenzamido) -5-carboxyvaleramido] - 3- (2-methyl-1,3,4 -thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, yield 84%.



   The IR and NMR spectra showed good agreement of this compound with the product prepared according to Example XXII.



   (2) 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- (2-methyl-1, 3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, Yield 86%.



   The IR and NMR spectra of this compound showed good agreement with the product prepared according to Example XXI.



   (3) 713- (D-5-phthalimido-5-carboxyvaleramido) -3- [2- (2-hydroxyethylthio) - 1,3, 4-thiadiazol-5-yl] thiomethyl-3-cephem-4-carboxylic acid, Yield 81%.



   The IR and NMR spectra of this compound showed good agreement with the product prepared according to Example XXIV (1).



   (4) 7t3- (D-phthalimido-5-carboxyvaleramido) -3- (2-carbamoyl-methylthio-l, 3,4-thiadiazol-5-yl) thiomethyl-3-cephem 4-carboxylic acid, yield 88% .



   The IR and NMR spectra of this compound showed good agreement with the product prepared according to Example XXIV (2).



   Example XXXI
3.14 g of 7P-amino-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid, 1.84 g of sodium hydrogen carbonate and 1.4 g of 5-mercapto-1- were dissolved methyl-1H-tetrazole, the solution was adjusted to a pH of 5.5, stirred and heated for 1 hour at 60 ° C. After cooling, the reaction mixture was washed with 20 ml of dichloromethane and the pH of the aqueous layer adjusted to 3.3, then was stirred under ice cooling for one hour.



  The resulting precipitate was filtered off and washed with water, methanol and acetone. After drying, 2.7 g of 7ss-amino-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained.



   IR (KBr): 1795 cm 1 NMR (o in D2O + NaHCO3): 3.61 & BR <3.98 (2H, ABq, J = 18Hz, 2-CH2), 4.21 (s, NCH3), 5.21 (d, J = 4.5Hz, 6-H), 5.60 (d, J = 4.5Hz, 7-H)
Example XXXII
3.14 g of 7ss-amino-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid, 0.84 g of sodium bicarbonate and 2.60 g of 5-mercapto-1- [2 - (N, N-dimethylamino) ethyl 1H-tetrazole dissolved, the resulting solution was 60 min. stirred at 55 ° C. After cooling, 15 ml of acetone were added to the reaction solution and the mixture was passed over a column with 10 g of active alumina.

  The column was washed with 30 ml of water-acetone (1: 1) and the washing water obtained was combined with the eluate, then the acetone was distilled off under reduced pressure. 6.0 ml of Amberlite IR-120 in acid form were added to the remaining solution and the mixture was stirred for 30 minutes while cooling with ice. The insoluble substances were filtered off and the filtrate was concentrated. The concentrate was added dropwise to about 30 times its volume of ethanol, the solid solid was filtered off and washed with ethanol, and after drying, 3.28 g of 7ss-amino-3-1- [2- (N, N-dimethylamino ) ethyl] - 1H-tetrazole-5-yl-thiomethyl-3-cephem-4-carboxylic acid obtained.



   IR (KBr): 3450, 1780, 1620, 1540 cm-1 NMR (o in D2O): 3.07 (6H, s), 3.70 (2H, ABq, J = 17Hz), 3.85 (2H, t, J = 6Hz) , 4.25 (2H, ABq, J = 12Hz), 4.8-5.2 (4H, m)
Example XXXIII
3.14 g of 7ss-amino-3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid were added to 30 ml of water together with 1.84 g of sodium bicarbonate and 1.6 g of 2-mercapto-5- Dissolved methyl-1,3,4-thiadiazole, the resulting solution was adjusted to a pH of 6.4 and then stirred at 60 "C for 1 hour.



  After cooling, the reaction solution was washed with dichloromethane, and the pH of the aqueous layer was adjusted to 3.5 with ice cooling, then stirred for 1 hour. The precipitate was filtered off and washed with water, methanol and acetone, then dried. 2.9 g of 7ss-amino-3- (2-methyl-1,3,4-thiadizol-5-yl) thiomethyl3-cephem-4-carboxylic acid were obtained.



      (IR (KBr): 1795cm- 'NMR (8 in D2O + NaHCO3): 2.87 (3H, s thiadiazole -CH3), 3.53 & 3.95 (2H, Abq, J = 18Hz, 2-CH2), 4.10 & 4.46 (2H , Abq, J = 13Hz, 3-CH2), 5.17 (1H, d, J = 4.5Hz, 6-H), 5.58 (1H, d, J = 4.5Hz, 7-H) Example XXXIV
In 1 ml of water containing 120 mg of the sodium salt of 5-mer capto-1H-1,2,3-triazole and 40 mg of sodium hydroxide, 282 mg of 7ss-amino-3- (3-oxobutyryloxy) - were cooled with ice. Dissolved methyl-3-cephem-4-carboxylic acid, the resulting solution was mixed with 1N-HCl to adjust its pH to 5.5 with stirring and stirred at 55 C for a further hour. 5 ml of methanol was added to the reaction solution and the mixture was cooled to room temperature.

 

  The pH of the cooled mixture was adjusted to 3.9 by adding 1N-HCl with stirring, and the resulting mixture was stirred for an additional hour with ice cooling. The filled insoluble substances were filtered off and washed with water and methanol. Then the insoluble substances were dried naturally first and then over phosphorus pentoxide. 190 mg of 7ss-amino-3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid were obtained.



     
IR (KBr): 1800, 1525 cm
Example XXXV
7.05 g of 7- [L-phthalimido-5-carboxyvaleramido] -3-hydroxymethyl-3-cephem-4-carboxylic acid-ditriethylamine salt were dissolved in 50 ml of dichloromethane, then 1.5 ml of triethylamine were added to the solution at 0 ° C. , after which within 10 min.



  2.0 ml of diketene were added dropwise at -5 to 0 C. The mixture was stirred for a further 50 min at -5 to 0 C and 40 ml of water were added, then the pH was adjusted to 6.0 with 2N-HCl. The aqueous layer was washed with 10 ml of dichloromethane, then 2.25 g of 5-mercapto-1- [2 (N, N-dimethylamino) ethyl] -1H-tetrazole was added and the pH was adjusted to 5.5. The solution was 40 min.



  Stirred at 60 C, then the insoluble substances were filtered off. 15.0 g of sodium chloride and 50 ml of saturated aqueous sodium chloride solution were added to the filtrate. The mixture was adjusted to pH 2.0 with 4N HCl. The precipitated solids were filtered off, washed with a saturated aqueous sodium chloride solution and water and dried. 6.75 g of 7ss- (D-5-phthalimido-5-carboxyvaleramido) -3- {1- [2-N, N-dimethylamino) ethyl-1H-tetrazol-5-yl} thiomethyl-3- Obtained cephem-4-carboxylic acid hydrochloride.



   IR (KBr): 3370, 1775, 1715, 1640cm NMR (# in d6-DMSO): 1.30-2.40 (6H, m), 3.5.8 (9H, m), 5.04 (1H, d, J = 5Hz), 5.60 (1H, q, J = 5.8Hz), 7.90 (4H, s), 8.86 (1H, d, J = 8Hz) Example XXXVI
In 3 ml of a phosphate buffer solution with a pH of 6.4, 79 mg of 5-mercapto-2-methyl-1,3, 4-thiadiazole, 50 mg of sodium bicarbonate and 243 mg of 7ss- [2- (1H-tetrazole-1 - yl) acetamido] -3- (3-carboxypropionyloxy) -methyl-3-cephem-4carboxylic acid disodium salt and the resulting solution was heated at 60 C for 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography on 250 ml of Sephadex LH-20 and eluted.

  The fractions containing the desired product were combined and lyophilized. Sodium 7ss [2- (1H-tetrazol-1-yl) acetamido] -3- (2-methyl-1,3,4-thiadiazol-5-yl) thiomethyl-3-cephem-4-carboxylate was obtained.



     NMR (o in D2O): 2.78 (3H, s, -CH3), 3.60 (2H, ABq, J = 18Hz, 2-CH2), 4.25 (2H, ABq, J = 13Hz, 3 CH2), 5.12 (lH, d, J = 4.5Hz, 6-H), 5.58 (2H, s, -CH2CO-), 5.70 (1H, d, J = 4.5Hz, 7-H), 9.15 (1H, s, tetrazole-H) example XXX VII
In 3 ml of a phosphate buffer solution with a pH of 6.4, 280 mg of 7ss- [Dat-butoxycarbonylamino-a- (p-hydroxylphenyl) acetamido] 3 - (3-oxobutyryloxy) methyl-3-cephem-4-carboxylate and 120 mg of sodium salt of 5-mercapto-l H-1,2,3-triazoi dissolved, the resulting solution was 60 min.



  heated to 60 C. After cooling to room temperature, the reaction solution was subjected to column chromatography on Amberlite XAD-2 and the combined eluate, which contained the desired product, was freeze-dried. Sodium 7ss- [D-? -T-butoxycarbonylamino- ?- (p-hydroxyphenyl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3 -cephem-4-carboxylate obtained.



   IR (KBr): 3400, 1762, 1678 cm- '
NMR (D2O): # 1.46 (9H, s -C (CH3) 3), 3.00-4.12 (4H, m, 2- CH2, 3-CH2), 5.00 (1H, d, J = 4.5Hz, 6-H ), 5.60 (1H, d, J = 4.5Hz, 7-H), 6.78-7.42 (4H, m,
EMI15.1
   7.71 (1H, s, triazole-4-H)
175 mg of the sodium 7ss- [Dat-butoxycarbonylamino-a- (p-hydroxyphenyl) acetamido] -3- (1H-1,2,3-triazol-5-yl) -thiomethyl-3-cephem-4 thus prepared carboxylate were dissolved in 4 ml of formic acid, the resulting solution was stirred at room temperature for 2 hours.

  The reaction solution was subjected to distillation under reduced pressure and then azeotroped three times with toluene to remove the formic acid, then it was dried over phosphorus pentoxide overnight. The foamy material thus obtained was stirred with 15 ml of water-methanol (8: 2) and the mixture was filtered, then treated with activated carbon and then filtered through Celite. The filtrate was freeze-dried, the 7- [D-? - (p-hydroxyphenyl) acetamido] -3- (1H-1,2,3-triazol-5-yl) thiomethyl-3-cephem-4- receive carboxylic acid. This product was in good agreement with the standard determined by thin layer chromatography and liquid chromatography.



      Example XXX VIII
In 10 ml of water, 908 mg of 7ss- [2- (2-imino-3-thiazo-lin-4-yl) acetamido] -3- (3-oxobutyryloxy) methyl-3-cephem-4-carboxylic acid, 450 mg of 5-mercapto -1- [2- (N, N-dimethylamino) ethyl] -1H-tetrazole and 168 mg sodium bicarbonate were dissolved and the resulting solution was heated to 55 C for 60 min.

 

  A content of 7ss- [2- (2-imino-4-thiazolin-4-yl) -acetamido] -3- (1 - [2- (N, N-dimethylamino) ethyl] - was determined in the reaction mixture by means of liquid chromatography. 1H-tetrazol-5-yl-} thiomethyl-3-cephem-4-carboxylic acid (yield: 81% based on the starting cephalosporin) was determined .. The reaction solution was adjusted to a pH of 5.8 and by column chromatography on Amberlite XAD- 2 cleaned.



   IR (KBr): 1765 cm- 'NMR (DzO): Ï 3.06 (6H, s, -N (CH3) 2), 3.5-4.8 (10H, m), 5.12 (1H, d, J = 5Hz, 6- H), 5.65 (1H, d, J = 5Hz, 7-H), 6.62 (1H, s-thiazoline-H)


    

Claims (6)

 PATENT CLAIMS 1. Process for the preparation of cephem compounds of the formula: EMI1.1  in which R1 is hydrogen or an acyl group and R3 is the residue of a nitrogen-containing, heterocyclic thiol compound and its salts, characterized in that a compound of the formula: EMI1.2  in which Rl has the meaning given above and W denotes an acetonyl group or one of the groups -X-COOH and -X OH, in which X represents an organic radical, or a salt thereof with a nitrogen-containing heterocyclic thiol compound or a salt thereof.  2. The method according to claim 1, characterized in that the acyl group Rl of the formula: EMI1.3  in which R4 corresponds to acetyl, haloacetyl, phenyl, p-hydroxyphenyl, thienyl, 2-imino-4-thiazclin-4-yl, 2-oxo-4-thiazolin-4-yl, tetrazolyl, phenoxy or 3-amino-3 -carboxypropyl and R5 are hydrogen, sulfo, amino or hydroxy and the amino and carboxyl groups in R4 and R5 can be protected.  3. The method according to claim 2, characterized in that the protective group of the amino group is one of the following: phthaloyl, benzoyl, p-nitrobenzoyl, toluoyl, naphthoyl, p-tert. -Butylbenzoyl, p-tert-butylbenzenesulfonyl, phenylacetyl, benzenesulfonyl, phenoxyacetyl, toluenesulfonyl, chlorobenzoyl, acetyl, valeryl, capryl, n-decanoyl, acryloyl, pivaloyl, Camphorsulfonyl, methanesulfonyl, chloroacetyl, t-butoxycarbonyl, ethoxycarbonyl, iso-bornyloxycarbonyl , Phenyloxycarbonyl, trichloroethoxycarbonyl, benzyloxycarbonyl, t3-methylsulfonylethoxycarbonyl, methylcarbamoyl, phenylcarbamoyl, naphthylcarbamoyl and 2-methoxycarbonyl-1-methylvinyl.  4. The method according to claim 1, characterized in that Rl 2- (2-imino-4-thiazolin-4-yl) acetyl, W acetonyl and R3 (1 - [2- (N, N-dimethylamino) ethyl] - 1 Represent H-tetrazolj-yl) thio and 5-mercapto-1 - [2- (N, N-dimethylamino) ethyl] - 1H-tetrazole is used as nitrogen-containing, heterocyclic thiol compound.  5. The method according to claim 1, characterized in that Rl D-5-phthalimido-5-carboxyvaleryl, W acetonyl and R3 (1 j2- (N, N-dimethylamino) ethyl] - 1 H-tetrazol-5-yl) thio represent and 5-mercapto-1 - [2- (N, N-dimethylamino) ethyl] - 1H-tetrazole is used as nitrogen-containing, heterocyclic thiol compound.  6. The method according to claim 1, characterized in that R1 represents D-5-phthalimido-5-carboxyvaleryl, W acetonyl and R3 (1-methyl-1H-tetrazol-5-yl) thio and 5-mercapto-1 methyl-1H -tetrazole is used as nitrogen-containing, heterocyclic thiol compound.  The invention relates to a new process for the preparation of gephem compounds which correspond to the following formula: EMI1.4  in which R1 is hydrogen or an acyl group and R3 is the residue of a nitrogen-containing, heterocyclic thiol compound.  The process according to the invention consists in that a compound of the formula: EMI1.5  in which R1 has the meaning given above and W is an acetonyl group or one of the groups -X-COOH and -X OH means wherein X represents an organic radical, or a salt thereof with a nitrogen-containing, heterocyclic thiol compound or a salt thereof.    As is known, the reaction by which the 3-acetoxymethyl group of a cephalosporin compound is substituted with a nucleophilic reactant causes a simultaneous decomposition of the starting material, intermediate and end product and leads to an extended reaction time. Therefore, lower yields are achieved [A.B. Taylor, J. Chem. Soc., 7020 (1965)].  Therefore, research has been conducted into a denvate that has a group that is easier to substitute than the acetoxy group.  In order to solve the above-mentioned problems, extensive studies have been made and it has been found that the use of diketene or of compounds of formula m or IV, which are mentioned below as acylating agents, the O-acylation of the (3-hydroxymethyl group of the 3- Hydroxymethyl compound (or) cephalosporadesinic acid) enables high yield and that the O-acylated cephalosporin thus produced can be very easily substituted by a nucleophilic compound. The present invention is based on this finding.    The above-mentioned compounds of formula (I) include, for example, those compounds in which R1 is hydrogen, phenylacetyl, phenoxyacetyl, 5-anüno-5-carboxyvaleryl, the amino and / or carboxyl group of which is or may be protected, or one of the groups that can be in the 6- or 7-position of penicillin or gephalosporin derivatives ** WARNING ** End of CLMS field could overlap beginning of DESC **.