CH609700A5 - Process for the preparation of cephalosporin derivatives - Google Patents

Abstract

7 alpha -Methoxy-3-cephem-4-carboxylic acids of the formula I below are prepared. In this, R<1> is a group which does not take part in the reaction, R<3> is an optionally substituted hydrocarbon radical or a heterocyclic group and A is an alkylene group. The novel process comprises reacting a mercaptan R<3>SH with a carboxylic acid corresponding to the above formula I or with a corresponding carboxylic ester in which a halogen atom is in the place of R<3>S; when a carboxylic ester is used, the ester is subsequently cleaved. The products of the process include novel compounds with valuable antibacterial properties. <IMAGE>

Description

  

  
 

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

 



   PATENT CLAIMS
1. Process for the preparation of compounds of the formula:
EMI1.1
 where Rl is a group not involved in the reaction, R3 is an optionally substituted hydrocarbon group or a heterocyclic group which has at least one ring heteroatom selected from nitrogen, oxygen and sulfur atoms in the monocyclic or bicyclic ring, and A is a straight-chain or branched alkylene group, characterized in that a compound of the formula:
EMI1.2
 in which Rl and A have the above meanings and X is a halogen atom and R2 is the carboxyl group or an esterified carboxyl group, with a compound of the formula:

  : R3-SH (III) if R3 has the above meaning or is reacted with a metal salt thereof and, in those cases in which R2 represents an esterified carboxyl group, converts the compound thus obtained into the free acid.



   2. The method according to claim 1, characterized in that Rl is the hydrogen atom, a lower alkyl radical, an acyloxymethyl radical, a carbamoyloxymethyl radical or an aromatic heterocyclic thiomethyl radical of the monocyclic type, which has at least one nitrogen, oxygen and / or sulfur atom in the ring, R3 a straight-chain or branched hydrocarbon group which has 1 to 6 carbon atoms and can carry as substituents hydroxyl, azido, cyano, nitro, acylamino, alkoxy, phenyl, cyclohexadienyl, cyclohexyl or alkoxycarbonyl group, or a phenyl group - or naphthyl group, which can have at least one halogen atom or an alkyl, alkoxy, cyano, nitro or acylamino group as a substituent, or a saturated or unsaturated, 5- or 6-membered, monocyclic hydrocarbon group,

   or 2 imidazolyl, 1,2,4-triazol-3-yl, 1,3, 4-thiadiazol-2-yl, 2-pyridyl, 2-pyrimidyl, purin-6-yl, 2-benzothiazolyl, 2-benzoxazolyl, represents s-triazolo [4,3-a] pyridin-3-yl or 2-thiazolyl and A represents a straight-chain or branched, lower alkylene group having 1 to 6 carbon atoms.



   3. The method according to claim 1, characterized in that Rl 5- (1-methyltetrazolyl) -thiomethyl, carbamoyloxymethyl or acetoxymethyl, R3 cyanomethyl, 1-cyanoethyl, 2 hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl and A is methylene.



   4. The method according to claim 1, characterized in that the metal salt is an alkali salt, for. b. the sodium, potassium or lithium salt, or an alkaline earth metal salt is used.



   5. The method according to claim 1, characterized in that R2 is the carboxyl group and the reaction is carried out in a mixture of water and a water-miscible organic solvent, e.g. B. methanol or ethanol takes place.



   6. The method according to claim 1, characterized in that the compound of formula III is in free form and the reaction in the presence of an alkali, for. B. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate.



   The present invention relates to a new process for the preparation of 7o: -Methoxy-3-cephem-4-carboxylic acids, which have a substituent in the 3-position and a substituted thioalkanoylamino radical in the 7,8-position and correspond to the following formula:
EMI1.3
 wherein Rl represents a group not participating in the reaction, R3 represents an optionally substituted hydrocarbon radical or a heterocyclic group which has at least one ring heteroatom selected from nitrogen, oxygen and sulfur atom in the monocyclic or bicyclic ring, and A represents a straight-chain or branched alkylene group .



   As examples of the radical Rl in the above formula I, i. H.



  for the group not participating in the reaction, the hydrogen atom, lower alkyl radicals, e.g. B. the methyl group, acyloxymethyl radicals, e.g. B. the acetoxymethyl group or carbamoyloxymethyl group, and aromatic, heterocyclic thiomethyl radicals of the monocyclic type which have at least one nitrogen, oxygen and / or sulfur atom in the ring, e.g. B. the 5- (1-methyltetrazolyl) -thiomethyl- and 2- (1,3,4-thiadiazolyl) -thiomethyl group mentioned.



   The hydrocarbon radicals R3 can be, for example, straight-chain or branched hydrocarbon radicals having 1 to 6 carbon atoms, e.g. B. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl or propargyl, name, such hydrocarbon radicals substituents such. B. hydroxyl, azido, cyano or nitro groups, acylamino groups, e.g. B. acetylamino and tert-butoxycarbonylamino groups, alkoxy groups, e.g. B. methoxy and ethoxy groups, phenyl, cyclohexyldienyl and cyclohexyl groups and alkoxycarbonyl groups, e.g. B. methoxycarbonyl and ethoxycarbonyl groups, can carry.

  As monocyclic or bicyclic aryl radicals R3, there may be mentioned, for example, optionally substituted benzene and naphthalene rings, these rings being, for example, halogen atoms, such as chlorine or bromine, alkyl radicals as substituents. z. B. methyl and ethyl radicals, alkoxy radicals, e.g. B. methoxy and ethoxy, cyano groups, nitro groups and acylamino, z. B. Acet



  ylamino or tert-butoxycarbonylamino groups may have. As aliphatic. monocyclic hydrocarbon radicals R3 can be 5- and 6-membered, saturated and unsaturated, monocyclic hydrocarbon radicals, eg. B. Cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl and cyclohexadienyl radicals. As monocyclic or bicyclic.



  heterocyclic radicals come aromatic and non-aromatic, heterocyclic rings with at least one nitrogen.



  Oxygen and / or sulfur atom in the ring in question. such as B.



  2-imidazolyl-, 1, 2,4-triazol-3-yl-, 1, 3,4-thiadiazol-2-yl-, 2-pyndyl-2-pyrimidyl-. Purin-6-yl-. 2-benzothiazolyl, 2-benzoxazolyl, s-triazolo [4,3-ajpyridin-3-yl, and 2-thiazolyl groups in question. The alkylene group A can be straight-chain and branched, lower alkylene radicals having 1 to 6 carbon atoms, such as methylene, trimethylene. Propylene, tetramethylene, 2-methyltetramethylene, pentamethylene and hexamethylene groups.



   For the preparation of 7 B-acylamino-7n-methoxy-cephalosporinverbindungen various methods have been described in the literature, such. B. a process which consists in that a 7 ss-o-aminoadipoylamino-7cr-methoxycephalosporin compound obtainable by a fermentation method with formation of the corresponding diacylated compound and with cleavage of the aminoadipoyl group (cf.

  Japanese Unexamined Patent Publication No. 931/1972), further a process which consists in acylating a 7-amino-7-methoxycephalosporin compound obtained by chemical synthesis to form a 7ss-acylamino compound (see the Japanese Unexamined Patent Publication mentioned above), furthermore, a method which consists in converting a 7a-H compound, namely a cephalosporin compound, into an acylamine intermediate and methoxylating this intermediate to form a 7 cc-methoxycephalosporin compound (see Japanese Patent Application Laid-Open No. 62791/1973), etc. .

  In the previously known processes mentioned above, in which a 7ss-methoxycephalosporin compound is used as the starting material, the 7ss-acylation is carried out using a reactive derivative, e.g. B. an acid chloride. This acylation method is extremely disadvantageous if you have an acyl group that is derived from a substituted thioalkanecarboxylic acid, eg. B. 1,3,4-thiadiazolthioacetic acid or 1,2,4-triazol- ylthioacetic acid. derives, wants to introduce because it is often difficult or in certain cases even impossible to prepare a reactive derivative of such an acid. Come in addition.



  that such a reactive derivative can also be unstable or can be obtained in poor yield. Furthermore, the yield in the acylation reaction is extremely poor.



   On the basis of experiments for the preparation of 7α-methoxycephalosporin compounds, a process has now been developed, thanks to which 7a-methoxycephalosporin compounds, which have a substituted thioalkanoylamino group in the 7-position, are obtained under mild conditions in extremely high yield compared to the previous processes can without having to accept the disadvantages mentioned above. This new process can be used for the production of various types of cephalosporin derivatives.



   The aim of the present invention is therefore a new and interesting, advantageous process for the preparation of 7cr-methoxycephalosporin compounds.



   According to the invention, the compounds of the above general formula I are obtained by adding a 7p-haloalkanoylamino-7a-methoxy-3-cephem compound of the following formula:
EMI2.1
 wherein Rl and A have the above meanings and X represents a halogen atom and R2 represents the carboxyl group or an esterified carboxyl group, with a sulfhydryl compound of the formula:
R3-SH (III) in which R3 has the above meaning or reacts with a metal salt thereof and, in those cases in which R2 represents an esterified carboxyl group, converts the reaction product obtained into the corresponding free acid.



   In the above formula II, the halogen atoms X used are preferably chlorine and bromine. If the radical R2 represents an esterified carboxyl group, the type of ester is not of particular importance as long as this ester does not destroy the cephem ring during or after the condensation reaction and this ester can be easily split subsequently. As such esters, for example, alkylsilyl esters, e.g. B. the trimethylsilyl ester, lower alkyl ester, e.g. the methyl, ethyl and tert-butyl esters, benzyl esters, p-methoxybenzyl esters, benzhydryl esters, phenacyl esters, p-bromophenacyl esters and 2,2,2-trichloroethyl esters.



   The metal salts of sulfhydryl compounds of the formula III can usually be alkali or alkaline earth metal salts, e.g. B. sodium, potassium, lithium, calcium or barium salts, use, preferably sodium, potassium or lithium salts will be used.



   In carrying out the present process, the reaction can be easily carried out by bringing a compound of the above formula II into contact with a compound of the formula III or a metal salt thereof. In order to make the reaction easy, the reaction will preferably be carried out in the presence of a solvent.



  In particular in those cases in which a metal salt of a compound of the general formula III is used, the reaction takes place in the presence of a solvent.



  Any solvents which do not take part in the reaction can be used in this process.



  Examples include water and organic solvents, e.g. B. dialkyl ketones such as acetone and methyl ethyl ketone, halogenated alkyl compounds, e.g. B. chloroform, methylene chloride and dichloroethane, lower alkanols, e.g. B. methanol or ethanol, and dimethylformamide. Mixtures of two or more such solvents can also be used.

 

   If a compound of the formula II with a carboxyl group in the 4-position is used, a mixture of water with another solvent will preferably be used for the reaction.



   In the present reaction kn the compound of the formula III or a corresponding metal salt generally in an equimolar amount, based on the compound of the formula II, or in a slight excess, namely in an amount of about 1 to 1.1 moles per mole of a Compound of formula II can be used.



   The conversion takes place with advantage at approximately neutral pH. However, the reaction can also be carried out even more easily if the product obtained in this way is carried out in a manner known per se if one works in a weakly alkaline medium, for example by chromatography or in some other way. If a compound of formula II is used as a further purification.



  In those cases in which an esterified carb alkali is added in the 4-position and the reaction is therefore present in the desired compound under a weak alkoxyl group, the reaction mixture is preferably carried out under conditions. When the reaction is complete, an alkali mixed with water can be used, for example, sodium solvent can be removed from the reaction hydroxide, potassium hydroxide, sodium carbonate or potassium mixture by distillation, and the residue can be used with a non-water carbonate. The reaction temperature is not of miscible solvent extract, the extract with water is of particular importance.

  The reaction is generally carried out by washing and removing the solvent by distillation, at room temperature, but you can also at a higher temperature whereupon the esterified compound is obtained. Those who have won or work at a lower temperature. The Reak- nene connection can be in a manner known per se, for. B.



  tion time can depending on the reaction temperature, depending on the reaction by chromatography or otherwise, further purify, but mediums and other factors vary, but it is generally such a compound directly in the generally about 2 to 30 hours. In those cases, 15 corresponding free acid converted.



  in which the compounds of the formula II exhibit as radical X the cleavage of the ester radical or the conversion of the chlorine atom, the conversion to ester into the free acid is normally dependent on the type of ester. This relatively long duration, i.e. H. after about 10 to 30 hours, for example by alkaline or acidic hydrolysis, can be ended. by reduction with hydrogen or in some other way
After the reaction has ended, the 20 according to the invention can be carried out. After conversion into the free acid, the desired compound is obtained in a manner known per se from which the desired product is obtained in the same way as the above reaction mixture. In those cases which have been described in, one can thus recover from the reaction mixture.



  which have a carboxyl group in the 4-position of the compound obtained in some of the compounds obtainable according to the invention reaction, the reac- are new compounds and are acidic in the Japanese patent mixture and in those cases in which a 25 application No. 132441 / 1973, 132442/1973, 142097/1973, solvent other than water is used, which is described in 92129/1974 and 92131/1974. Remove these new Ver solvents by distillation, whereupon the bonds are valuable compounds, which are excellent reaction product with a suitable solvent, eg. B. having antibacterial properties against various patho ethyl acetate or the like, extracted, have the extract with gene bacteria.

  Examples of such compounds water washes, dries and the solvent is distilled off, 30 and their antibacterial effects are found in the following, whereupon the desired product is obtained. If necessary, Table I.



      Tables
Minimum inhibitory concentration (mcg / ml)
EMI3.1

S. aureus E. coli Sh. Bex-Klebsiella Prot. Salm. ent.



  Y A 209 P R NIHJ (R) neri 2a 806 846 vulgaris Gaertner
EMI3.2


<tb> NCCH2S- <SEP> N <SEP> --rJ <SEP> 0.2 <SEP> 0.8 <SEP> 0.8 <SEP> 0.8 <SEP> 0.8 <SEP> 0, 8 <SEP>> 200 <SEP> 1.5 <SEP> 0.2
<tb> <SEP> SX <SEP>, N
<tb> <SEP> N
<tb> <SEP> CH3
<tb> NCCHS- <SEP> - <SEP> 0.4 <SEP> 0.8 <SEP> 1.5 <SEP> 3.1 <SEP> 1.5 <SEP> 1.5 <SEP> 400 < SEP> 0.8 <SEP> 0.4
<tb> <SEP> CH3
<tb> <SEP> N
<tb> <SEP> CH3
<tb> HOCH2CH2S <SEP> N <SEP> 'N <SEP> 0.8 <SEP> 1.5 <SEP> 1.5 <SEP> 1.5 <SEP> 3.1 <SEP> 1.5 < SEP> 400 <SEP> 6.2 <SEP> 1.5
<tb> <SEP> s-J) 5T
<tb> <SEP> N
<tb> <SEP> CH3
<tb>
Table I (continued)
S. aureus E. coli Sh. flex- Klebsiella Prot. Salm. ent.



  YA 209P R NIHJ (R) neri 2a 806 846 vulgaris Gaertner NCCH2S OCONH2 0.8 3.1 1.5 1.5 3.1 3.1> 200 6.2 1.5 NCCH2S OCOCH3 0.2 0.8 1 , 5 15 3.1 1.5> 400 6.2 0.8
EMI4.1


<tb> HCasCCH2S <SEP> N <SEP> N <SEP> 0.2 <SEP> 0.8 <SEP> 3.1 <SEP> 3.1 <SEP> 3.1 <SEP> 3.1 <SEP > 400 <SEP> 3.1 <SEP> 0.8
<tb> <SEP> II
<tb> <SEP> N
<tb> <SEP> CH3
<tb> N3CHS <SEP> -s <SEP> N <SEP> - <SEP> 0.4 <SEP> 0.4 <SEP> 3.1 <SEP> 3.1 <SEP> 1.5 <SEP> 3.1 <SEP>> 200 <SEP> 1.5 <SEP> 0.8
<tb> <SEP> / N
<tb> <SEP> N
<tb> <SEP> CH3
<tb>
EMI4.2
 0.2 0.8 3.1 3.1 3.1 6.2> 400 3.1 0.8 N3CH29 OCONH2 0.2 1.5 3.1 6.2 3.1 3.1> 400 3, 1 1.5
EMI4.3
 OCOCH3 0.2 0.8 3.1 6.2 6.2 3.1> 400 3.1 1.5 G.H.- OCONH2 0.8 3.1 25 25 12.5 25> 400 25 12.5 Cefalotin

     10.1 6.2 25 12.5 6.2> 200 6.2 6.2
The compounds of formula II, which can be used as starting materials in the present process, are also new compounds and can easily be prepared by known methods. They also have antibacterial properties, but are even more valuable as starting materials for the synthesis of the even more effective antibacterial compounds obtainable according to the invention.



   The invention is illustrated by the following examples
Example I.
7 - (1,2,4-Triazol-3-yl-thioacetamido) -7 a-methoxy 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
12 mg of 3-mercapto-1,2,4-triazole are dissolved in 0.12 mol of an aqueous 1N sodium hydroxide solution and the solution with an aqueous solution of sodium hydrogen carbonate, which contains 42 mg of 7 7ss-bromoacetamido-7a-methoxy-3-carbamoyl - Contains oxymethyl-3-cephem-4-carboxylic acid, added. The mixture is stirred at room temperature for 2 hours and the pH is adjusted to approximately 2.5 by adding 1N hydrochloric acid.

  The mixture is then extracted with ethyl acetate and the organic layer is dried over anhydrous sodium sulfate and the solvent is distilled under reduced pressure to give 48 mg of a crystalline residue. The residue thus obtained is treated over a silica gel plate using a mixture of methanol and chloroform (mixing ratio 50:50) and the solvent is distilled off, 33 mg of the pure, desired product being obtained in the form of a powder.

 

  Nuclear magnetic resonance spectrum (CD3CN + D2O), δ ppm: 5.00 (singlet, H in 6-position) 3.90 (singlet, -S-CH-O-) 3.37 (singlet, OCH3 in 7-position
CH3OH ultraviolet absorption spectrum, max
263 Infrared Absorption Spectrum (KBr), v cm-l:
1770 thin layer chromatography (silica gel): (a) developer solvent: mixture of n-butanol, acetic acid and water in a ratio of 5: 4: 1 Rf value = 0.37 (b) developer solvent: mixture of methanol and
Chloroform in a ratio of 1: 1 Rt value = 0.28.



   If one works according to the above methods using a corresponding 7 (3-chloroacetamido derivative instead of 7B-bromoacetamido-7α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, similar results are obtained.



   Example 2
7 ss- (imidazol-2-yl-thioacetamido) -7 α-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
20 mg of 2-mercaptoimidazole are dissolved in 0.2 ml of ln sodium hydroxide and the resulting solution with a solution of 117 mg of 7 7ss-bromoacetamido-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid added in 0.2 ml of ln sodium hydroxide. The mixture is then left to stand for 2 hours at room temperature and the pH is adjusted to 2.5 by adding 2N phosphoric acid. The mixture is then extracted with ethyl acetate and the aqueous layer is freeze-dried and extracted with methanol.

  The portion soluble in methanol is separated on a silica gel plate using a mixture of methanol and chloroform (50:50) and extracted with methanol. The solvent is distilled from the extract, 80 mg of the pure, desired product being obtained in the form of a powder.



  Nuclear Magnetic Resonance Spectrum (CD3CN + D20), 6 ppm: 7.09 (singlet, H of the imidazole) 5.02 (singlet, H in 6-position) 3.75 (singlet, -S-CH2-CO-) 3.39 (Singlet, OCH3 in 7-position) Ultraviolet absorption spectrum, X max (phosphoric acid buffer with pH 6.86) mll:
257 Infrared Absorption Spectrum (KBr), vcm-1:
1765 thin layer chromatography (silica gel): (a) developer solvent: mixture of n-butanol, acetic acid and water in a ratio of 5: 4: 1 Rf value = 0.21 (b) developer solvent:

  Mixture of methanol and chloroform in a ratio of 1: 1 Rt value = 0.31
If one works according to the above methods using a corresponding 7 B-chloroacetamido derivative instead of 7 7ss-bromoacetamido-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid, similar results are obtained.



   Example 3 7 ss- (1 3,4-thiadiazol-2-yl-thioacetamido) -7 a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
A solution of 117 mg of 7ss-bromoacetamido-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid in 0.2 ml of ln sodium hydroxide becomes a solution of 23.6 mg of 2-mercapto
1,3,4-thiadiazole in 0.2 ml of ln sodium hydroxide was added and the mixture was stirred for 2 hours at room temperature and then the pH was adjusted to 2.5 by adding 2N phosphoric acid. It is then extracted five times using 15 ml of ethyl acetate each time and the ethyl acetate layer is then dried over sodium sulfate and the solvent is distilled off to obtain 69 mg of a caramel.

  This caramel is deposited on a silica gel plate using a mixture of methanol and chloroform (mixing ratio 50:50). Then it is extracted with methanol. The solvent is distilled off from the extract, 34 mg of the desired compound being obtained in the form of a powder.



  Nuclear Magnetic Resonance Spectrum (CD3CN + D2O), 6ppm: 9.30 (singlet, H of the thiazole) 5.03 (singlet, H in 6-position) 4.16 (singlet, S-CH2-CO-) 3.46 (singlet , OCH3 in 7-position ultraviolet absorption spectrum, Xmax (phosphoric acid buffer of pH 6.86) with
263 Infrared Absorption Spectrum (KBr), acm 1:
1760 thin layer chromatography (silica gel): (a) developer solvent: mixture of n-butanol, acetic acid and water in a ratio of 5: 4: 1 Rf value = 0.49 (b) developer solvent:

  Mixture of methanol and chloroform in a ratio of 1: 1 Rf value = 0.29
If one works in the above manner using a corresponding 7 7ss-chloroacetamido derivative instead of 7 P-bromoacetamido-7a-methoxy-3-carbamoyloxymethyl-3cephem-4-carboxylic acid, similar results are obtained.



   Examples of compounds obtainable in the same manner as in the above examples and their properties are shown below.



   The symbols A, B, C, D (a) and (b), which are used below, refer to the following physical properties: A: Nuclear magnetic resonance spectrum (in CD3CN + D2O, unless otherwise stated), 6 ppm B: Ultraviolet absorption spectrum (in phosphoric acid buffer medium with a pH value of 6.86), Xmax mF C: Infrared absorption spectrum (KBr), vcm-t D: Thin-layer chromatography (silica gel) (a) obtained Rf value, provided that a mixture of n Butanol, acetic acid, water are used in a mixing ratio of 5: 4: 1 (b) Rf value obtained when a mixture of methanol and chloroform is used in a mixing ratio of 1: 1.



     7ss- (5-methyl-1,3,4-thiadiazol-2-ylthioacetamido) -7a-methoxy-3carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 5.02 (singlet, H in 6-position)
4.05 (singlet, S-CH2CO-)
3.43 (singlet, OCH3 in 7-position)
2.64 (singlet, H of the thiadiazole) B: 263 C: 1770 D: (a) = 0.45, (b) = 0.38 7 ss-propargylthioacetamido-7a-methoxy-3-carbamoyloxymethyl-3- cephem-4-carboxylic acid A: (DMSO-d6):
5.15 (singlet, Hin 6-position)
3.40 (multiplet, -CH2-SCH2 and OCH3 in 7-position) B: 242.265 C: 1780 7ss-Cyanomethylthioacetamido-7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A:

   (DMSO-d6):
5.06 (singlet, H in 6-position)
3.58 (singlet, NC-CH2SCH2) B: 246.265 C: 1720, 1775 713- (5-methyl-1,2,4-triazol-3-yl-thioacetamido) -7ot-methoxy-3-carbamoyloxymethyl-3-cephem- 4-carboxylic acid A: 5.02 (singlet, H in 6-position) 4.05 (singlet. SCH2CO-) 3.43 (singlet, OCH3 in 7-position) 2.64 (CH3 of the imidazole) B: 263 C: 1780 D: (a) = 0.39. (b) = 0.29 7p- (5-ethyl-1,2,4-triazol-3-yl-thioacetamido) -7ot-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 5.13 (singlet, Hin 6 position)
4.00 (singlet, S-CH2-CO)
3.52 (singlet.

  OCH3 in 7 position)
2.83 and 1.31 (quartet and triplet, CHsCH des
Triazoles) B: 262 C: 1765 D: (a) = 0.46, (b) = 0.33 7ss- (5-propyl-1,2,4-triazol-3-ylthioacetamido) 7-a-methoxy- 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 5.07 (singlet, H in 6-position)
3.95 (singlet, S-CH2CO-) 3.49 (singlet, OCH in 7-position) B: 263 C: 1765 D: (a) = 0.51, (b) = 0.44 713- (5th -Phenyl- 1, 2,4-triazol-3-ylthioacetamido) -7ot-methoxy- 3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 4.94 (singlet, Hin 6-position)
3.92 (singlet, S-CH2-CO-)
3.38 (singlet, OCH in 7-position)
7.3-8.0 (H of benzene) B: 253.235 C: 1765 D:

   (a) = 0.61, (b) = 0.53 7ss- (4-phenyl-1,2,4-triazol-3-ylthioacetamido) -7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 4.99 (singlet, Hin 6-position)
3.99 (singlet, SCH2CO-)
3.41 (singlet, OCH3 at 7-position) B: 260 C: 1765 D: (a) = 0.43 (b) = 0.38 7ss- (4-phenyl-5-methyl-1,2,4 -triazol-3-ylthioacetamido) - 7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 5.00 (singlet, Hin 6-position)
3.92 (singlet, SCH2CO-)
3.42 (singlet, OCH3 in 7-position)
2.19 (singlet, CH3 of the triazole) B: 260 C: 1765 D: (a) = 0.41, (b) = 0.41 7ss- (2-pyridylthioacetamido) -7a-methoxy-3-carbamoyloxymethyl -3-cephem-4-carboxylic acid A:

   5.02 (singlet, Hin 6-position)
3.89 (singlet, SCH20-)
3.39 (singlet, OCH3 in 7-position)
7.0-8.5 (H of pyridine)
B: 266.239
C: 1770
D: (a) = 0.57, (b) = 0.43 7P- (4-methyl-2-pyrimidylthioacetamido) -7ot-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 5.02 ( Singlet, H in 6-position)
3.93 (singlet. SCH2CO-)
3.43 (singlet, OCH3 in 7-position)
2.42 (singlet, CH3 of the pyrimidine)
B: 242.270
C: 1780
D: (a) = 0.51, (b) = 0.39
7ss- (2-pyrimidylthioacetamido) -7a-methoxy-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid A: 5.04 (singlet, H in 6-position)
3.96 (singlet, SCH2CO-)
3.46 (singlet, OCH3 in 7-position)
7.22 and 8.58 (triplet and doublet, H of the pyrimidine) B: 242.265 C: 1760.1700 D:

   (a) = 0.43, (b) = 0.43 7ss- (8-purinylthioacetamido) -7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 4.99 (singlet, H in 6 position)
3.37 (singlet, OCH3 in 7-position)
8.65 and 8.70 (H of the purine) B: 287 C: 1770 D: (a) = 0.35, (b) = 0.18 7ss- (6-purinylthioacetamido) -7a-methoxy-3-carbamoyloxy - methyl-3-cephem-4-carboxylic acid A: 5.01 (singlet, Hin 6-position)
4.14 (singlet, SCII2C)
3.43 (singlet, OCH3 in 7-position)
8.31 and 8.63 (H of the purine) B: 278 C: 1765 D: (a) = 0.40, (b) = 0.20 7ss- (2-Benzimidazolylthioacetamido) -7a-methoxy-3-carba - moyloxymethyl-3-cephem-4-carboxylic acid A: 4.95 (singlet, H in 6-position)
4.16 (singlet, SCH2CO-)
3.41 (singlet, OCH3 in 7-position) B: 281.287 C: 1780.1680 D:

   (a) = 0.48, (b) = 0.51 7ss- (2-Benzoxazolylthioacetamido) -7a-methoxy-3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid A: 5.05 (singlet, H in 6 position)
4.14 (singlet, SCH2CO-)
3.50 (singlet, OCH in 7-position) B: 283.276.245 C: 1780.1720 D: (a) = 0.61, (b) = 0.48 7P- (2-benzthiazolylthioacetamido) -7o-methoxy-3 -carbamoyl- oxymethyl-3-cephem-4-carboxylic acid A: (CD30D):
5.04 (singlet, H in 6-position)
3.45 (singlet, OCH3 in 7-position) B: 297.271 C: 1770 D: (a) = 0.58, (b) = 0.48 7ss- (s-triazolo- [4,3-a] - pyridyl-3-thioacetamido) -7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 4.94 (singlet, H in 6-position)
3.95 (singlet, SCH2CO-)
3.40 (singlet, OCH3 in 7-position) B: 269 C:

   1770.1690 D: (a) = 0.29, (b) = 0.39 7ss- (2-naphthylthioacetamido) -7a-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid A: 4.92 (Singlet, Hin 6 position)
3.72 (singlet, SCH2-CO-)
3.29 (singlet, OCH3 in 7-position)
7.3-7.9 (H of naphthalene) B: 248.270 (shoulder) C: 1765 D: (a) = 0.61, (b) = 0.60 7ss- (2-thiazolinylthioacetamido) -7a-methoxy- 3-carbamoyl-oxymethyl-3-cephem-4-carboxylic acid A: 5.08 (singlet, Hin 6-position)
3.92 (singlet, SCH2CO)
3.50 (singlet, OCH3 in 7-position) B: 258.239 C: 1770.1690 D: (a) = 0.49, (b) = 0.49 7ss-Cyclohexylthioacetamido-7a-methoxy-3-carbamoyloxymethyl -3-cephem-4-carboxylic acid A:

   5.08 (singlet, H in 6-position)
3.81 (singlet, SCH2CO-)
3.48 (singlet, OCH3 in 7-position)
1.0-2.0 (CH2 of cyclohexane) B: 266 D: (a) = 0.56, (b) = 0.50 7p- (n-Propylthioacetamido) -7a-methoxy-3-carbamoyloxymethyl-3- cephem-4-carboxylic acid A: (CD30D):
5.04 (singlet, H in 6-position)
3.45 (singlet, OCH3 at 7-position) B: 265 C: 1770 D: (a) = 0.55, (b) = 0.55 7ss- (n-pentylthioacetamido) -7a-methoxy-3-carbamoyloxy - methyl-3-cephem-4-carboxylic acid A: (CD30D):
5.04 (singlet, H in 6-position)
3.46 (singlet, OCH) in 7-position) B: 265 C: 1770 D:

   (a) = 0.60, (b) = 0.54
Example 4 7ss- (2-Butylthioacetamido) -7 α-methoxy-3 carbamoyloxymethyl-3-cephem-4-carboxylic acid
45 mg of sec-butanethiol are dissolved together with 0.5 ml of an aqueous 1N sodium hydroxide solution in aqueous 50% methanol, whereupon 0.5 ml of 7β-bromoacetamido-7ot-methoxy-3-carbamoyloxymethyl-3 -cephem-4-carboxylic acid is added. The mixture is then shaken for 2 hours and methanol is distilled off under reduced pressure. The aqueous layer is extracted three times with ethyl acetate and dried over sodium sulfate.

  The solvent is then distilled off, giving crude 7ss- (2-butylthioacetamido) -7ot-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid benzhydryl ester. This crude product is dissolved in 0.1 ml of anisole and 1.5 ml of trifluoroacetic acid are added to the solution. The mixture is then left to stand at room temperature for 6 minutes and then concentrated to dryness under reduced pressure. The solid product is dissolved in 20 ml of ethyl acetate and 20 ml of 0.2 molar phosphoric acid buffer solution (pH = 7.5) and the mixture is shaken and then left to stand, two phases being formed. The aqueous layer is washed once more with ethyl acetate and the pH of the aqueous layer is adjusted to 2.5.

  The aqueous layer is then extracted four times with 20 ml of ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure to give a caramel. This caramel is separated off and purified over a silica gel plate using a mixture of methanol and chloroform in a mixing ratio of 50:50, 115 mg of the desired product being obtained in the form of a powder.



  Nuclear magnetic resonance spectrum (CD30D), Ï ppm: 5.08 (singlet, H in 6-position) 3.58 (singlet, OCH3 in 7-position)
CHIOH ultraviolet absorption spectrum, max
267 (E = 9140) Infrared absorption spectrum (KBr), vcm-1:
1795,1720,1680 Thin layer chromatography (silica gel): (a) Developer solvent: Mixture of n-butanol, acetic acid and water in a ratio of 5: 4: 1
Rf value = 0.59 (b) Developing solvent:

  Mixture of chloroform and methanol in the ratio of 1: 1 Rf value = 0.60
Example 5 7 ss- (1,3,4-thiadiazol-2-yl-thioacetamido) -7 a-methoxy-3-acetoxymethyl-3-cephem-4-carboxylic acid
33 mg of 2-mercapto-1,3,4-thiadiazole are dissolved in 0.24 ml of ln sodium hydroxide solution and this solution is then mixed with a solution of 0.27 millimoles (100 mg) of 7ss-chloroacetamido-7a-methoxy- 3 -acetoxymethyl-3-cephem-4-carboxylic acid was added to 0.5N sodium hydrogen carbonate. The mixture is then shaken for 3 hours at room temperature and the pH is adjusted to 2.5 by adding 0.1N phosphoric acid. The mixture is then extracted three times with ethyl acetate and the ethyl acetate layer is dried over sodium sulfate.

  The solvent is distilled off from the dried ethyl acetate layer, whereby 113 mg of a caramel are obtained. This product is deposited on a silica gel plate using chloroform which contains 40% methanol as a solvent and extracted with methanol. The solvent is distilled off from the extract, 69 mg of the desired product being obtained.



  Nuclear magnetic resonance spectrum (CD3CN + D2O), Ï ppm: 9.23 (singlet, H of the thiadiazole) 5.00 (singlet, H in position 6) 4.73 (doublet, CH2 in position 3) 4.11 (singlet , SCH2-CO) 3.42 (singlet, OCH3 in 7-position) 1.98 (singlet, O-CO-CH3) ultraviolet absorption spectrum, Xmax (phosphoric acid buffer with pH 6.86) mol:
263 (± = 8789) Infrared Absorption Spectrum (KBr), acm¯ ':
1760 thin layer chromatography (silica gel): developing solvent:

  Mixture of methanol and chloroform in a ratio of 1: 1 Rt value = 0.45
Examples of compounds obtainable in the same manner in the above examples and their properties (hereinafter referred to as A, B, C, D, (a) and (b) in the above-mentioned manner) are given below: 3-acetoxymethyl-7ss- cyanomethylthioacetamido- ia-methoxy- 3 -cephem-4-carboxylic acid A: (CDtCN):
5.06 (singlet, H in 6-position) 4,765.06 (quartet, -CH20CO- in 3-position)
3.60 (singlet.

  NCCH2S or SCH2CO)
3.52 (singlet, OCH3 in 7-position)
3.42 (singlet, NCCH2S or SCH2CO) 3.32-3.55 (quartet, H in 2-position)
2.02 (singlet, OCOCH3) B: 247 (E = 8000)
267 (E = 8400) C: 1775 3-Acetoxymethyl-7ss-propargylthioacetamido-7a-methoxy-3-cephem-4-carboxylic acid A: (DMSO-dU):
5.05 (singlet, H in 6-position)
4.9-4.6 (quartet, -CH20CO- in 3-position)
3.36 (singlet, OCH3 in 7-position)
3.2-3.5 (multiplet, 2-position, H2, -CH and-SCH-)
3.05 (triplet, HCC)
1.98 (singlet, OCOCH3) B: 245 (E = 7800)
268 (E = 8200) C:

   1775
83 mg of the carboxylic acid thus obtained are added to 8 ml of water, the mixture is gradually mixed with 17 mg of sodium hydrogen carbonate and the homogeneous solution thus obtained is subjected to freeze-drying to obtain a sodium salt of the above-mentioned carboxylic acid in the form of an amorphous powder.



      3-Acetoxymethyl-7-azidomethylthioacetamido-7tt-methozy- 3-cephem-4-carboxylic acid A: (DMSO-d6):
5.14 (singlet, H in 6-position)
4.69-4.98 (quartet, -CH2-OCO- in 3-position)
4.51 (singlet, N3CH2S-)
3.40 (singlet, 7-position, OCH3, S-CH2-CO)
3.3-3.6 (quartet, H2 in 2-position)
2.00 (singlet.

  OCO-CH3) B: 247 (E = 7800)
269 (E = 8000) C: 1775 3 -acetoxymethyl-7 P- (2-imidazolyl) -thioacetamido-7a-methoxy-3-cephem-4-carboxylic acid A: 7.11 (singlet, H in 4- and 5- Position of the imidazole)
5.02 (singlet, H in 6-position)
4.78 (broad singlet, H2 in 3-position)
3.78 (singlet, -S-CH2CO-)
3.38 (singlet, OCH3 in 7-position)
2.02 (singlet, -O-COCH3) B: 265 C: 1760 D:

   (b) = 0.46
Example 6
7 8-2- (1,3,4-thiadiazolyl) -thioacetamido-7 ot-methoxy-
3- (1 -methyl-tetrazol-5-yl) -thiomethyl-3-cephem
4-carboxylic acid
33 mg of 2-mercapto-1,3,4-thiadiazole are dissolved in 0.24 ml of ln sodium hydroxide and this solution is mixed with a solution of 117 mg (0.27 millimoles) of 7ss-chloroacetamido-7a-methoxy-3- (1H - 1-methyl-1H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid in 0.5N sodium hydrogen carbonate added. The mixture obtained in this way is shaken for 3 hours at room temperature and the pH is adjusted to 2.5 by adding 0.1n phosphoric acid.

  The mixture is then extracted three times with ethyl acetate and the extract is dried over sodium sulfate and the solvent is distilled off, giving 125 mg of a caramel. This caramel is deposited over a silica gel plate using a mixture of methanol and chloroform in a mixing ratio of 50:50 and then extracted with methanol. The solvent is distilled off from the extract, 70 mg of the desired product being obtained in the form of an amorphous powder.



  Nuclear magnetic resonance spectrum (CD3CN + D2O), Ï ppm: 9.28 (singlet, H in the 5-position of the thiadiazole) Ultraviolet absorption spectrum, kmaY mF (phosphoric acid buffer with a pH of 6.86):
266 (E = 9270) Infrared Absorption Spectrum (KBr). v cm- '
1760 thin layer chromatography (silica gel): developing solvent:

  Mixture of chloroform and methanol in a ratio of 1: 1 Rt value = 0.38
Examples of compounds obtainable in the same manner as in the above example and their properties (hereinafter referred to as A, B, C, D, (a) and (b) as indicated above) are given below: 7ss- (2-imidazolyl) - thioacetamido-7a-methoxy-3- (1-methyl-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid A: 7.03 (singlet, H in 4- and 5-position of the imidazole)
4.95 (singlet, H in 6-position)
3.84 (singlet, CH3 in position 1 of the tetrazole ring)
3.36 (singlet, OCH3 at 7-position) B: 265 (E = 7200) C: 1760 D: (b) = 0.36 7ss-Cyanomethylthioacetamido-7a-methoxy-3- (1-methyl-1H-tetrazole -5-yl) -thiomethyl-3-cephem-4-carboxylic acid A:

   5.10 (singlet, Hin 6-position)
4.3-4.6 (quartet, CH2-S in 3-position)
3.98 (singlet, CH3 in position 1 of the tetrazole ring)
3.70 (singlet, -NCCH2S or -SCH2CO)
3.5-3.7 (quartet, H2 in 2-position)
3.60 (singlet, -NCCH2S or -SCH2CO)
3.50 (singlet, OCH3 in 7-position) B:

   274 (E = 9000) 7a-methoxy-7ss-propargylthioacetamido-3- (1 -methyl- 1 H-tetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid A: (DMSOd6)
5.05 (singlet, H in 6-position)
4.2-4.3 (quartet, CH2-S in 3-position)
3.90 (singlet, CH3 in the 1-position of the tetrazole ring) around 3.5 (multiplet, OCH3 in the 7-position,

   H2, -CH2-SCH1CO in 2-position)
3.20 (triplet, HC = -C-)
Example 7 7 t3- (1, 3,4-Thiadiazol-2-yl-thioacetamido) -7 a -methoxy-3- (1 -methyltetrazol-5 -yl) -thiomethyl-3-cephem
4-carboxylic acid
To a solution of 596 mg of 2- [7ss-bromoacetamido-7a-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-3-cephem-4 carbonyl] -s-triazolo- [4,3-a] pyrid-3-one in 30 ml of acetone is added to a solution of 86 mg of 2-mercapto-1,3,4-thiadiazole, whereupon 84 mg of sodium hydrogen carbonate in 8 ml of water and the solution obtained according to the above information are added for 1 hour stirs at room temperature.

  The solvent is then distilled off under reduced pressure and the residue is treated with 50 ml of ethyl acetate and then washed with water and dried over anhydrous magnesium sulfate. The solvent is distilled off, crude 2-r7 B- (1,3,4-thiadiazol-2-ylthioacetamido) - 7 a-methoxy3- (1 -methyltetrazol-5-yl) -thiomethyl-3 -cephem-4- carbonylj-s-triazolo- [3,4-ajpyrid-3-one obtained as a powder.



  Nuclear Magnetic Resonance Spectrum (CDCL3), o ppm: 3.43 (singlet, O-CH3 in 7-position) 3.90 (singlet, N-CH3 in 3-position of the tetrazole) 4.25 (singlet, -SCH2-CO in 7 position)
EMI9.1


<tb> 5.24 <SEP> (singlet, <SEP> 6-position, <SEP> H
<tb> <SEP> -N-N.H
<tb> 6.3-7.9 <SEP> (multiplet, <SEP> 4-position, <SEP> -C ¯NX <SEP> H
<tb> 9.08 <SEP> (7-position, <SEP> thiadiazole) <SEP> h
<tb> Infrared absorption spectrum (Nujol), ycm-l
1770.1700.1650 Ä THF ultraviolet absorption spectrum, X m nm: max
227,261,359 Thin Layer Chromatography (silica gel): (a) Developer solvent: containing 10% methanol
Chloroform Rf value = 0.56 (b) Developing solvent:

  Mixture of n-butanol, acetic acid and water in a ratio of 4: 1: 1 Rt value = 0.47
600 mg of copper acetate monohydrate are added to a solution of the compound obtained according to the above information in a mixture of 15 ml of tetrahydrofuran and 7.5 ml of water. The mixture obtained is then stirred for 5 hours at room temperature and then mixed with 50 ml of ethyl acetate and 7.5 ml of a 0.5 molar citric acid solution. The insolubles are filtered off, and the organic layer is washed and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain a caramel. This product is purified by thin layer chromatography using a mixture of n-butanol, acetic acid and water (mixing ratio 4: 1: 1) as the solvent system.

  In this way the desired product is obtained.



  Nuclear magnetic resonance spectrum (CD3CN + D2O), ö ppm: 3.46 (singlet, O-CH3 in 7-position) 3.94 (singlet, 3-position, tetrazole N-CH3) 5.02 singlet, 6-position, 9, 28 (singlet, 7-position,
EMI9.2
 Infrared absorption spectrum (KBr), nxm-1:
1760 ultraviolet absorption spectrum (in phosphoric acid buffer of pH 6.86), Xmax nm:
266 thin layer chromatography (silica gel): developing solvent:

  Mixture of chloroform and methanol in the ratio of 1: 1 Rf value = 0.38
Example 8 7,3- (2-Carboxyphenylthioacetamido) -7 ot-methoxy-3- (1-methyl-tetrazol-5-yl) -thiomethyl-3-cephem
4-carboxylic acid
To a solution of 596 mg of 2- [7ss-bromoacetamido-7a-methoxy-3- (1 -methyltetrazol-5-yl) -thiomethyl-3-cephem-4carbonyl] -s-triazolo- [4,3-a] - pyrid-3-one in 30 ml of acetone is added to a solution of 152 mg of thiosalicylic acid and 173 mg of sodium hydrogen carbonate in 8 ml of water. The resulting mixture is stirred for 30 minutes at room temperature. The solvent is then distilled off under reduced pressure and the residue thus obtained is treated with 50 ml of ethyl acetate and then washed with water and dried over anhydrous magnesium sulfate.

  The solvent is distilled off under reduced pressure, crude 2- [7 f3- (2-carboxyphenylthioacetamido) -7ot-methoxy-3 - (1 -methyltetrazol-5-yl) -thiomethyl-3-cephem-4-carbonyl] - s-triazolo- [3,4-a] -pyrid-3-one is obtained as a powdery residue.



   The product thus obtained is dissolved as such in a mixture of 15 ml of tetrahydrofuran and 7.5 ml of water, and 600 mg of copper acetate monohydrate are then added. The resulting mixture is stirred for 5 hours at room temperature and then 50 ml of ethyl acetate and 7.5 ml of a 0.5 molar citric acid solution are added. The insolubles are filtered off, and the organic layer is washed three times with an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. After the solvent has been distilled off under reduced pressure, the residue is purified by thin layer chromatography over silica gel, using a mixture of n-butanol, acetic acid and water (mixing ratio 4: 1: 1) as the solvent system. In this way you get to the desired product.



  Nuclear magnetic resonance spectrum (CD3CN + D20), Ï ppm: 7.2-7.6 (multiplet, proton in the phenyl part) 5.13 (singlet, 6-position,
EMI9.3
 4.07 (singlet, 3-position, tetrazole N-CH3) 3.47 (singlet, 7-position, -OCH3) Infrared absorption spectrum (KBr), v cm-1:
1775 ultraviolet absorption spectrum, imaz nm:
253 Thin-layer chromatography (silica gel): (a) Developer solvent: mixture of n-butanol, acetic acid and water in a ratio of 4: 1: 1 Rf value = 0.36 (b) Developer solvent:

  Mixture of chloroform,
Methanol and water in a ratio of 6: 4: 1 Rr value = 0.20
Example 9
7 ss- (2-Hydroxyäthylthioacetamido) -7-methoxy-3- (1 -methyltetrazol-5 -yl) -thiomethyl-3 -cephem -
4-carboxylic acid
In 20 ml of water which contains 84 mg of sodium hydrogen carbonate, 434 mg of 7ss-chloroacetamido-7c-methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-3-cephem-4-carboxylic acid are dissolved and this solution is then added with 156 mg of thioglycol were added. The mixture thus obtained is stirred at room temperature for 3 hours, the pH being maintained at a pH of 8.0 to 8.5 by adding an in sodium hydroxide solution.

  The pH is then adjusted to 2.0 to 2.5 by adding IL * n hydrochloric acid and the mixture is freeze-dried. The residue is then extracted with methanol and the solvent is distilled off. The residue obtained is purified by silica gel chromatography using a mixture of n-butanol, acetic acid and water (mixing ratio 4: 1: 1) as developer solvent, giving 360 mg of the desired product as a powder.



  Nuclear magnetic resonance spectrum (CDCN + D2O), ö ppm: 5.20 (singlet, 6-position, 4.15-4.25 (quartet, 3-position,
EMI10.1
 3.90 (singlet, 3-position, tetrazole
EMI10.2
   3.44 (sinlet, 7-position, - () CH3) 3.30 (singlet, 7-position,
EMI10.3
 3.68 and 2.74 (triplet, 7-position, HO-CH2CH2-S-) infrared absorption spectrum (KBr), ycm- ': 1740, 1675 ultraviolet absorption spectrum, kmax with (phosphoric acid buffer of pH 6.86):
270 (± = 9450)
The output connections can be made as follows:

  :
Example A
7 ß-Bromoacetamido-7 ot-methoxy-3-carbamoyloxymethyl-3-cephem-4-carboxylic acid
A beaker is charged with 808 mg of bromoacetyl bromide and 1.030 g of bis-trimethylsilyltrifluoroacetamide and the mixture obtained is left to stand for 20 minutes at room temperature. The mixture is then treated with 5 ml of methylene chloride, whereupon the resulting mixture is mixed with a solution of 879 mg of 7ss- (D-tert-butoxycarbonylamino-5'-carboxyvaleramido) -7-methoxy-3-carbamoyloxymethyl-3-cephem -4-dibenzhydryl carboxylate was added in 5 ml of methylene chloride. The beaker is then washed with 100 ml of methylene chloride and the washing liquid is combined with the mixture. The mixture is left to stand for 2 hours at room temperature with the exclusion of moisture.



  The reaction mixture is then treated with a mixture of ice and common salt with 1 g of sodium hydrogen carbonate while cooling, whereupon the reaction mixture is mixed with 20 ml of a 5% aqueous sodium bicarbonate solution and shaken sufficiently for 30 minutes. The methylene chloride layer is combined with the washing liquids obtained when the aqueous layer is washed with 10 ml of methylene chloride, and the mixture is washed twice with 20 ml of a 20% aqueous sodium chloride solution.

  The organic layer is dried over sodium sulfate and the solvent is distilled off under reduced pressure, whereby 1.194 g of crude 7P- [D-5'-tert-butoxycarbonylamino-5'-carboxyvaleryl) -bromoacetylaminoj-3-carba-moyloxymethyl-7a -methoxy-3-cephem-4-carboxylic acid benzhydryl ester is obtained in the form of a yellow caramel.



   The yellow caramel obtained in this way is dissolved in 1 ml of anisole and 2 ml of trifluoroacetic acid and the solution obtained is left to stand for 5 minutes at room temperature and the solvent is distilled under reduced pressure. The yellow, viscous paste obtained is dissolved in 20 ml of ethyl acetate and 20 ml of a 0.2 molar phosphoric acid buffer at a pH of 7.5 and the solution is transferred to a separatory funnel and shaken thoroughly. After the phases have separated, the pH of the aqueous layer is adjusted to 2.5 by adding n-hydrochloric acid and the aqueous layer is extracted five times with 20 ml of ethyl acetate and dried over sodium sulfate. The solvent is then removed under reduced pressure to give 300 mg of the desired product in the form of a caramel.



  Nuclear magnetic resonance spectrum (CDsCN + D2O), Ï ppm: 5.12 (singlet, H in 6-position) 3.95 (singlet, BrCH2CO) 3.53 (singlet, OCH3 in 7-position) Ultraviolet absorption spectrum, k CH3CH, with: Max
263 Infrared Absorption Spectrum (KBr), v cm-l:
1780, 1700 thin layer chromatography (silica gel): (a) developer solvent: mixture of n-butanol,
Acetic acid and water in a ratio of 5: 4: 1 Rt value = 0.53 (b) Developer solvent:

  Mixture of methanol and
Chloroform in a ratio of 1: 1 Rt value = 0.44
Example B.
7 B-chloroacetamido-7 cr-methoxy 3 -carbamoyloxymethyl-3-cephem-4-carboxylic acid
In a manner similar to that in Example A, the reaction is carried out in such a way that chloroacetyl chloride is used instead of bromoacetyl bromide, the after-treatments being carried out in the same way as in Example A. In this way the desired product is also obtained in the form of a caramel.



  Nuclear Magnetic Resonance Spectrum (CD3CN + D2O), 6 ppm: 5.1 (singlet, H in 6-position) 3.48 (singlet, OCH3 in 7-position) 4.11 (singlet, SICH20) Ultraviolet absorption spectrum, Xmax, with (phosphoric acid buffer of pH 6.86):
264 Infrared Absorption Spectrum (KBr), v cm-l:
1780.1700 thin layer chromatography (silica gel): developer solvent: mixture of methanol and chloroform in a ratio of 1: 1, Rf value = 0.35
Example C
3-acetoxymethyl-7 P-chloroacetamido-7 a-methoxy 3-cephem-4-carboxylic acid
438.5 mg of 3-acetoxymethyl-7ss-chloroacetamido-7a-methoxy-3-cephem-4-carboxylic acid benzhydryl ester are dissolved in 0.4 ml of anisole, whereupon 0.8 ml of trifluoroacetic acid is added to this solution.

  The mixture is then shaken for 5 minutes at room temperature. The reaction mixture is then quickly concentrated to dryness and the residue is washed with n-hexane and dissolved in 5 ml of a 0.25 molar phosphoric acid buffer solution (pH = 7.5) and the solution is made neutral by adding a 5% aqueous sodium hydrogen carbonate solution and washed with ethyl acetate washed. The pH of the aqueous layer is adjusted to 2.0 by adding 60% strength phosphoric acid, and the oily substance which has precipitated is extracted with ethyl acetate. Then the extract is washed with water and dried over anhydrous sodium sulfate. The solvent is then distilled off, 276 mg of the desired product being obtained in the form of an amorphous powder.



  Nuclear Magnetic Resonance Spectrum (CD3CN + D2O), 6 ppm: 5.08 (singlet, H in 6-position) 4.08 (singlet, C1CH2CO) 3.55 (singlet, OCH3 in 7-position) Thin layer chromatography (silica gel): Developer solvent: Mixture of chloroform and methanol in a ratio of 9: 1 Rr value = 0.41
Example D 7ss-Chloroacetamido-7 a-methoxy-3- (1-methyltetrazole-
2-yl) thiomethyl-3-cephem-4-carboxylic acid
27.6 g of the disodium salt of 7ss- (D-5-amino-5-carboxy-valeramido) 3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid are dissolved in 1090 ml of a 5% aqueous dipotassium phosphate solution and the 715 ml of acetone were added to the solution.

  8.1 g of 4-dimethylaminopyridine are then added to the solution and the pH is adjusted to 9.5 by adding an aqueous 2.5N sodium hydroxide solution. Then 34.5 ml of tert-butoxycarbonylazide are added, whereupon the mixture is shaken for 4 hours at room temperature while maintaining a pH of 9.0 to 9.5. The reaction mixture is then left to stand overnight at 4OC and then 1000 ml of ethyl acetate are added and the mixture is shaken sufficiently. The aqueous layer is collected and an additional 1000 ml amount of ethyl acetate is added. The pH of the aqueous layer is then adjusted to 2.5 by adding concentrated hydrochloric acid while maintaining a temperature of 0 to 20 ° C.

  The organic layer is separated and the aqueous layer is further extracted twice with 1200 ml of ethyl acetate. The organic layers are combined and washed with a saturated aqueous sodium chloride solution until the pH of the washing liquid has reached 4-5. Then it is dried with anhydrous sodium sulfate. After the solvent has been distilled off from the solvent, 22.1 g of 7 ss- (D-5-tert-butoxycarbonylamino-5-carboxyvaieramido) 3-carbamoyloxymethyl-7a-methoxy-3-cephem-4-carboxylic acid are obtained . The compound thus obtained is added to a phosphoric acid buffer solution with a pH of 7.0, which contains 10 g of 1-methyl-5-mercaptotetrazole, and the mixture is shaken at 95 ° C. for 30 minutes.

  The pH is then adjusted to 2.5 while cooling with ice and adding hydrochloric acid. The reaction mixture is then extracted with ethyl acetate and the extract is washed with a saturated aqueous sodium chloride solution until the pH of the washing liquids has reached approximately 4 to approximately 5.



  The extract is then dried over anhydrous sodium sulfate. The solution thus obtained is then mixed with an ether solution which contains 20 g of diphenyldiazomethane and the mixture is shaken for 2 hours.



  It is then washed successively with a 20% strength sodium chloride solution and a 5% strength aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is distilled off from the solution and the residue is dissolved in chloroform, adsorbed on a column loaded with silica gel and eluted with a mixture of chloroform and methanol (mixing ratio 1 mol% per 1 mol%). After the solvent has been distilled off from the eluent, the 7 p- (D-5-tert-butoxycarbonylamino-5-carboxyvaleramido) -7a methoxy-3- (1-methyltetrazol-5-yl) -thiomethyl-3 is obtained -cephem-4-carboxylic acid dibenzhydryl ester.

  5 millimoles of the compound thus obtained are then dissolved in 50 ml of chloroform and the solution is added to a mixture of 2.26 g of chloroacetyl chloride and 2.26 g of bis-trimethylsilyltrifluoroacetamide, this solution having previously been left to stand for 30 minutes at room temperature. The mixture obtained is kept at 40 ° C. for 100 hours. The reaction mixture is poured into a 5% strength aqueous sodium hydrogen carbonate solution and the mixture is shaken for 30 minutes. The organic layer is then collected and washed with a 20% sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent is distilled off from the washed solution and the residue is dissolved in 5 ml of anisole and 10 ml of trifluoroacetic acid.

  The solution is shaken for 5 minutes at room temperature and concentrated to dryness under reduced pressure. The residue is dissolved in a 1 molar phosphoric acid buffer solution (pH = 7.5) and extracted with ethyl acetate, whereupon the aqueous layer is collected and the pH is adjusted to 2.5 by adding 1N hydrochloric acid. Then it is extracted with ethyl acetate. The extract is dried over anhydrous sodium sulfate and the solvent is distilled off from the solution, 7ss-
Chloracetamido-7-a-methoxy-3- (1-methyltetrazol-2-yl) -thio-methyl-3-cephem-4-carboxylic acid is obtained in the form of an amorphous powder.

 

Claims (1)

PATENT CLAIMS 1. Process for the preparation of compounds of the formula: EMI1.1 where Rl is a group not involved in the reaction, R3 is an optionally substituted hydrocarbon group or a heterocyclic group which has at least one ring heteroatom selected from nitrogen, oxygen and sulfur atoms in the monocyclic or bicyclic ring, and A is a straight-chain or branched alkylene group, characterized in that a compound of the formula: EMI1.2 in which Rl and A have the above meanings and X is a halogen atom and R2 is the carboxyl group or an esterified carboxyl group, with a compound of the formula: : R3-SH (III) if R3 has the above meaning or is reacted with a metal salt thereof and, in those cases in which R2 represents an esterified carboxyl group, converts the compound thus obtained into the free acid. 2. The method according to claim 1, characterized in that Rl is the hydrogen atom, a lower alkyl radical, an acyloxymethyl radical, a carbamoyloxymethyl radical or an aromatic heterocyclic thiomethyl radical of the monocyclic type, which has at least one nitrogen, oxygen and / or sulfur atom in the ring, R3 a straight-chain or branched hydrocarbon group which has 1 to 6 carbon atoms and can carry as substituents hydroxyl, azido, cyano, nitro, acylamino, alkoxy, phenyl, cyclohexadienyl, cyclohexyl or alkoxycarbonyl group, or a phenyl group - or naphthyl group, which can have at least one halogen atom or an alkyl, alkoxy, cyano, nitro or acylamino group as a substituent, or a saturated or unsaturated, 5- or 6-membered, monocyclic hydrocarbon group, or 2 imidazolyl, 1,2,4-triazol-3-yl, 1,3, 4-thiadiazol-2-yl, 2-pyridyl, 2-pyrimidyl, purin-6-yl, 2-benzothiazolyl, 2-benzoxazolyl, represents s-triazolo [4,3-a] pyridin-3-yl or 2-thiazolyl and A represents a straight-chain or branched, lower alkylene group having 1 to 6 carbon atoms. 3. The method according to claim 1, characterized in that Rl 5- (1-methyltetrazolyl) -thiomethyl, carbamoyloxymethyl or acetoxymethyl, R3 cyanomethyl, 1-cyanoethyl, 2 hydroxyethyl, propargyl, azidomethyl or 3-isoxazolyl and A is methylene. 4. The method according to claim 1, characterized in that the metal salt is an alkali salt, for. b. the sodium, potassium or lithium salt, or an alkaline earth metal salt is used. 5. The method according to claim 1, characterized in that R2 is the carboxyl group and the reaction is carried out in a mixture of water and a water-miscible organic solvent, e.g. B. methanol or ethanol takes place. 6. The method according to claim 1, characterized in that the compound of formula III is in free form and the reaction in the presence of an alkali, for. B. sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate or potassium hydrogen carbonate. The present invention relates to a new process for the preparation of 7o: -Methoxy-3-cephem-4-carboxylic acids, which have a substituent in the 3-position and a substituted thioalkanoylamino radical in the 7,8-position and correspond to the following formula: EMI1.3 wherein Rl represents a group not participating in the reaction, R3 represents an optionally substituted hydrocarbon radical or a heterocyclic group which has at least one ring heteroatom selected from nitrogen, oxygen and sulfur atom in the monocyclic or bicyclic ring, and A represents a straight-chain or branched alkylene group . As examples of the radical Rl in the above formula I, i. H. for the group not participating in the reaction, the hydrogen atom, lower alkyl radicals, e.g. B. the methyl group, acyloxymethyl radicals, e.g. B. the acetoxymethyl group or carbamoyloxymethyl group, and aromatic, heterocyclic thiomethyl radicals of the monocyclic type which have at least one nitrogen, oxygen and / or sulfur atom in the ring, e.g. B. the 5- (1-methyltetrazolyl) -thiomethyl- and 2- (1,3,4-thiadiazolyl) -thiomethyl group mentioned. The hydrocarbon radicals R3 can be, for example, straight-chain or branched hydrocarbon radicals having 1 to 6 carbon atoms, e.g. B. methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, vinyl, allyl, propenyl, butenyl, pentenyl, hexenyl, ethynyl or propargyl, name, such hydrocarbon radicals substituents such. B. hydroxyl, azido, cyano or nitro groups, acylamino groups, e.g. B. acetylamino and tert-butoxycarbonylamino groups, alkoxy groups, e.g. B. methoxy and ethoxy groups, phenyl, cyclohexyldienyl and cyclohexyl groups and alkoxycarbonyl groups, e.g. B. methoxycarbonyl and ethoxycarbonyl groups, can carry. As monocyclic or bicyclic aryl radicals R3, there may be mentioned, for example, optionally substituted benzene and naphthalene rings, these rings being, for example, halogen atoms such as chlorine or bromine, alkyl radicals as substituents. z. B. methyl and ethyl radicals, alkoxy radicals, e.g. B. methoxy and ethoxy, cyano groups, nitro groups and acylamino, z. B. Acet ** WARNING ** End of CLMS field could overlap beginning of DESC **.