FI72521B - FOERFARANDE FOER FRAMSTAELLNING AV CEFALOSPORINDERIVAT. - Google Patents

Description

72521 1 Process for the preparation of cephalosporin derivatives Förfarande för framställning av cephalosporin derivatives 5

The invention relates to a process for the preparation of a 7,3-acylamino-3-heterocyclylthiomethyl-7α-methoxy-3-cephem-4-carboxylic acid derivative of the formula (I) in a female: 52 x "" "tO m 15 (r N'Y ^ CH2R3

COOH

20 (wherein represents a thienylacetyl, cyanomethylthioacetyl or haloacetyl group; 2 R represents a methoxy group; 3 R represents a substituted 1H-tetrazol-5-ylthio group; and X represents a sulfur atom to prepare pharmaceutically acceptable salts thereof).

The present invention relates to a process for the preparation of β-lactam antibiotic derivatives, in particular cephalosporin and cefamycin derivatives, many of which are valuable antibiotics.

The cephalosporin and cefamycin derivatives, which are considered to be the most interesting antibiotics, are still most commonly prepared by isolating naturally produced cephalosporin or cefamycin (i.e., a compound analogous to cephalosporins but containing a methoxy group instead of a hydrogen atom in the 7c <position). compounds then chemically to obtain the desired cephalosporin or cefamycin antibiotic. The most common chemical modifications applied to these starting materials are substitution or exchange acylation of the 3-position group of the starting material, in which the acyl substituent of the amino group at the 7/3 position of the starting material is replaced by another acyl group. The present invention relates to this exchange acylation reaction.

The acyl group attached to the 7/3 amino group in the cephalosporin and cefamycin starting materials is generally a complex group containing amino and carboxy groups that must be protected before the starting material can be chemically modified in any way. These compounds also have a carboxy group in the 4-position and this also needs protection. For example, the main starting material for the preparation of cefamycin antibiotics is cefamycin C, which is 7/5 - (D-5-amino-5-carboxivaleramido) -3-carbamoyloxymethyl-7-methoxy-3-cephem-4-carboxylic acid. To convert this compound to some particularly useful antibiotics, it is necessary to convert the carbamoyloxymethyl group at the 3-position to a heterocyclylthiomethyl or amidinothiomethyl group and replace the 5-amino-5-carboxyvaleryl group at the 7/6 position with various other acyl groups. In general, such a process is performed in the following steps: (i) protecting the amino group on the 7/3 side chain; (ii) converting the carbamoyloxy group at the 3-position in the side chain to a selected thiomethyl group; (iii) esterifying carboxy groups at the 4-position and 7/3 side chain; (iv) subjecting the product to an exchange acylation reaction to replace the thus protected 5-amino-5-carboxyvaleryl group in the 7/3 side chain with a desired acyl group; and li 3 72521 1 (v) deprotecting the carboxy group at the 4-position.

The present invention relates primarily to steps (iii) to (v) and to step (i) with respect to the selection of a protecting group.

5

When carrying out any chemical process on a commercial scale, yields are a particularly decisive factor in assessing the economic viability of the process, and this is especially true when the starting material itself is a natural product that can only be prepared in relatively low yields. In particular, the acylation reaction, which is step (iv) in the procedure outlined above, tends to give low yields and can be a serious barrier to the commercial exploitation of compounds known to have significant therapeutic value.

15

We have found that the yields depend very much on the nature of the amino protecting group in the 7 / e position of the substituent, the substituent in the 3-position and the protecting group selected for the carboxy group in the 4-position, and thus the correct combination is chosen from the various groups available. very high yields can be achieved. We have now found that the combination of: an electron-withdrawing group protecting the amino group in the 7/3 side chain, a heterocyclylthiomethyl or amidinothiomethyl group (especially hetercyclylthiomethyl) as a 3-substituent and an optionally substituted phenacyl group as a carboxy-protecting group position allows the exchange acylation reaction to take place in very high yields.

However, one component of this otherwise desirable combination is in itself a notable source of difficulty, namely the phenacyl or substituted phenacyl group used to protect the carboxy groups. Difficulties occur when the phenacyl or substituted phenacyl group is removed in the deprotection step (v) in the above reaction sequence. One advantage of phenacyl groups in the protection of carboxy groups is that the phenacyl esters obtained are particularly stable under acidic conditions. However, this means that rather harsh methods must be used to remove them.

72521 1 One known method for removing phenacyl protecting groups is to use zinc with acetic acid or formic acid. As described in J.Org.Chem. (1973) No. 17, pp. 2994-2996, when using this reaction for a compound having an amidinothiomethyl or hetero-5-cyclylthiomethyl group in the 3-position, a reaction occurs simultaneously to give the corresponding 3-exomethylene compound in high yields, together with a small amount of 3- with a methyl compound. This causes a significant reduction in the yield of the desired compound.

Another method for removing phenacyl protecting groups is to use the sodium or potassium salt of thiophenol. However, if the compound to be treated in this way has a heterocyclylthiomethyl group in the 3-position, this removal reaction results in a change in the position of the double bond of the cefem backbone, resulting in a very high proportion of 2-cephem isomers in the final product. In the case of this bag, the yields of the desired compound are very significantly reduced.

We have now surprisingly found that the phenacyl protecting group can be selectively removed without the above-mentioned disadvantages by reacting the starting material in the presence of an inert solvent with an acid selected from zinc and inorganic acids, monoesters of dibasic inorganic acids and sulfonic acids.

Accordingly, the process of the present invention for the preparation of a compound of formula (I) is characterized in that the process comprises the following steps: (a) reacting a compound of formula (II): , CH (CH 2) 3 CO-NH - 1 - f "> COOCH 1 -C 0 ° N y ^ CH 2 R 3n 35 'Ύ ^ \\ cooc ^ -c ^ 0" G, 5 72521 2 3 1 X is as defined above, 4 R represents a hydrogen atom or a halogen atom, and 5 represents a benzenesulfonylamino group with a compound of formula (111): R * -Y (III) 10 (where R is as defined above and Y represents a halogen atom) in a halogenated aliphatic hydrocarbon solvent of formula (IV) to the corresponding compound: 15 o2. i (Hl r'-NH-iΊ 20 0> -NY ^ CH2R3 C00CH2-CC ^

XX

25 12 3 4 (wherein R, R, R, R and X are as defined above); (b) reacting this compound of formula (IV) with zinc and an acid selected from the group consisting of monoesters of dibasic inorganic acids and sulfonic acids in an inert solvent to give a compound of formula (I); and (c) if necessary, forming a salt of this compound of formula (I) to obtain a pharmaceutically acceptable salt thereof.

This particular combination of reagents and protecting groups surprisingly allows the process according to the invention to be carried out in very good yields of the final product, the yields being exceptionally good when the process is carried out under the preferred conditions described in more detail below.

5

The invention is particularly valuable in the preparation of cefamycin derivatives, i.e. compounds of formula (I) wherein R is a methoxy group and X is sulfur. Accordingly, the invention is described below, particularly in connection with the preparation of such derivatives. It should be understood, however, that it can be equally applied, with the same advantages, to the preparation of cephalosporin derivatives (R represents a hydrogen atom and X represents a sulfur atom) as well as to β-lactam antibiotics analogous to cefamycins and cephalosporins, where X represents an oxygen atom or a methylene group, manufacturing. The compounds of formula (II) to be used as starting materials are selected accordingly.

In the acyl halide R 1 -Y used in step (a) of the process of this invention, the nature of the group represented by R 1 is determined solely by the nature of the R 1 group to be attached to the final product, the compound of formula (I) or a salt thereof. As such, the group referred to as R 1 can be selected from a very wide range of groups known to impart excellent antibiotic potency or other valuable properties to the final product. Examples of groups which R 1 may represent in the acyl halide R 1 -Y and thus in the compound of formula (I) include phenylacetyl, phenoxyacetyl, thienylacetyl, monochloroacetyl, dichloroacetyl, monobromoacetyl, dibromoacetyl and cyanomethylthio thienylacetyl, monochloroacetyl, dichloroacetyl, monobromoacetyl, dibromoacetyl and cyanomethylthioacetyl groups are particularly preferred. It is to be understood, however, that these are presented only as non-limiting examples of the many possible acyl groups that will be readily apparent to those skilled in the art. When the acyl group represented by the compound of formula (I) contains a second reactive group (e.g. a hydroxy, amino or carboxy group), this second reactive group is preferably protected before the reaction of the acyl halide R 1 -Y of formula (II). and in this case deprotection may be necessary at some stage in the reaction sequence, as is well known in the art.

The halogen atom represented by II 7 72521 1 Y in the acyl halide R * -Y is preferably a chlorine or bromine atom.

The second starting material in the process according to the invention is 2

5 kainen compound. Preferred atoms or groups represented by R and X

mean in this compound, the nature has been discussed above and is determined by the nature of the compound of formula (I) to be prepared. Likewise, the preferred groups represented by R in the compound of formula (II) are determined according to what is desired in the corresponding position in the compound of formula (I).

3

When R represents a heterocyclylthio group, many different heterocyclic groups are possible, both substituted and unsubstituted.

Preferred heterocyclic groups which may form part of this heterocyclylthio group are 1H-tetrazol-5-yl, 1,3,4-thiadiazol-2-yl and 1,2,3-triazol-5-yl groups. These heterocyclic groups may be substituted or unsubstituted and, when substituted, may have one or more, preferably only one, substituents. Substituents are preferably selected from alkyl groups (preferably methyl), halogen atoms and dialkylaminoalkyl groups (preferably dimethylaminoethyl). Of the substituted and unsubstituted heterocyclylthio groups that can be used, we prefer 1-methyl-1H-tetrazol-5-yl, 1- (β-dimethylaminoethyl) -1H-tetrazol-5-yl, 5-methyl-1,3,4 -thiadiazol-2-yl and 1-methyl-1H-1,2,3-25 triazol-5-yl groups.

4

When R in the compounds of formulas (II) and (IV) represents a halogen atom, it is preferably a chlorine or bromine atom, i.e. the protecting group of the carboxy group at the 4-position of the cephem backbone and the carboxy group at the 5-position of the valeramido side chain is preferably a phenacyl group, a chlorophenacyl group or a bromophenacyl group.

in the compound of formula (II) means an amino group having an electron-withdrawing group as a substituent. Suitable electron withdrawing groups include: substituted benzoyl groups having a nitro, chloro, cyano or (C 1 -C 3 alkoxy) carbonyl (e.g. methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl) substituent, s 72521 1 preferably in the ortho or para position; arylsulfonyl groups, preferably benzenesulfonyl; or phthaloyl groups. Of these, the most preferred electron-withdrawing group is a benzenesulfonyl group.

The first step of the process according to the invention comprises an exchange acylation reaction between a compound of formula (III) and an acyl halide R 1 -Y in a halogenated aliphatic hydrocarbon solvent. Suitable halogenated aliphatic hydrocarbon solvents include methylene chloride, chloroform, trichlorethylene, 1,2-dichloroethane, 1,1,1-trichloro-ethane and 1,1,2-trichloroethane, most preferably 1,2-dichloroethane.

The amount of acyl halide R 1 -Y is preferably equimolar or greater relative to the compound of formula (II.), For example the molar ratio of acyl halide: compound of formula (II) is preferably 1: 1 to 10: 1 and more preferably 5: 1 to 10. : 1. The temperature at which the reaction is effected may vary over a wide range, but is preferably from 50 ° C to 100 ° C. The progress of the reaction can be monitored by thin layer chromatography. At a temperature in the preferred range, the time required for the reaction usually ranges from 10 minutes to 10 hours.

20

The exchange acylation reaction proceeds more uniformly if it is carried out in the presence of an acid scavenger, for example propylene oxide, butylene oxide, styrene oxide or phenyl glycidyl ether.

The compound of formula (IV) obtained in the first step of the reaction can be recovered and purified by distilling off the solvent from the reaction mixture, adding diisopropyl ether to the residue, and isolating the powder thus produced. Alternatively, the product may be recovered and purified by chromatographic methods or by any other method known in the art. Intermediate isolation and purification of the product may not be necessary before proceeding to the second step of the process of the invention.

In a second step of the process, the phenacyl group or haloienyl group protecting the A-carboxy group in the cephem backbone is removed by reacting a compound of formula (IV) with zinc and an acid. According to the present invention, the acid is an inorganic acid, a dibasic

II

9,72521 1 monoester or sulfonic acid of an organic acid. Suitable inorganic acids include sulfuric acid, hydrochloric acid, nitric acid and fluorosulfuric acid. Preferred monoesters of dibasic inorganic acids are monoalkyl esters of sulfuric acid, preferably monoethyl sulfuric acid.

Preferred sulfonic acids are alkanesulfonic acids and haloalkanesulfonic acids, preferably methanesulfonic acid, ethanesulfonic acid or trifluoromethanesulfonic acid. The most preferred acids are methanesulfonic acid and monoethyl sulfuric acid.

The reaction in the second step of the process of the invention is carried out in an inert solvent. The nature of the solvent to be employed is not critical, provided that it is inert in the sense that it will not adversely affect the reaction. In view of the use of acids in the process of the invention, preferred solvents are aqueous organic solvents, for example aqueous methanol, acetone, acetonitrile or tetrahydrofuran, of which aqueous acetone is most preferred for the solubility and economy of the starting material. Zinc is preferably used in an amount of 1 equivalent or more per equivalent of ester of formula (IV), more preferably 1-2 equivalents of zinc per equivalent of compound of formula (IV). The temperature required for the reaction varies over a very wide range, although the temperature is preferably below room temperature in order to minimize side reactions. The preferred temperature is in the range of -50 ° C to + 5 ° C, more preferably -20 ° C to -30 ° C. The time required for the reaction will vary depending on the reaction temperature and reagent, but will generally be completed within 10 minutes to 7 hours.

After complete removal of the phenacyl or halofenacyl protecting group, the resulting compound of formula (I) can be recovered from the reaction mixture by conventional means. For example, a suitable recovery procedure comprises: diluting the reaction mixture with water; removing insoluble material by filtration; extracting the filtrate as a suitable organic solvent (e.g. ethyl acetate) and removing the solvent by distillation from the extract. The crude product thus obtained can then be further isolated (by conversion to a crystalline salt) by reacting it with a suitable base such as dicyclohexylamine, dimethylbenzylamine, picoline or lutidine. Alternatively, the crude product may be purified by chromatographic methods or by any other method well known to those skilled in the art.

The resulting compound of formula (I) may, if desired, be converted into a pharmaceutically acceptable salt by conventional means; the nature of the salt is not critical provided that the potency of the free base is not unduly impaired. Suitable salts include: metal salts such as lithium, sodium, potassium, calcium or magnesium; ammonium salt and salts with organic amines such as cyclohexylammonium, or tri-ethylammonium salts. Sodium and potassium salts are most preferred.

The compound of formula (II) used as a starting material in the process of the invention can be obtained by protecting the amino group in the 15 7/3 side chain of cefamycin C or cephalosporin or another β-lactam analogue with a suitable electron-withdrawing group (as exemplified above). ), converting the carbamoyloxymethyl group in the 3-position to a heterocyclylthiomethyl or amidinothiomethyl group and then acylating the carboxy groups in the 7/3 side chain and in the 4-position with a phenacyl group or a halophenacyl group. In a preferred embodiment of the method 20 of the invention, the substituents at the 3- and 7-positions of cefamycin C (which can be obtained by culturing various microorganisms) can be converted to the desired groups in a substantially continuous manner to prepare a cefamycin derivative, thus preparing compounds with stronger antibacterial activity.

25

The invention is further illustrated by the following examples.

Example 1 7β-Chloroacetamido-7H-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (a) 7 / S - (D-5-Benzenesulfonylamino-5-carboxivaleramido) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid di (dicyclohexylamine) salt To 72521 To 70 g of ββ- (D-5-benzenesulfonylamino-5-carboxivaleramido) -3-carbamoyloxymethyl-7α-methoxy-3-cephem-4-carboxylic acid (purity 85%) was added 175 g of 1-methyl-5- mercapto-1H-tetrazole, 12 ml of water and 3 ml of acetone and the solution thus obtained were then stirred at a temperature of 65 ° C to 75 ° C for 20 minutes while the water and acetone were gradually removed by distillation under reduced pressure. To the reaction mixture were then added 200 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous layer of this mixture was adjusted to 1.5 by adding hydrochloric acid. To the mixture was added 50 g of sodium chloride, and the mixture was stirred thoroughly. The ethyl acetate layer was separated and the aqueous layer was extracted twice with 100 ml of ethyl acetate each time. The extracts were combined with the separated ethyl acetate layer, and then the whole mixture was evaporated to dryness under reduced pressure. 1.6 liters of diisopropyl ether was added to the obtained residue, and the mixture was stirred well until the initially viscous substance formed a powder. This powder was collected by filtration, washed with diisopropyl ether and dissolved in 500 ml of ethanol. To this solution was added 43.2 g of dicyclohexylamine, and the resulting mixture was allowed to stand in an ice bath for 1 hour to precipitate white crystals. These crystals were collected by filtration, washed with ethanol and dried to give 76.4 g of crude 7β- (D-5-benzenesulfonylamino-5-carboxivaleramido) -7β-methoxy-3- (1-methyl-1H-tetrazole). -5-yl) thiomethyl-3-cephem-4-carboxylic acid di (dicyclohexylamine) salt. The mother liquor was concentrated by evaporation under reduced pressure, and a small amount of ethanol was added to the resulting residue. This mixture was allowed to stand for about 6 days to precipitate crystals which were collected by filtration and dried to give a further 8.2 g of crystals of the crude di (dicyclohexylamine) salt (total yield 84.6 g, 83.0% of theory).

30 g of the crystals thus obtained were dissolved in 5 ml of methanol, and the concentrated solution was concentrated by evaporation under reduced pressure to give a syrupy substance. To this syrupy substance was added 5 ml of ethanol, and the mixture was allowed to stand to precipitate a pure product, melting at 143-145 ° C (with decomposition).

35

Elemental analysis: calculated C H N OS. 2 (C H N) 23 27 7 9 3 12 24 72521 1 C 55.94%; H 7.45%; N 12.39%; S 9.33% found C 56.21%; H 7.33%; N 12.56%; S 9.58%.

5 (b) 7β- (D-Benzenesulfonylamino-5-carboxivaleramido) -7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-sphera-4-carboxylic acid diphenyl ester 10 In solution, containing 4.4 g of phenacyl bromide in 50 ml of dimethylformamide, 10 g of 7 '- (D-5-benzenesulfonylamino-5-carboxivaleramido) -7c-methoxy-3- (1-methyl-1H-tetrazole) were gradually added. 5-yl) thiomethyl-3-cephem-4-carboxylic acid di (dicyclohexylamine) salt (purity 96%, determined by high performance liquid chromatography) at 0-5 ° C for 15 minutes. The mixture was then stirred at ambient temperature for 30 minutes. At the end of this time, 200 ml of ethyl acetate was added and the insoluble matter (mainly dicyclohexylamine hydrobromide) was collected by filtration and washed with a small amount of ethyl acetate. The washings were combined with the original ethyl acetate solution and all were washed twice, each time with 50 ml of water. The solution was then concentrated by evaporation under reduced pressure to give 9.2 g of the title compound as a foamy solid.

NMR Spectrum (CDCl 3) δ ppm: 1.5-2.95 (7H, multiplet); 3.43 (3H, singlet); 3.58 (2H, broad singlet); 3.78 (3H, singlet); 4.38 (2H, singlet); 5.00 (1H, singlet); 5.07 (2H, singlet); 5.45 (2H, broad singlet); Δ 6.0-6.15 (1H, doublet); 7.22-8.02 (15H, multiplet).

li 13 72521 1 (c) Phenyl acyl-7-chloroacetamido-7-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 3-cephem-4-carboxylate

To the whole of the product obtained in step (b) were added 200 ml of 1,2-dichloroethane and 10 ml of monochloroacetyl chloride, and then the mixture was stirred at reflux for 4 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and 100 ml of diisopropyl ether was added to the residue. The mixture was stirred sufficiently to precipitate a powder which was then collected by filtration to give 11.04 g of crude phenazyl-7β-chloroacetamido-7'-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl -3-cephem-4-carboxylate (purity 44.7%, corrected yield for impurities 93% of theory). This product was purified by column chromatography through silica gel, eluting with a 3: 1 (v / v) mixture of benzene and ethyl acetate, to give pure product.

Nuclear Magnetic Resonance Spectrum (CDCl 3) δ PPm: 3.57 (3H, singlet); 3.68 (2H, singlet); 3.92 (3H, singlet); 4.13 (2H, singlet); 4.50 (2H, broad singlet); 5.08 (1H, singlet); Δ 5.55 (2H, singlet); 7.25-8.07 (5H, multiplet).

7,3-chloroacetamido-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thio-methyl-3-cephem-4-carboxylic acid 30 1.0 g of phenacyl-7β-chloroacetamido-7 ° C- Methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate (purity 90.1%, determined by high performance liquid chromatography) was dissolved in a mixture of 20 ml of acetone and 1 ml of water. The mixture was then cooled to -30 ° C, after which 5.0 ml of monoethyl sulfuric acid and 1.0 g of zinc powder were added.

The mixture was then stirred at -30 ° C to -25 ° C for 2.5 hours. At the end of this time, the reaction mixture was filtered. The insoluble solid 14 72521 L was washed with 50 mL of ethyl acetate and the washings were combined with the filtrate. The mixture was then shaken and the ethyl acetate layer was separated. The aqueous layer was extracted twice with 30 ml of ethyl acetate each time, and the extracts were combined with a separated ethyl acetate layer. The combined ethyl acetate solution was washed with saturated aqueous sodium chloride solution, and then the solvent was removed by distillation under reduced pressure to give 0.857 g of the title compound, 70.3% pure. The corrected yield for impurities was 85% of theory.

NMR Spectrum (deuteroacetone) δ ppm: 3.5 (3H, singlet); 3.67 (2H, singlet); 3.98 (3H, singlet); 4.42 (2H, broad singlet); 5.08 (1H, singlet).

Example 2 7β-Cyanomethylthioacetamido-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (a) The procedure described in Example 1, step (b) the corresponding diphenyl ester was synthesized from 10 g of 7 / 3- (D-5-benzene-25-sulfonylamino-5-carboxivaleramido) -7o-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3 -cephem-4-carboxylic acid di (dicyclohexylamino) salt. As in Example 1, step (c), the product obtained was then refluxed with 8.5 g of cyanomethylthioacetyl chloride (instead of monochloroacetyl chloride) for 6 hours with stirring, and then the reaction mixture was treated as described in Example 1, step (c) to give 12.1 g. Crude phenacyl 7,3-cyanomethylthioacetamido-7 * * -methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 3-cephem-4-carbosylate (purity 38.0%, corrected for impurities yield 78.0% of theory). This product was purified by column chromatography through 33 silica gels, eluting with a 2: 1 mixture of chloroform and ethyl acetate (v / v).

Il 152525 1 NMR spectrum (deuteroacetone) δ ppm: 3.53 (3H, singlet); 3.60 (2H, singlet); Δ 3.73 (4H, multiplet); 3.96 (3H, singlet); 4.50 (2H, broad singlet); 5.15 (1H, singlet); 5.63 (2H, singlet); Δ 7.46-8.2 (5H, multiplet); 8.58 (1H, broad singlet).

(b) 1.0 g of phenacyl 7/9-cyanomethylthioacetamido-7-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl 3-cephem-4-carboxylate (purity 88 , 7%, determined by high performance liquid chromatography) was dissolved in 20 ml of acetone and 2 ml of water, then treated and the product was purified as described in Example 1, step (d) to give 0.847 g of crude 7 / cyanomethylthioacetamido-7c <-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid (purity 73.7% as determined by high performance liquid chromatography, impurity corrected yield 88.0%).

Nuclear Magnetic Resonance Spectrum (deuteroacetone) δ PPm: δ 3.50 (3H, singlet); 3.60 (2H, singlet); 3.5-3.7 (2H, quartet); 3.70 (2H, singlet); 3.90 (3H, singlet); 4.3-4.6 (2H, quartet); 5.10 (1H, singlet).

Example 3 35 7-Methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-7β- (2-thienylacetamido) -3-cephem-4-carboxylic acid

Following the procedure described in steps (a) to (c) of Example 1, i.e. 72521 1 but using 2-thienylacetyl chloride instead of monochloroacetyl chloride in step (c), phenacyl-7c * -methoxy-3- (1-methyl-1H-tetrazole) was prepared. 5-yl) thiomethyl 7β- (2-thienylacetamido-3-cephem-4-carboxylate).

1.0 g of this compound was dissolved in 20 ml of acetone and 2 ml of water as a solution, which was then cooled to -30 ° C. To the solution were added 5.0 ml of methanesulfonic acid and 1.0 g of zinc powder, and the resulting mixture was then stirred at -30 ° C for 2.5 hours. The reaction mixture 10 was then worked up and the product was isolated as described in step (d) of Example 1 to give 0.85 g of the title compound.

Nuclear Magnetic Resonance Spectrum (deuteroacetone) δ ppm: 3.42 (3H, singlet); 3.53 and 3.76 (2H, AB doublet, J = 18 Hz); 3.92 (2H, singlet); 3.96 (3H, singlet); 4.28 and 4.50 (2H, AB doublet, J = 14 Hz); Δ 5.04 (1H, singlet); 6.8-7.1 (2H, multiplet); 7.2-7.4 (1H, multiplet); 8.27 (1H, broad singlet).

Example 4 7β-Dichloroacetamido-7α-methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid 30β-Bromophenyl-7,3-dichloroacetamido 7 <* - Methoxy-3- (1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylate was prepared following essentially the same procedure as described in Example 1, steps (a) to (c), except that in step (b) p-bromophenyl bromide (instead of phenacyl bromide) was used and in step (c) dd-35 chloroacetyl chloride (instead of monochloroacetyl chloride) was used. 1.0 g of this compound was dissolved in 20 ml of acetone and 2 ml of water, and the solution thus obtained was cooled to -30 ° C. To this solution were added 17,72521 L of 5.0 ml of monoethyl sulfuric acid and 1.0 g of zinc powder, and the mixture was stirred at -30 ° C for 2 hours. The reaction mixture was then worked up and the product was isolated as described in Example 1, step (d) to give 0.8 g of the title compound.

Δ NMR spectrum (deuteroacetone) δ ppm: 3.48 (3H, singlet); 3.80 (2H, broad singlet); Δ 3.98 (3H, singlet); 4.40 (2H, broad singlet); 5.05 (1H, singlet); 6.46 (1H, singlet).

15 20 25 30 35

Claims (14)

Claims 18,72521 A process for the preparation of a 7β-acylamino-3-heterocyclylthiomethyl-7α-methoxy-3-cephem-4-carboxylic acid derivative of the formula (I) 5 i §2 X CH 2 R 3 111 COOH 15 (wherein R 1 represents a thienylacetyl, cyanomethylthioacetyl or haloacetyl group; 2 R represents a methoxy group; 3 20. represents a substituted 1H-tetrazol-5-ylthio group; and X represents a sulfur atom and for the preparation of its pharmaceutically acceptable salts, known therefrom; that the process comprises the steps of: (a) reacting a compound of formula (II): o5, un 30 i 8 * x Ti ^ Oi, li 19 72521 1 2 3 * (wherein R, R and X are as defined above; R represents a hydrogen atom or a halogen atom; and R "* represents a benzenesulfonylamino group with a compound of formula (IIi): R * -Y (III) 10 (where R 1 is as defined above and Y represents a halogen atom) in a halogenated aliphatic hydrocarbon solvent to give a compound of formula (IV) : 15 R1-NH- | -fS m 20 0 C00CH2-CC2 .X 25 25 12 3 4 (wherein R, R, R, R and X are as defined above) (b) reacting this compound of formula (IV) zinc and with an acid selected from the group consisting of monoesters of dibasic inorganic acids and sulfonic acids in an inert solvent to give a compound of formula (I); and (c) if necessary, forming a salt of this compound of formula (I) to obtain a pharmaceutically acceptable salt thereof. 20 72521 Process according to Claim 1, characterized in that it represents a thienylacetyl, monochloroacetyl, dichloroacetyl or cyanomethylthioacetyl group. Process according to Claim I or 2, characterized in that Y represents a chlorine or bromine atom. Process according to one of Claims 1 to 3, characterized in that R represents a 1-methyl-1H-tetrazol-5-ylthio group. 10 Process according to one of the preceding claims, characterized in that R represents a hydrogen, chlorine or bromine atom. Process according to one of the preceding claims, characterized in that step (a) is carried out in the presence of a solvent which is 1,2-dichloroethane. Process according to one of the preceding claims, characterized in that the molar ratio of the compound of the formula (III) to the compound of the formula (II) in step (a) is from 1: 1 to 10: 1. Process according to Claim 7, characterized in that the molar ratio of the compound of the formula (III) to the compound of the formula (11) in step (a) is from 5: 1 to 10: 1. Process according to one of the preceding claims, characterized in that step (a) is carried out at a temperature of 50 ° C to 100 ° C. 30 Process according to one of the preceding claims, characterized in that the acid used in step (b) is methanesulfonic acid or monoethyl sulfuric acid. Process according to one of the preceding claims, characterized in that step (b) is provided as the solvent 1 in water-containing acetone. 21 72521 Process according to one of the preceding claims, characterized in that in step (b) zinc is used in an amount of 1-2 equivalents per equivalent of the compound of formula (IV). Process according to one of the preceding claims, characterized in that step (b) is carried out at a temperature of -20 ° C to -30 ° C. 10 15 20 25 30 35 22 72521