HU202537B - Process for producing cefemcarboxylic acid derivatives - Google Patents

Abstract

The present invention relates to a novel process for the preparation of compounds of formula (Ib) wherein R 2 is an alkali metal cation and R 3 is -S-Y wherein Y is a tetrazolyl group which may be substituted with C 1-4 alkyl or sulfomethyl. The process consists in removing formyl from formyl-containing compounds as a hydroxyl protecting group in an acidic medium using a lower alcohol. Ί * H ~ C-ORg Scope of the description: 3 pages, Figure 1 (lb) HU 202 537 B -1-

Description

The present invention relates to a novel process for the preparation of compounds of formula Ib, wherein

R2 is an alkali metal cation, R3 is -SY, wherein Y is tetrazolyl substituted with a C1-C4 alkyl group or a sulfomethyl group. , < ¹

Compounds of formula Ib are cephalosporin-type antibiotics (e.g., cefamandol, cefamandol naphtha, 7- (D-2-formyloxy-2-phenyl) -acetamido-3 - [(1-methyl-1H-tetrazole-5-) il) -thiomethyl] -3-ce-fem-4-carboxylic acid monosodium salt cefnocid) They are known classes of compounds, which, together with their protected forms, are described in numerous patents and publications.

In the compounds of formula (Ib), R3 is -S-Y. Preferably, Y is a heterocyclic group as described in several publications. A preferred heterocyclic group is tetrazolyl, which may be substituted with C 1-4 alkyl or sulfomethyl. Particularly preferred heterocyclic groups are, for example, 1-methyl-1H-tetrazol-5-yl and 1- (sulfomethyl) -1H-tetrazol-5-yl.

It is known that cephalosporin-type compounds may be in the form of free acids or salts, such as alkali or alkaline earth metal salts, in particular alkali metal salts such as sodium salts.

The acylamino side chain attached to the 7-position of the cephem ring system of the compounds of formula (Ib) contains an asymmetric carbon atom, so it can be in D or L form. In the case of cafalosporin derivatives, it has often been observed that only one of these two epimeric forms exerts the desired antimicrobial activity.

For the compounds described below, derivatives of D - (-) mandelic acid are preferred

The formyl group is generally removed by hydrolysis in aqueous or slightly alkaline solution, for example, as disclosed in German Patent No. 2,018,600. As a result of the elements, some by-products are formed, thereby darkening the reaction mixture; in addition, the reaction time is long and generally requires working at temperatures above room temperature. Cephalosporin derivatives are known to be unstable under alkaline pH conditions: Compounds are much less stable than weakly alkaline media (at pH 8-9), for example by hydrolysis of the formyl protecting group.

The present invention provides a method for the removal of a formyl protecting group. This method involves the decomposition of the formic acid ester with an aliphatic alcohol of formula (V) wherein R 1 is a C 1-4 straight or branched alkyl group. This reaction is conveniently carried out in a slightly acidic medium under mild conditions as illustrated in Scheme 1.

This deprotection method of the present invention permits the rapid, careful and essentially quantitative yield of the compounds of formula Ib. It is due to the acidic medium and the mild conditions that almost no by-products or colorants are formed during the removal of the formyl group, which is a significant advantage over the alkaline hydrolysis disclosed in German Patent 2,018,600.

The deprotection may be accomplished, for example, by dissolving a formyl-protected compound of formula (Ia) in an alcohol of formula (V), wherein R is as defined above, and adding the resulting solution to an acid of formula (Ib). This reaction is generally carried out in an excess of the alcohol (V) as a solvent. As the alcohol of formula (V), it is preferable to use straight or branched aliphatic alcohols having from 1 to 4 carbon atoms: methanol, ethanol and isopropanol are preferred, with methanol being most preferred. Strong organic or inorganic acids may be used to catalyze the ester exchange reaction: concentrated hydrochloric acid is preferred. This reaction is preferably carried out using an acidic ion exchange resin such as Dowex 50 WX 4 or 8. The temperature of the ester exchange reaction is not critical, preferably at a temperature of -10 ° C to 50 ° C, preferably at room temperature.

As noted above, the compounds of formula Ib are known antibiotics or protecting groups thereof. The use of these antibiotics as antimicrobial agents is particularly warranted, as shown by the in vitro serial dilution assays, for example, in the concentration range of 0.0150 µg / ml, and in in vivo mice, e.g., 0.100 mg / kg body weight. and bacterial strains such as Staphylococcra aurera, Streptococcra pyogenes, Streptococcra faecalis, E. pneumoniae, Serr atia marcescens, Salmonella Heidelberg, Salmonella typhimurium, Salmonella enteritidis and Neisseria gonorrhoeae.

These antibiotics are thus useful as antibacterial agents. For this purpose, the daily dose will depend on the compound employed and the route of administration and the nature of the treatment. Satisfactory results can be obtained with a daily dose of about 1 to about 6 g, preferably administered 2 to 4 times daily in divided doses of 0.25 to 3 g or in a sustained release form.

The following examples illustrate the process of the invention. Temperatures are given in degrees Celsius.

Example 1

7- [D- (2-Hydroxy-2-phenyl) -acetamido] -3 - [(1-methyl-1H-tetazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid preparation of the sodium salt (cefamandol sodium salt)

To a solution of 9.8 g of cefamandole naphtha in 60 ml of methanol is added 1 ml of concentrated hydrochloric acid with stirring at room temperature and the mixture is stirred for 40-50 minutes.

-2H20 202537Β minutes while the deformylation is complete The cefamandole thus obtained is isolated in a known manner, for example, as disclosed in German Patent No. 2018,600. Accordingly, the reaction mixture was treated with 3 g of sodium acetate in 30 ml of methanol and the thus formed sodium salt of cefamandole was precipitated by the addition of 250 ml of isopropanol to give the title product as a yellow powder (8.8 g, 91%); its spectral data is the same as in the literature.

Example 2

7- [D- (2-Hydroxy-2-phenyl) -acetamido] -3 - [(1-methyl-1H-tetazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid sodium salt (cefamandol sodium salt)

To a solution of 4.9 g of O-formyl cedamandole in 30 ml of methanol was added Dewox 50 WX4 H ⁺ strongly acidic ion exchange resin, stirred at 20 ° C for one hour, and then checked by TLC to confirm that the deformation was complete. The ion exchanger was filtered off, washed thoroughly with a small amount of methanol and the combined filtrate was concentrated on a rotary evaporator to a volume of 20 ml. To the residue was added 11 ml of 1 M isopropanolic ethylhexanoic acid to precipitate the cefamandole sodium salt. Dilute with 50 ml isopropanol to increase the yield to give the title compound in 93% yield.

Example 3

7- [D- (2-Hydroxy-2-phenyl) -acetamido] -3 - [(1-sulfomethyl-1H-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid disodium salt (cephicicide) )

11.8 g of 7- [D- (2-Hydroxy-2-phenyl) -acetamido] -3 - [(1-sulfomethyl-1H-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid A solution of the monosodium salt in methanol (100 ml) was treated with concentrated hydrochloric acid (2 ml) and the solution was kept at 30 ° C for 30 minutes. During this time, the deformation reaction was complete. At this time, the pH of the reaction mixture was adjusted to 2.5 with 5N sodium hydroxide solution, and the reaction mixture was concentrated in vacuo to about 50 mL, filtered and added dropwise to 700 mL of isopropanol. The solid precipitate was filtered, washed with isopropanol and dried under vacuum. Yield: 10.9 g (93%) containing about 4% water.

The monosodium salt used as starting material is prepared from the disodium salt as follows.

Disodium salt (prepared according to Example 2 of Hungarian Patent No. 196213) was suspended in 100 ml of dry acetone and treated with 20 g of Dowex 50 WX8 resin washed with dry acetone. After stirring for one hour at room temperature, the The drug content of the solution was determined by high performance liquid chromatography and treated with an equivalent amount of a 1 M solution of ethyl hexanoic acid in isopropanol. The monosodium salt was precipitated and the yield was increased by adding 100 ml of isopropanol.

Example 4

Preparation of 7- [D- (2-Hydroxy-2-phenyl) -acetamido] -3 - [(1-sulfomethyl-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid sodium salt

A mixture of sodium salt of 7-amino-3 - [(1-sulfomethyl-tetrazol-5-yl) -thiomethyl] -3-cephem-4-carboxylic acid (19.3 g) in dry dimethylformamide (50 ml) was treated with triethyl (6.7 ml). The clear solution thus obtained was added to a solution of 16.5 g of O-formyl-D - (-) - thio-mandelic acid S- (benzothiazol-2-yl) ester in 100 ml of dichloromethane and the mixture was stirred for 3 hours. After stirring for 1 hour at 0 ° C and for 5 hours at 20 ° C, the dichloromethane is removed on a rotary evaporator and the viscous residue is stirred with 300 ml of isopropanol. The O-formylcephenicide precipitates in the form of its sodium triethylamine salt. To remove the formyl group, this intermediate is dissolved in 200 mL of methanol and treated with 30 g of a strongly acidic ion exchanger in Dowex 50 WX8 H ^+. The ion exchanger is stirred for 1 hour at 20 ° C and the resin is filtered off under vacuum. Concentrate to 50 ml with 60 ml of 1M A solution of sodium hexane in ethyl isopropanol was added and the mixture was diluted with isopropanol (300 mL) to give the title product as a white crystalline powder (23 g, 90.5%).

Claims (1)

A process for the preparation of compounds of formula Ib wherein: R2 is an alkali metal cation and R3 is -Y Y is C 1 -C 4 alkyl or sulfomethyl-substituted tetrazolyl, characterized in that a compound of formula (Ia) wherein R 2 and R 3 are as defined in the present invention is an aliphatic alcohol of formula (V) wherein R 1 is C 4 straight or branched alkyl groups are reacted under acidic conditions