FI82472B - Process for preparing cephalosporin - Google Patents

Description

1 82472

Process for the preparation of cephalosporins The application is divided by division 854577.

The invention relates to a new process for the preparation of a compound of formula Ib / 'VcH-CO-NH -, - f5'! (Ib) ^ OH J - CHZ «3

0 T

coor2 wherein R2 represents hydrogen or a carboxyl group protecting group conventional in cephalosporin chemistry and R3 represents a group S-Y, wherein Y is a lower alkyl or sulfomethyl substituted tetrazolyl group or an alkali metal salt thereof.

The compounds of formula Ib represent a known class of cephalosporin antibiotics (e.g. Cefamandole, Cefaman-20 dole nafat and Cefonicid) which are extensively described in patents and publications, as well as their protected forms.

As is known in the art of cephalosporins, the compounds may be in the form of free acids or salts, for example alkali and alkaline earth metal salts, especially alkali metal salts such as sodium salts. In addition, the compounds may also be in the form of esters, for example in the form of pivaloyloxymethyl ester (R 2 = pivaloyloxymethyl). Carboxylic acid protecting groups which R 2 may denote are generally known and include, for example, acetoxymethyl, 1-acetoxyethyl, 1-ethoxycarbonyloxyethyl, 4-indanoyl or preferably hexanoylmethyl, phthalidyl, carbethoxymethoxymethyl, 3-carbethoxy-1-acetonyl or trialkyl. , especially trimethyl-35 silyl.

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The process according to the invention for the preparation of the compounds of the formula Ib is characterized in that the protecting group is removed from the compound of the formula Ia W? -ch2r3 (Ia) CH ° C00R-2 H * 10 by treatment with an aliphatic alcohol of formula V H-R6 (V) 15 under acidic conditions, wherein R6 represents lower, straight or side chain alkyl.

Removal of the formyl group usually takes place by saponification in an aqueous, weakly alkaline solution, e.g. as described in DE-A-20 2 018 600. This causes partial formation of by-products and results in dark coloration of the reaction solutions. In addition, long reaction times and temperatures above room temperature are usually required. Cephalosporin derivatives are known to be unstable in the alkaline region. Even in a weakly alkaline medium (pH 8-9), such as that used to saponify formyl-protected compounds of formula Ib, they are significantly less stable than in the weakly hap-Pamella region.

The invention therefore relates to a process for the deprotection of formyl derivatives in which the ester radical of the formic acid ester is exchanged under mild conditions with an aliphatic alcohol. The process is conveniently carried out in an acidic medium under mild conditions as shown in the following reaction scheme: li 3 82472 / T = r \ -CH-CO-NH-1-

VjJ — NyJ-ch2r3 »ho-r6

c Ia CHO COOR, t V

5 H 0 rVcH-CO-NH ^ -f ^ 1 + H- £ -OR6 V-t OH 0ΗΛ

Ib COOR2 This deprotection according to the invention makes it possible to prepare rapidly, carefully and practically quantitatively the compounds of the formula Ib from the compounds of the formula Ia, i.e. from the compounds of the formula I described in FI application 854577, in which Rx denotes a formyl group. Due to the mild conditions in the acidic medium, almost no by-product or pigment formation occurs, indicating a considerable advantage over the alkaline saponification described in DE patent 2,018,600.

Deprotection can be accomplished, for example, by dissolving a formyl-protected compound of formula Ia in an alcohol of formula V, treating with an acid, and preparing a compound of formula Ib under these conditions. The reaction is usually carried out in an excess of an alcohol of formula V which is used as a reaction partner as well as a solvent. Suitable alcohols of formula V are aliphatic alcohols having 1 to 4 carbon atoms, in which case the aliphatic chain may be branched. The preferred alcohols are methanol, ethanol and isopropanol, with methanol being preferred. Strong organic or inorganic acids can be used as acids in the catalysis of the ester exchange reaction. The primary acid is concentrated hydrochloric acid. The reaction is carried out primarily using an acidic ion exchanger, for example DOWEX 50 WX 4 or 8. In the ester exchange reaction, temperature is not critical and a suitable temperature is between -10 and + 50 ° C, preferably room temperature.

The compounds of the formula Ib and I are, as already mentioned, generally known antibiotics or protected forms thereof. In particular, these antibiotics have been recommended for use as antibacterial agents, as demonstrated by in vitro studies in mice using a serial dilution assay at concentrations of, for example, 0.0150 pg / ml and in vivo experiments at doses ranging from 0.1 to 100 mg per kg body weight. against strains such as Staphylococcus aureus. Streptococcus pyogenes, Streptococcus faecalis, E. coli, Proteus vulgaris, Proteus mirabilis, Proteus morganii. Shigella dysenteria, Shigella sonnei, Shigella flexneri, Alcaligenes faecalis, Klebsiella aerogenes, Klebsiella pneunomiae, Serrata mar-20 cescens, Salmonella Heidelberg, Salmonella typhimurium. Against Salmonella enteritidis and Nesseria gonorrhoae.

Antibiotics are therefore useful as antibacterial agents. The dose to be administered for this purpose depends on the compound used and the mode of administration, as well as the nature of the treatment. Satisfactory results are obtained with a daily dose of about 1 to 6 g to be administered, given as appropriate divided doses of 0.25 to 3 g 2 to 4 times during the day or in delayed form.

The following examples illustrate the invention; in the examples, all temperatures are expressed in degrees Celsius.

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5,82472

Example 1 7- (D-2-Hydroxy-2-phenyl) acetamido-3- [1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, sodium salt (Cefamandole-Na ) 8.4 g of D - (-) - mandelic acid in 100 ml of dry dichloromethane are treated with 12 g of N, O-bis-trimethylsilylacetamide and stirred for 30 minutes at room temperature. The resulting O-trimethylsilyl-D - (-) - mandelic acid solution is cooled to -15 ° C. 17.4 g of tri-10 phenylphosphine, 22 g of bis-benzthiazol-2-yl disulphide and 5 g of N-methylmorpholine are added and the mixture is stirred for 1 hour at -15 to 10 ° C. 14.8 g of 7-amino-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid are suspended in 100 ml of dry dichloromethane. 10.2 g of Ν, Ο-bis-trimethylsilylacetamide are added and the mixture is stirred at room temperature until a clear solution is formed. This solution is cooled to -15 ° C and added to the active ester solution. Stirring is continued for 2 hours at -10 ° C and then overnight at 0 ° C. Most of the mixture 20 is evaporated on a rotary evaporator and the oily residue is dissolved in 200 ml of preheated isopropanol at 40 ° C, 50 ml of a 1 molar isopropanol solution of sodium methylhexanoate are added and cooled to 20 ° C, after which the final product begins to precipitate. After 1 hour, the mixture is cooled to 0 ° C and stirred for 2 hours to increase the yield. The product is filtered off, washed with isopropanol and dried at 40 ° C under vacuum. 19.4 g of a white crystalline powder are obtained (89%). According to the TLC method of USP XX, the product is identical to the USP-Standard.

Example 2 7- (D-2-Formyloxy-2-phenyl) acetamido-3 - [(1-sulfomethyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, disodium salt 9.6 g of bis-benzthiazol-2-yl disulphide and 7.6 g of 35 triphenylphosphine are dissolved in 50 ml of dichloromethane cooled to -15 ° C. 5.2 grams of O-foryl-D - (-) - mandelic acid are added and stirred for 2 hours at -15 ° C. 10.5 grams of the sodium salt of 7-amino-3- [1-sulfomethyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid in 25 ml of dry dimethylformamide are treated With 3.25 ml of triethylamine to give a clear solution which is added to the above solution, taking care that the internal temperature does not rise above 0 ° C. Stir for 12 hours at 0 ° C for 10 hours and then for 4 hours at room temperature. The dichloromethane is removed on a rotary evaporator and the viscous residue is dissolved in 250 ml of isopropanol previously treated with 40 ml of a 1 molar solution of sodium ethylhexanoate. Stirring is continued for 2 hours at 150 ° C, then filtered and washed with isopropanol. 13.5 g (93.3%) of the title compound are obtained in the form of a white powder.

NMR: 830 (s) formyl proton; 7.35 (m) phenyl protonite; 6.05 (s) benzyl proton; 5.5 (d) H7; 5.0 (s) CH 2 -SO 3; 4.85 (d) H6; 4.30 (d) CH 2 (exo); 3.45 (d) CH 2 (ring).

Example 3 7- (D-2-Hydroxy-2-phenyl) acetamido-3 - [(1-sulfomethyltetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, disodium salt (Cefonicid) 8 g of 7- (D-2-formyloxy-2-phenyl) acetamido-3 - [(1-sulfomethyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid monosodium salt are dissolved in 100 ml. to methanol and treated with 2 mL of concentrated HCl. The solution is kept at 30 ° C for 30 minutes, during which time quantitative deformylation occurs. The pH of the reaction mixture is then adjusted to 2.5 5-norm. NaOH and then the reaction mixture is concentrated in vacuo to about 50 ml, filtered and then added dropwise with stirring to 700 ml of isopropanol. The precipitated solids are filtered off, washed with isopropanol and

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7 82472 is dried in vacuo. This gives 10.9 g of the title product with a water content of about 4% (yield 93%).

The monosodium salt used as a starting material can be obtained from the disodium salt as follows.

5 10 g of the disodium salt (prepared, for example, according to Example 2) are suspended in 100 ml of dry acetone and treated with 20 g of D0WEX 50 WX8, previously washed with dry acetone. Stir for one hour at room temperature, after which the ion exchanger is filtered off. After determination of the initial concentration by HPLC, the clear solution is treated with one equivalent of a single molar isopropanol solution of sodium ethyl hexanoate to precipitate the monosodium salt. An additional 100 ml of isopropanol is added to increase the yield.

Example 4 7- (D-2-Formyloxy-2-phenyl) acetamido-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl-3-cephem-4-carboxylic acid, monosodium salt (Cefamandole-20 naphtha) ) 9 g of O-formyl-D - (-) - mandelic acid are dissolved in 100% dry dichloromethane and cooled to -15 ° C. 15.7 g of triphenylphosphine, 20 g of bis-benzthiazol-2-yl disulphide and 5 g of triethylamine are added and the mixture is stirred for 1 hour at -15 ° C. 14.8 g of 7-amino-3- [1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid are suspended in 100 ml of dry dichloromethane. 10.2 g of N, O-bis-trimethylsilylacetamide are added and the mixture is stirred at room temperature until a clear solution is formed. This solution is cooled to 15 ° C and then added to a solution of mandelic acid active ester. Stir for 1 hour at -10 ° C and then for 12 hours at 0 ° C. The mixture is evaporated to approximately dryness on a rotary evaporator at 20 ° C and the oily residue is dissolved in 200 ml of 35 isopropanol. Add 50 ml of a 8 molar solution of sodium ethylhexanoate 8 82472, whereupon the precipitation of the final product begins to approach. After stirring for 2 hours at 0 ° C, the product is isolated by filtration, washed with cold isopropanol and dried. 21.6 g of 5 (93.3%) of the title compound are obtained in the form of a white crystalline powder. IR, UV and NMR correspond to the values in the literature. Example 5 7- (D-2-Hydroxy-2-phenyl) acetamido-3 - [(1-sulfomethyltetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, sodium salt 19.3 g The sodium salt of 7-amino-3 - [(1-sulfomethyltetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid in 50 ml of dry dimethylformamide is treated with 6.7 ml of triethylamine to give a clear 15 a solution which is then added to a solution of 16.5 g of O-formyl-D- (-) - thiomannic acid S- (benzthiazol-2-yl) ester in 100 ml of dichloromethane. Stir at 0 ° C for 3 hours and 5 hours at 20 ° C. The dichloromethane is removed on a rotary evaporator and the viscous residue is taken up in 300 ml of isopropanol, whereupon the O-formyl cefonicide precipitates as the Na-triethylamine salt. To remove the formyl radical, the intermediate is dissolved in 200 ml of methanol and treated with 30 grams of D0WEX 50 WX8, a strongly acidic ion exchanger in the H + form. The mixture is stirred for 1 hour at 20 [deg.] C., after which the ion exchanger is filtered off. The reaction mixture is concentrated in vacuo to about 50 ml and treated with 60 ml of a 1 molar solution of sodium ethylhexanoate in isopropanol and then with 300 ml of isopropanol, whereupon the final product crystallizes out. 23 g (90.5%) of a white crystalline powder are obtained.

Example 6 7- (D-2-Hydroxy-2-phenyl) acetamido-3- [1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, sodium salt (Cefamandole Na) 9.8 g of cefamandolenafat are dissolved in 60 ml of

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9 82472 tanol. This solution is treated at room temperature with thorough mixing with 1 ml of conc. HCI. The solution is then allowed to stand for 40-50 minutes, at which point deformylation occurs quantitatively.

Isolation of the Cefamandole thus formed can be carried out in a known manner, e.g. as disclosed in DE patent 2,018,600. To this end, the reaction mixture is treated with a solution of 3 g of Na acetate in 30 ml of methanol and Cefamandole Na The salt is isolated by precipitation with 250 ml of isopropanol. 8.8 g of the title compound are obtained in the form of a white powder (yield 91%), the spectroscopic values of which correspond to those of the literature. Example 7 7- (D-2-Hydroxy-2-phenyl) acetamido-3 - [(1-methyl-1H-tetrazol-5-yl) thiomethyl] -3-cephem-4-carboxylic acid, sodium salt (Cefamandole -Na) 4.9 g of O-formyl-cefamandole are dissolved in 30 ml of methanol. Add 5 g of D0WEX 50 WX 4 (strongly acidic ion exchanger in H * form) and stir for 20 hours at 20 ° C, after which, by TLC check, the deformylation is complete. The ion exchanger is filtered off and washed thoroughly with a small amount of methanol, and the combined filtrates are concentrated to 20 ml on a rotary evaporator. Addition of 11 ml of a 1 molar solution of sodium hexanoate in isopropanol precipitates the sodium salt of Cefamandole. An additional 50 ml of isopropanol (93% yield) is added to increase the yield.

Claims (6)

A process for the preparation of a compound of formula Ib 5 wherein R 2 represents hydrogen or a conventional carboxyl protecting group in cefafosporin chemistry and R 3 represents a group SY, wherein Y is tetrazolyl substituted by lower alkyl or sulfomethyl or an alkali metal salt thereof, characterized in that the protecting group 15 is removed from the compound of formula Ia (-CH-CO-NH-rS-O-ch-2). (Ia) CHO « C00R2 H by treatment with an aliphatic alcohol of formula V HO-R5 (V) 25 under acidic conditions, wherein R6 represents lower, straight or side chain alkyl. 11 82472 For the preparation of a compound with the formula Ib C VcH-CO-NH -, - f S ^ J- \ iyj-CH2R3 (Ib) coor2 10 color R2 is a compound or an inert cephalosporin having a carboxylic acid group and R3 is used group SY, color Y is a tetrazolyl substituent with an alkyl group or a sulfomethyl, or an alkali metal salt of the same name, a solid group having the same value as a compound of formula Ia (ia) 0 J - CH R 20. X 2 The H + genome is used in the presence of aliphatic aikoho1 in formula V 25 H0-R6 (V) i Sura förhällanden, varvid R6 betecknar en lägre alkyl med rak eller förgrenad kedja.