CS242013B1 - Sodium salts of 7-(5-aryl-2-furyl)-2-tetrazolylacetamido)cephaelosporane acids and method of their preparation - Google Patents

Description

The present invention relates to the sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cephalosporanoic acids of the general formula I

wherein R is methyl, methoxy, chloro, bromo, or nitro in the o-, m-, or p-position of the phenyl core, and methods for their preparation.

In the author's certificate no. 232 344 discloses a process for the preparation of 5- [5- (substituted phenyl) -2-furyl] -2-tetrazolylacetic acids which were used as starting materials in the preparation of the subject 7- [5- (5-aryl-2-fury) 1) Cephalosporanoic acids -2-tetrazolylacetamido and salts thereof.

These novel hitherto unwritten sodium salts of 7-heteroaryl acetamidocephalosporanoic acids exhibit antibacterial activity, as shown in Table 1.

Table 1

In vitro and antibacterial activities of the sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] -cephalosporanoic acids of formula I, wherein R is as defined below

microorganism 3-CH3 4-CHSO MIC ((Ug / ml) 2-CH 3 O) 4-C1 Bacillus subtilis Bs 5/58 4 1 1 2 Bacillus cereus Bcm 4/58 1 0.5 1 1 Bacillus pumilis Bac 2/65 64 1 2 2 Sarcina lutea Sar 5/58 1 1 1 2 Sarcina subflava Sar 6/58 1 1 1 2 Escherichia c-oli Esk 67/59 4 2 2 2 Staphylococcus aureus Man 78/71 2 16 8 4 Staphylococcus epidermis M 12/63 > 128 > 128 > 128 > 128 Streptococcus pyogenes A 1/49 128 8 128 128 Pseudomonas aeruginosa Ps 133/71 128 128 128 128 Proteus mirabilis Prmi 7/44 4 > 128 128 4 Proteus vulgaris PrH 4/42 > 128 > 128 > 128 > 128 i + / _P ARC / j _»p, iv Table 1 (Cont'd) microorganism 3-C1 2-C1 MIC (Mg / ml) 4-Br 2-NO2 Bacillus subtilis Bs 5/58 0.5 4 1 16 Bacillus cereus Bcm 4/58 4 2 2 8 Bacillus pumilis Bac 2/65 2 2 1 8 Sarcina lutea Sar 5/58 8 4 16 16 Sarcina subflava Sar 6/58 64 4 32 8 Escherichia coli Esk 67/59 2 1 2 16 Staphylococcus aureus Man 78/71 16 8 32 8 Staphyloeoccus epidermis M 12/63 > 128 > 128 > 128 > 128 Streptococcus pyogenes A 1/49 8 128 64 128 Pseudomonas aeruginosa Ps 133/71 128 128 128 128 Proteus mirabilis Prmi 7/44 > 128 0.25 > 128 16 Proteus vulgaris PrH 4/42 > 128 > 128 > 128 > 128

The compounds of the invention are prepared by:

1. N-Acylation reaction of an organic or inorganic salt of 7-aminocephalosporanoic acid (7-ACKJ of formula II)

wherein R ¹ represents sodium, potassium, triethylammonium, diethylammonium, dimethylphenylammonium with 5- (5-aryl-2-furyl) -2-tetra-6-zolylacetic acid chlorides of formula III

wherein R has the same meaning as in formula I, followed by acidification of the thus prepared organic and resp. inorganic salts of 7- (5- (5-aryl-2-furyl) -2-tetrazolylacetamide) or phthaleporanoic acids of formula IV

N O

CH (IV) wherein R is as defined in formula I and R ¹ is as defined in formula II to the corresponding 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cephalosporanoic acid of general formula of formula V

CH ₃ (VI wherein R is as defined in formula I. These are further converted to the subject sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido) -cephalosporanoic acids of formula I.

2. N-Acylation reaction of an organic or inorganic salt of 7-aminocephalosporanoic acid (7-ACKJ of formula II)

wherein R ¹ represents sodium, potassium, triethylammonium, diethylammonium, dimethylphenylammonium, with mixed 5- (5-aryl-2-furyl) -2-tetrazolylacetic anhydrides and pivalic acid of the general formula VI

wherein R has the same meaning as in formula I, followed by acidification of the thus prepared organic and resp. of inorganic salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamide] -cephalosporanoic acids of formula IV

wherein R has the same meaning as in formula I and R ¹ has the same meaning as in formula II, to the corresponding 7- [5- (5-aryl-2-furyl] -2-tetrazolylacetamido] cep alosporanic acid of general formula IN

wherein R is as defined in Formula I. These are further converted to the subject sodium salts of 7- (5- (5-aryl-2-furyl) -2-tetrazolylacetamido) cephalosporanoic acids of Formula I.

A first process for the preparation of the compounds of the invention is carried out by preparing a soluble organic salt from 7-aminocephalosporanoic acid by suspending 7-ACK in dichloromethane and adding a secondary or tertiary aliphatic or aliphatic-aromatic amine at a temperature of -40 to 30 ^° C, suitably triethylamine. and a temperature of -5 to 25 ° C. To the thus prepared organic salt of 7-ACK soluble in dichloromethane is added 5- (5-aryl-2-furyl) -2-tetrazolylacetic acid chloride dissolved in chloroform, tetrahydrofuran, acetone, dioxane and other inert solvents at a temperature of -40 to 30 ° C, preferably in dichloromethane and at a temperature of -5 ° C to 0 ° C. The reactants are stirred for 1 to 3 hours at -40 ° ^C to 30 ^° C, preferably at -5 ° C to 25 ° C. The 5-aryl-2-furyl) -2-tetrazolylacetamido] cephalosporanoic acid is acidified with dilute mineral acids to the corresponding 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cep alosporanoic acid, which is dissolved in a mixture of acetone and ethanol, preferably acetone and methanol, and by adding methanolic sodium acetate solution, the subject sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cephalosporanoic acids are prepared therefrom. , preferably ethanol.

A first process for preparing the compounds of the invention is also carried out by preparing a soluble inorganic salt from 7-ACK by suspending 7-ACK in 50% aqueous tetrahydrofuran, aqueous dioxane, preferably aqueous acetone, and adding an aqueous solution of potassium bicarbonate at -5 to 50 ° C. ° C, preferably sodium bicarbonate at 0-5 ° C. To the thus prepared inorganic salt of 7-ACK dissolved in the above solvents is added 5- (5-aryl-2-furyl) -2-tetrazolylacetic acid chloride dissolved in tetrahydrofuran, dioxane at a temperature of -40 to 30 ^° C, preferably in acetone at a temperature of -10 to -5 ° C. The reactants are stirred for 1 to 3 hours at a temperature of -40 to 30 ° C, preferably at -10 to 25 ° C. The resulting inorganic salts of 7- [5- (5-aryl-2-furyl-2-tetrazolylacetamido) cephalosporanoic acids are acidified with dilute mineral acids to the corresponding 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cep alosporanoic acid, which are dissolved in a mixture of acetone and ethanol, preferably acetone and methanol, and by addition of methanolic sodium acetate solution, form the subject sodium salts of 7- [5- (5-aryl-2-furyl) -2- These are precipitated from the concentrated solution by a higher alcohol, preferably ethanol.

In a second process for the preparation of the compounds of the invention, it is preferable to prepare 5- (5-aryl-2-furyl) -2-tetrazolylacetic acid and pivalic acid mixed anhydride by reacting the 5- (5-aryl) organic salt. -2-furyl-2-tetrazolylacetic acid with pivaloyl chloride in acetone, dioixane at a temperature of -40 to 30 ° C, preferably at -10 to 0 ° C. The mixed anhydride is then reacted preferably with the triethylammonium salt of 7-aminocephalosporanoic acid in 50% aqueous tetrahydrofuran, aqueous dioxane at a temperature of -40 to 30 ° C, preferably in aqueous acetone and a temperature of -25 to 25 ° C for 1 to 3 h. The resulting organic salts of 7- [5- (5-aryl-2) -furyl) -2-tetrazolylacetamido-iodophthalosporanoic acids are acidified with dilute mineral acids to the corresponding 7- (5- (5-aryl-2-furyl) -2-tetrazolylacetamido) cephalosporanoic acids, which are dissolved in a mixture of acetone and ethanol at 30 ° C. to 60 ° C, preferably in admixture of acetone and methanol at 50 ° C and addition of methanolic sodium acetate solution gives the subject sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylacetamido] cep alosporanic acid. These precipitate from the concentrated solution with a higher alcohol, preferably ethanol.

Further, the invention is exemplified without being limited to these only.

Example 1

7- (5- (5- (3-Chlorophenyl) -2-furyl) -2-tetrazolylacetamidoicephalosporanoic acid, sodium ¹ )

1.36 g (5 mmol) of 7-aminocephalosporanoic acid are suspended in 25 ml of dichloromethane. To the cooled suspension at 0 degrees Celsius was added 0.84 ml (6 mmol) of triethylamine, the mixture was stirred for 50 min until the acid dissolved and filtered. To the cooled filtrate to -5 ° C was added 0.73 ml (5.25 mmol) of triethylamine again, and at -5 ° C to 0 ° C, 1.61 g (5 mmol) of 5- (5- (3-) 3- chloride was added. chlorophenyl) -2-furyl] -2-tetrazolylacetic acid, dissolved in 25 ml of dichloromethane, stirred at 0 ^° C for 1 h and at room temperature for 1 h, then dichloromethane was distilled off and 30 ml of water were added to the residue. After stirring for 15 min, a white emulsion was formed which was overlaid with 150 ml of ethyl acetate and acidified to pH 2 with 15% hydrochloric acid with stirring. The acetate layer was separated, dried over sodium sulfate, stirred with activated carbon, filtered and the filtrate evaporated. Crude 7- (5- (5- (3-chlorophenyl) -2-furyl) -2-tetrazolylacetamido) (cef alosporanoic acid) was dissolved in a mixture of 20 ml of methanol and 15 ml of acetone at 50 ° C and this solution was a solution of 0.41 g (5 mmol) of sodium acetate melted in 10 ml of methanol is added in one portion. for the sodium salt of the corresponding] acylated cephalosporic acid, it is concentrated to a quarter volume, 25 ml of ethanol are added to the residue, and the salt is filtered off and washed with ethanol, acetone and ether. Yield 67%. T. t. 186 to 187 ^σ Ο.

For C23H18ClN6O7SNa calculated and determined, respectively: 47.55 resp. % C, 47.61; H, 3.08; 14.50% N and 6.10, respectively. 6.21% Cl.

Example 2

7- (5- (5- (2-Chloro-phenyl) -2-furyl) -2-tetrazolylacetamide) -cephalosporanoic acid, sodium salt

Prepared in a manner analogous to Example 1 from 1.61 g (5 mmol) of 5- (5- (2-chlorophenyl) -2-furyl-1-2-tetrazolylacetic acid chloride), yield 65%, m.p. 181 ° C.

For C 18 H 18 ClN 2 O 2 S 2 S 8 calculated and found, respectively, 47.55 and 47.55, respectively. 47.66%, 3.12 and 3.17% of H, 14.46, respectively. 14.52% N and 6.10, respectively. 6.28% Cl.

Example 3

7- (5- (5- (4-Bromo-phenyl) -2-furyl) -2-tetrazolylacetamide) -cephalosporanoic acid, sodium salt

Prepared in a manner analogous to Example 1 from 1.84 g (5 mmol) of 5- [5- (4-bromophenyl) -2-furyl] -2-tetrazolylacetic acid chloride. Yield 66%. T. t. 183 ^DEG- 185 ^DEG C.

For C 13 H 18 BrN 5 O 7SNa calculated and found, respectively: 44.17 and 44.17, respectively. 44.26%, 2.90 and 3.06% H, 13.43, respectively. 13.33% N.

Example 4

7- {5- [5- (4-Methoxy-phenyl) -2-fluoro] -2-tetrazolylacetamido-cephalosporanoic acid, sodium salt

Prepared in analogy to Example 1 from 1.60 g (5 mmol) of 5- (5- (4-methoxyphenyl) -2-furyl) -2-tetrazolytacetic acid chloride in 60% yield, mp 198 to 200 ° C.

For CzdHHHsNeOeSNa calculated, respectively. found: 50.00, resp. % C, 3.67; 3.55 pere. H and 14.57, respectively. 14.66% N.

Example 5

7- (5- (5- (2-Methoxyphenyl) -2-furyl) -2-tetrazolylacetamido (cephalospranic acid) sodium salt

Prepared in a manner analogous to Example 1 from 1.60 g (5 mmol) of 5- (5- (2-methoxyphenyl) -2-furyl) -2-tetrazolylacetic acid chloride in a yield of 61%, m.p. to 192 ° C.

For C, HHztNNsOeSNa calculated, respectively. found: 50.00, resp. C, 50.18; H, 3.67 and 3.47, respectively; 14.70% N.

Example 6

7- {5- [5- (2-Nitrophenyl) -2-furyl] -2-tetrazolylacetamide /cephalosporanoic acid, sodium salt

Prepared in a manner analogous to Example 1 from 1.67 g (5 mmol) of 5- (5- (2-nitrophenyl) -2-furyl] -2-tetrazolylacetic acid chloride, yield 55%, m.p. 163). to 164 ° C.

For C 23 H 18 N 7 O 9SNa calculated, respectively. found: 46.10, respectively. C, 46.64; H, 3.06 and 3.00, and 16.57, respectively. 16.70% N. Example 7

7- (5- (5- (3-Methylphenyl) -2-furyl) -2-tetrazolylacetamido-cephalosporic acid sodium salt)

1.36 g (5 mmol) of 7-aminocephalosporanoic acid is suspended in 16 ml of 50% aqueous acetone and a solution of 0.69 g (8.2 mmol) of sodium bicarbonate in 3 ml of water is added at -5 to 0 ^{° C.} The mixture was stirred for 50 min until the acid dissolved and filtered. To the cooled filtrate to -10 ° C was added 1.51 g (5 mmol) of 5- (5- (3-methylphenyl) -2-furyl] -2-tetrazolylacetic acid chloride) dissolved in 25 ml of dry acetone and The reaction mixture was stirred at -10 to -5 ° C for 1 h and at room temperature for 2 h before acetone was distilled off, the aqueous layer was overlaid with 150 mL of ethyl acetate and acidified to pH 2 with 15% hydrochloric acid with stirring. layer was separated, dried over sodium sulfate, stirred with charcoal, filtered and evaporated to dryness to give crude 7- {5- [5- (3-methylphenyl) -2-furyl] -2- tetrazolylacetamido (cephalosporic acid, which was converted to the sodium salt according to the procedure described in Example 1. Yield 63%, mp 175-176 ° C).

Calcd for C24H21N6O7SNa, resp. found: 51.42, respectively. % C, 51.46;% H, 3.77 and 3.60; 15.21% N. Example 8

7- (5- (5- (4-Chloro-phenyl) -2-furyl) -2-tetrazolylacetamide) -cephalosporanoic acid sodium salt

To a suspension of 1.36 g (5 mmol) of 7-aminocephalosporanoic acid in 16 mL of 50% aqueous acetone was added triethylamine (1.14 mL, 8.2 mmol) at -5 to 0 ^{° C.} acid.

1.52 g (5 mmol) of 5- [5- (4-chlorophenyl) -2-furyl] -2-tetrazolylacetic acid are dissolved in 30 ml of acetone and 0.8 ml ( To a cooled solution of triethylammonium salt of 5- [5- (4-chlorophenyl) -2-furyl] -2-tetrazolylacetic acid at -10 ° C is added a solution of 0.81 g (6.72 mmol). of pivaloyl chloride in 5 ml of dry acetone The stirred mixed anhydride solution was stirred for 30 min at -10 ° C, then cooled to -25 ° C and a filtered solution of 7-aminocephalosporanoic acid triethylammonium salt was added at this temperature. After stirring for 1 h at -25 ^° C and 2 h at room temperature, acetone is evaporated, the emulsion aqueous layer is overlaid with 150 ml of ethyl acetate and acidified to pH 2 with 15% hydrochloric acid with stirring. The acetate layer is separated, dried, activated carbon, evaporated to dryness and the crude acylated cephalosporic acid thus obtained The residue was adjusted to sodium salt according to the procedure described in Example 1. Yield 57%. T. t. Mp 190-192 ° C.

Calcd for C23H16ClN6O7SNa, resp. found: 47.55, respectively. C, 47.62; 3.11 pere. N, 14.46, respectively. 14.38% N and 6.10, respectively. 6.01% Cl.

Claims (7)

242D13 11 12 Example 6 7- {5- [5- (2-Nitrophenyl) -2-furyl] -2-tetrazolylacetamido-cephalosporanic acid sodium salt Prepared in analogy to Example 1 of 1, 5- (5- (2-nitrophenyl) -2-furyl) -2-tetrazolyl-acetic acid, 67 g (5 mmol), 55% yield, mp 163-164 ° C. respectively calculated: 46.10 and 46.64% C, 3.06 and 3.00% H respectively, and 16.57 and 16.70%, respectively. 7- (5- (5- (3-Methylphenyl) -2-furyl) -2-tetrazolyl acetamido] -cephalospholanic acid 1.36 g (5 mmol) of 7-aminocephalosporanic acid is suspended in 16 ml of 50% aqueous, of acetone and a solution of 0.69 g (8.2 mmol) of sodium bicarbonate in 3 ml of water is added at -5 to 0 CG. The mixture is stirred for 50 minutes until the acid is dissolved and filtered. - 10 ° C is added 1.51 g (5 mmol) of 5- (5- (3-methylphenyl) -2-furyl) -2-tetrazolyl acetic acid chloride, dissolved in 25 ml of dry alcohol. and the reaction mixture is stirred for 1 hour at -10 to -5 ° C and 2 hours at room temperature. Thereafter, acetone is distilled off from the mixture, the aqueous layer is overlaid with 150 ml of ethyl acetate, and acidified to pH 2 with 15% hydrochloric acid with stirring. The acetate layer is separated, dried over sodium sulphate, mixed with activated charcoal. filtered and the filtrate evaporated to dryness. Crude 7- {5- [5- (3-methylphenyl) -2-fluoryl] -2-tetrazolylacetamido (cephalosporate acid, which was adjusted to the sodium salt by the procedure of Example 1) was obtained. 175 DEG-176 DEG C. For C24H21N6O7SNa, calculated: 51.42% and 51.46% C, 3.77% and 3.60% respectively. Example 8 Sodium salt of 7- (5- (5- (4-chlorophenyl) -2-furyl) -2-tetrazolyl acetamido-cephalosporanic acid To the suspension 1 1.14 ml (8.2 mmol) of triethylamine was added to 36 g (5 mmol) of 7-amino-phospho-sporanic acid in 16 ml of 50% aqueous acetone at -5 to 0 CO. 1.52 g (5 mmol) of 5- [5- (4-chlorophenyl) -2-furyl] -2-tetrazolyl acetic acid are dissolved in 30 ml of acetone and at 0-5 degrees Celsius triethylamine (0.8 ml, 5.7 mmol) was added and a solution of 5- [5- (4-chlorophenyl) -2-fluoryl] -2-tetrazolyl acetic acid triethyl ammonium salt was added to the cooled solution. 0 81 g (6.72 mmol) of pivaloyl chloride in 5 mL of dry acetone. The resulting mixed anhydride solution was stirred for 30 minutes at -10 ° C, then cooled to -25 ° C and a filtered solution of the 7-aminocephalosporanic acid triethylammonium salt was added thereto. The reaction mixture is stirred at -25 ° C for 1 h at room temperature. Thereafter, the acetone is evaporated off, the emulsion aqueous layer is layered with 150 ml of ethyl acetate and acidified with 15% hydrochloric acid at pH 2 with stirring. The acetate layer is separated, dried, purified with activated carbon, evaporated to dryness and the crude na-acylated thus obtained is evaporated. cefalo-sporanic acid is adjusted to the sodium salt according to the procedure described in Example 1. Yield 57%. Mp 190-192 ° C. For C 23 H 16 ClN 6 O 7 SNa calculated, respectively. found: 47.55, respectively. 47.62% C, 3.12, respectively. 3,11pere. N, 14.46, respectively. 14.38% N and 6.10 and 6.0% Cl, respectively. SUBJECT MATTER 1. Sodium salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolyl acetamido] cephalosporanic acids of general formula I wherein R is methyl, methoxy, chloro, bromo, or nitro at the position-, m-, or p-phenyl nucleus. 2. A preparation of the compounds of general formula (I) according to claim 1, characterized in that the inorganic or organic salt of the 7-aminocephalosporanic acid of the general formula (II) is present. wherein R 1 is sodium, potassium, triethylaluminum, diethylammonium and dimethylphenylammonium, N-acylated with chlorides of 5- (5-aryl-2-fluoro) -2-tetrazolyl acetic acids of formula III wherein R is the same as in formula I. The resulting organic, respectively. inorganic salts of 7- [5- (5-aryl-2-furyl) -2-tetrazolylation of the tos-milk cef alosporanic acids of general formula IV N - N o J. NH · N • λ COOR1 O (IV) wherein R is the same as in formula (Ia) and R1 is the same as in formula (II), acidified with diluted mineral acids to the corresponding 7- [5- (5-aryl-2-furyl) -2-tetrazolyl acetamido] cephalosporanic acids of formula V wherein R has the same meaning as in Formula I, which is further treated with sodium acetate of the respective sodium salt of the 7- [5- (5-aryl-2-furyl-2-tetrazolylacetamido] cep] alosporanic acid salt of Formula I. 3. A process for the preparation of compounds of general formula I according to claim 1, characterized in that the inorganic or organic salt of 7-aminocephalosporanic acid of the general formula II wherein R1 is sodium, potassium, triethylammonium, diethylammonium and dimethylphenylammonium, N-acylated by mixed 5- (5-aryl-2-furyl) -2-tetrazolyl acetic acid anhydrides and pivalic acid of general formula VI where R has the same meaning as in formula I. The resulting organic, respectively. inorganic salts of 7- [5- (5-aryl-2-furyl] -2-tetrazolyl acetic acid-phosphoric acid of general formula IV I 242013 13 16 wherein R is the same as in formula (Ia) and R1 is the same as in formula (II), acidified with diluted mineral acids to the corresponding 7- [5- (5-aryl-2-furyl) -2-tetrazolyl acetamido] cephalosporanic acid of the general formula IN wherein R is the same as in formula I, which are further treated with sodium acetate of the respective sodium salt of 7- [5- (5-aryl-2-furyl-2-tetrazolyl acetamido] cephalosporanic acid of formula I) of Formula I below. 4. The process of clauses 2 and 3, wherein the reaction is carried out in an inert solvent such as tetrahydrofuran, acetone, dioxane, aqueous tetrahydrofuran, or aqueous dioxane, conveniently in dichloromethane or aqueous acetone. 5. The process of clauses 2 and 3, wherein the reaction is carried out at a temperature of -40 to 30 ° C, preferably at -10 to 25 ° C. 6. Process according to claim 2, characterized in that 7- [5- (5-aryl-2-furyl) -2-tetra-acetyl acetamidojcephalosporanic acid is converted to the subject sodium salt in acetone in a mixture of acetone and alcohol at the heart rate. 30 to 60 ° C, conveniently in a mixture of acetone and methanol at 50 ° C. Severografla, n. P., Race 7, Most Price 2,40 Kčs