CS242014B1 - 7- [5- (5-Aryl-2-furyl) -1-tetrazolylacetamido] cephalosporanic acid and their preparation - Google Patents

Abstract

The solution concerns the preparation of 7-[5-(5-aryl-2-furyl)-1-tetrazolylacetamido] cephalosporanic acids of general formula I, which are characterized by antibacterial activity. The method of preparation is based on N-acylation of inorganic), or of the organic salt of 7-aminocephalosporanic acid with 5-(5-aryl-2-furyl)-1-tetrazolylacetic acid chlorides in inert chlorinated organic solvents, or anhydrous, or aqueous ketones and cyclic ethers. The method of preparation is also based on N-acylation of inorganic), or organic) salts of 7-aminocephalosporanic) acid with mixed anhydrides of 5-(5-aryl-2-furyl)-1-tetrazolylacetic acids and pivalic acid) in inert chlorinated solvents, or anhydrous or aqueous ketones and cyclic ethers.

Description

The present invention relates to 7- [5- (5-aryl-2-furyl) -1-tetrazolylacetamido] cephalosporane selines of formula I

wherein R is hydrogen, methyl, methoxy, chloro, bromo, trifluoromethyl, or a nitro group at the o-, m-, or p-phenyl position, and methods for their preparation.

In the author's certificate no. 233 434 discloses a process for preparing 5- [5- (substituted phenyl) -2-furyl] -1-tetrazolylacetic acids which have been used as starting materials in the preparation of the subject 7- [5- (5-aryl-2-phenyl) -2- uryl) -1-tetrazolylacetamido] cep alosporanic acids.

These novel 7-heteroacylacetamidocephalosporanoic acids not yet described in the literature have antibacterial activity, as shown in Table 1.

Table 1

In vitro antibacterial activities of 7- [5- (5-aryl-2-furyl) -1-tetrazolylacetamido] -cephalosporanoic acids of formula I, wherein R is as defined below

microorganism H MIC (µg / ml) 2-CH 3 O 3-CH3 4-CH3 O Bacillus subtilis Bs 5/58 2 0,125 0,125 1 Bacillus cereus Bcm 4/58 8 0,125 0,125 0.5 Bacillus pumilis Bac 2/65 2 0,125 0,125 1 Sarcina lutea Sar 5/58 16 0.5 0.5 4 Sarcina subflava Sar 6/58 16 2 4 8 Escherichia coli Esk 67/59 16 0,125 0,125 4 Staphylococcus aureus Man 78/71 32 64 128 16 Staphylococcus epidermis M 12/63 > 128 > 128 > 128 > 128 Streptococcus pyogenes A 1/49 128 128 128 8 Pseudomonas aeruginosa Ps 133/71 128 128 128 > 128 Proteus mirabilis Prmi 7/44 > 128 > 128 128 > 128 Proteus vulgaris PrH 4/42 128 128 128 > 128 microorganism Table 1 4-C1 (Cont'd) MIC (X / ml) 3-C1 2-C1 2,6-Cl2 Bacillus subtilis Bs 5/58 0,125 0,125 0,125 0,125 Bacillus cereus Bcm 4/58 0,125 0,125 0,125 0,125 Bacillus Pumilis Bac 2/65 0,125 0.25 0,125 0,125 Sarcina lutea Sar 5/58 0,125 0,125 0,125 0,125 Sarcina subflava Sar 6/58 0,125 0.5 0,125 0,125 Escherichia coli Esk 67/59 0,125 0.5 0,125 0,125 Staphylococcus aureus Man 78/71 0,125 0.25 32 32 Staphylococcus epidermis M 12/63 0,125 > 128 0,125 0,125 Streptococcus pyogenes A 1/49 of Pseudomonas aeruginosa 0,125 64 0,125 0,125 Ps 133/71 > 128 > 128 > 128 > 128 Proteus mirabilis Prmi 7/44 > 128 > 128 > 128 > 128 Proteus vulgaris PrH 4/42 128 > 128 128 128

Table 1 (continued)

microorganism

4-Br

MIC (Mg / rnl)

3-CF3 2-CF3 2-NO

Bacillus subtilis Bs 5/58 2

Bacillus cereus Bcm 4/58 1

Bacillus pumilis Bac 2/65 4

Sarcina lutea Sar 5/58 2

Sarcina subflava Sar 6/58 4

Escherichia coli Esk 67/59 4

Staphylococcus aureus

Man 78/71

Staphylococcus epidermis M 12/63> 128

Streptococcus pyogenes A 1/49 128

Pseudomonas aeruginosa Ps 133/71 128

Proteus mirabilis Prmi 7/44> 128

Proteus vulgaris PrH 4/42> 128

1 0,125 0,125 1 0.5 0,125 2 0,125 0,125 8 0.5 0.5 32 0,125 0,125 16 0,125 0,125 16 64 32 > 128 0,125 > 128 64 0,125 128 > 128 > 128 > 128 > 128 > 128 128 > 128 128 128

The compounds of the invention are prepared by:

An N-acylation reaction of an organic or inorganic salt of a 7-aminocephalosporanoic acid (7-ACK) of formula II

wherein R ¹ represents sodium, potassium, triethylammonium, diethylammonium, dimethylphenylammonium with 5- (5-aryl-2-furyl) -1-tetrazolylacetic acid chiorides of formula III

o (ni) 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) -1-tetrazolylacetamido] -cephalosporanoic acids of general formula IV »

(IV) wherein R has the same meaning as in Formula I and R ^{1 has} the same meaning as D in Formula II. The compounds of the invention are prepared by:

2. The N-acylation reaction of an organic or inorganic salt of 7-aminocephalosporanoic acid (7-ACK) of formula II

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

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) -1-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.

A first process for the preparation of the compounds according to the invention is to prepare 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. 5- (5-aryl-2-furyl) -1-tetrazolylacetic acid chloride dissolved in chloroform, tetrahydrofuran, acetone, dioxane and other inert solvents at -40 to 30 ° is added to the thus prepared 7-ACK potassium salt dissolved in dichloromethane. C preferably in dichloromethane and at a temperature of -5 to 0 ° C. The reactants are stirred for 1 to 3 hours at -40 to 30 ° C, preferably at -5 to 25 ° C. The resulting organic salts of 7- [5- (5-aryl-2-furyl) -1-tetrazolylacetamide orcephalosporanoic acids are treated by acidification with dilute mineral acids to the corresponding 7-heteroaryl acetamidocephalosporanoic acids of the invention.

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 ¹ at 0 to 5 ° C. To the thus prepared inorganic salt of 7-ACK dissolved in said solvents is added 5- (5-aryl-2-furyl) -1-tetrazolylacetic acid chloride dissolved in tetrahydrofuran, dioxane at a temperature of -40 to 30 ° C, preferably in acetone at -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) -1-thiazolyl acetamide orcephalosporanoic acids are treated by acidification with mineral acids to the corresponding 7-heteroaryl acetamidocephalosporic acids of the invention.

In a second process for the preparation of the compounds according to the invention, it is preferable to prepare mixed 5- (5-aryl-2-furyl-1-tetrazolylacetic acid anhydride and pivalic acid anhydride in acetone, dioxane, suitably in tetrahydrofuran by reaction of an organic salt Of 5- (5-aryl-2-furyl) -1-tetrazolylocic acid with pivaloyl chloride at a temperature of -40 to 30 ° C, preferably at -10 to 0 degrees Celsius, and the mixed anhydride is then reacted preferably with triethylammonium salt of 7-aminocephalosporanoic acid in 50% aqueous tetrahydrofuran, aqueous dioxane, or aqueous acetone at a temperature of -40 to 30 ° C, preferably -25 to 25 ° C for 1 to 3 h. The resulting organic salts of 7- [5- (5-aryl-2- The furyl) -1-tetrazolylacetamide orcephalosporanoic acids are treated by acidification with dilute mineral acids to the corresponding 7-heteroarylacetamidophthalosporanoic acids of the invention.

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

Example 1

7- (5- [5- (3-Chloro-phenyl) -2-furyl] -1-tetrazolylacetamide orcephalosporanoic acid

7-Aminocephalosporanoic acid (1.36 g, 5 mmol) was suspended in dichloroethane (25 ml), and triethylamine (0.84 ml, 6 mmol) was added to the cooled slurry at 0 degrees Celsius, stirred for 50 min until the acid dissolved and filtered. triethylamine (0.73 ml, 5.25 mmol) was added to the filtrate at -5 ° C, and 5- (5- (3-chlorophenyl) - chloride (1.61 g, 5 mmol) was added at -5 to 0 ° C. 2-furyl-1-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 was added to the residue. After stirring, a white emulsion is formed which 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, stirred with activated carbon, filtered and evaporated to dryness. 7- (5- (5- (3-chlorophenyl) -2-furyl) - 1-Tetrazolylacetamide / cep alosporanoic acid is dissolved in dimethylformamide (2.5 ml) at 40 ° C and diluted with ethanol; It is crystallized, filtered, washed with ethanol, acetone, ether and dried. Yield 61%. T. t. 189 to 191 ’C.

Calcd for C23H19ClN6O7S, resp. determined: 49.42, resp. % C, 49.26; H, 3.54; 15.09% N and 6.34 and 6.20% Cl, respectively.

Example 2

7- {5- [5- (2-Chloro-phenyl) -2-furyl] -1-tetrazolylacetamide orcephalosporanoic acid

Prepared in analogy to Example 1 from 1.61 g (5 mmol) of 5- (5- (2-chlorophenyl) -2-furyl) -1-tetrazolylacetic acid chloride in 60% yield, m.p. 176-177. C.

Calcd for C23H19ClN6O7, resp. determined: 49.42, resp. % C, 49.21; 3.48 percent H, 15.03, respectively. 15.17% M and 6.34, respectively. 6.22% Cl.

Example 3

7- {5- [5- (4-bromophenyl) -2-furyl] -1-tetrazolylacetamido {cephalosporanoic acid

Prepared in a manner analogous to Example 1 from 1.84 g (5 mmol) of 5- (5- (4-bromophenyl) -2-furyl) -1-trazolylacetic acid chloride, yield 60%. Mp 198-199 ° C.

For C18HwBrNcO2S calculated, respectively. determined: 45.78, resp. 45.66% C, 3.17% resp. H, 3.23; 13.88% N.

Example 4

7- {5- [5- (3-Trifluoromethyl-phenyl) -2-furyl] -1-tetrazolylacetamido; cephal: sporanoic acid

Prepared in a manner analogous to Example 1 from 1.78 g (5 mmol) of 5- [5- (3-trifluoromethylphenyl) -2-furyl] -1-tetrazolylacetic acid chloride (yield 58%), m.p. 189 ° C.

For C 21 H 19 F 3 N 6 O 7 S calculated, respectively. determined: 48.65, resp. % C, 48.34; 3.41% H, 14.18 resp. 14.32% N.

Example 5

7- [5- (2-Trifluoromethylphenyl) -2-furyl] -1-tetrazolylacetamidocephalosporanoic acid

Prepared in a manner analogous to Example 1 from 1.78 g (5 mmol) of 5- (5- (2-trifluoromethylphenyl) -2-furyl] -1-tetrazolylacetic acid chloride, yield 60%, m.p. 178 up to 180 ^° C

For C 24 H 19 F 3 N 6 O 7 S calculated, respectively. determined: 48.65, resp. % C, 48.31; 3.37% H and 14.18, respectively. 14.41% N.

Example 6

7- (5- (5- (4-methoxyphenyl) -2-furyl) -1-tetrazolylacetamido-cephalosporanoic acid

Prepared in a manner analogous to Example 1, starting with 1.8 g (5 mmol) of 5- (5- (4-methoxyphenyl) -2-furyl) -1-tetrazolylacetic acid chloride, yield 59%, m.p. 188 [deg.] C.

Calcd for C24H22N5O5S, resp. found: 51.98, respectively. % C, 51.75; 4.10% H and 15.15, respectively. 15.32% N.

Example 7

7- {5- [5- (2-Methoxy-phenyl) -2-furyl-1-tetrazolylacetamide] -cephalosporanoic acid

Prepared in analogy to Example 1 from 1.6 g (5 mmoles) of 5- (5- (2-methoxyphenyl) -2-furyl] -1-azolylacetic acid chloride. Yield 60%. mp 180-182 ° C.

For C 24 H 22 N 6 O 8 S calculated, respectively. found: 51.98, respectively. % C, 51.76; 4.68% H and 15.15, respectively. 15.28% N.

Example 8

7- {5- [5- (phenyl) -2-furyl] -1-tetrazolylacetamide

Prepared in analogy to Example 1 from 1.44 g (5 mmol) of 5- (5- (phenyl) -2-furyl) -1-tetrazolylacetic acid chloride (yield 61%), m.p. 184 ° C.

For C 23 H 20 N 6 O 7 calculated, respectively. found: 52.66, respectively. % C, 52.43; 3.78% H and 16.02, respectively. 15.96%.

Example 9

7- {5- (5- (3-methylphenyl) -2-furyl) -1-tetrazolylacetamido {cephalosporanoic acid

Prepared in a manner analogous to Example 1 from 1.51 g (5 mmol) of 5- [5- (3-methylphenyl) -2-furyl] -1-tetrazolylacetic acid chloride. Yield 61%. T. t. Mp 177-179 ° C.

For C 24 H 22 NBO 7 S calculated, respectively. found: 53.52, respectively. % C, 53.36; 4.14% H and 15.60, respectively. 15.54% N.

Example 10

7- {5- [5- (2-Nitrophenyl) -2-furyl] -1-tetrazolylacetamide orcephalosporanoic acid

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 1.67 g (5 mmol) of 5- [5- (2-nitrophenyl) -2-furyl] -1-tetrazolylacetic acid chloride, dissolved in 25 ml of dry acetone and the reaction mixture is stirred at -10 to -5 ° C for 1 h and at room temperature for 2 h. Acstone was distilled off from the mixture, the aqueous layer was poured over 150 ml of ethyl acetate and acidified to pH 2 with 15% hydrochloric acid with stirring. to dryness. The crude 7- (5- (5- (2-nitrophenyl) -2-furyl) -1-tetrazolyl acetamide) or cephalosporic acid was dissolved in dimethylformamide and further processed as in Example 1. Yield 49%, mp 131-132 ^C C.

For C 23 H 19 N 7 O 6 S calculated, respectively. found: 48.50, resp. % C, 48.42; 3.36; 3.44 pere. H and 17.21, respectively. 17.43% N.

Example 11

7- {5- [5- (2,6-Dichloro-phenyl) -2-furyl] -1-tetrazolylacetamide orcephalosporanoic acid

To a suspension of 1.36 g (5 mmol) of 7-aminocephalosporanoic acid in 16 mL of 50% aqueous acetone at -5 to 0 ° C was added 1.14 mL (8.2 mmol) of triethylamine. The mixture was stirred for 50 min until the acid dissolved.

1.69 g (5 mmol) of 5- [5- (2,6-dichlorophenyl) -2-furyl] -1-tetrazolylacetic acid are dissolved in 30 ml of acetone and 0, 8 ml (5.7 mmol) of triethylamine. To a cooled solution of 5- [5- (2,6-dichlorophenyl) -2-furyl] -1-tetrazolylacetic acid triethylammonium salt at -10 ° C was added a solution of 0.81 g (6.72 mmol) of pivaloyl chloride in 5 mL of dry acetone. The resulting 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 thereto. The reaction mixture was stirred at -25 ° C for 1 h and at room temperature for 2 h. Acetone was evaporated, the emulsion aqueous layer was overlaid with 150 ml of ethyl acetate and acidified to pH 2 with 15% hydrochloric acid with stirring. The acetic layer was treated to purified 7- (5- (5- (2,6-dichlorophenyl) - 2-Furyl] -1-tetrazolyl acetamido -cephalosporanoic acid similar to Example 1. Yield 61%, mp 201-202 ° C.

For C 13 H 18 Cl 2 N 6 O 7 S calculated, respectively. determined: 46.55, respectively. C, 46.60; 3.10% H and 14.16, respectively. 14.02% N and 11.94, respectively. 11.88% Cl.

Example 12

7- {5- [5- (4-Chloro-phenyl) -2-furyl] -1-tetrazolylacetamide or cephalosporic acid

1.36 g (5 mmol) of 7-aminocephalosporanoic acid are suspended in 40 ml of tetrahydrofuran. To the cooled suspension at 0 ° C, 0.84 ml (6 mmol) of triethylamine is added, the mixture is stirred for 55 min until the acid dissolves and filtered.

1.52 g (5 mmol) of 5- [5- (4-chlorophenyl) -2-furyl] -1-tetrazoilylacetic acid are dissolved in 80 ml of acetone and 0.8 ml (5 ml) of acetone are added at 0-5 ° C. , 7 mmol) of triethylamine. To a cooled solution of 5- (5- (4-chlorophenyl) -2-furyl) -1-tetrazoleacetic acid triethylammonium salt at -10 ° C is added a solution of 0.81 g (6.72 mmol) of pivaloyl chloride in 5 mL of dry acetone. a solution of the resulting mixed anhydride is stirred for 45 minutes at -10 DEG C., and filtered at-10 ^C C is treated with a solution of triethylammonium 7-aminocephalosporanic acid. the mixture was stirred for 1 hour at 10 ° The organic solvents are distilled off, the residue is taken up in 100 ml of water to a white emulsion, which is overlaid with 150 ml of ethyl acetate and acidified with stirring with 15% chloro242014 hydrochloric acid to pH 2. The acetate layer is separated, dried over sodium sulfate, stirred with activated carbon, filtered and the filtrate evaporated to dryness Crude 7- {5- [5- (4-chlorophenyl) -2-furyl] -1-tetrazclylacetamido (cephalosporanoic acid was treated as in Example 1) Yield 60%, m.p. 200 ° C.

For C 23 H 19 ClNO 0 O 7 S calculated, respectively. determined: 49.42, resp. % C, 49.19; 4.56 pere. H, 15.03, respectively. 15.26% N and 6.34, respectively.

6.12% Cl.

Claims (5)

OBJECT OF THE INVENTION 1- [5- (5-Aryl-2-furyl) -1-tetrazolylacetamide O '] cephalofuranic acid of the general formula I in which R represents hydrogen, methyl, methoxy, chlorine, bromine, trifluoromethyl, or nitro in the o-position -, m-, or p-phenyl core. 2. A process for preparing compounds of the formula I according to claim 1, characterized in that the inorganic or organic salt of 7-aminocephalosporanic acid of formula II wherein R ¹ is Na, K, triethyl ch ₅ (IV) benzylammonium, diethylammonium, and dimetylfenylamónium N-acylated with 5- [5-aryl-2-furyl] -1-tetrazolylacetic acid chlorides of formula III wherein R is the same as in formula I and the resulting organic and resp. inorganic salts of 7- [5 - (5-aryl-2-furyl-1-j íetrazolylacetamidojcefalosporánových acid of formula IV wherein R has the same meaning as the formula I, in b and R ¹ have the same meaning as in formula II, the dilute mineral 0kyslia acids. 3. The method of preparing compounds of the formula I according to claim 1, characterized in that the inorganic or organic salt of 7-aminocephalosporanic acid of formula II wherein R ¹ is sodium, potassium, triethylammonium, diethylammonium, and dimetylfenylamónium N-acylated with the mixed anhydride of 5- (5-aryl-2-furyl) -1-tetrazolylacetic acids and pivalic acid of the general formula V wherein R has the same meaning as in the formula I and the resulting organic, respectively. inorganic salts of 7- [5- (5-aryl-2-furyl) -1-tetrazolylacetamido] -cephalosporanoic acids of the general formula IV ch ₅ (IV) wherein R has the same meaning as in t> I and R ¹ has the same meaning as in the formula II, is acidified with dilute mineral acids. 4. The process according to claim 2, wherein the reaction is carried out in an inert organic solvent, e.g. tetrahydrofuran, acetone, dtoxane, aqueous tetrahydrofuran, or aqueous dioxane, suitably in dichloromethane, or aqueous acetone. 5. Process according to claim 2, characterized in that the reaction is carried out at temperatures of -40 to 30 ^° C, preferably at -10 to 25 ° C.