DE1445685B - 7 (alpha aminophenylacetamino) cephalo sporanic acid - Google Patents

Description

1 445 68b 1 2

The 7- (a-aminophenylacctamino) -ccphaIosporansaurc with the formula

NH, O

I "Il /

CH - C - NH - CH - HC O = C N

CH ₂

C - CH ₂ - O - C - CH ₃

C ^
COOH

regarding the minimum inhibitory concentration on some gram-negative microorganisms as superior to the α-aminobenzylpenicillin proven.

This compound can also be used in the form of its salts, for example as a water-soluble compound Sodium, potassium, lithium, ammonium and substituted ammonium salts and as less water soluble Calcium, procaine, quinine and dibenzylethylenediamine salt.

The compounds are prepared by adding 7-aminocephalosporanic acid or one of its Salts with that on the amino group by a carbobenzoxy, carboallyloxy, tert-butoxycarbonyl or Trityl group protected phenylglycine in the presence of a carbodiimide or with one in the same way acylated protected chloride, bromide, azide, activated ester or mixed anhydride of phenylglycine, splitting off the protective group from the compound obtained and optionally the compound obtained in this way converted into a salt.

The acylation with the reactive derivative of phenylglycine is carried out in water or a suitable organic solvent, under practically neutral conditions and at or below room temperature, e.g. B. between the freezing point of the reaction mixture and about 2O ⁰ C, the 7-aminocephalosporanic acid is dissolved together with a sufficient amount of sodium bicarbonate or another suitable alkaline compound in aqueous 50 percent by volume acetone, so that the concentration of 7-aminocephalosporanic acid is about 1 to 4 Weight percent is. The solution is cooled to about 0 to 5 ^° C. and a solution of the acylating agent in about 20% excess is added while stirring and cooling. If the pH value of the mixture does not remain constant, it can be kept in the neutral range by adding sodium bicarbonate or introducing carbon dioxide. After the addition of the acylating agent has ended, the reaction mixture is stirred further and allowed to warm to room temperature. The reaction product is then acidified to pH about 2 with hydrochloric acid and extracted with an organic solvent such as ethyl acetate. The ethyl acetate extract is adjusted to a pH of about 5.5 with sodium, potassium or ammonium hydroxide or another base which contains the desired cation and extracted with water. The aqueous solution is separated off and evaporated to dryness. The residue is taken up in the smallest possible amount of warm methanol and the desired product is deposited by cooling or evaporation, if necessary with the addition of ethanol as a precipitant. The crystalline product obtained is filtered off, washed with acetone and dried.

Before or after the crystallization, the protecting group may be by hydrogenation under mild conditions in the presence of a palladium catalyst, or removed by brief treatment under weakly acidic conditions at elevated temperature (up 2minutige treatment with dilute acetic acid at 50 to 100 ⁰ C z. B. 30) .

The acylation can also be carried out at room temperature with the phenylglycine protected on the amino group in the presence of an equimolar amount of a carbodiimide, such as Ν, Ν'-diisopropylcarbodiimide, N, N'-dicyclohexylcarbodiimide, N, N'-bis (p-dimethylaminophenyl) -carbodiimide, N-ethyl-N '- (4 "-äthylmorpholinyl) -carbodiimide, are executed.

The acylating agent, which contains an asymmetric carbon atom, can also be optically active Form can be used. The optical antipodes are generated in the usual way by resolving the racemate won, e.g. B. fractionated by reacting the free acid with cinchonine, strychnine or brucine Crystallization and acidification of the separated diastereoisomeric salts. The obtained in this way Free acids can be used for acylation after the amino group has been protected in conjunction with a carbodiimide, or they can by conventional methods be converted into the corresponding acid halide or a mixed anhydride, wherein extreme conditions must be avoided so that no racemization occurs.

example 1
7- (Da-aminophenylacetamino) -cephalosporanic acid

d, l-Phenylglycine is prepared in the usual way by reaction with cinchonine, fractional crystallization of the diastereoisomeric salts obtained and acidification, to obtain the Ph, enylglycine antipodes, cleaved.

D-phenylglycine produced in this way is reacted in the usual way with carbobenzoxychloride, to obtain the N-carbobenzoxy-D-phenylglycine.

0.60 g of N-carbobenzoxy-D-phenylglycine are dissolved in 10 ecm of dry tetrahydrofuran. The solution is cooled in an ice-salt bath and, while stirring within 10 minutes with 0.29 cc of triethylamine, followed by 0.29 cc of isobutyl chloroformate, followed by further stirring for 10 minutes at -5 ⁰ C. Meanwhile, 0.57 g of 7-aminocephalosporanic acid and 0.29 ecm of triethylamine are dissolved in 5 ecm of tetrahydrofuran and 5 ecm of water, and the solution is centrifuged to remove a dark-colored sludge. The clarified solution is in

Chilled in an ice bath and slowly added to the reaction mixture, taking another half hour in the ice bath and stirred for a further hour at room temperature. The reaction mixture is a homogeneous solution with a pH of about 6. The solution becomes a semi-solid in vacuo Evaporated residue. 35 ecm of water and a few drops are added to the residue Triethylamine added to raise the pH to 8. The resulting aqueous solution is extracted sequentially with 50 cc and 35 cc portions of ethyl acetate, the pH at each Extraction with hydrochloric acid was adjusted to 2. The extracts are combined, nitrated, over sodium sulfate dried, the solvent stripped off and the residue dried in vacuo. 7- (N-carbobenzoxy-D-a-aminophenylacetaminoJ-cephalosporanic acid is obtained in the form of a yellow-white, amorphous solid mass with a yield of 1.10 g.

1.0 g of this substance are in a 150 ecm warm 95% ethyl alcohol dissolved. 1.0 g of a 5% palladium-carbon catalyst is added to the solution, and the mixture is at room temperature and normal pressure by bubbling hydrogen hydrogenated over a period of 3 hours with stirring. The hydrogenation mixture is filtered. the consisting of the catalyst and the desired product solid phase is in ethyl acetate and Suspended water and adjusted to a pH of 2 with hydrochloric acid. The suspension is used for removal the catalyst filtered. The aqueous phase is separated from the filtrate and evaporated in vacuo, wherein the desired 7- (D-α-aminophenylacetamino) -cephalosporanic acid is obtained.

35 Example 2

7- (d, l-a-aminophenylacetamino) -cephalosporanic acid

To a solution of 1.48 g Ν, Ν'-dicyclohexylcarbodiimide 2.05 g of dI-N-carbobenzoxy-a-aminophenylacetic acid are added to 100 ecm of tetrahydrofuran given, followed by a solution of 2 g of 7-aminocephalosporanic acid in 7.2 ecm of aqueous 1 normal Sodium hydroxide solution and the mixture is stirred at room temperature overnight. The tetrahydrofuran and the water is drawn off in vacuo. The oil obtained is dissolved in water, filtered and with extracted to a pH of 2 with ethyl acetate, hydrochloric acid being used to adjust the pH. The ethyl acetate extract is separated off and the solvent is stripped off in vacuo. The residue is washed with ether, redissolved in ethyl acetate and at a pH value of 6.5 with water extracted using aqueous potassium hydroxide solution to adjust the pH. The extract obtained is im Evaporated to dryness in vacuo. The obtained UI is redissolved in methanol and gradually Evaporation of the methanol and simultaneous addition of ethanol precipitated as an amorphous solid mass. It 278 mg of 7- (a-carbobenzoxyamino-a-phenylacetamino) -cephalosporanic acid are obtained obtained in the form of the potassium salt.

The material obtained in this way is subjected to selective hydrogenolysis as in Example 1 to to remove the carbobenzoxy protecting group from the α-amino group of the side chain, taking 200 mg 7- (d, l-a-aminophenylacetamino) -cepnalosporanic acid can be obtained as the end product.

Example 3
7- (d, la-aminophenylacetamino) -cephalosporanic acid

2.1 ecm of triethylamine are added to a mixture of 230 ecm of dioxane and 15 ecm of acetone, followed by 4.25 g of dJ-N-carbobenzoxy-a-aminophenylacetic acid. The resulting solution is ^{cooled to 0} ° C. and a solution of 2.04 g of isobutyl chloroformate in 15 ecm of acetone is added dropwise with stirring over the course of 15 minutes. When the addition is complete, the mixture is left to stand at 0 ° C. for 10 minutes.

It is then with a solution of 4.1 g of 7-aminocephalosporanic acid and 2.1 ecm of triethylamine in 15 ecm of water added. This mixture is 2 hours left to stand at room temperature. It is then diluted with 300 ecm of water and twice with Ether washed. The washed solution is acidified to pH 2 with 1 normal hydrochloric acid and extracted with 300 ecm ethyl acetate. The ethyl acetate extract is washed once with water and then extracted at a pH of 6.5 with 100 ecm of water, the pH adjustment with 1 normal potassium hydroxide solution is carried out. The aqueous extract is separated off and dried in vacuo evaporated. The crystalline residue obtained is recrystallized from methanol, 2.5 g 7 - (d, l - N - carbobenzoxy - α - aminophenylacetamino) -cephalosporanic acid obtained in the form of the potassium salt will.

The intermediate product obtained in this way is selectively hydrogenated as in Example 1, the 7- (d, l-a-aminophenylacetamino) -cephalosporanic acid is obtained as the desired end product.

Claims (1)

Claims: 1. 7- (a-aminophenylacetamino) -cephalosporanic acid with the formula NH ₂ O CH - C - NH - CH - HC O = C N and their pharmaceutically acceptable salts.
2. Process for the preparation of compounds CH, COOH CH, O-C-O CH, according to claim 1, characterized in that 7-aminocephalosporanic acid or one of its Salts with the one on the amino group by a carbobenzoxy, carboallyloxy, tert-butoxycarbonyl or trityl protected phenylglycine in the presence of a carbodiimide or with a equally protected chloride, bromide, azide, activated ester or mixed anhydride of the phenylglycine, cleaves the protective group from the compound obtained and the The compound obtained in this way is optionally converted into a salt.