DE2411260A1 - PROCESS FOR THE OBTAINING SALT OF ANTIBIOTICS WITH NATURAL AMINO ACIDS - Google Patents

Description

PATENT LAWYERS

■ MUNICH 22 · WIDENMAYERSTRASSE 48 1 BERLIN-DAHLEM 33 · PODBIELSKIALLEE M

BERLIN: DIPL.-ING. R. MÜLLER-BÖRNER MUNICH: DIPL.-ING. HANS-H. WEY

Munich, March 8, 1974 26 248

Antonio Gallardo, SA,
Barcelona (Spain)

Process for obtaining salts from antibiotics
with natural amino acids

The invention relates to a process for obtaining salts of antibiotics of the following structure:

R ₁ -CH-CONH ^

2CXJH

■ with natural amino acids such as lysine, histidine and arginine. In the above formula, R _{1 is} an aryl, heteroaryl or heteroarylthio group, and R is hydrogen

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CRLINl TCUCFON (OS 11) 76 29 O7 MUNICH: TELEPHONE (OS 11) 22 ββ ■ ·

* ·· ¹¹ PKOPINDU ·. TELEX CM MMT KABELl PROPINDUS TELEX (M 24944

or the Nii _o group and Η -OOC-CH ^ group.

Hydrogen or the

The cephalosporanic acid type antibiotics of the above formula are insoluble in water so they cannot be administered by injection. On the other hand cause the water-soluble sodium and potassium salts give pain on injection. In contrast are the amino acid salts on which the present invention relates to being water soluble and causing practically no pain when injected. aside from that they are much more stable.

These salts are obtained by mixing the respective antibiotic with the desired amino acid in an aqueous, alcoholic or aqueous-alcoholic medium or in other xjolar solvents such as dimethylformamide and diraethyl sulfoxide. As the action progresses the antibiotic dissolves and when the salt formation is over, a clear solution is obtained. the The temperature at the beginning of the salt formation can be between 0 and 60 ° C. Then when the salt is in the solution, it can be done by lyophilization, by evaporation of the solvent in vacuo at a temperature of 25 to 60 C or by precipitation with a non-polar solvent such as ethyl ether, petroleum ether or cyclohexane, separated and isolated. In the latter case, the precipitate is filtered off with the same non-polar solvent washed and finally dried in vacuo.

The salts obtained have the following general formula

-CH-CONH ^

-CH ₂ R ₃

COO

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It is

H ₃ N-CH ₂ -CII ₂ -CH ₂ -CH ₂ -CH-COOh or

■ ΠΝ +

C-III-CH ₂ -CH ₂ -CH ₂ -CH-COOH or

^H 2 ^{N <} II " ^W NH ₂

-CH ₂ -CH-COOH. NHo

and R ₁ , H ₂ and R ₃ have the meanings given above.

The invention is explained in detail below with the aid of examples.

example 1

7- (D- # f-amino- <3f ~ pheny! Acetamido) -3-methy 1-3-cephem-4-carboxylate of lysine.

A suspension of 3.72 g of 7- (D-of-aminoc <-phenylacetamido) -3-methyl-cephem-4-carboxylic acid monohydrate of 90 % in 130 ml of water is prepared, after which a solution of 1 , 46 g of lysine in 20 ml of water are added. The suspension is stirred at room temperature for 19 minutes and then heated to 40 ° C. until the suspension has completely dissolved and the formation of the salt is complete. The solution was filtered and lyophilized until one 4.6 g of the desired product with a microbiological activity of 71.3%, based on Cephalexin-mono- bydrat (theoretical content 71.4%) is obtained. Melting point: 170 to 174 ° C (d).

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example

7- (D-ff-amino-cf-pheny! Acetamido) -3-methyl-3-cephera-4-carboxylate of arginine.

To a suspension of 3.72 g of 7- (D - * "- amino-Rf'-phenylacetamido) -3-methyl-3-cephem-4-carboxylic acid monohydrate from 9ö% in 150 ml of water are added with stirring 1, 75 g of arginine base are added The solution is stirred for 5 minutes at room temperature and then heated for a further 3 minutes at 40 ° C. until the salt has formed and everything has dissolved pH 7.0 is lyophilized until 3.8 g of the desired product are obtained, which has a peak activity of 70.1 % (theoretical value 70.1%) with respect to cephalexin monohydrate ° C (d).

Example 3

7- (2-Thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylate of lysine.

To a suspension of 1.2 g of Y- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid in 35 ml of water, a solution of 0.44 g of lysine in 10 ml of water and 6 ml of methanol is added with vigorous stirring. One heats up then the solution at 55 to 60 ° C for 10 minutes until complete dissolution. Then this solution is filtered, removed the methanol by distillation in vacuo and lyophilized until 1.5 g of the desired product is obtained receives. The iodometric analysis shows a content of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carbomic acid of 72.8% (theoretical content 73.0%). Melting point: 135 to 130 ° C.

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Example 4

7- (2-Thienylaeetamido) -3-acetoxymethyl-3-cephem-4-carboxylate of arginine.

A suspension of 1.2 g of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid in 35 ml of water is prepared, after which 52 g of arginine base are added with stirring. The solution is stirred at 35 ° C. for 7 minutes. Then it is filtered and obtained from the filtrate by lyophilizing 1, og of the desired salt. The iodometric analysis shows a content of 7- (2-thienylacetamido) -4-acetoxymethyl-3-cephem-4-carboxylic acid of 9.0 % (theoretical content 69.5 %) . Melting point: 19ό to 202 ° C (d).

Example 5

7 ^ ei- (4-pyridylthio) acetamidoJ-3-acetoxymethyl3-cephem-4-carboxylate of arginine.

To a suspension of 1.3 g of 7-j] o <- (4-l- ⁾ yridylthio) acetamido ^ - 3-aceto.; Ymethyl-3-cephem-4-carboxylic acid in 35 ml of water is added while stirring , Add 53 g of arginine base. The suspension is stirred at room temperature for 5 minutes until the salt has formed and complete dissolution has occurred. The solution is filtered and lyophilized until 1.7 g of the desired product is obtained. The iodometric analysis against cophapyrin sodium gives 73.9 % (theoretical value 74.5%). Melting point: 162 to 166 ° C (d).

Example 3

7- (2-Thieny lacetamido) -3-acetoxyrmethyl-3-cephem-4-carboxylate of lysine.

0.4 g of 7- (2-thienylacetamido) -3-acetoxymethyl-3-cephem-4-carboxylic acid is placed in a flask equipped with a stirrer and 25 ml of methanol. 1.15 g are added with stirring

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90% lysine and then 1.5 ml of water. The solution is heated on a water bath for a few minutes at 40 ° C ₁ until dissolution is complete. It is then filtered and precipitated with about 250 ml of ethyl ether. The precipitate obtained is filtered off and dried in vacuo. A product is obtained which has the same properties as the product obtained according to Example 3.

Example 7

7- (2-Thienylacetamido) -3-acetoxymethyl-3-cephee-4-carboxylate of arginine.

Following the procedure explained in Example 6, one obtains the above product with the corresponding starting materials. The iodometric analysis shows a content of 69.3% (theoretical content 69.5%).

Patent claims:

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Claims (3)

Patent claims: . Process for the production of salts from antibiotics of the general formula R ₁ -CH-CONH-i ■ ·· t ¹¹ 2 COOH with natural amino acids such as lysine, histidine and arginine, where R is an aryl, heteroaryl or heteroarylthio group the formula R _{2 is} hydrogen or di · HIIg group and R _{3 is} hydrogen or the -OOC-CHg group, characterized in that in a solvent such as water, methanol, ethanol, acetone, dimethylformamide, dimethyl sulfoxide or a mixture thereof at a Temperature between 0 and 60 ° C converts. 2. The method according to claim 1, characterized in that loan the product by precipitation with a non-polar solvent, such as petroleum ether, ethylbenzyl ether or Cyclohexane, and subsequent filtration isolated. 409837/1111 3. The method according to claim 1, characterized in that the product obtained is separated off by evaporating the solvent or the solvent mixture. 409837/1111