DE2012912A1 - Process for the manufacture of penicillins - Google Patents

Description

PATENT LAWYERS
8 MUNICH 2. H ILBLESTR ASS E 2O

Dr. Berg Dipl.-Ing. Stopf, 8 Munich 2, HllblestraBe 20

Our Zeldien 19 421 date 8 MUTZ 1970 Attorney's file 19 421 '- ■■ -

Tarchominskie Zaklady Farmaceutyczne "POLFA" Przedsiebiorstwo Panstwowe, Warszawa / Poland

Inventor: Emil Taazner ,. Wojciech Gruszecki, Barbara Rzeszotarska, Maria Gdulewicz and Edward Zukowski.

Process for the production of penicillins

The invention relates to a process for the preparation of penicillins by acylation of the amino group of 6-aminopenicillanic acid with organic acids whose carboxyl group is activated.

- 2 009882/2203

The previous methods for activating the carboxyl group for this purpose are based on converting it into active esters or derivatives of anhydride character: mixed anhydrides, chlorides, bromides and acid iodides.

The use of active esters has the advantage that their excess can be used, for example, by means of an ordinary Extraction can remove, whereby the final product is obtained in pure form.

The active ones. However, esters cause weak activation of the carboxyl group and are useful in many Cases not for the acylation of 6-aminopenicillanic acid, even with the use of special catalysts. These Appearance occurs especially in the acylation with sterically hindered acids, where the reaction rate the aminolysis is usually very low and the yields are vanishingly small

The methods using mixed anhydrides and acid halides are free from these disadvantages, and With their help, 6-aminopenicillanic acid can be acylated with practically any acid.

A disadvantage of this process, however, is the pronounced hydrolyzability of these substances; the initial

009882/2203 _, _

■ - 3 -. ■ ■.

Carboxylic acids are difficult to separate from the end products and cause a reduction in the yield and the quality of the penicillins obtained in this way

The invention relates to a new method of manufacture of penicillins of the formula II by acylation of 6-aminopenicillanic acid or its salts with fluorides of the carboxylic acids of the general formula I in an organic solvent with the addition of water.

The salts of 6-aminopenicillanic acid are usually the calcium or magnesium salt

This method has the advantages of both of the above Method, however, is free from their disadvantages.

The acid fluorides as acylating compounds take a middle position between the active esters and Chlorides of carboxylic acids, ie. they are more active than the active esters and at the same time have no tendency towards rapid hydrolysis like the acid chlorides or Anhydrides. For example, the fluoride of 3- (o-chlorophenyl) -5-methyloisoxasolo-4-carboxylic acid distills with water vapor practically without decomposition.

■ ■■■ -. - 4 - ■;

009882/2203.

In addition to the stability of the acid fluorides, there is also their selectivity in the acylation of the amino group. The acid fluorides react quickly with amines under mild conditions even with great steric hindrance, and if so If the reaction proceeds in an organic solvent with the addition of water as a medium, hydrolysis of this can occur Connection cannot be established.

For acylation you can use an excess of the acylating fluoride, which after the reaction by simple Extraction is removed again. This makes it possible to increase the productivity of the synthesis in the To increase the ratio to the starting 6-aminopenicillanic acid, without the risk of contaminating the end product with the free carboxylic acid formed during hydrolysis

By using the proposed acid fluorides instead of φ the most commonly used acid chlorides for acylation the amino group of 6-aminopenicillanic acid achieves considerable advantages.

The process can be carried out at pH 6 to 8, i.e. in an interval that is most favorable for penicillin. the Acid fluorides can, thanks to their greater volatility, »lower boiling points and ease of crisis

009882/2203

stabilization in a very pure state. won. this creates the possibility of obtaining end products in a pure state. The above-mentioned procedure enables the preservation of pure substance after condensation directly through filtration, neutralization and evaporation the solvent from the mixture after acylation.

The process eliminates a number of technical opera- tions. functions to purify the product, with only small amounts of relatively little contaminated as a by-product Wastewater will be formed, which is essential is·

The above-mentioned procedure can be carried out using conventional ones and cheaper organic solvents perform.

The process for the production of penicillins according to The invention is illustrated below with the aid of examples.

example 1

216 mg of 6-aminopenicillanic acid of about 905 * purity were suspended in 4 ml of water and cooled to ⁰ ° C. in a bath. An appropriate amount of Ca (OH) _{2 is then added} in order to obtain a pH in the range from 7.2 to 7.8. Usually 60 to 70 mg of base is sufficient for this purpose.

009882/2203

190 mg of CX-phenoxybutyric acid fluoride, dissolved in 8 bis, are then added to this solution with constant stirring Add 10 ml of acetone and stir the whole thing for half an hour long.

The temperature is increased to 25 ⁰ O with continued rumbling and the reaction mixture is kept under these conditions for 1 hour. The pH is kept within the limits 6.0 to 7 »5.

At the end of this period of time, the solution is filtered, the acetone is evaporated off and 2 ml of 3 # strength sodium bicarbonate solution is used and 5 ml of ethyl ether added. After pouring and putting down, the phases are separated

Then 5 ml of ether and a piece of ice are added to the aqueous layer and the mixture is acidified to pH 2 to 3 with 1 HCl. To The ether layer is shaken out, washed with water and dried using MgSO.

After evaporation of the solvent, 330 mg of one are obtained snow-white precipitate of penicillin in the form of a free acid, which can be converted into a salt, e.g. by adding of 0.1 η NaOH in methanol can be converted.

By evaporating the methanol under reduced pressure

009882/2203 - 7 -

the sodium salt of penicillin is obtained in the form of a white crystalline substance

The minimum inhibitory concentration of this penicillin is for Staph. aureus 207 - P 0.06 / µg / ml.

Example 2

216 mg of 100% 6-aminopenicillanic acid are suspended in 3 ml of water and sets Ca (OH) p or CaO under conditions as in example 1 too. '

Then put 264 mg of 3- (o-chlorophenyl) -5-methylisoxasol-4-carboxylic acid fluoride, dissolved in 8 ml of acetone, with stirring and simultaneous cooling within a half an hour.

With constant stirring within 1.5 hours at room temperature, the pH was kept within the limits 6.2 to 7.0. Then the acetone was evaporated and the water solution filtered through a membrane filter.

. The clear Waeserlösung containing only penicillin salt, / was evaporated under "reduced pressure at a temperature not exceeding 30 ⁰ C to give 450 mg of the sodium salt corresponding penicillins, the inhibition of the development of the Staph aureus 207 - yet P.

009882/2203

at a concentration of 0.5 / µg / ml. The substance obtained meets all standard requirements.

The fluoride of 3- (o-chlorophenyl) -5-methylisoxasol-4-carboxylic acid was obtained by heating for half an hour on 5 * g of technical chloride of 3 - (- o-chlorophenyl) -5-methylisoxasol-4-carboxylic acid with 3, 3 g of 90% KSO ₂ F at a temperature of 100 to 120 ° C. After this period of time had elapsed, the fluoride obtained was distilled off under reduced pressure. This compound is a solid body with a melting point of 58 ⁰ O and a boiling point of 153 ° / 2O mm Hg, which distills with steam without decomposition.

Elemental analysis set

9t C. 9t H 9t N 9t F calculated: 55, 16 3.34 5.87 7.95 won: 55, 34 3.09 6.07 7.57

Spectrum in infrared »1820 cm -1 / CO-F /: 1605 cm" * ¹ , 1430 cm ". Other acid fluorides can also be obtained by this process.

Physico-chemical data of these compounds of general formula I and of the penicillins of general formula II obtained with them are compiled in Table I.

009882/2203

Table I.

E Boiling molar concentration found. yield

point weight neter content of pure

of salary # F Penicil-

Acid $ F line fluoride $> ■

C ₆ H ₅ CH ₂ - 88 ° / 20 mmHg 138.15 13.8 i3.2 80 C ₆ H ₅ OCH ₂ - 73 ° / 10 mmHg 154.13 12.3 11.7 86

C ₆ H ₅ O (CH ₃ ) -.

CH- 85 ^O / 20miaHg 169.1? 11.2 10.7 80

C ₆ H ₅ O- (CH ₃ CH ₂ ) -

CH-. 95-96 ° maHg 183.19 10.0 9.9 98

118 ° / 38mmHg

Patent claims

- 10 - 009882/2203

Claims (1)

Patent claims: 1 \ J Process for the preparation of semisynthetic penicillins of the formula II with acylation of the amino group of 6-aminopenicillanic acid by means of acid halides, characterized in that the 6-aminopenicillanic acid or its salts are acylated by means of carboxylic acid fluorides of the general formula I in an organic solvent and / or with the addition of water . 2. Process according to claim 1, characterized in that the acylation is carried out with the calcium or magnesium salt of 6-aminopenicillanic acid 3 · The method according to claim 1 or 2, characterized in that one from the water solution after the reaction pure crystalline penicillin in salt form is obtained by evaporation 4. The method according to any one of claims 1 to 3, characterized in that the acylation in the range of pH 6.0 to 8.0. 5. The method according to any one of claims 1 to 4, characterized in that the acylation with a Excess acid fluorides carried out ^{IV / My} 009882/2203