SU419038A3 - Method for producing 6-aminopenicillanic acid derivatives - Google Patents

Description

This invention relates to an improved process for the preparation of 6-amnopenicillanic acid derivatives, which have an antibiotic effect.

There are known methods for producing acarboxybenzylpenicillin by reacting phenylmalonic acid dichloride with sodium 6-aminopenicillanoic acid sodium in an aqueous medium, followed by hydrolysis of the acid chloride obtained and isolating the products in a known manner.

The disadvantages of the known methods include the low yield and purity of the target products, the use of large volumes of water, a combustible solvent (ether), the difficulty of separating carbenicillin from the organic medium, and the difficulty of removing impurities from the aqueous solution, since sodium salts of by-products precipitate along with the carbenicillin upon evaporation of the aqueous solution.

In order to simplify the process and obtain high quality products with high yield, a method is proposed for the preparation of 6-aminopenicillanic acid derivatives of general formula I

S CH-,

CH-CO-HN

1 fcH5 -N-L COOH

d

Cun

where R is phenyl, naphthyl, a heterocyclic single or double bond residue containing at least one heteroatom selected from the group consisting of nitrogen, oxygen and sulfur, and these radicals may contain one or more substituents - a halogen atom, lower alkyl , lower alkoxy, nitro, amino, alkylthio, alkylamino, dialkylamino, hydroxy.

Heterocyclic groups are, for example, furyl, tisnil, pyridyl, pyrazinyl, pyrrolyl, piperazinyl, morpholinyl, quinolyl, isoquinolyl.

The method consists in the fact that trnalkylsilyl ether of the general formula II

(RljSi-HN

where R is lower alkyl, acylated with malonic acid dihalide of the general formula III

-SOX

Rch

SOH

where R is as defined above;

X is a halogen atom,

in the presence of a weak base and the resulting product of the sheath, her formula IV

Si (R%

B-CH-00-N COX

COOSi (B%

where R, R and X are as defined above,

is hydrolyzed, for example, with water in the presence of a base, such as hydrate of oxide, a christmas tree, for example sodium hydroxide, an alkali metal carbonate or ammonia. Moreover, if the hydrolysis occurs under the action of a weakly alkaline solution, then the compound of formula I is isolated in the free form of act1 | wiem acid and extracted with ethnyl acetate. The free dicarboxylic acid of formula I can be suspended in a solvent that is not miscible with water (for example, in methylene chloride), and the sodium salt of diethyl acid can be added to precipitate the disodium salt of this acid.

The yield of products is 62-80%.

Trialkylsilyl ester 6-amipopenitsillanovoy acid was prepared by treating 6-aminopenitsillanoBOy acid trimethylchlorosilane in a solvent not containing a hydroxyl group such as methylene chloride, dichloroethane, chloroform, tetrahydrofuran, in the presence of a strong base, such as triethylamine, and a weak base, e.g. B, L-dimethylaniline or pyridine, which serves as an agent for binding the released acid.

Compounds of formula IV are not described in the literature.

Example 1. 6.51 g (0.03 mol) of 6-aminopsnicillanic acid (6-APC) are suspended in 65 ml of methylene chloride in a 500-ml four-necked flask equipped with a stirrer, thermometer, dropping funnel, reflux condenser, calcium chloride tube and a tube for nitrogen delivery. Then, 8.4 ml (6.0 g; 0.06 mol) of triethylamine was introduced into the flask and the mixture was stirred at room temperature in a nitrogen atmosphere for 60 minutes before 6-amyopenicillanic acid was dissolved in the solution. Next, the mixture is cooled to -10 ° C, after which iribavla solution of 6.5 g (0.06 mol) of trimethylchlorosilane in 25 ml of methylene chloride and a solution of 4.02 g

(0.03 mol) N, N - dimethylaniline in 15 ml of methylene chloride.

The reaction mixture is heated to 40 ° C under a stream of nitrogen and refluxed for 60 minutes. Then, at (-20) - (-25 ° C), a solution of 6.5 g (0.03 mol) of phenyl-maloic acid dichloride is introduced into 60 ml of methylene chloride. The reaction mixture is maintained at the indicated temperature for 30 minutes, after which it is decomposed by spraying 150 ml of sodium hydroxide solution at (-10) - (-15) ° C and vigorous stirring, and is continued to be stirred for 30 minutes at РЫ 7-8 and temperature 0-5 ° С .

The resulting two layers are separated and the aqueous phase is washed with methylene chloride (2 x 50 ml). The aqueous layer containing dvuhpatrievuyu1 carbspitsillina, washed with 200 ml of ethyl acetate and 1 and. pacTJSOpoM sol)

the acids are acidified to pI 2 while cooling to O-5 (;. the layers are separated, the aqueous phase is extracted with ethyl acetate (2 x 50 ml), the ethyl acetate layers are combined, dried and evaporated at 20 ° C. The precipitate containing carbenicillic acid is suspended in 100 ml of methylene chloride, then 8.4 ml of triethylamine is added at 0 ° C and the reaction mixture is stirred at the same temperature for 2 hours. sodium diethyl acetic acid. A mixture kept in the refrigerator overnight, amorphous precipitated

 the product is filtered off and the catalyst is washed with acetone. The melting point of the obtained product is 217-220 ° C. The infrared spectrum provides a band of swiches, characteristic of carbenicillin. According to the results of the titration

product purity reaches 90%.

Example 2. 6-Triethylamine salt of aminopenicillanic acid is prepared, but for example 1, from 4.5 g (0.02 mol) of 6-APC in 50 ml of methylene chloride and from 5.6 ml (0.04 mol)

triethylamine. After cooling the mixture to -10 ° C, a diluted solution of 6.9 ml (0.04 mol) of trimethylchlorosilane and 20 ml of methylene chloride or 1.6 ml of pyridine in 5 ml of methylene chloride is added. Mixture

heated in a stream of nitrogen for 60 minutes to 35-40 ° C, after which a solution of 5.0 g (0.02) / g-hl ;; rphenylmalonyl dichloride in 50 ml of methylene chloride (-20) - (-25) is poured ° s The reaction mixture is stirred

At this temperature for 20 minutes, decompose with 10% potassium bicarbonate solution and set RP 7. The phases are separated, the aqueous phase is washed with ethyl acetate and acidified with 2N. hydrochloric acid to RP 2. Of

The ethyl acetate phase containing α-carboxyp, α-chlorobenzyl pepticillanic acid, 50% sodium diethyl acetate solution precipitates the disodium salt of this acid and filtered. 6.7 g of powdered is obtained.