DE2307564A1 - PROCESS FOR THE PRODUCTION OF PENICILLIN DERIVATIVES - Google Patents

Description

Dr. Ing.Dr. Jur. F. Dr. rar. nat. B. Dr. rer. nat. D. Dipl.-Ing. Ch. REDIES REDIES TURK & GILLE "U / b64

PATENT LAWYERS

4 DOtseldorf-Denrath 3 Erlch-Ollonhauer-Strasse DRK medical center Garath Telephone (0211) 7010 38 Telex 8582 841 rrtg d Telegrams: Returgl Düsseldorf

lhrZ »lct> en: Uiwtr ZelchMi: Date:

687

Applicant; ARTUR PEREIRA DA LUZ,

Al, I ·· »· andar, Rua Luciano Cordeiro, Lisbon / Portugal

Process for the production of penicillin derivatives

The invention relates to a new process for the preparation of penicillin derivatives, which are interesting intermediates for Represent the manufacture of semi-synthetic penicillins. In particular, it relates to a new method of manufacture of 6-aminopenicillanic acid and derivatives thereof from known and easily accessible natural penicillins.

The preparation of 6-aminopenicillanic acid of the formula I given below

Br.Ha / bgr H ₂ N-CH-CH C ^

O = C fl ^ H-.C OH

(D ο 309848/1172

was first described by K. Sakaguchi and S. Murao in "J. Agric. Chem. Soc. Japan", 2J5, Ί11 (1950), under the name penicillin. The authors stated that it was obtained by enzymatic cleavage of the amide bridge of the benzylpenicillin side chain. However, this method was not described in sufficient detail to be reproducible and it was only later that 6-aminopenicillanic acid was isolated and correctly identified by FR Bachelor et al. "Nature", I83, 257 (1959), using a different method: treatment of the fermentation broth of Penicillium chrysogenum under conditions similar to those used for the production of penicillins, but without the addition of the side chain precursor compound. Despite the fact that the isolation of 6-aminopenicillanic acid was of great theoretical value since it is the core common to all penicillin molecules, the immediate practical interest in it has been limited because the yield is low and the purification is difficult.

Since 6-aminopenicillanic acid has almost no biological activity, its utility resides solely in the possibility that it can be used as a starting material for the synthesis of penicillins represented by the following general formula

N i: H C OH

\ ⁿ

in which the side chain bound via the peptide bridge contains the radical R, which cannot be introduced by direct fermentation. In fact, the semi-synthetic penicillins are produced in this way by acylation of 6-aminopenicillanic acid on the 6, -araino group using various methods. For the preparation of the necessary for these syntheses

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6-aminopenicillanic acid, various methods of enzymatic hydrolysis of the amine bond have been developed, whereby one started from the natural penicillins, namely penicillin G and V.

This enzymatic cleavage has already been the subject of extensive investigations. The resulting procedures however, take a long time and must be carried out under well-controlled conditions with regard to sterility and They have to deal with large volumes of liquid from which the desired 6-aminopenicillanic acid is only difficult to obtain can be isolated. In addition, the acid obtained by this process must be purified and there are already many Adsorption and recrystallization processes for this purpose. However, these process measures reduce the yield and even then, the purified product still contains impurities that are difficult to eliminate and with Patients who are treated with the semisynthetic penicillins produced from them have allergic reactions.

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can call.

These disadvantages can be avoided by methods of chemical cleavage of the amide bond. It should be emphasized, however, that the chemical cleavage of penicillins must be carried out under very mild conditions, whereby the lability of the ß-lactam rings must be taken into account. That is why the penicillin molecule must modified by esterification of the carboxylic acid group and conversion of the amide bond into an easily hydrolyzable imine bond will. The ester group must then be split off under mild conditions. The choice of ester group is very important because they not only make the carboxylic acid group effective must protect, but must also be easily removable.

The present invention now relates to a process in which a natural penicillin is used as the starting material,

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which is converted into an organometallic ester using an organic tin derivative. That way The products obtained have not yet been described and they are very valuable intermediates for synthesis of penicillins. The process according to the invention is further characterized in that the new organometallic esters the natural penicillins by reacting with an imine-forming one Reagent can be converted into compounds that do not need to be isolated, and by removing the side chain can be easily hydrolyzed with liberation of the 6-amino groups. The compound obtained in the form of an ester can, if desired, be hydrolyzed with the formation of free 6-aminopenicillanic acid or it can also be used for the production of semi-synthetic penicillins are used.

Those occurring when carrying out the method according to the invention Reactions are described in more detail below. First is a natural penicillin of formula II, in which the radical R can be aliphatic or aromatic and in the latter case an aryl, aralkyl, aryloxyalkyl group, preferably a benzyl or phenoxymethyl group, with an organotin compound of the following general formula III or IV treated

R ² R ² Pi

R ⁴

(III)

wherein R , R ^ and R, which can be the same or different, are aliphatic or aromatic organic radicals, for example alkyl, aralkyl or alkoxy radicals, and X is a reactive group, for example a lower alkoxy, hydroxy group or a halogen atom.

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The reaction products are new penicillin esters of the following general formula V

Ϊ CH- 0 - O C- I.
C - -CH - ~ -Sn ™ -NH I.
- N— 0 == NS"
'\ y ^Δ C. _CH — C - Π
0

if desired, isolated and for subsequent use can be cleaned.

These compounds have exceptionally good stability in obvious contrast to the known organotin esters of amino acids. Because of this stability, it is possible to use these compounds in the presence of protonic solvents or to use even in the presence of water without being subject to hydrolysis. This is extremely beneficial as this eliminates the precautionary measures of other procedures and it is also possible to postpone cleaning Perform standard methods including recrystallization. However, the esters of the formula V are sensitive to strong (inorganic or organic) acids and bases, which they hydrolyze. By carefully choosing the concentration, it is possible to hydrolyze the penicillin molecule, without cleavage of the ß-lactam ring occurs. Another very beneficial feature of using the above Esters in the operations leading to the hydrolysis of the side chain is their solubility in a large number of organic ones Solvents.

According to the process of the invention, the new esters of the formula V using an imine-forming reagent in the corresponding imine compounds transferred. The best results are obtained when the imine-forming reagent is a halide

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is used, which provides the iminohalide derived from the above-mentioned new organotin esters of penicillins. The halide is preferably a chloride, bromide or iodide of phosphorus, for example phosphorus oxychloride, phosphorus pentachloride or phosphorus pentabromide. This reaction can be carried out with advantage in the presence of an organic base, for example in the presence of a tertiary amine, such as pyridine, dimethylaniline, quinoline, triethylamine, etc. The presence of the organic bases has the advantage that the acid released during the conversion is neutralized, thereby avoiding any destruction of the penicillin core. The used for carrying out this reaction medium, it should be a non-polar organic solvent, and the imino compound obtained in the reaction does not need to be isolated and can be used in solution for the next stage in general. If it is at the imine-forming reagent is a halide, and wherein the reaction product is a iminohalide, it is preferably converted by reaction with a lower alcohol in an iminoether.

As an alternative to the method described above, the imino ethers can be synthesized directly from the new organotin esters of natural penicillins described here by reacting them with the appropriate imine-forming reagents, such as the Meerwein reagent, dimethyl sulfate and a benzenesulfonyl chloride / pyridine mixture. Since the imino ethers hydrolyze easily, the action of water can release the desired trisubstituted tin 6-aminopenicillanate. If the 6-aminopenicillanates themselves are not desired, they can, if desired, be hydrolyzed after purification. The hydrolysis is carried out in an aqueous medium using an acid or a base under mild conditions. The free 6-aminopenicillanic acid falls in

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highly pure form when their isoelectric point is reached. The total yield can reach 3 ¹ I and 35 g of 6-Aminopeniciliansäure per 100 million International Units penicillin.

The reactions occurring are explained in the attached reaction scheme. Furthermore, the practical application of the invention is illustrated in more detail by the following examples, without, however , being restricted thereto.

example 1

* ♦ »5 g (10 mmol) of the benzylpenicillin-N-ethylpiperidine salt were suspended in 100 ml of ethyl acetate and the mixture was heated to 50 ° C. under a nitrogen atmosphere. While the temperature and the flow rate of the nitrogen were kept constant, 3.38 g (11 mmol) of tributyltin hydroxide were added very quickly. The reaction vessel was closed and connected to a Dean-Stark trap which was gently refluxed for 15 minutes. Do the waste cool leave, always under a nitrogen stream, most of the solvent was removed under vacuum. Acetone was added to make up to the initial volume , the solution was filtered to remove a certain turbidity which was due to unreacted penicillin and evaporated to dryness under vacuum. The viscous resin obtained was recrystallized from acetone / petroleum ether and a white, crystalline powder was obtained with the following elemental analysis:

Analysis for C ₃₈ H ₁₄ ^ N ₂ O ₁₁ SSn . C 53.91 H 7.11 N 4, 1/8 Jl

found C 53.8 H 7.2 N 1.7 %

3.1 g (5 mmol) this? Product were suspended in 80 ml of carbon tetrachloride in a flask protected from moisture. 5 ml (62 mmol) of freshly distilled pyridine were added with stirring

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added and then the mixture was cooled to -15 ° C. At this temperature, 1.04 g (5 mmol) of phosphorus pentachloride were added. After stirring for one hour at -15 ° C, 20 ml of methanol are added with vigorous stirring and cooling at -15 ° C. The addition had to be done carefully in order to avoid undesirable heating. Stirring was continued for 2 hours with the reaction bottle removed from the cooling bath. At the end of this period the temperature had reached 5 C was reduced to 0 ⁰ C and 50 ml vmrden added a cooled sodium bicarbonate solution. The extraction was repeated three times, the extracts were combined and washed with a small amount of butyl acetate. The chromatographic thin-layer analysis (silica gel plates, elution with butanol / xthanol / water (4/2/2) and development by spraying with iodine starch) showed the presence of 6-aminopenicillanic acid. A sample of the solution was freeze dried to give a solid product which was dissolved in water basified with sodium hydroxide and treated with activated charcoal. The piltrate was brought to pH 4.3 with hydrochloric acid to obtain crystals of 6-aminopenicillanic acid, which was identified by thin layer chromatography, by the ninhydrin test and by its infrared spectrum. Alicino iodometric titration, "Anal.Chem" J52., 648 (1967) showed that it had a purity of 98.355. The melting point was 208 to 208.5 ° C (uncorrected) with decomposition, Ια] « = + 269.8 in water (this corresponds to a purity of 99.7 / 0

B. e I s ρ i el 2

A suspension of Ί.5 g (10 mmol) of N-ethylpiperidine benzyl penicillanate in 100 ml of freshly distilled benzene was heated to 65 ° C. under a nitrogen atmosphere. While the nitrogen flow and the temperature were kept constant, 2.6 ml (5 mmol) of tributyltin oxide were added. The reaction flask was connected to a Dean-Stark trap and 30 minutes

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distilled for a long time, the reflux ratio being adjusted so that 15 ml of benzene distilled during this period. A very small amount of activated carbon was added and the mixture was filtered with the aid of a filter aid filtered. After evaporation under reduced pressure on a thin-film rotary evaporator, a light-colored one was obtained Resin residue, which is then dissolved in acetone and after recrystallization from hexane into a white crystalline powder was convicted. Analysis of this powder showed that it was identical to that obtained in the first reaction step of Example 1 Product was identical.

3.1 g (5 mmol) of this product were subjected to amidolysis, the imine chloride being formed first and then the imino ether under conditions very similar to those in Example 1 . The end product was again 6-aminopenicillanic acid.

Example 3

A suspension of 3.72 g (10 mmol) of potassium penicillin G in 100 ml of ethyl acetate was heated under nitrogen at 50 ⁰ C and at this temperature quick 2.66 ml (10 mmol) of tributyltin chloride were added. The reaction flask was closed, connected to a Dean-Stark trap, and heated under mild reflux conditions for 10 minutes under nitrogen. After cooling, the solvent was removed by evaporation on a rotary evaporator under reduced pressure. After restoring the initial volume with acetone, the mixture was filtered and again evaporated to dryness in a rotary evaporator. The viscous resin obtained was used in the subsequent stages without further purification. For this purpose the product with 50 ml of dichloromethane was added to a moisture-proof reaction flask and were 7, ¹ ml I N-dimethylaniline was added

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and the flask was cooled to -25 ° C. While the temperature was kept constant, 1.66 g (8 mmol) of phosphorus pentachloride was slowly added to it. The reaction mixture was stirred for 1 1/2 hours, quickly - ² JO cooled ⁰ C and then 50 ml n-propanol was quickly added dropwise. The n-propanol had been cooled ^{to -JO 0 C beforehand.} The reaction mixture was stirred for 3 hours, allowing the temperature to gradually rise to -10 ° C. 10 ml of the cooled sodium bicarbonate solution were added and stirring was resumed, allowing the temperature to rise freely to 0C. The two phases formed were separated from one another, the extraction was repeated twice and the combined extracts were washed with butyl acetate. The pH was adjusted to 4.3 by adding concentrated ammonia, the 6-aminopenicillanic acid crystallizing out directly and being identified as in the above example. The amount obtained was 1.9 g and the product had a melting point of 208 to 209 ° C. (decomposition). Concentration and re-extraction of the organic phase gave a second crop of 0.16 g with a melting point of 206 to 207.5 ⁰ C (decomposition).

Example 4

To a solution of 2.7 ml of tributyltin oxide in 100 ml of dry toluene which had been heated to reflux temperature, Ί.5 g of N-ethylpiperidine benzyl penicillanate were added. The reaction mixture was refluxed using a Dean-Stark trap for 10 minutes and the reflux ratio was adjusted so that the volume of the solvent was reduced by ήθ%. After allowing to cool, it was filtered and the filtrate was concentrated in vacuo until the volume was reduced to 20 ml. The solution was poured into hexane with stirring and the powdery product obtained was filtered off, washed with ice-cold acetone, overnight

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dried under reduced pressure and used for the subsequent reactions without further purification.

3.1 g of the product were suspended in chloroform in a flask protected from moisture and, after the addition of 5 ml of quinoline, the mixture was stirred for 30 minutes at room temperature. After cooling to -1O ° C was added a solution of 1.66 g of phosphorus pentachloride in chloroform at -30 ⁰ C and stirred for two hours at -30 ⁰ C. Thereafter, 20 ml of methanol was added at -30 ⁰ C under cooling and vigorous stirring, which took one hour. Then 20 ml of dimethylformamide were added and distillation was carried out under reduced pressure (1 mm Hg) at room temperature until a final volume of 25 ml was reached. A further 20 ml of dimethylformamide were added and the distillation was continued under reduced pressure at 36 ^° C. until the boiling stopped. To the remaining solution, 750 mg (5 mmol) of potassium thiophenolate was added and the mixture was poured into acetone / ether. The voluminous precipitate formed was filtered off, washed with acetone / ether and dissolved in 25 ml of distilled water. By adjusting the pH of the solution to M.3 with hydrochloric acid, a crystalline precipitate of 6-amino penicillanic acid was obtained. The amount was 2.1 g and the product was analyzed and identified as in the above examples.

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Claims (5)

PATENT CLAIMS !. ^ Process for the preparation of penicillin derivatives, the valuable intermediates for the synthesis of semi-synthetic penicillins represent, in particular of 6-aminopenicillanic acid and its derivatives, characterized in that that he a) a penicillin of the general formula Ί Ii V / " R C NH CH CH O = C N -'CH C OH (II) 0 or a salt thereof, in which R can mean an aliphatic or aromatic organic radical, with an organic tin derivative reacts one of the following general formulas -Sn-D-Sn R ³ π " (in) wherein R, R ^ and R, which are the same or different can, aliphatic ^ or aromatic organic radicals, and X a suitable for the formation of organotin esters mean reactive group, b) converts the organotin esters with an imine-forming agent to produce the corresponding imino compound and, if necessary, convert it into an imino ether 309848/1172 leads, c) for the production of the corresponding organotin derivative the 6-aminopenicillanic acid cleaves the imine bond and, if desired, the ester with liberation of the 6-aminopenicillanic acid hydrolyzed. 2. ' Process according to claim 1, characterized in that one a halide is used as an imine-forming agent and an imine halide is obtained as an imino compound which is obtained by reaction is converted with a lower alkanol into the corresponding · imino ether. 3. The method according to claim 1 or 2, characterized in that a compound of formula II is used in which R is an aryl, arabic or aryloxyalkyl radical, preferably denotes a benzyl or phenoxymethyl radical. 4. The method according to claim 1 or 2, characterized in that a compound of formula III or IV is used in which R, R ^ and R ^{H are} alkyl, aralkyl or oxyalkyl radicals and the reactive group X is a lower alkoxy, hydroxy group or represent a halogen atom. 5. The method according to claim 2, characterized in that caß one as an imine-forming agent, a phosphorus halide from the group consisting of phosphorus oxychloride, phosphorus pentabromide and phosphorus pentachloride used. 309848/1172 4H Blank page