DE2026506C3 - Process for the preparation of penicillin salts - Google Patents

Description

where X is the acyl radical of an oc-phenoxypropion- or butyric acid, a «-halo or α-alkoxyphenylacetic acid or a 3-aryl-5-alkylisoxazolyl-4-carboxylic acid and Me for a potassium, sodium or stand half a calcium cation, by acylation of 6-aminopenicillanic acid, whose Carboxyl group and optionally also its 6-amino group through silyl radicals of the general formula

ι '

-SiR ₂

wherein Ri to Rj are alkyl groups with 1 to 3 carbon atoms, are substituted and conversion of the silylated penicillins obtained into salts, characterized in that the solution of the penicillin silyl ester obtained after the acylation in an aprotic organic, anhydrous and alcohol-free solvent without prior solvolysis with a water- and alcohol-free solution of a compound of the general formula R ₄ -O-Me, in which R _{4 represents} the acyl radical of a fatty acid or a dialkylmalonic acid, for the phenyl radical or for a group of the general formula

Si R ,,

in the ri to r? Are alkyl or phenyl groups and separating the deposited salt and optionally, if the silyl derivative of penicillin is more contained as a silyl group, desilylation by treatment with a hydrous solvent completed.

2. The method according to claim 1, characterized in that the groups Ri to R _{3 are} methyl groups and the compound of the general formula R ₄ -O-Me is the sodium, potassium or calcium salt of a-ethylhexanoic acid.

X -NH-CH-CH

CH ₃

/ C-CH ₃

CO-N CH -COOMe

ίο

wherein X is the acyl radical of a-phenoxypropion or -butyric acid, a «halo or cc-alkoxyphenylacetic acid or a 3-aryl-5-alkylisoxazolyl-4-carboxylic acid and Me for a potassium, sodium or a half Calcium cation stands.

Such alkali or alkaline earth salts of penicillins are known in principle

Their production has so far essentially been based on in the following ways:

1) Neutralization of a solution of the free acid form of penicillin in organic or organic-aqueous Solvents by alkalis, amines, salts

weak acids with appropriate bases or metal alcoholates, etc. Isolation of the salts took place depending on the solubility and stability of the products by evaporation of the Dissolution and / or filtration of the precipitated crystals, in some cases also by filtration by adding solvents in which the desired salts are insoluble or sparingly soluble, precipitated products.

2) Double conversion of amine salts of penicillins which are soluble in organic solvents MetaJlbalzen certain fatty acids, such as B. the a-ethylhexanoic acid or with alcoholates etc. in suitable solvents, such as. B. chlorinated hydrocarbons, acetone, butyl acetate etc.

In the known method described under 1), in particular in organic solvents as free acids soluble penicillins are used. Here, however, it is when inorganic or metal salts are used organic acids is worked, it is necessary that the antibiotic used is significantly more acidic than that Acid component of the salt used. Especially when using water-containing organic Solvents often encounter difficulties in isolating the penicillin salts with this procedure when these products are hygroscopic or relatively unstable.

In all known processes for the preparation of in particular penicillin alkali or alkaline earth salts the carboxyl group capable of salt formation in the corresponding starting solutions free or in the form an amine salt bound before.

The method according to the invention differs

now fundamentally from the prior art that the carboxyl group of the penicillin in question in the for The starting product used for salt formation is neither in free form nor in salt form, but in form an ester derived from a trialkylsilanol. the

b5 Production of such »penicillin silyl esters« takes place in known manner (see e.g. DE-PS 1159 449, GB-PS 9 64 449, GB-PS 10 08 468 and many other references) by acylation of 6-aminopenicillanic acid,

20 26 50Ö

their carboxyl group and optionally also their 6-amino group through silyl radicals of the general formula

1'

-Si-R ₂

R ₃

IO where Rj to Rj are alkyl groups with 1 to 3 carbon atoms

~ men mean, are substituted.

It is known from the prior art that the penicillin silyl esters are replaced by water, alcohols or others Proton-active compounds are cleaved to form the free acids. For the production of penicillin salts so one has always proceeded in such a way that one from the penicillin silyl esters by hydrolysis or alcoholysis etc. produced the free penicillic acid and then converted this into the salts in a manner known per se.

Surprisingly, it has now been found that penicillin salts from silyl derivatives of penicillins also can be obtained without intermediate cleavage of the silyl ester group or preparation of the free acid by converting the solution of penicillin silyl esters obtained after the acylation in aprotic organic, anhydrous and alcohol-free solvents without prior solvolysis with an anhydrous and alcohol-free one Reacts solution of a compound of the general formula R4 —O —Me, in which R4 represents the acyl radical a fatty acid or a dialkylmalonic acid, for the phenyl radical or for a group of the general formula

in which R5 to Rr are alkyl or phenyl groups and separating the deposited salt and optionally if the silyl derivative of penicillin has more than one Containing silyl group, the desilylation was completed by treatment with a hydrous solvent. The process according to the invention can be represented by the following general reaction equation:

R-COOSi-R ₂ + R ₄ -O-Me

R ₄ -O-Si-R ₂ + R-COOMe

Therein means (Ri to R ₄ and Me have the same meaning as above):

R is the group of the following formula:

X-N-CH

CH ₃

O = C

-N L-

wherein X stands for the acyl radical of a -phenoxypropionic or butyric acid, of a -halo or α-alkoxyphenylacetic acid or an S-aryl-S-alkylisoxazolyl ^ -carboxylic acid and Y for a hydrogen atom or for the group

-Si-R ₂

R ₃

stands;

Those penicillin silyl esters in which Ri, R ₂ and R3 each represent a methyl group are preferred.

Compounds of the formula R ₄ -O-Me are, for example, the sodium, potassium or calcium salts of butyric acid, isobutyric acid, α-ethylbutyric acid, isoamylethyl acetic acid, dialkylmalonic acids or, in particular, ethylhexanoic acid. Furthermore, the compounds of the formula R ₄ -O-Me can be the potassium or sodium compounds of phenol, of a trialkyl, in particular of trimethylsilanol, or of triphenylsilanol.

The silyl derivatives of penicillins are easily soluble in anhydrous aprotic solutions. As can be seen from equation 1, by-products of the salt formation reaction _{according to the invention, if R 4 is} an acyl radical, are the silyl esters of the _{acids contained in the compound of the formula R 4} -O-Me or the silyl ethers of compounds of the formula R ' ₄ OH, in which With the exception of acyl, R ' _{4 has the same meaning as R 4} . The side problems arising in the reaction

<to products have the same good solubility as the Penicillin silyl derivatives in a wide variety of aprotic solvents and are therefore of the the salts formed by the process according to the invention are easily separable.

That the method according to the invention actually takes the route shown in equation I could be proven by the fact that the silyl ester of a penicillin with an absolutely anhydrous solution of the Sodium salt of a-ethylhexanoic acid was reacted in absolute ether. (The solution of the sodium salt the a-ethylhexanoic acid was obtained completely anhydrous by having a little more than that of the Production of the water contained in it added an equivalent amount of N-methyl-N-trimethylsilylacetamide and thus converted the water into hexamethyldisiloxane). After the reaction, the sodium salt of Separated penicillins and examined the remaining solution by gas chromatography. It turned out that that this solution contains the trimethylsilyl ester of «-ethylhexanoic acid (in addition to the N-methylacetamide from the drying of the sodium ethylhexanoate solution or hexamethyldisiloxane and a small amount of excess N-methyl-N-trimethylsilylacetamide) contained.

According to the invention, the penicillin salts are expediently prepared as follows:

An anhydrous and alcohol-free solution (A) of the compound R ₄ -O-Me is obtained with stirring and

Exclusion of moisture combined with solution (B) of an equivalent of the penicillin silyl ester in ether, where you can add both solution A to solution B and solution B to solution A.

In most cases, the penicillin salt separates out spontaneously. Filtration with exclusion of humidity and washing with absolute ether provides the salt in very good purity if the monosilyl derivative of penicillin was assumed.If the silyl derivative of penicillin contains more than one silicon group, washing with a solvent that is not extremely dried is recommended, whereby the then the small amounts of water exposed to the action complete the desilylation of the silyl derivative of penicillin which has already precipitated as a salt.

In the process according to the invention, for example, open or cyclic solvents can be used as solvents Ether, saturated hydrocarbons or halogenated hydrocarbons, aromatic hydrocarbons, but also esters of carboxylic acids are used.

The solution of the penicillin silyl ester should expediently be as free as possible from salts that occur in the Formation of this silyl compound could have arisen. (Examples are amine salts such as triethylamine hydrochloride noticeably soluble in chlorinated hydrocarbons and other solvents). Possibly can be obtained from the solution of the penicillin silyl esters contained therein by adding Suitable solvents, such as ether, petroleum ether, benzene, in which the salts are not, but the silyl derivatives are readily soluble, remove. The solution then obtained can be used for the reaction according to the invention will.

To prepare an absolutely anhydrous solution of a carboxylic acid salt of the formula R ₄ -O-Me, the procedure is that a carboxylic acid, such as. B. the nc-ethylhexanoic acid, dissolves in absolute tetrahydrofuran, an equivalent amount of a base (z. B. solid sodium or potassium hydroxide, calcium oxide) is added and, after the solid components have been dissolved, anhydrous sodium sulfate is added to make up most of the amount during the neutralization to remove the resulting water. It is filtered and the desiccant, which now contains water, is washed with tetrahydrofuran. After evaporation of the solution, the residue is dissolved in a suitable dry aprotic solvent or solvent mixture, ζ. B. a mixture of tetrahydrofuran / ether 1:20, dissolved and then the water content is determined in a measured sample of this solution. Finally, an amount of securing agent equivalent to the amount of water determined, in particular trimethylsilylacetamide or N-methyl-N-trimethylsilylacetamide, is added.

The method according to the invention brings with it a considerable enrichment of the technology. It allows namely the production and isolation of penicillin salts under extremely gentle conditions, whereby In addition, these salts can be obtained immediately in dry form and thus a hydrolysis or Risk of decomposition during manufacture, isolation and in the processes required by the bekarr' ° n Removal of anhu. ^ MJcin water is avoided. The penicillin salts are always with high yield and good, for the process according to the invention Part of very high purity obtained. This is all the more surprising as it is in the case of the one according to the invention Method is the first way ever (also regardless of the field of penicillin salt production

treatment) in which a salt is produced from the ester of a carboxylic acid without saponification as an intermediate of the ester to the free acid takes place

The following examples serve to further illustrate the invention.

example 1

A solution of 4.87 g of the trimethylsilyl ester of 6 - («- phenoxybutyramido) penicillanic acid in 70 ml of absolute ether is poured into the anhydrous solution of 0.01 mol of the sodium salt of α-ethylhexanoic acid in tetrahydrofuran / ether 1:20. Precipitation occurs immediately. After 30 minutes, suction filtered with exclusion of moisture, washed with absolute ether and dried in vacuo at 50-6O ⁰ C The yield is 4.1 g = 102% of theory with an iodometrically determined Penicillin content of 97%.

Example 2

a) 5.1 g of 6-aminopenicillanic acid were dissolved in 50 ml of anhydrous, alcohol- or acetic acid-free ethyl ester in a manner known per se by adding 6.5 ml of triethylamine and 5.9 ml of trimethylchlorosilane converted into the disilyl derivative. The reaction mixture was quinoline with 2.8 ml and then mi <4.6 g of α-phenoxybutyric acid chloride added. It was stirred for a further hour, then filtered with strict exclusion of moisture and the The residue was washed 3 times with 15 ml of absolute ethyl acetate each time. The combined filtrates were evaporated to approx. 125 ml in vacuo

b) 0.02 mol of the sodium salt of 2-ethylhexanoic acid are absolute in a mixture of 5 ml Tetrahydrofuran and 45 ml of absolute ether and dissolved after determining the water content Addition of the equivalent amount of N-methyl-N-trimethylsilylacetamide made anhydrous. The so obtained solution is added to the solution obtained in section a) and then under Stir mixed with 220 ml of absolute petroleum ether. The reaction mixture is cooled and some Left for hours. The precipitate is the sodium salt of 6 - («- phenoxybutyramido) penicillanic acid. The product is filtered off with suction, washed with ether and dried in vacuo. yield 7.2 g = 90% of theory with an iodometrically determined penicillin content of 90%.

Example 3

A solution is prepared as in Example 2a and this is mixed with a solution of the potassium salt of 2-Ethylhexanoic acid in tetrahydrofuran (this latter solution was made from 1.23 g of potassium hydroxide and 3.17 g 2-Ethylhexanoic acid prepared in tetrahydrofuran and after predrying with sodium sulfate by adding with N-methyl-N-trimethylsilylacetamide accordingly the determined water content made waterfiei). The reaction mixture is stirred with 200 ml added absolute petroleum ether and then cooled. The precipitate which crystallizes out on standing is suctioned off, washed with ether and dried in vacuo. The potassium salt is obtained in this way 6 - («- Phenoxybutyramido) penicillanic acid in a yield of 7.8 g = 93.5% of theory, and with a iodometrically determined penicillin content of 87% of theory.

Claims (1)

Patent claims: 1. Process for the preparation of penicillin salts the general formula S CH ₃ X-NH-CH-CH C-CH ₃ CO-N CH-COOMe The invention relates to the method for producing penicillin salts, which is characterized by the claims the general formula