DE1963818A1 - Process for the preparation of penicillin derivatives - Google Patents

Description

DR. BERG DIPL.-ING. STAPF

PATENT LAWYERS 8 MUNICH Z. HILBLESTRASSE 2O

Dr. Barg Dipl.-Ing. Darning, 8 Manchen 2, Hilbtesträfle 20

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Attorney file 19 153 Be / Soii

date

Dec. 19, 1969

American Home Products Corporation New York / USA -

"Process for the preparation of penicillin derivatives ¹¹

This invention relates to the manufacture of penicillin derivatives and a process for the preparation of the acid addition salts of arainopenicillin and its esters and amides exhibiting bactericidal activity Treating an aqueous solution of an aminopenicillin

AHE-5030-f

—2—

009831/1901

SAD

19.638-1 i ■; ■■

or a salt thereof with a sulfonic acid or a salt thereof, then adjusting the pH of the reaction mixture to between 0.5 »preferably 1.5 and 3j5 and separation of the precipitated reaction product *

One procedure of this general kind is according to the Dutch Patent application 299,854 (U.S. Patent 5,180,862) known, in which an aqueous solution containing an aminopenicillin, of the general formula - (I)

CH-C-NH-CK

(I) CH-COOH

wherein the radicals R ¹ , R ^ and Ή? either a hydrogen atom, a nitro, di (lower) alkylamino, (lower) alkanoylamino (lower) alkanoyloxy, (lower) alkyl, (lower) alkoxy or sulfamyl group, a chlorine, Iodine, bromine or fluoratora or a trifluoromethyl, (lower) alkylthio, (lower) alkylsulfonyl, carb (lower) alkoxy, benzyl, phenethyl, cycloheptyl, cyclohexyl or cyclopentyl group or a salt thereof, for example a sodium, potassium, calcium, aluminum, ammonium salt or a substituted ammonium salt, such as a trialkylamine, procaine, dibenzylamine, N-benzyl-β-phenethylamine, 1-ephenamine, N, N ^I: -dibenzylethylenediamine-, dehydroabiethyl-

009831/1901 " ⁵ "

amine ^ ·, NjN'-bis-dehydroabiethylethylenediamine or N- (lower) -alkylpiperidine salt or its easily hydrolyzable esters or amides (obtained by means of chemical or enzymatic hydrolysis converted into the free acids and regarded as suitable starting materials can) with a recommended concentration of 25 to 100 mg aminopenicillin per ml solution with a water-soluble arylsulfonic acid or a salt thereof of the formula (R ^ -SQ ^) M, in which the radical M is a hydrogen atom. an optionally substituted ammonium group, an alkali or alkaline earth metal and χ is an integer equal to the value of M and R. through residues of the general formulas (II) and (III) is shown

(III)

C C. Π Q

wherein the radicals R, R, R 'and R each represent a hydrogen atom, an alkyl group having 1 to 12 carbon atoms, a (lower) -alkoxy-, hydroxy-, (lower) -alkylthio-, nitro-, (lower) -alkanoylamino, (lower) -alkanoyloxy, bulfamyl group, a chlorine, iodine, bromine, fluorine atom, a trifluoromethyl, (lower) -alkylsulfonyl-, carb (lower) -alkoxy-, Benzyl, phenethyl, cycloheptyl, cyclohexyl or cyclopentyl group can be (with naphthalene as examples

0 0 9 8 3 1/19 01

sulfonic acid, p-nonylbenzenesulfonic acid, p-toluenesulfonic acid and p-Oymolsulfonsäure are to be considered), treated the pH of the solution is then to between approximately 1.5 and 3.5 and thereby a relatively insoluble reaction product of the aminopenicillin and the aryl sulfonic acid is formed, which is then separated off

In this way one obtains an oc-aminobenzylpenicillin-

Aryl sulfonate of the general formula (IV)

CH-COOH

12 5 H-

wherein the radicals R, R, R ^ and R explained above Have meaning or are their easily hydrolyzable esters or amides, which by means of chemical or enzymatic hydrolysis converted into the corresponding free acids and thus fall within the scope of this invention.

If the term "(lower) -alkyl ¹¹ group is used here and in the claims, this includes straight and branched hydrocarbon radicals with from about 1 to about 6 carbon atoms, to which, for example, groups such as methyl, ethyl, n-propyl-, i-

009831/1901 ~ ⁵ ~

196381a

Eropyl, η-butyl, t-butyl, n-pentyl, n-hexyl groups and belong like that. The term "(lower) alkoxy" groups denotes hydrocarbonoxy groups with from approximately 1 to about 6 carbon atoms, which are straight and branched can be, and they include methoxy, ithoxy, n-propoxy, i-propoxy, n-butoxy, t-butoxy, n-pentoxy, n-hexyloxy groups and the like. Use of the term "(Lower) -alkanoyl" group refers to acyl groups with 1 to about 6 carbon atoms, such as Porrayl, acetyl, Propionyl, butyryl groups and the like. Under of the term "Oarbo (lower) alkoxy" group are carbonyl groups to understand those with (lower) alkaxy groups, as defined above, are substituted. The term "Cyolo (lower) -alkyl" group used here includes cyclohexyl, Gyclopentyl and Öyoloheptyl groups »Under the Expression (lower) alkylene group are methylene, ethylene, To understand propylene and butylene groups

It has now been found that the preceding process can be improved by the inventive method ₉ when sulfonic acids or their salts of the general

Q ΊΟ ΊΊ Q

iOriael R ^ -R -B -SO ₅ H, wherein Hr is a substituted or

ok

unsubstituted aryl group © _s H is an oxygen atom or a direct bond and R is a phenylene or alkylene group, used, whereby new acid addition salts are prepared which have the advantage of fairly low Uos

009831/1901

have ability in an aqueous medium. this makes possible the use of sulfonic acids in solutions containing aminopenicillins in a concentration less than 25 mg / ml, "for example 10 or 14 mg / ml in contrast to concentrations of 25 to 100 mg / ml of the known methods, contain. In addition, the new acid addition salts can easily be extracted from the solutions containing them because of their excellent filterability.

It has now been found that, in general, any penicillin, containing an amino group _s for preparing the novel compounds of this invention can be used, and the method by which these new Sulfonsäuresalss werdenj produced can be used hieraŭ to the aminopenicillin from mixtures of separate _s contain other products from Nelaenreactions that occur in the production of the desired aminopenicillin.

The present invention therefore provides a process for the preparation of new bactericidal acid addition salts of a Aminopenicillins of the general formula

CH-COOH

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9831/1901

or of an ester or amide thereof, in which H. a Amino group-containing aliphatic or aromatic radical, R is an optionally substituted aryl group, preferably a phenyl, biphenyl, naphthyl, phenylcarbamyl or phenylcarbamylnaphthyl group, R is a

11 • Oxygen atom or a direct bond and R one Phenylene or alkylene (optionally lower alkylene) group is what an aqueous solution of an aminopeni-

cillins of the general formula ■ I

«-C-NH-CH CH

I I

CO M- -CH-COOH

or its salt, ester or amide, in which R is as given above Has meaning at a pH of 0.5 to 5 »5 with a

Q 10 11 sulfonic acid of the general formula R-R -R -SO, H or

9 10 11 a salt thereof, wherein the radicals R, R and R the have the meaning given above, treated and the precipitation of the acid addition salt isolated, if desired, the acid addition salt with a weak base or in treated in a weakly basic medium to form the free base form of aminopenicillin and / or if if desired, an amide or an ester group is removed chemically or enzymatically with formation of the free acid. the Invention therefore provides the aminopeni-

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BATH

cillinsulfonate in anhydrous or hydrated form to disposal.

As mentioned above, the invention is applicable to any aminopenicillin and the group R can be any aliphatic or aromatic radical containing the amino group. In known penicillins of this type, the amino group is usually, although not always, an α-amino group and the invention particularly relates to penicillinsulfonates in which the group R is an amino-substituted lower alkyl, cycloalkyl, cycloalkenyl;, benzcycloalkyl, aryloxy (lower) -alkyl or aralkyl radical, which can be substituted with a large number of non-interfering groups. The invention relates in particular to penicillins in which R is an α-aminobenzyl, α-aminocycloalkyl, α-aminocycloalkenyl or α-amino.-1- or -2-indanyl radical, each of these radicals being a large number of non-interfering groups «The amino group can be primary, secondary or tertiary, for example -NR ^a R, where R ^{a is} a hydrogen atom, a lower alkyl or phen (lower) alkyl group and R is a hydrogen atom or an alkyl group such as -CR R '- as in the ketone adducts with aminopenicillins, in which the radicals R ". ■ and R ^Y -, if they occur separately, a hydrogen atom, a lower alkyl or phenyl group or, if they are together with the carbon atom with which they

. -9-009831 / 1901

are linked, occur, form a cycloalkyl ring, while the free valence given above is with the 6-APS nitrogen atom connected is*

The invention provides in a preferred embodiment a process for the production of novel bactericidal Acid addition salts of an α-aminobenzylpenicillin of the general ! Formula '(XIII)

- CH
NH _a . flF-R * co -N-CH-COOH

or an ester or amide thereof, in which the radicals E ₁ R and R * each represent a hydrogen atom, a nitro, di (lower) alkylamino, (lower) alkanoylamino, _s (lower) alkanoyloxy, (lower) - alkyl, (lower © re) alkoxy, sulfamyl ^ roup, a halogen atom (fluorine, chlorine \ bromine or iodine), a ₉ Srifluoriaethyl-, (lower) alkylthio ~ _s (lower) alkylsulfonyl, Garb (lower ) -alkoxy-, phen (lower) -alkyl- ₅ such as benzyl, ehenethyl and ehenpropyl, qyeloalkyl, for example oyoloheptyl, cyclohexyl or cyclopentyl groups, M an optionally substituted (for example by R) aryl group, preferably a phenyl, biphenyl, naphthyl, phenylcarbamyl or phenylcarbamylnaphthyl group, R is an oxygen atom or a direct bond

009831/19 01

BATH ORIGINAL

- ίο -

11th
and R is a phenylene or alkylene (for example lower alkylene -) group, for which an aqueous solution of an α-aminobenzylpenicillin or a salt thereof of the general formula (I) - as defined above, or an ester or amide the same at a pH of 1.5 to 3.5 nilt a water-soluble sulfonic acid of the general

Q ΊΟ 11
Formula RR -R -SCUH or a salt thereof, wherein

α 'in 11
the radicals R, R and R have the meaning given above, treated and the precipitation of the salt of the general formula (XIII) isolated and _s, if desired, the acid addition salt with a weak base or in a weakly basic medium to form the free base form of a -Aminobenzylpenicillins treated and / or if desired _? an amide or ester group chemically or .enzymatically removed with formation of the free acid.

Further preferred types of penicillins to which the invention leads are those of the general formula

wherein the radicals R and R ^ a hydrogen atom ■, a are lower alkyl, lower alkoxy, phenyl or phenoxy group and η = 1 or 2 (see Belgian patent

-11-

0098317.1901

BATH ORIGINAL

718 100), those of the general formula

O C "" ^ Il C- CH-COOH -NH-CH- I. co— -CH j -N ■

where η is an integer from 2 to 9 and R is a hydrogen atom or a lower alkyl group, especially 6- (1- arainocyclopentanecarboxamido) -penicillanic acid _} 6- (1-amino ~ cyclobutanecarboxamido) -penicillanic acid _T 6- (1-Aminoeyclohexanecarboxamido) -penicillanic acid and 6- (1-aminocyclooctanecarboxamino) -penicillanic acid; also those of the general formula

co-

Trv

CO

IN

.crt-coon

14 15
where R and R ^ are a hydrogen atom, a lower alkyl, lower alkoxy, phenyl or phenoxy group and η = 1 or 2 - and those of the general formula

, COr NiH-CH-

CH

Cp-

COOH

CO-M -

COOH

BATH

• ■ '- 12 - ■■, -.-_ ■

"wherein R ^{a is} a hydrogen atom, a lower alkyl or

1fi 17 is phen (lower) alkyl group, the best R and R when they are separate, ^{1 are} a hydrogen atom, a lower alkyl or phenyl group or when together with the carbon atom to which they are connected they are a cyclo ( lower) alkyl ring and the broken line denotes a double bond in one of the two positions (see German patent application P 1958 382.5)

16 17 penicillins with 'ketones of the formula R .00.B', as in the last given general formula explains a

1fi 17

-GR R 'group, which with the as-amin ο group and is connected to the 6-APS-Stiekstoffatoraen. A general this is a well-known example of this type of educt Acetone adduct of ampicillin, namely hetacillin.

The penicillins provided as starting materials can be in the form of their salts, such as sodium, potassium, calcium, aluminum * and ammonium salts. They can also be in the form of their substituted ammonium salts, as well as their trialkylamine, procaine, dibenzylamine, N ^ benzyl-ß-phenethylamine, 1-ephenamine, N ₁ K ¹ -dibenzylethylenediamine, dehydroabiethylamine, NjN '-bis-Dehydroabiethyläthylenediamine- and N- (lower) -Alkylpiperidinsalzen as well as in the form of their easily hydrolyzable esters or amides, which by means of chemical or enzymatic hydrolysis

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can be converted into the free acids and. all in all can be regarded as suitable starting materials «

If the α-carbon atom of the acyl group with which the Aminosulfonate group is linked, an asymmetric carbon atom is »can Arainopenicillinarylsulfonate in the form of two optically active diastereoisomers and can also be obtained as mixtures of the two optically active isomers »

The aqueous solution containing an aminopenicillin of the general Formula (I) can be obtained by dissolving a crystalline aminopenicillin in water, but the advantages of the process are particularly pronounced if an impure solution of an aminopenicillin is used as the starting material Such a solution is obtained, for example, that 6-aminopeniGillanic acid with acylated with a suitable acylating agent. The mixture that is formed during the reaction can, in addition to the desired aminopenicillin, also the unreacted 6-aminopenicillanic acid and products that contain through Hydrolysis or side reactions caused by acylating agents are formed.

It is preferred to use a solution containing 10 to 25 fflg aminopenicillin per ml contains «This amount is available the © rapfohlenen 25 to 100 mg / rsl of known methods against

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above. If necessary, the solution can be concentrated by keeping it for a few minutes at a temperature of 30 to 40 ^° C. and under reduced pressure. If the aqueous solution of aminopenicillin also contains organic impurities {that when using the reaction mixture obtained by acylation of 6-aminopenicillanic acid, an organic solvent such as methyl isobutyl ketone is added to the solution. Other solvents that can serve this purpose are, for example, other (lower) ketones and (lower) aliphatic esters, such as amyl acetate, ethyl acetate, propyl acetate and butyl acetate, '.. halogenated lower hydrocarbons and aromatic hydrocarbons. In general, any solvent that does not work with water is miscible, can be used. The presence of the solvent promotes crystallization and a purer product is thereby formed.

A concentrated aqueous solution is usually used in preparing the sulfonic acid addition salts of the invention the free sulfonic acid used, although both the water-soluble Ammonium salts or substituted ammonium salts as well as alkali metal or alkaline earth metal sulfonates are suitable are. In general, the sulfonic acid becomes lower Temperature, for example at a temperature between approximately 0 ° and 25 ° C, preferably between 0 ° and 10 0, with the aqueous solution that contains the aminopenicillin *

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ORIGINAL

1983818

holds, mixed. This is done to prevent the disintegration of the product and to avoid loss of solvent and crystallization to speed up the product. During the formation of the aminopenicillin sulfonate, the pH should be the Solution between 0.5 and 4.5 »preferably between 1.5 and 3.5, are held. During the addition of the sulphonic acid the pH of the solution can be higher than 3.5 '", however if the desired session is generally not met

unless the pH is adjusted to the range between 0.5 and 3 * 5. If the amount of sulfonic acid used is insufficient to adjust the pH to the desired range of approximately 0.5 to 3.5, but is sufficient to completely form the desired product, an inorganic acid such as HGl or H ₂ SO ^, can be added to adjust the pH. The pH can generally be adjusted by adding an acid or, if necessary, by adding a base such as sodium hydroxide or a tertiary amine such as triethylamine. A preferred pH range is 1.5 to 2.0. The reaction mixture is stirred until crystallization has ended. The product can then be separated off after precipitation, for example by filtration. It can then be washed with water and / or an organic solvent such as methyl isobutyl ketone and, if desired, dried.

- ".- ■ '-16-0098 3 1/1901

The new sulfonates of the aminopenicillins of this invention have valuable antibacterial properties and they can, can be used as therapeutic agents without modification when administered parenterally or orally, they act against gram-positive and gram-negative bacteria such as the corresponding aminopenicillins they are valuable intermediates for the production of the corresponding series of aminopenicillins by means of treatment a weak base such as an amine * or in a weak one basic medium.

For example, the aminopenicillin sulfonate can be converted to the corresponding aoinopenicillin by the process of US Pat tertiary amine, such as triethylamine, or by the use of an inorganic base such as an alkali metal or ammonium hydroxide or carbonates. When the aminopenicillin is D-6- (2-amino-2-phenylacetamido) -penicillanic acid (ampicillin), it is preferred to get this in its anhydrous form. This can be effected, that preferably also with a small amount free the Ampicillinsulfönat at a temperature of 50 ° to 100 ⁰ C with an amine or ammonia and a water miscible organic solvent and

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1983818

Water mixes. Bas medium suitably contains 50 to 95% by volume _o solvent and this is preferably isopropanol · The amine may be any primary, secondary or tertiary amine and triethylamine is preferred.

When the aminopenicillin sulfonate is in the form of an ester or Amide is present, this is appropriate hydrolyzed chemically or using an enzyme with formation of the corresponding free acid. Such Ester group can be an arylmethyl, for example benzyl, 2-thienylmethyl or 2-purylmethyl group or an oyanoinethyl or optionally substituted phenacyl group or an activated ester group such as an acyloxymethyl ester (see South African! Patent 68/5952) or another methyl ester group, one or two Electron-removing groups such as acyl, imido, oyano-, Carbalkoxy, orbamyl, garbobenzoxy or orbaryloigr groups (see British Patent 1,164-457) are, whereby the respective ester group by means of esterase enzyme, by mild acid hydrolysis, by hydrogenolysis or by ultraviolet photolysis, depending on suitability, can be removed. Similar agents are suitable for the easily hydrolyzable amide groups.

The following compounds or you © salts-used mphenylsulfonic acid (lormel V), bi

-18-00983171901

phenylatnersulfonic acid (formula VI), 3- (2-carbanilidophenoxy) ~ propanesulfonic acid (Formula VII), 3- (l-NaphthQxy) propane sulfonic acid (Formula VIII), 3- (2-naphthoxy) propanesulfonic acid (Formula IX), 3- (2-phenylphenoxy) propanesulfonic acid (Formula X), 3- (4-phenylphenoxy) propanesulfonic acid (Formula XI), 3- (i-carbanilido-2-naphthoxy) propanesulfonic acid (formula XII). (see Appendix).

The following processes explain the production

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-19 «

of the sulfonic acids used in the invention and the examples explain their use for the production of aminopenicillin sulfonic acid addition salts according to the invention.

Manufacturing 1

To a solution of 1 kg of biphenyl in 5.5 1 of methylene chloride, 425 ml of chlorosulfonic acid are added dropwise over about 50 minutes at reflux temperature. The reaction mixture with the already partially crystallized biphenylsulfonic acid is left under reflux for 2.5 hours. After cooling to 14 ^° C., the crystals formed are filtered, washed on the filter with 1.5 1 of methylene chloride and air-dried. Yield 14-21 g biphenylsulfonic-Mohohydrat (87 #), melting point 158-142 ⁰ C.

Manufacturing 2

To a solution of 100 g of diphenyl ether in 500 ml of methylene chloride, heated to reflux temperature, 58 ml of chlorosulfonic acid are added dropwise in about 50 minutes. After all of the chlorosulfonic acid has been added, the mixture is refluxed for one hour. Then the reaction mixture is diluted with 500 ml of benzene and 10 ml of distilled water are added. After cooling to ⁰ ° C., the crystal mass is filtered and washed with 200 ml of benzene. after drying melting point is obtained 156 g of diphenyl ether sulfonic acid monohydrate (865ε) 76 to 81 ⁰ C.

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Manufacturing 3

75 »3 g sodium hydroxide, dissolved in 4-1 alcohol, and then 400 g salicylanilide are added to a three-necked 5-1 flask. After heating to about 75 ^° C., 176 ml of propanesuitone are quickly added dropwise, with some cooling being used. The mixture is then maintained for a further 2 hours under reflux and then cooled to about 6 ⁰ C. The precipitate is filtered and washed with 250 ml of alcohol. The yield is 528.5 g (73 »6 #) sodium 3- (2-carbanilidophenoxy) propane sulfonate, melting point. 165 ° to 168 ⁰ O. A small amount of the sodium salt was purified by crystallization and treating with activated carbon. The melting point is then 166 to 168 ⁰ O. "

Analysis: the gross formula requires _{C 16} H ₁₆ NO ₅ -SNa ^ H _{2 O}

% ·. 48.84 0.5.12 H, 3.56 N, 8.15 S, 5.85 Na found ^: 48.12 G, 5.21 H, 3.60 N, 8.23 S, 5.80 N / A.

Manufacturing 4

According to the method described in preparation 3, tt-naphthol, ß-naphthol, 2-hydroxydiphenyl, 4-hydroxydiphenyl and 2-hydroxy-i-naphthol anilide with propane sultone implemented with the formation of:

Sodium 3- (1-naphthoxy) propane sulfonate, melting point 160

up to 165 ° C.

Sodium 3- (2-naphthoxy) propane sulfonate

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196381S

Sodium 3- (2-phenylphenoxy) propane sulfonate, melting point

159 to 141 ⁰ C

Sodium (4-phenylphenoxy) propane sulfonate, melting point

250 to 255 C

Sodium 3- (1 ~ earbanilido-2-naphthOxy) -propansulfohat,

Melting point 212 to 215 Ο «

The corresponding free acids can be made from the salts by adding concentrated hydrochloric acid or sulfuric acid. In this way, for example 3- (2-naphthoxy) propanesulfonic acid, melting point 106 to 108 ⁰ O, is obtained.

example 1

To 24-1 ml of a 29% solution of biphenylsulfonic acid 28 ml of triethylamine are added. This solution comes with 200 ml of methyl isobutyl ketone and 5730 ml of filtered reaction mixture with a pH of 3 »? mixed, this being an additional 12.9 g of 6-aminopenicillanic acid, 52.0 g of D - (-) - a-aminabenzylpenipillin (13 mg / ml).

10 ml of 4N HpSQ ^ are added to the mixture thus obtained at 22 ° G, so that the pH changes to 3.2 and the crystallization of D (-) - a-amiobenzylpenicillin biphenylsulfonate begins. After stirring for 15 minutes, a further 5 nil 4N HoSG ₂ I are added. The mixture is then further acidified until a pH of 2.1 is reached and the same

009031/1901

early it is cooled until the temperature is lowered ^{to 2 0 C »}

The crystal needle suspension is filtered, the pint cake is first ^{washed with 300 ml of water at 0} ° C., then acidified to pH 2.0 with biphenylsulfonic acid and then treated with 300 ml of methyl isobutyl ketone, nitration and washing take place calmly. After drying, 94 g of D (-) - <x: aminobenzylpenicillin biphenylsulfonate with a content of 54-2 / Ug / mg (purity 93.4 $), corresponding to a yield of 97.8 $.

4-6.6g of anhydrous DC -) - a-aminobenzylpenicillin can be obtained from the acid addition salt with a purity of 98 »9 ^ through Reaction with triethylamine at 75 ° C in 85 # isopropanol solution can be obtained.

Example 2

To 1600 ml of filtered aqueous reaction mixture with a pH of 4-8, which contains 26.1 g of D (-) - oc: -aminobenzylpenicillin 10.5 S unreacted 6-aminopenicillanic acid

-a '

held, are fiühren and cooling to +2 ⁰ C, first 100 ml of methyl isobutyl ketone and then 85 ml of 40 $ strength Diphenyläthersulfonsäurelösung _f "added Thereafter, the pH is adjusted to 2.5 with 4N H ₂ SQ ^. After 2.5 hours of stirring at +2 ⁰ O, the crystal mass is filtered and three-

• -23-

009831/1901

^ 'SADORfGIMAL

times with 25 ml parts of a 1 # solution of diphenyl ether sulfonic acid and then washed with 100 ml of methyl isobutyl ketone. The filtration processes run smoothly. After drying, 48.2 g of D (-) ~ a-aminobenzylpenicillin diphenyl ether sulfonate are obtained with a D (-) - a - aminobenzylpenicillin content of 507 / tig / mg, corresponding to a yield of 93 _t #

Example 5

To 1605 ml of a clear solution of 21 * 6 g of D (-) - a-aminobenzylpenicillin (15.5 mg / ml) and 11.9 g of unreacted 6-aminopenicillanic acid with a pH of 4.85, 40 g of sodium 5- (2-carbanilidophenoxy) propane sulfonate and 20 ml of methyl isobutyl ketone were added. After thorough cooling and gradual lowering of the temperature from 20 ^° C. to +1 ^° C., the pH value is reduced to 2.0 by adding a 4N solution dropwise.

After stirring for a further 2 hours at 1 ^° C., the crystal mass, which consists of plates, is filtered and washed with 50 ml of water of pH 2.0 and 25 ml of methyl isobutyl ketone and dried. 43.8 g of acid addition salt with a content of 485 μg / mg are obtained, corresponding to a yield of 98. After conversion to anhydrous D (-) - a-aminobenzylpenicillin, this salt gave 10 g of the product with a purity of 98,

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009831/1901

: ■■ "■;. ■■ - a4 - ■ ■■■. '':'-'y ■

Example 4 '

1050 ml of a clear solution of pH 4.9 »<Ü © additionally contains 3t75 g of unreacted 6-aminopenicillanic acid, 16.9 SD (-) - a-aminobenzylpenicillin (16.1 mg / ml), is adjusted to pH 3, 1 set at 3 ⁰ O by adding 4N HpSQ ^ * After adding 50 ml of methyl isobutyl ketone, a solution of 22 g of 3- (2-naphthoxy) propanesulfonic acid in 50 oil of water is slowly added at a temperature of 1.5 to 3 ⁰ O added with stirring. This lowers the pH to 1.6 and the acid addition salt precipitates in the form of broad needles. After filtering and washing, first twice with 10 ml of ice water and then twice with 25 ml of methyl isobutyl ketone, 29 »5 g of D (-) -a-aminobenzylpenicillin-3 ⁱ - (2-Naphthox3i> ⁱ propanesulfonate obtained. The D (-) - a-aminobenzylpenicillin content of the same is 532 / Ug / mg (yield 93 ^).

In the previous examples, solutions of D (-) - a-aminobenzylpenicillin used. It is clear, however, that also with other α-aminobenzylpenicillins as above explained, can be started and that both these as also ampicillin sulfonic acid salts with every sulfonic acid of the Formula R-R -R -SO, H, especially those after the Process 1 to 4 were obtained, can form

Example 5

Following the procedure of Example 1, the following

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- 25 - "■ - ■ -, '■' ..

Bipiienyl sulfonate derivatives using the suitable substituted α-aminobenzylpenicillins produced ?:

α-Ainino-4-i-methylbenzylpenicillin-bipnenylsulfonate a-Araino-Φ-ethylbenzylpenicillin-biphenylsulfonate a-ATnino- ^ trifluorometb.ylbenzylpenicillin- 'biphenylsulfonate a ~ Amino-3-sulfamylbenzylpenfoillin-Biphenylsulfonat ^ a-Atnino-2, ^ dicIilorbenzylpenicillin-'Biptienylsulfonat

α-Amino ^ -nitrobenzylpenicillin-Bipixenylsulfonat ^

α-AIIsino-2-aodbenzylpenicillin-'bipllenylsulfonate. *

α-Amino-4-ethoxybenzylpenicillin - biphenyl sulfate a-AHjino - ^ - aeetamidobenzylpenicillin-biphenylsulfonate α-Amino-4-dimethylaffinobenzylpenicillin-biphenylsulfonate a-Amino ~ 2 ~ aGetoxybenzylpenicillin-bipbenylsulfonate α-Άΐηΐηο-4-fluorobenzylp eni c illin-bipiienylsulfonate α-Atniixo-Si ^ -dibromobenzylpenicillin-biphenylsulfonate α-Ainino-4-raethylthiobenzylpenioillin-Biplienylsulfonat α-Amino-J-propylthiobenzylpenicillin-bipnenyl sulfonate

a-Amino-4-cyeloiieptylb enzylp enicillin-Bipheriylsulfonat '

a-Amino - ^ - cyclopentylbenzylpeniGillin-Biphenylsulfonat a-Amino-SiS'-diiDetb.ylsulfonylbenzylpenioillin-Biphenylsulfo-

nat

a-Amino - ^ - ethylsulfonylbenzylpenicillin-biphenylsulfonate a-An5ino ~ $ -carbomethoxybenzylp eni c illin-Biphenylsulfonat α-Amino-3-butylbenzylpenioillin-biphenylsulfonate a-AiBino- ^ oyclohexylbenzylpenicillin-Biphenylsulfonat, α-Affliiio-4 (benzyl) benzyl penic illio-biphenyl sulfonate

-26- 009831/1901

OfilGIHAL INSPECTED

α-Amino-3-propylbenzylpenieillin -.- Biphenylsulfonate α-Amino- ^ phenethylbenzylpenicillin-biphenylsulfonate α-Amino - ^ - phenpropylbenzylpenicillin-biphenylsulfonate α-Amino ^ -inethoxybenzylpenicillin-biphenylsulfonate α-Amino-4-propoxybenzylpenicillin-biphenylsulfonate α-Amino-4-butoxybenzylpenicillin-biphenylsulfonate α-Amino ^ -propionyloxybenzylpenicillin-biphenylsulfonate

Be ispiel 6

To 305 rol filtered aqueous solution with a content of 4-5 * 0 g of 6- (1-Aroinocyclohexancarboxamido) -penicillansäure _J 42 ml of methyl isobutyl ketone and then - ^ ühren 120 ml of a 33 ^ aqueous solution of Biphenyläther ~ sulfonic acid at 10 ⁰ G added. The pH is adjusted to 2.0 with triethylamine. After stirring for 16 hours at 0 to 5 °, the mixture is filtered and the crystalline one

Product with cold water and then with methyl isobutyl ketone washed. The yield of 6- (1-aminocyclohexanecarboxamido) penicillanic acid phenoxybenzenesulfonate was? 2 g on a dry basis »

For this addition salt may 34.0 g of anhydrous 6- (1-Aminocyclohexancarboxamido) # -penicillansaure be obtained by reaction with triethylamine at 8O ⁰ C in isopropanol solution with a purity of 99

-27-009831 / 1901

ORIGINAL INSPECTED

Example 7

"To 750 ml of an aqueous solution which contains approximately 102 g of 6- (1-aminocyclohexanecarboxamido) -penicillanic acid, 77 μl of methyl isobutyl ketone and then, with stirring at 10 ⁰ O, 290 μl of a solution which contains 77 g of biphenylsulfonic acid are added. The pH becomes adjusted to 2.0 with triethylamine and the mixture is stirred for 3 hours at 5 to 10 ⁰ C, the yield of 6- (1-Aminocyclohexancarboxamido) -penicillansäure-biphenyl disulphonate is 156 g! Drockenbasis.

For this addition salt may anhydrous 6- (1-Aminoöyclohexancarboxaraido) -penicillansäure having a purity of 98jli by Üesetzen with triethylamine at 25 ⁰ C in methanol are obtained ·

Example 8

Following the procedure of Example 1, the following Biphenylsulfonate derivatives using the appropriate one Aminopenicillins can be obtained:

6- (indan ~ 2-amino-2-carboxainido) penicillanic acid biphenyl sulfonate .

6- (2-Amino-hexahydro-2-indancarboxamido) -penicillanic acid biphenylsulfonate

6-Ci-amino-3-cyclopentene-1-carboxamido) penicillanic acid biphenyl sulfonate

-28- 009831/1901

Claims (2)

\ - 28 - Patent claims: Process for the preparation of new bactericidal acid addition salts of an arainopenicillin of the general formula - CH -CH in- or an ester or amide thereof, - in which R is an amino group which is an aliphatic or aromatic radical contains, R ^{7 is} an optionally substituted aryl group, R is an oxygen atom or a direct bond and R is a phenylene or alkylene (for example lower alkylene) group, characterized in that an aqueous solution of an aminopenicillin of the general IOr π el - c '~ t * H- CM-CH C ^ CH ii I. M - cü-cootj or its salt, ester or amide, in which R has the meaning given above, at pH 0.5 to 3 »5 with a sulfonic acid of the general formula RRR-SO ₅ H or a Q 10 ΛΛ ■ - ■ "■ Salt thereof, wherein R ^, R and R are those given above -29-009831 / 1901 Have meaning treated and the precipitation "of the acid addition salt isolated and, if desired, the acid addition salt with a weak base or in a weak treated basic medium to form the free base form of aminopenicillin and / or, if desired, a Amide or ester group removed chemically or enzymatically with formation of the free acid. 2. Bactericidal acid addition salt of an aminopenicillin of the general formula - co— ■ "" ι ( or its ester, amide or salt, in which E is an amino group containing an aliphatic or aromatic radical such as substituted or unsubstituted lower alkyl, cycloalkyl, cycloalkenyl, benzcycloalkyl, Aryloxy (lower) alkyl or aralkyl radical, R one 1Q is optionally substituted aryl group, R is an oxygen atom or a direct bond and R a phenylene or alkylene (e.g. lower alkylene) group is. 009831/1901 sr Blank page