DE1670128A1 - Adducts of penicillin derivatives and aminoaryldisulfonic acids and process for their preparation - Google Patents

Description

· - ..EN I Λ Μ Λ Ä! : ί

.U. If. G. vOLf ^; r .- \ M BÜr -. 'ΐϋ DH. KAHL OKU:. '"Ί ί Ot ₁ CH

P 1β 70 128.3
Bristol-Myers Company
East Syracuse, New York

Munich, March 16, 197O

Adducts of penicillin derivatives and aminoaryldisulfonic acids and process for their preparation.

The invention relates to new synthetic compounds which are useful as antibacterial agents, as Nutritional additives in animal feed, as agents for the treatment of mastitis in cattle, as therapeutic Agents in poultry and animals, including humans, in the treatment of infectious diseases in particular, caused by gram-positive and gram-negative bacteria. They are addition products (Adducts) of an ad-aminophenyl- (or -thienyl) -methylpenicillin or an oC-amino-substituted one Phenyl (or substituted thienyl) methyl penicillins with an aminoaryldisulfonic acid.

The invention also relates to methods of isolating et-aminophenyl (or thienyl) methylpenicillin and oc-amino-substituted phenyl- (or substituted thienyl) methylpenicillin from contaminated Reaction mixtures containing such penicillins using said addition products.

Documents (Art. 7 5 1 /.Iss. 2, Mr. I SzAz. 3 of the Amendment 3 of September 4, 1987)

ÖÖ9833 / 19S?

Antibacterial agents, such as benzylpenicillin, have been used in the treatment of infections in the past proven to be very effective by gram-positive bacteria, but such agents suffer from the serious disadvantage against numerous bacterial strains, e.g. most gram-negative bacteria to be ineffective. The compounds according to the invention are particularly valuable because against both gram-positive and gram-negative bacteria when administered parenterally or orally have a strong antibacterial effectiveness and are also very resistant to destruction by acids,

oC-aminobenzylpenicillin, oC-amino-benzyl f penicillins, OEC Aminothienylmethylpenicillin and oC-amino Thienylmethylpenicilline are known in the technical literature and are described for example in US Patent 2,985,648 and Belgian Patent 631,631 described. According to this literature, the penicillins are prepared by reacting 6-aminopenicillanic acid with an acylating agent, such as acid chloride, acid bromide, acid anhydride, mixed anhydride, etc. of a derivative of OL-aminophenyl (or substituted phenylacetic acid or cC-aminothienyl (or substituted thienyl) ) acetic acid, the amino group being protected by a carbobenzoxy or other suitable protecting group After the acylation reaction has been completed, the protecting group is removed from the amino group, for example by reaction with hydrogen in the presence of a catalyst.

The terms "a (or 'the') flC-aminobenzylpenylcillin" and "a (or 'the') oC-Aminöthienylmethylpenicillin" also include oc-amino substituted benzy! penicillins and oC-amino-substituted thienylpenicillins as well

oL- aminobenzylpenicillin and oC-aminothienylmethylpenicillin as such. In the same way, expressions wiö "a (or 'the') cC-aminophenylacetic acid" are intended to "lind" a

009833/1957

(or 'the ¹ ) OC-aminothienylacetic acid "include the oc-amino-substituted phenylacetic acids and cXL-amino-substituted thienylacetic acids as well as oC-aminophenylacetic acid and oC-aminothienylacetic acid as such.

The known working methods for the production of the o (_ -Aminobenzylpenlcilline and the trt.-Arainothienylmethylpenicillin by the acylation of 6-aminopenicillanic acid lead to the production of mixtures, which in addition to the desired penicillin unreacted 6-aminopenicillanic acid, hydrolyzed acylating agent and products of side reactions, such as the products of the acylating agent reacted with themselves and / or with the desired penicillin. Because these compounds have similar solubility properties in different media it is often difficult to isolate the desired penicillin from the other reaction products.

The invention is therefore also directed to an improved process for the preparation of an oC-aminobenzylpenioillin or an oe-aminothienylmethylpenicillin from its mixture with others, obtained by the acylation of 6-aminopenicillanic acid with an acylation derivative of an oC-aminophenyl- or an oil-aminothienyl acetic acid To create reaction products. Another aim of the invention is to produce new water-insoluble derivatives of these penicillins.

The invention relates to compounds of the general

.S ^ CH

mean formula O NH - C Il
C - j (DR ² -CH- ,H C. I. R ¹ SO, O NH ₂ .

CH, N CH - COOH

009633/1957

in the R the group

(II) H ₂ N

HO, S

(HI)

or

(V)

or

and Br, R and R ^ are each hydrogen, the nitro, a di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, a (lower) alkyl group (including straight and branched chain saturated aliphatic groups with 1 up to 6 carbon atoms inclusive), a (lower) alkoxy, sulfamyl group, chlorine, iodine, bromine, fluorine, trifluoromethyl, a (lower) alkylthio, (lower) alkylsulfonyl, Garbo (lower) alkoxy group, benzyl, phenethyl, cycloheptyl, Represent cyclohexyl and cyclopentyl as well as easily hydrolyzed esters or amides which can be converted to the free acid form by chemical or enzymatic hydrolysis. The hydrates of the compounds of formula I and the anhydrous compounds are also included in the scope of the invention.

Preferred compounds according to the invention are the 1: 1 molar addition product of (-) - oC-amino-2-thienyl-

009833 / 19S7

methylpenicillin and 7-amino-1,3-naphthalenedisulfonic acid, the 1: 1 molar addition product of (-) - oC-amino-2-thienylmethylpenicillin and 6-amino-l,; 5-naphthalenedisulfonic acid, the 1: 1 molar addition product of (-) - <* _- aminobenzylpenicillin and 7-amino-1,2-naphthalenedisulfonic acid and the 1: 1 molar addition product of (-) - o ^ -aminobenzylpenioillin and 6-amino-1,3-naphthalenedisulfonic acid.

The method according to the invention for the production of adducts from penicillin derivatives with aminoaryl sulfonic acids is characterized in that an aqueous solution containing a penicillin of the formula

(VI)

2 "
R-CH-C-CH

NH,

C '

C.
dd

CH - COOH

(in which R has the preceding meaning) or contains salts thereof with a water-soluble aminoaryldisulfonic acid the formula

(VII) H ₂ N

HO, S

(VIII)

or HO S

or converts their salts, adjusts the pH of the reaction mixture to about 1.0 to 4.0 and that here The solid reaction product formed by the penicillin and the aminoarylsulfonic acid is separated off.

Suitable salts of aminoaryldisulfonic acid for use in the process according to the invention are the ammonium,

009833/1957

substituted ammonium, alkali and alkaline earth metal salts.

As can be seen from the examples, the addition products produced by the process according to the invention are invariably the 1: 1 molar addition product of the particular penicillin and aminoaryldisulfonic acid. It is believed that this is due to the formation of an "inner
Salt or inner salt "within the aminoaryldisulfonic acid, ie between the amino group and one of the sulfo groups, can be traced back, which leads to a configuration that has only one sulfo group available for the reaction with the <X_ -amino group of penicillin. However, it is It can be seen that the above-mentioned mechanism has only been given in an effort to explain this novel reaction, and that
the present invention is in no way limited thereto.

The oC-carbon atom of the acyl group (to which the amino group is attached) is an asymmetric carbon atom, so that the compounds according to the invention in two optically active isomeric forms (the D- and L-diastereomers) and in a mixture atr both optically active forms can exist; all such isomeric forms of the compounds are included within the scope of the invention.

In connection with the above consideration of the diastereomers according to the invention it can be seen that, due to the presence of asymmetric carbon atoms in the 6-arenopenicillanic acid nucleus, many other isomers are possible besides the two isomers caused by the asymmetric carbon of the side chain. Such other isomers are not _V 1edoch currently important as 6-aminopenicillanic acid, which is the product of fermentation,

009833/1957

has only one configuration and one such 6-aminopenicillanic acid is currently used in the preparation of the compounds according to the invention will.

The terms (-) - <x -aminobenzylpenicillin as used herein and (-) - oe -aminothienylmethylpenicillin does not refer to the rotation of the penicillin molecule in its entirety / which is in general (+) 7, but rather rather on the (-) - rotation of the derivative of oil aminophenylacetic acid or cC-aminothienylacetic acid, from which the penicillin was made, i.e. it relates to the configuration of the above asymmetric 0 ^ carbon atom of the acyl group des Penicillins. Similarly, the expression (+) - <\ relates. -Aminobenzylpenicillin and (+) - * _ -Aminothienylmethylpenicillin on the (+) rotation of this asymmetric OC carbon atom. If no character is specially specified is meant the DL mixture.

The aqueous solution containing a c \ _- aminobenzylpenicillin or an oil aminothienyl methyl penic illin as in the preceding Contains formula YI defined can be obtained by using the appropriate crystalline penicillin is dissolved in water. However, the maximum benefits of the invention are obtained using an impure solution obtained, which contains an oC-aminobenzylpenicillin or an oc -aminothienylmethylpenicillin. Significantly is the aqueous solution containing the penicillin by the acylation of 6-aminopenicillanic acid with a suitable acylating agents as described in U.S. Patent 2,985,648 and Belgian patent 631,631. This reaction mixture can additionally to the desired α-aminobenzylpenicillin or O ^ -aminothienylmethylpenicillin unreacted 6-arenopenicillanic acid and hydrolysis or side reaction products

009833/1957

of the acylation agent. Numerous other side reaction products are often also present as impurities. The solution containing the α-aminobenzylpenicillin or qC -aminothienylmethylpenicillin can also be the mother liquor remaining after the recrystallization of the corresponding penicillin.

The solution preferably contains between 25 to 100 μg of the desired penicillin per ml of the solution. If this If necessary, the solution can be concentrated by keeping the solution at a temperature from JO to 40 ° C brings several minutes under a partial vacuum.

If the aqueous solution containing the oC -aminobenzylpenicillin or oc-aminothienylmethylpenicillin also contains organic impurities, such as in the reaction mixture obtained by acylation of 6-aminopenicillanic acid, a water-immiscible organic solvent, preferably methyl isobutyl ketone, is added to the solution. admitted. Other solvents that can be used include other (lower) ketones, (lower) aliphatic esters such as butyl acetate, halogenated (lower) hydrocarbons such as methylene chloride, aromatic hydrocarbons such as toluene, and mixtures thereof with each other or with methyl isobutyl ketone. In general, any water immiscible solvent can be used. The presence of the solvent facilitates crystallization and gives a purer product. The volume ratio of the organic solvent to the aqueous phase is not critical. Thus, for each volume of water present, there can also be as much as two volumes or more of the organic solvent or less than 1/10 volume of the organic solvent.

009833/1957

Preferred aminoaryldisulfonic acids which can be used in accordance with the practice of the invention include the isomeric aminobenzenedisulfonic acids, such as 2-amino-l, 4-benzenedisulfonic acid, and the isomeric aminonaphthalenedisulfonic acids, such as 7-amino-1,3-naphthalenedisulfonic acid, 6-amino-l, j5-naphthalenedisulphonic acid, 3-amino-1,5-naphthalenedisulphonic acid, 8-amino-1,5-naphthalenedisulfonic acid, 3-amino-2,7-naphthalenedisulfonic acid and 2-amino-1,5-naphthalenedisulfonic acid. The aminoaryldisulfonic acids that can be used are described in the art and many of them are commercially available. It is preferably a concentrated aqueous solution of the free Acid used, although the water-soluble ammonium or substituted ammonium, alkali and alkaline earth metal salts these acids can also be used. About 1 to 2 moles of the aminoaryldisulfonic acid are preferred per mole of flC-aminobenzylpenicillin or iC-aminothienylmethylpenicillin used in the solution.

The aminoaryldisulfonic acid is generally treated with the aqueous solution containing the penicillin at low temperatures Temperatures, i.e. at temperatures between about 0 to 10 ° C, brought into contact with the decomposition of the To limit product and losses of the solution to a minimum and to accelerate the crystallization of the product. The pH of the solution during the formation of the aminoaryldisulfonic acid addition product of the

oC-aminobenzylpenicillins or oC-aminothienylmethylpenicillins should be within the range of about 1 to 4.0. The pH of the solution can be higher than 4.0, e.g. about 4.5, during the addition of the arylsulfonic acid, but the desired salt will not form, until the pH is within the range of about 1.0 to 4.0; the preferred pH is in the range of 1.5 to 2.0. If the pH value by adding the aminoaryldisulfonic acid not on the area within

009833/1957

1.0 to 4.0, a mineral acid such as HCl or HgSO ^, added to adjust the pH will.

The crystallization of the aminoaryldisulfonic acid addition product of cC-aminobenzylpenicillin or o6-aminothienylmethylpenicillin can be initiated by vaccination if necessary. After the precipitation of the Product is finished, it is recovered by any suitable means such as filtration. The product can then washed with water and / or an organic solvent such as methyl isobutyl ketone and then dried will.

When the aminoaryldisulfonic acid adduct of the particular oC-aminobenzylpenicillin or cC-aminothienylmethylpenicillin is obtained in a hydrated form, it can easily be converted into the anhydrous form. This can be achieved by slurrying the hydrate in a large volume of dry acetone, for example about 10 ml of acetone per gram of hydrate. The amount of acetone used should be such that there is less than 2 wt. # Water in the acetone slurry after the hydrate (which may initially be moist or wet) is slurried in the acetone. The suspension is then stirred for about 5 hours at about 25 to 30 ^° C., filtered, the filter cake is washed with about five volumes of dry acetone and dried ^{at about 50 ° C.}

Since the aminoaryldisulfonic acid salts of a ^ -amino benzylpenicillins or oC-aminothienylmethylpenicillins, the are produced in accordance with the practice of the invention, have valuable antibacterial properties, they can be used directly as therapeutic agents. They have about the same effectiveness against gram-positive and gram-negative bacteria at parent?, -

009833 / 19S7

ral or oral administration as the corresponding Penicillins. In their anhydrous form these compounds are in methanol, ethanol, formamide, dimethylformamide and pyridine soluble and insoluble in other common solvents. In addition, they are valuable intermediates for the production of the corresponding pure OC-aminobenzy! penicillins or uC-aminothienylmethylpenicillins.

The adduct of an oL-aminobenzylpenicillin or an OL-aminothienylmethylpenicillin with an aminoaryldisulfonic acid, as is produced by the process of the invention, can be converted to the corresponding oC-aminobenzylpenicillin or o ^ .- afflinothienylmethylpenicillin by neutralization, such as, for example, by suspending the addition product in water Einregeln the pH of the suspension to be converted to about 6.0 to 8.0 and preferably about 6.7 to 1 2,. The adjustment of the pH of the solution is preferably achieved by adding a tertiary amine such as triethylamine, preferably at about room temperature. Other alkaline substances such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, sodium carbonate, ammonium carbonate, potassium carbonate, etc. can also be used. The adjustment of the pH causes the precipitation of the corresponding penicillin trihydrate to begin. The pH of the solution is then adjusted to about 4.5 to 4.6 by the addition of an acid such as HCl and it is cooled to precipitate completely. After the precipitation of the penicillin trihydrate has ended, it can be recovered by filtration. The product can then be washed with water and / or an organic solvent such as methyl isobutyl ketone and dried.

According to a preferred and particularly elegant procedure for obtaining penicillin from its addition product with an aminoaryldisulfonic acid, this is

009833/1957

Addition product with an amine or a mixture of amines of the general formula

(IX) CH ₃ CH, HR ^

CH ,. - C - CH ₀ - C - CH ₀ - CH = CH - CH ₀ - N - C - R ² 2 ι 2 t 2 2 - t

CH, CH, R ^

2 "5 4

(in which R, Br and R each mean an aliphatic hydrocarbon radical totaling 11 to 14 carbon atoms) in a water-immiscible organic solvent, whereupon the amphoteric penicillin is precipitated and can be obtained by filtration. Preferably the penicillin is isolated in the form of a trihydrate and the amine solvent medium should therefore contain at least 3 moles of water per mole of penicillin. To obtain the penicillin trihydrate, it is essential to bring the penicillin-aminoaryldisulfonic acid addition product into contact with the amine at a temperature below 60.degree. The preferred temperature range is between about 0 ° and 35 ° C. When temperatures above about 60 ° C are used, the anhydrous penicillin is formed.

The class of amines described above consists of liquids and these amines or mixtures thereof are added to the solution in their free base form. The amount of such amines is used generally varies between about 68-250 wt -.%, Preferably 85-150 wt -.% Of penicillin Aminoaryldisulfonsäure-adduct. Although greater amounts of amine can be used, no significant benefit is obtained using more than about 250 parts by weight of the penicillin-aminoaryldisulfonic acid adduct.

Amines of Formula IX above are commercially available. Such a mixture of secondary amines, in which every second

009833/1667

dary amine has the structure of formula IX, is sometimes referred to as "liquid amine composition No. I." and is a clear amber liquid having the following physical properties: viscosity at 25 ⁰ C of 70 Centipoisej spec. Density at 20 ⁰ C of 0.845; Refractive index at 25 ⁰ C of 1.467; Distillation range at 10 mm: up to 160 ° C - 4 %; 160 to 210 ⁰ C - 5 %} 210 Dis k ^ D ° C - 74 %; above 220 ⁰ C - 17 #.

The water-immiscible organic solvent, in which the penicillin-aminoaryldisulfonic acid addition product is brought into contact with the amine is preferred Methyl isobutyl ketone. Other solvents that can be used include other (lower) alkyl ketones, (lower) alkyl esters, such as butyl acetate, halogenated (lower) Hydrocarbons such as chloroform or methylene dichloride, aromatic hydrocarbons such as toluene, (lower) alkyl ethers, such as diamyl ethers, water-immiscible (lower) alkenols and mixtures thereof with one another or with methyl isobutyl ketone. The amount of solvent used is not critical and large amounts of solvent can be used as the penicillin hydrates obtained are not soluble in these substances. As the penicillin trihydrates are also relatively insoluble in water, there may be a considerable amount of water in the system, without reducing the yield of the desired product to any great extent.

Much higher yields of <o-aminobenzylpenicillins and oC-aminothienylmethylpenicillins can be achieved by the process according to the invention can be obtained from the reaction mixtures in which these penicillins are obtained by the acylation of 6-aminopenicillanic acid were produced than was previously possible in a large-scale process. Furthermore are the oc -aminobenzylpenicillins and <X_-aminothienylmethylpenicillins obtained in a state of greater purity than previous processes.

009833/1957

The Minimum Counteracting or Inhibitory Concentration (MIC) against various microorganisms has been determined for those produced by the method according to the invention Addition products determined. The results together with the corresponding MIC values for (-) - oL-aminobenzylpenicillin themselves, are listed in the table below.

The following examples illustrate the invention.

009833/1957

Tabel

Minimum inhibitory concentrations (mcg / ml) Adduct A Adduct B Adduct C Adduct D (-) - <* .- Amino benzyl-
Denicillin Organisms medium 0.016 0.012 0.016 0.024 0.008 DlplococcuB pneumonlae HIB ⁺ 0.016 0.012 0.012 0.008 0.010 Streptococcus pyogenes HIB 0.062 0.062 0.062 0.047 0.031 Staphylococcus aureus Smith HIB 0.062 0.062 0.062 0.062 0.031 Staph. aureus smith HIB ⁺⁺ Escherichla coll ATCC 38,000 19,000 25,000 25,000 9.7 8739 HIB 0.25 0.25 0.25 0.25 0.13 Sections * enterltldls HIB l ⁷ 1.6 1.6 4.7 1.6 Samonella typhosa HIB 6.3 1.6 2.4 6.3 1.6. Klebelella pneumonlae HIB Mycobacterlum smegmatls 100 100 100 100 100 No. 607 HIB 100 100 100 100 100 PseudomonuB seruglnosa HIB

O O CO CO

- * HIB «cardiac infusion fluid (broth) adduct A ■ 1: 1-molar adduct of (-) - (X-aminobenzyl- ^ £ penicillin and o-amino-l ^ -naphthallndi- '

2 + - 5 % accumulated human sulfonic acid

Serum added Adduct B »l: l-molar adduct of (-) - oe-aminobenzyl-

penicillin and 7-amino-1,3-naphthalenedi- ++ »50 % accumulated human sulfonic acid

Serum added adduct C »l: l-molar adduct of (-) - oc-amino-2-thienyl-

methylpenicillin and 6-amino-1,3-naphthalenedisulfonic acid

Adduct D = l: l-molar adduct of (-) - oc-amino-2-thienyl-

methylpenicillin and 7-amino-1,3-naphthalene- _c _ disulfonic acid ^ ₃

example 1

To a rapidly stirred solution of the sodium salt of (-J - ^ - aminobenzylpenicillin (l ₍ 0 g, 0.0027 mol) in 20 ml of water at 25 ^° C., 0.94 g (0.0027 mol) of the disodium salt of 6 -Amino-l, j ^ naphthalenedisulphonic acid. The pH is adjusted to 1.7 with hydrochloric acid, whereupon a crystalline solid is precipitated. It is stirred for a further 30 minutes and the mixture is then filtered. The crystalline solid is washed with Mefchylisabutylketon ^ in the yakuum via PnOj-ge

dries and weighed 0.4 g. The product is the oil addition product of (-) - (X.-aminobenzylpenicillin and 6-amino-l, 5-naphthalenedisulfonic acid, has an effectiveness of 525 meg. (-) - AL-aminobenzylpenieillin per milligram.

Example 2

Part A '. A Lösung'des Na'triumsslzes of - (-) - c <-Aminobenzylpenicillin 0 _S O g, 0,008l mol) in βθ ml of ice water was büschichtet with j5Q ml methyl isobutyl ketone and stirred rapidly while * 3.5 g (0.0112 mole ) Solid 6-amino-I ^ 3-naphthalenedisulfonic acid were slowly added. The mixture was acidified to pH 1.7 with hydrochloric acid and the resulting slurry was stirred and chilled in ice for 1 hour and filtered. The crystalline contaminant was washed with 20 ml of iced water and a small amount of methyl isobutyl ketone. It has been found that the product, the i-sl-Arxlagerungsprodukt of 6-Amlno-l ₅ ~ J5 ~ naphthalendisulfonic Ä- Aminob @ nzylpenicIllin and weighed 4.0 g / after it has been dried under vacuum (-) -.

Part B. The product made in Part A above is when it is in a hydrated form ®r »

0 0 9 8 3 3/1957

xfird hold, slurried in 50 ml of dry acetone, and the slurry stirred for 3 hours at 25 to 30 ⁰ C and filtered. The filter cake is washed with 20 ml of dry acetone and dried at 50 ⁰ C. The product, the anhydrous 1: 1 addition product of (-) - oc-amino benzylpenicillin and 6-amino- _{1,3-naphthalenedisulfonic acid 3} is very heat-stable.

Part C. A 2.0 g portion of the product obtained in Part B above is suspended in about 30 ml of water. The pH of the suspension is adjusted to 7.5 by adding triethylamine, whereupon a crystalline material begins to separate out. The pH of the mixture is then adjusted to about 4.5 by adding βη-HCl. The mixture is allowed to crystallize for about half an hour and the precipitated crystalline material collected by filtration and dried. The product was determined by infrared analysis to be essentially pure (-) - vC-aminobenzylpenicillin.

Example 3

A solution of 3.0 g (0.008l mol) of the sodium salt of (_) _,; C_Aminobenzylpenicillin in 60 ml of water is mixed with 30 ml of methyl isobutyl ketone coated and stirred rapidly while 3.5 g (0.0112 mol) of 7-amino-1,3-naphthalenedisulfonic acid be added slowly. The mixture obtained has a pH of 5.9. Sufficient hydrochloric acid is added to control the pH of the mixture to 1.7 whereupon a crystalline solid forms. Which resulting slurry is stirred for an additional 2 hours at OC and filtered. The solid is with a small portion of methyl isobutyl ketone, with 20 ml of iced water, which is adjusted to a pH value of 2.0 with hydrochloric acid was, and with another small portion

00983 3/1957

Washed methyl isobutyl ketone. It was found that the product, the 1: 1 adduct of (-) - c £ -aminobenzylpenicillin and T-amino-l ^ -naphthalenedisulphonic acid, after drying in vacuo over P ₂ , weighed 0.-4.95 g.

Example 4

2.7 g (0.0089 mol) of 6-amino-1,3-naphthalenedisulfonic acid are dissolved in a mixture of 10 ml of water and 40 ml of acetone. To this solution 2.5 g (0.0072 mol) of (-J-oC-aminobenzylpenicillin are added and the resulting solution has a pH value of 1.5. When 50 ml of acetone are added, the solution becomes fine needle-like crystals The mixture is filtered and the crystalline contaminant is dried in vacuo over ^i> 2 ° 5. It is found that the product, the 1: 1 adduct of (-J-oc-aminobenzylpenicillin and 6-amino-1 , 3-naphthalenedisulfonic acid, weighed 5.2 g.

Example 5

5.0 g (0.143 mol) oc-aminobenzylpenicillin are dissolved in a mixture of 20 ml of water and 80 ml of acetone. A solution of 5.4 g (0.0178 mol) of 6-amino-1,3-naphthalenedisulfonic acid in 7 ml of water is slowly added to this solution with a pH of 2.0, which is kept under stirring. The solution obtained has a pH of 1.0. The solution is cooled to 0 ⁰ C, whereupon a crystalline Peststoff is slow. 100 ml of acetone are added, the solution is stirred for a further JO minutes and filtered. The solid product, the 1: 1 adduct of (Xj-aminobenzylpenicillin and 6-amino-1,3-naphthalenedisulfonic acid, is washed with acetone, dried in vacuo and has a weight of 5.1 g.

009833/1957

Example 6

To a stirred solution of 5.0 g (Q, 0.145 Mo3 (-) - oC-aminobenzylpenicillin in 20 ml of water and 80 ml of acetone at 0 ° C., 4.55 g (0.54.5 mol) of 6-amino-1,5-naphthalenedisulfonic acid are slowly added given, the pH of this solution is found to be 2.1. Another portion of 0.5 g 6-Amino-1,3-naphthalene disulfonic acid is added and the pH drops to 1.75. A third portion of 0.25 g (for a total of 0.0618 mol) of 6-amino-1,5-naphthalenedisulfonic acid is added and it is noted that the pH the solution is 1.6. The addition of 15 ml of acetone causes vigorous precipitation of crystalline solid. Further small portions of acetone (100 ml in total) are added at intervals of 50 minutes. the The slurry that forms is filtered and the product, the l: l addition product of <\ .- aminobenzylpenicillin and ö-Amino-l ^ -naphthalenedisulfonic acid, is dried under vacuum and shows a weight of 5.2 g and an effectiveness of 480 micrograms (-) - Λ, -aminobenzylpenicillin each Milligram. A second crop of product is obtained from the mother liquor weighing 1.29 g and shows an effectiveness of 415 meg (-) - <3L-aminobenzylpenicillin per milligram.

Example 7

Part A. One gram (0.0027 mol) of the sodium salt of (-) - µC-amine © benzylpenicillin is dissolved in 20 ml of water to form a solution with a pH of 9.2. 0.816 g (0.0027 mol) of 7-amino-1,5-naphthalenedisulphonic acid are added to this solution to form a clear solution with a pH of 6.8. The pH is adjusted to 4.0 with hydrochloric acid, at which point the solution becomes cloudy. The addition of more hydrochloric acid to a pH value of 1.7 causes the formation of a strong lower

0 09833/1957

Impact of crystalline solid. 100 ml of water will be added and the slurry is stirred for 15 minutes at room temperature and filtered. The plague was with Washed small portions of water and methyl isobutyl ketone, dried in vacuo over P 0 and showed a weight of 0.82 g. The product identified by infrared analysis as a hydrate of the 1: 1 addition product of (-) - oC-aminobenzylpenicillin and 7-amino-l, 3-naphthalenedisulfonic acid has been shown to have an effectiveness of 510 meg. (-) - <* .- aminobenzylpenicillin per milligram.

Part B. Part of the product prepared in Part A above (2.0 g) is slurried in 25 ml of dry acetone, stirred for J> hours at 25 to 50 ^° C. and filtered. The solid is washed with 10 ml of dry acetone and dried at 50 ⁰ C. The product, l; l adduct of (-) -o (- benzylpenicillin amino and 7-amino-l _{i-naphthalenedisulphonic} 3, is very heat stable.

Example 8

500 ml of an aqueous reaction mixture containing "(-) - # L-aminobenzylpenicillin was formed by the acylation of 6-aminobenzylpenicillin and ^{stripped from acetone and methyl isobutyl ketone in vacuo at a temperature below 40 °} C. The solution obtained has a pH of 2.7 »250 ml Methylisobuty! ketone are added and the mixture stirred at 0 ° C, during 1O ₅ 5 S (0.0547 mole) of 7-amino-1,3-naphthalenedisulfonic acid was added slowly. when At the end of the addition, the mixture has a pH of 1.7 and a small amount of oily crystals has formed. The mixture is ^{stirred at 0 °} C. for a further 2.5 hours, during which time a heavy precipitate of crystalline solid forms forms = The slurry is filtered and the solid with a

0098 3 3/1957

small portion of methyl isobutyl ketone, washed with 60 ml of iced water and with another small portion of methyl isobutyl ketone. It has been found that the product, the l: l-adduct of oC-aminobenzylpenicillin and 7-amino-l, 5-naphthalene disulfonic acid, after drying in vacuo over P ₂ ^{0 5, a Ge} wieht of 14.2 g and an efficacy from 500 meg. (-J-oC-aminobenzylpenicillin per milligram.

Example 9

Part A; Preparation of the starting materials 1. OL, - (2-thienyl) hydantoin

875 g (17.84 mol) sodium cyanide and 4.050 g (4l, 8 mol) Ammonium carbonate is dissolved in 12 liters of distilled water solved. A solution of 1000 g (8.92 mol) of oC-thiophenaldehyde in 12 liters of methanol is added to this solution. To prevent oxidation of the aldehyde, addition and subsequent reaction are carried out under a nitrogen blanket carried out. The mixture is stirred for 4 hours heated to 50 to 55 ° C, during which time their color changes from white to deep yellow. The reaction mixture is cooled to room temperature and filtered and the pesticide washed with two 1 liter portions of methanol.

The piltrate combined with the waste liquors is concentrated to approximately one third of its original volume under reduced pressure. The pH of the solution is adjusted with conc. Hydrochloric acid slowly adjusted to 2.0, taking the necessary precautions for the release of the large amount of released HCN. The solution is heated for 10 minutes at 95 to 10O ⁰ C and 200 g of decolourising charcoal are added. The solution is heated for an additional 5 minutes and filtered. The charcoal cake is washed with 500 ml of water and the piltrate combined with the waste liquor becomes

009833/1957

Chilled in an ice bath for 1 hour, with a light yellow crystalline precipitate is obtained which is collected by filtration and washed with a small amount of water. It is found that the product, dC- (2-thienyl) hydantoin, after drying weighs about 950 g.

2. DL-op-amino-2-thienylessic acid

1000 g (5.5 mol) O ^ - (2-thienyl) hydantoin to be 4000 ml of 20 $ aqueous sodium hydroxide solution strength, and the mixture kept IJ hours under reflux conditions. 50 g of bleached charcoal are added and the mixture is stirred for about 5 minutes. The hot reaction solution is filtered and the filter cake is washed with a displacement device. The filtrate combined with the waste liquor is cooled and slowly acidified to pH 7.0 with glacial acetic acid . the resulting slurry is cooled to 15 to 2O ⁰ C, filtered and the filter cake washed with one liter of cold water. the filter cake is suspended in 2 liters of distilled water and sufficient conc. hydrochloric acid is added to dissolve the crude product (which is The resulting pH is about 1.0). A small amount of tarry product is found to be insoluble. 50 g of bleaching charcoal are added, the mixture is stirred for 5 minutes and filtered hot. The filter cake is washed with 200 ml of water and this is combined with the waste liquor Adjust the filtrate to pH 4.5 using NHhOH

adjusted and quenched in an ice bath for 1 hour. The resulting slurry is filtered and washed with 250 ml of iced water. The solid product, DL-oL amino-2-thienylacetic acid, is dried at 45 to 50 ⁰ C.

3. (-) - ut -Amino-2-thienylacetic acid

1620 g (7.0 mol) of d-10 vapor sulfonic acid are in 9.7 liters of isopropanol dissolved at 60 ° C. This solution is heated to just below its boiling point and 1000 g

009833/1957

(6.36 mol) DL-oc-amino-2-thienylacetic acid are added with stirring. The mixture is heated at boiling point for a few minutes to achieve essentially complete solution and filtered hot through a heated filter. The filtered solution is slowly stirred and cooled to room temperature over a period of 6 hours. To terminate the crystallization, they are left to remain at room temperature for a further 10 hours. The crystal! ne solid is collected by filtration, washed with 3 liters of isopropanol and dried at 45 to 50.degree. The product, the d-10-warrior sulfonic acid salt of (-) -c \ _- amino 2-thienylacetic acid, weighed 850 g.

1000 g of the d-10-steam sulfonic acid salt of - ^ - Amino-2-thienylacetic acid are distilled in 3 liters. Wasser.aufschlammt and the pH of the slurry is adjusted to 5.5 by slowly adding NHhOH. After the pH has been adjusted to 5.5, an additional 2 liters of methanol are added to the slurry and the slurry is stirred for an additional 20 minutes. If necessary, the pH value is adjusted again in order to be kept at 5 * 5. The suspension is ^{cooled to 0} ° C. for 1 hour, filtered and the filter cake is washed with 1 l of a cold methanol-water solution (two parts of methanol to one part of water) and with 3 l of methanol. The solid product, (-) - ^ c-Amino-2-thienylacetic acid, is dried at 45 to 50 ⁰ C and had a weight of about g 330th It melts with decomposition at 189-191 ⁰ C and has a polarization rotation of / iy ^"2 / ^ = -73/7 ^O C (concentration equal to 1.0% in water).

4. (-.) - -Amino-2-thienylacetyl chloride hydrochloride

Dry hydrogen chloride gas is made into a suspension of 17 g (0.108 mol) (-) - 'JL-amino-2-thienylacetic acid in 200 ml Methylene dichloride for 8 minutes at room temperature blown in. The suspension is stirring

009833/1957

cooled to -1O ⁰ C and 29 g (0.141 mol) of PCl ₅ are added. The mixture is stirred for a further 3 hours at a temperature of -8 ° to -5 ⁰ C and another 3 hours at 0 ° to 2 ° C. The suspension is filtered and the solid material is washed with a small portion of methylene dichloride and dried _{over P 2} ^{0 K in vacuo.} The product, (-) - 0L-amino-2-thienylacetylchloride hydrochloride, weighs 21.2 grams.

Part B; Production of (-) - ^ -amino-2-thienylmethylpenic ill in

23.8 g (0.11 mol) of 6-aminopenicillanic acid are dissolved in 275 ml of ice water by adding dilute NaOH to a pH of 7.2. 1280 ml of cold acetone are added to this solution (a total of 320 ml). The solution is ^{cooled to 0} ° C. and the pH value is adjusted to 2.5 with hydrochloric acid. 21.2 g (0.1 mol) of (-) - X ^ -amino ^ -thlenyl-acetylchloride hydrochloride are added to the stirred solution over a period of 20 minutes. Addition of dilute NaOH kept between 2.5 and 3.0. At the end of Reakticns time of 20 minutes, the temperature increased to 5 ⁰ C. The pH is adjusted to 2.9 and stirring is continued for an additional 15 minutes. 2560 ml of methyl isobutyl ketone are added and after thorough mixing the aqueous layer is separated. The methyl isobutyl ketone layer is extracted with a second 200 ml portion of water and with a third 100 ml portion of water. The combined aqueous layers are adjusted to a 5H value of 4/7, 250 ml of methyl isobutyl ketone is added, and the mixture is approx. 350 ml concentrated, at which point in time a crystalline solid forms. The mixture is filtered and the pesticide material is washed with small portions of water and methyl isobutyl ketone and dried over Ρ _Λ 0 p-dried in a vacuum.

009833/1957

cillin trihydrate. a weight of 10.7 g and inhibits that Growth of Staphylococcus aureus Smith.

Part C; Manufacture of the investment product of C-) -CC- Aminothienylmethylpenicillin and 7-AmInO-1, 3-naphthalenedisulfonic acid

The mother liquor from part B, above, combined with the methyl isobutyl ketone liquor, is ^{cooled to 0 °} C .; a solution of 50.0 g (0.099 mol) of 7-amino-1,3-naphthalenedisulfonic acid in 200 ml of water is added. The pH is adjusted from 3.7 to 2.4, whereupon crystallization begins. The pH is measured with conc. Adjusted HCl to 1.8 and stir the resulting slurry in an ice bath for 1 hour and filter. The solid material is washed with small portions of ice water and methyl isobutyl ketone and dried _{over P 2} ^{0 R in vacuo.} The product, the 1: 1 molar addition product of (-) - x-amino-2-thienylmethylpenicillin and 7-amino-1,3-naphthalenedisulfonic acid, has a weight of

Example 10

Part A : 47.6 g (0.22 mol) of 6-aminopenicillanic acid are dissolved in 640 ml of ice water by adding dilute NaOH to a pH of 7.2. 2.56 l of cold acetone are added to this solution, the solution is ^{cooled to 0 °} C. and the pH value is adjusted by adding 45 ml of conc. HCl adjusted to 3.5. The solution is stirred and 6l, 0 g (0.288 mol) of (-) -, *, - Amino-2-thienylacetylchloride hydrochloride (prepared according to the procedure of Example 9) are added over a period of 20 minutes while the pH is between 2.8 and 3.3 is held. The reaction mixture is stirred for a further 20 minutes and 6.4 1 of methyl isobutyl ketone are added. The aqueous layer is separated and the methyl isobutyl ketone layer is extracted with two additional 200 ml portions of water. The combined aqueous layers are on

009833/1957

adjusted to pH 4.7, 400 ml of methyl isobutyl ketone are added and the mixture is concentrated under vacuum until crystallization begins. The crystalline solid is removed by filtration, washed with small portions of ice water and methyl isobutyl ketone and flashed with Skellysolve B to a semi-dry solid. After drying in vacuo over P ₂ ⁰ C the product was (-) - CX_-amino-2-thienylmethylpenicillintrihydrat, g a weight of 22.5.

Part B: The united with the liquor from the above Part A mother liquor is cooled to 0 ⁰ C and a solution of 45 g (0.148 mol) of 7-amino-1,3-naphthalenedisulfonic acid ^ rol JOO in water was added. The pH value is adjusted to 1.6 and the resulting slurry is stirred for 1 hour. The crystalline solid is removed by filtration, washed with small portions of ice water and methyl isobutyl ketone and dried in vacuo over PpO ^. The product, the 1: 1 molar addition product of (-) - p (, - amino-2-thienylmethylpenicillin and 7-amino-1,5-naphthalenedisulfonic acid, weighs 18.0 g.

Example 11

Part A ; (-) - OL-Amino-2-thienylmethylpenicillin (5.0 g; 0.085 mol) is slurried in 50 ml of water, the slurry is cooled in an ice bath and 30 ml of methyl isobutyl ketone are added. A solution of 4.5 g (0.015 mol) of 6-amino-1,5-naphthalenedisulfonic acid in 10 ml of water is slowly added to this mixture. Crystallization begins immediately and the pH is kept at 1.7 by periodically adding triethylamine while the last portions of the aminonaphthalenedisulfonic acid are being added. The resulting heavy slurry is stirred in an ice bath for 2 hours and the solid is removed by filtration, with small portions of ice water,

009 * 33/1957

Methyl isobutyl ketone and Skellysolve B and dried in vacuo over P ₂ O 5 · g ^etrocknet The product, 1: 1 molar adduct of (-) - oG-amino-2-thienylmethylpenicillin and 6-amino-1,3-naphthalenedisulfonic acid, having a weight of

Part B : The adduct obtained in Part A above is slurried in a mixture of 50 ml of methyl isobutyl ketone, 10 ml of water and 7.5 ml of liquid amine No. 1 (Liquid Amine No. 1) and stirred for 4 hours at room temperature. The solid product is removed by filtration, washed with a small portion of methyl isobutyl ketone and dried in vacuo. The product, (-) - oc ~ Amino-2-thienylmethylpehic illin trihydrate, weighs 2.96 g, contains 11.3 % water as determined by Karl Fischer analysis, and has a biological activity or potency of (equivalent) 1.077mcg (-) - oC-aminobenzylpenicillin per milligram.

Example 12

The procedure of Example 11, Part B, is repeated using 15 ml of water and 15 ml of liquid amine # 1. The product, (-) - oil-amino-2-thienylmethyl-penicillin trihydrate, has a weight of 2.7 g, contains 12.8 % water, as determined by Karl-Fisehery analysis, and has a biological effectiveness equivalent to 1.040 meg ( -) -. x-aminobenzy! penicillin per milligram

009833/1957

Claims (1)

means, .Br, R and R ^ each hydrogen, nitro,
Di (lower) alkylamino-, (lowerjalkanoylamino-i
(lower jalkanoyloxy-i a (lower) alkyl group
(including straight and branched chain saturated aliphatic groups with 1 to 6 carbon atoms 'inclusive), one (lower) _{alkoxy- 1} sulfaray-1 group, chlorine, iodine, bromine, fluorine, trifluoromethyl, one (lower) alkylthlo-,.' ( low) Alkyisulfonyl-, Garbo (lower) alkoxy group, Benzyli phenethyl, cycloheptyl, cyclohexyl or cyclopentyl mean. ~ 1! - ¹ '-; ig? Av4. 9. 0 0 9 8 3 3/1957 2. The 1: 1 molar adduct of an oC-Amino thienyImethylpenicillin and 2-amino-1,4-benzenedisulfonic acid, 7-amino-1, j5-naphthalenedisulphonic acid, 6-amino-l, j5-naphthalenedisulphonic acid, I-amino-l ^ -naphthalenedisulfonic acid, 8-Amino-1,5-naphthalenedisulphonic acid, ^ -amino- ^ iY-naphthalenedisulphonic acid or 2-amino-1,5-naphthalenedisulphonic acid. 5. The IrI molar adduct of a compound of the formula OS ^ ^CH 3 L> X1 - L> - vll ——— ^, π. Ο · »> ί '^ CKL C N - CH - COOH it 0
and an aminonaphthalene disulfonic acid. 4. The 1: 1 molar adduct of an oC-aminobenzyne! Penicillin and 2-amino-l, 4-benzenedisulfonic acid, 7-amino-l, 5-naphthalenedisulfonic acid, 6-amino-l, 3-naphthalenedisulfonic acid, 5-amino-1,5-naphthalenedisulfonic acid, 8-amino-1,5-naphthalenedisulf onic acid, j5-amino-2,7-naphthalenedisulphonic acid or 2-amino-1,5-naphthalenedisulfonic acid. 5. The 1: 1 molar adduct of (-) - oC-amino-2-thienyl-methylpenicillin and an aminonaphthalene disulfonic acid. 6. The 1: 1 molar adduct of (-) - oC-amino-2-thienyl-methylpenicillin and 7-amino-1,3-naphthalenedisulfonic acid. 7. The l; l-molar adduct of (-) - oC-amino-2-thienylmethylpenicillin and 6-amino-1,3-naphthalenedisulfonic acid. 8. The 1: 1 molar adduct of (-) - oC-aminobenzy! Penicillin and 7-amino-1,5-naphthalenedisulfonic acid. 009833/1957 .- 30- The 1: 1 molar adduct of .. (-) - flC-aminobenzylpenicillin and o-amino-liJ-naphthalenedisulfonic acid. 10. Process for the preparation of adducts from penicillin derivatives and aminoaryldisulfonic acids, characterized in that an aqueous solution containing a penicillin of the formula ^ S ^ ^ CR IT - CH NH _n Il C-CH CH Il 'CIL CH - COOH contains, (in which R the group , 5 or R R- Around and R ^, R and R ^ are each hydrogen, the Nitro group, a di (lower) alkylamino, (lower) alkanoylamino, (lower) alkynoyloxy group, a (lower) alkyl group (including straight and branched chain saturated aliphatic groups with 1 to 6 carbon atoms inclusive), a (lower) alkoxy, sulfamyl group, chlorine, iodine, bromine, fluorine, Trifluoromethyl, a (lower) alkylthio, (lower) alkylsulfonyl, Carbo (lower) alkoxy group, benzyl, phenethyl, Mean cycloheptyl, cyclohexyl or cyclopentyl) or their salts with a water-soluble aminoaryldisulfonic acid according to the formula 009833/1957 SO ^ H or or their salts reacts, the pH of the reaction mixture to a value within the range of sets about 1.0 to 4.0 and the resulting crystalline reaction product of penicillin and the Aminoaryidisulfonic acid wins. 11. The method according to claim 10, characterized in ge k e η η that the penicillin from (-) - oC-amino-2-thienylmethylpenicillin and the aminoary1-disulfonic acid 2-amino-l, 4-benzenedisulfonic acid, 7-amino-1,3-naphthalene disulfonic acid, 6-amino-1,3-naphthalenedisulfonic acid, 3-amino-l, 5-naphthalenedisulfonic acid, 8-amino-1,5-naphthalenedisulfonic acid, J-Amino-SiT-naphthalenedisulfonic acid or 2-amino-1,5-naphthalenedisulfonic acid is. 12. The method according to claim 10, characterized in that the penicillin from (-) - <x, -aminobenzylpenicillin and the aminoaryldisulfonic acid 2-amino-l, 4-benzenedisulfonic acid, T-amino-ljJ-naphthalenedisulfonic acid, 6-amino-l, 3-naphthalenedisulfonic acid, 3-amino-l, 5-naphthalenedisulphonic acid, 6-amino-l, 5-naphthalenedisulphonic acid, 3-amino-2,7-naphthalenedisulfonic acid or 2-amino-1,5-naphthalenedisulfonic acid is. 13. Procedure for the recovery of a penicillin from its contaminated solution, thereby g e k e η η- 009833/1957 ζ e ic η e t that one is a contaminated watery Solution containing a penicillin formula R ² - CH - C - CH CH C N It CH - COOH contains, (in which · R the group or and R · ^, R and R ^ are each hydrogen, the Nitro group, a di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, a (lower) alkyl group, (including straight and branched chains saturated aliphatic groups with 1 to 6 carbon atoms including) a (lower alkoxy, suIgamyl group, Chlorine, iodine, bromine, fluorine, trifluoromethyl, a (lower) alkylthio, (lower) alkylsulfonyl, carbo (lower) alkoxy group, Benzyl, phenethyl, cycloheptyl, Cyclohexyl and cyclopentyl mean) and their salts in the presence of an organic, water-immiscible solvent with a water-soluble amino » aryl disulfonic acid of the formula SO ₃ H or HO ₃ S 0 0 9833/1957 or their salts reacts, the pH of the reaction mixture to a value within the range of adjusts about 1.0 to 4.0, the solid reaction product formed in the process of penicillin and aminoaryldisulfonic acid separated, suspended in water, the pH of the suspension to a value within the Adjusts the range from about 6.0 to 8.0 and separates the resulting penicillin. 14. The method according to claim 4, characterized in that g e k e η η - ζ e i c h η et that the penicillin from (-) - pc-amino-2-thienylmethylpenicillin consists and Äminoaryldisulfonsäure from the group of 2-amino-1,4-benzene-I disulfonic acid, 7-amino-1,5-naphthalenedisulfonic acid, 6-amino-l, 3-naphthalenedisulphonic acid, 3-amino-l, 5-naphthalenedisulphonic acid, 8-amino-l, 5-naphthalenedisulfonic acid, 3-amino-2,7-naphthalenedisulfonic acid or Is 2-amino-1,5-naphthalenedisulfonic acid. 15 · Method according to claim 1J>, thereby geke η η - shows that the penicillin consists of (-) - o (_- amino-3-thienylmethylpenicillin and the aminoaryldisulfonic acid from the group of 2-amino-1,4-benzenedisulfonic acid, 7-amino-l> 3-naphthalenedisulfonic acid, 6- Amino-1,3-naphthalenedisulfonic acid, j5-amino-1,5-naphthalenedisulfonic acid, 8-amino-1,5-naphthalenedisulfonic acid, 5-amino -2, 7-naphthalenedisulfonic acid or 2-amino-1,5-naphthalenedisulfonic acid, l6. Process according to Claim 1>, characterized in that the penicillin is composed of (-) - <λ_-aminobenzylpenicillin consists and the AminoaryIdisulfonsäure from the group of 2-amino-l, 4-benzenedisulphonic acid, 7-amino-l, 3-naphthalenedisulphonic acid, 6-amino-l, 3-naphthalenedisulphonic acid, J5-amino-1,5-naphthalenedisulphonic acid, 8-amino-l, 5-naphthalenedisulphonic acid, 00983 3/1957 > -Amino-2,7-naphthalenedisulfonic acid or 2-amino-1,5-naphthalenedisulfonic acid is. 17 · Procedure for the preparation of the anhydrous 1: 1 molar Analgeration product of a penicillin and an aminoaryldisulfonic acid, characterized in that an aqueous solution, which is a penicillin formula CH I! - CH CH CH. -CH - COOH contains (in R the group R ' or "5 4 ¹ p
and R, R and R ^ are each hydrogen, the = nitro, a di (lower) alkylamino, (lower) alkanoylamino, (lower) alkanoyloxy, a (lower) alkyl group (including straight and branched chain saturated aliphatic groups having 1 to 6 carbon atoms inclusive), a (lower) alkoxy, sulfamyl group, chlorine, iodine, bromine, fluorine, trifluoromethyl, a (lower) alkylthio, (lower) alkylsulfonyl, carbo (lower) alkoxy group, benzyl , Phenethyl, cycloheptyl, cyclohexyl and cyclopentyl) and their salts with a water-soluble aminoaryldisulfonic acid of the formula 0 09833/195 7 SO _a H sr I. SO ₅ H or HO S I I H ₂ N HO, S or their salts reacts, the pH of the reaction mixture to a value within the range of sets about 1.0 to 4.0, then the resulting hydrate of the 1: 1 molar addition product of penicillin and the aminoaryldisulfonic acid separates, the hydrate is slurried in acetone and then from the Slurry the anhydrous 1: 1 molar addition product of penicillin and .der aminoaryldisulfonic acid wins. Process for the production of medicaments, characterized in that an aqueous Solution of (-) - 0C-Amino-2-thienylmethyipenicillin or their salts with 7-amino-1,3-naphthalenedisulfonic acid or their salts reacts, the pH of the reaction mixture to a value within the range of 1.0 to 4.0 adjusts, whereby the 1: 1 molar addition product of (-) - Ct-amino-2-thienylmethylpenicillin and 7-amino-1,3-naphthalenedisulfonic acid is formed, and the penicillin is obtained therefrom in pure form. 19. Process for the manufacture of pharmaceuticals, thereby characterized that one has an aqueous Solution of (-) - oC-Amino-2-thienylmethylpenicillin or its salts with 6-AmiJK> -l, ^ naphthalenedisulphonic acid or their salts reacts, the pH of the reaction mixture to a value within the range of 1.0 to 4.0 adjusts, whereby the 1: 1 molar addition product of (-) - oC-amino-2-thienylmethylpenicil- 0 0 9 8 3 3/19 5 7 lin and 6-amino-l, j5-naphthalenedisulphonic acid and the penicillin is obtained from it in its pure form. 009833/1957