DE1670128C3 - Method of cleaning penicillins - Google Patents

Description

•

HO ₃ S

NH,

SO ₃ H

or their salts reacts, the pH of the reaction mixture to a value of about 1.0 adjusts to 4.0, separates the solid reaction product formed, suspended in water, the Adjusts the pH of the suspension in a manner known per se to about 6.0 to 8.0 and the resulting Separates penicillin.

35 desired penicillin to contain unreacted 6-aminopenicillanic acid, hydrolyzed acylating agent, and products of side reactions such as the products of the acylating agent reacted with itself and / or with the desired penicillin. Because these compounds can have similar solubility properties in different media, it is often difficult to isolate the desired penicillin from the other reaction products.

In Belgian patent 6 39 025 and USA patent 31 57 640 are methods of formation of addition compounds of berzol and naphthalenesulfonic acids with i-aminobenzylpenicilines described. From these addition compounds, it is true that purified α-aminobenzylpenicillinc can be obtained obtained, but the methods described fail in the purification of a-aminothienylmethylpeniällinen, since the addition compounds have too great a solubility, recovery not allowed from the impure aqueous solutions.

In contrast, it was surprisingly found that aminonaphthalene disulfonic acid adducts of the α-aminothienylmethylpenicillins are sufficiently insoluble to permit the extraction of pure addition products to allow impure aqueous solutions.

The object on which the invention is based is thus achieved in that an aqueous Solution of the penicillin in the presence of an organic, water-immiscible solvent with a water-soluble acid of the general formula

HO ₃ S

NH,

SO, H

or converts their salts, the pH of the reaction

The invention relates to a method for cleaning 40 tion mixture to a value of about 1.0 to 4.0 a penicillin of the general formula I adjusts, separates the solid reaction product formed, suspended in water, the pH of the suspension in a known manner to about 6.0 to

CH-C-NH

NH ₂

8.0 adjusts and separates the resulting penicillin. In the process according to the invention, intermediate the compounds of the general formula II

55

or its salts.

(i-Aminothienylmethylpenicillins are for example in U.S. Patents 29 85 648 and 3198 804 and Belgian Patent 6 31631 described. According to this literature, the penicillins are produced by reacting 6-aminopcnicillanic acid with the acid chloride, acid bromide, acid anhydride or mixed anhydride of «-aminothienyl acetic acid, with the amino group is protected by a carbobenzoxy or other suitable protecting group. After completion the acylation reaction is the protecting group from the amino group for example by Removed reaction with hydrogen in the presence of a catalyst.

The known working methods for the production of the ri-aminothienylmethylpenicillins by acylation of 6-aminopenicillanic acid lead to the production of mixtures which, in addition to the gc-

CH-C-NH-CH-CH

CH,

NH ₂ X

(H)

C-

-N-

CH,

CH-COOH

wherein X is the group of the general formula

60 NH,

HO ₃ S-

SO ₃ H

means.

In particular, intermediate - depending on

the choice of the method according to the invention Preferably, the solution contains between 25 to

aminonaphthalene disulfonic acid used - the 100 mg of the desired penicillin per ml of the solution.

l: l-molar addition product of (- »-,., - amino- If this is necessary, the solution can be concentrated

2-thicnylmethylpenicillin and 7-amino-1,3-naph-

thalinedisulfonic acid, the 1: 1 molar addition temperature of 30 to 40 ⁰ C for several minutes below one

duV »of (-) - u-amino-2-thienylmethylpenicillin and partial vacuum.

6-Amino-1,3-naphthalenedisulfonic acid is formed. To which the "-aminothienylmethylpenicillin

Suitable salts of the aminonaphthalenedisulfonic acid-containing aqueous solution are mixed with water

for use in the immiscible organic solvent according to the invention, preferably

Drive the ammonium, substituted Ammo- 10, methyl isobutyl ketone, added. Other lo-

sodium, alkali and alkaline earth metal salts. solvents that can be used include

As can be seen from the examples, other (lower) ketones, (lower) aliphatic esters, produced by the process according to the invention, such as butyl acetate, halogenated (lower) hydrocarbons Addition products are invariably the hydrogen, such as methylene chloride, aromatic carbon: l-molar Addition product of the particular hydrogen, such as toluene, and mixtures thereof Penicillins and aminonaphthalene disulfonic acid. It with each other or with methyl isobutyl ketone. The Anwird assumed that this is due to the formation of an essence of the solvent facilitates the crystalline The "inner salt" of aminonaphthalene disulfonic acid, sation and results in a purer product. The voluminous. H. between the amino group and one of the sulfo ratio of the organic solvent to the groups, which leads to a confi- 20 aqueous phase is not critical. So can for each Guration leads to only one sulfo group for the volume of water present two volumes Settlement with the u-amino group of penicillin to or more organic solvent present Has disposal. be.

The a-carbon atom of the acyl group (to which preferred aminonaphthalenedisulfonic acids, the

the amino group is attached) is an asymmetric _2J measure of practicing the invention

Carbon atom, so that the compounds can be used according to are 7-Aminc-l, 3-naph-

of the invention in two optically active isomeric formaldisulfonic acids, 6-amino-1,3-naphthalenedisulfonic acid

men (the D- and L-diastereomers) as well as in an acid, 3-amino-l, 5-naphthalenedisulfonic acid, 8-amino-

Mixture of the two optically active forms exi- 1,5 - naphthalenedisulfonic acid, 3 - amino - 2,7 - naph-

can stare; All such isomeric forms of the ₃₀ thalindisulfonsäure and 2-amino-1,5-naphthalene

Compounds within the scope of the invention are disulfonic acid. The aminonaphthalene disulfonic acids,

closed that can be used are in technology

The term (-) - u-aminothienyl- used herein is described, and many of which are commercially available-

Methylpenicillin does not refer to the twist borrowed. It is preferably a concentrated aqueous one

of the penicillin molecule in its entirety [which uses 35 free acid solution, although the

very generally (+) is], but rather on the water-soluble ammonium or substituted am-

(-) - Rotation of the derivative of, i-aminothienyl acigmonium, alkali and alkaline earth metal salts of these

acid from which the penicillin was made, acids can also be used. Preferential

d. that is, it relates to the configuration of the pre-

-mentioned asymmetric ( "-Kohlenstoff- ₄₀ disulfonic acid per mole of a-Aminothienylmethylpenicillin

atoms of the acyl group of penicillin. Used in a similar way in the solution.

Way refers to the expression (f) -u-aminothienyl- The aminonaphthalene disulfonic acid is in all-

methylpenicillin on the (+) rotation of this asymmetric with the aqueous one containing penicillin-

metric a carbon atom. If there is no sign of the solution at low temperatures, i. H. at

is particularly indicated, the DL mixture is meant. 45 temperatures between about 0 and 10 ⁰ C, in contact

The aqueous solution containing a u-aminothienylmethyl- tion brought about the decomposition of the product and penicillin as defined in the above general form of loss of the solution to a minimum mel I, can thereby be obtained, as well as the crystallization of the Product to accelerate the crystalline penicillin in question in water. The pH of the solution is dissolved during the formation. However, the maximum benefits of the aminonaphthalenedisulfonic acid addition product are achieved using an impure product of the fi-aminothienylmethylpenicillio in the range of about 1 to 4.0. The cillin contains. Significantly, the peni pH of the solution can be higher than 4.0, e.g. B. cillin-containing aqueous solution through the acy- about 4.5, during the addition of the arylsulfonic acid, lation of 6-aminopenicillanic acid with a suitable 55 but the desired salt will not form until the acylating agent is obtained, as is the case in the USA - the pH is within the range of about 1.0 patent specification 29 85 648 and the Belgian patent to 4.0; the preferred pH is in the range described in 6 31631. This reaction from 1.5 to 2.0. If the pH value cannot be brought to the range a - aminothienylmethylpenicillin unreacted 60 within 1.0 to 4.0 in addition to the desired aminonaphthalenedisulfonic acid by adding the mixture, a 6-aminopenicillanic acid and hydrolysis or minor mineral acid, such as Contains HCl or H ₂ SO ₄ , for adjusting reaction products of the acylating agent. the pH value can be added.
Numerous other side reaction products are often also present as impurities. The acid addition product of α-aminothienyl-aminothienylmethylpenicillin can, if necessary, be initiated by vaccination after recrystallization of the fen. After the precipitation of the corresponding penicillin remaining parent product is complete, it will be treated by any suitable means, e.g. B. by filtration, obtained.

The product can then be mixed with water and / or an organic solvent such as methyl isobutyl ketone, washed and then dried.

When the aminoaryldisulfonic acid addition product of the particular -amothienylmethylpenicillin is obtained in a hydrated form, it can easily be converted to the anhydrous form. This can be achieved by soaking the hydrate in a large volume of dry acetone, e.g. B. about 10 ml of acetone per gram of hydrate, is slurried. The amount of acetone used should be such that there is less than 2 weight percent water in the acetone slurry after the hydrate (which may initially be moist or wet) is slurried in the acetone. The slurry is then stirred for about 3 hours at about 25 to 3O ⁰ C, filtered, the filter cake washed with about five volumes of dry acetone and dried at about 50 ° C.

The aminonaphthalene disulfonic acid salts of an α-aminothienylmethylpenicillin are anhydrous in their own Form soluble in methanol, ethanol, formamide, dimethylformamide and pyridine and in others insoluble in usual solvents.

The addition product of an aminothienylmethyl penicillin with an aminonaphthalene disulfonic acid, as occurs in the process according to the invention, the corresponding α-aminothienylmethylpenicillin can be obtained by neutralization, like ζ Β. by suspending the addition product in water and adjusting the pH of the suspension to about 6.0 to 8.0 and preferably about 6.7 to 7.2, being transformed. The adjustment of the pH value of the solution is preferably carried out by the addition a tertiary amine, such as triethylamine, preferably achieved at about room temperature. Other alkaline Substances such as sodium hydroxide, ammonium hydroxide, potassium hydroxide, sodium carbonate, ammonium carbonate or potassium carbonate can also be used. Adjusting the pH value 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 becomes cooled to complete precipitation. After the precipitation of the penicillin trihydrate has ended, can it can be obtained by filtration. The product can then be mixed with water and / or an organic Solvents such as methyl isobutyl ketone. washed and dried.

According to a preferred and particularly elegant procedure for obtaining the penicillin This addition product becomes his adduct with an aminonaphthalene disulfonic acid with an amine or a mixture of amines of the general formula Hl

CH,

CH,

HR ⁴

CH ₃ -C-Ch ₂ -C-CH ₂ -CH = CH-CH ₂ -NCR ²

CH ₃ CH, R "

(III)

(in which R ² , R ³ and R ⁴ each represent an aliphatic hydrocarbon radical with a total of 11 to 14 carbon atoms) in a water-immiscible organic solvent.

whereupon the amphoteric penicillin is precipitated and can be recovered by filtration. The penicillin is preferably isolated in the form of a trihydrate, and the amine solvent medium should therefore contain at least 3 mol of water per mol of penicillin. To achieve the Penicillintrihydrats it is essential to bring the penicillin Aminonaphihalindisuifonsäure-adduct with the amine at a temperature below 6O ⁰ C into contact. The preferred temperature range is between about 0 and 35 ° C. If temperatures are used above about 6O ⁰ C, 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 that is used will generally vary between about 68 and 250 percent by weight, and preferably 85 to 150 percent by weight of the penicillin-aminonaphthalene disulfonic acid adduct. Although greater amounts of amine can be used, no significant benefit is obtained using more than about 250 weight percent of the penicillin-aminonaphthalene disulfonic acid adduct.

Amines of the above general formula III are commercially available. Such a mixture of secondary amines wherein each secondary amine has the structure of the general formula IH 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 70 centipoise; spec. Weight at 20 ° C 0.845; Refractive index at 25 ° C 1.467; Distillation range at 10 mm: up to 160 ⁰ C - 4%; 160 to 210 ⁰ C -5%; 210 to 220 ° C - 74%; above 220 ° C-17%.

The water-immiscible organic solvent in which the penicillin-aminoaryldisulfonic acid addition product is brought into contact with the amine, is preferably methyl isobutyl ketone. Other solvents that are used may 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) alkanols 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 obtained Penicillin trihydrates are not soluble in these substances. Since the penicillin trihydrates are also proportionate in water are insoluble, there can be a significant amount of water in the system without reduce the yield of the desired product to any great extent.

Much greater yields of α-aminothienylmethylpenicillins can be obtained by the process according to the invention can be obtained from the reaction mixtures in which these penicillins are obtained by acylation of 6-aminopenicillanic acid than was previously possible in a large-scale process was possible. In addition, the (z-aminothienylmethylpenicillins are in a state greater purity than previous processes.

The following examples explain the process according to the invention.

example 1

Part A

(-) - «- Amino-2-thienylmethylpenicillin (3.0 g; 0.0085 mol) is slurried in 50 ml of water, the slurry is cooled in an ice bath, and 30 ml of methyl isobutyl ketone is added. A solution of 4.5 g (0.015 mol) of 6-amino-1,3-naphthalenedisulfonic acid in 10 ml of water is slowly added to this mixture. Crystallization sets in 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 thick slurry is stirred in an ice bath for 2 hours and the solid removed by filtration, washed with small portions of ice water, methyl isobutyl ketone and petroleum ether and dried in vacuo over P ₂ O ₅ . The product, the 1: 1 molar adduct of (-) - «- amino-2-thienylmethylpenicillin and 6-amino-1,3-naphthalenedisulfonic acid, weighs 4.5 g.

part B

The adduct obtained in Part A above is dissolved in a mixture of 50 ml of methyl isobutyl ketone, 10 ml of water and 7.5 ml of a mixture of secondary amines (the mixture of secondary amines is a mixture in which each secondary amine has the structure of formula III has: it is a clear, amber liquid having the following physical properties:. viscosity at 25 ° C 70 cps; a specific gravity at 20 ^c C 0,845; refractive index at 25 C 1.467: distillation range at 10 mm: up to 160 ⁰ C. -4%; 160 to 210 ^° C. -5%; 210 to 220 ^° C.-74%; above 220 ^° C.-17%), slurried 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, (-) - «- amino-2-thienylmethylpenicillin trihydrate. has a weight of 2.96 g, contains 11.3% water as determined by Karl Fischer analysis, and has a biological activity or potency of 1.077 γ (-) -H-aminobenzylpenicillin per milligram.

B e i s ρ i e 1 2

The procedure of Example 1, Part B, is followed using 15 ml of water and 15 ml of a mixture of secondary amines (the mixture of secondary amines is a mixture in which each secondary amine has the structure of Formula III; it is a clear, amber liquid having the following physical properties:. viscosity at 25 ⁰ C 70 centipoise; specific gravity at 20 ° C 0.845; refractive index at 25 ° C 1.467; distillation range at 10 mm: up to 16O ⁰ C 4%; 160 up to 210 ⁰ C - 5%; 210 to 220 ⁰ C - 74%; above 220 ⁰ C - 17%), repeated. The product, (-) -a-amino-2-thienylmcthy1penicillin trihydrate, weighs 2.7 g, contains 12.8% water as determined by Karl Fischer analysis, and has a biological activity equivalent to 1.040 γ ( -) - <j-aminobenzylpenicillin per milligram.

The purification process according to the invention can also be used with mother liquors that are used during production of K-aminothienylmethylpenicillins.

Example 3
Part A

Production of (-) - «- amino-2-thienylmethylpenicillin

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 3.5 with hydrochloric acid. 21.2 g (0.1 mol) of (-) -a-amino-2-thienyl-acetyl chloride hydrochloride are added to the solution, which is kept stirring, over a period of 20 minutes. The pH is maintained between 2.5 and 3.0 during the reaction by periodically adding dilute NaOH. At the end of the reaction time of 20 minutes, the temperature has risen to 5 ° 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 a third 100 ml portion of water. The combined aqueous layers are adjusted to pH 4.7. 250 ml of methyl isobutyl ketone is added and the mixture concentrated under vacuum to approximately 350 ml, at which point a crystalline solid forms. The mixture is filtered and the solid material is washed with small portions of water and methyl isobutyl ketone and dried _{in vacuo over P 2} O _5. The product obtained, (- Ju-Amino-2-thienylmethylpenicillin trihydrate, has a weight of 10.7 g.

part B

Production of the adduct of

(- (- «- Aminothienylmethylpenicillin and

7-amino-1,3-naphthalenedisulfonic acid

The mother liquor from Part A, above, combined with the methyl isobutyl ketone liquor, is cooled to OC: a solution of 30.0 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 _{in vacuo over P 2} O _5. The product, the 1: 1 molar addition product of (-) - «- amino-2-thienylmethylpenicillin and 7-amino-1,3-naphthalenedisulfonic acid. has a weight of 14.5 g.

509 650/59

Claims (1)

Claim: Process for cleaning a penicillin of the general formula I. O
Il 4th Ii
-C \ / -CH- i
NH, NH or its salts, characterized that an aqueous solution of penicillin in the presence of an organic, water-immiscible solvent with a water-soluble acid of the general formula IO