FI60017C - FOERFARANDE FOER FRAMSTAELLNING AV 6-AMINOPENICILLANSYRADERIVAT - Google Patents

Description

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England-England (QB) 5 ^ 1 ^ / 73 (71) Leo Pharmaceutical Products Ltd. A / S (Livens Kemiske Fabrik

Produktionsaktieselskab), EK-2750 Ballerup, Denmark-Damnark (DK) (72) Frantz Johannes Lund, Lyngby, Denmark-Danmark (DK) 7M Oy Roister Ab (5 * 0 Method for the preparation of 6-aminopenicillanic acid derivatives -Förfarande för framställning av 6- This invention relates to a process for the preparation of 6-aminopenicillanic acid derivatives and their pharmaceutically acceptable non-toxic salts.

The general formula of the compounds prepared by the process of the invention is

R, \ R0 H H

J I 3 Ξ Ξ O nti "^ N-C = N ^ = Ξ / \ / 3

Rf -σ \ h3 (I)

o = c-N-QH

V ^ C00H

wherein R 3, R 2 and R 3 represent the same or different substituents and each represents a -C 1-4 alkyl group, a monocyclic carbocyclic aryl group or an aralkyl group in which R 3 may further denote hydrogen, uv ® 2 60017 and and R 1 together with the nitrogen atom to which they are attached, may represent a heterocyclic ring system of 5 to 10 atoms, which optionally comprises, in addition to said nitrogen atom, a further nitrogen or oxygen atom.

More specifically, R 2 and R 3 represent, for example, a C 1 -C 4 alkyl group whose carbon chain may be straight or branched, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, a monocyclic carbocyclic aryl group, e.g. phenyl, an aralkyl group such as a mono- or bicyclic Aralkyl group, e.g. benzyl or phenethyl, 1- or 2-naphthylmethyl; in addition, R 1 and R 2 together with the nitrogen atom may denote heterocyclic groups having 5 to 10 atoms and optionally having another heteroatom in the ring, such as an O or N atom, e.g., forming a fully or partially hydrogenated ring system, e.g. piperidyl, morpholinyl, hexahydro-1H-azepin-1-yl, hexahydro-1 (2H) -azoquinyl or octahydro-1H-azon-1-yl,

The compounds of formula I can be isolated as amphoteric ions or salts, e.g., alkali metal salts and ammonium or amine salts, or as salts of strong acids such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, tartaric acid or maleic acid.

Salts may also be formed with other antibiotics which are acidic or basic in nature, and in particular with acidic antibiotics with which the compounds of the invention form synergistic mixtures, such as with penicillins.

It is particularly advantageous to use acids which, with the compounds of the invention, form salts which, in view of their absorbency and clinical use, have the desired properties. Examples of such salts are pamoate. or naphthylate, or salts containing probenecid, the latter compound slowing down the excretion of the compounds of the invention, with the result that they linger longer in the blood,

The compounds of the invention are most conveniently used for parenteral therapy.

Thus, the compounds are most preferably administered by injection of a sterile aqueous solution of the amphoteric ion itself or a suitable salt thereof, or a suspension of the suspension as such or in the form of a buffer.

Compounds of formula I have so far been prepared as described in the descriptions of our English Patents Nos. 1,293,590 and 1,315,566 to give general formula II

R1 \ f 3 \ N-C = R, (II)

/ O

R2 wherein R1, R2 and R1 are as defined above and R1 is O or S, a reactive derivative of the corresponding amide or thioamide, e.g. a compound of general formula III is R1 '\ R3 J> NC = (O-Alk ) 2 (III) R 2 wherein R 1, R 2 and R 2 are as defined above and Alk represents a lower alkyl group, to react with a 6-aminopenicillanic acid derivative represented by the general formula IV

H H

Η2Ν · ν? z ^ c-or ^ ch3 (IV)

0 = C-N-CH

V

C 20 R 4 wherein R 2 represents an unsubstituted or substituted alkyl or aralkyl group, or with a silyl ester of 6-aminopenicillanic acid.

When -COOR 4 represents an ester group, after the reaction, cleavage of said ester group must be carried out in order to obtain compounds of the invention

It has now been found that compounds of formula I can be advantageously prepared by reacting a reactive derivative of a compound of formula II with a salt of 6-aminopeoylanic acid (6-APA), mainly a strong tertiary amine salt, in a suitable solvent at about room temperature and about - At a temperature between 50 ° C,

Reactive derivatives of compounds of formula II are acid amide acetals of formula III, di-small alkyl sulphate complexes of compounds of formula II or acid amide halides obtained by reacting a compound of formula II with a halogenating agent.

It is surprising that this process gives very pure products in excellent yields (about 70-90%) because it is well known that reactive derivatives of amides often react with acids. esters.

In addition, this method is simpler than previously known methods. It is carried out in one step, whereas instead the previous method involves, for example, the preparation of a silyl ester or benzyl ester of 6-APA, followed by conversion to an amidinopenicillanic acid ester and then cleavage of the ester group.

The reaction is carried out in one step by dissolving or suspending the reactants in an organic solvent mainly in the absence of water, since the reactive derivatives of the compounds of formula II are hydrolyzed in the presence of water.

The reaction conditions depend on the reagents used in the process and are therefore described in more detail below,

When, in the application of this method, an acid amide acetal is used as the reactant, the reaction media are mainly methylene chloride, chloroform, acetone with a small amount of formamide, methanol and methyl formate. A strong tertiary amine must be present in the first three reaction media in order to obtain the compounds of formula I in high purity with the desired sermons, whereas in e.g. methanol the reaction can be carried out without the addition of a tertiary amine due to the ability of the weakly basic acid amide acetal to form 6- With APA in this medium.

Examples of strong 600,617 tertiary amines to be used as mentioned above are triethylamine and N, N-diisopropylethylamine, whereas, for example, pyridine, N-methylmorpholine or triethanolamine are too weak for this purpose.

The above reaction can be carried out using equivalent amounts of reactants, but it is preferred that a slight excess of acid amide acetal and tertiary amine be used (in each case about 20-30%). Of course, the 6-APA salt and tertiary amine can be used as starting material, either using previously prepared salt or by reacting 6-APA in part with a tertiary amine before the acid amide acetal. increased. The reaction is carried out at about or below room temperature, mainly at a temperature between 0 and 5 ° C, although the reaction may be carried out at lower temperatures, e.g. about * 25 ° C. The reaction time depends on the temperature used and the reaction medium and whether or not a tertiary amine has been added, but it is usually 1 to 6 hours.

When a di-small alkyl sulfate complex is used as a reagent in this process, the preferred reaction media are methylene chloride or methanol. In this case, a concentrated tertiary amine must be used to protect at least one equivalent of the final compound of formula I and the β-lactam ring of 6-APA against a di-small alkyl sulfate complex which would otherwise cause said β-lactam ring to open. It is recommended that about 1.5-3 equivalents of tertiary amine and an excess of di-small alkyl sulfate complex (about 20-30%) be used. When methylene chloride is used as the reaction medium, it is most suitable that most of the 6-APA is allowed to dissolve in tertiary as the amine salt before the addition of the di-small alkyl sulfate complex. The temperature is preferably about 0-5 ° C, although higher temperatures (approximately the same as room temperature) and lower temperatures (about -10 ° C) may equally well be used. The reaction time depends on the temperature used, the reaction medium and the reactants, although it is usually 1-6 hours.

When an acid amide halide is used as the reactant in this process, only methylene chloride, chloroform and other similar neutral media can be used as the reaction medium because the acid amide halides are highly reactive. In this case, it is preferred that 2-3 equivalents of tertiary amine be used to protect the final product and the β-lactam ring of 6-APA.

It is preferred that most of the 6-APA be allowed to dissolve as the tertiary amine salt before the acid amide halide is added. The reaction must be carried out at low temperatures starting at about -50 ° C. The reaction temperature is allowed to rise to about 0 ° C and the reaction is complete after about 3/4 hours,

The resulting reaction mixture containing a permanent tertiary amine salt of a compound of formula I, or in some cases the amphoteric ion itself, is filtered to remove any unreacted 6-APA residue and the clear solution is then evaporated to dryness in vacuo. The residue is dissolved in a suitable solvent, from which the acid of formula I is precipitated by adding another solvent in which the acid is sparingly soluble or mainly by releasing the amphoteric ion by adding an inorganic or organic acid. It is recommended, especially in the preparation of large amounts, that any remaining reaction medium residues be removed by adding a higher boiling solvent, e.g. methyl ethyl ketone, alternatively together with the acid used to liberate the amphoteric ion, after which the solvent mixture is evaporated off in vacuo. The combination of tertiary amine, solvent and acid may be appropriately selected taking into account the amphoteric ion to be precipitated and the fact that the amine salt formed during the neutralization is caused to dissolve in the solvent.

P-toluenesulfonic acid dissolved in acetone or methyl ethyl ketone can be used to release the amphoteric ion, although other acids and solvents may be used as well, depending on the reagents used.

The starting materials used in the above embodiments are known compounds, or can be prepared by conventional methods for preparing analogous compounds.

This method gives a very pure crude product (97-93%, determined by iodometric titration).

For reasons of stability, it is important that the final product contains as few impurities as possible, even even small amounts of impurities significantly impair stability, f v / • i 7 60017 Thus, the crude product can be further purified by recrystallization from a suitable solvent or solvent mixture. In some cases, it may be advantageous to convert the crude product to a hydrate, which is then recrystallized from a suitable solvent or mixture of solvents, e.g., formamide-acetone, to give the desired anhydrous compound of formula I.

The compounds of formula I can be isolated as such or as their salts, e.g. as alkali metal salts and ammonium or amine salts, or as salts of pharmaceutically acceptable strong acids such as hydrochloric acid, phosphoric acid, nitric acid, p-toluenesulfonic acid, tartaric acid and maleic acid.

Included within the scope of the invention are all possible isomeric forms of the compounds of formula I which depend on the various substituents, the configuration of the 6-aminopenicillanic acid moiety corresponding to the structure obtained in the fermentation process.

The compounds of formula I have valuable bactericidal properties and very low toxicity as described in the patent specifications of British Patent Nos. 1,293,590 and 1,315,566.

The invention is further illustrated by the following embodiments.

Example 1 O- (O-oxahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (2.98 ml). g) stirred in methylene chloride (40 ml) at 0-5 ° C for 2.5 hours. After filtration, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in acetone (50 ml). The solution was neutralized by adding with stirring p-toluenesulfonic acid monohydrate (1.9 g) dissolved in acetone (25 ml) and adding seed crystals at room temperature. The mixture was kept at 0.5 ° C for 1.5 hours and filtered. Yield 82%, purity 97%.

Example 2 6-Z (Hexahydro-1H-azepin-1-yl) -methyleneamino] -7-penicillanic acid

A suspension of 6-aminopenicillanic acid (2.48 g) in 8,600 g of 40 ml of chloroform was stirred for 4.5 hours at 0.5 ° C with triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl with acetal (2.25 g). The resulting cloudy solution was filtered through Dicalite. The filtrate was evaporated to dryness in vacuo to give an oil which was dissolved in acetone (50 ml). The pure compound was accompanied by the addition of a solution of p-toluenesulfonic acid monohydrate (1.9 g) in acetone (25 ml) at room temperature for half an hour and then for 1 hour at 0-5 ° C with stirring. The crystalline compound was filtered off, washed with acetone and dried. desiccator.

Yield 70%, purity 98.5%,

Example 3 6- [N- (Hexahydro-1H-azepin-1-yl) -methyleneamino] -7-penicillanic acid 6-Aminopenicillanic acid (2.48 g) was suspended in formamide (0.5 ml) and acetone (25 ml, Merck pa). to the mixture. Triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (2.37 ml) were added. The mixture was stirred for 5 hours at 0 ° C and filtered using Dicalite. At 0-5 ° C, a solution of p-toluenesulfonic acid monohydrate (1.9 g) in acetone (25 ml) and seed crystals were added with stirring. The precipitate formed was filtered off and washed with acetone. Yield 67%, purity 98%.

Example 4 6- [N- (Hexahydro-1H-azepin-1-yl) -methylamino] -penicillinic acid 6-Aminopenicillanic acid (2.48 g), N, Ν-diisopropylethylamine (1 , 95 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (2.37 ml) were stirred for 3.5 hours at 0-5 ° C in methylene chloride (40 ml). After filtration through "Dikalite" and evaporation of the filtrate to dryness, the oily residue was dissolved in tert-butanol (50 ml). Hydrogen chloride dissolved in isopropanol (8 N, 1.44 mL) was added with stirring at room temperature, followed by additional tert-butanol (20 mL). The precipitate was filtered off, washed with tert-butanol and ether, and dried. Yield 69%, purity 97%,

Example 5 6-Z (Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillanic acid 6-Amino-penicillanic acid (2.48 g), triethylamine (1.62 ml) Φ · ΰ '

'.V

9,60017 and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (2.37 mL) were stirred for 3 hours at 0-5 ° C in methylene chloride (40 mL).

After filtration through "Dicalite", the filtrate was evaporated to dryness in vacuo, glacial acetic acid (0.66 ml) was added to the residue dissolved in acetone (50 ml) with stirring. The precipitate formed was filtered off with suction and dried. Yield 57%, purity 98%. Example 6 6-Z (Hexahydro-1H-azepin-1-yl) -methyleneamino] -7-penicillanic acid

Following the procedure of Example 5, but substituting benzoic acid (1.4 g) for acetic acid, the title compound was obtained in good yields. Yield 70%, purity 97%.

Example 7 6- (Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (2, 37 ml) was stirred in methylene chloride (40 ml) at 0-5 ° C for 3.5 hours. After filtration using "Dicalite", the filtrate was evaporated to dryness in vacuo. To the residue dissolved in acetone (15 ml) was added ether (60 ml) at room temperature with stirring. The mixture was kept at 0-5 ° C for 1.5 hours and filtered to give a crystalline compound. Yield 70%, purity 97.5%. Example 8 6-Z (Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid 6-aminopenicillanic acid (10.0 g), triethylamine (7.0 ml) and 1-hexamethyleneiminecarboxyaldehyde dimethyl acetal (10, 9 ml) was stirred in methanol (50 ml) at 0-5 ° C for 1.5 hours. After filtration, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in methyl ethyl ketone (45 ml) containing p-toluenesulphonic acid monohydrate (8.0 g). The solvent was removed in vacuo and methyl ethyl ketone (50 ml) was added to the residue. The pH was adjusted to 7.2 by adding triethylamine. After stirring for 1 hour at 0.5 ° C, the crystals were filtered off and washed with methyl ethyl ketone. Yield 83%, purity 99%,

Example 9 6-Z "(Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penicillan-10,600-acid 6-aminopenicillanic acid (10.0 g) and 1-hexamethyleneimine-carboxaldehyde-dimethyl acetal (10.9 ml) was stirred in methanol (50 ml) at 29-25 [deg.] C. for 5 hours, after filtration the filtrate was evaporated to dryness in vacuo and the residue was suspended in methyl ethyl ketone (45 ml), the solvent was removed in vacuo and methyl ethyl ketone (50 ml) was added to the residue. was adjusted to 7.5 by the addition of p-toluenesulfonic acid monohydrate After stirring for 1 hour at 0-5 ° C, the crystals were filtered off and washed with methyl ethyl ketone in 78% yield, 99.5% purity.

Example 10 6- (7-Hexahydro-1H-azepin-1-yl) -methyleneamino [7-penicillanic acid 6-aminopenicillanic acid (21.6 g), triethylamine (23.6 ml) and K-formylhexamethyleneimine-dimethyl sulfate complex ( 32.9 g) was stirred in methanol (85 ml) at 0-5 ° C for 2 hours. After filtration, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in methyl ethyl ketone (110 ml) containing p-toluenesulphonic acid monohydrate (14.3 g). The solvent was removed in vacuo and methyl ethyl ketone (110 ml) was added to the residue, the pH was adjusted to 7.3 by the addition of triethylamine. After the mixture was stirred at 0-5 ° C for 1 hour, the crystals were filtered off and washed with methyl ethyl ketone. Yield 74%, purity 98%.

Example 11 6 - [(Hexahydro-1H-azepin-1-yl) -methylamino] -penicillanic acid 6-Aminopenicillanic acid (21.6 g) and triethylamine (17.8 ml) were mixed in methylene chloride ( 85 ml) at 0-5 ° C for 2 hours.

After adding 1-hexamethyleneiminecarboxaldehyde dimethyl acetal (22.4 g) to the mixture, stirring was continued at 0-5 ° C for 2 hours. The reaction mixture was then filtered and the filtrate was evaporated to dryness in vacuo. The residue was dissolved in methyl ethyl ketone (110 ml) containing p-toluenesulfonic acid monohydrate (19.0 g). The solvent was removed in vacuo and methyl ethyl ketone (110 ml) was added to the residue, the pH was adjusted to 7.3 by the addition of triethylamine.

13 6001 7

After stirring for 1 hour at 0-5 ° C? the crystals were filtered off and washed with methyl ethyl ketone. Yield 84%, purity 99%. Example 12 6 - [(Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillanic acid 6-Aminopenicillanic acid (21.6 g) and triethylamine (31.4 ml) were stirred in methylene chloride (85 ml) at 0-5 °. C. After adding N * -formylhexamethyleneimine dimethyl sulfate complex (32.9 g) to the mixture, stirring was continued at 0-5 ° C for 2 hours, then the reaction mixture was filtered and the filtrate was evaporated to dryness in vacuo. was dissolved in methyl ethyl ketone (100 ml) containing p-toluenesulfonic acid monohydrate (19.0 g), the solvent was removed in vacuo and methyl ethyl ketone (110 ml) was added to the residue, the pH was adjusted to 7.2 by adding triethylamine.

After stirring for 1 hour at 0-5 ° C, the crystals were filtered off and washed with methyl ethyl ketone. Yield 68%, purity 97.5%.

Example 13 6 / "(Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penililic acid 6-aminopenicillanic acid (2.2 g), pyridine (0.81 ml) and 1-hexamethyleneiminecarboxaldehyde dimethyl acetal ( 5.5 ml) was stirred in methanol (30 ml) at 0-5 ° C for 1.5 hours, the resulting cloudy solution was filtered using a filter aid, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in acetone (50 ml).

The solution was neutralized by adding p-toluenesulfonic acid monohydrate (1.9 g) and seeds at 0-5 ° C with stirring. The formed crystals were filtered off and washed with acetone (10 ml) and ether (20 ml). Yield 65%, purity 97%,

Example 14 6-Zaoxahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid 6-Aminopenicillanic acid (2.2 g) and triethylamine (4.2 ml) were stirred in dry chloroform (25 ml) for 1 hour at room temperature. The resulting solution was cooled to -45 ° C. 1.82 g of acid amide chloride prepared by reacting N-formyl-hexarethyleneimine and oxalyl chloride with dry yt V. dissolved in chloroform (15 ml) was slowly added, raising the temperature to -25 ° C. . The temperature was raised to 0 ° C within 3A hours. The solution was evaporated to dryness in vacuo. The residue was stirred with acetone (25 ml) and filtered. The filtrate was evaporated to dryness in vacuo and the residue was dissolved in methyl ethyl ketone. The amphoteric ion was precipitated by the addition of p-toluenesulfonic acid (1.7 g). Yield 62%, purity 97%.

Example 15 6-Z (O-oxahydro-1H-azepin-1-yl) -methyleneamino-penicillanic acid 27 g of the product prepared according to Examples 1-1a were suspended in acetone (50 ml) and dissolved with the addition of water (32 ml). Upon addition of acetone (200 mL), pure trihydrate precipitated. It was filtered off, washed with acetone and air dried.

Example 16 6-ZT (Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid p-toluenesulfonate

A solution of p-toluenesulfonic acid monohydrate (9.5 g) in isopropanol (50 ml) was added with stirring at room temperature to a suspension of 6- [7-hexahydro-1H-azepin-1-yl) -methyleneamino] -enicillanic acid. trihydrate (19 g) in isopropanol (100 ml). The resulting solution was filtered and the salt was precipitated by the addition of isopropyl ether (100 ml), followed by the addition of seed and more isopropyl ether (50 ml). The crystals were filtered off with suction and washed with isopropyl ether. Yield 78%, purity 100% (C, H, N analysis matched). - + 182 ° (c = 1, 0.1-n HCl).

Example 17 6-Z- (Hexahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid Benzene sulfonate 6-Z * (hexahydro-1H-azepin-1-yl) -methyleneamino -penis illanic acid trihydrate (19 g) in acetone (125 ml) was dissolved by slow addition of benzenesulfonic acid (8 g) dissolved in acetone (125 ml) with stirring at 0-5 ° C, followed by spontaneous precipitation. benzenesulphonate. It was filtered off with suction, washed with acetone (25 ml) and ether (25 ml) and recrystallized from methanol, ether (110-200 ml). Yield 80%, purity 100% (C, H, N analysis matched). Δ <<7 ^ = + 192 ° (c = 1, 0.1-n HCl).

m * # 'Λ 13 6001 7

Example 18 6- [N- (Hexahydro-1H-azepin-1-yl) -methyleneamino] -penicillanic acid maleate monohydrate

To a stirred suspension of 6-Z "(hexahydro-1H-azepin-1-yl) -methyleneamino7'-penicillanic acid trihydrate (19 g) in acetone (125 ml) was added at room temperature maleic acid (6 g) dissolved in acetone (125 ml). The resulting solution was filtered and the salt precipitated by the addition of cyclohexane (100 ml) The solubility of the maleate in water (5%) is inferior to that of p-toluenesulfonate and benzenesulfonate, Yield 87.5%, purity 100% (C, H, N analysis matched) = + 200 ° (c = 1, 0.1-n HCl).

Example 19 (O-Zaxahydro-1H-azepin-1-yl) -methyleneamino-7-penicillanic acid 2-naphthalenesulfonate

Filtered solution of 6-7 (hexahydro-1H-azepin-1-yl) -methyleneamino] -7-penicillanic acid trihydrate (3.8 g) and 2-naphthalenesulfonic acid trihydrate (2.6 g) in acetone (50 ml). , was evaporated to dryness in vacuo. The residue was triturated with ether (75 ml) and crystallized on trituration with ethyl acetate (25 ml).

The salt is slightly soluble in water. Yield 60%, purity 100% (C, H, N analysis matched). = + 169 ° (c = 1, 0.1-n HCl).

Example 20

Sodium 6 - [(hexahydro-1H-azepin-1-yl) -methyleneamine] 7-penicillanate

A mixture of 6 - [((hexahydro-1H-azepin-1-yl) methylene amino] penicillanic acid trihydrate (11.4 g) in isopropyl ether (50 ml) was dissolved by adding a stirred solution of sodium hydroxide. 2-ethylhexanoate (5.1 g) in acetone (45 ml), whereupon the salt precipitated spontaneously. Isopropyl ether (75 ml) was added and the precipitate was filtered off. The salt was recrystallized from 95% n-propanol ether. Yield 81%, purity 98%.

Example 21 6- (N, N-Dimethylformamidino-Nf) * penicillanic acid

A suspension of 6-aminopenicillanic acid (2.48 g) in 40 ml of methylene chloride was stirred for 2 hours at 0-5 ° C with triethylamine (1.62 ml) and 1,1-dimethoxytrimethylamine (1.55 g). with. The resulting slightly cloudy solution was filtered using JH '·' '1 4 6001 7 "Dicalite" and the filtrate was evaporated to dryness in vacuo. The oily residue was dissolved in acetone (50 ml) and p-toluenesulfonic acid monohydrate (2.14 g) was added with stirring at 0-5 ° C. The precipitate was filtered off, washed with acetone and recrystallized from acetone-water-acetone (10-8-30 ml). The analytically pure product thus obtained had a melting point of 173-174 ° C (decomposes). Yield 90%.

= + 318 ° (c - 1, H 2 O),

Example 22 6- (N, N-Dipropylformamidino-N · ') - penicillanic acid

A suspension of 6-aminopenicillanic acid (5.0 g) in 80 ml of methylene chloride was stirred for 3.75 hours at 0-5 ° C with triethylamine (3.24 ml) and N- (dimethoxymethyl) dibutylamine (5.25 g). ). After the filtrate was evaporated to dryness in vacuo, the oily residue was dissolved in acetone (50 ml). Upon addition of p-toluenesulfonic acid monohydrate (3.8 g), a solid formed as a precipitate which was crystallized from 96% ethanol-ethyl acetate (50-125 mL) to give an analytically pure compound with a melting point of 154-156 ° C (dec). Yield 64%.

= + 305 ° (c = 1, H 2 O).

Example 23 6- (N-Ethyl-N-methylformamidino-N ') - penicillanic acid 6-Aminopenicillanic acid (4.96 g), triethylamine (3.24 ml) and N- (dimethoxymethyl) -N-methylbenzylamine (5.84 ml) ) was mixed? hours in methylene chloride (80 mL) at 0-5 ° C. After filtration using a filter aid, the filtrate was evaporated to dryness in vacuo. the oily residue was dissolved in acetone (75 ml) and an amphoteric ion precipitated on addition of p-toluenesulfonic acid monohydrate (3.8 g). 2.8 g of crude product was dissolved in warm 63% ethanol (30 ml). Addition of acetone (60 ml) gave an analytically pure compound with a melting point of 55-167 ° C (dec). Yield 83%.

Example 24 6- (N-Pyrrolidinoformamidino-N1) -penicillanic acid

A mixture of 6-aminopenicillanic acid (4.96 g), triethylamine (3.24 ml) and 1-dimethoxymethylpyrrolidine (3.78 g) in methylene chloride (80 ml) was stirred for 4.75 hours at 0-5 ° C: in. After filtration, the filtrate was evaporated to dryness in vacuo, leaving 1 mM 600 15 in oil, which was dissolved in acetone (100 ml). The title compound precipitated on addition of p-toluenesulfonic acid (3.8 g) at room temperature. an analytically pure compound with a melting point of 172.5-173.5 ° C (decomposes).

Yield 76% = + 306 ° (c = 1, HgO).

Example 25 B-ZOaxahydro-1 (2H) -azoquinylX7-methyleneaminopenicillanic acid 6-Aminopenicillanic acid (7.44 g), triethylamine (4.36 ml) and 1-heptamethyleneiminecarboxyaldehyde dimethyl acetal (9.7 g) were mixed. in methylene chloride (120 mL) for 2.5 hours at 0-5 ° C. After filtration, the filtrate was evaporated to dryness in vacuo and the residue was dissolved in acetone (150 ml). The solution was neutralized by adding p-toluenesulfonic acid monohydrate (5.2 g) in acetone (75 ml) at 0-5 ° C with stirring for 1.5 hours. The precipitate was filtered off, washed with acetone and recrystallized from water / acetone to give an analytically pure compound with a melting point of 1619-170 ° C (dec). Yield 73.5%, λmax = + 309 ° (c = 1, HgO).

Example 26 6- (N-Morpholinoformamidino-N ') penicillanic acid 6-Aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 4-morpholinecarboxaldehyde dimethyl acetal (2.10 g) were stirred for 4 hours in methylene chloride (40 ml). ) At 0-5 ° C. After the filtrate was evaporated to dryness in vacuo, the residue was dissolved in acetone (75 ml). Addition of p-toluenesulfonic acid monohydrate (2.14 g) precipitated a solid which was recrystallized from acetone-water-acetone (5 ~ 3.5-15 ml) to give an analytically pure compound with a melting point of 172.5-174 °. C (decomposes). Yield 69.5%. Z> 7q ° = + 275 ° (c = 1, H 2 O).

Example 27 6- (N, N-Dimethylbenzamidino-N1) -penislilanoic acid

Following the procedure described in Example 7 and substituting N, N-dimethylbenzamide dimethylacetate for 1-hexamethyleneiminecarboxyaldehyde dimethyl acetal, 6- (N, N-dimethylbenzamidino-N1) -penicillanic acid is formed as a white amorphous ε. f «JO». £> vt 6001 7 16 as a powder soluble in water. Yield 87%, The product was chromatographed (Merck silica gel) using the following solvent systems: n-butanol-ethanol-water (8: 2: 2), = 0.10 and n-propanol-water (7: 3), Rf ·: 0.24, NMR spectrum (10% w / v D2O): (1H c 1.54) C (!) <CB3> for 2 uS I (3W c 3.10) N ( CH3) 2 III I "3.45) C (3) H 1H s" ^ 30 CH 1H d "5> ° 1 (J = (b) C h 1H d" 5'24 (J = {o) ^ ^ 5H m "7.4-7.9

Claims (3)

17 6001 7 A process for the preparation of 6-aminopenicillanic acid derivatives of the general formula I d Ro H H K1 | 3! X-C = N ^ j f / S \ ^ CH- R / -O C <T (I) R2 ^ CH3} 0. CNC? XoOH wherein, R 1 and R 2 represent the same or different substituents and each represents a C 1 -C 4 alkyl group, a monocyclic carbocyclic aryl group or an aralkyl group, wherein R 8 may further represent hydrogen and R 1 and R 2 together with its nitrogen atom, to which they are attached may represent a heterocyclic ring system of 5 to 10 atoms, optionally comprising, in addition to said nitrogen atom, a further nitrogen or oxygen atom, and pharmaceutically acceptable, non-toxic salts thereof, characterized in that the formula II = R5 (II) R2 wherein R1, R11 and Rail have the meanings defined above, and R [. represents an O or S atom, a reactive derivative of the corresponding compound which is a) a compound of formula III R 1 R 3 X r 1 pN-C = (O-Alk) 2 (III) R 2 wherein Railia has the meanings given above, and Alk denotes a lower alkyl group, b) a di-small alkyl alkyl sulphate complex of compound II, or c) an acid amide halide obtained by reacting compound II; with a strong tertiary amine salt, the reaction being carried out in a suitable solvent and at a temperature between about room temperature and about -50 ° C. Process according to Claim 1, characterized in that the reactive derivative of the compound II is a compound of the formula III in which Alk denotes methyl. Process according to one of Claims 1 and 2, characterized in that the reactive derivative of the compound II is reacted with the triethylaryl salt of 6-aminopenicillanic acid, 19 6001 7