NO147565B - PROCEDURE FOR PREPARING DERIVATIVES OF 6-AMINOPENICILLANIC ACID - Google Patents

Abstract

Process for the preparation of derivatives of 6-aminopenicillanic acid.

Description

The present invention relates to an improved process for the production of derivatives of o-aminopenicillanic acid.

The compounds produced according to the method according to the present invention have the general formula where R^, R_ and R., are the same or different substituents and each means a C2_~C4 alkyl radical or a phenyl or benzyl group, R^ may also mean hydrogen' and R-^ and R£ together with the nitrogen atom can mean a 5-8 membered heterocyclic ring, in which one of the members can be an oxygen atom.

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

Salts can also be prepared with other antibiotics of an acidic or basic nature, and then especially with acidic antibiotics, with which the present compounds form synergistic mixtures, such as e.g. penicillins.

It is appropriate to use acids which form salts with the prepared compounds, and which have

sheath properties with regard to absorption and use in clinical practice. Examples of such salts are pamoate or nafsylate, or salts containing probenecid, whereby the latter compound delays the excretion of the active compounds, resulting in prolonged action.

The prepared compounds are suitably used for parenteral treatment.

Thus, the compounds are advantageously administered by injection of an aqueous, sterile solution or suspension of the zwitterion itself or of a suitable salt thereof alone or in combination with a buffer.

The compounds of formula I have hitherto been prepared as described in British Patent Nos. 1,293,590 and 1,315,566, namely by adding a reactive derivative of an amide or a thio-amide of the general formula II

where y R2 and have the meaning stated above, and

where R^ means 0 or S,

e.g. a compound of the general formula (III)

where R^, R2 and R^ have the meaning indicated above, and

where Alk means a lower alkyl radical,

react with a 6-aminopenicillanic acid derivative of the general formula IV

where R 1 means an unsubstituted ore

substituted alkyl or aralkyl group 5 or with a silyl ester of 6-aminopenicillanic acid.

When -COOR^ denotes an ester group, the reaction must be followed by a cleavage of said ester group to thereby give the compounds of formula I.

It has now been found that the compounds of formula I with advantage

can be prepared by allowing a reactive derivative of a compound of formula II

react with a salt of 6-aminopenicillanic acid ("6-APA"),

and the method is characterized by what is stated in the characterizing part of the claim.

It is surprising that the present process results in excellent yields (about 70 to 90%) and high purity products, as it is well known that reactive derivatives of amides often react with acids. thus, acid amide halides can react with acids to form acid halides, while acid amide acetals can form esters during such a reaction.

Furthermore, the present method is simpler than previously known methods. It can be carried out in one step, while previous methods include the production of e.g. a silyl ester or a benzyl ester of 6-APA, followed by conversion into the amidinopenicillanic acid ester and finally cleavage of the ester group.

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

The reaction conditions depend on the reactants used, and

is therefore described in more detail below.

When an acid amide acetal is used as reactant in the present method, the preferred reaction medium is methylene chloride, chloroform, acetone with a smaller amount of formamide, methanol and methyl formate. In the first three reaction media, the presence of a strong tertiary amine is necessary to obtain the desired yields of the compounds of formula I with high purity, while ff-ex. in methanol the reaction can be carried out without the addition of a separate tertiary amine due to the fact that the weakly alkaline acid amide acetal is able to form a salt with "6-APA" in this medium.

As examples of strong tertiary amines, which can be used according to the above, mention can be made of triethylamine and N,N-diisopropylethylamine, while e.g. pyridine, N-methylmorpholine or triethanolamine are too weak for this purpose.

The above reaction can be carried out using equivalent quantities of the reactants, but it is however preferred to use a smaller excess of the acid amide acetal and of the tertiary amine (in most cases approx. 20 - 30%). As starting material, it is of course possible to use a salt of "6-APA" and the tertiary amine, either by using a salt previously prepared, or by allowing "6-APA" to partially react with the tertiary amine before adding the acid amide acetal. The reaction is carried out at approx. room temperature or below, preferably at a temperature between 0

and 5°C, but the reaction can be carried out at even lower temperatures, e.g. at approx. -25°C. The reaction time depends on the temperature and the reaction medium used and whether a tertiary amine is used or not. It will last from 1 -

6 hours.

When in the present method a di-lower alkyl sulphate complex is used as reactant, the preferred reaction medium is methylene chloride or methanol. Here it is necessary to use at least one equivalent of a strong tertiary amine to protect the (3-lactam ring in the final compound of formula I and in "6-APA" against the di-lower alkyl sulfate complex, which would otherwise lead to an opening of said ( 3-lactam ring. It is preferred to use about 1.5 - 3 equivalents of the tertiary amine, and an excess of the di-lower alkyl sulfate complex (about 20 - 30%). By using methylene chloride as the reaction medium, it is convenient allowing most of the "6-APA" to dissolve as a tertiary amine salt for addition of the di-lower alkyl sulfate complex. The preferred reaction temperature is 0 - 5°C, but both higher (about room temperature) and lower temperatures (about -10° C) can be used.The reaction time depends on the temperature, the reaction medium and the reactants used, and will amount to 1-6 hours.

When in the present method an acid amide halide is used as reactant, only methylene chloride, chloroform and a similar inert reaction medium can be used because the acid amide halides are very reactive. In this case it is convenient to use 2-3 equivalents of a tertiary amine to protect the (3-lactam ring in the final product and in "6-APA". It is convenient to allow most of the "6-APA" to dissolve as a tertiary amine salt for addition of the acid amide halide. The reaction should be carried out at low temperatures and with an initial temperature of approximately -50° C. The reaction temperature is allowed to increase to approximately 0° C, and the reaction is completed in the course of approximately 3/4 hour.

The resulting reaction mixture, containing the stable tertiary amine salt of one or more compounds of formula I, or in certain cases the zwitterion itself, is filtered to remove any residual unreacted "6-APA" and the clear solution is then evaporated in vacuo . The remaining residue is dissolved in a suitable solvent, in which the acid of formula I is precipitated by adding another solvent, in which the acid is only slightly soluble, or preferably by releasing the zwitterion by adding an inorganic or organic acid. It is preferred, and especially when producing large quantities, to remove any remaining residues of the reaction medium by adding a high-boiling solvent, e.g. methyl ethyl ketone and, if desired, together with the acid used to release the zwitterion, and then evaporation of the solvent mixture in vacuo. The combination of tertiary amine, solvent and acid can suitably be chosen so that the zwitterion is precipitated and the

the amine salt formed during the neutralization is kept dissolved in the solvent.

To release the zwitterion, p-toluenesulfonic acid dissolved in acetone or methyl ethyl ketone can be used, but other acids and solvents can also be used, depending on the reactants used.

The starting materials used in the above-mentioned embodiments are well-known compounds, or they can be produced using conventional methods for producing analogous compounds.

The present method results in a crude product with high purity (97 - 98% determined by iodometric titration).

For reasons of stability, it is important that the final product contains as few contaminants as possible, as even small amounts of contamination residues reduce stability.

The raw product can thus be further purified by recrystallization from a suitable solvent or a mixture of solvents. In certain cases, it may be appropriate to transfer the crude product to its hydrate form, which is thus re-crystallized from a suitable solvent or a mixture of solvents, e.g. formamide - acetone, to form the desired anhydrous compound of formula I.

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

The compounds produced occur in several isomeric forms

depending on the different substituents,

while the 6-aminopenicillanic acid residue has the same configuration as that obtained by the fermentation process.

The compounds of formula I possess valuable antibacterial activity and toxicity is extremely low as described in British Patent Nos. 1,293,590 and 1,315,566.

The invention shall be further illustrated by means of the following examples.

EXAMPLE 1

6- f (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml), and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (2.98 g) were stirred in methylene chloride (40 ml) at 0 - 5°C for 2.5 hours. After filtration, the filtrate was evaporated in vacuo and the residue was taken up in acetone (50 ml). The solution was neutralized by adding p-toluenesulfonic acid monohydrate (1.9 g) in acetone (25 ml) with stirring and adding crystal seed for crystallization at room temperature. The mixture was kept at 0-5° for 1.5 hours and then filtered. Yield (U): 82%, Purity (R): 97%.

EXAMPLE 2

6-f(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid A suspension of 6-aminopenicillanic acid (2.48 g) in 40 ml of chloroform was stirred for 4.5 hours at 0 - 5°C with triethylamine (1.62 ml) and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (2.25 g). The resulting slightly cloudy solution was filtered with "Dicalite". The filtrate was evaporated in vacuo to give an oil which was taken up in acetone (50 mL). The pure compound was precipitated by adding a solution of p-toluenesulfonic acid monohydrate (1.9g) in acetone (25ml) with stirring at room temperature for 1/2 hour, followed by one hour at 0-5°C. The crystalline compound was filtered off, washed with acetone and dried in a desiccator.

U: 82%, R: 98.5%

EXAMPLE 3

6-|" (hexahydro-1H-azepin-1-yl)-methyleneaminoj-penicillanic acid 6-aminopenicillanic acid (2.48 g) was suspended in a mixture of formamide (0.5 ml) and acetone (25 ml, Merck p.a.) .1.62

ml of triethylamine and 2.37 ml of 1-hexamethyleneiminecarboxaldehyde-dimethylacetal were added. The mixture was stirred for 5 hours at 0°C and then filtered with "Dicalite". At 0 - 5°C a solution of p-toluenesulfonic acid monohydrate (1.9 g) in 25 ml of acetone was added with stirring and addition of crystal seed for crystallization. The precipitate that formed was filtered off and washed with acetone. U: 67%, R: 98%

EXAMPLE 4

6-f(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), 1.95 ml of N,N-diisopropylethylamine and 2.37 ml of 1-hexamethyleneiminecarboxaldehyde- dimethyl acetal was stirred for 3.5 hours at 0-5°C in 40 ml of methylene chloride. After filtration with "Dicalite" and evaporation of the filtrate, the oily residue was dissolved in tert-butanol (50 ml). With stirring, 8-n, 1.44 ml of hydrogen chloride in isopropanol was added at room temperature, followed by an additional amount of 20 ml of tert-butanol. The precipitate was filtered off, washed with tert-butanol and ether and dried. U:69%,R:97%

EXAMPLE 5

6-[" (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.48 g), triethylamine (1.62 ml) and 1-hexamethyleneiminecarboxaldehyde-dimethyl acetal (2.37 ml)

was stirred for 3 hours at 0-5°C in methylene chloride (40 ml). After filtration with "Dicalite", the filtrate was evaporated in vacuo. To the residue in acetone (50 ml) was added glacial acetic acid (0.66 ml) with stirring. The precipitate that formed was sucked off and dried. U: 57%, R: 98%

EXAMPLE.' 6

6-1 (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid By following the procedure in example 5, but by replacing acetic acid with benzoic acid (1.4 g), a good yield of the desired compound was obtained. U: 70%, R: 97%

EXAMPLE 7

6- I (hexahydro-1H-azepin-1-yl)-methyleneamino|-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 with "Dicalite", the filtrate was evaporated in vacuo. To the residue in acetone (15 mL) was added ether (60 mL) with stirring at room temperature. The mixture was kept at 0-5°C for 1.5 hours and then filtered to give the crystalline compound. U: 70%, R: 97.5%

EXAMPLE 8

6-|~ (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (10.0 g), triethylamine (7.0 ml) and 1-hexamethyleneiminecarboxaldehyde-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 in vacuo and the residue was taken up in methyl ethyl ketone (45 ml) containing p-toluenesulfonic acid monohydrate (8.0 g). The solvent was removed in vacuo and methyl ethyl ketone (50 mL) was added to the residue. The apparent pH was adjusted to 7.2 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 83%, R: 97%

EXAMPLE 9

6-[~ (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (10.0 g) and 1-hexamethyleneimine carboxaldehyde dimethyl acetal (10.9 ml) were stirred in methanol (50

ml) at 20 - 25°C for 5 hours. After filtration, the filtrate was evaporated 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. The apparent pH was adjusted to 7.5 by addition of p-toluenesulfonic acid monohydrate. After stirring for one hour at 0 - 5°C, . the crystals filtered off and washed with methyl ethyl ketone.

U: 78%, R: 99.5%

EXAMPLE 10

6- 1" (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (21.6 g), triethylamine (23.6 ml) and N-formylhexamethyleneimine-dimethylsulphate complex (32.9 g) were stirred in methanol (85 ml) at 0-5°C for 2 hours. After filtration, the filtrate was evaporated in vacuo and the residue taken up in methyl ethyl ketone (110 ml), containing p-toluenesulfonic acid monohydrate (14.3 g). The solvent was removed in vacuo and methyl ethyl ketone (10 mL) was added to the residue. The apparent pH was adjusted to 7.3 by addition of triethylamine. After stirring for one hour at 0-5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 74%, R: 98%

EXAMPLE 11

6-f (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (21.6 g) and triethylamine (17.8 ml) were stirred in methylene chloride (85 ml) at 0 - 5° in 2 hours. After addition of 1-hexamethyleneimine carboxaldehyde dimethyl acetal (22.4 g), stirring was continued at 0-5°C for 2 hours. The reaction mixture was then filtered and the filtrate evaporated in vacuo. The residue was taken up 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 apparent pH was adjusted to 7.3 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 84%, R: 99%

EXAMPLE 12

6-f(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 for 2 hours. After addition of N-formylhexamethyleneimine-dimethylsulphate complex (32.9 g), stirring was continued at 0-5°C for 2 hours. The reaction mixture was then filtered off and the filtrate was evaporated in vacuo. The residue was taken up 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 apparent pH was adjusted to 7.2 by addition of triethylamine. After stirring for one hour at 0 - 5°C, the crystals were filtered off and washed with methyl ethyl ketone. U: 68%, R: 97.5%

EXAMPLE 13

6-| (hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.2 g), pyridine (0.81 ml), and 1-hexamethyleneimine carboxaldehyde dimethylacetal (5.5 ml) were stirred in methanol (30 ml) at 0 - 5°C for 1.5 hours. The resulting slightly cloudy solution was filtered with filter aid. The filtrate was evaporated in vacuo. The residue was dissolved in acetone (50 mL). The solution was neutralized by adding p-toluenesulfonic acid monohydrate (1.9 g) with stirring and

addition of crystal seeds for crystallization at 0 - 5°. The crystals that formed were filtered off and washed with

acetone (10 mL) and ether (20 mL). U: 65%, R: 97%

EXAMPLE 14

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid 6-aminopenicillanic acid (2.2 g) and triethylamine (4.2 ml) were stirred in dry chloroform (25 ml) for one hour at room temperature . The resulting solution was cooled to -45°C. 1.82 g of the acid amide chloride, which was prepared by reaction between N-formylhexamethyleneimine and oxalyl chloride, in dry chloroform

(15 ml) was slowly added, whereby the temperature rose to -25°c. In the course of 3/4 hours the temperature was allowed to rise to 0°c. The solution was evaporated in vacuo. The residue was stirred with acetone (25 mL) and filtered. The filtrate was evaporated in vacuo and the residue was taken up in methyl ethyl ketone. In case of addi-

ning of p-toluenesulfonic acid (1.7 g) the zwitterion was precipitated.

U: 62%, R: 97%

EXAMPLE 15

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate

27 g of a product prepared according to examples 1-14

was suspended in acetone (50 mL) and dissolved by the addition of water (32 mL). On addition of acetone (200 ml) the pure trihydrate was precipitated. It was filtered off, washed with acetone and air-dried.

EXAMPLE 16

6- f (hexahydro- 1H- azepin- 1- yl)- methyleneamino]- 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-[(hexahydro-1H-azepin-1-yl)methyleneamino|-penicillanic 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 crystal seed for crystallization, and a further addition of isopropyl ether (50 mL). The crystals were sucked off and washed with isopropyl ether. U: 78%,R:100% [a]^°:+182° (C=l, 1. ON HC1)

EXAMPLE 17

6-[(hec. sahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid benzenesulfonate

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (19 g) in acetone (125 mL) was dissolved by slow addition of benzenesulfonic acid (8 g) in acetone (125 mL) with stirring at 0 - 5°C, whereupon the benzene sulphonate precipitated spontaneously. It was suctioned off, washed with acetone (25 ml) and ether (25 ml) and recrystallized from methanol-ether (110 - 200 ml).

U: 80%, R: 100% [a]^°:+192°(C=1, 0.IN HCl)

EXAMPLE 18

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]- penicillanic acid maleate monohydrate

To a stirred suspension of 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (19 g) in acetone (125 ml) was added a solution of maleic acid (6 g) in acetone (125 ml )

added at room temperature. The solution formed was filtered and the salt was precipitated by addition of cyclo-

hexane (100 mL). The solubility of the maleate in water (5%) is lower than that of p-toluenesulfonate and benzenesulfonate.

87%, R: 100% [a]^°+200° (C=1, 0. IN HCl)

EXAMPLE 19

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid-2-naphthalenesulfonate

A filtered solution of 6-[(hexahydro-1H-azepin-1-yl)-methyleneamino]-penicillanic acid trihydrate (3.8 g) and 2-naphthalene-sulfonic acid trihydrate (2.6 g) in acetone (50 ml ) was evaporated in vacuo. The residue was triturated with ether (75 ml) and crystallized by trituration with ethyl acetate (25 ml). The salt is slightly soluble in water. U:60%,R:100% [a]^°:169 (C=1, 0.IN HCl)

EXAMPLE 20

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

6-[(hexahydro-1H-azepin-1-yl)-methyleneamino|-penicillanic acid trihydrate (11.4 g) in isopropyl ether (50 ml) was dissolved by adding a solution of sodium 2-ethyl hexanoate (5.1 d)

in acetone (45 ml) with stirring at room temperature, whereupon the salt precipitated spontaneously. Isopropyl ether (75 mL) was added and bottom

the case was filtered out. The salt was recrystallized from 95% n-propanol ether. U: 81%, R: 98%

EXAMPLE 21

6-(N,N-dimethylformamidino-N')-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). The resulting slightly cloudy solution was filtered with "Dicalite" and the filtrate was evaporated 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.

(fission). [α]^°: + 318° (c = 1, H 2 O). U: 90%

EXAMPLE 2 2

6-(N,,N-dipropylformamidino-N1)-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)-dipyrpyralnine (5.25 g). After evaporation in vacuo of the filtrate, the oily residue was dissolved in acetone (50 ml). Addition of p-toluenesulfonic acid monohydrate (3.8 g) precipitated a solid which was crystallized from 96% ethanol-ethyl acetate (50 - 125 ml).

to give the analytically pure compound with a melting point of 154 - 156°C (decomposition). [oc]£°: + 305° (c=1, H 2 O) . U: 64%

EXAMPLE 2 3

6-(N-benzyl-N-methylformamidino-N')-penicillanic acid 6-aminopenicillanic acid (4.96 g), triethylamine (3.24 ml), and N-(dimethoxymethyl)-N-methylbenzylamine (5.84 g) was reshuffled in

2 hours in methylene chloride (80 ml) at 0 - 5°C. After filtration with a filter aid, the filtrate was evaporated in vacuo. The oily residue was taken up in acetone (75 mL) and the zwitterion was precipitated by addition of p-toluenesulfonic acid monohydrate

(3.8g) .

2.8 g of the crude product was dissolved in hot 60% ethanol (30 ml). Addition of acetone (60 ml) gave the analytically pure compound with a melting point of 165 - 167°C (decomposition).

[αj^°: +280° (c = 1, 0.1-n HCl). U: 83%

EXAMPLE 24

6-(N-pyrrolidinoformamidino-N')-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 - 5°C. After filtration, the filtrate was evaporated in vacuo to give

an oil which was dissolved in acetone (100 ml). On addition of p-toluenesulfonic acid (3.8 g) at room temperature, the title compound was precipitated. After half an hour at 0 - 5°c, the precipitate was filtered off and recrystallized from water-acetone

and 90% isopropanol-acetone to give the analytically pure compound with a melting point of 172.5 - 173.5°C (decomposition).

[cc]£°: + 306° (c = 1, H 2 O). U: 76%

EXAMPLE 25

6-[(hexahydro-1(2H)- azocinyl)]-methyleneaminopenicillanic acid 6-aminopenicillanic acid (7.44 g), triethylamine (4.86 ml) and 1-heptamethyleneimine carboxaldehyde dimethyl acetal (9.7 g) were stirred in methylene chloride (120 ml) for 2.5 hours at 0 - 5°C.

After filtration, the filtrate was evaporated in vacuo and the residue was taken up in acetone (150 ml). The solution was neutralized by the addition of p-toluenesulfonic acid monohydrate (5.2 g)

in acetone (75 ml) with stirring at 0 - 5°C for 1.5 hours. The precipitate was filtered off, washed with acetone and recrystallized from water-acetone to give the analytically pure compound with a melting point of 169-170°C (decomposition).

[α]p°: + 309° (c=1, H 2 O). U:73%

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 evaporation in vacuo of the filtrate, the residue was taken up in acetone (75 ml).

Addition of p-toluenesulfonic acid monohydrate (2.14 g) caused precipitation of a solid which was crystallized from acetone-water-acetone (5-3.5-15 ml) to give the analytically pure compound with a melting point of 172.5 - 174°C. (fission).

[<x]£°: +275° (c = 1, H 2 O). U: 69.5%

EXAMPLE 27

6-(N,N-dimethylbenzamidino-N')-penicillanic acid

By following the procedure described in example 7

and by replacing 1-hexamethyleneimine carboxaldehyde dimethylacetal with N,N-dimethylbenzamide dimethylacetal, 6-(N,N-dimethylbenzamidino-N')-penicillanic acid is prepared as a white amorphous powder, soluble in water. Thin-layer chromatography (Merck silica gel HF2^) was carried out in the following solvent systems: n-butanol-ethanol-water (8:2:2), Rf = 0.10 and n-propanol-water (7:3), R = 0.24. U: 87%

NMR spectrum (10% w/v D2°)

Claims (1)

Process for the production of derivatives of 6-amino-penicillanic acid with the general formula where R^, R2 and R^ are the same or different substituents and each means a C-^-C^ alkyl radical or a phenyl or benzyl group, wherein R^ can also mean hydrogen and R^ and R^ together with the nitrogen atom can mean a 5-8 membered heterocyclic ring, in which one of the members can be an oxygen atom, and pharmaceutically acceptable, non-toxic salts or hydrates thereof, characterized in that a reactive derivative of a compound of formula II where R^, R2 and R^ have the meanings given above and where R5 means 0 or S, is reacted with a salt of 6-amino-penicillanic acid in an inert reaction medium,"which reactive derivatives are constituted by: a) an amidacetal with the formula III in which R^, R2 and R^ have the previously given meanings and Alk stands for a lower alkyl group, using a salt of 6-aminepenicillanic acid with a strong tertiary amine or the salt with the amidacetal, in which case methanol is used as the reaction medium, the reactants are used in equivalent amounts or the amide acetal and the tertiary amine in a small excess, and the reaction is carried out at a temperature in the range -25°C - 30°C, preferably in the range 0 and 5°C for a period of 1 to 6 h, or b) a di-lower alkyl sulfate complex of the compound of formula II, using a salt of 6-aminopenicillanic acid with a strong tertiary amine, and the tertiary amine is used in an amount of at least one equivalent, preferably in an amount of 1.5 - 3 equivalents together with an excess of the reactive derivative and where the reaction is carried out at -10°C - 30°C, preferably in the range 0 - 5°C for a period of 1 - 6 h, or c) an amide halide obtained by reacting a compound of formula II with a halogen erating agent, using a salt of 6-aminopenicillanic acid with a strong tertiary amine and the tertiary amine is used in an amount of 2 - 3 equivalents and the reaction is carried out at an initial low temperature, preferably approx. -50°C, rising to approx. 0°C for a period of 45 min. - 60 min., after which the resulting compound of formula I is recovered either as a free acid, a zwitterion or as a salt, possibly in the form of a hydrate.