DE935667C - Process for the preparation of phenanthridinium salts - Google Patents

Description

Process for the preparation of phenanthridinium salts The invention relates to a process for the preparation of phenanthridinium salts.

Various derivatives of phenanthridine were investigated some time ago some of them have been found to be antibacterial and trypanocide Possess properties.

It was also found that minor changes in structure this class of compounds has a very considerable influence on the biological Have activity, and it is therefore important to figure out through syntheses the more readily available phenanthridine compounds in compounds with other substituents can be converted.

It has now been found that phenanthridinium salts with at least a primary amino group in the 2- or 3-position and an acylated amino group in the phenanthridine nucleus or in a g-aryl substituent if 2- or 3-aminophenanthridinium salts, which has another amino group in the phenanthridine nucleus or in a g-aryl substituent possess, with about one mole of an acylating agent in aqueous, aqueous-alcoholic or alcoholic solution to react.

So z. B. gives the 2, 7-diamino-g-phenyl-io-methylphenanthridinium chloride, the trypanocid known under the name "dimidium chloride" [formula (I) A = Cl; R = CHJ, on treatment with 1 mol of acetic anhydride in the manner indicated above, a good yield of a monoacetylamino compound which is identical to the already known 7-acetylamino-2-amino-g-phenyl-io-methylphenanthridinium chloride [formula (II)) : A. = .C1; R = R '= C H3]. This substance has been synthesized in a multistage process [Walls, Journal of the Chemical Society (London), 1950, pp. 35z4]. The method is not limited to chlorides; also other salts, e.g. B. bromides; Sulphates or ethanesulphonates are suitable. Your choice depends, among other things, on the solubility in the solvents preferred for the reaction, namely water, methanol, ethanol or mixtures of these solvents.

The method is also applicable to salts other than those at where R in the above formula represents the CH. group, e.g. B. R = C, H5.

Anhydrides other than acetic anhydride react in a similar way. The reaction is quite general with aliphatic, aromatic and arylaliphatic Anhydrides feasible. So z. B. a mixed form-acetic anhydride a monoformyl derivative (in the above formula R '= H), propionic anhydride a monopropionyl derivative (R '= ethyl), n-butyric anhydride a monobutyryl derivative (R' = n-propionyl) - and Benzoic anhydride is a monobenzoyl derivative (R '= phenyl).

Since an excess of anhydride is avoided, the amount of is formed Very little diacyl derivative. The acid anhydrides can by the. corresponding acid chlorides be replaced; however, this offers no advantages, because then larger amounts of diacyl derivatives are formed and the separation of the reaction products becomes more difficult.

The invention is not limited to the phenanthridinium salts of the above Formula limited, but applies in general to 2- or 3-ariinophenanthridinium salts, which has another amino group in the phenanthridine nucleus or in a g-aryl substituent contain. So z. B. the 2, 7-diamino-g-a-thienylio-methylphenanthridinium chloride converted into the 7-acetylamino-2-amino-g-a-thienyl-io-methylphenanthridinium chloride. The 2,7-diamino-g-pnitrophenyl-io-methylphenanthridinium chloride goes into the 7-acetylamino-2-amino-g-p-nitrophenyl-iomethylphenanthridinium chloride and the 7-acetylamino-2-amino-g-p-aminophenyl-lo-methylphenanthridinium chloride in the 7-acetylamino-2-amino-9-p-acetylaminophenyl-io-methylphenanthridinium chloride via.

From 2-amino-g-p-aminophenyl-io-methylphenan-. thridinium chloride [Caldwell R: Walls, Journal of the 'Chemical Society (London), 1948, p. 193] arises 2 = amino - g -p -acetylaminophenyl- i o -methylphenanthridinium chloride.

The new process also gives connections that were previously were not manufactured and have now been found to be a therapeutic activity against infections in cattle caused by Babesia species (Hemosporidia), unfold. These new compounds are io-alkylphenanthridinium salts, preferably the io-methylphenanthridinium salts of the following phenanthridines 7-propionylamino-2-amino-g-phenylphenanthridine, 7 n-Butyrylamino-2-amino-g-phenylphenanthridine, 7-acetylamino-2-amino-g-p-aminophenylphenanthridine and 7-acetylamino-3-amino-g-phenylphenanthridine. The invention is illustrated by the examples described in more detail.

Example za) Acetic anhydride (0.6 cc) was added to a refluxed solution of 2,7-diamino-g-phenyl-io-methylphenanthridinium chloride (2 g) in water (20 cc) and methanol (20 cc). After boiling for 30 minutes, the solution, the color of which had turned from purple to red, was cooled. The 7-acetylamino-2-amino-g-phenyl-io-methylphenanthridinium chloride crystallized with a total yield of 8oo mg in dark red prisms, which were recrystallized from methanol and had a melting point of about 268 ° with decomposition.

b) The same product was obtained if only methanol was used as the solvent was used.

c) 2,7-Diamino-g-phenyl-io-methylphenanthridinium chloride (5 g) was dissolved in water (50 ccm) and shaken at 100 ° with acetic anhydride (1.5 ccm). The 7-acetylamino-2-amino-g-phenylio-methylphenanthridinium chloride began to crystallize out immediately and was isolated after 30 minutes (49).

d) The corresponding ethanesulfonate can also be obtained. To a suspension of 2,7-diamino-g-phenyl-io-methylphenantbridinium bromide (5 g) one equivalent of silver ethane sulfonate was added in boiling ethanol. That Silver bromide was removed by filtration and then the boiling filtrate with acetic anhydride (1.5 ccm) treated. After 30 minutes the solution was concentrated to a small amount. The ethanesulfonate (3, z g) slowly crystallized out. From a small volume Water it was recrystallized into tiny brick-red needles, which by filtering were isolated: the thixotropic mass was stirred into acetone and filtered again and washed with acetone.

e) The 7-acetylamino-2-amino-g-phenyl-io-methylphenanthridinium bromide was made from a solution of 2,7-diamino-g-phenyl-io-methylphenanthridinium bromide made in methanol.

Example 2 2,7-Diamino-g-phenyl-io-methylphenanthridinium chloride (4 g) was dissolved in hot water (40 cc) and the solution mixed with form-acetic anhydride (i, 2 ccm) shaken. A precipitate of 7-formylamino-2-amino-g-phenylio-methylphenanthridinium chloride immediately fell in dull red microscopic crystals. After lingering for 3 minutes on the Steam bath, the mixture was cooled and the 7-formylamino-2-amino-g-phenylio-methylphenanthridinium chloride isolated (1i g). It was recrystallized from methanol in dull red prisms.

7-Pro pio n y1 amine o-2-amino-g-phenyl-io-methylphenanthridinium chloride and the corresponding ethanesulfonate (dull red prisms that decompose at around 258 °) were prepared in the same way using propionic anhydride.

The 7 n-butyrylamino-2-amino-g-phenyl-io- ° methylphenanthridinium chloride and the corresponding ethanesulfonate (dull red prisms which decomposed at about 250 ' ) were obtained in a similar manner.

The 7-benzoylamino-2-amino-g-phenyl-io-methylphenanthridinium chloride was best prepared from 2,7-diamino-g-phenyl-io-methylphenanthridinium chloride and benzoic anhydride in a refluxed solution in methanol. Example 3 A solution of 2,7-diamino-g-phenyl-io-ethylphenanthridinium bromide (1.5 g) in hot water (15 cc) was shaken with acetic anhydride (0.4 cc). Precipitation of crystals of 7-acetylamino-2-amino-g-phenylio-ethylphenanthridinium bromide began immediately. After treatment at 100 ° for 30 minutes, the reaction mixture was cooled and the reaction product (1.2 g) was isolated. Example 4 2,7-diamino-g, io-dimethylphenanthridinium chloride (2 g) was dissolved in hot water (25 cc) and the solution was shaken with acetic anhydride (0.8 cc). The reaction mixture was then heated at 100 ° for 30 minutes. On cooling, the 7-acetylamino-2-amino-g, io-dimethylphenanthridinium chloride (1.6 g) crystallized out in pale red needles; F. 277 to 278 ° with decomposition.

Example 5 3,7-Diamino-g-phenyl-io-methylphenanthridinium chloride (8 g) was dissolved in methanol (60 cc). The solution was refluxed with acetic anhydride (2.4 cc) for 30 minutes. After standing at 5 ° overnight, crystals separated out and were isolated and recrystallized from water. The 7-acetylamino-3-amino-g-phenyl-io-methylphenanthridinium chloride (2 g) crystallized out in yellow prisms which melted with decomposition at about 28 °. Example 6 2,7-Diamino-ga-thienyl-io-methylphenanthridinium chloride (2 g) was dissolved in methanol (20 cc) and refluxed with acetic anhydride (0.7 cc). The solution lost its characteristic blue color and turned deep red. After 15 minutes the solution was cooled so that the 7-acetylamino-2-amino-ga-thienyl-io-methylphenanthridinium chloride crystallized out in needles (1.49) with a coppery sheen. When recrystallized from methanol, these needles formed dark red prisms which decomposed at about 263 °.

Example 7 As the procedure of the previous example applied to the 2, 7-diamino-g-p-nitrophenyl-io-methylphenanthridinium chloride was used, the 7-acetyl compound crystallized from the reaction mixture in high yield the end.

Example 8 A solution of 7-acetylamino-2-amino-g-p-aminophenyl-io-methylphenanthridinium chloride (i g) in boiling methanol (40 cc) was treated with acetic anhydride (0.3 cc). After refluxing for 3 minutes, concentrate to a small amount and cooling, red needles separated out (0.9 g). When recrystallizing from methanol formed this salt which is believed to be 7-acetylamino-2-amino-g-p-acetylaminophenyl-io-methylphenanthridinium chloride acts, thin, elongated, slightly scarlet leaflets that are in a temperature range melted from 24o to 28o °. Example g A solution of 2-amino-g-p-aminophenyl-iomethylphenanthridinium chloride (50o mg) in water (10 ccm) at 100 ° was shaken with acetic anhydride (0.15 ccm). After 30 minutes' treatment at 100 °, a little ammonium chloride was added and the solution cooled. The 2-amino-g-p-acetylaminophenylio-methylphenanthridinium chloride crystallized on cooling in orange prisms (5oo mg), which melted at 222 to 224 ° with decomposition.

Claims (2)

PATENT CLAIMS: i. Process for the preparation of phenanthridinium salts with at least one primary amino group in the 2- or 3-position and an acylated amino group in the phenanthridine nucleus or in a g-aryl substituent, characterized in that there are 2- or 3-aminophenanthridinium salts which have another amino group in the phenanthridine nucleus or in a g-aryl substituent, reacted with about 1 mole of an acylating agent in aqueous, aqueous-alcoholic or alcoholic solution. 2. The method according to claim i, characterized in that the acylating agent the anhydride of an aliphatic acid having from 1 to 4 carbon atoms is used.