NO170697B - PROCEDURE FOR RESTORING UNDERGROUND PIPES - Google Patents

Description

Process for the preparation of phenazine derivatives.

The invention relates to a hitherto unknown method for the production of phenazine derivatives. 1,6-phenazinediol-5,10-dioxide (iodinine) is a known compound with a broad spectrum of antibacterial properties. Iodinine was first isolated from Chromobacterium iodinum. The compound was subsequently synthesized by oxidation of 1,6-dihydroxyphenazine, which is achieved through de-ethylation of 1,6-diethoxyphenazine corresponding to the Wohl-Aue reaction. According to the present invention, a new method for the production of iodinine and analogues thereof was found by starting from a 1,6-dioxyphenazine, acc. 1,6-dibenzyloxyphenazine.

The object of the invention consists in a method for the production of phenazine derivatives with the general formula

where means lower alkyl or benzyl.

This method is characterized by reacting a 10-oxide or a 5,10-dioxide of a phenazine compound with the general formula

where R_ means lower alkyl or benzyl and

has the above meaning,

with a halide from group III in the periodic table at low temperature, e.g. room temperature, in the case of using a 10-oxide of a compound of formula VI in a single step, the reaction product obtained is treated with a hydroperoxide and the desired reaction product is isolated from the reaction mixture.

The method according to the invention is explained in more detail by the following formula chart. In the preceding formulas and R2 means lower alkyl or benzyl.

The term "lower alkyl" refers to straight chain saturated hydrocarbons of 1 to 7 carbon atoms, such as methyl, ethyl, propyl, n-propyl, n-butyl and the like. Particularly preferred are straight-chain alkyl residues with 1 to 3 carbon atoms, i.e. methyl, ethyl and propyl.

The analogues of iodine are prepared by oxidation of a 1,6-di-substituted phenazine derivative of formula I with a hydroperoxide, obtaining a mixture of an N-mono-oxide of formula II and an N,N-dioxide of formula III. This mixture can be easily separated by fractional crystallization or chromatography. Hydroperoxides, which can be used to carry out this oxidation, are hydrogen superoxide or peroxyacids, especially the organic peroxyacids, such as lower alkanoylperoxyacids, e.g. peracetic acid, trifluoroperacetic acid, perpropionic acid etc. or perbenzoic acids, e.g. perbenzoic acid, m-chloroperbenzoic acid etc. The oxidation with a hydroperoxide is conveniently carried out in the presence of an inert organic solvent, such as a hydrocarbon, e.g. benzene, toluene or the like. When hydrogen peroxide is used, the preferred solvent is acetic acid or a solvent mixture with acetic acid. The reaction can easily be carried out at room temperature, as the reaction is completed in the course of approx. 15 - 20 hours. Higher or lower temperatures can likewise be used with a correspondingly shorter or longer reaction time. The phenazine starting materials of formula I are known compounds or analogues of known compounds, which are readily accessible by means of the Wohl-Aue reaction. The starting materials for this method include the symmetrical compounds, such as 1,6-dimethoxyphenazine, 1,6-diethoxyphenazine, 1,6-di-n-propyloxyphenazine, 1,6-dibenzyloxyphenazine, and the unsymmetrical derivatives, such as 1-methoxy-6- ethoxyphenazine, l-methoxy-6-n-propyloxyphenazine, 1-ethoxy-6-n-propyloxyphenazine, l-benzyloxy-6-methoxyphenazine, l-benzyloxy-6-ethoxyphenazine, 1-benzyloxy-6-n-propyloxyphenazine. ' in the N,N-dioxides of formula III are converted according to the invention into 1-hydroxy-6-OR^-phenazine-5,10-dioxides of formula V. The partial dealkyleri.ng herein. debenzylation of compounds with formula III is carried out according to the invention by treatment with a halide from group III in the periodic table, e.g. the bromides and chlorides, such as boron trichloride, aluminum bromide, aluminum chloride and the like. They are usually obtained by treating the starting materials of formula III with one of the less active halides from group III or alternatively additionally by using milder reaction conditions, e.g. lower temperatures. Generally, the chlorides from group III are less active with respect to the ether cleavage than the corresponding bromides and consequently the partial ether cleavage is effected preferably by using a chloride from group III, e.g. aluminum chloride. The reaction is conveniently carried out by adding a solution of a halide from group III, e.g. aluminum chloride, in an inert organic solvent, such as ether, tetrahydrofuran, dioxane and the like, to a solution of the intermediate of formula III in a non-polar solvent, such as a hydrocarbon, e.g. benzene, chloroform or the like, using room temperature. The reaction is usually completed at room temperature within a few hours. Higher or lower temperatures can likewise be used with a correspondingly shorter or longer reaction time.

In another embodiment of the method according to the invention, the analogues of iodine can be obtained via the mono-N-oxide of formula II, which precipitates as a by-product in the oxidation of 1,6-di-substituted phenazines of formula I corresponding to reactions (b) and (c) in the diagram. Cleavage of the ether group in the 1-position in the mono-N-oxide with formula II is effected according to the invention through the addition of a solution of a halide from group III, e.g. aluminum bromide, aluminum chloride and the like in the presence of an inert organic solvent, such as benzene/ether etc, to dissolve a compound of formula II in a non-polar solvent, such as benzene, chloroform or the like, and carrying out the reaction at room temperature in the course of 1 to 2 hours. Higher or lower temperatures can be used with a corresponding change in the reaction time.

The mono-N-oxide of formula IV is transferred to the corresponding N,N-dioxide of formula V by oxidation with a hydroperoxide analogous to the above-mentioned oxidation of a phenazine derivative of formula I. In practical terms, they are used in the diagram with (b) and ( d) designated reactions on symmetrical compounds to avoid separation of the mixtures, which is achieved by partial cleavage of unsymmetrical compounds. The method according to the invention contains an easy preparative approach to the compounds of formula V based on the observation that the N-oxide group accelerates the ether cleavage due to anchimeric influence.

The compounds of formulas II, III and IV are valuable starting materials. intermediate products in the synthesis of the compounds of formula V. Certain of the aforementioned compounds have pronounced antimicrobial activity with a broad spectrum of action. Compounds of formula V are particularly active against yeast, mold, fungi, mycobacteria etc. They are e.g. active against B. subtilis, E. coli, M. phlei, S. aureus, Ps. aeruginosa, S. cerevisiae, P. varioti and C. albicans. Consequently, these compounds can be used as germicides, they are particularly suitable as internal germicides for the treatment of infectious diseases.

The process end products can be transferred to common pharmaceutical administration forms using excipients. In addition, e.g. organic or inorganic inert carrier materials, such as water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gum arabic, polyalkylene glycols, petroleum jelly, etc. serve. The pharmaceutical preparations can be used in solid form, e.g. as tablets, chewable tablets, suppositories, capsules or in liquid form, e.g. as solutions, suspensions or emulsions. The pharmaceutical additives may contain preservatives, stabilisers, wetting or emulsifying agents, salts to change the osmotic pressure and buffers. They can also in-

keep other therapeutically active materials.

EXAMPLE 1

To a solution of 50 mg of 1,6-dimethoxyphenazine-5,10-dioxide in

A solution of 25 mg of aluminum chloride in 7 ml of ether is added to 5 ml of chloroform. The reaction mixture is stirred for 14 hours at room temperature. The reaction mixture is then diluted with 30 ml of chloroform and washed with 40 ml of water. The layers separate,

and the aqueous layer is extracted five times, each time with 30 ml of chloroform. The organic layers are combined, washed with some water, dried over sodium sulphate and evaporated to dryness. The residue is dissolved in chloroform and chromatographed on acidic alumina. After removal of unreacted starting material by elution with chloroform, the column packing is deactivated by adding a small amount of water and extracted six times, each time with 30 ml of chloroform. The resulting red solution is evaporated to dryness. The residue thus obtained is pure 1-hydroxy-6-methoxyphenazine-5,10-dioxide with a melting point of 125 - 135° (decomposition).

The 1,6-dimethoxyphenazine-5,10-dioxide used above as starting material can be prepared as follows: The solvent in 120 ml of a 5% perbenzoic acid solution in chloroform is replaced by benzene by repeated addition of benzene and partial evaporation. The benzene solution, which makes up approx. Add 2.4 g of 1,6-dimethoxyphenazine to 200 ml and stir for approx. 15 hours at room temperature. Thereby, the color of the solution changes from yellow to reddish orange. The solution is then extracted twice, each time with 100 ml of a 5% aqueous sodium carbonate solution. The benzene layer is washed with 100 ml of water. The combined aqueous extracts are extracted twice, each time with 100 ml and twice each time with 50 ml of chloroform. The combined chloroform extracts are washed with 100 ml of water. The combined benzene and chloroform extracts are dried over sodium sulfate and evaporated to dryness. The rest dissolves in approx.

50 ml chloroform and chromatographed on silicic acid, 1,6-dimethoxyphenazine-5-oxide with melting point 192° (decomposition) and 1,6-dimethoxyphenazine-5,10-dioxide with melting point 190 - 191°

(cleavage) is achieved.

In an analogous way, the following compounds, which can also be used in the method according to the invention, can be obtained: 1,6-diethoxyphenazine-5,10-dioxide

1,6-dipropyloxyphenazine-5,10-dioxide

1,6-dibenzyloxyphenazine-5,10-dioxide

1,6-diethoxyphenazine-5-oxide

1,6-dipropyloxyphenazine-5-oxide

1,6-dibenzyloxyphenazine-5-oxide.

The 1,6-dimethoxyphenazine-5,10-dioxide used as starting material can also be prepared as follows: To a suspension of 4.5 g of 1,6-dimethoxyphenazine in 500 ml of benzene, a solution of 20 g of m-chloroperbenzoic acid in 500 ml of benzene. The reaction mixture is stirred for 15 hours at room temperature. The red solution obtained is washed twice, each time with 100 ml of a 10% sodium carbonate solution. The aqueous phase is extracted three times, each time with 100 ml of chloroform. The chloroform extracts are combined with the benzene extracts, washed once with water, dried over sodium sulphate and evaporated. The residue is re-dissolved in chloroform and chromatographed on silica gel, obtaining a fraction of pure 1,6-dimethoxyphenazine-5-oxide with melting point 192° (decomposition) and a second fraction of pure 1,6-dimethoxyphenazine-5,10- dioxide with melting point 190 - 191° (decomposition). 1-Methoxy-6-ethoxyphenazine-5,10-dioxide which can be used as starting material instead of 1,6-dimethoxyphenazine-5,10-dioxide can be prepared as follows: For a suspension of 10 g of 1-methoxy-6-ethoxyphenazine in 500 ml of benzene is added a seeding of 40 g of m-chloroperbenzoic acid in 300 ml of benzene. The resulting suspension is then stirred for 16 hours at room temperature, and the reaction mixture is filtered from separated m-chloroperbenzoic acid. The filtrate is washed twice, each time with 150 ml of 5% sodium carbonate solution. The aqueous layers are extracted twice more, each time with 100 ml. chloroform. The combined organic layers are dried over sodium sulfate and evaporated. The residue is dissolved in chloroform and chromatographed on silica gel, thereby obtaining l-methoxy-6-ethoxyphenazine-5,10-dioxide with melting point 155 - 156° (decomposition), 1-methoxy-6-ethoxyphenazine-5-oxide and l-methoxy -6-ethoxyphenazine-10-oxide.

In an analogous way, the following compounds, which can also be used in the method according to the invention, can be prepared: 1-methoxy-6-propyloxyphenazine-5,10-dioxide

1-Methoxy-6-benzyloxyphenazine-5,10-dioxide

1-ethoxy-6-propyloxyphenazine-5,10-dioxide

1-ethoxy-6-benzyloxyphenazine-5,10-dioxide

(as well as the corresponding 5-oxides and 10-oxides).

EXAMPLE 2

To a solution of 27 2 mg of 1,6-dimethoxyphenazine-5,10-dioxide

in 25 ml of chloroform, a solution of 133 mg of aluminum chloride in 7 ml of ether is added. The reaction mixture is stirred for 15 hours at room temperature. The reaction mixture is then diluted with 100 ml of chloroform and washed with 150 ml of water. The aqueous layer is extracted with 100 ml and then eight times, each time with 50 ml of chloroform. The combined organic phases are washed with 100 ml of water, dried over sodium sulphate and evaporated to dryness. The resulting mixture is separated by chromatography on acid alumina. After elution of the starting material, the column material is suspended in 100 ml of chloroform and deactivated by adding 5 ml of water. The chloroform is decanted off and the aluminum oxide is washed six times, each time with 75 ml of chloroform. The combined organic solutions are evaporated to dryness and give 1-hydroxy-6-methoxyphenazine-5,10-dioxide with a melting point of 125 - 135° (decomposition).

EXAMPLE 3

Dissolve 150 mg of 1,6-dimethoxyphenazine-5-oxide in 3 ml of benzene and 3 ml of chloroform. A solution of 200 mg aluminum bromide in 3 ml benzene is added dropwise. The reaction mixture is then stirred for 20 minutes at room temperature and then poured onto ice. The organic layer is separated, the aqueous layer is diluted with water and extracted several times with chloroform. The combined organic layers are dried over sodium sulfate and evaporated in a vacuum (approx. 25 Torr). The residue is dissolved in chloroform and filtered through silica gel. The filtered solution is evaporated, dissolved in chloroform and chromatographed on active alumina (activity 2). After elution of the unreacted starting material, the column material is slurried in chloroform. After deactivation by adding a small amount of water, 1-hydroxy-6-methoxyphenazine-10-oxide is dissolved in chloroform. The extraction of the column material with chloroform is repeated twice. The combined solutions are dried over sodium sulfate and evaporated. Pure 1-hydroxy-6-methoxyphenazine-10-oxide is obtained with a melting point of 220 - 225° (decomposition).

In an analogous manner, the following compounds, which can also be used in the method according to the invention, can be prepared: l-hydroxy-6-ethoxyphenazine-10-oxide l-hydroxy-6-propyloxyphenazine-10-oxide

1-hydroxy-6-benzyloxyphenazine-10-oxide.

A solution of 500 mg of m-chloroperbenzoic acid in 10 ml of benzene is added to a suspension of 242 mg of 1-hydroxy-6-methoxyphenazine-10-oxide in 10 ml of benzene. This suspension is then stirred for 24 hours at room temperature. The reaction mixture is filtered and chromatographed directly on acidic alumina. The fractions containing the pure l-methoxy-6-hydroxyphenazine-5,10-dioxide are evaporated and crystallized from acetone, whereby l-hydroxy-6-methoxyphenazine-5,10-dioxide is obtained with a melting point of 125 - 135° (decomposition) .

Claims (1)

Process, for the preparation of phenazine derivatives of the general formula where means lower alkyl or benzyl, characterized by reacting a 10-oxide or a 5,10-dioxide of a phenazine compound with the general formula where R 2 means lower alkyl or benzyl and R 2 has the above meaning, with a halide from group III in the periodic table at low temperature, e.g. room temperature, in the case of using a 10-oxide of a compound of formula VI in a single step, the obtained reaction product is treated with a hydroperoxide, and that the desired reaction product is isolated from the reaction mixture.