DE2016467A1 - Process for the preparation of phenazine derivatives - Google Patents

Description

η w * 20Ί6467

Dr, hu ^ lftoier

PATENTWALK

Z & APR.

RAN 4410/59

F. Hofifmann-La Roche & Co. Aktiengesellschaii, Basel / Switzerland

Μη / 3/18/70

Process for the preparation of phenazine derivatives

Iodinine (1,6-3ihydroxyphenazine-5 »10-dioxide) can be obtained, inter alia, by submerged cultivation of Pseudomonas iodinine, a culture of which is deposited at the American Type Culture Collection in"', Washington, DC under the number 9897. These Compound is mono-O-alkylated in the presence of an alkylating agent under suitable reaction conditions Because of the extremely low solubility of iodinine and its salts in common solvents it has not been possible to date to obtain good yields of the monoalkylation product a process whereby good yields of the alkylation product of iodinine can be obtained,

0 09848 / 193s o «, q _INA , _mpECTeo

in particular of l-hydroxy-o-methoxyphenazine-SjlO-dioxide, which is known as the antibiotic myxin. Myxin used to be made by fermentation and also synthetically by labor Process produced in very low yields.

The present invention relates to a process for the monoalkylation of iodinine, l-hydroxy-6-lower alkoxyphenazine-5 »10-dioxides are obtained in which the lower alkoxy group contains 1-7 carbon atoms.

The method according to the invention is characterized in that that he

a) reacting a monoalkali metal salt of 1,6-dihydroxyphenazine-5,10-dioxide in an aprotic, polar, organic solvent with about 1 to about 2 moles of an alkylating agent per mole of salt and
^ b) l-Hydroxy-o-lower-alkoxyphenazine-SilO-dioxide wins.

According to a preferred embodiment of the invention ' According to the method, the monoalkali metal salt used as the starting material is 1,6-dihydroxyphenazine-5,10-dioxide by reacting 1,6-dihydroxyphenazine ~ 5> 10-dioxide with a equimolar amount of one. Alkali metal lower alkoxide in the same aprotic, polar, organic solvents, as used in step a) above, prepared.

09846/1939

The method according to the invention is therefore preferred

Carried out in such a way that iodinine can be converted into the corresponding MaioaU ^ üroetaHsalz converts, with one as the reaction medium aprotic, polar, organic solvent used, the iodinine partially and the alkali metal salt of iodinine essentially completely dissolves, a homogeneous single phase system being formed after the iodinine is completely dissolved has been implemented. Then, while maintaining the homogeneous system, the salt with a common alkylating agent monoalkylated, after which the product is obtained in high yields. The aprotic, polar, organic solvent that best fulfills these criteria is hexamethyl phosphoric acid triamide,

According to a less preferred embodiment

■■■ "■" ^ -

the procedure carried out in such a way that one iodinine according to conventional, known methods in an aqueous medium converts the salt into the corresponding monoalkali metal sal isolated and then in an aprotic, polar, organic Monoalkylated solvents, e.g. dimethylformamide, dimethyl sulfoxide or hexamethylphosphoric acid trlamide. Optional can the salt in an aprotic, polar, organic solvent, z »B. Dimethylformamide or dimethyl sulfoxide (which are less preferred than hexamethylphosphoric triamide), and then in the same Alkylate reaction medium. These processes give better yields than the known processes which are exclusive be carried out in aqueous media.

009846/1939

According to a preferred embodiment of the invention In the process, iodinine is converted into the corresponding mono-lower alkyl derivatives converted under conditions that ensure high yields and the use of im allow substantial equivalent amounts of the alkylating agent.

The inventive method is by selective

P Monoalkylation of the monoalkali metal salt of iodinine in one aprotic, polar, organic solvents. According to a particularly preferred embodiment, the monoalkali metal salt is beforehand by reacting iodinine with an equimolar amount of an alkali metal lower alkoxide therein Reaction medium prepared as subsequently for the further implementation. However, the present invention includes generally the use of the monoalkali metal salt of iodinine prepared in any suitable manner. The salt ™ can therefore be used in both aqueous and organic media are formed.

The salt formation can be carried out by reacting iodynine with an alkali metal compound. Is preferred Salt formation carried out in such a way that iodinine is dispersed in an aprotic, polar, organic solvent which Iodinine partially and completely dissolves the monoalkali metal salt of iodinine, e.g. hexamethylphosphoric acid triamide, and then iodinine with an alkali metal lower alkoxide

009846/1939

to form the monoalkali metal salt in solution.

The present invention also encompasses manufacture of the monoalkali metal salt of iodinine using other aprotic, polar, organic solvents as reaction media, e.g. dimethylformamide or dimethyl sulfoxide. These solvents partially dissolve the monoalkali metal salts of iodinine, whereby a heterogeneous reaction medium is formed * and are therefore opposite to hexamethylphosphoric acid triamide, which forms a homogeneous reaction medium, not preferred. In every case, use is permitted an aprotic, polar, organic solvent die subsequent monoalkylation of the iodinine salt without its isolation, because according to the invention the aprotic, polar, organic solvents are the reaction medium for the monoalkylation stage represents;

In the event that an aqueous reaction medium is used in the Formation of the monoalkali metal salt of iodinine is to be used, the process can be carried out, for example, by suspending iodinine be carried out in aqueous alkali metal hydroxide. Large excesses of concentrated base are required to bring about the formation of the salt and its precipitation. to lead.

Before mixing the obtained salt with the aprotic, polar

organic solvent in which the monoalkylation is carried out

009846/1339

can be brought into contact, it must be isolated by filtration and drying. This embodiment is quite feasible, but gives relatively low yields compared to the most preferred embodiment the invention. However, both embodiments are superior to the process in which aqueous media are used in both stages. The mentioned export ungsforms are easy to adapt on a larger scale reversible, they give higher yields and proceed with less competing side reactions, i.e. without hydrolysis of the Alkylating agent and without thermal decomposition of the starting material and the product.

The organic solvents suitable for the process according to the invention are aprotic, polar, organic Solvents capable of dissolving the monoalkali metal salts of iodinine. The aprotic, polar, organic solutions " agents vary in their ability to produce the monoalkali metal salts to solve from iodinine. The most preferred aprotic, polar, organic solvent is hexamethyl phosphoric acid triamide, because it completely dissolves the monoalkali metal salts of iodinine, forming a homogeneous, single-phase reaction system after the partially soluble iodinine has been implemented. This is advantageous because the mono- ' alkali metal salt does not need to be isolated before the monoalkylation, side reactions are reduced to a minimum and high yields are obtained. Other, suitable, aprotic,

009846/1939

- γ -

polar, organic solvents are dimethylformamide and dime thy lsulf oxide. These solvents form heterogeneous systems and the yields are lower than in a homogeneous system.

The reaction conditions under which the monoalkali metal salts of iodinine are formed can be varied. The .Reaktionstemperatur can vary up to about 70 ⁰ C, for example, from about 10 ⁰ C, the room temperature, for example is preferably about 20 ° C to about 25 ° C. The relative molar ratio of iodinine: alkali metal lower alkoxide or alkali metal hydroxide is only critical insofar as there should not be too great an excess of the alkoxide, which causes the formation of dialkali metal salts of iodinine and / or monoalkali metal salts of the monoalkylation product in the subsequent dialkylation . In order to form the monoalkali metal salt, it is expedient for the reactants to be present in an approximately equimolar ratio.

Suitable alkali metal lower alkoxides are the sodium or potassium lower alkoxides, containing 1-4 carbon atoms, either in straight or branched chains. The preferred one Alkali metal lower alkoxide is potassium t-butoxide. The alkali metal lower alkoxides are used when an aprotic, polar, organic solvent is the reaction medium represents the formation of the salt.

009846/1939

The reaction time can vary within wide limits, but the reaction is usually within about 3 to about 20 hours to end. It is useful allow the reaction to run for at least about 10 hours to ensure complete conversion.

The most preferred reaction conditions for the formation of the mono-alkali metal salt of Iodinin are room temperature, eg, about 20-25 ⁰ C, and about 12 hours of reaction time, with about equimolar amounts of the reactants, for example Iodinin and Kaliüm-t-butoxide, in an aprotic polar organic solvents, preferably hexamethylphosphoric triamide, can be used. The origin of the monoalkali metal salt of iodinine does not play a decisive role in the present process. The practically quantitative formation of the salt in situ in solution, especially when hexamethylphosphoric triamide is the solvent, makes it unnecessary to isolate the salt for subsequent monoalkylation reactions. Isolation of the salt is only necessary if an aqueous reaction medium is used for the formation of the salt and an aprotic, polar, organic solvent is used as the reaction medium for the monoalkylation reaction.

An advantage of the preferred embodiment of the The method according to the invention thus consists in the fact that the monoalkali metal salt is formed by iodinine in solution and

009846/1939

need not be isolated, but alkylated directly with high yields to the monoalkyl derivatives of iodinine can be. The method according to the invention is also advantageous because it does not require large volumes of solvents and reactants to obtain comparable amounts of the final product. The method according to the invention somlt - because of the associated savings in space and manpower, represents an economical process.

The inventive, selective monoalkylation of Monoalkali metal salt of iodinine is preferably carried out in such a way that the reaction solution obtained above treated with an alkylating agent. The solution is there from the monoalkali metal salt of iodinine, dissolved in e.g. hexamethylphosphoric acid triamide, the salt being based on any Ways-can-be-preserved. However, it is preferred to have a solution prepared by the method described above for. To use formation of the monoalkali metal salt. Appropriate Alkylating agents are, for example, dialkyl sulfates, alkyl iodides and Alkyl tosylates. Preferred are alkylating agents which Contain 1-7 carbon atoms in the alkyl groups. For example, if a methyl substituent is desired, dimethyl sulfate or Methyl iodide used.

The amount of the alkylating agent used can vary from about 1 to about ^1} 2 moles of the alkylating agent per mole of Alkaiimetallsalz Iodinin have to be sufficient

009846/1939

proven. Preferably about 1.5 moles of alkylating agent are used per mole of alkali metal salt of iodinine. This quantity Alkylating agent is sufficient to ensure a quick, complete reaction. Larger amounts do not offer any substantial Advantages.

The reaction conditions for the alkylation can also be varied; however, suitable reaction conditions which ensure high yields are temperatures of about 10 ^° C. to about 70 ^° C. The reaction time required to complete the reaction is generally between about 1 and about 15 hours. The preferred embodiment of the process is that a homogeneous, single-phase solution of the monopotassium salt of .Iodinin in hexamethylphosphoric triamide at room temperature, for example about 20 ⁰ C to 25 ° C, with about 1.5 moles of alkylating agent was added and the reaction in about 3 hours completed.

The end products, i.e. l-hydroxy-6-lower-alkoxyphenazine-5,10-dioxide, can be isolated by conventional methods. You can e.g. by adding water to the Reaction solution are precipitated. Cold water, e.g. ice water, is preferably used. The products can then can be obtained from the suspension obtained, either by extraction or by filtration. You can can then be purified by chromatography and / or crystallization.

009846/1339

The yields of 1-hydroxy-6-lower-alkoxyphenazine-5,10-dioxides achieved after carrying out the process according to the invention are generally between about 10 $ and about 75 $ *, calculated on iodinine. If the above-mentioned preferred embodiment of the process according to the invention is used, the yields are generally between about J) 0% and about 75%, calculated on the basis of iodinine.

The invention is illustrated by the following examples.

example 1

130 g of potassium t-butoxide are added with stirring to a suspension of 2.44 g of iodinine in 150 ml of hexamethylphosphoric triamide. The mixture is stirred at room temperature for 5 hours, an emerald green solution of the monopotassium salt of iodinine in hexamethylphosphoric acid triamide being formed. 1.4 ml of dimethyl sulfate is added and stirring is continued. After a further 3 hours, the reaction mixture is poured into 1000 ml of ice water. The aqueous mixture is extracted with 3 x 500 ml of ethyl acetate. The organic extracts are washed with 2-300 ml of water. The aqueous washing liquids are extracted with 2 × 250 ml of benzene. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The residue is "in 2ÖÖ ml

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SAD OBlGINAU

The solution obtained is filtered through a sintered glass funnel. The piltrate is passed through a chromatography column (prepared from a slurry of 100 g of silica gel in methylene chloride). The column is eluted with a mixture of methylene chloride and ethyl acetate (2 + 1) . The pure product containing fractions are combined and evaporated under reduced pressure. The residue is dissolved in 100 ml of boiling methylene chloride-W. The solution is diluted with 150 ml of warm acetone. After cooling to obtain l-hydroxy-6-methoxyphenazin- 5,10-dioxide in crystalline form, yield $ 69 calculated on iodinine.

Example 2

A suspension of 7.32 g of iodinine in 450 ml of hexamethylphosphoric acid triamide 4.2 g of potassium t-butoxide are added. "The mixture is stirred at room temperature for 12 hours. JO ml of 1-bromo-3-methylbutane are then added and stirring is continued for 10 more hours. The reaction mixture is then poured into ice water and three times extracted with ethyl acetate. The organic extracts are diluted with benzene, washed with water, over Magnesium sulfate dried and evaporated to dryness under reduced pressure. The solid residue is dissolved in methylene chloride dissolved and chromatographed on silica gel. the

SAD OKlGINAU 0098A6 / 1939

6- (5-methylbutoxy) -l-phenazinol-5,10-oxide containing Fractions are combined and evaporated. The product obtained is recrystallized from methylene chloride / acetone. Yield J5C $ calculated on iodinine.

Example 3

1 g of iodinine is dissolved in a solution of 25 g of sodium hydroxide dispersed in 100 ml of water. The reaction mixture is stirred at room temperature for 1 hour. The received Precipitate is filtered off and washed with methanol, acetone and Aether washed. The obtained blue pestilence is in 500 ml Chloroform dispersed and at room temperature for 30 minutes touched. The mixture is then filtered. The filter cake consists mainly of the monosodium salt of iodinine.

800 mg of the monosodium salt of iodinine are suspended in 1.0 ml of dimethylformamide and mixed with 10 ml of methyl) odide. The reaction mixture is stirred at room temperature for 6 hours. The reaction mixture is then mixed with 50 ml Diluted chloroform and filtered. The solid obtained is washed with chloroform. The filtrate is made up to 10 ml concentrated, diluted with 100 ml of water and extracted with chloroform. The organic phase is poured over sodium sulfate and filtered. The filtrate is concentrated and chromato-

0 0 9 8 4 6 / '1 9 3 g Sad

graphed. The fractions containing the desired product are combined, diluted with chloroform, over sodium sulfate dried, then filtered and evaporated under reduced pressure. 1-Hydroxy-6-methoxyphenazine-5> 10-dioxide is obtained. Yield $ 10.3 calculated on iodinine.

Example 4

The monosodium salt of iodinine is prepared from 17 g of iodinine according to the information described in Example 3. This is suspended in 2 "C ml of dimethyl sulfoxide and mixed with 10 ml of dimethyl sulfate Stirred at room temperature for 15 hours, then diluted with 200 ml of chloroform and filtered. The filter deficit is washed with β 500 ml of chloroform.

The combined filtrates are washed thoroughly with 3 x 150 ml Washed with water, removing the dimethyl sulfoxide. The organic layer is dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue is dissolved in chloroform and analyzed by chromatography on 400 g of florinil in chloroform. The the Product containing fractions are under reduced pressure evaporated. The Rlu-icsfcaid is crystallized from acetone, where one obtains 1.-Hydrv / .y-o-rnetho ryphena: *, in-5 »10-d loxLd. Yield $ 27 based on iodinine.

,. ,. BAD OWGLAL

0098 ^ 8/1939

Claims (14)

-.15 - Claims Process for the preparation of phenazine derivatives, characterized in that one a) a monoalkali metal salt of 1,6-dihydroxyphenazine-5i10-dioxide in an aprotic, polar, organic solvent with about 1 to about 2 moles of an alkylating agent per Mol of salt converts and. -.- ■■ " b) l-Hydroxy-6-lower alkoxyphenazine-50-dioxide is obtained. 2. The method according to claim 1, characterized in that step a) is carried out at a temperature of about 10 ^° C. to about 70 ^° C., preferably at room temperature. 3. The method according to claim 1 or 2, characterized in that that the reaction time of stage a) is about 1 to about 15 hours. k. Process according to one of Claims 1-3, characterized in that the solvent is hexamethylphosphoric acid triamide. 5. The method according to any one of claims 1-4, characterized characterized in that the monopotassium salt is used as the starting material of 1,6-dihydroxyphenazine-5,10 ~ dioxide used. 6. The method according to any one of claims 1-5 »characterized in that the alkylating agent is dimethyl sulfate used, the product l-hydroxy-6-methoxyphenazine-5,10-dioxide represents. 7. The method according to any one of claims 1-6, characterized in that a solution of the monopotassium salt of 1,6-dihydroxyphenazine-5,10-dioxide in hexamethylphosphoric acid triamide reacted with about 1.5 pounds of dimethyl sulfate per mole of salt at room temperature within about j5 hours, after which 1-hydroxy-6-methoxyphenazine-5,10-dioxide is obtained. 8. The method according to any one of claims 1-7, characterized in that the used as starting material Monoalkali metal salt of 1,6-dihydroxyphena7Jn-5 * 10-dioxide by reacting 1,6-dihydroxyphenazine-5,10-dioxide with ^ an equimolar amount of an alkali metal lower alkoxide j η the same aprotic, polar, organic solvent väe in stage a) of claim 1 produces. 9. The method according to claim 8, characterized in pjekennzeicl.net, that the resulting solution of the monoalkali metal salt of l, 6-dihydroxyphenazine-5ilO-dioxide is reacted further without the Isolate compound from solution. 10. The method according to claim 8 or 9, characterized in that the UrnGeti-.ung at a ?! ¹ temperature of ütw; i 009846/1939 SAD 10 ° C to about 70 ° C, preferably at room temperature. 11. The method according to any one of claims 8-10, characterized characterized in that the reaction is carried out within a reaction time of about 3 to about 20 hours. 12. The method according to any one of claims 8-11, characterized in that the solvent hexamethylphosphoric triamide used. 13. The method according to any one of claims 8-12, characterized characterized in that the alkali metal lower alkoxide used is potassium t-butoxide. 14. The method according to any one of claims 8-13 * Dihydroxy ■ characterized that one l, 6-ü «e * iieepphenazin-5» 10-dioxide with an approximately equimolar amount of potassium t-butoxide in hexamethylphosphoric acid trlamide at room temperature within ,it about 10 hours and the product continues to react without isolating / from the solution. 09846/1939