Process for exchanging anions in phenothiazinium derivatives

Abstract

A process for producing a phenothiazinium compound comprising the step of: reacting phenothiazine, in the presence of a halogen, with at least one amine selected from the group consisting of: wherein Z is CH2, O, S, SO2, NH, NCH3, NC2H5, NCH2CH2OH or NCOCH3, and R1 and R2 are each independently linear or branched CnH2nY; and replacing the halogen with a non-halide counteranion.

Description

RELATED APPLICATIONS

This is a Continuation-in-Part Application of U.S. patent application Ser. No. 10/960,811, filed on Oct. 7, 2004, which is incorporated in its entirety herein by reference.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to a novel process for exchanging anions in phenothiazinium derivatives.

2. Discussion of the Background Art

There has been recent advances in the use of compounds having a photosensitizing chromophoric system, a sulphonamido functionality and a carboxy functionality as a photosensitizer in photodynamic therapy (PDT), in photochemical internalization in the production of a cancer vaccine or in the diagnosis or detection of medical conditions.

These photosensitizing chromophoric systems are preferably residue of a metal-free phthalocyanine, a methyl phthalocyanine, a benzoporphyrin, a purpurin, a chlorin, a bacteriochlorin, a tetraarylporphyrin, a porphycene or a texaphyrin, more preferably a residue of a metal phthalocyanine, a chlorin or a bacteriochlorin, especially a residue of a metal phthalocyanine, as set forth in US-2003/0180224, which is incorporated herein in its entirety.

Such phenothiazinium compounds are disclosed in WO-02/096896 as comprising the following formula (I):
wherein A and B are each independently selected from the group consisting of:
wherein Z is CH₂, O, S, SO₂, NH, NCH₃, HC₂H₅, NCH₂CH₂OH or HCOCH₃ and R¹ and R² are each independently linear or branched C_nH_2nY, where n is 1-6, Y is H, F, Cl, Br, I, OH, OCH₃, OC₂H₅, OC₃H₇, CN or OCOCH₃, and where X^p− is a counteranion and P is 1, 2 or 3.

Unfortunately, WO-02/096896 does not teach a commercially acceptable synthesis route for the manufacture of such phenothiazinium compounds, or any synthesis route for that matter.

K. J. Mellish et al. (Photochem. Photobiol., 2002, 75/4, 392-397) describes the synthesis of a series of tetraalkyl-iodide-derivatives of phenothiazine by an elaborate procedure. The phenothiazine is halogenated first and isolated, and then reacted at room temperature with the appropriate N,N-dialkylamine. The compounds are isolated by an elaborated work-up procedure using, e.g., halogenated solvents and only characterized by mass spectrometry. The purity cannot be derived from the data given.

N. Leventis et al. (Tetrahedron, 1997, 53/29, 10083-10092) describes the synthesis of a series of thiazine dyes. The synthesis is performed in two steps by halogenating phenothiazine in glacial acetic acid and then reaction with the corresponding amine in ethanol. The last step requires work up with chloroform and then isolation by column chromatography using chloroform/MeOH. The evaporation of the organic fractions is followed by recrystallization. This extensive procedure is not practicable for a large-scale synthesis.

L. Strekowski et al. (J. Heterocycl. Chem. 1993, 30/4, 1693-1695) describes the synthesis of dialkylamino-phenothiazin-derivatives with two different amino groups and I₃⁻ as the counterion. The compounds are synthesized in a two-step synthesis.

K. W. Loach (J. Chrom., 1971, 60, 119-129) describes the purification and analysis of a series of thiazine dyes. It concedes that in former literature “published procedures appear to give incomplete resolution of complex mixtures or separate them very slowly.” The paper describes only analytical separations, using mixtures of alcohol/chloroform/acetic acid which are disadvantageous because of the use of halogenated solvents and the mixture not being stable over more than 24 hours. Also, the separations had to be performed in the dark as the compounds showed significant photodecomposition. Also see U.S. Pat. No. 3,641,016 (Korosi et al.).

Copending U.S. patent application Ser. No. 10/960,811 is directed to an easy one-pot/one-step synthesis with crystallization right from the reaction mixture; eliminates the use of halogenated solvents and methanol during the reaction which also adds to process safety, as methanol/bromine mixtures are hazardous; eliminates the use of halogenated solvents and methanol in the work up; completely eliminates the need to use chromatography which is expensive, causes photodecomposition of material, requires the use of halogenated solvents and silica and causes inconsistent purity results; improves the yield using higher reaction temperature; and results in consistent, high purity yields which are reproducible.

While the described production procedure for phenothiazinium dyes with a halide counter ion is favorable compared to procedures described previously, the counter-anion being a halide may pose a problem in some applications and processing steps because halides may cause corrosion, especially when stainless steel devices are used (as is often practiced in production facilities).

The present inventor have developed a novel process for exchanging anions in phenothiazinium derivatives which reduces or eliminates the corrosion problems caused by the conventional halide-based phenothiazinium dyes.

SUMMARY OF THE INVENTION

The present invention pertains to a method for exchanging an anion AA (preferably halide) of a 3,7-amino-phenothiazinium salt for another anion BB.

The halide counteranion AA (or any other unwanted counteranion) of phenothiazinium is replaced, according to the present invention, by anion BB via at least one process step selected from the group consisting of:

• • (a) using ion exchange resins;
  • (b) using the concept that a strong acid can replace a weak acid in its salt: e.g. (b1) using a stronger acid than the corresponding acid that is formed from the original counteranion to drive the weaker acid out, (b2) adding suitable strong acids to weaker acids to make these acidic enough to drive the original anion out (e.g., adding sulfuric acid to acetic acid), (b3) driving the acid that is formed from the original counteranion out of the mixture, e.g. using oxidation to remove the evolving HX as X₂ (where applicable, e.g. in the case of X═Cl⁻, Br⁻ . . . ), if necessary with the aid of a gas stream, co-distillation or X₂-scavenging chemicals e.g. containing double bonds; and
  • (c) using solubility differences: e.g. (c1) introducing new anions of salt AX into the phenothiazine salt BY by exploiting the insolubility of the newly formed salt AY or BX in a suitably chosen solvent. If the new phenothiazine salt BX stays in solution, AY is filtered off and BX is isolated from the solution (e.g. by evaporation, precipitation . . . ). If the new phenothiazine salt BX precipitates out, it is harvested by filtration and dried. (c2) preferably: using silver salts that form a less soluble salt with the original counteranion.

If the desired anion cannot be introduced by the above means directly (e.g., because of lacking acidity or lacking solubility differences), the above-mentioned methods can be combined, preferably forming a less soluble hydroxide salt according to c1) or a), then adding an acid of the desired anion which would normally have been too weak to replace the original anion according to b1).

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

A process for producing a phenothiazinium compound comprising the step of: reacting phenothiazine, in the presence of a halogen, with at least one amine selected from the group consisting of:
wherein Z is CH₂, O, S, SO₂, NH, NCH₃, NC₂H₅, NCH₂CH₂OH or NCOCH₃, and R¹ and R² are each independently linear or branched C_nH_2nY, and wherein the phenothiazinium compound has the general formula:
wherein A and B are each selected from the group consisting of:
wherein Z is CH₂, O, S, SO₂, NH, NCH₃, NC₂H₅, NCH₂CH₂OH or NCOCH₃ and R¹ and R² are each independently linear or branched C_nH_2nY, where n is 1-6, Y lo is H, F, Br, I, OH, OCH₃, OC₂H₅, OC₃H₇, CN or OCOCH₃, and where X⁻ is a halide counteranion; and replacing the halide counteranion with a non-halide counteranion.

The non-halide counteranion is at least one selected from the group consisting of: mono- or di-carboxylic acid anions having a carbon chain length of between about 1 to 6 (e.g., formate, acetate, propionate etc.) hydrogensulfate, sulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, cyanate, nitrate, sulfide, and other anions derived from non-organic acids.

The step of replacing the halide counteranion is at least one selected from the group consisting of: exchanging the halide counteranion with the non-halide counteranion via an ion exchange resin; forming an acid of the halide counteranion and thereafter adding a stronger acid than the acid of the halide counteranion to thereby drive the weaker acid or the halide counteranion out of the phenothiazinium compound forming an acid of the halide counteranion and driving the acid of the halide counteranion out of the phenothiazinium compound using oxidation to remove the evolving HX as X₂; and introducing a non-halide counteranion salt to a salt of the halide counteranion containing phenothiazine mixture, and separating and removing the halide counteranion, wherein a non-halide counteranion salt of phenothiazine produced.

Alternatively, the step of replacing the halide counteranion comprises: forming a less soluble hydroxide salt of the halide counteranion; and adding an acid of the non-halide counteranion to the hydroxide salt.

A process for producing a phenothiazinium compound comprising the step of: reacting phenothiazine, in the presence of a bromine, with at least one dialkylamine; and replacing the bromine with a non-halide counteranion.

A phenothiazinium compound can be prepared from a mixture of 1-propanol/THF and the bromination in the presence of di-n-propylamine so that the amination takes place immediately after bromination in a simple one-pot/one-step synthesis process. This eliminates the need for isolation by extraction and/or chromatography, especially the elimination of chromatography due to the fact that it disadvantageously uses vast amounts of halogenated solvents and silica. The phenothiazinium compound synthesized according to the aforementioned process crystallizes out of the reaction mixture and is harvested by simple filtration. This results in a very high quality crystallized phenothiazinium compound (i.e., greater than 96% after crystallization determined by high performance liquid chromatography (HPLC)) versus 30-60% HPLC purity after conventional column chromatography.

This process can be used after a one step halogenation/amination procedure (e.g., bromination/amination) which produces phenothiazinium compounds from phenothiazine. This process eliminates the use of undesirable halogenated solvents throughout the synthesis process, since such a process typically requires the use of methanol in the halogenation step of phenothiazine which reacts violently with bromine.

A process for producing a phenothiazinium compound comprising the step of: reacting phenothiazine, in the presence of a halogen, with at least one amine selected from the group consisting of:
wherein Z is CH₂, O, S, SO₂, NH, NCH₃, NC₂H₅, NCH₂CH₂OH or NCOCH₃, and R¹ and R² are each independently linear or branched C_nH_2nY; provided that each amine is the same or different as the other amine.

The phenothiazinium compound preferably has the general formula:
wherein A and B are each selected from the group consisting of:
wherein Z is CH₂, O, S, SO₂, NH, NCH₃, NC₂H₅, NCH₂CH₂OH or NCOCH₃ and R¹ and R² are each independently linear or branched C_nH_2nY, where n is 1-6, Y is H, F, Br, I, OH, OCH₃, OC₂H₅, OC₃H₇, CN or OCOCH₃, and where AA⁻ is a halide counteranion.

The halogen is selected from the group consisting of: bromine, iodine, chlorine and mixtures thereof. The amine is diiso- or di-n-alkylamine, e.g., diisopropylamine, diisobutylamine, diisopentylamine, di-n-propylamine, di-n-butylamine, di-n-pentylamine, or n-alkyl-iso-alkyl-amine, e.g., ethyl-isopropylamine.

It is preferable that the reaction occur at a temperature in the range between about −5° C. to +55° C., more preferably between about −5° C. to +20° C., and most preferably between about 50° C. to 55° C.

The starting material phenothiazine preferably has the formula:

The process according to the present invention may further comprise the step of filtering the phenothiazinium compound.

It is preferable that the reaction is carried out in a single reactor, wherein the phenothiazine and amine are mixed together, followed by addition of the halogen.

Preferably, the present invention involves a process for producing a phenothiazinium compound comprising the step of: reacting phenothiazine, in the presence of a bromine, with at least one dialkylamine. According to this embodiment, the phenothiazinium compound has the general formula:
wherein A and B are each selected from the group consisting of:
wherein R¹ and R² are each independently linear or branched C_nH_2nY, n is 1 to 6, and where AA⁻ is a bromide counteranion. Preferably, the dialkylamine is selected from the group consisting of: diisopropylamine, diisobutylamine, diisopentylamine, di-n-propylamine, di-n-butylamine, di-n-pentylamine, ethyl-isopropylamine and mixtures thereof.

The present invention pertains to a method for exchanging an anion AA (preferably halide) of a 3,7-amino-phenothiazinium salt for another anion BB.

The halide counteranion AA (or any other unwanted counteranion) of phenothiazinium is replaced, according to the present invention, by anion BB via at least one process step selected from the group consisting of:

• • (a) using ion exchange resins;
  • (b) using the concept that a strong acid can replace a weak acid in its salt: e.g. (b1) using a stronger acid than the corresponding acid that is formed from the original counteranion to drive the weaker acid out, (b2) adding suitable strong acids to weaker acids to make these acidic enough to drive the original anion out (e.g. adding sulfuric acid to acetic acid), (b3) driving the acid that is formed from the original counteranion out of the mixture, e.g. using oxidation to remove the evolving HX as X₂ (where applicable, e.g. in the case of X═Cl⁻, Br⁻ . . . ), if necessary with the aid of a gas stream, co-distillation or X₂-scavenging chemicals e.g. containing double bonds; and
  • (c) using solubility differences: e.g. (c1) introducing new anions of salt AX into the phenothiazine salt BY by exploiting the insolubility of the newly formed salt AY or BX in a suitably chosen solvent. If the new phenothiazine salt BX stays in solution, AY is filtered off and BX is isolated from the solution (e.g. by evaporation, precipitation . . . ). If the new phenothiazine salt BX precipitates out, it is harvested by filtration and dried. (c2) preferably: using silver salts that form a less soluble salt with the original counteranion.

If the desired anion cannot be introduced by the above means directly (e.g., because of lacking acidity or lacking solubility differences), the above-mentioned methods can be combined, preferably forming a less soluble hydroxide salt according to c1) or a), then adding an acid of the desired anion which would normally have been too weak to replace the original anion according to b1).

EXAMPLE 1

3 g of a phenothiazinium salt was dissolved with stirring in 70 g concentrated H₂SO₄. A clear, green solution forms as Br₂-fumes evolve (as HBr is a weaker acid than H₂SO₄, Br⁻ is driven out and then oxidized to Br₂ which evolves from the mixture). The mixture was then heated to 35° C. and a vacuum of 50 mbar was applied. The mixture foamed slightly. After 30 minutes, the green solution was mixed into 120 mL water under cooling, the temperature was 15-38° C. Immediately, brownish-bronze needles precipitated. The mixture was then diluted with another 50 mL of water and left standing overnight at room temperature. The solid was filtered, washed with 50 ml water and dried at 50° C. Ion chromatography showed complete replacement of the Br in the salt. HPLC confirmed the identity of the compound.

Claims

1. A process for producing a phenothiazinium compound comprising the step of:

reacting phenothiazine, in the presence of a halogen, with at least one amine selected from the group consisting of:

wherein Z is CH2, O, S, SO2, NH, NCH3, NC2H5, NCH2CH2OH or NCOCH3, and R1 and R2 are each independently linear or branched CnH2nY, and wherein said phenothiazinium compound has the general formula:

wherein A and B are each selected from the group consisting of:

wherein Z is CH2, O, S, SO2, NH, NCH3, NC2H5, NCH2CH2OH or NCOCH3 and R1 and R2 are each independently linear or branched CnH2nY, where n is 1-6, Y is H, F, Br, I, OH, OCH3, OC2H5, OC3H7, CN or OCOCH3, and where X− is a halide counteranion; and

replacing said halide counteranion with a non-halide counteranion.

2. The process according to claim 1, wherein said non-halide counteranion is at least one selected from the group consisting of: mono- or di-carboxylic acid anions having a carbon chain length of between about 1 to 6, hydrogensulfate, sulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, cyanate, nitrate, sulfide, and other anions derived from non-organic acids.

3. The process according to claim 1, wherein said step of replacing said halide counteranion is at least one process selected from the group consisting of:

(a) exchanging said halide counteranion with said non-halide counteranion via an ion exchange resin;

(b) forming an acid of said halide counteranion and thereafter adding a stronger acid than said acid of said halide counteranion to thereby drive said weaker acid or said halide counteranion out of said phenothiazinium compound;

(c) forming an acid of said halide counteranion and driving said acid of said halide counteranion out of said phenothiazinium compound using oxidation to remove the evolving HX as X2; and

(d) introducing a non-halide counteranion salt to a salt of said halide counteranion containing phenothiazine mixture, and separating and removing said halide counteranion, wherein a non-halide counteranion salt of phenothiazine produced.

4. The process according to claim 1, wherein said step of replacing said halide counteranion comprises: forming a less soluble hydroxide salt of said halide counteranion; and adding an acid of said non-halide counteranion to said hydroxide salt.

5. The process according to claim 1, wherein said halogen is selected from the group consisting of: bromine, iodine, chlorine and mixtures thereof.

6. The process according to claim 1, wherein said amine is a dialkylamine selected from the group consisting of: diisoalkylamine, di-n-alkylamine and n-alkyl-iso-alkyl-amine.

7. The process according to claim 6, wherein said dialkylamine is selected from the group consisting of: diisopropylamine, diisobutylamine, diisopentylamine, di-n-propylamine, di-n-butylamine, di-n-pentylamine, ethyl-isopropylamine and mixtures thereof.

8. The process according to claim 1, wherein said reaction occurs at a temperature in the range between about −5° C. to 55° C.

9. The process according to claim 1, wherein said phenothiazine has the formula:

10. The process according to claim 1, further comprising:

filtering said phenothiazinium compound.

11. The process according to claim 1, wherein said reaction is carried out in a single reactor.

12. The process according to claim 11, wherein said phenothiazine and said amine are mixed together, followed by addition of said halogen.

13. The process according to claim 8, wherein said reaction occurs at a temperature in the range between about −5° C. to 20° C.

14. The process according to claim 8, wherein said reaction occurs at a temperature in the range between about 50° C. to 55° C.

15. A process for producing a phenothiazinium compound comprising the step of:

reacting phenothiazine, in the presence of a bromine, with at least one dialkylamine; and

replacing said bromine with a non-halide counteranion.

16. The process according to claim 15, wherein said non-halide counteranion is at least one selected from the group consisting of mono- or di-carboxylic acid anions having a carbon chain length of between about 1 to 6, hydrogensulfate, sulfate, phosphate, hydrogenphosphate, dihydrogenphosphate, cyanate, nitrate, sulfide, and other anions derived from non-organic acids.

17. The process according to claim 15, wherein said step of replacing said bromine is at least one process selected from the group consisting of:

(a) exchanging said bromine with said non-halide counteranion via an ion exchange resin;

(b) forming an acid of said bromine and thereafter adding a stronger acid than said acid of said bromine to thereby drive said weaker acid or said bromine out of said phenothiazinium compound;

(c) forming an acid of said bromine and driving said acid of said bromine out of said phenothiazinium compound using oxidation to remove the evolving HX as X2; and

(d) introducing a non-halide counteranion salt to a salt of said bromine containing phenothiazine mixture, and separating and removing said bromine, wherein a non-halide counteranion salt of phenothiazine produced.

18. The process according to claim 15, wherein said step of replacing said bromine comprises: forming a less soluble hydroxide salt of said bromine; and adding an acid of said non-halide counteranion to said hydroxide salt.

19. The process according to claim 15, wherein said phenothiazinium compound has the general formula: wherein A and B are each selected from the group consisting of: wherein R1 and R2 are each independently linear or branched CnH2nY, n is 1 to 6, and where X− is a bromide counteranion.

20. The process according to claim 15, wherein said dialkylamine is selected from the group consisting of: diisopropylamine, diisobutylamine, diisopentylamine, di-n-propylamine, di-n-butylamine, di-n-pentylamine, ethyl-isopropylamine and mixtures thereof.

21. The process according to claim 15, wherein said dialkylamine is di-n-propylamine.

22. The process according to claim 15, wherein said dialkylamine is di-n-butylamine.

23. The process according to claim 15, wherein the bromination takes place in the presence of an alcohol.

24. The process according to claim 15, wherein said reaction occurs at a temperature in the range between about −5° C. to 55° C.

25. The process according to claim 15, wherein said phenothiazine has the formula: