Process for producing methylene blue

Abstract

The present disclosure provides a method for producing 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride of formula (I). TIFF2023515614000014.tif3652 The method includes preparing a wet crude 3,7-dibromophenothiazin-5-ium bromide (III) from phenothiazine (II) together with a promoter, a catalyst, and a brominating agent in the presence of an organic solvent; preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide; preparing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide; and then 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide. The method involves purifying 3,7-bis-(dimethylamino)-phenothiazine-5-ium chloride (I) and removing metal components from the chloride (I) using a metal scavenger. This method eliminates the additional step of an ion exchange column in the reaction and provides a product purity of 99-99.5%.

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention relates to a method (or process) for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazine-5-ium chloride (I). More specifically, the present invention relates to a method (or process) for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazine-5-ium chloride (I) of the following formula (I) in high purity.

[0002] [ka] [Background technology]

[0003] BACKGROUND OF THE INVENTION 3,7-Bis-(dimethylamino)-phenothiazine-5-ium chloride (also known as methylthioninium chloride, methylene blue, or MTC) is a well-known phenothiazine dye for hair, leather, and cellulose fibers; a redox indicator; a photosensitizer for singlet oxygen generation; an antioxidant; a preservative stain for fixed biological tissues; and a diagnostic agent for renal function testing. Methythioninium chloride (MTC), also known as methylene blue, is a low-molecular-weight (319.86) water-soluble tricyclic organic compound.

[0004] Methylene blue has many applications in various fields (e.g., biology and chemistry). At room temperature, it appears as a solid, odorless, dark green powder; however, when dissolved in water, it produces a blue solution. Methylene blue should not be confused with methyl blue (another histological stain), new methylene blue, or methyl violet (commonly used as a pH indicator).

[0005] Methylene blue is a component of a frequently prescribed urinary tract analgesic / anti-infective / antispasmodic known as "Prosed" (a combination drug that also contains phenylsalicylate, benzoic acid, hyoscyamine sulfate, and methenamine (also known as hexamethylenetetramine, not to be confused with "methanamine").

[0006] Methylene blue is also a well-known phenothiazine dye and redox indicator, and has been used as a redox mediator, an intercalator in nanoporous materials, and an optical probe in biophysical systems. See, for example, Color Index (Vol. 4, 3rd edition, 1971), Lillie et al., 1979, and references cited therein. Currently, methylene blue is used to treat methemoglobinemia, a condition that occurs when the blood is unable to deliver oxygen to the body where it is needed.

[0007] Methylene blue is also used as a medical dye (e.g., to stain certain areas of the body before or during surgery), a diagnostic agent (e.g., as an indicator dye to detect certain compounds present in urine), a mild urinary tract disinfectant, an irritant for mucosal surfaces, the treatment and prevention of kidney stones, and the diagnosis and treatment of melanoma.

[0008] Methylene blue was first described in a German patent in 1877 (Badische Anilin- und Soda-Fabrik, 1877). There, methylene blue was synthesized by nitrosylation of dimethylaniline, followed by reduction to form N,N-dimethyl-1,4-diaminobenzene, followed by oxidative coupling in the presence of hydrogen sulfide (HS) and iron(III) chloride (FeCl3). Therefore, this patent uses more metal ions, thereby increasing the metal content of the product. Summary of the Invention [Problem to be solved by the invention]

[0009] (Prior Art and Its Drawbacks) Canadian Patent Application No. CA2579169C relates to the field of chemical synthesis and purification, and more specifically to a method for synthesizing and purifying certain 3,7-diamino-phenothiazin-5-ium compounds, including methythioninium chloride (MTC), also known as methylene blue, which comprises the steps of nitrosylation; nitrosyl reduction with thiosulfonic acid formation; oxidative coupling; Cr(VI) reduction; isolation and purification of the zwitterionic intermediate; ring closure; chloride salt formation, and one of the following steps: sulfide treatment; dimethyldithiocarbamate treatment; carbonate treatment; ethylenediaminetetraacetic acid (EDTAT) treatment; organic extraction, and recrystallization. The invention also relates to the resulting compounds, compositions containing them (e.g., tablets, capsules), and their use in methods of pathogen inactivation, methods of medical treatment and diagnosis, etc. (e.g., tauopathies, Alzheimer's disease (AD), skin cancer, melanoma, viral, bacterial, or protozoal diseases). The present invention now provides an improved method (or process) for the production (or preparation) of high purity methylene blue having reduced metal content in the final formula (I). The above patent applications fail to provide (or do not disclose) an improved method for producing high purity 3,7-diamino-phenothiazin-5-ium compounds, and also fail to disclose (or do not disclose) a method for reducing the metal content of the 3,7-diamino-phenothiazin-5-ium compounds.

[0010] European Patent Application No. EP 3375777 A1 relates to a method (or process) for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide or chloride; a method for converting 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide to 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride; and purification of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride by crystallization from aqueous hydrochloric acid to provide pharmaceutically acceptable 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride of Formula I shown below (methylthioninium chloride, methylene blue, MTC).

[0011] [ka]

[0012] However, the above patent application discloses a method (or process) for producing (or preparing) 3,7-bis-(dimethylamino)-phenothiazine-5-ium bromide or chloride using phenothiazine in the presence of a metal catalyst. In the above patent application, an ion exchange column step is added for purification, which increases the number of processing steps, making the process more costly and complicated. In contrast, the present invention provides an improved method (or process) for the production (or preparation) of methylene blue, which eliminates the additional step of an ion exchange column, thereby reducing the cost of the process. Thus, the above applications fail to provide (or do not disclose) an improved method (or process) for the production (or preparation) of methylene blue with high purity.

[0013] US Patent Application No. US20090291943A1 relates to a process for producing diaminophenothiazinium compounds, which includes a step for purifying the derivatives. In contrast, the present invention provides an improved method (or process) for the production (or preparation) of methylene blue with high purity and high yield, which reduces the metal component (or metal content) in the final formula I. Furthermore, the above patent applications fail to (or do not disclose) reducing the metal components (or metal content) present in methylene blue. In contrast, the present invention provides a reduction in the metal component (or metal content) in methylene blue.

[0014] U.S. Patent Application No. US20200010438A1 relates to a method for producing 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide, which uses phenothiazine as a starting material and includes the following steps (a) and (b): (a) Treating phenothiazine with diiodine (or diiodine) (b) treating the reaction medium obtained directly from step (a) above with dimethylamine However, the above patent applications disclose different processes using different reagents, and also fail to (or do not disclose) reducing the metal component (or metal content) in methylene blue. Thus, the above applications fail to provide (or do not disclose) an improved method (or process) for the production (or preparation) of methylene blue with high purity.

[0015] Thus, there is an unmet need for an improved method (or process) for producing (or preparing) methylene blue in high yield and high purity.

[0016] (Disadvantages of the prior art) As listed below, conventional methylene blue manufacturing methods (or processes) have many disadvantages (or drawbacks). 1. Conventional methods (or processes) fail to provide an improved method (or process) for producing (or preparing) methylene blue with high purity. 2. In most of the conventional methods (or processes), the percentage of metals contained in methylene blue is high. 3. Most of the conventional methods (or processes) use an additional process (or step) of an ion exchange column to produce (or prepare) methylene blue. 4. In most of the existing prior art methods (or processes), methylene blue contains a high percentage of impurities, which reduces the efficiency and increases the cost of the product.

[0017] (Object of the invention) The primary object of the present invention is to provide a method (or process) for producing (or preparing) methylene blue with a high percentage of purity. Another object of the present invention is to provide a method (or process) for the manufacture (or preparation) of methylene blue that achieves pharmaceutical grade. It is yet another object of the present invention to provide a method or process for the production of methylene blue, which has a low percentage of metal content. Yet another object of the present invention is to provide a method (or process) for the production (or preparation) of methylene blue which eliminates the additional step of an ion exchange column in the reaction. Yet another object of the present invention is to provide a method (or process) for producing (or preparing) methylene blue which reduces the percentage of organic and inorganic impurities, thereby increasing the efficiency of the process and reducing the cost of the process. [Means for solving the problem]

[0018] (Summary of the Invention) Method (or process) for producing (or preparing) 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride (I) The process includes the following steps:

[0019] [ka]

[0020] (a) preparing 3,7-dibromophenothiazine-5-ium bromide (III) from phenothiazine (II) in the presence of an organic solvent, together with a promoter (or accelerator), a catalyst and a brominating agent; (b) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide; (c) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide; (d) Purifying the product and removing metal components (or metal contents or metal content) from 3,7-bis-(dimethylamino)-phenothiazine-5-ium chloride (I) with a metal scavenger. DETAILED DESCRIPTION OF THE INVENTION

[0021] (Detailed Description of the Invention) The present invention provides a method (or process) for producing (or preparing) methylene blue with high purity. The method of methylene blue eliminates the additional step of an ion exchange column in the reaction. The present invention reduces the percentage of organic and inorganic impurities, thereby improving the efficiency and reducing the cost of the process. The method of methylene blue consists of reacting phenothiazine (II) with p-toluenesulfonic acid (PTSA), a promoter.

[0022] [ka]

[0023] The catalyst is selected from, but is not limited to, a metal catalyst and a boron trifluoride-acetic acid complex. Here, the boron trifluoride-acetic acid complex contains water. For example, boron trifluoride hydrate (BF3·H2O). Complexes of boron trifluoride-acetic acid with alcohols, ethers, carboxylic acid esters, or nitriles include boron fluoride-ethyl acetate complex (C4H8O2·BF3), boron fluoride-methylbenzoate complex, boron fluoride-methanol complex (BF3-CH3OH), boron fluoride-ethanol complex (BF·C2H5OH), boron fluoride-glycol complex (BF3-(CHOH)2), boron trifluoride-etherate (C4H 10 BF3O), boron trifluoride-methyl amyl ether complex (BF3·C6H 14 The boron trifluoride complex may be selected from, but is not limited to, boron trifluoride-anisole complex (BF3·C6H5OCH3), boron trifluoride-tetrahydrofuran complex (BF3-C4H8O), boron trifluoride-dioxane complex (BF3-C4H8O2), boron trifluoride-acetonitrile complex (BF3-CHCN), boron trifluoride-benzonitrile complex (BF3·CH5CN), and boron trifluoride complex with o,m,p-toluonitrile. The metal catalyst is selected from, but not limited to, Group VIII metals of the periodic table (eg, iron, cobalt, nickel). In other embodiments, the metal catalyst is selected from, but is not limited to, Group IB metals of the periodic table (eg, copper and / or silver). In other embodiments, the metal catalyst is selected from metals in Groups IIIB and IIIA of the periodic table.

[0024] The brominating compound (or brominating compound or brominating agent) is selected from, but not limited to, 1,3-dibromo-5,5-dimethylhydantoin and bromine. 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) is prepared by adding dimethylamine (DMA) and an organic solvent. The organic solvent is selected from polar and nonpolar solvents, including, but not limited to, ethyl acetate, methanol, acetic acid, isopropyl alcohol, aqueous hydrochloric acid (or aqueous hydrochloric acid), hydrochloric acid (HCl), chloroform, and polar protic and aprotic solvents, such as dichloromethane, methyl acetate, butyl acetate, and mixtures thereof.

[0025] Metal scavengers remove metal impurities from the product. Metal scavengers include polymeric resin materials, silica-based micropores, silicycle triamine, Quadrasil MP, Aliquat 336, AMPA-functionalized silica gel (≥99%), bipyridine (polymer-bound) (100-200 mesh), cysteine-functionalized silica gel, 3-(diethylenetriamino)propyl-functionalized silica gel, DL-dithiothreitol (polymer-bound), DMT-functionalized silica gel, DOTA-functionalized silica gel, ethylenediaminetriacetic acid acetamide (polymer-bound), 3-(ethylenediamino)propyl-functionalized silica gel, 2-mercaptoethylamine (polymer-bound), 3-mercaptopropyl-functionalized silica gel, mixtures of metal scavengers on silica gel, N-propyldiethanolamine-functionalized silica gel (≥99%), or QuadraPure® AEA, QuadraPure® AMPA (macroporous), QuadraPure® BDZ, Quadr The metal scavengers may be selected from, but are not limited to, aPure® BZA, QuadraPure® EDA, QuadraPure® IDA (macroporous), QuadraPure® MPA, QuadraPure® TU (macroporous), 3-(1-thioureido)propyl, triamine tetraacetate (silica supported), silica gel functionalized with triamine tetraacetate sodium salt, silica gel functionalized with triamine tetraacetate, triamine tetraacetate sodium salt (silica supported), N,N,N'-trimethylethylenediamine (polymer bound), Biotage® MP-TMT, ISOLUTE® Si-TMT, ISOLUTE® Si-Thiol, ISOLUTE® SCX-2, ISOLUTE® Si-Trisamine, or Phosphon SPM32. <1 ppm to 10 ppm More preferably, the metal components (or metal contents) are reduced to within the range of <1 ppm to 3 ppm.

[0026] In a preferred embodiment, the improved method (or process) of the present invention for producing (or preparing) methylene blue comprises the following steps:

[0027] Process (a) Preparation of 3,7-dibromophenothiazine-5-ium bromide (i.e., formula (III)) from phenothiazine (II) As shown in Scheme 1, phenothiazine (II) is charged into a round-bottom flask under a nitrogen gas atmosphere together with p-toluenesulfonic acid (PTSA), a catalyst, and a brominating agent in the presence of an organic solvent. Here, the catalyst is selected from, but not limited to, a metal catalyst and a boron trifluoride-acetic acid complex. The compound for bromination (or brominating compound or brominating agent) is selected from, but not limited to, 1,3-dibromo-5,5-dimethylhydantoin and bromine. The organic solvent is selected from, but not limited to, ethyl acetate, methanol, acetic acid and chloroform.

[0028] [ka]

[0029] The reaction is stirred at a temperature of -20°C to -30°C to prepare 3,7-dibromophenothiazin-5-ium bromide (III).

[0030] [ka]

[0031] Process (b) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide(IV) To the product (3,7-dibromophenothiazin-5-ium bromide (III)) obtained in the above process (a) (or step (a)), 40% dimethylamine (DMA) solution is added in the presence of an organic solvent while stirring the reaction mass at −25° C. to −30° C. to obtain the above-titled product (3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV)).

[0032] [ka]

[0033] Process (c) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride(I) The 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) obtained in the above process (b) (or step (b)) is dissolved in an organic solvent, followed by the addition of 0.5 M HCl solution. The reaction mixture is refluxed at a temperature of 40°C to 80°C for 2 to 3 hours. A metal scavenger is added to the reaction mixture at a temperature of 50°C and allowed to stand at a temperature of 15°C to 20°C. The product is washed with cold organic solvent and dried to obtain the above-titled product (3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)).

[0034] [ka]

[0035] The present invention provides a method (or process) for producing (or preparing) methylene blue, which eliminates the additional step of an ion exchange column in the reaction and provides a purity of 99-99.5%. [Example]

[0036] Example Example 1(A) Phenothiazine (II) (100 g) was charged into a round-bottom flask under nitrogen gas atmosphere. Ethyl acetate was then added at room temperature. To this mixture, boron trifluoride-acetic acid complex (19 g) was added. The temperature was lowered to -20 °C. PTSA·HO (p-toluenesulfonic acid) (6 gm) was added to this mixture. Bromine solution (64 ml) was then added dropwise. The reaction was maintained at -20 to -25 °C for 2 hours. Methanol was added to this mixture. 40% aqueous DMA (450 g) solution was then added dropwise. The reaction mass was washed with ethyl acetate (200 ml) solution to obtain crude 3,7-bis-(dimethylamino)-phenothiazine-5-ium bromide (IV).

[0037] Example 1(B) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride(I) 3,7-bis-(dimethylamino)-phenothiazine-5-ium bromide (137 g) obtained as above was placed in another round-bottom flask under nitrogen gas atmosphere. Methanol (520 ml) was added to this mixture. The reaction was maintained at 50-55°C with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol, and dried. A mixture of methanol and 0.5 M HCl solution was added to this mass, and the reaction was heated at 50-55°C with constant stirring for 1 hour. The reaction was cooled, followed by filtration and washing with methanol to obtain the above-titled product.

[0038] Example 2(A) Phenothiazine (II) (7.5 kg) was charged into a round-bottom flask under nitrogen gas atmosphere. Ethyl acetate was then added at room temperature. To this mixture, aluminum chloride (22.5 gm) was added. The temperature was lowered to -25°C, followed by dropwise addition of bromine solution (15 kg). The reaction was maintained at -20 to -25°C for 2 hours. Methanol was added to the mixture. Subsequently, 40% aqueous DMA solution was added dropwise. The reaction mass was washed with ethyl acetate (200 ml) solution to obtain crude 3,7-bis-(dimethylamino)-phenothiazine-5-ium bromide (IV).

[0039] Example 2(B) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride(I) 3,7-bis-(dimethylamino)-phenothiazine-5-ium bromide (6.35 g) obtained as above was placed in another round-bottom flask under nitrogen gas atmosphere. Methanol (3.8 L) was added to this mixture. The reaction was maintained at 50-55°C with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol, and dried. A mixture of methanol and 0.5 M HCl solution was added to this mass. The reaction was heated at 50-55°C with constant stirring for 1 hour. The reaction was cooled, followed by filtration and washing with methanol to obtain the above-titled product.

[0040] Example 3(A) Purification of methylene blue Methylene blue (75 g) obtained by the above method was charged into a round-bottom flask under nitrogen gas atmosphere. Subsequently, methanol (137 ml) was added at room temperature. To this mixture, 0.5 M HCl solution (548 ml) was added. The reaction was heated to 50-55°C with constant stirring. To this mixture, silicycle triamine (2.0 gm) was added. The reaction was maintained at 55-60°C with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol, and dried to obtain pure product (I).

[0041] Example 3(B) Methylene blue (75 g) obtained by the above method was charged into a round-bottom flask under a nitrogen gas atmosphere. Subsequently, 0.2 M HCl solution (1100 ml) was added at room temperature. The reaction was heated to 50-55°C with constant stirring. To this mixture, Quadrasil MP (2.0 g) was added. The reaction was maintained at 55-60°C with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol, and dried to obtain pure product (I).

[0042] Example 3(C) Methylene blue (50 g) obtained by the above method was poured into a round-bottom flask under a nitrogen gas atmosphere, followed by the addition of 0.2 M HCl solution (733 ml) at room temperature. The reaction mixture was heated to 50-55°C with constant stirring. Aliquat 336 (0.25 g) was added to the mixture. The reaction mixture was maintained at 55-60°C with constant stirring for 1 hour. The product thus obtained was filtered, washed with methanol, and dried to obtain pure product (I).

[0043] [Table 1]

[0044] [Table 2]

[0045] [Table 3]

[0046] The present invention is exemplified by HPLC, where methylene blue is obtained with a purity of 98-99.7%. Metal components are detected by an ICP-MS (inductively coupled plasma mass spectrometry) device. The disclosure of this specification may include the following aspects. (Aspect 1) A method for producing 3,7-bis(dimethylamino)-phenothiazine-5-ium chloride (I), the method comprising the following steps (a) to (d):

change

Claims

1. A method for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride (I), the method comprising the following steps (a) to (d): 【Chemical 1】 (a) reacting phenothiazine (II) with a promoter, a catalyst and a brominating agent in the presence of an organic solvent; 【Chemistry 2】 from 3,7-dibromophenothiazin-5-ium bromide (III) 【Chemistry 3】 preparing (b) 3,7-dibromophenothiazin-5-ium bromide (III) to 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) 【Chemistry 4】 preparing (c) preparing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride (I) from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV); (d) purifying 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) and removing metal components from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I) with a metal scavenger; A method comprising:

2. 2. The method for producing 3,7-bis(dimethylamino)-phenothiazine-5-ium chloride according to claim 1, wherein the catalyst is selected from metal catalysts and boron trifluoride-acetic acid complexes.

3. 2. The method for producing 3,7-bis(dimethylamino)-phenothiazine-5-ium chloride according to claim 1, wherein the promoter is p-toluenesulfonic acid (PTSA).

4. The method for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein dimethylamine (DMA) is used in step (b).

5. 2. The process for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein the brominating agent is selected from bromine and 1,3-dibromo-5,5-dimethylhydantoin.

6. 2. The process for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein the organic solvent is selected from ethyl acetate, methanol, acetic acid, isopropyl alcohol, hydrochloric acid (HCl), chloroform, dichloromethane, methyl acetate, butyl acetate, and mixtures thereof.

7. The metal scavenger is selected from the group consisting of polymer resin materials, silica-based micropores, AMPA-functionalized silica gel (≧99%), bipyridine (polymer-bound), cysteine-functionalized silica gel, 3-(diethylenetriamino)propyl-functionalized silica gel, DL-dithiothreitol (polymer-bound), DMT-functionalized silica gel, DOTA-functionalized silica gel, ethylenediaminetriacetic acid acetamide (polymer-bound), 3-(ethylenediamino)propyl-functionalized silica gel, 2-mercaptoethylamine (polymer-bound), 3-mercaptopropyl-functionalized silica gel.

2. The method for producing 3,7-bis(dimethylamino)-phenothiazin-5-ium chloride according to claim 1, wherein the metal scavenger is selected from the group consisting of silica gel, silica gel functionalized with N-propyldiethanolamine (≧99%), 3-(1-thioureido)propyl functionalized silica gel, triamine tetraacetate (silica supported), silica gel functionalized with triamine tetraacetate sodium salt, triamine tetraacetate functionalized silica gel, triamine tetraacetate sodium salt (silica supported), and N,N,N'-trimethylethylenediamine (polymer bound), and the metal content is reduced to within the range of <1 ppm to 10 ppm.

8. 2. The method for producing 3,7-bis(dimethylamino)-phenothiazine-5-ium chloride according to claim 1, wherein the proportion of organic impurities is in the range of 0.1 to 0.35%.

9. The method for producing 3,7-bis(dimethylamino)-phenothiazine-5-ium chloride according to claim 1, wherein the purity rate is 99-99.5%.

Images