A Process for the Preparation of Methylene Blue

Abstract

Provided herein is a process for preparation of 3,7-bis-(dimethylamino)-phenothian-5-ium chloride: Formula (I). The said process comprises preparing 3,7-dibromophenothiazin-5-ium bromide wet Crude(III) from phenothiazine (II) along promoter, catalyst and brominating agent in presence of 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 subsequently purifying and removing metal content through metal scavenger from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I). The present process eliminates the additional step of ion exchange column in the reaction and provides 99 to 99.5 percentage of product purity.

##STR00001##

Claims

1. A process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride (I); wherein said process comprises the steps; ##STR00010## (a) Preparing of 3,7-dibromophenothiazin-5-ium bromide wet Crude(III) from phenothiazine (II) along promoter, catalyst and brominating agent in presence of organic solvent; (b) Preparing of 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) from 3,7-dibromophenothiazin-5-ium bromide; (c) Preparing of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride from 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide; (d) Purifying and removing metal content through metal scavenger from 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I).

2. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein catalysts are metal catalyst and boron trifluoride acetic acid complex.

3. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein said promotor is p-toluene sulfonic acid (PTSA).

4. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, using the reagent dimethylamine (DMA).

5. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein said brominating agents are selected form but not limited to bromine and 1,3-dibromo-5,5-dimethylhydantoin.

6. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein said organic solvent are selected from but not limited to the ethyl acetate, methanol, acetic aid isopropyl alcohol, hydrochloride acid (HC1), chloroform, dichloromethane, methylacetate, butylacetate and mixture thereof.

7. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein said metal scavenger are selected from but not limited to polymers resins materials, silica based micropores, silicycle triamine, Quadrasil MP, Aliquat 336, 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, mixture of metal scavengers on silica gel, N-Propyldiethanolamine-functionalized silica gel ≥99 percentage or QuadraPure® AEA, QuadraPure® AMPA macroporous, QuadraPure® BDZ, QuadraPure® BZA, QuadraPure® EDA, QuadraPure® IDA macroporous, QuadraPure® MPA, QuadraPure® TU macroporous, 3-(1-Thioureido) propyl, Triamine tetraacetate, silica-supported, Triaminetetraacetate, sodium salt-functionalized silica gel, Triaminetetraacetic acid-functionalized silica gel, triamine tetracetate, 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, phosphonic S SPM32 are within the range of <1 ppm to 10 ppm and more preferably <1 ppm to 3 ppm.

8. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein percentage organic impurities is in the range of 0.1 to 0.35 percentage.

9. The process for preparation of 3,7-bis (Dimethylamino)-phenothiazin-5-ium chloride as claimed in claim 1;, wherein the percentage purity is in the range of 99 to 99.5 percentage.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0028] The present invention provides a process for the preparation of methylene blue with high purity.

[0029] The present process of methylene blue eliminates the additional step of ion exchange column in the reaction. The invention reduces the percentage of organic and inorganic impurities thereby increases efficiency and reduces the cost of the process.

[0030] The process of methylene blue consist of phenothiazine (II) which reacts with a promotor, p-toluene sulfonic acid (PTSA).

##STR00005##

[0031] The catalysts are selected as but not limited to metal catalyst and boron trifluoride acetic acid complexes. Wherein, the boron trifluoride acetic acid complexes with water such as boron trifluoride hydrate (BF.sub.3.H.sub.2O). The complexes of boron trifluoride acetic acid with alcohols, ethers, carboxylic acid esters, and nitriles are selected but not limited to boron fluoride ethyl acetate complex (C.sub.4H.sub.8O.sub.2.BF.sub.3), boron fluoride methyl benzoate complex, boron fluoride methanol complexes (BF.sub.3—CH.sub.3OH), boron fluoride ethanol complex (BF.C.sub.2H.sub.5OH), boron fluoride glycol complex BF.sub.3—(CHOH).sub.2, boron trifluoride etherate (C.sub.4H.sub.10BF.sub.3O), boron trifluoride methyl amyl ether complex BF.sub.3.C.sub.6H.sub.14O, boron trifluoride anisole complex BF.sub.3.C.sub.6H.sub.5OCH.sub.3, boron trifluoride tetrahydrofuran complex BF.sub.3—C.sub.4H.sub.8O, boron trifluoride dioxan complex BF.sub.3—C.sub.4H.sub.8O.sub.2, boron trifluoride acetonitrile complex BF.sub.3—CHCN, boron trifluoride benzonitrile complex BF.sub.3.CH.sub.5CN, boron trifluoride complexes with o-, m- and p-toluonitrile. Said metal catalyst is selected from, but not limited to the group VIII metals of the Periodic Table, for example, iron, cobalt, nickel. In other embodiments, said metal catalyst is selected but not limited to in the group IB metals of the Periodic Table, for example, copper and/or silver. In other embodiments, said metal catalyst is selected in the group IIIB & IIIA metals of the Periodic Table.

[0032] The bromination compounds are selected from but not limited to 1,3-dibromo-5,5-dimethylhydantoin and bromine. The 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) is prepared by adding Diemethylamine (DMA) and organic solvents. The organic solvents are selected from polar solvents and non polar solvents but not limited to the ethyl acetate, methanol, acetic aid isopropyl alcohol, aqueous hydrochloric acid, hydrochloride acid (HCl), chloroform and polar protic and aprotic solvents such as dichloromethane, methylacetate, butylacetate and mixture thereof.

[0033] The metal scavenger eliminates the metal impurities from the product. The metal scavenger are selected from but not limited to polymers resins 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, Mixture of metal scavengers on silica gel, N-Propyldiethanolamine-functionalized silica gel ≥99 percentage or QuadraPure® AEA, QuadraPure® AMPA macroporous, QuadraPure® BDZ, QuadraPure® BZA, QuadraPure® EDA, QuadraPure® IDA macroporous, QuadraPure® MPA, QuadraPure® TU macroporous, 3-(1-Thioureido) propyl, Triamine tetraacetate, silica-supported, Triaminetetraacetate, sodium salt-functionalized silica gel, Triaminetetraacetic acid-functionalized silica gel, Triamine tetracetate, sodium salt, silica-supported, N,N,N′-Trimethylethylenediamine, polymer-bound, Biotage® MP-TMT or ISOLUTE® Si-TMT or ISOLUTE® Si-Thiol or ISOLUTE® SCX-2 or ISOLUTE® Si-Trisamine or Phosphonics SPM32. Said metal scavengers reduce the metal content within the range of <1 ppm to 10 ppm in the methylene blue; wherein more preferably <1 ppm to 3 ppm.

[0034] In a preferred embodiment the present improved process for preparation of methylene blue, which comprising the steps of;

Step (a): Preparing of 3,7-dibromophenothiazin-5-ium bromide i.e Formula (III) from Phenothiazine (II)

[0035] Phenothiazine (II) is charged into round bottom flask under nitrogen gas atmosphere along with p-toluene sulfonic acid (PTSA), catalyst and brominating agent in presence of organic solvents, as shown in scheme 1. Wherein, the catalyst are selected from but not limited to metal catalyst and boron trifluoride acetic acid complex. The bromination compounds are selected from but not limited to 1,3-dibromo-5,5-dimethylhydantoin and bromine. The organic solvents are selected from but not limited to ethyl acetate, methanol, acetic acid and chloroform.

##STR00006##

[0036] The reaction is stirred at the temperature −20° C. to −30° C. to prepare 3,7-dibromophenothiazin-5-ium bromide (III).

##STR00007##

Step (b): Preparing of 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV)

[0037] To the product 3,7-dibromophenothiazin-5-ium bromide (III) which is obtained in above step (a), 40% of dimethylamine (DMA) solution is added in presence of organic solvent while stirring the reaction mass at −25° C. to −30° C. to give the product, 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV).

##STR00008##

Step (c): Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)

[0038] 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) obtained in above step (b) is dissolved in organic solvent followed by the addition of 0.5M HCl solution. The reaction is refluxed for 2 to 3 hours at 40° C. to 80° C. temperature. The metal scavenger is added to the reaction mixture at 50° C. temperature and allowed to settle at 15° C.-20° C. temperature. The product washed with cold organic solvent and dried to give the product 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)

##STR00009##

[0039] The present invention provides a process for preparation of methylene blue which eliminates the additional step of ion exchange column in the reaction and provide 99 to 99.5 percentage of purity.

EXAMPLES

Example-1 (A)

[0040] Phenothiazine (II) (100 g) is charged into Round bottom flask under Nitrogen gas atmosphere followed by the addition of ethyl acetate at room temperature. To this mixture Boron trifluoride acetic acid complex (19 g) was added. The temperature was brought to −20° C. PTSA.H.sub.2O (p-toluene sulfonic acid) (6 gm) was added to this mixture followed by the drop-wise addition of bromine solution (64 ml). The reaction was maintained for 2 h at −20 to −25° C. To this mixture, methanol was added followed by the drop wise addition of 40% aqueous DMA (450 g) solution. The reaction mass washed with ethyl acetate (200 ml) solution to obtain 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) as crude.

Example-1(B) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)

[0041] 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (137 g) which is obtained as above is taken into separate round bottom flask under nitrogen gas atmosphere. To this mixture, methanol (520 ml) was added. The reaction was maintained at 50-55° C. with constant stirring for 1 h. The product thus obtained was filtered and washed with methanol and dried. To this mass, a mixture of methanol and 0.5M HCl solution was added. The reaction was heated at 50-55° C. for 1 hour with constant stirring. The reaction was allowed to cool followed by filtration and washing with methanol to give the product.

Example-2 (A)

[0042] Phenothiazine (II) (7.5 kg) is charged into Round bottom flask under Nitrogen gas atmosphere followed by addition of ethyl acetate at room temperature. To this mixture aluminium chloride (22.5 gm) was added. The temperature was brought to −25° C. followed by the drop wise addition of bromine solution (15 kg). The reaction was maintained for 2 h at −20 to −25° C. To this mixture, methanol was added followed by the drop wise addition of 40% aqueous DMA solution. The reaction mass washed with ethyl acetate (200 ml) solution to obtain 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (IV) as crude.

Example-2(B) Preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride (I)

[0043] 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide (6.35 g) which is obtained as above is taken into separate round bottom flask under nitrogen gas atmosphere. To this mixture, methanol (3.8 l) was added. The reaction was maintained at 50-55° C. with constant stirring for 1 h. The product thus obtained was filtered and washed with methanol and dried. To this mass a mixture of methanol and 0.5M HCl solution was added. The reaction was heated at 50-55 ° C. for 1 hour with constant stirring. The reaction was allowed to cool followed by filtration and washing with methanol to give the product.

Example-3 (A) Purification of Methylene Blue

[0044] Methylene blue (75 g) as obtained by the above method is charged into Round bottom flask under Nitrogen gas atmosphere followed by addition of methanol (137 ml) at room temperature. To this mixture 0.5M HCl solution (548 ml) was added. The reaction was heated at 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 h. The product thus obtained was filtered and washed with methanol and dried to give the pure product (I).

Example-3 (B)

[0045] Methylene blue (75 g) as obtained by the above method is charged into Round bottom flask under Nitrogen gas atmosphere followed by addition of 0.2M HCl solution (1100 ml) at room temperature. The reaction was heated at 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 h. The product thus obtained was filtered and washed with methanol and dried to give the pure product (I).

Example-3 (C)

[0046] Methylene blue (50 g) as obtained by the above method is charged into Round bottom flask under Nitrogen gas atmosphere followed by addition of 0.2M HCl solution (733 ml) at room temperature. The reaction was heated at 50-55° C. with constant stirring. To this mixture Aliquat 336 (0.25 g) was added. The reaction was maintained at 55-60° C. with constant stirring for 1 h. The product thus obtained was filtered and washed with methanol and dried to give the pure product (I).

TABLE-US-00001 TABLE 1 Results of different batches of Example-1 and 2 are described here. Example No. Ingredient/Parameters (1) (2) Reactant Phenothiazine Phenothiazine Catalyst Boron trifluoride acetic Aluminium chloride acid complex Bromination Bromine Bromine Dimethylamine 35-40% (Aq DMA) 35-40% (Aq DMA) % Purity 99.40% 99.50% % Impurities-A 0.40% 0.26%

TABLE-US-00002 TABLE 2 Results of different batches of Example-3 (A, B & C) are described here. Example No. Ingredient (A) (B) (C) Metal scavengers Silicycle Quadrasil Aliquat triamine MP 336 % Purity 99.6 99.6 99.6 Impurities Impurities A 0.31 0.32 0.30 (%) Unspecified 0.04 0.05 0.05 impurities Total impurities 0.09 0.13 0.10 other than A *HPLC method and specifications according to USP and European Pharmacopoeia.

TABLE-US-00003 TABLE 3 Metal contents (ppm) in results of different batches of Example-3 (A, B & C) are described below; Metal Content (ppm) Sr. No. As Al Cd Cr Cu Fe Hg Mo Ni Pb Zn Mn Sn Ex. 3 (A) 0.01 7.4 0.02 0.67 0.49 8.2 0.08 1.89 0.41 0.19 2.4 — — Ex. 3 (B) 0.01 8.2 — 0.08 1.21 11.7 — 3.63 0.15 0.06 1.8 0.1 — Ex. 3 (C) 0 7.8 0 0 0.04 7.9 0 0.12 0 0 1.3 0.1 0

[0047] The illustration of the present invention is performed by HPLC, in which 98 to 99.7 percentage of purity is obtained by the methylene blue. The metal content is detected through ICP-MS (inductively coupled plasma-mass-spectrometry) device.