Process for the preparation of methylene blue
Provided herein is a process for preparation of 3,7-bis-(dimethy-lamino)-phenothiazin-5-ium chloride: Formula (I). The said process comprises preparing 3,7-dibromophenothiazin-5-iumbromide wet Crude(III) from phenothiazine (II) alongpro-moter, 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.
1. A process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of formula (I):
wherein said process comprises the steps of:
(a) preparing 3,7-dibromophenothiazin-5-ium bromide wet crude of formula (III)
by reacting phenothiazine of formula (II)
along with a promoter, catalyst and brominating agent in the presence of an organic solvent;
(b) preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide of formula (IV)
from the 3,7-dibromophenothiazin-5-ium bromide of formula (III)
(c) preparing of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of formula (I) from the 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide of formula (IV); and
(d) purifying and removing metal content from the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride of formula (I), using a metal scavenger.
2. The process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of claim 1 , wherein the catalysts are selected from metal catalyst and boron trifluoride acetic acid complex.
3. The process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of 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 of claim 1 , using the reagent dimethylamine (DMA).
5. The process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of claim 1 , wherein said brominating agents are selected from bromine and 1,3-dibromo-5,5-dimethylhydantoin.
6. The process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of claim 1 , wherein said organic solvent is selected from ethyl acetate, methanol, acetic acid isopropyl alcohol, hydrochloride acid (HCl), chloroform, dichloromethane, methylacetate, butylacetate and mixtures thereof.
7. The process for preparation of 3,7-bis (dimethylamino)-phenothiazin-5-ium chloride of as claim 1 , wherein said metal scavenger is selected from polymers 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, mixtures of metal scavengers on silica gel, N propyldiethanolamine-functionalized silica gel, 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 and wherein the metal scavenger is present in an amount 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 of claim 1 , wherein the percentage of 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 of claim 1 , wherein the percentage purity is in the range of 99 to 99.5 percentage.