Method for preparation of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or bromide
The present invention relates to: a process for preparing 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide or chloride; a method of converting 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide to 3,7-bis-(di-methylamino)-phenothiazin-5-ium chloride; and the purification of 7-bis-(di-methylamino)-phenothiazin-5-ium chloride by crystallization from aqueous solution of hydrochloric acid, leading to a pharmaceutically acceptable 3,7-bis-(di-methylamino)-phenothiazin-5-ium chloride (methylthioninium chloride, methylene blue, MTC) of formula I below reported.
1. A process for producing 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or bromide comprising the steps of:
a) reacting chlorine or bromine with phenothiazine, to produce 3,7-dichloro-phenothiazin-5-ium chloride or 3,7-dibromo-phenothiazin-5-ium bromide respectively;
b) adding dimethylamine to the reaction mixture of step a), to produce 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide respectively;
wherein steps a) and b) are carried out without isolation and/or purification of the intermediate formed in step a);
wherein step a) is carried out at a temperature of less than about 10° C.;
wherein step b) is carried out in a suitable solvent system selected from dichloromethane, acetic acid, methylacetate, ethylacetate, butylacetate, chloroform or mixtures thereof; and
wherein step a) is carried out in the presence of a metal catalyst.
2. The process of claim 1 , wherein step a) is carried out at a temperature of less than about 5° C.; or less than about 0° C., or less than about −10° C., between about −20° C. and about −10° C., or at about −15° C.; and further optionally wherein step b) is carried out at a temperature of less than about 20° C., or less than about 10° C., or between about −20° C. and about 10° C., or at about −15° C.
3. The process of claim 1 or 2 , wherein step a) is carried out in ethylacetate; and optionally wherein step b) is carried out in a solvent system selected from methanol, water, ethylacetate, butylacetate or mixtures thereof, or selected from methanol, ethylacetate or mixtures thereof.
4. The process of claim 2 , wherein step a) is carried out at a temperature of between about −20° C. and about −10° C. and step b) is carried out at a temperature of between about −20° C. and about 10° C.
5. The process of claim 1 , the metal catalyst is an iron salt; or iron (III) chloride, or iron (II) sulfate.
6. The process of claim 1 , further comprising step c):
c) purifying the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step b); optionally wherein the purification step c) further comprises slurring the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step b) with dichloromethane, methylacetate, ethylacetate, butyl acetate, methanol, ethanol, 2-propanol, aqueous hydrochloric acid, water or mixtures thereof.
7. The process of claim 1 further comprising:
eluting the 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step b) through an ion exchange column, to exchange bromide with chloride.
8. The process of claim 1 further comprising:
dissolving the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step b) in an aqueous solution of hydrochloric acid and filtering the solution of 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide.
9. The process of claim 1 further comprising:
crystallizing the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step b), wherein the crystallization is carried out in methanol, ethanol, 2-propanol, aqueous hydrochloric acid, water or mixtures thereof.
10. The process of claim 3 , wherein the solvent system in step b) is methanol or ethylacetate or mixtures thereof.
11. The process of claim 6 , wherein purification step c) is conducted at a temperature of from about −5° C. to about 60°.
12. The process of claim 8 , wherein hydrochloric acid is at a concentration from about 0.05 molar to about 2.0 molar solution.
13. The process of claim 9 , wherein the crystallization is carried out in hydrochloric acid at a concentration from about 0.05 molar to about 2.0 molar solution in water.
14. The process of claim 6 further comprising step d):
d) eluting the purified 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step c) through an ion exchange column, to exchange bromide with chloride.
15. The process of claim 6 further comprising:
crystallizing the purified 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride or 3,7-bis-(dimethylamino)-phenothiazin-5-ium bromide obtained in step c), wherein the crystallization is carried out in methanol, ethanol, 2-propanol, aqueous hydrochloric acid, water or mixtures thereof.
16. The process of claim 15 , wherein the crystallization is carried out in hydrochloric acid at a concentration from about 0.05 molar to about 2.0 molar solution in water.
17. The process of claim 7 further comprising:
crystallizing the 3,7-bis-(dimethylamino)-phenothiazin-5-ium chloride, wherein the crystallization is carried out in methanol, ethanol, 2-propanol, aqueous hydrochloric acid, water or mixtures thereof.
18. The process of claim 17 , wherein the crystallization is carried out in hydrochloric acid at a concentration from about 0.05 molar to about 2.0 molar solution in water.