# US 12,215,234 B2 · Process for the purification of methylene blue

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- Number: US 12,215,234 B2
- Document ID: US12215234B2
- Status: Granted
- Kind: B2
- Application number: 17/023,544
- Filed: 2020-09-17
- Published: 2022-02-17
- Granted: 2025-02-04
- Earliest claimed: 2019-09-21
- Assignees: RK Pharma Solutions LLC
- Applicants: RK Pharma Solutions LLC
- Inventors: Ravishanker Kovi; Jayaraman Kannappan; Hemant Mande; Dusanapudi Naga Venkata Raghavulu
- Web page: https://patentgrep.com/patent/US12215234B2

## CPC

- C07D 279/18: [b, e]-condensed with two six-membered rings
- C09B 21/00: Thiazine dyes
- C09B 67/0034: {Mixtures of two or more pigments or dyes of the same type}
- C09B 67/0096: {Purification; Precipitation; Filtration}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- C09B: ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES {, e.g. PIGMENTS}; MORDANTS; LAKES (fermentation or enzyme using processes to synthesise a desired chemical compound C12P)

## Abstract

The present application provides method for producing methylene blue that includes the steps of providing a reaction mixture having one or more methylene blue intermediates; precipitating metal from the reaction mixture; and producing therefrom crude methylene blue. The crude may further be purified, resulting in methylene compounds having low impurities, preferably having a purity greater than about 97%, having Azure B impurity no greater than 2.5%, and/or a total metal content no greater than 77 ppm. Formulations containing such compounds are also provided.

## Claims

### Claim 1

A method for producing methylene blue comprising:
a) providing a reaction mixture comprising one or more methylene blue intermediates;
b) reducing the metal content therein by precipitation during solvent extraction under basic conditions wherein the basic condition is between about pH 9 and about pH 11; to form a reaction mass;
c) producing crude methylene blue by further adjusting the pH of the reaction mass to an acidic pH with acid;
d) purifying the crude methylene blue by treatment with polar solvent to remove the impurity at 0.94 RRT;
e) producing methylene blue having purity greater than about 97% by repeating steps (b) and (c) followed by purification using water and THF; wherein, providing the reaction mixture comprises,
I. reacting N,N-dimethylaniline
N,N-dimethylaniline
with sodium nitrite in hydrochloric acid to obtain an in-situ nitroso compound;
nitroso compound
II. reducing the in-situ nitroso compound
nitroso compound
in the presence of zinc and hydrochloric acid to obtain in-situ p-amino-N,N-dimethyl aniline;
p-amino-N,N-dimethyl aniline
III. reacting the in-situ p-amino-N,N-dimethyl aniline
p-amino-N,N-dimethyl aniline
with sulfuric acid and zinc chloride in the presence of sodium thiosulfate pentahydrate, sodium dichromate, and aluminium sulphate octahydrate to obtain an in-situ thiosulfonic acid compound;
thiosulfonic acid compound
IV. treating the in-situ thiosulfonic acid compound
thiosulfonic acid compound
with another molecule of N,N-dimethylaniline in the presence of sodium dichromate and zinc chloride to yield an in-situ di-cyclic compound;
Di-cyclic compound
and
V. allowing the in-situ di-cyclic compound
Di-cyclic compound
to undergo a cyclisation reaction in the presence of manganese oxide to yield methylene blue crude;
Methylene blue crude.

### Claim 2 (depends on 1)

The method of claim 1, comprising purifying the methylene blue crude using a polar solvent comprising acetic acid to obtain methylene blue.