# US 11,078,169 B2 · Method for preparing 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 11,078,169 B2 - Document ID: US11078169B2 - Status: Granted - Kind: B2 - Application number: 16/490,480 - Filed: 2018-02-16 - Published: 2020-01-09 - Granted: 2021-08-03 - Earliest claimed: 2017-03-02 - Assignees: Provepharm Life Solutions - Applicants: Provepharm Life Solutions - Inventors: Michel Feraud; Babak Sayah; Stéphane Queru; Marina Laurent - Web page: https://patentgrep.com/patent/US11078169B2 ## CPC - C07D 279/18: [b, e]-condensed with two six-membered rings - C07D 285/15: Six-membered rings - A61P 7/00: Drugs for disorders of the blood or the extracellular fluid - A61P 25/00: Drugs for disorders of the nervous system - A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics - C09B 21/00: Thiazine dyes - C09B 67/0096: {Purification; Precipitation; Filtration} - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - 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) - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## Abstract Method for preparing 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide, the method resulting in a high purity while being very simple to implement and producing high yields. The method uses phenothiazine as a starting material and includes the following steps: a) treating phenothiazine with diiodine, b) treating the reaction medium directly obtained from step a) with dimethylamine. ## Claims ### Claim 1 A process for preparing 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide, the process using phenothiazine as a starting product and comprising the following steps: a) treating phenothiazine with diiodine in the presence of a solvent, wherein in step a), the solvent is chosen from: an aromatic solvent or acetonitrile, or mixtures thereof; and b) treating the reaction medium directly resulting from step a) with dimethylamine. ### Claim 2 (depends on 1) The process as claimed in claim 1, wherein the treatment with diiodine is carried out with an amount of diiodine, relative to the phenothiazine, that is in a range of from 2.5 molar equivalents to 3.5 molar equivalents. ### Claim 3 (depends on 1) The process as claimed in claim 1, wherein, before step b), the reaction medium resulting from step a) is conditioned at a temperature that is in a range of from 5° C. to 50° C. ### Claim 4 (depends on 1) The process as claimed in claim 1, wherein the treatment with dimethylamine is carried out with at least 7 molar equivalents of dimethylamine relative to the phenothiazine. ### Claim 5 (depends on 1) The process as claimed in claim 1, wherein in step a), the solvent is chosen from: toluene or acetonitrile, or mixtures thereof. ### Claim 6 (depends on 1) The process as claimed in claim 1, wherein, in step b), the dimethylamine is introduced into the reaction medium in a form of a solution in water. ### Claim 7 (depends on 1) The process as claimed in claim 1, wherein a precipitate forms at the outcome of the treatment of step b), and the precipitate is recovered by filtration. ### Claim 8 (depends on 1) The process as claimed in claim 1, wherein the phenothiazine used as the starting product has an organic purity greater than or equal to 98% measured by high performance liquid chromatography, with detection at 246 nm. ### Claim 9 (depends on 1) The process as claimed in claim 1, wherein the phenothiazine used as the starting product comprises less than 20 ppm of metal contaminants. ### Claim 10 (depends on 1) A process for producing a composition comprising 3,7-bis(dialkylamino)phenothiazin-5-ylium iodide, the process comprising the process for preparing the 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide as claimed in claim 1, wherein in the composition, the 3,7-bis(dialkylamino)phenothiazin-5-ylium iodide represents at least 95% of the composition, and the % is measured by HPLC with detection at 246 nm. ### Claim 11 (depends on 1) A process for producing 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride, the process comprising: a) producing the 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide according to the process as claimed in claim 1, and b) converting the 3,7-bis(dimethylamino)phenothiazin-5-ylium iodide into 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride. ### Claim 12 (depends on 11) A process for producing a composition having a 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride content of greater than or equal to 97% as % of area measured by high performance liquid chromatography with detection at 246 nm, the process comprising producing the 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride according to the process as claimed in claim 11. ### Claim 13 (depends on 11) A process for producing a composition comprising less than 20 ppm of metal contaminants, measured by inductively coupled plasma mass spectrometry, the process comprising producing the 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride according to the process as claimed in claim 11. ### Claim 14 (depends on 11) A process for producing a medicament comprising 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride, the process comprising producing the 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride according to the process as claimed in claim 11, and introducing the 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride into a pharmaceutically acceptable medium. ### Claim 15 (depends on 14) The process as claimed in claim 14, wherein the medicament is intended for the treatment of a pathological condition selected from: a tauopathy, a tau protein aggregation disease, mild cognitive impairment (MCI), methemoglobinemia, a viral infection, a bacterial infection, a parasite infection, malaria, a hepatitis C virus (HCV) infection, a human immunodeficiency virus (HIV) infection, a West Nile virus (WNV) infection, Parkinson's disease (PD), septic shock, Alzheimer's disease (AD), and degenerative diseases of the central nervous system.