Methods of chemical synthesis of diaminophenothiazinium compounds including methylthioninium chloride (MTC)

A method of synthesis of a diaminophenothiazinium compound comprising the steps of, in order:

• nitrosylation (NOS), in which an N,N-disubstituted-3-optionally substituted aniline, 1, is 4-nitrosylated to give said N,N-disubstituted-3-optionally substituted-4-nitrosyl aniline, 2:
• nitrosyl reduction (NR), in which an N,N-disubstituted-3-optionally substituted-4-nitrosyl aniline, 2, is reduced to form said N,N-disubstituted-1,4-diamino-5-optionally substituted benzene, 3:
• thiosulfonic acid formation (TSAF), in which an N,N-disubstituted- 1 ,4-diamino-5-optionally substituted benzene, 3, is oxidized in the presence of a thiosulfate to give said thiosulfuric acid S-{2-(amino)-3 -(optionally substitute d)-5 -(disubstituted-amino)-phenyl } ester, 4:
• oxidative coupling (OC), in which a thiosulfuric acid S-{2-(amino)-3-(optionally substituted)-5-(disubstituted amino)-phenyl} ester, 4, is oxidatively coupled to an N,N-disubstituted-3-optionally substituted-aniline, 5, using an oxidizing agent that comprises Cr(VI), to give a [4-{2-(thiosulfate)-4-(disubstituted amino)-6-(optionally substituted)-phenyl-imino}-3-(optionally substituted)-cyclohexa-2,5-dienylidene]-N,N-disubstituted ammonium, 6:
• wherein all of the preceding steps are completed in the same reaction vessel,
• ring closure (RC), in which said isolated and purified [4-{2-(thiosulfate)-4-(disubstituted amino)-6-(optionally substituted)-phenyl-imino}-3-(optionally substituted)-cyclohexa-2,5-dienylidene]-N,N-disubstituted ammonium, 6, is subjected to ring closure to give a 3,7-bis(disubstituted-amino)-1,9-(optionally substituted) -phenothiazin-5-ium salt, 7:
• chloride salt formation (CSF), in which said 3,7-bis(disubstituted-amino)-1,9-(optionally substituted)-phenothiazin-5-ium salt, 7, is reacted with chloride, to give a 3, 7-bis(disubstituted-amino)-1,9-(optionally substituted)-phenothiazin-5 -ium chloride salt, 8:
• wherein each of R1 and R9 is independently selected from:
• —H:
• C1-4alkyl;
• C2-4alkenyl;
• and halogenated C1-4alkyl;
• each of R3NA and R3NB is independently selected from:
• C1-4alkyl;
• C2-4alkenyl;
• and halogenated C1-4alkyl;
• and each of R7NA and R7NB is independently selected from:
• C1-4alkyl;
• C2-4alkenyl and halogenated C1-4alkyl.

A method of synthesis of a diaminophenothiazinium compound comprising the steps of, in order:

• nitrosylation (NOS), in which an N,N-disubstituted-3-optionally substituted aniline, 1, is 4-nitrosylated to give said N,N-disubstituted-3-optionally substituted-4-nitrosyl aniline, 2:
• nitrosyl reduction (NR), in which an N,N-disubstituted-3-optionally substituted-4-nitrosyl aniline, 2, is reduced to form said N,N-disubstituted-1,4-diamino-5-optionally substituted benzene, 3:
• thiosulfonic acid formation (TSAF), in which an N,N-disubstituted-1,4-diamino-5-optionally substituted benzene, 3, is oxidized in the presence of a thiosulfate to give said thiosulfuric acid S-{2-(amino)-3-(optionally substituted)-5-(disubstituted-amino) -phenyl} ester, 4:
• oxidative coupling (OC), in which a thiosulfuric acid S-{2-(amino)-3-(optionally substituted)-5-(disubstituted amino)-phenyl} ester, 4, is oxidatively coupled to an N,N-disubstituted-3-optionally substituted-aniline, 5, using an oxidizing agent that comprises Cr(VI), to give a [4-{2-(thiosulfate)-4-(disubstituted amino)-6-(optionally substituted)-phenyl-imino}-3-(optionally substituted)-cyclohexa-2,5-dienylidene]-N,N-disubstituted ammonium, 6:
• ring closure (RC), in which said isolated and purified [4-{2-(thiosulfate)-4-(disubstituted amino)-6-(optionally substituted)-phenyl-imino}-3-(optionally substituted)-cyclohexa-2,5-dienylidene]-N,N-disubstituted ammonium, 6, is subjected to ring closure to give a 3,7-bis(disubstituted-amino)-1,9-(optionally substituted)-phenothiazin-5-ium salt, 7:
• wherein all of the preceding steps are completed in the same pot,
• chloride salt formation (CSF), in which said 3,7-bis(disubstituted-amino)-1,9-(optionally substituted)-phenothiazin-5-ium salt, 7, is reacted with chloride, to give a 3, 7-b i s(disubstituted-amino)-1,9-(optionally substituted)-phenothiazin-5-ium chloride salt, 8:
• wherein each of R1 and R9 is independently selected from:
• —H, C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl, each of R3NA and R3NB is independently selected from:
• C1-4alkyl, C2-4alkenyl, and halogenated C1-4alkyl, and each of R7NA and R7NB is independently selected from:
• C1-4alkyl, C2-4alkenyl and halogenated C1-4alkyl.