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

Patent metadata

Field	Value
Publication number	US-9765042-B2
Application number	US-201415027400-A
Country	US
Kind code	B2
Filing date	Oct 6, 2014
Priority date	Oct 7, 2013
Publication date	Sep 19, 2017
Grant date	Sep 19, 2017

Abstract

Methods of synthesizing and purifying certain 3,7-diamino-phenothiazin-5-ium compounds (referred to herein as “diaminophenothiazinium compounds”) including Methythioninium Chloride (MTC) (also known as Methylene Blue) are provided.

First claim

The invention claimed is:

1. A method of synthesis of a diaminophenothiazinium compound comprising the steps of, in order:
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;
each of R 1 and R 9 is independently selected from: —H; C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl;
each of R 3NA and R 3NB is independently selected from: C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl;
each of R 7NA and R 7NB is independently selected from: C 1-4 alkyl; C 2-4 alkenyl; and halogenated C 1-4 alkyl; and

and wherein;
the nitrosyl reduction (NR), thiosulfonic acid formation (TSAF), and oxidative coupling (OC) steps are completed in a single reaction vessel.

2. A method of synthesis according to claim 1 , wherein said thiosulfate comprises Na 2 S 2 O 3 .

3. A method of synthesis according to claim 1 , wherein said oxidation in said thiosulfonic acid formation (TSAF) step is by reaction with an oxidizing agent that comprises Cr(VI).

4. A method of synthesis according to claim 1 , wherein said oxidation in said thiosulfonic acid formation (TSAF) step is by reaction with an oxidizing agent that comprises Na 2 Cr 2 O 7 .

5. A method of synthesis according to claim 1 , wherein said reduction in said nitrosyl reduction (NR) step is by reaction with a reducing agent that comprises Fe(O).

6. A method according to claim 1 , wherein said reduction in said nitrosyl reduction (NR) step is by reaction with a reducing agent that comprises metallic iron.

7. A method according to claim 6 , wherein metallic iron is used in excess, and wherein the excess metallic iron is not removed from the reaction mixture after reaction completion.

8. A method of synthesis according to claim 1 , wherein said reduction in said nitrosyl reduction (NR) step is performed under acidic conditions.

9. A method of synthesis according to claim 1 , further comprising, before said nitrosyl reduction (NR) step, the additional step of:
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:

10. A method according to claim 9 , wherein said nitrosylation is performed using a nitrite.

11. A method of synthesis according to claim 10 , wherein said nitrosylation is performed using a sodium nitrite.

12. A method of synthesis according to claim 9 , wherein said nitrosylation is performed under acidic conditions.

13. A method according to claim 9 , wherein the nitrosylation step (NOS) is completed in the same reaction vessel as the nitrosyl reduction (NR), thiosulfonic acid formation (TSAF), and oxidative coupling (OC) steps.

14. A method according to claim 1 further comprising
after the step of oxidative coupling (OC), the step of
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 X is one or more anionic counter ions to achieve electrical neutrality.

15. A method according to claim 14 , wherein the ring closure (RC) step is completed in the same reaction vessel as the nitrosyl reduction (NR), thiosulfonic acid formation (TSAF), and oxidative coupling (OC) steps.

16. A method according to claim 1 , further comprising
after the step of oxidative coupling (OC), and before the step of ring closure (RC) if present, the step of
isolation and purification of zwitterionic intermediate (IAPOZI), in which said [4-{2 -(thiosulfate)-4-(disubstituted amino)-6-(optionally substituted)-phenyl-imino}-3-(optionally substituted)-cyclohexa-2,5-dienylidene]-N,N-disubstituted ammonium, 6, is isolated and purified.

17. A method according to claim 16 , wherein isolation and purification is by filtration followed by washing.

18. A method of synthesis according to claim 14 , comprising said ring closure (RC) step, and the subsequent additional step of:
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:

19. A method of synthesis according to claim 18 , wherein the chloride is hydrochloric acid.

20. A method of synthesis according to claim 19 , wherein chloride salt formation (CSF) is performed at pH of 0 to 2.

21. A method of synthesis according to claim 20 , wherein chloride salt formation (CSF) is performed at pH of about 1.

22. A method of synthesis according to claim 19 , wherein chloride salt formation (CSF) is performed at 20 to 30° C.

23. A method of synthesis according to claim 22 , wherein chloride salt formation (CSF) is performed at a about 25° C.

24. A method of synthesis according to claim 18 , wherein said chloride is sodium chloride.

25. 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-{

Assignees

• Wista Lab Ltd

Inventors

• Sinclair James Peter
• Nicoll Sarah Louise
• Storey John Mervyn David

Classifications

• C07D279/18 Primary

  [b, e]-condensed with two six-membered rings · CPC title

• C07C381/02

  Thiosulfates · CPC title

• C07C209/68

  from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton · CPC title

• C07C209/38

  by reduction of nitroso groups · CPC title

• Y02A50/30

  Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change · CPC title