Process for the preparation of diaminophenothiazinium compounds having a high degree of purity
A process for the preparation of diaminophenothiazinium compounds is described, which allows achieving quickly and effectively a high degree of purity of the same.
1. Process for the preparation of diaminophenothiazinium compounds of formula A having a degree of purity higher than 95%, said process comprising the steps of:
1) providing a crude diaminophenothiazinium compound of formula A:
wherein R 1 , R 2 , R 3 , R 4 are, independently of one another,
a saturated or unsaturated, linear, branched, or cyclic, C1-C6 alkyl group, optionally substituted with one or more functional groups selected from a halogen atom, a C1-C4 alkoxy, a C1-C4 alkyloxycarbonyl, or —CONH 2 ,
an aryl group optionally substituted with one or more functional groups selected from a C1-C4 alkyl group, a halogen atom, a C1-C4 alkoxy, a C1-C4 alkyloxycarbonyl, or —CONH 2 , or
a hydrogen atom,
R 5 , R 6 , R 7 , R 8 , R 9 , R 10 is selected, independently of one another, from
a hydrogen atom,
a saturated or unsaturated, linear, branched, or cyclic, C1-C6 alkyl group, optionally substituted with one or more functional groups selected from a halogen atom, a C1-C4 alkoxy, a C1-C4 alkyloxycarbonyl, or —CONH 2 ,
an aryl group optionally substituted with one or more functional groups selected from a C1-C4 alkyl group, a halogen atom, a C1-C4 alkoxy, a C1-C4 alkyloxycarbonyl, or —CONH 2 , or
a halogen atom,
and wherein X− is an organic or inorganic anion,
2) synthesizing a compound of formula B:
wherein R 1 -R 10 are as in the formula A,
R 11 is
a hydrogen atom,
a carbonyl or thiocarbonyl group functionalized with
a phenyl or benzyl group, optionally substituted with C1-C4 alkyl groups, a halogen atom, C1-C4 alkoxy, or a nitro group,
a linear, branched or cyclic C1-C8 alkyl group,
a C1-C8 alkylamino group,
a C1-C8 alkoxy group, or
a phenyloxy or benzyloxy group, optionally substituted on the aromatic ring with C1-C4 alkyl groups, a halogen atom, C1-C4 alkoxy, or a nitro group,
by reaction of the crude diaminophenothiazinium compound of formula A with a reducing agent and a protective agent comprising the group R 11 , and
3) obtaining the diaminophenothiazinium compound of the Formula A having a degree of purity higher than 95%, through oxidation of the compound of the Formula B by a stable free radical agent, said stable free radical agent being proxyl (2,2,5,5-tetramethyl-1-pyrrolidinyloxy), 3-carboxyl-proxyl, 3-carbamoyl-proxyl, 2,2-dimethyl-4,5-cyclohexyl-proxyl, 3-oxo-proxyl, 3-hydroxylimine-proxyl, 3-aminomethyl-proxyl, 3-methoxy-proxyl, 3-t-butyl-proxyl, 3-maleimido-proxyl, 3,4-di-t-butyl-proxyl, 3-carboxylic-2,2,5,5-tetramethyl-1pyrrolidinyloxy, TEMPO (i.e. 2,2,6,6-tetramethyl-1-piperidinyloxy), NHAc-TEMPO, 4-C1-6-alkyloxy-TEMPO, 4-benzoxyloxy-TEMPO, 4-methoxy-TEMPO, 4-carboxylic-4-amino-TEMPO, 4-chloro-TEMPO, 4 hydroxylimine-TEMPO, 4-hydroxy-TEMPO, 4-oxo-TEMPO, 4-oxo-TEMPO-ethylene ketal, 4-amino-TEMPO, 2,2,6,6-tetraethyl-1-piperidinyloxy, 2,2,6-trimethyl-6-ethyl 1-piperidinyloxy, di-t-butyl nitroxide, di-t-butyl nitroxyl, diphenyl nitroxide, diphenyl nitroxyl, t-butyl-t-amyl nitroxide, DOXYL (4,4-dimethyl-1-oxazolidinyloxy), 2-di-t-butyl-doxyl, 5-decane-doxyl, 2-cyclohexane-doxyl, 2,5-dimethyl-3,4-dicarboxylic-pyrrole, 2,5-dimethyl-3,4-diethylester-pyrrole, 2,3,4,5-tetraphenyl-pyrrole, 3-cyano-pyrroline-3-carbamoyl-pyrroline, 3-carboxylic-pyrroline, 1,1,3,3-tetramethylisoindoline-2-yloxyl, 1,1,3,3-tetraethylisoindolin-2-yloxyl, 5-cyclohexyl porphyrexide nitroxyl, 2,2,4,5,5-pentamethyl-[DELTA]3-imidazoline-3-oxide-1-oxyl, galvinoxyl, 1,3,3-trimethyl-2-azabicyclo[2,2,2]octane-5-one-2-oxide, 1-azabicyclo[3,3,1]nonane-2-oxide, 2-Azaadamantane N-Oxyl (AZADO), 9-Azabicyclo[3.3.1]nonane N-oxyl (ABNO), 9-Azanoradamantane N-oxyl (Nor-AZADO), or a mixture thereof.
2. The process of claim 1 , wherein said crude diaminophenothiazinium compound of formula A is crude Methylene blue, Methylene Blue zinc double salt or a mixture thereof.
3. The process of claim 1 , wherein step 3) is a one-pot synthesis step.
4. The process of claim 1 , wherein said stable free radical agent is TEMPO, NHAc-TEMPO, 4-C1-6-alkyloxy-TEMPO, 4-benzoxyloxy-TEMPO, 4-methoxy-TEMPO, 4-carboxylic-4-amino-TEMPO, 4-chloro-TEMPO, 4 hydroxylimine-TEMPO, 4-hydroxy-TEMPO, 4-oxo-TEMPO, 4-oxo-TEMPO-ethylene ketal, 4-amino-TEMPO, 2,2,6,6-tetraethyl-1-piperidinyloxy, 2,2,6-trimethyl-6-ethyl 1-piperidinyloxy, 1,3,3-trimethyl-2-azabicyclo[2,2,2]octane-5-one-2-oxide, 1-azabicyclo[3,3,1]nonane-2-oxide, 2-Azaadamantane N-Oxyl (AZADO), 9-Azabicyclo[3.3.1]nonane N-oxyl (ABNO), 9-Azanoradamantane N-oxyl (Nor-AZADO), or a mixture thereof.
5. The process of claim 4 , wherein said stable free radical agent is TEMPO, NHAc-TEMPO, 4-methoxy-TEMPO, 4-carboxylic-4-amino-TEMPO, 4-chloro-TEMPO, 4 hydroxylimine-TEMPO, 4-hydroxy-TEMPO, 4-oxo-TEMPO, 4-amino-TEMPO, 2-Azaadamantane N-Oxyl (AZADO), 9-Azabicyclo[3.3.1]nonane N-oxyl (ABNO), 9-Azanoradamantane N-oxyl (Nor-AZADO), or a mixture thereof.
6. The process of claim 5 , wherein said stable free radical agent is TEMPO, 4-hydroxy-TEMPO, 2-Azaadamantane N-Oxyl (AZADO), or a mixture thereof.
7. The process of claim 6 , wherein said stable free radical agent is 4-hydroxy-TEMPO.
8. The process of claim 1 , wherein said stable free radical agent is the only oxidant agent used in step 3).
9. The process of claim 1 , wherein, at the end of step 3), the resulting product is recovered from the reaction mixture by precipitation and washing.
10. The process of claim 1 , wherein in step 3) said stable free radical agent is added as an aqueous solution comprising up to 60% by weight of stable free radical agent, preferably comprising 10-50% by weight of stable free radical agent.
11. The process of claim 1 , wherein said degree of purity higher than 97%.