Process for preparing diaminophenothiazinium compounds
Process for preparing compounds of the diaminophenothiazinium type of formula (II) below. The products have a high degree of purity and are useful for the preparation of medicaments. In which the R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 groups having the same definition as in formula (I), and R representing a group chosen from: a phenyl or benzyl group, optionally substituted with one or more functions chosen from: a C 1 -C 4 alkyl, a halogen atom, a C 1 -C 4 haloalkyl and a nitro group, a linear, branched or cyclic C 1 -C 8 alkyl group, a C 1 -C 8 alkylamino group, a C 1 -C 8 alkoxy group, a phenyloxy or benzyloxy group optionally substituted on the aromatic nucleus with one or more functions chosen from: a C 1 -C 4 alkyl, a halogen atom, a C 1 -C 4 haloalkyl and a nitro group, Z representing an atom chosen from O and S.
1. A process for preparing a compound corresponding to formula (I) below:
in which each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 is chosen, independently of the others, from the group constituted of:
a hydrogen atom,
saturated or unsaturated, linear, or branched C 1 -C 6 alkyl groups, or C 3 -C 6 cycloalkyl groups, optionally substituted with one or more functions chosen from a halogen atom, and a C 1 -C 6 alkoxy, C alkoxycarbonyl or —CONH 2 function,
aryl groups optionally substituted with one or more functions chosen from: a C 1 -C 4 alkyl, a halogen atom, and a C 1 -C 6 alkoxy, C 1 -C 6 alkyloxycarbonyl or —CONH 2 function,
X − represents an organic or inorganic anion,
wherein the process comprises at least one step during which a compound of formula (II):
in which R represents a group chosen from:
a phenyl or benzyl group, optionally substituted with one or more functions chosen from: a C 1 -C 4 alkyl, a halogen atom, a C 1 -C 4 haloalkyl and a nitro group,
a phenyloxy or benzyloxy group optionally substituted on the aromatic nucleus with one or more functions chosen from: a C 1 -C 4 alkyl, a halogen atom, a C 1 -C 4 haloalkyl and a nitro group,
Z represents an atom chosen from O and S,
is subjected to a purification step, this step comprising at least one filtration through a filtration support chosen from: a silica gel, a neutral, basic or acidic alumina gel, a microporous membrane, a resin grafted with metal-capturing groups, and fibers grafted with metal-capturing groups,
and thereafter a step for deprotection of the amine of the phenothiazine ring of the compound of formula (II), wherein the deprotection step of compound (II) to produce compound (I) is achieved in a one-pot process.
2. The process as claimed in claim 1 , in which R 1 , R 2 , R 3 , R 4 , R 5 and R 6 , which may be identical or different, are chosen from a hydrogen atom and a C 1 -C 4 alkyl.
3. The process as claimed in claim 1 , in which one or more of the following requirements are met:
R 5 , R 8 , R 9 and R 10 represent H,
X represents Cl or OH,
R 1 , R 2 , R 3 and R 4 , which may be identical or different, are chosen from a hydrogen atom and methyl,
R 6 represents a hydrogen atom,
R 7 represents a hydrogen atom,
Z represents O.
4. The process as claimed in claim 1 , in which the compound of formula (I) is methylene blue.
5. The process as claimed in claim 1 , in which the compound of formula (I) is chosen from:
Azure A,
Azure B,
Azure C.
6. The process as claimed in claim 1 , in which the filtration support is a silica gel.
7. The process as claimed in claim 1 , in which, for the filtration, the compound of formula (II) is solubilized in a solvent chosen from dichloromethane, chloroform, ethanol, isopropanol, methanol, acetonitrile, ethyl acetate, tetrahydrofuran, or a mixture of these solvents.
8. The process as claimed in claim 1 , in which the deprotection is carried out by a means chosen from: quinones, HNO 3 , HClO 4 , I 2 , H 2 SO 4 , H 2 O 2 and a treatment with ultraviolet radiation.
9. The process as claimed in claim 1 , wherein the deprotection is implemented with solvents comprising less than 0.01 ppm metal residues, in reactors not comprising any metal parts.
10. The process as claimed in claim 1 , wherein the deprotection is implemented in a solvent chosen from: ethyl acetate, acetonitrile, tetrahydrofuran and acetone.
11. The process as claimed in claim 8 , wherein the deprotection is carried out with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
12. The process as claimed in claim 11 , wherein the deprotection is implemented with from 0.80 to 1.1 molar equivalents of DDQ relative to the compound (II).
13. The process as claimed in claim 12 , wherein the deprotection is implemented with from 0.85 to 1.05 molar equivalents of DDQ relative to the compound (II).
14. The process as claimed in claim 11 , wherein the deprotection is implemented at a temperature of between −40° C. and −5° C.
15. The process as claimed in claim 1 , which also comprises a step for ion exchange, by treatment with HCl.
16. A process for preparing a medicament comprising Methylene Blue, wherein this process comprises the preparation of Methylene Blue according to the process of claim 1 and the adjunction to this Methylene Blue of a pharmaceutically acceptable support.
17. The process as claimed in claim 1 , wherein the compound of formula (I) comprises less than 3% of impurities measured by HPLC under the conditions of the European Pharmacopeia 5.4 and less than 20 μg/g of total metal content.