Process for the preparation of isosulfan blue
Isosulfan blue and processes for the preparation thereof are provided. A process is also provided for preparation of the intermediate, 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2), used in the preparation thereof and a procedure for the isolation of benzaldehyde-2,5-disulfonic acid, di-sodium salt of the formula (3). Also provided is a process for the preparation of an isoleuco acid of formula (4), which upon oxidation gives rise to isosulfan blue of pharmaceutical grade which can be used for preparation of pharmaceutical formulations. The isolation and purification procedures provided in the process provide substantially pure isosulfan blue with HPLC purity 99.5% or greater.
1. A process of preparing isosulfan blue acid, said process comprising:
i) combining isoleuco acid of the formula (4):
with a mild oxidizing agent to provide said isosulfan blue acid.
2. The process of claim 1 , further comprising the step of recovering said isosulfan blue acid.
3. The process of claim 2 , further comprising the step of purifying said recovered isosulfan blue acid.
4. The process of claim 3 , wherein said purification comprises recrystallization.
5. The process of claim 4 , wherein said recrystallization occurs in a solvent comprising an alcohol.
6. The process of claim 5 , wherein said alcohol is aqueous isopropyl alcohol.
7. The process of claim 3 , wherein said purification consists of recrystallization.
8. The process of claim 2 , wherein said recovery of said isosulfan blue acid occurs by precipitation from solvent.
9. The process of claim 8 , wherein said solvent is an ether.
10. The process of claim 9 , wherein said ether is isopropyl ether.
11. The process of claim 1 , wherein said isoleuco acid is combined with said mild oxidizing agent in the absence of a strong acid.
12. The process of claim 1 , wherein said isosulfan blue acid is obtained in a purity of at least 99% as measured by HPLC.
13. The process of claim 12 , wherein said isosulfan blue acid is obtained in a purity of at least 99.5% as measured by HPLC.
14. The process of claim 1 , wherein said mild oxidizing agent is not lead oxide, chloranil, or iron phthalocyanine/oxone.
15. The process of claim 1 , wherein said mild oxidizing agent is silver oxide.
16. The process of claim 1 , wherein combining said isoleuco acid of formula (4) with said mild oxidizing agent occurs in a polar solvent.
17. The process of claim 16 , wherein said polar solvent is selected from the group consisting of water, alcohol, and mixtures thereof.
18. A process of preparing pharmaceutical grade N-[4-[[4-(diethyl amino) phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt, said process comprising:
i) combining isoleuco acid of formula (4):
with a mild oxidizing agent to provide isosulfan blue acid,
ii) recovering said isosulfan blue acid;
iii) combining said isosulfan blue acid with a solvent to prepare an isosulfan blue acid mixture; and
iv) adjusting the pH of said isosulfan blue acid mixture.
19. The process of claim 18 , wherein the pH of said isosulfan blue acid mixture is adjusted using a base.
20. The process of claim 19 , wherein said isosulfan blue acid mixture is adjusted to a pH greater than 6.0.
21. The process of claim 19 , wherein said base is an aqueous carbonate base.
22. The process of claim 21 , wherein said aqueous carbonate base is aqueous sodium carbonate.