Process for the preparation of indocyanine green
The present invention involves an improved process for the preparation of Indocyanine green of Formula (I) having high purity of about 99%, wherein the process comprises steps of reacting 1,1,2-trimethyl-1H-benzo[e]indole with 1,4-butane sulfone in boiling solvent to give 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate. Followed by reacting 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate of Formula (IV) and N-phenyl-N-((1E,3E,5E)-5-(phenylimino)penta-1,3-dienyl)acetamide of formula (V) in presence of sodium acetate and alcohol; and extracting the title compound formula (I) with an ester solvent.
1. A process for preparation of Indocyanine green of Formula (I) having high purity,
wherein the process comprises steps of:
a) reacting 1,1,2-trimethyl-1H-benzo[e]indole of Formula (II)
with 1,4-butane sultone of Formula (III)
in boiling solvent to give 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate of Formula (IV);
b) condensing 4-(1,1,2-trimethyl-1H-benzo[e]indolium-3-yl)butane-1-sulfonate of Formula (IV)
and N-phenyl-N-((1E,3E,5E)-5-(phenylimino)penta-1,3-dienyl)acetamide of formula (V)
in presence of sodium acetate and an alcohol; and
c) extracting the Indocyanine green of formula (I) with an ester solvent.
2. The process according to claim 1 , wherein preparation of the N-phenyl-N-((1E,3E,5E)-5-(phenylimino)penta-1,3-dienyl)acetamide of formula V comprises
reacting (E)-N,N′-((1E,3E)-penta-1,3-diene-1-yl-5-ylidene)dianiline or hydrochloride of compound of formula (VI) with an acetic an-hydride in presence of an organic base
3. The process according to claim 1 , wherein the solvent in step-(a) is sulfolene, toluene, xylene or silicone oil.
4. The process according to claim 1 , wherein the reaction in step-(a) is performed at a solvent reflux temperature ranging from 110° C. to 150° C.
5. The process according to claim 1 , where the reaction in step-(b) is performed at a temperature range from 50° C. to solvent reflux temperature.
6. The process according to claim 1 , wherein the alcohol in step-(b) is selected from methanol, ethanol, and isopropanol.
7. The process according to claim 1 , wherein the ester solvent in step-(c) is methyl acetate or ethyl acetate.
8. The process according to claim 1 , wherein the process comprises a further step of purification.
9. The process according to claim 8 , wherein the purification is carried out in a solvent selected from C 1 to C 5 alcohols.
10. The process according to claim 8 , wherein the purification is carried out in ketonic solvents.
11. The process according to claim 2 , wherein the solvent is a chlorinated solvent.
12. The process according to claim 11 , wherein the chlorinated solvent is methylene dichloride or ethylene dichloride.
13. The process according to claim 2 , wherein the reaction is performed at a temperature range from room temperature to about 90° C.
14. The process according to claim 2 , wherein the organic base is methyl amine, dimethyl amine, or triethyl amine.
15. The process according to claim 6 , wherein the alcohol in step-(b) is methanol.
16. The process according to claim 7 , wherein the ester solvent in step-(c) is ethyl acetate.
17. The process according to claim 10 , wherein the Ketonic solvents are selected from acetone and acetonitrile in water.
18. The process according to claim 12 , wherein the chlorinated solvent is methylene di-chloride.
19. The process according to claim 14 , wherein the organic base is triethyl amine.