PROCESS FOR PREPARATION OF ISOSULFAN BLUE

• US 20120078007A1
• Filed: 12/02/2011
• Published: 03/29/2012
• Est. Priority Date: 05/11/2007
• Status: Active Grant

• Current Assignee: Mylan Institutional LLC (Pfizer Inc.)
• Original Assignee: Apicore, LLC (Mylan N.V.)
• Inventors: Kovi, Ravishanker, Nampalli, Satyam, Tharial, Peter Xavier
• Granted Patent: US 9,353,050 B2
• Time in Patent Office: Days
• US Class Current: 562/59
• CPC Class Codes: C07C 303/02 of sulfonic acids or halides thereof
• CPC Class Codes: C07C 303/22 from sulfonic acids, by reactions not involving the formation of sulfo or halosulfonyl groups; from sulfonic halides by reactions not involving the formation of halosulfonyl groups
• CPC Class Codes: C07C 309/46 having the sulfo groups bound to carbon atoms of non-condensed six-membered aromatic rings
• CPC Class Codes: C07C 309/52 the carbon skeleton being further substituted by doubly-bound oxygen atoms

Abstract

A process for the preparation of isosulfan blue (Active Pharmaceutical Ingredient) is 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 mild 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.

Claims

1. N-[4-[[4-(diethyl amino)phenyl] (2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt containing 1.0% or less impurities.

2. The compound according to claim 1 having a purity between 99.0% and 99.5% by HPLC.

3. The compound according to claim 1 having less than 20 ppm silver.

4. The compound according to claim 3 having a purity greater than 99.5% by HPLC.

5. The compound according to claim 1 prepared by a process comprising combining a suspension of isoleuco acid of the formula

6. The compound according to claim 5 wherein the process comprises sulfonation of 2-chlorobenzaldehyde to obtain 2-chlorobenzaldehyde-5-sulfonic acid sodium salt of the formula

7. The compound according to claim 6 wherein the process of preparing 2-chlorobenzaldehyde-5-sulfonic acid, sodium salt of formula (2) comprises reacting 2-chlorobenzaldehyde with sulfuric acid.

8. The compound according to claim 5 wherein the polar solvent is methanol.

9. The compound according to claim 5 wherein the isoleuco acid of the formula

10. The compound according to claim 5 wherein the process comprises recrystallization of N-[4-[[4-(diethylamino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium using a solvent selected from the group consisting of a polar solvent, a non-polar solvent and a combination thereof to afford HPLC purity greater than 99.5%.

11. A solution containing N-[4-[[4-(diethyl amino)phenyl] (2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt containing 1.0% or less impurities.

12. The solution according to claim 11 wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity between 99.0% and 99.5% by HPLC.

13. The solution according to claim 11 having less than 20 ppm silver.

14. The solution according to claim 13 wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity greater than 99.5% by HPLC.

15. A composition consisting essentially of N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt containing 1.0% or less impurities.

16. The composition according to claim 15 wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity between 99.0% and 99.5% by HPLC.

17. The composition according to claim 15 having less than 20 ppm silver.

18. The composition according to claim 17 wherein the N-[4-[[4-(diethyl amino)phenyl](2,5-disulfophenyl)methylene]-2,5-cyclohexadien-1-ylidene]-N-ethylethanaminium, sodium salt has a purity greater than 99.5% by HPLC.