Highly pure phentolamine mesylate
This invention provides methods for synthesizing phentolamine mesylate from phentolamine and methanesulfonic acid in the presence of acetone and water. The methods of the present invention provide highly pure phentolamine mesylate. The invention also provides highly pure phentolamine mesylate.
1. Phentolamine mesylate exhibiting an X-ray powder diffraction (XRPD) pattern comprising a peak at 6.87±0.2 degrees 2-theta, a peak at 11.65±0.2 degrees 2-theta, a peak at 13.15±0.2 degrees 2-theta, a peak at 18.86±0.2 degrees 2-theta, a peak at 20.32±0.2 degrees 2-theta, a peak at 20.85±0.2 degrees 2-theta, a peak at 21.07±0.2 degrees 2-theta, and a peak at 21.36±0.2 degrees 2-theta; comprising 0% water by weight to 8% water by weight of the phentolamine mesylate as determined by Karl Fischer titration; and comprising less than 1% of another impurity by weight of the phentolamine mesylate.
2. The phentolamine mesylate of claim 1 , wherein the phentolamine mesylate comprises 0% water by weight to 6% water by weight of the phentolamine mesylate.
3. The phentolamine mesylate of claim 2 , wherein the phentolamine mesylate comprises 0% water by weight to 3% water by weight of the phentolamine mesylate.
4. The phentolamine mesylate of claim 1 , wherein the other impurity is Compound 1 having the structure
5. The phentolamine mesylate of claim 1 , wherein the other impurity is an alkyl methanesulfonate.
6. The phentolamine mesylate of claim 1 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
7. The phentolamine mesylate of claim 1 , comprising less than 0.3% of the impurity by weight of the phentolamine mesylate.
8. The phentolamine mesylate of claim 7 , wherein the phentolamine mesylate comprises less than 0.1% of the other impurity by weight of the phentolamine mesylate.
9. The phentolamine mesylate of claim 2 , comprising less than 0.3% of the impurity by weight of the phentolamine mesylate.
10. The phentolamine mesylate of claim 3 , comprising less than 0.3% of the impurity by weight of the phentolamine mesylate.
11. The phentolamine mesylate of claim 9 , comprising less than 0.1% of the impurity by weight of the phentolamine mesylate.
12. The phentolamine mesylate of claim 10 , comprising less than 0.1% of the impurity by weight of the phentolamine mesylate.
13. The phentolamine mesylate of claim 2 , wherein the other impurity is Compound 1 having the structure
14. The phentolamine mesylate of claim 3 , wherein the other impurity is Compound 1 having the structure
15. The phentolamine mesylate of claim 8 , wherein the other impurity is Compound 1 having the structure
16. The phentolamine mesylate of claim 7 , wherein the other impurity is Compound 1 having the structure
17. The phentolamine mesylate of claim 9 , wherein the other impurity is Compound 1 having the structure
18. The phentolamine mesylate of claim 10 , wherein the other impurity is Compound 1 having the structure
19. The phentolamine mesylate of claim 2 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
20. The phentolamine mesylate of claim 3 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
21. The phentolamine mesylate of claim 8 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
22. The phentolamine mesylate of claim 7 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
23. The phentolamine mesylate of claim 9 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
24. The phentolamine mesylate of claim 10 , wherein the other impurity is N-(2-aminoethyl)-2-[(3-hydroxyphenyl)(4-methylphenyl)amino]-acetamide, 2-chloromethyl-4,5-dihydro-1H-imidazole, or 3-hydroxy-4′-methyldiphenylamine, or a salt thereof.
25. The phentolamine mesylate of any one of claims 1 - 6 and 7 - 24 , wherein the phentolamine mesylate comprises less than 10% of amorphous phentolamine mesylate by weight of the phentolamine mesylate.