Preparation of metal mesoporphyrin compounds
View Patent ↗A method of preparing metal mesoporphyrin compounds is described. A metal mesoporphyrin compound may be formed by forming a novel mesoporphyrin IX intermediate compound and then converting the mesoporphyrin IX intermediate to a metal mesoporphyrin compound through metal insertion. The novel intermediate compound may be formed by a catalytic hydrogenation of hemin in acid and subsequent recovery.
1. A method of producing a metal mesoporphyrin compound comprising: isolating a mesoporphyrin formate; and converting the mesoporphyrin formate to a metal mesoporphyrin compound.
2. The method of claim 1 , wherein the mesoporphyrin formate is converted directly to the metal mesoporphyrin compound.
3. The method of claim 1 , wherein the mesoporphyrin formate is first converted to mesoporphyrin dihydrochloride and the mesoporphyrin dihydrochloride is converted to the metal mesoporphyrin compound.
4. The method of claim 3 , wherein the mesoporphyrin dihydrochloride is reacted with an insert metal to form the metal mesoporphyrin compound.
5. The method of claim 3 , further comprising purifying the mesoporphyrin formate in the presence of a metal scavenger.
6. The method of claim 5 , wherein the metal scavenger includes Si-thiol.
7. The method of claim 4 , further comprising catalytically hydrogenating hemin in the presence of an acid to form the mesoporphyrin formate.
8. The method of claim 7 , wherein the catalytic hydrogenation of the hemin occurs in two steps.
9. The method of claim 8 , further comprising heating a mixture of hemin and a hydrogenation catalyst under pressure at a first temperature for a first period of time and subjecting the mixture to a second temperature under pressure for a second period of time.
10. The method of claim 9 , wherein the first temperature is higher than the second temperature.
11. The method of claim 1 , wherein the metal mesoporphyrin compound is a metal mesoporphyrin halide.
12. The method of claim 10 , further comprising: a) subjecting a reaction mixture of hemin and a hydrogenation catalyst in an acid to hydrogen pressure of about 30-65 psi and then raising the temperature to about 85-95° C. and maintaining the temperature within that range for a period of about 1-3 hours; b) subjecting the reaction mixture to a further hydrogen pressure of about 30-65 psi at a temperature range of about 45-50° C. for a period of about 24-48 hours; and c) recovering the mesoporphyrin formate from the reaction mixture by precipitation of the mixture with a solvent.
13. The method of claim 7 , wherein the acid is formic acid.
14. The method of claim 12 , wherein the solvent is an ether.
15. The method of claim 14 , wherein the solvent is methyl tert-butyl ether.
16. The method of claim 15 , wherein the hydrogenation catalyst is palladium on carbon.
17. The method of claim 1 , wherein the quantity of metal mesoporphyrin compound formed by a single performance of the method exceeds 0.1 kg.
18. The method of claim 1 , further comprising purifying the metal mesoporphyrin compound, including: a) dissolving the metal mesoporphyrin compound in an aqueous basic solution to obtain a dissolved metal mesoporphyrin compound; b) treating said dissolved metal mesoporphyrin compound with charcoal to obtain a treated metal mesoporphyrin compound; c) adding said treated metal mesoporphyrin compound to a first aqueous acid solution to obtain a precipitated metal mesoporphyrin compound; d) triturating said precipitated metal mesoporphyrin halide in a second aqueous acid solution at elevated temperature to obtain a substantially pure metal mesoporphyrin compound; and e) drying said substantially pure metal mesoporphyrin compound.
19. The method of claim 18 , wherein the metal mesoporphyrin halide is tin (IV) mesoporphyrin IX dihydrochloride.
20. The method of claim 19 , further comprising reacting the mesoporphyrin IX dihydrochioride with tin to form tin (IV) mesoporphyrin IX dichioride.
21. The method of claim 1 , wherein the mesoporphyrin formate is isolated in substantially pure, solid form.
22. The method of claim 21 , wherein the mesoporphyrin formate is converted to mesoporphyrin IX dihydrochloride.
23. The method of claim 22 , further comprising reacting the mesoporphyrin IX dihydrochloride with tin to form tin (IV) mesoporphyrin IX dichioride.
24. The method of claim 23 , wherein the quantity of tin (IV) mesoporphyrin IX dichioride formed by a single performance of the method exceeds 0.1 kilograms.
25. The method of claim 21 , further comprising purifying the mesoporphyrin formate with a metal scavenger.
26. The method of claim 25 , wherein the metal scavenger includes a silica bound metal scavenger.
27. The method of claim 23 , further comprising purifying the tin (IV) mesoporphyrin IX dichioride includes trituration in hot acid at an elevated temperature.
28. The method of claim 27 , wherein the acid is HCl.
29. The method of claim 11 , wherein the metal mesoporphyrin halide is mesoporphyrin IX dihydrochloride.
30. The method of claim 18 , wherein the metal mesoporphyrin compound is a metal mesoporphyrin halide.
31. The method of claim 4 , wherein the mesoporphyrin dihydrochloride is reacted with the insert metal in the absence of any acetate ions.
32. The method of claim 23 , wherein the mesoporphyrin dihydrochioride is reacted with the tin in the absence of any acetate ions.
33. The method of claim 17 , wherein the quantity of metal mesoporphyrin compound formed by a single performance of the method exceeds 1 kg.
34. The method of claim 18 , wherein the quantity of metal mesoporphyrin compound formed by a single performance of the methods exceeds 1 kg.
35. The method of claim 23 , wherein the quantity of tin (IV) mesoporphyrin IX dichloride formed by a single performance of the methods exceeds 1 kg.
36. Tin (IV) mesoporphyrin IX dichioride produced by a single performance of the method of claim 23 .