High-purity large-scale preparation of stannsoporfin
Large scale (bulk) compositions comprising high-purity stannsoporfin are disclosed, as well as methods of synthesizing such compositions.
1. A method of making stannsoporfin comprising:
a. exposing a metallic hydrogenation catalyst to a hydrogen atmosphere to form pre-hydrogenated catalyst;
b. contacting hemin with the pre-hydrogenated catalyst to form mesoporphyrin IX or salt thereof;
c. contacting a solution or suspension of tin (II) oxide or tin (II) salt with the mesoporphyrin IX or salt thereof under conditions suitable to form stannsoporfin.
2. The method of claim 1 further comprising step d) purifying the stannsoporfin via hot acid trituration, followed by treatment at high pH at or above pH 9 followed by re-acidification, and subsequent hot acid trituration.
3. The method of claim 1 , further comprising, after step b., a step b1) of isolating the mesoporphyrin IX or salt thereof as mesoporphyrin IX formate.
4. The method of claim 3 , further comprising, after step b1), an additional step b2) of purifying the mesoporphyrin IX formate.
5. The method of claim 3 , further comprising, after step b1), a step of b2) converting the mesoporphyrin IX formate into mesoporphyrin IX dihydrochloride.
6. The method of claim 3 , further comprising after step b1) the steps of: b2) treating the mesoporphyrin IX formate with diatomaceous earth, activated carbon, and formic acid to form a mesoporphyrin IX formate suspension in formic acid; b3) filtering the mesoporphyrin IX formate suspension in formic acid to form a formic acid solution of mesoporphyrin IX formate; b4) adding a 1N hydrochloric acid solution to the solution of mesoporphyrin IX formate to form a mesoporphyrin IX dichloride.
7. The method of claim 6 wherein the adding the 1N hydrochloric acid solution comprises: adding a first portion of the 1N hydrochloric acid solution; adding mesoporphyrin IX dichloride seed crystals with agitation; and adding a second portion of the 1N hydrochloric acid solution with vigorous stirring.
8. The method of claim 1 , wherein the metallic hydrogenation catalyst is selected from the group consisting of palladium, palladium on carbon, platinum, platinum on carbon, nickel and nickel-aluminum.
9. The method of claim 8 , wherein the metallic hydrogenation catalyst is palladium on carbon.
10. The method of claim 1 , wherein the exposing in step a. comprises adding formic acid to the metallic hydrogenation catalyst under a nitrogen atmosphere to form a metallic hydrogenation suspension, replacing the nitrogen atmosphere with the hydrogen atmosphere, and adjusting the temperature of the metallic hydrogenation suspension to 80-90° C. for about 1-3 hours to form the pre-hydrogenated catalyst; wherein the metallic hydrogenation catalyst is palladium on carbon, and the hydrogen atmosphere is 50-70 psi.
11. The method of claim 1 , wherein in step c., the solution or suspension of tin (II) oxide is a tin (II) oxide formic acid solution or suspension or a tin (II) oxide acetic acid solution or suspension and wherein the mesoporphyrin IX or salt thereof is first converted to a mesoporphyrin IX or salt thereof formic acid solution or suspension or a mesoporphyrin IX or salt thereof acetic acid solution or suspension by the addition of formic acid or acetic acid.
12. The method of claim 11 wherein the mesoporphyrin IX or salt thereof formic acid solution or suspension or the mesoporphyrin IX or salt thereof acetic acid solution or suspension is added to the tin (II) oxide formic acid solution or suspension or the tin (II) oxide acetic acid solution or suspension.
13. The method of claim 12 wherein the mesoporphyrin IX or salt thereof formic acid solution or suspension is added over a period of 3-9 hours; the tin (II) oxide acetic acid solution or suspension is maintained at a temperature of 25-115° C. and the contacting is maintained for an additional 2 to 48 hours after the mesoporphyrin IX or salt thereof formic acid solution or suspension is added.
14. The method of claim 1 , wherein in step c. the contacting comprises treating the mesoporphyrin IX or salt thereof with a solution or suspension of tin (II) salt in an organic solvent under oxidizing conditions to form stannsoporfin.
15. The method of claim 12 , wherein the treating comprises heating the mesoporphyrin IX or salt thereof and the solution or suspension of tin(II) salt in the organic solvent to reflux, in a reaction vessel with vigorous agitation, then introducing a 6% oxygen in nitrogen atmosphere to the vessel and maintaining reflux for 100-130 hours to form the stannsoporfin; wherein the tin (II) salt is SnCl 2 , and the solvent is acetic acid.
16. A method of making stannsoporfin comprising:
a. adding formic acid to palladium on carbon under a nitrogen atmosphere to form a palladium on carbon suspension; replacing the nitrogen atmosphere with a hydrogen atmosphere of 50-70 psi, and adjusting the temperature of the palladium on carbon suspension to 80-90° C. for about 1-3 hours to form a pre-hydrogenated palladium on carbon catalyst in formic acid;
b. contacting hemin with the pre-hydrogenated palladium on carbon catalyst in formic acid to form mesoporphyrin IX formate; treating the mesoporphyrin IX formate with diatomaceous earth, activated carbon, and formic acid to form a mesoporphyrin IX formate suspension in formic acid; filtering the mesoporphyrin IX formate suspension in formic acid to form a formic acid solution of mesoporphyrin IX formate;
c. adding a first portion of the 1N hydrochloric acid solution to the mesoporphyrin IX formate suspension in formic acid; adding mesoporphyrin IX dichloride seed crystals with agitation; and adding a second portion of the 1N hydrochloric acid solution with vigorous stirring to form a mesoporphyrin IX dichloride;
d. treating the mesoporphyrin IX dichloride with formic acid to form a mesoporphyrin IX dichloride formic acid solution; adding the mesoporphyrin IX dichloride formic acid solution over a period of 3-9 hours to a tin (II) oxide acetic acid solution or suspension that is maintained at 25-115° C. with stirring to form a reaction mixture; maintaining the reaction mixture for an additional 2 to 48 hours to form the stannsoporfin;
e. purifying the stannsoporfin via hot acid trituration, followed by treatment at high pH at or above pH 9 followed by re-acidification, and subsequent hot acid trituration.