Process for the preparation of calcobutrol

Patent metadata

Field	Value
Publication number	US-9447053-B2
Application number	US-201013508198-A
Country	US
Kind code	B2
Filing date	Nov 2, 2010
Priority date	Nov 4, 2009
Publication date	Sep 20, 2016
Grant date	Sep 20, 2016

Abstract

A process for the preparation of the calcium complex of 10-(2, 3-Dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclodecane-4,7-triacetic acid, also known as Calcobutrol, starting from the pure gadolinium complex (Gadobutrol) is disclosed. Also disclosed is Calcobutrol with a hitherto unknown level of purity.

First claim

The invention claimed is:

1. A process for the preparation of a calcium complex of 10-(2,3-Dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid comprising:
a) de-complexing a gadolinium complex of 10-(2,3-Dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid with a de-complexing agent to give a solution of a free ligand and a precipitated gadolinium salt,
b) removing the precipitated gadolinium salt,
c) binding the free ligand in the solution resulting from step b) to an acidic ion exchange resin,
d) eluting the acidic ion exchange resin with an aqueous alkaline solution to give an eluate comprising the free ligand,
e) treating the eluate with a second acidic ion exchange resin to acidify the eluate comprising the free ligand, and
f) complexing the free ligand with Ca 2+ ions from a calcium ion source to give a resulting calcium complex, and crystallizing the resulting calcium complex to give a crystallized calcium complex.

2. The process according to claim 1 , wherein the de-complexing agent in step a) is an oxalate ion source or a phosphate ion source.

3. The process according to claim 2 , wherein the de-complexing agent in step a) is oxalic acid.

4. The process according to claim 1 , wherein the de-complexation reaction according to step a) is carried out in water at temperatures from 75 to 100° C.

5. The process according to claim 1 , wherein the aqueous alkaline solution of step d) is a solution of ammonia or a volatile amine, or mixtures thereof.

6. The process according to claim 5 , wherein the aqueous alkaline solution in step d) is a solution of ammonia, dimethylamine, methylamine, ethylamine, trimethylamine, iso-propylamine, or mixtures thereof.

7. The process according to claim 6 , wherein the aqueous alkaline solution in step d) is a solution of ammonia.

8. The process according to claim 1 , wherein the free ligand resulting from step e) is isolated by freeze-drying.

9. The process according to claim 1 , wherein the free ligand resulting from step e) is reacted directly with the calcium ion source without isolating the free ligand first.

10. The process according to claim 1 , wherein the calcium ion source in step f) is calcium carbonate, calcium oxide, or calcium hydroxide.

11. The process according to claim 1 , wherein a pH in step a) before adding the de-complexing agent is higher than 2.

12. The process according to claim 1 , wherein the crystallized calcium complex is the calcium complex of 10-(2,3-Dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid having a purity of 99.0% or more.

13. The process according to claim 1 , wherein the crystallized calcium complex is the calcium complex of 10-(2,3-Dihydroxy-1-(hydroxymethyl)propyl)-1,4,7,10-tetraazacyclodecane-1,4,7-triacetic acid having a purity of 99.4% or more.

Assignees

• Platzek Johannes
• Trentmann Wilhelm
• Bayer Ip Gmbh

Inventors

• Platzek Johannes
• Trentmann Wilhelm

Classifications

• C07D257/02 Primary

  not condensed with other rings · CPC title

• A61K51/04

  Organic compounds · CPC title

• A61K49/06

  Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations · CPC title

• C07F3/04

  Calcium compounds · CPC title