Process for manufacture of gadofosveset trisodium monohydrate

Patent metadata

Field	Value
Publication number	US-10106562-B2
Application number	US-201414774944-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 13, 2013
Publication date	Oct 23, 2018
Grant date	Oct 23, 2018

Abstract

This application relates to a process for making a pharmaceutically acceptable formulation of gadofosveset trisodium monohydrate, wherein the process uses no more than one chromatographic purification for removal of impurities.

First claim

What is claimed is:

1. A process for preparing a pharmaceutically acceptable formulation of gadofosveset trisodium monohydrate, comprising:
(i) reacting (R)-2-amino-3-((2-aminoethyl)amino)propan-1-ol trihydrochloride with at least five equivalents of tert-butyl 2-bromoacetate to form a solution comprising a compound of Formula (1):

(ii) after (i), treating the solution with diethanolamine in an amount sufficient to consume any remaining tert-butyl 2-bromoacetate;
(iii) reacting 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole) with the compound of Formula (1) to form a compound of Formula (2):

(iv) hydrolyzing and oxidizing the compound of formula (2) in the presence of hydrochloric acid and hydrogen peroxide to form a compound of Formula (3):

followed by further hydrolysis in the presence of hydrochloric acid to form fosveset; and
(v) reacting an aqueous solution of said fosveset with gadolinium oxide, followed by reaction with sodium hydroxide to form gadofosveset trisodium monohydrate;
wherein said process comprises no more than one chromatographic purification for removal of impurities.

2. The process of claim 1 , wherein, in (v), an excess of gadolinium oxide is reacted with the aqueous solution of the fosveset.

3. The process of claim 2 , wherein, in (v), about 1.01 molar equivalents of gadolinium oxide is reacted with the aqueous solution of the fosveset.

4. The process of claim 1 , further comprising, prior to (i):
(b) reacting dichloro((4,4-diphenylcyclohexyl)oxy)phosphine with 1H-imidazole to form the 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole).

5. The process of claim 4 , further comprising, prior to (b):
(a) reacting 4,4-diphenylcyclohexanol with phosphorous trichloride to form the dichloro((4,4-diphenylcyclohexyl)oxy)phosphine.

6. The process of claim 1 , further comprising filtering an aqueous solution of gadofosveset trisodium monohydrate at a pH greater than 7.5.

7. The process of claim 6 , wherein the solution is filtered at a pH of about 9 to about 12.

8. The process of claim 7 , wherein the solution is filtered at a pH of about 10.5.

9. The process of claim 1 , further comprising treating an aqueous solution of gadofosveset trisodium monohydrate with a strong acid cation exchange resin.

10. The process of claim 9 , wherein the pH of the solution of gadofosveset trisodium monohydrate after said treating is adjusted to about 6 to about 7.

11. The process of claim 10 , wherein the pH of the solution after said treating is adjusted to about 6.5.

12. The process of claim 9 , wherein the resin comprises polystyrene crosslinked by divinylbenzene.

13. The process of claim 1 , wherein the formulation comprises equal to or less than 0.6% w/w, 0.5% w/w, 0.4% w/w, 0.3% w/w, 0.2% w/w, 0.1% w/w, 0.09% w/w, 0.08% w/w, 0.07% w/w, 0.06% w/w, or 0.05% w/w total impurities based on gadofosveset trisodium.

14. The process of claim 1 , further comprising, after (ii):
adding the solution of the compound of Formula (1) to a mixture of water and heptane, separating the organic phase, and extracting the organic phase with water to form an organic solution of the compound of Formula (1); and
filtering the organic solution through a column of silica gel.

15. The process of claim 1 , comprising, prior to (i):
(i-a) reacting L-serine methyl ester hydrochloride with di-tert-butyl dicarbonate in the presence of triethylamine in a solvent comprising toluene to form N-(tert-butoxycarbonyl)- L -serine methylester;
(i-b) after (i-a), washing the solution with an aqueous brine solution;
(i-c) after (i-b), reacting the N-(tert-butoxycarbonyl)- L -serine methylester in toluene with 1,2-ethylenediamine to form a solution of (S)-tert-butyl (1-((2-aminoethyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate in a solvent comprising toluene;
(i-d) after (i-c), concentrating the solution to form a solid, slurrying the solid, concentrating the slurry to form a solid, and crystallizing the solid from a solvent comprising tetrahydrofuran;
(i-e) after (i-d), reacting (S)-tert-butyl (1-((2-aminoethyl)amino)-3-hydroxy-1-oxopropan-2-yl)carbamate with diborane produced in situ to form (R)-tert-butyl (1-((2-aminoethyl)amino)-3-hydroxypropan-2-yl)carbamate; and
(i-f) after (i-e), reacting (R)-tert-butyl (1-((2-aminoethyl)amino)-3-hydroxypropan-2-yl)carbamate with hydrochloric acid in water to form (R)-2-amino-3-((2-aminoethyl)amino)propan-1-ol trihydrochloride.

16. The process of claim 5 , comprising, prior to step (a), hydrogenating 4,4-diphenylcyclohex-2-enone in tetrahydrofuran in the presence of Raney nickel and hydrogen.

Assignees

• Lantheus Medical Imaging Inc

Inventors

• Anklekar Tarakeshwar
• Haller Jan
• Champion Nicolas
• Herkenrath Franz-Willi

Classifications

• C07F9/6506 Primary

  having the nitrogen atoms in positions 1 and 3 · CPC title

• C07F9/117 Primary

  with cycloaliphatic alcohols · CPC title

• A61K49/106

  the complex-forming compound being cyclic, e.g. DOTA · CPC title

• A61K31/685

  one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin · CPC title

• C07F9/146

  containing P-halide groups · CPC title