Process for manufacture of gadofosveset trisodium monohydrate

Patent metadata

Field	Value
Publication number	US-2016016979-A1
Application number	US-201414774944-A
Country	US
Kind code	A1
Filing date	Mar 13, 2014
Priority date	Mar 13, 2013
Publication date	Jan 21, 2016
Grant date	—

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, wherein said process comprises no more than one chromatographic purification for removal of impurities.

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

3 . The process of claim 1 , comprising:
(a) reacting 4,4-diphenylcyclohexanol with phosphorous trichloride to form dichloro((4,4-diphenylcyclohexyl)oxy)phosphine; (b) reacting dichloro((4,4-diphenylcyclohexyl)oxy)phosphine with 1H-imidazole to form 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole); (c) reacting 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole) with a compound of Formula (1):

to form a compound of Formula (2):

(d) 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 fosvoset;
(e) 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.

4 . The process of claim 3 , further comprising filtering an aqueous solution of gadofosveset trisodium monohydrate at a pH greater than 7.5.

5 . The process of claim 4 , wherein the solution is filtered at a pH of about 9 to about 12.

6 . The process of claim 5 , wherein the solution is filtered at a pH of about 10.5.

7 . The process of claim 3 , further comprising treating an aqueous solution of gadofosveset trisodium monohydrate with a strong acid cation exchange resin.

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

9 . The process of claim 8 , wherein the pH of the solution after said treating is adjusted to about 6.5.

10 . The process of any one of claims 7 to 9 , wherein the resin comprises polystyrene crosslinked by divinylbenzene.

11 . The process of any one of claims 3 to 10 , wherein the formulation comprises equal to or less than 0.6%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, or 0.05% total impurities based on gadofosveset trisodium.

12 . The process of any one of claims 3 to 11 , further comprising, prior to (c):
(i) reacting (R)-2-amino-3-((2-aminoethyl)amino)propan-1-ol trihydrochloride with tert-butyl 2-bromoacetate in the presence of a diisopropylethylamine and potassium iodide in a solvent comprising dimethylformamide to form a solution comprising a compound of Formula (1);
(ii) after (i), treating the solution with diethanolamine at about 40° C. to about 60° C.;
(iii) after (ii), adding the solution 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
(iv) after (iii), filtering the organic solution through a column of silica gel.

13 . The process of claim 12 , 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.

14 . The process of any one of claims 3 to 13 , comprising, prior to step (a), hydrogenating 4,4-diphenylcyclohex-2-enone in tetrahydrofuran in the presence of Raney nickel and hydrogen.

15 . A process of preparing a pharmaceutically acceptable formulation of gadofosveset trisodium monohydrate, comprising:
(a) reacting 4,4-diphenylcyclohexanol with phosphorous trichloride to form dichloro((4,4-diphenylcyclohexyl)oxy)phosphine; (b) reacting dichloro((4,4-diphenylcyclohexyl)oxy)phosphine with 1H-imidazole to form 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole); (c) reacting 1,1′-(((4,4-diphenylcyclohexyl)oxy)phosphinediyl)bis(1H-imidazole) with a compound of Formula (1):

to form a compound of Formula (2):

(d) 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 fosvoset;
(e) reacting an aqueous solution of fosveset with gadolinium oxide, followed by reaction with sodium hydroxide to form gadofosveset trisodium monohydrate.

16 . The process of claim 15 , further comprising, prior to (c):
(i) reacting (R)-2-amino-3-((2-aminoethyl)amino)propan-1-ol trihydrochloride with tert-butyl 2-bromoacetate in the presence of a diisopropylethylamine and potassium iodide in a solvent comprising dimethylformamide to form a solution of a compound of Formula (1); (ii) after (i), treating the solution with diethanolamine at about 40° C. to about 60° C.; (iii) after (ii), adding the solution 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 (iv) after (iii), filtering the organic solution through a column of silica gel.

17 . The process of claim 16 , 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 sol

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