Process for the preparation of iopamidol

Patent metadata

Field	Value
Publication number	US-9950991-B2
Application number	US-201415033737-A
Country	US
Kind code	B2
Filing date	Nov 4, 2014
Priority date	Nov 5, 2013
Publication date	Apr 24, 2018
Grant date	Apr 24, 2018

Abstract

The present invention discloses a process for the preparation of Iopamidol of formula (II) and comprising the following steps: a) reacting the Compound (I) wherein X is OR2 or R3, and wherein R2 and R3 are a Ci-C6 linear or branched alkyl, C3-C6 cycloalkyl, C6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl and phenyl, with the acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide the acetyloxy derivative of Compound (I); b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH comprised from 0 to 7, by adding water or a diluted alkaline solution such as sodium hydroxide or potassium hydroxide, freeing the hydroxyls from the boron-containing protective groups, obtaining the N—(S)-2-(acetyloxy)propanoyl derivative of Compound (II); c) alkaline hydrolysis to restore the (S)-2-(hydroxy)propanoyl group and to obtain Iopamidol (II) and optional recovery of the boron derivative from the solution obtained in step b). The boron-containing protective group is versatile, efficient and recyclable. A one-pot synthesis, without intermediate isolation is provided, leading to a decreasing of recovered and recycled solvents and a significant increasing in the yield, representing a significant advantage in terms of cost-effectiveness of the entire process and environmental awareness.

First claim

The invention claimed is:

1. A process for preparation of Iopamidol (II) comprising the following reaction:

wherein X is OR 2 or R 3 , and wherein R 2 and R 3 are individually a C 1 -C 6 linear or branched alkyl, C 3 -C 6 cycloalkyl, or C 6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and phenyl;
and comprising the following steps:
a) reacting Compound (I) with an acylating agent (S)-2-(acetyloxy)propanoyl chloride in a reaction medium to provide an intermediate, N—(S)-2-(acetyloxy)propanoyl derivative of Compound (I);
b) hydrolyzing the intermediate from step a) with an aqueous solution at a pH from 6 to 7 comprising:
adding water or a diluted alkaline solution,
freeing hydroxyls from the boron-containing protective groups,
obtaining an aqueous mixture of an acetyloxy derivative of Iopamidol (II) and a boron-derivative, and
optionally recovering the boron-derivative; and

c) hydrolyzing the acetyloxy derivative of Iopamidol (II) to obtain Iopamidol (II).

2. The process according to claim 1 , wherein X is OR 2 .

3. The process according to claim 1 , wherein X is R 3 .

4. The process according to claim 1 , wherein said reaction medium in step a) is an anhydrous organic solvent.

5. The process according to claim 1 , wherein said reaction medium in step a) is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, N-methylpyrrolidone N-ethylpyrrolidone, tetramethylurea, N,N′-dimethylethyleneurea (DMEU), and N,N′-dimethylpropyleneurea (DMPU), optionally in an admixture with a co-solvent.

6. The process according to claim 1 , wherein in step b) the optional recovering of the boron-derivative is carried out by chromatography or by co-solvent extraction.

7. The process according to claim 1 , wherein said Compound (I) is prepared starting from a Compound of formula (IV), according to the following reaction:

and comprising:
reacting the Compound of formula (IV) with a boric acid in an R 2 OH alcohol or a borate ester B(OR 2 ) 3 , to provide the Compound of formula (I), wherein X is OR 2 ; or
reacting the Compound of formula (IV) with a boronic acid R 3 —B(OH) 2 or a boroxine of formula (III):

to provide the Compound of formula (I), wherein X is R 3 .

8. The process according to claim 7 , wherein the borate ester B(OR 2 ) 3 is used.

9. The process according to claim 8 , wherein the borate ester B(OR 2 ) 3 is selected from the group consisting of tri-n-butyl borate, tri-n-propyl borate, and tri-ethyl borate.

10. The process according to claim 7 , wherein said Compound (I) is prepared by reacting the Compound of formula (IV) with the boronic acid R 3 —B(OH) 2 or the boroxine (III).

11. The process according to claim 10 , wherein the boronic acid R 3 —B(OH) 2 is selected from the group consisting of phenylboronic acid, tolylboronic acid, and butylboronic acid; and the boroxine of formula (III) is selected from the group consisting of tri-phenylboroxine and tri-methylboroxine.

12. The process according to claim 10 , which comprises recovering the boron-derivative by a co-solvent extraction with a co-solvent, wherein said co-solvent is an organic water-immiscible solvent selected from the group consisting of 4-methyl-2-pentanone, 2-pentanone, 3-pentanone, dibutyl ether, 2-methyl-tetrahydrofurane, ciclopentylmethyl ether, methyl isopropyl ketone, methyl isopentyl ketone, ethyl acetate, butyl acetate, pentyl acetate, isopentyl acetate, and isopropyl acetate.

13. The process according to claim 1 , which is a one-pot process.

14. The process according to claim 7 , wherein said Compound of formula (IV) is prepared by iodinating Compound (V):

15. The process according to claim 14 , wherein said Compound (V) is prepared according to the following reaction scheme:

wherein:
i) the 5-nitroisophthalic acid (5-NIPA) is treated with an R 1 OH alcohol, wherein R 1 is a linear or branched C 1 -C 4 alkyl, to provide the corresponding diester (VI);
ii) the 5-nitro group of the diester (VI) is reduced to the corresponding 5-amino group to provide the Compound (VII); and
iii) the two ester groups of Compound (VII) are reacted with 2-amino-1,3-propandiol to provide the Compound (V).

16. A process for the preparation of Iopamidol (II) according to the following reaction scheme:

wherein X is OR 2 or R 3 , and wherein R 2 and R 3 are individually a C 1 -C 6 linear or branched alkyl, C 3 -C 6 cycloalkyl, or C 6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and phenyl, comprising:
i) treating the 5-nitroisophthalic acid (5-NIPA) with an R 1 OH alcohol, wherein R 1 is a linear or branched C 1 -C 4 alkyl, to provide the diester (VI);
ii) reducing the 5-nitro group of the diester (VI) to provide the Compound (VII);
iii) reacting the two ester groups of Compound (VII) with 2-amino-1,3-propandiol to provide the Compound (V), 5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-1,3-benzenedicarboxamide;
iv) iodinating the Compound (V) at positions 2, 4, 6, to provide the Compound (IV), 5-Amino-N,N′-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide;
v) treating the Compound (IV) with a boronic acid R 3 —B(OH) 2 , a borate ester B(OR 2 ) 3 , or a boroxine of formula (III),

 to provide the Compound of formula (I); and
vi) transforming the Compound of formula (I) into Iopamidol (II) according to claim 1 .

17. The process according to claim 1 , further comprising isolating and purifying Iopamidol (II).

18. The process according to claim 17 , wherein said purifying step is to pharmaceutical grade.

19. A Compound of formula (I)

wherein X is OR 2 or R 3 , and wherein R 2 and R 3 are individually a C 1 -C 6 linear or branched alkyl, C 3 -C 6 cycloalkyl, or C 6 aryl, optionally substituted with a group selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and phenyl.

20. The Compound of claim 19 , wherein X is selected from the group consisting of phenyl, methyl substituted phenyl, methyl, and butyl.

21. The Compound of claim 20 , wherein X is phenyl.

22. A method of converting Compound of formula (I)

to an intermediate, N—(S)-2-(acetyloxy)propanoyl derivative of Compound (I), comprising reacting Compound (I)

Assignees

• Bracco Imaging Spa

Inventors

• Battistini Elisa
• Buonsanti Federica
• Imperio Daniela
• Lattuada Luciano
• Napolitano Roberta

Classifications

• Y02P20/55

  Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups · CPC title

• C07F5/04

  Esters of boric acids · CPC title

• C07C201/12 Primary

  by reactions not involving the formation of nitro groups · CPC title

• C07C231/02 Primary

  from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines · CPC title

• C07C231/12

  by reactions not involving the formation of carboxamide groups · CPC title