Process for the monotopic preparation of intermediate organo-iodinated compounds for the synthesis of ioversol

Abstract

A process for preparing an organo-iodinated compound, comprising the following steps: a) acylating 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below: ##STR00001## to obtain an intermediate compound Ya; b) chlorinating the intermediate compound Ya to obtain an organo-iodinated intermediate compound Yb; c) amidating the organo-iodinated intermediate compound Yb to obtain an intermediate compound Yc; and d) deprotecting the intermediate compound Yc, the steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc.

Claims

1. A process for preparing an organo-iodinated compound, comprising the following steps: a) acylating 2,4,6-triiodo-5-aminoisophthalic acid of formula (A) below: ##STR00015## with a compound of formula (I) below:
R.sub.2—C(O)CI  (I), wherein R2 is a -CH.sub.2-GP group and GP is a leaving group selected from the group consisting of a halide, an acetate, a mesylate, a tosylate, and a triflate to obtain an intermediate compound Ya of formula (Ya) below: ##STR00016## wherein the compound of formula (I) is present in an amount between 1 and 1.5 molar equivalents with respect to the amount of the 2,4,6-triiodo-5-aminoisophthalic acid; b) chlorinating the intermediate compound Ya to obtain an organo-iodinated intermediate compound Yb of formula (II) below: ##STR00017## wherein R.sub.1 is H; c) amidating the organo-iodinated intermediate compound Yb in the presence of an inorganic base and of an amine of formula (IV) below:
R.sub.3—NH.sub.2  (IV), wherein R3 represents an alkyl group comprising 1 to 6 carbon atoms, said alkyl group optionally being substituted by one or more hydroxyl groups, or a salt thereof to obtain an intermediate compound Yc of formula (Yc) below: ##STR00018## and d) deprotecting the intermediate compound Yc to obtain to organo-iodated compound Yd of formula (Yd) below: ##STR00019## the steps a), b), c) and d) being carried out without isolation of at least one intermediate compound chosen from Ya and Yc.

2. The preparation process of claim 1, free of a step of separating the intermediate compound Ya from the reaction medium obtained at the end of step a).

3. The preparation process of claim 1, free of a step of separating the intermediate compound Yc from the reaction medium obtained at the end of step c).

4. The preparation process of claim 1, wherein R2 is —CH.sub.2Cl or ##STR00020##

5. The preparation process of claim 1, wherein the steps a), b), c) and d) are carried out without isolation of the intermediate compounds Ya and Yc.

6. The preparation process of claim 1, wherein the steps a), b), c) and d) are carried out without purification of the intermediate compound Yb.

7. The preparation process of claim 1, free of addition of a nonsolvent of the intermediate compound Ya during step a) and between steps a) and b).

8. The preparation process of claim 1, wherein the steps a), b), c) and d) are carried out in a single reactor.

9. The preparation process of claim 1, wherein the steps a), b), c) and d) are carried out in the presence of a solvent selected from the group consisting of dimethylacetamide, propylene carbonate, acetonitrile, tetrahydrofuran, and mixtures thereof.

10. The preparation process of claim 1, wherein step b) is carried out in a solvent that is a mixture of propylene carbonate and dimethylacetamide.

11. The preparation process of claim 1, wherein step c) is carried out in the presence of an aqueous solution.

12. The preparation process of claim 9, wherein: the solvent of step a) is dimethylacetamide; and/or the solvent of step c) and/or of step d) is a mixture of dimethylacetamide and an aqueous solution.

13. The preparation process of claim 1, wherein the chlorination of step b) is carried out in the presence of a chlorinating agent selected from the group consisting of thionyl chloride, phosphorus oxychloride, phosphorus trichloride, oxalyl chloride, phosphorus pentachloride, methanoyl dichloride, and mixtures thereof.

14. The preparation process of claim 1 further comprising: adding a nonsolvent of the intermediate compound Yb into the reaction medium obtained at the end of step b), whereby the intermediate compound Yb precipitates from the reaction medium and a reaction medium comprising a liquid phase and a precipitate is obtained; separating the precipitate and the liquid phase; and dissolving of the separated precipitate in a solvent of the intermediate compound Yb to obtain a solution used to carry out step c).

15. The preparation process as claimed in claim 1, wherein the amidation of step c) is carried out with 3-amino-1,2-propanediol.

16. The preparation process as claimed in claim 1, wherein the deprotection of step d) is carried out with sodium hydroxide, hydrochloric acid, or a mixture thereof.

Description

EXAMPLES

(1) The term “V” is understood to denote a volume ratio, namely the volume of a reagent or of a solvent relative to 1 kg of AATI.

(2) The term “eq.” is understood to denote a molar equivalent number, namely the ratio between the number of moles of a reagent and the number of moles of AATI.

Example 1: Synthesis According to the Invention of an Ioversol Synthesis Intermediate

(3) Synthesis Scheme

(4) MP602 Starting from AATI

(5) ##STR00013##
Acylation Step:

(6) 2-chloro-2-oxoethyl acetate (also known as AAC) (281 g, 1.15 eq.) is dissolved in dimethylacetamide (DMAC) (1.35 l) and AATI (1 kg, 1.0 eq.) is gradually added at 50° C. The reaction medium is mixed for 6 hours at 50° C. Propylene carbonate (1.15 l) is added and the reaction is cooled to 5° C.

(7) Chlorination Step:

(8) Thionyl chloride SOCl.sub.2 (745 g, 3.5 eq.) is added at 5° C. over 2 hours and the reaction medium is mixed for 5 hours at 5° C.

(9) The reaction medium is added to an aqueous solution of sodium acetate (AcONa) so as to precipitate the “DiCOA-like” synthesis intermediate. The suspension is filtered and the solid portion is redissolved in DMAC (1.5 ml) to obtain a solution.

(10) Amidation Step:

(11) A mixture of aminopropanediol (APD) (359 g, 2.2 eq.) and an aqueous 30% sodium hydroxide (NaOH) solution (359 ml) is added to the solution over 6 hours. The reaction medium is mixed for 2 hours at 12.5° C.

(12) Deprotection Step:

(13) Water (1 l) and an aqueous 30% sodium hydroxide (NaOH) solution (359 ml) are added at 50° C. over 2 hours and 30 minutes. 37% hydrochloric acid (HCl) (900 ml) is then added at 50° C. and the reaction is cooled to 5° C. The suspension is filtered, washed with an isopropanol (IPA)/water mixture and dried. The yield obtained is 83% and the purity obtained is 99%.

Example 2: Synthesis of Ioversol from the Synthesis Intermediate Obtained According to the Invention

(14) The compound obtained in example 1 is then alkylated using 2-chloroethanol or ethylene oxide. The compound thus obtained is then purified and dried in order to obtain ioversol.

(15) ##STR00014##