Synthesis of iopamidol and preparation of iopamidol synthesis intermediate

Abstract

The invention discloses a method for preparation of (S)-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-[(2-hydroxy-1-oxopropyl)amino]-2,4,6-triiodo-1,3-benzenedicarboxamide (iopamidol) shown in the formula I from 5-amino-N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-2,4,6-triiodo-1,3-benzenedicarboxamide shown in the formula II. The method comprises the following steps that a, the compound shown in the formula II and a mixed anhydride as an appropriate protective agent undergo a reaction to produce a mixed ester shown in the formula III; b, the mixed ester shown in the formula III and (S)-2-(acetoxy)propionyl chloride undergo a reaction so that an amino group at the 5th site is acylated and a compound shown in the formula IV is obtained; and c, the compound shown in the formula IV undergoes a hydrolysis reaction under acidic or alkaline conditions or undergoes an alcoholysis reaction so that all acyl groups of the compound shown in the formula IV are removed and the iopamidol shown in the formula III is obtained. The invention relates to a synthesis intermediate of the iopamidol shown in the formula III.

Description

technical field

[0001] The present invention relates to a preparation of iopamidol (i.e. (S)-N,N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]- Novel process for 5-[(2-hydroxy-1-oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide) and novel intermediates prepared by said process . Background of the invention

[0002] The known iopamidol is (S)-N, N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]-5-[(2-hydroxyl-1 -Oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide:

[0003]

[0004] It is one of the most widely used non-ionic X-ray contrast agents in the world.

[0005] It was first described in US 4001323, where its synthesis was reported by two routes outlined in the following schemes.

[0006] Synthetic route (1):

[0007]

[0008] The above-mentioned synthetic route is still widely used in industry, but one of its shortcoming is that in the early stage of the whole route, before amidation with 2-amino-1,3-propanediol, the protected Chiral synthon (S)-2-(acetyloxy...

Examples

preparation example Construction

[0049] The reaction of step a) for the preparation of compounds of formula (III) is preferably in which there is a slightly stoichiometric excess of a suitably selected "mixed anhydride" relative to the compound of formula (II) and optionally a catalytic amount (generally 0.01 to 0.1 molar / 1 mole of compound of formula (II)) in N,N-dimethylacetamide solution of 4-(dimethylamino)pyridine of compound of formula (II). Optional 4-(dimethylamino)pyridine can be added to the reaction mixture as such or supported on the resin.

[0050] Four moles of "mixed anhydride" must be used per mole of starting compound (II). But in general, there is a slight excess, such as about 10%, 20% or even 25%, preferably a molar excess of up to about 50%; it is preferred to use five moles of "mixed anhydride" per mole of starting compound (II).

[0051] The reaction of step a) is generally carried out at room temperature, but can also be carried out at lower or higher temperatures, for example, a tem...

Embodiment 1

[0077] Preparation of N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-nitro-1,3-benzenedicarboxamide

[0078]Add 5-nitro-isophthalic acid dimethyl ester (120g, 0.50mol), 2-amino-1,3-propanediol (136g, 1.50mol), methanol (960mL) in a 2000mL three-necked flask, stir and heat Return to reflux for 24 hours; cool down to 20°C, filter, wash the filter cake twice with methanol (20mL×2), and dry to obtain 178.4g of the product, with a yield of 99.5%.

[0079] 1 H-NMR, 13 C-NMR, IR and MS were consistent with the shown structure.

Embodiment 2

[0081] N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (compound of formula (II)) preparation of

[0082] Suspend the N,N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]-5-nitro-1,3-benzenedicarboxamide (120g, 0.34mol) prepared in Example 1 in 90 ℃ water (1200mL), stirring, acetic acid to adjust the pH to below 5; under the protection of nitrogen, add 30g of Raney nickel (wet weight), replace the nitrogen with hydrogen and pressurize to 1.4MPa, keep at 90 ℃ for more than 6 hours. After the reaction is complete, filter.

[0083] The filtrate was warmed up to 50°C, and potassium iodide dichloride (KICl 2 , 263g, 1.11mol) aqueous solution, after the dropwise addition, continue to keep warm at 90°C and stir the reaction for more than 3 hours; after the reaction is completed, recover excess iodine by sublimation method.

[0084] The reaction solution was cooled to 20°C, filtered, and the filter cake was washed with 50 mL×4 water, and dried to ob...

technical field

[0001] The present invention relates to a preparation of iopamidol (i.e. (S)-N,N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]- Novel process for 5-[(2-hydroxy-1-oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide) and novel intermediates prepared by said process . Background of the invention

[0002] The known iopamidol is (S)-N, N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]-5-[(2-hydroxyl-1 -Oxopropyl)-amino]-2,4,6-triiodo-1,3-benzenedicarboxamide:

[0003]

[0004] It is one of the most widely used non-ionic X-ray contrast agents in the world.

[0005] It was first described in US 4001323, where its synthesis was reported by two routes outlined in the following schemes.

[0006] Synthetic route (1):

[0007]

[0008] The above-mentioned synthetic route is still widely used in industry, but one of its shortcoming is that in the early stage of the whole route, before amidation with 2-amino-1,3-propanediol, the protected Chiral synthon (S)-2-(acetyloxy...

Examples

preparation example Construction

[0049] The reaction of step a) for the preparation of compounds of formula (III) is preferably in which there is a slightly stoichiometric excess of a suitably selected "mixed anhydride" relative to the compound of formula (II) and optionally a catalytic amount (generally 0.01 to 0.1 molar / 1 mole of compound of formula (II)) in N,N-dimethylacetamide solution of 4-(dimethylamino)pyridine of compound of formula (II). Optional 4-(dimethylamino)pyridine can be added to the reaction mixture as such or supported on the resin.

[0050] Four moles of "mixed anhydride" must be used per mole of starting compound (II). But in general, there is a slight excess, such as about 10%, 20% or even 25%, preferably a molar excess of up to about 50%; it is preferred to use five moles of "mixed anhydride" per mole of starting compound (II).

[0051] The reaction of step a) is generally carried out at room temperature, but can also be carried out at lower or higher temperatures, for example, a tem...

Embodiment 1

[0077] Preparation of N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-nitro-1,3-benzenedicarboxamide

[0078]Add 5-nitro-isophthalic acid dimethyl ester (120g, 0.50mol), 2-amino-1,3-propanediol (136g, 1.50mol), methanol (960mL) in a 2000mL three-necked flask, stir and heat Return to reflux for 24 hours; cool down to 20°C, filter, wash the filter cake twice with methanol (20mL×2), and dry to obtain 178.4g of the product, with a yield of 99.5%.

[0079] 1 H-NMR, 13 C-NMR, IR and MS were consistent with the shown structure.

Embodiment 2

[0081] N,N'-bis[2-hydroxy-1-(hydroxymethyl)ethyl]-5-amino-2,4,6-triiodo-1,3-benzenedicarboxamide (compound of formula (II)) preparation of

[0082] Suspend the N,N'-bis[2-hydroxyl-1-(hydroxymethyl)ethyl]-5-nitro-1,3-benzenedicarboxamide (120g, 0.34mol) prepared in Example 1 in 90 ℃ water (1200mL), stirring, acetic acid to adjust the pH to below 5; under the protection of nitrogen, add 30g of Raney nickel (wet weight), replace the nitrogen with hydrogen and pressurize to 1.4MPa, keep at 90 ℃ for more than 6 hours. After the reaction is complete, filter.

[0083] The filtrate was warmed up to 50°C, and potassium iodide dichloride (KICl 2 , 263g, 1.11mol) aqueous solution, after the dropwise addition, continue to keep warm at 90°C and stir the reaction for more than 3 hours; after the reaction is completed, recover excess iodine by sublimation method.

[0084] The reaction solution was cooled to 20°C, filtered, and the filter cake was washed with 50 mL×4 water, and dried to ob...

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