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Novel preparation method of iopromide

A technology for iopromide and triiodoisophthalic acid is applied in the field of preparation of obtaining two kinds of iopromide, can solve the problems such as the inability to improve the yield of the synthesis process, and achieves the effects of solving color and luster and removing bismer by-products

Active Publication Date: 2013-03-13
浙江海昌药业股份有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0045] Therefore, the preparation of (19) according to PCT patent WO2009134030 method will also generate the by-product (bismer) of compound (5), which can be removed by simple crystallization method The by-product (bismer) generated in the process can only be used to improve the purity of compound (19), but not to improve the yield of the synthetic process

Method used

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  • Novel preparation method of iopromide
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  • Novel preparation method of iopromide

Examples

Experimental program
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Effect test

Embodiment 1

[0061] 5-amino-3-(2,3-dihydroxypropylacetyl)-2,4,6-triiodoisophthalic acid (63.2 g, 100mol), methoxyacetic anhydride (97.2 g, 600 mmol ), DMAP (0.63 g, 5.1 mmol) were mixed and heated to 100 ° C, stirred for 20 hours, and the reaction of the raw materials was basically completed. After washing with solvent, 74.1 g of the title compound was obtained as a white solid, with an HPLC purity ≥ 98% and a yield of 85.6%.

[0062] LC-MS: 848.8 ( theoretical value 848.13). 1 H NMR (DMSO-d 6 , 500MHz) 13.98(s, 1H); 10.11~10.00(2s, 1H); 8.95~8.82(m, 1H); 5.22~5.18(m, 1H); 4.44~4.40(m, 1H); 4.31~4.27( m, 1H); 4.10~4.00(m, 6H); 3.58~3.53(m, 1H); 3.47~3.40(m, 4H); 3.32(s, 3H); 3.31(s, 3H);

Embodiment 2

[0064] 5-Amino-3-(2,3-dihydroxypropylacetyl)-2,4,6-triiodoisophthalic acid (63.2 g, 100 mmol) was dissolved in 31.5 g DMAC and triethylamine ( 1.1g, 10mmol), cooled to below 20°C, slowly dropwise added methoxyacetyl chloride (43.4g, 400mmol), kept the temperature not exceeding 20°C during the dropwise addition, and slowly raised the temperature to 80°C, and kept the temperature for 1 Hours, HPLC detection monoamide content ≥ 95%. Distill the solution to dryness under reduced pressure, add 150ml mixed organic solvent, heat to dissolve, cool to crystallize, filter, wash with a small amount of mixed organic solvent to obtain 71.6g of the title compound as a white solid, HPLC purity ≥ 96%, yield 79.8%.

[0065] Step 1-a

Embodiment 3

[0067] 5-Methoxyacetamido-3-(2,3-dihydroxypropylacetyl)-2,4,6-triiodoisophthalic acid (70.4 g, 100mol) and methoxyacetic anhydride (81.0 g, 500 mmol), DMAP (0.63 g, 5.1 mmol) were mixed and heated to 100°C, stirred for 5 hours, and the monoamide content was ≥98% by HPLC. Distill the solution to dryness under reduced pressure, add 150ml of mixed organic solvent, heat to dissolve, cool to crystallize, filter, wash with a small amount of mixed organic solvent to obtain 72.3g of the title compound as a white solid, HPLC purity ≥ 98%, yield 83.6%.

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Abstract

The invention relates to a preparation method of iopromide. The preparation method comprises the following steps of: on the basis of using 5-amino-3-(2,3-dyhydroxy propylamino formyl)-2,4,6-triiodo isophthalic acid shown in a formula II or 5-methoxyl acetamido-3-(2,3-dyhydroxy propylamino formyl)-2,4,6-triiodo isophthalic acid shown in a formula II-1 as a starting material, protecting amino in a position 5 of the formula II and two hydroxyls in (2,3-dyhydroxy propylamino formyl) in a position 3 or two hydroxyls in (2,3-dyhydroxy propylamino formyl) in a position 3 of the formula II-1 by using methoxyl acetyl, so as to generate a compound shown in a formula III; chloridizing by utilizing a chloridizing agent, so as to prepare a corresponding acyl chloride compound shown in a formula IV; then reacting with methylamino propylene glycol to generate a compound shown in a formula V; and hydrolyzing and purifying so as to prepare high-purity iopromide.

Description

technical field [0001] The present invention relates to a preparation method for obtaining two kinds of iopromide (formula I). Specifically: the method involves the use of 5-amino-3-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodoisophthalic acid [formula II] or 5-methoxyacetamido -3-(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodoisophthalic acid [Formula II-1] is the starting material; The two hydroxyl groups in the 3-position (2,3-dihydroxypropylcarbamoyl) or the two hydroxyl groups in the 3-position (2,3-dihydroxypropylcarbamoyl) of [Formula II-1] adopt formaldehyde After protection of the oxyacetyl group, 5-methoxyacetamido-3-(2,3-dimethoxyacetoxypropylaminoformyl)-2,4,6-triiodoisophthalic acid [formula III ], [formula III] reacts with thionyl chloride to prepare 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid-3-(2,3-dimethoxyacetyl hydroxypropyl )] Amide chloride [formula IV], [formula IV] reacts with 3-methylamino-1,2-propanediol to obtain 5-methoxyacetamido-2,4,6-triiodo...

Claims

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Application Information

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IPC IPC(8): C07C237/46C07C231/12
Inventor 张怀义刘颖平许志杰
Owner 浙江海昌药业股份有限公司
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