CN1314659C - Method for preparing ioxitalamic acid - Google Patents
Method for preparing ioxitalamic acid Download PDFInfo
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- CN1314659C CN1314659C CNB2006100381140A CN200610038114A CN1314659C CN 1314659 C CN1314659 C CN 1314659C CN B2006100381140 A CNB2006100381140 A CN B2006100381140A CN 200610038114 A CN200610038114 A CN 200610038114A CN 1314659 C CN1314659 C CN 1314659C
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Abstract
The present invention relates to a method for preparing ioxitalamic acid, which belongs to the technical field of the synthesis of X-ray contrast agents and organic compounds. The ioxitalamic acid has a chemical name of 5-acetamido-N-(2-hydroxyethyl)-2, 4, 6-triiodo m-formamide benzoic acid, and is a crude drug of ionic X-ray contrast agent developing meglumine and a key intermediate of nonionic X-ray contrast agent ioxilan. The present invention adopts methyl 5-nitroisophthalate as raw materials, and an amidation reaction, a catalysis reduction reaction, an iodination reaction and an atetylate reaction are carried out on the raw materials so as to prepare the ioxitalamic acid. The method of the present invention has the advantages of mild reaction conditions, short operating procedures and easy realization of large industrial production.
Description
Technical field
The present invention relates to the preparation method of ioxitalamic acid, belong to Baryan and organic compound synthesis technical field.This compound is the bulk drug of ionic x-ray contrast medium Telebrix 350, is again the key intermediate of non-ionic x-ray contrast medium ioxitol.
Background technology
Ioxitalamic acid, chemical name: 5-acetamido-N-(2-hydroxyethyl)-2,4, formamide benzene formic acid between the 6-triiodo, the commodity of its preparation are called Telebrix 350, structural formula (I):
Ioxitalamic acid, its preparation Telebrix 350 is in ionic x-ray contrast medium, has best hydrophilic molecules structure, compare with other ionic x-ray contrast medium, Local security and whole body security are better, the chance that causes allergic reaction lowers greatly, so Telebrix 350 is a kind of most widely used general and safest ionic x-ray contrast medium, is applicable to CT examination, arteriovenous radiography and urography etc.
In addition, ioxitalamic acid is again the crux intermediate of non-ionic x-ray contrast medium ioxitol, and ioxitol be develop in recent years have more low-viscosity, a non-ionic x-ray contrast medium of Hyposmolality more, can in blood vessel, use widely, use under the arachnoid membrane and the body cavity planted agent with and gastrointestinal examination etc.
The synthetic route of ioxitalamic acid reported in literature is as follows:
1. English Patent GB1146133 report, preparing described method by it is to be starting raw material with the 5-nitroisophthalic acid, carries out the ethyl ester reaction successively, hydrolysis reaction, amidate action, reduction reaction, iodination reaction and acetylization reaction make ioxitalamic acid.Reaction scheme is as follows:
Ethyl ester reaction in this synthetic route is that 5-nitroisophthalic acid and dehydrated alcohol carry out esterification and obtain 5-nitroisophthalic acid diethyl ester, the reaction that is hydrolyzed then obtains 5-nitroisophthalic acid mono ethyl ester, therefore the total recovery that patent is reported this two-step reaction is 37%, and it is low to adopt this method to prepare the yield of 5-nitroisophthalic acid mono ethyl ester.In addition, reduction reaction in this synthetic method is with ammonium sulfide nitro to be reduced, produce ammonia and excessive ammonium sulfide foam in the reaction, produce sulfurous gas and elemental sulfur during to the aftertreatment of reaction solution, therefore make reductive agent with ammonium sulfide, not only environment is easily produced pollution, and the yield of this reduction reaction is on the low side.
2. English Patent GB 1275745 report, preparing described method by it is to be starting raw material with 5-nitroisophthalic acid mono-methyl, carries out acyl chloride reaction successively; amidate action; hydrolysis reaction, reduction reaction, iodination reaction and acetylization reaction make ioxitalamic acid.Reaction scheme is as follows:
Acyl chloride reaction in this synthetic route is to react with sulfur oxychloride and 5-nitroisophthalic acid mono-methyl, produce a large amount of hydrogen chloride gas and sulfur dioxide gas in the reaction, and excessive sulfur oxychloride pollutes to environment easily all.In addition, make from 5-nitroisophthalic acid mono-methyl that formamide benzene formic acid need pass through acyl chloride reaction between the 5-nitro, amidate action and hydrolysis reaction are because reactions steps is long, so the preparation cost height.
Therefore, above-mentioned two kinds of synthetic methods need to improve, should design one more reasonable, cost is low, meets the synthetic route of suitability for industrialized production.
Summary of the invention
The object of the present invention is to provide a kind of 5-acetamido-N-(2-hydroxyethyl)-2,4, the benzoic preparation method of methane amide between the 6-triiodo adopts a design more reasonable, and cost is low, meets the synthetic route of suitability for industrialized production.
Technical scheme of the present invention: with 5-nitroisophthalic acid mono-methyl is starting raw material, carries out amidate action successively, catalytic reduction reaction, and iodination reaction and acetylization reaction make, and reaction scheme is as follows:
A) amidate action: 5-nitroisophthalic acid mono-methyl (compound V) carries out amidate action with thanomin in methyl alcohol, compound (V): the mol ratio of thanomin 1: 2.5, in the there-necked flask that agitator and reflux condensing tube are housed, add 5-nitroisophthalic acid mono-methyl and methyl alcohol under the room temperature, add thanomin after waiting to stir again, be warming up to 30～60 ℃ then, stir and finish reaction after 30～60 hours, boil off part methyl alcohol under the decompression, in debris, add distilled water, after stirring, with hydrochloric acid adjust pH to 1, leave standstill, the solid filtering of separating out, the washing, dry 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid;
B) catalytic reduction reaction: 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid (compound IV) is carried out catalytic reduction reaction with the Pd/C catalyzer, compound (IV): the mol ratio of sodium hydroxide 1: 1, compound (IV): the mass ratio of Pd/C 1: 0.16, described Pd/C catalyzer is that the Pd mass content is 5%, under the room temperature 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid is dissolved in the aqueous sodium hydroxide solution, add the Pd/C catalyzer again, feed hydrogen then, be warming up to 50～90 ℃ simultaneously, the normal pressure catalytic hydrogenation finishes reaction after 6～30 hours.With reacting liquid filtering, filter cake behind distilled water wash, merging filtrate.Stir down, in filtrate, add concentrated hydrochloric acid, obtain 5-amino-N-(2-hydroxyethyl)-benzoic aqueous hydrochloric acid of a methane amide, need not purifying and directly supply next step iodination reaction to pH value to 1.
C) iodination reaction: 5-amino-N-(2-hydroxyethyl)-formamide benzene formic acid (compound III) is carried out iodination reaction with iodine monochloride, compound (III): the mol ratio of iodine monochloride 1: 3,5-amino-N-(2-the hydroxyethyl)-formamide benzene aqueous formic acid that the preceding step is obtained is warming up to 60 ℃, stir and add iodine monochloride solution down, be warming up to 70～90 ℃ then, stir and finished reaction in 1～4 hour.Be cooled to 15 ℃, filter, the distillation washing, dry 5-amino-N-(2-hydroxyethyl)-2,4, formamide benzene formic acid between the 6-triiodo.Described iodine monochloride solution is to be dissolved in the 2mol/L sodium chloride aqueous solution with iodine monochloride to make iodine monochloride: the mol ratio of sodium-chlor 1: 1.
D) acetylization reaction: with excessive acetic anhydride via and 5-amino-N-(2-hydroxyethyl)-2; 4; formamide benzene formic acid (Compound I I) carries out acylation reaction between the 6-triiodo; and use sulphuric acid catalysis; compound (II): diacetyl oxide: the mol ratio of the vitriol oil 1: 20～25: 0.18; in reaction flask, add 5-amino-N-(2-hydroxyethyl)-2 under the room temperature; 4; formamide benzene formic acid and diacetyl oxide between the 6-triiodo; drip the vitriol oil after waiting to stir; be warming up to 50～90 ℃ then, react and finish reaction after 2～10 hours.Boil off diacetyl oxide under the decompression, residue is dissolved in the methyl alcohol, adds distilled water again, after stirring, the dropping sodium aqueous solution, after the stirring at room 2 hours,, filter with concentrated hydrochloric acid adjust pH to 1, the distillation washing, dry 5-acetamido-N-(2-hydroxyethyl)-2,4, formamide benzene formic acid (Compound I) between the 6-triiodo.
Beneficial effect of the present invention: the starting raw material in the synthetic method of the present invention is a 5-nitroisophthalic acid mono-methyl, and it has manufacturer production at home, buys easily.Synthetic 5-nitroisophthalic acid mono ethyl ester in the described method of English Patent GB1146133, yield is low, the cost height.
In addition, the synthetic method that English Patent GB1275745 provides also is that employing 5-nitroisophthalic acid mono-methyl is a starting raw material, but when preparation 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid, the synthetic method that English Patent GB1275745 provides is that 5-nitroisophthalic acid mono-methyl and sulfur oxychloride carry out acyl chloride reaction, carry out amidate action with thanomin then, the reaction that is hydrolyzed in the presence of alkali at last makes, reactions steps is long, the total recovery of three-step reaction has only 75%, and adopt sulfur oxychloride to carry out acyl chloride reaction in the reaction, big for environment pollution.And the present invention adopts 5-nitroisophthalic acid mono-methyl and thanomin direct reaction, just makes by single step reaction, and yield reaches 85%.
Reactions steps b among the present invention) be the catalytic hydrogenation reduction reaction, adopt the Pd/C catalyzer, need not purifying after the reaction and directly carry out next step iodination reaction, the total recovery of this two-step reaction surpasses 93%, yield height and environmentally safe.And the employing of the reduction reaction described in English Patent GB1275745 PdO/C is a catalyzer, and reduction finishes purified 5-amino-N-(2-the hydroxyethyl)-formamide benzene formic acid that obtains in back, and then carries out iodination reaction, and wherein the yield of iodination reaction has only 45%.In addition, reduction reaction described in the English Patent GB 1146133 adopts ammonium sulfide to be reductive agent, and is big for environment pollution, and reduction reaction and two step of iodination reaction total recovery have only 70%.
Therefore, the synthetic route reaction conditions gentleness of the present invention's design, reactions steps shortens, steady quality, the yield height, cost is low, is fit to industrialized production.
Embodiment
Embodiment 1
5-nitro-N-(2-hydroxyethyl)-methane amide is benzoic synthetic:
In the there-necked flask that agitator and reflux condensing tube are housed, add 90g (0.4mol) 5-nitroisophthalic acid mono-methyl and 500mL methyl alcohol under the room temperature, treat to add 61g (1.0mol) thanomin again after the stirring and dissolving, be warming up to 50 ℃ then, stir and finish reaction after 48 hours.Boil off 200mL methyl alcohol under the decompression, in debris, add 600mL distilled water, after stirring, with 5mol/L aqueous hydrochloric acid adjust pH to 1, left standstill 24 hours, with the solid filtering of separating out, the distillation washing, dry product 86.4g, yield is 85%, m.p.136～138 ℃.
Embodiment 2
5-amino-N-(2-hydroxyethyl)-methane amide is benzoic synthetic:
51g (0.2mol) 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid is dissolved in 200mL (1mol/L) aqueous sodium hydroxide solution, stir and add 8g (5%) Pd/C catalyzer down, feed hydrogen then, be warming up to 75 ℃ simultaneously, the normal pressure catalytic hydrogenation finishes reaction after 10 hours.With reacting liquid filtering, filter cake behind distilled water wash, merging filtrate.Stir down, in filtrate, add concentrated hydrochloric acid, need not purifying and directly supply next step (embodiment 3) reaction to pH value to 1.
Embodiment 3
5-amino-N-(2-hydroxyethyl)-2,4, methane amide is benzoic synthetic between the 6-triiodo:
5-amino-N-(2-the hydroxyethyl)-formamide benzene aqueous formic acid that the preceding step (embodiment 2) is obtained is warming up to 60 ℃, stir adding iodine monochloride solution down, this iodine monochloride solution is to be dissolved in 300mL (2mol/L) sodium chloride aqueous solution with 100g (0.61mol) iodine monochloride to make.Be warming up to 80 ℃ then, stir and finished reaction in 2 hours.Be cooled to 15 ℃, filter, the distillation washing, dry product 112g, yield is 93% (in 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid), m.p.243～245 ℃.
Embodiment 4
5-acetamido-N-(2-hydroxyethyl)-2,4, methane amide is benzoic synthetic between the 6-triiodo:
In reaction flask, add 120g (0.2mol) 5-amino-N-(2-hydroxyethyl)-2,4 under the room temperature, formamide benzene formic acid and 400mL diacetyl oxide between the 6-triiodo, the back of waiting to stir drips the 2mL vitriol oil, is warming up to 80 ℃ then, reacts and finishes reaction after 4 hours.Boil off diacetyl oxide under the decompression, residue is dissolved in the 400mL methyl alcohol, adds 300mL distilled water again, after stirring, drips 90mL (5mol/L) aqueous sodium hydroxide solution.Dropwise, stir after 2 hours,, filter with concentrated hydrochloric acid adjust pH to 1, the distillation washing, dry product 118g, yield is 89.5%, m.p.272～274 ℃.
Claims (1)
1. a 5-acetamido-N-(2-hydroxyethyl)-2; 4; the benzoic preparation method of methane amide between the 6-triiodo; it is characterized in that with 5-nitroisophthalic acid mono-methyl be starting raw material; successively through amidate action, catalytic reduction reaction, iodination reaction; last acetylization reaction makes, and reaction scheme is as follows:
A) amidate action: 5-nitroisophthalic acid mono-methyl and thanomin carry out amidate action in methyl alcohol, 5-nitroisophthalic acid mono-methyl: the mol ratio of thanomin 1: 2.5, in the there-necked flask that agitator and reflux condensing tube are housed, add 5-nitroisophthalic acid mono-methyl and methyl alcohol under the room temperature, add thanomin after waiting to stir again, be warming up to 30～60 ℃ then, stir and finish reaction after 30～60 hours, boil off part methyl alcohol under the decompression, in debris, add distilled water, after stirring, with hydrochloric acid adjust pH to 1, leave standstill, the solid filtering of separating out, distillation washing, dry 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid;
B) catalytic reduction reaction: 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid is carried out catalytic reduction reaction with the Pd/C catalyzer, 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid: the mol ratio of sodium hydroxide 1: 1,5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid: the Pd/C catalyst quality was than 1: 0.16, under the room temperature 5-nitro-N-(2-hydroxyethyl)-formamide benzene formic acid is dissolved in the aqueous sodium hydroxide solution, add the Pd/C catalyzer again, feed hydrogen then, be warming up to 50～90 ℃ simultaneously, the normal pressure catalytic hydrogenation finishes reaction after 6～30 hours, with reacting liquid filtering, filter cake is behind distilled water wash, merging filtrate, stir down, in filtrate, add concentrated hydrochloric acid to pH value to 1, obtain 5-amino-N-(2-hydroxyethyl)-benzoic aqueous hydrochloric acid of a methane amide, need not purifying and directly supply next step iodination reaction; Described Pd/C catalyzer is that the Pd mass content is 5%;
C) iodination reaction: 5-amino-N-(2-hydroxyethyl)-formamide benzene formic acid is carried out iodination reaction with iodine monochloride, 5-amino-N-(2-hydroxyethyl)-formamide benzene formic acid: the mol ratio of iodine monochloride 1: 3,5-amino-N-(2-the hydroxyethyl)-formamide benzene aqueous formic acid that the preceding step is obtained is warming up to 60 ℃, stir and add iodine monochloride solution down, be warming up to 70～90 ℃ then, stir and finished reaction in 1～4 hour, be cooled to 15 ℃, filter, the distillation washing, dry 5-amino-N-(2-hydroxyethyl)-2,4, formamide benzene formic acid between the 6-triiodo; Described iodine monochloride solution is to be dissolved in the 2mol/L sodium chloride aqueous solution with iodine monochloride to make iodine monochloride: the mol ratio of sodium-chlor 1: 1;
D) acetylization reaction: with excessive acetic anhydride via and 5-amino-N-(2-hydroxyethyl)-2; 4; formamide benzene formic acid carries out acylation reaction between the 6-triiodo; and use sulphuric acid catalysis; 5-amino-N-(2-hydroxyethyl)-2,4, formamide benzene formic acid between the 6-triiodo: diacetyl oxide: the mol ratio of the vitriol oil 1: 20～25: 0.18; in reaction flask, add 5-amino-N-(2-hydroxyethyl)-2 under the room temperature; 4, formamide benzene formic acid and diacetyl oxide between the 6-triiodo, the back of waiting to stir drips the vitriol oil; be warming up to 50～90 ℃ then; react and finish reaction after 2～10 hours, boil off diacetyl oxide under the decompression, residue is dissolved in the methyl alcohol; add distilled water again; after stirring, the dropping sodium aqueous solution, stirring at room is after 2 hours; with concentrated hydrochloric acid adjust pH to 1; filter, the distillation washing, dry 5-acetamido-N-(2-hydroxyethyl)-2; 4, formamide benzene formic acid between the 6-triiodo.
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|---|---|---|---|
| CNB2006100381140A CN1314659C (en) | 2006-01-24 | 2006-01-24 | Method for preparing ioxitalamic acid |
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| CNB2006100381140A CN1314659C (en) | 2006-01-24 | 2006-01-24 | Method for preparing ioxitalamic acid |
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| CN1314659C true CN1314659C (en) | 2007-05-09 |
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| CN103265449A (en) * | 2013-05-30 | 2013-08-28 | 四川铂瑞生物医药有限公司 | Synthesis of 5-amino-2,4,6-triiodo-N, N'-bis(2,3-dihydroxy propyl)-1,3-benzenedicarboxamide |
| CN109912445A (en) * | 2019-02-26 | 2019-06-21 | 兄弟科技股份有限公司 | The synthetic method of iohexol impurity F and its application in iohexol impurity G, impurity H and impurity M synthesis |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1146133A (en) * | 1967-07-10 | 1969-03-19 | Guerbet Lab Andre | Improvements in or relating to a new benzoic acid derivative, process for its preparation and opacifying composition containing the same |
| GB1275745A (en) * | 1968-06-10 | 1972-05-24 | Nyegaard & Co As | 2,4,6-triiodobenzoic acid derivatives and their use as x-ray contrast agents |
| US5698739A (en) * | 1989-07-05 | 1997-12-16 | Schering Aktiengesellschaft | Carboxamide non-ionic contrast media |
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2006
- 2006-01-24 CN CNB2006100381140A patent/CN1314659C/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1146133A (en) * | 1967-07-10 | 1969-03-19 | Guerbet Lab Andre | Improvements in or relating to a new benzoic acid derivative, process for its preparation and opacifying composition containing the same |
| GB1275745A (en) * | 1968-06-10 | 1972-05-24 | Nyegaard & Co As | 2,4,6-triiodobenzoic acid derivatives and their use as x-ray contrast agents |
| US5698739A (en) * | 1989-07-05 | 1997-12-16 | Schering Aktiengesellschaft | Carboxamide non-ionic contrast media |
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