CN102344387A - Method for producing free iodine by adding potassium iodide during iodine monochloride solution preparation process - Google Patents
Method for producing free iodine by adding potassium iodide during iodine monochloride solution preparation process Download PDFInfo
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- CN102344387A CN102344387A CN2010102411838A CN201010241183A CN102344387A CN 102344387 A CN102344387 A CN 102344387A CN 2010102411838 A CN2010102411838 A CN 2010102411838A CN 201010241183 A CN201010241183 A CN 201010241183A CN 102344387 A CN102344387 A CN 102344387A
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- iodine
- potassium iodide
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Abstract
Generally, the invention relates to preparation methods of nonionic X-ray contrast media of iohexol, ioversol and iodixanol. Further, the invention relates to a modification method of an iodination reaction which is a crucial step in industrial preparations of nonionic X-ray contrast media. Specifically, the invention relates to a method for producing free iodine in an iodine monochloride solution by adding a small amount of potassium iodide.
Description
The cross reference of related application
According to the 119th article the 5th (35U.S.C. § 119 (e)) of United States Code the 35th volume, the right of priority of the U.S. Provisional Application that the application requires to submit on July 21st, 2009 number 61/227,082, whole disclosures of this provisional application are incorporated this paper by reference into.
Technical field
Briefly say, the present invention relates to the preparation of non-ionic type x-ray contrast agent.Say that further it relates to committed step---the method for unwanted by product in the iodination reaction that reduces in the non-ionic type x-ray contrast agent industrial preparation.Specifically, it relates in the preparation of the iodine chloride aqueous solution through adding a spot of potassiumiodide to form the method for free-iodine.
Background of invention
The non-ionic type x-ray contrast agent is one type of very important medical compounds, and output is very big.5-[N-(2; The 3-dihydroxypropyl)-acetamido]-N; N '-two (2; The 3-dihydroxypropyl)-2; 4,6-three iodos-different phthalic diamide (" Schering AG) "), N, N '-two (2; The 3-dihydroxypropyl)-and 5-[(2-glycolyl)-(2-hydroxyethyl) amino]-2; 4,6-three iodos-benzene-1,3-diformamide (" ioversol ") and 1; Two (the acetamido)-N of 3-; N '-two [3, two (2,3-dihydroxypropyl-aminocarboxyl)-2 of 5-; 4,6-phenyl triiodide base]-2-hydroxy propane (" Visipaque 320 ") is the important example of this compounds.They contain one or two triiodide phenyl ring.
The industrial production of Schering AG), ioversol and Visipaque 320 relates to the rapid chemosynthesis of multistep.Final drug substance must meet the purity rubric of the strictness of regulator's formulation.Though purity is vital, it is also important that through optimizing each synthesis step to reduce production costs.Even the little improvement in the reaction design also can cause practicing thrift significantly in the scale operation.
Improvement of the present invention relates to and is used for amino-N with 5-, and N '-two (2, the 3-dihydroxypropyl)-different phthalic diamide (or ABA) changes into 5-amino-N; N '-two (2; The 3-dihydroxypropyl)-2,4, the iodination reagent of the different phthalic diamide of 6-three iodos (compd B) is an iodine chloride.Referring to scheme 1; In addition referring to United States Patent (USP) the 6th, 441, No. 235 and the 6th, 274, No. 762.The present invention relates to prepare improving one's methods of the iodine chloride aqueous solution.
Scheme 1
Summary of the invention
The present invention provides the method for the iodination reagent in synthesizing of optimization non-ionic type x-ray contrast agent.Specifically, method of the present invention comprises potassiumiodide is joined the iodine chloride aqueous solution to form the step of free-iodine.
Detailed Description Of The Invention
The aqueous solution of iodine chloride is used as iodinating agent in most of x-ray contrast agents (comprising Schering AG) and Visipaque 320) synthetic.Iodine chloride can pass through several method production, and one of them relates to the following reaction between iodine and the sodium chlorate:
3I
2+ NaClO
3+ 6HCl → 6ICl+NaCl+3H
2O (reaction 1)
Be used for iodate as an x-ray contrast agent synthetic part be substituted aromatic acid (substituted aromate) the typical concentration of the iodine chloride aqueous solution be about 40-60w/w%, preferably about 45-55w/w%.We find that have a spot of free-iodine in the iodine chloride aqueous solution, this is desirable in iodination reaction.Specifically, having found to be used for the iodine chloride solution of iodination reaction can cause the amount of chlorinated secondary product to increase if lack free-iodine, is that chlorine atom rather than iodine atom are introduced on the phenyl ring in chlorinated secondary product.In Schering AG) and Visipaque 320 synthetic situation, observe this monochloro by product and in follow-up purification step, be difficult to remove.
Though the existence of free-iodine is desirable, will be retained to minimum level, with in optimizing materials efficient aspect the iodine, because iodine is the most expensive a kind of in the raw material of this technology at present from reacting the excessive iodine of stoichiometry that 1 when beginning added.Therefore, this requirement that makes full use of raw material iodine can cause some batches after reaction 1 is accomplished, not have detectable iodine to stay.In addition, the iodine form of small-particle or thin slice (for example with) that adds additional quantity in this is unpractical in stage.
We find, can add a spot of potassiumiodide and after accomplishing in reaction 1, obtain required free molecule iodine.The iodide ion of the potassiumiodide that is added is chlorinated the iodine oxidation and forms iodine:
KI+ICl→I
2+KCl
This is the not only convenient but also cheap mode that in the iodine chloride aqueous solution, obtains required excess molecular iodine.Potassiumiodide can be divided into several aliquots and add, carry out extraction test then, detect whether obtained free-iodine.
Following examples further specify the present invention, but can not be interpreted as embodiment scope of the present invention are confined to wherein described concrete scheme.
Embodiment
Embodiment 1
With iodine (2700kg, 10.6kmol), hydrochloric acid (35%, 2285kg, 21.9kmol), water (250kg, 13.3kmol) and sodium-chlor (475kg 8.1kmol) mixes under 20 ℃ in reactor.Under vigorous stirring, in 3-4 hour, (43w/w%, 864kg 2.6mol) carefully join reactor with the aqueous solution of sodium chlorate.Under medium stirring, under 50 ℃, continue to react at least 10 hours.Draw negative findings (not having color in the organic phase) with methylene dichloride extractive reaction sample in the presence of hydrochloric acid, this shows in the prepared iodine chloride solution does not have free-iodine.
Potassiumiodide is divided into several aliquots adds (every part of about 2-4kg).After adding less than the 15kg potassiumiodide, free-iodine test (dichloromethane extraction) draws positive findings.
All patents, journal of writings, publication and other documents more than discussing and/or quote from are all incorporated this paper by reference into.
Claims (1)
1. a method for preparing the iodine chloride aqueous solution that is used for synthetic non-ionic type x-ray contrast agent wherein adds potassiumiodide to form free-iodine in the said iodine chloride aqueous solution.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102411838A CN102344387A (en) | 2010-07-21 | 2010-07-21 | Method for producing free iodine by adding potassium iodide during iodine monochloride solution preparation process |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2010102411838A CN102344387A (en) | 2010-07-21 | 2010-07-21 | Method for producing free iodine by adding potassium iodide during iodine monochloride solution preparation process |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN102344387A true CN102344387A (en) | 2012-02-08 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2010102411838A Pending CN102344387A (en) | 2010-07-21 | 2010-07-21 | Method for producing free iodine by adding potassium iodide during iodine monochloride solution preparation process |
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| Country | Link |
|---|---|
| CN (1) | CN102344387A (en) |
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2010
- 2010-07-21 CN CN2010102411838A patent/CN102344387A/en active Pending
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| C06 | Publication | ||
| PB01 | Publication | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20120208 |