CN104230731B - The preparation method of contrast medium intermediate triiodo isophthaloyl chlorine - Google Patents
The preparation method of contrast medium intermediate triiodo isophthaloyl chlorine Download PDFInfo
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- CN104230731B CN104230731B CN201410497364.5A CN201410497364A CN104230731B CN 104230731 B CN104230731 B CN 104230731B CN 201410497364 A CN201410497364 A CN 201410497364A CN 104230731 B CN104230731 B CN 104230731B
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- amino
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- thionyl chloride
- triiodo isophthaloyl
- isophthaloyl chlorine
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- 0 CC(Cc(c(I)c(c(C)c1C(Cl)=O)N)c1I)=* Chemical compound CC(Cc(c(I)c(c(C)c1C(Cl)=O)N)c1I)=* 0.000 description 1
Abstract
The invention discloses a kind of preparation method of contrast medium intermediate triiodo isophthaloyl chlorine.It comprises the following steps: by 5-amino-2,4,6-tri-triiodoisophthalic acid, thionyl chloride and DMF join in isobutyl acetate, reacting by heating is complete, reaction solution is poured in frozen water by cooling, adds saturated sodium bicarbonate solution to pH to 11-13, separates out yellow solid and filters, with the purification of isobutyl acetate recrystallization, drying, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine.The easy easy handling of present method, overall production rate and the more original method of product purity improve greatly.Post-processing operation is simple, efficiently.And the alkali DMF added in this patent, in aftertreatment, can remove with water, simple and convenient.After a small amount of Sucrose Acetate base ester recrystallization, gained purified product, detects high purity 99.5% through HPLC.
Description
Technical field
The present invention is specifically related to a kind of preparation method of contrast medium intermediate triiodo isophthaloyl chlorine.
Background technology
X-ray contrast agent is a kind of important diagnostic medication in radiodiagnosis.Wherein as most widely used in Schering AG), iopamidol, ioversol etc. with non-ionic contrast agent again, with fastest developing speed, be widely used at present the contrast examination of many pathologies in urinary tract, blood vessel, ventricle, the ventricles of the brain, lymphatic, gastrointestinal contrast agent and CT examination, had that radiography density is high, toxicity is low, the feature of stable performance.
Major part non-ionic contrast agent under many circumstances, all by 5-amino-2,4, the synthesis of 6-tri-triiodoisophthalic acid acyl chlorides obtains, such as, in the iopamidol synthetic method reported in English Patent GB1472050, by 5-amino-2,4,6-triiodoisophthaloyl dichloride synthesis iopamidol, the Schering AG) preparation method provided in Chinese patent 2006100531275, and the conventional iodine mykol preparation method described in this patent, be also all with 5-amino-2,4,6-tri-triiodoisophthalic acid acyl chlorides is starting raw material, through 4 step Reactive Synthesis Schering AG)s.Therefore, replacing amino-2,4,6-tri-triiodoisophthalic acid of 5-more reasonable as the intermediate of synthesis non-ionic contrast agent with 5-amino-2,4,6-triiodoisophthaloyl dichloride, is the inevitable choice of non-ionic contrast agent synthesis technique development.
TimWhartonandLonJ.Wilson adopts 5-amino-2 in document Bioorganic & MedicinalChemistry10 (2002) 3545 – 3554,4,6-tri-triiodoisophthalic acid refluxes 6 hours in a large amount of thionyl chloride, after having reacted, thionyl chloride is spin-dried for, add extraction into ethyl acetate, wash one time with saturated sodium-chloride and sodium bicarbonate aqueous solution, collect organic phase, use column chromatography purified product, productive rate 89.3%.
The method is carried out in the absence of a solvent in thionyl chloride, serious industrial safety sex chromosome mosaicism will be caused, be difficult on the one hand solid state starting product be added a step by a step in the thionyl chloride of heat, on the other hand, the feed way of two kinds of reagent cold mixing and continuous heating can produce fugitive reaction, brings unpredictalbe impact.Generate sulfurous gas and hydrogen chloride gas after thionyl chloride decomposes, cause topsoil.And the method aftertreatment trouble, need column chromatography purified product, and productive rate is low, is unfavorable for industrialization scale operation.
Wistrand etc. have employed following synthetic method in patent WO2009/005365, by 5-amino-2,4,6-tri-triiodoisophthalic acid, thionyl chloride and pyridine, 1, are heated to 70 DEG C in 2 ethylene dichloride, another part thionyl chloride dropwise added in 1.5 to 2 hours, mixture, 85 DEG C of reactions six hours, afterwards by mixed reactant cool to room temperature, is poured in frozen water.Separate out yellow mercury oxide, filter, being flushed to pH value with water after air drying is 5, and filter cake puts into vacuum drying oven 50 DEG C of dryings 3 hours, obtains 5-amino-2,4,6-triiodoisophthaloyl dichloride.
The method adopts substep to add thionyl chloride, and operating process is more complicated, is unfavorable for industrial expanding production.And the thionyl chloride total amount that adds of substep is more than the amount 4 times of the thionyl chloride of the present invention, there is potential safety hazard and not environmentally.Adopt the method to only have the productive rate of 96%, lower than productive rate of the present invention, illustrate that the present invention uses less thionyl chloride to be enough to make to react completely, the thionyl chloride of excessive use is sheerly wasted.
Zambon team have employed following synthetic method in patent WO96/16927: at-30 DEG C, thionyl chloride is slowly added methylene dichloride is housed, triethylamine, in the reaction flask of water, then adds 5-amino-2,4,6-tri-triiodoisophthalic acid, stirred after 1.5 hours, another part thionyl chloride slowly be added drop-wise in reaction solution, reflux 28 hours at 43 DEG C, react, be cooled to room temperature, slowly added the aqueous solution of methylene dichloride, separate out a large amount of solid, suction filtration, dry, obtain 5-amino-2,4,6-tri-triiodoisophthalic acid acyl chlorides.
What adopt in the method is that the triethylamine of 2 equivalents participates in reaction as alkali, and only adopts the DMF of 1% to participate in reaction in the present invention, and greatly reduce the consumption of alkali, and productive rate is higher, purity is also higher.And method substep slowly adds thionyl chloride in above-mentioned patent, operating process is more complicated, is unfavorable for industrial expanding production.
Summary of the invention
The object of the invention is to provide a kind of 5-amino-2,4, the simple method for preparing of 6-tri-triiodoisophthalic acid acyl chlorides, this synthetic method is simple, reactions steps is short, easy to operate, and organic solvent consumption is little, aftertreatment is simple, product purity is high, and product yield is high, and purity is high, environmental protection pressure is little, is convenient to industrial production.
For achieving the above object, adopt technical scheme as follows:
A preparation method for contrast medium intermediate triiodo isophthaloyl chlorine, comprises the following steps:
By 5-amino-2,4,6-tri-triiodoisophthalic acid, thionyl chloride and DMF join in isobutyl acetate, reacting by heating is complete, reaction solution is poured in frozen water by cooling, adds saturated sodium bicarbonate solution to pH to 11-13, separates out yellow solid and filters, with the purification of isobutyl acetate recrystallization, drying, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine.
By such scheme, with molar ratio computing, amino-2,4,6-tri-triiodoisophthalic acid of 5-: thionyl chloride=1:2 ~ 1:2.5; Amino-2,4,6-tri-triiodoisophthalic acid of 5-: DMF=1:0.01 ~ 1:0.02.
By such scheme, the concentration joining amino-2,4,6-tri-triiodoisophthalic acid of 5-in Sucrose Acetate base ester is 0.03mol/L ~ 0.035mol/L.
By such scheme, temperature of reaction is 70 ~ 100 DEG C, and the reaction times is 4 ~ 6 hours.
By such scheme, during with isobutyl acetate recrystallization, its consumption is 3 ~ 3.5ml/g.Namely each gram treats recrystallization solid 3 ~ 3.5ml isobutyl acetate.
Reaction equation involved by synthetic method of the present invention and technical process as follows:
Present method adopts the disposable thionyl chloride adding 2.5 equivalents, have relative to general method and reduce greatly, thionyl chloride is by public security department's control, belong to hazardous substance, have intense stimulus smell, easily decompose and produce sulfurous gas, hydrogenchloride etc. easily produce the gas of acid rain, cause topsoil, so the usage quantity of thionyl chloride will be reduced as much as possible.
Adopt Sucrose Acetate base ester to make solvent, this solvent boiling point is high, easily reclaims, and low toxicity, LD5015400mg/kg (rat oral) is the water white liquid with soft fruit ester fragrance, often make fruit essence, for allocating banana, pineapple, Rubus idaeus and pears taste essence; Modulation spices, makes the blender of rose, and literature method adopts 1,2-methylene chloride as solvent, and this solvent toxicity is comparatively large, and 670mg/kg (rat oral), boiling point is lower, volatile.
Post-processing operation is simple, efficiently, is directly poured in frozen water by reaction solution, slowly drips saturated sodium bicarbonate solution, separates out yellow solid, filters, obtain thick product, and productive rate is up to 99%.And in patent WO2009/005365, report reaction solution is poured in frozen water, namely separate out solid, and in actually operating, do not have solid to separate out.And the alkali DMF added in present method, in aftertreatment, can remove with water, simple and convenient.
Beneficial effect of the present invention is:
The easy easy handling of present method, overall production rate and the more original method of product purity improve greatly.
Decrease the consumption of thionyl chloride, adopt the thionyl chloride of 2.5 equivalents to be enough to reaction is carried out completely so that high yield is highly purified.
Present method post-processing operation is simple, efficiently.And the alkali DMF added in this patent, in aftertreatment, can remove with water, simple and convenient.
By obtained crude product in present method, after a small amount of Sucrose Acetate base ester recrystallization, gained purified product, detects high purity 99.5% through HPLC.
Figure of description
The high-efficient liquid phase chromatogram of Fig. 1: embodiment 1 products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.
The infrared absorpting light spectra of Fig. 2: embodiment 1 products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.
The carbon-13 nmr spectra figure of Fig. 3: embodiment 1 products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.
Embodiment
Following specific embodiment explains technical scheme of the present invention further, but not as limiting the scope of the invention.
Contrast medium intermediate triiodo isophthaloyl chlorine preparation process of the present invention is as follows:
By 5-amino-2,4,6-tri-triiodoisophthalic acid, thionyl chloride and DMF join in Sucrose Acetate base ester, reacting by heating is complete, reaction solution is poured in frozen water by cooling, adds saturated sodium bicarbonate solution to pH to 11-13, separates out yellow solid, filtration, purification, drying, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine.
Optimally, with molar ratio computing, amino-2,4,6-tri-triiodoisophthalic acid of 5-: thionyl chloride=1:2 ~ 1:2.5; Amino-2,4,6-tri-triiodoisophthalic acid of 5-: DMF=1:0.01 ~ 1:0.02.
Optimally, the concentration joining amino-2,4,6-tri-triiodoisophthalic acid of 5-in Sucrose Acetate base ester is 0.03mol/L ~ 0.035mol/L.
Optimally, temperature of reaction is 70 ~ 100 DEG C, and the reaction times is 4 ~ 6 hours.
Optimally, during with isobutyl acetate recrystallization, its consumption is 3 ~ 3.5ml/g.
Embodiment 1
By 5-amino-2,4,6-tri-triiodoisophthalic acid 10g (18mmol), thionyl chloride 3.3ml (45mmol) and DMF19.7mg (1.5%, 0.27mmol) joins in 600ml Sucrose Acetate base ester, reacting by heating 6h at 70 DEG C, be cooled to room temperature, reaction solution is poured in 1000ml frozen water, slowly add saturated sodium bicarbonate solution, until pH=12, separate out a large amount of yellow solid, filtration obtains solid 12g, with 36ml isobutyl acetate recrystallization, dry, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine 10.5g, productive rate is 99.1%.
Accompanying drawing 1 is the high-efficient liquid phase chromatogram (SYMMETRYC185 μm, 4.6*250mmColumn, column temperature 30 DEG C, wavelength 254nm, water: acetonitrile=20:80) of the present embodiment products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.By figure gained, be principal product peak at about 7.24min, have three substantially negligible impurity peaks at 5.24,6.82,10.98min place respectively.By area normalization method, can this product purity up to 99.5%.
Accompanying drawing 2 is the infrared absorpting light spectra (IR spectrum test instrument: BrukerVECTOR-22, test condition: KBr compressing tablet) of the present embodiment products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.By Tu Ke get, at 3469,3370cm
-1place is N-H peak, at 1769cm
-1place is C=O peak, and consistent with the spectrogram of bibliographical information, this compound is correct as seen.
Accompanying drawing 3 is the carbon-13 nmr spectra figure (NMRVARIANMercuryPlus400 type test condition: 400MHz) of the present embodiment products therefrom 5-amino-2,4,6-triiodo isophthaloyl chlorine.By Tu Ke get, this structure has the carbon that five class chemical environments are different, lays respectively at 170.26,170.01,149.10,148.62,148.22ppm, consistent with the spectrogram of bibliographical information, and this compound is correct as seen.
Embodiment 2
By 5-amino-2,4,6-tri-triiodoisophthalic acid 30g (54mmol), thionyl chloride 9.4ml (135mmol) and DMF40mg (consumption is 1%, 0.54mmol) joins in 1800ml Sucrose Acetate base ester, reacting by heating 6h at 70 DEG C, be cooled to room temperature, reaction solution is poured in 2000ml frozen water, slowly add saturated sodium bicarbonate solution, until pH=12, separate out a large amount of yellow solid, filtration obtains solid 37g, with 119ml isobutyl acetate recrystallization, dry, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine 31.6g, productive rate is 98.8%.
Embodiment 3
By 5-amino-2,4,6-tri-triiodoisophthalic acid 100g (180mmol), thionyl chloride 33ml (450mmol) and DMF260mg (consumption is 2%, 3.6mmol) joins in 5143ml Sucrose Acetate base ester, 100 DEG C of reacting by heating 4h, be cooled to room temperature, reaction solution is poured in 7000ml frozen water, slowly add saturated sodium bicarbonate solution, until pH=12, separate out a large amount of yellow solid, filtration obtains solid 120g, with 360ml isobutyl acetate recrystallization, dry, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine 105.5g, productive rate is 99.2%.
Claims (2)
1. a preparation method for contrast medium intermediate triiodo isophthaloyl chlorine, is characterized in that comprising the following steps:
By 5-amino-2,4,6-tri-triiodoisophthalic acid, thionyl chloride and DMF join in isobutyl acetate, react 4 ~ 6 hours at 70 ~ 100 DEG C, reaction solution is poured in frozen water by cooling, adds saturated sodium bicarbonate solution to pH to 11-13, separates out yellow solid and filters, with the purification of isobutyl acetate recrystallization, drying, obtain 5-amino-2,4,6-triiodo isophthaloyl chlorine;
Wherein, the concentration joining amino-2,4,6-tri-triiodoisophthalic acid of 5-in Sucrose Acetate base ester is 0.03mol/L ~ 0.035mol/L; By the ratio of molar weight, amino-2,4,6-tri-triiodoisophthalic acid of 5-: thionyl chloride=1:2 ~ 1:2.5; Amino-2,4,6-tri-triiodoisophthalic acid of 5-: DMF=1:0.01 ~ 1:0.02.
2. the preparation method of contrast medium intermediate triiodo isophthaloyl chlorine as claimed in claim 1, when it is characterized in that with isobutyl acetate recrystallization, its consumption is 3 ~ 3.5ml/g.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4001323A (en) * | 1974-12-13 | 1977-01-04 | Savac Ag | Water-soluble, non-ionizing hydroxy-containing amide derivatives of 2,4,6-triiodo-isophthalic acid |
| EP0118347A1 (en) * | 1983-02-25 | 1984-09-12 | Guerbet S.A. | Non-ionic compounds with an iodinated or brominated benzenic structure, and opacifying products containing them |
| CN1154689A (en) * | 1995-05-23 | 1997-07-16 | 弗鲁克泰明公司 | Method for prepn. of diacyl-chloride |
| CN101891696A (en) * | 2009-05-22 | 2010-11-24 | 史命锋 | Poly-iodo acromatic compound and preparation method and application thereof |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1271107B (en) * | 1994-11-29 | 1997-05-26 | Zambon Spa | PROCESS FOR THE PREPARATION OF A USEFUL INTERMEDIATE IN THE SYNTHESIS OF ORGANIC COMPOUNDS |
| NO20073382L (en) * | 2007-06-29 | 2008-12-30 | Ge Healthcare As | Contrast Agents |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4001323A (en) * | 1974-12-13 | 1977-01-04 | Savac Ag | Water-soluble, non-ionizing hydroxy-containing amide derivatives of 2,4,6-triiodo-isophthalic acid |
| EP0118347A1 (en) * | 1983-02-25 | 1984-09-12 | Guerbet S.A. | Non-ionic compounds with an iodinated or brominated benzenic structure, and opacifying products containing them |
| CN1154689A (en) * | 1995-05-23 | 1997-07-16 | 弗鲁克泰明公司 | Method for prepn. of diacyl-chloride |
| CN101891696A (en) * | 2009-05-22 | 2010-11-24 | 史命锋 | Poly-iodo acromatic compound and preparation method and application thereof |
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