CN102363600B - Iomeprol preparation method - Google Patents
Iomeprol preparation method Download PDFInfo
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- CN102363600B CN102363600B CN 201110325492 CN201110325492A CN102363600B CN 102363600 B CN102363600 B CN 102363600B CN 201110325492 CN201110325492 CN 201110325492 CN 201110325492 A CN201110325492 A CN 201110325492A CN 102363600 B CN102363600 B CN 102363600B
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229960000780 iomeprol Drugs 0.000 title abstract description 16
- NJKDOADNQSYQEV-UHFFFAOYSA-N iomeprol Chemical compound OCC(=O)N(C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NJKDOADNQSYQEV-UHFFFAOYSA-N 0.000 title abstract description 16
- 238000006243 chemical reaction Methods 0.000 claims abstract description 28
- 125000003368 amide group Chemical group 0.000 claims abstract description 21
- 239000002994 raw material Substances 0.000 claims abstract description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 21
- FDQSRULYDNDXQB-UHFFFAOYSA-N benzene-1,3-dicarbonyl chloride Chemical compound ClC(=O)C1=CC=CC(C(Cl)=O)=C1 FDQSRULYDNDXQB-UHFFFAOYSA-N 0.000 claims description 21
- 150000001875 compounds Chemical class 0.000 claims description 20
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- 239000002904 solvent Substances 0.000 claims description 13
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 12
- UFNGEZFIBCOLBF-UHFFFAOYSA-N NC(=O)C1=CC=CC(C(N)=O)=C1I Chemical compound NC(=O)C1=CC=CC(C(N)=O)=C1I UFNGEZFIBCOLBF-UHFFFAOYSA-N 0.000 claims description 11
- VGCXGMAHQTYDJK-UHFFFAOYSA-N Chloroacetyl chloride Chemical compound ClCC(Cl)=O VGCXGMAHQTYDJK-UHFFFAOYSA-N 0.000 claims description 9
- 229940059260 amidate Drugs 0.000 claims description 9
- NPUKDXXFDDZOKR-LLVKDONJSA-N etomidate Chemical compound CCOC(=O)C1=CN=CN1[C@H](C)C1=CC=CC=C1 NPUKDXXFDDZOKR-LLVKDONJSA-N 0.000 claims description 9
- 239000000706 filtrate Substances 0.000 claims description 9
- QQVIHTHCMHWDBS-UHFFFAOYSA-N isophthalic acid Chemical compound OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 claims description 9
- WFAFGNCZWMJZCK-UHFFFAOYSA-N 2-hydroxy-n-methylacetamide Chemical compound CNC(=O)CO WFAFGNCZWMJZCK-UHFFFAOYSA-N 0.000 claims description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 8
- 150000001263 acyl chlorides Chemical class 0.000 claims description 8
- 239000001632 sodium acetate Substances 0.000 claims description 8
- 235000017281 sodium acetate Nutrition 0.000 claims description 8
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 7
- 239000000460 chlorine Substances 0.000 claims description 7
- 229910052801 chlorine Inorganic materials 0.000 claims description 7
- 239000007787 solid Substances 0.000 claims description 7
- 230000021736 acetylation Effects 0.000 claims description 6
- 238000006640 acetylation reaction Methods 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 230000000640 hydroxylating effect Effects 0.000 claims description 6
- 238000010992 reflux Methods 0.000 claims description 6
- 238000010025 steaming Methods 0.000 claims description 6
- 238000001291 vacuum drying Methods 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- KLSJWNVTNUYHDU-UHFFFAOYSA-N Amitrole Chemical compound NC1=NC=NN1 KLSJWNVTNUYHDU-UHFFFAOYSA-N 0.000 claims description 5
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 5
- 238000010792 warming Methods 0.000 claims description 5
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- 230000006837 decompression Effects 0.000 claims description 3
- 235000019441 ethanol Nutrition 0.000 claims description 3
- 239000011347 resin Substances 0.000 claims description 3
- 229920005989 resin Polymers 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims description 2
- -1 filter Substances 0.000 claims 1
- 239000002872 contrast media Substances 0.000 abstract description 7
- 239000000126 substance Substances 0.000 abstract description 3
- 230000000694 effects Effects 0.000 abstract description 2
- XTVNXCZBYOQITB-UHFFFAOYSA-N 5-(dimethylamino)-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound CN(C=1C(=C(C(=C(C(=O)O)C1I)I)C(=O)O)I)C XTVNXCZBYOQITB-UHFFFAOYSA-N 0.000 abstract 1
- 238000007112 amidation reaction Methods 0.000 abstract 1
- 238000005660 chlorination reaction Methods 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 238000005805 hydroxylation reaction Methods 0.000 abstract 1
- 238000009776 industrial production Methods 0.000 abstract 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 abstract 1
- 238000010189 synthetic method Methods 0.000 description 10
- HZDNNJABYXNPPV-UHFFFAOYSA-N (2-chloro-2-oxoethyl) acetate Chemical compound CC(=O)OCC(Cl)=O HZDNNJABYXNPPV-UHFFFAOYSA-N 0.000 description 7
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 238000002601 radiography Methods 0.000 description 5
- 238000005917 acylation reaction Methods 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 230000003204 osmotic effect Effects 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 230000035484 reaction time Effects 0.000 description 3
- 241000282326 Felis catus Species 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 210000000576 arachnoid Anatomy 0.000 description 2
- 229960004756 ethanol Drugs 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 238000007069 methylation reaction Methods 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 1
- ZPOLNCDBPYJDSE-UHFFFAOYSA-N 3-[4-[bis(2-chloroethyl)amino]phenyl]-2-formamidopropanoic acid Chemical compound O=CNC(C(=O)O)CC1=CC=C(N(CCCl)CCCl)C=C1 ZPOLNCDBPYJDSE-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 description 1
- 206010019909 Hernia Diseases 0.000 description 1
- AMDBBAQNWSUWGN-UHFFFAOYSA-N Ioversol Chemical compound OCCN(C(=O)CO)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I AMDBBAQNWSUWGN-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 230000010933 acylation Effects 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 238000013189 cholangiography Methods 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 229960000935 dehydrated alcohol Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 238000006206 glycosylation reaction Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000003317 industrial substance Substances 0.000 description 1
- 150000002500 ions Chemical class 0.000 description 1
- 229960004647 iopamidol Drugs 0.000 description 1
- XQZXYNRDCRIARQ-LURJTMIESA-N iopamidol Chemical compound C[C@H](O)C(=O)NC1=C(I)C(C(=O)NC(CO)CO)=C(I)C(C(=O)NC(CO)CO)=C1I XQZXYNRDCRIARQ-LURJTMIESA-N 0.000 description 1
- 229960004537 ioversol Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000003352 sequestering agent Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000007487 urography Methods 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
An Iomeprol preparation method belongs to the technical field of non-ionic X ray contrast agent preparation. The chemical name of Iomeprol is 5-[N-methyl-2-ethoxyl amido]-N,N'-dual(2,3-dihydroxy propyl)-2,4,6-triiodide-1,3-benzenedicarboxamide. The preparation method comprises the following steps of: using 5- dimethylamino-2,4,6-triiodoisophthalic acid as a starting raw material, respectively performing a sulfonyl chlorination reaction, a chloroacctylation reaction, an amidation reaction and a hydroxylation reaction to prepared the Iomeprol product. The medicament is a new-generation non-ionic X ray contrast agent with excellent security and contrast effect. The preparation method has advantages of stable quality, high yield and low cost, and is applicable to be used to realize industrial production.
Description
Technical field
A kind of preparation method of Iomeprol belongs to the non-ionic x-ray contrast medium preparing technical field.The chemistry of Iomeprol is called 5-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1, the 3-benzenedicarboxamide is a kind of non-ionic x-ray contrast medium of new generation that shows excellent security and radiography effect.
Background technology
The chemical name of Iomeprol: 5-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-, three iodo-1, the 3-benzenedicarboxamide, the english common name of this compound is Iomeprol, and the commodity of its preparation are called Iomiron, the structure formula I:
Iomeprol is a kind of non-ionic x-ray contrast medium of being developed by Italian Bracco company, in Italy in May, 1993, in Britain's listing that goes through in December, 1992.Iomeprol is the nonionic compound, soluble in water that has imported chemically stable hydrophilic group at the triiodo phenyl ring.Compare with non-ionic x-ray contrast medium (for example iopamidol, ioversol and Schering AG) etc.) of the same type, under same concentration, have minimum osmotic pressure and lower viscosity.In building-up process, owing to there is not the Cu ion to sneak into, not adding sequestrant (EDTA-2Na-1Ca etc.) is safe therefore.In addition, because osmotic pressure reduces the high concentrate formulation that can be made into 400mg/mL.
Therefore, Iomeprol be develop in recent years have more low-viscosity, a non-ionic x-ray contrast medium of Hyposmolality more.Because Iomeprol is water-soluble fine, osmotic pressure is also low, chemical property is also more stable, can tolerate high-temperature sterilization, can be made into the injection liquid supply the market, can in blood vessel, use widely and (be applicable to angiography, urography, phlebography and radiography strengthen cat scanner), use under the arachnoid membrane and (be applicable to adult and children's waist, chest and cervical spinal radiography, and be applied under the arachnoid membrane injection pond cat scanner of the laggard capable end) and body cavity in application (arthrography, endoscopic retrograde pancreatography (ERP), endoscope retrogradation cholangiography and the ductus pancreaticus radiography (ERLP) that coincide, the hernia radiography, hysterosalpingography, sialography) and gastrointestinal examination etc.
About synthesizing of Iomeprol, European patent EP 0026281A1 discloses its two kinds of synthetic methods.
First kind of synthetic method is with 5-amino-2; 4; 6-triiodo m-phthalic acid is starting raw material; carry out the n-formyl sarcolysine glycosylation reaction earlier, again with sulfur oxychloride react diacid chloride, carry out acylation reaction with alpha-Acetoxyacetyl chloride then; then with 3-amino-1; the 2-propylene glycol carries out amidate action, with the sodium hydroxide reaction that is hydrolyzed, makes with the dehydrated alcohol recrystallization at last again.Synthetic route is seen formula 1:
The synthetic route of formula 1 Iomeprol
Used alpha-Acetoxyacetyl chloride is because of poor stability in this synthetic route, buy on the market less than, need to adopt by Mono Chloro Acetic Acid as raw material, through being hydrolyzed into oxyacetic acid, react again acetoxy acid, last and sulfur oxychloride react alpha-Acetoxyacetyl chloride (synthetic route is seen formula 2), complicated process of preparation, total recovery is low, the cost height, finally cause the Iomeprol production cost to rise, be not suitable for big production.
The synthetic route of formula 2 alpha-Acetoxyacetyl chlorides
Second kind of synthetic method is with 5-amino-2; 4; 6-triiodo m-phthaloyl chloride is starting raw material; carry out acylation reaction with alpha-Acetoxyacetyl chloride earlier; then with 3-amino-1; the 2-propylene glycol carries out amidate action, and again with the sodium hydroxide reaction that is hydrolyzed, last and methyl iodide carries out methylation reaction and makes (synthetic route is seen formula 3).This method is the same with preceding a kind of synthetic method, has used comparatively expensive alpha-Acetoxyacetyl chloride.In addition, the final step methylation reaction has used expensive methyl iodide in this synthetic method, and the yield that methylates not high (77%), so the preparation cost of this method is higher, is not suitable for industrialized production.
The synthetic route of formula 3 Iomeprols
Therefore two kinds of synthetic methods providing of this patent need to improve, should design one more reasonable, cost is low, is fit to 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-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-, three iodo-1, the preparation method of 3-benzenedicarboxamide, adopt a design more reasonable, cost is low, is fit to the synthetic route of suitability for industrialized production.
Technical scheme of the present invention: a kind of 5-[N-methyl-glycolamide base]-N; N '-two (2; the 3-dihydroxypropyl)-2,4,6-three iodo-1; the preparation method of 3-benzenedicarboxamide; with 5-methylamino-2,4,6-triiodo m-phthalic acid is starting raw material; carry out acyl chloride reaction, chlorine acetylation, amidate action and hydroxylating successively and make, reaction scheme is seen formula 4.
The synthetic route of formula 4 Iomeprols:
A) acyl chloride reaction: 5-methylamino-2,4,6-triiodo m-phthalic acid (compound V) carries out acyl chloride reaction with sulfur oxychloride, make solvent with ethyl acetate, compound (V): sulfur oxychloride: the mol ratio of ethyl acetate is controlled to be 1:3:19, in the there-necked flask that agitator and reflux condensing tube are housed, adds 5-methylamino-2 under the room temperature, 4,6-triiodo m-phthalic acid is dissolved in the ethyl acetate, after waiting to stir, adds sulfur oxychloride, be warming up to 50 ~ 80 ℃ then, stir and finished reaction in 3 ~ 6 hours, after decompression boils off ethyl acetate and sulfur oxychloride down, after the residue adding ethyl acetate, boil off solvent again, through frozen water washing, dry 5-methylamino-2,4,6-triiodo m-phthaloyl chloride, i.e. compound (IV);
B) chlorine acetylation: 5-methylamino-2,4,6-triiodo m-phthaloyl chloride (compound IV) carries out chlorine acetylation with chloroacetyl chloride, make solvent with N,N-dimethylacetamide, compound (IV): the mol ratio of chloroacetyl chloride is controlled to be 1:1.5, under 50 ℃ with 5-methylamino-2,4,6-triiodo m-phthaloyl chloride is dissolved in the N,N-dimethylacetamide, be cooled to 10 ℃ then, be added dropwise to chloroacetyl chloride, be warming up to 50 ~ 90 ℃ after dropwising, stir and finished reaction in 1 ~ 3 hour, be cooled to 10 ℃, be added dropwise to frozen water, filter, wash through frozen water, dry 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride, i.e. compound (III);
C) amidate action: with 3-amino-1,2-propylene glycol and 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride (compound III) carries out amidate action, is catalyzer with the triethylamine, compound (III): 3-amino-1, the 2-propylene glycol: the mol ratio of triethylamine is controlled to be 1:2.7:2.7, under the room temperature with 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride is dissolved in N, the N-N,N-DIMETHYLACETAMIDE, be cooled to 10 ℃ then, add 3-amino-1,2-propylene glycol and triethylamine, be heated to 20 ~ 50 ℃ then, stir and finished reaction in 8 ~ 15 hours, be chilled to after-filtration below 10 ℃, with filtrate after evaporated under reduced pressure, residue is dissolved in the methyl alcohol, add water and stir evenly, leave standstill, with the solid filtering of separating out, washing, dry 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide, i.e. compound (II).
D) hydroxylating: with sodium acetate and 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide (compound ii) carries out hydroxylating in the aqueous solution, and compound (II): the mol ratio of sodium acetate is controlled to be 1:3～6, in flask, add 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide and water after waiting to stir, add sodium acetate, after the back flow reaction 24 hours, the pressure reducing and steaming solvent.The residue dissolve with methanol filters, and filtrate boils off methyl alcohol, and vacuum-drying gets solid, and is soluble in water, adds gac, and reflux 30min filters.Filtrate is successively by 732 Zeo-karbs and 717 anionite-exchange resin, and pressure reducing and steaming solvent again is after the resistates vacuum-drying, through ethyl alcohol recrystallization, get 5-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-, three iodo-1, the 3-benzenedicarboxamide.
Beneficial effect of the present invention: compare with two kinds of synthetic methods among the patent EP0026281A1; adopt chloroacetyl chloride to replace expensive alpha-Acetoxyacetyl chloride that the amino on 5 of the phenyl ring is carried out acylation reaction in the synthetic method of the present invention; the synthesis yield in this step reaches 94%; in addition; chloroacetyl chloride belongs to common industrial chemicals; buy at home easily, need not special preparation.Compare with second kind of synthetic method among the patent EP0026281A1, final step is hydrolysis reaction in the synthetic method of the present invention, and the raw material of employing is cheap sodium acetate, and side reaction is few, and yield reaches 86%, has reduced cost.
Therefore, the synthetic route reaction conditions gentleness of the present invention's design, steady quality, the yield height, cost is low, is suitable for industrialized production.
Embodiment
Embodiment 1
5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:
In the there-necked flask that agitator and reflux condensing tube are housed, 76g(0.133mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthalic acid is dissolved in 250mL(2.53mol) in the ethyl acetate, after waiting to stir, add 29mL(0.4mol) sulfur oxychloride, be warming up to 50 ℃ of acyl chloride reaction temperature then, stir and finished reaction in 6 hours.After treating that ethyl acetate and sulfur oxychloride boil off under the decompression, residue boils off solvent and washs through frozen water after adding the 100mL ethyl acetate, dry product 68.9g, yield is that 84.9%(is with 5-methylamino-2,4,6-triiodo m-phthalic acid meter), m.p.167 ~ 169 ℃.
Embodiment 2
5-methylamino-2,4,6-triiodo m-phthaloyl chloride synthetic:
The acyl chloride reaction temperature is 80 ℃, and in 3 hours reaction times, all the other are operated with embodiment 1.
Embodiment 3
5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:
In reaction flask, add 36.6g(0.06mol under the room temperature) 5-methylamino-2,4,6-triiodo m-phthaloyl chloride and 80mL N,N-dimethylacetamide, heating in water bath to 50 ℃, after the stirring and dissolving, be cooled to 10 ℃, begin to drip 10.2g(0.09mol) chloroacetyl chloride, dropwising the back heats up 50 ℃, stirred 3 hours, and be cooled to 10 ℃, be added dropwise to the 150mL frozen water.Filter, through the frozen water washing, dry product 38.7g, yield be 94%(with 5-methylamino-2,4,6-triiodo m-phthaloyl chloride meter), m.p.194 ~ 196 ℃.
Embodiment 4
5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride synthetic:
The chlorine acylation temperature is 90 ℃, and in 1 hour reaction times, all the other are operated with embodiment 3.
Embodiment 5
5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:
In reaction flask, add 41.2g(0.06mol under the room temperature) 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride and 80mL N, the N-N,N-DIMETHYLACETAMIDE after the stirring and dissolving, is cooled to 10 ℃, add 16g(0.16mol) triethylamine and 14.6g(0.16mol) 3-amino-1, the 2-propylene glycol is heated to 20 ℃ then, stirs and finishes reaction in 15 hours, be chilled to after-filtration below 10 ℃, after evaporated under reduced pressure, residue is dissolved in the 160mL methyl alcohol with filtrate, adds 200mL water and stirs evenly, leave standstill, with the solid filtering of separating out, the washing, dry product 43.4g, yield is that 91%(is with 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride meter), m.p.204 ~ 207 ℃.
Embodiment 6
5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:
The amidate action temperature is 50 ℃, and in 8 hours reaction times, all the other are operated with embodiment 5.
Embodiment 7
5-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide synthetic:
In reaction flask, add 47.7g(0.06mol) 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide, 250mL water, stir and to add 26g(0.32mol down) sodium acetate, back flow reaction is after 24 hours, the pressure reducing and steaming solvent.The residue dissolve with methanol filters, and filtrate boils off methyl alcohol, and vacuum-drying gets solid, is dissolved in the 150mL water, adds gac 1.8g, and reflux 30min filters.Filtrate is successively respectively by 732 Zeo-karbs and 717 anionite-exchange resin, and pressure reducing and steaming solvent again is after the resistates vacuum-drying, add 180mL ethanol and carry out recrystallization, get white solid 40.1g, HPLC detects purity greater than 99.0%, and yield is that 86%(is with 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide meter), m.p.〉280 ℃.
1H-NMR?(DMSO-D
6)δ（ppm）：2.91(s,4H)，3.21~3.36（m,4H）,?3.41~3.65（m,4H）,?3.85（s,2H）,?3.98（m,2H）,?4.1~?4.5（m,5H）,?8.2~?8.4（d,?2H）；
13C-NMR（D
2O）δ（ppm）33.2，44.7，60.7，64.6，71.2，90.1，99.8，99.9，145.5，150.5，150.6，171.3，171.4，173.9。
Claims (1)
1. 5-[N-methyl-glycolamide base]-N; N '-two (2; the 3-dihydroxypropyl)-2,4,6-three iodo-1; the preparation method of 3-benzenedicarboxamide; it is characterized in that with 5-methylamino-2,4 6-triiodo m-phthalic acid is starting raw material; carry out acyl chloride reaction, chlorine acetylation, amidate action and hydroxylating successively and make, reaction scheme is as follows:
A) acyl chloride reaction: compound (V) 5-methylamino-2,4,6-triiodo m-phthalic acid and sulfur oxychloride carry out acyl chloride reaction, make solvent with ethyl acetate, compound (V): sulfur oxychloride: the mol ratio of ethyl acetate is controlled to be 1:3:19, in the there-necked flask that agitator and reflux condensing tube are housed, adds 5-methylamino-2 under the room temperature, 4,6-triiodo m-phthalic acid is dissolved in the ethyl acetate, after waiting to stir, adds sulfur oxychloride, be warming up to 50 ~ 80 ℃ then, stir and finished reaction in 3 ~ 6 hours, after decompression boils off ethyl acetate and sulfur oxychloride down, after the residue adding ethyl acetate, boil off solvent again, through frozen water washing, dry 5-methylamino-2,4,6-triiodo m-phthaloyl chloride, i.e. compound (IV);
B) chlorine acetylation: compound (IV) 5-methylamino-2,4,6-triiodo m-phthaloyl chloride and chloroacetyl chloride carry out chlorine acetylation, make solvent with N,N-dimethylacetamide, compound (IV): the mol ratio of chloroacetyl chloride is controlled to be 1:1.5, under 50 ℃ with 5-methylamino-2,4,6-triiodo m-phthaloyl chloride is dissolved in the N,N-dimethylacetamide, be cooled to 10 ℃ then, be added dropwise to chloroacetyl chloride, be warming up to 50 ~ 90 ℃ after dropwising, stir and finished reaction in 1 ~ 3 hour, be cooled to 10 ℃, be added dropwise to frozen water, filter, wash through frozen water, dry 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride, i.e. compound (III);
C) amidate action: with 3-amino-1,2-propylene glycol and 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride carries out amidate action, is catalyzer with the triethylamine, compound (III): 3-amino-1, the 2-propylene glycol: the mol ratio of triethylamine is controlled to be 1:2.7:2.7, under the room temperature with 5-[N-methyl-2-chloracetyl amido]-2,4,6-triiodo m-phthaloyl chloride is dissolved in N, the N-N,N-DIMETHYLACETAMIDE, after being cooled to 10 ℃, add 3-amino-1,2-propylene glycol and triethylamine, be heated to 20 ~ 50 ℃ then, stir and finished reaction in 8 ~ 15 hours, be chilled to after-filtration below 10 ℃, with filtrate after evaporated under reduced pressure, residue is dissolved in the methyl alcohol, add water and stir evenly, leave standstill, with the solid filtering of separating out, washing, dry 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide, i.e. compound (II);
D) hydroxylating: with sodium acetate and 5-[N-methyl-2-chloracetyl amido]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-, three iodo-1, the 3-benzenedicarboxamide carries out hydroxylating in the aqueous solution, compound (II): the mol ratio of sodium acetate is controlled to be 1:3～6, adds 5-[N-methyl-2-chloracetyl amido in flask]-N, N '-two (2, the 3-dihydroxypropyl)-2,4,6-three iodo-1,3-benzenedicarboxamide and water after waiting to stir, add sodium acetate, after the back flow reaction 24 hours, pressure reducing and steaming solvent, residue dissolve with methanol, filter, filtrate boils off methyl alcohol, and vacuum-drying gets solid, soluble in water, add gac, reflux 30min filters, filtrate is successively by 732 Zeo-karbs and 717 anionite-exchange resin, pressure reducing and steaming solvent again is after the resistates vacuum-drying, through ethyl alcohol recrystallization, get 5-[N-methyl-glycolamide base]-N, N '-two (2,3-dihydroxypropyl)-2,4,6-three iodo-1, the 3-benzenedicarboxamide.
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| US4352788A (en) * | 1979-08-09 | 1982-10-05 | Bracco Industria Chimica S.P.A. | Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and X-ray contrasting materials containing these |
| CN101654417A (en) * | 2009-09-01 | 2010-02-24 | 江苏省原子医学研究所 | Preparation method of X-ray contrast agent ioversol intermediate |
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| US4352788A (en) * | 1979-08-09 | 1982-10-05 | Bracco Industria Chimica S.P.A. | Derivatives of 2,4,6-triiodo-isophthalic acid, processes for their synthesis and X-ray contrasting materials containing these |
| CN101654417A (en) * | 2009-09-01 | 2010-02-24 | 江苏省原子医学研究所 | Preparation method of X-ray contrast agent ioversol intermediate |
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