CN110590591B - Preparation method of iodixanol and iohexol impurities - Google Patents
Preparation method of iodixanol and iohexol impurities Download PDFInfo
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- CN110590591B CN110590591B CN201910914146.XA CN201910914146A CN110590591B CN 110590591 B CN110590591 B CN 110590591B CN 201910914146 A CN201910914146 A CN 201910914146A CN 110590591 B CN110590591 B CN 110590591B
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- 239000012535 impurity Substances 0.000 title claims abstract description 43
- 229960004359 iodixanol Drugs 0.000 title claims abstract description 14
- NBQNWMBBSKPBAY-UHFFFAOYSA-N iodixanol Chemical compound IC=1C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C(I)C=1N(C(=O)C)CC(O)CN(C(C)=O)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NBQNWMBBSKPBAY-UHFFFAOYSA-N 0.000 title claims abstract description 14
- 229960001025 iohexol Drugs 0.000 title claims abstract description 13
- NTHXOOBQLCIOLC-UHFFFAOYSA-N iohexol Chemical compound OCC(O)CN(C(=O)C)C1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I NTHXOOBQLCIOLC-UHFFFAOYSA-N 0.000 title claims abstract description 13
- 238000002360 preparation method Methods 0.000 title claims abstract description 13
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 239000002904 solvent Substances 0.000 claims abstract description 23
- ZJNFSGVGNJTJDC-UHFFFAOYSA-N 5-acetamido-3-n,3-n-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound CC(=O)NC1=C(I)C(C(N)=O)=C(I)C(C(=O)N(CC(O)CO)CC(O)CO)=C1I ZJNFSGVGNJTJDC-UHFFFAOYSA-N 0.000 claims abstract description 21
- IIHOIAOMFRCCKR-UHFFFAOYSA-N 2-(2,3-dihydroxypropyl)benzene-1,3-dicarboxamide Chemical compound NC(=O)C1=CC=CC(C(N)=O)=C1CC(O)CO IIHOIAOMFRCCKR-UHFFFAOYSA-N 0.000 claims abstract description 19
- PPPFYBPQAPISCT-UHFFFAOYSA-N 2-hydroxypropyl acetate Chemical compound CC(O)COC(C)=O PPPFYBPQAPISCT-UHFFFAOYSA-N 0.000 claims abstract description 19
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 claims abstract description 19
- BYBCYVOWLSVLFO-UHFFFAOYSA-N 5-chloro-4-hydroxypentanoic acid Chemical compound ClCC(O)CCC(O)=O BYBCYVOWLSVLFO-UHFFFAOYSA-N 0.000 claims abstract description 12
- NNIBUEQIBYRALP-UHFFFAOYSA-N (3-chloro-2-hydroxypropyl) acetate Chemical compound CC(=O)OCC(O)CCl NNIBUEQIBYRALP-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 66
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 21
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 20
- 238000001914 filtration Methods 0.000 claims description 20
- 239000011347 resin Substances 0.000 claims description 19
- 229920005989 resin Polymers 0.000 claims description 19
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 11
- RBTARNINKXHZNM-UHFFFAOYSA-K iron trichloride Chemical compound Cl[Fe](Cl)Cl RBTARNINKXHZNM-UHFFFAOYSA-K 0.000 claims description 11
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- XNWFRZJHXBZDAG-UHFFFAOYSA-N 2-METHOXYETHANOL Chemical compound COCCO XNWFRZJHXBZDAG-UHFFFAOYSA-N 0.000 claims description 7
- 229940113088 dimethylacetamide Drugs 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 6
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 5
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 5
- 238000010790 dilution Methods 0.000 claims description 4
- 239000012895 dilution Substances 0.000 claims description 4
- 230000008020 evaporation Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 3
- -1 2-hydroxy-3-chloropropylacetic acid ester Chemical class 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000003756 stirring Methods 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 12
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 8
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 8
- 239000012044 organic layer Substances 0.000 description 8
- 239000001632 sodium acetate Substances 0.000 description 8
- 235000017281 sodium acetate Nutrition 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 description 5
- 239000006227 byproduct Substances 0.000 description 5
- 238000004321 preservation Methods 0.000 description 5
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 4
- 230000003213 activating effect Effects 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000003480 eluent Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 230000008014 freezing Effects 0.000 description 4
- 238000007710 freezing Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 238000005374 membrane filtration Methods 0.000 description 4
- GBMDVOWEEQVZKZ-UHFFFAOYSA-N methanol;hydrate Chemical compound O.OC GBMDVOWEEQVZKZ-UHFFFAOYSA-N 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 238000002390 rotary evaporation Methods 0.000 description 4
- 238000000926 separation method Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- 239000012043 crude product Substances 0.000 description 3
- 229910021578 Iron(III) chloride Inorganic materials 0.000 description 2
- 238000007865 diluting Methods 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- BHCBLTRDEYPMFZ-UHFFFAOYSA-N 5-acetamido-1-n,3-n-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound CC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)NCC(O)CO)=C1I BHCBLTRDEYPMFZ-UHFFFAOYSA-N 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
- 239000002253 acid Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 208000012839 conversion disease Diseases 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 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
- 239000012467 final product Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/22—Separation; Purification; Stabilisation; Use of additives
- C07C231/24—Separation; Purification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/24—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran
- C07C67/26—Preparation of carboxylic acid esters by reacting carboxylic acids or derivatives thereof with a carbon-to-oxygen ether bond, e.g. acetal, tetrahydrofuran with an oxirane ring
Abstract
The invention discloses a preparation method of iodixanol and iohexol impurities, which comprises the following steps: step one, preparing 2-hydroxy-3-chloropropyl acetate; and step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide. The impurities are easy to generate in the preparation process of iodixanol and iohexol, are difficult to separate, have great influence on the purity, and the related preparation method of the impurities does not exist in the prior art.
Description
Technical Field
The invention relates to the technical field of chemical synthesis, in particular to a preparation method of iodixanol and iohexol impurities.
Background
5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide is a key intermediate of contrast agents iodixanol and iohexol. In the reaction process, the impurities are generated along with the continuous hydrolysis of the 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, the polarity of the impurities is very close to that of iodixanol, and the impurities are difficult to remove from the beginning of the reaction to the final product, so that the quality of the product is seriously influenced, and therefore, the research on the impurities is necessary, but no related preparation method of the impurities exists in the prior art at present.
The specific information of the impurities is as follows:
name: 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide
The molecular formula is as follows: c21H28I3N3O10
Molecular weight: 863.18
Structural formula (la):
disclosure of Invention
The invention aims to provide a preparation method of iodixanol and iohexol impurities, which aims to overcome the defects of the prior art.
The invention adopts the following technical scheme:
a method for preparing iodixanol and iohexol impurities comprises the following steps:
step one, preparing 2-hydroxy-3-chloropropyl acetate;
and step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
Further, in the second step, 5-acetamido-2, 4, 6-triiodo-N, N '-bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent are mixed, the pH is adjusted to 10-13, the temperature is controlled to be 0-40 ℃, 2-hydroxy-3-chloropropylacetate is dropwise added within 0.5-4h, the reaction is kept for 5-24h, the pH is adjusted to 2-8 after the reaction is finished, the mixture is filtered and concentrated, XAD-18, XAD-1600N, LX-16 or LX-18 macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
Further, in the second step, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent are mixed, the pH value is adjusted to 11-13, the temperature is controlled to be 15-30 ℃, 2-hydroxy-3-chloropropylacetate is dropwise added within 1-3h, the heat preservation reaction is carried out for 10-18h, the pH value is adjusted to 4-7 after the reaction is finished, the mixture is filtered and concentrated, and XAD-1600N or LX-16 macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
And further, mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, adjusting the pH to 11.5-12, controlling the temperature to be 20 ℃, dropwise adding 2-hydroxy-3-chloropropylacetate within 2h, preserving the temperature for reaction for 16h, adjusting the pH to 6 after the reaction is finished, filtering, concentrating, and purifying by XAD-1600N macroporous resin to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
Further, the second solvent in the step (II) comprises water, N-methyl pyrrolidone, ethylene glycol monomethyl ether, dimethyl acetamide or methanol, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide after the mixture is mixed, and the pH is adjusted by hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid after the reaction is finished.
Further, the second solvent in the step comprises ethylene glycol monomethyl ether or dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by sodium hydroxide or sodium methoxide after the mixture is mixed, and the pH is adjusted by phosphoric acid or acetic acid after the reaction is finished.
Further, the second solvent of the step comprises dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and a solvent, the pH is adjusted by sodium methoxide after the mixture is mixed, and the pH is adjusted by acetic acid after the reaction is finished.
And further, reacting epichlorohydrin and acetic acid serving as raw materials under the action of a catalyst anhydrous ferric chloride, and performing post-treatment after the reaction is finished to obtain the 2-hydroxy-3-chloropropyl acetate.
Further, the first step is firstly reaction at low temperature; and then heating for reaction.
Further, the step one post-treatment comprises evaporation, dilution, filtration, washing, drying, concentration or comprises precipitation, evaporation, dilution, filtration, washing, drying, concentration.
The invention has the beneficial effects that:
1. the impurities are easy to generate in the preparation process of iodixanol and iohexol, are difficult to separate, have great influence on the purity, and the related preparation method of the impurities does not exist in the prior art.
2. The invention achieves the effect of reducing the generation of byproducts by controlling various process conditions, and prepares high-purity finished product impurities by macroporous resin purification, and the conversion rate is higher.
Detailed Description
The present invention will be further explained with reference to examples. The following examples are provided only for illustrating the present invention and are not intended to limit the scope of the present invention.
A method for preparing iodixanol and iohexol impurities comprises the following steps:
taking epoxy chloropropane and acetic acid as raw materials, firstly reacting at low temperature under the action of a catalyst anhydrous ferric chloride, and then heating for reaction; after the reaction is finished, evaporating, diluting, filtering, washing, drying and concentrating or precipitating, evaporating, diluting, filtering, washing, drying and concentrating to obtain 2-hydroxy-3-chloropropylacetic acid ester;
step two, mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with a solvent, wherein the solvent comprises water, N-methylpyrrolidone (NMP), ethylene glycol monomethyl ether, Dimethylacetamide (DMA) or methanol, preferably ethylene glycol monomethyl ether or DMA, and more preferably DMA; adjusting the pH to 10-13, preferably 11-13, more preferably 11.5-12 (the pH is adjusted to be more critical, the pH is lower, the compound III cannot be dissolved in the solvent, the pH is higher, the destruction of the compound IV can be promoted, and the reaction conversion rate is influenced) by using triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide, preferably sodium hydroxide or sodium methoxide, more preferably sodium methoxide; controlling the temperature at 0-40 deg.C, preferably 15-30 deg.C, more preferably 20 deg.C, within 0.5-4h, preferably 1-3h, more preferably 2h, and dropwise adding 2-hydroxy-3-chloropropyl acetate; keeping the temperature for reaction for 5-24h, preferably 10-18h, more preferably 16 h; adjusting the pH to 2-8, preferably 4-7, more preferably 6 (the pH is critical for terminating the reaction, and the reaction system is viscous, gelatinous, and unstable due to the use of tai acid, and the resin adsorption is reduced due to the subsequent column chromatography), filtering, concentrating, adding XAD-18, XAD-1600N, LX-16 or LX-18 macroporous resin, preferably XAD-1600N or LX-16 macroporous resin, more preferably XAD-1600N macroporous resin, purifying to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
The synthesis process is as follows:
example 1
150g of 1.62mol of epichlorohydrin is put into a reaction bottle, and the temperature is reduced to 10 ℃ by a freezing tank for standby; weighing 106.8g of 1.78mol of acetic acid, adding 5g of 0.03mol of anhydrous ferric trichloride, and uniformly stirring; slowly dripping acetic acid containing ferric trichloride into epoxy chloropropane twice, wherein the time for each time is about 2 hours, and the temperature is preferably controlled to be 10-15 ℃; after the dropwise addition is finished, stirring for 5h at the temperature (keeping the temperature, reducing the reaction rate and the generation of byproducts, reacting for 5h until the total amount of the reaction is about 1/3, and continuously reacting until the temperature is increased); after stirring, heating to 50-55 ℃, and reacting for 28h under the condition of heat preservation; after the reaction is finished, adding 2.53g of 0.03mol of sodium acetate, uniformly stirring (optionally, directly carrying out subsequent rotary evaporation without adding the sodium acetate), and removing redundant acetic acid by using a rotary evaporator; then adding 200ml of 3.12mol of dichloromethane to dilute the reaction solution, and filtering; the filtrate was washed with a 7 wt% aqueous potassium carbonate solution to wash the organic layer; the organic layer was dried over anhydrous magnesium sulfate and concentrated to give 205g of 2-hydroxy-3-chloropropylacetate as a colorless oily substance with a purity of 95% or higher.
Putting 200g of 0.27mol of 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide into a reaction bottle, adding 200ml of 2.15mol of DMA, adjusting the pH to 11.5-12 by using sodium methoxide, controlling the temperature to 20 ℃, slowly dropping 42.72g of 0.28mol of prepared 2-hydroxy-3-chloropropyl acetate for 2 h; after the dropwise addition is finished, reacting for 16h at the temperature; after the reaction is finished, adjusting the pH value to 6 by using acetic acid, filtering the reaction solution, and concentrating the reaction solution to be dry by using a high vacuum oil pump to obtain 243g of impurity crude product 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with the purity of 70%.
Dissolving 100g of crude impurity in 400g of water to prepare a 20 wt% aqueous solution; activating 1000ml of XAD-1600N macroporous resin, and uniformly loading the feed liquid on a resin column; performing column separation by using 3 v/v% methanol water solution as eluent; taking the collected liquid part, dehydrating by adopting a membrane concentration mode, stopping membrane filtration when the concentration of the feed liquid is higher than 0.2g/ml, and performing reduced pressure concentration to dry; adding 200ml of 2.62mol of isopropanol, stirring and dispersing the materials, filtering, and drying at the temperature of 60 ℃ in vacuum to obtain a finished product of the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 63g, wherein the purity is not less than 97%, and the weight yield is 63%.
The mass spectrum of the impurity product prepared in this example is shown in fig. 1.
Example 2
150g of 1.62mol of epichlorohydrin is put into a reaction bottle, and the temperature is reduced to 10 ℃ by a freezing tank for standby; weighing 106.8g of 1.78mol of acetic acid, adding 5g of 0.03mol of anhydrous ferric trichloride, and uniformly stirring; slowly dripping acetic acid containing ferric trichloride into epoxy chloropropane twice, wherein the time for each time is about 2 hours, and the temperature is preferably controlled to be 10-15 ℃; after the dropwise addition is finished, stirring for 5h at the temperature (keeping the temperature, reducing the reaction rate and the generation of byproducts, reacting for 5h until the total amount of the reaction is about 1/3, and continuously reacting until the temperature is increased); after stirring, heating to 50-55 ℃, and reacting for 28h under the condition of heat preservation; after the reaction is finished, adding 2.53g of 0.03mol of sodium acetate, uniformly stirring (optionally, directly carrying out subsequent rotary evaporation without adding the sodium acetate), and removing redundant acetic acid by using a rotary evaporator; then adding 200ml of 3.12mol of dichloromethane to dilute the reaction solution, and filtering; the filtrate was washed with a 7 wt% aqueous potassium carbonate solution to wash the organic layer; the organic layer was dried over anhydrous magnesium sulfate and concentrated to give 205g of 2-hydroxy-3-chloropropylacetate as a colorless oily substance with a purity of 95% or higher.
Putting 200g of 0.27mol of 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide into a reaction bottle, adding 200ml of 2.53mol of ethylene glycol monomethyl ether, adjusting the pH to 12.5-13 by using sodium hydroxide, controlling the temperature to 30 ℃, slowly dropping 42.72g of 0.28mol of prepared 2-hydroxy-3-chloropropyl acetate for 3 hours; after the dropwise addition is finished, reacting for 18h at the temperature; after the reaction, the pH was adjusted to 7 with phosphoric acid, the reaction solution was filtered and concentrated to dryness with a high vacuum oil pump to obtain 246g of crude 5- [ N- (2-hydroxypropyl acetate) acetylamino ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide as an impurity with a purity of 62%.
Dissolving 100g of crude impurity in 400g of water to prepare a 20 wt% aqueous solution; activating 1000ml of LX-16 macroporous resin, and uniformly feeding the feed liquid on a resin column; performing column separation by using 3 v/v% methanol water solution as eluent; taking the collected liquid part, dehydrating by adopting a membrane concentration mode, stopping membrane filtration when the concentration of the feed liquid is higher than 0.2g/ml, and performing reduced pressure concentration to dry; adding 200ml of 2.62mol of isopropanol, stirring and dispersing the materials, filtering, and drying at the temperature of 60 ℃ in vacuum to obtain 52g of impurity finished product 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, wherein the purity is not less than 95%, and the weight yield is 52%.
Example 3
150g of 1.62mol of epichlorohydrin is put into a reaction bottle, and the temperature is reduced to 10 ℃ by a freezing tank for standby; weighing 106.8g of 1.78mol of acetic acid, adding 5g of 0.03mol of anhydrous ferric trichloride, and uniformly stirring; slowly dripping acetic acid containing ferric trichloride into epoxy chloropropane twice, wherein the time for each time is about 2 hours, and the temperature is preferably controlled to be 10-15 ℃; after the dropwise addition is finished, stirring for 5h at the temperature (keeping the temperature, reducing the reaction rate and the generation of byproducts, reacting for 5h until the total amount of the reaction is about 1/3, and continuously reacting until the temperature is increased); after stirring, heating to 50-55 ℃, and reacting for 28h under the condition of heat preservation; after the reaction is finished, adding 2.53g of 0.03mol of sodium acetate, uniformly stirring (optionally, directly carrying out subsequent rotary evaporation without adding the sodium acetate), and removing redundant acetic acid by using a rotary evaporator; then adding 200ml of 3.12mol of dichloromethane to dilute the reaction solution, and filtering; the filtrate was washed with a 7 wt% aqueous potassium carbonate solution to wash the organic layer; the organic layer was dried over anhydrous magnesium sulfate and concentrated to give 205g of 2-hydroxy-3-chloropropylacetate as a colorless oily substance with a purity of 95% or higher.
Adding 200g of 0.27mol of 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide into a reaction bottle, adding 200ml of 2.07mol of NMP, adjusting the pH value to 10-10.5 by triethylamine, controlling the temperature to 0 ℃, slowly dropping 42.72g of 0.28mol of prepared 2-hydroxy-3-chloropropyl acetate for 0.5 h; after the dropwise addition is finished, reacting for 5 hours at the temperature; after the reaction is finished, the pH value is adjusted to 2 by hydrochloric acid, the reaction solution is filtered and concentrated to be dry by a high vacuum oil pump, and 247g of impurity crude product 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with the purity of 53% is obtained.
Dissolving 100g of crude impurity in 400g of water to prepare a 20 wt% aqueous solution; activating 1000ml of XAD-18 macroporous resin, and uniformly loading the feed liquid on a resin column; performing column separation by using 3 v/v% methanol water solution as eluent; taking the collected liquid part, dehydrating by adopting a membrane concentration mode, stopping membrane filtration when the concentration of the feed liquid is higher than 0.2g/ml, and performing reduced pressure concentration to dry; adding 200ml of 2.62mol of isopropanol, stirring and dispersing the materials, filtering, and drying at the temperature of 60 ℃ in vacuum to obtain the finished product of the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide 43g, wherein the purity is not less than 95 percent, and the weight yield is 43 percent.
Example 4
150g of 1.62mol of epichlorohydrin is put into a reaction bottle, and the temperature is reduced to 10 ℃ by a freezing tank for standby; weighing 106.8g of 1.78mol of acetic acid, adding 5g of 0.03mol of anhydrous ferric trichloride, and uniformly stirring; slowly dripping acetic acid containing ferric trichloride into epoxy chloropropane twice, wherein the time for each time is about 2 hours, and the temperature is preferably controlled to be 10-15 ℃; after the dropwise addition is finished, stirring for 5h at the temperature (keeping the temperature, reducing the reaction rate and the generation of byproducts, reacting for 5h until the total amount of the reaction is about 1/3, and continuously reacting until the temperature is increased); after stirring, heating to 50-55 ℃, and reacting for 28h under the condition of heat preservation; after the reaction is finished, adding 2.53g of 0.03mol of sodium acetate, uniformly stirring (optionally, directly carrying out subsequent rotary evaporation without adding the sodium acetate), and removing redundant acetic acid by using a rotary evaporator; then adding 200ml of 3.12mol of dichloromethane to dilute the reaction solution, and filtering; the filtrate was washed with a 7 wt% aqueous potassium carbonate solution to wash the organic layer; the organic layer was dried over anhydrous magnesium sulfate and concentrated to give 205g of 2-hydroxy-3-chloropropylacetate as a colorless oily substance with a purity of 95% or higher.
Adding 200g of 0.27mol of 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide into a reaction bottle, adding 200ml of 11.1mol of water, adjusting the pH to 12.5-13 by using lithium hydroxide, controlling the temperature to 40 ℃, slowly dropping 42.72g of 0.28mol of prepared 2-hydroxy-3-chloropropyl acetate for 4 hours; after the dropwise addition is finished, reacting for 24 hours at the temperature; after the reaction is finished, the pH value is adjusted to 8 by using sulfuric acid, the reaction solution is filtered and concentrated to be dry by using a high vacuum oil pump, and 251g of impurity crude product 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with the purity of 36% is obtained.
Dissolving 100g of crude impurity in 400g of water to prepare a 20 wt% aqueous solution; activating 1000ml of LX-18 macroporous resin, and uniformly feeding the feed liquid on a resin column; performing column separation by using 3 v/v% methanol water solution as eluent; taking the collected liquid part, dehydrating by adopting a membrane concentration mode, stopping membrane filtration when the concentration of the feed liquid is higher than 0.2g/ml, and performing reduced pressure concentration to dry; adding 200ml of 2.62mol of isopropanol, stirring and dispersing the materials, filtering, and drying at the temperature of 60 ℃ in vacuum to obtain 28g of impurity finished product 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, wherein the purity is not less than 90 percent, and the weight yield is 28 percent.
Claims (6)
1. A preparation method of iodixanol and iohexol impurities is characterized by comprising the following steps:
step one, preparing 2-hydroxy-3-chloropropyl acetate: taking epoxy chloropropane and acetic acid as raw materials, reacting at the low temperature of 10-15 ℃ under the action of a catalyst of anhydrous ferric trichloride, heating to 50-55 ℃ for reaction, and performing post-treatment after the reaction is finished to obtain 2-hydroxy-3-chloropropyl acetate;
step two, taking 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and 2-hydroxy-3-chloropropylacetate as raw materials, reacting in a solvent, and performing post-treatment after the reaction is finished to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, wherein the specific operation is as follows:
mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and solvent, adjusting pH to 10-13, controlling temperature at 0-40 deg.C, dropwise adding 2-hydroxy-3-chloropropylacetic acid ester within 0.5-4h, reacting for 5-24h while maintaining temperature, adjusting pH to 2-8 after reaction, filtering, concentrating XAD-18 and XAD-1600N, purifying with LX-16 or LX-18 macroporous resin to obtain 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide as impurity;
wherein the second solvent is selected from water, N-methyl pyrrolidone, ethylene glycol monomethyl ether, dimethyl acetamide or methanol, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and the solvent, the pH is adjusted by triethylamine, sodium hydroxide, lithium hydroxide or sodium methoxide after the mixture is mixed, and the pH is adjusted by hydrochloric acid, sulfuric acid, acetic acid or phosphoric acid after the reaction is finished.
2. The preparation method of iodixanol and iohexol impurity as claimed in claim 1, wherein the second step is mixing 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide with solvent, adjusting pH to 11-13, controlling temperature at 15-30 deg.C, dropwise adding 2-hydroxy-3-chloropropylacetate within 1-3h, keeping temperature for reaction for 10-18h, adjusting pH to 4-7 after reaction, filtering, concentrating, purifying XAD-1600N or LX-16 macroporous resin to obtain 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
3. The preparation method of iodixanol and iohexol impurity as claimed in claim 1, wherein in the second step, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide and solvent are mixed, pH is adjusted to 11.5-12, temperature is controlled at 20 ℃, 2h is dropwise added with 2-hydroxy-3-chloropropylacetate, reaction is kept for 16h, pH is adjusted to 6 after reaction is finished, filtration and concentration are carried out, XAD-1600N macroporous resin is purified to obtain the impurity 5- [ N- (2-hydroxypropyl acetate) acetamido ] -2,4, 6-triiodo-N, N' -bis (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide.
4. The process of claim 1, wherein the second solvent is selected from the group consisting of ethylene glycol monomethyl ether or dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, sodium hydroxide or sodium methoxide, and phosphoric acid or acetic acid is used to adjust the pH after the reaction.
5. The process of claim 1, wherein the second solvent is dimethylacetamide, 5-acetamido-2, 4, 6-triiodo-N, N-bis- (2, 3-dihydroxypropyl) -1, 3-benzenedicarboxamide, and the solvent are mixed and then the pH is adjusted with sodium methoxide, and acetic acid is used to adjust the pH after the reaction.
6. The process of claim 1, wherein the step one post-treatment comprises evaporation, dilution, filtration, washing, drying, concentration or comprises precipitation, evaporation, dilution, filtration, washing, drying, concentration.
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