CN118108618A - Production process of iodixanol - Google Patents
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- 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 31
- 229960004359 iodixanol Drugs 0.000 title claims abstract description 31
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 22
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 238000000746 purification Methods 0.000 claims abstract description 18
- 238000003756 stirring Methods 0.000 claims description 32
- 150000001875 compounds Chemical class 0.000 claims description 26
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 15
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 13
- 239000004327 boric acid Substances 0.000 claims description 13
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 239000011347 resin Substances 0.000 claims description 9
- 229920005989 resin Polymers 0.000 claims description 9
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 6
- 238000004042 decolorization Methods 0.000 claims description 3
- 229910052799 carbon Inorganic materials 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 238000010612 desalination reaction Methods 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 abstract description 12
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 12
- 238000001514 detection method Methods 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 10
- 239000012535 impurity Substances 0.000 description 9
- 239000000543 intermediate Substances 0.000 description 9
- 239000006185 dispersion Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 238000000926 separation method Methods 0.000 description 6
- 238000001694 spray drying Methods 0.000 description 6
- 239000006227 byproduct Substances 0.000 description 5
- 238000003384 imaging method Methods 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 238000005804 alkylation reaction Methods 0.000 description 4
- 239000008213 purified water Substances 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- QZRGKCOWNLSUDK-UHFFFAOYSA-N Iodochlorine Chemical compound ICl QZRGKCOWNLSUDK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 230000029936 alkylation Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000026045 iodination Effects 0.000 description 3
- 238000006192 iodination reaction Methods 0.000 description 3
- 238000001953 recrystallisation Methods 0.000 description 3
- 238000005070 sampling Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 3
- MQDLKAADJTYKRH-UHFFFAOYSA-N 1-aminopropane-1,2,3-triol Chemical compound NC(O)C(O)CO MQDLKAADJTYKRH-UHFFFAOYSA-N 0.000 description 2
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 238000007487 urography Methods 0.000 description 2
- XUKUURHRXDUEBC-SXOMAYOGSA-N (3s,5r)-7-[2-(4-fluorophenyl)-3-phenyl-4-(phenylcarbamoyl)-5-propan-2-ylpyrrol-1-yl]-3,5-dihydroxyheptanoic acid Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-SXOMAYOGSA-N 0.000 description 1
- YIPGLACOACNFML-UHFFFAOYSA-N 1-n,3-n-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide Chemical compound OCC(O)CNC(=O)C1=C(I)C=C(I)C(C(=O)NCC(O)CO)=C1I YIPGLACOACNFML-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 238000007126 N-alkylation reaction Methods 0.000 description 1
- 238000010934 O-alkylation reaction Methods 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical group CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- WETWJCDKMRHUPV-UHFFFAOYSA-N acetyl chloride Chemical compound CC(Cl)=O WETWJCDKMRHUPV-UHFFFAOYSA-N 0.000 description 1
- 239000012346 acetyl chloride Substances 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 238000002583 angiography Methods 0.000 description 1
- 239000003957 anion exchange resin Substances 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 239000003729 cation exchange resin Substances 0.000 description 1
- 229940023913 cation exchange resins Drugs 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000011033 desalting Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-M ethanimidate Chemical compound CC([O-])=N DLFVBJFMPXGRIB-UHFFFAOYSA-M 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000002920 hazardous waste Substances 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 239000012521 purified sample Substances 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 239000000523 sample Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a production method of iodixanol, which uses a double-planetary dispersing mixer to carry out double polymerization reaction, has short reaction period and high conversion rate, thereby leading the subsequent purification process to be simple and being beneficial to commercial production.
Description
Technical Field
The invention relates to the field of medicine preparation.
Background
Iodixanol (Iodixanol), chemical name 5,5'- ((2-hydroxy-1, 3-propane) bis (acetimidate)) bis (N, N' -bis (2, 3-dihydroxypropyl) -2,4, 6-triiodo-1, 3-benzenedicarboxamide, developed by nychid, norwegian, is a new type of non-ionic X-ray contrast agent, the only one that is isotonic with plasma when used in blood vessels, for cardiovascular imaging, cerebrovascular imaging, peripheral arterial imaging, abdominal angiography, urography, venous imaging and CT enhancement examination in adults, cardiovascular imaging, urography and CT enhancement examination in children, iodixanol injection was marketed in europe 1994, in the united states in 1996, in china in 2001.
Iodixanol is directly injected into blood to exert drug effect, and the dosage is large, so the quality of iodixanol bulk drug is highly required. And further has high requirements on the synthesis, separation and purification process of iodixanol.
Various synthetic routes and methods have been reported to produce iodixanol, such as the synthetic route disclosed in U.S. patent No. 6441235 as follows:
The method takes a compound (2) as a starting material, the compound (2) reacts with methanol to form a compound (3) under the catalysis of sulfuric acid, then the compound (3) is ammonolyzed to form a compound (4) under the action of amino glycerol, the compound (5) is reduced by hydrogenation, iodine chloride is used as an iodination compound (6), the iodination compound is reacted with acetic anhydride to synthesize a key intermediate (7), and the generated compound (7) reacts with epichlorohydrin to obtain iodixanol.
Analysis of synthetic route:
① The process route has six steps of reactions, long route, long production period and low total yield.
② In the fourth step of the route, the compound (6) is synthesized, iodine monochloride is used as an iodination reagent, and the iodine monochloride has high toxicity, corrosiveness, uneasy control of the reaction process and easy corrosion of equipment, and has no advantages.
③ When iodixanol is synthesized in the last step of the route, the conversion rate of the compound (7) is between 40% and 60%, the excessive alkylation reaction is more dominant, the conversion rate is low, and the subsequent purification steps are complicated.
Synthesis route two
The synthetic route disclosed in patent WO 9637458 is shown in the following figure: the method takes a compound (II) as a starting material, performs chlorination with thionyl chloride to form (III), reacts with acetyl chloride to form (IV), then reacts with amino glycerol to form a key intermediate, and finally reacts with epoxy chloropropane to obtain iodixanol.
Analysis of synthetic route:
① The four-step reaction of the route uses sulfoxide chloride reagent, is corrosive to equipment, and has inconvenient treatment of the generated hazardous waste, the compounds (III) and (IV) are acyl chloride, the post-treatment operation is inconvenient, and the production environment has great harm to personnel.
② The third step of the route is the same as the first process, the effective conversion rate of the intermediate (V) is lower, the excessive alkylation byproducts are more, and the subsequent separation and purification processes are complicated.
To sum up: the process is long, the production period is long, and the conversion rate of the double polymerization reaction is low.
Synthetic route three
Literature reports (ref ：Hans-Rene Bjorsvik,Hanno Priebe,Jan Cervenka et.ASletctive Process for N-Alkylation in Competition with O-Alkylation:Boric Acid,Boraax,and Metaborate as a Cheap and Effective Protecting Group Applicable for Industrial-Scale Synthetic Processes[J].Organic Process Research&Development2001,5,472-478.), uses boric acid to protect the propylene glycol groups of key intermediates to reduce excessive alkylation byproducts, and adds epichlorohydrin for polymerization reaction, then adjusts acid to remove boric acid protection to obtain iodixanol.
Analysis of synthetic route:
The route improves a key intermediate double polymerization reaction system, in an alkaline water solution, boric acid is used for protecting an intermediate, then the intermediate is polymerized with epoxy chloropropane, the conversion rate is improved to be close to 80%, the excessive alkylation byproducts are reduced, the boric acid is removed by acid regulation, and iodixanol is obtained through macroporous resin separation and purification and recrystallization. The route still has the problem of complex subsequent separation and purification steps, and the reaction system is in a heterogeneous state due to poor solubility of the intermediate in water, the viscosity is high, the reaction rate is slow, and the reaction period is generally more than 48 hours.
In summary, the existing iodixanol related synthesis process has the main problems that the conversion rate of iodixanol generated by key intermediate double polymerization reaction is generally low, so that the subsequent separation and purification process is complicated, the production period is long, and the commercial production is not facilitated.
Disclosure of Invention
In order to solve the technical problems, the invention adopts a technical scheme that: the double polymerization reaction is carried out by using a double-planetary dispersing mixer, the reaction period can be shortened by 50%, only 24 hours are needed, the conversion rate is high, the subsequent purification process is simple, and the commercial production is facilitated.
The iodixanol reaction steps of the invention are as follows:
(1) Adding water, potassium hydroxide and a compound 4 into a double-planetary dispersing mixer, and stirring for dissolution;
(2) Starting dispersing and stirring, adding boric acid, cooling to 10-20 ℃, adding epichlorohydrin, and reacting completely;
(3) And (3) after purification, drying to obtain iodixanol.
The double-planet dispersing stirrer utilizes the revolution/rotation principle, and in the stirring process, two planet stirring frames respectively run according to the own axle center and simultaneously rotate around the same axle center along the container wall, so that high-viscosity materials at each corner can be uniformly mixed. Meanwhile, the revolution high-speed dispersing plate can fully crush and disperse materials in the revolution process. The stirring mode of the equipment can effectively promote the double polymerization reaction to be carried out, so that the effective conversion rate of the reaction is improved to more than 90%, and the reaction period is shortened to about 24 hours. After the reaction is finished, the product quality can reach the medicinal level (meeting the current USP and EP standards) through a simple purification process without recrystallization, so that the subsequent separation and purification difficulty is greatly reduced, and the production period is shortened.
The main impurity structure of iodixanol double polymerization reaction is as follows:
The impurity B is a reactant of the double polymerization reaction (the compound 4 in the synthetic route of the invention), the impurity A, the impurity C and the peralkyl impurity are main byproducts of the double polymerization reaction, and the synthetic route of the invention finally improves the effective conversion rate of the double polymerization reaction and reduces the generation of the byproducts.
In the production method of the present invention, the amount of the compound 4 to be used may be at least 100 to 150kg, and for example, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150kg and the like may be selected. Of course, the amount of compound 4 used depends on the size of the reaction vessel, and if the reaction vessel is increased, the amount of compound 4 used may be increased.
In the production method of the present invention, the amount of potassium hydroxide may be 3.0 to 3.2 equivalents, and for example, 3.0, 3.1, 3.2 equivalents, etc. may be selected. The equivalent weights (eq) in the present invention are all based on compound 4 as calculated basis, as follows.
In the preparation process of the present invention, the amount of water to be used is mainly sufficient for dissolving property, and may be selected to be 0.9 to 2 times by weight, for example, 0.9, 1.0, 1.5, 2.0 times by weight, etc., based on the weight of the compound 4.
In the preparation method of the present invention, the boric acid may be used in an amount of 2.0 to 2.2 equivalents, for example, 2.0, 2.1, 2.2 equivalents, etc.
In the preparation process of the present invention, epichlorohydrin may be used in an amount of from 0.50 to 0.60 equivalent, for example, 0.50, 0.55, 0.60 equivalent, etc.
In the preparation method, the stirring frequency in the step (1) is 20-30 revolutions per minute; the frequency of the dispersing and stirring in the step (2) is 380-420 revolutions/min. In the present invention, the stirring members used in the steps (1) and (2) are different. The component used in the step (1) is a planetary stirring component (also called a main stirring component), and the component used in the step (2) is a dispersion stirring component (also called a dispersion disk).
For the purification of iodixanol, macroporous resins (macroporous adsorption resins) known in the art may be used, or anion and cation exchange resins may be used.
Activated carbon decolorization is one of the conventional purification methods, and this step can be added if necessary.
The term "drying" as used herein means removing the solvent. Conventional drying means may be employed, such as spray drying, freeze drying, natural evaporation, drying, and the like. The drying mode may be selected according to the purity of the target compound and the increase or decrease of the relevant substances.
Drawings
FIG. 1 HPLC chromatogram of the reaction solution of example 1
FIG. 2 example 1 HPLC profile of iodixanol finished product
FIG. 3 HPLC chromatogram of comparative reaction solution
FIG. 4 HPLC chromatogram after comparative example spray drying
FIG. 5 HPLC chromatogram after comparative example recrystallization
Detailed Description
The double-planetary dispersing mixer is purchased from Nantong Hengli mechanical equipment Co., ltd., model: PDM-2000L.
The high performance liquid chromatography in the invention adopts the detection method of iodixanol related substances in European pharmacopoeia (EP 10.0).
Example 1
Purified water (45L) was added to a double planetary dispersion mixer, stirring was started, stirring frequency was set at 25 rpm, potassium hydroxide (3.0 eq,11.26 kg) was added, stirring was performed to dissolve, and then compound 4 (50 kg) was added, stirring was performed to dissolve. Stirring was started for 400 revolutions per minute, boric acid (2.0 eq,8.3 kg) was added, the temperature of the solution was reduced to 10 ℃, epichlorohydrin (0.57 eq,3.52 kg) was added, and the reaction was carried out at 10 ℃ for 24 hours and sampling HPLC detection was carried out (the detection result is shown in FIG. 1). After the basic reaction of the raw materials is finished, the raw materials are subjected to post-treatment, decolorization by active carbon and desalination by anion-cation resin, and spray drying is carried out to obtain 38.12kg of iodixanol, wherein the total yield is 81.6%, and the quality meets the USP and EP standard requirements (the detection result is shown in figure 2).
Example 2
Purified water (100L) was added to a double planetary dispersion mixer, stirring was started, stirring frequency was set at 25 rpm, potassium hydroxide (3.0 eq,22.5 kg) was added, stirring was performed to dissolve, and then compound 4 (100 kg) was added, stirring was performed to dissolve. Stirring was started for 400 revolutions per minute, boric acid (2.0 eq,16.6 kg) was added, the temperature of the solution was reduced to 10 ℃, epichlorohydrin (0.57 eq,7.04 kg) was added, and the reaction was carried out at 10 ℃ for 24 hours, sampling HPLC detection. After the basic reaction of the raw materials is finished, carrying out post-treatment, purifying by macroporous resin, and spray drying to obtain 77.63kg of iodixanol, wherein the total yield is 83.1%.
Example 3
Purified water (45L) was added to a double planetary dispersion mixer, stirring was started, stirring frequency was set at 25 rpm, potassium hydroxide (3.0 eq,6.76 kg) was added, stirring was performed to dissolve, and then compound 4 (30 kg) was added, stirring was performed to dissolve. Stirring was started for 400 revolutions per minute, boric acid (2.0 eq,5.0 kg) was added, the temperature of the solution was reduced to 10 ℃, epichlorohydrin (0.57 eq,3.52 kg) was added, and the reaction was carried out at 10 ℃ for 24 hours and sampling HPLC detection was carried out. After the basic reaction of the raw materials is finished, the 24.7kg iodixanol is obtained by macroporous resin purification and spray drying after the post-treatment, and the yield is 79.3%.
Comparative example
To the glass lining reactor, 45L of purified water and potassium hydroxide (3.0 eq,11.26 kg) were added, and the mixture was dissolved by stirring, and Compound 4 (50 kg) was added and dissolved by stirring. Boric acid (2.0 eq,8.3 kg) was added, the temperature of the solution was reduced to 10 ℃ and stirred, epichlorohydrin (0.57 eq,3.52 kg) was added, the reaction was carried out at 10 ℃ for 48 hours and the sample was subjected to HPLC detection (the detection result is shown in FIG. 3), the basic reaction of the raw material was completed, and the post-treatment was the same as in example 1: the post-treatment comprises purifying by industrial chromatographic column, decolorizing by activated carbon, desalting by anion-cation resin, spray drying to obtain 32.27kg (detection result is shown in figure 4, and the standard of crude drug is not met), and recrystallizing in 60L anhydrous ethanol and 30L isopropanol mixed solvent to obtain 28.72kg iodixanol (detection result is shown in figure 5), with total yield of 55.3%.
The results of the iodixanol double polymerization reaction of examples and comparative examples are shown in the following table:
Table 1 HPLC data for the reaction solutions of examples and comparative examples
As can be seen from the data in Table 1, the reaction solution of example 1, which was reacted with a double planetary dispersion mixer, had a main peak of 92.07% (FIG. 1, RT= 23.261 min) and a peralkyl impurity of approximately 5%, whereas the reaction solution of comparative example had a main peak purity of only 75.83% (FIG. 3, RT 25.197) and a peralkyl impurity of as high as 16.11%, which is significantly inferior to that of the example.
The reaction solutions of the examples and the comparative examples were subjected to post-treatment purification, and the detection data of the purified samples are shown in Table 2:
table 2 example and comparative iodixanol HPLC data
As can be seen from the data in Table 2, the impurity A, B, C of the spray-dried product in example 1 is not detected, and the quality of the spray-dried product meets the pharmacopoeia requirements. The comparative reaction liquid is purified according to the same post-treatment mode, the obtained spray-dried product has higher impurity, wherein the impurity A does not meet the pharmacopoeia requirements (less than or equal to 0.10 percent), and the spray-dried product can meet the pharmacopoeia requirements only by refining again.
Claims (10)
1. The production method of iodixanol is characterized by comprising the following steps: it comprises the following steps:
(1) Adding water, potassium hydroxide and a compound 4 into a double-planetary dispersing mixer, and stirring for dissolution;
(2) Starting dispersing and stirring, adding boric acid, cooling to 10-20 ℃, adding epichlorohydrin, and reacting completely;
(3) And (3) after purification, drying to obtain iodixanol.
2. The production method according to claim 1, characterized in that: the amount of compound 4 used is 100 to 150kg.
3. The production method according to claim 1, characterized in that: the dosage of potassium hydroxide is 3.0-3.2 equivalents.
4. The production method according to claim 1, characterized in that: the amount of water is 0.9-2 times by weight of compound 4.
5. The production method according to claim 1, characterized in that: the dosage of boric acid is 2.0-2.2 equivalents, and the dosage of epichlorohydrin is 0.50-0.60 equivalents.
6. The production method according to claim 1, characterized in that: the dosage of the epichlorohydrin is 0.50 to 0.60 equivalent.
7. The production method according to claim 1, characterized in that: in the step (1), the stirring frequency is 20-30 revolutions per minute.
8. The production method according to claim 1, characterized in that: the frequency of the dispersing and stirring in the step (2) is 380-420 revolutions/min.
9. The method of claim 1, wherein: the reaction in the step (2) is carried out for 24 hours.
10. The production method according to claim 1, characterized in that: the purification method comprises one or more of active carbon decolorization, anion-cation resin desalination and macroporous resin purification.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211513488.9A CN118108618A (en) | 2022-11-29 | 2022-11-29 | Production process of iodixanol |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202211513488.9A CN118108618A (en) | 2022-11-29 | 2022-11-29 | Production process of iodixanol |
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