CN116354843A - Improved method for synthesizing iopromide and application of iopromide in injection - Google Patents
Improved method for synthesizing iopromide and application of iopromide in injection Download PDFInfo
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- CN116354843A CN116354843A CN202111609147.7A CN202111609147A CN116354843A CN 116354843 A CN116354843 A CN 116354843A CN 202111609147 A CN202111609147 A CN 202111609147A CN 116354843 A CN116354843 A CN 116354843A
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- iopromide
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- active ester
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- propanediol
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- DGAIEPBNLOQYER-UHFFFAOYSA-N iopromide Chemical compound COCC(=O)NC1=C(I)C(C(=O)NCC(O)CO)=C(I)C(C(=O)N(C)CC(O)CO)=C1I DGAIEPBNLOQYER-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 229960002603 iopromide Drugs 0.000 title claims abstract description 58
- 238000000034 method Methods 0.000 title abstract description 10
- 238000002347 injection Methods 0.000 title abstract description 7
- 239000007924 injection Substances 0.000 title abstract description 7
- 230000002194 synthesizing effect Effects 0.000 title abstract description 5
- 150000002148 esters Chemical class 0.000 claims abstract description 21
- KQIGMPWTAHJUMN-UHFFFAOYSA-N 3-aminopropane-1,2-diol Chemical compound NCC(O)CO KQIGMPWTAHJUMN-UHFFFAOYSA-N 0.000 claims abstract description 10
- ROJNTQLNMWYIQO-UHFFFAOYSA-N 2,4,6-triiodo-5-[(2-methoxyacetyl)amino]benzene-1,3-dicarbonyl chloride Chemical compound COCC(=O)NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I ROJNTQLNMWYIQO-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000000746 purification Methods 0.000 claims abstract description 7
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims abstract description 6
- FPIRBHDGWMWJEP-UHFFFAOYSA-N 1-hydroxy-7-azabenzotriazole Chemical compound C1=CN=C2N(O)N=NC2=C1 FPIRBHDGWMWJEP-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000006243 chemical reaction Methods 0.000 claims abstract description 5
- 238000000926 separation method Methods 0.000 claims abstract description 5
- 150000001263 acyl chlorides Chemical class 0.000 claims description 6
- 229940125782 compound 2 Drugs 0.000 claims description 5
- 229940125904 compound 1 Drugs 0.000 claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 4
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052757 nitrogen Chemical group 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 238000010189 synthetic method Methods 0.000 claims 1
- WOMTYMDHLQTCHY-UHFFFAOYSA-N 3-methylamino-1,2-propanediol Chemical compound CNCC(O)CO WOMTYMDHLQTCHY-UHFFFAOYSA-N 0.000 abstract description 8
- 238000004519 manufacturing process Methods 0.000 abstract description 5
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 239000012535 impurity Substances 0.000 description 12
- 239000000203 mixture Substances 0.000 description 11
- 238000001914 filtration Methods 0.000 description 10
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 8
- 239000000706 filtrate Substances 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000011347 resin Substances 0.000 description 6
- 229920005989 resin Polymers 0.000 description 6
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 239000002872 contrast media Substances 0.000 description 4
- 238000004090 dissolution Methods 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 229940126214 compound 3 Drugs 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000004537 pulping Methods 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 101000777134 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 43 Proteins 0.000 description 2
- 102100031311 Ubiquitin carboxyl-terminal hydrolase 43 Human genes 0.000 description 2
- 125000003368 amide group Chemical group 0.000 description 2
- 238000005915 ammonolysis reaction Methods 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 230000007062 hydrolysis Effects 0.000 description 2
- 238000006460 hydrolysis reaction Methods 0.000 description 2
- 238000009776 industrial production Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 2
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 2
- 229960000281 trometamol Drugs 0.000 description 2
- -1 2, 3-dihydroxy-1-propyl Chemical group 0.000 description 1
- HTMLEVJUDKJYBH-UHFFFAOYSA-N 2,2-dihydroxypropanamide Chemical group CC(O)(O)C(N)=O HTMLEVJUDKJYBH-UHFFFAOYSA-N 0.000 description 1
- JJKWHOSQTYYFAE-UHFFFAOYSA-N 2-methoxyacetyl chloride Chemical compound COCC(Cl)=O JJKWHOSQTYYFAE-UHFFFAOYSA-N 0.000 description 1
- FBJVWRITWDYUAC-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarbonyl chloride Chemical compound NC1=C(I)C(C(Cl)=O)=C(I)C(C(Cl)=O)=C1I FBJVWRITWDYUAC-UHFFFAOYSA-N 0.000 description 1
- JEZJSNULLBSYHV-UHFFFAOYSA-N 5-amino-2,4,6-triiodobenzene-1,3-dicarboxylic acid Chemical compound NC1=C(I)C(C(O)=O)=C(I)C(C(O)=O)=C1I JEZJSNULLBSYHV-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000289690 Xenarthra Species 0.000 description 1
- RXDLGFMMQFNVLI-UHFFFAOYSA-N [Na].[Na].[Ca] Chemical compound [Na].[Na].[Ca] RXDLGFMMQFNVLI-UHFFFAOYSA-N 0.000 description 1
- 238000005917 acylation reaction Methods 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- UEAVLBXLOZNDHT-UHFFFAOYSA-K calcium;sodium;2-[2-[bis(carboxylatomethyl)amino]ethyl-(carboxymethyl)amino]acetate Chemical compound [Na+].[Ca+2].OC(=O)CN(CC([O-])=O)CCN(CC([O-])=O)CC([O-])=O UEAVLBXLOZNDHT-UHFFFAOYSA-K 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000004042 decolorization Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/14—Preparation of carboxylic acid amides by formation of carboxamide groups together with reactions not involving the carboxamide groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
- A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/16—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms condensed with carbocyclic rings or ring systems
- C07D249/18—Benzotriazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
An improved method for synthesizing iopromide includes such steps as reaction of 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride as intermediate of iopromide with 3-amino-1, 2-propanediol or 3-methylamino-1, 2-propanediol, reaction with 1-hydroxybenzotriazole or 1-hydroxy-7-aza-benzotriazol to obtain active ester as intermediate of iopromide, and separation and purification. The iopromide obtained by the method has high purity, and is suitable for the production of iopromide injection.
Description
Technical Field
The invention relates to an improved method for synthesizing iopromide, belonging to the field of pharmaceutical chemistry.
Background
Iopromide is a nonionic contrast agent developed by the company AG, first-come, germany, under the trade name Ultravist, and has good safety due to its low adverse effects, and sales in the global contrast agent market are in the first place.
Disclosure of Invention
A general synthesis method of iopromide is reported by U.S. Pat. No. 5, 4364921, 5-amino-2, 4, 6-triiodo isophthalic acid is taken as a starting material, thionyl chloride is used for chlorating to obtain an intermediate 5-amino-2, 4, 6-triiodo isophthaloyl chloride, then acylation reaction is carried out with methoxy acetyl chloride to obtain an intermediate 5-methoxy acetamido-2, 4, 6-triiodo isophthaloyl chloride, then 3-amino-1, 2-propanediol is used for ammonolysis to obtain an intermediate N- (2, 3-dihydroxy-1-propyl) -5-methoxy acetamido-3-chloroformyl-2, 4, 6-triiodo benzamide, and finally 3-methylamino-1, 2-propanediol is used for ammonolysis and purification to obtain iopromide.
The synthetic route is as follows:
the method has shorter synthetic route steps and simpler operation, and because the structural characteristics of the iopromide are different from those of most contrast agents, namely, two dihydroxypropionamide structures of benzene rings are asymmetric structures, one amide group is replaced by a hydrogen atom, and one amide group is replaced by a methyl group, a large amount of symmetrical disubstituted impurities (a compound 3 and a compound 4) are inevitably generated in the process of synthesizing an acyl chloride intermediate (a compound 2). The following are provided:
the symmetrical disubstituted impurity structures (compound 3 and compound 4) are similar to iopromide, and can be removed by adopting a mode of repeated crystallization, or are separated and purified by adopting a macroporous resin column, and Chinese patent CN102351735 reports that a large amount of organic solvents are required to be used for repeated crystallization and purification, so that the operation is complicated, the product yield is reduced, and the production cost is increased. Therefore, there is a need for removing symmetrical disubstituted byproducts by an economical and efficient process to obtain iopromide in high yields and purity, meeting the needs of iopromide production.
In order to solve the defects of the existing synthesis method, the company discovers a novel synthesis method, namely, an intermediate 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride is reacted with 3-amino-1, 2-propanediol or 3-methylamino-1, 2-propanediol to obtain an acyl chloride intermediate (compound 3 and compound 4), then the acyl chloride intermediate is reacted with 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazole to obtain an active ester of the iopromide intermediate (compound 1 and compound 2), and after separation and purification, the iopromide intermediate is reacted with 3-methylamino-1, 2-propanediol or 3-amino-1, 2-propanediol, and the iopromide is obtained through macroporous resin purification.
The synthetic route is as follows:
wherein R is 2 Represents a hydrogen atom or a nitrogen atom.
In general, since the acid chloride is more reactive than the active ester, it can be reacted directly with an ammonia-containing substrate to form an amide without the need to additionally convert the acid chloride to the active ester for further reaction. However, in the synthesis of iopromide, the acid chloride intermediate (compound 2) is unstable in nature, and more hydrolysis products are generated during the separation from the symmetrical disubstituted impurities, introducing new impurities, so that the direct separation of the acid chloride intermediate is not feasible in industrial production.
In experiments, the acyl chloride intermediate can be gently reacted with 1-hydroxybenzotriazole or 1-hydroxy-7-azabenzotriazol to be completely converted into the corresponding active ester intermediate of iopromide, the solubility of the acyl chloride intermediate and the active ester of the symmetrical disubstituted impurity are obviously different, the solubility of the active ester of the iopromide intermediate in water is very small, and the symmetrical disubstituted impurity of iopromide can form hydrogen bonds with polar solvents due to a plurality of hydroxy functional groups in the structure, can be easily dissolved in water, and can be effectively separated by simply pulping with water or aqueous methanol and aqueous ethanol. Since the iopromide active ester intermediate is less reactive than the acid chloride, no hydrolysis products are produced during pulping and new impurities are added.
According to the invention, crystalline iopromide intermediate active ester can be obtained by simply pulping, symmetrical disubstituted byproducts which cause the purity of the iopromide to be reduced can be simply removed, no additional purification step is needed, the high-purity iopromide can be obtained with high yield, the production cost is obviously reduced, and the method is more suitable for industrial production.
Because the iopromide has similar structure with impurities and is difficult to separate, the iopromide raw material with lower purity requirement and higher impurity limit (such as the impurity of the iopromide Luo Anzong specified by USP43 is less than 3.0%) in the pharmaceutical requirement. The iopromide injection used as the contrast agent has large dosage, common specifications (62.34 g/100ml, 76.89/100ml and the like), and large total impurity amount can cause more adverse reactions and influence the medication safety. The iopromide bulk drug obtained by the invention has high purity, total impurities are less than 0.5%, the quality standard exceeds the existing pharmacopoeia standard (such as USP43/EP10.0/BP 2021), and the iopromide bulk drug is suitable for the production of iopromide injection.
The present invention is further illustrated by the following examples and comparative examples, and various substitutions and alterations, which are made according to the ordinary skill and familiar means in the art, are included in the scope of the present invention, except for the following examples.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
Step 1 preparation of iopromide intermediate active ester (Compound 1)
Example 1: in a three-necked flask, 30g of 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride, 100ml of dimethylacetamide and 9ml of diisopropylethylamine were added, stirred and dissolved, 4.5g of 3-amino-1, 2-propanediol was added, the mixture was reacted at 10-20℃for 8 hours, 7.9g of 1-hydroxybenzotriazole, 9.3g of potassium carbonate and the mixture was reacted at 20-30℃for 2 hours. Inorganic salts were removed by filtration, the filtrate was concentrated under reduced pressure, 200ml of water was added to the residue, and the residue was slurried at 10-20℃for 2 hours, and filtered to give 25.8g of an active ester of an intermediate of iopromide.
Example 2: in a three-necked flask, 30g of 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride, 100ml of dimethylacetamide and 9ml of diisopropylethylamine were added, followed by stirring to dissolve, adding 4.5g of 3-amino-1, 2-propanediol, reacting at 10-20℃for 8 hours, then adding 7.9g of 1-hydroxy-7-azabenzotriazole and 9.3g of potassium carbonate, and reacting at 20-30℃for 2 hours. Inorganic salts are removed by filtration, the filtrate is concentrated under reduced pressure, 50ml of methanol and 200ml of water are added to the residue, the mixture is pulped for 2 hours at 10-20 ℃, and 24.2g of iopromide intermediate active ester is obtained by filtration.
Step 1: preparation of iopromide intermediate active ester (Compound 2)
Example 3: in a three-necked flask, 50 g of 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride, 150ml of dimethylacetamide and 15ml of diisopropylethylamine were added, followed by stirring to dissolve, 9.5g of 3-methylamino-1, 2-propanediol was added and reacted at 10-20℃for 6 hours, 13g of 1-hydroxybenzotriazole and 15.5g of potassium carbonate were added and reacted at 20-30℃for 2 hours. Inorganic salts were removed by filtration, the filtrate was concentrated under reduced pressure, 100ml of 95% ethanol and 100ml of water were added to the residue, and the mixture was slurried at 10-20℃for 2 hours, and filtered to give 22.6g of iopromide intermediate active ester.
Example 4: 50 g of 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride, 150ml of dimethylacetamide and 15ml of diisopropylethylamine are added into a three-necked flask, the mixture is stirred and dissolved, 9.5 of 3-methylamino-1, 2-propanediol is added into the mixture to react for 6 hours at the temperature of 10 to 20 ℃, 13g of 1-hydroxy-7-azabenzotriazole and 15.5g of potassium carbonate are added into the mixture to react for 2 hours at the temperature of 20 to 30 ℃. Inorganic salts were removed by filtration, the filtrate was concentrated under reduced pressure, 100ml of 95% ethanol and 100ml of water were added to the residue, and the mixture was slurried at 10-20℃for 2 hours, and filtered to give 23.1g of an active ester of an intermediate of iopromide.
Step 2: synthesis of iopromide
Example 5: into a three-necked flask, 20g of the iopromide intermediate active ester obtained in example 1, 100ml of dimethylacetamide and 4.8ml of diisopropylethylamine were added, and the mixture was stirred and dissolved, followed by addition of 5.1g of 3-methylamino-1, 2-propanediol, and reaction at a temperature of 70-80℃for 8 hours. Then, the filtrate was concentrated under reduced pressure, water was added to the residue for dissolution, activated carbon was decolorized and filtered, and the obtained solution was purified by a macroporous resin column packed with XAD1600 to obtain Luo Anke 15.8.8 g of iopromide with a purity of 99.76%.
Example 6: into a three-necked flask, 20g of the iopromide intermediate active ester obtained in example 2, 100ml of dimethylacetamide and 4.8ml of diisopropylethylamine were added, and the mixture was stirred and dissolved, and then 5.1g of 3-methylamino-1, 2-propanediol was added, and the temperature was raised to 70-80℃to react for 8 hours. Then concentrating the filtrate under reduced pressure, adding water to the residue for dissolution, decolorizing and filtering by using active carbon, and purifying the obtained solution by using a macroporous resin column filled with XAD1600 to obtain 16.3 g of iopromide with the purity of 99.81%.
Example 7: 35g of the iopromide intermediate active ester obtained in example 3, 180ml of dimethylacetamide and 8.5ml of diisopropylethylamine were added into a three-necked flask, stirred and dissolved, 7.8g of 3-amino-1, 2-propanediol was added, and the temperature was raised to 70-80 ℃ to react for 12 hours. Then, the filtrate was concentrated under reduced pressure, water was added to the residue for dissolution, activated carbon was used for decolorization and filtration, and the obtained solution was purified by a macroporous resin column packed with XAD1600 to obtain 26.3 g of iopromide with a purity of 99.72%.
Example 8: 35g of the iopromide intermediate active ester obtained in example 4, 180ml of dimethylacetamide and 8.5ml of diisopropylethylamine were added into a three-necked flask, stirred and dissolved, 7.8g of 3-amino-1, 2-propanediol was added, and the temperature was raised to 70-80 ℃ to react for 12 hours. Then concentrating the filtrate under reduced pressure, adding water to the residue for dissolution, decolorizing and filtering by using active carbon, and purifying the obtained solution by using a macroporous resin column filled with XAD1600 to obtain 27.2 g of iopromide with the purity of 99.65%.
Example 9: injection prepared from iopromide synthesized by the method
Prescription composition:
iopromide 7689g
Tromethamine 24.2g
Calcium sodium edetate 1.0g
Proper amount of 10% hydrochloric acid
Water for injection is added to 10.0L
The operation is as follows: adding iopromide, tromethamine, calcium disodium edentate and about 80% of water into a preparation tank, heating for dissolving, regulating pH to 7.2-7.8 with 10% hydrochloric acid, filtering, adding injectable water to full amount, stirring, filtering with a sterilizing filter, packaging, and sterilizing with a sterilizing cabinet to obtain iopromide injection.
Claims (3)
1. A synthetic method of iopromide is characterized in that iopromide is synthesized through the following chemical reaction, namely 5-methoxyacetamido-2, 4, 6-triiodoisophthaloyl dichloride reacts with 3-amino-1, 2-propanediol to obtain an acyl chloride intermediate (compound 2) which reacts with 1-hydroxybenzotriazole or 1-hydroxy-7-aza-benzotriazole to obtain an iopromide intermediate active ester (compound 1), and the iopromide intermediate active ester reacts with corresponding aminopropanediol after separation and purification; the synthetic route is as follows:
2. the compound 1 according to claim 1, wherein R1 represents a hydrogen atom or a methyl group.
3. The compound of claim 2 wherein R2 represents a hydrogen atom or a nitrogen atom.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111609147.7A CN116354843A (en) | 2021-12-27 | 2021-12-27 | Improved method for synthesizing iopromide and application of iopromide in injection |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202111609147.7A CN116354843A (en) | 2021-12-27 | 2021-12-27 | Improved method for synthesizing iopromide and application of iopromide in injection |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001113A (en) * | 2014-04-18 | 2015-10-28 | 沈阳中海生物技术开发有限公司 | Iopromide preparation method |
| CN105017062A (en) * | 2014-04-18 | 2015-11-04 | 沈阳中海生物技术开发有限公司 | New method for preparing iopromide |
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2021
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105001113A (en) * | 2014-04-18 | 2015-10-28 | 沈阳中海生物技术开发有限公司 | Iopromide preparation method |
| CN105017062A (en) * | 2014-04-18 | 2015-11-04 | 沈阳中海生物技术开发有限公司 | New method for preparing iopromide |
Non-Patent Citations (1)
| Title |
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| 陆悠玲: "碘普罗胺的专利合成路线浅谈", 广 东 化 工, vol. 42, no. 6, 30 March 2015 (2015-03-30), pages 90 - 91 * |
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