73334-07-3

Basic information

• Product Name: Iopromide
• Synonyms: 1,3-benzenedicarboxamide,n,n’-bis(2,3-dihydroxypropyl)-5-((methoxyacetyl)amino;6-triiodo-)-n-methyl-4;shl414c;IOPROMIDE;N,N'-Bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(2-methoxyacetyl)amino]-N'-methylbenzene-1,3-dicarboxamide;1,3-Benzenedicarboxamide, N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-5-[(methoxyacetyl)amino]-N-methyl-;Ultravist;Ultravist 300
• CAS NO: 73334-07-3
• Molecular Formula: C18H24I3N3O8
• Molecular Weight: 791.11
• EINECS: 277-385-9
• Product Categories: Amines;Aromatics;Diagnostic;Intermediates & Fine Chemicals;Pharmaceuticals;Isotope Labelled Compounds
• Mol File: 73334-07-3.mol
• Article Data: 15

Chemical Properties

• Melting Point: broad (160?C transition)
• Boiling Point: 840.9 °C at 760 mmHg
• Flash Point: 462.4 °C
• Appearance: off-white to white powder
• Density: 2.173 g/cm³
• Vapor Pressure: 5E-30mmHg at 25°C
• Refractive Index: 1.709
• Storage Temp.: Hygroscopic, -20?C Freezer, Under Inert Atmosphere
• Solubility: Freely soluble in water and in dimethyl sulfoxide, practically insoluble in ethanol (96 per cent) and in acetone.
• PKA: 10.62±0.70(Predicted)
• Stability: Hygroscopic
• CAS DataBase Reference: Iopromide(CAS DataBase Reference)
• NIST Chemistry Reference: Iopromide(73334-07-3)
• EPA Substance Registry System: Iopromide(73334-07-3)

Safety Data

• Hazard Codes: N
• Statements: 50/53
• Safety Statements: 60-61
• RIDADR: UN 3077 9 / PGIII
• WGK Germany: 3
• RTECS: CZ2230000
• Hazardous Substances Data: 73334-07-3(Hazardous Substances Data)

Usage

Description

Iopromide is a non-ionic, water-soluble X-ray contrast agent for intravascular administration. Iopromide can cause acute kidney injury and is used in animal models of contrast-induced nephropathy.

Chemical Properties

White Solid

Uses

Contrast molecule

Definition

ChEBI: A dicarboxylic acid diamide that consists of N-methylisophthalamide bearing three iodo substituents at positions 2, 4 and 6, a methoxyacetyl substituent at position 5 and two 2,3-dihydroxypropyl groups attached to the amide nitrogens. A ater soluble x-ray contrast agent for intravascular administration.

Brand name

Ultravist (Berlex).

General Description

Iopromide is a low-osmolar,nonionic monomer with 48% bound iodine content. It is indicatedfor use in angiography, excretory urography, andnumerous CT procedures.

InChI:InChI=1/C18H24I3N3O8/c1-24(4-9(28)6-26)18(31)12-13(19)11(17(30)22-3-8(27)5-25)14(20)16(15(12)21)23-10(29)7-32-2/h8-9,25-28H,3-7H2,1-2H3,(H,22,30)(H,23,29)

Synthetic route

C26H32I3N3O12 → iopromide (73334-07-3)

Conditions	Yield
With sodium methylate In methanol at 75℃; for 8h;	100%
Stage #1: C26H32I3N3O12 With sodium hydroxide at 50℃; for 4h; Stage #2: With hydrogenchloride pH=2-3;	99%

3-methylamino-propane-1,2-diol (40137-22-2) + 3-[(2,3-dihydroxypropylaminoformyl)]-2,4,6-triiodo-5-[(methoxyacetyl)amino]benzoic acid methyl ester → iopromide (73334-07-3)

Conditions	Yield
With N-ethyl-N,N-diisopropylamine Large scale;	95%

3-Amino-1,2-propanediol (616-30-8, 13552-31-3) + 5-[(2-methoxy)acetamido]-3-(2,3-dihydroxy-N-propyl(methyl)carbamoyl)-2,4,6-triiodobenzoyl chloride → iopromide (73334-07-3)

Conditions	Yield
With sodium carbonate In N,N-dimethyl acetamide at 20℃; for 2h;	92%

C18H27N3O8 (1009809-16-8) → iopromide (73334-07-3)

Conditions	Yield
In water at 70 - 90℃; for 6h;	88.1%
With Iodine monochloride In water at 70 - 85℃; for 3h; Temperature; Concentration;	82.3 g

C25H30I3N3O13 → iopromide (73334-07-3)

Conditions	Yield
With sodium hydroxide at 20℃; for 5h;	86%

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid [(2,3-dihydroxy-N-methylpropyl)-(2,3-diacetoxypropyl)]diamide (1193076-40-2) → iopromide (73334-07-3)

Conditions	Yield
With water; sodium hydroxide In N,N-dimethyl acetamide at 20 - 25℃; for 10h;	85%
With water; sodium hydroxide at 20 - 25℃; for 10h; Industry scale;

5-methoxyacetamido-N-methyl-N,N'-diallyl-2,4,6-triiodoisophthalamide → iopromide (73334-07-3)

Conditions	Yield
With osmium(VIII) oxide; water; 4-methylmorpholine N-oxide In acetone at 20℃; for 13h;	85%
With osmium(VIII) oxide; 4-methylmorpholine N-oxide In water; acetone at 20℃; for 12h;	55.8 g

5-methoxyacetamido-2,4,6-triiodoisophthalic acid {[(2-oxo-1,3-dioxolan-4-yl)methyl]-(2,3-dihydroxy-N-methylpropyl)}diamide → iopromide (73334-07-3)

Conditions	Yield
With water; sodium hydroxide at 50℃; for 0.5h;	85%
With sodium hydroxide In water at 20 - 50℃; for 0.5h;	85%

2,4,6-triiodo-5-(2-methoxyacetamido)-N1-methyl-N1,N3-bis-((2-oxo-1,3-dioxolane-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
With sodium hydroxide at 20℃; for 3h;	80%

C30H40I3N3O16 → iopromide (73334-07-3)

Conditions	Yield
With sodium hydroxide at 0 - 50℃;	80%

C46H40I3N3O12 → iopromide (73334-07-3)

Conditions	Yield
With sodium hydroxide at 0 - 50℃;	80%
Stage #1: C46H40I3N3O12 With sodium hydroxide at 0 - 50℃; for 4h; Stage #2: With hydrogenchloride In water at 0 - 20℃; pH=7;

2,4,6-triiodo-5-(2-methoxyacetamido)-N1-methyl-N1,N3-bis-((2-oxo-1,3,2-dioxathiolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
With sodium hydroxide at 20℃; for 3h;	75%

5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride + 3-methylamino-propane-1,2-diol (40137-22-2) + pyrographite (7440-44-0) → iopromide (73334-07-3)

Conditions	Yield
With tributyl-amine In dichloromethane; water; N,N-dimethyl-formamide

N1-(2,3-dihydroxypropyl)-N1-methyl-5-nitro-N3-((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 30003 Torr 2: hydrogenchloride; sodium iodide dichloride / water / 80 °C 3: pyridine / 1,2-dimethoxyethane / 6 h / 50 °C 4: sodium hydroxide / 5 h / 20 °C View Scheme

N1-(2,3-dihydroxypropyl)-N1-methyl-5-amino-N3-((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; sodium iodide dichloride / water / 80 °C 2: pyridine / 1,2-dimethoxyethane / 6 h / 50 °C 3: sodium hydroxide / 5 h / 20 °C View Scheme

5-nitro-1,3-benzenedicarboxylic acid, monomethyl ester (1955-46-0) → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 7 steps 1.1: acetonitrile / 7 h / 75 - 80 °C 2.1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 3.1: oxalyl dichloride / dichloromethane / 1 h / 0 - 20 °C 3.2: 2.5 h / -10 °C 4.1: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 30003 Torr 5.1: hydrogenchloride; sodium iodide dichloride / water / 80 °C 6.1: pyridine / 1,2-dimethoxyethane / 6 h / 50 °C 7.1: sodium hydroxide / 5 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 20 °C 1.2: 4.5 h / 0 °C 2.1: N,N-dimethyl-formamide / 5 h / 70 - 80 °C 3.1: thionyl chloride / 2 h / 10 - 20 °C 4.1: zinc / methanol / 0.17 h 4.2: 5 h / 20 °C 5.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 6.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 7.1: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 7 steps 1.1: oxalyl dichloride / dichloromethane / 20 °C 1.2: 4.5 h / 0 °C 2.1: N,N-dimethyl-formamide / 6 h / 70 - 80 °C 3.1: thionyl chloride / 2 h / 10 - 20 °C 4.1: zinc / methanol / 0.17 h 4.2: 5 h / 20 °C 5.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 6.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 7.1: sodium hydroxide / 3 h / 20 °C View Scheme

3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoic acid (122731-58-2) → iopromide (73334-07-3)

Conditions

Yield

Multi-step reaction with 6 steps 1.1: triethylamine / N,N-dimethyl-formamide / 1 h / 0 - 20 °C 2.1: oxalyl dichloride / dichloromethane / 1 h / 0 - 20 °C 2.2: 2.5 h / -10 °C 3.1: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 30003 Torr 4.1: hydrogenchloride; sodium iodide dichloride / water / 80 °C 5.1: pyridine / 1,2-dimethoxyethane / 6 h / 50 °C 6.1: sodium hydroxide / 5 h / 20 °C View Scheme

3-nitro-5-(((2-oxo-1,3-dioxolan-4-yl)methyl)carbamoyl)benzoic acid → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: oxalyl dichloride / dichloromethane / 1 h / 0 - 20 °C 1.2: 2.5 h / -10 °C 2.1: palladium 10% on activated carbon; hydrogen / methanol / 5 h / 20 °C / 30003 Torr 3.1: hydrogenchloride; sodium iodide dichloride / water / 80 °C 4.1: pyridine / 1,2-dimethoxyethane / 6 h / 50 °C 5.1: sodium hydroxide / 5 h / 20 °C View Scheme

3-((2,3-dihydroxypropyl)methylcarbamoyl)-5-nitrobenzoic acid methyl ester → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N,N-dimethyl-formamide / 6 h / 70 - 80 °C 2.1: thionyl chloride / 2 h / 10 - 20 °C 3.1: zinc / methanol / 0.17 h 3.2: 5 h / 20 °C 4.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 5.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 6.1: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: N,N-dimethyl-formamide / 6 h / 70 - 80 °C 2: triethylamine / tetrahydrofuran / 1 h / 10 - 20 °C 3: palladium 10% on activated carbon / methanol / 20 °C / 30003 Torr 4: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 5: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 6: sodium hydroxide / 3 h / 20 °C View Scheme

N1,N3-bis-(2,3-dihydroxypropyl)-N1-methyl-5-nitroisophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 5 steps 1.1: thionyl chloride / 2 h / 10 - 20 °C 2.1: zinc / methanol / 0.17 h 2.2: 5 h / 20 °C 3.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 4.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 5.1: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: triethylamine / tetrahydrofuran / 1 h / 10 - 20 °C 2: palladium 10% on activated carbon / methanol / 20 °C / 30003 Torr 3: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 4: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 5: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon; hydrogen / water / 7 h / 20 °C / 30003 - 33753.4 Torr 2: potassium iodide; sodium chloride; Iodine monochloride; sulfuric acid / water / 24 h / 50 °C 3: N,N-dimethyl acetamide / 0 - 30 °C 4: sodium hydroxide / 0 - 50 °C View Scheme
Multi-step reaction with 5 steps 1: palladium 10% on activated carbon; hydrogen / water / 7 h / 20 °C / 30003 - 33753.4 Torr 2: potassium iodide; sodium chloride; Iodine monochloride; sulfuric acid / water / 24 h / 50 °C 3: triethylamine / N,N-dimethyl acetamide / 50 °C 4: N,N-dimethyl acetamide / 3.5 h / 10 - 30 °C 5: sodium methylate / methanol / 8 h / 75 °C View Scheme
Multi-step reaction with 5 steps 1.1: hydrazine hydrate / 10 - 15 °C 2.1: potassium iodide; sodium chloride; sulfuric acid; Iodine monochloride / water / 8 h / 50 °C 3.1: triethylamine / N,N-dimethyl acetamide / 50 °C 4.1: N,N-dimethyl acetamide / 3.5 h / 10 - 30 °C 5.1: sodium hydroxide / 4 h / 50 °C 5.2: pH 2-3 View Scheme

N-methyl-5-nitro-N1,N3-bis-((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: palladium 10% on activated carbon / methanol / 20 °C / 30003 Torr 2: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 3: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 4: sodium hydroxide / 3 h / 20 °C View Scheme

N-methyl-5-amino-N1,N3-bis-((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 2: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 3: sodium hydroxide / 3 h / 20 °C View Scheme

5-amino-2,4,6-triiodo-N1-methyl-N1,N3-bis-((2-oxo-1,3-dioxolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 2: sodium hydroxide / 3 h / 20 °C View Scheme

N-methyl-5-nitro-N1,N3-bis-((2-oxo-1,3,2-dioxathiolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 4 steps 1.1: zinc / methanol / 0.17 h 1.2: 5 h / 20 °C 2.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 3.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 4.1: sodium hydroxide / 3 h / 20 °C View Scheme

N-methyl-5-amino-N1,N3-bis-((2-oxo-1,3,2-dioxathiolan-4-yl)methyl)isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 2: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 3: sodium hydroxide / 3 h / 20 °C View Scheme

methyl 3-((2,3-dihydroxypropyl)carbamoyl)-5-nitrobenzoate → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 6 steps 1.1: N,N-dimethyl-formamide / 5 h / 70 - 80 °C 2.1: thionyl chloride / 2 h / 10 - 20 °C 3.1: zinc / methanol / 0.17 h 3.2: 5 h / 20 °C 4.1: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 5.1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 6.1: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 6 steps 1: N,N-dimethyl-formamide / 5 h / 70 - 80 °C 2: triethylamine / tetrahydrofuran / 1 h / 10 - 20 °C 3: palladium 10% on activated carbon / methanol / 20 °C / 30003 Torr 4: hydrogenchloride; sodium iodide dichloride / water / 20 - 80 °C 5: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 6: sodium hydroxide / 3 h / 20 °C View Scheme
Multi-step reaction with 5 steps 1: 1,8-diazabicyclo[5.4.0]undec-7-ene / N,N-dimethyl-formamide / 20 - 25 °C 2: palladium 10% on activated carbon; hydrogen / water / 7 h / 20 °C / 30003 - 33753.4 Torr 3: potassium iodide; sodium chloride; Iodine monochloride; sulfuric acid / water / 24 h / 50 °C 4: N,N-dimethyl acetamide / 0 - 30 °C 5: sodium hydroxide / 0 - 50 °C View Scheme

5-amino-2,4,6-triiodo-N1-methyl-N1,N3-bis-((2-oxo-1,3,2-dioxathiolan-4-yl))isophthalamide → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 2 steps 1: N,N-dimethyl acetamide / 10 h / 0 - 20 °C 2: sodium hydroxide / 3 h / 20 °C View Scheme

2,4,6-triiodo-5-aminoisophthalic acid (35453-19-1) → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 4 steps 1: sulfuric acid / 4 h / Reflux; Large scale 2: 1,4-dioxane / 4 h / Reflux; Large scale 3: N-ethyl-N,N-diisopropylamine / 1,2-dimethoxyethane / 18 h / Reflux; Large scale 4: N-ethyl-N,N-diisopropylamine / Large scale View Scheme

dimethyl 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylate (154921-11-6) → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1: 1,4-dioxane / 4 h / Reflux; Large scale 2: N-ethyl-N,N-diisopropylamine / 1,2-dimethoxyethane / 18 h / Reflux; Large scale 3: N-ethyl-N,N-diisopropylamine / Large scale View Scheme

3-amino-5-(2,3-dihydroxy-n-propylaminoformyl)benzoic acid methyl ester → iopromide (73334-07-3)

Conditions	Yield
Multi-step reaction with 3 steps 1.1: sulfuric acid / 12 h / 40 °C 2.1: sodium methylate / methanol / 6 h / Reflux 2.2: 3 h / 30 - 50 °C 3.1: Iodine monochloride / water / 3 h / 70 - 85 °C View Scheme

iopromide (73334-07-3) → 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid [(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide + 5-methoxyacetylamino-2,4,6-triiodo-isophthalic acid [(2,3-dihydroxy-N-methyl-propyl)-(2,3-dihydroxypropyl)]-diamide

Conditions	Yield
In propan-1-ol at 65℃; for 48h; Purification / work up;
In water at 208 - 209℃; under 15001.5 Torr; Purification / work up;

Upstream product

• 28179-47-7 5-aminoisophthalic acid monomethyl ester 
• 76350-04-4 5-methoxyacetylamino-2,4,6-triiodoisophthalic acid (2,3-dihydroxypropyl)amide chloride 
• 1071506-72-3 5-amino-3-allylcarbamoyl-2,4,6-triiodobenzoyl chloride 
• 76350-03-3 5-Methoxyacetamido-2,4,6-triiodoisophthaloyl chloride 
• 1955-04-0 methyl 5-nitro-3-chloroformylbenzoate 
• 154361-51-0 5-amino-N₁,N₃-bis(2,3-dihydroxypropyl)2,4,6-triiodo-N₁-methylisophthalamide 
• 616-30-8 3-Amino-1,2-propanediol 
• 37441-29-5 5-amino-2,4,6-triiodoisophthalic acid dichloride 

Relevant articles and documents

Preparation method and application of iopromide intermediate (by machine translation)

The invention relates to a preparation method of an iopromide intermediate and an application thereof in preparation of iopromide. The method comprises the following steps: compound VI compound is subjected to reduction reaction under the action of Raney nickel/hydrazine hydrate to obtain the compound V compound. The reaction is carried out under normal pressure, the operation is simple and safe, the generated intermediate impurities are less, and the reaction is more suitable for industrial production. The method is used for preparing iopromide, can avoid the generation of a diacylated by-product, can effectively reduce the generation of by-products in the preparation process, can be easily separated and purified, and can obtain high-purity iopromide with high yield. (by machine translation)

Preparation methods of iopromide and intermediate of iopromide

The application of the invention relates to preparation methods of iopromide and an intermediate of the iopromide. The method specifically comprises the following steps: conducting a reduction reaction, an iodination reaction and an acylation reaction on a compound shown in the formula VI to prepare a compound shown in the formula III, and further preparing to obtain the iopromide. The method notonly avoids the generation of double acylation byproducts, but also effectively reduces the generation of byproducts in the preparation process, the intermediate is easy to separate and purify, and ahigh-purity product is obtained at a relatively high yield.

The new method of preparing [...] (by machine translation)

The invention relates to a preparation method of iopromide. 5-methoxylacetamido-2,4,6-triiodo m-phthalic acid[(2-oxo-1,3-dioxolame-4-yl)methyl]amido chloride (Formula V) and 5-methoxylacetamido-2,4,6-triiodo m-phthalic acid{[(2-oxo-1,3-dioxolame-4-yl)methyl]-(2,3-dyhydroxyl-N-methyl propyl)}diamide (Formula VI) are introduced to be used as intermediates. Even if there is no additional purification step, a bismer by-product generated during the reaction also can be removed by introduction of the intermediates and high-purity iopromide can be prepared at high yield.