92339-11-2

Basic information

• Product Name: Iodixanol
• Synonyms: Acupaque;DU-6807;Iodixanol (200 mg);5,5'-[(2-Hydroxy-1,3-propanediyl)bis(acetyliMino)]bis[N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-;odixanol;IODIXANOL;1,3-benzenedicarboxamide,5,5’-((2-hydroxy-1,3-propanediyl)bis(acetylimino))bis;n’-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-(
• CAS NO: 92339-11-2
• Molecular Formula: C₃₅H₄₄I₆N₆O₁₅
• Molecular Weight: 1550.18
• EINECS: 1533716-785-6
• Product Categories: Aromatics;Diagnostic;Intermediates & Fine Chemicals;Pharmaceuticals
• Mol File: 92339-11-2.mol
• Article Data: 29

Chemical Properties

• Melting Point: 262-267°C (dec.)
• Boiling Point: 1250.9 °C at 760 mmHg
• Flash Point: 710.3 °C
• Appearance: almost white powder
• Density: 1.266 ±0.003
• Vapor Pressure: 0mmHg at 25°C
• Refractive Index: n 1.4128 ±0.0003
• Storage Temp.: Refrigerator
• Solubility: Freely soluble in water, sparingly soluble in methanol, practically insoluble in methylene chloride.
• PKA: 11.04±0.46(Predicted)
• CAS DataBase Reference: Iodixanol(CAS DataBase Reference)
• NIST Chemistry Reference: Iodixanol(92339-11-2)
• EPA Substance Registry System: Iodixanol(92339-11-2)

Safety Data

• Hazardous Substances Data: 92339-11-2(Hazardous Substances Data)

Usage

Chemical Properties

White Solid

Originator

OptiPrep,Nycomed Pharma,Norway

Uses

Nonionic, dimeric x-ray contrast medium. Diagnostic aid (radiopaque medium).

Definition

ChEBI: A dimeric, non-ionic, water-soluble, radiographic contrast agent, used particularly in coronary angiography.

Manufacturing Process

Dimethyl 5-nitroisophthalate (215 g) and 1-amino-2,3-propandiol (196 g)were refluxed in methanol (500 ml). After twenty hours the solution was cooled and stored in a refrigerator overnight. The product 5-nitro-N,N'- bis(2,3-dihydroxypropyl)-isophthalamide was filtered and washed with methanol. Yield: 270 g (84%). M.p. 128-132°C.5-Nitro-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide (18.1 g) was suspended in water (250 ml), conc. hydrochloric acid (4.2 ml) and 10% PdO/charcoal (0.5 g) were added, and the mixture hydrogenated in a Parr apparatus for one day. After filtration the filtrate was heated at 80-90°C and 3.88 M NaICl2 (42.5 ml) was added through a dropping funnel over 1 hour. The solution was heated for 2.5 hours. After cooling to 20°C 5-amino-2,4,6-triiodo-N,N'- bis(2,3-dihydroxypropyl)-isophthalamide crystallized out.5-Amino-2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide (110 g) was suspended in acetic anhydride (480 ml) and heated to 50°C. Concentrated sulfuric acid (3 ml) was then added. The starting material was dissolved after a few minutes, and the reaction mixture was heated at 60°C for 75 min. After cooling the residue dissolved in methanol (300 ml) with water (150 ml) the solution was heated to 50°C and the pH adjusted to about 10.5 by 10 N sodium hydroxide. After 4-5 hours the pH didn't decrease, and the hydrolysis was complete. The reaction mixture was cooled to 20°C and neutralized by adding hydrochloric acid. After stirring overnight 5-Acetamido- 2,4,6-triiodo-N,N'-bis(2,3-dihydroxypropyl)-isophthalamide was filtered and washed with water. Yield: 94 g (80%). Melting point 275°C, dec.2-Methoxyethanol (300 ml) and sodium hydroxide (20 g) was added to the reactor at 50°C, and 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodoisophtalamide (304 g) was added after two hours of stirring. All solids were allowed to dissolve overnight before cooling to 30°C and adjustment to pH 12 with diluted hydrochloric acid. Epichlorohydrin (11 g) was added to the solution after further cooling to 15°C, and the reaction was allowed to proceed for 51 hours. As a result 1,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3- dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane was obtained.

Brand name

Visipaque (GE Healthcare).

General Description

Iodixanol is a viscous, isosmolar,nonionic, water-soluble dimer with 49% iodine content.It is formulated as an isotonic solution for intravascular injectionand indicated for excretory urography, angiography,and CT procedures.

InChI:InChI=1/C35H44I6N6O15/c1-13(52)46(30-26(38)20(32(59)42-3-15(54)9-48)24(36)21(27(30)39)33(60)43-4-16(55)10-49)7-19(58)8-47(14(2)53)31-28(40)22(34(61)44-5-17(56)11-50)25(37)23(29(31)41)35(62)45-6-18(57)12-51/h15-19,48-51,54-58H,3-12H2,1-2H3,(H,42,59)(H,43,60)(H,44,61)(H,45,62)

Upstream product

• 31127-80-7 N,N'-bis(2,3-dihydroxypropyl)-5-acetamido-2,4,6-triiodoisophthalamide 
• 106-89-8 epichlorohydrin 
• 96-23-1 1,3-Dichloro-2-propanol 
• 28659-12-3 1,3-dichloro-2-(6-(3,4,5,6-tetrahydro-2H-pyranoxy))propane 
• 76820-35-4 5-Amino-N,N'-bis[2,3-dihydroxypropyl]-1,3-benzenedicarboxamide 
• 76820-34-3 5-nitro-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide 
• 13290-96-5 dimethyl 5-nitroisophthalate 
• 616-30-8 3-Amino-1,2-propanediol 

Relevant articles and documents

An intermediate of iodoxanol and a method for preparing iodixanol thereof

The present invention provides a method for preparing iodoxasol intermediates of iodoxaol, the intermediate formula VI of iodkesarol VI: 5,5'-[(2-hydroxy-1,3-propanedioxy)bis (acetylimino)] bis [N,N'-bis(2,3-dihydroxypropyl)-1,3-benzenedicarboxamide], iodized by formula VI to obtain iodoxaol finished products; the present invention provides a new synthetic idea of first forming a dimer and then iodizing, The prepared iodoxaol finished product: the total impurity content ≤ 1.0%, the impurity G content ≤0.5%; the method of the present invention has mild reaction conditions, low damage to the equipment, simple process, green environmental protection and low cost, can ensure the continuous production of high-quality products, has a high application value, suitable for industrial production.

Preparation method of iodixanol

The invention provides a preparation method of iodixanol, which comprises the following steps: (1) reacting 5-amino-2,4,6-triiodoisophthalate (I) with acetic anhydride to obtain 5-acetamido-2,4,6-triiodoisophthalate (II), and reacting the 5-acetamido-2,4,6-triiodoisophthalate (II) with acetic anhydride to obtain iodoxanol (II); (2) reacting the 5-acetamido-2,4,6-triiodoisophthalate (II) with 1,3-dichloro-2-propanol (or 1,3-dibromo-2-propanol and epichlorohydrin) to generate 5,5'-((2-hydroxypropane-1,3-diyl)bis(acetamido))bis(2,4,6-triiodoisophthalate ethyl ester); and (3) carrying out ammonolysis reaction on the 5,5'-((2-hydroxypropane-1,3-diyl)bis(acetamido))bis(2,4,6-triiodoisophthalate ethyl ester) and 1-amino-2,3-propylene glycol to obtain the iodixanol (IV). The purity of the crude iodixanol product is greater than 95%, the highest content of single impurity is lower than 1.5%, and the content of other single impurities in the product is lower than 1%, so that the difficulty of purifying the product is reduced, the requirement on production equipment is reduced, and the method is suitable for large-scale production and is beneficial to improving the industrial production efficiency.

Iodixanol and synthesis method thereof

The invention belongs to the technical field of macromolecules, and discloses iodixanol and a synthesis method thereof. With a compound 5-acetamido-N, N'-bis(2, 3-dihydroxypropyl)-2, 4, 6-triiodo-isophthalamide as a raw material, an intermediate compound 5-acetamido-N, N'-bis(2, 3-dimethyl-1, 3-dioxolan-4-yl)methyl)-2, 4, 6-triiodo-isophthalamide is produced through addition of acetic acid and concentrated sulfuric acid. In allusion to the defects of the existing methods for preparing the iodixanol, through production of the novel intermediate compound, production of difficultly removed O-alkylated impurities during a reaction is avoided. The invention provides a method for synthesizing the iodixanol, which is more reasonable, higher in yield and higher in purity. By the method, the reaction cost is lower.

DESALINATION OF A COMPOSITION COMPRISING A CONTRAST AGENT

The invention relates to industrial preparation of contrast agents, and further to an improved process for the purification of contrast agents. In particular, it relates to a process for reducing the salt content of compositions comprising an MR contrast agent or an X-ray contrast agent, such as a non-ionic iodinated monomeric compound or a non-ionic iodinated dimeric compound.

DESALINATION OF A COMPOSITION COMPRISING A CONTRAST AGENT

The invention relates to industrial preparation of contrast agents, and further to an improved process for the purification of contrast agents. In particular, it relates to a process for reducing the salt content of compositions comprising an MR contrast agent or an X-ray contrast agent, such as a non-ionic iodinated monomeric compound or a non-ionic iodinated dimeric compound.

Preparation and Purification of Iodixanol

An improved synthesis method for preparation of iodixanol, and a purification process through macroporous adsorption resin chromatographic column and recrystallization are provided. The synthesis method relates to dimerization of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide (compound A) to prepare iodixanol, wherein excessive side reactions such as alkylation are effectively inhibited by controlling the pH of the reaction mixture with a boron-containing acidic substance or salts thereof such as boric acid. In this way, the conversion rate of compound A to iodixanol is 85-90%. The iodixanol crude product is purified by a macroporous adsorption resin chromatographic column, obtaining iodixanol product with recovery of 90-95% and purity of 96-98%. The iodixanol crude product is recrystallized in mixed solvent containing 2-methoxyethanol, obtaining iodixanol product with recovery of 90-95% and purity of greater than 99%.

REDUCTION OF FUSED BICYCLIC IMPURITIES IN TRIIODINATED X-RAY CONTRAST MEDIA

The present disclosure generally relates to an improved process for alkylating a triiodo-substituted arylamide to form a compound suitable for use as an X-ray contrast agent. More particularly, the present disclosure is directed to such a process that limits the formation of fused bicyclic impurities, such as Impurity G, in the alkylation reaction mixture.

SYTNHESIS OF IODIXANOL IN METHANOL

This invention relates to the synthesis of iodixanol (1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), more specifically to the dimerisation of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide with methanol as solvent.

Alternative dimerisation reagents for synthesis of iodixanol

This invention relates to the synthesis of iodixanol. In particular, it relates to alternative dimerisation reagents in the conversion of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A") to iodixanol.

PREPARATION AND PURIFICATION OF IODIXANOL

An improved synthesis method for preparation of iodixanol, and a purification process through macroporous adsorption resin chromatographic column and recrystallization are provided. The synthesis method relates to dimerization of 5-acetamido-N, N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodo-isophthalamide (compound A) to prepare iodixanol, wherein excessive side reactions such as alkylation are effectively inhibited by controlling the pH of the reaction mixture with a boron-containing acidic substance or salts thereof such as boric acid. In this way, the conversion rate of compound A to iodixanol is 85-90%. The iodixanol crude product is purified by a macroporous adsorption resin chromatographic column, obtaining iodixanol product with recovery of 90-95% and purity of 96-98%. The iodixanol crude product is recrystallized in mixed solvent containing 2-methoxyethanol, obtaining iodixanol product with recovery of 90-95% and purity of greater than 99%.