- An intermediate of iodoxanol and a method for preparing iodixanol thereof
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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.
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- Preparation method of iodixanol
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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.
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Paragraph 0027-0028; 0030; 0039-0040
(2020/11/26)
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- Iodixanol and synthesis method thereof
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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.
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Paragraph 0042-0043; 0046; 0051; 0056
(2018/10/11)
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- DESALINATION OF A COMPOSITION COMPRISING A CONTRAST AGENT
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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.
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Paragraph 0035
(2013/11/05)
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- DESALINATION OF A COMPOSITION COMPRISING A CONTRAST AGENT
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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.
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Page/Page column 12
(2012/07/13)
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- Preparation and Purification of Iodixanol
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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%.
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Page/Page column 5-6
(2012/11/13)
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- PREPARATION AND PURIFICATION OF IODIXANOL
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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%.
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Page/Page column 18
(2011/06/23)
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- Synthesis of iodixanol in 1-methoxy-2-propanol and water or methanol
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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 a solvent mixture comprising 1-methoxy-2-propanol and water or methanol.
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Page/Page column 7
(2011/02/19)
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- Synthesis of iodixanol in methanol
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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.
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Page/Page column 7
(2011/02/19)
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- Synthesis of iodixanol in water
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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 water as solvent.
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Page/Page column 7
(2011/02/19)
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- SYNTHESIS OF IODIXANOL IN WATER
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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 water as solvent.
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Page/Page column 5
(2011/02/18)
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- SYTNHESIS OF IODIXANOL IN 1-METHOXY-2-PROPANOL AND WATER OR METHANOL
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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 a solvent mixture comprising 1-methoxy-2-propanol and water or methanol.
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Page/Page column 5
(2011/02/18)
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- ALKYLATION OF TRIIODO-SUBSTITUTED ARYLAMIDES IN AN AQUEOUS MIXED SOLVENT SYSTEM
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The present disclosure is directed to a process for preparing an alkylated triiodo-substituted arylamide, such as iodixanol, the process comprising contacting a triiodo-substituted arylamide, such as 5-acetamido-N,N'-bis(2,3-dihydroxylpropyl)-2,4,6-triiodoisophthalamide, and an alkylating agent in the presence of a base and a mixed solvent system comprising a non-aqueous solvent and water, wherein the volume ratio of the non-aqueous solvent to water is greater than 1:1. The process advantageously enables the concentration of any impurities or undesirable byproduct from the reaction to be reduced, while increasing the yield of the desired reaction product.
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Page/Page column 19-20; 26-27
(2011/04/25)
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- REDUCTION OF FUSED BICYCLIC IMPURITIES IN TRIIODINATED X-RAY CONTRAST MEDIA
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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.
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Page/Page column 31-32
(2011/04/25)
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- SYTNHESIS OF IODIXANOL IN METHANOL
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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.
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Page/Page column 5
(2011/02/18)
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- Alternative dimerisation reagents for synthesis of iodixanol
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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.
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Page/Page column 3
(2011/02/26)
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- Processing crude iodixanol mixture by nanofiltration
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This invention relates generally to industrial preparation of iodixanol (1,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), a non-ionic X-ray contrasting agent. It further relates to a method for preparing a crude mixture of the dimcrisation reaction from 5-acctamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamidc ("Compound A") to iodixanol for the crystallization of iodixanol. In particular, it relates to an industrial procedure of simultaneously reducing the salt content and the alcoholic dimerisation solvent using a nanofiltration system prior to the crystallization of iodixanol.
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- PROCESSING CRUDE IODIXANOL MIXTURE BY NANOFILTRATION
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This invention relates generally to industrial preparation of iodixanol (1,3-bis(acetamido)-N,N′-bis[3,5-bis(2,3-dihydroxypropylaminocarbonyl)-2,4,6-triiodophenyl]-2-hydroxypropane), a non-ionic X-ray contrasting agent. It further relates to a method for preparing a crude mixture of the dimerisation reaction from 5-acetamido-N,N-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”) to iodixanol for the crystallization of iodixanol. In particular, it relates to an industrial procedure of simultaneously reducing the salt content and the alcoholic dimerisation solvent using a nanofiltration system prior to the crystallization of iodixanol.
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Page/Page column 2-3
(2011/02/18)
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- Synthesis of iodixanol in propyleneglycol
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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 propyleneglycol as solvent.
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Page/Page column 7
(2011/02/25)
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- SYTNHESIS OF IODIXANOL IN PROPYLENEGLYCOL
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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 propyleneglycol as solvent.
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Page/Page column 5
(2011/02/18)
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- Alternative dimerisation reagents for synthesis of iodixanol
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This invention relates generally to non-ionic X-ray contrast agents. It further 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.
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Page/Page column 4
(2010/04/30)
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- Injectable Radio-Opaque Compositions for Tissue Augmentation
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Injectable radio-opaque compositions for tissue augmentation and in particular hard tissue augmentation, and kits and methods of using thereof are described herein. The injectable compositions form porous, biologically degradable, fibrin matrices. The compositions are formed from fibrinogen, thrombin or another agent that causes the fibrinogen to crosslink, and strontium salts. Optionally an iodinated contrast agent is further incorporated in the composition. In certain aspects, the compositions have substantially no exothermicity when forming the matrix and the resulting matrices exhibit mechanical properties typically seen in elastomers. Adequate radio-opacity is achieved through the incorporation of strontium salts in combination or not with iodinated contrast agents.
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- PURIFICATION PROCESS OF IODIXANOL
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A process for the manufacture of iodixanol by performing a purification process of the crude product in a solvent comprising n-propanol. The crude product may be obtained in aqueous solution from dimerisation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide ("Compound A").
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Page/Page column 7; 8
(2008/06/13)
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- PURIFICATION OF IODIXANOL
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A process for the manufacture of iodixanol by performing a purification process of the crude product in a solvent comprising ethanol. The crude product may be obtained in aqueous solution from dimerisation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide ("Compound A").
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Page/Page column 7-10
(2008/06/13)
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- Process for the crystallisation of sterically hindered compounds
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A process for the crystallisation of a sterically hindered organic compound from a saturated or supersaturated solution of said compound in a solvent therefor, characterised in that crystallisation is effected under elevated pressure at a temperature above the boiling point of said solution at atmospheric pressure and up to the boiling point of said solution at said elevated pressure.
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- A selective process for n-alkylation in competition with o-alkylation: Boric acid, borax, and metaborate as a cheap and effective protecting group applicable for industrial-scale synthetic processes
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This paper describes a selective process for the N-alkylation of substrates that contain 1,2-diol groups. The developed approach utilises temporary protection of the diol groups by boric acid, Borax, or metaborate. The introduction of the boron-containing groups into the substrate may provide, in addition to affording the intended protection of the hydroxyl groups that may otherwise act as nucleophilic sites, the advantages of improved solubility of the substrate in water that is used as solvent. Moreover the N-alkylation and the deprotection of the diols are performed in one pot, and the formation of undesired O-alkylated by-products is significantly reduced. The paper gives examples from the synthesis of several X-ray contrast agents used in medical imaging diagnostics: iohexol (Ominipaque, Nycomed Imaging); iopentol (Imagopaque, Nycomed Imaging); iodixanol (Visipaque, Nycomed Imaging); ioversol (Optiray, Mallinckrodt).
- Bjorsvik, Hans-Rene,Priebe, Hanno,Cervenka, Jan,Aabye, Arne W.,Gulbrandsen, Trygve,Bryde, Arnt Christian
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p. 472 - 478
(2013/09/07)
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- Multivariate Data Analysis of Molecular Descriptors Estimated by Use of Semiempirical Quantum Chemistry Methods. Principal Properties for Synthetic Screening of 2-Chloromethyloxirane and Analogous Bis-alkylating C3 Moieties
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The principal properties of 106 different bis-alkylating C3 moieties have been calculated and evaluated in the synthesis of 3,3',5',5'-tetrakis(2,3-dihydroxypropylcarbamoyl)2,2',4,4',6,6'-hexaiodo-N,N'-(2-hydroxypropane-1,3-diyl)diacetanilide.Sixteen molecular descriptors, most of them estimated by means of semiempirical quantum chemistry methods were used to describe the bis-alkylating C3 moieties.Hence, a 106*16 data matrix was obtained.This data matrix was subjected to principal componen't analysis (PCA) in order to estimate the principal properties.Based upon a uniform spread in the principal properties, 13 bis-alkylating C3 reagents were selected to be used in laboratory experiments in an attempt to describe the variation in yield in the synthesis of 3,3',5',5'-tetrakis(2,3-dihydropropylcarbamoyl)-2,2',4,4',6,6'-hexaiodo-N,N'-(2-hydroxypropane-1,3-diyl)diacetanilide.The relationship between the yield, two experimental descriptors and the principal properties as well as the two-factor interactions and quadratic terms of these were modelled by the partial least-squares (PLSR) method.The results from this modelling shows that the principal properties, and hence the molecular descriptors, contain useful information for design of screening experimental plans where bis-alkylating C3 moieties need to be evaluated.
- Bjoersvik, Hans-Rene,Priebe, Hanno
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p. 446 - 456
(2007/10/02)
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- X-ray contrast agents
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Compounds of the general formula: STR1 (where R is a group --CH(CH2 OH)2 or --CH2 CH(OH)CH2 OH and A is a group --CH2 CH(OH)CH2 -- or --CH2 CH(OH)CH(OH)CH2 --) possess a package of favourable parameters which render them of particular use not only in all forms of intravascular visualisation but also in myelography. The compounds are prepared by reaction of an appropriate 5-acetylamino-N,N'-bis(hydroxypropyl)-2,4,6-triiodoisophthalamide with an agent effective to introduce the appropriate hydroxyalkylene group such as for example epichlorohydrin or 1,4-dichloro-2,3-dihydroxybutane.
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- Contrast media comprising a non-ionic contrast agent with low levels of sodium & calcium ions
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The physiological acceptability of contrast media, especially media for use in angiography, may be enhanced by inclusion of sub-plasma levels of sodium and calcium and, optionally, potassium and/or magnesium, for example 30 mM Na, 0.15 mM Ca, 0.9 mM K and 0.1 mM Mg.
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