- Contrast medium of the impurity F synthetic method and its impurity G contrast medium, impurity H and impurity M application in the synthesis of
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The invention relates to a synthesis method of contrast medium impurities, in particular to a contrast medium impurity F synthetic method and its in the contrast medium impurity G, impurity H and M application in the synthesis of the impurity, which belongs to the field of medical technology. The method is to 5 - nitro - 1, 3 - benzene dicarboxylic acid dimethyl ester (formula 2 compound) and 2, 3 - dihydroxy propylamine as raw materials of formula 3 compound, type 3 compound with hydrogen reduction reaction [...] 4 compound, of formula 4 with a compound obtained by reaction of the impurity F [...] contrast medium. The invention relates to 5 - nitro - 1, 3 - benzene dicarboxylic acid dimethyl ester (formula 2 compound) as the starting material, the synthesis of 5 - amino - N, double-N' - (2, 3 - dihydroxy-propyl) - diiodo - 1, 3 - benzene dicarboxylic amide (formula 1 compounds) and then to of formula 1 as the starting material for the synthesis of impurity G, impurity H and impurity M, for the contrast medium quality control to provide acceptable impurity reference substance.
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Paragraph 0041; 0042
(2019/07/05)
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- Method for preparing iohexol
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The invention discloses a method for preparing iohexol. The method comprises the following steps: using a compound I: 5-[acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-phenyldicarbonamide,glycerol-chlorohydrin or analogues thereof as raw materials, using disodium hydrogen phosphate or dipotassium phosphate as an acid dressing agent, reacting in a solvent, after ending the reaction, acquiring the iohexol through post-treatment. Through using buffer base of the disodium hydrogen phosphate or the dipotassium phosphate as the acid dressing agent, reaction conditions are moderate relatively, and a defect in a reaction process that a pH is unstable is overcome. So the iohexol prepared by the method is less and small in impurity, especially the impurity of alkoxy can be controlled byless than 0.5%, a yield is high, and the yield can reach 90-98%. The method is green and environment-friendly, and simple in operation.
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Paragraph 0028-0049
(2019/08/07)
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- Novel energy-saving environment-friendly continuous preparation method of iohexol
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The invention relates to a novel energy-saving environment-friendly continuous preparation method of iohexol. The preparation method specifically comprises the following steps: (1) acylation reaction:carrying out a reaction on a compound of a formula [2] with acetic anhydride in an environment of hydrochloric acid to obtain a compound of a formula [3]; (2) transesterification: carrying out a reaction on the compound of the formula [3] with a small-molecule liquid alcohol under an appropriate condition to obtain a compound of a formula [4], (3) alkylation reaction: carrying out a reaction on the compound of the formula [4] with 3-chloro-1,2-propylene glycol under the condition of a mixed solution of methanol and sodium methoxide, carrying out neutralization, filtering and desolvation to obtain an iohexol crude product; (4) purification: purifying the iohexol crude product to obtain an iohexol pure product. The method comprises carrying out the transesterification reaction on the liquidalcohol with 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3-diacetoxypropyl)-1,3-phthalamide, then carrying out an alkylation reaction with the alkylating reagent 3-chloro-1,2-propylene glycol in a methanol solution of the sodium methoxide, carrying out neutralization by using a methanol solution of hydrochloric acid, carrying out filtering, carrying out desolvation on the obtained filtrate, and thenpurifying the obtained iohexol crude product to obtain the iohexol pure product.
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Paragraph 0035; 0047; 0048
(2018/07/28)
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- Energy-saving environment-friendly continuous preparation method of iohexol
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The invention relates to an energy-saving environment-friendly continuous preparation method of iohexol. The preparation method comprises the following steps: (1) acylation reaction: carrying out a reaction on a compound of a formula [2] with acetic anhydride in an environment of hydrochloric acid to obtain a compound of a formula [3]; (2) transesterification: carrying out a reaction on the compound of the formula [3] with a small-molecule liquid alcohol under an appropriate conditions to obtain a compound of a formula [4]; (3) alkylation reaction: carrying out a reaction on the compound of the formula [4] with and 3-chloro-1,2-propanediol under a condition of a mixed solution of methanol and sodium methoxide to obtain an iohexol crude product; and (4) purification: purifying the iohexol crude product to obtain an iohexol pure product. According to method, the transesterification reaction is carried out on the liquid alcohol with 5-acetylamino-2,4,6-triiodo-N,N'-bis(2,3-diacetoxypropyl)-1,3-phthalamide, then the alkylation reaction is carrred out with the alkylation reagent 3-chloro-1,2-propanediol in a methanol solution of the sodium methoxide, and the obtained iohexol crude product is purified to obtain the pure iohexol product.
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Paragraph 0027; 0033; 0034
(2018/07/28)
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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 0036
(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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- 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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- 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 15-16
(2011/06/23)
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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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- 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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- 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; 23-26
(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 34-35
(2011/04/25)
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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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- PROCESS FOR THE MANUFACTURE OF IOHEXOL
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A process for the production of iohexol comprises alkylating 5-Acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6- triiodoisophthalamide using 2(2-methoxy-ethoxy)-ethanol as solvent in the presence of a base, and optionally isolating crude iohexol from the reaction mixture. Preferably, the alkylating agent is 1-chloro-2,3 propanediol and the base is an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide.
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Page/Page column 5-6
(2008/06/13)
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- PROCESS FOR IOHEXOL MANUFACTURE
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The present invention relates to a process for the manufacture of iohexol, 5-[N- (2,3-dihydroxypropyl) -acetamido]-N,N'-bis(2,3 -dihydroxypropyl)-2,4,6-triiodoisophtalamide by selecting a solvent comprising a C1-C5-monoalkylether of a C3-C10 alkylene-glycol.
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- INDUCER FOR DIFFERENTIATION OF EMBRYO STEM CELLS INTO ECTODERMAL CELLS, METHOD OF OBTAINING THE SAME AND USE THEREOF
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A method for obtaining a solution having activity to induce differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell, which comprises culturing a stromal cell in a culture comprising a polyanionic compound and recovering the culture; a solution having activity to induce differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell, which is obtainable by the method; and an agent for inducing differentiation of an embryonic stem cell into an ectodermal cell or ectoderm-derived cell.
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- Process for the preparation of n,n-substituted 5-amino-1,3-benzenedicarboxamides
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The invention relates to a process for the preparation of a compound of formula (I), wherein R represents a 2,3-dihydroxy-1-propyl or a 1,3-dihydroxy-2-propyl radical, via direct amidation of a dialkyl ester of 5-amino-1,3-benzenedicarboxylic acid of formula (V), wherein R1 represents a straight or branched (C1-C4)-alkyl group, with at least the stoichiometric amount of an amine of formula H2NR.
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- Process for the preparation of crystalline and solvent free iohexol
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The object of the present invention is an industrial process for the purification and removal of residual solvents from iohexol, based on the suspension of crystalline iohexol, eventually containing residual solvents above 100 ppm, in a fluid wherein it has a low solubility, followed by heating, filtration and drying. The process allows the formation of crystalline iohexol with no residual organic residual solvent above 100 ppm and with an increased purity level.
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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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- PROCESS FOR THE PREPARATION OF IOPAMIDOL
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The present invention discloses a process for the preparation of pure non-ionic contrast agents. The invention also includes a method for purifying the non-ionic contrast agents.
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- A PROCESS FOR THE PREPARATION OF 5- ACETYL (2,3-DIHYDROXYPROPYL)AMINO]-N,N'-BIS (2,3-DIHYDROXYPROPYL)-2,4,6- TRIIODO-1,3-BENZENEDICARBOXAMIDE
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A process for the preparation of 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (I), starting from 5-amino-1,3-benzenedicarboxylic acid of formula (II), comprising the following steps: step a) is the reaction in heterogeneous phase between 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid and thionyl chloride in a solvent selected from the group consisting of: straight or branched (C7-C16) hydrocarbons, (C7-C8) aromatic hydrocarbons, 1,1,1-trichloroethane, n-butyl acetate, diglyme (diethylene glycol dimethyl ether), in the presence of catalytic amounts of a tertiary amine, to give compound (III); step b) is the acetylation reaction of compound (III) with glacial acetic acid both as the solvent and the reagent and thionyl chloride; step c) is the formation of compound (V) by reaction of the compound (IV) with 1-amino-2,3-propanediol, by reaction of compound (IV) in a dipolar aprotic solvent, selected from the group of dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO) or N-methyl-pyrrolidinone; step d) is the alkylation of the compound (V) in aqueous solution at basic pH, by addition of a sodium hydroxide-calcium hydroxide mixture, with 3-chloro-1,2-propanediol or epichlorohydrin, at a temperature of 40-90 DEG C.
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- Process for the preparation of 5-(acetyl(2,3-dihydroxypropyl)amino-N,N-bis(2,3-dihydroxypropyl)-2,4,6-t riiodo
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A process for the preparation of 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide of formula (I), starting from 5-amino-1,3-benzenedicarboxylic acid of formula (II), comprising the following steps: step a) is the reaction in heterogeneous phase between 5-amino-2,4,6-triiodo-1,3-benzenedicarboxylic acid and thionyl chloride in a solvent selected from the group consisting of: straight or branched (C7 -C16) hydrocarbons, (C7 -C8) aromatic hydrocarbons, 1,1,1-trichloroethane, n-butyl acetate, diglyme (diethylene glycol dimethyl ether), in the presence of catalytic amounts of a tertiary amine, to give compound (III); step b) is the acetylation reaction of compound (III) with glacial acetic acid both as the solvent and the reagent and thionyl chloride; step c) is the formation of compound (V) by reaction of the compound (IV) with 1-amino-2,3-propanediol, by reaction of compound (IV) in a dipolar aprotic solvent, selected from the group of dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide (DMSO) or N-methyl-pyrrolidinone; step d) is the alkylation of the compound (V) in aqueous solution at basic pH, by addition of a sodium hydroxide-calcium hydroxide mixture, with 3-chloro-1,2-propanediol or epichlorohydrin, at a temperature of 40-90° C.
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- Process for the preparation of iohexol
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Provided is a novel process for the preparation of iohexol having reduced number of isolated intermediates and significantly reduces or eliminates the use of ion-exchange resins required to desalinate the final product.
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- Process for the preparation of iohexol
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Provided is a novel process for the preparation of iohexol having improved yields and purity, reduced number of isolated intermediates, and significantly reduced volume of ion-exchange resins required to desalinate the final product.
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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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- Method for apparatus for a defined serumfree medical solution useful for corneal preservation
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A defined serumfree medical solution for applications in Ophthalmology, that contains one or more cell nutrient supplements which maintains and enhances the preservation of eye tissues, including human corneal tissues at low temperatures (2° C. to 15° C.). This solution is composed of a defined aqueous nutrient and electrolyte solution, supplemented with a glycosaminoglycan(s), a deturgescent agent(s), an energy source(s), a buffer system(s), an antioxidant(s), membrane stabilizing components, antibiotic(s), ATP precursors and nutrient cell supplements.
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- Chemical compounds
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Compounds of the formula: STR1 wherein R represents the group --CH2 CH2 OH or --CH2 CHOHCH2 OH, particularly in racemic or optically active form, are employed as active ingredients in X-ray contrast agents for intracerebral, but particularly for vascular use. The compounds are prepared by reacting 5-(N-acetamido)-2,4,6-triiodo-N,N'-bis-(2,3-dihydroxypropyl)isophthalamide or an O-acetyl derivative thereof with an appropriate hydroxyalkylating agent and subsequently, if necessary, hydrolysing any unwanted O-acetyl groups.
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