- Preparation method of iodixanol hydrolysate
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The invention discloses a preparation method of an iodixanol hydrolysate. The preparation method comprises the following steps: in ionic liquid, condensing and hydrolyzing 5-acetamido-2,4,6-triiodo-1,3-benzenedicarboxamide and epoxy chloropropane under the action of a solid base catalyst to obtain the product 5-(acetamido)-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide, wherein the solid base catalyst takes a metal oxide as a first active component, takes one or more of corresponding metal hydroxide, carbonate and bicarbonate as a second active component, and takes strongly basic anion exchange resin as a carrier. The catalyst is simple in preparation process, good in activity, long in service cycle, high in product yield, good in purity and free of trace impurities limited by drugs. Equipment is not corroded in the production process, product post-treatment is convenient, the production cost is low, and the method is economical, practical, green and environmentally friendly.
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Page/Page column 0042-0052
(2020/09/12)
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- 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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- 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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- 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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- MECHANOCHEMICAL SYNTHESIS OF RADIOGRAPHIC AGENTS INTERMEDIATES
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The present invention generally relates to a process using a mechanochemical approach exploiting the mechanical milling of reactants for the manufacturing of acetyl Iopamidol and, more generally, of key intermediates of radiographic contrast agents, and of the contrast agents themselves.
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Page/Page column 27
(2018/06/30)
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- ALTERNATIVE ACETYLATION PROCESS IN THE SYNTHESIS OF NON-IONIC XRAY CONTRAST AGENTS
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An alternative acetylation process for the synthesis of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ( Compound A ), an intermediate in the industrial preparation of non-ionic X-ray contrast agents, is described. The process can be performed on an industrial scale to produce Compound A with improved purity and improved yields compared to the established processes.
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Page/Page column 7
(2015/06/18)
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- Formation of N,O-acetalsin the production of x-ray contrast agents
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Acetylation of 1 with acetic anhydride, an important step in the preparation of iohexol, gave the corresponding acetanilide and minor amounts of a few byproducts, whose structures have been elucidated. Among the byproducts were some 1,3-oxazolidines which survived when the reaction was quenched by adding methanol and water under strong acidic conditions.
- Haland, Torfinn,Sydnes, Leiv K.
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p. 1181 - 1190
(2014/12/10)
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- PREPARATION OF INTERMEDIATES OF X-RAY CONTRAST AGENTS
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The present invention relates to a process for the preparation of iodinated X-ray contrast agents and in particular to key intermediates thereof. It particularly relates to an improved process for preparation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound A) or N,N'-bis(2,3-dihydroxypropyl)-5-formamido-2,4,6-triiodoisophthalamide (Compound C), which are intermediates in the industrial preparation of non-ionic X-ray contrast agents. More particularly the invention provides a process for deacylation of the acylated hydroxyl groups of an intermediate compound of Compound A and Compound C.
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Page/Page column 14; 15
(2014/05/24)
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- CONTINUOUS ACETYLATION PROCESS IN SYNTHESIS OF NON-IONIC X-RAY CONTRAST AGENTS
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This invention relates to an improved method for the synthesis of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, it relates to a continuous process of acetylation of 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (“Compound B”) followed by the removal of acetic anhydride.
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Page/Page column 3
(2011/02/18)
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- CONTINUOUS DEACETYLATION AND PURIFICATION PROCESS IN SYNTHESIS OF NON-IONIC X-RAY CONTRAST AGENTS
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This invention relates to an improved method for the synthesis of 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, it relates to a continuous process of deacetylation of the acetylated hydroxyl group in 5-amino-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide (“Compound B”) followed by crystallisations, filtration, and washing of Compound A.
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Page/Page column 3
(2011/02/18)
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- Acetylation using reduced volume of acetic acid anhydride for synthesizing non-ionic X-ray contrast agents
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This invention relates to an improved method for the synthesis of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A"), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, it relates to acetylation of 5-amino-N, N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide ("Compound B") using a reagent and solvent mixture containing between about 1.5 and about 3.0 liter of acetic anhydride and acetic acid per kilogram of Compound B. Preferably, following the acetylation reaction, the reagent and solvent mixture is distilled for re-use.
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Page/Page column 4; 5
(2011/02/19)
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- Solvent reduction in crystallisation of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide, an intermediate for non-ionic X-ray contrast agents
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This invention relates to an improved method for cystallising 5-acetamido-N,N'- bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A"), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, the present invention provides an industrial process for crystallisation of Compound A by evaporating methanol and water from the mother liquor after an initial crystallisation of Compound A. Specifically, the mother liquor is maintained at more than about 75 % (v/v) of water and less than about 25 % (v/v) of methanol.
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Page/Page column 5
(2011/02/26)
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- A continuous deacetylation and purification process in the synthesis of non-ionic X-ray contrast agents
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This invention relates to an improved method for the synthesis of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A"), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, it relates to a continuous process of deacetylation of the acetylated hydroxyl group in 5-amino-N,N'-bis(2,3-dihydroxypropyt)-2,4,6-triiodo-1,3-benzenedicarboxarriide ("Compound B") followed by crystallisations, filtration, and washing of Compound A.
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Page/Page column 4-5
(2011/02/26)
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- A continuous acetylation process in the synthesis of non-ionic X-ray contrast agents
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This invention relates to a method for the synthesis of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ("Compound A"), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, it relates to a continuous process of acetylation of 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-1,3-benzenedicarboxamide ("Compound B") followed by the removal of acetic anhydride.
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Page/Page column 4
(2011/02/26)
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- Solvent reduction in crystallisation of intermediate for non-ionic X-ray contrast agents
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This invention relates to an improved method for crystallizing 5-acetamido-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide (“Compound A”), an intermediate in the industrial preparation of non-ionic X-ray contrast agents. In particular, the present invention provides an industrial process for crystallization of Compound A by evaporating methanol and water from the mother liquor after an initial crystallization of Compound A following the acetylation reaction. Specifically, the mother liquor is maintained at more than about 75% (v/v) of water and less than about 25% (v/v) of alcoholic solvent.
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Page/Page column 5-6
(2010/07/14)
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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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- DETERMINATION OF KIDNEY FUNCTION
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The present invention provides an isotopically labelled marker of formula (I): where R1 -R5 are as defined herein; characterised in that one or more of the H, N, C or O atoms in the compound of formula (I) is replaced with one or more of2H, 13C, 15N, 17O or 18O respectively, methods for using the inventive marker in detecting the presence or absence of a filtration marker in a sample, measuring the rate of glomerular filtration in a subject and/or diagnosing kidney disease and/or damage in a subject.
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Page/Page column 23; 25
(2010/11/26)
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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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- 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 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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- 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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