# US 2014/0155648 A1 · Manufacture of a Triiodinated Contrast Agent > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2014/0155648 A1 - Document ID: US20140155648A1 - Status: Published application - Kind: A1 - Application number: 14/128,782 - Filed: 2012-02-02 - Published: 2014-06-05 - Earliest claimed: 2011-06-24 - Assignees: Hovione Inter Ltd. - Inventors: Jose Manuel Galindro; Ana Cristina Cruz; João José Bandarra; William Heggie - Web page: https://patentgrep.com/patent/US20140155648A1 ## CPC - C07C 231/02: from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines - C07C 231/18: by stereospecific synthesis - C07C 231/24: Separation; Purification - C07C 235/16: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring - C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS ## Abstract A new compound, (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid, of formula II (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid. Said new compound is of use for the production of triiodinated contrast agent, especially lopamidol, with low content of acetyl and hydroxyacetyl analogs. The new compound may be formed from 5-amino-2,4,6-triiodoisophtalic acid by acylating with (S)-1-chloro-1-oxopropan-2-yl acetate. The new compound may then be converted to the respective acid dichloride by reacting with a chlorinating reagent, which is a further object of the present invention, followed by the amidation with 2-amino-1,3-propanediol and acetate hydrolysis. ## Claims ### Claim 1 A compound, (S)-5-(2-acetoxypropanamido)-2,4,6-triiodoisophthalic acid, of formula II ### Claim 2 (depends on 1) A process to prepare a compound of formula II according to claim 1 comprising the step of acylating 5-amino-2,4,6-triiodoisophtalic acid with an acyl halide. ### Claim 3 (depends on 2) A process according to claim 2 wherein the acyl halide is an acyl chloride, such as (S)-1-chloro-1-oxopropan-2-yl acetate. ### Claim 4 (depends on 2) A process according to claim 2 wherein the acyl halide is used in a ratio of at least 1.5:1 relative to the 5-amino-2,4,6-triiodoisophtalic acid. ### Claim 5 (depends on 2) A process according to claim 2 wherein the acylating step is carried out in an aprotic polar solvent. ### Claim 6 (depends on 5) A process according to claim 5, wherein the aprotic polar solvent is dimethylacetamide (DMA). ### Claim 7 (depends on 6) A process according to claim 6, wherein from 1 ml to 5 ml of DMA is used per 1 gram of 5-amino-2,4,6-triiodoisophtalic acid. ### Claim 8 (depends on 2) A process according to claim 2 wherein the reaction is carried out at a temperature of from 40° C. to 60° C. ### Claim 9 (depends on 8) A process according to claim 8 wherein the temperature is maintained for a set period of time of from 5 to 9 hours. ### Claim 10 (depends on 9) A process according to claim 9 wherein, after the temperature has been maintained for the set period of time, the reaction mixture is stirred at a temperature of from 15° C. to 25° C., until conversion to the compound of formula II. ### Claim 11 (depends on 2) A process according to claim 2 wherein the solution containing the compound of formula II is added to water from which the compound of formula II may be separated by filtration. ### Claim 12 (depends on 11) A process according to claim 11 wherein the solution containing the compound of formula II is added to water in a ratio of from 5:1 to 16:1 relative to the polar aprotic solvent. ### Claim 13 (depends on 11) A process according to claim 11 wherein the solution containing the compound of formula II is added to water at a temperature of from 15° C. to 25° C. ### Claim 14 (canceled) ### Claim 15 A process to prepare a triiodinated contrast agent, comprising the step of converting the compound of formula II to the respective acid dihalide, (S)-1-((3,5-bis(halocarbonyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2-yl acetate by reaction with a halidating reagent in a polar solvent. ### Claim 16 (depends on 15) A process according to claim 15 wherein the temperature of the said reaction is set at from 25° C. to 50° C. ### Claim 17 (depends on 15) A process according to claim 15 wherein the polar solvent is acetonitrile, N-methylpyrrolidone, or DMA. ### Claim 18 (depends on 15) A process according to claim 15 wherein the polar solvent is used in a ratio of 5:1 relative to the compound of formula II. ### Claim 19 (depends on 15) A process according to claim 15 wherein the compound of formula II is converted to the respective acid dichloride, (S)-1-((3,5-bis(chlorocarbonyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2-yl acetate by reaction with a chlorinating agent. ### Claim 20 (depends on 19) A process according to claim 19 wherein the chlorinating agent is phosphorus pentachloride. ### Claim 21 (depends on 15) A process according to claim 15 wherein the reaction mixture after complete reaction is added to water in a ratio of about 2:1 relative to the quantity of the polar solvent to isolate the acid dihalide of the compound of formula II. ### Claim 22 (depends on 15) A process according to claim 15 wherein the reaction mixture after complete reaction is added to water at a temperature of from 0° C. to 10° C. to isolate the acid dihalide of the compound of formula II. ### Claim 23 (depends on 22) A process according to claim 22 wherein the acid dihalide is further purified by suspension in a mixture of water and isopropyl alcohol. ### Claim 24 (depends on 22) A process according to claim 22 wherein the acid dihalide of the compound of formula II is used directly as a wet solid without drying or as a dried solid after drying in the next chemical step. ### Claim 25 (depends on 15) A process according to claim 15, comprising an amidation step to convert the acid dihalide, (S)-1-((3,5-bis(halocarbonyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2-yl acetate to the compound of formula IV (S)-1-((3,5-bis((1,3-dihydroxypropan-2-yl)carbamoyl)-2,4,6-triiodophenyl)amino)-1-oxopropan-2-yl acetate by reaction with 2-amino-1,3-propanediol. ### Claim 26 (depends on 25) A process according to claim 25, comprising a step of acetate hydrolysis of the compound of formula IV to provide lopamidol. ### Claim 27 (depends on 15) A process according to claim 15 wherein the iodinated contrast agent is lopamidol. ### Claim 28 (canceled) ### Claim 29 (canceled) ### Claim 30 (depends on 8) A process according to claim 8 wherein the solution containing the compound of formula II is added to water from which the compound of formula II may be separated by filtration.