Study On The Synthesis Process Of Contrast Agent Iohexol

Iohexol,chemical name 5-[acetyl(2,3-dihydroxypropyl)amino]-N,N’-bis(2,3–dihdrox ypropyl)-2,4,6-Triiodo-1,3-phthalic acid amide,trade name OMNIPAQUE,Chinese trade name Ou Nai Paike,is a high-security,non-ionic monomer iodine contrast agent.Iohexol was successfully developed by Norway nekomin pharmaceutical in the early 1980s.It was first marketed in Norway and Sweden in 1982 and was approved by the US Food and Drug Administration(FDA)to be listed in the United States in 1985.Clinical indications include cardiovascular angiography,coronary angiography,urography,CT enhanced scan and myelography.In 2016,the market sales of Iohexol was about 2.4 billion,ranking first among X-ray contrast agents.Therefore,the research on the high-efficiency synthesis process of Iohexol has high application value.After comprehensive consideration of the literatures,we designed a synthetic scheme with 5-amino-2,4,6-triiodoisophthalic acid and thionyl chloride as the raw materials,via substitution,amidation,acetylation,hydrolysis,alkylation,resolution,salifying these steps to get the end product,we also refined the purity and yield of end product by the optimization of reaction conditions.The characterization of intermediates and end-product were accomplished by ~1H-NMR、MS and so on.The main work are as follows:1)Study and optimization of the synthesis of intermediate M-1 5-amino-2,4,6-triiodoisodecanoyl chloride.The intermediate M-1 5-amino-2,4,6-triiodoisodecanoyl chloride was prepared from S-1 5-amino-2,4,6-triiodoisophthalic acid and thionyl chloride.After optimization of experimental conditions,the optimum synthetic process was determined as follows:the molar ratio of S-1 to thionyl chloride was 1:4.4,being reacted at 80℃for4h,the yield of M-1could reach 96.1%,HPLC purity was 98.6%(according to area normalization method).2)Study and optimization of the synthesis of intermediate M-2 5-amino-N,N,-bis(2.3-dihydroxypropyl)-2,4,6-triiodo-1,3-phthalamide.Intermediate M-1 and 3-amino-1,2-propanediol were used as starting materials to form intermediate M-2 5-amino-N,N,-bis(2.3-dihydroxypropyl)-2,4,6-three Iodine-1,3-phthalic acid amide.After optimization of experimental conditions,the optimum synthetic process was determined as follows:the molar ratio of M-1 to 3-amino-1,2-propanediol and triethylamine was 1:2.5:3.0,being reacted at 55℃for 3h,the yield of M-2 could reach86.2%,HPLC purity was 98.7%(according to area normalization method).3)Study and optimization of the synthesis of intermediate M-3 5-acetamideN,N,-bis(2,3-diacetyloxypropyl)-2,4,6-triiodo-1,3-phthalamideSynthesis of intermediate M-3 5-acetamideN,N,-bis(2,3-diacetyloxypropyl)-2,4,6-tr iiodo-1,3-phthalamide was prepared from intermediate M-2 and acetic anhydride.After optimization of experimental conditions,the optimum synthetic process was determined as follows:the molar ratio of M-2 to acetic anhydride and p-toluenesulfonic acid was1:7.6:0.05,being reacted at 110℃for3h,the yield of M-3 could reach 85.8%,HPLC purity was 98.4%(according to area normalization method).4)Study and optimization of the synthesis of intermediate M-4 5-acetamido-N,N,-bis(2.3-dihydroxypropyl)-2,4,6-triiodo-1,3-phthalamide.Synthesis of intermediate M-4 5-acetamido-N,N,-bis(2.3-dihydroxypropyl)-2,4,6-triiodo-1,3-phthalamide was prepared from intermediate M-3 and sodium hydroxide.After optimization of experimental conditions,the optimum synthetic process was determined as follows:the molar ratio of M-3 to sodium hydroxide was 1:5.0,being reacted at 40℃for1h,the yield of M-4 could reach 80.7%,HPLC purity was 98.9%(according to area normalization method).5)Study and optimization of the synthesis process of iohexol.Synthesis of iohexol was prepared from intermediate M-4 and glycidol.After optimization of experimental conditions,the optimum synthetic process was determined as follows:the molar ratio of M-4 to glycidol and boric acid was 1:1.2:2.2,being reacted at25℃for 22h,and the crude product was treated with XAD1600 macroporous resin,Amberlite FPC11Na cationic resin and Amberlite FPA91 Cl anion resin.After recrystallization from n-butanol,the yield was 68.7%and HPLC purity was 99.5%(according to area normalization method).The final product was structurally confirmed by H-NMR,C-NMR,DEPT90,DEPT135,COSY,HSQC and HMBC spectra.