Process for the purifying of iopamidol

Abstract

A process for purifying Iopamidol which uses a butanol as solvent is described. Iopamidol is obtained with high yields, also starting from aqueous solutions of the same and has characteristics in accordance with those required by pharmacopoeia.

What is claimed as new and desired to be secured by Letters Patent of the United States is: 
     
       1. A process for purifying L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) (Iopamidol) comprising the steps of: dissolving a crude solid of Iopamidol in sec-butanol; and   crystallizing pure Iopamidol therefrom, wherein said pure Iopamidol has less residual solvent than said crude Iopamidol.   
     
     
       2. The process of claim 1, wherein the weight of Iopamidol to the volume of solvent is 3 to 20. 
     
     
       3. A process for purifying L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) (Iopamidol) comprising the steps of: treating an aqueous solution of Iopamidol with sec-butanol, to obtain a mixture containing Iopamidol; and   .[.crystallizing pure Iopamidol therefrom, dissolving a crude solid of Iopamidol in sec-butanol; and.].   crystallizing pure Iopamidol therefrom, wherein said pure Iopamidol has less residual solvent than said crude Iopamidol.   
     
     
       4. The process of claim 3, wherein said aqueous solution of Iopamidol is the product of a synthesis of Iopamidol. .Iadd. 
     
     
       5.  A process for purifying L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), comprising the steps of: treating a crude solid of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) with sec-butanol; and   crystallizing L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) therefrom. .Iaddend..Iadd.6. The process of claim 5, wherein said L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) is treated with a volume as measured in ml of sec-butanol which is 3 to 20 times the weight as measured in grams of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide). .Iaddend..Iadd.7. A process for purifying L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), comprising the steps of:   (i) adding sec-butanol to an aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) to obtain a suspension comprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), water, and sec-butanol; and   (ii) crystallizing L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) from said suspension comprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), water and sec-butanol. .Iaddend..Iadd.8. The process of claim 7, wherein said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) has been contacted with charcoal and filtered to remove said charcoal prior to said adding sec-butanol. .Iaddend..Iadd.9. The process of claim 7, wherein said sec-butanol is added to said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in a volume as measured in ml which is 3 to 20 times the weight as measured in grams of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide). .Iaddend..Iadd.10. The process of claim 7, wherein said sec-butanol is added to said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in a volume as measured in ml which is 3 to 12 times the weight as measured in grams of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3 dihydroxyisopropylamide). .Iaddend..Iadd.11. The process of claim 7, wherein said sec-butanol is added to said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in a volume as measured in ml which is 3 to 10 times the weight as measured in grams of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) in said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide). .Iaddend..Iadd.12. The process of claim 7, wherein said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) is concentrated to a concentration of 70 to 75% (w/w) prior to said adding sec-butanol. .Iaddend..Iadd.13. The process of claim 7, wherein said aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) is maintained at a temperature between 80 and 85° C. during said adding sec-butanol. .Iaddend..Iadd.14. A process for purifying L-5-a-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), comprising the steps of:   (i) adding charcoal to a first aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) to obtain a mixture;   (ii) filtering said mixture to obtain a second aqueous solution of L-5-a-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide);   (iii) concentrating said second aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) to a concentration of 70% to 75% (w/w), to obtain a third aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide);   (iv) heating said third aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide);   (v) adding sec-butanol to said heated aqueous solution of L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), to obtain a suspension comprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), water, and sec-butanol;   (vi) maintaining said suspension comprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), water and sec-butanol at a temperature of 80 to 85° C. for a time of about 30 minutes and then cooling said suspension comprising L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide), water, and sec-butanol, to obtain a cooled suspension;   (vii) stirring said cooled suspension for about 2 hours and then filtering said cooled solution to obtain solid L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide);   (viii) washing said solid L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide) with sec-butanol, to obtain washed solid L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide); and   (ix) drying said washed solid L-5-α-hydroxypropionylamino-2,4,6-triiodo-isophthalic acid bis-(1,3-dihydroxyisopropylamide). .Iaddend.