Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines

Definitions

• This invention relates generally to large-scale synthesis of non- ionic X-ray contrast agents. It further relates to 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.
• the process can be performed on an industrial scale to produce Compound A with improved purity and improved yields compared to the established processes.
• Non- ionic X-ray contrast agents constitute a very important class of pharmaceutical compounds produced in large quantities.
• 5-[N-(2,3-dihydroxypropyl)-acetamido]-N,N'- bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide ("iohexol") 5-[N-(2-hydroxy-3- methoxypropyl)acetamido]-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodo-isophthalamide
• iopentol and 1 ,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropyl-aminocarbonyl)- 2,4,6-triiodophenyl]-2-hydroxypropane
• iodixanol 1 ,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropyl-aminocarbonyl)- 2,4,6-triiodophenyl]-2-hydroxypropane
• iodixanol 1 ,3-bis(acetamido)-N,N'-bis[3,5-bis(2,3-dihydroxypropyl-aminocarbonyl)- 2,4,6-triiodophenyl]-2-hydroxypropane
• iodixanol marketed under the trade name Visipaque®, is one of the most used agents in diagnostic X-ray procedures. It is produced in large quantities by GE Healthcare in Lindesnes, Norway. The industrial production of iodixanol involves a multistep chemical synthesis as shown in Scheme 1 below. See also U.S. Patent No.
• Compound A is a key intermediate in both the industrial scale synthesis of such non-ionic X-ray contrast agents.
• Compound A is prepared by the acetylation of 5-amino-N,N'-bis(2,3- dihydroxypropyl)-2,4,6-triiodoisophthalamide (Compound B).
• the acetylation is achieved by using a mixture of acetic anhydride and acetic acid as the acetylating reagent.
• acetylation not only is Compound A produced but several by-products are formed as well.
• the present invention provides an alternative acetylation process for producing Compound A that can be performed on both a laboratory and/or industrial scale. In a preferred embodiment of the invention, the process is performed as a batch process. The present invention provides an alternative acetylation process for producing Compound A that can be performed as either a batch process or a continuous process. In a preferred embodiment of the invention, the process is performed as a batch process.
• an acid catalyst e.g. para-toluene sulfonic acid (PTSA)
• the present invention provides process comprising the steps of:
• an acid catalyst preferably, para-toluene sulfonic acid (PTSA)
• PTSA para-toluene sulfonic acid
• the present invention also provides an industrial scale process comprising the steps of:
• the present invention also provides an industrial scale process comprising the steps of:
• an acid catalyst preferably, para-toluene sulfonic acid (PTSA)
• PTSA para-toluene sulfonic acid
• an alternative acetylation process is provided.
• Compound B is added to a mixture of acetic anhydride and acetic acid.
• the resulting slurry is then heated to approximately 60 °C.
• a catalytic amount of an acid catalyst is added.
• a suitable acid catalyst include, for example, a sulfonic acid such as methanesulfonic acid, para- toluenesulfonic acid (PTSA) and sulphuric acid. Of these, para-toluenesulfonic acid (PTSA) is preferred.
• the acid catalyst can be added as a solid or as a solution.
• Suitable solvents to form such a solution include acetic acid, acetic anhydride or a mixture of acetic acid and acetic anhydride.
• the addition is performed carefully while the temperature is controlled.
• the PTSA is added as a solid in several portions.
• the PTSA is added as a solution where PTSA is dissolved in a small volume of acetic acid.
• the PTSA is added as a solution where PTSA is dissolved in a small volume of acetic anhydride.
• the PTSA is added as a solution where PTSA is dissolved in a small volume of a mixture of acetic acid and acetic anhydride.
• the rate/speed of the addition of the acid catalyst, preferably PTSA is such that the maximum reaction temperature is maintained at about 65-85 °C. In general, the addition time will be over several hours in order to control the exothermic reaction.
• the rate/speed of the addition of the acid catalyst, preferably PTSA, is such that the maximum reaction temperature is maintained at about 70- 80 °C.
• addition of the acid catalyst, preferably PTSA produces a reaction mixture comprising overacetylated Compound A with lower levels of byproducts compared to the established acetylation process.
• the reaction mixture comprising overacetylated Compound A can then be deacetylated using a deacetylating agent.
• a deacetylating agent There is no particular restriction upon the nature of the deacetylating agent used, and any
• deacetylating agent commonly used in conventional reactions may equally be used here.
• suitable deacylating agents include aqueous inorganic bases including alkali metal carbonates, such as sodium carbonate, potassium carbonate or lithium carbonate; and alkali metal hydroxides, such as sodium hydroxide, potassium hydroxide or lithium hydroxide.
• alkali metal hydroxides particularly sodium hydroxide or potassium hydroxide, and most preferably sodium hydroxide are preferred.
• the reaction mixture comprising overacetylated Compound A can be deacetylated by the addition of base, such as sodium hydroxide, to form Compound A which in turn can then be purified (e.g., crystallization) and isolated by techniques known in the art.
• Example 1 the temperature were held at about 120 °C for approximately 2 hours to form over-acetylated Compound A, before moving on to the next deacetylation process step to form Compound A.
• Example 2 the solution was cooled in a reactor jacket to 70 °C immediately after reaching the maximum temperature of approximately 120-125 °C. The cooling rate was about 1 °C/minute, and the solution was held at 70 °C overnight to form over-acetylated Compound A before moving on to the next deacetylation process step to form Compound A.
• Deacetylation After acetylation, the reaction solution containing over-acetylated Compound A was concentrated under reduced pressure, before methanol and water was added prior to the deacetylation step. Sodium hydroxide was then added to methanol- water reaction mixture to carry out the deacetylation. The resulting reaction mixture was then further diluted with water before crystallization.
• the reaction mixture was analysed by HPLC prior to the crystallization step, and the total level of by-products formed during the acetylation synthesis was 1.38 % in Example 1, and 1.34 % in Example 2. The majority of the by-products being formed during the acetylation step. Both experiments resulted in a total concentration of Compound A and by-products in the mother liquor separated in the filtration step after the crystallization of 1.1 g/100 mL.
• Acetylation For each of Examples 3 and 4, Compound B (200 g) was added to a mixture of acetic anhydride (150.4 mL) and acetic acid (141.6 mL) to form a slurry. PTSA (1.6 g) was separately dissolved in a small amount of acetic anhydride (3.0 mL). The slurry was heated to approximately 60 °C, before the PTSA solution was added over a period of approximately 2 hours to form over-acetylated Compound A, before moving on to the next deacetylation process step to form Compound A.
• Example 3 the temperature was held at 80-85 °C while PTSA solution was added, and kept at 80 °C overnight.
• Example 4 the temperature was held at 65-70 °C while PTSA was added, and kept at 65 °C overnight.
• the reaction mixture was analysed by HPLC prior to the crystallization step, and the total level of by-products formed during the acetylation synthesis was 0.11 % in Example 3, and 0.10 % in Example 4.

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• 2014
  • 2014-12-08 WO PCT/EP2014/076885 patent/WO2015082719A1/en not_active Ceased
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  • 2014-12-08 ES ES14809013.7T patent/ES2638645T3/es active Active
  • 2014-12-08 US US15/100,683 patent/US9688614B2/en active Active
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