Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/04—X-ray contrast preparations
  • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
  • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
  • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
  • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C231/00—Preparation of carboxylic acid amides
  • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to a process for the preparation of iodinated X-ray contrast agents and in particular to a process for preparing loforminol, a contrast agent useful in X-ray imaging. More particularly, the invention relates to preparation of loforminol from a compound mixture comprising 1 -formylamino-3,5-bis(2,3- bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene, a key intermediate in the process for preparing loforminol.
• contrast media containing iodinated contrast agents are usually classified as ionic monomers such as diatrizoate (GastrografenTM), ionic dimers such as ioxaglate (HexabrixTM), nonionic monomers such as iohexol (OmnipaqueTM), iopamidol (IsovueTM), iomeprol (lomeronTM) and the non-ionic dimer iodixanol (VisipaqueTM).
• ionic monomers such as diatrizoate (GastrografenTM), ionic dimers such as ioxaglate (HexabrixTM), nonionic monomers such as iohexol (OmnipaqueTM), iopamidol (IsovueTM), iomeprol (lomeronTM) and the non-ionic dimer iodixanol (Visipaque
• Contrast media containing iodinated contrast agents are used in more than 20 million of X-ray examinations annually in the USA and the number of adverse reactions is considered acceptable. However, since a contrast enhanced X- ray examination will require up to about 200 ml contrast media administered in a total dose, there is a continuous drive to provide improved contrast media.
• X-ray contrast media containing a chemical compound as the active pharmaceutical ingredient(s) having two triiodinated phenyl groups linked by a linking group are usually referred to as dimeric contrast agents or dimers.
• dimeric contrast agents or dimers During the years a wide variety of iodinated dimers have been proposed.
• one contrast medium having an iodinated non-ionic dimer as the active pharmaceutical ingredient is on the market ⁇ the product VisipaqueTM containing the compound iodixanol.
• WO2009/008734 of the applicant a novel dimeric contrast agent named loforminol is disclosed. The properties of this is described in more detail in the publications Chai et al.
• non-ionic X-ray contrast media involves the production of the chemical drug, the active pharmaceutical ingredient (API), i.e. the contrast agent, followed by the formulation into the drug product, herein denoted the X-ray composition.
• API active pharmaceutical ingredient
• WO2009/008734 of the applicant provides a synthetic route for preparing the API loforminol.
• loforminol can e.g., as provided by the general preparation description and Example 1 of WO2009/008734, be synthesized from 5- amino-N,N'-bis-(2,3-dihydroxy-propyl)-2,4,6-triiodo-isophthalamide (compound (4)), which is commercially available.
• This compound is known from the synthesis of both iohexol and iodixanol and can also be prepared from 5- nitroisophthalic acid for instance as described in WO2006/016815, including hydrogenation and subsequent iodination e.g. by iodine chloride, I CI.
• 5-amino-2,4,6-triiodoisophthalic acid may be used, which is commercially available precursor, e.g. from Sigma-Aldrich.
• the free amino group of the isophthalamide compound (compound (4)) is then acylated and the hydroxyl groups in the substituents may also be protected by acylation.
• the protecting groups may be removed for example by hydrolysis to give N 1 ,N 3 -bis(2,3-dihydroxypropyl)-5- formylamino-2,4,6-triiodoisophthalamide. In a dimerization step this is reacted e.g. in a bisalkylation of epichlorohydrin to provide the loforminol contrast agent compound.
• compound 3 is a mixture comprising 1 - formylamino-3,5-bis(2,3-bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene, and X is then a formyl group.
• X is then a formyl group.
• each synthetic step it is important to optimize the yield, minimize the production of impurities, but also to minimize time and costs spent.
• the problem to be solved by the present invention may be regarded as the provision of optimizing the process for preparation of loforminol from the compound (3) of scheme 1 , i.e.
• the invention is hence directed to a process comprising a hydrolysis of compound (3) and a dimerization reaction to provide loforminol.
• Compound (1 ) is increased.
• preparation of Compound (1 ) can be done in a cost-efficient and environmentally friendly process involving in situ hydrolysis of the protecting groups of compound (3), followed by a bis-alkylation, also denoted a dimerization, by using water as the only solvent.
• a process taking considerably shorter time than the state of art process has been identified.
• the invention provides a process for preparation of Compound (1 )
• each X individually denotes hydrogen, a formyl group (-CO-H) or an acetyl group (-CO-CH3);
• Compound (3) is a mixture of different compounds with both formyl and acetyl protecting groups. This comes as a result of the earlier formylating step wherein compound (3) is prepared from compound (4) preferably using mixed anhydrides.
• compound 3 comprises a mixture of compounds wherein all X groups are individually formyl or acetyl.
• the main component of compound (3) is 1 - formylamino-3,5-bis(2,3-bis(formyloxy)propan-1 -ylcarbamoyl)-2,4,6-trioodobenzene.
• all X groups denote formyl.
• the process comprises the sequential steps of i) suspending compound (3) in water;
• step ii) adjusting the pH of the solution of step i) to 10.0-12.5;
• the generated salts are believed to increase the reaction rate by coordinating the dialkylating agent used in the bis-alkylation and/or stabilising the transition state of the reaction.
• the process provides a high yield. It has been found that the reaction from compound (3) to compound (1 ) can be performed in less than 24 hours, such as less than 20 hours, and providing a yield of 90 % or higher, such as 93 % or up to or above 95 %.
• the water- only-step of the process of the invention provides about 20 % higher yield and saves about one day in production time, compared to the prior art process as described in Example 2 of WO2009/008734.
• step i) water is used as the single solvent, and no addition of other solvents or additives, such as e.g. boric acid, has surprisingly been found needed.
• the starting material compound (3) is preferably a fine powder with low acid content.
• the mixture of compound (3) may in one embodiment comprise some rests of antisolvents, such as alcohols, but no alcohol is needed to be added.
• a short chain alcohol may be used to optimize the preparation of this in powder form, and it has been found beneficial that the compound (3) as used as the starting material in the currently claimed process is not dried completely, but comprises 0-15 % alcohol, and a rest alcohol content of 0-7 %, and most preferably 2-5 %, is appropriate.
• the rest alcohol in compound (3) is typically a short chain alcohol being a C1 -C6 straight or branched alcohol, or a mixture of such.
• the alcohol may be monohydroxylated or
• step ii hence before the bis-alkylation reaction the pH is adjusted to 10.0-12.5, and more preferably to 1 1 .0-1.8, and most preferably to 1 1 .0-11 .2, by the addition of a base to the compound (3) suspension.
• the pH adjustment is preferably done stepwise to neutralise acids and to avoid too sudden heat generation.
• the base is selected from strong water-soluble bases such as sodium hydroxide and potassium hydroxide wherein a sodium hydroxide solution (e.g. 50%) is preferred.
• the addition of the base provides a base-driven hydrolysis of the protecting ester groups of compound (3), wherein formyl- and acetyl salts, such as sodium formyl- and sodium acetyl salts, are generated as bi products.
• this pH adjustment provides the optimal pH conditions for the bis-alkylation.
• the pH adjustment is performed using a pH-stat system to ensure that the pH is kept stationary.
• Such pH system includes both an acid and a base, for instance HCI and NaOH solutions.
• the bis-alkylation (dimerization step) via a 2-hydroxypropane bridge preferably takes place by addition of an appropriate amount of a dialkylating agent to the basic solution of step (ii).
• a dialkylating agent is selected from dihalo-substituted alkanol or halo- substituted heterocycloalkyl, such as 1 ,3-dichloro-2-propanol, 1 -chloro-2,3-propanol, 1 ,3-dibromo-2-hydroxypropane and epichlorohydrin (EPI), wherein EPI is particularly preferred.
• the process further comprises the step of adding a dialkylating agent to the basic solution of step ii).
• the dialkylating agent is added to the basic aqueous solution in one or more portions, such as in 1 to 5 portions, preferably 3 equal portions. About 2 molar equivalents of compound (3) is reacted and bridged with one molar equivalent of the dialkylating agent. A slight molar excess of the dialkylating agent may be used due to a slight consumption of the dialkylating agent by the base. During and after the addition the reaction mixture is kept under stirring for a period needed to run the bis-alkylation reaction to completion. This may take 5-20 hours, preferably 10-15 hours.
• the temperature Before, during and/or after the hydrolysis, the temperature may also be adjusted, such as being cooled below room temperature, e.g. to 12-16 °C or lower. In a preferred embodiment, the temperature is adjusted to about 15 °C before addition of the dialkylating agent. Particularly preferred, the pH is adjusted to 1 1 .0-1 1.2 and the temperature is adjusted to about 15 °C before the addition, and these conditions are kept to the bis-alkylation has run to completion.
• the compounds prepared, such as compound (1 ), may be purified in any convenient manner, e.g. by washing, by preparative chromatography, by
• Compound mixture (3) and compound (1 ) as prepared by the claimed process comprise optical active isomers and will exist in several isomeric forms due to chiral carbon atoms.
• the compounds exhibit exo/endo isomerism due to the restricted rotation of the N-CO bond in the formyl function caused by the proximity of the bulk iodine atom.
• the compounds prepared according to the invention may be used as contrast agents and may be formulated with conventional carriers and excipients to produce diagnostic contrast media.
• the invention provides loforminol (compound (1 )), and a diagnostic composition comprising loforminol, prepared according to the process of the invention, wherein the composition comprises at least one physiologically tolerable carrier or excipient, e.g. an aqueous solution for injection optionally together with added plasma ions or dissolved oxygen.
• the contrast agent composition of the invention may be in a ready to use
• concentration or may be a concentrate form for dilution prior to administration.
• the invention further embraces use of loforminol prepared according to the process of preparation, and a diagnostic composition containing such, in X-ray contrast examinations.
• the dialkylation reaction time was prolonged in this example to ensure completion and maximize the yield.
• the reaction can be quenched considerably earlier, such as 10-12 hours, without significant loss of yield.

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• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Health & Medical Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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• 2013
  • 2013-09-17 BR BR112015004580A patent/BR112015004580A2/pt not_active IP Right Cessation
  • 2013-09-17 AU AU2013323982A patent/AU2013323982B2/en not_active Ceased
  • 2013-09-17 US US14/430,148 patent/US9827334B2/en not_active Expired - Fee Related
  • 2013-09-17 JP JP2015534550A patent/JP6325547B2/ja active Active
  • 2013-09-17 MX MX2015003913A patent/MX365249B/es active IP Right Grant
  • 2013-09-17 EP EP13766870.3A patent/EP2900631B1/en not_active Not-in-force
  • 2013-09-17 WO PCT/US2013/060092 patent/WO2014052092A1/en not_active Ceased
  • 2013-09-17 RU RU2015107017A patent/RU2642436C2/ru not_active IP Right Cessation
  • 2013-09-17 KR KR1020157007423A patent/KR20150061634A/ko not_active Ceased
  • 2013-09-17 ES ES13766870T patent/ES2702275T3/es active Active
  • 2013-09-17 CA CA2881853A patent/CA2881853A1/en not_active Abandoned
• 2015
  • 2015-02-13 IN IN1186DEN2015 patent/IN2015DN01186A/en unknown

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